Synthesis of new benzimidazolium salts and their application in the asymmetric arylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2016.06.023

A series of novel chiral benzimidazolium salts, the precursor of N-heterocyclic carbene ligands, were designed and synthesized from 1,2-dibromobenzene. In situ prepared corresponding carbenes were tested in asymmetric Rh-catalyzed arylation of aromatic aldehydes, affording chiral diarylmethanols with high yields and moderate enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2016.06.023

Accepted Manuscript
Synthesis of new benzimidazolium salts and their application in the asymmetric
arylation of aldehydes
Wei-Ping He, Bi-Hui Zhou, Ya-Li Zhou, Xiang-Rong Li, Li-Mei Fan, Hao-Wen
Shou, Jie Li
PII:
S0040-4039(16)30683-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.023
TETL 47750
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 April 2016
3 June 2016
6 June 2016
Please cite this article as: He, W-P., Zhou, B-H., Zhou, Y-L., Li, X-R., Fan, L-M., Shou, H-W., Li, J., Synthesis of
new benzimidazolium salts and their application in the asymmetric arylation of aldehydes, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.023
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Synthesis of new benzimidazolium salts and
their application in the asymmetric arylation
of aldehydes
Leave this area blank for abstract info.
Wei-Ping Hea,b, Bi-Hui Zhoua,b, Ya-Li Zhoua, Xiang-Rong Lia, Li-Mei Fana, Hao-Wen Shoua, and Jie Lia,*
a School of Medicine, Zhejiang University City College, No. 48, Huzhou Road, Hangzhou 310015, PR China
bCollege of Pharmaceutical Sciences, Zhejiang university, Hangzhou 310058, China

1
Tetrahedron Letters
Synthesis of new benzimidazolium salts and their application in the asymmetric
arylation of aldehydes
Wei-Ping Hea,b, Bi-Hui Zhoua,b, Ya-Li Zhoua, Xiang-Rong Lia, Li-Mei Fana, Hao-Wen Shoua, and Jie Lia,
a School of Medicine, Zhejiang University City College, No. 48, Huzhou Road, Hangzhou 310015, PR China
bCollege of Pharmaceutical Sciences, Zhejiang university, Hangzhou 310058, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of novel chiral benzimidazolium salts, the precursor of N-heterocyclic carbene ligands,
were designed and synthesized from 1,2-dibromobenzene. In situ prepared corresponding
carbenes were tested in asymmetric Rh-catalyzed arylation of aromatic aldehydes, affording
chiral diarylmethanols with high yields and moderate enantioselectivities.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbene
Benzimidazolium salt
Rh-catalyzed
Diarylmethanol
 Corresponding author. Tel.: +86 571 88016565; fax: +86 571 88018442; e-mail: lijie@zucc.edu.cn (J. Li)

2
Tetrahedron Letters
Introduction
with 2c as the starting materials (Scheme 2). To compare
catalysts 1f−h to catalyst 1c, Rh-catalyzed asymmetric additions
of PhB(OH)2 to 2-naphthaldehyd using these catalysts were
performed under above-described conditions. All three of the
new catalysts reached similar conversions and 1h performed the
best enantioselectivity (37% ee).
