An efficient palladium-catalyzed Negishi cross-coupling reaction with arylvinyl iodides: facile regioselective synthesis of E-stilbenes and their analogues

Article abstract of DOI:10.1016/j.tetlet.2007.08.047

A general synthetic route for the Pd-catalyzed cross-coupling of an arylzinc reagent with arylvinyl iodides (Negishi cross-coupling) has been developed. The system permits efficient and selective preparation of E-stilbenes and their analogues. It also functions effectively at low levels of catalyst loading without the need for an additional ligand and tolerates a wide range of functional groups including heteroaromatic substrates. A systematic study of various parameters was performed and correlated with catalyst-substrate activity.

Full text of DOI:10.1016/j.tetlet.2007.08.047

Tetrahedron Letters 48 (2007) 7269–7273
An efficient palladium-catalyzed Negishi cross-coupling
reaction with arylvinyl iodides: facile regioselective
synthesis of E-stilbenes and their analogues
M. Shahjahan Kabir,a Aaron Monteb and James M. Cooka,*
aDepartment of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
bDepartment of Chemistry, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA
Received 12 June 2007; accepted 13 August 2007
Available online 16 August 2007
Abstract—A general synthetic route for the Pd-catalyzed cross-coupling of an arylzinc reagent with arylvinyl iodides (Negishi cross-
coupling) has been developed. The system permits efficient and selective preparation of E-stilbenes and their analogues. It also func-
tions effectively at low levels of catalyst loading without the need for an additional ligand and tolerates a wide range of functional
groups including heteroaromatic substrates. A systematic study of various parameters was performed and correlated with catalyst–
substrate activity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Palladium-catalyzed cross-coupling reactions of unsatu-
rated organohalides and sulfonates with organometallic
reagents are well established and powerful methods for
the construction of carbon–carbon bonds.1 The most
widely used Pd-catalyzed cross-coupling reactions,
which involve the formation of C(sp2)–C(sp2) bonds,
are couplings between aryl- or vinylhalides with organo-
tin (Stille) or organoborane (Suzuki–Miyaura) re-
agents;2 organozinc (Negishi) and organomagnesium
(Kumuda) reagents are employed to a lesser extent.
In addition to Stille and Suzuki–Miyaura couplings, Pd-
catalyzed Mizoroki–Heck reactions between styrene and
arylhalide are well-known processes for the synthesis of
stilbenes, albeit with less regioselectivity. The latter reac-
tion produces mixtures of three products: Z- and
E-stilbenes and a coupled product with exocyclic
carbon–carbon double bonds (1,1-diphenylethylene).4
The regiochemistry of the Mizoroki–Heck reaction can
be controlled in some cases by careful choice of reaction
conditions and, more importantly, by crucial choice of a
supporting ligand.5 Despite the widespread use of
boronic acids in Suzuki–Miyaura cross-couplings and
the advantages associated with these reagents, difficul-
ties still remain.6 Problems include the frequent need
for recrystallization of the arylboronic acid prior to
use, the tendency to form varying amounts of boroxines,
the propensity to undergo competitive protodeborona-
tion during cross-coupling, as well as the preparation
and application of hindered boronic acids. In addition
to these problems, the presence of either electron donat-
ing or withdrawing groups may reduce the stability of
the arylboronic acid. The lesser reactivity of aryltin
(Stille coupling) reagents requires the use of highly polar
solvents and harsh reaction conditions, in addition to
the well-known toxicity of organotin compounds.7
Stilbenoids have been isolated from various plant spe-
cies and are currently attracting considerable attention
because of their wide range of biological activity and
potential therapeutic value.3 In some cases these anti-
microbial agents are active against drug resistant strains
of tuberculosis and anthrax3a and have recently
attracted our attention. Classical synthetic approaches
to this class of compounds involve Wittig type reactions,
dehydration of 1,2 diarylethanols and metal-catalyzed
reactions.4
Keywords: Negishi cross-coupling; Regioselective synthesis of E-stil-
benes; Arylvinyl iodides; Metal-catalyzed one-pot synthesis.
In cases where the aforementioned problems exist in tra-
ditional metal-catalyzed reactions, a potential solution
would be to employ an alternative nucleophilic partner
*
Corresponding author. Tel.: +1 414 229 5856; fax: +1 414 229
5530; e-mail: capncook@uwm.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.047

