One-pot synthesis of 2-substituted thieno[3,2-b]indoles from 3-aminothiophene-2-carboxylates through in situ generated 3-aminothiophenes

A convenient protocol for one-pot synthesis of thieno[3,2-b]indoles, bearing aromatic, thien-2-yl or styryl fragments at C-2 position, from easily accessible 5-substituted 3-aminothiophene-2-carboxylates using the Fischer indolization reaction, was developed during this study. Two main steps of this approach are the saponification of the starting 3-aminoesters with sodium hydroxide and next treatment of the crude 3-aminoacids sodium salts with arylhydrazines in glacial acetic acid solution. The latter step includes in situ decarboxylation of the freed 3-aminothiophene-2-caboxylic acids to the 3-aminothiophenes and their acid promoted reaction with arylhydrazines to initially form arylhydrazones of 5-substituted thiophene-3(2H)-ones, which smoothly cause indolization to afford the desired thieno[3,2-b]indoles.     

Improved preparation of alkyl 2-(3-indolyl)-3-nitroalkanoates under fully heterogeneous conditions: stereoselective synthesis of alkyl (E)-2-(3-indolyl)-2-alkenoates

Ethyl 3-nitro-2-alkenoates can be generated starting from nitroalkanes and ethyl 2-oxoacetate under heterogeneous conditions that minimize work-up procedures, avoid any purification step and direct manipulation of the nitroalkene system. Reaction of ethyl 3-nitro-2-alkenoates, formed in situ from their acetoxy precursors, with indoles in the presence of basic alumina affords ethyl 2-(3-indolyl)-3-nitroalkanoates that are central intermediates for the preparation of tryptamines and carboline alkaloids. A base promoted elimination of nitrous acid from these nitroindolyl derivatives readily produces ethyl 2-(3-indolyl)-2-alkenoates with high E stereoselectivity. The latter compounds can be used as Michael acceptors in intra- and intermolecular reactions with nucleophilic reagents.     

Diastereoselective synthesis of cyclic 1,3-aminoalcohols bearing CF3(CCl3)-groups

An aldol-type reaction of cyclic imines and cyclic lactims with carbonyl compounds activated by electron withdrawing trifluoromethyl or trichloromethyl groups proceeded without any catalyst under mild condition. β-Hydroxymethyl substituted cyclic imines or imidates are formed as a result of the reaction. The reduction of the prepared imines leads stereoselectively to the cyclic 1,3-aminoalcohols. Application of methyl trifluoropyruvate in this transformation opens an opportunity for the synthesis of γ-aminoacids derivatives which contain pyrrolidine moiety.     

Convenient synthesis of bis(indolyl)alkanes by dithiocarbohydrazone Schiff base/Zn(ClO_4 )_2 6H_2 O catalyzed Friedel–Crafts reaction of indoles with imines

A new, convenient and excellent yield procedure for the preparation of bis(indolyl)methanes(BIMs) by Friedel–Crafts reaction of indoles with imines in the presence of dithiocarbohydrazone Schiff base/ Zn(ClO4)2 6H2 O as a highly stable, effective and readily available catalyst is described. Moderate to good yields(up to 99% yield) were obtained with both substrates for imine derivatives. This procedure is simple, practical and economic.     

One-step synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines and their use in the synthesis of highly functionalized 2,3,5,6,7- and 2,3,4,5,7-substituted indoles

A three-component, one-step method for the synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines involving reaction of alkyl aldehyde, malononitrile and aryl aldehyde in presence of morpholine is reported. Highly functionalized 2,3,5,6,7- and 2,3,4,5,7-substituted indoles were prepared from these dicyanoanilines by reaction with ethyl bromoacetate. These substituted dicyanoanilines and indoles have a potential to be converted into various other compounds taking advantage of various functional groups present in these molecules.     

