Cu(OAc)2/malononitrile/water: A simple reaction system for synthesis of aromatic nitriles from aldoximes

Article abstract of DOI:10.3184/174751918X15411700157951

A simple method for the preparation of nitriles in moderate to good yield has been achieved by treatment of aromatic and heterocyclic aldoximes with malononitrile in water at reflux in the presence of copper acetate as catalyst. Arylaldoximes with an electron-donating group showed the highest reactivity, their conversion being achievable at room temperature.

Full text of DOI:10.3184/174751918X15411700157951

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 DECEMBER, 595–597
RESEARCH PAPER 595
Cu(OAc)2/malononitrile/water: a simple reaction system for synthesis of
aromatic nitriles from aldoximes
Xiaoyun Ma*, Daqin He and Zhengjian Chen
School of Chemistry and Materials Science, Guizhou Education University, Guiyang 550018, P.R. China
A simple method for the preparation of nitriles in moderate to good yield has been achieved by treatment of aromatic and heterocyclic
aldoximes with malononitrile in water at reflux in the presence of copper acetate as catalyst. Arylaldoximes with an electron-donating
group showed the highest reactivity, their conversion being achievable at room temperature.
Keywords: nitrile, aldoxime, copper salt, malononitrile
Nitriles are important intermediates in organic synthesis and
numerousmethodsfortheirsynthesishavebeenreported.Among
these methods, the conversion of an aldoxime into a nitrile
is considered to be one of the most efficient and convenient
methods. Usually, this conversion is achieved either via the
dehydration of aldoximes using various dehydration reagents
such as acid anhydrides,1 thionyl chloride and its derivatives,2
acids,3 phosphorus-containing compounds,4 or by treating
aldoximes with a variety of metal catalysts, our interest being
in copper salts.5–11 Recently we reported the preparation of
aromatic and heterocyclic nitriles by treating the corresponding
aldehydes with hydroxylamine and CuO in refluxing MeCN.12
We now report an improved method in which the oximes
are not formed in situ but are used as starting materials and
malononitrile replaces acetonitrile, Cu(OAc)2 replaces CuO
and water is the solvent.
in 71% yield (Table 1, entry 3). Increasing the amounts of
malononitrile (from 0.5 to 1.0 equiv.) inhibited the formation
of by-products (benzaldehyde and benzamide) leading to an
increased yield of benzonitrile of 84% (Table 1, entry 4). As
well as Cu(OAc)2·H2O, the catalytic activities of other copper
salts and NiCl2·6H2O were also examined (Table 1, entries 5–9).
These metal salts showed some level of catalytic activity, but
the catalytic activities were inferior to that of Cu(OAc)2·H2O. In
the case of CuCl2·2H2O, benzaldoxime disappeared in 1.5 h, but
the selectivity for nitrile formation was relatively lower (Table
1, entry 7). CuO and NiCl2·6H2O exhibited poor catalytic
activities, benzonitrile being obtained in low yield and most
of the benzaldoxime remained unreacted (Table 1, entries 8 and
9).
