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.     

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles

Abstract  

An efficient synthesis method for the preparation of a series of new (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles was developed. The reaction of (Z)- and (E)-3-styrylchromones with hydrazine hydrate afforded the corresponding (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles, except for nitro derivatives, where both (Z)- and (E)-4′-nitro-3-styrylchromones afforded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations is discussed and the stereochemistries of all products were established by NMR experiments.     

Chiral synthesis of (R)-( -)-mellein and (3R,4aS)-( + )-ramulosin

By employing an intramolecular Diels-Alder reaction as the key-step, (R)-(—)-mellein 1a (a metabolite of Aspergittus melleus) and (3R,4aS)-( +)-ramulosin 2 (a metabolite of Pestalotia ramulosa) were synthesised from ethyl (R)-3-hydroxybutanoate 3a.     

Facile one pot multicomponent synthesis of novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives

An efficient base catalyzed one pot multicomponent reaction of aryl/hetryl chalcones, thiosemicarbazide and 1-(benzofuran-2-yl)-2-bromoethan-1-one was developed to synthesize the novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives.     

Synthesis of conjugated (1E,3E)- and (1Z,3Z)-1,4-di(n-pyridyl) (or n-quinolyl)-1,3-butadienes from n-(2′-chloroethenyl)pyridine (or quinoline)

The homocoupling reaction between the conjugated n-(2-chloroethenyl)pyridine; n, 2-, 3- and 4- (or quinoline; n, 2- and 4-) mediated by zero-valent nickel complexes at room temperature affords to the corresponding 1,4-diaryl-1,3-butadiene, always as the 1E,3E stereoisomer. The yield in 1,4-diaryl-1,3-butadiene increases with the nickel catalyst and hence, the active zero-valent nickel catalyst is not regenerated during the homocoupling reaction.The stereospecific synthesis of (1Z,3Z)-1,4-di(4′-pyridyl)-1,3-butadiene stereoisomer was efficiently carried out by partial hydrogenation of the appropriate 1,4-di(4′-pyridyl)-1,3-butadiyne.     

Practical synthesis of methyl(E)-2-(3-(3-(2-(7-chloro-2- quinolinyl)ethenyl)phenyl)-3-oxopropyl)benzoate,a key intermediate of Montelukast

A novel and practical synthetic route is presented for the preparation of methyl-(E)-2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl) phenyl)-3-oxopropyl)benzoate,the key intermediate of Montelukast,a leukotriene antagonist.The main diarylpropane framework was prepared via a polarity conversation reaction resulting in an acyl anion equivalent followed by a nucleophilic substitution reaction.The overall yield of this approach was 61%.This method is simple for operation and suitable for industrial production.     

Synthesis of methyl epijasmonate and cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one

A novel and efficient synthesis of both (±)-methyl epijasmonate and (±)-cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one is described. The key step to establish the cis-stereochemistry on the 5-membered ring is an ionic Diels–Alder reaction, which is high yielding and highly regioselective. Subsequent key steps include oxidative cleavage of the six-membered ring, Wittig coupling and for the synthesis of epijasmonate, the haloform reaction.     

1-( p -Fluorophenyl)-2-(2′-pyridyl)ethanol and 1-( p -fluorophenyl)-2-(2′-pyridyl)ethene obtained from the condensation reaction of 2-picoline and p -fluorophenylaldehyde under catalyst-and solvent-free conditions

The novel intermediate 1-(p-fluorophenyl)-2-(2′-pyridyl)ethanol or 2-[2′-(1-hydroxy-1-(p-fluorophenyl)ethyl]pyridine and the corresponding novel dehydration compound 1-(p-fluorophenyl)-2-(2′-pyridyl)ethene or 2-[p-fluorophenylvinyl]pyridine were obtained from the condensation reaction of p-fluorophenylaldehyde and 2-picoline under catalyst-and solvent-free conditions. The intermediate 1-(p-fluorophenyl)-2-(2′-pyridyl)ethanol was obtained at 42 h reaction time and temperature of 120°C, respectively. ¹H-NMR, IR spectroscopic data of the 1-(p-fluorophenyl)-2-(2-pyridyl)ethanol clearly showed the presence of the-CH₂-CHOH-group. The compound was obtained as a white powder with m.p. 121–122°C and a yield of 8%. For 1-(p-fluorophenyl)-2-(2-pyridyl)ethene, the reaction conditions were similar, but the reaction temperature was increased to yield the double bond in the 1-(p-fluorophenyl)-2-(2′-pyridyl)ethene. At the reaction temperature of 140°C, the compound was a slightly brown powder with a m.p. of 78°C and yield of 18%. ¹H-NMR, IR spectroscopic data for the 1-(p-fluorophenyl)-2-(2′-pyridyl)ethene showed the presence of a double bond in trans configuration (-CH=CH-), characteristic of a styrylpyridine.     

