Copper catalyzed nitrile synthesis from aryl halides using formamide as a nitrile source

Article abstract of DOI:10.1039/c3ra48075e

A copper iodide/triphenyl phosphine catalyzed simple and efficient protocol has been developed for cyanide free cyanation of aryl halide using formamide as a cyanide source. The reaction works well to furnish aryl nitriles using an inexpensive and easily available copper catalyst with triphenyl phosphine and phosphorus oxychloride. Under the optimized reaction conditions, a variety of electron-donating and electron-withdrawing aryl halides were efficiently converted into the respective nitriles in moderate to excellent yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra48075e

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Copper catalyzed nitrile synthesis from aryl halides
using formamide as a nitrile source†
Cite this: RSC Adv., 2014, 4, 13405
*
Ashok B. Khemnar and Bhalchandra M. Bhanage
Received 31st December 2013
Accepted 27th February 2014
DOI: 10.1039/c3ra48075e
www.rsc.org/advances
A copper iodide/triphenyl phosphine catalyzed simple and efficient of hazardous gases limiting their applications. Next, the non
protocol has been developed for cyanide free cyanation of aryl halide toxic trimethylsilyl cyanide was also explored as a cyanide
using formamide as a cyanide source. The reaction works well to source for the cyanation reaction.11 However; the trimethyl-
furnish aryl nitriles using an inexpensive and easily available copper silyl cyanide was prepared by using metal cyanide source. In
catalyst with triphenyl phosphine and phosphorus oxychloride. Under addition, it is highly moisture sensitive and produces
the optimized reaction conditions, a variety of electron-donating and hydrogen cyanide by-product which limits its application for
electron-withdrawing aryl halides were efficiently converted into the the nitrile synthesis.
respective nitriles in moderate to excellent yields.
Recently, the cyanation of various organic moieties were also
carried out by C–H activation using metal cyanide source, but
the formation of cyano complex causes metal poisoning which
is undesirable.12 Hence, a simple and efficient protocol for the
transformation of aryl halides into the corresponding nitriles is
highly desirable. The progress towards more sustainable
protocol for nitrile synthesis had been made from aryl halides.13
Subsequently, some groups have developed a metal cyanide free
cyanation for nitrile synthesis.14 In this context, we have recently
reported the nitrile synthesis from aryl halides using palladium
and rhodium catalyst along with xantphos ligand.15 In contin-
uation of our interest, herein we report an cost efficient and
attractive protocol for the synthesis of nitriles from aryl halides
using inexpensive and easily available copper catalyst along
with triphenyl phosphine ligand (Scheme 1). The protocol
sounds to be more economical as it circumvents the use of
expensive noble metal catalyst and phosphine ligands like
xantphos.
Introduction
The aryl nitriles are important building blocks in pharma-
ceuticals, agrochemicals, heterocycles, natural products,
therapeutic drugs, pigments etc.1 In addition, nitriles are
easily transformed into variety of functional groups like
amines, aldehydes, amides, ketones, tetrazoles, carboxylic
acids and amidines.2 The well known method for nitrile
synthesis is the transition metal catalysed cyanation of aryl
halide. Conventionally, nitriles were synthesized by Sand-
meyer and Rosenmund-von Braun reactions using stoichio-
metric amount of CuCN at 150–250 ꢀC.3 Whereas,
industrially more preferred method for the nitrile synthesis
involves the reaction of toluene derivatives with oxygen and
ammonia at 300–550 ꢀC using xed-bed heterogeneous
catalyst i.e. ammoxidation.4 Subsequently, the cyanation of
aryl halides were also carried out by using different cyana-
tion reagent such as KCN,5 Zn(CN)2,6 CuCN,7 NaCN8 and
acetone cyanohydrins.9 Furthermore, some groups have
reported the formation of nitriles by using nickel, copper
and palladium catalyst.10 Although, these protocols have
various applications, they suffer from one or more draw-
backs such as limited substrate scope, harsh reaction
conditions, metal cyanides as cyanide source and liberation
Results and discussion
The reaction of 4-iodotoluene (1a) with formamide (2a) using
copper catalyst and phosphine ligand was chosen as a model
reaction for the optimization study. The results are summarized
in Table 1. Initially, we have screened various copper precursors
such as CuI, CuBr, CuCl, CuO, CuBr2, Cu(OAc)2$H2O and
CuSO4$5H2O for cyanation of 1a (Table 1, entries 1–7), in which
CuI was found to be the best catalyst providing an excellent
yield of the desired product p-tolunitrile (3a) (Table 1, entry 1).
The reaction selectively provided the desired nitrile product and
aldehyde formation was not observed. However, the catalysts
Department of Chemistry, Institute of Chemical Technology, Matunga,
