E-Stilbene derivatives synthesized by stereoselective reductive coupling of benzylic gem-dibromide promoted by Cu/polyamine

Article abstract of DOI:10.1016/j.tetlet.2017.05.072

Stereoselective reductive coupling reaction of benzylic gem-dibromide promoted by Cu/polyamine produces E-stilbene derivatives with high yield under mild conditions. It provides a short pathway to synthesize symmetrical and asymmetrical E-stilbene derivatives using cheap reagents and alkenyl-free starting material together with easy workup.

Full text of DOI:10.1016/j.tetlet.2017.05.072

Accepted Manuscript
E-Stilbene Derivatives Synthesized by Stereoselective Reductive Coupling of
Benzylic gem-dibromide Promoted by Cu/Polyamine
Hua Cao, Qi Wang
PII:
S0040-4039(17)30661-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.072
TETL 48965
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 March 2017
16 May 2017
19 May 2017
Please cite this article as: Cao, H., Wang, Q., E-Stilbene Derivatives Synthesized by Stereoselective Reductive
Coupling of Benzylic gem-dibromide Promoted by Cu/Polyamine, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.05.072
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E-Stilbene Derivatives Synthesized by Stereoselective Reductive
Coupling of Benzylic gem-dibromide Promoted by Cu/Polyamine
Hua Cao, Qi Wang*
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of
Polymer Science & Engineering, Zhejiang University, Hangzhou, 310027, P. R. China.
*Corresponding Author: wangq@zju.edu.cn.
KEYWORDS: reductive coupling, carbon-carbon double bond; stilbene derivatives;
gem-dibromide
ABSTRACT: Stereoselective reductive coupling reaction of benzylic gem-dibromide promoted by
Cu/Polyamine produces E-stilbene derivatives with high yield under mild conditions. It provides
a short pathway to synthesize symmetrical and asymmetrical E-stilbene derivatives using cheap
reagents and alkenyl-free starting material together with easy workup.
1

Introduction
Reductive coupling of alkyl halide is an important method for construction of carbon-carbon
bond. gem-Dihalo compounds can be reductively coupled to 1,2-disubstituted ethylene
2-5
11-14
compounds by different metals or metal complexes, such as V,1 Pd,
Ni,6-10 Co,
Ti,15,16
Mg,17,18 Cr,19,20 In,21 Cu,22and Fe.23 The stereoselectivity and productivity of these reductive
coupling reactions varied with the type of the metal involved. Mataka et al reported the
formation of mixture of E- and Z-stilbene by reductive coupling of benzal bromide catalyzed by
Pd(Ph3P)4.3 Rieke et al reported the synthesis of mixture of E- and Z-stilbene via reductive
coupling of benzal bromide catalyzed by highly reactive metallic nickel.7 The homocoupling of
benzal bromide catalyzed by titanocene monochloride yielded 74% of E-stilbene, which
proceeds via a free radical mechanism.16 The reaction of benzal chloride with copper metal in
DMSO gave 41 % E-stilbene as a major reaction product.22 Among above reductive coupling
reactions, a few examples show that the C=C bond is constructed through direct coupling of
carbene or carbenoid intermediate,9,22 while the formation of C=C bond via step-by-step
dehalogenation is a more popular pathway for generation of C=C bond. 3,7,16
Stilbene and its derivatives are important chemical compounds due to their different biological
activities.24 The synthesis of stilbene has been extensively investigated and documented in
several reviews.24-26 The common synthetic methods include the Wittig reaction,27 the Perkin
reaction,28 the Meerwein reaction29 or Mc-Murry couplings,30 and Horner−Wadsworth−Emmons
reaction31. These methods do not usually afford exclusively one isomer. The Mizoroki−Heck32
and Heck−Matzuda reactions33 are two promising methods generating E-stilbenes.
In this paper, we report formation of E-C=C double bond through stereoselective reductive
coupling of benzylic gem-dibromide in the presence of Cu/polyamine under mild conditions.
The protocol can be applied to produce various symmetric and asymmertric E-stilbene
possessing various functional groups.
2

