Organocatalytic Atroposelective Construction of Axially Chiral N-Aryl Benzimidazoles Involving Carbon-Carbon Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.0c02214

Axially chiral compounds widely occur in natural products, biologically active molecules, ligands, and catalysts, and their efficient and enantioselective synthesis is highly desirable. Herein, we report a novel method for the atroposelective construction of axially chiral N-aryl benzimidazoles with chiral phosphoric acid as the organocatalyst via reaction of N1-(aryl)benzene-1,2-diamines with multicarbonyl compounds. The present method provided the target products in high yields (up to 89percent) with excellent enantioselectivity (up to 98percent ee).

Full text of DOI:10.1021/acs.orglett.0c02214

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Letter
Organocatalytic Atroposelective Construction of Axially Chiral
N‑Aryl Benzimidazoles Involving Carbon−Carbon Bond Cleavage
Ningning Man, Zhenbang Lou, Yuming Li, Haijun Yang, Yufen Zhao, and Hua Fu*
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ABSTRACT: Axially chiral compounds widely occur in natural products,
biologically active molecules, ligands, and catalysts, and their efficient and
enantioselective synthesis is highly desirable. Herein, we report a novel
method for the atroposelective construction of axially chiral N-aryl
benzimidazoles with chiral phosphoric acid as the organocatalyst via
reaction of N1-(aryl)benzene-1,2-diamines with multicarbonyl compounds.
The present method provided the target products in high yields (up to
89%) with excellent enantioselectivity (up to 98% ee).
N-Aryl benzimidazoles are widely found in numerous bio-
logically active molecules. For example, they are applied as the
inhibitors of some enzymes such as lymphocyte-specific kinase
(Lck),1 nonpeptide thrombin,2 5-lipoxygenase,3 factor Xa
(FXa),4 and poly(ADP-ribose)polymerase (PRAP).5 They
act as the antagonists of nonpeptide luteinizing hormone-
releasing hormone (LHRH),6 N-methyl-D-aspartate
(NMDA),7 and a neuropeptide Y Y1 receptor.8 N-Aryl
benzimidazoles are also key core structures of herbicides,
fungicides, veterinary medicines,9 dyes,10 and high-temperature
polymers.11 Therefore, the synthesis of N-substituted
benzimidazoles attracts much attention,12 in which one of
the most common approaches to benzimidazoles is the
coupling of substituted 1,2-diaminoarenes with carboxylic
acids or their equivalents. Axially chiral compounds are
important structures in natural products and biologically active
molecules,13 and they also are privileged cores of chiral ligands
and catalysts.14 Recently, great advances have been achieved in
asymmetric synthesis of axially chiral backbones.15,16 However,
to the best of our knowledge, the atroposelective synthesis of
N-aryl benzimidazoles is very limited thus far. Very recently,
Miller and co-workers have developed atroposelective cyclo-
dehydration of 2,2,2-trifluoro-N-(2-(arylamino)aryl)-
acetamides catalyzed by phosphothreonine-embedded peptidic
phosphoric acids and C2-symmetric chiral phosphoric acids
(Scheme 1a).17
workers have represented the phosphorous-acid-catalyzed
synthesis of benzimidazoles through cyclocondensation of
substituted benzene-1,2-diamines and β-ketoesters via the
selective C−C bond cleavage (Scheme 1b).21 In 2017, Tan
and co-workers reported the axially chiral N-triflylphosphor-
amide-catalyzed atroposelective synthesis of arylquinazolinones
through coupling of N-aryl anthranilamides with 4-methox-
ypentenone (Scheme 1c),22 but the poor results were observed
when the diketone derivatives replaced 4-methoxypentenone
as the substrates. Since Akiyama and Terada’s initiative
discovery in 2004,23 the axially chiral phosphoric acids
(CPAs) have become an important organocatalyst in the
asymmetric synthesis.24 Inspired by the results above, herein,
we report an organocatalytic atroposelective construction of
axially chiral N-aryl benzimidazoles involving carbon−carbon
bond cleavage (Scheme 1d).
Initially, reaction of N1-(naphthalen-1-yl)benzene-1,2-dia-
mine (1a) with 2 equiv of acetylacetone (2a) was performed in
the presence of 10 mol % of CPA ((R)-C1) and MgSO4 in
toluene at 30 °C for 24 h. To our delight, the desired product,
(S)-3a, was obtained in 40% yield (89% ee) as the result of the
cleavage of the C−C bond in 2a (Table 1, entry 1).
Subsequently, we commenced screening the optimal reaction
conditions to further improve the yield and ee value of (S)-3a.
