Facile synthesis of multisubstituted buta-1,3-dienes via Suzuki-Miyaura and Kumada cross-coupling strategy of 2,4-diiodo-buta-1-enes with arylboronic acids and Grignard reagents

Article abstract of DOI:10.1039/b504071j

One-pot Suzuki-Miyaura-type and Kumada-type cross-coupling reactions of 2,4-diiodo-buta-l-enes with arylboronic acids and alkyl/aryl magnesium bromides were carried out in the presence of accessibly simple catalysts under mild conditions. As a result, some 1,1,2-trisubstituted buta-1,3-dienes were obtained including the Tamoxifen-type, which have potential adjuvant therapy in women who have suffered from breast cancer and cyclooxygenase-2-type (COX-2-type) inhibitors, some of which have been proved to elicit efficient anti-inflammatory analgesic activities and less adverse gastrointestinal side effects and to be very useful in the prophylactic treatment of a wide variety of cancers and neurodegenerative disorders. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504071j

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C O M M U N I C A T I O N
Facile synthesis of multisubstituted buta-1,3-dienes via Suzuki–
Miyaura and Kumada cross-coupling strategy of 2,4-diiodo-
buta-1-enes with arylboronic acids and Grignard reagents†
Li-Xiong Shaoa and Min Shi*b
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
b East China University of Science and Technology, P.O. Box 422, 130 Mei Long Lu, Shanghai,
200237, China. E-mail: mshi@pub.sioc.ac.cn
Received 21st March 2005, Accepted 1st April 2005
First published as an Advance Article on the web 12th April 2005
One-pot Suzuki–Miyaura-type and Kumada-type cross-
coupling reactions of 2,4-diiodo-buta-1-enes with aryl-
boronic acids and alkyl/aryl magnesium bromides were
carried out in the presence of accessibly simple catalysts
under mild conditions. As a result, some 1,1,2-trisubstituted
buta-1,3-dienes were obtained including the Tamoxifen-
type, which have potential adjuvant therapy in women who
have suffered from breast cancer and cyclooxygenase-2-type
(COX-2-type) inhibitors, some of which have been proved
to elicit efficient anti-inflammatory analgesic activities and
less adverse gastrointestinal side effects and to be very useful
in the prophylactic treatment of a wide variety of cancers
and neurodegenerative disorders.
(COX-2-type) inhibitors,25 some of which have been proved
to elicit efficient anti-inflammatory analgesic activities and less
adverse gastrointestinal side effects26–27 and to be very useful
in the prophylactic treatment of a wide variety of cancers and
neurodegenerative disorders,28 can be obtained conveniently.
Herein we wish to report the results in detail.
Firstly, we carried out the typical Suzuki–Miyaura-type cross-
coupling reactions of diiodides 1 with some arylboronic acids 2
in the presence of a palladium catalyst. For our optimization
studies, we chose to focus on the Suzuki–Miyaura coupling
reaction of 1,1-diphenyl-2,4-diiodo-buta-1-ene 1a (0.25 mmol)
with phenylboronic acid 2a (0.30 mmol) in the presence of
Pd(PPh3)4 catalyst (0.025 mmol) and various bases and solvents.
Parts of these results are summarized in Table 1. After several
trials and errors, we were pleased to find out that the reaction of
1a with 2a in a mixed solvent of THF–H2O (3 : 1) under reflux in
the presence of KOH as a base proceeded smoothly to give the
coupling product 3a in 82% yield as the sole product (Table 1,
entry 7). Coupling product 3a was also obtained in somewhat
lower yields, either in the case of K2CO3–Ag2O, Cs2CO3–Ag2O
as the base (Table 1, entries 5 and 6) or in the combination of
other solvents such as DME–H2O, toluene–H2O, DMF–H2O,
benzene–H2O, 1,4-dioxane–H2O (Table 1, entries 10–14). In the
presence of other bases such as K2CO3, NaHCO3, K3PO4, KF,
CsOH, CsF, the coupling product 3a was obtained in much
Conjugated dienes constitute an important functionality among
organic compounds and are widely distributed among natural
products.1–11 In recent years, they have emerged as a distinct
class by themselves due to their increasing utility in organic
synthesis and also due to their interesting physical properties.
