Sulfated tungstate catalyzed activation of nitriles: addition of amines to nitriles for synthesis of amidines

Article abstract of DOI:10.1016/j.tetlet.2016.07.073

An efficient and mild method for the synthesis of amidines by direct nucleophilic addition of amines to nitriles using sulfated tungstate as heterogeneous catalyst is described. Highlight of the method is its applicability for the synthesis of amidines using a wide variety of amines including ammonia as ammonium acetate and nitriles. Catalyst is mildly acidic, stable, easy to prepare and separate from the reaction mass.

Full text of DOI:10.1016/j.tetlet.2016.07.073

Accepted Manuscript
Sulfated tungstate catalyzed activation of nitriles: addition of amines to nitriles
for synthesis of amidines
Sachin D. Veer, Kamlesh V. Katkar, Krishnacharya G. Akamanchi
PII:
S0040-4039(16)30931-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.073
TETL 47935
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
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19 July 2016
22 July 2016
Please cite this article as: Veer, S.D., Katkar, K.V., Akamanchi, K.G., Sulfated tungstate catalyzed activation of
nitriles: addition of amines to nitriles for synthesis of amidines, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.07.073
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Graphical Abstract
Sulfated Tungstate Catalyzed Activation of Nitriles:
Addition of Amines to Nitriles for Synthesis of
Amidines
Leave this area blank for abstract info.
Sachin D. Veer, Kamlesh V. Katkar and Krishnacharya G. Akamanchi*

1
Tetrahedron Letters
Sulfated tungstate catalyzed activation of nitriles: addition of amines to nitriles for
synthesis of amidines
Sachin D. Veer, Kamlesh V. Katkar and Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and mild method for synthesis of amidines by direct nucleophilic addition of amines
to nitriles using sulfated tungstate as heterogeneous catalyst is described. High light of the
method is its applicability for synthesis of amidines using wide variety of amines including
ammonia as ammonium acetate and nitriles. Catalyst is mildly acidic, stable, easy to prepared
and separate from reaction mass.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Sulfated tungstate
Heterogeneous catalysis
Amines
Nitriles
Amidines
Introduction
Our group has successfully developed sulfated tungstate, a
mildl acidic, non corrosive, stable, reusable, heterogeneous,
Amidines are of immense value in organic synthesis1-2. For
medicinal chemists amidine is a potent pharmacophore unit for
drug design, and also amidines are intermediates for construction
of heterocyclic moieties and active pharmaceutical ingredients
such as pentamidine and furamidine3. Amidines are widely used
as building blocks in synthesis of heterocycles4 such as 1,2,4-
green catalyst for many organic transformations like amidation
and formylation13. Sulfated tungstate is an amorophus powder
with surface area of 1.9 m2 g-1, particle size 1.49 μm, thermally
stable up to 200 °C, acidity is 373 mV which is greater than that
of silicagel and tungstic acid with elemental distribution mapping
by EDAX showing tungsten: oxygen: sulfur signal ratio of 69.13:
30.55: 0.31 wt%. Many of these reactions use amines as one of
the reactants as in amidation by direct reaction between
carboxylic acids and amines13a, Willgerodt-Kindler reaction for
synthesis of thiomorpholides13b, Strecker synthesis13c, Kindler
thiadiazoles4a,
imidazoles4b,
triazines4i,
aminophenanthridines4c,
pyrimidinones4d, pyridines4e,
purines4f, pyrimidines4g,
triazaphenalenes4h,
tetrazoles4i,
thiadiazines4j,
oxazolotriazoles4k, and diazirines4l, which have applications in
many fields5-6. There are different strategies for synthesis of
reaction13d
,
N-formylation13e
,
transamidation13f and N-
amidines
including
reductive
deprotection
of
O-
monoalkylation of primary amines13g. In all these reactions it has
been observed that nucleophilicity of amines was not
compromised and reactions were facile giving high yields, clearly
indicating activation of electrophilic counter part by the catalyst.
In the present work this feature of the catalyst is exploited to
activate nitriles by sulfated tungstate without compromising on
nucleophilicity of amines, leading to facile addition of amine to
form amidines with added advantage is heterogeneous nature of
the catalytic reaction and easy work up procedure.
benzylamidoximes7, catalytical addition of terminal alkynes to
carbodiimides8, and nucleophilic addition of amines to nitriles9.
Ready availability of variety of amines and nitriles makes
nucleophilic addition of amines to nitriles as useful strategy for
synthesis amidines. Moreover, it is one of the simplest methods
and has 100% atom economy. Direct addition to amines to
nitriles has always been a challenge, especially, if nitriles are not
activated. The additions are made possible when nitriles are
activated either by electron withdrawing groups10 or by
employing forcing conditions in the presence of Lewis acids11
such as AlCl311a, ZnCl211a, aluminium amide11b, CaCl211c, SmI211d
and Ytterbium amide11e. Alternatively, amidines are made
available from corresponding nitriles via imidate formation as in
Pinner synthesis12. This clearly indicates that there is scope for
development of heterogeneous solid acid catalyst for synthesis of
amidines.
Results and Discussion
Preliminary investigations were conducted using 1:1 mole
ratio of benzylamine and benzonitrile as building blocks and
DMF as solvent (Scheme 1).
Scheme1. Synthesis of N-benzylbenzimidamide from benzylamine and
*Corresponding author. Tel.: +912233611111/2222; fax: +91-22-
33611020; e-mail: kgap@rediffmail.com
benzonitrile