On the basis of the above results, we could conclude that
the optimal conditions for the conversion of benzaldoxime
to benzonitrile is by treatment with Cu(OAc)2·H2O and
malononitrile in water at reflux for 1–2 h. This optimum
method was then applied to other aryl and heteroaryl aldoximes
(1; R = various) and the yields of the corresponding nitriles (2;
R = various) are shown in Table 2. Substrates bearing strong
electron-donating groups showed relatively high reactivity and
the reaction could be completed within 60 min (Table 2, entries
2–4). In contrast, the conversion of aldoximes with an electron-
withdrawing group required a longer time (Table 2, entries 7
and 8). In the case of 4-(dimethylamino)benzaldoxime, use
of ethanol in place of water could reduce the generation of by-
products and improve the product yield (Table 2, entry 3). An
Results and discussion
For our optimisation studies, we selected benzaldoxime (1; R =
Ph) as a model substrate to investigate the influence of ratio of
reactants and various metal salts on the yields of benzonitrile
(2; R = Ph) (Scheme 1). The results are listed in Table 1. As
shown in the table, use of copper(II) acetate alone resulted
in no product and the yield of benzonitrile is very low when
malononitrile was used alone (Table 1, entries 1 and 2). When
both Cu(OAc)2·H2O and malononitrile were used, the reaction
was completed within 2 h and benzonitrile was obtained
NOH
conditions
N
Table 2 Yields of a series of nitriles (2; R = various) prepared by reaction
of an aldoxime (1; R = various) with malononitrile in the presence of
Cu(OAc)2 in water (Scheme 1)a
R
R
H
H
reflux
2O,
1
2
Entry Nitrile
R
Time (h)
Yield (%)b
Scheme 1
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
1.5
1
1
84
86
75c
83
78
85
80
91d
88
Table 1 Optimisation of the reaction conditions (catalyst, duration of
reaction) for the conversion of benzaldoxime (1a; R = Ph) to benzonitrile
(2a; R = Ph) (Scheme 1)a
Entry Malononitrile (equiv.) Catalyst (0.05 equiv.) Time (h) Yield (%)b
4-MeO–C6H4
4-N(CH3)2–C6H4
4-OH–C6H4
4-Me–C6H4
3-MeO–4-MeO–C6H3
4-NO2–C6H4
2-Cl–C6H4
(E)-C6H5–CH=CH
9-Anthryl
4-Pyridyl
1
1.5
1.5
2
1
2
3
4
5
6
7
8
9
–
Cu(OAc)2·H2O
–
2
6
0
5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(NO3)2·3H2O
CuSO4·5H2O
CuCl2·2H2O
CuO
1.5
1.5
1.5
1.5
1.5
1.5
1.5
71
84
75
73
55
30
39
2
9
1.5
1.5
2
10
11
12
2j
2k
2l
87
81
63
2-Thienyl
1
aReaction conditions: a stirred mixture of an oxime (2 mmol), malononitrile (2 mmol) and
Cu(OAc)2 (0.1 mmol) in water (8 mL) was refluxed for various times.
bIsolated yield.
cEthanol was used in place of H2O.
d4 mmol malononitrile was used.
NiCl2·6H2O
aReaction conditions: a stirred mixture of benzaldoxime (1a; R = Ph), malononitrile and a
catalyst in water (8 mL) was reacted for various times.
bIsolated yield.
* Correspondent. E-mail: maxiaoyun821215@163.com

596 JOURNAL OF CHEMICAL RESEARCH 2018
Table 3 Yields of a series of nitriles containing electron-attracting groups (2;
R=various)preparedbyreactionofthecorrespondingaldoxime(1;R=various)
with malononitrile and Cu(OAc)2 (Scheme 1)a
Experimental
Reagent grade chemicals were purchased from Aladdin Reagent
(Shanghai, P.R. China) and were used without further purification.
Melting points were determined on a Thomas Hoover capillary
apparatus and were uncorrected. NMR spectra were obtained on a
Bruker DPX-500 or a DPX-400 spectrometer (1H NMR at 500 or
400 Hz, 13C NMR at 125 or 100 Hz) in CDCl3 or DMSO-d6 using TMS
as internal standard. Chemical shifts (δ) are given in ppm and coupling
constants (J) are given in hertz (Hz). Thin layer chromatography
(TLC) was performed on precoated silica gel 60 F254 plates. Yields
refer to the isolated yields of the products after purification by silica-
gel column chromatography (300 mesh). Aldoximes were synthesised
according to a literature method.16 All the nitriles are known
compounds and they were characterised by melting points or NMR
spectra.
Entry
Nitrile
2b
2c
2d
2f
R
Yield (%)b
1
2
3
4
5
4-MeO–C6H4
4-N(CH3)2–C6H4
4-OH–C6H4
3-MeO–4-MeO–C6H3
2-Thienyl
81
70
80
77
56
2l
aReaction conditions: a stirred mixture of an aldoxime (2 mmol), malononitrile (4 mmol)
and Cu(OAc)2 (0.10 mmol) in EtOH/water (1:1) (8 mL) was allowed to react at 25 °C for
24 h.
bIsolated yield.