Chiral diarylmethanols are structural core involved in a
variety of pharmacologically significant compounds and
therefore represent important synthetic targets.1 Besides
asymmetric hydrogenation of diarylketones, catalytic asymmetric
addition of aryl organometallic reagents to aldehydes provides a
direct route for synthesis of enantiomerically enriched
diarylmethanols.2 Arylboronic acids are among the most
convenient reagents due to their low toxicity, compatibility to a
broad range of functional groups and high stability in water and
air.3 Since Miyaura first reported the Rh-catalyzed asymmetric
addition of organoboronic acids to aldehydes in 1998,4 much
attention has shifted to a practical strategy: either to improve
enantioselectivity or accelerate the reaction by using new catalyst
systems.5
During the past 20 years, complexes with N-heterocyclic
carbenes (NHCs) have gathered considerable interests from the
organic chemistry community and have been widely used in
homogeneous metal catalysis.6 A logical extension of this
development is the application of these ligands in stereoselective
catalysis, the easy introduction of chiral elements into NHCs and
the facile preparation of their precursors have made chiral NHCs
promising chiral ligands in metal-based asymmetric catalysis.7 In
2005, Bolm reported the synthesis of a variety of chiral
imidazolium salts and their application in the asymmetric
arylation of aldehydes.8 However, the ligand did not show
satisfactory enantioselectivity (38% ee). This study was followed
by those of the groups of Shi and Ma, but only moderate
enantioselectivities were obtained.9 Obviously, it is still desirable
to develop or find more active chiral catalysts and efficient
catalytic systems for 1,2-addition of organoboronic acids to
aldehydes. Herein, we wish to report the synthesis a series of new
chiral benzimidazolium salts and their application in asymmetric
Rh-catalyzed arylation of aromatic aldehydes.
Results and discussion
Synthesis of benzimidazolium salts. The synthesis of the
benzimidazolium salt 1a as N-heterocyclic carbene precursor is
representatively shown in Scheme 1. Buchwald-Hartwig
coupling of 1,2-dibromobenzene with (S)-α-methylbenzylamine
gave the monosubstituted product 2a in 85% yield. A second
Buchwald-Hartwig coupling proceeded well with this substituted
aniline, producing the differentially substituted diamine 3a in an
excellent 91% yield. Finally, treatment of diamine with HCl in
CH(OEt)3 gave the benzimidazolium salt 4a in 89% yield. The
hygroscopic chloride salt 4a which became gels on exposure to
the atmosphere was difficult to handle on the benchtop, but this
problem was solved by anion metathesis with NaI to give 1a.
Other benzimidazolium salts 1b−e were prepared in the same
manner. All of the benzimidazolium salts 1a−e were purified and
fully characterized by NMR and mass spectrometry.
Table 1. Comparison of NHC precursors
Entrya
Ligand
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
92
93
99
99
90
99
95
99
3
1
23
13
6
28
21
37
1a
1b
1c
1d
1e
1f
Asymmetric arylation of aldehydes in the presence of 1.
With the novel benzimidazolium salts 1a−e in hand, we turned
our attention to their application in Rh-catalyzed asymmetric
additions of arylboronic acids to aromatic aldehydes. We began
to screen benzimidazolium salts 1a−e in enantioselective
phenylation of 2-naphthaldehyde (5a) with PhB(OH)2 (6a). The
results are shown in Table 1. At first, reactions were carried out
with the use of Rh(OAc)2 in DME/H2O (5:1) according to
Fürstner’s procedure (Table 1, entries 1-5).10 Diarylmethanol
7aa was obtained in high yield with each of the benzimidazolium
salts 1a−e (90-99%), 1c possessing a t-butyl group as R
substituent gave 23% enantioselectivity. We hypothesized that
the bulky t-butyl group of catalyst 1c resulted in better
enantioselectivity. Thus, three additional benzimidazolium salts
(1f−h) were prepared with different ortho positions of the N-
bound aryl rings. As shown in Scheme 2, the precursors 1f−h
were prepared by applying the same three-step sequence to 1a−e
1g
1h
a Reaction condition: [Rh(OAc)2]2 (3 mol %), ligand (3 mol %), NaOtBu (2
equiv), arylboronic acids (2 equiv), N2, DME/H2O (5:1), 100 oC, 16 h.
b Isolated yields.
c Determined by chiral HPLC (CHIRALCEL OD Column) analysis.
