Yu. V. Shklyaev

Synthesis of 1(2H)-Isoquinolones. (Review)

Methods published over the last 10 years for the production of substituted 1(2H)-isoquinolones, including those involving the use of organometallic compounds, are discussed.

Three-component synthesis of 3,4-dihydroisoquinoline derivatives

A simple and convenient method for the synthesis of 1-substituted 3,3-dimethyl-3,4-dihydroisoquinolines was developed. The method is based on the [2+2+2] cyclization of alkyl- or alkoxybenzenes with isobutyraldehyde and nitriles.

Synthesis and Rearrangement of 1-Substituted 3,3,7-Trimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

We previously synthesized 3,3-dimethyl-1-methylthio-2-azaspiro[4.5]deca-1,6,9-trien-8-one by threecomponent condensation of anisole, 1,2-epoxy-2methylpropane, and nitriles in the presence of concentrated sulfuric acid [1]. An analogous result was obtained in the reaction of anisole with isobutyraldehyde and nitriles [2]. Taking into account that the product composition strongly depends on the nature and position of substituents in the aromatic ring [3], we thought it reasonable to examine the same transformation of anisole homologs, in particular of methyl o-tolyl ether. We have fount that introduction of a methyl group into the ortho-position of anisole does not change the reaction direction. Addition of an equimolar mixture of methyl o-tolyl ether, isobutyraldehyde, and methyl thiocyanate to concentrated sulfuric acid at 035oC, followed by dilution of the reaction mixture with cold water and neutralization of the aqueous phase with ammonium carbonate, leads to formation of 3,3,7-trimethyl-1-methylthio-2-azaspiro[4.5]deca1,6,9-trien-8-one (IIa) in 67% yield. The isolated product was a single enantiomer whose configuration was not determined. The presence of an asymmetric spiro-carbon atom in molecule IIa is confirmed by the H NMR spectrum, where splitting of signals from diastereotopic protons of the CH2 and 3-CH3 groups is observed. Spiro compounds IIb and IIc, formed in the reactions with ethyl cyanoacetate and cyanoacetamide, undergo dienone3phenol rearrangement during isolation. As a result, amides III and IV were obtained. The relatively ready hydrolysis of structurally related ____________ * This study was financially supported by the Russian Foundation for Basic Research (project no. 01-03-96 479). spiro compounds with carbonyl-containing groups (derived from anisole) was noted by us previously [4]. 3,3,7-Trimethyl-1-methylthio-2-azaspiro[4.5]deca-1,6,9-trien-8-one (IIa). A mixture of 12.2 g (0.1 mol) of methyl o-tolyl ether, 7.2 g (0.1 mol) of isobutyraldehyde, and 7.3 g (0.1 mol) of methyl thiocyanate was added dropwise over a period of 15320 min to 50 ml of 96% sulfuric acid stirred at 035oC. The mixture was stirred for 30 min, poured into 300 ml of water, and extracted with 50 ml of toluene. The aqueous phase was separated and neutralized with (NH4)2CO3 to pH 839. The precipitate was filtered off, washed with water, dried, and recrystallized twice from methanol. Yield 15.75 g (67%), mp 63364oC. IR spectrum, n, cm: 1660 (CIO), 1630 (CIC), 1605 (CIN), 1580. H NMR spectrum, d, ppm: 1.36 s and 1.39 s (6H, 3-CH3), 1.82 s (3H, 7-CH3), 2.18 s and 2.20 s (2H, 4-H),

Five-membered 2,3-dioxoheterocycles: LXIV. Reactions of 1-methyl-3,4-dihydroisoquinolines with 5-arylfuran-2,3-diones and (Z)-alkyl 4-aryl-2-hydroxy-4-oxobut-2-enoates. Crystal and molecular structure of (2Z,5Z)-3-hydroxy-5-{8,8-dimethyl-2,3,8,9-tetrahydro[1,4]dioxino[2,3-g]isoquinolin-6(7H)-ylidene}-1-phenylpent-2-ene-1,4-dione

Abstract5-Arylfuran-2,3-diones and (Z)-alkyl 4-aryl-2-hydroxy-4-oxobut-2-enoates react with 3,3-dialkyl-1-methyl-3,4-dihydroisoquinolines to give (2Z,5Z)-1-aryl-3-hydroxy-5-[3,3-dialkyl-3,4-dihydroisoquinolin-1(2H)-ylidene]pent-2-ene-1,4-diones whose structure has been proved by XRD analysis.

