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This is to certify that the

dissertation entitled

Selective Carbon-Carbon Bond Formation: Catalysis,
Mechanism, and Asymmetric Induction

presented by
Nancy Sue Barta

has been accepted towards fulfillment
of the requirements for

Ph . D . degree in Chemistry

2 Major professor

 

 

Date 9-12 “Q4

 

MS U is an Affirmative Action/Equal Opportunity Institution 0- 12771

 

LIBRARY
Michigan State
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TO AVOID FINES Mum on or bier. dd. duo.

DATE DUE DATE DUE DATE DUE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SELECTIVE CARBON-CARBON BOND FORMATION:
CATALYSIS, MECHANISM, AND ASYMMETRIC INDUCTION

By

Nancy Sue Barta

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1994

ABSTRACT

SELECTIVE CARBON-CARBON BOND FORMATION:
CATALYSIS, MECHANISM, AND ASYMMETRIC INDUCTION

By

Nancy Sue Barta

One of the most significant challenges faced by synthetic organic chemists is the
selective formation of carbon-carbon bonds. The following work describes the selectivity
of carbon-carbon bond formation from three different perspectives. Catalysis and
regioselectivity of bond formation is examined through the 3-aza-Cope rearrangement.
Ziegler-Nana polymerization models are used as tools for investigation of the activation of
transition-metal-carbon bonds toward olefin insertion in the formation of five- and six-
membered carbocycles. Lastly, the extent of asymmetric induction in the formation of
quaternary carbon centers was determined for the aza-annulation of [i-enamino esters with
acrylate derivatives.

The [3,3] sigmatropic rearrangement of N—alkyl-N-allyl enamines was accelerated
through the use of a number of Lewis acids. Organoaluminum reagents provided the most
efficient rearrangement, and the yields of the rearranged and reduced 6,8-unsaturated
amines ranged from 59 to 99%. The rearrangement of both phenyl and alkyl substituted N-
alkyl-N-allyl enamines occurred exclusively through a [3,3] sigmatropic shift for either

protic or Lewis acid catalysis.

Intramolecular olefin insertion in the selective formation of five- and six-membered
rings was used as a model for Ziegler-Nana polymerization of a-olefins. Both a- and B~
deuterium isotope effects were shown for the first time in a titanium system modeling 0L-
olefin polymerization. Promotion of the intramolecular olefin insertions with
methylaluminoxane resulted in inverse alpha kinetic isotope effects (kH/kD=0.88 and 0.95
3.0.03) and normal isotope effects for the beta position (kH/kD=1.06 :l:0.03). These
findings were compared with the MgX2 promoted cyclizations which resulted in alpha
effects of kH/kD=l.22 and 1.28 :l:0.03 and beta effects of kH/kD=l.09 and 1.10 $0.03.
The intramolecular olefin insertion reaction was also utilized to show the existence of chain
transfer/ligand transposition processes, and to provide evidence for the intramolecular
nature of these processes in titanium systems.

Stereoselective carbon-carbon bond formation was effectively illustrated through
the aza—annulation of [i-keto esters with a variety of acrylate derivatives. Annulated
products were obtained in yields ranging from 43 to 87% with 84-96% de, and the effects

of solvent, temperature, reaction time and chiral auxiliary were examined.

FOR MOM, DAD, AND JOHN

Thank you for all of your love and support throughout the years. I never could

have gotten to this point -or past it- without the three of you in my life. All my love.

iv

ACKNOWLEDGMENTS

I would like to express my deepest gratitude to Dr. John R. Stille. Your
enthusiasm for science and the art of teaching is unparalleled. I have learned so much from
working with you. Thank you for setting the example which helped me to see the value of
persistence, hard work and dedication. You have made such a difference for the students
who were fortunate enough to benefit from your stay at Michigan State, and your strength
of character in the face of the unexpected is inspirational. I hope that you are always able to
enjoy the team work and camaraderie that you have found at Lilly.

My thanks also to the members of the Stille group past and present. Petr-good luck
with the rest of your graduate career, your positive attitude will get you through. Iyer-keep
the catalysts coming, and thank you for all that you have helped me to learn about
organometallic synthesis. Adam-I really enjoyed working with you, and wish you the best
of luck. It was great having you there to remind me that this is not a problem! Carol-I
hope UNL gets you where you want to be, and thanks for your constant willingness to
help. Paul-I appreciate your staying in touch after your departure. Best wishes always.
Art-thanks for your friendship, and keep working hard. Greg-I learned more from you
than you will ever know. Thank you for sharing your enthusiasm and insights. Jon-What
can I say that you don’t already know? I shall never forget all that you have contributed to
my graduate career, and I will always treasure otu' friendship.

To those of you here at MSU that have made life more enjoyable, thanks! Kerry,
Michelle, Sara, Cory, Chris, and Matt- I am glad that you always had the time to talk. To
the Wagner group (Ali, Bob, and Marty)-thanks for adopting me, and good luck getting
out. Lisa-thank you so much for your fiiendship and for all of your assistance from

references to wardrobe consultations. Keep smiling, or you might get flowers! Dr.

Dunbar-thanks for your encouragement and support, I really appreciate your concern for
my scientific development. Dr. Nocera-thanks for your help and your letters of
recommendation. Dr. Funkhouser-I could never thank you enough for all you have done
for me and for the Stille group as a whole. Best wishes always.

Finally, I would like to thank those people who have contributed to my scientific
and personal development along the way. Dr.’s Carr and Baumgarten-thank you for
always believing in me and for making teaching a priority. Mrs. Lois Mayo, your quest for
life-long learning will always stand out in my memory. Thank you for caring and for being
such a positive role model. Michelle and Jon-how I would have survived without your
humor via e-mail is beyond me. I am glad that I did not have to find out. Karen and
Deanna, your unquestioning support of my endeavors shall never be forgotten. My love

and prayers always for you and your new families.

TABLE OF CONTENTS

LIST OF TABLES ................................................................................................................ X
LIST OF FIGURES ............................................................................................................ xii
LIST OF SCHEMES .......................................................................................................... xiv
LIST OF ABBREVIATIONS ............................................................................................. xvi

CHAPTER I. LEWIS ACID ACCELERATION OF THE 3-AZA-COPE

REARRANGEMENT
BACKGROUND AND SIGNIFICANCE ............................................................................ 1
Acceleration of the Claisen Rearrangement. ............................................................... 5
Acceleration of the Aromatic 3-Aza-Cope Rearrangement. ........................................ 9
Acceleration of the Aliphatic 3-Aza-Cope Rearrangement ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 10
EXPERIMENTAL GOALS ................................................................................................ 13
EXPERIMENTAL DESIGN ............................................................................................... 13
RESULTS AND DISCUSSION ......................................................................................... 16
CONCLUSIONS ................................................................................................................ 24
EXPERIMENTAL SECTION ............................................................................................. 26
REFERENCES AND NOTES ............................................................................................ 39

CHAPTER II. MECHANISTIC STUDIES OF INTRAMOLECULAR
ZIEGLER-NATTA OLEFIN INSERTIONS: a-AND B-
DEUTERIUM ISOTOPE EFFECTS AND CHAIN
TRANSFER PROCESSES

BACKGROUND AND SIGNIFICANCE .......................................................................... 42

Historical Aspects of Ziegler-Nana Olefin Insertion Processes ............................... 42
Proposed Mechanisms for Ziegler-Nana Polymerizations ....................................... 45

The A gostic Interaction ............................................................................................ 47
Definition ..................................................................................................... 47

Theoretical Explorations .............................................................................. 48

Experimental Evidence ................................................................................ 49

Related Kinetic Isotope Effect Studies ..................................................................... 50
Intramolecular Cyclizations ..................................................................................... 52
EXPERIMENTAL GOALS ................................................................................................ 56
SYSTEM DESIGN ............................................................................................................. 57
RESULTS AND DISCUSSION ......................................................................................... 59
Substrate Preparation and Cyclization Methods ....................................................... 59
Normalization ........................................................................... 62
tat-Deuterium Isotope Effects ................................................................................... 64
flDeutcn'um Isotope EffeCts .................................................................................... 66
Combined a— and B-Deuterium Isotope Effects ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 67
Mechanistic Implications ......................................................................................... 67

Chain Transfer Reactions ........................................................................................ 71
CONCLUSIONS ................................................................................................................ 73
EXPERIMENTAL SECTION ............................................................................................. 74
REFERENCES AND NOTES ............................................................................................ 84

CHAPTER III. THE REACTION OF B-ENAMINO ESTERS WITH
ACRYLATE DERIVATIVES: FORMATION OF
QUATERNARY CENTERS THROUGH ASYMMETRIC

AZA-ANNULATION
BACKGROUND AND SIGNIFICANCE .......................................................................... 89
Formation of Quaternary Centers ............................................................................ 89
Ala-Annulation History ........................................................................................... 92

Development of Aza-Annulation Methodology ....................................................... 94

Applications of Aza-Annulation methodology ......................................................... 95
EXPERIMENTAL GOALS ................................................................................................ 98
SYSTEM DESIGN ............................................................................................................. 98
RESULTS AND DISCUSSION ......................................................................................... 99

Substrate Variation in the Aza-Annulation with Acryloyl Chloride ,,,,,,,,,,,,,,,,,,,,,,,,,, 99

Asymmetric Induction as a Function of Chiral Auxiliary ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 103

Temperature Dependence of Asymmetric Induction ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 106

Asymmetric Induction and Acrylate Activation ..................................................... 107

Acrylate Substitution Patterns and Asymmetric Induction .................................... 108

Mechanistic Implications ....................................................................................... 1 12
CONCLUSIONS .............................................................................................................. 1 14
EXPERIMENTAL SECTION .......................................................................................... 1 15
REFERENCES AND NOTES .......................................................................................... 122
APPENDIX I

Ziegler-Nana Olefin Insertions With MAO-Raw Data. ......................................... 125
APPENDIX 11

List of Related Publications ................................................................................... 133

LIST OF TABLES

CHAPTER I. LEWIS ACID ACCELERATION OF THE 3-AZA-COPE

REARRANGEMENT
Table 1. Catalytic Acceleration of the 3-Aza-Cope Rearrangement. -------------------------------- 18
Table II. Studies of [3,3] Rearrangement Promoted by Aluminum Reagents ------------------ 20
Table III. 3-Aza-Cope Rearrangement and Imine Reduction. ............................................ 22
Table IV. 3- Ala-Cope Rearrangement and Imine Reduction. ............................................ 23

CHAPTER II. MECHANISTIC STUDIES OF INTRAMOLECULAR
ZIEGLER-NATTA OLEFIN INSERTIONS: a- AND B-
DEUTERIUM ISOTOPE EFFECTS AND CHAIN
TRANSFER PROCESSES

Table I. Selective Formation of Five-Membered Carbocycles ........................................ 53
Table II. Selective Formation of Six-Membered Carbocycles ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 53
Table 11]. Relative Rates For Competitive Cyclization of 41a and 41b ,,,,,,,,,,,,,,,,,,,,,,,,,,, 63

Table IV. Normalized a-Deuterium Isotope Effects for the Cyclization of
4la and 41b ...................................................................................................... 65

Table V. Normalized B-Deuterium Isotope Effects for the Cyclization of
418 and 41b ...................................................................................................... 67

CHAPTER III. THE REACTION OF CHIRAL B-ENAMINO ESTERS WITH
ACRYLATE DERIVATIVES: FORMATION OF
QUATERNARY CENTERS THROUGH ASYMMETRIC
AZA-ANNULATION

Table I. Asymmetric Induction with Respect to Substrate Variation ,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 100

Table II. Asymmetric Induction and Chiral Auxiliary Variation ..................................... 104

Table III. Asymmetric Induction and Temperature Variation for the Conversion
of 63 to 75

Table IV. The Effect of Acrylate Reagent on the Formation of 66., ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 108

LIST OF FIGURES

CHAPTER I. LEWIS ACID ACCELERATION OF THE 3-AZA-COPE

REARRANGEMENT
Figure 1. [3,3] Sigrnatropic Rearrangements .................................................................... 1
Figure 2. Transition States For the Thermal Claisen Rearrangement. ................................ 2
Figure 3. Reduction and Heterocycle Formation ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4
Figure 4. Possible Aza-Cope Transition States ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 7

CHAPTER II. MECHANISTIC STUDIES OF INTRAMOLECULAR
ZIEGLER-NATTA OLEFIN INSERTIONS: or- AND [3-
DEUTERIUM ISOTOPE EFFECTS AND CHAIN
TRANSFER PROCESSES

Figure 1. Various Agostic Interactions ............................................................................ 48
Figure 2. Ziegler-Nana a-Olefin Polymerization Model. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 57
Figure 3. Summary of Kinetic Isotope Effects. ............................................................... 68

CHAPTER III. THE REACTION OF CHIRAL B-ENAMINO ESTERS WITH
ACRYLATE DERIVATIVES: FORMATION OF
QUATERNARY CENTERS THROUGH ASYMMETRIC

AZA-ANNULATION
Figure 1. Nitrogen Heterocycles with Quaternary Carbon Centers... ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 89
Figure 2. B-Amino Acid Isostcres ................................................................................... 96
Figure 3. Electron Deficient Olefins for Aza-Annulation... .............................................. 99

Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.

Figure 9.

Figure 10.
Figure 11.

Figure 12.
Figure 13.
Figure 14.

Figure 15.
Figure 16.

Partial 1H NMR of 64 ................................................................................... 101

Partial 1H NMR of 66.... ............................................................................... 101
Partial 1H NMR of 68 ................................................................................... 102
Partial 1H NMR of 70 ................................................................................... 102
Partial 1H NMR of 72 ................................................................................... 103
Partial 1H NMR of 75 ................................................................................... 105
Partial 1H NMR of 77 ................................................................................... 105
Comparison of Chiral Auxiliaries .................................................................. 106
Partial 1H NMR of 78 ................................................................................... 109
Partial 1H NMR of 82 ................................................................................... 110
Partial 1H NMR of 84 ................................................................................... 112
Enamincracial Selectivity ............................................................................. 112
Mechanistic Alternatives For Aza-Annulation ................................................ 113

LIST OF SCHEMES

CHAPTER I. LEWIS ACID ACCELERATION OF THE 3-AZA-COPE

Scheme 1.
Scheme 11.
Scheme III.

Scheme IV.
Scheme V.
Scheme VI.
Scheme VII.
Scheme VIII.
Scheme IX.
Scheme X.

REARRANGEMENT

Energetics of the Claisen Rearrangement. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 3
Energetics of the 3-Aza-Cope Rearrangement ............................................... 4
Acceleration of the Claisen Rearrangement via Organoaluminum

Complexes .................................................................................................... 6
Pd(0) Catalyzed [3,3] Rearrangement ........................................................... 7
Regioselectivity of the Claisen Rearrangement .............................................. 8
Selectivity of the 3-Aza-Cope Rearrangement ............................................. 12
Preparation of 47 and 48 Via the 3-Aza-Cope Rearrangement ,,,,,,,,,,,,,,,,,,, 13
Preparation of Rearrangement Substrates .................................................... 14
Regioselectivity Study Strategy ................................................................... 16
Preparation of Secondary Amine 56 ........................................................... 16

CHAPTER ILMECHANISTIC STUDIES OF INTRAMOLECULAR

Scheme 1.
Scheme II.
Scheme III.

Scheme IV.
Scheme V.

ZIEGLER-NATTA OLEFIN INSERTIONS: a- AND B-
DEUTERIUM ISOTOPE EFFECTS AND CHAIN
TRANSFER PROCESSES

The Direct Insertion Mechanism ................................................................. 45
The Metathesis Mechanism ......................................................................... 46
The Modified Green-Rooney Mechanism ................................................... 47
Evidence For a-H Activation in a MAO/Zirconocene System. .................... 51
Isotope Effects in Scandocene Catalysis of Olefin Insertion ,,,,,,,,,,,,,,,,,,,, 52

xiv

Scheme VI.
Scheme VII.
Scheme VIII.
Scheme IX.
Scheme X.
Scheme XI.
Scheme XII.
Scheme XHI.

Chain Termination/Chain Transfer Pathways ............................................. 55

Chain Transfer Processes in Olefin Insertion Reactions .............................. 59
Preparation of Cyclization Substrates ......................................................... 61
Competitive Cyclizations of 41 ................................................................... 62
Calculation of the Alpha K H/K D for 418.. .................................................. 64
Calculation of the Beta KH/KD for 418 ...................................................... 66
Potential Ligand Catalyst/Cocatalyst Interactions ........................................ 70
Chain Transfer Processes in Olefin Insertion Reactions ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 72

CHAPTER III. THE REACTION OF CHIRAL B-ENAMINO ESTERS WITH

Scheme 1.

Scheme 11.
Scheme III.
Scheme IV.
Scheme V.

Scheme VI.

ACRYLATE DERIVATIVES: FORMATION OF
QUATERNARY CENTERS THROUGH ASYMMETRIC
AZA-ANNULATION.

Conjugate Addition to Chiral Imines ........................................................... 92
Formation of [i-Amino Acid Isosteres ......................................................... 95
Preparation of (i)-Tashirornine .................................................................. 96
Synthesis of (i)-5-Epipumiliotoxin C ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 97
Preparation of (i)-Lupinine ........................................................................ 97
General Formation of 8-Lactams ................................................................. 98

XV

Bn

n—BuLi
C6H6

Cpl!

DIPA
DMF
DMSO

EtzO
EtOAc
EWG
GLC

LIST OF ABBREVIATIONS

Acetyl (CH3C(O))

Benzyl

n-Butyl

n-Butyllithium

Benzene

Cyclopentadienyl
Pentamethyl Cyclopentadienyl
Deuteron (2H)
Diisopropylamine
N,N-Dimethylformamide
Dimethyl sulfoxide

Ethyl

Diethyl ether

Ethyl Acetate

Electron withdrawing group
Gas liquid chromatography
Lithium aluminum deuteride
Lithium aluminum hydride
Lithium diisopropylamide

Methylaluminoxane

xvi

Mng

Ph

nPr
iPr

stOH

Methyl

Magnesium dihalide (X=Br or Cl)
N-Bromosuccinimide

Phenyl

n-Propyl

Isopropyl

Triethylamine

Tetrahydrofuran

para-Toluene sulfonic acid

CHAPTER I
LEWIS ACID ACCELERATION OF THE 3-AZA-COPE
REARRANGEMENT

 

BACKGROUND AND SIGNIFICANCE

The research described herein involving the 3-aza-Cope rearrangement (l to 2,
Figure 1) parallels much of the reported findings for the well known Claisen rearrangement
(3 to 4, Figure 1),1 the oxygen analog of the 3-aza-Cope rearrangement. The Claisen
rearrangement is an extremely useful reaction in organic synthesis because it is a carbonf
carbon bond forming process that can selectively generate as many as two new

stereocenters as well as establish double bond geometry.

”,0: "" .103: 6:: —’ <0
2

1

 

Figure l. [3,3] Sigmatropic Rearrangements

The Claisen rearrangement is a concerted and nonsynchronous process, which
proceeds through a well defined six-membered transition state in either a boat- or chair-like
conformation.2 The chair conformation has been reported as the preferred transition state
by Schmid and coworkers.2 As illustrated in Figure 2, the stereochemical outcome of the
' rearrangement depends upon several factors. The first factor is the geometry of the olefins

of both the allyl and the vinyl substituents, and the second major factor is the transition

state conformation: boat vs. chair. In addition, the C-4 stereochemistry can influence the
outcome of this sigmatropic rearrangement. The thermal Claisen rearrangement is known
to proceed predominantly through a chair-like transition state in which a substituent in the
allylic position occupies a pseudo-equatorial orientation (8, Figure 2).“).8'i As a result of
the equatorial orientation of the allylic substituent, theresultant double bond predominantly
has the [5 configuration. The concerted nature of this reaction and the rigidity of the six-
membered chair transition state work together to define the orientation of the two new
stereogenic centers (9) based on the olefin geometry of the rearrangement precursor.
Failure to control double bond geometry in the allyl vinyl ether substrate for the Claisen
rearrangement results in incomplete selectivity of the vicinal stereocenters in the

rearrangement product.

MWMO 180 o MOW MD #MIU MD
'9
Me
6

 

H H H
Me H M0 H 0M0 H
OWN Me 180 e 0W3 M“ _. Y Ma
HH MeH HHM°H ‘ HI-llvloH
7 a c

Figure 2. Transition States For the Thermal Claisen Rearrangement

Simple comparisons of the bond energies involved in the Claisen and the 3-aza-
Cope rearrangements are shown in Schemes I and H. The Claisen rearrangement (3-t4,
Scheme I) has AE=-24 kcal/mol, with the formation of the carbon-oxygen double bond
being the strongest driving force. Similarly, the energy difference in the 3-aza-Cope
rearrangement (lo-911, Scheme I) is AE=-21 kcal/mol. The overall difference between

the two rearrangement processes is 3 chmol. This energy difference arises from the

more favorable formation of a carbon-oxygen double bond in the Claisen rearrangement
relative to formation of the carbon-nitrogen double bond in the 3-aza-Cope rearrangement.
Therefore, the thermal [3,3] Claisen rearrangement occurs at lower temperatures than the 3-
aza-Cope rearrangement as has been previously reported.1»3 Accordingly, thermal 3-aza-
Cope rearrangements have attenuated synthetic utility due to the high temperatures required
for complete conversion of starting material to product. Many important functional groups
present in natural products are too sensitive to withstand the reaction conditions required
for the thermal 3-aza-Cope rearrangement.3 Therefore, this rearrangement is restricted to
early incorporation in synthetic pathways, prior to introduction of sensitive functional
groups. In addition to the potentially destructive high temperatures required for
rearrangement, isolation of the resulting imine can be difficult, so the product is typically
hydrolyzed to the corresponding aldehyde or ketone. This hydrolysis provides a 8,8-
unsaturated carbonyl compound, which is the same product that can be obtained from the
Claisen rearrangement of the corresponding allyl vinyl ether. Acceleration of the 3-aza-
Cope rearrangement and development of a means of isolation that does not require
hydrolysis of the rearrangement product are both essential in order for this reaction to

become synthetically useful.

Scheme 1. Energetics of the Claisen Rearrangement.

=.-.. '5 W
2 0.0 2(146)
2 co 2(86)

1 6-0 1(83)
547 [ AE - -24 kcal/mol]

 

 

3 cc 3133)
1 mo 11145)
571

 

A
ox’
3
“El
1 0.0 War
0’.)
4

4

Scheme 11. Energetics of the 3—Aza-Cope Rearrangement.

 

 

 

A 2 0.0 2(146)
n’ "J 2 GM 2(73)
1° 1 C-C 1(33)
521 [ AE . .21 kcal/mon
AEl
1 C-N mm
3 3 cc 363)
,N
n , c-c 1(146)
1‘ 542

Several features of the 3-aza-Cope rearrangement, however, provide potential for
increased synthetic utility in comparison to the related Claisen rearrangement. Olefin
geometry is more effectively controlled during enamine formation than during allyl vinyl
ether formation.“ Also, the presence of the N -alkyl group potentially facilitates
asymmetric induction through the use of allyl enamines derived from amino acid sources.4
Since a wide variety of N-alkyl-N-allyl enamines are accessible,5 and due to the number of
potential applications of 8,8-unsaturated imines, acceleration of the 3-aza-Cope
rearrangement is of synthetic interest. An alternative to isolation of the sensitive imine is
reduction of the rearrangement product to yield 8,e-unsaturated amines which are also
synthetically valuable since such amines can be cyclized via a number of known pathways

to nitrogen containing heterocycles (Figure 3).5

Me

/ 7C)
LnMH \3 1‘
——->
H
R
15

Figure 3. Reduction and Heterocycle Formation.

Acceleration of the Claisen Rearrangement. There have been a number of
reports in which the Claisen rearrangement was accelerated through the use of Lewis
acids.7rli.i Lewis acids such as TiCl4, Et20:BF3, SnCl4, and ZnBr2 were not effective
for acceleration of the [3,3] sigmatropic shift. To date, the only Lewis acid complexes that
have shown promise for acceleration of the Claisen rearrangement have been
organoaluminum complexes.8 Takai, et al. have reported that EtzAISPh and Et2AlCl/PPh3
give 8,8-unsaturated aldehydes from allyl vinyl ethers at room temperature.8 However,
this acceleration process was not catalytic, as 2.2-2.5 equivalents of aluminum were
required to effect rearrangement. Both i-Bu3Al and i-BuzAlI-I drive rearrangement, but in
situ reduction of the resulting carbonyl functionality could not be avoided.3 AlMe3 was
also an effective rearrangement promoter, but addition of a methyl group to the carbonyl
carbon always followed rearrangementfhlv8a

Recently, Yamamoto reported the rearrangement of allyl vinyl ethers (16—0174-18,
Scheme III) at temperatures as low as -78 °C using a number of bulky aryloxy aluminum
reagents.9 In addition to remarkable acceleration of the Claisen rearrangement,
Yamamoto's work has generated great interest due to the different olefin geometry
selectivity available based on the steric demands of the aluminum complex (Scheme III).
For bis-(2,6-diphenylphenoxy) methyl aluminum (Reagent A), rearrangement resulted in
the same product mixture as the thermal rearrangement. However, variation in the steric
constraints and the electronic contribution of the aluminum reagent, through the use of
Reagent B (bis-(2,6-di-t-butyl-4—bromo)phenoxy) methyl aluminum) instead of Reagent
A, changed the conformation of the chair transition state. In order to accommodate the -
more sterically demanding Lewis acid, the allylic n-butyl group was forced into a pseudo-
axial position rather than the normal equatorial position? This conformation change

resulted in the preferential formation of 18.9

6
Scheme III. Acceleration of the Claisen Rearrangement via

Organoaluminum Complexes

- 1

~ ’ O
« / QO'E’DNM' P’CLMe
O

 

 

 

 

17
nar’K/‘Me \ 1
16 :Cépbéff: _ noun
Me
13
REAGENT TEMPERATURE RATIO (17:18)
None 250°C 92:8
Ph .
A Go)...“ -20°C(15-30 min) 99:1
2
9.1
9'69“!“ -78°C(15 min) 16:84
a, 2

 

Yamamoto's evidence for variable transition states in the Lewis acid promoted
Claisen rearrangement9 prompted further investigation into the mechanism of carbon-
carbon bond formation in the analogous 3-aza-Cope rearrangement. There are two
mechanistic extremes possible for this six-atom rearrangement (Figure 4). The first
possible path is an ionic transition state in which bond breakage precedes bond formation.
An ion pair transition state of this nature can potentially give rise to both [1,3] and [3,3]
rearrangement products. A second mechanistic extreme is described as a concerted
transition state in which bond breakage and bond formation occur simultaneously. The

concerted transition state only allows for the formation of [3,3] rearrangement products.

As seen for the Claisen rearrangement, various means of reaction acceleration favor

different mechanistic pathways.9 Therefore, it is necessary to define the limits of [1,3] vs.

[3,3] regioselectivity for the Lewis acid promoted 3—aza-Cope rearrangement.

1.9319

1!an
lBU~N‘:‘¢(m
Me

BMW‘s?

/\

[1,3] PRODUCTS [3,3] PRODUCTS

 

QQNQEBIED.
H M
HEAL? .BuLnfi n‘ H R2
a ‘0 ' . s
'80 \cyll Ra 3);: H
I Mr - M.
H H HHMa
Char Boat

\/

[3,3] PRODUCTS ONLY

Figure 4. Possible Ala-Cope Transition States.

Both [1,3]10 and [3,3]11 rearrangements of allyl vinyl ethers are possible through

palladium catalysis. As shown by Bosnich, in the case of the [1,3] rearrangement, the

reaction is reported to proceed through a 1t-allyl palladium intermediate following oxidative

addition to the Pd(O) species. 12 The [3,3] rearrangement is presumed to proceed through a

cyclic zwitterionic intermediate for Pd(II) catalysis (48, Scheme IV). 1?

Scheme IV. Pd(O) Catalyzed [3,3] Rearrangement.

H+

ll

XYY

Z

19

A :43,
XTY z

20 21

Murahashi has shown that palladium (0) complexes, in the presence of protic acid
cocatalysts, are effective in transforming enamines to imines; a process which on the
surface is similar to the 3-aza-Cope rearrangement.13 However, the palladium catalyzed
rearrangement proceeded through a (1t-allyl)palladium complex that resulted from oxidative
addition of palladium to the protonated enamine.l3 Both [1,3] and [3,3] rearrangement
products were obtained during this process, therefore, the palladium catalyzed reaction is
not a sigmatropic process, but rather proceeds through an ionic intermediate.

Interestingly, Yamamoto also observed the formation of [1,3] rearrangement
products using the complexes A and B when the allyl vinyl ether had a phenyl substituent
in the allylic position (22, Scheme V).9 The presence of both [1,3] and [3,3]
rearrangement products implied the intervention of an ionic intermediate rather than a

concerted chair-like transition state?

Scheme V. Regioselectivity of the Claisen Rearrangement.

°“ .——.-“°°°'* “”° ——- 0 CL
22 [3.3] [1.3]
24

 

REAGENT [3,31 [1,3]

R1

1 Q0)...
2 45% 13%
R1

1&1
B Br—QO>AIMe
a, 2

31% 49%

 

Acceleration of the Aromatic 3-Aza-Cope Rearrangement.
Investigations into acceleration of the 3-aza-Cope rearrangement has lagged considerably
behind those pertaining to the Claisen rearrangement. The majority of reported studies
describe acceleration of the aromatic 3-aza-Cope rearrangement. Jolidon and Hansen have
shown that the thermal rearrangements of aromatic enamines were accomplished at
temperatures of 200-350 °C, and that these carbon-carbon bond forming processes were, in
fact, [3,3] sigmatropic shifts that exhibited a preference for a chair-like transition state.14
Attempts to decrease the required temperature for the 3-aza-Cope rearrangement included
the use of both protic and Lewis acids.14 Acceleration of this rearrangement has been
accomplished at temperatures as low as 50-70 °C for a,a-dimethyl substituted allyl
enamines with the aid of protic acids such as H2SO4, H3PO4, CF3C02H and HCl.1i For
monosubstituted systems, the required temperatures remained above 100 °C.14

Both ZnC12 and EtzozBFg were effective in promoting the aromatic 3-aza-Cope
rearrangement.” For the rearrangement of N—allylaniline, 0.7 equivalents of ZnClz in
refluxing xylene gave a 42% yield of o-allylaniline. 1° Et2O:BF3 appeared to be more
efficient in promoting the rearrangement of the same substrate, as a 73% yield of o-
allylaniline was obtained.15 The [3,3] nature of this rearrangement was clearly seen from
the lack of inversion of a substituted allyl group with ZnC12 as the catalyst (Equation 1).15
Enamine 25 rearranged to give a mixture of amines 26 and 27 (78:12 ratio), and the
noninverted crotyl group of amine 27 resulted from two consecutive [3,3]

rearrangements.16

NH2
NH2 Me M‘
21101, M.

