Synthesis of methyl (E)-2-[(3S,4S)-4-hydroxy-3-(pent-3-yloxy)-pyrrolidin-2-ylidene]propanoate and its unusual recyclization

Methyl (2E,4S,5S)-5-hydroxy-6-mesyloxy-2-methyl-4-(pent-3-yloxy)hex-2-enoate was synthesized from l-tartaric acid. Attempted substitution of the mesyloxy group by the reaction with NaN₃ directly led to methyl (E)-2-[(3S,4S)-4-hydroxy-3-(pent-3-yloxy)pyrrolidin-2-ylidene]propanoate. The latter on treatment with CF₃COOH and then NaOH gave methyl (2E)-2-methyl-4-[(S)-oxiran-2-yl]-4-(pent-3-yloxy)but-2-enoate.     

Novel (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles from (E)- and (Z)-3-styrylchromones: the unexpected case of (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles

An efficient synthetic method for the preparation of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles has been developed. The reaction of (E)- and (Z)-3-styrylchromones with hydrazine hydrate afforded the corresponding (E)- and (Z)-4-styrylpyrazoles, respectively, saved 4′-nitro-derivatives where both (E)- and (Z)-4′-nitro-3-styrylchromones afforded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations was discussed and the stereochemistry of all products was assigned by NMR experiments.     

Modified synthesis of methyl (1R,2R,3E,5R)-3-(hydroxyimino)-5-methyl-2-(1-methylethyl)-cyclohexanecarboxylate from (R)-4-menthen-3-one

A modified stereospecific synthesis of potentially biologically and pharmacologically active methyl (1R,2R,3E,5R)-3-(hydroxyimino)-5-methyl-2-(1-methylethyl)cyclohexanecarboxylate from (R)-4-menthen-3-one was developed using sequential 1,4-conjugate addition of Norman reagent catalyzed by CuI?CBF₃?Et₂O?CCuCl₂ and ozonolysis?Creduction of the intermediate (R,R,R)-vinylmenthone by hydroxylamine hydrochloridein MeOH.     

Methyl (3R,5R)-3,5-dihydroxydecanoate in the asymmetric synthesis of Idea Leuconoe pheromone and formal syntheses of (+)-(3R,5R)-3-hydroxydecano-5-lactone, verbalactone, and Tolypothrix pentaether

A simple and efficient asymmetric synthesis of (5S,7R)-7-hydroxydodecano-5-lactone, a component of the giant danaine butterfly Idea leuconoe pheromone, and formal syntheses of (+)-(3R,5R)-3-hydroxydecano-5-lactone, verbalactone, and Tolypothrix pentaether have been accomplished starting from methyl (3R,5R)-3,5-dihydroxydecanoate. The latter is obtained from methyl 3-[(tributylstannyl)methyl]but-3-enoate using Keck allylation in the key step of the construction of its carbon skeleton.     

Regioselective cycloaddition of C-carbamoylnitrones to methyl (E)-2-(2-phenylcyclopropylidene)acetate and methyl (E)-2-methylidene-3-phenylcyclopropane-1-carboxylate

N-Aryl-C-(arylcarbamoyl)nitrones regioselectively add to methyl 2-(2-phenylcyclopropylidene)-acetate and methyl 2-methylidene-3-phenylcyclopropanecarboxylate to give in each case two diastereoisomeric 5-oxa-6-azaspiro[2.4]heptane-4-carboxylates.     

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.     

Convenient synthesis of enantiopure (R-) and (S-)-3-fluoro-3-aminomethylpyrrolidines

(R-)- and (S-)-3-fluoro-3-aminomethylpyrrolidines were synthesized from methyl α-fluoroacrylate in eight steps. α-Phenylethylamine was used as a chiral auxiliary to separate the racemic mixture. The overall synthesis yield was 31%.     

Reactions of 5-[3-(trifluoromethyl)-phenyl]furan-2-carbaldehyde

The Knoevenagel condensations of 5-[3-(trifluoromethyl)phenyl]furan-2-carbaldehyde with seven compounds containing an active methyl or methylene group have been studied. The compounds used were: methyl 2-cyanoacetate, malononitrile, 2-furylacetonitrile, acetophenone, 2-thioxo-1,3-thiazolidin-4-one (rhodanine), 5,5-dimethylcyclohexane-1,3-dione (dimedone), and methyl 2-azidoacetate. The effect of microwave irradiation on the condensation reactions was studied and compared with “’classical”’ conditions. Thermolysis of methyl 2-azido-3-{5-[3-(trifluoromethyl)phenyl]-2-furyl}propenoate afforded methyl 2-[3-(trifluoromethyl)phenyl)]-4H-furo[3,2-b]pyrrole-5-carboxylate. (2E)-3-{ 5-[3-(Trifluoromethyl)phenyl]-2-furyl}propenoic acid was converted to the corresponding azide, which was cyclized on heating into 2-[3-(trifluoromethyl)phenyl)]-4,5-dihydrofuro[3,2-c]pyridin-4-one. The latter after successive action of POCl₃ and NH₂NH₂-Pd/C gave 2-[3-(trifluoromethyl)-phenyl]furo[3,2-c]pyridine. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 825–831, June, 2006.     