Dienes have attracted a great deal of attention as they ex-
hibit exceptional reactivity in cycloadditions and electrocyclic
reactions. The most common use of dienes is in Diels–Alder
reactions (both inter- and intramolecular) and in thermal and
photochemical reorganization to furnish diverse carbo- and
heterocyclic frameworks, which find application in synthesis
of natural products and non-natural products.12 In view of
such diverse applications and future potential, newer synthetic
methods for assembling dienes under mild and efficient reaction
conditions are being continually explored. Indeed, in the last
few years, synthetic activity directed towards these substrates
has witnessed explosive growth,13 in which transition metal-
catalyzed carbon–carbon bond-forming reactions are one of
the most important reactions.14 As part of our program on the
transformation of 2,4-diiodo-buta-1-enes derived from the ring-
opening of methylenecyclopropanes (MCPs) with iodine,15 we
have synthesized some cross-conjugated products in moderate
to high yields via a Heck-type reaction16–18 under simple
conditions.19 In fact, 2,4-dihalobutenes have attracted con-
siderable attention because of their versatility as a building
block or starting substrate in organic synthesis20 and in the
pharmaceutical industries.21 In order to consummate the trans-
formation of the corresponding diiodides, we also carried out the
Suzuki–Miyaura-type reaction22 and Kumada-type reaction23
in which some multisubstituted buta-1,3-dienes, including the
1,1,2-triarylsubstituted buta-1,3-dienes which are mimics of
Tamoxifen24 having potential adjuvant therapy in women who
have suffered from breast cancer and cyclooxygenase-2-type
Table 1 Suzuki–Miyaura-type reaction of 1a (0.25 mmol) with 2a
(0.30 mmol) under different reaction conditions
Yield (%)c
Entrya Solvent
Baseb
Temp./Time 3a
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
THF–H2O
K2CO3
NaHCO3
K3PO4
Reflux/24 h
Reflux/24 h
Reflux/24 h
Reflux/24 h
Reflux/24 h
27 29
11 23
30 35
71 17
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
DME–H2O
Toluene–H2O
DMF–H2O
KF
K2CO3–Ag2Od
47
50
82
—
—
—
Cs2CO3–Ag2Od Reflux/24 h
KOH
CsOH
CsF
KOH
KOH
KOH
Reflux/58 h
Reflux/32 h
Reflux/32 h
Reflux/58 h
21 31
—
68
22
—
—
—
—
—
100 ◦C/48 h 67
100 ◦C/48 h 17
Benzene–H2O KOH
Dioxane–H2O KOH
Reflux/58 h
75
100 ◦C/58 h 65
a Tetrabutylammonium chloride (TBAC) (0.25 mmol) as the addi-
tive. b Otherwise specified, 1.2 mmol base was used. c Isolated yields.
d M2CO3–Ag2O (1.2 mmol–0.3 mmol).
† Electronic supplementary information (ESI) available: Spectroscopic
data (1H, 13C, and NOESY NMR spectra data), HRMS for all the new
compounds and detailed descriptions of the experimental procedures.
