Sulfenocyclization of unsaturated ureas and thioureas

Summary A general method for the formation of cyclic sulfenylated 2-oxazoline, 2-thiazolines, 5,6-dihydro-4H-1,3-oxazines, and 5,6-dihydro-4H-1,3-thiazines is described. The procedure employs arylsulfenyl chloride and ethyldiisopropylamine to generate an episulfonium ion intermediate from which the cyclic products arise by internal nucleophilic displacement.

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Sulfenocyclisierung ungesättigter Harnstoffe und Thioharnstoffe

Zusammenfassung Eine allgemeine Methode zur Herstellung cyclischer sulfenylierter 2-Oxazoline, 2-Thiazoline, 5,6-Dihydro-4H-1,3-oxazine und 5,6-Dihydro-4H-1,3-thiazine wird beschrieben. Aus Arylsulfenylchlorid und Ethyldiisopropylamin entsteht ein Episulfoniumion als Zwischenprodukt; dieses bildet durch nucleophile Umlagerung die cyclischen Produkte.

     

Syntheses of copolymers containing pendant cyclic iminoethers and crosslinking reactions of these copolymers with dithiols and dicarboxylic acids

Copolymers containing pendant cyclic iminoethers were prepared by radical copolymerizations of 2-vinyl-2-oxazoline (VOZO), 5-methyl-2-vinyl-2-oxazoline (MVOZO), 4,4-dimethyl-2-vinyl-2-oxazoline (DMVOZO), 4,4-dimethyl-2-vinyl-5,6-dihydro-4H-1,3-oxazine (DMVOZI), and 4,4,6-trimethyl-2-vinyl-5,6-dihydro-4H-1,3-oxazine (TMVOZI) with styrene, methyl methacrylate (MMA), and ethyl acrylate (EA) using AIBN as an initiator. In addition, the monomer reactivity ratios of VOZO, MVOZO, DMVOZO, and DMVOZI with styrene and MMA were determined. The crosslinking reactions of these copolymers with polyfunctional thiols such as 6-(N,N-dibutyl)amino-1,3,5-triazine-2,4-dithiol (DBDT), 4,4′-oxydi(benzenedithiol) (OBDT), and pentaerythritol tetrathioglycolate (PETT), and dicarboxylic acids such as succinic acid, adipic acid, and sebacic acid were carried out at several reaction temperatures. From these results, it was found that the order of reactivity of pendant cyclic iminoethers to the thiols was VOZO > DMVOZO ≥ DMVOZI > MVOZO > TMVOZI, and that of the cyclic iminoethers to the carboxylic acids was VOZO > MVOZO ≥ DMVOZI > TMVOZI ≥ DMVOZO. Furthermore, the order of reactivity of the thiols to the cyclic iminoethers was DBDT > OBDT > PETT, and that of the dicarboxylic acids to the cyclic iminoethers was succinic acid > adipic acid > sebacic acid.     

Ring-opening polymerization of six- and seven-membered cyclic pseudoureas

The cationic ring-opening polymerization of six-membered cyclic pseudoureas, 2-(1-pyrrolidinyl)- ( 2a ) and 2-morpholino-5,6-dihydro-4H-1,3-oxazine ( 2b ), was examined, which proceeded in two different ways, depending on the nature of initiator. The polymerization of 2 with methyl p-toluenesulfonate or trifluoromethanesulfonate (MeOTf) produced poly[(N-carbamoylimino)trimethylene], while that with benzyl chloride or bromide or methyl iodide gave a polymer consisting of 1,3-diazin-2-one-1,3-diylalkylene unit (the main component) and (N-carbamoylimino)trimethylene unit. The cationic ring-opening polymerization of seven-membered cyclic pseudourea, 2-(1-pyrrolidinyl)-4,5,6,7-tetrahydro-4H-1,3-oxazepine ( 3 ) was also examined. The polymerization of 3 with MeOTf as initiator gave poly{[N-(1-pyrrolidinycarbonyl)imino]tetra-methylene}. With benzyl chloride, on the other hand, no polymerization of 3 proceeded but, instead, the quantitative isomerization of 3 to 1,1′-carbonyldipyrrolidine took place. The polymerization mechanism of 2 and 3 as well as the isomerization mechanism of 3 were discussed with comparing them to the polymerization mechanism of five-membered pseudoureas. © 1977 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 933–945, 1997     

