Reduced Thiopyrans

Reduced Thiopyrans.—The tetrahydrothiopyran-3,5-dione (73) has been synthesized by treatment of the keto-diester (72) with butoxide, and it is cyclized by barium hydroxide to the furothiopyrone (74), which is a potential synthon for natural furans. Partial reduction of the dione (73) and dehydration gave the dihydrothiopyrone (75). 

Bernasconi, C. Capellini, A. Corbella, M. Ferrari, P. Gariboldi, G. Jommi, and M. Sisti, Gazz. Chim. Itai, 1979, 109, 5. 

Acrolein has been cyclized, in excellent yield, with hydrogen sulphide and copper in triethylamine, at -10 °C, to 5,6-dihydro-2//-thiopyran-3-carboxalde-hyde, whose oxime has a slightly sweet taste.When sulphonyl diacetonitrile (76) reacts with a/8-unsaturated ketones under basic conditions, 3,4-dihydro-2H-thiopyran-2-carboxamides (77 R = Me or Ph) are obtained in moderate yields.  

Thermolysis of the 3,4-dihydro-2//-thiopyran (82) in the presence of dienophiles such as maleic anhydride, styrene, and norbornene gave adducts such as (84) and (85). The thiochalcone (83) is assumed to be an intermediate. The ylide (87), prepared from methyl 6-vinylthian-2-carboxylate (86) and methyl fluorosulphonate, undergoes a 2,3-sigmatropic ring-expansion to methyl l-(methylthio)cyclohept-3-enecarboxylate (88) the cyclopentane (89) is formed as a by-product.  

Horse-liver alcohol dehydrogenase reduced racemic tetrahydrothiopyran-4-ones stereospecifically to a mixture of the cis- and the trans-alcohols (92). The synthesis of several of the ketones (91 = Me, Et, Pr, or Ph) from tetra- 

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The partially reduced thiopyrans are 3,4-dihydro-2//-thiopyran 20 and 3,6-dihydro-2//-thiopyran 21 and the fully reduced compound is tetrahydrothiopyran or thiane 22. The benzologues are 3,4-di hydro-2//-1 -benzothiopy ran or thiochroman 23 and 3,4-dihydro-l//-2-benzothiopyran or isothiochroman 24. The fully saturated derivatives of 23 and 24 are known as thiadecalin and isothiadecalin, respectively. 

Diphenyl-4-oxothiopyran-3-carboxaldehyde (100) was produced in high yield by an unusual oxidation of 4-chloro-2,6-diphenyl-2//-thiopyran-3-carboxaldehyde by Se02 as well as from the hydroxymethylene compound (Scheme 1). Numerous potentially useful conversions of reduced thiopyrans and thiopyrans have been described. ... 

Eq. (3), with lithium diisopropylamide (LDA) to a lithiospecies and in its subsequent reaction with C02 affording via the corresponding 4-carboxylic acid its ethyl ester 59. In the alternative version perchlorate 48e is electro-chemically reduced in acetonitrile to an anionic species that was converted either to a 3 1 mixture of isomers 56 (R = f-Bu) and 60 or to 4//-thiopyran 56 (R = PhCH2) with f-BuI or PhCH2Br, respectively (90ACS524). The kinetics of the benzylation procedure was followed by cyclic voltammetry [88ACS(B)269]. 

Further 4//-thiopyrans as well as 2//-analogs were reduced mainly to their corresponding tetrahydro derivatives. In addition, the hydrogenation of 4//-thiopyran-5,5-dioxides have been described. 

Pentasubstituted tricyclic 4//-thiopyran 48 ( = 2, R = Me) was also prepared by the reduction of the corresponding thiopyrylium salt 227b with LiAlH4.269 The reduction with zinc proceeds via a dimeric 4//-thiopyran intermediate.272 Ion 229 (R = Ph, n = 2) was reduced with zinc in hydrochloric acid to a mixture of 2//-thiopyran 230 (R = Ph, n = 2), 4//-thio-pyran 232, and the corresponding perhydrothiopyran.100... 

Only rare reports of the conversion of thiopyrones to thiopyrans are available. Unsubstituted 4-thiopyrone (335) was reduced with aluminum hydride to the corresponding 4-thiopyranol (2).5,90 A precipitate formed during the reaction of thiopyrone 336a with thionyl chloride was regarded to be a 4H-thiopyran derivative (336b).325... 

Thienyimethanol (360a) underwent allylic rearrangement to 4-hydroxy-2//-pyran (2) with oxalic acid at 20°C for 6 days.341 2-Thienylmethylamine (360b) with nitrous acid (Demyanov reaction) gave a mixture of 360a and 2.3 An 86% yield of a mixture of 2,6-di-te/ -bu tyl-2//- and 4//-thiopyrans 362 and 363 was obtained when 2,5-dihydrothiophene ketone 361 (readily accessible by Birch reduction of 2-pivaIoyl-5-ter/-butylthiophene) was reduced with zinc and sodium hydroxide in the presence of trimethylsilyl chloride.286... 

