Rapid method of converting primary amides to nitriles and nitriles to primary amides by ZnCl2 using microwaves under different reaction conditions

Article abstract of DOI:10.1080/00397910701230147

A rapid and facile method for the conversion of primary amides to nitriles using inexpensive and readily available ZnCl2 in aqueous acetonitrile and their regeneration using ZnCl2-H2O-THF in the presence of acetamide under microwave irradiation in good yields is reported. The reactions go to completion within a minute. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701230147

This article was downloaded by: [Fudan University]
On: 03 June 2013, At: 14:38
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Rapid Method of Converting Primary Amides
to Nitriles and Nitriles to Primary Amides
by ZnCl2 using Microwaves under Different
Reaction Conditions
Krishnappa Manjula a & Mohamed Afzal Pasha a
a Department of Studies in Chemistry, Central College Campus, Bangalore
University, Bangalore, India
Published online: 11 May 2007.
To cite this article: Krishnappa Manjula & Mohamed Afzal Pasha (2007): Rapid Method of Converting Primary
Amides to Nitriles and Nitriles to Primary Amides by ZnCl2 using Microwaves under Different Reaction
Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:9, 1545-1550
To link to this article: http://dx.doi.org/10.1080/00397910701230147
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 37: 1545–1550, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701230147
Rapid Method of Converting Primary
Amides to Nitriles and Nitriles to Primary
Amides by ZnCl2 using Microwaves under
Different Reaction Conditions
Krishnappa Manjula and Mohamed Afzal Pasha
Department of Studies in Chemistry, Central College Campus, Bangalore
University, Bangalore, India
Abstract: A rapid and facile method for the conversion of primary amides to nitriles
using inexpensive and readily available ZnCl2 in aqueous acetonitrile and their regen-
eration using ZnCl2–H2O–THF in the presence of acetamide under microwave
irradiation in good yields is reported. The reactions go to completion within a minute.
Keywords: microwave irradiation, nitriles, primary amides, ZnCl2
INTRODUCTION
The preparation of amides and nitriles are important synthetic transformations
in organic synthesis. Methods for the preparation of nitriles by dehydration of
carboxamide using triphenylphosphine/carbontetrachloride,[1] PyBOP,[2]
COCl2/DMSO,[3] PPSC,[4] and CH3O2CNSO2NEt3[5] have been documented
in the literature, and hydration of nitriles to amide is achieved by H2O2,[6]
MnO2/SiO,[7] and Pt(II) complexes.[8]
Maffioli et al.[9] have reported a mild and reversible conversion of primary
amides into nitriles by PdCl2 in aqueous acetonitrile for the forward reaction and
PdCl2–H2O–THF in the presence of acetamide for the backward reaction.
Received in India September 28, 2006
Address correspondence to Mohamed Afzal Pasha, Department of Studies in
Chemistry, Central College Campus, Bangalore University, Bangalore 560 001,
India. E-mail: m_af_pasha@yahoo.co.in
1545

1546
K. Manjula and M. A. Pasha
In continuation of our work on ZnCl2,[10] we report herein the use of
ZnCl2 as a catalyst for the dehydration of primary amides into nitriles and
hydration of nitriles into amides under microwave irradiation using different
reaction systems (Scheme 1).
Scheme 1.
RESULTS AND DISCUSSION
Primary amides were dehydrated into nitriles in high yields rapidly under
microwave irradiation (Scheme 2) in the presence of ZnCl2–H2O–MeCN.
This is the first procedure for the synthesis of nitriles by direct reaction of
primary amides using ZnCl2 under aqueous conditions.
Scheme 2.
To standardize the reaction, different Lewis acids were used to
convert benzamide into benzonitrile under different reaction conditions, and
results are summarized in Table 1. Table 2 indicates the versatility of the
reaction.
It was interesting to find out that hydrolysis of nitrile occurred with ZnCl2
in 1:1 H2O–THF in the presence of acetamide under microwave irradiation.
These results are summarized in Table 3.
Scheme 3.