N
Synthesis of nitriles; general procedure
C
N
C
Cu2+
N
C
Aldoxime (2 mmol), Cu(OAc)2·H2O (0.1 mmol), malononitrile
(2 mmol) and H2O (8 mL) were added to a 25 mL round-bottom flask
equipped with a magnetic stirrer. The mixture was heated to reflux for
1–2 h. After cooling to room temperature, ethyl acetate (30 mL) was
added to the reaction mixture. The separated organic layer was washed
with saturated aqueous sodium bicarbonate (1 × 15 mL) and water
(1 × 15 mL) and then dried with Na2SO4 and evaporated. The residue
was purified by column chromatography on silica gel (ethyl acetate/n-
hexane) to give the corresponding nitriles.
NOH
H
malononitrile
H
HO
Ph
Cu(OAc)2 H2O
N
O
Ph
CN
H2N
Scheme 2
ortho substituent appears to have an effect on the yield of the
reaction; two equiv. of malononitrile were used to avoid the
formation of aldehyde by-product when 2-chlorobenzaldoxime
was converted to the corresponding nitrile (Table 2, entry 8).
Thiophene-2-carbaldehyde oxime showed high reactivity and
the reaction was completed after a relatively short reaction
time of 1 h. However, in this case, the corresponding nitriles
were obtained in relatively low yields and the yield of the
corresponding amide was appreciable (Table 2, entry 12).
In addition, it should be noted that aliphatic aldoximes could
not effectively be converted to the corresponding nitriles
in this reaction system; various by-products were formed and
separation was difficult.
In the course of the study on conversion of aldoximes with
electron-donating groups to the corresponding nitriles, we
found that the conversion of these aldoximes could be achieved
at room temperature. As shown in Table 3, treatment of such
aldoximes with Cu(OAc)2·H2O and malononitrile (2.0 equiv.)
in a mixed solvent of ethanol and water at room temperature for
a relatively long time (24 h) gave nitriles in moderate to good
yield.
Benzonitrile (2a): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:15) to give
benzonitrile as a colourless liquid (173 mg, 84%); 1H NMR (400 MHz,
CDCl3): δ 7.48 (t, J = 8.0 Hz, 2H), 7.61 (m, 1H), 7.66 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 112.5, 118.8, 129.1, 132.1, 132.7. The
1H and 13C NMR data of this compound are in good agreement with the
reported data.17
4-Methoxybenzonitrile (2b): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:4) to give
4-methoxybenzonitrile as a white solid (229 mg, 86%); m.p. 57–58 °C
(lit.2 m.p. 58 °C); 1H NMR (500 MHz, CDCl3): δ 3.87 (t, J = 5.0 Hz, 3H),
6.96 (m, 2H), 7.60 (m, 2H);13C NMR (125 MHz, CDCl3): δ 55.5, 104.0,
114.8, 119.2, 133.9, 162.9. The 1H and 13C NMR data of this compound
are in good agreement with the reported data.18
4-(Dimethylamino)benzonitrile (2c): The residue was purified by
column chromatography on silica gel (ethyl acetate/n-hexane = 1:10) to
give 4-(dimethylamino)benzonitrile as a white solid (219 mg, 75%); m.p.
71–73 °C (lit.5 m.p. 70–72 °C); 1H NMR (500 MHz, CDCl3): δ 3.05 (t, J
= 5.0 Hz, 6H), 6.64 (m, 2H), 7.47 (m, 2H);13C NMR (125 MHz, CDCl3):
δ 39.9, 97.5, 111.5, 120.6, 133.3, 152.5. The 1H and 13C NMR data of this
compound are in good agreement with the reported data.17
4-Hydroxybenzonitrile (2d): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:3) to give
4-hydroxybenzonitrile as a white solid (198 mg, 83%); m.p. 110–112 °C
(lit.19 m.p. 110 °C); 1H NMR (500 MHz, DMSO-d6): δ 6.91 (m 2H), 7.65
(m, 2H), 10.61 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 102.9, 116.5,
119.3, 134.3, 160.4. The 1H and 13C NMR data of this compound are in
good agreement with the reported data.17
4-Methylbenzonitrile (2e): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:10) to give
4-methylbenzonitrile as an oil (183 mg, 78%); 1H NMR (500 MHz, CDCl3):
δ 2.43 (d, J = 3.0 Hz, 3H), 7.28 (m, 2H), 7.55 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 21.8, 109.4, 119.1, 129.8, 132.0, 143.7. The 1H and 13C NMR data
of this compound are in good agreement with the reported data.17
Regarding the mechanism of the reaction, we thought that
the reaction mechanism is likely to be similar to that reported
previously.5,6,12–15 A proposed mechanism is shown in Scheme
2. The coordination of malononitrile to copper ion results in an
enhanced electrophilicity of the nitrile carbon facilitating the
nucleophilic addition of benzaldoxime, the resulting complex
disproportionating to give benzonitrile and 2-cyanoacetamide.
