A novel and convenient protocol for synthesis of a-haloacrylates

Article abstract of DOI:10.1021/ol702859y

A novel and convenient protocol for synthesis of a-haloacrylates starting from phosphonium ylide and aldedyde or alcohol was described. Halodimethylsulfonium halide was used for the first time in halogenation of phosphonium ylide. Good yield as well as a

Full text of DOI:10.1021/ol702859y

ORGANIC
LETTERS
2008
Vol. 10, No. 4
593-596
A Novel and Convenient Protocol for
Synthesis of -Haloacrylates
r
Biao Jiang,* Ying Dou, Xiangya Xu, and Min Xu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 354 Fenglin Road, Shanghai 200032,
P. R. China
jiangb@mail.sioc.ac.cn
Received December 2, 2007
ABSTRACT
A novel and convenient protocol for synthesis of
r-haloacrylates starting from phosphonium ylide and aldedyde or alcohol was described.
Halodimethylsulfonium halide was used for the first time in halogenation of phosphonium ylide. Good yield as well as a high Z/E ratio were
shown in representative cases, and an umpolung dimethyl sulfide−ylide species might be involved as an intermediate.
R-Haloacrylates are important functional intermediates and
broadly used in the synthesis of polymers,1 biologically active
molecules,2 as well as natural products,3 especially when they
were explored as good substrates in transition metal-catalyzed
coupling reactions for synthesis of trisubstituted olefins.4
Among the variety synthetic methods developed for synthesis
of R-haloacrylates,5,6 Wittig reaction starting from R-halo-
phosphonium ylide and the corresponding aldehyde was still
one of the most mild and straightforward synthetic protocols.7
However, the methods for preparation of R-halophosphonium
ylide were quite limited,8 many of which suffered from the
use of hazardous9 or expensive halogenation reagents,10 harsh
reaction conditions,11 and unavoidable side reactions.12
(5) (a) Forti, L.; Ghelfi, F.; Pagnoni, U. M. Tetrahedron Lett. 1995, 36,
3023. (b) Kruper, W. J., Jr.; Emmons, A. H. J. Org. Chem. 1991, 56, 3323.
(c) Alami, M.; Crousse, B.; Linstrumelle, G. Tetrahedron Lett. 1995, 36,
3687. (d) Buschmann, E.; Schafer, B. Tetrahedron 1994, 50, 2433. (e) Satoh,
T.; Itoh, N.; Onda, K.; Kitoh, Y.; Yamakawa, K. Bull. Chem. Soc. Jpn.
1992, 65, 2800. (f) Ishihara, T.; Shintani, A.; Yamanaka, H. Tetrahedron
Lett. 1998, 39, 4865.
(6) For CrCl2- and Fe(0)-mediated olefination of aldehyde wth trihalo-
acetates, see: (a) Barma, D. K.; Kundu, A.; Zhang, H. M.; Mioskowski,
C.; Falck, J. R. J. Am. Chem. Soc. 2003, 125, 3218. (b) Falck, J. R.; Bejot,
R.; Barma, D. K.; Bandyopadhyay, A.; Joseph, S.; Mioskowski, C. J. Org.
Chem. 2006, 71, 8178.
(7) (a) Ohno, H.; Mizutani, T.; Kadoh, Y.; Aso, A.; Miyamura, K.; Fujii,
N.; Tanaka, T. J. Org. Chem. 2007, 72, 4378. (b) Humphrey, J. M.; Liao,
Y. S.; Ali, A.; Rein, T.; Wong, Y. L.; Chen, H. J.; Courtney, A. K.; Martin,
S. F. J. Am. Chem. Soc. 2002, 124, 8584. (c) Smith, A. B., III; Beauchamp,
T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y. P.; Arimoto, H.; Jones,
D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654. (d) Braun, N.
A.; Buerkle, U.; Feth, M. P.; Klein, I.; Spitzner, D. Eur. J. Org. Chem.
1998, 8, 1569. (e) Tago, K.; Kogen, H. Tetrahedron 2000, 56, 8825. (f)
Sano, S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998, 777.
(8) (a) Huang, Z. Z.; Yu, X. C.; Huang, X. J. Org. Chem. 2002, 67,
8261. (b) Scha¨fer, B. Tetrahedron 1993, 49, 1053.
(1) (a) Egen, M.; Voss, R.; Griesebock, B.; Zentel, R.; Romanov, S.;
Torres, C. S. Chem. Mater. 2003, 15, 3786. (b) Babu, G. N.; Narula, A.;
Hsu, S. L.; Chien, James, C. W. Macromolecules 1984, 17, 2749. (c) Marvel,
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Org. Chem. 2005, 70, 6746. (b) Mironiuk. P. E.; Kolaczkowska, E.; Sas,
W. Tetrahedron Lett. 2002, 43, 8351. (c) Franzen, R.; Kronberg, l.
Tetrahedron Lett. 1995, 36, 3905.
(3) (a) Lavilla, R.; Coll, O.; Bosch, J.; Orozco, M.; Luque, F. J. Eur. J.
Org. Chem. 2001, 3719. (b) Toyota, M.; Asano, T.; Ihara, M. Org. Lett.
2005, 7, 3929.
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Markl, G. Chem. Ber. 1961, 64, 2996.
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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.
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Am. Chem. Soc. 1984, 106, 6082. (b) Markl, G. Chem. Ber. 1962, 65, 3003.
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1315.
10.1021/ol702859y CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/23/2008

