Asymmetric Ring Opening/Cyclization/Retro-Mannich Reaction of Cyclopropyl Ketones with Aryl 1,2-Diamines for the Synthesis of Benzimidazole Derivatives

Article abstract of DOI:10.1002/anie.201604735

A highly efficient asymmetric ring-opening/cyclization/retro-Mannich reaction of cyclopropyl ketones with aryl 1,2-diamines has been realized using a chiral N,N′-dioxide/Sc^IIIcatalyst. Benzimidazoles containing chiral side chains were generated under mild reaction conditions in excellent outcomes (up to 99 % yield and 97 % ee). This method also provides efficient access to chiral benzimidazole-substituted amide and cycloheptene derivatives.

Full text of DOI:10.1002/anie.201604735

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604735
German Edition: DOI: 10.1002/ange.201604735
Heterocycle Synthesis
Asymmetric Ring Opening/Cyclization/Retro-Mannich Reaction of
Cyclopropyl Ketones with Aryl 1,2-Diamines for the Synthesis of
Benzimidazole Derivatives
Yong Xia, Lili Lin, Fenzhen Chang, Yuting Liao, Xiaohua Liu,* and Xiaoming Feng*
Abstract: A highly efficient asymmetric ring-opening/cycliza-
tion/retro-Mannich reaction of cyclopropyl ketones with aryl
1,2-diamines has been realized using a chiral N,N’-dioxide/ScIII
catalyst. Benzimidazoles containing chiral side chains were
generated under mild reaction conditions in excellent outcomes
(up to 99% yield and 97% ee). This method also provides
efficient access to chiral benzimidazole-substituted amide and
cycloheptene derivatives.
results. The process is thought to proceed through nucleo-
philic ring opening of the cyclopropyl ketone to generate A,
then intramolecular nucleophilic addition to afford the
intermediate B, with subsequent dehydration to give the
2,3-dihydropyrrole product (path a, Scheme 1).[8a,h,k]
B
enzimidazoles, particularly bearing chiral side chains, are
ubiquitously found in natural products and biologically active
compounds.[1] Consequently, substantial efforts have been
dedicated to developing efficient methods toward their
preparation.[2] The most common synthetic strategies are
focused on the construction of benzimidazole backbones by
using chiral precursors.[3] With regard to the catalytic asym-
metric transformation, several successful examples involving
the direct enantioselective functionalization of prochiral
benzimidazole compounds have been developed by the
groups of Hartwig,[4] Guo,[5] and Terada.[6] However, these
strategies often require additional steps to prepare either the
chiral precursors or prochiral benzimidazoles. Thus, discovery
of a new strategy for constructing benzimidazole backbones
and simultaneously establishing stereochemistry in their side
chains is highly desirable.
Scheme 1. Proposed pathway for the synthesis of benzimidazoles.
Inspired by these results, we recently questioned whether
it is possible to capture B by using another nucleophilie. We
envisaged that if 1,2-diaminobenzene was used as a nucleo-
philie, the capture process might be brought to fruition
through a 5-exo-tet cyclization[15] to give C, and would be
facilitated by the good leaving ability of water (path b,
Scheme 1). And then, C could undergo retro-Mannich[16]
reaction to deliver the benzimidazole. Thus, a straightforward
synthetic method for enantioenriched benzimidazole deriva-
tives through a catalytic asymmetric ring opening/cyclization/
retro-Mannich sequence of cyclopropyl ketones with ben-
zene-1,2-diamines might be realized. It was noteworthy that
the dehydration of B to give chiral 2,3-dihydropyrrole might
be a competitive process (path a). Herein, we describe our
efforts on developing a new ring-opening/cyclization/retro-
Mannich reaction of cyclopropyl ketones with benzene-1,2-
diamines in the presence of a chiral N,N’-dioxide/metal
complex as the catalyst for the enantioselective synthesis of
benzimidazole derivatives.
