Synthesis via pummerer intermediates. II.. Disproportionation reactions of 3-(methylsulfinyl)chromones and 3-(methyl-sulfinyl)quinolinones with hydrochloric acid

Sulfoxides ( 1 and 10 ) gave oxidation-reduction products when treated with 5N hydrochloric acid. 8-Methoxy-3-(methylsulfinyl)-4H-benzopyran-4-one (1) gave 8-methoxy-3-(methylthio)-4H-1-benisopyran-4-one ( 4 ) and 8-methoxy-3-(methylsulfonyl)-4H-1-benzopyran-4-one ( 5 ), whereas 1-melhyl-3-(methylsulfinyl)-4(1H)quinolinone ( 10 ) gave 1-methyl-3-(methylthio)-4(1H)-quinolinone ( 12 ) and 1-methyl-4(1H)-quinolinone ( 13 ).     

Synthesis of the (2<Emphasis Type="Italic">S</Emphasis>,4<Emphasis Type="Italic">S</Emphasis>)-stereoisomers of 4-(indol-1-yl) and 4-arylamino derivatives of 5-oxoproline,proline, and 2-hydroxymethylpyrrolidine

Nucleophilic substitution of the halogen atom in dimethyl (S)-4-bromoglutamate followed by removal of the protecting groups and closure of a lactam ring afforded (2S,4S)-4-(indolin-1-yl)-5-oxoproline. The indoline fragment was oxidized into the indole fragment to give (2S,4S)-4-(indol-1-yl)-5-oxoproline; reduction of the carbonyl groups with BH3 yielded (2S,4S)-4-(indol-1-yl)prolines and (2S,4S)-2-hydroxymethyl-4-(indol-1-yl)pyrrolidines. Reduction of (2S,4S)-4-arylamino-5-oxoprolines with BH3 to the corresponding (2S,4S)-4-arylaminoprolines and (2S,4S)-4-arylamino-2-hydroxymethylpyrrolidines was studied.     

The electron-impact induced fragmentation of substituted 4-styrylquinolines

The fragmentation of 4-styrylquinoline (I), 4-(p-nitrostyryl)-quinoline (II), 4-(p-chlorostyryl)-quinoline (III), 4-(p-hydroxystyryl)-quinoline (IV), 4-(p-methoxystyryl)-quinoline (V), 4-(p-dimethylaminostyryl)-quinoline (VI) and 4-(p-cyanostyryl)-quinoline (VII) under electron-impact in the mass spectrometer is reported. The role and the influence of substituents on the fragmentation scheme is discussed. The loss of the substituents from the molecular ion is correlated with LCAOMO quantities.     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

Synthesis and anticonvulsant activity of 3-[3-[(dimethylamino)-methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine

Wolff-Kishner reduction of 3-amino-4-(o-chlorobenzoyl)pyridine ( 3 ) afforded 3-amino-4-(o-chlorobenzyl)pyridine ( 5 ), which on subsequent reaction with triethyl orthoformate and then acetyl hydrazide yielded 1-acetyl-2-[N-[4-(o-chlorobenzyl)pyridin-3-yl]formimidoyl]hydrazone ( 7 ). Cyclization of hydrazone 7 gave 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 8 ), which on Jones oxidation yielded 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ). The Mannick reaction of 3-(3-methyl-4H-l,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ) with aqueous formalin and dimethylamine hydrochloride afforded 3-[3-[(dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)-pyridine ( 10 ). 3-[3-[(Dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine ( 10 ) exhibited good anticonvulsant activity in the subcutaneous pentylenetetrazole anticonvulsant screen indi cating that an appropriately substituted-pyridine ring moiety can serve as a bioisostere of a chlorobenzene ring with respect to anticonvulsant activity.     

Reduction of 4-arylidene-1,3-(2H,4H)isoquinolinediones

Catalytic hydrogenation of some 4-arylidene-1,3-(2H,4H)isoquinolinediones (1) afforded the corresponding 4-arylmethyl-1,3-(2H,4H)isoquinolinediones (2) , but reduction of 1 by sodium borohydride gave 4-arylmethyl-1(2H)isoquinolones (isocarbostyrils, 3). Compounds of type 1 studied had aryl substituents phenyl, 3,4-dimethoxyphenyl, 3,4-methyleneoxyphenyl and 2-furyl. In one example of sodium borohydride reduction of an N-methylisoquinolinedione derivative (1) the heterocylic ring was opened, and 2-(1-hydroxymethyl-2-phenylethenyl)-N-methylbenzamide (4) was obtained from 4-benzylidene-2-methyl-1,3-(2H,4H)isoquinolinedione.     

