Thiopyran Derivatives

In a reinvestigation of earlier work, it has been shown that alkaline hydrolysis of the 2,6-bismethylthio-4/T-thiopyran-4-one (29) gives the 2-hydroxy-compound (30) as the main product. Methylation with diazomethane yields the ethers, i.e. (31) and its isomer, 2-methoxy-6-methylthio-3,5-diphenyl-4/f-thiopyran-4-one. Treatment of compound (31) with phosphorus pentasulphide gives the thione (32), which reverts to the starting material (29) at its melting point. 

The preparation has been described of stable sesquifulvalene analogues, (33) and (34), by condensations between the appropriate 4/f-thiopyran-4-one and either 1,2,3,4-tetrachlorocyclopentadiene or 4,5-dichlorocyclo- 

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.  

Studies on the photochemistry of 4/f-thiopyran derivatives have continued. 2,6-Dimethyl-4 -thiopyran-4-one (36 R = Me, X = O) differs from the analogous 2,6-diphenyl compound in giving a cage dimer on irradiation. 2,6-Diphenyl-4/T-thiopyran-4-thione (36 R = Ph, X = S) is converted into the corresponding thiopyran-4-one on irradiation in the presence of oxygen and methylene blue, and similarly, 4 -thiopyran-4-thione gives 4fT-thiopyran-4-one. A cage dimer has been obtained from 

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Note 5. At room temperature the 3,3-sigmatropic rearrangement begins. The anmonia, still present during the work up, will cause ring closure of the allenic dithioester to a 2-ff-thiopyran derivative. 

Treatment of 2,7-di-/ert-butylthiepin (1) either directly with bromine at — 78 °C, or with pyridinium bromide perbromide at room temperature, gives the thiophene compound 2. In contrast, bromination with bromine-1,4-dioxane complex or pyridinium bromide perbromide in the presence of acetic acid leads to the thiopyran derivative 3.87 To account for these results a homothiopyrylium ion has been proposed as a common intermediate, formed by electrophilic bromination at C4 in the first step. 

Diels-Alder cycloadditions of enaminothiones with electrophilic die-nophiles (83AHC145, section III,G) have been widely used for the preparation of various thiopyran derivatives. In addition to expected 2H-thiopyrans, 4//-isomers were trapped as intermediates or even as final products. Nitroolefines (90T1951), olefinic carbonyl derivatives [80JH405 85JOC1545 92JCS(P1)2603] allenedicarboxylic esters... 

Although the aromatizations of 2-methoxy-2//-thiopyran derivative 63 (R = R = Ph, 83ZC333 86JPR373) or similar compounds 131 (86JPR567, 86JPR573) to perchlorate 48e or appropriate chloride with some acidic reagents resemble the above-mentioned conversions, they are not oxidation processes. 

However, the homochiral 2- -(/ )-(-)-a-[(2-naphthyl)ethylamino]-4-phenyl-l-thiabuta-l,3-diene reacts with dienophiles when activated by acetyl chloride to give the exo product, exemplified by the cyclopenta[fc]thiopyran derivative (24) <96TL123>. 

The first examples of intramolecular diene transmissive HDA reactions have been reported. Thus, the divinyl thioketones, derived from the ketones by treatment with Lawesson s reagent, spontaneously cyclise to the thiopyran derivative (27) and react further as shown <96CC811>. 

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>. 

A number of 2-thiopyran derivatives with one carbonyl group as acceptor (66,67 Table 13) has been studied by Kretschmer et al. (80). The conformations with respect to the C,—C2 and C2=C3 bonds (ZZ, ZE, EZ, or EE) were analyzed with lanthanide shift reagents. With compounds 66 (R] = H, R2 = Ph, and... 

Thieno[2,3- ]thiopyran derivatives, 164, show effective activity as carbonic anhydrase inhibitors, especially as intraocular pressure-lowering agents <1999JME2641>. 

Reaction of various aldehydes with hydrogen sulfide leads to substituted thiophenes, dihydrothiophenes, dithiolanes and trithiolane, as well as to six-membered ring thiopyran derivatives and dithiins. Ledl (33) obtained 2,4-dimethylthiophene (1, R Me) as a product of the reaction of propionaldehyde with hydrogen sulfide in the presence of ammonia. Sultan (29) reported the formation of 2,4-diethylthiophene (1, R - Et), 2,4-dibutyl-thiophene (1, R - Bu), and their dehydro derivatives from the reaction of ammonium sulfide with butyraldehyde and caproaldehyde (hexanal), respectively. The mechanism suggested for their formation is depicted in Scheme 1. Space limitations do not allow us to discuss the mechanism here in detail (for additional information, see ref. 29). 

Analogous cyclizations with 1,5-diketones show that ring closure readily occurs in protic solvents such as acetic acid92"94 or alcohols.94"96 Typical examples include the preparations of 4//-thiopyran derivatives 43, 45, and 47a from the corresponding l,5-diphenyl-l,5-diones 44 and 46, respectively.92,93... 

Thiopyran derivatives may be formed when a sulfide participates in an aldol transformation. An excellent example is the formation of 2H-thiopyran-5-carbaldehyde (19a) from benzaldehyde and acetaldehyde in the presence of sodium disulfide (Scheme 11 A).196... 

