Synthetic and structural studies of some chloro-substituted methyl 2,1-benzisoxazole-3-carboxylates and related compounds

Methyl 5-chloro- and 5,7-dichloro-2,1-benzisoxazole-3-carboxylates have been synthesized by treatment of o-nitromandelic and 5-chloro-2-nitroamandelic methyl esters, respectively, with thionyl chloride under appropriate reaction conditions. The structural assignments of both heterocyclic products were based on elemental and spectral analyses, and their conversion to the corresponding 5-chloro- and 5,7-dichloro substituted 2,1-benzisoxazole-3-carboxylic acids and isatins. Methyl α-chloro-o-nitrophenylacetate and o-nitrophenylcarbomethoxymethinyl sulfite were also obtained from reactions of methyl o-nitromandelate and thionyl chloride. A possible reaction mechanism involving two consecutive nucleophilic substitutions of methyl o-nitromandelate with thionyl chloride was proposed to account for the formation of methyl 5-chloro-2,1-benzisoxazole-3-carboxylate.     

Reaction of methyl 3-phenyl-3-chloro-2-oxopropionate with thiosemicarbazones

The reaction of methyl 3-phenyl-3-chloro-2-oxopropionate with thiosemicarbazones proceeds via the intermediate formation of methyl [S-(1-alkylideneisothiosemicarbazidyl)]-3-phenyl-2-oxopropionate hydrochlorides, which then cyclize to novel 4-methoxycarbonyl-5-phenyl-2-substituted thiazoles. Hydrolysis of the intermediate products and the thiazoles obtained therefrom with simultaneous distillation of the carbonyl compound affords 2-hydrazino-4-methoxy-carbonyl-5-phenylthiazole.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1422–1426, June, 1991.     

Unique regio- and stereoselectivity in Pd-catalyzed chlorocarbonylation reaction of 2-phenylethynyl selenides and 2-alkylethynyl selenides. Highly stereoselective synthesis of 2-seleno-3-chloroacrylates

Regio- and stereoselectivity in the chloropalladation carbonylation reaction of different acetylenic selenides in the presence of 0.05 equiv of PdCl2 and 3 equiv of cupric chloride under 1 atm of carbon monoxide affording 2-seleno-3-chloroacrylates were investigated. Opposite stereoselectivities were observed with 2-phenylethynyl selenides and 2-alkylethynyl selenides: the reactions of 2-phenylethynyl selenides afforded (E)-2-seleno-3-chloro-3-phenylacrylates, while the reactions of 2-alkylethynyl selenides gave (Z)-2-seleno-3-chloro-3-alkylacrylates. A chloropalladation carbonylation mechanism for this reaction was proposed. The regio- and stereoselective chloropalladation of the carbon-carbon triple bond in acetylenic selenides affords 1-enylpalladium intermediates, in which the palladium atom connects with the carbon atom bonding with the selenium atom. Carbonylation in the presence of an alcohol affords 2-seleno-3-chloroacrylates.     

Reactions of arenediazonium tetrafluoroborates with 3-chloro-2-methylpropene in the presence of potassium chloride,bromide, and thiocyanate

Arenediazonium tetrafluoroborates reacted with 3-chloro-2-methylpropene in the presence of potassium chloride, bromide, and thiocyanate to give the corresponding 1-aryl-3-chloro-2-halo(thiocyanato)-2-methylpropanes. The presence of a copper salt is a necessary condition for the reaction to occur. The yields of the corresponding 1-aryl-3-chloro-2-halo-2-methylpropanes in the Meerwein reaction were approximately twice as low. Introduction of a methyl group to C2 in the 3-chloropropene molecule does not change the reaction regioselectivity.     

A novel synthesis of 5-chloro-3-methoxycarbonyl-1-arylpyrazoles from arylazomethylenetriphenylphosphoranes

The reaction of arylazomethoxycarbonylmethylenetriphenylphosphoranes 1 with chloroform and sodium hydroxide in the presence of benzyltriethylammonium chloride (TEBA) as phase transfer catalyst directly affords 5-chloro-3-methoxycarbonyl-1-arylpyrazoles 3 .     

