Letter
Organocatalytic Atroposelective Construction of Axially Chiral
N‑Aryl Benzimidazoles Involving Carbon−Carbon Bond Cleavage
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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
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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