An efficient synthesis of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles and cyanomethyl appended pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2006.11.136

A series of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles 5a-j and aryl/heteroaryl tethered pyrimidin-4-yl acetonitriles 6a-e has been synthesized in excellent yields through base catalyzed ring transformation of suitably functionalized 2H-

Full text of DOI:10.1016/j.tetlet.2006.11.136

Tetrahedron Letters 48 (2007) 549–553
An efficient synthesis of (E)-(2-arylpyrazino[1,2-a]pyrimidine-
4-ylidene)acetonitriles and cyanomethyl appended pyrimidinesI
Ramendra Pratap, Shom Prakash Kushwaha, Atul Goel and Vishnu Ji Ram*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 24 August 2006; revised 13 November 2006; accepted 22 November 2006
Available online 12 December 2006
Abstract—A series of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles 5a–j and aryl/heteroaryl tethered pyrimidin-4-yl
acetonitriles 6a–e has been synthesized in excellent yields through base catalyzed ring transformation of suitably functionalized
2H-pyran-2-ones 3 using 2-aminopyrazine 4a and arylamidinium salts 4b, separately.
Ó 2006 Elsevier Ltd. All rights reserved.
An extensive literature survey revealed that the chemis-
try of pyrazino[1,2-a]pyrimidine ring system I, first
reported by Eble and co-workers1 in 1968, is poorly
developed. The chemistry of pyrazino[2,3-d]pyrimidines
II has been widely explored while that of pyrazino-
[1,2-c]pyrimidines III are still underdeveloped (see Fig. 1).
condensation of methyl 2-benzoylamino-3-dimethyl-
aminopropanoate with 2-aminopyrazine. This method
was further improved9 by using methyl (Z)-[(benzyloxy-
carbonyl)amino]-3-dimethylaminopentanoate
as
a
reagent for the condensation reaction with 4a. Hexa-
hydropyrazino[1,2-a]pyrimidine derivatives have also
been synthesized10 in six steps from 4-chlorophenyl-
alanine, allyl chloroformate, 2,2-(diethoxymethyl)isopro-
pylamine, 3-amino-2-benzyloxycarbonylaminopropionic
acid and 2,4-dichlorophenylsulfonyl chloride followed
by the cyclization of the intermediate formed. Some of
the reduced compounds are very useful in the treatment
of metabolic disorders10 such as obesity and diabetes.
These diverse pharmacological activities and the lack
of efficient synthetic methodologies encourage us to
develop a concise synthetic route to these compounds.
The therapeutic importance of pyrazino[1,2-a]pyrimi-
dine ring system I in the treatment of migraine,2 ulcers,3
depression1,4 and anorexia5 has made it an indispensable
class of compounds. These compounds also exhibit
NF-kB549 inhibitory activity.6
Previously, these compounds have been synthesized4–7
by heating a mixture of diethyl ethoxymethylenemalon-
ate or diethyl phenylmalonate with 2-aminopyrazine
4a. The other method8 commonly used for the construc-
tion of pyrazino[1,2-a]pyrimidines is through the
Pyrimidine rings are an integral part of various natural
products.11 They serve as building blocks for numerous
pharmaceuticals and occupy a unique place in hetero-
cyclic and medicinal chemistry. This class of compounds
also has coordinating ability similar to pyridyl ligands in
supramolecular metallo-gridlike architecture12 and in
novel inorganic–organic hybrid molecular wires.13 In
addition, they are pharmacologically active and display
anticonvulsant,14 anti-inflammatory,15 antibacterial16
and antimycotic17 activities.
N
N
N
N
N
N
N
N
N
N
I
II
III
Figure 1. Pyrazino[1,2-a]pyrimidine I, pyrazino[2,3-d]pyrimidines II
and pyrazino[1,2-c]pyrimidines III.
