APPLICATION OF MECHANISTIC REVELATIONS TOWARDS DEVELOPMENT OF
NOVEL REACTIONS
By
Kumar Dilip Ashtekar

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry – Doctor of Philosophy
2014

ABSTRACT
APPLICATION OF MECHANISTIC REVELATIONS TOWARDS DEVELOPMENT OF
NOVEL REACTIONS
By
Kumar Dilip Ashtekar
Mechanistic investigations of the sought-after organic reactions-the Morita Baylis
Hilman reaction and halofunctionalization of olefins has led to insightful and critical
mechanistic discernments. Tools such as quantum chemical computational analysis,
labeling experiments, kinetic isotopic effects, and kinetics studies (RPKA) were employed
towards a comprehensive analysis of these reactions. These mechanistic revelations
were applied towards development of three novel reactions a.) [4+2] formal cycloaddition
towards

asymmetric

synthesis

of

dihydropyrans,

b.)

halenium

ion

initiated

diastereoselective cascade spiroketalization of alkenoic ketones and c.) Iodenium ion
initiated cascade towards a diastereoselective synthesis of tricyclic molecules with an
octahydroquinoline core. This dissertation describes in detail the tools that were involved
in probing the mechanistic nuances and a rational approach designed towards reaction
discovery and optimization endeavors.

ACKNOWLEDGEMENTS

I can never thank enough the people that have been a part of my everyday life
during my doctoral studies. Certainly, I won’t be here in the first place if it wasn’t for my
parents. Everything I have and what I am today, is because of their unconditional love
and support. It is not the discoveries that I made or the knowledge I have gained are
important to me, but the contribution of everyone who made this journey possible is
invaluably an integral part of my life and I am indebted to all of them. It will be the
memories with everyone that I have amassed at Michigan State University will define the
true treasure I have earned during my doctoral studies.
The Borhan group has always been more of family rather than a ‘lab’, held
together and nurtured by Babak and Chrysoula. It is the comfort of being a part of this
family and enjoying chemistry with all my friends kept me going all these years. I never
felt I was working for a boss, rather I worked with a very good friend. Although new
members become a part of this group every year, I never liked that old members had to
leave, and now it is my turn. I do not know if I will remember all the experiments I ever
performed in this lab, but I will always cherish the memories I have with everyone and I
am grateful to all of them for making my journey at MSU an unforgettable and treasured
experience.

iii

TABLE OF CONTENTS

LIST OF TABLES ............................................................................................................. vi
LIST OF FIGURES .......................................................................................................... viii
LIST OF SCHEMES ........................................................................................................ xii
KEY TO SYMBOLS AND ABBREVIATIONS .................................................................. xiii
CHAPTER I: A MECHANISTICALLY INSPIRED APPROACH TOWARDS THE DEVELOPMENT OF A
CATALYTIC ASYMMETRIC FORMAL [4+2] ADDITION OF ETHYL-2,3-BUTADIENOATE WITH
ACYCLIC ENONES ................................................................................................................ 1
I.1 Introduction ....................................................................................................... 1
I.2 Mechanistically inspired approach .................................................................... 3
I.3 Results and discussions ................................................................................... 4
I.3.1 Preliminary results ............................................................................... 4
I.3.2 Optimization of reaction variables and development of an
asymmetric protocol ............................................................................. 7
I.3.3 Elucidation of mechanistic nuances of the formal [4+2]
addition .............................................................................................. 13
I.3.4 Stereoselective functionalization of substituted dihydropyrans ......... 17
I.4 Application towards synthesis of ‘Danishefsky-type’ chiral dienes ................. 18
I.5 Experimental Section ...................................................................................... 21
I.5.1 General Information ........................................................................... 21
I.5.2 General procedure for formal [4+2] addition of ethyl 2,3butadienoate and acyclic enones ....................................................... 22
I.5.3 Characterization of products ............................................................. 23
I.5.4 Synthesis of I-24b ............................................................................. 39
I.5.5 General Procedure for synthesis of chalcones .................................. 40
I.5.6 Quantum Mechanical Modeling Studies ............................................ 48
REFERENCES .................................................................................................... 49
CHAPTER II: NUCLEOPHILE ASSISTED ALKENE ACTIVATION-ELECTRONIC AND STRUCTURAL
IDENTITY OF OLEFINS IN HALOFUNCTIONALIZATION REACTIONS ......................................... 53
II.1 Introduction .................................................................................................... 53
II.2 Results and discussion .................................................................................. 54
II.2.1 Preliminary results and mechanistic arguments against
the classical intermediates .............................................................. 54
II.2.2 Mechanistic background ................................................................. 64
II.2.3 Computational analysis for probing alternative pathways ............... 65
II.3 Nucleophile Assisted Alkene Activation (NAAA)............................................ 71
II.3.1 The classical perception of halonium ions ...................................... 71
II.3.2 Halenium affinity (HalA) as a mechanistic probe ............................ 71
II.3.3 Kinetic isotope studies in chlorocyclization of II-1, II-2 and II-3 ...... 81
II.3.4 Imperative role of nucleophile ......................................................... 93
II.3.5 Regiospecificity of a conformationally constrained nucleophile ...... 99

iv

II.3.6 Interaction of nucleophile with olefin π-system inabsence of
halenium ion donor .......................................................................... 102
II.3.7 Unconstrained nucleophilic reach: Insinuation of ‘early’ or
‘late’ transition states ....................................................................... 114
II.3.8 Effect of electrophilicity of halenium ion and nucleophlicity of
olefin in halocyclization reactions ..................................................... 116
II.4 Summary ..................................................................................................... 119
II.5 Experimental Section ................................................................................... 122
II.5.1 General Information ...................................................................... 122
II.5.2 Kinetic isotope effects and rate studies ........................................ 123
II.5.2.1 13C KIEs for halocyclization of II-1, II-2 and II-3: .................. 124
II.5.2.2 Kinetics of II-1 vs II-1-D2: ..................................................... 130
II.5.2.3 Kinetics of II-3 vs II-3-D2: ..................................................... 131
II.5.2.4 Competitive halocyclization of II-1 vs II-3: ............................ 132
II.5.2.5 Kinetics of II-2 vs II-2-D2: ..................................................... 133
II.5.2.6 Kinetics of II-1 vs II-1-OD: .................................................... 134
II.5.2.7 Kinetics of II-1 vs II-1*: ......................................................... 136
II.5.2.8 Kinetics of II-2 vs II-2*: ......................................................... 140
II.5.2 Synthesis of substrates and intramolecular halocyclization of
alkenes ............................................................................................. 143
II.5.3 Halocyclization reactions .............................................................. 164
II.6 Quantum mechanical modeling studies ....................................................... 194
REFERENCES .................................................................................................. 195

v

LIST OF TABLES

Table I-1. Preliminary results for [4+2] addition reaction................................................... 5
Table I-2. Solvent screening and concentration studies ................................................... 9
Table I-3. Substrate scope for the catalytic asymmetric formal [4+2] addition ................ 11
Table I-4. Substrate scope for the catalytic asymmetric formal [4+2] addition of
dienones ........................................................................................................ 19
Table I-5. Preliminary results for one-pot protocol for consecutive [4+2] addition .......... 20
Table II-1. anti:syn ratios for the deuterium labeled styryl substrates. The plot of
ratios
vs.
concentration
suggest
a
bimolecularity
for
chlorolactonization of II-2-D whereas a more complex scenario in
case of II-1-D. For entries 1-6, the reagent concentration equals that
of the substrate .............................................................................................. 87
Table II-2. anti:syn ratios for the deuterium labeled styryl substrates. The
carboxylate in II-5-D displays a high preference for anti-addition as
well as a linear trend of anti/syn with concentration in contrast to II-1D .................................................................................................................... 89
Table II-3. anti:syn ratios for halolactonization of II-1-D. The halolactonization
displays a high preference for anti-addition with increasing size of the
halenium ion .................................................................................................. 90
Table II-4. Solvent effect on anti:syn ratio for halolactonization of II-1. ........................... 91
Table II-5. Dependence of anti:syn ratio on the acidity of DCDMH vs
monochlorohydantoin. The following chlorolactionization of II-1-D was
performed at 0.05 M substrate concentration ................................................ 92
Table II-6. Halolactonization of II-6 and II-7. 1,3-dichloro-5,5-dimethylhydantoin
(DCDMH), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS).
a
Isolated yields. bRatios were determined by 1H NMR analysis (500
MHz). Values in parenthesis are for reactions that were catalyzed
using 20 mol% quinuclidine as an amine base .............................................. 95
Table II-7. a. Halolactonization of II-8 b. Halolactonization of II-9. 1,3-dichloro5,5-dimethylhydantoin (DCDMH), N-bromosuccinimide (NBS), Niodosuccinimide (NIS). aIsolated yields. bRatios were determined by
1
H NMR analysis (500 MHz). cRatios could not be determined by
crude 1H NMR analysis. Values in parenthesis are for reactions that
were catalyzed using 20 mol% quinuclidine as an amine base ..................... 97

vi

Table II-8. Halolactonization of II-10 and II-11 displaying the role of a
conformationally rigidified nucleophile in determining the
regioselectivity of the overall addition. aIsolated yields. bRatios were
determined by 1H NMR analysis (500 MHz) .................................................. 98
Table

II-9. a. Halolactonization of alkenoic acid II-12 and II-13. b.
Halolactonization of alkenoic acid II-14 and II-15.aIsolated yields.
b
Ratios were determined by 1H NMR analysis (500 MHz). cNo
isomerization observed for the recovered olefinic substrate. dNo
isomerization of the olefinic substrate was observed during the
course of the reaction. e52% conversion. f19% conversion ......................... 101

Table II-10. Correlation of basicity to nucleophilic activation of an olefin by
carboxylic acid. Effect on 1H and 13C resonances of II-12 (at room
temperature in CDCl3) upon treatment with bases ...................................... 105
Table II-11. Halolactonization of substrates II-16 to II-19. aIsolated yields.
b
Ratios were determined by 1H NMR analysis (500 MHz). cNo
isomerization observed for the recovered olefinic substrate. dNo
isomerization of the olefinic substrate was observed during the
course of the reaction .................................................................................. 115
Table II-12. Effect of electrophilicity of halenium ion source on regioselectivity of
halofunctionalization reaction ...................................................................... 116
Table II-13. Effect of nucleophilicity of olefin on regio- and stereoselectivity of
halofunctionalization reaction ...................................................................... 118
Table II-14. Effect of enhanced nucleophilicity of the nucleophile on regio- and
stereoselectivity of halofunctionalization reaction ........................................ 119
Table II-15. Standard curve for alkenoic acid II-1. Slope = 0.0626, Intercept = 0.00038, R2 = 0.9996 ................................................................................... 130

vii

LIST OF FIGURES

Figure I-1. A prototypical Morita Baylis-Hillman reaction .................................................. 1
Figure I-2. Phosphine8 and quinuclidine9 catalytic pathway for allene ester
mediated addition reaction ............................................................................... 2
Figure I-3. Hypothetical pathways for a formal [4+2] addition reaction............................. 3
Figure I-4. Proposed mechanism for the formal [4+2] addition.......................... …………6
Figure I-5. Catalyst screening for development of asymmetric formal [4+2]
addition ............................................................................................................ 8
Figure I-6. ESI-MS based analysis during the formation of I-15a-(S). ............................ 14
Figure I-7. Putative intermediates in the formal [4+2] addition reaction. ........................ 15
Figure I-8. Origin of enantioselectivity (diastereomeric transition states TS1
and TS2 determined at B3LYP/6-31G*/SM8 level). The gauche
interactions (highlighted in red bonds) makes TS2 energetically less
favored than TS1 ........................................................................................... 16
Figure II-1. a. Catalytic asymmetric chlorolactonization of alkenoic acids. b.
Proposed working models ............................................................................. 54
Figure II-2. Deuterium labeling of 1,1-alkenoic acid II-1D reveal high
enantiofacial selectivity of the initial chlorenium attack, and
predominant formation of the syn-adduct ...................................................... 55
Figure II-3. A geometry minimization of II-1 with Cl+ ion always reveals a
chloromethyl carbenium ion with no evidence for bridging tendency
of chlorine atom. The following calculations were performed at the
B3LYP/6-31G* (SM8) level of theory ............................................................. 57
Figure II-4. A restricted (dihedral angle) geometry minimization of II-1 with Cl+
ion also reveals a chloromethyl carbenium ion with no evidence for
bridging tendency of chlorine atom. The following calculations were
performed at the B3LYP/6-31G* (SM8) level of theory. ................................. 58
Figure II-5. Path A and path B represent the rate determining-classically
perceived intermediates (I and II) involved in electrophilic addition to
alkenes. ......................................................................................................... 64
Figure II-6. The HalA (Cl) scale based on theoretical estimates of over 500
chlorenium ion acceptors ............................................................................... 68

viii

Figure II-7. HalA (Cl) predictions at the B3LYP/6-31G*/SM8(CHCl3) level of
theory predicts the alkenoic acid II-1 to be inefficient to capture the
chlorenium atom from DCDMH ...................................................................... 69
Figure

II-8. Calculated transition state structure for the asymmetric
chlorolactonization of II-1 catalyzed by (DHQD)2PHAL at the
B3LYP/6-31G*/SM8(CHCl3) level of theory ................................................... 70

Figure II-9. a. Relative HalA values (B3LYP/6-31G*/SM8-CHCl3)for some
prototypical alkenes in comparison to 1-methylcyclohexene. b.
Relative HalA values of anions of commonly used halenium ion
donors in comparison to 1-methylcyclohexene. Values in
parenthesis are absolute HalA values. c. Classical mechanistic
perception leading to charged intermediates. d. Competition
between neutral and anionic acceptors for capture of chlorenium ion
(complex-A) and competition between two neutral acceptors
(complex-B) ................................................................................................... 72
Figure II-10. Classical perception of halofunctionalization of olefins .............................. 74
Figure II-11. 1H NMR spectra, (CDCl3, rt, dark). a. N-chlorosuccinimide (NCS),
b. tetra-n-butylammonium succinimidate, c. 1,3-dichloro-5,5dimethylhydantoin (DCDMH), d. a 1:1 mixture of succinimide anion
and DCDMH, the 1H NMR resonances depict the succinimide anion
abstracts the chlorenium ion completely from DCDMH owing to the
higher HalA value of succinimide anion (ΔHalA = 8.9 kcal/mol) .................... 75
Figure II-12. 1H NMR spectra, (CDCl3, rt, dark): a. N-chlorosuccinimide (NCS),
b. tetra-n-butylammonium succinimidate, c. tetra-n-butylammonium
1,5,5-trimethylhydantoin-1-ide (TMH anion), d. a 1:1 mixture of NCS
and TMH anion, the 1H NMR resonances depict the TMH anion
being inefficient to abstract the chlorenium ion from NCS owing to
the lower HalA value of TMH anion (ΔHalA = 2.9 kcal/mol) ........................... 76
Figure II-13. 1H NMR spectra, (CDCl3, rt, dark): a. α-methylstyrene, b. Nchlorosuccinimide (NCS), c. equimolar ratio of a-methylstyrene and
NCS, d. 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), e. a 1:1
mixture of a-methylstyrene and DCDMH. The unchanged 1H NMR
resonances of NCS and DCDMH in spectra c and e illustrate the
fact that α-methylstyrene, owing to its lower HalA (Cl) value, is
inefficient to capture the Cl+ atom from either donors to form
charged products. f. Chlorination of α-methylstyrene using TCCA ................ 77
Figure II-14. Computational predictions for possible chlorenium atom transfer
(B3LYP/6-31G*/SM8-CHCl3) ......................................................................... 79
Figure II-15. Path A and path B represent the rate determining-classically
perceived intermediates (I and II) involved in electrophilic addition to

ix

alkenes. Path C represents the nucleophile assisted activation
pathway ......................................................................................................... 82
Figure II-16. Predicted transition state for chlorolactoniaztion of II-1 depicting
the proton transfer from the carboxylic acid moiety to the carbonyl of
chlorohydantoin ............................................................................................. 86
Figure II-17. Predicted molecularity from computational analysis for syn and
anti addition during the chlorolactonization of II-1. The concomitant
proton transfer stabilizes the TS for chlorolactonization as the
nucleophile polarizes the p-system of the olefin. These predictions
are corroborated by experimental RPKA analysis ......................................... 88
Figure II-18. a. Classical prediction for the outcome of halolactonization of II-6
b. NAAA prediction for regioselectivity of halolactonization of II-6
and II-7 based on enhanced nucleophile strength ......................................... 94
Figure II-19. Comparison of classical approach (path A and B) vs the regiodefined capture of the halenium by nucleophile pre-polarized πsystem (path C) ........................................................................................... 100
Figure II-20. NMR resonances of olefinic C and H (at room temperature in
CDCl3) displaying the interaction of a remotely tethered nucleophile
with the π-system upon modulation of the nucleophilic strength.................. 104
Figure II-21. 1H and 13C resonances of II-13 (at room temperature in CDCl3)
over a range of concentration (1.0 M to 0.001 M) ........................................ 106
Figure II-22. a. 1H and 13C resonances of alkenoic acid II-12 predicted at the
B3LYP/EDF2
level of theory. The conformers were initially
subjected to geometry optimization at the B3LYP/6-31G*/SM8
(CHCl3) level. b. Orbital energies of II-12 and II-13 at HF/6-31G ................. 107
Figure II-23. a. Modulation of HOMO energy of olefin in II-1 upon its interaction
with a nucleophile. b. Experimental evidence by 1H NMR ........................... 108
Figure II-24. Orbital energies of II-6 and II-7 in comparison to 1,5dimethylcyclohexa-1,4-diene. ...................................................................... 110
Figure II-25. 1H NMR resonances of alkenoic acids and their corresponding
salts ............................................................................................................. 112
Figure II-26. Accessing ‘late’ vs ‘early’ transition state based on NAAA
hypothesis .................................................................................................... 114
Figure

II-27. Comparison of TS for catalyzed and uncatalyzed
bromolactonization of II-1. For clarity, the TS only for anti-addition
(predominant
stereoisomer
formed
during
bromo
and
iodolactonization of II-1) in bromolactonization is shown. The

x

dashed boxes below represent the experimental 13C KIEs for the
catalyzed and uncatalyzed bromo and iodo-lactonization ........................... 126
Figure II-28. Plot of concentration (mmol) against time (min) comparing rates of
chlorolactonization of II-1 and II-1-D2 (Set I). The plot displays a
second order polynomial fit (R2=0.98 for II-1 and, R2=0.96 for II-1D2) ................................................................................................................ 131
Figure II-29. Plot of concentration (mmol) against time (min) comparing rates of
chlorolactonization of II-2 and II-2-D2 (Set I). Second order
polynomial fit (R2=0.99 for II-2 and, R2=0.97 for II-2-D2) .............................. 134
Figure II-30. Plot of concentration (mmol) against time (min) comparing rates of
chloroetherification of II-1 and II-1-OD. Second order polynomial fit
(R2=0.999 for II-1 and, R2=0.999 for II-1-OD) .............................................. 135
Figure II-31. Crude 1H NMR spectrum for II-20c-I ........................................................ 190

xi

LIST OF SCHEMES

Scheme I-1. Rh (II) mediated cyclopropanation of I-24a-S and crystal structure
of I-24b .......................................................................................................... 17
Scheme I-2. One-pot protocol for consecutive [4+2] additions ....................................... 18
Scheme II-1. Stereoselectivity observed for II-1 and II-2, argues against the
chloromethylcarbenium ion as a putative intermediate. ................................. 61
Scheme II-2. Probing the possibility of racemization of II-2a under standard
reaction conditions employed for asymmetric chlorolactonization ................. 62
Scheme II-3. The rate determining-classically perceived intermediates (A and
B) fail to explain the following observed rate differences............................... 63
Scheme II-4. The rate determining-classically perceived intermediates (A and
B) fail to explain the observed rate differences, whereas the
nucleophile assisted activation pathway predicts the barriers
(B3LYP/6-31G*/SM8-CHCl3) for halofunctionalization, which are in
accordance to the observed rates ................................................................. 80
Scheme II-5. a, b. 13C KIE results predicted at the B3LYP/6-31G* level of
theory and its validation by experimental results. c, d. Secondary
KIE (2H) for halolactonization of II-1 and II-2. e, f. Primary 18O KIE
experimental results for II-1 and II-2 .............................................................. 84

xii

KEY TO SYMBOLS AND ABBREVIATIONS

Symbols
Å

Angstrom

cm-1

Wavenumber

M

Molar

mM

Millimolar

mg

Milligram

mmol

Millimole

>

Larger than

<

Less than

CHCl3

Chloroform

DMF

Dimethylformamide

ESI

Electrospray Ionization

Et3N

Triethylamine

EtOAc

Ethyl Acetate

HalA

Halenium Affinity

HOMO

Highest Occupied Molecular Orbital

HRMS

High-Resolution Mass Spectrometry

LUMO

Lowest Unoccupied Molecular Orbital

m. p.

Melting Point

mbar

Milibarr

MgSO4

Magnesium Sulfate

NAAA

Nucleophile Assisted Alkene Activation

n.a.

Not Applicable

n.d.

Not Determined

xiii

Na2SO4

Sodium Sulfate

NaH

Sodium Hydride

NaHMDS

Sodium bis(trimethylsilyl)amide

NaOH

Sodium Hydroxide

NMR

Nuclear Magnetic Resonance

IR

Infrared

xiv

CHAPTER I: A MECHANISTICALLY INSPIRED APPROACH TOWARDS THE DEVELOPMENT
OF A CATALYTIC ASYMMETRIC FORMAL [4+2] ADDITION OF ETHYL-2,3-BUTADIENOATE
WITH ACYCLIC ENONES
I.1. Introduction.
The Morita Baylis-Hillman reaction has been extensively studied for its utility to forge C-C
bonds catalyzed by nitrogen and phosphorus based Lewis bases.1-3 Recent advancements
include the development of catalytic asymmetric variants.4-7 A stereotypical Morita Baylis-Hillman
reaction and its established mechanism are depicted in Figure I-1. The robustness of this reaction
in terms of its atom economy and utility of the resulting products have led towards an extensive
exploration of electrophiles that can serve as good Michael acceptors. Allene esters are one such
class of Michael acceptors, which expand the repertoire of products resulting from the Baylis-

Figure I-1. A prototypical Morita Baylis-Hillman reaction

O
R1

N

CO2R 2
H

OH

or PR 3

N

R1

(catalytic)

CO2R 2
HO

R1
N

fast

R 3N

O

N

O
R 3N

OR2

HO

O
OR2

R1

proton
transfer
slow

H

H

O

fast
OR2

R 3N

O

	
  

OR2

fast

R1

1	
  

O

R1

CO2R 2

Hillman reaction. The subsequent reactions add to the complexity of the final structures.7 In the
latter context, the use of chiral nitrogen or phosphorus based Lewis bases have been reported
with various secondary electrophiles;8-15 however development of a reaction with acyclic enones
as secondary electrophiles has not been explored until recently.16

Figure I-2. Phosphine8 and quinuclidine9 catalytic pathway for allene ester mediated
addition reaction.
O

O

Ph 3P
O

CO2Et

CO2Et

I-3a

I-2

CO2Et

I-3b

O
I-1

CO2Et

N
I-4

CO2Et

H

XR3

H

O

I-2
X = P or N

OEt

OEt

OEt

H

O

XR3

XR3

XR3
I-5a

O

I-5c

I-5b

Phosphine catalyzed pathway (X = P)
O

CO2Et

O

O
I-5b

PR 3

PR 3
CO2Et

I-1

- PR 3

I-6a
O
I-5c

O
PR 3

PR 3

CO2Et
I-6d

I-6c

I-1

I-3a

I-6b
CO2Et

O

H+
transfer

H+
transfer
- PR 3

I-3b

Quinuclidine catalyzed pathway (X = N)
O

O
5b

I-1

	
  

NR 3
CO2Et

H+
transfer

O
NR 3
CO2Et

"slow"

I-7a

I-7b

2	
  

- NR 3

I-4

I.2. Mechanistically inspired approach.

As shown in Figure I-1, the rate determining step (RDS) in a Baylis-Hillman reaction is the
proton transfer step followed by a ‘fast’ expulsion of the catalyst. Considering our endeavor in
developing synthetic routes to heterocyclic nuclei,17-19 our interest was piqued by the possibility of
exploiting the slow proton transfer event associated with an amine catalyzed Baylis-Hillman
reaction and syphoning the reaction pathway towards a cyclized product. This can be
implemented by an appropriate choice of secondary electrophile, thus allowing a robust access to
a library of complex dihydropyrans as key intermediates for constructing complex motifs.20-26
Figure I-2 illustrates the divergence in products obtained from the reaction of I-1 with
allenoate I-2, catalyzed with either phosphines8 or amines.9 Two main factors seem to contribute
to the formation of cyclic products in the phosphine catalyzed pathway: (a) the presence of ‘d’
orbitals on phosphorus that support an expanded valence shell, enable the reaction of the
transient enolates I-6a and I-6c in the manner depicted to generate ylides I-6b and I-6d; (b) a
rapid proton transfer in ylides I-6b and I-6d initiates catalyst turnover. Nitrogen, on the other hand,
cannot exhibit similar genre of reactivity, as the lack of ‘d’ orbitals precludes ylide formation under

Figure I-3. Hypothetical pathways for a formal [4+2] addition reaction.
Path A
EtO 2C

R3

O

OEt
NR 3

R 3 R1

O

R2

R1

R3
EtO 2C

R2

α-attack

R 3N

R3

O

NR 3 I-9

?

R3

EtO 2C

oxy-anion
trap

R3

O
[4+2] adduct

R 3 = H (I-2) or CH 3 (I-8)

Path B
EtO 2C

O

OEt
NR 3

O
R 3N

R1

R2

R1
O

3	
  

?

oxy-anion
trap

O

γ-attack

I-10

	
  

R2

NR 3

EtO

R2

EtO 2C

O

[4+2] adduct

R1

the mild reaction conditions. Consequently, proton transfer leading to the illustrated elimination
(Figure I-2, I-7a→ I-7b), albeit slowly,27 results in the formation of α-substituted allenes.
Our venture into the use of acyclic enones was based on the assumption that the
increased conformational flexibility of the enolate intermediate could lead to a facile ring closure in
preference to the slow proton transfer. As depicted Figure I-3, cyclization of the hard oxyanion
onto the hard enamine, as opposed to that observed with phosphine catalysis (cyclization of the
softer carbon onto the softer vinylphosphonium, see Figure I-2) would yield a specific
dihydropyran product based on whether the reaction proceeds through path A or path B. Either
pathway will be a manifestation of a regioselective attack of the amine-allene ester adduct on the
secondary electrophile-chalcone. An α-attack of the amine-allene ester adduct on the chalcone
will result in the formation of I-9 whereas, a γ-attack of the same adduct on the chalcone will yield
intermediate I-10. Cyclization of this intermediate oxyanion (I-10) via interamolecular Michael
addition seems more feasible in comparison to its counterpart I-9, which would require
intermediacy of a putative primary methylene anion.

I.3. Results and discussions.

I.3.1. Preliminary results.

To probe the experimental outcome and validate our hypothesis, a variety of enones as
possible secondary electrophiles were screened for reactivity with allene ester I-2. Allene ester I8, incapable of proton transfer, was also chosen to further facilitate the cyclization of I-9 or I-10. In
the event, treatment of acyclic enones (see Table I-1) with ethyl-2-methyl-2,3-butadienoate (I-8) in
the presence of 20 mol % DABCO provided no product and the secondary electrophile was
recovered unreacted. The inertness of I-8 in this reaction may be attributed to sterics as a result of
the α-methyl group substitution, rendering the intermediate enolate incapable of attacking the

	
  

4	
  

secondary electrophile (enone). To the contrary, ethyl-2,3-butadienoate (I-2) provided good yields
of the formal [4 + 2] adducts, albeit via the unanticipated attack of the γ-enolate derived from the
activation of I-2 with DABCO (Figure 3, enolate I-2a). In fact, previous studies with I-2 only report
products that arise from α-substitution during the Baylis-Hillman reaction.9,10 Figure I-4 illustrates

Table I-1. Preliminary results for [4+2] addition reaction.
CO2Et
I-2

electrophile

Ph

Ph

I-10a

Ph
I-10

yieldsa

products

O
1

Products

Electrophile (1.0 equiv)
toluene, rt, 48 h

(2.0 equiv)

entry

20 mol % DABCO

CO2Et

O

Ph

Ph

70%
(76%) b

O

EtO 2C

Ph

15% c

I-10b
Ph

O
2

I-11a

Ph
O

I-11

CO2Et

55%

Ph
3

I-12a

CHO

Ph

O

I-12

CO2Et

75%

O
4

Ph

No Reaction

Ph

---

I-13
a

Isolated yields after column chromatography. Due to thermal sensitivity of the products
solvents were removed under vacuum without heating. bReaction was performed in presence
of 4 Å MS. cNot observed under anhydrous conditions.

	
  

5	
  

the proposed mechanism leading to the observed products in Table I-1, highlighting the γsubstitution of the allene ester (I-2a→ I-2b)	
   and subsequent oxygen trap (I-2b→ I-2c) to yield the
dihydropyran without proton transfer. Although product I-10a, formed by the γ-attack of the allene
predominates, a minor fraction of α-substituted allene product I-10b was observed (Table I-1,
entry 1). Optimization of reaction conditions revealed that the presence of adventitious water
leads to the formation of I-10b. The same reaction charged with 4Å molecular sieves under argon
atmosphere yields I-10a exclusively. As shown in Table I-1, several secondary electrophiles with
varying substitution patterns were employed to investigate the scope of this reaction. Enones I-11
and I-12 provide the corresponding dihydropyran product as anticipated (Table I-1, entries 2 and
3). Dypnone (I-13), a β,β-disubstituted enone (entry 4), did not yield product, presumably
Figure I-4. Proposed mechanism for the formal [4+2] addition.
R2

EtO 2C

O
R2

20-50 mol % DABCO
R1

toluene (0.1M),
rt, 48 h

R1

CO2Et

O

R2

OEt

O

N
N

R1
EtO

O

OEt
R2

R 3N

O

O

O

R 3N
R1
O

O

NR 3
R2

EtO
O
R1

	
  

6	
  

R2

R1

CO2Et

indicating the intolerance of the reaction to increased sterics at the β-position of the enone. It is
noteworthy that the isolated mass balance of the latter reactions was the unreacted enone. The
allene ester I-2 does decompose at room temperature regardless of the absence or presence of
the secondary electrophile, an observation that was helpful in further optimization of this reaction,
leading to high yields of products as will be described below.
I.3.2. Optimization of reaction variables and development of an asymmetric protocol.
To explored the possibility of enantiocontrol at C4, several cinchona alkaloids (and their
derivatives) were employed as chiral amine catalysts for the Baylis-Hillman reaction. Chalcone I10 was chosen as the model substrate in the reaction of I-2 as the primary electrophile using 10
mol % of the chiral amine for initial screening efforts; the reactions were performed in toluene at
room temperature. Preliminary results were encouraging since every catalyst that furnished the
desired product displayed enantioselectivity, with most surpassing 90% ee. Not surprisingly, the
monohydrochloride salts of cinchonine (I-G) and cinchonidine (I-H) did not yield product,
suggesting that the quinuclidine nitrogen is necessary to carry out catalysis.
Although the initial screening delivered the desired products in good enantiomeric excess,
the low yields (10-20%) were clearly a problem. Surprisingly, increasing catalyst loading up to 30
mol % did not make any quantifiable difference in the isolated yields. Hatekeyama’s catalyst (I-E),
which reportedly enhances the rate of reaction through hydrogen bonding with secondary
electrophiles,6 marginally improved the yield (30%), although the ee suffered in the process
(59%). Any attempt to externally activate the secondary electrophile by addition of acidic or basic
additives led to faster decomposition of I-2. A screen of different solvents with a large range of
polarities was not conclusive, with comparable efficiencies for both polar and nonpolar solvents.
We next resorted to a concentration study, mindful of the tendency for cinchona alkaloids
to aggregate at high concentrations (which often leads to deterioration of their catalytic and

	
  

7	
  

stereoinductive ability).28,29 Gratifyingly, the highest yields were obtained under neat reaction
conditions (see Table I-2), providing the products in both synthetically useful quantities, and also,
maintaining high enantiomeric excess.

Since, the catalyst and chalcone are both solids, the

loading of I-2 up to 3-4 equivalents was necessary to provide medium with efficient mixing.
Figure I-5. Catalyst screening for development of asymmetric formal [4+2] addition.

O

CO2Et

10 mol % catalyst
toluene, (0.09 M), rt
∗

24-48 h

I-2
(2 equiv)

I-10

CO2Et
O
I-10a (R or S)

OMe

OMe
OH

O
N

N

H

N

OH
N

N

H

N

(+)-Quinidine (I-B)
I-10a-S, 19% yield, 94% ee

OMe
Hydroquinidine-9phenanthryl ether (I-A)
I-10a-S, 20% yield, 98% ee

H

Dihydroquinidine (I-C)
I-10a-S, 17% yield, 96% ee

OH
N
O

H

OMe

N
O

O

O

O

O

N

N

H

O

OH

N
N

H
Hatekeyama's catalyst (I-E)
I-10a-S, 30% yield, 59% ee

N

(DHQ) 2AQN (I-D)
I-10a-R, 15% yield, 94% ee

N
(-)-Quinine (I-F)
I-10a-R, 12% yield, 82% ee

N
O

OH
N
N

HH

Cl

(+)-Cinchonine
Hydrochloride (I-G)
no reaction

	
  

N

H
H

N
Cl

OH
N
(-)-Cinchonidine
Hydrochloride (I-H)
no reaction

8	
  

N

H

OMe
Hydroquinidine-4methyl-2-quinolyl ether (I-I)
I-10a-S, 10% yield, 97% ee

Table I-2. Solvent screening and concentration studies.
O

I-10

EtO 2C

10 mol% Quinidine (I-B)

I-2
(2.0 equiv)

solvent (0.18M), rt,
4Å MS, 48 h

O
I-10a-(S)

CO2Et

Entry

Solvent/Conditions

Rel. Polarityd

Yield

Product

% eec

1

MeOH (3Å MS)

0.762

10%

I-10a-S

33

2

CH3CN

0.460

17%

I-10a-S

95

3

DMF (3Å MS)

0.386

N.R.

---

---

4

Acetone

0.355

20%

I-10a-S

98

5

CH2Cl2

0.309

Trace

I-10a-S

N.D.

6

CHCl3

0.259

Trace

I-10a-S

N.D.

7

EtOAc

0.228

N.R.

---

---

8

THF

0.207

N.R.

---

---

9

Ether

0.117

15%

I-10a-S

N.D.

10

Benzene

0.111

Trace

I-10a-S

N.D.

11

Hexanes

0.009

N.R.

---

---

12

Cyclohexane

0.006

N.R.

---

---

13

Toluene (0.09M)

0.099

19%

I-10a-S

94

14

Toluene (0.9M)

0.099

52%

I-10a-S

96

15

Toluene (1.8M)

0.099

61%

I-10a-S

95

16

Toluene (3.0M)

0.099

65%

I-10a-S

95

17

Toluene (9.0M)

0.099

80%

I-10a-S

95

18

neat, 5 equiv. I-2a

---

91%

I-10a-S

95

19

neat, 3 equiv. 2, cat. I-A

---

93%

I-10a-S

97

20

neat, 3 equiv. 2, cat. I-Fa

---

67%

I-10a-R

84

21

neat, 3 equiv. 2, cat. I-C

a

---

89%

I-10a-S

94

22

neat, 3 equiv. 2, cat. I-D

---

89%

I-10a-R

88

b

	
  
catalyst loading was 20 mol%. breaction was performed on 1g scale of chalcone. cratios
were determined by chiral HPLC analysis. dPolarity relative to water (H2O = 1.000)2b.
(N.R. = No Reaction, N.D. = Not Determined).
a

	
  

9	
  

The increased concentration along with the higher equivalence of I-2 leads to a faster
reaction rate prior to its degradation via non-productive pathways. It is also noteworthy that no
significant deleterious effects result from the self-aggregation of cinchona alkaloids or their
derivatives, most probably because stereochemical induction results after the addition of the
catalyst to the allenoate (I-2). Aggregation of the zwitterionic intermediate is less likely as
compared to the neutral catalyst.
The scope of the reaction was tested with a number of enones as secondary electrophiles,
employing the best four catalysts (I-A through 1-D) displayed in Figure I-5. It is evident from the
results that electron donation through R1 does not favor the formation of transient oxyanion upon
attack of the amine-allenoate adduct and therefore furnishes low product yield (Table I-3, entries 2
and 9). Although, electron withdrawing R2 groups gave better yields (entries 4, 5 and 8), the yields
are not affected dramatically by electron donating groups (entries 6, 7, 11 and 16). Aliphatic
enones provided the desired products in lower yields (Table I-3, entries 13-15); presumably,
under basic condition, the rate of self-condensation via aldol reaction is faster than the desired
formal [4+2] addition. 1H NMR studies of the crude reaction mixture validates this premise.
Aromatic and heteroaromatic enones were stable under the reaction condition and
furnished good yields of the desired products with excellent enantioselectivity. Moreover, we were
able to access both enantiomers by a simple switch of the pseudo-enantiomeric catalyst.
Regardless of electronic and steric factors, the enantioselectivity of the reaction was not greatly
influenced by the substitution pattern on either R1 or R2.

	
  

10	
  

Table I-3. Substrate scope for the catalytic asymmetric formal [4+2] addition.
CO2Et

O
R1

R2

R2

(1.0 equiv)

*

10 mol% catalyst
neat, 48 h, rt

R1

(3 equiv)

O

CO2Et

(R or S)

Entry

R1

R2

Catalyst

Product

Yield

%ee

1

Ph

Ph

I-A

10a-S

93%

97

I-Ba

10a-S

87%

95

a

I-C

10a-S

89%

94b

I-D

10a-R

89%

88

I-A

14a-S

39%

96

I-Ba

14a-S

31%

96

I-Ca

14a-S

N.D.

N.D.

I-D

14a-R

42%

82

I-A

15a-S

97%

97

a

I-B

15a-S

>99%

97b

I-Ca

15a-S

94%

97

I-D

15a-R

94%

90

I-A

16a-S

81%

97

a

16a-S

74%

90

a

I-C

16a-S

81%

91

I-D

16a-R

55%

89

I-A

17a-S

92%

96d

I-Ba

17a-S

94%

93d

I-Ca

17a-S

89%

93d

I-D

17a-R

82%

91d

I-A

18a-S

60%

96d

I-Ba

18a-S

62%

95d

I-Ca

18a-S

68%

95d

I-D

18a-R

52%

83d

2

3

4

p-OMe-C6H4

p-NO2-C6H4

Ph

Ph

α-naphthyl

p-CN-C6H4

I-B

5

6

Ph

Ph

p-Br-C6H4

p-OMe-C6H4

Enantiomeric ratios were determined by chiral HPLC. aCatalyst loading was 20 mol%.
b
Reactions were performed on 1 g scale of chalcone. cEnantiomers could not be resolved by
HPLC analysis. dReactions were performed using 4 equiv of allenoate (I-2).

	
  

11	
  

Table I-3. (cont’d)
Entry

R1

R2

Catalyst

Product

Yield

%ee

7

p-NO2-C6H4

p-OMe-C6H4

I-A

19a-S

58%

95d

I-Ba

19a-S

61%

93d

I-Ca

19a-S

64%

93d

I-D

19a-R

49%

84d

I-A

20a-S

66%

90d

I-Ba

20a-S

60%

88d

I-Ca

20a-S

63%

86d

I-D

20a-R

50%

92d

I-A

21a-S

16%

95

I-Ba

21a-S

16%

94

I-Ca

21a-S

N.D.

N.D.

I-D

21a-R

15%

85

I-A

22a-S

>99%

97d

I-Ba

22a-S

63%

96d

I-Ca

22a-S

85%

95d

I-D

22a-R

63%

81d

I-A

8

9

10

11

12

13

p-CH3-C6H4

p-MeO-C6H4

o-MeO-C6H4

o-Br-C6H4

m-Br-C6H4

CH3

p-Cl-m-NO2-C6H3

p-Br-C6H4

p-F-C6H4

2-furanyl

p-Ph-C6H4

n-C5H11

23a-S

61%

96

a

I-B

I-23a-S

46%

93

I-Ca

I-23a-S

68%

93

I-D

I-23a-R

52%

79

I-A

I-24a-S

98%

98b

I-Ba

I-24a-S

96%

96

a

I-C

I-24a-S

98%

96

I-D

I-24a-R

70%

79

I-A

I-25a-S

12%

86

I-Ba

I-25a-S

10%

87

a

I-C

I-25a-S

N.D.

N.D.

I-D

I-25a-R

11%

77

Enantiomeric ratios were determined by chiral HPLC. aCatalyst loading was 20 mol%.
b
Reactions were performed on 1 g scale of chalcone. cEnantiomers could not be resolved by
HPLC analysis. dReactions were performed using 4 equiv of allenoate (I-2).

	
  

12	
  

Table I-3. (cont’d)
Entry

R1

R2

Catalyst

Product

Yield

%ee

14

H

Ph

I-A

I-12a-S

45%

95

a

I-12a-S

36%

96

a

I-C

I-12a-S

38%

95

I-D

I-12a-R

30%

80

I-A

I-26a-S

13%

N.D.c

I-Ba

I-26a-S

18%

N.D.c

I-Ca

I-26a-S

17%

N.D.c

I-D

I-26a-R

12%

N.D.c

I-A

I-27a-S

>99%

97d

I-Ba

I-27a-S

85%

94d

I-Ca

I-27a-S

91%

95d

I-D

I-27a-R

58%

77d

I-A

I-28a-S

51%

95d

I-Ba

I-28a-S

48%

92d

I-Ca

I-28a-S

42%

92d

I-D

I-28a-R

36%

87d

I-B

15

16

17

H

o-Cl-C6H4

p-I-C6H4

n-C3H7

p-OMe-C6H4

p-Br-C6H4

Enantiomeric ratios were determined by chiral HPLC. aCatalyst loading was 20 mol%.
b
Reactions were performed on 1 g scale of chalcone. cEnantiomers could not be resolved by
HPLC analysis. dReactions were performed using 4 equiv of allenoate (I-2).

I.3.3. Elucidation of mechanistic nuances of the formal [4+2] addition.

Figure I-4 depicts a putative mechanism for the formation of the desired dihydropyran
products.

Several attempts to investigate the mechanistic underpinnings via NMR studies failed

to provide any conclusive evidence. The transient adducts could not be observed as individual
species under the NMR time scale as evident by broadning of the spectral lines. Gratifyingly,
evidence for the proposed mechanism was obtained from ESI-MS analyses of reaction
intermediates. Figure I-6a depicts mass spectrum of a 1:1 mixture of quinidine (I-B) with allene
ester I-2. Present in the mass spectrum is clear evidence for addition of the cinchona alkaloid I-B

	
  

13	
  

to allene ester I-2 (structure I- B1). In the absence of an enone, a second equivalent of allenoate
I-2 functions as the secondary electrophile (structure I-B2). Addition of 1.0 equiv of enone I-15 to
the latter mixture yields the spectrum in Figure I-6b, with evidence for the anticipated intermediate

Figure I-6. ESI-MS based analysis during the formation of I-15a-(S).
O
OMe

OMe
CO2Et

OH

ACN:H2O
(3:1)

OH

N
N

??

O

N
Catalyst I-B
(Quinidine)

I-15

O2N

N

(1.0 equiv)

O

I-2B

*a.
I-B

OMe
OH

OMe
N

OH

O

N

N
I-B1

O

O

N
O

O
I-B2

O

*b.
I-B1

OMe

OMe
OH

N

O

O
I-B

OH

N

N
O

N

O

I-B3

O

I-B4

O
O

O2N
O
NO 2

*The samples were injected within 2 min after the mixing of reactants.

	
  

14	
  

Figure I-7. Putative intermediates in the formal [4+2] addition reaction.
LB
(Lewis Base)

LB-Electrophile A--Electrophile A

Path A
LB-Electrophile A

LB-Electrophile A--Electrophile B
Electrophile A
LB-Electrophile B--Electrophile B
Electrophile B

Path B

LB-Electrophile B
LB-Electrophile B--Electrophile A

(structure I-B3) on route to the observed product (I-15a-S). Under the reaction conditions
employed, a second addition of I-2 to the adduct I-B3 is also observable (structure I-B4).
Furthermore, the relative ratio of I-B:I-B1 changes dramitically upon inclusion of enone I-15 in the
reaction mixture, as observed by the intensity of corresponding spectral lines. As depicted in
Figure I-7, the results obtained from ESI-MS studies clearly indicate that the reaction mixture
comprises of several adducts in equilibrium, which syphon into the final product via an irreversible
ring closure of the oxyanion. A detailed computational work on this reaction was recently
published by Yu and co-workers27 which supports the initially proposed mechanism (Figure I-4).
To probe the basis for stereoinduction, an exhaustive DFT calculation at the B3LYP/631G* level using toluene as solvent, was performed. A large number of possible reaction
trajectories (>20) for the approach of chalcone relative to the adduct of catalyst I-B and I-2 were
examined. The results revealed that the difference in energy for the two diastereomeric transition
states is 2.5 kcal/mol in favor of the observed (S)-	
   enantiomer (Figure I-8). This is in excellent
agreement with the experimentally observed selectivity of 98:2 er. The two transition states in
Figure I-8 orient the reacting molecules such that a close proximity of the counter ions
(electrostatic stabilization) is achieved. The gauche interaction encountered in TS2 (highlighted
bonds in red) makes this transition state energetically more demanding than the orientation
suggested in TS1.

