Pyridine-substituted hydroxythiophenes. V. Preparation of 5-(2-, 3-and 4-pyridyl)-2-hydroxythiophenes

5-(2-, 3- and 4-Pyridyl)-2-t-butoxythiophenes have been prepared in very good yields by Pd(0) catalyzed cross-coupling of the three isomeric bromopyridines with 5-trimethylstannyl-2-t-butoxythiophene derived from 2-bromothiophene via 2-t-butoxythiophene. Dealkylation of 5-(2-, 3- and 4-pyridyl)-2-t-but-oxythiophenes with boron trifluoride etherate in dichloromethane at room temperature led to predominant formation of rearranged products, 5-(2- and 3-pyridyl)-3-t-butyl-3-thiolene-2-ones, together with a small amount of 5-(2- and 3-pyridyl)-2-hydroxythiophenes as a mixture of two tautomeric keto forms in the case of the 2-pyridyl and the 3-pyridyl isomers, and exclusive formation of rearranged product in the case of the 4-pyridyl isomer. However, dealkylation of 2-methoxy-5-(2-, 3- and 4-pyridyl)thiophenes, prepared similarly to the 5-(2-, 3- and 4-pyridyl)-2-t-butoxythiophenes, with boron tribromide under the same reaction conditions as above resulted exclusively in the tautomeric mixture of 5-(2- and 3-pyridyl)-3-thiolene-2-ones and 5-(2- and 3-pyridyl)-4-thiolene-2-ones in the case of the 2-pyridyl and 3-pyridyl isomers. In the case of the 4-pyridyl isomer polymerization took place.     

Furopyridines. XXVIII. Reactions of 3-bromo derivatives of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine and their N-oxides

Bromination of 3-bromofuro[2,3-b]- 1a , -[3,2-b]- 1b and - [3,2-c]pyridine 1d afforded the 2,3-dibromo derivatives 2a, 2b and 2d , while the -[2,3-c]- compound 1c did not give the dibromo derivative. Nitration of 1a-d gave the 2-nitro-3-bromo compounds 3a-d . The N-oxides 4a-d of 1a-d were submitted to the cyanation with trimethylsilyl cyanide to yield the corresponding α-cyanopyridine compound 6a-d . Chlorination of 4a and 4d with phosphorus oxychloride gave mainly the chloropyridine derivatives 7a, 7′a and 7d , while 4b and 4c gave mainly the chlorofuran derivatives 7′b and 7′c accompanying formation of the chloropyridine derivatives 7b, 7′b and 7c . Acetoxylation of 4a and 4b with acetic anhydride yielded the acetoxypyridine compounds 8a, 8′a and 8b , while 4c and 4d gave the acetoxypyridine 8′c, 8′d and 8′d , pyridone 8c and 8d , acetoxyfuran 8′c and dibromo compound 9c and 9′c.     

Extraction of hydrochloric and nitric acid with 1-{[2-(2,4-Dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]-methyl)-1H-1,2,4-triazole and (RS)-1-(4-Chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-yl-methyl)-pentan-3-ol

Extraction of hydrochloric and nitric acid with 1-{[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]-methyl}-1H-1,2,4-triazole (propiconazole) and hydrochloric acid with (RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-yl-methyl)-pentan-3-ol (tebuconazole) was studied. It is established that extraction of acids proceeds with the formation of monosolvates as an exothermic process. Effective extraction constants of acids are evaluated. By means of the IR and ¹H NMR spectroscopy it was shown that the protonaccepting center of tebuconazole is N⁴ atom of the triazole ring.     

