Bis(2,2,2-trifluoroethyl)bromophosphono-acetate, a novel HWE reagent for the preparation of (E)-α-bromoacrylates: A general and stereoselective method for the synthesis of trisubstituted alkenes

Article abstract of DOI:10.1021/ol006074x

(Equation presented) A novel reagent, methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate (3a), was designed and prepared in order to efficiently synthesize (E)-α-bromoacrylates, which are useful precursors for various C-C bond formations. Honer-Wadswo

Full text of DOI:10.1021/ol006074x

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1975-1978
Bis(2,2,2-trifluoroethyl)bromophosphono-
acetate, a Novel HWE Reagent for the
Preparation of (E)-r-Bromoacrylates: A
General and Stereoselective Method for
the Synthesis of Trisubstituted Alkenes
Keiko Tago and Hiroshi Kogen*
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi,
1-chome Shinagawa-ku, Tokyo, 140-8710 Japan
hkogen@shina.sankyo.co.jp
Received May 18, 2000
ABSTRACT
4
A novel reagent, methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate (3a), was designed and prepared in order to efficiently synthesize
(E)-r-bromoacrylates, which are useful precursors for various C−C bond formations. Honer−Wadsworth−Emmons (HWE) reaction of various
aldehydes with 3a in the presence of t-BuOK and 18-C-6 gave the corresponding (E)-r-bromoacrylate derivatives with high stereoselectivity.
Using the (E)-r-bromoacrylate as a key intermediate, a general stereoselective synthesis of trisubstituted alkenes via Pd-catalyzed cross-
coupling was developed.
The highly stereoselective construction of trisubstituted
alkenes is one of the most challenging problems in synthetic
organic chemistry.1 Indeed, many skillful and selective
synthetic methods for the preparation of this important
functional group have been devised for decades.2 However,
the need for a general and stereoselective method for the
efficient synthesis of trisubstituted alkenes still remains.1 At
present, vinyl bromides are widely used as precursors for
C-C bond formation with conservation of olefin geometry,
using reactions such as Suzuki coupling,3 or Stille coupling.4
Therefore, we anticipated that a stereoselective construction
of trisubstituted bromoalkenes, for example, R-bromoacrylate
derivatives, would provide a useful method to synthesize
various trisubstituted olefins.
Although there are limitations to the stereoselective
construction of tri- and tetrasubstituted alkenes, Wittig and
Horner-Wadsworth-Emmons (HWE) reactions are power-
ful and attractive methods for the construction of various
alkenes.5 This is because they provide a direct introduction
of the C-C double bond from carbonyl compounds. It is
(1) Kelly, S. E. In ComprehensiVe Organic Synthesis, Additions to C-X
π Bonds, Part 1; Schreiber, S. L., Ed.; Pergamon Press: Oxford 1991; Vol.
1, Chapter 3.
(2) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. (b)
Kocienski, P. J.; Pritchard, M.; Wadman, S. N.; Whitby, R. J.; Yeates, C.
L. J. Chem. Soc., Perkin Trans. 1 1992, 3419. (c) Martin, S. F.; Daniel, D.;
Cherney, R. J.; Liras, S. J. Org. Chem. 1992, 57, 2523 and references therein.
(d) Denmark, S. E.; Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386. (e)
Pelter, A.; Colclough, M. E. Tetrahedron 1995, 51, 811. (f) Studemann,
T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 93. (g) Kawasaki,
T.; Ichige, T.; Kitazume, T. J. Org. Chem. 1998, 63, 7525.
(3) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(4) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
10.1021/ol006074x CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/03/2000

