Selective conversion of aldehydes into nitriles and primary amides in aqueous media

Article abstract of DOI:10.3184/174751912X13385625425135

A simple and selective conversion of aldehydes into the corresponding nitriles and primary amides in aqueous ammonia has been developed. The aldehydes were efficiently converted to the corresponding nitriles in moderate to excellent yields using tetrabutylammonium iodide/tert-butyl hydroperoxide system. The primary amides, however, can be selectively synthesised only in the presence of tert-butyl hydroperoxide.

Full text of DOI:10.3184/174751912X13385625425135

460 RESEARCH PAPER
AUGUST, 460–462
JOURNAL OF CHEMICAL RESEARCH 2012
Selective conversion of aldehydes into nitriles and primary amides in
aqueous media
Liang Wang*, Chen Shen, Hai-ping Wang, Wei-you Zhou, Fu-an Sun, Ming-Yang He and
Qun Chen
Jiangsu Province Key Laboratory of Fine Petro-ChemicalTechnology, Changzhou University, Changzhou 213164, P. R. China
A simple and selective conversion of aldehydes into the corresponding nitriles and primary amides in aqueous
ammonia has been developed. The aldehydes were efficiently converted to the corresponding nitriles in moderate to
excellent yields using tetrabutylammonium iodide/tert-butyl hydroperoxide system. The primary amides, however,
can be selectively synthesised only in the presence of tert-butyl hydroperoxide.
Keywords: selective oxidation, aldehydes, nitriles, primary amides, aqueous ammonia
Nitriles and amides are very important organic compounds
not only because of their interesting biological properties, but
also their use as versatile starting materials for many other
important compounds.1–3 Generally, the most common
procedure for preparation of nitriles is the nucleophilic
displacement of substrates bearing suitable leaving groups
with inorganic cyanide ions.4–7 An alternative procedure is
the dehydration of aldoximes and aldimines that was formed
in situ by condensation of aldehydes with hydroxylamine or
ammonia.8–13 On the other hand, conventional methods for the
synthesis of amides involve reactions between carboxylic acids
or their activated analogues and amines.14 Other important
methods include hydrolysis of nitriles,15 metal-catalysed
aminocarbonylation,16,17 modified Staudinger reaction,18
Schmidt reaction,19 Ritter reaction20 as well as the Ugi
reaction.21 Recently, thedirectoxidativeamidationofaldehydes
to provide the corresponding amides have received increasing
attention due to its high atom-economy and the sole by-product
is H2.22–24
While acknowledging the pioneering work in these fields,
some drawbacks remain. For example, transition-metal
catalysts are used in some cases, which impact cost and metal
contamination of the products. The harsh reaction conditions,
harmful organic solvents, expensive reagents and formation of
toxic by-products also extremely limited their application.
Thus, simple and convenient methods for the preparation of
nitriles and amides under mild conditions in environmentally
benign solvents are highly desirable. We now report an efficient
and selective conversion of aldehydes into the corresponding
nitriles and primary amides in aqueous ammonia using
tetrabutylammonium iodide (TBAI) as catalyst and tert-butyl
hydroperoxide (TBHP) as co-oxidant (Scheme 1).
of 20 mol% of TBAI (Table 1, entry 2). Encouraged by the
results, we optimised the reaction conditions for the selective
synthesis of benzonitrile. It was found that the temperature had
a large influence on the reaction. Reaction at room temperature
gave the product in only 13% yield. Decreasing the temperature
andtheamountofthecatalystgavealoweryieldofbenzonitrile.
Furthermore, no reaction was observed in the absence of
TBHP. Other commercially available oxidants such as H2O2
and NaOCl were tested but no conversion was detected. Finally,
various amines including inorganic and organic ammonium
salts were checked in the presence ofTABI andTBHP, however,
these ammonium salts were completely inactive in this reaction.
