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dissertation entitled

DEVELOPMENT OF ALKALI METAL IN SILICA GEL (M-SG) AS A
REAGENT IN ORGANIC REACTIONS

presented by
PARTHA NANDI

has been accepted towards fulfillment
of the requirements for the

PhD degree in Chemistry

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5I08 K:IProj/Acc&Pres/ClRC/DateDue.indd

DEVELOPMENT OF ALKALI METAL IN SILICA GEL (M-SG) AS A REAGENT
IN ORGANIC REACTIONS

BY

Partha Nandi

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree

DOCTOR OF PHILOSOPHY
Chemistry
2009

ABSTRACT

DEVELOPMENT OF ALKALI METAL IN SILICA GEL (M-SG) AS A REAGENT
IN ORGANIC REACTIONS

By

Partha Nandi

This thesis dissertation describes development of alkali metal absorbed in
silica gel as reagents (M-SG reagents) for organic reactions. Importance and
background of alkali metal mediated reactions are described in Chapter 1. Alkali
metals in silica gel (M-SG) reagents are a class of material that is made by
absorbing the alkali metals or their alloys in the nanoporous silica (pore diameter
~ 190 A) by treatment of heat. The development, physical and chemical nature of
the reagent is described in Chapter 2. Chapter 3 describes the preparation and
analysis of the M—SG reagents.

Chapter 4 describes desulfonation (primarily focused on detosylation
reactions but demesylation was also shown feasible) reactions of amines using
Stage-l M-SG reagents. This methodology work with both primary and secondary
amines and with both alkyl and aryl substituents. More challenging detosylations
of protected aziridine and peraza[2.2.2] ligand that failed in many other traditional
deprotection methods were feasible under the current protocol.

Chapter 5 describes another class of cleavage reactions namely
deallylation and debenzylation reactions of amines using stage I M—SG reagents.
The deallylation reactions are feasible with both aliphatic and aromatic tertiary

allyl amines yielding secondary amines in moderate yields. This methodology is

extended to cleavages of tertiary benzyl and substituted benzyl groups such as
benzhydryl and trityl groups and cleavage reactions of O-benzyl groups.

Chapter 6 is focused on de-arylation reactions of triaryl and diaryl
phosphines. The diaryl phosphide solutions can be cleanly generated under the
reaction conditions and can be used for further reactions. Alternatively, in same
reaction pot it can be alkylated and subjected to further dearylation reaction
condition. This would yield dialkylated aryl phosphines. Monoaryl
dialkylphosphines were however resistant to dearylation reactions. The
usefulness of this procedure was demonstrated in the preparation of DIOP
Hgand.

Chapter 7 describes Birch reduction with stage I M-SG reagents. In
addition to substrate scope of the reaction, this work describes a reduction
method that is devoid of liquid ammonia and corresponding cooling or any other

additives.

dedicated to my parents and family

iv

ACKNOWLEDGEMENTS

I would like to thank Professor Jackson and Professor Dye for
being great mentors. Their acute breadth and depth of knowledge and
teaching helped a lot in carrying out the research described here. The
constant encouragements and helpful discussions helped to broaden my
horizons and motivated me to work harder in achieving my goals. The
openness to ask questions, propose solutions and the emphasis for critical
thinking were important attributes that made the work environment both
fun and challenging. I am grateful for the travel opportunities to attend
scientific meetings and symposia made available by funding from MSU,
ICMR and SiGNa Chemistry. These travels were enjoyable, excellent
learning opportunities and allowed me to make new friends and network
beyond MSU. I am thankful to both Prof. Dye and Prof. Jackson for
offering me the rare opportunity to train and work with a number of
motivated and hard working undergraduate and highschool students.

I was fortunate to have friends like Supriyo, Sampa and Amit as
classmates. We had a great time both in and outside academia. I am
thankful to Misha and Simona for being a great labmates. Their teaching
and discussions particularly in the early days of graduate school was
helpful. Co-workers Tulika and Karrie were impressive labmates.
Undergraduate coworkers Philip, Peter, Andrea, Mike, Bryan, Seth, Chris,

Frank, and Kunil were fun to work with and made the work environment

more enjoyable. High school students Sherry, Peyton and Tom were great
people to get to know and work with.

I would like to thank Dr. Daniel Holmes, Dr. Kermit Johnson and Dr.
Rui Huang for their valuable helps with NMRs and GC-MS. My committee
members — Prof. Baker, Wulff and McCusker were helpful with their
guidance. I thank Prof. Daniel Jones for his teaching of mass spectrometry
and helpful discussions.

Overall I am proud to be a part of MSU’s great community and
workplace. I will miss the great people and environment of MSU.

I am thankful to Michael Lefenfeld, Paul Vogt, Brian Bodnar and
Michael Costanzo and SiGNa Chemistry for the funding and helpful
discussions.

I owe a great deal to my previous chemistry mentors; Prof.
Namboothiri at the Indian Institute of Technology, Bombay and Prof. Rao
at the Visva-Bharati university, Santiniketan for their inspirations and
preparing me for the graduate school.

Finally, I am thankful to my parents and family for their continuous
support and encouragement without which all this Would have been

impossible.

vi

TABLE OF CONTENTS

List of Tables ....................................................................................................... ix
List of Figures ...................................................................................................... x
List of Abbreviations ............................................................................................ xi
List of Schemes ................................................................................................ xiii
1. Nature of alkali metal absorbed in porous silica gel (M-SG) reagents ..... 1
2.1 Background ............................................................................................... 1
2.2 M-SG reagents .......................................................................................... 3
2.3 References ................................................................................................ 15
2. Chemistry of sodium, potassium and their alloys ................................ 17
2.1 Background ................................................................................ 17
2.2 Reduction of carbon-carbon multiple bonds, carbonyls, imines, amides &
Esters ....................................................................................... 20
2.3 Cleavage of carbon-carbon, carbon—heteroatom, S-N, N-N bonds .......... 24
2.4 Catalytic reaction ...................................................................................... 34
2.5 Applications in organometallic and inorganic syntheses ........................... 35
2.6 Initiation of polymerization ......................................................................... 37
2.7 Future scope and conclusions .................................................................. 39
2.8 References ........ . ........................................................................................ 41

3. Alkali-metals in silica gel (M-SG): A new reagent for desulfonation of

amines ........................................................................................................... 51
3.1 Background ............................................................................................... 51
3.2 Results and discussions ............................................................................ 54
3.3 Conclusions .............................................................................................. 60
3.4 Experimental section ................................................................................. 61
3.5 References ................................................................................................ 65
4. Preparation of diphenyl phosphide and substituted phosphines using
alkali metal in silica gel (M-SG) ........................................................................ 69
4.1. Background .............................................................................................. 69
4.2 Results and discussion ............................................................................. 71
4.3 Conclusion ................................................................................................ 78
4.4 Experimental ............................................................................................. 79
4.5 References ................................................................................................ 84

vii

5. Reductive amine deallyl — and debenzylation with alkali metal in silica gel

(M-SG) reagents ................................................................................................ 90
5.1 Background ............................................................................................... 90
5.2 Results and discussion ............................................................................. 91
5.3 Conclusion .................................................................................. 98
5.4 Experimental section ....................................................................... 99
5.5 References ................................................................................ 101

6. Birch reduction at room temperature with alkali metals In silica gel

(NazK-SG(I)) reagent .......................................................................... 104
6. 1 Background .............................................................................. 104
6.2 Results and discussions .............................................................. 106
6.3 Conclusions .............................................................................. 111
6.4 Experimental section .................................................................. 112
6.5 References ............................................................................... 1 15

8. Appendix: Preparation, assay and handling of M-SG reagents ............ 118
A1 Preparation .............................................................................. 118
A2 Assays .................................................................................... 122
A3 Passivation with dry oxygen ......................................................... 127

viii

Table 1.1
Table 3.1

Table 4.1

Table 5.1
Table 5.2
Table 6.1

LIST OF TABLES

Various stages of alkali metal in silica gel ....................................... 5
Evaluation of substrate scope ........................................................ 56

Preparation of monosubstituted diarylphosphines from

triarylphosphine ............................................................................. 74
Deallylation of tertiary amines ........................................................ 93
Other amine deprotections ................................................... 95
Birch reduction using NazK-SG(I) ......................................... 106

ix

Figure 1.1

Figure 1.2

Figure 1.3

Figure A.1

Figure A.2

LIST OF FIGURES

Images in dissertations are presented in color

Morphology of silica gel ................................................................. 4

Effect of pore size on the relative amplitude of signals from' Na(0) to
Na(+) at 10% (wt/wt) loading of sodium in silica gel ...................... 7

Effect of metal loading (wt/wt)% on the relative amplitude of signals
from Na-SG(I) made from silica gel of 150 A pore size ................. 8

D80 showing melting endotherm of Na-SG(I) 20% (w/w) with time
at 150 °C ........................................................................ 124

080 of a NazK-SG (l) sample before and after taming ............. 127

1806
Boc
BuOH
Cbz
CD
DBB
DIOP
DME
DMF
DSC
EDA
EtOH
Et20
EXAFS
Fmoc
GC/MS
HMDS
i-PrOH

LDA

LIST OF ABBREVIATIONS

1 8-Crown-6

tert-butyloxycarbonyl

butanol

carbobenzyloxy

circular dichroism

Di-tertbutylbiphenyl
[2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)dioxolane]
1 ,2-dimethoxyethane
N,N-dimethylformamide

differential scanning calorimetry
Ethylenediamine

Ethanol

Diethylether

Extended X-ray absorption fine spectra
9-fluorenylmethyloxycarbonyl

Gas Chromotography/Mass Spectrometry
Hexamethyldisilazane

isopropanol

lithium diisopropylamide

xi

PDF
THF
MAS-NMR
M-SG
MeOH
Ms
PCBs
SET
SG
RT
EtOAc
XPS
Ts

XRD

Pair distribution function

tetrahydrofuran

Magic angle spinning nuclear magnetic resonance spectroscopy

alkali metal in silica gel

Methanol

methanesulfonyl or mesyl
polychlorinated biphenyls

single electron transfer reaction
silica gel

room temperature

ethyl acetate

X-ray photoelectron spectroscopy
paratoluenesulfonyl

X-ray diffraction

xii

CHAPTER 1

NATURE OF ALKALI METAL ABSORBED IN POROUS SILICA
GEL (M-SG) REAGENTS

1.1 BACKGROUND

Theoretical studies of adsorption of metal atoms (Cu, Pd and Cs) on

regular and defect sites of Si02 surfaces indicate that the bridging oxygens,

Si—O—Si of silica are unreactive.1 The weak dispersion interaction between
metal and these sites is the dominant factor. The weakness of this interaction
indicates that given a chance, the metals could aggregate and form local
clusters. The adsorbed metals in the Si—O—Si framework were found to be
neutral in all cases (Pd, Cu) except for Cs. The reactivity of lithium metal with
silica is very different than that with sodium due to the unusually high ionic

potential of the cation.2

Contrary to the theoretical predictions the weakening of glass in the
presence of alkali metal and alkali metal derived bases has been known for a
long time.3 The glass-alkali metal interaction, however, is still not fully
understood. Powdered glass turns black upon absorbing sodium vapor,4 but
then recovers its clarity between 200-500 °C under high vacuum?“6 The

discoloring and the photoemission spectra of sodium on oxidized Si(113)

surface indicates ionization of the sodium at room-temperature to form Na+

—O—Si.7 Theoretical calculations to determine the vibrational properties of

closely related species such as amorphous SiOz and Na28i409 have been

performed. One important finding of this study is that the bond polarizability of
O-Si is a strong function of near neighboring silicon bridging via oxygen,

degree of polymerization of silica, and presence of sodium.8

Stereochemical ordering around sodium in amorphous silica has been
investigated via XPS and EXAFS methods in ultra high vacuum conditions.9
Mazzara and coworkers9 inferred that alkali metal ions occupy the available
sites in the silica network, which reduces the stress without bringing in
additional constraints. The EXAFS studies indicated that once inserted in the
silica, the sodium atoms are surrounded with a first shell of oxygen atoms,

mostly from Si—O—Si bridges.

1.2 M—SG REAGENTS:

In 2005 alkali metals absorbed in porous silica gel were reported.10
The porous silica gel (average pore diameter of 150 A, Davisil 646 from
Grace) used for these preparations has a large void volume (z 1 cm3/g). The
grain size is of the order of 0.2-0.5 mm, making these materials easily
handled granular substances. It is to be noted that a grain is an aggregate of
much smaller particles (see Figure 1.1 below). These powders have a high
internal surface area compared to the external surface area. The internal
pores are large enough to hold metal nanocrystals that individually contain
some 60,000 metal atoms. This silica gel consists of 10-20 nm size particles,
interconnected by filament oxide strands to form channels and pores in the

same size range.

MAI
' |

\
H O @9 I
\ 5 W _ ._,O
Nao+ 06:30}; / ___.Na 0 3'. \7~”+1/2H2
(f; O\Sia0 f\O\Si'Ogsz
\O’ \O/‘LLL O ‘0/

Scheme 1.1: Reaction of residual Si-OH groups with alkali metal

Addition of alkali metal can remove any residual Si—OH groups (also
referred to as defect sites) via the above reaction to evolve H2 (Scheme 1.1).

Prior to adding alkali metal, the above commercial silica gel is initially heated
at 200-300 °C to remove absorbed water and then heated at 600 °C to

remove some of the surface Si—OH groups (Scheme 1.2).

 

“7.
o )1
I. O
9’ "‘04 s'i I,
O- o 0’ (‘0’
H +3 6000 I 0_§+H20
H~ O‘Si-O
9 .145 x...
P',Si~o I
mo \ “W”
‘ 3

Scheme 1.2: Dehydration from adjacent Si-OH groups

When this reaction occurs, the amount of H2 formed by a subsequent
reaction with water is less than that expected from the amount of alkali metal
used in the preparation. For example, if we prepare 40 wt % NazK-SG we

might, because of this reaction, obtain hydrogen equivalent to only 38 wt%

metal. This would tell us that about 2% of the metal had been used to reduce
surface groups and produce M+. On a molar basis for this example, about

5% of the Si atoms would carry OH groups after calcination.

It has not been possible to determine which particular defect sites are

responsible for sticking or the first hand attachment of metal.

 

Figure 1.1: Morphology of silica gel (reproduced with permission from Grace
Davisil web site)

The loading of the metals such as Na or alloys of Na-K could be as
high as 35-40 % w/w. Table 1.1 summarizes different versions or “stages” of
M-SG reagents. M-SG (0) refers to shiny black solid where the metal alloy is
slowly added to silica gel at ambient temperature. M-SG (I) refers to annealed
version of M-SG (0) (e.g., for alloys of Na-K in SG), where the shiny
appearance of M-SG (0) is lost and transformed into a less air reactive solid.

Samples of M-SG (I) were found to be almost non reactive on slow exposure

to dry air or dry 02.

Table 1.1. Various Stages of Alkali Metal in Silica Gel

 

 

 

 

 

 

 

 

 

 

Designation Temperature of Comments
Preparation

Stage 0 Room Applicable only to
Temperature to 40 liquid metals and
°C. alloys

such as Na—K
alloys.

Stage I 120—150 °C for Produces hydrogen
6—10 h Na-K with EtOH. (Note:
alloys, 165 °c for Some Stage IIA is
10 h for Na-SG. always formed as

well .

Stage "A Some is formed No H2 formed with
when Stage I is EtOH, but reacts
prepared at 100- with H20
165 0' completely. May

have formed
M+—O‘—Si species.

Stage ”3 Temperature kept Probably contains
below 300 °C for Si-Si bonds but still
24 h. has Na°.

Stage "0 Heated to 400 °C Reaction has
for 24 h. removed Na° and

produced elemental
Si but not NaSi.
Does not produce
Hz with EtOH.

Stage "0 Na—SG heated to Na has reacted with
400-450 °C for 24 Si to produce NaSi.
h and has at least Produces Hz with
40% Na EtOH.

