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Cite this: Org. Biomol. Chem., 2014, 12, 8641
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Regioselective π-extension of indoles with rhodium enalcarbenoids – synthesis of substituted carbazoles† Kuldeep Singh Rathore, Mandeep Harode and Sreenivas Katukojvala* An efficient Rh(II) carboxylate and Brønsted acid catalyzed direct π-extension of indoles to 4-substituted carbazoles is developed. The reaction involves a regioselective C-3 functionalization of indole by a
Received 7th August 2014, Accepted 4th September 2014
rhodium enalcarbenoid and a Brønsted acid assisted cyclocondensation. In addition a twofold regioselective π-extension of pyrroles to 4,8-disubstituted carbazoles has also been developed. The utility of the
DOI: 10.1039/c4ob01693a
methodology was demonstrated with the synthesis of analogues of an hepatitis C virus replication inhibi-
www.rsc.org/obc
tor and a secreted phospholipase A2 (sPLA2) inhibitor.
Introduction Carbazole structural motifs are present in various biologically active natural products, pharmaceuticals and functional materials (1–6, Fig. 1).1,2 As a result development of efficient synthetic methodologies for the functionalized carbazoles continues to be an active area of research.1a,g,3–9 The versatile methodologies include transition metal catalyzed intramolecular C–C coupling of diarylamines,4 C–N coupling of 2-arylanilines or its variations.5 The intermolecular versions include C–C and C–N bond coupling of arylamine with haloarenes, or twofold C–N coupling of primary amines with biaryls.6 One of the appealing strategies for carbazoles involves transition metal catalyzed direct π-extension of readily available indole motif itself.7,8 In this context, the Miura group has developed an efficient [2 + 2 + 2] annulation of indole-carboxylic acids 7 with internal alkynes 8 using the Pd(II)–Cu(II)–Li(I) trimetallic system leading to tetrasubstituted carbazoles 9 under high temperature conditions (Scheme 1a).7 Recently, the Itami group has discovered a formal [2 + 2 + 2] annulation of indoles 10 with electron deficient olefins 11 using the Pd(II)–Cu(II)– Ag(I) trimetallic system (Scheme 1b).8 This protocol involves a large amount of trimetallic system and high temperature and delivers moderate yields. Very recently, we have disclosed a
Department of Chemistry, Indian Institute of Science Education & Research, Bhopal, Madhya Pradesh 462066, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details, characterization and NMR spectral data. CCDC 1005568–1005570. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c4ob01693a
This journal is © The Royal Society of Chemistry 2014
Fig. 1
Carbazole motif in bioactive compounds and materials.
direct synthesis of indoles by Rh(II) catalyzed [4 + 2] benzannulation of pyrroles using a new class of enalcarbenoids 15.10a In continuation to our studies on the synthetic applications of enalcarbenoids 15, herein, we report an efficient Rh(II) and Brønsted acid catalyzed direct π-extension of indoles 13 to carbazole-4-carboxylates 16 (Scheme 1c). In addition, we also developed a regioselective twofold π-extension of pyrroles 17 to carbazole-4,8-dicarboxylates 19 via indole 18.
Org. Biomol. Chem., 2014, 12, 8641–8645 | 8641
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Organic & Biomolecular Chemistry
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Table 1
Optimization of π-extensiona,b
Entry
Rh2Ln (mol%)
14a/13a
T (°C)/solvent
% Yield
1 2 3 4 5 6 7 8 9 10 11 12
Rh2(OAc)4 (2) Rh2(Oct)4 (2) Rh2(esp)2 (2) Rh2(TFA)4 (2) Rh2(R-DOSP)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (1) Rh2(OAc)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (2)
1.5/1 1.5/1 1.5/1 1.5/1 1.5/1 1/1.5 2.5/1 3/1 2.5/1 2.5/1 2.5/1 2.5/1
40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 61/CHCl3 84/C2H4Cl2 40/Toluene
42 31 26 14 20 32 68 69 45 10
Published on 04 September 2014. Downloaded by University of Reading on 12/02/2018 20:21:15.
