Other Fused Systems

Other Fused Systems.— The nitration of the aromatic borazarothieno-pyridines, such as (656) and (657), has been studied in detail. Through Raney-nickel desulphurization of (656) and (657), borazaro-analogues of 

Gronowitz, T. Dahlgren, J. Namtvedt, C. Roos, G. Rosen, B. Sjoberg, and U. Forsgren, Acta Pharm. Suecica, 1971, 8, 623. 

The acetylation of thienocyraantrene has been studied. In connection with work on neurotropic and psychotropic substances, derivatives of (662) have been synthesized. -  

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The present review, which surveys the literature to mid-1972, has been restricted to monocyclic 1,2,3-triazoles, since much of the chemistry of benzotriazoles and other fused systems has little in common with monocyclic triazole chemistry. The aim has been to give a broad survey of methods of synthesis and reactions of triazoles few references are included from before 1960, as these are available from earlier reviews. 

Oxazines and thiazines were considered together in CHEC(1984) and this meant that the review was restricted. In CHEC-II(1996) <1996CHEC-II(6)383>, the individual heterocycles and their derivatives were reviewed separately, which allowed for a thorough coverage. This trend is continued in this edition where the 1,3-thiazines and their derivatives are discussed, and this includes a review of the chemistry, syntheses, and applications. It does not include the vast literature dealing with cephems and related systems and other fused systems are not included unless their chemistry illustrates some significant property of the 1,3-thiazine heterocycle itself. 

There are many other fused systems, of which pyrene is a more complex example. An interesting system is the C,., carbon afbtrope, buckminsterfullerene, which consists of 12 five- and 20 six mernbered rings fused together to form the so-called buckybaH" Many polycyclic hydrocarbons are potent carcinogens. 

Nucleophilic cyclisations onto palladium-complexed alkenes have been used to prepare indoles, benzofu-rans and other fused systems. The process can be made catalytic in some cases by the use of reoxidants such as p-benzoquinone or copper(II) salts. 

The pyrazine ring is stable to permanganate oxidation, and this accounts for a variety of pyrazinecarboxylic acids that have been prepared from quinoxalines, benzo-fused quinoxalines including phenazines, and pyrido-fused pyrazines . In other fused systems, particularly pter-idines, the pyrimidine ring is easily hydrolyzed under either acidic or basic conditions to give numerous 3-aminopyrazinecarboxylic acid derivatives. 

In the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) 1,3-thiazines and 1,3-oxazines were reviewed together indeed, much of their chemistry is similar, providing justification for this arrangement. However, there are areas in which this is not so, and in this edition the two types of heterocycle are treated separately. This allows a more focused approach, but as Quiniou and Guilloton <90AHC(50)85> have already pointed out, one feature which complicates any survey of 1,3-thiazines is the interrelationship of these compounds to cephalosporins. The literature dealing with cephems and related systems is vast and requires individual treatment, so here the emphasis is on the synthesis and reactions of simple 1,3-thiazines and their benzo derivatives. Other fused systems are not included unless their chemistry illustrates some important property of the 1,3-thiazine heterocycle itself. 

Relatively few reports appeared on oxepine systems in 2004. The preparation of benzene oxide/oxepine has been observed in the gas phase reaction of benzene with oxygen atoms. Further reaction of this product with these atoms then gave a mixture of products including a compound thought to be oxepin-4,5-epoxide or oxepin-2,3-epoxide <04MI391>. Of relevance to this work is the report of the first observation of a 4,5-benzoxepin-2,3-oxide by H NMR <04TL4789>. Other fused systems have been of interest. The synthesis of a novel bicyclic oxepinopyrimidine 62 has been described. Acetylation of the alcohol 60 afforded the acetate derivative 61 which was then cyclised to the oxepine derivative 62 plus 63 on treatment with concentrated HCl <04H(63)2523>. 

Further work is required to establish the orientation of two other fused systems derived from pyrido[2,3-h]pyrazines. As the assignment of the phenacyl compound 137 as the 3-oxo derivative is uncertain, the structure of the furo compound 138, obtained on treatment of compound 137 with phosphorus pentoxide in concentrated sulfuric acid at 100° must also... 

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). 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Other C—C fused systems are also available by utilization of 1,4-dicarbonyl-type systems. The substituted pyrimidinethione (59) on treatment with polyphosphoric acid readily formed the thiazolo[5,4-d]pyrimidine system (60) without any of the alternative ring closure product (65JOC1916). 

Scheme 3 illustrates two general annulation procedures, one with the a-halogenoketone moiety incorporated in a cyclic system leading to C—C fused systems. The other, with the heteroatoms already incorporated in a heterocycle, results in a product with a heteroatom at a fusion point. 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Ring contraction and intramolecular cyclization constitute a convenient route to ring-fused systems that would be difficult to synthesize in other ways. H- 1,2-Diazepines (538) undergo electrocyclic ring closure to the fused pyrazole system (539) (71CC1022). Azepines also undergo similar valence bond isomerizations. 

E. C. Taylor and his co-workers have demonstrated an important principle in the ring-opening of pyridopyrimidines and other fused pyrimidine systems to o-aminonitriles. They have demonstrated that based-catalyzed cleavage of a 4-substituted pyrimidine will occur provided that (a) the anion formed by the attack by the base at the 2-position can be stabilized by appropriate structural features in the remainder of the molecule and (b) that the substituent attached to the 4-position is capable of departure with its bonding pair of electrons in... 

Other fused pyridazines, i.e. furo- and benzo-fused derivatives, sometimes also partly give the corresponding 1,2-diazocine systems.910... 

Ring-fused 2-pyridone structures where the additional ring is fused over the nitrogen will be covered in this section. Other ring-fused systems can be obtained simply by using suitable cychc starting materials or by conducting intramolecular reactions, examples for the preparation of such systems can be found in the papers discussed in Sect. 2.2 [42,43]. 

In fused ring systems, the positions are not equivalent and there is usually a preferred orientation even in the unsubstituted hydrocarbon. The preferred positions may often by predicted as for benzene rings. Thus it is possible to draw more canonical forms for the arenium ion when naphthalene is attacked at the a position than when it is attacked at the p position, and the a position is the preferred site of attack,though, as previously mentioned (p. 682), the isomer formed by substitution at the p position is thermodynamically more stable and is the product if the reaction is reversible and equilibrium is reached. Because of the more extensive delocalization of charges in the corresponding arenium ions, naphthalene is more reactive than benzene and substitution is faster at both positions. Similarly, anthracene, phenanthrene, and other fused polycyclic aromatic hydrocarbons are also substituted faster than benzene. 

Three different fused systems have been reported in the literature thieno[3, 2 4,5]thieno[2,3-c]pyridine (f/r-thiophenes), thieno[2, 3 4,5]thieno[2,3-c]pyridine (tram- thiophenes) and thicno[3,2-g]thicno [3,2-d pyridine derivatives. So far, the parent thienothienopyridines have only been prepared via the corresponding pyrylium salts (see below) all others are benzo or extended carbocyclic derivatives, for example, thienothienoquinolines. 

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... 

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