l-Proline catalyzed domino Michael addition of N-substituted anilines

Here we report l-proline catalyzed 3-component reaction of indoles, aldehydes and N-substituted anilines in water as solvent at room temperature for the synthesis of 3-(α,α-diarylmethyl)indoles. The reaction is in fact a Michael addition of N-substituted anilines to alkylideneindolenines. The reaction is very clean, high yielding and having broad substrate scope. A tentative mechanism is proposed.     

Morita-Baylis-Hillman reaction of indole-2-carboxaldehyde: new vistas for indole-annulated systems

DABCO-mediated Morita-Baylis-Hillman reactions of several 1-substituted-indole-2-carboxaldehydes are disclosed. It was discovered that carboethoxy or tert-butoxycarbonyl groups installed at N-1 undergo cleavage under the reaction conditions to afford 2-substituted indoles. Utility of the N-substituted adducts for preparing a variety of annulated indoles has been exemplified.     

Michael reaction of indoles with 3-(2′-nitrovinyl)indole under solvent-free conditions and in solution. An efficient synthesis of 2,2-bis(indolyl)nitroethanes and studies on their reduction

Michael reaction of 3-(2′-nitrovinyl)indole with eight 3-unsubstituted indoles on TLC-grade silica gel furnished unsymmetrical bis(indolyl)nitroethanes in 7-12 min under microwave irradiation and in 8-14 h at rt. In contrast, the p-TsOH-catalysed reaction of the nitrovinylindole with the 3-unsubstituted and two 3-substituted indoles in solution under reflux furnished both unsymmetrical and symmetrical bis(indolyl)nitroethanes, the latter resulting from novel tandem Michael addition-elimination-Michael addition reactions. The synthesis of a 2′,3″-bis(indolyl)nitroethane, the precursor core structure of two bioactive marine metabolites, and the reduction of 2,2-bis(3′-indolyl)nitroethane to the corresponding ethylamine, isolated as its N-acetyl derivative, have been achieved. Significantly, attempted hydrolysis of three nitronates, derived from the corresponding bis(indolyl)nitroethanes, with buffered aqueous TiCl₃ has led to the first isolation of oximes (syn/anti-mixture) as the only products.     

An efficient, microwave-assisted, one-pot synthesis of indoles under Sonogashira conditions

A microwave-assisted, one-pot, three-component coupling reaction for the synthesis of indoles has been developed. The reaction is carried out in two steps under standard Sonogashira coupling conditions from an N-substituted/N,N-disubstituted 2-iodoaniline and a terminal alkyne, followed by the addition of acetonitrile and an aryl iodide. A variety of polysubstituted indoles have been prepared in moderate to excellent yields using the present method.     

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.     

Synthesis of 7-bromo, 7-phenylethynyl, 7-azido,and 7-nitro derivatives of N-acetyl-1,3a,4,8b-tetrahydrocyclopenta[b]indole

7-Bromo-, 7-phenylethynyl-, 7-azido-, 7-nitro-, and 5,7-dinitro-substituted N-acetyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles have been synthesized starting from anilines and 3-chlorocyclopentene. The NMR spectra of N-acetyl-7-nitro-1,3a,4,8b-tetrahydrocyclopenta[b]indoles displayed no signal doubling typical of the other 7-substituted derivatives.     

Synthesis of 2-substituted indoles by iridium (III)-catalyzed CH functionalization of N-phenylpyridin-2-amines

A highly regioselective synthesis of 2-substituted indoles was realized through Ir(III)-catalyzed CH functionalization of N-phenylpyridin-2-amines followed by the reaction with sulfoxonium ylides and intramolecular cyclization under mild conditions. The reaction completed with broad range of substrate scopes and gave various 2-substituted indoles in up to 98% yields.     

New synthesis of 3-substituted indoles using lithium trimethylsilyldiazomethane

Lithium trimethylsilyldiazomethane smoothly reacted with N-tosyl-o-acylanilines to give 3-substituted indoles in good to high yields.     

Iodine-catalyzed C3-formylation of indoles using hexamethylenetetramine and air

An efficient iodine-catalyzed chemoselective 3-formylation of free (N–H) and N-substituted indoles was achieved by using hexamethylenetetramine (HMTA) in the presence of activated carbon under air atmosphere. This new method could provide 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this catalytic formylation of indoles procedure can be applied to gram-scale synthesis.     

Novel synthesis of fused indoles and 2-substituted indoles by the palladium-catalyzed cyclization of N-cycloalkenyl-o-haloanilines

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline.     

Regioselective N- and C2-electrophilic substitution of 3-substituted indoles

The reaction of 3-substituted indoles with 2-cyclohexenone under Lewis acid mediated conditions with Bi(NO₃)₃·5H₂O has been investigated. We have demonstrated that electrophilic substitution of 3-substituted indoles with 2-cyclohexenone will readily occur at the nitrogen. Furthermore, the extent of regioselectivity is dependent on reaction solvent and the C3-substituent. Excellent conversion is obtained with good to excellent isolated yields of N- and C2-adducts. In general, more polar, aprotic solvents (CH₃CN) give greater N-selectivity whereas with polar protic solvents (CH₃OH) an increase in the C2-adduct is observed.     