On the basis of the successful synthesis of benzonitrile, the
optimised conditions were then applied to a range of other
aldehydes. As shown in Table 2, most aldehydes underwent
oxidation to afford the corresponding nitriles in good to excel-
lent yields. The electronic properties of the substituents on the
benzene ring did not show an obvious influence on the reaction.
Both aromatic aldehydes bearing electron-donating groups
and electron-withdrawing groups gave the products in high
yields within a reasonable time (Table 2, entries 1–9). The
heterocyclic aldehyde, 2-furaldehyde, also survived in this
oxidation system to afford the 2-furonitrile in 90% yield. In the
case of aliphatic aldehydes, the reactions were conducted
Table 1 Optimisation studies for the conversion of benzalde-
hyde to benzonitrilea
Entry
Amine
Catalyst
/mmol
Oxidant
/mmol
T/°C Yield
/%b
Initial studies were carried out by treating benzaldehyde
with aqueous ammonia under different conditions. The results
are summarised in Table 1. Interestingly, the blank reaction
using TBHP as oxidant without a catalyst provided the
benzamide as the sole product in 95% yield (Table 1, entry 1),
whereas 92% yield of benzonitrile was obtained in the presence
1
2
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH3.H2O
NH4Cl
–
TBHP (3)
TBHP (3)
80
80
80
60
rt
80
80
80
80
80
80
80
80
80
80
95c
92
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.1)
TBAI (0.05)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
KI (0.2)
3
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
H2O2 (1.2)
NaOCl (1.2)
–
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
90
4
74
5
13
6
85
7
71
8
NRd
NRd
NRd
81
9
10
11
12
13
14
15
TBAI (0.2)
TBAI (0.2)
NRd
NRd
NRd
NRd
HCOONH4
CH3COONH4 TBAI (0.2)
(NH4)2CO3
TBAI (0.2)
a Reaction conditions: benzaldehyde (1 mmol), NH3.H2O (3 mL),
12 h.
Scheme 1 Selective synthesis of nitriles and primary amides.
b Isolated yields.
c Benzamide was the product.
d No reaction.
* Correspondent. E-mail: lwcczu@126.com

JOURNAL OF CHEMICAL RESEARCH 2012 461
Table 2 Oxidation of aldehydes into nitriles with TBAI and
carried out with various aldehydes under the optimised
conditions. The results are shown in Table 3. All the aromatic
aldehydes exhibited good reactivity for the reaction, affording
the corresponding amides in 83–97% yield. The reactivity of
pentanal, however, was relatively lower and a moderate yield
was obtained.
TBHP in aqueous ammoniaa
Entry
R
t (h)
Yield/%b
Mp/°Clit.
According to the above results, the mechanism in Scheme 2
was proposed. For the preparation of amide, the reaction
between aldehyde and aqueous ammonia may proceed by a
hemiaminal intermediate c, which subsequently oxidised to
amides by TBHP.24 While in the presence of TBAI, the colour
of the reaction mixture was changed to brown, which means
the I− was oxidised to the iodine. The iodine then accelerated
the reaction between aldehyde and aqueous ammonia to form
imine. The imine intermediate further reacted with iodine to
give N-iodo aldimine b, which was finally converted into
nitrile by β-elimination of HI with ammonia.33
1
2
C6H5-
12
12
16
12
12
12
12
12
12
12
16
24
24
92
90
85
95
90
82
93
87
89
90
82
65
60
Oil6
Oil25
4-MeC6H4-
4-MeOC6H4-
4-ClC6H4-
3-ClC6H4-
2-ClC6H4-
4-BrC6H4-
4-FC6H4-
3
58–60(58–59)26
90–92(91–92)26
38–40(39–40)25
43–45(42–44)25
110–112(110–115)27
32–34(32–34)27
38–40(37–38)25
Oil28
4
5
6
7
8
9
4-CF3C6H4-
2-Furyl-
C6H5CH2-
CH3(CH2)3-
CH3(CH2)5-
10
11
12
13
Oil28
Oil25
Oil25
In summary, a simple and efficient method for conversion
of aldehydes into the corresponding nitriles and amides in
aqueous ammonia has been developed using the combination
of TBAI and TBHP. The present method avoids the use of
expensive metal catalysts, harmful solvents and harsh
conditions. The excellent yield, high selectivity and atom
economy make our methods more environmentally benign and
acceptable.
