Synthesis of 3-substituted 4H-1-benzothiopyran-4-ones

3-Substituted 2-phenyl-4H-1-benzothiopyran-4-ones (thioflavones) were prepared to test antimicrobial activity. It was found that 3-(phenyl)thiochromone derivatives (isothioflavones) were prepared by the Meerwein reaction of thiochromone with p-nitrobenzenediazonium ion. 3-(Formyl)thioflavone exhibits weak antimicrobial activity against Trichophytons and Candida.     

Synthesis and absorption spectra of 2-substituted 5,8-dimethoxy-4H-1-benzothiopyran-4-one 1,1-dioxides

2,3-Dibromo-5,8-dimethoxy-4H-1-benzothiopyran-4-one (thiochromone) 1,1-dioxide which was a starting material to prepare sulfone analogues of 1,4-naphthoquinone dyes was easily prepared from 5,8-dimethoxythiochroman-4-one by oxidation and bromination. The reactions of 2,3-dibromo-5,8-dimethoxythiochromone 1,1-dioxide 4 with aliphatic and aromatic amines in ethanol below 20° gave 2-substituted derivatives 12a-e and at higher reaction temperature the amination gave 2-arylamino derivatives 13c-e debrominated at C -3. The visible absorption spectra of these derivatives were investigated by the PPP MO method.     

Stepwise Oxidation of Thiophene and Its Derivatives by Hydrogen Peroxide Catalyzed by Methyltrioxorhenium(VII)

The oxidation of thiophene derivatives by hydrogen peroxide is catalyzed by methyltrioxorhenium(VII) (CH(3)ReO(3)). This compound reacts with hydrogen peroxide to form 1:1 and 1:2 rhenium peroxides, each of which transfers an oxygen atom to the sulfur atom of thiophene and its derivatives. Complete oxidation to the sulfone occurs readily by way of its sulfoxide intermediate. The rates for each oxidation step of dibenzothiophenes, benzothiophenes, and substituted thiophenes were determined. The rate constants for the oxidation of the thiophenes are 2-4 orders of magnitude smaller than those for the oxidation of aliphatic sulfides, whereas the rate constants are generally the same for the oxidation of the thiophene oxides and aliphatic sulfoxides. The rate constant for conversion of a sulfide to a sulfoxide (thiophene oxide) increases when a more electron-donating substituent is introduced into the molecule, whereas the opposite trend was found for the reaction that converts a sulfoxide to a sulfone (thiophene dioxide). Mechanisms consistent with this are proposed. The first trend reflects the attack of the nucleophilic sulfur atom of a thiophene center on a peroxide that has been electrophilically activated by coordination to rhenium. The second, more subtle, trend arises when both sulfoxide and peroxide are coordinated to rhenium; the inherently greater nucleophilicity of peroxide then takes control.     

Bacterial dioxygenase- and monooxygenase-catalysed sulfoxidation of benzo[b]thiophenes

Asymmetric heteroatom oxidation of benzo[b]thiophenes to yield the corresponding sulfoxides was catalysed by toluene dioxygenase (TDO), naphthalene dioxygenase (NDO) and styrene monooxygenase (SMO) enzymes present in P. putida mutant and E. coli recombinant whole cells. TDO-catalysed oxidation yielded the relatively unstable benzo[b]thiophene sulfoxide; its dimerization, followed by dehydrogenation, resulted in the isolation of stable tetracyclic sulfoxides as minor products with cis-dihydrodiols being the dominant metabolites. SMO mainly catalysed the formation of enantioenriched benzo[b]thiophene sulfoxide and 2-methyl benzo[b]thiophene sulfoxides which racemized at ambient temperature. The barriers to pyramidal sulfur inversion of 2- and 3-methyl benzo[b]thiophene sulfoxide metabolites, obtained using TDO and NDO as biocatalysts, were found to be ca.: 25-27 kcal mol(-1). The absolute configurations of the benzo[b]thiophene sulfoxides were determined by ECD spectroscopy, X-ray crystallography and stereochemical correlation. A site-directed mutant E. coli strain containing an engineered form of NDO, was found to change the regioselectivity toward preferential oxidation of the thiophene ring rather than the benzene ring.     

