THE CE‘iEMESTRY {3F AMEDE ENOLATES
AND A STUDY OF ESTER ENOUXTE
STABiLiTY

Dissertatian for ‘ahe Degree of Ph. D.
MICWGAN STATE UNIVERSITY
RéCHARD RAUL WOODB‘JRY
1976

  
   
   

  

LIBRARY "
Michigan State
University

This is to certify that the

thesis entitled

The Chemistry of Amide Enolates
and a Study of Ester Enolate Stability

presented by
Richard Paul Woodbury

has been accepted towards fulfillment
of the requirements for

Ph. D. degree in Chemistry

 

 

Z é” Z/:7£—:{<

Major professor

Date ' /3 7&9

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ABSTRACT

THE CHEMISTRY OF mm ENOLATES AND A STUDY OF ESTER ENOLATE STABILITY
By

Richard P. Woodbury

N,N-dimethylacetamide reacts with lithium diis0pr0pylamide in tetra-
hydrofuran at 00 to give the corresponding lithium amide enolate. The
stability of lithio N,N-dimethylacetamide was tested and solutions of this
enolate were stable for 30 hours. Due to the enolate's stability, lithio
N,N—dimethylacetamide was easily studied with 1H and 13C NMR and was

assigned the oxygen-metalated structure 2.

H 0L1

I

H N(CH3) 2'
2

Lithio N,N—dimethylacetamide reacts with a variety of alkyl halides,
epoxides, and carbonyl compounds to form carbon alkylated amides, Y-hy-
droxyamides, and B-hydroxyamides resPectively. Lithio N,N-dimethy1aceta-
mide also reacts with trimethylchlorosilane to yield 93%rof 2-trimethy1-
silyl-N,N-dimethylacetamide. Other amide enolates were also silylated and
the results were found to vary depending on the structure of the amide.
Increased substitution at the alpha carbon of the enolate favors oxygen—
silylated products, while increasing the size of the substituents on the

nitrogen favors carbon-silylated products.

Richard P . Woodbury
The enolate of 2-trimethylsily1-N,N—dimethylacetamide was generated
and its stability was tested in a similar procedure as used with N,N-
dimethylacetamide. Lithio trimethylsilyl-N,Nedimethylacetamide was
found to be stable for 93 hours at room temperature. The structure of
lithio trimethylsilyl-N,N-dimethylacetamide was elucidated with 1H and
130 NMR and the oxygen-metalated structure g3 was assigned.

0L1

SicH=c’

(CH3)3 \N(CH

3)2
22

Lithio trimethylsilyl-N,N—dimethylacetamide reacts with ketones and
N,N-dimethylamides to form.a, B-unsaturated amides and enamino amides g3
resPectively.

(CH ) N
3 2R>C=CH00N(CH3)2

24

Esters react with lithium diisoproPylamide in tetrahydrofuran at -780
to form stable solutions of ester enolates. Solutions of ester enolates
were warmed to 25° and the rate of decomposition measured. A table of
relative rates for a variety of ester enolates has been compiled. From
this table, other rate experiments, and trapping experiments, some insight

into the mechanism of ester enolate decomposition was found.

THE CHEMISTRY OF AMIDE ENOLATES

AND A STUDY OF ESTER ENOLATE STABILITY

By

Richard Paul Woodbury

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1976

To

Janet, With All My Love

11

ACKNOWLEDGEMENTS

The author wishes to extend his appreciation to Dr. Michael Rathke
for his assistance and dedication throughout this project. Thanks are
also given to Dr. Harold Hart for his inspiration as teacher and scholar
and for serving as Second Reader. Special thanks are extended to my
loving parents for all their encouragement and support throughout the
years.

The financial SUpport of Michigan State University and the National
Science Foundation is gratefully acknowledged.

Appreciation is also extended to Chip Millard, Chuck HOppin, and
Gary VanKempen who have all provided a variety of activities outside of
the lab, and assistance on the 0.0. The author also wishes to thank past
and present members of Dr. Rathke's research group who have always
provided an enjoyable atmoSphere in the lab.

Finally. the author wishes to thank Janet, for her encouragement,
patience during the past four years, typing of this thesis, and mostly for
her love. Without her all of this would not have been possible.

iii

TABLE OF CONTENTS

CHAPI‘ERI

PREPARATION OF AMIDE ENOLATES

Page
I NPRODUCI‘ION I I e o I o o e e o 0 2
RESULTS 0 o o e e e o o e e e l 6

Preparation of Lithio N,N-dimethylacetamide . . . . 6
Proton NMR of Lithio N,Nedimethylacetamide . . . . 11
13c NMR Spectrum of Lithio N,N-dimethylacetamide . . . 11
DISCUSSION . . . . . . . . . . . 16
Preparation of Lithio N,N—dimethylacetamide . . . . 16
The Proton NMR Spectrum of Lithio N,N-dimethylacetamide. . 17
The 13C NMR Spectrum of Lithio N,N-dimethylacetamide . . 19
EXPERIMENTAL . . . . . . . . . . . 20
1. Materials . . . . . . . . . . 20
2. Preparation of Lithium Diisopropylamide . . . . 20
3. Preparation of Lithio N,N—dimethylacetamide . , , 20
h. Decomposition, Quenching, and Analyses . . . . 22

5. Preparation of Lithio N,Nedimethylacetamide for NMR
Analysis . . . . . . . . . . 23

iv

TABLE OF CONTENTS - Continued

REACTIONS OF AMIDE ENOLATES

INTRODUCTION . . . .

RESULTS

Alkylation of Lithio N,N-dimethylacetamide

Reactions of Lithio N,N—dimethylacetamide with Ketones

and Aldehydes . . .

CHAPTER 2

Reactions of Lithio N ,N-dimethylacetamide With Epoxides.

Silylation of Amide Enolates .

DISCUSSION . . . .

Reaction of Lithio N,N-dimethylacetamide with Alkyl Halides,
Aldehydes, Ketones, and Epoxides

Reaction of Lithium Amide Enolates with Silylating

Reagents . . . .

Emmm MAI, O O O I

1.

Materials . . .
Alkyl Halides . .

Carbonyl Compounds .

Amines, Acid Chlorides, THF and n-Butyllithium

Silylating Reagents
Eponcides . . .

Amides . . .

Alkylation of Lithio N,N—dimethylacetamide
Reaction of Ketones with Lithio N,N-dimethylacetamide

Reaction of Aldehydes with Lithio N,N-dimethylacetamide
Reaction of Epoxides with Lithio N,N-dimethylacetamide

Silylation of Lithium.Amide Enolates

V

Page
25

29
29

31
31
33
38

38

45
“5
N6

TABLE OF CONTENTS - Continued

7. Product Analyses . . . . . . .

CHAPTER 3

REACTIONS OF SILYLATED AMIDE ENOLATES

INTRODUCTION . . . . . . . . . .

RESULTS I I I I I I I I I I I

Preparation and Stability of Lithio Trimethylsilyl-
N ' N-dimethylacetalnide e o o e o I o

The 1H and 13c Spectra of Lithio Trimethylsilyl—N,N-
dimethylacetamide . . . . . . . .

Reaction of Lithio Trimethylsilyl—N,N-dimethylacetamide
with Epoxldes e I e o e I e e 0

Reactions of Lithio Trimethylsilyl-N,N-dimethylacetamide
with Aldehydes and Ketones . . . . . .

Reaction of Lithio Trimethylsilyl-N,N-dimethylacetamide
with Esters and Acid Chlorides . . . . .

Reactions of Lithio Trimethylsilyl-N,N-dimethylacetamide
flth Amid-es I I I I I I I I I

Reactions of Enamino Amides . . . . . .

DISCII$ION I I I I I I I I I I I

Preparation and Stability of Lithio Trimethylsilyl—N,N-
dimethylacetamide . . . . . . . .
The 1H and 130 NMR Spectra of Lithio Trimethylsilyl-

N,Nedimethylacetamide . . . . . . .

Reactions of Lithio Trimethylsilyl-N,N-dimethylacetamide
with Ketones and Aldehydes . . . . . .

Reactions of Lithio Trimethylsilyl-N,N-dimethylacetamide
with Simple N,N—dimethyl Carboxylic Acid Amides . .

Reactions of Lithio Trimethylsilyl-N,N-dimethylacetamide
with Esters and Acid Chlorides . . . . .

Vi

Page
1+6

52

55

58

59

61
62
66

66

67

69

7O

72

TABLE OF CONTENTS - Continued

Reactions of Lithio Trimethylsilyl-N,N-dimethylacetamide

with Epoxides . . . . . . . . .
Reactions of Enamino Amides . . . . . .

EXPERIMENTAL . . . . . . . . ,. .
1. Materials . . . . . . . . .
2. The Preparation of Lithio Trimethylsilyl—N,N-

9.

10.
11.

12.
13.
1b,.

15.

dimethylacetamide Using Lithium Diisopropylamide .

The Preparation of Lithio Trimethylsilyl-N,N-
dimethylacetamide Using n—Butyllithium . . .

Decomposition and Analyses of Lithio Trimethylsilyl-

N,N-dimethy1acetamide . . . . . .
Preparation of Lithio Trimethylsilyl-N,N-dimethylacetamide
for NMR Analyses . . . . . . .
Reactions Between Lithio Trimethylsilyl—N,N—
dimethylacetamide and Epoxides . . . . .
Reactions of Aldehydes and Ketones with Lithio
Trimethylsilyl-N,N—dimethylacetamide . . .
Reaction of Lithio Trimethylsilyl-N,N-dimethylacetamide
with Esters and Acid Chlorides . . . . .
Reactions of Simple Carboxylic Acid Amides with Lithio
Trimethylsilyl-N,N-dimethylacetamide . . .

Preparation of N,N-dimethylacetoacetamide. . .

Preparation of 3-dimethylamino-N,Nedimethyl-
crontonamide . . . . . . . .

Hydrolysis of B-dimethylamino-N,N-dimethyl-
crotonamide . . . . . . . .

Reaction of B-dimethylamino—N,N—dimethylcrotonamide
with Lithium.Diisopr0pylamide Followed by Attempted
Silylation and Alkylation . . . . . .

Alkylation of B-dimethylamino-N,N—dimethylcrotonamide
and Allyl Bromide . . . . . . .

Attempted Reaction Between Lithio Trimethylsilyl-N,N-
dimethylacetamide and B-dimethylamino-N,N-dimethyl—
crotonamide . . . . . . . .

Vii

Page
71+
76
79
79

79

79

81

81

81

82
82

82

83

83

83

TABLE OF CONTENTS - Continued

Page
16. Product Analyses . . . . . . . . 8h
CHAPTER 4
STABILITY OF ESTER ENOLATES IN SOLUTION
INTRODUCTION . . . . . . . . . . . 89
RESIJLTS I I I I I I I I I I I I 91

Quenching and Decomposition Studies of Ester Enolates . , . 91

Decomposition Studies of Solutions of Ester Enolates
Containing Lithium Alkoxides . . . . . . . 95

Decomposition Studies of Solutions of Ester Enolates
Containing Excess Lithium Diisopropylamide . . . . 96

Decomposition of "Amine-Free" Lithio t-Butyl Acetate . . 96
Attempted Trapping of Possible Ketene Intermediates . . 102
Attempted Isolation of Ketene Intermediates . . . . 106
Attempted Identification of Ketene in Solution by IR . . 106
DISCUSSION . . . . . . . . . . . 108
Rate Studies . . . . . . . . . . 111
Attempted Observation of Ketene by IR . . . . . 117

Deuterium Studies . . . . . . . . . 117

Conclusion . . . . . . . . . . 117
EmmNTAL I I I I I I I I I I I 11 9
1. Materials . . . . . . . . . . 119

2. Procedure for the Decomposition of Ester Enolates . . 119

3. Decomposition Studies of Ester Enolates in the Presence
of Lithium Alkoxides . . . . . . . . 120

h. Decomposition of Ester Enolates in the Presence of
Excess Lithium DiisoprOpylamide . . . . . 121

viii

TABLE OF CONTENTS - Continued

Page
. Decomposition of "Amine-Free" Lithio t-Butyl Acetate . 121

5
6. Analyses of Decomposition Products . . . . . 122
7. Isolation of Lithio t-Butyl Acetoacetate . . . . 122
8. Reaction of Lithio t-Butyl Acetate with Ketene . . 123
9. Ketene Trapping Experiments . . . . . . 123
10. Reactions of Esters with Lithium Dimethylamide . . 12H
11. Attempted Isolation of Ketene Intermediates . . . 124
12. Attempted Identification of Ketene Using IR . . . 125
13. Product Analyses . . . . . . . . 125

BIBLIOGRAPI'IY o o o e e o o o o o o 127

ix

10.

ll.
12.

130

14.
15.

16.
17.

LIST OF TABLES

Quenching Results of Lithio N,N-dimethylacetamide . .

13C Chemical Shifts for N,N-dimethylacetamide and
Lithio N,N-dimethylacetamide . . . . . .

Alkylation of Lithio N,N—dimethylacetamide . .
Reactions of Carbonyls with Lithio N,N—dimethylacetamide
Silylation of Amide Enolates . . . . . .

Quenching Studies of Lithio Trimethylsilyl-N,N-
dimethylacetamide . . . . . . . .

Reaction of Lithio N ,N-dimethylacetamide with
Various ElectrOphiles . . . . . . .

Elemental Analyses of New Y—Hydroxy Amides . . .

1H Chemical Shifts for Lithio Trimethylsilyl-N,N-
dimethylacetamide in Pyridine . . . . . .

13C Chemical Shifts for Lithio Trimethylsilyl-
N,N-dimethylacetamide . . . . . . .

Yields of Enamino Amides . . . . . . .
Elemental Analyses for Some Enamino Amides . . .

enching Results of Ester and Amide Enolates
10% Excess Base) . . . . . . . .

Quenching Results of Ester Enolates and Lithium.Alkoxides

Quenching Results of Ester Enolates in the Presence
of Excess Base . . . . . . . . .

Decomposition of "Amine-Free" Lithio t-Butyl Acetate .

NMR Data for Lithio t—Butyl Acetoacetate . . .

Page
10
15
3o
32
35

36

39

56

57
63
87

93.94
97

98
99
103

LIST OF FIGURES

Stability of N,N-dimethylacetamide . .

1H NMR of Lithio N,N-dimethylacetamide in Pyridine

1H NMR of N,N-dimethylacetamide in Pyridine .

Enolate Anion . . .

Resonance Structures for N,N-dimethylacetamide

Reaction Apparatus . .

Reactions of Ester Enolates

Three Phase Test for Reactive Intermediates

Comparison of Relative Rates
Comparison of Relative Rates
Comparison of Relative Rates

Comparison of Relative Rates

t-Butyl and Ethyl Esters

Ethyl Esters (Predicted)

Ethyl Esters

t-Butyl Esters

Page
8

12
13
17
18
21
89

11C

111

112

112

112

CHAPTERl

PREPARATION OF AMDE ETDLATES

INTRODUCTION

Protons in the alpha position of carboxylic acid amides can be
removed with base to form enolate anions .1. If the nitrogen of the
amide has at least one hydrogen, then the proton on the nitrogen is

preferentially removed to give the resonance stabilized anion 2 (eq. 1).1

//
RCHZC\
NHR’

H

- o o o
/
RCHC’ .—-> RCH=C< and/or RCH2c(’ 4——0RCH20<0 (1)
o 9 "' \
a' R'
.1. .2.

The anion 2 above can be alkylated, which provides a method for N-

alkylation of amides.2 O-alkylation 3 is sometimes a side reaction

(eq. 2).

9°
acnzcfir
l (2)
R' u
I .. ,0 (1,0.
+ R X —. RCHZC\N/R, , + RCHZ \\N
_ I I
RCH C’ 0 R, R,
2 \\N
1'2. 2

To alkylate at the alpha carbon of an N-substituted amide, it is

necessary to generate the dianion (eq. 3).

 

3 2101112 K K 1) R'X 1} 8
RCHZCNHR ————> RCHCONR t RCHCNHR (3)
liq. m3 2) NHuCI

A variety of condensations and alkylations at the alpha carbon have been
reported using the dianion of N-substituted amides.3-5

In the late 1950's, it was reported that certain N,N-disubstituted
amides are pharmalogically active as analgesics,6’7 oxytocics, and
diuretics.8 These amides were usually synthesized by generation of the
enolate anion, followed by alkylation at the alpha carbon. In most of
these early examples the alpha position was substituted with a carbanion

stabilizing substituent (i.e. -¢; -COR, etc.) (eq. 4).

 

o .. o R'NCH on C1 ,0
¢-CH C” JESS-c ¢~CHC’( 2 2 2 fi- ¢-CHC’ (u)
2 ‘NR NR \NR
2 2 | 2 ,
CHz‘mzNRz

These enolate anions were generated in liquid ammonia or refluxing benzene

with bases such as: NaNH mm and Neal.

2’ 2
More recently, several authors have reported the formation and
alkylation of sodium enolates from simple N,N-disubstituted amides

(eq. 5)-9

refluxing 06H6

 

or 1i . NH R'x 0
RCHZC‘z: q 3 a -——-> RCHC.<’ (5)
(0113)2 NaNHZ R. N(CI{3)2

10

Whitefield reported that attempts to form amide enolates with lithium

amide or sodium ethoxide were unsuccessful.

In 1972, Durst and LeBelle11

found that treatment of'simple mono-
cyclic N-methyl or N-phenyl B-lactams with lithium diisopropylamide in

THF at -780 formed stable lithium amide enolates (eq. 6).

2 I.iN(i-Pr)2 + 2
H R1 ; Li : ‘—-R1
N THE -78° - ,5 (6)

Lithium enolates were also formed with simple N,N-disubstituted amides by
12

 

 

Normant and co-workers using Li/HNRZ/HMPT. They varied the temperature

from -780 to +150 and used a variety of amines from HNEt to HN(1-PT)2

(eq- 7)-

2

Li+

0 EtZNH , L1 "'
1’ :» RCHC
HMPT, PhH N

,oLi

, ~——+ RCH=C\N/ (7)
l

The above survey summarizes the several methods for the preparation

~e
\
‘N:

RCHZC

 

I
I

N
I

of amide enolates described in the literature. The primary objective of
this investigation was to find a general procedure for the preparation of
amide enolates using lithium diisopropylamide (eq. 8).
o
'4
n—BuLi + (i-Pr)2NH -—-- LiN(i-Pr)2 + H—CC

' /
-———> LiCC

O
I
I \N”
I

+ (i-Pr)2NI-I

To find the most convenient procedure, several temperatures and a variety
of solvents were tested. After a general procedure was found, the
stability of lithio N,N-dimethylacetamide was investigated.

A second objective of this investigation was to isolate a lithium
amide enolate as a crystalline solid. This enolate would be free of all

solvent and other reagents, thus providing the Opportunity to study its

1

structure using H and 13C NMR.

RESULTS

Preparation of Lithio N,N-dimethylacetamide

Lithium diis0propylamide was prepared quantitatively by adding
diisopropylamine drapwise to a solution of n-BuLi in pentane at 00
(eq. 9) e

Pentane
n-BuLi + (i-Pr)2NH —3-—v- (i-Pr)2NH + Butane
o

(100%) (9)

The solvent was removed under reduced pressure and lithium diisoPropyl-
amide was left as a white solid. The solid amide base was dissolved in
THF and immediately cooled to -78°, followed by the addition of N,N-
dimethylacetamide. Lithio N,N-dimethylacetamide was formed quantitatively

after 15 minutes of stirring at -78° (eq. 10).