Donor–acceptor (D–A) cyclopropanes[7] have been rec-
ognized as one of most useful reagents able to generate
polyfunctional reactive intermediates through a ring-opening
process. In the last decade, the use of D–A cyclopropanes for
the preparation of open-chain 1,3-bifunctionalized, carbocy-
clic and heterocyclic scaffolds has experienced a renais-
sance.[8–13] And many reports on the enantioselective nucle-
ophilic ring-opening reactions of D–A cyclopropanes have
appeared. Recently, our group has demonstrated that a chiral
N,N’-dioxide/ScIII complex[14] was able to catalyze the ring-
opening reaction of cyclopropyl ketones with amines effi-
ciently, thus generating chiral 2,3-dihydropyrroles in excellent
[*] Y. Xia, Dr. L. L. Lin, F. Z. Chang, Y. T. Liao, Prof. Dr. X. H. Liu,
Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
E-mail: liuxh@scu.edu.cn
To evaluate our hypothesis, the cyclopropyl ketone 1a and
o-diaminobenzene (2a) were reacted in the presence of
a chiral N,N’-dioxide metal complex (Table 1). To our delight,
when Sc(OTf)3 complexed with L-PiPr3, derived from (S)-
pipecolic acid, was used, the ring-opening/cyclization/retro-
Mannich reaction occurred. And the benzimidazole 3aa was
generated in 95% yield with 91% ee as expected, without the
xmfeng@scu.edu.cn
Prof. Dr. X. M. Feng
Collaborative Innovation Center of Chemical Science and Engineer-
ing, Tianjin (China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604735.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Substrate scope with respect to the cyclopropyl ketones.[a]
Entry R1, R2
3
Yield [%][b] ee [%][c]
1
2
3
4
Ph, Ph (1a)
4-MeC6H4, Ph (1b)
4-MeOC6H4, Ph (1c) 3ca
3aa
3ba
97
98
99
96
94
96
94
87
96
85
96
97
86
73
92
98
95
95
89
94
95 (R)
94
94
95
80
94
92
93
90
86
97
97
4-FC6H4, Ph (1d)
3da
3ea
3 fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
5[d] 4-ClC6H4, Ph (1e)
Entry
Metal
L
Yield [%][b]
ee [%][c]
6
7
8
4-BrC6H4, Ph (1 f)
3-MeC6H4, Ph (1g)
3-ClC6H4, Ph (1h)
2-MeC6H4, Ph (1i)
3,4-Cl2C6H3, Ph (1j)
1-naphthyl, Ph (1k)
2-naphthyl, Ph (1l)
vinyl, Ph (1m)
1
2
3
4
5
6
7
Sc(OTf)3
Yb(OTf)3
L-PiPr3
L-PiPr3
L-PiPr3
L-PiPr3
L-RaPr3
L-PrPr3
L-PiPr2
95
83
trace
97
<5
33
95
91
48
n.d.
95
40
82
9
Ni(ClO4)2·6H2O
ScCl3·6H2O
ScCl3·6H2O
ScCl3·6H2O
ScCl3·6H2O
10[e]
11
12
13[e]
89
14[f,g] Me, Ph (1n)
[a] Unless otherwise noted, all reactions were carried out with 1a
(0.22 mmol), 2a (0.1 mmol), L/metal (1:1, 10 mol%) in CHCl2CHCl2
(0.5 mL) under nitrogen at 358C for 48 h. [b] Yield of isolated product.
[c] Determined by HPLC analysis on a chiral stationary phase. OTf=tri-
fluoromethanesulfonate.
15
16
Ph, 4-MeC6H4 (1o)
Ph, 4-FC6H4 (1p)
17[f]
(1q)
3qa
3aa
98
98
62
94
observation of the 2,3-dihydropyrrole side product (entry 1).
Further investigation with other metal salts led to poorer
results (entries 2 and 3). Then the counterion of the metal
salts was evaluated. Pleasingly, when ScCl3·6H2O was used,
a slight improvement on the reactivity and enantioselectivity
was observed (entry 4). Next, the structure of ligand was
investigated. It was found that the steric hindrance of the
amide moieties as well as the amino-acid backbone of the
ligand influenced the reaction greatly. Decreasing the steric
bulk of the amide substituent, or either using the l-ramipril-
derived L-RaPr3 or (S)-proline-derived L-PrPr3 as ligands
resulted in poorer outcomes (entries 5–7). Thus, the opti-
mized reaction conditions entailed the use of L-PiPr3/
ScCl3·6H2O as the catalyst in CHCl2CHCl2 at 358C for
48 hours (entry 4).