It is noteworthy that the two nitrile groups are equivalent in
malononitrile and the nitrile group in 2-cyanoacetamide may
also react with aldoxime.
Conclusions
In conclusion, we describe a simple method for the conversion
of aldoximes to nitriles in an environmentally friendly aqueous
media by the combined use of a copper salt as catalyst and
malononitrile. Using this method aldoximes, including aromatic
aldoximes and heterocyclic aldoximes, were converted into
the corresponding nitriles in moderate to good yield. Some as
aldoximes having electron-donating groups could be converted
into the corresponding nitriles at room temperature.
3,4-Dimethoxybenzonitrile (2f): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:6) to give
3,4-dimethoxybenzonitrile as a white solid (277 mg, 85%); m.p.
66–67 °C (lit.20 m.p. 65–66 °C); 1H NMR (500 MHz, CDCl3): δ 3.91 (d, J
= 3.0 Hz, 3H), 3.94 (d, J = 2.5 Hz, 3H), 6.91 (dd, J1 = 8.0 Hz, J2 = 3.0 Hz,
1H), 7.08 (m, 1H), 7.29 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 56.07,
56.13, 103.9, 111.3, 114.0, 119.2, 126.4, 149.2, 152.9. The 1H and 13C NMR
data of this compound are in good agreement with the reported data.17

JOURNAL OF CHEMICAL RESEARCH 2018 597
Acknowledgement
This work was supported by the Construction Project of Key
Laboratories from the Education Department of Guizhou Province
(Grant Nos QJHKY[2015]329 and QJHKY[2018]001).
4-Nitrobenzonitrile (2g): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:5) to give
4-nitrobenzonitrile as a white solid (236 mg, 80%); m.p. 146–147 °C
(lit.21 m.p. 148 °C); 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.4 Hz,
2H), 8.36 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 116.8,
118.3, 124.3, 133.5, 150.1. The 1H and 13C NMR data of this compound
are in good agreement with the reported data.17
Received 23 October 2018; accepted 29 October 2018
Paper 1805714
https://doi.org/10.3184/174751918X15411700157951
Published online: 22 November 2018
2-Chlorobenzonitrile (2h): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:15) to give
2-chlorobenzonitrile as a white solid (250 mg, 91%); m.p. 43–44 °C
(lit.18 m.p. 42.1–43.8 °C); 1H NMR (400 MHz, CDCl3): δ 7.38 (m, 1H),
7.54 (m, 2H), 7.68 (m, 1H);13C NMR (100 MHz, CDCl3): δ 113.5, 115.9,
References
1
R.G. Kalkhambkar, S.D. Bunge and K.K. Laali, Tetrahedron Lett., 2011,
52, 5184.
1
127.1, 130.0, 133.8, 134.0, 136.9. The H and 13C NMR data of this
compound are in good agreement with the reported data.17
2
3
4
D. Patil and D. Dalal, Synth. Commun., 2013, 43, 118.
D. Li, F. Shi, S. Guo and Y. Deng, Tetrahedron Lett., 2005, 46, 671.
X.-L. Zhang, S.-R. Sheng, M.-H. Wei and X.-L. Liu, Phosphorus Sulfur,
2017, 192, 513.
(E)-Cinnamonitrile (2i): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:10) to give
1
(E)-cinnamonitrile as an oil (227 mg, 88%); H NMR (400 MHz,
5
6
7
M. Zarghani and B. Akhlaghinia, Appl. Organomet. Chem., 2015, 29, 683.
Á. Kiss and Z. Hell, Synth. Commun., 2013, 43, 1778.
G. Saidulu, N. Anand, K. Rao, A. Burri, S.-E. Park and D. Burri, Catal.
Lett., 2011, 141, 1865.
