A Convenient One-Pot Synthesis of Spirocyclic Pyrido[1,2-a]indole Derivatives from 3-(2-Bromoethyl)indole

Abstract

A convenient one-pot approach for the synthesis of spirocyclic pyrido[1,2-a]indole derivatives is described. The method involves treatment of 1,3-diketones and 1,3-ketoesters with base to generate dianions, which react with 3-(2-bromoethyl)indole to construct a spirocyclopropyl ring and an N-heterocyclic ring sequentially in moderate to very good yields.The indole unit represents a key structure among natural products and pharmaceutically important compounds. 1 The synthesis of pyrido[1,2-a]indole derivatives, a class of tricyclic compounds 1, has drawn considerable attention due to their biological activity and synthetic interest. 2 Although a variety of strategies has been developed to generate these heterocyclic derivatives, 3,4 the popular methods mainly involve the cyclization catalyzed by metal compounds such as Pd(II), 3b,5 Sm(II), 3a and Ni(II) complexes. 3d Solid-phase synthesis has also been used to construct the pyrido[1,2-a]indole derivatives via radical cyclization. 6 Spiroindolenine (2) first synthesized by Closson also contains an indole subunit. 7 Compound 2 can be readily accessed from 3-(2-bromoethyl)indole 8 and was recently used as a electron-deficient adduct to synthesize pyrrole derivatives. 9While numerous approaches to 1 and 2 ( Figure 1) are available, there are no reports describing easy access to the related spiropyrido[1,2-a]indole 3 (Figure 1), in spite of the fact that such a protocol would provide important approaches to a range of natural product precursors. 10 Inspired by the protocol originally described by Closson, we reasoned that the dianions generated from 1,3-diketones and 1,3-ketoesters 11 would be good candidates to undergo reaction with 3-(2-bromoethyl)indole to simultaneously construct the spiro ring in 2 and the N-heterocyclic sixmembered ring in compound 1 to produce 3. A convenient one-pot approach to spirocyclic pyrido[1,2-a]indole derivatives is reported herein.To initially examine this approach, 2,4-pentadione (4a) was treated with two equivalents of sodium hydride in tetrahydrofuran at 0 °C and then two equivalents of n-butyllithium followed by the addition of 3-(2-bromoethyl)indole (Scheme 1). 12The reaction worked well to afford a novel spirocyclic pyrido[1,2-a]indole compound 5a in 85% isolated yield. The success of this reaction encouraged us to investigate its generality and scope. Two other 1,3-diketones (4b,c) and a 1,3-ketoester (4d) were reacted with 3-(2-bromoethyl)indole using the same procedure. The data for these reactions is summarized in Table 1. The data in Table 1 shows the reaction proceeds to produce spirocyclic pyrido[1,2-a]indole derivatives for all four 1,3-diketones and 1,3-ketoesters (4a-d). Moderate to good yields (66-85%) were achieved and all products were purified and characterized by NMR, and HRMS. 13 Figure 1 N N1 2 N R 1 R 2 3 pyrido[1,2-a] indole skeleton spiroindolenine spiropyrido[1,2-a] indole skeleton Scheme 1 One-pot transformation from 3-(2-bromoethyl)indole to spirocyclic pyrido[1,2-a]indole derivatives R 1 O O R 2 N H ...