Synthesis and cyclo-oligomerization of 2-(bromomethyl)-3-aryl-2-propenoic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.04.053

2-Bromomethyl-3-aryl-2-propenoic acids have been synthesized from Baylis-Hillman adducts derived from aromatic aldehydes and t-butyl acrylates as new precursors in MBH chemistry. Further triolides were synthesized by the cyclo-oligomerization of 2-bromome

Full text of DOI:10.1016/j.tetlet.2009.04.053

Tetrahedron Letters 50 (2009) 3892–3896
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Tetrahedron Letters
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Synthesis and cyclo-oligomerization of 2-(bromomethyl)-3-aryl-2-propenoic
acid derivatives
*
Yusuf Zulykama, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Bromomethyl-3-aryl-2-propenoic acids have been synthesized from Baylis–Hillman adducts derived
from aromatic aldehydes and t-butyl acrylates as new precursors in MBH chemistry. Further triolides
were synthesized by the cyclo-oligomerization of 2-bromomethyl-3-aryl-2-propenoic acids in the pres-
ence of Cs2CO3 demonstrating the synthetic utility of these motifs.
Received 24 February 2009
Revised 13 April 2009
Accepted 15 April 2009
Available online 18 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Morita Baylis–Hillman (MBH) reaction1–4 has found wide appli-
cability by virtue of its functional density, the diversity of function-
ality realized by the widening of the substrate scope,1 and further
functionalization by nucleophilic substitution.5 These striking
features have contributed to the synthesis of multifunctional
derivatives,6 heterocycles,7 carbocycles8, and several biologically
relevant molecules1e,h through MBH chemistry.
R'
R'
OH
R''
COOH
Br
t
48% HBr
R''
COOBu
H2SO4
DCM
R'''
R'''
2a-h
1a-h
Scheme 1.
In continuation of our interest in MBH chemistry,9 in this Letter
we report the synthesis of 2-bromomethyl-3-aryl prop-2-enoic
acids as new precursor in Baylis–Hillman chemistry and have dem-
onstrated their utility in the synthesis of triolides.
corresponding to the t-butyl group and the presence of allylic
protons at d 4.22 ppm in the 1H NMR spectrum confirmed the
formation of the desired product 2a.16 Analogously 2-bromo-
methyl-3-aryl-2-propenoic acid derivatives (2b–h) were
synthesized and the results are assembled in Table 1.
Difference NOE experiment was carried out to assign the stereo-
chemistry of 2a (Fig. 1). Irradiation of methylene protons led to the
enhancement of the aromatic peak at d 7.62 ppm by 26.3%. Further
irradiation of the olefinic proton led to enhancement of the aro-
matic proton at d 7.62 ppm by 7.2%. No enhancement was observed
in the olefinic signal on irradiating the methylene protons indicat-
ing that they are trans and thus possess E stereochemistry.
MBH acetates10 and halides11 as precursors have dominated the
arena of BH chemistry. Most chemical transformations in the MBH
chemistry essentially involved hydrolysis of the ester functional-
ity.12 It occurred to us that carboxylic acid functionality instead
of ester would be more suited for further chemical transforma-
tions. Schneider et al. have reported the synthesis of 2-bromo-
methyl-2-butenoic acid moiety via
a three-step procedure
starting from the MBH adducts of acetaldehyde and methyl
acrylate.13 Ciganek obtained a mixture of 2-(methoxymethyl)-3-
aryl-2-propenoic acid and methyl 2-(methoxymethyl)-3-aryl-2-
propenoate by the tandem vicinal difunctionalization of methyl
acrylate with sodium methoxide and aromatic aldehydes. The ester
was subsequently treated with HBr in acetic acid at 60 °C to furnish
the 2-(bromomethyl)-3-aryl-2-propenoic acid.14 Thus we envis-
aged the synthesis of 2-bromomethyl-3-aryl-2-propenoic acids
from t-butyl acrylate derived MBH adduct as depicted in Scheme
1 in a single step intending to add a new entry to the list of existing
MBH precursors (MBH acetates and bromides).
The synthesis of c-butyrolactones and c-butyrolactams from 2-
bromomethylacrylic acid clearly highlights the synthetic utility of
the structural framework.17 In addition Schneider et al. oligomer-
ized 2-bromomethyl-3-phenyl-2-propenoic acid in acetonitrile
using DBU as base to tri- and tetrolides at room temperature. They
also obtained triolides, tetrolides, pentolides, and heptolides when
the reaction was carried out at 45 °C.13
Intrigued by this report and realizing the role of Cs2CO3 as an
efficient macrocyclization reagent in organic synthesis,18 we trea-
ted a solution of 2-bromomethyl-3-phenyl-2-propenoic acid (2a)
in DMF with one equivalent of Cs2CO3. Stirring the reaction mix-
ture at room temperature for an hour furnished product 3a in
30% yields. The 1H NMR spectrum of the product displayed shift
in the position of the allylic protons but did not give any clue on
the degree of oligomerization. Single-crystal XRD studies19 of 3b
To this end, we added HBr (8 mL) dropwise followed by H2SO4
(8 mL) to a solution of 1a15 in DCM at 0 °C and continued the stir-
ring of the reaction mixture until the TLC indicated the disappear-
ance of the starting compounds. The absence of signals
* Corresponding author. Tel.: +91 44 24911289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.053

