Synthesis and selected reactions of ethyl 5-(1-chloroethyl)-2-methylfuran-3-carboxylate

Ethyl 2-methylfuran-3-carboxylate is smoothly chloroethylated at 0°C in the 5 position of the ring. The resulting halide alkylates secondary amines but eliminates HCl with sodium diethyl phosphite under the Michaelis-Becker reaction conditions and with trimethyl phosphite under the Arbuzov reaction conditions. In the reaction with sodium diethyl phosphite, small amounts of 5-[1-(diethoxyphosphoryl)ethyl]furan-3-carboxylate and 5-ethylfuran-3-carboxylate are formed. In the Arbuzov reaction at a 1: 1.22 furan: trimethyl phosphite molar ratio, methyl 2,4-dimethyl-1-methoxy-1-oxo-1λ⁵-1,2-dihydrophospheto[3,2-b]furan-5-carboxylate was isolated.     

Three-component coupling reactions of isoquinolines, dimethyl acetylenedicarboxylate and indoles: a facile synthesis of 3-indolyl-1,2-dihydro-2-isoquinolinyl-2-butenedioate

A three-component coupling of isoquinolines, dimethyl acetylenedicarboxylate (DMAD) and indoles is achieved for the first time to produce dimethyl (E)-2-[1-(1H-3-indolyl)-1,2-dihydro-2-isoquinolinyl]-2-butenedioates in excellent yields and with high selectivity. The reaction proceeds smoothly at room temperature without a catalyst. Quinoline, DMAD and indole also undergo smooth coupling to furnish dimethyl (E)-2-[2-(1H-3-indolyl)-1,2-dihydro-1-quinolinyl]-2-butenedioate under similar conditions. This method is very useful to functionalize both indoles and aza-aromatic compounds in a one-pot operation.     

An efficient ultrasonic-assisted synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives

Dihydropyrimidinone derivatives were prepared by tri-component reaction of ethyl aceto acetate, aldehydes and thiourea in the presence of modified montmorillonite nanostructure as a catalyst and used as key intermediates for the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyri midine-6-carboxylate derivatives with use of diethyl and dimethyl acetylene dicarboxylate by two methods: (a) in methanol as a solvent under ultrasonic irradiation at ambient temperature (b) in methanol as a solvent at ambient temperature (conventional magnetic stirring). Ultrasound-assisted synthesis provides excellent yields in short reaction times (15–25 min) at room temperature.     

Reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with aldehydes

The reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with a electrophilic reagent (anisaldehyde) was studied. It was shown that condensation of the latter with 2-(4-oxo-3,4-dihydro-2-quinazolyl)- and 2-(1H-benzo[d]imidazol-2-yl)-2-(tetrahydro-2-furanylidene)acetonitriles in the presence of secondary amines or acids takes place with elimination of the furan fragment and the formation of 3-aryl-2-(4-oxo-3,4-dihydro-2-quinazolinyl)- and 2-(1H-benzo[d]imidazol-2-yl)acrylo-nitriles.     

Synthesis,Crystal Structure and Spectroscopic Properties of 1,2-Benzothiazine Derivatives:An Experimental and DFT Study

1,2-Benzothiazine derivatives methyl 3-methoxy-4-oxo-3,4-dihydro-2H-benzo[e] [1,2]thiazine-3-carboxylate 1,1-dioxide(1) and methyl 2-ethyl-3-hydroxy-4-oxo-3,4-dihydro-2Hbenzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide(2) were synthesized, and characterized by spectroscopic techniques; 1H-NMR and infrared(IR) spectroscopy. Crystals of 1 and 2 were grown by slow evaporation of methanol and ethyl acetate, respectively and their crystal structures were investigated by single-crystal X-ray diffraction analysis. Geometric properties were calculated by the B3 LYP method of density functional theory(DFT) at the 6-31G+(d) basis set to compare with the experimental data. Simulated properties were found in strong agreement with the experimental ones. Intermolecular forces have also been modeled in order to investigate the strength of packing and strong hydrogen bonding was observed in both compounds 1 and 2. Electronic properties such as Ionization Potential(IP), Electron Affinities(EA) and coefficients of the highest occupied molecular orbital(HOMO) and the lowest unoccupied molecular orbital(LUMO) of com- pounds 1 and 2 were simulated for the first time.     

