E

'A" N E' ' ww m-M-w ,, , w . \, . A, , ., V ‘ __ ‘ V , _.,A . ., .E . E h _‘ ., WT. H .- . E ' ;.v-.‘-,‘n
-1_ :"M ”9.3-3. :1‘. pr. r,‘ ‘. ".1‘.‘. v . u. ,. .. ' w .. H E u, ‘_ ." "A. .,., ‘ “H V. .M‘IHM‘ " ‘ E. on” .. .w‘... E . M “; ‘ . .E ..E
v 51:75.} ‘T‘- V-".. '. ’ '

PREPARATION AND REACTIONS OF ALPHA.- .
TRlMETHYLSILYL ESTER ENoLATEs; ,

Dissertation for theDegree of Phi 'D.‘ »
MICHIGAN STATE UNIVERSITY * :-
. STEPHEN LEE HARTZELL , , -~ ’
. 1975

is

This is to certify that the
thesis entitled
PREPARATION AND MAGIONS (l'
ALPHA mmurrsnn. mm mom-rm
presented by
Stophon' I.» Hudson

has been accepted towards fulfillment
of the requirements for

Ph 0 Do degree in CIR-181:1?

WMWQ (QM

Major professor

Date ‘/0/(°/75’

0-7639

is“ fiw
>5G'm3m'wp' full.
. ‘ sfi

 

‘Illur I l . l4 ‘illl 2. lll‘nl‘l ‘1 I!!! :0 ll 1111511.jl 111!

 

 

 

 

 

 

~_ ' '
'1 -‘~"‘ .

TT‘

   
   
   
  
  
  
  
 
  

h M halo est-u“ :~ -. . t 11‘1 w. mwwcpylcvclohcxfluldo 1t.-

1
. t Ll
f‘.‘u ‘ .-
ufutan at a“ : .. :mnpev a: reg to give rm; curt-smut. . .

.:- lfl‘ ,

 

mar mun. 1K1 v:,,»,j;;.1‘,-.,-.,—. 301 nun»: of “that“ “WK

  
      
 

t... t-butvi 'nmu- emu, L tw.‘ ’.\'-33Cei“‘y and khan-.1

ta wen qua-lied r'fi jl'u'lfi 'nyiltw‘h‘ch new to 3130

D “3 of mcnvv with: r. tank 9—,“ " Hiram-mt“: in

‘ titan Cerulean”. mu: Eixich‘f‘u“ 33‘ k\.-’:‘> r. 0-- ,i:vdw.ng

mats in L11; "iv-EH;

‘Mm dllouprixtufle'éfJo “Hwy. 13'” s-iqugy‘: Ja‘pr‘f‘ “A 14!.”

to give: arable : annex-”gs: m rew‘.‘ um. -.v’ '; 1:,th

mate; fng-huty? 1—Ca'5DGl‘sfiit-11V’."4-:‘i:' .'.~ H‘s-M11,

"m frm the reacuon a! itch‘.“ E fits: m uric/t“ ‘wk nmfiflm ‘
:1”. M’ “Iii-d i‘Ctill'h‘l!$‘..-, s:'/.-r ~ ”Etrbw‘? “15:: .‘v; "
imbue L- tctuhydmscrn u ‘ww awn‘murx " ‘ '
m of "‘0 carbon “ifiafld $513: , «:1er g 8' m
h A. httahydmfurn unkntw 3 ram '.~.".‘L- nah r
4:,

tour!“ with mm: ups why-wan ~¢ fig!“ M T‘iy’

l

.4

' "ms-«unturned «mo 3 MM! 2148‘s

l

 

ABSTRACT

PREPARATION AND REACTIONS OF ALPHA TRIMETHYLSILYL ESTER ENOLATES
By

Stephen L. Hartzell

Alpha halo esters react with lithium isopropylcyclohexylamide in
tetrahydrofuran at dry ice temperatures to give the corresponding
a-halo ester enolates. Tetrahydrofuran solutions of lithiated ethyl
chloroacetate, t-butyl bromoacetate, t—butyl chloroacetate, and t—butyl
dichloroacetate were quenched with dilute hydrochloric acid to give
632 to 962 of recoverable ester. Lithio t-butyl chloroacetate in
tetrahydrofuran condenses with aldehydes and ketones to produce
glycidic esters in fair yields.

Lithium diisopropylamide reacts with t-butyl acetate at low
temperatures to give stable tetrahydrofuran solutions of lithio
t-butyl acetate. Igggfbutyl a—trimethylsilylacetate is obtained in
good yields from the reaction of lithio t-butyl acetate with trimethyl-
chlorosilane. Iggtfbutyl a-trimethylsilylacetate is metalated with
lithium diisopropylamide in tetrahydrofuran to give indefinitely
stable suspensions of the carbon silylated ester enolate at dry ice
temperatures. Tetrahydrofuran solutions of lithio t-butyl a—tri-
methylsilylacetate condense with aldehydes and ketones to give the

corresponding a,B-unsaturated esters in excellent yields.

 

 

Stephen L. Hartzell

The carbon silylated ester enolate reacts with trimethylchloro—
silane at low temperatures to give t—butyl bis(trimethylsilyl)acetate
in moderate yields. Lithium diisopropylamide generates lithio t-butyl
bis(trimethylsilyl)acetate at low temperatures in tetrahydrofuran.
Aliphatic and aromatic aldehydes condense withythe bis carbon silylated
ester enolate to produce u—trimethylsilyl a,B-unsaturated esters in
good yields. However, ketones fail to react with the ester enolate.

N—Acylimidazoles condense with lithio t—butyl a-trimethylsilyl—
acetate in tetrahydrofuran at low temperatures to produce, after
hydrolysis, B-keto esters in excellent yields., Lithio t-butyl aceto-
acetate is obtained directly from the reaction of N—acetylimidazole

with the carbon silylated ester enolate after removal of the solvent.

 

 

PREPARATION AND REACTIONS OF

ALPHA TRIMETHYLSILYL ESTER ENOLATES

By

Stephen Lee Hartzell

A DISSERTATION

Submitted to

Michigan State University

in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1975

 

 

 

ACKNOWLEDGEMENT

The author wishes to extend his appreciation to Dr. Michael W.
Rathke for his guidance, assistance, and inspiration throughout this
investigation. Thanks are also given to Dr. William H. Reusch for
his many helpful comments in the preparation of this thesis.

The author hopes his parents wishes and expectations of him have
been fulfilled and appreciates their interest and encouragement.

The author wishes to thank his wife, Paula, for her patience,
encouragement, and the typing of this thesis.

Finally, the author is grateful for the financial support of
Michigan State University and the Petroleum Research Fund of the

American Chemical Society.

11

 

 

TABLE OF CONTENTS

CHAPTER I
THE GENERATION OF GPHALO ESTER ENOLATES
Page
INTRODUC T ION . O I O O O I I O O U 2
RESULTS . . . . . . . . . . . 7

DISCUSSION . . . . . . . . . . . 13

EXPERIMENTAL . . . . . . . . . . 21
I. Materials . . . . . . . . . 21
II. Preparation, Decomposition, and Quenching Analysis
of Ester Enolates . . . . . 21
A. Preparation of Egrthutyl Chloroacetate . . . 22
B. Preparation of EEEEfButyl Dichloroacetate . . 22
C. Preparation of Lithio Egrthutyl Chloroacetate . 23

D. Decomposition of Lithio tert-Butyl Chloroacetate . 23
III. Darzens Condensation of Lithio Halo Ester Enolates . 24

IV. Reaction of Lithio Ester Enolates with Trimethyl—
chlorosilane . . . . . . . . 25

V. Product Analysis . . . . . . . . 25

iii

 

 

TABLE OF CONTENTS - continued

CHAPTER II
THE PREPARATION OF a,B-UNSATURATED ESTERS

WITH C-SILYLATED ESTER ENOLATES

 

Page
INTRODUCTION . . . . . . . . . . 29
RESULTS . . . . . . . . . . . 33
DISCUSSION . . . . . . . . . . . 43
EXPERIMENTAL . . . . . . . . . . 54
I. Materials . . . . . . . . . 54
II. Preparation of t-Butyl a,B—Unsaturated Esters . . 54
A. General Procedure . . . . . . . 55
B. Product Analysis . . . . . . . 55

III. Preparation of tert—Butyl a—Trimethylsilyl
G ,B-Unsaturated Esters . . . . . . 59
A. General Procedure . . . . . . . 59
B. tert-Butyl u-Trimethylsilylacrylate . . . 60
C. Product Analysis . . . . . . . 62

IV. Reaction of t—Butyl 2-Sily1ated Unsaturated Esters . 63

A. tert-Butyl 2—Trimethylsilyl-Z-butenoate with
Methyl Grignard . . . . 63

B. tert-Butyl 2-Trimethylsily1acry1ate with Methyl
Grignard . . . 63

C. tert-Butyl 2-Trimethylsilylacrylate with
Lithio t-Butyl acetate . . . . . 64

 

D. tert-Butyl 2—Trimethylsilylacrylate with
3-Pentanone Enolate . . . . . 65

 

iv

 

TABLE OF CONTENTS - continued

CHAPTER III

THE REACTION OF ACYL COMPOUNDS WITH

ol-TRIMEETHYLSILYL ESTER ENOLATES

Page

INTRODUCTION . . . . . . . . . . 67

RESULTS . . . . . . . . .2 . . 74

' DISCUSSION . . . . . . . . . . . 82
EXPERIMENTAL . . . . . . . . . . 88

I. Materials . . . . . . . . . 88

II. Preparation of N-Acylimidazoles . . . . . 88

’ III. Preparation of B-Keto Esters . . . . . . 89
A. tert-Butyl Cinnamoylacetate . . . . . 89

B. Product Analysis . . . . . . . 90
C. Isolation of Lithio tert-Butyl Acetoacetate . . 91
IV. Reactions Involving Dianion Systems . . . . 91

A. Lithio tert-Butyl Acetoacetate with
Trimethylchlorosilane . . . . . . 91

B. Lithio tert-Butyl Trimethylsilylacetoacetate
with Benzaldehyde . . . . . . . 92

V. Reactions Involving Monoanion Systems . . . . 92

A. Ethyl 3—Pyrrolidinocrotonate with
Trimethylchlorosilane . . . . . . 92

B. Ethyl 4-Trimethylsilyl-3—pyrrolidinocrotonate
with Benzaldehyde . . . . . 93

 

 

 

TABLE OF CONTENTS - continued

BIBLIOGRAPHY

Preparation of Ethyl 3— —Trimethylsiloxy-
crotonate . . .

Ethyl 3—Trimethylsiloxycrotonate with
Benzyl bromide .

 

tert—Butyl 4-Trimethylsilylacetoacetate with
Benzaldehyde . . . .

vi

Page

93

94

94

96

 

 

 

LIST OF TABLES

Page
Quenching Results of a-Halo Ester Enolates . . . . 8
Yields of Glycidic Esters Using Lithium Halo Ester Enolates 10
Results of Silylation of Ester Enolates . . . 19
Reaction of Carbonyl Compounds with Lithio tert-Butyl
Trimethylsilylacetate . . . . . . . 35
Reaction of Aldehydes with Lithio tLrt-Butyl
bis(trimethylsily1)acetate . . . 39
Elemental Analysis of the a,B—Unsaturated Esters . . . 58
Reaction of Acid Chlorides with Imidazole . . . . 75
Reaction of N-Acylimidazoles with Lithio tLrt-Butyl
Trimethylsilylacetate . . . 77

 

  
  
  
  
 
   

.(
".
I
I;
'3' . . LIST OF FIGURES
‘ nil. .4-
, 'n‘ Page

~g; ‘ldisible u-Halo Ester Enolate Decomposition Routes . . 13
Enter Enolate Resonance Hybrid . . ' . . . . 29
Reaction Apparatus . . . . . . . . 56
Reaction Apparatus . . . . . . . . 61

Possible Reaction Paths for Lithio t-Butyl
Trimethylsilylacetate with Acylating Reagents . . . 68

 

   
   
    
   
  
  
  
  

1,Q'u’rotonn Sn -: -'-x~ :an- nadir. aw': 1"».- tern-wood“
e
.., .
" M '3‘“ I" 35‘4‘» “if l.‘-.’"Hi:“- M!“- bum. tutti“! (W. I).
'. Chum: calmer l-":'F .mnufil.‘ gown-H4 M14? 1- M13."

’ trnttnnn, using net-.3 51m.» '1. 5.1“”

I " A '4‘ , -‘ - .4 '
HO rmnejr‘it-i'a (1)
5: x
CHAPTER I

. I

,b
A a, 1m cmdmsariot. vmprovs 81335-‘6:,»~ ~ ,rsnv" first.“
‘v' ‘ ., mum OP o-IALO ESTER nouns

An u-hnlo ester Team: «1;; rag-guru, u 9W1.

fl din presence of a natal Alkalild or gun was". no ‘ 3

 

I

INTRODUCTION

The a—protons in o-halo esters are acidic, and the corresponding
ester enolates can be obtained through acid-base reactions (eq. 1).
In the past, these enolates were normally generated only in equili—

brium concentrations, using metal alkoxide bases.

—9 -

ac — COOR — c —-— COOR (1)
‘ BB |
x x

The Darzens condensation employs this approach to prepare glycidic
esters (eq. 2,3)5’2 An o—halo ester reacts with a ketone or aromatic

aldehyde in the presence of a metal alkoxide or amide base. The

ac ~— c0011 HE — coon + ROH (2)
l ‘ Ron
x x
i T"

- ,
__ _ _l a_c_cn_ R —C—CHCO0R 3
HT COOR + C <____ I I C00 -—-€> l ( >

X X

reaction is usually most successful with a—chloro esters. Alpha-iodo
esters, and o-bromo esters to a lesser extent, often alkylate enolizable
1
ketones to give y-keto esters (eq. 4). In addition, formaldehyde and
C

NaNH
HSCOCH(CH3)2 + ICH COOEt -—--2-9 C6H5COC(CH3)2CHZCOOEt (4)

6 2

monosubstituted acetaldehydes usually give poor yields of the desired
products.1 The scope of the reaction is further limited by the
availability of the appropriate a—halo ester.

The Reformatsky reaction is a second method used to obtain

metalated o-halo esters (eq. 5,6).3’4 5’6’7'8'9 is

An o-dihalo ester
reduced in an irreversible fashion with zinc metal to produce a halo-
zinc ester enolate (1).5 Because of the instability of the zinc
enolate, I is usually trapped as it is formed by reaction with a

carbonyl compound.

