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THE SYNTHESIS OF ESTERS OF DI TERT BUTYLACETIC
ACID AND THEIR ATTEMPTED REACTION WITH STRONG BASES

By

Graylon Denston Copedge

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements

for the degree of

MASTER OF SCIENCE

Department of Chemistry

1979

 

ABSTRACT

THE SYNTHESIS OF ESTERS OF DI-TERT-BUTYLACETIC
ACID AND THEIR ATTEMPTED REACTION WITH STRONG BASES

By

Graylon D. Copedge

Di-t-butylketene prepared by a modified version of
a method developed by Newman, was converted into the
esters of di-t-butylacetic acid, by reaction with various
alcohols in the presence of Lewis acids.

An attempt was made to prepare the enolate conjugate
base of these esters to determine if decomposition to
di-t—butylketene occurs. Though ester enolates are stable
indefinitely at -78°, upon warming they decompose to
B-keto esters, there is evidence that this decomposition
occurs through a ketene intermediate. Surprisingly, di-

t-butylacetic acid esters were found to be inert to LDA.

ACKNOWLEDGMENTS

The author wishes to extend appreciation to Dr.
Michael w. Rathke for his advice and guidance throughout
this work. Thanks are also given to Dr. William Reusch

for his time and interest in this work.

11

 

Chapter

TABLE OF CONTENTS

LIST OF TABLES. . . . . . . . . . . .

INTRODUCTION. . . . . . . . . . . . .
RESULTS . . . . . . . . . . . .
I. Synthesis of Di-t-butylketene.

II. Preparation of the Ester Series.
III. Reactions of Esters with Bases
DISCUSSION. . . . . . . . . . . .
EXPERIMENTAL. . . . . . . . . . . . .

I. Materials. . . . . . . . .

II. Preparation of 2,2,h,H-Tetra-
methyl-3-pentanone (II). .

III. Preparation of l,l-Di-t-
butylethanol (III) . . . .

IV. Preparation of l,l-Di-t-
butylethylene (IV) . . . .

V. Preparation of 2,2—Di-t-
butylethanol (V) . . . . .

VI. Preparation of Di-t-butyl-
acetic acid (VI) . . . . .

VII. Preparation of Di-t-butyl-
acetyl chloride (VII). . .

VIII. Preparation of Di-t-butyl—
ketene (VIII). . . . . . .

IX. Preparation of Ethyl Di-t-

 

butylacetate (IX). . . . .

iii

Page

(DODH

10
11
1h
16
16

l6

17

18

18

19

20

20

20

 

Chapter
X. Preparation of t-Butyl
Di—t-butylacetate (X). . .
XI. Reactions of Esters with
Strong Bases . . . . . . .
A. Materials. . . . . .
B. Apparatus and General
Procedure. . . . . . .
C. Mixture of IX and LDA.
D. Mixture of X and LDA .
E. 1H NMR of 1:1 Mixture of
X and LDA. . . . . . .
F. Mixture of X and n—
Butyllithium . . . . .
G. Mixture of X and
Methyllithium. . . .
H. Mixture of X and Sodium
Amide O 0 O O O O O O O
BIBLIOGRAPHY O O O O O O O O O O 0

iv

Page

21

21
21

21
22
23

2A

2A

2A

25
26

LIST OF TABLES

Table Page

I Results of Quenching 1:1
Mixtures of X and Base. . . . . . . . . . 13
II Results of Quenching 1:1

Mixtures of IX and Base . . . . . . . . . 23

INTRODUCTION

In this thesis we will present a method for the
synthesis of di-t-butylketene by a modified version of
the procedure developed by Newman (13). We will also
describe reactions of this ketene with various alcohols
in the presence of Lewis acids, which lead to esters of

di—t-butylacetic acid.

 

(CH ) (CH )
3 3 ROH 3 3 o
=C=O A + ) H—C-OR
H
(CH3)3 (CH3)3

Our purpose in making these esters is to prepare and
study their enolate conjugate bases under various condi-
tions to determine whether decomposition to di-t-butyl-
ketene occurs.