2
Tetrahedron Letters
Reactions were carried out using 20 wt% of sulfated tungstate
amines, including anilines and 1-naphthylamine and benzonitrile
were viable but reactions were very slow giving comparatively
lower yields in 18h (Table 2, entries 12-17). Many aliphatic
amines including primary n-butylamine and phenylethylamine,
at different temperatures of rt, 50 °C, 80 °C, 100 °C and 120 °C.
Amidine formation was observed at 80 °C but at very slow rate
and gave 18% yield in 24 h (Table 1, entry 3), whereas at 120 °C
the reaction was faster
and gave
90% yield of N-
sterically
hindered
secondary
diisopropylamine,
and
benzylbenzamidine in 12 h (Table 1, entry 5). Therefore further
studies were conducted at 120 °C.
dibenzylamine, cyclohexylamine reacted well with benzonitrile
giving corresponding amidines in comparable yields (Table 2,
entries 18-21 and 24). It is note worthy that ethylene diamine on
reaction with veleronitrile gave expected imidazoline in high
yield of 80% (Table 2, entry 23) by first forming amidines
followed by cyclisation to form five membered ring. Imidazoline
moiety is found in many drugs including losartan, eprosartan and
etomidate14. Therefore this method could be very valuable for
their synthesis. Significant result is the formation of benzamidine
by reaction between ammonium acetate and benzonitrile (Table
2, entry 22) indicating that method could be useful for synthesis
of even unsubstituted amidines. All these results clearly establish
the suitability of the method for wide variety of amines including
ammonia as ammonium acetate. As far as nitriles counterpart is
concerned, reactions were possible with both aromatic and
aliphatic nitriles. Aromatic nitriles (Table 2, entries 1-5, 7-8, 12-
15, 17-22, 24) including heteroaromatic nitrile (Table 2, entry 6),
reacted smoothly. In all cases yields were better with
unsubstituted benzonitrile giving highest yield of 90% with
benzylamine (Table 2, entry 1). Steric effect, typical of ortho
substituents as in case of o-chlorobenzonitrile, was not observed
and the reaction between benzylamine and o-chlorobenzonitrile
was equally facile giving 85% yield in the same reaction time of
12 h (Table 2, entry 5). Reactions of acetonitrile with
benzylamine and aniline were also possible however yield was
slightly lower in case of reaction between acetonitrile and aniline
giving 65% (Table 2, entries 9 and 16). Reaction between
chloroacetonitrile and benzylamine gave chloroacetamidine
(Table 2, entry 10). This result is significant because, the method
shows chemoselectvity with chlorine not getting displaced and
α-chloroamidines are useful synthons for construction of
heterocycles15.
To identify the influence of sulfated tungstate on the reaction
and how much amount is optimum, a set of reactions were
carried out with subsequently increasing amounts in the range of
0-30 wt%. From the results, it was concluded that sulfated
tungstate is required for the reaction, because in the absence of it
the reaction did not occur (Table 1, entry 6). A 20 wt% was
found optimum amount because further increase in quantities did
not show any advantage (Table 1, entry 12).
Table 1. Optimization of reaction conditionsa
Entry
Sulfated tungstate
(wt%)
Temperature
[°C]
Time [h]
Yieldb
1
2
20
20
20
20
20
-
rt
24
24
24
24
12
12
12
12
12
12
12
12
NRc
NRc
18
50
3
80
4
100
120
120
120
120
120
120
120
120
58
5
90
6
NRc
7
5
38
8
10
15
20
25
30
56
9
78
10
11
12
90
91
90
aReaction condition: benzylamine (1 g, 9.34mmol) and benzonitrile (0.96 g,
9.34 mmol) in DMF as a solvent. bIsolated yield, cNR= No reaction.
In conclusion, it can be said that a one-step protocol for
synthesis of amidines by nucleophilic addition of amines to
nitriles in presence of sulfated tungstate as mild, chemoselective,
stable, heterogeneous catalyst has been developed. High light of
the method is its applicability for synthesis of amidines using
wide variety of amines including ammonia as ammonium acetate
and nitriles.
To explore the generality and scope of the method, reactions
were examined with structurally diverse aromatic and aliphatic,
amines and nitriles, as shown in Table 2.
Considering amines as counterpart reactions of benzylamines
with variety of nitriles, both aliphatic, aromatic and
heteroaromatic, were smooth and gave corresponding amidines in
high yields (Table 2, entries 1-11). Reactions between aromatic
Table 2. Synthesis of amidines of different classes of amines and nitriles using sulfated tungstate as catalyst

