synthesis and catalytic functionalization of biologically active indoles

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1 Palladium-catalyzed Coupling Reactions of Indoles 41 many researchers have established some flexibility in the conditions, no general method is yet available for all substrates for this reaction. [112,113] One application of the Sonogahsira cross coupling of indoles was described by Witulski and co-workers. [91] The authors developed a strategy for the synthesis of functionalized indoles via transition metal-catalyzed reactions. Sonogashira as well as Suzuki reactions with 3,5-bis-halogenated indoles or their 2-azabioisosteres and indazoles led to the preparation of conjugated serotonin derivatives. In order to test the feasibility of the Sonogashira reaction in sequential palladium-catalyzed reactions in the indole series, they attempted to synthesize a variety of 3-alkynyl indoles structurally related to serotonin (Table 6). The direct iodination followed by N-protection of the indole nitrogen resulted 3-iodoindole derivatives 132a-h. These coupling reactions of iodoindoles with a set of terminal alkynes proceeded under mild conditions and gave the according coupling products 133a-m. Table 6. Sonogashira coupling reactions starting from 3-iodoindole derivatives. R 1 I N R H R 2 PdCl 2(PPh 3) 2 (5 mol%) CuI (10 mol%) Et 3N/DMF, 20 °C, 12 h 132a-h 133a-m Entry 132 R R 1 R 2 R 1 N R R 2 133 Yield [%] 1 a Boc H CH2NMe2 a 69 2 a Boc H CH2NHTos b 81 3 b Tos H CH2NHTos c 84 4 c Boc OMe CH2NMe2 d 97 5 c Boc OMe N O e 93 6 d SO2Ph OMe CH2NMe2 f 94 7 d SO2Ph OMe CH2NHTos g 96 8 d SO2Ph OMe CH2OH h 91 9 e Tos OMe Ph I 76 10 f Boc Br CH2NHTos j 91
1 Palladium-catalyzed Coupling Reactions of Indoles 42 Table 6. Sonogashira coupling reactions starting from 3-iodoindole derivatives, continued. Entry 132 R R 1 R 2 133 Yield [%] 11 g SO2Ph Br CH2NMe2 k 88 12 h Tos Br CH2NHTos l 90 13 h Tos Br CH2OH m 79 All reactions were carried out at room temperature in the presence of 5 mol% PdCl2(PPh3)2 and 10 mol% CuI as catalysts. The corresponding new 3-alkynyl indoles 133a-m were obtained in good to excellent yields after purification by column chromatography. To avoid any couplings at the N-1-position it was necessary to protect the nitrogen atom in all cases. Thereby the choice of the protecting group played no significant role. As well as the substituent R 1 on the benzene moiety of the indole showed no significant influence on the course of the coupling reaction. Interestingly for the derivatives, which had an iodine, atom in 3position and a bromine atom at the 5-position were exclusively functionalized at the 3-position when the reactions ran at room temperature (Table 6, entries 10- 13). In the next step they examined Sonogashira-Sonogashira sequential crosscouplings in the indole series. Arylbromides were less reactive than the parent iodides in palladium cross-coupling reactions. The conversion of 5-bromoindole into its bis-alkynylated derivative did not proceed at room temperature but required heating at 70 °C. In these cases an additional amount of PPh3 was necessary to stabilize the active catalyst in one hand and to keep the overall efficiency catalysis on the other hand. Table 7 shows the coupling reaction of 3-alkynyl-5bromoindoles 133j-l with different terminal alkynes to bisalkynylated indole derivatives 134a-d. In comparison with the first Sonogashira coupling reaction, ran this coupling reaction with up to 3 days relatively slow. Therefore they used a higher catalyst loading of PdCl2(PPh3)2 and 2-3 equiv of monoalkynes. Under this optimized conditions the reaction advanced two days to give the according indole products 134a-d. All Sonogashira reactions proceeded smoothly affording a large range of new alkynylated indoles, which are analogues of serotonin especially 5HT4-5HT7 receptors.
Page 1 and 2: Leibniz-Institut für Katalyse e. V
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Table 2. Reaction of different amin
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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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Publikationen 1 Titanium-Catalyzed
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