Rhodium-catalyzed asymmetric conjugate addition of organoboronic acids to nitroalkenes using chiral bicyclo [3.3.0] diene ligands

Article abstract of DOI:10.1002/anie.201001883

(Figure Presented) Old before l diene: An efficient rhodium/ diene-catalyzed asymmetric conjugate addition of organoboronic acids to challenging nitroalkene substrates that lack α substituents has been developed. Chiral bicyclo[3.3.0] dienes were found to

Full text of DOI:10.1002/anie.201001883

Communications
DOI: 10.1002/anie.201001883
Asymmetric Catalysis
Rhodium-Catalyzed Asymmetric Conjugate Addition of
Organoboronic Acids to Nitroalkenes Using Chiral Bicyclo[3.3.0]
Diene Ligands**
Zhi-Qian Wang, Chen-Guo Feng, Shu-Sheng Zhang, Ming-Hua Xu,* and Guo-Qiang Lin*
In recent years, the use of transition-metal-catalyzed reac-
In 2007, we reported our discovery of a new family of C2-
symmetric chiral diene ligands bearing a simple bicyclo[3.3.0]
backbone; these ligands were successfully applied in the
rhodium-catalyzed enantioselective arylation of N-tosylaryli-
mines and the 1,4-addition of arylboronic acids to a,b-
unsaturated carbonyl compounds under mild conditions.[8]
Inspired by these successes, we wondered whether these
rhodium/diene complexes could also act as effective catalysts
for the asymmetric addition of boronic acids to nitroalkenes.
In spite of the recent significant advances, there has been no
report on the use of chiral diene ligands[9] in this field.
Our initial investigation was carried out by examining the
reaction of nitrostyrene 2 with para-anisylboronic acid (3) in
the presence of chiral diene ligand 1a (3 mol%) under the
reaction conditions previously reported[8a] for the arylation of
N-tosylarylimines with arylboronic acids (Scheme 1). How-
À
tions have been an important and general method in carbon
[1]
À
carbon and carbon heteroatom bond-forming synthesis.
Among them, the rhodium-catalyzed asymmetric conjugate
addition of organoboronic acids to electron-deficient olefins,
pioneered by Miyaura, Hayashi, and co-workers,[2] has been
established as one of the most powerful and convenient tools
for the enantioselective synthesis of b-substituted functional-
ized compounds. In particular, excellent results were achieved
in the addition to a,b-unsaturated carbonyl compounds.[3]
However, despite the great synthetic importance of nitro
compounds,[4] it is surprising that far fewer studies reported
the efficient asymmetric addition of boronic acids to nitro-
alkenes, most likely because of the difficulty in controlling the
reaction stereoselectivity.[5] In fact, high enantioselectivities
were only achieved by the Hayashi group in the asymmetric
addition of organoboronic acids to a-substituted 1-nitro-
alkenes using a rhodium/binap (binap = 2,2-bis(diphenyl-
phosphanyl)-1,1 -binaphthyl) catalyst.[6] In other reports,[7]
low levels of enantiomeric enrichment (< 50% ee) were
often observed with general 1-nitroalkene substrates that lack
a substitutents. Therefore, the development of a capable
catalyst system for efficient asymmetric boronic acid addition
to nitroalkenes is highly desirable. Herein, we report our
preliminary results on the rhodium-catalyzed asymmetric
addition of organoboronic acids to nitroalkenes that lack
a substitutents; high enantiocontrol is afforded using chiral
bicyclo[3.3.0] diene ligands.
Scheme 1. Initial attempts on using bicyclo[3.3.0] diene ligand.
ever, the result was disappointing. The addition product 4a
was obtained in only 9% yield, albeit with moderate
enantioselectivity (40%), and a large amount of starting
material 2 was recovered. Considering the known catalytic
cycle for the 1,4-addition of organoboron reagents to
activated alkenes,[10] it is likely that the low yield can be
attributed to poor catalyst regeneration from its rhodium
nitronate intermediate in the hydrolysis step. Indeed, we were
pleased to find that the reaction provided much better yield
(70%) and enantioselectivity (68%) when performed in the
presence of a stoichiometric amount of rhodium/1a catalyst.
This result indicates the possibility of related asymmetric
catalysis by new chiral rhodium/diene complex. A potential
solution to the catalyst regeneration problem could be by
tuning the reaction conditions.
[*] Z.-Q. Wang, C.-G. Feng, S.-S. Zhang, Prof. Dr. M.-H. Xu,
Prof. G.-Q. Lin
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
345 Lingling Road, Shanghai 200032 (China)
Fax: (+86)21-5080-7388
E-mail: xumh@mail.sioc.ac.cn
lingq@mail.sioc.ac.cn
Prof. Dr. M.-H. Xu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
555 Zuchongzhi Road, Shanghai 201203 (China)
To achieve an efficient catalytic process, the reaction
conditions were carefully screened. One concern was that the
in situ generation of the rhodium/diene catalyst would be
facilitated by acidic conditions. After extensive studies, we
found that the expected catalytic cycle took place when
potassium acid fluoride (KHF2) was employed in the reaction
(Table 1). Further optimization of the conditions led to the
[**] We thank the National Natural Science Foundation of China, the
Chinese Academy of Sciences, the Shanghai Municipal Committee
of Science and Technology (09JC1417300, 08QH14027), and the
Major State Basic Research Development Program (2010CB833302)
for their generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001883.
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Angew. Chem. Int. Ed. 2010, 49, 5780 –5783

