Wittig reactions in water media employing stabilized ylides with aldehydes. Synthesis of α,β-unsaturated esters from mixing aldehydes, α-bromoesters, and Ph3P in aqueous NaHCO3

Article abstract of DOI:10.1021/jo070665k

(Chemical Equation Presented) Water is demonstrated to be an effective medium for the Wittig reaction over a wide range of stabilized ylides and aldehydes. Despite sometimes poor solubility of the reactants, good chemical yields normally ranging from 80 to 98% and high E-selectivities (up to 99%) are achieved, and the rate of the reactions in water is unexpectedly accelerated. The efficiency of water as a medium in the Wittig reaction is compared to conventional organic solvents ranging from carbon tetrachloride to methanol. The aqueous Wittig reaction works best when large hydrophobic entities are present, such as aromatic, heterocyclic aromatic carboxaldehydes, and long-chain aliphatic aldehydes with triphenylphosphoranes. The E/Z-isomeric ratio of the Wittig products appears dependent on the electron-accepting/donating capacity and the location of the substituents present in the aromatic ring. The effect of additives, such as benzoic acid, LiCl, and sodium dodecyl sulfate (SDS), on the Wittig reaction has been explored. The Wittig reaction can also be conducted in the presence of acidic entities, such as phenols and carboxylic acids. In addition, large α-substituents in the aliphatic aldehydes do not jeopardize the reaction. It is also demonstrated that hydrates of aldehydes can be used directly in the aqueous Wittig reaction as substrates. The scope of the aqueous Wittig reaction is extended to 24 examples of one-pot mixtures of Ph₃P, α-bromoesters, and aldehydes in sodium bicarbonate solution (at 20°C for 40 min to 3 h) to provide Wittig products of up to 99% yield and up to 98% E-selectivity. Since water is inexpensive, extremely easy to handle, and represents no environmental concerns, it should be considered a possible medium for new organic reactions.

Full text of DOI:10.1021/jo070665k

Wittig Reactions in Water Media Employing Stabilized Ylides with
Aldehydes. Synthesis of r,â-Unsaturated Esters from Mixing
Aldehydes, r-Bromoesters, and Ph3P in Aqueous NaHCO3
Amer El-Batta, Changchun Jiang, Wen Zhao, Robert Anness, Andrew L. Cooksy, and
Mikael Bergdahl*
Department of Chemistry and Biochemistry, San Diego State UniVersity,
San Diego, California 92182-1030
bergdahl@sciences.sdsu.edu
ReceiVed March 31, 2007
Water is demonstrated to be an effective medium for the Wittig reaction over a wide range of stabilized
ylides and aldehydes. Despite sometimes poor solubility of the reactants, good chemical yields normally
ranging from 80 to 98% and high E-selectivities (up to 99%) are achieved, and the rate of the reactions
in water is unexpectedly accelerated. The efficiency of water as a medium in the Wittig reaction is
compared to conventional organic solvents ranging from carbon tetrachloride to methanol. The aqueous
Wittig reaction works best when large hydrophobic entities are present, such as aromatic, heterocyclic
aromatic carboxaldehydes, and long-chain aliphatic aldehydes with triphenylphosphoranes. The E/Z-
isomeric ratio of the Wittig products appears dependent on the electron-accepting/donating capacity and
the location of the substituents present in the aromatic ring. The effect of additives, such as benzoic acid,
LiCl, and sodium dodecyl sulfate (SDS), on the Wittig reaction has been explored. The Wittig reaction
can also be conducted in the presence of acidic entities, such as phenols and carboxylic acids. In addition,
large R-substituents in the aliphatic aldehydes do not jeopardize the reaction. It is also demonstrated that
hydrates of aldehydes can be used directly in the aqueous Wittig reaction as substrates. The scope of the
aqueous Wittig reaction is extended to 24 examples of one-pot mixtures of Ph3P, R-bromoesters, and
aldehydes in sodium bicarbonate solution (at 20 °C for 40 min to 3 h) to provide Wittig products of up
to 99% yield and up to 98% E-selectivity. Since water is inexpensive, extremely easy to handle, and
represents no environmental concerns, it should be considered a possible medium for new organic reactions.
Introduction
ground-breaking discovery, however, it was not until recently
that the potential of water as a medium in organic reactions
has gained widespread focus.3 It is not entirely surprising that
little research has been conducted in this area during the
intervening years, given likely concerns over the reactant
solubility, impeding catalytic activity, and possible obstruction
of functional groups. Nonetheless, significant advances in recent
years3c have been made toward conducting organic reactions
A quarter of a century ago, Breslow1 and Grieco2 demon-
strated that hydrophobic interactions can have a considerable
effect on the rate of organic reactions in water. Despite this
* To whom correspondence should be addressed. Phone: (619) 594-5865.
Fax: (619) 594-4634.
(1) (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816-
7817. (b) Breslow, R.; Maitra, U.; Rideout, D. C. Tetrahedron Lett. 1983,
24, 1901-1904. (c) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25,
1239-1240.
(2) Grieco, P. A.; Garner, P.; He, Z. Tetrahedron Lett. 1983, 24, 1897-
1900.
(3) For recent reviews on organic reactions in water, see: (a) Lindstro¨m,
U. M.; Anderson, F. Angew. Chem., Int. Ed. 2006, 45, 548-551. (b) Li,
C.-J.; Chen, L. Chem. Soc. ReV. 2006, 35, 68-82. (c) Lindstro¨m, U. M.
Chem. ReV. 2002, 102, 2751-2772.
10.1021/jo070665k CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007
5244
J. Org. Chem. 2007, 72, 5244-5259

Wittig Reactions in Water Employing Ylides and Aldehydes
in water via the attraction between hydrophobic moieties of the
reactants.4
Various conditions have been reported to improve the Wittig
reaction, such as increasing temperature19 or pressure,20 using
additives,21 irradiation with microwaves22 or light,23 sonication,24
silica gel,18 ionic solvents,25 and recently neat water.13 A few
recent reports that described the influence of aqueous LiCl26a,b
and a surfactant27 have also appeared. The efficiency of the
aqueous LiCl/LiOH system using PPh3, R-bromoesters, and
aldehydes in Wittig reactions was also reported.26c Recent
advances also include generation of phosphorus ylides in solid-
state reactions by mixing phosphonium salts with anhydrous
K2CO3 and subsequent Wittig reaction in a solvent-free environ-
ment.28 In the synthesis toward stilbene type products, Aggarwal
et al. recently prepared a new class of semistabilized ylides from
phosphites, where these ylides displayed very high E/Z-
selectivity compared to that of the corresponding triphenylphos-
phonium derivatives conventionally used in Wittig reactions.29
Although water has been applied as a medium for Wittig
reactions employing elegantly modified water-soluble phospho-
nium salts,30,31 the application of water as the essential medium
for performing Wittig reactions utilizing poorly water-soluble
stabilized ylides is very limited. Herein we present an extension
of our initial report13 pertaining to the Wittig reaction employing
hydrophobic triphenylphosphoranes in water as the single
reaction medium.32 Specifically, we examined the relative rates
of the Wittig reactions in water compared to those conducted
in conventional organic solvents. Furthermore, the influence of
additives on the course of the Wittig reaction in water is
reported. We also present an extension of our work utilizing
the aqueous in situ preparation of ylides and their subsequent
In water, there is a strong association between hydrophobic
surfaces, and in addition, water excludes nonpolar functional
groups reducing the Gibbs energy of solvation. Due to this
“hydrophobic effect,”5 water not only increases the reaction rates
but also improves the selectivities of the Diels-Alder [4 + 2]
cycloaddition reaction even though the reactants are poorly
soluble in water. Considerable experimental and theoretical work
has been done to explain the mechanism behind this phenom-
enon. Several interpretations have been proposed, including the
hydrophobic association of the reactants,1a micellar catalysis,1b
solvophobicity,6 Lewis acid-like catalysis by enhanced hydrogen
bonding at the transition state,7 cohesive energy density,8 and
ground-state destabilization.9 In a recent paper, Sharpless
postulated the possibility of unique properties of the molecules
at the macroscopic phase boundary between water and insoluble
hydrophobic moieties in order to rationalize the “on water”
phenomenon.4 Besides the Diels-Alder cycloadditions,10 Clais-
en rearrangements,11 ene reactions,4 Claisen/Diels-Alder cy-
cloaddition,12 and recently Wittig reactions13 have been reported
to undergo rate increases in spite of the poor solubility of the
reactants when conducted in water media.
The Wittig reaction14 is a very important tool in synthetic
organic chemistry since it generates a carbon-carbon double
bond normally with a high level of regioselectivity.15 Despite
the long history of the Wittig reaction, it is still under intense
mechanistic investigation both by NMR spectroscopy16 and by
computational modeling.17 The geometrical Z-alkene product
is preferred for a nonstabilized ylide, while the E-alkene is
generally the main product when a stabilized ylide is employed.
Traditional olefination reaction conditions that provide an excess
of the E-alkenes include the use of a stabilized ylide and an
aldehyde often in solvents ranging from benzene or toluene to
DMF or DMSO. It has been recognized that Wittig reactions
employing stabilized ylides with aldehydes proceed more slowly,
especially in nonpolar solvents.18
(19) Fodor, G.; To¨mo¨sko¨zi, I. Tetrahedron Lett. 1961, 2, 579-582.
(20) (a) Nonnenmacher, A.; Mayer, R.; Plieninger, H. Liebigs Ann. Chem.
1983, 2135-2140. (b) Isaacs, N. S.; El-Din, G. N. Tetrahedron Lett. 1987,
28, 2191-2192.
(21) Lithium salts: (a) House, H. O.; Jones, V. K.; Frank, G. A. J. Org.
Chem. 1964, 29, 3327-3333. (b) Hooper, D. L.; Garagan, S.; Kayser, M.
M. J. Org. Chem. 1994, 59, 1126-1128. Benzoic acid: (c) Flisza´r, S.;
Hudson, R. F.; Salvadori, G. HelV. Chim. Acta 1964, 47, 159-162. (d)
Ru¨chardt, C.; Panse, P.; Eichler, S. Chem. Ber. 1967, 100, 1144-1164. (e)
Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.;
Samuelsson, B.; Hammarstro¨m, S. J. Am. Chem. Soc. 1980, 102, 1436-
1439. (f) Marriott, D. P.; Bantick, J. R. Tetrahedron Lett. 1981, 22, 3657-
3658. (g) Thiemann, T.; Thiemann, C.; Sasaki, S.; Vill, V.; Mataka, S.;
Tashiro, M. J. Chem. Res., Synop. 1997, 248-249. Phase transfer catalyst:
(h) Stafford, J. A.; McMurry, J. E. Tetrahedron Lett. 1988, 29, 2531-
2534. Cyclodextrins: (i) Westman, G.; Wennerstro¨m, O.; Raston, I.
Tetrahedron 1993, 49, 483-488.
(22) (a) Xu, C.; Chen, G.; Fu, C.; Huang, X. Synth. Commun. 1995, 25,
2229-2233. (b) Spinella, A.; Fortunati, T.; Soriente, A. Synlett 1997, 93-
94. (c) Wu, J.; Wu, H.; Wei, S.; Dai, W.-M. Tetrahedron Lett. 2004, 45,
4401-4404.
(23) Matikainen, J. K. Kaltia, S.; Hase, T. Synlett 1994, 817-818.
(24) Silveira, C. C.; Perin, G.; Braga, A. L. J. Chem. Res., Synop. 1994,
492-493.
(25) Boulaire, V. L.; Gre´e, R. Chem. Commun. 2000, 2195-2196.
(26) (a) Wu, J.; Li, D.; Zhang, D. Synth. Commun. 2005, 35, 2543-
2551. (b) Wu, J.; Zhang, D.; Wei, S. Synth. Commun. 2005, 35, 1213-
1222. (c) Wu, J.; Yue, C. Synth. Commun. 2006, 36, 2939-2947.
(27) Orsini, F.; Sello, G.; Fumagalli, T. Synlett 2006, 1717-1718.
(28) Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am.
Chem. Soc. 2002, 124, 6244-6245.
(29) Aggarwal, V. K.; Fulton, J. R.; Sheldon, C. G.; de Vicente, J. J.
Am. Chem. Soc. 2003, 125, 6034-6035.
(30) Russel, M. G.; Warren, S. J. Chem. Soc., Perkin Trans. 1 2000,
505-513.
(4) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275-3279.
(5) (a) Otto, S.; Engberts, J. B. F. N. Org. Biomol. Chem. 2003, 1, 2809-
2820. (b) Breslow, R.; Groves, K.; Mayer, M. U. Pure Appl. Chem. 1998,
70, 1933-1938. (c) Breslow, R. Acc. Chem. Res. 1991, 24, 159-164.
(6) Schneider, H.-J.; Sangwan, N. K. J. Chem. Soc., Chem. Commun.
1986, 1787-1789.
(7) Kelly, T. R.; Meghani, P.; Ekkundi, V. S. Tetrahedron Lett. 1990,
31, 3381-3384.
(8) Gajewski, J. J. J. Org. Chem. 1992, 57, 5500-5506.
(9) Blokzijl, W.; Engberts, J. B. F. N. Angew. Chem., Int. Ed. Engl. 1993,
32, 1545-1579.
(10) (a) Li, C.-J. Chem. ReV. 2005, 105, 3095-3165. (b) See also ref 3b
and references therein.
(11) Grieco, P. A.; Brandes, E. B.; McCann, S.; Clark, J. D. J. Org.
Chem. 1989, 54, 5849-5851.
(12) Nicolaou, K. C.; Xu, H.; Wartmann, M. Angew. Chem., Int. Ed.
2005, 44, 756-761.
(13) Dambacher, J.; Zhao, W.; El-Batta, A.; Anness, R.; Jiang, C.;
Bergdahl, M. Tetrahedron Lett. 2005, 46, 4473-4477.
(14) (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44-68.
(b) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318-1330. (c) Wittig,
G. Science 1980, 210, 600-604 and references herein.
(15) (a) Maerckar, A. Org. React. 1965, 14, 270-490. (b) Maryanoff,
B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927. (c) Kolodiazhnyi, O. I.
Phosphorus Ylides, Chemistry and Application in Organic Synthesis; Wiley-
VCH: Weinheim, Germany, 1999.
(31) Using phosphonates in Wittig-Horner reactions in aqueous media,
see: (a) Villieras, J.; Rambaud, M. Synthesis 1983, 300-303. (b) Rambaud,
M.; Vecchio, A.; Villieras, J. Synth. Commun. 1984, 14, 833-841. (c)
Villieras, J.; Rambaud, M.; Graff, M. Tetrahedron Lett. 1985, 26, 53-56.
(d) Mouloungui, Z.; Delmas, M.; Gaset, A. J. Org. Chem. 1989, 54, 3936-
3941.
(16) Bangerter, F.; Karpf, M.; Meier, L. A.; Rys, P.; Skrabal, P. J. Am.
Chem. Soc. 1998, 120, 10653-10659.
(17) Robiette, R.; Richardson, J.; Aggarwal, V. K.; Harvey, J. N. J. Am.
Chem. Soc. 2006, 128, 2394-2409.
(32) For an excellent review of water as an additive in various organic
reactions, see: Ribe, S.; Wipf, P. Chem. Commun. 2001, 299-307.
(18) Patil, V. J.; Ma¨vers, U. Tetrahedron Lett. 1996, 37, 1281-1284.
J. Org. Chem, Vol. 72, No. 14, 2007 5245

