Benzo-fused heterocycles, synthesis

Another important aspect of aryne chemistry that has found application in benzo-fused heterocycles synthesis is MCRs, which generally include the first addition of nucleophiles to arynes and subsequent interception of the aryl anion intermediate with other electrophiles. If the nucleophile and electrophile are not part of the same molecule, the overall process is a unique multicomponent coupling, where the aryne is inserted between the other two coupling partners to afford the final product 85 (Scheme 39). This highly efficient transition-metal-free methodology has been applied to the S5mthesis of valuable benzo-fused heterocycles and has foxmd application in natural product synthesis. 

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

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

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. 

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... 

The diazotization of aromatic amines with a nucleophilic substituent at the ortho position is a common method of synthesis of benzo-fused heterocyclic compounds with two or more contiguous nitrogen atoms. Benzotriazoles (9), benzotriazinones (10), and benzothiadiazoles (11) are examples of heterocyclic ring systems that can be prepared in this way. 

The Heck reaction is applicable to the synthesis of benzo-fused heterocycles including indolines, 1,2-dihydroquinolines, and benzopyrans. Influence of reaction conditions on diastereoselectivity is witnessed in the cyclization leading to geissoschizol and its isomer. Reaction of 2-cyanothiophene with aryl halides introduces the aryl group to the 5-position."... 

Palladium Catalysis in the Synthesis of Benzo-Fused Heterocycles... 

Scheme 5.28 Three-component synthesis of benzo-fused heterocycles.

Synthesis of chiral heterocycles by domino organocatalytic processes has also been intensively studied. In particular, various benzo-fused heterocycles, such as chiral chromans, " thiochromanes, hydro-quinolines, dihydropyranes, or thiopyranes were investigated. These organocatalytic sequence were typically initiated by a hetero-Michael addition of a sulfur, oiqrgen or nitrogen nucleophile, which triggers the formation of an enolate/enamine that adds to the ortho electrophile terminating the cascade reaction. An elimination step or an additional cyclisation step follows (Scheme 8.25). 

A soln. of N-ethylbenzisoxazolium fluoroborate in acetonitrile added to a 20%-soln. of Na-thiocyanate 2-thio-4-ethyliminobenzo[l,3]oxazine-2,4-dione. Y 80%. — The N-ethylbenzisoxazolium cation can combine rapidly with all nucleophilic elements of the first row of the periodic table and at least one member of the second to furnish mostly in high yield a variety of unusual intermediates for the synthesis of new benzo-fused heterocyclics, many of them hitherto inaccessible. F. e. s. D. S. Kemp and R. B. Woodward, Tetrahedron 21, 3019 (1965). 

Rossi and colleagues extended the Bunnett-Beugelmans indole synthesis to carbazoles (Scheme 12) [87, 88]. The reaction may be run in liquid anunonia, DMSO, or THE For the process in equation 1, there is no reaction in the dark after 60 minutes, and an S l mechanism was implicated. The yields are generally very good to excellent, and the methodology was adapted to the synthesis of other benzo-fused heterocycles [88],... 

The intramolecular trapping of benzyne intermediates with tethered nucleophiles is a powerful strategy for the synthesis of benzo-fused heterocycles. In this field, 7-functionalized benzoxazoles 59 and benzothiazoles 60 have been prepared by anionic cyclization of the corresponding lithiated benzyne (thio)amides and (thio)carbamates, which were generated from 3-haloaniline derivatives (Scheme 12.34) [55]. Related to this, substituted indolines 61 have also been accessed by benzyne-mediated cyclization-functionalization from Boc-protected (2-bromo-4-methoxy)phenetylamines using Mg(TMP)2 2LiCl as a base. This methodology has also been applied to the preparation of functionalized carbazoles (Scheme 12.34) [56]. 

As appropriately substituted o-disubstituted benzene derivatives are feadily available, this procedure has found widespread application in the synthesis of benzo-fused flve-membered heterocycles. Examples abound in the various chapters in these volumes and the following few examples illustrate the general trend. 

Many other nitrogen- and sulfur-containing rings are available from reactions of the Willgerodt-Kindler type. Benzo- and pyridino-fused thia-zoles, for example, are formed from anilines (benzeneamines) and amino-pyridines, respectively.25 Asinger26 has reviewed the scope of these reactions in heterocyclic synthesis. 

Abstract The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or... 

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