Mechanism of the oxidation of sulfides by dioxiranes. 1. Intermediacy of a 10-S-4 hypervalent sulfur adduct

Earlier studies established that dimethyldioxirane (1a) reacts with sulfides 2 in two consecutive concerted electrophilic oxygen-transfer steps to give first sulfoxides 3 and then sulfones 4. The same sequential electrophilic oxidation model was assumed for the reaction of sulfides 2 with the strongly electrophilic methyl(trifluoromethyl)dioxirane (1b). In this paper we report on a systematic and general study on the mechanism of the reaction of simple sulfides 2 with DMDO (1a) and TFDO (1b) which provides clear evidence for the involvement of hypervalent sulfur species in the oxidation process. In the oxidation of sulfides 2a-c, diphenyl sulfide (2d), para-substituted aryl methyl sulfides 2e-i, and phenothiazine 2k with 1b, the major product was the corresponding sulfone 4, even when a 10-fold excess of sulfide relative to 1b was used. The sulfone:sulfoxide 4:3 ratio depends among other factors on the dioxirane 1a or 1b used, the sulfide substitution pattern, the polar, protic, or aprotic character of the solvent, and the temperature. The influence of these factors and also deuterium and (18)O tracer experiments performed allow a general mechanism to be depicted for these oxidations in which the key step is the reversible cyclization of a zwitterionic intermediate, 6, to form a hypervalent sulfur species, 7. The classical sequential mechanism which establishes that sulfides are oxidized first to sulfides and then to sulfones can be enclosed in our general picture of the process and represents just those particular cases in which the zwitterionic intermediate 6 decomposes prior to undergoing ring closure to afford the hypervalent sulfurane intermediate 7.     

1H chemical shifts in NMR. Part 27: proton chemical shifts in sulfoxides and sulfones and the magnetic anisotropy, electric field and steric effects of the SO bond

The (1)H chemical shifts of a series of sulfoxide and sulfone compounds in CDCl(3) solvent were obtained from experiment and the literature. These included dialkyl sulfoxides and sulfones (R(2)SO/R(2)SO(2), R = Me, Et, Pr, n-Bu), the cyclic compounds tetramethylene sulfoxide/sulfone, pentamethylene sulfoxide/sulfone and the aromatic compounds p-tolylmethylsulfoxide, dibenzothiopheneoxide/dioxide, E-9-phenanthrylmethylsulfoxide and (E) (Z)-1-methylsulfinyl-2-methylnaphthalene. The spectra of the pentamethylene SO and SO(2) compounds were obtained at -70 degrees C to obtain the spectra from the separate conformers (SO) and from the noninverting ring (SO(2)). This allowed the determination of the substituent chemical shifts (SCS) of the SO and SO(2) functional groups, which were analyzed in terms of the SO bond electric field, magnetic anisotropy and steric effect for long-range protons together with a model (CHARGE8d) for the calculation of the two and three bond effects. After parameterization, the overall root mean square (RMS) error (observed-calculated) for a dataset of 354 (1)H chemical shifts was 0.11 ppm. The anisotropy of the SO bond was found to be very small, supporting the dominant single bond S(+)--O(-) character of this bond.     

(E)-3-(2-Alkyl-10H-phenothiazin-3-yl)-1-arylprop-2-en-1-ones: Preparative, IR, NMR and DFT study on their substituent-dependent reactivity in hydrazinolysis and sonication-assisted oxidation with copper(II)nitrate

A series of novel 3(5)-aryl/ferrocenyl-5(3)-phenothiazinylpyrazoles and pyrazolines were obtained by substituent-dependent regioselective condensation of the corresponding (E)-3-(2-alkyl-10H-phenothiazin-3-yl)-1-aryl/ferrocenylprop-2-en-1-one with hydrazine or methylhydrazine in acetic acid. The different propensity of the primary formed beta-hydrazino adducts to undergo competitive retro-Mannich reaction was interpreted in terms of tautomerisation equilibrium constants calculated by DFT using a solvent model. The regioselectivity of the cyclisation reactions with methylhydrazine and the substituent-dependent redox properties of pyrazolines were also rationalized by comparative DFT calculations performed for simplified model molecules. On the effect of ultrasound-promoted oxidation with copper(II)nitrate phenothiazine-containing pyrazolines, enones and oxo-compounds were selectively transformed into sulfoxides. Only one sulfoxide enone was partially converted into an oxirane derivative. The structure of the novel products was determined by IR and NMR spectroscopy including COSY, HSQC, HMBC and DNOE measurements.     