 

 

The DSC of the material after annealing at 120-160 °C (stage I M-
SG) did not show the same endotherm as the precursor metal or its alloy.
Instead, it showed a broad melting endotherm. The DSC also showed an

exotherm after 90-120° C corresponding to 400-700 J/g (depending on

metal and percent loading). MAS 23Na NMR revealed that the Na is
partially ionized in the Na-SG (I). The extent of the ionization was found to
be a function of the percent of Na loaded, the average pore size and the
temperature.11 Noticeable peak broadening in the MAS 23Na NMR was
observed. In contrast a sharp peak of Na° is seen with Na absorbed in y-
alumina. This broadening of the peak could be ascribed to a variety of
environments of Na in the pores of silica gel; e.g., the metallic nature of
Na on the surface of silica might be different from that inside the metallic
cluster deep inside the pore. The peak broadening was also seen in a
mesoporous Na-SG sample, suggesting that the broadening is not due to
the distribution of pore sizes alone. Heating of the Na-SG sample in the
sealed quartz MAS NMR tube showed an increase in Na” over Na°,
signifying an increase in the ionization of the metal (this experiment was
performed by Prof. James L. Dye). This increment in ionization with
temperature was not observed with Na in alumina. In what way the porous
silica gel support assisted in the ionization of the metal or caused the

broadening of Na peaks remained a mystery. Figure 1.2 and Figure 1.3
shows MAS 23Na NMR spectra, where the Na+ signals appear at 0 ppm,
whereas the Na° appears at ~1100 ppm. The shift of Na° signals at a
more downfield region compared to Na+ can be explained by the Knight

shift.12 Knight shift is due to the conduction electrons of sodium. The shift

comes mainly from two sources — (1) Pauli paramagnetic spin

 

 

1.6 — |

    

Average Pore Slze

 

 

1.4 d
150 A

— 60A

1.2 a
30 A

 

 

 

 

 

 

 

1300 1200 1100 1M m 0
Chemical Shift (ppm) J

Figure 1.2. Effect of silica gel pore size on the relative amplitudes of
the signals from Na° and Na+ at 10% (wt/wt) loading of Na in silica gel.

The curves are diplaced vertically for clarity.

 

   
     
  

 

 

‘5 " Lllll_etal Loading
_ 40%
— 30%
—" 20%

1.0 - _ 10%

 

 

 

 

 

 

I
T I I T I T I T T
11m 1200 1100 1!!” 100 0 41!] -200

 

Chemical Shift (ppm)

 

 

 

Figure 1.3. Effect of metal loading (% wt/wt) on the relative amplitudes
of the signals from Na0 and Na+ in Na-SG(I) made from silica of ~150 A
pore size. The curves are diplaced vertically for clarity.

The fate of the electron post-ionization is unclear. Possibilities to be

considered are - (i) delocalization of the electron into a band of Si02, (ii)
Partial breakage of Si-O—Si bonds in silica to form Si-O'Na+ and Na+Si', (iii)

expanding the coordination number of Si and subsequent formation of a

valence electron silyl anion (iv) ionization of metal to form M+ and M' can be
considered. Powder XRD analysis of 25 wt % and 40 wt % Na—SG (l) yielded
metallic peaks of Na° that are identical in line width was independent of

loading. The Scherrer equation13 gives a relation between the line width and

particle size. In this equation, t = 0.9l/BCosOB, t is thickness, B is full width at

half maxima, l is a lattice dimension and 03 is the angle of diffraction. This

equation yields the same crystallite sizes of about 100 A for both loadings.
This surprising result indicates that the metal is not uniformly distributed
among the pores, but rather tends to form full and empty pores. In other
words, surface energy effects tend to cause small metal particles to

agglomerate into larger ones.

Pair distribution function (PDF) studies indicated the presence of

crystalline sodium nanoparticles with coherence lengths up to 40 A. The PDF

of NazK-SG-I showed similar order, but had the simple bcc structure of Na

rather than the known hexagonal structure of NazK. Although in both cases,
large thermal factors indicated significant disorder, the metal ‘particles were
not liquid, in spite of the fact that NazK was above its melting temperature.
Together with the previously described changes in the melting endotherm for
Stage I NazK-SG, this provides additional evidence for the formation of Na-

rich particles in the pores, perhaps by preferential ionization of potassium.

The PDF of Stage "0 Na-SG is dominated by the crystal structure of

NaZSiO3. The addition of the known structure of Na4Si4 improved the data fit

10

 

 

considerably. So we concluded that the stoichiometric overall reaction that

occurs when Na-SG is heated at 450 °C is the production of Stage lID.
5Na + 3Si02—+ 2NaZSi03 + NaSi

Stage I M-SG was surprisingly non-reactive in air. This is in sharp
contrast to other dispersed forms of alkali metals such as sodium sand or
sodium in alumina gel. What protects the stage I M-SG from ready oxidation
in air is not yet clear. Na-K alloy in contrast undergoes oxidation in air to
make superoxides and peroxides that can subsequently lead to violent

reactions.14 Potentially, the relatively small entry channels that lead into the
pores can get partially oxidized and block subsequent passage of 02 deeper
into the pore. The fate of absorbed 02 in M-SG (I) is unknown. The MAS 23Na
NMR spectra of Na-SG that was exposed to dry air and freshly made Na-SG

(not exposed to 02) were identical with no significant differences in the Na+

peak. Interestingly, the DSC of stage I M-SG exposed to dry 02 showed an

additional exotherm just above the melting temperature of Na that was absent
in freshly prepared stage I M-SG. Due to the high ratio of the area of internal

surfaces relative to the outside surface of the particles, the majority of M° can
remain un-oxidized. Thus, this material can liberate H2 in near quantitative

amounts on reaction with water.

The usefulness of M-SG(I) was shown in flow syntheses,

desulfurization reactions, Wurtz coupling and Birch reductions. This type of

11

M-SG reagent offers a new alternative to conventional methods of alkali metal
delivery for reduction, such as solutions in liquid ammonia, dispersions in oil,
liquid alloys of Na-K, K intercalated in graphite (CaK), Na-Hg, sonication in
organic solvents, refluxing in xylene, or using lumps of metal with electron
transfer agents such as naphthalene or di-tert-butyl-biphenyl (DBB). Synthetic
methodologies were developed by using M-SG materials, including (i)
desulfonation of amines,15 (ii) reductive cleavage of aryl C-P bonds in
phosphines16 (iii) reductive deallylation, debenzylation, debenzhydrylation and
detritylation17 (iv) BouveauIt-Blanc reaction for ester reduction18 (v) C—X
cleavage reactions such as Wurtz coupling, reduction of chlorofluorocarbons

and polychlorinated biphenyls (vi) Birch reduction.19

M-SG (I) reagents were found to react with water rapidly to give off H2.
However, a lower reactivity was found with all alcohols (e.g., t—BuOH, i-PrOH,
n-BuOH, EtOH, MeOH). Only up to 70-90% of the expected amount of H2

was liberated on reaction with lVl-SG (I) and EtOH in 2 h and the yield did not

improve to any significant extent with longer time. Studies were performed to

examine the effect of temperature and time on the extent of H2 evolution from
EtOH and M-SG (I). With Na2K-SG (0) and K2Na-SG (0), the reaction with
EtOH yields more than 90% of the expected amount of H2 and the remainder
was liberated on reaction of the alcohol-reacted product with water. With
increasing temperature of annealing the yield of H2 from EtOH decreased and

that from water increased. The portion of the M-SG (I) that did not react with

12

alcohol but reacted with water to evolve hydrogen was termed stage IIA M-
SG. The presence of stage IIA in stage I M-SG can partially explain why

excess M-SG (l) is often required for organic reactions with this material.

Stage "A M-SG has not been fully characterized. The isolation of pure
stage IIA from mixtures has not been possible. The 23Na NMR of Na-SG (I)
that had been reacted and washed with EtOH showed only a Na+ peak. Stage

“A M—SG could be viewed as originating from breakage of Si—O—Si bonds in
strained rings leading to the formation of Si—O’Na+ and Na+Si". The silyl

anion at this point is still connected to three oxygens and may be inert in the
reaction with alcohols. Alternatively, Si—Si bonds may already have formed.
Attempts to monitor the nature of Si during the course of reaction via solid
state 29Si NMR were unsuccessful due to the long relaxation time and

quadrupolar nature of the Si nucleus.

To summarize, the reaction between alkali metal and silica gel is
believed to be complex and consists of a multitude of different processes.
Physical characterizations such as solid state NMR, DSC, powder XRD,
Raman spectroscopy and PDF studies revealed some important aspects of
this reaction, such as the ionization of the metal in the pores, net enthalpy of

the reaction, differential melting behavior of metals in the pores, and the
nature of M0 and M+ during the course of the reaction. However, the fate of

the electron after ionization of the metal remained elusive. The nature of

stages IIA, IIB, MC and IID is still largely speculative. How discrete these

13

stages are in terms of uniformity and identity of their chemical constituents
needs to be answered. To understand M-SG materials better, studies on the
metal-silica interactions by varying pore sizes, surface areas and modes of

thermal treatment are necessary.

14

1.3 REFERENCES:

 

10.

11.

12.
13.

14.

15.

16.

17.

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Maschhoff, B. L.; Zavadil, K. R.; Armstrong, N. R. App]. Surface Sci,
1986, 27, 285.

Burns, J. A. Glass Technol., 1965, 6, 17.

Samuneva, B.; Djambaski, P.; Avramova, K. J. Non-cryst. Solids, 1989,
112, 385.

Lau, J.; McMillan, P. W. J. Mater. Sci., 1982, 17, 2715.
Lau, J.; McMillan, P. W. J. Mater. Sci, 1984, 19, 881.

Hwang, C. C.; An, K.; Park, R.; Kim, J.; Lee, J.; Park, C.; Kimura, A.;
Kakizaki, A. J. Vac. Sci. Technol. A, 1998, 16, 1073.

Zotov, N.; Ebbsjo, l.; Timpel, D.; Keppler, H. Phys. Rev. B, 1999, 60,
6383.

Mazzara, C.; Jupille, J.; Flank, A. M.; Lagarde, P. J. Phys. Chem. B, 2000,
104, 3438.

Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson, J. E.;
Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338.

Shatnawi, M.; Paglia, G.; Dye, J. L.; Cram, K. C.; Lefenfeld, M.; Billinge, S.
J. L. J. Am. Chem. Soc. 2007, 129, 1386.

Knight, w. D. Phys. Rev. 1950, 77, 852.

HP. Klug & L.E. Alexander, X-Ray Diffraction Procedures, 2"d Ed., John
Wiley & Sons Inc., 1974, p 687-703.

Desreumaux, J.; Calais, M.; Adriano, R.; Trambaud, S.; Kappenstein, C.;
Nguefack, M. Eur. J. Inorg. Chem. 2000, 2031.

Nandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.; Lefenfeld, M.; Vogt, P.
F.; Jackson, J. E. Org. Lett., 2009, 10, 5441.

Nandi, P.; Dye, J. L.; Bentley, P.; Jackson, J. E. Org. Lett., 2009, 11,
1689.

Nandi, P.; Dye, J. L.; Jackson, J. E. Tetrahedron Lett., 2009, 50, 3864.

15

 

18. Bodnar, B. S.; Vogt, P. F. J. Org. Chem. 2009, 74, 2598.
19. Nandi, P.; Dye, J. L.; Jackson, J. E. J. Org. Chem. 2009, 74, 5790.

16

W

CHEMISTRY OF SODIUM, POTASSIUM AND THEIR
ALLOYS

2.1 BACKGROUND

Alkali metals are known for their high reduction potentials and the
resulting high chemical reactivities. The history of alkali-metal mediated
reactions dates back to 1807 when Sir Humphrey Davy first isolated sodium in
its elemental form by the electrolysis of NaOH.1 Since then a variety of
reactions have been developed that use alkali metal in some form or other.
This review discusses two members of this family; namely sodium and
potassium, together with their alloys.2 Numerous powerful reducing systems3
have been developed from these metals, so the main focus here will be on
reductions, reductive cleavages and the formation of superbases, highlighting
advances made in recent years in controlling and exploring their chemical
reactivity, handling and modes of delivery.

Historically, alkali metal dispersions such as sodium sand in oil and
alkali metals dissolved in liquid ammonia have been widely used in organic
reductions.4 Both of these most common routes have limitations.5 Metal-
ammonia mediated reactions require the use of low temperature conditions
and are therefore energy intensive. The use of a large excesses of ammonia

or the introduction of finely dispersed reactive solid alkali metals are

17

particularly challenging for industrial scale processes.6 Sodium dispersions in
hydrocarbon oil require extra process steps to remove the hydrocarbons either
before or after reaction. The relatively milder alkali metal mercury amalgams
have been widely useful but the toxicity of mercury limits their use in large
scale reactions especially those of pharmaceutical interest. Use of alloys is

not intrinsically safer; indeed, the liquid alloy of sodium and potassium is

pyrophoric and dangerous to handle, as it can readily form explosive K02.7

More recently developed delivery systems include alkali metal “tamed” by
intercalation in graphite or by dispersion in NaCl, polyethylene, alumina, and
silica. These systems will be discussed below.

An interesting feature of alkali metals, extensively studied in our
laboratories, is that except for lithium, they can exist not only in +1 and
elemental (0) oxidation states but also as anionsa'9 (M') under suitable
conditions. Typically crown ether or cryptand complexation of the cations
enables formation of these metal anion species, known as alkalides.‘°'11
These powerful reducing agents readily effect two-electron reductions.”
Although the solvated electron had been long recognized in ammonia and
amine solutions,13 work at MSU has also led to isolation of the solid
electn'des, 1‘ crystalline salts in which the electrons behave as anions and are
separated from the metal counter-cations by crown ethers and cryptands.
Applications of alkalides and electrides'5 as reagents in synthesis remain

nearly unexplored because their preparation requires scrupulously dry

solvents and sublimed complex ligands. In addition, except for two recent

18

examples (themselves challenging synthesis targets), solid alkalides and
electrides are unstable at room temperature,16 decomposing by electron
attachment and C-0 cleavage of the complexant’s vicinal ether linkages.
Replacement of the ether oxygens in cryptand[2.2.2] by tertiary amines
enabled the recently reported formation of the first room-temperature stable
alkalides17 and electride.18

A parallel, contemporary approach to address shelf-life and other
problems of alkalide-electride research led to the development of inorganic
electrides.19 Alkali metal dispersed in alumina-silicate zeolite cages were
considered similar to electrides and some even contained alkali metal
anions.20 All-silica zeolites were found to be suitable for the preparation of
inorganic electrides.21 In 2005 the adsorption of alkali metals (Na, K and their
alloys) into silica gel was reported.22 A number of interesting physical and
chemical aspects of these new reagents/materials have been studied.23 The
physical and chemical reactivity studies indicate that most of the alkali metals
in the pores of silica gel remain in the elemental form. The reducing power of
the encapsulated metals can be harnessed in a variety of reactions. What
makes these new reagents useful compared with most other forms of alkali

metal dispersions are their non-reactivity with dry air. Sodium and its alloys
with potassium in silica gel (Na-SG and Na2K-SG in particular) can be “tamed”
by slow treatment with dry 02 in such a way that it does not undergo further

oxidation in dry air. Even after such “taming”, the material can still fully react

with water or alcohol to evolve hydrogen.24

19

This tutorial review highlights the recent advances in reactions that use
sodium, potassium and their alloys and also showcases the differences in
intrinsic reactivities and selectivities based on various delivery modes of the
metals to the substrates. While the development of new reactions based on
transition metal catalysts (e.g., for hydrogenation reactions, debenzylations)
and on electrochemical reductions provide alternatives to alkali metal
reactions, the benign nature of the products of alkali metal based reagents,

their relatively low cost and high reactivity are advantageous.

2.2 REDUCTION OF CARBON-CARBON MULTIPLE BONDS, CARBONYLS,
IMINES, AMIDES, AND ESTERS:
Reductions are the most important reactions of elemental alkali metals.

