Rapid Syntheses of Heteroaryl-Substituted Imidazo[1,5-a]indole and Pyrrolo[1,2-c]imidazole via Aerobic C2–H Functionalizations

Abstract

Here we report an aerobic Pd(0) catalyzed C2-H functionalization of indoles and pyrroles with tethered N-methoxylamide as the directing group. A Pd(0)-initiated mechanism overcomes the directing or poisoning effect from a wide range of heterocycles including pyridine, pyrimidine, and thiazole. The imidazo[1,5-a]indole products are transformed to bioactive analogs after one-step manipulations, demonstrating the potential utility of this reaction in drug discovery.

Recent Advances in Functionalization of Pyrroles and their Translational Potential

“…A Pd(0)‐ initiated mechanism conquers the coordinating or poisoning impact from a wide scope of heterocycles including pyridine, pyrimidine, and thiazole. The imidazo[1,5‐a]indole derivatives are changed to bioactive analogs after one‐venture manipulation, exhibiting the possible practicality of this reaction in drug discovery [53] …”

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

“…The Yu group found that isocyanides are also active in C−H activation reactions of indole‐ N ‐carboxamides (Scheme ) . By treating indole‐ N ‐carboxamides or aza‐indole‐ N ‐carboxamides 105 and tert ‐butyl isocyanide 106 with 5 mol % Pd 2 (dba) 3 at 60 °C in methanol and air, a type of intriguing medicinally important imidazo[1,5‐a]indole and pyrrolo[1,2‐c]imidazole 107 could be constructed in good yields.…”

“…The Yu group found that isocyanides are also active in CÀ H activation reactions of indole-N-carboxamides (Scheme 27). [37] By treating indole-N-carboxamides or aza-indole-N-carboxamides 105 and tert-butyl isocyanide 106 with 5 mol % Pd 2 (dba) 3 at 60°C in methanol and air, a type of intriguing medicinally important imidazo[1,5-a]indole and pyrrolo[1,2-c]imidazole 107 could be constructed in good yields. Of note, when indole-Ncarboxamides were functionalized with various heteroaryl groups, corresponding products 110 bearing diverse heterocycles could be isolated efficiently.…”

Chemo‐ and Regioselective Synthesis of Functionalized 1H‐imidazo[1,5‐a]indol‐3(2H)‐ones via a Redox‐Neutral Rhodium(III)‐Catalyzed [4+1] Annulation between Indoles and Alkynes

“…(i) Alkynes are used as unconventional C 1 synthons to fulfil an unusual [4+1] annulation, which is rare as alkynes normally act as C 2 synthons to undergo [n+2] cycloaddition in C−H annulations of indoles; (ii) a highly chemoselective [4+1] annulation, in which the competitive background reactions such as [3+2] annulation, [4+2] annulation and C−H alkenylation are inhibited; (iii) a highly regiospecific [4+1] annulation with the C−H activation occurred at C2 over C7 position of the indole and C−C/C−N bonds both formed at the distal sp hybridized carbon of the alkyne moiety; (iiii) a mild redox‐neutral transformation without the addition of any external oxidants, which results in good compatibility of various functional groups. Despite the elegant synthesis of 1 H ‐imidazo[1,5‐ a ]indol‐3(2 H )‐ones from indoles with hazardous diazo compounds, [11a,16] 4‐hydroxyphenylboronic acid under silver oxidants [17] or isocyanides under air oxidation, [18] our method stands as the first example of 1 H ‐imidazo[1,5‐ a ]indol‐3(2 H )‐one synthesis via a redox‐neutral Rh(III)‐catalyzed [4+1] annulation of N ‐carbamoyl indoles exploiting alkynes as C 1 synthons. Regarding the large occurrence of the 1 H ‐imidazo[1,5‐ a ]indol‐3(2 H )‐one motif in pharmaceutical agents (Figure 1), [19] our approach is quite attractive as it offers a facile and rapid access to highly functionalized 1 H ‐imidazo[1,5‐ a ]indol‐3(2 H )‐ones from readily available materials through Rh(III)‐catalyzed chemo‐ and regioselective [4+1] annulation.…”