Copper‐catalyzed CN Coupling and Cyclization of 2‐(2‐Bromophenyl)‐1H‐indoles with Primary Amides Leading to Indolo[1,2‐c]quinazolines

Abstract

It is well-known that indole-fused quinazolines, indolo [1,2-c]quinazolines exhibit biological activities such as antibacterial and antifungal properties (Scheme 1). 1,2 Since the synthesis of indolo [1,2-c]quinazolines by thermal cyclization of 2-(2-aminophenyl)indoles with acyl cyanides followed by HCl treatment, many synthetic methods for such a hybrid scaffold are well documented. 3,4 Several groups have shown that indolo[1,2-c]quinazolines can be formed by condensation of 2-(2-aminophenyl)indoles with aromatic aldehydes and subsequent treatment with powdered KMnO 4 for oxidative cyclization. 1,2,5 Such a hybrid scaffold formation was also exemplified by palladium-catalyzed cyclocarbonylation of bis(o-trifluoroacetamidophenyl)acetylene with aryl or vinyl halides and triflates 6 and cyclization of 1-(N-arylimino)indoles formed by additionelimination between indoles and N-aryltrifluoroacetimidoyl chlorides. 7 It is also reported that 2-(2-halophenyl)indoles are coupled and cyclized with (aryl)methaneamines, amidine hydrochlorides, and amino acids in the presence of a copper catalyst to give indolo [1,2-c]quinazolines. 8-10 Wang et al. recently reported on synthesis of indolo[1,2-c]quinazolines from N-{2-[(2-aminophenyl)ethynyl]phenyl}amides by ZnBr 2 -promoted domino hydroamination-cyclization. 11During the course of our continuing studies directed towards cyclization reactions, 12 we have identified several new synthetic methods for N-fused hybrid scaffolds. 13 Under these circumstances, this report describes coppercatalyzed coupling and cyclization of 2-(2-bromophenyl)-1H-indoles with primary amides leading to indole-fused quinazolines, indolo[1,2-c]quinazolines.Treatment of 2-(2-bromophenyl)-1H-indole (1a) with an equimolar amount of formamide (2a) in DMF at 130 C for 24 h in the presence of a catalytic amount of CuI (10 mol %) along with Cs 2 CO 3 afforded indolo[1,2-c]quinazoline (3a) in 10% isolated yield with several unidentifiable products (Table 1, entry 1). Higher reaction rate and yield were observed with further addition of L-proline as a ligand (entry 2). It is known that the catalytic system of CuI combined with L-proline effectively catalyzes coupling and cyclization of 2-bromobenzamides with terminal alkynes leading to 3-alkylideneisoindolin-1-ones. 14 The molar ratio of [2a]/[1a] affected the yield of 3a and the yield increased with the increase of the molar ratio up to 2.0 along with complete conversion of 1a (entry 3). Lower reaction temperature resulted in a decreased yield of 3a (entry 4). The reaction proceeded using other amino acids such as glycine, L-phenylalanine, N,N-dimethylglycine, and 4-hydroxy-Lproline in place of L-proline, but the yield of 3a was generally lower than that by the use of L-proline except for 4-hydroxy-L-proline, which exhibited similar activity as Lproline (entries 5-8).Among bases examined under the employed conditions, Cs 2 CO 3 was shown to be the base of choice (entries 3 and 9-11). When used with L-proline and Cs 2 CO 3 , copper catalysts such as CuCl, CuBr...

Rapid Access to 2,2-Disubstituted Indolines via Dearomative Indolic-Claisen Rearrangement: Concise, Enantioselective Total Synthesis of (+)-Hinckdentine A

“…With the objective of achieving an asymmetric synthesis of hinckdentine A, indolic alcohol 18 , required for the pivotal Claisen rearrangement, was prepared from the known indoloquinazoline 16 , which was synthesized on decagram scale from 2-aminoacetophenone (Scheme ). ,, Friedel–Crafts glyoxylation of 16 followed by CBS reduction of the ketone and DDQ addition to reform the amidine afforded indolic alcohol 18 in an 81% yield and 90% ee. Despite its structural and steric complexity, and the presence of an unexplored functional group attached to the indole nitrogen, alcohol 18 underwent a clean Claisen rearrangement upon heating with 3 equiv of DMAA in toluene to afford the desired product, thereby installing the required two-carbon unit at C17a (hinckdentine A numbering).…”

Mild Copper-Catalyzed, l-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate

“…Ma and co-workers described that, by using L-proline as an additive, the copper-catalyzed cross-coupling reactions under mild conditions gave N-arylazoles in excellent yields [33,34]. This discovery was followed by several studies to improve C-N coupling conditions with the effect of L-proline as a ligand [35][36][37]. In view of these research studies, copper-catalyzed N-arylation of amines has become one of the most attractive and highly efficient methods to synthesize these compounds due to excellent catalytic selectivity and high functional group compatibility, as well as low toxicity and economic attractiveness [36].…”