The results are summarized in Table 1 (see Table S1 in SI for
more details).
On the other hand, the cleavage of C−C bonds is a topic of
significant importance in synthetic organic chemistry. How-
ever, acquiring the selective C−C bond cleavage still is a great
challenge because of the inherent inert nature and ubiquity of
the C−C bonds.18 In the past decades, various interesting
carbon−carbon bond cleavage methods have been devel-
oped,19 in which transition metal catalysis is overwhelming.20
To realize environmentally friendly and sustainable chemistry,
it is highly desirable to develop a transition-metal-free method
for carbon−carbon bond cleavage. In 2015, Zhou and co-
As shown in Table 1, other chiral phosphoric acids, (R)-
C2∼(R)-C9 (10 mol % relative to the amount of 1a), were
Received: July 3, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02214
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. (a) Atropisomer-Selective Cyclodehydration of
Axially Chiral 2,2,2-Trifluoro-N-(2-
Table 1. Optimization of the Reaction Conditions
(arylamino)aryl)acetamides, (b) Phosphorous-Acid-
Catalyzed Synthesis of Benzimidazoles, (c) Axially Chiral N-
Triflylphosphoramide-Catalyzed Atroposelective Synthesis
of Arylquinazolinones, and (d) Our Protocol for
Organocatalytic Atroposelective Construction of Axially
Chiral N-Aryl Benzimidazoles
b
c
entry
CPA T (°C) time (h) yield of 3a (%)
ee of 3a (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C9
C1
C1
C1
C1
C1
C1
C1
30
30
30
30
30
30
30
30
30
50
60
70
60
60
60
60
24
24
24
24
24
24
24
24
24
24
24
24
20
16
20
20
40
35
33
41
55
41
44
53
45
75
86
82
86
74
76
88
89
21
21
5
82
44
31
67
66
88
88
88
88
88
88
92
9
10
11
12
13
14
d
15
16
e
a
Reaction conditions: N1-(naphthalen-1-yl)benzene-1,2-diamine (1a)
(0.1 mmol, 1.0 equiv), acetylacetone (2a) (0.2 mmol, 2.0 equiv), CPA
((R)-C1∼(R)-C9) (10 μmol, 10 mol %), MgSO4 (50 mg), toluene
(2.0 mL), temperature (oil bath, 30−70 °C), time (16−24 h) in a
b
c
sealed Schlenk tube without extrusion of air. Isolated yield. The ee
values were determined by HPLC analysis on a chiral stationary phase
d
e
using a Daicel Chiralpak AD-H column. Na2SO4 as the additive. 3 Å
molecular sieve (MS) as the additive.
first investigated, and the results showed that the BINOL-
derived CPAs with various substituents on the 3,3′-position
did not improve yield and ee value of (S)-3a simultaneously
(entries 2−9). To promote the cleavage of the C−C bond in
2a, the temperature was surveyed (entries 10−12). Gratify-
ingly, we found that 60 °C was a suitable temperature to give
(S)-3a in 86% yield with 88% ee, almost without loss of
enantioselectivity (comparing entries 1 and 11). We attempted
to shorten the reaction time (entries 13 and 14), and a 20 h
reaction was feasible (comparing entries 11 and 13). Another
two additives, Na2SO4 and 3 Å molecular sieve (MS), were
attempted (entries 15 and 16), and 3 Å MS afforded 88% yield
and 92% ee (entry 15). It should be pointed out that absolute
configuration of product 3a was determined by comparing the
structure of (S)-3t (the absolute configuration of 3t was
assigned to be (S)-form by X-ray diffraction analysis (see SI for
details)).
