A novel synthesis of aryl tethered imidazo[4,5-b]pyrazin-2-ones through in situ ring construction and contraction

Article abstract of DOI:10.1016/j.tetlet.2006.12.021

An innovative synthesis of aryl tethered 1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4 and 6 has been delineated through base catalyzed ring transformation of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1 and methyl 6-aryl-4-methylsulfanyl-2H-py

Full text of DOI:10.1016/j.tetlet.2006.12.021

Tetrahedron Letters 48 (2007) 1281–1285
A novel synthesis of aryl tethered imidazo[4,5-b]pyrazin-2-ones
through in situ ring construction and contractionI
Ramendra Pratap,a Abhijeet Deb Roy,b Raja Royb and Vishnu Ji Rama,*
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
bDivision of SAIF, Central Drug Research Institute, Lucknow 226 001, India
Received 28 August 2006; revised 29 November 2006; accepted 7 December 2006
This Letter is dedicated to Professor Wolfgang Pfleiderer, University of Konstanz Germany, on the occasion of his 80th birthday
Abstract—An innovative synthesis of aryl tethered 1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4 and 6 has been delineated through
base catalyzed ring transformation of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1 and methyl 6-aryl-4-methylsulfan-
yl-2H-pyran-2-one-3-carboxylates 5 with 7-acetyl-1,3-dimethyllumazine 2 with subsequent ring contraction of the fused pyrimidine
to an imidazole ring. An additional product, methyl [6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-4-thiophen-
2-ylpyran-2-ylidene]acetate 8b, was also isolated from the reaction of 5 and 2, as a minor constituent.
Ó 2006 Elsevier Ltd. All rights reserved.
The imidazo[4,5-b]pyrazine ring system is present as a
substructure in several marine natural products such
as dibromophakellstatin1 I, phakellin2 II and palau’-
amine3 III with diverse pharmacological activities,
including antibacterial,4 immunosuppressant,5 antineo-
plastic,6 antifungal,7 antihypertensive,8 diuretic, bron-
chodilatory,9 cardiac-stimulatory9 and pesticidal10
(Fig. 1).
O
N
NH
O
Br
N
HN
N
NH
O
Br
HN
N
II
I
H
A comprehensive literature survey showed that the
chemistry of the imidazo[4,5-b]pyrazine ring system
has not been explored extensively. It was first prepared11
through the condensation of 2,3-diaminopyrazine with
an acid chloride or by fusion with urea. Acylation of
the diamine followed by ring closure in hot diphenyl
ether or heating 2,3-diaminopyrazine with an acid are
N
N
H2N
HO
H3C
HN
H
N
N
N
H
O
N
HN
O
N
N
H3C
Cl
CH2NH2
H2N
other methods which has also been reported.10
A
IV
III
Curtius reaction of 3-aminopyrazine-2-carboxylic acid
azide proved to be a versatile route9 for the synthesis
of 1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-ones. An
alternative route has also been developed12 through
Figure 1. Structures of dibromophakellstatin I, phakellin II and
palau’amine III and 1,3-dimethylimidazo[4,5-b]pyrazin-2-one IV.
the condensation–cyclization of 2-amino-3-pyrazine-
carboxylic acid with hydroxylamine in moderate yield.
This ring system has also been prepared from the
reaction of 2,5-diamino-3,6-dicyanopyrazine with alkyl
isocyanate, but in poor yield.13 Further, nucleosides of
this class of compounds have been prepared14 through
Keywords: Imidazo[4,5-b]pyrazine; 2H-Pyran-2-ones; Ring trans-
formation.
q CDRI Communication No. 7067.
*
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.2006.12.021

