Highly Efficient Microwave-assisted One-Pot Synthesis of Aromatic Nitriles from Aromatic Aldehydes

Article abstract of DOI:10.1134/S1070428019050191

A highly efficient and environmentally benign protocol is described for the microwave-assisted one-pot synthesis of aromatic nitriles from aromatic aldehydes by the reaction with hydroxylamine hydrochloride in DMSO, which involves the intermediate formation of aldoximes and subsequent dehydration. The developed synthetic methodology can be readily accomplished with various aldehydes containing both electron-donor and electron-acceptor groups, providing excellent yields of the target products in shorter reaction times (1–2 min) compared to previously reported methodologies.

Full text of DOI:10.1134/S1070428019050191

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 5, pp. 702–706. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 5, pp. 817.
Highly Efficient Microwave-assisted One-Pot Synthesis
of Aromatic Nitriles from Aromatic Aldehydes
P. L. Pujaria, P. V. Thorata, A. B. Mahipala, and R. S. Bhondwea,*
a Post Graduate Department of Chemistry, Tuljaram Chaturchand College, Baramati, Maharashtra, 413102 India
*e-mail: r.s.bhondwe@gmail.com
Received December 7, 2018; revised December 15, 2018; accepted December 22, 2018
Abstract—A highly efficient and environmentally benign protocol is described for the microwave-assisted
one-pot synthesis of aromatic nitriles from aromatic aldehydes by the reaction with hydroxylamine
hydrochloride in DMSO, which involves the intermediate formation of aldoximes and subsequent dehydration.
The developed synthetic methodology can be readily accomplished with various aldehydes containing both
electron-donor and electron-acceptor groups, providing excellent yields of the target products in shorter
reaction times (1–2 min) compared to previously reported methodologies.
Keywords: microwave irradiation, aryl nitriles, green protocol, DMSO
DOI: 10.1134/S1070428019050191
toxic reagents, prolonged reaction time, low isolated
yields, and tedious workups. Searching for an efficient
and economical method for the synthesis of nitriles
starting from aromatic aldehydes, we initially screened
various conventional methods but often ended with
low selectivities and yields. Therefore, to obtain
sufficiently clean and pure products in good yields
remained as a challenge for us.
INTRODUCTION
Nitriles are widely used key intermediates in many
organic transformations. Due to the versatility of this
functional group, it has been used as a synthon for
preparing various functional derivatives, such as
amines, carboxylic acids, amides, aldehydes, etc. The
use of nitriles as key starting materials in the synthesis
of such pharmaceutically important heterocyclic
compounds as triazoles, oxazoles, imidazoles, and
others has also been reported [1, 9]. Furthermore, the
pharmacophore moieties of some important drug
molecules, for example, Letrozole (aromatase
inhibitor), Zaleplon, Vildagliptin, and Rilipivirine
(anti-HIV), Neratinib (anticancer), and Escitalopram
(antidepressant) contains nitrile as one of the
functional groups [14]. The synthesis of aromatic
nitriles is a well-documented topic [3–8]. One of the
common nitrile synthesis by transition metal−mediated
cyanation makes use of toxic reagents (NaCN, KCN,
CuCN, etc.) and leads to a build-up of the skeleton by
one carbon atom. An attractive alternative synthetic
approach to nitriles involves either dehydration of
aldoximes or conversion of aldehydes using
hydroxylamine hydrochloride [8–16]. However; many
of the reported protocols are not fully satisfactory and
feature some shortcomings, specifically, the use of
Recently, microwave-assisted organic transfor-
mations have gained considerable attention.
Microwave heating is a greener and an alternative
approach compared to conventional heating. Among
the reported microwave-assisted syntheses of aromatic
nitriles one employs iodine and aqueous ammonia [2],
while the other involves aminosulfonic acid and
alumina [5]. Both of these methods suffer from either
formation of an explosive intermediate (NI3·NH3) or
use of toxic reagents and additives. In the pursuit of a
better synthetic approach, we have developed simple,
rapid, and efficient one-pot green protocol for the
synthesis of aromatic nitriles by the reaction of
aromatic aldehydes with hydroxylamine hydrochloride
in DMSO under microwave irradiation.
RESULTS AND DISCUSSION
Initially, we selected 3-nitrobenzaldehyde 1b as the
starting compound to optimize the reaction conditions
702

