Access to Functionalized 2-Phenyl-4-(Indol-3-yl)-4 H -Chromenes via Coupling of 2-Hydroxychalcones and Indole in PEG-400/H 2 O under Catalyst-free Conditions

4 H -Chromenes, particularly those appended with functionalized benzene rings at C-4  and annulated with heterocycles exhibit a wide array of bioactivities. An innovative molecular scaffold featuring a 4 H -chromene motif with a 3-indolyl substituent—an esteemed structural framework—anchored at C-4 was envisaged to expand the bioactivity spectrum of the resultant scaffold. This synthesis employs a straightforward domino approach towards the one-pot synthesis of 2-phenyl-4-(indol-3-yl)-4 H -chromenes, utilizing 2-hydroxy chalcones and indoles as readily available starting materials in a PEG-400/H 2 O (1:1) mixture under catalyst-free conditions. The protocol's green attributes include its atom-and step-economical nature, general applicability, procedural simplicity, hassle-free product isolation, and the use of a nontoxic, environmentally friendly reaction medium.


Scheme 1
The 3-substituted indole is a versatile heterocyclic structure found in various alkaloids with pharmacological significance, including antimicrobial, antitumor, and neurotransmitter agents [27,28].Integrating this moiety at the 4-position of the 4H-chromene motif was hypothesized to link their biological properties, potentially enhancing their bioactivity profile.Notably, the synthesis of indolyl chromenes is sparsely investigated.Threecomponent coupling of substituted indoles, salicylaldehydes, and malononitrile under indium chloride-catalysis in aqueous medium led to the above target [29].Synthesis of enantio-enriched 2-amino-4-(indol-3-yl)-4H-chromenes using N, N  -dioxide-Zn(II) complex in dichloromethane was also previously reported [30].Another direct approach to this target utilized the coupling of 2-hydroxy chalcones and indoles under the catalytic presence of iodine in refluxing toluene [31].The existing methods suffer from one or the other limitations, e.g., use of metal salts [29]/ligands [30], halogenated solvents [30], prolonged reaction time [20,21], and non-compatibility of N-methylindole as the nucleophilic partner [30,31].Therefore, I became interested in the rapid synthesis of 2phenyl-4-(3-indol-3-yl)-4H-chromenes, avoiding metal catalysts and halogenated solvents.Inasmuch as coordination with Lewis acid catalyst often leads to blocking of lone pair of nitrogen, thereby reducing nucleophilicity of indole, a catalyst-free procedure is also highly desirable.2-Hydroxychalcone containing electrophilic α,β-unsaturated enone moiety, and nucleophilic hydroxyl group has emerged as a modular building block capable of coupling with carbon nucleophiles to deliver structurally and functionally diversified molecular architectures through domino reactions [32,33].To realize our goal, coupling 2-hydroxy chalcones with indole is considered a straightforward, attractive approach.It relies on the high nucleophilic potential of C-3 of indole, and it was anticipated that indole would be a competent coupling partner of 1a notwithstanding the unreactive nature of α,β-unsaturated enone moiety of 1a, and unfavorable steric factor towards nucleophilic attack at its βcarbon.Herein, I reveal a catalyst-free protocol for the synthesis of 2-phenyl-4-(indol-3yl)-4H-chromenes using PEG-400/H2O (1:1, v/v) as the reaction medium.

Materials and Methods
Salicylaldehyde, acetophenone, and indoles were procured from E. Merck, India/ SRL, India, and were used as such.NMR spectra were measured on Bruker DPX-400(400MHz), and IR spectra were recorded as KBr pellets on a Perkin Elmer FTIR (L120-000A).Silica gel (60-120 mesh) used for chromatographic separations and purifications was supplied by Spectrochem, India.Solvents such as light petrol (b.p. 60-80 o C) and ethyl acetate were purchased from E. Merck, India, and used without further purification.Anhydrous sodium sulfate was used to dry organic extracts.Silica gel G and silica gel GF (3:1) were used for TLC experiments.

