The Baylis-Hillman reaction: One-pot stereoselective synthesis of methyl (2E)-3-aryl-2-hydroxymethylprop-2-enoates

Article abstract of DOI:10.1055/s-2000-8213

A facile, simple and one-pot conversion of methyl 3-aryl-3-hydroxy-2-methylenepropanoates into methyl (2E)-3-aryl-2-hydroxymethylprop-2-enoates via the sequential treatment with acetic anhydride/trimethylsilyl trifluoromethanesulfonate (TMSOTf) and potassium carbonate/methanol is described.

Full text of DOI:10.1055/s-2000-8213

1662
SHORT PAPER
The Baylis Hillman Reaction: One-Pot Stereoselective Synthesis of Methyl
(2E)-3-Aryl-2-hydroxymethylprop-2-enoates
Deevi Basavaiah,* Kisari Padmaja, Tummanapalli Satyanarayana
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
E-mail: dbsc@uohyd.ernet.in
Received 1 June 2000; revised 20 June 2000
ed in an operationally simple one-pot procedure directly
Abstract: A facile, simple and one-pot conversion of methyl 3-aryl-
into methyl (2E)-2-hydroxymethylalk-2-enoates.
3-hydroxy-2-methylenepropanoates into methyl (2E)-3-aryl-2-hy-
droxymethylprop-2-enoates via the sequential treatment with acetic
anhydride/trimethylsilyl trifluoromethanesulfonate (TMSOTf) and
potassium carbonate/methanol is described.
We have recently reported a convenient aqueous sulfuric
acid mediated isomerization of 3-hydroxy-3-aryl-2-meth-
ylenepropanenitriles into (E)- -cyanocinnamyl alco-
hols.13 Our attempts to extend a similar aqueous sulfuric
acid mediated isomerization reaction to methyl 3-hy-
droxy-2-methylenealkanoates were not successful. Based
on our recent report on the trimethylsilyl trifluo-
romethanesulfonate (TMSOTf) catalyzed isomerization
of methyl 3-aryl-3-acetoxy-2-methylenepropanoates into
methyl (2E)-3-aryl-2-acetoxymethylprop-2-enoates,14 we
envisioned that we can first prepare the required acetates
of methyl 3-hydroxy-2-methylenealkanoates, then these
molecules can be subjected to TMSOTf catalyzed isomer-
ization to provide (2E)-2-acetoxymethylalk-2-enoates.
Subsequent hydrolysis of the acetate group with potassi-
um carbonate/methanol can in principle provide the de-
sired (E)-allylic alcohols. Also we felt that all these three
operations can be very conveniently carried out in one pot
without isolating any compound in any step.
Key words: Baylis Hillman reaction, trimethylsilyl trifluo-
romethanesulfonate (TMSOTf), methyl (2E)-3-aryl-2-hydroxyme-
thylprop-2-enoates, one-pot stereoselective synthesis
The Baylis Hillman reaction has been and continues to
be an interesting carbon-carbon bond forming reaction
providing a useful class of densely functionalized mole-
cules whose applications in a variety of stereoselective
transformations have been well documented in the litera-
ture.1-14 In continuation of our interest in the development
of the Baylis Hillman reaction as a potential source for
stereoselective processes,9-14 we herein report simple,
convenient and one-pot stereoselective transformation of
methyl 3-aryl-3-hydroxy-2-methylenepropanoates, the
Baylis Hillman adducts obtained from the activated alk-
ene, methyl acrylate, into methyl (2E)-3-aryl-2-hy-
droxymethylprop-2-enoates via the successive treatment
with acetic anhydride/trimethylsilyl trifluoromethane-
sulfonate (TMSOTf), and potassium carbonate/methanol
in very good yields.
Accordingly, we have first selected methyl 3-phenyl-3-
hydroxy-2-methylenepropanoate (1a) as a substrate for
this purpose and various conditions were tried for one-pot
transformation. The best results were obtained when me-
thyl 3-phenyl-3-hydroxy-2-methylenepropanoate (1a)
(10 mM) was treated with acetic anhydride (12 mM) and
TMSOTf (cat. 11 mol%) at room temperature for two
hours in dichloromethane as a solvent, followed by the
treatment with potassium carbonate/methanol, after the
removal of the solvent dichloromethane, for one hour at
room temperature thus providing the desired methyl
(2E)-3-phenyl-2-hydroxymethylprop-2-enoate (3a)23 in
61% yield (Scheme). Encouraged by this successful re-
sult, we have prepared a representative class of methyl
(2E)-3-aryl-2-hydroxymethylprop-2-enoates (3b g) in
high yields using the corresponding Baylis Hillman ad-
ducts (Scheme and Tables 1, 2).
