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thesis entitled
"THE 97M» Esrs 0F 09,2, UN smuxmeo ESTER:

[KOH K ETON E s w rTH lruyL 61‘s (TKIFLUORO ETllyL) _-

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RETURNING MATERIALS:
Place in book drop to
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stamped below.

 

 

 

 

THE SYNTHESIS OF 1,3-UNSATURATED ESTEHS FROM KETONES
WITH ETHYL BIS(TRIFLUOROETHYL)PHOSPHONOACETATE

BY

EZZEDDINE BOUHLEL

A THESIS

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

MASTER OF SCIENCE

Department of Chemistry

1986

.frdfinr

 

 

 

497.0%

ABSTRACT

THE SYNTHESIS OF ¢,B-UNSATURATED ESTERS FROM KETONES
WITH ETHYL BIS(TRIFLUOROETHYL)PHOSPHONOACETATE

BY

EZZEDDINE BOUHLEL

In the presence of triethylanine and lithium
bromide, ethyl bis(trifluoroethyl)phosphonoacetate . reacts
with a variety of ketones including acetophenone and with
benzaldehyde to give «,3-unsaturated esters in good yields.

Under the same -conditions ethyl bis(trif1uoroethyl)-
phosphonoacetate was found to be unreactive towards hindered
ketones.

Compared to procedures with triethylphosphonoacetate
ethyl bis(trifluoroethyl)phosphonoacetate gives better
results with ketones including acetophenone which are
normally unreactive towards the Horner-Wadsworth-Ennons

olefinations.

ii

TO MY DAUGHTER, ZEINEB AND MY PARENTS

iii

ACKNOWLEGDEMENTS

I would like to acknowledge Dr. Rathke for his valuable
instructions and for his help in the preparation of this
dissertation. I also an grateful for the friendship and
help received from The Group (Shoes, Weipy and Dinitris) and
Tonya for her help in typing. I also would like to
acknowledge Dr. Reusch for his time and assistance in being
my Second Reader.

I would like to thank The Scientific Mission of Tunisia
for the Fellowship given me during my stay here at Michigan
State University. I would also like to express my
appreciation to Michigan State University for their partial
support in this endeavor. '

iv

TABLE OF CONTENTS

List of Tables.

Introduction. . . . .

Results and Discussion.

Experimental. . . . . . . . . . .
General.

General Procedure for the Preparation of Tri-
ethylphosphonoacetate 2. . . . . . . . . . .

General Procedure for the Preparation of Ethyl-
dichlorophosphonoacetate l4. . . . .

General Procedure for the Preparation of Ethyl-
bis(trifluoroethyl)phosphonoacetate ll .

General Procedure Used for the Modified HWE
Olefination Reaction . . . . . . . . . . .

General Procedure Used for the Isolation of the
Products «,fl-Unsaturated Esters. . . . . . . . .

Reaction of Cyclohexanone with 11 in the Presence
of Lithium Diisopropylamine.

Bibliography.

Page

vi

14
21
21

22

23

23

24

25'

28

29

Table

Table

Table

l

2

3

LIST OF TABLES

Reaction of a Variety of Carbonyl
Compounds with 11 in the Presence
of Triethylamine and Lithium
Bromide. . . . . . . . . . . .

Reaction of a Variety of Carbonyl
Compounds with 2 in the Presence of
Metal Halides. . . . . . . . . .

Reaction of Cyclohexanone with 11 in

the Presence of Lithium Diisopropyl-
amide. . . . . . . . . . . .

vi

16
18

19

INTRODUCTION

INTRODUCTION

The reaction of carbonyl compounds with phosphorus
ylides has had wide application in the synthsis of olefins.
One of the first used forms of this group of reactions is
the Wittig reaction in which carbonyl compounds are treated
with phosphonium ylides l to form an olefin and phosphine

oxide (Eq 1).“2

 

 

+ R1
- I 8 g. _ R]
R2 \
R2
l
+ R1.
1 + R4>._—_0 ——... 0-C:R3
_ M
RI R
____.. ):c( 3 . (m3 :0 (1)
' R2 R4
The scope, mechanism and stereochemistry of this

reaction have been investigated in detail and these studies

have been the subject of many publications.3‘2°

There are, however, several limitations to the Wittig
olefin synthesis, and this has led to the development of
various modified forms of this reaction. These involve the
use of other organophosphorus compounds which lend
themselves to carbanion formation.

One of these modifications of the Wittig synthesis was
developed by Horner, et. al.21, and by Wadsworth and

Bmmons22 (Eq. 2).

 

2 3
(RO)2P(O)CH2E 31$. R R CO 4» R2R3C-CHE'
* (2)
(RO)2P02
R = alkyl or phenyl
E = Resonance-stabilizing group.

The modified Wittig reaction, the Hornet-Wadsworth-
Rmmons olefination reaction (the HUB reaction), possesses
the following advantages over the conventional Wittig
reaction:

a) Phosphonate carbanions are known to be more nucleophilic
than similarly substituted phosphonium ylides.33-23 The
greater reactivity of phosphonate anions as compared to
phosphorus ylides is due to the fact that the
phosphonate group is not as effective in stabilizing a

negative charge because of ”back donation" from oxygen.

b)

e)

d)

The water-soluble phosphate ion formed in the HUB
reaction is much easier to separate from the olefin
product.

