Dihydro-2,4-benzothiepines

Oxidation of the dihydro-2,4-benzothiepines 283 (R = CHj, Ph, /-Bu) with m-chloroperbenzoic acid has been shown to be highly diastereoselective the resultant trans-sulfoxides 284 exist as an equilibrium mixture (observed at -60 °C in CDCI3) of the chair and boat forms with the substituents equatorially disposed [01JGU960],... 

A review covering homologation of heterocycles via lithiation-based reductive ring opening, electrophilic substitution, and cyclization includes applications to 2,7-dihydro benzothiepine derivatives <06AHC135>. 

According to the Hantzsch-Widman system, the seven-membered unsaturated hcterocyclc with one sulfur atom is named thiepin (1). The three different benzothiepins are assigned by the position of sulfur 1-benzothiepin (2), 2-benzothiepin (3) and 3-benzothiepin (4). Of the four possible dibenzothiepins only dibenzo[6,r/]thiepin (5) and dibenzo[A,/]thiepin (6) are of importance for synthesis, while the other two isomers, which contain unfavorable o-quinoid structures, exist mainly as the stable dihydro compounds, i.c. 5,7-dihydrodibenzo[c,t ]thiepin (7) and 6,1 l-dihydrodibenzo[6,c ]thiepin (8). Benzannulation over all double bonds results in tri-benzo[6,(7,/]thiepin (9). 

Dehydrohalogenation of 2-HaIo-2,3-dihydro- and 5-Halo-4,5-dihydro-l-benzothiepins... 

Dehydrohalogenation of 2-halo-2,3-dihydro- (1) and 5-halo-4,5-dihydro-l-benzothiepins (2) with strong bases leads to the formation of 1-benzothiepin (3). 

Starting material 2.5-dichloro-4,5-dihydro-l-benzothiepin, b Overall yield from corresponding ketone (see Section 2.1.3.1). 

Starting material 3-bromo-2,3-dihydro-l-benzothiepin 1.1-dioxide (see Houben-Weyl, Vol. 5/le, p97). 

A solution of 2,4-dichloro-2,.3-dihydro-1-benzothiepin (0.5 g, 2.16 mmol) in f-BuOH (14 mL) was added in one portion to a solution of f-BuOK (246 mg, 2.20 mmol) in t-BuOH (24 mL). After stirring for 50 min, the turbid orange solution was poured into H20 (150mL) and extracted with CHCl3. The extract was washed with H20 and dried (MgS04). The solvent was removed under reduced pressure to give a yellow oil [yield 330 mg (79%)] which was further purified by chromatography (alumina, petroleum ether). 

A solution of 2-bromo-4-chloro-5-phenyl-2,3-dihydro-1-benzothiepin (1.02 g, 2.84 mmol) in THF (3 mL) was added in one portion to a solution of DBN (0.52 g, 4.2 mmol) in THF (3 mL) at rt. After stirring for 2h, the red mixture, containing some precipitate, was poured into 10% aq HC1 (20 mL) and the aqueous solution was extracted with CHCl, (2x15 mL). The combined extracts were washed with H20, dried (MgS04) and carefully concentrated in vacuo at subambient temperature. The yellow oil, which solidified on cooling, was chromatographed [alumina (Merck 71707,25 g), hexane] to give colorless crystals yield 0.58 g (76%) mp 87-88 °C. 

The synthesis of 1-benzothiepin (7) has also been achieved, in 80% yield, by the reaction of 4,5-dihydro-l-benzothiepin-5-ol (6) with potassium hydride and -toluenesulfonyl chloride and subsequent elimination of p-toluenesulfonic acid with lerf-pentylpotassium 22... 

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. 

For the preparation of 3-benzothiepin 3,3-dioxide (11) a multiple-step synthesis has been described.82 Oxidation of 4,5-dihydro-3-benzothiepin-l(2//)-one to its S,S-dioxide with hydrogen peroxide in glacial acetic acid, is followed by the multiple-step preparation of dibromide 10, which is dehydrohalogenated by triethylamine to provide sulfone 11. 

