A concise synthesis of highly substituted imidazoles via copper-mediated oxidative C-H functionalization

Article abstract of DOI:10.1016/j.tetlet.2014.01.136

We herein report a simple and concise route for the synthesis of highly substituted imidazole derivatives via copper-mediated oxidative C-H functionalization in good to high yields. The advantage of the reaction lies in its mild reaction conditions and readily available starting materials.

Full text of DOI:10.1016/j.tetlet.2014.01.136

Tetrahedron Letters 55 (2014) 1835–1838
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A concise synthesis of highly substituted imidazoles via
copper-mediated oxidative C–H functionalization
Amit N. Pandya a, Devendra K. Agrawal a,b,
⇑
a Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA
b Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report a simple and concise route for the synthesis of highly substituted imidazole derivatives
via copper-mediated oxidative C–H functionalization in good to high yields. The advantage of the reaction
lies in its mild reaction conditions and readily available starting materials.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 6 January 2014
Revised 24 January 2014
Accepted 28 January 2014
Available online 6 February 2014
Keywords:
C–H functionalization
Imidazole
Oxidative dehydrogenation
Small heterocyclic molecules can play a critical role in the reg-
ulation of macromolecule targets in living systems. Such functions
make them a more powerful tool for understanding the various
biological pathways for basic research and as pharmacological
agents for curing diseases. As a representative of this class of com-
pounds, the imidazole scaffold is emerging as a valuable pharma-
cophore for biomedical research.1 The imidazole scaffold is
present in many natural products and is a bioactive substance in
human metabolism.2 There are many clinical drugs being used in
the different therapeutic areas based on the imidazole structure,
such as anti-cancer (dacarbazine), antihistaminic (cimetidine),
anti-parasitic (metronidazole), and antihypertensive (losartan)
(Fig. 1).
importance to explore novel and efficient synthetic approaches
for highly substituted imidazoles.
In recent years, transition metal-catalyzed cross-coupling
reactions of various reactive functional groups have attracted
great interest.13 More specifically, Li et al. have reported
cross-dehydrogenative coupling (CDC) reaction in the presence of
copper and oxidants.14 Similarly, Wang et al. have prepared
2-phenylquinazolines and oxazoles by using benzylamine as
one of the starting materials.15,16 Herein, we report the concise
O
H
N
H
N
Due to their importance, it has become an attractive target for
the synthetic and medicinal chemist. There are many synthetic
methodologies that have been developed for assembling and deco-
rating the imidazole ring with diverse functional groups. One of the
approaches is using the transition metal catalyzed direct C–H/N–H
functionalization3 and other approaches include using various cat-
NH2
N
S
N
N
HN
N
N
N
H
N
N
Cimetidine
Dacarbazine
Cl
N
5
alytic systems like I2,4 MgSO4, FeCl3Á6H2O,6 BF3-SiO2,7 DABCO,8
OH
N
zeolite-supported reagents,9 bioglycerol-based carbon catalyst,10
H
N
N
N
N
11
HgCl2, and CuI.12 Many reported methods involve expensive
O
N
N
O
N
starting material or catalytic systems. Therefore, it is still of great
HO
Metronidazole
Losartan
⇑
Corresponding author. Tel.: +1 (402) 280 2938; fax: +1 (402) 280 1421.
E-mail address: dkagr@creighton.edu (D.K. Agrawal).
Figure 1. Examples of significant imidazole containing pharmaceuticals.
http://dx.doi.org/10.1016/j.tetlet.2014.01.136
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1836
A. N. Pandya, D. K. Agrawal / Tetrahedron Letters 55 (2014) 1835–1838
Table 1
Optimization of the reaction conditions
O
O
N
NH2
Catalyst, Oxidant
NH
O
N
+
Additive, Solvent,
Base, rt
O
3a
2a
1a
Entry
Catalyst
Oxidant
Additive
Solvent
Yieldb (%)
1
2
3
CuI
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
I2
I2
I2
I2
I2
I2
CH3CN
DMF
THF
DMF
DMA
DMA
42
62
56
68
70
76
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
4
5
6a
Reaction conditions: (Z)-ethyl 3-(phenylamino) but-2-enoate (1a) (1 equiv), benzylamine (2a) (2 equiv), catalyst (20 mmol %), oxidant (2 equiv), additive (1 equiv). Reaction
was performed for 12 h.
a
In the presence of NaHCO3 (1 equiv).
Isolated yields.
b
gave good yields compared to t-butyl esters (3g, 3h). Further, aryl
O
O
O
H
N
H
N
amine provided the desired product in good to excellent yields, but
