Thorpe-Ingold effect in copper(II)-catalyzed formal hydroalkoxylation-hydroarylation reaction of alkynols with indoles

The use of Cu(OTf)₂ as a catalyst for tandem hydroalkoxylation-hydroarylation reaction of alkynes tethered with hydroxyl group is reported. The reaction proceeds at 60 °C or even at room temperature with 5 mol % catalyst loading and produces C-3-substituted indoles in good to high yields. The method was shown to be applicable to a broad range of indoles, containing electron-withdrawing and electron-donating substituents, and alkynol substrates bearing sterically demanding substituents in the tether. Interestingly, it was found that Thorpe-Ingold effect is operating for this cyclization reaction. Easy availability and low cost of Cu(OTf)₂ make this method attractive and amenable for large-scale synthesis compared to known literature methods.     

Indium trichloride catalyzed three component one-pot route to 1-hydroxymethyl-3-aminomethyl indoles

A one-pot synthesis of 1-hydroxymethyl-3-aminomethyl indoles 3 could be achieved in excellent yield by reacting indoles 1 with formaldehyde and secondary amines 2 in the presence of molecular sieves (3 Å) and catalytic amount of InCl₃ (10 mol %) in 1,4-dioxane at room temperature for 3-5 h.     

Applications of organocatalytic asymmetric synthesis to drug prototypes--dual action and selective inhibitors of n-nitric oxide synthase with activity against the 5-HT1D/1B subreceptors

The scope of MacMillan's organocatalytic asymmetric conjugate addition reaction of indoles and electron-rich aromatics to α,β-unsaturated aldehydes has been extended to the use of 3-amino crotonaldehydes as substrates. The aromatics used include indoles as well as an aniline and a furan. The scope and effect of the groups on nitrogen (R, R') has also been studied. The method has been applied to the concise synthesis of an advanced precursor to S-(+)-1, a drug prototype for the treatment of migraine headaches.     

Synthesis of substituted indoles using continuous flow micro reactors

Continuous flow micro fluidic devices for organic synthesis (‘micro reactors’) are becoming established in a number of facets of modern applied chemistry. As part of a concurrent research project with a pharmaceutical company for generation of materials of pharmaceutical interest within continuous flow environments, we present here, for the first time a series of indoles that have been produced within micro reactor systems. We have developed three different approaches to the synthesis, which are compared with traditional batch synthesis as well as each other in terms of ease of optimization, chemical suitability and versatility, and implications as to throughput. Typical throughputs of approach 1 (simulated classical synthesis) were in the region of 2 mgh⁻¹ of indoles such as tetrahydrocarbazole and cyclopentaindole. The second approach (based on Elk's modification of Fischer indole synthesis) gave throughputs of 5.7-8.9 mgh⁻¹ and the final approach (using heterocatalytic flow reactors) gave the highest throughputs of 12.7-20.1 mgh⁻¹. All throughputs are per single channel reactor system (i.e., one single reactor set up), and the latter two approaches produce viable output quantities for the syntheses of radiolabelled materials (where typically minute amounts of high purity materials are required from a rapid and safe production environment).     

One-pot synthesis of N-protected α-amino aldehyde acetals from three-component reaction of fluoroalkanesulfonyl azide, vinyl ether and alcohol

A facile one-step method has been developed for the synthesis of N-protected α-amino aldehyde acetals in moderate to good yields by three-component reaction of fluoroalkanesulfonyl azides, vinyl ethers and alcohol at 0 °C within 10 min. This practical synthetic method provides a convenient and expeditious access to N-per(poly)fluoroalkanesulfonyl α-amino aldehyde acetals.     

The first synthesis of β-amino phosphonates using cyclic sulfamidates

Cyclic sulfamidates (prepared from α-amino acids and β-amino alcohols) have been used for the first time for the synthesis of novel β-amino phosphonates (chiral and achiral) by treatment with dialkyl phosphites using sodium hydride. 2-Substituted and 1,2-disubtituted β-amino phosphonates have efficiently been prepared following this method. The products are formed in high yield (79-84%) within 8-12 h.     

Direct synthesis of 3-arylindoles via annulation of aryl hydroxylamines with alkynes

3-Arylindoles are produced in moderate to excellent yields from the reaction between aryl hydroxylamines and alkynes catalyzed by 10 mol % iron(II) phthalocyanine [Fe(Pc)]. Terminal and internal alkynes afford 3-aryl substituted indoles exclusively. Electron-donating and -withdrawing groups are tolerated on the aryl hydroxylamine. A few bioactive indoles are synthesized as well as several new indoles using this one-step intermolecular annulation procedure.     

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.     

Ruthenium-catalyzed functionalization of pyrroles and indoles with propargyl alcohols

Several ruthenium-catalyzed atom-economic transformations of propargyl alcohols with pyrroles or indoles leading to alkylated, propargylated, or annulated heteroaromatics are reported. The mechanistically distinct reactions are catalyzed by a single ruthenium(0) complex containing a redox-coupled dienone ligand. The mode of activation regarding the propargyl alcohols determines the reaction pathway and depends on the alcohols' substitution pattern. Secondary substrates form alkenyl complexes by a 1,2-hydrogen shift, whereas the transformation of tertiary substrates involves allenylidene intermediates. 1-Vinyl propargyl alcohols are converted by a cascade allylation/cyclization sequence. The environmentally benign processes are of broad scope and allow the selective synthesis of highly functionalized pyrroles and indoles generating water as the only waste product.     