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R. Pratap et al. / Tetrahedron Letters 48 (2007) 1281–1285
the condensation of a 4,5-diaminoimidazole nucleoside
with 1,2-diketones.
the base catalyzed ring transformation of 1 and 5 with
7-acetyl-1,3-dimethyllumazine 2 with subsequent con-
traction of the pyrimidine to an imidazole ring.
We report here a concise synthesis of 5-aryl-1,3-di-
methylimidazo[4,5-b]pyrazin-2-ones 4 and 6 through
6-Aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles
1 and methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-
3-carboxylates 5 were used for the ring transformation
with 7-acetyl-1,3-dimethyllumazine 2. The former were
obtained15 in two steps by stirring an equimolar mixture
of aryl methyl ketones and methyl 2-cyano-3,3-dimeth-
ylthioacrylate in the presence of powdered KOH in
DMSO, followed by amination with piperidine in
ethanol at reflux. Lactones 5 were prepared15 analo-
gously from the reaction of aryl methyl ketones
and methyl 2-carbomethoxy-3,3-dimethylthioacrylate.
7-Acetyl-1,3-dimethyllumazine 2 was prepared by acyla-
tion of 1,3-dimethyllumazine.16
Table 1. Synthesis of imidazo[4,5-b]pyrazin-2-ones 4
Compound
Structure
Time Yield
(h)
(%)
N
CN
N
4a
2
79
CH3
N
O
N
N
CH3
The reaction of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-
one-3-carbonitriles 1 with 7-acetyl-1,3-dimethyllumazine
2 in the presence of powdered KOH in dry DMF affor-
ded 5-aryl-1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4
in good yields. Analogously, the reaction of 5 with 7-
acetyl-1,3-dimethyllumazine under identical reaction
conditions produced a mixture of two products, 5-bi-
N
CN
4b
4c
4d
4e
4f
2.5
2.5
2
81
73
83
87
75
79
CH3
N
N
O
N
CH3
Cl
N
aryl-1,3-dimethylimidazo[4,5-b]pyrazin-2-ones
methyl 4-aryl-[6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-
imidazo[4,5-b]pyrazin-5-yl)pyran-2-ylidene]acetate 8.
6
and
N
The yields and reaction conditions for these reactions
are presented in Tables 1 and 2. The structures of the
final compounds 4, 6 and 8b were established unequivo-
cally using one- and two-dimensional NMR experiments
(see Supplementary data). Possibly, the first stage of the
reaction is the conversion of the acetyl to a biaryl17 to
form 7-biaryl-1,3-dimethyllumazine 3 as an intermediate
with subsequent ring contraction in a second step to
CN
CH3
N
N
N
O
N
CH3
Br
N
CN
CH3
N
N
Table 2. Synthesis of imidazo[4,5-b]pyrazin-2-ones 6 and 8b
O
N
H3C
N
Compound
Structure
Time Yield
(min) (%)
CH3
SCH3
N
COOCH3
CN
CH3
CH3
2.5
N
N
6a
45
50
39
35
N
N
N
O
O
N
CH3
H3CO
N
H3CO
N
CH3
SCH3
COOCH3
N
N
CH3
CN
6b
N
2
CH3
N
O
S
N
N
N
N
O
CH3
S
N
CH3
S
N
CN
H C
3
4g
2
CH3
N
8b
50
14
COOCH
N
N
3
N
N
N
O
O
O
N
N
CH3
H C
3

R. Pratap et al. / Tetrahedron Letters 48 (2007) 1281–1285
1283
Scheme 1. A plausible mechanism for the formation of 6-aryl-1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4.
yield 5-aryl-1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4
(Scheme 1).
aryl-1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 6 along
with pyran 8. Possibly, the weaker electron-withdrawing
properties of –COOMe compared to CN at position 3 of
the pyran ring facilitated the enolization followed by
successive Michael addition and elimination of methyl
mercaptan to yield 8 (Scheme 2 and Table 2). Separation
of the products was difficult but we succeeded in sepa-
rating the major constituent 6 through preparative
TLC. The minor constituent 8 was unstable.
Several attempts were made to detect the proposed
intermediate 3 from the reaction of 1 and 2 to ascertain
the course of the reaction through real time proton
NMR, but these failed.
Two other experiments with 1 and 2 were carried out
in the presence of light and in the dark. In the former
case, the reaction proceeded smoothly to provide 4 while
in the dark, 2 decomposed completely leaving behind
starting material 1. From these experiments, it was
concluded that light is essential for the activation and
progress of the reaction. A plausible mechanism is
depicted in Scheme 1.
All the compounds were characterized by spectroscopic
techniques.18
In summary, the reactions of suitably functionalized 2H-
pyran-2-ones with 7-acetyl-1,3-dimethyllumazine result
in the formation of 5-aryl-1,3-dimethylimidazo[4,5-b]-
pyrazin-2-ones in fair to excellent yields. Our approach
for the construction of this ring system is novel and
opens a new avenue for the synthesis of this class of
compounds within 2–3 h in high yields.
The reaction was generalized further by reacting methyl
6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates
5 with 2 under analogous reaction conditions, to give 5-

