Palladium-catalyzed cross-coupling of aryl chlorides with alkenylboronic acids with low E/Z isomerization

Article abstract of DOI:10.1016/j.tetlet.2008.07.050

Using a bulky electron-rich monodentate benzoferrocenyl phosphine as supporting ligand, an efficient protocol for stereoselective palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl chlorides with alkenylboronic acids was uncovered. Using this protocol, both trans- and cis-alkenylboronic acids can be coupled with high stereoselectivity giving the corresponding vinylarenes in good to quantitative yields. Electron-poor and -rich aryl chlorides including highly hindered ones are all suitable substrates for the reaction.

Full text of DOI:10.1016/j.tetlet.2008.07.050

Tetrahedron Letters 49 (2008) 5605–5607
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Tetrahedron Letters
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Palladium-catalyzed cross-coupling of aryl chlorides with alkenylboronic
acids with low E/Z isomerization
*
Muralidhara Thimmaiah, Xiang Zhang, Shiyue Fang
Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a bulky electron-rich monodentate benzoferrocenyl phosphine as supporting ligand, an efficient
protocol for stereoselective palladium-catalyzed Suzuki–Miyaura cross-coupling of aryl chlorides with
alkenylboronic acids was uncovered. Using this protocol, both trans- and cis-alkenylboronic acids can
be coupled with high stereoselectivity giving the corresponding vinylarenes in good to quantitative
yields. Electron-poor and -rich aryl chlorides including highly hindered ones are all suitable substrates
for the reaction.
Received 17 March 2008
Revised 25 June 2008
Accepted 7 July 2008
Available online 11 July 2008
Keywords:
Suzuki–Miyaura cross-coupling
Aryl chloride
Ó 2008 Elsevier Ltd. All rights reserved.
Alkenylboronic acid
Alkene isomerization
Benzoferrocene
Phosphine ligand
1. Introduction
that were used to activate aryl chlorides toward palladium-
catalyzed cross-coupling reactions, mixtures of E- and Z-isomers
The palladium-catalyzed Suzuki–Miyaura cross-coupling is one
of the most useful carbon–carbon bond formation reactions and
has found wide applications in the synthesis of bioactive complex
molecules.1 In this reaction, various aryl and vinyl halides or tri-
flates can be coupled with a wide range of aryl and alkenylboronic
acids; and the reaction is tolerant of certain functional groups such
as ketone, aldehyde, cyanide, and amide. Before late 1990s, aryl
and vinyl bromides, iodides, and triflates were generally used as
the electrophilic reaction partner of the transformation, and the
more available and less expensive aryl chlorides were not viable
substrates. This challenge has been overcome by Fu and Buchwald
and their co-workers and other research groups through the use of
electron-rich and bulky phosphine- and carbene-based ligands.2
These ligands can form highly active mono-coordinated unsatu-
rated organometallic species with palladium (0), which can acti-
vate the Ar–Cl bond toward cross-coupling reactions. Now, both
electron-rich and -poor aryl chlorides can be coupled with various
arylboronic acids to form biaryls including highly hindered ones
with high efficiency. However, despite these achievements in the
area, the cross-coupling of aryl chlorides with alkenylboronic acids
remains challenging. Because of the lower reactivity of aryl chlo-
rides compared with bromides and iodides and problems associ-
ated with alkenylboronic acids, under certain reported conditions
of vinyl arenes were obtained even though sterically pure
alkenylboronic acids were used.2d This problem has been partially
solved by Nolan and Andrus and their co-workers using bulky
N-heterocyclic carbenes as the supporting ligand. Under their con-
ditions, electron-poor and -rich aryl chlorides were successfully
coupled with trans-2-phenylvinylboronic acid with negligible
isomerization.3 However, in their reports, only one vinylboronic
acid was tested, and the trans-stilbene products are significantly
more stable than their cis-isomers. Recently, Denmark and his
co-worker used alkenylsilanolates instead of boronic acids to cou-
ple with aryl chlorides to give vinyl arenes; under their conditions,
excellent chemical yields (87–98%) and stereoselectivities (98.6–
99.9%) were obtained for more than 20 substrate combinations.4
However, compared with alkenylboronic acids, alkenylsilanolates
are sensitive to moisture and are less compatible with polar func-
tional groups. Moreover, many alkenylboronic acids are commer-
cially available while alkenylsilanolates are not. As a result, the
coupling of alkenylboronic acids with aryl chlorides to form vinyl-
arenes with high stereoselectivity and broader substrate scope is
still highly desired.
Recently, we reported the synthesis and characterization of
several monodentate benzoferrocenyl phosphine ligands, which
include 1 and 2 (Fig. 1), and their application in allylic alkylation.5
In the X-ray determined single crystal structure of 1, we noticed
that the lone pair on the phosphorus atom points to the endo face
of benzoferrocene. We therefore reasoned that coordination of this
* Corresponding author. Tel.: +1 906 487 2023; fax: +1 906 487 2061.
E-mail address: shifang@mtu.edu (S. Fang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.050