	
  

15	
  

Figure I-8. Origin of enantioselectivity (diastereomeric transition states TS1 and TS2
determined at B3LYP/6-31G*/SM8 level). The gauche interactions (highlighted in red bonds)
makes TS2 energetically less favored than TS1.
experimental result:

Ph

Ph

OH

Ph

10 mol%
Quinidine

CO2Et

O

*

toluene (0.9M)
48 h, rt

Ph

(3 equiv)

N
CO2Et

O

H

N

OMe

85% yield
98:2 er

Quinidine

theoretical result:
‡

TS1

‡

TS2
H

H
O

H
O

HO

H
N
O

H OH

H
O

N
O

O
N
O

H

Re face attack on chalcone
(S)-enantiomer
(favored by ~2.5 kcal/mol)

N
O

H

Si face attack on chalcone
(R)-enantiomer

ΔΔG‡(experimental) = 2.4 Kcal/mol
ΔΔG‡(calculated)

= 2.5 Kcal/mol B3LYP/6-31G*SM8 (Toluene)

In summary, exploiting the key mechanistic disparity (rate of proton tranfer) between
phosphine and amine catalysis, a hypothetical formal [4+2] reaction was designed and
successfully executed towards the construction of novel dihydropyrans. Gratifyingly, the
commercially available cinchona alkaloids catalysts displayed excellent levels of enantioinduction
to render this process catalytic and asymmetric. The insights gained upon development of this
mechanistically inspired approach towards syphoning a reaction pathway based on differencial
rates of proton transfer, offered us as well as several other research groups with novel

	
  

16	
  

approaches for extension of this methodology towards accessing different heterocyclic cores in a
catalytic asymmetric manner. 30-38
I.3.4. Stereoselective functionalization of substituted dihydropyrans.
The synthetic utility of this transformation is dictated by its ability to access both
enantiomers with excellent selectivity and its tolerance to various functional groups under solvent
free conditions at room temperature. Interestingly, by exploiting the stereocenter and the rigid
framework of these molecules one can imagine a plethora of electrophiles reacting at the
nucleophilic ‘enol ether’ in a stereoselective mode, moreover, upon electrophilic functionalization
at C3, the resulting oxacarbenium can undergo attack by nucleophiles, also in a stereoselective
manner. As a demonstration of its applicability, Rh2(OAc)4 mediated cyclopropanation of I-24a-(S)
provided product I-24b in 74% isolated yield as a single isomer by NMR (Scheme I-1). The crystal
structure of I-24b provides the absolute stereochemistry of the product, suggesting that the C4
substituent is the stereochemical driver in this reaction. It is noteworthy that the stereocenter at
the methine carbon, α to the carbethoxy group, is also controlled by the C4 substituent.

Scheme I-1. Rh (II) mediated cyclopropanation of I-24a-S and crystal structure of I-24b.

CO2Et
N2
(1.2 equiv)

O

Br

	
  

I-24a (S)
(98% ee)

CO2Et

Rh 2(OAc) 4
0.2 M CH2Cl2
rt, 4 h

H
EtO 2C
O

CO2Et

Br
I-24b
74% yield (83% brsm)
(single isomer by NMR)

17	
  

Crystal structure
of I-24b

I.4.1. Application towards synthesis of ‘Danishefsky-type’ chiral dienes.
Scheme I-2. One-pot protocol for consecutive [4+2] additions.
electronically and
sterically biased
diene
O
CO2Et R1

I-25

element of
stereocontrol

R2
R2

R
R

3
2

chiral amine
catalyst

R1

O
I-26

I-2

CO2Et

EWG

Diels-Alder
reaction

vinylogous
carbonate

EWG
R1

R2

*
* *
*
*
O

CO2Et

I-27
5 contiguous stereocenters

As depicted in Scheme I-1, employment of cinchona alkaloid catalyzed formal [4+2]
addition of acyclic enones and allenoate I-2 creates an asymmetric center at C4 with efficient
stereocontrol,

providing

a

handle

for

further

stereochemical

functionalizations

of

the

dihydropyrans. The encouraging result obtained from Rh (II) catalyzed cyclopropanation of I-24a
led us to expanding this methodology towards construction of ‘Danishefsky type’ dienes. As
shown in Scheme I-2, use of dibenzal acetones in place of simple enones should yield the
corresponding dihydropyrans (I-26) with tethered dienes that can be subjected to a concomitant
Diels-Alder reaction. This would furnish highly functionalized stereopentads such as I-27,
incorporating 5 contiguous stereocenters. The goal is to develop a one pot protocol to access
compounds I-27.
Table I-4 depicts the current substrate scope for formation of the intermediate dienes (I26). Although, these dienes displayed lower efficiency towards Diels-Alder reactions in
comparison to Danishefsky diene, elevated temperatures indeed furnished the desired Diels-Alder
adducts in high yields. The current ‘one-pot’ optimized conditions involve stirring a neat mixture
comprising of 10 mol% DHQD-9-phenanthryl ether as a chiral amine catalyst, 2.0-3.0 equiv. of
allene ester I-2 with enones I-26 at room temperature for 24-48 h. This is followed by an addition
of 1.5 equiv. dienophile in toluene (1M) to furnish the adducts I-27 in excellent yields and
enantioinduction. These products are excellent synthons for diastereoselective functionalization

	
  

18	
  

Table I-4. Substrate scope for the catalytic asymmetric formal [4+2] addition of dienones
O
CO2Et

R1

I-25

R2
R2

10 mol%
catalyst I-A, rt, 48 h

R1

O

CO2Et

I-26

I-2

O

entry

R1 = R 2

product

yield

% ee

1

C6H 5

I-26a

98%

98

2

p-OMe-C6H 4

I-26b

50%

94

3

o-Br-C6H 4

I-26c

93%

88

4

1-naphthyl

I-26d

77%

92

5

p-Br-C6H 4

I-26e

92%

94

N
N

H
OMe

Hydroquinidine-9phenanthryl ether (I-A)

Enantiomeric ratios were determined by chiral HPLC. Yields displayed are isolated yields.
Reaction represented in entry 1 was performed twice on 1.0 g scale of dibenzalacetone.

towards assembly of natural products incorporating the tetrahydropyranyl core. Table I-5
represents the results of the ‘one-pot’ protocol using dibenzalacetone I-25. Current efforts are
focused on exploring the scope of substituted dibenzal acetones and the dienophiles. The
mechanistic studies and substrate scope exploration related to this project is currently pursued by
Mr. Xinliang Ding (graduate student) and Mr. Christopher Rahn (undergraduate student) in Prof.
Borhan’s lab (MSU).	
  

	
  

19	
  

Table I-5. Preliminary results for one-pot protocol for consecutive [4+2] addition.

CO2Et

10 mol%
catalyst I-A,
rt, 48 h, 98%

I-2
(2.0 equiv)

entry

1

O

Ph

CO2Et

Diels-Alder
reaction

I-26a
98% ee
dienophile

O

O

O
O

NC

CN

NC

CN

2

R
R
Ph

O

O
H

20	
  

Ph

O

yield

Ph
I-27a-1
O

NC CNH Ph
NC
NC
Ph

H

*
* *
*
*
I-27a

product

Ph

	
  

dienophile
(1.5 equiv)
toluene (0.1M)
110 ºC, 2-3 h

Ph

dibenzalacetone
I-25
(1.0 equiv)

O

78%

CO2Et

I-27a-2
CO2Et

92%

CO2Et

I.5. Experimental section.
I.5.1. General information.

All reactions were carried out in flame dried glassware under an atmosphere of dry
nitrogen or argon. 4 Å molecular sieves were dried at 160 °C under 0.25 mtorr pressure prior to
use. Unless otherwise mentioned, solvents were purified as follows. THF and diethyl ether were
distilled from sodium benzophenone ketyl. Methylene chloride, acetonitrile and triethylamine were
dried over CaH2 and freshly distilled prior to use. DMF was dried over MgSO4, distilled and stored
over 4 Å molecular sieves. CHCl3 was initially washed with water to remove ethanol, distilled and
stored over 4 Å molecular sieves. Toluene was dried over CaH2, distilled and stored over 4 Å
molecular sieves at least for 48 hours prior to use. Where ever necessary, commercially available
enones were either distilled or recrystallized from appropriate solvents prior to use. Ethyl-2,3butadienoate was synthesized as per reported procedure.39 All the other commercially available
reagents and solvents were used as received unless otherwise mentioned.
1

H NMR spectra were obtained using either 300 MHz Inova, 500 MHz Varian or 600 MHz

Varian NMR spectrometer, while

13

C NMR spectra were measured on 75 MHz Inova, 125 MHz

Varian or 150 MHz Varian NMR spectrometer and referenced using deuterated chloroform, unless
otherwise mentioned. The corresponding chemical shifts are reported relative to chemical shift of
the residual solvent. Infrared spectra were reported on a Nicolet IR/42 spectrometer FT-IR (thin
film, NaCl cells). For HRMS (ESI) analysis, Waters 2795 (Alliance HT) instrument was used and
the reference used was Polyethylene Glycol (PEG).
Column chromatography was performed using Silicycle 60Å, 35-75 µm silica gel. Precoated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using
UV light, iodine, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in
EtOH stain. Chiral HPLC analysis was done using DAICEL CHIRALPAK OJ-H and OD-H

	
  

21	
  

columns. Optical rotations were measure in chloroform and acquired on a Jasco P‐2000
polarimeter at 20 °C and 589 nm.
I.5.2. General procedure for formal [4+2] addition of ethyl 2,3-butadienoate and acyclic
enones.

Asymmetric variant.

R2
O
R2

CO 2Et
R1

I-10 to I-28

10-20 mol% catalyst
neat, rt, 48 h

I-2
(3-4 equiv)

R1

O

CO 2Et

I-10a to I-28a
(R or S)

At room temperature, in a 1 dram vial flushed under nitrogen, 0.09 mmol of the enone was
transferred followed by 0.27-0.36 mmol (3-4 equiv) of ethyl-2,3-butadienoate. To this resulting
slurry was added 10-20 mol% of the corresponding catalyst (changing the order of addition of
reagents and catalyst does not make any difference in the isolated yields and enantioselectivity)
and the mixture was stirred at room temperature for 48 h. The resulting viscous dark brown gel
was diluted with 2-3 drops of dichloromethane and directly purified by silica gel chromatography
using hexanes-ethyl acetate as eluents.

	
  

22	
  

Racemic variant.
O
EtO 2C

I-2
(2.0 equiv)

R2

R2

R1

50 mol% DABCO
rt, 0.09 M toluene,
48 h

R1

O

CO 2Et

(±) I-10a to I-28a

At room temperature, in a 1 dram vial, 0.18 mmol (2 equiv.) of ethyl-2,3-butadienoate was
dissolved in dry toluene (1 mL, 0.09M). To this solution were added 0.09 mmol of the secondary
electrophile along with 2-5 mg (10-50 mol%) of 1,4-diazabicyclo [2,2,2] octane (DABCO) and the
resulting mixture was stirred at room temperature. The reaction was monitored by TLC. Usually in
about 48 h, the solvent was removed under a stream of nitrogen or under vacuum (do not heat
over a water bath) and residue was directly purified by silica gel chromatography using hexanesethyl acetate as eluents
Note: Do not heat the collective fractions (from silica gel chromatography) to remove the eluents.
The fractions should be concentrated mostly under the influence of vacuum.

I.5.3. Characterization of products.

Analytical data for dihydropyrans I-10a to I-28a:
Ph

Ph

CO 2Et

O

I-10a

(E)-ethyl-2-(4,6-diphenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate (I-10a): Using 10 mol%
catalyst I-A, 27.0 mg of pure product was isolated (93% yield). Pale yellow solid, mp 82 °C; 1H

	
  

23	
  

NMR (300 MHz, CDCl3) δ 7.62-7.65 (2H, m.), 7.22-7.41 (8H, m.), 5.78 (1H, d, J = 3.6 Hz), 5.71
(1H, s.), 4.08-4.15 (2H, m.), 3.69-3.78 (2H, m.), 3.16 (1H, dd, J = 10.2, 6.6 Hz.), 1.25 (3H, t, J =
7.2 Hz.) ppm; 13C NMR (75 MHz, CDCl3) δ 167.3, 166.4, 149.3, 143.1, 133.4, 128.7, 128.6, 128.4,
127.3, 126.9, 124.5, 103.4, 99.4, 59.6, 35.9, 30.8, 14.3 ppm; IR (film) 3080, 2980, 1707 (s), 1660
(s), 1643 (s), 1495, 1282, 1167, 1119 (s) 758 cm-1. HRMS (ESI) Calculated Mass for C21H21O3:
321.1491 ([M+H]+), Found 321.1505 ([M+H]+), chiral HPLC analysis was done using DAICEL
CHIRALPAK OJ-H column, Rt = 21.8 min (minor) and 26.6 min (major), I-10a-S (94% ee): 𝛼

!"
! =

-

139 (c = 0.1, CHCl3).

Ph
EtO 2C

O
Ph

I-10b

(E)-ethyl-5-oxo-3,5-diphenyl-2-vinylidenepentanoate (I-10b): Using 20 mol% DABCO, 4.5 mg
of 10b was isolated as a side product (15% yield). Colorless oil, 1H NMR (500 MHz, CDCl3) δ
7.90-7.93 (2H, m.), 7.5-7.54 (1H, m.), 7.40-7.44 (2H, m.), 7.25-7.32 (2H, m.), 7.16-7.20 (1H, m.),
5.25 (1H, dd, J = 2.5, 14.0 Hz), 5.15 (1H, dd, J = 3.0, 14.0 Hz), 4.23-4.54 (1H, m.), 4.06-4.15 (2H,
m.), 3.56 (1H, dd, J = 9, 17.5 Hz), 3.24 (1H, m.), 1.17 (3H, t, J = 7.0 Hz.) ppm;

13

C NMR (125

MHz, CDCl3) δ 213.1, 197.5, 166.0, 142.7, 137.0, 133.0, 128.6, 128.4, 128.1, 127.9, 127.8, 126.7,
104.3, 81.5, 61.1, 44.3, 39.0, 14.1 ppm; IR (film) 3080, 2982, 1942, 1713 (s), 1688 (s), 1597,
1448, 1248(s), 1101, 1047, 752 cm-1. HRMS (ESI) Calculated Mass for C21H21O3: 321.1491
([M+H]+), Found 321.1487 ([M+H]+).

	
  

24	
  

Ph

H 3C

CO 2Et

O

I-11a

(E)-ethyl-2-(6-methyl-4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate

(I-11a):

Using

20

mol% DABCO, 13.0 mg of pure product was isolated (55% yield). Colorless oil, 1H NMR (500
MHz, CDCl3) δ 7.18-7.29 (5H, m.), 5.48 (1H, s.), 4.93 (1H, d, J = 0.5 Hz), 4.05-4.09 (2H, m.),
3.41-3.59 (2H, m.), 3.30 (1H, dd, J = 8, 14.5 Hz), 1.90 (3H, t, J = 1 Hz.), 1.17-1.24 (3H, m.) ppm;
13

C NMR (125 MHz, CDCl3) δ 167.4, 166.9, 148.7, 143.6, 128.5, 127.2, 126.7, 102.8, 98.7, 59.5,

35.5, 30.8, 19.1, 14.3 ppm; IR (film) 3085, 2982, 1711 (s), 1649 (s), 1373, 1269, 1176, 1110 (s),
846 cm-1. HRMS (ESI) Calculated Mass for C16H19O3: 259.1334

([M+H]+), Found 259.1331

([M+H]+).
Ph

O

CO 2Et

I-12a

(E)-ethyl-2-(4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate (I-12a): Using 10 mol% catalyst
I-A, 10.0 mg of pure product was isolated (45% yield). Colorless oil, 1H NMR (300 MHz, CDCl3) δ
7.23-7.36 (4H, m.), 6.58 (1H, dd, J = 2.1, 6.3 Hz.), 5.41 (1H, s.), 5.22-5.25 (1H, m.), 4.07-4.20
(2H, m.), 3.58-3.69 (1H, m.), 3.15 (1H, dd, J = 7.5, 14.4 Hz.), 1.22-1.34 (3H, m.) ppm;

13

C NMR

(125 MHz, CDCl3) δ 167.2, 166.0, 142.8, 140.9, 128.6, 127.2, 126.8, 107.8, 99.3, 77.2, 59.6, 34.8,
31.0, 14.3 ppm; IR (film) 3080, 2982, 1711 (s), 1653 (s), 1371, 1223, 1163 (s), 1109 (s), 846, 756
cm-1. HRMS (ESI) Calculated Mass for C15H17O3: 245.1178 ([M+H]+), Found 245.1176 ([M+H]+).
Chiral HPLC analysis was done using DAICEL CHIRALPAK OJ-H column (1% isopropanol in n-

	
  

25	
  

hexanes at 1.0 mL/min), Rt = 11.5 min (minor) and 17.5 min (major), I-12a-S (95% ee): 𝛼

!"
! =

-

139 (c = 0.1, CHCl3).
Ph

O
O

CO 2Et

I-14a

(E)-ethyl-2-(6-(4-methoxyphenyl)-4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate

(I-14a):

Using 10 mol% catalyst I-A, 12.0 mg of pure product was isolated (39% yield). White solid, mp 91
°C, 1H NMR (500 MHz, CDCl3) δ 7.59-7.57 (2H, dd, J = 10.0, 3.0 Hz.), 7.32-7.35 (2H, m.), 7.247.30 (3H, m.), 6.91-7.93 (2H, dd, J = 10.0, 3.0 Hz.), 5.70 (1H, s.), 5.61 (1H, d, J = 4.0 Hz), 4.174.10 (2H, m.), 3.85 (3H, s.), 3.76-3.70 (2H, m.), 3.19-3.13 (1H, m.), 1.26 (3H, t, J = 7.5 Hz.) ppm;
13

C NMR (125 MHz, CDCl3) δ 167.3, 166.6, 160.1, 149.1, 143.4, 128.6,127.3, 126.8, 126.1,

125.9, 113.8, 101.6, 99.2, 59.6, 55.3, 35.9, 30.9, 14.3 ppm; IR (film) 3062, 2980, 2838, 1707 (s),
1646 (s), 1513, 1373, 1282, 1253(s), 1175, 1120(s), 1045, 836 cm-1. HRMS (ESI) Calculated
Mass for C22H23O4: 351.1596 ([M+H]+), Found 351.1586 ([M+H]+). Chiral HPLC analysis was done
using DAICEL CHIRALPAK OJ-H column (5% isopropanol in n-hexanes at 1.0 mL/min), Rt = 37.3
min (minor) and 54.7 min (major), I-14a-S (96% ee): 𝛼

	
  

26	
  

!"
! =

-161 (c = 0.05, CHCl3).

O
O 2N

CO 2Et

I-15a

(E)-ethyl-2-(4-(naphthalen-1-yl)-6-(4-nitrophenyl)-3,4-dihydro-2H-pyran-2-ylidene) acetate (I15a): Using 1 g of enone I-15 and 20 mol% catalyst I-B, 1.36 g of pure product was isolated
(>99% yield). Yellowish orange solid, mp 125 °C. 1H NMR (600 MHz, CDCl3) δ 8.23 (2H, d, J = 9.0
Hz.), 8.10 (1H, d, J = 9.0 Hz.), 7.90 (1H, d, J = 8.4 Hz.), 7.80 (2H, d, J = 9.0 Hz.), 7.78 (1H, d, J =
7.8 Hz.), 7.57 (1H, t, J = 7.2 Hz.), 7.51 (1H, t, J = 6.6 Hz), 7.43 (1H, t, J = 7.2 Hz.), 7.38 (1H, t, J =
6.0 Hz.), 6.08 (1H, d, J = 4.2 Hz.), 5.77 (1H, s.), 4.61-4.58 (1H, m.), 4.08-4.04 (2H, m.), 3.92 (1H,
dd, J = 15.0, 6.0 Hz.), 3.34 (1H, dd, J = 15.0, 8.4 Hz.), 1.17 (3H, t, J = 7.2 Hz.) ppm;

13

C NMR

(150 MHz, CDCl3) δ 166.8, 165.4, 147.9, 147.7, 139.3, 137.6, 134.1, 131.0, 129.2, 128.0, 126.6,
125.8, 125.5, 125.1, 124.3, 123.8, 122.7, 107.6, 100.6, 59.9, 32.0, 29.4, 14.2 ppm; IR (film) 3056,
2925, 2855, 1703 (s), 1656 (s), 1597, 1518 (s), 1344 (s), 1286, 1119(s), 1051, 858, 777 cm-1.
HRMS (ESI) Calculated Mass for C25H22NO5: 416.1498 ([M+H]+), Found 416.1492 ([M+H]+). Chiral
HPLC analysis was done using DAICEL CHIRALPAK OD-H column (30% isopropanol in nhexanes at 1.0 mL/min), Rt = 30.2 min (minor) and 39.8 min (major), I-15a-S (97% ee): 𝛼
(c = 0.1, CHCl3).

	
  

27	
  

!"
! =

-10

CN

Ph

CO 2Et

O

I-16a

(E)-ethyl-2-(4-(4-cyanophenyl)-6-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate

(I-16a):

Using 10 mol% catalyst I-A, 25.0 mg of pure product was isolated (81% yield). Crystalline pale
yellow solid, mp 123 °C. 1H NMR (600 MHz, CDCl3) δ 7.62-7.59 (4H, m.), 7.40-7.34 (5H, m.),
5.71-5.70 (2H, m.), 4.13-4.06 (2H, m.), 3.81 (1H, dd, J = 12.0, 6.6 Hz.), 3.55 (1H, dd, J = 15.0, 6.0
Hz.), 3.35 (1H, dd, J = 15.6, 7.2 Hz.), 1.23 (3H, t, J = 7.2 Hz.) ppm;

13

C NMR (125 MHz, CDCl3) δ

167.1, 165.1, 150.3, 148.5, 133.0, 132.5, 129.1, 128.5, 128.3, 124.6, 118.8, 110.9, 101.2, 100.3,
59.8, 36.0, 30.2, 14.3 ppm; IR (film) 3063, 2981, 2228, 1706 (s), 1649 (s), 1608, 1374, 1281,
1166, 1120(s), 1048, 846, 761 cm-1. HRMS (ESI) Calculated Mass for C22H20NO3: 346.1443
([M+H]+), Found 346.1447 ([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK
OD-H column (13% isopropanol in n-hexanes at 1.0 mL/min), Rt = 13.9 min (minor) and 17.3 min
(major), I-16a-S (97% ee): 𝛼

	
  

!"
! =

-94 (c = 0.1, CHCl3).

28	
  

Br

Ph

CO 2Et

O

I-17a

(E)-ethyl-2-(4-(4-bromophenyl)-6-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate

(I-17a):

Using 10 mol% catalyst I-A, 33.4 mg of pure product was isolated (96% yield). White solid, mp
129 °C. 1H NMR (600 MHz, CDCl3) δ 7.61 (2H, d, J = 6.6 Hz.), 7.42 (2H, dd, J = 11.4, 3.0 Hz.),
7.38-7.32 (3H, m.), 7.14-7.12 (2H, m.), 5.71 (1H, d, J = 4.8 Hz.), 5.69 (1H, s.), 4.13-4.07 (2H, m.),
3.72-3.69 (1H, m.), 3.58 (1H, dd, J = 15.0, 6.0 Hz.), 1.23 (3H, t, J = 7.2 Hz.) ppm;

13

C NMR (150

MHz, CDCl3) δ 167.2, 165.8, 149.7, 142.1, 133.2, 131.8, 129.1, 128.9, 128.5, 124.6, 120.7, 102.4,
99.8, 59.8, 35.4, 30.6, 14.3 ppm; IR (film) 3061, 2980, 1706 (s), 1648 (s), 1489, 1374, 1281,
1166, 1120(s), 1050, 847, 820, 760 cm-1. HRMS (ESI) Calculated Mass for C21H21O3Br: 399.0596
([M+H]+), Found 399.0592 ([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK
OJ-H column (5% isopropanol in n-hexanes at 1.0 mL/min), Rt = 23.9 min (minor) and 34.1 min
(major), I-17a-S (96% ee): 𝛼

!"
! =

-76 (c = 0.07, CHCl3).
OMe

CO 2Et

O

I-18a

(E)-ethyl-2-(4-(4-methoxyphenyl)-6-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate

(I-18a):

Using 10 mol% catalyst I-A, 19.0 mg of pure product was isolated (60% yield). White solid, mp 86

	
  

29	
  

°C. 1H NMR (600 MHz, CDCl3) δ 7.61 (1H, t, J = 2.4 Hz.), 7.38-7.35 (2H, m.), 7.32 (1H, tt, J = 7.2,
4.8, 1.8 Hz.), 7.18-7.16 (2H, m), 6.84 (2H, dt, J = 9.6, 5.4, 3.0 Hz.), 5.74 (1H, d, J = 4.2 Hz.), 5.68
(1H, s.), 4.14-4.08 (2H, m.), 3.78 (3H, s.), 3.70-3.67 (1H, m.), 3.64 (1H, dd, J = 15.0, 6.0 Hz.),
3.15 (1H, dd, J = 15.0, 7.8 Hz.), 1.23 (3H, t, J = 6.6 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ

167.3, 166.6, 158.5, 149.2, 135.2, 133.5, 128.7, 128.4, 124.5, 114.1, 103.7, 99.4, 59.6, 55.3,
35.1, 31.0, 14.3 ppm; IR (film) 3028, 2928, 1704 (s), 1649 (s), 1512, 1374, 1251, 1118 (s), 1046,
829, 761 cm-1. HRMS (ESI) Calculated Mass for C22H23O4: 351.1596 ([M+H]+), Found 351.1591
([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK OJ-H column (15%
isopropanol in n-hexanes at 1.0 mL/min), Rt = 18.3 min (minor) and 30.5 min (major), I-18a-S
(96% ee): 𝛼

!"
! =

-179 (c = 0.1, CHCl3).

OMe

O
O 2N

CO 2Et

I-19a

(E)-ethyl-2-(4-(4-methoxyphenyl)-6-(4-nitrophenyl)-3,4-dihydro-2H-pyran-2-ylidene) acetate
(I-19a): Using 10 mol% catalyst I-A, 21.0 mg of pure product was isolated (58% yield). Thick
yellow oil. 1H NMR (600 MHz, CDCl3) δ 8.31-8.09 (1H, m.), 7.76 (2H, dd, J = 11.4, 2.4 Hz.), 7.15
(2H, dd, J = 12.0, 3.0 Hz.), 6.87-6.84 (2H, m), 5.95 (1H, d, J = 4.2 Hz.), 5.72 (1H, s.), 4.15-4.09
(2H, m.), 3.78 (3H, s.), 3.74-3.74 (1H, m.), 3.67 (1H, dd, J = 15.6, 6.0 Hz.), 3.17 (1H, dd, J = 15.0,
7.8 Hz.), 1.24 (3H, t, J = 7.2 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ 166.9, 165.5, 158.7, 147.7,

147.4, 139.4, 134.3, 128.3, 125.1, 123.8, 114.2, 107.9, 100.3, 59.9, 55.3, 35.3, 30.6, 14.3 ppm; IR

	
  

30	
  

(film) 3076, 2981, 1708 (s), 1659 (s), 1515 (s), 1344 (s), 1286, 1171, 1119 (s), 860, 752 cm-1.
HRMS (ESI) Calculated Mass for C22H22NO6: 396.1447 ([M+H]+), Found 396.1447 ([M+H]+). Chiral
HPLC analysis was done using DAICEL CHIRALPAK OD-H column (10% isopropanol in nhexanes at 1.0 mL/min), Rt = 22.6 min (minor) and 42.9 min (major), I-19a-S (95% ee): 𝛼

!"
! =

-

262 (c = 0.15, CHCl3).

Cl
NO 2

CO 2Et

O

I-20a

(E)-ethyl-2-(4-(4-chloro-3-nitrophenyl)-6-(p-tolyl)-3,4-dihydro-2H-pyran-2-ylidene)acetate

(I-

20a): Using 10 mol% catalyst I-A, 24.4 mg of pure product was isolated (66% yield). Viscous
yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.76 (1H, d, J = 2.4 Hz.), 7.51-7.48 (3H, m.), 7.41 (1H, dd,
J = 8.4, 2.4 Hz.), 7.19 (2H, d, J = 8.4 Hz.), 5.72 (1H, s.), 5.63 (1H, d, J = 2.4 Hz.), 4.12-4.08 (2H,
m.), 3.80 (1H, dd, J = 11.4, 6.6 Hz.), 3.50 (1H, dd, J = 15.6, 6.6 Hz.), 3.41 (1H, dd, J = 15.0, 6.6
Hz.), 2.36 (3H, s.), 1.23 (3H, t, J = 7.2 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ 167.0, 164.7,

150.7, 143.8, 139.4, 132.2, 132.1, 130.0, 129.2, 125.4, 124.6, 124.4, 100.5, 99.6, 59.9, 35.1,
30.0, 21.3, 14.3 ppm; IR (film) 3071, 2982, 2927, 1707 (s), 1650 (s), 1537 (s), 1478, 1352, 1282,
1175, 1121(s), 1048, 823, 731 cm-1. HRMS (ESI) Calculated Mass for C22H21NO5Cl: 414.1108
([M+H]+), Found 414.1109 ([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK

	
  

31	
  

OD-H column (5% isopropanol in n-hexanes at 0.7 mL/min), Rt = 20.0 min (minor) and 26.5 min
(major), I-20a-S (90% ee): 𝛼

!"
! =

-275 (c = 0.07, CHCl3).

Br

O
MeO

CO 2Et

I-21a

(E)-ethyl-2-(4-(4-bromophenyl)-6-(4-methoxyphenyl)-3,4-dihydro-2H-pyran-2-ylidene)
acetate (I-21a): Using 10 mol% catalyst I-A, 6.2 mg of pure product was isolated (16% yield).
Brown yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.53 (2H, d, J = 9.0 Hz.), 7.41 (2H, d, J = 8.4 Hz.),
7.13 (2H, d, J = 8.4 Hz.), 7.89 (2H, d, J = 9.0 Hz.), 5.67 (1H, s.), 5.57 (1H, d, J = 4.2 Hz.), 4.154.07 (2H, m.), 3.81 (3H, s.), 3.69-3.58 (1H, m.), 3.56 (1H, dd, J = 15.0, 6.0 Hz.), 3.21 (1H, dd, J =
15.6, 8.4 Hz.), 1.23 (3H, t, J = 7.2 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ 167.3, 166.0, 160.1,

149.5, 142.3, 131.7, 129.1, 126.0, 125.9, 120.7, 113.8, 100.65, 99.6, 59.7, 55.4, 35.4, 30.7, 14.3
ppm; IR (film) 3072, 2980, 2937, 1733 (s), 1602 (s), 1512, 1490, 1371, 1257(s), 1173(s), 1117,
1028, 836, 732 cm-1. HRMS (ESI) Calculated Mass for C22H22O4Br: 429.0701 ([M+H]+), Found
429.0693 ([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK OJ-H column
(32% isopropanol in n-hexanes at 1.0 mL/min), Rt = 20.9 min (minor) and 33.7 min (major), I-21aS (95% ee): 𝛼

	
  

!"
! =

-123 (c = 0.1, CHCl3).

32	
  

F

OMe
CO 2Et

O

I-22a

(E)-ethyl-2-(4-(4-fluorophenyl)-6-(2-methoxyphenyl)-3,4-dihydro-2H-pyran-2-ylidene)
acetate (I-22a): Using 10 mol% catalyst I-A, 32.8 mg of pure product was isolated (>99% yield).
Thick pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.59 (1H, dd, J = 7.8, 1.8 Hz.), 7.30 (1H, m.),
7.26-7.23 (2H, m.), 7.00-6.97 (3H, m.), 6.94 (1H, d, J = 8.4Hz.), 5.97 (1H, d, J = 4.2 Hz.), 5.61
(1H, s.), 4.11-4.07 (2H, m.), 3.84 (3H, s.), 3.74-3.72 (1H, m.), 3.61 (1H, dd, J = 15.0, 6.0 Hz.),
3.18 (1H, dd, J = 15.6, 8.4 Hz.), 1.22 (3H, t, J = 7.2 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ

167.4, 166.7, 162.5 (d, 1JC,F = 243.2 Hz.), 157.1, 146.4, 139.1 (d, 4JC,F = 3.5 Hz.), 129.7, 128.9 (d,
3

JC,F = 8.0 Hz.), 128.2, 122.5, 120.5, 115.4 (d, 2JC,F = 21.2 Hz.), 111.3, 108.2, 98.9, 59.6, 55.6,

35.3, 31.1, 14.3 ppm; IR (film) 3071, 2979, 1706 (s), 1645 (s), 1508 (s), 1374, 1257, 1119 (s),
1051, 1023, 835, 755 cm-1. HRMS (ESI) Calculated Mass for C22H22O4F: 369.1502 ([M+H]+),
Found 369.1515 ([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK OD-H
column (1% isopropanol in n-hexanes at 0.7 mL/min), Rt = 15.9 min (minor) and 18.7 min (major),
I-22a-S (97% ee): 𝛼

	
  

!"
! =

-144 (c = 0.1, CHCl3).

33	
  

O
Br
CO 2Et

O

I-23a

(E)-ethyl-2-(6-(2-bromophenyl)-4-(furan-2-yl)-3,4-dihydro-2H-pyran-2-ylidene)acetate (I-23a):
Using 10 mol% catalyst I-A, 21.4 mg of pure product was isolated (61% yield). Thick brown oil. 1H
NMR (600 MHz, CDCl3) δ 7.59 (1H, d, J = 6.6 Hz.), 7.40 (1H, dd, J = 7.8, 1.8 Hz.), 7.34 (1H, dd, J
= 2.4, 1.2 Hz.), 7.30 (1H, dt, J = 4.8, 1.2 Hz), 7.21 (1H, m.), 6.29 (1H, t, J = 3.0 Hz.), 6.16 (1H, d, J
= 3.0 Hz.), 5.61 (1H, s.), 5.49 (1H, d, J = 4.8 Hz.), 4.15-4.12 (2H, m.), 3.83-3.80 (1H, m.), 3.58
(1H, dd, J = 15.0, 6.0 Hz.), 3.47 (1H, dd, J = 15.0, 7.2 Hz.), 1.25 (3H, t, J = 6.6 Hz.) ppm;

13

C

NMR (150 MHz, CDCl3) δ 167.2, 165.8, 155.1, 150.1, 141.8, 135.4, 133.3, 130.9, 130.4, 127.3,
122.5, 110.2, 105.4, 105.38, 99.9, 59.8, 29.7, 27.4, 14.3 ppm; IR (film) 3064, 2976, 1735, 1701
(s), 1651 (s), 1560, 1292, 1173, 1116 (s), 1045, 1021, 847, 780 cm-1. HRMS (ESI) Calculated
Mass for C19H18O4Br: 389.0388 ([M+H]+), Found 389.0387 ([M+H]+). Chiral HPLC analysis was
done using DAICEL CHIRALPAK OJ-H column (2% isopropanol in n-hexanes at 1.0 mL/min), Rt =
19.7 min (minor) and 24.2 min (major), I-23a-S (96% ee): 𝛼

	
  

34	
  

!"
! =

-112 (c = 0.1, CHCl3).

Br

O

CO 2Et

I-24a

(E)-ethyl-2-(4-([1,1'-biphenyl]-4-yl)-6-(3-bromophenyl)-3,4-dihydro-2H-pyran-2-ylide-ne)
acetate (I-24a): Using 1 g of enone I-24 and 10 mol% catalyst I-A, 1.28 g of pure product was
isolated (98% yield). Pale yellow solid, mp 102 °C. 1H NMR (600 MHz, CDCl3) δ 7.78 (1H, t, J =
1.2 Hz.), 7.57 (1H, t, J = 1.8 Hz.), 7.56-7.53 (4H, m.), 7.46 (1H, d, J = 6.0 Hz.), 7.42 (2H, t, J = 7.8
Hz.), 7.34-7.32 (3H, m.), 7.24 (1H, t, J = 6.6 Hz), 5.81 (1H, d, J = 3.6 Hz.), 5.73 (1H, s.), 4.16-4.08
(2H, m.), 3.80-3.77 (1H, m.), 3.72 (1H, dd, J = 15.0, 6.0 Hz.), 3.22 (1H, dd, J = 15.6, 8.4 Hz.), 1.24
(3H, t, J = 6.0 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ 167.1, 165.9, 148.0, 141.8, 140.8, 140.0,

135.4, 131.7, 129.9, 128.8, 127.7, 127.6, 127.5, 127.2, 127.0, 123.1, 122.7, 104.5, 99.9, 59.8,
35.6, 30.6, 14.3 ppm; IR (film) 3062, 2980, 2902, 1706 (s), 1658 (s), 1562, 1483, 1374, 1277,
1167, 1119(s), 1050, 847, 765 cm-1. HRMS (ESI) Calculated Mass for C27H24O3Br: 475.0909
([M+H]+), Found 475.0901 ([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK
OJ-H column (40% isopropanol in n-hexanes at 1.0 mL/min), Rt = 29.7 min (minor) and 77.6 min
(major), I-24a-S (98% ee): 𝛼

	
  

!"
! =

-93 (c = 0.1, CHCl3).

35	
  

CO 2Et

O

I-25a

(E)-ethyl-2-(6-methyl-4-pentyl-3,4-dihydro-2H-pyran-2-ylidene)acetate (I-25a): Using 10 mol%
catalyst I-A, 3.0 mg of pure product was isolated (12% yield). Colorless oil, 1H NMR (600 MHz,
CDCl3) δ 5.34 (1H,s.), 4.75 (1H, d, J = 3.6 Hz.), 4.12 (2H, q, J = 7.2 Hz.), 3.26 (1H, dd, J = 15.0,
6.0 Hz.), 2.73 (1H, dd, J = 15.0, 7.8 Hz.), 2.16 (1H, m.), 1.80 (3H, dd, J = 1.8, 1.2 Hz.), 1.32-1.27
(5H, m.), 1.25-1.20 (6H, m.), 0.86 (3H, t, J = 6.6 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ 168.4,

167.8, 147.4, 104.2, 98.0, 59.5, 35.4, 31.8, 29.7, 29.3, 28.4, 26.3, 22.5, 19.0, 14.4, 14.0 ppm; IR
(film) 2956, 2924, 2853, 1711 (s), 1647 (s), 1379, 1267, 1116(s), 1050 cm-1. HRMS (ESI)
Calculated Mass for C15H25O3: 253.1804 ([M+H]+), Found 253.1804 ([M+H]+). Chiral HPLC
analysis was done using DAICEL CHIRALPAK OJ-H column (100% n-hexanes at 0.7 mL/min), Rt
= 21.6 min (minor) and 27.1 min (major), I-25a-S (86% ee): 𝛼

O

!"
! =

-25 (c = 0.05, CHCl3).

COOEt

I-26a

(E)-ethyl-2-(4-propyl-3,4-dihydro-2H-pyran-2-ylidene)acetate (I-26a): Using 20 mol% catalyst
I-B, 3.5 mg of pure product was isolated (18% yield). Colorless oil, 1H NMR (600 MHz, CDCl3) δ
6.33 (1H, d, J = 6.6 Hz.), 5.45 (1H, s.), 5.02 (1H, dd, J = 6.0, 4.2 Hz.), 4.15-4.11 (2H, m.), 3.29
(1H, dd, J = 6.0, 15.0 Hz.), 2.86 (1H, dd, J = 15.0, 7.8 Hz.), 2.36-2.31 (1H, m.), 0.89 (3H, t, J = 7.2
Hz.) ppm;

	
  

13

C NMR (150 MHz, CDCl3) δ 167.54, 167.48, 139.8, 109.2, 98.6, 59.6, 37.3, 28.43,

36	
  

28.37, 19.8, 14.4, 14.0 ppm; IR (film) 3076, 2989, 1710 (s), 1651 (s), 1220, 1167, 1100 (s), 845
cm-1. HRMS (ESI) Calculated Mass for C12H19O3: 211.1329 ([M+H]+), Found 211.1331 ([M+H]+).
Chiral HPLC analysis could not be done as analytically desirable resolution of the enantiomers
was not possible using various chiral columns.

OMe

Cl
CO 2Et

O

I-27a

(E)-ethyl-2-(6-(2-chlorophenyl)-4-(4-methoxyphenyl)-3,4-dihydro-2H-pyran-2-ylidene)
acetate (I-27a): Using 10 mol% catalyst I-A, 35.0 mg of pure product was isolated (>99% yield).
Thick colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.47-7.45 (1H, m.), 7.42-7.40 (1H, m.), 7.30-7.25
(2H, m.), 7.23-7.20 (2H, m), 6.86-6.84 (2H, m.), 5.59 (1H, s.), 5.53 (1H, d, J = 3.5 Hz.), 4.12-4.06
(2H, m.), 3.78 (3H, s.), 3.70-3.62 (2H, m.), 3.18 (1H, dd, J = 15.0, 7.0 Hz.), 1.22 (3H, t, J = 7.0
Hz.) ppm;

13

C NMR (125 MHz, CDCl3) δ 167.3, 166.5, 158.6, 148.2, 135.0, 133.6, 133.0, 130.5,

130.2, 130.0, 128.4, 126.7, 114.1, 109.1, 99.4, 59.6, 55.3, 35.2, 31.1, 14.3 ppm; IR (film) 3064,
2980, 1704 (s), 1649 (s), 1512, 1350, 1251, 1116 (s), 1039, 850, 760 cm-1. HRMS (ESI)
Calculated Mass for C22H22O4Cl: 385.1207 ([M+H]+), Found 385.1209 ([M+H]+). Chiral HPLC
analysis was done using DAICEL CHIRALPAK OD-H column (1% isopropanol in n-hexanes at 0.7
mL/min), Rt = 19.4 min (minor) and 22.9 min (major), I-27a-S (97% ee): 𝛼
CHCl3).

	
  

37	
  

!"
! =

-114 (c = 1.6,

Br

O
I

CO 2Et

I-28a

(E)-ethyl-2-(4-(4-bromophenyl)-6-(4-iodophenyl)-3,4-dihydro-2H-pyran-2-ylidene) acetate (I28a): Using 10 mol% catalyst I-A, 24.0 mg of pure product was isolated (51% yield). Yellow solid,
mp 74 °C. 1H NMR (500 MHz, CDCl3) δ 7.70 (2H, dt, J = 9.0, 4.0, 2.5 Hz.), 7.42 (2H, dt, J = 9.0,
4.5, 2.5 Hz.), 7.33 (2H, dt, J = 9.2, 4.5, 2.5 Hz.), 7.10 (2H, dt, J = 9.0, 4.0, 2.5 Hz.), 5.71 (1H, d, J
= 4.5 Hz.), 5.68 (1H, s.), 4.13-4.08 (2H, m.), 4.07-3.66 (1H, m.), 3.58 (1H, dd, J = 15.0, 6.0 Hz.),
3.21 (1H, dd, J = 15.0, 7.5 Hz.), 1.23 (3H, t, J = 7.0 Hz.) ppm;

13

C NMR (125 MHz, CDCl3) δ

167.0, 165.4, 148.9, 141.8, 137.6, 132.8, 131.8, 129.1, 126.2, 120.8, 103.0, 100.1, 94.6, 59.8,
35.4, 30.4, 14.3 ppm; IR (film) 3076, 2924, 1703 (s), 1652 (s), 1487, 1282, 1118 (s), 1005, 887,
853 cm-1. HRMS (ESI) Calculated Mass for C21H19O3BrI: 524.9562 ([M+H]+), Found 524.9558
([M+H]+). Chiral HPLC analysis was done using DAICEL CHIRALPAK OD-H column (1%
isopropanol in n-hexanes at 1.0 mL/min), Rt = 15.7 min (minor) and 23.6 min (major), I-28a-S
(95% ee): 𝛼

	
  

!"
! =

-117 (c = 0.8, CHCl3).

38	
  

I.5.4. Synthesis of I-24b.

N2

COOEt

(1.2 equiv.)
O
Br

CO 2Et

H

Rh 2(OAc) 4
0.2 M CH 2Cl 2
rt, 4h

EtO 2C
O

CO 2Et

Br

I-24b
74% yield (83% brsm)
(single isomer by NMR)

I-24a-S
(98% ee)

In a 1 dram vial, initially purged with argon, was taken 100 mg (0.21 mmol) of I-24a-S
along with 5 mol% of Rh2(OAc)4 in CH2Cl2 (0.5 mL). The resulting green suspension containing 4Å
MS (10% by weight) was stirred at room temperature while a solution of 29 mg (0.25 mmol, 1.2
equiv.) of ethyl diazoacetate in CH2Cl2 (0.5 mL) was added drop wise over a period of 3 h (Note:
The addition has to be slow and dropwise or else significant amount of diethyl fumarate is formed
which co-elutes with the desired product during silica gel column chromatography and can only be
separated after successive recrystallizations of I-24b). After the addition was complete, the
resulting mixture was allowed to stir at room temperature for another hour. The solvent was then
partially evaporated under a stream of nitrogen and the slurry was loaded directly on a silica gel
column. A flash silica gel chromatography using ethyl acetate and hexanes as eluents afforded I24b as a crystalline white solid (88 mg, 74% yield).

Analytical data for I-24b:
Crystalline white solid, mp 147 °C. 1H NMR (600 MHz, CDCl3) δ 7.58-7.56 (4H, m.), 7.44-7.41
(3H, m.), 7.40-7.38 (2H, m.), 7.36 (1H, t, J = 1.2 Hz.), 7.34 (1H, tt, J = 6.6, 2.4, 1.2 Hz.), 7.22 (1H,

	
  

39	
  

d, J = 7.8 Hz.), 7.16-7.14 (1H, m.), 5.63 (1H, s.), 4.25-4.20 (2H, m.), 4.11 (2H, q, J = 7.2 Hz.),
3.98-3.94 (1H, m.), 2.44-2.39 (1H, m.), 2.30-2.25 (2H, m.), 1.29 (3H, t, J = 6.6 Hz.), 1.24 (3H, t, J
= 6.6 Hz.) ppm;

13

C NMR (150 MHz, CDCl3) δ 171.0, 167.6, 167.0, 142.2, 142.1, 140.7, 140.2,

130.9, 130.3, 128.8, 127.63, 127.61, 127.3, 127.1, 123.1, 122.7, 97.7, 63.3, 61.0, 59.6, 35.1,
31.0, 30.5, 14.4, 14.3 ppm; IR (film) 3057, 2981, 1730 (s), 1704 (s), 1644 (s), 1596, 1486, 1375,
1348, 1231, 1170 (s), 1119 (s), 1049, 763, 659 cm-1. HRMS (ESI) Calculated Mass for
C31H30O5Br: 561.1276 ([M+H]+), Found 561.1271 ([M+H]+), 𝑎

!"
! =

-50 (c = 0.15, CHCl3).