Étard reaction—III Oxidation of N-propylbenzene and methylcyclohexane with chromyl chloride

Étard oxidation of n-propylbenzene yields a number of products among which benzaldehyde, methyl benzyl ketone, propiophenone, 1-chloro-1-phenylpropane, 1-phenylpropan-1-ol, 1-phenyl-1-chloropropan-2-one and 1-phenyl-2-chloropropan-1-one were identified. The same products were obtained by treatment of 1-phenylpropene and 1,2-epoxy-1-phenylpropane with chromyl chloride. Presumably all these compounds result from a common intermediate possessing an epoxide like structure. The oxidation by chromyl chloride of methylcyclohexane also leads to a larger number of products than previously known, namely: 1-methyl-1-cyclohexanol, hexahydrobenzaldehyde, 1-methylcyclopentylaldehyde, 2-methylcyclohexanone and 1-methyl-1-chlorocyclohexan-2-one. The last three compounds were produced also in the reaction of 1-methylcyclohexene with chromyl chloride. The mechanism of these reactions is discussed.     

3-Chloroalkylfurans in the reaction with sodium diethyl phosphite

Reduction of 3-acylfurans with lithium alumohydride in ether yields stable secondary alcohols. By treatment with thionyl chloride in the presence of pyridine, they are converted to the corresponding chlorides. 3-(1-Chloroethyl)furan and 5-methyl-3-(1-chloroethyl)furan react with sodium diethyl phosphite to give two products: 3-(1-diethoxyphosphorylethyl)furans and 3-ethyl-2-(diethoxyphosphoryloxy)furans. The methyl group in position 5 of the furan ring increases the relative phosphate content of the mixture by a factor of approximately 2.5. Blocking of position 2 or both positions 2 and 5 of the ring with methyl groups leads to phosphoate formation only. The reaction of 2,5-dimethyl-3-(1-chloro-2-methylpropyl)furan also occurs according to the Michaelis-Becker scheme. The products of the side chain dehydrohalogenation with sodium diethyl phosphite were not found.     

A Facile Route to 9-Phosphorylated Neuraminic Acid Derivatives

The phosphitylation of 2-α-O-Benzyl-N-acetylneuraminic acid (2) and of the methyl 2-α-O-methyl-N-acetylneuraminate (3) with 2-chloro-4H-1,2,3-benzodioxaphosphorin-4-one (4) is described. The reaction affords a ready access to 9-phosphorylated derivatives of N-acetylneuraminic acid (1).     

Exploration of versatile reactions on 2-chloro-3-nitroimidazo[1,2-a]pyridine: expanding structural diversity of C2- and C3-functionalized imidazo[1,2-a]pyridines

Alternative strategies for functionalizing 2-chloro-3-nitroimidazo[1,2-a]pyridine have been developed. Suzuki–Miyaura cross-coupling reaction provided easily the corresponding 2-arylated compounds, and herefrom the nitro group was reduced into amine which afforded amides, anilines, and ureas in the 3-position. The amination of the key compound using a metal-catalyzed reaction was reported. This study highlighted the importance of the nitro group to facilitate the chlorine displacement. Other nucleophilic aromatic substitutions open a route to various products derived from imidazo[1,2-a]pyridine.     

Application of the hurd-mori-reaction for the synthesis of tricyclic annelated 1,2,3-thiadiazoles

The synthesis of methyl naphtho[1,2-d][1,2,3]thiadiazole-4-carboxylate 1a as well as the corresponding thienobenzo[1,2,3]thiadiazoles 1b and 1c is reported using the Hurd-Mori reaction in the key step. Treatment of the readily available tosylhydrazones 10a-c with thionyl chloride surprisingly affords the fully aromatic products 1a-c , instead of the expected annelated 4,5-dihydro[1,2,3]thiadiazoles 2a-c . Based on these results a mechanism for the aromatization step with thionyl chloride is proposed.     