Furopyridines. XX. Wittig-horner reaction of a phosphonate of reissert analogues of furo[3,2-c]-, -[2,3-c]- and -[3,2-b]pyridines

Furo[3,2-c]-( 1a ), -[2,3-c]- ( 1b ) and -[3,2-b]pyridine ( 1c ) were reacted with isopropyl chloroformate and trimethyl phosphite to give dimethyl 5-isopropoxycarbonyl-4,5-dihydrofuro[3,2-c]pyridine-4-phosphonate ( 2a ), dimethyl 6-isopropoxycarbonyl-6,7-dihydrofuro[2,3-c]pyridine-7-phosphonate ( 2b ) and dimethyl 4-isopropoxycarbonyl-4,7-dihydrofuro[3,2-b]pyridine-7-phosphonate ( 2c ) as unstable syrups. Reaction of 2b and 2c with n-butyllithium and then with benzaldehyde, p-methoxybenzaldehyde, p-cyanobenzalde-hyde or propionaldehyde afforded the normal Wittig reaction products 5b-H, 5b-OMe, 5b-CN, 5b-Et, 5c-H, 5c-H, 5c-OMe and 5c-CN , except for 2b with propionaldehyde. While, the same reactions of compound 2a and the reaction of 2b with propionaldehyde afforded the unexpected products, 5-isopropoxycar-bonylfuro[3,2-c]pyridinio-4-aryl-(or ethyl)methoxides 3a-H, 3a-OMe, 3a-CN and 3a-Et , 4-(1′-aryl(or ethyl)-1′-hydroxymethyl)furo[3,2-c]pyridines 4a-H, 4a-OMe, 4a-CN and 4a-Et accompanying formation of the normal products. Treatment of the normal Wittig reaction products with lithium diisopropylamide and then with acetone gave the derivatives alkylated at the 2-or the benzylic positions.     

Pyridine-substituted hydroxythiophenes. II. Alkylation of o-(2-, 3- and 4-pyridyl)-3-hydroxythiophenes: Regiospecific formation of o-pyridyl-3-alkoxythiophenes

The alkylation of o-(2-, 3- and 4-pyridyl)-3-hydroxythiophenes has been investigated. In the case of 4-(2-, 3- and 4-pyridyl)-3-hydroxythiophene systems, the soft alkylating reagent, methyl iodide, using sodium hydride as the base and dimethylimidazolidinone as the solvent, gave rise to a mixture of O-alkylated and O,C-dialkylated products in the proportions of 4.6–6.5 to 1. However, in the case of 2-(2-, 3- and 4-pyridyl)-3-hydroxythiophene systems, the same reaction conditions brought about exclusively O-alkylated compounds in yields of 45–53%. In both cases, the hard alkylating reagent, methyl p-toluenesulfonate, with the same base and solvent, only give O-alkylated compounds in yields of 51–77%. These latter conditions resulted in a good preparative route for the regiospecific formation of o-pyridyl-3-alkoxythiophenes by using ethyl 2-bromopro-pionate as well as methyl p-toluenesulfonate as alkylating reagents. The hydrolysis of the esters, derived from alkylation with ethyl 2-bromopropionate, has also been investigated.     

Chemistry of Iminofuran: XVI. Synthesis,Structure, Biological Activity,and Cyclization of 4-Oxo-2-(2-phenylaminobenzoylhydrazono)butanoic Acids

The reaction of (2-phenylaminobenzoyl)hydrazine with 4-aryl-2-hydroxy-4-oxobut-2-enoic and 2-hydroxy-5,5-dimethyl-4-oxohex-2-enoic acids results in the formation of 4-aryl-2-(2-phenylaminobenzoyl-hydrazono)-4-oxobutanoic and 5,5-dimethyl-2-(2-phenylaminobenzoylhydrazono)-4-oxohexanoic acids. The products in solutions are present as mixtures of a Z,E-hydrazono form and a cyclic pyrazolinic form, and under the action of acetic anhydride they cyclize in 5-aryl- and 5-tert-butyl-3-(2-phenylaminobenzoylhydrazono)-furan-2,3-diones. 4-Aryl-2-(2-phenylaminobenzoylhydrazono)-4-oxobutanoic and 5,5-dimethyl-2-(2-phenyl-aminobenzoylhydrazono)-4-oxohexanoic acids were tested for antinociceptive and anti-inflammatory activity.