Convenient method for the synthesis of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OMe) and 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT-OH) using microwave irradiation

A convenient method is described for the rapid synthesis of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OMe) from anethole and elemental sulfur using microwave irradiation. Various reaction conditions were applied to reduce the reaction time from several hours to 10 min, resulting in an improvement in yield and overcoming the undesired by-product formation associated with conventional methods. 5-(4-Hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT-OH) was obtained by the deprotection of ADT-OMe using pyridine hydrochloride under microwave irradiation.     

Reaction of 2-(2-oxoethylidene)furan-3(2H)-ones with isopropylidenehydrazides of aromatic carboxylic acids: Synthesis of 3-hydroxy-3-(2-oxoethyl)-2,3-dihydropyridazin-4(1H)-ones

3-Hydroxy-3-(2-oxoethyl)-6-phenyl-2,3-dihydropyridazin-4(1H)-ones were obtained by the reaction of methyl 3-oxo-5-phenylfuran-2(3H)-ylideneacetate or 2-[2-(4-chlorophenyl)-2-oxoethylidene]-5-phenylfuran-3(2H)-one with benzoic or p-nitrobenzoic isopropylidenehydrazides. Equilibrium C₍₅₎H and C₍₅₎H₂ tautomeric forms were detected in solutions of the 4-chlorophenyl derivatives in DMSO-d₆. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1156–1158, August, 2007.     

Enantioselective synthesis of Fmoc-l-3-(2-benzothienyl)alanine (2-BtAla) via diastereoselective alkylation of a glycine equivalent

Stereoselective alkylation of the anion derived from (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 2-chloromethylbenzothiophene afforded the corresponding trans-monosubstituted product, (2S,5R)-2-((1-benzo[b]thiophen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihyropyrazine in 88% yield. Hydrolysis of the alkylated product using 40% TFA/H₂O at 0?°C and subsequent protection of the α-amino functional group with Fmoc-OSu afforded Fmoc-l-3-(2-benzothienyl)alanine methyl ester in 88% yield. Hydrolysis of the methyl ester with aqueous LiOH gave Fmoc-l-3-(2-benzothienyl)alanine in 62% overall yield.     

Nitrile oxide cycloaddition routes to 2-(isoxazolyl)-benzoates and 2-(1,2,4-oxadiazol-3-yl)benzoates

Cycloaddition of aromatic nitrile oxides to methyl o-vinylbenzoate produced methyl 2-(3-aryl-2-isoxazolin-5-yl)benzoates; the isoxazolines were converted to methyl 2-(3-arylisoxazol-5-yl)benzoates. Reaction of the nitrile oxide from o-methoxycarbonylbenzohydroximinoyl chloride ( 11 ) with phenylacetylene, styrenes, and aromatic nitriles resulted in methyl 2-(5-phenylisoxazol-3-yl)benzoate, methyl 2-(5-aryl-2-isoxazolin-3-yl)-benzoates ( 15 ), and methyl 2-(5-aryl-1,2,4-oxadiazol-3-yl)benzoates, respectively. The isoxazolines 15 were converted to the corresponding isoxazoles 16 .     

A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation. Part 2: Synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid

Making use of amide activation, a convenient and short path synthesis of optically pure ω-heterocyclic-β-amino acids has been achieved from (1R,3R)- and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester. The key step of the synthesis involves a regiospecific ring-chain-transformation of the enaminones when subjected to 1,2-binucleophilic attacks. The method is illustrated by the synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid.     

Uncatalyzed addition of indoles and N-methylpyrrole to 3-formylchromones: synthesis and some reactions of (chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones

(Chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones have been obtained in good yields from 3-formylchromones on reaction with indoles and N-methylpyrrole under solvent-free conditions. Reactions of (chromon-3-yl)bis(indol-3-yl)methanes with guanidine carbonate and hydrazine hydrate proceed with the participation of the chromone ring system and lead to the formation of the corresponding pyrimidines and pyrazoles bearing the bis(indol-3-yl)methyl moiety.     

Synthesis and study of new derivatives of 6-[methoxy(phenyl)methyl]-2-(nitroamino)pyrimidin-4(3H)-one

New 6-[(2,6-dihalophenyl)(methoxy)methyl]-5-methyl-2-(nitroamino)pyrimidin-4(3H)-ones were synthesized by an original and efficient method involving regioselective O,O′-dimethylation of substituted mandelic acids in superbasic medium. The compounds obtained can serve as precursors to a novel series of non-nucleoside HIV-1 replication inhibitors.     

