A convenient regioselective synthesis of (2E)-2-[2,3,6-triarylpyrimidin- 4(3H)-ylidene]acetonitriles through ring transformation reactions

Article abstract of DOI:10.1016/j.tetlet.2012.11.044

We report a greener, economical, highly convenient and regioselective synthesis of (2E)-2-[2,3,6-arylpyrimidin-4(3H)-ylidene)acetonitriles derivatives 3. This is achieved by a strategy involving ring transformation reaction of 4-(methylthio)-2-oxo-6-aryl-

Full text of DOI:10.1016/j.tetlet.2012.11.044

Tetrahedron Letters 54 (2013) 343–346
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Tetrahedron Letters
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A convenient regioselective synthesis of (2E)-2-[2,3,6-triarylpyrimidin-
4(3H)-ylidene]acetonitriles through ring transformation reactions
⇑
Umesh D. Patil, Pramod P. Mahulikar
School of Chemical Sciences, North Maharashtra University, Jalgaon 425001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a greener, economical, highly convenient and regioselective synthesis of (2E)-2-[2,3,6-arylpyr-
Received 7 October 2012
Revised 6 November 2012
Accepted 10 November 2012
Available online 23 November 2012
imidin-4(3H)-ylidene)acetonitriles derivatives 3. This is achieved by
transformation reaction of 4-(methylthio)-2-oxo-6-aryl-2H-pyran-3-carbonitrile 1 with N-arylbenzami-
dine or N-arylpicolinamidine 2 in the presence of KOH/DMF catalyst at room temperature. This approach
a strategy involving ring
provides
a one-pot approach for the synthesis of symmetrical, unsymmetrical and heteroaryl
pyrimidin-4(3H)-ylidene)acetonitriles derivatives 3.
Keywords:
Nitrogen heterocycles
C–N coupling
Ring transformation reactions
Triaryl(pyrimidin-4-ylidene)acetonitrile
NC
SCH3
"Ar
CN
KOH/DMF
rt
Ar''
Ar'
NH
Ar'
2
N
HN
Ar
O
O
Ar
N
3
1
Ar = Ph-, 4-Cl-C6H4-, 4-Br-C6H4-, 4-CH3-C6H4-, 4-CH3O-C6H4-, 4-NO2-C6H4-, 2-napthyl.
Ar’ = Ph-, 4-Cl-C6H4-, 3-Cl-C6H4-, 2-py.
Ar’’ = 4-Cl-C6H4-, 2-py.
Ó 2012 Elsevier Ltd. All rights reserved.
Suitably functionalized 2H-pyran-2-ones are extensively em-
ployed in the design and synthesis of a wide variety of heterocyclic
compounds via ring transformation reaction.1–4 Recently, we have
reported the synthesis of 2,6-diaryl-4-sec-aminonicotinonitriles,
highly substituted unsymmetrical 2,2-bipyridines5 and 9,10-dihy-
dro-3-(pyridine-2-yl)-phenanthrene-2-carbonitriles using 2H-pyr-
an-2-ones as precursor.6
The importance of the pyridine ring is well known since many
of the biologically important and active molecules are present as
substructure in numerous natural products, exhibiting a wide
range of pharmacological activities.7–14 The potent biological activ-
ity of various vitamins and drugs7,8 is primarily attributed to the
presence of the pyrimidine ring in their molecular architect. Addi-
tionally, the wide ranges of biological activities are also found with
pyridines as shown by many herbicides,9 antiulcer,10 antitumour,11
antifungal,12 antiviral13 and free radical scavenger molecules.14
The properties of pyridine derivatives to form various metal com-
plexes have been explored for their use as sensitive analytical re-
agents. Recently such compounds have found applications as in
sensor systems, as luminescent agents, photosensitive materials,
etc. and hence have been studied in material science and supramo-
lecular chemistry.15
The substituted pyrimidine ring constitutes an integral part of
various natural products, nucleic acids, RNA and DNA. These serve
as building blocks for numerous pharmaceuticals and occupy a un-
ique place in heterocyclic and medicinal chemistry. Therefore,
substituted pyrimidines exhibit diverse pharmacological activities
such as antifilarial,16 anticancer,17 antibacterial,18 antimycotic,19
cardiotonic,20 diuretic,21 antileishmanial,22 antimalarial,23 anticon-
vulsant24 and anti-inflammatory. Exhibition and efficiency of such
activities have been reported to be dependent on the geometry and
type of substituents on the pyrimidine. These class of compounds
also possess coordination ability similar to that exhibited by pyri-
dyl ligands in supramolecular metallo-gridlike architecture25 and
in novel inorganic-organic hybrid molecular wires.26
⇑
Corresponding author. Tel.: +91 257 2257431; fax: +91 257 2258403.
