O2N X 1a,b,f,g PhS NC ButOK–DMF 0 °C VNS O2N X N C 2a,b,f,g O2N X H2N O2N X HN OHC 3b 4a,b,f,g H3O+ r.t. H3O+ heat X H2N X HN 6a–g 5a,b,f,g H2, 10% Pd–C, 40 lbf in–2 R H2N EtOH H2, 10% Pd–C, 40 lbf in–2 EtOH PATHWAY A (R = H) PATHWAY B X N 7a–f N R air Cl X = (a); N N CH3 (b,c,d,e); (f); N (g); R = H (a,b,f,g); Me (c); Bun (d); Ph (e) RC(OR¢)3 reflux NH2 NH CHO 8 N N 9 R1, R2 = Me 10 R1, R2 = Ph R1 R2 O 14 J. CHEM. RESEARCH (S), 1998 J. Chem. Research (S), 1998, 14–15 J. Chem. Research (M), 1998, 0180–0187 New Synthesis of Fused Pyrimidine Derivatives via ortho-(Isocyanomethyl)nitroaromatic Compounds Stanis ý law Ostrowski* Institute of Organic Chemistry, Polish Academy of Sciences, ul.Kasprzaka 44/52, PL 01-224 Warszawa, Poland An efficient synthesis of functionalized fused pyrimidine derivatives from the respective ortho-(isocyanomethyl)nitroarenes is described: hydrolysis of the isocyano group in the title isocyanides followed by catalytic reduction of the nitro group and subsequent cyclocondensation of the diamine formed with orthoesters leads to the final products.Since the early years of this century several studies on the synthesis and structure–activity relationships of pyrimidine derivatives have been reported.1,2 A pyrimidine nucleus is embedded in a large number of alkaloids, drugs, antibiotics, agrochemicals and antimicrobial agents.1 In addition, many simple fused pyrimidines (purines, pteridines) are biologically active by themselves2b,c or are essential components of very important naturally occurring substances.The availability of starting materials has been a limiting factor for the preparation of fused pyrimidine derivatives8,9 such as quinazolines and various tricyclic heteroaromatic compounds. Many of these products can be easily synthesized from the corresponding ortho-aminobenzylamines or their fused heteroanalogues.10 However, the rather difficult access to these key intermediates11a,b or to their precursors11c is a serious limitation for this synthesis.We have described lately12 a general method for the synthesis of ortho-isocyanomethyl nitro-aromatic/heteroaromatic compounds of type 2 (Scheme), based on the Vicarious Nucleophilic Substitution (VNS) of hydrogen. In this work a practical application of the above method for the synthesis of fused pyrimidines is described. One can expect that the wide spectrum of nitroarenes available as starting materials will broaden considerably the frontiers of this synthesis.The desired ortho-(N-formylaminomethyl)nitroaromatic compounds of type 3 or diamino intermediates 5 were effi- ciently obtained from the above isocyanides 2. Hydrolysis of these isocyanides under mild conditions (MeOH–H2O, catalytic amount of HCl, room temperature, 10 h) gave formamides such as 3b. Subsequent reduction of the nitro group (10% Pd–C, 40 lbf inµ2, EtOH, 4 h) followed by cyclisation was expected to afford a pyrimidine derivative of type 6 (Pathway A).Instead, this model compound 2-(N-formylaminomethyl)- 1-nitronaphthalene (3b), while hydrogenated under these conditions, gave small amounts of the desired product 6b (s10%) and N-(1-aminonaphthalen-2-ylmethyl)- formamide (8) in ca. 40% yield which cyclized efficiently to 6b only at 200 °C (EtOH, sealed tube, 10 h). Moderate amounts of the diamino derivative 5b were also found. The collected dihydro compound 6b underwent a spontaneous oxidation to 7b in ca. 45% yield (calculated on the starting isocyanide 2b). Additionally, the transformation of 5b into 6b in the reaction with triethyl orthoformate, then oxidation to 7b, raised the overall yield to 53%. The above approach, due to the number of various operations it required, had no practical value from an experimental point of view and was not therefore applied to the synthesis of other derivatives. The alternative pathway B was more efficient.For example, the exhaustive hydrolysis of 2b to 4b (concentrated HCl, MeOH–H2O, reflux, 1 h) and subsequent hydrogenation (10% Pd–C, EtOH, 40 lbf inµ2, 4 h) afforded diamine 5b, which was converted by treatment with triethyl orthoformate into the fused pyrimidine 7b in 58% overall yield. The last step · an aromatization of the dihydro derivative (6) · occurred spontaneously. In addition to its simplicity, the method B allowed functionalization at C-2 by using diverse orthoesters (see compounds 7c–e). All the synthesized products are listed in Table 1.In some cases, owing to condensation of the diamines (5) with two molecules of the orthoester, small quantities of the corresponding N-acetyl- or N-benzoyl-dihydropyrimidine derivatives (9 or 