I.5.5. General Procedure for synthesis of chalcones.

(Enones I-10 through I-14, I-25, and I-26 were procured from commercial sources.)
O
R1

O
H

O

6M NaOH, MeOH
R2

rt

R1

R2

In a 50 ml round bottom flask, 8.56 mmol of the respective acetophenone was charged
with the corresponding benzaldehyde (8.56 mmol) and the mixture was then dissolved in
methanol (8.0 mL). This solution was rapidly stirred at room temperature when, 6M NaOH (4.3
mL) was added dropwise. The reaction mixture warmed up rapidly forming a cloudy suspension.
Even though, in most cases the product crashed out of the solution within 5-10 min, the reaction
mixture was allowed to stir at room temperature for another hour (overnight in case of I-22). The
precipitated solid was filtered through a Buchner funnel, washed with water (50.0 mL) to remove
the alkali, dried and then recrystallized using appropriate solvents. For isolation of product I-22
(oil), the reaction mixture was allowed to stir overnight. It was then poured over ice (20 g) and the
resulting mixture was extracted with ethyl acetate (10 x 3 mL). The combined extracts were

	
  

40	
  

washed with brine, dried over sodium sulfate, concentrated and finally subjected to purification by
silica gel flash column chromatography.

O

O 2N

I-15

(E)-3-(naphthalen-1-yl)-1-(4-nitrophenyl)prop-2-en-1-one (I-15): 71% yield, recrystallized from
hot ethyl acetate and MeOH (EtOAc: MeOH = 5:1), bright yellow solid, mp 150-151 °C (lit.40 144146 °C) 1H NMR (600 MHz, CDCl3) δ 8.71 (1H, d, J = 15.6 Hz.), 8.36-8.34 (2H, m.), 8.22-8.17
(3H, m.), 7.96-7.89 (3H, m.), 7.61-7.52 (4H, m.) ppm;

13

C NMR (150 MHz, CDCl3) δ 188.9, 150.3,

143.8, 143.2, 134.0, 132.0, 131.9, 131.8, 129.7, 129.1, 127.5, 126.7, 125.6, 125.6, 124.1, 123.9,
123.4 ppm.

O

CN

I-16

(E)-4-(3-oxo-3-phenylprop-1-en-1-yl)benzonitrile (I-16): 91% yield, recrystallized from hot
ethanol, pale yellow solid, mp 157 °C (lit.41 140-141 °C) 1H NMR (500 MHz, CDCl3) δ 8.02-8.00
(2H, m.), 7.76 (1H, d, J = 15.5 Hz.), 7.75-7.69 (4H, m.), 7.62-7.58 (2H, m.), 7.53-7.50 (2H, m.)
ppm;

13

C NMR (125 MHz, CDCl3) δ 189.7, 142.1, 139.2, 137.7, 133.3, 132.7, 128.8, 128.7, 128.6,

125.1, 118.4, 113.5 ppm.

	
  

41	
  

O

Br

I-17

(E)-3-(4-bromophenyl)-1-phenylprop-2-en-1-one (I-17): 71% yield, recrystallized from hot
ethanol, pale yellow solid, mp 125 °C (lit.42 127-128 °C) 1H NMR (600 MHz, CDCl3) δ 8.00 (2H,
m.), 7.72 (1H, d, J = 18.6 Hz.), 7.60-7.56 (1H, m.), 7.56-7.48 (7H, m.) ppm;

13

C NMR (125 MHz,

CDCl3) δ 190.2, 143.3, 138.0, 133.8, 132.9, 132.2, 129.8, 128.7, 128.5, 124.8, 122.6 ppm.

O

OMe

I-18

(E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (I-18): 71% yield, recrystallized from hot
ethanol, pale yellow solid, mp 78 °C (lit.43 76-77.5 °C) 1H NMR (500 MHz, CDCl3) δ 8.00-7.98 (2H,
m.), 7.71 (1H, d, J = 15.5 Hz.), 7.60-7.54 (3H, m.), 7.49-7.46 (2H, m.), 7.40 (1H, d, J = 15.5 Hz.),
6.92 (2H, dt, J = 9.5, 5.0, 3.0 Hz.), 3.84 (3H, s.) ppm;

13

C NMR (125 MHz, CDCl3) δ 190.6, 161.7,

144.7, 138.5, 132.5, 130.2, 128.5, 128.4, 127.6, 119.8, 114.4, 55.4 ppm.

O

O 2N

OMe

I-19

(E)-3-(4-methoxyphenyl)-1-(4-nitrophenyl)prop-2-en-1-one (I-19): 71% yield, recrystallized
from hot ethanol, pale yellow solid, mp 185 °C (lit.44 177-178 °C) 1H NMR (500 MHz, CDCl3) δ

	
  

42	
  

8.32 (2H, d, J = 7.5 Hz.), 8.10 (2H, d, J = 7.0 Hz.), 7.80 (1H, d, J = 13.0 Hz.), 7.60 (2H, d, J = 7.5
Hz.), 7.34 (1H, d, J = 13.0 Hz.), 6.93 (2H, d, J = 7.0 Hz.), 3.85 (3H, s.) ppm;

13

C NMR (125 MHz,

CDCl3) δ 189.0, 162.3, 149.9, 146.7, 143.5, 130.6, 129.3, 127.0, 123.8, 118.9, 114.6, 55.5 ppm.
O
NO 2
Cl

I-20

(E)-3-(4-chloro-3-nitrophenyl)-1-(p-tolyl)prop-2-en-1-one (I-20): 82% yield, recrystallized from
hot ethyl acetate, crystalline dirty yellow solid, mp 158 °C. 1H NMR (600 MHz, CDCl3) δ 8.11 (1H,
d, J = 1.8 Hz.), 7.92 (2H, dd, J = 6.6, 1.8 Hz.), 7.72-7.69 (2H, m.), 7.59-7.56 (2H, m.), 7.30 (1H, d,
J = 8.4 Hz.), 2.43 (3H, s.) ppm;

13

C NMR (150 MHz, CDCl3) δ 188.8, 148.3, 144.4, 139.9, 135.2,

134.9, 132.5, 132.4, 129.5, 128.7, 128.2, 124.9, 124.4, 21.7 ppm. IR (film) 3070, 2914, 1660 (s),
1602 (s), 1527(s), 1476, 1339 (s), 1310, 1183, 979, 809 cm-1. HRMS (ESI) Calculated Mass for
C16H13NO3Cl: 302.0584 ([M+H]+), Found 302.0578 ([M+H]+).

O

MeO

Br

I-21

(E)-3-(4-bromophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I-21): 90% yield, recrystallized
from hot ethyl acetate, crystalline white solid, mp 157 °C (lit.45 152-153 °C). 1H NMR (600 MHz,
CDCl3) δ 8.01 (2H, dd, J = 7.2, 1.8 Hz.), 7.71 (1H, d, J = 15.6 Hz.), 7.53-7.47 (5H, m.), 6.97 (2H,
dd, J = 7.2, 2.4 Hz.), 3.87 (3H, s.) ppm;

13

C NMR (150 MHz, CDCl3) δ 188.3, 163.5, 142.5, 134.0,

132.1, 130.9, 130.8, 129.7, 124.5, 122.4, 113.9, 55.5 ppm.

	
  

43	
  

O

OMe

F

I-22

(E)-3-(4-fluorophenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (I-22): 87% yield, pale yellow oil.
1

H NMR (600 MHz, CDCl3) δ 7.60 (1H, dd, J = 7.2, 1.8 Hz.), 7.58-7.53 (3H, m.), 7.46-7.43 (1H,

m.), 7.29 (1H, d, J = 15.6 Hz.), 7.07-7.04 (2H, m.), 7.03-7.00 (1H, m.), 7.97 (1H, d, J = 8.4 Hz.),
3.87 (3H, s.) ppm;

13

C NMR (150 MHz, CDCl3) δ 192.6, 163.8 (d, 1JC,F = 250.1 Hz.), 158.1, 141.7,

132.9, 131.3 (d, 4JC,F = 2.9 Hz.), 130.3, 130.2 (d, 3JC,F = 8.6 Hz.), 129.1, 126.7 (d, 5JC,F = 2.3 Hz.),
120.7, 115.9 (d, 2JC,F = 21.8 Hz.), 111.6, 55.7 ppm. IR (film) 3072, 2934, 1658 (s), 1599 (s), 1507
(s), 1485, 1327, 1235 (s), 1159, 1021, 830, 759 cm-1. HRMS (ESI) Calculated Mass for
C16H14O2F: 257.0978 ([M+H]+), Found 257.0980 ([M+H]+).

O
O
Br

I-23

(E)-1-(2-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one (I-23):46 98% yield, brown oil, 1H NMR
(600 MHz, CDCl3) δ 7.61 (1H, d, J = 7.8 Hz.), 7.51 (1H, s.), 7.40-7.35 (2H, m.), 7.31-7.28(1H, m.),
7.18 (1H, d, J = 15.6 Hz.), 6.67 (1H, d, J = 3.6 Hz.), 6.48-6.47 (1H, m.) ppm;

13

C NMR (150 MHz,

CDCl3) δ 190.1, 151.0, 145.5, 141.1, 133.4, 132.2, 131.3, 129.1, 127.3, 123.5, 119.4, 116.7,
112.8 ppm.

	
  

44	
  

O

Br

I-24

(E)-3-([1,1'-biphenyl]-4-yl)-1-(3-bromophenyl)prop-2-en-1-one (I-24): 84% yield, recrystallized
from hot ethyl acetate and dichloromethane (EtOAc : DCM = 5:1), needle shaped crystalline
yellow solid, mp 132 °C. 1H NMR (600 MHz, CDCl3) δ 8.14 (1H, t, J = 1.8 Hz.), 7.95-7.93 (1H, m.),
7.85 (1H, d, J = 15.6 Hz.), 7.72-7.69 (3H, m.), 7.66-7.64 (2H, m.), 7.63-7.61 (2H, m.), 7.50-7.44
(3H, m.), 7.39-7.36 (2H, m.) ppm;

13

C NMR (150 MHz, CDCl3) δ 188.9, 145.2, 143.6, 140.1,

140.0, 135.6, 133.6, 131.5, 130.2, 129.1, 128.9, 128.0, 127.6, 127.1, 127.0, 123.0, 121.2 ppm. IR
(film) 3067, 2921, 1656 (s), 1606 (s), 1561, 1486, 1417, 1312, 1209, 763 cm-1. HRMS (ESI)
Calculated Mass for C21H16OBr: 363.0385 ([M+H]+), Found 363.0389 ([M+H]+).

Cl

O

OMe

I-27

(E)-1-(2-chlorophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (I-27): 89% yield, recrystallized
from hot ethanol, crystalline yellow solid, mp 81 °C (lit.47 80-81 °C). 1H NMR (500 MHz, CDCl3) δ
7.51-7.48 (2H, m.), 7.45-7.37 (4H, m.), 7.33 (1H, dt, J = 9.0, 7.5, 1.0 Hz.), 6.98 (1H, d, J = 16.0
Hz.), 6.90 (2H, dt, J = 10.0, 5.0, 3.0 Hz.), 3.82 (3H, s.) ppm;

13

C NMR (125 MHz, CDCl3) δ 193.9,

162.0, 146.4, 139.4, 131.2, 131.1, 130.4, 130.2, 129.2, 127.1, 126.8, 124.1, 114.5, 55.4 ppm.

	
  

45	
  

O

I

Br

I-28

(E)-3-(4-bromophenyl)-1-(4-iodophenyl)prop-2-en-1-one (I-28):48 64% yield, recrystallized from
hot chloroform, flaky crystalline light brown solid, mp 190 °C. 1H NMR (500 MHz, CDCl3) δ 7.85
(2H, dt, J = 8.5, 4.0, 2.0 Hz.), 7.74-7.69 (3H, m.), 7.55-7.53 (2H, m.), 7.48 (2H, dt, J = 8.5, 3.5, 1.5
Hz.), 7.43 (2H, d, J = 16.0 Hz.) ppm;

13

C NMR (125 MHz, CDCl3) δ 189.3, 143.9, 138.0, 137.3,

133.6, 132.3, 129.9, 129.8, 125.1, 122.0, 100.8 ppm.

O
O
Ph

ethyl

O
H

Ph
I-27a-1

CO2Et

O

(E)-2-((3aS,4R,9S,9aS,9bR)-1,3-dioxo-4,9-diphenyl-1,3,3a,4,8,9,9a,9b-octahydro-7H-

furo[3,4-f]chromen-7-ylidene)acetate : Crystalline white solid, mp 184-188 °C. 1H NMR (500
MHz, CDCl3) δ 7.44-7.43 (4H, m.), 7.42-7.40 (2H, m.), 7.38-7.34 (2H, m.), 7.23-7.22 (2H, m.),
5.73 (1H, dd, J = 3.0, 3.5 Hz.), 5.54 (1H, d, J = 2.0 Hz.), 4.33 (1H, dd, J = 3.0, 16.0 Hz.), 4.16 (2H,
ddd, J = 1.0, 7.0, 15.0 Hz.), 3.95 (1H, dddd, J = 3.0, 12.0, 13.5, 15.0 Hz.), 3.80-3.77 (1H, m.), 3.46
(1H, t, J = 9.5 Hz.), 3.33 (1H, dd, J = 5.0, 9.0 Hz.), 2.89 (1H, dddd, J = 3.0, 5.0, 7.0, 10.0 Hz.),
2.58 (1H, dddd, J = 2.0, 13.5, 16.0, 16.0 Hz.), ppm;

13

C NMR (125 MHz, CDCl3) δ 170.7, 168.7,

167.3, 166.9, 151.5, 140.2, 137.5, 133.0, 129.7, 129.2, 128.7, 128.5, 128.3, 128.0, 127.9, 127.5,
104.7, 98.0, 69.2, 64.0, 59.8, 47.8, 42.9, 42.8, 41.3, 35.1, 31.5, 14.3 ppm; IR (film) 3062, 2928,
2854, 1779 (s), 1701, 1629 (s), 1337, 1170, 1135 (s), 939, 703 cm-1. HRMS (ESI) Calculated
Mass for C27H25O6: 445.1651 ([M+H]+), Found 445.1653 ([M+H]+), 𝑎

!"
! =

The relative stereochemistry is assigned based on NOESY experiments.

	
  

46	
  

+74.5 (c = 1.0, CH2Cl2).

NC CNH Ph
NC
NC
Ph

O

I-27a-2

CO2Et

	
  e thyl 2-((4S,4aS,7S,E)-5,5,6,6-tetracyano-4,7-diphenyl-3,4,4a,5,6,7-hexahydro-2H-chromen2-ylidene)acetate : Off white solid, decomposes above 160 °C. 1H NMR (500 MHz, CDCl3) δ 7.517.46 (5H, m.), 7.42-7.37 (5H, m.), 5.75 (1H, dd, J = 2.0, 3.0 Hz.), 5.67 (1H, br. s.), 4.45 (1H, t, J =
3.0 Hz.), 4.09-4.05 (2H, m.), 3.66-3.58 (3H, m.), 3.54 (1H, ddd, J = 0.5, 7.0, 15.0 Hz.), 1.18 (3H, t,
J = 5.5 Hz.) ppm;

13

C NMR (125 MHz, CDCl3) δ 166.3, 164.4, 146.2, 137.7, 132.1, 130.5, 130.5,

129.6, 129.4, 129.0, 127.9, 111.0, 109.9, 109.3, 108.3, 105.6, 101.1, 60.1, 46.3, 44.9, 44.7, 41.5,
40.5, 32.7, 14.2 ppm; HRMS (ESI) Calculated Mass for C29H23N4O3: 475.1770 ([M+H]+), Found
475.1770 ([M+H]+).

	
  

47	
  

I.5.6. Quantum Mechanical Modeling Studies.
Full optimizations on all conformations of the model systems in simulated toluene as a
solvent were performed at the B3LYP/6-31G*/SM8 (toluene) level using the Spartan-10 software
running on Macintosh platform. To verify convergence and consistency of the optimizations, a
number of examples were re-optimized from multiple starting points; energetic variations of 0.02
kcal/mol or less were found among these calculated structures. To confirm that each structure
was a true minimum, vibrational analyses were performed; because analytical second derivatives
are not available in SM8 solvated wavefunctions, these analyses relied on finite difference
calculations. Their consistency was checked in multiple runs, and showed negligible variation. For
comparison, the relative enthalpies (ΔH°rel) calculated by including zero-point and thermal
corrections to 298.15 K are given in kcal/mol. Importantly, differences between relative E and
relative H° values are generally small enough that either set of data could be used to arrive at the
conclusions. All Transition State structures were validated as first-order stationary points (i.e. a
single imaginary frequency) by vibrational analysis. Single-point solvation energies in simulated
toluene were calculated at the B3LYP/6-31G*/SM8 level of theory. All values are in kcal/mol or
hartrees.

	
  

48	
  

REFERENCES

	
  

49	
  

REFERENCES

(1)

Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.

(2)

Baylis, A. B. H., M. E. D. In German Patent 2 1972; Vol. 155.

(3)

Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.

(4)

Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659.

(5)

Langer, P. Angewandte Chemie-International Edition 2000, 39, 3049.

(6)

Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121,
10219.

(7)

Chen, R.; Xu, S.; Wang, L.; Tang, Y.; He, Z. Chem. Commun. 2013, 49, 3543.

(8)

Du, Y. S.; Lu, X. Y.; Yu, Y. H. J. Org. Chem. 2002, 67, 8901.

(9)

Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394.

(10) Cowen, B. J.; Saunders, L. B.; Miller, S. J. J. Am. Chem. Soc. 2009, 131, 6105.
(11) Guan, X. Y.; Wei, Y.; Shi, M. J. Org. Chem. 2009, 74, 6343.
(12) Meng, X. T.; Huang, Y.; Chen, R. Y. Org. Lett. 2009, 11, 137.
(13) Voituriez, A.; Panossian, A.; Fleury-Bregeot, N.; Retailleau, P.; Marinetti, A. J. Am. Chem.
Soc. 2008, 130, 14030.
(14) Wallace, D. J.; Sidda, R. L.; Reamer, R. A. J. Org. Chem. 2007, 72, 1051.
(15) Zhao, G. L.; Huang, J. W.; Shi, M. Org. Lett. 2003, 5, 4737.
(16) Wang, X.; Fang, T.; Tong, X. Angew. Chem. Int. Ed. 2011, 50, 5361.
(17) Zheng, T.; Narayan, R. S.; Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2005, 127,
6946.
(18) Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2008, 130, 12228.
(19) Narayan, R. S.; Borhan, B. J. Org. Chem. 2006, 71, 1416.
(20) Schmidt, B.; Westhus, M. Tetrahedron 2000, 56, 2421.

	
  

50	
  

(21) Hayakawa, H.; Miyashita, M. Tetrahedron Lett. 2000, 41, 707.
(22) Gerth, K.; Washausen, P.; Hofle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 71.
(23) Coppi, L.; Ricci, A.; Taddei, M. J. Org. Chem. 1988, 53, 911.
(24) Connor, D. T.; Young, P. A.; Strandtmann, M. V. J. Org. Chem. 1977, 42, 1364.
(25) Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
(26) Zhang, Y.; Panek, J. S. Org. Lett. 2007, 9, 3141.
(27) Huang, G. T.; Lankau, T.; Yu, C. H. J. Org. Chem. 2014, 79, 1700.
(28) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee, J. Y.; Chin, J.; Song, C. E. Chem. Commun. 2008,
1208.
(29) Williams, T.; Pitcher, R. G.; Bommer, P.; Gutzwill.J; Uskokovi.M J. Am. Chem. Soc. 1969,
91, 1871.
(30) Chen, R. S.; Xu, S. L.; Wang, L. Y.; Tang, Y. H.; He, Z. J. Chem. Commun. 2013, 49, 3543.
(31) Du, D.; Jiang, Y.; Xu, Q.; Shi, M. Adv. Synth. Catal. 2013, 355, 2249.
(32) Feng, J. H.; Fu, X.; Chen, Z. L.; Lin, L. L.; Liu, X. H.; Feng, X. M. Org. Lett. 2013, 15, 2640.
(33) Francos, J.; Grande-Carmona, F.; Faustino, H.; Iglesias-Siguenza, J.; Diez, E.; Alonso, I.;
Fernandez, R.; Lassaletta, J. M.; Lopez, F.; Mascarenas, J. L. J. Am. Chem. Soc. 2012,
134, 14322.
(34) Niu, Z. Q.; He, X. W.; Shang, Y. J. Tetrahedron-Asymmetry 2014, 25, 796.
(35) Scheffler, U.; Mahrwald, R. Chemistry-a European Journal 2013, 19, 14346.
(36) Wang, Q.; Lian, Z.; Xu, Q.; Shi, M. Adv. Synth. Catal. 2013, 355, 3344.
(37) Wang, Y.; Shi, D. Q. Chinese Journal of Structural Chemistry 2013, 32, 521.
(38) Zhang, D. H.; Shi, M. ChemistryOpen 2012, 1, 215.
(39) Lang, R. W.; Hansen, H.-J. Org. Synth. 1990, Collective Vol. 7, p 232.

	
  

51	
  

(40) Chiaradia, L. D.; Mascarello, A.; Purificacao, M.; Vernal, J.; Cordeiro, M. N. S.; Zenteno, M.
E.; Villarino, A.; Nunes, R. J.; Yunes, R. A.; Terenzi, H. Bioorg. Med. Chem. Lett. 2008, 18,
6227.
(41) Batovska, D.; Parushev, S.; Slavova, A.; Bankova, V.; Tsvetkova, I.; Ninova, M.; Najdenski,
H. European Journal of Medicinal Chemistry 2007, 42, 87.
(42) Gorman, A.; Killoran, J.; O'Shea, C.; Kenna, T.; Gallagher, W. M.; O'Shea, D. F. J. Am.
Chem. Soc. 2004, 126, 10619.
(43) C., C. M.; Chopa, A. B. J. Chem. Soc.-Perkin Trans. 2 1974, 452.
(44) Kumar, A.; Sharma, S.; Tripathi, V. D.; Srivastava, S. Tetrahedron 2010, 66, 9445.
(45) Barnes, R. P.; Goodwin, T. C.; Cotten, T. W. J. Am. Chem. Soc. 1947, 69, 3135.
(46) Mukherjee, C.; Zhang, H. M.; Biehl, E. R. Heterocycles 2005, 65, 2347.
(47) Bradsher, C. K.; Brown, F. C.; Blue, W. B. J. Am. Chem. Soc. 1949, 71, 3570.
(48) Loudet, A.; Bandichhor, R.; Wu, L. X.; Burgess, K. Tetrahedron 2008, 64, 3642.

	
  

52	
  

CHAPTER II: NUCLEOPHILE ASSISTED ALKENE ACTIVATION-ELECTRONIC
STRUCTURAL IDENTITY OF OLEFINS IN HALOFUNCTIONALIZATION REACTIONS

AND

II.1. Introduction.

Electrophilic activation of carbon-carbon double bonds is one of the most versatile
functional group transformations in organic chemistry, offering robust access to a diverse range of
substructures.1 Stereoselective alkene functionalization reactions have attracted sustained
interest for the past four decades.2,3 The results have been a number of landmark alkene
functionalization

reactions

such

as

epoxidations,

dihydroxylations,

aminohydroxylations,

hydrogenations, cyclopropanations, hydrometalations, Diels-Alder reactions and aziridinations to
name a few.4-6 Mechanistically, most of these reactions are thought to proceed via electrophilic
activation of the alkene resulting in a cationic adduct followed by a concomitant attack of a
nucleophile that intercepts the cationic intermediate. Electrophilic halofunctionalization of olefins is
a sub-class of these reactions and arguably one of the most sought–after transformations in
organic chemistry that allows access to a myriad of indispensible products. This field is witnessing
an immense progress since the past few years, predominantly in the development of
stereoselective reactions.7-18 The key towards the success of any sought-after transformation
relies on a rational approach that is substantiated by its well-established mechanistic foundations.
Although halofunctionalization of olefins has seen great recent progress, the field of
stereoselective alkene halogenation has mainly advanced via a trial-and-error approach and is
still in its infancy when compared to other olefin functionalization reactions mentioned above.
To efficiently develop new halofunctionalization reactions, the detailed nature of attack on
alkenes by halenium ion donors must be understood, along with the structural and electronic
character of any resulting intermediates. Despite the enormous precedent dedicated towards
understanding the mechanistic underpinnings of haliranium ions,19-36 the factors that dictate the

	
  

53	
  

Figure II-1: a. Catalytic asymmetric chlorolactonization of alkenoic acids. b. Proposed working
models
a.
CO2H

(DHQD) 2PHAL (10%)
DCDPH (1.1 equiv)

R/Ar

H

H

N

H

O

N

O

O

Ph

H

N N

MeO

N Cl

Ph

OMe

N
Cl

N

(DHQD) 2PHAL

O

Cl
10 examples
up to 90% ee

CHCl 3/Hex (1:1)
-40 ºC, 3-6 h

Ar/R

O

N

O

DCDPH

b.
H
N

O

4.35 H
ppm,
singlet H

Cl

N
N
Cl

O

H

H

N
Cl

H

(DHQD) 2PHAL
(1 equiv)

Cl
N

CDCl 3, -40º C
500 MHz NMR

O

N
Cl

or

O
HA
HB

O
HA
HB

H

N
N
Cl

O

4.30 ppm, AB quartet
(JAB = 16.5 Hz)

kinetic and stereochemical stability of halonium ions and their electronic and structural identity in
solution still remains elusive.

II.2. Results and discussion.
II.2.1. Preliminary results and mechanistic arguments against the classical intermediates.
Over the past five years, efforts in our group have focused on developing catalytic
asymmetric halofunctionalization of alkenes and on elucidation of their mechanistic underpinnings.
Our early report in 2010 described the first catalytic, highly enantioselective chlorolactonization of

	
  

54	
  

1,1- disubstituted alkenoic acids using (DHQD)2PHAL as a chiral amine catalyst and 1,3-dichloro5,5-diphenylhydantoin (DCDPH) as a chlorenium source (Figure II-1a).37 Based on initial NMR
experiments, the proposed model invoked an ammonium ion (protonated or chlorinated) at the
quinuclidine centered nitrogen engaging either a hydrogen bonded complex or a tight ion pair
(Figure II-1b) resulting in the diastereotopic nature of the two protons on the hydantoin motif
embedded within the chiral cleft of the catalyst. Proceeding studies by Dr. Roozbeh Yousefi using
labeled substrate II-1D (Figure II-2) revealed that the addition across the 1,1-disubstituted olefin
ensues under the reaction conditions to yield predominantly a syn-adduct. This observation is
highly intriguing and at the same time, counterintuitive from a mechanistic viewpoint where, in the
field of halofunctionalization of alkenes, the classical notion of cyclic-bridged haliranium ions as
putative intermediates is firmly established. Kinetic studies (Reaction Progress Kinetic Analysis

Figure II-2: Deuterium labeling of 1,1-alkenoic acid II-1D reveal high enantiofacial selectivity of
the initial chlorenium attack, and predominant formation of the syn-adduct.
Nu
H

D

Ph

CO2H
II-1D

c

alkenoic acids
Cl

(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)
benzoic acid (1 equiv)
CHCl 3:hex (1:1), -40 ºC

1

2

Ph
Cl

6

Ph

H D
O
5

O Cl

D H
CO2H

Cl

O

Ph
5R,6R-II-2b
syn
89%

5S,6R-II-2a
anti
8%

H
D

O

D H
O

Ph
5S,6S-II-2c
syn
<0.3%

55	
  

O Cl

O
Ph
5R,6S-II-2d
anti
3%

O

6S (3%)

	
  

Cl

CO2H

6S (4%)

Ph

H D

6R (97%)

Cl

D
H

6R (96%)

carbocation

5R (91.3%)

5S (8.7%)

C6-epimers distinguishable by 1 H-NMR

C5-epimers separable by HPLC

techniques-RPKA, pioneered by the Blackmond group38) performed by Dr. Yousefi have aided in
determining the molecularity of the asymmetric chlorolactonization reaction. The reaction has
zero-order dependence on the substrate concentration (suggesting saturation kinetics of the
catalyst), and first order dependence on catalyst and chlorohydantoin concentrations. Taken
together, these results suggest that the rate-determining step in these transformations is either
the binding of the substrate to the catalyst or the transfer of the chlorine atom to the alkene in the
substrate-hydantoin-catalyst ternary complex.

Nevertheless, the predominant ‘syn’ addition of the halogen and the nucleophile across the
alkene, as probed from II-1D (Figure II-2), strongly argues against the intermediacy of a bridged
chloriranium ion.19 Hence, in accordance to the studies by Fahey, Poutsma, and Sauers,30-33,39 we
postulated

the

intermediacy

of

a

chloromethyl

carbenium

ion

in

the

asymmetric

chlorolactonization.19
Computational analysis to elucidate the possibility of bridged chloronium ion intermediate
(chloriranium ion):
The possibility of participation by a bridged chloronium species was assessed using
quantum chemical modeling at several levels of theory. In all cases, geometry optimization led to
+

structures with near tetrahedral angles for the key ∠C -C-Cl angle at the CH2Cl group; a bridged
chloronium was never found as an energy minimum, even when calculations were started with the
+

+

Cl atom centrally positioned as it is in C2H4Cl , the chloronium ion from (ethylene + Cl) ion.
Interestingly even in structures calculated in the “gas phase” (i.e. no solvent simulation), where
the otherwise unstabilized cation would benefit most from delocalization by bridging, no such
minimum was found. Figure II-3 depicts the geometry minimized model at the B3LYP/6-31G* level
obtained from chlorenium addition to substrate II-1. As noted, several symmetrically bridged

	
  

56	
  

+

Figure II-3: A geometry minimization of II-1 with Cl ion always reveals a chloromethyl
carbenium ion with no evidence for bridging tendency of chlorine atom. The following
calculations were performed at the B3LYP/6-31G* (SM8) level of theory.

end-on view of (II-1 + Cl)+ ion
∠C+-C-Cl = 108.8º (gas phase)
∠C+-C-Cl = 109.6º (SM8-CHCl3)

Lateral View of (II-1 + Cl)+

chloronium starting points were explored, but the end result was always found to be the open
chloromethyl carbenium ion shown above in Figure II-3.
If the chiral catalyst (DHQD)2PHAL, somehow held the aryl ring in an orientation that
inhibited effective conjugation with the cation center, perhaps the resulting destabilized cation
would compensate by distorting to a bridging mode. To probe this possibility, the intermediate
cation was geometrically minimized at the same levels of theory as described above, but now with
the phenyl ring constrained at an angle of 90º with respect to the π-system under consideration
(i.e. orthogonal to the 1,1-disubstituted olefin); see Figure II-4. Despite this enforced (and artificial)
switch in the electronics, there was little change to the local geometry at the –CH2Cl group, or to
the rotational potential energy surface. Furthermore, experimental results do show a response to
donor substitution on the aryl ring, indicating that resonance is not shut off between the phenyl
and the putative carbocation. These results clearly argue against the intermediacy of any bridged
chloronium species (chloriranium ion).

	
  

57	
  

+

Figure II-4: A restricted (dihedral angle) geometry minimization of II-1 with Cl ion also reveals a
chloromethyl carbenium ion with no evidence for bridging tendency of chlorine atom. The
following calculations were performed at the B3LYP/6-31G* (SM8) level of theory.

restricted dihedral
angle
End-on view of restricted (II-1 + Cl)+ ion
∠C+-C-Cl = 100.0º

Lateral view of restricted (II-1 + Cl)+ ion

Interestingly, the cation’s structure depicted above does have the C-Cl bond aligned
ideally for hyperconjugation with the cationic center. Regardless of bridging, if this structure were
in a deep enough energy well, it might function like a bridged intermediate by directing
nucleophilic attack to the opposite face. To probe this issue, we resorted to α-methylstyrene as a
more computationally tractable system, uncomplicated by the conformational dynamics of the
carboxylate side-chain. We then examined the potential energy (PE) surfaces for rotation about
+

the C -CH2Cl bond in the cation as calculated at the HF/6-31G*, MP2/6-31G*, B3LYP/6-31G*,
and B3LYP/6-311++G** levels. The validity of this model was confirmed by comparing the minima
+

from the above calculations based on the full substrate to the C9H10Cl ion structures obtained
from chlorenium addition to α-methylstyrene. As before, only open carbocation minimum energy
geometries were found. For instance, the B3LYP/6-31G* optimized structure does find a minimum
+

with the C-Cl bond aligned with the carbocation's empty 2p orbital, but it shows a ∠C -C-Cl angle
of 108.8º, and the face-switching barrier to rotation of the CH2Cl group is calculated to be only 1.6
kcal/mol in the gas phase, roughly half the value for methyl group rotation in ethane. This

	
  

58	
  

calculated number is further lowered to 0.9 kcal/mol (B3LYP/6-31G*/SM8) by simulated solvation
in CHCl3.
+

Conclusions from computational analysis of II-1 + Cl ion (cationic adduct):
(a) Based on the above calculations, assuming chlorenium delivery to the alkene forms an
ionic intermediate, it is an open chloromethyl benzylic carbenium ion, rather than a bridged
chloronium species.
(b) Although such chloromethyl carbenium ions have energy minima with the C-Cl bond
+

aligned with the carbocation's empty 2p orbital, and the ∠C -C-Cl angle is slightly smaller than the
tetrahedral angle, the face-switching barrier to rotation of the CH2Cl group is low as noted above.
Interestingly, a second minimum in which the chlorine lies in the plane of the cation is also found.
This structure, which offers no stereopreference to either face, is only 1.2 kcal/mol above the outof-plane minimum, and CHCl3 solvation lowers this difference to just 0.4 kcal/mol at the B3LYP/631G*/SM8 level. Overall, this ensemble of structures may be understood as conformationally free,
offering no stereodirection to the lactone closure step. We note here that Haubenstock and
Sauers arrived at essentially the same conclusions on their more sophisticated calculations on the
simpler styrene- and butadiene-derived systems.30,31
(c) The preference for the open chloromethyl carbenium ion form is not isolated to styryl
systems that can form stabilized benzylic cations; computational analysis of chlorenium addition
to 2-methylpropene displays similar behavior. This small system is amenable to calculations at
significantly more rigorous levels of theory. Rotation barriers for the resulting chloromethyl
carbenium ion evaluated at different levels of theory and based on gas-phase optimized
geometries are tabulated below:

	
  

59	
  

Level of Theory

Barrier to rotation in
gas phase (kcal/mol)

Barrier to rotation in

B3LYP/6-31G*

3.20

3.14**

B3LYP/6-311++G**

3.16

3.07*

G3MP2//B3LYP/6-31G*

4.19

2.44*

CHCl3 (kcal/mol)

*Solvation correction computed using B3LYP/6-31G* wavefunction
**Reoptimization in “solvent” lowers this barrier to 3.06 kcal/mol

Notably, even in this non-conjugated system, the calculated barriers to rotation of the C-C
bond (gas phase) are too low to imply any preference for the chlorine atom to bridge over. As
anticipated, an exhaustive computational analysis to probe the interaction of a “naked” chlorenium
+

ion (Cl ) and the alkenoic acid II-1, leads to transfer of charge from the highly electronegative
halenium atom to a carbon based cation. This analysis, however, does not capture the entirety of
the existing components in the reaction mixture, especially the counter anion of the halenium
donor.
Furthermore, a counterintuitive result, as shown in Scheme II-1, is highlighted by substrate
II-2. The electron donating methoxy substituent in II-2 is expected to readily form and stabilize the
proposed chloromethyl carbenium ion intermediate to a greater extent in comparison to substrate
II-1. Hence, one would expect a greater level of stereoinduction in the corresponding
chlorolactone II-2a. The results displayed in Scheme II-1 argue otherwise; II-2 was observed to be
the least selective substrate, yielding a nearly racemic product mixture. To probe the possibility of
product racemization under reaction conditions, the racemic product II-2a was subjected to
enantiomeric resolution via HPLC (see Scheme II-2a). The enantiomers were subjected
separately to the standard reaction conditions as shown in Scheme II-2b. The lactone product

	
  

60	
  

was found to be stereochemically stable under the standard reaction conditions. The possibility of
olefin to olefin transfer of the chlorenium as a stereo-randomizing pathway was also probed. The
results are detailed as follows (see Scheme II-2c):
Alkenoic acid II-2 was premixed with enantiopure HPLC isolates, with (+)-II-2a (R) in the
ratio 1:1 and with (-)-II-2a (S) in the ratio 5:1, respectively (ratios were confirmed by 1H NMR
analysis of the mixtures using appropriate delay time). In two separate experiments, these
mixtures were exposed to the standard reaction conditions. Interestingly, the results reveal that
the enantiopure lactone resisted racemization under the reaction conditions. It should be noted
that chlorolactonization of II-2 yields II-2a as a racemate under standard reaction conditions. In
the first reaction where 1:1 mixture of II-2:(+)- II-2a (R) is employed, the racemate arising from II-2
contributes one third of (-)-5(S) to the final product accounting for an enantiomeric ratio of

Scheme II-1. Stereoselectivity observed for II-1
chloromethylcarbenium ion as a putative intermediate.

and

II-2,

argues

against

O

(i)
OH

(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)

O

benzoic acid (1 equiv)
CHCl 3:hexane (1:1), 6h, -40 ºC,
85% yield

O
II-1

Cl
II-1a
84% ee

O

(ii)
OH

O

MeO
II-2

	
  

(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)
benzoic acid (1 equiv)
CHCl 3:hexane (1:1), 6h, -40 ºC,
91% yield

61	
  

O

MeO
Cl
II-2a
< 5% ee

the

Scheme II-2. Probing the possibility of racemization of II-2a under standard reaction conditions
employed for asymmetric chlorolactonization.
a.

O

O
HPLC
separation

O

MeO

MeO
using OJ-H
(analytical)
column.
IPA:hexanes
(1:3)
1 mL/min

Cl
(±) - II-2

Cl

O

O

MeO
Cl
(+) - II-2a(R)

(-) - II-2a(S)

>99% ee
Rt = 19.4 min
[α]D = + 23.7
(c = 0.93, CHCl 3)

>99% ee
Rt = 30.3 min

O

b.

O
(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)

O

MeO

O

MeO

benzoic acid (1 equiv)
CHCl 3:hexane (1:1), 6 h, -40 ºC

Cl
(+) - II-2a(R)

(+) - II-2a(R)

Cl

>99% ee

>99% ee

Cl
O

MeO

Cl

(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)

O

benzoic acid (1 equiv)
CHCl 3:hexane (1:1), 6 h, -40 ºC

(-) - II-2a(S)

O

MeO

O

(-) - II-2a(S)
>99% ee

>99% ee

c.

O

O

O

O

O

benzoic acid (1 equiv)
CHCl 3:hexane (1:1),
6h, -40 ºC

Cl
(+) - II-2a(R)

II-2

O

(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)

O
OH

O

Cl
(+) - II-2a(R)

52% ee

>99% ee

(1:1)

Cl
Cl

OH

O

O

O

O

(-) - II-2a(S)

II-2
(5:1)

	
  

O

(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)
O

benzoic acid (1 equiv)
CHCl 3:hexane (1:1),
6h, -40 ºC

>99% ee

O

O

(-) - II-2a(S)
17% ee

62	
  

O

~75:25, hence the observed 52% ee. Similarly, the 17% ee observed in the latter case can be
attributed to about 5/12th of the fractional contribution of (-)-II-2a (S) from II-2.
These results clearly demonstrates that once formed, either of the enantiomers, (+)-II-2a
(R) and (-)-II-2a (S) do not undergo ring opening under the reaction conditions causing errosion of
ees.
Another set of data that argues against the putative halomethyl carbenium ion pathway in
chlorolactonization of II-1 is the significant differences in rates of reactions when the carboxylic
acid moiety in II-1 is substituted by different nucleophiles. As shown in Scheme II-3 below, the
observed differences in rates cannot be possibly explained by considering the classical
hypothesis, which limits the rate determining intermediate to the interaction of a bare “naked”

Scheme II-3. The rate determining-classically perceived intermediates (A and B) fail to explain
the following observed rate differences.
O

Cl

Nuc

N

N Cl

O
DCDMH

Rxn time
CHCl3 (0.05 M)
rt

Nuc
Ph
Cl

O
Cl A

II-1

Nuc

72 h

OH

(i)

Ph
Cl

O

(A)

12 h

OH

(ii)

or

Cl

II-3

δ—

(B)

(iii)

II-4

δ+

H N

O
Ph
Cl

20 min

II-3a

O
Ph
Cl

O

II-1a
O

Rate detemining
intermediates?

O

(iv)

	
  

II-1a

O

A

O

Nuc

O

II-5

O

63	
  

NBu 4

< 2 min

O
Ph
Cl

II-1a

halenium ion and the olefin leading to the formation of either (A) or (B). Overall, these outcomes
call for a comprehensive mechanistic probing of halofunctionalization of alkenes in general.
II.2.2. Mechanistic background.	
  
Mechanistically, halofunctionalization of alkenes has been extensively studied since their
discovery. The exclusive formation of anti-adducts during halogenation of olefins let to the first
proposal by Kimball in 1937 for the intermediacy of symmetrically bridged haliranium ions (three
membered cyclic intermediates; see Figure II-5, intermediate I).10,40,41 As described above, studies
from our own lab as well as those of Fahey, Sauers and others, have reported firm evidence
against the intermediacy of haliranium ions in halofunctionalization reactions.19,30-32,42-44 The
observation of both syn and anti-adducts from halofunctionalizations of styrylic substrates suggest
instead halomethyl carbenium ions intermediates (Figure II-5, intermediate II).32 Furthermore, the
seminal work by Fahey, Poutsma, Williams and several others have demonstrated cases where
either of these classically perceived halonium ion intermediates (I or II) fail to provide an

Figure II-5. Path A and path B represent the rate determining-classically perceived
intermediates (I and II) involved in electrophilic addition to alkenes.
Classical Perception of Electrophilic Addition to Alkenes:
(X = H, F, Cl, Br, I, S, Se, HgL n)
h
at

A

X

A

-AH

P

A X

Nuc

H

(I)

X
Nuc

X

Nuc-H

A

Pa
th

-AH

B

H

Nuc

(II)

	
  

64	
  

explanation of the observed experimental outcomes. For instance, a.) trans-2-butene and
isobutylene exhibit similar rates for dichlorination even though the latter can form a more stable 3°
carbenium ion,22; b.) for dichlorination of a given alkene, a change in solvent polarity displays a
counterintuitive switch in the stereoselectivity where non-polar solvents strongly favor synaddition,19,22,32; c.) stereoselectivity of dichlorination is markedly different for stilbene,
acenaphthylene and phenanthrene where all three substrates have the ability to form a stabilized
benzylic cation,32,45; d.) dichlorination of trans di-tert-butylethylene gives products of methyl
migration (suggesting carbocationic intermediates) along with the desired dichloride adduct
whereas, the highly sterically encumbered cis analogue (anticipated to form a carbenium ion more
likely than its trans isomer as this event would relieve about 12 kcal/mol of steric strain) yields
exclusive anti-adducts with no trace of rearrangement products,34; and, e.) most strikingly,
addition of catalytic amounts of halide anions accelerates dihalogenation of olefins, establishing a
crucial role for a nucleophile in the rate determining step.20,46
II.2.3. Computational analysis for probing alternative mechanistic pathways.
Mechanistically, halofunctionalization of π-systems are thought to be well-understood
reactions; in Sophomore Organic chemistry texts show these as two-step processes: (1)
electrophilic attack on the alkene functionality to form a cationic adduct, and (2) interception of this
adduct by a nucleophile (Figure II-5, paths A and B) to yield the addition product. Olefins that
benefit from extended conjugation with aromatic substituents do not have any preference to form
the bridged haliranium ion intermediates; instead they may form the halocarbenium intermediate
as shown in path B. To probe the validity of this pathway in the asymmetric chlorolactonization of
II-1 initiated by (DHQD)2PHAL as a chiral amine catalyst and 1,3-dichloro-5,5-dimethylhydantoin
(DCDMH) as the terminal chlorenium source, we resorted to transition state analysis at the
B3LYP/6-31G*/SM8 (CHCl3) level of theory. Several starting points (geometries) were considered

	
  

65	
  

to obtain a transition state structure for the formation of the proposed chloromethyl carbenium ion.
However, none of the geometries led to a defined transition state towards formation of the
carbenium ion. In presence of the donor anion, the chlorenium atom could not be transferred to
olefin.
This observation led to an important question in halogenation chemistry: energetically,
what is the cost of transferring a halenium ion from its donor to an olefin? In other words, what are
the relative “Halenium Affinities” of the olefin and the donor anion and, can we quantify the
propensity of an alkene towards capture of a halenium ion from its donor? To address these
questions, we introduce a previously unexplored parameter -Halenium Affinity (HalA)- as a
quantitative descriptor of the bond strengths of various functional groups to halenium ions.47 The
HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a ‘free
halenium ion’. Alkenes in particular but other Lewis bases as well, such as amines, amides,
carbonyls and ether oxygens, etc. have been classified on the HalA scale. The influences of
subtle electronic and steric variations, as well as the less predictable anchimeric and
stereoelectronic effects, are intrinsically accounted for by HalA computations, providing
quantitative assessments beyond simple ‘chemical intuition’. Specifically, we define the HalA
value for a given Lewis base (:LB) as the DFT calculated (gas phase) energy change upon
+

attachment of a halenium ion (X ), as shown in the dashed box below. The acceptor fragment
may be neutral or anionic (i.e. the X-LB complex is cationic or neutral), leading to two distinct
cases:
+

+

neutral acceptor: ΔHrxn (X + :LB → X−LB )
+

anionic acceptor: ΔHrxn (X + :LB¯ → X−LB)

	
  

66	
  

The HalA values in kcal/mol are derived at T = 298.15 K (unless noted otherwise) as in equation
(1) and (2):
5
𝑯𝒂𝒍𝑨 =    −∆𝐸!"!# −    ∆𝑍𝑃𝐸 − ∆𝐸 ! !"# + 𝑅𝑇                                                  (1)
2
!!!!