known that the HWE reaction with diethoxybromophos-
phonoacetate 1 and Wittig reaction with the stabilized ylide
2 gave R-bromoacrylates with slightly predominant Z-isomer
(Scheme 1).6,7 On the other hand, only a few procedures for
the above fact, we designed a novel reagent, bis(2,2,2-
trifluoroethyl)bromophosphonoacetate, 3, anticipating that
(E)-R-bromoacrylates would be synthesized by the HWE
reaction since 3 is thought to be complementary to 1 in the
analogous reaction.
The novel reagent 3a was readily prepared from methyl
bis(2,2,2-trifluoroethyl)phosphonoacetate (4)2a using a pro-
cedure similar to that reported by McKenna et al. (Scheme
2).13 Treatment of 4 with freshly prepared sodium hypo-
Scheme 1
Scheme 2a
a (a) Aqueous NaOBr 85%; (b) SnCl2‚2H2O (0.96 equiv), EtOH,
the synthesis of (E)-R-bromoacrylates have been reported
in the literature.8 Thus, a general method for the synthesis
of (E)-R-bromoacrylates would be a beneficial synthetic
achievement. (E)-R-Fluoroacrylates are synthesized stereo-
selectively by the HWE reaction of diethoxyfluorophos-
phonoacetate with lithium base.9 However, it is apparent that
fluoroalkenes cannot be used as precursors for C-C bond
formation. Therefore, we investigated HWE reagents and
reaction conditions to develop a stereoselective synthetic
method for (E)-R-bromoacrylates from which precursors for
C-C bond formation could be readily synthesized. In this
Letter, we describe the preparation of the novel HWE reagent
3 and a general methodology for the construction of
trisubstituted alkenes, which involves the stereoselective
HWE reaction of 3 followed by stereospecific C-C bond
formation by Pd-catalyzed cross-coupling.
H2O, 70%.
bromide afforded dibromide, which was subsequently re-
duced by 1 equiv of SnCl2.14 A small amount of unreacted
dibromide and over-reduced product 4 were removed by flash
chromatography (dichloromethane/acetone ) 50:1) using
silica gel which was pretreated with dichloromethane con-
taining 4 N HCl in ethyl acetate.15 Finally, the residue was
distilled under reduced pressure (bp 85-87 °C, 0.4 mmHg)
to give pure 3a (60% yield from 4).
The results of the HWE reaction between 1a or 3a and
aldehydes using potassium tert-butoxide (t-BuOK) are sum-
marized in Table 1. Excess amounts of t-BuOK reduced the
While the HWE reaction using diethoxyphosphonoacetate
shows a preference for the formation of more stable
disubstituted E-olefins,5a,10 Still’s electrophilic bis(2,2,2-
trifluoroethoxy)phosphonoacetate reacts with aldehydes in
the presence of KHMDS and 18-crown-6 ether (18-C-6) to
afford Z-R,â-unsaturated esters selectively.2a,11,12 In view of
Table 1. Results of the HWE Reaction with 1a or 3a and
Benzaldehyde
(5) For review to see: (a) Wadsworth, W. S. Org. React. 1977, 25, 73.
(b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (c) Vedejs,
E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1.
runa
reagent
additive
time
16 h
16 h
2 h
yield, %b
E/Zc
(6) (a) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733. (b) Grinev, G. V.; Chervenyuk, G. I.; Dombrovskii, A. V. J.
Gen. Chem. USSR 1969, 39, 1223. (c) Semmelhack, M. F.; Brickner, S. J.
J. Am. Chem. Soc. 1981, 103, 3945. (d) Tanouchi, T.; Kawamura, M.;
Ohyama, I.; Kajiwara, I.; Iguchi, Y.; Okada, T.; Miyamoto, T.; Taniguchi,
K.; Hayashi, M. J. Med. Chem. 1981, 24, 1149. (e) Danishefsky, S.;
Chackalamannil, S.; Harrison, P.; Silvestri, M.; Cole, P. J. Am. Chem. Soc.
1985, 107, 2474.
1
2
3
4
1a d
1a
3a
none
18-C-6
none
94
93
65
94
1/5
1/14
10/1
30/1
3a
18-C-6
20 min
a 1 equiv of benzaldehyde, 1.1 equiv of 1a or 3a, 1.05 equiv of t-BuOK,
and 1.3 equiv of additive (runs 2 and 4) were used. b Isolated yield.
c Determined by 1H NMR (400 MHz) analysis of the products. d For
preparation of 1a, see ref 13.
(7) (a) Gonzalez, M. S. P.; Aciego R. M. D.; Herrera, F. J. L. Tetrahedron
1988, 44, 3715. (b) Sato, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1991, 56, 2278.
(8) (a) Nakamura, I.; Harada, K. Heterocycles 1978, 9, 473. (b) Kolsaker,
P.; Brobakke, K. Acta Chem. Scand. B 1981, 35, 701. (c) Bestmann, H. J.;
Dostalek, R.; Zimmermann, R. Chem. Ber. 1992, 125, 2081. These
procedures generally lack of efficiency because of multiple steps or
limitation of substrate.
(9) Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. ReV. 1996, 96, 1641 and
references therein.
yield and stereoselectivity.16 Therefore, phosphonoacetates
were used slightly in excess of t-BuOK. As we anticipated,
HWE reactions with 3a proceeded with high E-selectivity
(10) Etemad-Moghadam, G.; Seyden-Penne, J. Tetrahedron 1984, 40,
5153.
(11) Hensel, M. J.; Fuchs, P. L. Synth. Commun. 1986, 16, 1285.
(12) For another Z-selective HWE reagent, see: (a) Ando, K. Tetrahedron
Lett. 1995, 36, 4105. (b) Ando, K. J. Org. Chem. 1997, 62, 1934.
(13) McKenna, C. E.; Khawli, L. A. J. Org. Chem. 1986, 51, 5467.
(14) SnCl2‚2H2O, which was purchased from Aldrich Chemical Co., gave
the best result for reduction.
1976
Org. Lett., Vol. 2, No. 13, 2000