With the optimized conditions in hand, the substrate scope
was surveyed for reaction of substituted N1-(aryl)benzene-1,2-
diamines (1) with multicarbonyl compounds (2) under
catalysis of (R)-C1. As shown in Scheme 2, we first
investigated reaction of N1-(naphthalen-1-yl)benzene-1,2-dia-
mine (1a) with three β-dicarbonyl compounds, acetylacetone
(2a), ethyl acetoacetate (2b), and 1-phenylbutane-1,3-dione
(2c), and 2a−2c provided higher reactivity (78−88% yields)
and excellent enantioselectivity (91 or 92% ee) (see (S)-3a), in
which 2c gave the lowest yield. Subsequently, different
substituted N1-(aryl)benzene-1,2-diamines (1) were used as
the partners of 2a−2c. The substrates containing 4-
substituents including methyl (see (S)-3b), fluoro (see (S)-
3c), chloro (see (S)-3d), and bromo (see (S)-3f) in the
benzene-1,2-diamine part of 1 afforded the satisfactory ee
values (84−94% ee), but some yields (61−89%) were slightly
lower relative to 1a. Reactions of the substrate containing 6-
chloro with 2a−2c were smoothly performed, and 72−76%
yields and 85−92% ee values were obtained (see (S)-3e). Next,
we inspected variation of the aryl part in 1. When two N-
heterocyclic groups, isoquinolyl-5-yl and quinolin-5-yl, in 1
were used as the aryl substituents, the chiral phosphoric-acid-
catalyzed reactions with 2a and 2c were not obviously affected
by the nitrogen atoms, but 2b exhibited lower enantioselec-
tivity (77 or 81% ee) (see (S)-3g and (S)-3h). When the aryl
part in 1 was 2-benzhydrylphenyl (see (S)-3i) or isopropyl-
phenyl (see (S)-3j), the former with bigger steric hindrance
provided higher ee values. Furthermore, dimethyl 1,3-
acetonedicarboxylate (2d) was applied as the partner of 1
(Scheme 2). To our delight, the corresponding products ((S)-
3k∼(S)-3s) were obtained in 60−82% yields with 86−96% ee.
Finally, methyl isobutyrylacetate (2e) and methyl butyrylace-
tate (2f) were attempted as the substrates, and they afforded
moderate yields (50−77%) and excellent ee values (87−94%
B
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Scheme 2. Substrate Scope of N1-(Aryl)benzene-1,2-
Scheme 3. Substrate Scope of N1-(Aryl)benzene-1,2-
diamines (1) and Multicarbonyl Compounds (2) in the
diamines (1) and Alkyl 2-Oxocyclopentanecarboxylate (2)
a
a
Reactions
in the Reactions
a
Reaction conditions: N1-(aryl)benzene-1,2-diamine (1) (0.1 mmol,
1.0 equiv, 0.05 M), alkyl 2-oxocyclopentanecarboxylate (2) (0.2
mmol, 2.0 equiv, 0.1 M), (R)-C1 (10 μmol, 10 mol %), 3 Å MS (∼50
mg), toluene (2.0 mL), temperature (oil bath, 60 °C), time (20 h) in
a sealed Schlenk tube. Isolated yield, and the ee values were
determined by HPLC analysis with chiral columns. Absolute
configurations of products 3w−3aj were determined by comparing
the structure of (S)-3t.
and excellent enantioselectivity (93−98% ee) (see (S)-3x∼(S)-
3ae). When the aryl part in 1 was changed into quinolyl-5-yl or
1,2,3,4-tetrahydroquinolin-8-yl, products (S)-3af and (S)-3ag
were obtained in high yield (two 81%) and excellent ee values
(96% and 97% ee, respectively). Next, 2h was used as the
substrate, and three desired target products, (S)-3ah, (S)-3ai,
and (S)-3aj, were provided in 65−86% yields with 95−98% ee.
These reactions could tolerate similar functional groups to
those in Scheme 2.
To explore the mechanism of the reaction above, reaction of
1a with 2e was performed in the presence of (R)-C1 at room
temperature for 20 h, and enamine 4 was obtained in 64%
isolated yield with a small amount (8% yield) of (S)-3t
appearing (Scheme 4). Subsequently, enamine 4 was treated
under the standard conditions, and the reaction provided (S)-
3t in 72% yield with 92% ee (see Scheme S6 in SI for more
details). The results above indicated that reaction of 1 with 2
leading to 3 in Schemes 2 and 3 could undergo an enamine
intermediate. Therefore, a reaction pathway of this organo-
catalytic atroposelective construction of axially chiral N-aryl
benzimidazoles is proposed.
a
Reaction conditions: N1-(aryl)benzene-1,2-diamine (1) (0.1 mmol,
1.0 equiv, 0.05 M), multicarbonyl compound (2) (0.2 mmol, 2.0
equiv, 0.1 M), (R)-C1 (10 μmol, 10 mol %), 3 Å MS (∼50 mg),
toluene (2.0 mL), temperature (oil bath, 60 °C), time (20 h) in a
sealed Schlenk tube. Isolated yield and the ee values were determined
by HPLC analysis with chiral columns. Absolute configurations of
products 3a∼3s, 3u, and 3v were determined by comparing the
structure of (S)-3t.
ee). The present reactions could tolerate some functional
groups including C−F, C−Cl, and C−Br bonds, ether and
ester groups, and N-heterocycles.
