Copper-catalyzed tandem intramolecular cyclization/coupling reaction: solvent effect on reaction pathway

In this study, we developed direct methods for the synthesis of 3-substituted indoles from o-alkynylanilines by utilizing a copper-catalyzed tandem intramolecular cyclization/coupling reaction under mild and simple reaction conditions. Our investigation revealed that choice of the aprotic polar solvents and additives such as camphorsulfonic acid is critical in this reaction.     

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.     

Synthesis of new 3-arylindole-2-carboxylates using β,β-diaryldehydroamino acids as building blocks. Fluorescence studies

Several new methyl 3-arylindole-2-carboxylates were synthesized in high yields using a metal assisted [Pd(OAc)₂/Cu(OAc)₂, DMF, 130 °C] intramolecular C-N cyclization of β,β-diaryldehydroamino acids, developed by us, thus extending the scope of this reaction. The latter were obtained by a bis-Suzuki coupling of a β,β-dibromodehydroalanine with arylboronic acids bearing either electron-donating groups (EDGs) or electron-withdrawing groups (EWGs). We were able to establish general conditions for this coupling reaction [PdCl₂dppf·CH₂Cl₂ 1:1 (20 mol %), boronic acid (5 equiv), Cs₂CO₃ (1.4 equiv), THF/H₂O 1:1, 80 °C]. This strategy constitutes a novel, general and unprecedented approach to the synthesis of 3-arylindole-2-carboxylates. The fluorescence of the differently substituted indoles prepared was studied in several polar and non-polar solvents. In general the new indoles exhibit a solvent sensitive emission. The indoles with EDGs (OCH₃ and SCH₃) have reasonable fluorescence quantum yields in all solvents except in water. The indole with the cyano groups shows high fluorescent quantum yields in all solvents studied, despite the lower solvent sensitivity of its emission. The indole with the acetyl groups only exhibits reasonable fluorescence quantum yields in protic solvents. These studies show that the new 3-arylindole-2-carboxylates are good candidates to be used as fluorescent probes.     

Synthesis and structure of an air-stable binuclear complex of bis(ethylcyclopentadienyl)zirconium perfluorooctanesulfonate and its catalytic application in one-pot three-component aza-Friedel–Crafts reactions

An air-stable Lewis acidic binuclear complex of bis(ethylcyclopentadienyl)zirconium perfluorooctanesulfonate (1a) was successfully synthesized by the reaction of (CH₃CH₂Cp)₂ZrCl₂ with C₈F₁₇SO₃Ag. The complex 1a was characterized by different techniques and found to have the nature of air-stability, water tolerance, thermal-stability, and strong Lewis-acidity. In addition, its solubility was higher than that of our previously reported uninuclear zirconocene bis(perfluorooctanesulfonate). This complex showed high catalytic efficiency, good recyclability, and reusability in the one-pot three-component aza-Friedel–Crafts reactions of indoles with aldehydes and N,N-dimethylaniline. The yields of the corresponding 3-diarylmethyl indoles are higher than those from the traditional Lewis acidic catalysts.     

Density functional studies of influences of Ni triad metals and solvents on oxidative addition of MeI to [M(CH3)2(NH3)2] complexes and C-C reductive elimination from [M(CH3)3(NH3)2I] complexes

Three metal square planar complexes of the type [M(CH₃)₂(NH₃)₂] (M = Ni, Pd, Pt), with a systematic variation in the metals, are chosen to investigating their S_N2-type oxidative addition reactions with methyl iodide by using the B3LYP levels of theory. The oxidative addition was found to take place via a transition state with a nearly linear arrangement of the I-CH₃-M moiety. Solvation effects in these oxidative addition reactions were also investigated. Considering the nature of the metal centre and solvation effects, the following conclusions emerge: (i) addition of MeI is exothermic for all three metals, and Pt is predicted to react with a much lower barrier than either Pd or Ni. The results describe that the MeI addition would be expected to be more favourable with the complex bearing the third-row metal (platinum) as compared to the other triad metals, nickel or palladium, in which case a more strongly bound MeI adduct is formed with a lower activation barriers and the reaction being more exothermic; (ii) the reaction is very difficult to occur in low polar solvents, such as benzene, due to the high barrier which is induced by dissociation of iodide anion from methyl group, but the reaction easily occurs in polar solvents, such as acetonitrile; this is attributed to the ability of polar solvents to solvate and therefore stabilize the related polar intermediate ion pair. Ethane reductive elimination from the M(VI) complexes fac-[M(CH₃)₃(NH₃)₂I] were also studied, indicating that the Ni(IV) and Pd(IV) complexes are very prone to undergo the reductive elimination while the Pt(IV) analogous is less reactive towards the reductive elimination. The results indicate that in contrast to the Me-Me reductive elimination, the S_N2 oxidative addition reaction of MeI to M(II) is much less sensitive to the nature of the metal centre, suggesting that the nucleophilicity of M(II) in [M(CH₃)₂(NH₃)₂] does not change significantly as one moves from M = Ni to Pt.     