,o -789 o
(i-Pr),,NLi + CHBC/ ——e LiCHZCf + (i-Pr) 21m
“ \N(CH3)2 THF N(CH3)2
(10)

Reaction at 0° also generated lithio N,N-dimethylacetamide in 97% yield.
The reactions above were quenched with 1.1 equivalents of glacial acetic
acid and centrifuged. Yields were determined by analyzing (glpc) for
recovered N,N—dimethylacetamide from quenched reaction mixtures. Due to
the solubility of N,N—dimethylacetamide in aqueous solutions, quenching
the reaction mixtures with 2M acetic acid resulted in less then 10%

6

recovery of the starting amide (eq. 11).

 

0° 2M HOAc/H o o
maize/<0 —> 3+ CH3C<N (11)
MCH3 )2 THF (CH

<10%

After generation at 00 in THF, the reaction mixture was warmed to
250 and stirred for 60 hours. Seventy-five percent of the starting
material was recovered following quenching with 1.1 equivalents of
glacial acetic acid. In Figure 1, the results of this stability study
are illustrated by plotting the percent of recovered amide versus time.
Besides starting amide, small quantities of N,N-dimethylacetoacetamide
4 were also found in the reaction mixtures.

0

CH3- -ii-CH 22-'(i-N(C}13)

E

In similar experiments using pentane as a solvent, the results were
very different. Lithium diisopropylamide is not soluble in pentane at
-78°. Addition of N,N—dimethylacetamide to this heterogeneous solution
produced little change. After being stirred for 15 minutes, the reaction
mixture was quenched at -780 with 1.1 equivalents of glacial acetic acid,

and less than 10% of the starting amide was recovered (eq. 12).

H ( ) Pentane HOAc CEO
0 +' i-Pr NLi ----* ‘---' CH
3 ‘n(cn3)2 2 -78° 3 M0113)2

< 10% (12)

casseroonflsfiosnrzé no sidearm 4 among

Anaconvosae
on no om mm on m: 3 mm on mm om m.“ 3 n

 

l
O
tn
% of Recovered Amide

 

At 0°, lithium diisopropylamide is soluble in pentane. Addition of
N,Nrdimethylacetamide at this temperature instantly produced a white
solid. This su3pension was stirred for 15 minutes and quenched with
glacial acid followed by saturation with anhydrous magnesium sulfate.
Again, less than 10% of the starting amide was recovered. The results

with several quenching reagents can be found in Table l.

Quenching Results of Lithio N,N—dimethylacetamide

10

TABLE 1

a,b

 

 

Reagent 95 Recovery
HOAc/neat 10%
2M CHBSOBH/THF‘ 72%
2M HOAc/THF 75%
2M HCI/Hzo-Ngso,+ 10%
2M HCl/HZO-KZCO3 82%
6M HCl/HZO-K2C03 65%
Sat'd. NaHZPOu/HZO N396

 

8'All reactions run in pentane.

hAnalyzed using glpc.

ll
Proton NMR of Lithio N,N—dimethylacetamide

Addition of N,N-dimethylacetamide to a solution of lithium diiso-
pr0pylamide, in pentane at 0°, produced a precipitate. Removal of the
solvent and volatile diisoPropylamine under reduced pressure gave lithio
N,N—dimethylacetamide as a white solid. The amide enolate was only
stable under a moisture-free inert atmoSphere. Exposure of the white
solid to the atmosphere caused it to become brown and charred. The amide
enolate was dissolved in pyridine to form a clear, yellow solution lM in
concentration. A sample of this solution was carefully transferred to an
NMR tube under a nitrogen atmosphere and sealed. Any contact with
moisture produced a yellow-orange solution, presumably indicating pro-
tonation and condensation of the enolate.

The proton NMR Spectrum of this solution exhibits two partially
resolved one-proton doublets at 3.16 and 2.93 ppm (relative to TMS).

There is also a sharp sixrproton singlet at 2.63 ppm (Figure 2). Attempts
to produce a highly resolved proton NMR Spectrum of lithio N,N-dimethyl-
acetamide in either deuterated benzene or carbon tetrachloride were
unsuccessful.

The proton NMR spectrum of the starting material, N,Nedimethyl-
acetamide, was taken in pyridine for comparison. The spectrum consisted
of two broad three-proton singlets at 2.97 and 2.77 ppm and a sharp three-

proton singlet at 1.93 ppm (Figure 3).
13C NMR Spectrum of Lithio N,Nudimethylacetamide

The 13C NMR spectrum of lithio N,N-dimethylacetamide was obtained

using the same sample used in obtaining the 1H NMR Spectrum. This was

12

 

Il'rfifITWV-IIIUIf‘TIIrij-I
I
0

11' T r I I 'I'"' l 1. r v I I. v t T ‘ V_ I_ _ , fr I t .I
- 2A0 ’ - 4 180 «

m-cw—

 

w-— “<.- —.--— ~

 

 

 

 

 

 

 

ova-”.1....u-ov-d -v<~
I
'

 

 

 

 

 

 

 

Figure 2. 1H NMR of lithio N,N—dimethylacetamide in Pyridine

13

 

I 1* I f

T

 

 

R'-

~
" .
In . n i
..
on. I
..
. .
.
a. o
_
1 . 1 iii
,.
_

.......

o
I. t. '0.|,.. 'l‘|in‘$.. 1...}! .l .i.

. . o
A ..9.I’.V’ ._., l‘.’ov!'l¢..t!ui 10.. . 1 .
. . . .\ . o . .
I'TTIII‘V r o ‘

. . m
. Z .0 ..
V . . .n .1
._ .. .

_

...

1 . . . . .. .
. ’.EI§|"I“ 'IIIIEII-o’II D
. . . .

.
.

. .
p

I
.
. J I! .
a
a
I 1
.
.
I l I ”-1 I
. ..
. .
1. .
.
I .o

u.

 

.. .. .. :...:. .
u o. v '-

. ~
. .
1.1L IL.’."|.I’LD..T"
..
.4 .
. .. o. .
o .. ..

 

 

 

 

:
~¢ou¢w ~.
i

 

 

. .
. .‘II‘III‘

 

 

.
o
a
I l ' III‘II- I
. -
. o
p 7 I l
a
In

L

 

1.0

2.0

3.0

.1!)

 

I )

 

Figure 3. 1H NMR of N ,N-dimethylacetamide in Pyridine

l4

accomplished by taking the sealed 4 mm tube and placing it inside the
larger 7 mm tube. Masking tape was wrapped around the 4 mm tube
approximately one inch from the top, to match the inside diameter of the
larger tube. This, and forcing glass wool around the top of the 4 mm
tube, prevented any movement within.

The data obtained from the 13C NMR Spectra of N,N—dimethylacetamide
are found in Table 2. For comparison, samples were also run in dioxane
and deuterated chloroform. A11 chemical shifts are in ppm relative to

TMS.

15

TABLE 2

13C Chemical Shifts for N,N-dimethylacetamide and Lithio N,N—dimethyl-

 

 

 

 

acetamide
Pyridine CHCl3
b
CH (1: c a 21 42 21 no
a 3 ’CII I I I
I 3 b 169 58 170 26
d CH3 . . .
0. 37-50 37-95
d. 3u.6u 34.95
Pyridine Dioxane
a- 55-99 57-00
b 0
LiCHZCé’ G; b. 169.39 169.31
a CH3 d. 39.53 40.12
* 23.32 none

 

0
* Extraneous peak - possibly due to CH C?

3\
N(CH3)2

DISCUSSION

Preparation of Lithio N,N—dimethylacetamide

The enolate of N,N-dimethylacetamide has been generated in a simple
procedure and was found to be stable. The method of choice was treat-
ment of N,N—dimethylacetamide with lithium diisopropylamide in THF at 0°.
This procedure provided a solution of enolate which was stable for 15

hours (eq. 13).

O O

o o 25
Chad” + (i-Pr)2NLi ———o ‘ LiCHZC”0 ——+-
\N(CH3)2 THF \N(CH3)2 THF
+ 15 hours
H ,/o
———o CH C
3 13
100%

Ester enolates, in comparison, are stable only at -78°.13 Warming THF
solutions of ester enolates to 25° results in complete decomposition with-

in several hours (eq. 14).

O

 

I “780 I 25
H-CCOZR + (i-Pr)2NLi -—- LiCCOZR —>
I THF ' Condensation
0 14
I u I ( )
H-C-C-C—COZR

l6

17

As can be seen from the stability studies, care must be taken when
solutions of amide enolates are quenched. Since simple amides are easily
extracted from organic solvents, aqueous quenching reagents must be
avoided. The inability to recover the starting amide quantitatively in
pentane is not due to the enolate instability, but rather the inefficiency
of pentane as a quenching medium. The absence of any condensation pro-
ducts provides evidence for this. Lithio N,N-dimethylacetamide was
generated quantitatively in pentane. This result was evident from NMR
studies of the enolate and from reactions between isolated enolate and
carbonyl compounds (Chapter 2), which produced nearly quantitative yields

of products.
The Proton NMR Spectrum of Lithio N,Nedimethylacetamide

The structure of enolates can be visualized as a hybrid of two

resonance structures (Figure 1+) ,

,0

Cl +
M
m2
\ M+
I or CH "3670
2 \x
_ M+
CH2 \(
Figure h. Enolate Anion
or as tautomeric structures (eq. 15).
0 M
/ L.___
new (3’ CH =c’O (15)

2‘x ’ 2‘x

18

The actual structure of a particular enolate probably depends on the
metal cation and it's degree of association with the enolate. The data
fcund from the 1H NMR experiment provides strong evidence that lithio

N,N—dimethylacetamide exists as an oxygen-metalated structure 5.

0L1

CH2=C<N(CH

i5

3)2

The proton NMR Spectrum of N,N-dimethylacetamide reveals that the methyl

substituents on the nitrogen are non-equivalent. This is due to the large

amount of double bond character in the nitrogen-carbon bond é (Figure 5) 1h
0 . -
/
CH3C< o————o~ CH3Q3?
N CH -
( 92 Elena
3
§

Figure 5. Resonance Structures for N,N—dimethylacetamide

In the Spectrum of the enolate, the two methyl groups of the amide were
found to be equivalent, indicating free rotation between the carbon and
nitrogen. Also found in this Spectrum was a doublet of doublets, as
would be expected, fer a pair of non-equivalent vinyl protons on the same
carbon. If the enolate had the carbon metalated structure 2, only a
single resonance for the equivalent methylene protons would have been
observed. A pair of broad singlets for the non-equivalent methyl groups

on the nitrogen might have been expected, as is observed with N,N—dimethyl-
acetamide itself.

l9

,0
I
LiCH2C\

N/

I
CH

CH

2

A similar Spectrum was found for O-trimethylsilyl-N,N-dimethylacetamide

_8_ (doublet of doublets at 2.86 and 2.96 and a sharp singlet at 2.l&9).15

3)3
92

H OSi(CI-I
\C—C/

H’ - ‘N(CH

_8_

The 136 NMR spectgum of Lithio N,N—dimethylacetamide

Data from the 13c Spectrum of lithio N,N-dimethylacetamide and N,N-
dimethylacetamide support the conclusions drawn from the 1H NMR experi-
ments. The 130 NMR Spectrum of N,N—dimethylacetamide also showed that
the two methyl groups on the nitrogen are not equivalent. However, in
the spectrum of the enolate only a single peak was found for these methyl
groups, indicating free rotation of the nitrogen-carbon bond, as expected
for an oxygen metalated structure. The alpha carbon of the enolate was
found approximately 35 ppm downfield from this same carbon in the
starting amide. Even though the chemical shift (56-57 ppm) of the alpha
carbon is not indicative of an alkenyl carbon (lOO-lho ppm)16 a down-
field Shift would be expected in going from the amide to the amide

enolate.

EXPERIMENTAL

l . Materials

N,Nrdimethylacetamide and diiSOpropylamine were obtained from Aldrich
Chemical Company and distilled prior to use. The amide was stored over
molecular sieves. Tetrahydrofuran was commercially available and dis-
tilled from the sodium ketyl of benzophenone. The pyridine used in the
NMR experiments was distilled from BaD and stored over molecular sieves.
The n-BuLi was obtained from Aldrich as 1.6M solutions in hexane and was
used without further purification. All reagents were stored under a dry

nitrogen atmosphere.

2. Preparation of Lithium.Diisopropylgmide

The reaction apparatus, shown in Figure 6, was charged with 5 m1 of
dry pentane and cooled to 0°. Then 3.hh ml (5.5 mmoles) of 1.6M anuLi
was added, followed by dropwise addition of 0.77 ml (5. 5 mmoles) of
diiSOpropylamine. The reaction mixture was warmed to room temperature
and stirred for 5 minutes. The solvent was then removed under reduced

pressure, leaving a white solid.

3. ‘gzgpggatigg_g§;§£thio N,Nrdimethylacetamide

Lithium diisOpropylamide (5.5 mmoles) was prepared as described
above, dissolved in 10 ml of’THF, and was cooled to 0°. Then.0.h8 ml
(5.0 mmoles) of N,N-dimetmlacetamide was added drOpwise and stirred for
15 minutes.

20

21

 

]—--' To Mercury Bubbler

 

 

Gas Inlet Valve ——> ’ ‘

 

 

 

4—-~
Rubber Septum

CD

Magnetic Stirrer

 

 

 

Figure 6. Reaction Apparatus

22

4. Decompgsition, Quenching, and Analyses

The lithio N,N—dimethylacetamide was prepared as described above.
After the enolate was stirred for 15 minutes, the reaction vessel was
warmed to 25 1’ 0. 5°. Periodically 0.5 ml aliquots were removed and
quenched inversely. A variety of queching reagents (2M HCl/HZO, 2M

HOAc/I-IZO, 2M HOAc/THF, 2H CH H, saturated NaZHPOh/HZO, 6M Hal/H20,

3303
glacial HOAc) were tested and in each case 1.1 equivalents of the
quenching reagent was used. Quenching with aqueous reagents resulted in
loss of the N,N—dimethylacetamide. Saturation with anhydrous potassium
carbonate recovered some of the amide, but not all. Saturation with
anhydrous magnesium sulfate was even less effective in recovering the
amide. The most successful quenching reagent found was 1.1 equivalents
of glacial acetic acid. The reaction mixture was then diluted with ethyl
ether, centrifuged, and was decanted to remove the lithium salt. The
reaction mixture was then analyzed using glpc with a Six foot by % inch
column. The column packing is crucial, since amides seriously tail on
common SE-BO and Carbowax columns (Chromosorb W). The most efficient
packing found was 3% Carbowax on neutral Chromosorb G. The only decompo-
sition product isolated was N,Nedimethylacetoacetamide fly This compound
was isolated with preparative glpc and a 1H NMR spectrum taken with a
Varian.T-6O Spectrometer.

N,Nrdimethylacetoacetamide -

I
00H23N(CH3)2 NHR(CC1,+): 63.38(S,2H), 62.90(s,6H), 66.LIv(s. 3H).

 

““3
H
%c=cncn(c1{3)2 mm(001u): clu.70(s,ln),55.00(s,1H),52-81(s.6H).

 

61.81+(s,3}{) .

23

5. Preparation of Lithio N,N-dimethylacetamide for NMR Analysis

A 0.5M solution (5.0 mmoles in 10 ml pentane) of lithium diisopro-
pylamide, in pentane at 0°, was prepared as described above. One
equivalent (0.48 ml, 5.0 mmoles) of N,N—dimethylacetamide was added dr0p-
wise at 0°. The white solid, lithio N,N—dimethylacetamide, started to
precipitate from the solution immediately. After the solution was
stirred at 00 for 15 minutes, the solvent and diisopropylamine were
removed under reduced pressure. The enolate was dissolved in 5 ml of dry
pyridine, and transferred with teflon tubing and N2 pressure to a nitrogen
flushed NMR tube. The NMR tube was immediately sealed. All NMR Spectra

were run on a Varian.T-60 NMR Spectrometer.

CHAPTER 2

REACTIONS OF AMIDE ENOLATES

24

INTRODUCTION

In Chapter 1 it was established that stable amide enolates could be
generated with lithium.diisopr0pylamide in.THF at 0°. The stability of

these enolates Should be a key factor in their synthetic utility.

9-12 ,

Several authors 17 have reported alkylation of various amide

enolates (eq. 16).

| ,0 base RX 0

l
turf-(N, <00 —- R-f-6(<N/ + Hbase (16)
l l

 

Each of the reported procedures employed temperatures below 0°. In
general, when.primary alkyl halides were used, yields were 75-85% of the
monoalkylated product. Reactive alkylating reagents, such as benzyl
halides and allyl halides, gave yields that ranged from 85-90%fl Yields
of alkylations with secondary alkyl halides were lower due to the compet-
ing elimination reactions.

Durst11

reported the condensation of several carbonyl compounds with
the enolates of substituted B-lactams. A variety of B-hydroxy and
8 -keto amides were prepared using acetone, benZOphenone, cyclohexanone,

and methyl benzoate (eq. 17).

25

26

 

 

 

 

H0
(CH ) d R R1
3 2 l ‘ R2
/ N
0’ ‘R
M... (17)
0 H R
u __ 1
00 R2
I— N
0’ \R

B -Hydroxyamides were also prepared by Seebach and Crouse17 from simple
N,N—dimethylamides ani a variety of aldehydes and ketones. Yields in
these reactions ranged from 5-50%. One exception was with benzophenone,
where the 8-hydroxyamide was produced in a 90% yield. The enolates of
these simple amides were generated using lithio s-trithiane at -20° (eq.
18).

O

)3 /—s n —20 [on
on + S ———-> CH =0 (18)
3<N(CH3)2 \—s)<1‘3L THF 2 ‘N(0H3)2

Although alkylation and condensation reactions with N,N—disubstituted
amide enolates have been investigated extensively, reactions with epOJddeS

ard Silylating reagents have been studied little (eq. 19).

O

 

 

 

’/
LiCI-I c

2 \

"(“92 R-m/flwz '2
/A+ :—
\ _ (19)
Li

’0 (CH3)331C1 ?

CH =0
2 \N(CH3)2

27

Two simple amide enolates have been prepared and silylated.18

Using
lithium diisoproplyamide as a base at -78° in THF, trimethylsilyl—N,N-
dimethylacetamide was prepared in a 78% yield (eq. 20). With N—acetyl-

aziridine the 0-silyl derivative was obtained in a 33% yield (eq. 21).

 

0 —78° (CH ) SiCl(TMCS)
CH C: + (l-Pr)2NLi —-——o- 3 3 f
3 N(C}13)2 THF
(20)
(CI-I ) SiCH c”0
3 3 2 \N(°*‘3)2
(78%)
/ -78° TMCS ,03i(cn )
01130( + (i-Pr)2NLi ———> ———... CH2=C\N 3 3 (21)

(33%)

Lutsenko and co-workers19 have reported the preparation of 0-tri-

methylsilyl-N,N-dimethylacetamide § using ketene and dialkylaminosilanes

 

(eq. 22).
_ o - ° Si CH
(0113)331N(cm3)2 + 0112=c=0 10 t E- 0H2=0<:(m:3):)3 (22)
§

They also reported the isomerization of the 0—Silyl amide § to trimethyl—

silyl-N,N—dimethylacetamide 2 (eq. 23).

 

0
cnzac’ Si<w3)3 = (0H3)33i0H20:’0 (23)
\N(CH3)2 . N(CH3 2

£3. 2

28

This isomerization occurs at room temperature after 2-3 days, or it can
be catalyzed by heat or by trimethylhalosilanes.