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Chemie
Table 1: Exploration and optimization of the conjugate addition reaction.
Entry[a]
3 [equiv]
KHF2 [equiv]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
1.1
1.5
1.5
1.5
1.5
1.5
1.5[d]
5
5
3
2
1
0
0
14
14
1
1
1
76
97
98
96
92
60
91
68
68
70
70
70
68
69
Scheme 2. Proposed reaction mechanism.
19
1
[a] The reaction was carried out on a 0.5 mmol scale with [{RhCl-
(C2H4)2}2] (0.0075 mmol), diene 1g (0.0165 mmol, 1.1 equiv to Rh) in
toluene/H2O at 1008C. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis. [d] The corresponding trifluoroborate
p-MeOC6H4BF3K was used.
formation of addition product in 98% yield and 70% ee when
nitrostyrene 2 was treated with a small excess of para-
anisylboronic acid (1.5 equiv) in the presence of 3 equivalents
of KHF2 in toluene/water (10:1) at 1008C for 1 hour by the
catalysis of rhodium/1a (3 mol%; Table 1, entry 3). Since
KHF2 in aqueous conditions can react with organoboronic
acids to generate potassium organotrifluoroborates,[11,12]
which are also capable of transmetalation with rhodium for
addition reactions to unsaturated substrates, we speculated
that the transformation was actually promoted by an organo-
trifluoroborate species formed in situ. To better understand
the reaction, several control experiments were performed. It
was found that the direct use of the corresponding potassium
trifluoroborate (p-MeOC6H4BF3K) in the presence of water
did give comparable results (91% yield, 69% ee; Table 1,
entry 7). In contrast, a significant decrease in the reaction rate
was observed using boronic acid under identical conditions
(Table 1, entry 6). The presence of excess KHF2 also had a
detrimental effect on the reaction rate (Table 1, entries 1 and
2). In line with most 1,4-addition processes, a small amount of
water was essential for good conversion, and almost no
reaction occurred under anhydrous conditions. Although the
exact mechanism remains unclear, and the possibility of an
equilibrium between the fluoroborate and the boronic acid is
not ruled out, these results may suggest a pathway of fast
transmetalation between the rhodium nitronate (A/A’) and
the relevant organoborate intermediate (B/C) benefited by
hydrolysis of potassium organotrifluoroborate (Scheme 2). It
is worth noting that the fluoride ions may also play an
important role in stabilizing the various catalytic intermedi-
ates.[13]
Scheme 3. Evaluation of catalytic activities of chiral diene ligands.
n.r.=no reaction.
under same conditions; however, only trace amounts of
product was observed. As the catalytic asymmetric addition of
organoboronic acids to a-unsubstituted nitroalkenes with
high enantiocontrol remains unprecedented,[14] this result
represents a rather promising achievement.
To explore the scope of this rhodium/diene catalyzed
process, a variety of boronic acids with diverse steric and
electronic properties were tested with aliphatic and aromatic
nitroalkenes (Table 2). Under the optimized conditions, we
were pleased to find that the addition reactions universally
gave the expected products in very high yields and moderate
to good ee values. Excellent enantioselectivities (95–97%)
were observed in the cases using sterically more hindered
arylboronic acids, such as 1-naphthylboronic acid and 2-
tolylboronic acid (Table 2, entries 8, 10, 12, and 14). The
electron-withdrawing group on the phenyl ring of the boronic
acids was helpful for obtaining high enantioselectivity
(Table 2, entries 2–4). In contrast, the electronic properties
of the substituent on the phenyl ring of the substrates did not
seem to affect the reaction stereoselectivity significantly
(Table 2, entries 8 and 11–13). More interestingly, when
aliphatic 2-nitrovinylcyclohexane was subjected to the con-
jugate addition with 4-anisylboronic acid, the same level of
enantioselectivity was observed (Table 2, entry 16). The use
of linear nitroolefin 1-nitrohexene as the substrate resulted in
appreciably lower enantioselectivity compared to 2-nitro-
vinylcyclohexane; however, a dramatic increase in the
selectivity was obtained when sterically encumbered 2-
tolylboronic acid was employed (Table 2, entries 17 and 18).
It is worth noting that these results are among the best in the
asymmetric addition of organoboronic acids to nitroalkenes