E-mail address: mahulikarpp@rediffmail.com (P.P. Mahulikar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.044

344
U. D. Patil, P. P. Mahulikar / Tetrahedron Letters 54 (2013) 343–346
NC
or an orthoester in combination with ammonia as a potential
NCN surrogate reagent has been reported in the synthesis of
pyrimidines.30 Tris(formylamino)methanes,31 2-amino-2-form-
ylmalonaldehyde32 and 3-methyl-5-nitro-3H-pyrimidin-4-one33
have also been used as 1,3-dicarbonyl equivalents in pyrimidine
synthesis. A simple cyclocondensation of amidine salts with chal-
cones also yields pyrimidines.34
SCH3
CN
"Ar
HN
KOH/DMF
rt
Ar''
Ar'
NH
Ar'
N
Ar
O
O
Ar
N
1
2
3a-p
Scheme 1. Synthesis of (2E)-2-[2,3,6-arylpyrimidin-4(3H)-ylidene]acetonitriles
3a–p from 2H-pyran-3-carbonitrile 1 and amidine 2.
Presently a number of methods are available for the synthesis of
pyrimidine, although the synthesis of N-substituted pyrimidines or
direct introduction of a specific substituent into the pyrimidine nu-
cleus has been a tedious, challenging and fascinating area in the
chemistry of natural products having this ring system. In the vast
array of literatures on pyrimidines, we noted that the chemistry
of (2E)-2-[2,3,6-arylpyrimidin-4(3H)-ylidene]acetonitriles has not
been much explored. Probably, this may be due to lack of a concise,
straightforward protocol for the construction of (2E)-2-[2,3,6-aryl-
pyrimidin-4(3H)-ylidene)acetonitriles. Hence, we explored the
possibility of the synthesis by formulating a strategy which is
short, greener and efficient as an alternative to the established
procedures. We present a new methodology which leads to the
successful synthesis of (2E)-2-[2,3,6-arylpyrimidin-4(3H)-yli-
dene)acetonitriles via ring transformation reaction of 2H-pyran-
3-carbonitrile with amidine at room temperature.
Table 1
Synthesis of (2E)-2-[2,3,6-arylpyrimidin-4(3H)-ylidene]acetonitriles 3a–p from 2H-
pyran-3-carbonitrile 1 and amidine 2
Entry no Ar
Ar0
Ar00
Yieldsa (%) Mp (°C)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
C6H5
4-Cl–C6H4
4-CH3–C6H4
C6H5
C6H5
C6H5
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
4-Cl–C6H4 48
4-Cl–C6H4 43
4-Cl–C6H4 49
4-Cl–C6H4 47
39
40
56
57
48
172–174
206–208
174–176
180–182
200–202
196–198
244–246
222–224
192–194
152–154
174–176
196–198
206–208
218–220
202–204
194–196
4-CH3O–C6H4 C6H5
2-Naphthyl
C6H5
4-Cl–C6H4
4-Br–C6H4
C6H5
2-Pyridyl
2-Pyridyl
2-Pyridyl
4-CH3O–C6H4 2-Pyridyl
4-Cl–C6H4
4-Cl–C6H4 2-Pyridyl
49
48
56
57
31
43
48
4-Br–C6H4
4-CH3–C6H4
4-Cl–C6H4 2-Pyridyl
4-Cl–C6H4 2-Pyridyl
We achieved the synthesis of (2E)-2-[2,3,6-arylpyrimidin-
4(3H)-ylidene)acetonitriles 3a–p through base induced ring
transformation of suitably functionalized 4-(methylthio)-2-oxo-
4-CH3O–C6H4 4-Cl–C6H4 2-Pyridyl
4-NO2–C6H4
2-Naphthyl
4-CH3–C6H4
4-Cl–C6H4 2-Pyridyl
4-Cl–C6H4 2-Pyridyl
3-Cl–C6H4 2-Pyridyl
6-aryl-2H-pyran-3-carbonitriles
1 with N-arylbenzamidine or
a
The yields are based on the estimation using column chromatography.