The pyrimidine ring, being electron deficient, resists elec-
trophilic substitution and facilitates nucleophilic addi-
tion and substitution reactions.18 A common approach
for the construction of pyrimidine rings is through
condensation of the 1,3-dicarbonyl compounds with
Keywords: 4-Pyrimidinyl acetonitrile; Pyrazino[1,2-a]pyrimidines; 2H-
Pyran-2-ones; Ring transformation.
q CDRI Communication No. 7066.
*
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623405; e-mail: vjiram@yahoo.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.136

550
R. Pratap et al. / Tetrahedron Letters 48 (2007) 549–553
amidines.19 However, 2,4,6-triaryl pyrimidines are con-
structed stepwise.19 The use of formamide or an ortho-
ester in combination with ammonia20 as a potential
surrogate NCN reagent has been reported in the syn-
thesis of pyrimidines. Tris(formylamino)methanes,21
2-amino-2-formylmalonaldehyde22 and 3-methyl-5-nitro-
3H-pyrimidin-4-one23 have also been used as 1,3-dicar-
bonyl equivalents in pyrimidine synthesis. A simple
cyclocondensation of amidine salts with chalcones also
yields pyrimidines.24
the ring nitrogen of pyrazine and C-4 of the pyran ring
with elimination of the secondary amine. The reaction of
3 with the arylamidinium salts possibly commenced with
the attack of the nucleophile at C-6 with ring closure
involving the C-4 position of the pyran ring and con-
comitant loss of carbon dioxide and the amine to yield
6 (see Scheme 2).
All the compounds synthesized are listed in Tables 1 and
2 and were characterized by spectroscopic techniques.27
Herein, we report an innovative and efficient synthesis of
pyrazino[1,2-a]pyrimidines 5 and (2,6-diaryl-pyrimidin-
4-yl)acetonitriles 6 via base catalyzed ring transforma-
tions of suitably functionalized 2H-pyran-2-ones using
2-aminopyrazine and arylamidinium salts as nucleo-
philes, respectively. To the best of our knowledge this
is the first report on the synthesis of these classes of
compounds through a ring transformation reaction of
6-aryl-4-amino-2H-pyran-2-one-3-carbonitriles 3 with
2-aminopyrazine and arylamidinium salts.
The configuration of the geometrical isomers of 5 was
ascertained on the basis of NOE experiments. Irradia-
(CH2)n
N
N
N
NH2
H2N Ar'
NH.H2SO4
4b
CN
+
Ar
O
O
4a
3
The 6-aryl-4-amino-2H-pyran-2-one-3-carbonitriles
3
have been conveniently prepared in two steps. The first
step is the formation of 6-aryl-4-methylsulfanyl-2H-pyr-
an-2-one-3-carbonitriles 2 from the reaction of an aryl
methyl ketone with methyl 2-cyano-3,3-dimethylthio-
acrylate 1 as described earlier.25 Amination26 of 2 with
a sec-amine in refluxing ethanol gave 6-aryl-4-amino-
2H-pyran-2-one-3-carbonitriles 3 which were used as the
synthons for ring transformation reactions (Scheme 1).
O
O
(CH2)n
(CH2)n
CN
N
O
O
N
CN
Ar'
NH
NH
N
N
N
Ar
Ar
H
Thus, a mixture of 6-aryl-4-amino-2H-pyran-2-one-3-
carbonitrile 3 and 2-aminopyrazine 4a was stirred in
DMF at room temperature for 1 h followed by the addi-
tion of powdered KOH. The stirring was continued for
an additional 1 h and thereafter the mixture was poured
onto crushed ice with vigorous stirring and neutralized
with 10% aqueous HCl. The resulting precipitate was
filtered, washed with water and purified by column
chromatography.