Lipase-mediated kinetic resolution of (RS)-1-bromo-3-[4-(2-methoxy-ethyl)-phenoxy]-propan-2-ol to (R)-1-bromo-3-(4-(2-methoxyethyl) phenoxy) propan-2-yl acetate

A novel biocatalytic method for the enantioselective synthesis of (R)-bromo-3-[4-(2-methoxy-ethyl) phenoxy]-2-propanol [(R)-BMEPP], a precursor for the synthesis of (S)-metoprolol, an anti hypertensive drug is described. We have developed kinetic resolution of rac-BMEPP by transesterification using Candida rugosa lipase and vinyl acetate as the acyl donor affording the product with excellent conversion (49%) and ee (>99%). Various reaction parameters (source of enzyme, reaction media, and concentration of substrate and acylating agent) for the enzymatic kinetic resolution have been reported.     

Syntheses of (E)- and (Z)-3-styrylchromones

Several (E)- and (Z)-3-styrylchromones were prepared by two different methodologies, the Wittig reaction of chromone-3-carboxaldehyde with benzylic ylides and the Knoevenagel condensation of chromone-3-carboxaldehyde with phenylacetic acids in the presence of potassium tert-butoxide under microwave irradiation. The Knoevenagel reaction followed by a decarboxylation offered an efficient and diastereoselective method for preparing (E)-3-styrylchromones in a shorter reaction time. It was also demonstrated that phenylacetic acid can also be substituted with success by phenylmalonic acid. The stereochemistry of all products was assigned by NMR experiments.     

Facile stereoselective synthesis of (E)- and (Z)-α-substituted cinnamates: stereospecific dehydration reaction with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and copper(II) chloride

A highly stereoselective method for the synthesis of (E)- and (Z)-α-substituted cinnamates in good yield has been achieved by dehydration reaction of anti- and syn-α-substituted-β-hydroxyphenylpropiolate using EDC. This facile method has been used to synthesize various (E)- and (Z)-α-substituted cinnamates and (E)- and (Z)-α-alkylidene-γ-butyrolactones. The reaction mechanism of this highly stereospecific dehydration using EDC can be elucidated by the ω-dimethylamino group of EDC, which is believed to facilitate the deprotonation step.     

Preparation, crystal structure, and spectroscopic, chemical, and electrochemical properties of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)-1,3-butadiene compared with those of (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene

Wittig reaction of 3-[4-(dimethylamino)phenyl]propanal (5) with (3-guaiazulenylmethyl)triphenylphosphonium bromide (4) in ethanol containing NaOEt at 25 °C for 24 h under argon gives the title (2E,4E)-1,3-butadiene derivative 6E in 19% isolated yield. Spectroscopic properties, crystal structure, and electrochemical behavior of the obtained new extended π-electron system 6E, compared with those of the previously reported (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene (12), are documented. Furthermore, reaction of 6E with 1,1,2,2-tetracyanoethylene (TCNE) in benzene at 25 °C for 24 h under argon affords a new Diels-Alder adduct 8 in 59% isolated yield. Along with spectroscopic properties of the [π4+π2] cycloaddition product 8, the crystal structure, possessing a cis-3,6-substituted 1,1,2,2-tetracyano-4-cyclohexene unit, is shown. Moreover, reaction of 6E with (E)-1,2-dicyanoethylene (DCNE) under the same reaction conditions as the above gives no product; however, this reaction in p-xylene at reflux temperature (138 °C) for four days under argon affords a new Diels-Alder adduct 9 in 54% isolated yield. Although reaction of 6E with DCNE in toluene at reflux temperature (110 °C) for four days under argon provides 9 very slightly, reaction of 6E with dimethyl acetylenedicarboxylate (DMAD) in toluene at reflux temperature for two days under argon yields a new Diels-Alder adduct 10, in 58% isolated yield, which upon oxidation with MnO₂ in CH₂Cl₂ at 25 °C for 1 h gives 11, converting a (CH₃)₂N-4″ into CH₃NH-4″ group, in 37% isolated yield. The crystal structure of 11 supports the molecular structure 10 possessing a partial structure cis-3,6-substituted 1,2-dimethoxycarbonyl-1,4-cyclohexadiene. The title basic studies on the above are reported in detail.     

Total synthesis of (S)-(+)-curcudiol, and (S)-(+)- and (R)-(-)-curcuphenol.

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (+/-)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of(S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.     

Synthesis and spatial structure of 4-(2-hydroxyethyl)-5-(2-hydroxyphenyl)-2H-1,2,4-triazolo-3(4H)-thione

By reaction of 2-vinyloxyethyl isothiocyanate with salicylic acid hydrazide a synthesis of the corresponding thiosemicarbazide was performed. Alkaline hydrolysis of the latter led to an intramolecular heterocyclization into 1,2,4-triazole derivative. When cyclization was carried out in the water-alkali medium, 2-vinyloxyethyl fragment was shown to be hydrolyzed to form 4-(2-hydroxyethyl)-5-(2-hydroxyphenyl)-2H-1,2,4-triazolo-3(4H)-thione, whose spatial structure was established by XRD analysis.     

Total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolol K1, (R)-(-)-pyridindolol K2, and (R)-(-)-pyridindolol.