(2E)-2-Hydroxymethylalk-2-enoic acids and their esters
are useful synthons for synthesis of various biologically
active molecules.15-22 However, there are only a few meth-
ods available in the literature for synthesis of these impor-
tant molecules.18-22 It is interesting to note that (m)ethyl
3-hydroxy-2-methylenealkanoates, the Baylis Hillman
adducts obtained from (m)ethyl acrylate, have been a ma-
jor source for obtaining these (2E)-2-hydroxymethylalk-
2-enoic acid derivatives. Thus, (m)ethyl 3-hydroxy-2-me-
thylenealkanoates have been transformed into the desired
(m)ethyl (2E)-2-hydroxymethylalk-2-enoates in three dif-
ferent elegant ways. The first involves a three step se-
quence,
bromination-formylation-hydrolysis,20
the
However, our attempts to extend this methodology to me-
thyl 3-hydroxy-2-methylenenonanoate under the similar
reaction conditions were unsuccessful. And also our at-
tempts to directly transform methyl 3-phenyl-3-hydroxy-
2-methylenepropanoate (1a) into methyl (2E)-3-phenyl-
2-hydroxymethylprop-2-enoate via the treatment with tri-
methylsilyl trifluoromethanesulfonate (TMSOTf) (with-
out using acetic anhydride) were not successful.
second deals with bromination-acetylation-hydrolysis,18
while the third method uses DEAD/PPh3 (Mitsunobu con-
ditions) reagent to first obtain the O-protected alcohol,
which on hydrolysis provides the desired (E)-allylic alco-
hols.19,22 All these methods, though simple, involve at
least two steps. In view of the importance of these mole-
cules we felt that it would be desirable and more useful if
methyl 3-hydroxy-2-methylenealkanoates can be convert-
Synthesis 2000, No. 12, 1662–1664 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
The Baylis Hillman Reaction: One-Pot Stereoselective Synthesis
1663
Table 1 Syntheses of Methyl (2E)-3-Aryl-2-hydroxymethylprop-2-
enoates (3a−g)a
O
OH
O
Ac2O / TMSOTf (cat.)
CH2Cl2, RT, 2h
OMe
OAc
OMe
Ar
Ar
Alcohol
1a
Ar
Product
3ab
3bb
3c
Yield (%)
1a-g
Phenyl
61
69
60
77
74
70
64
2a-g
1b
p-chlorophenyl
p-tolyl
1c
Ar = phenyl, 4-chlorophenyl, 4 -methylphenyl
4 -ethylphenyl, 4 -isopropylphenyl,
2-methylphenyl, naphth-1-yl
K2CO3 /MeOH
RT, 1h
1d
p-ethylphenyl
p-isopropylphenyl
o-tolyl
3d
1e
3e
O
1f
3f
OMe
Ar
1g
naphth-1-yl
3g
OH
3a-g
a All reactions were carried out in 10 mM scale of alcohols (1a−g) and
yields refer to the isolated yields based on the alcohols (1a−g).
b We observed that there is formation of small amounts (≈ 5%) of pre-
sumably the (Z)-isomer as indicated by a singlet δ ≈ 6.9 with low in-
tensity in the 1H NMR of the crude products (3a, 3b). However, the
pure (E)-isomers were obtained after silica gel column chromatogra-
phy.24
60-77%
overall yields from 1 a-g
Scheme
During preparation of this manuscript, a similar type of
work was reported by Kim and co-workers.25 They have
described an interesting synthesis of ethyl (2E)-3-aryl-2-
hydroxymethylprop-2-enoates via the treatment of ethyl
3-aryl-3-hydroxy-2-methylenepropanoates (2 mM) with
trifluoroacetic acid (2 mL) at 60 70 C for 20 hours. A
quick comparison of our work with Kim’s elegant work
clearly indicates that Kim’s method is a one step reaction
requiring 20 hours, while our procedure is a two step one-
Table 2 Data for Products (3a−g)a
Product
3a
Rfb
IR (neat)c
1H NMR (CDCl3/TMS, 200 MHz); , J (Hz)
13C NMR (CDCl3/TMS, 50 MHz);
v (cm−1)
0.49