There are two methods by which ester enolates may be
prepared, one method utilizes the action of zinc metal

on a-haloesters (Reformatsky reaction) (1)

Zn
-§_C02R—-+ Zn§-C 02R

However, the zinc enolates are unstable at the tempera-
tures required for their formation and their usefulness
depends on the availability of the corresponding a—halo-
esters. The second method consists of treating the ester
with a relatively strong (pka of an ester E 25) (2) organic
base.

In an early study of ester enolates Hauser (3) used
sodium triphenylmethane as a base, and observed reaction
of the enolates with acid chlorides. He later developed
(A) an alternative procedure in which enolates of t-butyl-
esters were generated in liquid ammonia using lithium
amide as a base; such enolates proved to be stable at
-37°.

Dialkylamide salts are strong (pka of amine >3u) (2)
soluble, nonnucleophilic bases capable of generating ester
enolates quantitatively at —78°. At this temperature the
resulting enolates are indefinitely stable.

Disilyl analogues of dialkylamide bases can also be
used to prepare enolates of esters. Sodium bis(trimethyl-
sily1)amide generated the enolate of ethyl acetate (5),
which upon reaction with trimethylchlorosilane, produced
a mixture of ethyl trimethylsilylacetate (22.3%) and
O-trimethylsilyl-O-ethyl ketene acetal (13.7%). Lithium
bis(trimethylsily1)amide, formed in hexane by the reaction
of the amine with a commercial butyllithium solution,

generated the enolate quantitatively at -78° in

tetrahydrofuran (6). However attempts to use this pro-
cedure to prepare other ester enolates were unsuccessful.
Lithium isopropylcyclohexylamide or lithium diiso-
propylamide, react with a wide variety of esters at low
temperatures in tetrahydrofuran to produce quantitatively

solutions of the corresponding lithium ester enolates (7)

C

THE
Li + H- CO2C2H5-38—o9
H(CH3)2
L1§C0202H5 +
H(CH3)2

This represented the first general method for the
preparation of stable solutions of ester enolates. In a
later study lithio t-butyl acetate was obtained in quanti-
tative yield as a stable white solid free of amine (7)
using lithium diisopropylamide in hexane and evaporating
off the solvent and amine.

Ester enolates, unlike ketone enolates, are unstable
upon warming to room temperature. The resulting decomposi—
tion to B-keto esters may occur by three pathways: (a)
direct coupling of the ester enolate with a second mole

of enolate; (b) removal of a proton from the solvent or

amine and condensation of the ester thus formed with another
mole of enolate, a rapid process (8); (c) elimination of
metal alkoxide and reaction of the resulting ketene with a

second mole of enolate.

   

 

 

_ a
2-i-cozR
BH H b @
iii-0023 .n) 1430212 -%- -C-C02R
-MOR c:J
Mg-C02R~———€p -f=c=o -FLCOZR

A study of the kinetic behavior of the decomposition
of ester enolates (9) provided evidence against direct
enolate coupling. Thus solutions of lithio t-butyl acetate,
lithio ethyl isobutyrate, and lithio ethyl hexanoate showed
first order decomposition kinetics. In the case of mechan-
ism (b) it was discovered (10) that solutions of lithio
t-butyl acetate, which are prepared free of amine, also
formed condensation products at room temperature

25°C H o+
2LiCH2COZC(CH3)3 EE;——EZ-—3+> CH3COCHZCOZC(CH3)3
,
(90% GLC)

+ (CH3)3COH

The ketene pathway to B-keto ester formation was sug-
gested by Vaughan (11) for the self-condensation of the
reagent prepared from ethyl a-bromoisobutyrate and zinc

metal
BanC(CH3)2C02C2H5 + (CH3)2C=C=O + BanOC2H5
(CH3)ZC=C=O + BanC(CH3)2002C2H5 +
Ho+
uni-'5?(CH3)2CHCOC(CH3)2CO202H5

Ketene intermediates have also been proposed for the
E1CB mechanism of hydrolysis of malonic and B-keto esters
(12).