                                𝐸

!

!"#

𝑇 =
!!!

𝑁ℎ𝑣!
!!!
! /!" −
𝑒

1

                                                                          (2)
+

where; ΔE(elec) = E(electronic)(X-LB adduct) – [E(electronic)(:LB) + E(electronic) (X )]; zero point
energy change ΔZPE = ZPE(X-LB adduct) – ZPE(:LB); ΔE’(vib) = E’(vib)(X-LB adduct) – E’(vib)(:LB)
i.e. difference in temperature dependence of vibrational energy; N is Avogadro’s number:
6.022×10

23

mol−1, h is Planck’s constant: 6.62606957(29)×10−

34

J·s, and ni is the i

th

vibrational

frequency. Finally, the 5/2 RT quantity accounts for translational degrees of freedom and the ideal
gas value for the change from two particles to one. The ground state energy of the halenium ion is
calculated for its triplet state.
Qualitative reactivity ranking of potential halogen attack sites using HalA computations can
be made using the HalA table (see Figure II-6) whereas quantitative comparison of affinities can
be established by computing the full structures using optimum solvation models. Figure II-6
provides the HalA (Cl) scale for various functional groups to allow a qualitative comparison. As
shown, functional groups (acceptors) undergoing extended conjugation with the substituents
attached, span a larger range of HalA. For instance, alkenes, alkynes, amines, aromatic
compounds etc. whose HOMO can be easily altered based on the electronics of the substituents,
display a wider range of HalA values in comparison to epoxides or alcohols where the attached
substituents can only exert a weaker inductive effect. The HalA scale has been experimentally
verified by analysis of the equilibrium ratios of various chloropyridinium salts. Ms. Nastaran
Marzijarani performed an exhaustive survey of experiments on chloropyridinium salts and

	
  

67	
  

Figure II-6. The HalA (Cl) scale based on theoretical estimates of over 500 chlorenium ion
acceptors.
Thiols and Sulfides

Epoxides

Aromatics
Tertiary Amines
Heterocycles
Secondary Amines

Enones

Phosphines
Primary Amines
Aliphatic alcohols

Alkenes
Alkynes
Pyridines

Phenols

100

124

148

172

196

220

HalA (Cl) scale in kcal/mol for common functional groups

displayed that the predicted HalA values are in excellent agreement with the experimentally
determined ratios.
A relative comparison of halenium affinities can facilitate (a) a rational approach towards
choice of compatible nucleophiles (especially when the nucleophilic atom is embedded within
motifs that have similar steric/electronic profiles) (b) it can account for the modulation of HalA
values of alkenes by the anchimeric assistance of neighboring functionalities; this aspect
underscores the importance of quantitatively evaluating HalA values on full structures rather than
on truncated models. Furthermore, subtle electronic perturbations leading to modulations of HalA
values are also accounted for in the calculations, (c) accurate predictions of chemoselectivity
towards development of halenium initiated cascade/Domino reactions, and (d) most importantly,

	
  

68	
  

Figure II-7. HalA (Cl) predictions at the B3LYP/6-31G*/SM8(CHCl3) level of theory predicts the
alkenoic acid II-1 to be inefficient to capture the chlorenium atom from DCDMH.
Cl
N

HalA (Cl)
181.1 kcal/mol

O
N

O

Cl

path a

OH

Ph
Cl

OH

Ph

HalA (Cl) alkenoic
acid
167.4 kcal/mol II-1

O

path b

-H

O
(DHQD) 2PHAL (10 mol%)
DCDMH (1.1 equiv)
benzoic acid (1.0 equiv)
CHCl 3:Hexanes (1:1), -40 ºC
85% yield, 84% ee

Cl

O

O

Ph

II-1a
-H

Cl

OH

Ph
O
O

Cl

N

O

HalA (Cl)
181.1 kcal/mol

N
Cl

this tool can be employed as an indirect probe to verify the possibility of halenium ion transfer
between two acceptors.
Application of HalA computation to cholorolactonization reveals that the alkenoic acid II-1
cannot compete in terms of its halenium affinity to capture a chlorenium atom from DCDMH. The
olefin has a 13.7 kcal/mol lower HalA (Cl) in comparison to the anion of the chlorenium donor.
However, the reaction does proceed in practice and goes to completion at -40 ºC in about 6 h.
This raises an imperative question as to what phenomenon allows compensation for the 13.7
kcal/mol difference in HalA values? An exhaustive search for transition state structure led us to an
interesting finding wherein, the nucleophile plays a key role by interacting with the olefin and
eventually exalts its HOMO energy, allowing it to capture the halenium ion. Figure II-8 depicts the
calculated transition state for the above chlorolactonization where two molecules of the alkenoic
acid are involved in strong H-bonding interactions with the two most basic sites on the catalyst
(the quinuclidine nitrogens). This interaction serves benefits the reaction in multiple ways: a. the

	
  

69	
  

Figure II-8. Calculated transition state structure for the asymmetric chlorolactonization of II-1
catalyzed by (DHQD)2PHAL at the B3LYP/6-31G*/SM8(CHCl3) level of theory.
DCDMH
(DHQD)2PHAL
(grey)

3.7 Å

(yellow)
2.1 Å

2.6 Å

1.7 Å

Front View

Alkenoic acid
II-1
(green)

Side View

substrate based olefin is occluded within the chiral cleft of (DHQD)2PHAL, b. the H-bonded
complex enhances the nucleophilic character of the carboxyl moiety promoting a stronger prepolarization of the olefin via nucleophile-olefin interaction (enhancing its HOMO energy) and, c.
the C2-carbonyl of DCDMH is electrostatically attracted to the ammonium center, allowing a predisposition of the reactants in a spatial setting, enhancing the rate of the reaction as well as
imparting the observed enantioinduction.
Among all the features, the assistance of nucleophile is of utmost importance towards
initiating the chlorenium atom transfer. To further probe this hypothesis, which we dub as
“Nucleophile Assisted Alkene Activation” (NAAA), the following theoretical and experimental
studies are presented.
	
  

	
  

	
  

70	
  

II.3. Nucleophile Assisted Alkene Activation (NAAA)
II.3.1. The classical perception of halonium ions.

In path A or B in Figure II-5, the conventional mechanism would view the electrophilic
halenium attack to form bridged halonium or an open halo-carbenium ion as the rate-determining
step. This allows the electronic nature of substituents directly attached to the olefin to influence
the formation of intermediate I (either symmetrically or asymmetrically bridged) and/or
intermediate II. Three inferences arise from this picture: (i) The reaction rate should be governed
by the first step, forming intermediates I or II; (ii) the stereo-preference and regioselectivity of the
nucleophilic attack should be dictated by the stereoelectronic identity of I and II; and, (iii)
nucleophilic attack (step 2) should have no significant bearing on the rate of the overall addition.
Despite these well-defined features, numerous previously reported experimental outcomes are not
well explained by this classical scenario. The major drawback in this analysis is the uncharted role
of the nucleophile and the counter anion of the halenium donor.
II.3.2. Halenium affinity (HalA) as a mechanistic probe.
As described earlier, the HalA scale ranks potential halenium ion acceptors based on their
ability to stabilize a free halenium ion. Although this is an indirect approach, the HalA values serve
as quantitative descriptors of the bond strengths of various functional groups to halenium ions. To
probe the classical approach, wherein a donor transfers a halenium ion onto an olefin leading to a
haliranium ion (or halocarbenium ion) in proximity with its donor counter anion, we resorted to
comparison of their relative HalA values (Figure II-9). The SM8 model for simulated chloroform (a
typical solvent for halogenation reactions) was employed for this HalA assessment. The role of
the byproduct anion after halenium ion delivery has received relatively little attention in
mechanistic descriptions of electrophilic halogenations. A handful of reports have explored
bridged halonium ions with counterions such as trifluoromethylsulfonate, BF4¯

	
  

71	
  

Figure II-9. a. Relative HalA values (B3LYP/6-31G*/SM8-CHCl3)for some prototypical alkenes
in comparison to 1-methylcyclohexene. b. Relative HalA values of anions of commonly used
halenium ion donors in comparison to 1-methylcyclohexene. Values in parenthesis are absolute
HalA values. c. Classical mechanistic perception leading to charged intermediates. d.
Competition between neutral and anionic acceptors for capture of chlorenium ion (complex-A)
and competition between two neutral acceptors (complex-B).

a.

b.

X
+ Neutral
Halenium ion Acceptor

ΔHalA1 a
(F)
Neutral
Acceptors Kcal/mol

Ph

+ Anionic
X
Halenium ion Acceptor

Acceptor X
cationic adduct

ΔHalA1 a ΔHalA1 a ΔHalA1 b
(Cl)
(Br)
(I)
Kcal/mol Kcal/mol Kcal/mol

0.0
(369.2)

0.0
(152.1)

0.0
(125.5)

0.0
(93.8)

1.3

4.4

4.0

3.9

Acceptor X
neutral adduct

ΔHalA1 a ΔHalA1 a ΔHalA1 a ΔHalA1 b
(F)
(Cl)
(Br)
(I)
Anionic
Acceptors Kcal/mol Kcal/mol Kcal/mol Kcal/mol
F−

15.6

---

---

---

Cl−

---

15.4

---

---

Br −

---

---

28.3

---

---

---

---

124.2

---

39.0

42.3

---

---

41.9

45.1

133.0

---

29.0
(X=Cl)

33.4
(X=Br)

---

-4.9

---

---

---

---

8.0

---

---

I−
O

7.7

8.7

7.3

8.4

Ph

N
1.2

3.4

3.1

4.9

4.2

2.2

1.7

4.0

-6.9

-3.2

0.6

2.8

O

Ph
Ph

S

O

N

O

O

N

O

N

c.

Acceptor

Acceptor + Donor X

classical mechanistic perception
a
b

Donor

B3LYP/6-31G*/SM8 (CHCl 3)
B3LYP/6-31G*/LANL2DZ (gas phase)

d.

anionic
acceptor
(TCCA anion)
1.72 Å

neutral
acceptor
(styrene)

	
  

X

X
O OO O
S
S
N
Ph
Ph
O
Cl
N
N
O

neutral
acceptor
(Et 2S)

1.74 Å
2.93 Å

Complex-A

N
Cl

neutral
acceptor
(styrene)

72	
  

O

Complex-B
2.79 Å

1.96 Å

and antimony (VI) halides, anions with extremely low halenium affinity.35,48-52 In contrast, the most
commonly employed halenium donors in halo-functionalization of olefins are imide-based
reagents or dihalogens themselves, whose counter anions have higher halenium affinities
(compare HalA values in Figure II-9 a and b).	
  
To validate the HalA assessments, a theoretical competition for a chlorenium ion was set
up between dichloroisocyanurate anion (with the lowest HalA-Cl value among imide based donors
studied to date) and styrene as the alkene acceptor (Figure II-9 d, complex A). The B3LYP/631G*/SM8 (CHCl3) level of theory reveals only a weak Van der Waals interaction between styrene
and the chlorine in this complex, without a trace of olefin re-hybridization. The TCCA imide
nitrogen, on the other hand, retains its N-Cl bonding at a distance (1.74 Å) almost equidistant to
the other two N-Cl bonds (1.72 Å). A similar competition between diethylsulfide (mimicking the
chlorenium ion donor-chlorodiethylsulfonium hexachloroantimonate)53 and styrene finds the
chlorenium ion again shared unequally between the two ‘neutral’ acceptors. However; in this case
the styrene is the stronger acceptor, pulling the chlorine close (1.96 Å; see complex B). Since
reaction of neutral species to form ionic products in general is energetically uphill in organic
solvents, transfer of chlorenium ion to olefins by expulsion of an anionic donor is not an optimum
choice for a reaction pathway (Figure II-9 c). Due to the high electronegativity of halogens, during
a halofunctionalization reaction, the halenium atom will break the bond to the donor atom only
after it has acquired enough electron density from the acceptor. Hence, to ensure complete
transfer of halenium ion from a donor haloimide to an acceptor alkene, the HalA of the anionic
imidate (after the N-X bond is severed) should be less than the corresponding alkene. In essence,
anionic species will always outcompete a neutral acceptor to capture a halenium ion (Figure II-9 b
and d). Yet reagents such as TCCA are not only successful but also highly reactive in electrophilic
halofunctionalizations of alkenes. What enables olefins to react with these imide based halenium

	
  

73	
  

ion donors? The following series of experiments provides evidence for activation by the
nucleophilic partner, presumably by exalting the HOMO of the π-system and thereby increasing its
nucleophilicity. This hypothesis accords with the Salem-Klopman equation that quantifies the
degree of perturbation of molecular orbitals upon interaction of electrophiles and nucleophiles with
a π-system.54,55 The following set of experimetnal results validate the HalA predictions.
As

represented

in

Figure

II-10,

the

classical

mechanistic

perception

of

halofunctionalization of olefins predicts the transfer of a halenium ion from a donor to an olefin
leading to a bridged haliranium ion (or halocarbenium ion) in proximity with its donor counter
anion. To elucidate the thermodynamics of this process, we resorted to comparison of HalA
values. The SM8 model for simulated chloroform (a typical solvent for halogenation reactions) was
employed for this HalA assessment.
A competition reaction was set up between tetra-n-butylammonium succinimidate (anionic

Figure II-10. Classical perception of halofunctionalization of olefins.
Application of HalA to address the energy cost for formation of charged intermediates

Donor based
anion

Halogen based
cation

A
A
X

Aδ
Xδ

X

step 2

X

fast
-AH

−

+

Nuc

stereospecific
adducts

H Nuc

step 1
slow
(RDS)

Carbenium
ion
A

(X = F, Cl, Br and, I)

X

step 2
fast
-AH
H Nuc

	
  

74	
  

X

Nuc

syn and anti
adducts

Figure II-11. 1H NMR spectra, (CDCl3, rt, dark): a. N-chlorosuccinimide (NCS), b. tetra-nbutylammonium succinimidate, c. 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), d. a 1:1
mixture of succinimide anion and DCDMH, the 1H NMR resonances depict the succinimide
anion abstracts the chlorenium ion completely from DCDMH owing to the higher HalA value of
succinimide anion (ΔHalA = 8.9 kcal/mol).
a.

O

Ha
Ha
NCS

b.

N

HalA (Cl) = 194.0 kcal/mol

O

H 3C
H 3C

3

N

N Cl

1

O

Ha

succinimide anion

N(nBu) 4

O

Cl

O

O

Ha
Ha

c.

Ha

N Cl

DCDMH

HalA (Cl) of 1-chloro5,5-dimethyl hydantoin
anion (N 3)
= 181.1 kca/mol

O

d.
succinimide + DCDMH
anion
(1:1)

-CH3

O

CDCl 3
N Cl

N

N

Cl

Ha

-CH3

rt
O

N(nBu) 4 O

acceptor) and 1,3-dichloro-5,5-dimethylhydantoin-DCDMH (neutral donor) to study the possible
transfer of chlorenium atom, see Figure II-11. The succinimidate anion (spectrum b) has a 8.9
kcal/mol higher HalA (Cl) value than the N3 anion of monochlorohydantoin, hence for the above
competition reaction, we can predict the succinimidate anion to abstract a chlorine atom from the
N3-Cl bond of DCDMH to produce N-chlorosuccinimide and a N3 anion of monochlorohydantoin.
As anticipated, the exclusive formation of N-chlorosuccinimide (NCS) is observed (spectrum d)
upon reaction of an equimolar ratio of succinimidate anion and DCDMH.
On the contrary, a similar competition reaction between NCS and tetra-n-butylammonium
salt of 1,5,5-trimethylhydantoin N3 anion (TMH anion) does not lead to transfer of chlorine atom
(spectrum d, Figure II-12). TMH anion has a 2.9 kcal/mol lower HalA (Cl) value than succinimidate
anion and hence, it is inefficient to capture the chlorenium atom from NCS. Instead, it engages a

	
  

75	
  

Figure II-12. 1H NMR spectra, (CDCl3, rt, dark): a. N-chlorosuccinimide (NCS), b. tetra-nbutylammonium succinimidate, c. tetra-n-butylammonium 1,5,5-trimethylhydantoin-1-ide (TMH
anion), d. a 1:1 mixture of NCS and TMH anion, the 1H NMR resonances depict the TMH
anion being inefficient to abstract the chlorenium ion from NCS owing to the lower HalA value
of TMH anion (ΔHalA = 2.9 kcal/mol).
a.

O

Ha
Ha
NCS

b.

Ha

N Cl
O

O

Ha
Ha

N

HalA (Cl) = 194.0 kcal/mol

O

c.

Ha

succinimide anion

N(nBu) 4

O
H 3C

N

N

HalA (Cl) = 191.1 kcal/mol

O

d.
NCS + TMH anion
(1:1)

-CH3

TMH anion

N(nBu) 4

CDCl 3

Ha

O
N Cl

O
N

rt

O

N

CH 3
N(nBu) 4

Ha
-CH3

O

weak halogen bonding with the chlorenium atom as indicated by the minuscule downfield shift
(0.02 ppm) of N1-CH3 resonance and a 0.1 ppm upfield shift of the NCS methylene proton
resonance.
Following the validation of HalA predictions, we studied the possibility of halenium ion
transfer to α-methylstyrene using different chlorenium ion sources in the absence of a
nucleophile. Trichloroisocyanuric acid (TCCA), inheriting an excellent leaving group attached to
the chlorenium atom (HalA of dichloroisocyanurate anion = 160.1 kcal/mol), is predicted by HalA
computations to deliver a chlorenium ion to electron rich alkenes such as α-methylstyrene (HalA =
160.8). This stands out to be an exceptional case as the alkene by itself has a higher HalA (Cl)
than the donor anion by 0.7 kcal/mol.

	
  

76	
  

To verify this prediction, we studied the

1

H NMR resonance of α-methylstyrene in

presence of several chlorenium sources. As shown in Figure II-13, chlorenium sources such as
+

NCS and DCDMH, whose imidate anion (formed after Cl delivery) has higher HalA (Cl) value
than α-methylstyrene are inefficient to effect chlorination of the olefin. The olefinic 1H NMR

Figure II-13. 1H NMR spectra, (CDCl3, rt, dark): a. α-methylstyrene, b. N-chlorosuccinimide
(NCS), c. equimolar ratio of α-methylstyrene and NCS, d. 1,3-dichloro-5,5dimethylhydantoin (DCDMH), e. a 1:1 mixture of α-methylstyrene and DCDMH. The
unchanged 1H NMR resonances of NCS and DCDMH in spectra c and e illustrate the fact
that α-methylstyrene, owing to its lower HalA (Cl) value, is inefficient to capture the Cl+ atom
from either donors to form charged products. f. Chlorination of α-methylstyrene using
TCCA.

O

N

N

O
O

O

N

Cl

Cl
ΔHalA (Cl)

0.0 kcal/mol

a.

33.2 kcal/mol

O

20.3 kcal/mol

N
N

O
N

Cl
O
-0.7 kcal/mol

CH 3
Ha

Ha

-CH3

Hb

Hb

α-methylstyrene

b.

Hc
Hc
NCS

O

Hc

N Cl
O

c.
Ha

α-methylstyrene + NCS (1:1)

Hb

d.

-CH3

O

H 3C
H 3C
Cl

Hc

N

-CH3

N Cl
O

DCDMH

e.
Ha
f.
He Hf

	
  

Ha

Hb

-CH3 -CH3

α-methylstyrene + DCDMH (1:1)

Hb

Hd

Cl

CH 3

α-methylstyrene
+
TCCA (1:1)

Hd

Ha
Hb

77	
  

(2:1)

Hf
He

-CH3

resonances (Figure II-13, spectrum c and e) of α-methylstyrene do not indicate any strong
halogen bonding interactions between the olefin and the chlorenium source. However, TCCA,
whose counter anion has a 0.7 kcal/mol lower HalA than α-methylstyrene, is effective to yield αchloromethylstyrene as shown in spectrum f.
These examples underscore the importance of HalA as a mechanistic probe towards
accurately predicting halenium ion transfers. Due to the high electronegativity of halogens, during
a halofunctionalization reaction, the halenium atom will break the bond to the donor atom only
after it has acquired enough electron density from the acceptor. Hence, to ensure a complete
transfer of halenium ion from a donor haloimide to an acceptor alkene, the HalA of the anionic
imidate (after the N-X bond is severed) should be less than the corresponding alkene, which is not
a common instance as seen from the experiments described above. In essence, anionic species
will always outcompete a neutral acceptor to capture a halenium ion. All the above results taken
together with the detailed and exhaustive studies from other labs30,31,42,44 demonstrates that
formation of charged intermediates, such as the haliranium ion (bridged halonium ion) bearing a
cationic halonium is unlikely under prototypical halofunctionalization reactions involving imide
based reagents or dihalogens in general.
Note: Unless otherwise mentioned, all NMR experiments shown above, were performed in CDCl3
at 0.05 M substrate concentration, at room temperature. Experiments involving halenium ion
sources were performed in absence of light to avoid radical halogenation. In case of treatment of
α-methylstyrene with DCDMH and TCCA, mixing of the reactants in CDCl3 was performed at 0 ºC
in the absence of light and the mixture was eventually warmed to room temperature over a course
of 3 min (in an amber glass NMR tube). All spectra were acquired within 5 min of mixing
reactants.

	
  

78	
  

Now, we can apply the HalA values towards probing the non-catalytic chlorolactonization
of II-1. Comparing the HalA(Cl) values for an unactivated olefin (~165 kcal/mol) with a common
+

Cl donor such as the monochlorohydantoin anion (181.1 kcal/mol) in chloroform, one predicts no
chlorenium transfer, a result of the much higher HalA value of the donor anion compared to the
+

olefin (Figure II-14b). Naked Cl to II-1 would be expected to attack without barrier to form a

Figure II-14. Computational predictions for possible chlorenium atom transfer (B3LYP/631G*/SM8-CHCl3).
HO 2C

a.

Cl

Chloromethyl carbenium ion
∠C+-C-Cl = 109.6°;
barrier to rotation C+-C-Cl = 3.14 kcal/mol

O

b.

Cl N

N Cl

1.9 Å

HO 2C
O

TS for
Cl+ transfer

4.2 Å

extended conformer
(unactivated olefin)

HalA(Cl)
167.4 kcal/mol

resting state
Van der Waals complex
HalA(Cl) of activated
donor anion
‡ 173.6 kcal/mol

c.
O

O
O

H

δ+
δ−

Cl N

N Cl
O

O

coiled conformer
(nucleophile induced
HalA(Cl)
pre-polarization)
173.3 kcal/mol

	
  

O
Ph
Cl

TS for asynchronuos
concerted addition

79	
  

Scheme II-4: The rate determining-classically perceived intermediates (A and B) fail to explain
the observed rate differences, whereas the nucleophile assisted activation pathway predicts the
barriers (B3LYP/6-31G*/SM8-CHCl3) for halofunctionalization, which are in accordance to the
observed rates.
O

Cl
Nuc

N

N Cl

O
DCDMH

Rxn time

Nuc
Ph
Cl

CHCl3 (0.05 M)
rt

TS‡ barriers
(kcal/mol)

O

72 h

OH

(i)
II-1

Ph
Cl

O

Cl

27.7

δ−

2
O

12 h

nucleophile induced
pre-polarization

16.7

Ph
Cl

II-3

3
A

O
δ+

δ—

O

(iii)

II-4

δ+

δ+ Nuc

OH

(ii)

O

A δ−

H N

20 min

X

O

‡

14.3

Ph
Cl

O

δ−

δ+ Nuc

2
O

O

(iv)

chloromethyl

II-5

NBu 4

< 2 min

O
Ph
Cl

O

carbenium

ion

(Figure

II-14a)

but

8.8

Nucleophile
participation in RDS

2

the

actual

reagent-

1,3-dichloro-5,5-

+

dimethylhydantoin (DCDMH) can only transfer Cl to one conformation of the olefin where the
nucleophile is able to interact with the π-system. This geometry positions the carboxylic acid in
close proximity to the C2 of the olefin (Figure II-14c). Calculations show that this nucleophilic
interaction with the olefin raises the energy of its π bonding orbital (the HOMO) by 0.10 eV,
enabling it to compete with the donor anion for the chlorenium atom, and in effect increasing the
HalA of the now activated olefin. Upon DCDMH association, this conformation shows N-Cl bond
elongation and leads to a transition state for chlorolactonization. This detailed scenario predicts
that the reaction precedes via nucleophile assisted alkene activation (NAAA), which depends not

	
  

80	
  

only on the nucleophilicity of the olefin (as measured by HalA), but also on the source of the
chlorenium. The HalA of the olefin, a composite of the olefin with all its interactions including the
suggested nucleophilic activation, is higher as compared to the isolated, unperturbed olefin
moiety. The transition state calculations on the reactions depicted in Scheme II-4 with
conformations favorable to NAAA yield activation energies consistent with the observed reaction
rates. In other words, the ordering of reaction times, II-1 > II-3 > II-5 (carboxylate, the most
nucleophilic substrate in the list) is consistent with the ordering of the calculated reaction barriers
27.7 > 16.7 > 8.8 kcal/mol, respectively.
II.3.3. Kinetic isotope studies in chlorocyclization of II-1, II-2 and II-3.
Scheme II-5 displays a sampling of experimental and theoretical methods used to
investigate the concerted (albeit asynchronous) nucleophilic activation of olefin/halenium capture
en route to halocyclizations. Chlorolactonization (more than bromo- or iodolactonization) provides
ample opportunity to substrate II-1 to proceed via a tertiary benzylic carbenium ion. To probe
whether NAAA competes with this stepwise pathway, we have used natural abundance KIE
measurements

and

heavy

atom

labeling

studies

to

probe

the

transition

states

of

halofunctionalization reactions. Using a blend of theoretical predictions (from calculated transition
structures) and experimental results of

13

C KIE experiments, the hybridization states of the

olefinic carbons at the transition state during halofunctionalization reactions can be probed. To
interpret

13

C KIE values, we considered the three possible alternative pathways depicted in

Figure II-15. (i) Path A involves the classic bridged haliranium ion wherein both olefinic carbons
undergo modest rehybridization during formation of intermediate (I). However, the benzylic
stabilization in II-1, will render the haliranium ion asymmetric (C(benzylic)-Cl bond longer than
C(homobenzylic)-Cl bond). If formation of this haliranium intermediate is the RDS, the benzylic

	
  

81	
  

carbon should be least affected by isotope substitution and hence, the magnitude of

13

C KIE at

the benzylic carbon should be lower than that on the chloromethylene carbon. (ii) For Path
2

2

B-intermediate (II), the benzylic carbon would experience no hybridization change (sp to sp ),
yielding an isotope effect near unity, whereas the fully rehybridized carbon β to phenyl should
show a substantial KIE. (iii) Finally, the new proposed Path C entails nucleophile involvement in
the RDS, with the magnitude of the isotope effect reflecting the electronic nature of the

Figure II-15. Path A and path B represent the rate determining-classically perceived
intermediates (I and II) involved in electrophilic addition to alkenes. Path C represents the
nucleophile assisted activation pathway.
Classical Perception of Electrophilic Addition to Alkenes:
(X = H, F, Cl, Br, I, S, Se, HgL n)

A

X

Pa

th

A

-AH

A X

H

Nuc

X

(I)

Nuc
Nuc-H
Pa

X

th

A
-AH

B

H

Nuc

(II)
Nucleophile Assisted Alkene Activation: NAAA
(X = F, Cl, Br, I)

A

A X
Path C

X

δ+

δ+

δ−

H
Nuc

A

H

Nuc

X

‡

X

-AH

δ−

Nuc

syn adduct
X

Nuc-H

Nuc
H δ+
pre-polarization
of olefin

	
  

δ+

H

Nuc

asynchronus
concerted TS
(syn or anti addition)

82	
  

Nuc
anti adduct

nucleophile as well as the substitution pattern of the olefin. Since, the nucleophile assists the prepolarization of the alkene, the benzylic carbon should display a higher magnitude of

13

C KIE in

comparison to the chloromethyl carbon. The experimental KIEs may also be compared with those
from theoretically calculated transition states for these three paths.
Scheme II-5 illustrates the use of isotopic tools to decipher transition state characteristics
in the chlorolactonization of II-1. Here, a clear case can be made for the nucleophile playing a role
in activating the olefin. The relative magnitude of

13

C KIE on the benzylic vs the homo benzylic

carbon clearly argues against Path A (Figure II-15) and hence, it can be excluded (Scheme II-5a).
Similar but more thorough studies by the Sauers group30 and from our own lab agree in reasoning
against bridging haliranium ions. Based on these studies (where the donor anion is not invoked),
upon capture of a halenium ion, II-1 can be envisioned to undergo formation of a tertiary benzylic
halomethyl carbenium ion (Path B, Figure II-15). This provides an excellent opportunity to probe
2

for the existence of the putative halocarbenium ion by H as well as

13

C KIEs. A series of labeled

substrates were synthesized and tested to probe the possible role of intermediate III. The C-H
bonds alpha to the carbenium center would be expected to contribute to the cation’s stabilization
2

via hyperconjugation and hence, the secondary H KIE at that site should be a sensitive probe for
the cation’s intermediacy. Since it would be less stabilized by neighboring D than by H atoms,
halocarbenium ion formation should be slower in the labeled substrate II-1-D2 and II-2-D2 than in
the parent.
Furthermore,

13

C KIE experiments (natural abundance measurements pioneered by

Singleton and coworkers), in conjunction with quantum chemical transition state predictions can
also probe the changes in hybridization state of the benzylic carbon in the RDS.56,57

	
  

83	
  

Scheme II-5. a, b.

13

C KIE results predicted at the B3LYP/6-31G* level of theory and its
2

validation by experimental results. c, d. Secondary KIE ( H) for halolactonization of II-1
and II-2. e, f. Primary

18

O KIE experimental results for II-1 and II-2.

a.

1.011 (5) O
1.016

‡

O

CO2H
Ph

1.000
1.002

Ph
Cl

1.4 Å
2.4 Å

II-1

1.008 (5)
1.013

1.9 Å
13 C

KIE experimental and
predicted values
B3LYP/6-31G*/SM8 (CHCl 3)
Non-unity KIE at the quaternary carbon argues against a carbocationic intermediate

"Control"

b.

1.001 (5) O
1.008

‡
1.7 Å

O

Ar
Cl

CO2H
Ar

2.0 Å

II-2
Ar = 4-OMe-C6H 4

1.010 (4)
1.012
13 C

c.

1.000
1.001

KIE experimental and
predicted values

B3LYP/6-31G*/SM8 (CHCl 3)
No KIE at the quaternary carbon clearly suggests a carbocationic intermediate
O
DCDMH
KH /KD = 0.995
(1.1
equiv)
OH
O
Ph
Ph
CHCl3 (0.05M),
X X O
X II-1a, X = H
Cl
rt, 72 h
X
II-1, X = H
II-1a-D2, X = D
II-1-D2, X = D
Secondary KIE being unity a carbocationic intermediate seems implausible

"Control"

d.

OH

Ar

DCDMH
(1.1 equiv)

O

KH /KD = 1.183

O
X X O
CHCl3 (0.05M),
Ar
X
II-2, X = H
4 h, 10 °C
X
II-2a, X = H
II-2-D2, X = D
Cl
II-2a-D2, X = D
Ar = 4-OMe-C6H 4
Secondary KIE implicates a carbocationic intermediate

XH

Ph
X
II-1, X = 16 O
II-1*, X = 18 O

O

DCDMH
(0.1 equiv)

e.

II-1 + II-1*
(1:1)
CHCl3 (0.05M),
rt, 1 h

O

K16 O /18 O =
1.026

Ph
Cl

II-1a and II-1a*

A significant primary KIE invokes an irrefutable role of nucleophile in the TS

"Control"

f.

XH

Ar
X

II-2 + II-2*
(1:1)

O

DCDMH
(0.1 equiv)
CHCl3 (0.05M),
rt, 1 h

O
Ar
Cl

K16 O /18 O =
1.009

II-2, X = 16 O
II-2a and II-2a*
II-2*, X = 18 O, Ar = 4-OMeC6H 4
A minimal primary KIE suggest the nucleophile is not involved in the RDS

	
  

84	
  

The results observed under prototypical conditions for halocyclization are summarized in
Scheme II-5a. Surprisingly, substrate II-1 (certainly capable of forming a tertiary benzylic
carbenium ion) exhibit no evidence for a chlorocarbenium intermediate. The benzylic carbon
shows a non-unity

13

2

C isotope effect of 1.011 (Scheme II-5a), while the near-unity H KIE for II-1-

D2 (Scheme II-5c) argues against carbenium ion development at that site, at least in the RDS. A
quantum chemically evaluated transition state for chlorolactonization of II-1 explicitly supports this
idea, showing instead an asynchronous concerted addition of the carboxylic acid and the
chlorenium atom across the styrylic moiety (Scheme II-5a). This process avoids charge buildup on
any of the reactants. The transition state calculations also reveal a concomitant proton transfer
from the carboxylic acid moiety to the carbonyl oxygen of the hydantoin (H-O distance of 1.4 Å)
during the addition reaction (see Figure II-16). Proton transfer in the transition state should lead to
a non-zero KIE for chlorolactonization of II-1-OD. In fact cyclization of II-1 vs II-1-OD does show a
substantial KIE, a strong corroboration of the notion that the remote nucleophile is involved in
accelerating the reaction. These interpretations were confirmed by findings for substrates II-2 and
II-2-D2 (employed as a ‘control’), in which a resonance-stabilized carbenium ion can form. There,
the unity

13

C KIE at the quaternary carbon and

2

H secondary KIE of 1.183 support the

intermediacy of a halomethyl carbenium ion (Scheme II-5b and II-5d) with hyperconjugative
stabilization from the neighboring C-H bonds. Furthermore, in comparison to the classical
mechanisms, NAAA invokes a strong and obligatory role for the nucleophile during the course of
the reaction. To probe the influence of the nucleophile directly, KIE of the carboxylic acid oxygen
atoms was investigated. Clearly one would not expect an

18

O KIE if the carboxylic acid was not

involved in the RDS or as a player in determining the course of the reaction. This, in fact, is the
case with the ‘control’ substrate II-2, which proceeds mainly via the benyzlic carbocation, with

	
  

85	
  

Figure II-16. Predicted transition state for chlorolactoniaztion of II-1 depicting the proton transfer
from the carboxylic acid moiety to the carbonyl of chlorohydantoin.
KH /KD = 1.511

proton
transfer
O

O
O

δ+

Cl N

H/D

δ−

‡

N Cl

O
O

O

coiled conformer
(nucleophile induced
pre-polarization)

Ph
Cl

TS for asynchronuos
concerted addition

K16O/K18O = 1.009 (Scheme II-5f). In stark contrast, a substantial

18

O KIE is observed for the

chlorocyclization of II-1 (K16O/K18O = 1.026). The latter data clearly shows the direct involvement of
the nucleophile, as preselection of

16

O in favor of

18

O must have been determined prior to capture

of the chlorenium ion. This data paints a scenario that is in agreement with the transition state
calculations described above (Scheme II-5a), highlighting the crucial role of the nucleophile in
activating the olefin.
Kinetics of chlorolactonization of II-1 (syn vs anti addition):

Although the experimental KIE of 1.511 for II-1 vs II-1-OD corroborates the theoretically
predicted value of 2.2, the computational analysis is based on the TS for syn-addition (Figure II16). Experimentally, the reaction also yields an anti-adduct. Interestingly, the value for syn:anti
addition varies based on the concentration of the reagent. The following set of experiments
demonstrates the effect of concentration on chlorolactonization of II-1a.
The vinylidene group of the styryl substrates (II-1-D and II-2-D) offers an additional handle
to probe the nature of intermediates in these reactions. Our recently reported synthesis of
substrate II-1-D enabled us to probe the relative stereochemistry of the overall addition.19 Using

	
  

86	
  

Table II-1. anti:syn ratios for the deuterium labeled styryl substrates. The plot of ratios vs.
concentration suggest a bimolecularity for chlorolactonization of II-2-D whereas a more complex
scenario in case of II-1-D. For entries 1-6, the reagent concentration equals that of the substrate.

H

D

DCDMH
(1.0 equiv)

OH

Ar

O
II-1-D, Ar = C6H 5
II-2-D, Ar = p-OMe-C6H 4
Entry

CDCl 3, rt

H D
Cl

O
Ar

H D
O

Cl

O

O

Ar

syn addition : anti addition

ratio
ratio
Sunstrate
(anti:syn) (anti:syn)
conc.
from II-1-D from II-2-D
(M)

1

1.0

2.30

1.20

2

0.5

2.05

0.70

3

0.1

1.13

0.46

4

0.05

0.90

0.43

5

0.025

0.73

--

6

0.0125

0.67

0.35

7

0.0125
(0.1 M DCDMH)

1.03

--

the same probe we elucidated the effects of reactant concentration on the overall addition.
Interestingly, the non-catalyzed reaction displayed a significant concentration effect onthe ratio of
syn:anti adducts (Table II-1). The anti-adduct was predominant at higher concentrations while the
syn-adduct dominated at lower concentrations. The effective concentration of the chlorenium
donor was elucidated to be the key factor in controlling the syn:anti ratio (entry 7, Table II-1). The
concentration of the reagent (or any basic moiety) is the key feature that determines the
stereochemical course of halofunctionalization of olefins. Furthermore, substrate II-1-D showed
non-linear effects of concentration on syn:anti ratios whereas a linear trend was seen with
substrate II-2-D. If the RDS of the reaction involves a 1:1 (substrate : reagent) complex, then the
bimolecular reaction should display a linear trend as seen for II-2-D. These studies highlight the

	
  

87	
  

1.7 Å
proton transfer

proton transfer

1.4 Å

TS for syn-addition

TS for anti-addition

II-1 : DCDMH = 1:1

II-1 : DCDMH = 1:2

Figure II-17. Predicted molecularity from computational analysis for syn and anti addition during
the chlorolactonization of II-1. The concomitant proton transfer stabilizes the TS for
chlorolactonization as the nucleophile polarizes the π-system of the olefin. These predictions are
corroborated by experimental RPKA analysis.
idea that during the RDS of chlorolactonization of II-1-D, more than one molecule of the
chlorenium source is involved. To verify this hypothesis, we initiated transition state analysis for
syn and anti addition, the summary of which is depicted in Figure II-17. The syn-addtion (a cyclic
TS with minimal separation of charge) requires one molecule each of II-1 and DCDMH, whereas,
the anti-addition commences only when a basic moiety (such as one more molecule of DCDMH)
is involved in accepting the proton from the carboxylic acid moiety. The concomitant proton
transfer serves to stabilize the TS structure as the nucleophilic oxygen polarizes the olefin’s πsystem. In essence, either DCDMH (during the initial stages of conversion) or 1-chloro-5,5-

	
  

88	
  

Table II-2. anti:syn ratios for the deuterium labeled styryl substrates. The carboxylate in II-5D displays a high preference for anti-addition as well as a linear trend of anti/syn with
concentration in contrast to II-1-D.
H

D
OY

Ph
O

DCDMH
(1.0 equiv)

H D
Cl

CDCl 3, rt

O
Ph

H D
O

Cl

O

O

Ph

syn addition : anti addition

II-1-D, Y = H
II-5-D, Y = NBu 4

Conc. (M) of
alkenoic acid
(and DCDMH)

anti/syn
from II-1-D

anti/syn from
II-5-D

1.2

2.4

16.5

1

2.3

15.7

0.5

2.1

13.4

0.1

1.1

11.5

0.05

0.9

--

0.025

0.7

--

0.0125

0.7

10.1

	
  
dimethylhydantoin (towards the latter stages as the reaction progresses) can serve as a potential
base to favor the trimolecular transition state leading to the formation of anti-product. Hence, at
higher reagent concentration (favoring the trimolecularity) the anti-adduct dominates while, at
lower reagent concentration (lower local concentration reduces the probability for trimolecularity)
the syn-adduct is preferentially formed. To corroborate the results from computational analysis,
we performed a detailed study using ‘RPKA’ analysis, pioneered by Blackmond and co-workers.38
The kinetic studies revealed a reaction that is first order in the alkenoic acid and 3/2 order in
DCDMH. This result supports the fact that more than one molecule of the reagent (DCDMH) is

	
  

89	
  

involved in the RDS of this chlorolactonization. Analyses of the kinetic complexities of these
processes are in progress.
Furthermore, to highlight the fact that anti-addition on II-1 requires trimolecularity, we
measured the anti/syn ratios in halolactonization of II-5-D (seeTable II-2). The carboxylate in II-5D does not require assistance of a third component to serve as base, hence, as in II-2, the
carboxylate II-5-D also displays a linear trend and an enhanced preferenced towards antiaddition. A similar behaviour is observed when halolactonization of II-1-D was performed in
presence of 20 mol% base (quinuclidine or DABCO).19 Finally, the dependence for anti:syn
addition in the halolactonization of II-1-D has been catagorized as follows:

a. Halenium ion dependence:

As anticipated, with increasing size of the halenium ion, the sterically congested TS
leading to syn adduct becomes more energetic in comparison to the TS for anti-addition. This
leads to a higher anti:syn ratio in the halolactonization of II-1-D. As shown in Table II-3, the
preference for anti adduct increases in the expected order: Cl < Br < I.

Table II-3. anti:syn ratios for halolactonization of II-1-D. The halolactonization displays a high
preference for anti-addition with increasing size of the halenium ion.
Concentration (M) of II1-D (and halenium
source)

anti/syn for
chlorolactonization

anti/syn for
bromolactonization

anti/syn for
iodolactonization

1.0

2.3

19

>20

0.5

2.1

--

--

0.1

1.1

9.5

>20

0.05

0.9

9.05

--

0.025

0.7

--

--

0.0125

0.7

8.3

>20

	
  

90	
  

b. Solvent dependence:

Although the observed results cannot be generalized to known solvent effects, non-polar
solvents seem to promote the anti-adduct in chlorolactonization of II-1-D with acetone being an
exception (Table II-4).

c. Dependence of anti:syn ratio on the acidity of DCDMH vs monochlorohydantoin:

As described above, the TS leading to the formation of anti-adduct from II-1 requires a
third component (apart from II-1 and DCDMH) that can engage H-bonding interaction with the
carboxylic acid while it is activating the olefin (see Figure II-17). During the early stages of the
reaction, this role can be fulfilled by DCDMH. However, with the depletion of DCDMH (as the
reaction progresses), the byproduct monochlorohydantoin has to engage the H-bonding
interaction (with -COOH of II-1) to stabilize the TS for anti-addition. Since, the N-H in
monochlorohydantoin, by itself is relatively acidic (pKa = 7.17),58 the TS leading to anti-addition
should be less favored, especially towards the later stages of the reaction. Our 1H NMR analysis
display a slight decrease in the anti-addition during the latter stages of chlorolactonization of II-1-D

Table II-4. Solvent effect on anti:syn ratio for halolactonization of II-1.

	
  

Solvent
(conc. of II-1-D = 0.05M)

anti/syn from II-1-D

Acetone

10

Hexanes

4.5

Carbon Tetrachloride

3.5

Acetonitrile

3.5

HFIP

1.9

DMF

1.7

91	
  

Table II-5: Dependence of anti:syn ratio on the acidity of DCDMH vs monochlorohydantoin. The
following chlorolactionization of II-1-D was performed at 0.05 M substrate concentration.

time (h)

anti/syn from 1a-D

1

1.03

10

0.90

20

0.85

70

0.85

(Table II-5).

Most importantly, these studies highlight the enabling role of nucleophile and corroborate
the computationally derived hypothesis for the molecularity of syn and anti addition processes in
halofunctionalization of II-1. This hypothesis is further validated by the following K16O/K18O studies
using

18

O enriched II-1 to provide a definitive evidence towards the participation of nucleophile in

electrohilic addition to olefins.	
  	
  
The isotope effects and variable syn:anti ratio results above firmly argue against an open
carbenium ion intermediate in cyclization of II-1. Our own previous studies and reports from other
groups

as

well

have

questioned

the

generality

of

the

bridged

haliranium

ions

in

halofunctionalizations. The subtleties encountered just in investigating the halofunctionalization of
olefins call for further comprehensive analysis in order to understand the continuum of possible
mechanistic pathways operating in several electrophilic addition reactions. The following studies
with several aliphatic and aromatic probes validate the generality of NAAA hypothesis.

	
  

92	
  

II.3.4. Imperative role of nucleophile.
In their halofunctionalization studies, Williams, Dangat and Wirth made the intriguing
observation that catalytic amounts of nucleophilic anions substantially enhance reaction
rates.20,46,59 Furthermore, in chlorofunctionalizations of 1-phenylpropenes, Fahey reported
significant variations in product distribution merely by varying the choice of nucleophile. These
experimental results point to nucleophile participation in determining reaction rates and
stereoselectivities.20,32,46 Moreover, based on HalA predictions, the π-systems of the olefins shown
in Figure II-9 are incapable of abstracting the chlorenium ion by themselves, from any of the
commonly used imide-based halenium donors. The NAAA hypothesis entails interaction of a
nucleophile with the olefin’s π-system (to raise its HOMO energy) leading to capture of an
electrophile. To probe the NAAA hypothesis, we selected the intramolecular halolactonization of
the dienoic acid II-6 as a model reaction (Figure II-18). The nucleophilicity of the carboxylic acid
moiety’s is easily altered by addition of basic additives, while the rigidity of the cyclic framework
restricts the conformational freedom of the carboxylate nucleophile. The intramolecular
halolactonization of substrate II-6 and its tetra n-butylammonium (TBA) salt II-7 were therefore
studied in detail. Based on classical hypothesis, the olefin-halenium adduct can be defined by
either intermediates A or B (Figure II-18). If initial attack on the π-bond forms the haliranium ion,
the tertiary carbon would be expected to bear the greatest positive character or even exist as an
open carbenium ion.

22,60

The nucleophile would then close the ring by attack on the most

electrophilic site, the tertiary carbon, to form product II-6a. Given that chlorenium ions do not
exchange between halogenated alkenes,35 intermediates A and B (Figure II-18a) should be both
rate and product-determining. Therefore, altering the nucleophilicity should not significantly alter
the overall regioselectivity or rate.