25—27

Conventionally, Na or K in ammonia (the so-called “dissolving metal

conditions”, Scheme 1a) serve as powerful reducing agents for aromatics”29

30,31 2 33,34

(Birch reduction), carbonyls, internal alkynes,3 allenes and imines,
enamino ketones,35 conjugated ketones and amides. Unlike metal-ammonia
solutions, Na-K alloy in THF in the presence of 18-Crown-6 (which forms K”
and Na') reduces an internal alkyne directly to the alkane (Scheme 1b), and
reduces toluene to a mixture of 1- and 3-methyl cyclohexenes, thus
demonstrating the different reducing behavior of alkalides compared with
elemental metals.”37 Inclusion of t-BuOH as an in situ proton source
facilitates reduction but requires an excess of reducing agent.38 With ketones,
alkalide solutions in aprotic solvents afford primarily a mixture of enolate and
alcoholate.39 Sodium and isopropanol under refluxing conditions reduce or,oc-

20

disubstituted terminal amides to a-amino alcohol40 and 1,3-diimines“1 to y-
diamines. Peptide bonds in proteins have been subjected to sodium-ammonia
reduction, reduction of aromatic substituents of or-substituents (e.g., Phenyl
ring of phenylalanine) and cleavage of the amide bonds (e.g., with proline
amides) were the predominant outcomes of this studies.42 Reduction of
aliphatic nitrile to imine is reported with sodium in pentane.43 Under aprotic
conditions, the bimolecular reduction of ketones with Na in the presence of a
catalytic amount of bromobenzene is known to give pinacol or glycols."""‘46

In recent years, alkali metals dispersed into a variety of supports have
become important. For instance, CgK has been successfully used to reduce
the double bond of conjugated acids, carbonyls,38 and imines (Scheme 1d, 1e,
1f). Sodium on alumina is used to reduce ketones, esters and oximes.47 We
have recently reported an ammonia free, room temperature Birch reduction of
polyaromatic compounds that are readily capable of forming radical anions. In
most of these reactions, the carbanion salt of the alkali metal is formed Which
is subsequently quenched by water (Scheme 19).48

The Bouveault-Blanc reduction49 refers to the reduction of an ester with
sodium and alcohol (typically ethanol). Sodium serves as a single electron
donor reagent and alcohol serves as a proton source. With bulk sodium this
reaction gives a mixture of desired alcohol product along with the acyloin
condensation product (usually in high yield if the amount of proton source is

not adequate).50 Sodium and potassium dispersions on polyethylene, sodium

chloride, glass and TiO2 were reported to be effective reagents for acyloin

21

condensation.51 Recently sodium in silica gel was reported as an effective
alternative to conventional LiAIH4-mediated ester reduction (Scheme 1h).52 It

is interesting to note here that Barret, Barton and coworkers observed that the
reduction pathway of esters with alkalide solutions in the presence of t-BuNH2

leads to the formation of an alkane and a carboxylate anion instead of alcohol

or acyloin products.”54

22

COOH COOH
1. Na/NH3, EtOH A
2. H30+

 

(28)

85%

NaK (2.5 mmol)/ t-BuOH
A WC4H9 (32)
18C6 (27 mol%), 0 °C, 2 h

76% (cis : trans = 1:3)

0 0002” NaK (9 mmol)/ t-BuOH $00021) (36)
18C6 (cat)

86%

\ 1. C8K(5 equiv)
HMDS, THF, 10 mins (46)

2. H20 85%

0
0H 1.C K 6e uiv
55°C, THF, 1 h

2. H20 86%

f N\ 1. CBK(5 equiv) _ N
O \O THF, 30 mins 0 \O (46)
2. H20

83%

cc coo
2. H20

97%

 

f

 

 

O.
O EZO

 

%

 

 

(O

 

 

(3025t K-polyethylene

h C00 E, 5 CE ‘5”

2

89%OH

O
. \ OMe 1. M-SG, MeOH, 0 °C \ OH
| I _R > I _R (52)

/ 2. H20 /

Scheme 2.1: Representative examples of reductions with alkali metals. Numbers
in parentheses are corresponding references.

23

2.3 CLEAVAGE OF CARBON-CARBON, CARBON—HETERO ATOM (N, P, O,
S, HALOGENS) BONDS, S—N, N—N BONDS:

Reductive cleavage reactions with alkali metals are well known.
Typically molecules with low lying LUMOs can readily accept electrons from
Na, K or Na-K alloys. The liquid-liquid reaction with Na-K alloys or Na-Hg are
preferred for this purposes rather than Na or K metal alone. Metal dispersions
in hydrocarbon oil, dissolved metal reaction conditions and Na with an
electron transporter such as naphthalene, ethylenediamine (EDA) are used for

conducting the cleavage reactions.

2.3.1 Cleavage of C—C bonds:
Reductive removal of cyanides can be achieved (Scheme 1.2 a) with

03K.55 K/Al2O3 has been used to reductively cleave alkyl cyanides in good

yield.56 1-benzyl naphthalene is reductively cleaved with Na-K alloy in
presence of glyme to afford naphthalene and toluene (Scheme 1.2 b)
regioselectively.57 Similarly, Na-K alloy in the presence of HMPA in THF is
known to cleave (Scheme 1.2 d) 1,2-dinaphthylethane.58 Potassium in 1,2-
dimethoxyethane (DME) is known to cleave diarylfluorenes.59 Bibenzyl is
cleaved at the benzylic position with Cs-K-Na alloy (Scheme 1.2 e).60 Similar
cleavage reactions are observed for bibenzyl, diphenyl methane and related
substrates with Na-K—glyme-triglyme combinations.‘51 Na-K alloy has been
used to carry out Grob-type fragmentation reactions of 2-halo-adamantanone

systems.62 C-C cleavage reactions are known for strained ring and fused ring

24

compounds?”6 Rabinovitz recently observed a unique sequential reductive
dimerization followed by reductive cleavage in indenocorannulene."37 In all of
the examples below, a low lying n' LUMO seemed necessary in order for the

cleavage reaction to occur.

 

a. a K/Al203 (5 equiv; (1 (53)
O O/WVCN 0W

 

 

hexane, 1 h 0
Ph 90%
b. 1. Na- K alloy, 54)
glyme-triglyme, 0°C:
2. ROH
NaK, 0°C __ 54
c. PhZCHz glyme mg'yme PhCH3 + PhCHZQ ( )
43% 33%

 

OCH2M
(56)
d 0 0O THF/HMPA

- H
e. PhCHZCH2-< (12:2227 PhCHZCOOl-l O+>JCOO (57)
38% 33%
—75°c, 2 h

f0) NaK-ether Faié (59)

86%

 

 

Scheme 2.2: Examples of reductive C—C cleavage with alkali metals

25

2.3.2 Cleavage of C—N bonds:

Reductive amine debenzylations, debenzhydrylations and detritylations
are known under dissolving metal reaction conditions.‘5‘3'69 Recently, we
reported amine debenzylation and deallylation reactions (Scheme 2.3) with M-
SG reagents (Na-SG and Na2K-SG).70 These reactions were found to be
versatile, effectively deprotecting both aromatic and aliphatic amines. For
secondary allyl amines the under the M-SG reaction conditions, isomerization
of the allyl group was observed that led to a mixture of enamines and imines

and the desired allyl cleavage was not observed.

CN '___,
‘E 2. H20 N“ (70)

1. M- SG
2 H20 0 0
Scheme 2.3: Examples of C—N cleavage

2.3.3 Cleavage of C—P bonds:

Aryl C—P cleavage with alkali metal ammonia solutions,71 sodium
dispersion in oil,”73 ultrasonically dispersed potassium74 and sodium
naphthalide solutions75 have been reported in the literature. Metal-ammonia
solutions can lead to over-reduction (of aromatic rings) in addition to aryl C-P
cleavage. In other cases, the diarylphosphide solution is subsequently reacted
with suitable electrophiles to form diphenyl phosphines”77 Compared to Li,

26

Na/K-mediated cleavage of triaryl phosphines is advantageous because the
other product of the reaction, the arylmetal salt is consumed by protonation
with the solvent for Na and K, while for Li the PhLi has to be quenched in a
separate step using t-BuCl at -10°C.78 Recently we have reported (Scheme

2.4) a room temperature cleavage reaction of triarylphosphine with alkali
metal in silica gel reagents (Na2K-SG and Na-SG). We found that adding

ethylenediamine in these reactions causes significant rate acceleration. We
have extended this methodology to provide a second aryl-phosphorous
cleavage (after a 1St electrophilic quenching step) in the same pot using

additional equivalents of M-SG reagent.79

AT\P,AI' 1. M_SG:AT\P,AI' 1 . M-SGAAr\P/E.

I I (79)
Ar 2. E-X E 2. E-X E

 

 

Scheme 2.4: Cleavage of arylphosphines

2.3.4 Cleavage of C—0 bonds:

Cleavage of ethereal C—O bonds under dissolving metal reaction
conditions is well precedented in the literature.80 Allyl and benzyl ethers“82
are cleaved with alkali metal dispersions in THF. Cleavage of C—OBn with Na-
Hg is used for making long chain conjugated polyolefins (Scheme 2.5 a).83 A

similar reaction was observed with Na-K alloy.84 Methoxy aryl ethers can be

27

cleaved at alkyl-oxygen or aryl-oxygen bonds to obtain phenols or arenes
respectively.‘35'86 Remarkable differences were observed in the rates of
cleavage of dimethoxy substituted benzenes.87 Recently aryl-methoxy
cleavage was coupled with activation of the benzylic position and the products
were subsequently alkylated.88 The outcomes of these reactions were heavily
influenced by choice of alkali metal and were reasoned due to differential ion-
pairing between the alkali metal cations and the aromatic radical anions. Note
that the decomposition of alkalide and electrides themselves do represent
cleavage but they are mostly reactive because of being vicinal.17 Phthalans
(Scheme 2.5 b) have been reductively cleaved with Li, Na, K and Na—K alloy in

aprotic solvents.89

 

R __ _ R Na/H __
a 1 ; 2 g > R1m R2 (83)
082 082 ores 95% OTBS

 

96)
G) (9
cat. NpH CH2 M

M = Li, Na, Na-K, K

Scheme 2.5: Examples of C—0 cleavage

2.3.5 Cleavage of C—S bonds:

Alkali metal mediated C—S bond cleavage90 is of importance in

destroying diarylsulfides contaminants in fuels. Desulfonation of alkyl

28

sulfonate esters is reported with CsK67 (Scheme 2.6a, 2.6b), sodium-
amalgams”95 (Scheme 2.6c, 2.6d, 2.6e) potassium96 (Scheme 2.6f) and
sodium naphthalide.97 Cleavage of the sulfinyl group at the final step of Julia
olefination is reported with sodium-amalgam.98 Dithianes are reductively
cleaved with sodium-ammonia in good yield.99 Na-K alloys have proven to be
more effective than Na or K metals in removing sulfur impurities from

benzene.100 M-SG reagents can also desulfurize diaryl sulfides26 (Scheme

 

 

 

 

 

2.69).
O 1.CgK (4 equiv), THF 0”
a Ph802\/U\/\/OH 2. H20 A M0... (67)
so Ph 77%
2 1. CgK(Large excess)
D W = W
ether, 1 h (67)
2. H20 77% (Z:E 35:65)
C TS Na-Hg, MeOI—L
(93)
90% OH
(1:? Na/Hg,0°C, 1h M94. M}
(94)
40% 54%
R0 B
9 Na- -,Hg MeOH EDD
(95)
SOZP“ B = u, 47%
B=T, 50%
f \ K))1- rt R (K
C32 3. MeOH 2 2 (98)
54% 28%

HQ (3 O—O

Scheme 2.6: Examples of C—S Cleavage
29

2.3.6 Cleavage of C—X (halogen) bond:

The cleavage of C—X (X = F, Cl, Br, I) bonds is widely used for
generation of carbanions to form metal alkyl salts, reductive coupling
reactions101 (e.g., the Wurtz reaction), generation of carbenes and subsequent
reactions,102 preparation of polycarbynes103 (Scheme 2.7a),

5 and polymethylcyclosilanes.106 The

polyphenylcarbyne,104 polysilynes,10
mechanism of Wurtz coupling reactions has been debated with radical and

SN2 pathways being considered.‘°7'108 Reductive coupling reactions are also

109,110 111-113

applied in preparation of strained rings and in total syntheses.

Dehalodeuteration has been accomplished with Na-Hg and D20114 (Scheme
2.7b). Similar deuterium incorporation on haloaromatic substrates is achieved
with Na-Hg in Mach115 (Scheme 2.7c). Alkali metals have become important
in a number of environmental remediation processes such as dehalogenation
of PCBs and chlorofluorocarbons.116 Although C—F bonds are kinetically more
resistent to reductive cleavage than C—Cl, C—Br and C—l bonds, with alkalide

solutions they react rapidly,“7v118

30

. Rear—mama «04)

 

CI THF
R=Me,Ph
”I“ Na/Hg,D2O_ 01H (115)
H C02H H CO2H
68%
DMD—K DHD (“D

Me OD 99%

Scheme 2.7: Examples of C—X cleavage

2.3.7 Cleavage of S—N bonds:

119—121 122-

Metal ammonia solutions and sodium naphthalide ‘25 have
been used to cleave‘zs'127 the tosyl group of para-toluenesulfonamides.
Sodium amalgams have been used to carry out similar reactions (Scheme 2.8
a).128 Alkalide solutions cleave sulfonamide and sulfonate esters.129 Recently

we have developed a method to do these deprotections (Scheme 2.8 b, c)
with M-SG reagents (using Na-SG and Na2K-SG).130 At room temperature

stirring the reactions with M-SG reagent, (except for the tosyl aziridine)
followed by a water quench afford deprotected amines in good yields. This
method was applicable to deprotection of primary amines and cleavage of

other related sulfonamides (i.e., mesyl and benzene sulfonamides).

31

R
1 R2 R3 R1 R2

 
 

 

 

 

a 0 0R4 Na/Hg $0 S3 (130)
N48: MeOH/THF 4
pTol NH2
55-91%
Cy. 1. Na2K-SG(I), rt
b c ,N7TS 2 H o *Cy2NH (132)
y ' 2 81%
Ts , H
( )
LK/Ph 2. H2O L\\/Ph
51%

Scheme 2.8: Examples of S—N cleavage

2.3.8 Cleavage of N—N bonds:

Reductive N—N bond cleavage under dissolving metal conditions is

observed in cases where a low lying rt acceptor orbital is in close proximity.131

This cleavage reaction provides access to useful chiral amine ligands.132 In
some cases trans annular N-N bond cleavage can lead to formation of a large
ring.133 Cleavage of N—N bonds with Na-Hg in azide leads to formation of
amines.134 We have found tandem N—N bond cleavage and reduction of
benzophenone hydrazone to afford benzhydryl amine.71 In the case of allyl

benzotriazole we observed N—N cleavage with M-SG reagent leading to

aniline.71

32

O N 0
Gui!) Na/NH3 5 (135)
a N l:
N
o o H
\ Na-H \
MeOH

 

 

86%
N,NH2 NHZ
l 1.M-SG g .J‘ (71)
C
O O 2.H20 O 0
70%

Scheme 2.9: Examples of N—N cleavage

2.3.9 Other Cleavages:

Studies of Na-naphthalide mediated reductive cleavage reactions of
aryl phosphates found a preference for C—O cleavage in the inverse addition

mode (i.e., [arenide] > [substrate]). During normal addition of Na-naphthalide,

‘35 preferential P—O cleavage was

([arylphosphate substrate] > [arenide])
observed in THF. Reaction of Ph2P—PPh2 with sodium generates
diphenylphosphide salts.136 Likewise, C—Sb bonds were found to be cleaved

with sodium in ammonia.137 Trialkylgallium (R3Ga) compounds can be reduced

with alkali metals in benzene to afford RgGaPh‘ and R3GaH".138 Subvalent

33

silicon species generated from the cleavage reaction of
dichIorobis(diethylamino)silane and related compounds undergo spontaneous
unusual aromatic C-H insertion reaction with benzene and biphenyl to afford

aryl-substituted aminosilanes.139

2.4 Catalytic Reactions:

There are many industrial processes that are based on the presence of
catalytic amounts of Na and Na-K alloy. Na supported on alumina is used for
isomerization of 5-vinyl norbornene (VNB) to 5-ethylidene norbornene
(ENB).“‘°"“1 This reaction can be carried out in a fluidized bed in quantitative
yield.142 Sodium and potassium based superbases are also known to be
effective for this (Scheme 2.10a) transformation.“3"“ A similar superbase
derived from potassium is used for isomerization of 1-hexene.‘45 Side chain
alkylation of alkyl benzene (e.g., Scheme 2.10b) is accomplished by NaK alloy
in THF or by superbases derived from Na or K.“6'15° Heterogeneous bases
derived from Na, K and Cs in zeolite are known to be effective for alkylation of

toluene to ethylbenzene with methanol.151

34

 

a M Na In COIIOIdaI Al203> M (141’ 142)

NaK
b O +N——" (147,150)
/

Scheme 2.10 : Examples of catalytic reactions using alkali metals

2.5 Applications in Organometallics and Inorganic Syntheses:

Organosilicon and organo-mercury compounds have been made
(Scheme 2.11a, 2.11b) using alkalI metals.152 Recently this strategy was
employed in the stereoselective synthesis of disubstituted piperidine.‘53
Unusual organo-cobalt compounds have been made by using Na-Hg.154 Na-
Hg has found applications in the preparation of metal imido complexes
(Scheme 2.11d) of Fe155 and M0156"57 A metallacyclopentadiene (Scheme
2.11e) based on Ti was made by reductively coupling dialkylacetylene and

Ti(OAr)2CI2.158 N-based tetrameric aluminum(l) compound was made using

Na-K alloy as reducing agent.159
An organoplatinum metallacycle was prepared by reductive coupling of

dibromoolefin in presence of Pt(PPh3)4 and Na-Hg.‘6° Tetra-tert-

butylboratetetrahedrane was made from the reduction of Me3CBF2 by Na-K

alloy.161 Sodium-potassium alloys as well as alkalide solutions in THF or Me2O

35

have been found to be kinetically and theromodynamically effective in
reducing a variety of metal salts into metal nanoparticles (with particle sizes
as low as 3-15 nm).162 Low valent titanium reagents are made from the
reduction of TiCl3 with Na-arenide, Na-Hg and Na-K alloy.163 Aromatic radical
anions generated with alkali metals have been extensively used by Reike in
preparing metal nanoparticles.164 Reduction of As with Na-K alloy followed by
a quench with Me3SiCl yields trimethylsilylarsine.165 A water soluble poly-
hydroxylated derivative of C60 were made by vigorous stirring of C60 and Na-K
alloy in presence of oxygen.166 Anionic boron compounds such as
dimesitylphenylborane dianion167 have been made with Na-K alloy as reducing

agent

36

 