3
Entry
1
R1
PhCH2
R2
H
R3
Ph
Product
Time (h)
12
Yieldb
90
2
PhCH2
H
p-CH3-Ph
12
82
3
4
PhCH2
PhCH2
H
H
p- H3CO -Ph
p-F-Ph
12
12
80
88
5
6
7
PhCH2
PhCH2
PhCH2
H
H
H
o-Cl-Ph
4-pyridinyl
PhCH2
12
12
16
85
82
80
8
9
PhCH2
PhCH2
H
H
p-Cl-PhCH2
16
12
82
78
CH3
10
PhCH2
H
Cl-CH2
12
82
11
12
PhCH2
Ph
H
H
CH3CH2
Ph
12
18
75
70
13
14
p-CH3-Ph
H
H
Ph
Ph
18
18
62
68
p-H3CO-Ph
15
p-F-Ph
H
Ph
18
72
16
17
Ph
H
H
CH3
Ph
18
18
65
68
1-naphthyl
18
19
cyclo-C6H11
H
H
Ph
Ph
18
18
72
75
CH3(CH2)3

4
Tetrahedron
20
21
(CH3)2CH
PhCH2
(CH3)2CH
PhCH2
Ph
18
12
63
76
Ph
22d
H
H
Ph
18
68
23
24
H2N(CH2)2
Ph(CH2)2
H
H
CH3(CH2)3
Ph
16
12
80
72
aReaction conditions: amine (1.0 equiv), nitrile (1.0 equiv) and sulfated tungstate (20 wt% ) at 120 °C,in DMF as solvent. bIsolated yield. dAmmonia is used as
1
ammonium acetate. cAll products are known and were identified by their melting point, IR and HNMR spectra, according to the literature.
Galka, C. H.; Gade, L. H. Monatshefte fur Chemie, 2005, 136,
Acknowledgments
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e) Wang, J.; Xu, F.; Cai, T.; Shen, Q. Org. Lett. 2008, 10, 445.
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Rousselet, G.; Capdevielle, P.; Maumy, M. Tetrahedron Lett.
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Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.; Duckworth,
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1987, 52, 1017.
The author (SDV) is grateful to the University Grant
Commission (UGC), India and Centre for Green Technology,
University of Mumbai for financial assistance.
References and notes
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G. Green Chem. 2010, 12, 1707; b) Salim, S.D.; Pathare, S.P.;
Akamanchi, K. G. Catal. Comm. 2011, 12, 78; c) Pathare, S. P.;
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P. Chaudhari, S. P.; Akamanchi, K. G. Appl. Cata. A: Gen. 2012,
125, 425; e) Pathare, S. P. Sawant, R. V.; Akamanchi, K. G.
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Akamanchi, K. G. RSC Advances. 2013, 3, 7697; g) Pathare, S. P.;
Akamanchi, K. G. Appl. Catal. A: Gen. 2013, 452, 29.
14. a) Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.;
Pridgen, L. N. J. Org. Chem. 1997, 62, 8449; b) Asproni, B.;
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P.; Sanna, E.; Biggio, G. J. Med. Chem. 2005, 48, 2638.
15. Abdelaal, S. M.; Baue, L.; J. hetrocyclic, chem.1968, 25, 1849.
16. Sulfated tugstate was prepared as per the reported procedure.13a
General:1H NMR (300 MHz)of all the products were recorded at
300MHz in CDCl3 as solvent and chemical shift values are
expressed in δ units relative to tetramethylsilane (Me4Si) signal as
internal reference in CDCl3. IR spectra were recorded as KBr
pellet. Purity of all compounds was established using the common
HPLC conditions: isocratic elution: (0.05% CF3COOH,