0.50
0.53
3476, 1689,
1630
2.60 (t, 1 H, J = 6.5), 3.86 (s, 3 H), 4.49 (d, 2 H, J
= 6.5),7.32 7.53 (m, 5 H), 7.83 (s, 1 H)
51.94, 57.42, 128.41, 129.06, 129.51,
130.94, 134.45, 142.56, 168.29
3b
3489, 1685,
1627
2.61 (t, 1 H, J = 6.5), 3.86 (s, 3 H), 4.45 (d, 2 H, J
= 6.5), 7.40 (m, 4 H), 7.77 (s, 1 H)
51.99, 57.08, 128.62, 130.85, 131.29,
132.80, 135.14, 141.26, 167.99
3c
3470, 1709,
1631
2.38 (s, 3 H), 2.54 (t, 1 H, J = 6.6), 3.86 (s, 3 H),
4.51 (d, 2 H, J = 6.6), 7.22 (d, 2 H, J = 7.8), 7.37
(d, 2 H, J = 7.8), 7.81 (s, 1 H)
21.26, 51.99 57.70, 129.26, 129.70,
130.11, 131.68, 139.47, 142.76,
168.52
3d
3e
0.54
0.54
3470, 1709,
1630
1.24 (t, 3 H, J = 7.6), 2.50 2.78 (m, 3 H), 3.85 (s,
3 H), 4.50 (d, 2 H, J = 6.7), 7.23 (d, 2 H, J = 7.4),
7.39 (d, 2 H, J = 7.4), 7.81 (s, 1 H)
15.26, 28.70, 52.04, 57.79, 128.11,
129.83, 130.16, 131.96, 142.82,
145.82, 168.59
3477, 1709,
1630
1.26 (d, 6 H, J = 6.8), 2.53 (t, 1 H, J = 6.7), 2.93
(sept, 1 H, J = 6.8), 3.85 (s, 3 H), 4.51 (d, 2 H, J =
6.7), 7.26 (d, 2 H, J = 8.8), 7.40 (d, 2 H, J= 8.8),
7.81 (s, 1 H)
23.72, 33.95, 52.00, 57.74, 126.65,
129.84, 130.17, 132.08, 142.76,
150.37, 168.55
3f
0.51
0.52
3420, 1701,
1631
2.31 (s, 3 H), 2.66 (t, 1 H, J = 6.8), 3.87 (s, 3 H),
4.39 (d, 2 H, J = 6.8), 7.14 7.34 (m, 4 H), 7.89 (s,
1 H)
19.89, 52.11, 58.08, 125.87, 129.09,
129.20, 130.09, 131.47, 133.77,
136.94, 141.46, 168.29
3g
3503, 1705,
1635
2.67 (t, 1 H, J = 6.8), 3.93 (s, 3 H), 4.43 (d, 2 H, J
= 6.8), 7.44 7.61 (m, 4 H), 7.81 7.98 (m, 3 H),
8.37 (s, 1 H)
52.17, 58.33, 124.38, 125.25, 126.21,
126.61, 127.26, 128.54, 129.49,
131.45, 131.60, 132.81, 133.35,
140.56, 168.13
a Satisfactory elemental analyses were obtained for 3a−g (C 0. 47%, H 0. 58%).
b Eluent = 25% EtOAc in hexanes.
c Molecules 3a, 3b, 3g were obtained as crystalline solids ( mp for 3a = 57-58 °C, 3b = 55-56°C, 3g = 63-65°C, and IR spectra were recorded
as KBr plates), and the remaining ones as colorless liquids.
Synthesis 2000, No. 12, 1662–1664 ISSN 0039-7881 © Thieme Stuttgart · New York

1664
D. Basavaiah et al.
SHORT PAPER
(6) Hoffmann, H. M. R.; Eggert, U.; Poly, W. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1015.
(7) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S.
J. Am. Chem. Soc. 1999, 121, 10219.
(8) Sugahara, T.; Ogasawara, K. Synlett 1999, 419.
(9) Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.;
Pandiaraju, S. Tetrahedron Lett. 1997, 38, 2141.
(10) Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.;
Sarma, P. K. S.; Kumaragurubaran, N. J. Org. Chem. 1999,
64, 1197.
comparable in both cases (our procedure and the Kim’s
method).
In conclusion, we have developed a convenient operation-
ally simple one-pot procedure for the stereoselective
transformation of methyl 3-aryl-3-hydroxy-2-methyl-
enepropanoates into methyl (2E)-3-aryl-2-hydroxymeth-
ylprop-2-enoates.
(11) Basavaiah, D.; Suguna Hyma, R.; Padmaja, K.; Krishnama-
charyulu, M. Tetrahedron 1999, 55, 6971.
(12) Basavaiah, D.; Bakthadoss, M.; Pandiaraju, S. Chem.
Commun. 1998, 1639.
(13) Basavaiah, D.; Kumaragurubaran, N.; Padmaja, K. Synlett
1999, 1630.
(14) Basavaiah, D.; Muthukumaran, K.; Sreenivasulu, B. Synthesis
2000, 545.
(15) Edwards, J. D.; Matsumoto, T.; Hase, T. J. Org. Chem. 1967,
32, 244.
(16) Campi, E. V.; Dyall, K.; Fallon, G.; Jackson, W. R.;
Perlmutter, P.; Smallridge, A. J. Synthesis 1990, 855.