PtCl4-catalyzed cyclization of N-acetyl-2-alkynylanilines: A mild and efficient synthesis of N-acetyl-2-substituted indoles

An efficient synthesis of N-acetyl-2-substituted indole derivatives via direct intramolecular hydroamination of N-acetyl-2-alkynylaniline derivatives was developed. The reaction could be applied to a wide range of substrates employing only 1–2?mol% of PtCl₄ as the catalyst to furnish the desired indole products in moderate to excellent yields. The current protocol is efficient, reliable and scalable, and could serve as an important tool for convenient and rapid access to this important class of N-heterocyclic skeleton from readily available substrates.     

CuI-catalyzed intramolecular cyclization of 3-(2-aminophenyl)-2-bromoacrylate: synthesis of 2-carboxyindoles

A new approach was described for the synthesis of substituted 2-carboxyindole using 3-(2-aminophenyl)-2-bromo-acrylates through a CuI-catalyzed intramolecular coupling. The reactions were mild, rapid and with good to excellent yields.     

A novel convenient approach to the synthesis of 2-substituted analogs of ornithine and homolysine

A novel efficient method for the synthesis of earlier unknown 2-substituted analogs of ornithine and homolysine from substituted 5-aminopentyl- and 3-midopropylhydantoins (prepared from cyclic imines and amino and amido ketones) was developed. Hydrolysis of hydantoins with a solution of Ba(OH)₂ gave the target amino acids in high yields.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2749–2753, December, 2004.     

Convenient synthesis of tryptophols and tryptophol homologues by hydroamination of alkynes

A novel method is presented for the one-pot synthesis of substituted 3-(2-hydroxyethyl)- and 3-(3-hydroxypropyl)indoles (tryptophols and homotryptophols) from aryl hydrazines and silyl-protected ω-(hydroxyoalkyl)alkynes. Various tryptophol derivatives were prepared directly in good yield with excellent regioselectivity via a domino reaction sequence consisting of a titanium-catalyzed hydroamination of the alkyne, [3+3]-rearrangement of the resulting aryl hydrazone, and subsequent deprotection of the hydroxy group.     

Synthesis of 4-substituted 3-(indol-3-yl)maleimides and azepines with annelated indole and maleimide nuclei

A series of 4-substituted 3-(indole-3-yl)maleimides has been synthesized. Upon the action of CH₃SO₃H in TFA, the 3-(indole-3-yl)-4-(arylalkylamino)-maleimides undergo cyclization to give 12b,13-dihydro-4bH-indolo[3,2-d]pyrrolo[3,4-b][1]benzazepine-5,7(6H,8H)-dione derivatives.     

Facile synthesis of indoles by K2CO3 catalyzed cyclization reaction of 2-ethynylanilines in water

The cyclization reaction of 2-ethynyl-N-sulfonylanilides proceeded efficiently in water with the presence of a catalytic amount of K₂CO₃ under transition metal-free condition to give indoles in high yields. The recovery and reusability of the present catalytic system were investigated.     

Synthesis of 2-(3-Indolyl)-1H-benzimidazoles from 2-Acylmethyl-1H-benzimidazoles

The interaction of 2-acetyl(aroyl)methyl-1H-benzimidazoles with phenylhydrazine on heating in trifluoroacetic acid proceeds by a type of Fischer reaction with the formation of 2-[2-methyl(aryl)-3-indolyl]-1H-benzimidazoles.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 206–209, February, 2005.     

FeCl3-catalyzed alkylation of indoles with 1,3-dicarbonyl compounds: an expedient synthesis of 3-substituted indoles

Indoles undergo smooth alkylation at the 3-position with 1,3-dicarbonyl compounds in the presence of 20 mol % of FeCl₃ under mild reaction conditions to produce a wide range of 3-substituted indoles in excellent yields and with high E-selectivity.     

A convenient synthesis of 2-substituted indoles by the reaction of 2-(chloromethyl)phenyl isocyanides with organolithiums

The reaction of 2-(chloromethyl)phenyl isocyanides, readily available by dehydration of the respective N-[2-(chloromethyl)phenyl]formamides, with organolithiums produced 2-substituted indoles in satisfactory yields through addition of organolithiums to the isocyano carbon followed by intramolecular substitution reaction of the resulting imidoyl anion intermediates.     

