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68 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
Coupling of a benzyl bromide and a resin-bound stannane in the presence of a protected guanidine (Scheme 51), en route to solid-phase synthesis of bradykinin antagonists, is also reported in this patent.101
Palladium-catalyzed allylic substitution has been demonstrated recently.102 Polymer-bound malonates and acetoacetates were alkylated with allylic acetates using Pd(PPh3)4 as catalyst (Scheme 52). Palladium-catalyzed carbon-nitrogen bond formation between a support-bound secondary amine and two bis-allylic templates had been shown previously.103 The products 42 were cleaved from the resin with DIBAL to give the diols in low to moderate yield. The polymer-bound (3-keto esters displayed high reactivity, with dialkylation being observed under these conditions. Monoalkylation was only seen with more sterically hindered acetates (such as cyclic allylic acetates), and allylic chlorides (using one equivalent of BuLi as base). When an allylic carbonate, diallyl carbonate, was used, no addition of base was necessary since the leaving group carbonate decar-boxylates to generate an alkoxide which may itself act as a base. The yield from this reaction (76% of 43) was the highest obtained in the study. The
2.5. MISCELLANEOUS REACTIONS 69
R1 = OMe, Me, Bn
X = OAc, 02C0Me
20 mol% Pd(PPh3)4 5 eq. BSA, THF reflux 6-15 h
10% Pd(0), no base THF, 25 °Ñ, 1 h
0°C, 12 h
reaction was performed with less palladium (10 mol %) and at room temperature for only 1 h.
Combination of the work described above with prior studies by the same group on y-alkylation of polymer-bound acetoacetate (with LDA and an alkylating agent such as iodoethane) enabled the monoanion 44 (Scheme 53) to be used for allylic alkylation under palladium catalysis. This allows the one-pot regioselective dialkylation of acetoacetate in 51% yield for the four-step process, including reductive cleavage. This method does suffer from the slight disadvantage inherent in such a dianion strategy that, unlike
70 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
(³) LDA, THF, 0 °Ñ
(ii) EtI, 0 °Ñ
20 mol% Pd(PPh3? BSA, KOAc, THF
most solid-phase reactions, excess reagents may not be used for the first alkylation.
Another solution to the limited availability of boronic acids is derivati-zation of a halide before the palladium-catalyzed coupling with another, support-bound halide. For example, palladium-catalyzed coupling of support-bound aryl bromides with zinc organometallics to form a number of biaryls was reported (Scheme 54).104 The protocol is simplified by the in situ preparation of the organozinc, followed by the immediate addition of the resin. Catalytic PdCl2(dppf), Pd(PPh3)4, PdCl2(PPh3)2, and PdCl2(P(o-tol)3)2 were all found to be highly effective, with the Pd(II) catalysts presumably generating the required Pd(0) in situ. Moderate to good yields were obtained when the reaction was performed at ambient temperature over 18 h. Meta- and ortho-substituted aryl bromides gave similar results. Transesterification was successfully used to cleave product from the resin.
(i) ArMgBr + ZnBr2 y*
Pd(ll), THF, 25 ®C, 18 h ìåÎ^Ã^²
---------------------> [I I
(ii) NaOMe, THF:MeOH
70 SC, 12 h Ó J
After completion of this chapter, Snieckus et al. published examples of the solid-phase Stille105 and Suzuki106 reactions in which were included stannanes and boronic acids synthesized in solution via a directed ortho metalation procedure,107 ultimately allowing for the construction of a range of tricyclic structures.
2.6. CONCLUDING REMARKS
Palladium-catalyzed transformations greatly enhance the scope of solid-phase synthetic chemistry. A number of fundamental pharmacophores are accessible through a variety of reliable manipulations that may be performed in high yield under mild conditions. This area continues to grow, as solution-phase chemistry is adapted to provide better methods for carbon-carbon bond formation in combinatorial chemistry. We view these advances as central to the field and look forward to future developments.
1. Duncia, J. V.; Carini, D. J.; Chiu, A. Ò.; Johnson, A. L.; Price, W. A.; Wong, P. Ñ.; Wexler, R. R.; Timmermans, P. Â. M. W. M. The Discovery of DUP-753, a Potent, Orally Active Nonpeptide Angiotensin-II Receptor Antagonist, Med. Res. Rev. 1992, 72, 149-191.
2. Pavia, M. R.; Cohen, M. P.; Dilley, G. J.; Dubuc, G. R.; Durgin, T. L.; Forman, F. W.; Hediger, Ì. E.; Milot, G.; Powers, T. S.; Sucholeiki, I.; Zhou, S.; Hangauer, D. G. The Design and Synthesis of Substituted Biphenyl Libraries, Bioorg. Med. Chem. 1996, 4, 659-666.