Benzothiepins 13 and their 2,3-dihydro precursors 12 can be oxidized by two equivalents of 3-chloroperoxybenzoic acid to afford the sulfones 15 and 14, respectively, in moderate to good yields.2,9 83 Sulfones 15 can be prepared using two routes, the reverse order (oxidation, followed by elimination) also being possible (see Section 2.1.2.1. for a description of the elimination reactions). The preferred route must be decided for individual cases. 

Dihydro-l-benzothiepin 1-oxide (21) is obtained in 77% yield when 19 is treated with sodium periodate in glacial acetic acid at 0 °C, while a second method ultilizing sulfuryl chloride at — 70°C gives the dichlorosulfurane intermediate 20 and ultimately the sulfoxide 21 in 79% yield.86... 

In the case of 2,3-dihydro-l-benzothiepin 1-oxide (5), alkylation with iodomethane and silver (I) tetrafluoroborate leads to the methoxysulfonium salt 6 in 65% yield.86... 

A versatile route to 3-benzoheteropines has been reported starting from o-phthalaldehyde, including the first preparations of 3-benzarsepines and the parent 3-benzothiepin and 3-benzoselenepins <96CC2183>. l,7-Dihydro-l//-dibenzo[c,c]tellurepin has been prepared from 2,2 -bis(bromomethyl)biphenyl and potassium tellurocyanate and its complexes with palladium and ruthenium species have been studied, a number of mono- and binuclear complexes are formed <96RTC427>. 

Benzodithiepins have not been much studied but 7-chloro-2,3-dihydro-51 /-l,4-dithiepin has been prepared by the action of base on 2-(2-chloroethylthio)-5-chlorobenzyl isothiouronium chloride (72HC(26)667, p. 787). l,5-Benzothiepin-2-one has recently been... 

Racemic l,ll-dimethyl-5,7-dihydrodibenzo[c,< ]thiepine A-oxide 24 and A,A-dioxide 25 and 10,12-dihydro-4/7,6/7-[2]benzothiepino[6,5,4- i/][2]benzothiepine 30, based on bridged biphenyl structures, were resolved into enantiomers by chromatography on swollen microcrystalline TAC <2000HCA479>. The first-eluted enantiomers were assigned to have the (A)-configuration by comparison of the experimental CD spectra with spectra calculated by the CNDO/S method (see also Sections 13.03.3.1 and 13.03.3.3). 

A new method for a-phenol annulation involving base-induced cycloaromatization of readily available 4-bis (methylthio)-3-buten-2-one 114 was applied to 3,4-dihydro-l-benzothiepin-5(2//)-one 113 (Scheme 14) <2002JOC5398>. Equimolar quantities of the benzothiepinone 113 and 114 in the presence of sodium hydride were stirred in dimethylformamide (DMF) at 25 °C. Treatment of the reaction mixture with/>-toluenesulfonic acid in refluxing benzene furnished the phenol-annulated dihydrothiepine 116 in 62% yield. The reaction sequence involved formation of conjugate addition-elimination adduct 115, followed by intramolecular aldol condensation and cycloaromatization, affording 116. 

The useful ring closure providing benzothiepines involved the formation of both S-C bonds by reaction of diaryllithium or divinyllithium organometallic species with S2+ equivalents. Another method for formation of both S-C bonds toward dihydro- and tetrahydrothiepines and thiepines is the nucleophilic substitution reaction of S2 equivalents (Na2S or Li2S) with dibromides. Synthesis of thiepines by the related stepwise formation of two S-C bonds was also described. 

Dihydro-1-benzothiepin is converted into 2,3-dihydro-l-benzo-thiepin 1-oxide with sulfuryl chloride in 79% yield or with sodium periodate in 77% yield (equation 562) [5%]. 

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