the aliphatic amine and unsubstituted amine did not yield the de-
sired product (Fig. 2). This is due to the electron withdrawing prop-
erty of aryl amine not present in aliphatic and unsubstituted
amine. Thus, aryl amine is more nucleophilic and thus more likely
to undergo cyclization than aliphatic and unsubstituted amine
(Scheme 1).
H
N
HN
O
N
O
N
O
Ph
Cu2+
Cu2+
Ph
Cu2+
Ph
Figure 2. The amine functionality of b-enamino esters.
On the basis of the mechanism discussed in the literature,14
a
route for the synthesis of highly substituted imidazole via copper-
mediated oxidative C–H functionalization from benzylamine and b-
enamino esters.
plausible reaction mechanism is shown in Scheme 2. Initially, base
is involved in the hydrogen abstraction from 1a to give carbanion,
which generates 4 via enolization process in the presence of I+. The
nucleophilic substitution of benzylamine to intermediate 4 pro-
vides 5. Oxidative dehydrogenation and coordination of Cu2+ ion
give 6, which undergoes intramolecular cyclization and oxidation
of 7, give the desired product 3a.
In conclusion, we have developed a concise route for the
synthesis of highly substituted imidazoles via copper-mediated
oxidative C–H functionalization from readily available starting
materials. The notable advantages of the method lie in its mild
reaction conditions and low cost, less toxicity, and environmen-
tally benign metal catalyst. This approach could be helpful for
the generation of small heterocyclic libraries for the high through-
put screening.
We initiated an investigation of the reaction using b-enamino
esters (1a) and benzylamine (2a) as starting point in the presence
of a copper source, iodine, and t-BuOOH (TBHP) in hexane at room
temperature. The desired product was isolated in 42% yield by the
use of CuI as catalyst and acetonitrile as solvent. Then we opti-
mized the reaction condition with different reaction parameters,
including catalysts and solvents. Initially, we tried different sol-
vents like DMF, THF, and DMA at room temperature with Cu(OAc)2
ÁH2O and CuI as catalysts. To our delight, the yield was increased by
70% when changing the solvent to DMA in the presence of
Cu(OAc)2ÁH2O catalyst (Table 1, entry-5). Further, we checked the
reaction with NaHCO3 as base with the improved reaction solvent
(DMA), and to our surprise, the yield was increased by 76% (Table 1,
entry-6). With the optimized conditions in hand, we synthesized a
series of highly substituted imidazoles with various substitutions
with good to high yields.
Acknowledgments
In order to check the functional group tolerance and scope of
the substrate, we synthesized highly substituted imidazoles using
this protocol by various benzylamine and b-enamino esters. The
reaction with the electron withdrawing group (–Cl) present in
the aromatic ring of benzylamine (3c, 3g) resulted in an excellent
yield compared to the unsubstituted aromatic ring (3a, 3h), but
it gave a similar yield when b-enamino methyl ester (3i, 3j) was ta-
ken as the starting material. Furthermore, the introduction of elec-
tron releasing substituent (3f) at b-enamino ester decreased the
yield moderately. The functionality of b-enamino esters was
checked by introducing various esters and amines to b-enamino
esters. Compounds with ethyl (3a–3f) and methyl (3i, 3j) esters
This project was supported by the National Institute of Health
research Grant R01HL104516 and R01HL120659 to D.K.A. We
thank Dr. James Fletcher (Department of chemistry, Creighton Uni-
versity) for helping in recording Mass and NMR spectra.
Supplementary data
Supplementary data (general experimental procedures, mass
and NMR spectral data for representative compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.01.136.

A. N. Pandya, D. K. Agrawal / Tetrahedron Letters 55 (2014) 1835–1838
1837
Scheme 1. Copper-mediated oxidative functionalization of b-enamino esters with different benzylamine derivatives. Reaction conditions: b-enamino esters (1a) (1 equiv),
benzylamine derivatives (2a) (2 equiv), NaHCO3 (1 equiv), Cu(OAc)2ÁH2O (20 mmol %), TBHP (2 equiv), I2 (1 equiv). Reaction was performed for 12 h.
Base
H
Ph
Ph
O
N
O
O
N
Base
I2
Base
I2
Ph
O
N
O
O
NH
Ph
I
I
1a
HN
4
5
TBHP
Cu2+
O
H
O
O
H
N
O
Ph
O
N
N
O
-H+
[o]
-H+
[o]
N
Ph
N
Ph
Ph
N
Ph
Ph
Cu2+
6
7
3a
Scheme 2.

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A. N. Pandya, D. K. Agrawal / Tetrahedron Letters 55 (2014) 1835–1838
9. Sivakumar, K.; Kathirvel, A.; Lalitha, A. Tetrahedron Lett. 2010, 51, 3018.
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