Highly Convenient, One-Pot Synthesis of Nitriles from Aldehydes Using the NH2OH·HCl/NaI/MeCN System

Article abstract of DOI:10.1055/s-2003-41408

Direct transformation of both aliphatic and aromatic aldehydes to the corresponding nitriles, can be easily performed by the reaction of an aldehyde with a slight excess of hydroxylamine hydrochloride, in refluxing acetonitrile and in the presence of 0.5 equivalents of sodium iodide as catalyst.

Full text of DOI:10.1055/s-2003-41408

LETTER
1841
Highly Convenient, One-Pot Synthesis of Nitriles from Aldehydes Using the
NH2OH·HCl/NaI/MeCN System
H
ighly Convenie
n
t,
One-Pot
Synthesis of
N
itriles from
r
Aldehy
t
des o Ballini,* Dennis Fiorini, Alessandro Palmieri
Dipartimento di Scienze Chimiche, Università di Camerino, Via S.Agostino 1 – 62032 Camerino-Italy
Fax +39(073)7402297; E-mail: roberto.ballini@unicam.it
Received 25 July 2003
NaI (1 equiv.),
O
Abstract: Direct transformation of both aliphatic and aromatic al-
dehydes to the corresponding nitriles, can be easily performed by
the reaction of an aldehyde with a slight excess of hydroxylamine
hydrochloride, in refluxing acetonitrile and in the presence of 0.5
equivalents of sodium iodide as catalyst.
NH2OH.HCl (1.3 equiv.)
solvent, reflux, 1 h
CN
H
0-95%
1a
2a
Scheme 1
Key words: aldehydes, hydroxylamine hydrochloride, sodium io-
dide, catalysis, nitriles
moved and less expensive, we choosed this solvent as the
most appropriate for further use.
Transformation of aldehydes into nitriles is of high value
because of the versatility of nitriles as starting materials
for the synthesis of thiazoles, 2-oxazolines, tetrazoles,
imidazoles, triazoles and benzamides possessing a broad
spectrum of biological activities.1 Moreover, the former
can be converted to amides, carboxylic acids, amines, ke-
tones, and esters.2
Table 1 Tested Solvents for the One-Pot Formation of 2a
Solvent
CH3CN
DMF
Yield (%) of 2a
95
89
13
0
Nitriles can be obtained by dehydration of aldoximes pre-
pared from the corresponding aldehydes under several
conditions.3 Such direct conversion provides an attractive
approach for this purpose,4 and recent developments in-
clude treatment by a range of different techniques and
reagents such as N-methyl-2-pyrrolidinone (NMP)-mi-
crowave irradiation,4e ammonium acetate-microwaves,4f
wet alumina/MeSO2Cl,4g AlCl3/KI,4h HY-Zeolite-micro-
waves,4i MeSO2Cl/graphite.4j However, these procedures
suffer from some drawbacks which includes the use of
hazardous and/or expensive and/or commercially non-
available reagents, long reaction time, low yields, drastic
reaction conditions, the help of microwave irradiation,
and tedious workup procedures.
THF
CH2Cl2
CH3NO2
0
In turn, we investigated for the best substrate/NaI ratio
(Scheme 2) and, as reported in Table 2, using 0.5 equiva-
lents of NaI the yield of formation of 2a was comparable
with that observed with one mole of the catalyst, while
lower amounts of the catalyst gave a mixture of the nitrile
2a and of the aldoxime 3a.
NaI (x equiv.),
NOH
NH2OH.HCl (1.3 equiv.)
MeCN, reflux, 1 h
H
We report herein a result obtained in our laboratory for a
very simple and efficient protocol on the one-pot transfor-
mation of aldehydes into nitriles by their treatment with
NH2OH·HCl, in the presence of a catalytic amount of the
user-friendly salt sodium iodide (NaI).
1a
2a +
2a = 48-95%
3a
Scheme 2
The method was firstly tested (Scheme 1) through the re-
action of hydrocinnamaldehyde 1a with a slight excess
(1.3 mol) of NH2OH·HCl and in the presence of one mole
of sodium iodide as catalyst, under refluxing conditions
(1 h) with different solvents. We found that the reaction
required polar solvents and that CH3CN or DMF were the
most effective in order to convert 1a to the corresponding
nitrile 2a (Table 1). Since CH3CN is more readily re-
As detailed in the Figure 1 is evident that the best results
in terms of ratio 2a/3a are obtained with at least 0.5 equiv-
alents of NaI and this means that the catalyst plays an im-
portant role in the dehydration of 3a to 2a.
In order to verify the generality of our procedure, we test-
ed our method (1.3 mol of NH2OH·HCl and 0.5 moles of
NaI in refluxing acetonitrile) with several substrates
(Scheme 3) and, as reported in Table 3, we obtained good
yields (75–98%) of nitriles 2a–o with both aromatic and
aliphatic aldehydes.
Synlett 2003, No. 12, Print: 29 09 2003. Web: 28 08 2003.
Art Id.1437-2096,E;2003,0,12,1841,1843,ftx,en;D14003ST.pdf.
DOI: 10.1055/s-2003-41408
© Georg Thieme Verlag Stuttgart · New York

