Benzothiepins, synthesis

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). 

The first known synthesis of a benzothiepin, 3-benzothiepin-2,4-dicarboxylic acid, was in 1953.3 3 Many claimed syntheses of monocyclic thiepins were later proven erroneous. The determination of who had synthesized the first monocyclic thiepin can be based on the criterion of the observation of the decay in low temperature HNMR spectra,78 or of isolation.18... 

Benzothiepins 2 can be synthesized by a double Knoevenagel condensation starting from phthalaldehydes I and diesters of thiodiglycolic acid, or diphenacyl sulfide.33-63 " 66 In principle, this is an extension of Hinsberg s synthesis of thiophenes (see Houben-Weyl, Vol. E6a, p 282) which employs 1,4-dialdehydes rather than 1,2-dicarbonyl compounds. 

For the synthesis of 3-benzothiepin 3,3-dioxide by an elimination route, see Section 2.1.4.1. 

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. 

In practice, the [2 + 2] cycloadduct of 3-(pyrrolidin-l-yl)-l-benzothiophene (3) and dimethyl acetylenedicarboxylate isomerizes at 40°C to give the 3,4,5-trisubstituted 1-benzothiepin 5.12 In this synthesis cycloadduct 4 is not isolated. 

The broad use of this rearrangement for thiepin synthesis has been demonstrated by its application in the preparation of thermolabile 3-benzo- and 1-benzothiepins. Thus, thermolabile ethyl 3-benzothiepin-2-carboxylate (5) can be generated from the diazo precursor by the action of a palladium catalyst at — 10°C and low temperature ( — 40°C) chromatography.5... 

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. 

The synthesis of 1 -benzothiepin 1 -oxide (23) can be achieved via complex formation with tricarbonyl iron, and quantitative oxidation of the coordination compound 22 with 3-chloroperoxy-benzoic acid. Subsequent irradiation at — 50 C provides 23, which crystallized as yellow needles after low-temperature (-40 C) chromatography, and was characterized by 1H NMR spectroscopy at — 30 C23 before loosing sulfur within one hour at 13°C to give naphthalene. 

The greater lability of 1-benzothiepin 1-oxides, compared to the parent compounds, may lead to differences in chemical behavior. Thus, treatment of the tricarbonyliron complex of 1-benzo-thiepin 1-oxide (8, X = SO) with ammonium cerium(IV) nitrate in acetone at — 30 °C leads, with the loss of sulfur monoxide, to naphthalene. In contrast, the iron ligand can be removed selectively from the corresponding 1-benzothiepin by ammonium cerium(IV) nitrate.23 92 For the synthesis of 1-benzothiepin 1-oxide, see Section 2.1.4.1,... 

Irradiation of 1-benzothiepins 1 in tetrahydrofuran with a high-pressure 450-W mercury lamp and a Pyrex filter at 0"C for four hours results in a reversal of the thiepin-synthesis method startingfrom 3,4-benzo-2-thiabicyclo[3.2.0]hept-3,6-dienes (see Section 2.1.3.3.), giving the photoproducts 2 along with some of the corresponding naphthalenes.1019... 

The enantioenriched sulfoxide intermediate 72 (R = CH2OH), obtained by asymmetric 5-oxidation with a chiral oxaziridine (89 11 enantiomeric ratio), has provided a highly enantioselective synthesis of the benzothiepin derivative 71 (4R, 5R). The aldehyde intermediate 72 (R = CHO) was cyclized asymmetrically to 71 (4R, 5R) with >98 2 enantiomeric ratio. Base treatment (f-BuOK, -10°C, THF) of the racemic benzothiepin 73... 

An indole ring can be fused to a benzothiepine via Fisher synthesis to give benzothiepino[5,4-fc]indole (2006BMCL3233). 

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. 

Oda, T., Notoya, K., Gotoh, M.. Taketomi, S., Fujisawa, Y, Makino, H., and Sohda, T., Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation, J. Med. Chem., 42, 751, 1999. 

Benzo[6]thienylvinyl isocyanate thermal cyclization, 4, 748 Benzothiepanes synthesis, 7, 586, 587 1 - Benzothiepin, 2-ethoxycarbonyl-stability, 7, 558... 

H-2-Benzo[c]thiepin-5-one, 4,5,6,7-tetrahydro-synthesis, 4, 823, 7, 585 [l]Benzothiepino[3,4-d]selenazoles synthesis, 6, 345 Benzothiepins... 

Benzothiepines stabilized with substituents are obtained by this method <73JOC3978, 78JOC3379, 90CE853> however, it was difficult to achieve the synthesis of the parent member from the alcohol (205) or the halide (206). A convenient route to 1-benzothiepine (2) was found. Thus, ketone (204),... 

Thiepine oxides are thermally less stable than the corresponding thiepines and thiepine dioxides 2,7-di-(-butylthiepine 1-oxide (25) was detected only at low temperatures <94JCS(P1)2631>. 1-Benzo-thiepine 1-oxides stabilized by substituents were prepared and isolated by oxidation of the corresponding thiepines <75AG(E)812> (see Section 9.03.4.3). However, synthesis of labile 1-benzothiepine 1-oxide (26) failed under either oxidative or traditional reaction conditions. Alternatively, (26) was derived from 1 -benzothiepine 1 -oxide (30) (tricarbonyl)iron at — 50 °C by oxidative removal of Fe(CO)3 <88AG(E)1717>. 

Aramaki, Y. et al. (2004) Synthesis of 1-benzothiepine and 1-benzazepine derivatives as orally active CCRS antagonists. Chemical eC Pharmaceutical Bulletin, 52 (2), 254-258. 

The synthesis of dihydrobenzothiepinone 80 by a previously reported gold-catalyzed oxidation of sulfoxide-tethered alkyne 77 was the subject of a detailed experimental and theoretical mechanistic study (13JA8512).A theoretical study showed that the previously proposed mechanism involving benzothiepine formation by a Friedel—Crafts cyclization onto an oxo-car-bene 81 is unlikely and that a [3,3]-sigmatropic rearrangement of the first cyclization intermediate 78 is more favorable. 

One Sulphur Atom.— The synthesis of the 2,3- and 2,7-dihydrothiepins (96) and (98) by cycloaddition of DMADC to (95) and (97), respectively, has been described, reaction occurring via isolable cyclobutene intermediates. Unlike the parent compoiind (99 X = lone pair) which ring-contracts rather than give the 1-benzothiepin, the sulphone (99 X = Og) may be dehydrated on acid treatment to the corresponding 1-benzothiepin dioxide. The sul-phoxide (99 X = O) undergoes SO-elimination under the same conditions, consistent with the 1-benzothiepin monoxide as an intermediate however, this compound could not be isolated. A successful route to substituted 1-benzothiepins is enol-acetylation of keto-precursors such as (100). In the... 

The scope of the synthesis of 4-chloro-l-benzothiepins from benzothio-pyranones (121) has been extended by introducing a 5-alkyl or -aryl group via Grignard addition. The ring-expansion of a 3-benzothiepinone to the 4,1-benzothiazocine (122) by a Beckmann rearrangement has been described. ... 

---