Synthesis and chemistry of some pyridazine nucleosides related to certain 5-substituted pyrimidine nucleosides

Condensation of 3,4-dichloro-6-[(trimethylsilyl)oxy] pyridazine ( 3 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β- D -ribofuranose ( 4 ), by the stannic chloride catalyzed procedure, has furnished 3,4-dichloro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl) pyridazin-6-one ( 5 ). Nucleophilic displacement of the chloro groups and removal of the benzoyl blocking groups from 5 has furnished 3-chloro-4-methoxy-, 3,4-dimethoxy-, 4-amino-3-chloro-, 3-chloro-4-methylamino-, 3-chloro-4-hydroxy-, and 4-hydroxy-3-methoxy-1-β- D -ribofuranosylpyridazin-6-one. An unusual reaction of 5 with dimethylamine is reported. Condensation of 4,5-dichloro-3-nitro-6-[(trimethylsilyl)oxy]pyridazine with 4 yielded 4,5-dichloro-3-nitro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl)pyridazin-6-one ( 24 ). Nucleophilic displacement of the aromatic nitro groups from 24 is discussed. Condensation of 3 with 3,5-di-O-p-toluoyl 2-deoxy- D -erythro-pentofuranosyl chloride ( 28 ) afforded an α, β mixture of 2-deoxy nucleosides. The synthesis of certain 3-substituted pyridazine 2′-deoxy necleosides are reported.     

Stereoselective preparation of 1-chloro-(E,E)-1,3-dienes. Application to the synthesis of methyl eleostearate.

The nickel (or palladium) catalyzd reaction of alkenylalanes with (E)-di-chloroethylene affords 1-chloro-(E,E)-1,3-dienes under mild conditions. The syntheses of methyl -eleostearate which is reported to be a feeding deterrent for the boll weevil on cotton, and one of its isomers, methyl punicate, are described.     

3,7-disubstituted bicyclo [3.3.1] nonanes—II : Synthesis and conformation of some 3,7-disubstituted 9-oxobicyclo [3.3.1] nonanes

Condensation of pyrrolidine enamines of 4-alkylcyclohexanones with methyl α-(bromomethyl)acrylate affords methyl 7β- and 7α-alkyl-9-oxobicyclo [3.3.1] nonane-3α-carboxylates in a ratio of 3:2. The mechanism of the annelation reaction is discussed. The conformations of the reaction products and their epimers have been studied by means of PMR spectroscopy.     

Reaction of the N,N-dimethylamide and methyl ester of 3-phenyl-3-chloro-2-ketopropionic acid with triphenylphosphine

Conclusions The dimethylamide of 3-phenyl-3-chloro-2-ketopropionic acid reacts with Ph₃P to give -(N,N-dimethyloxamoyl)benzyltriphenylphosphonium chloride. In the presence of methanol, this reaction gives dimethyl(phenylpyruvoyl)amide and Ph₃PO.2. The methyl ester of 3-phenyl-3-chloro-2-ketopropionic acid reacts with Ph₃P to give methoxycarbonylstyryloxytriphenylphosphonium chloride, which, upon heating in benzene at reflux, gives methyl -chlorocinnamate and Ph₃PO.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1395–1396, June, 1989.     

The Diels-Alder Reaction of Dienes Derived from Substituted 3-(Phenyl-Thio)-3-Sulfolenes

Substituted 3-(phenylthio)-3-sulfolenes (3) and (4) are good precursors for 2-(phenylthio)-1,3-butadienes (5) and (6). The Diels-Alder reaction of the dienes derived from (3) and (4) with various dienophiles was studied. It was found that heating of sulfolenes (3) with methyl propiolate and N-phenylmaleimide afforded the Diels-Alder adducts of (5) directly and with complete regio- and stereospecificity. The same reaction with methyl vinyl ketone gave a mixture of endo and exo addition products. If sulfolenes (3) were first converted to the dienes (5) using lithium aluminum hydride and then reacted with methyl vinyl ketone in the presence of anhydrous zinc chloride, the stereoselectivity could be improved. Sulfolenes (4) also underwent cycloreversion/cycloaddition with methyl acrylate, methyl vinyl ketone, and N-phenylmaleimide, but gave mostly the double bond-isomerized cycloaddition products. The regiochemistry of cycloaddition was delicately dependent on the dienophiles used.     

