Synthesis of amides via copper-catalyzed amidation of aryl halides using isocyanides

Article abstract of DOI:10.1016/j.tetlet.2014.05.032

An efficient method for intermolecular CC cross-coupling reactions between isocyanides and aryl halides, catalyzed by copper(I) oxide, is developed. This transformation serves as a direct method for the preparation of benzamides in aqueous DMSO, in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2014.05.032

Accepted Manuscript
Synthesis of amides via copper-catalyzed amidation of aryl halides using iso-
cyanides
Issa Yavari, Majid Ghazanfarpour-Darjani, Mohammad J. Bayat
PII:
S0040-4039(14)00821-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.032
TETL 44623
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 January 2014
20 April 2014
7 May 2014
Please cite this article as: Yavari, I., Ghazanfarpour-Darjani, M., Bayat, M.J., Synthesis of amides via copper-
catalyzed amidation of aryl halides using isocyanides, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.05.032
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Graphical Abstract
Synthesis of amides via copper-catalyzed amidation of aryl halides using isocyanides
Issa Yavari*, Majid Ghazanfarpour-Darjani, Mohammad J. Bayat
1

Synthesis of amides via copper-catalyzed amidation of aryl
halides using isocyanides
Issa Yavari*, Majid Ghazanfarpour-Darjani, Mohammad J. Bayat
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
ABSTRACT
An efficient method for intermolecular C-C cross-coupling reactions between isocyanides and
aryl halides, catalyzed by copper(I) oxide, is developed. This transformation serves as a direct
method for the preparation of benzamides in aqueous DMSO, in moderate to good yields.
Keywords:
Aryl halide
Isocyanide
Amidation
C-C cross-coupling
Copper(I) oxide
* Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
2

The development of metal-catalyzed cross-coupling reactions has revolutionized the
formation of C-C bonds.1-3 However, the use of toxic carbon monoxide and expensive transition
metal catalysts has limited the scope of these types of coupling reactions.4, 5
Isocyanides are derivatives of carbon that are similar to carbon monoxide.6 Recently, Jiang
and co-workers reported a method for the synthesis of amides via palladium-catalyzed C-C
coupling of aryl halides with isocyanides in the presence of CsF in aqueous DMSO.7 This report,
prompted us to describe our results on the direct aminocarbonylation of aryl halides using
isocyanides in the presence of Cu2O, which constitutes a synthesis of benzamides via copper-
catalyzed C-C cross-coupling of aryl halides with isocyanides (see Scheme 1).8
Scheme 1. Reaction between isocyanides and aryl halides.
Cyclohexyl isocyanide (1) and iodobenzene (2a) were selected for initial development of the
reaction conditions. When 1 and 2a were treated with cesium carbonate and CuI in 80% aqueous
DMSO at 85 °C for five hours, N-cyclohexylbenzamide (3a) was obtained in 14% yield. The
presence of a ligand had a beneficial effect on this transformation. Among the various ligands
tested for optimization of the reaction conditions, 4,7-dimethoxy-1,10-phenanthroline (L3) gave
the best yields (see Table 1).
3

Table 1. Reaction of cyclohexyl isocyanide (1a, 1.5 mmol), iodobenzene (2a, 1.0 mmol), Cu
source (10 mol%), ligand (0.2 mmol), and base (1.5 mmol) at 85 °C for 5 h under argon
Entry
1
Catalyst
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
AgI
Base
Ligand
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
Solvent
Yield (%)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOH
80% aq DMSO
80% aq DMSO
80% aq DMSO
80% aq DMSO
80% aq DMSO
80% aq DMSO
80% aq DMSO
80% aq DMF
80% aq MNP
80% aq MeCN
H2O
41
62
85
53
30
72
12
65
57
42
-
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
80% aq DMSO
80% aq DMSO
80% aq DMSO
80% aq DMSO
80% aq DMSO
-
CuCl
CuI
45
63
34
8
CuBr
Cu(Ac)2
4