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R. Pratap et al. / Tetrahedron Letters 48 (2007) 1281–1285
Scheme 2. A plausible mechanism for the formation of methyl [4-aryl-6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)pyran-2-
ylidene]acetate 8.
7. Kinnel, R. B.; Gehrken, H. P.; Scheuer, P. J.; Gravalos, D.
G.; Faircloth, G. T. Eur. Pat. Appl. 1994, EP 626,383;
Chem. Abstr. 1995, 122, 114884j.
8. Grabowski, E. J. J.; Tristram, E. E.; Tull, R. J. Ger. Offen,
1,920,173, 15th January 1970; Chem. Abstr. 1970, 72,
1000757g.
Acknowledgements
The authors thank CSIR, New Delhi, for financial sup-
port and the Sophisticated Analytical Instrument Facil-
ity, CDRI, Lucknow, for providing spectroscopic data.
9. Jones, J. H.; Holtz, W. J.; Gragoe, E. J., Jr. J. Med. Chem.
1973, 16, 537–542.
10. Tong, Y. C. J. Heterocycl. Chem. 1975, 12, 1127–1131.
11. Schipper, E.; Day, A. R. J. J. Am. Chem. Soc. 1952, 74,
350–352.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.12.021.
12. Hershenson, F. M.; Bauer, L.; King, K. F. J. Org. Chem.
1968, 33, 2543–2544.
13. Shirai, K.; Fukunishi, K.; Yanagisawa, A.; Takahashi, H.;
Matsuoka, M. J. Heterocycl. Chem. 2000, 37, 1151–1156.
14. Sharma, R. A.; Bobek, M.; Cole, F. E.; Bloch, A. J. Med.
Chem. 1973, 16, 643–647.
References and notes
1. Jacquot, D. E. N.; Zoellinger, M.; Lindel, T. Angew.
Chem., Int. Ed. 2005, 44, 2295–2298.
2. (a) Poullennec, K. G.; Kelly, A. T.; Romo, D. Org. Lett.
2002, 4, 2645–2648; (b) Jacquot, D. E. N.; Hoffmann, H.;
Polborn, K.; Lindel, T. Tetrahedron Lett. 2002, 43, 3699–
3702.
15. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A. J.
Chem. Res. (S) 1991, 98–99; (b) Ram, V. J.; Verma, M.;
Hussaini, F. A.; Shoeb, A. Liebigs Ann. Chem. 1991, 1229–
1230; (c) Ram, V. J.; Haque, N.; Singh, S. K.; Hussaini, F.
A.; Shoeb, A. Indian J. Chem. 1993, 32, 924.
16. Baur, R.; Kleiner, E.; Pfleiderer, W. Liebigs Ann. Chem.
1984, 1798–1814.
17. (a) Ram, V. J.; Nath, M.; Srivastava, P.; Sarkhel, S.;
Maulik, P. R. J. Chem. Soc., Perkin Trans. 1 2000, 3719–
3723; (b) Ram, V. J.; Srivastava, P.; Agarwal, N.; Sharon,
A.; Maulik, P. R. J. Chem. Soc., Perkin Trans. 1 2001,
1953–1959.
3. Kinnel, R. B.; Gehrken, H. P.; Scheuer, P. J. J. Am. Chem.
Soc. 1993, 115, 3376–3377.
4. Du, H. Diss. Abstr. Int. B. 2005, 65, 3464.
5. Kinnel, R. B.; Gehrken, H. P.; Swati, R.; Skoropowski,
G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281–3286.
6. Boyd, M. R.; Pettit, G. R.; McNutty, J.; Herald, D. L.;
Doubek, D. L.; Chapuis, J. C.; Schmidt, J. M.; Tackett, L.
P. J. Nat. Prod. 1997, 60, 180–183.
18. General procedure for the synthesis of 5-aryl-1,3-dimethyl-
imidazo[4,5-b]pyrazin-2-ones (4): An equimolar mixture