H
N
"-61”. 140°C 6"} t m (1)
25

10

Other Lewis acids examined for acceleration of the aromatic 3-aza-Cope
rearrangement include AlCl3, TiCl4, SbCls, and CuCl.1'I AlCl3, TiCl4, SbC15 and ZnClz
were used for promoting rearrangement in indole systems (Equation 2).” AlCl3 was the
only remotely efficient catalyst in these systems giving a 43% isolated yield of 29 from

28.

Me
Cf» AICI, (1 eq)
———>
N M, PhH.80°C. 2h N (2)
23 29 H

Copper chloride has shown marginal promise for catalysis of the acetylenic 3-aza-
Cope rearrangement (30431, Equation 3), giving yields of 25-66% depending on the

substitution pattern of the aromatic ring. 13

 

H H
| MO I MO
N m CUCI (1 eq) = W
R-U Dioxane. 9" (3)
75 °C, 2111'
30 31

Work from these labs has recently provided a systematic study of the Lewis acid
acceleration of N-alkyl-N-allylanilines.19 This investigation revealed that rearrangement of
such aromatic systems was possible at temperatures between 111 and 140 °C. AlCl3,
ZnClz, and Et20:BF3 (1.2 equiv. each) were shown to be the Lewis acids of choice to

provide rearrangement within 48 hours.19

Acceleration of the Aliphatic 3-Aza-Cope Rearrangement. Very few
attempts have been reported for acceleration of the aliphatic 3-aza-Cope rearrangement.

Initially, variation of the C(2) substituent (Y) was examined as a means of rearrangement

11

acceleration (Equation 4)?0-21 By placing an electron donating alkoxy substituent at this
position, the rearrangement was accomplished at 190 °C.?1 The use of a dialkylamino
substituent gave rearrangement at 200 °C,?2 but the rearrangement of N-allyl amide enolates

was successful at 135 °C?3

Y Y
FL N’K [3.3] 9‘ fl (4)
|\/ '
32 33

Another approach to rearrangement acceleration was to decrease the electron density
on nitrogen through the formation of quaternary nitrogen centers. Brannock has shown
that the 3-aza-C0pe rearrangement was promoted at temperatures as low as 80 °C by first
allylating an N,N-dimethylenamine with allyl bromide (34, Equation 5124 The
rearrangement also proceeded at 80 °C following methylation of an allyl enamine (37) with
methyl tosylate (Equation 6)?4 Although these methods are effective, symmetrical allyl
groups must be used due to the competitive nature of C versus N allylation. In addition,
the resultant imines were not isolated, but rather hydrolyzed to the corresponding 8,8-

unsaturated carbonyl compounds.24

Me\ M“ —’ Me’vm —> (5)
INN M. amp Me
Me Me 34 “67 "’
Me

’N’NM" MeOTs “LN’VW ”8°” 9:3;

Kim ' ”bk/M“ 211420

(6)

12

Prior to this investigation, Lewis acid catalysis of the aliphatic 3-aza-Cope
rearrangement had only been reported on two occasions?5’26 In 1978, Hill reported that
TiCl4 could be used to catalyze enamine formation, and these enamines (if allylic)
rearranged to imines in refluxing benzene, and even to a significant extent at room
temperature?5 Hill was able to show that the TiC14 Catalyzed rearrangement also exhibited
chair-like character in the transition state and gave selectivity comparable to that obtained
for the thermal process.3 For example, rearrangement of enamine 39 gave the same ratio
of 41:42 (90:10) for both thermal and catalyzed rearrangement, and the asymmeuic

induction was also the same (67%) (Scheme VI)?5

Scheme VI. Selectivity of the 3-Aza-Cope Rearrangement.

Fh Fh
\ H1 \ “1
N "Me [3.31 Me
Melk/ Me
39 40
111.0:
“'1‘ \‘HI' 9“ "‘91
QM. * Me Me
Me
41 42

As recently as 1989, Bailey reported the use of TiCl4 for the preparation of
aldehydes 47 and 48 having excesses of 90% and 98% respectively (Scheme VII)?6
Chiral amine 43 was condensed with 2-phenylpropionaldehyde (44) in refluxing toluene to
give enamine 45, which was not isolated. In situ treatment of 45 with TiCl4 at 55 °C,
followed by hydrolysis gave aldehydes 47 and 48. In contrast to the remarkable
selectivities, the overall yields were quite low, 06-56%). Reaction times and catalyst

concentrations were not reported?5

13
Scheme VII. Preparation of 47 and 48 Via the 3-Aza-Cope Rearrangement.

Eh o ‘3‘
M93 NH + ph H Toluene Me’KN/‘(Fh
VMO Me 111°C VMJQ
43 44 45
$1101. 55°C
Fh F11 Ph
:- Hot ,
“Aug; __3__,O um +0 um
Me "’Me Me
46 47 48

The myriad of readily available Lewis acids lends a great deal of flexibility to the
development of the 3-aza-Cope rearrangement as a synthetic tool. The undertaking of this
study was anticipated to provide some of the missing information, and increase the

synthetic utility of this selective carbon—carbon bond forming process.

EXPERIMENTAL GOALS

The goals of this work were to systematically define the range of Lewis acids that
can be used to efficiently accelerate the sigmatrOpic rearrangement of N—alkyl-N-allyl
enamines.27 The benefits of Lewis acid promotion with respect to decreased reaction time,
reduced reaction temperature and ease of product isolation were explored. In addition, the
regioselectivity of the aza-Cope rearrangement under Lewis acid promotion conditions was

investigated.
EXPERIMENTAL DESIGN

Optimization of Lewis acid promoted rearrangement conditions began with the

preparation of enamine 51 from allyl amine and isobutyraldehyde (Scheme VIII). Imine

14

49 was isolated in 75% yield, and acylation with the appropriate acid chloride gave
enamides 503 and 50b in good yield. The enamides were very stable and easily purified
by column chromatography. Therefore, the substrates were stored as the enamides and

reduced just prior to use to give enarrrines 51a and 51b in high yields.

Scheme VIII. Preparation of Rearrangement Substrates.

NH NMe 512° ‘ NNM‘
K, + 0 Me RT'16|; m
75wi
a
E N
R OCI
mason,
1.51:
- 3. Me
51- RaiPr(90%YIeid) RAN/\(M‘ UN” a N’\( 50oR-iPr(90%Yteid)
51bR-C.H,,(99%Yield) KIM“ “PM '\/ Mo 50bR-C.H,1(84%Yieid)

Due to comparative costs and availability of the required acid chlorides, initial
optimization of rearrangement conditions, as monitored by GC, were performed with
enamine 51a. For isolated yields, however, an increase in molecular weight was
desirable, so enamine 51b was used. The sigmatropic rearrangement and reduction
process is shown in Equation 7. Since this method does not require hydrolysis of the
imine, isolated yields are reported for the rearranged and reduced fire-unsaturated amine
53b. The limiting parameters set for this rearrangement study were a maximum reaction

time of 24 hours and maximum temperature of 111 °C (refluxing toluene).

m m
(\N’V m fl. RAN m UNH4 F1": m
| Me or "' ' "' (7)
”Lo
51 52 53

15

In order to elucidate the mechanistic pathway, experiments were designed in which
the rearrangement of unsymmetrically substituted allyl enamines was examined. This
strategy is illustrated in Scheme IX.

The formation of a single product from each reaction would be expected (54455,
56457) if the reaction proceeded exclusively via a concerted [3,3] pathway. If, however,
the pathway was ionic in nature, both the [1,3] and [3,3] rearrangement products would be
observed (54-+55+57, 56455-67) for each reaction. Two classes of substrates were
examined (54 and 56), so that variation in charge stabilization ability could also be used to
probe the prOpensity for the formation of ionic intermediates.

Yamamoto's studies discussed previously showed intervention of an ionic
intermediate for substrates with an allylic phenyl substituent.9 This allylic phenyl
substituent could, potentially, provide sufficient charge stabilization for the formation of a
cationic fragment which would allow formation of the [1,3] rearrangement product. A
terminal phenyl substituent on the allyl fragment would not be expected to provide such
effective stabilization during the bond breaking process. An alkyl substituent in either
position would also be less effective than the allylic phenyl substituent for charge
stabilization. For these reasons, the first class of substrates was substituted with an alkyl
group (54a, R=nPr, 56b, R=nPr) and the second was substituted with a phenyl group
(54b, R=Ph; 56b , R=Ph). Both phenyl substrates (69 and 73) as well as alkyl substrate
61 were originally prepared by Ms. Meg Landis, and the details are given in the
Experimental Section for completeness.28 Amine 60 was prepared from trans-2-
cyclohexen-l-ol (58) via the tosylate and subsequent reaction with isobutyl amine as

shown in Scheme X.

16
Scheme IX. Regioseiectivity Study Strategy.

. Me
IBU\ NNW liq m
R/K/ “—’ [331

‘ x’l‘fl

 

.8“ 1.11,.

I \

N‘N: a: 12.1191
b: R-Ph

 

 

18.! CE"? i3) J:

57

Scheme X. Preparation of Secondary Amine 56.

2 ToeCl —> MD
nPr ) 88% Yield v nPr

Me

0‘1 1) nBuU OTe M‘kNHz M81",,“
nPr

S 50

5
RESULTS AND DISCUSSION

The results for protic acid (HCl) and several non-aluminum metal halide promoted
rearrangements are given in Table 1.29 Although the rearrangement of 5111 was complete
within 6 hours at 111 °C using only 0.3 equivalents of HCl, the isolated yield was
maximized at 85% by using 0.5 equivalents. Lower temperatures with 0.5 equivalents did
not increase the yield even with increased reaction times. As TiCl4 has been reported to be
effective for similar transformations,” its use was examined under a variety of conditions.
Using more than 0.1 to 0.2 equivalents was not beneficial, perhaps due to increased

substrate oligomerization, however, a respectable isolated yield (73%) could be obtained

17

via TiCl4 catalysis with 0.1 equivalents. TiCl4, therefore, was more effective for
promotion of the aliphatic 3-aza-Cope rearrangement than it was for promotion of the
Claisen rearrangementlliii An attempt to modify the Lewis acidity of TiCl4 was made by
exchanging two chloride ligands with 2,6-diphenylphenoxide ligands. This catalyst gave
comparable GC yields, but slightly decreased isolated yields due to difficulties in separating
the final Sat-unsaturated amine from the 2,6-diphenylphenol.

EtzozBF 3 gave good GC results for the rearrangement at 111°C with 0.5
equivalents of the Lewis acid, however, the isolated yields did not reflect this level of
efficiency. The effectiveness of Et20:BF3 in promotion of the 3-aza-cope rearrangement is
in contrast to the results reported for acceleration of the Claisen rearrangement, but parallels
the results reported for acceleration of the aromatic 3-aza-Cope rearrangement.15

Both SnC14 and ZnClz were also examined, and even at 111 °C for 48 hours, SnCl4
was only able to affect 84% conversion, and gave an extremely low yield (14%). Although
ZnClz gave complete conversion with 1.0 equivalent at 111 °C within 24 hours, 10— 15% of
an unidentified side product was formed in each case. Further exposure to the reaction
conditions resulted in degradation of the rearrangement product. Despite the fact that Sad;
and ZnC12 are good catalysts for the aromatic 3-aza-C0pe rearrangement, the results for the

accelerations of the aliphatic 3-aza-Cope were not as good.15»17

18

Table 1. Catalytic Acceleration of the 3-Aza-Cope Rearrangement.“

 

 

 

Me H Mn
(\N’\' Va _H’_)C> RAU Nb flit R/\ N Me
9 "‘ MEI.
51 52 53
YIELDS
CATALYST EQUIV TIME TEMP GLCb ISOLATEDC
HCl 0.3 6 hr 111 °C 70%
0.5 3 hr 111 °C 82% 85%
0.5 6 hr 80 °C 64%
0.8 6 hr 111 °C 82%
TiCl4 0.1 24 hr 111 °C 83% 73%4
0.3 24 hr 111 °C 64%
0.5 24 hr 111 °C 56%
0.5 24 hr 80 °C¢ 8%
(ArO)2TiC12 0.5 24 hr 111 °C 80% 71%
0.5 48 11: 111 °C 87%
5120:3123 0.5 24 hr 111 °C 82% 59%
0.5 24 hr 80 °d 59%
1.0 9 hr 111 °C 75%
1.5 5 hr 111 °C 70%
SnCi4 0.1 48 his 111 °C 14%
21102 1.0 12 hr 111 °C 86%

1.0 24 hr 1L1 °C 74%

{All reactions were run 0.2 M in toluene. D Rearrangement of 51a to 52a (R=iPr)
was performed on a 1.0 mmol scale. Yields were determined by capillary gas
chromatographic (GLC) analysis of the quenched reaction mixture (10% w/v
MeONa/MeOH) using internal standards and correcting for detector response. Values
were based on reaction substrate. C Isolated yields of 53: (R=cyclohexyl) after
rearrangement of 51b (5 mmol and reduction of 5 b. 0.2 equiv of catalyst
required on 0.5 mmol scale. 18% conversion. 97% conversion. 8 84%
conversion.

19

Since aluminum catalysts have been successfully utilized to accelerate the Claisen
rearrangement,8 a series of aluminum complexes were studied for their effectiveness for
promotion of the transformation of 51 to 53. As reported for promotion: of the Claisen
rearrangement with EtzAlSPh and EtzAlCl/PPh3,8 all of the aluminum catalysts examined
promoted the rearrangement, but only when employed in stoichiometric amounts (Table II).
This is clearly seen from the results of ClAlMez where 0.2 equivalents and 0.5 equivalents
gave a maximum of 19% and 60% conversion of 51a to 53a respectively.

As expected, increasing the Lewis acidity of the aluminum complex lowered the
temperature required for complete conversion of substrate to product. Both ClAlMe2 and
ClelMe promoted the rearrangement at 50 °C with isolated yields of 91% and 87%
respectively. These results represented a decrease of 200 °C in reaction temperature for the
3-aza-Cope rearrangement. In addition, promotion of the 3-aza-Cope rearrangement with
AlMe3, ClAlMez, or C12AlMe did nOt result in ligand addition as reported for the Claisen
rearrangement of allyl vinyl ethers.7av3a A1C13 was also examined as a potential catalyst,
however, yields of the rearranged product were unacceptably low (63% at 80 °C) despite
the fact that AlCl3 was one of the only Lewis acids to efficiently promote the 3-aza-Cope
rearrangement in indole systems.19 Lastly, bis-(2,6-diphenylphenoxy) methyl aluminum
was employed to affect the rearrangement. The aryloxy aluminum reagent was quite
effective for promotion of the 3-aza-Cope rearrangement which parallels the Claisen
rearrangement results reported by Yamamoto.9 Yields for the 3-aza-Cope rearrangement of
N-alkyl-N-allyl enamines were optimum with the aryloxy aluminum catalyst after 24 hours
at 40 °C ( 87% GC, 80% isolated).

Table II. Studies of [3,3] Rearrangement Promoted by Aluminum

Reagents.“

R/\N’\' M“ ””5

 

 

 

RAN mm m R": "BM;
K, Me "Tr" :j'
MLn
51 52 53
YIELD
CATALYST EQUIV TIME TEMP GLCb ISOLATEDC

AlMe3 0.5 12 hr 111 °C 100%

1.0 12 hr 111 °C 100% 99%
1.5 6 hr 111 °C 100%
1.5 24 hr 80 °C 100%
ClAlMe2 0.2 24 hr 111 °C 50%4
0.5 34 hr 80 °C 71%
1.0 24 hr 25 °C 54%
10 mm mm M%

1.0 24 hr 50 °c 88% 91%
1.0 9 11: 60 °C 83%

1.0 5 hr 80 °C 96% 96%

ClelMe 1.0 24 hr 50 °C 79% 87%

1.0 12 hr 80 °C 91% 84%

(Ar0)2AlMe 1.0 24 hr 40 °C 87% 80%
1.0 12 hr 60 °C 84%
Cl3Al 1.0 24 hr 50 °C 36%
10 mm mm m%

 

 

1AM reactions were run 0.2 M in toluene. ”Rearrangement of 51a to 52a
(R=iPr) was performed on a 1.0 mmol scale. Yields were determined by capillary
gas chromatographic (GLC) analysis of the quenched reaction mixture ( 10% w/v
MeONa/MeOH) using internal standards and correcting for detector response.

Values were based on reaction substrate. C Isolated yields 0
after rearrangement of 5111 (5 mmol) and reduction of 52b.
product. e 60% conversion.

‘5

3b (R=cyclohexyl)
19% conversion to

21

Table III illustrates the condensation, rearrangement and reduction process for the
alkyl substituted enamines 62 and 66, and summarizes the findings of the regioselectivity
study.30 The catalysts examined were a protic acid (HCl, 0.5 equiv.), the metal halide
TiCl4 (0.2 equiv.), and two organoaluminum complexes AlMe3 and bis(2,6-
diphenylphenoxy)methyl aluminum (1.0 equiv. each), all of which have previously been
shown to efficiently promote the 3-aza-C0pe rearrangement.23 For each reagent, it is clear
that the rearrangement was a [3,3] sigmatropic process, as the products of [1,3]
rearrangement were not observed. For amine 61, condensation with isobutyraldehyde was
easily accomplished with p-toluenesulfonic acid in refluxing benzene. The reaction was
driven to completion by azeotropic removal of the water with a modified Dean-Stark trap
designed in these labs.31 Enamine 62 was not isolated, rather, the benzene was Simply
removed by rotary evaporation, replaced with toluene, and the rearrangement promotion
complex was added. When enamine 62 was treated with HCl in refluxing toluene for 6
hours, and then reduced with LiAlI-I4, 64 was isolated in 69% yield as the only reaction
product. Similar treatment using TiCl4 for 24 hours at reflux resulted in a single
rearrangement product which was isolated in 79% yield. AlMe3 also gave exclusively
[3,3] rearrangement, and 64 was isolated in 80% yield. Contrary to the findings of
Yamamoto regarding the use of bis(2,6-diphenylphenoxy)methyl aluminum for the
rearrangement of allyl vinyl ethers, 64 was isolated in 61% yield without evidence for
formation of 68.3 In all cases, only the E alkene isomer of the final amine was observed,
as shown by the presence of the characteristic E alkene absorption at 970 cm'l, and the
absence of the Z alkene absorption in the region of 690 cm‘l.32

Amine 65 could not be easily condensed with isobutyraldehyde in the presence of
p-toluenesulfonic acid. As a result, a "one-pot" procedure for the condensation,
rearrangement and reduction was developed for the formation of imine 67 with HCl and
TiCl4. Enamine 66 was isolated for rearrangement with AlMe3. It is important to note

that p-toluenesulfonic acid would not promote rearrangement of 62 or 66 even in refluxing

22
toluene. For the rearrangement of 65, again only [3,3] rearrangement was observed, with

isolated yields ranging from 76-87%.

Table III. 3-Aza-Cope Rearrangement and Imine Reduction.

 

M OAr M Me [3.3] M Me Me

afi/\Nl-l Me [VWMO] m V" Hernia-4.3“?“ Mo

“ta/'\/ .1... 111/KI m... '41. am, 111.

61 a t‘ , a u
(1.31)?
,’ \
MO
ON Me

Me vnPr O nPr

Me Me
MW .. m.» a «rum—Matt"-
M. Mo 7mm m 2111.01 M.
nPr m nPr
6? O

 

CONDITIONS PRODUCT

 

ENAMINE‘ REAGENT" Tlme(h)/ RATIO YIELD‘
Temp(-C)‘ (64:68)‘

6 2 HCl 6/111 >99:1 69%
TiCl4 24/111 >99:1 79%

AlMe3 24/111 >99:l 80%

(Aron/1W 24/111 >99:1 61%

6 6 HCl 30/111 1:>99 76%
TiCi4 30/111 l:>99 78%8

AlMe3 8/111 1:>99 87%

(AronAIMef 30/111 1:>99 85%

 

1Enamines were generated in situ by condensatio of the corresponding allyl amine with
isobutyraldehyde in either benzene or toluene. eagent (equiv.)z HCl (0.5), st0H
(0.05), TiCl4 (0.2), AlMe3 (1.1), and (Ar0)2AlMe (1. ). CRearrangements were run 0.2
M at reflux in toluene (1 11 °C) or qenzene (80 °C). In each case, the product of [1,3]
rearrangement was not detected by H NMR capillary GC. ‘Overall iso ted yield of
condensed, rearranged, and reduced products. ArO=2,6-diphenyl phenoxy. ction
of starting material. ‘Forrnation of 64 or 68 was not observed.

23

Table IV. 3-Aza-C0pe Rearrangement and Imine Reduction.

 

   

 

 

 

NH Mo M‘Y\ N/\<M M‘ mm 11m:°\'/‘H MMa
”PNJV ”T’°“ ”‘3th MW»: "311
Q I) ‘x ’I 72
[1.31‘1'
M. ,’ \
m 0““; MVCMO mM‘Y‘d‘ToZMMVNM‘t/h
Mo Ph w MO I; Ph
73 re
CONDITIONS PRODUCT
ENAMINE“ REAGENT" Tlme(h)/ RATIO YIELD‘
Tenn-CL (72:76)“!
7 0 BC] 48/80 >99:l 81%
stOH 48/80 >99:1 80%
TiCl4 48/80 >99:l 80%
7 4 HCl 24/111 11
TiCl4 24/111 i
AlMe3 5/111 l:>99 56%
(Aroma/16f 18/111 1: >99 55%

 

7Enarnines were generated in situ by condensatiorg of the corresponding ally lamine with

isobu

tyraldehyde in either benzene or toluene.

Reagent (equiv.:) HCl (0. 5), stOH

(0.05), TiCi4 (0. 2), AlMe3 (1.1), and (ArO)2AlMe (1)1). CRearrangements were run 0. 2

M at reflux In toluene (111 °C) or
rearrangement was not detected cedy

condensed, rearranged, and redu products. fArO=2 ,6-diphenyl phenoxy.
starting material.

qenzene (80 °C).
HNMR for capillary GC.

In each case, the product of [1,3]
‘Overall I lated yield of
ction of
Formation of 72 or 76 was not observed.

24

The results for the rearrangement of the phenyl substituted enamines are shown in
Table IV. The presence of a phenyl substituent in the allylic position accelerated
rearrangement to the extent that p-toluenesulfonic acid was sufficiently Strong to promote
complete rearrangement in refluxing toluene. Since enamine 70 rearranged under
condensation conditions, recourse to the previously described "one-pot" method was
necessary. Again, only [3,3] rearrangement products were formed during the
rearrangement process with HCI, p-toluenesulfonic acid and TiC14. Because enamine 70
could not be isolated, rearrangement with each of the two aluminum complexes could not
be investigated. The rearrangement of enamine 70 was quite facile perhaps due to charge
stabilization from the phenyl substituent. While this ability to stabilize positive charge
facilitated rearrangement, it was not sufficient to allow intervention of a cationic
intermediate. Therefore, [1,3] rearrangement products were not observed.

Amine 73 was easily condensed in the presence of p-toluenesulfonic acid, but
would not rearrange with this catalyst. The use of HCl or TiC14 only destroyed the
enamine, perhaps due to the stryene-like nature of the vinylic phenyl substituent.
Fortunately, the rearrangement could be effected with the aluminum complexes, and only
[3,3] rearrangement was observed giving 55% and 56% yields of amine 76 for the two

aluminum complexes.

CONCLUSIONS

As indicated by the results of this study, the initial premise that the 3-aza-Cope
rearrangement can be efficiently accelerated through the use of both protic and Lewis acids
was correct. A variety of reagents could be used for this rearrangement, and in most cases
conditions were found for isolation of the desired products in good yields. The utilization

of aluminum reagents allowed for a decrease of 200 °C from the temperature required for

25

uncatalyzed rearrangement. This study also showed that isolation of the rearrangement
product after subsequent reduction provided an avenue for the efficient selective preparation
of Sta-unsaturated amines.

Due to the decreased temperatures now required for complete rearrangement, the
fact that the Lewis acid promoted aza-Cope rearrangement was completely selective for the
[3,3] pathway, and the efficiency of isolation of the 5,8-unsaturated amines, the synthetic

utility of the 3-aza-Cope rearrangement has now been increased significantly.

EXPERIMENTAL SECTION

General Methods. All reactions were carried out performing standard inert
atmosphere techniques to exclude moisture and oxygen, and reactions were performed
under an atmosphere of either nitrogen or argon. Benzene, toluene, tetrahydrofuran
(THF), and Eth were distilled from sodium/benzophenone immediately prior to use.
Triethylamine was heated at reflux over calcium hydride for a minimum of 12 h and then
distilled immediately prior to use. Solutions of HCl (1.0 M in Et20), LiAlH4 (1.0 M in
TI-IF), and ClelMe (1.0 M in hexanes) were obtained from Aldrich Chemical Co.
Solutions of AlMe3 and ClAlMe2 (1.0 M in toluene) were prepared from neat
organoaluminum compounds obtained from Aldrich Chemical Co. Cyclohexanecarbonyl
chloride, isobutyryl chloride, allyl amine, T104, and Et20:BF3 were distilled prior to use.
Additions were made with gas tight syringes, or via cannula transfer under nitrogen.
Unless Specified, concentration of solutions after workup was performed on a Bitchi rotary
evaporator.

Gas chromatographic (GLC) analyses were carried out on a Perkin-Elmer 8500
instrument with a 50 m RSL—200 capillary column (5% methyl phenyl silicone) and an FID
detector at a 220 °C injector temperature, and a 300 °C detector temperature. Helium gas
pressure was set at 15 psi with a flow rate of 2 mL/min. NMR spectra were obtained on
Varian Gemini 300 or VXR-300 spectrometers with CDC13 as solvent. Data are reported
as follows: chemical shift relative to residual CHC13 (7.24 ppm), multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, sept = septet), integration, and coupling. Infrared

spectra were recorded on a Nicolet 42 FT-IR instrument.

26

27

N-Allylisobutylideneamine (49): Allylamine (3.54 g, 62 mmol) was added
to a flask containing 100 mL of EIZO and 14 g of 4A molecular sieves. Over the period of
10 min, isobutyraldehyde (4.47 g, 62 mmol) was added dropwise at 25 °C. After being
stirred at ambient temperature overnight, the solution was filtered and the remaining solids
were washed with two 50 mL portions of EtZO. The mixture then was distilled under
nitrogen at atmospheric pressure to give 49 (5.13 g, 46.0 mmol) in 75% yield (bp 112-114
°C): 1H NMR (300 MHz) (CDCl3) 8 1.05 (d, 6 H, J = 6.9 Hz), 2.42 (dsept, l H, J =
4.9, 6.9 Hz), 3.95 (d, 2 H, J = 5.6 Hz), 5.05 (dd, 1 H, J = 1.8, 10.3 Hz), 5.10 (dd, 1 H,
J = 1.8, 17.2 Hz), 5.93 (ddt, 1 H, J = 10.3, 17.2, 5.6 Hz), 7.51 (d, 1 H, J = 4.9 Hz);
13C NMR (75.5 MHz) (CDCl3) 6 19.3, 34.1, 63.2, 115.5, 136.1, 170.9; IR (neat) 3083,
3013, 2967, 2932, 2874, 2824, 2674, 1466, 1456, 1437, 1366, 1103, 1019, 995, 916

cm‘l.

Synthesis of 508 by Acylation of 49: To 50 mL of dry THF were added 6
(3.34 g, 30 mmol) and NEt3 (3.54 g, 33 mmol). The solution was cooled to 0 °C and
isobutyryl chloride (3.50 g, 33 mmol) in 20 mL of THF was added dropwise over a 30
min period. After being heated at reflux for 1.5 h, the solution was cooled to ambient
temperature and filtered through a pad of silica on a glass frit, and the solids were washed
with two portions of Et20. The solvents were removed under reduced pressure, and the
crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent -
50:50 Et20:petroleum ether). The solvents were evaporated and the enamide was isolated
via Kugelrohr distillation under vacuum to give 50a (4.88 g, 27 mmol) in 90% yield (bp
55-65 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) s 1.02 (d, 6 H, J = 6.8 Hz), 1.57
(s, 3 H), 1.70 (s, 3 H), 2.65 (sept, 1 H, J = 6.8 Hz), 3.89 (d, 2 H, J = 6.2 Hz), 5.04 (dd,
1 H, J = 1.6, 11.3 Hz), 5.06 (dd, 1 H, J = 1.6, 16.0 Hz), 5.74 (ddt, l H, J = 11.3, 16.0,
6.2 Hz), 5.85 (S, l H); 13C NMR (75.5 MHz) (CDCl3) 5 17.3, 18.8, 21.5, 30.9, 50.0.

28
116.9, 123.5, 133.4, 135.9, 177.7; IR (neat) 3083, 2975, 2936, 2876, 1653, 1472,
1404, 1242, 1208, 1092, 993, 920 car]. Anal. Calcd for C7H15N: C, 74.27; H, 13.36;
N, 12.37. Found: C, 74.43; H, 13.69; N, 12.21.

