p-TsOH mediated solvent and metal catalyst free synthesis of nitriles from aldehydes via Schmidt reaction

Article abstract of DOI:10.1016/j.tetlet.2017.04.100

A new and efficient protocol for the conversion of aldehyde into nitriles by modified Schmidt reaction. The reaction is carried out under solvent free condition using sodium azide as a source of nitrogen and catalysed by p-toluene sulphonic acid in presence of silica surface with no side product. This transformation gives good to excellent yield for numerous aromatic, aliphatic and heterocyclic nitriles using very simple reagent. This method has avoided the use of transition metal catalyst, toxic cyanide, hazardous solvent and offers a greener, simple and environment friendly procedure.

Full text of DOI:10.1016/j.tetlet.2017.04.100

Accepted Manuscript
p-TsOH mediated solvent and metal catalyst free Synthesis of Nitriles from
Aldehydes via Schmidt Reaction
Bijeta Mitra, Gyan Chandra Pariyar, Rabindranath Singha, Pranab Ghosh
PII:
S0040-4039(17)30563-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.100
TETL 48892
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
30 March 2017
22 April 2017
29 April 2017
Please cite this article as: Mitra, B., Pariyar, G.C., Singha, R., Ghosh, P., p-TsOH mediated solvent and metal catalyst
free Synthesis of Nitriles from Aldehydes via Schmidt Reaction, Tetrahedron Letters (2017), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2017.04.100
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p-TsOH mediated solvent and metal catalyst free SL ye na vt he et hs ii ss a or ef a Nb il ta rn ikl ef so rf ra bo smt ra Ac tl idn ef oh .y des
via Schmidt Reaction
Bijeta Mitra, Gyan Chandra Pariyar, Rabindranath Singha, Pranab Ghosh*
O
NaN , p-TsOH
3
0
R
N
silica, 120 C
R
H
6
9-90%
R= aryl, aliphatic, napthyl, heterocyclic

1
Tetrahedron Letters
journal homepage: www.els evier.com
p-TsOH mediated solvent and metal catalyst free Synthesis of Nitriles from
Aldehydes via Schmidt Reaction
Bijeta Mitra, Gyan Chandra Pariyar, Rabindranath Singha, Pranab Ghosh*
Department of Chemistry, University of North Bengal, Dt. Darjeeling, West Bengal, India.
Tel.: +91 (0353) 2776381; fax: +91 (0353) 2699001.
E-mail address: pizy12@yahoo.com (P. Ghosh).
ARTICLE INFO
ABSTRACT
Article history:
Received
A new and efficient protocol for the conversion of aldehyde into nitriles by modified Schmidt
reaction. The reaction is carried out under solvent free condition using sodium azide as a source
of nitrogen and catalysed by p-toluene sulphonic acid in presence of silica surface with no side
product. This transformation gives good to excellent yield for numerous aromatic, aliphatic and
heterocyclic nitriles using very simple reagent. This method has avoided the use of transition
metal catalyst, toxic cyanide, hazardous solvent and offers a greener, simple and environment
friendly procedure.
Received in revised form
Accepted
Available online
Keywords:
Aldehyde
Nitrile
Sodium azide
p-toluene sulphonic acid
Silica
2017 Elsevier Ltd. All rights reserved.
2
The well known Schmidt reaction has been used as a
0
Introduction
synthetic tool to convert ketone and carboxylic acid to their
21
Organonitrile derivatives have diverse utility as bioactive
1
molecules (figure.1). They act as a precursor and intermediate
22
corresponding amide
aldehydes are converted to a mixture of formanilides and nitrile
and amine
respectively whereas
2
for pharmaceuticals, agrochemicals, polymers, dye etc. In
23
Scheme 1) . Schmidt reactions of aldehydes have limitations
(
addition its usefulness has been widely recognized as a functional
group in organic synthesis. Several preparations like alcohol,
due to the formation of mixture although it is great for ketones
and acids. In this reaction, the amounts of the two products
3
amine, ester, amide including many heterocyclic compounds
23
depend on the amount of the sulphuric acid used . So, selectivity
of Schmidt reaction of aldehydes to one of the two possible
such as 1,2-diarylimidazol, thiazole, tetrazole etc can be carried
out using suitable nitrile precursors.
24
products is very important. Preparation of nitrile from aldehyde
by this method has also been reported previously by using triflic
2
acid.
Classical method for nitrile synthesis are Sandmeyer
5
4
5
6
reaction , ammoxidation of aldehydes , Kolbe nitrile synthesis ,
7
hydrocyanation of alkenes and Rosenmund-von Braun reaction.
8
9
Nitrile can be prepared from alcohol , amines, amides,
10
11
1
azides and carbonyls this include oxidative rearrangement of
2
13
O
NC
CN
H
N
CN
1
4
15
16
Et
2
N
S
alkene, methyl arenes and benzyl or allyl halides, but these
methods result in the corresponding higher homologs. Literature
survey also reveals that aldehydes get converted into nitrile by
HO
HO
O
O
N
N
N
NO
2
1
7
NC
using hydroxyl amine hydrochloride in presence of FeCl
1
3
or
-CTAB NPs . It was also prepared from
OH
8
Tanaproget
CN
also in presence of Fe
oxime by using FeCl
3
O
4
Entacapono
Lersivirine
1
9
3
in silica surface
N
Me Me
HN3
N
N
N
N
CN
MeO
Me
CN
R CHO
R NHCHO + R CN
MeO
MeO
N
N
S
H SO
2
O
4
Scheme 1. Schmidt reaction
MeO
Cyamemazine
Zaleplon
Verapamil
_
_________
Corresponding author. Tel.: +91(0353) 2776381; fax: +91(0353)
699001; e-mail: pizy12@yahoo.com (P. Ghosh).
Fig 1. potent bioactive organonitrile derivative
∗
2

