synthesis and catalytic functionalization of biologically active indoles

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1 Palladium-catalyzed Coupling Reactions of Indoles 5 Kumar and co-workers developed an attractive method for the substitution of indoles with novel 7-bromo-5,6-dihydroindole-2-ones. [13] This type of coupling partner is isosteric to indoles and is believed to possess similar biological activity. [14] O B O O PdCl2(PPh3) 2 N O Ph N H Br N Ph THF, H2O KF, Bu4NI 5 6 HN 7 68% Scheme 2. Suzuki-Miyaura cross-coupling reation of 5-pinacol-indole with 7-bromo dihydroindole- 2-one. Scheme 2 shows an example of the coupling of the non-protected indole pinacol ester 5 by using a dual-solvent system, KF as base, and Bu4NI as phase-transfer catalyst. Here, the desired product 7 is obtained in good yield (68%). Obatoclax 11 is known to be biological active and shows potent anticancer activity in several animal tumor models. This novel indolylprodigiosin derivative has the ability to antagonize multiple members of the B-cell lymphoma family of antiapoptotic proteins. [15] The three-step synthesis involves a haloformylation reaction [16 , ] followed by a Suzuki cross-coupling reaction with an indole-2-boronic acid 9 to give compound 10a (Scheme 3). The Suzuki reaction proceeded rapidly in the presence of 3 mol% Pd(OAc)2 and 12 mol% PPh3. However, an excess of boronic acid is required for an acceptable yield. The mixture of different solvents slowed down the decomposition of indole-2-boronic acid 9 and raised the yield additionally. Subsequent hydrolysis of both the enamine and the N-methoxy carbonyl group afforded the indolylpyrrole aldehyde 10b. The final step includes the acid mediated condensation of 10b with 2,4-dimethyl-1H-pyrrole to provide the HCl-salt of Obatoclax 11. Notably, this three-step synthesis was recently applied to the production of Obatoclax on kg-scale to support clinical studies. Sapi and co-workers described a short synthesis of fused indole heterocycles via palladium-catalyzed cross-coupling. [17]
1 Palladium-catalyzed Coupling Reactions of Indoles 6 Br OMe NH N 8 Pd(OAc) 2 (3 mol%) PPh3 (12 mol%) B(OH) 2 dioxane,H2O, N toluene N N 9 O O 80-90 °C O 10a O N H 11 Obatoclax N HN OMe Scheme 3. Suzuki-Miyaura coupling key step in the synthesis of Obatoclax. N H 10b N OMe N hydrolysis OMe O (48 % over two steps) Therefore the authors investigated the reaction of 5-bromoindole 12 and 2-(2,2dimethylpropionylamino)phenyl boronic acid [18] 14 (Scheme 4). Using Pd(PPh3)4 as catalyst system and 10% aqueous NaHCO3 solution or Na2CO3 as base in DME, the corresponding diaryl compound 17 is formed in 66% yield. Because of problems in the deprotection of the pivaloyl- protecting group, the authors also performed the cross coupling of 12 with the N-Boc-protected 2-aniline boronic acid 15 under the same conditions with a yield of 55%. They got higher yields of the same coupling product, using 1H-indole boronic acid 13 with N-Boc-protected 2bromoaniline 16 (66%). Y Y N H 12 Br 13 B(OH) 2 20 NH 2 X R R X 14 NHPiv B(OH) 2 15 NHBoc B(OH) 2 16 NHBoc Br N H Pd(PPh 3) 4 (3-6 mol%) 10% NaHCO 3aq or Na 2CO 3 (2.4 equiv) DME,� R R 17 NHPiv 18 NHBoc NH 2 19 from 18 Scheme 4. Palladium-catalyzed Suzuki-Miyaura reaction to indole derivatives. N H SiO 2, microwave N H H
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1092 N. Schwarz et al. LETTER Table
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1094 N. Schwarz et al. LETTER 2,6-d
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3 Publications 84 3.2 Zinc-Promoted
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Table 2: Reaction of N-methyl-N-phe
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Am. Chem. Soc. 2002, 124, 15168 - 1
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A novel palladium catalyst for the
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Table 2. Reaction of different amin
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3 Publications 94 Experimental Data
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3 Publications 96 (q); 115.3 (d, J
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3 Publications 98 3.4 Palladium-Cat
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PAPER Coupling Reactions of Electro
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3 Publications 108 3.5 Synthesis of
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Scheme 2 Ti-catalyzed synthesis of
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mixture was used for the synthesis
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7.11 (ddd, 1H, J = 8.0 Hz, J = 7.0
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FULL PAPER DOI: 10.1002/ejoc.200800
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Synthesis of Potential 5-HT 6 Recep
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FULL PAPER DOI: 10.1002/ejoc.200700
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Synthesis of Indole-2,3-dicarboxyla
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3 Publications 132 3.8 Selective Re
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8 7 N R N R OH CO2Et CO2Et OH indol
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mixture was stirred at 78 C for 3 m
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3.89 (s, 2H, H-10), 4.27 (s, 2H, H-
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DOI: 10.1002/cssc.200700160 General
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Zn-Catalyzed Hydroamination of Term
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Zn-Catalyzed Hydroamination of Term
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3 Publications 146 3.10 Zn-Catalyze
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Over the past years, we investigate
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3 Publications 150 3.11 First Synth
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4608 K. Alex et al. / Tetrahedron L
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Publikationen 1 Titanium-Catalyzed
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synthesis and catalytic functionalization of biologically active indoles

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