synthesis and catalytic functionalization of biologically active indoles

More documents

Recommendations

Info

3 Publications 115 3.6 Palladium-Catalyzed Amination and Sulfonylation of 5-Bromo-3-[2-(diethylamino)ethoxy)indoles to Potential 5HT6 Receptor Ligands Nicolle Schwarz, Anahit Pews-Davtyan, Dirk Michalik, Karolin Krüger, Annegret Tillack, Antoni Torrens, José Luis Diaz, Matthias Beller, Eur. J. Org. Chem. 2008, 5425-5435. Contributions: In this paper I contributed to a significant amount of the argumentation and the synthetic work. I performed synthesis about half of the compounds. My contribution as co-author of this paper is more than 60%.
FULL PAPER DOI: 10.1002/ejoc.200800638 Palladium-Catalyzed Amination and Sulfonylation of 5-Bromo-3-[2- (diethylamino)ethoxy]indoles to Potential 5-HT 6 Receptor Ligands Nicolle Schwarz, [a] Anahit Pews-Davtyan, [a] Dirk Michalik, [a] Annegret Tillack, [a] Karolin Krüger, [a] Antoni Torrens, [b] José Luis Diaz, [b] and Matthias Beller* [a] Keywords: Indole / Sulfonylation / Amination / Palladium A general and efficient palladium-catalyzed amination of 5bromo-3-[2-(diethylamino)ethoxy]indoles has been developed. Best results are obtained in the presence of Pd(OAc) 2 and 2-[di(1-adamantyl)phosphanyl]-1-phenylpyrrole as ligand. Subsequent sulfonylation gave novel indole deriva- Introduction Among the known biologically active amines, especially indoles continue to attract significant synthetic and medicinal interest. [1] A variety of substituted indoles bind selectively to different receptors with high affinity and have been referred as “privileged pharmacological structures”. Thus, it is not surprising that indoles have become an important component in many of today’s pharmaceuticals. [2] 5-Hydroxytryptamine 6 (5-HT 6) receptors are an essential subtype of the identified serotonin receptors 5-HT 1–7. [3] Their selective attraction for a wide range of drugs used in central nervous system related diseases (e.g. Alzheimer’s disease, anxiety, and schizophrenia) has stimulated significant recent work in this field. [4] In addition, 5-HT 6 receptor ligands are known to facilitate the reduction of food intake, fat absorption and body weight in genetic and dietary models of obesity. Interestingly, the 5-HT 6 receptor has no known functional splice variants and it appears to be expressed almost exclusively in the central nervous system (CNS). [5] Since the discovery of selective ligands for 5-HT 6 receptors by high-throughput-screening in 1998, several medicinal-chemistry-driven approaches have delivered novel lead structures. Among the active compounds the majority are indole derivatives, especially with tryptamine scaffold (Figure 1). [6] For some time we have been interested in the improvement and exploration of methodologies for the synthesis and functionalization of indoles. [7,8] For example, we developed a one-pot synthesis of tryptamines and trypto- [a] Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany Fax: +49-381-1281-51113 E-mail: matthias.beller@catalysis.de [b] ESTEVE, Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain tives, which are of interest as potentially biological active 5- HT 6 receptor ligands. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) pholes via titanium-catalyzed hydrohydrazination of chloro- and silyloxo-substituted alkynes. [9] Based on this work, more recently we studied the catalytic hydrohydrazination of propargyl alcohol derivatives to give 3-silyloxy-2-methylindoles (Scheme 1). [10] Figure 1. 5-HT 6 receptor ligands containing indoles or indole-like structures. Scheme 1. Catalytic synthesis of 3-siloxyindoles. In continuation of these studies, we report here the synthesis of novel 3-[2-(diethylamino)ethoxy]-2-methylindoles, [11] their palladium-catalyzed amination and subsequent sulfonylation of the corresponding coupled indoles. Eur. J. Org. Chem. 2008, 5425–5435 © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5425
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
Page 7 and 8:
Table of Contents Preface .........
Page 9 and 10:
List of Abbreviations Ac Acetyl aq
Page 11 and 12:
Preface The search for drugs is an
Page 13 and 14:
1 Palladium-catalyzed Coupling Reac
Page 15 and 16:
Page 17 and 18:
Page 19 and 20:
Page 21 and 22:
Page 23 and 24:
Page 25 and 26:
Page 27 and 28:
Page 29 and 30:
Page 31 and 32:
Page 33 and 34:
Page 35 and 36:
Page 37 and 38:
Page 39 and 40:
Page 41 and 42:
Page 43 and 44:
Page 45 and 46:
Page 47 and 48:
Page 49 and 50:
Page 51 and 52:
Page 53 and 54:
Page 55 and 56:
Page 57 and 58:
Page 59 and 60:
Page 61 and 62:
Page 63 and 64:
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76: 1 Palladium-catalyzed Coupling Reac
Page 89 and 90: 3 Publications 3.1 Titanium-Catalyz
Page 91 and 92: 1092 N. Schwarz et al. LETTER Table
Page 93 and 94: 1094 N. Schwarz et al. LETTER 2,6-d
Page 95 and 96: 3 Publications 84 3.2 Zinc-Promoted
Page 97 and 98: Table 2: Reaction of N-methyl-N-phe
Page 99 and 100: Am. Chem. Soc. 2002, 124, 15168 - 1
Page 101 and 102: A novel palladium catalyst for the
Page 103 and 104: Table 2. Reaction of different amin
Page 105 and 106: 3 Publications 94 Experimental Data
Page 107 and 108: 3 Publications 96 (q); 115.3 (d, J
Page 109 and 110: 3 Publications 98 3.4 Palladium-Cat
Page 111 and 112: PAPER Coupling Reactions of Electro
Page 119 and 120: 3 Publications 108 3.5 Synthesis of
Page 121 and 122: Scheme 2 Ti-catalyzed synthesis of
Page 123 and 124: mixture was used for the synthesis
Page 125: 7.11 (ddd, 1H, J = 8.0 Hz, J = 7.0
Page 129 and 130: Synthesis of Potential 5-HT 6 Recep
Page 139 and 140: FULL PAPER DOI: 10.1002/ejoc.200700
Page 141 and 142: Synthesis of Indole-2,3-dicarboxyla
Page 143 and 144: 3 Publications 132 3.8 Selective Re
Page 145 and 146: 8 7 N R N R OH CO2Et CO2Et OH indol
Page 147 and 148: mixture was stirred at 78 C for 3 m
Page 149 and 150: 3.89 (s, 2H, H-10), 4.27 (s, 2H, H-
Page 151 and 152: DOI: 10.1002/cssc.200700160 General
Page 153 and 154: Zn-Catalyzed Hydroamination of Term
Page 155 and 156: Zn-Catalyzed Hydroamination of Term
Page 157 and 158: 3 Publications 146 3.10 Zn-Catalyze
Page 159 and 160: Over the past years, we investigate
Page 161 and 162: 3 Publications 150 3.11 First Synth
Page 163 and 164: 4608 K. Alex et al. / Tetrahedron L
Page 165 and 166: Publikationen 1 Titanium-Catalyzed
show all

synthesis and catalytic functionalization of biologically active indoles

Create successful ePaper yourself

Delete template?

Save as template?