10) were formed as by-products. To avoid this side-process, the condensation with the orthoester was carried out in boiling ethanol (procedure C). Lower temperatures and dilution of the reaction mixture improved selectivity. The condensation was stopped at the stage of the dihydro compounds (6), giving also considerably higher yields.This procedure was demonstrated for the preparation of 6e (84%) and 6g (61%). The product 6e when left at room temperature quickly started to undergo spontaneous aromatization to 7e. *E-mail: Stan@ichf.edu.pl SchemeN N Cl 7a N N 7b N N 7c Me N N 7d N N 7e Ph N NH 6e Ph [ox.] 7f N N N N Me 6g N NH N J. CHEM. RESEARCH (S), 1998 15 Compound 7f exemplifies the application of the above methodology to the synthesis of purines using imidazole derivatives.Approaches to purines from imidazoles are not exhaustively described in the literature.16 Currently we are in the midst of exploring this new type of synthetic possibility with the use of methods from our laboratory17 and the complete results will be published soon.18 This work was supported by the State Committee for Scientific Research, Grant 2 P303 087 07. Techniques used: 1H NMR, MS, TLC References: 18 Tables: 1 Schemes and Figures: 4 Received, 6th May 1997; Accepted, 25th June 1997 Paper E/7/03092D References cited in this synopsis 1 D.J. Brown, in The Chemistry of Heterocyclic Compounds, The Pyrimidines, ed. E. C. Taylor, Wiley, New York, 1994. 2 (a) W. L. F. Armarego, in The Chemistry of Heterocyclic Compounds, Fused Pyrimidines, Part I: Quinazolines, ed. D. J. Brown, Interscience, New York, 1967; (b) J. H. Lister, ibid., Part II: Purines, ed.D. J. Brown, Wiley–Interscience, New York, 1971; (c) D. J. Brown, ibid., Part III: Pteridines, ed. E. C. Taylor, Wiley, New York, 1988; (d) T. J. Delia, ibid., Part IV: Miscellaneous Fused Pyrimidines, ed. E. C. Taylor, Wiley, New York, 1992. 8 Bischler’s synthesis: A. Bischler, Ber. Dtsch. Chem. Ges., 1891, 24, 506; W. L. F. Armarego and J. I. Smith, J. Chem. Soc. C, 1966, 234; Riedel’s synthesis: A. Riedel, Ger. Pat. 174941, 1905; M. T. Bogert and E. M. McColm, J.Am. Chem. Soc., 1927, 49, 2650; W. L. F. Armarego, J. Chem. Soc., 1962, 561; Niementowski’s synthesis: S. Niementowski, J. Prakt. Chem., 1895, 51(2), 564; ref. 2(a), pp. 74–78. 9 (a) D. Chakravarti, R. N. Chakravarti, L. A. Cohen, B. Dasgupta, S. Datta and H. K. Miller, Tetrahedron, 1961, 16, 224; (b) S. C. Pakrashi, J. Bhattacharyya, L. F. Johnson and H. Budzikiewicz, Tetrahedron, 1963, 19, 1011; (c) G. C. Mu�noz and R. Madro�nero, Chem. Ber., 1962, 95, 2182. 10 (a) B. R. Baker, R.E. Schaub, J. P. Joseph, F. J. McEvoy and J. H. Williams, J. Org. Chem., 1952, 17, 164; (b) N. J. Leonard and M. J. Martell Jr., Tetrahedron Lett., 1960, 25, 44; (c) S. C. Bell and S. J. Childress, J. Org. Chem., 1962, 27, 1691; (d) T. Goto, Y. Kishi, S. Takahashi and Y. Hirata, Tetrahedron, 1965, 21, 2059. 11 (a) H. E. Zaugg and W. B. Martin, Org. React., 1965, 14, 52; (b) S. Kano, Y. Tanaka, S. Sugino and S. Hibino, Synthesis, 1980, 695; (c) Y. Tomioka, K. Ohkubo and M.Yamazaki, Chem. Pharm. Bull., 1985, 33, 1360. 12 M. Maikosza, A. J. Kinowski and S. Ostrowski, Synthesis, 1993, 1215. 13 K. Schofield and T. Swain, J. Chem. Soc., 1949, 1367. 14 T. Koyama, T. Hirota, F. Yagi, S. Ohmori and M. Yamata, Chem. Pharm. Bull., 1975, 23, 3151. 15 A. Bendich, P. J. Russell Jr. and J. J. Fox, J. Am. Chem. Soc., , 76, 6073. 16 (a) J. Sarasin and E. Wegmann, Helv. Chim. Acta, 1924, 7, 713; (b) A. H. Cook and E. Smith, J. Chem. Soc., 1949, 2329, 3001; (c) G. Shaw and D. N. Butler, J. Chem. Soc., 1959, 4040; (d) R. N. Naylor, G. Shaw, D. V. Wilson and D. N. Butler, J. Chem. Soc., 1961, 4845; (e) K. Kadir, G. Shaw and D. Wright, J. Chem. Soc., Perkin Trans. 1, 1980, 2728; (f) K. E. Andersen and E. B. Pedersen, Liebigs Ann. Chem., 1985, 921; (g) P. R. Birkett, H. King, Ch. B. Chapleo, D. F. Ewing and D. Mackenzie, Tetrahedron, 1993, 49, 11029. 17 (a) S. Ostrowski, Synlett, 1995, 253; (b) S Ostrowski, Heterocycles, 1996, 43, 389. 18 S. Ostrowski, in preparation. Table 1 Fused pyrimidine derivatives Mp (T/°C)b Product Procedure Yield (%)a (solvent) B A B B B B C B C 52 53 58 44e 60 21f 84g 21 61 135–137 (CHCl3)c 95–98 (CHCl3–MeOH)d 82 (subl.) oil 149–151 (CHCl3) semi-crystalline 171–173 (CHCl3)h semi-crystalline aTotal yields based on the isocyanide (2). bUncorrected. cLit. mp 143 °C.13 dLit. mp 102–103 °C.14 eTraces of 9 were found. fSmall amount of 10 was isolated (s5% yield). gSmall amount of 7e was formed (6%), also product 6e decomposed slowly to yield 7e. hLit., mp 183–184 °C.15