HIGHLY EFFICIENT MICROWAVE-ASSISTED ONE-POT SYNTHESIS
Table 1. Optimization of reaction conditions
703
O2N
CN
O2N
CHO
O2N
OH
.
NH2OH HCl
N
+
1b
2b
3b
Yield, %a
Entry no.
Solvent
Co-oxidant
Temperature
Time
Nitrile 2
Oxime 3
90%
–
1
2
DMSO
DMSO
I2
I2
RT
4 h
6 h
ND
90–100°C
92%
3
4
5
DMSO
DMSO
DMSO
I2
–
MW (180W)
RT
60 s
4 h
94%
ND
NDb
50%
–
–
90–100°C
6 h
94%
6
7
8
DMSO
DMF
–
I2
–
MW (180W)
MW (180W)
MW (180W)
60 sec
80 sec
80 sec
98%
Trace
Trace
NDc
80%
85%
DMF
a
Isolated yield.
Not detected.
b
(Table 1). We started with the previously reported [6]
DMSO–I2 reaction system. The reaction with
hydroxylamine hydrochloride in the presence of
DMSO–I2 gave 3-nitrobenzaldoxime (3b) after stirring
for 4 h at room temperature (Table 1, entry 1), while
under conventional heating [16] at 100°C (Table 1,
entry 2) the target 3-nitrobenzonitrile 2b was detected
in the reaction mixture only after 6 h (TLC). To our
surprise, microwave irradiation at 180 W (with 15-s
intervals) led to the formation of nitrile 2b in an
excellent yield (94%) in as short as 60 s. Inspired by
these first results we investigated the necessity of
molecular iodine for this transformation. Surprisingly,
we found that even in absence of I2 (Table 1, entry 6)
3-nitrobenzonitrile was obtained in quantitative yield
and superior in color. To obtain evidence for the
necessity of DMSO for this transformation, we carried
out the reaction in the high- boiling aprotic polar
solvent DMF (Table 1, entries 7 and 8). The
subsequent FTIR analysis revealed formation of
aldoxime 3b and only traces of nitrile 2b. This result
confirmed the importance of DMSO for the conversion
of aldehydes to nitriles. Thus, we found that the best
conditions for the one-pot conversion of aromatic
aldehydes to nitriles were microwave irradiation at
180 W in a DMSO solvent. Further on we checked
whether the developed methodology works with
aromatic aldehydes containing electron-donor and
electron-acceptor substituents. Commercially available
aldehydes with various functional groups, such as OH,
OMe, NO2, and Cl, in the ortho-, meta-, and para-
positions, converted into corresponding nitriles in good
yields (Table 2). 2-Methoxynaphthalene-1-carbonitrile
2k was obtained in excellent yield (94%) starting with
2-methoxynaphthalene-1-carbaldehyde successfully
prepared from 2-methoxynaphthalene by the
Vilsmeier–Haack reaction. The methodology was
extended to heterocyclic aldehydes. Furfural gave 2-
furonitrile 2j in 68% yield and 3-(4-nitrophenyl)-1-
phenyl-1H-pyrazole-4-carbaldehyde 1l prepared by a
known procedure [23] was converted into 3-(4-
nitrophenyl)-1-phenyl-1H-pyrazole-4-carbonitrile 2l
in 90% yield. We found that all the aldehydes
irrespective of whether they contain electron-donor or
electron-acceptor substituents convert into the
corresponding nitriles in good- to-excellent yields
(Table 2).
The plausible reaction mechanism is shown below
(Scheme 1). Aldehyde 1 reacts with hydroxylamine
hydrochloride forms aldoxime 3 and HCl. The released
acid protonates DMSO to generate a hydroxy-
sulfonium salt (activated DMSO), whose reaction with
aldoxime 3 to form intermediate 4 and subsequent
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

PUJARI et al.
704
Table 2. Substrate and product scope for the synthesis of aromatic nitrilesa
O
.
NH2OH HCl
CN
2a_2l
R
H
R
DMSO, MW
1a_1l
Aldehyde no.
Nitrile no.
R
Time, s
75
Yield, %b
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
C6H5
86
98
85
90
90c
95
92
92
3-NO2C6H4
2-NO2C6H4
4-NO2C6H4
4-Cl C6H4
60
90
90
75
4-Br C6H4
2-OH C6H4
4-OMeC6H4
105
90
1g
1h
2g
2h
75
1i
2i
75
84
HO
OMe
1j
2j
75
90
68
94
O
OMe
1k
2k
NO2
N
1l
2l
75
90
N
a
b
c
Reaction conditions: aldehyde (1.0 equiv.), hydroxylamine hydrochloride (1.1 equiv), DMSO, 180 W.
Isolated yield.
Yield after recrystallization.
dehydration of the latter under microwave irradiation
CONCLUSIONS
affords nitrile 2.
In this study, FTIR spectroscopy played an
important role both in characterization of the interme-
diate products and in efficient optimization of the
reaction conditions. The FTIR spectrum of 3-nitroben-
zonitrile 2b displays a sharp band at 2233 cm–1, which
is a characteristic band of the C≡N group. Intermediate
3-nitroaldoxime 3b gives a broad band at 3300 cm–1
assignable to the oxime OH group. The incomplete con-
version is confirmed by the observation in the spectrum
of both the nitrile and oxime absorption bands.
In conclusion, we have successfully developed a
one-pot, highly efficient and green protocol for the
synthesis of aromatic nitriles starting from
commercially available aldehydes. This synthetic
technique makes use of an inexpensive solvent DMSO
and is cost effective, metal free, additive free,
operationally simple, and clean. Due to mild reaction
conditions and shorter reaction time, this method
works with many functional groups and provides high
yields of the target products.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

