An efficient stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes from unactivated Baylis-Hillman adducts using NaBH4/CuCl 2·2H2O

Article abstract of DOI:10.1016/j.tetlet.2004.10.088

A convenient and facile stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes has been achieved by treatment of unactivated Baylis-Hillman adducts with NaBH₄ in the presence of CuCl ₂·2H₂O at room temperature for 15 min.

Full text of DOI:10.1016/j.tetlet.2004.10.088

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9225–9227
An efficient stereoselective synthesis of (E)- and (Z)-trisubstituted
alkenes from unactivated Baylis–Hillman adducts
using NaBH4/CuCl2Æ2H2Oq
Biswanath Das,* Joydeep Banerjee, Anjoy Majhi and Gurram Mahender
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 25 August 2004; revised 8 October 2004; accepted 14 October 2004
Abstract—A convenient and facile stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes has been achieved by treatment of
unactivated Baylis–Hillman adducts with NaBH4 in the presence of CuCl2Æ2H2O at room temperature for 15min.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Trisubstituted alkene moieties have been widely ob-
served in several natural bioactive compounds including
different pheromones and antibiotics.1 The biological
properties of these alkenes are highly dependent on their
isomeric purity. Various trisubstituted alkenes with de-
fined stereochemistry have also been used as key inter-
mediates for the synthesis of other stereospecific
compounds.2 Thus a limited number of methods have
been developed for stereoselective preparation of trisub-
stituted alkenes.2,3 Here we present our efforts toward
the synthesis of (E)- and (Z)-trisubstituted alkenes from
the unactivated Baylis–Hillman adducts, 3-hydroxy-2-
methylene-alkanoates 1 and 3-hydroxy-2-methylene-alk-
anenitriles 2.
We initially observed that treatment of 1 with NaBH4
alone afforded a mixture of trisubstituted alkene 3, the
corresponding 1,3-propane diol and the saturated alco-
hol in the approximate ratio of 5:2:3. Previously the
reaction of 1 with NaBH4 was reported8 to yield the cor-
responding 1,3-propane diols as the major products.
During the present study we first considered the reduc-
tion of 1b (R = 2-Cl–C6H4 and EWG = –COOMe) with
NaBH4 in the presence of different metallic chlorides to
examine the variation of yields of the products (Table 1).
It was observed that NaBH4 in combination with a
metallic chloride (except with LiCl) afforded the trisub-
stituted alkene, 3b as the major product along with the
corresponding saturated alcohol in minor amounts
(ꢀ5%). CuCl2 is the metallic chloride of choice in terms
The Baylis–Hillman reaction involves the coupling of
activated vinylic systems with electrophiles under the
catalytic influence of a tertiary amine, usually DABCO.4
The adducts 1 (derived from acrylate esters) and 2 (de-
rived from acrylonitrile) have been utilized for stereose-
lective syntheses of various functionalized molecules.4b,5
In continuation of our work6 on the synthesis of trisub-
stituted alkenes derived from Baylis–Hillman adducts
we have studied the effect of the reactions of these ad-
ducts with a combination of NaBH4 and a metallic
chloride.7
Table 1. Reduction of 1b (R = 2-Cl–C6H4, EWG = –COOMe) with
NaBH4 in the presence of different metallic chloridesa
Entry
Metal ion
Isolated yield (%) of alkeneb
1
2
3
4
5
6
7
8
Li+
15
82
70
72
7
Cu2+
Co2+
Ni2+
Zn2+
Al3+
In3+
Ce3+
12
55
68
a Treatment of 1b (1equiv) with NaBH4 (1.5equiv) and CuCl2Æ2H2O
(1.5equiv) in methanol at room temperature for 15min.
b In entry 1 the corresponding 1,3-propane diol was the major product
(76%); the corresponding saturated alcohol was formed as a minor
product (ꢀ5%) in each case.
Keywords: Unactivated Baylis–Hillman adduct; (Z)- and (E)-Trisubsti-
tuted alkenes; NaBH4/CuCl2Æ2H2O; Metallic halides; Stereochemistry.
q Part 55 in the series, Studies on Novel Synthetic Methodologies.
*
Corresponding author. Tel./fax: +91 40 7160512; e-mail:
biswanathdas@yahoo.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.088