2
Tetrahedron Letters
One pot synthesis promises numerous advantages in
2
economical and environment aspects as in one pot synthesis
observed that with increasing the amount of acid, the yield of
the products get increased. When the reaction was performed
with 1 mmol of acid the yield was only 31%, but when the
reaction was proceeded with 3 mmol of p-TsOH yield of
product was 88% (entry 3, table 2). So, the sharp increase in the
yield of nitrile with increase in the amount of p-TsOH indicated
that the reaction was acid catalysed.
6
there is no need of separating intermediate which help to reduce
the energy consumption, solvent waste and reaction time.
Although, as per literature survey, a large number of protocol has
been reported, it is evident that most of the one pot synthesis
suffer from use of metal catalyst, harsh reaction conditions,
longer reaction time, low yield, work-up difficulties and waste of
toxic metal salt or solvents.
Table 2.
In most of the protocol metal salts are used as a
1
7,18,19
a
0
Optimisation of p-TsOH at 120 C
catalyst
which gives toxic metal at the end of the reaction
b
and sometimes it leads to metal contamination which may not be
desired. We have thus concentrated our investigation in
generating a metal free protocol for this purpose. The use of
silica is often considered as a green approach. In recent years,
silica is used as a reaction medium in many organic reactions to
avoid hazardous solvent which may cause chemical pollution. In
other words, silica gel is non-toxic and has a high thermal and
chemical stability.
Entry
p-TsOH(mmol)
Time(h)
Yield(%)
1
2
3
1
2
3
3
3
3
31
48
88
a
3
Reaction of aldehyde (1 mmol), NaN (2 mmol), p-TsOH (1-3 mmol) in
silica gel 60-120 mesh (1g) on magnetic stirrer.
b
NaN , p-TsOH
3
Isolated yield
R CHO
0
R CN
silica, 120 C
Table 3.
R= aryl, aliphatic, napthyl, heterocyclic
a
p-TsOH catalysed synthesis of nitrile
Aldehyde
Scheme 2. p-TsOH catalysed nitrile synthesis from aldehyde
b
Entry
Time (h)
Product
Yield(%)
CHO
CN
1
3.5
86
HO
HO
Therefore, we have developed a metal catalyst free and
solvent free solid supported method to prepare nitrile from
aldehyde devoid of side product and moreover it is cost efficient,
environment friendly and has high functional group tolerance
OMe
OMe
CHO
CN
2
4
74
O
2
N
2
O N
CHO
CHO
CN
CN
3
4
3
90
77
(
Scheme 2).
3.5
Result and Discussion
NO
2
NO
2
OH
OH
CN
5
3
88
For the reaction protocol, o-vanillin was taken as the starting
material. The model reaction comprising of o-vanillin (1 mmol),
sodium azide (2 mmol) in silica (1g) at room temperature gave
no product both in absence and presence of the acid even after
CHO
OMe
OMe
CHO
CN
6
7
3
83
85
2
4h (entry 1, 2 table 1). The same reaction when carried out in
presence of 3 mmol p-TsOH, increased the yield upto 42%
entry 3, table 1). Finally we optimized the reaction temperature
HO
HO
CHO
OH
CN
OH
3.5
(
0
to obtain 88% of the product in 3h at 120 C and when the same
reaction was carried out in absence of acid, no product was
CHO
CHO
CN
8
9
3
2
2
81
79
81
Me
2
N
2
Me N
Table 1.
CN
a
Optimisation of temperature
0
Temperature( C)
MeO
MeO
b
Entry
Time(h)
p-TsOH(mmol)
Yield(%)
CHO
CN
1
0
1
2
3
4
5
6
RT
RT
50
24
24
9
Nil
3
-
-
CHO
CN
11
1.5
2
85
79
69
3
42
68
88
-
1
1
2
3
CHO
CN
90
5
3
O
O
CHO
CN
4
120
120
3
3
10
Nil
14
3
5
76
-
CHO
CN
a
Reaction of aldehyde (1 mmol), NaN (2 mmol) in presence of p-TsOH as
well as in absence of the acid and silica gel 60-120 mesh (1g) on magnetic
stirrer
3
COCH3
1
1
5
6
No reaction
No reaction
COCH
3
5
-
b
Isolated yield
HO
a
3
Reaction condition: Aldehyde (1 mmol), NaN (2 mmol), p-TsOH (3 mmol)
0
and silica gel 60-120 mesh (1g) on a magnetic stirrer at 120 C at different
formed even after 10h. So, the reaction is catalysed by p-toluene
sulphonic acid which is shown in table 2. Further, it was
time interval.