The objective of this investigation was to explore the reactions of
Simple amide enolates with various Silylating reagents and epoxides.
The reactions of lithio N,N-dimethylacetamide with alkylating reagents
and carbonyl compounds were also explored and the results compared with

previous investigations.

RESUDTS

Alkylation of Lithio N,Nedimethylacetamide

Lithio N,N—dimethylacetamide was prepared by drOpwise addition of
.N,Nrdimethylacetamide to a THF solution of lithium diis0pr0pylamide at
00 (eq. 2h).

0 0° 0
(313ch + (i-Pr)2NLi -———o Licnzc/f
(CH3)2 THF M01192
0 . 5M
,0Li (2n)

CH2=C\N(CH

3)2

This stable amide enolate was alkylated by adding an organic halide to a

THF solution of lithio N,N—dimethylacetamide at 0° (eq. 25).

4° 0° ,/0
LiCH20\ + RX -————-- R-cmzc\N (25)
N(CH3)2 mm (0}13)2
0 o m

Yields of these reactions varied, depending on the structure of the
alkylating reagent. Primary and reactive alkyl halides gave the best

results (Table 3). There was no evidence of any O-alkylated products.

29

30

TABLE 3

Alkylation of Lithio N,N—dimethylacetamide

 

 

0
L101! ’ + RX —o RCH CON(CH )
2 2 3 2
‘N(0H3)2
RX % Yielda
¢CfizBr 99%
CHBCHZCHzBr 90%
CHBI 62%
(CH3)2CHBr 26%

 

8‘ Yields determined by glpc

31
Reactions of Lithio I‘m-dimethylacetamide with Ketones and Aldehydes

Dr0pwise addition of ketones to a THF solution of lithio N,N-dimeth—

ylacetamide at 0° produced nearly quantitative yields of the correSpond-

ing B-hydroxyamides (eq. 26) (Table 3).

0 0 0o H+ 0H
LiCH c” + 5k —. ———. -c':—0H CON(CH )
2 \N(m3)2 m I 2 3 2 (2°)
0. 514

These reactions were complete within 15 minutes and were quenched with
two equivalents of glacial acetic acid. All products were identified
using 1H NMR and IR.

Under similar conditions, lithio N,N-dimethylacetamide reacted with
aldehydes to produce 60-70% yields of the B -hydroxyamides. Self-conden-
sation of the aldehydes was expected to be a competing reaction at this
temperature . Quantitative yields of the B -hydroxyamides were obtained
by dr0pwise addition of the aldehyde to a THF solution of the enolate at
-78° (eq. 27) (Table 1+).

0° 0K -78° 11" ?H

The reactions were quenched after 15 minutes at -78° with two equivalents

of glacial acetic acid.
Reactions of Lithio N,N—dimethylacetamide with Epoxides

The high stability of lithio N,N—dimethylacetamide is .shown by its

reactions with epoxides. Dr0pwise addition of pr0pylene oxide to a THF

32
TABLE h

Reactions of Carbonyls with Lithio N,N-dimethylacetamide

0 0H
II I
LiCH200N(CH3)2 + /c\—- -(ll—CH200N(CH3)2

 

jk % Yield

 

OW 97%

8
011300113 99%
8
0113011 98%
II
on CH CH 91%

 

33

solution of enolate at 0°, produced only negligible amounts of the

Y'-hydroxyamide (eq. 28).

0 25
LiCH c”° + \ 2 / (28)
2 ‘N(0H3)2 3

. CHBCHCHZFHZCON(CH3)2

(85%)

The temperature was increased to 250 and the solution was stirred for
longer periods of time with no substantial effect on the results. The
solution was refluxed for 3 hours, which led to an 85% yield of the de-
sired product. With the sterically more hindered cyclohexene oxide, the

‘r—hydroxyamide was produced in only a 57% yield (eq. 29).

LiCH 090 reflux (:::I::: CON(CH ) (29)
+ =
2 \N(CH3)2 [:::I:D ‘ 2 3 2

THF
(57%)

 

Both of the Y-hydroxyamides gave satisfactory elemental analyses and
their structures were confirmed by 1H NMR and IR. Attempts to isolate
products from the reaction of lithio N,Nedimethylacetamide with styrene

oxide by glpc were unsuccessful.
Silylation of Amide Enolates

Reacting a THF solution of lithio N,N—dimethylacetamide at 00 with
trimethylchlorosilane produced a mixture of C-Silyl (93%) and 0-Silyl
(7%) products (eq. 30).

34

0 0°
Lion2 <h(033)2 + (0H3)33101 -;;;—-' (0H3)35i00N(0H3)2 +
(93%)
OSi CH (30
CH2=C< ( 3)3 )
N(CH3)2
(7%)

To increase the amount of 0-silyl product, a bulkier Silylating
reagent was used. Use of t-butyldimethylchlorosilane altered the product
ratio in the desired direction, although C-silylation still predominated.
The yield of O-Silyl product was increased still further (75% O—silyl) by
adding hexamethylphOSphoramide to the reaction mixture (Table LI) .

Other simple amide enolates were Silylated in a similar procedure.
The results of these experiments are found in.Table 5.

C-silyl-N,Nedimethylacetamide is stable to dilute solution of acetic
acid. The stability of the silylamide was.tested by quenching THF
solutions with various quenching reagents. The silylamide is extremely
soluble in aqueous solutions. Saturation of the aqueous layer with
anhydrous potassium carbonate is necessary to recover the silylamide.
Quenching with dilute solutions of hydrochloric acid readily removes the
trimethylsilyl group and leaves N,N-dimethylacetamide as the major pro-
duct. Results of this study are found in Table 6.

In the preparation of C-silylamides 'the reaction mixtures were
quenched using a minimal amount of 1M acetic acid solution in H20. This
removed the O-silylamides and lithium chloride which are by-products of
this reaction. Using this procedure, trimethylsilyl-N,N-dimethylacetamide

was isolated in 80-85% yield.

35

TABLE 5

Silylation of Amide Enolates

 

 

Silylating Yields°

Reagent Amide 0-SilyI_—C-silyl
a

TMCS CH3C0N(CH3)2 7% 93%

TMCS CH300N(CHZCH3) 2 93%

T1408 CH30H200N(CH3)2 90% 10%

TMCS CHBCHZCH200N(CH3)2 99% 15;
b

TDCS CH300N(CH3)2 35% 65%

TDCS(HMPA) CH300N(CH3)2 75% 25%

TDCS CH CHZCON(CH3)2 99% 1%

3

 

a’Trimethylchlorosilane

b

tert-butyldimethylchlorosilane

c all yields are determined by glpc analyses

Quenching Studies of Trimethylsilyl-N ,N-dimethylacetamide

36

TABLE 6

 

 

Quenching Saturation a b
Reagent Reagent I II
H20 mm 0% 0%
H20 K2003 96% trace
1)! HOAc K2003 99% trace
2H HOAc K2003 99% trace
1)! H01 K2003 16% 83%
2!! H01 K2003 20% 78%

 

a
(0113)33i0H200N(0H

b
0113001“ch 2

3)2

37

The stability of O-silylamides has been tested using a variety of
quenching reagents. The 0-trimethylsilylamides are labile to both dilute
acetic and hydrochloric acids. A THF solution of 0-trimethylsilylamide
at room temperature was converted quantitatively to N,N-dimethylacetamide
using either dilute acetic or hydrochloric acids. The O—silylamides
were isolated by careful acidification at 0°, followed by distillation.

Solutions of 0-tert-butyldimethylsilylamides were quantitatively
recovered using dilute acetic acid. Quenching these solutions with dilute
hydrochloric acid converts the O-Silylamide quantitatively to N,N—dimethr
ylacetamide. These amides were isolated by a procedure similar to that

used for the C-silylamides.

DISCUSSION

Reaction of Lithio N,N-dimethylacetamide with Alkyl Halidesi‘Aldehydesi
Ketones and Epoxides

Amide enolates have previously been generated with a variety of

bases, in many different solvents, and at several different temperatures

These authors have also reported alkylations and condensations of amide

(eq. 32>.9'11- 17
| /0 I [0
/ + — reflux -+ - I
H-C-C + M Base -——————-5 M C-
I \N/ to -78° | c\f'{/ (32)

enolates with alkyl halides and carbonyl compounds (eq. 33).

0
I 0 I | 0
NFC-0” / 20K —<'3-cf'-c” (33)

/
—-2

II

With the exception of 2-bromopr0pane, yields of alkylation reported in
this work were found to be greater than or equal to those previously
reported. Yields found in this study and those reported by other authors

are presented for comparison in Table 7.

38

39

TABLE 7

Reaction of Lithio N,N-dimethylacetamide with Various ElectrOphiles

 

 

 

 

This Work

at 0: Literature Methods
Electrophile (Li enolate) g _b _q _d_
01131 62% 68% use 59% -_
CHBCHZBr -- 75% -- -- --
CI-IBCHZCHzBr 90% -- -- -- --
CHBCHZCHZCHéBr -- -- 5M5 Q5 .fi‘
(0119201132: 26% 75% 10% -- 86%
¢CHzBr 99% -- 53% -- --
0113000113 99% -- -- 80% --

92: -- —- 80x --
CHBCHO 98% -- -- -- --
CHBCHZCHO 91% -- -- -- 51%
a ref. 9 0 ref. 11 using B-lactams
b Using N,N—dimethylacetamide (1

ref. 10 ref. 17 yields before

purification - N,N—di—
methylacetamide

(+0

The poor yield found with 2-bromopropane was due to the competing
elimination reaction. Since substitution is favored at lower tempera—
tures, greater yields of alkylation with secondary alkyl halides could
possibly be obtained by lowering the temperature.

The high yields of B—hydroxyamides obtained in the reaction between
lithio N,Nédimethylacetamide and carbonyl compounds provides easily

accessible precursors to a variety of!!, 8 -unsaturated amides (eq. 3“).

OH

| 2 ‘N/ / ‘N/

l l
The preparation of 'Y-hydroxyamides by the reaction of lithio N,N-
dimethylacetamide with epoxides is unique and only possible due to the
enolates' stability at elevated temperatures. For example, the analogous
reaction between the ester enolate lithio t-butyl acetate and cyclohexene
oxide resulted in only 8% of the ‘Y-hydroxy ester 19 (eq. 35).21

25°(12 hrs.) (Imzcoz‘k (35)
’
Licnzcoz—f + 030 OR

toluene
IQ (8%)

 

The reaction mixture of lithio N,N—dimethylacetamide and styrene
oxide was refluxed for several hours and analyzed by glpc. There was no
evidence of any high boiling products or starting material. Attempted
recrystallization left only an oil. Attempted distillation of this oil

was unsuccessful.

#1
Reaction of Lithium Amide Enolates with Silylatipg Reagents

The reactions of ketone and ester enolates with trialkylhalosilanes
have been studied extensively. Ketone enolates have been found to

silylate exclusively on the oxygen to form trialkylsilyl enol ethers
21-26
(eq. 36).

on OSi(CH )
. 3 3

Ester enolates, on the other hand, silylate on either the carbon or

oxygen depending on the structure of the ester (eq. 37).27

\c ,031(0113)3

I
LitiCOzR + (CI-13)3 / -.=c:\0R

l
8101 _- (0H3)331<':00212 +

(37)

The ratio of 0 to C silylation.depends on the substitution at the alpha
carbon and on the substitution in the aloohol portion of the ester.

Hith lithio N,Nedimethylacetamide, Silylation occurs predominately
to form the more stable C—silylamide. Increasing the substitution at the
alpha carbon dramatically changed the ration of 0 to 0 products to
predominately 0-silylamide. This predominance of 0-silyl product is
attributed to the inaccessability of the alpha carbon of the enolate.

Changes in substitution on the nitrogen produced little change in
the ratio of 0- to c- silyl products (eq. 38). As with N,N-dimethyl-

acetamide, N,Nediethylacetamide produced predominately C-silyl product.

42

LiCI-IZCIIO ((313)33101 ——o CH2: :081(CH3)3 +
\"(02H5)2 N(02”5)2
(7%)
(’0
(0H3)3310H2 \N(CZH5)2 (38)
(97%)

With ester enolates, a similar trend occurs. As R becomes bulkier, the

product ratio changes to favor the C-silyl ester (eq. 39).

 

TMCS A ,03i (c313)3
LiCHZCOZR r (0H3)33i01120023 + CH2=C\OR
3 (39)
Hill (99%) (1%)
Et (“5%) (55%)

In conclusion, substitution at the a-carbon of amide enolates
favors formation of 0-silylamides, while substitution on the nitrogen

favors C-silylamides.

EXPERIMENTAL

1. Materials

Alkyl Halides

All of the alkyl halides were commercially available and were used
without further purification.
Carbonyl Compounds

All of the aldehydes and ketones were obtained commercially and were
used without further purification.
Amines, Acid Chlorides, THF, and n-Butyllithium

The diisoprOpylamine, obtained from Aldrich Chemical Company, was
distilled from calcium hydride and stored under nitrogen. The anhydrous
dimethylamine and acid chlorides were obtained commercially and used
without further purification. The THF was distilled from sodium benzo—
phenone and stored under nitrogen. The n-BuLi was obtained from Aldrich
as a 1.6M solution in hexane and was used without further purification.
SilylatingrReagents

The trimethylchlorosilane, obtained from Aldrich, was distilled and
stored under nitrogen. The t-butyldimethylchlorosilane was prepared as
described by Corey, et. al.20 This silane was used as a 3.6M solution in
pentane.
Epoxides

The pr0pylene oxide and cyclohexene oxide were obtained commercially

and were used without further purification.

“3

inure
N,Nrdimethylacetamide, which was obtained commercially, was distilled
and stored over molecular sieves. The other N,N-dimethylamides were
prepared by the following representative procedure. In a three-necked,
500-ml round-bottomed flask, fitted with a constant addition funnel, a
reflux condenser, and a magnetic stirrer, was placed 200 ml (3.0 moles)
of anhydrous dimethylamine and 500 ml of benzene. This solution was
cooled to 0° and 86.u ml (1.0 mole) of propanoyl chloride was added drop-
wise through the addition funnel. After all of the acid chloride had
been added, the reaction mixture was allowed to stir for one hour. Water
(100 ml) was added and the mixture was extracted with chloroform. The
organic layer was separated and dried over anhydrous potassium carbonate.

The solvent was removed and the N,NedimethylprOpanamide distilled.
2. Alkylation of Lithio N,Nrdimethylacetamide

Alkylation with benzyl bromide will be representative of all alkyla-
tion reactions. A 50-ml round-bottomed flask, with septum inlet and gas
inlet valve (see Figure 6), was flame-dried, and flushed with nitrogen.
The flask was charged with a 0.5M THF solution containing 2 mmoles of
lithio N,Nedimethylacetamide as described in Chapter 1. This solution
was cooled to 0° and 0.26 ml (2.2 mmoles) of benzyl bromide was added
dropwise. The reaction mixture was left to stir for 30 minutes at room
temperature. This was followed by the addition of pentane, filtration of

the lithium bromide, and analysis by glpc.

45

3. The Reaction of Ketones with Lithio N,N—dimethylacetamide

 

The procedure for the reaction with cyclohexanone will be repre-
sentative. A 50-ml round-bottomed flask (see Figure 6) was flame-dried
and flushed with nitrogen. A 0.5M solution of lithio N,N—dimethylaceta-
mide (2 mmoles) in.THF was prepared as described in Chapter 1. This
solution was cooled to 00 and 0.22 ml (2.2 mmoles) of cyclohexanone was
added dr0pwise. The reaction mixture was left to stir for 15 minutes at
room temperature. After being stirred, the reaction was quenched with
0.22 ml (4.0 mmoles) of glacial acetic acid and diluted with ethyl ether.
The lithium acetate was removed by filtration and the product was

analyzed by glpc.
4. Reaction of Aldehydes with Lithio N,N~dimethylacetamide

The procedure is identical to the reaction with ketones except that
the aldehyde is added dr0pwise at -78° and stirred for 15 minutes. The

solution was then quenched at —780 and warmed to room temperature.

5. Reaction of Epoxides with Lithio N,N-dimethylacetamide

 

The reaction between propylene oxide and lithio N,Nedimethylacetamide
will be representative. A 0.5M solution containing 2 mmoles of lithio
N,Nedimethylacetamide in.THF, was prepared in a 50-ml round-bottomed
flask (Figure 6) as described in Chapter 1. The reaction flask was fitted
with a reflux condenser with a gas inlet valve at the t0p. To this
solution was added 0.15 ml ( 2.2 mmoles) of propylene oxide. The reaction
mixture was refluxed for three hours, cooled to room temperature, and
quenched with 0.22 ml (4.0 mmoles) of glacial acetic acid. The lithium

acetate was removed by filtration and the product was analyzed by glpc.

46
6. Silylation of Lithium Amide Enolates

The following procedure for the preparation of trimethylsilyl-N,N-
dimethylacetamide is representative of the general technique. A solution
of 5.0 mmoles of lithio N,N—dimethylacetamide in THF was prepared as
described in Chapter 1. This solution was cooled to 0° and 0.70 ml (5.5
mmoles) of trimethylchlorosilane was added dronise. The reaction
mixture was allowed to warm to room temperature and stir for 30 minutes.
This was followed by dilution with 5 ml of ethyl ether and extraction of
the lithium chloride with 1 ml of 6% HOAc. A minimal amount of aqueous
acid must be used since the product is extremely soluble in aqueous
solutions. The organic layer was separated and dried with anhydrous
KéCOB. Glpc analysis (6 foot column -23% Carbowax on Chromosorb C) of the
organic layer indicated 93% of the C-silylamide.

with 0-silylated products, the reaction mixtures were quenched at 0°

with an equivalent amount of cold, dilute acetic acid.
7 . _lfiroduct Analyses

All 1H NMR spectra were taken on a Varian.T-60 spectrometer. The
IR Spectra were recorded on a Perkianlmer Model 237B Grating Infrared
Spectrophotmeter. The elemental analyses found in Table 8 were done by
Spang Microanalytical Laboratory, Ann Arbor, Michigan.

N,Nrdimethylacetamide

BP165°. (0.937 8/m1)- M(CCI,,): 62.97(s.3H).62.77(s.3H).

61.93(s,3H).
3+Phenyl-N,N-dimethylpropanamide

NMR(CClu)I 67.3(s,5H), 62.8(s,6H), 62.8(t,2H), 62.4(t,2H).

47

N IN—dimetgylpentanamide
31> 62° (0.7 mm). (0.913 8/m1)- Mme”): 52.97(s.3H).
62.87(s,3H), 62.33(t,2H), 61.47(m,4H), 61.00(t,3I-I).

