Preparation of α-haloacrylate derivatives via dimethyl sulfoxide-mediated selective dehydrohalogenation

Article abstract of DOI:10.1021/ol7021142

(Chemical Equation Presented) Dimethyl sulfoxide causes α/β-dihalopropanoate derivatives to undergo efficient, selective dehydrohalogenation to form α-haloacrylate analogues. A variety of α-halo Michael acceptors were prepared in dimethyl sulfoxide under mild, base-free conditions, including the preparation of α-bromoacrolein and α-chloro- and bromoacrylonitriles. Synthesis of these molecules has been reported in the literature to be difficult. Among all the existing dehydrohalogenation procedures, this protocol is the most facile, practical, and environmentally benign process.

Full text of DOI:10.1021/ol7021142

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4607-4610
Preparation of
r-Haloacrylate
Derivatives via Dimethyl
Sulfoxide-Mediated Selective
Dehydrohalogenation
Wei Li,* Jianchang Li, Zhao-Kui Wan, Junjun Wu, and Walter Massefski
Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park DriVe,
Cambridge, Massachusetts 02140
weili@wyeth.com
Received August 28, 2007
ABSTRACT
Dimethyl sulfoxide causes
A variety of -halo Michael acceptors were prepared in dimethyl sulfoxide under mild, base-free conditions, including the preparation of
-bromoacrolein and -chloro- and bromoacrylonitriles. Synthesis of these molecules has been reported in the literature to be difficult. Among
all the existing dehydrohalogenation procedures, this protocol is the most facile, practical, and environmentally benign process.
r,â-dihalopropanoate derivatives to undergo efficient, selective dehydrohalogenation to form r-haloacrylate analogues.
r
r
r
Recent reports on new methods for the preparation of
R-haloacrylates reflect the renewed interest in the synthesis
of these useful building blocks1 and prompted the submission
of this communication. Acrylate derivatives are not only used
as Michael acceptors,2 but are also frequently employed as
dienophiles or dipolarophiles in cycloaddition reactions.3
With an additional vinyl halogen atom at the R-position to
the carbonyl, it is not surprising that R-haloacrylate analogues
have found more synthetic application due to this added
functional handle. For example, â,γ-unsaturated esters and
lactones can be easily obtained by reaction of the R-halo-
acrylate analogues with dialkyl phosphonates,4 and vinyl-
oxiranes can be prepared through reaction of aldehydes with
lithium dienolates.5 The halogen atom could also readily
undergo metal-halogen exchange,6 allowing for homologa-
tion of the parent structure through C-alkylation. The
R-haloacrylate analogues not only increase their utility as
Michael acceptors7 or dienophiles in cycloaddition chemis-
try,8 but they can also serve as the functionalized vinyl halide
in transition metal-mediated coupling reactions.9 With the
(5) Hudlicky, T.; Fleming, A.; Lovelace, T. C. Tetrahedron 1989, 45,
3021.
(6) (a) Grossman, G.; Poncioni, M.; Bornand, M.; Jolivet, B.; Neuburger,
M.; Sequin, U. Tetrahedron 2003, 59, 3237. (b) Thibonnet, J.; Vu, V. A.;
Berillon, L.; Knochel, P. Tetrahedron 2002, 58, 4787.
(7) Selected examples: (a) Saoudi, A.; Hamelin, J.; Benhaoua, H. J.
Chem. Res. Synop. 1996, 11, 491. (b) Chen, C.; Xi, C.; Jiang Y.; Hong, X.
Tetrahedron Lett. 2004, 45, 6067. (c) Gutke, H.; Braun, N. A.; Spitzner,
D. Tetrahedron 2004, 60, 8137. (d) Prostenic, M.; Salzman, N. P.; Carter,
H. E. J. Am. Chem. Soc. 1955, 77, 1856. (e) Martin, A. R.; Caputo, J. F. J.
Org. Chem. 1974, 39, 1811. (f) Martin, A. R.; Mallick, S. K.; Caputo, J. F.
J. Org. Chem. 1974, 39, 1808.
(8) (a) Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549. (b)
Zhou, G.; Hu, Q.; Corey, E. J. Or. Lett. 2003, 5, 3979. (c) Sun, P.; Chang,
M.; Chiang M.; Chang, N. Org. Lett. 2003, 5, 1761.