If R, R, and R3 are all alkyl, the reactions shown in Eq. (10) proceed rapidly at room temperature unselectively. However, 4//-thiopyran derivatives 244 were isolated in 90 to 94% yields from the reaction of ethyl lithio-... 

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... 

The rearrangement of dihydropyran sulfoxide 290 to 2//-thiopyran derivative 291302 was mentioned in Section IV,E. An unusual dehydrochlorination of 3-thiabicyclo[3.1.0]hexane S,5-dioxides 364 aifording 2H-... 

If a 2f/-pyran or 2//-thiopyran derivative 459 possesses in substituents A or B an active methylene fragment, for example PhCH2, RCOCH2 or N02CH2, the corresponding valence-bond tautomers 460 or 462 may undergo intramolecular ring closure to substituted benzenes. The equilibria shown in Scheme 22 are shifted toward such products. 

Complex 2//-thiopyran derivatives 291 afforded 25% of isomeric thiophene 581 on heating at 240°C in a nitrogen atmosphere.302... 

Benzo-2//-pyrans and their thia analogs, e.g., heterocycles not treated in this chapter, are photochemically labile and form reversible photochromic systems with open-chain and colored photoisomers. This behavior was observed for 2-benzyl-2,4,6-triphenyl-2//-species 467a,b (Y = H)399,409 and naturally occurring 2//-pyran 92a452a but only at about 77K. At room temperature, these as well as other 2//-pyrans are photochemically stable. Only 2,2,4,6-tetramethyl-2//-pyran (176) was photochemically changed to its exocyclic double bond isomer 308a.404 An irreversible photolysis of 2-azido-2//-thiopyran derivative 212b (R = H) has been discussed in reference 254. 

Solvent effect on H-NMR spectra of condensed 4//-thiopyran derivatives 20a were explored during consideration of the geometry of 4//-thiopyran rings in solutions.55... 

Mass spectra of 4//-thiopyran derivatives contain strong peaks of molecular ions M+, but general fragmentation patterns have not yet been discussed.152,277,283... 

The applications of thiopyrans are generally restricted to those areas in which de novo synthetic approaches are not prohibitively expensive. High volume usage, therefore, is only found to be suggested for the very simplest members of the family, while the widest range of thiopyran derivatives has been investigated in the field of medicinal chemistry. 

The use of isopropylidine acetals (112) as tethers in the intramolecular Diels-Alder reactions of dienes with alkenes facilitates the formation of civ-fused cycloadducts (113) from an endo transition state (Scheme 41).218 The intramolecular Diels-Alder reaction of 4-[tris-(2-mcthylcthyl)silyl]oxy-2//-thiopyran derivatives with potential dienophiles tethered at C(2), C(3), C(5), and C(6) positions yielded cycloadducts when the dienophiles were activated with a carbomethoxy group.219 By the substitution of a phenylsulfonyl group on the dienophile of 2-benzopyran-3-ones, it is possible to enhance exo addition during intramolecular Diels-Alder cyclizations to yield a predominance of trans-fused hexaphenanthrenes related to natural products.220 The intramolecular Diels-Alder reaction of 2-furfuryl fumarates has been investigated by molecular mechanics (SIBFA)/continuum reaction field computations.221 The intramolecular 4 + 2-photo-cycloaddition of A-benzylcinnamamides (114) in the presence of C(,H6 gives 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones (115) with high stereoselectivity (Scheme 42).222... 

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

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>. 

Thiopyran, derived from ethyl vinyl sulfide, is converted into thiopyrylium fluoroborate by reaction with triphenylcarbenium fluoroborate in 54% overall yield (Scheme 235) <2001EJ02477>. 3-Benzoylisothiochromene is oxidized to the 2-benzothiopyrylium salt in a similar manner <1994J(P1)3129>. 

In another example, direct irradiation of compound 38 yields cyclopropane 39 and the thiopyrane derivative 40, arising from secondary photolysis of 39 (Sch. 13). The formation of 39 is rationalized based on a di-7r-methane rearrangement involving the participation of two benzo [6] thiophene rings present in 38 [29]. 

The isolation of the isomeric axial and equatorial sulfoxides (94) and (95), from the preparation of a series of hexahydrothiopyrano[4,3-c]pyrazoles (93), prompted a study (79JOC2513) to determine what effect the introduction of an S—O bond had on the carbon shifts of the methylene carbons a to sulfur. When the oxygen atom is situated in an axial position as in isomer (94), it has a deshielding effect of +17 ppm on the / carbon atoms and a shielding effect on the carbons y (—10 ppm and — 9 ppm) and 5 (— 3 ppm) relative to the carbon atoms in the unsubstituted derivative (93). The trends are similar for the equatorial derivative (94). The magnitude and trends are comparable to reported data on monocyclic thiopyran derivatives. The chemical shifts of the carbon atoms of the sulfone derivative are comparable to the signals in both sulfoxides (94) and (95). 

The THP derivatives (130 X = H, Cl) have been deprotected and the resulting alcohols (131) oxidized with PCC yielding the chiral heterocycles (132) <92JOC1930>. Dehydration of a 1 1 mixture of the diastereoisomers (133) with phosphorus oxychloride gives the thiopyrano[4,3-c]thiopyran derivative (134) (48% yield) <84J0C5136>. 

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