The first decomposition of an ester enolate leading
to the isolation of a ketene (10) involved the enolate of
t-butyl 2,2—bis(trimethylsily1)acetate, prepared by the
addition of the ester to an equivalent amount of lithium
diisopropylamide at -78°. Warming solutions of the enolate
to room temperatures gave the relatively stable bis(tri-
methylsilyl)ketene. Steric hindrance by the bulky tri-
methylsilyl groupings favored isolation of ketene rather

than condensation products.

 

1(CH3)3
H0020(CH3)3 + LiNECH(CH3)2]2
i(CH3)3
i(CH )
THF 3 2
_780 L1 CO2C(CH3)3 + HNECH(CH3)2]2
1(CH3)3
1(CH )
THF 3 3
i —) LiOC(CH.,)3 + I---C'=O
25°, 30 min '
i(CH3)3 (85%, GLC)

Ketene intermediates in the decomposition of lithium
ester enolates can be isolated (as by the example of
bis(trimethylsilyl)ketene) provided the reaction with
alkoxide or with ester enolate can be prevented. Increased
substitution at the methylene carbon of a ketene has been
shown to result in unreactive ketenes. Di-t-butylketene
is known to be remarkably unreactive (l3), hence the esters
of di-t-butylacetic acid were chosen for this study. It
was desired to know if ketene is formed by loss of lithium
alkoxide from such ester enolates and if so, how the rate
of decomposition is affected by the structure of the

alkoxide leaving group.

(”3’3 '0 (CH3)3
L1 ‘ C-OR + LiOR + =C=O
(CH3)3 (CH3)3

RESULTS

I. Synthesis of Di-t-butylketene

Di-t-butylketene was prepared by a modified version
of the procedure developed by Newman (13) for synthesizing
highly branched aliphatic compounds. The steps in the

synthesis are outlined as follows:

g 2eq KH B
(CH3)2CH CH(CH3)2 -—--€> (CH3)3C C(CH3)3

 

2eq CHBI
I II
CH Li H
i—a>(CH3)3C C(CH3)3
H3
III
30012 @H2 1) BH 3H%°H Cro3
III—’(CH ) c C(CH ) —-—-3?(CH ) c c CH) ..___)
H202
IV V
o H 001
Z 2 3001 i Et N
(CH3)3C HC(CH3)§—--—%»(CH3)3C HC(CH3)3—-—1fi>(CH3)3C C(CH3)3
VI VII VIII

Permethylation of diisopropyl ketone I was achieved by
treatment of I with a twofold excess of potassium hydride
and methyl iodide. This procedure (1“) gave a greater
yield (60-70%) and provides a simpler route to hexamethyl-
acetone II than the classical method used by Newman.
Treatment of II with excess methyl lithium gave 2,2,3,h,h-
pentamethyl-B-pentanol III in 71% yield. This was de-
hydrated with thionyl chloride and pyridine to the olefin
l,l-di-t-butylethylene IV in 86% yield. The olefin was
then converted into 2,2-di-t-butylethanol V in 60-70%
yield by treatment with diborane (prepared by treating
sodium borohydride with borontrifluoride etherate instead
of aluminum chloride as done by Newman), followed by oxida-
tion with alkaline hydrogen peroxide and hydrolysis.
Oxidation of V with chromium trioxide in aqueous acetic
acid containing sulfuric acid gave di-t-butylacetic acid
VI in 76% yield. This acid was converted to the acid
chloride VII in 70-90% yield by the action of excess
thionyl chloride. A better procedure for elimination of
the acid chloride VII to ketene VIII than that described
by Newman involved the use of triethylamine in place of
sodium amide. This gave a greater yield of di—t-butyl-
ketene than that obtained by Newman, as well as providing

a much simpler procedure.

10

II. Preparation of the Ester Series

The esters of di-t-butylacetic acid were prepared by
addition of the appropriate alcohols to VIII in the pres-

ence of a Lewis acid catalyst.

