Ring-Enlargement and Ring-Opening Reactions of 1,2-Thiazetidin-3-one 1,1-Dioxides with Ammonia and Primary Amines as Nucleophiles

The N-benzyl- and N-alkyl-substituted 1,2-thiazetidin-3-one 1,1-dioxides 1b – d reacted readily with NH₃ and primary amines via ring opening. The reaction with NH₃ proceeded at −78°→room temperature yielding ring-opened adducts via nucleophilic attack of NH₃ at the sulfonyl group, whereas the reactions with amines at room temperature yielded products via attack at the carbonyl group. The N-unsubstituted analogue 1a , when reacted with benzylamine in refluxing EtOH, also gave a product of ring opening via nucleophilic attack at the carbonyl group of 1a . The transamidation-like reactions of the 2-(aminoalkyl)-1,2-thiazetidin-3-one 1,1-dioxides 19a – d proceeded via six-, seven-, and eight-membered intermediates, giving the ring-enlarged eight-, nine-, and ten-membered products 21 – 24 (Schemes 8 and 9), respectively, in 42 – 87% yields. The products resulted from the nucleophilic attack of the amino group of the side chain at the carbonyl C-atom. The structure of the eight-membered product 24 with an asymmetrically situated methyl substituent was established by X-ray crystallography.     

Synthesis of 1,2,5-Thiadiazepine Derivatives by Ring Enlargement of 1,2-Thiazetidin-3-one 1,1-Dioxides with 3-Amino-2H-azirines

At 0° in MeCN, 2,2-disubstituted 3-amino-2H-azirines 1 and 4,4-disubstituted 1,2-thiazetidin-3-one 1,1-dioxides 7 react smoothly to give 1,2,5-thiadiazepin-6-one 1,1-dioxides of type 8 (Scheme 2). The reaction mechanism of this regiospecific ring enlargement to seven-membered heterocycles follows previously described pathways. The structures of 7a and 8b were established by X-ray crystallography (see Figs. 1 and 2).     

Synthesis of Tetrahydrothiophene 1,1-Dioxides Fused to Oxazolidin-2-one and Morpholin-2-one Fragments

While developing methods of synthesis of sulfolanes fused through the C³–C⁴ bond to oxazolidin-2- one and morpholin-2-one fragments, the reactivity of cis- and trans-isomeric amino alcohols of the sulfolane series toward a number of cyclizing agents was studied. The cis isomers reacted with dimethyl acetylenedicarboxylate and triphosgene to afford the corresponding morpholin-2-ones and oxazolidin-2-ones, whereas the trans isomers gave rise to open-chain aminofumarates and urea derivatives, respectively. The reactions of both cis- and trans-amino alcohols with oxalic acid derivatives (diethyl oxalate, oxalyl chloride) led to the formation of exclusively acyclic mono- and/or diamides.     

New 6-Arylsulfonyl-1,2-benzoisothiazol-3(2H)-one 1,1-Dioxides Derived from Diphenyl Sulfone Monosulfonyl Chlorides

Various methods were studied for the oxidation of 2-methyl-5-(phenylsulfonyl)benzenesulfamide and its derivatives. The oxidation by sodium dichromate in sulfuric acid was found most efficient. The effects of temperature, concentration, reagent ratio, and time of the oxidation reaction on the yield of the desired product were investigated. Conditions were proposed for obtaining the desired product in yields up to 95%. A synthesis was developed for a series of new saccharin derivatives.     

Synthesis and Structure of Bromonitrothiolene 1,1-Dioxides

A procedure was developed for preparing mono- and dibromo derivatives of 4-nitro-2- and 3-thiolene 1,1-dioxides, and their structures were studied. The molecular geometry and structural parameters of 4-bromo-3-methyl-4-nitro-2-thiolene 1,1-dioxide were determined by single crystal X-ray diffraction.     