Synthesis of 1-substituted 2-azaspiro[4.5]deca-6,9-dien-8-ones and 2-azaspiro[4.5]deca-1,6,9-trien-8-ones by condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles

Abstract1-Substituted 3,3,7,9-tetramethyl-2-azaspiro[4.5]deca-6,9-dien-8-ones and 3,3,7,9-tetramethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized by three-component condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles in concentrated sulfuric acid.

Synthesis and Antiinflammatory and Analgesic Activity of 2H-3,3-Dimethyl-3,4-dihydroisoquinolin-1-ones

The reactions of substituted arenes with isobutyric aldehyde and methylthiocyanate yield 1-methylthio-3,4-dihydroisoquinolines. The subsequent treatment with AcOH/AcONa yields 2H-3,3-dimethyl-3,4-dihydroisoquinolin-1-ones, some of which exhibit pronounced antiinflammatory and analgesic properties.

Synthesis and antiinflammatory and analgesic activity of amidines of 3,4-dihydroisoquinoline series

A series of substituted 1-arylamino-3,4-dihydroisoquinolines have been synthesized using reactions of 1-methylthio-3,3-dimethyl-3,4-dihydroisoquinolines with substituted anilines and 2-aminothiazoles. The products were tested for analgesic and antiinflammatory activity.

Five-membered 2,3-dioxo heterocycles: LXIX. Direct heterocyclization of [3,4-dihydroisoquinolin-1(2H)-ylidene]-acetamides with 5-arylfuran-2,3-diones. Crystalline and molecular structure of (3E,5Z)-3-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]-5-(2-oxo-2-phenylethylidene)pyrrolidine-2,4-dione

Abstract5-Arylfuran-2,3-diones react with (Z)-2-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]acetamides to give (3E,5Z)-5-(2-aryl-2-oxoethylidene)-3-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]-pyrrolidine-2,4-diones. The crystalline and molecular structures of one of the products were determined by X-ray analysis.

Reactions of polyfluorocarbonyl compounds with 1,3,3-trimethyl-3,4-dihydroisoquinoline and its derivatives

Abstract1,3,3-Trimethyl-3,4-dihydroisoquinolines, which exist in the imine form, undergo C- hydroxyalkylation upon reaction with hexafluoroacetone and esters of trifluoropyruvic acid at the C1 CH3 group at 20°C. The products with the ketoesters are converted upon heating to γ-lactams. Derivatives of 1,3,3-trimethyl-3,4-dihydroisoquinoline substituted at C1 CH3 group and existing in the enamine form, react with esters of trifluoropyruvic acid at 20°C to give exclusively γ-lactams and do not give reaction products with hexafluoroacetone.

Synthesis, crystal structure, and spectra of 9(E)-phenanthrene-9,10-dione[(1Z)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]hydrazone and its cation-anion complex with copper(I) bromide

The reaction of 1-hydrazino-3,3-dimethyl-3,4-dihydroisoquinoline with 9,10-phenanthrenequinone gave (9E)-phenanthrene-9,10-dione[(1Z)-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]hydrazone (L). The reaction of L with copper(II) bromide gave the complex (LH)[CuBr2]. The crystal structures of the monohydrate L · H2O (I) and the isolated complex (LH)[CuBr2] (II) were determined by X-ray diffraction. The structural units of I are pseudo-centrosymmetric dimers in which the L and water molecules are combined by strong hydrogen bonds. The active H atom is located at the N(1) atom of the isoquinoline fragment of the L molecule. The L molecule occurs in the crystal as the cis, trans isomer with respect to exocyclic C=N bonds at the isoquinoline and phenanthrenequinone fragments, respectively. Complex II has a cation-anion structure. The LH+ cation as the cis, cis isomer is protonated at N(2) and stabilized by two intramolecular hydrogen bonds. In the CuBr2− anion, the copper atom in the oxidation state +1 has a linear coordination, the C-Br bond length is 2.185(4) ± 0.005 Å, and the BrCuBr angle is 179.8(4)°. The main ion-ion interactions in structure II are shortened contacts involving bromine atoms, which combine cations and anions into a three-dimensional framework.