     

2-(o-Hydroxyanilido)alkylnitriles vs. 2-[1-(o-hydroxyanilido)alkyl]-benzoxazoles as products from o-aminophenol and cyanohydrins

The reaction of o-aminophenol with cyanohydrins leads to the formation of novel benzoxazoles 2 or the expected 2-(o-hydroxyanilido)alkylnitriles 3 or mixtures of these two, depending on the alkyl substituents on the cyanohydrin. The formation of benzoxazoles 2 was found to be due to the intrinsic instability of the corresponding 2-(o-hydroxyanilido)alkylnitriles, such as 4 .     

Reaction of 2-chloro-3-(4-N,N-dimethylaminoanilino)-1,4-naphthoquinone with cyclic amines (piperidine,morpholine, and pyrrolidine)

It was shown that the reaction of 2-chloro-3-(4-N,N-dimethylaminoanilino)-1,4-naphthoquinone with piperidine in the absence of a solvent gives not only a product of replacement of the chlorine atom by a piperidino group, 3-(4-N,N-dimethylaminoanilino)-2-piperidino-1,4-naphthoquinone, but also 2-(4-N,N-dimethylaminoanilino)-1,4-naphthoquinone and 2-(4-N,N-dimethylaminoanilino-2-piperidino)-1,4-naphthoquinone. The latter compounds are the only reaction products formed in dimethyl sulfoxide. The reaction with morpholine occurs in a similar way, whereas that with pyrrolidine gives only a product of replacement of the chlorine atom by hydrogen.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2451–2454, December, 1995.     

Novel Synthesis of 1-(1,2,3,5,6,7-Hexahydro- s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]urea,an Anti-inflammatory Agent

Abstract

A novel synthesis of the anti-inflammatory agent 1-(1,2,3,5,6,7- hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl] urea 1 is described. Sulfonamide 5 was prepared starting from ethyl 3-furoate 2. Key steps were a one-pot sulfonylation with chlorosulfonic acid in methylene chloride followed by pyridinium salt formation and reaction with phosphorus pentachloride to provide ethyl 2-(chlorosulfonyl)-4-furoate 7. This sulfonyl chloride was treated with ammonium bicarbonate to form sulfonamide 8, followed by treatment with excess methyl magnesium chloride to provide 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide 5. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 16 was prepared from indan in five steps. The formation of the desired sulfonyl urea was carried out both with the isolated isocyanate 16 and via an in situ method.     

Stereoselective Synthesis and Alkylation of N-Methylmorpholinium 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine-2-thiolate. Molecular and Crystal Structure of 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-2-methallylthio-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine

The condensation of 2-chlorobenzaldehyde with cyanothioacetamide and 2-thenoyltrifluoroacetone in the presence of N-methylmorpholine takes place stereoselectively and leads to the formation of N-methylmorpholinium 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine-2-thiolate. The latter was used to synthesize the corresponding 2-alkylthiotetrahydropyridines. The structure of 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-2-methallylthio-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine was determined by X-ray crystallographic analysis.     

Synthesis of the Enantiomerically Enriched Macrocyclic Lactones (+)-(S)- and (−)-(R)-Phoracantholide I and (+)-(S)-Tetradecan-13-olide

Synthesis of two naturally occurring macrocyclic lactones is described. (?)-(R)-Phoracantholide I ((?)- 1 ; Scheme 2) was synthesized by asymmetric and chemoselective reduction of the side-chain C?O group of (?)4-(1-nitro-2-oxocyclohexyl)butan-2-one ((?)- 6 ) with (R)-Alpine-Hydride (47% ee). It was shown that the formation of only one diastereoisomer of the hemiacetal 5 , by methylation with (i-PrO)₂TiMe₂ of ketoaldehyde (?)- 2 is thermodynamically controlled. (+)-(S)-Tetradecan-13-olide ((+)- 10 ) was obtained by reduction of diketone (±)- 11 with optically active borohydrides followed by denitration (Scheme 3).     

Oxidizing Reactions of Azines. 7. Imination of 4-Aryl-1,2,3,6-tetrahydropyridines by Arylamines in the Presence of Potassium Permanganate. Molecular Structure of 1-Methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine

On treating 4-aryl substituted 1-methyl-1,2,3,6-tetrahydropyridines with potassium permanganate in the presence of arylamines a previously unknown intermolecular oxidative imination reaction occurs leading to the formation of 2-(arylimino)-1,2,5,6-tetrahydropyridines. The molecular structure of 1-methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine was studied by X-ray analysis and it was shown that the hydropyridine ring of the molecule has a sofa conformation and its amidine fragment is in the E-configuration.     