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M. S. Kabir et al. / Tetrahedron Letters 48 (2007) 7269–7273
Table 1. Preparation of arylvinyl iodides under optimized conditions
CHO
I
CrCl2 (6.0 equiv), CHI3(2.0 equiv)
R
R
dry THF, 0 °C,2-5 h
Entry
1
Aldehydes
Arylvinyl iodides
Time (h)
2.5
Yield (%)
87
E/Za
I
CHO
94:6
HO
CHO
HO
I
2
3
4
3.0
5.0
2.5
92
84
82
94:6
92:8
100:0
OMe
OMe
MeO
CHO
MeO
I
OMe
CHO
OMe
I
Cl
Cl
a E/Z ratio was determined by analysis of the 1H NMR spectrum of the crude material.
such as an arylzinc reagent. Recently, a simple proce-
dure has been developed to prepare arylvinyl iodides
(electrophilic partners) in high yield and excellent regio-
selectivity based on the adaptation of a reported proce-
dure (Table 1, entries 1–4).8
Several features of this method are noteworthy. First,
easy access to various arylvinyl iodides with excellent
regioselectivity (Table 1, entries 1–4) is available.10 Sec-
ond and most importantly, mixtures of E- and Z-iso-
mers of arylvinyl iodides gave only regioselective
E-stilbenes. Unlike the Heck reaction, wherein a mixture
of isomeric arylvinyl coupled products is formed (i.e.,
Z-, E-, and exocyclic isomers),4 only the E-isomer is
observed with this process.10 Third, low levels of catalyst
loading (2 mol %) with no additional ligand and no
co-solvent is required for these transformations. Fourth,
nucleophilic partners such as arylzinc reagents gave cou-
pled products at moderate (rt to 70 ꢁC) reaction temper-
atures. In addition to the above, the present method
gives better yields for heterocyclic stilbene analogues
than previously reported.4d,11,12
Since a facile preparation of the arylvinyl iodides was in
hand, it was decided to use them with the aforemen-
tioned arylzinc reagents to prepare functionalized stil-
benes and their analogues.
To these authors’ knowledge, previously there has been
no report of a general efficient Pd-catalyzed Negishi
cross-coupling reaction for the regioselective synthesis
of E-stilbenes and their analogues from arylvinylhalides,
except for the preparation of a Z-stilbene from a Z-aryl-
vinyl bromide.9
Initial studies indicated that the coupling of an arylvinyl
iodide with an arylzinc reagent in the presence of
Pd(PPh3)4 gave only the corresponding E-regioisomer
of the stilbene (Table 2, entry 3). The arylzinc reagents
were typically prepared from their corresponding
Herein we report a simple and general procedure for the
preparation of the E-stilbene class of compounds from
arylvinyl iodides employing a Pd-catalyzed Negishi
protocol.
Table 2. Effect of reaction conditions on the yields of aryl–arylvinyl one-pot Negishi couplings
Br
n
-BuLi (3.0 equiv)
THF, -78 C,1 h
ZnCl2 (3.0 equiv)
-78 C,1 h rt, 1 h
ZnBr
MeO
Pd2(dba)3 (2 mol%)
°
MeO
1.0 (equiv)
I
MeO
1.5 (equiv)
°
MeO
70 °C,5 h
Entry
Change from standard conditions
Yield (%)
1
2
3
4
5
6
7
None
No Pd2(dba)3
Pd(PPh3)4
Pd2(dba)3 and P(Cy)3
Cosolvent (THF/NMP; 2:1)
DMF
74
0
62
72
33
0
DMA
0