N /H \SIASI/
a 2:3'ASi/ a 9 /Hg .9\ (153)
' ' —4NaCl \ ._ '
Cl C /SIVS\
b Na/Hg
Me SiCI——-—> Hg(SiMe )
3 —4NaCl 3 2
F30 I Hg(SiEt3)2 F30 _ HgSiMeg —Me3S£ F3C>=C=<F (153)
F30 CF3 —Me3Sil F30 CF3 -H9 F3C F

 

 

 

 

 

C
N2, Na-Hg I I (156)
V \/Fe\/N
N2 N2
(9
N e ,aNa
Kl Ii
N -H /T HF
l a 9 N (157)
d M llill
o..,, / 0...,
Ar(R)N’ \ "N(R)Ar Ar(R)N \ "N(R)Ar
N(R)Ar N(R)Ar
Et Et
9 Ara. .CI Na-Hg A'OA A (159)
,Ti + 2EtCCEt s .0
AFC ’ ‘0 /
CI ATO Et
Et
f .(. 3' Na/Hg lPt’PPh3 (161)
G Br 7 \PPh3
Pt(PPh3)4

Scheme 2.11: Examples of alkali metal mediated reactions in organometallic

and inorganic synthesis

37

2.6 Initiation of Polymerization:

Use of alkali metals for the anionic polymerization of 1,3 butadiene has
been known for a long time.168 Solutions of alkalides and electrides in THF
were first used for anionic polymerization by Boileau, Kaempf, Lehn and
Schue.169 Jedlinkski et al. have reported ring opening of B-lactone rings
(Scheme 2.12a, 2.125) with K anion generated from K and 18-Crown-6.17° The
generated radical anion accepts another electron from K to form a carbanion
which is subsequently quenched with suitable electrophiles or used in a block
copolymerization reaction. Similar strategies with the potasside ions yielded
dianion of propylene oxide and dianion of styrene which were subsequently
used for coploymerization reactions to afford styrene-ester block
copolymers.""172 In addition, an unusual methyl methacrylate carbanion was

generated using sodide via a 2 e transfer process.173

38

 

 

 

 

O
A 47 {OM condition for A:
n excess CH3OK/18C6 (171)

 

 

o
a l .".’A
8
_ +
b / K 1806(K) .
A CH
0

O
B A condition for B: Low temperature,
0 nCH3OK/1806, tartarate ester additive

o recombination with K0 +

 

 

 

2—CH—o- K+ + K e K ’CHz—CH—o- K+
Protonation
(solvent)
1. n (07 v
l 2. H+ _ ,
OCHZCH OH A c K (172)
H n H

polymerization

Scheme 2.12: Examples of alkali metal mediated polymerization reaction

2.7 Future Scope and Conclusions:

With the rapid depletion of non-renewable petroleum based chemical
inventory, discovery of new pathways that transform biomass into chemical
feed-stocks are gaining increased significance. Reduction reactions may hold
the key to these transformations as most of the biomass can be viewed as
oxidized forms of hydrocarbons. Even 150 years after their discovery, they still
remain some of the most powerful reductants in syntheses. New discoveries
made in the last 50 years are mostly centered on new delivery modes of
reactive alkali metals, the discovery of new reactions and the discovery of
alkali metal anions. The chemistry of these latter highly reactive species is still

largely unexplored. So far attempts to observe solvent-induced CD for alkalide

39

solutions in enantiopure crown ethers have been unsuccessful suggesting
weak interactions between anions and the crown complexants.174 Chiral
induction in reactions of alkalides and electrides therefore remains a
challenge.

For a long time the relatively high cost of crown ethers and cryptands
and short shelf-life of alkalides and electrides in solutions were prohibitive to
industrial developments in the field. However, with the discovery of new room
temperature stable inorganic electrides, mapping out their chemical reactivity
may become an attractive direction.175

Alkali metals absorbed in silica gel have also been shown to be
effective reagents for carrying out a variety of reactions. There are chemical
details such as the fate of the electrons derived from the ionization of the
metal on the surface that also need to be addressed. The possibility of “fine-
tuning" the reduction potentials of encapsulated alkali metals in porous
support depending upon the solvent used (solvent-M-SG surface) and surface
interactions (e.g., ionizations and unusual bonding of metal to the
heterogeneous support) are intriguing.

In addition to being powerful reducing agents, alkali metals such as Na,
K are also useful in making powerful superbases for both homogeneous and
heterogeneous reactions. The ability to control basicity, size and shapes of
the heterogeneous superbases offer unique opportunities for development of
new and efficient chemical processes.

In summary, in this section, we have showcased the major

40

 

developments in the chemistry of alkali metals in our group and elsewhere in
last more than 50 years of research. The focus of this discussion was alkali
metals in their zero-valent and anionic forms and modes of delivery of the

reducing power in reactions.

41

 

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51

CHAPTER 3

ALKALI-METALS IN SILICA GEL (M-SG): A NEW
REAGENT FOR DESULFONATION OF AMINES

3.1 BACKGROUND

In organic synthesis, many protecting groups have been developed
for the amine functionality.‘ In pharmaceutical chemistry, amine protections
are often accomplished with groups such as Cbz (carbobenzyloxy), Boc (t-
butoxycarbonyl) and Fmoc (9-fluorenylmethyloxycarbonyl).2 But for some
uses these protecting groups are too labile. Sulfonamides, formed by
reaction of amines with sulfonyl chlorides, are more robust, and have the
advantage of being easy to isolate and purify by recrystallization. But
practical desulfonation of sulfonamides, p-toluenesulfonamides specifically,
can be difficult. This problem has arisen in our own ongoing work on
functionalized polyamine cages for assembly of organic alkalides and
electrides.3

Existing methods for sulfonamide deprotection can be broadly

t’4-10

grouped as: (a) strong acid treatmen (b) cleavage by strong

11-14 15-15

bases/nucleophiles, (c) microwave irradiation, (d) photoreduction‘7'

19”” and (f) metal-

‘8 with various reagents, (e) electrochemical reduction,
based reductive cleavage?"39 Acidic deprotections of tosylated amines use

severe conditions such as sto.,_“'5 48% HI3r,6 AcOH-HCIO4,7 HBr with

51

PhOH,8 and HF-pyridine with anisole.9 Of recent interest is a “green” phase
transfer catalyzed cleavage by NaOH and KOH that deprotects tosylated
aromatic and heteroaromatic amines.14 But for secondary amine
detosylation, many of these procedures are too harsh and/or reagent—
intensive, or lack generality due to limited substrate scope, functional group
intolerance, or demanding separations on workup. Super-electron-donor
(SED) reagent bisimidazolylidene reagent in presence of refluxing DMF is
shown to be capable of desulfonating activated secondary amines.40
However, with unactivated aliphatic toluene sulfonamides this reaction fails.

The last and most general group, metal-based reductions, use
powerful reagents such as sodium naphthalenide,“36 Ni(acac)2 with
Grignard reagent,23 Li-NH330 or Na-NH3,31'32 Al-Hg25 and Na-Hg,26 Red-
Al,29 Na-isopropanol,21 Mg-MeOH,36 low valent titanium reagents,26
mischmetal with TiCI4,27 Sml2 with Bu;,SnH24 and Sml2 with pyrrolidine in

water.41 Although they generally produce the desired amines in good
yield, these approaches can be difficult to scale42 up and suffer from
issues such as: a) reagent instability, b) moisture sensitivity, c) reagent
pyrophoricity, d) difficult removal of reagent by-products, e) the need for
cryogenic reaction temperatures, f) reagent toxicity, 9) waste handling
and h) high cost. There remains a need for a simple general
desulfonation which harnesses the reductive power of alkali metals

without the associated safety and economic issues.

52

Recently, solid alkali metal-based reductions in organic solvents
became easier with the finding that these metals can be made
significantly less pyrophoric by thermal absorption into nano-structured
silica to form the metal-silica gel (M-SG) reagents.“3“5 Herein, we report

a novel method to cleave toluenesulfonamides to amines by using M-
SG.46 Specifically, we have used M-SG (Stage I) where M is Na or Na2K.

The overall general transformation is analogous to sulfonamide cleavage
by alkali metal arenides and is thought to proceed via two single-electron
transfers with subsequent cleavage to form the alkali metal amide and
sulfinate salt (Scheme 3.1).4749 As described below, treatment with M-

SG is a mild and general procedure to desulfonate protected amines.

R1 R1
\ M-SG \ e e
N-H-Ar —> NQM69 + Ar802 M
2’ ” THF 2’
R O
1 1
R\ R\ e e
/N9M®+ HA —> /N—H + M A
R2 R2

Scheme 3.1: M-SG-mediated desulfonation of protected secondary
amines (Ar = p-tolyl)

53

3.2 RESULTS AND DISCUSSION

Various sulfonamide substrates were investigated to explore the

scope of M-SG desulfonations (Table 3.1). The reactions were conducted
in ethereal solvents, typically in THF with 2.5-5 equivalents of Na2K-SG(I)
at room temperature over 8 hours and subsequently quenched with water,
except where noted.50 Detosylation with Na2K-SG (I) tolerates phenyl

(entries 1, 2, 4, 9, 11) and ether moieties and is successful for both
primary (entry 9) and secondary amines (entries 1- 8, 11). The reaction’s

success with the bulky aza-cryptand (entry 8) where both HBr/AcOH and
Na-NH3 methods failed promises to be useful in our ongoing synthetic

studies of azacryptands directed to preparation of alkalides and
electrides.3 Perhaps most interesting, however, is the (modified) reaction’s
success in detosylating aziridine, a special class of secondary amine (vide

infra).

Modifications and Extensions:

For reactions in 1,2-dimethoxyethane (entries 7 and 9), the addition
of a catalytic amount (20 mol% relative to the sulfonamide starting
material) of ethylenediamine (EDA) accelerates N-S bond cleavage,
bringing reactions to completion in 3-4 hours instead of the 8-10 hours
seen without EDA.

The mesyl moiety is cleanly cleaved from 4-benzylpiperidine, a

simple secondary amine (entry 10), suggesting that the tosyl group’s aryl

54

ring is not critical to the electron capture and reductive cleavage process.
Similarly, in a preliminary study, the benzenesulfonyl group was removed
from bis-(2-methoxyethyl)amine with essentially the same efficiency as

tosyl group cleavage.

55

Entry

Table 3.1: Evaluation of substrate scope.

 

10

11

 

 

 

Substrate Proggct Yield
Ph. ,Ph \ , a
'7‘ Ph I? Ph 93
Ph Ts H b
\$/’ PhAN/r 81
C T$0 H 09
H?" Y CY‘N’CY 81 '
Ts H
a
mos H-~:>s ..
Ph Ph
0
ts—N‘ ‘o H-N 0‘ 75
U L/
Ts H a
t l. 85
\O/\/ \/\O/ \O/\/ \/\O/
/—\ / \ a.d
Ts-N N-Ts HTN NT” 76
\__/ \_/
Ts H
\/ \/ l/ \/
W N \N/\\ F N \N/\\ 683
N N N N N‘\'N‘\‘N N
~\ V ~\ V
/L_/\ /L_J\
h
P \/\NHTS Ph\/\NH2 763,d,f
N's—NOT HTNO—T 893
Ph Ph
T5 t1
N N 613'e
/_\./\Ph MPh

alsolated yield, inelds from NMR, cIsolated as HCI salt dDME used as
solvent at 60 °C (in all other cases THF was used as reaction solvent at
room temp). e 3 eq Na-SG(|) was used at —60 °C in THF (in all other
cases Na2K-SG was used) fSeq Na2K-SG was used, in all other cases 3-
4 eq Na2K-SG were used. 9 Similar yields were observed in runs with 4-6

eq. Na2K-SG(I) and solid acids such as (NH4)2HPO4, NH4CI, HCO2NH4
included in situ.

As entries to the strained aziridine (azacyclopropane) framework,
the N-tosyl protected aziridines are relatively easily synthesized.51 Their
desulfonations, however, are synthetically challenging.52 For example, 2-
benzyl-N-tosylaziridine gives substantial ring opening products on

treatment with Na/NH3, Sml2, or phenyldimethylsilyl lithium.”53 At ambient

temperatures, MglMeOH,24 activated by sonication, does give modest
aziridine yields.49 And Li/arenide (arene = naphthalene or 4,4’-di-t-
Bubiphenyl [DBB]), or Na/naphthalene deprotections are also effective at

low, but not at ambient, temperatures.54

Attempts at our usual M-SG deprotection (Na2K-SG in THF, room

or low temperature; H2O quench) of 2-benzyl-N-tosylaziridine showed both

desulfonation and ring opening. However, the milder Na-SG reagent in
THF cleanly detosylates 2-benzyl-1-tosylaziridine at —60 to —78 °C without
any electron transporting species (Table 3.1, Entry 11). Not surprisingly
Na-naphthalide generated from Na-SG at -50 °C also gave 67% yield of
the desired product.

In the general M-SG desulfonation procedure, as an alternative to a
post-reduction aqueous quench, the quenching proton source can be
included with the M-SG reductant. Organic-soluble proton sources such as
acetic acid or alcohols reacted directly with the M-SG, evolving hydrogen
and diminishing reducing capacity. However, relatively insoluble solid
proton sources in intimate contact with M-SG can neutralize the soluble

amide shortly after its formation without direct rapid reaction of the proton

57

source with the M-SG. In the detosylation of Cy2NTs solid inorganic acid

salts, such as (NH4)2HPO4, NaH2PO4, NH4CI and potassium hydrogen

phthalate were found to react with the metal amides, affording clean
dicyclohexyl amine product in THF at room temperature.

To demonstrate one-pot detosylation and trapping with a non-
proton electrophile, the M-SG(I) deprotection was applied to N-tosyl
pyrrole (5), with benzoyl chloride serving as the electrophile in the final
quench (Scheme 3.2). This reaction was complete in 6 hours with an 85%

yield of N-benzoyl pyrrole (6).

fl 1. Na2K-SGL2 fl

 

It i
T3 2. PhCOCI COPh
5 6

Scheme 3.2: Generation of alkali metal amide and electrophilic quenching in

situ. Conditions: THF, 25 °C, 6 hr.

As a first probe of selectivity, Ph2NTs and Cy2NTs, simple time

course studies by 1H NMR were run in single substrate reactions and a 1:1
mixed substrate reaction. For these rate studies, solvents freshly distilled

from NaK alloy were used and 1.5 eq of M-SG(I) was found to be sufficient

to drive the reactions to completion. As expected, deprotection of Ph2NTs
by Na2K-SG(I) is ca. two-fold faster than that of Cy2NTs. No evidence of

competitive inhibition was seen, i.e., the rate of detosylation of Cy2NTs did
not slow down to any significant extent in the presence of an equal

amount of Ph2NTs, and the 2:1 rate ratio was observed in the mixture as
58

well, suggesting (a) independent reactions and (b) that there is little
difference in electron accepting ability or access to the metal sites

between these two substrates, despite the very large difference between

the pKa values of the Ph2NH and Cy2NH product amines.

59

3.3 CONCLUSIONS

In summary, M-SG materials (Na or Na-K alloys absorbed in silica
gel) can act as efficient reagents for removing sulfonyl protecting groups

from primary and secondary amines. These M-SG reagents offer simple
alternatives to the other alkali-metal based reagents such as Na-NH3 or

Na-arenides often used for sulfonamide deprotections in total syntheses.

60

3.4 EXPERIMENTAL SECTION

3.4.1. Procedure for Preparation of Sulfonamides:

A secondary amine (10.5 mmole) in a 100 mL round bottom flask equipped

with a magnetic stir bar is dissolved in 40 mL THF. A THF solution (20 mL) of
sulfonyl chloride (10 mmole) is then added, followed by a slight excess of Eth

(1.3-1.6 mL, 1-1.2 9, 10-12 mmol) and the reaction is stirred overnight. The
solvent is evaporated off and the reaction mixture is extracted with brine and
ethyl acetate. The organic layer is concentrated under aspirator vacuum and
purified by column chromatography (neutral alumina column with 20% EtOAc in

hexane) to afford the corresponding sulfonamide derivative in 60-95% yield.

3.4.2: Representative Procedures for Desulfonation of Amines:

Prior to carrying out any deprotection reaction, the reducing ability of M-
SG (I) is tested by measurement of hydrogen evolution upon reaction with
ethanol in a closed system equipped with a digitized pressure gauge. The
volume of hydrogen produced is used to calculate the number of equivalents of

alkali-metal(s) in a given reagent.

