J. Org. Chem. 1997, 62, 3109-3118
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Dipolar Cycloaddition Reactions of Dihydropyrimidine-Fused Mesomeric Betaines. An Approach toward Conformationally Restricted Dihydropyrimidine Derivatives1 C. Oliver Kappe* Institute of Organic Chemistry, Karl-Franzens-University Graz, A-8010 Graz, Austria
Karl Peters and Eva-Maria Peters Max-Planck-Institut fu¨ r Festko¨ rperforschung, Heisenbergstrasse 1, D-70506 Stuttgart, Germany Received January 22, 1997X
The bimolecular and intramolecular cycloaddition potential of various 4-aryldihydropyrimidinefused mesomeric betaines was investigated. Dihydropyrimidine-fused isothiomu¨nchnones and isomu¨nchnones were found to undergo 1,3-dipolar cycloaddition reactions with electron-deficient dipolarophiles such as DMAD, methyl propiolate, methyl vinyl ketone, or N-methylmaleimide. In contrast, cross-conjugated mesomeric thiazinium betaines underwent 1,4-dipolar cycloaddition reaction with electron-rich dipolarophiles such as ynamines or ketene acetals. In general, these cycloadditions show a high degree of regioselectivity, facial selectivity, and exo/endo diastereoselectivity. Intramolecular variations of the above processes involving o-alkenylaryl-tethered dihydropyrimidine-fused isomu¨nchnones lead to polycyclic dihydropyrimidine analogs that closely mimic the proposed receptor-bound conformation of dihydropyridine calcium channel modulators. These cycloadducts are the result of an endo-addition of the π-bond to the carbonyl ylide dipole embedded in the isomu¨nchnone system. The relative stereochemistry of these cycloadducts was established by single-crystal X-ray analysis. Introduction 4-Aryl-1,4-dihydropyridines of the nifedipine type (DHPs, e.g., 1) were first introduced into clinical medicine in 1975 and are still the most potent group of calcium channel modulators available for the treatment of cardiovascular diseases.2 Dihydropyrimidines of type 2 (DHPMs) show a very similar pharmacological profile, and in recent years, several lead compounds were developed (e.g., 3) that are equal in potency and duration of antihypertensive activity to classical and second-generation dihydropyridine drugs.3,4 Despite many studies on the structure-function relationships of this type of calcium channel modulators, there still remains debate on the exact stereochemical/ conformational requirements for activity.5 In 1995, a * To whom correspondence should be addressed. Fax: (43)-(316)3809840. E-mail:
[email protected]. X Abstract published in Advance ACS Abstracts, April 15, 1997. (1) Synthesis and Reactions of Biginelli Compounds. 7. Part 6: Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron 1997, 53, 2803-2816. (2) (a) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug. Res. 1987, 16, 309. (b) Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9, 291-324. (3) (a) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.; Ishihara, T.; Funahashi, K.; Satah, F.; Morita, M.; Noguchi, T. J. Med. Chem. 1989, 32, 2399-2406. (b) Atwal, K.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutas, J. Z.; Malley, M. F.; Floyd, D. M. J. Med. Chem. 1990, 33, 1510-1515. (c) Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. J. Med. Chem. 1990, 33, 2629-2635. (d) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 34, 806-811. (e) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254-3263. (f) Grover, G. J.; Dzwonczyk, S.; McMullen, D. M.; Normadinam, C. S.; Sleph, P. G.; Moreland, S. J. J. Cardiovasc. Pharmacol. 1995, 26, 289-294. (g) Negwer, M. Organic-Chemical Drugs and their Synonyms; Akademie Verlag: Berlin, 1994; p 2558. (4) (a) Atwal, K. S.; Moreland, S. Bioorg. Med. Chem. Lett. 1991, 1, 291-294. (b) Alajarin, R.; Vaquero, J. J.; Alvarez-Builla, J.; Fau de Casa-Juana, M.; Sunkel, C.; Priego, J. G.; Gomez-Sal, P.; Torres, R. Bioorg. Med. Chem. 1994, 2, 323-329.
S0022-3263(97)00121-7 CCC: $14.00
detailed structure-activity profile for a series of DHPM derivatives was reported, leading to a general bindingsite model for DHP/DHPM calcium channel modulators.6 The stereochemical relationship between the aryl group and the dihydropyrimidine ring was found to be one of the factors having a pronounced effect on the biological activity.5,6 It was proposed that in the receptor-bound conformation the substituted aryl ring is positioned axially, perpendicular to, and bisecting the boatlike dihydropyridine/dihydropyrimidine ring, with the 4-aryl substituent X adopting a synperiplanar (relative to C4H) orientation.6
(5) For a recent review, see: Goldman, S.; Stoltefuss, J. Angew. Chem. 1991, 103, 1587-1605; Angew. Chem., Int. Ed. Engl. 1991, 30, 1559-1578 and references therein. (6) For a more detailed discussion, see: Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.; McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem. 1995, 38, 119-129. For a commentary, see: Triggle, D. J.; Padmanabhan, S. Chemtracts: Org. Chem. 1995, 8, 191-196.