Br Br
EtOOC— C— COOEt + Zn ——> EtOOC — C ——CO0Et (5)
Ar AnBr
I
Br

EtOOC—(ll -—COOEt + —C '-

 

ZnBr

(6)
—c ~r-OH c -—OZnBr

H+

EtOOC -—C -— COOEt (— EtOOC— (i -—-COOEt

(712) Br Br

 

 

The two most common side reactions of the halozinc reagent are
condensation with the starting a-halo ester10 or enolization of the
carbonyl component. This latter reaction is especially prevalent with
aliphatic a1dehydes.11’12

Recently, a two—step Reformatsky sequence was developed involving

13’14’15 However, this

initial generation of halozinc ester enolates.
method apparently has not been extended to the dihalo esters.

Direct proton removal from an ester (pka=24)16 with lithium dialkyl-
amide bases provides a convenient method to generate ester enolates
from simple aliphatic esters. These strong bases (pka of NH3>34)17

18soluble in many organic solvents, and capable

are weakly nucleophilic,

of quantitatively generating ester enolates at low temperatures.
Lithium isopropylcyclohexylamide GI)(LiICA), formed in hexane by

reaction of the amine with a commercial n—butyllithium solution,

quantitatively generated the ester enolate of tert-butyl acetate at

-78° in THF (eq. 7,8).19 Lithium diisopropylamide CIII)(LiDPA)19 and

hexane Q

NH + n-BuLi—é NLi +n—butane (7)
II
THF
NLi + CH CO0C(CH ) ———————) LiCH COOC(CH ) + NH (8)
3 3 3 -78° 2 3 3

lithium bis(trimethylsily1)amide20 (LiHMDA) (IV) are prepared and

frequently employed in a similar fashion.

[wqt

)\ (CH3)3S\

NLi /////NLi
II

I IV

An investigation was undertaken to extend this two-step reaction
sequence to the formation of a—halo ester enolates (eq. 9), which could
then be used as discrete synthetic intermediates without the complica-

tions caused by the presence of the generating base.

LiICA __
xcn2c00R-——) XCHCOOR

(9)

o
/ \ -X” |
— (l: --— CHCOOR (—-—-— — (I: — THCOOR

The actual anion formation might be demonstrated by successful
Darzens condensation or Silylation with trimethylchlorosilane (TMCS)21

(eq. 9,10).

H OSi(CH
\_/

X COOR

_ TMCS 3)3
CHCOOR——9 (CH3)381(|JHCOOR + (10)

X X

 

 

 

The stability of a-halo ester enolates could be determined by glpc

analysis for recoverable ester from quenched ester enolate solutions

(eq. 11).
LiICA H+
XCHZCOOR a Li(lIHCOOR ——-—9 XCHZCOOR (11)
X

 

RESULTS

Qgenching and Decomposition of o-Halo Ester Enolates

Several o-halo esters were reacted with LiICA in THF at -78°.
After 10 to 120 minutes, these solutions were quenched with dilute
hydrochloric acid followed by glpc analysis for recovered ester. The
chloro esters were returned in higher yields than the bromo esters.
Ethyl bromoacetate and t—butyl bromoacetate were recovered in 112 and
632 yields respectively. Ethyl chloroacetate, t-butyl chloroacetate,
and t-butyl dichloroacetate were returned in 80, 83, and 96% yields

respectively (eq. 12) (Table 1).

LiICA _ 3N HCl
xca cooc<cn ) —-———9xcucooc(cu ) ————)xca cooc(cn ) (12)
2 3 3 THF _78. 3 3 _78. 2 3 3
Q

When warmed to 25° for 100 minutes, the lithio t-butyl chloro-
acetate solution gave, on quenching, only a five per cent return of the
chloro ester. After stirring overnight in THF at 25°, lithio t—butyl
chloroacetate gave t-butyl 2,4—dichloro-3-oxobutanoate (V) and 1,3-
dichloroacetone (VI) as the major isolable products (eq. 13). This
eater enolate was allowed to react at 25° in presence of cyclohexene
or l-octene for 3 hours. Glpc analysis indicated a 1002 recovery of

unchanged olefin.

 

TABLE 1

Quenching Results of o—Halo Ester Enolates

 

 

Ester Solvent Temp. °C Time (min.) 2 Returna

Ethyl

bromoacetate THF -78 15 11

Ethyl

chloroacetate THF —78 110 80

t—Butyl

bromoacetate THF —78 10 63

t-Butyl

chloroacetate THF -78 30 83
THF v78 120 75
THF 25 100 5
Pentane -78 30 27

t-Butyl .

dichloracetate THF -78 120 96

 

a Determined by glpc analysis of aliquots quenched with 3N hydrochloric
acid.

 

 

+

RT H
Eucooc cu ‘ -——-—————€> +
I ( 3)3 THF ---€> (IIHZCOCHCOOC(CH3)3 (lZHZCOCH2 (13)
l l
Cl overnight C1 C1 C1 Cl

V VI

Darzens Condensation of a—Halo Ester Enolates

Darzens condensation of the a-halo esters provided additional
evidence for enolate formation. The lithium enolates of ethyl chloro-
acetate and t-butyl chloroacetate reacted with aldehydes or ketones at
-78° in THF to give the corresponding glycidic esters in 40 to 64%
yields (eq. 14) (Table 2). These condensations gave predominately the
trans glycidic esters in the case of ethyl B—phenylglycidate and

t-butyl B-ethylglycidate.

0
R H
THF, -78°
HWT/ \b/’

(14)
then to RT Rh;

c16hcooc(cn + RCOR?

3)3
COOC(CH3)3

The stereoisomers of ethyl B-phenylglycidate were separated on an
SE-30 column. The first eluted glycidic ester exhibited a coupling
constant of 2H2 for the oxirane protons, consistent for the trans
isomer.22 It was assumed that the stereoisomers of t-butyl B-ethyl-
glycidate were eluted in the same order on an SE-30 column.

The corresponding chlorohydroxy esters were isolated from the

condensation of lithio t—butyl chloroacetate with propionaldehyde and

butyraldehyde (eq. 15).

10

TABLE 2

Yields of Glycidic Esters Using Lithium Halo Ester Enolates

 

 

Ester Substrate Z Yieldc Cis/Trans Lit. Yielde
Ratio

Ethyl a

chloroacetate Benzaldehyde 64 16/84 50

t-Butyl » b

chloroacetate Acetone 40 (77.5) 60

t-Butyl d

chloroacetate Butyraldehyde 50

t—Butyl

chloroacetate Propionaldehyde (56.5) 7.5/92.5 20-30

 

a Isolated yields.
b Glpc yields are parenthesized.

c All compounds exhibited spectral properties consistent with assigned
structures.

d Tentatively identified as t-butyl 2-chloro—3-hydroxyhexanoate.

e Literature yield comparison to the ethyl glycidic esters (reference 1).

 

 

11

l) THF, -78°, 1 hour

 

 

ClCHCOOC(CH3)3 + cn3cnzcno
2) RT, 1 hour
15
w ( )
o
H cooc ca on
\C/ \ / ( 3)3 l
/ —c\H + cu3cn2cmlmc000(caa)3
CH3CH2 CI
56.5%

Reaction of GPHalo Ester Enolates with Trimethylchlorosilane

The lithium t—butyl ester enolates reacted with TMCS to give the
C-silylated ester together with a minor product observed by glpc
analysis (eq. 16). The minor product was sensitive to acid and pre-
sumed to be the 0—sily1ated ketene acetal, since such compounds are
usually readily hydrolized by such treatment (eq. 17). 21 Lithio
t-butyl chloroacetate silylated exclusively at carbon. The reaction
of lithio t-butyl dichloroacetate with TMCS gave 972 C- and 3X

O-silylation.

C1
_- TMCS I C1\\ l/OSi(CH3)3
Cl CCOOC(CH ) ---—--—€’ ClCCOOC(CH ) + C==3C (15)
2 3 3 THF 3 3
-78° Si(CH3)3 Cl COOC(CH3)3

then RT

 

 

12

C1 [IOSi(CH3)3 H+/H20 I
C=C "fl CHCOOC(CH ) + (CH ) SiOSi(CH ) (17)
\\ Do I 3 3 3 3 3 3
C1 COOC(CH3)3 CI

The lithium enolates of t—butyl chloroacetate and t-butyl dichloro—
acetate in THF at -78° gave VII and VIII in isolated yields of 66 and

852 respectively.

c1
Cl — cucooc (CH3) 3 |
c1ccooc<cn3)3
31(ca )
3 3 Si(CH3)3
VII VIII

Lithio ethyl bromoacetate, generated with either LiHMDS or LiDPA
in THF at -78°, gave several unidentified products from reaction with
TMCS. Attempted condensation of ethyl bromoacetate with benzaldehyde
or acetone employing LiICA or LIHMDS again resulted in several

unidentified products. The aldehyde was returned unchanged.

 

I- __._.____ ___,

DISCUSSION
Decomposition of Lithio t-Bgtyl Chloroacetate

From the quenching experiments, lithio t—butyl chloroacetate (IX)
was found to be reasonably stable at -78°. At room temperature, IX

decomposed to t-butyl 2,4-dichloro-3-oxobutanoate (eq. 18).

H+
---ۤCH2COCHCOOC(CH

RT, THF

c1'c'ucooc (ca (18)

) )
3 3 overnight 3 3

IX C1 C1

The o-halo ester enolate IX could conceivably decompose by three
pathways. The ester anion might react by proton abstraction from the
solvent or amine to give the starting halo ester which then condenses
with another molecule of IX. Alternatively, the halo ester enolate

could collapse to a ketene or a carbene (Figure 1).

 

BH XCHCOOR
xcazcoorz ———————>
slow H+
-RO- H\\ - +
XEHCOOR ——9 x/c=c=o XCHCOOR > H 4, (inzcoclzucmR
x x
-x' HECOOR

HECOOR ————-> ROOCCH=CHCOOR

Figure 1. Possible o-Halo Ester Enolate Decomposition Routes

13

 

 

m.._.-

—-—————- __.-

14

Carbenes react with olefins to give cyclopropane derivatives.2
Experiments in which IX was decomposed in the presence of cyclohexene
or l-octene failed to give any cyclopropane product. The olefin was
recovered unchanged even after total decomposition of the starting

enolate had occurred, arguing against a carbene intermediate (eq. 19).

(cu ) cooc H
3 3 \ /
c
l-octene
CH (CH ) ca—cu
RI, THF 3 2 5 2
_ -c1'
c10acooc(cn3)3-----—)_accooc(cu3)3 (19)
VIII [:::fl
[:::]:>cncooc(cu3)3
RT, THF

0f the two remaining decomposition routes, a ketene intermediate
appears most attractive. Thus, a ketene intermediate was proposed to
account for the slow dimerization of Reformatsky reagents upon heating
or standing. The zinc enolate was assumed to collapse to a ketene
which was trapped by a second molecule of the zinc reagent to give

x (eq. 20, 21).2“'25

BanCCOOR -—-9 >0 a=C=O + ROZnBr (20)

'L‘n\

 

15

OZnBr
\ I H I l
Banclzc00R + /c=c =0 4————)—C—C—0R —> Hclzcocllcoon (21)
I
c—o

_(

X

In one case a ketene, rendered unreactive by bulky substituents,26
has been isolated from a solution of a lithium ester enolate. Lithio
t-butyl 1,l-bis(trimethylsilyl)acetate gave bis(trimethylsily1)ketene
in quantitative yield on warming to 25° (eq. 22).27

_ THF
[(CH3)3Si]2CCOOC (cs3)3 -25—°) [(CH3)3Si] 2c=c=o (22)

Reaction of o-Halo Ester Enolates with Aldehydes and Ketones

After our research was initiated, the Darzens condensation of ethyl
bromoacetate was reported, using LiHMDS as base.28 Borch reported THF
solutions of the ester enolate were stable at -78° for one hour. The
addition of aldehydes or ketones to the ester enolate gave excellent

yields of the ethyl glycidic esters (eq. 23).

o
LiHMDS _ CH3CH2CHO Ht.“ / \ /C°°C2H5
BrCH cooc H ————> nrcucooc H ———) c—c
2 2 5 THF _78. 2 5 J: \
' CH3CH2 s (23)

Our attempts to duplicate this procedure with ethyl bromoacetate,

using LiHMDS, LiICA, or LiDPA as the base, were unsuccessful.

 

 

LA. -

16

Addition of TMCS, acetone, or benzaldehyde to the ester enolate
solution gave several unidentified products and returned the aldehyde.
However, acceptable yields of the t-butyl glycidic esters were

obtained from the reaction of lithio t-butyl chloroacetate with
aldehydes and ketones (Table 2). The reaction was complete within
two hours under mild reaction conditions. No attempts were made to
maximize the glycidic ester yields.

Because t-butyl chloroacetate apparently has not been condensed
with acetone, butyraldehyde or propionaldehyde using the metal
alkoxide bases, 3 comparison with the literature yield of ethyl
glycidic esters was made (Table 2).1 The lithium ester enolate method
appears competitive, especially with the monosubstituted acetaldehydes.
These reactive aldehydes probably suffer self—condensation with the

metal alkoxide bases (eq. 24).

o
I u
CHCOR o o
X ||||l _
caccca + R0
0 I /\
_H X
-ccu (24)
I l B o' o
fines H
cucuccu
l /\

Darzens condensation of ethyl chloroacetate with benzaldehyde gave
predominately the trans isomer as did condensation of t-butyl chloro-

acetate with propionaldehyde. Because the configuration of t-butyl

 

 

 

 

17

B-ethylglycidate could not be determined from the coupling constants
of the oxirane protons, the cis/trans isomer ratio was determined by
assuming the elution order on an SE—30 column to be the same as for
ethyl B-phenylglycidate isomers.

The trans glycidic ester is often favored in the Darzens conden-
sation. Thus, condensation of benzaldehyde with ethyl o-chloro—
phenylacetate gave exclusively the isomer trans to the carboalkoxy

function (eq. 25).29

o
(c113)3co'1<+ C6115 C6H5
————>
CGHSCHCOOEt + cénscno (25)
c1 (“9300“ a coon:
752

The hydroxychloro ester, glycidic ester, and starting materials
were isolated from the Darzens condensation of propionaldehyde and

t-butyl chloroacetate (eq. 26). This is consistent for a rate-limiting

0
_ THF H+ H\ / \ /COOC(CH3)3
C1CHC00C(CH3)3 + CH3CH2CH0 -—-€’ C-—-C (26)
.73° fl / \
CH33H2 H

OH

+ CHBCHZCHTHCOOC(CH3)3

C1

 

 

__.——-—‘._

A,E_~__._____—E

18

ring-closure step permitting an equilibration of the aldol inter-
mediates (eq. 28). Such an equilibrium might explain the cis/trans

isomer ratio of 7.5/92.5 for the propionaldehyde adduct.