(1) (a) Yin, J.; Gallis, C. E.; Chisholm, J. D. J. Org. Chem. 2007, 72,
7054. (b) Chen, S.; Wang, J. Org. Chem. 2007, 72, 4993. (c) J. Barma, D.
K.; Kundu, A.; Zhang, H.; Miokowski, C.; Falck, J. R. J. Am. Chem. Soc.
2003, 125, 3218.
(2) Richard, D. J.; Schiavi, B.; Joullie, M. M. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11971.
(3) Chang, M.; Hsu, R.; Tseng, T.; Sun, P.; Chang, N. Tetrahedron 2004,
60, 5545.
(4) Hirao, T.; Fujihara, Y.; Kurokawa, K.; Ohshiro, Y.; Agawa, T. J.
Org. Chem. 1986, 51, 2830.
(9) Selected references: (a) Bellur, E.; Langer, P. Eur. J. Org. Chem.
2005, 22, 4815. (b) Sorg, A.; Blank, F.; Brueckner, R. Synlett 2005, 8,
1286. (c) Majo, V. J.; Prabhakaran, J.; Simpson, N. R.; Van Heertum, R.
L.; Mann, J. J.; Kumar, J. S. D. Bioorg. Med. Chem. Lett. 2005, 15, 4268.
10.1021/ol7021142 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/02/2007

rapidly increasing application of such coupling reactions in
synthetic and medicinal chemistry,10 alternate synthetic
methods for these building blocks are of constant interest.
The existing synthetic procedures in the literature are often
associated with complicated operations and lack of general-
ity.11 This is true especially for the preparation of R-bromo
acrolein derivatives due to the high reactivity of the aldehyde.
Here we report a set of new general synthetic procedures
for the preparation of a variety of such derivatives con-
veniently via dimethyl sulfoxide (DMSO)-mediated dehy-
drohalogenation from the R,â-dihalo precursors with high
yields (Scheme 1).
Table 1. Formation of R-Haloacrylates in DMSO
Scheme 1. Formation of R-Bromoacrylates in DMSO
We have recently reported that sulfoxides convert R,R-
dihalomethylarenes to the corresponding aldehydes12 through
oxygen transfer from the sulfoxide to the gem-dihalo
compounds. We were interested to see if subjection of the
R,â-dihalo substrates to DMSO under similar conditions
would provide new synthetic applications. Thus, a variety
of R,â-dihalo compounds were treated with DMSO and very
interesting results were obtained. We have previously
reported that the 1,2-di-actiVated dihalopropanoates (R )
phenyl), upon heating in DMSO, undergo reductive de-
bromination to generate the corresponding olefin.13 Herein,
we communicate further that the mono-actiVated analogues
(R ) H, Alkyl, Scheme 1) prefer the dehydrohalogenation
pathway, leading to the exclusive formation of R-haloacrylate
derivatives. No reductive dehalogenation byproducts were
observed.
Table 1 lists the representative examples and reaction
conditions. Most of the Vic-dihalo starting materials in the
table are commercially available, or could be prepared
conveniently from the corresponding acrylate precursors
through known olefin halogenation reactions.14 Although the
reaction occurs in neat DMSO, it was observed that addition
of trace amounts of water (∼5%) accelerated the reaction.
The conversion of the R,â-dihalo substrates to R-halo-
acrylate derivatives in DMSO proceeded smoothly, and both
R,â-dichloro and dibromo precursors underwent dehydro-
halogenation to give the corresponding R-haloacrylates in
excellent yields. The dichloro analogues (entries 1 and 2,
Table 1) appear to be less reactive than the corresponding
bromo counterparts (entries 3 and 4) as they required higher
reaction temperatures or longer reaction times. The acids
have similar reactivity to the corresponding esters. In the
case of a substituent at the C-3 carbon (entry 5), the reaction
afforded the (Z)-ethyl 2-bromobut-2-enoate in high yield
(91%). The geometry of the double bond was established
through NMR experiments and is in agreement with the
literature.15 The R,â-dibromoketones (entries 6 and 7)
afforded the R-bromovinylketones in good yield under similar
conditions.
