Syntheses from thiopyrans

Sec. III.A] PYRANS, THIOPYRANS, AND SELENOPYRANS III. Synthesis from Acyclic Precursors... 

The dihydrobenzoxathiin 408, a potent selective estrogen receptor alpha modulator, is metabolized to the bridged dibenzo[, 4]thiopyran derivative 409. It seems logical to assume that 409 is formed by initial cleavage of the O-C bond followed by an intramolecular acylation to generate the thiopyran ring. A 19-step total synthesis from resorcinol confirmed the structure of 409 (Equation 115) <20050L411>. 

Sulfur heterocycles. Some papers report on the synthesis of thiopyrans from cyanothio-acetamides and various ylidenemalononitriles. Subsequent rearrangement yielded pyridinethiones. So arylidenemalononitriles (179) yielded 225 in cold ethanol with catalysis of triethyl amine. Refluxing 225 in ethanol/triethylamine gave 226. ... 

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>. 

For the synthesis ofthiepins and oxepins, [(ri3-C3Hs)PdCl]2-catalyzed decomposition of 4-diazomethyl-4-methyl-4/f-thiopyrans 387) or -pyrans38] ) is the method of choice. Purely thermal decomposition of the former diazo compounds would require higher temperatures and thus would cause extrusion of sulfur from the primarily formed thiepin, yielding a benzene derivative. 

When studying the carcinogenic activity of polycyclic hydrocarbons and their antdogs containing thiophene rings (cf. Tilak "), Tilak et al synthesized both thienothiophene 1 and its isomer 2 in low yield from 2-thienyl dimethoxyethyl sulfide (23) and 3-thienyl diethoxyethyl sulfide (24), respectively, by the method developed for synthesis of thiophenes and thiopyrans - [Eqs. (10) and (11)]. The compounds 23 and 24 were prepared from 2- and 3-mercaptothiophenes. ... 

A [4-f2] cycloaddition was the key step in the synthesis of substituted dihydrothiopyrans from 2-alkenyl-l,3-oxathianes and an alkene. The reaction was mediated by a Lewis acid. It is assumed that the Lewis acid attacks the oxygen of the heterocycle which upon ring opening gives the highly reactive cationic heterodiene which reacts with alkenes to the thiopyrans in 31-88% yield (Scheme 75) <2000TL371>. 

Compound 99 reacts with alkynes to generate thieno[2,3-f]thiopyranthiones and thieno[3,2-f]thiopyranthiones. The ratio of isomers is typically 1 1. The reaction proceeds via a cycloaddition reaction and an unprecedented molecular rearrangement (Equation 35) <20050L791>. Thieno[2,3-f]- and [3,2-f]thiopyrans can be prepared from thiophene-2-carbaldehyde in a multistep synthesis that leads to the thienothiopyrans in excellent yields <1999J(P1)2639>. 

The synthesis of 4//-thiopyrans from 1,5-dicarbonyl compounds consists of the cyclization of 1,5-dioxo precursors with hydrogen sulfide in the presence of protic acids or with various phosphorus polysulfides. 

The first approach to 2//-thiopyrans from acetylenes resembles the synthesis of oxa analogs 92a,b. In contrast to the latter, intermediates like 100 have been directly used as starting compounds. 

The preparation of unsubstituted 2//-thiopyran (6, up to 82%) from 3-propynyl vinyl sulfide seems to be the simplest example.21,23 Similarly, homologs 101a,21 cyanides 101b,146 ketones 101c,141 and ethyl esters lOld148 were prepared in satisfactory yields. The same approach was subsequently explored for the synthesis of 15 and similar condensed systems21,43,137 (see also 5,5-dioxides in Section V,G,3). 

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. 

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. 

An aldol reaction is also involved in the synthesis of 4-(tetrahydro-477-thiopyran-4-cyclohexylidene-4 -ylidene)-tetrahydro-4/7-thiopyran 284 from tetrahydro-477-thiopyran-4-carboxylic acid and 4-(tetrahydro-477-thiopyran-4-ylidene)cyclohexanone (Scheme 39) <2000JOC4584>. 

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>. 

Cleavage of the hetero ring of 3-nitrobenzo[A]thiophene is the first step in a synthesis of ( )-2-aryl-l-[2-(methylsul-fonyl)phenyl]-l-nitroethenes (Scheme 176). The sulfonyl-stabilized anion derived from these alkenes by metallation adds in Michael fashion to the nitrovinyl unit to form 4-nitrothiochroman 1,1-dioxides as an inseparable mixture of two diastereomers. The overall process corresponds to expansion of a thiophene ring to a thiopyran unit <2004T4967>. 

Heterocycles containing One Sulphur Atom Thiopyrans. - A convenient synthesis of 2-phenylthiopyran-4-one (217) has been developed from methyl styryl ketone and ethyl formate. The enolate... 

Synthesis by Cycloaddition.—Further details have been given of high-pressure Diels-Alder addition of maleic anhydride to thiophen, and we note the formation of Diels-Alder adducts from 2//-thiopyran, of the dimer (132), and of the adduct (133). ... 

An efficient synthesis of thiopyrylium tluoroborate involves the quantitative dehydrogenation of 2//-thiopyran, which is prepared from ethyl vinyl sulfide. A single crystal X-ray study showed the cation to be planar <01EJO2477>. 

The synthesis of the thiathiophthens (13) from 4ZT-thiopyran-4-thiones (11), involving ring opening with sodium sulphide and oxidation of the resulting dianion (12) with ferricyanide, has been described in detail. The method provides a convenient route to the parent compound and succeeds with the symmetrically substituted thiopyrans (11 = Ph,... 

Details have been given for the synthesis of 6a-thiathiophthens (see Chapter 8) from 4 -thiopyran-4-thiones. Analogous reactions with 4H-thiopyran-4-selenones lead to 6a-selenathiophthens. ... 

Compounds in which other heterocyclic rings (pyrazoles, isoxazoles, imidazoles ) are fused to thiopyrans have been described. The interesting thiazolium salts (56) were prepared by allowing the betaines (55) to react with 4-thioxothiazolidin-2-ones. Application of the Fischer indole synthesis and the Friedlander reaction to tetrahydrothiopyran-3-one led to the exported indolo-and quinolino-derivatives. Ring closure of (57) under acidic conditions afforded the rearranged product (58). Syntheses of benzothiopyrano[4,3,2-flfe]-quinazolines (59) from 1-amino-thioxanthones and of their S- and 7V-oxides have been described. ... 

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