N-arylpicolinamidine 2 in DMF using KOH as the base. The
synthetic scheme is depicted in Scheme 1.
The precursors, 2H-pyran-3-carbonitriles 1 were prepared by
stirring an equimolar mixture of ethyl 2-cyano-3,3-bis(methyl-
thio)acrylate, suitable acetophenone and KOH in DMF.35 On the
other hand, amidines 2 were prepared from corresponding nitrile
and amine.36 The salient feature of this procedure is to provide a
one-pot synthesis of symmetrical, unsymmetrical and heteroaryl
pyrimidin-4(3H)-ylidene)acetonitriles. To the best of our knowl-
edge this is the first report on the synthesis of these classes of
compounds through a ring transformation reaction of 2H-pyran-
3-carbonitrile 1 with N-arylbenzamidine or N-arylpicolinamidine
The pyrimidine ring, being electron deficient, resists electro-
philic substitution and facilitates nucleophilic addition and substi-
tution reactions. Numerous synthetic strategies have been
developed for the construction of pyrimidines, such as condensa-
tion of the 1,3-dicarbonyl compounds with amidines,27 tri-substi-
tuted pyrimidines are synthesized by heating acetyl acetone and
aldehyde in the presence of 2 equiv of ammonium acetate,28 cyano
crotonamide derivatives on condensation with diethoxyalkyl-
amine gives N-substituted pyrimidines.29 The use of formamide
Figure 1. ORTEP diagram showing the molecular structure of 3p with atomic numbering scheme.

U. D. Patil, P. P. Mahulikar / Tetrahedron Letters 54 (2013) 343–346
345
b
compared to the arylamine group and the degree of nucleophilicity
of the nature of N-1 compared to N-3.
SCH3
4
3
3 CN
2
5
6
Ar''
Ar'
HN
We have described a ‘green’, novel, concerted, economical, effi-
cient and a highly selective synthetic protocol for pyrimidin-4-yli-
dene acetonitriles, that is, N-substituted pyrimidines 3a–p. As an
illustrative application of this strategy, symmetrical, unsymmetri-
cal and heteroaryl derivatives of pyrimidin-4-ylideneacetonitrile
derivatives were successively synthesized. The developed method
is far superior to the known literature procedures in terms of ease
of work-up, use of economical and readily available reagents, in the
absence of catalysts or source of external energy and mild reaction
condition. Also, it is felt that the methodology provides a general
route for creating molecular diversity by selecting the reactants
as per the requirement of the substituents on the aryl rings. Possi-
ble reaction pathways are suggested.
2
HN
Ar
O1
O
1
a
2
a route
1
a route X
O
O
O
b route
Ar''
NH
CN
N
Ar''
CN
HN
O
NC
H3CS
H3CS
Ar''
N
Ar'
N
Ar
Ar
Ar
N
Ar''
5
Ar'
-NHAr''
-CO2
SCH3
O
Ar''
NH
CN
N
O
H3CS
N
N
Ar'
Ar'
Ar
Ar
Supplementary data
Supplementary data (general experimental procedures of 2H-
pyran-3-carbonitriles (1) and amidines (2), spectroscopic data,
copies of LCMS, 1H NMR, 13C NMR and check cif file of compound
3p) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2012.11.044.
SCH3
CN
SCH3
Ar''
N
_
N
Ar
N
Ar'
N
Ar'
Ar
4
_SCH3
References and notes
N
1. Farhanullah; Samrin, F.; Ram, V. J. Tetrahedron Lett. 2007, 48, 8213.
2. Ram, V. J.; Agarwal, N.; Saxena, A. S.; Farhanullah; Sharon, A.; Maulik, P. R. J.
Chem. Soc., Perkin Trans. 1 2000, 1426.
Ar''
N
3. Goel, A.; Singh, F. V. Tetrahedron Lett. 2005, 46, 5585.
4. Goel, A.; Verma, D.; Dixit, M.; Raghunandan, R.; Maulik, P. R. J. Org. Chem. 2006,
71, 804.
