(Z)-α-haloacrylates: An exceptionally stereoselective preparation via Cr(II)-mediated olefination of aldehydes with trihaloacetates

Article abstract of DOI:10.1021/ja029938d

(Z)-α-Fluoro-, (Z)-α-chloro-, and (Z)-α-bromoacrylates were obtained with unprecedented yield and stereocontrol (>99%) via addition of the corresponding commercial trihaloacetates to aldehydes at room temperature using stoichiometric Cr(II) salts or catal

Full text of DOI:10.1021/ja029938d

Published on Web 02/21/2003
(Z)-r-Haloacrylates: An Exceptionally Stereoselective Preparation via
Cr(II)-Mediated Olefination of Aldehydes with Trihaloacetates
D. K. Barma,† Abhijit Kundu,† Hongming Zhang,‡ Charles Mioskowski,*,§ and J. R. Falck*,†
Department of Biochemistry, UniVersity of Texas Southwestern Medical Center, Dallas, Texas 75390-9038,
Department of Chemistry, Southern Methodist UniVersity, Dallas, Texas 75275, and
UniVersite´ Louis Pasteur de Strasbourg, Faculte´ de Pharmacie, Laboratoire de Synthe`se Bio-Organique 74,
route du Rhin 67 401 Illkirch, France
Received December 27, 2002 ; E-mail: j.falck@utsouthwestern.edu
Table 1. Synthesis of (Z)-R-Haloacrylates 3
R-Halo-R,â-unsaturated esters, also known as R-haloacrylates,
are broadly useful intermediates. Applications range from the
preparation of R-amino acids, heterocycles, polymers, and aziridines
to natural products and pharmaceuticals.1 With the advent in recent
years of efficient transition metal catalyzed cross-couplings, R-
haloacrylates have also been widely exploited for the stereospecific
synthesis of trisubstituted olefins.2 However, procedures for the
preparation of R-haloacrylates, inter alia, dehydrohalogenation,3
rearrangements,4 alkoxycarbonylation,5 deoxygenation of glycidic
esters,6 thermal eliminations,7 and Wittig/Horner-Emmons/
Peterson-type condensations,8 often suffer from poor stereo-
selectivities, unsatisfactory yields, costly reagents, and/or lengthy
procedures. As part of our continuing investigations into the utility
of organochromium reagents in synthesis,9 we report herein the
preparation of (Z)-R-fluoro-, (Z)-R-chloro-, and (Z)-R-bromo-
acrylates 3 in excellent yields10 with unprecedented stereocontrol
(>99%) via room-temperature olefination of aldehydes with com-
mercial trihaloacetates 1 mediated by stoichiometric Cr(II) salts or
by catalytic Cr(II) with a regeneration system11 (eq 1). While the
intermediate Reformatsky-type adduct12 2 can be isolated in good
yield, the overall transformation follows a dramatically different
course than magnesium- and zinc-induced additions and does not
require strong Lewis acids.13
The results from the Z-olefination of a panel of typical aldehydes
are summarized in Table 1. For simple, aliphatic aldehyde 4 or
branched aldehyde 7, stirring with 4 equiv of commercial CrCl2
and methyl trichloroacetate14 at room temperature for 0.5 h
generated methyl (Z)-R-chloroacrylates 5 (entry 1) and 8 (entry 2),
respectively, in excellent yields. None of the (E)-isomers could be
detected by NMR analysis of the crude reaction mixtures, indicating
>99% stereochemical purity. Notably, catalytic Cr(II), coupled to
a Mn/TMSCl regeneration system,11 gave comparable results.
Condensation of chiral glyceraldehyde 9 likewise proceeded without
incident and gave rise to ester 1015 (entry 3) exclusively in nearly
quantitative yield.