The enhanced reactivity of the phosphonate carbanions
allows much the s—carbon to be elaborated by alkylation
(Eq. 3), whereas the phosphonium ylides do not generally

undergo easy alkylation.

(RO)2P(O)CHE + R'x _. (RO)2P(O)CHR'E +X" (3)

Phosphonates are readily availablez‘ from the Arbuzov
reaction or the Michaelis-Becher reaction. The former,
involving the reaction of trialkylphosphite with an
alkylhalide, is the most commonly used method. Thus, the
phosphonates are less expensive than the corresponding

alkylphosphonium salts.

The HUB reaction can be used to synthesize a variety of

compounds. It has been used in the intermolecular synthesis

of ring compounds containing butenolide moieties25 (Kg. 4).

With epoxides it yields substituted cyclopropanes2° (Kg. 5).

The HUB reaction has been used in many industrial

processes and bis-phosphonates have been tested as

polymerizing reagents.27

  

 

CH2 - OCOC'IH - P(C6H5 )3Br
=0 CH3
NaH (DMSO) 1 (4)
5 I X

493
VCH3 . (C2H50)2P(O)CH2COCH3 —-a- CH3COVCH35)

One of the most used and important HUB reagents,
triethylphosphonoacetate 2 employs an ester function as the

electron-withdrawing group.

(EtO)2P(O)CH2CO2Et
2
Triethylphosphonoacetate 2 and closely related

derivatives have been applied to the synthesis of many
natural products including prostaglandinsza, juvenile
hormones29 and many isoprenoid compounds30 including
carotene.31

The mechanism widely accepted for the HWE reaction is
analogous to that of the Wittig reaction (Eqs. 6-9).

The first step, the formation of the anion 3 stabilized
by an electron-withdrawing group (ester function in the case

of 2) and. the P(O) function, may or may not be an

(EtO)2P(0)CH2C02Et

(EtO)2P(O)CHC02Et

3

/

(EtO)2P(O)-C "H

\21“

R'/ z \C02Et

+

(EtO)2P(O)0

(8)

\c c025:
"' 11 «H

.__.. (EtO)2P(0)CHC02Et (6)

3

R'CHO (7)

\\

(Et0)2P(O) _.c.- m“

(Et0)2P(0)O

(9)

equilibrium process depending upon the base used. With
sodium hydride or other strong bases, anion formation is
irreversible.

The second step is a reversible aldol condensation that
gives two possible- diasteriomeric oxyanions (4 and 6).
There is no direct evidence that cyclic intermediates are
involved but it is thought that the oxyanions decompose via
a syn elimination in an irreversible fashion to give olefin
(qu. 8 and 9). The erythro form 4 gives the z olefin,
while the threo form 5 leads to the E olefin.32

In contrast to aldol condensations33 the HUB
olefination reaction using triethylphosphonoacetate 2 gives
the olefinic product regiospecifically and in one step. The
formation of 3,7-unsaturated esters complicates the acid-
catalyzed dehydration of fi-hydroxyesters formed by aldol

reactions (89. 10).34

RI RCHQ'C =CHC02C2H5

RCH2é-CH2C02C2H5 —— ( l 0)
H R'
RCH :é‘CH2C02C2H5

In the case of the HUB olefination reaction, only a few
cases of the formation of 3,7-unsaturated esters have been

reported.35

The R"! olefination reaction using 2 often gives the
olefinic product with a high degree of stereochemical
control of the newly-made double bond. In many cases, only 8
esters are formed when triethylphosphonoacetate 2 reacts

with aliphatic aldehydes (figs. 11 and 12).33

£02Et
NaH l-PrCHO
-—-—a> -——————m-
one I

(EtO)2P(O)CH2C02Et '5 (l I )
3h (rt)
cozst
NaH t-BuCHO —/ ( I 2)

EtO mom co Et _. ___._...
( )2 H2 2 one 15 x
3h (rt)

The 8:2 ratio of the product olefin is dependent on

temperature (Eqs. l3-l5).37'

| - pn
(swarm-cu + PhCHO fl. \_/ .

-7ec —/ (13)
,1, WM ennui
10:90
(£t0),fi:,4-c~ . PhCHO $1" ph\__/ . —/ (14)
He -__\tN p‘r—H\CN
4K):60 '

0
Ph .
(Et0)2yCH-CN + PhCHo. flfli. \—/ .

—\c~ ..

50:50

(l5)
N

3k

e

In general, thermodynamically-controlled 3H8
olefination reactions give 8 olefins. This is a result of
thermodynamic control upon the. reversible formation and
interconversion of the erythro and threo oxyanions 4 and 5
(figs. 8 and 9) and their decomposition to olefins.
Kinetically-controlled RUE olefination reactions usually
give the z olefins37, presumably because oxyanion 4 is
formed faster than oxyanion 5.