Recently, halodimethylsulfonium halide, particularly bro-
modimethylsulfonium bromide (BDMS),13 has been found
to be an effective halogenation reagent. For example,
regioselective R-monobromination of R-keto esters and 1,3-
diketones,14 p-bromination of phenol and anilines,15 and
bromination of alkylic alcohol.16 Moreover, chlorodimeth-
ylsulfonium chloride (CDMS) is not only a well-known
Swern oxidation intermediate for the preparation of aldehyde
or ketone from alcohol but also a highly selective chlorination
reagent for allylic and benzylic alcohol.17 However, since
the substrates scope is relatively limited, utilizations of
halodimethylsulfonium halide in halogenation are still needed
to be further explored. Herein, we reported a convenient
method for one-pot synthesis of R-haloacrylates from phos-
phonium ylide and alcohol or aldehyde, and the halodim-
ethylsulfonium halide was utilized as newly halogenation
reagent for in situ generation of R-halophosphonium ylide.
As part of our research program to develop new synthetic
methodologies, we discovered that benzaldehyde could be
easily converted into R-bromophenylacrylate in 88% yield
with high Z/E ratio (9/1) by treatment with a premixed
solution of phosphonium ylide, BDMS, and Et3N in dichlo-
romethane (Scheme 1). Moreover, it was found that excess
Table 1. One-Pot Synthesis of Methyl R-Bromoacrylates
Using BDMS
entry
R
product
yielda (%)
Z/Eb
1c
2
3
4
5
6
7
8
9
4-NO2Ph
2-Cl-4-Cl-Ph
4-F-Ph
4-OMe-Ph
3,4-OCH2O-Ph
2-naphthyl
2-pyridyl
2-thiophenyl
2-furyl
1b
1c
1d
1e
1f
1g
1h
1i
97
98
91
86
90
99
81
87
94
13:1
12:1
9:1
6:1
9:1
14:1
5:1
5:1
1j
8:1
a Isolated yield. b Determined by 1H NMR. c Reaction was accomplished
within 4 h
To investigate the reaction mechanism, methyl cinnamate
was treated directly with 2.5 equiv of BDMS and 8 equiv of
Et3N at -78 °C in dichloromethane. The mixture was stirred
at room temperature for 24 h. It was found that no
R-bromophenylacrylate was detected by NMR analysis of
the crude product, which ruled out the Wittig olefination-
bromation pathway18 and, in turn, strongly suggested that a
rapid generated R-bromoylide intermediate might be involved
in the process.
Scheme 1. One-Pot Synthesis of Methyl
R-Bromophenylacrylate Using BDMS
A plausible mechanism for generation of R-bromoylide
was shown in Scheme 2. At first, electrophilic attack on the
amount of BDMS was crucial for the transformation, for
example, when the amount of BDMS was decreased from
2.5 to 1.5 equiv, a mixture of R-bromophenylacrylate and
phenylacrylate was generated.
Scheme 2. Plausible Mechanism for Generation of
R-Bromoylide
Prompted by the above results, other aromatic aldehydes
were also investigated under identical conditions. As shown
in Table 1, R-bromoacrylates were generated from the
corresponding aldehyde in good yield as well as high Z/E
ratio. Aromatic substrates with electron-withdrawing groups
gave much better yield and shorter reaction time (Table 1,
entry 1).
(13) For other synthetic applications of BDMS, see: (a) Olah, G. A.;
Arvanaghi, M.; Vankar, Y. D. Synthesis 1979, 721. (b) Olah, G. A.; Vankar,
Y. D.; Arvanaghi, M.; Surya Prakash, G. K. Synthesis 1979, 720. (c) Chow,
Y. L.; Bakker, B. H. Synthesis 1982, 648.
(14) Khan, A. T.; Ali, M. A.; Goswami, P.; Choudhury, L. H. J. Org.
Chem. 2006, 71, 8961.
(15) (a) Olah, G. A.; Ohannesian, L.; Arvanaghi, M. Synthesis 1986,
868. (b) Langhlois, Y.; Pouilhes, A.; Genin, D.; Andriamialisoa, R. Z.;
Langlois, N. Tetrahedron 1983, 39, 3755. (c) Glemarec, C.; Wu, J. C.;
Remaud, G.; Bazin, H.; Olvanen, M.; Lonnberg, H.; Chattopadhyaya, J.
Tetrahedron 1988, 44, 1273. (d) Meyeri, G.; Keve, T. Synth. Commun.
1989, 19, 3415.
R-carbon of phosphonium ylide by cationic sulfur of BDMS
afforded the ylide-BDMS adduct A. With the assistnace of
base, dehydrobromination took place to deliver labile dim-
ethyl sulfide-ylide species B. The latter then served as
umpolung ylide8 and subsequently reacted with bromide
anion nucleophile to achieve the final R-bromophosphonium
ylide.
(16) (a) Urukawa, N.; Inoue, T.; Aida, T.; Oae, S. J. Chem. Soc., Chem.
Commun. 1973, 212. (b) Das, B.; Venkateswarlu, K.; Krishnaiah, M.; Holla,
H.; Majhi, A. HelV. Chim. Acta 2006, 89, 1417. (c) Kende, A. S.; Johnson,
S.; Sanfilippo, P.; Hodges, J. C.; Jungheim, L. N. J. Am. Chem. Soc. 1986,
108, 3513.
(17) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13,
4339.
In contrast with BDMS, synthetic application of chlo-
rodimethylsulfonium chloride (CDMS) as halogenation
(18) Chow mentioned that BDMS could brominate R,â-unsaturated
ketone, but for conjugated ester substrate, only sluggish addition happened.
See: Chow, Y. L.; Bakker, B. H. Can. J. Chem. 1982, 60, 2268.
594
Org. Lett., Vol. 10, No. 4, 2008

