One‐Pot Synthesis of 3‐(Benzo[e]indol‐2‐yl)‐2‐oxindoles from Isatin‐derived Propargylic Alcohols and N‐Acetyl‐2‐aminonaphthalenes

Abstract

3-Aryloxindoles have been used as important synthetic intermediates of many biologically important 3,3-disubstituted oxindoles and indolines.1,2 Typically, 3-aryloxindoles have been prepared by the cyclization of α-aryl acetanilides, 2a-d palladium or nickel-catalyzed arylation of oxindoles, 2e-j arylation of 3-diazooxindoles with arenes or aryl boron reagents, 2k-p or arylation of isatins using aryl Grignard reagents and subsequent reduction. 2q-tThe reported aryl moieties of 3-aryloxindoles included phenyl, substituted phenyl, and heteroaryl groups including thiophene, 2k,m,q pyrrole, 2p or indole. 2o,q Recently, we reported an efficient one-pot synthesis of 3-naphtho[2,1-b] furanyl-2-oxindoles from isatin-derived propargylic alcohols and 2-naphthols. 3 The naphtho[2,1-b]furan ring was formed via Michael type 5-exo-dig cyclization of the corresponding allene intermediate.As a continuing study, we reasoned out that a replacement of 2-naphthol to N-acetyl-2-aminonaphthalene (2a) would afford 3-(benzo[e]indol-2-yl)-2-oxindole derivative 3a, as shown in Scheme 1. 2-Oxindoles bearing benzo [e] indole moiety at the 3-position have not been reported, to the best of our knowledge. 4 The reaction of 2a and the Boc carbonate of isatin-derived propargylic alcohol 1a in the presence of p-TsOH (10 mol %) in 1,2-dichloroethane (DCE) for 1 h afforded 3a in a reasonable yield (47%). Compound 3a might be formed via regioselective FriedelCrafts allenylation 5 of 2a to form an allene intermediate I and a following Michael type 5-exo-dig cyclization. The formation of spirooxindole II, which could be formed via 6-endo-dig cyclization of I, was not observed. The selective 5-exo-dig cyclization might be attributed to the presence of an electron-withdrawing carbonyl group of isatin moiety. The formation of a trace amount of N-deacetylated compound 4a (<5%) was observed (vide infra). The reaction of 2-aminonaphthalene and 1a in the presence of p-TsOH in refluxing DCE did not produce 4a. The protonation of 2-aminonaphthalene under the acidic condition would render the C-1 position of naphthalene ring less nucleophilic. 6 In order to increase the yield of 3a, the reaction of 1a and 2a was examined under the reaction conditions shown in Table 1. The reaction at low temperature (40 C, 4 h) afforded 3a in a slightly lower yield (43%, entry 2). The reaction proceeded even at 25 C (entry 3). However, the reaction was slow and 3a was obtained in low yield (35%) even after 10 h. The reaction in CH 3 CN was less effective (entry 4). The use of InCl 3 (entry 5) or Yb(OTf ) 3 (entry 6) showed a similar result to that of p-TsOH. The use of Cu(OTf ) 2 (entry 7) was less efficient. It is interesting to note that the use of Bi(OTf ) 3 in refluxing DCE (entry 8) afforded 4a as a major product (49%).7 The reaction at 40 C (entry 9) gave 3a as a major product (47%). When we carried out the reaction at 25 C, 3a was obtained in good yield (55%). 8,9 Encouraged by the successful results, we prepared various Boc carbonates 1a-1h 10 and aminonaphthalene de...