3
b
Isolated yield
Supplementary Data
Supplementary data associated with this article can be found,
in the online version, at
Finally the optimised reactant ratio and condition showed that
aldehyde (1 mmol), sodium azide (2 mmol) , p-TsOH (3 mmol)
0
and silica gel mesh 60-120 (1g) at 120 C to be the best
combination to furnish maximum yield of the desired product
(
90%) in 3 h (entry 4, Table 3). No side product was obtained
References and notes
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acid are soluble in water, product separation is much easier. For
the generalisation of our scheme, aldehyde 1-14 was successfully
converted to their corresponding nitriles under the optimised
reaction condition. Aldehydes such as heterocyclic aldehydes
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C.; Chow, H.-F.; Wong, K.-B. Eur. J. Med. Chem. 2013, 59, 1–6.
(
entry 12, table 3), aliphatic aldehydes
(entry 14, table 3),
aldehyde with napthyl moiety both 1 and 2 position (entry 10,11,
table 3) furnished good yield. Aromatic aldehyde having both
electron withdrawing (entry 4, table 3) and electron donating
group (entry 8, table 3) give good yield. But when same reaction
was carried out with acetophenone (entry 15, table 3) and its
derivative no nitrile was obtained. Therefore, it can be concluded
that the reaction is highly selective for aldehyde.
2
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Plausible mechanism for p-TsOH catalysed one pot synthesis
of nitrile from aldehyde was shown in scheme 3. At first p-TsOH
3 3
reacts with NaN and produces HN , then p-TsOH activate the
4
2
414–4422; (d) Bosch, L.; Vilarrasa, J. Angew. Chem., Int. Ed.
007, 46, 3926–3930; (e) Aureggi, V.; Sedelmeier, G. Angew.
carbonyl carbon, afterwards nucleophilic attack done by HN
3
.
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desired product.
2
O
R
gives the
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-
2
H O
p-TSA
HN3
1
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1
480–1483; (b) Ghorbani-Vaghei, R.; Veisi, H. Synthesis. 2009,
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-
N2
H
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N
H
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2
N
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CHO
6
2
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011, 76, 4606–4610.
1
4. (a) Shargi, H.; Sarvari, M. H. Synthesis 2003, 243–246; (b) Zhu,
J.-L.; Lee, F.-Y.; Wu, J.-D.; Kuo, C.-W.; Shia, K.-S. Synlett 2007,
Scheme 3. Plausible mechanism for the fomation of nitrile from aldehyde
1
317–1319; (c) Augustine, J. K.; Atta, R. N.; Ramappa, B. K.;
Boodappa, C. Synlett. 2009, 3378–3382 (d) Sridhar, M.; Reddy,
M. K. K.; Sairam, V. V.; Raveendra, J.; Godala, K. R.; Narsaiah,
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Conclusion
11943–11948; (f) Erman, M. B.; Snow, J. W.; Williams, M. J.
Tetrahedron Lett. 2000, 41, 6749–6752; (g) Carmeli, M.; Shefer,
N.; Rozen, S. Tetrahedron Lett. 2006, 47, 8969–8972; (h)
Telvekar, V. N.; Patel, K. N.; Kundaikar, H. S.; Chaudhari, H. K.
Tetrahedron Lett. 2008, 49, 2213–2215; (i) Sharghi, H.; Sarvari,
M. H. Tetrahedron. 2002, 58, 10323–10328; (j) Reddy, K. R.;
Maheswari, C. U.; Venkateshwar, M.; Prashanthi, S.; Kantam, M.
L. Tetrahedron Lett. 2009, 50, 2050–2053.
In conclusion, we have developed a solvent free and metal
catalyst free method to prepare nitrile from aldehyde, sodium
azide, p-TsOH in silica medium using the Schmidt reaction
protocol. Advantages of the protocol include cost efficiency, use
of no transition metal, no toxic cyanide, functional group
tolerance, environment friendly, simple work up process and no
side product.
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1
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Acknowledgments
One of the authors (BM) is thankful to CSIR, New Delhi, for
financial support.
2
2
0. Ghosh, P.; Pariyar, C.G.; Saha, B.; Subba, R. Synlett. 2016,
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1. (a) Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511. (b) Schmidt,
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V. A.; Gidaspov, B. V. Russ. Chem. Rev. 1978, 47, 1084.

