Recent advances in the application of indoles in multicomponent reactions

Indoles are some of the most versatile and common nitrogen-based heterocyclic scaffolds and are frequently used in the synthesis of various organic compounds. Indole based compounds are very important among heterocyclic structures due to their biological and pharmaceutical activities. The last decade, in particular, has witnessed considerable activity towards the synthesis of indole derivatives due to the possibilities for the design of polycyclic structures by the incorporation of multiple fused heterocyclic scaffolds in an attempt to achieve promising new heterocycles with chemical and biomedical relevance. In this study, we provide an overview on recent applications of indole in the multicomponent reactions for the synthesis of various heterocyclic compounds during the period of 2012 to 2017.


Introduction
Heterocyclic compounds are important tools in our daily life having an extensive variety of applications such as sanitizers, 1 pharmaceuticals 2,3 and antioxidant compounds, 4,5 corrosion inhibitors, 6,7 dye stuff, 8 copolymers, 9,10 and as building blocks in the synthesis of organic compounds and natural products. Multicomponent reactions (MCRs) have been extensively used for the synthesis of heterocyclic compounds. [11][12][13] MCRs represent a great tool in organic synthesis for the construction of variety-oriented series of building blocks with potentially interesting biological activities. [14][15][16][17] The attractiveness of the MCR approach is its easy operation, high selectivity and yield by using minimum synthetic requirements. Indole scaffolds have been known for their value in the development of new compounds of pharmaceutical interest. [18][19][20] Up to date, several  21,22 Herein, in continuation of our studies towards the synthesis of heterocyclic compounds and multicomponent reactions, [23][24][25][26][27][28][29][30][31][32] and since there is a wide range of reactions that include indole in the preparation of heterocyclic compounds, this review presents the recent applications of indole in the synthesis of diverse heterocyclic compounds during the period from 2012 to 2017. This review rst discusses indoles' C-3 carbon atom reactivity applicable to electrophilic reactions, followed by MCRs in which the N position of indole is reacted as a nucleophile to afford N-substituted indole products. In Section 2.3, indole cycloaddition reactions have been discussed including cycloaddition reactions of the C2-C3 p-bond (Section 2.3.1) and the C-N sigma bond (Section 2.3.2). Finally, in Section 2.4, miscellaneous reactions of indole will be reviewed.

Multicomponent reactions of indoles
The indole structure is a heterocyclic compound which easily participates in chemical reactions. Its bonding sites are analogous to pyrrole. As shown in Scheme 1, indole is reactive at four different positions including the carbon atom 3, nitrogen atom 1, the C2-C3 p-bond and the C2-N sigma bond. Indole can be protonated with strong acids such as hydrochloric acid, which protonates the C3 position, more easily than the N atom. The cycloaddition reaction is another reaction of indole compounds. The C2-C3 p-bond of indole has a propensity towards cycloaddition reactions but cycloaddition reactions of the C2-N sigma bond are also observed.

The C-3 position reactions of indoles
Gámez-Montaño's group reported the one-pot Ugi-azide 33 multicomponent reaction of indole 1, isocyanides 2, aldehydes 3 and TMSN 3 4 (Scheme 2). In the rst step, intermediate A was obtained, and then N-acylation was performed between A and chloroacetyl chloride to give the intermediate B, which underwent an S N 2 reaction with the potassium ethyl xanthogenate salt to give the nal xanthates 5 (Scheme 2). 34 The one-pot multicomponent reaction of 3-acetylindole 1, aromatic aldehydes 3, ethyl cyanoacetate 6, and ammonium acetate 7 in the presence of piperidine as catalyst was established to access several 6-indolylpyridine-3-carbonitrile derivatives 8 (Scheme 3). 35 The anti-proliferative activities of products were evaluated and showed good results.
Indole 1, carbon disulde 9 and substituted a-bromo propiophenones 10 were reacted via a three component domino [3 + 2] heterocyclization reaction for the preparation of twocarbon-tethered 1,3-oxathiole-indole pair compounds 11 (Scheme 4). 36 The results showed that functional groups such as bromide and chloride provide ample opportunity for further functional group manipulations, for example, by modern crosscoupling reactions.