1842
R. Ballini et al.
LETTER
Table 2 Tested Catalyst’s Ratio in the Formation of 2a
Table 3 Nitriles 2a–o Prepared
% (mol) of NaI
Yield (%) of 2a
Yield (%) of 3a
Entry
R
Time (min) Yield (%)a
of 2b
94
88
75
83
85
89
94
98
96
83
86
83
75
0
10
48
60
63
71
80
93
95
44
35
30
22
7
a
b
c
d
e
f
C6H5CH2CH2-
C6H5CH=CH-
C6H5CH=C(CH3)-
2-NO2C6H4CH=CH-
CH3(CH2)2CH(CH3)-
CH3(CH2)5CH2-
CH3(CH2)7CH2-
CH3(CH2)9CH2-
CH3(CH2)11CH2-
C6H5-
60
80
20
100
120
90
30
40
50
0
84
100
0
g
h
i
85
88
90
l
130
120
140
150
m
n
o
p-O2NC6H4-
p-MeOC6H4-
p-MeC6H4-
a Yield of pure, isolated product.
b All the products were characterized by comparison with pure, au-
thentic samples prepared by standard methods.
Figure 1 Trend of the formation of 2a by different amount of the ca-
talyst (NaI)
In conclusion, a new, efficient and highly convenient sys-
tem for the one-pot conversion of aldehydes into nitriles
has been realized. The significant features of the system
are as follows: (i) chemoselectivity of the method in the
presence of a keto group, (ii) good to excellent yields are
obtained with both aromatic and aliphatic aldehydes, (iii)
simple work up and (iv) the catalyst and chemicals needed
are extremely user-friendly and cheap.
NaI (0.5 equiv.),
NH2OH.HCl (1.3 equiv.)
O
MeCN, reflux, 1-2.5 h
R
C
N
R
H
75-98%
1
2
Scheme 3
Further experimental work, in order to elucidate the
mechanism of this synthetic procedure is currently in
progress in our laboratory.
We then investigated the chemoselectivity of the reaction
by treatment of one mole of hydrocinnamaldehyde 1a and
one mole of 4-heptanone 4 with one mole of hydroxyl-
amine hydrochloride under our conditions (Scheme 4).
We found the almost quantitative conversion of 2a to 3a
(91% yield), while a 93% of 4 was recovered together
with 3% of the ketoxime 5.
General Procedure for the One-Pot Preparation of Nitriles 2.
The aldehyde 1 (10 mmol) was added, at r.t., to a stirred mixture of
NH2OH·HCl (0.9 g. 13 mmol) and NaI (0.75 g, 5 mmol) in MeCN
(40 mL). The reaction was allowed to react, under reflux and by stir-
ring, for the appropriate time (Table 3). After that, aq Na2S2O3 (5%,
70 mL) was added to the cooled mixture and the stirring was further
continued for 15 min until the red-brown colour disappeared. The
mixture was then extracted with CH2Cl2 (3 × 50 mL), the organic
layer was dried with Na2SO4, evaporated and the crude nitrile 2 was
purified by flash chromatography using EtOAc/cyclohexane as elu-
ent.
O
CN
H
NaI (0.5 equiv.),
NH2OH.HCl (1 equiv.)
1a
2a (91%)
+
+
MeCN, reflux, 1 h
O
NOH
Acknowledgment
This work was supported by the University of Camerino, by MIUR-
Italy (Project: Il Mezzo Acquoso nelle Applicazioni Sintetiche dei
Nitrocomposti Alifatici), and by Fondazione della Cassa di Rispar-
mio della Provincia di Macerata-Italy.
4
5 (3%)
Scheme 4 Chemoselectivity of the reaction
Synlett 2003, No. 12, 1841–1843 © Thieme Stuttgart · New York