C1CH2C00R + LiICA-—-——) ClCHCOOR + ICA (27)
l 0—
CIERCOOR + —c ”—96 — c -— CHCOOR (28)
Cl
0-
—c —CHCOOR ——) -—C—CHCOOR + 01' (29)
c1

Silylation of o—Halo Ester Enolates

The lithium chloro and dichloro ester enolates silylated with TMCS
predominately on carbon. The preference for C-silylation was not
particularly surprising for steric reasons. For example, lithio

t-butyl acetate is almost exclusively C—silylated (eq. 30) (Table 3)21

(cu3)351cnzcooc(cr13)3
_ TMCS 98%
cu cooc(cn ) (30)
2 3 3 THF -78°
’
H\\ ’,os1(cn3)3

C—
H” “OC(CH3)3
22

 

19

TABLE 3

Results of Silylation of Ester Enolates

Ester Solvent Silane Z Z
C-silylation O-silylation

 

 

Ethyl acetate

Ethyl acetate

Methyl acetate
t-Butyl
acetate
t—Butyl
butanoate

Ethyl
isobutyrate

Ethyl hexanoate

Ethyl 1-cyclo—
hexylacetate

Ethyl crotonate

THF
THF—HMPA(ZOZ)

THF-HMPA
(1 eq~)

THF
THF
THF-HMPA(ZOZ)

THF

THF
THF—HMPA(2OZ)
THF-HMPA(1 eq.)
THF

THF-HMPA
(1 eq-)

THF-HMPA
(1 eq-)

BDCS

45

90

<1

40

99

99

60

<1

<1

<1

<1

<1

<1

<1

55

<99

60

<1

<1

40

99

99

99

99

99

99

99

 

aBDCS E t—Butyldimethylchlorosilane

 

 

 

20

However, lithio ethyl isobutyrate is silylated predominately on

oxygen (eq. 31) (Table 3).21

CH3

(CH3)3SiC-——COOC2H5

CH3

cu Ecooc H <12 (31)
3| 2 5 THF, -78°

CH3

CH3\ /OSi(CH3)3
C===C\\

1” oc H

3

CH 2 5

99%

Thus it appears that substitution on the alcohol portion of the
ester favors C—silylation while substitution on the alpha carbon

favors O-silylation.

 

—————.—~v

 

EXPERIMENTAL
I. Materials

Ethyl bromoacetate, ethyl chloroacetate, and t—butyl bromoacetate
Were commercially available and used without further purification.
Tert-butyl chloroacetate and t—butyl dichloroacetate were prepared and
purified by vacuum distillation.

All aldehydes and ketones were commercially available and used
after distillation. They were stored under a dry nitrogen atmosphere.
Trimethylchlorosilane was obtained from Aldrich and distilled

(bp 57°/atm. pressure) prior to use. Diisopropylamine (bp 83°/atmt
pressure) was distilled and stored over molecular sieves. Isopropyl-
cyclohexylamine and hexamethyldisilazane were commercially available
and used without further purification. THF was commercially available

and stored over molecular sieves.

II. Preparation, Decomposition, and Quenching Analysis of Ester

Enolates

Tert—butyl chloroacetate is representative of all esters used
for conversion into the enolate and ester recovery. Glpc analysis
utilized a 1/4 inch by 6 foot SE-30 column. Each reaction run had an

appropriate internal standard.

21

 

22
A. Preparation of tert—Butyl Chloroacetate

Into a 200 ml flask fitted with a stir bar, Vigreux condenser

' with an attached bent adapter and receiver, one mole (116 ml) of
benzoyl chloride and one-half mole (47.25 g) of chloroacetic acid

were heated to reflux. After ninety minutes, chloroacetyl chloride
had completed distillation at 83° yielding 45.4 g (80%) of a colorless
liquid.

Chloroacetyl chloride (45.4 g, 0.4 mole) was placed with 50.5 ml
(0.4 mole) of N,N—dimethylaniline in a 500 ml flask equipped with a
stir bar, dropping funnel, and thermometer. Tert—butyl alcohol (37.5
ml, 0.4 mole) was added dropwise to the flask maintaining the tempera-
ture under 30° with the aid of an ice bath. The mixture was stirred
for an additional 45 minutes at room temperature after the addition
was completed. After pouring the reaction mixture into 75 m1 of water,
the layers were separated, the aqueous phase washed with ether and
combined with the crude ester. The organic phase was washed thrice
with 102 sulfuric acid, then with 10% sodium hydroxide solution, and
dried over anhydrous sodium sulfate. The product distilled at 56—9°/

0

13 mm (lit.3 48-9/11 mm) giving 37.8g (63%) of a colorless oil.

 

B. Preparation of tert-Butyl Dichloroacetate

The acid chloride was prepared as described for chloroacetyl

chloride. A one—half mole reaction gave 53.6 g (72.7%) of a colorless

oil distilling at 106° (lit.31 106°).

Dichloroacetyl chloride (0.36 mole) and DMF (.364 mole, 28.4 ml)

were placed together in a 500 ml flask immersed in an ice bath. The

5..., ,

 

 

 

23
procedure is carried out in the manner described for the monochloro-
ester. The dichloroester distilled at 48—9°/3 mm yielding 42 g (61%)

of a colorless oil.
C. Preparation of Lithio tert-Butyl Chloroacetate

A 50 ml flask equipped with a stir bar, septum, gas inlet valve,
and mercury bubbler was flame dried while a stream of dry nitrogen was
flowing through the system. A 2.4 M (2.1 ml, 5 mmoles) aliquot of
commercial n-butyllithium in hexane was added to the flask. The flask
was immersed in an ice bath and 0.85 ml (5 moles) of N—isopropylcyclo—
hexylamine was added dropwise with stirring. After the evolution of
butane had ceased, the hexane was removed by vacuum which was broken
with nitrogen. The white solid was dissolved in 5 ml of THF and
cooled in an acetone—dry ice bath. Tert-butyl chloroacetate (0.5 ml,
4 mmoles) was added dropwise, and after 15 minutes, a yellow color had
developed. After 30 minutes, the reaction was quenched with 5 ml (3N,
15 moles) of HCl. Upon warming to room temperature, 0.62 ml (4 moles)
of n-butyl benzene (internal standard) was added, and the resulting
solution extracted with pentane. The organic layer was dried over
anhydrous sodium sulfate before glpc analysis. Recovery of tert-butyl

chloroacetate was 83%.

D. Decomposition of Lithio tert-Butyl Chloroacetate

The lithio ester enolate (40 mmoles) was generated as previously
described. The enolate was stirred at room temperature overnight and
quenched with 100 mmoles (33 m1) of 3N HCl at 0°. The aqueous

solution was extracted with ether, and the organic phase dried with

 

24
sodium sulfate. An initial glpc trace showed one major product.
However, a white solid and high boiling liquid were collected. The
solid was a decomposition product from the initial oil since attempted
vacuum distillation transformed the liquid into a white solid. This
same decomposition resulted on an SE—30 column when 50 m1 injections
were made. The solid gave a positive Beilstein test and melted at

42-3° (111:.32

42.5°) consistent with 1,3-dichloroacetone. The oil was
identified by spectral properties which were consistent with t—butyl

2,4-dichloroacetoacetate.
III. Darzens Condensation of Lithio Halo Ester Enolates

The procedure for tert-butyl 8,8—dimethylglycidate is representa-
tive. Twenty millimoles of LiICA in 20 ml of THF was prepared in the
usual manner. The basic solution was cooled with a dry ice-acetone
bath, and the ester (2.0 ml, 20 mmoles) was added drapwise with stir-
ring. After five minutes, acetone (1.84 ml, 20 mmoles) was added
slowly to the yellow solution. The mixture was stirred for one hour
at —78° and an additional hour at 25°, quenched with 13 ml of 3N
acetic acid and extracted with ether. The organic extracts were
washed with water, saturated sodium bicarbonate solution, and dried
over anhydrous sodium sulfate. The product was vacuum distilled
yielding 1.32 g (40%) of a colorless liquid.

The chlorohydroxyester was isolated by glpc from the pgppfbutyl
B-ethylglycidate preparation. The chlorohydroxy ester was the only
product isolated from the t—butyl B-prOpylglycidate preparation. This
latter reaction mixture was stirred for 2.5 hours at —78° followed

by quenching.

25

IV. Reaction of Lithio Ester Enolates with Trimethylchlorosilane

This procedure is representative for all ester enolate silylations.
One-half mole of lithio N,N-diisopropylamide is prepared in a similar
manner to LiICA. After the lithium amide was dissolved in 300 m1 of
dry THF and cooled in a dry ice-acetone bath, 500 millimoles of t—butyl
acetate was added over a 20 minute period and stirred for an additional
5 minutes. The TMCS was rapidly added, the bath removed, and the
mixture warmed to room temperature. The mixture was cooled to 0°, an
equal volume of pentane added, the organic phased washed with 3N
sodium hydroxide and finally dried over sodium sulfate. The solvent
was removed on the rota-evaporator and the product vacuum distilled
giving 130 g (69%) of a colorless liquid.v

Egppfbutyl chlorotrimethylsilylacetate and Eggpfbutyl dichloro-

trimethylsilylacetate gave 66% and 85% yields respectively.

V. Product Analysis

 

The products synthesized were examined by NMR and/or IR. TMS was

the internal standard for NMR spectra.
Chloroacegyl chloride

Bp 83°. NMR (CC14): 6 4.5 (s, 2H).
tert-Butyl chloroacetate

~Bp 56-9°/13 mm. NMR(CC14): 6 3.88 (s, 2H), 6 1.48 (s, 9H).

26

1,3—Dichloroacetone
Mp 42-3°. NMR(CC14): 6 4.3 (s).
tert-Butyl 2,4-dichloroacetoacetate

NMR(CC14): 6 4.9 (s, 1H), 6 4.4 (s, 2H), 6 1.6 (s, 9H). IR(neat):

1750 cm'1 (broad, c=0).
tert-Butyl 2-chloro—3-hydroxyhexanoate

Bp 74—8°/O.3 mm. NMR(CC14): 5 0.8-1.1 (m, 7H), 5 1.5 (s, 9H),

6 3.8-4.2 (m, 2H), 6 4.66 (broad, 1H).
Ethyl ijhenylglycidate

Bp llO°/O.8 mm. NMR(CC14): 6 3.25, 6 3.95 (d, J=2Hz, trans, 2H),

6 7.3 (s, 5H), 6 4.2 (q, 2H), 6 1.25 (t, 3H).
tert—Butyl §,B-dimethy1glycidate

BplL0-4l°/0.5 mm. NMR(CC14): 6 2.98 (m, 2H), 6 1.6 (m) and
5 1.52 (8), total 11H, 6 1.0 (t, 3H). IR(neat): 1740 can'(C=0).

1725 cm-1(shou1der. c=0).

tert-Butyl 3—hydroxyr2-chloropentanoate

Refractive index ngs 1.4444. NMR(CCl4): 6 3.6-4.2 (m, 2H),

5 2.9 (s, 1H, disappeared with D20), 6 1.5 (s, 9H), 6 1.0 (t, 3H).

IR(neat): 3200-3600 cm'1 (on), 1725 cm'1 (broad, c=0).

27

tert-Butyl o-trimethylsilylacetate

Bp 67°/13 mm. Density 0.84. NMR(CC14): 6 1.7 (s, 2H), 6 1.4

(s, 9H), 6 0.1 (s, 9H). IR(neat):l725 cm-1 (broad, c=0).
tert—Butyl a-chloro-o-trimethylsilylacetate

Bp 50—4°/l.0 mm. NMR(CC14): 6 3.64 (s, 1H), 6 1.48 (s, 9H),

6 0.18 (s, 9H). IR(neat): 1740 cm-1 and 1700 cm-1 (shoulder, C=C).
tert-Butyl o,g-dichloro-a-trimethylsilylacetate

Bp 65-7°/2 mm. NMR(C014): 6 1.56 (s, 9H), 6 0.30 (s, 9H).

IR(neat): 1750 and 1725 cm-1 (C=C).

CHAPTER II

THE PREPARATION OF a,B-UNSATURATED ESTERS

WITH C-SILYLATED ESTER ENOLATES

28

INTRODUCTION

Lithium ester enolates are ambident anions capable of combining

with an electrOphile at either carbon or oxygen (Figure 2).

//O O
-—-C-——-C<: (§——€> C====C
I OR OR

Figure 2. Ester Enolate Resonance Hybrid

These metalated esters preferentially react at carbon with alkyl
halides19 or acyl halides33 giving chain-extended esters and B-keto

esters respectively (eq. 1).

RX l
/—-—-9 R ——-c —— COOR
—E— COOR A (1)
RCOX |

RCOCCOOR
Silyl halides give both C- and O-silyl products in relative

amounts depending on the structure of the ester, the silylating agent,

and the reaction conditions (eq. 2) Lithio tert-butyl acetate is almost

29

3O

 

 

TMCS
) (CH3)BSiCCOOR
o /
_ II
—(|: —-c -—-OR (2)
TMCS \\ l/OR
); C====C
/ \
OSi(CH3)3

exclusively silylated at carbon to provide a convenient synthesis

of t-butyl trimethylsilylacetate (eq. 3).21

TMCS
LiCHzCOOCCCH3)3 THF -78£> (CH3)3SiCH2COOC(CH3)3 (3)

 

The trimethylsilylmethyl lithium and magnesium compounds, I and
II, are synthetically useful intermediates for preparing olefins.
Tetramethylsilane is metalated34with the reactive n—butyllithium—

N,N,N,N-tetramethylethylenediamine (TMEDA) complex35 (eq. 4). Tri-

hexane
(CH ) SiCH + n—BuLi-TMEDA———) (CH ) SiCH Li (4)
3 3 3 3 3 2
A 3 days
I 362

‘methylsilylmethyl magnesium chloride is prepared in a Grignard

fashion36 (eq. 5).