Recruitment of enzyme activity in albumin by molecular imprinting

The catalytic activity of bovine serum albumin (BSA) modified physically by molecular imprinting using transition-state analogue (TSA) as a template molecule was studied. The resultant imprinted serum albumin (Imp-BSA) showed the rate acceleration of dehydrofluorination reaction from (4R,4S)-4-fluoro-4-(4-nitrophenyl)butan-2-one ( 1 ) and followed the type of Michaelis-Menten reaction in ethyl acetate solution. The enzymatic activity of Imp-BSA was competitively inhibited by (4R,4S)-4-hydroxy-4-(4-nitrophenyl)butan-2-one ( 4 ).     

Synthese der diastereomeren 4-Amino- und 4-Hydroxy-3-(p-chlorphenyl)-valeriansäuren. Kristallstruktur von cis-4-(p-bromphenyl)-5-methyl-2-pyrrolidinon

Synthesis of 4-amino- and 4-hydroxy-3-(p-chlorophenyl)-valeric acids. X-ray structure of cis-4-(p-bromophenyl)-5-methyl-2-pyrrolidinone The syntheses of diastereomeric 4-amino- and 4-hydroxy-3-(p-chlorophenyl)-valeric acids and of their ring closure products (lactones and lactams), starting from 3-(p-chlorophenyl)-4-oxo-valeric acid, are described. A single-crystal X-ray structure analysis of cis-4-(p-bromophenyl)-5-methyl-2-pyrrolidinone is given. Some aspects of the biochemistry of threo-3-(p-chlorophenyl)-4-amino-valeric acid are presented.     

Electrochemical Fluorination of Dithiocarbonates Using a Triarylamine Mediator

Electrochemical oxidation of O-(4-chlorobenzyl) S-methyl dithiocarbonate using tris(2,4-dibromophenyl)amine as a redox mediator was studied by cyclic voltammetric measurements. The triarylamine mediated anodic fluorodesulfurization of O-(4-chlorobenzyl) and O-(4-bromobenzyl) S-methyl dithiocarbonates provided 4-chloro- and 4-bromobenzyl fluorides, respectively in moderate yields. On the other hand, similar anodic fluorination of O-(2-phenethyl) S-octyl dithiocarbonate and O-(4-bromophenyl) S-methyl dithiocarbonate afforded 2-phenethyl trifluoromethyl ether and difluoro(methylthio)methyl 4-bromophenyl ether, respectively. Mechanistic aspects are also discussed.     

4H-Chromenone Glycosides from Eranthis hyemalis (L.) SALISBURY

Investigation of the tubers of Eranthis hyemalis (Ranunculaceae) afforded six chromenone glycosides. Their structures have been elucidated mainly by spectroscopic (FAB-MS, 2D-NMR techniques) and chemical methods (acidic and enzymatic hydrolysis) as 9-{[(β-D -glucopyranosyl)oxy]methyl}-8,11-dihydro-5-hydroxy-2-methyl-4H-pyrano[2,3-g][1]benzoxepin-4-one ( 1 ), 9-{[(β-D -gentiobiosyl)oxy]methyl}-8,11-dihydro-5-hydroxy-2-methyl-4H-pyrano[2,3-g][1]benzoxepin-4-one( 2 ), 9-{[(β-D -glucopyranosvl)oxy]melhyl}-8,11-dihydro-5-hydroxy-2-(hydroxy-methyl)-4H-pyrano[2,3-g][1]benzoxepin-4-one( 3 ), 8-{(2E)-4-[(β-D -glucopyranosyl)oxy]-3-methylbut-2-enyl}-5,7-dihydroxy-2-methyl-4H-1-benzopyran-4-one ( 4 ), 8-{(2E)-4-[(β-D -glucopyranosyi)oxy]-3-methylbut-2-enyl}-5,7-dihydroxy-2-(hydroxymethyl)-4H-1-benzopyran-4-one ( 5 ), and 7-{[(β-D -glucopyranosy1)oxy]methyl}-2,3-dihydro-2-(l-hydroxy-1-methylethyl)-4-methoxy-5H-furo[3,2-g][1]benzopyran-5-one ( 6 ). Compound 2 exhibited negative inotropic activity.     