The total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolols (1, 5, and 6) are described. The two key steps involved are (1) a thermal electrocyclic reaction of the 3-alkenylindole-2-aldoxime 10 and (2) a thermal cyclization of 3-alkynylindole-2-aldoxime 11 to construct the beta-carboline N-oxides 8, which upon heating with acetic anhydride and sequential treatment with trifluoromethanesulfonic anhydride gave the triflates 18. The Stille coupling reaction of 18 with vinylstannane, followed by cleavage of MOM ether, afforded the 1-ethenyl-3-hydroxymethyl-beta-carboline (7a). Subsequent acetylation of 7a yielded the acetate 7b, which was subjected to the Sharpless asymmetric 1,2-dihydroxylation by AD-mix-beta to produce (R)-(-)-pyridindolol K2 (6). Selective acetylation of 6 was effected by Ac(2)O and collidine to form (R)-(-)-pyridindolol K1 (5). By contrast, hydrolysis of 6 provided (R)-(-)-pyridindolol (1).     

Asymmetric total syntheses of (-)-antofine and (-)-cryptopleurine using (R)-(E)-4-(tributylstannyl)but-3-en-2-ol

The asymmetric total syntheses of the representative phenanthroindolizidine and phenanthroquinolizidine alkaloids, (-)-antofine and (-)-cryptopleurine, are described. An efficient synthetic pathway to the key intermediate 12, in enantiomerically pure form, was achieved by using a chiral building block (R)-9 and the Overman rearrangement with a total transfer of chirality. The problem of constructing the pyrrolidine and piperidine rings was successfully addressed, primarily by using a ring-closing metathesis reaction and a cross-metathesis reaction, respectively.     

Stereoselective Syntheses and Biological Properties of (E)-α-(Methoxyimino)-2-[1-(aryloxy)methyl]-benzeneacetates

(E)-α-(Methoxyimino)-2-[1-(aryloxy)methyl]-benzeneacetates, the analogues of Kresoxim-methyl, were stereoselectively synthesized with the coupling reaction of 2-methylphenyldiazonium chloride and methyl 2-hydroxyiminoacetate in the presence of CuSO4/Na2SO3 as a key step, and it was first found that the coupling reaction could give the key intermediate material(E)- and(Z)-methyl 2-(hydroxyimino)-2-o-tolylacetate with a molar ratio of 14∶1. The(E)-configurations of all these compounds were assigned on the basis of their 2D-NOESY spectra of 1H NMR. The preliminary bioassays indicate that most of the compounds show an activity against a wide variety of fungi.     

Synthesis of 2-[2H]-2-(1-methylalkyl)succinic acids

We describe a specific procedure for the synthesis of deuterium-labelled 2-(1-methylalkyl)succinate established via alkylation of diethyl malonate,Krapcho decarboxylation reaction with D_2O and hydrolysis reaction.Two novel compounds,2-[~2H]-2-ethylsuccinic acid and 2-[~2H]-2-(1-methylheptyl)succinic acid were prepared via this synthetic route and characterized by mass spectrometry and 'H NMR.The results showed that the 2-(1-methylalkyl)succinic acids were deuterated at the β-position,which is considered as an important reaction centre in the anaerobic degradation of n-alkanes.     

Synthesis of 5-polyfluoroalkyl-4-( p -tolyl-sulfonyl)pyrazoles and 4-polyfluoroalkyl-5-( p -tolylsulfonyl)pyrimidines from 1-dimethylamino-2-( p -tolylsulfonyl)-polyfluoro-1-alken-3-ones

1-Dimethylamino-2-(p-tolylsulfonyl)polyfluoro-1-alken-3-ones were obtained from hydrates of 3,3,3-trifluoro-1-(p-tolylsulfonyl)-2-propanone and 3,3,4,4,5,5-hexafluoro-1-(p-tolylsulfonyl)-2-pentanone under conditions of the Vilsmeier-Haack-Arnold reaction. The analogous reaction of 3,3-difluoro-1-(p-tolylsulfonyl)-2-propanone hydrate leads to 3-chloro-1-dimethylamino-4,4-difluoro-2-(p-tolylsulfonyl)-1,3-butadiene. The feasibility of using 1-dimethylamino-2-(p-tolylsulfonyl)-polyfluoro-1-alken-3-ones in reactions with nitrogen binucleophiles has been demonstrated for the regioselective synthesis of pyrazoles and pyrimidines. The structure of 1-phenyl-4-(p-tolylsulfonyl)-5-trifluoromethyl-1H-pyrazole was confirmed by X-ray diffraction structural analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1052–1058, July, 2007.     

Regioselective synthesis of (E)-3-[2-(arylmethylene)-1-(arylsulfonyl)hydrazino]-2-propenoates via the reaction of arylsulfonyl hydrazones and alkyl propiolates in the presence of triphenylphosphine

A regioselective method for the synthesis of (E)-3-[2-(arylmethylene)-1-(arylsulfonyl)hydrazino]-2-propenoates is described. The reaction takes place between arylsulfonyl hydrazones and alkyl propiolates in the presence of triphenylphosphine as the catalyst.