	
  

93	
  

Figure II-18. a. Classical prediction for the outcome of halolactonization of II-6 b. NAAA
prediction for regioselectivity of halolactonization of II-6 and II-7 based on enhanced
nucleophile strength.
a.

O
δ

O Y

−

O

O

CHCl3 (0.05M), rt

δ+

O

O

X+ source
(1.1 equiv)

X

X

II-6a

II-6, Y = H
II-7, Y = NBu 4

II-6b

ΔH (rel) = 0.0 kcal/mol

OH

10-11 kcal/mol

OH

O

O
d2

X

d1

X

d1 > d2

A

B

b.
H
O

CH 3

O
II-6

Reversal of
Intrinsic Polarity

δ+

δ−

CH 3

?

NBu 4

O

CH 3

O

Intrinsic Polarity
of olefin

δ−

δ+

II-7

CH 3

Reversed Polarity

A X

A X
O

δ+

X

O

	
  

‡

H
O

δ−

A

O

TS-1

Thermodynamic
product
O
ΔH (rel)
0.0 kcal/mol
X II-6a

TS-2

Kinetic
O
product
ΔH (rel) in kcal/mol
= 10.5 (X=Cl)
= 10.5 (X=Br)
= 11.0 (X=I)

94	
  

‡

δ−

O

δ−

A

X

O

II-6b

X

On the contrary, if the reaction proceeds through a nucleophile assisted pathway,
substrate II-6 bearing a weakly nucleophilic carboxylic acid moiety should give the same product
(II-6a) via a asynchronous concerted pathway (Figure II-18b). Furthermore, enhancing the
nucleophilic character of the carboxyl group in II-6 may cause a reversal in the intrinsic polarity of
the olefin leading to a contemporaneous capture of the halenium atom at the tertiary carbon
yielding the 4-exo-halolactones- II-6b. The regioselectivity of these strained products will be
governed by the conformation preference of the “activated” nucleophile. Moreover, the rate of the

Table II-6. Halolactonization of II-6 and II-7. 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), Na

b

bromosuccinimide (NBS), N-iodosuccinimide (NIS). Isolated yields. Ratios were determined
1

by H NMR analysis (500 MHz). Values in parenthesis are for reactions that were catalyzed
using 20 mol% quinuclidine as an amine base.
II-6
or
II-7

O

O
O

CHCl3 (0.05M), rt

X

II-6a

O

II-6b X

Entry

Substrate

Halenium
donor

Time
(min)

Overall
yielda

ratiob
II-6a :II-6b

1

II-6

DCDMH

240
(30)

84%
(88%)

>98:2
(10:1)

2

II-6

NBS

180
(30)

97%
(>99%)

>98:2
(11:1)

3

II-6

NIS

180
(30)

89%
(90%)

>98:2
(>98:2)

4

II-7

DCDMH

>2

95%

2:1

5

II-7

NBS

>2

>99%

2.5:1

6

II-7

>2

93%

>98:2

Cl

O
N

N Cl

O
DCDMH

	
  

Halenium donor
(1.1 equiv)

NIS
O

O

N Br

N I

O
NBS

O
NIS

95	
  

Crystal
structure of II-6b-Cl

reaction will be dictated by the strength of the nucleophile; stronger the nucleophilicilty-faster the
rate. As anticipated, the weak nucleophile in II-6 under non-catalyzed halolactonization conditions
(Table II-6, entry 1) did proceed as anticipated to furnish regioselectively, the 5-endo-halolactones
II-6a. Screening of achiral amine catalysts revealed that addition of 20 mol% of quinuclidine gave
an 8-fold rate enhancement (values in parenthesis under entry 1). Interestingly, in this case, about
9% of the thermodynamically disfavored chlorolactone II-6b-Cl was also isolated. Formation of
this 4-exo cyclization product under prototypical halolactonization conditions raises the following
questions: a.) Why would the classically expected, bridged chloronium ion (more appropriately
‘chloriranium ion’) furnish the strained-ring product II-6b-Cl under base catalyzed conditions?; and
b.) is it the nature of the base used or the presence of the internal nucleophile that enables
formation of such a strained product (a β-lactone and a quaternary chloride fused to a
cyclohexene framework)? To address the latter question, the tetra-n-butylammonium salt (II-7)
was subjected to chlorolactonization under the same conditions (entry 4), yielding 33% of product
II-6b-Cl and displaying another 15-fold rate enhancement.
Halolactonization of the free acid II-6 gave the corresponding 5-endo halolactones II-6a
(Table II-6) with all halogenating agents. On the other hand, addition of 20 mol% basic amine
(quinuclidine) as a catalyst, or the use of salt II-7 resulted not only in significant rate acceleration,
but also in formation of the 4-exo-lactones II-6b. This regiochemical switch clearly suggests a
central role for the nucleophilic partner in the addition. Reaction of the substrate with enhanced
nucleophilicity forms a kinetic product that is not only at odds with the intrinsic polarity of the πsystem, but also strained, and thus thermodynamically disfavored by over 10.0 kcal/mol over the
5-endo lactone. The exclusive anti-addition observed for the overall addition (confirmed by 1H
NMR and X-ray structure) in products II-6a and II-6b rules out the formation of a carboxyl
hypohalide (-CO2-X) as an intermediate, due to its tendency to undergo syn addition.

	
  

96	
  

To test the validity of increased nucleophilicity as the defining influence for regioselectivity,
we resorted to haloetherification of the same core. Substrate II-8 incorporates an alcohol moiety,
more nucleophilic than the carboxylic acid in II-6, but neutral, unlike the carboxylate in II-7. As
anticipated, the non-catalyzed bromoetherification of II-8 gave a higher 4- exo:5-endo product
Table II-7. a. Halolactonization of II-8 b. Halolactonization of II-9. 1,3-dichloro-5,5dimethylhydantoin (DCDMH), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS). aIsolated
yields. bRatios were determined by 1H NMR analysis (500 MHz). cRatios could not be
determined by crude 1H NMR analysis. Values in parenthesis are for reactions that were
catalyzed using 20 mol% quinuclidine as an amine base.
OH

a.

Halenium donor
(1.1 equiv)

O

O

CHCl 3 (0.05M), rt

X
II-8a

II-8b

II-8

Entry

Substrate

Halenium
donor

Time
(min)

Overall
yielda

ratiob
II-8a : II-8b

1

II-8

DCDMH

40
(15)

64%
(75%)

n.ac

2

II-8

NBS

30
(10)

81%
(92%)

5:1
(5:1)

3

II-8

NIS

30
(10)

86%
(89%)

>98:2
(>98:2)

b.

H
N

O

Ph Halenium donor
(1.1 equiv)

Ph N

Ph N
O

CHCl 3 (0.05M), rt

X

II-9

	
  

X

II-9a

O

II-9b

X

Entry

Substrate

Halenium
donor

Time
(min)

Overall
yielda

ratiob
II-9a : II-9b

1

II-9

DCDMH

600

78%

>98:2
(E:Z = 1:1)

2

II-9

NBS

8400

88%

>98:2
(E:Z = 1:1)

3

II-9

NIS

10800

76%

>98:2
(E:Z = 1:1)

97	
  

ratio (II-8b-Br: II-8b-Br) than the corresponding bromolactonization of II-6, see Table II-7.
Furthermore, addition of quinuclidine as a base additive did not make any difference to the
regioselectivity of this reaction. This result is consistent with the fact that an amine base cannot
deprotonate the alcohol before it has engaged the nucleophilic attack; however, the base does
help to stabilize the TS for haloetherification (H-bonding interactions) and hence, an enhancement
in the observed rate. On the other hand, lowering the nucleophilicity by incorporating amide

Table II-8. Halolactonization of II-10 and II-11 displaying the role of a conformationally
rigidified nucleophile in determining the regioselectivity of the overall addition. aIsolated yields.
b
Ratios were determined by 1H NMR analysis (500 MHz).
CO2Y

Halenium donor
(1.1 equiv)

CHCl3 (0.05M), rt
II-10, Y = H
II-11, Y = NBu 4

O

O
O
X

O

X
II-10a

II-10b

Substrate

Halenium
donor

Time
(min)

Overall
yielda

ratiob
II-10 a : II-10b

II-10

DCDMH

480

73%

<2:98

II-10

NBS

840

86%

<2:98

II-10

NIS

840

75%

1:20

II-11

DCDMH

>2

91%

<2:98

II-11

NBS

>2

>99%

<2:98

II-11

NIS

>2

80%

<2:98

Crystal Structures

II-10b-Cl

	
  

II-10b-Br

98	
  

II-10a-I

functionality in substrate II-9 furnished solely the 5-endo cyclized products II-9a, and only after a
relatively longer reaction time. Iodofunctionalization of either of these substrates failed to form the
4-exo products. This could be due to the overriding steric cost of bearing an iodo-substituent on a
quaternary carbon.
Dihydrobenzoic acid (II-10), in which the olefin sites have unbiased intrinsic polarities,
favored the 4-exo products almost exclusively when its tetra-n-butylammonium (TBA) salt (II-11)
was the alkene substrate (Table II-8). As an important note, based on electron withdrawing
inductive effect of the carbonyl group in II-10 and II-11, the classical pathway will predict an
opposite sense of regioselectivity towards formation of halolactones II-10b.
The findings above reveal the nucleophile’s key role in directing halofunctionalization
reactions. The increased nucleophilicity not only accelerates rates by orders of magnitude but also
overrides the intrinsic polarity of the olefin towards electrophilic halenium attack. These results,
however, are not sufficient to rule out the existence of haliranium ions as possible intermediates.
To probe further, open-chain substrates and their corresponding TBA salts were examined for
regioselectivity and rate enhancement as follows.

II.3.5. Regiospecificity of a conformationally constrained nucleophile.
Substrate II-12 (Figure II-19) incorporates a cis-olefin in conjugation with a phenyl ring.
The aliphatic side chain incorporating the carboxylic acid at its terminus is conformationally
contrained by allylic strain due to the cis-geometry of the olefin. Considering the classical
mechanism (paths A or B, Figure II-19), the carboxylic acid side chain in intermediate-I from path
A should be conformationally free as the olefinic carbons are now re-hybridized to a non-planar
geometry, alleviating the allylic strain. Benzylic stabilization then would render the haliranium ion
asymmetric, guiding the regioselectivity of the overall addition to favor the 6-endo product (d1>d2,
intermediate-I, Figure II-19). Stereodefined products, with syn-orientation of the phenyl and

	
  

99	
  

Figure II-19. Comparison of classical approach (path A and B) vs the regio-defined capture of
the halenium by nucleophile pre-polarized π-system (path C).
A d1 X

HO
(I)

A X

X

Path B

H

CO2H
Pa
th
C

H

‡
-AH

H

H
Ph

O
pre-polarization
of olefin

5-exo
product

−

X

H

O

Ph

H

Aδ
δ−

O

O

A
X

X

HO

(II)
II-12

O
O
6-endo
product

-AH

A

Ph

"SN 2" Ph

O

"

A

X

-AH

H

H

N1

th
Pa

d1 > d2

d2

δ+

Ph

δ+

"S

(X = F, Cl, Br, I)

O

O
H

δ+

(III)

δ+

O asynchronus

H

concerted TS

halogen, would thus be expected from intermediate-I. However, based on reports from Sauers
and from our lab (based on ab initio estimations of styrylic systems with ‘naked halenium ions’ in
the absence of donor counter anions), path B is more likely; intermediate-II should have low
+

rotational barrier (<3.5 kcal/mol) along the C -C-X bond.19,30,31 Again, the 6-endo regioselectivity
would be expected, but relative stereospecificity would be governed thermodynamically, favoring
anti-products with both phenyl and halogen moieties in equatorial orientation.
In the case of Path C, the nucleophile donates into the alkene, raising the HOMO energy
of its π-system. The conformational constraints imposed by the cis-olefin’s allylic strain bias its
reach to the homobenzylic carbon (intermediate-III). This pre-activated olefin then undergoes
contemporaneous attack by the electrophilic halenium at the benzylic carbon and the carboxylate
nucleophile at the neighboring site, ultimately furnishing 5-exo products, opposite to the sense of
regioselectivity predicted for paths A or B. As seen in Table II-9, the experimental outcomes

	
  

100	
  

Table II-9. a. Halolactonization of alkenoic acid II-12 and II-13. b. Halolactonization of alkenoic
a

b

1

acid II-14 and II-15. Isolated yields. Ratios were determined by H NMR analysis (500 MHz).
c

No isomerization observed for the recovered olefinic substrate.

d

No isomerization of the
e

f

olefinic substrate was observed during the course of the reaction. 52% conversion. 19%
conversion.
a.

CO2Y

Halenium
donor
(1.1 equiv)

O

b.

O

Halenium
donor
(1.1 equiv)

CO2Y

O
O

CHCl3
Ph
(0.05M), rt
II-12, Y = H
II-13, Y = NBu 4

X

X

Ph
II-12a

Ph
II-12b

nBu

II-14, Y = H
II-15, Y = NBu 4

O

O
O

O

CHCl3
(0.05M), rt

X

X

nBu

II-14a

Overall
yielda

nBu

II-14b

Substrate

Halenium
donor

Time
(h)

Overall
yielda

ratiob
II-12a : II-12b

Substrate

Halenium
donor

Time
(h)

II-12

DCDMH

144

no
reaction

--c

II-14

DCDMH

96

35%e,c

<2:98

II-12

NBS

28

89%

<2:98

II-14

NBS

96

15% f,c

<2:98

II-12

NIS

30

86%

<2:98

II-14

NIS

72

85%

<2:98

II-13

DCDMH

12

78%

<2:98d

II-15

DCDMH

1

90%

<2:98

II-13

NBS

1

96%

<2:98

II-15

NBS

1

94%

<2:98

II-13

NIS

1

93%

<2:98

II-15

NIS

1

87%

<2:98

ratiob
II-14a : II-14b

support the mechanism of path C. Substrate II-12 exclusively yields the 5-exo halolactones (II12b). Boosting the nucleophilicity (substrate II-13) does not make any difference to the observed
regioselectivity, but the reaction rate is significantly higher. Thus, the putative Van der Waals
complex A (Figure II-9d) of the olefin and the halenium donor reagent requires the nucleophile’s
assistance to re-hybridize the olefin’s sp2 carbons. Path C (Figure II-19) thus bypasses the
benzylic stabilization invoked in paths A and B, explaining the observed regiochemistry.
Moreover, the recovered staring material from the chlorolactonization of II-12 and II-14 did not
undergo isomerization, suggesting that mechanistic pathways (such as path A or B) that caould
lead to stereorandomization are not operational. Substrates II-14 and II-15, lacking the possibility
of benzylic stabilization, show a similar effect where the kinetically favored 5-exo products (II-14b)
are formed exclusively. Furthermore, as reported by Denmark et al. the Z-alkenoic alcohols

	
  

101	
  

display similar regiopreferences with enhanced reaction rates in comparison to the corresponding
alkenoic acids.61

II.3.6. Interaction of nucleophile with olefin π-system in absence of halenium ion
donor.
If a nucleophile interacts with the π* of C=C to alter its HOMO energy, then such an interaction
should exist even in the absence of an electrophile. To probe this possibility, we resorted to NMR
studies in CDCl3 as a solvent. The NMR shifts of the olefinic protons and carbons in CDCl3 should
show effects when the electronics of a remotely tethered nucleophile are modified. As shown in
Figure II-20, our NMR studies clearly demonstrate the ‘through-space’ interaction of a remotely
tethered nucleophile with the π–system of olefins. The olefinic components (H and C) in free acid
II-12 display proton resonances at 6.50 ppm for Ha and 5.62 ppm for Hb while the corresponding
13

C resonances appear at 130.4 and 129.8 ppm. Changing the tethered nucleophile to a primary

alcohol (more nucleophilic than carboxylic acid) in II-12-OH leads to upfield shifts of the distal
olefinic Ha’s and corresponding carbons (C-Ha) whereas the more proximal Hb and C(-Hb)
experience de-shielding (downfield shift) relative to their parent acid. It is important to note that
inductive effects will not result in a shielding effect of an atom (C-Ha) located five bonds away and
a de-shielding effect on an atom (C-Hb) that is four bonds away. This differential effect can be
attributed to the interaction between the non-bonding electrons of the nucleophile and the π*
orbitals of olefin. The extended conjugation as a result of a ‘through-space’ interaction leads to a
kinetically governed conformational preference of the side chain such that the electron density
increases at C-Ha (shielding effect), see Figure II-20, dashed box. Consistent with the reactivity
patterns, increasing the nucleophilicity extends and magnifies this polarization; carboxylic acid II12 treated with 1.0 equiv of an organic base (quinuclidine), and the tetra-n-butyl ammonium salt II13 display the same trend with enhanced effect.

	
  

102	
  

Furthermore, treatment of II-13 with substituted pyridines display an enhanced polarization
of the olefin with increasing pKa of the pyridine derivative. Table II-10 represents the effects on 1H
and

13

C resonances of the olefin upon altering the nucleophile strength of a functionality tethered

remotely on the alkene. To fine-tune these effects we resorted to NMR studies of substrate II-12
upon its treatment with bases exhibiting a range of pKa values. Table II-10 displays an ascending
trend of nucleophile assisted olefin activation as the basicity of the added base increases. Weak
bases such as 4-cyanopyridine, 2,6-di-tert-butylpyridine and pyridine (entries 1-3) whose
conjugate acid has a pKa similar to the carboxylic acid (pKa assumed to be approximately 4.5),62
do not affect the 1H and

13

C resonances of the olefin to any observable extent. In contrast,

stronger Lewis bases, 2,4,6-lutidine, DABCO and quinuclidine result in an upfield shift of the distal
carbon C5(-Ha) and the corresponding proton Ha whereas, the de-shielding (downfield shift) is
observed for the more proximal C4(-Hb) and Hb. The magnitude of this effect depends on the pKa
of the base employed. It is important to note that the ability to modulate nucleophilic character of a
carboxylic acid by varying the basicity of the Lewis base provides with a handle to guide the
course of the reaction; thermodynamic or kinetic.

	
  

103	
  

Figure II-20. NMR resonances of olefinic C and H (at room temperature in CDCl3) displaying the
interaction of a remotely tethered nucleophile with the π-system upon modulation of the
nucleophilic strength.

Ha

Ha

II-12

Increased electron
density leads to
shielding of H a and
C-H a

Hb

Hb
CO2H

Ph

Ha
II-12-OH

Ha

CH2OH

Ha

Hb O

Ha

δ−

O

δ 13C-Hb
(ppm)

130.4

129.8

129.4

132.0

128.6

132.6

127.8

133.7

Hb

Hb

Ph

H a δ− δ+ H b
R
Nuc

δ 13C-Ha
(ppm)

δ+

Hb

H N

Ph

II-12 + quinuclidine

kinetically favored
5-exo mode of
interaction of nucleophile
with π* of olefin

Ha

Ha

Hb

Hb

CO2 NBu 4

II-13
Ph

Ha

Hb
Nuc

Entry

Ph
Ph

2

Ph

3

Ph

4

Ph

5

6

	
  

H

1

CO2H
II-12

CO2Me
II-12-OMe

CH2OH
II-12-OH

II-12 + 1.0 equiv.
quinuclidine

Ph

CO2 NBu 4
II-13

δ Ha
(ppm)

δ Hb
(ppm)

δ 13 C-Ha

δ 13 C-Hb

(ppm)

(ppm)

6.41

5.68

133.0

128.8

6.48

5.62

130.4

129.8

6.49

5.64

130.3

130.2

6.44

5.66

129.4

132.0

6.34

5.66

128.6

132.6

6.30

5.73

127.8

133.7

104	
  

Table II-10. Correlation of basicity to nucleophilic activation of an olefin by carboxylic acid.
Effect on 1H and 13C resonances of II-12 (at room temperature in CDCl3) upon treatment with
bases.
(II-12), pK a ~ 4.5

CO2H
Ph

Base

none

1

2

NC

N

Enhanced activation of olefin

Increasing Basicity

3
tBu

N

Hb
O

δ+ H
Base

(1.0 equiv)

(1.0 equiv)

Entry

Base

H a δ−
Ph

0.05 M
CDCl 3, rt

O

pK a of
conjugate
acid (in H 2O)

δ Ha
(ppm)

δ Hb
(ppm)

δ 13 C-Ha

δ 13 C-Hb

(ppm)

(ppm)

---

6.48

5.62

130.4

129.8

1.90

6.48

5.63

130.2

130.0

4.95

6.48

5.63

130.4

129.9

5.21

6.45

5.66

130.5

129.5

7.43

6.43

5.66

129.7

130.9

8.82

6.39

5.64

129.2

131.6

11.0

6.34

5.66

128.6

132.6

15.5

6.30

5.73

127.8

133.7

tBu

4
N

5
N

6

N
N

7
N

8

	
  

nBu 4N OMe

105	
  

Figure II-21. 1H and 13C resonances of II-13 (at room temperature in CDCl3) over a range of
concentration (1.0 M to 0.001 M)
13

13

δ C-Ha

δ C-Hb

127.5

133.2

127.8

133.5

128.0

133.6

0.05 M

127.8

133.7

0.01 M

128.1

133.7

0.001 M

not determined

Molarity (M)

Ha

Hb
Ha

CO2 NBu 4

II-13

1.0 M

Hb

Ph

0.5 M

0.1 M

The 1H and

13

C resonances observed are concentration independent. To verify whether

the change in 1H and

13

C resonances of the olefinic moiety were due the proposed ‘through-

space’ interaction and not because any aggregation effect, we studied the NMR of II-13 under
different concentrations. Figure II-21 depicts the 1H and

13

C resonances of II-13 in CDCl3 at room

temperature at different concentrations ranging from 1.0 M to 0.001 M. The unchanged 1H and

13

C

resonances over a wide range of concentration imply absence of aggregation or any
concentration dependent phenomenon that can potentially affect the observed chemical shifts.
Similarly, II-12, II-12-OH and the acid-base complex II-12 with quinuclidine (Figure II-20, entries,
2, 4 and 5) did not show any effect of concentration of their corresponding chemical shifts.

	
  

106	
  

These observations are consistent with quantum chemical NMR shift calculations on the
lowest energy conformations of II-12, II-12-OH and II-13 at the B3LYP/EDF2 level of theory. The
additional examples shown below substantiate the same hypothesis of ‘through-space’
interaction. The carboxylate salts display an enhanced activation of the olefin in comparison to the
corresponding free acids.
Alkenoic acids and the corresponding carboxylates were then subjected to conformational
search at the B3LYP/6-31G* (gas phase) level of theory. Geometry optimization was performed
1

13

Figure II-22. a. H and C resonances of alkenoic acid II-12 predicted at the B3LYP/EDF2
level of theory. The conformers were initially subjected to geometry optimization at the
B3LYP/6-31G*/SM8 (CHCl3) level. b. Orbital energies of II-12 and II-13 at HF/6-31G*.
a.

ΔH(rel)
in kcal/mol
B3LYP/6-31G*/
SM8 (CHCl 3)

Ha

Predicted 1H and 13 C resonances (B3LYP/EDF2)
δ Ha
(ppm)

δ Hb
(ppm)

δ 13 C-Ha

δ 13 C-Hb

(ppm)

(ppm)

0.0

6.50

5.80

131.9

130.7

0.2

6.49

6.16

130.9

131.9

Hb

Ph
O
HO
extended chain
staggered conformer

H a δ− δ+ Hb
Ph
O
H

3.2 Å

Boltzman gated average-predicted vs (experimental)

O
conformer exhibiting
'through-space'
interaction

6.48

5.80

132.0

130.8

(6.48)

(5.63)

(130.4)

(129.8)

Orbital energies (eV) evaluated at HF/6-31G*/SM8 (CHCl 3)

b.

HOMO LUMO ΔE (LUMO-HOMO)
(eV)
(eV)
(eV)
-8.2

3.2

HOMO LUMO ΔE (LUMO-HOMO)
(eV)
(eV)
(eV)

11.3

-7.6

	
  

11.2
II-13

II-12

3.2 Å

3.6

ΔΔE (LUMO-HOMO) = 0.1 eV
= 2.3 kcal/mol

107	
  

3.1 Å

on these conformers at the B3LYP/6-31G*/SM8 (CHCl3) level of theory. To confirm that each
structure was a true minimum, vibrational analyses were performed. These optimized structures
were evaluated for a.) orbital energies at the HF/6-31G*/ SM8 (CHCl3) level of theory and, b.)
NMR prediction at the B3LYP/EDF2 level of theory.
Substrate II-12 and II-13 were subjected to the above quantum chemical computational
analysis. As shown in Figure II-22a, the two conformers of II-12, extended and coiled, although
have similar energies (ΔH = 0.2 kcal/mol), their NMR resonances are quite different. As one would

Figure II-23. a. Modulation of HOMO energy of olefin in II-1 upon its interaction with a
1

nucleophile. b. Experimental evidence by H NMR.
a.

HOMO
-8.4 eV
Ph

O
HO
extended chain
staggered conformer of II-1
HOMO
-8.3 eV
δ− δ+ Ph
3.0 Å

O
H

II-1
O

conformer exhibiting
'through-space'
interaction
b.

Ha

Hb
OH

Ph
II-1

Ha

Hb

O

Hb
O NBu 4

Ph

Ha

Ha

II-5 O

	
  

108	
  

Hb

predict, the extended chain conformer exhibits downfield resonances (1H and

13

C) at the benzylic

position relative to the homobenzylic position. In contrast the coiled conformer displays a switch in
13

the

C resonances as the nucleophile engages a ‘through-space’ interaction with the

homobenzylic carbon. In this conformer, the C5=C4…..O=C interaction causes de-shielding
(downfield shift) of the homobenzylic carbon (C4) whereas the distal C5 carbon experiences
shielding effect as a result of accumulation of electron density. This effect is also evident by an
increase of 0.1 eV in the HOMO energy of the olefin in the coiled conformer of II-12. As with any
carboxylic acid, II-12 will also tend to engage itself in the stronger intermolecular H-bonding
interactions forming the carboxylic acid ‘dimers’, thus favoring the extended conformer over the
coiled one. A Boltzmann gated NMR prediction at the B3LYP/EDF2 level of theory leads to the
same conclusion as the Boltzmann averaged NMR resonances of the conformers of 1f have more
contribution from the extended conformer.
The computational analysis of II-13 also validate the Nucleophile Assisted Alkene
Activation (NAAA) hypothesis. In this case, the lowest energy conformer was found to be the
coiled conformer (see Figure II-22b), as estimated at the B3LYP/6-31G*/SM8 (CHCl3) level of
theory. It is energetically favored over the extended conformer by 0.3 kcal/mol. Furthermore, as
shown in Figure II-22b, the HOMO energy of the π-system in II-13 is elevated by 0.5 eV (11.5
kcal/mol) in comparison to II-12, thus, predicting the carboxylate in II-13 to be a stronger olefin
activator.	
  Similarly, as shown in Figure II-23, interaction of the carboxylic acid with the π-system of
the olefin in II-1 raises the olefin HOMO energy by 0.1 eV. This effect is more pronounced in
substrates II-6 and II-7, which incorporate a conformationally rigid framework (Figure II-24). The
conformational rigidity of the cyclohex-1,4-diene framework is manifested in the extent of olefin
activation by the nucleophile. The HOMO-LUMO energy gap in the parent alkene is attenuated by
0.3 eV upon incorporating the weakly activating carboxylic acid in II-6. The salt II-7 further

	
  

109	
  

Figure II-24. Orbital energies of II-6 and II-7 in comparison to 1,5-dimethylcyclohexa-1,4diene.
HOMO
(eV)

LUMO
(eV)

ΔE (LUMO-HOMO)
(eV)

-8.8

5.1

13.9

1,5-dimethylcyclohexadiene

ΔΔE
(eV)

0.3

CO2H
II-6

-9.1

4.5

13.6

1.4
CO2 N(nBu) 4
II-7

-7.5

4.7

12.2

mitigates the energy gap by another 1.4 eV. Overall, the interaction of nucleophile with the πsystem not only raises the HOMO energy, but also attenuates the HOMO-LUMO energy gap.
More importantly, these studies imply that the interaction between the nucleophile and the
olefin may be a key mechanistic feature of electrophilic addition reactions in general. For instance,
the thiourea catalyzed hydroamination reported by Jacobsen’s lab involves activation of an alkene
by a tethered hydroxylamine where the intrinsic α-effect leads to enhanced nucleophilicity of the
amine nitrogen that allows polarization of the alkene without assistance of any metal ion.63
Similarly, the exquisite regioselectivity reported by Sigman et. al. in the Pd(II) catalyzed
functionalization of alkenes indicates a key role of the tethered alcohol nucleophile.

64

Finally, the

inverse electron demand Diels-Alder reaction mediated tetrazine ligation with trans cyclo-octene
reported by Fox et. al. displays several fold rate enhancement upon placement of a remotely
tethered nucleophilic alcohol moiety on the trans cyclo-octene, capable of polarizing the oleffin by
exalting its HOMO energy.65,66 As a class, olefins have similar HOMO energies, NAAA (in general)

	
  

110	
  

attenuates the HOMO-LUMO gap allowing them to react with a variety of electrophiles (with a
wide range of LUMO energies).
Finally, the examples in Figure II-25 display the same interaction between a nucleophile
and an olefin regardless of the substitution pattern on the olefin. The conformation preference of
the nucleophile dictates which of the olefinic carbons it interacts with. The proximal carbon
displays a downfield shift in NMR as this interaction leads to a partially formed C-O bond. The
distal olefinic carbon on the other hand displays upfield shift in NMR as the π-system is polarized
by the nucleophilic moiety. This effect becomes more pronounced as the nucleophilicity is
enhanced.

	
  

111	
  

1

Figure II-25 H NMR resonances of alkenoic acids and their corresponding salts
a.
CO2H
Ha

Ha
H 3C

Ha

O N(nBu) 4

Ha

Ha

H 3C

II-7

O

CH 3
δ−

δ+

CH 3

-CH3

N(nBu) 4

O

Ha

Ha

CH 3
II-6

O

b.

-CH3

CH 3

CO2H
Ha

Ha

Hb

Hb

O

Ha

Hb

Hb

O N(nBu) 4

Ha
Hb

II-10

Ha

II-11

O

N(nBu) 4

O
δ+

Hb

δ−

c.
Ha

Ha

Hb

Hb
CO2H

Ph

II-12

Ha

Ha

Hb

Hb
CO2 NBu 4

Ph

	
  

II-13

112	
  

Figure II-25. (cont’d)
d.

Ha

Ha

Hb

CO2H

Ph
Hb

II-16

Ha

Ha, b

CO2 NBu 4

Ph
Hb

e.
Ha

II-17

Ha

Hb

CO2H
Hb

II-18

Ha
CO2 NBu 4

Ha, b
Hb

II-19

Ha

f.

Ha

Hb

Hb
CO2H

O

II-20
Ha

Ha

CO2 NBu 4

O

Ph

g.

II-21

Ha

II-22

Ph

Ha
CO2H

Ha

Ha

CO2 NBu 4
II-23

	
  

Hb

Hb

113	
  

II.3.7. Unconstrained nucleophilic reach: Insinuation of ‘early’ or ‘late’ transition
states.
For substrate II-12, the regiospecificity is governed by the conformational preference of the
nucleophile tethered on the side chain of a cis-olefin. Conversely, for a trans-alkenoic acid, the
stereoisomeric trans olefin, bears no restriction on the reach of the nucleophile to either of the
olefinic carbons. Although kinetically, a 5-exo ring closure would be favored, modulation of the
electronics on the nucleophile may enable access to the thermodynamically favored 6-endo
product as well. Based on the electronegativity of the halenium atom and the strength of the
nucleophile, the reaction path for halofunctionalization of a trans alkenoic acid can be directed
either though a ‘late’ or an ‘early’ transition state (Figure II-26). For instance, given the order of
electronegativity of halogens, (I < Br < Cl < F) the acceptor-halogen bond strength for a given
acceptor also increases in the same order. Hence, by virtue of its relatively high electronegativity,
a chlorenium atom in a halofunctionalization reaction will break the bond to its donor only after it
has acquired enough electron density from its acceptor (and ‘later’ than would an ionium atom), in
a process analogous to the familiar SN2 reaction at carbon. The lower the HalA value of a generic
olefin, the more contribution from the nucleophile is required to complete the departure of the
Figure II-26. Accessing ‘late’ vs ‘early’ transition state based on NAAA hypothesis.
Aδ

δ−

−

R

X δ+

R

Donor

δ−

kinetically
driven

A X

δ

H

X

−

O

O

δ+

‡

A

δ+

OH
early transition state
δ+

R

X
δ+

Acceptor

H

CO2H

OH
O
R

δ−
δ+

thermodynamically
driven

	
  

5-exo
products

O

114	
  

X

δ+

Aδ

−

O
R

‡

O

6-endo
products

X
−

Aδ
late transition state

donor, pushing the transition state later. In turn, the later the resulting transition states, the more
sensitive they are to thermodynamic parameters. In accord with the trend of electronegativity
among halogens, a donor bearing a chlorine atom should lead to a late transition state as
compared to the same donor bearing a bromine or iodine atom. Hence, for substrate II-16 (Table
II-11a), where the nucleophile has easy access to both the olefinic carbons, a late transition state
(involving a chair conformation) will be more likely in chlorofunctionalization vs. bromo- or
iodofunctionalization.
As anticipated, the chlorolactonization of II-16 as well as its more nucleophilic counterpart
II-17, favors the thermodynamic lactone II-16a-Cl, whereas, enhancing the nucleophilicity
reverses the regioselectivity for bromo- and iodolactonization of substrate II-17 (Table II-11a)
towards the kinetic products II-16b. Substrates II-16 and II-17 are excellent probes, revealing the
fact that regioselectivity in electrophilic addition reactions can be switched simply by modulating

Table II-11. Halolactonization of substrates II-16 to II-19.
1

a

Isolated yields.

b

Ratios were

c

determined by H NMR analysis (500 MHz). No isomerization observed for the recovered
d

olefinic substrate. No isomerization of the olefinic substrate was observed during the course of
the reaction.
Halenium
donor
(1.1 equiv)

a.
CO2Y
Ph
II-16, Y = H
II-17, Y = NBu 4

O

CO2Y

O
O

CHCl3
(0.05M), rt

X

Et

Ph

Ph
II-16a

Halenium
donor
(1.1 equiv)

b.

O

X
II-16b

II-18, Y = H
II-19, Y = NBu 4

O

O
O

O

CHCl3
(0.05M), rt

X

Et

II-18a

Et
II-18b

X

Substrate

Halenium
donor

Time
(h)

Overall
yielda

ratiob
II-16a : II-16b

Substrate

Halenium
donor

Time
(h)

Overall
yielda

ratiob
II-18a : II-18b

II-16

DCDMH

144

20%c

>98:2

II-18

DCDMH

96

70%

1:1.8

II-16

NBS

120

74%

>98:2

II-18

NBS

96

85%

1:4.3

II-16

NIS

30

80%

7.7:1

II-18

NIS

2

85%

1:5.0

II-17

DCDMH

18

79%

4.8:1

II-19

DCDMH

0.5

70%

1:2.1

II-17

NBS

4

87%

1:13.5

II-19

NBS

0.5

89%

1:41

II-17

NIS

2.5

78%

1:7.4

II-19

NIS

0.5

81%

1:45

	
  

115	
  

the nucleophilicity of a given nucleophile and the electron deficiency of the electrophile involved.
Substrate II-18 on the other hand lacks the benzylic stabilization and hence the conformational
preference of the nucleophile dominates in deciding the regioselectivity. Comparably, bromo- and
iodolactonizations of II-19 promote the kinetic products via early transition states, as boosting the
nucleophilicity enhances the regiopreference towards formation of products II-18b (Table II-11b).
II.3.8. Effect of electrophilicity of halenium ion and nucleophlicity of olefin in
halocyclization reactions.
The interplay of these effects have been discussed as follows:
(i) Leaving group ability (HalA) of halenium ion donor:
For substrate II-12, the regiospecificity is governed by the conformational preference of the
nucleophile tethered on the side chain of a cis-olefin (Table II-12a, path C). Conversely,
involvement of a relatively more electrophilic halenium ion source may lead to formation of a tight
Van der Waals complex causing re-hybridization of the olefinic carbons thus, channeling the
reaction via path B. Hence, modulation of the electronics on the halenium donor may allow us to

Table II-12. Effect of electrophilicity of halenium ion source on regioselectivity of
halofunctionalization reaction.
(X = F, Cl, Br, I)

a.
A

X

H
th
Pa

H

(I) HO

A

O

A X

Ph
CO2H
II-12

H

Pa
th
C

H

δ−

O

O

	
  

-AH

O

Ph
X

Ph
II-12c

Ph
X
II-17a

Entry

Halenium
donor

ΔHalA a

Time
(h)

Overall
yieldb

ratioc
12a :12b :17a

1

NCS

0.0
(194.0)

180

no
reaction

--

2

DCDMH

-12.9

144

no
reaction

--

3

Dichloramine-T

-13.7

48

70%

1.0 : 1.1 : 1.4

4

NBS

0.0
(170.6)

28

89%

>98 : <1.0 : <1.0

5

DBDMH

-11.7

5

58%

4.4 : 1.0 : 5.0

6

Br 2

-16.8

0.5

96%

<1.0 : 4.3 : 1.0

H

H
Ph

δ+
pre-polarization
H
of olefin
(III)

O
X

TS-2 ‡

−

X

H

O

5-exo
product

d1 > d2

Aδ

X

O

O

II-12b

Ph

HO

A

X

N2

d2

H

(II)

"

A
Path B

O
O
6-endo
products

-AH

X

d1
δ+

Ph

"S

Ph

CHCl3 (0.05M), rt

O

O
O

II-12

"SN1 "

δ—

Ph

X

-AH

O

Halenium
donor
(1.1 equiv)

CO2H

O
δ+

O asynchronus

H

concerted TS

116	
  

direct the reaction path though a ‘late’ or an ‘early’ transition state. Although the olefin moiety can
engage itself in a weak Van der Waals interaction with a halenium ion (attached to its donor), the
addition across the π–system will occur only with the aid of nucleophile participation via an
asynchronous concerted pathway. The extent of re-hybridization of the olefinic carbons in the
halenium ion-olefin complex, will depend on the leaving group ability of the donor anion and the
electronic nature of the olefin. Hence, a tight Van der Waals complex that can re-hybridize the
olefinic carbons to an extent that involves the resonance of the phenyl ring, will certainly direct the
regioselectivity of addition to favor the 6-endo products. Table II-12 displays this switch in
regioselectivity as the HalA value of the donor anion drops (i.e. the leaving group ability of the
halenium ion donor increases).
(ii) Nucleophilicity of olefin:

On the contrary, substrate II-20 with enhanced electron density on the olefin yields a mixture
of syn and anti δ-lactones II-20a and II-20b, respectively (Table II-13). The pre-activated olefin
due to the enhanced electron donating resonance effect of the p-methoxyphenyl moiety, does not
require assistance of the nucleophile to exalt its HOMO energy. The formation of isomeric
products imply multiple pathways being operational under the reaction conditions. Product II-20a
arises from a halomethyl cabenium ion, II-20b might result from the same carbenium intermediate
or it may be the result of NAAA pathway. Finally, product II-20c (not formed using the free acid II20) is the outcome of NAAA pathway. Furthermore, employment of the salt II-21 yields the 5-endo
bromo and iodo-lactones II-20c-Br and II-20c-I, demonstrating the effect of enhanced
nucleophilicity that outcompetes the intrinsic polarization of the olefin by the electron-rich aromatic
nucleus.
	
  

	
  

117	
  

Table II-13. Effect of nucleophilicity
halofunctionalization reaction.
CO2Y

Halenium
donor
(1.1 equiv)
Ar
CHCl3
II-20, Y = H (0.05M), rt
II-21, Y = NBu 4
Ar = p-OMe-C6H 4

of olefin on regio-

O

O
O

O
X

Ar
X
II-20b

X
II-20 a

of

O
O

Ar

and stereoselectivity

Ar
II-20 c

Substrate

Halenium
donor

Time
(h)

Overall
yielda

ratiob
a: b: c

II-20

DCDMH

12

80%

2.3 : 1.0 : <1.0

II-20

NBS

48

73%

1.3 : 1.0 : <1.0

II-20

NIS

5

66%

1.0 : 4.0 : <1.0

II-21

DCDMH

1

67%

1.0 : 1.3 : <1.0

II-21

NBS

0.7

32%

2.0 :1.0 : 46.0

II-21

NIS

1

--

<1.0 : <1.0 : >98.0

(iii) Strength of nucleophile vs nucleophilicity of olefin:

Substrate II-22 and its salt II-23, incorporates a trisubstituted E-olefin in conjugation with a
phenyl ring (Table II-14). Hence, it has ample opportunity to form a tertiary benzylic cation to yield
a γ-lactone with scrambling of stereochemical information of the starting olefin. Furthermore, the
conformation of the nucleophile being unconstrained, it can access either of the olefinic carbons to
channel the reaction via NAAA pathway. Although kinetically, the 4-exo cyclization mode will be
favored, the nucleophile will have to work against the intrinsic polarity of the olefin. Therefore, the
free acid II-22 (weak nucleophile) predominantly yields product II-22b. Substrate II-23,
incorporating a strong nucleophile also favors the same 5-endo products, however it does yield

	
  

118	
  

Table II-14. Effect of enhanced nucleophilicity of the nucleophile on regio- and
stereoselectivity of halofunctionalization reaction.
Ph

Halenium donor Ph
(1.1 equiv)

O

YO2C CHCl3 (0.05M), rt
II-22, Y = H
II-23, Y = NBu 4

Ph

X

Ph

O

O
O

O

II-22a

II-22b

O
II-22c

Substrate

Halenium
donor

Time
(h)

Overall
yielda

ratiob
a:b:c

II-22

DCDMH

96

71%

1.0 : 20.0 : <1.0

II-22

NBS

10

69%

<1.0 : 49.0 : <1.0

II-22

NIS

3

82%

<1.0 : 49.0 : <1.0

II-23

DCDMH

0.5

76%

3.8 : 1.3 : 1.0

II-23

NBS

0.5

88%

6.4 : 7.6 : 1.0

II-23

NIS

0.5

81%

>49.0 : <1.0 : <1.0

Ph

X H

O

reaction
conditions

Ph
O

-HX
II-22c O

O

about 10-20% of the 4-exo products suggesting a central role for the nucleophilic partner in the
addition reaction.
1.4. Summary.
Electrophilic addition to alkenes is certainly not as simple as it is perceived through
classical mechanistic pathways. We have probed every facet of this reaction using
halofunctionalization as a prototypical reaction and elucidated the key role played by every
component that partakes in this reaction. Following is a brief account of the above studies:

	
  

119	
  

a. Halofunctionalization reactions begin with a SN2 attack of a Lewis base acceptor on a
halenium atom (attached to its donor), displacing the donor anion as shown in equation
(1):
LB: + X–D à LB+–X + D–……………..(1)
As in every SN2 reaction, the forward reaction will be feasible only if the Lewis base (LB:)
is a stronger nucleophile in comparison to the donor anion (D–).
b. A hypothetical delivery of halenium atom to an alkene via commonly employed imidebased reagents or dihalogens, yield anions that have higher HalA values compared to
weak Lewis base acceptors such as olefins.47 Hence, in accordance to equation (1), haloimides or dihalogens are inefficient towards transfer of halenium atoms to olefins without
any external aid from nucleophiles. Experiments probed by HalA values validate this
conclusion.
c. Although, there is precedence for existence of bridged halonium ions,23-27,35,48,50 the
conditions under which they are generated are however, very specific (not prototypical).
Attachment of a halenium ion on an alkene as a bridged halonium ion requires counter
anions such as trifluoromethanesulfonate, p-toluenesulfonate, tetrafluoroborate or
antimony (VI) halides that are extremely weak nucleophiles, inheriting very low HalA
values.
d. For olefins that enjoy extended conjugation from aromatic rings (e.g. II-1-5), the bridged
halonium ion does not exist even with a ‘naked’ halenium ion. Several groups30,31,42-44
including ours19,47 have reported this fact by thorough computational analysis and

13

C

perturbation experiments for aliphatic as well as aromatic substituted olefins.
e. The aliphatic and aromatic substituted olefins employed as a probe for stereo- and
regioselectivity in halofunctionalization reactions (II-1-23) clearly demonstrate the enabling
role of nucleophile. The ground state kinetic conformational preference of a tethered

	
  

120	
  

nucleophile dictates the direction of polarization, which eventually decides the regio- and
stereoselectivity for the overall addition. The nucleophilic strength on the other hand
governs the rate of the reaction. This effect of nucleophile on the π-system of alkenes
(raising HOMO energy) is observed via NMR analysis, even in the absence of any external
electrophile.
f.

Electron rich olefins such as II-2 (or enol ethers, enamines etc.) that have HalA value
greater than the donor anion, may not require the assistance of nucleophile and the
reaction then proceeds through a β-halocarbenium intermediate.

All the above results taken together with the detailed and exhaustive studies from other
labs30,31,42,44 demonstrates that formation of charged intermediates, such as the haliranium ion
(bridged halonium ion) bearing a cationic halonium is unlikely under classical halofunctionalization
reactions involving imide based reagents or dihalogens in general. As a class, olefins have similar
HOMO energies, the assistance of nucleophile (in general) attenuates the HOMO-LUMO gap
allowing them to react with a variety of electrophiles (with a wide range of LUMO energies).
Currently, the efforts in our lab are focused on probing the validation of this hypothesis in several
electrophilic addition reactions of olefins other than halofunctionalization of olefins and applying
this mechanistic finding in conjunction with HalA to develop new stereoselective reactions of
olefins. The shift in paradigm of the mechanistic picture now provides us with a handle to control
the path of addition reactions; thermodynamic or kinetic.