(CH3 3 ROH ‘0 H3’3
=c=o —-H—-) H— -OR

(CH (CH3 )3

3)3
This provides a simpler method of preparation of the
esters than the more conventional methods such as esteri-
fication of the acid VI with the alcohols in the presence
of acid catalyst, or acylation of the alcohols by the acid
chloride. Such reactions were expected to be more dif-
ficult to effect, since in each case a tetrahedral inter-
mediate would be generated. Such intermediates would be
disfavored by branching at the a and 8 carbon atoms (15).
Also, when R is tertiary, carbonium ion formation and
elimination predominate under these conditions.

Ethyl Di-t-butylacetate IX, was prepared by adding
VIII to a stirred solution of ethanol and a drop of sul-
furic acid. Distillation (22 mm, 90°) gave IX in greater
than 90% yield.

t-Butyl-Di-t-butylacetate X, could not be prepared in
the same way as IX. Instead borontrifluoride etherate was

added to a solution of VIII and tertiary butyl alcohol

11

in methylene chloride, and after a vigorous reaction oc-
curred, GLC analysis showed the ketene peak had disappeared
and a new peak had appeared. This reaction required only
3-5 minutes, and distillation (0.3 mm, 61°) gave X in

quantitative yield.

III. Reactions of Esters with Bases

In a typical experiment one equivalent of ethyl ester
IX was added to a stirred solution of lithium diisopropyl-
amide LDA in tetrahydrofuran at -78°. This solution was
stirred for 15 minutes, then warmed to room temperature
and stirred an additional 5 minutes. After quenching with
water, pentane and an internal standard (tridecane) were
added and the mixture was dried over anhydrous potassium
carbonate. Analysis of the supernatant liquid showed a
93-95% recovery of IX. When the 1:1 mixtures of IX and
LDA was stirred for longer periods (1 to 8 hours) quenching
resulted in a 85-95% recovery of IX. If the mixture was
refluxed for an hour, 80% recovery of IX was observed.
When the same experiments were tried with the t—butyl
ester X similar results were obtained.

These results presented two possibilities: One, the
enolates of both esters are formed and are stable with
respect to decomposition to ketene. Two, the enolates

of the esters are not formed in the presence of LDA.

12

To determine whether the enolate anion was formed,
the 1H NMR of a 1:1 mixture of LDA and X in benzene was
taken and found to be identical to the 1H NMR of the
reactants.

Further experiments involving 1:1 mixtures of X and

other bases were conducted, the results are given in

Table I.

13

Table I. Results of Quenching 1:1 Mixtures of X and Base.

 

 

 

Reaction Period Recovered

Base (Solvent) (Temperature) Ester, 5a
LDA (THF) 1 h (reflux) 90-96
LDA/TMEDAb (THF)° 2 d (reflux) 80
n-butyllithium (THF) 5 min (A0°) 100
n-butyllithium/TMEDA
(THF) 5 min (NO°) 100
methyllium/TMEDA
(THF) 30 min (HO-50°) 9A
methyllium/TMEDA
(pentane) 10 h (25°) 87
sodium amide (Et20)d 9 h (25°) 91

 

 

aDetermined by GLC analysis.
bN,N,N',N'-tetramethylethylenediamine.

0The ratio of base to X was 5:1.

dThe ratio of base to X was approximately 100:1.

DISCUSSION

The exter X proved to be inert to LDA as Opposed to
its silyl analogue, t-butyl 2,2-bis(trimethylsilyl)acetate.
This is a surprising result and X represents the only
known ester to be inert to LDA.

Steric hindrance to the approach of base is probably
the major cause of the inactivity of X. The importance
of such steric effects can be noted by comparing the
relative rates of base catalyzed deuteration (16) of the
CH2 group in 2-butanone with the more hindered CH2 group

in A,A-dimethyl-2-pentanone.

CH3QEHCH3 krel = “1.5

CH3fiiHC(CH3)3 krel = 0.45

H-CH2@CH2C(CH3)3 krel = 5.1

This steric hindrance effect should be less in the
silyl analogue due to the longer bond length of the Si-C
bond (1.87 X) as opposed to the C-C bond (1.5u K) (17).

l“

15

The rather slow rate of exchange at the CH3 group of
A,h-dimethyl—2-pentanone may also reflect a steric factor

arising from the bulky nature of the neopentyl group (16).