El-Batta et al.
SCHEME 1
the corresponding 2,2,2-trichloroethoxyphosphorane to give ester
3. The E/Z-isomeric ratios seem consistent with one another
even though these geometrical isomeric ratios are to some extent
lower than the ratios obtained when conducting the Wittig
reaction in conventional organic solvents.
Encouraged by the surprising impact of water as a medium
in these initial Wittig reactions employing the triphenylphos-
phoranes, we conducted a broader investigation of this reaction
by determining the yields and E/Z-ratios utilizing various
conventional organic solvents and comparing them to the same
reactions conducted in water (Table 1). We intentionally selected
two aldehydes that are known to give modest to low E/Z-ratios
(o-anisaldehyde and cinnamaldehyde) upon exposure to stabi-
lized ylides. Methoxycarbonylmethylenetriphenylphosphorane
was added to the aldehydes in 5 mL of the medium, and the
mixture was then vigorously stirred for either 1 or 2 h at 20
°C. In order to be able to measure the relative rate of the Wittig
reaction, the ylide was hydrolyzed using 1.0 M hydrochloric
acid to ensure that no Wittig product is formed during the
extraction with organic solvent. The E/Z-ratio was then deter-
mined for the crude material, and the yield and the mass balance
were calculated after isolation of product and starting material.
Although there are a few differences between o-anisaldehyde
and cinnamaldehyde, a general trend is that the Wittig reaction
is fastest in methanol and slowest in THF or acetonitrile. It is
also the case that the reactions in water, despite the low solubility
of the reagents, are faster than all the scrutinized organic solvents
except methanol. The faster the Wittig reaction proceeds, the
lower the E/Z-selectivity observed; hence water as a medium
gives somewhat lower E/Z-ratios than those obtained with
organic solvents.
Wittig reaction in water. Aside from the application of this work
to greener chemistry,33 these results contribute a valuable
methodology for carbon-carbon double bond construction in
water in synthetic organic chemistry.
Results and Discussion
Water is described as a “medium” rather than a “solvent” in
the following context34 since the reactants appear to be highly
insoluble during the course of the aqueous Wittig reactions.
Demonstrated herein is the Wittig reaction utilizing stabilized
ylides in water as a very efficient medium. Although the starting
materials and products appear to be poorly soluble in the
medium, the rate of the reaction is unexpectedly fast in water.
In a separate project, enoate 2 is an important fragment of one
specific target molecule. Conceivably, ester 2 could be obtained
from aldehyde 1 and an efficient carbon-carbon double
formation reaction. Indeed, compound 2 has previously been
synthesized from optically active aldehyde 1 in a Wittig reaction
conducted in either refluxing CH2Cl2 (70%, 4 weeks!)35 or
refluxing CH3CN (95%, 18 h).36 With these data at hand, we
examined the corresponding Horner-Wadsworth-Emmons
(HWE) reaction utilizing the corresponding phosphonate enolate
with aldehyde 1 in an aprotic solvent (Scheme 1). Although
this reaction provided a good yield (82%) of intermediate 2,
the reaction was detrimental to the γ-stereocenter which
epimerized completely. This result underscores the importance
of using less basic olefination reagents such as the corresponding
(Wittig) phosphorane in the synthesis of ester 2.
Additional Wittig reactions in water were then studied in order
to determine the efficacy of this novel reaction system employ-
ing various phosphoranes and aldehydes. Excellent yields (up
to 98%) and very high E/Z-isomeric ratios (up to 99:1) of the
olefination products were obtained, particularly when aromatic
carboxaldehydes were utilized (Table 2).
Water is used as a medium in the formation of products 7-10
in high yields (20 °C, 1 h). Particularly, water as a medium is
noticeable in the formation of chalcone (6, entry 1) since
benzaldehyde has been reported to undergo the same Wittig
transformation in refluxing benzene for 3 days (entry 2).39
Methoxycarbonylmethylenetriphenylphosphorane undergoes a
rapid Wittig reaction with benzaldehyde in water at ambient
temperature to form a high yield of methyl cinnamate (7) in 60
min (entry 3). As a notable comparison, when substituting water
as a medium with MeOH to provide homogeneous reaction
conditions, a complete conversion of benzaldehyde to product
is obtained, but the E/Z-ratio is significantly depleted to 3:1 for
cinnamate 7. On the other hand, a considerably higher E/Z-
ratio is obtained when employing water as a medium. Consis-
tently high yields and E/Z-ratios of the Wittig reactions are
obtained in water with various phosphoranes (entries 4-6). As
a comparison between the efficiency of water and ionic liquids
in conducting Wittig reactions, benzalacetone (10) has been
obtained in more or less the same yield and E/Z-ratio either in
1.0 M solution of [Bmim][BF4]25 at 60 °C (2.5 h) or (as
described herein) using water at 20 °C (1 h) (entry 6). Even
though the aqueous Wittig reaction appears heterogeneous, these
Inspired by the reports by Breslow,1 Grieco,11 and the recent
work of Sharpless4,37 and Nicolaou12 investigating aqueous
organic transformations, we tested the Wittig reaction in water.
Even though the substrate (1), reagents, and products seem
insoluble during the course of the reaction in water, the isolated
yield of esters 2 and 3 were good (67-73%) and no epimer-
ization occurred at the γ-stereocenter. These rapidly stirred or
shaken reactions could be conducted in capped drum vials (20
mL) either for a shorter time at 90 °C utilizing 1.8 equiv of the
phosphorane38 or for a longer time at 20 °C using 1.5 equiv of
(33) (a) Tucker, J. L. Org. Process Res. DeV. 2006, 10, 315-319. (b)
Clark, J. H.; Tavener, S. Org. Process Res. DeV. 2007, 11, 149-155.
(34) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry,
3rd ed.; Wiley-VCH: Weinheim, Germany, 2003.
(35) Kazmierczak, F.; Helquist, P. J. Org. Chem. 1989, 54, 3988-3992.
(36) Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116,
1753-1765.
(37) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021. (b) Demko, Z. P.; Sharpless, K. B. J. Org. Chem.
2001, 66, 7945-7950. (c) See also: van Mersbergen, D.; Wijnen, J. W.;
Engberts, J. B. F. N. J. Org. Chem. 1998, 63, 8801-8805.
(38) Presumably the ylide is slowly hydrolyzed by water; see: Bestmann,
H. J.; Arnason, B. Chem. Ber. 1962, 95, 1513-1527.
(39) Bestmann, H. J.; Arnason, B. Chem. Ber. 1962, 95, 1513-1527.
5246 J. Org. Chem., Vol. 72, No. 14, 2007

Wittig Reactions in Water Employing Ylides and Aldehydes
TABLE 1. Rate Study of the Wittig Reaction in Different Mediaa
a The reactions were conducted on a 1 mmol scale in 5 mL of medium. b 5 mL of 1.0 M HCl(aq) was added after the time indicated. c Isolated product
1
yield and recovered aldehyde in parenthesis. d Determined using H NMR of crude reaction mixtures.
initial results demonstrate that water is a very useful component
for facilitating the olefination process and does not jeopardize
the E/Z-selectivity of the resulting alkenes (6-10).
Also, in water, we observed that p-anisaldehyde reacts slowly
with ylides (even though p-anisaldehyde is a liquid at 20 °C)
to give 66% yield of product 15 after 4 h at 20 °C. At the same
time, heating the same reaction to 90 °C for 30 min increased
the yield of 15 to 90% without affecting the E/Z-ratio (entry
13). The effect of electron-donating groups has been previously
reported to reduce the rate of the Wittig reaction in MeOH.40
The efficiency of water as a reaction medium compared to
organic solvents is evident in view of the fact that this Wittig
reaction has been reported utilizing p-anisaldehyde and the same
ylide in refluxing CH2Cl2 (4 h, 8%),20a in refluxing benzene (2
days, 73%),20a or in an ionic liquid at 60 °C (3 days, 82%)25
(entries 13-15). As a comparison, the Wittig reaction conducted
in water using the corresponding 3,4-methylenedioxybenzalde-
hyde or 3,4-dimethoxybenzaldehyde gives cinnamates 19 and
The Wittig reaction in water is a straightforward protocol
that works favorably between various ylides and countless types
of aromatic carboxaldehydes having either electron-donating or
electron-withdrawing groups present. In general, it is noticed
that even though the solid aldehydes are rapidly stirred or
vigorously mixed in water they seem to form aggregates which
react more slowly with the phosphoranes in comparison to the
readily dispersed liquid aldehydes in water. Therefore, distribut-
ing the aldehyde molecules more readily in water by applying
heat is also an effective way of increasing the rate and the yield
of the aqueous Wittig reactions. Conceivably, the rate of the
hydrolysis of the phosphorus ylides with water is slower than
the reaction between ylides and aldehydes. An elevated reaction
temperature when using solid aldehydes such as p-nitro- (entry
8), p-cyano- (entry 10), or p-bromobenzaldehyde (entry 11)
provides high yields of the corresponding products.
(40) (a) Goetz, H.; Nerdel, F.; Michaelis, H. Naturwissenschaften 1963,
50, 496-497. (b) Vicente, J.; Chicote, M. T.; Ferna´ndez-Baeza, J.;
Ferna´ndez-Baeza, A. New J. Chem. 1994, 18, 263-268.
J. Org. Chem, Vol. 72, No. 14, 2007 5247

El-Batta et al.
TABLE 2. Wittig Reactions of Various Aromatic Aldehydes and Stabilized Ylides in Watera
a The reactions were conducted on a 1 mmol scale in 5 mL of deionized water. b Isolated purified material. c Crude reaction mixtures analyzed by 500
MHz 1H NMR. d Reflux PhH, 3 days.39 e [Bmim][BF4], 60 °C, 2.5 h.25 f Reflux PhH, 12 h.41 g MeOH, 30 °C, 3 h.40a h 4 h at 20 °C gave 66% 15
(E/Z-ratio: 92:8). i Reflux CH2Cl2, 4 h.20a j [Bmim][BF4], 60 °C, 72 h.25 k MeOH, 20 °C, 3 h. l Reflux THF, 12 h.43 A ) 1.2 equiv of ylide, 20 °C; B )
1.5 equiv of ylide, 90 °C; C ) 1.2 equiv of ylide, 90 °C; D ) 1.5 equiv of ylide, 20 °C; Trce ) 2,2,2-trichloroethoxy.
22 in outstanding chemical yields and excellent E/Z-ratios after
1 h at 90 °C (entries 22 and 25). It is also worth noting that
strong electron-donating groups (e.g., amines) can be present,
hence the slowly reacting p-Me2N-substituted benzaldehyde does
not react with the ylide in water at 20 °C, but after 2 h at 90
°C, it affords product 17 in 81% yield (entry 18). However,
when conducting this reaction in MeOH, this alternative
procedure provides 78% of 17 at 20 °C after 5 h, but the E/Z-
ratio is significantly diminished to 3:1 (entry 19). This lowering
of E/Z-ratios appears to be a common effect of applying MeOH
as a solvent. In addition, the corresponding reaction in CH2Cl2
(reflux 4 h)20a has been reported to be fruitless (entry 20), which
again underscores the impact of water over CH2Cl2. It is also
interesting that the Wittig reaction in water works well with
substrates having acidic unprotected functional groups present;
hence the presence of a carboxylic acid group (vide infra) or
phenolic groups, such as p-hydroxybenzaldehyde, gives the
corresponding cinnamate product 16 in 92% after heating the
reaction for 1 h at 90 °C (entry 16). In sharp contrast, the same
reaction in refluxing CH2Cl2 (4 h)20a has been reported to
provide only 8% of 16.
The presence of electron-withdrawing groups in the aromatic
ring increases the rates of the Wittig reaction in water. At
present, we are unable to draw a wider general conclusion
regarding the electronic contribution of these substituents being
responsible for the rate of the reaction. The aqueous Wittig
reactions utilizing the pentafluorobenzaldehyde (entry 23) or
the o-chlorobenzaldehyde (entry 28) are complete in less than
5 min at 20 °C. The E/Z-ratio of product 20 was very high (99:
1) compared to the lower E/Z-ratio observed for 24 (81:19)
utilizing o-chlorobenzaldehyde. In contrast, solid aldehydes, such
as the 4-chloro-3-fluorobenzaldehyde (entry 24) or the 2-ni-
trobenzaldehyde (entry 27), require longer reaction time for
completion in water. The observed E/Z-ratios of the products
are generally slightly lower when utilizing some of the ortho-
substituted benzaldehydes. Though the evident ortho-substituted
5248 J. Org. Chem., Vol. 72, No. 14, 2007

Wittig Reactions in Water Employing Ylides and Aldehydes
TABLE 3. Wittig Reactions of Various Aldehydes and Stabilized Ylides in Watera
a The reactions were conducted on a 1 mmol scale in 5 mL of deionized water. b Isolated purified material. c Crude reaction mixtures analyzed by 500
i
MHz 1H NMR. d [Bmim][BF 4], 60 °C, 12 h.25 e Reflux THF, 12 h.46 f Reflux PhMe, 4 h.47 g Reflux PhH, 19 h.44 h Reflux CH2Cl2, 4 h.45 E/Z-ratio is
sensitive to the silica gel (purification) applied; SiO2 column gave ∼50% (E/Z ) 99:1). A ) 1.0-1.2 equiv of ylide, 20 °C; B ) 1.5 equiv of ylide, 20 °C;
C ) 1.5 equiv of ylide, 90 °C; TIPS ) triisopropylsilyl.
steric effect appears to be one factor of influence, electronic
effects should not be ruled out as shown below. For example,
it is interesting that o-nitrobenzaldehyde (entry 27) and p-
nitrobenzaldehyde (entry 9) gave roughly the same E/Z-ratios.42
We also note that when relatively sizable electron-donating
ortho-substituents are present, such as with the o-benzyloxy-
or the o-methoxy-substituted benzaldehydes, a quite low E/Z-
ratio is observed for the products (4, 25) obtained in the aqueous
Wittig reaction. In significant contrast, the o-methyl-substituted
carboxaldehydes provide E/Z-ratios of up to 94:6 and good
yields of up to 92% of 26 and 27. In this case, it appears as if
the methyl groups have no influence on the isomeric ratio of
the products (entry 3 vs entry 31). Naphthalene-2-carboxalde-
hyde reacts nicely with the ylide in water giving 98% of ester
28 after applying heat for 30 min. Ester 28 has also been
prepared via the same Wittig reaction in refluxing THF, but
required 12 h.43
In sharp contrast to the preceding examples that employed
common aromatic carboxaldehydes, the solid heterocyclic
aromatic aldehydes required heat in order to produce acceptable
yields of the products when conducting Wittig reactions in water.
Thus, pyrrole-, quinoline-, and pyridinecarboxaldehydes do not
pose any problem and provide high yields and for the most part
excellent E/Z-ratios of the corresponding products (33-36). The
E/Z-ratio was modest employing 3-pyridinecarboxaldehyde
(entry 9) but was exceptional when using 2- or 4-quinolinecar-
boxaldehyde (entries 6 and 7). Both of these aldehydes react
nicely with the ylides in water giving 89% of ketone 34 and
92% of ester 35 after applying heat. As a comparison to the
Wittig reactions in water, esters 35 and 36 have been synthesized
in refluxing benzene for 19 h44 or refluxing CH2Cl2 for 4 h,45
respectively (entries 8 and 10).
The Wittig reaction in water is also applicable to aliphatic
aldehydes (entries 11-17) where high yields of the correspond-
ing R,â-unsaturated methyl-, tert-butyl-, and 2,2,2-trichloroethyl
ester (3) are obtained by utilizing various ylides. The yields of
products 37-39 increase as the alkyl chain for the aliphatic
aldehyde is extended. In contrast, the smaller aliphatic aldehydes
produce low yields of the olefination product when the Wittig
Extending our study to heterocyclic aromatic aldehydes (Table
3), we find that the liquid thiophenecarboxaldehydes (entries
1-3) react without difficulty with the phosphoranes in water
at 20 °C.
(41) Nam, N.-H.; You, Y.-J.; Kim, Y.; Hong, D.-H.; Kim, H.-M.; Ahn,
B. Z. Bioorg. Med. Chem. Lett. 2001, 11, 1173-1176.
(42) See also Table 4.
(43) Hamilton, G. S.; Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.;
Vaal, M. J.; Li, J.-H.; Thomas, C.; Huang, W.; Sauer, H.; Ross, D. T.;
Soni, R.; Chen, Y.; Guo, H.; Howorth, P.; Valentine, H.; Liang, S.; Spicer,
D.; Fuller, M.; Steiner, J. P. J. Med. Chem. 2002, 45, 3549-3557.
(44) Rodriguez, J. G.; Benito, Y. J. Heterocycl. Chem. 1988, 25, 819-
821.
(45) Agarwal, K. C.; Knaus, E. E. J. Heterocycl. Chem. 1985, 22, 65-
69.
J. Org. Chem, Vol. 72, No. 14, 2007 5249