Furopyridines. XXIV. Nitration,chlorination, acetoxylation and cyanation of 2,3-dihydrofuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine N-Oxides

Nitration of 2,3-dihydrofuro[3,2-b]- N-oxide 3b and -[2,3-c]pyridine N-oxide 3c afforded the nitropyridine compounds 4b, 5b and 6 from 3b and 4c, 5c, 5′c and 7 from 3c , while -[2,3-b]- N-oxide 3a and -[3,2-c]pyridine N-oxide 3d did not give the nitro compound. Chlorination of 3b and 3c with phosphorus oxychloride yielded mainly the chloropyridine derivatives 15b, 15′b from 3b and 15c and 15′c from 3c , whereas 3a and 3d gave pyridine derivatives formed through fission of the 1–2 ether bond of the furo-pyridines 13a , 14 and 13d . Acetoxylation of 3b and 3c gave 3-acetoxy derivatives 18b and 18c and the parent compound 1b and 1c . Acetoxylation of 3a yielded compounds formed through fission of the 1–2 bond 16 and 17 and 3d gave furopyridones 19 and 19 ′. Cyanation of 3b and 3c yielded mainly the cyanopyridine compounds 20b, 20c and 20′c . Cyanation of 3a and 3d gave the cyanopyridine compounds 20a , 20d and 20′d accompanying formation of the pyridine derivatives 21a, 21d and 21′d .     

Furopyridines. XIII. Reaction of 2-methylfuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridines with lithium diisopropylamide

Lithiation of 2-methylfuro[2,3-b]- 1a , -[2,3-c]- 1c and -[3,2-c]pyridine 1d with lithium diisopropylamide at ?75° and subsequent treatment with deuterium chloride in deuterium oxide afforded 2-monodeuteriomethyl compounds 2a, 2c and 2d , while 2-methylfuro[3,2-b]pyridine 1b gave a mixture of 1b, 2b , 2-methyl-3-deuteriofuro[3,2-b]pyridine 2′b and 2-(1-proynyl)pyridin-3-ol 5 . The same reaction of 1a at ?40° gave 3-(1,2-propadienyl)pyridin-2-ol 3 and 3-(2-propynyl)pyridin-2-ol 4 . Reaction of the lithio intermediates from 1a, 1c and 1d with benzaldehyde, propionaldehyde and acetone afforded the corresponding alcohol derivatives 6a, 6c, 6d, 7a, 7c, 7d, 8a, 8c and 8d in excellent yield; while the reaction of lithio intermediate from 1b gave the expected alcohols 6b and 8b in lower yields accompanied by formation of 3-alkylated compounds 9, 11, 12 and compound 5 . While reaction of the intermediates from 1a, 1b and 1d with N,N-dimethylacetamide yielded the 2-acetonyl compounds 13a, 13b and 13d in good yield, the same reaction of 1c did not give any acetylated product but recovery of the starting compound almost quantitatively.     

3-Ferrocenyl-3-(1-naphthyl)cyclopropene. Synthesis, structure, and chemical transformations

Crystalline 3-ferrocenyl-3-(1-naphthyl)cyclopropene was prepared by dehydrobromination ofZ- andE-2-bromo-1-ferrocenyl-1-(1-naphthyl)-cyclopropanes by Bu^tOK in DMSO. The resulting compound and the startingZ-monobromocyclopropane were characterized by X-ray diffraction analysis. The obtained cyclopropene reacts with 1,3-diphenylisobenzofuran to give a [4+2]-cycloadduct. The small ring opens upon treatment with HBF₄ etherate to afford isomericZ- andE-prop-1-enes and 1-ferrocenyl-3H-benzo[e]indene. Thermolysis of this cyclopropene results in the formation of 1-ferrocenyl-9bH-benzo[e]indene. In all cases, opening of the small ring is accompanied by exclusive alkylation of the naphthalene moiety. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 499–506, March, 1998.     