 

The enhanced acidity of a Si-C-H grouping compared
with C-C-H may also be an important factor in the different
reactivity of t-butyl 2,2-bis(trimethylsilyl)acetate and
t-butyl di-t-butylacetate with strong bases. Such acidity
is due to the vacant d-orbitals of silicon which are of
suitable energy for back bonding with a filled 2p orbital
on the adjacent carbon atom, thus stabilizing an adjacent

carbanion (18).

EXPERIMENTAL

I. Materials

All reagents were obtained commercially from Aldrich
Chemical Company, Inc. unless otherwise stated.

Diisopropyl ketone was purified by simple distillation
and stored under argon over molecular sieves. Methyl
iodide was distilled and stored in a dark bottle over
copper wire. Potassium hydride was obtained commercially
from Ventron Corp. as a 23.6% 1n mineral oil dispersion.
The dispersion was standardized by measuring the gas given
off when a sample of known volume was treated with water.
Methyllithium was obtained as a 1.6M solution in ether
and used as received. Tetrahydrofuran was dried over
sodium benzophenone ketyl, distilled and stored under
argon over molecular sieves. Diglyme was purified by
distillation from lithium aluminum hydride under reduced

pressure and stored under argon over molecular sieves.

II. Preparation of 2,2,U,h—Tetramethyl-3-pentanone (II)

A 5000 mL three neck round bottom flask was equipped
with a mechanical stirrer, dry ice condenser, and mercury

bubbler. The system was heated in an oven and flushed

l6

17

with argon. The flask was charged with 732 ml (AOAB mmol)
of potassium hydride in mineral oil, and immersed in an
ice water bath. THE (1000 ml) was added followed by drop-
wise addition of 285-mL (202h-mmol) of diisoprOpyl ketone
over a A h period. Methyl iodide 126 m1 (“0&8 mmol) was
added dropwise over a 3 h period. The reaction mixture
was refluxed for l h, then immersed in an ice water bath.
A second addition of methyl iodide 126 ml (AOA8 mmol) was
added dropwise over a 3 h period. The mixture was allowed
to stir for l h and the unreacted potassium hydride quenched
cautiously with water. The aqueous layer was extracted
with ether and the combined organic layers distilled to
give 173 g, 60% yield, of 2,2,A,A—tetramethyl-3-pentanone;
bp 15A° (760 mm);]TINMR (CClu, internal MeuSi) 61.2 (8);

IR (neat) 1670 cm'l.

III. Preparation of l,l-Di-t-butylethanol (III)

A 3000 ml three neck round bottom flask was equipped
with a mechanical stirrer, condenser, and mercury bubbler.
The system was heated in an oven and flushed with argon.
The flask was charged with 678 ml of 1.6M methyllithium
in ether, to this was added 140 ml (810 mmol) of II.

After refluxing for l h excess methyllithium was destroyed
carefully with water. The aqueous layer was extracted
with ether and the ether removed from the combined organic

layers under reduced pressure leaving behind an oil.

18

Crystallization at -78° from pentane gave 181.5 8, 76%
yield, of l,l-di-t-butylethanol: mp uz-uu°;1H NMR (001“,
internal MeuSi) 61.05 (s, 18H), 61.13 (s, 3H).

IV. Preparation of 1,1-Di-t-butylethylene (IV) (13)

A 1000 ml three neck round bottom flask was equipped
with a mechanical stirrer. To this flask was added a solu-
tion of 131 g of III in 500 m1 of pure dry pyridine.
Thionyl chloride (90 m1) purified by distillation from
raw linseed oil, was added dropwise so that the tempera-
ture never exceeded 20° during the addition. The liquid
phase was passed through a filter to remove pyridine hydro-
chloride. Distillation from potassium hydroxide pellets
produced a cloudy liquid which was dried over calcium
hydride to yield 88 g, 86% of 1,1-di-t-butylethy1ene:
bp 150° (760mm);]TINMR (001“, internal MeuSi) 61.28 (s,
18H), 6A.95 (s, 2H).