Conversion of Primary Amides to Nitriles
1547
Table 1. Dehydration of benzamide (1 mmol) with different Lewis acid and reaction
conditions
Reaction
condition
Entry Lewis acid
Solvent
Time
Yield (%)
ND
a
1
2
3
NiCl2
1 mL H2O/MeCN ¼ 1:1 MW/
Reflux
1 mL H2O/MeCN ¼ 1:1 MW/
Reflux
1 mL H2O/MeCN ¼ 1:1 MW/UI 2 min/
30 min
1 mL H2O/MeCN ¼ 1:1 MW/HP 2 min/1 h
1 mL MeCN MW/UI 2 min/
30 min
2 min/8 h
a
SnCl2
2 min/8 h
ND
ND
a
AlCl3
4
5
CuCla
ND
ND
a
ZnCl2
b
c
a
6
7
8
ZnCl2
ZnCl2
ZnCl2
1 mL H2O/MeCN ¼ 1:1 MW/HP 2 min
30
60
94
1 mL H2O/MeCN ¼ 1:1 MW
1 mL H2O/MeCN ¼ 1:1 MW
90 s
30 s
a1 mmol.
b0.1 mmol.
c0.5 mmol.
Notes: MW ¼ Microwave irradiation (320 W); reflux ¼ 808C; UI ¼ ultrasound
irradiation; HP ¼ hot plate (1508C); ND ¼ not detected.
CONCLUSION
The present procedure provides an efficient, rapid, facile, and reversible
method for the conversion of primary amides to nitriles. With addition of
acetamide, the reaction was reversed to hydrolyze nitrile into amide.
Table 2. Microwave-promoted dehydration of primary amides to nitriles with ZnCl2
Melting/boiling point
(8C)
Reaction
time (s) Yield (%)
Entry
Substrate
Benzamide
p-Toluamide
Found
Report
a
b
c
d
e
f
30
30
20
20
35
30
20
30
94
70
82
75
72
60
80
65
188–190 191–193[1]
103–105 103–106[1]
p-Chlorobenzamide
p-Hroxybenzamide
p-Nitrobenzamide
p-Methoxybenzamide
m-Chlorobenzamide
m-Toluamide
90–92
91–93[2]
110–112 111–113[1]
146–148 146–149[2]
57–59
38–40
89–90
57–59[1]
39–42[2]
89–90[1]
g
h

1548
K. Manjula and M. A. Pasha
Table 3. Microwave-promoted hydration of nitriles to primary amides with ZnCl2
Melting point (8C)
Reaction
time (s) Yield (%)c
Entry
Substrate
Benzonitrile
p-Tolunitrile
Found
Reported
a
b
c
d
e
f
40
45
35
30
40
40
35
40
60
45
55
50
62
57
58
40
126–127 128–129a
156–158 158–160a
170–172 172–176a
161–163 161–162a
198–201 199–201b
163–165 164–167b
132–134 134–135b
p-Chlorobenzonitrile
p-Hydroxybenzonitrile
p-Nitrobenzonitrile
p-Methoxybenzonitrile
m-Chlorobenzonitrile
m-Tolunitrile
g
h
92–93
93–95a
aLancaster Research Chemicals, 2002–2003.
bAldrich Handbook of Fine Chemicals.
cIsolated yield, and in all the cases, unreacted nitriles were recovered and recycled.
EXPERIMENTAL
All amides were prepared from carboxylic acid and urea using pyridine,[11]
solvents and Lewis acids were purchased from BDH/MERCK, and all
solvents were distilled before use. All the reactions were carried out using a con-
ventional (unmodified) household microwave oven (LG, Little Cheff, 230 V,
ꢀ50 Hz). Reactions were monitored with thin-layer chromatography (TLC)
by comparison with the authentic samples. Melting points/boiling points
were taken in open capillaries using paraffin bath and corrections are applied
wherever necessary.[12] Yields refer to the isolated yields of the products after
purification by silica-gel column chromatography. The IR spectra of the
products were recorded on Nicolet 400D FT-IR spectrophotometer.
General Procedure
Conversion of Primary Amides to Nitriles
A mixture of ZnCl2 (0.136 g, 1 mmol) in 1:1 water/acetonitrile (1 ml) was taken
into a Pyrexw cylindrical tube; benzamide (0.121 g, 1 mmol) was then added.
The mixture was homogenized and irradiated in a commercial microwave oven
(320 W) (Scheme 3). At the end of irradiation (30 s), the mixture was cooled
to room temperature and extracted with dichloromethane (5 ml). The organic
layer was dried over anhydrous sodium sulphate, and the solvent was removed
under vacuum. The crude product was chromatographed on a short column of
silica gel using 2.5% EtOAc in light petroleum as eluent to get benzonitrile
(0.097 g, 94%).