a Reaction conditions: aldehyde (1 mmol), NH3.H2O (3 mL), TBAI
(0.2 mmol), TBHP (1.2 mmol), 80 °C.
b Isolated yields.
sluggishly and the required nitriles were obtained in moderate
yields by prolonging the reaction time (Table 2, entries 12 and
13). Moreover, trace amides as by-products were detected in
all cases.
Since benzamide could be selectively obtained in the
presence of TBHP (Table 1, entry 1), we next investigated the
optimal conditions for the synthesis of benzamide. It was
found that a 93% yield of product was obtained with 1.2 equiv.
of TBHP at 80 °C within 12 h. To explore the generality and
scope of the reaction, the oxidative amidation reaction was
Experimental
All reagents were obtained from local commercial suppliers and used
1
without further purification. H and 13C NMR spectra were recorded
on a Bruker Advance III 500 analyser. GC and MS analyses were per-
formed on a HP5890-GCQ instrument. All the products are known
compounds and were identified by comparing of their physical and
spectra data with those reported in the literature.
Conversion of aldehydes into nitriles; general procedure
Table 3 Oxidative amidation of aldehydes with TBHPa
Aldehyde (1 mmol), ammonia water (3 mL, 25–28% aqueous
solution), TBAI (74 mg, 0.2 mmol) and TBHP (1.2 mmol, 70%
aqueous solution) were added to a test tube under air. Then the reaction
mixture was stirred in an oil bath at 80 °C for an appropriate time as
indicated by TLC. After the reaction was complete, the mixture was
cooled to room temperature, and the solid products were collected by
simple filtration, whereas liquid products were extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was washed with
H2O (3 × 10 mL). Then the organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. If necessary, the product was puri-
fied by column chromatography on silica gel with EtOAc–petroleum
ether as the eluent.
Entry
R
t/h Yield/%b
M.p. /°Clit.
1
2
C6H5-
12
12
12
12
12
12
12
12
12
12
24
93
88
91
95
92
83
93
84
97c
90
67
125–126(125–127)29
159–160(161–163)29
164–167(166–167)30
177–179(178–180)31
135–136(135–137)31
139–140(140–141)31
190–193(190–192)32
154–156(153–154)32
198–200(199–201)30
182–184(182–183)32
104–106(102–104)30
4-MeC6H4-
4-MeOC6H4-
4-ClC6H4-
3-ClC6H4-
2-ClC6H4-
4-BrC6H4-
4-FC6H4-
3
4
5
6
7
Conversion of aldehydes into amides; general procedure
8
9
4-NO2C6H4-
4-CF3C6H4-
CH3(CH2)3-
Aldehyde (1 mmol), ammonia water (3 mL, 25–28% aqueous solution)
and TBHP (1.2 mmol, 70% aqueous solution) were added to a test
tube in air. Then the reaction mixture was stirred in an oil bath at
80 °C for an appropriate time as indicated by TLC. After the reaction
was complete, the mixture was cooled to room temperature, and the
solvent was removed under reduced pressure. The amide products
were isolated and purified by column chromatography on silica gel.
10
11
a Reaction conditions: aldehyde (1 mmol), NH3.H2O (3 mL),
TBHP (1.2 mmol), 80 °C.
b Isolated yields.
c CH3CN was the solvent.
Scheme 2

462 JOURNAL OF CHEMICAL RESEARCH 2012
11 S. Iida and H. Togo, Synlett, 2007, 407.
12 S. Iida and H. Togo, Synlett, 2008, 1639.
This project was funded by the Priority Academic Program
Development (PAPD) of Jiangsu Higher Education Institu-
tions.