Syntheses based on 3H-benz[e]indole o-quinones

Some 4,5-dioxo-4,5-dihydro-3H-benz[e]indoles have been alkylated. The N-alkyl derivatives were used in the synthesis of 8-oxoindenol[2,1-b]pyrroles and 2-aminomethyl-3-methyl (and benzyl)-4,5-dioxo-4,5-dihydrobenz[e]indole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 611–614, May, 1989.     

Promiscuous Candida antarctica lipase B-catalyzed synthesis of β-amino esters via aza-Michael addition of amines to acrylates

An efficient protocol for the regioselective aza-Michael addition of amines with acrylates using CaL B as a biocatalyst at 60 °C has been developed. The reaction is applicable to a wide variety of primary and secondary amines with different acrylates to synthesize the corresponding β-amino esters with good yields. An alternative route for the synthesis of higher β-amino esters through the additional transesterification step is also studied and was found effective.     

Ruthenium‐Catalyzed Functionalization of Pyrroles and Indoles with Propargyl Alcohols

Several ruthenium‐catalyzed atom‐economic transformations of propargyl alcohols with pyrroles or indoles leading to alkylated, propargylated, or annulated heteroaromatics are reported. The mechanistically distinct reactions are catalyzed by a single ruthenium(0) complex containing a redox‐coupled dienone ligand. The mode of activation regarding the propargyl alcohols determines the reaction pathway and depends on the alcohols’ substitution pattern. Secondary substrates form alkenyl complexes by a 1,2‐hydrogen shift, whereas the transformation of tertiary substrates involves allenylidene intermediates. 1‐Vinyl propargyl alcohols are converted by a cascade allylation/cyclization sequence. The environmentally benign processes are of broad scope and allow the selective synthesis of highly functionalized pyrroles and indoles generating water as the only waste product.     

An efficient synthesis of 3-(indol-3-yl)quinoxalin-2-ones with TfOH-catalyzed Friedel-Crafts type coupling reaction in air

An efficient one-pot synthetic approach to access a variety of 3-(indol-3-yl)quinoxalin-2-ones from various quinoxalin-2-ones and very wide scope of indoles through TfOH-catalyzed Friedel-Crafts type coupling reaction in DMF has been developed. Only 10 mol % Brønsted acid as a catalyst, air as an oxidizer, and very wide range of substrates are the prominent advantages of this method.     

An FeCl3-catalyzed highly C3-selective Friedel-Crafts alkylation of indoles with alcohols

The FeCl₃-catalyzed C3-selective Friedel-Crafts alkylation of indoles using allylic, benzylic and propargylic alcohols has been developed. The reaction was performed in the presence of a catalytic amount of inexpensive anhydrous FeCl₃ (10 mol %) in nitromethane under mild conditions. This method can also be used for the alkylation of pyrrole.     

Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with α‐Carbonyl Alkyl Bromides and Indoles

A new iron‐facilitated silver‐mediated radical 1,2‐alkylarylation of styrenes with α‐carbonyl alkyl bromides and indoles is described, and two new C?C bonds were generated in a single step through a sequence of intermolecular C(sp³)?Br functionalization and C(sp²)?H functionalization across the alkenes. This method provides an efficient access to alkylated indoles with broad substrate scope and excellent selectivity.     

Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide

A Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide is described. Asymmetric allylic substitution using acyclic β-keto esters with a nitrogen functional group at the α-carbon as prochiral nucleophiles proceeded in the presence of 5 mol % of Pd catalyst, 10 mol % of chiral diaminophosphine oxide 1j, BSA, and appropriate additives, affording the corresponding quaternary α-amino acid derivatives in excellent yield and in up to 92% ee.     

First heterogeneously palladium-catalysed fully selective C3-arylation of free NH-indoles

A simple heterogeneously palladium-catalysed procedure for the selective C3-arylation of indoles is reported. Under relatively standard reaction conditions (Pd-catalyst, K₂CO₃, dioxane, reflux), using only 1 mol % [Pd(NH₃)₄]/NaY as the catalyst, indoles substituted or not at position 2 gave up to 92% conversion (i.e., 85% isolated yield) towards the expected C3-arylated indole.     

InBr3 as a versatile and highly efficient catalyst for the synthesis of 3-allyl- and 3-benzylindoles

Indoles undergo smooth alkylation with allylic and benzylic alcohols in the presence of 10 mol % of InBr₃ under mild conditions to produce 3-allyl- and 3-benzyl indoles, respectively, in excellent yields and with high selectivity. This is the first example of the alkylation of indoles with benzylic alcohols using InBr₃ as an acid catalyst.     

Synthetic application of in situ generation of N-acyliminium ions from α-amido p-tolylsulfones for the synthesis of α-amino nitriles

In the presence of catalytic amount of bismuth bromide (5 mol %) the α-amido p-tolylsulfones are converted into N-acyliminium ions, which undergo the nucleophilic addition of trimethylsilyl cyanide (TMSCN) to provide the N-protected α-amino nitriles in very good yield. A variety of α-amido p-tolylsulfones were prepared from aromatic as well as aliphatic aldehydes for the synthesis of α-amino nitriles.     

A new and facile access to the 2-(indol-3-yl)-3-nitriloquinolines based on Friedländer annulations

Preparation of 2-(indol-3-yl)-3-nitriloquinolines via Friedländer quinoline synthesis using 3-cyanoacetylindoles possessing an α-methylene group and ortho-amino arylketones have been described. This reaction took place in PEG-400 as a green solvent and it is catalyzed with polyphosphoric acid (PPA) to give novel types of quinolines containing both indoles and cyano functions in one step under thermal and microwave conditions.