Heterocyclizations of 1-(Benzothiazol-2-yl)-4-phenylthiosemicarbazide

1-(Benzothiazol-2-yl)-4-phenylthiosemicarbazide reacted with methyl iodide in the presence of sodium acetate in boiling ethanol to give 2,2′-dithiobis[N-(5-methylsulfanyl-4-phenyl-4H-1,2,4-triazol-3-yl)-benzenamine]. The reaction of the title compound with dimethyl acetylenedicarboxylate in dioxane led to the formation of methyl 3-(benzothiazol-2-yl)-2-(2-methoxy-2-oxoethyl)-2,3-dihydro-1,3,4-thiadiazole-2-carboxylate.     

Synthesis,anti-inflammatory and analgesic activity of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid derivatives

The title compounds 3a–l have been synthesized by the reaction of thiocarbohydrazide with substituted phenoxy acetic acid to obtained substituted 1,2,4-triazoles (1). Compound 1 was treated with various substituted aromatic aldehydes which results in 4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-2H-1,2,4-triazol-3(4H)-thiones (2a–g), further 2a–g is converted to 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3a–l) derivatives by the reaction with chloroacetic acid. All the newly synthesized compounds were evaluated for in vivo anti-inflammatory and analgesic activities. Among the series 2-[4-(2,4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3d), 2-[4-(4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3e), 2-[4-(2,4-dichlorobenzylideneamino)-5-[(2,4-dichlorophenoxy)methyl]-4H-1,2,4-triazol-3-yl thio] acetic acid (3j) and 2-[5-[(2,4-dichlorophenoxy)methyl)]-4-(4-chlorobenzylideneamino)-4H-1,2,4-triazol-3-yl thio] acetic acid (3k) showed significant anti-inflammatory activity with P < 0.001 (63.4%, 62.0%, 64.1% and 62.5% edema inhibition, respectively), as compared to the standard drug diclofenac (67.0%) after third hour respectively and also compounds 3j, 3k exhibited significant analgesic activity with P < 0.001 (55.9% and 54.9% protection, respectively) and less ulcerogenic activity as compared with standard drug aspirin (57.8%).     

Synthesis 5-(pyrazolin-3-ylmethylidene)-2-thiohydantoins and 2-alkylsulfanyl-5-(pyrazolin-3-ylmethylidene)-3,5-dihydro-4<Emphasis Type="Italic">H</Emphasis>-imidazol-4-ones

A reaction of 3-allyl- and 3-phenylthiohydantoins with 1,5-diphenyl- and 1-phenyl-substituted 3-formyl-2-pyrazolines was used to obtain a series of 5-(pyrazolin-3-ylmethylidene)-2-thioxotetrahydro-4H-imidazol-4-ones, the subsequent alkylation of which with methyl iodide or ethyl chloroacetate gave the corresponding 2-alkylthio-5-(pyrazolin-3-ylmethylidene)-3,5-dihydro-4H-imidazol-4-ones in the yields from 30 to 77%. The oxidation of (5Z)-3-phenyl-5-[(1,5-diphenylpyrazolin-3-yl)methylidene]-2-methylsulfanyl-4,5-dihydroimidazol-4-one with lead tetraacetate led to the corresponding pyrazole in 48% yield.     

Diastereoselective addition of organozinc reagents to 2-alkyl-3-(arylsulfanyl)propanals

The preparation of compounds incorporating the 3-hydroxy-2-methyl-1-alkyl moiety of high diastereomeric purity is described. Such compounds can serve as potential building blocks for the preparation of several kinds of natural products. Diastereoselective synthesis of two potential pine sawfly pheromone components, one the pure racemic threo-isomer of 3-methylpentadecan-2-ol and the other the racemic erythro-isomer of 3-methyltridecan-2-ol are described. The diastereoselective addition of R₂Zn (R=Me, Et and n-Bu) to several 2-alkyl-3-(arylsulfanyl)propanals in the presence of a Lewis acid and CH₂Cl₂ as solvent was studied. An excellent diastereomeric ratio (95/5 anti-Cram/Cram) was obtained with 2-[(phenylsulfanyl)methyl]pentanal, 2-[(phenylsulfanyl)methyl]decanal and 2-[(phenylsulfanyl)methyl]dodecanal and Me₂Zn in the presence of TiCl₄.     

3-(Furyl)-3-(diethoxyphosphoryl)acrylates: Synthesis and reaction with nitromethane

A series of 3-(furyl)-3-(diethoxyphosphoryl)acrylates was synthesized by the reaction of 2- and 3-furoyl phosphonates with ethoxycarbonylmethylenetriphenylphosphorane. It was shown that in all cases diethoxyphosphoryl and ester groups were in trans-position with respect to the double bond disregarding the structure of the furan fragment. Potassium fluoride catalyzed addition of nitromethane to the compounds synthesized was studied. It was found that this reaction proceeded regioselectively to form 2-[(furyl)(diethoxyphosphoryl) methyl]-3-nitropropanoic acids.