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.     

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).     

Synthesis of Polysubstituted Ferrocenesulfoxides

The purpose of the study is to design synthetic methodologies, especially directed deprotometalation using polar organometallic reagents, to access polysubstituted ferrocenesulfoxides. From enantiopure 2-substituted (SiMe₃, PPh₂) S-tert-butylferrocenesulfoxides, a third substituent was first introduced at the 5 position (SiMe₃, I, D, C(OH)Ph₂, Me, PPh₂, CH₂NMe₂, F) and removal of the trimethylsilyl group then afforded 2-substituted ferrocenesulfoxides unreachable otherwise. Attempts to apply the “halogen dance” reaction to the ferrocenesulfoxide series led to unexpected results although rationalized in light of calculated pK_a values. Further functionalizations were also possible. Thus, new enantiopure, planar chiral di- and trisubstituted ferrocenes have been obtained, in addition to several original 2-substituted, 2,3- and 2,5-disubstituted, 2,3,5-trisubstituted and even 2,3,4,5-tetrasubstituted ferrocenesulfoxides, also enantiopure.     

Synthesis of symmetrical and unsymmetrical 3,3-di(indolyl)indolin-2-ones under controlled catalysis of ionic liquids

Three ionic liquids, [BMIM][BF₄] doped with 60 mol % of LiCl ([BMIM][BF₄]-LiCl), N,N,N,N-tetramethylguanidinium trifluoroacetate (TMGT), and N,N,N,N-tetramethylguanidinium triflate (TMGT_f) were found useful as catalyst solvents for controlled 3-indolylation of isatins. Our investigation revealed that the reaction between isatin and indoles in [BMIM][BF₄]-LiCl or TMGT_f media stops at the step of addition of the two components providing 3-indolyl-3-hydroxyindolin-2-ones while the ionic liquid TMGT runs the reaction further through accompanying Friedel-Crafts substitution to afford symmetrical 3,3-di(indol-3-yl)indolin-2-ones. To take advantage of the difference between the effects of these ionic liquids on the reaction progress, we planned a two-step protocol for the efficient synthesis of unsymmetrical 3,3-di(indol-3-yl)indolin-2-ones.     

Synthesis of polyfunctionalized methylphosphine oxides

N,N-Dialkylamino(diphenylphosphoryl)chloromethanes, a new type of organophosphorus compounds, were synthesized. On dissolving in polar and low polar solvents, N,N-dialkylamino(diphenylphosphoryl)chloromethanes dissociate spontaneously with the P??C bond cleavage to form the diphenylphosphinite anion Ph₂PO^?. This was confirmed by the reaction of N,N-dimethylamino(diphenylphosphoryl)chloromethane with electrophilic substrates to form the corresponding addition or substitution products of Ph₂PO^?. The capability of spontaneous generating the diphenylphosphinite anion considers accessible N,N-dimethylamino(diphenylphosphoryl)chloromethane as a synthetic equivalent of the diphenylphosphinite anion.     

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.     

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.     

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.     