4
Tetrahedron Letters
2
2. Smith, P. A. S.; Horwitz, J. P. J. Am. Chem. Soc. 1950, 72, 3718
mesh (1g) in mortar and pestle. The resultant solid mixture was
poured into a round-bottom flask (50 ml) and allowed to stir on
magnetic stirrer at 120° for an appropriate time. The progress of
the reaction was monitored by thin-layer chromatography (TLC).
After completion of the reaction, the reaction mixture was
extracted with ethyl acetate (4×15 ml) and washed several times
with water. The combined organic mixture dried over anhydrous
2
2
3. Datta, S. K.; Grundmann, C.; Bhattacharyya, N. K. J. Chem. Soc.
C 1970, 2058. McEwen, W. E.; Conrad, W. E.; Vanderwerf, C. A.
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4. (a) Pavlov, P. A. Chem. Heterocycl. Compd. 2001, 37, 1199 and
references cited therein. (b) Suzuki, H.; Nakaya, C. Synthesis
1
992, 641. (c) Suzuki, H.; Hwang, Y. S.; Nakaya, C.; Matano, Y.
Synthesis. 1993, 1218. (d) Nishiyama, K.; Watanabe, A. Chem.
Lett. 1984, 13,773. (e) Nishiyama, K.; Oba, M.; Watanabe, A.
Tetrahedron. 1987, 43, 693.
2 4
Na SO , concentrated and purified by column chromatography on
silica gel 60-120 mesh using petroleum ether/ethyl acetate as an
eluent to afford pure nitrile. The desired isolated product was
1 13
characterised by IR, H NMR and C NMR spectroscopy.
2
2
5. Rokade, V. B ; Prabhu, R. K. J. Org. Chem. 2012, 77, 5364−5370.
6. (a) An, X.-D.; Yu, S. Org. Lett. 2015, 17, 5064–5067. (b) Shargi,
H.; Sarvari, M. H. Synthesis. 2003, 243–246. (c) Zhu, J.-L.; Lee,
F.-Y.; Wu, J.-D.; Kuo, C.-W.; Shia, K.-S. Synlett 2007, 1317–
1
319. (d) Augustine, J. K.; Atta, R. N.; Ramappa, B.
K.;Boodappa, C. Synlett. 2009, 3378–3382. (e) Sridhar, M.;
Reddy, M. K. K.; Sairam, V. V.; Raveendra, J.; Godala, K. R.;
Narsaiah, C.; Ramanaiah, B. C.; Reddy, C. S. Tetrahedron Lett.
2
1
012, 53, 3421–3424. (f) Cos_kun, N.; Arikan, N. Tetrahedron.
999, 55, 11943–11948. (g) Erman, M. B. J.; Snow, W.;
Williams, M. J. Tetrahedron Lett. 2000, 41, 6749–6752. (h)
Carmeli, M.; Shefer, N.; Rozen, S. Tetrahedron Lett. 2006, 47,
8
969–8972. (i) Telvekar, V. N.; Patel, K. N.; Kundaikar, H. S.;
Chaudhari, H. K. Tetrahedron Lett. 2008, 49, 2213–2215. (j)
Sharghi, H.; Sarvari, M. H. Tetrahedron. 2002, 58, 10323–10328.
(
k) Reddy, K. R.; Maheswari, C. U.; Venkateshwar, M.;
Prashanthi, S.; Kantam, M. L. Tetrahedron Lett. 2009, 50, 2050–
053.
2
.
2
7. General procedure for synthesis of nitrile from aldehyde:
Aldehyde (1 mmol) , sodium azide (2 mmol) and p-toluene
sulphonicacid (3 mmol) were finely mixed with silica gel 60-120

5
p-TsOH mediated solvent and metal
catalyst free Synthesis of Nitriles from
Aldehydes via Schmidt Reaction
Bijeta Mitra, Gyan Chandra Pariyar,
Rabindranath Singha, Pranab Ghosh*
Department of Chemistry, University of North
Bengal, Dt. Darjeeling, West Bengal, India.
Tel.: +91 (0353) 2776381; fax: +91 (0353)
2
699001.
E-mail address: pizy12@yahoo.com (P. Ghosh).
HIGHLIGHTS OF THE WORK
1
. Safe and mild reaction condition for a wide
variety of substrates.
2
3
4
5
. Solvent and metal catalyst free
. Simple and easy workup procedure.
. Cost and time effective.
. Environmental friendly.