El-Batta et al.
TABLE 4. Influence of Additives on the Wittig Reactions
SCHEME 2
Conducted in Watera
reactions were conducted in water.48 Smaller aldehydes have a
greater propensity to form hydrates with water, and as a
consequence, they could be less prone to undergo the aqueous
Wittig reaction. The same argument might explain the challenges
employing smaller aliphatic R-substituted aldehydes. When
applying relatively large R-branched aliphatic aldehydes, the
yields of the Wittig products formed in water are again high.
Although the aqueous Wittig reactions generally proceed more
slowly when employing R-substituted aldehydes (Scheme 1),
it is still possible to obtain high yields of product if the aldehydes
are exposed to the ylides for a longer duration or elevated
reaction temperature. For example, the very bulky R-OTIPS-
substituted 3-butenealdehyde49 (entry 17) gives high yields and
E/Z-ratios of the Wittig products formed in water after heating
the reaction at 90 °C for 2 h.
Glyoxylic acid undergoes a rapid Wittig reaction in water at
20 °C (entry 21), which is unexpected given that the aldehyde
exists mainly as a hydrate in water (∼99%).50 When following
the Wittig reaction in D2O at 20 °C (Scheme 2) using NMR,
the methine signal of the hydrate of glyoxylic acid (δCH ) 5.2
ppm) slowly disappears in the presence of the ylide. The Wittig
product (42) is then formed along with triphenylphosphine oxide,
which makes the reaction more heterogeneous over time. NMR
analysis confirmed the formation of the product, as well as the
resultant incorporation of deuterium (D/H ∼ 10/1) at the
R-olefinic carbon of ester 42. In a separate experiment, it was
confirmed that the proton/deuterium exchange can easily occur
if there is a significant concentration of D2O. The incorporation
of the deuterium at the R-carbon is due to the basicity of the
ylide prior the Wittig reaction. These results show that, even if
the aldehyde molecule is masked as its hydrate, the Wittig
product is still obtained.
Carrying out the Wittig reaction with glyoxylic acid unfor-
tunately creates problems with the workup procedure. Specif-
ically, it is a challenge to isolate and purify the major
geometrical isomer of mono-tert-butyl fumarate (42). The
isolated yield typically is around 50%, although the chemical
yield of the reaction is much higher.51 Isolation and purification
of product 42 on a 1.2-1.5 mmol scale from triphenylphosphine
oxide was best conducted using a short silica gel column.
Moreover, the trans-42 isomer is sensitive to acid-base
extraction and partially isomerizes to the corresponding cis-42
isomer (mono-tert-butyl maleate).
a The reactions were conducted on a 1 mmol scale in 5 mL of deionized
water. b Isolated purified material. c Crude reaction mixtures analyzed by
500 MHz 1H NMR. d 10 mol % vs aldehyde. e Sodium dodecyl sulfate, 30
mol %.
Several variations on the reaction conditions of the Wittig
reaction have appeared in efforts to improve the reaction
outcome.19-25 In light of the fact that additives such as lithium
halides21a,b or benzoic acid21c-g and recently aqueous LiCl26 and
a surfactant27 have been reported to improve the yield and E/Z-
ratios in Wittig reactions, we investigated the influence of those
additives on Wittig reactions conducted in water (Table 4).
Aldehydes 43 and 45 were exposed to ylides I and II in neat
water at 20 °C. Even though the Wittig reactions are incomplete
after 2 h, they provide decent yields (up to 77%) and E/Z-ratios
(up to 94:6) of 44 and 12. Since the solid aldehyde (45) reacts
more slowly with ylides in neat water, heat was applied to the
system and the yield increased accordingly (entry 9). Heating
these reactions increases the yield of product but does not
necessarily decrease the E/Z-ratio significantly. The presence
of 5% DMSO as an additive increases the yield of the Wittig
reactions in water, presumably due to the increased dispersion
in the medium. Although DMSO dissolves aldehyde 45, it does
not improve the E/Z-ratio (entry 8). In contrast, water signifi-
cantly influences the E/Z-ratio of product 12 (entry 7). The
presence of either aqueous lithium chloride or benzoic acid
influences the aqueous Wittig reaction. For example, using 10
mol % of benzoic acid relative to the aldehyde increases the
yield and the E/Z-ratio of 44 (entry 4) and 12 (entry 10). The
presence of LiCl (10 mol %) has a positive effect on the yield
of the aqueous Wittig reactions (entries 5 and 11) but a minor
influence on the E/Z-ratio. It is conceivable that LiCl has a
(46) Kandula, S. R. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 6149-
6151.
(47) Ramage, R.; Griffiths, G. J.; Shutt, F. E. J. Chem. Soc., Perkin Trans.
1 1984, 1531-1537.
(48) Additional aldehydes scrutinized in water (yield %): pivaldehyde
(0), formaldehyde (0), isobutyraldehyde (40), and cyclohexanecarboxalde-
hyde (24).
(49) For preparation of 2-hydroxy-3-butenoic acid methyl ester, see:
Stach, H.; Huggenberg, W.; Hesse, M. HelV. Chim. Acta 1987, 70, 369-
374. TIPS protection of the alcohol (81%) and subsequent DIBAL-H
reduction in CH2Cl2 (90%) gave the desired aldehyde in 44% overall yield
(four steps).
(50) According to NMR analysis, see also: The Aldrich Library of 13C
1
and H NMR Spectra 1993, 1, 822.
(51) The reaction has previously been reported in 74% yield; see ref 13.
5250 J. Org. Chem., Vol. 72, No. 14, 2007

Wittig Reactions in Water Employing Ylides and Aldehydes
TABLE 5. Wittig Reactions Using Ph3P and r-Bromoesters in
Aqueous NaHCO3
Based on the concept of preparing phosphoranes in situ during
the Wittig process, we extended our work by simply mixing
Ph3P, R-bromoesters, saturated NaHCO3, and aldehydes using
water as the only medium. Based on the previous LiCl/LiOH
combination for Wittig reactions,26c we now report the use of a
saturated aqueous NaHCO3 solution to achieve the aqueous one-
pot Wittig reactions at +20 °C using Ph3P, R-bromoesters, and
aromatic carboxaldehydes (Table 5).
Triphenylphosphine (1.4-1.5 equiv), the appropriate R-bro-
moester (1.6-1.8 equiv), and aldehyde were charged to a
saturated aqueous NaHCO3 solution, and the mixture was stirred
or shaken for 1-3 h at 20 °C. After adjusting the pH to ∼5.5
using sulfuric acid, isolation, purification, and characterization
of the Wittig products were conducted (Table 5). The yields of
product obtained from the in situ preparation of the ylides are
generally excellent (82-99%), and the E/Z-ratios are for the
most part very good (up to 99:1). Although these Wittig
reactions do not require heating, the results obtained generally
follow the results obtained using the phosphorus ylides in water
previously presented (Tables 2 and 3). Hence the electron-
donating, electron-withdrawing groups, and the location of the
substituents in the ring influence the E/Z-ratio. The normally
less reactive p-anisaldehyde (entry 7) and the m-benzyloxyben-
zaldehyde (entry 9) react fast in the aqueous basic media.
Similarly, the o-benzyloxybenzaldehyde (entry 12) did not
require heating and gave a decrease in the E/Z-ratio, as noted
earlier for the phosphorus ylides (Table 2). Likewise, the
o-substituted tolylaldehydes (entries 11 and 13) generated an
increased E/Z-ratio under basic reaction conditions similar to
the results obtained using phosphorus ylides with aldehydes in
water. With the observation of the nucleophilic nitrogen
substituting the bromide on the R-bromoester, it is not entirely
surprising that the p-Me2N-substituted benzaldehyde gave a low
yield during the basic aqueous Wittig reaction (entry 3).
Several models have been proposed to explain the observed
E/Z-product ratio and the selectivity of the Wittig reaction
depending on what types of ylides are employed.52 The model
which best accounts for the experimental results was developed
by Vedejs et al.53 Along with the overwhelming corroboration
for the formation of the oxaphosphetane intermediates,52b,54 this
model53a is based on extensive practical experimentation and
on computational methodology to simulate the Wittig reaction
process. Very recently, however, Aggarwal and Harvey17
reported calculations of the transition state for the salt-free Wittig
reaction of stabilized ylides. Their model explains the high
(52) (a) Schlosser, M.; Schaub, B. J. Am. Chem. Soc. 1982, 104, 5821-
5823. (b) Mari, F.; Lahti, P. M.; McEwen, W. E. J. Am. Chem. Soc. 1992,
114, 813-821.
a The reactions were conducted on a 1 mmol scale using saturated
NaHCO3 (5 mL), 1.4-1.5 equiv of PPh3, and 1.6-1.8 equiv of R-bro-
moester. b Isolated purified material. c Crude reaction mixtures analyzed by
1H NMR. d Reaction conducted at 90 °C.
(53) (a) Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1-157.
(b) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1988, 110, 3948-3958. (c)
Vedejs, E.; Fleck, T.; Hara, S. J. Org. Chem. 1987, 52, 4637-4639.
(54) (a) Trindle, C.; Hwang, J.-T.; Carey, F. A. J. Org. Chem. 1973, 38,
2664-2669. (b) Ho¨ller, R.; Lischka, H. J. Am. Chem. Soc. 1980, 102, 4632-
4635. (c) Rose, I. A. J. Am. Chem. Soc. 1984, 106, 6117-6119. (d) Volatron,
F.; Eisenstein, O. J. Am. Chem. Soc. 1987, 109, 1-14. (e) Rzepa, H. S. J.
Chem. Soc., Perkin Trans. 2 1989, 12, 2115-2119. (f) Mari, F.; Lahti, P.
K.; McEwen, W. E. Heteroat. Chem. 1991, 2, 265-276. (g) Naito, T.;
Nagase, S.; Yamataka, H. J. Am. Chem. Soc. 1994, 116, 10080-10088.
(h) Restrepo-Cossio, A. A.; Cano, H.; Mari, F.; Gonzalez, C. A. Heteroat.
Chem. 1997, 8, 557-569. (i) Restrepo-Cossio, A. A.; Gonzalez, C. A.; Mari,
F. J. Phys. Chem. A 1998, 102, 6993-7000. (j) Lu, W. C.; Wong, N. B.;
Zhang, R. Q. Theor. Chem. Acc. 2002, 107, 206-210. (k) Seth, M.; Senn,
H. M.; Ziegler, T. J. Phys. Chem. A 2005, 109, 5136-5143.
stabilizing effect on the phosphoranes thus preventing the ylide
from reacting with water.26a
The use of surfactants employing a n-Bu3P/SDS mixture has
been reported to slightly increase the yield in Wittig reactions,27
but SDS was not observed to influence the yield for the aqueous
reactions using either of the triphenylphosphoranes (entries 6
and 12). It is possible that SDS enhances separation of the ylide
from the aldehyde, similar to an effect of an organic solvent,
acting against the “hydrophobic repellent” effect of the water.
J. Org. Chem, Vol. 72, No. 14, 2007 5251

El-Batta et al.
organic layers were dried over MgSO4. After removal of the solvent,
the crude material was dried and the E/Z-ratio was determined using
1H NMR spectroscopy. The crude product was subsequently purified
using chromatography on a silica gel column. The crude material
was purified by flash chromatography employing silica gel 60 Å.
The yield was determined on >98% pure products.
Typical Procedure for Wittig Reactions in Aqueous Sodium
Bicarbonate Using Aldehydes, R-Bromoesters, and Triph-
enylphosphine. Preparation of Compounds 46-67. A 20 mL
scintillation vial, fitted with a magnetic stir bar, was charged with
triphenylphosphine (1.4-1.5 mmol), saturated aqueous NaHCO3
(5.0 mL), appropriate R-bromoester (1.6-1.8 mmol), and aldehyde
(1.0 mmol). The vial was capped, and the content was stirred,
alternatively shaken, for 1-4 h, and the pH was adjusted to ∼5.5
using sulfuric acid (1.0 M). Isolation, purification, and characteriza-
tion of the Wittig product were conducted as indicated above.
5(R)-(tert-Butyldimethylsilyloxy)-4(R),6-dimethyl-2(E)-hep-
tenoic acid methyl ester (2).35 2 was obtained from a Wittig
reaction between aldehyde 135 (0.307 mmol, 75 mg) and (meth-
oxycarbonylmethylene)triphenylphosphorane (0.553 mmol, 184 mg)
in water (3 mL) at 90 °C for 2 h. The crude product was purified
using flash chromatography (2.5% Et2O/pentane, Rf 0.30) to give
67% (62 mg) of 2 as a clear oil (E/Z-ratio: 87/13): 1H NMR (500
MHz, CDCl3) δ 7.00 (dd, CHâdCHR, J ) 15.8, 7.8 Hz, 1H), 5.79
(dd, CHâdCHR, J ) 15.8, 1.3 Hz, 1H), 3.73 (s, OCH3, 3H), 3.38
(dd, OCH, J ) 4.8 Hz, 1H), 2.51 (m, CH-CHdCH, 1H), 1.72 (m,
CH(CH3)2, 3H), 1.05 (d, CH3-CH, J ) 6.7 Hz, 3H), 0.91 (s, (CH3)3-
Si, 9H), 0.89 (d, CH3-CH, J ) 6.8 Hz, 3H), 0.85 (d, CH3-CH, J
) 6.7 Hz, 3H), 0.05, 0.03 (2s, CH3-Si, 3H each); 13C NMR (125
MHz, CDCl3) δ 167.2, 153.3, 119.7, 80.1, 51.4, 41.0, 32.0, 26.1,
20.3, 18.4, 17.6, 15.1, -3.7, -3.8; FTIR (film, cm-1) 1728, 1254,
1055. HRMS (EI, DCI/NH3) calcd for [C16H33O3Si]+ 301.2199,
found 301.2197.
5(R)-(tert-Butyldimethylsilyloxy)-4(R),6-dimethyl-2(E)-hep-
tenoic acid 2′,2′,2′-trichloroethyl ester (3). 3 was obtained from
a Wittig reaction between aldehyde 135 (0.615 mmol, 150 mg) and
(2,2,2-trichloroethoxycarbonylmethylene)triphenylphosphorane57
(0.992 mmol, 416 mg) in water (5.0 mL) at 20 °C for 18 h. The
crude product was purified using flash chromatography (2.5% Et2O/
pentane, Rf 0.40) to give 73% (189 mg) of 3 as a clear oil (E/Z-
ratio: 85/15): 1H NMR (500 MHz, CDCl3) δ 7.22 (dd, CHâd
CHR, J ) 15.9, 7.3 Hz, 1H), 5.89 (dd, CHâdCHR, J ) 15.9, 1.2
Hz, 1H), 4.82 (d, OCH2, J ) 12.0 Hz, 1H), 4.79 (d, OCH2, J )
12.0 Hz, 1H), 3.44 (dd, OCH, J ) 4.8, 4.8 Hz, 1H), 2.58 (m,
CHCH3, 1H), 1.75 (m, CH(CH3)2, 1H), 1.09 (d, CH3-CH, J ) 6.7
Hz, 3H), 0.92 (s, (CH3)3Si, 9H), 0.91 (d, CH3-CH “partly hidden”,
J ) 6.8 Hz, 3H), 0.86 (d, CH3-CH, J ) 6.8 Hz, 3H), 0.06, 0.05
(2s, CH3-Si, 3H each); 13C NMR (125 MHz, CDCl3) δ 164.8,
156.0, 118.5, 79.9, 74.0, 41.2, 31.9, 26.2, 26.1, 20.4, 18.4, 17.8,
14.4, -3.7, -3.9; FTIR (film, cm-1) 1738, 1650, 1253, 838; MS
m/z 419 (M + 2, 2%), 417 (M+, 4%), 401 (35%), 359 (100%),
287 (30%), 187 (85%).
FIGURE 1. TS models to account for the E/Z-selectivity.
E-selectivity of product using a stabilized ylide by the consider-
ably puckered oxaphosphetane-type transition state (Figure 1).
From our rate study conducted in various solvents (Table 1),
the Wittig reactions conducted in protic media, such as methanol
and water, give slightly lower E-selectivity for the o-alkoxy-
substituted aromatic aldehydes compared to p-alkoxy-substituted
aldehydes. However, the E/Z-ratios vary over a rather narrow
range, and the observed effects could be consistent with more
than one proposed enhancement mechanism. Although it is
suspected that water molecules lower the energy of the transition
state for the Wittig reaction, the exact role of water in
accelerating the rate of the Wittig reactions is still not clear.
Conclusions
The desire to use water as a “solvent” in organic chemistry55
stems from the fact that water is extremely inexpensive and
easy to handle and represents no environmental concerns.
Although the hydrophobic effect5,56 is instrumental in biological
systems, water has been generally ignored in organic reactions,
due to solubility problems and its amphoteric nature. However,
gradually increasing interest in aqueous organic reactions has
been apparent, dating from the work of Breslow1 and Grieco2
to more recent studies by Sharpless4,37 and Nicolaou.12 Extend-
ing this methodology to a fundamental alkene synthesis, we
report here the enhancement of reactivity in Wittig reactions
by water, perhaps due to its ability to stabilize the polar transition
state of the reaction. Water may also be disposed to participate
in the Wittig reaction based on its protic nature.
Water has been shown to be an effective medium for the
Wittig reaction employing stabilized ylides or in situ formed
stabilized ylides and aldehydes. This work demonstrates that
water solubility of the reagents and substrates is not essential,
even when pronounced hydrophobic entities are present. These
results further support the suggestion that water should be
routinely considered as a medium for organic synthesis, for
reasons both of environmental consideration and of chemical
efficacy.
3-(2′-Methoxyphenyl)-(E)-propenoic acid methyl ester (4).58
Typical procedure (Table 1): 4 was obtained from a Wittig reaction
between 2-methoxybenzaldehyde (0.9 mmol, 122 mg) and (meth-
oxycarbonylmethylene)triphenylphosphorane (1.1 mmol, 366 mg)
in water (4.0 mL) at 20 °C. After 1 h, CH2Cl2 (5 mL) was added
and the reaction was quenched by the addition of 1 M HCl (2.0
mL). The mixture was shaken or stirred vigorously for an additional
5 min, and the organic layer was separated. The aqueous phase
was extracted with CH2Cl2 (3 × 2 mL), and the combined organic
layers were dried over MgSO4, filtered, and evaporated. The crude
material was transferred to a silica column (2 × 8 cm), and the
product (4, 81%) and recovered aldehyde (9%) were collected as
Experimental Section
Typical Procedure for Wittig Reactions Using Aldehydes and
Ylides in Water. Preparation of Compounds 2-42, 44. A 20
mL scintillation vial, fitted with a magnetic stir bar, was charged
with ylide (1.2-1.5 mmol), the appropriate aldehyde (1.0 mmol),
and deionized water (5.0 mL). The vial was capped, and the content
was stirred, alternatively shaken, for 1-4 h. Optionally, the vial
was heated to 80-90 °C at 1 atm for a maximum of 2 h. After
cooling the heterogeneous reaction mixture to +20 °C, the aqueous
phase was extracted with CH2Cl2 (3 × 5 mL) and the combined
(57) Seuring, B.; Seebach, D. Justus Liebigs Ann. Chem. 1978, 12, 2044-
2073.
(58) Peterson, J. R.; Russel, M. E.; Surjasasmita, I. B. J. Chem. Eng.
Data 1988, 33, 534-537.
(55) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media;
Wiley: New York, 1997.
(56) Breslow, R. Acc. Chem. Res. 2004, 37, 471-478.
5252 J. Org. Chem., Vol. 72, No. 14, 2007

