One-pot facile synthesis of polysubstituted pyridines via tandem reaction of the Blaise reaction intermediates and 3-formylchromones

A novel tandem one-pot method for the synthesis of polysubstituted pyridine derivatives has been developed via Knoevenagel-type reaction and subsequent 6π electrocyclization of the Blaise reaction intermediates and 3-formylchromones. Short reaction time, moderate to good yields and excellent functional group tolerance have been accomplished in this protocol.     

Synthesis of new tridentate chiral aminoalcohols by a multicomponent reaction and their evaluation as ligands for catalytic asymmetric Strecker reaction

A one-step, multicomponent Mannich-type reaction between phenols, paraformaldehyde, and β-aminoalcohols in the presence of LiCl afforded N-2-hydroxybenzyloxazolidines with high ortho-selectivity. Hydrolytic or reductive ring opening of the oxazolidines provided a series of N-salicyl-β-aminoalcohols in 84-92% overall yield. The synthesized compounds were evaluated as ligands for a titanium-catalyzed catalytic asymmetric Strecker reaction. The reaction employing 10 mol % of catalyst provided the Strecker products in excellent yields and up to 98% ee.     

Visible-light-driven Cadogan reaction

Visible-light-driven photochemical Cadogan-type cyclization has been discovered. The organic D-A type photosensitizer 4CzIPN found to be an efficient mediator to transfer energy from photons to the transient intermediate that breaks the barriers of deoxygenation in Cadogan reaction and enables a mild metal-free access to carbazoles and related heterocycles. DFT calculation results indicate mildly endergonic formation of the intermediate complex of nitrobiarenes and PPh₃, which corresponds with experimental findings regarding reaction temperature. The robust synthetic capacity of the photoredox Cadogan reaction systems has been demonstrated by the viable productivity of a broad range of carbazoles and related N-heterocycles with good tolerance of various functionalities.     

Stereodivergent synthesis of 1,4-bifunctional compounds by regio- and diastereoselective Pd-catalyzed allylic substitution reaction

Highly stereoselective synthesis of 1,4-bifunctional compounds was accomplished via 1,2-asymmetric induction to α-oxyaldehyde and α-oxyketone followed by regio- and diastereoselective Pd-catalyzed allylic substitution reaction. We found that trifluoroacetate is a suitable leaving group for the allylic substitution reaction. Various nucleophiles containing carbon, nitrogen, and sulfur can be applied to the method. Both 1,4-syn- and 1,4-anti-adducts were synthesized with high stereoselectivity by using stereodivergent reduction of the propargyl alcohols followed by allylic substitution reaction.     

Iodine-catalyzed tandem oxidative coupling reaction: A one-pot strategy for the synthesis of new coumarin-fused pyrroles

The simple and facile strategy for the synthesis of 2,3-disubstituted-chromeno[4,3-b]pyrrole-4(1H)-ones has been established. This method describes the Kornblum oxidation reaction of acetophenones, followed by the Knoevenagle treatment of the resulted (het)arylglyoxals with active methylene compounds and consequently iodine-activated Michael type reaction with 4-amino coumarin in a one-pot manner to afford disubstituted chromeno[4,3-b]pyrrole-4(1H)-one derivatives.     

Palladium-catalyzed Heck reaction of in-situ generated benzylic iodides and styrenes

A palladium-catalyzed Heck reaction of in-situ generated benzylic iodides and styrenes has been achieved. The reaction proceeds in a one-pot manner through 1) addition perfluoroalkyl iodides to styrenes to give benzylic iodides, 2) followed by a palladium-catalyzed Heck coupling of the resulting benzylic iodides with the same alkenes in high regio- and stereoselectivity. A variety of perfluoroalkylated alkenes were obtained in moderate to excellent yields.     

About the Leuckart reaction of chiral 2-norbornanones bearing electron-withdrawing groups: reaction of bridgehead triflates and triflamides

The mechanism of the Leuckart reaction of 3,3- and 7,7-dimethyl-2-oxo-1-norbornyl triflates and triflamides, synthesised by us starting from (1R)-camphor and (1R)-fenchone, has been studied. Strikingly, the electron-withdrawing capacity of the bridgehead substituents has demonstrated not to be enough to control the Wagner-Meerwein rearrangement during the course of the reaction, so that only both enantiomers of a 3,3-dimethylnorbornanediamine derivative have been obtained as final products. As a result, the total synthesis of these interesting chiral compounds has been optimised and shortened until three overall steps starting from (1R)-fenchone.     

