Preparation of 3-arylmethylindoles as selective COX-2 inhibitors

The 3-arylmethylation of indoles using TMSOTf/Et₃SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO₂ and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. In addition, the viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. For indoles bearing both a 6-MeSO₂ and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, an unprecedented Pd(0) mediated arylorganozinc coupling with the requisite substituted 3-methylcarbonatomethylindole proved successful in affording the desired 2-cyano-6-MeSO₂-3-arylmethylindoles effective as selective COX-2 inhibitors.     

Synthesis of diversely functionalized hexahydropyrrolo[2,3-b]indoles using domino reactions, olefination, isomerization and Claisen rearrangement followed by reductive cyclization

Hexahydropyrrolo[2,3-b]indoles 6 were synthesized in five steps from indolin-3-one 8 by a general and efficient method, in which elements of molecular diversity were readily added onto the 3a-position of the pyrrolo[2,3-b]indole ring system. Horner-Wadsworth-Emmons reaction of 2-allyloxyindolin-3-ones 7, derived from indolin-3-one 8 and a variety of allylic alcohols, smoothly proceeded with successive Claisen rearrangement to give the corresponding 3-allyl-3-cyanomethylindolin-2-ones 15. Indolin-2-ones 15 were converted into pyrrolo[2,3-b]indoles 6 using partial hydrolysis followed by reductive cyclization with LiAlH(4). Synthesis of N-methylated pyrrolo[2,3-b]indole derivatives 23 and 26 is also described.     

Synthesis of 3-(2-N,N-diethylaminoethoxy)indoles as potential 5-HT6 receptor ligands

The synthesis of new pharmaceutically interesting 3-(2-N,N-diethylaminoethoxy)indole derivatives is described. Starting from 3-silyloxy-2-methylindoles, deprotection and in situ aminoalkylation provided 3-(2-N,N-diethylaminoethoxy)indoles in good yield. Further sulfonylation of these novel indoles gave access to potential 5-HT(6) receptor ligands.     

Chemoselective functionalization of α-carbolines at the C-2, C-3, C-4, and C-6 positions using Suzuki-Miyaura reactions

The synthesis of 2-, 3-, 4-, and 6-substituted pyrido[2,3-b]indoles (α-carbolines) by palladium-catalyzed cross-coupling reactions from the corresponding halopyrido[2,3-b]indoles is described. A sequential and a one-pot chemoselective double Suzuki-Miyaura coupling route is presented for the synthesis of symmetrically and unsymmetrically disubstituted pyrido[2,3-b]indoles.     

Direct synthesis of fused indoles by gold-catalyzed cascade cyclization of diynes

A direct, concise, and atom-economical synthetic method for the generation of fused indoles, using a gold-catalyzed cascade cyclization of diynes, has been developed. The reaction gave various fused indoles, such as aryl-annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino- or oxepinoindole derivatives in good to excellent yields, through an intramolecular cascade 5-endo-dig hydroamination followed by a 6- or 7-endo-dig cycloisomerization, without producing theoretical byproduct. Three of the resulting indoles exhibited potent antifungal activities against T. mentagrophytes and T. rubrum, demonstrating the practical application of the described cascade reaction for drug discovery.     

Gold(I)-catalyzed intermolecular hydroarylation of alkenes with indoles under thermal and microwave-assisted conditions

An efficient method for intermolecular hydroarylation of aryl and aliphatic alkenes with indoles using a combination of [(PR(3))AuCl]/AgOTf as catalyst under thermal and microwave-assisted conditions has been developed. The gold(I)-catalyzed reactions of indoles with aryl alkenes were achieved in toluene at 85 degrees C over a reaction time of 1-3 h with 2 mol% of [(PR(3))AuCl]/AgOTf as catalyst. This method works for a variety of styrenes bearing electron-deficient, electron-rich, and sterically bulky substituents to give the corresponding products in good to high yields (60-95%). Under microwave irradiation, coupling of unactivated aliphatic alkenes with indoles gave the corresponding adducts in up to 90% yield. Selective hydroarylation of terminal C=C bond of conjugated dienes with indoles gave good product yields (62-81%). On the basis of deuterium-labeling experiments, a reaction mechanism involving nucleophilic attack of Au(I)-coordinated alkenes by indoles is proposed.     

Cobalt‐Catalyzed C−H Nitration of Indoles by Employing a Removable Directing Group

A mild and efficient C(sp²)?H nitration of 3‐substituted indoles, by using the economical and non‐toxic cobalt nitrate hexahydrate [Co(NO₃)₂ ? 6 H₂O] as a catalyst and tert‐butyl nitrite (TBN) as the nitro source, is reported. This approach provides a unique methodology involving a site‐selective C?N bond formation for preparation of C‐2 substituted nitro indoles. Utilization of the tBoc as the removable directing group enhances the synthetic utility of the method.     

