An expedient synthesis of substituted indoles

Condensation of carboxylic acid esters with organodilithium reagents derived from N-trimethylsilyl-o-toluidine or N-trimethylsilyl-o-ethyl aniline affords substituted indoles.     

Exploring the oxidative cyclization of substituted N-aryl enamines: Pd-catalyzed formation of indoles from anilines

The direct Pd-catalyzed oxidative coupling of two C-H-bonds within N-aryl-enamines 1 allows the efficient formation of differently substituted indoles 2. In this cross-dehydrogenative coupling, many different functional groups are tolerated and the starting material N-aryl-enamines 1 can be easily prepared in one step from commercially available anilines. In addition, the whole sequence can also be run in a one-pot fashion. Optimization data, mechanistic insight, substrate scope, and applications are reported in this full paper.     

Rapid synthesis of diversely functionalized 3,4,7-trisubstituted indoles

Synthetic approaches are described for the synthesis of 4-alkoxyindole-7-carboxamides and 4-alkoxy-3-cyanoindole-7-carboxamides, which are useful intermediates in medicinal chemistry research. Two strategies were employed, highlighted by a Bartoli indole synthesis or a sequential and regioselective use of chlorosulfonyl isocyanate to install both the 3-cyano and 7-carboxamido groups. These routes are scalable and afford diversely functionalized indoles for further elaboration.     

Palladium-catalyzed, modular synthesis of highly functionalized indoles and tryptophans by direct annulation of substituted o-haloanilines and aldehydes

One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-haloanilines and aldehydes has been developed. Coupling of ortho-iodoaniline with aldehyde is realized under mild ligandless conditions [Pd(OAc)2, DABCO, DMF, 85 degrees C], whereas X-Phos is found to be the ligand of choice for coupling reactions involving ortho-chloroanilines/ortho-bromoanilines and aldehydes. A variety of ortho-haloanilines with different electronic properties are suitable substrates, and aldehydes including chiral ones participated in this reaction without racemization. Coupling of (S)-2-N,N-di-tert-butoxycarbonyl-5-oxopentanoate, derived from L-glutamic acid, with ortho-haloanilines provides a rapid access to the ring-A-substituted tryptophans in good to excellent yields.     

Stereoselective synthesis of fused heterocycles from substituted o-Benzoquinones and anilines

The reaction of trisubstituted o-benzoquinones with substituted anilines gives unstable o-benzoquinone imines which undergo intramolecular cyclization to 4aH-phenoxazine derivatives. Dimerization of the latter according to Diels-Alder yields complex heterocyclic systems, 7a,14a,15a,15b-tetrahydro-14,16-dioxa-5,9-diaza-8,15-ethenohexaphenes. Effective shielding of the carbonyl groups in 3,6-di-tert-butyl-4-isopropyl-o-benzoquinone makes it inactive toward substituted anilines.     

Preparation of a fully substituted purine library

A library of tetra-substituted purine analogues was readily prepared via parallel synthesis. This strategy relies on a key cyclization of a 4,5-diaminopyrimidine with either a carboxylic acid or its derivative to construct the 2,8,9-trisubstituted 6-chloropurine core. Further elaborations of this core allow the introduction of other diversity points. This methodology is demonstrated through the preparation of a 135-membered library of tetra-substituted purines in good yields and high purity.     

Iridium- and ruthenium-catalysed synthesis of 2,3-disubstituted indoles from anilines and vicinal diols

A straightforward and atom-economical method is described for the synthesis of 2,3-disubstituted indoles. Anilines and 1,2-diols are condensed under neat conditions with catalytic amounts of either [Cp*IrCl(2)](2)/MsOH or RuCl(3)·xH(2)O/phosphine (phosphine = PPh(3) or xantphos). The reaction does not require any stoichiometric additives and only produces water and dihydrogen as byproducts. Anilines containing methyl, methoxy, chloro and fluoro substituents can participate in the cyclocondensation. Meta-substituted anilines give good regioselectivity for 6-substituted indoles, while unsymmetrical diols afford excellent regioselectivity for the indole isomer with an aryl or large alkyl group in the 2-position. The mechanism for the cyclocondensation presumably involves initial formation of the α-hydroxyketone from the diol. The ketone subsequently reacts with aniline to generate the α-hydroxyimine which rearranges to the corresponding α-aminoketone. Acid- or metal-catalysed electrophilic ring-closure with the release of water then furnishes the indole product.     

