synthesis and catalytic functionalization of biologically active indoles

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