The copper-catalyzed N-arylation of indoles

A general method for the N-arylation of indoles using catalysts derived from CuI and trans-1,2-cyclohexanediamine (1a), trans-N,N'-dimethyl-1,2-cyclohexanediamine (2a), or N,N'-dimethyl-ethylenediamine (3) is reported. N-Arylindoles can be produced in high yield from the coupling of an aryl iodide or aryl bromide with a variety of indoles.     

Palladium-/copper-catalyzed regioselective amination and chloroamination of indoles

A palladium-/copper-catalyzed intermolecular C-H amination reaction of indoles has been developed. This reaction proceeds in good to excellent yields to produce a variety of 2-amino-substituted indoles and exhibits excellent regioselectivity at room temperature. Furthermore, chloroamination of indoles provides a simple method for the construction of C-N and C-Cl bonds in one step.     

Remarkable effect of N-substituent on enantioselective ruthenium-catalyzed propargylation of indoles with propargylic alcohols

Ruthenium-catalyzed enantioselective propargylation of indoles with propargylic alcohols affords the corresponding beta-propargylated indoles in good yields with a high enantioselectivity (up to 95% ee). A remarkable effect of the nature of the N-substituent of indoles is observed for the enantioselectivity of the propargylated indoles. The preparative method described in this paper may provide a novel protocol for asymmetric Friedel-Crafts alkylation of indoles using propargylic alcohols as a new type of electrophiles.     

Platinum-catalyzed intramolecular alkylation of indoles with unactivated olefins

Reaction of 1-methy-2-(4-pentenyl)indole (1) with a catalytic amount of PtCl2 (2 mol %) in dioxane that contained a trace of HCl (5 mol %) at 60 degrees C for 24 h led to the isolation of 4,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazole (2) in 92% yield. Platinum-catalyzed cyclization of 2-(4-pentenyl)indoles tolerated substitution at each position of the 4-pentenyl chain. Furthermore, the protocol was applicable to the synthesis of tetrahydro-beta-carbolinones and was effective for cyclization of unprotected indoles. 2-(3-Butenyl)indoles underwent platinum-catalyzed cyclization with exclusive 6-endo-trig regioselectivity. Mechanistic studies established a mechanism for the platinum-catalyzed cyclization of 2-alkenyl indoles involving nucleophilic attack of the indole on a platinum-complexed olefin.     

A regiocontrolled synthesis of substituted indoles by palladium-catalyzed coupling of 2-bromonitrobenzenes and 2-bromoacetanilides

The palladium-catalyzed cross-coupling reaction of 2-bromonitrobenzenes or 2-bromoacetanilides with ethylene has been used to produce a variety of substituted indoles. The mild reaction conditions and selectivity inherent in the coupling reaction have been utilized to produce regiochemically pure 4-, 5-, 6-, and 7-substituted indoles.     

Ni(ClO4)(2)-catalysed regio- and diastereoselective [3+2] cycloaddition of indoles and aryl oxiranyl-dicarboxylates/diketones: a facile access to furo[3,4-b]indoles

Ni(ClO(4))(2)·6H(2)O-catalysed regioselective and diastereoselective [3+2]-annulations of aryl oxiranyl-dicarboxylates and indoles via selective C-C bond cleavage of oxirane were revealed. The cycloadditions proceed smoothly with high regio- and diastereoselectivity under mild conditions leading to 1H-furo[3,4-b]indoles in good to excellent yields.     

Scope and mechanism of the Pd(II)-catalyzed arylation/carboalkoxylation of unactivated olefins with indoles

Treatment of 1-methyl-2-(4-pentenyl)indole (5) with a catalytic amount of [PdCl2(MeCN)2] (2; 5 mol %) and a stoichiometric amount of CuCl2 (3 equiv) in methanol under CO (1 atm) at room temperature for 30 min gives methyl (9-methyl-2,3,4,9-tetrahydro-4-carbazolyl)acetate (6), which was isolated in 83% yield. A number of 2- and 3-alkenyl indoles undergo a similar palladium-catalyzed cyclization/carboalkoxylation to give the corresponding polycyclic indole derivatives in moderate to excellent yields with excellent regio- and diastereoselectivity. Under similar conditions, vinyl arenes undergo intermolecular arylation/carboalkoxylation with indoles to give 3-(1-aryl-2-carbomethoxyethyl) indoles in moderate yield with high regioselectivity. Stereochemical analyses of the palladium-catalyzed cyclization/carboalkoxylation of both 2- and 3-alkenyl indoles are in agreement with mechanisms involving outer-sphere attack of the indole on a palladium-olefin complex followed by alpha-migratory insertion of CO and methanolysis of the resulting acyl palladium intermediate. CuCl2 functions as the terminal oxidant in this palladium-catalyzed cyclization/carboalkoxylation of alkenyl indoles and also significantly increases the rate of reaction of 2 with the alkenyl indole to form the corresponding acyl palladium complex. Spectroscopic studies are in agreement with the intermediacy of a heterobimetallic Pd/Cu complex as the active catalyst in this reaction.     