Wittig Reactions in Water Employing Ylides and Aldehydes
one fraction using flash chromatography (20% EtOAc/hexane, Rf
0.50) (E/Z-ratio: 76/24): 1H NMR (500 MHz, CDCl3) δ 8.00 (d,
CHâdCHR, J ) 16.2 Hz, 1H), 7.50 (dd, aromatic, J ) 7.7, 1.7 Hz,
1H), 7.35 (m, aromatic, 1H), 6.98-6.92 (2m, aromatic, 2H), 6.53
(d, CHâdCHR, J ) 16.2 Hz, 1H), 3.89, 3.80 (2s, OCH3, 3H each);
13C NMR (125 MHz, CDCl3) δ 167.9, 158.4, 140.3, 131.5, 128.9,
123.5, 120.7, 118.4, 111.2, 55.5, 51.6; FTIR (CH2Cl2, cm-1) 1712,
1633, 1198, 909, 734; MS m/z 192 (M+, 10%), 161 (M - OMe,
100%).
5-Phenyl-2(E),4(E)-pentadienoic acid methyl ester (5).59 5 was
obtained from a Wittig reaction between cinnamaldehyde (1.0
mmol, 126 µL) and (methoxycarbonylmethylene)triphenylphos-
phorane (1.5 mmol, 502 mg) in water (5.0 mL) at 20 °C for 2 h.
The crude product was purified using flash chromatography (15%
Et2O/pentane, Rf 0.50) to give 98% (184 mg) of 5 as a white solid;
mp 64-67 °C (E/Z-ratio: 85/15): 1H NMR (500 MHz, CDCl3) δ
7.48-7.43 (m, aromatic and olefinic, 3H), 7.35, 7.30 (2m, aromatic
and olefinic, 3H), 6.92-6.84 (m, olefinic, 2H), 5.99 (d, olefinic, J
) 15.3 Hz, 1H), 3.77 (s, OCH3, 3H); 13C NMR (125 MHz, CDCl3)
δ 167.5, 144.8, 140.6, 136.0, 129.1, 128.8, 127.2, 126.2, 120.8,
51.6; FTIR (CH2Cl2, cm-1) 1716, 1628, 996, 760.
3-Phenyl-(E)-propenoic acid 2′,2′,2′-trichloroethyl ester (9).60
9 was obtained from a Wittig reaction between benzaldehyde (1.0
mmol, 102 µL) and (2,2,2-trichloroethoxycarbonylmethylene)-
triphenylphosphorane57 (1.2 mmol, 540 mg) in water (5.0 mL) at
20 °C for 1 h. The crude product was purified using flash
chromatography (15% Et2O/pentane, Rf 0.70) to give 93% (258
mg) of 9 as a clear oil (E/Z-ratio: 94/6): 1H NMR (500 MHz,
CDCl3) δ 7.82 (d, CHâdCHR, J ) 16.0 Hz, 1H), 7.57 (m, aromatic,
2H), 7.41 (m, aromatic, 3H), 6.54 (d, CHâdCHR, J ) 16.0 Hz,
1H), 4.88 (s, OCH2, 2H); 13C NMR (125 MHz, CDCl3) δ 165.2,
147.1, 134.0, 130.9, 129.0, 128.4, 116.4, 95.2, 74.1; FTIR (film,
cm-1) 1732, 1635, 1450, 1307, 1148, 766, 707. HRMS (EI, DCI)
calcd for [C11H9O2Cl3] 277.9668, found 277.9660.
4-(4′-Nitrophenyl)-3(E)-buten-2-one (12).61 12 was obtained
from a Wittig reaction between 4-nitrobenzaldehyde (1.0 mmol,
151 mg) and (methylcarbonylmethylene)triphenylphosphorane (1.5
mmol, 478 mg) in water (5.0 mL) at 90 °C for 2 h. The crude
product was purified using flash chromatography (10% EtOAc/
hexane, Rf 0.40) to give 96% (183 mg) of 12 as a yellow solid; mp
101-106 °C (E/Z-ratio: 87/13) {lit.61 mp 104-105 °C}: 1H NMR
(500 MHz, CDCl3) δ 8.26 (m, aromatic, 2H), 7.70 (m, aromatic,
2H), 7.52 (d, CHâdCHR, J ) 16.3 Hz, 1H), 6.81 (d, CHâdCHR, J
) 16.3 Hz, 1H), 2.42 (s, CH3CO, 3H); 13C NMR (125 MHz, CDCl3)
δ 197.4, 148.6, 140.7, 140.0, 130.4, 128.8, 124,2, 28.0; FTIR
(CHCl3, cm-1) 1675, 1523, 1347, 735.
°C for 20 min. The crude product was purified using flash
chromatography (15% Et2O/pentane, Rf 0.40) to give 78% (187
mg) of 14 as a white solid; mp 77-83 °C (E/Z-ratio: 89/11): 1H
NMR (500 MHz, CDCl3) δ 7.62 (d, CHâdCHR, J ) 16.0 Hz, 1H),
7.51 (m, aromatic, 2H), 7.37 (m, aromatic, 2H), 6.42 (d, CHâd
CHR, J ) 16.0 Hz, 1H), 3.80 (s, OCH3, 3H); 13C NMR (125 MHz,
CDCl3) δ 167.1, 143.4, 132.1, 129.4, 124.5, 118,5, 51.7; FTIR (CH2-
Cl2, cm-1) 1715, 1636, 836.
3-(4′-Methoxyphenyl)-(E)-propenoic acid methyl ester (15).63
15 was obtained from a Wittig reaction between 4-methoxyben-
zaldehyde (1.0 mmol, 121 µL) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 90
°C for 30 min. The crude product was purified using flash
chromatography (15% ether/pentane, Rf 0.40) to give 90% (172
mg) of 15 as a white solid; mp 76-80 °C (E/Z-ratio: 92/8): 1H
NMR (500 MHz, CDCl3) δ 7.63 (d, CHâdCHR, J ) 16.0 Hz, 1H),
7.44 (m, aromatic, 2H), 6.88 (m, aromatic, 2H), 6.29 (d, CHâd
CHR, J ) 16.0 Hz, 1H), 3.80, 3.77 (2s, OCH3, 3H each); 13C NMR
(125 MHz, CDCl3) δ 167.5, 161.3, 144.3, 129.6, 127.0, 115.2,
114.2, 55.2, 51.3; FTIR (CHCl3, cm-1) 1719, 1639, 1178, 823.
3-(4′-Hydroxyphenyl)-(E)-propenoic acid methyl ester (16).64
16 was obtained from a Wittig reaction between 4-hydroxyben-
zaldehyde (1.0 mmol, 122 mg) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.5 mmol, 502 mg) in water (5.0 mL) at 90
°C for 1 h. The crude product was purified using flash chroma-
tography (20% EtOAc/hexane, Rf 0.40) to give 92% (163 mg) of
16 as a white solid; mp 128-133 °C (E/Z-ratio: 95/5): 1H NMR
(500 MHz, CDCl3) δ 7.65 (d, CHâdCHR, J ) 16.0 Hz, 1H), 7.42
(m, aromatic, 2H), 6.86 (m, aromatic, 2H), 6.30 (d, CHâdCHR, J
) 16.0 Hz, 1H), 6.06 (br s, HOAr, 1H), 3.80 (s, OCH3, 3H); 13C
NMR (125 MHz, CDCl3) δ 168.2, 158.0, 144.9, 130.0, 127.1, 115.9,
115.0, 51.8; FTIR (CH2Cl2, cm-1) 3385, 1686, 1634, 1265, 739.
3-(4′-Dimethylaminophenyl)-(E)-propenoic acid methyl ester
(17).65 17 was obtained from a Wittig reaction between 4-dimethy-
laminobenzaldehyde (1.0 mmol, 149 mg) and (methoxycarbonyl-
methylene)triphenylphosphorane (1.5 mmol, 502 mg) in water (5.0
mL) at 90 °C for 2 h. The crude product was purified using flash
chromatography (10% EtOAc/hexane, Rf 0.40) to give 81% (166
mg) of 17 as a yellow solid; mp 132-135 °C (E/Z-ratio: 90/10)
{lit.65 mp 134-135 °C}: 1H NMR (500 MHz, CDCl3) δ 7.63 (d,
CHâdCHR, J ) 15.9 Hz, 1H), 7.41 (m, aromatic, 2H), 6.66 (m,
aromatic, 2H), 6.22 (d, CHâdCHR, J ) 15.9 Hz, 1H), 3.77 (s,
OCH3, 3H), 3.01 (s, (CH3)2N, 6H); 13C NMR (125 MHz, CDCl3)
δ 168.3, 151.8, 145.4, 129.8, 122.3, 112.2, 111.9, 51.4, 40.1; FTIR
(CH2Cl2, cm-1) 1701, 1600, 1265, 735.
4-(3′-Benzyloxyphenyl)-3(E)-buten-2-one (18). 18 was obtained
from a Wittig reaction between 3-benzyloxybenzaldehyde (1.0
mmol, 212 mg) and (methylcarbonylmethylene)triphenylphosphorane
(1.5 mmol, 478 mg) in water (5.0 mL) at 90 °C for 2 h. The crude
product was purified using flash chromatography (10% EtOAc/
hexane, Rf 0.40) to give 98% (247 mg) of 18 as a clear oil (E/Z-
ratio: 95/5): 1H NMR (500 MHz, CDCl3) δ 7.47 (d, CHâdCHR,
J ) 16.2 Hz, 1H), 7.45-7.42 (m, aromatic “partly hidden”, 2H),
7.42-7.37 (m, aromatic, 2H), 7.36-7.29 (m, aromatic, 2H), 7.16-
7.13 (m, aromatic, 2H), 7.02 (m, aromatic, 1H), 6.68 (d, CHâd
CHR, J ) 16.2 Hz, 1H), 5.09 (s, OCH2Ph, 2H), 2.37 (s, CH3O,
3H); 13C NMR (50 MHz, CDCl3) δ 198.3, 159.2, 143.3, 136.7,
135.9, 130.0, 128.7, 128.1, 127.50, 127.47, 121.3, 117.3, 114.2,
70.2, 27.5; FTIR (film, cm-1) 1669, 1610, 1257, 697. Anal. Calcd
for C17H16O2: C, 80.93; H, 6.39. Found: C, 80.55; H, 6.59.
3-(3′,4′-Methylenedioxyphenyl)-(E)-propenoic acid tert-butyl
ester (19). 19 was obtained from a Wittig reaction between 3,4-
methylenedioxybenzaldehyde (1.04 mmol, 156 mg) and (tert-
butoxycarbonylmethylene)triphenylphosphorane (1.2 mmol, 452
3-(4′-Cyanophenyl)-(E)-propenoic acid methyl ester (13).62 13
was obtained from a Wittig reaction between 4-cyanobenzaldehyde
(1.0 mmol, 131 mg) and (methoxycarbonylmethylene)triph-
enylphosphorane (1.5 mmol, 502 mg) in water (5.0 mL) at 90 °C
for 2 h. The crude product was purified using flash chromatography
(10% EtOAc/hexane, Rf 0.40) to give 86% (161 mg) of 13 as a
white solid; mp 98-103 °C (E/Z-ratio: 87/13): 1H NMR (500
MHz, CDCl3) δ 7.70-7.59 (multiplets, aromatic and olefinic, 5H),
6.52 (d, CHâdCHR, J ) 16.0 Hz, 1H), 3.83 (s, OCH3, 3H); 13C
NMR (125 MHz, CDCl3) δ 166.4, 142.3, 138.6, 132.6, 128.3, 121.4,
118.2, 113.4, 51.9; FTIR (CHCl3, cm-1) 1720, 1641, 731.
3-(4′-Bromophenyl)-(E)-propenoic acid methyl ester (14).59
14 was obtained from a Wittig reaction between 4-bromobenzal-
dehyde (1.0 mmol, 185 mg) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.5 mmol, 502 mg) in water (5.0 mL) at 90
(59) Shen, Y.; Xin, Y.; Zhao, J. Tetrahedron Lett. 1988, 29, 6119-6120.
(60) (a) Just, G.; Grozinger, K. Synthesis 1976, 457-458. (b) See also:
Ram, R. N.; Meher, N. K. Org. Lett. 2003, 5, 145-147.
(61) Schiemenz, G. P.; Becker, J.; Sto¨ckigt, J. Chem. Ber. 1970, 103,
2077-2083.
(62) Patel, B. A.; Ziegler, C. B.; Cortese, N. A.; Plevyak, J. E.; Zebovitz,
T. C.; Terpko, M.; Heck, R. F. J. Org. Chem. 1977, 42, 3903-3907.
(63) Thiemann, T.; Watanabe, M.; Tanaka, Y.; Mataka, S. New J. Chem.
2004, 28, 578-584.
(64) Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941-2946.
(65) Schiemenz, G. P.; Thobe, J. Chem. Ber. 1966, 99, 2663-2668.
J. Org. Chem, Vol. 72, No. 14, 2007 5253