Synthesis of esters of oxathiinecarboxylic and dithiinecarboxylic acids and their derivatives

Conclusions The reaction of the methyl ester of 3-phenyl-3-chloro-2-ketopropionic acid with mercaptoethanol and 1,2-dithioglycol gives derivatives of oxathiine and dithiine. The oxidation of these products gives the corresponding sulfones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1670–1672, July, 1988.     

Novel heterocycles. 9. Synthesis of the benzofuro[2,3-c][1,2]thiazine ring system

The treatment of 2-coumaranone with the Vilsmeier reagent affords three products: 2-chloro-3-benzofurancarboxaldehyde ( 3 ), 3-dimethylaminomethylene-2-(3H)benzofuranone ( 4 ), and 3-dimethylaminomethylene-2,3-dihydro-2-oxo-6-benzofurancarboxaldehyde ( 5 ). Both 4 and 5 are isolated as a mixture of E and Z isomers. The reaction of 3 with the anion of N-methylmethanesulfonamide affords the title compound 1-methyl-1H-benzofuro[2,3-c][1,2]-thiazine 2,2-dioxide ( 6 ). Spectral data is also discussed.     

Studies on electrophilic addition reaction of 2,3-allenoates with PhSeCl

β-Organoselenium substituted butenolides were prepared from 2,3-allenoates and PhSeCl in the presence of water. The yields of the products depend largely on the structures of 2,3-allenoates. The addition of water is crucial for some of this electrophilic cyclization. The reaction of simple unsubstituted methyl 2,3-butadienoate afforded methyl 4-chloro-3-phenylselanylbut-2(Z)-enoate in good yield and stereoselectivity.     

Electrosynthesis of cyclopropanes at the electrolysis of solutions of methyl esters of Di- and trichloroacetatic acids in aprotic media in the presence of acrylonitrile

The potentiostatic (galvanostatic) electrolysis of methyl esters of trichloroacetic acid on mercury (steel) cathodes in the cathodic compartment of a diaphragm cell in the presence of acrylonitrile affords a mixture of two stereoisomers of methyl ester of 1-chloro-2-cyanocyclopropanecarboxylic acid. The process involves a stage of dehalogenation of the original methyl ester followed by the reaction of the formed anion with acrylonitrile and proceeds more efficiently on a mercury cathode in the dimethylformamide medium with the current efficiency of 94% and the substance yield of 25%. In contrast to methyl trichloroacetate, the electrolysis of methyl dichloroacetate proceeds by an indirect mechanism involving its deprotonation on the steel cathode and by the cleavage of the C-Cl bond on the mercury cathode. In both cases, the acrylonitrile addition leads to formation of the corresponding cyclopropane structures. Moreover, the process is the most efficient on the steel cathode in the MeCN medium. In the latter case, the current efficiency of methyl ester of 1-chloro-2-cyanocyclopropanecarboxylic acid is 31% and substance yield is 41%. Peculiarities of these processes are discussed.     

Thieno[2,3-d]pyrimidines. I. A new method for the preparation of esters and amides of thieno[2,3-d] pyrimidine-6-carboxylic acids

A novel method for the preparation of esters and amides of thieno[2,3-d]pyrimidine-6-carb-oxylic acids was described. A typical example was the direct formation of ethyl 5-amino-2-methylthiothieno[2,3-d]pyrimidine-6-earboxylate(IIIa) from 4-chloro-2-methylthio-5-pyrimidine-carbonitrile (Ia) and ethyl mercaptoacetate in refluxing ethanol containing sodium carbonate. Displacement of the methylthio group in IIIa by various amines gave the corresponding amino derivatives. The reactions of IIIa and related compounds with acetylating agents such as acetic anhydride or chloroacetyl chloride gave various products. Treatment of 5-carbethoxy-4-chloro-2-phenylpyrimidine(IV) with methyl mercaptoacetate afforded the dechloro intermediate diester Va, which cyclized on reaction with sodium ethoxide to form methyl 5-hydroxy-2-phenylthieno-[2,3-d]pyrimidine-6-carboxylate (Vla). The synthesis was expanded to include the preparation of various new 2,4,5-trisubstituted thieno[2,3-d]pyrimidine-6-carboxylic acid esters and amides (Charts I-V).