Oxidative induction of beta-turn conformations in cyclic peptidomimetics: conformational analyses as indicators of configuration

Solid-phase syntheses of the cyclic peptidomimetics 1-4 were performed. Sulfide 1 and sulfoxide 3 did not tend to exist in beta-turn conformations in solution, but the sulfone 2 and the epimeric sulfoxide 4 did. The assignment of configuration of the sulfoxides is based on the conformational analyses.     

Reaction of magnesium alkylidene carbenoids with lithium alpha-sulfonyl carbanions: a novel synthesis of tri- and tetra-substituted allenes from 1-chlorovinyl p-tolyl sulfoxides and sulfones

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from ketones and chloromethyl p-tolyl sulfoxide, with ethylmagnesium chloride or isopropylmagnesium chloride at below -78 degrees C gave magnesium alkylidene carbenoids in about 90% yields. The reaction of the generated carbenoids with lithium alpha-sulfonyl carbanions was found to afford tri- and tetra-substituted allenes. Both cyclic ketones and acyclic ketones were useful in this procedure. However, the 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes gave only rearranged products, acetylenes, under the reaction conditions. The magnesium alkylidene carbenoid derived from an optically active 1-chlorovinyl p-tolyl sulfoxide was treated with lithium alpha-carbanion of 1-naphthyl phenyl sulfone; however, the obtained allene was found to be racemic. The mechanism of this reaction is also discussed.     

Oxidation of organic sulfides by vanadium haloperoxidase model complexes

In addition to halide oxidation, the vanadium haloperoxidases are capable of oxidizing sulfides to sulfoxides. Four vanadium complexes with tripodal amine ligands, K[VO(O(2))(heida)] (1), VO(2)(bpg) (2), K[VO(2)(ada)] (3), and K(2)[VO(O(2))(nta)] (4), previously shown to perform bromide oxidation (Colpas, G. J.; Hamstra, B. J.; Kampf, J. W.; Pecoraro, V. L. J. Am. Chem. Soc. 1996, 118, 3469-3477), have now been shown to oxidize aryl alkyl sulfides to the corresponding sulfoxides. The oxidation was observed by the disappearance of thioanisole's ultraviolet absorption at 290 nm, by the change in the aromatic region of the (1)H NMR spectrum of the sulfides, and by changes in the complexes' (51)V NMR spectra. The amount of methyl phenyl sulfide oxidized in 3 h was 1000 equiv (per metal complex). The oxidation product is almost exclusively sulfoxide, with very little sulfone (less than 3% over a 3 h experiment) formed. This is consistent with an electrophilic oxidation mechanism, as had been proposed for oxidation of bromide by 1-4. The rate was found to be first order in substrate concentration, similar to the rate law observed for bromide oxidation. Unlike the bromide oxidation, the equivalent of acid required for peroxovanadium complex activation is not consumed. The complexes 1-4 are not reactive with styrene or cyclooctene. The relevance of these reactions to the mechanism of the vanadium haloperoxidases and, more generally, peroxovanadium oxygenation of sulfides will be discussed.     

Preparation of 4-hydroxy-3-substituted, 2H-1-benzopyran-2-ones and 2H-1-benzothiopyran-2-ones from carboxylic esters and methyl salicylates or methyl thiosalicylate

C(α)-Carboxylic acid esters were treated with excess lithium diisopropylamide, condensed with methyl salicylates or methyl thiosalicylate, followed by acid cyclization to either 4-hydroxy-3-substituted, 2H-1-benzopyran-2-ones (coumarins), or 2H-1-benzothiopyran-2-ones (thiocoumarins).     

1H, 13C, 17O NMR and quantum‐chemical study of the stereochemistry of the sulfoxide and sulfone derivatives of 3‐arylidene‐1‐thioflavan‐4‐one epoxides

The oxidation of the trans,cis‐( 2 ) and trans,trans‐epoxides ( 3 ) of differently substituted (Z)‐3‐arylidene‐1‐thioflavan‐4‐ones ( 1 ) with dimethyldioxirane (DMD) yielded the appropriate sulfoxides ( 4, 5 ) and sulfones ( 6, 7 ). The structures were elucidated by the extensive application of one‐ and two‐dimensional ¹H, ¹³C and ¹⁷O NMR spectroscopy. The conformational analysis was achieved by the application of ³J(C,H) coupling constants, NOESY responses and ab initio calculations. The preferred ground‐state conformers (twisted envelope‐A, twisted envelope‐B for 6 and twisted envelope‐A, envelope‐B for 7 ) were obtained as global minima of the theoretical ab initio MO study and also the examination of the ¹⁷O and ¹³C chemical shifts, calculated for the global minima structures of the sulfone isomers by the GIAO method. Analogous results, obtained for the sulfoxide isomers ( 4, 5 ), not only led to the preferred conformers but also gave evidence for the trans arrangement of the 2‐Ph group and the oxygen atom of the S?O group. Chemical shift differences between the isomers, sulfoxides and sulfones were corroborated by ab initio calculations of the anisotropic effects of the oxirane ring and the S?O and SO₂ groups. Copyright © 2003 John Wiley & Sons, Ltd.     