See http://www.rsc.org/suppdata/ob/b5/b504071j/
1 8 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 2 8 – 1 8 3 1
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Table 2 Suzuki–Miyaura-type reaction of diiodides 1 (0.25 mmol) with arylboronic acids 2 (0.30 mmol) under the optimized conditions
Entry
Diiodides 1 (R1/R2)
2, Ar
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a (C6H5/C6H5)
2b (p-ClC6H4)
3b, 72
3c, 68
3d, 99
3e, 70
3f, 88 (1 : 1)c
3g, 67
3h, 70
3i, 78
1a
2c (p-CH3C6H4)
1a
1a
2d (o-CH3C6H4)
2e (2-Benzo[1,3]dioxol-5-yl)
1b (p-MeOC6H4/C6H5)b
2a (C6H5)
1c (p-MeC6H4/p-MeC6H4)
2c
2a
2d
2e
2b
2a
2c
2d
2e
2a
2a
2a
1c
1c
1c
3j, 70
1d (p-ClC6H4/p-ClC6H4)
3k, 83
3l, 82
1d
1d
3m, 75
3n, 77
3o, 73
3p, 79
3q, 85
3r, 59
1d
1d
1e (C6H3/H)d
1f (Me/p-EtOC6H4)e
1g (p-CH3OC6H4/H)d
a Isolated yields. b E : Z = 1 : 1. c E : Z ratio d 1e and 1g were used as Z-isomer (Supporting Information†).33 e 1f were used as E-isomer (Supporting
Information†)
Table 3 The optimization of the Kumada-type cross-coupling reaction
lower yields along with the uncoupled product 4 in most cases
(Table 1, entries 1–4, 8, 9).
To survey the generality of this transformation, we next
investigated the reaction using other diiodides 1 and a variety of
arylboronic acids 2 under the optimized conditions. The results
are summarized in Table 2. As can be seen from Table 2, for the
diaryl substituted substrate 1, the reactions proceeded smoothly
to give the corresponding 1,1,2-triaryl-buta-1,3-dienes 3b–o in
good to high yields (Table 2, entries 1–14). The substituents
on the benzene ring of diiodides 1 and arylboronic acids 2
did not significantly affect the yields of the coupling products,
namely, the reaction could tolerate various functional groups
for the synthesis of the skeleton of 1,1,2-triaryl-buta-1,3-dienes.
It should be noted that these triaryl substituted buta-1,3-dienes
have a core structure of triarylethylene many of which have
been tested with regard to their mammary tumor inhibiting
properties.29 Tamoxifen, which is now widely used for the
treatment of advanced breast cancer, also can be synthesized
from product 3f in a shorter way.30–32 For the unsymmetrical
disubstituted diiodides 1 (one is hydrogen or methyl group and
the other is aryl group), the reactions also gave the corresponding
products 3p–r in good to high yields (Table 2, entries 15–17).
On the other hand, for our investigation on the Kumada-
type cross-coupling reaction, we initially chose diiodide 1a
(0.25 mmol) and methylmagnesium bromide as the sub-
strates using NiCl2(dppp) (0.025 mmol) as the catalyst, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as the base34 and Et2O
as the solvent. Preliminary studies showed that the reaction
gave the product 5a in 53% yield when a solution of 1a,
DBU and the solvent was stirred at room temperature in the
presence of Na2SO4 for 8 h, then NiCl2(dppp) and 3 equiv.
of methylmagnesium bromide were added successively and the
resulting mixtures were stirred for a further 8 h (Table 3,
entry 1). Further studies showed that the addition sequence of
the reactants, the base, and the amount of methylmagnesium
bromide affected the reaction dramatically. When the steps
described above were reversed, the reaction was disordered (low
yielding) (Table 3, entry 2). When the reaction was carried out
in a one-pot procedure in the presence of the base, the coupling
product 5a was obtained in 31% yield (Table 3, entry 3). These
results suggest that in order to get a higher yield of 5a, the
elimination of the homoallylic iodide by DBU is essential before
Kumada-coupling reaction takes place, i.e. only the Kumada-
Entry
CH3MgBr [equiv.]