Reduction of 50a to 518: To a flask containing LiAlI-I4, (2.51 g, 66 mmol)
was added 300 mL of Eth, and the suspension was cooled to 0 °C. Amide 508 (10.87 g,
60 mmol) in 30 mL of EtzO was added dropwise over a 45 min period. The solution was
warmed to room temperature and stirred for six hours. After the solution was cooled to 0
°C, the reaction was quenched by addition of 2.5 mL of H20, followed by 2.5 mL of 15%
aqueous NaOH, and then again by 7.5 mL of H20. The solution was stirred for 1.5 h and
then dried with K2CO3. The solids were removed by filtration, and the solvent was
removed under reduced pressure. Enamine 51a was isolated via Kugelrohr distillation:
(bp 54-55 °C, 8 mmHg, 9.84 g, 98% yield). 1H NMR (300 MHz) (CDCl3) 8 0.83 (d, 6
'H, J = 6.6 Hz), 1.58 (d, 3 H, J = 1.3 Hz), 1.58 (tsept, 1 H, J = 7.3, 6.6 Hz), 1.65 (d, 3
H, J -- 1.3 Hz), 2.25 (d, 2 H, J -- 7.3 Hz), 3.15 (dt, 2 H, J = 1.6, 1.6, 6.2 Hz), 5.02
(ddt, 1 H, J = 2.0, 10.2, 1.6 Hz), 5.08 (ddt, 1 H, J = 2.0, 17.2, 1.6 Hz), 5.22 (qq, 1 H,
J = 1.3, 1.3 Hz), 5.81 (ddt, 1 H, J = 10.2, 17.2, 6.2 Hz); 13C NMR (75.5 MHz)
(CDCl3) 8 17.4, 20.4, 22.0, 27.4, 59.6, 63.1, 115.9, 122.8, 135.8, 136.9; IR (neat)
3081, 3009, 2955, 2926, 2870, 2803, 1676, 1644, 1468, 1449, 1377, 1337, 1194, 1117,
1101, 995, 916 cm-1.

General Procedure for Rearrangement of 51a to 52: All flasks used in
rearrangement studies were heated under vacuum for 20-30 minutes and then purged with
argon for 10 minutes. A solution containing 51a (0.167 g, 1 mmol), o-xylene (0.121 mL,
1 mmol, internal GLC standard) and 5 mL of toluene was cooled to -78 °C. After an initial
gas chromatograph was taken, the Lewis acid reagents (see Tables I and II for equiv.)
were added at -78°C or the HCl was added at 0°C. For C13Al and (ArO)2A1Me accelerated

29
nations, a solution of 51a was added to the catalyst in 25 mL of toluene via cannula at
-78°C. All aliquots for analysis were removed from the reaction vessel via cannula,
quenched in Ergo with 10% w/v solution of NaOMe in MeOH, and was dried over
N a2804 or K2C03 prior to GLC analysis.

Preparation of 50b by Acylation of 49: Imine 49 (2.44 g, 22 mmol) and
NEt3 (3.69 mL, 26.4 mmol) were taken up in 150 mL of THF and cooled to 0°C.
Cyclohexanecarbonyl chloride (3.50 g, 24 mmol) in 35 mL of THF was added dropwise
over a 2 h period. The reaction was allowed to warm to room temperature during the
addition, and then was brought to reflux for 2.5 h. After cooling the solution to ambient
temperature, solids were removed by filtration through a pad of silica on a glass frit, and
then washed with two portions of Bt20. The solvents were removed via rotary
evaporation, and the remaining oil was purified by column chromatography (silica, 230-
400 mesh; eluent: 30:70 Etzozpetroleum ether) and isolated via Kugelrohr distillation to
give 501): (75-100°c, <1 mmHg, 3.35 g, 69% yield). 1H NMR (300 MHz) (CDCl3) 8
1.21 (m, 4 H), 1.43 (m 2 H), 1.61 (m, 4 H), 1.60 (s, 3H), 1.75 (s, 3H), 2.38 (m, 1H),
3.96 (d, 1 H, J= 6.2 Hz), 5.02 (d, 1 H, J=ll.5 Hz), 5.04 (d, 1 H, J: 15.8 Hz), 5.72 (
ddt, 1 H, J: 11.5, 15.8, 6.2 Hz), 5.82 (s, 1 H). 13c NMR (75.5 MHz) (CDCl3) 5 17.6,
21.8, 25.7, 28.9, 41.5, 50.0, 116.7, 123.3, 133.3, 135.9, 176.0. IR (neat) 3101, 2930,
2855, 1653, 1451, 1427, 1342, 1256, 1206, 1123, 990, 918, 895, 831 cm -1. Anal.
Calcd for C11H19N0: C, 72.88; H, 10.56; N, 7.73. Found: C, 72.54; H, 10.28; N,
7.72.

Two-Step Synthesis of SOD from Allylamine: Allylamine (2.20 g, 30.0
mmol) and isobutyraldehyde (1.74 g, 30.0 mmol) were taken up in 85 mL of benzene. A
Dean-Stark trap was fitted on the apparatus and the solution was heated to reflux to

azeotropically remove the resulting water. After being heated 19-22 h, the water was

30

removed, 4A molecular sieves were added to the Dean-Stark trap, and reflux was continued
for 2 h. The solution was cooled to ambient temperature and NEt3 (3.03 g, 30.0 mmol)
and cyclohexanecarbonyl chloride (4.40 g, 30.0 mmol) were added, sequentially, and then
heated at reflux for 3 h. After benzene was removed under reduced pressure, the crude oil
was purified by flash column chromatography (silica, 230-400 mesh; eluent: 30:70
EtzOzpetroleum ether). The solvents were evaporated and the enamide was distilled under
vacuum to give 4.53 g 50b (20.5 mmol, 68% yield). Spectroscopic data was identical to
that reported for the product obtained by acylation of isolated 49.

Reduction of 50b to Slb: Enamide 501) (4.71 g, 21.0 mmol) in 40 mL of
Et20 was added dropwise to a suspension of LiA1H4 (0.89 g, 23.0 mmol) in 300 mL of
Et20 at 0°C over a 1 h period. The reaction mixtrne was warmed to room temperature and
then stirred for 5 h. The LiAlH4 was quenched at 0 °C through slow addition of 0.9 mL of
H20, 0.9 mL of 15% NaOH, and then 2.7 mL of H20. After being stirred for 1 h, the
solids were removed by filtration, and the solvents were removed via rotary evaporation to
give an oil. The oil was isolated via Kugelrohr distillation to give 4.15 g 5 lb: (70-80°C, 5
mmHg, 95% yield).1H NMR (300 MHz) (CDCl3) 5 0.83 (m, 2 H), 1.15 (m 4 H), 1.30
(m, 1 H), 1.59 (s, 1H), 1.65 (s, 3H), 1.75 (s, 3H), 2.30 (d, 2 H, J= 7.2 Hz), 3.14 (d, 2
H, J: 6.1 Hz), 5.02 (dd, 1 H, J=10.2, 2.0 Hz), 5.09 (dd, 1 H, J= 17.3, 2.0 Hz), 5.22 (
s, l H), 5.81 (ddt, 1 H, J= 17.3, 10.2, 6.1). 13C NMR (75.5 MHz) (CDCl3) 5 17.6,
22.3, 26.2, 26.9, 31.6, 37.1, 59.6, 61.9, 115.7, 122.0, 135.7, 136.8. IR (neat) 3091,
2923, 2851, 2797, 1650, 1600, 1449, 1374, 1337, 1283, 1263, 1178, 1123, 993, 9163,
843 cm -1.

Representative Procedure for Charge-Accelerated 3-Aza-Cope
Rearrangement and Reductive Workup (51b to 53b): All flasks used in

rearrangement studies were heated under vacuum for 20-30 minutes and purged with argon

31

for 10 minutes. The electrophilic reagents (see Tables I and II for equiv.) were added to a
solution containing 51b (1.04 g, 5.0 mmol) in 25 mL of toluene to give a final
concentration of 0.2 M of 51b. Lewis acids were added at -78°C, and HCl was added at
0°C. For C13Al and (Ar0)2A1Me accelerated reactions, a solution of 51b was added to the
catalyst in 25 mL of toluene via cannula at -78°C. The reaction mixture was heated until
complete conversion of 51b to 52b had occurred (see Tables I and II for temperatures
and reaction times). Following rearrangement, the reaction was placed in an ice bath and
5.5 mL of 1.0 M LiAlH4 solution was added. After 3 h, the reduction was quenched at 0
°C through slow addition of 0.2 mL of H20, 0.2 mL of 15% NaOH, and then 0.6 mL of
H20. The solids were removed by filtration through sodium sulfate on a glass frit.
Solvents were removed by rotary evaporation and the oil was isolated via Kugelrohr

distillation to give 53b.

531); (bp 70—80°C, < 1 mmHg): 1H NMR (300 MHz) (CDCl3) 6 0.89 (s, 6 H),
1.31 (m 4 H), 1.40 (m, 1 H), 1.72 (m, 6H), 1.96 (d, 2H, J= 7.5 Hz), 2.28 (s, 2H), 2.37
(d, 2 H, J: 6.8 Hz), 4.97 (d, 1 H, J=16.6 Hz), 4.98 (d, 1 H, J: 12.2 Hz), 5.78 ( ddt, 1
H, J: 16.6, 12.2.7.5 Hz). 13c NMR (75.5 MHz) (CDCl3) 6 25.5, 26.1, 26.8, 31.4,
37.6, 44.7, 57.8, 60.5, 116.6, 135.7. IR (neat) 3350, 3074,2923, 2853, 2807, 2753,
1639, 1462, 1447, 1364, 1127, 995,913 cm -1. Anal. Calcd for C14H27N: c, 80.31; H,
13.00; N, 6.70. Found: c, 79.00; H, 12.49; N, 6.85.

53a: (bp 50-60 °C, 8 mmHg): 1H NMR (300 MHz) (CDCl3) 6 0.85 (s, 6 H),
0.86 (d, 6 H, J = 6.6 Hz), 0.87 (bs, 1 H), 1.71 (tsept, 1 H, J = 6.9, 6.6 Hz), 1.98 (d, 2
H, J = 7.5 Hz), 2.29 (s, 2 H), 2.35 (d, 2 H, J = 6.9 Hz), 4.99 (m, 2 H), 5.79 (ddt, 1 H, J
= 9.2, 17.9, 7.5 Hz); 13c NMR (75.5 MHz) (CDCl3) 6 20.6, 25.5, 27.9, 34.4, 44.7,
59.1, 60.3, 116.6, 135.7; IR (neat) 3359, 3077, 3005, 2957, 2872, 2811, 1640, 1466,
1385, 1364, 1121, 995, 912 cm-1. Anal. Calcd for C11H23N: c, 78.04; H, 13.69; N,
8.27. Found: C,77.64; H, 13.87; N, 7.68.

32

3-(N-(2-methylprop-l-yl)amino)-l-hexene (61). The appropriate
trichloroacetamide ( 102 nnnol)33 was hydrolyzed in 200 mL of 6 N NaOH for 48 n. The
organic portion was exu'acted using 3 x 100 mL of Et20, and the solution was carefully
concentrated on a rotary evaporator below 0 °C. A flask containing the resulting amine and
isobutyraldehyde (7.3 g, 101 mmol) in benzene (0.2 M) was equipped with a Dean-Stark
trap that contained 4A molecular sieves. The mixture was heated to reflux until imine
formation was complete. Solid LiAlH4 (3.86 g, 102 mmol) was added slowly over 20 min
at 0 °C, the solution was stirred for l h, and then AlMe3 (25.4 mL, 2.0 M in toluene, 50.8
mmol) was added dr0pwise via cannula over a period of 30 min at 0 °C. After 24 h, the
solution was quenched at 0 °C by the sequential addition of 4.0 mL of H20, 4.0 mL of
15% w/v aq. NaOH, and 12.0 mL of H20, and then the mixture was stirred for 4 h. The
aluminum salts were removed by filtration, and the combined filtrate and washings were
concentrated and distilled (80 °C, 35 mmHg) to give 61 (3.2 g, 20.5 mmol) in 20% overall
yield; 1H NMR (300 MHz, CDC13) 6 0.86 (d, J =6.6 Hz, 6 H), 0.87 (t, J =6.9 Hz, 3 H),
1.2-1.5 (m, 4 H), 1.65 (nonet, J =6.6 Hz, 1 H), 2.26 (dd, J =11.5, 6.6 Hz, 1 H), 2.38
(dd, J =11.5, 7.1 Hz, 1 H), 2.90 (dt, J=5.5, 7.5 Hz, 1 H), 4.98-5.07 (m, 2 H), 5.53
(ddd, J=l7.6, 9.5, 8.1 Hz, 1 H), N-H not observed; 13C NMR (75.5 MHz, CDC13) 5
14.1, 19.1, 20.7, 20.8, 28.4, 37.9, 55.4, 61.8, 115.3, 141.9; IR (neat) 3337, 3077,
2959, 2872, 1641, 1117 cm '1; HRMS calcd for C10H21N m/z (MH+)156.1676, found
156.1762.

3-(N-(Z-methylprop-l-yl)amino)-3-phenyl-l-propene (69). A flask
containing the corresponding amine (7.0 g, 53 mmol)33 and isobutylaldehyde (3.79 g, 53
mmol) in benzene (0.2 M) was equipped with a Dean-Stark trap that contained 4A
molecular sieves. The mixture was heated at reflux for 2 h until imine formation was

complete by gas chromatographic analysis. Solid LiAlH4 (2.0 g, 53 mmol) was added at 0

33

°C, and the mixture was warmed to room temperature and stirred for 10 h. The reaction
was quenched at 0 °C by the sequential addition of 2.0 mL of H20, 2.0 mL of 15% w/v
aq. NaOH, and 6.0 mL of H20. After stirring for 4 h, the aluminum salts were removed
by filtration, and the combined filtrate and washings were concentrated and distilled to give
69 (8.1 g, 42.8 mmol) in 81% yield (65 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 8
0.89 (d, J =6.6 Hz, 6 H), 1.34 (bs, 1 H), 1.65 (nonet, J = 6.6 Hz, 1 H), 2.19 (dd, J
=6.9, 11.4 Hz, 1 H), 2.35 (dd, J =6.6, 11.4 Hz, 1 H), 4.14 (d, J =7.1 Hz, 1 H), 5.06
(ddd, J =0.9, 1.5, 10.1 Hz, 1 H), 5.19 (dt, J =17.1, 1.6 Hz, 1 H), 5.85 (ddd, J=7.1,
10.1, 17.1 Hz, 1 H), 7.22-7.39 (m, 5 H); 13c NMR (75.5 MHz, CDC13) 6 20.67,
20.72, 28.4, 55.6, 66.2, 114.7, 127.0, 127.2, 128.2, 141.4, 143.2; IR (neat) 3310,
3027, 2955, 2870, 1620, 1116 cm ‘1 ; HRMS calcd for C13H19N m/z 189.1513, found
189.1520.

(E)-l-(N-(Z-methylprop-l-yl)amino)hex-2-ene (65). A small amount of
1,10-phenanthraline was added to a solution of 2-hexen-1-ol (4.01 g, 40 mmol) in 250 mL
of THF.22 The solution was cooled to -78 °C, and n-BuLi (28 mL, 1.6 M in hexanes) was
added until the orange 1,10-phenanthraline endpoint was visible. Tosyl chloride (7.63 g,
40 mmol) was added in a single portion, and the mixture was stirred at -78 °C for 72 hr.

The reaction was worked up by diluting with 500 mL cold petroleum ether, and washing
with 2 x 100 mL of cold 50% sat. aq. NaHC03 followed by 1 x 100 mL of sat. aq.

NaHC03. The aqueous layers were combined and extracted with 1 x 70 mL of petroleum
ether, and the combined organic fractions were dried over K2C03. After filtration and
concentration of the mixture, the tosylate was taken up in 200 mL of Et20, dried, filtered,
and concentrated in the same manner. The crude tosylate was then added to isobutyl amine
(17.5 g, 240 mmol) at 0 °C, and stirred at room temperature for 24 h. Excess isobutyl
amine was removed in vacuo, and the remaining oil was purified by Kugelrohr distillation

(25 mmHg, 80-100 °C) to give 65 (5.47 g, 35.3 mmol) in 88% yield; 1H NMR (300

34

MHz, CDC13) 6 0.84 (t, J=7.4 Hz, 3 H), 0.85 (d, J=6.8 Hz, 6 H), 1.33 (sext, J=7.4 Hz,
2 H), 1.68 (nonet, J=6.8 Hz, 1 H), 1.94 (m, 2 H), 2.35 (d, J=6.8 Hz, 2 H), 3.12 (d,
J=5.0 Hz, 2 H), 5.40-5.58 (m, 2 H), N-H not observed; 13C NMR (75.5 MHz, CDC13)
6 13.6, 20.7, 22.4, 28.3, 34.4, 52.0, 57.5, 128.6, 132.3; IR (Neat) 3301, 2959,2872,
2810, 1670, 1121, 970 em-l. HRMS calcd for C10H21N m/z 155.1669, found
155.1683.

(E)-3-(N-(2-methylprop-l-yl)amino)phenylprop-l-ene (73). A mixture
of cinnamaldehyde (15 g, 114 mmol) and isobutylamine (8.1 g, 111 mmol) in 380 mL of
Et20 was stirred over K2C03 (~15 g) for 12 h. The mixture was filtered and the solids
were washed with 50 mL of Et20. Acetic acid (34 g, 570 mmol) was added to the
combined organic fractions and the solution was stirred at room temperature for 30 min.
NaBH4 (1.12 g, 29 mmol) was added slowly over 20 min at 0 °C, and the mixture was
warmed to room temperature and stirred for 8 h. The reaction was quenched at 0 °C with a
mixture of sat. aq. N a0H/so1id NaOH, and the organic layer was separated and dried
(K2C03). The solution was concentrated and then pmified via column chromatography by
eluting the column first with a petroleum etherzEt20 (80:20) to remove nonpolar impurities,
and then with Et20 to give the crude 73. Short path distillation gave 73 (3.2 g, 16.9
mmol) in 15% yield (bp 9095 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 6 0.91 (d, J
=6.7 Hz, 6 H), 1.33 (bs, l H), 1.76 (nonet, J =6.7 Hz, 1 H), 2.42 (d, J =6.7 Hz, 2 H),
3.38 (dd, J =6.3, 1.2 Hz, 2 H), 6.31 (dt, J =15.9, 6.2 Hz, 1 H), 6.51 (bd, J=15.9 Hz, 1
H), 7.16-7.39 (m, 5 H); 13C (75.5 MHz, CDC13) 8 20.7, 28.4, 52.1, 57.5, 126.2,
127.2, 128.4, 128.7, 131.0, 137.1; IR (neat) 3316, 3026, 2955, 2870, 2810, 1599.
1119, 966 em-l; HRMS calcd for C13H19N m/z 189.1513, found m/z 189.1510.

Preparation of N-(2-methyl-l-propenyl)-N-((E)-hex-2-en-l-yl)-2-
methylpropanamide. The trichloroacetamide (33.7 mmol, 8.20 g)33 was added to 200
mL of 6 N NaOH, and heated at reflux for 15 h. Following hydrolysis, the amine was

35

separated, and the aqueous layer was washed with 2 x 15 mL portions of benzene. The
organic layers were combined with 15 mL additional benzene, isobutyraldehyde (100
mmol, 7.21 g) was added, and the mixture was heated at reflux with azeotropic removal of
water using a glass trap containing molecular sieves. After 20 h, Et3N (36 mm, 5.03 mL)
was added, and the mixture was cooled to 0 °C. Isobutyryl chloride was added via syringe
over a 10 min period. The reaction was then stirred for 36 h, filtered through a pad of
silica, and washed with petroleum ether. The solvents were concentrated, and the crude
enamide was purified by column chromatography (1:9 EtOAczpetroleum ether). Kugelrohr
distillation (60-70 °C, <1 mmHg) gave 3.28 g of the enamide (44% yield). 1H NMR (300
MHz, CDC13) 8 0.83 (t, J=7.2 Hz, 3 H), 1.01 (d, J=6.7 Hz, 6 H), 1.32 (sext, J=7.2 Hz,
2 H), 1.54 (s, 3 H), 1.70 (s, 3 H), 1.92 (q, =6.9 Hz, 2 H), 2.68 (hept, J=6.7 Hz, 1 H),
3.91 (d, J=6.3 Hz, 2 H) 5.35 (dt, J=15.3, 6.3 Hz, 1 H), 5.47 (dt, J=15.3, 6.5 Hz, 1 H),
5.79 (bs, 1 H); 13C NMR (75.5 MHz, CDC13) 8 13.5, 17.6, 19.1, 21.8, 22.2, 31.1,
34.2, 49.3, 123.3, 124.7, 133.8, 135.6, 177.2; IR (Neat) 2967, 2874, 1736, 1653,
1406, 1236, 970 cm'l. HRMS calcd for C14H25N0 m/z 223.1936, found 223.1940.

Preparation of N-((E)-hex-2-en-l-yl)-N-(2-methyl-l-propyI)-(2-
methyl)propeny1amine (66). The enamide (4.0 mmol, 0.89 g) was taken up in 5 mL
dry Et20, and LAH (5.0 mol, 5 mL, 1.0 M in THF) was added dmpwise over a 15 min
period. After 1.5 h, the mixture was cooled to 0 °C and quenched as described for the
workup of the LiA1H4 reduction to make 61. After 1.5 h, MgSO4 was added, and the
mixture was stirred for an additional 30 min. The solids were removed by filtration, and
the mixture was concentrated. The enamine was purified by Kugelrohr distillation (60-65
°C, <1 mmHg) to give 0.83 g of 66 (99% yield). 1H NMR (300 MHz, coc13) 6 0.82 (d
J=6.7 Hz, 6 H), 0.89 (t, J=7.4 Hz, 3 H), 1.30-1.42 (m, 3 H), 1.58 (s, 3 H), 1.65 (s, 3
H), 1.96 (m, 2 H), 2.22 (d, J=7.3 Hz, 2 H), 3.08 (d, J=4.3 Hz, 2 H), 5.19 (bs, 1 H),
5.36-5.56 (m, 2 H); 13C NMR (75.5 MHz, CDC13) 8 13.6, 17.7, 20.7, 22.3, 22.5,

36
27.6, 34.5, 58.9, 62.9, 122.4, 128.1 132.4, 135.7 IR (Neat) 2965, 2803, 1673, 1468,
1377, 1188, 970 cm‘1 (in heptane). HRMS calcd for C14H27N m/z 209.2143, found

209.2126.

General Procedures for Isobutyraldehyde Condensation and 3-Aza-
Cope Rearrangements with 61 and 65: A mixture of the secondary amine (1.0
equiv., 2-5 mmol, 0.2 M in solvent), isobutyraldehyde (3.0 equiv., 6-15 mmol), and
stOH (0.0025 equiv.), was taken up in benzene (or toluene for 65) and heated to reflux.
The mixture was subject to azeotropic removal of water,31 and reaction progress was
monitored by GLC for disappearance of amine. Once the condensation was complete (12-
24 h), he mixture was cooled to room temperature and the benzene was removed in vacuo.
The crude enamine was taken up in toluene (0.2 M), and the appropriate reagent was added
at room temperature (see Table I). After complete rearrangement in refluxing toluene, the
imine was reduced at 0 °C by the addition of LiAlH4 (1.1 equiv., 1.0 M in THF). After
stirring for 6 h, the reaction was quenched by the sequential addition of H20 (1 mL/1.0 g
LiAlH4), 15% w/v aq. NaOH (1 mL/1.0 g LiAlH4), and then H20 (3 mL/1.0 g LiAlH4).
The quenched mixture was stirred at room temperature overnight, filtered through K2C03,
concentrated, and purified by Kugelrohr distillation to give the corresponding product of

condensation, rearrangement, and reduction (see Table I for yields).

(E)-l-(N-(Z-methylprop-l-yl)amino)-2,2-dimethyl-4-octene (64): (bp
70-80 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 6 0.83 (s, 6 H), 0.86 (t, J=7.3 Hz,
3 H), 0.86 (d, J=6.6 Hz, 6 H), 1.35 (sextet, J=7.2 Hz, 2 H), 1.72 (nonet, J=6.6 Hz, 1
H), 1.87-1.99 (m, 4 H), 2.28 (s, 2 H,), 2.35 (d, J=6.9 Hz, 2 H), 5.35-5.41 (m, 2 H).
N-H not observed; 13c NMR (75.5 MHz, CDC13) 6 13.7, 20.6, 22.8, 25.6, 28.0, 34.4,
34.8, 43.4, 59.1, 60.4, 126.9, 132.7; IR (Neat) 3352,2959, 2872, 2810, 1670, 1120.
970 em-l. HRMS calcd for C14H29N m/z 211.2293, found: 211.2281.

37

l-(N-(Z-methylprop-l-yl)amino)-2,2-dimethyl-3-propyl-4-pentene
(68): (bp 70-80 °C, <1 mmHg): 1H NMR (300 MHz, @013) 6 0.78 (s, 6 H), 0.85 ((1,
=6.1 Hz, 6 H), 0.86 (t, J=6.7 Hz, 3 H). 0.99-1.19 (m, 2 H), 1.30-1.42 (m, 2 H), 1.69
(nonet, J=6.6 Hz, 2 H), 4.90 (dd, J=10.3, 2.4 Hz, 1 H), 4.98 (dd, J=10.3, 2.4 Hz, 1 H),
5.55 (dt, 1: 17.0, 10.3 Hz, 1 H), N-H not observed; 13c NMR (75.5 MHz, CDC13) 6
14.1, 20.6, 21.1, 23.3, 23.6, 27.9, 30.5, 36.2, 51.0, 59.1, 59.6, 115.7, 140.2; IR
(Neat) 3310, 3075, 2959, 2872, 2811, 1638, 1119, eta-1. HRMS calcd for C14H29N

rn/z: 211.2293, found: 211.2264.

(E)-l-(N-(2-methylprop-l-yl)amino)-2,2-dimethyl-5-phenyl-4-
pentene (72): (bp 70-80 °C, <1 mmHg): 1H NMR (300 MHz, CDC13) 6 0.89 (d,
J=6.7 Hz, 6 H), 0.93 (s, 6 H), 1.74 (nonet, J=6.7 Hz, 1 H), 2.15 (dd, J=7.3, 0.8 Hz, 2
H), 2.36 (s, 2 H), 2.39 (d, J=6.9 Hz, 2 H), 6.25 (dt, J=7.3, 15.9 Hz, 1 H), 6.38 (bd,
J=15.9 Hz, 1 H), 7.15-7.37 (111,5 H), N-H not observed; 13c NMR (75.5 MHz, CDC13)
6 20.6, 25.7, 27.9, 35.1, 43.8, 59.0, 60.4, 125.9, 126.8, 127.7, 128.4, 131.9, 137.8;

IR (Neat) 3325, 3083, 3061, 3027, 2955, 2870, 2811, 1599, 1117, 966 cm‘l. HRMS
calcd for C17H27N m/z 245.2143, found 245.2172.

l-(N-(z-methylprop-l-y|)amino)-2,2-dimethyI-3-phenyl-4-pentene
(76): (bp 70-80°C, <1 mmHg ): 1H NMR (300 MHz, (21303) 6 0.82 (s, 3 H), 0.87 (d,
=6.7 Hz, 3 H), 0.89 (d, J=6.7 Hz, 3 H), 0.90 (s, 3 H), 1.70 (nonet, J=6.7 Hz, 1 H),
2.20 (d, J=11.7 Hz, 1 H), 2.31 (d, J=7.0 Hz, 2 H), 2.34 (d, J=11.7 Hz, 1 H), 3.25 (bd,
J=10.1 Hz, 1 H), 5.01-5.09 (m, 2 H), 6.28 (m, 1 H), 7.10-7.30 (m, 5 H), N-H not
observed; 13c NMR (75.5 MHz, CDC13)8 20.7, 23.6, 23.7, 28.1, 37.6, 57.3, 59.0,
59.3, 116.2, 126.0, 127.8, 129.3, 138.8, 142.5; IR (Neat) 3320, 3077, 3069, 3029,

38
2057, 2872, 2811, 1636, 1601, 1117 Cm'l; HRMS calcd for C17H27N m/z 245.2143,
found 245.2206.

(1)

(2)

(3)
(4)

(5)

(6)

(7)

(8)

REFERENCES AND NOTES

For reviews on [3,3] sigmatropic rearrangements see: (a) Rhoads, S. J.; Raulins,
N. R. Org. React. (N. Y.) 1975,22, 1. (b) Ziegler, F. E. Acc. Chem. Res.
1977, 10, 227. (c) Bennett, G. B. Synthesis 1977, 589. (d) Bartlett, P. A.
Tetrahedron 1980, 36, 3. (e) Gajewski, J. Hydrocarbon Thermal Isomerizations;
Academic: New York, 1981. (f) Hill, R. K. Chirality Transfer via Sigmatropic
Rearrangements. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New
York, 1984; Vol 3, p. 503. (g) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (h)
Blechert, S. Synthesis 1989, 71. For a review on the catalysis of the Cope and
Claisen rearrangements, see: (i) Lutz, R. P. Chem. Rev. 1984, 84, 205. (j)
Overman, L. E. Angew. Chem. Int. Ed. Engl. 1984, 23, 579.

(a) Vittorelli, P.; Winkler, T.; Hansen, H. -J.; Schmid, H. Helv. Chim. Acta
1968, 51, 1457. (b) Hansen, H. -J.; Schmid, H. Tetrahedron, 1974, 30, 1959.

Hill, R. K.; Gilman, N. w. Tetrahedron Lett. 1967, 1421.

(a) Lul , J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J. L.; Yi, N. J. Org.
Chem. 987, 52, 1487. (b) Moriwake, T.; Hamano, S.-I.; Saito, S.; Torii, 8.
Chem. Lett. 1987, 2085. (c) Moriwake, T.; Hamano, S.-I.; Saito, 8.; Torii, S.
J. Org. Chem. 1989, 54, 4114. (d) Luly, J. R.; Hsiao, C.-N.; BaMaung, N.;
Plattner, J. J. J. Org. Chem. 1988, 53, 6109. (e) Rosegay, A.; Taub, D. Synth.
Commun. 1989, 1137. (f) Sasaki, N. A.; Hashimoto, C.; Pauly, R. Tetrahedron
Lett. 1989, 30, 1943. (g) Jegham, 8.; Das, B. C. Tetrahedron Lett. 1989, 30,
2801.

(a) Tsunoda, T.; Sasaki, 0.; Ito, S. Tetrahedron Lett. 1990, 31, 727. (b)
Brannock, K. C.; Burpitt, R. D.; J. Org. Chem. 1961, 26, 3576. (c) Musahashi,
S. -I.; Makabe, Y. Tetrahedron Lett. 1985, 26, 5563. (d) Musahashi, S. -I.;
Makabe, Y.; Kunita, K. J. Org. Chem. 1989, 53, 4489. (e) Hiroi, K.; Abe, J.
Tetrahedron Lett., 1990, 31, 3623. (1) Gilbert, J. C.; Seneratne, K. P. A.
Tetrahedron Lett. 1984, 25, 2303. (g) Cook, G. R.; Stille, J. R. J. Org. Chem.
1991, 56, 5578.

