Stereoselective synthesis of (R)- and (S)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acids, -carboxylates and -carboxamides

(R)-Monomethyl 2-methyl-2-(2-nitrophenoxy)malonates obtained by PLE catalyzed hydrolysis of the corresponding dimethyl malonates undergo solvent-dependent enantioselective cyclization to afford (R)-methyl 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates and (S)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acids, respectively. These compounds are easily converted to enantiomerically and diastereomerically pure carboxamides, which are used as peptidomimetic building blocks.     

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids 4a, b, 6a -e is presented. After the condensation of o-aminothiophenols with diethyl 2-bromo-2-methylmalonate in the presence of KF as a catalyst the nitrogen in the fused derivatives 3a, b , was alkylated to provide 5a-f , the corresponding esters 3a, b, 5a-f were hydrolysed.     

Synthesis of alkyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates as peptidomimetic building blocks

A general synthesis of new alkyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate peptidomimetic building blocks from the corresponding alkyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates through carbanion oxidation is described.     

Enantioselective synthesis of (R)- and (S)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamides

Enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamides bearing different substituents in the aromatic ring are obtained by the cyclization of (R)-monomethyl 2-methyl-2-(2-nitrophenoxy)malonates with the participation of the carboxy and methoxycarbonyl group, respectively.     

Synthesis of 2-Aryl-4-(R-sulfanylmethyl)-3-methyl-6,7-dihydro-2<Emphasis Type="Italic">H</Emphasis>-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyridazin-7-ones

Bromination of ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates gave ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazol-3-carboxylates which were used to alkylate benzenethiol and heterocyclic thiones at the sulfur atom. Reactions of the resulting S-alkylation products with hydrazine or methylhydrazine involved closure of pyridazine ring to afford 2-aryl-3-methyl-4-[phenyl(or hetaryl)sulfanylmethyl]-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones.     

Stereoselective synthesis of 2-alkylidene-3,4-dihydro-3-oxo-2h-1,4-benzothiazines

Metallation of 4-methyl-3,4-dihydro-3-oxo--2H-1,4-benzothiazine with LDA and subsequent reaction with aldehydes leads to diastereomeric aldols 4 and 5. Acetylation followed by acetic acid elimination of the aldols provides a stereoselective and high yield route to 2-alkylidene-3,4-dihydro-3-oxo-2H-1,4-benzothiazines.     

Microwave-assisted one-pot regioselective synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines

A protocol for regioselective one-pot synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines under controlled microwave heating has been developed. Starting from commercially available 2-aminophenols, a base-mediated regioselective O-alkylation took place with 2-bromoalkanoates to give the acyclic intermediates, which underwent spontaneously an intramolecular amidation reaction to furnish 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines in 44-82% yields. For the acyclic intermediate possessing an electron-withdrawing group, microwave heating was necessary for the annulation reaction.     

A pentacyclic condensation product from 2,4-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

2,4-Dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid on preparation of a mixed anhydride, followed by reduction with sodium borohydride, affords 5,7a,13,13b-tetramethyl-2,10-dinitro-5a,7,7a,13,13a,13b-hexahydro-5H-[1,4]benzoxazino[3′,2′:4,5]pyrano[3,2-b][1,4]benzoxazine (3), the structure of which was established unambiguously by X-ray analysis.     

Spiro[(2,3-dihydro-2-oxo-imidazo[1,2-a]pyridine)-3,3-(3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide)]-A novel product derived from piroxicam

A novel compound, spiro[(2,3-dihydro-2-oxo-imidazo[1,2-a]pyridine)-3,3-(3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide)] (3) , was isolated during an attempt to convert 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide ( 1 ) (Piroxicam) to an O-trifluoromethanesulfonyl ester. A possible mechanism is offered to explain this unusual transformation.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of N,N-disubstituted 4-amino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides and of 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 3-amino-2-methyl-1-phenyl-2-propen-1-ones (I) and 3-amino-1,2-diphenyl-2-propen-1-ones (II) occurred in good to moderate yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides. Polar 1,4-cycloaddition of dichloroketene to I and II occurred only in the former case, giving in good to moderate yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-5-methyl-6-phenyl-2H-pyran-2-ones which were dehydrochlorinated with DBN to N,N-disubstituted 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones. In the reaction of 2-methyl-1-phenyl-3-diphenylamino-2-propen-1-one with dichloroketene, a product was isolated which was proven by uv, ir, nmr and chemical evidence to be the dipolar ion VI, the supposed intermediate of the polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted enaminones.     

Conformationally tailored N-[(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)carbonyl]proline templates as molecular tools for the design of peptidomimetics. Design and synthesis of fibrinogen receptor antagonists

The proline peptide bond was shown by 2D proton NMR studies to exist exclusively in the trans conformation in benzyl (2S)-1-[[(2S)-2-methyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-11], benzyl (2S)-1-[[(2S)-2-methyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-9], and in the corresponding 6-amino and 7-amino carboxylic acids (S,S)-3 and (S,S)-4. On the other hand, the diastereomers (R,S)-11 and (R,S)-9 containing an (R)[2-methyl-6/7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety, and the diastereoisomers (R,S)-3 and (R,S)-4 incorporating an (R)[6/7-amino-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety were found to exist as equilibria of trans(63-83%) and cis(17-37%) isomers. These conformationally defined templates were applied in the construction of RGD mimetics possessing antagonistic activity at the platelet fibrinogen receptor.     