Y. Zulykama, P. T. Perumal / Tetrahedron Letters 50 (2009) 3892–3896
3893
Table 1
Syntheses of 2-(bromomethyl)-3-aryl-2-propenoic acid derivatives
Entry
MBH adduct
2-Bromomethyl-3-aryl-2-propenoic acid
Mp (°C)
Yield (%)b
OH
COOH
t
t
t
COOBu
COOBu
1
158
75
Br
160a
2a14
1a
OH
COOH
2
3
190
170
78
76
Cl
Br
Cl
2b
2c
1b
OH
COOH
Br
COOBu
CH3
CH3
1c
OH
COOH
Br
t
COOBu
4
5
6
7
188
198
180
73
75
70
H3C
H 3C
2d
1d
Cl
OH
COOH
Br
t
COOBu
Cl
Cl
Cl
2e
1e
OH
COOH
t
COOBu
Br
NO2
NO2
2f
1f
OH
t
COOBu
COOH
Br
216
71
60
218a
1g
2g14
OH
COOH
t
COOBu
8
245
OHC
Br
OHC
2h
1h
a
Literature melting point.
Isolated yield.
b
7.2%
COOH
Br
and 3c (Fig. 2 and 3) obtained by crystallizing the respective pure
products from acetone confirmed the products as triolides.
Having established the products as triolides, next it was our
concern to improve the yields. Cyclo-oligomerization of 2e was
26.3%
Figure 1. Difference NOE studies of 2a.

3894
Y. Zulykama, P. T. Perumal / Tetrahedron Letters 50 (2009) 3892–3896
Figure 2. ORTEP diagram of 3b.
Figure 3. ORTEP diagram of 3c.
Table 2
Optimization studies for the cyclo-oligomerization of 2e
R'''
Entry
Concentration
Yield (%)
R''
R'
R'
O
1
2
3
4
0.03
0.04
0.05
0.12
30
46
61
31
R''
O
O
COOH
Br
O
R'''
Cs2CO3
O
O
R'''
R'
0.04 - 0.05 M
DMF
R''
2a-h
carried out at various concentrations and the results are presented
in Table 2. It is evident from the Table 2 that good yields of the tri-
olides were obtained only when the cyclo-oligomerization was
conducted in 0.04–0.05 M DMF solution.20 The triolides 3a–h were
synthesized under optimized conditions (Scheme 2 and Table 3).
R'
R'''
R''
3a-h
Scheme 2.