Ring-transformation of 1,2,4-oxadiazines. Raney nickel hydrogenation of Z-3-aryl-5,6-dihydro-5-(substituted)methylene-4H-1,2,4-oxadiazine derivatives

Raney nickel hydrogenation of Z-3-aryl-5-(ethoxycarbonyl)methylene-5,6-dihydro-4H-1,2,4-oxadiazine ( 1a-c ) affords 2-aryl-6-hydroxymethyl-4-pyrimidinone ( 2 ) and ethyl (2-aryl-4-oxazolyl)acetate ( 3 ). A similar hydrogenation of Z-5-arylcarbarnoyl)methylene-5,6-dihydro-3-phenyl-4H-1,2,4-oxadiazine ( 1d-f ) gives E-4-(arylcarbamoyl)methylene-2-phenyl-2-oxazoline ( 5 ), 4-(arylcarbamoyl)methyl-2-phenyloxazole ( 6 ), and Z-4-(aryl-carbamoyl)methylene-2-phenyl-2-oxazoline ( 7 ).     

Design and synthesis of novel rofecoxib analogs as potential cyclooxygenase (COX‐2) inhibitors: Replacement of the methylsulfonyl pharmacophore by a sulfonylazide bioisostere

A group of rofecoxib analogs, having a sulfonylazide (SO₂N₃) substituent in place of the methanesulfonyl (SO₂CH₃) pharmacophore at the meta‐position viz 3‐(4‐methyl, 4‐methoxy, or 4‐ethoxyphenyl)‐4‐(3‐sulfonylazidophenyl)‐2(5H)furanone ( 7a‐c ) and para‐position viz 3‐phenyl‐4‐(4‐sulfonylazidophenyl)‐2(5H)furanone ( 7d ), 3‐(4‐fluoro, or 4‐chlorophenyl)‐4‐(4‐sulfonylazidophenyl)‐2(5H)furanone ( 7e‐f ) of the C–4 phenyl ring, and 4‐(1‐oxido‐4‐pyridyl)‐3‐phenyl‐2(5H)furanone ( 12 ) were designed and synthesized for evaluation as selective cyclooxygenase‐2 (COX‐2) inhibitors. In vitro COX‐1/COX‐2 enzyme inhibition studies showed that 3‐phenyl‐4‐(4‐sulfonylazidophenyl)‐2(5H)furanone ( 7d ) inhibited COX‐1 selectively (COX‐1 IC₅₀ = 0.6659 μM; COX‐2 IC₅₀ > 100 μM) and 3‐(4‐fluorophenyl)‐4‐(4‐sulfonylazidophenyl)‐2(5H)furanone ( 7e ) inhibited both enzymes (COX‐1 IC₅₀ = 0.8494 μM; COX‐2 IC₅₀ = 1.7661 μM). A molecular modeling study was performed where 3‐(4‐fluorophenyl)‐4‐(4‐sulfonylazidophenyl)‐2(5H)furanone ( 7e ) was docked in the active site of murine COX‐2 isozyme, which showed that the sulfonylazido group inserts deep into the 2°‐pocket of COX‐2 where it undergoes both H‐bonding (Gln¹⁹², Phe⁵¹⁸) and weak electrostatic (Arg⁵¹³) interactions.     

Synthesis of isomeric 2-oxazolidinones from (1<Emphasis Type="Italic">R</Emphasis>,2<Emphasis Type="Italic">R</Emphasis>)-and (1<Emphasis Type="Italic">S</Emphasis>,2<Emphasis Type="Italic">S</Emphasis>)-2-amino-1-(4-nitrophenyl)-1,3-propanediols

A synthesis is reported for (4R,5R)-and (4S,5S)-4-hydroxymethyl-5-(4-nitrophenyl)oxazolidin-2-ones and (1′R,4R)-and (1′S,4S)-4-[hydroxy(4-nitrophenyl)methyl]oxazolidin-2-ones from (1R,2R)-and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediols. The effect of the experimental conditions on the formation of these compounds was studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1562–1570, October, 2007.     