LETTER
Highly Convenient, One-Pot Synthesis of Nitriles from Aldehydes
1843
Moiller, J.; Parratt, J. S.; Turner, N. J. J. Chem. Soc., Perkin
Trans. 1 1994, 1679. (g) Luo, F.-T.; Jeevanandam, A.
Tetrahedron Lett. 1998, 39, 9455.
References
(1) (a) Chichiro, M.; Nagamoto, H.; Takemura, I.; Kitano, K.;
Komatsu, H.; Sekiguchi, K.; Tabusa, F.; Mori, T.;
(3) (a) Cohen, M. A.; Sawden, J.; Turner, N. J. Tetrahedron Lett.
1990, 31, 7223. (b) Yamada, H. Chimia 1993, 47, 69.
(c) Luo, F.-T.; Jeevanandam, A. Tetrahedron Lett. 1998, 39,
9455. (d) Bandgar, B. P.; Jagtap, S. R.; Ghodeshwar, S. B.;
Wadgaonkar, P. P. Synth. Commun. 1995, 25, 2993.
(e) Miller, C. P.; Kaufman, D. H. Synlett 2000, 1169.
(f) Lingaiah, N.; Narender, R. Synth. Commun. 2002, 32,
2391. (g) Iranpoor, N.; Firouzabadi, H.; Aghapour, G. Synth.
Commun. 2002, 32, 2535.
(4) (a) Wang, E.-C.; Lin, G.-J. Tetrahedron Lett. 1998, 36,
4047. (b) Kamal, A.; Arifuddin, M.; Rao, N. V. Synth.
Commun. 1998, 28, 4507. (c) Webb, K. S.; Levy, D.
Tetrahedron Lett. 1995, 36, 5117. (d) Ali, S. L.; Nikalje, M.
D.; Dewkar, G. K.; Paraskar, A. S.; Nikale, M. D.; Sudalai,
A. J. Chem. Res., Synop. 2000, 30. (e) Chakraborti, A. K.;
Kaur, G. Tetrahedron 1999, 55, 13265. (f) Das, B.;
Ramesh, C.; Madhusudham, P. Synlett 2000, 1599.
(g) Sharghi, H.; Sarvari, M. H. Tetrahedron 2002, 58,
10323. (h) Boruah, M.; Konwar, D. J. Org. Chem. 2002, 67,
7138. (i) Srinivas, K. V. N. S.; Reddy, B. E.; Das, B. Synlett
2002, 625. (j) Sharghi, H.; Sarvari, M. H. Synthesis 2003,
243.
Tomonnaga, M.; Yabuuchi, Y. J. Med. Chem. 1995, 38,
353. (b) Serrano, J. L.; Sierra, T.; Gonzales, Y.; Bolm, C.;
Weickhardt, K.; Magnus, A.; Moll, G. J. Am. Chem. Soc.
1995, 117, 8321. (c) Diana, G. D.; Cutcliffe, D.; Volkots, D.
L.; Mallamo, J. P.; Bailey, T. R.; Velico, N.; Oglesby, R. C.;
Nitz, T. J.; Wetzel, J.; Giranda, V.; Pevear, D. C.; Dutko, F.
J. J. Med. Chem. 1993, 36, 3240. (d) Khanna, I. K.; Weier,
R. M.; Yu, Y.; Xu, X. D.; Koszyk, F. J.; Collins, P. W.;
Koboldt, C. M.; Veenhuizen, A. W.; Perkins, W. E.; Casler,
J. J.; Masferrer, J. L.; Zhang, Y. Y.; Gregory, S. A.; Seibert,
K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1634.
(e) Medwid, J. B.; Paul, R.; Baker, J. S.; Brockman, J. A.;
Du, M. T.; Hallet, W. A.; Hanfin, J. W.; Hardy, R. A.;
Tarrant, M. E.; Torley, I. M.; Wrenn, S. J. Med. Chem. 1990,
26, 4351. (f) Judkins, B. D.; Allen, D. G.; Cook, T. A.;
Evans, B.; Sardharwala, T. E. Synth. Commun. 1996, 26,
4351.
(2) (a) March, J. Advanced Organic Chemistry; Wiley: New
York, 1992, 907. (b) Corey, E. J.; Cheng, X. M. The Logic of
Chemical Synthesis; Wiley: New York, 1989. (c) Ho, T. L.
Tactics of Synthesis; Wiley: New York, 1994. (d) Cohen,
M. A.; Sawden, J.; Turner, N. J. Tetrahedron Lett. 1990, 31,
7223. (e) Yamada, H. Chimia 1993, 47, 69. (f) Crosby, J.;
Synlett 2003, No. 12, 1841–1843 © Thieme Stuttgart · New York