Synthesis with 1,2-Oxazines. II. Synthesis and Properties of 2,3-dimethyl-5,6-dihydro-4H-1,2-oxaziniumiodide

Preparation of 2,3-Dimethyl-5,6-dihydro-4H-1,2-oxaziniumiodide was achieved by N-alkylation of 3-methyl-5,6-dihydro-4H-1,2-oxazine. Reactions with C-nucleophiles led to the corresponding N-methyl-perhydro-1,2-oxazine derivatives. Reaction with sodium hydride in triglyme led to 3-methyl-4-aza-1,3-pentadiene.     

Synthesis and characterization of [2-(2-phenyl-5,6-dihydro-4H-1,3-oxazinyl)] tellurenyl chloride

The synthesis and characterization of the first examples of two tellurium compounds based on 2-phenyl-5,6-dihydro-4H-1,3-oxazine substrate are described. Intramolecular Te?N interaction in [2-(2-phenyl-5,6-dihydro-4H-1,3-oxazinyl)] tellurenyl chloride is established by single X-ray crystallography.     

Rearrangements of the aminoalkylation products of tetrahydro-2H-1,3-oxazine-2-thione

The nature of the compounds afforded by the rearrangement of the aminopropylation and aminoethylation products of tetrahydro-2H-1,3-oxazine-2-thione (I) has been investigated. In both instances compounds that can be considered to result from ring opening at either the C-O or C-S bond of a hypothetical bicyclic intermediate of structure IV were obtained. The compounds required for identification of the rearrangement products have been prepared by the reaction of the 2-methylthio derivatives of 2-thiazoline, 5,6-dihydro-4H-1,3-thiazine, and 5,6-dihydro-4H-1,3-oxazine with the appropriate hydroxyalkylamine or mercaptoalkylamine.     

Syntheses and crosslinking reactions of self-curable copolymers containing pendant cyclic iminoethers and carboxylic acid groups

Soluble copolymers containing both pendant cyclic iminoethers such as 4,4-dimethyl-2-oxazoline or 4,4,6-trimethyl-4H-dihydro-1,3-oxazine and carboxylic acid were successfully synthesized by radical copolymerizations of 4,4-dimethyl-2-vinyl-2-oxazoline, 4,4-dimethyl-2-isopropenyl-2-oxazoline, or 4,4,6-trimethyl-2-vinyl-4H-dihydro-1,3-oxazine with methacrylic acid and styrene, methyl methacrylate, or ethyl acrylate using AIBN as an initiator in benzene or DMF at 60 or 80°C. The crosslinking reaction of the copolymers obtained did not occur by heating at 70°C. However, these copolymers quantitatively produced gel products by heating at 130°C. The rate of crosslinking reaction of the copolymer increased with increasing pendant cyclic iminoether and carboxylic acid groups. The rate of crosslinking was also affected by the molecular motion of the polymer chain. Our results show that the copolymers of more sterically hindered 2-vinyl-2-oxazolines are more stable and so they can be crosslinked in a controlled manner and at higher temperatures than the previously studied polyoxaziline system.     

Synthesis and reactions of 3-halomethyl-substituted oxazine N-oxides

A series of 3-halomethyl-5,6-dihydro-1,2-oxazine N-oxides (halogen = Cl, Br, I) is prepared from 4-phenyl-3,6,6-trimethyl-5,6-dihydro-4H-oxazine N-oxide by means of a silylation/halogenation sequence. The obtained halogenated N-oxides undergo reactions typical of cyclic six-membered nitronates including 1,3-dipolar cycloaddition, addition of nucleophiles, and substitution of the halogen by C-, S-, and N-nucleophiles.     