We then optimized the experimental conditions using 1h as
ligand, a number of parameters were varied using phenylboronic
acid and 2-naphthaldehyde as model substrates. In place of
NaOtBu, KOtBu, LiOtBu and LiOH gave same results. Probing of
solvents revealed that EtOH/DME (5:1) is better than other
solvents (Table 2, entry 7). Different rhodium sources were also
investigated with 1h (Table 2, entries 10−12), [Rh(OAc)2]2
emerged as the best choice of catalyst precursors. Further screen

3
of reaction temperature indicated that lower temperature can
afford the desired product with higher enantioselectivity. Upon
lowering the reaction temperature to 50 oC, a 98% conversion and
43% ee were observed, and 50% ee was obtained at 30oC (Table
2, entry 13−14). However, the reaction did not proceed at all
when the temperature was lowered to 0oC (Table 2, entry 15).
examined in the asymmetric arylation of aromatic aldehydes
using 1h as catalyst. The results are summarized in Table 3. In
most cases, the reaction proceeded with notable efficiency (up to
99% isolated yield) and moderate enantioselectivity. The best
enantioselectivity
was
obtained
starting
from
4-
(trifluoromethyl)benzaldehyde (56% ee, entry 12).
Having established the optimal catalytic condition, various
substrates with different steric and electronic properties were
Table 2. Optimization of the reaction conditions
Entrya
1
2
3
4
5
6
7
Solvent
Metal source
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
RhCl3·3H2O
[Rh(COD)Cl]2
[Rh(C2H4)2Cl]2
[Rh(OAc)2]2
[Rh(OAc)2]2
[Rh(OAc)2]2
Temperature
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
50 oC
Yield (%)b
ee (%)c
25
14
34
37
31
26
41
40
37
35
3
Dioxane
DME
57
37
99
99
96
93
36
99
94
95
92
90
98
98
−
DME/H2O (10:1)
DME/ H2O (5:1)
DME/ H2O (3:1)
MeOH
MeOH/DME (5:1)
Ethanol/DME (5:1)
Ethanol
Ethanol/DME (5:1)
Ethanol/DME (5:1)
Ethanol/DME (5:1)
Ethanol/DME (5:1)
Ethanol/DME (5:1)
Ethanol/DME (5:1)
8
9
10
11
12
13
14
15
5
43
50
−
30 oC
0 oC
a Reaction condition: [Rh(OAc)2]2 (3 mol %), 1h (3 mol %), NaOtBu (2 equiv), arylboronic acids (2 equiv), N2, 16 h.
b Isolated yields.
c Determined by chiral HPLC (CHIRALCEL OD Column) analysis.
Table 3. Scope of methodology
Entrya
1
2
3
4
5
6
7
8
Ar1
Ar2
Yield (%)b
90 7ab
87 7ac
99 7ad
87 7ba
88 7bb
99 7bc
99 7bd
94 7ca
81 7cd
69 7cc
88 7cd
98 7da
67 7db
45 7dc
85 7dd
97 7ed
99 7fa
63 7ga
81 7ha
99 7ia
ee (%)c
47
27
41
54
53
40
50
50
52
34
43
56
47
19
37
44
51
52
46
52
35
53
31
28
2-Naphthyl 5a
2-Naphthyl 5a
2-Naphthyl 5a
1- Naphthyl 5b
1- Naphthyl 5b
1- Naphthyl 5b
1- Naphthyl 5b
2-MeOPh 5c
2-MeOPh 5c
2-MeOPh 5c
2-MeOPh 5c
4-CF3Ph 5d
4-CF3Ph 5d
4-CF3Ph 5d
4-CF3Ph 5d
Ph 5e
3,4-diMePh 5f
4-EtPh 5g
4-NO2Ph 5h
2-FPh 5i
3,5-diFPh 5j
4-ClPh 5k
2-Furyl 5l
4-FPh 6b
2-MePh 6c
4-MeOPh 6d
Ph 6a
4-FPh 6b
2-MePh 6c
4-MeOPh 6d
Ph 6a
4-FPh 6b
2-MePh 6c
4-MeOPh 6d
Ph 6a
4-FPh 6b
2-MePh 6c
4-MeOPh 6d
4-MeOPh 6d
Ph 6a
Ph 6a
Ph 6a
Ph 6a
Ph 6a
Ph 6a
Ph 6a
Ph 6a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
99 7ja
99 7ka
99 7la
2-Thienyl 5m
99 7ma
a Reaction condition: [Rh(OAc)2]2 (3 mol %), 1h (3 mol %), NaOtBu (2 equiv), arylboronic acids (2 equiv), N2, 50 oC, 16 h.
b Isolated yields.
c Determined by chiral HPLC (CHIRALCEL OD and AD Column) analysis.