Results and Discussion
To find suitable reaction conditions for the realization of the target compounds, a set of optimization experiments were performed under various conditions using an assembly of 2-hydroxychalcone 1a and indole 2a in a 1:1 millimolar ratio.The results of these initial exploratory experiments are shown in Table 1.First, an agitated neat mixture of 1a and 2a was heated at 90-100 C for 4 h.The reaction did not proceed to any significant extent, and TLC monitoring indicated only trace formation of a product, with the rest of the starting materials remaining unchanged (entry 1, Table 1).Heating the reaction mixture in toluene at reflux temperature for 8 h resulted in the isolation of the anticipated product 3aa in a modest 40 % yield (entry 2).I explored PEG-400 as an additive to toluene (0.1 g/mL) in view of its reported efficiency as a phase transfer catalyst [3].The yield improved substantially to 65 % under the same conditions (entry 3).This observation suggests a facilitatory role of the liquid polymer in the coupling process.I also screened a few protic and aprotic polar solvents (EtOH, H2O, CH3CN), but they were found to be ineffective (entries 4-6).The reaction was also performed under aqueous micellar conditions in the presence of sodium dodecyl sulfate (SDS) above its critical micellar concentration in order to solubilize the nonpolar reactants, but it did not work satisfactorily (30 %, 8 h, entry 7).Next, I switched over to PEG-400 as the reaction medium in view of its supportive role as an additive to toluene.The reaction rate was substantially accelerated, and the reaction delivered 42 % yield upon exposure for 4 h at 70-80 C (entry 8).The reaction under Lproline and CeCl3.7H2O(each 10 mol%) catalysis in PEG-400 was also not very promising (entries 9, 10).At this stage, I screened aqueous solutions of PEG, and to our gratification, an aqueous PEG solution (PEG-400/H2O: 1:1 v/v) outperformed all solvents examined so far.1a and 2a underwent smooth coupling upon heating in it for 4 hours to provide 3aa selectively and cleanly in 95 % yield (entry 11).Different mixtures of PEG-400 and H2O were also assessed, but none of them could surpass it (entries 12-13).Another significant observation was the sharp drop in yield upon lowering of temperature from 70-80 C to 40 C, suggesting the marked dependence of yield upon temperature (entry 14).Table 1.Optimization experiments for the synthesis of 3aa.
a Reactions were performed on 1 mmol scale.NR stands for reaction.
With the optimized reaction condition in hand, I investigated its substrate scope for various 4 / -substituted 2-hydroxy chalcones and indoles substituted in both rings.The results of these experiments are exhibited in Table 2.The protocol proved successful in all cases (11 examples) studied.It was demonstrated that the presence of electron-releasing 4 / -OMe in 2-hydroxychalcone 1c lowered the yield of the product 3ca (80 %) with unsubstituted indole as its reaction partner, and it also required extended time (5 h) (entry 3).Presumably, decreased electrophilicity of the enone moiety accounts for the result.Similar lower yields were also scored in the case of coupling of 1a with 2-methylindole (2b) and N-methylindole (2d).Notably, a previous report of I2-catalyzed reaction of N-methylindole [13] was unsuccessful and yielded a trace of product and a complex mixture.However, the electronic nature of 5-substituents of the indole (5-OMe, 5-CN) had no perceptible influence as both 2e and 2f rapidly and efficiently afforded excellent yields of the corresponding coupling products 3ae and 3af (entries 10, 11).a Reaction were performed on 1 mmol scale.
The method also worked for 7-azaindole 4, and the replacement of the benzene ring with an electron-withdrawing pyridine ring had little effect on yield and facility (82 %, 4 h) (Scheme 2).

Scheme 2
The coupling products were characterized by the spectral features (FTIR, 1 H-, 13 C-NMR, elemental analysis data).The melting points of known compounds 3aa, 3ba, 3ca, and 5 were in good agreement with their literature value [31].
The success of the domino reaction-based current protocol primarily hinges upon the efficient formation of the key Michael adduct intermediate, which was favored in nonpolar toluene rather than polar protic or aprotic media (EtOH, H2O, CH3CN).The electrophilic activation of carbonyl by hydrogen bond donor activity of water is a necessary but not sufficient facilitator of the key C-C bond construction.The co-solvent, PEG, decreases the polarity of its aqueous solution, consequently increasing the solubility of the chalcone and indole.This is further coupled with the facilitatory role of ether groups interspersed between methylene units as hydrogen bond bases.It boosts the nucleophilicity of the 2-hydroxy group of chalcone, helping the subsequent C-O bond formation that leads to the chromene ring.Therefore, water and PEG-400 offer complementary roles through their hydrogenbonded structures, facilitating synergistic electrophilic and nucleophilic activation.Finally, dehydration is mainly driven by the extension of conjugation with the 2-phenyl group.This step is presumably very temperature-dependent.The tentative mechanistic scenario of the domino C-C and C-O bond formations is depicted in Scheme 3.

Conclusion
Herein, a simple domino method is presented for the one-pot synthesis of 2-phenyl-4-(indol-3-yl)-4H-chromenes, utilizing 2-hydroxy chalcones and indoles as easily obtainable starting materials in PEG-400/H2O (1:1) mixture under catalyst-free conditions.Under optimized conditions at 70-80 °C, the reaction efficiently proceeded with a diverse range of substrates, giving excellent yields in the range 80 to 97 %.Water and PEG play a complementary role in this process, activating the carbonyl group and enhancing solubility.The protocol's green credentials lie in its efficient use of atoms and steps, its broad applicability, straightforwardness, easy product isolation, and the utilization of a nontoxic, environmentally friendly reaction medium.