For representative examples of heterocycle formation from d,e-unsaturated
secondary amines, see: (a) Tokuda, M.; Yamada, Y.; Suginome, H. Chem. Lett.
1988, 1289. (b) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem.
Soc. 1989, I I I , 1923; (c) Hamana, H.; Ikota, N.; Ganem, B. J. Org. Chem.
1987, 52, 5492. (d) Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1990, 38,
2712.

(a) Takai, K.; Mori, 1.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1984,
57, 446. (b) Hill, R. K.; Khatri, H. N. Tetrahedron Lett. 1978, 4337.

Lewis acid promotion of the Claisen rearrangement has been achieved with
aluminum complexes. (a) Takai, K.; Mori, 1.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1981, 22, 3985. (b) Stevenson, J. W. 8.; Bryson, T. A.
Tetrahedron Lett. 1982, 23, 3143. (c) Mori, 1.; Takai, K.; Oshima, K.; Nozaki,
H. Tetrahedron 1984, 40, 4013. (d) Maruoka, K.; Nonoshita, K.; Banno, H.;

39

(9)

(10)

(11)

(12)
(13)

(14)
(15)
(16)
(17)

(18)
(19)
(20)

(21)

(22)
(23)
(24)

40

Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 7922. (e) Maruoka, K.; Banno,
H.; Nonoshita, K.; Yamamoto, H. Tetrahedron Lett. 1989, 30, 1265. (f) Piers,
15.; Fleming, F. F. J. Chem. Soc., Chem. Commun. 1989, 1665. (g)
Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc.
1990, 112, 316. (h) Yamamoto, H.; Maruoka, K. Pure & Appl. Chem. 1990,
62, 2063. (i) Maruoka, K.; Banno, H.; Yamamoto, H. J. Am. Chem. Soc.
1990, 112, 7791. (i) Paquette, L. A.; Friedrich, 0; Rogers, R. D. J. Org.
Chem. 1991, 56, 3841. (k) Philippo, C. M. G.; Vo, N. H.; Paquette, L. A. J.
Am. Chem. Soc. 1991, 113, 2762.

(a) Maruoka, K.; Nonoshita, K.; Banno, H.; Yamamoto, H. J. Am. Chem. Soc.
1988, 110, 7922. (b) Maruoka, K.; Banno, H.; Nonoshita, K.; Yamamoto, H.
Tetrahedron Lett. 1989, 30, 1265. (c) Nonoshita, K.; Banno, H.; Maruoka, K.;
Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316. (d) Yamamoto, H.;
Maruoka, K. Pure & Appl. Chem. 1990, 62, 2063.

(a) Trost, B.M.; Runge, T.A. J. Am. Chem. Soc. 1981, 103, 7550. (b) Trost,
B.M.; Runge, T.A.; Jungheirn, L.N. J. Am. Chem. Soc. 1980, 102, 2840.

(a) van der Baan, J.L.; Bickelhaupt, F. Tetrahedron Lett. 1986, 27, 6267. (b)
Hayashi, T.; Yamamoto, A.; Ito, Y. Synth. Commun. 1989, 19, 2109. (c)
Mikami, K.; Takahashi, K.; Nakai, T. Tetrahedron Lett. 1987, 28, 5879.
Schenck, T. G.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2058.

(a) Murahashi, S.-I.; Makabe, Y. Tetrahedron Lett.1985, 26, 5563. (b)
Murahashi, S.—I.; Makabe, Y.; Kunita, K. J. Org. Chem. 1988, 53, 4489.

Jolidan, 8.; Hansen, H.J. Helv. Chim. Acta. 1977, 60, 978.
Hurd, C. D.; Jenkins, W.W. J. Org. Chem. 1957, 221418.
Schmid, M.; Hansen, H.J.; Schmid, H. Helv. Chim. Acta 1973, 56, 105.

Ingadaé38.; Nagai, K.; Takayanag, Y.; Okazaki, M. Bull. Chem. Soc. Jpn. 1976,
4 , 5 .

Dillard, R. D.; Parey, D. 13.; Bevslay, D.N. J. Med. Chem. 1973, I6, 251.
Beholz, L. G.; Stille, J.R. J. Org. Chem. 1993, 58, 5095.

(a) Kurth, M. J.; Decker, O. H. W.; Hope, H.; Yanuck, M. D. J. Am. Chem.
Soc. 1985, 107, 443. (b) Kurth, M. J.; Decker, O. H. W. J. Org. Chem. 1986,
51, 1377.

(a) Ireland, R. F..; Willard, A. K. J. Org. Chem. 1974, 39, 421. (b) Kurth, M.
J .; Decker, O. H. W. J. Org. Chem. 1986, 51, 1377, and references therein.

Corbier, J.; Cresson, P.; Jelenc, P. C. R. Acad. Sci. Paris 1970, C270, 1890.
Tsunoda, T.; Sasaki, O; Ito, S. Tetrahedron Lett. 1990, 31, 727.

(a) Brannock, K. C.; Burpitt, R. D. J. Org. Chem. 1961, 26, 3576. (b) Gilbert,
J. C.; Seneratne, K. P. A. Tetrahedron Lett. 1984, 25, 2303.

(25)
(26)
(27)

(28)

(29)
(30)

(31)

(32)

(33)

41
Hill, R. K.; Khatri, H. N. Tetrahedron Lett. 1978, 4337.
Bailey, P. 0; Harrison, M. J. Tetrahedron Lett. 1989, 30, 5341.
Cook, G.R. Masters Thesis, Michigan State University, 1991. Preliminary results
for the acceleration of the [3,3] rearrangement of N-alkyl-N-allyl enamines with
HCl, TiC14, and AlMe3 were previously obtained by Greg Cook. His assistance
throughout this project is greatly appreciated.

Ms. Landis established the procedure for the preparation of 56, 69, and 57 while
doing undergraduate research in Professor Stille's labs. See also reference 25.

Cook, G. R.; Barta, N. S.; Stille, J. R. J. Org. Chem. 1992, 57, 461.

Barta, N. 8.; Cook, G. R.; Landis, M. S.; Stille, J. R. J. Org. Chem. 1992, 5 7,
7188.

Barta, N. S.; Paulvannan, P.; Schwarz, J. B.; Stille, J. R. Synth. Commun.
1994, 24, 583.

Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. "Spectometric Determination of
Organic Compounds" Fourth Ed. John Wiley and Sons, New York, 1981.

Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901.

CHAPTER II

MECHANISTIC STUDIES OF INTRAMOLECULAR ZIEGLER-NATTA
OLEFIN INSERTIONS: 01- AND B-DEUTERIUM ISOTOPE EFFECTS AND

CHAIN TRANSFER PROCESSES

 

BACKGROUND AND SIGNIFICANCE

Historical Aspects of Ziegler-Natta Olefin Insertion Processes.

In 1963, the Nobel prize in chemistry was awarded to Karl Ziegler and Guilio Natta
for their discovery of a remarkable class of catalysts.1 These highly active catalysts
facilitated selective polymerization of alkenes and dienes. As originally introduced, the
Ziegler-Natta catalysts were defined as a transition metal compound with an organometach
compound of group I, II or 111.1

Industrial use of Ziegler-Natta catalyst systems quickly replaced widely used
preparations of polyethylene which employed radical catalysis at high pressures (1000-
3000 atrn) and high temperatures (150-230 °C).l Using Ziegler-Natta catalysts, propylene
and other a-olefins can be polymerized into isotactic or syndiotactic structures
preferentially over the statistical atactic structures.l The nature of these unexpected
selectivities has prompted many questions regarding the specifics of olefin insertion under
the influence of Ziegler-Natta catalysis. The widely accepted mechanism of olefin insertion

resulting from Ziegler-Natta catalysis has two principal steps: 1) coordination of the alkene

42

43

to the active metal center, and 2) insertion of the activated monomer into a metal carbon

bond (eq 1).1

R
i/ i/ R K
_ _ == Coordnation _ Insertion j /
z; + —= 4+1 _—"71|1’ —- fl.— (1)
1 2 3 4

Most Ziegler-Natta catalyst systems are heterogeneous, but some homogeneous
systems are known.121 The "Cp2Ti" systems are homogeneous systems and have been
studied in great detail for elucidation of the elementary steps of this polymerization
process.2 Despite the fact that these systems become heterogeneous as polyethylene forms,
the "Cp2Ti" system is one of the best understood Ziegler-Natta systems examined to date.
Various opinions regarding the nature of the active center exist, but the formation of a
complex between the titanium and the aluminum cocatalyst is generally accepted}:3

The stereoregularity associated with olefin polymerization processes is important
for defining the physical properties of the resultant polymer,1 and a variety of
stereoselectivities have been observed in the polymerization of propylene and styrene using
assorted Ziegler-Natta catalysts and various cocatalyst.3'5 Homogeneous a-olefin
polymerization became a great deal more efficient through the introduction of
methylaluminoxane (MAO) as a Ziegler-Natta cocatalyst.3 MAO, which is formed through
the slow addition of water to trimethyl aluminum (for details, see the Experimental
Section), rapidly became one of the most used aluminum reagents as both isotactic and
syndiotactic polymer formation could be affected through the use of this reagent.3 For
example, Cp2TiR2/MAO systems give isotactic polypropylene for both R=Me and R=Ph.3
Both Cp22rMe2/MAO4and Cp22rCl25 catalyst systems provide atactic polypropylene,
while reaction of propylene with szTiC12/MAO5 produces syndiotactic polystyrene. In

44

addition, cationic catalyst systems with either titanium or zirconium polymerize propylene
in an atactic fashion.5

Two process that have been identified that play a role in the stereosclection of
polymerization: 1) enantiomorphic site control (5)7 and 2) chain end control (6).7 Catalytic
systems subject to enantiomorphic site control have sterically demanding ligands which
dominate the directing effect of the asymmetric polymer chain. The ligand directs approach
of the incoming monomer, and this control prevents the propagation of unfavorable
monomer insertions.7 In instances of chain end control, stereoregulation is achieved
through 1.3-asymmetric induction relative to the newly formed stereocenter at the position
B—to the transition metal.7 With this type of control, errors in olefin insertion are carried on

in the polymerization process.

it EnmuontaphieSitoContol @ x CWEMCOUN

+ P \+ P
T. : n/W\/Y\r
/ Me Me Me Me Me Q/a “1° “'9 M° ”9 ”9
5 5

 

Variations in polymerization outcome raise the issue of defining the controlling
factors at work in homogeneous Ziegler-Natta polymerization systems. While there has
been a great deal of speculation as to the mechanism of olefin insertion, details of the
process have not been proven unequivocally with respect to the role of the Lewis acid
additive and participation of the growing polymer chain. Once the controlling featm'es have
been identified, new polymerization systems can be designed for increased efficiency of

polymer formation.

45

Proposed Mechanisms for Ziegler-Natta Polymerization.
There are three fundamental mechanistic proposals for the Ziegler-Natta
polymerization of a-olefins.3'lo
1) the direct insertion mechanism8 (Cossee and Arlrnan)
2) the metathesis mechanism9 (Greene and Rooney)
3) the modified Greene and Rooney mechanism10 (Brookhart and Green)
Through consideration of the interactive role of the growing polymer chain, each of these
mechanisms provides partial explanations for the experimental observations associated with
olefin insertion in Ziegler-Natta catalyst systems. I
The direct insertion mechanism is characterized by a loosely coordinated four-
centered transition state 9.8 According to Cossee, the active center for olefin insertion is an
ion of a transition metal that is octahedrally coordinated and has one vacant site and one
alkyl group in the coordination sphere. Another key aspect of this mechanistic proposal is
coordination of the olefin to the dx2-y2 orbital of the transition metal through'a 1t-bond.8
This type of M-alkene coordination has been shown in a number of cases, and plays an

important role in the theoretical studies of olefin insern'on.11

Scheme 1. The Direct Insertion Mechanism.

p
F" P, P‘ \ I
H, C/ a H. C/ H‘ C" H- C
|/ I/ I; |
/I /I /l ‘ 71"
7 8 9 10

The metathesis mechanism was proposed by Green and Rooney in 1978.9 This
pathway is characterized by the formation of a metal carbene/alkylidene species (13) prior

to formation of a metallocyclobutane intermediate ( 14). The alkylidene species forms

46

through transfer of an tat-hydrogen from the polymer chain to the transition metal.
Formation of the metallocyclobutane intermediate helps to explain the stereoregularity

observed in the polymerization of propylene.9

Scheme 11. The Metathesis Mechanism.

P P
P\c/ -é/ \c/
H’1/ = Ll/ II,
—M- ——* Me" —-> H-M
11 12 13
p l
H_\_ ’ P‘c/
I ‘— (12- I
—M/ H-M
/
l /|
15 14

Following the characterization of 16 in 1982,12 Green and Brookhart presented a
modified mechanism for olefin insertion that reflected an interaction between an a-
hydrogen and the transition metal center of the Ziegler-Natta catalyst.10 Steric restrictions
in the insertions step could be decreased through such an interaction (referred to as an
agostic interaction), and the bidentate nature of the M--H--C bonding could influence the

stereoregularity of olefin insertion.lo

 

I":
{mo
1;:

s
s‘

‘r\ I;
\

f
\
9-
I
I

a 8

 

 

 

47

Scheme III. The Modified Green-Rooney Mechanism.

p

P I P\ P
Ic’ H-c’ /°~- ubc’

H l/ = I/ 1* I/

—M— —> - <— ——> \M —> I

/ / ‘s /
17 18 19 20

The direct insertion mechanism8 and the metathesis mechanism9 represent two
extremes on an olefin insertion mechanistic continuum. The first extreme does not involve
the alkyl chain in any way, while the second extreme involves complete transfer of a
hydrogen from the alkyl chain. The third mechanism is the medium which demonstrates
the potential role of agostic interactions in olefin insertion with Ziegler-Natta catalysts.10
The modified Greene-Rooney mechanism suggests that agostic interactions could
contribute to defining the stereoregularity of polymer formation. 10 Experimental insights
gained over the years have prompted this exploration of the role of a- and B-hydrogen

interactions in the polymerization of a—olefins with Ziegler-Natta catalysts.

The Agostic Interaction.
Definition. The term "agostic", from the Greek word "0110mm" means "to clasp
or to hold oneself".13 In 1983, this term was introduced by Brookhart in the context of

organometallic chemistry. Accordingly,

"...the term agostic will be used to discuss the various
manifestations of covalent interactions between carbon-
hydrogen groups and transition metal centers in organometallic
compounds. The word agostic will be used to refer specifically
to situations in which a hydrogen atom is covalently bonded
simultaneously to both a carbon atom and to a transition metal

atom. " 13

48

There are various types of agostic interactions that have been observed and/or
implicated in studies regarding the insertion of olefins into metal-carbon bonds (Figure
1).14 The three most prominant types of agostic interactions are:14

1) tit-agostic interactions in M-alkyl complexes (21)
2) (it-hydrogen interactions in alkylidene complexes (22)

3) B-agostic interactions in M-alkyl complexes (23).

c
“’i "’11 1/ 7°
\M \M \M

21 22 23

Figure 1. Various Agostic Interactions.

For the purposes of this work, emphasis will be placed on interactions resembling
21 and 23. A number of organometallic complexes have been examined for potential
agostic interaction,” however, these ground state interactions only tell part of the olefin
insertion story. Of equal or greater interest is the impact agostic interactions have on the
formation of active intermediates and transition states. Such transition states were explored

in detail in this study.

Theoretical Explorations. Numerous theoretical studies have been designed to
probe agostic interactions in metal-alkyl species.14'15 Several extended Huckel molecular
orbital calculation studies for iron based systems have been reported, and these studies
explored the effect of ligand variation on the nature of the proposed agostic interactions. 17
These reports also indicated that for electronic considerations, the agostic M-H-C
interaction is a highly bent open system rather than a closed three membered ring.18
Theoretical investigations of actinide systems revealed that for Cp21h(C2H5)2, both 01- and
B- hydrogens can come close to the Th center without weakening the Th-C bond. 19

49

Systems modeling Ziegler-Natta olefin polymerization catalysts have also been the
subject of many theoretical studies?“26 Deviations from the ideal octahedral metal field
have been shown for do hexacoordinated metal alkyl complexes, and the ideal field was not
a minimum on the potential energy surface.20 Transition states stabilized by agostic
interactions of migrating alkyl groups have been demonstrated for zirconocene cations.21
The existence of Zr-HB-C two electron interactions have been theoretically determined in
compounds modeling proposed Ziegler-Natta polymerization intermediates.22
Methyltitanium systems have been examined by ab initio molecular orbital calculations23 as
well as paired interacting orbital calculations.24 Such calculations have shown that methyl
distortions are due to direct interaction between the CH“ bond and the unoccupied Ti-d
orbital.23 Another study involving titanium as the metal center prompted Jolly and
Marymck to report that the mechanistic pathway proposed by Cossee and Arlman was
possible even without the involvement of agostic interactions.25 The model system
employed was Cp2Ti-CH3+ + C2H4 ---> Cp2TiC3H7+. However, when C12Ti-CH3+ +
C2H4 ---> Cp2TiC3H7+ was used, strong agostic interactions were reported.25 When
zirconocene was examined as the transition metal for catalysis of olefin insertion, agostic

interactions were again implicated as possible reaction intermediates.26

Experimental Evidence. In addition to the theoretical investigations of agostic
participation, a great deal of physical evidence also supports the existence of such
interactions.27'31 In 197 8, Williams et al. reported the results of a neutron diffraction
study in which strong C-H-M interactions were shown for the first time (M=Fe).27 In
1979, neutron diffraction evidence was also reporwd for similar interactions in an electron-
deficient tantalum-neopentylidene complex.28 Since that time, B—CH agostic interactions
have also been shown for alkenyl zirconocene complexes,29 and both alpha30 and beta31
agostic interactions have been shown for zirconium— and titanium-alkyl complexes as early

as 1982. Now that agostic interactions in the catalyst resting state have been identified and

50

characterized, the potential role similar interactions play in the insertion of olefins in
polymerization processes becomes an increasingly intriguing issue, and this is the direction

that this study has taken.

Related Kinetic Isotope Effect Studies.

In 1985, Grubbs et al. examined the role of a-activation through an elegant study
utilizing kinetic isotope effects in intramolecular olefin insertion reactions which introduced
a direct probe for the analysis of C-H activation (eq. 2).32 The intramolecular insertion
system placed the olefin in the optimum position for insertion, and a high local
concentration of olefin was created while maintaining the desired 1:1 stoichiometry of the
olefin relative to the transition metal center. This system was designed to model the

polymerization of ethylene, and involved both a transition metal catalyst and a Lewis acid

cocatalyst.32
L
RA»
’/ D 1) Insertion 0
1+ 24 2) HCI “'9
GP trans/cis
1.00 $0.05

By selective deuteration of the a-carbon, and analysis of the stereochemical
outcome of cyclization, a cis/trans ratio of 1.00 $0.05 was observed.32 From these
results, Grubbs concluded that a-activation does not have a significant effect on the rate or
stereochemistry of this olefin insertion reaction designed to model Ziegler-Natta
polymerization conditions.32

Similarly, Brintzinger and coworkers reported a cis/trans ratio of 1.01 $0.02 for
the hydrocyclization of (5,3 )-1,6-dideuterio—l,5-hexadiene when Cp22rC12 activated by

MAO was employed as the catalytic system.33 However, utilization of a less

51

conformationally restricted intermolecular insertion reaction with the same catalytic
activation gave markedly different results (Scheme IV).33 The intermolecular insertion of
appropriately labeled l-hexene revealed a preference for formation of erythro 6-deuterio-5-
deuteriomethylundecane (erythro/threo = 1.30 :1:O.03).33

The formation of primarily erythro 28 indicates a preference for transition state (a-
H)-27 over (t)t-D)-27.33 These findings provide the first experimental evidence for an a-
agostic interaction in the transition state for olefin insertion promoted by a
zirconocene/MAO catalytic system. Experimental evidence of this nature supports the

modified Green-Rooney mechanism in which a-agostic activation is proposed.10

Scheme IV. Evidence For a-H Activation in a MAO/Zirconocene System.

a o D
09, H R R . R R
f, 42%/+11 m w~éH
Cp\ Ho 1“ (ot-H)-27 W2!
+Zr H
99' H
as H H
C9, ,0 R R . RR
R\u 32‘2th m wa
r! GP 0 H H 2) H” H H H
o
o (a-D)-27 ma
R-nau amaze/ma

1.& i013

Intramolecular hydrocyclizations of deuterium labeled dienes did reveal kinetic
isotope effects in the formation of cyclopentane products when a scandium catalyst was
employed in the absence of a Lewis acid cocatalyst (Scheme V).34 Again, these results
support the modified Green-Rooney mechanism because of the detectable role of the or-
hydrogen in the rate determining step of olefin insertion.10 The isotope effects observed

are also suggested to rationalize the fact that active catalysts are 14-electron metal centers

52
with two vacant orbitals.34 One vacant orbital is for coordination of the olefin, and the

other is said to accommodate the agostic interaction.

Scheme V. Isotope Effects in Scandocene Catalysis of Olefin Insertion.

Me
[OPSC(H)(PM93)] CHzD [0936(H)(PM°3)1 - MO
W 0 H2. 4 atm F G D \ “‘PMOG

7 M ' Me a:
RT 628' M. ‘ H
29 trans/cis Me
1.19 t0.04:1
Me

 

Intramolecular Cyclizations.

The work described herein is part of a research program originally designed for the
exploration of stereochemical and regiochemical control in the reaction of an activated
carbon with an olefin for the formation of five- and six-membered carbocycles.35 Based
on some intriguing results obtained in the study of carbocycle formation, this portion of the
investigation has been aimed at further clarification of the role of the cocatalyst and the
growing polymer chain in the regulation of olefin insertion.” Results previously reported
from these labs have shown outstanding selectivities in the formation of substituted and

unsubstituted cyclopentanes under Ziegler-Natta olefin insertion conditions (Table 0.353

53

Table I. Selective Formation of Five-Membered Carbocycles.

 

 

 

 

co 0' H , H 0;: on H , H H H
\ifl’LRIfi'" Ra ——>E‘A'°'2 TM F" —>”°' "jalfi‘, 9’ as
/ R4 _7aoc I 4 R4

Cp H 09 H H

as H as H R‘ H
30 31 32
R2 R3 R4 R5 R6 trans:cis (32) Yield (32)
a H H H H H -" 85%
b H H H H Me """' 79%
c H H H Me H "- 93%
d H H Me H H 94:6 93%
e H Me H H H 0:100 93%
1’ Me H H H H 100:0 94%

Further investigations revealed that six-membered ring formation serves as a better
intramolecular model for the olefin insertions associated with Ziegler-Natta polymerization
(Table II).35c The increased flexibility of the transition state for cyclohexane formation
more accurately reflects the conformational freedom of the intermolecular insertions of

Ziegler-Natta olefin polymerization processes.35¢

Table II. Selective Formation of Six-Membered Carbocycles.

 

 

a: Ra Ra
szcm:::[ns ewc'z yd» HCI R3
—- omen _—__>
R‘ 3‘ Mo R‘
as as R‘
33 34 S
Rz {.1 R4 Rs trans:cis (35) Yield (35)
a H H H Me 99:1 89%
h H H Nb H 3:97 78%
c H M: H H 50:50 41%
d H iPr H H 23:77 47%
e w , H H H 81:19 71%
f iPr H H H 92:8 63%

 

54

Other interesting features identified through these studies include the acceleration of
cyclization due to the presence of a substituent in the position beta to the transition metal.35c
Also, product selectivity for the cyclization of 33c varied with the variations of Lewis acid
additive.35 These selectivities include 80:20 transzcis for EtAlCl2 (-78 °C), 75:25 for MAO
(-78 °C), and 33:67 for ng2 (25 °C).3621 The currently accepted mechanisms for similar
olefin insertion processes describe selectivity as arising from an a-hydrogen agostic
interaction independent of cocatalystlvs'10 The findings from these labs indicate that these
homogeneous catalyst systems do not necessarily proceed through a common cationic
intermediate with the Lewis acid additive simply serving as a non-participating anion.35

This study was designed to show the involvement of a- and B-hydrogens in the
insertion of olefins in homogeneous catalytic systems in the presence of a cocatalyst. In
addition to the role of the alkyl chain in activation of the Ti-C bond toward olefin insertion,
chain transfer processes which were previously observed353 were investigated in greater
detail.

For a number of years, researchers have known that B-H and B-Me migrations
compete with olefin insertion in the termination of alkene oligomerization in Ziegler-Natta
systems with do early transition metal catalysts.” The understanding of these chain
termination process is important in order to control chain length in polymerization
reactions. To date, such process have not been identified in titanium systems, so the
intramolecular olefin insertion was used as a probe to monitor chain transfer processes with
respect to solvent dependence, monomer substituent or Lewis acid activation of olefin

insertion.

55

Scheme VI. Chain Termination/Chain Transfer Pathways.

LnM Wt.“

 

 

For Ziegler-Natta polymerization systems, chain termination through B-hydrogen
transfer has been pr0posed.37 There have been a number of investigations into these
processes through end group analysis in polymerization reactions.33'45 Scheme VI
illustrates some of the possible chain termination processes.38 Typically, termination of the
growing polymer chain (36) results in the formation of the terminal olefin product (37),
and the new polymer-metal complex 38.38 There are two possible pathways for the
formation of the observed products. The first is through B—hydrogen elimination to give
complex 39 which can undergo olefin exchange in the presence of an additional monomer
unit. Insertion of the monomer into the metal-hydrogen bond forms 38. An alternative
mechanistic possibility is the simultaneous transfer of hydrogen to the monomer,
coordination to the metal, and elimination of terminal olefin 37 .33

There have been a number of studies confirming the existence of chain transfer
processes that have been reported.39'45 Teuben has proposed that the B-Me transfer may
be thermodynamically more favorable than B-hydrogen transfer based on ab initio

calculations.39 Similar preferences have been confirmed experimentally for cationic Hf and

56

Zr catalyst systems for cyclopolymerization,4o ethene polymerization,41 and propene
polymerizationfllv“2 Polymerization systems catalyzed by Cp'2MCl2jMAO (M=Zr, Ht)
have shown both B-Me and B-H transfer for the polymerization of propylene,43 while
polymerization of 1-butene was characterized by termination exclusively through B-H
elimination to aluminum.433 The transfer of B-alkyl groups has also been reported in the
related lanthanide model system for propene polymerization.“ Bercaw and coworkers
have provided a wealth of evidence for both B—hydrogen transfer and B-alkyl transfer in
polymerization systems with scandocene catalysts.45 Bercaw et al. have investigated the
different effects of B-substituent variations on alkyl transfer process“5b as well as the extent
of competition between B—hydrogen transfer and B-alkyl transfer.“c Because titanium
systems have been the subject of fewer studies, experiments were designed to show the
existence of chain transfer processes in our intramolecular olefin insertion model of Ziegler-

Natta polymerization.

EXPERIMANTAL GOALS

The goals of this work were to use intramolecular olefin insertion in the selective
formation of six-membered rings to model interactions between the Ziegler-Natta
catalyst/cocatalyst complexes and the growing chain of a poly-a-olefin. This system was
to be utilized to explore both a— and B-deuterium isotope effects in Ziegler-Natta olefin
polymerization model systems. The single olefin insertion process was also used to probe
chain transfer/ligand transposition processes in the formation of both five- and six-

membered carbocycles.

57
SYSTEM DESIGN

The system used in our studies was designed to model the polymerization of a-
olefins in the presence of a Lewis acid cocatalyst. This was accomplished through
examination of the intramolecular insertion of olefins tethered to titanium by an alkyl chain

substituted [3 to the metal by a second alkyl chain (41, Figure 2).36

 

 

 

H HR H
c CIT F‘—
p2 ' aR-nPr
b R-nBu
h——a
41

 

 

 

Figure 2. Ziegler-Natta (ll-Olefin Polymerization Model.

The intramolecular olefin insertion of 41 presented intriguing challenges for the
study of competitive insertion rates. The or-hydrogens of these substrates are
diastereotopic, and there is only one B-hydrogen present. Therefore, the effects of the B-
alkyl substituent or B—hydrogen participation could not be determined through monitoring
internal competition. For these reasons, a system was designed in which the competitive
rates of cyclization were determined for the simultaneous reaction of 41a and 41b as well
as the appropriately labeled analogs. This approach allowed for determination of the effects
of the 0t- and [or B-interactions in the rate determining step of olefin insertion in a system
modeling the polymerization of l-pentene and 1-hexene for both homogeneous (MAO) and
heterogeneous (Mng)46 catalyst systems.

Intramolecular olefin insertions which result in the formation of 6-membered
carbocycles have previously been identified as a sensitive probe for Ziegler-Natta olefin
insertion, as well as an accurate model for polymerization.35 The accuracy of this model is
attributed to the presence of a high local concentration of olefin relative to the transition

metal center, while an overall 1:1 stoichiometry is maintained. Due to the significance of

58

findings previously reported from these labs,36 both MgX2 and MAO were examined as
Lewis acid additives in the competitive olefin insertion reactions of 41a and 41b. Because
of the increased use in industrial polymerization processes, MAO was selected as the
cocatalyst of choice for this study. Since previous investigations indicated that Mng and
MAO behave differently in the intramolecular olefin insertion process, MgX2 was utilized
for comparison in this investigation.

The nature of this competition study requires that the difference in cyclization rates
attributable to the change in B-substituent be quantified. Through comparison of the
relative rate of cyclization of 41a and 41b without deuterium labeling, a normalization
factor can be obtained. Such a value allows for the calculation of kH/lq) values from
competitive cyclizations of 01- and/or B-deuterium labeled substrates. An equally as
informative value can be obtained via the cyclization of (a-D)-41a vs. (a-D)-41b.

Previous studies from this group revealed that intramolecular olefin insertions
promoted by MgX2 were solvent dependent.36a When CH2C12 was used as the solvent for
cyclization, high conversion to a single cyclized product was efficiently achieved.
However, the use of toluene as the cyclization solvent provided for the formation of several
additional cyclic and acyclic products. Chain transfer was a likely explanation for the
formation of several sideproducts.36a This ligand transposition was examined in greater
detail throughout the cyclization of 42 and 43 (Scheme VII).