The preparation of 3,5-disubstituted tetrahydro-4H-1,3,5-oxadiazine-4-thiones,tetrahydro-4H-1,3,5-thiadiazin-4-ones,and tetrahydro-4H-1,3,5-thiadiazine-4-thiones

The reaction of 1,3-disubstituted thioureas with formaldehyde under acidic conditions with removal of water yielded 3,5-disubstituted tetrahydro-4H-1,3,5-oxadiazine-4-thiones. When hydrogen sulfide was bubbled through the reaction mixture, the corresponding tetrahydro-4H-1,3,5-thiadiazine-4-thiones were formed. Similarly, starting from 1,3-disubstituted ureas, a number of tetrahydro-4H-1,3,5-thiadiazine-4-ones were prepared. The latter compounds were also oxidized to the corresponding sulfoxides and sulfones.     

Enantioselective synthesis of (+)- and (-)-dihydroepiepoformin and (+)-epiepoformin

[reaction: see text] The enantioselective synthesis of both enantiomers of dihydroepiepoformin (1) and (+)-epiepoformin (2) was achieved from (p-tolylsulfinyl)methyl-p-quinols (SR)- or (SS)-3 and (4R,SR)-4, respectively. Key features include the stereocontrolled conjugate addition of AlMe3 to p-quinol 3 and retrocondensation to the ketone functionality, previous to oxidation of the beta-hydroxy sulfoxide moiety of advanced intermediates to the corresponding sulfone.     

Photoisomerization of 2H,6H-thiin-3-one 1-oxides to 3H,7H-[1,2]oxathiepin-4-ones

Oxidation of 2H, 6H-thiin-3-ones 1a – c with 3-chloroperbenzoic acid affords the corresponding 1-oxides 2a – c . On irradiation (350 nm) in either benzene or MeCN, these cyclic sulfoxides 2 isomerize to 3H, 7H-1,2-oxathiepin-4-ones 3 . The tetramethyl derivative 3a is isolated by flash chromatography at ?10°, but, at higher temperatures, it undergoes ring contraction and H₂O elimination to give 4,4-dimethyl-2(2-methylprop-2enylidene)thietan-3-one ( 4 ). Diemthyloxathiepinones 3b and 3c undergo ring contraction in MeOH to afford 1-(4-methylthiophen-2-yl)ethanone ( 5 ) and two diastereoisomeric 4,4-dimethyl-2-methoxy-2-(1-methoxyethyl)thietan-3-ones ( 6 and 7 , respectively).     

Bis-β-sulfanylethylester and cyclic disulfide-S-oxides as precursors of bifunctionalized anionic derivatives with two oxidized sulfurs

The cyclic disulfide and the bis-β-sulfanyl ethyl ester derived from dithiol, N,N′-1,2-phenylenebis(3-methyl-3-sulfanylbutanamide) were used as precursors to prepare upon oxidation the cyclic disulfide-S-oxides and the thioether sulfur oxidized species including thioether/sulfoxide, bis-sulfoxide, sulfoxide/sulfone, and bis-sulfone. Ring cleavage with KOH/EtOH of the cyclic disulfide-S-monooxide followed by reaction of the opened intermediate with ethyl acrylate afforded the sulfinate/β-sulfanyl ethyl ester derivative. Selective oxidation with 1 and 2 equiv of (3S)-3-tert-butyl-3-methyl-2-(phenylsulfonyl)oxaziridine or with 3 equiv of DMD led to the isolation of a series of compounds containing a sulfonate and a β-sulfanyl, a β-sulfinyl, and a β-sulfonyl ethyl ester. Retro-Michaël reaction applied to the β-sulfonyl/β-sulfinyl and bis-β-sulfonyl derivatives enabled to produce compounds containing a sulfinate and a β-sulfinyl or a β-sulfonyl ethyl ester as well as the bis-sulfinate dianion. DMD oxidation of the latter afforded the bis-sulfonate dianion. All these anionic species were characterized by ¹H NMR, mass spectrometry, HRMS or elemental analysis. Sulfenates in such pseudopeptidic structures could not be isolated from the ring cleavage of the cyclic disulfide-S-dioxide or from a retro-Michaël reaction applied to the β-sulfinyl ethyl ester. A cyclization reaction leading to an isothiazolidin-3-one is likely to occur as observed from the ring cleavage of the cyclic disulfide-S-dioxide. Finally, Ni(II) and Co(III) have been inserted into the disulfinate dianion leading to the corresponding diamidato/disulfinato complexes S-bonded to Ni(II) or Co(III) centers.     