PAPER
Cite this: Org. Biomol. Chem., 2014, 12, 8641
View Journal | View Issue
Regioselective π-extension of indoles with rhodium enalcarbenoids – synthesis of substituted carbazoles† Kuldeep Singh Rathore, Mandeep Harode and Sreenivas Katukojvala* An efficient Rh(II) carboxylate and Brønsted acid catalyzed direct π-extension of indoles to 4-substituted carbazoles is developed. The reaction involves a regioselective C-3 functionalization of indole by a
Received 7th August 2014, Accepted 4th September 2014
rhodium enalcarbenoid and a Brønsted acid assisted cyclocondensation. In addition a twofold regioselective π-extension of pyrroles to 4,8-disubstituted carbazoles has also been developed. The utility of the
DOI: 10.1039/c4ob01693a
methodology was demonstrated with the synthesis of analogues of an hepatitis C virus replication inhibi-
www.rsc.org/obc
tor and a secreted phospholipase A2 (sPLA2) inhibitor.
Introduction Carbazole structural motifs are present in various biologically active natural products, pharmaceuticals and functional materials (1–6, Fig. 1).1,2 As a result development of efficient synthetic methodologies for the functionalized carbazoles continues to be an active area of research.1a,g,3–9 The versatile methodologies include transition metal catalyzed intramolecular C–C coupling of diarylamines,4 C–N coupling of 2-arylanilines or its variations.5 The intermolecular versions include C–C and C–N bond coupling of arylamine with haloarenes, or twofold C–N coupling of primary amines with biaryls.6 One of the appealing strategies for carbazoles involves transition metal catalyzed direct π-extension of readily available indole motif itself.7,8 In this context, the Miura group has developed an efficient [2 + 2 + 2] annulation of indole-carboxylic acids 7 with internal alkynes 8 using the Pd(II)–Cu(II)–Li(I) trimetallic system leading to tetrasubstituted carbazoles 9 under high temperature conditions (Scheme 1a).7 Recently, the Itami group has discovered a formal [2 + 2 + 2] annulation of indoles 10 with electron deficient olefins 11 using the Pd(II)–Cu(II)– Ag(I) trimetallic system (Scheme 1b).8 This protocol involves a large amount of trimetallic system and high temperature and delivers moderate yields. Very recently, we have disclosed a
Department of Chemistry, Indian Institute of Science Education & Research, Bhopal, Madhya Pradesh 462066, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details, characterization and NMR spectral data. CCDC 1005568–1005570. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c4ob01693a
This journal is © The Royal Society of Chemistry 2014
Fig. 1
Carbazole motif in bioactive compounds and materials.
direct synthesis of indoles by Rh(II) catalyzed [4 + 2] benzannulation of pyrroles using a new class of enalcarbenoids 15.10a In continuation to our studies on the synthetic applications of enalcarbenoids 15, herein, we report an efficient Rh(II) and Brønsted acid catalyzed direct π-extension of indoles 13 to carbazole-4-carboxylates 16 (Scheme 1c). In addition, we also developed a regioselective twofold π-extension of pyrroles 17 to carbazole-4,8-dicarboxylates 19 via indole 18.
Org. Biomol. Chem., 2014, 12, 8641–8645 | 8641
View Article Online
Paper
Organic & Biomolecular Chemistry
Published on 04 September 2014. Downloaded by University of Reading on 12/02/2018 20:21:15.
Table 1
Optimization of π-extensiona,b
Entry
Rh2Ln (mol%)
14a/13a
T (°C)/solvent
% Yield
1 2 3 4 5 6 7 8 9 10 11 12
Rh2(OAc)4 (2) Rh2(Oct)4 (2) Rh2(esp)2 (2) Rh2(TFA)4 (2) Rh2(R-DOSP)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (1) Rh2(OAc)4 (2) Rh2(OAc)4 (2) Rh2(OAc)4 (2)
1.5/1 1.5/1 1.5/1 1.5/1 1.5/1 1/1.5 2.5/1 3/1 2.5/1 2.5/1 2.5/1 2.5/1
40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 40/CH2Cl2 61/CHCl3 84/C2H4Cl2 40/Toluene
42 31 26 14 20 32 68 69 45 10