El-Batta et al.
mg) in water (5.0 mL) at 90 °C for 1 h. The crude product was
purified using flash chromatography (20% EtOAc/hexane, Rf 0.60)
to give 98% (253 mg) of 19 as a white solid; mp 73-76 °C (E/
Z-ratio: 95/5): 1H NMR (500 MHz, CDCl3) δ 7.49 (d, CHâdCHR,
J ) 15.9 Hz, 1H), 7.01 (d, aromatic, J ) 1.7 Hz, 1H), 6.97 (dd,
aromatic, J ) 8.0, 1.7 Hz, 1H), 6.79 (d, aromatic, J ) 8.0 Hz,
1H), 6.19 (d, CHâdCHR, J ) 15.9 Hz, 1H), 5.98 (s, OCH2O, 2H),
1.52 (s, C(CH3)3, 9H); 13C NMR (50 MHz, CDCl3) δ 166.4, 149.3,
148.3, 143.2, 129.1, 124.0, 118.2, 108.5, 106.5, 101.4, 80.3, 28.2;
FTIR (CH2Cl2, cm-1) 1702, 1631, 1151, 800. Anal. Calcd for
C14H16O2: C, 67.73; H, 6.50. Found: C, 67.54; H, 6.89.
δ 8.11 (d, CHâdCHR, J ) 15.9 Hz, 1H), 8.03 (dd, aromatic, J )
8.5, 1.1 Hz, 1H), 7.66 (m, aromatic, 2H), 7.56 (m, aromatic, 1H),
6.37 (d, CHâdCHR, J ) 15.9 Hz, 1H), 3.82 (s, OCH3, 3H); 13C
NMR (125 MHz, CDCl3) δ 166.0, 139.9, 133.4, 130.3, 130.2, 129.0,
124.8, 122.7, 51.8; FTIR (film, cm-1) 1718, 1522, 1348, 757.
3-(2′-Chlorophenyl)-(E)-propenoic acid methyl ester (24).69
24 was obtained from a Wittig reaction between 2-chlorobenzal-
dehyde (1.05 mmol, 148 mg) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 20
°C for 5 min. The crude product was purified using flash
chromatography (20% EtOAc/hexane, Rf 0.52) to give 97% (200
mg) of 24 as a yellow oil (E/Z-ratio: 81/19): 1H NMR (500 MHz,
CDCl3) δ 8.08 (d, CHâdCHR, J ) 16.0 Hz, 1H), 7.59 (dd, aromatic,
J ) 7.4, 2.1 Hz, 1H), 7.39 (m, aromatic, 1H), 7.30-7.23 (m,
aromatic, 2H), 6.42 (d, CHâdCHR, J ) 16.0 Hz, 1H), 3.81 (s,
OCH3, 3H); 13C NMR (125 MHz, CDCl3) δ 166.8, 140.5, 134.8,
3-(Pentafluorophenyl)-(E)-propenoic acid methyl ester (20).66
20 was obtained from a Wittig reaction between pentafluoroben-
zaldehyde (1.02 mmol, 199 mg) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 20
°C for 5 min. The crude product was purified using flash
chromatography (20% EtOAc/hexane, Rf 0.56) to give 86% (220
132.6, 130.9, 130.1, 127.6, 127.0, 120.4, 51.7; FTIR (film, cm-1
1721, 1636, 761.
)
1
mg) of 20 as a clear oil (E/Z-ratio: 99/1). H NMR (500 MHz,
CDCl3) δ 7.64 (d, CHâdCHR, J ) 16.5 Hz, 1H), 6.74 (d, CHâd
CHR, J ) 16.5 Hz, 1H), 3.84 (s, OCH3, 3H); 13C NMR (50 MHz,
CDCl3) δ 166.3, 145.7, 141.7, 137.8, 128.3, 125.9, 109.9, 52.0;
19F NMR (188 MHz, CDCl3) δ -141.0, -152.6, -163.0; FTIR
(film, cm-1) 1726, 1651, 1523, 1200, 737.
3-(2′-Benzyloxyphenyl)-(E)-propenoic acid methyl ester (25).
25 was obtained from a Wittig reaction between 2-benzyloxyben-
zaldehyde (1.1 mmol, 234 mg) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 90
°C for 1 h. The crude product was purified using flash chroma-
tography (20% EtOAc/hexane, Rf 0.60) to give 91% (268 mg) of
25 as a clear oil (E/Z-ratio: 73/27): 1H NMR (500 MHz, CDCl3)
δ 8.08 (d, CHâdCHR, J ) 16.2 Hz, 1H), 7.48 (dd, aromatic, J )
7.7, 1.6 Hz, 1H), 7.40-7.31 (m, aromatic, 4H), 7.30-7.21 (m,
aromatic, 2H), 6.94-6.86 (m, aromatic, 2H), 6.52 (d, CHâdCHR,
3-(4′-Chloro-3′-fluorophenyl)-(E)-propenoic acid methyl ester
(21). 21 was obtained from a Wittig reaction between 4-chloro-3-
fluorobenzaldehyde (1.0 mmol, 118 µL) and (methoxycarbonyl-
methylene)triphenylphosphorane (1.5 mmol, 502 mg) in water (5.0
mL) at 20 °C for 1 h. The crude product was purified using flash
chromatography (20% EtOAc/hexane, Rf 0.50) to give 95% (204
mg) of 21 as a white solid; mp 91-94 °C (E/Z-ratio: 96/4): 1H
NMR (500 MHz, CDCl3) δ 7.59 (d, CHâdCHR, J ) 16.0 Hz, 1H),
7.41 (dd, aromatic, J ) 8.3, 8.0 Hz, 1H), 7.29 (dd, aromatic, J )
9.8, 2.0 Hz, 1H), 7.23 (dd, aromatic, J ) 8.3, 2.0 Hz, 1H), 6.41 (d,
CHâdCHR, J ) 16.0 Hz, 1H), 3.82 (s, OCH3, 3H); 13C NMR (125
MHz, CDCl3) δ 166.8, 158.3, 142.3, 135.0, 131.1, 124.5, 122.9,
119.8, 115.4, 51.9; 19F NMR (188 MHz, CDCl3) δ -115.9; FTIR
(CHCl3, cm-1) 1717, 1644, 1266, 739; MS m/z 216 (M + 2, 20%),
214 (M+, 60%), 183 (M - OCH3, 100%), 155 (M - CO2CH3,
40%). Anal. Calcd for C10H8ClFO2: C, 55.96; H, 3.76. Found: C,
55.61; H, 4.07.
J ) 16.2 Hz, 1H), 5.08 (s, OCH2Ph, 2H), 3.73 (s, OCH3, 3H); 13
C
NMR (50 MHz, CDCl3) δ 167.6, 157.2, 134.0, 136.4, 131.2, 128.7,
128.5, 127.8, 127.0, 123.7, 120.9, 118.3, 112.7, 70.2, 51.3; FTIR
(film, cm-1) 1715, 1632, 1170, 735; MS m/z 269 (M + 1, 55%),
268 (M+, 30%), 237 (M - OCH3, 65%), 208 (100%), 91 (30%).
3-(2′,5-Dimethylphenyl)-(E)-propenoic acid methyl ester (26).70
26 was obtained from a Wittig reaction between 2,5-dimethylben-
zaldehyde (1.0 mmol, 141 µL) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 20
°C for 2 h. The crude product was purified using flash chroma-
tography (10% EtOAc/hexane, Rf 0.47) to give 92% (175 mg) of
26 as a clear oil (E/Z-ratio: 94/6): 1H NMR (500 MHz, CDCl3) δ
7.95 (d, CHâdCHR, J ) 15.9 Hz, 1H), 7.34 (s, aromatic, 1H), 7.07
(m, aromatic, 2H), 6.34 (d, CHâdCHR, J ) 15.9 Hz, 1H), 3.80 (s,
OCH3, 3H), 2.38, 2.31 (2s, CH3Ar, 3H each); 13C NMR (125 MHz,
CDCl3) δ 167.4, 142.6, 135.7, 134.6, 133.1, 130.8, 130.7, 126.9,
118.5, 51.5, 20.8, 19.2.
3-(3′,4′-Dimethoxyphenyl)-(E)-propenoic acid methyl ester
(22).67 22 was obtained from a Wittig reaction between 3,4-
dimethoxybenzaldehyde (1.0 mmol, 166 mg) and (methoxycarbo-
nylmethylene)triphenylphosphorane (1.5 mmol, 502 mg) in water
(5.0 mL) at 90 °C for 1 h. The crude product was purified using
flash chromatography (20% EtOAc/hexane, Rf 0.20) to give 90%
(200 mg) of 22 as a clear oil (E/Z-ratio: 99/1): 1H NMR (500
MHz, CDCl3) δ 7.63 (d, CHâdCHR, J ) 15.9 Hz, 1H), 7.10 (dd,
aromatic, J ) 8.3, 2.0 Hz, 1H), 7.04 (d, aromatic, J ) 2.0 Hz,
1H), 6.86 (d, aromatic, J ) 8.3 Hz, 1H), 6.30 (d, CHâdCHR, J )
3-(2′-Methylphenyl)-(E)-propenoic acid methyl ester (27).71
27 was obtained from a Wittig reaction between 2-methylbenzal-
dehyde (1.0 mmol, 116 µL) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 20
°C for 2 h. The crude product was purified using flash chroma-
tography (10% EtOAc/hexane, Rf 0.44) to give 89% (157 mg) of
27 as a clear liquid (E/Z-ratio: 93/7): 1H NMR (500 MHz, CDCl3)
δ 7.97 (d, CHâdCHR, J ) 15.9 Hz, 1H), 7.53 (d, aromatic, J )
7.4 Hz, 1H), 7.29-7.23 (m, aromatic, 1H), 7.22-7.16 (m, aromatic,
2H), 6.35 (d, CHâdCHR, J ) 15.9 Hz, 1H), 3.80 (s, OCH3, 3H),
2.43 (s, CH3Ar, 3H); 13C NMR (125 MHz, CDCl3) δ 167.4, 142.5,
137.6, 133.4, 130.8, 130.0, 126.39, 126.31, 118.9, 51.6, 19.7.
3-(2′-Naphthyl)-(E)-propenoic acid methyl ester (28).72 28 was
obtained from a Wittig reaction between naphthyl-2-carboxaldehyde
15.9 Hz, 1H), 3.90 (br s, OCH3, 2 × 3H), 3.79 (s, OCH3, 3H); 13
C
NMR (125 MHz, CDCl3) δ 167.6, 151.2, 149.2, 144.7, 127.4, 122.5,
115.5, 111.1, 109.8, 55.94, 55.87, 51.5; FTIR (film, cm-1) 1713,
1636, 1514, 1259, 808.
3-(2′-Nitrophenyl)-(E)-propenoic acid methyl ester (23).68 23
was obtained from a Wittig reaction between 2-nitrobenzaldehyde
(1.0 mmol, 151 mg) and (methoxycarbonylmethylene)triphen-
ylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 90 °C for
1 h. The crude product was purified using flash chromatography
(20% EtOAc/hexane, Rf 0.30) to give 92% (190 mg) of 23 as a
light yellow oil (E/Z-ratio: 88/12): 1H NMR (500 MHz, CDCl3)
(69) Shi, L.; Wang, W.; Wang, Y.; Huang, Y.-Z. J. Org. Chem. 1989,
54, 2027-2028.
(70) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123,
337-338.
(66) Albe´niz, A. C.; Espinet, P.; Mart´ın-Ruiz, B.; Milstein, D. J. Am.
Chem. Soc. 2001, 123, 11504-11505.
(67) Nam, N.-H.; You, Y.-J.; Kim, Y.; Hong, D.-H.; Kim, H.-M.; Ahn,
B. Z. Bioorg. Med. Chem. Lett. 2001, 11, 1173-1176.
(68) Nakao, K.; Murata, Y.; Koike, H.; Uchida, C.; Kawamura, K.;
Mihara, S.; Hayashi, S.; Stevens, R. W. Tetrahedron Lett. 2003, 44, 7269-
7271.
(71) Zhang, Z.; Zha, Z.; Gan, C.; Pan, C.; Zhou, Y.; Wang, Z.; Zhou,
M.-M. J. Org. Chem. 2006, 71, 4339-4342.
(72) Hamilton, G. S.; Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.;
Vaal, M. J.; Li, J.-H.; Thomas, C.; Huang, W.; Sauer, H.; Ross, D. T.;
Soni, R.; Chen, Y.; Guo, H.; Howorth, P.; Valentine, H.; Liang, S.; Spicer,
D.; Fuller, M.; Steiner, J. P. J. Med. Chem. 2002, 45, 3549-3557.
5254 J. Org. Chem., Vol. 72, No. 14, 2007