Steric requirements are very important in the HHS
olefination reaction. The phosphonate anions are more
reactive towards aldehydes than ketones. Some ketones are
.totally unreactive towards the phosphonate anions. Simple
cyclohexanones are normally reactive towards the HUB
olefination reaction but cyclohexanones, substituted at the
2 position, are unreactive if the substituent is in the
equatorial position.3"3’ In steroidal systems, the
phosphonate anion 3 reacts with 3-keto steroids but give no

reaction with 6-keto, 7-keto, l7-keto or 20-keto steroids.39

3

The generation of the phosphonate anion 3 usually
involves the use of strong bases such as sodium hydride,

lithium diisopropylamide (LDA) or metal alkoxides.

These procedures are expensive and the bases used may
react with sensitive functional groups in the substrate
and/or the reagent.

Recently, the HHS olefination reaction was carried out
under mild conditions using triethylamine as base in the

presence of metal salts (Eq. 16).40

o
| . EtO
(Et0)2llCH2C02Et '"1 ' R3" 1.. (l6)

Et Et

 

2
6

It is assumed that metal cation coordination enhances
the acidity of 2 allowing anion formation with weak bases.
In the presence of a potassium cation, the pk of
triethylphosphonoacetate 2 has been found to be 19.2
(dimethylsulfoxide solution) and, in the presence of a
lithium cation, 12.2 (diglyme solution).‘1 The difference in
acidity can be attributed to tighter chelation of the
lithium cation resulting in a stronger metal-oxygen bond in
the enolate 6. Thus, the nature of the metal M has a great
influence on the stability of 6 and on the acidity of 2.

Phosphonates, which have no carboethoxy group, are
expected to be poorer chelating agents with metal cations.
The acidities of these show a less-pronounced dependency on
the nature of the metal cation present. For example,

phosphonate 7, which has no carboethoxy group, has only a 4

10

pk unit difference in the presence of lithium and potassium

cations.

(Et0)2P(O)CH3
7

For the modified HWE olefination reaction‘9 using
triethylamine and metal salts, it was found that the use of
lithium and magnesium halides promotes the reaction.and that
the reagent obtained with lithium halides is more reactive
than the reagent obtained with magnesium halides.

Excellent yields were obtained with aldehydes and with
the reactive ketone cyclohexanone. Unfortunately, simple
methylketones such as acetophenone or acetone were
unreactive to triethylphosphonoacetate 2 in the presence of
either magnesium bromide or lithium bromide. We considered
that the lack of reactivity observed with ketones is due to
a very slow “rate of decomposition of the betaine
intermediate.

Increasing the rate of decomposition of the betaine
seems to be the solution to this problem. We considered that
this can be accomplished by changing the structure of the
phosphonate by adding electron-withdrawing groups or using
five atom rings on phosphorus.

Electron-withdrawing groups X (Eq. 17) would activate

the P(O) group towards alkoxide attack by withdrawing

11

electron density from phosphorus and, thus, speeding up the

formation and decomposition of the cyclic intermediate 8.

xfi fi

——CHCO2R __CHc02R
X l X t i . OLEFINS (l7)
-0 CR'Rz R'Rz
8

The use of phosphonates bearing five atom rings‘3 on
phosphorus should: (a) lead to more rapid closure to a five-
coordinate intermediate 9 (Eq. 18) (release of ring strain
upon passing from the tetrahedral to the trigonalbipyramid
structure); and (b) reduce the rate of inversion to the

phosphonate and carbonyl compound for the same reasons.

_..OLEF|N$(I8)

o f -
.«O
/\J_cnc02R {Liv HCOQR

R'R’ ' R‘R2

Structures 10-13 are phosphonates that have either
electron-withdrawing groups or five atom rings on phosphorus
which we considered could be used as olefinating reagents in

the HUB olefination reaction.

12

CF3CH20

cracuzo

0
ll
/\C02Et
1 1

film...
I 3

There are two compelling reasons for using 11 as the

 

olefinating reagent in the HWE reaction

1. The synthesis of 11 is described in the literature.‘3

2. W. Clark Still used 11 to carry out the stereoselective
synthesis of Z m-unsaturated esters from a variety of
aliphatic and aromatic aldehydes. It was concluded that
the two powerful electron-withdrawing groups (CF30H2
groups) are responsible for the Z selectivity by

speeding up the elimination of the initial adduct.

With these facts in hand, we decided to synthesize ll
(Eqs. 19 and 20) and examine its properties as an
olefinating reagent with ketones in the presence of

triethylamine and metal salts (Eq. 21). It was hoped that

13

good yields of the corresponding olefins could be obtained

under these conditions.

(Et0)2P(O)CH2C02Et . 2pc|5 ____,, Cl2P(O)CH2C02Et (19)
I4

14 . 2CF3CH20H _, (crscuzommmcuzcoza (20)

Et N
R'iR2 +r1x+ ll __T:_F.... R,R2C:CHC02Et (21)

RESULTS AND D ISCUSS ION

RESULTS AND DISCUSSION

The reaction of 3~pentanone with the standard
phosphonate 2 in the presence of triethylamine and "lithium

bromide in tetrahydrofuran (Sq. 22) was examined.