Properties and Reactions of Substituted 1,2-Thiazetidine 1,1-Dioxides: Synthesis of N-Substituted 4,4-dimethyl-1,2-thiazetidin-3-one 1,1-dioxides,and a new base-catalyzed rearrangement to thiazolidin-4-one 1,1-dioxides

Alkylation of 3-oxo-1,2-thiazetidine 1,1-dioxide 2 yields the N-alkylated 3-oxo-β-sultams 3a-i . Solvolysis with NaOH or NH₃ selectively opens the N? S bond forming the sulfonate carboxamides 4 and the sulfonamidocarboxamides 7 , respectively. Furthermore, the hitherto unknown compounds of type 5 are prepared, representing a strained four-membered ring with a diacylated, sulfonated N-atom. Depending upon the reaction conditions, 3b-d and 3g are rearranged by base-catalyzed reactions into the substituted 4-oxothiazolidine 1,1-dioxides 9 or 10. Structures are elucidated by spectroscopic methods, established by crystal-structure analyses, and a possible way of formation is proposed. Furthermore, some side reactions and transformations are reported.     

Cyclosulfamides as Constraint Dipeptides: The Synthesis and Structure of Chiral Substituted 1,2,5-Thiadiazolidine 1,1-Dioxides: Evaluation of the Toxicity

A general synthesis for the preparation of chiral N-N′ substituted 1,2,5-thiadiazolidine 1,1-dioxides has been developed beginning with proteogenic amino acid, sulfuryl chloride, and dibromoethane. The selected chemistry and spectral properties of these compounds are examined. Overall, routes described are applicable to the synthesis of a variety of constrained dipeptidal sulfamides representing novel peptidomimetic scaffolds.     

Synthetic Modification of 1,3-Thiazolidin-4-One 1,1-Dioxides

Abstract

The reactivity of EWG (electron withdrawing group)-activated methylene group in 1,3-thiazolidin-4-one 1,1-dioxides were investigated. Novel derivatives of 1,3-thiazolidin-4-one 1,1-dioxides were prepared (the heterocyclic core was modified with carboxamide and carboxthioamide moieties as carbonyl group analogues). The products, which have functional groups for possible future modifications, are described and characterized.     

Synthesis of 1,2,5-Thiadiazolidin-3-one 1,1-Dioxide Derivatives and Evaluation of Their Affinity for MHC Class-II Proteins

1,2,5-Thiadiazolidin-3-one 1,1-dioxide derivatives (±)- 1a – d and (±)- 2 were designed by molecular modeling as MHC (major histocompatibility complex) class-II inhibitors. They were prepared from the unsymmetrically N,N′-disubstituted acyclic sulfamides (±)- 4a – d (Scheme 1) and (±)- 11 (Scheme 2). These N-alkyl-N′-arylsulfamide precursors were synthesized by nucleophilic substitution of either a sulfamoyl-chloride or a N-sulfamoyloxazolidinone. Extension of base-induced cyclization methods from aliphatic to aromatic sulfamides gave access to the desired target molecules. The N-alkyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives (±)- 3a – c were also prepared by the oxazolidinone route (Scheme 4) for coupling to a tetrapeptide fragment. The X-ray crystal structure of 1,2,5-thiadiazolidin-3-one 1,1-dioxide (±)- 21a was solved, and the directionality of the H-bond donor (N−H) and acceptor (SO₂) groups of the cyclic scaffold determined (Figs. 1 and 2). The pK_a value of the N−H group in (±)- 21a was determined by ¹H-NMR titration as 11.9 (Fig. 3). Compounds (±)- 1a – d were shown to inhibit competition peptide binding to HLA-DR4 molecules in the single-digit millimolar concentration range.     

Reaction of 1-chloromethyl-4,5-dichloropyridazin-6-one

Reaction of 1-chloromethyl-4,5-dichloropyridazin-6-one with some nucleophiles such as sodium methoxide, sodium azide, 2-mercaptopyrimidine and phenol gave 2, 3, 4, 7, 8 and 10 . 5-Chloro-4-phenoxypyridazin-6-one ( 10 ) was also synthesized from 8 through 9.     