Wittig Reactions in Water Employing Ylides and Aldehydes
(1.0 mmol, 156 mg) and (methoxycarbonylmethylene)triphen-
ylphosphorane (1.5 mmol, 502 mg) in water (5.0 mL) at 90 °C for
30 min. The crude product was purified using flash chromatography
(20% EtOAc/hexane, Rf 0.40) to give 98% (210 mg) of 28 as a
white solid; mp 79-83 °C (E/Z-ratio: 90/10): 1H NMR (500 MHz,
CDCl3) δ 7.91 (br s, aromatic, 1H), 7.86-7.79 (m, aromatic “partly
hidden”, 3H), 7.85 (d, CHâdCHR “partly hidden”, J ) 16.0 Hz,
1H), 7.65 (dd, aromatic, J ) 8.6, 1.6 Hz, 1H), 7.52-7.46 (m,
aromatic, 2H), 6.54 (d, CHâdCHR, J ) 16.0 Hz, 1H), 3.83 (s,
OCH3, 3H); 13C NMR (50 MHz, CDCl3) δ 167.5, 144,9, 134.3,
133.3, 131.9, 129.9, 128.7, 128.6, 127.8, 127.2, 126.7, 123.5, 118.0,
51.7; FTIR (CH2Cl2, cm-1) 1716, 1638, 1265, 739.
164.6, 145.8, 134.0, 128.9, 128.3, 124.1, 114.9, 81.5, 28.0; FTIR
(CH2Cl2, cm-1) 1707, 1631, 1265, 739. Anal. Calcd for C11H13-
NO4S: C, 51.75; H, 5.13; N, 5.49; S, 12.56. Found: C, 51.75; H,
5.33; N, 5.53; S, 12.62.
3-(2′-Pyrrole)-(E)-propenoic acid tert-butyl ester (33). 33 was
obtained from a Wittig reaction between pyrrole-2-carboxaldehyde
(1.0 mmol, 95 mg) and (tert-butoxycarbonylmethylene)triph-
enylphosphorane (1.5 mmol, 565 mg) in water (5.0 mL) at 90 °C
for 2 h. The crude product was purified using flash chromatography
(10% EtOAc/hexane, Rf 0.20) to give 84% (162 mg) of 33 as a
clear oil (E/Z-ratio: 99/1): 1H NMR (500 MHz, CDCl3) δ 12.27
(br s, NH, 1H), 6.99 (m, aromatic, 1H), 6.68 (d, CHâdCHR, J )
12.6 Hz, 1H), 6.46 (m, aromatic, 1H), 6.24 (m, aromatic, 1H), 5.45
(d, CHâdCHR, J ) 12.6 Hz, 1H), 1.52 (s, O(CH3)3, 9H); 13C NMR
(50 MHz, CDCl3) δ 168.8, 133.8, 129.3, 122.5, 118.0, 110.0, 109.9,
80.5, 28.2; FTIR (film, cm-1) 3265, 1684, 1600, 1233, 754. Anal.
Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.40;
H, 7.67; N, 6.98.
1-Phenyl-3-(2′-quinolinyl)-(E)-propenone (34).74 34 was ob-
tained from a Wittig reaction between quinoline-2-carboxaldehyde
(1.0 mmol, 157 mg) and (benzoylmethylene)triphenylphosphorane
(1.5 mmol, 571 mg) in water (5.0 mL) at 90 °C for 2 h. The crude
product was purified using flash chromatography (10% EtOAc/
hexane, Rf 0.40) to give 89% (231 mg) of 34 as a orange solid; mp
114-116 °C (E/Z-ratio: 99/1) {lit.74 mp 113-115 °C}: 1H NMR
(500 MHz, CDCl3) δ 8.18 (d, aromatic, J ) 8.4 Hz, 1H), 8.15 (d,
CHâdCHR “partly hidden”, J ) 15.5 Hz, 1H), 8.15-8.09 (m,
aromatic, 3H), 7.94 (d, CHâdCHR, J ) 15.5 Hz, 1H), 7.81 (m,
aromatic, 1H), 7.74 (m, aromatic, 1H), 7.65 (d, aromatic, J ) 8.4
Hz, 1H), 7.62-7.49 (m, aromatic, 4H); 13C NMR (50 MHz, CDCl3)
δ 190.6, 153.5, 148.4, 143.5, 137.9, 136.8, 133.0, 130.1, 129.9,
128.8, 128.7, 128.2, 127.6, 127.3, 127.1, 121.4; FTIR (CH2Cl2,
cm-1) 1621, 1265, 737.
3-(4′-Quinolinyl)-(E)-propenoic acid methyl ester (35).75 35
was obtained from a Wittig reaction between quinoline-4-carbox-
aldehyde (1.0 mmol, 157 mg) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.5 mmol, 502 mg) in water (5.0 mL) at 90
°C for 2 h. The crude product was purified using flash chroma-
tography (10% EtOAc/hexane, Rf 0.40) to give 92% (196 mg) of
35 as a white solid; mp 47-49 °C (E/Z-ratio: 99/1) {lit.75 mp 48-
50 °C}: 1H NMR (500 MHz, CDCl3) δ 8.92 (d, aromatic, J ) 4.5
Hz, 1H), 8.41 (d, CHâdCHR, J ) 15.9 Hz, 1H), 8.15 (m, aromatic,
2H), 7.78-7.74 (m, aromatic, 1H), 7.64-7.60 (m, aromatic, 1H),
7.52 (d, aromatic, J ) 4.5 Hz, 1H), 6.64 (d, CHâdCHR, J ) 15.9
Hz, 1H), 3.88 (s, OCH3, 3H); 13C NMR (50 MHz, CDCl3) δ 166.4,
150.0, 148.7, 139.9, 139.3, 130.2, 129.7, 127.3, 126.0, 124.2, 123.2,
118.1, 52.0; FTIR (CH2Cl2, cm-1) 1720, 1644, 1176, 732.
3(3′-Pyridinyl)-(E)-propionic acid methyl ester (36).72 36 was
obtained from a Wittig reaction between pyridine-3-carboxaldehyde
(1.0 mmol, 94 µL) and (methoxycarbonylmethlene)triphenylphos-
phorane (1.5 mmol, 502 mg) in water (5.0 mL) at 20 °C for 1 h.
The crude product was purified using flash chromatography (10%
EtOAc/hexane, Rf 0.40) to give 88% (143 mg) of 36 as a orange
solid; mp 37-41 °C (E/Z-ratio: 81/19): 1H NMR (500 MHz,
CDCl3) δ 8.75 (d, aromatic, J ) 2.2 Hz, 1H), 8.61 (dd, aromatic,
J ) 4.8, 1.6 Hz, 1H), 7.84 (m, aromatic, 1H), 7.68 (d, CHâdCHR,
J ) 16.1 Hz, 1H), 7.32 (dd, aromatic, J ) 7.9, 4.8 Hz, 1H), 6.51
(d, CHâdCHR, J ) 16.1 Hz, 1H), 3.82 (s, OCH3, 3H); 13C NMR
(50 MHz, CDCl3) δ 166.7, 151.0, 149.7, 141.1, 134.2, 130.2, 123.7,
120.1, 51.9; FTIR (CH2Cl2, cm-1) 1718, 1641, 1172, 807.
2(E)-Heptenoic acid methyl ester (37).76 37 was obtained from
a Wittig reaction between pentanal (1.0 mmol, 106 µL) and
3-(2′-Thiophenyl)-(E)-propenoic acid methyl ester (29).73 29
was obtained from a Wittig reaction between 2-thiophenecarbox-
aldehyde (1.0 mmol, 94 µL) and (methoxycarbonylmethylene)-
triphenylphosphorane (1.2 mmol, 400 mg) in water (5.0 mL) at 20
°C for 1 h. The crude product was purified using flash chroma-
tography (15% Et2O/pentane, Rf 0.40) to give 95% (160 mg) of 29
as a light yellow solid; mp 45-47 °C (E/Z-ratio: 92/8): 1H NMR
(500 MHz, CDCl3) δ 7.79 (d, CHâdCHR, J ) 15.7 Hz, 1H), 7.36
(d, aromatic, J ) 5.1 Hz, 1H), 7.25 (d, aromatic, J ) 3.6 Hz, 1H),
7.04 (dd, aromatic, J ) 5.1, 3.6 Hz, 1H), 6.24 (d, CHâdCHR, J )
15.7 Hz, 1H), 3.79 (s, OCH3, 3H); 13C NMR (125 MHz, CDCl3) δ
167.2, 139.5, 137.2, 130.9, 128.4, 128.1, 116.6, 51.6; FTIR (CH2-
Cl2, cm-1) 1701, 1635, 1205, 742. HRMS (DEI) calcd for
[C8H8O2S] 168.0245, found 168.0241.
3-(5′-Bromo-2′-thiophenyl)-(E)-propenoic acid methyl ester
(30). 30 was obtained from a Wittig reaction between 5-bro-
mothiophene-2-carboxaldehyde (1.0 mmol, 119 µL) and (meth-
oxycarbonylmethylene)triphenylphosphorane (1.5 mmol, 502 mg)
in water (5.0 mL) at 20 °C for 5 min. The crude product was
purified using flash chromatography (15% Et2O/pentane, Rf 0.40)
to give 89% (221 mg) of 30 as a white solid; mp 60-64 °C (E/
Z-ratio: 91/9): 1H NMR (500 MHz, CDCl3) δ 7.64 (d, CHâdCHR,
J ) 15.6 Hz, 1H), 6.99 (d, aromatic, J ) 3.9 Hz, 1H), 6.97 (d,
aromatic, J ) 3.9 Hz, 1H), 6.11 (d, CHâdCHR, J ) 15.6 Hz, 1H)
3.77 (s, OCH3, 3H); 13C NMR (125 MHz, CDCl3) δ 167.0, 141.1,
136.4, 131.2, 131.1, 117.0, 116.0, 51.8; FTIR (CH2Cl2, cm-1) 1717,
1624, 1165, 795. HRMS (EI) calcd for [C8H7BrO2S] 245.9350,
found 245.9356.
3-(5′-Methyl-2′-thiophenyl)-(E)-propenoic acid tert-butyl ester
(31). 31 was obtained from a Wittig reaction between 5-methylth-
iophene-2-carboxaldehyde (1.0 mmol, 108 µL) and (tert-butoxy-
carbonylmethylene)triphenylphosphorane (1.5 mmol, 565 mg) in
water (5.0 mL) at 20 °C for 1 h. The crude product was purified
using flash chromatography (10% EtOAc/hexane, Rf 0.40) to give
97% (217 mg) of 31 as a clear oil (E/Z-ratio: 90/10): 1H NMR
(500 MHz, CDCl3) δ 7.64 (d, CHâdCHR, J ) 15.6 Hz, 1H), 7.01
(d, aromatic, J ) 3.4 Hz, 1H), 6.68 (dq, aromatic, J ) 3.4, 1.0 Hz,
1H), 6.02 (d, CHâdCHR, J ) 15.6 Hz, 1H), 2.48 (d, CH3Ar, J )
1.0 Hz, 3H), 1.51 (s, O(CH3)3, 9H); 13C NMR (50 MHz, CDCl3) δ
166.4, 143.4, 137.8, 136.4, 131.1, 126.4, 117.6, 80.3, 28.2, 15.8;
FTIR (film, cm-1) 1701, 1624, 1147, 799; MS m/z 224 (M+, 100%),
168 (M - C4H8, 45%), 151 (M - C4H9O, 35%), 135 (38%). Anal.
Calcd for C12H16O2S: C, 64.24; H, 7.19; S, 14.29. Found: C, 64.23;
H, 7.36; S, 14.15.
3-(5′-Nitro-2′-thiophenyl)-(E)-propenoic acid tert-butyl ester
(32). 32 was obtained from a Wittig reaction between 5-ni-
trothiophene-2-carboxaldehyde (1.0 mmol, 157 mg) and (tert-
butoxycarbonylmethylene)triphenylphosphorane (1.5 mmol, 565
mg) in water (5.0 mL) at 90 °C for 1 h. The crude product was
purified using flash chromatography (10% EtOAc/hexane, Rf 0.40)
to give 94% (240 mg) of 32 as an orange solid; mp 87-92 °C
(E/Z-ratio: 86/14): 1H NMR (500 MHz, CDCl3) δ 7.84 (d,
aromatic, J ) 4.3 Hz, 1H), 7.56 (d, CHâdCHR, J ) 15.8 Hz, 1H),
7.16 (d, aromatic, J ) 4.3 Hz, 1H), 6.35 (d, CHâdCHR, J ) 15.8
Hz, 1H), 1.53 (s, O(CH3)3, 9H); 13C NMR (50 MHz, CDCl3) δ
(74) Wachter-Jurcsak, N.; Radu, C.; Redin, K. Tetrahedron Lett. 1998,
39, 3903-3906.
(75) Rodriguez, J. G.; Benito, Y. J. Heterocycl. Chem. 1988, 25, 819-
821.
(76) De Lombaert, S.; Ghosez, L. Tetrahedron Lett. 1984, 25, 3475-
3478.
(73) Westman, J. Org. Lett. 2001, 3, 3745-3747.
J. Org. Chem, Vol. 72, No. 14, 2007 5255

El-Batta et al.
(methoxycarbonylmethylene)triphenylphosphorane (1.5 mmol, 502
mg) in water (5.0 mL) at 20 °C for 1 h. The crude product was
purified using flash chromatography (15% Et2O/pentane, Rf 0.80)
to give 80% (114 mg) of 37 as a clear oil (E/Z-ratio: 82/18): 1H
NMR (500 MHz, CDCl3) δ 6.97 (dt, CHâdCHR, J ) 15.6, 7.1 Hz,
1H), 5.82 (dt, CHâdCHR, J ) 15.6, 1.6 Hz, 1H), 3.72 (s, OCH3,
3H), 2.20 (dq, methylene, J ) 7.1, 7.0, 1.6 Hz, 1H), 1.48-1.40
(m, methylene, 2H), 1.39-1.30 (m, methylene, 2H), 0.91 (t,
CH3CH2, J ) 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 167.2,
149.7, 120.8, 51.3, 31.9, 30.1, 22.2, 13.8; FTIR (film, cm-1) 1728,
1658, 1174.
2(E)-Octenoic acid methyl ester (38).77 38 was obtained from
a Wittig reaction between hexanal (1.0 mmol, 120 µL) and
(methoxycarbonylmethylene)triphenylphosphorane (1.5 mmol, 502
mg) in water (5.0 mL) at 20 °C for 1 h. The crude product was
purified using flash chromatography (15% Et2O/pentane, Rf 0.80)
to give 84% (131 mg) of 38 as a clear oil (E/Z-ratio: 81/19): 1H
NMR (500 MHz, CDCl3) δ 6.97 (dt, CHâdCHR, J ) 15.6, 7.0 Hz,
1H), 5.82 (dt, CHâdCHR, J ) 15.6, 1.6 Hz, 1H), 3.72 (s, OCH3,
3H), 2.19 (dq, methylene, J ) 7.0, 7.0, 1.6 Hz, 2H), 1.46 (m,
methylene, 2H), 1.31 (m, methylene, 4H), 0.89 (t, CH3CH2, J )
7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 167.2, 149.8, 120.8,
51.3, 32.2, 31.3, 27.7, 22.4, 13.9; FTIR (film, cm-1) 1728, 1658,
1172; MS m/z 156 (M+, 10%), 141 (M - CH3, 2%), 125 (M -
OCH3, 10%), 113 (100%), 81 (50%).
2(E)-Decenoic acid methyl ester (39).78 39 was obtained from
a Wittig reaction between octanal (1.04 mmol, 133 mg) and
(methoxycarbonylmethylene)triphenylphosphorane (1.5 mmol, 502
mg) in water (5.0 mL) at 20 °C for 1 h. The crude product was
purified using flash chromatography (20% EtOAc/hexane, Rf 0.60)
to give 86% (164 mg) of 39 as a clear oil (E/Z-ratio: 80/20): 1H
NMR (500 MHz, CDCl3) δ 6.97 (dt, CHâdCHR, J ) 15.6, 7.0 Hz,
1H), 5.83 (dt, CHâdCHR, J ) 15.6, 1.6 Hz, 1H), 3.72 (s, OCH3,
3H), 2.19 (dq, methylene, J ) 7.0, 7.0, 1.6 Hz, 2H), 1.50-1.40
(m, methylene, 2H), 1.32-1.22 (m, methylene, 8H), 0.88 (t,
CH3CH2, J ) 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 167.2,
149.8, 120.9, 51.3, 32.2, 31.8, 29.12, 29.06, 28.06, 22.6, 14.1; FTIR
(film, cm-1) 1728, 1658, 1171.
3H), 1.13-1.04 (br m, Si(i-Pr)3, 21H); 13C NMR (50 MHz, CDCl3)
δ 167.1, 149.8, 138.6, 119.2, 115.3, 73.4, 51.6, 18.0, 12.3; FTIR
(CH2Cl2, cm-1) 2946, 1731, 1165, 883; MS m/z 298 (M, 0.5%),
i
255 (M - Pr, 100%), 145 (43%).
2(E)-Butenedioic acid mono-tert-butyl ester (42).80 42 was
obtained from a Wittig reaction between glyoxylic acid, 50 wt %
solution in water (1.36 mmol, 201 mg) and (tert-butoxycarbonyl-
methylene)triphenylphosphorane (1.36 mmol, 512 mg) in water (5.0
mL) at 20 °C for 30 min. The crude product (est. 75%, 175 mg;
E/Z-ratio: ∼70:30) was purified through a silica gel plug (25%
EtOAc/hexane, Rf 0.20) to give 30-50% (117 mg) of fumaric acid
mono-tert-butyl ester (E-42) as a white solid; mp 65-68 °C (E/
Z-ratio: 99/1): 1H NMR (500 MHz, CDCl3) δ 6.86 (d, olefinic, J
) 15.8 Hz, 1H), 6.76 (d, olefinic, J ) 15.8 Hz, 1H), 1.52 (s,
1
C(CH3)3, 9H); H NMR (DMSO-d6) δ 13.1 (b, CO2H, 1H); 13C
NMR (50 MHz, CDCl3) δ 169.6, 163.9, 137.7, 131.6, 82.3, 28.0;
FTIR (CH2Cl2, cm-1) 2983, 1707, 1154, 908; MS m/z 172 (M+,
28%), 57 (C4H9, 100%).
3-(4′-Bromo-2′-thiophenyl)-(E)-propenoic acid methyl ester
(44). 44 was obtained from a Wittig reaction between 4-bro-
mothiophene-2-carboxaldehyde (1.1 mmol, 210 mg) and (meth-
oxycarbonylmethylene)triphenylphosphorane (1.5 mmol, 502 mg)
in water (5.0 mL) at 80 °C for 2 h. The crude product was purified
using flash chromatography (20% EtOAc/hexane, Rf 0.40) to give
99% (245 mg) of 44 as a yellow solid; mp 64-67 °C (E/Z-ratio:
96/4): 1H NMR (500 MHz, CDCl3) δ 7.67 (d, CHâdCHR, J )
15.8 Hz, 1H), 7.25 (s, aromatic, 1H), 7.15 (s, aromatic, 1H), 6.24
(d, CHâdCHR, J ) 15.8 Hz, 1H), 3.79 (s, OCH3, 3H); 13C NMR
(50 MHz, CDCl3) δ 166.7, 140.2, 135.8, 132.3, 125.1, 117.9, 110.9,
51.8; FTIR (CH2Cl2, cm-1) 1713, 1632, 1265, 739. Anal. Calcd
for C8H7BrO2S: C, 38.88; H, 2.86; S, 12.94. Found: C, 38.76; H,
3.11; S, 12.64.
3-(4′-Dimethylaminophenyl)-(E)-propenoic acid ethyl ester
(48).81 48 was obtained from a Wittig reaction between 4-dimethyl-
aminobenzaldehyde (1.0 mmol, 149 mg), triphenylphosphine (1.5
mmol, 393 mg), and ethyl bromoacetate (1.8 mmol, 200 µL) in
saturated NaHCO3 (5 mL) at 20 °C for 2 h. The crude product was
purified using flash chromatography (20% EtOAc/hexane, Rf 0.30)
to give 32% (70.1 mg) of 48 as a yellow solid; mp 74-76 °C (E/
Z-ratio: 99/1): 1H NMR (500 MHz, CDCl3) δ 7.62 (d, CHâdCHR,
J ) 15.9 Hz, 1H), 7.42 (m, aromatic, 2H), 6.67 (m, aromatic, 2H),
6.22 (d, CHâdCHR, J ) 15.9 Hz, 1H), 4.23 (q, OCH2, J ) 7.2 Hz,
4-Methyl-2(E)-hexenoic acid tert-butyl ester (40).79 40 was
obtained from a Wittig reaction between 2-methylbutyraldehyde
(1.09 mmol, 94 mg) and (tert-butoxycarbonylmethylene)triph-
enylphosphorane (1.5 mmol, 565 mg) in water (5.0 mL) at 20 °C
for 1 h. The crude product was purified using flash chromatography
(20% EtOAc/hexane, Rf 0.40) to give 77% (153 mg) of 40 as a
clear oil (E/Z-ratio: 99/1): 1H NMR (500 MHz, CDCl3) δ 6.76
(dd, CHâdCHR, J ) 15.6, 7.7 Hz, 1H), 5.70 (dd, CHâdCHR, J )
15.6, 1.1 Hz, 1H), 2.19 (m, methine, 1H), 1.48 (s, OC(CH3)3, 9H),
1.45-1.35 (m, methylene, 2H), 1.03 (d, CH3CH, J ) 6.7 Hz, 3H),
(t, CH3CH2, J ) 7.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 166.3,
2H), 3.01 (s, N(CH3)2, 6H), 1.32 (t, CH3CH2, J ) 7.2 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 167.9, 151.8, 145.1, 129.7, 122.4, 112.7,
111.9, 60.1, 40.2, 14.4; FTIR (CH2Cl2, cm-1) 1701, 1601, 1265,
738; MS m/z 219 (M+, 100%), 174 (M - OEt, 38%), 146 (M -
CO2Et, 25%).
3-(4′-Chlorophenyl)-(E)-propenoic acid ethyl ester (49).81 49
was obtained from a Wittig reaction between 4-chlorobenzaldehyde
(1.0 mmol, 141 mg), triphenylphosphine (1.5 mmol, 393 mg), and
ethyl bromoacetate (1.8 mmol, 200 µL) in saturated NaHCO3 (5
mL) at 20 °C for 2 h. The crude product was purified using flash
chromatography (20% EtOAc/hexane, Rf 0.40) to give 99% (208
mg) of 49 as a light yellow oil (E/Z-ratio: 89/11): 1H NMR (500
MHz, CDCl3) δ 7.62 (d, CHâdCHR, J ) 16.0 Hz, 1H), 7.45 (m,
aromatic, 2H), 7.36 (m, aromatic, 2H), 6.40 (d, CHâdCHR, J )
16.0 Hz, 1H), 4.27 (q, OCH2, J ) 7.1 Hz, 2H), 1.34 (t, CH3CH2,
J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.7, 143.1,
153.1, 121.4, 79.9, 37.9, 28.8, 28.1, 18.9, 11.6; FTIR (film, cm-1
)
1716, 1652, 1153, 985; MS m/z 185 (M + 1, 55%), 184 (M+, 30%),
129 (95%), 111 (100%).
4-Triisopropyloxy-2(E),5-hexadieneoic acid methyl ester (41).
41 was obtained from a Wittig reaction between 2-triisopropyloxy-
3-butenal49 (0.515 mmol, 125 mg) and (methoxycarbonylmethyl-
ene)triphenylphosphorane (0.77 mmol, 257 mg) in water (3.0 mL)
at 90 °C for 2 h. The crude product was purified using flash
chromatography (5% EtOAc/hexane, Rf 0.43) to give 83% (128
mg) of 41 as a clear oil (E/Z-ratio: 88/12): 1H NMR (500 MHz,
CDCl3) δ 6.89 (dd, CHâdCHR, J ) 15.6, 4.6 Hz, 1H), 6.06 (dd,
CHâdCHR, J ) 15.6, 1.7 Hz, 1H), 5.76 (m, CH2dCH, 1H), 5.28
(ddd, CH2dCH, J ) 17.1, 1.3, 1.3 Hz, 1H), 5.14 (ddd, CH2dCH,
J ) 10.3, 1.3, 1.3 Hz, 1H), 4.87 (m, CHOSi, 1H), 3.74 (s, OCH3,
136.1, 133.0, 129.20, 129.18, 118.9, 60.6, 14.3; FTIR (film, cm-1
)
1709, 1640, 1265, 908; MS m/z 211 (M + 1, 100%), 165 (M -
OEt, 48%), 102 (25%).
3-(4′-Chlorophenyl)-(E)-propenoic acid benzyl ester (50). 50
was obtained from a Wittig reaction between 4-chlorobenzaldehyde
(1.0 mmol, 141 mg), triphenylphosphine (1.6 mmol, 420 mg), and
(77) Bo¨rner, C.; Dennis, M. R.; Sinn, E.; Woodward, S. Eur. J. Org.
Chem. 2001, 2435-2446.
(80) Koerber-Ple, K.; Massiot, G. J. Heterocycl. Chem. 1995, 32, 1309-
(78) Kandula, S. R. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 6149-
1315.
6151.
(81) Chen, Y.; Huang, L.; Ranade, M. A.; Zhang, X. P. J. Org. Chem.
2003, 68, 3714-3717.
(79) Bressette, A. R.; Glover, L. C., IV. Synlett 2004, 738-740.
5256 J. Org. Chem., Vol. 72, No. 14, 2007

