Dibenzo thiepins

Elimination of sulfur from methyl dibenzo[/),/]thiepin-10-carboxylatcs 15 (R2 = Me) can be achieved in moderate yields (39-55%) upon refluxing in diethyl phthalate in the presence of copper bronze.60 For the dibenzo[A,/]thiepin-10-carboxylic acids 15 (R2 = H), the loss of sulfur is accompanied by decarboxylation. Thus, treatment of these acids with copper bronze in refluxing quinoline for four hours gives the corresponding phenanthrenes 16 (R3 = H) in moderate yield (50%). However, the exposure time to high temperatures influences the product formation. Thus, the decarboxyiated dibenzothiepins are obtained after refluxing for only five minutes.60... 

Dibenzo[/),/]thiepin-10(l 1H)-one (1) is an important synthon for the transformation of thiepins into other heterocycles. Oxidation with selenium(IV) oxide gives dibenzo[7>,/]thiepin-10,l 1-dionc (2), in 45% yield,38 which can be condensed with a series of benzaldchydes in the presence of ammonium acetate to provide the substituted 2-aryldibenzo[2,3 6,7]thiepino[4,5-t/]imidazoles 3, known to have anti-inflammatory properties.38... 

One equivalent of bromine is added smoothly to the C10-C11 -double bond, which has nearly olefinic character, of dibenzo[/>,/]thiepin in 88% yield (see Section 2.I.4.3.).3... 

Dibenzo[/>,/]thiepin derivative (39) has been obtained by cyclization of 2-arylthio-5-nitrophenylpyruvic acid (38) in the presence of polyphosphoric acid 33>. The use of this Friedel-Crafts type reaction is restricted to the synthesis of the stable di- and tri-annelated thiepins such as 40 33), 41 7), and 42 34). 

A neat synthesis of the chiral 10,ll-dibenzo[ / thiepine 79 from the chiral precursor 78 has been described. Cyclisation of the lithiated intermediate was mediated via reaction with sulfur W.v(i mid azole) <06OBC2218>. 

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

Theoretical studies on thiepine-thianorcaradiene (benzene sulfide) valence isomerization have been of continuous interest. In addition, hypervalency of sulfur in thiepines has been theoretically studied. The interest in fused systems, such as dibenzo[/)/]thiepines, toward pharmacologically active compounds is growing. In the last decade, many reports on the synthesis, characterization, and utilization of enantiomerically pure dihydro- and tetrahydrothiepines and thiepanes have appeared. 

The X-ray structures of dinaphtho[2,l l, 2 -< ]thiepin-3-(5//)-thione 27 and 3-(67/-dibenzo[ ]thiepin-ll-ylidene)-propyldimethylamine hydrochloride cobalt chloride complex 28 have also been reported <2000MI395, 1997MI15>. 

A new method, shape signatures, in the area of computer-aided molecular design has been studied <2003JME5674>. The method has been demonstrated to work well in selecting molecules on the basis of shape and polarity and has been applied to a receptor-based strategy. Dibenzo[ /]thiepine appears in the hit list for 57/-benz[ /]azepin. 

Since damotepine (257) was found to show sedative activity <66NEP6514187>, a variety of modified dibenzo[ /]thiepines have been prepared and their physiological activities have been researched. Zotepine (258) has psychosedative and antipsychotic activity <78CPB3058>. Citatepine (259) was found to have neuroleptic, psychosedative activity, and to be a potential dopamine antagonist. <83EUP125484>. A lH-dibenzo[2,3 6,7]thieno[4,5-c]pyrrole derivative (260) (CGP-19865) was... 

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). 

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). 

Dibenzo[7>,/]thiepins, e.g. 2, are obtained from 2-(arylsulfanyl)benzenepyruvic or -acetic acids by intramolecular Friedel-Crafts acylation, followed by elimination of water or hydrochloric acid.3 60... 

Polyphosphoric acid is a commonly used catalyst for this reaction however, in some cases a mixture of hydrogen bromide/acetic acid gives better results. Acylation of the S-phenyl-, V-(4-tolyl)- or S-(l-naphthyl)-substituted thiobenzenepyruvic acids 3a-c affords the corresponding dibenzo[A,/]thiepins in satisfactory yields, while reaction of the S-(4-methoxyphenyl) or S-(2-naphthyl) derivatives fails to provide any thiepin.60 The intramolecular Friedel-Crafts acylation of 2-(arylsulfanyl)benzeneacetic acids also yields the corrresponding dibenzothiepins in this case the use of hydrogen fluoride sometimes results in purer products.38 The applicability of this method is restricted to the synthesis of stable bisannulated thiepins. 

Dibenzo[/>,rf]thiopyrylium tetrafluoroborate (1) reacts with ethyl lithiodiazoacetate at — 120 C to form the diazo compound 2 which, with dimeric ( 3-allyl)chloropalIadium at 20 C, gives ethyl dibenzo[ ,d]thiepin-6-carboxylate (3), via a carbene intermediate.5 Compound 3 is quite stable the ethoxycarbonyl group can be hydrolyzed by alkali and decarboxylated to give the corresponding parent compound 4 in good yield. 

Substituted dibenzo[6,/]thiepins can be generated from thioxanthene derivatives by the rearrangement of carbocation 1. Compared with other possible cations, the tropylium ion type 1C is favored because of its resonance energy. Depending on the reaction conditions, the thiepin cation can react to give thiepins by loss of a proton, or by trapping a nucleophile, followed by elimination. 

The parent dibenzo[6,/] thiepin (3) has been prepared by two methods, which are of equal value. 

Alternatively, diazomcthanc can be added to thioxanthylium perchlorate (4) over 30 minutes at 0°C, and the reaction solution then poured into propan-2-ol. After concentration, the residue is dissolved in acetic anhydride and treated with boron trifluoride-diethyl ether complex at 0 C, to provide dibenzo[6,/]thiepin in 55 % overall yield16 (cf. Houben-Weyl, Vol. 10/4, p 834). 

Only sulfoxidation, and no elimination, occurs when the hydrochloride of 2 (R = Me) is treated with sodium periodate at room temperature.3 Ketone 4, which represents the tautomeric form of dibenzo[6,/]thiepin-10-ol, can be sulfoxidized with hydrogen peroxide at room temperature to provide sulfoxide 5 in 56% yield however, at reflux temperature oxidation occurs additionally at the carbon atom next to the oxo group and sulfone 6 is isolated in 79% yield.3... 

Potassium permanganate does not oxidize the sulfur atom in dibenzo[ft,/]thiepin (1), rather attacking the C —C double bond, which is very similar in reactivity to that in (Z)-stilbene, to provide various oxidation products, formed from ring opening or ring contraction, depending upon the acetone or water reaction medium.20... 

One equivalent of bromine was added to dibenzo[7 /]thiepin (1) and then the isolated dibromide was treated with 1-methylpiperazine in benzene at room temperature. Upon crystallization, 10-bromodibenzo[/),/]thiepin (2) was obtained in 51 % yield.3... 

Chlorodibenzo[, /]thiepin (4) can be obtained in 62% yield from dibenzo[6,/]thiepin-10(ll//)-one (3) in the presence of phosphoryl chloride and zinc(II) chloride, but a one-step ring-closure synthesis (sec Section 2.1.1.1.) yields 4 in 86% yield.3... 

The ester group of in ethyl dibenzo[/>,c/]thiepin-7-carboxylate can be hydrolyzed by alkali to the free acid in 93 % yield. Subsequent decarboxylation in quinoline at 150°C with copper as catalyst provides dibenzo[/ ,r/]thiepin in 60% yield.5... 

The selective insertion of diphenylacetylene in the cyciopaiiadated sulfide complex 1 leads to the stable organometallic complex 2, which can be depalladated with silver(I) tetrafluoroborate to give a mixture of the dibenzothiepinium salt 3 and the dibenzo[Z>,z ]thiepin 4.91 Demethyla-tion of 3 to yield 4 is complete after refluxing overnight in chlorobenzene. The synthetic scope of this method for thiepin derivatives is limited due to their thermal instability, but the method is very suitable for the synthesis of 1//-2-benzothiopyrans.91... 

Also, the different stabilities of 3-benzothiepins are reflected by the conditions of sulfur extrusion dibenzo[A,d]thiepin (13) is desulfurized by triphenylphosphane in refluxing xylene, while ethyl 3-benzothiepin-2-carboxylate (14) (see Section 2.1.3.4.) already loses sulfur at room temperature with a half-life of 54 minutes.5... 

Reaction of 1 with semicarbazide hydrochloride gives the semicarbazone 4, in 74 % yield, which can be oxidized by selenium(IV) oxide to provide dibenzo[2,3 6,7]thiepino[4,5-rf][l,2,3]selenadi-azole (5) in 80 % yield. Thermolysis of selenadiazole 5 leads, with subsequent release of nitrogen, to diradical 6, which can either dimerize to 7 or lose selenium to give the intermediate cycloalkyne. The latter can be trapped by dienes as cycloadducts.93 Thus, the thermolysis of 5 in the presence of 2,3,4,5-tetraphenylcyclopenta-2,4-dienone gives the cycloadduct 1,2,3,4-tetraphenyltribenzo-[/ ,<7,/]thiepin (8) in 14% yield. 

In contrast, cycloaddition of the thiazuleno derivative 9, prepared from dibenzo[fr,/]thiepin-10,11-dione (2), with diphenylacetylene yields 77% of the same product 8.94 Other cycloadducts from 9, and from its S, 5-dioxide, were also obtained in good yields. 

Table 3 presents the hyperfme splitting constants of some sulfur-containing aromatic radical anions. The series studied included the monoxides and dioxides of dibenzothio-phene 1, thioxanthene 2, thioxanthone 3, dibenzo[b,/] thiepin 4 and dithienothiophene dioxide 5. 

CN 3-dibenzo[t,e]thiepin-ll(6//)-ylidene-7V,7V-dimethyl-l-propanamine hydrochloride... 

This synthetic approach involves rearrangement of the incipient carbonium ion derived from the readily available six-membered ring compounds. Acid catalyzed 15,16) and solvolysis 17) reactions of 17a and 17b, respectively, afforded dibenzo[6/]-thiepin (9) which was also obtained by reaction of thioxanthylium ion (18) with diazomethane 18,19). 

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