© 1997 American Chemical Society
3110 J. Org. Chem., Vol. 62, No. 10, 1997 Scheme 1
Kappe et al.
stereocenter in the dipole and (ii) the application of the intramolecular variation of this methodology toward the construction of conformationally restricted dihydropyrimidine derivatives.
Results and Discussion
Herein we describe synthetic methodology leading toward novel types of conformationally restricted dihydropyrimidine derivatives of type 5 that closely mimic the recently proposed receptor-bound conformation of DHP/DHPM calcium channel modulators (see above). Our strategy toward these polycyclic dihydropyrimidines is outlined in Scheme 1 and involves an intramolecular 1,3-dipolar cycloaddition reaction of an o-alkenylaryltethered dihydropyrimidine-fused mesomeric betaine as the key step (6 f 5). In recent years, mesomeric beatines of this general type, i.e., isomu¨nchnones (1,3-oxazolium4-olates)7,8 and isothiomu¨nchnones (1,3-thiazolium-4olates),7,9 have proven to be very useful intermediates in a variety of synthetic applications.7-9 The carbonyl ylide or thiocarbonyl ylide dipoles, respectively, incorporated in these mesoionics have been demonstrated to undergo both bimolecular and intramolecular cycloaddition reactions with relative ease.7-9 There are also a number of examples involving bimolecular and intramolecular 1,4dipolar cycloaddition reactions of related six-membered analogs, i.e., of cross-conjugated heteroaromatic 1,3thiazinium betaines.10,11 In the present paper, we investigate the dipolar cycloaddition chemistry of dihydropyrimidine-fused fiveand six-membered mesomeric betaines. Of particular interest to us are (i) stereochemical aspects in these cycloaddition reactions relating to the presence of a (7) For reviews of the cycloaddition chemistry of isomu¨nchnones and isothiomu¨nchnones, see: (a) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 123-141. (b) Newton, C. G.; Ramsden, C. A. Tetrahedron 1982, 38, 2965-3011. (c) Ollis, W. D.; Ramsden, C. A. Adv. Heterocycl. Chem. 1976, 19, 1-122. (8) (a) Padwa, A.; Austin, D. J.; Price, A. T.; Weingarten, M. D. Tetrahedron 1996, 52, 3247-3260. (b) Padwa, A.; Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T. J. Org. Chem. 1994, 59, 1418-1427 and references cited therein. (9) (a) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; Higes, F. J.; Jimenez, J. L.; Palacios, J. C. J. Org. Chem. 1996, 61, 3738-3748. (b) Padwa, A.; Kinder, F. R.; Nadler, W. R.; Zhi, L. Heterocycles 1993, 35, 367-383 and references cited therein. (10) For reviews and classifications of this type of heteroaromatic betaines, see: (a) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985, 41, 2239-2329. (b) Friedrichsen, W.; Bo¨ttcher, A.; Kappe, T. Heterocycles 1982, 19, 1082-1148. (11) For more recent examples, see: Padwa, A.; Coats, S. J.; Semones, M. Tetrahedron 1995, 51, 6651-6668 and references therein.
Whereas dihydropyridines of the nifedipine type (DHPs) are generally prepared by the well-known Hantzsch synthesis,12 the aza-analogs 2 (DHPMs) are readily available through the Biginelli dihydropyrimidine synthesis (Scheme 1)13 or other related methods.13,14 These dihydropyrimidine derivatives are inherently asymmetric and have the advantage that the (thio)amide moiety embedded in the dihydropyrimidine ring allows a selective functionalization of the biologically less important “right-hand side” of the molecule (see above),13 a process that is more troublesome in the dihydropyridine series.15 We began by first exploring the intermolecular cycloaddition properties of a series of dihydropyrimidinefused betaines in order to establish the general viability of dipolar cycloaddition reactions in this series of fused mesoionics. Our studies commenced with the synthesis of dihydropyrimidine-fused isothiomu¨nchnone 8 (Scheme 2). The required dihydropyrimidine-2-thione 7 was readily available by condensation of benzaldehyde, ethyl acetoacetate, and N-methylthiourea under standard Biginelli conditions.16 Thioisomu¨nchnone 8 was obtained as a stable, orange-red solid by sequential addition of R-bromophenylacetyl chloride and triethylamine to a solution of 7 in chloroform, following a protocol developed by Potts et al.17,18 Thioisomu¨nchnone 8 reacted smoothly with dimethyl acetylenedicarboxylate (DMAD) and methyl propiolate at ca. 100 °C in toluene to produce pyridopyrimidines 10a,b in high yields. The intermediate primary cycloadducts 9a,b could not be isolated and underwent clean extrusion of sulfur (9 f 10). In the reaction with methyl propiolate complete regioselectivity was observed, no trace of the other isomer being observed. The position