Ruthenium-catalyzed regioselective synthesis of 2-substituted indoles via ring-opening of epoxides by anilines

Anilines react with epoxides in dioxane at 180°C in the presence of a catalytic amount of a ruthenium catalyst along with tin(II) chloride to afford 2-substituted indoles in moderate to good yields.     

The pyrrole approach toward the synthesis of fully functionalized cup-shaped molecules

[reaction: see text] A novel method for the synthesis of new highly functionalized cyclotrimers is described. The method consists of an original synthesis of beta-dibromosubstituted pyrroles, metalation, cycloaddition, and cyclotrimerization. The sequence is highly compatible with common functional groups and allows the construction of cup-shaped molecules functionalized both at the upper and bottom rim. This feature makes the newly formed structures useful scaffolds for the development of supramolecular receptors.     

Silica chloride catalyzed one-pot synthesis of fully substituted pyrazoles

Silica chloride catalysted one pot cyclocondensation of aldehydes,ethyl acetoacetate and phenyl hydrazine leading to substituted pyrazoles has been reported.     

Domino rhodium(I)-catalysed reactions for the efficient synthesis of substituted benzofurans and indoles

Rhodium(I) catalysts promote the transformation of o-alkynyl phenols and anilines to the corresponding benzo[b]furans and indoles. The reaction is postulated to proceed via a transient 3-rhodium heterocycle intermediate, which can be trapped with suitable electrophiles to give poly-substituted heterocycles. In the case of mono-substituted electron-withdrawn electrophiles, excellent yield and selectivity for conjugate addition versus Heck-Mizoroki reaction can be achieved. In the case of 2-alkynyl pyridine electrophiles, novel 2-(benzofuran-3-yl)vinylpyridines are formed.     

Efficient synthesis of substituted thieno[3,2-e]indoles

Efficient cyclization reactions of 5-aminobenzothiophene derivatives with internal and terminal acetylenes, giving 7- and 8-substituted thieno[3,2-e]indoles, are described. The reaction of 4-iodo-5-(methylsulfonamido)benzothiophene with terminal alkynes gave 7-substituted thienoindoles using general Sonogashira reaction conditions. Reaction of 5-amino-4-iodobenzothiophene with internal acetylenes, using Larock's heterocyclization reaction conditions, gave 7,8-disubstituted thieno[3,2-e]indoles.     

Ni- and Pd-catalyzed synthesis of substituted and functionalized allylic boronates

Two highly efficient and convenient methods for the synthesis of functionalized and substituted allylic boronates are described. In one procedure, readily available allylic acetates are converted to allylic boronates catalyzed by Ni/PCy(3) or Ni/PPh(3) complexes with high levels of stereoselectivity and in good yields. Alternatively, the borylation can be accomplished with commercially available Pd catalysts [e.g., Pd(2)(dba)(3), PdCl(2), Pd/C], starting with easily accessed allylic halides.     

Reaction of the carbonate radical with substituted anilines

Rate constants for the reaction of carbonate radical with aniline and some parasubstituted anilines have been determined by the flash photolysis technique. Using σ⁺ para values the rate constants at pH 8.5 correlate very well with the Hammett equation yielding ρ= − 1. The carbonate radical oxidises aniline giving the anilino radical. The products so formed have been identified through studies under conditions of continuous irradiation.     

Zinc-catalyzed multicomponent reactions: Facile synthesis of fully substituted pyridines

A first example of environmentally benign zinc complex catalyzed one-pot four-component reaction between malononitrile, ketone, ammonium acetate and aromatic aldehyde for the facile synthesis of fully substituted pyridines just within 2?min in environmentally friendly solvent ethanol has been optimized.     

Synthesis of regiospecifically substituted quinolines from anilines

A protocol for the synthesis of quinolines substituted on both pyridine and benzo-fused rings is reported. The method is based on the formylation of a substituted N-(tert-butoxycarbonyl)aniline followed by direct cyclisation and aromatisation of the intermediate product obtained by condensation of the formed N-Boc o-aminobenzaldehyde with an enolisable carbonyl compound. Yields up to 88% have been obtained.     

Efficient synthesis of substituted biaryl anilines and biaryl phenols via a Suzuki cross-coupling reaction

An efficient synthesis of biaryl building blocks with multiple point diversities via a Suzuki cross-coupling reaction using a commercially available preformed Pd catalyst 1 was reported. Substituted biaryl anilines and phenols were obtained in one step from commercially available aryl halides.