The substrate with respect to the cyclopropyl ketones was
investigated under the optimized reaction conditions. As
summarized in Table 2, the reaction was suitable for a variety
of cyclopropyl ketones, and excellent levels of reactivity and
enantioselectivity were achieved. Cyclopropyl ketones with
either electron-rich or electron-poor substituted aryl groups
(R1) at the 2-position were efficiently converted into the
corresponding products with excellent results (entries 1–9).
For the dichloro-substituted substrate 1j, a prolonged reac-
tion time was needed and the corresponding product was
obtained in 84% yield with 94% ee (entry 10). In addition,
naphthyl-substituted substrates were suitable for this reac-
tion, thus producing the desired products with excellent
results (entries 11 and 12). Notably, a vinyl-substituted cyclo-
propane was also compatible in this catalytic system, and the
product was isolated in good yield with excellent enantiose-
lectivity (entry 13). However, when the aliphatic-substituted
cyclopropyl ketone 1n was submitted to this catalytic system,
only trace amounts of the product were observed. By using
18[h] Ph, Ph (1a)
[a] Unless otherwise noted, all reactions were performed with
1 (0.22 mmol), 2a (0.1 mmol), L-PiPr3 (10 mol%), and ScCl3·6H2O
(10 mol%) in CHCl2CHCl2 (0.5 mL) under nitrogen at 358C for 48 h.
[b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] The absolute configuration was determined to be R
by X-ray analysis.[17] [e] Reaction time was 96 h. [f] Sc(OTf)3 (10 mol%)
was used instead of ScCl3·6H2O and LiCl (0.1 mmol) was used as
additive. [g] At 608C for 96 h. [h] The reaction was carried out on a gram
scale.
Sc(OTf)3 instead of ScCl3·6H2O and using LiCl as the
additive, the reactivity increased and 3na was generated in
73% yield with 86% ee (entry 14). The electronic nature of
the para-substituted benzoyl group at the 1-position of
cyclopropanes had no obvious influence on the outcomes
(entries 15 and 16). Remarkably, the spirocyclopropane 1q
also proved to be a viable substrate, thus delivering the eight-
membered ring product 3qa in 98% yield with 62% ee
(entry 17). This method provides promising access to chiral
eight-membered N-heterocyclic motifs. However, no benzi-
midazole product was observed when 2-phenyl-cyclopropane-
1,1-dimethylketones were used. In addition, the absolute
configuration of 3ea was determined to be R by X-ray
crystallography.[17] Furthermore, when the reaction of 1a with
2a was carried out on a gram scale, 3aa was isolated with
results similar to those obtained on milligram scale (entry 18
vs. entry 1).
Next, the spectrum of o-diaminobenzenes was probed and
the results are listed in Table 3. Generally, good to excellent
yields and excellent enantioselectivities were obtained for
both electron-donating and electron-withdrawing substitu-
ents on the aryl groups (3ab–aj, 4ab–ag). Remarkably,
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Table 3: Substrate scope with respect to o-diaminobenzenes.[a]
Scheme 2. a) Transformation of 3aa into 5: 1) NH2OH·HCl, pyridine,
EtOH; 2) PCl5, toluene, 08C. b) Transformation of 3ma into 6:
3) [Ph3PCH3]+IÀ, nBuLi, THF, reflux; 4) Grubbs-Hoveyda 2 (20 mol%),
toluene, 1058C.
thesis in the presence of the Grubbs–Hoveyda second-
generation catalyst (Scheme 2b).