R. Pratap et al. / Tetrahedron Letters 48 (2007) 1281–1285
1285
of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitrile
(0.5 mmol), 7-acetyl-1,3-dimethyllumazine (117 mg, 0.5
mmol) and KOH (34 mg, 0.6 mmol) in DMF (3.0 mL)
was stirred under nitrogen for 2–2.5 h. Completion of the
reaction was monitored by TLC, then excess DMF was
removed under reduced pressure. Thereafter, the reaction
mixture was poured onto crushed ice with vigorous
stirring, neutralized with 10% HCl (5.0 mL), and the
precipitate obtained was filtered, washed with water, dried
and purified by neutral alumina column chromatography,
eluting with 20% hexane in chloroform.
isolated in 35–39% yields were identified as methyl
(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-
5-yl)-6-methylsulfanyl-4-arylbenzoates. The minor prod-
uct could not be isolated due to instability at room
temperature. In only one case, we did succeed in isolating
the minor constituent from the reaction mixture as methyl
[6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyr-
azin-5-yl)-4-thiophen-2-yl-pyran-2-ylidene]acetate (8b) in
low yield.
Methyl 5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]-
pyrazin-5-yl)-40-methoxy-3-methylsulfanyl-biphenyl-4-carbo-
xylate (6a): Cream coloured solid; yield 39%; mp 180–
182 °C; IR (KBr): 2945, 2364, 1730, 1661, 1602, 1512,
1453, 1336, 1283, 1251, 1184, 1058, 1022, 881, 836,
5-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyr-
azin-5-yl)-40-methoxy-3-(piperidin-1-yl)-biphenyl-4-carbo-
nitrile (4e): White powder; yield 87%; mp 194–196 °C; IR
(KBr): 3010, 2926, 2862, 2367, 2340, 2201, 2143, 1722,
1658, 1586, 1553, 1452, 1353, 1266, 1090, 1010, 970, 825,
740 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 2.55 (s, 3H,
;
SCH3), 3.51 (s, 3H, NCH3), 3.54 (s, 3H, NCH3), 3.75 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 7.00 (d, J = 8.1 Hz, 2H,
ArH), 7.54–7.57 (m, 4H, ArH), 8.23 (s, 1H, ArH); 13C
NMR (CDCl3, 75 MHz): 17.52, 25.76, 25.87, 52.04, 55.39,
114.43, 115.50, 121.27, 124.84, 126.15, 128.35, 131.32,
132.08, 133.37, 136.80, 138.26, 142.94, 144.31, 153.85,
159.90, 168.87; MS (FAB): 451 (M++1); HRMS: (EI,
70 eV) calcd for C23H22N4O4S 450.13618 (M+) found for
m/z 450.13651.
1
764 cmꢀ1; H NMR (CDCl3, 400 MHz): d 1.63–1.65 (m,
2H, CH2), 1.81–1.84 (m, 4H, CH2), 3.27 (t, J = 5.21 Hz,
4H, CH2NCH2), 3.55 (s, 3H, NCH3), 3.57 (s, 3H, NCH3),
3.87 (s, 3H, OCH3), 7.01 (d, J = 8.72 Hz, 2H, ArH), 7.20
(d, J = 1.12 Hz, 1H, ArH), 7.38 (d, J = 1.24 Hz, 1H,
ArH), 7.56 (d, J = 8.68 Hz, 2H, ArH), 8.31 (s, 1H, ArH);
13C NMR (CDCl3, 100 MHz): d 24.07, 25.93, 25.96, 26.19,
53.62, 55.42, 103.54, 114.02, 114.44, 116.58, 116.92,
117.97, 119.21, 120.71, 128.45, 132.09, 134.70, 138.65,
143.11, 143.37, 145.81, 153.97, 159.05, 160.19; MS (FAB):
455 (M++1); HRMS: (EI, 70 eV) calcd for C26H26N6O2
454.21172 (M+) found for m/z 454.21154.
General procedure for the synthesis of methyl (1,3-dimethyl-
2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-6-methyl-
sulfanyl-4-arylbenzoate (6): This was prepared analogously
by the reaction of methyl 6-aryl-4-methylsulfanyl-
2H-pyran-2-one-3-carboxylates and 7-acetyl-1,3-dimethyl-
lumazine. The mixture of two products obtained was
separated by preparative TLC. The major products
Methyl [6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]-
pyrazin-5-yl)-4-thiophen-2-yl-pyran-2-ylidene]acetate (8b):
Deep red solid; yield: 14%; mp: 157–159 °C; IR (KBr):
3084, 2366, 1724, 1677, 1586, 1551, 1494, 1455, 1421, 1371,
1286, 1226, 1142, 1092, 1007, 948, 919, 880, 810, 735 cmꢀ1
;
1H NMR (CDCl3, 200 MHz): d 3.59 (s, 3H, OCH3), 3.75
(s, 3H, NCH3), 3.78 (s, 3H, NCH3), 5.13 (s, 1H, CH), 7.16
(dd, J = 3.82 and 3.86 Hz, 1H, ArH), 7.35 (d, J = 1.7 Hz,
1H, ArH), 7.47–7.55 (m, 3H, ArH), 8.26 (s, 1H, ArH);
HRMS: (EI, 70 eV) calcd for C19H16N4O4S 396.08923
(M+) found for m/z 396.08955.