5606
M. Thimmaiah et al. / Tetrahedron Letters 49 (2008) 5605–5607
reacted with trans-2-phenylvinylboronic acid in refluxing 1,4-diox-
FeCp*
ane in the presence of the pre-catalyst Pd2(dba)3 and the base
Cs2CO3. Within 1 h, 86% conversion was achieved as indicated by
GC–MS. After 24 h, an isolated yield of 90% of stilbene was
obtained. The reaction was 100% stereoselective, only trans product
was formed; no cis isomer could be detected by analyzing the
crude reaction mixture with GC–MS, NMR, and TLC (Table 1, entry
1).
1, R = Ph
2, R = Cy
Cp* = C5Me5
Cy = C6H11
PR2
Figure 1.
class of ligands with palladium would produce mono-coordinated
unsaturated organometallic species. Because benzoferrocene, like
ferrocene,6 is electron-rich, these ligands might represent a new
class of bulky electron-rich ligands, and therefore should be useful
for Suzuki–Miyaura coupling of aryl chlorides with alkenylboronic
acids. Our studies showed that this was indeed the case and more
significantly, the reactions were stereoselective for both trans- and
cis-alkenylboronic acids. Here we report our results.
Encouraged by these results, we next studied the generality of
this reaction. Under the same conditions, the coupling between
chlorobenzene and substituted phenylvinylboronic acids gave low-
er but still good yields (entries 2 and 3). The reactions gave better
results for 2-alkyl substituted alkenylboronic acids than for 2-aryl
substituted ones; both examples of the former shown in Table 1
gave 92% yield within 1 h (entries 4 and 5). Significantly, in all
cases, high stereoselectivity was achieved as indicated by 1H
NMR and GC. The lowest trans selectivity was 98% (entry 5); others
were virtually completely stereoselective (entries 2–4).
2. Results and discussion
It is well-known that Suzuki–Miyaura coupling is sensitive to
steric hindrance. In addition, electron-rich chloroarenes are more
difficult substrates than electron-poor ones.2d,3a Accordingly, we
challenged our coupling protocol with the highly hindered and
electron-rich 2-chloro-1,3-dimethylbenzene (entries 6 and 7).
The reactions proceeded with similar efficiency as those with
Because ligand 2 is more electron-rich and sterically hindered
than 1 and several other ligands we prepared, it was expected to
be most active for activating aryl chlorides. This was indeed the
case as we demonstrated earlier,5b and therefore 2 was chosen
for the current study. Thus, using 2 as ligand, chlorobenzene was
Table 1
Palladium-catalyzed cross-coupling of aryl chlorides with trans-alkenylboronic acids
Entry
Ar–Cl
Boronic acid
Product
Yielda (%)
90c
E/Zb
>99:1
B(OH)2
Ph
1
Ph–Cl
Ph
Ph
Ph
B(OH)2
Ph
2
3
Ph–Cl
Ph–Cl
74c
60c
>99:1
>99:1
Ph
B(OH)2
Ph
Me
Me
4
5
Ph–Cl
Ph–Cl
92
92
>99:1
98:1
B(OH)2
Heptyl
Ph
Ph
Ph
Heptyl
Ph
Ph
B(OH)2
Ph
Me
Cl
Me
B(OH)2
6
84
>99:1
Me
Me
Me
Me
Heptyl
Ph
7
8
90
60c
99
97
>99:1
>99:1
>99:1
>99:1
B(OH)2
Heptyl
Ph
Cl
Me
Me
Cl
B(OH)2
MeO
MeO
Ph
NO2
Cl
B(OH)2
9
Ph
NO2
Heptyl
NO2
Cl
10
B(OH)2
Heptyl
NO2
Reaction conditions: aryl chloride, 1 equiv; boronic acid, 1 equiv; Pd2(dba)3, 1.5 mol %; 2, 3.6 mol %; Cs2CO3, 2 equiv; 1,4-dioxane; reflux; 1 h.
a
Isolated yield.
b
Determined by 1H NMR analyses; results were close to those from GC analyses.
c
Yield after 24 h.