Table 2. Results of the HWE Reaction with 1a or 3a and a Range of Aldehydes
1
1
a See the corresponding footnotes in Table 1. b Isolated yield. c Determined by H NMR analysis of the products. d Z-product cannot be detected by H
NMR analysis. e At -20 °C. f At -40 °C. g Aldehyde was distilled before use in the reaction. h Without 18-C-6.
(runs 3 and 4) in contrast to the same reaction with 1a (runs
1 and 2). Furthermore, stereoselectivity and/or yield were
markedly improved using 1.3 equiv of 18-C-6 as an additive
(runs 2 and 4). When using LHMDS as a base, a higher
temperature (even at room temperature) was needed for the
HWE reaction to proceed with 3a, and both the yield and
stereoselectivity were significantly decreased (38%, E/Z )
2:1).
To examine the availability of (E)-R-bromoacrylates,
trisubstituted alkenes 7 and 9 were synthesized as shown in
Scheme 3. From acrylate 5, a precursor for the coupling
Scheme 3a
For further evaluation of the applicability of this E-
selective reaction, we examined the HWE reaction using 3a
with various aldehydes. As shown in Table 2, olefination of
most aldehydes with 3a in the presence of t-BuOK and 18-
C-6 gave (E)-R-bromoacrylates17 with high stereoselectivities
and excellent yields. The reaction with aromatic aldehydes
proceeded rapidly and gave (E)-R-bromoacrylates stereo-
selectively with high yields (runs 1-5). Conjugated alde-
hydes and branched aliphatic aldehydes were slightly less
reactive, but high stereoselectivity still remained (runs 6, 8,
and 13). E/Z ratio and reactivities were extremely diminished
when using 1a instead of 3a (runs 7, 11, 12, and 14). This
HWE reagent 3a provides an efficient and highly stereo-
selective method to obtain various (E)-R-bromoacrylates,
which are very useful precursors for various C-C bond
formations.
a (a) DIBAL-H, CH2Cl2, -78 °C, 88%; (b) TBSCl, imidazole,
DMF, rt, 96%; (c) n-Bu3SnCHdCH2, Pd(PPh3)4, THF, rt, 66%;
(d) 8, 9-BBN, THF, rt then 6, PdCl2(dppf), Ph3As, Cs2CO3, DMF,
50 °C, 81%.
reaction was readily synthesized in two steps. 7 was
synthesized by Stille coupling of 6 with vinylstannane, and
Suzuki coupling of 6 and 8 gave trisubstituted olefin 9 in
good yields. The combination of stereoselective bromo-
olefination and C-C bond formation affords a useful and
general synthetic method for a wide range of trisubstituted
alkenes. This protocol has considarable potential for the
construction of complex molecules.
(15) Reagent 3a is unstable even under weakly basic conditions. Usual
silica gel column chromatography caused decomposition of 3a. The purified
3a was enough to stable to be stored in a freezer (-20 °C) over 3 years
without decomposition.
(16) Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725.
(17) Geometry of R-bromoacrylates were determined by NOE analysis
of the allylic alcohol which was derived from DIBAL-H reduction of
corresponding ester.
In conclusion, the novel HWE reagent 3a was designed
and prepared. (E)-R-Bromoacrylates were synthesized stereo-
selectively and efficiently from 3a with various aldehydes
Org. Lett., Vol. 2, No. 13, 2000
1977

in the presence of t-BuOK and 18-C-6. Using the product
(E)-R-bromoacrylate as a key intermediate, we succeeded
in developing a general protocol for the highly stereoselective
synthesis of trisubstituted alkenes via Pd-catalyzed cross-
coupling.
reaction, and the synthesis of 7 and 9 and the characterization
of R-bromoacrylates and compounds 6, 7, and 9. This
material is available free charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental details
for the preparation of 3a, the general procedure for the HWE
OL006074X
1978
Org. Lett., Vol. 2, No. 13, 2000