Synthesis of optically active polynucleotide analogs with polytrimethylenimine backbones and thymine moieties

Polynucleotide analogs with polytrimethylenimine backbones and optically active 2-(thymin-1-yl)propionic acids as pendants were prepared. Linear polytrimethylenimines were obtained by ring-opening polymerization of 2-phenyl-5,6-dyhydro-4H-1,3-oxazine and subsequent hydrolysis of the resulting polymers. 2-(Thymin-1-yl)propionic acids were reacted with N-hydroxy succinimide to form active esters. Optical purities of active esters were determined by NMR with chiral chemical shift reagents. The polynucloetide analogs and related monomer and dimer model compounds were prepared by grafting reactions using active esters.     

Molecular structures of methyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazol-5-carboxylate and methyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazol-3-carboxylate

The structure of methyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazol-5-carboxylate is determined by X-ray crystallography and further used to elucidate the structure of methyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazol-3-carboxylate, using the data of homo- and heteronuclear 2D NMR correlation spectroscopy.     

Bildung von 5,6-Dihydro-1,3(4H)-thiazin-4-carbonsäure-estern aus 4-Allyl-1,3-thiazol-5(4H)-onen

Formation of Methyl 5,6-Dihydro-l, 3(4H)-thiazine-4-carboxyiates from 4-Allyl-l, 3-thiazol-5(4H)-ones . The reaction of N-[1-(N, N-dimethylthiocarbamoyl)-1-methyl-3-butenyl]benzamid ( 1 ) with HCl or TsOH in MeCN or toluene yields a mixture of 4-allyl-4-methyl-2-phenyl-1,3-thiazol-5(4H)-one ( 5a ) and allyl 4-methyl-2-phenyl-1,3-thiazol-2-yl sulfide ( 11 ; Scheme 3). Most probably, the corresponding 1,3-oxazol-5(4H)-thiones B are intermediates in this reaction. With HCl in MeOH, 1 is transformed into methyl 5,6-dihydro-4,6-dimethyl-2-phenyl-1,3(4H)-thiazine-4-carboxylate ( 12a ). The same product 12a is formed on treatment of the 1,3-thiazol-5(4H)-one 5a with HCl in MeOH (Scheme 4). It is shown that the latter reaction type is common for 4-allyl-substituted 1,3-thiazol-5(4H)-ones.     

Synthesis and Structure of Quaternary Salts Derived from 2-Anilino- and 2-Benzylamino-5,6-dihydro-4H-1,3-thiazine

Substituted phenacyl bromides react with 2-anilino-5,6-dihydro-4H-1,3-thiazine at the exocyclic nitrogen atom and with 2-benzylamino-5,6-dihydro-4H-1,3-thiazine at the nitrogen atom in the ring. The structure of the reaction intermediates was elucidated, and their cyclization into 1-benzyl-2-aryl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazinium bromides was performed.     

Synthesis of poly(ethylene glycol methyl ether)-b-poly(ethylenimine) and its derivatives containing thymine and amino acids as pendants

Poly(ethylene glycol methyl ether)tosylate was prepared and used to initiate the polymerization of 2-methyl-2-oxazoline. The resulting poly(ethylene glycol methyl ether)-b-poly(N-acetyl ethylenimine) was hydrolyzed and neutralized to give poly(ethylene glycol methyl ether)-b-poly(ethyl-enimine) (PEO–PEI). 2-(thymin-1-yl)propionic acid, N-Cbz-alanine, N-Cbz-proline, N-Cbz-O-t-Bu-serine. and N-FMOC-proline were grafted onto the PEO–PEI copolymer; attempts were then made to remove the Cbz and FMOC protecting groups.     

Electrophilic cyclization of <Emphasis Type="Italic">N</Emphasis>-allyl(propargyl)-5-amino-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-4-carboxamides. Synthesis of 4-[(dihydro)oxazol-2-yl]-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-5-amines

