Direct asymmetric Mannich reaction of phthalides: facile access to chiral substituted isoquinolines and isoquinolinones

The first Mannich reaction employing phthalides using a quinidine-based multifunctional catalyst has been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in excellent yields, with good diastereo- and enantioselectivities. Convenient synthesis of chiral isoquinolinones and isoquinolines has also been demonstrated.     

Enantioselective iridium-catalyzed hydrogenation of 3,4-disubstituted isoquinolines

Reining in the outliers: An efficient approach for enantioselective hydrogenation of 3,4-disubstituted isoquinolines was successfully developed. When isoquinolines are treated with [Ir(cod)Cl](2) /(R)-synphos in the presence of 1-bromo-3-chloro-5,5-dimethyl-hydantoin (BCDMH), the chiral 3,4-disubstituted tetrahydroisoquinoline derivatives are obtained with ee?values as high as 96?% (see scheme; cod=1,5-cyclooctadiene).     

Hydrolysis of 2-substituted and 1,2-disubstituted imidazolines

The mechanism and kinetics of hydrolysis of 2-substituted and 1,2-disubstituted imidazolines in acid, neutral, and alkaline solutions were studied. The influence of the substituents at the 1-and 2-positions of the imidazoline ring on the hydrolytic resistance of these compounds was demonstrated.     

Iridium-catalyzed asymmetric trans-selective hydrogenation of 1,3-disubstituted isoquinolines

The development of the first asymmetric trans-selective hydrogenation of 1,3-disubstituted isoquinolines is reported. Utilizing [Ir(cod)Cl]₂ and a commercially available chiral Josiphos ligand, a variety of differentially substituted isoquinolines are hydrogenated to produce enantioenriched trans-tetrahydroisoquinolines in good yield with high levels of enantioselectivity. Directing group studies demonstrate that the hydroxymethyl functionality at the C1 position is critical for hydrogenation to favor the trans-diastereomer. Preliminary mechanistic studies reveal that non-coordinating chlorinated solvents and halide additives are crucial to enable trans-selectivity.

trans-Selective asymmetric hydrogenation of 1,3-disubstituted isoquinolines.     

Dual reactivity of 1,2-disubstituted dihydro-N-heteroaromatic systems. 2. Mechanism of the dehydrogenation of N-acyldihydroquinolines and isoquinolines with 2,2,6,6-tetramethyl-1-oxopiperidinium perchlorate

The mechanism of the heterolytic dehydrogenation of various N-acyl derivatives of -substituted 1,2-dihydroquinolines and isoquinolines with 2,2,6,6-tetramethyl-1-oxopiperidinium perchlorate was investigated.See [1] for Communication 1.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 78–84, January, 1981.     

Dual type of reactivity op 1,2-disubstituted dihydro-N-heteroaromatic systems. 11. Aromatization of N-sulfonyl-1,2-dihydroquinolines and isoquinolines containing an α-indolyl or pyrrolyl substituent

When N-sulfonyl-1,2-dihydroquinolines and isoquinolines, containing an indolyl or pyrrolyl substituent at the -position, react with trityl perchlorate, this substituent is split off, and N-sulfonyl quinolinium and isoquinolinium cations and tritylindole or tritylpyrrole are formed. A similar reaction with 2,2,6,6-tetramethyl-1-oxopiperidinium perchlorate proceeds with splitting of hydrogen or retention of the -substituent, which leads to the corresponding -substituted N-sulfonylquinolinium and isoquinolinium cations.For Part 10, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1516–1518, November, 1986.     

Metal-free synthesis of 3,3-disubstituted oxindoles via 1,2-alkylarylation of activated alkenes with alcohols

Metal-free synthesis of 3,3-disubstituted oxindoles utilizing N-arylacrylamides and simple alcohols is developed. It provides an efficient method for preparing a series of hydroxyl-containing oxindole derivatives. This reaction is proposed to proceed through oxidative radical cyclization mechanism. The remarkable features of the reaction are metal-free condition and excellent functional group tolerance.     

Nucleophilic substitutions on bromotriazolopyridines - an improved route to 2,6-disubstituted pyridines and to 1,3-disubstituted isoquinolines

A regiospecific synthesis of 2,6-disubstituted pyridines and of 1,3-disubstituted isoquinolines is described.     

Aromatization reactions of some N-acyl-1,2-dihydroquinolines and isoquinolines

The proton and hydride lability of the -hydrogen atom in various -substituted N-acyl-1,2-dihydroquinolines and N-acyl-1,2-dihydroisoquinolines was investigated. It was shown that splitting out of both a hydride ion and an -substituent as carbanions is possible in the presence of strong electron-acceptor substituants in the position under the influence of electrophilic agents. A new transhetarylation reaction consisting in the migration of the heterocyclic residue from one compound with a labile hydrogen atom to another was found.Communication XVII of the series Reactions of Cyclic Ammonium Cations; see [1] for the previous communication.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 529–533, April, 1972.     