Cyclization of Nitriles: LIX. Synthesis and Properties of 1-(2-Thienyl)-4-cyano-5,6,7,8-tetrahydro-3(2H)- isoquinolinethione Derivatives. Molecular and Crystal Structure of 3-Isobutylsulfanyl-1-(2-thienyl)-4-cyano-5,6,7,8- tetrahydroisoquinoline

By condensation of 2-(2-thenoyl)-1-cyclohexanone with cyanothioacetamide a new compound of aseries of chalcogen-containing isoquinolines with a thiophene fragment in its structure was prepared. It wasdemonstrated that alkylation of the compound with haloalkanes, their derivatives, in particular with thosehaving electron-withdrawing substituents furnished 3-alkylthio-4-cyano-5,6,7,8-tetrahydroisoquinolines.Some of the latter underwent cyclization into 3-amino-2-R-5-(2-thienyl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline.     

New Chiral Diamines of the Dioxolane Series: (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(diphenylaminomethyl)- 1,3-dioxolane and (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(methyl- aminomethyl)-1,3-dioxolane

The reaction of sodium diphenylamide with 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane gave (+)-(4S,5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane, which was brought into complex formation with cobalt chloride. Treatment of 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane with sodium N-methylanilide resulted in cleavage of the SÄO bond in the p-toluenesulfonate moiety with formation of N-methyl-N-phenyl-p-toluenesulfonamide and 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane disodium salt. Diethyl (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate reacted with methylamine to give the corresponding dicarboxamide which was reduced with lithium aluminum hydride to (4S,5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane having chiral carbon and nitrogen atoms.     

Furopyridines. XIX. Reaction of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine with acetic anhydride

Acetoxylation of N-oxide of furo[2,3-b]- 2a , -[3,2-b]- 2b , -[2,3-c]- 2c and -[3,2-c]pyridine 2d with acetic anhydride afforded compounds substituted normally at the α- or γ-position to the ring nitrogen, 3a, 4a, 4b, 3d, 4d, 8 and 9 , and in addition compounds substituted on the furan ring, 5a, 6a, 5b, 6b, 7b, 5c and 7c which were unexpected compounds. The structures of these compounds were established from the ir, nmr and mass spectra, and x-ray crystal analysis of 5b .     

Palladium-catalyzed asymmetric allylation and complex formation involving P,N-bidentate derivatives of (S)-2-(anilinomethyl)pyrrolidine

P,N-Bidentate (S)-2-(anilinomethyl)pyrrolidine derivatives and their complexes with rhodium(i) and palladium(ii) were synthesized. It was demonstrated that these compounds can be used in the Pd-catalyzed asymmetric allylation for the synthesis of chiral methyl 2-phenyl-2-(2-phenyl-o-carboranyl-1)pent-4-enoate.     

Unusual behavior of 3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one towards some phosphorus reagents: Synthesis of novel diethyl 2-phosphonochromone,diethyl 3-phosphonopyrone and 1,3,2-oxathiaphosphinines

The chemical reactivity of 3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one (1) towards some phosphorus reagents was studied. The enaminone 1 was cyclized into diethyl 2-phosphonochromone 2 via its treatment with diethyl phosphite in basic medium. However, its reaction with triethoxy phosphonoacetate gave the substituted pyrone phosphonate 3. In addition, two novel examples of 4-(dimethylamino)-6-(2-hydroxyphenyl)-2-sulfido-4H-1,3,2-oxathia-phosphinines 6 and 7 were obtained from treatment of enaminone 1 with O,O-diethyl dithiophosphoric acid and Lawesson’s reagent. When enaminone 1 was also treated with phosphorus decasulfide, it was turned into 4H-thiochromene-4-thione while its treatment with phosphorus tribromide, phosphorus oxychloride, or phenylphosphonic dichloride, 4H-4-oxo-chromene was isolated in all cases. The possible reaction mechanisms of the formation of these products were discussed. The structures of newly isolated products were established by elemental analysis and spectral tools.