An improved synthesis of pyrrolo[1,2-c]pyrimidine derivatives by cyclocondensation of pyrrole-2-carboxaldehydes with tosylmethyl isocyanide followed by desulfonylation of the resulting 2-tosylpyrrolo[1,2-c]pyrimidines with sodium amalgam is described.We thank the Comissió Interdepartamental de Reserca i Innovació Tecnológica (CIRIT) for financial support (project QFN91-4619 ) and the Ministerio de Educación y Ciencia for a grant (J.M.M.

García Navío, José Luis

Minguez Ortega, José Miguel

Vaquero López, Juan José

Álvarez-Builla Gómez, Julio

An improved synthesis of pyrrolo[1,2-c]pyrimidine derivatives by cyclocondensation of pyrrole-2-carboxaldehydes with tosylmethyl isocyanide followed by desulfonylation of the resulting 2-tosylpyrrolo[1,2-c]pyrimidines with sodium amalgam is described.We thank the Comissió Interdepartamental de Reserca i Innovació Tecnológica (CIRIT) for financial support (project QFN91-4619 ) and the Ministerio de Educación y Ciencia for a grant (J.M.M.)Comissió interdepartamental de Recerca i Innovació Tecnológica-CIRI

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Pergamon Tetrahedron Letters, Vol. 37, No. 24, pp. 4263-4266, 1996 Copyright © 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved P I I :  S0040-4039(96)00812-X 0040-4039/96 $15.00 + 0.00 Improved Synthesis of Pyrrolo[1,2-c]pyrimidine and Derivatives Jos6 M. Minguez, Juan J. Vaquero, Jos6 L. Garcfa-Navio, Julio Alvarez-BuiUa* Departamento de Qufmica Org~inica, Universidad de Alcal~, 28871-Alcal~ de Henares, Madrid, Spain Abstract. An improved synthesis of pyrrolo[1,2-c]pyrimidine derivatives by cyclocondensation of pyrrole-2- carboxaldehydes with tosylmethyl isocyanide followed by desulfonylation of the resulting 2-tosylpyrrolo[1,2-c]- pyrimJdines with sodium amalgam is described Copyright © 1996 Elsevier Science Ltd We became interested in pyrrolo[ 1,2-c]pyrimidine 1 as a starting material for a straightforward synthesis of new N-bridged azole systems 3 in which one of the coplanar azole rings is positively charged by quaternization of its bridgehead nitrogen. Such systems exist as a tricyclic cation or alternatively, if internal compensation of the positive charge is accomplished, 2 as a conjugated mesomeric betaine. We hoped that either the cationic or the heterobetalne structures might exhibit interesting electronic properties associated with charge transfer between the azole-azolium moieties. - - y  R s N / X--  R ~ 3 2 1 Y = O , S ,  NR Scheme 1 The retrosynthetic analysis for the target heterobetalne system is shown in Scheme 1. A 1,3-dipolar cycloaddition reaction between a pyrrolo[ 1,2-c]pyrimidinium salt 2 and heterocumulenes was considered to be the key step in building up the tricyclic system. Hence, our initial synthetic proposal involved a known preparation of the pyrrolo[1,2-c]pyrimidine l a  (R l = H) as precursor to salt 2a. However, the seven steps synthesis of la  described by Rapoport, 3 which is the only reported procedure (Scheme 2) gives an overall yield of less than 1%. This extremely low yield stimulated us to develop an alternative procedure for the synthesis of la  and some of its derivatives. In this paper, we report on this improved method along with its scope and limitations. 