To gain some insight on the mechanism of this reaction,
several control experiments were carried out. Firstly, the
direct ring-opening product 7am was generated in 80% yield
when N-methyl-1,2-benzenediamine (2m) was employed
(Scheme 3a), thus indicating that ring-opening might be the
[a] Unless otherwise noted, all reaction conditions were the same as
detailed in Table 2. The ratio of 3/4 (products derived from substitutions
at either the 5- or 6-positions, respectively) was determined for the
isolated products except for that of 3ab/4ab, which was determined by
1H NMR analysis of the crude reaction mixture. [b] Sc(OTf)3 (10 mol%)
was used instead of ScCl3·6H2O and LiCl (0.1 mmol) was used as
additive. [c] At 608C for 96 h.
regioselectivities were discovered when unsymmetric substi-
tuted o-diaminobenzenes were examined. The regioisomers
of MeO-, F-, Cl-, Br-, and NO2-substituted benzimidazoles
were distinguished well and they could be separated by flash
chromatography on silica gel (3ac–ag, 4ac–ag), but the Me-
substituted substrate offered an inseparable mixture (3ab,
4ab). For the symmetric substituted o-diaminobenzenes, both
electron-rich and electron-deficient substituents gave excel-
lent results (3ah–aj). When a naphthyl-substituted substrate
was employed, an excellent result (92% yield, 95% ee) was
obtained. Heteroaryl thiophene-3,4-diamine also reacted with
the cyclopropyl ketone to generate the chiral thienoimidazole
derivative 3al in 89% ee, albeit with a moderate yield (56%),
by employing the Sc(OTf)3/LiCl catalytic system. Ethane-1,2-
diamine and cyclohexane-1,2-diamine were also investigated,
however, no ring opening/cyclization/retro-Mannich products
were observed.
To evaluate the synthetic potential of the methodology,
additional transformations were carried out. The benzimida-
zole derivative 3aa was easily transformed into the amide 5 in
moderate yield and high enantioselectivity through an
oximation/Beckmann rearrangement sequence (Scheme 2a).
Meanwhile, the cycloheptene compound 6 was obtained by
a Wittig olefination of 3ma, followed by ring-closing meta-
Scheme 3. Control experiments.
first step (Scheme 1). When m-diaminobenzene was used,
only the 2,3-dihydropyrrole 8an was isolated (Scheme 3b). It
revealed that the two amino groups should be installed at
a suitable position to undergo 5-exo-tet cyclization. Notably,
when 3-chlorobenzene-1,2-diamine was subjected to this
catalytic system, the 4-chloro-substituted benzimidazole 3ao
was obtained along with the formation of the 2,3-dihydro-
pyrrole 8ao (Scheme 3c), which suggested that the reaction
might proceed via the formation of intermediate
B
(Scheme 1).[18]
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In summary, we have accomplished the first asymmetric
ring opening/cyclization/retro-Mannich reaction of cyclo-
propyl ketones with o-diaminobenzenes to construct benzi-
midazoles and simultaneously establish stereochemistry in
their side chains. A chiral N,N’-dioxide/ScIII complex could
efficiently accelerate the asymmetric process, and the corre-
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reaction conditions and exhibits broad substrate scope. Addi-
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Experimental Section
Reaction conditions: ScCl3·6H2O (0.01 mmol), L-PiPr3 (0.01 mmol)
and the cyclopropyl ketone 1a (0.22 mmol) were stirred in
CHCl2CHCl2 (0.5 mL) at 358C for 0.5 h under nitrogen atmosphere.
Then 2a (0.1 mmol) was added. The reaction was stirred at 358C for
48 h, and then directly purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to afford the desired product
3aa (97% yield, 95% ee.).
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Acknowledgements
We thank the National Natural Science Foundation of China
(21572136, 21290182, and 21321061) for financial support.
Keywords: asymmetric catalysis · enantioselectivity ·
heterocycles · scandium · small ring systems
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[17] CCDC 1414840 (3ea) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[18] For more details, see the Supporting Information.
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Received: May 15, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Heterocycle Synthesis
Y. Xia, L. L. Lin, F. Z. Chang, Y. T. Liao,
X. H. Liu,* X. M. Feng*
&&&& — &&&&
Asymmetric Ring Opening/Cyclization/
Retro-Mannich Reaction of Cyclopropyl
Ketones with Aryl 1,2-Diamines for the
Synthesis of Benzimidazole Derivatives
Scandalous Sc: The title reaction pro-
ceeds in the presence of a chiral N,N’-
dioxide/ScIII catalyst. A variety of benz-
imidazoles bearing chiral side chains
were obtained with excellent results. This
method provides novel access to chiral
benzimidazole-substituted amide and
cycloheptene derivatives.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!