One-pot synthesis of (E)-a-chloro-a,β-unsaturated esters

Article abstract of DOI:10.3184/030823409X460678

Chlorination of a phosphonate anion derived in situ from methyl bis(2,2,2-trifluoroethoxylphosphonoacetate 2 followed by the addition of aldehydes constitutes a stereoselective single flask procedure for the preparation of E-configured a-chloro-a,β-unsatu

Full text of DOI:10.3184/030823409X460678

JOURNAL OF CHEMICAL RESEARCH 2009
JULY, 405-406
RESEARCH PAPER 405
One-pot synthesis of (E)-a-chloro-a,f3-unsaturated
Usama Karama*
esters
Department of Chemistry, College of Science King Saud University PO Box 2455, Riyadh
- 11451, Saudi Arabia
Chlorination
of
a
phosphonate
anion derived in situ from methyl bis(2,2,2-trifluoroethoxylphosphonoacetate
2 followed by the addition of aldehydes constitutes a stereoselective single flask procedure for the preparation of
E-configured a-chloro-a,13-unsatu rated esters.
Keywords: olefination, a-chloro-a,13-unsaturated esters, Homer-Wadsworth-Emmons reaction, methyl bis(2,2,2-trifluoroethoxy)
chlorophosphonoacetate
a-Chloro-a,13-unsaturated
esters (a-chloroacrylates)
are
Result and discussion
important intermediates in organic synthesis, for example, for
the preparation of biologically active compounds. 1 They are
useful and versatile building blocks.2-1oMany methods for
the synthesis of a-chloro-a,13-unsaturated esters have been
developed.11-16
However, most of these methods are limited by their poor
stereoselectivity, low yields and the involvement of multisteps
transformations. The need for a general and stereoselective
method for the efficient synthesis of (E)-a-chloroacrylates
therefore still remains. In particular, the Homer-Wadsworth-
Emmons (HWE) reaction17,18is one of the most powerful
and attractive methods for this purpose. Tago and Kogen19,20
reported a synthesis of the novel HWE reagent methyl
In view of the above results, I first decided to use Qing and
Zhang's procedure, using N-chlorosuccinimide (NCS) as
chlorinating agent to generate the reagent 1. However this
gave many side products and thereafter we modified Tago and
Kogen's methodology by preparing methyl bis(2,2,2-trifluoro-
ethoxy)chlorophosphonoacetate 1 in situ from methyl bis
(2,2,2-trifluoro ethoxy)phosphonoacetate 2 and NCS in the
presence of tert-BuOK and 18-C-6 at -78 °C. After 2 hours
31p NMR spectroscopy showed methyl bis(2,2,2-trifluoro-
ethoxy)phosphono acetate to be completely chlorinated. The
novel reagent 1 which formed in situ was then allowed to react
in a HWE reaction with various aldehydes (see Scheme I).
As shown in Table I, the reaction with aromatic aldehydes
gave (E)-a-chloro-a,13-unsaturated esters stereoselectively
and good yield (87-75%) (entries 1-3). The aromatic
aldehyde possessing an electron-donating group (entry 2)
was less reactive and less stereoselective. Aliphatic aldehydes
and conjugated aldehydes were slightly less reactive but high
stereoselectivity still remained. In all reactions, the E and
Z isomers were not separated, but E/Z ratios were readily
determined by 1H NMR spectroscopy. The vinylic proton of
the Z isomer was downfield from the signal of the E isomer
and the methoxy protons of E isomer were downfield from
the signal of the Z isomer. This assignment was confirmed
by NOE analysis of the allylic alcohol derived from the
corresponding esters by DIBAL reduction.
bis(2,2,2-trifluoroethoxy)bromophosphonoacetate
and the
condensation of this novel reagent with aldehydes in HWE
reactions in the presence of tert-BuOK and 18-C-6 to give
the corresponding (E)-a-bromo-a,13-unsaturated esters with
high stereoselectivity. The reagent was prepared in 35%
overall yield by treatment of methyl bis(2,2,2-trifluoro-
ethoxy)phosphonoacetate 2 with sodium hypobromite and
subsequent reduction of the methyl bis(2,2,2-trifluoroethoxy)
dibromophosphonoacetate using I equivalent of SnCI2.
Recently Qing and Zhang21 reported on the bromination
of a phosphonate anion in situ (NaH/Br2) followed by the
condensation of aldehydes in presence ofNaH to give (E)-a-
bromo-a,13-unsaturated esters with high stereoselectivity and
good yield (87-44%).
For further evaluation of the E-selectivity reaction methyl
bis(2,2,2-trifluoroethoxy)iodophosphonoacetate was prepared
by the same procedure by using N-iodosuccinimide NIS as
iodination agent. The HWE reaction with various aldehydes
gave no selectivity (E/Z I : I)
I now report the in situ preparation of the analogous novel
HWE reagent methyl bis(2,2,2-trifluoroethoxy)chlorophos-
phonoacetate 1 and its condensation with aldehydes in a one-
pot procedure to give (E)-a-chloro-a,13-unsaturated esters
with high stereoselectivity and good yield.
I) tert-BuOK
18-C-6
o
p
II
NCS, THF,-78°C
CO CH3
2
(CF3CH20h '-.../
•
2) tert-BuOK
18-C-6
2
RCHO,-78°C
Scheme
1
* Correspondent. E-mail: karama@ksu.edu.sa

