Tandem Silver‐Catalyzed Cyclization/Nucleophilic Functionalization of 2‐Alkynylindole‐3‐carbaldehyde Oximes to Afford New 2,4‐Disubstituted γ‐Carbolines

Abstract

Highly substituted pyrido[4,3‐b]indole derivatives were synthesized through a straightforward one‐pot silver‐catalyzed process involving 2‐alkynylindole‐3‐carbaldehyde oximes. The tandem cyclization/nucleophilic addition sequence was optimized and applied to a wide range of nucleophiles, which reacted regioselectively at the pyrido[4,3‐b]indole C4 position. The scope and limitations of the methodology were evaluated and the final compounds were obtained in fair to very good yields. This versatile method proved to be compatible with various chemical functionalities or (hetero)cycles.

Metal-Involving Synthesis and Reactions of Oximes

“…) to furnish ortho-substituted pyridines 298 (17−99% isolated yields Scheme 135, a). 557 The reaction proceeded via addition of AgOTf (10 mol %) to oxime 296 in CH 2 Cl 2 at RT for 18 h followed by treatment with [PBr(NC 4 H 8 ) 3 ](PF 6 ) (1.5 equiv), a nucleophile R 3 X (1.1 equiv; 297), and NEt i Pr 2 (3.7 equiv) and maintaining the reaction mixture at RT for an additional 18 h. The reaction also occurred easily when 4-MeC 6 H 4 SO 2 Cl was used instead of [PBr(NC 4 H 8 ) 3 ](PF 6 ), whereas in the presence of PhCOCl, it did not proceed for such nucleophiles as 4oxypyridine, MeOH, and EtOH. A plausible mechanism of this reaction includes activation the CC bond by the silver(I) center with subsequent nucleophilic attack of the oxime N atom to the electrophilically activated CC moiety to give the pyridine N-oxide ring (b; see also Schemes 106 and 107 for details in similar Pd II and Au I -catalyzed processes).…”

“…A reported modification of the reaction given in Scheme allows the functionalization of pyridine N -oxides before their reduction to the appropriate pyridines. Alkynyl aldoximes 296 reacted with the nucleophilic agents R 3 X ( 297 ; R 3 H = R 4 OH, R 4 SH, R 4 CO 2 H, R 4 NH 2 , HBH 3 – ; R 3 (−) = CN – , N 3 – ) to furnish ortho-substituted pyridines 298 (17–99% isolated yields Scheme , a) . The reaction proceeded via addition of AgOTf (10 mol %) to oxime 296 in CH 2 Cl 2 at RT for 18 h followed by treatment with [PBr­(NC 4 H 8 ) 3 ]­(PF 6 ) (1.5 equiv), a nucleophile R 3 X (1.1 equiv; 297 ), and NEt i Pr 2 (3.7 equiv) and maintaining the reaction mixture at RT for an additional 18 h. The reaction also occurred easily when 4-MeC 6 H 4 SO 2 Cl was used instead of [PBr­(NC 4 H 8 ) 3 ]­(PF 6 ), whereas in the presence of PhCOCl, it did not proceed for such nucleophiles as 4-oxypyridine, MeOH, and EtOH.…”

Regioselective Synthesis of New 2,4-(Het)aryl-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidines Involving Palladium-Catalyzed Cross-Coupling Reactions

“…In order to tackle the usefulness of 9 as a building block and taking advantage of the presence of the amide group, we began by the regioselective functionalization of the C-4 position using a C-O direct activation involving PyBroP and Et 3 N to generate the required in situ generated O -phosphonium leaving group [ 35 , 36 ]. The second step required the addition of boronic acid, base, water and catalyst source.…”