Wittig Reactions in Water Employing Ylides and Aldehydes
benzyl bromoacetate (1.4 mmol, 221 µL) in saturated NaHCO3 (5
mL) at 20 °C for 2 h. The crude product was purified using flash
chromatography (10% EtOAc/hexane, Rf 0.34) to give 84% (228
mg) of 50 as a white solid; mp 65-68 °C (E/Z-ratio: 92/8): 1H
NMR (500 MHz, CDCl3) δ 7.67 (d, CHâdCHR, J ) 16.0 Hz, 1H),
7.46-7.43 (m, aromatic, 2H), 7.42-7.32 (m, aromatic, 6H), 6.45
(d, CHâdCHR, J ) 16.0 Hz, 1H), 5.25 (s, OCH2Ph, 2H); 13C NMR
(125 MHz, CDCl3) δ 166.5, 143.7, 136.3, 136.0, 132.9, 131.1,
129.3, 129.2, 128.6, 128.3, 118.5, 66.5; FTIR (CH2Cl2, cm-1) 1715,
1638, 1265, 739; MS m/z 274 (M + 2, 10%), 273 (M + 1, 5%),
272 (M+, 20%), 237 (35%), 226 (85%), 165 (M - C7H7O, 100%),
91 (60%). HRMS (EI, DCI/NH3) calcd for [C16H17NO2Cl]+
(MNH+) 290.0948, found 290.0946.
93/7): 1H NMR (500 MHz, CDCl3) δ 7.54 (d, CHâdCHR, J )
16.0 Hz, 1H), 7.45-7.36 (2m, aromatic, 2H each), 7.35-7.24 (2m,
aromatic, 1H each), 7.12-7.09 (m, aromatic, 2H), 6.98 (m,
aromatic, 1H), 6.34 (d, CHâdCHR, J ) 16.0 Hz, 1H), 5.08 (s,
OCH2Ph, 2H), 1.53 (s, C(CH3)3, 9H); 13C NMR (125 MHz, CDCl3)
δ 166.2, 159.1, 143.4, 136.7, 136.2, 129.8, 128.6, 128.1, 127.5,
120.9, 120.6, 116.7, 113.9, 80.5, 70.1, 28.2; FTIR (film, cm-1) 1703,
1422, 1264, 738; MS m/z 310 (M+, 5%), 254 (M, 85%), 237 (M -
OtBu, 82%), 91 (C7H7, 100%). Anal. Calcd for C20H22O3: C, 77.39;
H, 7.14. Found: C, 77.23; H, 6.85.
3-(2′,5′-Dimethylphenyl)-(E)-propenoic acid ethyl ester (55).84
55 was obtained from a Wittig reaction between 2,5-dimethylben-
zaldehyde (1.0 mmol, 142 µL), triphenylphosphine (1.5 mmol, 393
mg), and ethyl bromoacetate (1.8 mmol, 200 µL) in saturated
NaHCO3 (5 mL) at 20 °C for 2 h. The crude product was purified
using flash chromatography (10% EtOAc/hexane, Rf 0.25) to give
97% (194 mg) of 55 as a light yellow oil (E/Z-ratio: 92/8): 1H
NMR (500 MHz, CDCl3) δ 7.94 (d, CHâdCHR, J ) 15.9 Hz, 1H),
7.36 (s, aromatic, 1H), 7.08 (2d, aromatic, “partly overlap”, 2H),
6.34 (d, CHâdCHR, J ) 15.9 Hz, 1H), 4.26 (q, OCH2, J ) 7.1 Hz,
2H), 2.39, 2.32 (2s, Ar-CH3, 3H each), 1.34 (t, CH3CH2, J ) 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 167.1, 142.4, 135.7, 134.6,
133.2, 130.8, 130.7, 127.0, 119.0, 60.4, 20.9, 19.3, 14.3; FTIR (film,
cm-1) 1706, 1635, 1265, 908; MS m/z 205 (M + 1, 100%), 189
(M - CH3, 5%), 159 (M - OEt, 15%), 130 (18%).
3-(2′-Benzyloxyphenyl)-(E)-propenoic acid tert-butyl ester
(56). 56 was obtained from a Wittig reaction between 2-benzyl-
oxybenzaldehyde (1.0 mmol, 217 mg), triphenylphosphine (1.4
mmol, 366 mg), and tert-butyl bromoacetate (1.6 mmol, 240 µL)
in saturated NaHCO3 (5 mL) at 20 °C for 3 h. The crude product
was purified using flash chromatography (10% EtOAc/hexane, Rf
0.20) to give 92% (285 mg) of 56 as a colorless oil (E/Z-ratio:
72/28): 1H NMR (500 MHz, CDCl3) δ 8.01 (d, CHâdCHR, J )
16.1 Hz, 1H), 7.55-7.51 (m, aromatic, 1H), 7.46-7.35 (m,
aromatic, 4H), 7.34-7.23 (m, aromatic, 2H), 6.97-6.90 (m,
aromatic, 2H), 6.45 (d, CHâdCHR, J ) 16.1 Hz, 1H), 5.15 (s,
OCH2Ph, 2H), 1.52 (s, C(CH3)3, 9H); 13C NMR (125 MHz, CDCl3)
δ 166.7, 157.2, 138.7, 136.7, 131.1, 129.9, 128.6, 128.5, 128.0,
127.1, 121.0, 120.7, 112.8, 80.1, 70.4, 28.2; FTIR (film, cm-1) 1702,
1632, 1422, 1265, 738; MS m/z 311 (M + 1, 5%), 255 (100%).
Anal. Calcd for C20H22O3: C, 77.39; H, 7.14. Found: C, 77.04; H,
6.89.
3-(2′-Methylphenyl)-(E)-propenoic acid benzyl ester (57). 57
was obtained from a Wittig reaction between 2-methylbenzaldehyde
(1.0 mmol, 120 µL), triphenylphosphine (1.2 mmol, 319 mg), and
benzyl bromoacetate (1.3 mmol, 215 µL) in saturated NaHCO3 (5
mL) at 20 °C for 3 h. The crude product was purified using flash
chromatography (10% Et2O/pentane, Rf 0.70) to give 90% (227
mg) of 57 as a colorless oil (E/Z-ratio: 94/6): 1H NMR (500 MHz,
CDCl3) δ 8.02 (d, CHâdCHR, J ) 15.9 Hz, 1H), 7.54 (m, aromatic,
1H), 7.44-7.31 (m, aromatic, 5H), 7.31-7.25 (m, aromatic, 1H),
7.22-7.18 (m, aromatic, 2H), 6.41 (d, CHâdCHR, J ) 15.9 Hz,
1H), 5.26 (s, OCH2Ph, 2H), 2.43 (s, CH3Ph, 3H); 13C NMR (125
MHz, CDCl3) δ 166.8, 142.9, 137.7, 136.1, 133.3, 130.8, 130.0,
128.6, 128.22, 128.20, 126.4, 126.3, 118.9, 66.3, 19.7; FTIR (film,
cm-1) 1709, 1634, 1313, 1168, 723; MS m/z 252 (M+, 5%), 206
(100%), 161 (M - C7H7, 87%), 145 (M - C7H7O, 95%), 91 (12%).
Anal. Calcd for C17H16O2: C, 80.93; H, 6.39. Found: C, 80.58; H,
6.23.
3-(4′-Methoxyphenyl)-(E)-propenoic acid ethyl ester (51).81
51 was obtained from a Wittig reaction between 4-methoxyben-
zaldehyde (1.0 mmol, 122 µL), triphenylphosphine (1.5 mmol, 393
mg), and ethyl bromoacetate (1.8 mmol, 200 µL) in saturated
NaHCO3 (5 mL) at 20 °C for 2 h. The crude product was purified
using flash chromatography (10% EtOAc/hexane, Rf 0.20) to give
94% (194 mg) of 51 as a colorless oil (E/Z-ratio: 93/7): 1H NMR
(500 MHz, CDCl3) δ 7.64 (d, CHâdCHR, J ) 16.0 Hz, 1H), 7.47
(m, aromatic, 2H), 6.90 (m, aromatic, 2H), 6.30 (d, CHâdCHR, J
) 16.0 Hz, 1H), 4.25 (q, OCH2, J ) 7.2 Hz, 2H), 3.84 (s, OMe,
3H), 1.33 (t, CH3CH2, J ) 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 167.3, 161.4, 144.3, 129.7, 127.3, 115.8, 114.3, 60.3,
55.4, 14.4; FTIR (film, cm-1) 1716, 1635, 1248, 829; MS m/z 206
(M+, 100%), 161 (M - OEt, 25%).
3-(4′-Methoxyphenyl)-(E)-propenoic acid benzyl ester (52).82
52 was obtained from a Wittig reaction between 3-benzyloxyben-
zaldehyde (1.0 mmol, 121 µL), triphenylphosphine (1.6 mmol, 420
mg), and benzyl bromoacetate (1.4 mmol, 221 µL) in saturated
NaHCO3 (5 mL) at 20 °C for 2 h. The crude product was purified
using flash chromatography (20% EtOAc/hexane, Rf 0.37) to give
86% (230 mg) of 52 as a white solid; mp 45-47 °C (E/Z-ratio:
91/9): 1H NMR (500 MHz, CDCl3) δ 7.68 (d, CHâdCHR, J )
15.9 Hz, 1H), 7.48-7.44 (m, aromatic, 2H), 7.43-7.30 (m,
aromatic, 5H), 6.89 (m, aromatic, 2H), 6.35 (d, CHâdCHR, J )
15.9 Hz, 1H), 5.24 (s, OCH2Ph, 2H), 3.82 (s, OCH3, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.1, 161.5, 144.8, 136.3, 129.8, 128.6,
128.24, 128.19, 127.2, 115.4, 114.4, 66.2, 55.4; FTIR (CH2Cl2,
cm-1) 1709, 1635, 1604, 1265, 908, 734; MS m/z 268 (M+, 100%),
223 (73%), 161 (M-PhCH2O, 74%), 134 (80%), 91 (95%).
3-(3′-Benzyloxyphenyl)-(E)-propenoic acid ethyl ester (53).83
53 was obtained from a Wittig reaction between 3-benzyloxyben-
zaldehyde (1.0 mmol, 212 mg), triphenylphosphine (1.5 mmol, 393
mg), and ethyl bromoacetate (1.8 mmol, 200 µL) in saturated
NaHCO3 (5 mL) at 20 °C for 2 h. The crude product was purified
using flash chromatography (10% EtOAc/hexane, Rf 0.30) to give
99% (280 mg) of 53 as a white solid; mp 39-40 °C (E/Z-ratio:
92/8): 1H NMR (500 MHz, CDCl3) δ 7.64 (d, CHâdCHR, J )
16.0 Hz, 1H), 7.45-7.36 (2m, aromatic, 2H each), 7.35-7.25 (m,
aromatic, 2H), 7.12 (m, aromatic, 2H), 6.99 (m, aromatic, 1H), 6.40
(d, CHâdCHR, J ) 16.0 Hz, 1H), 5.08 (s, OCH2Ph, 2H), 4.26 (q,
OCH2CH3, J ) 7.2 Hz, 2H), 1.33 (t, CH3CH2, J ) 7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 166.9, 159.1, 144.4, 136.7, 135.9,
130.0, 128.6, 128.1, 127.5, 121.0, 118.7, 117.0, 114.0, 70.1, 60.5,
14.3; FTIR (CH2Cl2, cm-1) 1708, 1639, 1266, 742; MS m/z 282
(M+, 86%), 237 (M - OEt, 23%), 208 (45%), 191 (M - C7H7,
100%), 91 (28%).
3-(3′-Benzyloxyphenyl)-(E)-propenoic acid tert-butyl ester
(54). 54 was obtained from a Wittig reaction between 3-benzyl-
oxybenzaldehyde (1.0 mmol, 217 mg), triphenylphosphine (1.4
mmol, 366 mg), and tert-butyl bromoacetate (1.6 mmol, 240 µL)
in saturated NaHCO3 (5 mL) at 20 °C for 3 h. The crude product
was purified using flash chromatography (10% EtOAc/hexane, Rf
0.25) to give 96% (297 mg) of 54 as a colorless oil (E/Z-ratio:
3-(Pentafluorophenyl)-(E)-propenoic acid benzyl ester (58).
58 was obtained from a Wittig reaction between pentafluoroben-
zaldehyde (1.0 mmol, 123 µL), triphenylphosphine (1.6 mmol, 420
mg), and benzyl bromoacetate (1.4 mmol, 221 µL) in saturated
NaHCO3 (5 mL) at 20 °C for 2 h. The crude product was purified
using flash chromatography (10% EtOAc/hexane, Rf 0.30) to give
82% (269 mg) of 58 as a white solid; mp 62-64 °C (E/Z-ratio:
(82) Imashiro, R.; Seki, M. J. Org. Chem. 2004, 69, 4216-4226.
(83) Dong, L.; Miller, M. J. J. Org. Chem. 2002, 67, 4759-4770.
(84) Jia, C.; Lu, W.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.;
Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252-7263.
J. Org. Chem, Vol. 72, No. 14, 2007 5257

El-Batta et al.
98/2): 1H NMR (500 MHz, CDCl3) δ 7.68 (d, CHâdCHR, J )
16.5 Hz, 1H), 7.43-7.32 (m, aromatic, 5H), 6.79 (d, CHâdCHR, J
) 16.5 Hz, 1H), 5.27 (s, OCH2Ph, 2H); 13C NMR (125 MHz,
CDCl3) δ 165.8, 145.7, 141.8, 137.8, 135.6, 132.2, 128.7, 128.5,
128.4, 126.0, 109.9, 67.0; 19F NMR (188 MHz, CDCl3) δ -140.6,
-152.2, -162.7; FTIR (CH2Cl2, cm-1) 1720, 1500, 1265, 739; MS
m/z 328 (M+, 12%), 283 (65%), 221 (M - PhCH2O, 70%), 91
(100%). Anal. Calcd for C16H9F5O2: C, 58.55; H, 2.76. Found:
C, 58.26; H, 2.85.
3-(Pentafluorophenyl)-(E)-propenoic acid tert-butyl ester (59).
59 was obtained from a Wittig reaction between pentafluoroben-
zaldehyde (1.0 mmol, 196 mg), triphenylphosphine (1.4 mmol, 366
mg), and tert-butyl bromoacetate (1.6 mmol, 240 µL) in saturated
NaHCO3 (5 mL) at 20 °C for 40 min. The crude product was
purified using flash chromatography (10% EtOAc/hexane, Rf 0.40)
to give 84% (194 mg) of 59 as a white solid; mp 37-38 °C (E/
Z-ratio: 98/2): 1H NMR (500 MHz, CDCl3) δ 7.54 (d, CHâdCHR,
J ) 16.5 Hz, 1H), 6.66 (d, CHâdCHR, J ) 16.5 Hz, 1H), 1.54 (s,
C(CH3)3, 9H); 13C NMR (125 MHz, CDCl3) δ 165.3, 145.6, 141.6,
137.9, 128.4, 127.1, 110.2, 81.6, 28.1; FTIR (CH2Cl2, cm-1) 1709,
1500, 1265, 739; MS m/z 295 (M + 1, 78%), 239 (100%). HRMS
(EI) calcd for [C13H11O2F5]+ 294.0679, found 294.0668.
3-(2′-Nitrophenyl)-(E)-propenoic acid tert-butyl ester (60). 60
was obtained from a Wittig reaction between 2-nitrobenzaldehyde
(1.0 mmol, 156 mg), triphenylphosphine (1.4 mmol, 366 mg), and
tert-butyl bromoacetate (1.6 mmol, 240 µL) in saturated NaHCO3
(5 mL) at 20 °C for 1.5 h. The crude product was purified using
flash chromatography (10% EtOAc/hexane, Rf 0.20) to give 99%
(194 mg) of 60 as a yellow solid; mp 60-62 °C (E/Z-ratio: 85/
15): 1H NMR (500 MHz, CDCl3) δ 8.01 (d, CHâdCHR, J ) 15.7
Hz, 1H), 8.01 (m, aromatic, “partly hidden”, 1H), 7.65-7.62 (m,
aromatic, 2H), 7.54-7.50 (m, aromatic, 1H), 6.30 (d, CHâdCHR,
J ) 15.7 Hz, 1H), 1.54 (s, C(CH3)3, 9H); 13C NMR (125 MHz,
CDCl3) δ 165.0, 148.4, 138.7, 133.4, 130.8, 130.0, 129.1, 125.3,
124.8, 81.2, 28.2; FTIR (CH2Cl2, cm-1) 1710, 1638, 1152, 976;
MS m/z 249 (M+, 60%), 232 (50%), 221 (53%), 120 (53%), 102
(100%), 89 (78%). Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07;
N, 5.62. Found: C, 62.89; H, 5.78; N, 5.78.
3(3′-Pyridinyl)-(E)-propionic acid ethyl ester (61).85 61 was
obtained from a Wittig reaction between 3-pyridinecarboxaldehyde
(1.0 mmol, 96 µL), triphenylphosphine (1.5 mmol, 393 mg), and
ethyl bromoacetate (1.8 mmol, 200 µL) in saturated NaHCO3 (5
mL) at 20 °C for 1 h. The crude product was purified using flash
chromatography (20% EtOAc/hexane, Rf 0.16) to give 81% (143
mg) of 61 as a colorless oil (E/Z-ratio: 87/13): 1H NMR (500
MHz, CDCl3) δ 8.75 (br s, aromatic, 1H), (br m, aromatic, 1H),
7.83 (dt, aromatic, J ) 7.9, 1.8 Hz, 1H), 7.67 (d, CHâdCHR, J )
16.1 Hz, 1H), 7.33 (dd, aromatic, J ) 7.9, 4.9 Hz, 1H), 6.51 (d,
CHâdCHR, J ) 16.1 Hz, 1H), 4.29 (q, OCH2CH3, J ) 7.2 Hz,
2H), 1.35 (t, CH3CH2, J ) 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.3, 151.0, 149.7, 140.9, 134.2, 130.3, 123.7, 120.6,
60.8, 14.3; FTIR (film, cm-1) 1712, 1421, 1265, 735; MS m/z 178
(M + 1, 100%), 132 (M - OEt, 47%), 104 (28%).
157.8, 145.0, 136.2, 130.0, 128.6, 128.25, 128.24, 127.2, 115.9,
115.3, 66.3; FTIR (CH2Cl2, cm-1) 3363, 1708, 1606, 1265, 738.
3-(5′-Methyl-2′-thiophenyl)-(E)-propenoic acid ethyl ester
(63).87 63 was obtained from a Wittig reaction between 5-methyl-
2-thiophenecarboxaldehyde (1.0 mmol, 129 mg), triphenylphosphine
(1.5 mmol, 393 mg), and ethyl bromoacetate (1.8 mmol, 200 µL)
in saturated NaHCO3 (5 mL) at 20 °C for 1 h. The crude product
was purified using flash chromatography (10% EtOAc/hexane, Rf
0.40) to give 99% (194 mg) of 63 as a light yellow oil (E/Z-ratio:
93/7): 1H NMR (500 MHz, CDCl3) δ 7.69 (d, CHâdCHR, J )
15.6 Hz, 1H), 7.04 (d, aromatic, J ) 3.5 Hz, 1H), 6.70 (dq, aromatic,
J ) 3.5, 0.9 Hz, 1H), 6.10 (d, CHâdCHR, J ) 15.6 Hz, 1H), 4.23
(q, OCH2CH3, J ) 7.2 Hz, 2H), 2.49 (d, CH3Ar, J ) 0.9 Hz, 3H),
1.32 (t, CH3CH2, J ) 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 167.1, 143.9, 137.6, 137.4, 131.5, 126.5, 115.6, 60.3, 15.8, 14.4;
FTIR (film, cm-1) 1702, 1624, 1422, 1265, 738; MS m/z 197 (M
+ 1, 62%), 151 (M - OEt, 100%).
3-(5′-Bromo-2′-thiophenyl)-(E)-propenoic acid tert-butyl ester
(64). 64 was obtained from a Wittig reaction between 5-bromo-2-
thiophenecarboxaldehyde (1.0 mmol, 192 mg), triphenylphosphine
(1.4 mmol, 366 mg), and tert-butyl bromoacetate (1.6 mmol, 240
µL) in saturated NaHCO3 (5 mL) at 20 °C for 1.5 h. The crude
product was purified using flash chromatography (5% Et2O/pentane,
Rf 0.50) to give 99% (286 mg) of 64 as a light yellow oil (E/Z-
ratio: 91/9): 1H NMR (500 MHz, CDCl3) δ 7.54 (d, CHâdCHR,
J ) 15.7 Hz, 1H), 6.99 (d, aromatic, J ) 3.9 Hz, 1H), 6.95 (d,
aromatic, J ) 3.9 Hz, 1H), 6.06 (d, CHâdCHR, J ) 15.7 Hz, 1H),
1.51 (s, C(CH3)3, 9H); 13C NMR (125 MHz, CDCl3) δ 165.8, 141.4,
135.2, 131.0, 130.7, 119.5, 115.3, 80.8, 28.2; FTIR (film, cm-1
)
1701, 1626, 1264, 739; MS m/z 290 (M + 2, 42%), 288 (M+, 52%),
233 (100%). HRMS (EI, DCI/NH3) calcd for [C11H17NO2SBr]+
(MNH+) 306.0163, found 306.0156.
3-(4′-Bromo-2′-thiophenyl)-(E)-propenoic acid ethyl ester
(65).87 65 was obtained from a Wittig reaction between 4-bromo-
2-thiophenecarboxaldehyde (1.0 mmol, 192 mg), triphenylphosphine
(1.5 mmol, 393 mg), and ethyl bromoacetate (1.8 mmol, 200 µL)
in saturated NaHCO3 (5 mL) at 20 °C for 1 h. The crude product
was purified using flash chromatography (20% EtOAc/hexane, Rf
0.30) to give 98% (255 mg) of 65 as a white solid; mp 62-63 °C
(E/Z-ratio: 88/12): 1H NMR (500 MHz, CDCl3) δ 7.66 (d, CHâd
CHR, J ) 15.8 Hz, 1H), 7.25, 7.15 (br s, aromatic, 1H each), 6.24
(d, CHâdCHR, J ) 15.8 Hz, 1H), 4.25 (q, OCH2CH3, J ) 7.2 Hz,
2H), 1.32 (t, CH3CH2, J ) 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.3, 140.4, 135.6, 132.3, 125.1, 118.5, 110.9, 60.7,
14.3; FTIR (CH2Cl2, cm-1) 1708, 1631, 1265, 908, 734; MS m/z
261 (M+, 60%), 260 (M - 1, 100%), 215 (M - HOEt, 60%).
HRMS (EI, DCI/NH3) calcd for [C9H10SO2Br]+ (MH+) 260.9585,
found 260.9576.
3-(4′-Bromo-2′-thiophenyl)-(E)-propenoic acid tert-butyl ester
(66). 66 was obtained from a Wittig reaction between 4-bromo-2-
thiophenecarboxaldehyde (1.0 mmol, 192 mg), triphenylphosphine
(1.4 mmol, 366 mg), and tert-butyl bromoacetate (1.6 mmol, 240
µL) in saturated NaHCO3 (5 mL) at 20 °C for 1.5 h. The crude
product was purified using flash chromatography (5% Et2O/pentane,
Rf 0.80) to give 99% (286 mg) of 66 as a colorless oil (E/Z-ratio:
99/1): 1H NMR (500 MHz, CDCl3) δ 7.56 (d, CHâdCHR, J )
15.8 Hz, 1H), 7.22, 7.12 (br s, aromatic, 1H each), 6.18 (d, CHâd
CHR, J ) 15.8 Hz, 1H), 1.52 (s, C(CH3)3, 9H); 13C NMR (125
MHz, CDCl3) δ 165.6, 140.6, 134.6, 131.9, 124.7, 120.5, 110.8,
80.9, 28.2; FTIR (film, cm-1) 1703, 1629, 1265, 739; MS m/z 290
(M + 2, 24%), 288 (M+, 32%), 233 (44%), 217 (100%).
3-(2′-Thiophenyl)-(E)-propenoic acid tert-butyl ester (67).88
67 was obtained from a Wittig reaction between 2-thiophenecar-
boxaldehyde (1.0 mmol, 100 µL), triphenylphosphine (1.4 mmol,
366 mg), and tert-butyl bromoacetate (1.6 mmol, 240 µL) in
3-(4′-Hydroxy)-(E)-propenoic acid benzyl ester (62).86 62 was
obtained from a Wittig reaction between 4-hydroxybenzaldehyde
(1.0 mmol, 122 mg), triphenylphosphine (1.6 mmol, 420 mg), and
benzyl bromoacetate (1.4 mmol, 221 µL) in saturated NaHCO3 (5
mL) at 20 °C for 2 h. The crude product was purified using flash
chromatography (33% EtOAc/hexane, Rf 0.37) to give 64% (163 mg)
of 62 as a white solid; mp 87-89 °C (E/Z-ratio: 94/6) {lit.86 mp
90-92 °C}: 1H NMR (500 MHz, CDCl3) δ 7.67 (d, CHâdCHR,
J ) 16.0 Hz, 1H), 7.43-7.31 (m, aromatic, 7H), 6.83 (m, aromatic,
2H), 6.34 (d, CHâdCHR, J ) 16.0 Hz, 1H), 5.54 (br s, HOPh,
1H), 5.25 (s, OCH2Ph, 2H); 13C NMR (125 MHz, CDCl3) δ 167.4,
(85) Kikukawa, K.; Maemura, K.; Kiseki, Y.; Wada, F.; Matsuda, T. J.
Org. Chem. 1981, 46, 4885-4888.
(86) Guo, W.; Li, J.; Fan, N.; Wu, W.; Zhou, P.; X, C. Synth. Commun.
2005, 35, 145-152.
(87) Berthelot, P.; Vaccher, C.; Flouquet, N.; Debaert, M.; Luyckx, M.;
Brunet, C. J. Med. Chem. 1991, 34, 2557-2560.
(88) Lautens, M.; Mancuso, J.; Grover, H. Synthesis 2004, 2006-2014.
5258 J. Org. Chem., Vol. 72, No. 14, 2007

Wittig Reactions in Water Employing Ylides and Aldehydes
saturated NaHCO3 (5 mL) at 20 °C for 1.5 h. The crude product
was purified using flash chromatography (20% Et2O/pentane, Rf
0.50) to give 99% (208 mg) of 67 as a light yellow oil (E/Z-ratio:
92/8): 1H NMR (500 MHz, CDCl3) δ 7.68 (d, CHâdCHR, J )
15.6 Hz, 1H), 7.34 (d, aromatic, J ) 5.0 Hz, 1H), 7.21 (d, aromatic,
J ) 3.7 Hz, 1H), 7.03 (dd, aromatic, J ) 5.0, 3.7 Hz, 1H), 6.17 (d,
CHâdCHR, J ) 15.6 Hz, 1H), 1.52 (s, C(CH3)3, 9H); 13C NMR
(125 MHz, CDCl3) δ 166.1, 139.8, 136.0, 130.4, 127.97, 127.93,
119.1, 80.5, 28.2; FTIR (film, cm-1) 1701, 1627, 1392, 1150, 971,
853; MS m/z 210 (M+, 28%), 155 (75%), 137 (M - tBuO, 100%),
121 (88%).
Foundation (Blasker), the San Diego State University Founda-
tion, Pfizer Pharmaceuticals, and CSUPERB for a Howell award.
The authors thank Dendreon Pharmaceuticals and Dr. Dave
Duncan (Corvas) for chemicals and utensils used in this
study. The authors also thank Dr. LeRoy Lafferty for NMR
support.
Supporting Information Available: General and chemical
1
information plus copies of relevant H and 13C NMR spectra of
compounds 2-42, 44, 46-67. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was funded by the Petrol-
eum Research Fund (Grant 41199-AC1), the San Diego
JO070665K
J. Org. Chem, Vol. 72, No. 14, 2007 5259