Polyfunctionalized indole derivatives 35 and 36 were generated from the Yonemitsu-type 46 trimolecular condensation of indoles 1 with aldehydes 3 and 1,3-dicarbonyl compounds 34, such as malonates and acetoacetates using Lewis acid catalysts under microwave irradiation. The formation of bis-indolic derivative 36 can be easily rationalized in the one pot reaction, where a double addition of indole to the aldehyde is assumed. As already suggested by Gao and Wu, 47 the adduct 35 is probably converted into a reactive indolenine derivative A 48 by the loss of an active methylene fragment, which reacts with another molecule of indole (Schemes 12 and 13). 49 Macroporous copper oxide (mpCuO) was also used as catalyst in this reaction and the same products were isolated in good yields. 50 Docking studies against enoyl acyl carrier protein reductase predicted that the compounds bind at the active site with high binding affinity values. In another study, Li et al. used L-proline as catalyst in this reaction. 51 The results are summarized in Table  1.
Khala-Nezhad et al. developed the use of trimethylsilyl iodide (TMSI) as a multifunctional agent in the one-pot synthesis of 9-(1H-indol-3-yl)xanthen-4-(9H)-ones 37 from the reaction of indoles 1, 2-methoxybenzaldehydes 3 (as O-methyl protected salicylaldehydes) and b-dicarbonyl compounds 24 (Scheme 14). 52 The functionalized indole-3-yl pyridines 40 were prepared via an efficient one-pot condensation of cyanoacetylindoles 1, 3-formylchromones 38 and ammonium acetate 7 under stannous chloride 39 mediation in DMF (Scheme 15). 53 Wan and co-workers used polyethylene glycol (PEG-200) in a three-component reaction of indoles 1, aldehydes 3, and malononitrile 15 to afford 3-indole derivatives 41 in good to excellent yields (Scheme 16). 54 L-Proline, 55 tetrabutylammonium uoride (TBAF), 56 Zn-salphen, 57 Cu(OAc) 2 (ref. 58) and Cu(III) 59 were also used as catalysts in this reaction and the results are shown in Table 2. Singh's group described a highly efficient methodology for the synthesis of 3-amino-alkylated indoles 44 via the one-pot three-component Mannich 60 type reaction of amines 42, alcohols 43 and indoles 1. Treatment of amines 42 and alcohols 43 with KOH in toluene in the presence of (Fe(NO 3 ) 3 $9H 2 O/ TEMPO) 61 as catalyst, yielded iminium ion A. Then, the iminium ion A was reacted with indoles 1 to obtain novel 3substituted indoles 44 (Scheme 17). 62 In another study, ferric hydrogen sulfate (FHS) 63 was applied as catalyst and the same products were prepared in 87-98%. It was observed that electron-withdrawing groups on the aldehyde reacted rapidly and were better reagents in this reaction. Furthermore, Nmethylaniline showed better reactivity in comparison with Nethylaniline due to the low steric effects. N-Alkylanilines were used in excess to avoid the formation of bis(indolyl)alkanes. 64 The reaction was also catalyzed by L-proline, 65 Amberlite, IRA-400 Cl resin 66 and polyaniline-uoroboric acid-dodecyl hydrogen sulfate salt (PANI-HBF 4 ). 67 Catalyst-free conditions in MeOH have also been reported in 72 h by 28-99% yields. 68 A comparison of different catalysts and experimental setups is given in Table 3.
Mahmoodi and co-workers developed the one-pot cyclocondensation of mono-or bis(indole-3-carbaldehyde) 1 or 45, 69,70 thiosemicarbazide 46, and phenacyl bromides 47 in the presence of a catalytic amount of AcOH for the preparation of the novel mono-and bis(indol-3-yl)hydrazineyl thiazole derivatives 48 and 49 (Scheme 18). 71 The products were evaluated for in vitro antibacterial activity against Gram-positive and Gram-negative bacteria. Some of the products have good antibacterial activity. The product 48 with OCH 3 as a donating group exhibited high activity against Gram-positive bacteria.
