Thiepins

Thiepins.—Monocyclic thiepins are generally thermally unstable because of their propensity to extrude sulphur via valence tautomerization to the thianor-caradiene form, e.g. (153). This conversion is, however, disfavoured by bulky groups at the 2- and 7-positions, which sterically destabilize (153). Thus although (152 R = Pr ) readily extruded sulphur at —70°C, it has now been reported that (152 R = Bu ) is remarkably stable (tj/2 = 7.1 h at 131 °C). This compound was prepared from a 2,6-di-t-butyl-4-methylthiopyrylium salt by treatment with ethyl lithiodiazoacetate to give (151), followed by ring-expansion, using a palladium catalyst. 

Arbuzov, E. N. Klimovitskii, A. B. Remizov, and G. N. Sergeeva, Izv. Akad. Nauk SSSR, 

Arbuzov, O. A. Erastov, S. Sh. Khefagurova, and T. A. Zyablikova, Izv. Akad. Nauk SSSR, 

The reaction of the complex (157) with divinyl sulphone gave the dihydro-thiepin 1,1-dioxide (159) instead of the expected triene (158) the latter is probably the primary product, and is converted into (159) by an intramolecular Diels-Alder reaction and subsequent isomerizations/°  

The anions derived from (160) and its enol ether were acylated and alkylated to give 1-benzothiepins, e.g. (161) thermal desulphurization then gave the expected naphthalenes.1-Benzothiepin 1-oxides (162) were prepared by two routes, and were decomposed at 30 or 50 °C to give naphthalenes by loss of SO the 1,1-dioxides that were produced by further oxidation of (162) were much more thermally stable. 

In a continuation of recent work on the preparation of stabilized thiepins, Murata has followed the preparation of (160) with the simpler system (161). The enhanced stability of (160) was attributed principally to the effect of the bulk of the t-butyl groups, which disfavours ring-closure to the thianorcara- 

The 2-methylenethiepin 1-oxide (164) has been prepared by the thermolysis of (162). A 3-elimination produces the sulphenic acid (163), which cyclizes to give (164).  

In a new, general route to cyclic j3-oxosulphonium salts, the 3-oxo-thiepinium perchlorate (166) was prepared by adding the phenylthio-diazo-ketone (165) to perchloric acid in chloroform.  

A high-yielding synthesis of thiepan has been achieved by allowing 1,6-dibromohexane to react with sodium sulphide under concentrated and heterogeneous conditions.  

Sulphonium methanides, e.g. (167), which are prepared by the reaction of thiachroman-4-ones with dimethyl diazomalonate, rearranged in the presence of base to give 1-benzothiepins, e.g. (169). This reaction parallels the recent conversion of sulphonyUmines into 1,2-benzothiazepines (e.g., see ref. 104). 

Pfister-Guillouzo, D. Gonbeau, and J. Deschamps, J. Mol. Structure, 1972,14,81,95 Bull. 

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The thiepin system 31 is formed quantitatively by ring expansion of the diazoacetate derivative 30 via carbene formation catalyzed by 7r-allylpalladium chloride and its intramolecular insertion[31], The 4-diazomethyl-4//-pyrane 32 is expanded to the oxepine 33 in quantitative yield with the same catalyst[32]. 

Diene moieties, reactive in [2 + 4] additions, can be formed from benzazetines by ring opening to azaxylylenes (Section 5.09.4.2.3). 3,4-Bis(trifluoromethyl)-l,2-dithietene is in equilibrium with hexafluorobutane-2,3-dithione, which adds alkenes to form 2,3-bis-(trifluoromethyl)-l,4-dithiins (Scheme 17 Section 5.15.2.4.6). Systems with more than two conjugated double bonds can react by [6ir + 2ir] processes, which in azepines can compete with the [47t + 27t] reaction (Scheme 18 Section 5.16.3.8.1). Oxepins prefer to react as 47t components, through their oxanorcaradiene isomer, in which the 47r-system is nearly planar (Section 5.17.2.2.5). Thiepins behave similarly (Section 5.17.2.4.4). Nonaromatic heteronins also react in orbital symmetry-controlled [4 + 2] and [8 + 2] cycloadditions (Scheme 19 Section 5.20.3.2.2). 