M. S. Kabir et al. / Tetrahedron Letters 48 (2007) 7269–7273
7271
arylbromides. Halogen-lithium exchange followed by
transmetallation with anhydrous Zn(II)chloride fur-
nished the desired arylzinc reagent. Subsequent reaction
with an arylvinyl iodide in the presence of Pd2(dba)3
catalyst gave the cross-coupled product. The Pd2(dba)3
was a more effective catalyst than Pd(PPh3)4 (Table 2,
entries 1 and 3). As expected, no cross-coupled product
was observed in the absence of the Pd2(dba)3 catalyst
(Table 2, entry 2). Alternatively, no substantial increase
in yield was observed when Pd2(dba)3 was used with the
ligand P(Cy)3 (Table 2, entry 4). The use of polar
solvents (Table 2, entries 6 and 7) led to an aryl
acetylene for b-hydride elimination occurred and no
cross-coupled product was observed. Use of the cosol-
vent NMP with THF also gave significant amounts of
aryl acetylene (>30%), along with a low yield of the
cross-coupled product (33%; Table 2, entry 5).
good to excellent yields of stilbenes in the presence of a
variety of common functional groups, including cyano,
alkoxy, TBDPS, halide, and alkyl substituents. The reac-
tion occurred efficiently at low levels of catalyst loading
(2 mol %) without any supporting ligand. Heteroarylzinc
reagents gave cross-coupled products at room tempera-
ture in 2 h with excellent yields (>80%, Table 3, entries
2, 3, 9, 10, 12, and 13). No aryl acetylene which would
originate from b-hydride elimination13 was observed in
these processes. In contrast to heteroarylzinc reagents,
conventional arylzinc reagents gave slightly lower yields
(65–78%, Table 3, entries 1, 4–8, 11, and 14) and required
higher temperatures of 70 ꢁC over a 3–5 h period. Varia-
tions in electronic character (Table 3, entries 5–8) gave
no noticeable change in yields. A small amount of aryl
acetylene (ꢀ5–10%) was observed in reactions using con-
ventional arylzinc reagents at higher temperatures.
Cross-coupling between hydroxy-substituted arylvinyl
iodides and an arylzinc reagent did not proceed without
protection of the hydroxyl group (Table 3, entries
11–13). Despite the need for protection of hydroxy-
substituted arylvinyl iodides, the cross-coupling and
deprotection steps can be accomplished efficiently in a
one-pot process, as expected (Scheme 1).
As a result of this study, the standard conditions, as
exhibited in entry 1 of Table 2, were chosen to further
investigate substrate scope and reactivity of this process.
Examination of the data in Table 3 demonstrates that the
use of Pd2(dba)3 in THF at either rt or 70 ꢁC provided
Table 3. Pd-catalyzed Negishi cross-coupling reactions of arylvinyl iodides with arylzinc reagentsa
Entry
Arylbromide
Arylvinyl iodides
E-stilbenes
Temp (ꢁC)
Time (h)
3
Yieldb (%)
78
Br
I
1
70
S
S
I
I
2
3
rt
rt
2
2
86c
81c
Br
S
Br
S
MeO
MeO
MeO
I
MeO
Br
Br
4
5
6
70
70
70
5
5
5
74
63
72
OMe
OMe
OMe
OMe
MeO
I
CH3
CH3
CH3
OMe
I
Br
MeO
H3C
OMe
Br
MeO
MeO
I
I
MeO
CN
CN
7
8
70
70
5
5
70
61
OMe
OMe
CN
OMe
Br
MeO
NC
Br
OMe
S
MeO
I
S
MeO
9
rt
2
88c
OMe
OMe
(continued on next page)