Ar
N
Ar'
3
5. Bhosale, S. V.; Patil, U. D.; Kalyankar, M. B.; Nalage, S. V.; Patil, V. S.; Desale, K. R.
J. Heterocycl. Chem. 2010, 47, 691.
6. Patil, U. D.; Mahulikar, P. P. J. Heterocycl. Chem. 2012. April 2012, accepted,
Manuscript no. JHET-12-0032.
Scheme 2. The plausible mechanism for the formation of substituted compounds
3a–p.
7. Pharmaceutical Chemistry, Drug Synthesis; Roth, H. J., Kleeman, A., Eds.; Prentice
Hall Europe: London, 1998; Vol. 1, p 407.
8. Li, A.-H.; Moro, S.; Forsyth, N.; Melman, N.; Ji, X.-d.; Jacobson, K. A. J. Med. Chem.
1999, 42, 706.
9. Kawamura, S.; Hamada, T.; Sato, R.; Sanemitsu, Y.; Sandmann, G.; Babczinski, P.
J. Agric. Food Chem. 1991, 39, 2279.
10. Moffett, R. B.; Rober, A.; Skaletzky, L. L. J. Med. Chem. 1971, 10, 963.
11. Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J. J. Am. Chem. Soc. 1988,
110, 6471.
2. The detailed list of synthesized derivatives is given in Table 1. All
the synthesized compounds were isolated and purified.37 The as-
signed structure for 3 is supported by an X-ray crystallographic
structure determination (Fig. 1). CCDC 829798 contains the supple-
mentary crystallographic data for 3p.38 Even though, we found that
the overall yield ranges from 31% to 60%, the methodology is still
very useful since it is a one pot protocol which produces highly
functionalized pyrimidine.
12. Patil, U. D.; Nikum, A. P.; Nagle, P. S.; Mahulikar, P. P. J. Pharm. Res. 2012, 5,
1383.
13. Williams, D. R.; Lowder, P. D.; Gu, Y.-G. Tetrahedron Lett. 1997, 38, 327.
14. Teshima, Y.; Shin-ya, K.; Shimazu, A.; Furihata, K.; Chul, H. S.; Furihata, K.;
Hayakawa, Y.; Nagai, K.; Seto, H. J. Antibiot. 1991, 44, 685.
15. Kozhevnikov, V. N.; Kozhevnikov, D. N.; Nikitina, T. V.; Rusinov, V. L.;
Chupakhin, O. N.; Zabel, M.; Konig, B. J. Org. Chem. 2003, 68, 2882.
16. Singh, B. K.; Mishra, M.; Saxena, N.; Yadav, G. P.; Maulik, P. R.; Sahoo, M. K.;
Gaur, R. L.; Murthy, P. K.; Tripathi, R. P. Eur. J. Med. Chem. 2008, 43, 2717.
17. Jonak, J. P.; Zakrzewski, S. F.; Mead, L. H. J. Med. Chem. 1972, 15, 662.
18. Cieplik, J.; Stolarczyk, M.; Pluta, J.; Gubrynowicz, O.; Bryndal, I.; Lis, T.;
Mikulewicz, M. Acta Pol. Pharm. Drug Res. 2011, 68, 57.
19. Keutzberger, A.; Gillessen, J. Arch. Pharm. 1985, 318, 370.
20. Dorigo, P.; Fraccarollo, D.; Santostasi, G.; Maragno, I.; Floreani, M.; Borea, P. A.;
Mosti, L.; Sansebastiano, L.; Fossa, P.; Orsini, F.; Benetollo, F.; Bombieri, G. J.
Med. Chem. 1996, 39, 3671.
21. Wright, W. B.; Tomcufeik, A. S.; Marisco, J. W. J. U.S. 4325955, 1982; Chem.
Abstr. 1982, 97, 23818q.
22. Ram, V. J. Arch. Pharm. (Weinheim) 1991, 324, 837.
23. Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med. Chem.
2005, 13, 4645.
24. Eddington, N. D.; Cox, D. S.; Roberts, R. R.; Butcher, R. J.; Edafiogho, I. O.;
Stables, J. P.; Cooke, N.; Goodwin, A. M.; Smith, C. A.; Scott, K. R. Eur. J. Med.
Chem. 2002, 37, 635.
