Cationic Cobalt(III) Catalyzed Indole Synthesis: The Regioselective Intermolecular Cyclization of N‐Nitrosoanilines and Alkynes

Abstract

The unique regioselectivity and reactivity of cobalt-(III) in the direct cyclization of N-nitrosoanilines with alkynes for the expedient synthesis of N-substituted indoles is demonstrated. In the presence of ac obalt(III) catalyst, high regioselectivity was observed when using unsymmetrical meta-substituted N-nitrosoanilines.M oreover,i nternal alkynes bearing electron-deficient groups,w hich are almost unreactive in the [Cp*Rh III ]-catalyzed system, displayg ood reactivity in this transformation.Indole motifs are widespread in natural products,b ioactive compounds,and other functional molecules. [1] In light of their importance,n umerous useful methods have been developed for their preparation, [2] including the well-established Fischer indole synthesis. [3] Alternatively,intermolecular cyclization of ortho-halogenated anilines with alkynes is the frequently used in the construction of indoles. [4] Importantly,t he directed transition-metal-catalyzed CÀHbond functionalization strategy has been employed in cyclization reactions for broader substrate scope and higher atom economy. [5] According to this strategy,t he precious transition-metal-catalyzed (e.g.,p alladiumn, rhodium, ruthenium, gold) intermolecular cyclizations of anilines,o ri ts derivatives,w ith alkynes through CÀH annulation for the construction of indoles have been developed. [6] In the past decades,t he development of the first-row transition-metal-catalyzed transformation has attracted attention because these base metals are earth-abundant, inexpensive,have variable oxidation states,and are less toxic, etc. [7] In contrast to the instability and the sensitivity of the low-valent earth-abundant metal catalysts to air and moisture, the high-valent earth-abundant metals such as iron(III) [8] and cobalt(III) [9] are stable and easily prepared, and have exhibited incredible potential in C À Ha ctivation in recent years.D espite these elegant works,t he intermolecular CÀH cyclization of aniline derivatives with alkynes,c atalyzed by either iron(III) or cobalt(III), has not been achieved.More recently,b yu sing the N-nitrosoanilines as starting materials,w hich are readily prepared through av ery simple process (Scheme 1a), [10] an interesting rhodium-catalyzed Scheme 1. Cobalt-catalyzed regioselective indole synthesis through CÀHfunctionalization. Cp* = C 5 Me 5 .

3d Transition Metals for C–H Activation

“…1000 In a related concept, Liang and Jiao reported a C−H/N−N functionalization process for the synthesis of indoles 677 from N-nitrosoanilines 679 and alkynes 6 using the well-defined cationic cobalt complex [Cp*Co(MeCN) 3 ][SbF 6 ] 2 (Scheme 344b). 1001 In both procedures, the N−N bond acted as formal internal oxidant and thus the reaction did not demand an external oxidant. Zhu exploited the cobalt(III)-catalyzed C−H/N−N activation technique to the annulation of alkynes 6 by arylhydrazine 680 to construct substituted indoles 677 under relatively mild reaction conditions (Scheme 344c).…”

Metal-Promoted Heterocyclization: A Heterosynthetic Approach to Face a Pandemic Crisis

“…Recently, Co(III) catalysts have attracted the interest of chemists due to their versatility and selectivity in various chemical transformations. Liang and Jiao, in their work, proposed an interesting indole synthesis approach triggered by an inexpensive cationic cobalt(III) complex starting from readily accessible N-nitrosoanilines 46 and substituted alkynes 47 (Scheme 23) [68]. Stable and easily accessible 2-alkynylanilines 44 are employed in this intramolecular cyclization catalyzed by PtCl 4 in mild conditions with a high tolerance toward various functional groups.…”

Photodriven Photocatalyst/Metal-Free Direct C–C/C–N Bond Formation: Synthesis of Indoles via EDA Complexes

“…The crude product was purified by silica gel flash chromatography using the mixture of petroleum ether/ethyl acetate (PE/EA = 5/1) as an eluent to afford the target compound 3a (0.463 g, yield of 56%). Diethyl 1-Methyl-1H-indole-2,3-dicarboxylate (3a): 22 yellow liquid, 70% yield (19 mg); IR (KBr, cm −1 ) 3055, 2982,2816,1704,1613,1532,1469,1411,1336,1246,1157,1106,1035,922,860,787,753,620; 1 H NMR (400 MHz, CDCl 3 , ppm) δ 8.15−8.13 (d,J = 8 Hz,1H),2H),1H), 4.51−4.46 (q, J = 8 Hz, 2H), 4.41−4.36 (q, J = 8 Hz, 2H), 3.82 (s, 3H), 1.45−1.42 (t, J = 8 Hz, 3H), 1.41−1.39 (t, J = 8 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 , ppm) δ 164.2, 162. 9,136.8,135.0,125.4,124.3,122.5,122.3,110.1,108.0,62.3,60.2,31.3,14.4,14.1;MS (EI,70 eV) m/z 275,243,216,185,159,129,102,77. Diethyl 5-Fluoro-1-methyl-1H-indole-2,3-dicarboxylate (3b): red solid, 62% yield (18 mg); mp 78−80 °C.…”