Reports have indicated that the presence of an olefin can trigger chain transfer as
well as olefin insertion.47 Because of these results, our intramolecular olefin insertion
methodology was quite appropriate for study of the insertion of olefins into a titanium-alkyl
bond. Bromide 42, after treatment with magnesium, can be transmetallated to titanocene
dichloride to generate alkyl titanocene 45. Olefin insertion would give 41 which, upon
hydrolysis, could give the expected cyclopentane product. Elimination of the B-hydrogen
from the same intermediate gives 49, and hydrolysis would yield 50. Chain

transfer/ligand transposition of 45 would give intermediate 46 which could undergo

59

insertion and hydrolysis to give 53. In addition, intermediate 46 could be reduced and
hydrolyzed to 51, or simply hydrolyzed to 51. Because 51 can arise with or without the
chain transfer/ligand transposition process, the formation of 52 and 53 was used as the

primary indicator of the chain transfer process.

Scheme VII. Chain Transfer Processes In Olefin Insertion Reactions.

R R
a: R=Me. n-1 Br
1): R-Me, n:2 Br
02 9391'). out n n
0 43

 

 

 

1R1) M9 111R Mo
2) 053211012 2) szTTCl-‘y
Chain- R
lnsert‘on Ln” TL“
l—p
LnM\‘I“ LnM n

47

./ \wm ~51 \21/ \ 1
ME) A) 3;) .3113. .3“

RESULTS AND DISCUSSION

Substrate Preparation and Cyclization Methods. The preparation of
cyclization substrates used in this study is illustrated in Scheme VIII.353 The appropriately
substituted diethyl malonates were purchased from Aldrich Chemical Company, and were
easily alkylated with 4-bromopentene after treatment with NaH. Deethoxycarboxylation
provided 56, which was a key intermediate for the preparation of all substrates used for the

60
cyclization reactions. The two step preparation of the alkylated ester could typically be
accomplished in 80-90% yield.

Incorporation of deuterium alpha to the ester was most easily achieved by treatment
with LDA followed by addition of nBuLi for deprotonation of the diisopropyl amine, and
subsequent quenching with D2048 This procedure generally resulted in >97% deuterium
incorporation in 89-92% overall isolated yield. Reduction of 56 or (B—D)-56with LiAlH4
gave the corresponding alcohols in excellent yields. Formation of (a-D)-57 and (cc-D, [3-
D)-57 was achieved in high yields by reduction of the ester with LiAlD4.

Treatment of the requisite alcohols with NBS and PPh3 gave the desired bromides
in 68-94% yield“9 Once isolated, the bromides were stored in a -20 °C freezer, and passed
down a short column of basic alumina prior to use. The organometallic species (41) was
prepared by Grignard formation and transmetallation to Cp2TiCl2.

Cyclization results for both MAO and MgX2 promoted reactions will be presented
here for comparison and completeness.50 The MAO promoted olefin insertions were
performed by isolation of the alkyl titanocene complex which was subsequently taken up in
toluene. The organometallic species was isolated since the byproduct of transmetallation,
MgX2, can promote intramolecular olefin insertion at room temperature. This olefin
insertion was not surprising since isotactic polypropylene can be obtained through the use
of the heterogeneous Cp2TiCl2/MgCl2j TiCl4/A1Et3 catalyst system.51 However, Grignard
formation and transmetallation in the presence of THF allowed for isolation of the
alkyltitanium with less than 9% cyclization.

Aliquots of the organometallic solution were treated with MAO, and cyclization was
shown to be very efficient, yet measurable at -45 °C, and the entire reaction was cooled to
-78 °C and quenched with anhydrous HCl at the desired time intervals.52 Parallels between
this MAO promoted intramolecular cyclization system and Ziegler-Natta polymerization

were clearly demonstrated by the formation of cyclohexane-capped oligomers (2-7

61

monomer units as shown by mass spectral analysis) when l-hexene (10.0 equiv) was

added to the organometallic solution in the presence of MAO.

Scheme VIII. Preparation of Cyclization Substrates.“

Etoacn eoacn

.. -‘~ e6
54
F—
a:R-nPr /
szi=nBu
H R o R
“’33 —c- ea):
5‘ (00156

:3 :0 :0 Z)

 

 

Y = OH (a- -D)-57 (B— D)- 57 (a- -D ,B-D)-57
1 I

Y . Br 5 (a-D)-58 (B—D)—58 (a-D.B—D)—58
l 9

Y - MnBr 9 (a-D)-59 (Bow-59 (a—D.B—D)—59
11

Y . TlCle2 41 (tr-0H1 (B-DH‘I (a-D.B—D)-41

 

“Reaction conditions: (a) i. NaH. DMF, ii. 4-bromopentene (b: 99%); (b) H2O, DMSO,
LiCl, 180 °C (a: 90% from 5411, b: 86%):(c) i. LDA, ii. n-BuLi, iii. D20 (a: 89%, b: 92%):
(d) i. LiAlHa, ii. H2O 00-98%); (e) i. LiAlDa, ii. H2O (92-95%); (D NBS, PPh3 (68-94%);
(g) 4 equiv. of Mg, (h) szTiCl2.
Reactions promoted by MgX2 were performed by allowing the transmetallated
solution to warm to room temperature. At the desired time intervals, aliquots were

removed from the MgX2 promoted reactions, cooled to -78 °C, and quenched with

anhydrous HCl. The deuterium isotope effects reported in this study for both MAO and

62

MgX2 were'obtained through the competitive cyclization of the appropriately labeled propyl
(413) and butyl (41b) substrates as illustrated in Scheme IX.

Scheme IX. Competitive Cyclizations of 41.

nPr "OX2 rBJ
()I'x2 or
we Y MAO
<— ——by
v
01: 41.

‘—§

nPr nPr
at , at

[v.cm;x.c1.at J

:5
“4:; .

i2}.

 

Normalization. As illustrated in Scheme IX, the relative rates of cyclization of
the propyl and butyl substituted substrates was determined through examination of the
product distribution resulting from cyclization of equimolar amounts of 41a and 41b. The
cyclizations were quenched, and the hydrolysis products were quantified through capillary
gas chromatographic analysis. The competitive cyclization of 41a and 41b allowed for
determination of the combined steric and electronic contributions of the propyl [5-
substituent relative to that of the butyl B—substituent with respect to cyclization rate.53 In
addition, the competetive cyclization of (a-D)-41a and (a-D)-41b gave the same
information which verified the internal consistency associated with this experimental

design.

63

Table III. Relative Rates For Competitive Cyclization of 41a and 41b“

nPr MgX2 nPr oar MgX2 neu
or or
m V Y we
h + —->
Y Y
61. 41a 41b 81b

[ Y=Cp2XTi;X=Cl,Br ]

 

 

 

Relative Rates”

 

 

Entry 41a:41b Mgfic MAOd

1 a-Hza-H 1.14:1.00 1.33:1.00
2 a-D:0t-D 1.19:1.00 1.43:1.00
3 a-Hza-D 1.43:1.00 1.26: 1.00
4 a—Dza-H 1.00:1.09 1.51:1.00‘
5 B—Dzfi-D 1.15:1.00 1.33:1.00
6 B-Hzfi-D 1.25:1.00 1.41:1.00
7 B—Dzfi-H 1.00:1.05 1.25: 1.00
8 a-H,B-H:a-D,B-D 1.55: 1 .00 —

\O

o-D,8-D:o-H,8-H 1.00:1.20 —

“Relative amounts determined by capillary GC (ref. 23). bUnless noted
otherwise, errors in these values are 1:0.02 or $0.03. CReaction conditions:
i. 1.0 equiv. of 58a, 1.0 uiv. of 58b Mg, Et20. 25 °C, ii. Cp2TiCl2,
toluene, -30 °C to 25 °C. = Cl, Br. dReaction conditions: i. 1.0 equiv.
of 58:1, 1.0 equiv. of 58b, Mg, THF, 35 °C, ii. Cp2TiCl2, CH2C12, -30
° to 25 °C, iii. Removal of inorganic salts, iv. 41, toluene, MAO, -45
°C. ‘Values 3 10.04.

For MgX2 promoted cyclizations, 61a and 61b were formed in a ratio of
1.14:1.00 (Table 111, entry 1).54 A greater difference in the rate of cyclization was
observed for the MAO promoted cyclization (1.33:1.00).55 When deuterated substrates
were examined, cyclization promoted with MgX2 resulted in a relative rate of formation of
1.19:1.00 for (a—D)-6la to (a-D)-6lb, and MAO promoted cyclization gave a ratio of

1.43:1.00 (Table 111, entry 2). The stereosclectivity of cyclization was shown to be

64

dependent upon reaction conditions. MgX2 promoted cyclization (25 °C) reflected a
preference for the formation of cis ~63 (40:60 trans/cis), while promotion with MAO
resulted in a trans/cis ratio of 60:40. This variation in reaction selectivity paralleled that
observed for the cyclization of 33e (Table II). The greater selectivity for the cyclization of
33e (90:10 for MAO) is a result of the greater steric requirements of the isopropyl
substituent.56

The normalization values (Table III, entries 1-3), when incorporated in the
evaluation of the remainder of the cyclization studies, allowed for the accurate
determination of the actual deuterium isotope effects associated with the intramolecular

olefin insertions.

a-Deuterium Isotope Effects. Table 111, entries 3 and 4 shows the results for
the competitive cyclization of 41a and (a-D)-41b as well as for (a-D)-41a and 41b
respectively. The difference between the two Lewis acid additives is clearly illustrated in
these two reactions. Deuteration decreases the cyclization rate for MgX2 promoted
cyclizations, whereas the insertion rate is increased for MAO accelerated reactions. While
large deuterium isotope effects seem immediately obvious at this point, the relative rate
differences based on B-alkyl substituent variation (propyl vs. butyl) must be taken into

account in order to obtain the actual kH/kp values for the cyclization of 41.

Scheme X. Calculation of the Alpha Icy/k0 for 418.

41a 4113
I < 410 > ' (ta-0H1!) \
__4ta — kl 41a
(a-DHTB ' k0

(oz-DH“ (ix-DH“)

(MW—“Ll/

65

Application of either normalization factor (Table III, entries 1 and 2) provides the
actual kH/kp values for the cyclization of 41, and comparison of these two kH/kD values
illustrates the internal consistency inherent in the experimental design. Scheme X shows
the way in which the normalized values are calculated, and the results are given in Table
IV. Following equation I for the MgX2 promoted cyclization gives kH/kD =1.14 o
1.09:1.24 :l:0.03. Similarly, equation 11 gives Icy/k0 =l/1.19 0 1.43:1.20 i003. The
average of these two values results in a kH/kD propyl=1.22 $0.03. Analysis of the
cyclization of 41b gives a Icy/k0 butyl value of 1.28 :l:0.03.

Intramolecular olefin insertion promoted by MAO shows an opposite effect on the
rate of insertion caused by (rt-deuteration. For 41a, a kH/kD of 0.88 :l:0.04 is obtained,
and for 41b, the value is 0.95 :l:0.04. This unexpected inverse isotope effect is evidence
that the rate of insertion is enhanced by the presence of an or-deuterium label. It is also
interesting to note that the magnitude of the deuterium isotope effect increases for smaller
B-substituents. Because of this, it is reasonable to anticipate and even greater isotope effect
in the polymerization of propylene when catalyzed by MAO.

Table IV. Normalized a-Deuterium Isotope Effects for the Cyclization
of 41a and 41b.“

nPr Max, nPr 1181 We rat
or or
m V V . MAo
‘— + —>
Y Y
01. 41. 41b G15

 

 

 

Lewis Acid Substrate 11’ 11‘ Average kH/kp
MgX2 418 1.24 :l:0.03 1.20 :l:0.03 1.22 :l:0.03
MgX2 41b 1.25 :l:0.03 1.30 :l:0.02 1.28 :l:0.03
MAO 41a 0.88 $0.04 0.88 i004 0.88 :l:0.04
MAO 41b 0.95 i004 0.95 :l:0.04 0.95 i004

 

“Calculated from the values in Table III. bCalculated from equation I , Scheme X.
CCalculated from equation 11, Scheme X.

66

B-Deuterium Isotope Effects. The B-deuterium isotope effects were obtained
in much the same way as described above. To monitor internal consistency, an additional
normalization value was obtained through the relative rate of cyclization of (B-D)-41a with
respect to (B-D)-4lb (Table 111, entry 5). MgX2 promotion of olefin insertion for 41a vs.
(B-D)-41b and for (B-D)-4la vs. 41b again reflected positive isotope effects (Table III,
entries 6 and 7). Normalization of the raw data as shown in Scheme 1X, gives the Icy/k0
values shown in Table V. These results indicate that the B-hydrogen is involved in the
propagation step of the Ziegler-Natta polymerization of Ot-olefins.

In comparison to the MgX2 promoted reactions, the MAO promoted reactions also
show a positive isotope effect for deuteration in the B-position (Table 111, entries 6 and 7,
Table IV). Normalization of the rates of cyclization gives a B-deuterium isotope effect of
1.09 (propyl) and 1.10 (butyl) for MgX2 promoted cyclizations, and 1.06 3:004 for both
the propyl and butyl substrates for MAO activation. Again experimental evidence is

provided through these studies for a deuterium isotope effect for this Ziegler-Natta olefin

polymerization model.

Scheme XI. Calculation of the Beta kH/kp for 41a.

41a 41b
1 ( 41b ) ' (tam-41:) \
42— = 'ki 41a
15'0”“ kD

 

(B-DHta (1)-owe

'1 (MW-“7V

67

Table V. Normalized B-Deuterium Isotope Effects for the Cyclization of
41a and 41b.“

 

 

 

 

 

nPr Moxz nPr neu “OX2 0&1
Of or
MAO Y Y MAO
v + v
are 41a 41b 61b
fv-cozxn; x.c1.at ]

Lewis Acid Substrate I” 11‘ Average kH/kp
MgX2 41a 1.09 $0.02 1.09 $0.02 1.09 $0.02
MgX2 41b 1.10 $0.02 1.10 $0.02 1.10 $0.02
MAO 41a 1.06 $0.04 1.06 $0.04 1.06 $0.04
MAO 41b 1.06 $0.04 1.06 $0.04 1.06 $0.04

“Calculated from the values in Table III. bCalculated from equation 1, Scheme XI.

CCalculated from equation 11, Scheme XI.

Combined 01- and B-Deuterium Isotope Effects. The observation of
positive 01- and B—isotope effects for MgX2 promoted olefin insertion reactions prompted
an investigation into the nature of the combined effect. This was examined through the
competitive cyclization of 41a vs. (a-D, B-D)-4lb and of (at-D, B-D)-4la vs. 41b. The
relative rates of cyclization are shown in Table 111, entries 8 and 9. The normalization
process revealed cooperative isotope effects of 1.37 and 1.36 $0.02 for 413 and 41b,
respectively.

Mechanistic Implications. Figure 3 summarizes the observed kinetic isotope
effects observed in this investigation. The variation of deuterium isotope effect resulting
from the use of different Lewis acid additives shows that the same mechanistic pathway is
not necessarily operative for both the heterogeneous (MgX2) and the homogeneous (MAO)
catalyst model systems as is often proposed for Ziegler-Natta polymerization systems.1

This effect could be due to the difference in the nature of the Lewis acid additive, or due to

68

the difference in temperature required for olefin insertion under either set of conditions as

has been reported for the changes in stereoregularity of polymer formation}:5

 

Max; IMO
41a: kn/kp'fi .09 41a: [qr/qul .06

41b:kH/k])1=1.10 l J “ERR/[£174.06
‘0 H R R H
41a:kn/kp=1.37 Y Y
41bzhflkD=L$ 5?: GE
f lucky/Mas

 

 

0

41azkH/kp=1.22 .
: - . 41b: .95
41b kH/kD-l 28 L___t 14;]ka

_—_J
Y-szcm
a:R-iPr.b:R-n8u

Figure 3. Summary of Kinetic Isotope Effects.

 

 

 

 

 

The deuterium isotope effects observed in this investigation contrast those reported
by Grubbs from his studies of intramolecular olefin insertions in the formation of five-
membered rings.32 Whereas Grubbs did not observe an alpha isotope effect, this
investigation revealed a positive interaction in the case of MgX2 promoted cyclizations, and
an inverse effect for MAO promotion. The is0tope effects measured in this study of a
titanium system with MgX2 promotion are comprable to the reports of Brintzinger33 and
Bercaw34 in which measureable isotope effects were observed. It is interesting to note that
the isotope effects observed by Bercaw and coworkers did not involve a Lewis acid.34

The mere existence of the deuterium isotope effects shows that the alkyl chain is
involved in the rate determining step of olefin insertion. Earlier studies have demonstrated
that activation of the catalyst occurs by complexation of the transition metal with the Lewis
acid additive which creates an electron deficient transition metal center.” Following
activation, the main function of the cocatalyst is that of a bulky anion serving to stabilize the

cationic transition metal complex. In light of the observed kinetic isotope effects,

69

ramifications of the involvement of the alkyl chain must be taken into account in
mechanistic descriptions of olefin insertion reactions. Such ligand-catalyst/cocatalyst
interactions provide insight into the potential causes of stereosclectivity in polymer
formation.

When describing the interactions of the growing polymer chain model with the
catalyst/cocatalyst system, there are several possibilities for ligand coordination that need to
be considered. Scheme XH depicts several of these possibilities. Both MgX2 and MAO
are known to display an extended framework represented as -X-M-X-M-, where M=metal,
and X=halogen or oxygen.58 Following activation of the catalyst system, three of the

major types of possible ligand interaction are:

A) A gostic interaction with the transition metal.
B) Agostic interaction with the cocatalyst.
C) Combined bridging alkyl ligand and agostic

interaction with the cocatalyst.59

As illustrated in Scheme X11, a positively chaged transition metal center is created
through complexation with the cocatalyst framework. Involvement of the growing polymer
chain model with the transition metal are shown for all three types of ligand interaction.
Structures 64, 65, 67, and 68 depict ligand-metal contact a single site on. the alkyl chain,

while 66 accounts for the combined a and B effects through a-hydrogen interaction with
the transition metal and B-hydrogen coordination with the metal of the cocatalyst. The
combined interactions shown for 69 demonstrate the possibility of the reverse interactions,
specifically, a-hydrogen interaction with the cocatalyst metal and fi-hydrogen coordination

to the transition metal.

70

Scheme XII. Potential Ligand Catalyst/Cocatalyst Interactions.

 

 

111-Interactions B—Interactions 01- and B-Interactlons
X X X
ox filx\ M’x\ Max fi’KM’X\ M’x 'M/x\ okfi, 3
m” ‘1’ ‘x’ ‘x’ ‘it’ ‘x’ ‘x’ ‘X’~\ ‘x’
H R , H R H R
@ epzrt’ Cp2Ti Cp2Tl
H + H H H H
64 65 66
®
X X X X X
ox M/x\ M’x\ 'Mox filk ’x\ fi’x 'Mlx\ rkfi’m 3'
1 HH R 1 H R . H R
Cp2Tl szT1 szT\
a . . . H
H H H
67 68 6
GD

 

 

70 ‘ 71 72

 

Combined bridging alkyl ligand and agostic interaction with the cocatalyst is shown
in line C in Scheme XII. Due to the polaraization of the carbon-titanium bond, the carbon
can interact with the metal of the cocatalyst framework as in 70, 71, and 72, thereby
enhancing the activation of olefin insertion. Although the interactions are more complex,
a— and B- agostic interactions are still possible under such ligand coordinating conditions.

Any of these ligand interactions could be responsible for the weakening Tr-C bond

and the corresponding increase in reactivity toward olefin insertion for the MgX2 promoted

71

systems. The inverse a-deuterium isotope effect resulting from MAO accelerated
cyclization suggests ground state stabilization through an agostic interaction, as the OLD-
substrate would be expected to react more readily. Although the exact nature of the agostic
interactions remains undetermined, involvement of the growing polymer chain model with
the cocatalyst framework has been shown through the identification of these 0t- and B-
deuterium isotope effects. Interaction between the growing polymer chain and the
cocatalyst helps to explain the selectivities observed in the Ziegler-Natta polymerization of
olefins.

Chain Transfer Reactions. The cyclization of 42a, 42b, and 43a in toluene
was performed under a variety of conditions which revealed evidence in support of the fact
that chain transfer under these conditions is an intermolecular process (Scheme XIII).50
‘ For the cyclization of 42a, a dependence of the formation of ligand transposition products
on reaction concentration was observed. At 0.1M 52a and 53a were formed in 11% and
2% respectively. As the concentration was increased from 0.25M to 0.60M, the amount of
formation of the products arising from chain transfer/ligand transposition increased. This
dependence upon concentration suggests that the formation of the cyclization side products
is an intermolecular process. Introduction of a B—deuterium, however, shut down the chain
transfer processes.

The reverse reaction, namely the cyclization of 46a, which results from Grignard
formation and subsequent transmetallation of 43, resulted in formation of 14% of the chain
transfer product 48a. The major product of this reaction was that of hydrolysis of 46a.
Other substrates examined include 42b and 42c. The effect of the formation of a six-
membered ring was demonstrated by the cyclization of 42b. The increased tether length
had little effect on the formation of the chain transfer products, which also supports the
proposal that the ligand transposition in an intermolecular process. Bromide 42c, which
was used to model the polymerization of styrene, revealed increased competition from the

B—hydrogen elimination process.

72

Scheme XIII. Chain Transfer Processes In Olefin Insertion Reactions.

R F1
.3 R=Me. "=1 81'
b2 mm, 1182 Br
0: Raph. n=1 1: 11

Q 0
11m 11)::

 

 

 

 

2) camel2 2) comet.2

Chain—

1....6 .0... “:5 5:) ...... {a
\.

/ 1 \w/ \ l
....:5 .55.. “3:5 .15. .{5 “35>

O
42- (0.10117) 67% ' 21% 11% 2%
42a (0.25 M) 71% 5% 12% 12% <2%
42- (0.44 M) 57% ' 18% 21% 4%
42: (0.60 M) 54% - 17% 23% 7%
(80) 42a (0.25 M) 60% 15% 14% <2% <2%
43. (0.25 M) 14% <2% 5% 81% <2%
42b (0.25 M) 61% 13% 12% 12% 2%
42¢ (0.25 M) 45% 24% 4% 10% 8% <2%

'AcammscouldmbemubhmeneeMasdmtinpuhy.

73
CONCLUSIONS

For the first time, a-hydrogen interactions have been shown for a titanium based
catalyst system, and, this is the first reported system modeling the polymerization of an a-
olefin in either the heterogeneous (MgX2) or the homogeneous (MAO) promoted system.
In addition, a B-hydrogen interaction has been shown for the first time in a Ziegler-Natta
catalyst/cocatalyst model system.

The kinetic isotope effects observed for the MgX2 promoted olefin insertion, 1.22
and 1.28 are comparable to those previously reported for systems that modeled the
polymerization of ethylene with zirconium61 and scandium62 catalysis. In contrast, the
MAO promoted olefin insertion reactions resulted in an unexpected inverse (at-isotope effect
(0.88 and 0.95 for 41a and 41b respectively). The quantification of this effect supports
the hypothesis that the role of the Lewis acid additive in olefin insertion reactions is not
independent of the nature of the Lewis acid. The isotope effects measured in this study
reflect the difference in Stereoselectivities for the cyclization of 33e and 41, as well as the
reported variations in the stereoregularity of polymer formation in titanium and zirconium
systems.

Cyclization reactions of 42 and 43 provide evidence that chain transfer in titanium
systems is an intramolecular process. These results are the first reported for titanium

mediated olefin insertion systems.

EXPERIMENTAL SECTION

General Methods. All reactions were conducted under nitrogen or argon
atmospheres. THF, Et20, toluene, and benzene were distilled from sodium/benzophenone
prior to use. Hexane was stirred over sulfuric acid, and after 5 d, the hexane was washed
sequentially with H20, saturated aqueous NaHCO3, dried (CaClz), and distilled from
sodium/benzophenone/teu‘aglyme. The Mg used for formation of the Grignard reagents
was activated prior to use by washing with 10% HCl, H20, acetone, and finally with Et20.
The turnings were then flame dried in vacuo, and stored in a desiccator. 4-Bromo-l-
pentene53 and MAO64 were prepared according to literature procedure.

NMR spectra were obtained on a Varian Gemini 300 or a VXR-300 instrument with
CDCl3 as solvent. Signals are reported in units of ppm relative to C(IH)C13 or l3‘CHC13.
Analytical gas chromatography (GC) was performed with a 50 m RSLZOO column (5%
methyl phenyl silicone equivalent to 8213-54 or DB-S).

Activation of Magnesium. The Mg used for formation of the Grignard reagents
was activated prior to use by washing with 10% H0, H20, acetone, and finally with Et20.
The turnings were then flame dried in vacuo, and stored in a desiccator. Immediately prior
to use, the reaction vessel containing the Mg was heated under vacuum for 15 min, purged

with argon, evacuated and purged again with argon.

Diethyl 2-(4-pentenyl)-2-(propyl)-propanedioate (55a). NaH (1.89 g, 79
_ mmol) was suspended in DMF (61 mL), and 54a (14.78 g, 73 mmol) was added dropwise
at room temperature over a 15 min period, and the resulting solution was stirred until all of
the NaH was consumed (approx. 45 min). At this point, 4-bromo-1-pentene (10.0 g, 67
mmol) was added slowly, and the reaction was heated at 65 °C until the bromide was

consumed (3-12 h). Upon completion of the alkylation, the mixture was cooled to 0 °C,

74

75

diluted with H20 (120 mL), and the aqueous layer was extracted with Et20 (3 x 60 mL).
The organic extracts were washed with H20 (3 x 30 mL) followed by saturated aqueous
NaCl. The Et20 layer was dried (MgSO4), concentrated, and carried on without further
purification.

Ethyl 2-propyl-6-heptenoate (56a). Crude diester 55a (26.3 g, 97 mmol) and
LiCl (7.9 g, 186 mmol) were taken up in DMSO (196 mL), and H20 (1.8 mL, 100 mmol)
was added. The mixttn'e was heated in an oil bath at 180 8C until reaction was complete by
NMR analysis (8-12 h). Dilution with H20 (120 mL) was followed by extraction with
Et20 (3 x 60 mL). The organic layers were combined and washed with H20 (2 x 30 mL),
saturated aqueous NaHCO3 (2 x 30 mL), and saturated aqueous NaCl (2 x 30 mL). The
Et20 layer was then dried (MgSO4), concentrated, and distilled via Kugelrohr (oven temp
80-90 °C, <1 Torr) to give 56a (17.68 g, 90 mmol) in 90% yield from 54a: 1H NMR
(300 MHz, CDC13) 8 0.85 (t, J = 7.3 Hz, 3 H), 1.20.1.59 (m, 12 H), 2.00 (q, J = 7.3
Hz, 2 H), 2.30 (m, 1 H), 4.09 (q, I: 7.3 Hz, 2 H), 4.90 (m, l H), 4.95 (m, 1 H), 5.74
(ddt, J = 17.0, 10.1, 7.3, 1 H); 13C NMR (75 MHz, CDC13) 8 14.0, 14.3, 20.6, 26.7,
31.9, 33.6, 34.7, 45.5, 60.0, 114.6, 138.5, 176.5; IR (Film) 3078, 2959, 2937, 2874,
1734. 1641, 1460, 1379, 1177; 911 cm“.

56h: (18.27 g, 86 mmol) in 86% yield from 54b: 1H NMR (300 MHz, CDC13) 5
0.85 (t, J = 7.1 Hz, 3 H), 1.14—1.50 (m, 12 H), 1.51-1.65 (m, 2 H), 2.00 (q, I = 7.1 Hz,
2 H), 2.31 (m, 1 H), 4.10 (q, J= 7.1 Hz, 2 H), 4.91 (m, 1 H), 4.98 (m, 1 H), 5.75 (ddt,
J = 17.0, 10.1, 7.1, 1 H); 13C NMR (75 MHz, CDC13) 8 13.9, 14.3, 22.6, 26.7, 29.6.
31.9, 32.2, 33.6, 45.6, 60.0, 114.6, 138.5, 176.5.

Ethyl 2-propyl-2-deuterio-6-heptenoate ((B-D)-56a). A solution of LDA
was prepared by adding n-BuLi (2.5 M in hexanes, 17.0 mL, 43 mmol) to a 0 °C solution
of iPerH (6.5 mL, 46 mmol) in THF (55 mL). Stirring was continued for 30 min, and

76

the mixture was cooled to -78 °C. Compound 56a (7.64 g, 39 mmol) was added dropwise
to the LDA solution and stirred for 50 min. n-BuLi (23.2 mL, 2.5 M in hexanes, 58
mmol) was added to the reaction mixture at -78 °C (to deprotonate iPerH), and the
mixture was stirred for 30 min. The reaction was then quenched with D20 (25 mL),
warmed to ambient temperature, and the aqueous layer was extracted with Et20 (3 x 30
mL). The Et20 solution was washed with 1M HCl (2 x 30 mL), saturated aqueous
NaHCO3 (2 x 60 mL), saturated aqueous NaCl (60 mL), dried (MgSO4), filtered, and
concentrated to an oil. The crude oil was distilled under reduced pressure (oven temp 70-
80 °C, <1 Torr) to give (B-D)-56a (6.8 g, 35 mmol, 89% yield): 1H NMR (300 MHz,
CDC13) 8 0.86 (t, J= 7.1 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), 1.28-1.46 (m, 6 H), 1.50-
1.63 (m, 2 H), 2.00 (q, J = 6.6 Hz, 2 H), 4.09 (q, J = 7.1 Hz, 2 H), 4.90 (m, 1 H), 4.96
(m, l H), 5.73 (ddt, J = 17.1, 10.4, 6.6 Hz, 1 H); 13C NMR (75 MHz, CDC13) 8 14.0,
13.9, 20.1, 26.2, 31.4, 33.2, 34.1, 59.5, 114.2, 138.1, 176.0; IR (Film) 3079, 2959.
2934, 2873, 2860, 2145, 1732, 1641, 1460, 1035.911 cm“.

(B-D)-56b: (7.55 g, 35 mmol, 92% yield); Spectral data were similar to those
obtained for 56h with the following exceptionsle NMR (300 MHz, CDC13) 8 2.31 was
absent; 13C NMR (75 MHz, CDC13) 8 45.6 was absent; IR (Film) 2130 cm’1 (00) was

present.

