4//-Thiopyran-4-ones, 2,3-dihydro

Halo-l-benzothiepins 4 can be synthesized by the treatment of 7a-halobenzo[fe]cyclopropa-[e]thiopyran-7-ols 2 with hydrogen bromide and subsequent hydrogen bromide elimination from the 2,4-dihalo-2,3-dihydro-l-benzothiepins 3 by l,5-diazabicyclo[4.3.0]non-5-ene (DBN).9 The alcohols 2 are prepared by Grignard reaction of the corresponding 7a-halobenzo[ft]cyclopropa[c]thiopyran-7-ones l18 and are used for the synthesis without purification. The intermediate dihalodihydro-l-benzothiepins 3 are not isolated due to their thermal lability related and more stable compounds are described in Section 2.1.2.1. 

Radical promoted reactions feature in a synthesis of 3-substituted derivatives of 2,3-dihydro- and tetrahydro- thiopyran-4-ones from the 3-methylene compounds <96SL261> and in the formation of 2-methyltetrahydroselenopyran from a selenoalkyl (phenyltelluro)formate <96JOC5754>. 

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... 

Enamines derived from thiopyran-3-one, although tautomeric, tend to exist predominantly in conjugation with the sulfur atom the Fischer indole reaction, when applied to that ketone, affords solely the systems fused 2,3 on to the thiopyran (Scheme 10) (76CL5). 4-Amino-3,4-dihydro-2Ff-thiopyrans readily eliminate ammonia or amines on heating or treatment with acid, with formation of 2H- thiopyrans <78CR(C)(286)553). 

The synthetic approach reported in Scheme 50 has also been applied to the synthesis of 6a, 7-dihydro-6//[l]benzothiopyrano[3,4-c][l,5] benzothiazepine (162) starting from 5 and 3-phenylmethylene-4//-1 -benzo-thiopyran-4-one (161) (Scheme 52) (81MI1 820MR133 83MI1). >H-NMR investigations proved that the phenyl group at C-7 exists in a quasi-equatorial position, analogous to that in the isosteric benzopyrano derivatives. 

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. 

Ward, D. E. Gai, Y. Lai, Y. A general method for the synthesis of 3-substituted tetrahydro-and 2,3-dihydro-4H-thiopyran-4-ones. Synlett 1996, 261-262. 

The use of phosphonodifluorodithioacetate as a 2ji component in cycloadditions with a variety of dienes provides simultaneous direct access to fluorine and phosphorus containing 3,6-dihydro-2/7-thiopyrans, for example, 217 and their 3-ones 218. Complex signals result from the heteronuclear couplings <2002TL2033>. 

Although methyl 4-oxotetrahydrothiopyran-3-carboxylate and the corresponding 2,3-dihydro-4//-thiopyran-4-one exist as a mixture of keto and enol forms in solution, the 2,3-dihydro sulfoxide is present only as the ketone. However, the sulfone and the tetrahydro sulfoxide and sulfone are present exclusively in the enolic form. The picture is further complicated in the solid state, where the dihydro compound and its sulfoxide exist exclusively as the keto structure but the sulfone is found as the enol (Table 27) <1986J(P2)1887>. The related 2-esters of tetrahydrothiopyran-3-one 268 exist as a ca. 1 2 mixture of keto and enol <1981T2633>. 

Protected 5,6-dihydro-477-thiopyran-4-one is lithiated at the 2-position allowing the introduction of a 2-SnMe3 function to give compound 312. Sequential reactions with propenoyl chloride and H2S yield the thiopyrano[3,2-4]-thiopyran system (Scheme 53) <1998EJO 989>. 

The 3-methylene derivatives of both 2,3-dihydro- and tetrahydro- 4/7-thiopyran-4-ones undergo a radical-promoted addition of alkyl and aryl halides producing 3-substituted thiopyran l-ones (Equations 52 and 53) <1996SL261>. 

Activated alkyl halides react with sodium thiosulfate to form the Bunte salts 438 which, on treatment with base, generate thiocarbonyl compounds <1984CC922>. Trapping with 1,3-dienes affords 3,6-dihydro-2-//-thiopyrans in satisfactory yields and in a one-pot reaction, although with unsymmetrical dienes the regio and diastereo selectivities are not good (Scheme 143) <1996JOC4725>. 