We further extended our investigation to the formation of
R-bromo acrolein analogues. Although the R-bromo acrolein
moiety possesses three diverse functional groups for which
many types of transformations can be envisioned, its
synthetic application can only be found scattered in the
literature due to lack of proper synthetic procedures, espe-
cially for the small aliphatic acrolein molecules. For example,
the literature protocols for the preparation of R-bromoacrolein
(entry 1 of Table 2) were very limited, and the one most
frenquently cited was published more than a half century
ago.16 The procedure employed a steam-distillation and
afforded the R-bromoacrolein in low yield. Due to the
(10) (a) Romagnoli, R.; Baraldi, P. G.; Tabrizi, M. A.; Bermejo, J.;
Estevez, F.; Borgatti, M.; Gambari, R. J. Med. Chem. 2005, 48, 7906. (b)
Beria, I.; Baraldi, P. G.; Cozzi, P.; Caldarelli, M.; Geroni, C.; Marchini,
S.; Mongelli, N.; Romagnoli, R. J. Med. Chem. 2004, 47, 2611.
(11) (a) Hamelin, J.; Saoudi, A.; Benhaoua, H. Synthesis 2003, 14, 2185.
(b) Kendall, J. T.; Lamal, D. M. J. Fluorine Chem. 1997, 83, 171.
(12) Li, W.; Li, J.; DeVincentis, D.; Mansour, T. S. Tetrahedron Lett.
2004, 45, 1071.
(13) Li, W.; Li, J.; Lin, M.; Wacharasindhu, S.; Tabei, K.; Mansour, T.
S. J. Org. Chem. 2007, 72, 6016.
(14) (a) Johnson, J. R.; McEwen, W. L. Organic Syntheses; Wiley: New
York, 1941; Collect. Vol. I, p 521. (b) Snyder, H. R.; Brooks, L. A. Organic
Syntheses; Wiley: New York, 1943; Vol. II, p 171.
(15) Chang, M.; Hsu, R.; Tseng, T.; Sun, P.; Chang, N. Tetrahedron
2004, 60, 5545.
4608
Org. Lett., Vol. 9, No. 22, 2007

Scheme 2
Table 2. Formation of the R-Haloacroleins
We further expanded our investigations to the preparation
of R-haloacrylonitriles from their corresponding Vic-dihalo
precursors (Table 3). The reaction proceeded very smoothly
Table 3. Formation of the R-Haloacrylonitriles
unavailability and instability of the starting R,â-dibromo-
propionaldehyde, we tested the generality of the DMSO
procedure for the preparation of this class of compounds
starting from the bromination of the commercially available
acrolein and other aliphatic acrolein analogues and then
treated the crude dibromo intermediate with DMSO at 60
°C. Extraction of the reaction mixture with pentane after
addition of water provided the desired aldehydes. The two-
step consecutive operation is simple and gives the desired
R-bromoacrolein analogues in 85-95% yield (Table 2). The
resulting products were clean and could be used without
further purification.
For â-monosubstituted enals (entries 2, 3, and 4 of Table
2), the starting olefin favors the E-configuration. It was
confirmed by NMR that the R-brominated products have
Z-configuration after the consecutive bromination-dehydro-
bromination pathway. This reaction outcome indicates that
the original trans-relationship of the alkyl and the aldehyde
with respect to the double bond is retained. The mild reaction
conditions also allowed for the preparation of 2-bromo-3-
methylbutenal with high yield (entry 5 of Table 2). Synthesis
of this compound has been found to be difficult in the
literature, requiring a sophisticated procedure and resulting
in low yield.17
at 80 °C with excellent yields. When the reaction progress
was monitored by H NMR in DMSO-d6, a clean spectrum
1
was obtained showing only the conversion of the starting
material to product. Again, both dichloro and dibromo
precursors afforded the desired products. The Vic-dichloride
is less reactive than the corresponding bromide, similar to
the trend observed in Table 1. It was also observed that the
dehydrohalogenation was less stereoselective (entries 3 and
4 of Table 3) when there was a â-substitution. In these cases,
a mixture of E/Z isomers was obtained.