1,3-dipolar cycloaddition chemistry for the preparation of novel indolizinone-based compounds

[Chemical reaction: See text] Starting from methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydroindolizine-8-carboxylate, obtained by a Rh(II)-catalyzed 1,3-dipolar cycloaddition reaction of 1-(2-benzenesulfonyl-2-diazoacetyl)pyrrolidin-2-one and methyl acrylate, several indolo- and furano-fused indolizinones were efficiently prepared. In the first case, a palladium-mediated C-N coupling of the triflate with a variety of substituted anilines provided the desired methyl 5-oxo-6-(arylamino)-1,2,3,5-tetrahydroindolizine-8-carboxylates in high yield. Methyl 6-(2-bromophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate as well as its decarboxylated analogue, 6-(2-bromophenylamino)-2,3-dihydro-1H-indolizin-5-one, were synthesized in excellent yield and were found to undergo an intramolecular Heck cyclization to give 1,2,3,6-tetrahydroindolizino[6,7-b]indol-5-ones. To prepare furano-fused indolizinones, methyl 6-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate was etherified with different allyl halides, and the resultant allyl ethers were subjected to a thermal Claisen rearrangement to give the corresponding methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,4-tetrahydroindolizine-8-carboxylates. Cyclization under Wacker oxidation conditions afforded methyl 2-methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-s-indacene-4-carboxylates in near-quantitative yield.     

Triphenylphosphine-Catalyzed Simple Synthesis of Dimethyl 1-Aryl-4-ethoxy-5-oxo-4,5-dihydro-1 H -pyrrole-2,3-dicarboxylates

Ethyl 2-arylamino-2-oxo-acetates undergo a complex reaction with dimethyl acetylenedicarboxylate in the presence of triphenylphosphine to produce dimethyl 1-aryl-4-ethoxy-5-oxo-4,5-dihydro-1 H -pyrrole-2,3-dicarboxylates in good yields. Dynamic NMR study of dimethyl 1-(2-methylphenyl)-4-ethoxy-5-oxo-4,5-dihydro-1 H -pyrrole-2,3-dicarboxylate shows a fairly high energy barrier ( j G p = 53.2 kJmol m 1 ) for rotation around the N-aryl single bond, which leads to an observable atropisomerism.     

Sequential approach to the synthesis of 'U and Z' shaped polycyclic heteroarenes

The synthesis of three new classes of heteroarenes, built through the sequential fusion of naphthalene, benzo/naphtho[b]oxepine and thiochromene rings with pyran and pyrimidine ring systems to give 'U and Z' shaped structural frameworks is reported. The methodology is based on the synthesis of pyran fused intermediates, 1-methylthio-3-oxo-5,6-dihydro-3H-benzo[f]chromene-2-carbonitrile (3), 4-methylthio-2-oxo-5,6-dihydro-2H-benzo/naphtho[b]pyrano[2,3-d]oxepine-3-carbonitriles (10, 20) and 4-methylthio-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles (15) from the reaction of 2-tetralone, benzo/naphtho[b]oxepin-5-ones and thiochromen-4-ones with methyl 2-cyano-3,3-dimethylthioacrylate respectively. Further condensation of intermediates 3, 10, 20 and 15 with amidines led to the formation of tetracyclic 'U' shaped 4-amino-2-aryl-7,8-dihydro-5-oxo-5H-naphtho[2,1-b]pyrimido[4,5-d]pyrans (8) and 'Z' shaped 4-amino-2-aryl-5-oxo-12,13-dihydro-5H-benzo/naphtho[b]oxepino[5,4-b]pyrimido[4,5-d]pyrans (12, 22) and 4-amino-2-aryl-5-oxo-5,12-dihydrothiochromeno[4,3-b]pyrimido[4,5-d]pyrans (17). Compound 12f forms a chain of dimers through N-HO interactions as indicated by the X-ray structure analysis, and the quantum chemical calculations performed at the MP2 level indicate that this interaction energy is 10 kJ mol(-1).     

Triphenylphosphine-Mediated Synthesis of the E/Z Isomers of Methyl 6-(1,2-Di(methoxycarbonyl))-8-(ethyl Carbamoylformyl)-2-oxo-2H-chromene-4-carboxylate

Triphenylphosphine-mediated reaction of dimethyl acetylenedicarboxylate with ethyl (2-hydroxyphenylcarbamoyl)formate in boiling toluene produces a mixture of methyl 8-(ethyl carbamylformyl)-2-oxo-2H-chromene-4-carboxylate and the E/Z isomers of methyl 6-(1,2-di(methoxycarbonyl)-8-(ethyl carbamoylformyl)-2-oxo-2H-chromene-4-carboxylate in moderate yields.     