Results and discussion
Figure 1 1H NMR spectrum of product 2a obtained by simple workup with added DMSO as
internal standard.
The gem-dibromide, p-tert-butyl benzal bromide (1a) was treated with copper powder and
polyamine as ligand in THF. The crude product was passed through a short silica column to
remove copper and its complex, and no further purification was made. The resulting product
1
(2a) was measured by H-NMR using DMSO as an internal standard for estimation of yield.
Although the yields are not as high as 100%, the products with high purity can be obtained after
1
simple workup, which is evidenced by the H-NMR (Figure 1). No signals derived from
by-product are detected except trace of solvent, which indicates that purification of the product
is very simple.
The reaction conditions, such as the type of ligand, substrate concentration and temperature,
were screened using 1a as substrate and the results are summarized in Table 1. For various
polyamines used as ligand, tris(2-pyridylmethyl)amine (TPMA) and N, N, N’, N’’,
N’’-pentamethyldiethylenetriamine
(PMDETA)
gave
higher
yields
than
tris(2-dimethylaminoethyl)amine (Me6TREN) and 2,2’-bipyridine (runs 1-4 in Table 1). Low and
high concentration of substrate afforded in relatively low yields (runs 4-7 in Table 1). The yield
o
decreased when the temperature was lower than 30 C (runs 4, 8-11 in Table 1). At low
concentration, the longer reaction time was required to achieve high yield (runs 5, 12 in Table
1).
3

Table 1 The influence of reaction conditions on coupling reaction of p-tert butyl benzal
bromides (1a) promoted by Cu/liganda
Cu/Ligand
t-Bu
t-Bu
CHBr2
t-Bu
3hr, THF
2a
1a
Run
1
[1a]
0.1
Ligand
Temp.(oC)
Yield of E-isomer (%)b
Bipyridine
Me6TREN
PMDETA
TPMA
30
30
30
30
30
30
30
15
40
50
60
30
60
76
82
90
91
65
91
83
83
93
93
91
96
90
2
0.1
3
0.1
4
0.1
5
0.02
0.05
0.2
TPMA
6
TPMA
7
TPMA
8
0.1
TPMA
9
0.1
TPMA
10
11
12c
13d
0.1
TPMA
0.1
TPMA
0.02
0.1
TPMA
TPMA
a
b
general condition: [1a]:[ligand]:[Cu]=1:2:2, 3 hours, THF. Yield of E-stilbene was determined by
c
d
1H-NMR using added DMSO as internal standard after simple work-up. reaction time was 12 hours.
[1a]:[ligand]:[CuBr]=1:2:2.
4

Table 2. The coupling reaction of substituted benzal bromides promoted by Cu/TPMAa
1.1 equiv. Cu
1 equiv. TPMA
Ar
Ar CHBr2
Ar
40oC, 1 hr, THF
2
1
Me
tBu
tBu
Me
2c, p-Me, 85% (80%)b
2a, 91%
2b, 81%
2d, o-Me, 84%
MeO
EtOOC
Ac
COOEt
Ac
OMe
MeO
2e, 70%
2f 80%
2g, 80%
Ph
O
Ph
O
OMe
OMe
OMe
MeO
MeO
2i, 85%
2h, 78%
a) reaction conditions: [1]=0.05 M. Yield was determined by 1H-NMR. b) in methanol/THF(1:1)
Various benzal bromides were prepared by bromination of substituted toluene with NBS or
bromination of benzaldehyde with boron tribromide, and the coupling reactions promoted by
Cu/TPMA were also carried out. As shown in Table 2, all products were E-stilbenes derivatives
and the yields were beyond 70%. The yield of 2b is twice that of coupling reaction of benzal
bromide promoted by Cu in DMSO.22 The coupling yields of p-methyl benzal bromide (1c) was
almost the same as that of o-methyl benzal bromide (1d), which suggests the steric effect is not
obvious. Good yields were achieved for substrates having different substitutes, such as alkyl,
ester, acetyl and alkyloxy groups. When half of the solvent was replaced by methanol, the yield
slightly decreased. These results indicate such reaction is well tolerated to different functional
groups. With respect to the same reductive coupling reaction mediated by other metals or
metal complex, our method has some advantages, such as cheap reagents, alkenyl-free starting
materials, short routes, satisfied yield and easy workup.
5