entry
aldehyde
acrylate
yield (%)
1
4 R ) PhCH2CH2
5 X ) Cl, R′ ) Me
6 X ) F, R′ ) Et
8 X ) Cl, R′ ) Me
10 X ) Cl, R′ ) Me
99
98
99
99
2
3
7 R ) PhCH(CH3)
4
5
6
7
11 R ) Ph
12 X ) Cl, R′ ) Me
14 X ) Cl, R′ ) Me
16 X ) Cl, R′ ) Me
18 X ) Cl, R′ ) Me
19 X ) Br, R′ ) Me
20 X ) F, R′ ) Et
22 X ) Cl, R′ ) Me
24 X ) Cl, R′ ) Me
26 X ) Cl, R′ ) Me
27 X ) Br, R′ ) Me
29 X ) Cl, R′ ) Me
31 X ) Cl, R′ ) Me
100
99
98
98
98
98
99
99
99
98
98
91a
13 R ) cinnamyl
15 R ) 4-CF3C6H4
17 R ) 4-MeOC6H4
8
9
10
21 R ) 3-(MeO)-4-Bn-C6H3
23 R ) 3-BrC6H4
25 R ) piperonyl
11
12
28 R ) 4-Me2NC6H4
30 R ) 3-indolyl
a Required 8 equiv of CrCl2.
catalytic, with a variety of functional groups was demonstrated by
the smooth condensations of benzyloxy 21 (entry 8), bromide 23
(entry 9), methylenedioxy 25 (entry 10), dimethylaniline 28 (entry
11), and indole 30 (entry 12) to give (Z)-R-haloacrylates 22, 24,
26,16,17 27,17,18 29, and 31, respectively.
Access to (Z)-R-fluoroacrylates, in contrast, proved initially
elusive. Methyl trifluoroacetate was refractory under all conditions
and could be recovered unchanged. However, commercial methyl
dibromofluoroacetate readily condensed with aliphatic and aromatic
aldehydes under the standard conditions to give (Z)-R-fluoro-
acrylates, for example, 68h and 20,7b respectively.
While the details have yet to be elucidated, we favor a reaction
mechanism involving the oxidative addition of Cr(II) into a C-Cl
bond via two consecutive single electron transfers,19 and subsequent
addition to the aldehyde carbonyl. Subsequent E2-elimination of
the resultant Reformatsky-type adduct 2 (eq 1) affords R-halo-
acrylate 3. Of the possible antiperiplanar conformations, conformer
A (Scheme 1) is favored because it minimizes the steric interactions
between the ester and R group. Selective metalation of the chloride
furthest from the chromate ester ensures the observed Z-stereo-
chemistry.
Aryl and conjugated aldehydes, represented by benzaldehyde (11)
and cinnamaldehyde (13), behaved analogously and evolved methyl
(Z)-R-chlorocinnamate4 12 (entry 4) and Z,E-diene 14 (entry 5),
respectively, as the sole products. Neither electron-withdrawing
(entry 6) nor electron-donating (entry 7) substituents significantly
influenced the reaction rate or yields as illustrated in the conversion
of p-trifluoromethylbenzaldehyde (15) to 16 and p-methoxybenz-
aldehyde (17) to 18.4 The latter reaction was equally facile using
methyl tribromoacetate and supplied (Z)-R-bromo analogue 19. The
compatibility of the reaction conditions, both stoichiometric and
† University of Texas Southwestern Medical Center.
‡ Southern Methodist University.
Consistent with this proposal, the corresponding dihalohydrins
3212a-37 could be isolated in good yield under conditions of
§ Universite´ Louis Pasteur de Strasbourg.
9
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J. AM. CHEM. SOC. 2003, 125, 3218-3219
10.1021/ja029938d CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
75, 2326. (c) Dollt, H.; Zabel, V. Aust. J. Chem. 1999, 52, 259. (d)
Mironiuk-Puchalska, E.; Kolaczkowska, E.; Sas, W. Tetrahedron Lett.
2002, 43, 8351.
(2) (a) Stille: Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373. (b)
Sonogashira: Dai, W.-M.; Wu, J.; Fong, K. C.; Lee, M. Y. H.; Lau, C.
W. J. Org. Chem. 1999, 64, 5062. (c) Suzuki: Zhou, S. M.; Yan, Y. L.;
Deng, M. Z. Synlett 1998, 198. (d) Rossi, R.; Bellina, F.; Bechini, C.;
Mannina, L.; Vergamini, P. Tetrahedron 1998, 54, 135. (e) Zhang, X.;
Qing, F.-L.; Yu, Y. J. Org. Chem. 2000, 65, 7075. (f) Qing, F.-L.; Zhang,
X. Tetrahedron Lett. 2001, 42, 5929.
(3) Forti, L.; Ghelfi, F.; Pagnoni, U. M. Tetrahedron Lett. 1995, 36, 3023.