Reactions of arylaldehydes and N-sulfonated imines with dimethyl acetylenedicarboxylate catalyzed by nitrogen and phosphine lewis bases

[reaction: see text] In the reaction of arylaldehydes or N-sulfonated imines (0.5 mmol) with dimethyl acetylenedicarboxylate (DMAD) (0.6 mmol) catalyzed by pyridine or DMAP (20 mol %), we found that (E)-2-aryl-but-2-enedioic acid dimethyl ester 1 or (E)-2-[aryl-(toluene-4-sulfonylimino)methyl]-but-2-enedioic acid dimethyl ester 2 was formed in good yields at 60 degrees C in THF. A plausible mechanism has been proposed.     

Tetrahydroquinolizinium ylides: preparation and 1,3-dipolar cycloaddition

By the Cu(II)-catalyzed reaction of 2-(4-diazo-3-oxoalkyl)pyridines (2), 4-alkoxycarbonyl (or 4-acyl)-3-oxo-1,2,3,4-tetrahydroquinolizinium ylides (3) were obtained in high yields. From the cycloaddition reaction of 3 with acetylenic esters (propynoates or acetylenedicarboxylates) the labile [2 + 3] cycloadducts, 3-oxo-3H-2a,4,5,8a-tetrahydropyrrolo[2,1,5-de]quinolizine-2a-carboxylates (8 or 12), were identified, which further reacted with DMAD (dimethyl acetylenedicarboxylate) to afford azocine derivatives (15 or 16) and produced pyrrolodihydroquinolizines (9 or 20) by dealkoxycarbonylation.     

Heterocyclisation of substituted ylidenethiocarbonohydrazides using dimethyl acetylenedicarboxylate

A facile and rapid procedure for the synthesis of dimethyl-2-[3-amino-5-(2-methoxy-2-oxoethylidene)-4-oxothiazolidin-2-ylidenehydrazono]succinate, dimethyl {[2-alkylidenehydrazono)-5-(2-methoxy-2-oxoethylidene)-4-oxothiazolidin-3-yl)amino]succinate and methyl (4-amino-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-yl)acetate affording yields of 61–54 %, 22–18 % and 14–11 %, respectively, via a condensation reaction of dimethyl acetylenedicarboxylate (DMAD) with (substituted ylidene)thiocarbonohydrazides. One of the products was conclusively confirmed by single-crystal X-ray analysis. A mechanism for the formation of the products is presented.     

Oxidative Addition of Dimethyl Malonate to Styrenes Mediated by Cerium(Iv) Ammonium Nitrate: Some Novel Observations

The oxidative addition of dimethyl malonate to ring substituted styrenes leads to the formation of substituted dimethyl (2-oxo-2-phenylethyl) malonate and methyl 2-oxo-5-phenyltetrahydrofuran-3-carboxylate along with small amounts of substituted dimethyl [2-(nitrooxy)-2-phenylethyl] malonate and dimethyl 2-methoxy-2-phenylethyl) malonate. A tentative mechanism which supports the formation of these products is also presented.     

Heterocyclization of 1,1-dicyano-2-(trifluoromethyl)ethylenes with 1,3,3-trimethyl-3,4-dihydroisoquinoline and its derivatives

1,3,3-Trimethyl-3,4-dihydroisoquinolines react with 1,1-dicyano-2,2-bis(trifluoromethyl)ethylene to give 4-amino-6,6-dimethyl-2,2-bis(trifluoromethyl)-3-cyano-6,7-dihydro-2H-benzo[a]quinolizines. The reaction of 3,3-dimethyl-1-cyanomethylidene-1,2,3,4-tetrahydroisoquinoline and the methyl ester of 3,3-dicyano-2-(trifluoromethyl)acrylic acid leads to 5,5-dimethyl-3-oxo-2-(trifluoromethyl)-2-(dicyanomethyl)-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline.A. N. Nesmeyanov Institute of Heteroorganic Compounds, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 8, pp. 1888–1892, August, 1992.     

DABCO-catalyzed multi-component domino reactions for green and efficient synthesis of novel 3-oxo-3H-benzo[a]pyrano[2, 3-c] phenazine-1-carboxylate and 3-(5-hydroxybenzo[a]phenazin-6-yl) acrylate derivatives in water

An efficient, convenient and environmentally benign procedure for the synthesis of novel 3-oxo-3H-benzo[a]pyrano[2,3-c]phenazine-1-carboxylate and 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives has been developed by domino three-component condensation reaction between 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines and acetylenic esters in the presence of a catalytic amount of DABCO as an expedient, eco-friendly and reusable base catalyst in water. This green process produces biologically and pharmacologically significant heterocycles in a one-pot single operation and offers considerable advantages such as:operational simplicity, short reaction time, high yields, reusability of catalyst, absence of any tedious workup or purification and avoids hazardous reagents/solvents.     