Cu(CuBr)/L
Cu(CuBr)/L
Cu(CuBr)/L
Br
5
Br
Br
Ar
Ar
Br
Br
Ar
3
Ar
Ar
Ar
Ar
Ar
Br
CuBr/L or CuBr2/L
CuBr/L or CuBr2/L
CuBr/L or CuBr2/L
1
3
4
2
Scheme 1. Proposed mechanism of reductive coupling reaction of gem-dibromide promoted by
Cu(CuBr)/polyamine.
We propose that the C=C bond is generated by two steps shown in Scheme 1. The first step is
in-situ formation of vic-dibromide (4) via reductive coupling of gem-dibromide and the second
one is debromination of vic-dibromide resulting in C=C bond. Similar mechanism has been
previously proposed.3,7,16 With respect to the high temperature and long reaction time required
3
for reductive coupling of benzal bromide catalyzed by Pd(Ph3P)4 and nickel,7 the low reaction
temperature and short time required for coupling reaction promoted by Cu/polyamine suggests
the intermediate of the reaction is probably the radical, which is consistent with the facts that
the reaction is compatible with various functional groups. The coupling reaction of 1a promoted
by CuBr/TPMA was also conducted, since CuBr/TPMA is in-situ formed during the redox
reaction between benzal bromide and Cu/TPMA. According to the results of run 13 in Table 1,
CuBr is also an effective reagent for coupling of 1a. Because CuBr/TPMA is a one-electron
reductant, the reduction of alkylhalide must proceeds via single electron transfer (SET) resulting
in homolytic bond cleavage and radical intermediates 3. This strongly suggests that reductive
coupling reactions of benzal bromide by Cu/TPMA and CuBr/TPMA proceed via radical
mechanism. When meso-1,2-dibromo-1,2-diphenylethane (6), a derivative of 4, was treated
with Cu/TPMA under the same condition, nearly 100% of E-stilbene was obtained . (Figure S14)
The reduction of vic-dibromide via the “bridged“ bromine radical 5 generated by SET leading to
C=C bond was proposed by Roberts et al.34 The intermediate radical 5 is partially stabilized by
delocalization of the unpaired electron over the remaining bromine. We suggest that the
transformation of vic-dibromide 4 to E-stilbene derivatives 2 is probabaly via radical
intermediate 5 as well, which is shown in Scheme 1.
6

Table 3 Cross-coupling of two different benzal bromides promoted by Cu/liganda
OMe
OMe
OMe
OMe
OMe
OMe
OMe
tBu
Ac
MeO
2bi
2af
2fi
2cg
Run
Dibromide X
Dibromide Y
Composition of product (mol%)
MeO
2a:2af:2f=20:32:37 b
t-Bu
CHBr2
1
CHBr2
MeO
MeO
MeO
CHBr2
2
2f:2fi:2i=27:36:30 b
2b:2bi:2i=30:38:21c
CHBr2
MeO
MeO
CHBr2
MeO
MeO
CHBr2
CHBr2
3
4
2c:2cg:2g=20:31:23c
CHBr2
Ac
o
a) Reactions conditions: [X]:[Y]:[Cu]:[TPMA]=1:1:2.2:2, [X]=0.05M, 40 C, 3 hours. b) yield determined by
gavimetry. c) yield determined by 1H-NMR using DMSO as an internal standard after simple workup.
Cross-coupling of two different benzal bromides was also carried out and asymmetric E-stilbene
compounds in addition to self-coupling products were obtained, which are shown in Table 3. By
using commercial available reagent 3, 4, 5-trimethoxy toluene as starting material,
E-polymethoxystilbenes 2bi and 2fi can be prepared by two steps and the yields of
cross-coupling product are more than 30 mol%. The compounds 2af and 2fi were isolated and
characterized by NMR. (Figure S9-11 ) The current method is a short-route method for synthesis
of such compounds. Methoxylated derivatives of resveratrol had anticancer activity comparable
with or better than that of resveratrol against some human cancer cell lines.35 Stilbene 2bi has
been reported to be more active than resveratrol as inhibitors of TNFα-induced activation of
NFB.36
Conclusion
We have developed a simple protocol for synthesis of E-stilbene derivates through the
formation of E-C=C bond by stereoselective reductive coupling reaction of benzylic
gem-dibromide treated with Cu/polyamine under mild condition. It provides a short pathway to
7

synthesize symmetrical and asymmetrical E-polymethoxystilbenes.
Experimental
Benzal bromides were prepared by bromination of substituted toluene with NBS or
bromination of benzaldehyde with boron tribromide. All compounds were characterized by
NMR, EA and MS.
In a typical coupling reaction, for example, 30.6 mg of 1a (0.10 mmol), 29.0 mg of TPMA (0.10
mmol) and 7.1 mg of copper powder (0.11 mmol) were added to an ampule equipped with a
stir bar. The ampule was degassed, backfilled four times with N2, and then left under N2.
Deoxygenated 2 mL of THF was then added. The ampule was heated at 40 °C for 1 hours. The
ampule was immersed in liquid nitrogen and the mixture was diluted with CH2Cl2 and purified
by passing through a neutral alumina column. The crude product was obtained after removal of
1
solvent under vacuum, which was measured by H-NMR using DMSO as internal standard,
giving the yield of the corresponding compounds.
Supplementary Material
Details of experimenntal and data for characterization of related compounds.
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8