	
  

121	
  

II.5. Experimental section.
II.5.1. General information.
Molecular sieves (4Å) were dried at 160 °C under 0.25 mtorr pressure prior to use. Unless
otherwise mentioned, solvents were purified as follows. CHCl3 (amylene stabilized) was
purchased from Sigma Aldrich and incubated over 4Å MS for 48 h prior to use. Toluene and
CH2Cl2 were dried over CaH2 whereas THF and Et2O were dried over sodium (dryness was
monitored by colorization of benzophenone ketyl radical); they were freshly distilled prior to use.
NMR spectra were obtained using a 500 MHz and 600 MHz Varian NMR spectrometers and
referenced using the residual

1

H peak from the deuterated solvent. Infrared spectra were

measured on a Nicolet IR/42 spectrometer FT-IR (thin film, NaCl cells). Waters 2795 (Alliance HT)
instrument was used for HRMS (ESI) analysis with polyethylene glycol (PEG-400-600) as a
reference.
Column chromatography was performed using Silicycle 60Å, 35-75 µm silica gel. Precoated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using
UV light, iodine, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in
EtOH stain.
Halofunctionalization

reactions

were

performed

in

the

absence

of

light.

N-

chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), 1,3-dichloro-5,5dimethylhydantoin

(DCDMH),

1,3-dibromo-5,5-dimethylhydantoin

(DBDMH)

and

N-

chlorophthalimide (NCP) were re-crystallized prior to use. All other commercially available
reagents and solvents were used as received unless otherwise mentioned.

	
  

	
  

122	
  

II.5.2. Kinetic isotope effects and rate studies.
General considerations for 13C KIE measurements:
For each set of

13

C KIE experiment, two reactions were performed: 1. the first reaction that

led to 100% conversion of the starting alkenoic acid/alcohol and, b. a second reaction, that was
allowed to proceed to ~20% conversion of the starting material by adding about 20 mol% of the
halogenating reagent.
The scale for each reaction in a set was adjusted such that 1.0-1.5 mmol of the product
can be isolated in each case. For instance, the reaction that led to 100% conversion to produce
the chlorolactone II-1a was performed using 1.5 mmol of II-1, whereas the second reaction which
was allowed to proceed to ~20% conversion was performed using 7.0 mmol of II-1. In each of
these reactions, ~1.3 mmol of the product was isolated (>95% yield b.r.s.m). For

13

C KIE

measurements on the chloroether II-3a, reactions were typically performed on 12.0-15.0 mmol
scale. The product II-3a being volatile, the isolated yields were low (30-50%). Furthermore, for
every substrate, two sets of

13

C KIE measurements were performed (each set comprising the

100% and 20% conversion reactions).

	
  

123	
  

II.5.2.1. 13C KIEs for halocyclization of II-1, II-2 and II-3:
13

C KIE determination for II-1a:

The

13

C KIEs for II-1a were determined by product analysis. Two independent reactions

were run to 22 ± 2 % and 22 ± 2 % conversion and the product isolated. The

13

C isotopic

compositions of these samples were compared to samples of product isolated from 100%
conversion reactions (no isotopic fractionations). The 13C KIEs were determined in a standard way
from the isotopic enhancements and fractional conversions. All samples were prepared using a
constant 1.2 mmol of II-1a in 5 mm NMR tubes filled with CDCl3 to a constant height of 5 cm. All
13

C spectra were recorded at 125 MHz using inverse gated decoupling, 53 s (5 times T1) delays

between calibrated π/2 pulses, and a 7.0 s acquisition time. Six spectra each with 128 transients
were obtained for each four samples of II-1a (two samples per experiment). Integrations were
determined numerically using a constant integration region for each peak (10 times the peak width
at half height). A zero-order baseline correction was generally applied, but in no case was a firstorder (tilt) correction applied. The integration of one of the methylene peaks was set to 1.000
since the KIE at this position is expected to be negligible. The results for the two individual sets
are displayed below (values in black are experimental and values in red are predicted for the TS
calculated at the B3LYP/6-31G*/SM8-CHCl3).

1.011 (5)
1.010 (6)
1.016

O

0.999 (4)
0.995 (5)
1.002

O

1.000
1.000
1.002

Ph
Cl

0.990 (5)
0.996 (4)
1.008 (5) 1.001
1.009 (6)
1.013
13 C

	
  

KIE experimental and
predicted values

124	
  

The

13

C KIE determined for the chlorolactone II-1a qualitatively corroborates the NAAA

hypothesis. The quaternary carbon displays a larger KIE than the chloromethylene carbon. The
trend implies a higher degree of re-hybridization at the benzylic carbon in comparison to the
chloromethylene carbon during the transition state. Most importantly, when the nucleophilicity of
the carboxylic acid was enhanced by addition of catalytic amounts of base (20% DABCO), the KIE
at the quaternary carbon displayed a significant drop in comparison to the halomethylene carbon.
The DABCO (base) activated carboxylic acid is a better nucleophile in comparison to the free acid
(see Figure II-27). This activation allows the nucleophile to polarize the olefin (raise the HOMO
energy) from a longer distance (1.92 Å) to initiate the desired halofunctionalization via an early
transition state. On the other hand, to polarize the olefin to a similar extent in order to achieve the
desired halofunctionalization, the free acid (in an uncatalyzed reaction) has to rely on the weak
activation provided by another molecule of halenium ion donor (weak base). Hence, the desired
level of polarization can be achieved via a late transition state with a shorter C=O·····C=C distance
(1.78 Å). The magnitude of

13

C KIE being proportional to the extent of re-hybridization during the

TS, hence, we observed a lower KIE for the quaternary carbon for a catalyzed reaction (early TS)
in comparison to the uncatalyzed halofunctionalization (late TS). Conversely, the extent of rehybridization of the halomethylene carbon (in the transition state) is influenced more by the
halenium ion source, which remains unchanged in the catalyzed as well as the uncatalyzed
process.

	
  

125	
  

1.10 Å

1.70 Å

1.78 Å

1.92 Å

1.51 Å

1.00 Å

2.20 Å

2.04 Å

late

early TS

TS for uncatalyzed
bromolactonization
of II-1

TS for DABCO catalyzed
bromolactonization
of II-1

Bromolactone from 1a
O

1.025 (7)

O

1.007 (6)

O

O

Ph
Br

Ph
Br

1.000

1.003 (7)

1.000

1.003 (8)

from uncatalyzed
reaction

from 20% DABCO
catalyzed reaction

Iodolactone from 1a
O

1.024 (7)

O

Ph
I

O

1.016 (7)

O

Ph
I

1.000

1.018 (6)

1.000

1.022 (8)

from uncatalyzed
reaction

from 20% DABCO
catalyzed reaction

Figure II-27. Comparison of TS for catalyzed and uncatalyzed bromolactonization of II-1.
For clarity, the TS only for anti-addition (predominant stereoisomer formed during bromo and
iodolactonization of II-1) in bromolactonization is shown. The dashed boxes below represent
the experimental 13C KIEs for the catalyzed and uncatalyzed bromo and iodo-lactonization.

	
  

126	
  

13

C KIE determination for II-2a:

The

13

C KIEs for II-2a were determined by product analysis. Two independent reactions

were run to 18 ± 2 % and 20 ± 2 % conversion and the product isolated. The

13

C isotopic

compositions of these samples were compared to samples of product isolated from 100%
conversion reactions (no isotopic fractionations). The 13C KIEs were determined in a standard way
from the isotopic enhancements and fractional conversions. The samples for the first experiment,
18 ± 2 % and 100% conversion samples were prepared using a constant 1.3 mmol and the
samples for the second experiment, 20 ± 2 % and 100% conversion samples were prepared using
a constant 1.2 mmol of the chlorolactone II-2a in 5 mm NMR tubes filled with CDCl3 to a constant
height of 5 cm. All

13

C spectra were recorded at 125 MHz using inverse gated decoupling, 64 s (5

times T1) delays between calibrated π/2 pulses, and a 7.0 s acquisition time. Six spectra each
with 256 transients were obtained for each four samples of II-2a (two samples per experiment).
Integrations were determined numerically using a constant integration region for each peak (10
times the peak width at half height). A zero-order baseline correction was generally applied, but in
no case was a first-order (tilt) correction applied. The integration of one of the methylene peaks
was set to 1.000 since the KIE at this position is expected to be negligible. The results for the two
individual sets are displayed below (values in black are experimental and values in red are

1.001 (5)
0.999 (6)
O
1.008

0.993 (4)
0.989 (6)
1.002

O

1.000
1.000
1.001
Cl
0.992 (5)
0.995 (5)
1.010 (4) 1.001
1.009 (6)
1.012

O

13 C

	
  

KIE experimental and
predicted values

127	
  

predicted for the TS calculated at the B3LYP/6-31G*/SM8-CHCl3).
13

C KIE determination for II-3a:

The

13

C KIEs for II-3a was determined by product analysis. Two independent reactions

were run to 33 ± 2 % and 22 ± 2 % conversion and the product isolated. The

13

C isotopic

compositions of these samples were compared to samples of product isolated from 100%
conversion reactions (no isotopic fractionations). The 13C KIEs were determined in a standard way
from the isotopic enhancements and fractional conversions. The samples for the first experiment,
33 ± 2 % and 100% conversion samples were prepared using a constant 0.95 mmol and the
samples for the second experiment, 22 ± 2 % and 100% conversion samples were prepared using
a constant 1.0 mmol of II-3a in 5 mm NMR tubes filled with CDCl3 to a constant height of 5 cm. All
13

C spectra were recorded at 125 MHz using inverse gated decoupling, ~120 s (5 times T1)

delays between calibrated π/2 pulses, and a 7.0 s acquisition time. Six spectra each with 64
transients were obtained for each four samples of II-3a (two samples per experiment).
Integrations were determined numerically using a constant integration region for each peak (10
times the peak width at half height). A zero-order baseline correction was generally applied, but in
no case was a first-order (tilt) correction applied. The integration of one of the methylene peaks
was set to 1.000 since the KIE at this position is expected to be negligible.

1.014 (5)
1.016 (6)
1.014

1.000
1.000
1.002

O

1.004 (4)
1.003 (7)
1.006

Ph
Cl

1.004 (5)
1.002 (7)
1.018 (4) 1.004
1.020 (6)
1.015
13 C

	
  

KIE experimental and
predicted values

128	
  

General considerations for KH/KD measurements:

For following the kinetics of halofunctionalization reactions, Agilent 6850 series II GC and
Agilent

7890A

GC-MS

instruments

equipped

with

an

auto-sampler

were

used.

Halofunctionalization reactions were performed in 1.5 mL amber colored glass vials using
amylene stabilized dry chloroform at 0.05 M substrate concentration. The vials were placed in a
water bath (charging water in the auto-sampler bed) to avoid heat transfer from the instrument to
the reaction mixture in the vial. Undecane (0.05 M in CHCl3) was used as an internal standard.
Prior to every reaction, a standard curve was obtained for the starting compound and the
corresponding product using standard solutions. The slope and intercept involved in these
standard curves were accounted for during evaluation of the substrate and product concentration
before and during the course of the reaction.

Note: For every substrate/product, an initial injection was followed up by a blank injection
(amylene stabilized CHCl3) to verify presence of any residual compound. Based on this analysis
the sequence of auto-sampler can be adjusted to include appropriate number of blank injections
to remove the residual component, if any.

	
  

129	
  

II.5.2.2. Kinetics of II-1 vs II-1-D2:

The kinetics for chlorolactonization of II-1 and II-1-D2 were followed using Aglient 6850
Series II GC instrument equipped with a Agilent DB-5ms column (30m x 0.32 mm x 0.25 µm). The
reactions were performed in a 1.5 mL amber colored vial using 0.03 mmol of substrate in 0.6 mL
of amylene stabilized chloroform (0.05 M) containing undecane as an internal standard. The
temperature ramp used for analysis is as follows: DB-5ms; 60 ºC to 250 ºC - start temperature 60
ºC (hold time = 0.0 min) with increments of 20 ºC/min upto 250 ºC (hold time at 250 ºC = 12.0
min). Total time = 28.5 min.

Initially a standard curve was obtained for the alkenoic acid II-1 as shown in Table II-15
above. Using this data from standard curve, mmol of alkenoic acid were plotted against the ratio
of areas (sample:std) and a linear fit (y=mx+c) was employed to obtain the slope and intercept.
Similarly, standard curves for II-1-D2 and the products II-1a and II-1a-D2 were obtained and the
corresponding slopes and intercepts were used to calculate the reactant and product
concentration during the course of the reaction. The GC measurements were performed in
intervals of 30 min to follow the consumption of the starting alkenoic acid. As shown in Figure II28, the time (min) of the reaction was plotted against concentration (mmol) of the starting material

Table II-15. Standard curve for alkenoic acid 1a. Slope = 0.0626, Intercept = -0.00038,
R2 = 0.9996

Solution
1
2
3
4
5
6

	
  

Concentration
(mmol)
0.0500
0.0250
0.0125
0.0063
0.0031
0.0016

Area under internal
standard
(Rt = 3.6 min)
2223.3
4244.9
5024.4
5639.2
5833.1
6152.4

130	
  

Area under II-1
(Rt = 6.7 min)

Ratio of
Sample:Std

1783.2
1739.4
1047.9
638.2
304.0
148.9

0.8021
0.4098
0.2086
0.1132
0.0521
0.0242

Figure II-28. Plot of concentration (mmol) against time (min) comparing rates of
chlorolactonization of II-1 and II-1-D2 (Set I). The plot displays a second order polynomial fit
(R2=0.98 for II-1 and, R2=0.96 for II-1-D2).
and KH/KD was then evaluated.

Data for three individual sets of reactions was acquired as described above.

Set I: KH/KD = 0.996, Set II: KH/KD = 0.995, Set III: KH/KD = 0.995

Mean KH/KD = 0.995, Standard deviation = 0.001

II.5.2.3. Kinetics of II-3 vs II-3-D2:

The KH/KD estimations for II-3 and II-3-D2 was performed in a similar fashion to the
procedure explained above for chlorolactonization of II-1 and II-1-D2. The temperature ramp used
for analysis is as follows: DB-5ms; 60 ºC to 250 ºC - start temperature 60 ºC (hold time = 0.0 min)

	
  

131	
  

with increments of 20 ºC/min upto 250 ºC (hold time at 250 ºC = 12.0 min). Total time = 28.5 min.
Rt (internal standard-undecane) = 3.6 min, Rt (II-3 or II-3-D2) = 6.0 min, Rt (II-3a or II-3a-D2) = 6.5 min.

Data for three individual sets of reactions is as follows:

Set I: KH/KD = 1.000, Set II: KH/KD = 0.996, Set III: KH/KD = 0.991

Mean KH/KD = 0.996, Standard deviation = 0.005

II.5.2.4. Competitive halocyclization of II-1 vs II-3:

The competitive halocyclization of II-1 and II-3 were followed using a Aglient 6850 Series II
GC instrument equipped with a Agilent DB-5ms column (30m x 0.32 mm x 0.25 µm). The
reactions were performed in a 1.5 mL amber colored vial containing 0.03 mmol of each substrate
(1:1) in 0.6 mL of amylene stabilized chloroform (0.05 M) containing undecane as an internal
standard. To this mixture, 1.0 equiv of DCDMH was added and the measurements were initiated.
The temperature ramp used for analysis is as follows: DB-5ms; 60 ºC to 250 ºC - start
temperature 60 ºC (hold time = 0.0 min) with increments of 20 ºC/min upto 250 ºC (hold time at
250 ºC = 12.0 min). Total time = 28.5 min. The ratio K(II-3)/K(II-1) was estimated by taking a ratio of
individual slopes.

HO

CO2H
Ph
II-1
(1.0 equiv)

Ph
II-3
(1.0 equiv)

O

DCDMH
(1.0 equiv)
CHCl3
(0.05M),
rt, 16 h

O
Ph

II-1a

k(ene-alcohol) /k(ene-acid) = 4.7

	
  

132	
  

Cl

O
Ph
Cl

II-3a

The alkenoic alcohol II-3 was found to react about 5 times faster than the alkenoic acid II1. Although, both substrates incorporate the same 1,1-disubstituted olefin moiety, the fact that
alcohol II-3 (more nucleophilic) consumes the halogenating reagent about five times faster than
the acid II-1 (less nucleophilic), unequivocally establishes an imperative role of nucleophile in
halofunctionalization reactions.

II.5.2.5. Kinetics of II-2 vs II-2-D2:

The kinetics for chlorolactonization of II-2 and II-2-D2 were followed using a 500 MHz
Varian NMR instrument equipped with a cryogenic probe. The chlorolactonization of II-2 was
faster at room temperature (~50% conversion in 5 min). Hence, the chlorolactonization of II-2 and
II-2-D2 were performed at -10 ºC in a 5 mm diameter Wilmad NMR tube. The reactions were
performed in amber colored NMR tubes using 0.03 mmol of substrate in 0.6 mL of amylene
stabilized chloroform (0.05 M) containing undecane as an internal standard. The NMR instrument
was shimmed and equilibrated with the sample containing the alkenoic acid and internal standard.
The acquisition was started within 3 min after the addition of 1.0 equiv of DCDMH.

The NMR spectra were acquired in intervals of 5 min to follow the consumption of the
starting alkenoic acid. As explained for alkenoic acid II-1 above, the time (min) of the reaction was
plotted against concentration (mmol) of the starting material (see Figure II-29) and KH/KD was
then evaluated.

Data for three individual sets of reactions was acquired as described above.

Set I: KH/KD = 1.179, Set II: KH/KD = 1.187, Set III: KH/KD = 1.183

	
  

133	
  

Mean KH/KD = 1.183, Standard deviation = 0.004

Figure II-29. Plot of concentration (mmol) against time (min) comparing rates of
chlorolactonization of II-2 and II-2-D2 (Set I). Second order polynomial fit (R2=0.99 for II-2 and,
R2=0.97 for II-2-D2).
II.5.2.6. Kinetics of II-1 vs II-1-OD:

This KIE experiment was performed to validate the transition state for chlorolactonization
of II-1 (Figure II-30) estimated at the B3LYP/6-31G*/SM8 (CHCl3) level of theory. Based on the
predictions, the TS involves a concomitant proton transfer (from the carboxylic acid to the
carbonyl of hydantoin) during the chlorocyclization. Since the proton transfer event is associated
with the rate-determining step, the predicted KH/KD is 2.2. To corroborate the predictions, the
chlorolactonization of II-1 and II-1-OD was performed in CHCl3, similar to the procedure explained

	
  

134	
  

above for chlorolactonization of II-1 and II-1-D2. The temperature ramp used for analysis is as
follows: DB-5ms; 60 ºC to 250 ºC - start temperature 60 ºC (hold time = 0.0 min) with increments
of 20 ºC/min upto 250 ºC (hold time at 250 ºC = 12.0 min). Total time = 28.5 min.

Data for three individual sets of reactions is as follows:

Set I: KH/KD = 1.514, Set II: KH/KD = 1.498, Set III: KH/KD = 1.521

Mean KH/KD = 1.511, Standard deviation = 0.012

Figure II-30. Plot of concentration (mmol) against time (min) comparing rates of
chloroetherification of II-1 and II-1-OD. Second order polynomial fit (R2=0.999 for II-1 and,
R2=0.999 for II-1-OD).

	
  

135	
  

Although the experimental KIE of 1.511 for II-1 vs II-1-OD corroborates the theoretically
predicted value of 2.2, the computational analysis is based on the TS for syn-addition (Figure II17). Experimentally, the reaction also yields an anti-adduct. As explained above, the value for
syn:anti addition depends on several factors, most importantly, the concentration of the reagent.

Albeit, the enabling role of nucleophile is highlighted in these studies, corroborating the
computationally predicted TS for syn and anti addition in halofunctionalization of 1a. This
hypothesis is further validated by the following K16O/K18O studies using

18

O enriched 1a to provide

a definitive evidence towards the participation of nucleophile in electrohilic addition to olefins.	
  

II.5.2.7. Kinetics of II-1 vs II-1*:

The

18

O KIE for chlorolactonization of II-1 and II-1* was elucidated using a Aglient 7890A

GC instrument coupled to a Agilent 5975C EI-MS with triple axis detector. The GC was equipped
with a Agilent DB-5ms column (30m x 0.32 mm x 0.25 µm). The reactions were performed in a 1.5
mL amber colored vial using approximately 1:1 ratio of substrate II-1 and II-1* (0.015 mmol each)
in 0.6 mL of amylene stabilized chloroform (0.05 M). The temperature ramp used for analysis is as
follows: DB-5ms; 60 ºC to 320 ºC - start temperature 60 ºC (hold time = 0.0 min) with increments
of 20 ºC/min upto 320 ºC (hold time at 320 ºC = 1.0 min). Total time = 14.0 min.
The following steps were taken to elucidate the 18O KIE for chlorolactonization of II-1 and II-1*:

1. The spectrometer was modified to perform SIM (Selected Ion Monitoring) analysis. For
analysis of II-1 and II-1*, only three molecular ions corresponding to the alkenoic acids:
176.1 (2 x 16O), 178.1 (16O and 18O) and 180.1 (2 x 18O) were selected for analysis. For the
related chlorolactone products, the molecular ions (210, 212 and 214) displayed very low
intensities and the observed base peaks were 161, 163 and 165 resulting via loss of

	
  

136	
  

chloromethylene radical •(CH2Cl). Hence, to avoid the possible kinetic isotope effects
involved in this primary fragmentation, analysis of the product was excluded.
2. After the initial set up, 1.0 µL of the reaction mixture containing approximately 1:1 ratio of
II-1 : II-1* was injected to identify the

16

O:18O ratio. This injection was followed by a blank

injection (2.0 µL of amylene stabilized CHCl3). The blank run was anaylized for presence
of any residual II-1 or II-1*. If traces of the starting compunds were detected in the
spectrum, another blank injection of the same volume was performed and the
corresponding spectrum was analyzed for traces of any residual stating compound. This
analysis is essential for accurate determination of

16

O:18O ratio as one isotope serves as

an internal standard for the other. For the mixture of II-1 and II-1*, 2 blank runs were
followed after every injection.
3. The instrument was tuned prior to the KIE measurements and after the measurements.
Based on the level of H2O content (as displayed in the auto-generated tune report), we
observed differences in the ratio of 178.1 (16O and
is the most crucial factor in measurement of

18

18

O) and 180.1 (2 x

18

O) masses. This

O KIE. Although, the differential content of

unavoidable moisture resulted in different extent of

16

O-18O exchange in the starting

alkenoic acid, the overall ratio was observed to be constant. Hence, for elucidating the KIE
(K16O/K18O), a ratio of area under mass 176.1 : (178.1+180.1) was considered.
Furthermore, to ensure minimum change in the H2O content in one set of experiment, an
auto-tune report was generated prior to, and after all the measurements were made. If the
levels of H2O content were significantly different prior to and after the measurements, a
new experiment must be started over.
4. After adjusting all the parameters describe in step 1-3, three individual measurements
(each measurement being followed by two blank runs) were made to observe the

	
  

137	
  

consistency in measurement of

16

O:18O ratio in the mixture of labeled and unlabeled

alkenoic acid. A mean value was recorded with the associated standard deviation.
5. To this mixture of alkenoic acids, ~10 mol% of 1,3-dichloro-5,5-dimethylhydantoin
(DCDMH) was added and the reaction mixture was stirred for 3-4 h. The conversion of the
starting material was monitored by GC analysis every hour as described above.
6. Upon achievement of a steady measurement on starting compound consumption, the
reaction mixture was then subjected to step 4 and three more readings were acquired. The
mean reading and the standard deviation were recorded.
7. Finally, the KIE (K16O/K18O) was obtained as a ratio of area under mass 176.1 :
(178.1+180.1), see step 3 for details.
8. Steps 1-7 were repeated for 3 more times and the mean value for K16O/K18O was recorded
with the associated standard deviation..

	
  

138	
  

Data for three individual sets of reactions is as follows:

Set I:
16

O:18O (before reaction): a.) 1.201 b.) 1.201 and, c.) 1.201

mean value =1.201, standard deviation = 0.000
16

O:18O (12% conversion): a.) 1.176 b.) 1.177 and, c.) 1.171

mean value =1.175, standard deviation = 0.003
K16O/K18O (set I) = 1.022

Set II:
16

O:18O (before reaction): a.) 1.147 b.) 1.145 and, c.) 1.147

mean value =1.146, standard deviation = 0.001

16

O:18O (10% conversion): a.) 1.115 b.) 1.114 and, c.) 1.114

mean value =1.114, standard deviation = 0.001
K16O/K18O (set I) = 1.029

	
  

139	
  

Set III:
16

O:18O (before reaction): a.) 1.135 b.) 1.135 and, c.) 1.136

mean value =1.135, standard deviation = 0.001

16

O:18O (10% conversion): a.) 1.104 b.) 1.108 and, c.) 1.103

mean value =1.105, standard deviation = 0.003

K16O/K18O (set I) = 1.027

Mean K16O/K18O = 1.026, Standard deviation = 0.004

II.5.2.8. Kinetics of II-2 vs II-2*:

The

18

O KIE for chlorolactonization of II-2 and II-2* was elucidated as described above for

substrate II-1 and II-1*. These reactions were also performed in a 1.5 mL amber colored vial using
approximately 1:1 ratio of substrate II-2 and II-2* (0.015 mmol each) in 0.6 mL of amylene
stabilized chloroform (0.05 M). The temperature ramp used for analysis is as follows: DB-5ms
column; 60 ºC to 320 ºC - start temperature 60 ºC (hold time = 0.0 min) with increments of 20
ºC/min upto 320 ºC (hold time at 320 ºC = 10.0 min). Total time = 23.0 min.

	
  

140	
  

Data for three individual sets of reactions is as follows:

Set I:
16

O:18O (before reaction): a.) 1.061 b.) 1.160 and, c.) 1.160

mean value =1.060, standard deviation = 0.001

16

O:18O (9% conversion): a.) 1.050 b.) 1.050 and, c.) 1.052

mean value =1.051, standard deviation = 0.001

K16O/K18O (set I) = 1.0086

Set II:
16

O:18O (before reaction): a.) 1.192 b.) 1.196 and, c.) 1.200

mean value =1.196, standard deviation = 0.004
16

O:18O (10% conversion): a.) 1.189 b.) 1.186 and, c.) 1.183

mean value =1.186, standard deviation = 0.003

K16O/K18O (set I) = 1.0084

	
  

141	
  

Set III:
16

O:18O (before reaction): a.) 1.158 b.) 1.152 and, c.) 1.156

mean value =1.155, standard deviation = 0.003

16

O:18O (9% conversion): a.) 1.147 b.) 1.144 and, c.) 1.144

mean value =1.145, standard deviation = 0.002

K16O/K18O (set I) = 1.0087

Mean K16O/K18O = 1.009, Standard deviation = 0.0002

	
  

142	
  

II.5.3. Synthesis of substrates and intramolecular halocyclization of alkenes.
i. Synthesis of substrates II-6, II-7, II-10 and II-11:

CO2H

CO2H

CO2

Li / NH 3

n-Bu 4N OMe

-78 ºC, 89%

MeOH, rt
quant.
II-10

N

II-11

Dihydrobenzoic acid (II-10):
Compound II-10 was synthesized by Birch reduction as reported previously.67 Benzoic acid
(7.0 g, 57.3 mmol) was charged in a flame dried 250 mL three neck flask. One of the necks was
connected to nitrogen inlet at atmospheric pressure while a condenser was attached to the center
neck. The flask was purged with nitrogen for 1-2 min while rested in a -78 ºC bath (acetone/dry
ice). The third neck of the flask was then closed with a glass adapter and ammonia gas was
condensed until the total volume was 100 mL. To a vigorously stirred solution of benzoic acid in
liquid ammonia was added lithium (1.19 g 172.0 mmol, 3.0 equiv, cut into small pieces prior to
addition) in portions over a period of 30 min. After the addition was complete, the solution was
stirred for another 30 min and quenched carefully by addition of solid ammonium chloride (~15 g)
until the solution turned into a white gel. The flask was gradually warmed to room temperature
over 20 min while the ammonia was removed under a stream of nitrogen gas. The resulting solid
residue (free of ammonia) was dissolved in distilled water (30 mL) and cooled on an ice-water
bath. The solution was acidified to pH 2 using concentrated HCl (12 M). The product was
extracted in dichloromethane (3 x 20 mL). The organics were separated, dried over anhydrous

	
  

143	
  

Na2SO4, filtered, concentrated. Pure II-10 was obtained as colorless oil in 98% yield (8.1 g). It was
used immediately for further steps without prolonged storage.

Note: Compound II-10 undergoes rapid oxidation at room temperature. It can be stored as a
frozen solution in argon purged benzene at -80 ºC for about 2-3 weeks.
Analytical data for II-10:67 pale yellow oil; 1H NMR (500 MHz, CDCl3) δ 11.73 (1H, br s), 5.90 (2H,
m), 5.80 (2H, m), 3.76 (1H, m), 2.68 (2H, m) ppm;

13

C NMR (125 MHz, CDCl3) δ 178.9, 126.9,

121.5, 41.5, 25.8 ppm.

Tetrabutylammonium cyclohexa-2,5-diene-1-carboxylate (II-11):

A 50 mL flame dried round flask was charged with II-10 (2 g, 13.14 mmol) under nitrogen
atmosphere. To this solid was added was added commercially available ~20% tetra-nbutylammonium methoxide in methanol (20.0 mL) at room temperature. The resulting mixture was
concentrated using rotary evaporator and then subjected to 250 mtorr of pressure using a vacuum
pump. Since the commercially available solution is approximately 20% of n-Bu4NOMe in MeOH by
weight, the corresponding translucent gel obtained after concentration was evaluated by 1H NMR
to ensure 1:1 ratio of II-10 to the added base. The delay time (d1) for NMR analysis was adjusted
to 10 s to obtain accurate integration data. The resulting salt II-11 was then stored in a freezer at 20 ºC or used immediately for further reactions.
Analytical data for II-11: White gel; 1H NMR (500 MHz, CDCl3) δ 5.92 (2H, m), 5.53 (2H, m), 3.46
(1H, m), 3.18 (8H, AB quartet, J = 8.5 Hz), 2.51 (1H, m), 1.50 (8H, m), 1.30 (8H, sextet, J = 7.5
Hz), 0.86 (12H, t, J = 7.5 Hz) ppm;

13

C NMR (125 MHz, CDCl3) δ 177.7, 129.5, 121.4, 58.7, 50.1,

47.8, 35.9, 24.0, 23.2, 19.7, 13.6 ppm. IR (film) 3181, 2960 (s), 2874, 1678, 1633, 1580, 1435,
1314, 1117, 880, 793 cm-1.

	
  

144	
  

CO2H

CO2H

CO2

Na / NH 3

n-Bu 4N OMe

-78 ºC, 89%

MeOH, rt
quant.
II-6

N

II-7

3,5-dimethyldihydrobenzoic acid (II-6):
II-6 was synthesized as reported previously.68 Commercially available 3,5-dimethylbenzoic
acid was recrystallized from hot ethyl acetate and dried prior to use. 3,5-Dimethylbenzoic acid (5.0
g, 33.0 mmol) was charged in a flame dried 250 mL three neck flask. One of the necks was
connected to nitrogen inlet at atmospheric pressure while a condenser was attached to the center
neck. The flask was purged with nitrogen for 1-2 min while rested in a -78 ºC bath (acetone/dry
ice). The third neck of the flask was then closed with a glass adapter and ammonia gas was
condensed until the total volume was 150 mL. To a vigorously stirred suspension of 3,5dimethylbenzoic acid in liquid ammonia was added sodium (3.0 g, 130.4 mmol, 4.0 equiv), in
portions over a period of 30 min (part of the sodium clumps were cut into smaller pieces and
immediately added). After the addition was complete, the solution was stirred for another 30 min
and quenched carefully by addition of solid ammonium chloride (~12 g) at -78 ºC until the solution
turned into a white gel. The flask was gradually warmed to room temperature over 20 min while
the ammonia was removed under a stream of nitrogen gas. The resulting solid residue (free of
ammonia) was dissolved in distilled water (30 mL) and cooled on an ice-water bath. The solution
was acidified to pH 2 using concentrated HCl (12 M). The product was extracted in
dichloromethane (3 x 20 mL). The organics were separated, dried over anhydrous Na2SO4,
filtered, and concentrated. The crude white solid was recrystallized from hot ethyl acetate to yield

	
  

145	
  

4.51 g of pure II-6 as a crystalline white solid (89% yield). Crystalline II-6 (devoid of impurities) can
be stored in a freezer at -20 ºC under argon atmosphere for over a year without any traces of rearomatization.

Note: If the commercially available 3,5-dimethylbenzoic acid is not purified prior to use, II-6 is
obtained as a yellowish solid. The resulting impurities can then be removed by multiple
recrystallizations from hot ethyl acetate, however with a significant drop in isolated yield.
Analytical data for II-6: White solid, m.p. 117 °C (lit.68 105 °C); 1H NMR (500 MHz, CDCl3) δ 12.2011.20 (1H, br s), 5.50 (2H, m), 3.74 (1H, m), 2.48 (2H, dddd, J = 7.5, 8.5, 22.0, 30.0 Hz), 1.73 (6H,
s) ppm; 13C NMR (125 MHz, CDCl3) δ 179.6, 134.4, 115.6, 43.9, 35.6, 23.0 ppm.

Tetra-n-butylammonium-3,5-dimethylcyclohexa-2,5-diene-1-carboxylate (II-7):

Compound II-7 was synthesized using the procedure described above for II-11. The
resulting salt II-7 was used immediately for further reactions. It can be stored in a freezer at -20 ºC
under argon atmosphere for a month, after which the product begins to turn yellow.
Analytical data for II-7: White gel; 1H NMR (500 MHz, CDCl3) δ 5.69 (2H, m), 3.61-3.57 (1H, s),
3.32 (8H, AB quartet, J = 8.5 Hz), 2.39 (1H, m), 1.65 (6H, s), 1.64-1.57 (8H, m), 1.39 (8H, sextet,
J = 7.5 Hz), 0.95 (12H, t, J = 7.0 Hz) ppm;

13

C NMR (125 MHz, CDCl3) δ 177.7, 129.5, 121.4,

58.7, 50.1, 47.8, 35.9, 24.0, 23.2, 19.7, 13.6 ppm. IR (film) 3180, 2963 (s), 2876, 1698, 1653,
1584, 1465, 1385, 1109, 883, 790 cm-1.	
  	
  

	
  

146	
  

ii. Synthesis of substrates 1a-q:
Substrates II-1,69 II-2,70 II-3,70 II-2-OH,70 II-12,71 II-12-OH,72 II-14,73 II-16,74 II-18,75 II-18-OH,76 II20,77 and II-2278,79 were synthesized as reported previously. The corresponding tetra-nbutylammonium salts II-5, II-13, II-15, II-17, II-19, II-21 and II-23 were prepared as described
above for II-11.

OH

Ph
O

II-1

Analytical data for 4-phenylpent-4-enoic acid (II-1):69 White solid, m.p. 95 ºC; 1H NMR (500
MHz, CDCl3) δ 12.31 (1H, br. s), 7.49 (2H, d, J = 7.0 Hz), 7.41 (2H, t, J = 7.5 Hz), 7.36 (1H, t, J =
7.0 Hz), 5.42 (1H, br. s), 5.20 (1H, br. s), 2.94 (2H, t, J = 7.5 Hz), 2.62 (2H, t, J = 8.0 Hz);

13

C

NMR (125 MHz, CDCl3) δ 179.9, 146.5, 140.3, 128.4, 127.6, 126.0, 112.9, 33.0, 30.0 ppm.

OH

O

O

II-2

Analytical data for 4-(4-methoxyphenyl)pent-4-enoic acid (II-2):70 White solid, m.p. 95 ºC; 1H
NMR (500 MHz, CDCl3) δ 11.11 (1H, br. s), 7.33 (2H, m), 6.85 (2H, m), 5.23 (1H, br. s), 5.00 (1H,
br. s), 3.80 (3H, s), 2.80 (2H, t, J = 7.5 Hz), 2.51 (2H, t, J = 8.0 Hz);

13

178.7, 159.3, 145.8, 132.8, 127.2, 113.8, 111.4, 55.3, 32.9, 30.2 ppm.

	
  

147	
  

C NMR (125 MHz, CDCl3) δ

OH

Ph
II-3

Analytical data for 4-phenylpent-4-en-1-ol (II-3):70 colorless oil; 1H NMR (500 MHz, CDCl3) δ
7.43- 7.26 (5H, m), 5.33 (1H, s), 5.11(1H, s), 3.67 (2H, t, J = 6.5 Hz), 2.63 (2H, t, J = 7.0 Hz), 1.90
(1H, br. s), 1.72 (2H, m);

13

C NMR (125 MHz, CDCl3) δ 148.0, 141.0, 128.3, 127.3, 126.0, 112.5,

62.2, 31.5, 31.1 ppm.

O NBu 4

Ph
II-5

O

Analytical data for tetrabutylammonium 4-phenylpent-4-enoate (II-5): pale yellow oil; 1H NMR
(500 MHz, CDCl3) δ 7.43 (2H, d, J = 7.5 Hz), 7.26-7.23 (2H, m), 7.18 (1H, m), 5.22 (1H, br. s),
5.07 (1H, d, J = 0.5 Hz), 3.34 (8H, AB quartet, J = 8.5 Hz), 2.83-2.80 (2H, m), 2.39-2.36 (2H, m),
1.66-1.60 (8H, m), 1.39 (8H, sextet, J = 7.5 Hz), 0.96 (12H, t, J = 7.5 Hz);

13

C NMR (125 MHz,

CDCl3) δ 177.9, 149.0, 141.8, 128.0, 126.9, 126.1, 111.1, 58.9, 37.2, 32.3, 24.1, 19.8, 13.7 ppm.
IR (film) 3082, 2961, 2875, 1761, 1652, 1585 (s), 1455, 1387, 1153, 1028, 889, 781 cm-1.

	
  

148	
  

OH

O

II-2-OH

Analytical data for 4-(4-methoxyphenyl)pent-4-en-1-ol (II-2-OH):70 White solid, m.p. 46 ºC; 1H
NMR (500 MHz, CDCl3) δ 7.35 (2H, dd, J = 6.5, 2.0 Hz), 6.86 (2H, dd, J = 6.5, 2.0 Hz), 5.21 (1H,
br. s), 5.00 (1H, br. s), 3.79 (3H, s), 3.64 (2H, t, J = 6.5 Hz), 2.56 (2H, t, J = 7.0 Hz), 1.73-1.68
(2H, m), 1.46 (1H, br. s);

13

C NMR (125 MHz, CDCl3) δ 159.0, 147.2, 133.3, 127.1, 113.6, 111.0,

62.4, 55.2, 31.6, 31.2 ppm.

CO2H
Ph

II-12

Analytical data for (Z)-5-phenylpent-4-enoic acid (II-12):71 pale yellow oil; 1H NMR (500 MHz,
CDCl3) δ 7.32 (2H, t, J = 8.0 Hz), 7.26-7.20 (3H, m), 6.48 (1H, d, J = 11.5 Hz), 5.62 (1H, m), 2.692.62 (2H, m), 2.48 (2H, ddd, J = 1.5, 7.5, 9.0 Hz);

13

130.4, 129.8, 128.7, 128.2, 126.8, 34.1, 23.7 ppm.

	
  

149	
  

C NMR (125 MHz, CDCl3) δ 179.4, 137.0,

OH
Ph

II-12-OH

Analytical data for (Z)-5-phenylpent-4-en-1-ol (II-12-OH):72 colorless oil; 1H NMR (500 MHz,
CDCl3) δ 7.35-7.20 (5H, m), 6.44 (1H, d, J = 11.5 Hz), 5.66 (1H, dt, J = 7.0, 11.5 Hz), 3.64 (2H, t,
J = 6.5 Hz), 2.41 (2H, dq, J = 2.0, 7.5 Hz), 1.71 (2H, quint, J = 7.0 Hz), 1.52 (1H, br s);

13

C NMR

(125 MHz, CDCl3) δ 137.4, 132.0, 129.4, 128.7, 128.1, 126.6, 125.9, 62.3, 32.8, 24.8 ppm.

CO2

N

Ph

II-13

Analytical data for tetrabutylammonium (Z)-5-phenylpent-4-enoate (II-13): pale yellow oil; 1H
NMR (500 MHz, CDCl3) δ 7.30 (2H, d, J = 7.5 Hz), 7.26-7.23 (2H, m), 7.13 (1H, m), 6.30 (1H, d, J
= 12.0 Hz), 3.31 (8H, AB quartet, J = 8.5 Hz), 2.65 (2H, ddd, J = 1.5, 7.5, 15.5 Hz), 2.32 (2H, m),
1.60 (8H, m), 1.38 (8H, sextet, J = 7.5 Hz), 0.94 (12H, t, J = 7.5 Hz);

13

C NMR (125 MHz, CDCl3)

δ 177.9, 138.0, 134.2, 128.8, 127.9, 127.8, 126.0, 58.7, 38.6, 26.3, 24.0, 19.7, 13.7 ppm. IR (film)
3010, 2962 (s), 2876, 1760, 1648, 1587, 1490, 1381, 1152, 1029, 892, 770, 700 cm-1.

	
  

150	
  

CO2H

nBu

II-14

Analytical data for (Z)-non-4-enoic acid (II-14):80 colorless oil; 1H NMR (500 MHz, CDCl3) δ 11.50
(1H, br s), 5.42 (2H, m), 5.32 (1H, m), 2.37 (4H, m) 2.03 (2H, q, J = 6.5 Hz), 1.30 (4H, m), 0.87
(3H, t, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ 179.9, 131.9, 126.9, 34.2, 31.8, 26.9, 22.5, 22.3,
14.0 ppm.

nBu

CO2

N

II-15

Analytical data for tetrabutylammonium (Z)-non-4-enoate (II-15): colorless oil; 1H NMR (500
MHz, CDCl3) δ 5.40 (1H, m), 5.26 (1H, m), 3.36 (8H, AB quartet, J = 8.0 Hz), 2.35 (2H, dd, J =
7.0, 16.0 Hz), 2.18 (2H, dd, J = 6.0, 9.0 Hz), 2.02 (2H, m), 1.63 (8H, m), 1.40 (8H, sextet, J = 7.0
Hz), 1.27 (4H, m), 0.97 (12H, t, J = 7.5 Hz), 0.84 (3H, t, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ
178.5, 130.7, 129.0, 58.8, 39.1, 32.1, 26.9, 25.2, 24.1, 22.4, 19.8, 14.0, 13.7 ppm. IR (film) 3001,
2962, 2874, 1652, 1576, 1458, 1395, 1296, 1155, 1096, 885, 737 cm-1.

CO2H

Ph

II-16

Analytical data for (E)-5-phenylpent-4-enoic acid (II-16):74 crystalline white solid, recrystallized
from hot ethyl acetate, m.p. 89 ºC (lit.71 86.6 ºC); 1H NMR (500 MHz, CDCl3) δ 11.92 (1H, br s),

	
  

151	
  

7.39-7.23 (5H, m), 6.48 (1H, d, J = 16.0 Hz), 6.27-6.22 (1H, m), 2.58 (4H, m); 13C NMR (125 MHz,
CDCl3) δ 179.7, 137.2, 131.2, 128.5, 127.9, 127.2, 126.0, 33.8, 27.8 ppm.

CO2

Ph

N

II-17

Analytical data for tetrabutylammonium (E)-5-phenylpent-4-enoate (II-17): pale yellow oil; 1H
NMR (500 MHz, CDCl3) δ 7.28 (2H, d, J = 7.0 Hz), 7.21 (2H, t, J = 7.5 Hz), 7.10 (1H, m), 6.34
(2H, m), 3.33 (8H, AB quartet, J = 8.0 Hz), 2.52 (2H, m), 2.32 (2H, dd, J = 5.5, 8.0 Hz), 1.60 (8H,
m), 1.40 (8H, sextet, J = 7.5 Hz), 0.95 (12H, t, J = 7.0 Hz);

13

C NMR (125 MHz, CDCl3) δ 177.9,

138.4, 132.6, 128.6, 128.3, 126.3, 125.8, 58.7, 38.6, 30.8, 24.0, 19.7, 13.7 ppm. IR (film) 3058,
2961 (s), 2875 (s), 2740, 1766, 1649, 1575 (s), 1424 (s), 1384, 1153, 1068, 965, 880, 740 (s) cm1

.

CO2H
II-18

Analytical data for (E)-hept-4-enoic acid (II-18):81 colorless oil; 1H NMR (500 MHz, CDCl3) δ
11.64 (1H, br s), 5.51 (1H, dtt, J = 1.5, 6.5, 13.5 Hz), 5.38 (1H, dtt, J = 1.5, 6.5, 13.5 Hz), 2.40
(2H, dt, J = 1.0, 8.0 Hz), 2.27-2.32 (2H, m), 1.98 (2H, dquint. J = 1.5, 7.5 Hz), 0.94 (3H, t, J = 7.5
Hz); 13C NMR (125 MHz, CDCl3) δ 179.8, 133.6, 126.5, 34.2, 27.5, 25.5, 13.7 ppm.

	
  

152	
  

OH
II-18-OH

Analytical data for (E)-hept-4-en-1-ol (II-18-OH):76 colorless oil; 1H NMR (500 MHz, CDCl3) δ 5.46
(1H, dtt, J = 1.5, 6.5, 9.0 Hz), 5.37 (1H, dtt, J = 1.0, 6.5, 9.0 Hz), 3.60 (2H, t, J = 6.0 Hz), 2.04 (2H,
ddd, J = 1.5, 7.5, 15.0.), 1.96 (2H, m), 1.73 (1H, br s), 1.59 (2H, quint, J = 7.0 Hz), 0.93 (3H, t, J =
7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 132.7, 128.4, 62.4, 32.4, 28.8, 25.5, 13.9 ppm.

CO2

N

II-19

Analytical data for tetrabutylammonium (E)-hept-4-enoate (II-19): colorless oil; 1H NMR (500
MHz, CDCl3) δ 5.40 (2H, m), 3.32 (8H, AB quartet, J = 8.5 Hz), 2.28-2.24 (2H, m), 2.21-2.18 (2H,
m), 1.90 (2H, m), 1.61 (8H, m), 1.36 (8H, sextet, J = 7.5 Hz), 0.94 (12H, t, J = 7.5 Hz), 0.87 (3H, t,
J = 7.5 Hz);

13

C NMR (125 MHz, CDCl3) δ 178.1, 131.0, 129.8, 58.7, 29.9, 25.5, 24.0, 19.7, 13.9,

13.6 ppm. IR (film) 2963 (s), 2875 (s), 2742, 1758, 1651, 1543 (s), 1444, 1382, 1248, 1103, 1035,
966, 886, 740 cm-1.