31

ether
C1 + Mg ;(CH
reflux

3)381CH2MgC1 (5)

 

(CH3)351CH2

II

The silylated Grignard reagent II reacts with aldehydes and
ketones to give the B-silylcarbinol III after hydrolysis. The sodium
salt of III eliminates in refluxing THF providing the corresponding

olefin (eq. 6).37

 

 

 

O
(CH3)3SiCH2Mg01 +
l) ether
reflux
6 hours (6)
2) 11+
CH2 \V
1) NaH OH
1 THF
NaOSi(CH3)3 + <\ (CH3)3CSiCH2C
2) reflux
50% III

Reaction of lithium benzyltrimethylsilane with the carbonyl

component is reported to yield the olefin directly (eq. 7).38

Si(CH3)3
hexane H\\_ // CH6 5
CBC H + C 6H COC 6H -—-———-§)
6 S 65 65 TMEDA /’ ~\\t + LiOSi(CH3)3 (7)
Li CeH 5

CH6 5

32

This facile trimethylsiloxy elimination suggested that t-butyl
trimethylsilylacetate may be a synthetically useful precursor to
unsaturated esters. It was hoped stable THF solutions of lithio
t-butyl trimethylsilylacetate could be prepared using a lithium
dialkylamide base. The silylated ester enolate might then react with

aldehydes or ketones to provide the unsaturated ester directly (eq. 8).

LiNR
2 .—
(CH3)381CH2COOC(CH3)3-;;;—-€) (CH3)381CHCOOC(CH3)3
fl (8)
._c...

 

 

\ 4
c __cncooc (CH3) 3v

RESULTS
Preparation of Lithio tert-Butyl Trimethylsilylacetate

Treatment of lithio t-butyl acetate with TMCS in THF at -78° gave

t-butyl trimethylsilylacetate IV in 692 isolated yield (eq. 9).

TMCS

 

LiCH COOC(CH )-(CH SiCH COOC(CH3)3 (9)

2 3)3 3)3 2

THF, -78°

IV

Addition of IV to THF solutions of LiDPA at -78° quantitatively
generated lithio t-butyl trimethylsilylacetate within five minutes to
give a white precipitate of V (eq. 10) which was indefinitely stable
at dry ice temperatures, as determined by quenching aliquots with

dilute acid and analyzing for recovered ester.

 

LiDPA
‘ (CH

) z
3 3 THF, -78°

(CH SiCH COOC(CH SiCHCOOC(CH (10)

3)3 2 3)3 3)3

Li

Attempts to isolate V were undertaken. A white solid material
was isolable at ice bath temperatures under vacuum. This material
turned yellow if the ice bath was removed and rapidly charred upon

exposure to the atmosphere.

33

34

Reaction of Lithio tert—Butyl Trimethylsilylacetate with Aldehydes

and Ketones

A one molar solution of lithio t-butyl trimethylacetate readily
condensed with benzaldehyde at -78° in THF. 0n slowly warming the
mixture to room temperature complete elimination to t-butyl cinnamate
was complete in 30 minutes. This procedure was extended to a variety
of aldehydes and ketones to produce the corresponding u,B-unsaturated
esters in 92 to 982 yields (eq. 11) (Table 4). All a,B—unsaturated
esters prepared in this manner gave satisfactory elemental analyses

(Table 6) and their structures were confirmed by pmr.

I

+ R
_ , THF H xx
(CH ) SiCHCOOC(CH ) + R—C—R ——-> -——) c=cncooc (CH ) (11)
3 3 3 3 _78. f- 3 3
R

92-98%

Reaction of cyclohexanone with lithio t-butyl trimethylsilyl-

acetate gave only O.6Z of the corresponding nonconjugated ester (VI).

<:::>-—CH2COOC(CH3)3

VI
Quenching THF reaction mixtures of V and acetone, benzaldehyde, or
cyclohexanone at -78° with dilute HCl gave small amounts of the

corresponding B-hydroxy esters. Repeating the quenching procedure in

35

 

Hmmq.fi ooa\qoa Ammv om mAmmoquoumouUNAmmov maoumo<
mmwm.a “\maansafl Away mm mfimmuVouoomuumonmoumummeo sesameawamaaso
«maq.a w\omumm Away No mammovomoomunmoamoumommo sesameflmaououo
comm.H m.o\moaum0H Away am mammuvuwoumoumummou sesameawuamm
ammq.a He\mm AooV «m mammoVoNoomuumomoNAmmov sesameaausuanomH
as~q.a ooa\oma Ammv mm mAmmovumoomonmommu meagmvamumu<

QNNZ wmaa\mm mN .vaHw muoswoum vaoogaou ammonumo

 

 

eunumomamaflmaksumafiuH axusmuuumu casuaq saws mmasanoo Hhconumo mo cowuommm

36

.mmmeucmumm cfi mmamfiz woumHomH .mwamfiw undo A

.mwusuoouum wmcwfimmm zuHB mocmvuooum GH mowuummoua Hmuuomam wmufinfizxm muosuoua HH< m

 

mmn¢.H

oH\mNHuHNH Aomv mm mfimm0vu~oomou mcocmxonoaoso

 

NN

mmea\mm AN .vaofiw woosvoum mcsomaoo ahaonumu

 

A.ucouV s mqm<e

37

hexane solution gave larger amounts of the B—hydroxy esters, which were

isolated by preparative glpc (eq. 12).

 

1)CH3COCH3 OH
—- hexane, -78°
(C113)3SiCHCOOC(CH3)3 + ; (CH3)2CCHCOOC (C113)3
2)H
Si(CH3)3
202
(12)
CH H
3
+ ‘\C:=:C
H/ 00C CH
C 3 C ( 3’3
46%

Preparation of Lithio tert-Butyl bis(trimethylsilyl)acetate

Reaction of TMCS with a 1.67 molar solution of V, followed by
warming to room temperature, gave (glpc analysis) a mixture of 702 C-
and 302 O-silylated products (eq. 13). The C-silylated product, 5335:
butyl bis(trimethylsilyl)acetate, was isolated in 40% yield after the
acid catalyzed hydrolysis of the O-silyl ketene acetal (VII) to t-butyl

trimethylsilylacetate.

 

[(CH3)3Si]2CHCOOC(C83)3

TMCS 702 (40% isolated)
__ THF, -78°
(CH3)381CHCOOC(CH3)3 (13)
then
RT II\\ [IOSi(CH3)3
C===C
\

(C33)351 30: VII °C(C33)3

38

Reaction of Lithio tert-Butyl bis(trimethylsilyl)acetate with

Aldehydes and Ketones

 

The bis.silylated ester was converted into the ester enolate VIII
with LiDPA in THF at —78° (eq. 14). The bis silyl ester enolate was
then condensed with aliphatic or aromatic aldehydes in THF at -78° to
give 70 to 85% glpc yields of the corresponding o,8-unsaturated
trimethylsilyl esters. However, the reaction failed to give any con-
densation products with cyclohexanone or acetone, returning the bis

silylated ester unchanged (eq. 14) (Table 5).

 

 

LiDPA __
.__—__.) _
[(CH3)3Si]20HCOOC(CBB)3 o [(CFB)3Si]ZCCOOC(CH3)3 (14)
THF, -78
CH CHO CHaL.‘ /31(caa)3
3 i) ‘JJL:::C
THF' '78 H \COOC(CH3)3
80%
"' 15
[(013)331]20ccoc<c113)3 . ( )
CH Si(CH )
CHBCOCH3 V > 3)C --c 3 3
THF’ “78° A 0113 \cooc(cn3)3

39

.mmmmcuaouma ca mpamfim vmumaomw .mpamwh oaao

n

.mmusuosuum wmcwamom mafia woammuouom aw moauummoum Hmuuommm wmuanwsxm wuuavoua Had m

 

N.o\qm Aan 0A mAmmoVomooAmAmmovaHoummo sesameamanom
mm mAmmovomooAmAmm0vaHunmoumoumommu weAameAmaouoyo

. . m m N m m u N m A A
mmmq H q o\mo Aqu A move ooA A movflmHUImoumo A muv we sesame unnomH

. . m m N m m m A

emqs A m o\mm Ammv cm A move ouA A movfimmonmo :0 we emeamumu<
maom.A A.o\mOH Amev ma mAmmovoNooAmAmmovamHuumummoo meseweamucmm
noNz mmae\mm 3N .pamfim muosvoum mmhnmma<

 

mumumomfiakafimaxnumawuuvman ahusmluumu o«£ufiq aw“? mmwkzmva< mo cowuummm

 

m mqm<H

40

Reactions of tert-Butyl a-Trimethylsilyl a,B-Unsaturated Esters

Treatment of cis/trans t-butyl a—trimethylsilylcrotonate with
methyl Grignard in ether at 0° gave, after hydrolysis with aqueous

““4

identified by pmr, was recovered unchanged, apparently being more

C1, an unidentified material and the ketone (IX). The cis isomer,

resistant toward Grignard addition (eq. 16)."

H Si(CH3)

 

CH3 1’31(cn3)3 CH3MgI \\ ,x 3
:::C __) A + C:::C
H cooc(cn3)3 ether' 0° CH3 \\C00C(CH3)3
(16)
+ (CH3)ZCH?HCOCH3
Si(CH3)3
IX

Freshly prepared lithio t—butyl acetate added in a 1,4—fashion
to the silylated acrylate (X) to give, after hydrolysis, the t-butyl
glutarate (XII) (eq. 17). A sample of previously prepared solid

ester39 enolate gave no reaction under similar conditions.

41

 

I’Si(CH3)3
CH2===C
COOC(CH3)3
X
THF __
+ -—-) (CH ) cooccu CH CCOOC(CH ) (17)
_780 3 3 2 2| 3 3
Si(CH )
XI 3 3
LiCHZCOOC(CH3)3
NH4C1/H20
\/
(CH3)BCOOCCH2CH2CHCOOC(CH3)3
Si(CH3)3
XII
The lithium enolate of diethyl ketone combined in a Michael
reaction with t-butyl a—trimethylsilylacrylate (eq. 18).
O 0
“(C193 ll_ THF ll _
CHZ—C + CHZCHZCCHCH37 CHBCHZCCiHCHZCCOOC(CHB)3 (18)
COOC(CH )
CH
3 3 3 51(CH3)3

XIII

Both silylated ester enolates XI and XIII failed to cyclize in

THF solution at room temperature (eq. 19, 20).

42

(CH3 ) 3cooc COOC(CH3) OOC(CH3)
1(CH3 )3
(l9)
W1(CH )3
COOC(CH3)3
COOC(CH3 )3 RT
TH1>€ (20)
51(CH3 )3

DISCUSSION

Reaction of Lithio t-Butyl Trimethylsilylacetate with Aldehydes and

Ketones

Proton removal from t—butyl trimethylsilylacetate with LiDPA is
facile to produce lithio t-butyl trimethylsilylacetate. This ester
enolate rapidly condensed with aldehydes and ketones to give excellent
yields of a,B-unsaturated esters free from the non-conjugated isomer.
The reaction is particularly advantageous since the position of the
new double bond is certain. In addition, loss of the trimethyl-

siloxide group irreversibly rendered the product (eq. 21).

0' Si(CH )
C6H5CH0 A | 3 3
~* 0 H

 

(CH3)3SiCHCOOC(CH3)3 1:7 6 5 H-—-CHCOOC(CH3)3 (21)
THF, -78 J,
(CH3)3SiOLi + C6H5CH:::CHCOOC(CH3)3

Established preparations of a,B—unsaturated esters have usually
relied upon acid-catalyzed dehydration of B-hydroxy esters, which
usually gives a mixture of the conjugated and unconjugated esters

(eq. 22).40

43

44

 

“0 CH2C°°C235 1) POCl , benzene CHCOOCzus cnzcoczus
reflux 3 hours
> + (22)
2) H20
432 572

(642 combined yield)

In the silylated ester enolate sequence, the a,B-unsaturated
t-butyl esters are formed prior to quenching since the hydroxy ester
(XV) is stable to acid at room temperature (eq. 23). Replacing THF
with the nonpolar solvent hexane and quenching the reaction mixture
within five minutes at -78° afforded increased amounts of the hydroxy
ester derived from benzaldehyde, acetone, or cyclohexanone. The
olefin function is most likely formed by loss of lithium trimethyl-
siloxide from the intermediate XIV. The lithium trimethylsiloxide

grouping has been reported to be a good leaving group.

I:(\H3)3
_- 0 THF CHCOOC(CH3)3
(CH ) SiCHCOOC(CH ) +- -———-—€) (23)
-78°
XIV then to RT
Si(CH3)3

HO CHCOOC(CH CHCOOC(CH

3)3 3)3
+
LiOSi(CH3)3 + [:f:]

45

The conjugated aldehydes, cinnamaldehyde and crotonaldehyde,
gave excellent yields of the conjugated esters. Exclusive 1,2-
addition occurred providing a convenient synthesis for extended

conjugated esters (eq. 24).

__ THF
(CH3)3SiCHCOOC(CH3)3 + CH3CH=CHCHO -:7—8°> CH3CH:CHCH: CHCOOC(CH3)3
(24)

Acetaldehyde and isobutyraldehyde, possessing highly enolizable
hydrogens, were nevertheless smoothly converted into the corresponding

a,B-unsaturated esters (eq. 25).

THF

+ CH CHO —-—-9 CH3CHZCHCOOC(CH

) (25)
3 3 3 _78°

(CH3)3SiCHCOOC(CH 3)3

98%

Determination of Stereoisomerg

Acetaldehyde, isobutyraldehyde, and benzaldehyde condensed with
lithio t-butyl trimethylsilyl acetate to give a mixture of the
corresponding cis/trans conjugated ester (XVI-XVIII). The trans

a,B-unsaturated ester was favored in each of these cases.

46

H\C C./COOC (CH3)3 H\ /COOC(CH3)3 H\ /COOC ((2113)3
===. C===C ===
CH H (CH ) CH, \\H C(H’C C\H
3 3 2 6 5
XVI XVII XVIII
trans 7O 78 78
cis 3C 22 T 22

The cis/trans ratio for t-butyl cinnamate (XVIII) and t-butyl
4-methyl-2-pentenoate (XVII) were determined by glpc analysis. Pmr
spectra of XVII and XVIII revealed the major isolable products had
coupling constants of 16 Hz for the vinyl protons confirming the

1 The cis/trans

trans assignment (J=16 Hz, trans; J=ll Hz, cis).4
ratio for t-butyl crotonate (XVI) was determined by pmr analysis of

the mixture since the isomers were not readily separated on an SE-30
column. The major vinyl protons also had a coupling constant of 16 Hz.
The cis/trans ratio was conveniently determined from the integration
ratio of the allylic methyl groups. 'This was possible since the cis
methyl group B to a carbonyl function is generally found further

41’42’43 For example,

downfield than the corresponding trans B-methyl.
cis/trans methyl crotonate (XIX, XX) have chemical shifts of 62.14
and 6 1.88 respectively.41 Cis/trans t-butyl crotonate (XXI, XXII)

had nearly identical chemical shifts of 6 2.10 and 6 1.86.