//“\\ Et3 N
f '.' 2 + UBI‘ W (22)
lfihr

cozet

The GC yield of the corresponding «,3-unsaturated ester
(ethyl-S-ethyl-Z-pentenoate) was (53) which confirm the
unreactivity of simple methylketones with triethylphosphono-

acetate 2. The same reaction was conducted with 11 (Eq. 23)

and the GC yield was (702).

Et N '
+ H + “Br THF,2S _ (23)

IS hr
02Et

14

15

The results of these two reactions demonstrate the
potential of 11 as an olefinating reagent in the HWE
reaction.

Using the conditions from our study on 3-pentanone with
11, we studied the reaction of benzaldehyde and a variety of
ketones with 11 and the results are shown in Table l.

Lithium bromide is partially soluble in
tetrahydrofuran. However, addition of
ethyl bis(trifluoroethyl)phosphonoacetate 11 resulted in
complete dissolution of the salt and homogeneous solution.
Addition of triethylamine to this mixture resulted in
instantaneous formation of a precipitate presumed to be
ETaN.HBr. Subsequent addition of the carbonyl substrate to
the mixture resulted in no change of the precipitate formed.

Good yields are obtained with benzaldehyde and with
simple ketones (Entries 1-6). However, ketones such as 2,4-
dimethyl-3-pentanone, 2,4-tetramethy1—3-pentanone or 3,3-
dimethyl-Z—butanone (Entries 7-9) fail to react. In the
case of benzaldehyde (Entry 5), a 56:44 Z/E ratio of the
product 1,3-unsaturated ester (ethyl cinnamate) was
obtained. Acetophenone (Entry 6) gave 53:47 Z/E ratio of the
«,3-unsaturated ester (2-butanoic acid and 3-pheny1ester).

High E/Z ratios of «,3—unsaturated esters have been reported

for the HWE olefination reaction using
triethylphosphonoacetate 2, triethylamine and different
metal salts including lithium bromide.4° For example

benzaldehyde gave only (E) ethyl cinnamate. This procedure

16

Table 1. Reaction of a Variety of Carbonyl Compounds with 11 in the Presence of
Triethylamine and Lithium Bromide.

 

R'fiR’ + UBr +11 L R'R2C8CHC02Et
THF,25 C
24 hr
Carbonyl Yield” E/Zc
Entry Compound Product3 2: ratio

 

l Cyclohexanone . 79 ( 68)
025:
2 Cyclopentanone . 71 (52)
0,5:

El
3 3-Pentanone \J 73 (60)
m

[it 02Et
Ph
4 Benzophenone 51
pfloza
5 Benzaldehyde ”U 82 (65) 44/56

6 Acetophenone ”K /H- 75 47/53

7 Pinacolone 0
8 2 , 4-dimethyl-3-pentanone 0
9 2 , 4-tetramethyl-3-pentanone 0

 

3 All reactions carried out at 25°C on a 5 mol scale for. 24 hr reaction period.

b Yields of products determined by GC analysis. Yields in parentheses are
isolated yields.

C Determined by GC and 1H-llNR analysis.

17

using 11 appears to favor the Z isomer over the E. The
formation of the Z isomer in a greater proportion over the E
is probably due to the faster elimination of the initial
adduct when compared with adduct equilibrium (equilibration
of 4 to 5, Eq. 8 and 9).

In order to compare our procedure using 11 with the
original procedure using 2, we compare Entries 2 and 6 in
Table l to Entries 3 and 5 in Table 2. It is clear that the
reactivity towards ketones was enhanced considerably when
using phosphonate 11 as the olefinating reagent.

As a further test of our new procedure,
ethyl bis(trifluoroethyl)phosphonoacetate 11 was reacted
with cyclohexanone in the presence of lithium
diisopropylamine (LDA) a classical strong base. The results
of this reaction are shown in Table 3.

The results shown in Table 1 (weak base -
triethylamine) in the presence of a metal salt (lithium
bromide) seem much better than those with LDA shown in Table
3.

The purpose of this study was to increase the yields of
¢,B-unsaturated esters from ketones using a weak base
procedure and it appears that this goal has been achieved.
This procedure using 11, triethylamine and lithium bromide

has several advantages over other related HWE procedures.

18

Table 2. Reaction of a Variety of Carbonyl Compounds with 2 in the Presence of
Triethylamine and Metal Halides.‘

0

II
was2 + nx + 2 “3"

 

*;»R1RZC=03002Et
solvent, 25°C

 

 

3 hours
Carbonyl Metal
Entry Compound Halide Solvent Product Yield, X”
1 CsHsCHO LiBr (CHsCN) CsHSCH==308002Et 84
Mgflra (THF) 85
2 Cyclohexanone LiBr (CHsCN) (CH: )5 c=cficoa g t 85
3 Cyclopentanone LiBr (CH: CN) (C Hz )¢ C = C H002 E t 15
4 Acetone LiBr (cascu) 0
Mar: (THF) 0
5 Acetophenone LiBr (CHsCN) 0
MgBrz (THE) 0

 

' Reaction at 25°C for 12h, 25 mmol scale (carbonyl compound:7:EtaN:metal
halide - l:l:l.1:l.2)

b Isolated yield, based on weight of distilled product.