Water/CH3CN 50:50), flow rate = 1.0 mL/min, T = 25 °C, UV
detection at 254 nm with column Purosphere, RP-18e (5μm).
All the solvents were purchased from commercial sources and
were used without further purification.
1.
2.
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Soc.1959,81, 2214.
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Zienkiewicz, J.; Kaszynski, P.; Young, V. G. J. Org. Chem. 2004,
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l) W. H. Graham, J. Am. Chem. Soc. 1965, 87, 4396.
Chan, S. L. F.; Pallett, A. L.; Clews, J.; Ramsden, C. A.; Morgan,
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132, 14052.
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16788.
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Oxiey,M. W. Partridge, W. F.Short, J. Chem. Soc. 1947, 1110; c)
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H.; Spaziano, V. T.; Balasubramanian, T. M. J. Org. Chem. 1987,
52, 1017; e) Xu, F.; Sun, J.; Shen, Q. Tetrahedron Lett. 2002, 43,
1867.
Procedure for sulfated tungstate mediated synthesis of N-
benzylbenzamidine (Table 2 entry 1)
5.
6.
7.
8.
9.
Sulfated tungstate (0.2 g, 20 wt%) was added to a mixture of
benzylamine (1 g, 9.34 mmol) and benzonitrile (0.96 g, 9.34
mmol) in DMF(10 ml) and stirred at 120 °C for 12 h. Progress of
the reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was cooled to rt and filtered, washed
with ethyl acetate to recover the catalyst. Combined filtrate and
washings were concentrated under reduced pressure and the
residue obtained was chromatographed (silica gel #60-120; eluent:
hexane-ethyl acetate = 40 : 60) to get pure N-benzylbenzamidine
as white solid.;Yield:1.77 g 90%, white solid, mp 75-77 °C (lit17
77-78 °C). IR (KBr) 3287, 3035, 2868, 1662, 1534, 1385, 1241,
1
725, 699 cm-1. H NMR (300 MHz; CDCl3; Me4Si) δ= 7.31-7.22
(m, 10 H), 5.89 (s, 1 H), 4.50 (d, J=8.4Hz, 2H), 1.80 (s, 1 H).
HPLC retention time: 2.33 min.
10. Grivas, J. C.; Taurins, A. Can. J. Chem. 1961, 39, 761.
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17. Cooper, C.; Partridge, M. W. J. Chem. Soc. 1953, 255.

5
Supplementary Material
Supplementary data (experimental procedures, characterization
data and copies of IR and H NMR spectra of ethers) associated
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1
with this article can be found, in the online version,
athttp://dx.doi.org/10.1016/j.tetlet.XXXX
Highlights

The catalyst is well characterized, reusable, stable,
easy to prepare, mildly acidic and non corrosive
solid.




Mild reaction conditions and easy work up
procedure.
The catalyst activates nitriles without compromising
nucleophilicity of amines.
The method is applicable for synthesis of amidines
using wide variety of amines and nitriles.
Amidines are very useful substrates in organic
synthesis and medicinal chemistry.