A mild and regioselective Ullmann reaction of indazoles with aryliodides in water

A mild and regioselective Ullmann reaction of indazoles with aryliodides has been developed as a general method for the synthesis of 1-aryl-1H-indazoles. Water was used as the solvent wherein Tween 20 (2% w/w) was added to form aqueous micelles to improve solubility of starting materials and accelerate reaction rate. This aqueous protocol allows the Ullmann reaction to proceed at a mild temperature (60 °C) within a short reaction time (2 h), which typically requires high temperatures (≥100 °C) and prolonged duration (≥24 h). The protocol demonstrated broad substrate scopes with good isolated yields and high regioselectivity (N-1 arylation over N-2 arylation) for 25 examples examined.     

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction is described. The sequence of hydroboration of ω-alkenyl thiol ester with 9-BBN and the Liebeskind-Srogl reaction results in the formation of medium-sized carbocyclic ketones with good yield.     

Influence of reaction conditions on products of the Pictet-Spengler condensation

The Pictet-Spengler reaction with N-protected α-amino aldehydes was found to be very sensitive to reaction conditions. The outcome of the reaction can be controlled mainly by choice of solvent. Tetrahydro-β-carbolines were obtained in apolar solvents, while in polar media octahydro-bipyrroloindoles were the main compounds. Temperature, amount of acid and reaction time also influenced the final results of the PS reaction. Depending on conditions, products with opposite configuration of stereogenic centre, descended from amino aldehydes, were formed as byproducts.     

Selectivities in the reaction of vicinal diimines and acyl chlorides

The reaction of vicinal diimines and acyl chlorides in the presence of triethylamine produces 3-imino-β-lactams and/or bis-β-lactams chemo-, regio-, and stereoselectively, which are important intermediates in pharmaceutical and organic synthesis. The selectivities in the reaction have been investigated. The results indicate that all diimines react with various ketenes generated from acyl chlorides in the presence of triethylamine to give rise to cis-4-imino-β-lactams (mono-cis-β-lactams) diastereoselectively due to the electron-withdrawing property of the imino group in the vicinal diimines. Bis-β-lactams were obtained from diimines via the mono-cis-β-lactams as intermediates. Only ketenes with strong electron-donating substituents can react with the mono-cis-β-lactams to yield bis-β-lactams, affording a pair of C2-symmetric cis-bis-β-lactams with symmetric diimines, two or four pairs of diastereomeric bis-β-lactams with ketoaldehyde-derived unsymmetric diimines depending on the steric hindrance of their N-substituents. The current investigation provides very important information for the selective preparation of mono- and bis-β-lactams from vicinal diimines.     

Rate and equilibrium constants for Grignard reaction with alkoxysilanes and ketones

Kinetics of tetraethoxysilane reaction with n-butylmagnesium chloride, specifically solvated with dibutyl ether, diethyl ether, THF, and triethylamine, was studied in toluene. Also isopropylmagnesium chloride, isopropyltriethoxysilane, and diisopropylketone were involved in a similar investigation. The pseudo-first-order rate constants determined at a great excess of these organomagnesium compounds were used for separation of the appropriate equilibrium and rate constants. An advantage of the method consists in preclusion of non-specific solvation effects when effects of donor solvents are considered. In separate experiments, thermodynamic parameters were determined for rate and equilibrium constants, measured for the reaction of tetraethoxysilane with n-butylmagnesium chloride solvated with dibutyl ether in toluene, and also in bulk dibutyl ether. The implication of steric and solvation effects on this reaction is discussed.     