Simple thiazocine-2-acetic acid derivatives via ring-closing metathesis

A new protocol for synthesis of 2-heterocylylacetic acid derivatives involving conjugate addition of allyl mercaptan to an acrylate containing a tethered olefinic site followed by RCM (ring-closing metathesis) is described. In this series, sulfanyl derivatives were unreactive, while sulfoxide and sulfone analogues provided the corresponding thiazocines in fair to excellent yields. Use of the sulfoxide oxidation state as a protecting group for sulfides inert to RCM is demonstrated also. Thus, oxidation of sulfide 9 [N-allyl-N-[2-(allylthio)-4-(1H-indol-1-yl)-4-oxobutyl]-4-methylbenzenesulfonamide] followed by cyclization yielded the corresponding thiazocine sulfoxide 12. Deprotection (deoxygenation) of 12 was accomplished using Lawesson's reagent, producing 1-[[4-[4-(methylphenyl)sulfonyl]-3,4,5,8-tetrahydro-2H-1,4-thiazocin-2-yl]acetyl]-1H-indole (21) in 67% unoptimized yield.     

Effect of Organic Solvents on the Rate of Oxidation of Sulfoxides with Peroxy Acids

The reaction of sulfoxides with peroxy acids in various organic media was studied. The reaction mechanism involves the rapid formation of a sulfoxide­–peroxy acid intermediate which decomposes in the second stage to form carboxylic acid and the corresponding sulfone. The second stage is the rate-limiting step. The reaction medium significantly affects the rate of oxidation. The calculated activation parameters of the oxidation process indicate a compensation effect in the investigated reaction. Correlations between the main physicochemical parameters of solvents and the effective rate constants (k) of dimethyl sulfoxide oxidation with peroxy acids were found. Depending on the reaction conditions, the main factors affecting the k values are specific and nonspecific solvation of the reactants and structural factors.     

Sulfide and sulfoxide oxidations by mono- and diperoxo complexes of molybdenum. A density functional study

The molecular mechanism for the oxidation of sulfides to sulfoxides and subsequent oxidation to sulfones by diperoxo, MoO(O(2))(2)(OPH(3)) (I), and monoperoxo, MoO(2)(O(2))(OPH(3)) (II), complexes of molybdenum was studied using density functional calculations at the b3lyp level and the transition state theory. Complexes I and II were both found to be active species. Sulfide oxidation by I or II shows similar activation free energy values of 18.5 and 20.9 kcal/mol, respectively, whereas sulfoxides are oxidized by I (deltaG = 20.6 kcal/mol) rather than by II (deltaG = 30.3 kcal/mol). Calculated kinetic and thermodynamic parameters account for the spontaneous overoxidation of sulfides to sulfones as has been experimentally observed. The charge decomposition analysis (CDA) of the calculated transition structures of sulfide and sulfoxide oxidations revealed that I and II are stronger electrophilic oxidants toward sulfides than they are toward sulfoxides.     

Highly selective sulfoxidation of allylic and vinylic sulfides by hydrogen peroxide using a flavin as catalyst

A highly chemoselective oxidation of allylic and vinylic sulfides to the corresponding sulfoxides has been developed using flavin 1 as the oxidation catalyst and hydrogen peroxide as the terminal oxidant. The sulfoxides were formed in good to excellent yields in a highly selective manner even when an excess of the oxidant was used. Sulfone formation was completely suppressed to <0.5% (in one single case 1.5% sulfone was detected). No epoxidation of double bonds or interference with other functional groups was observed under the reaction conditions. The general applicability was demonstrated by the selective oxidation of various allylic and vinylic sulfides having different electronic properties. A number of functionalities including hydroxy, acetoxy, amino, silyloxy, and formyl groups are tolerated under these mild reaction conditions.