Synthese von N-Methyl- und N,N-Dimethylmerucathin sowie von N-Methyl- und N,N-Dimethylpseudomerucathin aus L-Alanin

Synthesis of N-Methyl- and N,N-Dimethylmerucathine and of N-Methyl- and N,N--Dimethylpseudomerucathine Starting from L -Alanine Starting form L -alanine, N-methylmerucathine (= (3R,4S)-4-(methylamino)1-phenyl-1-penten-3-ol; (3R,4S,)- 6 ), N,N-dimethylmerucathine (= (3R,4S)-4-(dimethylamino)-1-phenyl-1-penten-3-ol; (3R,4S)- 9 ), N-methylpseudomerucathine (= (3S,4S)-4-(methylamino)-1-phenyl-1-penten-3-01; (3S,4S)-6), and N,N-dimethylpseudomerucathine (= (3S,4S)-4-(dimethylamino)-1-phenyl-1-penten-3-ol; (3S,4S)- 9 ) were synthesized. The four compounds were analyzed by HPLC and compared with a natural khat extract.     

Four New Lariciresinol‐Based Lignan Glycosides from the Roots of Rhus javanica var. roxburghiana

The four new lariciresinol‐based lignan glycosides, (?)‐lariciresinol 4′‐(6″‐O‐feruloyl‐β‐D ‐glucopyranoside) ( 1 ), (?)‐lariciresinol 4′‐(4″,6″‐di‐O‐feruloyl‐β‐D ‐glucopyranoside) ( 2 ), 5,5′‐dimethoxylariciresinol 4′‐(4″,6″‐di‐O‐feruloyl)‐β‐D ‐glucopyranoside) ( 3 ), and 4‐O‐[α‐(1,2‐dihydroxyethyl)syringyl]‐5,5′‐dimethoxylariciresinol 4′‐(4″,6″‐di‐O‐feruloyl‐β‐D ‐glucopyranoside) ( 4 ), together with two known ones, lariciresinol 4′‐β‐D ‐glucopyranoside) ( 5 ) and tortoside B ( 6 ), were isolated from the BuOH extract of Rhus javanica var. roxburghiana roots, and their structures were established by means of various spectroscopic techniques.     

Synthesis and properties of the ionomer diblock copolymer poly(4‐vinylbenzyl triethyl ammonium bromide)‐b‐polyisobutene

A new amphiphilic diblock copolymer containing an ionomer segment, poly[(4‐vinylbenzyl triethyl ammonium bromide)‐co‐(4‐methylstyrene)‐co‐(4‐bromomethylstyrene)]‐b‐polyisobutene [poly(4‐VBTEAB)‐b‐PIB], was synthesized by the chemical modification of poly(4‐methylstyrene)‐b‐polyisobutene [poly(4‐MSt)‐b‐PIB]. First, the 4‐methylstyrene moiety in poly(4‐MSt)‐b‐PIB was brominated with azobisisobutyronitrile as an initiator at 60 °C in CCl₄, and then the highly reactive benzyl bromide groups were ionized by a reaction with triethylamine in a toluene/isopropyl alcohol (80/20 v/v) mixture at about 85 °C to produce the ionomer diblock copolymer poly(4‐VBTEAB)‐b‐PIB. The solubility of the ionomer block copolymer was quite different from that of the corresponding poly[(4‐methylstyrene)‐co‐(4‐bromomethylstyrene)]‐b‐polyisobutene {poly[(4‐MSt)‐co‐(4‐BrMSt)]‐b‐PIB}. Transmission electron microscopy observations demonstrated that all three diblock copolymers had microphase‐separation structures in which polyisobutene (PIB) domains existed in the continuous phase of the poly(4‐methylstyrene) segment or its derivative segment matrix. Dynamic mechanical thermal analysis measurements showed that poly[(4‐MSt)‐co‐(4‐BrMSt)]‐b‐PIB had two glass‐transition temperatures (T_g's), ?56 °C for the PIB segment and 62 °C for the poly[(4‐MSt)‐co‐(4‐BrMSt)] domain, whereas poly(4‐VBTEAB)‐b‐PIB showed one T_g at ?8 °C of the PIB domain; T_g of the poly[(4‐vinylbenzyl triethyl ammonium bromide)‐co‐(4‐methylstyrene)‐co‐(4‐bromomethylstyrene)] domain was not observable because of the strong ionic interactions resulting in a higher T_g and a retention of modulus up to 124 °C. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2755–2764, 2003     