Phosphineborane analogs of trimethylsilyl amides

The reaction of (CH₃)₂(BH₃)PCl with the lithium salts of acetamide, N-methyl acetamide, and N-methyl formamide produced the N(CH₃)₂(BH₃)P-monosubstituted amides. Attempts to employ the same procedure for the preparation of the bis-acetamide, the acetanilide and the N-methyl benzamide derivatives were unsuccessful. Variable temperature NMR spectroscopy revealed the presence of rotational isomers for the formamide with a population of 0.85 for the major rotamer which on the basis of the ³¹P-formyl proton coupling constants was assigned the structure where the (CH₃)₂(BH₃)P group is trans to carbonyl oxygen. The free energies of activation were determined to be 16.2 and 17.3 kcal/mol. For the other derivatives only one isomer could be detected down to—60°C. The compounds are similar to the trimethylsilyl analogs in structure and rotational populations, but the lower rotational barrier in the phosphineborane formamide derivative suggests a greater destabilization of the polar ground state amide resonance structure by the formal positive charge on phosphorus.     

Die Addition von Säuren an Alkinderivate mit Push-pull-Gruppen,

The addition of proton acids as HF, HCl, HBr, HOAc and phenol to alkyne-derivatives of the type (CH₃)₂N? C?C? CO? R( 1 ) yielding the adducts 2 to 6 is investigated. The stereochemical course of the reaction is mainly influenced by the structure of the alkyne 1 . Kinetic investigations show that the rate of the third-order-reaction increases from 1 a (R?H) to 1 b (R ? CH₃) and 1 c (R ? OCH₃) and decreases drastically in polar solvents. According to these results a reaction mechanism is outlined and discussed.     

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.     

Unusual nitrogen based heterocycles via allenic intermediates from the reaction of propargyl alcohols with P(III) substrates

The apparently simple reaction of the P(III) precursors [(RNH)P(μ-N-t-Bu)₂PY] (Y=NH-t-Bu, Cl), (OCH₂CMe₂CH₂O)PCl, and Ph₂PCl with functionalized propargyl alcohols is examined. In most cases, the final products are not the expected allenes but several previously unpredicted structural motifs, such as substituted oxazabenzocycloheptenones, indolinones, and fused heterocycles as revealed by X-ray crystallography. Mechanistic aspects of these novel reactions, as well as possible utility and the structural chemistry of the products are also discussed. The P–C or P–N bond cleavage of many of these compounds led to phosphorus-free 2-substituted indoles, quinolinones, and tetrahydroacridine.     

Synthesis of acetals containing a primary amino group

Amino acetals of the general formula MeCH(OR)(OXNH₂) (R = Et, Bu, X = CH₂CH₂, CH₂CH₂CH₂, CH₂CMe₂) were synthesized in 53?C91% yield by acid-catalyzed reaction of N-(2-hydroxyethyl)-, N-(3-hydroxypropyl)-, and N-(2-hydroxy-1,1-dimethylethyl)-2,2,2-trifluoroacetamides with vinyl ethers, followed by removal of the trifluoroacetyl protection by alkaline hydrolysis.     

A kinetic investigation of reaction of [Os(N)(CH2SiMe3)4][NBun4] with methyl iodide

A high oxidation state alkylnitridoosmium complex, [Os(N)(CH₂SiMe₃)₄][NBuⁿ₄] acts as a nucleophile in reactions with alkyl halides. Alkylimido complexes, Os(NR)(CH₂SiMe₃)₄, are produced. The reaction between [Os(N)(CH₂SiMe₃)₄]⁻ [NBuⁿ₄] and MeI is second order with k₂= 9.5 x 10⁻⁵ sec^t̄1 M⁻¹ at 23°C in CD₂Cl₂ under pseudo first order conditions. The entropy of activation, ΔS^≠, was found to be −10.6 ± 0.5 cal M⁻¹ K⁻¹ and the enthalpy of activation, ΔH^≠, was found to be 19.6 ± 0.2 kcal M⁻¹. The reaction proceeds faster in polar, non-coordinating solvents than in either non-polar solvents or in solvents which can coordinate to the osmium center.     

Trans-effect in the kinetics of reactions of mixed Cu(II) acetate solvates with N-methyloctaethylporphine

The kinetics of complex formation reaction of N-substituted octaethylporphine (H(N-Me)(β-Et)₈P] with copper(II) acetate in individual and mixed solvents based on DMSO, DMF, and Py is studied by spectrophotometry. An increase in the complex formation rate of this porphyrin with CuAc₂ in mixed solvents is explained in terms of the trans-effect of the ligands in the solvate sphere of the salt.