Template effects on the asymmetric cycloaddition reaction between 3,4-dimethyl-1-phenylarsole and diphenylvinylphosphine and their arsenic elimination reaction

The organopalladium complex containing ortho-metalated (S)-[1-(dimethylamino)ethyl]naphthalene as the chiral template was employed to promote the asymmetric cycloaddition reaction between 3,4-dimethyl-1-phenylarsole and diphenylvinylphosphine. It has been proven that the chiral template incorporating napthylamine is more efficient than the benzylamine based analogue as evidenced by the drastic improvement in stereoselectivity and reaction rate. However, when no chiral template was employed, trans-[PdI₂(3,4-dimethyl-1-phenylarsole)₂] reacted with trans-[PdI₂(diphenylvinylphosphine)₂] producing a structurally novel diiodo complex, as a result of an interesting selective cleavage of one As-C bond in the norbornene skeleton and subsequent rearrangements within the skeletal framework. The molecular structure of the diiodo product has been confirmed by X-ray crystallography. Structural analysis showed that in addition to the normal As-P five-membered ring, there is one new five-membered ring containing As-O bond being formed during the course of the reaction along with another seven-membered ring incorporating a hydroxy group.     

Complications in the Castagnoli-Cushman reaction: An unusual course of reaction between cyclic anhydrides and sterically hindered indolenines

Attempted reaction of indolenines (which represent rather sterically hindered cyclic imines) with a series of dicarboxylic acid anhydrides yielded no expected product, the Castagnoli-Cushman lactam. Instead, products presumably formed via N-acyliminium species trapping by a carboxylate anion. Among them, hydrolytically labile 2:2 adducts of an indolenine and a cyclic anhydride, containing a 16-membered cyclic core, are particularly intriguing. This result contradicts the recently reported successful Castagnoli-Cushman reaction of indolenines with homophthalic anhydride suggesting a mechanistic switch in the course of the reaction.     

Organocatalytic asymmetric cascade cyclization reaction of o-hydroxy cinnamaldehydes with diphenylphosphine oxide

A highly stereoselective asymmetric cascade cyclization reaction between o-hydroxycinnamaldehydes and diphenylphosphine oxide has been achieved with 84%-99% ee and 7:1-20:1 dr under the catalysis of L-prolinol silyl ether.     

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.     

Assessment of the regioselectivity in the condensation reaction of unsymmetrical o-phthaldialdehydes with alanine

One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogen-containing nucleophile. This fascinating reaction is revisited here in the context of the use of o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted o-phthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed across the eleven substrates led to the design of a disubstituted substrate that reacted with very high control. A gram-scale reaction followed by esterification gave one major regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel monodeuterated substrates led to an increased mechanistic understanding.     

Regioselective synthesis of 2,3-disubstituted 1-alkyl pyrrolo[2,3-b] quinoxalines through palladium-catalyzed Heck reaction of chalcones and evaluation of their anti-bacterial activities

The regioselective synthesis of 1-alkyl-2-aryl-3-acyl pyrrolo[2,3-b]quinoxalines through palladium-catalyzed Heck coupling reaction/heteroannulation was reported. The reaction of N-alkyl/benzyl-3-chloroquinoxaline-2-amines with chalcones catalyzed by Pd(OAc)₂ in the presence of KO^tBu, as the base, in DMSO afforded the desired products in good-to-high yields. The MIC and MBC determinations revealed that these compounds could be used in the future research works for the development of antibiotics.     

Synthesis of polyhydroquinoline derivatives through unsymmetric Hantzsch reaction using organocatalysts

A novel and green approach for efficient and rapid synthesis of polyhydroquinoline derivatives via unsymmetric Hantzsch reaction using organocatalysts at room temperature was reported. The process is a simple, environmentally friendly, rapid, and high yielding reaction for the synthesis of polyhydroquinoline derivatives. The catalytic efficiency of various small organocatalysts such as l-proline, trans-4-hydroxy-l-proline, l-thiaproline, dl-phenylglycine, and (−)-cinchonidine was studied under aqueous, organic, and solvent free conditions.     

Competitive thermal ene reaction and Diels-Alder reactions of 2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1,2-a]pyrimidin-4(4H)-ones

Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-3-(2-substituted and 2,2-disubstituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-ones gave azepine, the desired ene products, and/or pyran derivatives. The formation of the latter was responsible for the [4+2] cycloaddition reaction between the α,β-unsaturated ester carbonyl moiety as a diene part and the alkenylamino moiety as an ene one. The reaction features depended upon the kinds of substituents both on the vinyl and alkenyl counterparts; strongly electron-withdrawing substituents on the vinyl moiety or an electron-donating substituent on the alkenyl one changed the reaction feature from the ene reaction to the hetero Diels-Alder reaction.