Fused-Ring Heterocyclic Compounds

The names of the heterocycles in the previous section along with the rules for fusion in Section 1.4 are the basis for the following names. 

The final numbering begins at the most counterclockwise atom not involved in fusion, arranged to give the heteroatom the smallest possible number, in this case 1. 

Sulfur is higher-priority than nitrogen and the lowest number for it is 2. The 3 locates the nitrogen. In this case, no bracketed site of fusion is specified because the fusion must precede the atom numbered 1. This is usual when there is more than one heteroatom and the fusion is simply benzo. The presence of one divalent atom in a six-membered ring excludes another atom from double bonding, thus the indicated hydrogen. 

In choosing where to start numbering, and in which direction to proceed, a hierarchy of rules must be followed. Numbering always begins at a nonfused atom adjacent to a fused atom, but since there are several possible orientations for the molecule, a choice is made as follows  

Give the lowest possible number to the first heteroatom regardless of 

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Some heterocyclic compounds show aromatic character despite their lack of degenerate orbitals. This may involve one n electron from the heteroatom as in pyridine, or two as in pyrrole and furan, making a set of six n electrons in a ring [8]. Many fused-ring heterocyclic compounds are aromatic also. A ten % electron monocyclic example, 1,4-dioxocin does not show aromatic character [9]. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

The reaction of 2-mercapto-5-(phenylazo)-4,6-dimethylpyridine-2-carbonitrile with appropriate halogeno compounds yields S-alkylated products which can be cyclised to yield pyridothieno-pyrimidines (61a) or -triazines (61b) [94PS(90)85]. Related reactions have been employed to yield further fused ring heterocycles [95PS(104)143]. 

The properties of fused-ring heterocycles are generally similar to those of the simple heterocycles. Fused heterocyclic compounds are common in nature, and they are also used as drugs to treat a wide variety of illnesses. Figure 16-17 shows some fused heterocycles that occur naturally or are synthesized for use as drugs. 

Reactions of potentially high synthetic utility are intramolecular azo coupling reactions of heterocyclic diazonium ions to give new fused-ring heterocycles. Some examples are given in (25-27) . The use of heterocyclic diazo compounds in organic synthesis has recently been reviewed by Ti ler and Stanovink ,... 

Reactions with aromatic binucleophiles form fused ring heterocycles (00T7267). Thus, when the reaction is performed with 2-aminothiophenol, compound 99 is converted into 2-trifluoroacety 1-4/7-1,4-benzothiazine (identified by X-ray crystallography) (Scheme 106). In the case of thioethanolamine hydrochloride, the product is 2-trifluoroacetyl-47/-1,4-thiazine. 

Ab initio dipole moments are also available for numerous other heterocyclic compounds (heterocycles with fused rings, heterocycles with two or more heteroatoms, etc.). 

Cyclic acetals of ketoses are important and useful compounds. Among other applications, they can be used as intermediates in the synthesis of numerous, useful sugar derivatives and as substrates for studies of conformational principles in fused-ring, heterocyclic A personal contribution by the author. 

Substituted five-membered ring heterocyclic compounds and their fused counterparts offer a high degree of structural diversity and have proven to be broadly useful as therapeutic agents. In this respect, various approaches for the preparation of these privileged structures with drug-like properties have been developed on solid-phase strategies. ... 

Condensation of 2-24 with hydrazine hydrate and hydroxylamine hydrochloride was carried out. The pyrrole-fused heterocycles pyrrolo[3,2-ii]pyridazine 2-27 and pyrrolo[2,3-c]pyridinone 2-28 were generated in high isolated yields, respectively (Scheme 2.16). These further applications of 2-24 demonstrate that the two carbonyl groups on the pyrrole ring of 2-24 are useful for the preparation of other valuable pyrrole-fused A -heterocyclic compounds [59, 60]. 

Carboxylic acids and their anhydrides acy late a variety of benzene derivatives, fused ring systems, and heterocyclic compounds. An improved procedure for the preparation of l,4-difluoroanthracene-9,10-dione involves reacting phthalic anhydride and 1,4-difluorobenzene to prepare an intermediate carboxylic acid [35] Intramolecular acylation in polyphosphonc acid completes the synthesis (equahon 24). 

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. ... 

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). 

Monoalkylation of Af-tosylallylamine 10 with dibromoalkane 101 proceeded in 60-90% yield (Eq. 10 see also Scheme 3 and Eq. 2) [17]. The bromoalkyl-amines 102 were converted to nitro compounds 103. In situ transformation of 103 into nitrile oxides led to spontaneous cycloaddition with formation of isox-azolines fused to 5-, 6-, and 7-membered ring heterocycles 104 a-c. Under very high dilution conditions, 103 d was converted to 104 d, an isoxazoline fused to an 8-membered azocine, in low (10%) yield. 

Grubbs and coworkers [238] used the ROM/RCM to prepare novel oxa- and aza-heterocyclic compounds, using their catalyst 6/3-15 (Scheme 6/3.9 see also Table 6/3.1). As an example, 6/3-35 gave 6/3-36, by which the more reactive terminal alkene moiety reacts first and the resulting alkylidene opens the five-membered ring. In a similar reaction, namely a domino enyne process, fused bicyclic ring systems were formed. In this case the catalyst also reacts preferentially with the terminal alkene moiety. 

Pyrazolopyrazoloquinoline derivatives can be prepared by treatment of pyrazolidin-3-one with 2-chloroquinoline-3-carbaldehyde, which gives firstly the zwitterionic compound 283. Reduction with sodium borohydride followed by ring closure in basic media gives the fused tricyclic heterocycles (Scheme 77) <1991T9599>. 

The reactivity of heterocyclic compounds composed of three fused ring systems (6 6 6) has been classified below according to general types of reactions. 

This review of furan chemistry is meant to continue the earlier survey by Bosshard and Eugster1 and concentrates upon the period 1968 to the end of 1979. Like the earlier review, this one is limited to the chemistry of the monocyclic furan nucleus and does not deal, except incidentally, with fused rings such as benzofuran or its quinones. Nor does it deal in detail with dihydro- or tetrahydrofurans, nor with compounds like furylpyridine that contain some other heterocyclic nucleus as well. Some butenolides and tetronic acids are admitted to consideration since they are the carbonyl equivalents of hydroxyfurans regarded as enols, but side-chain reactions are wholly excluded unless the furan nucleus clearly affects them in some important way. 

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