2
Tetrahedron
Multicomponent reactions wherein three or more reactants are combined in a single vessel to form a complex
molecule have attracted considerable attention for the preparation of biologically active compounds due to the synthetic
simplicity of reducing the number of steps and the improvement of synthetic efficiency.1, 2 3-Substituted indoles are
valuable structural motifs because they exhibit potential biological activities in pharmaceutical and agrochemical fields.
Accordingly, the development of efficient methods for the preparation of 3-substituted indoles via Yonemitsu-type
trimolecular condensation has received significant attention (Scheme 1).3 Nevertheless, a large excess of unrecyclable
Lewis acids, high temperatures, or long reaction times were employed in these reactions.4, 5 Consequently, the search for
more efficient, simple, low cost, and environmentally benign methods for the preparation of 3-substituted indoles remains
a challenging task. Recently, a novel copper(II) sulfonato salen catalyst was utilized for the multicomponent reaction of
indoles, malononitrile, and benzaldehydes to afford 3-substituted indoles in good yields.6 However, the use of expensive
catalysts, additives, and long reaction times are not suitable for industrial processes.
Green methods using water or solvent-free conditions have been extensively studied due to their economic efficiency and waste
reduction.7 Thus, deep eutectic solvents (DESs), a type of ionic liquids formed by mixing a typical ammonium halide salt and
hydrogen bond donors or metal salts, have received increased interest.8-10 DESs are green solvents/catalysts with unique properties
and can be designed by changing the salt or hydrogen bond donor.11 DESs are non-toxic, non-volatile, thermostable,
recyclable, and biodegradable.12, 13 However, there have fewer reports on the use of DESs as catalysts for multicomponent reactions.
In continuation of our efforts in developing green processes, we report herein the multicomponent reactions of aldehydes, indoles,
and active methylene compounds in a DES formed from choline chloride and zinc chloride. The method is simple, efficient, and
cost-effective for the preparation of 3-substituted indoles. The reaction proceeded smoothly under solvent-free conditions, and the
desired products were obtained in good yields.
[CholineCl][ZnCl2]3 was synthesized following a literature procedure (see ESI).14 Next, we focused on screening for an
effective catalyst using the model reaction of indole, benzaldehyde, and diethyl malonate. Among the various metal halides and
DESs tested (Table 1), [CholineCl][ZnCl2]3 showed the best catalytic activity (Table 1, entry 8). Meanwhile, the reaction did not
afford the desired product when other DESs were employed as catalysts (Table 1, entries 9-11). Control experiments using only
choline chloride or zinc chloride were also tested. Lower yields were obtained under these conditions (Table 1, entries 12-13).
Then, the effect of the catalyst loading was investigated (Table 2). No product was obtained in the absence of
[CholineCl][ZnCl2]3 (Table 2, entry 1). The optimal loading was attained at 30 mol% [CholineCl][ZnCl2]3 (Table 2, entry 6). When
the catalyst loading was decreased from 30% to 5%, the yields decreased from 67% to 25% (Table 2, entries 2-5). However, at the
catalyst loading of 50%, only a slightly increased yield was observed (Table 2, entry 7). Further optimization showed that the
current method was most effective at room temperature for 6 h under sonication.
The recyclability of catalyst is the most critical feature for its upscaled application in industrial processes. The recovery of
[CholineCl][ZnCl2]3 could be easily accomplished through liquid-liquid extraction. The recycling test was conducted using the
reactions of indole and diethyl malonate with benzaldehyde, 4-nitrobenzaldehyde or 4-methoxybenzaldehyde, only indicating a
slight loss of catalytic activity over four cycles (Fig. 1). FT-IR spectra of freshly prepared and recovered [CholineCl][ZnCl2]3
showed no significant structural changes.
With the optimized conditions in hand, the reaction scope was studied with a number of aldehydes and indoles (Table 3). The
electronic effects of the benzaldehydes had little impact on the yield. Benzaldehydes bearing electron-donating groups (4-methoxy,
4-methyl, 4-hydroxy, and 4-tert-butyl) on the aromatic ring were beneficial and provided the desired products in good yields.
Benzaldehydes bearing electron-withdrawing groups, including 4-nitrobenzaldehyde and 4-fluorobenzaldehyde, gave the desired
products 4g (35%) and 4b (49%), respectively. The influence of substituents at the C5 position of the indole ring was also examined.
Good yields were obtained with an electron-rich methyl group. However, slightly lower yields were observed with 5-halogen
substituents (4m-t), which are deactivating. To further investigate the scope and limitations of the method, malononitrile was used
as a reagent. Remarkably, malononitrile reacted smoothly with indoles and aldehydes affording the desired products in higher
yields and shorter reaction times than diethyl malonate.
To study the reaction mechanism, some control experiments were tested. As presented in Table 1, the multicomponent reaction
in the presence of either choline chloride or ZnCl2 provided the desired product 4a in 0% and 34% yield, respectively. Based on
the control experiments and literature reports,4 a plausible mechanism was proposed (Scheme S1, ESI). We believe that formation
of the desired product could be explained by the role of [CholineCl][ZnCl2]3 in the following processes. The first step involves an
interaction between [CholineCl][ZnCl2]3 and dimethyl malonate. This coordination increases the acidity of the α-hydrogen
allowing an enolate intermediate to be easily formed. Next, the reactive intermediate attacks the benzaldehyde to generate
intermediate (A) via Knoevenagel adduct formation. Finally, the Friedel-Crafts alkylation of indole by the alkylidene malonate
leads to the expected product.
In conclusion, we have successfully developed a green and efficient method for the three-component reaction of indoles,
aromatic aldehydes, and active methylene compounds to synthesize the 3-substituted indoles. Mild reaction conditions, simple
workup protocol, no additives, and no toxic solvent are the notable features of the method. Moreover, the DES could be recovered
Tran, Minh-Nguyet Thi
