86 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 86–87 J. Chem. Research (M), 1997, 0616–0642 Syntheses of Some 1,2- and 1,4-Dihydropyridines and X-Ray Crystal Structures of 1-Dimethylamino- 5-ethoxycarbonyl-1,4-dihydro-3-methoxycarbonyl-2-methyl- 4-phenylpyridine, 3-Cyano-3,4-dihydro-5-methoxycarbonyl- 6-methyl-4-phenylpyridin-2(1H)-one and 5-Ethoxycarbonyl-1,4-dihydro-3-methoxycarbonyl- 1,2-dimethyl-4-phenylpyridine Max D. Pendleton,a Roy L. Beddoes,a Neil J. Andrew,a Michael Butters*b and John A.Joule*a aChemistry Department, The University of Manchester, Manchester M13 9PL, UK bProcess Research and Development, Pfizer Central Research, Sandwich, Kent CT13 9NG, UK We describe a synthesis of an a-unsubstituted 1,4-dihydropyridine 10 and its 1,2-dihydro isomer, and crystal structures of 10 and some by-products 5 and 6 obtained during the ring synthesis. Considerable interest in the synthesis of 1,4-dihydropyridines derives from their activity as calcium antagonists and thus for the development of drugs for the treatment of cardiovascular diseases.4 1,4-Dihydropyridines are also candidates for the treatment of multidrug resistance (MDR) during cancer chemotherapy,6 as possible thromboxane synthetase inhibitors, 7 PAF-acether antagonists,8 and antithrombotic-antihypertensive agents.10 An alternative to the usual means for the synthesis of 1,4-dihydropyridines2 is the partial reduction11 of pyridinium salts.The addition of 1,1-dimethylhydrazine to ethyl propiolate produced the imine 2, condensation of which with benzaldehyde provided the hydrazone 3.The heterocyclic ring was produced by the reaction of 3 with methyl 3-aminocrotonate in hot acetic acid giving the dihydropyridine 4 accompanied by two other compounds, the structures of which were established by X-ray determinations: 5 and 6. Oxidation of 4 with cerium(IV) ammonium nitrate17 produced 7, subsequent quaternisation giving the salt 8.Reduction of the salt 8 with sodium borohydride in the presence of sodium carbonate produced the 1,2-dihydropyridine 9, whereas reduction with sodium dithionite gave a mixture of the 1,4-dihydropyridine 10 (62%) with 9 (20%). X-ray Crystallography.·Data from crystals (5, approx. 0.30Å0.45Å0.56 mm; 6, 0.40Å0.42Å0.60 mm; 10, 0.25Å 0.35Å0.50 mm) were obtained using a Rigaku AFC5R diffractometer with graphite-monochromated CuKa radiation and a 12 kW rotating anode generator. Structures were solved by direct methods.19 All calculations were performed using the TEXSAN crystallographic software package.21 Data for 5.·There were 2982 unique (Rint=0.049) reflections in the 3134 collected.The final cycle of full-matrix leastsquares refinement was based on 2450 observed reflections [Ia3.00s(I)] and 227 variable parameters and converged (largest parameter shift was s0.01 times its esd) with unweighted and weighted agreement factors of R=0.064 and Rw=0.086.The standard deviation of an observation of unit weight was 3.50. Crystal data for 5. Colourless, prismatic, monoclinic, M, 344.41; V=1873.5(2) Å3; a=12.404(1), b=9.5640(6), c=15.8180(0) Å; b=93.260(6)°; space group P21/n (No. 14); Z=4; Dcalc=1.221 g cmµ3; F(000)=736; h, 0 to 13, k, 0 to 10, l, µ17 to 17. Data for 6.