Cu-catalyzed amidation of halogenated imidazoles

Article abstract of DOI:10.1039/c3cc49107b

An efficient methodology involving the Cu-catalyzed amidation of halogenated imidazoles has been successfully developed. The amidated product of 5-bromo-1-alkylimidazole was further applied to the synthesis of a new chiral imidazole nucleophilic catalyst for the kinetic resolution of secondary alcohols. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc49107b

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Cu-catalyzed amidation of halogenated
imidazoles†
Mo Wang,a Zhenfeng Zhang,*b Fang Xiea and Wanbin Zhang*ab
Cite this: Chem. Commun., 2014,
50, 3163
Received 29th November 2013,
Accepted 17th January 2014
DOI: 10.1039/c3cc49107b
www.rsc.org/chemcomm
An efficient methodology involving the Cu-catalyzed amidation of
halogenated imidazoles has been successfully developed. The ami-
dated product of 5-bromo-1-alkylimidazole was further applied to
the synthesis of a new chiral imidazole nucleophilic catalyst for the
kinetic resolution of secondary alcohols.
Amido and amino group-substituted imidazoles have been widely
utilized as bioactive compounds, especially for kinase inhibitors.1
The most commonly utilized method for the synthesis of amido-
imidazoles and aminoimidazoles is via cyclization to construct
specific imidazole rings.2 For the introduction of an amido or amino
Scheme 1 Comparison with Buchwald’s work.
group onto an already established imidazole ring, an indirect method stronger coordination ability such as 5-halogenated-1-alkyl-
involves reduction of a nitro group substituted imidazole followed imidazoles have not been reported.
by acylation or reductive amination.3 A direct approach utilizes
Compared to Pd, Cu is inexpensive and has been widely used in
the aromatic nucleophilic substitution of halogenated imidazoles C–N cross-coupling reactions.7 However, to the best of our knowl-
by amides or amines.4 However, these traditional routes usually edge, no work has been reported on the Cu-catalyzed amidation of
require harsh reaction conditions and suffer from limited substrate halogenated imidazoles. Herein, we report our results concerning
scope, often being applicable to only nitro-substituted halogenated the Cu-catalyzed amidation of halogenated imidazoles (Scheme 1).
imidazoles or 2-halogenated imidazoles. The development It is also worth mentioning that this methodology is applicable
of a general methodology for the amidation or amination of to other halogenated five-membered heterocycles containing two
halogenated imidazoles is thus highly desired.
heteroatoms. Furthermore, we used this methodology for the
Transition-metal catalyzed C–N cross-coupling reactions have the synthesis of an efficient chiral imidazole nucleophilic catalyst
potential to overcome the aforementioned limitations.5–7 Following which showed higher catalytic activity than the previously
pioneering work by Buchwald and Hartwig on Pd-catalyzed C–N developed DPI.9 This represents the first synthesis of such an
cross-couplings, the amidation and amination of a variety of aryl amino group activated imidazole nucleophilic catalyst.10
halides and pseudohalides have been realized.6 However, these
We first optimized the cross-coupling reaction conditions
protocols are not amenable to five-membered heterocyclic substrates between 5-bromo-1-methylimidazole and pyrrolidin-2-one (Table 1).
possessing two heteroatoms such as halogenated imidazoles.6i,8 Several types of ligands (10 mol%) were investigated using 10 mol%
Recently, Buchwald successfully applied a bulky biaryl phosphine CuI as Cu salt, 4.0 eq. of K2CO3 as base, and reacting at the
ligand to the Pd-catalyzed amidation of this class of substrate reflux temperature of dioxane (entries 1–8). Using ethane-1,2-
(Scheme 1).6i However, reactions using substrates possessing diol (L1) as a ligand, no reaction occurred (entry 1). Increasing
the coordinating ability of the ligand by using a more acidic
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China.
E-mail: wanbin@sjtu.edu.cn; Fax: +86 02154743265; Tel: +86 02154743265
b School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China
hydroxyl group (L2 or L4) or a greater electron-donating amino group
(L3 or L5) improved the yield (entries 2–5). The electron-donating
methyl groups on both N atoms (L6) can significantly improve the
coordinating ability of the diamine ligand resulting in a higher
yield (entry 6 vs. 5). However, tetramethylethane-1,2-diamine
(L7) only gave the desired product in 18% yield, presumably due
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc49107b
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Table 1 The optimization of reaction conditionsa
Entry
Ligand
Cu salt
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuBr2
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
DMF
NR
23
9
38
9
94
18
33
76
48
11
32
37
45
91
NR
NR
72
85
83
90
11
7
Scheme 2 The substrate scope. a All reactions were conducted under condi-
tions: 1 (0.5 mmol), 2 (0.6 mmol), L6 (0.05 mmol, 10 mol%), CuI (0.05 mmol,
10 mol%), K2CO3 (2.0 mmol, 4.0 eq.), dioxane (3 mL), reflux, and 24 h. b Isolated
yields for all data. c The data in brackets are the yields using iodoimidazoles.
9
10
11
12
13
14c
15d
16
17
18e
19 f
20g
21
22
23
The substrate scope was investigated as listed in Scheme 2.
Bromoimidazoles with bromine substituted at the 2-, 4-, and