Cross-coupling reaction on N-(3,5-dibromo-2-pyridyl)piperazines: regioselective synthesis of 3,5-disubstituted pyridylpiperazines

Unsymmetrical 3,5-disubstituted pyridylpiperazines were prepared from tribromopyridine in three coupling reactions. Key to the success of the syntheses is the palladium-catalyzed regioselective cross-coupling reaction in the 3-position of N-(3,5-dibromo-2-pyridyl)piperazines.     

First example of ring expansion of activated quinolines and isoquinolines: novel benzoazepines

Activated quinoline and isoquinoline undergo unexpected ring expansion by diazocarbonyl compounds via C-C insertion in the presence of 5 mol% of copper triflate to produce ethyl 1H-benzo[b]azepine-1-carboxylate and ethyl 3H-benzo[d]azepine-3-carboxylate, respectively, in excellent yields with a high degree of selectivity     

Diastereoselective and enantioselective synthesis of 1,2-disubstituted cycloalkanecarboxaldehydes

A highly useful method for diastereoselective and enantioselective synthesis of trans- and cis-1,2-disubstituted cycloalkanecarboxaldehydes (trans- and cis-10), useful chiral synthons having asymmetric tertiary and quaternary carbon atoms in vicinal positions in their rings, is devised starting from cycloalkenecarboxal-dehydes (5) t-Leucine t-butyl ester (2, R=Bu^t), a highly effective chiral auxiliary reagent in the present method, can be recovered for recycling without any loss of optical purity Some mechanistic explanations on the stereochemical courses of the reactions are presented     

Regio- and chemoselective addition of alkynyltin reagents to the 2-position of 3-acylpyridines activated by methyl chloroformate: selective synthesis of 2,3-disubstituted 1,2-dihydropyridines

Alkynyltin reagents add to the 2-position of 3-acylpyridines activated by methyl chloroformate regio- and chemoselectively to give 2,3-disubstituted 1,2-dihydropyridines, whereas alkynyl Grignard reagents suffer from a lack of regio- or chemoselectivity.     

Copper-catalyzed tandem synthesis of [1,2,3]triazolo[5,1-a]isoquinolines and their transformation to 1,3-disubstituted isoquinolines

2-Azido-3-(2-iodophenyl)acrylates react with terminal alkynes in the presence of a copper(II) catalyst without ligands to give a wide range of [1,2,3]triazolo[5,1-a]isoquinolines in good yields. These compounds favor expulsion of N₂ in refluxed acetic acid to form 1,3-disubstituted isoquinolines. The procedure is simple, economical, and efficient.     

Synthesis and antitumor evaluation of some 1,3-disubstituted tetrahydropyrimido[4,5-c]isoquinolines

Cyclocondensation of 6-amino-2,4-dioxopyrimidine or 2,4,6-triaminopyrimidine with 1-cyclohexenecarbox-aldehyde 13 afforded regiospecifically, tricyclic, angular 1,3-disubstituted tetrahydropyrimido[4,5-c]isoquin-olines 5 and 6 respectively. In addition, 2,4,6-triaminopyrimidine when condensed with 2-chloro-1-cyclohex-enecarboxaldehyde 14 , regiospecifically afforded the angular isomer 6 . However, the cyclocondensation of 2,6-diamino-4-oxopyrimidine with 13 was regioselective and afforded a mixture of the linear and angular tetrahydropyrimidoisoquinolines 2 and 4 . The growth of leukemia L-1210 cells in culture were inhibited 50% by 6 at 9 × 10^?8 M. Compounds 4 and 5 were not significantly active.     

Synthesis of 3,4-disubstituted isoquinolines via palladium-catalyzed cross-coupling of 2-(1-alkynyl)benzaldimines and organic halides

The palladium-catalyzed cross-coupling of readily available N-tert-butyl-2-(1-alkynyl)benzaldimines and aryl, allylic, benzylic, alkynyl halides, as well as a vinylic halide, provides a valuable new route to 3,4-disubstituted isoquinolines with aryl, allylic, benzylic, 1-alkynyl, and vinylic substituents, respectively, in the 4-position. The reaction appears to require an aryl group on the end of the acetylene furthest from the imine functionality. The reaction conditions have been optimized, and reasonably good yields have been obtained.     

Dual reactivity of 1,2-disubstituted dihydro-N-heteroaromatic systems

The effect of the nature of the electrophile and the heteroring on the direction of reactions involving the aromatization of -substituted N-acyl dihydro-N-heterocycles with perchlorates of various organic cations was studied. It is shown that hard and intermediate electrophilic agents (triphenylmethyl, triindolylmethyl, and acetylium perchlorates) split out the substituent from the dihydroheterocycles to give stable N-acyl salts of the corresponding bases. Soft acceptors (2,2,6,6-tetramethyl-1-oxopiperidinium perchlorate) split out a hydride ion in all cases to give -substituted N-acyl salts of the corresponding bases.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 946–950, July, 1979.