H H
\\ ,/
//’C===C\\
2.18 CH COOCH
3 3
XIX
'H\\ //H
C===C
2 10 CH // COOC(CH )
° 3 3 3
XXI

Comparison to Wittig Reaction

The Wittig reaction,44

47

1.88 CH3 H
C:::C
H COOCH3
XX
H
1.86 CH3\\C:::C
H COOC(CH3)3
XXII

45

including the phosphonate modification,

is presently the most useful method for converting aldehydes and

ketones into o,B-unsaturated esters. However, the silylated ester

enolate method offers an attractive alternative, being complete within

a short time at -78° in THF.

Phosphorus ylides react with similar

carbonyls either at room temperature or in refluxing solvents such

4
as benzene or ethanol. 4

Equations 2646 and 27 compare yields of

similar products using the different methods.

0 O

(EtO)2PCHCOOEt +

benzene

O=CHcooat
\
I

(26)

 

60-65°

66-772

+ O—cazcoosc

62 XXII

48

o
_ THF
(CH ) SiCHCOOC (CH ) + -——-> —CHcooc(CH ) (27)
3 3 3 3 _78. 3 3
902
+ Q—CHZCOOC(CH3)3
0.67.
xxxv

The Wittig method reportedly gave six per cent of the uncon-
jugated isomer (XXIII) (eq. 26).47 From the present procedure, only
0.6 per cent of the unconjugated isomer (XXIV) was detected by glpc

analysis.

tert-Butyl bis(trimethylsilyl)acetate

 

Tert-butyl bis(trimethylsilyl)acetate and O-trimethylsilyl-O-
t-butyl trimethylsilylketene acetal (VII) (eq. 13) were obtained
unexpectedly in a 70/30 ratio from the Silylation reaction. As
Table 3 illustrates, increased substitution at carbon promoted 0-
Silylation. For example, t-butyl acetate gave 99% C-silylation but
decreased to 602 with t—butyl butanoate. Thus, the 70% C—silylation
observed with t-butyl trimethylsilylacetate seems difficult to explain

solely on steric arguments.

49

Reaction of Lithio t—Butyl Trimethylsilylacetate with Aldehydes and

 

Ketones

Proton removal from t—butyl bis(trimethylsilyl)acetate with
LiDPA, requiring about one hour, encountered some difficulty. The
bis silylated ester enolate condensed with aldehydes affording con-
jugated vinyl silylated esters in excellent yields (eq. 28). Like
the mono silylated ester enolate condensation, the position of the
new double bond is certain and loss of the trimethylsiloxy group

irreversibly gives the a,B—unsaturated a-silylated ester.

 

c
c 6115:3110 sum... /51(CH3) 3
- ); r1C:::C
H COOC(CH )
797. 3 3
_ THF
[(c113)35112ccooc(CH3)3 . 0 (28)
-78
\/ /Si(CH3)3
x c

 

/\ 7 \COOC (CH

3)3

Presumably for steric reasons, the bis silyl ester enolate failed
to condense with acetone or cyclohexanone (eq. 28). Glpc analysis
only detected the his silylated ester and cyclohexanone in the
quenched reaction mixture. The bulky ester enolate might serve as
a base to generate the ketone enolate.

The reaction with crotonaldehyde gave exclusive 1,2-addition

providing an extended conjugated ester in excellent yield (eq. 29).

50

[(CH Si]2CCOOC(CH3)

3)3 3

THF, —78° SJL(CH3)3
+ ; CH3CH:CHCH=C (29)

then RT COOC(CHB)

 

3

CH3CH :CHCHO

Reactions of t-Butyl a—Trimethylsilyl 6,8—Unsaturated Esters

 

With the vinyl silylated esters easily accessible in good
yields, it was of interest to further investigate their synthetic
utility. Three major products were obtained from reaction of methyl
magnesium iodide with t-butyl 2-trimethylsilyl—2—butenoate. These
products consisted of a low boiling component A, a tentatively
identified ketone (IX), and the cis isomer of the starting ester
(eq. 16).

An ir spectrum revealed a carbonyl band at 1680 cm-1 consistent
with a saturated ketone. The pmr spectrum showed the trimethylsilyl
moiety at 6 0.06, most likely bonded to carbon.21 The pmr also
revealed a methyl group attached to the carbonyl moiety (singlet,

6 1.93). Both the pmr and ir spectra confirmed the absence of the

olefinic function.

(CH3)2CH('3HCOCH3
Si(CH3)3

IX

51

The pmr spectrum of the isolated ester was identical to a
previously obtained spectrum for cis t-butyl 2—trimethylsilyl-2—
butenoate. It was assumed the cis B-methyl group, in respect to the
carboalkoxy function, was shifted further downfield than the tran
B-methyl. The unexpected stability of the cis isomer was not further

investigated.

/’Si(CH3)3

Lo\/m
/

COOC(CH3)3

Pure compound A eluded isolation. A pmr spectrum was obtained
of the crude material only showing with certainty the trimethylsilyl
group at 6 0.27.

Solid lithio t-butyl acetate failed to undergo a Michael reaction
with t-butyl a-trimethylsilylacrylate. However, freshly prepared
solutions of lithio t-butyl acetate added to the vinyl silyl ester at

-78° in THF followed by warming to room temperature (eq. 30).

CH2C00C(CH3)3

TIIF, ”78° __ (30
+ > (CH ) COOCCH CH CCOOC(CH ) )
the RT 3 3 2 2| 3 3
Si(CH n
/’

3)3 Si(CH3)3
HC:C

 

COOC(CH3)3 XI

The enolate of diethyl ketone similarly gave the Michael

addition product (eq. 31).

52

 

O
CH3CH2CCHCH3
O
THF, -78°
\p _.
+ ,. CH3CH2CCHCH2CCOOC(CH3)3 (31)
Si(CH ) then RT | I
3 3 CH3 Si(CH3)3
H C:::C
2
XIII
COOC(CH3)3 .«

The silylated ester enolates XI and XIII are conceivably
precursors to the cyclobutanone (XXV) and the cyclobutene (XXVI)
(eq. 32, 33). Elimination of the trimethylsiloxy group from
intermediate XXVII would irreversibly render the cyclobutene (XXVI).
Unfortunately, XI and XIII apparently did not undergo cyclization
after 18 hours in THF at room temperature. The failure of XI
to undergo a Dieckmann condensation is not surprising since the
Dieckmann cyclization is normally only successful for five— and six-

membered rings.

COOC(CH3)3

COO COOC(CH3)3 RT ‘:
Si(CH3)3

(CH3)3 (32)
THF

i(CH3)3

 

53

 

 

0‘ Si(CH3)3
COOC(CH3)3 \AL——\
3 g COOC(CH3)3
Si(CH ) _. L———
3 3 /
x111 XXVII (33)
COOC(CH3)3

EXPERIMENTAL

I. Materials

Esters

The preparation of t-butyl trimethylsilylacetate is described in
Chapter I. Tertfbutyl bis(trimethylsily1)acetate (bp 61°/0.4 mm) is
prepared in a similar fashion.
Carbonyls

All aldehydes and ketones were commercially available. All
carbonyls, except acetone, were distilled and stored under a nitrogen
atmosphere. Acetone was stored over molecular sieves.

Amine and Solvent

 

N,N-Diisopropylamine (bp 83°/atm. pressure) was distilled and
stored over molecular sieves under a nitrogen atmosphere. Tetrahydro-

furan was used without further purification.
II. Preparation of t-Butyl a,B—Unsaturated Esters

Tert-butyl cyclohexylideneacetate is representative for the
preparation of a,B-unsaturated esters. Glpc analysis utilized a 1/4
inch by 6 foot SE-30 column. Each reaction run on a 5 mmole scale had

an apprOpriate internal standard.

54

55

A. General Procedure

 

A 100 ml round-bottomed flask equipped with magnetic stirring,
septum inlet, and mercury bubbler is flushed with nitrogen and immersed
in an iceawater bath. The flask is charged with a hexane solution of
n-butyllithium (12.5 ml, 25 mmole) and 3.6 ml (25 mmole) of diiso-
propylamine is injected over a 2 minute period. Following complete
addition, the hexane is removed under reduced pressure and the flask
is immersed in a dry ice—acetone bath and Eggtfbutyl trimethylsilyl-
acetate (5.5 ml, 25 mmoles) is added drOpwise over a 2 minute period.
After an additional 10 minutes of stirring, 2.6 m1 of cyclohexanone
(25 mmoles) is injected. The solution is then allowed to reach room
temperature and quenched by the addition of 25 ml of 3N hydrochloric
acid. Extraction with pentane and vacuum distillation of the organic
phase gives 4.5 g (90% yield) of Egrtfbutyl cyclohexylideneacetate,

bp 121-3°/l6 mm.

B. Product Analysis

 

tert—Butyl cyclohexylideneacetate

NMR(CC14): 6 5.43 (s, 1H), 6 2.97 (m, 2H), 6 2.13 (m, 2H),
5 1.60 (m, 6H), 5 1.43 (s, 9H). IR(neat): 1715 cm'1 (c=0), 1655 em’l

(C=C).
tert-Butyl cinnamate

NMR(CDC13): 6 7.5 (m, 6H), 6 7.83, 6 6.56, 6 6.30 (2 doublets,

l H, J=16Hz), 6 1.56 (s, 9H).

GAS
INLET VALVE

56

 

 

1+ T0 mom

BUBBLER

(I)

 

 

 

RUBBER SEPTUM

CD

 

 

 

MAGNETIC STIRRER

Figure 3. Reaction Apparatus

57

tert-Butyl 3~methy1—2~butenoate

NMR(CC14): 6 5.53 (broad, 1H), 6 2.13 (d, 3H, cis methyl), 6 1.87
(d, 3H, trans methyl),6 1.43 (s, 9H). IR(neat): 1715 cm"1 (C=C),

1600 cm'1 (C=C).

tert-Butyl 2—butenoate

 

NMR(CC14): 6 5.57-7.13 (multiplets, 2H), 6 1.80, 6 1.90, 6 2.03,
5 2.17 (4 doublets, 3H), 6 1.47 (s, 9H). IR(neat): 1720 cm—1 (C=C),

1660 cm-1 (C=C).
tert-Butyl 4—methy1—2—pentenoate

NMR(CC14): 6 6.90, 6 6.60, 6 5.57 (3 doublets, 2H), 6 2.33 (m, 1H),
6 0.97,6 1.10 (d, 6H), 6 1.43 (s, 9H). IR(neat): 1725 cm‘1 (c=0),

1655 cm'1 (C=C).

tert-Butyl 2,4-hexadienoate

 

NMR(CC14): 6 5.2—7.7 (multiplets, 4H), 6 1.87 (m, 3H), 6 1.50

(s, 9H).
tert-Butyl Sephenyl—Z,4epentadienoate

NMR(CC14): 6 5.4-8.2 (multiplets, 9H), 6 1.50 (s, 9H).
tert—Butyl 3epheny1—3—hydroxy—2-trimethylsilylpropanoate

NMR(CC14): 6 7.4 (s, 5H), 6 4.90 (d, 1H), 6 4.30 (broad, 1H),

6 2.57 (d, 1H), 6 1.40 (s, 9H), 6 0.20 (s, 9H).

58

TABLE 6

Elemental Analysis8 of the a,B-Unsaturated Esters

 

 

Ester Calculated Found

C 2 H 2 C 2 H 2
CHBCH=CHC02C(CH3)3 67.51 9.93 67.37 9.86
(CH3)2CHCH=CHC02C(CH3)3 70.56 10.62 70.56 10.67
CGHSCH=CHCOZC(CH3)3 76.30 7.78 76.18 7.72
CHBCH=CH-CH=CHC02C(CH3)3 71.45 9.58 71.18 9.43
CGHSCH=CH-CH=CHCOZC(CH3)3 78.10 7.86 78.21 7.94
(CH3)2C=C02C(CH3)3 69.20 10.32 69.33 10.37
<:::>>=:CHC02C(CH3)3 73.40 10.24 73.39 10.16

 

a Performed by Spang Microanalytical Laboratory, Ann Arbor, Michigan.

59

tert-Butyl 3-hydroxy—3-methy1—2—trimethylsilylacetate

 

NMR(CC14): 6 3.40 (broad, 1H, disappears with D20), 6 2.07 (s, 1H),

6 1.50 (s, 9H), 6 1.23 (s, 6H), 6 0.20 (s, 9H).
tert-Butyl 3-cyclohe§yl—3— hydroxy—Z-trimethylsiiylacetate

Elemental Analysis: Ca1c.: 62.85% C, 9.79% Si, 10.552H;

Found: 62.12% c, 10.44% Si, 9.22% H.

tert-Butyl legyclohexenylacetate

 

NMR(CC14): 6 5.37 (broad, 1H), 6 2.67 (s, 2H), 6 1.93 (m, 4H),

6 1.53 (m, 4H), 6 1.40 (s, 9H).
III. Preparation of tert—Butyl a—Trimethylsilyl a,B—Unsaturated Esters

A. General Procedure

 

The following procedure for the conversion of acetaldehyde into
Egggrbutyl 2-trimethylsilyl—Z-butenoate is representative for most
aldehydes. A 100 ml round—bottomed flask equipped with magnetic
stirring, septum inlet, and mercury bubbler is flushed with nitrogen
and immersed in an ice—water bath. The lithium diisoprOpylamide is
generated in a similar manner as described previously. The THF
solution of the lithium amide is cooled in a dry ice-acetone bath and
Egrtfbutyl bis(trimethylsilyl)acetate (13.3 ml, 50 mmoles) is added
dropwise over a 5 minute period. After an additional one hour of
stirring, 2.8 m1 of acetaldehyde (50 mmoles) is injected. The

solution is then allowed to reach room temperature and quenched by the

60

addition of 35 ml of 3N hydrochloric acid. After pentane extraction,
the organic phase is washed with saturated sodium bicarbonate. Vacuum
distillation of the organic layer gives 6.2 g (58% yield) of tert—butyl

2—trimethylsily1—2—butenoate, bp 59°/0.3 mm.
B. tert—Butyl o—Trimethylsilylacrylate

A 250 ml round—bottomed 3-necked flask, eduipped with a mechanical
stirrer, gas inlet valve, mercury bubbler, and rubber septum, is
flushed with nitrogen. After preparation of 100 mmoles of the lithium
amide, the bis silyl ester (26.6 ml, 100 mmoles) is added dropwise to
the -78° solution and stirred for one hour. Meanwhile, a 50 ml flask
containing 5 g of paraformaldehyde (170 mm formaldehyde), is fitted
with a T—tube through a rubber septum. A mercury bubbler, containing
excess mercury (pressure valve), and a 10 mm diameter glass tube are
attached to the T-tube (Figure 4). After the ester enolate is gener-
Iated, the glass tube is placed 2 cm above the surface of the reaction
mixture. With rapid stirring, the formaldehyde, produced by flame
heating paraformaldehyde, is entrained in a slow stream of nitrogen
flowing into the reaction flask. After 20 minutes, the addition is
complete, and the reaction mixture warmed to room temperature. A
mixture of 60 ml water and 150 ml pentane is added and the layers
separated. Vacuum distillation of the organic phase gives 6.7 g

(35% yield) of product, bp 34°/0.2 mm.

