Benzo-fused heterocycle

Aldose reductase inhihitors are expected to protect long-term diabetic patients from the consquences of the accumulation of sorbitol that is one of the consequences of the disease [see lidorestat (Chapter 7)]. A quinazo-lodione provides the nucleus for another potential drug in this class. The sequence for the preparation of this agent starts with the heterocycle 

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Synthesis of Functionalized Indole- and Benzo-Fused Heterocyclic Derivatives through Anionic Benzyne Cyclization... 

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... 

Several biologically useful medium-sized benzo-fused heterocycles have been efficiently constructed by combining the efficiency of the Ugi condensation with a post-condensation S Ar cyclization, using an internal amino or hydroxyl nucleophile, and a nitrohalobenzoic acid 63 (Fig. 16). By introducing the additional nucleophile into the amine component, benzodiazepinones 79 [72], benzodiazoci-nones 80 [72], their benzo-fused counterparts 81 [72], benzoxazepinones 82 [72] and their fused counterparts 84 [60] and finally benzoxazocinones 83 [72] have been obtained. For the first two systems, the already described UDC strategy was exploited, whereas for the oxa heterocycles, the alcoholic or phenolic hydroxyl did... 

Fig. 16 Synthesis of medium-sized benzo-fused heterocycles through tandem Ugi-SNAr processes...

The direct lithiation of benzo fused heterocyclic systems in the benzo ring is often less easy than in the heterocyclic ring or even at a substituent phenyl group. Thus, while A7-phenyl indole undergoes lithiation at both the 2- and the 2 -positions, /3-lithiation at the 7-position does not occur. The first observation of lithiation at the 7-position of an indole derivative was seen with tricarbonyl(T7 -l-methyl-2-trimethylsilylindole)chromium(0) 26, even though the major site of reaction was at C-4 (Scheme 28)... 

The second class of benzo-fused heterocycles accessible from benzofuroxans are benzimidazole oxides. In this case only one carbon from the co-reactant is incorporated in the product. With primary nitroalkanes 2-substituted l-hydroxybenzimidazole-3-oxides (46) are formed via displacement of nitrite, and / -sulfones behave similarly. The nitrile group of a-cyanoacetamides is likewise eliminated to alford 2-amide derivatives (46 R = CONRjX and the corresponding esters are formed in addition to the expected quinoxaline dioxides from acetoacetate esters. Under similar conditions secondary nitroalkyl compounds afford 2,2-disubstituted 2//-benzimidazole-1,3-dioxides (47). Benzimidazoles can also result from reaction of benzofuroxans with phosphorus ylides <86T3631>, nitrones (85H(23)1625>, and diazo compounds <75TL3577>. 

The naming of benzo-fusee heterocycle is discussed in Section 1.2,... 

The use of classical condensation reactions is important. Thus, the Dieckmann reaction (equation 38) and the Thorpe-Ziegler cyclization (equation 39) have been used for almost a century for the preparation of a wide range of monocyclic and benzo-fused heterocycles. The aldol condensation and related reactions have also been fairly widely exploited, especially for the synthesis of 4-quinolones (the Camps reaction, e.g. equation 40), and various extensions of this general approach are described in the monograph chapters. 

Most benzo-fused heterocyclic systems are constructed from a substituted benzene by synthesis of the heterocyclic ring. Similarly most bicyclic heterocycles with heteroatoms in both rings commence with a monoheterocycle and build on the second heterocycle. However, substituent modification and, to a lesser extent, substituent introduction are also important, particularly in the later stages of a synthesis, and we now survey available methods for this. 

Since thiophene, pyrrole and furan are more readily attacked by electrophiles than is benzene, in the corresponding benzo-fused heterocycles attack generally, but not invariably, occurs in the heterocyclic ring (Section 3.3.3.2.1). 

With [Ti6-(0-dichlorobenzene)FeCp]+, selective mono- and di-substitution can be achieved with a variety of N- and O- and stabilized C-nucleophiles.77 With a bisheteroatom nucleophile, benzo-fused heterocycles are produced (equation 23).74... 

Scheme 22 presents some selected aryl radical cyclizations. The first example shows that isomerization of the intermediate radicals is again a concern. This isomerization, which is usually called the neo-phyl rearrangement,101 is promoted by the activating aldehyde group in the case at hand.102-103 The other examples illustrate that aryl radical cyclizations provide practical routes to benzo-fused heterocycles.104-105... 

Given the diversity of systems, trends are difficult to correlate. Fully conjugated benzo systems, and those with cyclobuta and cyclopenta systems are planar. The fully conjugated systems are also aromatic and have typical aromatic properties corresponding to simpler (e.g. benzo-fused) heterocycles. 

Many benzo-fused heterocycles are obtained by elaboration of substituted benzenes, especially useful for benzobis- 1,3-types. The strategy of photocyclization of 1,2-diheterocyclic substituted ethenes is a versatile approach to angular fused systems, and, while it has some limitations, it may yet be further exploited for systems with more than one heteroatom per heterocyclic ring. Otherwise a linking of diheterocycles by a two-carbon bridge is necessary. For compounds with indole moieties the Fischer approach is often successful. 

It has been demonstrated that 2,4,6-trinitrotoluene (TNT) can serve as a useful precursor for the synthesis of indoles, as well as other benzo-fused heterocyclic systems. Thus e.g. the... 

Since thiophene, pyrrole, and furan are more readily attacked by electrophiles than is benzene, in the corresponding benzo-fused heterocycles attack generally, but not invariably, occurs in the heterocyclic ring (Section 3.3.3.2.1). Conversely in benzopyridines and benzazines, electrophilic attack usually occurs in the benzene ring (Section 3.2.3.2). Benzazoles occupy an intermediate position, but in most cases electrophilic attack occurs in the benzene ring (Section 3.3.3.2.1). 

N-(/3-hydroxy)amides are cyclized with DIPCD in the presence of a catalytic amount of Cu(OTf)2 to give 2-oxazolines. Similarly, N-(2-hydroxyethyl)thioamides and N-(2-hydroxyethyl)thioureas are converted with DCC in refluxing acetonitrile to give 2-oxazolines in 88-94% yield." Benzo-fused heterocycles 465 ( = 0,1,2) are obtained from the thiourea derivatives 464 and DCC (Yields 81-92%)... 

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