‘1

Table 3. Reaction of cyclohexanone with 11 in the Presence of Lithium

 

 

 

 

 

 

 

 

 

Diisopropylamine
THF T, 1 I 15 mn ! 15 mn
* "' t ’ -78 c ” -78 C
LDA '
T2,t2
Aes-
Quench with 0251;
H0
Entry THE (mL) T1 (°C) in (an) T2 (°C) t2 (hr) yield (X)
l 25 0 15 25 l 30
2 5 0 15 25 l 30
3 5 -78 5 25 l 65
4 5 -78 15 25 2 51
5 25 -78 5 25 5 55

 

 

20

-Inexpensive and readily-handled base.

-Mild conditions (weak base, room temperature) used to
carry out the reactions.

-Good yields obtained with simple ketones (usually
unreactive towards the HWE olefination reactions) and
thus a new route is opened to the synthesis of «,3-
unsaturated esters from ketones.

-The enhancement of the Z/E ratio of «,3-unsaturated
esters isomers and, thus, a procedure that can be used
for the preparation of Z isomers which are usually

difficult to obtain.

The major disadvantage of our procedure is the somewhat
difficult preparation of the olefinating reagent

ethyl bis(trifluoroethyl)phosphonoacetate 11.

EXPERIMENTAL

EXPERIMENTAL

GENERAL

Tetrahydrofuran (THF) and benzene were dried by
distillation under argon from sodium/benzophenone ketyl just
prior to use; triethylamine (TEA) was dried by distillation
under argon from calcium hydride; lithium bromide (LiBr,
Aldrich Chemical Company, 99+X) was dried in an abderhalden
flask over refluxing xylene at 0.3 torr and stored in a
desiccator and transferred under argon in a glove bag;
diethylether was taken from a freshly opened can of
anhydrous ether.

All reactions were performed under an atmosphere of
argon. Infrared spectra were recorded on a Pye-Unicam SP-IOO
Infrared Spectrometer or a Perkin-Elmer Model 167
Spectrometer with polystyrene as standard. Proton Nuclear
Magnetic Resonance Spectra (1H-NMR) were recorded on a
Varian T-60 at 60 MHz in 00013. or on a Bruker WM-250
Spectrometer at 250 MHz in CDCla. Chemical shifts are
reported in parts per million (6 scale) from internal
standard tetramethylsilane. Data are reported as followed:
chemical shifts (multiplicity: s=singlet, bs=broad singlet,
d=doub1et, ‘t=triplet, q=quartet, m=multiplet), coupling

constant (Hz). Electron impact (EI/MS, 70 eV) mass spectra

21

22

were recorded on a Finnigan 4000 with an INCOS 4021 data
system. Preparative 60 operations were performed on a Varian
920 Chromatograph equipped with a 6 ft x 0.25 in stainless-
steel column packed with 158 88-30 on chromasorb w.
Qualitative GLPC analyses were performed on a 5880A Hewlett—
Packard Gas Chromatograph equipped with a flame ionization
detector using helium as carrier gas and a 25 meter
capillary column (ID 0.25 nm) liquid-phase GB-l Column. 00
yields were determined using hydrocarbons as internal
standards. Flash column chromatography was performed
according to the procedure of Still, et. a1.“, by using the
DAVISIL 62 silica gel mentioned and eluted with the solvents
mentioned. The columns outer diameter (o.d.) is listed in

millimeters.

General Procedure for the Preparation of Triethylphosphono-
acetate 2.45

257 mL (1.5 mole) of triethylphosphite was added
dropwise (over 2 hours) to 166.3 mL (1.5 mole)
ethylbromoacetate at 0°C with energetic stirring. The
solution was stirred for 3 additional hours. The
ethylbromide was distilled off at low pressure. The crude
product triethylphosphonoacetate was purified by distillat
ion. bp: 128-13000 (6 torr). 303.5g (90.3%) of pure 2.

23

General Procedure for thggPrepgggtion of Ethylggichlorophog;
phonoacetate 14.

The following procedure is a slight modification of
that described by K. A. Petrov.°° 416g (2 moles) of
phosphoruspentachloride were added in portions over 1 hour
to 224g (1 mole) of triethlphosphonoacetate with vigorous
stirring. The mixture was heated for 5 hours to 115-120°C,
then dry sulfur dioxide (generated from sodium bisulfite and
sulfuric acid) was passed into the mixture for 20 minutes at
room temperature during which a noticeable heat evolution
occured. Thionylchloride and phosphorus oxychloride were
removed by distillation at atmospheric pressure. The
residue was subjected to vacuum distillation to obtain a
fraction with a bp: 75-80°C (0.05 torr). 133.6g (65.5%) of
pure 14.
1H NMR (60 MHz) (CD013): 6 1.32 (t, J=10Hz, 3H, CH3), 3.7

(d, J=22Hz, 2H, P-CHz), 4.40 (q, J=10Hz, 2H, CH2).