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9

Table 1 The influence of reaction conditions on coupling reaction of p-tert butyl benzal
bromides (1a) promoted by Cu/liganda
Cu/Ligand
t-Bu
t-Bu
CHBr2
t-Bu
3hr, THF
2a
1a
Run
1
[1a]
0.1
Ligand
Temp.(oC)
Yield of E-isomer (%)b
Bipyridine
Me6TREN
PMDETA
TPMA
30
30
30
30
30
30
30
15
40
50
60
30
60
76
82
90
91
65
91
83
83
93
93
91
96
90
2
0.1
3
0.1
4
0.1
5
0.02
0.05
0.2
TPMA
6
TPMA
7
TPMA
8
0.1
TPMA
9
0.1
TPMA
10
11
12c
13d
0.1
TPMA
0.1
TPMA
0.02
0.1
TPMA
TPMA
a
b
general condition: [1a]:[ligand]:[Cu]=1:2:2, 3 hours, THF. Yield of E-stilbene was determined by
c
d
1H-NMR using added DMSO as internal standard after simple work-up. reaction time was 12 hours.
[1a]:[ligand]:[Cu]=1:2:2.
10

Table 2. The coupling reaction of substituted benzal bromides promoted by Cu/TPMAa
1.1 equiv. Cu
1 equiv. TPMA
Ar
Ar CHBr2
Ar
40oC, 1 hr, THF
2
1
Me
tBu
tBu
Me
2c, p-Me, 85% (80%)b
2a, 91%
2b, 81%
2d, o-Me, 84%
MeO
EtOOC
Ac
COOEt
Ac
OMe
MeO
2e, 70%
2f 80%
2g, 80%
Ph
O
Ph
O
OMe
OMe
OMe
MeO
MeO
2i, 85%
2h, 78%
a) reaction conditions: [1]=0.05 M. Yield was determined by 1H-NMR. b) in methanol/THF(1:1)
11

Table 3 Cross-coupling of two different benzal bromides promoted by Cu/liganda
OMe
OMe
OMe
OMe
OMe
OMe
OMe
tBu
Ac
MeO
2bi
2af
2fi
2cg
Run
Dibromide X
Dibromide Y
Composition of product (mol%)
MeO
2a:2af:2f=20:32:37 b
t-Bu
CHBr2
1
CHBr2
MeO
MeO
MeO
CHBr2
2
2f:2fi:2i=27:36:30 b
2b:2bi:2i=30:38:21c
CHBr2
MeO
MeO
CHBr2
MeO
MeO
CHBr2
CHBr2
3
4
2c:2cg:2g=20:31:23c
CHBr2
Ac
o
a) Reactions conditions: [X]:[Y]:[Cu]:[TPMA]=1:1:2.2:2, [X]=0.05M, 40 C, 3 hours. b) isolated yield. c) yield
determined by 1H-NMR using DMSO as an internal standard.
12

Figure 1 1H NMR spectrum of product 2a after simple workup with added DMSO as internal
standard.
13

Cu(CuBr)/L
Cu(CuBr)/L
Cu(CuBr)/L
Br
5
Br
Br
Ar
Ar
Br
Br
Ar
3
Ar
Ar
Ar
Ar
Ar
Br
CuBr/L or CuBr2/L
CuBr/L or CuBr2/L
CuBr/L or CuBr2/L
1
3
4
2
Scheme 1. Proposed mechanism of reductive coupling reaction of benzal bromide promoted by
Cu(CuBr)/polyamine.
14

Highlights




Reductive coupling reaction of benzylic gem-dibromide by Cu/polyamine is achieved.
E-stilbene derivatives were obatined with high yield.
The method is well tolerated to different functional groups.
It provides a short pathway to synthesize symmetrical and asymmetrical E-stilbene.
15

Graphical Abstract
Leave this area blank for abstract info.
E-Stilbene Derivatives Synthesized by
Stereoselective Reductive Coupling of
Benzylic gem-dibromide Promoted by
Cu/Polyamine
Hua Cao, Qi Wang
R
1.1 equiv. Cu
1 equiv. TPMA
CHBr2
R
R
40oC, 1 hr, THF
1
2
16