/\

T0 MERCURY
BUBBLER

61

 

 

 

 

 

 

 

 

V

Figure 4. Reaction Apparatus

T0 MERCURY
BUBBLER

FORMALDEHYDE
GENERATING
FLASK

62

C. Product Analysis

 

tert—Butyl 2-trimethylsilyl—3-phenyl-2-propenoate

 

NMR(CCI 6 7.13 (s, 5H), 6 6.5 (s, 1H), 6 1.37 (s, 9H), 6 0.20

I."
(s, 9H). IR(neat): 1710 cm‘1 (c=0), 1600 cm'1 (C-C).

cis tert-Butyl 2-trimethylsilyl-Z—butenoate

NMR(CC14): a 6.0 (q. 1H), 6 1.90 (d, 3H), 5 1.47 (s, 9H), 0 0.10

(s, 9H). IR(neat): 1715 cm-1 (C=C), 1610 cm.1 (CaC).
trans tert-Butyl 2-trimethylsilyl-2-butenoate

NMR(CC14): a 6.90 (q. 1H), 6 1.87 (d, 3H),6 1.47 (s, 9H), 6 0.20

(s, 98). Density 0.90.
tert-Bugyl 24trimethylsily1-4-methyl-2jpentanoate

NMR(CC1 : 6 6.53, 6 5.60 (2 doublets, 13), 6 2.87 (m, 1H),

4)
6 1.43 (s, 9H), 6 1.0 (d, 6H),6 0.17, 6 0.10 (singlets, 9H). IR(neat):

1720 cm-1 (C=C), 1610 cm"1 (C=C).
tert-Butyl 2-trimethylsilyl-2,4—hexadienoate

NMR(C014): 6 5.6-7.4 (multiplets, 3H), 6 1.80 (d, 38), 6 1.47
(s, 9H), 6 0.13, 6 0.23 (singlets, 9H). IR(neat): 1705 cm-1 (C=C),

1640 cm’1 (c-C).

63

tert-Butyl 2-trimethylsilyl-2:pr9penoate

NMR(C014): 6 5.77, 6 6.50 (d, 2H), 6 1.47 (s, 9H), 6 0.17 (s, 9H).

IR(neat): 1700, 1720 cm.1 (C=C), 1590 cm.1 (C=C). Density 0.88.
IV. Reaction of t-Butyl 2-Sily1ated Unsaturated Esters
A. tert-Butyl 2-Trimethylsily1-2-butenoate with Mbthyl Grignard

A 50‘m1 round-bottomed flask, equipped with magnetic stirring,
septum inlet, and mercury bubbler, is flushed with nitrogen and
immersed in an icedwater bath. The flask is charged with 1.9 m1
of methyl magnesium iodide in ether (2.1 mmoles) and 0.50 ml of ester
(2.1 mmoles) is injected dropwise. After 15 minutes, the reaction
mixture is warmed to room temperature for one hour giving a white
precipitate. Ether is added and the reaction quenched with aqueous
ammonium chloride. Glpc isolated an impure lowbboiling fraction,
3-trimethylsilyl—4dmethyl—2-pentanone, and cis t-butyl 2—trimethylsily1—
2-butenoate as the only products from the reaction mixture.

An NMR spectrum of 3-trimethy1-4dmethyl-2-pentanone revealed
signals at 6 2.2 (m, 13), 6 2.03 (d, 13), 6 1.94 (s, 3H), 6 0.90
(m, 63), and 6 0.06 (s, 9E). The IR spectrum.showed a carbonyl band

at 1680 cm.1 (ketone).
B. tert-Butyl 2—Trimethylsilylacrylate with Methyl Grignard

The reaction flask, as described above, is charged with 3.6 ml of
methyl magnesium iodide (4 mmoles) and cooled in an ice-water bath.

The ester (0.90 ml, 4 mmoles) is injected into the reaction vessel

64

giving a white precipitate within a few minutes. The reaction is
quenched after 30 minutes with aqueous ammonium chloride. Glpc of the
organic phase showed an almost complete conversion of the acrylate
into t-butyl 2-trimethylsilylbutanoate. NMR(CC14): 6 2.0 (m, 13),

a 1.33 (m, 23), 0 1.40 (s, 9H), 5 1.0 (m, an), a 0.06 (s, 9H).

IR(neat): 1710 cm-1 (C=C).
C. tert-Butyl 2-Trimethylsilylacrylate with Lithio t-Butylacetate

Lithio t-butyl acetate (0.25 g, 2 mmoles) is placed into a 50 m1
round—bottomed flask and dissolved in 4 m1 of THF. The flask is
immersed in a dry ice-acetone bath and 2 mmoles of ester (0.45 ml)
is injected. .After 15 minutes, the reaction mixture is warmed to room
temperature and stirred for an additional 2 hours. After dilution
with pentane, the reaction is quenched with water. Glpc showed much
starting material and an abundant number of products. No t-butyl
acetate was detected.

The reaction was repeated with freshly prepared lithio t-butyl
acetate. Lithium diisopropylamide is generated in the usual manner.
To the IM solution of base at -78°, t-butyl acetate (0.53 ml, 4 mmoles)
is injected dropwise and stirred for 10 minutes. The acrylate
(0.90 ml, 4 mmoles) is added, diluted with pentane after 5 minutes, and
quenched with water. Tert-butyl 2-trimethylsilylglutarate was isolated
by preparative glpc. NMR(CC14): 6 1.40 (s, 183), 6 O.lO(s, 9H).6 1.87

(m, an). IR(neat): 1715, 1730 cm51 (c=0).

65

D. tert-Butyl 2-Trimethylsily1acry1ate with 3—Pentanone Enolate

Lithium diisopropylamide (20 mmoles) is prepared in the usual
manner and dissolved in 20 m1 of THF. The flask is immersed in a dry
ice-acetone bath and 2.1 m1 of 3—pentanone (20 mmoles) is injected.
After 10 minutes, the reaction is stirred for an additional 2 hours
at room temperature. After dilution with ether, the reaction is
quenched with water. Vacuum distillation of the organic phase gave
2.1 g (37! yield) of t-butyl 2-trimethylsi1yl-S—oxo-4-methylheptanoate.
NMR(CC14): 6 2.40 (m, 3H), 6 1.70 (m, 1H), 6 1.47 (s) and 6 1.07 (m)

total 173, and 6 0.17 (s, 9H). IR(neat): 1710 cm”1 (C=O)

CHAPTER III

THE REACTION OF ACYL COMPOUNDS WITH

a-TRIMETHYLSILYL ESTER ENOLATES

66

INTRODUCTION

Lithio tert-butyl trimethylsilylacetate (I) reacts with aldehydes
or ketones to give o,B—unsaturated esters (eq. 1).48 The products
are assumed to form by elimination of lithium trimethylsiloxide from

the intermediate II. This elimination occurs rapidly at dry ice

 

 

temperatures.
0 OLi
u THF
LiCHCOOC(CH) + —c- -—-—> -—-C—CHCOOC(CH)
Si(CH3)3 H Si(CH3)3
1 II
(1)
-(CH3)3SiOLi
==CHCOOC(CH3)3 <

It was of interest to further investigate the reactions of I.
In particular, reaction of I with acylating reagents could conceiv—
ably take three paths, two of which involve elimination of the

trimethylsilyl group (IV, V).

67

68

 

 

-LiX
> Rcocncooc(cn3)3
Si(CH3)3
Li OLi . .
I ROCK | L1081(~CH3):3
CHCOOC(CH ) ——-—> RC -— CHCOOC(CH ) sac === cucoocmn )
3 3 THF | | 3 3 I 3 3

Si(CH3)3 -78 x Si(CH3)3 x

- ' o1

xs1(ci3)3

 

> RC m- CHCOOC(CH3)3

0L1

Figure 5. Possible Reaction Paths for Lithio t~Buty1 Trimethylsilyl-
acetate with Acylating Reagents

Acyl halides, esters, and amides all might be used as successful
acylating reagents for silyl ester enolates. Although amides are
normally not very reactive toward nucleophilic attack, the N—acyl-
imidazoles (VI) are about as reactive as acyl halides or anhydrides.

9

For example, they react with water at room temperature (eq. 2).4

25°
NAN—COR + H20 ————9 NA

NH + RCOOH (2)

VI

69

The N-acylimidazoles are conveniently prepared by reaction
of an acid halide with two equivalents of imidazole (eq. 3),

or by reaction of carboxylic acids with carbonyl diimidazole.49

z/A\\ benzene + _
2 N/ NH + RCOCl ——-—> NANCOR + PIN/\NH Cl
reflux \‘-‘/. (3)

2 hours

The reaction path in Figure 4 which leads to the condensation
product IV would constitute a unique synthesis of an enamine50 if
an acylimidazole is employed. Regardless of the acylating reagent
or possible reaction path, the products (Figure 4) would all be
converted to a B-keto ester upon acid-catalyzed hydrolysis. B-Keto
esters are relatively acidic compounds, and the alpha proton flanked
by two carbonyl groupings is easily removed to give a B—keto ester
enolate (V) (eq. 4).

_ 0

B

RCOCH COOC(CHB) —-—) RC =CHCOOC (CI-13)3 + BH (4)

2 3

V

The condensation of I with an acylating reagent may give the
B-keto ester enolate (V) directly (eq. 5). Such enolates are known

to be stable51 and may be isolated in a similar fashion to lithio

t—butyl acetate.39

70

0..
_ ROCK |
(C113)381CIICOOC(C113)3 ———9 Rc—CHCOOC (CH3) 3
X Sl(“3’3 (5)
0...
| -(CH3)3SiX

 

RC =CHCOOC(CH3)3 e _

More Complex Enolate Sytems

The B—keto ester enolates are susceptible to additional proton

52’53 Thus, ethyl aceto-

removal with a strong base to give a dianion.
acetate reacts with two equivalents of potassium amide to give the

corresponding dianion (VI) (eq. 6). The low yield of the y-alkylated
product (VII) is probably due to incomplete dianion formation or slow

alkylation at liquid ammonia temperatures.52’53

2 KNH2 __ __ 1)CH31
CH COCH COOC H ——-——-—) CH COCHCOOC H ——-——> CH CH COCH COOC H
3 2 2 5 2 2 5 3 2 2 2 5
ether
liq. NH
1 hour ”‘1' NH3 (6)
2)NH4C1
37%
VIII

The use of n-butyllithium or LiDPA54 as bases to generate the

dianion gave more satisfactory results upon alkylation (eq. 7).53

71

 

 

 

NaH, THF __ n—BuLi
\ \
CH3COCH2COOCH3 o ,, CH3COCHCOOCH3 a ,
0 0
(7)
__ __ 1)CH31, 25°, 15 min.
CHZCOCHCOOCH3 2)H+ ,7 CH3CH2COCHZCOOCH3

99%

The y-position, the most basic site in the dicarbanionic B-keto
ester, apparently undergoes reaction exclusively with one equivalent
of an electrophilic reagent (eq. 7).53 Consequently, reaction of
TMCS with a B—keto ester dianion should give the y—silylated enolate
(VIII) (eq. 8). The dianion of VIII could conceivably undergo a

subsequent elimination reaction analogous to equation 1 (eq. 9).

OLi OLi
TMCS
LiCHZC —CHCOOC (C1113)3 E; (CH3) 381CH2C= CHCOOC (C33) 3 (8)
VIII
OLi 1)BuLi, 0' Si(CH3)3
THF I |
(CH3)381CH2C-——CHCOOC (CH3) 3 337-9 -(l3 —— CH -——-il......_...CHCOOC(C113)3
u -
-C- 0L1
(9)
OLi -
l (CH3)38i0

 

 

=CHC ::CHcooc (CH3) 3 <

72

Anions of B-enamino ketones also undergo alkylation exclusively
at the y-carbon affording chain extended B-keto esters (eq. 10).55
The B-enamino esters are conveniently prepared from a B-keto ester

and a secondary amine (eq. 11)56 and might be expected to react in

a similar fashion.

CH3C = CI-ICOCH3 { E f 5

 

N
THF _ l CH3:
+ ———-9 H c ::CHCOCH ———-) CH CH C=CHCOCH (10)
_60. 2 3 3 2 3
762
n—BuLi
O... I;
s .—
CH3COCH2COOC2H5 , 0113c._cncooc2H5 (11)
O
2 :7 IX
0111‘s 57%

Silylation of IX rather than alkylation should lead to a precursor

for further condensation, analogous to equation 1 (eq. 12, 13).

Q Q

| BuLi TMCS
CH c ::cacooc H -—-> ———) (CH ) SiCHC::CHCO0C H (12)
3 2 5 THF 3 3 2 5

IX

73

(3

u N
n-BuLi -C-= I

THF

<3

 

0—

(CH SiCH2

3)3
(13)

It was the intention of this investigation to explore the
synthetic utility of I. The possible products from different acyl—
ating reagents, Figure 5, appeared a promising way to extend the

silylated anion method to more complex systems.

RESULTS

Preparation of B-Keto Esters

Lithio Egrtfbutyl trimethylsilylacetate in THF at -78° was
reacted with a variety of acylating reagents. With acetyl chloride,
only a complicated mixture of products was obtained. With ethyl
acetate or N,N—dimethylacetamide, I was recovered unchanged. However,
reaction of I with N—acetylimidazole in THF at -78° gave, following
removal of the solvent, the lithiated B—keto ester V in 85%
yield (eq. 14). Reaction of I with a variety of N-acylimidazoles in
THF at dry ice temperatures, followed by quenching with dilute
hydrochloric acid, gave the corresponding B—keto esters (X) in 70 to

942 yields (eq. 15) (Table 8).

remove OLi
solvent I
RC :2: CHCOOC (C113)3 (l4)
R=CH3 85%
Si(CH3)3 V
CHCOOC(CH ) + N NCOR
3 3 o
| .— -78
Li
H+
RCOCHZCOOC(CH3)3 (15)
(X) 70-942

74

75

\nuu/ m 0

mm.