General Procedure For LiAlH4 Or LiAlD4 Reduction Of Esters to 57.
The reducing reagent (1.1 equiv. of LiAlH4 or LiAlD4) was suspended in Et20 (0.5 M) at
0 °C, and a solution of 56 in Et20 (1.0 equiv., 0.3 M) was added to the LiAlH4
suspension over a period of 30 min. Once addition was complete, the ice bath was
removed, and the mixture was stirred at room temperature until the reaction was complete
as determined by NMR analysis. The reaction mixture was cooled to 0 °C and quenched by
the slow sequential addition of H20 (1.0 mL/g reducing reagent), 15% NaOH (1.0 mL/g
reducing reagent), H20 (3.0 mL/g reducing reagent) and stirred until all of the solids turned

77

white. At this time, MgSO4 was added, and the mixture was stirred for an additional 30
min. The Et20 was decanted from the solids, which were washed thoroughly with Et20,
and the combined organic fractions were concentrated and distilled via Kugelrohr (oven
temp 70-80 °C, <1 Torr) to provide the desired alcohol.

573: (13.21 g, 85 mmol, 96% yield); 1H NMR (300 MHz, CDC13) 8 0.87 (t, J= 6.8
Hz, 3 H), 1.13-1.50 (m, 10 H), 1.98-2.05 (m, 2 H), 3.49 (d, J: 5.4 Hz, 2 H), 4.92 (m,
1 H), 4.96 (m, l H), 5.77 (ddt, J = 17.0, 10.2, 6.7 Hz, 1 H); 13C NMR (75 MHz,
CDC13) 8 14.4, 20.0, 26.1, 30.4, 33.2, 34.1, 40.2, 65.6, 114.4, 138.9; IR (Film) 3337,
3079, 2958,2930, 2872, 1641, 1460, 1040, 993, 911 cm".

57b: (10.82 g, 64 mmol, 90% yield); 1H NMR (300 MHz, CDC13) 8 0.85 (t, J=
7.0 Hz, 3 H), 1.20-1.50 (m, 13 H), 1.59 (s, l H), 2.02 (q, J=7.0 Hz, 2 H), 3.49 (d, J=
7.1 Hz, 2 H), 4.90 (m, 1 H), 4.95 (m, 1 H), 5.78 (ddt, J = 17.1, 10.7, 7.0 Hz, 1 H); 130
NMR (75 MHz, CDC13) 8 14.1, 23.1, 26.1, 29.1, 30.4, 30.5, 34.1, 40.4, 65.5, 114.3,
138.9.

(a-D)-57a: (5.58 g, 35 mmol, 94% yield); Spectral data were similar to those
obtained for 57a with the following exceptions: 1H NMR (300 MHz, CDC13) 8 3.49 was
absent; 13c NMR (75 MHz, CDC13) 6 65.6 was absent; IR (Film) 2197 cm" (CD) was
present.

(a-D)-57b: (4.43 g, 28 mmol, 80% yield); Spectral data were similar to those
obtained for 57h with the following exceptions; 1H NMR (300 MHz, CDC13) 8 3.49 was
absent; 13C NMR (75 MHz, CDC13) 8 65.5 was absent; IR (Film) 2190 cm-1 (CD) was
present.

(B-D)-57a: (4.93 g, 34 mmol, 98% yield); Spectral data were similar to those
obtained for 57a with the following exceptions: 1H NMR (300 MHz, CDC13) 8 1.16-1.42
(m, 9 H); 13C NMR (75 MHz, CDC13) 5 40.2 was absent; IR (Film) 2130 an1 (CD) was
present.

78

(B-D)-57h: (5.07 g, 30 mmol, 84% yield); Spectral data were similar to those
obtained for 57h with the following exceptions; 1H NMR (300 MHz, CDC13) 8 1.20-1.50
(m, 11 H); 13c NMR (75 MHz, CDC13) 5 40.4 was absent; IR (Film) 2135 cm1 (C-D)
was present.

(a-D,B-D)-S7a: (5.25 g, 33 mmol, 94% yield); Spectral data were similar to those
obtained for 57a with the following exceptions: 1H NMR (300 MHz, CDC13) 8 1.16-1.43
(m, 8 H), 8 3.49 was absent; 13C NMR (75 MHz, CDC13) 8 40.2 and 65.6 were absent;
IR (Film) 2197 and 2097 cm'1 were present.

General Procedure For The Bromination Of Alcohols to 58. PPh3 (3.15
g, 12.0 mmol) and alcohol 57 (1.15 g, 10.0 mmol) were combined in CH2C12 (20 mL),
and cooled to 0 °C. NBS (2.14 g, 12.0 mmol) was added over 2 h by means of a solid
addition funnel, stirred for l h at 0 °C, and an additional 3 h at ambient temperature. The
reaction mixture was concentrated to a slurry, and the resulting solids were dissolved in a
minimum of CH2C12. To this solution was added 50 mL of petroleum ether at ambient
temperature, and the mixture was then cooled to 0 °C. The supernatant was filtered via
cannula, with a piece of filter paper attached to the end of the cannula, using a positive
pressure of argon. The solids were washed sequentially with petroleum ether (2 x 25 mL)
at 0 °C as before. This filtration sequence was performed two additional times. The
organic fractions were combined and concentrated to approximately 15 mL, and then
filtered through a plug of basic alumina. Further concentration produced a residue, which
was purified by distillation (oven temp 65-75 °C, <1 Torr) to give the corresponding
bromide 58.

58a: (3.97 g, 18 mmol, 94% yield); 1H NMR (300 MHz, CDC13) 8 0.89 (t, J=
6.3 Hz, 3 H), 1.21-1.46 (m, 8 H), 1.61 (m, 1 H), 1.97-2.10 (m, 2 H), 3.43 (d, J = 2.8
Hz, 2 H), 4.93 (ddt, J = 10.2, 2.0, 1.1 Hz, 1 H), 4.98 (dq, J = 17.0, 2.0 Hz, 1 H), 5.78
(ddt, J = 17.0, 10.0, 6.7 Hz, 1 H); 13C NMR (75 MHz, CDC13) 8 14.2, 19.7, 25.8, 32.0,

79

33.8, 34.8, 39.1, 39.4, 114.5, 138.6; IR (Film) 3079, 2959, 2930, 2860, 1642, 1458,
1441, 992, 912 cm'l. HRMS calcd for ClongBr m/z 218.0670, obsd m/z 218.0708.

58b: (2.27 g, 10 mmol, 65% yield); 1H NMR (300 MHz, CDC13) 8 0.91 (t, J= 6.6
Hz, 3 H), 1.20-1.50 (m, 12 H), 1.62 (m, 1 H), 2.02-2.12 (m, 2 H), 3.45 (d, J = 4.8 Hz,
2 H), 4.93 (ddt, J = 10.1, 2.0, 0.86 Hz, 1 H), 5.05 (dq, J = 17.1, 2.0 Hz, 1 H), 5.81
(ddt, J = 17.1, 10.1, 6.6 Hz, 1 H); 13C NMR (75 MHz, CDC13) 8 14.0, 22.8, 25.8, 28.7,
32.0, 32.2, 33.8, 39.3, 39.4, 114.5, 138.6; IR (Film) 3079, 2959, 2930, 2859, 1642,
1458, 1441, 1237, 992, 912 cm'l.

(a-D)-58a: (3.58 g, 16 mmol, 88% yield); Spectral data were similar to those
obtained for 58a with the following exceptions: 1H NMR (300 MHz, CDC13) 8 3.43 was
absent; 13C NMR (75 MHz, CDC13) 8 39.4 was absent; IR (Film) 2250, 2190 cm'1 were
present; HRMS calcd for C10H17D28r m/z 220.0796, obsd m/z 220.0852.

(a-D)-58b: (4.05 g, 18 mmol, 66% yield); Spectral data were similar to those
obtained for 58h with the following exceptions: 1H NMR (300 MHz, CDC13) 8 3.45 was
absent; 13C NMR (75 MHz, CDC13) 8 39.4 was absent; IR (Film) 2197, 2097 cm'1 (C-D)
were present.

(B-D)-58a: ( 4.60 g, 22 mmol, 65% yield); Spectral data were similar to those
obtained for 5811 with the following exceptions: 1H NMR (300 MHz, CDC13) 8 1.61 was
absent; 13c NMR (75 MHz, CDC13) 8 39.1 was absent; IR (Film) 2097 cm'1 (C-D) was
present; HRMS calcd for ClongDBr m/z 219.0733, obsd m/z 219.0724.

(B-D)-58h: (4.60 g, 22 mmol, 65 % yield); Spectral data were similar to those
obtained for 58a with the following exceptions: 1H NMR (300 MHz, CDC13) 8 1.61 was
absent; 13c NMR (75 MHz, CDC13) 8 39.4 was absent; IR (Film) 2097 cm'1 (CD) was
present.

(a-D,B-D)-58a: (4.54 g, 20 mmol, 81% yield); Spectral data were similar to those
obtained for 58a.with the following exceptions: 1H NMR (300 MHz, CDC13) 8 1.61 and
3.43 were absent; 13C NMR (75 MHz, CDC13) 8 39.1 and 39.4 were absent; IR (Film)

80

2197, 2097, and 1995 cm'1 (C-D) were present; HRMS calcd for C10H15D3Br m/z
221.0859, obsd m/z 221.0830.

Preparation of Methylaluminoxane (MAO).54 Using standard Schlenk
techniques, Al(SO4)2~14H20 (18.6 g, 28 mmol) was taken up in toluene (125 mL) and
cooled to 0 °C. AlMe3 (25 mL, Aldrich) was carefully transferred into the reaction vessel
via cannula, the ice bath was removed, and the reaction was stirred at room temperature
under argon for 24 h. At this time, the solution was filtered through a Schlenk frit, and the
solvent was removed in vacuo to give a glass like solid. In an inert atmosphere box, the
solids were scraped free from the sides of the flask, and powdered. The solids were placed
under vacuum for an additional 3 to 6 h, and the resulting MAO (5.05 g, 33% yield) was
stored at -40 °C in the dry box. A fresh 0.5 M solution was made for each series of
cyclizations by taking 0.349 g MAO from the dry box in a stoppered Schlenk flask, and
diluting with toluene (12 mL). Note: The MAO solution was stored in the freezer at -20 °C

between cyclization runs, and was used within 48 h.

General Procedure For MgX2 Promoted Cyclizations.5O A mixture of the
appropriately labeled bromides 58a and 58b (1 mmol each) was added via gas tight
syringe over a 2 h period to activated Mg turnings (8.2 mmol, 0.20 g) suspended in Et20
(2 mL) at room temperature. Analysis of the protonolysis products generated from an
aliquot of the solution showed that 2-4 % cyclization had occurred during formation of the
Grignard reagent. The solution containing the Grignard mixture was stirred for an
additional 1-2 h at room temperature, and then was transferred via cannula to a -45 °C
suspension of Cp2TiC12 (2.4 mmol, 0.60 g) in CH2C12 (4 mL). The mixture was stirred
at this temperature for 1 h, dodecane was added as an internal standard, and the mixture
was warmed to room temperature. The reaction was monitored by capillary gas

chromatographic analysis of samples obtained by cannula transfer of a small amount of the

81

crude reaction mixture into approximately 0.3 mL of a 1 M solution of HCl in Et20 at -78
°C. This sample was then filtered through a small column of basic alumina prior to

injection onto the GC.

General Procedure For MAO Promoted Cyclizations. Activated Mg (1.0
g, 41.0 mmol) was placed in a Schlenk flask with a stir bar and flamed dried under vacuum
for 10-15 min. The flask was then allowed to cool under argon with vigorous stirring, at
which time the Mg was suspended in 10 mL of THF, and warmed to 45 °C. A mixture of
the appropriately labeled bromides 58a and 58b (5 mmol each) was added dropwise via
syringe to the Mg over a 2 h period. After addition was complete, the reaction was allowed
to stir at 45 °C for 3 h, and then cooled to ambient temperature. The Grignard solution was
transferred via cannula to a -45 °C solution of Cp2TiC12 (2.99 g, 12 mmol) in CH2C12 (35
mL), the Mg was washed with 5 mL THF, and the washings were transferred to the
reaction mixture. After the transmetallation was stirred at room temperature for 1 h, the
mixture was stored in the -20 °C freezer overnight. the solution was warmed to room
temperature, pumped down to a burgundy oil, and then taken up in hexane (30 mL).
Filtration of the hexane suspension was performed through a Schlenk frit, the solids were
washed with hexane (2 x 15 mL) and toluene (2 x 5 mL), and the resulting solution was
concentrated to an oil. The purified organometallic species was taken up in toluene (25
mL, to approximately 0.4M), and dodecane was added as an internal standard. This stock
solution was stored in the freezer (-20 °C) until used. Dodecane was added as an internal
standard, and the mixture was stored in the freezer (-20 °C) overnight. .

The organometallic solution was warmed to room temperature, and analysis of the
protonolysis products showed that 3-9 % cyclization had occurred prior to the addition of
MAO. Aliquots of the'organometallic solution (2.0 mL), were placed in evacuated and
argon purged flasks, and cooled to -78 °C. The MAO (0.70-0.72 mL) was added down the
side of the flask slowly, the mixture then was brought immediately to -45 °C, and stirred

82

for the indicated amount of time (5-20 min). The reaction was quenched by cooling the
mixture to -78 °C, and slowly adding anhydrous HCl in Et20, stirring for 5 min, and
warming to room temperature. The quenched solution was passed down a pipette column
of basic alumina prior to analysis by gas chromatography. Cis/trans assignments were

made by comparison to an authentic sample prepared independently.

General Procedure For Polymerization of l-Hexene. Activated Mg (0.29
g, 12.0 mmol) was placed in a schlenk flask with a stir bar and flamed dried under vacuum
for 10-15 min. The flask was then allowed to cool under argon with vigorous stirring, at
which time the Mg was suspended in 5 mL of THF, and warmed to 45 °C. Bromide 58a
was added dropwise via syringe to the Mg over a 1.5 h period. After addition was
complete, the reaction was allowed to stir at 45 °C for 3 h, and then cooled to ambient
temperature. The Grignard solution was transferred via cannula to a -45 °C solution of
Cp2TiC12 (0.82 g, 3.3 mmol) in CH2C12 (6.0 mL), the Mg was washed with 1 mL THF,
and the washings were transferred to the reaction mixture. After the transmetallation was
stirred at room temperature for 1 h, the mixture was pumped down to a burgundy oil, and
then taken up in hexane (10 mL). Filtration of the hexane suspension was performed
through a Schlenk frit, the solids were washed with hexane (2 x 3 mL) and toluene (l x 5
mL), and the resulting solution was concentrated to an oil. The purified organometallic
species was taken up in toluene (5 mL), and l-hexene (2.52g, 30 mmol) was added. The
mixture was cooled to -78 °C, and MAO (3.0 mL, 1.0 M soln in toluene) was added. The
mixture was stirred at -45 °C for 3 hours, cooled to -78 °C, quenched with anhydrous HCl
in ether, and the resultant solids were filtered and dried in vacuo. The solids were then

dissolved in CH2C12 and analyzed by mass spec.

Chain Transfer Cyclizations. Activated Mg turnings (4 mmol) were suspended

in Et20 (1.0 mL), and the bromide was added dr0pwise over a period of 2 h. The solution

83

was stirred at reflux for 3 h, and then transferred via cannula to a solution of Cp2TiC12 (2.4
mmol) in toluene (4 mL) at ambient temperature. Methylcyclohexane was added as an
internal standard for 42a , 42b, and 43a, and dicyclohexyl was used for 42¢. After 12 h,

aliquots were taken as described in 3 35 . and analyzed by capillary gas chromatography.

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REFERENCES AND NOTES

For recent reviews in Ziegler-Natta polymerization, see: (a) Kissin, Y. V.
Isospecific Polymerization of Olefins with Heterogeneous Ziegler-Natta Catalysts;
Springer-Verlag, New York, 1985. (b) Minsker, K. S.; Karpasas, M. M.; Zaikov,
G. E. Russ. Chem. Rev. 1986, 55, 17. (c) Tait, P. J. T.; Allen, G.; Bevington,
J. C. (Eds) Comprehensive Polymer Science; Pergamon Press, Oxford, 1989, Chap.
1. (d) Tait, P. J. T.; Watkins, N. D.; Allen, G. (Eds) Comprehensive Polymer
Science; Pergamon Press, Oxford, 1989, Chap. 2. (e) Krentsel', B. A.; Nekhaeva,
L. A. Russ. Chem. Rev. 1990, 59, 1193. (f) Skupinska, J. Chem. Rev. 1991,
91, 613. (g) Odian, G. Principles of Polymerization; Wiley, New York, 1991,
Chap. 8.

Sinn, H.; Kaminsky, W. Adv. in Organomet. Chem. 1980, I9, 99.

(a) Ewen, J. A. J. Am. Chem. Soc. 1984, 106, 6355. (b) Ewen, J. A. Catalytic
Polymerization of Olefins, T. Keii and K. Soga (Eds), Elsevier, New York, 1986,
p. 271. (c) Zambelli, A.; Ammendola, P.; Grassi, A.; Longo, P. Proto, A.
Macromolecules 1986, I9, 2703. (d) Zambelli, A.; Longo, P.; Ammendola, P.;
Grassi, A. Gazz. Chim. Ital. 1986, 116, 731.

(a) Sinn, H.; Kaminsky, W.; Vollmer, H.-J.; Woldt, R. Angew. Chem., Int. Ed.
Engl. 1980, I9, 390. (b) Sinn, H.; Kaminsky, W. Adv. Organomet. Chem.
1980, I8, 99.

Ishihara, N.; Kuramoto, M.; Uoi, M. Macromolecules 1988, 21, 3356.

Pellecchia, C.; Grassi, A.; Zambelli, A. Organometallics, 1994, I3, 298, and
references therein.

Barta, N. S.; Kirk, B. A.; Stille, J. R. J. Am. Chem. Soc. 1994, 0000. In press.

(a) Cossee, P. J. Catalysis 1964, 3, 80. (b) Arlman, E. J.; Cossee, P. J.
Catalysis, 1964, 3, 99. (c) Cossee, P. Recueil, 1966, 85, 1151.

(a) Ivin, K. J.; Rooney, J. J.; Stewart, C. D.; Green, M. L. H.; Mahtab, R. J.
Chem. Soc., Chem. Commun. 1978, 604. (b) Green, M. L. H. Pure & Appl.
Chem. 1978, 50, 27.

(10) Brookhart, M.; Green, M. H. L.; Wong, L.-L. Prog. Inorg. Chem. 1988, 36, 1.
(11) Ittel, S. D.; Ibers, J. A. Adv. Organomet. Chem. 1976, 14, 33.
(12) Dawoodi, 2.; Green, M. L. H.; Mtetwa, V. S. B.; Prout, K. J. Chem. Soc., Chem.

Commun. 1982, 1410.

(13) Brookhart, M.; Green, M. H. L. J. Organomet. Chem. 1983, 250, 395.
(14) Janiak, C. J. Organomet. Chem. 1993, 452, 63, and references therein.

84

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(16)
(17)
(18)
(19)

(20)
(21)
(22)
(23)
(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)
(34)

85

Kawamura-Kuribayashi, H.; Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1992,
114, 2359.

Eisenstein, 0.; Jean, Y. J. Am. Chem. Soc. 1985, 107, 1177.
Calhorda, M. J.; Martinho Simoes, J. A. Organometallics 1987, 6, 1188.
Fitzpatrick, N. J.; McGinn, M. A. J. Chem. Soc. Dalton Trans. 1985, 1637.

(a) Tatsumi, K.; Nakamura, A. J. Am. Chem. Soc. 1987, 109, 3195. (b)
Tatsumi, K.; Nakamura, A. Organometallics 1987, 6, 427.

Demolliens, A.; Jean, Y.; Eisenstein, O. Organometallics 1986, 5, 1457.
Prosenc, M.-H.; Janiak, C.; Brintzinger, H.-H. Organometallics 1992, 11, 4036.
Gleiter, R.; Hyla-Krypsin, 1.; Niu, S.; Erker, G. Organometallics 1993, 12, 3828.
Rieger, B. J. Organomet. Chem. 1992, 428, C33.

Shiga, A.; Kojima, 1,; Sasaki, T.; Kikuzono, Y. J. Organomet. Chen. 1988, 345,
275.

Jolly, C. A.; Marynick, D. 8.]. Am. Chem. Soc. 1989, III, 7968.

(a) Gleiter, R.; Hyla-Kryspin, 1.; Niu, S.; Erker, G. Organometallics 1993, 12,
3828. (b) ' Prosenc, M-H.; Janiak, C.; Brintzinger, H-H. Organometallics 1992,
II, 4036.

Williams, J. M.; Brown, R. K.; Schultz, A. J.; Stucky, G. D.; Ittel, S. D. J. Am.
Chem. Soc., 1978, [00:23, 7407.

Schultz, A. J.; Williams, J. M.; Schrock, R. R.; Rupprecht, G. A.; Fellmann, J. D.
J. Am. Chem. Soc., 1979, 101:6, 1593.

(a) Hyla-Kryspin, 1.;. Gleiter, R.; Krilger, C.; Zwettler, R.; Erker, G.
Organometallics 1990, 9, 517. (b) Erker, G.; Swettler, R.; Krilger, C.; Hyla-
Kryspin, I.; Gleiter, R. Organometallics 1990, 9, 524.

(a) Dawoodi, 2.; Green, M. L. H.; Mtetwa, V. S. B.; Prout, K. J. Chem. Soc.,
Chem. Commun. 1982, 1410. (b) Cayias, J. 2.; Babaian, E. A.; Hmcir, D. C. J.
Chem. Soc. Dalton Trans. 1986, 2743.

(a) Jordan, R. F.; Bradley, P. K.; Baenziger, N. C.; LaPointe, R. E. J. Am. Chem.
Soc. 1990, 112, 1289. (b) Dawoodi, 2.; Green, M. L. H.; Mtetwa, V. S. B.;
Prout, K. J. Chem. Soc., Chem. Commun. 1982, 802.

Clawson, L.; Soto, J.; Buchwald, S. L.; Steigerwald, M. L.; Grubbs, R. H. J. Am.
Chem. Soc. 1985, 107, 3377.

Krauledat, H.; Brintzinger, H.-H. Angew. Chem. Int. Ed. Engl. 1990, 29, 1412.
Piers, W. E.; Bercaw, J. E. J. Am. Chem. Soc. 1990, 112, 9406.

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(39)

(40)
(41)

(42)

(43)

(44)

(45)

(46)

(47)
(48)

(49)

86

(a) Young, J. R.; Stille, J. R. Organometallics 1990, 9, 3022. (b) Rigollier, P.;
Young, J. R.; Fowley, L. A.; Stille, J. R. J. Am. Chem. Soc. 1990, 112, 9441.
(c) Young, J. R.; Stille, J. R. J. Am. Chem. Soc. 1992, 114, 4936.

(a) Young, J. R. Ph.D. Thesis. Michigan State University, 1992. (b) Selection of
the n-propyl and n-butyl substituents was made based on reaction kinetics (methyl
and ethyl substituted ligands resulted in cyclization which was too rapid) and
analytical procedures (optimum separation in GC analysis). Young, J. R. Ph.D.
Thesis, Michigan State University, 1992.

(a) Henrici-Olivé, G.; Olive, S. J. J. Polym. Sci, Polym. Lett. Ed., 1974, 12, 39.
(b) Henrici-Olivé, G.; Olive, S. J. in J. C. W. Chien (ed.), Coordination
Polymerization , p. 291, Academic Press, New York, 1975.

Tsutsui, T.; Mizuno, A.; Kashiwa, N. Polymer, 1989, 30, 428.

Sini, G.; MacGregor, S. A.; Eisenstein, O.; Teuben, J. H. Organometallics, 1994,
13, 1049.

Kesti, M.R.; Waymouth, R. M. J. Am. Chem. Soc. 1992, 114, 3565.

Eshuis, J. J. W.; Tan, Y. Y.; Teuben, J. H.; Renkema, J. J. Mol. Cat. 1992, 62,
277.

(a) See reference 58. (b) Eshuis,]. J. W.; Tan, Y. Y.; Meetsma, A.; Teuben, J.
H.; Renkema, J.; Evens, G. G. Organometallics 1992, 11, 362.

(a) Resconi, L, Piemontesi, F.; Franciscono, G.; Abis, L.; Fiorani, T. J. J. Am.
Chem. Soc. 1992, 114, 1025. (b) Mise, T.; Kageyama, A.; Miya, S.; Yamazaki,
H.Chem.Lett. 1991,1525.

(21) Watson, P. L. J. Am. Chem. Soc. 1982, 104, 337; (b) Watson, P. L.; Roe,
D. C. J. Am. Chem. Soc. 1982, 104, 6471. (0) Watson, P. L. J. Am. Chem. Soc.
1982, 104, 1504.

(a) Bunel, E.; Burger, B. J.; Bercaw, J. E.; J. Am. Chem. Soc. 1988, 110, 976.
(b) Burger, B. J.; Thompson, M. E.; Cotter, W. D.; Bercaw, J. E. J. Am. Chem.
Soc. 1990, 112, 1566. (c) Hajela, S.; Bercaw, J. E. Organometallics 1994, I3,
1 147.

During the transmetallation process, a mixture of Cp2TiXR and MgX2 are formed, in
which the Br and Cl exchange to generate the various halogen combinations.

Ystenes, M. J. of Catalysis 1991, 129, 383.

Without the intermediate addition of nBuLi, only 65 to 75% deuterium incorporation
or to the carbonyl was achieved. Young, J. R. Ph. D. Thesis, Michigan State
University, 1992.

(a) Trippett, S. J. Chem. Soc. 1962, 2337. (b) Bose, A. K.; Lai, B. Tetrahedron
Lett. 1973,3937.

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(56)
(57)

(58)

(59)

87

After the initial exploration, all additional cyclization promoted by MgX2 were
performed by Brian A. Kirk, and his contributions to this project are greatly
appreciated.

(a) Soga, K.; Yanagihara, H. Makromol. Chem., Rapid Commun. 1987, 8, 273.
(b) Soga, K.; Yanagihara, H. Makromol. Chem. 1988, 189, 2839. (c) Soga, K.;
Park, J. R.; Uchino, H.; Uozumi, T.; Shiono, T. Macromolecules 1989, 22, 3824.

Product distributions were determined by capillary gas chromatographic analysis of
the quenched reaction mixture (HCl/EtzO) with the use of dodecane as an internal

standard and after correction for detector response.

The values given in Table III are averages of multiple experiments. The complete
data collected for the MAO promoted cyclization is given in Appendix I.

Ratios for relative rate differences were examined in the range of 3% to 30%
conversion to cyclic products for MgX2, and values represent the average of at least
five experimental runs. Beyond 30% conversion, mass balance of 62 and 63
dropped significantly, and accurate values for isotope effects could not be obtained.
The combined mass balance for the conversion of 58 to (62 + 63) ranged from 70 to
80% yield, and the transzcis ratio for the hydrolysis products (62a or 63b)was the
same (39:61 to 41 :59) for each experimental run.

Ratios for relative rate differences were examined in the range of 3% to 60%
conversion to cyclic products for MAO (ratios did not fluctuate significantly up to
60% cyclization), and values represent the average of five to thirteen experimental
runs. The transzcis ratio for the hydrolysis products (62a or 63b) was the same
(59:41 to 61:39) for each experimental run, and the yields for the conversion of 58 to
(62 + 63) were between 75 and 85%. Variation in the concentration of MAO and
41 in toluene, from 0.05 M to 0.3 M, did not affect the relative rates of cyclization
for 41a and 41b.

(a) See reference 1c. (b) See reference 55.

For examples of cationic polypropylene catalysts, see: Ti: (a) Bochmann, M.;
Jaggar, A. J.; Nicholls, J. C. Angew. Chem. Int. Ed. Engl. 1990, 29, 780. Zr:
(b) Jordan, R. F. Adv. Organomet. Chem. 1991, 32, 325. (c) Yang, X.; Stem,
C. L.; Marks, T. J. J. Am. Chem. Soc. 1991, 113, 3623.

In the absence of such a structural framework, as in the case of [EtAlC12]2, propylene
dimerization occurred. Goodall, B. L. Transition Metals and Organometallics as
Catalysts for Olefin Polymerization, W. Kaminsky and H. Sinn (Eds.), Springer-
Verlag, Berlin, 1988, p. 362.

(a) Kaminsky, W.; Kopf, J.; Thirase, G. Liebigs Ann. Chem. 1974, 1531. (b)
Kaminsky, W.; Kopf, J.; Sinn, H.; Vollmer, H.-J. Angew. Chem. Int. Ed. Engl.
1976, 15, 629. (c) Lvovsky, V. E.; Fushman, E. A.; D'yachkovsky, F. S. J.
Mol. Cat. 1981, 10, 43. (d) Waymouth, R. W.; Potter, K. S.; Schaefer, W. P.;
Grubbs, R. H. Organometallics 1990, 9, 2843. (e) Erker, G.; Albrecht, M.;
Kruger, C.; Werner, S.; Binger, P.; Langhauser, F. Organometallics 1992, II,
3517.(60) Barta, N. S.; Kirk, B. A.; Stille, J. R. J. Organomet. Chem. 1994,
0000. In press.

88
(61) Krauledat, H.; Brintzinger, H-H. Angew. Chem. Int. Ed. Engl. 1990, 29, 1412.
(62) Piers, W. E.; Bercaw, J. E. J. Am. Chem. Soc. 1990, 112, 9406.
(63) Kraus, G.; Landgrebe, K.; Synthesis 1984, 885.

(64) Kaminsky, W.; Hahnsen, H. U.S. Patenet number 4,544,762, October 1, 1985.
Example 1.

f

CHAPTER III

THE REACTION OF CHIRAL B-ENAMINO ESTERS WITH ACRYLATE

DERIVATIVES: FORMATION OF QUATERNARY CENTERS THROUGH
ASYMMETRIC AZA-ANNULATION.

 

BACKGROUND AND SIGNIFICANCE

Naturally occuning nitrogen heterocycles containing quaternary centers are quite
common and display potent biological activity.1 Several representative examples are
shown in Figure 1. (+)-Aspidospermidine (1) has a pentacyclic skeleton with two nitrogen
atoms and a quaternary center,l levorphanol (2) is a powerful analgesic,2 and (-)-nitlamine

(3) is an example of a naturally occurring spirocyclic system.1

H
l
"J
N: "149% d,”
t H OH
3

(+)-Aspidospennidine Levorphanol (-)-Nitramine

Figure l. Nitrogen Heterocycles with Quaternary Carbon Centers.

