synthesis and catalytic functionalization of biologically active indoles

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1 Palladium-catalyzed Coupling Reactions of Indoles 37 expected o- as well as to the unexpected o´-derived Heck and Suzuki products (Scheme 30). Their observations suggested the presence of a 1,4 rearrangement of the palladium moiety between o- and o´-positions of these biaryls. For a more general understanding of the scope and geniality of the palladium-migration several biaryls have been investigated and illustrated. One example is shown in Scheme 30. Therefore N-methylindole analogues 30 and 34 reacted with ethyl acrylate in the presence of Pd(OAc)2. Using the migration conditions compound 30 in attendance of Pd(OAc)2, dppm and CsPiv in DMF at 100 °C produced exclusively E-3-(1-methyl-3-phenylindole-2-yl)acrylate 120 in 94% yield in 24 h. By using migration conditions again indole acrylate 120 generated from 34 gave 77% yield. They reported that the 13% yield of indole acrylate 121 resulted of slow palladium equilibration. It might be due to unfavorable steric interactions imposed on the palladium when migrating to the relatively more hindered 2-position of the N-methylindole. They postulated that steric hindrance was a significant factor in this palladium-migration chemistry disfavoring sterically congested arylpalladium intermediates. 120 94% 121 0% I 30 N Me CO2Et 34 Pd(OAc) 2 (5 mol%) dppm (5 mol%) CsPiv (2 equiv) DMF, 100 °C, 24 h CO 2Et N Me N 120 121 Me N Me I 120 77% 121 13% Scheme 30. Aryl-aryl palladium-migration in Heck coupling of o-halobiaryls. CO 2Et
1 Palladium-catalyzed Coupling Reactions of Indoles 38 Following Heck reaction is engaged in the development of a scalable process for DG-041 125, a potent EP3 receptor antagonist, via tandem reaction (Scheme 31). [108] F Br 122 Br N H F Br N H CH 3 123 CO2H 124 HO O Cl 1. Pd(OAc) 2 P(o-tolyl) 3 CH 3CN, Et 3N 2. Pd(OAc) 2 P(o-tolyl) 3 Cl F N F CH 3 HN O Cl S S O O 125 DG-041 Scheme 31. Synthesis of DG-041, a potent EP3 receptor antagonist, via tandem Heck reaction. DG-041 125 is a small molecule antagonist of the EP3 receptor for prostaglandin E2 that is in the clinical development of treatment of peripheral artery disease. The key step in the reaction sequence contains of two sequential Heck reactions. The optimized process led to the development of a four-step sequence involving an intramolecular Heck cyclization followed by an intermolecular Heck coupling. It was performed in one pot and produced the highly substituted indole core 124. The conversion of compound 122 to the key intermediate 123 in one pot minimized the processing time and the number of unit operations. Treatment of 122 with the palladium/P(o-tolyl)3 system in acetonitrile in the presence of Et3N, catalyzed the transformation to intermediate 123 within 3 h under reflux. Upon completion of conversion, the reaction mixture was recharged with additional palladium/P(o-tolyl)3 followed by acrylic acid. The isolation of product 124 was facilitated by the discovery that it crystallized readily from the reaction mixture upon dilution with methyl-tert-butyl ether as its Et3N-salt with quantities of Et3N- Cl N H CH 3
Page 1 and 2: Leibniz-Institut für Katalyse e. V
Page 3 and 4: Für meine Eltern Siegfried und Ker
Page 5 and 6: Mein besonderer Dank gilt Dr. Anneg
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Page 9 and 10: List of Abbreviations Ac Acetyl aq
Page 11 and 12: Preface The search for drugs is an
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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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