406 JOURNAL OF CHEMICAL RESEARCH 2009
(E, E)-2-Chloro-5-phenylpenta-2,4-dienoic
acid methyl ester
Table
esters
1
One-pot synthesis
of (E}-a-chloro-a,~-unsaturated
(3d): IR (CDCI3) 3018, 2990, 1734, 1215 em-I; IH NMR (CDCI3,
400 MHz) 1) 7.86 (dd,J= 11.7 Hz,J= 15.4 Hz, 1H), 7.54-7.49 (m,
2H, aromatic-H), 7.38-7.33 (m, 3H, aromatic-H), 7.03 (d,J= 11.0 Hz,
Entry
R
Product
Time/h
Yield/Yo" E:~
1H), 6.80 (d, J
= 15.4 Hz, 1H), 3.87 (s, 3H); l3C NMR (CDCI3,
2
87
10:1
3a
100 MHz) 1) 163.2, 142.6, 141.6, 136.1, 129.3, 128.7, 128.9, 128.8,
127.6,124.0,52.8; MS (EI) m/z (%) = 224 (10),222 (24) [M +],105
(100); HRMS (EI). Ca1cd for C12Hl10235CI(M + ) 222.0448. Found:
222.0445.
(E)-2-Chloro-nonenoic acid methyl ester (3e): IR (CDCI3) 3018,
2976, 1743, 1215 em-I; IH NMR (CDCI3, 400 MHz) 1) 6.44 (t,
0 -
CH,O
2
3b
3c
4
75
81
5:1
b-
3
2
11:1
J
= 7.4 Hz), 3.80 (s, 3H), 2.52 (q, J = 7.4 Hz, 2H), 1.42-1.40 (m,
0 -
0
2H), 1.31-1.25 (m, 6H), 0.86 (t, J= 6.6 Hz, 3H); l3C NMR (CDCI3,
100 MHz) 1) 163.2, 145.9, 121.5,52.7,31.6,30.1,29.1,28.9,22.6,
14.1; MS (EI) m/z (%) = 205 (6), 203 (14), [M-H], 113 (100); HRMS
(EI). Ca1cd for CIOH170235CI(M-H) 203.0838. Found: 203.0838.
4
3d
4
76
10:1
b
(E)-2-Chloro-5,9-dimethyldeca-2,8-dienoic
acid methyl ester (3f):
~
5
6
2
2
79
78
10:1
15:1
3e
3f
IR (CDCI3) 3018, 2956, 1718, 1217 em-I; IH NMR (CDCI3, 400
MHz) 1) 6.46 (t,J= 8.1 Hz, 1H), 5.07 (t, J= 7.3 Hz, 1H), 3.81 (s, 3H),
2.60-2.49 (m, 2H), 2.04-2.02 (m, 2H), 1.74 (s, 3H), 1.65 (s, 3H),
1.41-1.39 (m, 1H), 1.28-1.21 (m, 2H), 0.92 (d, J= 6.6 Hz, 3H); l3C
NMR (CDCI3, 100 MHz) 1) 163.2, 144.7, 131.5, 124.3, 122.1,52.6,
~
"Yields were based on aldehydes. bThis ratio was determined
by 1H NMR spectroscopy.
37.0,36.8,36.7,25.8,25.5,
243 (7) [M-H], 59 (100); HRMS (EI). Ca1cd for Cl3H2I02CI (M-H)
243.1153. Found: 243.1151.
19.5, 17.7; MS (EI) m/z (%) = 245 (2.5),
Conclusion
In conclusion, I have described a single flask procedure for
the stereoselective and efficient preparation of (E)-a-chloro-
a,13-unsaturated esters.
I thank the Research Centre, College of Science, King Saud
University for financial support; Project No. (Chem/2007/63).
My thanks to Professor H.M.R. Hoffmann for his revision of
the English.
Experimental
IR spectra were recorded on a Perkin Elmer 883 and spectrophotometer.
IH NMR and l3C NMR spectra were recorded using a JEOL ECP400
instrument in CDCI3. HRMS and NOE analysis were performed by
the Department of Organic Chemistry of the University of Hannover,
Germany.
Received 22 January 2009; accepted 23 April 2009
Paper 09/0403 doi: 10.3184/030823409X460678
Published online: 13 July 2009
General procedure for the synthesis of (E)-a-chloro-a, 13-unsaturated
esters 3. A solution of2 (1.3 mmol) and 18-C-6 (1.3 mmol) in THF
(8 mL) was cooled to -78°C. Then (1.3 mmol) solid potassium
tert-butoxide was added to the solution. After stirring for 30 min at
-78°C, NCS (1.4 mmol) in THF (4 mL) and CH3CN (4 mL) was
added dropwise to the reaction mixture which was then stirred for
2 h at -78°C. Then 18-C-6 (1.3 mmol) and (1.3 mmol) potassium
tert-butoxide was added to the solution at the reaction mixture was
stirred for 30 min at -78°C. The aldehyde (I mmol) was the added
to the reaction mixture and stirring was continued. When the reaction
was complete, saturated aqueous NH4Cl was added to the solution
and the organic material was extracted with AcOEt. The combined
organic extracts were washed with H20 and brine, dried over Na2S04
and concentrated under reduced pressure. The residue was purified
by column chroatography on silica gel (petroleum ether: ethyl acetate
=20: I)
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6.47 (dd, J = 3.6, J = 1.5 Hz, 1H), 3.87 (s, 3H); l3C NMR (CDCI3,
100 MHz) 1) 163.4, 148.5, 144.5, 127.1, 118.3, 116.2, 112.7, 52.9;
MS (EI) m/z (%) = 188 (19), 186 (57) [M +],57 (100); HRMS (EI).
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=
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