Disproportionation has been observed frequently with thiopyrans and rarely with 4//-pyrans, and all cases involve a tetragonal carbon center (position 2 or 4) bearing at least one C—H bond. Some molecules of the substrate are aromatized to corresponding thiopyrylium or pyrylium ions and others reduced to dihydro or tetrahydro products. The relative abilities of pyrans and thiopyrans to disproportionate were interpreted within a proposed hydride transfer mechanism by a CNDO/2 method.45... 

The carbonyl group in condensed 4//-thiopyrans 20a was selectively reduced with LAH to give diastereomeric mixtures of hydroxy derivatives.61,370... 

The number of double bonds may be conserved or decreased with the Raney nickel catalyst. Thus bicyclic 2//-thiopyran 142 gave monocyclic diene (456).184 Partially reduced hydrocarbons 457 (R = Me, 4-Me2NC4H4) and/or 458 (R = Me, PhCH, 4-MejNQH,) were prepared from... 

The carbonyl groups in 4//-thiopyrans 20a were easily reduced to diastereomeric hydroxy derivatives 606a.61,370 The reaction of 20a with benzylmagnesium chloride gave benzylidene derivatives 606b370 and with phenylhydrazine the corresponding SchifF bases 606c.61,99... 

However, in the sulfone analogues of the thiopyrans the transannular interaction has been shown to extend to the 4-position, in that thiopyran-4-one 1,1-dioxide is electrochemi-cally reduced more readily than the sulfide (72MI22500). 

Ring expansion reactions are much better known and sulfolene substrates have received considerable investigation. Cyclopropanation with dichlorocarbene affords 6,6-dichloro-3-thiabicyclo[3.1.0]hexane 3,3-dioxides which may readily be ring enlarged by base or acid treatment. Base treatment, especially with LDA, cleanly affords 2//-thiopyran dioxides hydrochloric acid does likewise, but less cleanly, while hydrobromic acid treatment causes a more complex set of reactions leading to thiopyranones containing bromine in which the sulfur has been reduced. The intermediacy of thiopyrylium oxides has been invoked to rationalize the observations (Scheme 27) (81JOC4502). 

An analog of the (6S)-methylketosulfone towards Trusopt , 5,6 dihydro-(6S)-pro-pyl-4H-thieno[2,3fc]thiopyran-4-one 7,7-dioxide ( ketosulfone , Figure 13.28), the precursor to the carbonic anhydrase inhibitor L-683393 (Merck), could be reduced to the trans-hydroxysulfone 5,6 dihydro-(4S)-hydroxy-(6S)-propyl-4H-thieno[2,3F] thiopyran 7,7-dioxide by whole cells of the yeast Rhodotorula rubra MY 2169 from the Merck collection (Lorraine, 1996). Low water-solubility limited the optimum substrate concentration to 2 g L, as organic solvents added to increase solubility resulted in lower rates, which at 0.04 g (g dew)-1 h 1 were not high to start with. Diastereomeric excess ranged from 89 to 94% d.e., and decreased with increasing conversion. 

The ketones derived from thiopyrans are 2//-thiopyran-2-one 25 and 47/-thiopyran-4-one 26 and the benzologues are 2//-1 -benzothiopyran-2-one or thiocoumarin 27, 4//-l-benzothiopyran-4-one (thiochromone) 28, and 9//-thiox-anthen-9-one or simply thioxanth-9-one 29. The trivial names dihydrothiocoumarin and thiochroman-4-one are used for the partially reduced derivatives. l//-2-Benzothiopyran-l-one 30 is usually known as isothiocoumarin. The 2- and 3- aryl derivatives of 10, 28, and 31 are generally referred to as the thioflavonoids. 

Thiopyrylium salts can be also reduced by zinc in hydrochloric acid. Thus cation 77 (R = R = Ph, = 2) by treatment with Zn/HCl gave a mixture of 6//-thiopyran 269, 4//-thiopyran 270, and the corresponding thiadecaline [71KGS(S)85]. 

DiphenylthiopyryIium cation (154) is reduced by methylamine, ethy-lamine, benzylamine, or triethylamine in ethanol to give 12-72% of a highly insoluble and nonvolatile compound, the elemental analysis for which was consistent with its formulation as 4,6-diphenyl-2ff-thiopyran, but which may be an oligomer of this structure [80JCS(P1)1345]. 

Little is known of the reduction of thiopyrones. The parent compound (3) has been reduced to the 4l/-thiopyran-4-ol (75) by aluminum... 

The 2 -thiopyran (75) undergoes a disproportionation reaction, when treated with perchloric acid, to give a mixture of the corresponding thio-pyrylium salt (76) and the reduced compound (77) with a cis ring junction, the reaction being similar to those described previously for A -thio-chromenes and possibly involving a bridged sulphonium ion. 

Thiophosgene reacts with cyclohexa-1,3-diene to yield the adduct (17 R = Cl), which can be hydrolysed to the ketone or reduced with lithium aluminium hydride to the bicyclo[2,2,2]oct-5-ene. The related sulphone (18), made by addition of dimethyl acetylenedicarboxylate to 3-phenyl-2H-thiopyran 1,1-dioxide, undergoes a reverse Diels-Alder reaction at 220 C,... 

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