Metalation of Biginelli Compounds. A General Unprecedented Route to C-6 Functionalized 4-Aryl-3,4-dihydropyrimidinones Kamaljit Singh,* Sukhdeep Singh, and Aman Mahajan Department of Applied Chemical Sciences & Technology, Guru Nanak Dev University, Amritsar - 143 005, India Kamaljit19in@yahoo.co.in Received April 6, 2005 4-Aryl-6-methyl-3,4-dihydro-2(1H)-pyrimidinone esters (DHPMs) readily undergo metalation at the C-6 methyl (vinylogous ester) position on treatment with lithium diiso- propylamide at -10 °C. The resulting anion intermediates can be treated with electrophilic reagents to afford func- tionalized DHPMs that have been chemically elaborated mainly at the C-6 position. Di- and trianion formation is also possible at both the vinylogous methyl and NH positions when reactions are performed with excess equivalents of the base. A careful examination of the current literature has revealed that elaboration of C-6 of 4-aryl-6-methyl-3,4- dihydro-2(1H)-pyrimidinone esters (Biginelli DHPMs) 1 through reactions of the lithio salts with electrophiles are unprecedented. Strategies for the synthesis of the DHPM nucleus have varied from one-step to multistep approach, but the methods 1,2 for the peripheral elaboration are scarce 2e,f or of limited synthetic scope. The privileged DHPMs have emerged as the integral backbone of several calcium channel blockers, antihypertensive agents, R-1a- antagonists, and marine alkaloids. Most notable among these are the batzelladine alkaloids, which are found to be potent HIVgp-120-CD4 inhibitors. 3 The scaffold decoration 2h of DHPMs is highly important for creating structural diversity to produce “druglike” molecules for biological screening. In analogy with the 1,4-dihydropy- ridines (NADH analogues), 4 the elaborated DHPMs are considered to be conformationally flexible, and the con- sequent effects on the calcium channel modulatory activi- ties are well-documented. 5 To the best of our knowledge, the only report for the functionalization of the C-6 methyl group is through bromination (invariably plagued by gem-dibromination) and subsequent reaction with some nucleophiles. 2e,f In view of the potential usefulness of the C-6 elaborated DHPMs, 6 we have undertaken this in- vestigation, and in this note, we report the first rational synthesis of C-6 elaborated DHPMs. We initially examined the metalation of the simple 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydro-2(1H)- pyrimidinone 1a with LDA (-10 °C) and subsequent quenching at ambient temperature with d 4 -methanol to determine optimal conditions for vinylogous C-6 meth- ylmetalation. Deuterium distribution (%-d 1 incorporation and location) in the resultant product was determined by the high field 1 H and 13 C analyses and was found to be exclusively at the C-6 methyl (vinylogous ester) (100%- d 1 ) as indicated by the exclusive formation of 3a (entry 1, Table 1). No deuterium incorporation was observed at any other position in the molecule, which indicates the exclusive metalation of the least acidic and consequently the most nucleophilic C-6 position. The other two poten- tial nitrogen centered metalation/substitution sites if deuterated were exchanged under the aqueous workup conditions of the method. Moreover, no addition product resulting from nucleophilic attack at the ester group of 1a was observed. Use of 1.1 equiv of LDA gave no deuterium incorporation in the molecule. 7 Treatment of 1a with 2.1 equiv of freshly prepared n-BuLi (2.3 N in hexanes) in THF at -10 °C followed by stirring at room temperature (r.t.) for 3 h yielded the pale (1) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879 and references therein. (2) (a) Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1. (b) Kappe, C. O. QSAR Comb. Sci. 2003, 22, 630. (c) Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron 1999, 55, 12873. (d) Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864. (e) Zigeuner, G.; Hamberger, H.; Blaschke, H.; Sterk, H. Monatsh. Chem. 1966, 97, 1408. (f) Kappe, C. O. Liebigs Ann. Chem. 1990, 505. (g) Perez, R.; Beryozkina, T.; Zbruyev, O. I.; Haas, W.; Kappe, C. O. J. Comb. Chem. 2002, 4, 501. (h) Dallinger, D.; Kappe, C. O. Pure Appl. Chem. 2005, 77, 155. (3) (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043. (b) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc. 1995, 117, 2675. (c) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; DeBrosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J. J. Org. Chem. 1995, 60, 1182. (4) For a review, see: Goldmann, S.; Stoltefuss, J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1559. (5) Fabian, W. M. F.; Semones, M. A.; Kappe, C. O. J. Mol. Struct. (THEOCHEM) 1998, 432, 219. (6) Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem. 2004, 6, 884. (7) Use of n-BuLi was found not to yield satisfactory results. TABLE 1. Deuterium Incorporation and Condition Optimization for Metalation of Dihydropyrimidinone 1a entry electrophile (temp) base (equiv) product isolated yield (%) 1 d4-methanol (r.t.) LDA (3.1) 3a 70 2 EtBr (0 °C) n-BuLi (2.1) 3b 55 3 EtBr (0 °C) n-BuLi (3.1) 3b 50 4 EtBr (0 °C) n-BuLi (4.1) 3b 55 5 EtBr (0 °C) n-BuLi (5.1) 3b 56 6 EtBr (0 °C) LDA (3.1) 3b 60 7 EtBr (0 °C) LDA (4.1) 3b 71 6114 J. Org. Chem. 2005, 70, 6114-6117 10.1021/jo050675q CCC: $30.25 © 2005 American Chemical Society Published on Web 06/23/2005