Inspired by the results above, we attempted two cyclic β-
dicarbonyl compounds, methyl 2-oxocyclopentanecarboxylate
(2g) and ethyl 2-oxocyclopentanecarboxylate (2h), as the
partners of 1 (Scheme 3). We first investigated variation of
substituents in the benzene-1,2-diamine part of 1. Reaction of
1a with 2g led to (S)-3w in 79% yield with 98% ee. Other
substrates containing different substituents including 5-
methoxy, 4-methyl, 5-methyl, 6-methyl, 4-fluoro, 4-chloro, 6-
chloro, and 4-bromo showed high reactivity (67−89% yields)
As shown in Scheme 5, treatment of chiral phosphoric acid
(R)-C1 with two substrates 1 and 2 through hydrogen bonds
forms complex A. Then nucleophilic attack of amino in 1 to
C
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Scheme 4. Investigation on the Reaction Mechanism
Scheme 6. Applications of Our Method
Scheme 5. Possible Mechanism for the Organocatalytic
Atroposelective Construction of Axially Chiral N-Aryl
Benzimidazoles
carbonyl in 2 gives B, regenerating (R)-C1, and dehydration of
B leads to C. Recombination of C with the catalyst provides D,
and then intramolecular nucleophilic attack of the imino group
to carbon of imine in D affords F, freeing the catalyst.
Elimination of G from F via C−C bond cleavage gives the
target product (3). Meanwhile, isomerization of C leads to
enamine E, and then recombination of E with the catalyst
forms H. Intramolecular Michael addition of the imino group
to the enamine in H leads to I, freeing the catalyst.
Isomerization of I provides F, and the C−C bond cleavage
in F gives 3.
Figure 1. (a) Investigation on the stability of the axial chirality in (S)-
3a at different temperatures. (b) Rotational barrier studies of (S)-3a,
(S)-3k, and (S)-3w.
We investigated applications of our method (Scheme 6). At
first, we attempted the gram-scale synthesis of (S)-3aj under
the standard conditions with a lower catalyst loading (1 mol
%) and longer reaction time (48 h) (Scheme 6a), and the
product was obtained in 82% yield and 96% ee almost without
loss of enantioselectivity compared with the small-scale
reaction in Scheme 3, which indicated that the present method
was a very effective and practical approach to the axially chiral
N-aryl benzimidazoles. Subsequently, further modification of
(S)-3aj was performed as follows: reduction of (S)-3aj with
LiAlH4 led to (S)-5, and chlorination of (S)-5 with SOCl2
provided (S)-6. Reaction of (S)-6 in the presence of NaH (4
equiv) gave cyclic product (S)-7 in 77% yield with 95% ee
(Scheme 6b).
Furthermore, we investigated the stability of (S)-3a in three
solvents, toluene, isopropanol, and 1,2-dichloroethane, at
different temperatures (Figure 1a), and the progress of
racemization was traced by chiral HPLC. We found that
almost no racemization occurred below 90 °C for 24 h, but the
obvious racemization was observed above 90 °C. Based on the
results above, we also calculated the rotation barriers of N-aryl
benzimidazoles (see SI for details). As shown in Figure 1b, (S)-
3a containing 2-methyl with smaller steric hindrance at the 2-
site shows a lower rotational barrier. When 2-substituents of
the N-aryl benzimidazoles are bigger groups such as 2-
methoxy-2-oxoethyl (see (S)-3k) and 5-methoxy-5-oxopentyl
(see (S)-3w), the corresponding rotational barriers increase.
In summary, we have developed a novel organocatalytic
method for the atroposelective construction of axially chiral N-
aryl benzimidazoles via reactions of N1-(aryl)benzene-1,2-
diamines with multicarbonyl compounds, and the target
products were obtained in high reactivity with excellent
enantioselectivity. The method shows some obvious advan-
tages including environmentally friendly chiral phosphoric acid
as the organocatalyst, easy carbon−carbon bond cleavage of
the multicarbonyl compounds, high efficiency and enantiose-
lectivity, broad substrate scope and functional group tolerance,
and gram-scale reaction without loss of reactivity and
enantioselectivity.
D
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Full experiments and characterization data including H
and 13C NMR spectra and HPLC for the synthesized
products ((S)-3a−3aj and (S)-4−7) (PDF)
Accession Codes
CCDC 1963357 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Hua Fu − Key Laboratory of Bioorganic Phosphorus Chemistry
and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, China;
orcid.org/0000-0001-7250-0053; Email: fuhua@
mail.tsinghua.edu.cn
Authors
Ningning Man − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, China; orcid.org/0000-0003-2872-5970
Zhenbang Lou − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, China
Yuming Li − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, China
Haijun Yang − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, China
Yufen Zhao − Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02214
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (Grant No. 21772108) and National Key R&D Program
of China (2016YFD0201207) for financial support.
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