Y. Zulykama, P. T. Perumal / Tetrahedron Letters 50 (2009) 3892–3896
3895
Table 3
Cyclo-oligomerization of 2-(bromomethyl)-3-aryl-2-propenoic acid derivatives
Table 3 (continued)
Yield (%)a
Entry Triolide
Melting point (°C)
Yield (%)a
Entry Triolide
Melting point (°C)
NO2
O
O
O2N
O
O
O
O
O
O
1
137
61
O
O
O
O
6
160
55
57
53
3a13
NO2
3f
O
Cl
O
O
Cl
O
O
O
O
2
170
65
O
O
O
O
O
7
120
Cl
3b
3g
CHO
O
CH3
O
CH3
O
O
O
O
O
OHC
O
3
126
63
O
O
8
159
O
O
H3C
CHO
3c
3h
CH3
a
Isolated yield.
O
O
In conclusion, we have synthesized 2-bromomethyl-3-aryl-2-
propenoic acid derivatives (2) as promising precursors in MBH
chemistry and cyclo-oligomerized the 2-bromomethyl-3-aryl-2-
propenoic acid to triolides (3) using Cs2CO3 illustrating its syn-
thetic utility. Further work is underway in our laboratory to ex-
plore the synthetic utility of 2-bromomethyl-3-aryl-2-propenoic
acids in the synthesis of heterocyclic frameworks.
O
H3C
4
62
61
O
O
O
CH3
3d
Acknowledgement
Cl
Y.Z. thanks CSIR, India for the financial support.
References and notes
O
Cl
Cl
O
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5
182
64
O
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3e
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3-hydroxy-2-methylene-3-phenylpropanoate
(6 g, 25 mmol) (1a) in
dichloromethane (20 mL) was added HBr (48%, 8 mL) at 0 °C followed by the
dropwise addition of concentrated sulfuric acid (8 mL). The reaction
temperature was allowed to rise to room temperature and stirring continued
for 30 min. The reaction mixture was poured into ice cold water and extracted
with ethyl acetate (3 Â 100 mL). The combined organic layers were dried over
Na2SO4. The excess solvent was removed under reduced pressure and column
was purified (silica gel, 20% ethyl acetate in hexane) to furnish 2a.(2Z)-2-
(Bromomethyl)-3-(4-methylphenyl)-2-propenoic acid (2d): White solid. Mp
188 °C. IR (KBr): 1422, 1651, 1673, 2835 cmÀ1 1H NMR (500 MHz, DMSO-
.
d6): d 2.27 (s, 3H), 4.16 (s, 2H), 7.18 (d, J = 8 Hz, 2H), 7.47 (d, J = 8 Hz, 2H), 7.59
(s, 1H). 13C NMR (125 MHz, DMSO-d6): d 21.47, 55.87, 129.67, 130.40, 132.14,
132.47, 139.45, 141.62, 169.43. MS m/z 254 (M+), 256 (M++2) Anal Calcd for
C11H11BrO2: C, 51.79; H, 4.35. Found: C, 51.84; H, 4.32.
17. (a) Choudhury, P. K.; Foubelo, F.; Yus, M. Tetrahedron Lett. 1998, 39, 3581; (b)
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18. Flessner, T.; Doye, S. J. Prakt. Chem. 1999, 341, 186.
19. Detailed X-ray crystallographic data are available from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK for compound 3b (CCDC No. 698943) and 3c
(CCDC No. 698945).
20. Typical procedure for the syntheses of compounds 3a: Cesium carbonate (1.35 g,
4.2 mmol) was added to 2-(bromomethyl)-3-phenyl-2-propenoic acid 2a (1 g,
4.2 mmol) in DMF (100 mL) and the reaction mixture was stirred for 1 h. After
completion of the reaction as indicated by TLC, the reaction mixture was
poured into water and extracted with ethyl acetate (3 Â 50 mL). The combined
organic layers were dried over Na2SO4. The excess solvent was removed under
reduced pressure and column was purified (silica gel, 10% ethyl acetate in
hexane) to furnish 3a.(3E,7E,11E)-3,7,11-Tris(2-methylbenzylidene)-1,5,9-
trioxacyclododecane-4,8,12-trione(3c): White solid. Mp 126 °C. IR (KBr) :1630,
9. Zulykama, Y.; Perumal, P. T. Aust. J. Chem. 2007, 60, 205.
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Batra, S. Synthesis 2006, 63.
1171, 2934 cmÀ1 1H NMR (500 MHz, CDCl3): d 2.33 (s, 9H), 5.08 (s, 6H), 7.18–
.
7.30 (m, 12H), 7.96 (s, 3H). 13C NMR (125 MHz, CDCl3): d 20.08, 61.11, 125.98,
128.39, 128.98, 129.37, 130.42, 133.50, 137.35, 143.49, 166.63. MS m/z 523
(M+). Anal Calcd for C33H30O6: C, 75.84; H, 5.79. Found: C, 75.90; H, 5.77.