synthesis and catalytic functionalization of biologically active indoles

1 Palladium-catalyzed Coupling Reactions of Indoles 45
different heteroaryl halides with a range of alkynes in good yields. The ratios
between substrate and catalyst were nearby moderate to high in the process.
Various heteroaryl halides like indoles, thiophenes, pyridines and quinolines were
employed successfully. The examples of Sonogashira reaction of 5-bromoindole
with different alkynes are shown in Scheme 36. The bromo-substituted indole was
a suitable substrate for Sonogashira coupling. TON’s of 6000-8000 were obtained
for the coupling of 5-bromoindole 12 with phenylacetylene 136. Lower TON’s were
observed by the coupling with propargyl alcohol 142 and but-3-yn-1-ol 143. The
coupling products 144-146 were obtained in excellent yields up to 99%. The
results represent economically attractive procedures.
Br
12
N
H
H
H
H
136
142
143
Ph
OH
OH
[Pd(C 3H 5)Cl] 2/ligand E
K 2CO 3 (2 equiv)
CuI (0.05 equiv)
DMF, 100 °C, 20 h
Scheme 36. Sonogashira coupling reaction with 5-bromoindole.
HO
HO
Ph
144 (97%)
N
H
N
H
145 (99%)
N
H
146 (99%)
Because of the high price of palladium, their low catalyst loading is a practical
advantage and become increasingly important for industrial processes.
Sonogashira coupling reactions are not only possible with aryl halides especially
indole halides, but also with other substrates like 2-trifluoromethanesulfonyloxyindoles.
[118] Rossi and co-workers developed palladium-catalyzed reactions with
2-trifluoromethanesulfonyloxyindole-1-carboxylic acid ethyl ester and different
partners. [94] Compound 147 was synthesized first and its reactivity was tested
afterwards. The authors prepared 2-aryl, 2-heteroaryl, 2-allyl, and 2-vinyl indoles
148a-f in good to excellent yields by palladium-catalyzed coupling of 147 with
commercially available alkynes. Scheme 37 gives an account of the reaction with
different alkynes following the Sonogashira protocol.