N N—dimet 1 ro de
3? 46° (2 mm). (0.957 g/ml). NMR(CClu)I 62.93(s,3H). 62.84(s,3H),
62.17(q.2H), 61.03(t,3H). _—

3-Methyl-N ,N—dimethylbutanamide

 

3? 75° (0.9 mm). mama“): 62.9l(s,3H), 62.81(s,3H), 62.0(d,2H),
62.0(m,lH), 60.90(d,6H).
2- l-H cyclohexylL- N,N-dimethylacetamide
NMR(CC1,+)I 64.43(s,lH), 52.93(s.3n), 62.89(s,2H), 62.17(s,2H),
61.50(m,10H). “(“14)“ 3420 cm'1(0—H), 1635 cm'1(C=0).
3-Hydr03q-3-methyl-N ,N_—dimethylbutanamide
mama“): 64.54(s,lH), 62.94(s,3I-I), 62.86(s,3H), 62.24(s,2H),
61.l7(s,6H), 13(001u): 3450 cm'1(0-H), 1635 cm’1(0=0).
3—Hydroxy-N ,N-dimethylbutanamide

NMR(CCl 64.0(m,lH), 63.74(s,lI-I), 62.95(s,3H), 62.86(s,3H),

4)‘
62.27(t,2H), 61.07(d,3H). IR<°°14)’ 3480 cm'1(0-H), 1650 cm’1(C=0).

knydrpg-Nm-dimethyppentamide
lumen“): 83.87(s,1n), 63.52(m,lH), 62-93(s.3H), 62.84(s,3H),
62.24(d,2H), 61.37(m,21-I), 60.90(t,3H). 111ml“). 3475 cm’1(0-H),
1640 cm’1(c=0).

magma-N,N-dimethvlpentanamide
NMR(CClu): 63.57(m,1H), 63.10(s,lH), 62.97(s,3H), 62.83(s,3H),
52.33(t,2H), 61.67(m,2H), 61.10(d,3H). IR(CClu): 3425 cm'1(0—H),
1640 cm’1(c=0).

48

2:(2-Hydroxycyclohexyl)-N,N-dimethylacetamide
NMR(CClu): 62.97(s,3H), 62.83(s,3H), 62.77(m,lH), 62.40(d,2H),
61.0-2.1(m,9H).
2-Trimethylsilyl—N,Nrdimethylacetamide
NMR(CClu): 62.87(s,3H), 62.73(s,3H), 61.3o(s,2H), 60.07(s,9H).

' OSi(CH )
CH CH=C’ 3 3

3 \
N(CH3)2
NMR(CClu)I 63.50(q.lH), 62.40(s,6H), 51.43(d,3H). 60.l7(s,9H).

IR(CClu): 1660 cm?1(c=c).

CH
I 3
IOSi-C(CH3)3
3

CH2=C\ CH
N(033%

 

NMR(CC1u): 62.77(m,2H), 62.43(s,6H), 60.87(s,9H), 60.13(s,9H).
13(0014): 1640 cm71(C=c).

I3 /0

(CH ) C iCH C’

3 3 2 \
3H3 N(CH3)2

 

NMR(0014): 52.93(s.3H). 52.83(s.3H). 61.83(s.2H). 60.93(s.9H).
60.07(s.9H)- IR(CClu)I 1630 cm31(c=0).

CH
0-812C(CH )
CH30H=C’ l 3 3

3
M0113)2

 

NMR<cc1g): 63 50(q.1H). 62.37(s.6H). 61.43(d.3H).Iso.97(s.9H).
60.l3(s,9H). IR(CClu)I 1665 cm'1(C=C).

49

,03i(CH3)3
CH30R20H=C\
N(CR3)2

NMR(CClI+)I 63.57(t,lH), 62.5(s,6H), 61.42(m,2H). 61.01(t,3H),
60.27(s,9H).

.smwacodz .HopH4 ss< .hnopmnonmq Hmoaphamcdouoa: madam an eosuomnom m

 

and. sees ass as 3.2 are Namsvzaasesseswmae
mo

in

 

 

 

n+1. rm. S 8.8 on: :02 8.8 «AmrovzmmroHU
mo
we we we mlz .. we 8
downbeanogwm Hmoavowoona

 

moofis< axoneamI» 2oz mo mmomhame< HmPSoSon

m mnm<9

CHAPTER 3

REACTIONS OF SILYLATED AMIDE ENOLATES

51

INTRODUCTION

Lithio t-butyl trimethylsilylacetate 11 has been prepared by addi-
tion of t-butyl trimethylsilylacetate to a THF solution of lithium diiso-
propylamide at --780 (eq. 40).27

.780
(CH3)331CH 2°°§+' + (itPr)2NL1 -—3THE—. (CH 3)381§§°°§+' +

11 (40)

(i-Pr)2NH

Attempts to isolate ll were unsuccessful, but THF solutions of the enolate
are stable indefinitely at -78 0.27 Lithio t-butyl trimethylsilylacetate,
when treated with carbonyl compounds in.THF at -780 , produces a, B -

unsaturated esters in very good yields (eq. 41).27

E -78° H+ \
(CH ) SiCHCO + _. .._.. C=CH00
3 3 Li 5+- ’ \ THF / 2+ (41)

(92-98%)

The fermation of these a, B -unsaturated esters is thought to occur via
an elimination of lithium trimethylsilyl oxide at -78° prior to quenching
(eq. 42).27

0:0

I \
(CH3)331§11100§{- + / \- - -(|3HCO§+- —> /C=CH00§|- + LiOSi(CH3)3
Li0 Si(CH )
3 3
(42)

52

53

The purpose of this study was to deve10p a general procedure for the
preparation of lithio trimethylsilyl—N,N-dimethylacetamide and to inves-

tigate its stability and its structure, by NMR (eq. 43).

Li

(CH3)381CH200N(CH3)2 + (i-Pr)2NLi ——- (CHB)BSiCHCON(CH3)2

(43)

Reactions between lithio trimethylsilyl-N,N—dimethylacetamide and
carbonyl compounds were investigated with the hope of observing an elim-

ination reaction similar to that found with the analogous ester enolates
(eq. 44).

Li a

(CH SiCHCON(CH3)2 + /C\

) —->\C=CHCON(CH ) + LiOSi(CH
3 3 / 3 2

3)3
(44)
Since the 1,2 elimination of lithium trimethylsilyl oxide is extremely
facile in the reaction between silyl ester enolates and carbonyl come
pounds, lithio trimethylsilyl-N,N—dimethylacetamide was treated with
epoxides with the hope of forming cyc10pr0pane derivatives via a 1,3

elimination of lithium trimethylsilyl oxide (eq. 45) .

L1 /°\
(CH3)35iCH00N(CH3)2 + IICH-CH2 —9 HcliHCHzc':H00N(CH3)2 ——>

LiO Si(CH3)3
(45)
IICH—;CHC0N(CHB)2 + Li03i(CH3)3

2

Reactions between lithio trimethylsilyl-N,N-dimethylacetamide and

various carboxylic acid derivatives were also studied.

RESULTS

Preparation and Stability of Lithio Trimethylsilyl-N,N-dimethylacetamide

Since lithio N,N—dimethylacetamide can be generated quantitatively,
at 00 in THF, using lithium diisopropylamide (eq. 46), it seemed reason-
able to attempt to generate the enolate of trimethylsilyl-N,N—dimethyl-

acetamide by a similar procedure.

0

0 Ion
CH300N(CH3)2 + (i-Pr)2NLi THF—’ CH2=C\N(CHB)2 (46)

Treatment of trimethylsilyl-N,N—dimethylacetamide in THF at 00 with
lithium diisopr0pylamide produced lithio trimethylsilyl-N,N—dimethyl-
acetamide quantitatively (eq. 47).

0

Li
(CH3)BSiCHZCON(CH3)2 + (i-Pr)2NLi -;H—F—- (CH3)381CHCON(CH3)2

(47)
+ (i-Pr)2NH

The stability of a THF solution of silylamide enolate was tested by
stirring for 93 hours at room temperature. After 93 hours of stirring,
the solution.was quenched with two equivalents of glacial acid and 92% of

the starting amide was recovered (eq. 48).

55

< ) Li ( ) 2 5°/THF H"' < )
CH SiCHCCN CH = ——+ CH
3 3 3 2 93 hours 3 3

 

SiCHzCON(CI-I3)2

(92%) (48)

In search of a more convenient method, a THF solution of trimethyl-
silyl-N,N-dimethylacetamide was treated at 00 with n—butyllithium. Lithio
trimethylsilyl—N,N—dimethylacetamide was generated quantitatively and was

found to be stable for several hours (eq. 49).

0° Li 25°
(CH3)BSiCH200N(CHB)2 + n-BuLi Tm?” (CH3)BSiCHCON(CH3)2 m
+
____.. (w3)331m200N(m13)2 (49)

2 (89%)

After 35 hours at 25°, 89% of the silylamide 2 was recovered. Generation

of lithio N,N-dimethylacetamide, using n—BuLi, was not quantitative (eq.

50)-

O

0 THCS
CH3C0N(CH3)2 + n-BuLi Tm? —. (w3)381m2mn(w3)2
(56%) (50)

The 1H and 13C Spectra of Lithio Trimethylsilyl-N,Nédimethylacetamide

Using pentane as a solvent instead of THF, lithio trimethylsilyl-
N,N—dimethylacetamide was formed as an insoluble white solid. Removal
of the solvent under reduced pressure provided the Opportunity to study
the structure of the silylamide enolate using 1H and 13C NMR. The solid

amide enolate was dissolved in dry pyridine, transferred to an NMR tube,

56

and sealed under a nitrogen atmosphere. The 1H NMR chemical shifts for
lithio trimethylsilyl-N,N-dimethylacetamide and trimethylsilyl-N,N—
dimethylacetamide are found in Table 9. The same samples used in the

1H NMR experiments were also used in 13C NMR samples. The data obtained
from 130 NMR spectra of lithio trimethylsilyl-N,N—dimethylacetamide and

trimethylsilyl—N,N-dimethylacetamide are found in Table 10.
TABLE 9

1H Chemical Shifts for Lithio Trimethylsilyl-N,N-dimethylacetamide in
Pyridinea'

 

5
a. 0.13(s,9H)
(CH3)3SiCHZGON(CH3)2 b. 1.96(s,2H)
a. be Co&do c. 2.73(S,3H)
d. 2.80(s,3H)
3'- 0.33(S,3H)
Li
(CH3)3SiCHGON(CH3)2 b. 2.9o(s,1H)
a. b' c. c. 2.76(s,6H)

 

a All NMR data was obtained on a Varian T-6O NMR Spectrometer

130 Chemical Shifts for Lithio Trimethylsilyl-N,N—diemthylacetamide

57

TABLE 10

a,b

 

(m3)331CI{ZCon(CI{3)2
a. b. c. d.& 6.

Li
(CH3)BSiCHCON(GHB)2
a. b. c. d.

13222222

a. 0.58
b. 25.05
c. 171.28
d. 3h.95
e. 38.32
212292

a. 2.12
b. 59.03
c. 173.58
d. 39-57

313mm:
0 . 56
2n . 67
171 .10
3h.u6
37 . 72

 

a All chemical shifts are in.parts per million (ppm) from.TMS

b

All Spectra were obtained on a Varian OFT-20 Spectrometer

58
Reaction of Lithio Trimethylsilyl-N,N-dimetmglacetamide with Epoxides

A solution of lithio trimethylsilyl-N,N—dimethylacetamide in THF at
0°, was treated with one equivalent of prOpylene oxide. The reaction
mixture was warmed to room temperature, stirred for two hours, and then
quenched with 1.1 equivalents of glacial acetic acid. This resulted in

72% of the silylated Y-hydroxyamide _1_g (eq. 51).

( ) Li ( ) /°\ 0° 1m. H+
CH SiCHCON CH + CH CH-CH —-—> ——-' ---
3 3 3 2 3 2 THF 1 hour
(CH3)3510 (51)
CH3ww2m2mn(m3)2

12

There was no evidence of the desired cyclopmpane derivative l} in the

reaction mixture (eq. 52).

/GH2 \ /CH2\
CH CH CHCON(CH3)2 ;,’ » CHBCH—CHOOMCH3)2

 

L10 31(“35 ll (52)

The silylated Y-hydroxyamide _]_._2_ was identical to the product found when
lIr—hydroxy-Nm—dimethylacetamide was treated with triethylamine and tri-

methylchlorosilane (eq. 53).

0H 0
| 0
CHBCHCHZCHZCON (C113) 2 + (CH3)331C1 W CHBCFICHZCHZCON(CH3) 2

3 OSi(0H3)3

L2. (53)

59

Refluxing the reaction mixture did not increase the yield of 12 nor did
it produce the cycloproPane._3. Attempts to prepare l} by treating the
Silylated ‘Y-hydroxyamide £2 with lithium diisoprOpylamide under reflux

were unsuccessful (eq. 5h).

00 reflux
CIch':}ICHZCH200N(CH3)2 + (i—Pr)2NLi —T-H—Fv —. N.R.
(CH3)3310
(54)

When styrene oxide was treated with lithio trimethylsilyl-N,N-dimethyl-

acetamide, the major product was the Y-hydroxyamide‘lg (eq. 55).

.1..

Li ,,0\ 25° H
(CH3)3SiCHCON(CH3)2 + 0 —CH2 ——THF> —+ ¢CHCHZCH200N(CH3)2
OSi(CH3)3
(55)
lg

Reactions of Lithio Trimethylsilyl-N,Nedimethylacetamide with Aldehydes
and Ketones

Addition of cyclohexanone to a solution of lithio trimethylsilyl-
N,N-dimethylacetamide in.THF at 0° provided the a, B -unsaturated amide

Ilj in high yield (eq. 56).

Li 0° 15 min. H+
(9M%) .15 (56)

Following addition of the ketone the reaction mixture was warmed to 250
and stirred for 15 minutes. The reaction mixture was quenched with 1.1

equivalents of 1M acetic acid.

60

Addition of acetone to a THF solution of lithio trimethylsilyl-N,N-
dimethylacetamide at 0°, resulted in 86% of the corresponding 0 , B -

unsaturated amide (eq. 57).

00 CH

Li "
SiCHCON(CH3)2 + CH CCH __. /\C=CHCON(CH

(CH 3 3 THF

3)2
CH.
3 (86%) (57)

3)3

When acetone was added at -78°, the yield was increased to 9M%.
In a similar reaction, at either 00 or -78°, pr0panal and acetalde-
hyde gave negligible yields of the a, B -unsaturated amides (eq. 58).
00 or ~78°

Li
(CH3)BSiCHCON(CH3)2 + RCHZCHO Hi, CH3 :- RCHZCH=CHCON(CH3)2

K1096) (58)

 

Major amounts of the starting material and aldehyde condensation products

were observed in each case.

‘figaction of Lithio Trimethylsilyl-N,NedimethylacetamideAwith.Esters and
Acid Chlorides

Treatment of lithio trimethylsilyl-N,N-dimethylacetamide with ethyl
acetate and phenyl acetate at both 00 and -78°, resulted in two minor

products (3 a gig) and the starting silylamide (eq. 59).

 

Li 0° or -78° 25°
CH SiCHC0N CH + CH 00 R a _—.
( 3) ( 3)2 3 2 THF several
hours
(59)
CH gen @MCH ) C=CHC0N(CH
3 2 3 2 + CH3!) 92

R
g 16

61

Each of these products were identified by 1H NMR.
Addition of acetyl chloride to a THF solution of lithio trimethyl-
silyl-N,Nedimethylacetamide provided results similar to the above. Two

minor products (12 &‘Q) and major amounts of the starting material were
observed (eq. 60).

 

00 or —780
(CH3)BSiCHCON(CH3)2 + CH300C1 m w CH300N(i-Pr)2
.11
a u (60
+ CHBGCHZCN((IHB)2 )
.9.

Reactions of Lithio Trimethylsilyl-N,fl-dimethylacetamide with.Amides

Addition of N,Nedimethylacetamide to a solution of lithio trimethyl—
silyl-N,N—dimethylacetamide in.THF, followed by two hours of reflux gave
68% of the enamino amide 189 (eq. 61).

Li 66° (CH3)2N
(CH3)3SiCHCON(CH3)2 + CH300N(CI-13)2 /C=CHCON(CH3)2
CH
3
(sec) _1_8_e (61)

Longer periods of refluxing did not increase the yield of the enamino
amdde. The structure of the enamino amide was determined by NMR, IR,
elemental analysis (see experimental section) and the following indepen—
dent synthesis. Diketene was added dr0pwise to a solution of dimethyl-

amine in ethyl ether at -20° to produce the B-keto amide 3 (eq. 62).

62

49 0 0
CHE—C -20 u u
I + (CH ) NH —» CH CCH CN(CH )
3 2 ether 3 2 3 2
—-0 (62)
/ L»

This amide was stirred with dimethylamine in ether in the presence of

molecular sieves to generate the enamine 189 (eq. 63).

 

R a 00 (CH3)2N
CH CCH GN(CH ) + (CH ) NH ; \C=CHCON(CH )
3 2 3 2 3 2 molecular ’/ 3 2
sieves CH3 (63)

18b

The NMR and IR Spectra of 18% and 182 were found to be identical.
Table 11 lists other enamino amides which were prepared from lithio
trimethylsilyl-N,Nedimethylacetamide and a variety of N,Nedisubstituted

amides using a procedure similar to that described above.
Reactions of Enamino Amides

The enamine portion of the molecule was quantitatively hydrolyzed

after 5 minutes of stirring with 1.1 equivalents of 6H HCl (eq. 61»).

(CH ) N 0 0
3 2 \ 0 u n
C=CHO0N(CH ) + 6M HCl ——9 CH CCH CN(0H ) (6+)
01/ 3 2 M 3 2 3 2
3 E, (100%)

The B-keto amide 3 was identified using glpc and 1H NMR.
Several attempts were made to generate the enolate 12 of the enamino

amide using lithium diisoproplyamide in THF at -78° (eq. 65) .

63

TABLE 11

Yields of Enamino Amides

 

 

Li (CH ) N
3 2
(CH3)38101{00N(CH3)2 + R00N(CH3)2 ——-o R/C=CHCON(CH3)2
Amide Enamino Amide Yield
(0113),;
H00N(CI{3)2 /C=CH00N(CH3)2 65%
H
(on )2"
CH300N(CH3)2 /C=CHCON(CH3)2 68%
CH
3
(any;
CH30H200N(CH3)2 C=CH00N(CH3)2 65%
CHBCHZ
(any;
CHBGHZCHZCON(GR3)2 /C=-GH00N(CI~13)2 he:
CHBGHZCHZ
0‘" GM
N 40%
‘CH N\
3 CH

3

 

(CH3)2N\ l0 78o (CH3)2N\ [H
C=CHC + (i-Pr) NM ———> 0:0
/ \ 2 THF / ' "'.\
CH N(CH ) CH‘ - .=
Li+ 3 2
_1_§ 12 (65)

Addition of the enamino amide 18 to a THF solution of lithium diisopropyl—
amide at —78° resulted in the formation of a yellow solid. This yellow
solid dissolved upon warming, but reprecipitated when the solution was
cooled back to -78°. The reaction mixture was quenched at -78° with
trimethylchlorosilane in an attempt to silylate the possible enolate.
After the solution was quenched, it was analyzed using glpc and a product
with a longer retention time was found. All attempts to isolate this
product were unsuccessful and led to only starting material.

The reaction mixture containing the yellow solid was also quenched
with t-butyldimethylchlorosilane. Analyses using glpc indicated no major
products were formed. Attempts to alkylate the enolate 12 with methyl
iodide were also unsuccessful.

Addition of allyl bromide to a solution of the enamino amide 18 in

acetonitrile, refluxed for one hour. resulted in the alkylated B-keto-

amide g9 (eq. 66).

(6392“ CHBCN H20
C=CHCON(CH3)2 + CH2=CHCH2Br __. __..
CHl/ reflux reflux
3
(66)
CH CCHgMCH)
3 3 2
2CH=CH2

20

65

After the reaction mixture was refluxed for one hour, two equivalents of
water was added and the mixture was refluxed for an additional half-hour.
The organic layer was dried, analyzed using glpc, and the product
identified by its 1H NMR spectrum.