Shinde and Jeong developed the reaction between indole 1 and formaldehyde 3 with tertiary aromatic amines 42 in the presence of silica-supported tungstic acid (STA) as a heterogeneous acid catalyst under solvent-free conditions. The protocol was performed via the three component Mannich type Friedel-Cras addition for the preparation of N,N-dialkyl amino arylated indole derivatives 50 (Scheme 19). 72 Application of sodium dodecyl sulfate (SDS) as surfactant in this reaction was also reported by Kumar et al. resulting in 78-94% yields of products. 73 Mild aminoacylation of indoles 1 through a multicomponent process with ynol ethers 51 and sulfonyl azides 52 was established by Alford and Davies for the synthesis of oxo-tryptamines 53 (Scheme 20). 74 First, 4-alkoxy N-sulfonyltriazoles A 75 were generated from ynol ethers 51 and sulfonyl azides 52, and treated with indoles 1. Then, the obtained enol ethers B were converted to the amino ketones 53 for the a-aminoacylation of enols. 76 N-Methyl indole 1 was reacted with diazooxindole 54 and nitrostyrene 55 in the presence of [Ru] and squaramide as catalysts via an asymmetric Michael addition 77 for the synthesis of 3,3 0 -bis(indole) derivatives 56 (Scheme 21). 78 Novel spirooxindole-pyrrolidine compounds 61 and 62 were obtained through 1,3-dipolar cycloaddition of azomethine ylides generated from isatin 57 and sarcosine 59 or thioproline  79 Anticancer activity studies were carried out for the synthesized compounds against A549 lung adenocarcinoma cancer cell line. 80 Several of the products showed very high activity against the cancer cell line. Reddy and co-workers also studied this reaction in MeOH as solvent under reux conditions in 2-3 h giving 80-93% yields. The antimicrobial activity of all products were evaluated against several bacteria and fungi, and showed good activity. 81 A one-pot four-component condensation strategy was employed by Naureen's group for the discovery of indole-based tetra-arylimidazoles 64. This method involves the reaction of 2arylindole-3-carbaldehydes 1, substituted anilines 42, benzil 63 and ammonium acetate 7 in acetic acid (Scheme 23). 82 The antiurease activity of the synthesized compounds was evaluated and showed good results.
The same authors synthesized several new trisubstituted imidazoles, 3-(4,5-diaryl-1H-imidazol-2-yl)-2-phenyl-1H-indoles 65, via the condensation of substituted indole aldehydes 1, benzil 63 and ammonium acetate 7 in reuxing acetic acid (Scheme 24). 83 The products were evaluated for their a-glucosidase inhibition and showed signicant a-glucosidase inhibitory activity.  Andreana and his group utilized the one-pot reaction of 4nitroindolylacetaldehyde 1, methylamine 32, methyl isocyanide 66 and 3-hydroxyphenylpyruvic acid 67 for the synthesis of (AE)-thaxtomin A (TA) 68 as a herbicidal natural product. First, the prerequisite dipeptide A was isolated which through a base-mediated keto-amide cyclization reaction afforded two diastereomeric compounds B. Then, compound B was treated with KOH under microwave irradiation to provide the intended product 68 (Scheme 25). 84 This natural product was synthesized previously by Zhang et al. and has   Cleavage of an endocyclic C-N bond allowed the formation of a quinoline derivative F. 91 Then, compound 74 reacted with NH 2 group of quinoline F and nal product 76 was obtained.
Borah et al. investigated the one-pot multicomponent reaction of 3-(cyanoacetyl)-indoles 1, aromatic aldehydes 3 and ethyl acetoacetate 34 in the presence of InCl 3 under microwave irradiation to produce the functionalized 3-(pyranyl)-indole derivatives 78. When ammonium acetate 7 was used as the source of ammonia in this reaction, the one-pot four-component reaction was carried out and 3-(dihydropyridinyl)-indole derivatives 79 were obtained (Scheme 32). 92 The results show that electron donating groups (EDG) in the aldehyde increase the product yield, whereas electron withdrawing groups (EWG) decrease the yield of products.