CDCl3): δ 5.89 (d, J = 16.8 Hz, 1H), 7.39–7.46 (m, 6H); 13C NMR (100
MHz, CDCl3): δ 96.4, 118.1, 127.3, 129.1, 131.2, 133.6, 150.5. The 1H and
13C NMR data of this compound are in good agreement with the reported
data.17
8
9
N. Jiang and A.J. Ragauskas, Tetrahedron Lett., 2010, 51, 4479.
O. Attanasi, P. Palma and F. Serra-Zanetti, Synthesis, 1983, 741.
Anthracene-9-carbonitrile (2j): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:10) to give
anthracene-9-carbonitrile as an orange solid (353 mg, 87%); m.p.
174–175 °C (lit.22 m.p. 175–176 °C); 1H NMR (400 MHz, CDCl3): δ 7.57
(m, 2H), 7.70 (m, 2H), 8.05 (d, J = 8.4 Hz, 2H), 8.40 (d, J = 8.8 Hz, 2H),
8.64 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 105.4, 117.2, 125.2, 126.3,
10 X.-Y. Ma, Y. He, T.-T. Lu and M. Lu, Tetrahedron, 2013, 69, 2560.
11 X. Ma and M. Lu, J. Chem. Res., 2016, 40, 594.
12 X. Ma, J. Ao, Z. Chen and Y. Liu, J. Chem. Res., 2017, 41, 465.
13 J. Francos, P.J. González-Liste, L. Menéndez-Rodríguez, P. Crochet, V.
Cadierno, J. Borge, A. Antiñolo, R. Fernández-Galán and F. Carrillo-
Hermosilla, Eur. J. Inorg. Chem., 2016, 2016, 393.
14 H.S. Kim, S.H. Kim and J.N. Kim, Tetrahedron Lett., 2009, 50, 1717.
15 A.V. Makarycheva-Mikhailova, N.A. Bokach, M. Haukka and V.Y.
Kukushkin, Inorg. Chim. Acta, 2003, 356, 382.
1
128.87, 128.91, 130.6, 132.6, 133.2. The H and 13C NMR data of this
compound are in good agreement with the reported data.17
Isonicotinonitrile (2k): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:1) to give
isonicotinonitrile as a white solid (169 mg, 81%); m.p. 76–77 °C (lit.23
m.p. 77–78°C); 1H NMR (500 MHz, CDCl3): δ 7.55 (m, 2H), 8.84 (m,
2H); 13C NMR (125 MHz, CDCl3): δ 116.3, 120.4, 125.2, 150.8. The 1H
and 13C NMR data of this compound are in good agreement with the
reported data.17
Thiophene-2-carbonitrile (2l): The residue was purified by column
chromatography on silica gel (ethyl acetate/n-hexane = 1:15) to give
thiophene-2-carbonitrile as a colourless liquid (137 mg, 63%); 1H NMR
(500 MHz, CDCl3): δ 7.14 (m, 1H), 7.63 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 110.0, 114.2, 127.6, 132.5, 137.4. The 1H and 13C NMR data of
this compound are in good agreement with the reported data.17
16 R.S. Ramon, J. Bosson, S. Díez-González, N. Marion and S.P. Nolan, J.
Org. Chem., 2010, 75, 1197.
17 National Institute of Advanced Industrial Science and Technology, Spectral
database for organic compounds SDBS. http://sdbs.db.aist.go.jp/sdbs/cgi-
bin/direct_frame_top.cgi [accessed 5 November 2018].
18 Z. Dongliang, H. Yaping, Z. Erlei, Y. Rong, C. Chao, Y. Lei and X. Qing,
Adv. Synth. Catal., 2018, 360, 784.
19 S.K. Dewan and R. Singh, Synth. Commun., 2003, 33, 3085.
20 E.-C. Wang, K.-S. Huang, H.-M. Chen, C.-C. Wu and G.-J. Lin, J. Chin.
Chem. Soc., 2004, 51, 619.
21 N. Lingaiah and R. Narender, Synth. Commun., 2002, 32, 2391.
22 H.M.S. Kumar, P.K. Mohanty, M.S. Kumar and J.S. Yadav, Synth.
Commun., 1997, 27, 1327.
23 A. Leggio, E.L. Belsito, S. Gallo and A. Liguori, Tetrahedron Lett., 2017,
58, 1512.