Benzothiepine

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). 

Thiepin, as a seven-membered conjugated system with sulfur as heteroatom, is a member of the 8 7t-electron heteroannulenes which are antiaroinatic according to Hiickel s rule. In contrast to oxepin, thiepin is not stable at room temperature and no valence isomerism with an arene sulfide has been observed. Stable thiepins are obtained only when two bulky substituents, e.g. /ert-butyl, are introduced into positions 2 and 7. In benzothiepins the annellation effect of the aromatic rings contributes decisively to the stability of these compounds stability increases with an increasing number of fused benzene rings. 

Sulfur extrusion is the main decomposition pathway, with 1-benzothiepins being more stable than 3-benzothiepins. The required 6it disrotatory electrocyclic process leads to a loss of aromaticity for the [6]annulated benzene ring, whereas the [r/]benzene derivative 4 leads to a thianorcaradiene derivative with less disturbed aromaticity of the benzene ring. 

Thermodynamic parameters have been obtained from kinetic HNMR spectroscopic studies of the thermal decomposition of ethyl 2,7-di-to7-butyl-5-methylthiepin-4-carboxylaten and two 1-benzothiepin compounds.12 The activation parameters for sulfur extrusion are AH = 93.7 kJ mol - 1 and AS = — 112.6 J Kmol-1 (in [2H18]Decalin) for the thiepin derivative,11 and AH = 75.3 and 87.9 kJ mol1 and AS = —100.4 and —104.6J Kmol-1 (in [2Hs]toluene) for the benzothiepin compounds.12 The large negative activation entropy values are consistent with a high degree of order in the anticipated thianorcaradiene transition state of the sulfur extrusion reaction. 

Only limited IR spectroscopic data for (benzo)thiepins have been reported. The C —C double bond stretching frequency in 2,7-di-rm-butyl-4,5-dimethylthiepin is observed at 1620 cm-1 with weak intensity.13 Characteristic strong intensities are found for the S —O vibrations in sulfoxide (e.g., 1040 cm-1 for 5-methoxy-4-phenyl-l-benzothiepin-3(2//)-one 1-oxide14) and sulfone (e.g., 1120 and 1300 cm-1 for thiepin 1,1-dioxide15) derivatives. 

The dihedral angles between the base plane (C 2, C 3, C 6, C 7) and the bow (S, C 2, C 7) plane (a) and stern (C3, C4, C5, C6) plane (/ ) of (bcnzo)thiepins are between 44.6-58.6 and 22.8-40.8, respectively, with the most pronounced bending being observed for 3,5-dimethoxy-4-phenyl-l-benzothiepin 1-oxide (Table 4).26 For thiepins, and their 1-oxides and 1,1-dioxides, the single and double bond alternation is obvious in the carbon framework. 

Considering their potential antiaromatic character, thiepins are also of theoretical interest. HMO calculations of -resonance energies, using reference data from 27 acyclic polyenes containing sulfur, predict antiaromatic character for thiepin and 2-benzothiepin, whereas 1- and... 

The concept of relative hardness and topological resonance energy per electron as a measure of aromaticity, with a relative hardness value of zero as the border for antiaromaticity, failed for 1-benzothiepin,3 2... 

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. 

The thermolabile, unsubstituted 3-benzothiepin (3) can be synthesized by a double Wittig reaction, in analogy to the Knoevenagel condensation (vide supra). This is achieved by condensation of phthalaldehyde with the bis(triphenylphosphonium) salt of bis(bromomethyl) sulfide in the presence of lithium methoxide as base at — 30"C.68... 

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. 

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

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