Attempts to extend the enamino amide function by refluxing the

enamino amide 18 with lithio trimethylsilyl N,N—dimethylacetamide were

unsuccessful (eq. 67).

 

L1 (CH3)2N reflux
(CH3)3SiCH00N(CH3)2 + /C=CH00N(CH3)2 ,1 ,1 4
CH
3
is
6
\N’ \N’ ( 7)

I I ’
(1}I3C=CHC=GI-IGON(CH3)2 + LiOSi(CH3)3

DISCUSSION

Preparation and Stability of Lithio TrimethylSflJl-N,N-dimethylacetandde

It has been found that the enolate of trimethylsilyl-N,Nedimethyl-
acetamide can be generated quantitatively using lithium diisopropylamide

or nebutyllithium (eq. 68).

 

THF, 0°
(i-Pr)2NLi or Li
(0113)3510H2001v(C113)2 mm“ : (Cli3)3$imicon(m{3)2
(100%) (69)

Use of either of these bases provides an enolate which is stable for
several hours. It is not surprising that lithio N,Nedimethylacetamide

cannot be generated quantitatively using n-BuLi in a similar procedure
(eq. 70).

0° THCS
CH300N(CH3)2 + n-BuLi E‘ T (CH3)331CH200N(CH3)2

(55%) (70)

Without the bulky trimethylsilyl substituent at the alpha position, one
would expect nucle0phile attack at the carbonyl carbon to occur quite
readily (eq. 71).

 

Co on
CH300N(CH3)2 + n—BuLi m : CH3(i£-N(GH3)2 (71)
Bu
_2;

66

67

No attempt was made to isolate or identify this 1.2 addition product 21.
The major difference between the two methods for preparing lithio
trimethylsilyl-N,Nedimethylacetamide is convenience. With n—butyllithium,
one less reagent is used and several steps are avoided. The n—butyllith—

ium procedure was used to generated the enolate of trimethylsilyl—N,N-
dimethylacetamide in the reaction with ketones and amides. Yields were
comparable to those obtained when lithium.diiS0propylamide was used as the
base.

The lannd 13C NMR Spectra gf_Lithi9 TrimethylSilyl1H,N-dimethylacetamide

The enolate of trimethylsilyl—N,N—dimethylacetamide can be thought

of as having either an oxygen metalated g; or a carbon metalated g3

structure.
,oLi Li
(CH3)BSiCH=C\N(CH ) (CH3)3810HGON(CH3)2
3 2
2?. .22

The spectra of lithio trimethylsilyl-N,Nedimethylacetamide are somewhat
more difficult to interpret than the Spectra of lithio N,Nedimethylaceta-
mide, since the enolate does not have a pair of alpha protons. With a
pair of alpha protons, coupling would be expected in the 0-metalated
'Structure, but not in the C-metalated structure.

Evidence for an 0-metalated structure can be found by studying the
absorptions of the methyl substituents on the nitrogen. As in the spec-
trum of N,Nedimethylacetamide.§, the spectrum of trimethylsilyl-N,N-

dimethylacetamide 2 indicates two non-equivalent methyl substituents.

,0

CH C’ (CH )3 SiCH2 ((0
3 ‘1': CH3 62. 97 33 “EH/CH3 62. 80
CH3 52.77 CH3 62.73
.6. 9

In the enolate of trimethylsilyl-N,N—dimethylacetamide it would be ex-
pected that these methyl substituents would be equivalent in the O-meta-

lated structure 22 and non-equivalent in the C-metalated structure 23.

( ’0Li L1 0'
CH ) Si-CH=C CH (CH ) 810- -C’\
3 3 \N 3 equivalent 3 3 H + N ’CHB non-
l equivalent
CH CH
3 3
_2_2 .22

Since the proton NMR Spectrum of lithio trimethylsilyl-N,N-dimethylaceta-
mide reveals a sharp singlet at 6 2.76, the O-metalated structure 22 is
assigned.

Additional evidence is provided by the data obtained from 13C NMR
experiments. As is the case with lithio N,N-dimethylacetamide 8, the N-
methyl substituents on the enolate of trimethylsilyl-N,N-dimethylacetamide

22 were found to be equivalent.

,oLi ,0Li
CH2=C\N/CH3 (CH3)33iCH=C [CH3
gm 6 39.53 CH 6 39.31»
3 3
g 22

This can be compared to N,N-dimethylacetamide 6 and trimethylsilyl—N,N—

dimethylacetamide 2 where the N-methyl substituents are non-equivalent.

69

’10 ( ) C40
CH3°\N/CH CH3 3SiCH2 \N’CH
' Mme.afléo ' 5%A6
CH3 CH3 637.72

lax
Ixo

Reactions of Lithio Trimethylsiljl-N,N—dimethylacetamide with Ketones and
Aldehydes

Treatment of trimethylsilyl-N,N-dimethylaoetamide with n—butyllithium
provides a convenient pathway to the silylamide enolate. This silylamide
enolate readily condenses with ketones to form a , B -unsaturated amides
in high yields (eq. 72).
0

Li
H
(CH3)BSiCH00N(CH3)2 + l’c\\

0° H \
—. —-* /C=CHCON(CH3) 2 (72)

(86—9M5)

This method for preparing a , B -unsaturated amides is particularly advan-
tageous since only the a , B -unsaturated isomer is formed and none of the
B ,Y -unsaturated isomer. The usual synthesis of a , B -unsaturated car-
bonyl compounds28 involves acid-catalyzed dehydration of the 8 -hydroxy-
carbonyl compound. This procedure also leads to varying amounts of the

B . Y -unsaturated compound.

The formation of O , B -unsaturated amides can be realized through
the elimination of lithium trimethylsilyl oxide (eq. 73).
00
I \
-C—CHCON(CH ) -—-——- C=CHO0N(CH ) + LiOSi(CH ) (73)
32 Tm / 32 33
L10 Si(CH3)3

The ease of this elimination has been well documented in the reaction

7O

2
between lithium benzyltrimethylsilane and benzophenone (eq. 74), 9 and
also in the reaction between lithio t-butyl trimethylsilylacetate and

carbonyl compounds (eq. 75).27

fl hexane H\ [H .
(CH3)331?HL1 + ¢-C—¢ ':E;;;:" ¢/C=G\ + L1051(CH3)3
(7h)

Li -78° +
(CH3)BSiCH00§{- + / \ fr; /C=CH002 + L1031(CH3)3 (75)

0:0

With aldehydes, large amounts of starting silylamide and aldehyde
condensation products were observed. This is probably because the rate
of self—condensation of the aldehyde is greater than the rate of conden-
sation between the silylamide enolate and the aldehyde. With ketones,
self-condensation is less competitive since ketones are sterically more
hindered.

Reactions of Lithio Trimethylsilyl-N,N—dimethylacetamide with Simple
N,N-dimethyl Carboxylic Acid Amides
Refluxing a THF solution of lithio trimethylsilyl—N,Nedimethylaceta-

mide with simple N,N-dimethyl amides provides a convenient pathway to sub-

stituted enamino amides g5» (eq. 76).

Li reflux (CH3)2N
(CH3)35iCHC0H(CH3)2 + RCON(CH3)2 7F /C==CHCON(CH3)2
.2}: (76)

The formation of these enamino amides can be visualized as an attack on

the amide by the silylamide enolate, followed by the elimination of lithium

71

trimethylsilyl oxide (eq. 77) .

Li+
.. 9° slow Li? S."i(°H3)2 fast
(CH3)BSiCI-ICON(CH3)2 RC\ ———- HC-CHC0H(CH3)2 -—+ g
N CH
N<CH3)2 ( 3)2 (77)

Since the elimination step has been found to be fast, one would expect
that the required vigorous reaction conditions are necessary to force the
hindered enolate to attack the carbonyl function of the amide. Refluxing
of the solution of enolate is only possible when the enolate is very
stable, as is the case with lithio trimethylsilyl-N,N-dimethylacetamide.
Several authors have reported the preparation of enamino esters.

These methods involve addition of a secondary amine to B -keto esters
(eq. 78) 030,31

R R
a a -H o \N/
CHBCCHZCOR + RZNH —2—- CH30=CH00R + H20 (78)

An attempt was made to prepare enamino amides in a similar manner.
Treatment of the B -ketoamide 3 with dimethylamine at 0°, produced the

enamino amide _l_§ (eq. 79).

o CH3\N,CH3
u u 0 ,
_. _
CH30m20N(CH3)2 + (CH3)2NH ether CHBC—CHCON(C}I3)2
.1! molecular sieves .129. (79)

There are two disadvantages to this method. Since dimethylamine boils at
10°, the reaction conditions must be less vigorous than usual, and reac-
tion times are therefore longer. The second disadvantage is that there

is not a general method for the preparation of a variety of 8 -ketoamides.

72

AS reported earlier, the reaction between amide enolates and acid
chlorides leads to only minimal yields of B-ketoamides.

With these disadvantages in mind, it appears that the preparation of
enamino amides is best accomplished by treating lithio trimethylsilyl—N,N—
dimethylacetamide with N,N-dimethylamides.

Reactions of Lithio Trimethylsilyl-N,Nedimethylacetamide with Esters and
Acid Chlorides

 

The reaction between lithio trimethylsilyl-N,N—dimethylacetamide and
acid chlorides did not provide a convenient method for the preparation of
B -ketoamides, as was expected. Instead, a complicated mixture of minor
products (12 &.E) was formed in addition to a great deal of starting
material (eq. 80).

Li 0° or -78°
(CH3)33iCHcon(CH3)2 + CHBCOCI THI‘e—e' CH300N(i-Pr)2 +
(<1096) l2

 

u n (80)
CHBCCHZCH(CH3)2 + (CH3)35iCHzcon(CH3)2

((10%) & (>5o%)

It has been reported that the acylation of ester enolates is complicated
by the acidic nature of the product.32 It seems likely that this would
also be the case with amide enolates. Rathke and Hartzell reported
attempted acylations of lithio tert—butyl trimethylsilylacetate with
acetyl chloride, ethyl acetate, N,Nrdimethylacetamide and acetylimida—
zole.33 Only the reaction with acetylimidazole provided t-butyl aceto-
acetate. The other reactions resulted in complex mixtures and unchanged
starting material. No attempt was made to react lithio trimethylsilyl-

N,Nédimethylacetamide with acylimidazoles.

73

In the reaction between enolates and acid chlorides, one problem
could be the ease of formation of ketenes from acid chlorides in the
31+

presence of base. The formation of N,N—diisoprOpylacetamide‘12 could
be rationalized by a ketene mechanism or by direct reaction of the acid

chloride and diisopropylamine (eq. 81 and 82).

 

Li
(CH3)BSiCHCON(CH3)2 + 01130001 —_—. (CH3)33iCH2001~1(CH3)2 +
(i—Pr)2NH (81)
CH2=C=0 :- CH300N(i-Pr)2
12

CH C001 + HN(i--1>r)2 —- CH

3 CON(i-Pr)2 + HCl (82)

3

The reaction of esters and lithio trimethylsilyl-N,N—dimethylacetamide
results in a complex mixture of products. One side reaction probably
involves the enolization of the ester followed by either decomposition of
the enolate or reaction with another molecule of eSter to form. B-keto

esters (eq. 83).

 

Li H

(CH3)3SiCHCON(CH3)2 + CH300R —~ (CH3)331CH200N(CH3)2 +
L on 00 R CH3GOZR+ CH E go (83)
1 2 2 a 3 CH2 R

The formation of one of the minor products was rather surprising (eq. 8“).

Li 0 0° R0 0
(CH3)35iCHC0N(CH3)2 + 01130? —» /\C=CHL/< (an)
OR THF CH3 N(CH3)2

(00%)

71»

The formation of this O—alkylated B-ketoamide is another example of an
elimination of lithium trimethylsilyl oxide. Attempts to increase the

yield of this product were unsuccessful.
Reactions of Lithio Trimethylsilyl-N,N+dimethylacetamide with Epoxides

Since the 1,2 elimination of lithium trimethylsilyl oxide is fast
(eq. 85), a 1,3 elimination, to .form cycloPropane derivatives, seemed

feasible (eq. 86).

 

 

Li B LiOSi(CH )
3 \
(CH3)BSiCHCON(CH3)2 + /C\ 000 i- /C=CHCON(CH3)2 (85)
Li ,/ -LiOSi(CH ) CH2
.. _ 3 1. ‘
(CH3)35iCHCon(CH3)2 + R CH 2 ? lH/CHCOTKCHB)2
/
R (86)

In a similar reaction, Boskin and co-workers35 reported that treatment of
epoxides with the phoSphorane ester 25, under vigorous conditions, yielded
cyclopropanes (eq. 87).
/°\ 200°
RCH-CH2 + Ph3P=CH002Et —— J>-002Et (87)
‘22 R
Attempts to react C-silyl ester enolates with epoxides gave only
unreacted starting materials. This was probably due to the unreactive
nature of epoxides at -78°. With a more stable enolate, lithio trimethyl-
silyl-N,N-dimethylacetamide, a variety of reaction conditions could be
used.

Treatment of lithio trimethylsilyl-N,N—dimethylacetamide with

75

propylene oxide at 25° gives an 0—silylated Y-hydroxy amide 12a (eq. 88).

(H Li q /0\ 250 (I)Si(CH3)3
_ -————¢'
0 3)BSiCH00N(CH3)2 + CH3CH CH2 THF CHBCHCHZCHZCON(CH3)2
.132. (88)

It appears that formation of 12a involves the migration of the trimethyl-
silyl substituent followed by protonation at the alpha carbon (eq. 89).

Li+ q Si(CH3)3 081(0H3)3 H+

RCHCH CHCON(CH3)2-—> RCHCH CH00N(CH ————> 12:51 (89)

2 2 3)2

The migration of the trimethylsilyl group probably proceeds through a five

member cyclic transition state 26.

+

0 Li

R 011/ :"Si(CH )
-I 3 3
CH -CH

2 \
00N(CH3)2

26

There was no evidence of any cyclopropane derivatives being formed in the
reaction above.

In order to confirm the structure of lga, a completely independent
synthesis was attempted. Propylene oxide was added to a THF solution of
lithio N,N-dimethylacetamide at 0° and the mixture was stirred for 15 min-
utes. After stirring, the solution was quenched with trimethylchlorosilane

to produce 122 (eq. 90).

0 . o
) 25° TMCS 3’31“” )
LiCH con CH + CH CH-CH —. —.
2 ( 3 2 3 2 THF CHBCI-ICHZCI-IZCOMC113)2

1.12.12 (90)

76

The 1H Spectra of 12a and lgp were found to be identical. The Y -siloxy-
amide 12b was treated with lithium diis0propylamide, followed by refluxing
with the hOpe of forcing the 1,3 elimination. The starting material was

recovered unchanged. There was no attempt to use more vigorous conditions.

Reactions of Enamino Amddes

Enamino amides should be capable of a wide variety of reactions due
to their dual functionality. Besides reacting as enamines, enamino amides
could also possess properties similar to those of a , B -unsaturated amides.
Ionization, followed by alkylation or protonation at the alpha carbon to
give 8 , Y -unsaturate amide, seemed quite feasible.

Hydrolysis of the enamine portion of the molecule was the first

example of an enamine-type reaction (eq. 91).

CH3\N/CH3 0

CH C=CHCON(CH 6M HCl —+ CH gCH CON

This reaction was also used as evidence to confirm the structure of the
enamino amide.
Alkylation with allyl bromide provided more evidence that these

enamino amides would react in a manner similar to simple enamines (eq. 92).

CH CH
3‘N/ 3
| reflux reflux
CH C=CHCON(CH ) + CH =cH-CH Br -—-———- ————-
2 3 2 2 2
CH CN H o
3 2
" " (92)
CH CCHCN CH
3 | ( 3)2
CH CH=CH

2 2

77

It has been well documented that the enolates of a , B ~unsaturated esters

react almost exclusively at the alpha position to form 8 ,Y -unsaturated

36

esters. This includes alkylation and protonation (eq. 93 and 91+) .

—< -78° 0°

CH CH=CHC0 Et + NLi —» ——> CH =CH-CHCO Et (93)
3 2 2 I 2
THF CH I
3 CH3

 

CH CH=CHC0 Et + Md 4' 2 s CH =CH-CH C0 Et (87%)
3 2 THF 2 2 2
+
CHBCH=CHCOZEt (94)

Anions of B -enamino esters have been generated at --780 using n—BuLi and

can be Silylated exclusively at the Y -carbon (eq. 95).33 Enamino amides

Q

might be expected to react similarly.

Q

I -78° THCS ,
CH3C=CHC02C2H5 + n—BuLl TH; ——- (CH 3) 381m20=wm202H5
(95)

Treatment of N,N-dimethyl 8 -dimethylaminocrotonamide with lithium diiso-
propylamide at -78°, resulted in a yellow solid. It seemed likely that
this solid was the lithium enolate of the enamino amide. Attempts to
prove that the enolate was formed by protonation and alkylation were
unsuccessful. None of the B ,Y -unsaturated amide was observed. Moderate
success was found in the attempted Silylation of this enolate. Even

though the product was observed by glpc, attempts to isolate it led to

78

starting material. A trimethylsilyl substituent on the alpha 22 or
gamma 2§ carbon of the enamino amide would be expected to be very labile,

and this would explain the difficulty in isolation of a Silylated product.

CH3\N/CH3 CH3\N/CH3
I l
CH2=C-CH-C0N(CH32 ) (CH3)33iCH2 C=CHC0N(CH3 )2
Si(CH3 )3
31 2.6.3.

Reaction of the enamino amide l§ with lithio trimethyl-N,Nrdimethyl-

acetamide could lead to a second enamine function in the molecule (eq. 96).

“BxN/9H3
Li . reflux
(CH3)BSlCHCON(CH3)2 + CH3C=CHCON(CH3)2 T
:_L_$_
(CH3 )2 N N(CH3 )2
CH 2C=CHC=CHC0N(CH3 )2 (96)

3
(1’)

There was no evidence of any di-enamino amide being formed. Failure of

this reaction can be explained by steric inaccessibility of the enolate.

EXPERIMENTAL

1. Materials

The trimethylsilyl-N,N—dimethylacetamide was prepared as described in
Chapter 2. The n—butyllithium was obtained from Aldrich Chemical Company
and was used without further purification. The diisopropylamine was
obtained from Aldrich and was distilled from calcium hydride. The tetra-
hydrofuran, obtained commercially, was distilled from the sodium ketyl of
benzophenone and stored under nitrogen. The aldehydes, ketones, esters,
acid chloride, and epoxides were all obtained commercially and distilled
prior to use. The amides were prepared as described in Chapter 2.

2. The Preparation of Lithio Trimethylsilyl-N,Nsdimethylacetamide Using
Lithium.Diisgpropylamide

The lithium diiSOprOPylamide (5.5 mmoles) was prepared as described
in Chapter 1, dissolved in 10 ml of THF and the solution was cooled to
0°. Then 0.87 ml (5.0 mmoles) of trimethylsilyl-N,N—dimethylacetamide was
added dr0pwise and the reaction mixture stirred for 15 minutes at 0°.

3. The Preparation of Lithio TrimethylsilyleN,fl%dimethylacetamide Using
anutyllithium

The reaction vessel shown in Figure 6 was charged with 10 ml of’THF
and cooled to 0°. The silylamide (0.87 ml, 5.5 mmoles) was added. Then

3.44 ml (5.5 mmoles) of anuLi was added dr0pwise and the reaction mixture

was stirred at O0 for 10 minutes.