Preparation of Ethyl,bis(triflgproethyl)phosphonoacetagg
11.43

54.4 mL (0.4 mole) of ethyl dichlorophosphonoacetate 14
was dissolved in 480 mL benzene and cooled to 0°C in an ice
bath. To this solution, 58.26 mL (0.8 mole) of
trifluoroethanol and 105.25 mL triethylamine in 676 mL
benzene was added dropwise. After stirring for 1 hour at

25°C, the solvent was evaporated and the residue was

24

filtered. The solid EtaN.HCl was washed with ether and the
combined ether filtrates were evaporated. Vacuum
distillation of the residue gave 53.12g (403) of pure ll.
18 NMR (250 MHz) (CD013): 6 1.30 (t, J=10Hz, 3H, CH3), 3.16
(d, J=22Hz, 2H, P-CHa), 4.24 (q, J=10Hz, 2H, CH2), 4.47 (p,
J=10Hz, 4H, 2CF3CHz). EI/MS (70 eV): 332 (M, 65.12), 305
(29.07), 287 (base), 260 (29.65), 245 (27.76), 240 (36.87),
161 (20.66), 113 (10.43), 99 (17.13), 83 (33.77), 69
(36.00), 59 (6.40), 47 (23.18), 43 (25.73), 42 (78.20), 33
(62.02).

General Procedure Used for the Modified HWE Olefination
Reaction.‘°

The following procedure is representative of the
procedure used to obtain the results described in Table 1.
A 50 mL flask with a side arm, a septum inlet and a magnetic
stirrer was flame dried under argon. Anhydrous lithium
bromide (6 mmol, 0.521g)' was weighed in a glove bag and
transferred under a stream of argon to the flask.
Tetrahydrofuran (10 mL) and ethyl bis(trifluoroethyl)phos-
phonoacetate (1.177 mL, 5 mmol) were added and the mixture
stirred.an additional 10 minutes. The carbonyl compound was
then added and the reaction mixture stirred overnight at
25°C. After quenching with dilute HCl, the reaction mixture
was extracted with ethylether (3 x 10 mL). The organic
extracts were washed with a saturated sodium chloride

solution then combined and dried over magnesium sulfate.

25

General Procedures for the Isolation of the Products 1,!-

 

Unsaturated Esters.

The combined extracts described above were filtered and
the solvent removed in vacuo. The methods of purification
of the products used were short-path distillation or flash

column chromatography.

Ethyl Cyclohexylidene Acetate.‘7

Ethyl cyclohexylidene acetate was prepared from 11 and
cyclohexanone and purified by short-path distillation. bp:
50°C (0.2 torr). .
18 NMR (60 MHz) (00013): 6 1.23 (t, J=7Hz, 3H, 083), 1.62
(m, 6H, 3CH2), 2.10 (m, 2H, CH2), 2.84 (m, 2H, CH2), 4.10
(q, J=7Hz, 23, CH2), 5.60 (bs, 1H, CH=C). IR (neat): 1625
cm'1 (C=C). EI-MS (70 eV): 168 (M, 91.62), 140 (48.71), 123
(85.27), 80 (75.78), 67 (58.01), 55 (89.59), 41 (base), 39
(91.71).

Ethyl Cyclopentylidene Acetate.°7

Ethyl cyclopentylidene acetate was prepared from 11 and
cyclopentanone and purified by short~path distillation. bp:
93-96°C (20 torr).
1H NMR (60 M82) (0001:): 6 1.25 (t, J=7Hz, 3H, CH3), 1.70
(m, 4H, 2082), 2.40 (m, ZH, CH2), 2.74 (m, 28, CH2), 4.10
(q, J=7Hz, 23, 082), 5.76 (m, 1H, case). IR (neat): 1645

cm‘l (C=C). EI/MS (70 eV): 154 (M, 47.11), 126 (42.62), 109

26

(64.90), 97 (21.81), 79 (56.31), 69 (14.38), 67 (73.15), 55
(20.44), 53 (46.04), 41 (96.38), 39 (base).

Ethyl 3-Ethyl-2-pentenoate.°7
Ethyl 3-ethy1-2-pentenoate was prepared from 11 and 3-

pentanone. The crude product was purified by column
chromatography on silica gel (60-200 mesh, 100g, 50 mm o.d.,
hexane-ether 4:1, 25 mL fractions) using the flash
technique.

18 NMR (60 M82) (00013): 6 0.9-1.3 (m, 98, 3083), 2.14 (q,
J=882, 28, 082), 2.60 (q, J=882, 28, 082), 4.10 (q, J=7Hz,
28, 682), 5.62 (m, 1H, CH=C). IR (neat): 1640 cm‘1 (C=C).
EI/MS (70 eV): 156 (M, 46.74), 128 (19.15), 111 (86.02), 99
(53.34), 83 (15.09), 81 (37.69), 69 (33.23), 55 (base), 53
(35.93), 43 (66.90), 41 (69.90), 39 (54.55).