(CH2)n
(CH2)n
N
N
N
N
NH
C
N
Ar'
N
H
Ar
N
Ar
N
H
(CH2)n
N
H
N
C
N
C
(CH2)n
N
N
It is evident from the topography of 2H-pyran-2-ones 3,
that the C-2, C-4 and C-6 positions are electrophilic in
nature. However, the C-6 position is highly susceptible
to nucleophilic attack due to an extended conjugation
and the presence of an electron-withdrawing substituent
at position 3 of the pyran ring. The reaction of 3 with 4a
may be possibly initiated by the attack of the amino
group at C-6 of the pyran ring with ring opening fol-
lowed by decarboxylation and recyclization involving
C
N
Ar'
(CH2)n
H
N
Ar
N
N
-
Ar
N
(CH2)n
H
N
N
-
N
H
NC
N
Ar'
Ar
N
H
N
Ar
N
5
(CH2)n
(CH2)n
CN
N
N
SCH3
NC
COOCH3
N
H
CN
O
CN
O
ArCOCH3
H3CS
SCH3
DMSO/KOH
EtOH
Ar
N
Ar'
Ar
O
Ar
O
1
2
3
6
n = 1, 2
Scheme 2. A plausible mechanism for the formation of (2-arylpyr-
azino[1,2-a]pyrimidine-4-ylidene) acetonitriles 5 and (2,6-diaryl-pyr-
imidin-4-yl)acetonitriles 6.
Scheme 1. Synthesis of 6-aryl-4-amino-2H-pyran-2-one-3-carbonitriles
3.

R. Pratap et al. / Tetrahedron Letters 48 (2007) 549–553
551
Table 1. Reaction times and yields of the synthesized (E)-(2-aryl-
pyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles 5
Table 2. Reaction times and yields of the various (2,6-diaryl-pyrim-
idin-4-yl)acetonitriles 6
Compound Structure
Time (h) Yield (%)
Compound Structure
Time (h) Yield (%)
CN
N
NC
5a
N
1.5
88
6a
1.5
85
N
N
N
NC
CN
N
N
5b
2.0
2.0
89
84
N
N
6b
2.0
2.0
2.5
2.0
2.0
79
84
83
78
85
N
N
N
Cl
Cl
NC
CN
N
N
5c
6c
Br
N
NC
Br
CN
N
5d
2.5
2.0
2.0
1.5
83
78
85
79
N
N
N
6d
H3C
N
NC
S
N
CN
5e
N
N
N
6e
H3CO
N
NC
N
5f
Cl
N
CN
N
N
H3CS
6f
NC
N
N
N
5g
N
O
N
N
CN
N
O
6g
1.5
2.5
79
81
NC
N
N
5h
5i
5j
2.5
2.5
2.0
84
86
83
F
N
N
CN
NC
N
6h
N
N
N
N
Cl
N
CN
NC
N
6i
2.5
76
N
N
N
N
N
H3C
S
(continued on next page)

552
R. Pratap et al. / Tetrahedron Letters 48 (2007) 549–553
8. Stanovnik, B.; van de Bovenkamp, H.; Svete, J.; Havala,
Table 2 (continued)
A.; Simonicˇ, I.; Tisˇler, M. J. Heterocycl. Chem. 1990, 27,
359.
9. Toplak, R.; Svete, J.; Grdadolnik, S. G.; Stanovnik, B.
Collect. Czech. Chem. Commun. 1999, 64, 177.
10. Lennig, P.; Stengelin, S.; Klabunde, T.; Gossel, M.; Safar,
P.; Smrcina, M.; Spoonamore, J.; Merriman, G.; Klein, J.
T.; Whiteley, B.; Lanter C.; Bordeau, K.; Yang, Z. PCT
Int. Appl. 2006, WO 2006, 24390; Chem. Abstr. 2006, 144,
274545g.