Conversion of Primary Amides to Nitriles
1549
Conversion of Nitriles to Primary Amides
A mixture of ZnCl2 (0.136 g, 1 mmol) in 1:1 of water/THF (1 ml) taken into a
Pyrexw cylindrical tube; benzonitrile (0.103 g, 1 mmol) and acetamide
(0.118 g, 2 mmol) were added. The mixture was homogenized and irradiated
in a commercial microwave oven (320 W). At the end of irradiation (40 s), the
mixture was cooled to room temperature, extracted with dichloromethane
(5 ml), and washed with cold water (2 Â 5 ml). The organic layer was dried
over anhydrous sodium sulphate, and the solvent was removed under vacuum.
The crude product was chromatographed on a short column of silica using 5%
EtOAc in light petroleum as eluent to get benzamide (0.073 g, 60%).
REFERENCES
1. Yamato, E.; Sugasawa, S. Preparation of nitrile from primary amide (I). Tetra-
hedron Lett. 1970, 11, 4383–4384.
2. Bose, D. S.; Narsaiah, A. V. Use of pyBOP as a convenient activator for the nitriles
from primary amides. Synthesis 2001, 373–375.
3. Nakajima, N.; Ubukata, M. Preparation of nitriles from primary amides under
Swern oxidation conditions. Tetrahedron Lett. 1997, 38, 2099–2102.
4. Yokoyama, M.; Yoshida, S.; Imamoto, T. Organic reaction using trimethylsily
polyphosphate (PPSE): A convenient synthesis of nitriles from carboxamides.
Synthesis 1982, 591–592.
5. Claremon, D. A.; Phillips, B. T. An efficient chemoselective synthesis of nitriles
from primary amides. Tetrahedron Lett. 1988, 29, 2155–2158.
6. (a) Katrizky, A. R.; Pilarski, B.; Urogdi, L. Efficient conversion of nitriles
to amides with basic hydrogen peroxide in dimethyl sulfoxide. Synthesis 1989,
949–950; (b) Cacchi, S.; Misiti, D. Amides from nitriles using basic
hydrogen peroxide under phase-transfer catalysed conditions. Synthesis 1980,
243–244.
7. (a) Liu, K.-T.; Shih, M.-H.; Huang, H. -W.; Hu, C.-J. Catalytic hydration of nitriles
to amides with manganese dioxide on silica gel. Synthesis 1988, 715;
(b) Khadilkar, B. M.; Madyar, V. R. Totally selective dry microwave assisted
amide synthesis by hydration of nitrile using silica supported MnO2 reagent.
Synth. Commun. 2002, 32, 1731–1734.
8. (a) Ghaffar, T.; Parkins, A. W. A new homogeneous platinum containing catalyst
for the hyrolysis of nitriles. Tetrahedron Lett. 1995, 36, 8657–8660;
(b) Cobley, C. J.; Marco, V. D. H.; Abbadi, A.; Johannes, G. D. V. Platinum
catalysed hydrolytic amidation of unactivated nitriles. Tetrahedron Lett. 2000,
41, 2467–2470.
9. Maffioli, S. I.; Marzorati, E.; Marazzi, A. Mild and reversible dehydration
of primary amides with PdCl2 in aqueous acetonitrile. Org. Lett. 2005, 7,
5237–5239.
10. Pasha, M. A.; Jayashankara, V. P. Synthesis of 1,5-benzodiazepine derivatives
catalyzed by ZnCl2. Heterocycles 2006, 68, 1017–1023.; (b) Pasha, M. A.;
Swamy, N. R.; Jayashankara, V. P. One pot synthesis of 3,4-dihydropyrimidin-
2(1H)-ones/-thiones catalysed by ZnCl2: An improved procedure for the

1550
K. Manjula and M. A. Pasha
Biginelli reaction using microwaves under solvent free condition. Indian J. Chem.
2005, 44B, 823–826.
11. Pasha, M. A.; Jayashankara, V. P. Synthesis of amides from carboxylic acids and
urea in the presence of pyridine under microwave irradiation. J. Indian Chem. Soc.
2005, 82, 675–676.
12. Vogel, A. I. A Textbook of Practical Organic Chemistry; 5th edn.; Longman
Group Ltd: London, 1989, pp. 71, 86.