A sulfone-containing Brønsted acid ionic liquid was used in a one-pot reaction of indole 1, salicylaldehydes 3 and 1,1diphenylethylene 80 for the synthesis of substituted chromane derivatives 81 (Scheme 33). 93 A series of indole incorporated thiazolylcoumarins 83 were synthesized from the reaction of indole derivatives 1, Review multicomponent reaction of these reactants and organic azides 95 via click 102 chemistry (Scheme 40). 103 Indole 1 was reacted with anilines 42 and aldehydes 3 via an anhydrous ZnCl 2 catalyzed one-pot three-component reaction to afford diarylmethyl indoles 97 in toluene and 3-arylmethyl indoles 98 in MeOH. The reaction of indole 1 with benzaldehyde 3 in the presence of catalyst formed the azafulven A which reacted with another indole 1 to generate the kinetically stable bis(indolyl)methane B. In the presence of anilines, bis(indolyl) methane converted to the target products 97 (Schemes 41 and 42). 104 A series of biologically important 3-(1-arylsulfonylalkyl) indoles 100 were prepared by Huang et al. This process was carried out using a catalyst-free three-component reaction of indoles 1, carbonyl compounds 3, and arenesulnic acids 99 at room temperature (Scheme 43). 105 Bis(indolyl) methanes A were found as the key intermediates in this reaction.
The synthesis of bis(indolyl)methanes 101 was reported by Dhumaskar and Tilve via the reaction of two molecules of indole 1 with aldehydes 3 under solvent-free conditions without any catalyst (Scheme 44). 106 Two different methods were employed for this reaction. In method A, the mixture of aldehyde and indole was kept at ambient temperature in a test tube while in method B, the mixture was ground using a mortar and pestle. Method B resulted in the formation of products in shorter reaction times than method A. According to the results, anisaldehyde with an electron donating group at the para position and heptaldehyde failed to react completely. Mohammadi Ziarani and co-workers developed this reaction using the sulfonic acid functionalized silica (SiO 2 -Pr-SO 3 H) as catalyst and obtained the same products in short reaction times and good yields (5-20 min and 87-96% yields). 107 Mohammadi Ziarani and coworkers synthesized a novel class of symmetrical 3,3-di(indolyl)indolin-2-ones 102 from the  108 The antimicrobial activities of the products were tested and the results demonstrated that the MIC value of one of the products (R 1 ¼ R 3 ¼ H, R 2 ¼ Bn) against B. subtilis was equal to that of chloramphenicol. Geng's group developed the one-pot four component reaction of 3-(cyanoacetyl)indoles 1, aromatic aldehydes 3, 1-(9-butylcarbazol-3-yl)ethanone 103 and ammonium acetate 7 for the preparation of several 3-cyano-2-(1H-indol-3-yl)-6-(9-butylcarbazol-3-yl)pyridine derivatives 104. The reaction was performed using AcOH and ethane-1,2-diol (glycol) under microwave irradiation (Scheme 46). 109 Zn 2+ supported on montmorillonite KSF (Zn 2+ @KSF) as an efficient heterogeneous catalyst promoted the preparation of mono and bis-indolylimidazole derivatives 106 and 107. This reaction was carried out from the condensation of indole-3-  Table 4. Kundu and co-workers established a new synthetic protocol for the preparation of pyrido-and pyrimido-indoles 141 and 142 employing ethyl 2-amino-1H-indole-3-carboxylates 1, aromatic aldehydes 3, and terminal alkynes 13 in the presence of a Brønsted acid such as triuoroacetic acid (TFA) (Scheme 62). 127 When the reaction catalyzed by Yb(OTf) 3 as a Lewis acid, pyrimidoindoles 142 were prepared as the single products in 58-75% yield.
Tron's group have prepared heteroarylogous 1H-indole-3carboxamidines 143 utilizing a three-component interrupted Ugi reaction of N-alkyl-N-(1H-indol-2-ylmethyl)amines 1, 128 isocyanides 2 and carbonyl compounds 3 (Scheme 63). 129 Silvani et al.  134 The authors hypothesized that the introduction of a hydrogen-bond acceptor on the aldehyde moiety may help to orient the transition state and lower the activation barrier for the desired process. Thus, they employed substrates with a simple ether group in proximity to the aldehyde moiety, and encouragingly, the desired aza-Diels-Alder reaction proceeded cleanly to form the desired products with good yields and diastereoselectivities. The biological activity evaluation of the products showed that the cytotoxicities of products in human lung carcinoma and human cervical carcinoma cells exhibited inhibitory effects against cell proliferation with IC 50 values in the range of 15.0-27.5 mM.