With the catalytic system developed, we then focused our
efforts on the use of different chiral diene ligands to attain
excellent enantioselectivity. A series of bicyclo[3.3.0] dienes
with various R substituents were evaluated (Scheme 3). In
most cases, the reaction proceeded smoothly under the
catalysis of rhodium/1. The enantioselectivity could be
increased to 78% by using 2-naphthyl-substituted diene 1g
as the ligand. We also tested the use of an (R)-binap ligand
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Communications
Table 2: Asymmetric conjugate addition to nitroalkenes catalyzed by
[Rh]/1g.
fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinoline (7) in
good yield in three steps.
In summary, we have developed a rhodium-diene cata-
lyzed asymmetric conjugate addition of organoboronic acids
to challenging a-unsubstituted nitroalkene substrates, for
which chiral bicyclo[3.3.0] dienes were identified as superior
ligands. Under optimal conditions, the reaction proceeds with
high enantioselectivity to give a broad range of synthetically
useful chiral b,b-disubstituted nitroalkanes. The simple use of
boronic acids in combination with potassium acid fluoride as
reactive organoboron reagents is a promising alternative to
organotrifluoroborates in transition-metal-catalyzed reac-
tions. Further investigation on the reaction mechanism as
well as extensions of this new reaction system are underway in
our laboratories.
Entry[a]
R
Ar
4
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-tBuC6H4
3-ClC6H4
2-MeC6H4
2-Np
1-Np
Ph
2-MeC6H4
Ph
2-MeC6H4
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
96
96
92
91
95
92
99
85
99
92
99
85
95
97
99
90
81
95
78 (R)
89 (R)
92 (R)
92 (R)
81 (R)
81 (R)
92 (R)
97 (R)
84 (R)
95 (R)
89 (S)
97 (R)
82 (S)
97 (R)
85 (S)
84 (R)
61 (R)
86 (R)
9
10
11
12
13
14
15
16
17
18
Ph
4j
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
1-Np
C6H11
nBu
4a’
4k
4c’
4l
4j’
4m
4n
4o
Experimental Section
General procedure for the asymmetric conjugate addition reaction
(Table 2): Under a nitrogen atmosphere, a mixture of [{RhCl-
(C2H4)2}2] (2.9 mg, 0.007 mmol), diene ligand 1g (6.0 mg,
0.023 mmol), and arylboronic acid (0.75 mmol) in toluene (1 mL)
was stirred at 608C for 30 min. Then nitroalkene (0.5 mmol) in
toluene (1 mL) and aqueous KHF2 (3.0m, 0.5 mL) were added
successively. After being heated to reflux at 1008C for 4–7 h, the
reaction was cooled to room temperature and water (20 mL) was
added. The mixture was extracted with ethyl acetate and the
combined organic phases were washed with brine and dried over
anhydrous Na2SO4. After being concentrated under reduced pressure,
the residue was purified by column chromatography on silica gel to
afford the desired product 4.
4-MeOC6H4
4-MeOC6H4
2-MeC6H4
nBu
[a] The reaction was carried out on a 0.5 mmol scale with 1.5 equiv of
arylboronic acid, [{RhCl(C2H4)2}2] (0.0075 mmol), diene 1g
(0.0165 mmol, 1.1 equiv to Rh), and 3 equiv of KHF2 in toluene/H2O at
1008C for 4–7 h. [b] Yield of isolated product. [c] Determined by chiral
HPLC analysis. Np=napthyl.
that lack a substitutents. Gratifyingly, the stereochemistry of
the newly formed stereogenic center of product 4d (Table 2,
entry 4) was determined to be R by X-ray crystallography.[15]
Assuming an analogous reaction mechanism, the absolute
configuration of the products obtained was assigned as
indicated in the table.
To further demonstrate the synthetic utility of this
methodology, the transformation of nitroalkene 5 into
pharmaceutically interesting isoquinoline derivative 7 was
also carried out (Scheme 4). The enantioselective addition of
4-furophenylboronic acid to 5 in the presence of a rhodium/1g
catalyst afforded product 4p in 99% yield with 91% ee.
Raney nickel reduction followed by formamide formation
provided the intermediate 6, which underwent Bischler–
Napieralski cyclization to form optically active (S)-4-(4-
Received: March 30, 2010
Revised: April 22, 2010
Published online: July 7, 2010
Keywords: asymmetric catalysis · diene ligands ·
.
conjugate addition · nitroalkenes · rhodium
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Scheme 4. Synthesis of isoquinoline derivative 7.
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Angew. Chem. Int. Ed. 2010, 49, 5780 –5783
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