M. Thimmaiah et al. / Tetrahedron Letters 49 (2008) 5605–5607
5607
electron-neutral and unhindered chloroarenes; within 1 h, excel-
lent isolated yields of trans-alkenes were obtained. With the even
more electron-rich 4-chloroanisole as substrate, although the reac-
tion was slower, useful results were still obtained. When coupling
with trans-2-phenylvinylboronic acid, 60% yield was obtained after
24 h; and despite the long reaction time, only trans product was
isolated (entry 8). For electron-poor chloroarenes, the reactions
were very fast. For example, when 1-chloro-2-nitrobenzene was
coupled with 2-phenyl and alkyl substituted vinyl boronic acids,
the reactions only took 1 h to complete and quantitative isolated
yields were obtained (entries 9 and 10). Significantly, in both cases,
no cis-stereoisomer was detected in the crude reaction mixture.
We next extended the substrate scope to cis-alkenylboronic
acid. Under similar conditions described above, coupling of cis-pro-
penylboronic acid with electron-rich and -poor aryl chlorides all
gave cis-vinyl arene products with high selectivity (Table 2). We
first tested to use a 1:1 ratio of aryl chloride and boronic acid for
the reaction, but GC–MS showed that the former could not be con-
sumed completely even after long reaction time. However, when
the amount of aryl chlorides was reduced to 0.5 equiv, the reac-
tions were complete within 1 h when electron-poor chloroarenes
were used (entries 1 and 2). With electron-neutral and -rich chlo-
roarenes, the conversions were also high (entries 3–6). In all reac-
tion products, there were some trans-vinyl arenes (8–20%, see
Table 2) as indicated by GC–MS and 1H NMR (see Supplementary
data); we believe that this was mostly resulted from the trans-
boronic acid (ꢀ7% indicated by 1H NMR, see Supplementary data)
impurity contained in the starting cis-boronic acid, which was pur-
chased from Aldrich. In addition, cis-vinyl arenes generally have
higher boiling points than their trans-isomers, and the products
are volatile under vacuum. As a result, the actual selectivity for
the reaction is higher than that shown in Table 2. The yields of
the reaction ranged from good to excellent depending on the
nature of aryl chloride substrate. When electron-poor ones were
used, excellent isolated yields were obtained (entries 1 and 2).
With electron-neutral ones, yields were not reduced significantly
(entries 3 and 4). However, the reaction is sensitive to steric
hindrance, with 2-chloro-1,3-dimethylbenzene as substrate, the
yield was reduced to 62% (entry 5). Finally, when the more
electron-rich 4-chloroanisole was used, the reaction was sluggish
but still useful. After 24 h, good yields and stereoselectivity were
obtained (entry 6).
The use of Suzuki–Miyaura coupling to synthesize cis-vinyl-
arenes is particularly significant. To our best knowledge, there is
only one report that described coupling aryl iodides with cis-alken-
ylboronates in the presence of NaOEt to give cis products with high
selectivity (>84% to >98%).8 No such precedents involving coupling
aryl iodides, bromides, and chlorides stereoselectively with
cis-alkenylboronic acids could be found in literature. This may be
attributed to the ability of Pd(II) to isomerize cis-vinylarenes under
certain conditions.7
3. Conclusion
In conclusion, we have uncovered a catalytic protocol for the
synthesis of both cis- and trans-vinylarenes with low E/Z isomeri-
zation using Suzuki–Miyaura coupling. Considering the highly
functional group tolerance and other advantages of this important
carbon–carbon bond formation reaction,1d our protocol will find
useful in organic synthesis.
Acknowledgments
Financial supports from US NSF (CHE-0647129), MTU Chemis-
try Department, and MTU Research Excellence Fund; the assistance
from Mr. Jerry L. Lutz (NMR), Mr. Shane Crist (computation) and
Mr. Dean W. Seppala (electronics); and an NSF equipment grant
(CHE-9512445) are all gratefully acknowledged.
Table 2
Palladium-catalyzed cross-coupling of aryl chlorides with cis-alkenylboronic acids
Supplementary data
Entry
Ar–Cl
Boronic acid
Product
Yielda (%)
Z/Eb
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.050.
Cl
NO2
Me
1
95
92:8
Me
B(OH)2
NO2
Cl
References and notes
CHO
2
3
4
Me
85
81
83
90:10
80:20
88:12
Me B(OH)2
Me B(OH)2
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Reaction conditions: aryl chloride, 0.5 equiv; boronic acid, 1 equiv; Pd2(dba)3,
1.5 mol %; 2, 3.6 mol %; Cs2CO3, 2 equiv; 1,4-dioxane; reflux; 1 h.
a
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Determined by 1H NMR analyses; results were close to those from GC analyses.
b
Because the starting boronic acid contains ꢀ7% E-isomer as estimated by 1H NMR
(see Supplementary data) and generally Z-products have lower boiling points than
E-products, the actual selectivity is higher than shown.
c
Yield after 24 h.