Facile synthesis of novel 5-amino 1,3-disubstituted tetrahydropyrimidinones

The synthesis of novel, 5-amino 1,3-disubstituted tetrahydropyrimidinones, and 5-aminobarbiturates are presented.     

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.     

Facile synthesis of substituted isoquinolines

A facile three-step protocol toward methoxy isoquinolines 7 starting with substituted 2-allylbenzaldehydes 9 was described. The overall synthetic process of skeleton 7 was carried out using the Grignard addition, PCC-oxidation, and one-pot oxidative cleavage of the olefinic group of skeleton 9 with OsO₄–NaIO₄ followed by the condensation of the resulting 1,5-dicarbonyl compounds with NH₄OAc. Skeleton 9 was prepared in high yield via the known Claisen rearrangement of skeleton 8 and O-methylation. Papaverine 2 is also synthesized via the simple three-step synthetic protocol.     

Facile synthesis of substituted pyrrole-fused isocoumarins from ninhydrin

A simple and efficient procedure has been developed for the synthesis of substituted pyrrole-fused isocoumarins from easily available ninhydrin. The cyclic hemiaminal dihydroxy-indenopyrroles, the adducts of ninhydrin with enamines of acetylacetone, give pyrrole-fused isocoumarins upon heating in acidic medium. The process constitutes an interesting acid-catalyzed rearrangement to eight-membered lactams followed by intramolecular cyclization involving the amino and keto groups.     

An efficient regioselective copper catalyzed multi-component synthesis of 1,3-disubstituted pyrazoles

An efficient synthesis of unsymmetrically substituted 1,3-pyrazole derivatives has been developed via three-component coupling reaction involving 3-(dimethylamino)-1-phenylprop-2-en-1-one, hydrazine, and aryl halides in one pot process exhibiting high regioselectivity. The pyrazole synthesis proceeds via a sequential series of reactions such as Michael addition, heterocyclization, dehydration, and Ullmann cross-coupling.     

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.     

An effective BINAP and microwave accelerated palladium-catalyzed amination of 1-chloroisoquinolines in the synthesis of new 1,3-disubstituted isoquinolines

A facile and microwave accelerated reaction of 1-chloro-3-(4-chlorophenyl)isoquinoline with various heterocyclic amines, catalyzed by Pd, in the presence of BINAP additive and sodium carbonate as the base, leads to the formation of 3-(4-chlorophenyl)-1-(1H-1,2,3-triazol-1-yl)isoquinoline, 3-(4-chlorophenyl)-1-(1H-imidazol-1-yl)isoquinoline and 3-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)isoquinoline via Buchwald protocol in good yields. Similarly pyrazolylisoquinolines are also reported.     

Facile and convenient synthesis of 2,6-disubstituted 4H-1,3-oxazin-4-one derivatives

Facile and convenient methods for the preparation of a variety of 2,6-disubstituted 4H-1,3-oxazin-4-ones 3 by three complementary methods are described. Treatment of the branched aliphatic imidate 2c,d with diketene 1 in the presence of a catalytic amount of acetic acid affords 2-substituted 6-methyl-1,3-oxazin-4-ones 3c,d , whereas the unbranched imidate 2b,e gave oxazines 3b,e and pyrimidines 4b,e (Method A). The reaction of acyl Meldrum's acid 5 with imidate 2 afford 2,6-disubstituted oxazine 3, though the alkylimidate with acetyl Meldrum's acid yielded 3 and 5-acetyl-1,3-oxazine-4,6-dione 8 (Method B). The cylodehydration of acylacetylcarboxamide 13 with acid, such as 70% perchloric acid or fluorosulfonic acid, afforded 1,3-oxazines 3 (Method C).     

Highly efficient enantioselective synthesis of 1,3-disubstituted 2,5-diketopiperazine derivatives via microwave irradiation

Abstract

Chiral 2,5-diketopiperazine (2,5-DKP) derivatives have a broad range of biological activities in the medicinal field. The synthetic protocols of 1,3-disubstituted 2,5-DKPs via base-catalyzed cyclization of chloroacetamide have been reported. However, there are several drawbacks, such as an overly long reaction time, low to moderate yield, and racemization of the products. The sequence modified herein of 1,3-disubstituted 2,5-DKPs involves microwave-assisted cyclization. It increases yields and reduces reaction time. Furthermore, employing N-PMB protection prevents racemization, which frequently occurs in the base-catalyzed cyclization reaction. Consequently, the rapid synthetic method of enantiomerically pure 1,3-disubstituted 2,5-DKPs via microwave reaction was established successfully.     

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.     

Stereoselective synthesis of 1,4-disubstituted 1,3-diene

New synthetic methods for the preparation of 1,3-dienes are described.     

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.     

Short and efficient synthesis of coronene derivatives via ruthenium-catalyzed benzannulation protocol

[reaction: see text] TpRuPPh3(CH3CN)2PF6 (3 mol %) was very active in catalytic benzannulation of 1-phenyl-2-ethynylbenzenes in dichloroethane (60 degrees C, 36 h) to afford phenanthrene in 95% yield. This method is applicable to the synthesis of various polycyclic aromatic hydrocarbons via two- and four-fold benzannulations, including various substituted coronene derivatives (53-86% yields) using this catalyst at a moderate loading (10 mol %).     

A stereospecific synthesis of chiral 1,3-disubstituted bromoallenes

Optically active 1, 3-disubstituted propargyl alcohols undergo S_Ni′ rearrangements with thionyl bromide in the presence of propylene oxide to yield bromoallenes without loss of optical purity.     

Allene cross-metathesis: synthesis of 1,3-disubstituted allenes

[reaction: see text] Grubbs catalyst, Cl2(Cy3P)2Ru=CHPh, was found to catalyze the cross-metathesis of monosubstituted allenes to 1,3-disubstituted allenes in varying yields.     

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).     

A convenient method of synthesis of 1,3-disubstituted pyrroles

A method has been proposed for the detosylation of 3-substituted pyrroles by potassium in tetrahydrofuran with a simultaneous activation of the 1-position for the subsequent alkylation or acylation of the pyrrolepotassium derivative.Translated from Khimiya Geterotsiklicheskih Soedinenii, No. 5 pp. 634–635, May, 1991,