 

.qma .sumMH we 2 znuuomonuumo m u Hooomonuumo m o
o. 7\ __
o
\nlu,.un m m m m
am can .6 mm as zanxxz mo A may Hoooo A moo
o
m .mH Ao\.~H-OHHV em 2 znnuommuNmommo Hooommommommo
m 2”«\\ =
o
.qoa .s-m0H we 2 z.|.ummu Hooummo
o
as .uaa Amnes\amv 62 mm .6Hmaw possess mwfiuoaeo whoa

 

5 mafia.

maoumwaeH spas mmsauofleu saga so coauummm

76

.mpfiofih woumHomH m

 

ow

oONIOH

mm

Hooommco

 

a: .uaa

Ammas\amv a:

«N camps

uoopoum

mvfiuoacu vwofi

 

A.ucoov n mgm<a

Reaction of N—Acylimidazoles with
Lithio tert—Butyl Trimethylsilylacetate

77

TABLE 8

 

 

N-Acylimidazole Product Yield, 23
i‘
I /\
CH3C—N \N CHBCOCH2C00C(CH3)3 94
0
CH CH CH 6... \N CH CH CH coca COOC(CH ) 81
3 2 2 11 l 3 2 2 2 3 3
0
(CH ) cat—AN (CH ) ccocu COOC(CH ) 70
3 3 ‘ , 3 3 2 3 3
0
c H CH—CPC AN (3 H CH-CHCOCH COOC(CH ) (50
6 5 "' ‘ “—11 , 6 5 _ 2 3 3 )
0
II A (Q
Brcnzcnzcnzc -—N N cucooc (CH3) 3 75

E

 

a Glpc yields, isolated yields in parentheses.

78

Preparation of N-Acylimidazoles

The N-acylimidazoles were prepared by the method developed by

49 .
Staab. Reaction of two equivalents of imidazole with an acyl halide
in benzene gave the corresponding N—acylimidazoles in 47—87% isolated

yields (eq. 16) (Table 7).

 

//\\ benzene + _
2 N'/’ NH + RCOX > 1F¢;\\NCOR + HNlfl§§NH X (16)
\.__/ 2 hours \___/ \___/
47—87%

Condensation of I with 4-bromobutanoylimidazole gave the hetero-

cyclic ester X1 in 75% yield (eq. 17).

 

(CH3)381CHCOOC(CH3)3
+ f ; CHCOOC(CH3)3
o 2)25°, 12 hours
H [/4§§ 3)H+ x1 (17)
BrCH CH CH c-—N N

2 2 2 ‘___f

Preparation of B—Keto Ester Derivatives

The lithiated B—keto ester XII could be isolated directly from
the reaction of I with N—acetylimidazole (eq. 14). The O-silylated
derivative XIII was obtained in 76% yield from the reaction of
triethylamine, TMCS, and ethyl acetoacetate in THF at 25° (eq. 18).

Reaction of pyrrolidine with ethyl acetoacetate at room temperature

79

gave the B-enamino ester IX.

 

CH3COCH2C00C2H5 OSi(CH3)3
Et N + TMCS ;; ___
3 THF’25, CH3C___CHC00C2H5 (18)
x111 76%
OLi :N:
I l
CHBC-——CHCOOC(CH3)3 CH3C:::CHCOOC2H5

XII IX

Silylation or Alkylation of B-Keto Ester Derivatives

 

The metalated B-keto ester XII tolerated exposure to the
atmosphere for days without decomposition. Conversion of XII to a
dianion was accomplished by treatment with n—butyllithium in THF at
25°. Alternatively, this dianion was prepared by reaction of t-butyl
acetoacetate with two equivalents of LiDPA. Reaction of the dianion
with TMCS at -78° gave a 70% yield of the y-silylated material VIII.
The mono anion of the B-enamino ester IX, generated with n-butyllithium
in THF at -78°, was likewise silylated at the y—position to give XIV.
However, generation of the mono anion of XIII with LiDPA in THF
at -78° gave the a-alkylated product XV on reaction with benzyl

bromide.

80

?Li N:

(CH3)3SiCH2C===CHCOOC(CH3)3 (CH3)3SICH2C===CHCOOC2H5
VIII XIV
081(CH3)3
CH2::C---CHCOOC2H5
CH2C6HS
XV

Attempted Reaction of VIII and XIV with Benzaldehyde

Efforts to induce reaction of VIII with benzaldehyde in refluxing

THF resulted in the recovery of VIII (eq. 19). Reaction of the

dianion of VIII with benzaldehyde in THF, with or without HMPA or

TMEDA added, only resulted in the recovery of the v-silylated mono

anion (eq. 20). Interestingly, a camphor—like odor was detected from

the latter reaction when acetone was substituted for benzaldehyde.

OLi
THF
SiCH C:::CHCOOC(CH ) + C H CHO €> N.R. (l9)
2 3 3 6 5
reflux
24 hours

 

(CH3)3

81

 

l) 1 hour
OLi n-BuLi
THF, 25°
(CH3)BSiCH2C‘-'=:CHCOOC(CH3)3 ): VIII + unidentified (20)
2) C6HSCH0 materials
-78°, then
VIII 25°, 1 hour

Attempted generation of the B-enamino ester anion in THF at
room temperature, followed by the addition of benzaldehyde, returned

XIV unchanged (eq. 21).

I l) THF, 25°, 1 hour

n-BuLi

\/

(CH3)331CHZC :: CHCOOCZHS N.R. (21)
2) C H CHO, -78° then

6 5
25°, 1 hour

DISCUSSION

Preparation of B-Keto Esters

Treatment of lithio t-butyl trimethylsilylacetate with N—acetyl-
imidazole gave the lithium salt XII by selective elimination of the
imidazole and trimethylsiloxy moieties (eq. 22). The mechanism for

loss of these groups was not established.

 

0L1
THF, -78°
LiCHCOOC (C113)3 + N ANCOCH3 ; CHBC =CHCO0C (CH3 )3 (22)
\===/ then to
Si(CH3)3 RT
XII 852
I

The preparation of B-keto esters by acylation of ester enolates
is normally complicated by the acidic nature of the products33 This
usually results in the neutralization of 502 of the starting enolate.
The present procedure avoids this difficulty by directly generating
the anion of the B-keto ester, and also offers obvious advantages
when further synthetic sequences with the anion are desired. For
example, reaction of I with 4-bromobutanoy1imidazole, prepared in

THF and used immediately, gave in one step a 75% yield of tert—butyl

2-tetrahydrofurylideneacetate (eq. 23).

82

83

 

 

0
LiCHCO0C(CH ) + BrCH CH CH ICI—NAN THF
I 3 3 2 2 2 \‘==/ ':;;2"‘
Si(CH3)3
(23)
w
. OLi
0 1) 25°, 12 hours I
<:;:7F:CHCOOC(CH3)3 <2) H+ BrCHZCHZCH2C2::CHCOOC(CH3)3
x1

Cyclization of the lithiated intermediate through oxygen was
surprising. Although O-alkylation is frequently observed with rela-

61 the site of alkylation is

tively acidic methylene compounds,
dependent upon solvent, temperature, the counterion, and alkylating
reagent. For example, lithium enolates are normally alkylated at

carbon while the larger counterions, such as potassium, favor

O-alkylation (eq. 24).62

 

o OCH CH CH 0
H DMSO, K2C03 I 2 2 3
\ _—
CHBCCHZCOOCZHS , CH3C.....CHC00C2H5 + CH3cci'H000C2H5 (24)
CH3CH20H2C1 CH CH CH
2 2 3
reflux
69% 312

IfSilylation of tert-Butyl Acetoacetate

With the lithium salt XII on hand, the dianion could be gener-
ated with an appropriate strong base. However, it was more convenient

to generate the dianion directly from t-butyl acetoacetate with two

84

equivalents of LiDPA 54 (eq. 25)-

2 LiDPA __ _
CH3COCH2COOC(CH3)3 THF 0° ; CHZCOCHCOOC(CH3)3 (25)

 

Silylation of the dianion with one equivalent of TMCS gave VIII

(eq. 26), as expected from previous studies of alkylations in dianion

 

systems.53’.54’ 63
__ __ TMCS, THF, ._
x
CHZCOCHCOOC(CH3)3 o 1' (CH3)3SICH2COCHCOOC(CH3)3 (26)
-78 , then
to 25°
VIII 702

Attempted Reaction of Lithio t-Butyl y—Trimethylsilylacetoacetate

with Benzaldehyde

Our attempts to condense VIII with benzaldehyde to give a sub—
stituted cyclobutane were unsuccessful (eq. 27). Acidification of
the reaction mixture, after 24 hours at reflux in THF, returned

t-butyl acetoacetate.

85

 

 

 

 

 

 

0
__ C6H5CHO \/ H
(CH ) SiCH COCHCOOC(CH ) ) (CH ) SiCH CCHC00c(CH )
3 3 2 3 3 THF, reflux7\ 3 3 2 | 3 3
0-—CHC6H5
VIII
(27)
C6H COOC(CH3)3
\/ -(CH3)3SiO
'L—\\ < A
0

Attempted Reaction of the Dianion of VIII with Benzaldehyde

Apparently, attempts to generate the dianion of VIII with n-butyl-
lithium failed. Addition of HMPA or TMEDA did not appreciably
facilitate dianion formation. Addition of acetone to these reaction
mixtures resulted in camphoric odors after quenching, indicative of
tertiary alcohol formation. A 1,2-addition of base to the carbonyl
component would explain the presence of a tertiary alcohol reflecting
incomplete dianion formation (eq. 28). Failure to generate the
dianion system is not unusual since such reactions have been shown
sensitive to the base used, solvent, temperature and reaction

time.53’64

86

OLi 0H
"THF, —78° l aq. NH4CI I
CH C0CH + n-BuLi ,>:(CH3)ZC-—-Bu g> (CH3)2C--Bu

3 3 then 25°

 

(28)

Attempted Reaction at the y—Position of XIII and XIV

Compounds XIII and XIV were prepared in hopes their monoanions

would undergo alkylation or aldol condensation at the y-carbon. For

0

OSi(CH3)3 q
CH3c=CHCOOEt (IIHZC =—"’ CHCOOEt
Si(CH3)3
XIII XIV

example, the anion of 4-pyrrolidino-3—penten-2-one readily undergoes
reaction exclusively at the y-position (eq. 10).55 The silylated

enamino ester XIV was obtained in a similar fashion (eq. 29).

O O

 

N N
I n—BuLi TMCS
CH3c====CHCOOEt ;> > CHZC::::CHCOOEt (29)
THF, -78° —78° I ‘
then to 25° Si(CH3)3

Treatment of XIV with n-butyllithium in THF at -78° followed

by benzaldehyde addition returned starting material. Apparently the

87

C-trimethylsilyl group seriously interferes with proton removal
from the y-position in XIV.

Proton removal from the crotonate XIII with LiDPA and quenching
the anion with benzyl bromide gave the alkylated unconjugated ester

XV (eq. 30) and not the y-substituted product. This result was not

 

OSi(CH3)3 081(CH3)3
LiDPA C.6H5CHzBr I (30)
CH C =CHCOOEt 9 > CH =C—CHCO0Et
3 M 2
O
XIII '78 CH2C6Hs
xv

particularly surprising since such ester enolate systems are known

 

 

65,66
to react predominately at the alpha carbon (eq. 31).
LiICA C6HSCHzBr
CH CH =CHCOOEt 7‘ a CH :CHCHCOOEt (31)
3 o o 2
-78 0
CH2C6H5

62%

EXPERIMENTAL

I. 'Materials

Tert-butyl trimethylsilylacetate was prepared and purified as
described in Chapter 1. Tert-butyl and ethyl acetoacetate were
commercially available and used without further purification. Tri-
methy1Ch1orosilane was obtained from Aldrich and distilled (bp 57°/
atm. pressure) prior to use. DiiSOprOPylamine (bp 83°/atm. pressure)
was distilled and stored over molecular sieves. All acid chlorides
and imidazole were commercially available and used without further
purification. Tetrahydrofuran was stored over molecular sieves, and

the HMPA.was distilled from sodium before use.

II. Preparation of N—Acylimidazoles

The preparation of N-acetylimidazole is representative. A 250
ml round-bottomed flask, equipped with magnetic stirring, septum inlet,
and mercury bubbler, is flushed with nitrogen. The flask is charged
with 6.8 g (100 mmoles) of imidazole and 125 m1 of dry benzene.
After the imidazole has dissolved, 3.5 ml (50 mmoles) of acetyl
chloride is injected, and the mixture stirred for 3 hours. The
hydrochloride salt is removed by vacuum filtration followed by evapor-
ation of the filtrate. The crude imidazole is recrystallized from
benzene, washed with cold hexane, and dried in vacuum giving 3.75 g

(682) of product (mp 103-4°).
88

89

III. Preparation of B-Keto Esters

A. tert—Butyl Cinnamoylacetate

 

The following procedure for the conversion of cinnamoyl imidazole
into tertfbutyl cinnamoylacetate is representative. A 100 ml round-
bottomed flask equipped with magnetic stirring, septum inlet, and
mercury bubbler is flushed with nitrogen and immersed in an ice-water
bath. The flask is charged with a hexane solution of n—butyllithium
(12.5 ml, 25 mmoles), and 3.6 ml (25 mmoles) of diisopropylamine
is injected over a 2 minute period. Following complete addition, the
hexane is removed under vacuum, and the residue of lithium diiso-
propylamide is dissolved in 25 m1 of THF. The flask is immersed in a
dry ice-acetone bath, and t-butyl trimethylsilylacetate (5.5 ml, 25
mmoles) is added dropwise over a 2 minute period. After an addi-
tional 10 minutes of stirring, a warm solution of cinnamoyl imidazole
(4.95 g, 25 mmoles) in 25 ml of THF is added dropwise. The red
reaction mixture is stirred for an hour and then allowed to reach room
temperature followed by quenching with 25 m1 of 3N hydrochloric acid.
Addition of 100 m1 of pentane followed by separation and evaporation
of the organic phase gave 5.85 g (95%) of a yellow solid. Recrystall-
ization from methanol gave pure Egggfbutyl cinnamoylacetate; 3.1 g

(502), mp 87-87.S°.