25. Lehn, J.-M. Supramolecular Chemistry-Concepts and Perspectives; VCH:
Weinheim, 1995. Chapter 9.
All the synthesized compounds (3a–p, Table 1) were character-
ized by spectroscopic techniques and confirmed by elemental anal-
ysis for C, H and N.
We developed the approach for the synthesis of pyrimidin-4-
ylidene acetonitriles 3a–p based on the nucleophile induced ring
transformation of 2H-pyran-3-carbonitrile 1 with N-arylbenzami-
dine or N-arylpicolinamidine 2 as depicted in Scheme 2. It is evi-
dent from the topography of 2H-pyran-2-ones, that it may be
considered as a cyclic ketene hemimethylthio acetal with three
electrophilic centres, namely, C-2, C-4 and C-6 in its molecular ma-
keup. However, the C-6 position is highly susceptible to nucleo-
philic attack due to an extended conjugation and the presence of
an electron withdrawing substituent at position 3 of the pyran
ring.
The mechanism reported on Scheme 2 considers the following
steps: (a) nucleophilic addition of the N1 to the C6, (b) CO2 elimi-
nation with the corresponding ring cleavage, (c) recyclization
involving the N3 nitrogen of amidine and C4 of the pyrane ring,
(d) elimination of the thiomethyl group to yield (2E)-2-[2,3,6-aryl-
pyrimidin-4(3H)-ylidene)acetonitrile derivatives 3a–p. The possi-
bility of the formation of products 4 & 5 also exists but under the
given experimental conditions, only product 3 has been isolated.
This may be due to the facile elimination of the thiomethyl group
26. Harriman, A.; Ziessel, R. Coord. Chem. Rev. 1998, 171, 331.
27. Gompper, R.; Mair, H.-J.; Polborn, K. Synthesis 1997, 696.
28. Weis, A. L.; Rosenbach, V. Tetrahedron Lett. 1981, 22, 1453.
29. Granik, V. G.; Kaimanakova, S. I. Khim. Geterotsikl. Soedin. 1983, 6, 657.
30. Bredereckef, H.; Gompper, R.; Morlock, G. Chem. Ber. 1957, 90, 942.
31. Bredereck, H.; Gompper, R.; Schuh, H. G. V.; Theilig, G. Angew. Chem. 1959, 71,
753.

346
U. D. Patil, P. P. Mahulikar / Tetrahedron Letters 54 (2013) 343–346
32. Iuhas, P. C.; Georgescu, E.; Georgescu, F.; Draghici, C.; Caproiu, T. M. Rev. Roum.
Chim. 2001, 46, 55.
33. Nishiwaki, N.; Adachi, T.; Matsuo, K.; Wang, H.-P.; Matsunaga, T.; Tohda, Y.;
Ariga, M. J. Chem. Soc., Perkin Trans. 1 2000, 27.
34. Boykin, D. W.; Kumar, A.; Bajic, M.; Xiao, G.; Wilson, W. D.; Bender, B. C.;
McCurdy, D. R.; Hall, J. E.; Tidwell, R. R. Eur. J. Med. Chem. 1997, 32, 965–967.
35. Tominaga, Y.; Ushirogochi, A.; Matsuda, Y.; Kobayashi, G. Chem. Pharm. Bull.
1984, 32, 3384.
36. Patil, U. D.; Mahulikar, P. P. ISRN Organic Chemistry, 2012 Article ID 963195,
doi:http://dx.doi.org/10.5402/2012/963195.
suspension of KOH (230 mg, 4 mmol) and dry DMF (5 mL) for 30 min followed
by the addition of 2H-pyran-3-carbonitrile (1a, 490 mg, 2 mmol). Consumption
of the starting material was monitored by TLC. After completion of the reaction
(about 5–6 h), excess DMF was removed under reduced pressure and the
obtained residue was poured onto crushed ice with vigorous stirring and then
neutralized with 10% aqueous HCl solution. The separated solid was filtered,
washed with cold water and dried. The crude product was purified by silica gel
(200–400 mesh size) column chromatography using ethyl acetate/hexane (1:9)
as eluent.
38. These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
37. General procedure for the synthesis of (2E)-2-[2,3,6-arylpyrimidin-4(3H)-
ylidene)acetonitriles (3a–o): Amidine (2a, 390 mg, 2 mmol) was stirred in a