Non-classical Thiophens

Non-classical Thiophens.—Thiophens which formally require quadricovalent bonding about one or more sulphur atoms are usually called non-classical . Numerous examples have been described during the past decade (see Vol. 5, pp. 282-3). Tetraphenylthieno[3,4-c]thiophen (55) and its radical-cation and -anion have now been subjected to a detailed spectroscopic examination, and the results have been rationalized by M.O. models. Non-classical thiophens usually need several aromatic substituents for reasonable stability examples in which the stability is conferred, at least in part, by fusion to polycyclic nitrogen heterocycles, e.g. (56) and (57), have been described, but the degree of stability is not great (57), for example, has only a transient existence.  

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An interesting aspect of the type A heteropentalenes is the fact that each molecule is associated with two 1,3-dipolar fragments (45a<->45b) and, in principle, unsymmetrical systems can form two types of cycloadduct (46 or 47). In some cases the kinetically controlled product (46) is obtained at low temperature and the thermodynamically controlled product (47) is obtained at higher temperatures (see thieno[3,4-c]pyrroles, Chapter 3.18). For a given set of reaction conditions cycloaddition is usually site specific. For example, the non-classical thiophene derivatives of general structure (48) usually add across the thiocar-bonyl ylide fragment. This site selectivity is probably determined by the relative size of the HOMO coefficients at the alternative sites of addition. 

The non-classical system (182) has been synthesized, starting from 4,5-bis(chloromethyl)-l,2,5-thiadiazole, and characterized by the isolation of its dimer and adducts. The more complex but stable non-classical thiophens (183)—(185) have been prepared, starting from azomethine imine ylides, generated in situ from 1-aminopyridinium, 1-aminoquinolinium, or... 

Potts and co-workers have used phosphorus pentasulfide and pyridine as a standard reagent for constructing annelated diphenylthiophene rings from o-dibenzoyl compounds. Many of these annelated thiophenes can be written only in the tetracovalent sulfur or ylid dipolar form (96) and are thus termed nonclassical 123 other examples, particularly of the synthesis of non-classical thienoisothiazoles, have been reported by Gotthardt.124... 

The ability to form adducts was also found in the so-called non-classical thienothiophene (4). As described above (see Section II,B), the sulfoxide of 4,6-dimethyl-l//,3i/-thieno[3,4-c]thiophene (143) and l,3,4,6-tetraphenylthieno[3,4-c]thiophene 049) react with A -phenyl-maleimide to form endolexo pairs of adducts 144, 145 and 150,... 

Selenolopyrylium salts, 4, 1034-1036 Selenolo[2,3-c]pyrylium salts synthesis, 4, 969 Selenolo[3,2-b]pyrylium salts synthesis, 4, 1035 Selenolo[3,2-c]pyrylium salts synthesis, 4, 969 Selenoloselenophenes electrophilic substitution, 4, 1057 NMR, 4, 13 synthesis, 4, 135 UV spectra, 4, 1044 Selenoloselenophenes, alkyl-synthesis, 4, 967 Selenolo[2,3-b]selenophenes ionization potentials, 4, 1046 Selenolo[3,2-b]selenophenes dipole moments, 4, 1049 ionization potentials, 4, 1046 structure, 4, 1038, 1039 Selenolo 3,4-b]selenophenes H NMR, 4, 1042 synthesis, 4, 1067 Selenolo[3,4-c]selenopheneS non-classical reactions, 4, 1062 synthesis, 4, 1076 Selenolothiophenes electrophilic substitution, 4, 1057 H NMR, 4, 1041 UV spectra, 4, 1044 Selenolo[2,3- b]thiophenes... 

As a rule, Eg decreases as the quinoid character of the polymer backbone increases. The low Eg of polyisothionaphthene, a non-classical polythiophene derivative, results from the presence of the benzene ring which is built on the thiophene along the thiophene bond and stabilizes some quinoid contribution into the ground-state geometry. 

The (9)-heterophane (41) was obtained in 10% yield by a classical thiophen synthesis, heating the sodium salt of the keto-acid (40) with P4S10, and the (6)-heterophane (41a), with the shortest methylene bridge hitherto reported, was prepared from (41b). U.v. data are taken as evidence for the non-planarity of the thiophen ring in (41a). ... 

A heavily substituted non-classical thienol3,4-c]isothiazole (175) has been prepared in almost quantitative yield by the cyclization of the dibenzoylisothiazole (174) with phosphorus pentasulphide (Scheme 15). The precursor (174) is itself synthesized, albeit in low yield, from the oxathiazolium-olate (173), by a process akin to that described earlier (p. 286). The thiophen ring (but not the isothiazole ring) in (175) behaves as a masked ylide, and it undergoes cycloaddition reactions such as with dimethyl acetylenedicarboxylate, when the 2,1-benzisothiazole (178) is... 

The different acceptor strengths were rationalized on the basis of the resonance stabilities of the radical anions 45and 48 . Thus, the reduction of 45 to form the radical anion leads to an aromatic sextet. In contrast, the canonical structure of the radical anion of 48 involves tetravalent sulphur. These non-classical Kekule thiophenes are unstable compared with classical Kekule thiophenes [118]. 

Non-classical Thienofliiophens and Related Systems.—Phosphorus pentasulphide treatment of suitable vicinal dibenzoyl heterocycles has been established as a convenient pathway to tetraphenylthieno[3,4-c]thiophen, 5-methyl-1,3,4,6-tetraphenylthieno[3,4-c]pyrrole, and hexaphenylthieno[3,4-/]isothionaphthene, and their cycloaddition reactions have been studied. Further details on thieno-[3,4-c]pyrazole, thieno[3,4-c]furan, and thieno[3,4-c]pyrrole have appeared (see Volume 3, p. 449). 

Non-classical Thlenothiophens.—Detailed papers on the synthesis and chemical reactions of 1,3-disubstituted thieno[3,4-c]thiophens, e.g. (249) and (250), and on the stable tetraphenyl derivative (251), have appeared. ... 

In the case of duloxetme, a benzene ring has been replaced by a thiophene nucleus which is a commonly used approach during the process of lead modification. The number of atoms is not the same hence it may be described as a non-classical isostere The phenoxy group has also been transformed, which provides an example of a ring fusion, resulting in the presence of a naphthalenyl-oxy group. This dmg is non-selective, which makes it a mixed SERT/NAT inhibitor. It is indicated for the treatment of major depression, diabetic neuropathy and urinary incontinence. Duloxetine is used as the (S)-enantiomer hydrochloride salt and is available as capsules (30 mg). A typical adult daily dose for the treatment of major depression and diabetic neuropathy is 60 mg. In case of urinary incontinence, 40 mg twice daily have been recommended. 

A nice measure of the aromatic, i.e. non-diene-like character of thiophene can be gained from a comparison (Scheme 4) of the conditions necessary to force it to participate as a 1,3-diene in a Diels-Alder cycloaddition with maleic anhydride [7], compared with the classical reaction of furan. Lu et al. [8] shows how S-oxidation of thiophenes (utilisation of the pair of electrons on sulfur that is not involved in the aromatic sextet) reduces the aromaticity and allows cycloadditions to occur easily. 

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