Para-substituted regioisomer

The use of chloromethyl phenyl sulfone as a carbon nucleophile in the VNS reaction of 17 and 18 allowed one to obtain substitution products 27 and 28. In this case, the undesirable para-substituted regioisomer of 27 was formed in only 4% yield. Reduction of the nitro group in sulfones 27, 28 provided corresponding anilines 29 and 30, which gave good yields of imines 31, 32 with both electron-acceptor and electron-donor benzalde-hydes. Further cychzation under basic conditions provided access to 2-aryl substituted 5(6)-SF5-indoles 33 and 34 (Scheme 7). 

A homobimetallic rhodium catalyst derived from a P,N-ligand was found to allow for intermolecular direct arylations of unfunctionalized arenes [24]. Interestingly, aryl iodides, bromides-and even chlorides-could be employed as electrophiles, and a variety of valuable functional groups was tolerated by the catalytic system (Scheme 9.12). The C—H bond functionalization of toluene yielded ortho-, meta- and para-substituted regioisomers in a ratio of 71 19 10. Based on this observation and a Hammett correlation, a mechanism proceeding through radical intermediates was suggested. 

The Gassman indole synthesis provides a single regioisomer when ortho/para substituted anilines are employed, the yields of which are quite good generally. This provides some advantage in the preparation of 7-substituted indoles compared to other methods which normally give low yields, that is, the Fischer indole process. ... 

Regioselectivity (selective formation of one regioisomer, for example ortho vs para substitution in aromatic rings)... 

A final point to note with the Skraup reaction is that although ortho- and para-substituted amines lead to 8-substituted or 6-substituted quinolines respectively, mefa-substituted amines give a mixture of regioisomers, namely the 5-and 7-substituted quinolines. 

In an improved version of this prototype reaction, Shue [8] used 20 atm oxygen in the absence of mediators and achieved a turnover number (TON) =11. With other substrates, the turnover also remained modest, a record of TON = 20 having been achieved with furan derivatives [9]. Again, substituted arenes gave mixtures of regioisomers, with a shght preference for para-substitution. 

Another improvement was the use of different ligands in the cobalt-catalyzed Diels-Alder reaction, which led to both possible regioisomers selectively [14]. When bis(diphenylphosphino)ethane (dppe) was used as a ligand, the para-substituted product 24 was formed predominantly. In the presence of pyridine-imine ligands, the corresponding meta-substituted product 25 was generated predominantly (Scheme 13.13). 

Some reactions afford mixtures of products. Mixtures include diastereomers, such as endo and exo products (10.1 and 10.2) of a Diels-Alder cycloaddition, and regioisomers, such as ortho and para products (10.3 and 10.4) from an electrophilic aromatic substitution (Scheme 10.1). Even a reaction that forms products as subtly similar as enantiomers is technically a mixture of products. Isomeric mixtures violate the spirit of one compound, one well in combinatorial chemistry. Isomeric mixtures, however, are often unavoidable and therefore tolerated in compound libraries. Mixtures are also tolerated in libraries of compounds that have been derived from natural sources. Examples include extracts from finely ground vegetation and microbial broths. 

Cycloadditions that involve two unsymmetric reactants can lead to regioisomers. The regioselectivity of these adducts can be predicted with a high degree of success through the use of frontier molecular orbital theory.22 25 The ortho product (this nomenclature follows the analogy of disubstituted aromatic systems) is usually the preferred isomer from 1-substituted dienes, whereas 2-substituted dienes provide the para isomer as the major adduct. However, when a Lewis acid is used as a catalyst in the reaction, the ratio of these isomers can alter dramatically and, occasionally, can be reversed.22... 

If the aromatic ring is unsymmetrically substituted, the reaction may lead to a mixture of products. Thus wj-methoxybenzyl amine derivative 15 is transformed into vinyl tetrahydroisoquinolines 16 (major) and 17 (minor). Regioisomers 16 and 17 were formed by para and ortho cyclization. 

The physical properties of substituted benzenes resemble those of alkanes and alkenes of similar shape and molecular weight. Table 13.1 collects some physical properties for a number of common substituted benzenes. Notice the effects of symmetry. -Xylene melts at a much higher temperature than the ortho or meta isomer, for example. Many para isomers have high melting points, and crystallization can sometimes be used as a means of separating the para regioisomer from the others. 

The commercial availability of 2,4-difluoronitrobenzene (12) motivated us to investigate methoxide displacement of one of the fluorines, hoping to find conditions which favored displacement of the fluoro group para to the nitro substituent to provide 13 (Nu = OMe, Table 1). As summarized in Table 1, displacement with NaOMe favored displacement of the ortho fluorine, to provide the undesired regioisomer 14 (entries 1-3, Nu = OMe). The ratio of products varied with choice of solvent, from 1 2 (MeOH, DMF) to 1 8 (THF). Displacement with hydroxide was also studied (entries 4-7), but uniformly favored formation of Ae undesired ortho substitution product 14 (Nu = OH). 

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