Solvent
Yield (%)a 5a
1
3
3
3
3
4
4
4
4
Et2O
Et2O
Et2O
Et2O
Et2O
THF
CH3CN
DCE
53
2b
3c
4d
5
disordered
31
disordered
99
99
87
71
6
7
8
a Isolated yields. b The two steps were reversed. c The reaction was carried
out in a one-pot procedure. d The reaction was carried out in a one-pot
procedure in the absence of DBU.
type coupling reaction of 4 with methylmagnesium bromide
proceeds efficiently. This is the difference between Suzuki–
Miyaura type cross-coupling reaction and Kumada-type cross-
coupling reaction in the transformation of diiodides 1. The
control experiments shown in Scheme 1 disclosed that the reac-
tion of 2-iodo-1,1-diphenyl-buta-1-ene with methylmagnesium
bromide gave the product 1,1-diphenyl-buta-1-ene in 48% yield
rather than the desired coupling product and the reaction of
4 with methylmagnesium bromide gave the desired product 5a
in 50% yield.35 We believe that the buta-1,3-diene derivative 4
may act as a promoter in the subsequent Kumada-type coupling
reaction.36 Another strong evidence for this speculation is that
Scheme 1 Control experiments on the reaction of 2-iodo-1, 1-di-
phenyl-but-1-ene and 2-iodo-1, 1-diphenyl-buta-1,3-diene with methyl-
magnesium bromide (3.0 equiv.).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 2 8 – 1 8 3 1
1 8 2 9

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Table 4 The Kumada-type reaction of diiodides 1 (0.25 mmol) with
Acknowledgements
R3MgBr (1.0 mmol) with R3MgBr (1.0 mmol) in THF
We thank the State Key Project of Basic Research (Project 973)
(No. G2000048007), Chinese Academy of Sciences (KGCX2-
210-01), Shanghai Municipal Committee of Science and Tech-
nology, and the National Natural Science Foundation of China
for financial support (203900502, 20025206 and 20272069).
We gratefully acknowledge Dr Zhaoguo Zhang’s group for
providing all of the arylboronic acids mentioned in this article.
Entry Diiodides 1 (R1/R2)
R3
Yield (%)a 5
1
2
3
4
5
6
7
8
9
1c (p-MeC6H4/p-MeC6H4)
1d (p-C1C6H4/p-ClC6H4)
Me
Me
5b, 82
5c, 67
1h (p-MeOC6H4/p-MeOC6H4) Me
5d, 81
References
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1c
1h
Et
Et
Et
Me
Me
Me
5e, 68
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coupling reactions between diaryl substituted diiodides 1 with
p-thioanisole magnesium bromide, the corresponding products
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inflammatory-analgesic agent that is non-ulcerogenic and may
also exhibit anticancer activity (Fig. 1).37
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In summary, we have developed a versatile direct synthesis of
some multisubstituted buta-1,3-dienes via a Suzuki–Miyaura-
type reaction and a Kumada-type reaction under simple and
mild reaction conditions with no special ligands between 1,1-
disubstituted 2,4-diiodo-buta-1-enes with arylboronic acids and
Grignard reagents, respectively. Some of the products such as
the Tamoxifen-type and COX-2-type mimics, which may also
show biological activities, have been easily synthesized. Efforts
are in progress to detect the potential application of the products
obtained and the results will be reported in due course.
1 8 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 2 8 – 1 8 3 1

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33 Note: Substrates 1e and 1g were also obtained by the ring-opening
reaction of the corresponding MCPs with I2 as described in Ref. 19.
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the solvent and the concentration of the ring-opening reaction. For
example, for substrate 1g, when the reaction was carried out in 1,2-
dichloroethane (DCE) (2.0 mL) with equal molar amounts of the
corresponding MCP (8 mmol) and I2 (8 mmol), no desired product
was obtained. When the above reaction was carried out in THF
(3.0 mL), 1g was obtained as a mixture of E- and Z-isomers in a ratio
of 1 : 1. When the amount of THF was increased to 80 mL, 1g was also
obtained as a mixture of E- and Z-isomers in a ratio of 5 : 1. The best
result was obtained when THF was increased to 120 mL for the above
reaction and the Z-isomer of 1g was obtained in 67% yield as a sole
product.
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