Scheme 58
Scheme 59 The annulation of indoles 1, 2-amino benzyl alcohols 42 and benzaldehydes 3 in a two step three-component tandem reaction was used to form benzazepinoindoles 151. In the rst step, indoles were C-3 alkylated and the intermediates A were obtained. Then in the second step, intermediates A underwent a 7-endo-trig cyclization (the modied Pictet-Spengler cyclization reaction) to obtain the intended products 151 (Scheme 67). 135 A stereoselective Povarov reaction 136,137 catalyzed by iodine was developed by Wang and co-workers for the preparation of exo-tetrahydroindolo [3,2-c]quinoline derivatives 153. The procedure involved a reaction between indoles 1, aldehydes 3 and amines 152 in toluene (Scheme 68). 138 The results showed that only reactive amines could be included in this reaction to give the desired products 153 with high stereoselectivity. A stereoselective catalyst-free three-component reaction of 2isocyanoethylindole 1, malononitrile 15 and aldehyde 3 was developed for the construction of polycyclic spiroindolines 161 in high yields (up to 90%) with excellent levels of diastereoselectivity (Scheme 72). 142 The presence of an electronwithdrawing group on the aldehyde led to a decrease in yields of the products.
John and co-workers developed a multicomponent reaction involving N-protected 3-nitroindole 1 a primary amine 162 and an enolizable ketone 163 for the preparation of a series of functionalized pyrrolo [3,2-b]indoles 164 (Scheme 73). 143 It was found that the yield of product 164 decreased to 45% with 1phenylethylamine. With cyclohexylamine, the product 164 was obtained in moderate yield (53%) and with adamantylamine the MCR failed, proving that the reactivity decreases with an increase in the steric bulk of the amine component. The Lewis acid catalyzed three-component [3 + 2] cycloaddition reaction of pentafulvene 165 with in situ generated indolylmethanol A has been developed for the construction of pentaleno [1,2-b]indoles 166 (Scheme 74). 144 It was found that aromatic aldehydes bearing electron-withdrawing groups (R 3 ¼ Cl, Br, F) were tolerated well under the reaction conditions and afforded the cycloaddition products in moderate to good yields. However, aldehydes with electron-rich substituents (R 3 ¼ 2,4-OMe, Me) were unable to take part in the cycloaddition reaction.
The Ugi four-component condensation of indole-2-aldehyde derivatives 1, acids 28, anilines 42 and isocyanides 2 in the presence of orthogonal copper and palladium catalysts under microwave heating was accomplished for the synthesis of two important indole-fused heterocycles 174 and 175. First, the Ugi adduct A was obtained via the intramolecular cyclization conditions and served as a precursor in subsequent selective post-transformations. 5,6-Dihydroindolo[1,2-a]quinoxalines 174 were prepared by a copper catalyzed N-H arylation pathway, while 6,7-dihydroindolo[2,3-c]quinolones 175 were formed by palladium catalyzed C-H arylations without the protection of the indole N1 moiety (Scheme 78). 148 In another approach to synthesize these compounds, no catalyst has been employed in this reaction and the products were obtained in good yields. successively added to the mixture to produce corresponding indole-fused diketopiperazines A. 150 Then, compound A in the presence of amines formed the functionalized carboxamides 177 (Scheme 79). 151 The biological activities of products were evaluated and showed that most products have anti-leishmanial activity against intracellular amastigotes form of Leishmania donovani.

Conclusion and outlook
This review summarizes recent studies on the application of indoles in multicomponent reactions for the synthesis of a variety of heterocyclic compounds during the period of 2012 to 2017. Indole is a signicant nitrogen-based heterocycle with particular importance in the synthesis of complex heterocyclic scaffolds. Indole fragments have been recently attracting much attention due to their biological and pharmaceutical activities. Diversely multisubstituted indole substances are useful building blocks in pharmaceutical and organic syntheses. Consequently, the novel methodologies for the synthesis of complex heterocyclic frameworks involving indole are expected to receive further increasing attention in the future.

Conflicts of interest
There are no conicts to declare.

Acknowledgements
We are grateful for nancial support from the Research Council of Alzahra University and support of National Elites Foundation of Iran, Tehran.