HIGHLY EFFICIENT MICROWAVE-ASSISTED ONE-POT SYNTHESIS
705
Scheme 1.
S
HCl
+
O
OH
O
H
S
O
N
Cl
N
S
.
OH
NH2OH HCl
OH
N
Ar
Ar
H
Ar
H
_H2O
Ar
3
4
2
1
EXPERIMENTAL
4-Chlorobenzonitrile (2e). Yield (98%), white
solid, mp 92–94°C (93–94°C [6]). IR spectrum, ν, cm–1:
The IR spectra were measured on a Shimadzu
IRAffinty-1S FTIR spectrophotometer. The 1H and 13C
NMR spectra were taken on a Bruker Avance II
400 MHz Spectrometer at 400 MHz at SAFE, Punjab
University, Chandigarh, India. The reactions were
performed in a Samsung CE104VD microwave oven.
2223 s (CN), 1594–1483 s (CHarom), 825 m (C–Cl).
4-Bromobenzonitrile (2f). Yield (90%), white
solid, mp 110–112°C (109–112°C [5]). IR spectrum, ν,
cm–1: 3080 w (CHarom), 2235 s (CN), 1703–1614 m
(C=N).
2-Hydroxybenzonitrile (2g). Yield (90%), brown
oil, bp 96–98°C (96–98°C [6]). IR spectrum, ν, cm–1:
3267 br (OH), 2227 s (CN), 1662–1504 s (CHarom),
1305 m (C–OH), 761 s (1,2-disubstituted benzene).
Synthesis of nitriles 2 (general procedure).
Hydroxylamine hydrochloride, 0.55 g (0.72 mmol)
was added to a solution of 0.5 g (0.66 mmol) aldehyde
1 in 3 mL of DMSO. The reaction mixture was
subjected to microwave irradiation at 180 W (with 15-s
intervals) for 60–120 s. Reaction progress was monored
by TLC on aluminum coated silica gel (ethyl
acetate:hexane, 1 : 4). After the reaction had been
complete, the reaction mixture was cooled to room
temperature and poured on crushed ice, the reaction
product was extracted in ethyl acetate, the extract was
dried over Na2SO4 and concentrated in a vacuum, and
the residue was recrystallized.
4-Methoxybenzonitrile (2h). Yield (90%), white
solid, mp 54–56°C (58–68°C [6]). IR spectrum, ν, cm–1:
3080 w (CHarom), 2235 s (CN), 1703–1614 m (C=N).
4-Hydroxy-3-methoxybenzonitrile (2i). Yield
(98%), yellow oil, bp 84–86°C (84–86°C [22]). IR
spectrum, ν, cm–1: 3379 br (OH), 2223 s (CN), 1592–
1516 m (CHarom), 1288 m (C–O).
Furan-2-carbonitrile (2j). Yield (68%), brown oil,
bp 144–146°C (146–147°C). IR spectrum, ν,
cm–1: 2227 s (CN), 1662–1504 s (CHarom), 1305 m
(C–OH).
Benzonitrile (2a). Yield 90%, colorless oil, bp
188–190°C (193°C [5]). IR spectrum, ν, cm–1: 2227 s
(CN), 1662–1504 s (CHarom), 1305 m (C–OH).
3-Nitrobenzonitrile (2b). Yield 0.460 g (95%),
white solid, mp 114–116°C (117–118°C [5]). IR
spectrum, ν, cm–1: 3080 m (CHarom), 2235 s (CN),
1703–1614 m (C=N), 1529–1350 s (NO2).
2-Methoxynaphthalene-1-carbonitrile (2k). Yield
(90%), white solid, mp 92–94°C. IR spectrum, ν, cm–1:
3080 m (CHarom), 2235 s (CN), 1703–1614 m (C=N).
1H NMR spectrum (400MHz, CDCl3), δ, ppm: 7.98–
8.00 d (1H, Harom, J 8.0 Hz), 7.92–7.94 d (1H, Harom, J
8.0 Hz), 7.73–7.75 d (1H, Harom, J 8.0 Hz), 7.54–7.58
d.d (1H, Harom, J 12.0 Hz), 7.36–7.40 d.d (1H, Harom, J
12.0 Hz), 7.16–7.18 d (1H, Harom, J 8.0 Hz), 3.99 s
(3H, OCH3). 13C NMR spectrum (400 MHz, CDCl3),
δ, ppm: 161.5 (ArC-OCH3), 135.3 (ArCH), 133.4
(ArCH), 129.1 (ArCH), 128.5 (ArCH), 127.8 (ArCH),
125.0 (ArCH), 123.8 (ArCH), 115.8 (CN), 111.9
(ArCH), 94.9 (ArC–CN), 56.5 (ArC–OCH3).
2-Nitrobenzonitrile (2c). Yield 98%, white solid,
mp 112°C (108–109°C [5]). IR spectrum, ν, cm–1:
3080 m (CHarom), 2228 s (CN), 1705–1616 m (C=N),
1539–1340 s (NO2).
4-Nitrobenzonitrile (2d). Yield (98%), white solid,
mp 144–146°C (146–148°C [5]). IR spectrum, ν, cm–1:
3080 m (CHarom), 2235 s (CN), 1703–1614 m (C=N),
1535–1340 s (NO2).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