	
  

153	
  

CO2H
O

II-20

Analytical data for (Z)-5-(4-methoxyphenyl)pent-4-enoic acid (II-20):77 Recrystallized from hot
ethyl acetate. White solid, m.p. 67 ºC (lit.77 64-65 ºC); 1H NMR (500 MHz, CDCl3) δ 11.60 (1H, br
s), 7.20 (2H, d, J = 9.0 Hz), 6.87 (2H, dd, J = 3.0, 9.0 Hz), 6.40 (1H, d, J = 11.5 Hz), 5.20 (1H, dt,
J = 7.5, 11.5 Hz), 3.80 (3H, s), 2.65 (2H, ddd, J = 1.5, 7.0, 8.5 Hz), 2.49 (2H, dd, J = 7.5, 15.0 Hz);
13

C NMR (125 MHz, CDCl3) δ 179.4, 158.4, 129.9, 129.8, 129.7, 128.3, 55.2, 34.2, 23.7 ppm.

CO2
O

N

II-21

Analytical data for tetrabutylammonium (Z)-5-(4-methoxyphenyl)pent-4-enoate (II-21): pale
yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.24 (2H, d, J = 8.5 Hz), 6.78 (2H, m), 6.22 (1H, d, J =
12.0 Hz), 5.63 (1H, dt, J = 7.0, 11.5 Hz), 3.75 (3H, s), 3.32 (8H, AB quartet, J = 8.5 Hz), 2.63 (2H,
ddd, J = 1.5, 7.5, 9.0 Hz), 2.30 (2H, dd, J = 7.5, 9.5 Hz), 1.60 (8H, m), 1.38 (8H, sextet, J = 7.5
Hz), 0.94 (12H, t, J = 7.5 Hz);

13

C NMR (125 MHz, CDCl3) δ 177.9, 157.8, 132.7, 130.8, 130.0,

127.1, 113.3, 58.7, 55.2, 39.0, 26.5, 24.0, 19.7, 13.7 ppm. IR (film) 3175, 2961 (s), 2875, 1761,
1650, 1591 (s), 1511 (s), 1465, 1382, 1247, 1176, 1031, 842, 739 cm-1.

	
  

154	
  

Ph
CO2H
II-22

Analytical data for (E)-4-phenylpent-3-enoic acid (II-22):78,79 White solid, m.p. 75 ºC (lit.79 76-77
ºC); 1H NMR (500 MHz, CDCl3) δ 11.12 (1H, br s), 7.42 (2H, d, J = 7.0 Hz), 7.34 (2H, t, J = 7.0
Hz), 7.23 (1H, m), 5.95 (1H, dt, J = 1.5, 7.5 Hz), 3.33 (2H, d, J = 7.5 Hz), 2.10 (3H, s);

13

C NMR

(125 MHz, CDCl3) δ 178.3, 142.9, 138.7, 128.2, 127.2, 125.8, 118.3, 34.1, 16.2 ppm.

The E-geometry was established based on NOESY experiment.

NOESY data: (a) Irradiation at 5.95 ppm shows enhancement at 7.42 and 3.33 ppm, (b)
Irradiation at 3.33 ppm shows enhancement at 5.95 and 2.10 ppm and, (c) Irradiation at 2.10 ppm
shows enhancement at 3.33 and 7.42 ppm.

Ph
CO2

N

II-23

Analytical data for tetrabutylammonium (E)-4-phenylpent-3-enoate (II-23): pale yellow oil; 1H
NMR (500 MHz, CDCl3) δ 7.40 (2H, dd, J = 1.0, 7.5 Hz), 7.22 (2H, t, J = 7.5 Hz), 7.11 (1H, t, J =
7.5 Hz), 6.27 (1H, dt, J = 1.0, 7.0 Hz), 3.29 (8H, AB quartet, J = 8.5 Hz), 3.16 (2H, d, J = 7.0 Hz),
2.00 (3H, s), 1.58 (8H, m), 1.37 (8H, sextet, J = 7.5 Hz), 0.94 (12H, t, J = 7.0 Hz);

13

C NMR (125

MHz, CDCl3) δ 176.3, 144.3, 132.8, 127.8, 126.8, 125.8, 125.6, 58.7, 39.3, 24.0, 19.7, 15.9, 13.7

	
  

155	
  

ppm. IR (film) 3011, 2965 (s), 2876, 1770 (w), 1595 (s), 1464, 1377, 1153, 1061, 873, 757, 699
cm-1.

iii. Synthesis of isotopically labeled substrates:

OH

Ph

D 2O, rt

OD

Ph
O

O

II-1-OD

II-1

4-phenylpent-4-enoic acid-d1 (II-1-OD): Alkenoic acid II-169 (50 mg, 0.28 mmol) was suspended
in D2O (2 mL) in a 10 mL round bottom flask attached to a condenser. The resulting suspension
was warmed over a steam bath for 20 min and the suspension was concentrated to dryness using
a rotary evaporator. Another 2 mL of D2O was added to the residue and the process was repeated
three more times. Finally, the solid obtained was dried under vacuum (250 mtorr) for 12 h.

Analytical data for II-1-OD: white solid, m.p. 95 °C; NMR data is identical to previously reported
data for the unlabeled substrate.37,69 1H NMR (500 MHz, CDCl3) δ 7.39 (2H, d, J = 7.5 Hz), 7.33
(2H, t, J = 7.5 Hz), 7.27 (1H, m), 5.31 (1H, br s), 5.10 (1H, br s), 2.84 (2H, t, J = 7.0 Hz), 2.54 (2H,
t, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 179.4, 146.5, 140.4, 128.4, 127.7, 126.1, 113.0, 32.9,
30.1 ppm. IR (film) 3100-2200 (br), 1697, 1625, 1443, 1411, 1312, 1218, 1026, 900, 779, cm-1.

	
  

156	
  

O
Ar

CO2CH 3

NaOCH 3
CH 3OD

(i) Ph 3P=CH 2,
toluene

O H/D H/D
CO2CH 3

Ar
D D

(ii) NaOMe/MeOH
(iii) NaOH, H 2O

OH

Ar
D D

O

(3,3-d2)	
  -4-phenylpent-4-enoic acid (II-1-D2):	
  

CO2H
D D
II-1-D2

Recrystallized 4-oxo-4-phenylbutanoic acid82 (500 mg, 2.80 mmol) was dissolved in 2 mL
of methanol in a 10 mL round bottom flask. The solution was cooled at 0 ºC using an ice bath. To
this cold solution, thionyl chloride (0.22 mL, 2.95 mmol, 1.05 equiv) was added drop wise over 15
min. The reaction mixture was stirred for 30 min at 0 ºC. It was then diluted with DCM (10 mL) and
poured in a separatory funnel and washed with ice-cold 10% aq. NaHCO3 solution (5 mL). The
organics were washed with brine (2 mL), separated, dried over anhydrous Na2SO4 and
concentrated to obtain the corresponding methyl ester. It was used for the next step without any
further purification.

Crude methyl-4-oxo-4-phenylbutanoate (535 mg, 2.78 mmol) obtained above was
dissolved in CH3OD (2.5 mL) along with catalytic amount of NaOCH3 (26 mg, 0.47 mmol, 0.17
equiv). The reaction mixture was stirred for 12 h at room temperature. The solvent was partially
removed using a rotary evaporator and 2.5 mL of CH3OD were introduced to the reaction flask.
The mixture was allowed to stir for 12 h more after which the reaction mixture was diluted with
DCM (10 mL) and poured in a separatory funnel containing 5 mL of ice-cold saturated aq. NH4Cl
solution. The organics were washed quickly (<2 min) with the satd. aq. NH4Cl solution and then

	
  

157	
  

with brine solution (5 mL). The organics were separated, dried over anhydrous Na2SO4,
concentrated and dried under vacuuo to obtain the corresponding α-dideuterated keto-ester. It
was then subjected to the next step immediately without further purification.

A 25 mL flame dried flask was charged with methyltriphenylphosphonium bromide (1.01 g,
2.83 mmol, 1.1 equiv) and dry toluene (7.5 mL). The resulting suspension was cooled to 0 ºC on
an ice bath and 1.0 M NaHMDS in THF (2.83 mL, 2.83 mmol, 1.1 equiv) was added drop wise.
The suspension turned clear with a bright yellow color. The resulting ylide solution was then
stirred for 30 min at 0 ºC and then cooled further to -78 ºC (dry ice/acetone bath). To this cold
reaction mixture, a solution of crude methyl-4-oxo-4-phenylbutanoate-3,3-d2 (500 mg, 2.57 mmol,
1.0 equiv in 1 mL toluene) obtained above, was added at once. The reaction was eventually
warmed to room temperature over a period of 1 h and then placed in a pre-heated oil bath at 70
ºC. Heating was continued for 8 h after which the reaction mixture was cooled to room
temperature and poured in a separatory funnel containing saturated aq. NH4Cl solution (10 mL).
The organics were washed with brine, separated, dried over anhydrous Na2SO4, concentrated
and the product was dissolved in 20% ethyl acetate in hexanes (30 mL) and filtered through a pad
of silica (5 cm height, 2.5 cm diameter) using a frit funnel. The resulting solution of dideuterated
alkenoic ester was concentrated using a rotary evaporator, dissolved in CH3OH (5 mL) and
treated with 20 mol% NaOCH3. The reaction mixture was stirred for 8 h at room temperature. This
was necessary to remove the undesired labeling at the α-carbon of the ester functionality. The
reaction mixture was then concentrated to a volume of 2 mL followed by addition of NaOH (308
mg, 7.71 mmol, 3.0 equiv) pre-dissolved in water (1 mL). After stirring for further 8 h, the resulting
solution was cooled on an ice bath and treated with conc. HCl until the pH of the solution was 2.
The solution was diluted with ethyl acetate (10 mL) and poured in a separatory funnel containing
brine solution (5 mL). The organics were then washed with 10% aq. HCl followed by brine (2 mL).

	
  

158	
  

Finally, the solution was dried over anhydrous Na2SO4, concentrated and the crude product (II-1D2) was subjected to purification using silica gel flash chromatography with 25% ethyl acetate in
hexanes as eluent. Pure product (3,3-d2)-4-phenylpent-4-enoic acid (299 mg, II-1-D2) was
obtained as a white powder in 65% yield from its corresponding crude α-dideuterated keto-ester.
It was further purified by recrystallization from hot 20% ethyl acetate in hexanes. Recrystallized
product (230 mg) was collected in 2 crops in 50 % isolated yield (90% deuterium incorporation).
Note: All intermediates were verified by crude 1H NMR analysis and completion of reaction was
judged by TLC and 1H NMR. The intermediates may be purified if necessary, however H-D
exchange was observed in case of α-dideutero keto ester upon purification by silica gel column
chromatography.

Analytical data for (3,3-d2)-4-phenylpent-4-enoic acid (II-1-D2): White crystalline plates, mp. 82 ºC;
1

H NMR (500 MHz, CDCl3) δ 11.40 (1H, br s), 7.39 (2H, d, J = 7.5 Hz), 7.39 (2H, m), 7.33 (2H, m),

7.27 (1H, ddd, J = 1.0, 6.0, 8.5 Hz), 5.32 (1H, br s), 5.10 (1H, br s), 2.83 (0.2H, m, 10% residual
CH2), 2.51 (2H, m); 13C NMR (125 MHz, CDCl3) δ 179.4, 146.4, 140.4, 128.4, 127.7, 126.1, 113.0,
32.8, 29.7 (quint, J = 19.9 Hz) ppm. IR (film) 3100-2600 (br), 2360, 2330, 1955, 1894, 1813, 1696
(s), 1621, 1442, 1410, 1306, 1077, 902, 831, 779, 698 cm-1. HRMS (ESI) Calculated Mass for
C11H9D2O2: ([M-H]—) = 177.0890, Found ([M-H]—) = 177.0890.

	
  

159	
  

(3,3-d2)-4-(4-methoxyphenyl)pent-4-enoic acid (1e-D2):	
  

CO2H
O

D D
II-2-D2

The same procedure described above for II-1-D2 was employed for the synthesis of II-2D2. Using 500 mg of 4-(4-methoxyphenyl)-4-oxobutanoic acid,82 260 mg (52% overall yield) of
pure II-2-D2 was obtained (82% deuterium incorporation).

Analytical data for (3,3-d2)-4-(4-methoxyphenyl)pent-4-enoic acid (II-2-D2): White crystalline solid,
mp. 131 ºC; 1H NMR (500 MHz, CDCl3) δ 11.06 (1H, br s), 7.32 (2H, dd, J = 2.0, 7.0 Hz), 6.85
(2H, dd, J = 2.0, 7.0 Hz), 5.24 (1H, br s), 5.01 (1H, br s), 3.80 (3H, s), 2.80 (0.36H, m, 18%
residual CH2), 2.50 (2H, m);

13

C NMR (125 MHz, CDCl3) δ 178.7, 159.3, 145.7, 132.7, 127.1,

113.8, 111.4, 55.3, 32.8, 30.1 (quint, J = 19.0 Hz) ppm. IR (film) 3100-2600 (br), 2360, 2330,
1955, 1894, 1813, 1696 (s), 1621, 1442, 1410, 1306, 1077, 902, 831, 779, 698 cm-1. HRMS (ESI)
Calculated Mass for C12H11D2O3: ([M-H]—) = 207.0996, Found ([M-H]—) = 207.0999.

	
  

160	
  

General procedure for synthesis of 18O labeled alkenoic acids:83
18

O-labeled water was purchased as a normalized 99%

18

O solution (1%

16

O) from Cambridge

Isotope Laboratories, Inc.

CO2H

R
R = H, II-1
R = OMe, II-2

N
Br
H

(20 equiv)
18 O

EDC·HCl, (3 x 10 equiv)
DMF, rt, H 2O18

R

H

18 O

R = H, II-1*
R = OMe, II-2*

3 5-lutidine hydrogen bromide was prepared as follows:

Freshly distilled 3 5-lutidine (1mL) was placed in a 50 mL flame dried two neck flask under
argon atmosphere. Diethyl ether (15 mL) was added and the solution was cooled to 0 ºC using an
ice bath. Dry HBr gas (made by reacting anhydrous NaBr with conc. H2SO4) was bubbled through
this cold solution (vigorously stirred) for 2 min at a rate such that the temperature of the reaction
mixture was maintained below 2-5 ºC. The desired hydrobromide salt precipitated as a white solid.
It was filtered under nitrogen atmosphere and washed with diethyl ether (10 mL) followed by
pentanes (10 mL). The resulting solid was dried under vacuuo prior to use. This procedure gave
1.64 g of the desired salt in quantitative yield.
The 3,5-dimethylpyridine hydrobromide prepared above (425 mg, 4.52 mmol, 20 equiv)
was suspended in dry DMF (2 ml) under nitrogen. To this solution, EDC•HCl (430 mg, 1.12 mmol,
10 equiv, dried under vacuum for 5h prior to use),

18

OH2 (112 μL, 99%, 5.7 mmol, 50 equiv) and

the alkenoic acid (0.11 mmol) were added in sequence. The mixture was stirred at room
temperature for 18 h under argon atmosphere. A second portion of dry EDC•HCl (215 mg, 1.12

	
  

161	
  

mmol, 10 equiv) was added and the mixture was stirred for another 8 h at room temperature.
Finally, a third portion of dry EDC•HCl (215 mg, 1.12 mmol, 10 equiv) was added and stirring was
continued for another 15 hours. The reaction was diluted by adding 10 mL ethyl acetate, washed
with 0.1 M citric acid (3 x 10 ml) followed by brine (5 mL). The organics were separated, dried
over anhydrous Na2SO4, concentrated and subjected to purification using silica gel flash
chromatography with 25% ethyl acetate in hexanes as eluent. The alkenoic acids were then
recrystallized from hot ethyl acetate: hexanes (1:5).
4-phenylpent-4-enoic-1,1-18O2 acid (II-1*):

18 O

H

18 O

II-1*

Analytical data for 4-phenylpent-4-enoic-1,1-18O2 acid (II-1*): White crystalline plates, mp. 89 ºC,
NMR data is identical to the unlabeled substrate;37,69 1H NMR (500 MHz, CDCl3) 1H NMR (500
MHz, CDCl3) δ 11.40 (1H, br s), 7.39 (2H, d, J = 7.5 Hz), 7.39 (2H, m), 7.33 (2H, m), 7.27 (1H,
ddd, J = 1.0, 6.0, 8.5 Hz), 5.32 (1H, br s), 5.10 (1H, br s), 2.83 (2H, m), 2.51 (2H, m);

13

C NMR

(125 MHz, CDCl3) δ 179.4, 146.4, 140.4, 128.4, 127.7, 126.1, 113.0, 32.8, 29.7 ppm. IR (film)
3300-2600 (br), 1954, 1891, 1674(s), 1625, 1444, 1411, 1265, 1026, 901, 779, 703 cm-1. HRMS
(ESI) Calculated Mass for C11H1118O2: ([M-H]—) = 179.0849, Found ([M-H]—) = 179.0852.

	
  

162	
  

4-(4-methoxyphenyl)pent-4-enoic-1,1-18O2 acid (II-2*):

18 O

H

18 O

O
II-2*

Analytical data for 4-(4-methoxyphenyl)pent-4-enoic-1,1-18O2 acid (II-2*): White crystalline solid,
mp. 131 ºC, NMR data is identical to the unlabeled substrate;37 1H NMR (500 MHz, CDCl3) δ
11.06 (1H, br s), 7.32 (2H, dd, J = 2.0, 7.0 Hz), 6.85 (2H, dd, J = 2.0, 7.0 Hz), 5.24 (1H, br s), 5.01
(1H, br s), 3.80 (3H, s), 2.80 (2H, m), 2.50 (2H, m);

13

C NMR (125 MHz, CDCl3) δ 178.7, 159.3,

145.7, 132.7, 127.1, 113.8, 111.4, 55.3, 32.8, 30.1 ppm. IR (film) 3000-2550 (br), 1904, 1795,
1668 (s), 1623, 1515, 1423, 1254, 1030, 895, 840 cm-1. HRMS (ESI) Calculated Mass for
C12H13O18O2: ([M-H]—) = 209.0955, Found ([M-H]—) = 209.0956.

	
  

163	
  

II.5.3. Halocyclization reactions.

General Procedure:

X+ source
(1.1 equiv)

R3
R1

Nuc
R2

R3

Nuc

R2
R1 X

CHCl3 (0.05M),
rt

X
R2
R1

R3

Nuc

Unless otherwise mentioned, all reactions were performed at room temperature at 0.05 M
substrate concentration in amylene stabilized CHCl3. The reactions were conducted in absence of
light to avoid radical halogenation. Reactions were initially ran using 0.1 mmol of the substrate
and then scaled up at 1.0 mmol scale.

In a 10 mL flame dried round bottom flask, 1.0 mmol of the substrate was dissolved in
CHCl3 (50 mL, amylene stabilized) at room temperature under argon atmosphere. The flask was
then wrapped with an aluminum foil and placed in dark. To this homogenous solution, 1.10 mmol
of the halogenating reagent was added and then reaction was continued to stir until complete
consumption of the starting material (as judged by TLC and 1H NMR analysis). Upon completion
of the reaction, the contents were poured in a separatory funnel containing 50 mL of ice-cold
solution of 10% aq. sodium sulfite (Na2SO3). The organics were then washed with brine solution
(10 mL), separated, dried over anhydrous Na2SO4, filtered, concentrated and then subjected to
crude 1H NMR analysis using undecane (0.05 M) as internal standard. Purification was then
commenced using silica gel flash chromatography with ethyl acetate and hexanes as eluent.

	
  

164	
  

O
O
Ph
Cl

II-1a

Analytical data for 5-(chloromethyl)-5-phenyldihydrofuran-2(3H)-one (II-1a):37 colorless oil; 1H
NMR (500 MHz, CDCl3) δ 7.39-7.31 (5H, m), 3.71 (1H, d, J = 11.5 Hz), 3.67 (1H, d, J = 11.5 Hz),
2.77 (2H, m), 2.52 (2H, m);

13

C NMR (125 MHz, CDCl3) δ 175.4, 140.6, 128.7, 128.5, 124.7, 86.3,

40.9, 32.2, 28.9 ppm.

O
O

O
II-2a Cl

	
  
Analytical data for 5-(chloromethyl)-5-(4-methoxyphenyl)dihydrofuran-2(3H)-one (II-2a):37
colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.31 (2H, d, J = 8.5.), 6.90 (2H, d, J = 8.5.), 3.80 (3H,
s), 3.79 (1H, d, J = 12.0 Hz), 3.73 (1H, d, J = 12.0 Hz), 2.76 (2H, m), 2.49 (2H, m);

13

C NMR (125

MHz, CDCl3) δ 175.7, 159.8, 132.5, 126.2, 114.2, 87.0, 55.3, 52.2, 31.2, 29.0 ppm.

O
Ph
Cl

II-3a

	
  
Analytical data for 2-(chloromethyl)-2-phenyltetrahydrofuran (II-3a): colorless oil; 1H NMR (500
MHz, CDCl3) δ 7.42-7.39 (2H, m), 7.34 (2H, t, J = 7.5 Hz), 7.26 (1H, m), 4.07 (1H, dd, J = 7.0,
15.0 Hz), 3.92 (1H, dd, J = 7.0, 15.0 Hz), 3.70 (2H, m), 2.41 (1H, dt, J = 8.0, 12.5 Hz), 2.20 (1H,
ddd, J = 5.5, 8.0, 13.0 Hz), 2.07-1.99 (1H, m), 1.87-1.79 (1H, m);

	
  

165	
  

13

C NMR (125 MHz, CDCl3) δ

143.7, 127.9, 127.0, 125.3, 85.6, 68.4, 52.1, 35.3, 25.8 ppm. IR (film) 3060, 2954, 2875, 1601,
1493, 1449, 1301, 1217, 1132, 1060 (s), 1027, 986, 763, 727, 701 cm-1. HRMS (ESI) Calculated
Mass for C11H14ClO: ([M+H]+) = 197.0733, Found ([M+H]+) = 197.0733.
Note: Chloroether II-3a is highly volatile. Based on 1H NMR, the yields for chloroetherification of II3 were >90%, however the isolated yields ranged from 30-55%. Following the general procedure
described above, compound II-3a was purified via silica gel flash chromatography using
dichloromethane and pentanes (1:5) as eluents. The purified fractions were concentrated using
rotary evaporator (pressure should not be lower than 90 mtorr) with the flask immersed under icewater bath. Complete removal of residual dichloromethane led to poor isolated yields (10-15%). 	
  

O
O
Ph
Cl

D
II-1a-D2

Analytical

data

for

D

5-(chloromethyl)-5-phenyldihydrofuran-2(3H)-one-4,4-d2

(II-1a-D2):

colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.39-7.32 (5H, m), 3.83 (1H, d, J = 12.0 Hz), 3.75 (1H,
d, J = 12.0 Hz), 2.77 (1H, d, J = 18.0 Hz), 2.52 (1H, d, J = 18.0 Hz); 13C NMR (125 MHz, CDCl3) δ
175.7, 140.6, 128.8, 128.7, 124.9, 87.0, 52.1, 31.2 (quint, J = 19.5 Hz), 28.8 ppm. IR (film) 3068,
3032, 2961, 2410, 2366, 2251, 1955, 1782 (broad and strong), 1653, 1496, 1449, 1255, 1169,
1037, 930, 702 cm-1. HRMS (ESI) Calculated Mass for C11H10D2ClO2: ([M+H]+) = 213.0651, Found
([M+H]+) = 213.0650.

	
  

166	
  

8-chloro-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-6a-Cl):

O
O
Cl

II-6a-Cl

Analytical data for 8-chloro-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-6a-Cl): Pale yellow
oil, 1H NMR (500 MHz, CDCl3) δ 5.39 (1H, m.), 4.09 (1H, d, J = 4.5 Hz.), 3.23 (1H, dd, J = 4.5, 6.5
Hz.), 2.44 (1H, d, J = 19.0 Hz.), 2.23 (1H, d, J = 19.0 Hz.), 1.74 (3H, br s.), 1.47 (3H, s.); 13C NMR
(125 MHz, CDCl3) δ 171.5, 137.8, 114.2, 84.5, 58.5, 45.3, 38.8, 21.8 ppm. IR (film) 3007, 2978,
2840, 1780 (s), 1653, 1445, 1384, 1152, 928, 867 cm-1. HRMS (ESI) Calculated Mass for
C9H12ClO2: ([M+H]+) = 187.0526, Found ([M+H]+) = 187.0522.

5-chloro-3,5-dimethyl-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-6b-Cl):	
  

O

O

crystal structure
of II-6b-Cl
II-6b-Cl

Cl

Analytical data for 5-chloro-3,5-dimethyl-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-6b-Cl): Pale yellow
crystalline solid, mp = 46 ºC, 1H NMR (500 MHz, CDCl3) δ 5.45 (1H, m.), 4.56 (1H, dd, J = 1.5, 5.0
Hz.), 4.17 (1H, t, J = 6.0 Hz.), 2.42 (1H, dt, J = 1.5, 2.5, 17.0 Hz.), 2.33 (1H, d, J = 2.0, 17.0 Hz.),
1.78 (3H, s.), 1.70 (3H, s.);

13

C NMR (125 MHz, CDCl3) δ 166.9, 137.4, 111.0, 73.0, 64.0, 50.1,

39.5, 27.0, 23.8 ppm. IR (film) 3010, 2978, 2935, 1835 (s), 1670, 1448, 1380, 1255, 1121, 876

	
  

167	
  

cm-1. HRMS (ESI) Calculated Mass for C9H12ClO2: ([M+H]+) = 187.0526, Found ([M+H]+) =
187.0525.

8-bromo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-6a-Br):

O
O
Br

II-6a-Br

Analytical data for 8-bromo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-6a-Br): Pale yellow
oil, 1H NMR (500 MHz, CDCl3) δ 5.53 (1H, d, J = 7.0 Hz.), 4.19 (1H, d, J = 4.5 Hz.), 3.22 (1H, dd,
J = 4.5, 7.0 Hz.), 2.48 (1H, d, J = 18.5 Hz.), 2.27 (1H, d, J = 18.5 Hz.), 1.73 (3H, br s.), 1.46 (3H,
s.);

13

C NMR (125 MHz, CDCl3) δ 171.9, 137.6, 115.6, 84.7, 49.3, 45.4, 39.4, 22.0, 21.7 ppm. IR

(film) 3055, 2978, 2912, 1783 (s), 1656, 1446, 1383, 1271, 1196, 1148, 1070, 925, 868 cm-1.
HRMS (ESI) Calculated Mass for C9H12BrO2: ([M+H]+) = 231.0021, Found ([M+H]+) = 231.0021.

5-bromo-3,5-dimethyl-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-6b-Br):

O

O

II-6b-Br

Analytical

data

for

Br

5-bromo-3,5-dimethyl-7-oxabicyclo[4.2.0]oct-2-en-8-one

(II-6b-Br):

Pale

crystalline solid, decomposes upon heating above 45 ºC, 1H NMR (500 MHz, CDCl3) δ 5.51 (1H,
d, J = 6.5 Hz.), 4.78 (1H, d, J = 5.0 Hz.), 4.20 (1H, t, J = 6.0 Hz.), 2.46 (2H, m.), 1.93 (3H, s.), 1.81
(3H, s.); 13C NMR (125 MHz, CDCl3) δ 167.1, 138.3, 111.1, 73.5, 59.2, 50.5, 40.6, 28.3, 23.9 ppm.

	
  

168	
  

IR (film) 3048, 2974, 2932, 2873, 1833 (s), 1778, 1713, 1447, 1381, 1257, 1176, 1120, 1064, 867,
816 cm-1. HRMS (ESI) Calculated Mass for C9H12BrO2: ([M+H]+) = 231.0021, Found ([M+H]+) =
231.0020.

8-iodo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-6a-I):

O
O

I

II-6a-I

Analytical data for 8-iodo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-6a-I): Pale yellow oil,
1

H NMR (500 MHz, CDCl3) δ 5.55 (1H, d, J = 7.0 Hz.), 4.24 (1H, d, J = 4.5 Hz.), 3.17 (1H, dd, J =

4.5, 7.0 Hz.), 2.51 (1H, d, J = 18.5 Hz.), 2.32 (1H, d, J = 18.5 Hz.), 1.73 (3H, br s.), 1.46 (3H, s.);
13

C NMR (125 MHz, CDCl3) δ 172.5, 137.4, 118.3, 85.2, 46.3, 40.7, 27.0, 22.4, 21.8 ppm. IR (film)

3047, 2976, 2910, 1783 (s), 1656, 1445, 1384, 1305, 1184, 1143, 1066, 924, 862, 697 cm-1.
HRMS (ESI) Calculated Mass for C9H12IO2: ([M+H]+) = 278.9882, Found ([M+H]+) = 278.9884.

8-chloro-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-ene (II-8a-Cl):

O

Cl

II-8a-Cl

Analytical data for 8-chloro-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-ene (II-8a-Cl): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 5.52 (1H, d, J = 7.0 Hz.), 3.92 (2H, m.), 3.84 (1H, d, J = 6.5 Hz.), 2.75
(1H, dt, J = 4.0, 6.5 Hz.), 2.32 (1H, d, J = 18.5 Hz.), 1.95 (1H, d, J = 18.5 Hz.), 1.67 (3H, br s.),
1.30 (3H, s.);

	
  

13

C NMR (125 MHz, CDCl3) δ 135.1, 120.6, 79.9, 74.3, 61.6, 43.1, 41.9, 22.9, 21.9

169	
  

ppm. IR (film) 3027, 2935, 2866, 1708, 1645, 1600, 1493, 1447, 1345, 1055, 972, 760, 700 cm-1.
HRMS (ESI) Calculated Mass for C9H14ClO: ([M+H]+) = 173.0733, Found ([M+H]+) = 173.0736.

8-bromo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-ene (II-8a-Br):

O

Br

II-8a-Br

Analytical data for 8-bromo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-ene (II-8a-Br): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 5.53 (1H, dd, J = 1.5, 7.0 Hz.), 3.97 (1H, d, J = 3.0 Hz.), 3.92 (1H, m.),
3.85 (1H, d, J = 7.0 Hz.), 2.77 (1H, dt, J = 4.0, 7.0 Hz.), 2.37 (1H, d, J = 17.5 Hz.), 2.00 (1H, d, J =
17.5 Hz.), 1.66 (3H, br s.), 1.30 (3H, s.);

13

C NMR (125 MHz, CDCl3) δ 134.9, 121.7, 80.0, 74.5,

53.2, 43.8, 42.1, 22.9, 21.9 ppm. IR (film) 2962, 2927, 2869, 1833 (w), 1718, 1666, 1451, 1414,
1379, 1249, 1114 (s), 1029, 815 cm-1. HRMS (ESI) Calculated Mass for C9H14BrO: ([M+H]+) =
217.0228, Found ([M+H]+) = 217.0226.

5-bromo-3,5-dimethyl-7-oxabicyclo[4.2.0]oct-2-ene (II-8b-Br):
O

II-8b-Br

Br

Analytical data for 5-bromo-3,5-dimethyl-7-oxabicyclo[4.2.0]oct-2-ene (II-8b-Br): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 5.11 (1H, br s.), 4.58 (1H, d, J = 4.0 Hz.), 3.79 (1H, m.), 3.36 (1H, m.),
2.77 (1H, d, J = 19.0 Hz.), 2.50 (1H, d, J = 19.5 Hz.), 2.02 (3H, s.), 1.69 (3H, s.);

13

C NMR (125

MHz, CDCl3) δ 131.9, 116.7, 65.8, 65.4, 61.5, 43.6, 42.5, 34.1, 23.0 ppm. IR (film) 3020, 2920,

	
  

170	
  

2801, 1711, 1600, 1462, 1444, 1319, 1204, 1050, 1012, 749 cm-1. HRMS (ESI) Calculated Mass
for C9H14BrO: ([M+H]+) = 217.0228, Found ([M+H]+) = 217.0228.

8-iodo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-ene (II-8a-I):
O

I

II-8a-I

Analytical data for 8-iodo-3,5-dimethyl-6-oxabicyclo[3.2.1]oct-2-ene (II-8a-I): pale yellow oil, 1H
NMR (500 MHz, CDCl3) δ 5.55 (1H, d, J = 6.0 Hz.), 3.98 (1H, d, J = 3.5 Hz.), 3.89 (2H, m.), 2.76
(1H, m.), 2.41 (1H, d, J = 18.0 Hz.), 2.07 (1H, d, J = 18.0 Hz.), 1.66 (3H, s.), 1.33 (3H, s.);

13

C

NMR (125 MHz, CDCl3) δ 134.6, 123.8, 80.6, 74.7, 45.0, 43.2, 31.3, 23.0, 21.9 ppm. IR (film)
2967, 2983, 2866, 1724, 1607, 1448, 1378, 1334, 1211, 1096, 1012, 916, 810, 729 cm-1. HRMS
(ESI) Calculated Mass for C9H14IO: ([M+H]+) = 265.0089, Found ([M+H]+) = 265.0088.

8-chloro-3,5-dimethyl-N-phenyl-6-oxabicyclo[3.2.1]oct-2-en-7-imine (II-9a-Cl):

Ph N
O

Cl

II-9a-Cl
(E:Z = 1:1)

Analytical data for 8-chloro-3,5-dimethyl-N-phenyl-6-oxabicyclo[3.2.1]oct-2-en-7-imine (II-9a-Cl):
inseparable mixture of E and Z isomers (~1:1) colorless oil, 1H NMR (500 MHz, CDCl3) δ 7.297.25 (3H, m), 7.10-7.03 (5H, m.), 6.84 (2H, d, J = 7.5 Hz), 5.64 (1H, d, J = 6.5 Hz.), 5.37 (1H, d, J
= 6.5 Hz.), 4.16 (1H, d, J = 4.5 Hz.), 4.08 (1H, d, J = 4.5 Hz.), 3.36 (1H, dd, J = 4.5, 7.0 Hz.), 3.22
(1H, dd, J = 4.5, 7.0 Hz.), 2.45-2.18 (4H, m.), 1.74 (6H, m.), 1.50 (3H, s.), 1.41 (3H, s.);

	
  

171	
  

13

C NMR

(125 MHz, CDCl3) δ 164.7, 160.5, 148.1, 145.7, 138.5, 137.2, 136.1, 132.5, 129.3, 129.2, 129.2,
129.2, 128.8, 128.7, 128.7, 124.4, 124.2, 123.9, 123.5, 123.5, 123.5, 123.5, 121.4, 121.4, 121.4,
117.1, 116.1, 85.8, 83.9, 77.5, 77.5, 77.3, 77.0, 59.7, 59.3, 46.2, 41.7, 39.8, 39.8, 30.9, 26.5,
25.5, 22.3, 22.2, 22.1, 22.1, 21.4 ppm. IR (film) 3295, 3060, 2923, 1775, 1707, 1652, 1600, 1541,
1498, 1442, 1322, 1265, 1178, 1074, 754, 692 cm-1. HRMS (ESI) Calculated Mass for
C15H17ClNO: ([M+H]+) = 262.0999, Found ([M+H]+) = 262.0999.

Note: The complex nature of NMR spectrum can be attributed not only to the inseparable isomeric
(E and Z) forms, but also to the rotamers along the N-Ph bond. To validate this hypothesis, a
solution of 20 mg of II-9a-Cl in 1 mL THF/H2O (1:1) was treated with 1µL of 12M HCl for 12h at
ambient temperature. The resulting hydrolysis followed by purification, furnished 9 mg (63% yield)
of pure II-6a-Cl with spectral and physical properties as reported above.

8-bromo-3,5-dimethyl-N-phenyl-6-oxabicyclo[3.2.1]oct-2-en-7-imine (II-9a-Br):

Ph N
O

Br

II-9a-Br
(E:Z = 1:1)

Analytical data for 8-bromo-3,5-dimethyl-N-phenyl-6-oxabicyclo[3.2.1]oct-2-en-7-imine (II-9a-Br):
pale yellow oil, 1H NMR (500 MHz, CDCl3) δ 7.28-7.25 (3H, m), 7.10-7.02 (5H, m.), 6.84 (2H, d, J
= 8.0 Hz), 5.66 (1H, d, J = 6.5 Hz.), 5.39 (1H, d, J = 7.0 Hz.), 4.21 (1H, d, J = 4.0 Hz.), 4.13 (1H,
d, J = 4.0 Hz.), 3.36 (1H, dd, J = 4.5, 7.0 Hz.), 3.22 (1H, dd, J = 4.5, 7.0 Hz.), 2.49-2.22 (4H, m.),
1.75 (6H, m.), 1.50 (3H, s.), 1.42 (3H, s.);

13

C NMR (125 MHz, CDCl3) δ 164.5, 160.2, 147.8,

145.5, 138.2, 137.0, 135.8, 132.2, 129.0, 128.5, 124.2, 124.0, 123.6, 123.3, 121.2, 116.9, 115.9,
85.6, 83.7, 59.4, 59.0, 46.0, 41.4, 39.6, 39.5, 32.2, 30.7, 26.2, 25.4, 22.1, 21.9, 21.9, 21.2 ppm. IR

	
  

172	
  

(film) 3160, 2975, 2913, 2856, 1780, 1659, 1600, 1544, 1443, 1324, 1247, 1149, 1081, 925, 755
cm-1. HRMS (ESI) Calculated Mass for C15H17BrNO: ([M+H]+) = 306.04935, Found ([M+H]+) =
306.04937.

8-iodo-3,5-dimethyl-N-phenyl-6-oxabicyclo[3.2.1]oct-2-en-7-imine (II-9a-I):

Ph N
O

I

II-9a-I
(E:Z = 1:1)

Analytical data for 8-iodo-3,5-dimethyl-N-phenyl-6-oxabicyclo[3.2.1]oct-2-en-7-imine (II-9a-I): pale
yellow oil, 1H NMR (500 MHz, CDCl3) δ 7.30-7.25 (3H, m), 7.08-7.03 (5H, m.), 6.84 (2H, d, J = 7.5
Hz), 5.69 (1H, d, J = 6.5 Hz.), 5.42 (1H, d, J = 7.0 Hz.), 4.25 (1H, d, J = 4.0 Hz.), 4.18 (1H, d, J =
4.0 Hz.), 3.33 (1H, dd, J = 4.0, 7.0 Hz.), 3.18 (1H, dd, J = 4.0, 7.0 Hz.), 2.54-2.30 (4H, m.), 1.75
(6H, m.), 1.51 (3H, s.), 1.43 (3H, s.);

13

C NMR (125 MHz, CDCl3) δ 165.1, 160.9, 147.9, 145.5,

136.6, 135.4, 133.4, 129.1, 129.0, 128.5, 124.7, 123.9, 123.6, 123.3, 121.2, 120.7, 120.1, 119.8,
86.5, 84.4, 47.2, 42.6, 41.5, 41.4, 28.3, 27.8, 22.6, 22.4, 21.8, 21.8, 21.3 ppm. IR (film) 3054,
2969, 2915, 2850, 1771, 1654, 1599, 1538, 1442, 1327, 1245, 1180, 925, 757 cm-1. HRMS (ESI)
HRMS (ESI) Calculated Mass for C15H17INO: ([M+H]+) = 354.03549, Found ([M+H]+) = 354.03549.

	
  

173	
  

5-chloro-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-10b-Cl):	
  

O

O

crystal structure
of II-10b-Cl
II-10b-Cl

Cl

Analytical data for 5-chloro-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-10b-Cl): Pale yellow oil, 1H NMR
(500 MHz, CDCl3) δ 6.03 (1H, dt, J = 4.5, 9.5.), 5.87 (1H, dd, J = 7.5, 9.0 Hz.), 4.79 (1H, m.), 4.48
(1H, d, J = 3.0 Hz.), 4.28 (1H, t, J = 6.0 Hz.), 2.63 (2H, m.);

13

C NMR (125 MHz, CDCl3) δ 166.0,

127.5, 118.1, 70.6, 50.6, 49.0, 27.6 ppm. IR (film) 3050, 2957, 2854, 1826 (s), 1646, 1429, 1367,
1269, 1232, 1105 (s), 902, 863, 683 cm-1. HRMS (ESI) Calculated Mass for C7H8ClO2: ([M+H]+) =
159.0213, Found ([M+H]+) = 159.0212.

5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-10b-Br):	
  

O

O

II-10b-Br

crystal structure
of II-10b-Br
Br

Analytical data84 for 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-10b-Br):84 White crystalline
solid, mp = 99 ºC (lit.84 97 ºC) 1H NMR (500 MHz, CDCl3) δ 6.04 (1H, dt, J = 5.0, 10.0.), 5.89 (1H,
dd, J = 7.0, 9.5 Hz.), 4.92 (1H, m.), 4.53 (1H, d, J = 3.0 Hz.), 4.27 (1H, t, J = 6.0 Hz.), 2.71 (2H,
m.); 13C NMR (125 MHz, CDCl3) δ 166.0, 128.2, 118.3, 70.6, 49.1, 41.4, 27.9 ppm.

	
  

174	
  

8-iodo-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-10a-I):	
  

O
O

I

crystal structure
of II-10a-Cl
II-10a-I

Analytical data for 8-iodo-6-oxabicyclo[3.2.1]oct-2-en-7-one (II-10a- I): White solid, decomposes
above 47 ºC, 1H NMR (500 MHz, CDCl3) δ 5.89 (1H, d, J = 9.5.), 5.82 (1H, dd, J = 8.5, 8.5 Hz.),
4.73 (1H, m.), 4.54 (1H, t, J = 4.5 Hz.), 3.17 (1H, dd, J = 5.0, 6.5 Hz.), 2.81 (1H, dd, J = 2.5, 19.5
Hz.), 2.57 (1H, d, J = 19.5 Hz.);

13

C NMR (125 MHz, CDCl3) δ 171.9, 127.4, 124.1, 78.3, 43.4,

30.1, 17.0 ppm. IR (film) 3046, 2926, 1772 (s), 1537, 1412, 1333, 1220, 1145, 1083, 919, 690 cm1

. HRMS (ESI) Calculated Mass for C7H8IO2: ([M+H]+) = 250.9569, Found ([M+H]+) = 250.9568.

5-iodo-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-10b-I):

O

O

II-10b-I

I

Analytical data for 5-iodo-7-oxabicyclo[4.2.0]oct-2-en-8-one (II-10b-I): white solid with a purple tint
of liberated iodine indicating possible decomposition. Stored at -20 ºC as a 0.1 M solution in
CHCl3 or DCM in dark. Product is stable at room temperature for about 2-3 h and undergoes rapid
decomposition upon heating above 30 ºC, 1H NMR (500 MHz, CDCl3) δ 5.95 (1H, dt, J = 4.5,
10.0.), 5.87 (1H, m.), 4.86 (1H, dd, J = 3.0, 5.5 Hz.), 4.47 (1H, dd, J = 3.5, 3.5 Hz.), 4.21 (1H, t, J
= 6.0 Hz.), 2.61 (2H, m.); 13C NMR (125 MHz, CDCl3) δ 165.8, 129.2, 118.1, 71.6, 48.7, 28.5, 19.7

	
  

175	
  

ppm. IR (film) 3052, 2964, 1811 (s), 1652, 1426, 1358, 1127, 845 cm-1. HRMS (ESI) Calculated
Mass for C7H8IO2: ([M+H]+) = 250.9569, Found ([M+H]+) = 250.9566.

syn-5-chloro(phenyl)methyl)dihydrofuran-2(3H)-one (II-12b-Cl):	
  

O
O
Ph
II-12b-Cl

Cl

Analytical data for syn-5-chloro(phenyl)methyl)dihydrofuran-2(3H)-one (II-12b-Cl): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 7.45-7.41 (2H, m.), 7.38-7.32 (3H, m.), 4.96 (1H, d, J = 5.0 Hz), 4.904.86 (1H, m.), 2.46-2.37 (1H, m.), 2.29-2.15 (2H, m.), 2.13-2.05 (1H, m.);

13

C NMR (125 MHz,

CDCl3) δ 176.2, 136.1, 129.1, 128.8, 128.0, 81.9, 63.6, 28.0, 24.5 ppm. IR (film) 3032, 2916,
1781, 1444, 1411, 1332, 1165, 1153, 1035, 924, 875 cm-1. HRMS (ESI) Calculated Mass for
C11H12ClO2: ([M+H]+) = 211.0526, Found ([M+H]+) = 211.0525.

syn-5-bromo(phenyl)methyl)dihydrofuran-2(3H)-one (6b-Br):	
  

O

O

O

O

Ph II-12b-Br

II-12b-Br Br

Analytical

data61

crystal structure
of II-12b-Br

Br

Ph

for

syn-5-bromo(phenyl)methyl)dihydrofuran-2(3H)-one

(II-12b-Br):

white

crystalline solid, mp = 131 ºC, (lit.61 126-129 ºC), 1H NMR (500 MHz, CDCl3) δ 7.45-7.42 (2H, m.),

	
  

176	
  

7.36-7.30 (3H, m.), 4.97 (1H, d, J = 5.5 Hz), 4.90 (1H, ddd, J = 1.0, 5.5, 6.5 Hz.), 2.50-2.34 (2H,
m.), 2.26-2.19 (1H, m.), 2.04 (1H, dddd, J = 7.0, 8.5, 10.0, 13.5 Hz.);

13

C NMR (125 MHz, CDCl3)

δ 176.0, 136.8, 128.8, 128.4, 81.9, 55.2, 28.3, 25.6 ppm.

syn-5-iodo(phenyl)methyl)dihydrofuran-2(3H)-one (II-12b-I):	
  

O
O
I
II-12b-I

Ph

Analytical data61 for syn-5-iodo(phenyl)methyl)dihydrofuran-2(3H)-one (II-12b-I): pale crystalline
solid, decomposes above 85 ºC, (lit.61 mp = 90-94 ºC), 1H NMR (500 MHz, CDCl3) δ 7.44-7.43
(2H, m.), 7.32-7.26 (3H, m.), 5.10 (1H, d, J = 6.0 Hz), 4.65 (1H, dd, J = 7.5, 7.0 Hz.), 2.51-2.47
(2H, m.), 2.30-2.23 (1H, m.), 1.99-1.91 (1H, m.);

13

C NMR (125 MHz, CDCl3) δ 175.7, 139.1,

128.9, 128.7, 128.5, 82.8, 34.1, 28.7, 26.9 ppm.

syn-5-(1-chloropentyl)dihydrofuran-2(3H)-one (II-14b-Cl):

O
O
nBu

II-14b-Cl Cl

Analytical data for syn-5-(1-chloropentyl)dihydrofuran-2(3H)-one (II-14b-Cl): colorless oil, 1H NMR
(500 MHz, CDCl3) δ 4.67 (1H, ddd, J = 2.5, 6.0, 8.0 Hz.), 3.92 (1H, dt, J = 3.0, 7.5 Hz.), 2.65 (1H,
ddd, J = 6.0, 11.0, 17.0 Hz.), 2.50 (1H, ddd, J = 7.0, 10.5, 17.5 Hz.), 2.37-2.30 (1H, m.), 2.23-2.16
(1H, m.), 1.81 (2H, dd, J = 7.0, 7.5 Hz.), 1.57-1.49 (1H, m.), 1.42-1.25 (3H, m.), 0.89 (3H, t, J =
7.0 Hz.);

	
  

13

C NMR (125 MHz, CDCl3) δ 176.6, 80.5, 64.5, 33.8, 28.6, 28.1, 24.5, 22.1, 13.8 ppm.