·There were 2182 unique (Rint=0.049) reflections in the 2341 collected. The final cycle of full-matrix leastsquares refinement was based on 1589 observed reflections [Ia3.00s(I)] and 182 variable parameters and converted (largest parameter shift was s0.01 times its esd) with unweighted and weighted agreement factors of R=0.086 and Rw=0.130.The standard deviation of an observation of unit weight was 5.57. *To receive any correspondence.J. CHEM. RESEARCH (S), 1997 87 Crystal data for 6. Colourless prismatic, monoclinic, M, 270.29; V=1393.2(4) Å3; a=13.581(2), b=11.6960(8), c=8.7717(6) Å; b=90.700(8)°; space group P21/c (No. 14); Z=4; Dcalc=1.288 g cmµ3; F(000)=568; h, µ15 to 15, k, µ13 to 9, l, µ8 to 9. Data for 10.·There were 2462 unique (Rint=0.102) reflections in the 2621 collected. The final cycle of full-matrix least-squares refinement was based on 2168 observed reflections [Ia3.00s(I)] and 208 variable parameters and converged (largest parameter shift was s0.01 times its esd) with unweighted and weighted agreement factors of R=0.071 and Rw=0.103. The standard deviation of an observation of unit weight was 4.39.Crystal data for 10. Colourless, prismatic, triclinic, M, 315.37; V=831.0(2) Å3; a=10.279(1), b=13.837(2), c=5.921(1) Å; a=95.28(1), b=93.260(6), g=83.489(9)°; space group P�1 (No. 2); Z=2; Dcalc=1.260 g cmµ3; F(000)=336; h, µ8 to 11, k, µ15 to 15, l, µ6 to 6. We thank the EPSRC and Pfizer Central Research, UK, for CASE awards (to M. D. P. and N. J. A.) and support, and the SERC for funds for the purchase of the Rigaku AFC-5R diffractometer. Techniques used: IR, UV, 1H NMR, mass spectrometry, X-ray crystallography References: 22 Schemes: 1 Tables 1–9: Positional parameters and B(eq) values, intramolecular distances (non-hydrogen atoms) and intramolecular bond angles (non-hydrogen atoms) for 5, 6 and 10 Received, 22nd October 1996; Accepted, 13th December 1996 Paper E/6/07198H References cited in this synopsis 2 A.Hantzsch, Liebigs Ann. Chem., 1892, 215, 1. 4 F. Bossert, H. Meyer and E. Wehinger, Angew. Chem., Int. Ed. Engl., 1981, 20, 762; F.Bossert and W. Vater, Med. Res. Rev., 1989, 9, 291; S. Goldman and J. Stoltefuss, Angew. Chem., Int. Ed. Engl., 1991, 30, 1559; G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cucinotta, J. D. DiMarco, J. Gougoutas, A. Hedberg, M. Malley, J. P. McCarthy, R. Zhang and S. Moreland, J. Med. Chem., 1995, 38, 119. 6 K. Ohsumi, K. Ohishi, Y. Morinaga, R. Nakagawa, Y. Suga, T. Sekiyama, Y. Akiyama, T. Tsuji and T. Tsuruo, Chem. Pharm. Bull., 1995, 43, 818. 7 C. Ennis, S.E. Granger, V. C. Middlefell, M. E. Philpot and N. B. Shepperson, J. Cardiovasc. Pharmacol., 1989, 13, 511. 8 C. E. Sunkel, M. F. de Casa-Juana, L. Santos, M. M. G�omez, M. Villarroya, M. A. Gonz�alez-Morales, J. G. Priego and M. P. Ortega, J. Med. Chem., 1990, 33, 3205. 10 J. L. Archibald, G. Bradley, A. Opalko, T. J. Ward, J. C. White, C. Ennis and N. B. Shepperson, J. Med. Chem., 1990, 33, 646. 11 Key references are: W. Hanstein and K. Wallenfels, Tetrahedron, 1967, 23, 585; F. W. Fowler, J. Org. Chem., 1972, 37, 1321; E. Booker and U. Eisner, J. Chem. Soc., Perkin Trans. 1, 1975, 929; E. E. Knaus and K. Redda, Can. J. Chem., 1977, 55, 1788; D. L. Comins and N. B. Mantlo, J. Org. Chem., 1986, 51, 5456; K. Wallenfels, H. Schuly and D. Hofmann, Liebigs Ann. Chem., 1959, 621, 106; W. S. Caughey and K. A. Schellenberg, J. Org. Chem., 1966, 31, 1978; J.-F. Biellmann and H. J. Callot, Bull. Soc. Chim. Fr., 1969, 1299; Y.-S. Wong, C. Marazano, D. Gnecco and B. C. Das, Tetrahedron Lett., 1994, 35, 707. 17 J. R. Pfister, Synthesis, 1990, 689. 19 G. M. Sheldrick, SHELX-86, Universities of York and Louvain, 1985. 21 TEXSAN-TEXRAY Structure Analysis Package, Molecular Structure Corporation, 1985. Fig. 1 ORTEP plot of 5 Fig. 2 ORTEP plot of 6 Fig. 3 ORTEP plot