Organocatalytic Nazarov-type cyclization of 3-alkynyl-2-indolylmethanols: construction of axially chiral cyclopenta[b]indole scaffolds

Abstract

In recent years, it has become an urgent task to design new types of indole-based platform molecules for Nazarov-type cyclizations and develop organocatalytic Nazarov-type cyclizations for synthesizing indole derivatives. To fulfill this task, in this work, by changing the alkynyl terminal substituent from t-Bu to an aryl group, the reactivity of 3-alkynyl-2-indolylmethanols is modulated and the new platform molecules serve as competent substrates for Brønsted acid-catalyzed Nazarov-type cyclization. Based on this new reactivity, the first organocatalytic Nazarov-type cyclization of aryl-substituted 3-alkynyl-2-indolylmethanols with 2-naphthols is accomplished, leading to the efficient construction of a new class of axially chiral 3, 4-dihydrocyclopenta[b]indole scaffolds. This preliminary investigation of organocatalytic asymmetric Nazarov-type cyclization provides an optional strategy for the atroposelective construction of this new class of axially chiral cyclopenta[b]indole scaffolds. In addition, the first preparation of axially chiral 3, 4-dihydrocyclopenta[b]indole with optical purity is established through chiral resolution, which could serve as a complementary method to catalytic asymmetric approaches.

Cu(OTf)2–Phosphoric Acid-Catalyzed Tandem Oxa-Nazarov Cyclization and Dibromination of Conjugated 1,2-Diketones

“…(1) When 3.0 equiv of TEMPO was used, the reaction also worked well to give the product 3a in 86% yield (Scheme 4A), excluding the possibility of the radical reaction. (2) The binary-Lewis acid Cu(OTf) 2 /DPP-Na (1:1, 10 mol %) could promote the direct α-dibromination of 1a with NBS 2a to give the dibromide 9 in 62% yield (Scheme 4B), thus suggesting that this sodium salt should be used to facilitate the enol III formation of 1a and help suppress the oxa-Nazarov cyclization.…”

“…6, 174.7, 133.7, 128.9, 128.7, 127.5, 93.3, 86.1, 26.8 C{H} NMR (126 MHz, CDCl 3 ) δ 193.5, 172.9, 134.5 (q, 2 J C−F = 34.0 Hz), 130.7, 129.0, 125.8 (q, 3 J C−F = 3.78 Hz), 123.3 (q, 1 J C−F = 279.7 Hz), 95.1, 85.8, 26.7 2,4-Dibromo-5-(4-fluorophenyl)-2-methylfuran-3(2H)-one (3c). Prepared according to the general procedure II above and purified by a silica gel column with PE/EA (40:1) as the eluent; yellow oil (29.0 mg, 83% yield); 1 H NMR (500 MHz, CDCl 3 ) δ 8.29 (dd, J = 5.5, 8.5 Hz, 2H), 7.25 (t, J = 9.0 Hz, 2H), 2.17 (s, 3H) ppm; 13 4, 173.4, 140.1, 129.9, 129.3, 125.9, 93.6, 85.9, 26.7 2,furan-3(2H)-one (3e). Prepared according to the general procedure I above for 12 h and purified by a silica gel column with PE/EA (60:1) as the eluent; yellow oil (30.4 mg, 88% yield); 1 H NMR (500 MHz, CDCl 3 ) δ 8.15 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.16 (s, 3H) ppm; 13 C{H} NMR (126 MHz, CDCl 3 ) δ 193.…”

“…Prepared according to the general procedure I above for 12 h and purified by a silica gel column with PE/EA (60:1) as the eluent; yellow oil (30.4 mg, 88% yield); 1 H NMR (500 MHz, CDCl 3 ) δ 8.15 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.16 (s, 3H) ppm; 13 C{H} NMR (126 MHz, CDCl 3 ) δ 193. 6, 174.6, 144.9, 129.6, 128.8, 124.8, 92.5, 86.2, 26.9, 21.9 2,phenyl)-2-methylfuran-3(2H)-one (3f). Prepared according to the general procedure I above for 12 h and purified by a silica gel column with PE/EA (50:1) as the eluent; yellow oil (34.5 mg, 89% yield); 1 H NMR (500 MHz, CDCl 3 ) δ 8.20−8.19 (m, 2H), 7.58−7.56 (m, 2H), 2.16 (s, 3H), 1.37 (s, 9H) ppm; 13 C{H} NMR (126 MHz, CDCl 3 ) δ 192.…”

“…4, 172.8, 131.5 (d, 2 J C−F = 34.0 Hz), 131.7, 129.9 (q, 3 J C−F = 3.8 Hz), 129.6, 128.4, 125.3 (q, 3 J C−F = 5.0 Hz), 123.3 (q, 1 J C−F = 273. 2,. Prepared according to the general procedure I above for 12 h and purified by a silica gel column with PE/EA (50:1) as the eluent; yellow oil (25.6 mg, 74% yield), 1 H NMR (500 MHz, CDCl 3 ) δ 8.24 (d, J = 9.0 Hz, 2H), 7.65 (t, J = 8.5 Hz, 1H), 7.55 (t, J = 9.0 Hz, 2H), 2.50−2.42 (m, 1H), 2.33−2.25 (m, 1H), 1.10 (t, J = 7.5 Hz, 3H) ppm; 13 C{H} NMR (126 MHz, CDCl 3 ) δ 193.…”

“…Prepared according to the general procedure I above for 12 h and purified by a silica gel column with PE/EA (50:1) as the eluent: yellow oil (31.1 mg, 79% yield); 1 H NMR (500 MHz, CDCl 3 ) δ 8.23 (d, J = 7.5 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.61−2.55 (m, 1H), 2.41−2.36 (m, 1H), 2.14−2.00 (m, 2H) ppm; 13 C{H} NMR (126 MHz, CDCl 3 ) δ 193. 1, 175.1, 133.8, 129.0, 128.7, 127.4, 93.9, 88.8, 43.7, 36.5, 27.6 2,. Prepared according to the general procedure I above for 12 and purified by a silica gel column with PE/EA (50:1) as the eluent; yellow solid (19.0 mg, 78% yield), mp 88−90 °C; 1 H NMR (500 MHz, CDCl 3 ) δ 8.22 (d,J = 8.5 Hz,2H), 7.65 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 2.03 (s, 3H) ppm; 13 C{H} NMR (126 MHz,CDCl 3 ) δ 191.3,173.4,132.7,127.9,127.5,126.2,105.2,92.7,24.3 Procedure for Gram-Scale Reaction of 3a.…”