Compound Structure
Time (h) Yield (%)
CN
N
6j
2.0
2.0
1.5
83
85
85
N
N
H3CO
11. (a) Brown, D. J. In The Chemistry of Heterocyclic
Compounds; Weissberger, A., Ed.; The Pyrimidines;
Wiley-Interscience: New York, 1970; Vol. 16, (b) Lister,
J. H. In The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Eds.; Fused Pyrimidines,
Part II, The Purines; Wiley-Interscience: New York, 1971;
Vol. 24, (c) Hoffmann, M. G. In Houben-Weyl, Methoden
der Organischen Chemie; Schaumann, E., Ed.; G. Thieme:
Stuttgart, 1996; Vol. E9, (d) Hurst, D. T. In An Introduc-
tion to the Chemistry and Biochemistry of Pyrimidines,
Purines and Pteridines; Wiley: Chichester, 1980; (e) Bojar-
ski, J. T.; Mokrosz, J. L.; Barton, H. J.; Paluchowska, M.
H. Adv. Heterocycl. Chem. 1985, 38, 229; (f) Brown, D. J..
In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: Oxford, New
York, Toronto, Sydney, Paris, Frankfurt, 1984; Vol. 3,
Chapter 2.13.
12. (a) Lehn, J.-M. Supramolecular Chemistry-Concepts and
Perspectives; VCH: Weinheim, 1995, Chapter 9; (b)
Hanan, G. S.; Volkmer, D.; Schubert, U. S.; Lehn,
J.-M.; Baum, G.; Fenske, D. Angew. Chem., Int. Ed.
1997, 36, 1842; (c) Semenov, A.; Spatz, J. P.; Mo¨ller, M.;
Lehn, J.-M.; Sell, B.; Schubert, D.; Weidl, C. H.; Schubert,
U. S. Angew. Chem., Int. Ed. 1999, 38, 2547.
CN
N
6k
O
N
N
O
CN
N
6l
N
S
N
tion of the vinylic proton of 5a at d 4.33 and the C-5
proton at d 7.34 enhanced the signal intensity mutually
whilst leaving the signal intensity of the C-3 proton
at d 7.40 unaffected, thereby confirming the (E)-
configuration.
In summary, our methodology opens a new avenue for
the stereoselective synthesis of (E)-(2-arylpyrazino[1,2-a]-
pyrimidine-4-ylidene)acetonitriles 5 and cyanomethyl
appended pyrimidines 6 in high yields under mild reac-
tion conditions.
13. (a) Harriman, A.; Ziessel, R. Coord. Chem. Rev. 1998, 171,
31; (b) Harriman, A.; Ziessel, R. Chem. Commun. 1996,
1707.
14. (a) 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; (b) Eddington, N. D.; Cox, D.
S.; Roberts, R. R.; Stables, J. P.; Powell, C. B.; Scott, K.
R. Curr. Med. Chem. 2000, 7, 417; (c) Scott, K. R.;
Rankin, G. O.; Stables, J. P.; Alexander, M. S.; Eda-
fiogho, I. O.; Farrar, V. A.; Kolen, K. R.; Moore, J. A.;
Sims, L. D.; Tonnut, A. D. J. Med. Chem. 1995, 38, 4033;
(d) Edafiogho, I. O.; Alexander, M. S.; Moore, J. A.;
Farrar, V. A.; Scott, K. R. Curr. Med. Chem. 1994, 1, 159.
15. Dannhardt, G.; Bauer, A.; Nowe, U. Arch. Pharm. 1997,
330, 74.
Acknowledgement
V.J.R., A.G. and R.P. are thankful to the CSIR, New
Delhi, for the financial support and the Sophisticated
Analytical Instrument Facility, CDRI, Lucknow, for
providing spectroscopic data.
References and notes
16. Ahluwalia, V. K.; Kaila, N.; Bala, S. Indian J. Chem.,
Sect. B 1987, 26B, 700.
17. Keutzberger, A.; Gillessen, J. Arch. Pharm. 1985, 318, 370.
18. (a) Eicher, T.; Hauptmann, S. Chemie der Heterocyclen;
Georg Thieme: Stuttgart, New York, 1994; pp 398; (b)
Gilchrist, T. L. In Heterocyclenchemie; Neunhoeffer, H.,
Ed.; Wiley-VCH: New York, 1995; p 270.