3.4.2.1: Detosylation of secondary amines:

In a round bottom flask equipped with a glass-coated magnetic stir bar

and a rubber septum, dicyclohexyl-para-toluenesulfonamide (Cy2NTs, 335 mg, 1

61

mmol) and Na2K-SG(I) (400 mg, 40% w/w loading of metal alloy in silica gel, 5

mmol, 2.5 equiv*) are placed under an inert atmosphere. To this flask 3-5 mL of
rigorously anhydrous THF is added and stirred at room temperature for 6-8 h.
After this time the reaction mixture is quenched with 3-5 mL of water, and the
solids/aqueous layer are extracted via washing with an additional 20 mL (2X10
mL) of ether." After separation, the combined organics are passed through a

basic alumina plug to afford a clear solution that is concentrated on a rotary
evaporator. The product Cy2NH is obtained as a clear oily liquid (150 mg, yield =

83%).

*Because a two-electron S-N bond cleavage is this chapter’s focus, the molar
equivalency of the M-SG reactants is reckoned as, the total number of moles of
alkali metal therein. Thus, if reaction efficiency were perfect, one equivalent, so

termed, would cleave a mole of tosyl amides. Similarly, upon reaction with

ethanol, one equivalent of M-SG forms one mole of H2 gas.

**For these desulfonation procedures, it is observed that addition of
stoichiometric or near stoichiometric amounts of water (~100 (IL) in the
quenching step is not sufficient to phase separate the silica from the organic
solvent. Later gel formation (presumably via Ostwald ripening) is seen upon
concentrating the organic layer. This difficulty can be avoided by using excess

water (1.6 mL or more) and conventional drying of the organic phase by passing

through basic alumina or treatment with Na2SO4 prior to concentration.

62

3.4.2.2: Detosylation of a primary amine:
In a 100 mL roundbottom flask equipped with a glass-coated magnetic stir

bar and a rubber septum, N-(2-phenylethyl)toluenesulfonamide (275 mg, 1 mmol)
and Na2K-SG(I) (802 mg, 40% w/w loading of metal alloy in silica gel, 10 mmol, 5

equiv.) are assembled under an inert atmosphere. After DME (10 mL) is added,
the reaction is stirred at room temperature for 7 h, followed by quenching with 5

mL cold water. The organic layer is decanted and the residual solids washed with
an additional 2X10 mL portions of 320. The combined organic solution is passed

through a plug of basic alumina and the concentrated on a rotary evaporator to

afford phenethylamine as an oily liquid (92.3 mg, yield = 76.3%).

3.4.2.3: Detosylation of an aziridine:

In a He drybox, Na-SG(I) (1.519, 19.5 mmol) is placed in a 100 mL round
bottom flask equipped with a glass jacketed stir bar and rubber septum. To this
flask, after removal from the box, anhydrous THF (25 mL) is added by syringe
with gas venting via needle. The closed flask is chilled in a cryobath set at —60 °C
for 20 minutes; then a THF solution (10 mL) of 2-benzyl-1-tosylaziridine (900 mg,
3.14 mmol) is added via syringe. The reaction is stirred for 6 h at this
temperature with monitoring by TLC. At reaction completion, the organic layer is
decanted from the solids and quenched in a separate flask containing 0.4 mL
water. The silica gel residue is washed with 10X2 mL portions of ether and the
combined organics are dried over Na2SO4 and placed on a rotary evaporator for

63

solvent removal. Pure 2-benzylaziridine (256.4 mg, 61.4% yield) is isolated from
the resulting pale yellow oil by flash chromatography over deactivated silica gel

using ether/ethanol as eluting solvent.

64

3.5 REFERENCES:

 

10.

11.

12.
13.

14.

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Wuts, P. G. M.; Greene, T. W. In Protective Groups in Organic
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(a) Redko, M. Y.; Jackson, J. E.; Huang, R. H.; Dye, J. L. J.
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125, 2259. (c) Redko, M. Y.; Huang, R. H.; Dye, J. L.; Jackson, J.
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Tsunoda, T; Tanaka, A; Mase, T; Sakamoto, S. Heferocycles,
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Nolan, 0.; Gunnlaugsson, T. Tetrahedron Lett. 2008, 49, 1993.

Weisblat, D. |.; Magerlein, B. J.; Myers, D. R. J. Am. Chem. Soc.
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Snyder, H. R.; Heckert, R. E. J. Am. Chem. Soc. 1952, 74, 2006.

Oppolzer, W.; Bienayme, H.; Genovois-Borella, A. J. Am. Chem.
Soc. 1991, 113, 9660.

Moussa, Z.; Romo, D. Syn/eff, 2006, 3294.

Bajwa, J. S.; Chen, G.; Prasad, K.; Repic, 0.; Blacklock, T. J.
Tetrahedron Lett. 2006, 4 7, 6425.

Haskins, C. M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 599.
Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208.

Liu, Y.; Shen, L.; Prasad, M.; Tibbats, J.; Repic, 0.; Blacklock, T.
Org. Process Res. Dev. 2008, 12, 778.

Wellner, E; Sandin, H; Paakkbnen, L. Synthesis, 2003, 223.

Jebasingh, B.; Alexander, V. Synth. Commun. 2006, 36, 653.
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Lett. 2006, 47, 2409.

Hamada, T; Nishida, A; Yonemitsu, O. J. Am. Chem. Soc. 1986,
108, 140.

Nyasse, B.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S.; Ragnarsson,
U. J. Org. Chem. 1999,64, 7135.

Coeffard, V.; Thobie-Gautier, C.; Beaudet, l.; Grognec, E. L.;
Quintard, J-P. Eur. J. Org. Chem. 2008, 383.

Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Tetrahedron, 1992,
48, 4475.

Bisai, A.; Singh, V. K. Tetrahedron Left. 2007, 48, 1907.

Milburn, R. R.; Snieckus, V. Angew Chem, Int Ed. Engl. 2004,43,
892.

Zhou, Y.; Porco, J. A., Jr.; Snyder, J. K. Org. Left. 2007, 9, 393.

Carter, P; Fitzjohn, S; Magnus, P. J Chem Soc., Chem.
Commun. 1986, 1162.

Forshee, P. B.; Sibert, J. W. Synthesis, 2006, 5, 756.
Nayak, S. K. Synthesis, 2000, 1575.

Vellemae, E.; Lebedev, 0.; Maeorg, U. Tetrahedron Left. 2006, 49,
1373.

Holmes, A. 3.; Thompson, J; Baxter, A. J. G.; Dixon, J. J. Chem.
Soc. Chem. Commun. 1985, 37.

Wagler, T. R.; Burrows, C. J. J. Chem. Soc. Chem. Commun. 1987,
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Schulz, A. G.; McCloskey, P. J.; Court, J.J. J. Am. Chem. Soc.
1987, 109.6493.

Akhtar, T.; Cumpstey, l. Tetrahedron Left. 2007, 48, 8673.

Jordis, U.; Sauter, F.; Siddiqi, S. M.; Kuenberg, B.; Bhattacharya, S.
K. Synthesis, 1990, 925.

66

 

34.

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Ed. Engl. 2004, 43, 5342.

Burtoloso, A. C. B.; Correia, C. R. D. Tetrahedron, 2008, 64, 9928.

Knowles, H. 8.; Parsons, A. F.; Pettifer, R. M.; Rickling, S.
Tetrahedron, 2000, 56, 979.

Larghi, E. L.; Kaufman, T. S. Tetrahedron Left. 1997, 38, 3159.
Preiml, M.; Honig, H.; Klempier, N. J. Mol. Catal. B. 2004, 29, 115.

Schoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyama, Y.; Miclo, Y.;
Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368.

Anker, T.; Hilmersson, G. Org. Left. 2009, ASAP article

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SiGNa Chemistry has developed three categories of alkali metal-
nanostructured silica materials (M-SG): Stage 0 materials are
strongly reducing pyrophoric powders; Stage I materials are non-
pyrophoric, free-flowing black powders with reactivity equivalent to
neat alkali metals; and Stage II is less reducing, but reacts with
water to produce hydrogen at pressures from ambient to several
thousand psi. All three categories of M-SG, with different metals
and metal alloys absorbed, are available commercially.

Note that this chapter has been published in nearly identical
form as Nandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.;
Lefenfeld, M.; Vogt, P. F.; Jackson, J. E. Org. Lett., 2008, 10 ,
5441.

Closson, W. D.; Ji, 8.; Schulenberg, S. J. Am. Chem. Soc., 1970,
92, 650.

67

 

48 .
49.

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Alonso, D. A.; Anderson, P. G. J. Org. Chem. 1998, 63, 9455.

Fleming, |.; Frackenpohl, J.; lla, H. J. Chem. Soc. Perkin Trans. 1:
Org. and Bio-Org. Chem. 1998, 7, 1229.

Bergmeier, S. 0.; Seth, P. P. Tetrahedron Left. 1999, 40,
6181.

68

CHAPTER 4

PREPARATION OF DIPHENYL PHOSPHIDE AND SUBSTITUTED
PHOSPHINES USING ALKALI METAL IN SILICA GEL (M-SG)

4.1 BACKGROUND:

Diarylphosphides of alkali metals are important organic reagents for
many organic transformations such as dehydroxylation of d-hydroxy ketones,1
stereoselective reduction of gem-dihalides,2 regio- and stereospecific cleavage
of silylated and stannylated epoxides}5 demethylation of methylammonium
salts‘5 and methyl aryl ethers,7 stereoselective displacements of secondary
mesylates and tosylates in steroids,8 the Staudinger type reaction9 and
bromouracil functionalization.10 Diarylphosphides are also key building blocks
for the many substituted phosphine11'16 ligands that enable homogeneous
catalytic processes including hydroformylations,17 asymmetric hydrogenations
and other asymmetric syntheses”19

Literature routes to alkali metal phosphides generally use the reaction of
the alkali metal with diaryl-,2°'21 diarylhalo-,22 or triarylphosphines.23 This last
reaction”27 has the advantage that many triaryl phosphines are commercially
available and air stable.”30 Others are readily made via metathesis reactions
of arylsodium, aryllithium, or aryl Grignard reagents with PX3 where X can be a

halide, phenoxide, or alkoxide.31 Reductive cleavage of triarylphosphine is the

most used, but can be hard to run and especially to scale up since it requires

69

sodium dispersions in oil.3‘°"33 Classic metal ammonia reduction introduces
problems of handling, over reduction and operational safety. Solutions of Na-
naphthalide have been effective in preparing unsymmetrical diphosphines.34
However, the presence of co-reagents and/or impurities that arise from these
routes can introduce challenges in isolation, purification and subsequent
reactions?5

Alkali metals absorbed in porous silica gela‘s'37 provide an alternative
reagent that is non-pyrophoric in dry air, a free flowing dry powder and free of
contamination by oily hydrocarbons or ammonia. Herein, we report38 a new
method for preparation of diaryl phosphide salts of alkali metals that uses
triarylphosphine and alkali metal absorbed in silica gel. The clean
diarylphosphide solution thus generated can be decanted and used for
subsequent reactions. We report here on comparisons of sodium vs. sodium-
potassium alloys, and the effects of solvents and additives such as
ethylenediamine. The methods versatility is tested with various electrophile-
triarylphosphine pairings to form substituted diarylphosphines. These
monoalkylated phosphines can be further functionalized in a subsequent step to
afford aryldialkyl phosphines. This approach conveniently accesses substituted
phosphines while avoiding transition metals such as Pd or Ni used to mediate

couplings}39

70

4.2 RESULTS AND DISCUSSIONS:

The conditions for cleavage of triarylphosphines to diarylphosphides
were investigated by using triphenyl phosphine as a model substrate. Cleavage
of the aryl C—P bond was found to occur under ambient conditions in ether
solvents such as THF and DME at room temperature with 2.5 equivalents or

more of Na-SG(I) and Na2K-SG(I). The aryl-metal (e.g., phenyl sodium or

phenyl potassium) carbanion is formed initially, but does not survive under the
reaction conditions. Traces of electrophile functionalized aryl compounds were
seen in a few mid-reaction samples (Scheme 4.1), but never at reaction
completion. If need be, however, decomposition of the Ar-M (M = Na or K)
species can be ensured by brief warming of the reaction mixture to 40-50 °C. In
contrast, the cleavage of triarylphosphine with lithium metal gives phenyl lithium
and lithium diphenyl phosphide. Phenyl lithium in THF is long lived and has to
be quenched with tert—butyl chloride at a lower temperature in an additional
step.40 The alkali metal (Na or K) diarylphosphide salt solutions can be
quenched in situ or first decanted or filtered under inert atmosphere to remove
the M-SG solids and then quenched. Quenching with alkyl halides gave
alkyldiarylphosphines in good to high yields (for example 1-bromobutane

yielded n-butyldiphenyl phosphine in 77% yield).

71

 

 

Ar A Ar

I M-SG , l ,

A ,P\ 171989 + [PhM] RX R—P\
l’ Ar Ar Ar

Scheme 4.1. Reductive cleavage of triaryl phosphine to generate
diarylphosphide.

Cleavage occurred faster in 1,2-DME than in THF, and faster with Na2K-

SG(I) than with Na-SG(I). Reaction with Na-SG(I) was, however, accelerated by
addition of catalytic ethylenediamine (EDA), finishing in 3 h vs. the 6 h required
in its absence. The blue color seen in these reactions before phosphine
addition suggests formation of Na' ions in solution, presumably balanced by the

EDA-Na” complex. The faster rates seen when EDA is added to Na-SG(I) and
when Na2K-SG(I) was used in place of Na-SG(|) hint at a two-electron transfer

from Na‘ as opposed to sequential SET steps from elemental Na. Indeed,
addition of 18-Crown-6, a complexant known to form sodide with Na metal, led
to similar accelerations.“

The scope of this reaction was studied with different aryl substituents and
electrophiles as summarized in Table 4.1. The diphenyl phosphide product
reacts cleanly with both aliphatic and aromatic halide electrophiles (Entries 1-6).
The reductive cleavage takes place with more electron rich phosphines such as
tris(p-tolyl)phosphine and tris-(3,5)-xy|ylphosphines, but at a slower rate (Entries

7, 8). With tris(p-fluorophenyl) phosphine (Entry 9) even a modest excess of
Na2K-SG(I) and longer reaction time yielded only defluorination products, and

an 18-fold excess led to diphenylphosphide, as expected from plain

72

triphenylphosphine cleavage. No reaction was seen with tributylphosphine

(Entry 10).

73

Table 4.1. Preparation of monosubstituted diarylphosphines from
triarylphosphine.

 

 

Ar
I M-SG 69 .A' RX ’Ar
Ar’P\Ar = M R9 + [PhM] R-P\
Ar Ar
Entry PAr3 Electrophile Product Yield (%) or

Conv.

1 PPh3 nBuBr nBuPPh2 77°

2 PPh3 TMSCI TMSPPh2 80a

3 PPh3 Mel MePPh2 753

4 PPh3 CyBr CyPPh2 70b

5 PPh3 0st c6F5PPh2 70°

6 PPh3 4-lodo-tol (4-to|)PPh2 67°

7 P(4-tol)3 nBuBr "BuP(4-tol)2 74b

n n b

8 P(3.5-xylyl)3 BuBr BuP(3,5-xylyl)2 77

9 P(4-F-Ph)3 nBuBr "BuP(4-F-Ph)2 03

n . a

10 P Bu3 Mel No reactIon 0

11 PPh3 WW thPN 76b

In all cases 2.5-3 equiv. Na2K-SG(I) was used at room temperature in THF
unless mentioned otherwise.42 aConversion measured by 31P NMR;
bIsolated yield obtained from the quench of the electrophile in same pct;

74

(table 4.1 continued) 0Isolated yield from the decanting of Pth and

quench with electrophile in a separate flask.

Quenching of the diphenylphosphide with butyl or homoallyl bromides
achieved mono—functionalization in good yield (Entry 11), but activated
electrophiles such as benzyl- and allyl bromides formed quaternary salts.

Next we looked at cleavage reactions of monoalkyl diarylphosphines to
see if we could further functionalize them. The targets would be phosphines
bearing three different substituents, and hence chiral (albeit racemic).
Interestingly, alkyldiarylphosphines also underwent cleavage losing an aryl ring
to afford the corresponding alkyl aryl phosphide solutions. However, dialkyl
arylphosphines resist cleavage completely.

Understanding the factors controlling selectivity in the cleavage of
alkyldiarylphosphines may allow design and control of stereochemistry and redox
potentials of organometallic complexes.43 Such reactions have been studied44
but mostly in the context of P-arylated bisphosphines with varying spacers. 456°
For cleavage of the simpler butyldiphenylphosphine, we find nearly exclusive
dearylation to form butylphenylphosphide. This result seems sensible in terms of
the relative stabilities of phenyl vs butyl carbanion salts (pKa(R-H) = 43 and 50
respectively“), assuming they are formed directly in the cleavage. However,
since alkyl-H bond dissociation energies are typically 5-15 kcaI/mol lower than
aryl-H, if the severed group departed as a radical, diarylphosphide formation

might be expected. This latter process may explain the previously reported

75

selective cleavage of trimethylsilyldiphenylphosphine to form diarylphosphide,26 a

result we have conflrrned as well.

TR 9 @- R\ R'
P M /

M-SG R'X

O , O
R=R'="Bu=68%
R="BuR'=Cy=89%

 

_.