V. Preparation of 2,2-Di—t-butylethanol (V)

The apparatus for this preparation consisted of a
2000 ml three neck round bottom flask, which was equipped
with a condenser and mechanical stirrer. Boron trifluoride
etherate (80 ml) was added dropwise to a slurry composed
of 19.1 g of sodium borohydride, 106.3 g of IV and 135 m1
of diglyme maintained at 20° by a water bath. After

19

stirring for 1 h at room temperature and then overnight on
a steam bath, most of the diglyme was removed under reduced
pressure. Ethanol (100 ml) was added followed by dropwise
addition of 220 m1 of 6N sodium hydroxide. 215 m1 of 30%
hydrogen peroxide was added at a rate to maintain gentle
reflux. Excess peroxide was destroyed by careful addition
of a sodium bisulfite solution. Extraction with pentane
and removal of solvent under reduced pressure, followed

by crystallization from pentane at -78° gave 96 g, 70%
yield, of 2,2-di-t-butylethanol: mp 5A-55°;]11NMR (CClu,
external MeuSi) 61.05 (s, 18H), 61.32 (broad s, 1H),

63.61 (d,2H).

VI. Preparation of Di-t-butylacetic acid (VI)

To a stirred solution of 63.3 g of V in A50 ml of
sulfuric-acetic acid solution (made by adding 50 m1 of
concentrated sulfuric acid to 50 ml of water and diluting
to A50 ml with acetic acid) was added 250 m1 of chromic
acid solution (made by dissolving 106.6 g of chromic oxide
in 105 ml of water and diluting to 2A0 ml with acetic acid,
during 1.5 h. After standing overnight and heating on a
steam bath for 1 h, 200 ml of water was added and the or-
ganic product taken up in methylene chloride. Addition of
sodium hydroxide solution precipitated out the sodium salt
of the acid, which was then filtered off. Acidification

20

gave 52.u g. 76% yield, of di-t-butylacetic acid: 1H NMR
(001,, internal MeuSi) 51.13 (s, 18H), 52.1 (s, 1H),
510.2 (s, 1H0.

VII. Preparation of Di—t-butylacetyl Chloride (VII)

A mixture of 52.A g of VI and excess thionyl chloride
was refluxed for 1 h. Distillation at 105-110° (50mm)
gave 32 8, 55% of di—t-butylacetyl chloride: IR (neat)
1780 cm”1 2075 cm'l.

VIII. Preparation of Di-t-butylketene (VIII)

50 ml of triethylamine was added to a stirred solution
of 32 g of acid chloride and 100 m1 of methylene chloride.
The solution was allowed to stir overnight and triethyl-
ammonium chloride was removed by filtration. Distillation
50-53° (26mm) gave 18 g, 68% of di-t-butyl-ketene: 1H NMR

(001“, internal MeuSi) 61.18 (3); IR (neat) 2075 em'l.

IX. Preparation of Ethyl Di—t-butylacetate (IX)

3.3 m1 of VIII was added to a large excess of ethanol
and a drop of concentrated sulfuric acid. The mixture
was stirred overnight, distillation 90° (22mm) gave 3.2 g,
90% yield, of ethyl di-t-butylacetate: 1H NMR (CClu,
external MeuSi) 6A.0 (q, 2H), 62.15 (s, 1H), 61.33 (m, 3H),
61.12 (s, 18H); IR (neat) 17A0 cm'l; m/e 201, base peak 57.

21

X. Preparation of t-Butyl Di-t-butylacetate (X)

To a mixture composed of 9.3 m1 of VIII, 20 m1 of
methylene chloride and 10 m1 of t-butyl alcohol, was
added 1.23 ml of boron trifluoride etherate. The reaction
was vigorous and rapid, requiring approximately 5 min,
distillation 61° (0.3 mm) gave 11.“ g, 90% yield, of di-
t-butylacetate: 1H NMR (001“, internal MeuSi) 61.9 (s, 1H),
61.4 (s, 9H), 51.1 (s, 18H); IR (neat) l7uo cm'l; base

peak 57.