177	
  

IR (film) 2957, 2872, 1778 (s), 1596, 1460, 1419, 1254, 1179, 1121, 1052, 915, 802 cm-1. HRMS
(ESI) Calculated Mass for C9H16ClO2: ([M+H]+) = 191.0839, Found ([M+H]+) = 191.0841.

syn-5-(1-bromopentyl)dihydrofuran-2(3H)-one (II-14b-Br):

O
O
nBu

II-14b-Br

Br

Analytical data for syn-5-(1-bromopentyl)dihydrofuran-2(3H)-one (II-14b-Br): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 4.62 (1H, ddd, J = 3.0, 6.5, 8.0 Hz.), 4.02 (1H, ddd, J = 3.0, 5.5, 8.5
Hz.), 2.66 (1H, ddd, J = 5.5, 10.5, 16.0 Hz.), 2.51 (1H, ddd, J = 8.0, 10.5, 18.5 Hz.), 2.40-2.32
(1H, m.), 2.20-2.12 (1H, m.), 1.90-1.86 (2H, m.), 1.59-1.50 (1H, m.), 1.42-1.24 (3H, m.), 0.88 (3H,
t, J = 7.0 Hz.);

13

C NMR (125 MHz, CDCl3) δ 176.5, 80.9, 58.0, 34.2, 29.7, 28.2, 25.3, 21.9, 13.8

ppm. IR (film) 2958, 2871, 1780 (s), 1459, 1419, 1355, 1176, 1052, 1018, 913, 795 cm-1. HRMS
(ESI) Calculated Mass for C9H16BrO2: ([M+H]+) = 235.0334, Found ([M+H]+) = 235.0332.

syn-5-(1-iodopentyl)dihydrofuran-2(3H)-one (II-14b-I):	
  

O
O
nBu

II-14b-I

I

Analytical data85 for syn-5-(1-iodopentyl)dihydrofuran-2(3H)-one (II-14b-I): colorless oil, 1H NMR
(500 MHz, CDCl3) δ 4.32 (1H, ddd, J = 3.0, 7.0, 10.5 Hz.), 4.12 (1H, dt, J = 4.5, 8.0 Hz.), 2.66
(1H, ddd, J = 4.5, 10.5, 15.5 Hz.), 2.53 (1H, ddd, J = 8.5, 10.5, 19.0 Hz.), 2.40 (1H, dddd, J = 4.5,

	
  

178	
  

7.5, 10.5, 13.0 Hz.), 2.11-2.03 (1H, m.), 1.88 (1H, ddd, J = 4.5, 10.0, 14.5 Hz.), 1.75 (1H, ddd, J =
4.5, 10.0, 14.0 Hz.), 1.58-1.50 (1H, m.), 1.39-1.23 (3H, m.), 0.89 (3H, t, J = 7.5 Hz.);

13

C NMR

(125 MHz, CDCl3) δ 176.4, 81.8, 39.1, 35.3, 31.7, 28.6, 26.8, 21.8, 13.8 ppm. IR (film) 2956,
2871, 1779 (s), 1459, 1348, 1181, 1050, 991, 912, 805 cm-1. HRMS (ESI) Calculated Mass for
C9H16IO2: ([M+H]+) = 283.0195, Found ([M+H]+) = 283.0199.
anti-5-chloro-6-phenyltetrahydro-2H-pyran-2-one (II-16a-Cl):86

O
O
Cl

Ph

II-16a-Cl

Analytical data86 for anti-5-chloro-6-phenyltetrahydro-2H-pyran-2-one (II-16a-Cl): white waxy solid,
1

H NMR (500 MHz, CDCl3) δ 7.41-7.34 (3H, m.), 7.31-7.30 (2H, m.), 5.46 (1H, d, J = 6.0

Hz.), 4.30 (1H, dt, J = 4.5, 6.0 Hz.), 2.94 (1H, ddd, J = 7.0, 8.5, 16.0 Hz.), 2.69 (1H, dt, J = 5.5,
12.0 Hz.), 2.36-2.29 (1H, m.), 2.23-2.16 (1H, m.), 2.16 (1H, dt, J = 6.5, 12.5 Hz.);

13

C NMR (125

MHz, CDCl3) δ 169.1, 137.0, 129.0, 128.8, 126.2, 85.2, 56.2, 27.2, 26.6 ppm.
anti-5-bromo-6-phenyltetrahydro-2H-pyran-2-one (II-16a-Br):61

O
O
Br

II-16a-Br

Ph

Analytical data61 for anti-5-bromo-6-phenyltetrahydro-2H-pyran-2-one (II-16a-Br): white solid, mp
= 101 ºC (lit.61 104-106 ºC), 1H NMR (500 MHz, CDCl3) δ 7.41-7.34 (3H, m.), 7.31-7.30 (2H, m.),

	
  

179	
  

5.46 (1H, d, J = 6.0 Hz.), 4.30 (1H, dt, J = 4.5, 6.0 Hz.), 2.94 (1H, ddd, J = 7.0, 8.5, 18.0 Hz.), 2.69
(1H, dt, J = 5.5, 18.0 Hz.), 2.36-2.29 (1H, m.), 2.23-2.16 (1H, m.), 2.16 (1H, ddd, J = 6.5, 12.5,
14.5 Hz.);

13

C NMR (125 MHz, CDCl3) δ 169.0, 137.2, 129.0, 128.8, 126.4, 85.5, 47.2, 28.3, 27.5

ppm.
anti-5-(1-bromopentyl)dihydrofuran-2(3H)-one (II-16b-Br):61,84

O
O
Ph
II-16b-Br

Br

Analytical data61,84 for anti-5-(1-bromopentyl)dihydrofuran-2(3H)-one (II-16b-Br): White solid, 1H
NMR (500 MHz, CDCl3) δ 7.44-7.40 (2H, m.), 7.36-7.29 (3H, m.), 5.00 (1H, d, J = 7.0 Hz.), 4.924.88 (1H, m.), 2.53-2.45 (3H, m.), 2.29-2.19 (1H, m.);

13

C NMR (125 MHz, CDCl3) δ 176.0, 137.0,

129.1, 128.8, 128.2, 81.6, 55.4, 28.6, 26.4 ppm.
anti-5-iodo-6-phenyltetrahydro-2H-pyran-2-one (II-16b-I):61

O
O
I

II-16a-I

Ph

Analytical data61 for anti-5-iodo-6-phenyltetrahydro-2H-pyran-2-one (II-16a-I): white solid,
decomposes above 70 ºC (lit.61 mp = 68-76 ºC), 1H NMR (500 MHz, CDCl3) δ 7.40-7.36 (3H, m.),
7.31-7.29 (2H, m.), 5.53 (1H, d, J = 8.0 Hz.), 4.40 (1H, dt, J = 5.0, 8.5 Hz.), 2.82 (1H, dt, J = 7.0,
18.0 Hz.), 2.69 (1H, dt, J = 7.0, 18.0 Hz.), 2.47-2.32 (2H, m.);
169.1, 137.6, 129.2, 128.7, 126.8, 87.1, 30.5, 24.3 ppm.

	
  

180	
  

13

C NMR (125 MHz, CDCl3) δ

anti-5-(1-iodopentyl)dihydrofuran-2(3H)-one (II-16b-I):

O
O
Ph
II-16b-I

I

Analytical data61,87 for anti-5-(1-iodopentyl)dihydrofuran-2(3H)-one (II-16b-I): White solid, 1H NMR
(500 MHz, CDCl3) δ 7.40-7.39 (2H, m.), 7.31-7.25 (3H, m.), 5.11 (1H, d, J = 8.0 Hz.), 4.89-4.85
(1H, m.), 2.64-2.48 (3H, m.), 2.17-2.09 (1H, m.);

13

C NMR (125 MHz, CDCl3) δ 176.1, 139.1,

128.9, 128.7, 128.2, 82.5, 34.3, 29.3, 28.9 ppm.

anti-5-chloro-6-ethyltetrahydro-2H-pyran-2-one (II-18a-Cl):	
  

O
O

II-18a-Cl

Cl

Analytical data for anti-5-chloro-6-ethyltetrahydro-2H-pyran-2-one (II-18a-Cl): Compound II-18a-Cl
could not be separated chromatographically from its regioisomer, II-18b-Cl. The assignments are
based on 2D NMR experiments and the reported analytical data for the corresponding
bromolactones.88,89 1H NMR (mixture of II-18a-Cl: II-18b-Cl = 1.0:1.6) assignments are only made
for protons from II-18a-Cl that were distinctly resolved (500 MHz, CDCl3) δ 4.26 (1H, dt, J = 4.0,
8.0 Hz.), 3.98 (1H, ddd, J = 5.0, 7.5 Hz.), 2.78 (1H, td, J = 7.0, 14.5 Hz.), 1.03 (3H, t, J = 7.5 Hz.);
13

C NMR (125 MHz, CDCl3) δ 169.8, 84.6, 54.0, 28.4, 27.9, 26.4, 9.0 ppm.

	
  

	
  

181	
  

anti-5-(1-chloropropyl)dihydrofuran-2(3H)-one (II-18b-Cl):	
  

O
O
II-18b-Cl

Cl

Analytical data for anti-5-(1-chloropropyl)dihydrofuran-2(3H)-one (II-18b-Cl): colorless oil, 1H NMR
(500 MHz, CDCl3) δ 4.51 (1H, dd, J = 7.0, 14.0 Hz.), 3.90 (1H, ddd, J = 3.5, 6.5, 10.0 Hz.), 2.622.48 (2H, m.), 2.40-2.33 (1H, m.), 2.20-2.12 (1H, m.), 1.93 (1H, dddd, J = 3.5, 7.0, 10.5, 14.5 Hz.),
1.67 (1H, septet, J = 7.5 Hz.), 1.06 (3H, t, J = 7.5 Hz.);

13

C NMR (125 MHz, CDCl3) δ 176.4, 81.0,

65.5, 28.2, 27.4, 24.4, 10.5 ppm. IR (film) 2971, 2937, 2886, 1783 (s), 1459, 1421, 1336, 1176
(s), 1120, 1023, 914, 800 cm-1. HRMS (ESI) Calculated Mass for C7H12ClO2: ([M+H]+) = 163.0526,
Found ([M+H]+) = 163.0525.

anti-5-bromo-6-ethyltetrahydro-2H-pyran-2-one (II-18a-Br):	
  

O
O

II-18a-Br

Br

Analytical data for anti-5-bromo-6-ethyltetrahydro-2H-pyran-2-one (II-18a-Br): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 4.37 (1H, dt, J = 3.5, 8.0 Hz.), 4.05 (1H, dt, J = 5.0, 8.0 Hz.), 2.76 (1H,
td, J = 7.0, 17.5 Hz.), 2.55 (1H, td, J = 7.0, 17.5 Hz.), 2.47-2.41 (1H, m.), 2.27 (1H, ddd, J = 7.5,
7.5, 14.5 Hz.), 1.96 (1H, dddd, J = 3.5, 7.5, 11.0, 15.0 Hz.), 1.75 (1H, septet, J = 7.5 Hz.), 1.03
(3H, t, J = 7.5 Hz.);

	
  

13

C NMR (125 MHz, CDCl3) δ 169.9, 84.8, 45.0, 29.3, 28.9, 26.8, 8.9 ppm. IR

182	
  

(film) 2971, 2893, 1741, 1461, 1336, 1176, 1021, 990, 914, 800 cm-1. HRMS (ESI) Calculated
Mass for C7H12BrO2: ([M+H]+) = 207.0020, Found ([M+H]+) = 207.0021.

anti-5-(1-bromopropyl)dihydrofuran-2(3H)-one (II-18b-Br):	
  

O
O
II-18b-Br

Br

Analytical data for anti-5-(1-bromopropyl)dihydrofuran-2(3H)-one (II-18b-Br): colorless oil, 1H NMR
(500 MHz, CDCl3) δ 4.54 (1H, dd, J = 7.0, 14.5 Hz.), 3.99 (1H, ddd, J = 3.5, 7.5, 9.0 Hz.), 2.662.49 (2H, m.), 2.49-2.42 (1H, m.), 2.19-2.11 (1H, m.), 2.06 (1H, dddd, J = 3.5, 7.5, 11.0, 14.5 Hz.),
1.86-1.77 (1H, m.), 1.08 (3H, t, J = 7.5 Hz.); 13C NMR (125 MHz, CDCl3) δ 176.3, 81.0, 59.4, 28.4,
27.8, 25.9, 11.5 ppm. IR (film) 2977, 2912, 2854, 1783 (s), 1449, 1411, 1330, 1174, 1110, 1023,
904, 804 cm-1. HRMS (ESI) Calculated Mass for C7H12BrO2: ([M+H]+) = 207.0020, Found ([M+H]+)
= 207.0024.

anti-5-iodo-6-ethyltetrahydro-2H-pyran-2-one (II-18a-I):	
  

O
O

II-18a-I

I

Analytical data for anti-5-chloro-6-ethyltetrahydro-2H-pyran-2-one (II-18a-I): Compound II-18a-I
could not be separated chromatographically from its regioisomer, II-18b-I. The assignments are
based on 2D NMR experiments and the reported analytical data for the corresponding
bromolactones.88,89 1H NMR (mixture of II-18a-I : II-18b-I = 1:5) assignments are only made for

	
  

183	
  

protons from II-18a-I that were distinctly resolved (500 MHz, CDCl3) δ 4.44 (1H, dddd, J = 3.0,
7.5, 9.0, 10.5 Hz.), 4.09 (1H, ddd, J = 5.0, 9.0, 14.0 Hz.), 2.40-2.32 (1H, m.), 0.99 (3H, t, J = 6.0
Hz.); 13C NMR (125 MHz, CDCl3) δ 169.9, 85.9, 31.9, 30.8, 27.7, 22.0, 8.7 ppm.

anti-5-(1-iodopropyl)dihydrofuran-2(3H)-one (II-18b-I):	
  

O
O

II-18b-I

I

Analytical data for anti-5-(1-iodopropyl)dihydrofuran-2(3H)-one (II-18b-I): colorless oil, 1H NMR
(500 MHz, CDCl3) δ 4.38 (1H, dd, J = 7.5, 14.5 Hz.), 4.04 (1H, ddd, J = 3.5, 9.0, 12.5 Hz.), 2.622.46 (3H, m.), 2.04-1.90 (2H, m.), 1.83-1.74 (1H, m.), 1.04 (3H, t, J = 7.0 Hz.);

13

C NMR (125

MHz, CDCl3) δ 176.3, 81.8, 41.4, 29.1, 28.9, 28.7, 13.6 ppm. IR (film) 2967, 2934, 2877, 1782 (s),
1457, 1419, 1325, 1179 (s), 1035, 912, 796 cm-1. HRMS (ESI) Calculated Mass for C7H12IO2:
([M+H]+) = 254.9882, Found ([M+H]+) = 254.9882.

	
  

184	
  

syn-5-chloro-6-phenyltetrahydro-2H-pyran-2-one (II-12b-Cl):

O
O
Cl

II-12a-Cl

Ph

Analytical data for syn-5-chloro-6-phenyltetrahydro-2H-pyran-2-one (II-12a-Cl): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 7.41-7.33 (5H, m.), 5.60 (1H, d, J = 2.0 Hz.), 4.48 (1H, dd, J = 3.5, 5.5
Hz.), 2.99 (1H, dddd, J = 8.0, 11.0, 18.5, 18.5 Hz.), 2.74 (1H, ddd, J = 2.5, 7.5, 18.5 Hz.), 2.52
(1H, dddd, J = 3.0, 7.0, 11.0, 14.5 Hz.), 2.42-2.36 (1H, m.);

13

C NMR (125 MHz, CDCl3) δ 168.9,

136.2, 128.6, 128.3, 125.9, 82.1, 57.5, 28.6, 25.2 ppm. IR (film) 3010, 2929, 1710, 1615, 1530,
1240, 1184, 1041, 835 cm-1. HRMS (ESI) Calculated Mass for C11H12ClO2: ([M+H]+) = 211.05258,
Found ([M+H]+) = 211.05254.

syn-5-bromo-6-phenyltetrahydro-2H-pyran-2-one (II-12a-Br):

O
O
Br

II-12a-Br

Ph

Analytical data61 for syn-5-chloro-6-phenyltetrahydro-2H-pyran-2-one (II-12a-Br): pale oil, 1H NMR
(500 MHz, CDCl3) δ 7.39-7.32 (5H, m.), 5.47 (1H, d, J = 1.5 Hz.), 4.56 (1H, dd, J = 3.0, 5.0 Hz.),
3.01 (1H, dddd, J = 8.0, 11.0, 18.5, 18.5 Hz.), 2.75 (1H, ddd, J = 2.0, 7.5, 18.5 Hz.), 2.60 (1H,
dddd, J = 3.5, 7.5, 11.0, 14.5 Hz.), 2.48-2.42 (1H, m.); 13C NMR (125 MHz, CDCl3) δ 168.8, 137.0,
128.5, 128.3, 125.6, 81.9, 51.0, 29.3, 26.3 ppm.

	
  

185	
  

anti-5-chloro-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20a-Cl):

O
O

O
II-20a-Cl
Cl

Analytical data for anti-5-chloro-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20a-Cl): white
solid, 1H NMR (500 MHz, CDCl3) δ 7.23 (2H, d, J = 9.0 Hz.), 6.90 (2H, d, J = 9.0 Hz.), 5.38 (1H, d,
J = 6.5 Hz.), 4.25 (1H, ddd, J = 4.5, 6.5, 11.0 Hz.), 3.80 (3H, s.), 2.92 (1H, td, J = 8.0, 18.0 Hz.),
2.67 (1H, td, J = 6.5, 18.5 Hz.), 2.39-2.32 (1H, m.), 2.16 (1H, ddd, J = 6.5, 13.5, 13.5 Hz.);

13

C

NMR (125 MHz, CDCl3) δ 169.3, 160.0, 129.0, 127.7, 114.1, 85.0, 56.3, 55.3, 27.4, 27.0 ppm. IR
(film) 3015, 2958, 2919, 2839, 1746, 1614, 1516, 1455, 1250, 1178, 1030, 835 cm-1. HRMS (ESI)
Calculated Mass for C12H14ClO3: ([M+H]+) = 241.0632, Found ([M+H]+) = 241.0635.

syn-5-chloro-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20b-Cl):

O
O

O

II-20b-Cl
Cl

Analytical data for syn-5-chloro-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20b-Cl): low
melting white solid, 1H NMR (500 MHz, CDCl3) δ 7.29 (2H, d, J = 8.5 Hz.), 6.91 (2H, d, J = 8.5
Hz.), 5.54 (1H, d, J = 2.0 Hz.), 4.43 (1H, m.), 3.80 (3H, s.), 2.98 (1H, dddd, J = 7.5, 10.5, 18.5,
18.5 Hz.), 2.72 (1H, ddd, J = 2.0, 7.5, 18.5 Hz.), 2.50 (1H, dddd, J = 3.5, 7.5, 11.0, 14.5 Hz.),
2.41-2.35 (1H, m.);

13

C NMR (125 MHz, CDCl3) δ 169.0, 159.7, 128.3, 127.3, 113.7, 81.9, 57.8,

55.3, 28.6, 25.2 ppm. IR (film) 3002, 2917, 2850, 1741, 1618, 1516, 1462, 1348, 1252, 1176,

	
  

186	
  

1109, 1059, 911, 731 cm-1. HRMS (ESI) Calculated Mass for C12H14ClO3: ([M+H]+) = 241.0632,
Found ([M+H]+) = 241.0631.

anti-5-bromo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20a-Br):

O
O

O

II-20a-Br
Br

Analytical data for anti-5-bromo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20a-Br): white
solid, 1H NMR (500 MHz, CDCl3) δ 7.23 (2H, d, J = 9.0 Hz.), 6.90 (2H, d, J = 9.0 Hz.), 5.46 (1H, d,
J = 7.0 Hz.), 4.32 (1H, ddd, J = 4.5, 7.0, 11.5 Hz.), 3.80 (3H, s.), 2.91 (1H, td, J = 7.5, 18.0 Hz.),
2.68 (1H, td, J = 6.5, 18.5 Hz.), 2.43 (1H, dddd, J = 4.5, 6.5, 8.0, 11.5 Hz.), 2.27 (1H, ddd, J = 6.5,
13.5, 13.5 Hz.);

13

C NMR (125 MHz, CDCl3) δ 169.2, 160.1, 129.3, 127.8, 114.1, 85.3, 55.3, 47.4,

28.6, 28.0 ppm.
Analytical data for II-20a-Br is in accord with the literature data,77 however the reported relative
stereochemistry (syn) does not match the

1

H coupling constants and NOE results. Our

assignment of the relative stereochemistry of II-20a-Br is based on NOE results and 1H coupling
constants and comparison of the spectral data to compounds II-20a-Cl, II-20b-Cl, II-20b-Br and II20a-I.90

	
  

187	
  

syn-5-bromo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20b-Br):

O
O

O

II-20b-Br

Br

Analytical data for syn-5-bromo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20b-Br):
colorless oil, 1H NMR (500 MHz, CDCl3) δ 7.27 (2H, d, J = 8.5 Hz.), 6.90 (2H, d, J = 8.5 Hz.), 5.41
(1H, br s.), 4.51 (1H, m.), 3.80 (3H, s.), 3.00 (1H, dddd, J = 8.0, 10.5, 18.5, 18.5 Hz.), 2.74 (1H,
ddd, J = 1.5, 7.5, 18.5 Hz.), 2.56 (1H, dddd, J = 3.0, 7.0, 10.5, 14.5 Hz.), 2.47-2.42 (1H, m.);

13

C

NMR (125 MHz, CDCl3) δ 168.9, 159.7, 129.2, 127.0, 113.6, 81.8, 55.3, 51.5, 29.2, 26.3 ppm. IR
(film) 3031, 2926, 2850, 1735, 1721, 1612, 1515, 1251, 1180, 1033, 919, 733 cm-1. HRMS (ESI)
Calculated Mass for C12H14BrO3: ([M+H]+) = 285.01263, Found ([M+H]+) = 285.01263.

syn-5-(bromo(4-methoxyphenyl)methyl)dihydrofuran-2(3H)-one (II-20c-Br):

O

O

O

Br
II-20c-Br

Analytical data for syn-5-(bromo(4-methoxyphenyl)methyl)dihydrofuran-2(3H)-one (II-20c-Br):
white solid, 1H NMR (500 MHz, CDCl3) δ 7.36 (2H, d, J = 9.0 Hz.), 6.85 (2H, d, J = 9.0 Hz.), 4.96
(1H, d, J = 5.5 Hz.). 4.90-4.85 (1H, m.), 3.79 (3H, s.), 2.52-2.35 (2H, m.), 2.22 (1H, dddd, J = 5.5,
7.5, 10.0, 13.5 Hz.), 2.03 (1H, dddd, J = 7.0, 8.5, 10.0, 13.5 Hz.);

13

C NMR (125 MHz, CDCl3) δ

176.0, 160.0, 129.7, 129.5, 114.2, 82.2, 55.3, 55.2, 28.3, 25.7 ppm. IR (film) 3001, 2905, 2848,

	
  

188	
  

1725, 1611, 1513, 1464, 1249, 1179, 1034, 909.6, 733 cm-1. HRMS (ESI) Calculated Mass for
C12H14BrO3: ([M+H]+) = 285.01263, Found ([M+H]+) = 285.01261.

anti-5-iodo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20a-I):

O
O

O

II-20a-I
I

Analytical

data90

for

anti-5-iodo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one

(II-20a-I):

colorless oil, 1H NMR (500 MHz, CDCl3) δ 7.23 (2H, d, J = 9.0 Hz.), 6.89 (2H, d, J = 9.0 Hz.), 5.47
(1H, d, J = 8.0 Hz.), 4.36 (1H, td, J = 5.0, 8.5 Hz.), 3.80 (3H, s.), 2.81 (1H, td, J = 6.5, 18.0 Hz.),
2.70 (1H, td, J = 7.0, 18.5 Hz.), 2.52-2.46 (1H, m.), 2.39 (1H, ddd, J = 8.0, 15.5, 15.5 Hz.);

13

C

NMR (125 MHz, CDCl3) δ 169.4, 160.1, 129.8, 128.2, 114.0, 86.9, 55.3, 31.0, 30.7, 24.8 ppm.

syn-5-iodo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20b-I):

O
O

O
II-20b-I

I

Analytical data for syn-5-iodo-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (II-20b-I): colorless
oil, 1H NMR (500 MHz, CDCl3) δ 7.23 (2H, d, J = 9.0 Hz.), 6.89 (2H, d, J = 9.0 Hz.), 4.80 (1H, d, J
= 2.0 Hz.), 4.60 (1H, dd, J = 3.0, 6.0 Hz.), 3.80 (3H, s.), 3.00 (1H, dddd, J = 8.5, 11.0, 19.0, 19.0
Hz.), 2.78 (1H, ddd, J = 2.0, 7.0, 19.0 Hz.), 2.54-2.41 (2H, m.);

	
  

189	
  

13

C NMR (125 MHz, CDCl3) δ

168.8, 159.6, 130.7, 126.5, 113.6, 82.1, 55.3, 33.5, 30.7, 28.3 ppm. IR (film) 3009, 2929, 2856,
1709, 1163, 1516, 1260, 1145, 1034, 990, 829 cm-1. HRMS (ESI) Calculated Mass for C12H14IO3:
([M+H]+) = 332.9988, Found ([M+H]+) = 332.998772.

syn-5-(iodo(4-methoxyphenyl)methyl)dihydrofuran-2(3H)-one (II-20c-I):

O

O

O

I
6'c- I

Compound II-20c-I could not be purified by known analytical methods. This iodolactone is
unstable at room temperature and decomposes rapidly upon work up of the reaction mixture. Its
identity was confirmed based on crude 1H NMR analysis. Distinctly resolved protons are as

1

Figure II-31. Crude H NMR spectrum for II-20c-I.

O

O

O Hb
I Ha

Ha	
  

	
  

Hb	
  

190	
  

follows: 1H NMR (500 MHz, CDCl3) δ 7.37 (2H, d, J = 9.0 Hz.), 6.82 (2H, d, J = 9.0 Hz.), 5.12 (1H,
d, J = 5.5 Hz.). 4.62 (1H, ddd, J = 5.5, 7.	
  0, 12.5 Hz.), 3.78 (3H, s.), 2.28 (1H, dddd, J = 5.5, 8.0,
10.0, 16.0 Hz.), 1.95 (1H, dddd, J = 7.0, 9.0, 12.5, 16.0 Hz.) ppm. Figure II-31 depicts the crude
1

H NMR spectrum for II-20c-I.	
  

5-methyl-5-phenylfuran-2(5H)-one (II-22a):

Ph
O

II-22a

O

Analytical data78,91 for 5-methyl-5-phenylfuran-2(5H)-one (II-22a): colorless oil, 1H NMR (500 MHz,
CDCl3) δ 7.62 (2H, d, J = 5.5 Hz.), 7.36-7.28 (5H, m.), 6.03 (1H, d, J = 5.5 Hz.), 1.81 (3H, s.);

13

C

NMR (125 MHz, CDCl3) δ 171.2, 159.2, 138.2, 127.8, 127.3, 123.7, 118.3, 88.0, 25.3 ppm.

4-chloro-5-methyl-5-phenyldihydrofuran-2(3H)-one (II-22b-Cl):

Cl

Ph
O
II-22b-Cl

O

Analytical data for 4-chloro-5-methyl-5-phenyldihydrofuran-2(3H)-one (II-22b-Cl): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 7.40-7.31 (5H, m.), 4.67 (1H, dd, J = 3.5, 6.5 Hz.), 2.94 (1H, dd, J = 6.5,
17.5 Hz.), 2.77 (1H, dd, J = 3.0, 17.5 Hz.), 1.81 (3H, s.);

13

C NMR (125 MHz, CDCl3) δ 172.8,

141.8, 129.0, 128.5, 124.1, 88.9, 62.2, 39.4, 25.5 ppm. IR (film) 3062, 3003, 2938, 1789, 1602,
1496, 1447, 1380, 1217, 1133, 1073, 956, 768 cm-1. HRMS (ESI) Calculated Mass for C11H12ClO2:
([M+H]+) = 211.0526, Found ([M+H]+) = 211.0525.

	
  

191	
  

The relative stereochemistry was established by NOE studies:

a. Irradiation at 4.67 ppm shows enhancement at 2.94 and 7.42 ppm.
b. Irradiation at 1.81 ppm shows enhancement at 2.77 and 7.42 ppm.
4-bromo-5-methyl-5-phenyldihydrofuran-2(3H)-one (II-22b-Br):

Br

Ph
O
II-22b-Br

O

Analytical data92 for 4-bromo-5-methyl-5-phenyldihydrofuran-2(3H)-one (II-22b-Br): colorless oil,
1

H NMR (500 MHz, CDCl3) δ 7.39-7.32 (5H, m.), 4.70 (1H, dd, J = 4.0, 7.0 Hz.), 3.09 (1H, dd, J =

7.0, 18.5 Hz.), 2.91 (1H, dd, J = 4.0, 18.5 Hz.), 1.86 (3H, s.);

13

C NMR (125 MHz, CDCl3) δ 173.0,

141.1, 129.0, 128.5, 124.1, 88.4, 52.5, 40.2, 27.6 ppm.

4-iodo-5-methyl-5-phenyldihydrofuran-2(3H)-one (II-22b-I):

I

Ph
O
II-22b-I

O

Analytical data78 for 4-iodo-5-methyl-5-phenyldihydrofuran-2(3H)-one (II-22b-I): colorless oil, 1H
NMR (500 MHz, CDCl3) δ 7.43-7.31 (5H, m.), 4.63 (1H, t, J = 6.5 Hz.), 3.18 (1H, dd, J = 7.5, 18.0
Hz.), 2.99 (1H, dd, J = 6.5, 18.5 Hz.), 1.91 (3H, s.);
128.9, 128.4, 124.3, 88.1, 42.1, 30.5, 27.7 ppm.

	
  

192	
  

13

C NMR (125 MHz, CDCl3) δ 173.5, 140.7,

4-(1-phenylvinyl)oxetan-2-one (II-22c):
Ph
O

II-22c

O

Analytical data for 4-(1-phenylvinyl)oxetan-2-one (II-22c): colorless oil, 1H NMR (500 MHz, CDCl3)
δ 7.40-7.31 (5H, m.), 5.61 (1H, br s.), 5.55 (1H, br s.), 5.35 (1H, dd, J = 4.5, 5.0 Hz.), 3.73 (1H,
dd, J = 6.0, 16.5 Hz.), 3.22 (1H, dd, J = 4.5, 16.5 Hz.); 13C NMR (125 MHz, CDCl3) δ 167.5, 144.0,
136.4, 128.8, 128.6, 126.0, 114.3, 70.1, 44.9 ppm. IR (film) 3059, 2928, 2853, 1831 (s), 1787,
1718, 1575, 1496, 1446, 1406, 1268, 1131, 947, 897, 712 cm-1. HRMS (ESI) Calculated Mass for
C11H11O2: ([M+H]+) = 175.0759, Found ([M+H]+) = 175.0764.

5-(chloromethyl)-5-(4-methoxyphenyl)dihydrofuran-2(3H)-one-4,4-d2 (II-2a-D2):

O
O

O

D
II-2a-D2

Cl

D

Analytical data for 5-(chloromethyl)-5-(4-methoxyphenyl)dihydrofuran-2(3H)-one-4,4-d2 (II-2a-D2):
colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.30 (2H, d, J = 8.5.), 6.90 (2H, d, J = 8.5.), 3.80 (3H,
s), 3.79 (1H, d, J = 12.0 Hz), 3.70 (1H, d, J = 12.0 Hz), 2.75 (1H, d, J = 18.0 Hz), 2.51 (1H, d, J =
18.0 Hz);

13

C NMR (125 MHz, CDCl3) δ 175.8, 159.7, 132.4, 126.2, 114.1, 86.9, 55.3, 52.1, 30.9

(quint, J = 19.5 Hz), 28.9 ppm. IR (film) 3004, 2959, 2839, 2558, 2423, 2249, 2073, 1893, 1783
(s), 1612, 1515 (s), 1463, 1254, 1180, 1034, 835 cm-1. HRMS (ESI) Calculated Mass for
C12H12D2ClO3: ([M+H]+) = 243.0757, Found ([M+H]+) = 243.0756.

	
  

193	
  

II.6. Quantum mechanical modeling studies.

Full optimizations for all conformations of the ‘halenium ion’ acceptors and the
corresponding ‘Lewis base-halenium ion’ complexes were performed using density functional
calculations at the B3LYP/6-31G*/SM8(CHCl3) level in the Spartan-10 software running on
Macintosh and Linux platforms. To confirm that each structure was a true minimum, vibrational
analyses were performed. The HalA (Cl) values were calculated using the energies obtained from
a full geometry optimization of the structures in simulated chloroform at B3LYP/6-31G*/SM8 level
of theory. Alternatively, when the gas phase energies of the same structures were corrected for
solvation in simulated chloroform using the SM8 model available in the Spartan code to run single
point (i.e. B3LYP/6-31G*/SM8) calculations, the resulting data led to the same conclusion. To
verify convergence and consistency of the optimizations, a number of examples were re-optimized
from multiple starting points; energetic variations of 0.02 kcal/mol or less were found among these
calculated structures. Relative enthalpies ΔH°rel were calculated for the gas phase structures by
including zero-point and thermal corrections to 298.15 K. All transition state structures were
validated as first-order stationary points (i.e. a single imaginary frequency) by vibrational analysis.
All values are in kcal/mol, eV or hartrees. Importantly, neither the vibration nor the solvation
corrections introduced differences between relative E° and relative H° values that were large
enough to reorder the relative energy structures; thus, either set of data led to the same
conclusions.

	
  

194	
  

REFERENCES

	
  

195	
  

REFERENCES

(1)

Patai, S. Frontmatter; John Wiley & Sons, Ltd., 2010.

(2)

Crudden, Cathleen M.; Edwards, D. Eur. J. Org. Chem. 2003, 2003, 4695.

(3)

Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis;
Springer: Berlin, New York, 1999.

(4)

Faul, M. M.; Evans, D. A. In Asymmetric Oxidation Reactions; Katsuki, T., Ed.; Oxford
University Press: London, 2001, p 115.

(5)

Ojima, I. Catalytic asymmetric synthesis; 2nd ed.; Wiley-VCH: New York, 2000.

(6)

Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247.

(7)

van Summeren, R. P.; Romaniuk, A.; Ijpeij, E. G.; Alsters, P. L. Catal. Sci. Technol. 2012,
2, 2052.

(8)

van Pee, K. H.; Unversucht, S. Chemosphere 2003, 52, 299.

(9)

Tan, C. K.; Zhou, L.; Yeung, Y. Y. Synlett 2011, 1335.

(10) Roberts, I.; Kimball, G. E. J. Am. Chem. Soc. 1937, 59, 947.
(11) Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763.
(12) J, C.; L, Z. Synthesis 2014, 46, 586.
(13) Hennecke, U. Chem. Asian. J. 2012, 7, 456.
(14) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem. Int. Ed. 2012, 51, 10938.
(15) De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003, 68, 4999.
(16) Chen, G.; Ma, S. Angew. Chem. Int. Ed. 2010, 49, 8306.
(17) Castellanos, A.; Fletcher, S. P. Chem. Eur. J. 2011, 17, 5766.
(18) Brunel, Y.; Rousseau, G. J. Org. Chem. 1996, 61, 5793.
(19) Yousefi, R.; Ashtekar, K. D.; Whitehead, D. C.; Jackson, J. E.; Borhan, B. J. Am. Chem.
Soc. 2013, 135, 14524.

	
  

196	
  

(20) Williams, D. L.; Bienvenu.E; Dubois, J. E. J. Chem. Soc. 1969, 517.
(21) Solling, T. I.; Radom, L. Int. J. Mass. Spectrom. 1999, 185, 263.
(22) Poutsma, M. L. J. Am. Chem. Soc. 1965, 87, 4285.
(23) Olah, G. A.; Westerma.Pw; Melby, E. G.; Mo, Y. K. J. Am. Chem. Soc. 1974, 96, 3565.
(24) Olah, G. A.; Peterson, P. E. J. Am. Chem. Soc. 1968, 90, 4675.
(25) Olah, G. A.; Bollinger, J. J. Am. Chem. Soc. 1967, 89, 4744.
(26) Olah, G. A.; Bollinge, J. M. J. Am. Chem. Soc. 1968, 90, 947.
(27) Olah, G. A.; Bollinge, J. M.; Brinich, J. J. Am. Chem. Soc. 1968, 90, 6988.
(28) Halogen Bonding: Fundamentals and Applications; Metrangolo, P.; Resnati, G., Eds.;
Springer-Verlag: Berlin, 2008.
(29) McManus, S. P.; Peterson, P. E. Tetrahedron Lett. 1975, 2753.
(30) Haubenstock, H.; Sauers, R. R. Tetrahedron 2005, 61, 8358.
(31) Haubenstock, H.; Sauers, R. R. Tetrahedron 2004, 60, 1191.
(32) Fahey, R. C.; Schubert, C. J. Am. Chem. Soc. 1965, 87, 5172.
(33) Fahey, R. C.; McPherso.Ca J. Am. Chem. Soc. 1969, 91, 3865.
(34) Fahey, R. C. J. Am. Chem. Soc. 1966, 88, 4681.
(35) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232.
(36) Bienvenu.E; Dubois, J. E.; Pearson, D. W.; Williams, D. L. J. Chem. Soc. 1970, 1275.
(37) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132,
3298.
(38) Blackmond, D. G. Angew. Chem. Int. Ed. 2005, 44, 4302.
(39) Poutsma, M. L. Science 1967, 157, 997.
(40) Tarbell, D. S.; Bartlett, P. D. J. Am. Chem. Soc. 1937, 59, 407.
(41) Bartlett, P. D.; Tarbell, D. S. J. Am. Chem. Soc. 1936, 58, 466.
(42) Bogle, X. S.; Singleton, D. A. J. Am. Chem. Soc. 2011, 133, 17172.

	
  

197	
  

(43) McManus, S. P.; Ware, D. W. Tetrahedron Lett. 1974, 4271.
(44) Ohta, B. K.; Hough, R. E.; Schubert, J. W. Org. Lett. 2007, 9, 2317.
(45) Cristol, S. J.; Stermitz, F. R.; Ramey, P. S. J. Am. Chem. Soc. 1956, 78, 4939.
(46) Rao, T. S.; Jukar, R. N.; Dangat, V. T. Curr. Sci. 1986, 55, 483.
(47) Ashtekar, K. D.; Marzijarani, N. S.; Jaganathan, A.; Holmes, D.; Jackson, J. E.; Borhan, B.
J. Am. Chem. Soc. 2014, 136, 13355.
(48) Struble, M. D.; Scerba, M. T.; Siegler, M.; Lectka, T. Science 2013, 340, 57.
(49) Wang, Y. M.; Wu, J.; Hoong, C.; Rauniyar, V.; Toste, F. D. J. Am. Chem. Soc. 2012, 134,
12928.
(50) Braddock, D. C.; Hermitage, S. A.; Kwok, L.; Pouwer, R.; Redmond, J. M.; White, A. J. P.
Chem. Commun. 2009, 1082.
(51) Bennet, A. J.; Brown, R. S.; McClung, R. E. D.; Klobukowski, M.; Aarts, G. H. M.;
Santarsiero, B. D.; Bellucci, G.; Bianchini, R. J. Am. Chem. Soc. 1991, 113, 8532.
(52) Neverov, A. A.; Brown, R. S. J. Org. Chem. 1996, 61, 962.
(53) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303.
(54) Klopman, G. J. Am. Chem. Soc. 1968, 90, 223.
(55) Tomoda, S. Chem. Rev. 1999, 99, 1243.
(56) Singleton, D. A.; Szymanski, M. J. J. Am. Chem. Soc. 1999, 121, 9455.
(57) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357.
(58) Akdag, A.; Worley, S. D.; Acevedo, O.; McKee, M. L. J. Chem. Theory Comput. 2007, 3,
2282.
(59) Mizar, P.; Burrelli, A.; Gunther, E.; Softje, M.; Farooq, U.; Wirth, T. Chem. Eur. J. 2014, 20,
13113.
(60) Grunwald, E. J. Am. Chem. Soc. 1951, 73, 5458.
(61) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20655.

	
  

198	
  

(62) The SciFinder® prediction displays a pKa of 4.65 for 1f using Advanced Chemistry
Development (ACD/Labs) Software V11.02 (© 1994-2014 ACD/Labs)
(63) Brown, A. R.; Uyeda, C.; Brotherton, C. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2013, 135,
6747.
(64) Jensen, K. H.; Pathak, T. P.; Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2009, 131,
17074.
(65) Blackman, M. L.; Royzen, M.; Fox, J. M. J. Am. Chem. Soc. 2008, 130, 13518.
(66) Marenich, A. V.; Olson, R. M.; Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. J. Chem. Theory
Comput. 2007, 3, 2011.
(67) Kuck, D.; Schneider, J.; Grutzmacher, H. F. J. Chem. Soc.-Perkin Trans. 2 1985, 689.
(68) Grossel, M. C.; Cheetham, A. K.; James, D.; Newsam, J. M. J. Chem. Soc.-Perkin Trans.
2 1980, 471.
(69) Braddock, D. C.; Cansell, G.; Hermitage, S. A. Chem. Commun. 2006, 2483.
(70) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042.
(71) Tan, C. K.; Zhou, L.; Yeung, Y. Y. Org. Lett. 2011, 13, 2738.
(72) Zheng, T.; Narayan, R. S.; Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2005, 127,
6946.
(73) Jefford, C. W.; Wang, Y. J. Chem. Soc.-Chem. Commun. 1987, 1513.
(74) Perkins, R. J.; Xu, H. C.; Campbell, J. M.; Moeller, K. D. Beilstein J. Org. Chem. 2013, 9,
1630.
(75) Less, S. L.; Handa, S.; Millburn, K.; Leadlay, P. F.; Dutton, C. J.; Staunton, J. Tetrahedron
Lett. 1996, 37, 3515.
(76) Odinokov, V. N.; Vakhidov, R. R.; Shakhmaev, R. N.; Zorin, V. V. Chemistry of Natural
Compounds 1996, 32, 912.
(77) Tan, C. K.; Le, C. C.; Yeung, Y. Y. Chem. Commun. 2012, 48, 5793.

	
  

199	
  

(78) Garnier, J. M.; Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2007, 3281.
(79) Song, S.; Zhu, S. F.; Yang, S.; Li, S.; Zhou, Q. L. Angew. Chem. Int. Ed. 2012, 51, 2708.
(80) Francisco, C. G.; Freire, R.; Hernandez, R.; Salazar, J. A.; Suarez, E.; Delamora, G. A. G.;
Noguez, J. A.; Acosta, A.; Jimeno, O. Steroids 1983, 41, 267.
(81) Nagase, R.; Matsumoto, N.; Hosomi, K.; Higashi, T.; Funakoshi, S.; Misaki, T.; Tanabe, Y.
Org. Biomol. Chem. 2007, 5, 151.
(82) Mahmoodi, N. O.; Jazayri, M. Synth. Commun. 2001, 31, 1467.
(83) Seyfried, M. S.; Lauber, B. S.; Luedtke, N. W. Org. Lett. 2010, 12, 104.
(84) Armstrong, A.; Braddock, D. C.; Jones, A. X.; Clark, S. Tetrahedron Lett. 2013, 54, 7004.
(85) Gurjar, M. K.; Purandare, A. V. Indian J. Chem. Sect B-Org. Chem. Incl. Med. Chem.
1988, 27, 554.
(86) Abe, H.; Fukazawa, N.; Kobayashi, T.; Ito, H. Tetrahedron 2013, 69, 2519.
(87) Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004,
69, 2874.
(88) Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. F. J. Am. Chem. Soc. 2012,
134, 11128.
(89) Snider, B. B.; Johnston, M. I. Tetrahedron Lett. 1985, 26, 5497.
(90) Fang, C.; Paull, D. H.; Hethcox, J. C.; Shugrue, C. R.; Martin, S. F. Org. Lett. 2012, 14,
6290.
(91) Meyers, A. I.; Spohn, R. F. J. Org. Chem. 1985, 50, 4872.
(92) Tan, C. K.; Er, J. C.; Yeung, Y. Y. Tetrahedron Lett. 2014, 55, 1243.

	
  

200