 

 

—

Scheme 4.2: Reductive cleavage of diarylalkylphosphine to
alkylarylphosphide
Scheme 4.2 above summarizes results of cleavage of non-symmetric
phosphines. These reactions could be carried out via two sequential
dearylation/alkylation cycles in one pot without the need for isolation of the
intermediate monoalkylated phosphines. As long as sufficient M-SG was added
in the second cycle, no difficulties arose due to the presence of slight excesses
of alkyl halide quenchers such as 1-bromobutane and bromocyclohexane.
Overall product yields were between 68-89%. This approach did not, however,

extend to a third cycle; like their trialkyl congeners, the dialkylaryl phosphines
(e.g., Et2PPh) did not undergo any detectable cleavage reactions with M-SG

reagents.

76

Xciors MPPh2 X: PPh2
o OTs PPh2
65%

Scheme 4.3: Preparation of DIOP from diarylphosphide solution.

Finally as an illustration of its synthetic utility, this new method was used
to make the chiral ligand (Scheme 4.3) DIOP [2,2-dimethyl-4,5-
bis(diphenylphosphinomethyl)dioxolane]. DIOP is used widely as a ligand for
asymmetric versions of hydroforrnylation,52 hydrogenation,53'60 allylic
alkylation,‘S1 radical addition and polymerization62 reactions. This is an attractive
ligand as it can be directly accessed from tartaric acid via acetal formation,

esterification, reduction with LiAIH4 and activation by tosylate formation. The final
step involves a nucleophilic displacement of ‘OTs by ‘PPh2. K2Na alloy has been
used for this purpose in synthesis.°°"35 Here we have shown the effectiveness of

the more convenient and less hazardous Na2K-SG(I) reagent for accomplishing

the same reaction in comparable yields instead of using K2Na alloy.

77

4.3 CONCLUSIONS

To summarize, alkali metals absorbed in silica gel have been shown to be
efficient reagents for carrying out the cleavage and derivatization of di-and
triarylphosphines. The diaryl and alkyl aryl phosphides that this method cleanly
generates are useful as reagents and as building block for modified

arylphosphine ligands.

78

4.4 EXPERIMENTAL SECTION

4.4.1. General Information of estimation and purification of reagents:

Prior to carrying out any C-P cleavage reactions the reducing ability of M-
SG (I) was tested by measurement of the hydrogen evolved upon reaction with
ethanol in a closed system equipped with a digital pressure gauge. The volume
of hydrogen produced was used to calculate the number of equivalents' of alkali-
metal(s) in a given reagent. Available reducing equivalents were found to be
typically 10-25% less than indicated by the simple mass proportion of metal.

Thus, a 1 9 sample of 40% w/w Na2K-SG (I) would typically provide 11-13 mmol

of electrons, not the full 14.1 mmol computed from the original reagent’s recipe.
In the procedures below, the reported numbers of equivalents represent titration-

derived values.

Triphenylphosphine was recrystallized from hot ethanol. (D. D. Perrin, W. L. F.
Annarego, D. R. Perrin, Purification of Laboratory Chemicals, 2nd ed.;

Pergamon: New York, 1980; p 455)

79

4.4.2.1 Procedure for preparation of mono-functionalized phosphine :

In a 100 mL round-bottom flask equipped with a glass-coated magnetic

stir bar and a rubber septum, triphenylphosphine (PPh3, 526 mg, 2 mmol, 1

equiv.) and Na2K-SG(|) (871 mg, 40% w/w loading of metal alloy in silica gel,

9.8 mmol, 2.45 equiv* by titration, 3.07 equiv* by mass %) were placed under
an inert atmosphere. To this flask 10 mL of anhydrous THF was added and the
mixture was stirred at room temperature for 6-8 h, changing from colorless to
dark orange. To monitor the reaction’s progress, 100 uL aliquots of reaction
mixture were diluted with 1 mL THF, quenched with 20 pL of 1-bromobutane,
and analyzed by 3‘P NMR. Upon completion, the reaction was quenched with
1-bromobutane (750 uL, 955 mg, 7 mmol, added all at once), which changed
the color of the reaction mixture from intense orange to colorless. After stirring
for 10 minutes, residual unreacted M—SG was quenched by dropwise addition of
water (3-5 mL). After separation, the solids/aqueous layer were extracted via
washing with an additional 40 mL (2x20 mL) of toluene. The combined organics
were then passed through a celite pad in a sintered glass funnel to afford a

clear solution that was concentrated on a rotary evaporator. The product
"BuPPh2 was obtained as a clear oily liquid (374 mg, yield = 77%). The product

purity was verified by 1H, 13c, 31ID NMR and by GC-MS.

*Because a two-electron C-P bond cleavage is this paper’s focus, the molar

equivalency of the M-SG reactants is reckoned as one-half the total number of

80

moles of alkali metal therein. Thus, if reaction efficiency were perfect, one
equivalent, so termed, would cleave a mole of triaryl phosphine to Ar2PM and
NM. Similarly, upon reaction with excess ethanol, one equivalent of M-SG

corresponds to two moles of metal, and forms one mole of H2 gas.

4.4.2.2. Procedure for the preparation of di-functionalized phosphine:

In a 100 mL round bottom flask equipped with glass coated magnetic

stirrer and rubber septum triphenyl phosphine (524 mg, 2 mmol, 1 equiv.) and
Na2K-SG (I) (1 g, 10.2 mmol, 2.5 equiv) were assembled. To this flask 10 mL of

anhydrous THF was added and stirred at room temperature for 8 h. Cyclohexyl
bromide (300 pL, 400 mg, 2.45 mmol) in 2 mL THF was added dropwise to the

reaction cooled in an ice-bath. The reaction was stirred at room temperature for

another 1 h followed by addition of Na2K-SG (I) (1 .19, 11.3 mmol, 2.6 eq) under

inert atmosphere (in a N2 glove bag). 5 mL additional THF was added and the

reaction was stirred for another 6 h, followed by quench with 1-bromobutane
(330 (IL, 420 mg, 3 mmol). The reaction-was stirred for another 30 mins followed
by a water quench (~ 3-5 mL). The clear organic layer was extracted in toluene

(~ 100 mL) and filtered through a celite pad on a sintered funnel. A clear filtrate
was obtained that was dried under N2 stream. A clear liquid of n-butyl cyclohexyl
phenyl phosphine (n-BuCyPhP) weighing 440 mg was obtained (89% yield). The

product purity was verified by 1H, 13C, 31P NMR and by GC-MS (m/z = 248.1).

81

1H (8 in ppm): 7.53 (t, 7 Hz, 2H), 7.2-7.0 (m, 3H), 1.8 (d, 10 Hz, 1H), 1.7-
1.6 (m, 3H), 1.58-1.48 (m, 5H), 1.32-1.26 (m, 5H), 1.08-1.02 (m, 4H),

0.77 (t, 5 Hz, 3H).

‘30 (6 in ppm): 138.32 (d, 18.5 Hz), 133.83 (d, 19.6 Hz), 128.94, 128.43
(d, 7.1 Hz), 38.34 (d, 10.75 Hz), 30.07 (d, 15.1 Hz), 29.86 (d, 12.6 Hz),
28.92 (d, 15 Hz), 27.28 (d, 10 Hz), 27.16 (d, 10 Hz), 26.7, 25.00 (d, 14.3

Hz), 24.75 (d, 11.9 Hz), 13.95. 3‘P (8 in ppm): 44.7

4.4.2.2. Procedure for the preparation of DIOP :

In a dry box, triphenylphosphine (526 mg, 2.01 mmol) and Na2K-SG(I)
(847 mg, 9.27 mmol, 2.3 equiv.) were combined in a 100 mL round-bottom flask
equipped with glass coated magnetic stirrer and rubber septum. To this flask 10
mL freshly distilled anhydrous THF was added via a glass syringe. The reaction
was gently stirred overnight (8 h). The stirring was then stopped and a 3 mL
portion of the orange diphenylphosphide solution was withdrawn via syringe and
put into a separate flask containing a solution of 4,5-bis(tosyloxymethyI)-2,2-
dimethyI-1,3-dioxolan (238 mg, 0.5 mmol) in 3 mL THF in a N2 glove bag. The
color of diphenylphosphide was immediately discharged and the solution was
filtered through a celite pad in a glass sintered funnel in a glove-bag. The solid
was washed with 2x10 mL aliquots of toluene. The combined organics upon
solvent removal gave pale yellow oil that was triturated with a 1 mL portion of

ice-cold methanol to yield a white solid that was filtered and dried. The dried

82

residue weighed 161.5 mg (65%). (Procedure adapted from Murrer, B. A.;
Brown, J. M.; Chaloner, P. A.; Nicholson, P. M; Parker, D. Synthesis, 1979,

350).

83

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Doom, J. A. V.; Frijns, J. H. G.; Meijboom, N. RecI. Trav. Chim.
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Corbridge, D. E. C. "Phosphorus: An Outline of its Chemistry,
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Layman, W. J. Jr.; Welsh, G. W. Production of High Purity Alkali
Metal Diphosphide and Cycloalkyldiarylphosphines US. Patent
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9843986.

Chou, T. S.; Tsao, C. H.; Hung, S. C. J. Organomet. Chem.,. 1986,
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Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson, J. E.;
Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338.

SiGNa Chemistry has developed three categories of alkali metal-
nanostructured silica materials (M-SG): Stage 0 materials are
strongly reducing pyrophoric powders; Stage I materials are non-
pyrophoric, free-flowing black powders with reactivity equivalent to
neat alkali metals; and Stage II is less reducing, but reacts with
water to produce hydrogen at pressures from ambient to several
thousand psi. . All three categories of M-SG, with different metals
and metal alloys absorbed, are available commercially.

Note that this chapter has been published in nearly identical
form as Nandi, P.; Dye, J. L.; Bentley, R; Jackson, J. E. Org. Lett.,
2009, 11, 1689.

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Organomet. Chem. 1987, 323, C1.

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88

CHAP'LER 5

REDUCTIVE AMINE DEALLYL- AND DEBENZYLATION
WITH ALKALI METAL IN SILICA GEL (M-SG)

5.1 BACKGROUND:

Cleavage of the C-N bond is important in functional group
interconversions and in deprotection reactions such as deallylation and
debenzylation.“2 Reductive methods using metal ammonia solutions}4 Pd-
reagentsf"9 low valent Ti,10 or Ni-based reagents":12 have conventionally been

used for these transformations.13 Mild oxidative methods, such as the aziridine

debenzhydrylation with 03 followed by excess NaBH414 and the recently reported

debenzhydrylation of azetidinone with NBS and catalytic Br2 in the presence of

light15 offer useful strained ring deprotections. A particularly selective example is

the amine N-debenzylation with diisopropyl azodicarboxylate (DIAD)‘°'17 in a

sugar also protected with O-benzyl and N-tosyl groups. Though much more

common for alcohols, amine detritylation under acidic condition is known.18

t19

Grubbs’s catalys and other Ru and Rh(lll) based reagents”22 have proven

useful for efficient deallylation of amines. However, these agents initiate reaction

d23,24

by isomerization of the double bon which can be problematic for certain

substrates.25 Thiol-mediated radical cleavage of allylic amines have been used to

deprotect secondary amines.”27

89

The above deprotections represent elegant and selective tools for
organic synthesis. However, a single reagent able to generally cleave N-allylic
and -benzylic amines would enhance the toolbox. For example, sodium in
ammonia was used in the final step for global deprotection in the total synthesis
of an oligosaccharide natural product.28 Similarly, Li in isoprene was shown to be

capable of cleaving a variety of protecting groups bound to imidazole.29

90

5.2 RESULTS AND DISCUSSIONS:

Alkali metals absorbed in porous silica gel (or the M-SG reagents) are
free flowing dry powders that are free of contamination by oily hydrocarbons and
are non-pyrophoric upon brief exposure to dry air.“32 Our interest in exploring
the usefulness of these materials in amine deprotections such as amine
desulfonations33 prompted us to investigate reductive C-N cleavages in the
context of deallylation, debenzylation, debenzyhydrylation, and detritylation.
Although the focus of this section is on deallylation (Scheme 5.1), a few

examples of the other deprotections are also described herein?4

 

R1\ 1 N KSG(I) R1\
. a2 -
N A NH
_ /
R2/ —\— R2

2. H20
Scheme 5.1. Deallylation of allyl protected amines

Several allyl amine substrates were cleaved by treatment with Na2K-SG (I)

at ambient temperature in ethereal (e.g., THF and 1.2-DME) solution under an
inert atmosphere. These experiments are summarized in Table 6.1. A sub-
stoichiometric amount (20 mol%) of ethylenediamine (EDA) was found to be
necessary to activate reaction of the aliphatic substrates, which were then
cleanly deprotected over 16-24 h. Examples include N-allylpiperazine (Entry 1),
N-allylhexamethyldisilazane (Entry 2), N-allylpiperidine (Entry 3), and a hindered
substrate, N-allyl-dicyclohexylamine (Entry 4). Aromatic substrates (Entry 5, 6, 7)

reacted relatively faster, affording the corresponding amines in 8-10 h without the

91

need of EDA. Over—reduction of the aromatic rings was not observed in these

cases.

92

Table 5.1: Deallylation of tertiary amines:

Entry Reactant Product Yield
H
ff “I
a,d,f
v H
\ / \ /
/ N \ /|\N/ \ 906

alsolated yield, I”Isolated as HCI salt, °Conversion by NMR,dPerformed in

1,2-Dimethoxyethane (DME), eYield with Na-SG, f5 equiv. of metal was
used in this case.

93

The expected propene byproduct of deallylation was observed by
analysis of the gas phase via GC-MS. No 1,5-hexadiene, the allyl radical
homodimerization product, was seen in the reaction mixture. This finding
suggests that an allyl metal intermediate likely formed during the cleavage
reaction. However, attempts to trap the allyl metal reagent with electrophiles such
as benzophenone at —78 °C did not give any substantial nucleophilic adduct.
Apparently, the allylmetal species, if formed, does not survive for long in ethereal
solvent. Alkyllithiums in the presence of lithium alkoxide can readily abstract
protons from ethereal solvent above —60 °C.35 In a similar way, in the presence of
dialkylamide salts, allyl metal species could be highly aggressive in proton
abstraction reactions with ethereal solvents (typical procedures for preparation of
allylsodium is carried out in hydrocarbon solvents). In the case of N-allyl-

benzotriazole, besides the intended allyl group removal, loss of N2 was observed,

yielding aniline. Secondary N-allyl-amines, such as N-allyI-cyclohexyl amine, also
encountered difficulties in these deprotections. Although some cyclohexylamine

product was observable, a complex mixture of other products was obtained.

94

Table 5.2: Other amine deprotections

Entry Reactant Product Yield
N
/ \ N
1 Gk) 4;» 963’d
Ph H
2 Nk Q 82”
Ph H
N
(7 ~
/ \
3 j: (E 75‘11
Ph Ph
[1 ~
4 N A; 90°
Ph’I‘Ph H
Ph
NH2 H
5 PhtPh Ph’lzPh 95DI

C
6 1,, 100

alsolated yield, bIsolated as HCI salts,°Conversion by GC, d1,2-DME was used as
solvent

95

Exploratory work on reductive cleavages of other related protecting groups
of amines are summarized in Table 5.2 above. Effective removal of benzyl (Entry
1, 2), benzhydryl (Entry 3) and trityl (Entry 4, 5) groups were demonstrated. For
debenzylations (Entry 1, 2), the expected toluene byproduct was detected, while
debenzhydrylation and detritylation gave the corresponding diphenylmethane
and triphenylmethane products. It is noteworthy that the debenzylation of the
aliphatic amine piperidine (Entry 2) proceeded to completion without the need for
activation by ethylene diamine. From a brief exploration in oxygen deprotection
we also found that benzyl nopyl ether (Entry 6) cleanly yielded the bicyclic
alcohol nopol in less than 3 h. A more detailed study on debenzylation reactions

is underway and will be reported elsewhere.

“0*. c

70%

Scheme 5.2. One pot reduction and debenzhydrylation of benzophenone
hydrazone

An additional extension of this deprotection method was the
successful one-pot reduction/deprotection of benzophenone hydrazone
(Scheme 5.2), enabling reduction to amine via N-N bond cleavage, or full
reduction to the diphenylmethane. In the reaction above, the use of 2.5

equivalents of metal yielded benzhydryl amine as the predominant product

96

(NMR detection). However, with 5 equivalents of metal, diphenylmethane was

the major product.

97

5.3 CONCLUSIONS:

To summarize, alkali metals in silica gel (M-SG) are capable of reductive
cleavage of the C-N bonds in tertiary allyl, benzyl, benzhydryl and trityl amines.
The simplicity of the reaction, ease of work-up and isolation, low cost of the
reagent precursors, and low toxicity make this method a useful addition to

chemists’ toolbox.

