Thiopyrans, dihydro— from

Dihydro-2iy-thiopyrans, derived from dimethylbuta-1,3-dienes, Na2S203-5H20 and various activated alkyl h des, ring contract on treatment with a strong base leading to vinyl cyclopropanes and cyclopentenes <96JOC4725>. 

Figure 15 Molecular dimension of 3,6-dihydro-2H-thiopyran derived from microwave spectroscopy.

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>. 

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. 

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>. 

The preparation of thiopyrans from dihydro- and tetrahydrothiopyrans, based on elimination reactions, appears to be effective especially for the preparation of different 2//-thiopyrans and corresponding S,S-dioxides. 

This dominance of sulfur in the reactions with electrophiles is well brought out in the addition of carbenes to the-two monocycles. Tire allylic sulfide (5,6-dihydro-2jF/- thiopyran) only affords the products of reaction at sulfur, while the vinylic sulfide (3,4-dihydro-2f/-thiopyran), in which the alkene is a little more nucleophilic due to the small interaction with the heteroatom, shows dichotomous behaviour. Dichlorocarbene affords the cyclopropane product (78) in 70% yield, but the stabilized ylide (76) is produced from bismethoxycar-bonylmethylide and (75). In fact it is possible that the initial reaction with dichlorocarbene is reaction at sulfur and subsequent rearrangement of this less stabilized ylide. Schemes 6 and 7 illustrate the results and proposed mechanisms (77JOC3365,64JOC2211). 

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). 

Usually, 3- and 4-substituted thianes are prepared from the 3- and 4-oxothians by the common techniques applicable to alicyclic chemistry. Reduction affords alcohols which may be etherified or halogenated, while oximation and reduction produces the amino derivatives, which are also accessible via the halo compounds. 2-Alkoxy and 2-alkylthio compounds are made by acid catalyzed addition of alcohols and thiols to 3,4-dihydro-2H-thiopyran (75MI22502) in a reaction analogous to the use of dihydropyran for protection of alcohols as THP ethers. 

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. 

Figure 5 shows the molecular structures of rfs-2-nitro-7-(dimethylamino-)-9-(2,3,-dihydro-l J-f-naphtho[2,l-b]thiopyran-l -ylidene)-9J-f-thioxanthene ((P)-cis-17) and trans-dimethyl-[l-(2-nitro-thioxanthen-9-ylidene)-2,3-dihydro-lJ-f-ben-zo[f]thiochromen-8-yl]amine ((P)-trans-18). Anti-folded helical structures, in which the top and bottom parts are respectively tilted up and down relative to the plane of the central olefmic bond, are clearly observed. The extent of folding and twisting in these and related overcrowded alkenes can vary considerably. It should be emphasized that only minor deviation from planarity occurs at the central double bond (dihedral angles 5.4° (17) and 6.8° (18)), while normal bond lengths are found (1.353 A (17) and 1.338 A (18)).130,311... 

The relative trans stereochemistry of the substituents in the tetrasubstituted 3,4-dihydro-27/-thiopyran 85, an intermediate isolated from the [4+2] cycloaddition between an enaminothione and a nitroalkene, has been established by H NMR spectroscopy <1994JPR434>. The methylene units of 5-(diethylphosphono)-3,4-dihydro-277-thiopyran 86 appear as multiplets in the range 2.0-2.8 ppm and the vinyl proton (H-6) displays coupling to the P atom with V= 21.6Hz <20050BC924>. 

Cycloaddition strategies have also featured widely in the synthesis of variously substituted 3,6-dihydro-2//-thiopyrans from thiocarbonyl-containing precursors and dienes. Selected H NMR data for 3,6-dihydro-2//-thiopyr-ans feature in Figure 20. 

The sulfine 91 obtained from the room-temperature dimerization of thioacrolein. Y-oxide was characterized by key NMR data <1997TL1385> and by comparison with chemical shift data for the 3,4-dihydro-2//-thiopyran-l-oxide <1985AJC119>. 

The 13C NMR spectra (THF-. The following features are noteworthy from a comparison of their 13C NMR spectra. The chemical shift of C-4 has decreased by ca. 36 ppm which is indicative of an increase in charge density and Vqh for C-6 has increased by ca. 36 Hz which is suggestive of sp2 hybrid character for C-6 both features support a delocalized allylic anion. 

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>. 

Treatment of 3,6-dihydro-27/-thiopyrans with iVuodosuccinimide in the presence of a carboxylic acid results in ring contraction to a ir-4-iodo-5-carboxymethylthiolane. An iodonium ion is considered to be the initial product from which a bicyclic thiiranium species is generated which is attacked by carboxylate ion (Scheme 31) <2004EJ074>. 

Various 2-substituted iV-phenyl-6-phenylimino-3,6-dihydro-2//-thiopyran-4-amines, which are available from 6-substitutcd-5,6-dihydro-2//-thiopyran-2-thioncs, thermally rearrange to 5,6-dihydropyridine-2(l//)-thiones. A resonance stabilized thioamide anion is proposed as the intermediate (Scheme 107) <2001T8305>. 

The complexes 432 derived from the reaction of cinnamaldehyde with Ru-SH complexes 433 undergo [4+2] cycloaddition reactions with a range of electron-rich, electron-deficient, and strained dienophiles. The products are Ru complexes of di- or tri-substituted 3,4-dihydro-2/7-thiopyrans. Generally, the reaction shows high regioselectivity and good diastereoselectivity with a marked preference for the endo adducts (Scheme 139). Ethyl propynoate affords the 3,4-disubstituted-477-thiopyran <2006CEJ4821>. 

Further examples of the photolytic generation of thioaldehydes from phenacyl sulfides include the synthesis of 3,6-dihydro-27/-thiopyrans bearing a variety of functions at C-2 of which some are potent acyl-CoA-cholesterol acyl-transferase inhibitors (Equation 135) <1996BMC1493>. 

Numerous derivatives of 5,6-dihydro-4i/-thieno[2,3-6]thiopyran have been prepared from the ketone (70) (Scheme 19). Yields ranged from 53% to 76% (87JMC591). 

Cyclic enol ethers and their thio analogues are formed from keto alcohols and thiols Ac(CH2)30H gives the dihydro-furan 113 on distillation cf. 114 115 116 for the preparation of 3,4-dihydropyrans and -thiopyrans 116 (Z=0 or S). 

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