Effective Synthesis of Polysubstituted Pyrroles from (E)-Dimethyl 2-(Bromomethyl)-3-(diethoxyphosphoryl) Fumarate

Methyl 1-alkyl-4-(diethoxyphosphoryl)-5-oxo-2,5-dihydro-1H-pyrroles-3-carboxylate 4 was synthesized from the reaction of dimethyl 2-(bromomethyl)-3-(diethoxyphosphoryl) fumarate 3- E and primary amines in good yields.     

Microwave-induced generation and reactions of nitrile sulfides: an improved method for the synthesis of isothiazoles and 1,2,4-thiadiazoles

The 1,3-dipolar cycloaddition reactions of nitrile sulfides, generated by microwave-assisted decarboxylation of 1,3,4-oxathiazol-2-ones, have been investigated. By this approach ethyl 1,2,4-thiadiazole-5-carboxylates 3 were prepared in good yield by cycloaddition of the nitrile sulfides to ethyl cyanoformate. Similarly, reaction of benzonitrile sulfide with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 3-phenylisothiazole-4,5-dicarboxylate (5). In contrast, o-hydroxybenzonitrile sulfide, generated from the corresponding oxathiazolone 2d, reacted with DMAD to give methyl 4-oxo-4H-[1]benzopyrano[4,3-c]isothiazole-3-carboxylate (8) in high yield. A ca. 1:1 mixture of ethyl 3-phenylisothiazole-4- and 5-carboxylates (6,7) was formed from benzonitrile sulfide and ethyl propiolate. The corresponding reaction with diethyl fumarate gave diethyl trans-4,5-dihydro-3-phenylisothiazole-4,5-dicarboylate (10). 3-Arylisothiazoles, unsubstituted at both the 4- and 5-positions, were prepared from the reaction of 5-aryl-1,3,4-oxathiazolones with norbornadiene by a pathway involving cycloaddition of the nitrile sulfide to the norbornadiene, followed by retro-Diels-Alder extrusion of cyclopentadiene from the resulting isothiazoline cycloadduct 12. In summary, the use of microwave irradiation, rather than conventional heating methods, allows nitrile sulfide generation and reactions to be carried out in shorter times, with easier work-up and, in some cases, in higher yields.     

An efficient synthesis of 1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carbonitriles

Ethyl α-(dimethylaminomethylene)-2-cyanomethyl-4-phenylquinoline-3-carboxylate(2) as new synthons directed to 1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carbonitriles was obtained by the condensation of ethyl 2-cyanomethyl-4-phenylquinoline-3-carboxylate(1) and N,N-dimethylformamide dimethyl acetal(DMFDMA).Reaction of this enamine with primary amines(3) in HOAc-DMF at120 ℃then affords 2-substituted 1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carbonitrile derivatives(4) in good yields by a tandem addition-elimination-cyclization reaction.     

The reaction of 2-hetarylacetonitriles with heterocyclic haloaldehydes

The reaction of 4-oxo-3,4-dihydroquinazolyl-and benzimidazolylacetonitriles with 2-chloro-2-quinolinecarbaldehydes and 1-aryl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehydes gave the corresponding 3-(2-chloro-3-quinolyl)-2-(4-oxo-3,4-dihydro-2-quinazolyl)-2-propenenitriles and 3-(1-aryl-5-chloro-3-methyl-1H-4-pyrazolyl)-2-hetaryl-2-propenenitriles. Intramolecular cyclization of these compounds gives 15-oxo-15H-benzo[6,7][1,8]naphthyridino[2,1-b]quinazoline-6-carbonitriles, 1-aryl-3-methyl-11-oxo-1,11-dihydropyrazolo[4′,3′:5,6]pyrido[2,1-b]quinazoline-5-carbonitriles, and 1-aryl-3-methyl-1H-benzo[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyridine-5-carbonitriles.     

The reaction of methyl 3-amino-4-cyano-5-methylthiothiophene-2-carboxylate with dmad. A new synthesis of polyfunctionalized quinolines

The Reaction of Methyl 3-Amino-4-cyano-5-methylthiothiophene-2-carboxylate ( 2 ), which was prepared by the reaction of bis(methylthio)methylenepropanedinitrile ( 1 ) with methyl thioglycolate followed by dimethyl acetylenedicarboxylate (DMAD) in the presence of potassium carbonate in dimethyl sulfoxide gave the polyfunctionalized quinoline, pentamethyl 4-amino-5-mercaptoquinoline-2,3,6,7,8-pentacarbox-ylate ( 3 ). The oxidation of 3 with iodine in DMSO provided the novel ring system in the form of the derivative, pentamethyl 2H-isothiazolo[3,4,5-de]quinoline-3,4,6,7,8-pentacarboxylate ( 4 ).