Formation and Ring Contraction of Benzo[f][1,2]Thiazepine-1,1-Dioxides from and to Benzo[e][1,2]Thiazine-1,1-Dioxides

Alkoxide-promoted ring expansion of the novel ethyl 2-(6,7-dimethoxy-3-oxo-3,4-dihydrobenzo[e][1,2]thiazine-1,1-dioxide-2-yl)acetate 3a and analogous 4,4-diethyl derivative 3b and cyclization of methyl 2-[2-(phenylaminocarbonylmethyl sulfamoyl)-4,5-dimethoxyphenyl] acetate 9 to the corresponding new 3-carboxylates and 3-carboxanilide of 7,8-dimethoxy-4-hydroxy-2,5-dihydrobenzo[f][1,2]thiazepine-1,1-dioxide (5a,b and 10 respectively) is described. Compound 5a was deacylated upon treatment with sodium hydroxide followed by hydrochloric acid to give 7,8-dimethoxy-2,3-dihydrobenzo[f][1,2]thiazepine-1,1-dioxide-4 (5H)-one 8 and its N-ethyl derivative transferred to 6,7-dimethoxy-2-ethyl-3-oxo-3,4-dihydrobenzo[e][1,2]thiazine-1,1-dioxide 7 by the reaction with ethyl methyl ketone in the presence of pyrrolidine.     

Halo Derivatives of 2,4-Dinitrothiolene 1,1-Dioxides: Synthesis and Structure

Procedures were developed for preparing representatives of a new type of halonitrothiolene 1,1-dioxides: mono- and dihalo derivatives of 2,2,4-tri- and 2,4-dinitro-3-thiolene 1,1-dioxides. An X-ray diffraction study showed that 2,5-dinitro-2,3-dichloro-3-thiolene 1,1-dioxide molecules exist in the crystal as enantiomeric pairs; the five-membered rings have the envelope conformation, with deviation of the sulfur atom from the ring plane; the halogen atom and nitro group at the multiple bond are essentially coplanar with the ring.     

Synthesis and antiarrhythmic activity of 2,5-disubstituted 2,3-dihydro-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxides.

A series of 2,5-disubstituted 2,3-dihydro-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide derivatives were prepared and evaluated for the antiarrhythmic effect on ouabain-induced arrhythmias in guinea pigs. Most of the synthesized compounds showed the antiarrhythmic activity in this primary screening system. Some of the compounds with 2-(N,N-dimethylamino)ethyl, 2-(pyrrolidin-1-yl)ethyl and 2-oxo-2-(morpholin-4-yl)ethyl moieties on the 5-position of 1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide exhibited a potent antiarrhythmic activity. The structure-activity relationship of these compounds was discussed.     

A Synthetic and Stereochemical Study of 2,6-Diaroyl-3,5-Diaryl-4-Ethyltetrahydro-1,4-Thiazine-1,1-Dioxides

Double aza-Michael addition of ethylamine over 2,2'-sulfonylbis(1,3-diarylprop-2-en-1-ones) gave the previously unknown title compounds in moderate yields. The decreased yields of the title compounds compared to 2,6-diaroyl-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxides or the corresponding 4-methyl derivatives is explained on the basis of steric size of the nucleophile. The structure and stereochemistry of the thianes have been deduced from elemental analyses and spectroscopic data.     

Reaction of 3-methoxy-17-methylmorphinan-6-one with formaldehyde

Reaction of 3-methoxy-17-methylmorphinan-6-one ( 1 ) and formaldehyde with the presence of calcium hydroxide in aqueous dioxane gave 7,7-bis(hydroxymethyl)-3-methoxy-17-methyl-5-methylenemorphinan-6β-ol ( 2a ). Catalytic reduction of 2a yielded the 5α-methyl compound, 2b . Tosylation of 2a,b followed by lithium triethylborohydride reduction gave either 7α-methyl-6β,7β-oxetanes 4a,b or 7,7-dimethyl-6β-ols 5a,b , depending on reaction conditions. The C-6 ketones 6a,b were prepared by oxidation of 5a,b . One compound in this series, 6a , had antinociceptive activity.