Mumbai-400019, India. E-mail: bm.bhanage@gmail.com; bm.bhanage@ictmumbai.
edu.in; Fax: +91-22-33611020; Tel: +91-22-33612601
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra48075e
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Table 1 Optimisation of reaction conditions for nitrile synthesisa
Table 2 Substrate study for nitrile synthesisa
Entry
Catalyst (mol%)
Ligand (mol%)
Yieldb (%)
Entry
Aryl halide
Product
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Xantphos
DPPF
DPPM
DPPE
DPPP
DPPB
P(t-Bu)3
—
85 (00)c
69
74
42
35
N.R.
N.R.
N.R.
52
CuBr
CuCl
CuO
CuBr2
Cu(OAc)2$H2O
CuSO4$5H2O
—
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
1
2
80
83
3
4
77
82
9
10
11
12
13
14
15
16
17d
18e
19f
35
N.R.
N.R.
N.R.
N.R.
10
N.R.
48
87
5
6
88
92
PPh3
PPh3
PPh3
69
Reaction conditions: 4-iodotoluene (1 mmol), formamide (10 mL mmolꢁ1),
catalyst (20 mol%), ligand (20 mol%), POCl3 (2 mmol), 24 h, 140 ꢀC, N2
a
c
d
e
f
atmosphere. b GC yield. Aldehyde product. 120 ꢀC. 30 h. 18 h. PPh3
7
8
55
65
¼
triphenyl phosphine, xantphos
¼
4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene, DPPF ¼ 1,10-bis(diphenylphosphanyl)ferrocene, DPPM ¼
1,1-bis(diphenylphosphino)methane, DPPE ¼ 1,2-bis(diphenylphosphino)-
ethane, DPPP
¼
1,3-bis(diphenylphosphino)propane, DPPB
¼
1,4-
bis(diphenylphosphino)butane.
9
69
57
64
like CuBr, CuCl, CuO, CuBr2 furnished the p-tolunitrile (3a) in
moderate to good yield (Table 1, entries 2–5). Whereas,
Cu(OAc)2$H2O and CuSO4$5H2O were ineffective (Table 1,
entries 6–7). The product formation was not observed in the
absence of catalyst (Table 1, entry 8).
10
11
We further studied the effect of various phosphine ligands
like P(t-Bu)3, xantphos, DPPF, DPPM, DPPE, DPPP and DPPB on
reaction outcome (Table 1, entries 9–15). Among the various
screened ligands, PPh3 was found to be the best ligand (Table 1,
entry 1). However, reaction did not proceed in the absence of
ligand (Table 1, entry 16). Next, we have investigated the effect
of reaction temperature and time for the effective progress of
12
13
42
39
14
66
15
16
31 (30)c
33
17
40
Scheme 1 Copper catalyzed cyanation of aryl halide.
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Table 2 (Contd.)
p-hydroxy benzonitrile (3m) (Table 2, entry 13). Next, the het-
eroaromatic halide 5-iodo-1H-indole (1n) provided the desired
nitrile product 1H-indole-5-carbonitrile (3n) in good yield (Table
2, entry 14). Furthermore, the developed catalytic system was
also applied to less reactive aryl bromide derivatives (Table 2).
Interestingly, the various aryl bromide derivatives furnished the
corresponding nitriles in moderate yield (Table 2, entries
15–18). However, aryl chloride does not work under the opti-
mised reaction conditions (Table 2, entry 19).
Entry
18
Aryl halide
Product
Yieldb (%)
45
Conclusion
A simple and efficient catalytic system has been developed for
the selective cyanation of aryl halides. The present protocol
requires inexpensive and easily available copper iodide catalyst
along with triphenyl phosphine ligand for the nitrile synthesis.
The developed methodology tolerates wide range of electron
donating as well as electron withdrawing functional groups and
provides the respective nitrile products in moderate to excellent
yield under the optimized reaction conditions.
19
00
a
Reaction conditions: aryl halide (1 mmol), formamide (10 mL
mmolꢁ1), CuI (20 mol%), PPh3 (20 mol%), POCl3 (2 mmol), 24 h,
140 ꢀC, N2 atmosphere. b Isolated yield. c Temp. 150 ꢀC.
the reaction. It was observed that the yield of the desired
product decreased with decreasing the reaction temperature Acknowledgements
from 140 to 120 ꢀC (Table 1, entry 17). Hence, the optimum
The author A. B. Khemnar is greatly thankful to the Council of
Scientic and Industrial Research (CSIR), India for providing
senior research fellowship (SRF).
temperature for the nitrile synthesis was found to be 140 ꢀC.
Whereas, no signicant change in the yield of desired product
was observed with increasing the reaction time upto 30 h (Table
1, entry 18). While, decreasing the reaction time from 24 to 18 h
resulted in low yield of 3a (Table 1, entry 19). It shows that 24 h
was an optimum time required for the completion of cyanation
reaction. Subsequently, the reactions were carried out to study
the effect of ligand and catalyst loading, it was found that
20 mol% catalyst along with 20 mol% ligand provided
maximum yield of 3a (Table 1, entry 1).
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were aryl halide (1a, 1 mmol), formamide (10 mL mmolꢁ1),
ꢀ
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In order to broaden the scope of the developed protocol, a
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good to moderate yield (Table 2, entries 7–9). The halo
substituted aryl halides 1j, 1k, 1l furnished the respective
products 3j, 3k, 3l in a moderate yield (Table 2, entries 10–12).
The p-hydroxy iodobenzene (1m) also gave 39% yield of
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