Five-membered 2,3-dioxoheterocycles: LVIII. Reaction of methyl 1-Aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrol-2-carboxylates with substituted 1-methyl-3,4-dihydroisoquinolines. New approach to the synthesis of steroid 13-azaanalogs

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with substituted 1-methyl-3,4-dihydroisoquinolines with the formation of substituted 3-oxo-2,3,5,6-tetra-hydropyrrolo[2,1-a]-isoquinoline-2-spiro-2′-(1-aryl-3-aroyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrroles). A new approach was developed to the synthesis of 13-azagonanes, substituted benzo[f]pyrrolo[2,1-a]isoquinoline-9-spiro-2′-pyrroles.     

Applying density functional theory on tautomerism in 3,4-dihydropyrimidin-2(1H)-ones

In the present study, the density functional theory (DFT) and Gibbs free energy calculations were performed to investigate the stability and tautomerism of C4-substituted-3,4-dihydropyrimidin-2(1H)-ones. Three different forms are possible for the ethyl 3,4-dihydropyrimidinones (ethyl 4-aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-one-5-carboxylates, ethyl 4-aryl-2-hydroxy-6-methyl-1,4-dihydropyrimidine-5-carboxylates and ethyl 4-aryl-2-hydroxy-6-methyl-3,4-dihydropyrimidine-5-carboxylates) forms that the most stable form is ethyl 4-aryl-6-methyl-3,4-dihydropyrimidin-2 (1H)-one-5-carboxylates (keto-form). The obtained data showed that the substitution on the C4-substitut position can be effective on the equilibrium constant (K _eq).     

Transformations of methyl 6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinylacetate under oxidative conditions

The oxidation of methyl 6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinylacetate by reagents which oxidized the SMe group to SO₂Me gave the products of the further transformation of the corresponding 2-methylsulfonyl-substituted ester obtained: methyl 5,5-dichloro-6-methoxy-6-methyl-2,4-dioxohexahydro-3-pyrimidinylacetate (using Cl₂ in 70 or 50% MeOH), its mixture (about 1:10) with methyl 6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinylacetate (Cl₂ in 30% MeOH) or only to the latter compound (Cl₂ in H₂O, m-ClC₆H₄CO₃H in CHCl₃, H₂O₂ in MeOH). The reaction did not take place with NaOCl in DMF. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 901–905, June, 2006.     

Unambiguously confirmed structure of 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

To determine the structures of two isomeric products, 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (2) and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3) obtained by condensation of 2,3-diaminopyridine (1) with ethyl benzoylpyruvate [1–3], these compounds were hydrolyzed to give 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (4) and 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (5) , respectively [4,5]. Both hydrolysates 4 and 5 were hydrogenated to afford 2-methyl-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (6) and 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (7) . The latter compound was identical with an unequivocally synthesized compound providing proof for the structures of all these compounds.     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.     

4-Substituted-3,4-dihydro-3-methyl-2H-1,3-benzoxazin-2-ones. III (2,3). Solvolytic-reductive transformation of 4-(2-keto)-benzoxazin-2-ones into oxazin-2-ones

A series of 4-(2-keto-substituted)-3,4-dihydro-3-methyl-2H-1,3-benzoxazin-2-ones 1 (Table I) was synthesized by condensation of 3-alkyl-3,4-dihydro-4-hydroxy-2H-1,3-benzoxazin-2-ones 4 with ketones 5 having active alpha hydrogens. In the presence of alcoholic potassium borohydride, compounds 1 underwent reductive transacylation to give 1,3-oxazin-2-one derivatives 3 (Table III, a,b,c). When the other side of the ketone possessed substituents other than hydrogen, there were always also normal reduction products, i.e., secondary alcohols 2 (Table II) in addition to 3.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides and of N,N-disubstituted 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 4-amino-3-phenyl-3-buten-2-ones (III) occurred in good yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides, whereas N,N-disubstituted 4-amino-1-phenyl-3-buten-2-ones (IV) did not react at all. Polar 1,4-cycloaddition of dichloroketene to III and IV occurred partly in the case of aromatic N-substitution, with the exception of the morpholino derivative IVd, giving in low yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones (VII) in good yield. In some cases of aliphatic N,N-disubstitution of III and IV, cycloaddition led directly to N,N-dialkyl derivatives VII in low yield.     

Ethyl 5-amino-3-oxo-1,2-dihydro-1H-pyrazole-1-carboxylate in the selective synthesis of partially hydrogenated pyrazolo[3,4-b]pyridin-3-ones

Ethyl 5-amino-3-oxo-1,2-dihydro-1H-pyrazole-1-carboxylate undergoes selective cyclocondensation with 1,3-dicarbonyl compounds or their synthetic equivalents to give ethyl 3-oxo-1,2-dihydro-pyrazolo[3,4-b]pyridine-1-carboxylates which are readily converted to their 1-unsubstituted analogs.     

Synthesis and antiherpetic activity of novel purine conjugates with 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine

Chemistry of Heterocyclic Compounds - A method for the synthesis of novel purine conjugates with 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine containing fragments of ω-amino acids with...