Ethyl Cinnamate.°7

Ethyl cinnamate was prepared from 11 and benzaldehyde.
The crude product was purified by column chromatography on a
column of silica gel (60-200 mesh, 100g, 50 mm o.d.,hexane-
ether 4:1, 25 mL fractions) using the flash technique. A
mixture of E and Z isomers was obtained; the ratio was
determined by GC analysis. Found: 44:56 E/Z ratio.
18 NMR (250 M82) spectrum of mixture and assignments (based
on literature values of E isomer): 6 1.22 (t, J=7Hz, 083 for
Z isomer), 1.32 (t, J=7Hz, 38, 083 for E isomer), 4.15 (q,

3:782, 28, 082 for Z isomer), 4.25 (q, J:7Hz, 28, 082 for E

27

isomer), 5.95 (d, J=1282, 18, CH=C for Z isomer), 6.43 (d,
J=168z, 18, 08:0 for E isomer), 6.90 (d, J=1282, 18, CH=C
for Z isomer), 7.30 (m, 58, aromatic for E isomer), 7.55 (m,
58, aromatic for Z isomer), 7.68 (d, J=16Hz, 18, CH=C for E
isomer). IR (neat): 1630 cm'1 (C=C). EI/MS (70 eV): 176
(M, 30.83), 148 (13.89), 131 (base), 103 (50.76), 77
(48.31), 51 (39.10), 43 (6.80), 39 (11.42).

Ethyl 3-Phenyl-2-butenoate.°7
Ethyl 3-pheny1-2-butenoate was prepared from 11 and

acetophenone. A pure sample of the E isomer was obtained by
preparative GC.

18 NMR (E isomer) (60 MHz) (CDC13): 6 1.24 (bs, 38, 083),
2.50 (bs, 38, 683), 4.10 (q, J=7Hz, 28, 082), 6.04 (m, 18,
CH=C), 7.24 (m, 5H, aromatic). IR (neat): 1625 cm‘1 (C=C).
EI/MS (70 eV): 190 (M, 52.69), 161 (37.58), 145 (base), 117
(49.38), 115 (92.44), 102 (11.59), 91 (43.63), 51 (28.16),
39 (28.52).

Ethyl 3,3-Dipheny1-2-propenoate.
Ethyl 3,3-dipheny1-2—propenoate was prepared from 11

and benzophenone. A pure sample was obtained by preparative
GC.

18 NMR (60 MHz) (CDC13): 6 1.28 (t, J=7Hz, 38, 083), 4.06
(q, J=7Hz, 28, C82), 6.38 (s, 18, CH=C), 7.31 (s, 108,
aromatic). EI/MS (70 eV): 252 (M, 46.29), 251 (15.22), 223
(15.96), 207 (base), 180 (50.28), 179 (72.02), 152 (18.99),

28

105 (40.45),102 (12.92),89 (19.02), 77 (31.97), 51 (35.96),

43 (12.84).

Reaction of Cyclohexanone With 11 in the Presence of Lithium

 

Diisopropylamine.

 

A 50 mL flask with a side arm, a septum inlet and a
magnetic stirrer was flame dried under argon. THF and
diisopropylamine (0.7 mL, 5 mmol) were added, the mixture
was stirred 5 minutes at 0°C, then n—butyllithium (3.125 mL,
5 mmol) was added and the solution was stirred for t1 at T1.
11 (1.177 mL, 5 mmol) was added and the mixture was cooled
to —78°C and stirred for 15 minutes. Cyclohexanone (0.52
mL, 5 mmol) was added at —78°C and the mixture stirred for
15 minutes at —78°C then warmed to T2 and stirred for t2.
After quenching with dilute HCl, the mixture was analyzed by

CC for product presence.

* 5 minutes at 25°C in a water bath. Triethylamine (6 mmol,

0.83 mL) was added and the mixture

BIBLIOGRAPHY

(pancake)

10.

11.

12.

13.

14.

15.

16.

17.

B IBLIOGRAPHY

G. Wittig, U. Schollkopf Chem. Ber. 1954, 87, 1318.

J. I. G. Cadogan, ”Organophosphorus Reagents in Organic
Synthesis".

J. Levisalles Bull. Soc. Chim. fr. 1”, 1021.
S. Trippet Advan. Org. Chem. 1”), w, 1.

L. A. Yanovskaya Russ. Chem. Rev. 1%1, 30, 347.
S. Trippet Quart. Rev. Chas. Soc. 1%, 17, 406.
S. Trippet PureAppI. Chem. 1%, 9, 255.

L. D. Bergelson, M. M. Shemyakin PureAppI. Chem. 134,
9, 271.

U. Schllkopf, "Newer Methods of Preparative Organic
Chemistry", Vol. 3, W. Forest, Ed., Academic Press, New
York, N.Y., 1964, p. 111.

T. I. Crowell, "The Chemistry of Alkenes", S. Patai,
Ed., Interscience, London, 1%, Chapter 4.

A. Maercker Org. React. 135, .14, 270.
R. F. Hundson, ”Structure and Mechanism in Organo-
phosphorus Chemistry", Academic Press, New York, N.Y.,

1”, Chapter 7 .

8. 0. House, "Modern Synthetic Reactions", W. A.
Benjamin, New York, N.Y., 135, Chapter 8.

R. L. Reeves, "The Chemistry of the Carbonyl Group", 8.
Patai, Ed., Interscience, London, 186, Chapter 12.

A. W. Johnson, "Ylid Chemistry", Academic Press, New
York, N.Y., 1%6, Chapters 2-4.

M. E. Jones, 8. Trippet J. Chem. Soc. C. 136, 1090.

L. D. Bergelson, L. I. Barsukov, M. M. Shemyakin
Tetrahedron 1%7, 23, 2709 .

29

18.