79

80

h. Decomposition and Analysis of Lithio Trimethylsilyl-N,N-dimethyl—
acetamide

A 0.5 molar solution of lithio trimethylsilyl-N,N-dimethylacetamide
(5.0 mmoles) in THF was prepared as described above. After the enolate
was completely formed, the reaction vessel was warmed to 250 i 0.50.
Periodically 0.5 m1 aliquots were removed and quenched inversely with
1.5 equivalents (0.02 ml) of glacial acetic acid in 0.5 ml of ether. The
mixture was centrifuged and analyzed using glpc with a 6 foot by-% inch

column. The column packing used was 3% Carbowax on non-acid washed

Chromosorb G.

5. Preparation of Lithio Trimethylsilyl-N,N-dimethylacetamide for NMR
Analyses

A 0.5M solution of lithium diisoprOpylamide in pentane was cooled to
0°. Upon addition of 0.87 ml (5.0 mmoles) of trimethylsilyl-N,N-dimethyl-
acetamide, the enolate precipitated immediately. After the mixture was
stirred for 15 minutes at 0°, the pentane was removed under pressure and a
white solid remained. The enolate was dissolved in 5 ml of dry pyridine
and transferred to a nitrogen-flushed NMR tube and sealed immediately.

The 1H NMR Spectra were run on a Varian T-60 Spectrometer. The 130 NMR
Spectra were obtained using the same samples on a Varian OFT-20 Spectro-

1H NMR tube inside

meter. This was accomplished by placing the smaller
the larger 130 NMR tube and using teflon tape to keep the smaller tube
stationary. Deuterium oxide was placed in the 13C tube and used for the

locking Signal.

81

6. Reactions Between Lithio Trimethylsilyl-N,N—dimethylacetamide and

Epoxides

The reaction between prepylene oxide and the silylamide enolate will
be representative. A 0.5M solution of the silylamide enolate in THF was
prepared using n-BuLi as described above. Propylene oxide (0.38 ml, 5.5
mmoles) was added to the solution. The reaction mixture was stirred for
two hours, then quenched with 0.30 ml (5.5 mmoles) of glacial acetic acid.
The reaction mixture was diluted with ether and the lithium acetate was
removed by filtration. The reaction mixture was analyzed using glpc.

7. Reactions of Aldehydes agd Ketones With Lithio Trimethylsilyl-N,N—
dimethylacetamide

 

The reaction of cyclohexanone with the silylamide enolate will be
representative. A solution of 0.87 ml (5.5 mmoles) of trimethylsilyl-N,N-
dimethylacetamide in THF was cooled to 0°. Cyclohexanone (o.5n ml, 5.5
mmoles) was then added and the solution was stirred at room temperature
for 15 minutes. The reaction mixture was analyzed and the product

isolated using preparative glpc. The same procedure was used with alde—
hydes.

8. Reactions of Lithio Trimethylsilyl—N,N—dimethylacetamide with Esters
and Acid Chlorides

 

The reaction between ethyl acetate and the silylamide enolate will
be representative for reaction with esters and acid chlorides. A 0.5M
solution of lithium diisopropylamide (5.5 mmoles) in THF, prepared as
described earlier, was cooled to 0°. To this solution was added 0.87 ml
(5.0 mmoles) of the silylamide and the mixture was stirred for 15 minutes

at 0°. Ethyl acetate (o.5u ml, 5.5 mmoles) was then added dropwise, and

82

the reaction mixture was warmed to room temperature. After being stirred
for 2“ hours at room temperature, the reaction mixture was analyzed using
glpc. The solution was stirred an additional 24 hours, quenched with 1.1
equivalents (0.30 ml, 5.5 mmoles) of glacial acid, and analyzed a second
time with glpc.

9. Reactions of Simple Carboxylic Acid Amides with Lithio Trimethylsilyl-
N,N-dimethylacetamide

 

The preparation of the enamino amide from N,N-dimethylacetamide and
lithio trimethylsilyl-N,N-dimethylacetamide will be representative. A
0.5M solution of the silylamide enolate (5.0 mmoles) in.THF was prepared
as described above. N,N—dimethylacetamide (0.46 ml, 5.0 mmoles) was added,
the reaction mixture was refluxed for two hours and then cooled to room
temperature. The solution was diluted with 5 ml of ethyl ether and cooled
to 0°. The lithium salts were extracted with 1 ml of H20 and the organic
layer dried with anhydrous potassium carbonate. The reaction mixture was

analyzed both before and after quenching, using glpc.
10. Preparation of N,N-dimethylacetoacetamide

A solution of 19.8 ml (0.30 moles) of dimethylamine in 100 ml of ether,
was cooled to —200 using a dry-ice carbon tetrachloride bath. Freshly
distilled diketene (21.0 g, 0.25 moles) was added to the solution over a
period of one hour. The reaction mixture was refluxed for one hour, then

distilled under reduced pressure.
11. Preparation of B~dimethylamino-N,N—dimethylcrotonamide

A mixture of 1.22 ml (10 mmoles) of N,N-dimethylacetoacetamide, 1.32

ml (20 mmoles) of dimethylamine, and 10 g of Size 5A molecular sieves were

83

stirred for 3 days in 50 ml of ether at 0°. The product was isolated

using preparative glpc and analyzed using NMR.

12. gydrolysis of B-dimethylamino-N,N—dimethylcrotonamide

 

A solution of 0.15 ml (1.0 mmoles) of the enamino amide in 1.0 ml of
THF was cooled to 0°. Two equivalents (0.33 ml, 2.0 mmoles) of 6M hydro-
chloric acid was added and the reaction mixture was stirred for one hour
at room temperature. The reaction mixture was diluted with 2 m1 of
chloroform and the aqueous layer was saturated with anhydrous potassium
carbonate. The reaction was analyzed using glpc.
13. Reaction of B-dimethylamino-N,Nédimethylcrotonamdde with Lithium

Diisopropylamide Follpwed by Attempted Silylation and Alkylatigg

A one molar solution of (1.1 mmoles) lithium.diisoprOpylamide, in.THF,
was prepared as described earlier and cooled to -78°. Then 0.15 ml (1.0
mmoles) of the enamino amide was added dropwise and the mixture was
stirred for 15 minutes at -78°. The reaction mixture was warmed to room
temperature and stirred for another 15 minutes. This solution was cooled
to -78°, quenched with 0.28 ml (2.2 mmoles) of trimethylchlorosilane, and
stirred at that temperature for 15 minutes. The reaction mixture was
warmed to room temperature and analyzed using glpc. The same procedure was
used in the attempted alkylation where 0.14 ml (2.2 mmoles) of methyl
iodide was used in place of trimethylchlorosilane.
11+. Alkylation pf— 8-_di__n§thylamino-NpN-dimethylcrotonamide with Ally;

Bromide

To a solution of 0.31 ml (2.0 mmoles) of the enamino amide in 2.0 m1

of acetonitrile was added 0.19 ml (2.2 mmoles) of allyl bromide. This

84

20'

and refluxed for another hour. The reaction mixture was cooled to room

solution was refluxed for two hours, followed by addition of 0.5 ml H

temperature and diluted with ether. The organic layer was dried using

anhydrous porassium carbonate. The product was isolated using preparative

glpc.

15. Atte ted Reaction Between Lithio Trimethylsilyl-N,N—dimethylacetamide
and -dimethylamino-N,Nedimethylcrotonamide
A solution of 0.18 ml (1.0 mmole) of trimethylsilyl-N,N—dimethylaceta-
mide in 2.0 ml of THF was cooled to 0°. The enamino amide (0.16 ml, 1.1
mmoles) was then.added and the solution was refluxed for 2 hours. The
reaction mixture was cooled to room temperature and analyzed using glpc.

The lithium salts were removed with 0.5 ml of H 0, followed by saturation

2
of the aqueous layer with anhydrous potassium carbonate. The reaction

mixture was analyzed again using glpc.
16. Product Analyses

All 1H NMR Spectra were recorded on a Varian.T-60 Spectrometer. The
IR Spectra were recorded on a Perkianlmer Model 237B Grating Infrared
Spectrophotometer. The elemental analyses found in Table 12 were done by

Galbraith Laboratories, Knoxville, Tennessee.

CHBCHCHZCHZCON(CH3)2
3

OSi(CH3)
NMR(CClu): 63.81(m,lH), 52.94(S,3H), 52.84(S,3H), 62.21(t,2H),

dl.60(m,2H), 61.10(d,3H), 60.10(S,9H).

85

gal-CHCHZCHZCONwH
OSi(CH3)3

3)2

W* 67.16(S,5H), 64.75(t,1H), 62.94(s,6H), 62.27(t,2H),
61.94(m,2H),60.10(s,9H). IR(CClu): 1645 cm‘1(C=0).

O=CHCON(CH3) 2

NllR(CClu): 65.35(S,1H), 6 2.88(s,6H), 6 2.54(m,Z-I), 6 2.lo(m,2H),

61.57(m,5H). IR(CC14): 1640 cm‘1(C=0), 1625 cm‘1(C=C).

CH
3\
/C=CHCON(CH3)2
CH
3
mama“): 65.63(s.1H). 62.87(s.6H). 618301.311). 61.770.310-
IR(CCln): 1630 cm“1(C_—.0).
8 R
CHBCCHZCN (CH3) 2 N , N-dimethylacetoacetamide
mm(001u): 63.38(S,2H), 62.90(S,6H), 66.40(S,3H).
z“ 1
CH3 =CHCN(CH3)2
NMR(CC1,+): 614.70(S,1H), 65.00(S,1H), 62.8l(s,6H), 61.84(s,3H).
CH CH 0
3 2
,\C=CH00H(CH3)2

CH3
NMR(CClu): 64.97(S,1H), 63.70(q,2H), 62.9l(s,6H), 62.10(s,3H),
618006.311)-

86

CH 00N(i-‘.Pr)2 N,N-diisopropylacetamide

3
NMR(CClu): 63.37(m,2H), 61.89(S,3H), 51.20(d,12H).
(CH ) N
3 2 \
CH/C=CHCON(CH3)2
3
NMR(CClu): 64.50(S,1H), 62.87(S,6H), 62.83(s,3H), 62.80(S,3H),
62.23(S,3H).
(CH ) N H
3 2 \C=C’

I \
H CON(CH3)2

NMR(CClu): 67.07(d,lH), 64.63(d,1H), 62.87(S,6H), 62.85(S,3H),
62.83(s,3H), J=12hz. 13(0014). 1640 cm'1(c=0), 1575 cm‘1(C=C).

<:C,ICH00N(CH3) 2
I
N\

3

NMR(CClu): 64.60(S,1H), 63.20(m,4H), 62.83(S,6H), 62.70(S,3H),

CH

61.87(m,2H). IR(CClu)x 16w cm’1(c=0), 1585 cm'1(c=c).

(CH3)2N\
/
CHBCI‘I2

C=CHCON(CH3)2
NMR(CClu): 54.57(s.1n). 53.o1(s.6H). 62.97(s.3H). 52.9u(s.3H).
62.95(m,2H) , 51.210: .310 .

CHBCI-IZCH2\

lC=CHCON(CH3)2
(cupzn

NMR(CClu): 64.57(S,1H), 62.98(S,6H), 62.94(s,3H), 62.9l(s,3H),
620870111314)! 610540111211)! 61-07(t93fl)°

8?

 

 

0 0
u gN(CH)
CHBCC'HI 3 2
CHZCH=CH2
mama“): 65.54(m.1H). «5.046.210. 63.55(t.1H). 63.04(s.3H).
62.94(S,3H), 62.64(m,2H), 62.11(S,3H).
TABIE 12
Elemental Analyses for Some Enamino Amides
Enamino Amide Theoretical Experimental
(CH ) N
3 2 \ C 61.51 59-77
,C=CH°°N(CH3)2 H 10.32 10.00
CH3 N 17.93 16.81
”3’2“...” 3 52-2 32-3:
/ . o
H \GON(CH3)2 N 19.70 19.49
//CHCON(CH3)2
C C 64.25 58.56
| H 9.59 8.67

3

 

CHAPTER4

STABILITY OF ESTER EI‘DLATES IN SOLUTION

88

INTRODUCTION

Lithium ester enolates have been studied extensively during the past

several years, and found to react with a variety of reagents. They react

with copper (II) salts,37 halogens,38 alkyl halides,39 acid chlorides,32

ketones and aldehydesfl'o and trialkylhalosilanes,+1

to produce substituted
succinate esters, o-halogenated esters, chain-extended esters, B—keto

esters, B-hydroxy esters, and Silylated esters reSpectively (Figure 7).

l l
R0 C—C-C-CO R l \ ,OSiR

' 2
.. l l 2 3
x CCOZH I RBSiCCOZR + /,<1=C\OR

Cux

2

'\\\“ ””’d; Six
X2 I 3
8 LiCCOZH
-C-c-Cozn ' -f-C-Cozn

R-C-CO R

I 2

Figure 7. Reactions of Ester Enolates

Even though lithium ester enolates are used widely in synthesis, little is
known about their structure and stability in solution. Solutions of ester
enolates are generated at -78° in.THF and are stable indefinitely at this
temperature.39 .Warming the THF solutions above -78° leads to decomposi-

tion and the formation of B-keto esters (eq. 97).13

89

9O

0 o +
I -78 I 25 H I II I
H-Cco R + (i—Pr) NLi —» LiCCO R ——_. ——> H-C—C-C-COZR
I 2 2 THF I 2 l I
+ LiOR (97)

Even lithio t-butylacetate, which is stable at room temperature as a solid,
decomposes in solution.”2

Two possible pathways for the decomposition of ester enolates have
been proposed.13 The first is an "Inverse Claisen" mechanism in which
the enolate obtains a proton from an acid (HA, eq. 98) and reacts with a
second molecule of enolate (eq. 98). HA may be solvent molecules (THF) or,
more likely, dialkylamine.

| THF | LiCCO R

LiI'i‘CO R + HA -——-- LiA + HCC0 R ———r' 2 condensation

2 I 2 product
(98)

The second mechanism entails the formation of a ketene intermediate (eq.
99)-
I
LiCCO R

I \
LiCCOzR —> C=C=0 + LiOR ' 2» condensation
' I product (99)

 

The main objective of this study was to investigate the stability of
lithium ester enolates under a variety of conditions in order to give
information which would be useful in syntheses involving ester enolates.
It was also h0ped that this study would give some insight into the mechan-

ism of decomposition of Simple ester enolates.

RESULTS

Quenchinggand Decompgsition Studies of Ester'EnolateS

Ester enolates were generated in.THF at -780 using one equivalent

of lithium diisoprOpylamide (eq. 100).

O
I -78 I
H-CCO R + (i-Pr) NLi -—> LiCCO R (100)
I 2 2 THF I 2

The solution of ester enolate was quenched at e78o with either saturated
NaHéPOu or 2M hydrochloric acid to give quantitative recovery of the ester

in all cases studied (eq. 101).

l -78° _780 |
LiI|1C02R -—- _+_. H-clzoozn (101)
THF H

(100%)

The solution of enolate was warmed to 250 and quenched immediately, which
gave different results. When quenched with saturated NaHZPou, t-butyl
acetate and ethyl isobutyrate were recovered in 89% and 88% yields. The
use of the same quenching reagent with ethyl butyrate, gave yields of

recovered ester which ranged from 40-60% (eq. 102).

Li -78° 25° ( )
CHCH CHCO Et ———~-- _. CHCHCHCOEt 102
3 2 2 THE NaHZIroLP 3 2 2 2
40-60%

91

92

Other quenching reagents, such as 1M acetic acid in.THF, saturated

ammonium chloride, 1M methanesulfonic acid, and H 0 gave Similar incon-

2
sistent results. Finally, the use of 2M hydrochloric acid in water,
followed by saturation.with anhydrous potassium carbonate, gave 85-90%

recovered ethyl butyrate (eq. 103).

 

Li -78° 25°
CH CH CH t ————e CH CH CH 00 Et 10
3‘2sz THF ZMHCl 3222 (3)

(BS-90%)

Ester enolates that were generated with a 10% excess of lithium
diisopropylamide and quenched, gave 95-100%iyield of the starting ester.
These enolates were generated at -780 in THF and quenched with 2M HCl
(eq 0 1014') 0

—78° 250

I I
H—CCOZR + 1 .l(i-Pr)2NI.i ___. —. H-CCOZR (104)
I THF 2M HCl I

(95-10096)

Table 13 lists the results of the decomposition studies for a number of
esters. All of the ester enolates listed in Table 13 were prepared and
quenched as outlined in equation 104. For comparison, the results of
decomposition studies for two amide enolates are also listed. Procedures
for generation and quenching of amide enolates are described in Chapters
1 and 3. Due to the difficulty in analyzing for the volatile ethyl
acetate, solutions of lithio ethyl acetate were quenched with ethereal
solutions of cyclohexanone, and then quenched with 2M HCl. This gave the

B-hydroxy ester, which was analyzed by glpc (eq. 105).

93

TABLE 13

Quenching Results of Ester and Amide Enolates (10% Excess Base)a'

 

 

I -78° 25° I
H-CCOZR + l.l(i-Pr)2NLi -———. —;—-o H—CCOZR + condensation
I THF H I products
Ester (or Amide) Time(HourS) % Recovered
O 100
t-Butyl Acetate 2 55
4 l6
0 95
2 89
Ethyl Acetate 4 83
6 79
8 0
O 100
t-Butyl Propanoate 6 44
12 28
24 11
O 98
Ethyl Pr0panoate 6 90
12 73
24 15
0 99
t-Butyl Isobutyrate 6 19
12 8
O 96
6 91
Ethyl Isobutyrate 12 86
28 75
49 50

94

TABLE 13 CON'T.

 

 

Ester (or Amide) Time(HourS) % Recovered
0 94
4 77
Ethyl Butyrate 9 74
19 61
23 58
Ethyl Phenyl Acetate 48 95
Ethyl Diphenyl Acetate 48 99
0 99
N , N-dimethylacetamide 19 91
63 76
0 99
2 -Trimethylsilyl-N ,N-dimethyl- 24 99
acetamide 49 99
93 93

 

a All yields determined by glpc.

95

‘ -78° 2 5° 2 5° H0 CHZCOZEt
LiCHZGO2Et ‘-—""' "———-——" '—""’
THF 0 , ether 2” RC]. (95%) (105)

Qecomposition Studies of Solutions of Ester'EnolateS ContainingpLithium
Alkoxides

Lithium ethoxide was prepared by adding absolute ethanol to a pentane

solution of n-butyllithium at 0° (eq. 106).

O

0
n—BuLi + CHBCHZOH ———> CH30H20Li + Butane (106)
pentane

The solvent was removed under reduced pressure to leave a white solid. A
THF solution containing lithio ethyl isobutyrate at -78° was added and
then warmed to 25°. This resulted in a homogeneous solution of alkoxide
and enolate. Aliquots were removed periodically, quenched with 2M HCl,
and analyzed (glpc) for recovered ester.

Lithium ethoxide was also generated in situ. A THF solution contain-
ing 2.1 equivalents of lithium diisopropylamide was cooled to —78°. One
equivalent of absolute ethanol was added and the solution stirred for 15
minutes. Then one equivalent of ester was added and the solution was

stirred for another 15 minutes (eq. 10?).

 

-780

2.l(i-Pr) NLi + ROH ———~ (i—Pr) NH + (i-Pr) NLi +

2 THF 2 2
(107)

I o +
H-CCOZR I 25 H I
LiOR o : LiCC02R + LiOR -——. —. H-CCOZR
-78 /THF I THF I

The reaction mixture was warmed to 25° and aliquots were periodically

removed and quenched with 2M HCl.