19. For an efficient repetitive synthesis of (oligo)pyrimidines
based upon vinamidinium salt amidine condensations, see:
Gompper, R.; Mair, H.-J.; Polborn, K. Synthesis 1997,
696.
20. Bredereck, H.; Gompper, R.; Morlock, G. Chem. Ber.
1957, 90, 942.
21. Bredereck, H.; Gompper, R.; Schuh, H. G.; Theilig, G.
Angew. Chem. 1959, 71, 753.
1. Trepanier, D. L.; Rampy, L. W.; Shriver, K. L.; Eble, J.
N.; Shea, P. J. J. Med. Chem. 1968, 11, 1045.
2. Andres, C. J.; Scola, P. M.; Grant-Young, K. A. U. S.
Patent 222158, 2005; Chem. Abstr. 2005, 143, 360126g.
3. Matsutani, S.; Mizushima, Y. EP 329126, 1989; Chem.
Abstr. 1990, 112, 98557r.
4. Trepanier, D. L. (Dow Chemical Co.) U. S. Patent
3558,618, January 1971; Chem. Abstr. 1971, 74, 141870y.
5. Flohr, S.; Stengelin, S.; Gossel, M.; Klabunde, T.; Stahl,
P.; Safar, P.; Spoonamore, J.; Smrcina, M.; Klein, J. T.;
Merriman, G. H.; Whiteley, B. K.; Lanter, C.; Bordeau,
K. J.; Yang, Z., Ger. Offen. DE 10,305,885, 26 August
2004; Chem. Abstr. 2004, 141, 225526f.
22. Iuhas, P. C.; Georgescu, E.; Georgescu, F.; Draghici, C.;
Caproiu, T. M. Rev. Roum. Chim. 2001, 46, 55.
23. Matsunaga, T.; Tohda, Y.; Ariga, M. J. Chem. Soc.,
Perkin Trans. 1 2000, 27.
6. Kim, J.-W.; Cho, J.-H.; Han, T.; Lee, J.; Oh, C.-H. Bull.
Korean Chem. Soc. 2006, 27, 484.
7. Denin, F.; Blondeau, D.; Sliwa, H. J. Heterocycl. Chem.
1990, 27, 1639.

R. Pratap et al. / Tetrahedron Letters 48 (2007) 549–553
553
24. (a) Dodson, R. M.; Seyler, J. K. J. Org. Chem. 1951, 16,
461; (b) Al-Hajjar, F. H.; Sabri, S. S. J. Heterocycl. Chem.
1982, 19, 1087; (c) Simon, D.; Lafont, O.; Farnoux, C. C.;
Miocque, M. J. Heterocycl. Chem. 1985, 22, 1551; (d)
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.
25. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A.
Liebigs Ann. Chem. 1991, 1229; (b) Ram, V. J.; Verma, M.;
Hussaini, F. A.; Shoeb, A. J. Chem. Res. (S) 1991, 98.
26. Ram, V. J.; Nath, M.; Srivastava, P.; Sarkhel, S.; Maulik,
P. R. J. Chem. Soc., Perkin Trans. 1 2000, 3719.
27. General procedure for the synthesis of (2-arylpyrazino-
[1,2-a]pyrimidine-4-ylidene)acetonitriles (5a–j): A mixture
of 6-phenyl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbo-
nitrile (3a, 280 mg, 1 mmol) and 2-aminopyrazine (4,
1.2 mmol) was stirred for 1 h in DMF (5.0 mL) followed
by the addition of powdered KOH (84 mg, 1.5 mmol).