XI. Reaction of Esters with Strong Bases

A. Materials

All reagents were obtained commercially from Aldrich
Chemical Company, Inc.

Pentane was stored over molecular sieves and used
without further purification. N,N,N',N'-Tetramethylethylene-
diamine was used as received. Diisopropylamine was dis—
tilled from calcium hydride and stored under argon. n—
Butyllithium was obtained as a 1.6M solution in hexane

and used as received.

B. Apparatus and General Procedure

All reactions unless indicated otherwise were con-

ducted in a 5 to 10 ml round bottom flask with septum

22

inlet and containing a magnetic stir bar, the flask was
also equipped with a mercury bubbler. This system in all
cases was flame dried and flushed with argon.

All GLC analyses were performed on a Varian 920
Chromatograph using l/H inch by 6 foot stainless steel
column packed with 2.5% SE-30 on Chromosorb G NAW.

Lithium diisopropylamide LDA was prepared by injecting
n-butyllithium into the apparatus (described above) cooling
to 0° by an ice bath and injecting pentane (1 to 5 m1 as
required). One equivalent of diisopropylamine was added
dropwise while stirring vigorously, and stirring was
continued for 15 min. Solvent was evaporated under re-

duced pressure leaving behind a.white solid.

C. Mixture of IX and LDA

A typical experiment was as follows, 0.11 ml (0.5 mmol)
of ethyl ester was added to a stirred solution of 0.55
mmol of LDA in 1 ml of THF at —78°. The solution was
stirred for 15 min, then warmed to room temperature and
stirred an additional 5 min. After quenching with 0.5 ml
of water, 1 ml of pentane and 0.12 ml (0.5 mmol) of standard
(tridecane) were added, the mixture was then dried over
anhydrous potassium carbonate. GLC analysis of the

supernatant liquid gave a 93-95% recovery of IX. Table

23

II contains further experiments involving 1:1 mixtures
of IX and LDA, in each case 0.5 mmol of IX and 0.5 mmol

of LDA were mixed, and worked up as done above.

Table II. Results of Quenching 1:1 Mixtures of IX and
Bases.

 

 

Reaction Period

 

(Temperature) Recovered Ester %
1 h (25°) 9"
8 h (25°) 85
1 h (reflux) 80

 

 

D. Mixture of X and LDA

0.13 ml (0.5 mmol) of X was added to a stirred solu-
tion of 0.5 mmol of LDA in 1 m1 of THF at -78°. The mix—
ture was refluxed for 1 h, quenched with 0.5 ml of water
and worked up as in part A. GLC analysis (pentadecane
as standard) showed a 96% recovery of X. A similar experi—
ment was tried in which 0.26 m1 (1 mmol) of X was added
dropwise to a solution of 5 mmol of LDA in 6 ml of THF
and 0.75 ml (5mmol) of TMEDA at -78°. This mixture was
warmed to room temperature and stirred for two days. The
usual workup (see part A) and GLC analysis showed 80%

recovery of X.

2A

E. 1H NMR of 1:1 Mixture of x and LDA

0.26 ml (lmmol) of X in 1 m1 of benzene was added to
a solution of LDA in 3 ml of benzene at -78°. The mixture
was stirred for 5 min, then warmed to room temperature
and stirred an additional 15 min. 0.6 ml of this mixture
was injected into a NMR tube that was evacuated with argon.
The resultingliiNMR of the mixture showed the ester to be

unaffected by LDA, since the a-proton of the ester remained

in the NMR.

F. Mixture of X and n-butyllithium

0.26 ml (lmmol) of X was added to solution of 0.63 ml
of 1.6M n-butyllithium in 1 ml of THF at -78°. The mixture
was stirred for 5 min, warmed to “0° and stirred an ad-
ditional 5 min. Work up of the mixture followed by GLC
showed 100% recovery of X. The same experiment was tried
again with the exception that 0.15 ml (lmmol) of TMEDA

was added, GLC again showed 100% recovery of X.