It should be pointed out that prior reports on the prepara-
tion of R-halo acrylonitriles were limited, featuring quite
involved procedures to avoid competing radical polymeri-
zation (reaction in the dark, addition of radical inhibitors).18
Polymerization was not detected in our DMSO-mediated
process.
The process here accomplished a net result of R-bromi-
nation of the acrylate analogues with retention of the original
olefin configuration as shown in Scheme 2.
Dehydrohalogenations are often accomplished in the
presence of base, which removes the acidic proton R to the
carbonyl to form a carbon anion followed by â-dehalo-
genation. Since there is no base used in the DMSO-mediated
dehydrohalogenations, the reaction may occur via a keto-
(16) (a) Baker, R. H.; Tinsley, S. W.; Butler, D., Jr.; Riegel, B. J. Am.
Chem. Soc. 1950, 72, 393. (b) Smith, A. B.; Levenberg, P. A.; Jerris, P. J.;
Scarborough, R. M.; Wovkulich, P. M. J. Am. Chem. Soc. 1981, 103, 1501.
(c) Barlow, A. J.; Compton B. J.; Weavers. R. T. J. Org. Chem. 2005, 70,
2470. (d) Nicolaou, K. C.; Brenzovich, W. E.; Bulger, P. G.; Francis, T.
M. Org. Biomol. Chem. 2006, 4, 2119.
(18) (a) Sainz-Diaz, C. I.; Galvez-Ruano, E.; Hernandez-Laguna, A.;
Bellanato, J. J. Org. Chem. 1995, 60, 74. (b) Jaehnisch, K.; Seeboth, H.
Zentralinst, J. Prakt. Chem. (Leipzig) 1981, 323, 26.
(17) Smithers, R. H. J. Org. Chem. 1983, 48, 2095.
Org. Lett., Vol. 9, No. 22, 2007
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enol tautomerization process, during which the â-halogen
atom is eliminated while the enol tautomerizes back to the
keto form. The unique solvent properties of DMSO19 favor
the tautomerization process.
In the presence of base, the R-haloacrylate products with
E-configuration have been obtained from dehydrohalogena-
tion, which are the result of kinetic conditions.20 Under the
base-free conditions in DMSO, the Z double bond config-
uration of the olefin products from the reaction appears to
be a reflection of the thermodynamic process. To confirm
the thermodynamic feature of the DMSO-mediated dehy-
drohalogenation, we monitored the formation of 2-bromobut-
2-enenitrile (entry 3 of Table 3) in DMSO-d6. The reaction
was complete within 1 h with a Z/E ratio of 1.00/0.77 in
favor of the Z isomer (Figure 1). The population of the Z
isomer increases to 1.00/0.60 with continuous heating at the
same temperature for 8 h. Further heating for 24 h at the
same temperature afforded a stable Z/E ratio of 1.00/0.47
(Figure 1).
Figure 1. E/Z isomerization of 2-bromobut-2-enenitrile.
In summary, a general and practical procedure for the
conversion of activated R,â-dihalo compounds to the cor-
responding R-halo acrylate derivatives has been developed,
and a variety of these R-halo Michael acceptors were
prepared conveniently under mild and nearly neutral condi-
tions. The DMSO used in the reaction serves as a reagent,
as well as a solvent. Although dehydrohalogenation of R,â-
dihalo compounds with other agents has been reported, the
DMSO procedure is the most facile and environmentally
benign process for such a transformation.
Acknowledgment. The authors wish to thank Wyeth
Research colleagues Dr. Tarek Mansour for valuable dis-
cussions and his encouragement, Dr. Steve Tam for support,
and Drs. Nathan Fuller and Paul Morgan for help.
Supporting Information Available: Typical experimen-
tal procedures for the preparation of R-haloacrylates with
supporting analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) Fieser, F. L.; Fieser, M. Reagents for Organic Synthesis; John Wiley
& Sons, Inc.: New York, 1967; Vol. 1, 296.
(20) Cromwell, N. H.; Cram, D. J.; Harris, C. E. Organic Syntheses;
Wiley: New York, 1965; Collect. Vol. III, p 125.
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