The base-catalyzed Michael addition of 2-thionaphthol to methacrylonitrile and cyclization of the product with PPA gives 2-mcthyl-2,3-dihydro-1 //-naphtho 2,l-3]thiopyran-l-one 542 (Scheme 225) <2002JA5037>. 

The photocycloaddition of furan to 2,3-dihydro-2,2-dimethyl-477-thiopyran-4-one gives a mixture in which the major products are two trans-fused [4+2] adducts. Prolonged stirring with basic alumina results in initial conversion to the air-fused adducts and subsequently to 2,2-dimethylthiochroman-4-one (Scheme 228) <2005HCA1922>. 

Dihydro-277-thiopyran-6-yl trifluoromethanesulfonate undergoes a carbonylative Suzuki-Miyaura coupling with vinylboronic acids to give substituted 1 -(3,4-dihydro-2//-thiopyran-6-yl)prop-2-cn-l -ones together with minor amounts of the non-carbonylated coupled products <2007EJ02152>. 

An optimized inexpensive synthesis of tetrahydrothiopyran 4-one which lends itself to scale-up involves a Dieckmann cyclization of dimethyl 3,3 -thiobispropanoate <2007S1584>. Efficient conversions to 3,6-dihydro 4-trimethylsilyloxy-27/-thiopyran <2007S1584>, the corresponding 4-vinylstannane <2007JOC1507> and the 4-oxo-tetrahydro-27/-thiopyran-3-yl A-methyl-iV-phenylcarbamate <2007SL293> have been accomplished. 

A protected 5,6-dihydro-4//-thiopyran-4-one will lithiate at the 2-position allowing, for example, the introduction of a 2-SnMej group to give compound 551 <1998EJ01989>. 

Efficient syntheses of tetrahydrothiopyran-4-one and 3,6-dihydro-4-trimethylsilyloxy-277-thiopyran 58 from dimethyl 3,3 -thiobispropanoate have been described <07S1584>. Carbene insertion into a C-H bond of diazosulfones leads to tetrahydrothiopyran sulfones 59 with stereoselectivity for the trans disposition of the 2- and 3-substituents. When applied to diazosulfonates, the corresponding 1,2-oxathianes are produced <07OL61>. 

The cyclization of saturated 1,5-pentanediones with H2S and HCl is one of the most exploited reactions for the synthesis of thiopyrylium salts. These are generally formed together with the corresponding dihydro- or, more frequently, tetrahydro-thiopyrans, as a result of the disproportionation of 4//-thiopyran intermediates (Scheme I). The reaction is frequently performed in AcOH, which appears to facilitate the disproportionation processes (76KFZ80 81 KGS 1604). 

Cyclopenta[c]pyridin-7-one, 5,6-dihydro-3-methyl-1-propyl-, 57, 22 Cyclopenta-pyridines, see also Pyrindines Cyclopenta[h]pyrrole, 6-hydroximino-octahydro-1-methyl, 58, 22 Cyclopenta[h]selenopyran, 2,4a,5,6,7,7a-hexahydro-2-methyl-, synth, 55, 17 Cyclopenta[c]thiopyran, protonation, 60, 119... 

The alkenic bond in dihydro thiopyrans in one case is a thioenol system in the other it is effectively an isolated double bond. The thioenol readily adds alcohols or thiols (cf. dihydropyran) it has been suggested as a protecting group for alcohols, and is readily removable with Ag+ under neutral conditions (66JOC2333). If conjugated with a carbonyl function, thiols will add under basic conditions (equation 34) (81JA4597). 

Thiocarbonyl compounds of all kinds are excellent heterodienophiles. There has not been much systematic study of this class of reaction but it seems that such cycloadditions are generally regio-selective. One difference between carbonyl and thiocarbonyl Diels-Alder reactions is that the dihydro-thiopyran adducts from the latter dienophiles often undergo cycloreversion. The slow development of this field is peifaaps mainly due more to lack of methods for generating certain thiocarbonyl compounds than with difficulties in effecting cycloadditions. 

The key step in the synthesis of Trusopt , which is a topically active treatment for glaucoma, is the enantioselective reduction of 5,6-dihydro-6-methyl-4H-thieno[2,3b] thiopyran-4-one-7,7-dioxide (Fig. 19-1). 

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