Formation of Quaternary Centers. As a result of the biological significance
of natural products containing quaternary centers, a number of methods have been
developed for the formation of quaternary carbon centers.3 Some of the more commonly

used methods of formation include alkylation, rearrangement reactions, and cycloaddition

89

("I

90

reactions.3 One of the most prominent classes of ionic construction reactions is addition
alpha to a carbonyl group (eq. l).4 Rearrangement reactions effective in the formation of
quaternary carbon centers include the [2,3] sigmatropic shifts such as the [2,3]-Wiuig
rearrangement (eq. 2),5 and [3,3] sigmatropic shifts such as the 3-aza-Cope rearrangement
(eq. 3).6 Cycloaddition reactions, such as the Simmons-Smith reaction, that involve
geminally disubstituted alkenes also result in the efficient formation of quaternary carbon
centers (eq. 4).7 Among the most effective techniques for the Stereoselective construction
of quaternary centers is the Michael addition reaction,3 which is an application of ionic

construction.3

0 051m, 0
63““ —- (5“ ——~ ”'1
4 5 5 6
Me Me Me
WM. WM. Ma (2)
Me Me
“”929 110 cm 002
7 a 9
l.‘ Mo
HAN/V“ _, RAN M. _,a/‘~ M, (3)

10 11 12

M99" M99" M09"
Cb —- ggp CD
Moo Moo 0 M9

 

91

An important variation of the Michael addition reaction is the addition of imines to
electron deficient olefins. This process has been utilized as a step in the formation of
nitrogen containing heterocycles.1 The conjugate addition of imines to electrophilic alkenes
has been known since 1956, and several limitations accompanied the early synthetic
applications of such reactions.9 Two of the major drawbacks to the conjugate addition
method were the incomplete control of regioselectivity, and incomplete control of the
absolute configuration of the newly formed stereogenic center.9 In 1985, d'Angelo and
coworkers reported a new asymmetric conjugate addition reaction with chiral imines and
electrophilic alkenes (eq. 5).10 d'Angelo's reaction took place under neutral conditions to
encourage participation of the enamine tautomer (19 or 21, eq. 6) for greater
regioselectivity, and the asymmetry of the chiral imine was utilized to direct the orientation

of the new stereogenic center. 10

R.
0 WNHZ \ N 1‘ 002m 0
lb .____. M9 ————+- M9 (a
m/\ 002“
15 17 13

R‘ H R‘ R‘ H
\N/ \N \N/
-——————a- -———-——-»
é” ‘— 67” ‘— 6‘“ ‘6’
19 20 21

Conjugate addition of chiral imines to electrophilic alkenes is a deracemizing
alkylation reaction that occurs through the more substituted enamine tautomer (l9) and has
been quite effective for the formation of quaternary centers (Scheme 1).1 Reactions of this
nature typically result in 85-97% ee for substrates such as carbocyclic imines, (Y=CH2ll

or (CH2)212 or M”) or heterocyclic imines (Y=O,10 CHzNMe,15 or CH2815) with R:

 

92

Me, Et, OMe, or CH2C02R'. In these cases, the electrophilic alkenes included methyl

acrylate,l 1,120.15 vinyl ketones,12»13~15»16 acryloniu'ile,10 and phenyl vinyl sulphone.1 1’12

Scheme 1. Conjugate Addition to Chiral Imines.

O
”‘54” 1) SW ewe
H N Ir N W
{VB ——. ——>
Y ) 3 Y R COMO Y F1
2 3 fl

Stabilization of the chiral imine through conjugation with an electron withdrawing
group (R=COzR' or COR'), caused a decrease in reaction efficiency.l7 To counter this
rate retardation, the typical Michael receptor had to be used under high pressure or with
Lewis acids for effective reaction.l7 Only alkylidene malonates have been reported to
undergo effective conjugate addition without further assistance.18 A general regio- and
Stereoselective method for formation of quaternary centers without the use of high pressure

or Lewis acids is still needed in the repertoire of organic synthesis.

Aza-Annulation History. The addition of amines to electron deficient olefins
has shown promise as a synthetic tool in the formation of nitrogen containing heterocycles.
The reaction of cull-unsaturated acids and acid chlorides with imines was reported in 1971
by Hickmott and coworkers (eq. 7).19 The reaction was carried out both with and without
TEA, and the results showed that in the presence of TEA, a 80:20 mixture of the N-
acylated product (26) and the annulated product (27) was obtained. Without added TEA,
the ratio increased to 80:20 in favor of the cyclic product.19 In addition to these findings,
Hickmott showed that acyclic imines would also undergo similar reactions (eq. 8).19 With
acyclic imine 28, a 14% yield of the N-acylation product (30) was obtained, while the

 

93

annulated products (29a and 29b) were obtained as an inseparable 7 5:25 mixture of olefin

isomers in 38% combined yield.19

 

 

 

 

25 26 27

With TEA 50 5)

Without TEA Z) m

C) C)

O

mdk’ ”9 Cl a A
lwe Nb Nb) Nh)

28 29 30

The use of substituted a,B-unsaturated acid chlorides in the reaction with imines
has also been reported.20 Hickmott showed that the reaction of crotonyl chloride with N-
(2-methylcyclohexylidene)cyclohexyl amine resulted in 30% N-acylation (eq 9).20 This
reaction also gave amide 33 as a side product, and formation of the corresponding
annulated product was not detected.20 Ninomiya reported the formation of a 80:20 mixtlu'e
of annulation to N-acylation products in a combined yield of 66% for the reaction of a

tricyclic N-methyl imine with methacryloyl chloride.21

 

(3
C)
63H" \ N fiCl 00H" \Nfi 0
Nb IckH"
6 ”° = .. + 15: «1
Benzene M9 “4"

31 32 33

94

In addition to the reaction of imines and enamines with (LB-unsaturated acid
chlorides, similar reactions have been carried out with a,B-unsaturated acids,22 esters,23
amides,24 and anhydrides.25 Hickmott has demonstrated that the reaction of acid chlorides
with enamines stabilized by further conjugation can be utilized for the formation of
tetrahydro-Z-oxopyridines potentially through N -acylation followed by a [3,3]
rearrangement and cyclization.20 The potential for application of the annulation process

prompted interest from these labs in the further development of this methodology.

Development of Aza-Annulation Methodology. A detailed study of the
reaction of imines with activated acrylate derivatives was undertaken in these labs (eq. 5).26
In this investigation, cyclic and acylic imines were subjected to numerous annulation
conditions for the formation of niu'ogen containing heterocycles. The goal of this
methodological study was to find efficient annulation conditions for imine substrates that
were not in conjugation with other functionality. These conditions were explored through
variation of the methods used for the activation of the acrylate derivative. The influence of

acrylate substituents was also investigated.26

 

O
R‘ a2 x 0
\N as R1\NJ\ER2 9“" R2 R1\N R2
= + + 10)
(5 ms (5 "° 1° .3 ‘
34 35 36 37

The results of this methodology study indicated that the optimum annulation
conditions were achieved through the use of imines of cyclic ketones?‘5 When the imine of
n-butanal was subjected to annulation conditions, the major reaction product was that of N- ‘
acylation. Increasing the steric constraints of R1 proved to increase the selectivity of 8-

lactam formation (eq. 5). Substitution at the a-position of the acrylate derivative (R2=Me;

 

95

R3=H) did not affect the selectivity of product formation, however, B-substitution (R2=H;
R3=Me) hindered annulation and favored formation of the N-acylated product (35).26
Finally, this study showed the effect of different methods of activation of the
acrylate derivative.26 While acrylic acid was effective for the annulation reaction, acrylic
anhydride gave higher yields of the cyclic product. Although acrylic anhydride cleanly
gave the desired product, the use of this reagent required two equivalents of the valuable
acrylate unit. To avoid this waste, the sodium salt of acrylic acid was treated with ethyl
chloroformate to provide a mixed anhydride-type reagent that was equally as effective in the

annulation process.25

Applications of Aza-Annulation Methodology. Once the scope of the aza-
annulation reaction had been investigated,26 the optimum conditions were employed in a
wide range of synthetic pathways. One such pathway was the construction of B-amino
acid isosteres (Scheme 11).27 For these isosteres, 8—lactam systems were chosen because
of the conformational constraints provided by the cyclic skeleton. The isosteres were
obtained in good yields (56-91%) with cis to trans selectivities between 72:28 and >99:l.27
Additional examples of the B-amino acid isosteres formed through the use of this

methodology are given in Figure 2.27

Scheme II. Formation of B-Amino Acid Isosteres.

 

 

1) BnfiHsH X Pd/C. H2 X X
X P 3 _ an. ewe Nazcoa an. we at. ,EWG
OJV EWG 0| 7 N : N '1' N ‘
o
30 39 40 41

 

EWG- C(O)Me, C(O)Ph, 002131, COgMe.C(O)NHPh, P(O)(OEt)2. SOzMe, SOzPh
x-Me, 002M9;

 

c

tonal

condl
precr
confi
regk:

ehct

Scht

aHm
(Sci
lhro

96

Mo 0 0 Me O
my 05: %,.JL OE! H.Jj CN (It); Mo
0 o 0 ° C‘ 1‘ °

43 44

45

Figure 2. B-Amino Acid Isosteres.

The reaction of acryloyl chloride with N-alkyl enamines stabilized through
conjugation with an electron withdrawing group demonstrated the suitability of the aza-
annulation methodology for formation of the indolizidine ring system.28 Application of the
condensation/annulation/reduction process starting with 46 efficiently formed 43, a
precursor to (i)-tashiromine (Scheme III). Stabilization of the enamine through
conjugation with an electron withdrawing substituent provided for complete alkene
regioselectivity, thereby overcoming previous limitations of the reaction of imines with

elecu'on deficient olefins. 17
Scheme III. Preparation of (i)-Tashiromine.

0
o o 05! Pd/C, H2 0‘; OE:
05‘ c1 Nazcoa
. ——» . Ci):
\ TH:
H 87% E9556

918mm) (s)-Tasblromine

 

Synthesis of (:l:)-5-epipumiliotoxin C (52) was used to showcase this aza-
annulation process in the preparation of a decahydroquinoline alkaloid ring skeleton
(Scheme IV).29 The requisite cis ring fusion of epipumiliotoxin was efficiently obtained

through selective hydrogenation of the key bicyclic lactam intermediate 50, which was

97

prepared from 49 in 76% yield through aza-annulation. Overall, (i)-5-epipumiliotoxin C
was prepared in 6% yield from diketone 49.29

Scheme IV. Synthesis of (i)-5-EpipumiliotoxinC

O 1 ) BUN H2,
El 1120?)
o ""/\

49

 

(:t)- -5- -Epipumiliotoxin C

Finally, the quinolizidine (21:)-lupinine (56) was constructed through annulation of
an acyclic enamine stabilized through conjugation with an ethyl ester (Scheme V).30
Condensation of 54 with benzyl amine followed by annulation with acryloyl chloride gave
intermediate enamide 55 in 80%yield.3O Again, this synthesis illustrates the versatility of
the newly developed aza-annulation methodology in the preparation of biologically

important naturally occurring alkaloids.

Scheme V. Preparation of (2t)-Lupinine.

 

00:3 0H
1
”’5 1) BnNHz, g’
m = I N —.
\(l ‘—’ 0 31 —> N
Cl 0
0 w 2) 081
53 54 ° 55 56

(1)-Lupinine

98
EXPERIMENTAL GOALS

The goal of this work was to extend the aza-annulation methodology26 to include
formation of asymmetric quaternary carbon centers in nitrogen heterocycles. The general
applicability of this methodology was explored with respect to reaction temperature,

solvent, and chiral auxiliary variation.

SYSTEM DESIGN

The system utilized in this investigation was designed to probe the efficiency of the
aza-annulation methodology developed in these labs for the formation of asymmetric
quaternary carbon centers at the C-5 position of the 8-lactam framework (Scheme VI).
Lactam formation was accomplished via condensation of a B-ketoester with a chiral amine
or amino acid ester to form a stabilized enamine, which underwent aza-annulation with

electron deficient alkenes.

Scheme VI. General Formation of 8-Lactams.

Rs" R8"

at 57 BL 58 59

00,51 05:
tR‘ R‘
0| 0 E R3
0 N5 R“ =9 131,112 d ’
N n2
i 4 °
H H

Based on previous annulation studies,26 a number of acrylate derivatives were
employed as the electron deficient alkene fragment. These derivatives include acryloyl
chloride (60), acrylic anhydride (61), and a mixed anhydride of acrylic acid and ethyl
chloroformate (62) (Figure 3). In addition to variation the of acrylate derivative, the effects

of temperature, solvent and Chirality source on the outcome of the reaction were also

99

examined. The 8-lactams constructed through this aza-annulation process provide the
framework for more complex biologically active such as peptide mimetics, the preparation

of which is currently being investigated in these labs.3l

O O O O O
")k Cl ft OJ\|| {l 0’|L CE!
60 61 62

Figure 3. Electron Deficient Olefins for Aza-Annulation.
RESULTS AND DISCUSSION

Substrate Variation in the Aza-Annulation with Acryloyl Chloride.32
Efficient formation of 8-lactams was achieved through the annulation of enamines derived
from various B-keto esters and (R)-phenethylamine with acryloyl chloride. Undesired
amide side products were avoided during the condensation reaction through the use of
Et20:BF3.33 Prior to annulation, the catalyst was quenched by aqueous workup without
harm to the enamine product. After workup, the solvent was changed to THF, and reaction
with an electron deficient alkene resulted in formation of the desired 8-lactams.

Condensation of 63 with 73 followed by annulation gave bicyclic 8-lactam 64 in
85% isolated yield (Table I). The annulation process proved to be very selective in the
formation of the quaternary center (>97z3) as can be seen from the proton NMR spectra
(Figure 4). The spectra shows the signal for the methine proton of the chiral auxiliary, and
the double bond proton, and only one signal for each type of proton could be detected.
~ The stereochemical assignment which is addressed in the Mechanistic Implications section
was made based upon comparison with related Michael addition reaction products,17 and
this assignment has been confirmed by X-ray crystal structure.34 These reaction conditions

offer two primary advantages over similar Michael addition processes. First, the reactions

100

proceed at atmospheric pressure in 4-6 hours, and second, Lewis acid catalysis is not

required for complete reaction.

Table I. Asymmetric Induction with Respect to Substrate Variation.

 

Diastereotner
Substrate Product Ratio" Yield‘
c0251
51020
:0 £13 .
o o N
u “
Memflx H
5102‘; c0251
D 03 .
O O N
s .. a
1423‘ H
692° n. 8:3
973 92
0 Me 0 N
67 Me" a
Pit
5102C CHI \I 03;
' sea a
0 Me 0 N
a mu m
Fh H

O O
E o
0
+73.
2
Us
8

 

“Reaction conditions: (i) (R)-PhCHMeNH2 ((R)-73), 1360:1313,
benzene, reflux; (ii) acryloyl chloride, THF, reflux. ”Determined by
1H NMR of the crude reaction mixture. ‘Yield of the diastereomeric
mixture after cinematography.

101

00,61
0 N . ‘ ——

m"*H “ VtrrrrlrrTrjrrrr rr
an 6 5

 

Figure 4. Partial 1H NMR of 64.

Keto ester 65 could also be transformed efficiently to the corresponding 8-lactam
(66) through the same procedure. The diastereoselectivity (97:3, Figure 5) was also
comparable to that observed in the formation 64. Unfortunately, the 6-5 ring system of 66
was a great deal more sensitive toward hydrolysis, and could be isolated in 76% yield at

best after chromatography on a base washed silica gel column.

 

 

Major
00,51 \
O N
Me "9‘ a Mina 5
9'! H ‘
5.4.}

 

 

WM
52 80 59 5854 5.2 5.0 4.8“

Figure 5. Partial 1H NMR of 66.

102

Although the geometry of the enamine was restricted by the ring skeletons of 63
and 65, the degree of diastereoselectivity was n0t compromised through the use of acyclic
B-keto esters 67 , 69, and 7 l. Enamide 68 was obtained as a 97:3 mixture of
diastereomers as determined from the NMR signal for the double bond protons (Figure 6).
A 92:8 ratio of diastereomers was obtained for the formation of 70 (Figure 7), and a 94:6
ratio of 72 (Figure 8) was also obtained. The diastereomeric ratio of 72 was determined

bfrom the ratio of the methine proton of the chiral auxiliary.

 

 

 

 

 

C0751
«m
973
o N
M.;}‘H a
[MW
45 4 4 4 3 m
Figure 6 Partial 1H NMR of 68.
Maia Map
/ \
00,51
«032
922
o N Mint!
m"*H N MM
P" t
WVVII'YYVTOIIr—h 1' [1’17 Tr' 1' i
5 2 4 I8 994 4 6

Figure 7. Partial 1H NMR of 70.

103

 

' M...
r ’
55> M... j;
at“ . l M

F" “veg L..."

 

Figure 8. Partial 1H NMR of 72.

Hydrogen bonding between the enamine hydrogen and the carbonyl of the ester
functionality held the acyclic enamines in one conformation, thereby a highly selective
annulation process (Figure 11).1711 Little difference in selectivity was observed between 68
and 70, however, 70 was much more sensitive to the isolation conditions due to the
presence of a tertiary allylic ester, and could only be isolated in only 58% yield.
Interestingly, the spiro lactam could be easily isolated in 80% yield.

Asymmetric Induction as a Function of Chiral Auxiliary. In addition to
(R)-phenethyl amine, several other chiral amines were examined as auxiliaries for the
Stereoselective formation of quaternary centers through aza-annulation. Reaction of 63
with the ethyl ester of (R)-phenyl glycine (74) was achieved by isolation of the (R)-
phenylglycine ethyl ester hydrochloride salt which was then washed with aqueous sodium
bicarbonate into a benzene layer to which was added the B—keto ester and EtzozBF3. The
reaction with the methyl ester of L-valine (76) was accomplished in the same manner

(Table II).

104

Table II. Asymmetric Induction and Chiral Auxiliary Variation.

 

 

Diastereomer
Amine Product Ratio” Yield‘
0025:
Wu H O N
H‘ mu
73 H so
9025*
7921 as
8°ng 0 N
8020+ H
74 Fh '5
0025:
NH” (I) 57:43 as
W" H o N
iPr M9020"’\
'5 iPr H 7"

 

“Reaction conditions: (i) 1° amine, benzene, Et20:BF3, reflux:
(ii) acryloyl chloride, THF, reflux. ”Determined by 1H NMR of the
crude reaction mixture. ‘Yield of the diastereomeric mixture after

chromatography.

The ratio of diastereomers of 75 (79:21) was determined from the integration of the
1H NMR signals arising from the double bond proton (Figure 9). Condensation of 63
with 76, followed by aza—annulation gave 77 as a 57:43 ratio of diastereomers as

determined from the chiral auxiliary methine proton signal (Figure 10).

105

;\ M416
9“ ”t, / m
(I) m l l
O N
ché‘H
Hi 75

 

ITIITthfiIITIrIITITTT-

5.2 5.0

Figure 9. Partial 1H NMR of 75.

 

113 W“ ”"°‘
5743

o . \i n/

W.;} n ' “'2..-

Figure 10 Partial In NMR of 77.

In comparison to (R)-phenethyl amine, neither the phenyl glycine ethyl ester nor
the valine methyl ester was as effective for the selective formation of 5-lactams. The results
obtained for the variation of chiral auxiliary were interesting in that the phenyl-methyl
combination seemed to be quite unique. The selectivities observed for the three different
chiral auxiliaries can be rationalized through examination of the most stable enamine
conformations. Conjugation with the ester functionality favors almost exclusively the
enamine tautomer over the imine tautomer, and the orbital overlap in the enamino esters is
great enough that the enamine is planar. In addition, the hydrogen bonding between the
enamine proton and the carbonyl-oxygen of the ester group limits the conformational
freedom of these species. As a result, the selectivity of approach of the acrylate derivative

is then determined by the amount of rotation around the bond between the nitrogen and the

106

chiral auxiliary. Figure 11 illustrates the rotational constraints of each chiral auxiliary based
on the reported "A values".35 The difference in selectivity between R)-phenethyl amine
(A) and the phenyl glycine ethyl ester (B) arises from the difference in steric bias between
the methyl group and the ethyl ester group. Since the methyl group is sterically more
restricting, greater selectivities were obtained with (R)-phenethyl amine. Valine ethyl ester
is sterically less demanding compared to bOth (R)-phenethyl amine and phenyl glycine ethyl

ester, and as a result, the selectivities of annulation are lowest for the valine methyl ester.

 

 

 

 

H H H
H n. Hue 5702c HPh IPr Hcone
Fh
NJr =p A B c
, Me
so 0"”
H H H
3.0 H 1.7 12 H 3.0 215 H 1.27

 

 

Figure 11. Comparison of Chiral Auxiliaries.

Temperature Dependence of Asymmetric Induction. As described above,
the reaction of 63 with 74, followed by aza-annulation with acryloyl chloride, did not lead
to the highest selectivity for formation of the quaternary centers. However, this system
was quite suitable for examination of the effects of reaction conditions (solvent and
temperature) on product distribution. Reduction of the annulation temperature from 25 °C
to -33 °C resulted in diastereoselectivities comparable to those obtained for the use of 73
(98:2) (Table III). Increasing the annulation temperature from -33 °C to 0 °C showed a

small decrease in diastereoselectivity (93:7). The most notable reaction feature at this

107

temperature was the drastic difference between the isolated yields when dioxane was used
as the solvent for annulation (92:8, 24% yield). As expected, the diastereoselectivity
decreased as the reaction temperature increased. The yields also remained predictably low
for the reactions in which dioxane was used as a solvent. Interestingly, the reaction in
dioxane at reflux gave a very low yield with reversed product selectivity (36:64), perhaps
due to a more rapid decomposition of one isomer over that of the other, or epimerization

catalyzed by the HCl reaction byproduct.

Table III. Asymmetric Induction and Temperature Variation for the

Conversion of 63 to 75.

1) 74. Etzo:at=3. 092Et

5020.1) benzene. reflux m
0 N

o 2) .THF. remix 7
. I met
Fit

0 CI

 

 

 

7s
dbtereomer

solvent 7 °C ratio‘ yield‘
THF -33 98:2 77
THF 0 93:7 68
dioxane 0 92:8 24
THF 66 79:21 63
dioxane 66 82:18 43
dioxane 101 36:64 28

 

“Reaction conditions: (i) (R)-74, 63, benzene, EtzozBFg, reflux;
(ii) acryloyl chloride. bDetermined by 1H NMR of the crude reaction
mixture. ‘Yield of the diastereomeric mixture 75 after chromatography.

Asymmetric Induction and Acrylate Activation. The difference in reaction
selectivity as a function of acrylate derivative was also explored, and the results are shown

in Table IV. As previously described, the mixed anhydride species (62) was obtained

108

from the mixture of sodium acrylate and ethyl chloroformate (Table IV, X=OCOzEt).
Although the selectivity for the formation of 66 with the mixed anhydride was slightly
lower (90: 10) than that obtained for the use of acryloyl chloride (97 :3), the increase in yield
(87% and 64% respectively, Table IV) made this a synthetically favorable reaction .

Table IV. The Effect of Acrylate Reagent on the Formation of 66.

 

51020 benzene. reflux ‘
I) 2, 01>

,THFJ'BMX
° I ° N
G
5 “Ni"

 

 

 

O X
Fh
reagent diastereomer-
.x ratio‘ yield’
-Cl 973 64
.0200H.CH2 90:10 75
00028! 90:10 87

 

“Determined by 1H NMR of the crude reaction mixture.
”Yield of the diastereomeric mixture 66 after chromatography.

Acrylate Substitution Patterns and Asymmetric Induction. Variations in
the substitution pattern of the acrylate derivatives were also examined for effectiveness in
the simultaneous formation of two stereogenic centers. Annulation of the condensation
product of 73 and 63 with crotonyl chloride was significantly slower that the
corresponding reaction with acryloyl chloride (eq. 11). The reaction with crotonyl chloride
required heating at reflux for 48 hours, and these rather vigorous conditions contributed to
a low isolated yield of 78 (43%) after partial purification by column chromatography
(~90% pure). The prominent impurities from this reaction, were products of side reactions

with the acrylate derivative, including MeHC=CHCONHCHMePh, and further purification

109

of the reaction mixture gave only a 30% yield of 78 as mixture of stereoisomers (94:4:2,

Figure 12).

 

 

1) 73. 6190231: 0025!
510200 W.;a'ux (b (11)
o 2) crobnylchlotida O N
Q THFJOIUX ” 73
Me flu“
Rt
43%.th
Major
“‘ was: a
('13 "’
o N ‘
7|
“04*“ .
Fh Minor
1 l 1 r
/' ‘
,q“_,.q"/ .\-_..
WW!
5 a S 0 M 4 8

Figure 12. Partial 1H NMR of 78.

The stereochemical assignment for 78 was made by comparison of the spectral data
with that reported for 80 which was formed during the annulation of 79 (eq. 12).35 The
reported chemical shifts and coupling constants for the proton alpha to the lactam carbonyl
in 80 are 8:2.28 ppm, dd, J = 18.5, 12.3 Hz, and 8:2.66 ppm, dd, J = 18.5, 6.4 Hz.

The analogous protons in 78 are 5=2.25 ppm, dd, J = 18.1, 12.7 Hz, and 8:2.65 ppm,
dd, J = 18.1, 5.7 Hz.

m m Ma
F11“ H :tL H Fh °‘

(40-5093 Combined Yield)

Treatment of the condensation product of 73 and 63 with methacryloyl chloride
resulted in the formation of an inseparable mixture (52:48) of diastereomers of 82 (Figure
13). Although the selectivity was poor, treatment of the product mixture with NaH resulted
in equilibration to an 83:17 ratio of diastereomers epimeric at the position alpha to the

lactam carbonyl (eq. 13).

Mina
“I5 ”‘Ll ”‘1 ”i”
OmulH fl - Q

Rt
62 6.0 5.8 5.6 5.4 5.2!.»

Figure 13. Partial 1H NMR of 82.

(83:17)

 

£1020 ulnar.) 13. 550:3 Me? A l :
I I : (13)
O M. 0 N
THF,
a 2) I 33 °C m"* H I!
0 on F"
3) NCH 69% Vb“

l

Annulation with a mixture of 83 and ethyl chloroformate and the enamine derived

from the condensation of 73 with 63 resulted in a mixture of four products in a ratio of

111

64:23:9z4 (84, eq. 14). Silica gel chromatography facilitated separation into two mixtures
of two isomers each. The first mixture contained the original 64 and 9% isomers, and the
second was composed of the isomers that constituted 23 and 4% of the original mixture.
Treatment of the original reaction mixture or the separated mixtures with NaH, DBU or
stOH in order to encourage equilibration, resulted in the slow disappearance of all four

isomers.

Ma 0 (73:27)
1) 73, E50285. Y ‘70in

81020 benzene. reflux “Nm
= (14)
O O N

 

Act-1N
63 2) B m 0* H at
o om F"
000251. 91% Ytetd
THF, -33 °c

The four isomers in the original mixture reflect the incomplete asymmetric induction
in the formation of the quaternary center, as well as the existence of epimers at the carbon
alpha to the lactam carbonyl (Figure 14). As observed for the formation of 82, higher
selectivity is obtained at the quaternary center than at the C-2 position in the concomitant
formation of two stereogenic centers. Based on this observation, the ratio of C-2 epimers
of 84 were assigned as [64+9]:[23+4], or 73:27, and the ratio of isomers at the quaternary
center were 87: 13 ([64+23]:[9+4]). The 87:13 ratio at the quaternary center parallels the
90:10 ratio observed in the formation of 66 through annulation with a mixed anhydride

reagent (Table IV).

112

“-P‘ O

.9

 

 

'r
99

Figure 14- Partial 1!! NMR of 84.

Mechanistic Implications. Several mechanistically interesting observations

have been made through the course of this study. One such observation is the facial

selectivity in the reaction of the enamine with the acrylate derivative (Figure 15). As

discussed earlier, there is a hydrogen bonding interaction between the enamine hydrogen

and the carbonyl oxygen of the ester group (85). This conformational restriction creates a

facial bias for attack of the incoming acrylate derivative since one face of the enamino ester

is more hindered due to the larger group RL. The favored orientation of the stereogenic

center has the hydrogen toward the CH2 unit of the ketone substrate. 10.17.27 As illustrated,

the favored approach of the acrylate derivative would be from the bottom face of the

enamine, which would result in selective formation of the quaternary center.

 

Distavored
approach

 

00281
g“ R‘
5

Re
"if"

Figure 15. Enamine Facial Selectivity

, Additional observations that give information regarding the mechanism involved in
this process are the dependence of the selectivity upon temperature and acrylate derivative,
and the lack of selectivity in formation of a stereogenic center alpha to the lactam carbonyl.
The selectivity of Michael addition reactions has been reported to be independent of both
temperature3a and acrylate derivative,37 while the systems in this study have demonstrated
contrasting behavior. Also, the Michael addition reaction of a—(phenylthio)acrylate with
79 to give 87 gives complete selectivity at the alpha center reportedly through an aza-ene
type cyclic transition state. The cyclic transition state allows proton transfer to occur in a
concerted fashion which results in high selectivity at the a—center (eq. 15).l However, the
aza—annulation resulted in poor alpha selectivity, indicating a difference in the nature of the

reactive intermediates.36 The reactions of this study give good evidence that the same

113

mechanistic pathway is not followed in the annulation process.

Ms

W.;.”

Figure 16. Mechanistic Alternatives for the Aza-Annulation.

PhS
Y
51020

fl

63%Y'Ield

 

PhS EZN®
H

 

 

Me“
Ph

 

 

m

”Yb
—» 50ch

Hetero
Diels Alder

 

(15)

114

In the aza-annulation reaction, selectivity at the B—position and the ring juncture, as
well as the lack of selectivity at the a-center can be rationalized through alternative
concerted transition states (Figure 16). The 3-aza-Cope transition state forms a chair
through interaction of the carbonyl carbon with the enamine nitrogen. Since proton
abstraction is not involved in a process that proceeds through such a transition state,
avenues that allow for epimerization of the alpha center are not ruled out during bond
formation. Both the 3-aza-Cope transition state and the hetero Diels Alder transition state
are polarized to a greater extent than the aza-ene transition state which helps to explain the
greater reactivity observed in the aza-annulation reaction. The differences observed in the
aza-annulation reaction compared to the Michael reaction provide evidence that the two

reactions occm' through different pathways.