7272
M. S. Kabir et al. / Tetrahedron Letters 48 (2007) 7269–7273
Table 3 (continued)
Entry
Arylbromide
Arylvinyl iodides
E-stilbenes
Temp (ꢁC)
Time (h)
2
Yieldb (%)
84c
S
MeO
I
Br
S
MeO
10
rt
OMe
OMe
TBDPSO
TBDPSO
TBDPSO
I
I
I
HO
Br
11
12
70
rt
5
5
73
OMe
OMe
OMe
OMe
HO
S
S
82c
Br
Br
OMe
HO
S
S
13
14
rt
5
5
84c
65
OMe
I
Br
70
Cl
Cl
a All reactions are carried out in dry THF; ArBr/n-BuLi/ZnCl2/Arylvinyliodide/Pd2(dba)3 = 1.5:3.0:4.0:1.0:0.02.
b Isolated yield based on the amount of arylvinyl iodide.
c No aryl acetylene from b-hydride elimination was observed.
HO
Br
n
-BuLi (3.0 eqiv)
THF, -78 C,1 h
ZnCl2 (3.0 equiv)
-78 C,1 h, rt, 1 h
ZnBr
Pd2(dba)3 (2 mol%)
°
TBDPSO
(1.0 equiv)
MeO
°
I
MeO
70 °C,5 h; imidazole 1.2 (equiv)
TBAF(1.2 equiv), rt, 1.5 h
Scheme 1. One-pot Negishi coupling of protected arylvinyl iodide–arylzinc reagents, followed by deprotection with TBAF.
Since only full conversion of the arylvinyl iodide gave
the highest yields of cross-coupled product, the best
condition which was found, employed was a slight
excess of arylbromide (1.5 equiv) in the presence of
3.0 equiv of n-BuLi. Preliminary work indicated consis-
tent formation of a small amount of homocoupled prod-
uct (<5–10%), which was initially difficult to remove
from some reaction mixtures. It became apparent that
the initial use of 1.2 equiv of aryl bromide did not permit
full conversion of the arylvinyl iodides to the cross-
coupled products. The use of an excess amount of aryl-
bromide (1.5 equiv) provided full conversion, which
maximized the yield of cross-coupled product and
simplified the removal of unwanted homocoupled prod-
uct from the reaction mixtures.
creased the amount of aryl acetylene byproduct. Since
this optimization improved the yield and minimized
the formation of aryl acetylene, it was applied to further
reaction processes (Table 3). Indeed, it was found that
addition of the Pd2(dba)3 catalyst should be done ini-
tially, followed by rapid addition of the arylvinyl iodide,
and then immediately placing the reaction flask in a pre-
heated oil bath (70 ꢁC) provided the best yields of the
stilbenes.14
In summary, a simple and general procedure for the
construction of C(sp2)–C(sp2) bonds from arylvinyl iod-
ides and arylzinc reagents has been developed. The pro-
cess was applied to the preparation of many stilbenes
and their analogues which have antimicrobial activity.10
The system is very simple, effective and cheap when
compared to other Negishi cross-coupling reactions.
With respect to turnover numbers for competing reac-
tions of arylbromides and arylvinyl iodides, this process
has a much higher turnover number. Ready access to
versatile arylvinyl iodides should facilitate the further
development in the formation of C(sp2)–C(sp2) bonds
using Negishi cross-coupling protocols.
Interestingly, a simple control reaction with the arylvi-
nyl iodide and Pd2(dba)3 in THF at rt (stirred overnight)
also gave the aforementioned aryl acetylene in approxi-
mately 20% yield. This result, in addition to the insights
gained earlier (cf. Table 3, entries 2, 3, 9, 10, 12, and 13),
revealed that lower temperature and decreased reaction
times, as well as the order of the addition of reagents de-

M. S. Kabir et al. / Tetrahedron Letters 48 (2007) 7269–7273
7273
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Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992,
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Acknowledgments
We thank Matthew E. Dudley for technical help and
The Research Growth Initiative of the University of
Wisconsin-Milwaukee and the UW-System Applied Re-
search Grants Program for support of this work.
7. (a) Sander, H. L. T.; Deelman, B. J.; Koten, G. V. J.
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14. Typical procedure: Pd-catalyzed Negishi cross-couplings of
aryl halides and arylvinyl iodides. An oven dried round
bottomed flask containing a magnetic stir bar was sealed
with a rubber septum and then evacuated and backfilled
with argon (the sequence was repeated three times) while
cooling. The round bottomed flask was then charged with
arylbromide (1.5 equiv) and dry THF (2 mL). The solu-
tion which resulted was cooled to À78 ꢁC and then n-BuLi
(2.5 M in hexanes 3.0 equiv) was added via a syringe
through the septum, and the solution which resulted was
stirred at À78 ꢁC for 1 h. The dry ZnCl2 (3.0 equiv) was
then added in one solid portion by removal of the septum
at À78 ꢁC. The mixture which resulted was stirred for 1 h
at À78 ꢁC and the flask was removed from the cooling
bath and stirred at room temperature for 1 h. The
Pd2(dba)3 (2 mol %) catalyst was added to the reaction
mixture in one solid portion by removal of the septum and
this was followed by rapid addition of the arylvinyl iodide
in THF via a syringe through the resealed septum. A
previously flame dried reflux condenser was used to cap
the reaction flask and the top of the condenser was sealed
with a septum and teflon. The reaction was kept under an
argon atmosphere. The reaction mixture was immediately
placed in a preheated oil bath at 70 ꢁC and stirred
(magnetic stir) for 3–5 h or stirred at room temperature
for 2–3 h depending on the substrates until the arylvinyl
iodide had been completely consumed as indicated by
examination of a sample of the crude reaction mixture by
1H NMR spectroscopy. The reaction mixture was then
cooled to rt, diluted with water (4 mL), and extracted with
diethylether (4 · 10 mL). The combined organic phases
were dried over Na2SO4 and concentrated under reduced
pressure. The crude material was purified by flash chro-
matography on silica gel to give the pure cross-coupled
product (see Table 3 for yields).
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