98

5.4 EXPERIMENTAL SECTION
5.4-.1. General Information of estimation and purification of reagents:

Prior to carrying out any C-N cleavage reaction the reducing ability of M-
SG (I) was tested by measurement of the hydrogen evolved upon reaction with
ethanol in a closed system equipped with a digital pressure gauge. The volume
of hydrogen produced was used to calculate the number of equivalents' of alkali-
metal(s) in a given reagent. Available reducing equivalents were found to be

typically 10-25% less than indicated by the simple mass proportion of metal.
Thus, a 1 9 sample of 40% w/w Na2K-SG (I) would typically provide 11-13 mmol

of electrons, not the full 14.1 mmol computed from the original reagent’s recipe.
In the procedures below, the reported numbers of equivalents represent titration-

derived values.

5.4.2. Procedure for deallylation of tertiary allyl amine :

In a 100 mL round-bottom flask equipped with a glass-coated magnetic
stir bar and a rubber septum, N-allyl-3,5-dimethylpyrazole (92 (L, 136 mg, 1
mmol, 1 equiv.) and Na2K-SG(I) (400 mg, 40% w/w loading of metal alloy in silica

gel, 4.96 mmol, 2.48 equiv* by titration) were placed under an inert atmosphere.
To this flask 10 mL of anhydrous THF was added and the mixture was stirred at
room temperature for 8-10 h. The reaction was monitored by tlc to ensure

complete conversion. The reaction mixture was then quenched by addition of ~2

99

mL water. The organic layer was washed with additional 2x10 mL of ether and
the combined organics was dried over Na2SO4, filtered and concentrated on a

rotary evaporator. The product 3,5-dimethylpyrazole was isolated as solid. (86

mg, yield = 91%). The product purity was verified by 1H and 130 NMR.

For aliphatic allylamine such as N-allyl-N,N-dicyclohexylamine 20 mol% (15 pL of
EDA per mmol of allylamine substrate) was added to the reaction after adding

solvent and the reaction was carried out in the identical way.

*Because a two-electron C-N bond cleavage is this chapter’s focus, the molar
equivalency of the M-SG reactants is reckoned as one-half the total number of

moles of alkali metal therein. Thus, if reaction efficiency were perfect, one
equivalent, so termed, would cleave a mole of tertiary allylamine to R2NM and
AllylM. Similarly, upon reaction with excess ethanol, one equivalent of M-SG

corresponds to two moles of metal, and forms one mole of H2 gas.

5.4.2. Procedure for other deprotections:

Identical procedure to the above (5.4.1) was adapted in these cases

without the need of EDA.

100

5.5 REFERENCES

 

10.
11.

12.
13.

14.

15.

16.

Wuts, P. G. M.; Greene, T. W. In Protective Groups in Organic
Synthesis; Wiley-lnterscience: Hoboken, New Jersey, 2007:
Chapter 7.

Carey, J. S.; Laffan, D.; Thomson, 0.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337.

Rao, T. S.; Pandey, P. S. Synth. Commun. 2004, 34, 3121.

Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchin, D.; Roberts,
P. M.; Smith, A. D.; Rodiguez-Solla, H.; Thomson, J. E.; Toms, S.
M. Org. Biomol. Chem. 2007, 5, 1961.

Ohmura, M; Nakamura, A.; Hamasaki, A.;Tokunaga, M. EurJ Org.
Chem. 2008, 30, 5042.

Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. J. Org. Chem. 2007,
72, 9278.

Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G.
Tetrahedron Left. 1998, 39, 1313.

Garro-Helion, F.; Merzouk, A; Guibe, F. J. Org. Chem, 1993, 58, 6109.
Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.

Talukdar, S.; Nayak, S. K.; Banerji, A. J. Org. Chem, 1998, 63, 4925.

Kamijo, S.; Huo, Z.; Jin, T.; Kanazawa, C.; Yamamoto, Y. J. Org.
Chem. 2005, 70, 6389.

Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4679.

Deprotections with substituted benzyl groups (eg. p-methoxy-or p-
nitrobenzyl) will not be considered in this paper.

Patwardhan, A. P.; Lu, 2.; Pulgam, V. R.; Wulff, W. D. Org. Lett. 2005, 7,
2201. ‘

Laurent, M.; Belmans, M.; Kemps, L.; Ceresiat, M; Marchand-
Brynaert, J. Synthesis, 2003, 4, 570.

Kroutil, J.; Trnka, T.; Cerny, M. Synthesis, 2004, 3, 446.

101

 

17.
18.

19.
20.

21.

22.
23.

24.

25.

26.

27.

28.

29.
30.

31.

Kroutil, J.; Trnka, T.; Cerny, M. Org. Lett. 2000, 2, 1681.

Demitras, l.; Buyukkidan, B.; Elmastas, M. Turk. J. Chem. 2002, 26, 889.

Alcaide, B.; Almendros, P.; Alonso, J. M. Chem. Eur J. 2003, 9, 5793.

Cadierno, V.; Garcia-Garrido, S. E.; Gimeno, J.; Nebra, N. Chem.
Commun. 2005, 4086.

Kamijo, S.; Jin, T.; Huo, Z; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125, 7786.

Zacuto, M. J.; Xu, F. J. Org. Chem. 2007, 72,6298.

Krompiec, S.; Krompiec, M.; Penczek, R.; lgnasiak, H. Coord.
Chem. Rev. 2008, 252, 1819.

Escoubet, S.; Gastaldi, S.; Bertrand, M. P. Eur. J. Org. Chem.
2005,3855. ‘

Panayides, E.; Pathak, R.; De Koning, C.; Van Otterlo, W. Eur. J.
Org. Chem. 2007, 29,4953.

Bertrand, M. P.; Escoubet, S.; Gastaldi, S.; Timokhin, V. Chem.
Commun. 2002, 216.

Escoubet, S.; Gastaldi, S.; Timokhin, V. l.; Bertrand, M. P.; Siri, D.
J. Am. Chem. Soc. 2004, 126, 12343.

lserloh, U.; Dudkin, V.; Wang, Z.; Danishefsky, S. J. Tetrahedron
Lett. 2002, 43, 7027.

Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron, 2007, 63, 947.

Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson, J. E.;
Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338.

SiGNa Chemistry has developed three categories of alkali metal-
nanostructured silica materials (M-SG): Stage 0 materials are
strongly reducing pyrophoric powders; Stage I materials are non-
pyrophoric in moisture free air, black powders with reactivity
equivalent to neat alkali metals; and Stage II is less reducing, but
reacts with water to produce hydrogen at pressures from ambient to
several thousand psi. All three categories of M-SG, with different
metals and metal alloys absorbed, are available commercially.

102

 

32.

33.

34.

35.

Nandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.; Lefenfeld, M.;
Vogt, P. F.; Jackson, J. E. Org. Lett. 2008, 10, 5441.

For detailed procedure refer to the experimental section.

Note that this chapter has been published in nearly identical form as
Nandi, P.; Dye, J. L.; Jackson, J. E. Tetrahedron Left. 2009, 50, 3864.

Schlosser, M. Pure & Appl. Chem. 1988, 60, 1627.

103

CHAPTER 6

BIRCH REDUCTIONS AT ROOM TEMPERATURE
WITH ALKALI METALS IN SILICA GEL (Na2K-SG(I))

6.1 BACKGROUND

Conventional Birch reductions"3 of aromatic compounds are performed
with alkali metals in liquid ammonia (the so-called dissolving metal conditions)
in the presence of alcohols at or below the —33 °C reflux temperature of liquid
ammonia. The reaction outcome can be tuned by varying temperatures,
metals,” additives, proton sources or quenching agents. The Birch reductions
are often combined with other reactions in tandem sequences.7'14 A cathodic
Birch reduction has been reported for a limited class of substrates.15 The
hydroxide ion has been used as an electron source for the photochemical Birch
reduction of a naphthalene derivative.16 Birch reduction variants also include
reactions in THF with gaseous ammonia as a solvent component and the
reaction atmosphere.17

The class of substrates described herein can also be reduced by

l-"B'19 or Ianthanide20 salt- mediated hydrogenation reaction

transition meta
conditions by which complementary selectivities may be achieved.21 Toxicities
of transition metals22 and low temperature requirements of conventional Birch

reductions remain areas of concern for future process development research

and scale up.23 Additionally, alkali metal-arenide salts can form stable

104

 

complexes with ammonia, which can later cause violent reactions during
quenching.24

Alkali metals in silica gel?!”26 have been developed as dry, free-flowing,
powdered reagents.”28 The usefulness of these reagents in replacing
dissolved metal conditions has been illustrated in the context of several
reductive cleavage reactions.”31 These reagents are also found to be effective

in reduction of functionalized aromatic compounds and esters.32

105

6.2 RESULTS AND DISCUSSIONS

Herein we report33 the applications of the Na2K-SG(I) reagent in

reductions of polyaromatic hydrocarbons and conjugated aromatic systems. In

addition to conventional stirred-batch mode reaction conditions, we report here

on the feasibility of Na2K-SG (I) reagent’s use in flow reactor settings.

Table 6.1. Birch Reductions using Na2K-SG (l)

Entry Substrate Product Yield
Ph Ph
3 000 000 ..
Ph Ph
H
N N
4 O ‘0 O 0 DD
/
it it
. O
/
N N
R
\
. O 74
/
N N
H

10

O)

Table 6.1 continued:

M M 95

 

_ d
Ph _ Ph—\—Ph 90
9 Ph Ph
—\—Ph xPh 98
cr

aR=n-butyl, bReaction carried out in presence of HMDS

(Hexamethyldisilazane), °Conversion by 1H NMR, dConversion by GC-MS
(done with 2.5 equiv Na-SG) , others are isolated yields

Table 6.1 shows representative examples of Birch reductions performed
with Na2K-SG(I) reagent. Some of the products (eg. dialkylated phenazines“)
are attractive for photochromic and electrochromic applications.35 Reduced
acridine derivatives are important cores of therapeutic agents that target the
central nervous system.36

Entries 1-3 show reduction of anthracene and its alkyl and aryl

substituted derivatives. In these cases no other byproducts were observed.

This finding, verified by deuterium oxide (D20) quenching, suggests formation

107

of dianion salt intermediates, consistent with similar reports37 with Li. For entry
3 the ratio of cisztrans isomers was 1:2.

Entries 4-6 show reduction of N-heterocycles, i.e., reduction of acridine,
phenazine and quinoline respectively. Unlike quinoline, the reduction of

naphthalene was relatively sluggish and gave only 1,4-dihydronaphthalene as
product (determined by GC-MS) with 3 equivalents of Na2K-SG(I). Phenazine

(Entry 5) was isolated as the dialkylated product to provide increased stability
and ease of handling. Entry 7 shows reduction of phenanthrene. Alkenes and
alkynes conjugated to aromatic rings were shown to undergo reduction (Entries
8, 9) without any detectable reduction of aromatic rings. Presumably, these
reactions occur via dianion salts as has been previously reported for stilbene
and related olefins with sodium.38 Interestingly, in the absence of a proton
source, diphenyl acetylene underwent dimerization and cyclotrimerization to
give a mixture of 1,2,3,4-tetraphenyl butadiene (major) and hexaphenylbenzene
(minor). Entry 10 shows dehalogenation-Birch reduction done in tandem. Entry
11 shows the reduction of indene. Additional information about the functional
group compatibility of these reagents under essentially identical reaction
29—32

conditions has been reported in previous publications.

When applied to biphenyl and related polyaromatic hydrocarbons such
as pyrene and acenaphthene, the Na2K-SG(I) reduction gave mixtures despite

the clear generation of the arenides' colors. The mixtures can be understood in
terms of the distribution of negative charges among various positions in the

dianions.39 Not surprisingly, more electron rich rings such as xylene and

108

mesitylene did not undergo any detectable reduction. With 3,3’-dimethoxy
biphenyl, in addition to the desired Birch reduction, cleavage of Me—OAr and
MeO—Ar bonds was seen.

Some of the reactions above (Entries 1 and 7) were carried out in small
Pasteur pipette columns. In this method, a solution of the desired substrate in
THF was passed through the column (containing a total of 7.5 metal
equivalents) under an inert atmosphere. The collection flask contained enough
water to quench the ether solutions of dianions (e.g., dianion of anthracene)
generated in the column.

Entries 1, 7, 8, 9 were shown to be feasible with solid acids such as

NH4C| and HCO2NH4 as in situ proton sources. However, when t-BuOH was

used as a homogeneous proton source the reaction, assembled with 2.5
equivalents of metal, did not go to completion. When the number of reducing
equivalents was increased to 5, over-reduction of the product appeared along

with the desired target compound.
We have found that if the Na2K-SG(I) reagent is handled quickly in lab
air (~40 sec), reactions give essentially the same results for anthracene

reduction as those obtained with Na2K-SG(I) handled in a drybox. However,

exposing the Na2K-SG(I) in lab air for 30 minutes caused a loss of reducing

power to the extent of 45% (from 40% to 22%). These results are variable as a
function of humidity levels. Therefore we recommend that the end user exercise

standard precautions by handling this reagent like other air sensitive materials
such as LiAIH4, NaH, and Cu(l)Cl (e.g. storing in drybox or N2 glovebag or in

109

 

vacuum dessicator) or correct for the loss of reactivity by adding an excess of
the reagent during use. These reductions can be also carried out with Na-
SG(I)4° and K2Na-SG(I).

The procedure described here shows promise for development of flow
reactors that could rapidly generate a solution of alkali metal carbanion species
for reduction or other uses. Tandem reduction-alkylation (cf. entry 5, Table 1)

and reduction-dehalogenation (entry 10) have also been shown to be feasible

with the Na2K-SG(I) reagent.

110

6.3 CONCLUSIONS

In summary, as an alternative to classical liquid ammonia conditions, we
have provided a simple and convenient method for carrying out room
temperature Birch reductions of a series of polynuclear aromatic substrates in

THF in the absence of co-reagents.

111

6.4 EXPERIMENTAL SECTION

6.4.1. General Procedure for M-SG Birch reductions:

In a 100 mL round-bottom flask equipped with a glass-coated magnetic

stir bar and a rubber septum, anthracene (178 mg, 1 mmol, 1equiv.) and
Na2K-SG(|) (420 mg, 40% w/w loading of metal alloy in silica gel, 4.9 mmol,

2.45 equiv) were placed under an inert atmosphere (in a He dry-box). To this
flask 10 mL of anhydrous THF was added and stirred at room temperature for
6-8 h. The reaction color changed from colorless to dark blue. After this time
the reaction mixture is quenched with water (2 mL). It was added all at once
and the color of the reaction mixture changed from intense blue to colorless

and the reaction was allowed to stir for 10 minutes. The organic layer was
decanted and the solid residues were washed with additional 3x10 mL 320.

After separation, the combined organics were passed through a celite pad on
a sintered glass funnel to afford a clear solution that was concentrated on a
rotary evaporator. The product 9,10-dihydroanthracene was obtained as a
white solid (160-173 mg, yield = 88-97%). The product purity was verified by

1H, 130 NMR and by GC-MS (m/z = 180).
1H NMR (8 ppm): 7.29 (m, 2H), 7.19 (m, 2H), 3.93 (s, 2H)

13'0 NMR (8 ppm): 136.5, 127.3, 126, 36.

112

6.4.2. Procedure for the in-situ reduction :
In a 100 mL round bottom flask equipped with glass coated magnetic

stirrer and rubber septum diphenyl acetylene (178 mg, 1 mmol, 1 equiv.) and
Na2K-SG(I) (2 g, 20.4 mmol,0.5 equiv) was assembled. To this flask 2 mL

HMDS and 10 mL of anhydrous THF was added and stirred at room
temperature for 8 h. Reaction progress was monitored by tlc.The reaction was
stopped by a water quench (~ 1-2 mL). The clear organic layer was decanted
and the solid residues were washed with additional 2X10 mL ether and filtered
through a celite pad on a sintered funnel. A clear filtrate was obtained that was
dried under N2 stream. Bibenzyl was obtained as solid product (~165 mg,

90%). The product purity was verified by 1H, 130 NMR.

6.4.3. Procedure for the reduction in column:

In a Pasteur pipette glasswool was plugged and then packed with 19 of
Na2K-SG(I) (11.3 mmol, 7.5 equiv). The column was capped with a septum on

both ends. In a vial containing a 5 mL solution of anthracene (132 mg, 0.75
mmol, 1 equiv) in THF was prepared and was injected through this column via
a syringe. The solution of anthracene was allowed to flow under gravity and a
deep blue color from the generation of anthracenide anion was observed. The
eluted

solution was collected in a round bottom flask containing 1 mL of water as a
quenching agent.

After the passage of anthracenide anion the column was eluted with THF

113

 

(2 mL) to wash offrany residual product. The eluted organics were dried on
Na2SO4. Upon removal of the solvent by rotary evaporator, 9,10-

dihydroanthracene was obtained as white solid (108 mg, 80%).

114

6.5 REFERENCES:

 

1. Birch, A. J. J. Chem. Soc. 1944, 430.

2. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334.