CONCLUSIONS

Aza-annulation has been shown to be effective for the efficient regio- and
Stereoselective formation of nitrogen heterocycles containing quaternary centers. Such
heterocycles were obtained in yields from 43 to 87% with 84—96% de. The two step
condensation/annulation procedure has become a valuable synthetic procedure for the
preparation of potentially valuable heterocycles,38 as well as intermediates in the

preparation of naturally occurring alkaloids and nonnatural peptidomimetic molecules.31

EXPERIMENTAL SECTION.

General Methods. All reactions were carried out performing standard inert
atmosphere techniques to exclude moisture and oxygen, and reactions were performed
under an atmosphere of nitrogen. Azeotropic removal of H20 was assisted by the use of
4-A molecular sieves.39 Concentration of solutions after work up was performed by rotary
evaporator. Keto esters 63, 65, 67, and 71 were purchased from Aldrich Chemical
Company, and 69 was prepared as previously reported.40Acryloyl chloride was purchased
from Fluka and used without purification. The following reagents were purchased from
Aldrich Chemical Company: (R)- and (S)-alphaphenethyl amine, (ID-Phenyl glycine, L-
valine, EtzO:BF3, crotonyl chloride, and methacryloyl chloride. 2-Acetamido acrylix acid
was purchased from both Aldrich Chemical Company and Lancaster.

NMR Spectra were obtained on a Varian Gemini 300 instrument with CDC13 as the
solvent. 1H NMR spectral data are reported as follows: chemical shifts relative to residual
CHC13 (7 .24 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint =
quintet, sext = sextet, sept = scptet, b = broad), coupling, and integration. 13C signals are

reported in ppm relative to CDC13 (77.0 ppm).

General Procedure For Et20:BF3 Catalyzed Enamine Formation ((R)-
73):”a The B-keto ester (3.0 mmol) was combined with 73 (3.3 mmol) in benzene (23
mL), and EtzozBFg (0.15 mmol) was added at room temperature. The flask was fitted
with a modified Dean-Stark trap filled with 4-A molecular sieves, and the mixture was
heated at reflux until the reaction was complete as determined by NMR analysis (6-18 h).
The enamino ester was then washed with saturated aqueous NaHCO3 (15 mL), the
aqueous layer was extracted with Et20 (15 mL), and the combined organic layers were
washed with saturated aqueous NaCl. The organic fractions were then dried (MgSO4),
concentrated, taken up in THF“ (20 mL), and carried on without further purification.

115

116

General Procedure For Et20:BF3 Catalyzed Enamine Formation
(Amino Acid Ester Salts):33a The amino acid ester salt (9.0 mmol) was suspended in
benzene (13 mL) and washed with saturated aqueous NaHCO3. After the aqueous layer
was washed with benzene (10 mL), the benzene layers were combined, washed with
saturated aqueous NaCl, and dried (MgSO4). The benzene solution was then decanted into
the flask containing the B-keto ester (3.0 mmol), and EtzO:BF3 (0.2 mL) was then added.

Enamine formation was carried out as described above.

General Procedure For Ala-Annulation of Enamines (Acid Chloride
Method): The acid chloride (3.9 mmol) was added to a solution of the corresponding
enamine in THF (20 mL, vide supra). The reaction was stirred at the appropriate
temperature until complete as indicated by NMR analysis of a sample quenched with
saturated aqueous N aHCO3 and dried with MgSO4. When the reaction was complete, the
mixture was stirred with 10 mL of 10% NaOH, and then extracted with Et20 (3 x 10 mL).
The organic extracts were combined and washed with saturated aqueous N aCl, dried
(MgS O4), concentrated. and purified by column chromatography.

General Procedure For Aza-Annulation of Enamines (Anhydride
Method): Sodium acrylate (5.1 mmol) was suspended in THF (10 mL) and was treated
with acryloyl chloride (0.31 mL, 3.9 mmol) or ethyl chloroformate (3.9 mmol) and the
mixture was stirred at room temperature for 1h. The mixture containing the anhydride was
then transferred via cannula to a solution of the B—enamino ester in THF (10 mL), and the
mixture was stirred at the appropriate temperature until the reaction was complete. Work

up conditions were as described for the acid chloride reactions.

117

64: (60:40/Et20:petroleum ether, 0.83 g, 2.55 mmol, 85% yield), [(119 = -115.2,
(c = 1.3, CHC13); 1H NMR (300 MHz, CDC13) 51.28 (t, J = 7.1 Hz, 3 H), 1.45-1.65 (m,
2 H), 1.70-1.82 (m, 2 H), 1.72 (d, J = 7.1 Hz, 3 H), 1.93 (m, 1 H), 2.11 (m, 1 H), 2.22
(m, 1 H), 2.34 (ddd, J = 13.1, 6.5, 2.1 Hz, 1 H), 2.53 (ddd, J = 18.4, 12.3, 6.4 Hz, 1
H), 2.68 (ddd, J = 18.4, 6.5, 2.1 Hz, 1 H), 4.13-4.28 (m, 2 H), 5.02 (dd, J = 5.4, 3.0
Hz, 1 H), 6.35 (q, J = 6.9 Hz, 1 H), 7.17-7.36 (m, 5 H); 13c NMR (75 MHz, coc13) 8
14.2, 14.7, 18.4, 24.4, 30.3, 30.9, 35.4, 46.5, 50.5, 61.2, 112.2, 125.5, 126.2, 128.4,
133.7, 142.3, 168.8, 174.3; IR (Film) 3056, 2986, 2920, 1725, 1669, 1636, 1285, 741
cm'l; HRMS calcd for C20H25N03 m/z 327.1834, obsd m/z 327.1833.

66: (70:30/Et20:petroleum ether, 0.71 g, 2.28 mmol, 76% yield); [ab = -15.8, (c
= 5.6, CHC13); 1H NMR (300 MHz, coc13)6 1.21 (t, J = 7.1 Hz, 3 H), 1.60-1.78 (m, 2
H), 1.62 (d, J = 7.1 Hz, 3 H), 2.12 (ddt, J = 15.3, 9.0, 3.2 Hz, 1 H), 2.24 (dd, J = 12.9,
7.6 Hz, 1 H), 2.34 (m, 1 H), 2.44 (m, l H), 2.51-2.69 (m, 3 H), 4.12 (q, J = 7.1 Hz, 2
H), 4.63 (t, J = 2.8 Hz, 1 H), 6.22 (q, J = 7.1 Hz, 1 H), 7.12-7.30 (m, 5 H); 13C NMR
(75 MHz, c0013) 6 14.1, 14.2, 29.5, 30.3, 30.6, 35.7, 50.0, 55.2, 61.2, 110.4, 126.0,
126.6, 128.3, 137.9, 141.0, 169.0, 174.2; In (Film) 3056, 2986, 2942, 2857, 1725,
1667, 1636, 1379, 1265, 741, 704 cm'l; HRMS calcd for C19H23NO3 m/z 313.1677,
obsd m/z 313.1662.

68: (60:40/Et20:petroleum ether, 0.84 g, 2.76 mmol, 92% yield); [11]]; = -55.2, (c
= 3.4, CHC13); 1H NMR (300 MHz, CDC13) 5 1.25 (t, J = 7.1 Hz, 3 H), 1.40 (s, 3 H),
1.43 (s, 3 H, minor isomer), 1.67 (d, J = 7.1 Hz, 3 H), 1.67-1.76 (m, 1 H), 2.34 (ddd, J
= 13.4, 6.9, 4.4, Hz, 1 H), 2.60 (ddd, J = 18.3, 6.9, 4.1 Hz, 1 H), 2.73 (ddd, J = 18.3.
10.2, 6.9 Hz, 1 H), 4.09-4.20 (m, 2 H), 4.36 (d, J = 1.9 Hz, 1 H), 4.43 (d, J = 1.9 Hz,
1 H, minor isomer), 4.46 (d, J = 1.9 Hz, 1 H, minor isomer), 4.51 (d, J = 1.9 Hz, 1 H),
6.22 (q, J = 7.1 Hz, 1 H), 7.15-7.35 (m, 5 H); 13c NMR (75 MHz) (CDC13) 5 13.6,

118
14.1, 23.6, 29.7, 29.8, 46.8, 50.8, 60.9, 98.1, 125.4, 126.0, 127.9, 141.4, 143.7,
169.2, 173.5; IR (Film) 3063, 3032, 2982, 2942, 1728, 1667, 1628, 1449, 1381, 1356,
911, 734, 700 cm'l; HRMS calcd for C13H23NO3 m/z 301.1678, obsd m/z 301.1686.

70: (90:10/EtzOzpetroleum ether, 0.71 g, 1.74 mmol, 58% yield); [12]); = +74.6,
(c = 6.2, CHC13); 1H NMR (300 MHz, CDC13) 8 1.22 (t, J = 7.1 Hz, 3 H), 1.60 (d, J =
7.1 Hz, 2 H), 2.45 (tdd, J = 13.9, 4.8, 1.1 Hz, 1 H), 2.58 (td, J = 10.5, 6.4 Hz, 1 H),
2.73 (tdd, J = 1.1, 5.9, 16.0 Hz, 1 H), 2.94 (ddd, J = 16.0, 10.2, 5.9 Hz, 1 H), 4.23 (q,
J = 7.1 Hz, 2 H), 4.63 (m, 1 H, minor isomer), 4.65 (d, J = 1.9 Hz, 1 H), 4.81 (d, J =
1.9 Hz, 1 H, minor isomer), 5.13 (d, J = 1.9 Hz, 1 H), 6.11 (q,J = 7.1 Hz, 1 H), 7.21-
7.62 (m, 8 H), 8.02 (dd, J = 8.4, 1.2 Hz, 2 H); 13C NMR (75 MHz, CDC13) 8 13.9,
15.0, 27.2, 29.5, 51.7, 62.2, 80.5, 102.9, 126.3, 126.9, 128.5, 128.6, 129.3, 129.7,
133.6, 139.5, 141.2, 165.1, 168.6, 170.2; IR (Film) 3056, 2988, 1745, 1727, 1680,
1634, 1265, 738, 706 cm'l; HRMS calcd for C24H25N05 m/z 407.1733, obsd m/z
407.1736.

72: (70:30/Et20:petroleum ether, 0.68 g, 2.40 mmol, 80% yield); [11]); = +74.4,
(c = 3.0, CHC13); 1H NMR (300 MHz, CDC13) 8 1.48 (d, J = 6.9 Hz, 1 H, minor
isomer), 1.74 (d, J = 7.2 Hz, 3 H), 1.80 (ddd, J = 13.3, 6.4, 4.4 Hz, 1 H), 2.17 (ddd, J
= 12.9, 9.5, 8.2 Hz, 1 H), 2.35 (dtd, J = 12.9, 6.5, 2.5 Hz, 2 H), 2.59 (ddd, J = 17.5,
10.5, 6.6 Hz, 1 H), 2.83 (ddd, J = 17.5, 6.6, 4.5 Hz, 1 H), 3.98 (td, J = 9.5, 6.6 Hz, 1
H), 4.28 (d, J = 3.0 Hz, 1 H), 4.30 (td, J = 9.5, 2.8 Hz, 1 H), 4.51 (d, J = 3.0 Hz, 1 H),
5.08 (q, J = 7.0 Hz, 1 H, minor isomer), 6.17 (q, J = 7.4 Hz, 1 H), 7.20-7.40 (m, 5 H);
13C NMR (75 MHz, CDC13) 8 16.1, 28.2, 29.5, 34.3, 48.5, 52.4, 65.2, 98.4, 126.5,
127.0, 128.4, 140.2, 140.6, 168.8, 176.6; IR (Film) 3056, 2988, 2800, 1717, 1690.
1422, 1265, 739, 706 cm“; HRMS calcd for C17H19NO3 m/z 285.1365, obsd m/z
285.1370.

119

75: (70:30/Et20:petroleum ether, 0.73 g, 1.89 mmol, 63% yield); [0t]D = +1064,
(0 = 3.5, CHC13); 1H NMR (300 MHz, CDC13) 8 1.09 (t, J = 7.1 Hz, 3 H), 1.23 (t, J =
7.1 Hz, 3 H), 1.16-1.32 (m, l H), 1.33-1.56 (m, 1 H), 1.57-1.70 (m, l H), 1.78 (td, J =
12.0, 6.3 Hz, 1 H), 2.05—2.18 (m, 2 H), 2.21-2.33 (m, 2 H), 2.45 (ddd, J = 18.1, 11.9,
5.9 Hz, 2 H), 2.56 (ddd, J = 18.1, 6.3, 2.7 Hz, 2 H), 3.89-4.11 (m, 2 H), 4.22 (q, J =
7.1 Hz, 2 H), 5.05 (m, 1 H, minor isomer), 5.25 (dd, J = 4.4, 3.6 Hz, 1 H), 5.45 (s, 1
H, minor isomer), 5.79 (s, 1 H), 7.20-7.40 (m, 5 H); 13C NMR (75 MHz, CDC13) 8
14.0, 18.3, 24.1, 30.2, 30.5, 34.8, 46.5, 61.1, 61.3, 109.0, 127.4, 127.7, 128.7,
134.5, 136.4, 168.5, 169.1, 173.7; IR (Film) 3058, 2982, 2938, 2872, 1727, 1673,
1645, 1453, 1401, 1267, 1202, 1028, 738, 704 cm"; HRMS calcd for C22H27N05 m/z
385.1889, obsd m/z 385.1916.

77: (70:30/Et20:petroleum ether, 0.44g, 1.29 mmol, 43% yield, 57 :43 ratio of
diastereomers); 1H NMR (300 MHz, CDC13) characteristic peaks (both isomers) 8 0.78 (d,
J = 7.0 Hz, 3 H, minor), 0.85 (d, J = 7.0 Hz, 3 H, major), 1.10 (d, J = 6.4 Hz, 3 H,
minor), 1.61 (d, J = 6.4 Hz, 3 H, major), 3.63 (s, 3 H, major), 3.67 (s, 3 H, minor),
5.17 (dd, J = 3.1, 1.5 Hz, 1 H, major), 5.31 (dd, J = 3.1, 1.5 Hz, 1 H, minor); 13C
NMR (75 MHz, CDC13) (both isomers) 8 14.0, 14.1, 18.2, 18.4, 18.6, 18.7, 21.9, 22.1,
24.1, 24.3, 26.8, 28.5, 29.9, 30.1, 30.3, 30.5, 35.2, 46.5, 46.6, 51.8, 51.9, 61.1, 61.3.
61.8, 61.9, 76.5, 77.0, 77.1, 77.4, 107.6, 107.8, 136.6, 168.4, 168.7, 171.2, 173.7; IR
(Film) 3056, 2953, 2874, 2843, 1730, 1669, 1642, 1265, 1215, 1024, 745, 704 cm'l;
HRMS calcd for C13H27N05 m/z 337.1888 obsd m/z 337.1888.

78: (60:40/EtzOzpetroleum ether, 0.44 g, 1.29 mmol, 43% yield); [11]]; = -70.9, (c
= 1.9, CHC13); 1H NMR (300 MHz, CDC13) 8 1.03 (d, J = 6.8 Hz, 3 H), 1.2 (d, J = 7.1
Hz, 3 H), 1.60 (d, J = 7.1 Hz, 3 H), 1.73-1.89 (m, 2 H), 1.92-2.54 (m, 2 H), 2.25 (dd, J

120

= 18.1, 12.7 Hz, 1 H), 2.51 (m, 1 H), 2.65 (dd, J = 18.1, 5.7 Hz, 1 H), 4.00-4.20 (m, 2
H), 4.90 (dd, J = 5.5, 2.8 Hz, 1 H), 6.44 (q, J = 6.8 Hz, 1 H), 7.10-7.30 (m, 5 H); 13c
NMR (75 MHz, coc13) 8 14.1, 15.3, 18.7, 24.4, 32.8, 36.1, 38.5, 49.2, 49.8, 60.7.
112.2, 125.3, 126.0, 128.0, 128.2, 133.9, 142.2, 168.7, 172.1; IR (Film) 3056, 2986,
2944, 1721, 1665, 1634, 1265, 911, 738,708 cm‘l; HRMS calcd for C21H27NO3 m/z
341.1991, obsd m/z 341.1989.

82: (60:40 Et20/petroleum ether, 0.65 g, 1.89 mmol, 63% yield); 1H NMR (300
MHz, CDC13), (characteristic peaks both isomers) 8 1.61 (d, J = 7.3 Hz, 0.96 H), 1.67
(d, J = 7.1 Hz, 2.04 H), 4.95 (dd, J = 5.4, 2.9 Hz, 0.68 H), 5.17 (t, J = 3.9 Hz, 0.32
H), 5.90 (q, J = 7.2 Hz, 0.32 H), 6.26 (q, J = 7.3 Hz, 0.68 H); 13C NMR (75 MHz,
CDC13), (both isomers), 8 14.0, 14.1, 14.5, 15.4, 16.1, 18.3, 18.6, 23.9, 24.3, 34.5,
34.7, 34.9, 35.4, 38.2, 38.6, 40.0, 46.3, 47.4, 50.7, 52.5, 60.9, 61.1, 110.8, 117.5.
125.6, 125.8, 125.9, 126.1, 128.1, 134.4, 134.6, 142.3, 142.9, 171.9, 173.8, 174.4,
174.8; IR (Film) 3056, 2986, 2941, 1725, 1675, 1636, 1448, 1265, 748, 704 cm";
HRMS calcd for C21H27NO3 m/z 341.1991, obsd m/z 341.1982.

84: (solvent gradient, 70:30/EtOAczCH2C12-100% EtOAc, 1.01 g, 2.73 mmol,
91% yield); 1H NMR (300 MHz, CDC13) (characteristic peaks for 4 isomers), 8 4.78 (q, J
= 7.1 Hz, 0.04 H), 5.08 (dd, J = 2.8, 5.3 Hz, 0.64 H), 5.21 (t, J = 3.8 Hz, 0.09 H),
5.33 (t, J = 4.0 Hz, 0.23 H), 5.40 (q, J = 7.0 Hz, 0.09 H), 5.63 (t, J = 3.7 Hz, 0.04 H),
5.72 (q, J = 7.1 Hz, 0.23 H), 6.00 (q, J = 7.1 Hz, 0.64 H), 6.60 (d, J = 5.6 Hz, 0.09 H),
6.68 (d, J = 5.5 Hz, 0.68 H, two isomers), 6.72 (q, J = 5.8 Hz, 0.23 H); 13C NMR (75
MHz, CDC13), (all isomers), 8 13.9, 14.0, 14.1, 15.1, 15.2, 16.6, 17.8, 18.0, 18.1,
18.3, 18.9, 19.8, 23.0, 23.1, 24.0, 24.1, 24.3, 33.8, 34.1, 34.8, 35.0, 36.6, 36.9, 37.0.
46.3, 46.6, 46.9, 48.6, 49.9, 52.7, 54.1, 57.5, 61.1, 61.3, 61.5, 110.4, 111.6, 121.1.
125.6, 125.8, 126.2, 126.3, 126.9, 128.2, 128.3, 128.4, 133.3, 133.7, 141.3, 141.6.

121
142.0, 166.5, 168.0, 169.9, 170.1, 170.3. 173.7, 174.2; IR (Film) 3056, 2986, 2944,
1725, 1669, 1644, 1265, 740, 704 cm'l; HRMS calcd for C22H23NO4 m/z 370.2019,
obsd m/z 370.2082.

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REFERENCES AND NOTES

Review: d'Angelo, J.; Desmaéle, D.; Dumas, F.; Guingant, A. Tetrahedron:
Asymm. 1992, 3, 459.

Sdassi, H.; Revial, G.; Pfau, M.; d'Angelo, J. Tetrahedron Lett. 1990, 31, 875.

Reviews: (a) Martin, S. F. Tetrahedron 1980,36, 419. (b) Fuji, K. Chem. Rev.
1993, 93, 2037.

Ireland, R. R.; Marshall, D. R.; Tilley, J. W. J. Am. Chem. Soc. 1970, 92, 4754.
Rancher, S.; Gustavson, L. M. Tetrahedron Lett. 1986, 27, 1557.

See Chapter 1 and references therein.

House, H. O.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1971, 36, 2361.

(a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. Reactions 1959, 10, 179. (b)
House, H. 0. "Modern S nthetic Reactions" W. A. Benjamin, Menlo Park,
California, second edition, 972, 595.

(a) Krimm, H. US. Patent 2,768,962 (October 30, 1956), Chem. Abstr. 1957, 51,
6684b. (b) Krimm, H. Ger. Patent 948,157 (August 30, 1956), Chem. Abstr.
1957, 52, 18266e.

Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. J. Am. Chem. Soc. 1985, 107,
273.

(a) d'Angelo, J.; Revial, G.; Costa, P. R. R.; Castro, R. N.; Antunes, O. A. C.
Tetrahedron: Asymm. 1991, 2, 199. (b) Costa, P. R. R.; Castro, R. N.; Farias,
F. M. C.; Antunes, O. A. C.; Bergter, L. Tetrahedron: Asymm. 1993, 4, 1499.

(a) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J. J. Am. Chem. Soc. 1985,
107, 273. (b) Desmaéle, D.; d'Angelo, J. Tetrahedron Lett. 1989, 30, 345. (c)
Revial, G. Tetrahedron Lett. 1989, 30, 4121.

(a) d'Angelo, J.; Revial, G.; Volpe, T.; Pfau, M. Tetrahedron Lett. 1988, 29,
3712787 5(b) Sdassi, H.; Revial, G.; Pfau, M.; d'Angelo, J. Tetrahedron Lett. 1990,
Desmaéle, D.; d'Angelo, J.; Bois, C. Tetrahedron: Asymm. 1990, I, 759.

(a) Grishina, G. V.; Gaidarova, E. L. Kht'm. Geterotsl'kl. Soedin. 1992, 1072.
(1139 2(.‘vrils3h6i3a, G. V.; Gaidarova, E. L.; Aliev, A. E. Khl'm. Geterotsikl. Soedin.

Matsuyama, (H.; Ebisawa, Y.; Kobayashi, M.; Kamigata, N. Heterocycles 1989,

29, 449.

122

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123

(a) Tomioka, K. Seo, W.; Ando, K.; Koga, K. Tetrahedron Lett. 1987,28,
6637. (b) Guingant, A.; Hammami, H. Tetrahedron: Asymm. 1991, 2, 411. (c)
Guingant, A. Tetrahedron. Asymm. 1991, 2, 415. (d) Guingant, A.; Hammami,
H. Tetrahedron: Asymm. 1993, 4, 25. (e) Pinheiro, S.; Guingant, A.; Desmaéle,
D.; d'Angelo, J. Tetrahedron: Asymm. 1992.3,1003.

(a) Tomioka, K.; Ando, K.; Yasuda, K.; Koga, K. Tetrahedron Lett. 1986, 27,
715. (b) Tomioka, K.; Yasuda, K.; Koga, K. Tetrahedron Lett. 1986, 27, 4611.
(c) Tonrioka, K.; Yasuda, K.; Koga, K. J. Chem. Soc., Chem. Commun. 1987,
1345. (d) Brunner, H.; Kraus, J.; Lautenschlager, H.-J. Monatshefte flit Chemie
1988, 119, 1161. (e) Ambroise, L.; Chassagnard, C.; Revial, G.; d'Angelo, J.
Tetrahedron: Asymm. 1991, 2, 407. (f) Ando, K.; Yasuda, K.; Tomioka, K.;
Koga, K. J. Chem. Soc. Perkin Trans. 1 1994, 277.

Hickmott, P. W.; Sheppard, G. J. Chem. Soc. (C), 1971, 1358.

Hickmott, P. W.; Sheppard, G. J. Chem. Soc. (C), 1971, 2112.

Ninomiya, I.; Kiguchi, T. J. Chem. Soc., Chem. Commun. 1976, 624.

(a) Reference 23. (b) Danieli, B.; Lesma, G.; Palmisano, G. Gazz. Chim. Ital..
1981, 111, 257. (c) Heathcock, C. H.; Norman, M. H.; Dickman, D. A. J. Org.
Chem. 1990, 55 , 798.

(a) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. Jpn. 1972, 45, 2212.
(b) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto, A.; Panangadan, A.
K.; Hung, M.H.; Bravo, A. A.; Erpelding, A. M. J. Org. Chem. 1989, 54, 5659.
(c) Hua, D. H.; Park, J. G.; Katsuhira, T.; Bharathi, S. N. J. Org. Chem. 1993,
58, 2144. (d) Hua, D. H.; Bharathi, S. N.; Panangadan, A. K.; Tsujimoto, A. J.
Org. Chem. 1991, 56, 6998. (e) Hua, D. H.; Bharathi, S. N.; Robinson, P. D.;
Tsujimoto, A. J. Org. Chem. 1990, 55, 2128. (f) Hua, D. H.; Miao, S. W.;
Bravo, A. A.; Takemoto, D. J. Synthesis 1991, 970.

(a) Ninomiya, 1.; Naito, T.; Higuchi, S.; Mori, T. J. Chem. Soc., Chem. Commun.
1971, 457. (b) Hickmott, P.W.; Rae, B.; Pienaar, D.H.S. Afr. J. Chem. 1988,
41, 85.

Kametani, T.; Terasawa, H.; Ihara, M. J. Chem. Soc. Perkin Trans. 1 1976, 2547.
Paulvannan, K.; Stille, J. R. J. Org. Chem. 1992, 5 7, 5319.

Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 35, 8197.

Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59, 1613.

Paulvannan, K,; Stille, J. R. Tetrahedron Lett. 1993, 34, 6673.

Paulvannan, K.; Schwarz, J. B.; Stille, J.R. Tetrahedron Lett. 1993, 34, 215.

The use of this methodology in the preparation of nonnatural peptidomimetic
molecules is currently being investigated in these laboratories.

Barta, N.S.; Brode, A.; Stille, J. R. J. Am. Chem. Soc. 1994, 116, 6201.

 

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124

(a) Ando, K.; Takemasa, Y.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 1579.
(b) See reference 20.

Personal communication with James Audia, Lilly Research Labs.
Hirsch, J. A. Topics in Stereochemistry 1967, I, 199.

d'Angelo, J.; Guingant, A.; Riche, C.; Chiaroni, A. Tetrahedron Lett. 1988, 29,
2667.

The stereosclectivity of the Michael addition with imine substrates 17 was
independent of the type of electron deficient alkene used (vinyl sulfone, methyl

acrylate and ten-butyl acrylate).113

The products of the aza-annulations reported in this study have been submitted for
biological testing at Lilly Research Laboratories, Indianapolis, IN.

Dehydration of condensation reactions was performed with the use of a modified
Dean-Stark apparatus in which the cooled distillate was passed through 4-A molecular
sieves prior to return of the solvent to the reaction mixture. Barta, N. S.;
Paulvannan, K.; Schwarz, J. B.; Stille, J. R. Synth. Commun. 1994, 24, 583.
Cook, G.R. Ph. D. Thesis, Michigan State University (1993).

Dioxane was substituted here in the reactions indicated in Table III.

 

APPENDIX I

ZIEGLER-NATTA OLEFIN INSERTIONS WITH MAO
Legend For Data Tables

TIME: Given in minutes.

mL MAO: Amount of 0.5 M solution in toluene added to the reaction mixture.

%Prop t=0: Percentage of cyclization during formation and isolation of 43a.

%But t=0: Percentage of cyclization during formation and isolation of 43b.

%Prop - t=0: Amount of cyclization of 43a obtained during the reaction minus the
parsonage of cyclization that had occurred during formation and isolation of

%But- t=0: Amount of cyclization of 43b obtained during the reaction minus the

percentage of cyclization that had occurred during formation and isolation of
43b. -

c:t Prop: The ratio of cis to trans 46a formed during cyclization.

c:t Prop: The ratio of cis to trans 46b formed during cyclization.

K: The rate of cyclization of 43a relative to 43b.

COMMENTS: Indicates reaction runs that were not included in the average.
%cyc: Percentage of cyclization was not within the reaction parameters.
c/t: The cis:trans ratio fell outside the range typically observed.

b-H: Indicates that an excessive amount of b-hydrogen elimination had
occurred.

bad MAO: Indicates that the MAO solution was not acceptable.
low/high: Indicates that when all values fell within the reaction

parameters, the lowest and highest values were not included in
the average.

125

 

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APPENDIX II

 

 

Chapter I

Chapter 11

Chapter III

Related Publications

“Lewis Acid-Promoted 3-Aza-Cope Rearrangement of N-Alkyl-N-
Allylenamines.” Cook, G.R.; m Stille, J.R. J. Org. Chem.
1992,57, 461-467.

“Studies of the Regiospecific 3-Aza-Cope Rearrangement Promoted by
Electrophilic Reagents.” M; Cook, G.R.; Landis, M.S.; Stille,
J.R. J. Org. Chem. 1992, 57, 7188-7194.

“An Efficient Apparatus for Removal of H20 from Condensation
Reactions.” M; Paulvannan, K.; Schwarz, J.B.; Stille, J.R.
Synth. Commun. 1994, 24, $83-$90.

“a- and B—Deuterium Isotope Effects in the MgX2 and Methylaluminoxane
Promoted Intramolecular Olefin Insertion of Cp2TiClR Complexes. Insight
Into Cocatalyst Dependence and Chain End Control in Ziegler-Natta
Polymerization.” Mi; Kirk, B.A.; Stille, J.R. J. Am. Chem. Soc.
1994, I I 6, 0000. Accepted for Publication.

“Competitive Intramolecular Ti-C versus Al-C Alkene Insertions:
Examining the Role of Lewis Acid Cocatalysts in Ziegler-Natta Alkene
Insertion and Chain Transfer Reactions.” Mi; Kirk, B.A.; Stille,
J.R. J. Organomet. Chem. 1994. Accepted for publication.

“Asymmetric Formation of Quaternary Centers Through Aza-Annulation of
Chiral B-Enamino Esters with Acrylate Derivatives.” M.; Brode,
A.; Stille, J.R. J. Am. Chem. Soc. 1994, 116, 6201-6206.

133

MICHIGAN srnTE UNIV. Lrennnres
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