(4) Kruper, W. J., Jr.; Emmons, A. H. J. Org. Chem. 1991, 56, 3323.
(5) Alami, M.; Crousse, B.; Linstrumelle, G. Tetrahedron Lett. 1995, 36, 3687.
(6) Buschmann, E.; Schafer, B. Tetrahedron 1994, 50, 2433.
Table 2. Synthesis of Dihalohydrin 2
(7) (a) Satoh, T.; Itoh, N.; Onda, K.; Kitoh, Y.; Yamakawa, K. Bull. Chem.
Soc. Jpn. 1992, 65, 2800. (b) Ishihara, T.; Shintani, A.; Yamanaka, H.
Tetrahedron Lett. 1998, 39, 4865.
(8) (a) Chan, T. H.; Moreland, M. Tetrahedron Lett. 1978, 6, 515. (b)
Karrenbrock, F.; Schaefer, H. J. Tetrahedron Lett. 1979, 31, 2913. (c)
Villieras, J.; Perriot, P.; Normant, J. F. Synthesis 1978, 1, 31. (d) Braun,
N. A.; Buerkle, U.; Feth, M. P.; Klein, I.; Spitzner, D. Eur. J. Org. Chem.
1998, 8, 1569. (e) Huang, Z.-Z.; Wu, L.-L.; Zhu, L.-S.; Huang, X. Synth.
Commun. 1996, 26, 677. (f) Zapata, A.; Ferrer, G. F. Synth. Commun.
1986, 16, 1611. (g) Tago, K.; Kogen, H. Tetrahedron Lett. 2000, 56, 8825.
(h) Sano, S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998, 777.
(9) For additional examples of recent CrCl2-based methodology, see: (a) Baati,
R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. Tetrahedron Lett. 2002,
43, 2179. (b) Barma, D. K.; Kundu, A.; Baati, R.; Mioskowski, C.; Falck,
J. R. Org. Lett. 2002, 4, 1387. (c) Baati, R.; Barma, D. K.; Falck, J. R.;
Mioskowski, C. J. Am. Chem. Soc. 2001, 123, 9196.
entry
aldehyde
dihalohydrin
yield (%)
1
2
3
4
5
6
11
11
4
13
9
32
33
34
35
36
37
X ) Cl, R′ ) Me
X ) Br, R′ ) Me
X ) Cl, R′ ) Me
X ) Cl, R′ ) Me
X ) Cl, R′ ) Me (de 1:1.4)
X ) F, R′ ) Et
82
65
84
78
75
76
4
limiting chromium and low temperature (Table 2).12c Adduct 3712b
was prepared using commercial ethyl bromodifluoroacetate, whereas
the others were derived from the corresponding trichloro- or
tribromoacetates. Exposure of 32-36 to the original reaction
conditions gave rise, as expected, to only (Z)-R-haloacrylates in
yields comparable to those in Table 1.
In conclusion, we have validated a highly stereoselective
synthesis of (Z)-R-haloacrylates 3 via CrCl2-mediated olefinations
of aldehydes with commercial trihaloacetates and also described
the isolation of the dihalohydrin intermediate 2. Initial experiments
indicate this methodology has a wide scope. In contrast with most
organochromium reagents, ketones are suitable substrates for the
combination of trihaloacetate and CrCl2. In some instances,
remarkably high stereoselectivities are observed as in the case of
acetophenone (38), which furnished the tetrasubstituted olefin 3913
in a 75:1 Z/E ratio20 (eq 2), but modest yield. In yet another
(10) General Procedure for the Synthesis of (Z)-R-Haloacrylates (3)/Using
Stoichiometric Chromium: Methyl trihaloacetate16 (1) (1 mmol) and
aldehyde (1 mmol) in THF (2 mL) were added to a stirring suspension of
23
anhydrous CrCl2 (4.5 mmol) in THF (8 mL) at ambient temperature.