13 R. Ghorbani-Vaghei and H. Veisi, Synthesis, 2009, 945.
14 J.M. Humphrey and A.R. Chanberlin, Chem. Rev., 1997, 97, 2243.
15 V.Y. Kukushkin and A.J.L. Pombeiro, Chem. Rev., 2002, 102,1771.
16 Y.S. Lin and H. Alper, Angew. Chem. Int. Ed., 2001, 40, 779.
17 S. Cho, E. Yoo, I. Bae and S. Chang, J. Am. Chem. Soc., 2005, 127,
16046.
Received 17 April 2012; accepted 17 May 2012
Paper 1201268 doi: 10.3184/174751912X13385625425135
Published online: 8 August 2012
18 N. Shangguan, S. Katukojvala, R. Greenberg and L.J. Williams, J. Am.
Chem. Soc., 2003, 125, 7754.
19 L. Yao and J. Aubé, J. Am. Chem. Soc., 2007, 129, 2766.
20 J.J. Ritter and P.P. Minieri, J. Am. Chem. Soc., 1948, 70, 4045.
21 I. Ugi, R. Meyr, U. Fetzer, and C. Steinbrückner, Angew. Chem., 1959, 71,
386.
22 K.R. Reddy, C.U. Maheswari, M. Venkateshwar and M.L. Kantam, Eur. J.
Org. Chem., 2008, 3619.
23 C. Gunanathan, Y.B. David and D. Milstein, Science, 2007, 317, 790.
24 K. Ekoue-Kovi and C. Wolf, Org. Lett., 2007, 9, 3429.
25 Y.Z. Zhu and C. Cai, Monatsh. Chem., 2010, 141, 637.
26 M. Hatsuda and M. Seki, Tetrahedron, 2005, 61, 9908.
27 Online data from product catalog Sigma-Aldrich. http://www.sigmaaldrich.
com/technical-service-home/product-catalog.html
28 C.J. Zhu, L. Ji and Y.Y. Wei, Synthesis, 2010, 3121.
29 S. Cacchi, D. Misiti and F. La Torre, Synthesis, 1980, 243.
30 J.J. Shie and J.M. Fang, J. Org. Chem., 2003, 68, 1158.
31 G.V. Baelen and B.U.W. Maes, Tetrahedron, 2008, 64, 5604.
32 N.A. Owston, A.J. Parker and J.M.J. Williams, Org. Lett., 2007, 9, 73.
33 K.R. Reddy, C.U. Maheswari, M. Venkateshwar, S. Prashanthi and
M.L. Kantam, Tetrahedron Lett., 2009, 50, 2050.
References
1
2
3
K. Friedrick and K. Wallensfels, The chemistry of the cyano group, ed.
Z. Rappoport. Wiley-Interscience: New York, 1970.
R.C. Larock, Comprehensive organic transformations, VCH: New York,
1989.
I. Johansson, Kirk-Othmer encyclopedia of chemical technology: amides,
fatty acids, ed. J.I. Kroschwitz, Wiley, Hoboken, 2004.
R. Chidambaram, Tetrahedron Lett., 2004, 45, 1441.
K.M. Marcantonio, L.F. Frey, Y. Liu, Y. Chen, J. Strine, B. Phenix,
D.J. Wallace and C.Y. Chen, Org. Lett., 2004, 6, 3723.
J.M. Williams and C.Y. Yang, Org. Lett., 2004, 6, 2837.
A.W. Franz, L.N. Popa, T. Li and T.J.J. Muller, Tetrahedron Lett., 2008, 49,
3300.
4
5
6
7
8
9
J.K. Augustine, R.N. Atta, B.K. Ramappa and C. Boodappa, Synlett, 2009,
3378.
J.-L. Zhu, F.-Y. Lee, J.-D. Wu, C.-W. Kuo and K.-S. Shia, Synlett, 2007,
1317.
10 E. Choi, C. Lee, Y. Na and S. Chang, Org. Lett., 2002, 4, 2369.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.