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B. Das et al. / Tetrahedron Letters 45 (2004) 9225–9227
The stereochemistry of the reaction can possibly be
OH
EWG
explained by considering the transition state models A,
B, and C. Transition state A is more favored than B
when EWG = –COOMe and (E)-products are thus
formed, exclusively. On the other hand, C is somewhat
more favored than A when EWG = –CN, as –CN is
linear and hence (Z)-products are formed predomi-
nantly.
NaBH4/CuCl2.2H2O
MeOH, r.t., 15 min
R
EWG
R
71- 86%
EWG = -COOMe
EWG = -CN
1
2
3
4
EWG = -COOMe
EWG = -CN
Scheme 1.
R
R
H
H
H
R
of the yield of the alkene (Scheme 1). The activity of
NiCl2, CoCl2, and CeCl3 in combination with NaBH4
is somewhat weak while that of ZnCl2 and AlCl3 is poor.
Reduction with NaBH4/InCl3 produced 3b in 55% yield.
However, due to the stronger reducing capacity,9
NaBH4 in the presence of LiCl produced the corre-
sponding 1,3-propane diol as the major product (76%)
along with 3b (15%) and the saturated alcohol (9%).
COOMe
Me
C
EWG
Me
Me
N
OH
OH
OH
C
A
B
In conclusion, we have developed a simple and efficient
methodology for the stereoselective synthesis of (E)- and
(Z)-trisubstituted alkenes from unactivated Baylis–Hill-
man adducts by treatment with NaBH4 in the presence
of CuCl2Æ2H2O. The reducing system can easily be pre-
pared from readily available and inexpensive reagents.
The mild reaction conditions, experimental simplicity,
short reaction time, and high yields as well as selectivity
are the main advantages of the present protocol. The
synthesis of some bioactive naturally occurring mole-
cules applying this methodology is currently under pro-
gress in our laboratory.
Previously the trisubstituted alkenes 3 were prepared
from the unactivated Baylis–Hillman adducts 1 by treat-
ment with a low-valent titanium reagent10a or SmI2.10b
In the first case the conversion was conducted under re-
flux and the yields (50 or <50%) were unsatisfactory. In
the second case trisubstituted alkenes 3 were prepared
along with 1,5-hexadiene derivatives at various temper-
atures, and at low temperature the yields of the former
were poor.
In order to generate a series of trisubstituted alkenes the
Baylis–Hillman adducts, 3-hydroxy-2-methylene-alk-
anoates 1 and 3-hydroxy-2-methylene-alkanenitriles 2
were treated with NaBH4/CuCl2Æ2H2O in methanol.11
The reaction was conducted for 15min at room temper-
ature. The trisubstituted alkenes (3 and 4, respectively)
were formed in high yields (Table 2). The stereochemis-
try of the products was easily determined4b from the 1H
NMR spectra and the ratio of (E)- and (Z)-isomers was
determined from the 1H NMR spectra of the crude
products. It was observed that the product 3 was formed
with (E)-configuration while product 4 was obtained
with high (Z)-selectivity (Table 2).
Acknowledgements
The authors thank CSIR and UGC, New Delhi for
financial assistance.
References and notes
1. (a) Bradshaw, J. W. S.; Baker, R.; Howse, P. E. Nature
1975, 258, 230–231; (b) Rossi, R.; Carpita, A.; Messeri, T.
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Chem. Rev. 1993, 93, 1699–1733.
2. Marfat, A.; McGuirk, P. R.; Helquist, P. J. Org. Chem.
1979, 44, 3888–3901.
Table 2. Synthesis of (E)- and (Z)-trisubstituted alkenes 3 and 4 using
NaBH4/CuCl2Æ2H2Oa
3. (a) Masaki, Y.; Sakuma, K.; Kaji, K. J. Chem. Soc.,
Chem. Commun. 1980, 434–435; (b) Brown, H. C.;
Basavaiah, D. J. Org. Chem. 1982, 47, 5407–5409; (c)
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Entry
R
EWG
Isolated
yieldb (%)
E:Z
3a
3b
3c
3d
3e
3f
C6H5
COOMe 86
COOMe 82
COOMe 81
COOMe 78
COOMe 77
100:0
100:0
100:0
100:0
100:0
100:0
12:88
10:90
14:86
15:85
18:82
2-Cl–C6H4
4-Cl–C6H4
2,4-Cl2–C6H3
4-MeO–C6H4
CH3–CH(CH3)–CH2– COOMe 75
4a
4b
4c
4d
4e
C6H5
CN
CN
CN
CN
CN
83
80
78
74
71
2-Cl–C6H4
4-Cl–C6H4
4-MeO–C6H4
n-C4H9
a The structures of the alkenes were determined from their spectral (1H
NMR and MS) data.
b The corresponding saturated alcohol was formed as a minor product
(ꢀ5%) in each case.
6. (a) Das, B.; Banerjee, J.; Ravindranath, N.; Venkataiah,
B. Tetrahedron Lett. 2004, 45, 2425–2426; (b) Das, B.;

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A. Org. Lett. 2004, 6, 3349–3352.
The mixture was extracted with ether (3 · 10mL), the
combined organics dried over Na2SO4 and the solvent was
removed under reduced pressure. The residue was sub-
jected to column chromatography over silica gel using 5%
EtOAc in hexane as eluent to afford pure trisubstituted
alkene. The spectroscopic data of two representative
alkenes are given below.
7. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103,
5454–5459.
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11. General experimental procedure: The Baylis–Hillman
adduct (1 or 2) (2mmol) and CuCl2Æ2H2O (3mmol) were
dissolved in MeOH (5mL) and the mixture stirred for
5min. NaBH4 (3mmol) was added in small portions with
stirring. A vigorous gas evolution occurred and the
temperature of the mixture increased (35–40ꢁC). Stirring
was continued for 15min. Saturated aqueous NH4Cl
solution was added to neutralize the reaction mixture.
3b: 1H NMR (CDCl3, 200MHz): d 7.72 (1H, s), 7.41 (1H,
dd, J = 8.0, 2.0Hz), 7.32–7.20 (3H, m), 3.83 (3H, s), 1.98
(3H, s); 13C NMR (CDCl3, 50MHz): d 168.5, 136.0, 134.1,
131.2, 130.4, 129.6, 129.4, 127.8, 126.4, 52.1, 14.0; EIMS:
m/z 210, 212 (M+.); Anal. Calcd for C11H11ClO2: C, 62.71;
H, 5.23. Found: C, 62.78; H, 5.28.
3f: 1H NMR (CDCl3, 200MHz): d 6.76 (1H, t, J = 7.0Hz),
3.70 (3H, s) 2.08 (2H, t, J = 7.0Hz), 1.82 (3H, s), 1.71 (1H,
m), 0.94 (6H, d, J = 7.0Hz); 13C NMR (CDCl3, 50MHz):
d 168.4, 141.6, 130.8, 51.6, 31.9, 28.3, 22.5, 14.1; EIMS:
m/z 156 (M+.); Anal. Calcd for C9H16O2: C, 69.23; H,
10.26. Found: C, 69.14; H, 10.31.