of the methyl ester group in 10b was established unequivocally by determination of long-range 1H-13C connectivities through an HMBC NMR experiment,19 which confirms the expected and well-precedented regiochemistry of this bimolecular 1,3-dipolar cycloaddition.20,21 Recent semiempirical calculations on the FMO interactions in the cycloaddition of related (12) For reviews of the Hantzsch synthesis and related reactions, see: (a) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269-289. (b) Stout, D. M.; Meyers, A. J. Chem. Rev. 1982, 82, 223-243. (c) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1-42. (13) For a review of the Biginelli-condensation, see: Kappe, C. O. Tetrahedron 1993, 49, 6937-6963. (14) (a) O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 11851188. (b) Atwal, K. S.; O’Reilley, B. C.; Gougoutas, J. Z.; Malley, M. F. Heterocycles 1987, 26, 1189-1192. (c) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54, 5898-5907. (15) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291-314. (16) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26, 5564. (17) Potts, K. T.; Chen, S. J.; Kane, J.; Marshall, J. L. J. Org. Chem. 1977, 42, 1633-1638. (18) Potts, K. T.; Houghton, E.; Singh, U. P. J. Org. Chem. 1974, 39, 3627-3631. (19) Heteronuclear multiple-bond correlation (HMBC), see: Bax, A.; Summers, M. F. J. Am. Chem. Soc. 1986, 108, 2093-2094. 2-D NMR spectra of 10b and 17 are presented in the Supporting Information. (20) (a) Fischer, U.; Mo¨hler, H.; Schneider, F.; Widmer, U. Helv. Chim. Acta 1990, 73, 763-781. (b) Potts, K. T.; Bordeaux, K. G.; Kuehnling, W. R.; Salsbury, R. L. J. Org. Chem. 1985, 50, 1666-1676.
Dihydropyrimidine Calcium Channel Modulators Scheme 2
2-amino-substituted isothiomu¨nchnones with electrondeficient alkenes9a further support the here observed regiochemistry and allow the classification of this type of cycloaddition as HOMOdipol - LUMOdipolarophile-controlled (Sustmann type I)21 addition. The reaction of thioisomu¨nchnone 8 with olefinic dipolarophiles such as N-methylmaleimide is more complex. Treatment of dipole 8 with N-methylmaleimide in toluene at 110 °C for 20 min resulted in the formation of cycloadduct 11 in 63% isolated yield. Investigation of the crude reaction mixture by 1H-NMR revealed the presence of a number of minor byproducts that could, however, not be separated or identified (with the exception of 12, see below). Variations in the reaction conditions, i.e., performing the reaction at room temperature over a longer period of time or changing the solvent, did not raise the yield of 11 or reduce the number of byproducts. Due to the presence of the stereocenter at C-5 of the dipole, four diastereoisomeric cycloadducts can a priori (21) (a) Sustmann, R. Tetrahedron Lett. 1971, 2717-2720. (b) Sustmann, R.; Trill, H. Angew. Chem., Int. Ed. Engl. 1972, 11, 838840.
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be expected if facial and exo/endo diastereoselectivities are considered. According to recent computational studies on the conformation of 4-aryldihydropyrimidines of type 2,1 the dihydropyrimidine ring is not planar but adopts a boatlike conformation, with the 4-aryl substituent in axial position. This geometric arrangement has also been found to exist in the solid state for bicyclic derivatives related to 8.16 Due to the steric effect of the comparatively bulky axial phenyl group, attack of the dipolarophile anti to the phenyl substituent (i.e., from the less hindered “bottom-face” of the molecule) should be strongly favoured.
The relative stereochemistry of 11 was established by an X-ray analysis22 confirming that the isolated cycloadduct is the result of an “anti/exo-addition” of the dipolarophile to the isothiomu¨nchnone. Due to the complexity of the crude 1H-NMR spectrum, the presence of minor amounts of other diastereoisomers (90% purity): 1H-NMR (CDCl3) δ 1.09 (t, 3H, J ) 7.5 Hz), 2.47 (s, 3H), 3.68 (s, 3H), 4.02 (q, 2H, J ) 7.5 Hz), 5.14 (s, 1H), 5.42 (dd, 1H, J ) 11.0, 1.5 Hz), 5.66 (dd, 1H, J ) 17.0, 1.5 Hz), 6.35 (s, 1H), and 7.22-7.51 (m, 5H); complete equilibration of epimers took place within 30 min in CDCl3 at rt.
Acknowledgment. This work was supported by the Austrian Academy of Sciences (Austrian Programme for Advanced Research and Technology, APART 319) and the Austrian Science Foundation (FWF, Project P-11994CHE). Supporting Information Available: 2D-HMBC spectra of compounds 10b and 17 and ORTEP representations of X-ray structures for compounds 11, 21, 23, and 27a,b (8 pages) . This material is contained in libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information. JO970121Q