reagent was largely ignored, although selective chlorination
of allylic and benzylic alcohol was early discovered by
Corey.17 R-Chlorination of ketone by CDMS is also men-
tioned in the literature as a side reaction under typical Swern
oxidation conditions.19 Based on BDMS results, we then
turned our attention to investigate whether CDMS could be
utilized as a chlorination reagent for the transformation of
phosphonium ylide to chloroylide.
Likewise, benzaldehyde was employed as a model com-
pound, and CDMS was in situ generated by addition of oxalyl
chloride to a solution of DMSO in DCM at -78 °C. To our
delight, in a similar manner, the desired R-chloropheny-
lacrylate was obtained in 99% yield with a high Z/E ratio
(9/1), and only 1.5 equiv of CDMS was needed for the
transformation (Scheme 3). Notably, it is worth mentioning
nately, it was found that ketone failed to provide tetrasub-
stituted R-chloroacrylate under the same conditions.
Keeping in mind the fact that CDMS is a typical Swern
oxidation intermediate, in principle, it is possible to ac-
complish one-pot synthesis of R-chloroacrylate from alcohol.
Under such circumstances, the in situ generated CDMS
intermediate must serve as a bifunctional reagent, both as
chlorination reagent for transformation of phosphonium ylide
to R-chloro phosphonium ylide and as oxidation reagent for
conversion of alcohol to aldehyde.
As we expected, primary alcohol could be smoothly
transformed to R-chloroacrylate when the amount of CDMS
was increased to 2.5 equiv under similar conditions (Table
3).
Table 3. One-Pot Synthesis of R-Chloroacrylates from Primary
Alcohol under Swern Conditions
Scheme 3. One-pot Synthesis of Methyl
R-Chlorophenylacrylate under Swern Conditions
that the conversion could be achieved by simple sequential
addition of phosphonium ylide, Et3N, and benzaldehyde to
the solution of freshly prepared CDMS at -78 °C without
the need to prepare chloroylide in advance, and no competi-
tive phenylacrylate was detected.
Similarly, other aromatic aldehydes with either electron-
donating or -withdrawing groups underwent the desired
conversion (Table 2). Furthermore, aliphatic aldehyde could
Table 2. One-Pot Synthesis of Methyl R-Chloroacrylates under
Swern Conditions
entry
R
product
yielda (%)
Z/Eb
1
2
3
4
5
6
7
4-NO2Ph
2-Cl-4-Cl-Ph
4-Cl-Ph
3,4-OCH2O-Ph
2-naphthyl
2-furyl
2b
2c
2d
2e
2f
97
91
90
91
96
99
99
100:0
18:1
8:1
7:1
9:1
a Isolated yield. b Determined by GC. c Determined by 1H NMR. d Reac-
tion was accomplished within 4 h
2g
2h
100:0
11:1
A variety of benzylic alcohols provided the desired
R-chloroacrylates in excellent yield with good Z/E ratio; for
substrates bearing electron-withdrawing group, such as
4-nitrobenzylic alcohol, the reaction time was significantly
shortened to 4 h (Table 3, entry 5). Functional aliphatic
alcohol could also give satisfactory results (Table 3, entries
7-10). Although the synthetic protocol has some limitations,
for example, secondary alcohol could not give the corre-
sponding tetrasubstituted R-chloroacrylate, it provided a
useful alternative over conventional methods for the same
transformation, since our method can save at least two more
PhCH2CH2
a Isolated yield. b Determined by H NMR.
1
give excellent results as well (Table 2, entry 7). Unfortu-
(19) (a) Kuethe, J. T.; Wong, A.; Qu, C. X.; Smitrovich, J.; Davies, I.
W.; Hughes, D. L. J. Org. Chem. 2005, 70, 2555. (b) Wong, A.; Kuethe,
J. T.; Davies, I. W.; Hughes, D. L. J. Org. Chem. 2004, 69, 7761. (c) Beck,
B. J.; Aldrich, C. C.; Fecik, R. A.; Reynolds, K. A.; Sherman, D. H. J. Am.
Chem. Soc. 2003, 125, 12551. (d) Smith, A. B., III; Leenay, T. L.; Liu, H.
J.; Nelson, L. A. K.; Ball, R. G. Tetrahedron Lett. 1988, 29, 49.
Org. Lett., Vol. 10, No. 4, 2008
595