N-Allyl-5-amino-1H-pyrazole-4-carboxamides in reactions with polyphosphoric acid, with N-halosuccinimides in chloroform, and with (chlorosulfanyl)benzenes in nitromethane in the presence of lithium perchlorate underwent cyclization involving the N-allylamide fragment to give 4-[5-methyl(halomethyl)-4,5-dihydrooxazol-2-yl]-1H-pyrazol-5-amines and 2-(5-amino-1H-pyrazol-4-yl)-5-[(arylsulfanyl)methyl]-4,5-dihydro-1,3-oxazolium perchlorates, respectively. Analogous reactions of N-propargyl-5-amino-1H-pyrazole-4-carboxamides with polyphosphoric acid afforded 4-(5-methyloxazol-2-yl)-1H-pyrazol-5-amines, and with (chlorosulfanyl) benzenes, 2-(5-amino-1H-pyrazol-4-yl)-5-[(arylsulfanyl)methylidene]-4,5-dihydro-1,3-oxazolium perchlorates.     

Products from furans. VI. Synthesis of dihydro-2-disubstituted-2H-pyran-3(4H)-ones,tetrahydro-3-(aminomethyl)-2-(p-methoxyphenyl)-2-methyl-2H-pyran-3-ol derivatives and 6-(p-methoxyphenyl -6-methyl-7-oxa-1,3-diazaspiro[4,5]decane-2,4-dione

Hydrogenolysis of 5,6-dihydro-6-(p-methoxyphenyl)-6-methyl-5-oxo-2H-pyran-2-yl ethyl carbonate yielded dihydro-2-(p-methoxyphenyl)-2-methyl-2H-pyran-3(4H)-one, 3 . Subsequently cyanohydrin 4 , derived from 3 , on reduction afforded 3-(aminomethyl)tetrahydro-2-(p-methoxyphenyl)-2-methyl-2H-pyran-3-ol, 5 . The synthesis of N-dimethyl,N-isopropyl,N-imidazolyl as well as N-oxazolinyl derivatives of 5 is presented. The synthesis of 6-(p-methoxyphenyl)-6-methyl-7-oxa-1,3-diazaspiro[4,5]decane-2,4-dione 10 , a spiro hydantoin prepared from ketone 3 is also reported.     

Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with various bases (acetate, triethylamine, Na₂CO₃) to give either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to N isobenzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If ammonia was used in reaction with N,N′-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas in parallel reaction with the yields increasing with ammonia concentration. The formation of isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-dimethylhydrazine.     

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 ).     

Stereoselective Synthesis of trans-Olefins by the Copper-Mediated S(N)2' Reaction of Vinyl Oxazines with Grignard Reagents. Asymmetric Synthesis of D-threo-Sphingosines

The S_N2′ reaction of 6-vinyl-5,6-dihydro-4H-[1,3]oxazines with Grignard reagents in the presence of CuCN was studied, and high trans selectivity for the formation of double bond was observed with a variety of RMgX. The S_N2′ reaction, coupled with regioselective asymmetric aminohydroxylation reaction, provided a highly efficient route for the asymmetric synthesis of d-threo-N-acetylsphingosine.     

Features of the reaction of 4-bromobut-2-enylphosphonium salts with monosubstituted hydrazines

(4-Bromobut-2-en-1-yl)triphenylphosphonium bromide reacted with phenylhydrazine at 2°C in the presence of sodium carbonate to form triphenyl[4-(2-phenylhydrazinylidene)but-2-en-1-yl]phosphonium bromide in 62% yield. The obtained N-phenylhydrazine derivatives cyclized into the corresponding pyrazoline derivatives of phosphonium salts. Unlike phenylhydrazine, ethylhydrazine reacted with (4-bromobut-2-ene-1-yl)triphenylphosphonium bromide under the same conditions to afford triphenyl[(1-ethyl-4,5-dihydro-1Hpyrazol-3-yl)methyl]- and -[(1-ethyl-1H-pyrazol-3-yl)methyl]phosphonium bromides in yields of 60 and 40%.     

Reactions of 1,2,4-triazole derivatives with a “model” thiirane

Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a “model” thiirane, 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-2,6-diones proceed at the positions N¹ and N² of the triazole ring and yield 7-(5-R-3-R′-1,2,4-triazol-1-yl)methyl- and/or 7-(5-R′-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7-dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4-triazole reacted regiospecifically at the position N¹ forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3]thiazolo-[2,3-f]purine-2,4(1H,3H)-dione.