96

Both methods for the preparation of lithium alkoxides gave similar
results. Similar procedures were used with ethyl acetate-lithium ethoxide,
t-butyl acetate-lithium t-butoxide, and t-butyl isobutyrate-lithium t-but-
oxide experiments. The results of these experiments are in Table 14.
'Qeggmpositionigtudies of Solutions of Ester Enolates Containing Excess
Lithium.Diisopropylamide

Lithio t-butyl acetate and lithio ethyl isobutyrate were generated in
THF at -78° using two equivalents of lithium diisopropylamide. The pur-
pose of this study was to find out what effect a large excess of base
would have on the rate of decomposition. Samples were removed periodically

and quenched as described above. The results from this experiment are

found in Table 15.
Decomposition of "Amine-Free" Lithio t-Butyl Acetate

Addition of t-butyl acetate to a suspension of lithium diiSOprOpyl-
amide in pentane at -78°, gave a homogeneous solution after 15 minutes.
The reaction mixture was stirred for an additional 10 minutes and warmed
to 0°. At this temperature the solvent was removed under reduced pressure
to leave lithio t-butyl acetate as a white solid. The solid enolate was
dissolved in.THF at 250 and samples were periodically removed and quenched

with 2M H01 (eq. 108).

+ ( ) —78 + 25° 2M +
CH 00 + i-Pr NM ———> LiCH 00 _... .__. CH c0
3 2 2 pentane 2 2 THF HCl 3 2

"Amine—free" (108)

97

TABLE 14

Quenching Results of Ester Enolates and Lithium Alkoxidesa

 

 

I -78° 25°
.. —-—D _
H-c'icozn + 1.1(i Pr)2NLi + LiOR Tm? H+ H $00212 +
Condensation.ProductS
75 (without
Ester Alkoxide Time Recovered LiOR)
Ethyl Acetate LiOCz‘H5 0 94 95
3 89 85
6 87 79
10 o 0
t-Butyl Acetate Lioc(CH )3 0 100 (100
3 2 86 (55
4 82 (16
8 74
20 5
Ethyl Isobutyrate LiOC2H5 0 94 (96)
6 92 91
18 85 86
29 79 75
42 68 65
t-Butyl Isobutyrate LiOC(CH3)3 0 97 99
6 62 19
18(12) 39 8

 

a Samples were quenched with 2M HCl and analyzed using glpc.

98

TABLE 15

Quenching Results of Ester Enolates in the Presence of Excess Basea

 

 

I —78° 25° I
H-(fCOZR + 2(i-Pr)2NLi —> —;—e H-CCOZR + condensation
THF H ' products
Ester Timeb(l.l equiv.) % Recoveredc (1.1 equiv.)d
t-Butyl Acetate 0 100 (100)
0.25 42 (-)
1 23 (72)
2 18 55
Ethyl Isobutyrate 0 99 96
3 6) 80 91
13 12 49 86
23 28 38 75
44 49 24 50

 

a Yields determined by glpc.

b
Time was measured in hours.

c Yields of recovered ester with two equivalents of base.

d Yields of recovered ester with 1.1 equivalents of base.

99

In Table 16 the results of the decomposition study for "amine-free"
lithio t-butyl acetate are compared with those where amine is present
(Table 13).

TABLE 16

Decomposition of "Amine-Free" Lithio t—Butyl Acetate

 

 

 

Time (Rona—329;”? Recovered Time (323:2; Presgflifiecovered
0.0 100 . 0.0 100
O . 5 87 O . 5 86
1. 5 58 1.5 63
2 . 5 41 2 . 5 50
3 - 5 25 3 . 5 32

 

Determiniation of Decomposition Products

A THF solution of lithio t-butyl acetate was prepared at -78° using
lithium diisopropylamide. The solution was warmed to 2 5°, stirred for 24
hours, and quenched with saturated NaHzPOu. The major decomposition pro-
duct was isolated by preparative glpc and identified as t-butyl acetoace-
tate g9 by m (eq. 109).

 

-78° 2 5° NaHZPO °
CH300§|- + (i—Pr)2NLi ——«- . CIIBCCHZCOé-I—

32 (109)

100

The glpc yield of t-butyl acetoacetate was 85%.

In a Similar procedure with lithio ethyl acetate, ethyl acetoacetate
29 was isolated and identified. The glpc yield of ethyl acetoacetate was
65% (eq. 110).

-78° 250 NaHZPOn I
CH 002Et + (i—Pr)2NLi —-—. ——. —. CH CCHZCOZEt
3 THF 24 hrs. 3

2 (110)

Other products in these decomposition reaction mixtures were minor
and not identified. The absence of N,NrdiiS0propylacetamide was estab-
lished by glpc.

In the decomposition study where lithio ethyl isobutyrate was gener—
ated using two equivalents of lithium.diisopropylamide, the major decom-

position product after 24 hours was not the B -keto ester 3;, but N,N—diiso-

propylisobutyramide 3_2_ (eq. 111).

CH 0

I 3 -78 25° H+ fl
H-CCOZEt + 2(i-Pr)2NI.i —. ———. ——-. (0113)2CH00(0113)2002Et
ICH THF 24 hrs.
3 31 (111)

+ (CH3)2CHCOH(i-Br)2
3.2 (65%)

The majorIproduct'zg was isolated by preparative glpc and its structure
determined by NMR. In the decomposition mixture where 1.1 equivalents of
lithium.diisoprOpylamide was used, none of the N,N-diisoproPylamide was
observed by glpc. Retention times of the B-keto esters and N,N—diiso-
prepylamides are very similar and only B-keto esters were observed from

ethyl acetate, ethyl isobutyrate, ethyl butyrate, and t-butyl acetate

101

decomposition mixtures.
Attempts were made to quench decomposition mixtures of t-butyl ace-
tate with NaHzPou/DZO, and analyze forIdeuterium‘using NMR (eq. 112).

O O
-78 25 NaI-IZPOu/DZO

CHBCoZ-I— + (i-Pr)2NLi ——-o ——.

m e D-CH COCH 005l-

2 2

(112)

The NMR Spectra of the quenched decomposition mixture indicated approxr
imately a 80:20 ratio of ketozenol forms of t-butyl acetoacetate. Because
of this mixture, it was difficult to obtain Significant data on.deuterium
incorporation. A rough approximation indicated no deuterium at the 1'-
carbon and possibly 10% or less at the a-carbon.

Attempts were made to isolate the-enolate of t-butyl acetoacetate
from the decomposition mixtures and study its structure by NMR. A THF
solution of lithio t-butyl acetate was prepared at -780 using one
equivalent of lithium.diisoproPylamide. The reaction mixture was warmed
to 25° and stirred for 24 hours. The solvent was removed under reduced
pressure and the remaining residue was washed with pentane. The solid
enolate was placed under high vacuum to dry, and finally was dissolved
in C6D6 (eq. 113).

o o OLi
+ < > '78 25 ' at
CHCO + i—Pr NLi ——e ——_.. CH=C-CHC or
3 2 2 THF 24hrs. 2 2 2

33 on (113)
CH36=CHC0-2+

2‘1

The 1H NMR of this solution indicated that it was possibly a mixture of

both.33 and.34 (Table 17). For comparison, the enolate of t—butyl

102

acetoacetate was prepared and isolated (Table 17) (eq. 114).

a Li Li

-78 9

CH 000H 00 + (i-Pr)2 NLi—-t CH 30=CH00--|—+ CH2 =00H 00
3 2 2 m 2 2 2

(114)

Attempts were also made to react lithio t-butylacetate with ketene,
with the h0pe of preparing t-butyl acetoacetate in quantitative yield (eq.
115).

~78° on D 0

2 .
LiCHZCOZ + CH2=C=O 7H; CHZ=CCH2002 ——-- D-CH 2000H 2002+-

(115)

The reaction mixture was quenched with Hanzpou and the product was isola-
ted by preparative glpc. NMR Spectra of isolated products indicated less
then 10% deuterium at the d-carbon and none at the Y-carbon. Only 38%
of the B -ket0 ester and 48% of t-butyl acetate were found in the reaction

mixture .

Attempted Trappigg of Possible Ketene Intermediates

To a THF solution at -78° of lithio t-butyl acetate, was added a ten-
fold excess of dimethylamine. The solution was warmed to room temperature

and was stirred for 1 hour (eq. 116).

-73°
CHBCO§+- + (i-Pr)2NLi -——-—-» LiCH200§+- + 10(CH3)2NH
THF
7 (116)
25° I II
TIE... 0H300H2002 + CH3001i2001I(0113)2 + CH300N(CH3)2

29 i B

103

TABLE 17

mm Data for Lithio t-Butyl AcetoacetateaL

 

(9.)"

(B)°

 

 

1. 6 4.74(s,1H) 1. a 5.24(s(broad), l-2H)
2. 6 1.91(s.3H) 2. a 2.24(s(broad), 2-3H)
3. 61.54(s.9H) 3. 61.84(s.9H)
4. 61.71(S,9H)
a C6H6 was used as a reference.
0
b CH II II (1 Pr) ___.
BCCHZCO + - zNLi
c II 3 hrs.
01130-0 + (i-Pr)2NLi —.

104

The major product (65%) in the decomposition mixture was t-butyl aceto—
acetate‘gg. Also found as minor products were N,Nedimethylacetoacetate
(10$) 3 and N,N—dimethylacetamide (10%) g. The B—keto ester was isola-
ted by preparative glpc and identified with NMR. The minor products were
identified by comparing their retention times (glpc) with those of authen-
tic samples.

A Similar trapping experiment was attempted using lithio ethyl iso-
butyrate. A THF solution of lithio ethyl isobutyrate and a ten-fold
excess of dimethylamine was stirred at 25° for 24 hours (eq. 11?).

-78°
(CH3)2CHCOZEt + (i-Pr)2NI.i TIP—e LiC(CH3)2002Et + 10(CH3)2NH

THF H+ I
m __. (CH3)2CHCC(CH3)2002Et + (CH3)20H00N(0H3)2 +
3.1. 33 (117)
II
(CI-13)2CHCC(CH3)ZOON(CH3)2

35

The major product in this reaction was not only the B-keto ester 3;.
An equivalent amount of N,Nédimethylisobutyramide‘35 was also found.
These products were isolated by preparative glpc and were identified by
NMR. A minor product was tentatively identified as the B-ketoamide‘3é.
The NMR Spectrum of this product showed that it might be a mixture.

A THF solution of ethyl isobutyrate and a ten-fold excess of dimethyl-

amine was stirred for ten.days at room temperature (eq. 118).

 

105

THF,25°
(0H ) 0H00 t + (CH ) NH 4' N.R. (118)
3 2 2E 3 2 10 days

 

No N,N-dimethylisobutyramide 35 was formed in this reaction.
One equivalent of dimethylamine was added to a THF solution of lithio
ethyl isobutyrate and stirred for three days. A small amount of N,N-

dimethylisobutyramide was formed (eq. 119).

-780
(0H3)20H002Et + (i-Pr)2NLi W LiC(CH3)2C02Et + 1(CH3)2NH
o (119)
u
.———. (CH3)ZCHCON(CH3)2 + (CH3)20H00(0H3)2002Et

3 days

The major product was the B-keto ester.

In an attempt to find out if lithium dimethylamide could substitute
directly for the alkoxide portion of the ester, the following experiment
was performed. A THF solution of lithium dimethylamide was prepared and
cooled to -78°. Ethyl isobutyrate was then added and the solution stirred
for 15 minutes. The reaction mixture was warmed to room temperature and

stirred for an additional 15 minutes before it was quenched with 2M H01

(eq. 120).
< > < > '780 25° H+ < > ( )
CH CHCO 'I‘. + CH NLZ'L —' —-—- ——0- CH CHCON CH
3 2 2E 3 2 THF 15 min. 3 2 3 2
3.2 (120)

The major product of this reaction was N,N—dimethylisobutyramide 35. The
product was isolated using preparative glpc and was identified by NMR.

There was no evidence of formation of the B-keto ester.

106

In a Similar procedure as described above, ethyl formate was added at -780
to a.THF solution of lithium.dimethylamide. Again, the major product
formed was the amide 32 (eq. 121).

-78° 25° H+

H-002Et + (CH)2NLi —. ——_. ___. H00N(CH)2
3 THF 15 min. 3

32 (121)

Attempted Isolation of Ketene Intermediates

A THF solution of lithio ethyl isobutyrate was prepared at -780 using
lithium.diisoprOpylamide. The solution of lithio ethyl isobutyrate was
stirred for 30 minutes. A Slow stream of nitrogen was blown through the
reaction mixture and allowed to pass through a second vessel containing
THF cooled to -78°. After eight hours of passing nitrogen through this
system, a ten-fold excess of dimethylamine was added to the THF in the
collecting flask. This THF solution was analyzed using glpc and no
evidence of any N,N—dimethylisobutyramide or dimethyl ketene dimer was

found.
Attemptequdentification of Ketene in Solutiongby IR

A THF solution of lithio ethyl isobutyrate was prepared at -780 using
lithium.diis0pr0pylamide. The solution was warmed to room temperature and
stirred for 30 hours. Samples of the reaction mixture were removed per-
iodically and placed directly into IR cells. The infrared Spectra pro-

1 to 2200 cm-1 region, where a ketene

vided no transmittances in the 2000 cm-
would absorb.
A Similar experiment was attempted with lithio t-butyl acetate.

After the solution was stirred for 15 minutes at room temperature, small

107

transmittances (approximately one-eigth the Size of the C=O transmittance)
were found at 2050 cm-1 and 2100 cmfl' These transmittances were not
considered substantial enough to provide evidence for a ketene intermed-

iate.

DISCUSSION

Lithium ester enolates were generated quantitatively in.THF at -78°,

using lithium diisopropylamide (eq. 122).

O
I -78
H-CCOZR + (i-Pr)2NLi ——~ LiCCOZR + (i-Pr)2NH (122)
I THF I

Solutions of ester enolates rapidly condensed when warmed to 25°, and this

resulted in the formation of B-keto esters (eq. 123).

+ 0 0
l 25° H I II I II
Li(|200 R HC'I-C-C'i-OOR (123)

 

2 THF

Data from Table 13 indicates that the rate of decomposition varies widely
and depends on the structure of the enolate.

Two mechanisms for the formation of B—keto esters have been discussed
previously. The first, an "Inverse Claisen" mechanism, entails protonation
of the enolate by the amine or solvent. This is followed by rapid conden-
sation with another molecule of the enolate to give the fi-keto ester (eq.
124) .

I I
LiCOOzR + Proton Source -—D H-CCOZR
I (Solvent, HNR , etc.) I
2
I I I II I II
H-coozn + 1.1000211 H-C-C-C-COR (124)
I I I

108

109

The second mechanism, a ketene mechanism, entails the elimination of
an alkoxide moiety to form an intermediate ketene. This is followed by

attack on the ketene by the enolate to form the B—keto ester (eq. 125) .

l 2 5°

\
LiCOOZR -—> C=C=O + LiOR
I THF /
(125)
0 0
\ I III"
IC=C=O + LiCiOOZR _. H-I'J- -|-00B

Several reports of ketene intermediates in similar reactions are in
the literature. While pursuing the nature of the reagent in the
Reformatsky Reaction, Vaughn and Knoessu3 suggested the formation of a

ketene intermediate (eq. 126).

 

 

\ /0-ZnBr reflux - 3 hrs. /C=C\OR
/C=C\ ; 0=0=0 + RO-ZnBr :
OR C6H6/ether ( )
126
OR
-c|:—0-0-ZnBr
c—
/
‘0’
\
44

Bruice and Pratt have pr0posed an Ech mechanism involving a ketene

intermediate in the hydrolysis of 0- am p—nitr0pheny1 acetate esters

(eq. 127).

NO
2 O 2 . .
II II base (Inigo
OCCHCOEt —-0 OC-C- Et —"
R ‘ "' I, (127)
O O 0
II - 3 II II
EtOC-(i‘.=C=O + O —' EtOCIi'iHC-B
N02

R R

NO

110

It was reported that this ketene intermediate was trapped using aniline
buffers.

Rebek and co-workers35 have reported a technique for the detection of
reaction intermediates. This technique involves the generation of a reac—
tion intermediate from an insoluble polymeric precursor. The intermediate
is detected by trapping on a second solid phase susPended in the same
solvent. An acyl transfer to II has been observed when the precursor I
was treated with triethylamine in dioxane (Figure 8). This acylating
agent closely parallels the ketene intermediate suggested by Bruice in his

Ech reactions.

®-CH-@-O 3.30113 200Et . ® -CH§@-O- Solid
3‘\\1 ' Phase

 

 

— 6—
H OEt
ZC-C< Reagent
0 Solution

OI,

 

 

1\ I Solid
® -CH2-NH2 @ -CH 2NHCCH 2|COEt Phase
Figure 8. Three Phase Test for Reaction Intermediates

In the reaction between isoalkyloxazines and n—butyllithium, Meyers

and co-workers“6 have reported trapping a ketenimine intermediate (eq. 128).

0 0° 0
+ n-BuLi —. Ar 0L}
N FR THF N N=C=C\

Les OSi(CH3)

(128)

 

111

The ketenimine can be successfully isolated by trapping with trimethyl-

chlorosilane.
Rate Studies

One point which iS not clearly revealed in Tables 1 and 2, is that
in many of the rate studies, there was an unusually rapid increase in the
rate of decomposition at a certain point in the experiment. In most
cases, this occured after 50—60% of the enolate had decomposed. This
rapid change was often accompanied by a color change from yellow to orange
in the decomposition solution. With ethyl acetate, the enolate remained
relatively stable for 6-10 hours, then completely decomposed. These
results suggested that the rate data obtained are probably too complicated
for detailed kinetic analyses.

Comparison of relative rates of decomposition, between ethyl and
t-butyl ester enolates clearly indicates that the ethyl ester enolates

are the more stable (Figure 9).
LiC(CI-13)2002Et < LiC(CH3)2C02
LiCH(CH3)002Et < LiCH(CH3)002-I-

LiCH2002Et < LiCHZCOEI—

Figure 9. Comparison of’Relative Rates — t-Butyl and Ethyl Esters

These results are Opposite to those expected for an "Inverse Claisen"
mechanism. In this mechanism, one would expect that the more sterically
hindered t-butyl esters would condense at a Slower rate. The results

found in Figure 9 can be rationalized by a ketene mechanism. If steric

112

relief in the formation of a ketene is assumed to be the driving force,
the t-butyl ester enolates Should be less stable than the ethyl ester
enolates.

Even though the simple trend that t-butyl ester enolates are less
stable than ethyl ester enolates is possibly consistent with a ketene
mechanism, other trends are not as easily explained. For example, if
steric relief is indeed the driving force in the decomposition of ester
enolates, then lithio ethyl acetate Should be more stable than lithio

ethyl isobutyrate (Figure 10).
LiCHZCOZEt < LiCH(CH3)COZEt < LiC(CH3)ZCOZEt

Figure 10. Comparison of Relative Rates - Ethyl Esters (Predicted)

The results actually found, are just the Opposite (Figure 11).

LiCH(CH3)2002Et <LiCH(CH3)OOZEt < LiCHZCOZEt
Figure 11. Comparison of Relative Rates - Ethyl Esters (Observed)

The trend in stability of ethyl ester enolates is most consistent with the
"Inverse Claisen" mechanism.
Comparison of the stabilities of three t-butyl ester enolates provides

evidence that steric effects are important (Figure 12).