PUJARI et al.
706
5. Juncai, F., Bin, L., Yang, L., and Li, C., Synth.
3-(4-Nitrophenyl)-1-phenyl-1H-pyrazole-4-
Commun., 1996, vol. 26, p. 4545.
carbonitrile (2l). Yield 0.460 g (95%), white solid, mp
162–164°C. IR spectrum, ν, cm–1: 3080 m (CHarom),
2235 s (CN), 1703–1614 m (C=N), 1529–1350 s
6. Gaikwad, D.D., Renukdas, S.V., Kendre, B.V.,
Shisodia, S.U., Borade, R.M., Shinde, P.S., Chaudhary, S.S.,
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vol. 74, p. 3079.
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1
(NO2). H NMR spectrum (DMSO-d6), δ, ppm: 9.49 s
(1H, Harom), 8.42–8.40 d (2H, Harom, J 8.0 Hz), 8.25–
8.23 d (2H, Harom, J 8.0 Hz), 7.96–7.94 d (2H, Harom, J
8.0 Hz), 7.57–7.61 d.d (1H, Harom, J 8.0 Hz),7.44–7.48
d.d (1H, Harom, J 8.0 Hz). 13C NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 150.3 (ArCNO2), 147.7 (ArC),
138.1 (ArC), 136.7 (ArC), 136.1 (ArC), 129.6 (ArC),
128.2 (ArC), 127.3 (ArC), 124.2 (ArC), 119.3 (ArCH),
113.7 (CN), 91.4 (ArC–CN), 79.1 (ArCH), 79.0
(ArCH), 78.8 (ArCH), 78.5 (ArCH) [24].
12. Fong, C. and Li, M., RSC Adv., 2017, vol. 7, p. 1484.
13. Aspinall, H.C., Beckingham, O., Farrar, M.D., Greeves, N.,
and Thomas, C.D., Tetrahedron Lett., 2011, vol. 52, p. 5120.
14. Ghosh, P. and Subba, R., Tetrahedron Lett., 2013, vol. 54,
p. 4885.
15. Chill, S.T. and Mebane, R.C., Synth. Commun., 2009,
vol. 39, p. 3601.
16. Augustine, J.K., Bombrun, A., and Atta, R.N., Synlett,
2011, p. 2223.
ACKNOWLEDGEMENTS
The authors express sincere gratitude to Principal,
Tuljaram Chaturchand College, Baramati, Head, and
P.G. Coordinator Department of Chemistry and ARC
T.C. College for facility and financial support. The
authors are also grateful to Director, SAFE, Punjab
1
13
University, Chandigarh, for H and C NMR analysis.
The IR spectrometer was purchased through a DST–
FIST grant.
17. Patil, U.B., Shendage, S.S., and Nagarkar, J.M.,
Synthesis, 2013, vol. 45, p. 3295.
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2016, vol. 138, p. 2885.
19. Hyodo, K., Kitagawa, S., Yamazaki, M., and Uchida, K.,
Chem. Asian J., 2016, vol. 11, p, 1348.
20. Kim, J.N., Chung, K.H., and Ryu, E.K., Synth.
Commun., 1990, vol. 20, p. 2785.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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