4263 4264 The reported synthesis 3 of the parent pyrrolo[1,2-c]pyrimidine la which is outlined in Scheme 2, commences with 4-methylpyrimidine and butyl glyoxalate and contains a final step which furnishes a yield of only 9%. We initially chose a strategy whereby condensation of pyrrole-2-carboxaldehyde 4a with ethyl isocyanoacetate 4 would lead to the cyclocondensation product 5a which hopefully could be hydrolised to the corresponding acid 6a, then decarboxylated to give the desired pyrrolo[1,2-c]pyrimidine. Unfortunately 6a proved to be highly resistant to decarboxylation under various conditions, with la being obtained at best in 4% yield in the best case (refluxing in diphenyl ether for 48 h). Attempted decarbonylation of the aldehyde, which was obtained by treating the ester with DIBAL-H (62%), with Wilkinson's catalyst also failed. Consequently, we decide to attempt the cyclocondensation of the starting aldehyde with tosylmethyl isocyanide (TOSMIC) 4"5 in the hope that the resulting sulfone 7a would be more easily converted into la by reductive displacement of the tosyl group. 0 N "~''~" N Me . 7 ~ O , J ~  H v "CH~ 0 N ~ N  ~ 0 . , .  R R=H R=Ts N ' ~ N  OH 4 steps ~ L ~ , , ~ o ~  CH 3 ID 0 TsO'-- + ~ N ~'~ N Rh/250 °C 9% ~ l a  ~ , H  CNCH2COzEt /~"" N " '~ N "COz P " ~ . . , / . ~ . . . .  0 El See text 0 Y "If H 0 4a 5a:R=Et  6a :R=H 4% R 1 R 1 R 2 R 3 . ~  CNCHzSO2Ar 2 j ~ / N " ~ N  Na / Hg / Na2HPO 4 2 t,/~N,'~N R ~ CHO DBU ITHF f v -SO2A r THF I MeOH R l R 3 R3 H 4 7 I Ar = 4-H3C-C6H 4 Scheme 2 The reaction of pyrrole-2-carboxaldehyde with TOSMIC gave the cyclocondensation product 7a in good yield but removal of the tosyl group initially proved troublesome. For example, attempts to desulfonylate 7a with H4LiA1-NiCI26 afforded la in only 7% yield, while treatment with Na2S2047 gave la in just 18% yield. Numerous conditions were studied using amalgam, s and the best results were obtained with a 6% sodium amalgam and Na2HPO 4 in THF-MeOH. 8c Under these conditions la was obtained in 51% yield. 4265 Table. Pyrrolo[ 1,2-clpyrimidine Derivatives 1 Prepared Compd R 1 R 2 R 3 7 a I a No. Yield (%) mp (°C) Yield (%) mp (°C) a H H H 82 200-202 51 42-44 b H Br H 79 223-224 15 b > 300 c H Me H 58 180-181 77 235-237 d H n-Bu H 73 100-102 54 193-195 e H CH2--CHCH 2 H 61 237-238 46 > 300 f H COEMe H 69 210-212 12 c 98-99 g Me Et Me 69 191-192 83 272-274 h Me H H 76 203-205 74 56-57 N ~  i x(~,,,N~/ H H 80 98-99 55 147-149 a All the compounds exldbited spectral and analytical data consistent with their structure. Compounds lb-e, lg and li  were isolated and characterised as hydrobmmides, bA 45% yield of the debmmination product (la) was obtained, c A complex mixture was fomaed. The procedure was then applied to different substituted pyrrole-2-carboxaldehydes, the results of which are shown in the Table. As expected some functionalities were not compatible with the conditions used in the desulfonylation step. Thus, reductive desulfonylation of 7b was accompanied by extensive debromination, and lb  was obtained in only 15% yield. Similarly, only a 12% yield was obtained in the conversion of 7f into If  with a complex mixture being observed. The preparation outlined for l a  is representative of the general procedure. 9 To a mixture of 214 mg ( l . l  retool) of TOSMIC and 167 mg (1.1 retool) of DBU in 2 ml of dry THF under argon, 95 mg (l  mmol) of pyrrole-2-carboxaldehyde in 2 ml of anhydrous THF was added. The mixture was stirred at room temperature for 2 h and then neutralised with acetic acid. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using Hex-EtOAc (7:3) as eluent. Re.crystallization from CH3CN gave 223 mg (82%) of 7a. To 6 % sodium amalgam (184 rag, 8 mmol Na) under argon, a suspension of 639 mg (4.5 retool) of Na2HPO 4 in 15 ml of anhydrous MeOH was added. Subsequently, 272 mg (1 retool) of the sulfone 7a in anhydrous THF (10 ml) were added. The mixture was stirred at room temperature for 3 h, then it was hydrolyzed with water, and extracted with Et20 (3xl0  ml). The organic layer was dried over Na2SO 4, the solvent removed under reduced pressure, and the residue chromatographed on silica gel (CH2CI E- acetone, 9.5:0.5) to give the pyrrole[ 1,2-clpyrimidine l a  (60 mg, 51%). 4266 In conclusion, we have developed an efficient method for the synthesis of pyrrolo[ 1,2-c]pyrimidine and some derivatives by the reaction of pyrrole-2-carboxaldehydes with TOSMIC, followed by desulfonylation of the resulting 2-tosylpyrrolo[ 1,2-c]pyrimidines. Unlike the previously reported strategy this protocol allows the preparation of this system in synthetically useful yields, though it has some limitations arising from the reductive conditions used for the desulfonylation step. An alternative milder displacement of the tosyl goup is currently being investigated. Acknowledgement. We thank the Comissi6 Interdepartamental de Reserca i Innovaci6 Tecnol6gica (CIRIT) for financial support (project QFN91-4619 ) and the Ministerio de Educaci6n y Ciencia for a grant (J.M.M.) References and Notes 1. For reviews of pyrrolodiazines, see: (a) Amarnath, V.; Madhav, R. Synthesis, 1974, 837-859. (b) Kuhla, D.E.; Lombardino, J. G. Adv. Heterocyclic Chem. 1972, 21, 1-63. (c) Blewit, H. L. Chem. Heterocyclic Comp. 1977, 30, 117-178. (d) Maury, G. Chem. Heterocyclic Comp. 1977, 30, 179-244. 2. Pablo, M. S.; Gand~isegui, T.; Vaquero, J. J.; Garcfa, J. L.; Alvarez-Builla, J. Tetrahedron, 1992, 48, 8793. 3. Wong, J. L.; Brown, M. S.; Rapoport, H. J. Org. Chem. 1965, 30, 2398 4. Saikachi, H.; Tokujiro, K.; Ssaki, H.; van Leusen, A. M.; Chem. Pharm. Bull. 1982, 30, 4199. 5. (a) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. Tetrahedron,1972, 52, 5337. (b) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron, 1990, 46, 7587. (c) Haake, G.; Struve, D.; Montforts, F-P. Tetrahedron Lett., 1994, 35, 9703. 6. Ho, K. M.; Lain, C. H.; Luh, T-Y. J. Org. Chem. 1989, 54, 4474 7. Bremner, J.; Julia, M.; Launay, M.; Stacino, J-P. Tetrahedron Lett. 1982, 23, 3265. 8. Pascali, V.; Umani-Ronchi, A. J. Chem. Soc. Chem. Comm. 1973, 351. (b) Kiddie, J. J.; Green, D. L. C.; Thompson, C. M. Tetrahedron, 1995, 51, 2851. (c) Carr, R. V. C.; Williams, R. V.; Paquette, L. A. J. Org. Chem. 1983, 48, 4976. 9. (Ta): IR (KBr) a~ma x 1594, 1348, 1301, 1147 cm -I . 1H NMR (300 MHz, CDC13) 8 8.72 (s, 1H, H1) 8.25 (s, IH), 7.94 (d, 2H, J = 8.2 Hz), 7.49 (d, 1H, J = 2.9 Hz), 7.31 (d, 2H, J = 8.2 Hz), 7.02 (dd, 1H, J = 4.0 Hz, J = 2.9 Hz), 6.82 ( d, 1H, J = 4.1 Hz), 2.41 (s, 3H) ppm. MS (m/z, rel intensity) 272 (M +, 29), 207 (18), 139 (18), 106 (I00). Anal. calcd, for CI4H12N202S: C, 61.75; H, 4.44; N, 10.29; Found: C, 61.50; H, 4.58; N, 10.58. (la): IH NMR (300 MHz, CDCI3) 8 8.78 (s, 1H, Hi ) ,  7.36-7.38 (m, 2H), 7.22 (d, 1H, J = 6.4 Hz), 6.87 (dd, IH, J = 4.0 Hz J = 2.9 Hz), 6.43 (d, 1H, Hs, J = 4.0 Hz) ppm. 13C NMR (300 MHz, CDC13)8 138.54, 136.09, 130.91, 115.77, 113.12, 110.35, 99.27 ppm. MS (m/z, rel intensity) 118 (M ÷ , 100) , 91 (26), 80 (28), 63 (22). (Received in UK 11 April 1996; accepted 26 April 1996) 

Improved synthesis of pyrrolo[1,2-c]pyrimidine and derivatives

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