Sc(OTf)3-catalyzed alkylation of indoles with propargyl alcohols: an expeditious synthesis of 3-substituted indoles

Indoles undergo smooth alkylation with propargylic alcohols in the presence of 10 mol % of scandium triflate under mild conditions to produce 3-propargylated indoles in excellent yields with high selectivity.     

Synthesis and alkyne-coupling chemistry of cyclomanganated 1- and 3-acetylindoles, 3-formylindole and analogues

The syntheses are reported of new cyclomanganated indole derivatives (1-acetyl-κO-indolyl-κC²)dicarbonylbis(trimethylphosphite)manganese (2), (1-methyl-3-acetyl-κO-indolyl-κC²)tetracarbonylmanganese (4), (3-formyl-κO-indolyl-κC²)tetracarbonylmanganese (5a) and (1-methyl-3-formyl-κO-indolyl-κC²)tetracarbonylmanganese (5b). The unusually complicated crystal structure of 5b has been determined, the first for a cyclomanganated aryl aldehyde.The preparations of a mitomycin-related pyrrolo-indole and related products by thermally promoted and oxidatively (Me₃NO) initiated alkyne-coupling reactions of the previously known complex (1-acetyl-κO-indolyl-κC²)tetracarbonylmanganese (1) are reported for different alkynes and solvents. X-ray crystal structures are reported for the dimethyl acetylenedicarboxylate coupling product of 1 (dimethyl 1-methyl-l-hydroxypyrrolo[1,2a]-indole-2,3-dicarboxylate; 6a), and an unusually-cyclised triple insertion product 8 from the coupling of acetylene with 4, in which a cyclopentadiene moiety is η³-allyl-coordinated to Mn through only one double bond and an exocyclic carbon, but which rearranges on heating to an η⁵-cyclopentadienyl complex.     

Synthesis of unnatural 2- and 3-deoxyfuranose analogues

This Letter describes the synthesis of two racemic analogues of unnatural 3′-deoxy and 2′-deoxy sugars, where a phosphorus atom replaces the carbon atom in the 2′- or 3′-position. Two methods of four- and 5-steps were developed affording these new unnatural sugar analogues.     

Synthesis of 4- and 6-substituted nitroindoles

Enolizable ketones react with m-nitroaniline in the presence of strong base such as t-BuOK to give 4- and 6-substituted nitroindoles. The reaction proceeds via oxidative nucleophilic substitution of hydrogen in m-nitroaniline with enolate anions in positions ortho to the amino group giving anionic σ^H adducts that are additionally stabilized by intramolecular interaction between the amino and the carbonyl group. Spontaneous oxidation of the σ^H adducts followed by the Bayer type condensation of the produced ortho-aminonitrobenzyl ketones gives 4- and 6-substituted nitroindoles. The scope of this reaction and its basic mechanistic features are discussed.     

New routes for the synthesis of 3- and 5-substituted 2(1H)-pyrazinones

Various 3-(hetero)aryl, 3-alkyl and 3-alkenyl-2(1H)-pyrazinones were prepared by applying the Suzuki and Heck reaction methodology to 3,5-dichloro-2(1H)-pyrazinones. Furthermore, following hydrogenolysis of the 5-chloro substituent and regioselective 5-bromination, this palladium-catalysed cross-coupling approach could be extended to the synthesis of the analogous 5-substituted 2(1H)-pyrazinones.     

Atom-efficient synthesis of 2,6-diazacyclophane compounds through alcoholysis/reduction of 3-nitroarylmethylene-2,5-piperazinediones

Readily available cyclic dehydrodipeptides are convenient starting materials for atom-efficient synthesis of different compounds. A one-pot ring-opening/alcoholysis/hydrolysis process with 3-nitroarylmethylene-2,5-piperazinediones yielded N-3-nitroarylpyruvoylamino esters, which gave the corresponding amines by reduction of the nitro group. In the case of 2-nitroaryl compounds, an intramolecular reductive amination afforded N-indole-2-carbonylamino esters, while the intermolecular reductive amination of 3- and 4-nitroaryl derivatives allowed the synthesis of 2,6-diazacyclophanes. The amino compounds may be coupled with amino acids to get peptide-like derivatives.