90
"3. Product Analysis
tert-Butyl cinnamoylacetate

NMR(CDC13): 6 7.52 (m, 5H), 6 7.80, 6 7.00, 6 6.62 (all singlets,
2H), 6 5.17, 6 3.66 (2 singlets, 2H), 6 1.50 (overlapping singlets,

9H).

tert-Butyl acetoacetate

 

NMR(CC14): 6 4.67, 6 3.13 (2 singlets, 2H), 6 2.13, 6 1.83

(2 singlets, 3H),6 1.43 (s, 9H).

tert-Butyl 3-oxohexanoate

 

NMR(CC1 ° 6 3,16 (s, 2H), 6 2.30-2.60 (m, 2H), 6 1.46 (s, 9H),

4)°
6 1.16 (m, 2H), 6 0.90 (t, 3H).

tert-Butyl 3-oxo-4,4-dimethylpentanoate

 

NMR(CC14): 6 4.83, 6 3.30 (2 singlets, 2H), 6 1.46 (overlapping

singlets, 9H), 6 1.12 (s, 9H).
tert-Butyl 2-furylideneacetate

NMR(CDC13): 6 5.17 (broad, 1H), 6 4.12 (t, 2H), 6 3.03 (t, 2H),

6 2.03 (m, 2H), 6 2.46 (s, 9H).

91

C. Isolation of Lithio tert—Butyl Acetoacetate

 

The reaction flask and lithium amide are prepared as previously
described. To the THF solution of base at -78°, 1.1 ml (5 mmoles) of
t-butyl trimethylsilylacetate is added dropwise and stirred for 5
minutes. N-Acetylimidazole (0.55 g, 5 mmoles) is added, and the
reaction mixture allowed to warm to room temperature. After two
hours, pentane and water are added, the organic layer separated,
dried, and removed by vacuum leaving 0.7 g (852) of product. The
solid decomposes upon burning imparting a pink color to the flame and
leaving a charred residue. The lithium salt is soluble in pyridine
or DMF.

NMR(pyridine): 6 5.12 (s, 1H), 6 2.08 (s, 3H), 6 1.57 (s, 9H).

IV. Reactions Involving Dianion Systems

 

A. Lithio tert-Butyl Acetoacetate with Trimethylchlorosilane

Lithium diisopropylamide (10 mmoles) is prepared and dissolved
in 25 m1 of THF. The 100 ml round-bottomed flask is immersed in an
ice-water bath, and 0.85 ml (5 mmoles) of t-butyl acetoacetate is
injected. After 20 minutes, 5 mmoles (0.63 ml) of TMCS is added,
and the mixture stirred for another 15 minutes. The THF is removed
on the rota-evaporator, and the residue dissolved in ether. After
a few minutes the lithium chloride separates. ‘With a good vacuum, the
ether and amine are removed leaving a white solid. Lithio t-butyl
4-trimethylsilylacetoacetate is soluble in pyridine and imparts a

pink color to a flame upon burning.

92

NMR(pyridine): 6 4.93 (s, 1H), 6 1.97 (s, 2H), 6 1.50 (s, 9H),

6 0.12 (s, 9H).

8. Lithio tert-Butyl Trimethylsilylacetoacetate with Benzaldehyde

 

The procedure is general. The silylated monoanion (1.18 g,
5 mmoles) is dissolved in 15 m1 of THF and 5 mmoles of LiDPA in
THF or n-butyllithium in hexane is added at -78°. Alternatively,
the monoanion my be added to the base. In some trials, 1 mmole of
TMEDA or HMPA was added at this point. In some trials, the monoanion
and base were mixed at 0°. In any case, the mixture is stirred for one
hour at room temperature, cooled in a dry ice—acetone bath, 5 mmoles
of benzaldehyde added (or acetone), and the reaction mixture warmed
to 25°. After one hour, the THF is removed in vacuum leaving a
gel. washing the gel with ether gave a white solid. Treatment of
this material with aqueous ammonium chloride resulted in a camphoric
odor (when acetone is used) but glpc detected an array of products.
Removal of ether from the gel extract often resulted in as much as a

702 return of starting material.
V. Reactions Involving Monoanion Systems
A. Ethyl 3-Pyrrolidinocrotonate with Trimethylchlorosilane

A 500 ml round—bottomed flask equipped with magnetic stirring,
septum inlet, and mercury bubbler is charged with 9.16 g (50 mmoles)
of the enamine and 200 ml of THF. The contents, under nitrogen,
are cooled in a dry ice-acetone bath, and 23 ml (50 mmoles) of n-

butyllithium is injected. The mixture is allowed to reach room

93

temperature and after 90 minutes is cooled again to -78°. TMCS is
added drOpwise, and the mixture is stirred overnight at 25°. The
THF is removed by vacuum, the red oil dissolved in pentane separating
the lithium chloride. Vacuum distillation of the organic phase gave
ethyl 4-trimethy1silyl-3-pyrrolidinocrotonate (bp 118-120°/0.5 mm)
which seriously decomposed under these conditions.

NMR(CC14): 6 4.13 (s, 1H), 6 3.80 (q, 2H), 6 3.17 (m, 4H),

6 2.53 (s, 2H), 6 1.83 (m, 4H), 6 1.13 (t, 3H), 6 0.06 (s, 9H).
B. Ethyl 4-Trimethylsilyl-B-pyrrolidinocrotonate with Benzaldehyde

A 100 m1 round-bottomed flask, equipped as usual, is flushed
with nitrogen and charged with 1.13 g of the silylated enamine (5
mmoles) and 20 m1 of THF. The flask is immersed in a dry ice-acetone
bath and 2.45 ml of n-butyllithium in hexane is injected. The
mixture is stirred for 1 hour and allowed to reach 25°. After cooling
to -78°, 0.51 ml (5 mmoles) of benzaldehyde is added dropwise and
stirred for an additional hour coming to room temperature. The
reaction contents are mixed with pentane and water, the organic phase

dried, and subjected to glpc revealing no reaction had occurred.
C. Preparation of Ethyl 3-Trimethylsiloxycrotonate

A 2-liter round-bottomed flask, equipped with a dropping funnel,
condenser, and thermometer, is charged with 137 ml (1 mole) of
triethylamine and 145 ml (1.1 moles) of TMCS. The system is kept
under nitrogen and ethylacetoacetate added dropwise. The temperature

is maintained at 25° frequently requiring an icedwater bath. The

 

94

addition required 1 hour, and after 2 more hours, the amine hydro-
chloride is removed by filtration. The salt is washed with hexane,
the solvents combined, and removed by vacuum. The product distilled
at 75°l7mm giving 153 g (76%) of a colorless oil (density 1.06).
NMR(CC14): 6 4.87 (s, 1H), 6 3.97 (q, 2H), 6 2.13 (s, 3H),

6 1.10 (t, 3H),6 0.26 (s, 9H).
D. Ethyl 3-Trimethylsiloxycrotonate with Benzyl bromide

A 50 ml round-bottomed flask, equipped with magnetic stirring,
septum inlet, and mercury bubbler, is flushed with nitrogen.and flame
dried. LiDPA (5 mmoles) is prepared in the usual fashion, dissolved
in 10 ml of THF and immersed in a dry ice-acetone bath. The silyl
enol crotonate (0.95 ml, 5 mmoles) is injected and stirred for 15
minutes. The benzyl bromide (0.60 ml, 5 mmoles) is added, and the
flask is warmed to 25°. The solvent is removed on the rota-evaporator,
pentane added to the residue, and lithium bromide separated. The
pentane is removed by vacuum leaving an oil. The product is purified
by glpc.

NMR(CC14): 6 6.97 (m), 6 5.03, 6 4.83 (2 doublets), 6 3.90 (m),
a 2.92 (m), o 1.18 (t), a 0.20 (s). IR(neat): 1735 om'l (c=0),

1625 cm-1 (C=C).
E. tert-Butyl 4-Trimethylsilylacetoacetate with Benzaldehyde

A 50 ml round-bottomed flask, equipped with magnetic stirring,
septum inlet, and mercury bubbler, is flushed with nitrogen and

charged with 1.18 g (5 mmoles) of the lithium salt and 10 ml of THF.

 

95

The flask is immersed in an ice-water bath, and 0.51 ml (5 mmoles)
of benzaldehyde is injected. After 1 hour, glpc detected no
reaction had occurred. The mixture was refluxed for 24 hours, the
solvent removed, and an orange oil remained with an odor of
benzaldehyde. Washing the oil with pentane separated the unreacted

lithium salt.

B IBL IOGRAPHY

9.
10.
ll.
12.
13.
14.
15.
l6.

17.

18.

19.

B IBLIOGRAPHY

 

M. Newman and B. Magerlein, Org. Reactions, 5, 413 (1949).

M. Ballester, Chem. Rev., 52} 283 (1955).

 

 

R. Shriner, Org. Reactions, 1} l (1942).

'M. Rathke, Org. Reactions, 2%} 423 (1975).

 

F. Gaudemar—Bardone and M. Gaudemar, Bull. Soc. Chim. Fr., 3316
(1971).

 

B. Castro, J. Villieras, and N. Ferracutti, Bull. Soc. Chim. Fr.,
3521 (1969).

 

M. Gaudemar, Bull. Soc. Chim. Fr., 3113 (1966).

 

E. McBee, 0. Pierce, and D. Christman, J. Am. Chem. Soc., 739
1581 (1955).

 

 

R. Miller and F. Nord, J. Org. Chem.,r19, 728 (1951).

A. Hussey and M. Newman, J. Am. Chem. Soc., 39, 3024 (1948).

 

M. Newman, J. Am. Chem. Soc., €36 2131 (1942).

 

J. Frankenfeld and J. Werner, J. Org. Chem,,36, 3689 (1969).

 

A. Siegel and H. Keckeis, Monatsh. Chem.,f§4, 910 (1953).

 

C. Grob and P. Brenneisen, Helv. Chim. Acta, ’31, 1184 (1958).

 

J. Cure and M. Gaudemar, Bull. Soc. Chim. Fr., 2471 (1969).

 

R. Pearson and R. Dillon, J. Am. Chem. Soc., 13, 2439 (1953).

J. March, "Advanced Organic Chemistry: Reactions, 'Mechanisms, and
Structure", McGraw—Hill, Inc., 1968, p. 221.

H. House, "Modern Synthetic Reactions", 2nd edition, W.A. Benjamin,
Inc., 1972, p. 552.

M. Rathke and A. Lindert, J. Am. Chem. Soc., 9%, 2318 (1971).

96

 

20.

21.

22.

23.

24.

25.

26.

27.

28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.

42.

97

'M. Rathke, J. Am. Chem. Soc., 32, 3222 (1970).

 

M. Rathke and D. Sullivan, Synth. Commun., 3, 67 (1973).

 

K. Williamson, C. Lanford, and C. Nicholson, J. Am. Chem. Soc.,
86, 762 (1963).

 

W. Kirmse, Angew. Chem., 73, 161 (1961).

 

W. Vaughn, S. Bernstein, and'M. Lorber, J. Org. Chem., 30, 1790
(1965). ”

 

W. Vaughn and H. Knoess, J. Org. Chem., 32, 2394 (1970).

 

M. Newman, A. Arkell, and T. Fukunaga, J. Am. Chem. Soc., 82,
2498 (1959).

 

D. Sullivan, Ph.D. Thesis, Michigan State University, E. Lansing,
Michigan, 1974.

R. Borch, Tetrahedron Lett., 3761 (1972).

 

H. Zimmerman and L. Ahramijian, J. Am. Chem. Soc., 83, 5459 (1960).

 

R. Baker, Organic Syntheses, Coll. Vol. III, 144 (1955).

 

H. Brown, J. Am. Chem. Soc., 69, 1326 (1938).
E. Edwards, D. Evans, and H. watson, J. Chem. Soc., 1944 (1937).

M. Rathke and J. Deitch, Tetrahedron Lett., 2953 (1971).

 

D. Peterson, J. Organomet. Chem., 2, 373 (1967).

 

D. Peterson, J. Organomet. Chem., 8, 199 (1967).

 

C. Hauser and C. Hance, J. Am. Chem. Soc., 74, 5091 (1952).

 

T. Chan, E. Chang, and E. Vinokur, Tetrahedron Lett., 1137 (1970).

D. Peterson, J. Org, Chem., 3%, 780 (1968).

 

M. Rathke and D. Sullivan, J. Am. Chem. Soc., 25, 3050 (1973).

 

G. Ron and K. Nargrund, J. Chem. Soc., 2461 (1932).

R. Fraser and D. McGreer, Can. J. Chem., 32, 505 (1961).

 

L. Jackman and R. Wiley, J. Chem. Soc., 2881 (1960).

 

43.
44.

45.

46.

47.

48.

49.

so.

51.

52.

53.
54.

55.

56.

57.

58.
59.
60.
61.
62.
63.

64.

98

L. Jackman and R. Wiley, J. Chem. Soc., 2888 (1960).

House, Op. Cit.18

 

, pp. 682-709.

W. wadsworth, Jr. and W. Emmons, J. Am.'Chem.’Soc.,,8§, 1733
(1961). ”

 

W. wadsworth, Jr. and W. Emmons, Org. Synth.,,3§, 44 (1965).

K. Fung, K, Schmazl, and R. Mirrington, Tetrahedron Lett., 5017
(1969).

 

S. Hartzell, D. Sullivan, and M. Rathke, Tetrahedron Lett.,
1403 (1974).

 

H. Staab, Angew. Chem. Int. Ed. Engl.,,1, 351 (1962).

 

A. Cook, "Enamines: Synthesis, Structure, and Reactions,"
M. Dekkar, New York, 1969.

House, Op. Cit.18, pp. 520-530.

J. WOlfe, T. Harris, and C. Hauser, J. Org. Chem.,,ge, 3249
(1954).

 

 

L. Weiler, J. Am. Chem. Soc., 3%, 6702 (1970).

S. Huckin and L. Weiler, Tetrahedron Lett., 4835 (1971).

 

M. Yoshinoto, N. Ishida, and T. Hiraoka, Tetrahedron Lett., 39
(1973).

 

G. Berchtold, G. Harvey, and G. Wilson, Jr., J. Org. Chem., 39,
2642 (1965).

 

T. Wieland and G. Sneider, Justus Liebigs. Ann. Chem., 589, 159
(1953).

H. Staab. Chem. Ber., 9, 1927 (1956).

 

a. Stash, Chem. Ber., , 2088 (1956).

 

5%: S“’

H. Staab, M. Luking, and F. Durr, Chem. Ber., 22, 1275 (1962).
W. LeNoble, Synthesis, 1 (1970).

G. Brieger and M. Pelletier, Tetrahedron Lett., 3555 (1965).
S. Huckin and L. Weiler, Tetrahedron Lett., 2405 (1972).

S. Huckin and L. Weiler, J. Am. Chem. Soc., 26, 1082 (1974).

99

65. M. Rathke and D. Sullivan, Tetrahedron Lett., 4249 (1972).

 

66. J. Herrimann, G. Kieczykowaski, and R. Schlessinger, Tetrahedron

 

Lett., 2433 (1973).