4
A. N. PRASAD ET AL.
short reaction times. Interestingly, the prepared catalyst showed remarkable activity with-
out the addition of any external ligands and additives. In contrast, in the absence of catalyst
and presence of CuCl, CuBr catalysts, the reaction did not provide any satisfactory yields of
the desired 3-substituted indole product even after a prolonged reaction time but led to the
formation of trace amounts of by-products at ambient conditions (Entries 8–11). The mod-
erate yield was observed, when the reaction was performed in the presence of copper met-
allic powder (Entry 12).
After identification of the most efficient catalyst, to study the solvent effects on the MCR of
indole, benzaldehyde, and malononitrile, we performed the reaction in various solvents, and
these results are also shown in Table 1. The best results in terms of desired product yield were
obtained using water as reaction medium compared to conventional organic solvents under
ambient conditions (Entry 7). The increased product yields are probably due to many factors
including hydrophobic nature, the high cohesive energy density of water, and high polarity,
which helps many organic reactions to proceed with at high reaction rate, selectivity and pro-
vide excellent yields.[1a,27a] Poor catalytic activity, required temperature, and long reaction
times were observed for various organic solvents such as ACN, toluene, MeOH, THF, DMSO,
DMF, and acetone. (Entries 1–4, 13–16). We also studied the optimization reaction conditions
with different catalyst loads, such as 3, 5, and 7 mol% of catalyst. Interestingly, the 5 and
7 mol% catalysts also showed considerable activity (Entries 18, 19), but the yields were lower
than that of 10 mol% of the catalyst. However, when the reaction is performed under solvent-
free conditions, the yield was reasonable at room temperature (Entry 6).
Under optimal reaction conditions (catalyst, solvent, additive-free, temperature), a range
of reactions was performed to study the scope of this methodology using a variety of alde-
hydes (aromatic, aliphatic, and hetero aromatic), indole, and active methylene compounds
(malononitrile and ethyl 2-cyano acetate). An evaluation of the substrate scope explored by
this protocol is compatible, and all the substrates were tested giving moderate to good
yields of desired 3-substituted indoles (Table 2). As shown in Table 2, reactions of various
aromatic aldehydes containing electron-withdrawing, neutral, and electron-donating
groups at ortho, meta, and para positions with indole and active methylene compounds
were conducted smoothly, and the corresponding 3-substituted indoles were achieved in
good to excellent yields, and the results showed that the aldehydes with electron-withdraw-
ing groups were more reactive than donating groups. In particular, the reaction of 4-meth-
oxy benzaldehyde gave the corresponding 3-substituted indole with moderate yield due to
its strong donating nature of methoxy group (Entry 17). In addition, steric hindrances
seemed to have few effects toward the formation of the product yield. For instance, the
2-fluoro, 2-trifluoromethyl benzaldehyde substrates underwent MCR and gave moderate
yields of the desired products (Entries 4, 5, 11, 13). The hetero-aromatic aldehydes such
as 2-thiophenecaboxaldehyde, gave a good yield of desired products (Entries 7, 15).
Furthermore, aliphatic aldehydes such as nonanal underwent through MCR and afforded
good yields of the products (Entries 14, 19). Interestingly, the aldehyde and indole sub-
strates with ethyl 2-cyano acetate were coupled under optimized reaction conditions and
gave excellent yields of the desired products as an inseparable diastereomeric mixture[22]
(Entries 10–13, 15, 18, 19). Based on our research and literature,[22] the plausible mechan-
istic pathways are shown in Scheme 2 the one-pot MCR proceeds through the formation of
Knoevenagel adduct and then followed by the Michael addition of indole in the presence of
Cu(PPh3)Cl catalyst and resulted in 3-substituted indole.