After 0.5 h, the resultant reddish reaction mixture was quenched with
water, extracted thrice with ether, and the combined ethereal extracts were
evaporated. Chromatographic purification of the residue on SiO2 furnished
methyl (Z)-R-haloacrylate (3) in the indicated yields (Table 1). Using
Catalytic Chromium: Methyl trihaloacetate16 (1) (1 mmol) and aldehyde
(1 mmol) in THF (2 mL) were added to a stirring suspension of anhydrous
23
CrCl2 (50 mol %), Mn powder (4 mmol), and freshly distilled TMSCl
(6 mmol) in THF (8 mL) at ambient temperature. After 12 h, the resultant
reddish reaction mixture was quenched with water, extracted thrice with
ether, and the combined ethereal extracts were evaporated. Chromato-
graphic purification of the residue on SiO2 gave (Z)-R-haloacrylate (3) in
the indicated yields (Table 1). Preparation of Dihalohydrins (2): Methyl
trihaloacetate16 (1) (1 mmol) and aldehyde (1 mmol) in THF (2 mL) were
23
added to a stirring suspension of anhydrous CrCl2 (2.5 mmol) in THF
(8 mL) at 0 °C. After 12 h at 0 °C, the resultant reddish reaction mixture
was quenched with water, extracted thrice with ether, and the combined
ethereal extracts were evaporated. Chromatographic purification of the
residue on SiO2 gave dihalohydrin 3 in the indicated yields (Table 2).
(11) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
(12) (a) Fu¨rstner, A. Synthesis 1989, 571-590. (b) Yoshida, M.; Suzuki, D.;
Iyoda, M. Synth. Commun. 1996, 26, 2523. (c) Wessjohann, L.; Gabriel,
T. J. Org. Chem. 1997, 62, 3772.
(13) (a) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1980, 53, 1698. (b) For an exceptional example, see: Ishino, Y.; Mihara,
M.; Nishihama, S.; Nishiguchi, I. Bull. Chem. Soc. Jpn. 1998, 71, 2669.
(14) Comparable results were obtained with most other esters including ethyl,
tert-butyl, and benzyl.
(15) Hayon, A. F.; Fehrentz, J. A.; Chapleur, Y.; Castro, B. Bull. Soc. Chim.
Fr. 1983, 207.
variation, the efficient transformation of aldehyde 4 to (E)-
methacrylate 4021 using methyl 2,2-dichloroproprionate is unrivaled
by conventional reagents for its stereoselectivity and yield (eq 3).22
We anticipate Cr-mediated olefinations will find broad applicability
and plan to publish additional findings soon.
(16) Dhoubhadel, S. P. J. Indian Chem. Soc. 1976, 53, 951-952.
(17) Because of literature discord, the structures of chloride 24 and bromide
25 were confirmed by X-ray analysis and correlated to other examples in
Table 1.
(18) Sai, H.; Ogiku, T.; Nishitani, T.; Hiramatsu, H.; Horikawa, H.; Iwasaki,
T.Synthesis 1995, 582-586.
(19) Kochi, J. K.; Davis, D. D. J. Am. Chem. Soc. 1964, 86, 5264. (b) Kochi,
J. K.; Singleton, D. M. J. Am. Chem. Soc. 1968, 90, 1582.
(20) The Z/E-ratio was highly dependent upon the solvent composition, ranging
from 5:1 in THF alone to 75:1 in DMF/THF (1:1) at 0 °C.
(21) Shimagaki, M.; Shiokawa, M.; Sugai, K.; Teranaka, T.; Nakata, T.; Oishi,
T. Tetrahedron Lett. 1988, 29, 659.
Acknowledgment. Financial support from the CNRS, the Robert
A. Welch Foundation, and NIH (GM31278, DK38226) is gratefully
acknowledged.
Supporting Information Available: Physical and spectroscopic
data for all new compounds (PDF); X-ray crystallographic files (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
(22) (a) Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.; Kalesse, M.
Angew. Chem., Int. Ed. 2000, 39, 4364. (b) Still, W. C.; Gennari, C.
Tetrahedron Lett. 1983, 24, 4405. (c) Smith, A. B., III; Brandt, B. M.
Org. Lett. 2001, 3, 1685. (d) Rodriguez, C. M.; Martin, T.; Ramirez, M.
A.; Martin, V. S. J. Org. Chem. 1994, 59, 4461.
(23) While the physical appearance and color varied, equivalent results were
obtained using CrCl2 from different commercial sources, inter alia, Strem
and Aldrich Chem. Co.
References
(1) (a) Kakehi, A.; Ito, S. J. Org. Chem. 1974, 39, 1542. (b) Marvel, C. S.;
Weil, E. D.; Wakefield, L. B.; Fairbanks, C. W. J. Am. Chem. Soc. 1953,
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