19.

20.

21.

22.

23.

24.
25.

26.

27.

28.

29.

30.
31.
32.
33.

34.

30

A. J. Kirby, S. G. Warren, "The Organic Chemistry of
Phosphorus”, Elsevier, Amsterdam, 1”, Chapter 6.

M. Shlosser, E. F. Christmann Justus Liehiegs Ann.
Chem. 1”], 1, 708. ‘

M. Shlosser Top. Stereochem. 1970, 1, 5.

L. Horner, H. Hoffmann, H. G. Wippel, G. Klahre Chem.
Ber. 159, 92, 2499.

W. S. Wadswarth, W. D. Emmons J. Amer. Chem. Soc. lml,
a9, 1733.

L. Horner, W. Elink, H. Hoffmann Chem. Ber. 1m, 95,
3133.

A. E. Arbuzov, A. A. Dunin Her. 1927, so, 291.

H. G. Lehman, R. Wiechert Angeli. Chem. Int. Eng. Ed.
I”, 7, 300.

G. Sturtz Bull. Soc. Chim. Fr. 1”, 2349.

(a) BASF AG: Germ. Pat. 1S9, 1,108,219 and 1,112,072.
(b) G. Drefahl, 8. H. Hoerhold, H. E. Wildner: Germ.
Pat. 51,436 (Chem. Ahstr. 66:105346 h).

(a) O. G. Platema, 8. Deconig, H. O. Huisman J. Chem.
Soc. Perk. I. 1978, 304.

(b) D. Taub, et. a1., Chem. 00-. 1970, 1258.

(c) E. J. Corey, et. a1., J. Org. Chem. 1972, 37, 3043.

(a) 8. H. Dahm, B. M. Trost, H. J. Roller J. Amer.
Chem. Soc. 1W, %, 5292.

(b) H. Schultz, I. Sprung Angew. Chem. Intern. Ed.
Eng]. 1-, 8, 271.

(c) B. 8. Braun, et. a1., J. Econ. Entomol. 1-, 61,
866.

(d) G. W. E. Cavill, D. G. Laing, P. J. Williams Aust.
J. Chem. 1”, 22, 2145.

(e) J. S. Cochrane, J. 8. Hanson J. Chem. Soc. Perk. I
1972, 361.

0. P. Vig, R. C. Anand Indian J. Chem. 1%9, 1111.

J. D. Surmatis, R. Thommen J. Org. Chem. 1%, 34, 559.
W. S. Wadsworth J. Org. Reactions 1978, 25, 73.

M. W. Rathke Organic Reactions 1975, 22, 423.

R. L. Shriner Organic Reactions 1942, I, l.

35.

36.

37.

38.
39.
40.
41.

42.
43.
44.

45.

46.

47.

DJ.

(a) C. D. Quin, et. al., J. Org. Chem. 1971, 36‘, 1495.

(b) W. S. Wadsworth, W. D. Emmons Organic Synthesis
1%, 45, 44.

(c) R. J. Sunberg, I. O. Holcombe J. Org. Chem. 189,
34, 3273.

T. H. Einstle and E. Y. Mandanas J. Chem. Soc. Chem.
Co-. I”, 1699.

(a) A. Redjal, J. Seyden-Penne Tetrahedron Lett. 1974,
1733.

(b) G. Lefebvre, J. Seyden-Penne Chem. Soc. Chem.
Cm. 1970, 1308.

(c) G. Lavielle, M. Carpentier, P. Savinac Tetrahe-
dron Lett. 1973, 173.

(d) 8. Deschamps, G. Lefebvre, J. Seyden-Penne
Tetrahedron 1972, 28, 4209.

(e) D. Danion, 8. Carrie Tetrahedron 1912, 28, 4223.

A. 8. Dose, 8. T. Dahill J. Org. Chem. 1S5, 30, 505.

E. E. Harding, C. Y. Tseng J. Org. Chem. 1915, 40, 929.

M. W. Rathke, M. Nowak J. Org. Chem. 1”, 50, 2624.

The relative acidities change only slightly in the

change from DMSO to DME.

(a) E. S. Petrov, et. a1., Zh. Ohsch. A'himii. 1975,
45, 1529.

(b) E. S. Petrov, et. a1., Izv. Akad. Nauk. SSSR Ser.
Khim. 1976, 534.

E. Breuer, D. M. Bannet Tetrahedron Lett. 1977, 1141.

W. C. Still, 0. Gennari Tetrahedron Lett. 1-, 4405.

W. C. Still, A. Mitra, M. Khan J. Org. Chem. 1918, 41,
2923.

G. M. Kosolapoff, "Organophosphorus Compounds", Wiley,
New York, 1950, Chapter 7.

K. A. Petrov, F. L. Maklyaev, M. A. Korshunov J. Gen.

8. Tanaka, N. Yamagishi, R. Tanikaga, A. Kaji Bull.
Soc. Japan 1979, 52 (12), 3619.