LiCH(CH3)CO§I- < LiCHzoogI- < LiC(CH3)ZCO'2-I-
Figure 12: Comparison of Relative Rates - t-Butyl Esters (Observed)

The unexpected position of lithio t-butyl propanoate indicates other

113

factors are probably involved, and that the full magnitude of the steric
effect is not reached until lithio t-butyl isobutyrate.
In the experiments where a large excess of the lithium amide base

was used, the rate of decomposition was enhanced (eq. 129).

+ ( > "780 25° H+ + < %)
CH CO + i-Pr NLi _____.. -——-—o- ————b CH CO 55
3 2 2 THF 2 hrs. 3 2
+ (129)
-78° 25° H
011300;}- + 2(i—Pr)2NLi E. 7;; —. CH3002 (18%)

These results are totally inconsistent with the "Inverse Claisen" mechan-
ism. With a large excess of base present, the equilibrium in the first
step of this mechanism Should be forced to favor formation of the enolate
and not protonation (eq. 130).

I I
Lifoozn + HA —___. H-I'JCOZR + LiA (130)

I LiN(i-I>r)2 J

This mechanism would predict almost total stability of the enolate and not
an enhancement in the rate of decomposition. The enhancement in the rate
of decomposition can be explained if it is assumed that the excess base
solvates the lithium of the enolate. The rate of formation of the ketene
Should be enhanced by this association between the enolate and amide base.
Evidence for a molecular complex between carbanionic Species and diiSOpro-
pylamine has been reported.“7 A second explanation can be found if it is
assumed that fermation of a ketene intermediate is reversible. The excess

base could then trap the ketene, which would lead to rate enhancement.

114

Such a mechanism would require incorporation of lithium.diiSOPrOpylamide
in the products. N,NrdiiS0pr0pylisobutyramide has been observed as the
major product in the decomposition of lithio ethyl isobutyrate, in the
presence of excess base. No amide products have been observed in the
decomposition of Simple acetate enolates.

Isolation of N,Nedimethylisobutyramide and N,Nrdiispropylisobutyra-
mide, from decomposition solutions containing excess base, is most
consistent with the ketene mechanism (eq. 131).

25° H+
LiC(CH3)2C02Et + 10(CH3)2NH E» ——> (CH3)2CHCON(CH3)2
(131)
-78° 25o H+
(CH3)2CHCOZEt + 2(i-Pr)2NLi _l-TH—F. —» —¢- (0113)201100N(i-1>r)2
One possible explanation for the first reaction in equation 131 is a

proton transfer between the enolate and amine, followed by a direct substi-

tution of the alkoxide by the amide (eq. 132).
£——.
LiC(CH3)2002Et + (CH3)2NH __, (C113)2CH002Et + LiN(0H3 2 ‘-—-__,

(CH3)2CHCON(CI{3)2 + LiOEt (132)

Evidence supporting this mechanism is found in the experiments where ethyl
isobutyrate and ethyl formate are treated with lithium dimethylamide. Good

yields of the corresponding N,Nédimethylamides were obtained (eq. 133).

115

-78° 250 H+
(CH3)ZCHCOZEt + LiN(CH3)2 -——~ —. ——v (CH3)2CHCON(CH3)2
THF

(133)

-78° 25° H

H00 Et + LiN(CH3)2 _- = = H00N(CH
THF

 

2 3)2

The experiment reveals that direct substitution by lithium amides is
possible. On the other hand, it seems unlikely that the extremely hindered
lithium diisoprOpylamide could be involved in a direct substitution with
the bulky ethyl isobutyrate. The formation of N,N-diiSOprOpylbutyramide
would then be more consistent with a ketene mechanism.

When a solution of lithio t-butyl acetate containing lithium t-but-
oxide was stirred at 25°, the rate of decomposition was decreased compared

to the rate of a solution which did not contain the alkoxide (eq. 134).

+ + THF/25° H+ + (6%)
LiCH 00 + LiO ———* ——-O CH 00 8
2 2 2 hours 3 2
(134)
THF/2 5° H+
LiCHzOOZ-I- —2-h——> ——-* 61130051’ (55%)
ours

These data provide evidence for a reversibly formed intermediate (eq.
135) -

H\

_A
LiCHzOO-z-I— ‘___. H/0=0=0 + Lio-I- (135)

As would be expected, an increase in the lithium t-butoxide concentration
would force the equilibrium towards the enolate and thus decrease the

decomposition rate. The results found in this experiment are inconsistent

 

116

with the "Inverse Claisen" mechanism, Since addition of lithium alkoxides
should not have any effect on the decomposition rate.

As can be seen in Table 14, addition of lithium ethoxide to a decom-
position mixture of lithio ethyl acetate or lithio ethyl isobutyrate
produces no change in the rate of decomposition. These results are totally
inconsistent with a reversibly formed ketene mechanism. If ketene forma-
tion was irreversible, addition of lithium ethoxide Should have no effect
on the decomposition rate. Similarily, addition of excess base should not
effect the decomposition rate. Since addition of excess base increases
the decomposition rate, it must be assumed that the excess base increases
the rate by either complexing to the enolate (as discussed earlier) or by
competing with the enolate more effectively for the ketene than the

alkoxide competes with the enolate for the ketene (eq. 136)

\ - NIH2
-C-002R —-—e c=c=o + OH ——+ products
(136)
\ _ —C-002H
— C—COZR ———+ C=C=O + OR ___—+ product S
I /

An experiment which provides that most conclusive evidence for a
ketene mechanism has been performed by another member of this research
group.13 t-Butyl 1.1-bis (trimethylsilyl) acetate was treated with lithium

diisoPropylamide to generate an extemely hindered ester enolate (eq. 137).

-78° Li
(CH3)BSfl -:HCO§+- + (i-Pr)2NLi ——T-H—F—e ECHB)BSE] -000§I-
(137)

117

This enolate rapidly decomposes at 250 to form a stable ketene, which was

readily isolated (eq. 138).

 

Li 25° (CH ) Si
EH ) Si] -000§I- 3 )C=C=0 (138)
3 3 2 15 min. (CH3)BSi

The extreme stability of amide enolates (Chapter 1) can also be explained
in terms of a ketene mechanism. The second step in a ketene mechanism for
ester enolates is loss of an alkoxide moiety to generate a ketene intermed—
iate. Since dimethylamide is a stronger base than an alkoxide, it is
likely that the amide would be a poorer leaving group and less likely to
eliminate to form a ketene. A Similar Situation is found with the dianion
of acetic acid. This enolate is know to be extremely stable.“8 The stab-
ility of lithio trimethylsilyl—N,N-dimethylacetamide was expected to be
even greater due to the carbanion stabilizing effect of the silicon. This

expectation is consistent with the results found in Table 13.
Attempted Observation of Ketene by IR

The data obtained from IR Spectra of decomposition solutions are too

inconclusive to use as evidence for either mechanism.

Deuterium Studies

The NMR data obtained from decomposition solutions quenched with
NaHzPOL/DZO provided little insight into the structure of the lithio

t-butyl acetoacetate formed in the decomposition of lithio t-butyl acetate.
Conclusion

Most of the data presented earlier can be rationalized in terms of a

118

ketene mechanism. Since some of the data are partly ambiguous, it would

be difficult to completely rule out a non-ketene mechanism. Results from
the studies where excess base was used seem to completely rule out an
"Inverse Claisen" mechanism, Since the stability of the enolate is not
increased as would be expected. In.the trapping experiments using dimethyl-
amine, the expected N,N-dimethylamides were observed. However, experiments
have Shown that if ester enolates can convert dimethylamine to dimethyl-
amide, direct substitution of free ester iS possible. From results

obtained in this study, a mechanism involving the formation of free ester

seems very unlikely.

EXPERIMENTAL

1. Materials

Esters
All of the esters, obtained commercially, were washed with 5%Isodium
carbonate, dried with anhydrous potassium carbonate, and distilled from

phosphorus pentoxide.

THF and Amines

The THF and diisoproPylamide were obtained from Aldrich Chemical
Company. The THF was distilled from the sodium ketyl of benzophenone and
stored under nitrogen. The diiSOpropylamine was distilled from calcium
hydride and stored under nitrogen. The anhydrous dimethylamine was

obtained from.Eastman Chemicals and used without further purification.

Alcohols
The ethyl alcohol was refluxed over magnesium and a few dr0ps of

carbon tetrachloride for 2 hours, then this was distilled.

neButyllithium
The n—butyllithium.was obtained in 1.6M solutions of hexane from

Aldrich Chemical Company and titrated prior to use .49
2. Procedure for the Decomposition of Ester Enolates

The procedure using t-butyl acetate is representative. The apparatus

in Figure 6 was charged with 5 ml of pentane and 3.44 ml (5.5 mmoles, 1.6M)

119

 

120

of nebutyllithium. The solution was cooled to 0° followed by dr0pwise
addition of 0.77 ml (5.5 mmoles) of diisopropylamine. The solution was
stirred for 5 minutes at room temperature. Then the solvent was removed
under reduced pressure and the white solid was isolated. THF (10 ml) was
added and the solution cooled to -78°. At -78°, 0.67 ml (5.0 mmoles) of

t-butyl acetate was added and the solution of ester enolate was trans-

 

ferred, through teflon tubing using N2 pressure, to a Similar vessel E—
(Figure 6) which had been equilibrated to 25° 1 1°. The reaction vessel

was maintained at this temperature with a constant temperature bath. 5

Samples (0.5 ml) were removed periodically and quenched inversely using E

0. 5 ml of 2M HCl. The aqueous layer was carefully saturated with anhydrous ‘3

potassium carbonate. The organic layer was analyzed using glpc. With
ethyl acetate the 0.5 ml samples were inversely quenched with 0.030 ml
of cyclohexanone in 0.30 ml of ethyl ether, followed by addition of 0.5
ml of 2M HCl and saturation with anhydrous potassium carbonate.
3. Decomposition Studies of Ester Enolates in the Preeence of Lithium
Alkoxides
Procedure A
The procedure for t-butyl acetate and lithium t-butoxide is repre-
sentative. A THF solution at -780 of 10.5 mmoles of lithium diisopropyl—
amide was prepared as described in section 2. The t-butyl alcohol
(0.47 ml, 5.0 mmoles) was added dropwise and the solution was stirred at
-780 for 15 minutes. This was followed by the addition of 0.67 ml (5.0
mmoles) of t-butyl acetate. The reaction mixture was stirred for another

15 minutes at -780 and transferred and quenched as described in section 2.

121

Procedure B

A solution of 3.12 ml (5.0 mmoles, 1.614) of n-butyllithium in 10 ml
of pentane was cooled to 0°. This was followed by dr0pwise addition of
0.h7 ml (5.0 mmoles) of t-butyl alcohol. The solution was warmed to room
temperature and the solvent removed under reduced pressure. The flask
containing the solid lithium t-butoxide was cooled to -78° and a THF
solution of lithio t-butyl acetate (5.0 mmoles, as prepared in.section 2)
at -780 was added to the solid. The mixture was stirred until all of the
solid lithium t-butoxide was dissolved. This solution was transferred to
a third vessel equilibrated to 25°. Samples were removed and quenched as
described in section 2.
4. ‘Qecompositign of Ester Enolates in the Presence of’Exress Lithium

glisgpropylamide

The procedure in these experiments were identical to those described
in section 2. The only difference was that 1.1m ml (10 moles) of diiso-
prepylamine and 6.25 ml (10 mmoles) of n—butyllithium were used to prepare
lO mmoles of lithium diisoproPylamide. The enolate was generated, trans-

ferred, quenched, and analyzed as described in section 2.

5. ‘Qecgmposition of "Amine-Free" Lithio t—Butyl Acetate

 

A solution of 5 mmoles of lithium diisoproPylamide was prepared by
adding 0.70 ml (5.0 moles) of diisopropylamine to a 0. 94 solution at 0°
of 3.13 ml (5.0 mmoles) of nebutyllithium in.pentane. After the solution
was stirred for 5 minutes at room temperature, the pentane solution was
cooled to —78°. The t-butyl acetate (0.67 ml, 5.0 mmoles) was added
dropwise and the reaction mixture stirred for 15 minutes at -78°. The

reaction mixture was warmed to 00 and the solvent was removed under reduced

122

pressure, to leave lithio t-butyl acetate as a white solid. The solid
enolate was dissolved in 10 m1 of THF and the flask placed in a constant
temperature bath. Samples were removed periodically and quenched as

described in section 2.
6. Analyses of‘Decomposition.Products

Solutions of enolates were prepared as described in section 2 and
stirred for 24 hours at room temperature. The reaction mixtures were
quenched with 2M HCl and anlyzed using glpc. The chemical shifts of the

decomposition products are listed at the end of the Experimental section.
7. Isolation of Lithio t-Butyl Acetoacetate

A pentane solution of 25 mmoles of lithium.diisopropylamide was
prepared by adding 3.50 ml (25 mmoles) of diisoprOpylamine to a 1M pentane
solution of 17.12 ml (25 moles, 1.46M) of n-butyllithium. The solvent was
removed under reduced pressure and the solid base was isolated. THF (25
ml) was added and the solution was cooled to -78°. The t-butyl aceto-
acetate (4.08 ml, 25 mmoles) was added and the solution was stirred for
15 minutes. The reaction mixture was warmed to room temperature and the
solvent was removed under reduced pressure. The lithio t-butyl aceto-
acetate was washed with 25 ml of pentane and filtered. This enolate's
stability allows contact with the atmOSphere without decomposition. The
solid enolate was dissolved in either pyridine or deuterated benzene and
analyzed by NMR.

Lithio t-butyl acetoacetate was also isolated from decomposition
mixtures by removing all solvent under reduced pressure, washed with

pentane, filtered and dried under reduced pressure. The decomposition

123
mixture was prepared as described in section 2.

8. Reaction of Lithio t-Butyl Acetate with Ketene

Preparation of Ketene

Ketene was prepared by pyrolysis of 15 g of freshly distilled diketene
and was trapped in a bath of THF cooled to -78°. The THF solution of
ketene was titrated by adding an excess of sodium hydroxide solution and
titrating the excess base with hydrochloric acid. The molarity was found

to be 6.13M.

Reaction with Lithio t—butyl Acetate

A 0.5M THF solution of lithio t-butyl acetate (5.0 mmoles) was pre-
pared as described in section 2. To the THF solution, at -78°, was added
1.0 ml (6.13 mmoles) of the ketene solution. The reaction mixture was
stirred for 30 minutes at -78°, then.warmed to room temperature where it
was quenched with saturated NaHéPOu/D20 and dried with anhydrous magnesium

sulfate. The organic phase was analyzed with glpc and NMR.

9. Ketene TrappiggiExperiments

 

The procedure using t-butyl acetate and dimethylamine is representa-
tive. A 0.1M THF solution of lithio t-butyl acetate (5.0 mmoles) was
prepared as described in section 2. To this solution at -789 was added
3.30 ml (50 mmoles) of dimethylamine. The reaction mixture was stirred
for 15 minutes at -78° and then warmed to room temperature and stirred for
an.additional 24 hours. The solution was quenched with saturated nanépou/

H20, and analyzed with glpc.

124
10. Reactions of Esters with Lithium.Dimethylamide

The reaction between ethyl isobutyrate and lithium.dimethylamide is
representative. A 1M suspension of lithium dimethylamide (4.0 mmoles) was
prepared by adding 0.26 ml (4.0 mmoles) of dimethylamine to a solution of
2.54 ml (4.0 mmoles, 1.58M) of n-butyllithium in pentane, at 0°. The
lithium amide formed immediately as a white precipitate. The pentane was
removed under reduced pressure and the solid amide base was dissolved in
8.0 ml of THF. The THF solution was cooled to —78°, which caused the
immediate precipitation of the lithium.dimethylamide. Addition of 0.53
ml (4.0 mmoles) of ethyl isobutyrate was followed by the dissolution of
the precipitate. The solution was stirred for 15 minutes at -78°. and then
warmed to room temperature and stirred for an additional 15 minutes. The

reaction mixture was quenched with saturated NaHZPOu and analyzed with glpc.
11. Attempted Isolation of Retene Intermediates

A 1M solution of lithium isopropylcyclohexylamide (25 mmoles) was
prepared by addition of n.23 ml (25 mmoles) of N-isopropylcyclohexylamine
to a pentane solution of 15.9 ml (25 mmoles, 1.58M) of n-butyllithium at
0°. N—isapropylcyclohexylamine was used in place of diisOpr0py1amine
because it is much less volatile. The pentane was removed under reduced
presssure and 25 m1 of THF added. The THF solution was cooled to -78p and
ethyl isobutyrate (3.34 ml, 25 mmoles) was added dropwise. The mixture was
stirred at -780 for 15 minutes, then warmed to room temperature. A slow
stream of nitrogen was blown through the reaction mixture and then
bubbled through a trap containing THF cooled to -78°. After 8 hours the
trap was removed and 3.25 ml (50 mmoles) of dimethylamine was added. The

THF solution was analyzed by glpc.

125
12. Attempted Identification of Ketene Using IR

A 0.5M solution of lithio ethyl isobutyrate was prepared as described
in section 2. Samples of the reaction mixture were placed in an IR cell
and Spectra were run immediately. THF was placed in the reference cell.
13. Product Analyses

A11 1H Spectra were run on a Varian T-6O spectrometer. IR Spectra

were run on a Perkianlmer Model 2373 Grating Infrared Spectrophotometer.

CH3000H200§+' t-Butyl Acetoacetate

NMR(CCl,+): 63.10(S,2H), 62.06(S,3H), 61.36(s,9H) (little evidence

of enol form).

CHBGOCHZGOZEt Ethyl Acetoacetate

NMR(CClu): 64.00(q,2H), 63.26(S,2H), 62.10(S,3H), 61.20(t.3H).

GHBCOMi-jPr)2 N,N-diisopropylacetamide

NMR(CClu): 63.37(m.2H), 61.89(S,3H), 61.20(d,12H).

0L1
I
0H30=0H005+ Lithio t-Butyl Acetoacetate

NMR(CClu): a 4.74(S,1H), a l.9l(s,3H), 6 1.54(S,9H).

CH oocnzoonmn N,N—dimethylacetoacetamide (Keto form)

3 3)2

mama“); c 3.38(S,2H), c 2.90(S,6H), 5 2.18(s,3H).

126

OH

I
CH3C=CHCON(CH3)2 N,N-dimethylacetoacetamide (Enol form)

NMR(CClu): 614.70(s,lH), 65.00(s,lH), 62.81(S,6H), 61.84(S,3H).

CH CON(CH

3 3)2 N,N-dimethylacetamide

.

mama”): 62.97(s.3H). 52.77(s.3H). 51.93(s.3H)-

(CH3)ZCHCON(CH3)2 N,N-dimethylisobutyramide
NMR(CClu): 53.33(m,lH), 62.96(S,3H), 62.83(s,3H), 61.00(d,6H).
(0H3)20Hcoc(cn3)20023t
MINCE“): Git-0701.211). 62.70(q.1H). 61.27(s.6H). 61.27(t.3H).

61.00(d,6H).

CHBCHZCHZGOCMCHZCHBMOZEt

WHOM“): 5’4’003(Qa2H)1 63.07(t,1H), 62033(t92H)! 51.70(Qv2H)9

61.70(q,2H), 61.23(t,3H), 60.87(t,3H), 60.87(t,3H).

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