Heterocyclics of all sizes, as long as they are unsaturated, can serve as dipolarophiles and add to external 1,3-dipoles. Examples involving small rings are not numerous. Thiirene oxides add 1,3-dipoles, such as di azomethane, with subsequent loss of the sulfur moiety (Section 5.06.3.8). As one would expect, unsaturated large heterocyclics readily provide the two-atom component for 1,3-dipolar cycloadditions. Examples are found in the monograph chapters, such as those on azepines and thiepines (Sections 5.16.3.8.1 and 5.17.2.4.4). 

Dibenzo[b,/]thiepin, 10,11 -dihydroapplications, 7, 591 pharmacological activity, 7, 591 Dibenzothiepins synthesis, 7, 588 Dibenzo[6,/ thiepins applications, 7, 592 synthesis. 7. 587... 

Thieno[3,2-d]thiazolin-4-one, 2-acetamido-synthesis, 5, 138 Thieno[3,4-d]thiepins X-ray structure analysis, 7, 558 Thieno[2,3-h]thiinium perchlorate, 2,4-dimethyl-synthesis, 4, 1028... 

Tribenzo[6,d/]thiepin synthesis, 7, 587 Tribenzoxepins resolution, 7, 14 Tribenz[6,4/ oxepins synthesis, 7, 581... 

It now seems definitely proved that the thiothiophthene (86) rearranged reversibly to a thiophene (87) under the influence of alkali and not to a thiepin derivative, The dimethyl ether of (87) has been oxidized to 4-methylsulfonyl-2-thiophenecarboxylic acid (88)... 

Chloro-5-nitrobenzaldehyde, -acetophenone, or -benzophenone derivatives treated with 2-aminothiophenol under alkaline conditions provided good yields of the corresponding dibenzo[(3,/][l,4]thiepins. Similar treatment of 2-chloro-3,5-dinitrobenzophenone (318) provided 58% of dibenzo[(3,/][l,4]thiepin 321 and 20% of phenothiazine 323. Its formation can be easily explain by the Smiles rearrangement of the initially formed intermediate 320 into diphenylamine derivative 322, followed by denitrocyclization reaction leading to the corresponding product of denitrocyclization 323 (Scheme 49). When the reaction was done in pyridine, only this product was isolated in 50% yield (57JCS3818). 

Chemical Name 2-[(8-Chlorodibenzo[b,f] thiepin-10-vl)oxvl -N,N-dimethvlethanamine Common Name —... 

A suspension of 30 g of sodium hydride in benzene (30 ml) was added dropwise to 52 g of 8-chlorodibenzo[b,f] thiepin-10(11 H)-one dissolved in dimethylformamide (800 ml), and the mixture was heated at 100°C for 2 hours. To this, there were added 68 g of 2-dimethylamino-ethyl chloride, and the mixture was heated at 60°C for 39 hours. The reaction mixture, after cooled, was poured into ice-water, and the solution was extracted with ethyl acetate. The ethyl acetate layer, after washed with water, was extracted with 10% hydrochloric acid, when oil was precipitated. The aqueous layer, in which oil was precipitated, was washed with ether, made neutral with concentrated sodium hydroxide solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated to give oil, which was allowed to stand to provide solid. The solid was washed with petroleum ether and recrystallized from cyclohexane to yield 42.5 g of 8melting point 90°C to 91°C. Male-ate as colorless needle, melting point 204°C to 204.5°C. 

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. 

Thus, sulfur extrusion from the twisted naphtho[3,4-c/]thiepin is rapid, because in this case less energy is required to form the thianorcaradiene isomer than for a total loss of aromaticity. 

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. 

Besides a parent ion, the mass spectra of benzo- and dibenzothiepins show the corresponding naphthalene or phenanthrene radical cations as the base peak.2-16 The mass spectra of 1-benzo-thiepin 1-oxides and 1,1-dioxides show the same naphthalene radical cation, formed by loss of sulfur monoxide or sulfur dioxide, respectively.14 In contrast, in the mass spectrum of 2,7-di-terf-butylthiepin peaks resulting from the loss of sulfur are not found.17... 

Table 2. HNMR Spectra of (Bcnzo)Thiepins (Chemical Shifts in ppm)...

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