3. Birch, A. J.; Pure & Appl. Chem. 1996, 68, 553.

4. Zimmerman, H. E.; Wang, P. A. J. Am. Chem. Soc. 1993, 115, 2205.
5. Lebeuf, R.; Robert, F.; Landais, Y. Org. Left. 2005, 7, 4557.

6. Gueret, S. M.; O’Connor, P. D.; Brimble, M. A. Org. Left. 2009, 11, 963.
7. Clive, D. L. J.; Sunasee, R. Org. Left. 2007, 9, 2677.

8. Zvilichovsky, G.; Gbara-Haj-Yahia, l. J. Org. Chem. 2004, 69, 5490.

9. Taillier, C.; Bellosta, V.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2145.
10. Paul, T.; Malachowski, W. F.; Lee, J. J. Org. Chem. 2007, 72, 930.

11. Benkeser, R. A.; Burrous, M. L.; Hazdra, J. J.; Kaiser, E. M. J. Org.
Chem. 1963, 28, 1094.

12. Macielag, M.; Schultz, A. G. J. Org. Chem. 1986, 51,4983.
13. Smith, W. K.; Hardin, J. N.; Rabideau, J. Org. Chem. 1990, 55, 5301.
14. Malachowski, W. P.; Banerji, M. Tetrahedron Left. 2004, 45, 8183.

15. Kariv-Miller, E.; Swenson, K. E.; Zemach, D. J. Org. Chem. 1983, 48,
4210.

16. Yoshimi, Y.; lshise, A.; Oda, H.; Kanezaki, H.; Nakaya, Y.; Katsuno, K.;
ltou, T.; lnagaki, S.; Morita, T.; Hatanaka, M. Tetrahedron Lett. 2008, 49,
3400.

17. Altundas, A.; Menzek, A.; Giiltekin, D. D.; Karakaya, M. Turk. J. Chem.
2005, 29, 513.

18. Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004,
126,986.

19. Alonso, F.; Candela, P.; Gbmez, C.; Yus, M. Adv. Synth. Catal. 2003,
345, 275.

115

 

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

Tarnopolsky, A.; Hoz, S. J. Am. Chem. Soc. 2007, 129, 3402.
Yoon, B.; Wai, C. M. J. Am. Chem. Soc. 2005, 127, 17174.

Zereini, F.; Alt, F.“Palladium Emissions in the Environment: Analytical
Methods, Environmental Assessment and Health Effects” Springler
Berlin Heidelberg, 2006, Part 5, p-575.

Joshi, D. K.; Sutton, J. W.; Carver, S.; Blanchard, J. P. Org. Process
Res. Dev. 2005, 9, 99.

Stevenson, G. R.; Peterson, R. A. J. Org. Chem. 1984, 49, 3443.

SiGNa Chemistry has developed three categories of alkali metal-
nanostructured silica materials (M-SG): Stage 0 materials are strongly
reducing pyrophoric powders; Stage I materials are non-pyrophoric, free-
flowing black powders with reactivity equivalent to neat alkali metals; and
Stage II is less reducing, but reacts with water to produce hydrogen at
pressures from ambient to several thousand psi. . All three categories of
M-SG, with different metals and metal alloys absorbed, are available
commercially.

Shatnawi, M.; Paglia, G.; Dye, J. L.; Cram, K. C.; Lefenfeld, M.; Billinge,
S. J. L. J. Am. Chem. Soc. 2007, 129, 1386.

Dye, J. L.; Cram, K. D.;' Urbin, s. A.; Redko, M. Y.; Jackson, J. E.;
Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338.

Although these M-SG(I) reagents do not react with dry air, they can
degrade rapidly in ordinary moist lab atmospheres. Thus, appropriate
cautions should be exercised in handling these materials. Like the pure
alkali metals, these materials react vigorously and exothermically with
water to give off flammable hydrogen gas.

Nandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.; Lefenfeld, M.; Vogt, P.
F.; Jackson, J. E. Org. Lett. 2008, 10, 5441.

Nandi, P.; Bentley, P.; Dye, J. L.; Jackson, J. E. Org. Left. 2009, 11,
1689.

Nandi, P.; Dye, J. L.; Jackson, J. E. Tetrahedron Left. 2009, 50, 3864.

Bodnar, B. S.; Vogt, P. F. J. Org. Chem. 2009, 74, 2598.

116

 

33.

34.
35.

36.

37.
38.
39.

40.

Note that this chapter has been published in nearly identical form
as Nandi, P.; Dye, J. L.; Jackson, J. E. J. Org. Chem. 2009, 74, 5790.

Haarer, D.; Schmidt, 8.; Hagen, R.; Li, Y. Eur. Pat. Appl. 1024394, 2000.
Bettinetti, G. F.; Maffei, S.; Pietra, S. Synthesis. 1976, 11, 748.

Charbit, J. J.; Galy, A. M.; Galy, J. P.; Barbe, J. J. Chem. Eng. Data
1989, 34, 136.

MIJIIen, K. Helv. Chim. Acta. 1978, 61, 1296.
Seyferth, D. Organometallics. 2009, 28, 2.
M'L'Illen, K. Angew Chem. Int. Ed. Engl. 1987, 26, 204.

Costanzo, M. J.; Patel, M. N.; Petersen, K. A.; Vogt, P. F. Tetrahedron
Lett. 2009, 50, 5463.

117

APPENDIX

PREPARATION, ASSAYS AND HANDLING OF M-SG
REAGENTS

A.1 PREPARATION

A.1.1 Calcination of Silica-Gel

(1) 100 g silica gel (SG) (Davisil 646 from Grace) is placed in a porcelain tray and

heated at 200-250 °C for 4-6 h.

(2) The temperature of the furnace (T hermolyne 114300) after the above period

was raised to 600 °C and left at this temperature overnight (12-16 h)

(3) After the heating is turned off the $6 is covered with aluminum foil while it is
cooling down to minimize re-absorption of moisture. The SG is next transferred

into the He dry-‘box (VAC model M040-1).
3.1.2 General Preparation of M-SG (0)

(1) Freshly cut 46 g (2 moles) of Na and 39 g (1 mole) of K is assembled in a
flask inside the dry-box. The solid mixture started to gradually turn into liquid
alloy at the points of contact of Na and K pieces. With gentle swirling the

formation of liquid alloy is driven to completion.

118

(2) Any small amount of oxide that was present on the solid Na or K pieces
starts to appear on the liquid surface and is removed by carefully soaking it into a

Kimwipe held with a pair of forceps.

(3) 60 g of calcined SG is weighed out and spread in a stainless-steel tray
inside the dry-box. To this tray the Na2K alloy (~3-5g) is added with a Pasteur
pipette as small droplets. The droplets initially sit on the SG and then gradually
start to soak into the SG, turning it silvery. Upon thorough mixing it becomes
shiny black. These steps are repeated a few times with the rate of absorption
increasing as the process goes on. Though black in appearance, this material

still carries metal alloy on the surface and is pyrophoric when poured in air.

The above method is also used for preparation of K2Na-SG (0).

Caution: If the liquid Na2K or K2Na alloy is added all at once instead of drop wise

followed by pauses to allow uniform mixing with a spatula, a localized and highly

exothermic runaway reaction occurs which depletes the net reactivity of the

material.

119

A.1.3 Preparation of M-SG (I)
A.1.3.1 Na-SG(I)

(1) Sodium rods are peeled inside a He dry-box with a potato peeler to get rid of

any sodium oxide surface coating. This leaves shiny metallic pieces.

(2) Inside the dry-box, a 40 g chunk of the fresh sodium is cut into small pieces
(10-15), placed together with 60 g of calcined silica gel in a rotary steel Parr
reactor (Parr Instruments Company, model 452 HC, Item T-316033004 29118)

and sealed with a TEFLON or graphite gasket.

(3) The steel reactor is taken out of the dry-box and tumbled in a furnace (Cenco

Instruments 00., model 95052-16) set at 100 °C for 3-4 h.

(4) The furnace is heated to 165 °C and tumbled overnight (12-16 h). The heat is
then turned off and the reactor is allowed to cool in room temperature air for 1 h.
After it is transferred into the dry-box and opened, the reactor yields 100 g of

black free-flowing granular Na-SG (l).
A.1.3.2 Na2K-SG (I)

(1) Inside the He dry-box, 100 g of Na2K-8G (0) is placed in a steel Parr reactor

and sealed.

(2) The steel reactor is brought out from the dry box, placed in a furnace (Cenco
Instruments Co., model 95052-16) and tumbled initially at 100 °C for 3-4 h

followed by heating at 120 °C overnight (12-16 h). Return to the dry box and

120

opening results in recovery of a black free-flowing powder (the shiny appearance

of M-SG (0) is now gone), that is non pyrophoric when poured in dry air.

The preparation procedure for K2Na-SG(I) is identical to that of Na2K-SG(0),

except for the amounts of Na and K used.

Stage ”A (100-165 Dc for 12 h), "B (~ 300 Dc for 24 h) or IIC (~ 400 Dc for 24 h)

can be made by heating M-SG (I) samples to higher temperatures.

121

A.2 ASSAYS
A.2.1 H2 evolution

(1) In a He dry-box, ~300 mg of Na-SG (l) is placed in a dry 50 mL round bottom

flask equipped with a greased vacuum stopper and pumped down in a rough

pump.

(2) This flask is taken out of the box, hooked up to a vacuum line, and pumped
down to ~10“ torr. The vacuum line is connected to another flask containing

freeze-pump-thawed EtOH (~30-35 mL).
(3) The flask containing M-SG (I) is chilled in a liquid N2 Dewar flask.

(4) EtOH (~ 2-4 mL) is distilled onto the M-SG (l) via cold distillation for 3-5
minutes. The flask containing the M-SG + EtOH and the flask having outgassed

EtOH are closed.

(5) The M-SG + EtOH flask is allowed to warm up to room temperature and
equilibrate for ~2 h, enabling the reaction of EtOH with Na-SG. The pressure of
the resulting H2 gas in the known volume of the vacuum system is measured via
a digital pressure gauge (Cecomp electronics, model no. ARM76OB-5) and the
temperature is simultaneously noted. The flask is then chilled again in liquid N2

followed by pumping off of the H2 produced.

(6) The M-SG + EtOH flask is again allowed to warm up to room temperature and
the vapor pressure of the mixture is noted. This is usually close to the vapor

pressure of pure ethanol (38 torr at 298 K).

122

 

(7) This flask is chilled in liquid N2 bath and ~ 1 mL H2O (freeze-pump-thawed
through at least 2 cycles in a separate flask) is distilled onto the EtOH + M-SG (l)
mixture for 3 minutes. The flasks are closed and again allowed to warm up to

room temperature. The reaction flask is allowed to stand for 30 minutes.

(8) As in steps (5)—(6), the pressure reading of the mixture and H2 was recorded.
The flask is chilled in liquid N2 bath, followed by pumping off any H2 that is

produced.

(9) The reaction flask is warmed up to room temperature again and the vapor

pressure of the mixture is recorded.

From the pre-deterrnined total volume of the system, the pressure of H2 (vapor
pressure corrected) and the temperature, the molar quantity of H2 made in each
step is determined. From this the total amount of reducing power is computed.
The amount of H2 made in the 1“t (EtOH) and 2"Cl (H2O) quenching steps
corresponds to the respective amount of M-SG (l) and M-SG (ll) present in a
sample. For organic reductions, it is desirable to maximize the relative proportion

of stage I material.

A.2.2 Differential Scanning Calorimetry (DSC):

DSC (instrument model Q200 made by TA instruments) of M-SG samples ran in
hermetic (sample sealed inside the drybox) aluminum pan shows the

approximate amounts of metal or alloy inside the pore vs bulk metal outside. In

123

Figure A.1 below the melting endotherm of sodium in the pore appears ~ 80 °C
instead of 97.7 °C for the bulk sodium. Figure A.1 shows that the melting
endotherm of sodium slowly decreases with time from 8.25 J/g (22.46 min) to

6.77 J/g (345.24 min), indicative of consumption of metal and possibly leading to

the formation of stage IIA.

 

 

Cycle 1

Cycle 2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

E” w
E
3 Cycle3
.9
LL
8 w
G)
I
Cycle4

 

 

 

 

 

\BV’“

Temperature °C

 

 

 

 

 

 

 

 

 

 

 

Figure A.1. DSC showing melting endotherm of Na-SG(I) (made by
heating at 120 °C for 14 h) 20% (w/w) with time at 150 °C

A.2.3 Reaction with Biphenyl:

The formation of biphenylide salt from biphenyl and M-SG (0) (~ 50 mg)
happens in dry (dried under benzophenone, sodium still) THF (at ~ 0.1 M

concentration) and at room temperature almost instantaneously, while with M-SG

124

(I) (~50 mg), it takes more time (~ 5 min). The stage II M-SG does not react with

biphenyl.

A.2.4 Titration with standardized HCI solution:

Titration using phenolphthalein indicator with standardized HCI solution allows
quantitation of the total amount of metal present in the water-quenched M-SG
sample. The difference between the above H2 evolution measurements and the
overall metal titration provides a measure of the amount of reducing capacity lost

during preparation and handling.

125

A.3 PASSIVATION WITH DRY AIR OR DRY OXYGEN:

Stage I M-SG reagents (Na-SG and Na2K-SG) can be slowly exposed (by

inter—diffusion with helium or nitrogen or by passage of dry air through a column)
to dry air or to dry oxygen with little loss of reactivity or reducing power. We
believe that this passivation occurs by formation of metal oxide or peroxide at
the entry channels of the big pores that are filled with metal in the zero-valent
state. These reactive bound oxygen species (could be a peroxide) upon
reheating in a DSC pan shows a exothermic shoulder between 100—160 °C
(Figure A.3) that was not present in the freshly made sample (Figure A.3).
Presumably, due to a large ratio of the amount of metal in the pores to that of
exposed metal on the surface, this results in an insignificant loss of reducing
capacity and blocks entry of oxygen to access the metal in the pores. In water,
alcohol or organic solvents these metal oxide barriers could be dissolved and
the reducing power of the metals in the pores can be harnessed. This

passivation is not achieved when an evacuated flask containing M-SG (I) is
rapidly exposed to dry 02 or air. In this case a sudden thermal run-away

reaction occurs that converts most of the Stage I M-SG to stage II along with the

formation of metal oxide. The resulting material is almost completely inert in its
reaction with alcohols. But this material still reacts with water and gives off H2

and the total reducing capacity is almost fully retained from the original sample

that was not passivated under air.

126

0.6

0.0

 

 

Heat Flow (W/g)

   

 

 

 

 

 

 

 

 

Temperature ( °C)

 

 

 

Figure A.2. DSC of a freshly prepared Na2K-SG (I) sample (dashed line)
vs DSC of same sample after exposure to dry oxygen (solid line)

127

A.3.1 Procedure for taming M-SG (Na2K-SG-0, Na2K-SG-l or Na-SG-l):

1)

Inside a He glove box, 2-5 9 of Na-SG is placed In a 50 mL round
bottom flask. This flask, closed with a vacuum stopper, is brought out
and hooked up in a vacuum line equipped with a digital pressure

gauge.

2) Air (mostly oxygen, moisture and argon) is allowed to condense in an

3)

4)

5)

6)

open condenser trap in a Dewar flask filled with liquid N2..

The trap is opened briefly to the vacuum line such that the pressure
inside the vacuum system goes up from 0 torr to 500 torr.

The M-SG flask under He (the atmosphere it had from the glovebox) is
now opened and allowed to equilibrate with the dry oxygen gas in the
line for five minutes with gradual swirling of the M-SG flask.

The M-SG flask and entire vacuum line is now partially pumped down

from 530 torr to ~ 50 torr.
Fresh 02 mixture is again admitted slowly so that the pressure inside
rises again to 500—600 torr of an atmosphere more enriched in 02.

Step 3, 4 and 5 are repeated and the whole cycle is repeated another
2-3 times before completely evacuating the flask and returning the

sample into the He dry-box again for further analysis.

In multiple passivation or taming runs it was observed that the net

reducing power of the M-SG (measured by hydrogen evolution with

ethanol) remained essentially identical before and after passivation. This

128

 

strategy of taming gave best results with Na-SG and Na2K-8G; K2Na—3G

(I) was found to be more reactive (exothermic) to oxygen and a loss of
~20% of the reducing capacity was observed.

Exposures of tamed and untamed samples to ordinary lab air
resulted in similar losses of reducing capacities for all samples. While
exposure for ~5 minutes resulted in ca. 20% loss of reducing capacity,
nearly ~50% was lost after a 30 minute exposure. As expected, these
rates are sensitive to the air’s relative humidity and the degree of
annealing in a given sample (as judged by the DSC).

In light of their degradation by ambient moisture, end users of these

reagents are recommended to use a N2 bag or an Ar blanket and mass

samples in closed vials by difference for best results. Users not having
access to nitrogen or argon can briefly handle the reagent in lab air and
use an excess amount of the reagent to compensate for moisture-induced

loss of reducing capacity.

129