Other Fused Heterocyclic Compounds

The compounds that follow, in contrast to those in the preceding section, do not have any unifying theme, be it biological or chemical. They are consequently considered simply in order of the increasing number of heteroatoms present in the bicychc nucleus. 

The well-established antiarrhythmic agent disopyramide (57-1) comprises the starting material for a cycUzed version of that drug that is somewhat more potent-than the parent. Catalytic hydrogenation of (57-1) in the presence of an acid results in the selective reduction of the pyridine ring to give the corresponding piperidine. 

Treatment of the intermediate with acetic anhydride affords the acetamide (57-2). Reaction of the product with a base leads to an attack of the nitrogen on the secondary side chain amide on the newly introduced amide carbonyl with the formation of the cychc amidine. There is thus obtained the antiarrhythmic agent actisomide (57-3) [59]. 

One of the first so-called potassium sparing, nonthiazide diuretic agents contains a pterdine nucleus. This is reflected in the use of the pterdine staring material tetra-aminopyrimidine (38-2) in the synthesis. Thus, reaction of benzaldehyde with that polyamine and potassium cyanide leads to the formation of the cyanohydrinlike a-aminonitrile (63-2) from reaction of the most basic amino group. Treatment of the intermediate with a base leads to the addition of the amine to the nitrile to give the dihydropteridine (63-3). Simple exposure to air leads to dehydrogenation and the formation of triamterine (63-4) [65]. 

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This chapter is the second of a three-part series reviewing halogenation of aromatic heterocycles. Part 1 [93AHC(57)291] described halogenation methods and their application to five-membered systems. Part 3 will cover the benz and other fused heterocyclic compounds. Material published since 1978 is emphasized, although earlier references are included where... 

Naphthalene and other fused ring compounds are so reactive that they react with the catalyst, and therefore tend to give poor yields in Friedel-Crafts alkylation. Heterocyclic rings are also tend to be poor substrates for the reaction. Although some furans and thiophenes have been alkylated, a true alkylation of a pyridine or a quinoline has never been described.However, alkylation of pyridine and other nitrogen heterocycles can be accomplished by a free radical (14-23) and by a nucleophilic method (13-15). 

A synthesis for the benzene fused heterocycles of the type 10 and 11, which can be also applied to other fused heterocycle 12 would involve disubstituted starting compounds of the type 13 and 14 respectively, which by standard methods can be converted... 

Scheme 6 exemplifies the first path. Intramolecular cyclization of sulfonamides 1 is caused by action of a base, thus resulting in the formation of nitroaromatics fused with five- or six-membered heterocycles [22-24]. It should be emphasized that in some cases the formation of isomeric products can be observed due to a nucleophilic attack at the para-position relative to the nitro group. Also it is worth noting that the cyclic sulfamides 2 and 3 can be used as precursors to obtain some other N-heterocyclic compounds, such as isoindoles 4 [25] or 1,2,3,4-tetrahydroquinolines 5 [24] (Scheme 6). 

Hydrazino groups are also converted into H-compounds with mercury(II) oxide (74CR(C)-(278)427) in other reactions they have given hydrazones, or have been converted into pyrazoles and fused heterocyclic rings (77JAP(K)7785194), e.g. (72) -> (73). 

For most simple phenols this equilibrium lies well to the side of the phenol, since only on that side is there aromaticity. For phenol itself, there is no evidence for the existence of the keto form. However, the keto form becomes important and may predominate (1) where certain groups, such as a second OH group or an N=0 group, are present (2) in systems of fused aromatic rings and (3) in heterocyclic systems. In many heterocyclic compounds in the liquid phase or in solution, the keto form is more stable, although in the vapor phase the positions of many of these equilibria are reversed. For example, in the equilibrium between 4-pyridone (118) and 4-hydroxypyridine (119), 118 is the only form detectable in ethanolic solution, while 119 predominates in the vapor phase. " In other heterocycles, the hydroxy-form predominates. 2-Hydroxypyridone (120) and pyridone-2-thiol (122) are in equilibrium with their tautomers, 121 and 123, respectively. In both cases, the most stable form is the hydroxy tautomer, 120 and 122. ... 

The latter reagent also methylates certain heterocyclic compounds (e.g., quinoline) and certain fused aromatic compounds (e.g., anthracene, phenanthrene). The reactions with the sulfur carbanions are especially useful, since none of these substrates can be methylated by the Friedel-Crafts procedure (11-12). It has been reported that aromatic nitro compounds can also be alkylated, not only with methyl but with other alkyl and substituted alkyl groups as well, in ortho and para positions, by treatment with an alkyllithium compound (or, with lower yields, a Grignard reagent), followed by an oxidizing agent such as Bra or DDQ (P- 1511). 

A number of other ring systems have been prepared by intramolecular bis-annulation procedures. Pyrrolothiadiazolines 174 were prepared by condensation between hydrazides and compound 173 (Equation 14) <1998JPR676>. The thermally induced intra-intermolecular criss-cross cycloaddition of azine 175 in the presence of phenyl isocyanate leads to heterocyclic compound 176 containing three fused five-membered rings (Equation 15) <2002TL6431>. 

This lead has been pursued extensively at Wyeth-Ayerst, resulting in several additional series of active compounds (reviewed in [340]). Activity was retained by replacement of the quinoline by other benzo-fused heterocycles such as benzothiazole and A -methylbenzimidazole, but the benzoxazoles were inactive no correlation was seen between in vitro and in vivo activities... 

From Other Seven-Membered-Ring Compounds with Fused Heterocyclic... 

The natural cofactor of the AAHs, BH4 (Scheme 2), is a heterocyclic compound chemically classified as a pteridine that includes a fused pyrimidine and pyrazine rings. As many other naturally occurring pteridines BH4 has a pterin structure, which includes an amino substituent in position 2 and an oxo group in position 4 of the pyrimidine ring. The term biopterin is reserved for pterins with a dihydroxypropyl group in position 6. 

Halogenation of heterocycles five-membered rings, 57, 291 fused to other aromatic and heteroaromatic rings, 59, 245 six- and seven-membered rings, 58, 271 of heterocyclic compounds, 7, 1 Hammett equation, applications to... 

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