G. Mixture of X and Methyllithium

0.26 ml (lmmol) of X was added to a solution of 0.63
ml of 1.6M methyllithium in 0.5 ml of THF and 0.15 ml
(lmmol) of TMEDA at -78°. The mixture was stirred for
15 min at -78°, then warmed to A0-50° and stirred an

additional 30 min. Work up followed by GLC showed 9A%

25

recovery of X. When the same procedure was tried with a
1:5:5 mixture of X to methyllithium to TMEDA in 3 m1 of
pentane and the solution stirred at 25° for 10 h, upon GLC

analysis showed 87% recovery of X.

H. Mixture of X and Sodium Amide

A 100 m1 three neck round bottom flask was equipped
with a dry ice condenser, mechanical stirrer with Hersberg
stirrer, mercury bubbler, and rubber septum. This system
was flame dried and flushed with argon. Sodium amide was
prepared (19) by first adding 0.185A g of anhydrous ferric
chloride (oven dried) to flask, followed by condensation
of approximately 50 m1 of ammonia (Matheson Gas Co.). A
few pieces of sodium were then added with vigorous stirring,
to convert the iron salt into the catalytic form. The
rest of the sodium was then added 2.90 g (total) and after
1.5 h of stirring a gray precipitate of sodium amide formed.
X was then added in one portion at —78° and the solution
allowed to stir for l h at -78°. Then 60 m1 of ether was
added and the ammonia evaporated off in a stream of argon.
The solution was stirred for 9 h at room temperature, work

up followed by GLC analysis showed 91% recovery of X.

BIBLIOGRAPHY

10.

11.

12.

BIBLIOGRAPHY

R. Shriner, Org. Reactions, 1, (l9A2).

H. House, "Modern Syn. Reactions", 2nd ed., W. A.
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B. Hudson, Jr., R. Dick, C. Hauser, J. Amer. Chem.
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C. Hauser, W. Puterbaugh, ibid., 15, 1068 (1953).

 

C. ginger, E. Rochow, J. Organomet. Chem., 1, A76
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M. Rathke, J. Amer. Chem. Soc., 92, 3222 (1970).

 

(a) M. Rathke, A. Lindert, ibid., 93, 2318 (1971).
(b) M. Rathke, D. Sullivan, ibid., 95, 3050 (1973).

Yu—Neng Kuo, J. Yahner, C. Ainsworth, ibid., 93, 6321
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D. Sullivan, "The Reactions of Ester Enolates", Ph.D.
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D. Sullivan, R. Woodbury, M. Rathke, J. Org. Chem.,
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W. Vaughan, S. Berstein, M. Lorber, J. Org. Chem.,
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(a) W. Remero, R. Roth, M. Weiss, J. Org. Chem.,
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(b) B. Holmquist, T. Bruice, J. Amer. Chem. Soc.,
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(c) R. Prath, T. Bruice, ibid., 92, 5956 (1970).

 

 

 

 

(d) J. Rebek, D. Brown, S. Zimmerman, ibid., 91,
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(e) A. Meyers, E. Smith, M. Ao, J. Org. Chem., 38,
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26

 

13.

1A.
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27

M. Newman, A. Arkell, T. Fukunaga, J. Amer. Chem. Soc.,
82, 2A98 (1960).

 

A. Millard, M. Rathke, J. Org. Chem., A3, 183A (1978).

J. March, "Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure", p. 316, 2nd ed., McGraw
Hill (1977).

F. Carey, R. Sundberg, "Advanced Organic Chemistry
Part A: Structures and Mechanisms", p. 310, Plenum
Rosetta (1977).

A. Gordon, R. Ford, "The Chemist's Companion: A

Handbook of Practical Data, Techniques, and References"
John Wiley and Sons (1972).

E. Colvin, Chem. Review, 1, 1A (1979).

N. Khan, F. Deatherage, and J. Brown, Org. Syn.,
Coll. Vol., A, 851 (1963).

 

          

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