With optimized reaction conditions in hand, different substituted aryl halides and isocyanides
were subjected to this cross-coupling process to explore the scope of this transformation (Table
2).
Table 2. Copper-catalyzed synthesis of aryl amides 3 from aryl halides 1 and isocyanides 2
Entry
R
Ar
Product
Yield (%)
X = Br
81
X = I
85
76
83
80
91
78
88
82
84
80
85
79
76
X = Cl
32
1
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
t-Bu
Ph
3a
3b
3c
3d
3e
3f
2
o-tol
72
11
3
m-tol
80
30
4
4-MeO-C6H4
4-O2N-C6H4
2-thienyl
4-NC-C6H4
4-Cl-C6H4
Ph
72
23
5
85
48
6
73
22
7
81
36
3g
3h
3i
8
80
25
9
78
34
10
11
12
13
t-Bu
4-MeO-C6H4
4-O2N-C6H4
76
20
3j
t-Bu
80
45
3k
3l
Me3CCH2Me2C 4-Ac-C6H4
2,6-Me2-C6H3 Ph
77
23
73
10
3m
5

Chlorobenzene derivatives needed a higher catalyst loading (30%) and temperature (120 ºC)
to furnish products 3. In most cases the yields were low, except for derivatives bearing an
electron-withdrawing group on the aryl ring.
In conclusion, we have described a cheap and efficient method to convert aryl halides into
amides via a copper-catalyzed reaction of an aryl halide with an isocyanide. The chemistry is
optimized through a ligand screen which leads to the use of a dimethoxyphenathroline ligand.
Aryl iodides and bromides are particularly good substrates. This chemistry offers a useful
alternative to current palladium-catalyzed protocols and can be of general interest to the
synthetic community.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi .org/
References and notes
1. Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489.
2. Jensen, A. E.; Dohle, W.; Knochel, P. Tetrahedron 2000, 56, 4197.
3. Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH:
Weinheim, 1998.
4. Salvadori, J.; Balducci, E.; Zaza, S.; Petricci, E.; Taddei, M. J. Org. Chem. 2010, 75, 1841.
5. Brennfuuhrer, A.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2009, 48, 4114.
6. Tumanov, V. V.; Tishkov, A.; Mayr, H. Angew. Chem. Int. Ed. 2007, 46, 3563.
7. Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Org. Lett. 2011, 13, 1028.
6

8. Spectroscopic and analytical data for products 3i-3m have been reported.7 Melting points and
IR spectroscopic data of these derivatives were in complete agreement with the literature.
Typical procedure for the preparation of benzamides 3a-m:
To a mixture of Cu2O (0.015 mg, 0.1 mmol) and Cs2CO3 (0.555 g, 1.5 mmol) in 80%
aqueous DMSO (3 mL), was added the aryl halide (1.0 mmol) at room temperature under
argon. After 15 min, the isocyanide (1.5 mmol) was added, and the mixture stirred at 85 °C
for 5 h, then cooled to room temperature, diluted with H2O, and extracted with CH2Cl2 (2 × 5
mL). The combined organic layers were washed with brine (5 mL) and dried over MgSO4.
The solvent was removed and the residue purified by column chromatography on silica gel
(hexane/EtOAc 4:1) to give product 3.
N-Cyclohexylbenzamide (3a). Colorless solid, mp: 152-154 °C; yield: 0.17 g (85%). IR
1
(KBr) (νmax, cm-1): 3245, 3073, 2928, 1629, 1538, 1332, 1152. H NMR (500.1 MHz,
CDCl3): δH 1.18-1.27 (2H, m, CH2), 1.37-1.46 (4H, m, 2CH2), 1.77-2.01 (4H, m, 2CH2),
3.93-4.01 (1H, m, CH), 6.01 (1H, br s, NH), 7.41 (2H, t, 3J = 7.3 Hz, 2CH), 7.47 (1H, t, 3J =
7.0 Hz, CH), 7.75 (2H, d, 3J = 7.8 Hz, 2CH). 13C NMR (125.7 MHz, CDCl3): δC 24.9 (2CH2),
25.6 (CH2), 33.2 (2CH2), 48.7 (CH), 126.9 (2CH), 128.5 (2CH), 131.2 (CH), 135.2 (C),
166.6 (C=O). EI-MS: m/z (%) = 203 (M+, 1), 174 (16), 120 (83), 105 (67), 98 (65), 77 (100).
Anal. Calcd for C13H17NO (203.13): C, 76.81; H, 8.43; N, 6.89%. Found: C, 76.49; H, 8.34;
N, 6.95%.
7