Asymmetric intermolecular heck reaction of aryl halides

Article abstract of DOI:10.1021/ja412277z

The asymmetric intermolecular Heck reaction has been limited to aryl and vinyl triflates. Herein, we extend the reaction to aryl and vinyl bromides. Various cyclic olefins coupled with high enantioselectivity. Only bisphosphine oxides on a spiro backbone formed highly stereoselective Pd catalysts. The use of alcoholic solvents and alkylammonium salts were essential to promote halide dissociation from neutral arylpalladium complexes.

Full text of DOI:10.1021/ja412277z

Communication
pubs.acs.org/JACS
Asymmetric Intermolecular Heck Reaction of Aryl Halides
Chunlin Wu and Jianrong (Steve) Zhou*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
S
* Supporting Information
extensive experimentation, we were gratified to find a suitable
ABSTRACT: The asymmetric intermolecular Heck re-
action has been limited to aryl and vinyl triflates. Herein,
we extend the reaction to aryl and vinyl bromides. Various
cyclic olefins coupled with high enantioselectivity. Only
bisphosphine oxides on a spiro backbone formed highly
stereoselective Pd catalysts. The use of alcoholic solvents
and alkylammonium salts were essential to promote halide
dissociation from neutral arylpalladium complexes.
catalytic system (Figure 2). When the Pd/Xyl-SDP(O) catalyst
was used, the model reaction gave 96% ee and the selectivity “s”
between two olefinic isomers was 11:1 after 6 h at 80 °C.
he asymmetric intermolecular Heck reaction of aryl
T
triflates was first reported by Hayashi et al. in 1991.1
Since then, the reaction has served as a common testing ground
for chiral phosphorus ligands.2,3 Although an excellent ee was
obtained with simple cyclic olefins such as cyclopentene and
2,3-dihydrofuran, carbon electrophiles were mostly restricted to
aryl or vinyl triflates, which limited the synthetic value of the
intermolecular coupling. Recently, Sigman et al. realized the
asymmetric arylation of acyclic internal olefins in good ee, using
either aryldiazonium salts or arylboronic acids as arylating
agents.4
Previously, Overman5 and Shibasaki6 reported asymmetric
intramolecular Heck reactions using vinyl and aryl halides
(Figure 1). Some Heck products were used in natural product
synthesis, but the scope of the reaction remained rather limited.
To date, an asymmetric intermolecular Heck reaction of aryl
halides was never reported. It is difficult to displace a halide
ligand with a neutral olefin on Pd centers.
Figure 2. Ligand screening in the model Heck reaction.
(R)-Xyl-SDP(O), a bisphophsine oxide having a spiro-
bisindane skeleton, was highly active for the model reaction
of ArBr.7 The parent bisphosphine (R)-Xyl-SDP gave almost
racemic products. In comparison, both (R)-BINAP(O) and its
P-m-Xylyl derivative exhibited moderate stereoselectivity, 73%
ee and 58% ee, respectively.8 The parent bisphosphine (R)-
BINAP showed poor reactivity and gave <5% ee. (R)-BINAP
dioxide was inactive as a ligand. Pfaltz’s ligand, tBu-PHOX, was
also tested, but it showed very low activity with 85% ee.
Other reaction parameters, a benzoic acid additive (1 equiv),
iPr2NEt base (3 equiv), and ethylene glycol solvent were also
critical to this difficult transformation (Table 1). p-
NO2PhCO2H reacted with iPr2NEt to form an ammonium
Initially we chose a model reaction of p-tolyl bromide and
2,3-dihydrofuran and tried to find a suitable catalyst. After
−
salt R3NH+ArCO2 , which was very efficient in promoting
halide ionization from the neutral arylpalladium bromide (entry
1). Other aromatic carboxylic acids led to lower yields, while
acetic acid gave a much slower reaction (entries 2−6). When
ammonium salt iPr2NEt·HCl was used, the Heck reaction gave
a good result, but when the HOTf salt was used, the olefinic