(17) Kupchan, S. M.; Davies, V. H.; Fujita, T.; Cox, M. R.; Bryan,
R. F. J. Am. Chem. Soc. 1971, 93, 4916.
(18) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2151.
(19) Charette, A. B.; Cote, B. Tetrahedron Lett. 1993, 34, 6833.
(20) Beltaief, I.; Hbaieb, S.; Besbes, R.; Amri, H.; Villieras, M.;
Villieras, J. Synthesis 1998, 1765.
(21) Beltaief, I.; Besbes, R.; Amri, H.; Villieras, J. Tetrahedron
Lett. 1997, 37, 813.
Mps were recorded on a Superfit (India) capillary melting point ap-
paratus and are uncorrected. IR spectra were recorded on a JASCO-
FT-IR model 5300 or Perkin Elmer model 1310 spectrometer us-
ing samples as neat liquids or in KBr. 1H NMR (200 MHz) and 13
C
NMR (50 MHz) spectra were recorded in CDCl3 on a Bruker-AC-
200 spectrometer using TMS ( = 0 ppm) as internal standard. Ele-
mental analyses were recorded on a Perkin Elmer 240C-CHN ana-
lyzer. All the required Baylis Hillman adducts (starting materials)
were prepared by reaction of the corresponding aldehydes with me-
thyl acrylate in the presence of a catalytic amount of DABCO ac-
cording to the literature procedure.2,3
Isomerization of Baylis Hillman Adducts; General Procedure
To a stirred solution of the Baylis Hillman adduct (1a g, 10 mM)
and acetic anhydride (12 mM) in CH2Cl2 (20 mL), was added TM-
SOTf (0.2 mL, 11mol%, 0.245 g) at r.t. After 2 h, CH2Cl2 was re-
moved, MeOH (20 mL) and K2CO3 (30 mM, 4.14 g) were added and
the reaction mixture was stirred for 1 h at r.t. Then the solvent,
MeOH was removed under reduced pressure and the residue was di-
luted with H2O (10 mL) and extracted with Et2O (3 x 10 mL). The
combined organic layer was dried (Na2SO4). The solvent was evap-
orated and the crude product, thus obtained, was purified by column
chromatography (8% EtOAc in hexanes) to provide the desired
product (3a g). The isolated yields of the products (3a g) are given
in Table 1 and the spectral data along with elemental analyses and
Rf values are given in Table 2.
(22) Charette, A. B.; Cote, B.; Monroc, S.; Prescott, S. J. Org.
Chem. 1995, 60, 6888.
(23) 1H NMR spectrum of the crude product shows a peak of very
low intensity at
6.9 presumably indicating the presence of
minor amounts ( 5%) of the (Z)-isomer. However, pure (E)-
isomer was obtained after column chromatography. The E
stereochemistry was assigned by comparison of the 1H NMR
chemical shift value of the vinylic proton ( = 7.83) with that
of the corresponding ethyl ester ( = 7.76).20,25
Acknowledgement
(24) In 1H NMR spectrum of the 3-aryl-(2-substituted)-prop-2-
enoates, the -vinylic proton cis to the ester group
We thank DST (New Delhi) for funding this project. We thank the
UGC (New Delhi) for Special Assistance Program in organic che-
mistry in the School of Chemistry, University of Hyderabad. KP
and TSN thank UGC (New Delhi) for their research fellowships.
[(E)-isomer] appears at
trans to the ester group [(Z)-isomer] appears at
7.70, while the -vinylic proton
6.80.26,27,28
(25) Kim, H. S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J.;
Kim, J. N. Tetrahedron Lett. 2000, 41, 2613.
(26) Tanaka, K.; Yamagishi, N.; Tanikaga, R.; Kaji, A. Bull. Chem.
Soc. Jpn. 1979, 52, 3619.
References
(27) Basavaiah, D.; Pandiaraju, S.; Krishnamacharyulu, M.;
Synlett 1996, 747.
(28) Basavaiah, D.; Pandiaraju, S. Tetrahedron 1996, 52, 2261.
(1) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
(2) Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R.
Tetrahedron 1996, 52, 8001.
(3) Ciganek, E. In Organic Reactions, Vol. 51; Paquette, L. A.,
Ed.; Wiley: New York, 1997; pp 201 350.
(4) Matsumoto, S.; Okubo, Y.; Mikami, K. J. Am. Chem. Soc.
1998, 120, 4015.
Article Identifier:
1437-210X,E;2000,0,12,1662,1664,ftx,en;Z05100SS.pdf
(5) Chamakh, A.; Amri, H. Tetrahedron Lett. 1998, 39, 375.
Synthesis 2000, No. 12, 1662–1664 ISSN 0039-7881 © Thieme Stuttgart · New York