Catalytic asymmetric hydrogenation of indoles using a rhodium complex with a chiral bisphosphine ligand PhTRAP

Highly enantioselective hydrogenation of N-protected indoles was successfully developed by use of the rhodium catalyst generated in situ from [Rh(nbd)₂]SbF₆ and the chiral bisphosphine PhTRAP, which can form a trans-chelate complex with a transition metal atom. The PhTRAP–rhodium catalyst required a base (e.g., Cs₂CO₃) for the achievement of high enantioselectivity. Various 2-substituted N-acetylindoles were converted into the corresponding chiral indolines with up to 95% ee. The hydrogenations of 3-substituted N-tosylindoles yielded indolines possessing a stereogenic center at the 3-position with high enantiomeric excesses (up to 98% ee).     

Catalytic enantioselective synthesis of macrodiolides and their application in chiral recognition

New types of C₂-symmetric chiral macrodiolides are readily obtained via chiral N,N′-dioxide-scandium(iii) complex-promoted asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles. This protocol provides an array of enantioenriched macrodiolides with 16, 18 or 20-membered rings in moderate to good yields with high diastereoselectivities and excellent enantioselectivities through adjusting the length of the tether at the C3 position of indoles. Density functional theory calculations indicate that the formation of macrocycles is more favorable than that of 9-membered-ring lactones in terms of kinetics and thermodynamics. The potential utility of these intriguing chiral macrodiolide molecules is demonstrated in the enantiomeric recognition of aminols and chemical recognition of metal ions.

An asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles was achieved by using a chiral N,N′-dioxide-scandium(iii) complex.     

A novel TFA-mediated cyclo-dimerization of 1-substituted 3-alkenylindole derivatives to cyclopent[b]indoles

Reaction of 1-substituted 3-alkenyl-1H-indoles with an equimolar amount of trifluoroacetic acid in dichloromethane gave cyclic dimers, 1,3-trans-N,N′-disubstituted cyclopent[b]indoles, in 53-84% yields as sole products through an acid-mediated stereoselective cyclo-dimerization process. The structure of the cyclic dimer derived from 3-cyclopentylidenemethyl-1-methyl-1H-indole was elucidated by X-ray crystallographic analysis.     

Secondary-secondary diamine catalysts for the enantioselective Michael addition of cyclic ketones to nitroalkenes

Secondary-secondary diamines derived from S-proline are efficient catalysts for the ketone-nitroalkene Michael addition reaction. The stereoselectivity of the Michael addition is dependant on the pK_a of the N-substituted aminomethyl pendant in these diamines. N′-Aryl aminomethyl pyrrolidines provide γ-nitroketones with moderate to good enantiomeric excess (65-92%). Removal of the hydrogen-bond donor group by N-methylation results in a dramatic reduction of enantioselectivity (average ee 6%).     

Samarium triiodide-catalyzed conjugate addition of indoles with electron-deficient olefins

The SmI₃-catalyzed reaction of indoles with electron-deficient olefins generated the corresponding Michael adducts in high yields. The substitution on the indole nucleus occurred exclusively at the 3-position and N-alkylation products have not been observed.     

Application of modular nucleophilic glycine equivalents for truly practical asymmetric synthesis of β-substituted pyroglutamic acids

A new series of achiral glycine equivalents have been evaluated with respect to their synthetic utility for the production of β-substituted pyroglutamic acid derivatives. Among them, the piperidine-derived complex was found to be a superior glycine derivative for the Michael additions with various (R)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones representing a general and practical synthesis of sterically constrained β-substituted pyroglutamic acids. In particular, application of complex allowed for the first time preparation of the corresponding isopropyl derivatives thus increasing the synthetic efficiency and expanding generality these Michael addition reactions.     

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.     

Solid-state synthesis of novel 3-substituted indoles

Poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS] and N,N,N’,N’-tetrabromobenzene-1,3-disulfonamide [TBBDA] were used as efficient catalysts for the one-pot synthesis of 3-substituted indoles in good to high yields from indole, aldehydes, and arylamines under solid-state conditions at room temperature.     

Palladium-catalysed C–C coupling reactions in the enantioselective synthesis of 2,4-disubstituted 4,5-dehydropiperidines using galactosylamine as a stereodifferentiating auxiliary

Stereoselective synthesis of enantiomerically pure 2,4-disubstituted piperidine derivatives, which are considered interesting pharmacophoric structures, was achieved starting with a tandem Mannich–Michael reaction sequence on O-pivaloylated N-galactosyl aldimines. Subsequent conversion of the thus formed 2-substituted dehydropiperidinones into the corresponding enol triflates was carried out by conjugate hydride addition and trapping the enolate with N,N-bis(trifluoromethanesulfonyl)aniline. Their Suzuki–Miyaura coupling with aryl and heteroaryl boronic acids was performed under conditions compatible with the carbohydrate structure, in particular, with the sensitive N-glycosidic bond.