ratio was only 3:1 (entries 7−8). In comparison, the model
reaction gave a 56% yield, 3:1 s ratio, and 94% ee in the absence
Received: December 3, 2013
Figure 1. Intramolecular Heck reaction of aryl and vinyl halides.
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja412277z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Effect of Additives
entry
additive
conv (%) yield (%) s ratio ee (%)
1
p-NO2PhCO2H (6 h)
p-NO2PhCO2H (12 h)
PhCO2H
100
100
88
95
93
73
67
64
20
73
67
56
80
84
78
11
7
96
95
94
90
94
96
96
95
94
97
96
97
2
3
7
4
p-tBuPhCO2H
PhCH2CO2H
MeCO2H
86
9
5
80
8
6
60
37
8
7
iPr2NEt·HCl
iPr2NEt·HOTf
None
80
8
90
3
9
80
3
10
11
12
AgOTf
100
95
9
AgOBz
24
13
Figure 4. Asymmetric Heck reaction of cyclopentene.
Ag2CO3
90
on aryl rings were well tolerated. Some vinyl and heteroaryl
bromides also coupled well. m-Anisyl bromide and cyclo-
pentene coupled to give 87% ee. The Heck product can be used
in the asymmetric synthesis of Preclamor,7a a promising
of the acid additive (entry 9). The use of expensive silver salts
as halide abstractors also worked to give the desired product in
good selectivity (entries 10−12). Notably, the use of silver salts
in common solvents, e.g., toluene, ether, and 1,4-dioxane, led to
poor results.
In methanol, the model Heck reaction was slower, while, in
THF or dioxane, no Heck reaction took place. Previously, Xiao
reported that alcohols or alkylammonium salts promoted the
regioselective Heck reaction of vinyl ethers and styrene, by
assisting halide dissociation from Pd complexes via hydrogen
bonding.9 Recently, we also reported a similar regioselective
Heck reaction of aliphatic olefins and styrene.10 Based on DFT
calculations, we proposed a concerted substitution on the Pd
center, which was accelerated by hydrogen bonding between
incoming methanol and a leaving bromide anion.
antipsychotic agent for the treatment of schizophrenia.11
A
few examples of ArCl were included with an acceptable level of
ee.
N-Boc-2,3-dihydropyrrole, cycloheptene, and cyclooctene
can also couple well (Figure 5). For example, p-fluorophenyl
The Pd/Xyl−SDP(O) catalyst was successfully applied to the
Heck reaction of various aryl bromides with 2,3-dihydrofuran
and cyclopentene (Figures 3−4). In most cases, >90% ee was
observed and the ratio of olefinic isomers was >10:1. In
reactions of cyclopentene, methanol was a better solvent than
ethylene glycol. Ortho substituents and electronic perturbation
Figure 5. Asymmetric Heck reaction of N-Boc-2,3-dihydropyrrole,
cycloheptene, and cyclooctene.
bromide coupled with N-Boc-2,3-dihydropyrrole in 93% ee.
The resulting azacycle can be used to prepare BMS-394136,7a
which was developed for the treatment of cardiac arrhythmia.12
Cyclohexene, however, did not react. Its half-chair conforma-
tion prevented olefin binding and insertion on the Pd center.
Both the acidic additive and alcoholic solvent were crucial to
halide ionization from neutral Pd complexes. We prepared a
neutral arylpalladium complex A from Pd(dba)2, p-F-phenyl
Figure 3. Asymmetric Heck reaction of 2,3-dihydrofuran.
B
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Journal of the American Chemical Society
Communication
bromide, and (R)-Xyl-SDP(O) (Figure 6). When complex A
was treated with cyclopentene (5 equiv) in the presence of
ACKNOWLEDGMENTS
■
We thank Singapore National Research Foundation (NRF-
RF2008-10) and Nanyang Technological University for
financial support. We thank Johnson Matthey for a gift of
palladium salts.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures for Heck reaction and character-
ization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
jrzhou@ntu.edu.sg
■
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/ja412277z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX