CuI/BF3·Et2O cocatalyzed aerobic dehydrogenative reactions of ketones with benzylamines: Facile synthesis of substituted imidazoles

Article abstract of DOI:10.1021/ol302955u

A novel CuI/BF₃·Et₂O/O₂-mediated reaction utilizing ketones and benzylamines for the construction of substituted imidazoles in one step under mild conditions has been demonstrated. This protocol involved the removal of eight hydrogen atoms, the functionalization of four C(sp³)-H bonds and three new C-N bond formations.

Full text of DOI:10.1021/ol302955u

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6068–6071
CuI/BF3 Et2O Cocatalyzed Aerobic
3
Dehydrogenative Reactions of Ketones
with Benzylamines: Facile Synthesis of
Substituted Imidazoles
Zhong-Jian Cai, Shun-Yi Wang,* and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, China
shunyi@suda.edu.cn; shunjun@suda.edu.cn
Received October 26, 2012
ABSTRACT
A novel CuI/BF3 Et2O/O2-mediated reaction utilizing ketones and benzylamines for the construction of substituted imidazoles in one step under
3
mild conditions has been demonstrated. This protocol involved the removal of eight hydrogen atoms, the functionalization of four C(sp3)ꢀH
bonds and three new CꢀN bond formations.
Direct CꢀN bond formation has been considered an
effective and practical strategy for the construction of
heterocycles.1 Some excellent results about CꢀN bond
formations with copper catalysts have been achieved.2
For example, Buchwald’s,2g,3 Hartwig’s2h,4 and Ma’s groups2j
have reported a series of leading works in this area to establish
CꢀN bonds via cross-coupling reactions using organic
halide substrates with amines. Since the pioneering research
work by Buchwald in 2005,5 an increasing number of
N-heterocycles has been constructed by the CꢀN bond-
forming strategy through intramolecular amination via
CꢀH activation.6 From both environmental and eco-
nomical points of view, O2 is the ideal oxidant7 because
of its abundance, low cost, and lack of toxic byproduct.
Therefore, using a copper/O2 catalyst system to construct
heterocycles and drugs from simple and readily accessible
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2010, 132, 28. (b) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem.
(2) For some recent reviews of CꢀN bond formation with copper
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r
10.1021/ol302955u
Published on Web 11/20/2012
2012 American Chemical Society

substrates is compatible with the increasing requirements
for green chemistry and efficient process.
antitumor,13 and also pesticides.14 Recently, Shin’s group15
reported the Apoptozole (III, Figure 1), which has high
cellular potency to promote membrane trafficking of mu-
tant CFTR and its chloride channel activity in cystic fibrosis
cells. Therefore, methods for the preparation of highly sub-
stituted imidazoles as the basic scaffold are necessary.16
Despite many reported approaches17,18 available for pre-
paring the imidazole derivatives, the direct, region-defined
synthesis of highly substituted imidazoles from commer-
cially available starting materials has remained as one of
the most challenging tasks. Herein, we report a novel
CuI/BF3 Et2O19 cocatalyzed aerobic oxidative reaction
3
of ketones with benzylamines to the synthesis of highly
substituted imidazoles in the presence of O2 through
aerobic oxidation20ꢀ25 and dehydrogenative annulation
of ketone with benzylmaines.
Figure 1. Selected imidazoles.
The preparation of highly substituted imidazoles is one
of the most important fields in organic synthesis, which is
regarded as a privileged heterocyclic motif in many bio-
active natural products and pharmaceutical compounds,1
such as inhibitors of p38 MAP kinase (e.g., Losartan I,
Eprosartan II, Figure 1),8 glucagon receptors,9 plant
growth regulators,10 therapeutic agent,11 antibacterial,12
Initially, we treated 1a (1.0 equiv) and 2a (3.0 equiv) with
CuI and O2 (O2 balloon, 1 atm) under neat conditions at
50 °C for 24 h. Surprisingly, trisubstitued imidazole 3a
was formed in 44% yield (LC yield) instead of other
products such as imine, enamine, R-ketoamide26 or indole
derivative27 (Scheme 1). The structure of 3a was confirmed
by spectroscopic analysis and further confirmed by single-
crystal X-ray analysis.28
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Scheme 1. Reaction of 1a and 2a
In order to improve the yield of 3a, we further screened
different copper salts, solvents (see the Supporting In-
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vatives, see: (a) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Looper, R. E.
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Angew. Chem., Int. Ed. 2009, 48, 3116. (b) Mata, L.; Jimenez-Oses, G.;
Avenoza, A.; Busto, J. H.; Peregrina, J. M. J. Org. Chem. 2011, 76, 4034.
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Chem.;Eur. J. 2009, 15, 843.
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3
lyzed reactions, see: (a) Liu, Y.-J.; Wang, M.; Y, H.-J.; Liu, Q. Adv. Synth.
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Org. Lett., Vol. 14, No. 23, 2012
6069

Table 1. Optimization of the Reaction Conditionsa
Table 2. Imidazole Synthesis from Ketones with Benzyl-Aminea
cat.
temp
yield
[%]a
entry
(mol %)
additive (mol %)
[°C]
1
2
3
4
5
CuI (20)
none
none
50
50
50
40
40
44
CuBr (20)
<5
n.r.
67
CuBr2 (20) none
CuI (20)
CuI (20)
2,20-bipyridine (20)
4,40-di-tert-butyl-2,20-
62
bipyridine (20)
6
7
8
9
CuI (20)
CuI (20)
CuI (20)
CuI (20)
1,10-phenanthroline (20)
I2 (20)
40
40
40
40
37
62
BF3 Et2O (20)
75
83 [71]b
3
BF3 Et2O (10)
3
a Reaction conditions: 1a (2 mmol), 2a (6 mmol), neat, O2 (1 atm).
The yields were determined by LC analysis using biphenyl as the internal
standard. b Isolated yield.
formation), and reaction temperatures as well as additives.
As presented in Table 1, CuI showed higher catalytic
reactivity than other copper salts such as CuBr and CuBr2
for this reaction (Table 1, entries 1ꢀ3). It was found that
the use of N,N-ligands such as 2,20-bipyridine and 4,40-di-
tert-butyl-2,20-bipyridine as additives could promote the
reaction, and the yields of 3a were increased to 67% (LC
yield) and 62% (LC yield), respectively (Table 1, entries 4
and 5). In view of the effects of the ligands, we turned our
attention to the cheap Lewis acid as the additive instead of
the expensive ligands. When 20 mol % I2 or 20 mol %
a Reaction conditions: 1 (2 mmol), 2 (6 mmol), CuI (20 mol %),
BF3 Et2O (10 mol %), O2 (1 atm), 40 °C, 24 h.
3
BF3 Et2O was used as the additive, the desired product
3
could be obtained in 62% (LC yield) and 75% (LC yield)
yields, respectively (Table 1, entries 7 and 8). After screen-
ing the amount of BF3 Et2O, it was observed that 10 mol %
that substrate 2k possessing tert-butyl substituent at the
4-position of the aryl ring provided the desired imidazole
product 3k in 70% yield. When (2,4-difluorophenyl)-
methanamine 2l was treated with acetophenone 1a under
the analogous reaction conditions, 1,2,4-trisubstitued im-
idazole 3l was obtained in 50% yield. When aliphatic
ketone 3,3-dimethylbutan-2-one 4a instead of 1a was
subjected to the reaction with 2a under the optimized
reaction conditions, the desired imidazole derivative 5a
could also be obtained in 56% yield (Scheme 2).
3
BF3 Et2O as additive gave the best result and 3a could
be produced in 83% LC yield and 71% isolated yield
(Table 1, entry 9).
3
With the optimized conditions in hand, we next exam-
ined the scope of this oxidative reaction. The results were
summarized in Table 2. In most cases, moderate to good
yields of the corresponding imidazoles were delivered
under the optimized conditions. Notably, good yield of
1,2,4-trisubstitued imidazole 3e was obtained for substrate
1e bearing a strong electron-withdrawing group (76%
yield). In addition, when 1-(4- methoxyphenyl)-one 1g
containing electron-donating group was subjected to this
transformation, a moderate yield (54%) of the desired
product 3g was achieved as well. The structure of product
3g was also confirmed by single-crystal X-ray analysis.28
When other 1-phenylethanone derivatives bearing F, Cl,
Br, CH3, CF3 groups were applied to the reaction, the
desired products (3b, 3c, 3d, 3f, 3h) were also obtained in
moderate yields.
Scheme 2. Reaction of 4a and 2a
To better understand the mechanism of this reaction,
somecontrolexperimentswerecarried out(Scheme3). The
reaction of imine 6 with 2a under the CuI/BF3 Et2O/O2
Reactions of a variety of substituted benzylamines 2
with acetophenone 1a were also surveyed. It was found
3
conditions generated 3a in 70% yield (Scheme 3).
6070
Org. Lett., Vol. 14, No. 23, 2012

Similar reaction of 6 and 2m under the standard conditions
afforded the mixture of 3a, 3a0, 3a00 and 3m, which was
determined by the LCꢀMS analysis.
Scheme 4. Proposed Mechanism
Scheme 3. Control Experiments
zoles in one step by using ketones and benzylamines cata-
lyzed by commercially available CuI/BF3 Et2O in the
atmosphere of O2. BF3 Et2O showed high reactivity as a
3
3
cocatalyst combined with CuI. In addition, this reaction
provides a simple, easy-handling, and atom-economic way
to the synthesis of polysubstituted imidazoles under mild
conditions. This protocol involved the removal of eight
hydrogen atoms, the functionalization of four C(sp3)ꢀH
bonds and three new CꢀN bond formations in one mani-
pulation. Currently, studies toward enlarging the scope of
Both these results suggested that there was an equi-
librium between imine 6 with the mixture of 1a and 2a
under the reaction conditions and imine 6 was the inter-
mediate for this reaction. Furthermore, the reaction of 2,2-
dihydroxy-1-phenylethanone (7)29 with 2a under the stan-
dard conditions was investigated, respectively.30 It was
found that only trace of the desired product was detected
by LCꢀMS. This result implied that 2,2-dihydroxy-1-
phenylethanone was not the intermediate of the reaction.
On the basis of the above-mentioned results and the
literature reports,21,25,29,30 we proposed a plausible me-
chanism for the reaction (Scheme 4). Enamine 60 generated
via tautomerization of imine 6 from 1a and 2a would be
oxidized to B.25 Subsequently, the intermediate B was
attacked by another molecule of 2a to give intermediate
C. After the dehydration of C under Lewis acidic condi-
tions, the intermediate D was generated. Finally, inter-
mediate D underwent an annulation to give intermediate E
followed by the ensuing proton elimination to afford G.
Upon further oxidation of G, the desired product 3a was
yielded eventually.
the CuI/BF3 Et2O catalyst system to the synthesis of other
3
useful compounds via aerobic oxidative CꢀH amination
and further understanding the mechanism of the reaction
are ongoing.
Acknowledgment. We gratefully acknowledge the
Natural Science Foundation of China (No. 21042007,
21172162), the Young National Natural Science Founda-
tion of China (No. 21202111), the Young Natural Science
Foundation of Jiangsu Province (BK2012174), PAPD,
and Soochow University for financial support.
Supporting Information Available. Experimental pro-
cedures, CIF files for 3a and 3g, and full spectroscopic
data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have described a novel and efficient
approach for the preparation of highly substituted imida-
(30) When we were preparing this manuscript, Jiao’s group reported
the preparation of oxazoles by the reaction of amines and aryl acet-
aldehydes mediated by 1.5 equiv of CuBr2 using O2 as oxidant via CꢀH
functionalization: Xu, Z.-J.; Zhang, C.; Jiao, N. Angew. Chem., Int. Ed.
2012, 51, 11367.
(29) Several works related to the oxidation of acetophenone to 2,2-
dihydroxy-1-phenylethanone have been reported by Wu’s group: (a)
Zhu, Y.-P.; Lian, M.; Jia, F.-C.; Liu, M.-C.; Yuan, J.-J.; Gao, Q.-H.;
Wu, A.-X. Chem. Commun. 2012, 48, 9086. (b) Zhu, Y.-P.; Liu, M.-C.;
Jia, F.-C.; Yuan, J.-J.; Gao, Q.-H.; Lian, M.; Wu, A.-X. Org. Lett. 2012,
14, 3392. (c) Zhu, Y.-P.; Jia, F.-C.; Liu, M.-C.; Wu, A.-X. Org. Lett.
2012, 14, 4414.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
6071