Consumption of the starting material was monitored by
TLC. After completion of the reaction, excess DMF was
removed under reduced pressure and the residue was
poured onto crushed ice with vigorous stirring. Neutral-
ization with 10% aqueous HCl (5.0 mL) led to a precip-
itate which was filtered, washed with water, dried and
purified through neutral alumina column chromatography
using 10% hexane in chloroform as eluent. Compound 5a:
Yield 88%; mp 220–222 °C; column chromatography, 10/
90 hexane/CHCl3 v/v, Rf 0.38 (CHCl3); 1H NMR (CDCl3,
300 MHz) d 4.33 (s, 1H, CH), 7.34 (d, J = 4.95 Hz, 1H,
ArH), 7.40 (s, 1H, ArH), 7.48–7.50 (m, 3H, ArH), 7.85 (d,
J = 5.07 Hz, 1H, ArH), 8.02–8.06 (m, 2H, ArH), 8.86 (d,
J = 0.93 Hz, 1H, ArH); 13C NMR (CDCl3, 75 MHz) d
57.66, 105.06, 115.75, 125.59, 127.65, 129.38, 129.61,
134.10, 148.10, 154.06; IR (KBr) 2180 cmÀ1 (CN); mass
(ESI-MS) m/z 247 [M++1]; EI-HRMS: (M+) calcd for
C15H10N4 246.09055, found 246.09017. Compound 5b:
Yield 89%; mp 216–218 °C; column chromatography, 10/
90 hexane/CHCl3 v/v, Rf 0.32 (CHCl3); 1H NMR (CDCl3,
300 MHz) d 4.37 (s, 1H, CH), 7.34 (d, J = 5.37 Hz, 1H,
ArH), 7.37 (s, 1H, ArH), 7.47 (d, J = 8.85 Hz, 2H, ArH),
7.87 (d, J = 5.40 Hz, 1H, ArH), 8.00 (d, J = 8.46 Hz, 2H,
ArH), 8.62 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz) d
58.24, 104.86, 115.70, 117.89, 126.86, 127.86, 129.49,
132.53, 135.84, 141.62, 148.78, 150.25, 153.93; IR (KBr)
2197 cmÀ1 (CN); mass (ESI-MS) m/z 281 [M++1]; EI-
HRMS: (M+) calcd for C15H9ClN4 280.05157, found
280.05112.
Representative procedure for the synthesis of (6-phenyl-2-
pyridin-4-ylpyrimidin-4-yl)acetonitrile (6f): An equimolar
mixture of 6-phenyl-4-(piperidin-1-yl)-2H-pyran-2-one-3-
carbonitrile (280 mg, 1 mmol) and arylamidinium salt 4b
(1.2 mmol) in the presence of powdered KOH (84 mg,
1.5 mmol) in DMF (5.0 mL) was stirred for 2 h. Con-
sumption of the starting material was monitored by TLC.
After completion of the reaction, excess DMF was
removed under reduced pressure and the residue was
poured onto crushed ice with vigorous stirring. Neutral-
ization with 10% HCl (5.0 mL) gave a precipitate which
was filtered, washed with water, dried and purified by
silica gel column chromatography using 10% hexane in
chloroform as the eluent. Yield 85%; mp 155–157 °C;
column chromatography, 30/70 hexane/CHCl3 v/v, Rf
1
0.27 (CHCl3); H NMR (CDCl3, 300 MHz) d 4.05 (s, 2H,
CH2), 7.56–7.58 (m, 3H, ArH), 7.82 (s, 1H, ArH), 8.21–
8.25 (m, 2H, ArH), 8.40 (d, J = 6.06 Hz, 2H, ArH), 8.81
(d, J = 5.49 Hz, 2H, ArH); 13C NMR (CDCl3, 75 MHz) d
25.45, 112.47, 114.39, 120.82, 126.10, 127.86, 130.62,
134.45, 142.95, 149.23, 159.03, 161.63 and 164.54; IR
(KBr, cmÀ1) 2935, 2367, 2341, 2251, 1591, 1381, 1354,
1286, 1196, 1126, 1066, 994, 924, 845, 765; mass (ESI-MS)
m/z 273.4 [M++1]; EI-HRMS: (M+) calcd for C17H12N4
272.10619, found 272.10665.