Thiazole-fused Systems

Thiazole-fused Systems.—Starting from the hydroxynitrosothiophen (633), reduction and acetylation gave (634), which upon treatment with PgSs yielded the thienothiazole (635). The structure of (636), previously 

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The synthesis of hitherto inaccessible thienylpyrazolones has been described. The reaction of (174) with methyl bromoacetate, followed by base-catalysed cyclization, gave (175). The corresponding thiazole-fused system, on the other hand, was prepared through the reaction of 2-phenyl-5-chloro-4-formylthiazole with thioglycollic acid in the presence of sodium methoxide. Another route to thienothiazoles consists in the reaction of (104) with CSa and sodium hydroxide. ... 

Alkyl-3-chloro-4-cyano-l -hydrazino-5,6,7,8-tetrahydro-2,7-naphthal-pyridines react with nitrous acid to form the azides, which are in equilibrium with the tetrazoles (Scheme 29). Unlike other examples of this equilibrium, these appear to exist primarily as the azides. As such, they have a number of handles (such as the chloride and cyano), which allow them to be transformed into other fused systems including two new tet-racycles. Reaction of the azides with amines proceeded via nucleophilic substitution of the chloride at C-3.With more forcing conditions of higher temperature and an excess of the amine, the azido can be replaced by nucleophilic substitution, which is rare for these compounds. When the azides were treated with hydrazine, a pyrazole-fused system is formed.With ethyl mercaptoacetate, a thiazole-fused system is formed (14T8648). 

Most syntheses of imidazo-fused systems involve cyclization of amino substituted heterocycles (or their tautomers), suitably substituted at an adjacent ring position. This provides a convenient route to imidazo[2,1 -ft]thiazoles, imidazo[1,2- ]imidazoles (Scheme 4), imidazo[l,2-6]pyrazoles, imidazo[l,5- Jimidazoles and imidazo[l,5-c]thiazoles. 

The thiazole-2-thione (51) with an a-halo ketone gives the intermediate (52) which is cyclized by strong acid into the thiazolo[2,3-/ thiazolium salt (53) (77HC(30-i)l). A wide variety of [5,5]-fused systems are prepared in this way. 

The fully conjugated oxazole and thiazole ring systems possess aromatic stability, which is higher in the latter due to better electron-releasing properties of sulfur. In fused dihydroazole systems the resistance towards nucleophilic opening of the azole ring is less. 

Thiazole can be fused with pyridine in six different ways the sections on synthesis have been organized accordingly. Further fused systems arise from the diazines and the triazines and their areno and heteroareno homologues. 

The usual precursor to the thiazolo-fused systems is a cyclic thioamide or its tautomeric form . A convenient approach to the synthesis of bicyclic [5-5] systems, e.g., the tricyclic thiazolium salt 46 and 2,3-dihydroimidazo[2,l-A]thiazol-5-one 48, involves the N,S-dialkylation of appropriate precursors 45 and 47 with 1,2-dihaloalkanes (Scheme 31) <1999JMC2828, 2002EJC777>. 

On this basis it has been suggested that an increase in lipophilicity (tt), decrease in size (MR), increase in resonance effect ), and the absence of 4 or 5 substitution of the benzothiazolamine ring system would be favorable for anticonvulsant activity. This has been presented as an example of QSAR in fused systems. In the literature more study reports are available where the thiazole moiety existed as part of the fused ring systems [77]. 

For the synthesis of thiazole-fused [l,2,4,5]tetrazines, another approach was applied as shown by the example of the hexahydrothiazolo[l,2,4,5]tetrazinone (46) this compound was prepared by reaction of the hexahydrotetrazine thione (45) (R = Ar or (CH2)gC02Me) with chloroacetic acid (Equation (3)) <92MI 820-01,90IJC(B)148>. Another related case leading to the same ring system with an unsaturated thiazole moiety was also reported <92JIC693>. 

Fused Systems containing Thiazole.—A large number of polyheterocyclic systems have been prepared, but in most cases the methods of synthesis, and the properties of the products, are straightforward extensions of earlier work they will not, therefore, be further discussed. 

Pyrazole-, Thiazole-, and Imidazole-fused Thiophens and Related Systems.— The behaviour of thieno- and selenolo-t-3,2-i/]pyrazoles in formylation and bromina-tion reactions has been studied. In contrast to benzo[fe]thiophen, a substituent is directed into the a-position of the condensed thiophen ring. 2-Mercapto-thieno[3,2-prepared from 2-chloro-3-nitrothiophen and sodium disulphide followed by carbon disulphide. A benzo-fused system was prepared similarly from 3-bromo-2-nitrobenzo[6]thiophen. Derivatives of... 

Other heterocyclic systems prepared by a thionyl chloride reaction include fused thiazoles,71 thiatriazoles,72 oxathiins,73 and dithiins 74 some further examples are given in reviews.53... 

Fused ring systems can be prepared either from an azine precursor or from an oxazole or thiazole precursor. In the sections on the synthesis of these compounds the former method is grouped under Azine approach , the latter under Azole approach . 

Mesoionic systems may be readily substituted by electrophiles. Thus the thiazolo mesoion (342) will couple with diazonium salts despite their relatively weak electrophilicity (80KGS621). Substitution in a fused heteroaromatic betaine azine ring, e.g. (343), also takes place with ease. The resonance form (344) of the mesoion (343) shows that the electrophile will attack at C-6. The substitution in this position is also predicted by MO calculations (73JHC487). Similarly the pyridine ring in pyridinium olates is active towards electrophiles and is substituted in the positions ortho and para to the olate function. Bromination of the 5-methyl derivative (321 R = Me) occurs exclusively in the 7-position which is rationalized via the intermediate (345). In the absence of a 5-substituent, attack in either the 5- or 7-position occurs the dibromide is readily formed. No bromination in the thiazole ring is observed. The 2-bromo derivative (346) has been made, however, by condensation between the appropriate mercaptopyridine and 1,1,2,2-tetrabromoethane. 

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