5-positions showed significantly different activities. Amidation
of 2-bromoimidazole afforded the corresponding product 3b in
a yield of 43%, while the 4- and 5-position coupled products 3c and
3a were obtained in yields of 97% and 92%, respectively. Changing
the bromine group to an iodine group also gave good yield.11 The
same products 3a and 3c were obtained in yields of 71% and 93%
using 5- and 4-iodo-1-methylimidazoles, respectively, while 2-iodo-
1-methylimidazole afforded 3b in a yield of 66%. The substrates
possessing a 2-methyl substituent also gave 3d and 3e in good
yields of 85% and 89%, respectively. Besides pyrrolidin-2-one, other
lactams were also investigated using 5-bromo-1-methylimidazole as
CuI
CuI
CuI
CuI
CuI
THF
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Cu salt (0.05 mmol,
10 mol%), L (0.05 mmol, 10 mol%, unless otherwise noted), base
(2.0 mmol, 4.0 eq., unless otherwise noted), solvent (3 mL), reflux,
and 24 h. Yields were determined by 1H NMR. 5 mol% of L6.
b
c
d
e
f
g
20 mol% of L6. 1.0 eq. of K2CO3. 2.0 eq. of K2CO3. 6.0 eq. of K2CO3.
to the steric-hindrance around the two N atoms (entry 7). Use of a substrate. Imidazolidin-2-one showed a complex result with both
the bipyridine ligand (L8) also gave the product in a low yield of the desired product 3f and a coupled product 3f being obtained in
33% (entry 8). Using L6 as a suitable ligand, different Cu salts were yields of 25% and 37%, respectively. After protection of the free NH
studied in this reaction (entries 9–13). A complex of CuBr and L6 group with a methyl group, the relevant product 3g was obtained
led to the formation of the desired product in 76% yield (entry 9). in 70% yield. The analogous oxazolidin-2-one also afforded the
The yield was reduced to 48% when CuCl was used (entry 10). product 3h in a yield of 82%. Fused bromoimidazoles, which
Cu2O only afforded the product in 11% yield probably due to its have also been investigated by Buchwald in Pd-catalyzed amidation
poor solubility (entry 11). Cu(II) salts can also catalyze this reaction, reactions,6i gave coupled products 3i, 3j, and 3k in yields of 96%,
but lower yields were obtained (entries 12 and 13). It was found 85%, and 41%, respectively. This method was also applied to other
that less loading of ligand (5 mol%) reduced the yield to 45% while five-membered heterocycles containing two heteroatoms such as
higher loading of ligand (20 mol%) had no obvious effect on yield bromothiazole and bromopyrazole. Coupling of 4-bromothiazole with
(entries 14 and 15). The influence of base was also examined pyrrolidin-2-one afforded 3l in 96% yield while its 5-position isomer
(entries 16–20). Using K2CO3 provided the highest yield compared 3m was obtained only in a yield of 28%. Bromo-1-methylpyrazoles
to other bases such as Cs2CO3 or K3PO4 (entries 16 and 17). were also tested in this reaction to give the corresponding
Decreasing or increasing the amount of K2CO3 reduced the yield products 3n and 3o in yields of 75% and 76%, respectively.
of this reaction (entries 18–20). Several other solvents were also
The success in the cross-coupling of 5-bromo-1-methyl-
utilized in this reaction. Toluene gave a high yield of 90% while imidazole and pyrrolidin-2-one encouraged us to apply this metho-
others gave lower yields (entries 21–23).
dology to the synthesis of the nucleophilic catalyst (+)-Cy-PDPI,12
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(d) I. B. Seiple, S. Su, I. S. Young, A. Nakamura, J. Yamaguchi,
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Scheme 3 The synthesis of (+)-Cy-PDPI.
which possesses a pyrrolidin-1-yl substituent (Scheme 3). 3p
was conveniently synthesized in a good yield of 80% using the
above mentioned Cu-catalyzed C–N cross-coupling. By means
of preparative HPLC, both S and R isomers can be obtained in
yields of 48% and with >99% ees. After reduction with LiAlH4 in
THF, the desired target compound (+)-Cy-PDPI was obtained
in 66% yield. (+)-Cy-PDPI was further applied in kinetic resolu-
tion of secondary alcohols as a model reaction for testing a new
chiral nucleophilic catalyst. The preliminary results showed
that (+)-Cy-PDPI has high catalytic activity and good stereo-
control in the kinetic resolution of secondary alcohols.13
To summarize, an efficient synthetic procedure for the
Cu-catalyzed amidation of halogenated imidazoles has been
developed. Various substrates were tested to obtain the relative
products with up to 97% yield. The amidated product of
5-bromo-1-alkylimidazole was further applied to the synthesis
of a new chiral imidazole nucleophilic catalyst which showed
high catalytic activity and good stereocontrol in the kinetic
resolution of secondary alcohols.
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This work was partially supported by the National Natural
Science Foundation of China (21172143, 21172144, 21202096
and 21232004), the Nippon Chemical Industrial Co. Ltd, and
the Shanghai Jiao Tong University (SJTU). We thank Prof.
Tsuneo Imamoto and Dr Masashi Sugiya for helpful discussions
and the Instrumental Analysis Center of SJTU for determination
of HRMS.
Notes and references
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11 No reaction occurred using 5-chloro-1-methylimidazole as a sub-
strate using the same conditions.
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