steps without the need to prepare aldehyde and chloroylide,
respectively.
Unlike CDMS, only 45% yield was obtained when BDMS
was used to perform the one-pot synthesis of R-bromoacry-
late starting from alcohol (Scheme 4), the results probably
involved in situ halogenation of phosphonium ylide by
halodimethylsulfonium halide, which opened a simple way
for rapid access to R-haloacrylates from aldehyde and
phosphonium ylide with Z-selectivity. In addition, primary
alcohol could be directly transformed to corresponding
R-chloroacrylate in one pot by treatment with CDMS and
phosphonium ylide, in which CDMS served both as chlo-
rination and oxidation reagent. An umpolung dimethyl
sulfide-ylide species might be involved in the process,
further studies on the mechanism of this reaction are currently
underway.
Scheme 4. Synthetic Attempt Using BDMS as Bifunctional
Reagent
Acknowledgment. This work was supported by the
Shanghai Municipal Committee of Science & Technology
and the National Natural Science Foundation of China.
due to the weaker oxidative property of BDMS.20
In conclusion, a novel and efficient method for synthesis
of R-haloacrylates was described. The synthetic protocol
Supporting Information Available: General experimen-
tal procedures for synthesis of R-chloroacrylate and R-bro-
moacrylate. Characterization data and 1H NMR and 13C NMR
spectra for products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) Only a few examples using BMDS as oxidative reagent. See: (a)
Palomo, C.; Ontoria, J. M.; Odriozola, J. M.; Alzpurua, J. M.; Ganboa, I.
Chem. Commun. 1990, 248. (b) Cossio, F. P.; Lopez, C.; Oiarbide, M.;
Palomo, C. Tetrahedron Lett. 1988, 29, 4339. (c) Olah, G. A.; Vankar, Y.
D.; Arvanaghi, M. Tetrahedron Lett. 1979, 20, 3653.
OL702859Y
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