6-substituted indoles from o-halonitrobenzenes

o-Chloro- and o-bromonitrobenzenes are efficiently converted to 6-substituted indoles in a four step synthesis, proceeding through o-trimethylsilylethynylnitrobenzenes, o-nitrophenylacetaldehyde dimethylacetals and o-aminophenylacetaldehyde dimethylacetals as intermediates.o-Chloro- and o-bromonitrobenzenes are efficiently converted to 6-substituted indoles in a four step synthesis. R = CO₂Me(H), COPh, Ph, CF₃ and Me.     

Interaction of singlet molecular oxygen with melatonin and related indoles

Singlet molecular oxygen (1O2) is one of the major agents responsible for (photo)oxidative damage in biological systems including human skin and eyes. It has been reported that the neural hormone melatonin (MLT) can abrogate 1O2-mediated cytotoxicity through its purported high antioxidant activity. We studied the interaction of MLT with 1O2 in deuterium oxide (D2O), acetonitrile and methanol by measuring the phosphorescence lifetime of 1O2 in the presence of MLT and related indoles for comparison. Rose bengal (RB) was used as the main 1O2 photosensitizer. The rate constant (kq) for the total (physical and chemical) quenching of 1O2 by MLT was determined to be 4.0 x 10(7) M(-1) s(-1) in D2O (pD 7), 6.0 x 10(7) M(-1) s(-1) in acetonitrile, and 6.1 x 10(7) M(-1) s(-1) in methanol-d1. The related indoles, tryptophan, 5-hydroxyindole, 5-methoxytryptamine, 5-hydroxytryptamine (5-OH-T, serotonin), 6-hydroxymelatonin (6-OH-MLT) and 6-chloromelatonin quenched 1O2 phosphorescence with similar kq values. We also compared the photosensitized photobleaching rate of MLT with that of other indoles, which revealed that MLT is the most sensitive to 1O2 bleaching. Hydroxylation of the indole moiety in 5-OH-T and 6-OH-MLT makes them more sensitive to photodegradation. In the absence of exogenous photosensitizers MLT itself can generate 1O2 with low quantum yield (0.1 in CH3CN) upon UV excitation. Thus, the processes we investigated may occur in the skin and eyes during physiological circadian rhythm (photo)signaling involving MLT and other indoles. Our results indicate that all the indoles studied, including MLT, are quite efficient yet very similar 1O2 quenchers. This directly shows that the exceptional antioxidant ability proposed for MLT is unsubstantiated when merely chemical mechanism(s) are considered in vivo, and it must predominantly involve humoral regulation that mobilizes other antioxidant defenses in living organisms.     

A new synthesis of 3-arylthioindoles as selective COX-2 inhibitors using PIFA

The direct 3-arylthiolation of 2-substituted indoles using phenyliodine(III)bis trifluoroacetate (PIFA) in (CF₃)₂CHOH with a wide variety of benzenethiols has been accomplished. In particular, indoles bearing a 6-MeSO₂ and either a 2-methyl or 2-carboxymethyl substituent could be 3-arylthiolated in good to excellent yields to afford the corresponding 3-arylthioindoles as selective COX-2 inhibitors. In a study varying the electronic nature of the 5-substituent of 2-CO₂Et indoles, it was discovered that the yield of the reaction improved as the substituent became more electron withdrawing. This result was consistent with a proposed mechanism involving benzenethiol displacement of an intermediate 3-IPh indole complex.     

C‐2 Selective Arylation of Indoles with Heterogeneous Nanopalladium and Diaryliodonium Salts

A simple and efficient method to prepare synthetically useful 2‐arylindoles is presented, using a heterogeneous Pd catalyst and diaryliodonium salts in water under mild conditions. A remarkably low leaching of metal catalyst was observed under the applied conditions. The developed protocol is highly C‐2 selective and tolerates structural variations both in the indole and in the diaryliodonium salt. Arylations of both N?H indoles and N‐protected indoles with ortho‐substituted, electron‐rich, electron‐deficient, or halogenated diaryliodonium salts were achieved to give the desired products in high to excellent isolated yields within 6 to 15 h at room temperature or 40 °C.     

Direct annulation and alkylation of indoles with 2-aminobenzyl alcohols catalyzed by TFA

An efficient method for the annulation of indoles with 2-aminobenzyl alcohols, catalyzed by TFA, to furnish 5,6-fused indoline aminals is reported. This method can be extended to the alkylation of indoles at C3. 2-Aminobenzyl alcohols are used directly without recourse to protection of the aniline nitrogen or activation of the alcohol.     

An iodoacetamide-based free radical cyclisation approach to the 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one (paullone) system

A potentially versatile route to 2-(2-aminoaryl)indoles is described based on a palladium-mediated cyclisation of N-substituted indoles, together with free radical cyclisation of their N-benzyliodoacetamide derivatives to the 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one system.