Extension of 1h as NHC precursor for palladium-catalyzed
addition of phenylboronic acid to aromatic aldehyde was also
examined. As in previous reports,11 the use of CHCl3 as additive
is crucial for this Pd-catalyzed arylation, and the survey of
solvents revealed that toluene was the only suitable solvent for
this reaction. In the next step, four substrates with different
electronic properties were applied in the reaction with salt 1h as
catalyst precursor. As shown in Table 4, these aryl aldehydes can
be transformed to the corresponding diarylmethanols in moderate
yield (34-48%) but inferior ee values.

4
Tetrahedron
Table 4. Palladium-catalyzed reaction of phenylboronic acid to aromatic
Conclusion
aldehydes
In conclusion, a series of new chiral benzimidazolium salts
have been prepared and the single-crystal X-ray diffraction result
further confirmed the molecular structure of NHC−Rh complex
8. Their applicability in the asymmetric additions of arylboronic
acids to aromatic aldehydes has been demonstrated, and the
corresponding diarylmethanols were obtained with high yields
and moderate enantiomeric excesses (up to 56%). It is worth
mentioning that the palladium complex catalyst was also active
in this reaction by addition of a catalytic amount of chloroform to
the reaction mixture. Further work is in progress to utilize these
benzimidazolium salts in asymmetric Rh-catalyzed 1,2-addition
reactions of arylboronic acids with ketones.
Entrya
Ar1
Solvent
additive
−
Yield (%)b
−
48 7ba
−
−
ee (%)c
1
2
3
4
5
6
7
8
9
1-Naphthyl 5b Toluene
1-Naphthyl 5b Toluene
1-Naphthyl 5b DME
1-Naphthyl 5b CH2Cl2
1-Naphthyl 5b THF
1-Naphthyl 5b Xylene
2-Naphthyl 5a Toluene
2-MeOPh 5c
4-CF3Ph 5d
−
5
−
−
−
−
4
7
6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
−
trace
37 7aa
39 7ca
34 7da
Toluene
Toluene
Acknowledgments
a Reaction condition: Pd(OAc)2 (3 mol %), ligand (3 mol %), NaOtBu (2
equiv), arylboronic acids (2 equiv), N2, 100 oC, 24 h.
b Isolated yields.
We are grateful to the National Natural Science Foundation of
China (81302668) and Hangzhou Science and Technology
Information Institute of China (20150633B45).
c Determined by chiral HPLC (CHIRALCEL OD Column) analysis.
The X-ray crystal structure of NHC−Rh. We attempted to
prepare rhodium(I) complex of 1e using a mild transmetalation
method developed by Wang and Lin.12 Reaction of
benzimidazolium precursors with Ag2O in CH2Cl2 at room
temperature in the darkness gave rather unstable silver
complexes, observed by NMR spectroscopy, which decomposed
too quickly to be isolated. Direct addition of [Rh(COD)Cl]2 to a
freshly prepared solution of silver complexes yielded upon
workup the corresponding chiral complex 8, which were purified
by chromatography on silica gel (Scheme 3). The complex 8 is
air stable in solid state and X-ray-quality crystals of 8 was easily
grown by layering a CH2Cl2 solution of 8 with hexane. The
structure of the new chiral NHC−Rh complex 8 was confirmed
by X-ray diffraction (Fig. 1).
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://
References and notes
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6
Tetrahedron
Highlights
 Several new chiral benzimidazolium salts were
synthesized.
 These new ligands were highly effective
catalysts for the arylation of aldehydes.
 Various chiral diarylmthanols were obtained in
excellent yields and moderate ee.