Thermochemical study of the trans- and cis-isomeric forms of 4-(4-methoxystyryl)pyridine N-oxide

The trans and cis form of 4-(4-methoxystyryl)pyridine N-oxide were studied. The spectral characteristics of cis-4-(4-methoxystyryl)pyridine N-oxide were determined in acetonitrile. The melting and thermal decomposition processes of the trans and cisforms of 4-(4-methoxystyryl)pyridine N-oxide were studied by thermochemical methods. It was establish that the thermal decomposition of 4-(4-methoxystyryl)pyridine N-oxide begins with the cleavage of the bond between the pyridine and benzene rings.

     

Synthesis via pummerer intermediates. III. Rearrangements of 3-(methylsulfinyl)quinolinones, 3-(methylsulfinyl)cinnolinones, 3-(methylsulfinyl)chromanones and 3-(methylsulfinyl)chromones with acetic anhydride and with thionyl chloride

The reaction of 1-methyl-3-(methylsulfinyl)-4(1H)quinolinone ( 1 ) with acetic anhydride and thionyl chloride gave 3-[[(acetyloxy)methyl]thio]]-1-methyl-4(1H)quinolinone ( 2 ) and 3-[(chloromethyl)thio]-1-methyl-4(1H)quinolinone ( 3 ) respectively. 3-(Methylsulfinyl)-4(1H)cinnolinone ( 4 ) gave the corresponding products when treated under similar conditions. Treatment of 8-methoxy-3-(methylsulfinyl)-4H-1-benzopyran-4-one ( 11 ) with acetic anhydride and thionyl chloride gave bis addition vinyl Pummerer products 2,3-bis(acetyloxy)-2,3-dihydro-8-methoxy-3-(methylthio)-4H-1-benzopyran-4-one ( 12 ) and 2,3-dichloro-2,3-dihydro-8-methoxy-3-(methylthio)-4H-1-benzopyran-4-one ( 13 ), respectively.     

A new method for the synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines

The reaction of 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 4 with o-chlorobenzenediazonium chloride gave 3-[α-(o-chlorophenylhydrazono)-2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethyl]-2-oxo-1,2-dihydroquinoxaline 6 , whose refluxing in phosphoryl chloride/pyridine afforded 1-(o-chlorophenyl)-3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 7. The reactions of 6 and 7 with nitrous acid resulted in sulfur extrusion to provide 1-(o-chlorophenyl)-3-(4-methyl-4H-1,2,4-triazol-5-yl)1H-pyrazolo[3,4-b]quinoxaline 8 and 3-[α-(o-chlorophenylhydrazono)-4-methyl-4H-1,2,4-triazol-5-ylraethyl]-2-oxo-1,2-dihydroquinoxaline 9 , respectively.     

Synthesis and Characterization of Novel 1‐Methyl‐3‐(4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indazole Derivatives

A series of novel 1‐methyl‐3‐(4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indazoles was synthesized in three steps from 5‐(1‐methyl‐1H‐indazol‐3‐yl)‐4‐phenyl‐2H‐1,2,4‐triazole‐3(4H)‐thiones. 5‐(1‐Methyl‐1H‐indazol‐3‐yl)‐4‐phenyl‐2H‐1,2,4‐triazole‐3(4H)‐thiones were converted into 1‐methyl‐3‐(5‐(methylsulfonyl)‐4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indazoles upon methylation followed by treatment with aq. KMnO₄. The reaction of 1‐methyl‐3‐(5‐(methylsulfonyl)‐4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indazoles with Raney nickel resulted in desulphonylation to afford corresponding 1‐methyl‐3‐(4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐indazoles. All the new synthesized compounds were characterized by spectral techniques.