Synthesis of Polysubstituted Benzenes

FIGURE 14.84 On a benzene ring substituted 1,3 with a pair of metadirecting groups, both substituents direct further substitution to the same position. 

Accordingly, nitration of 1,3-dinitrobenzene gives only meta substitution (Fig. 14.85). 

FIGURE 14.85 Nitration of 1,3-dinitrobenzene gives a single product, 1,3,5-trinitrobenzene. 

Further substitution of a disubstituted aromatic ring containing an ortho/para director and a meta director at the 1- and 4-positions is similarly easy to predict. Both groups direct the next substitution ortho to the ortho/para-directing group. 

An example of this kind of reaction is the nitration of 4-nitrotoluene (Fig. 14.86). 

One of the surest ways to learn organic chemistry is to work synthesis problems. The ability to plan a successful multistep synthesis of a complex molecule requires a working knowledge of the uses and limitations of a great many organic reactions. Not only must you know which reactions to use, you must also know when to use them because the order in which reactions are carried out is often critical to the success of the overall scheme. 

The ability to plan a sequence of reactions in the right order is particularly important in the synthesis of substituted aromatic rings, where the introduction of a new substituent is strongly affected by the directing effects of other substituents. Planning syntheses of substituted aromatic compounds is 

During our previous discussion of strategies for working synthesis problems in Section 9.9, we said that it s usually best to work a problem backward, or retrosynthetically. Look at the target molecule and ask yourself, What is an immediate precursor of this compound Choose a likely answer and continue working backward, one step at a time, until you arrive at a simple starting material. Let s try some examples. 

Draw the target molecule, identify the substituents, and recall how each group can be introduced separately. Then plan retrosynthetically. 

This ring will give a mixture of isomers on bromination. 

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Scheme 16 Synthesis of polysubstituted benzenes via o/2/jo-alkylation/Mizomki-Heck coupling...

Synthesis of polysubstituted benzenes by a Diels-Alder reaction of cyclohexadienes with acetylenes, via bicyclooctadienes. 

The ethylene moiety of zircona- and hafnacyclopentane can be replaced with more strongly coordinating ligands. Trimethylphosphine induces retro-oxidative cyclization of a zirconacyclopentane and replaces one ethylene ligand to afford a monoethylene trimethylphosphine complex (Scheme 1.63) [82]. Alkynes, nitriles, and aldehydes also substitute the olefin moiety through retro-oxidative cyclization and re-oxidative cyclization to afford thermodynamically more stable zirconacy-cles (Scheme 1.64) [83]. The replacement reaction has been applied to the selective synthesis of polysubstituted benzenes and pyridines [84]. 

As shown above, a,o)-diynes are reactive substrates in [2 + 2 + 2]-cycloaddition chemistry. However, a limitation of the use of a,o)-diynes is the presence of a secondary fiised-ring system in the arene product. A more flexible synthetic strategy that does not need the tether is desired. [2 + 2 + 2] Cycloaddition of monoynes is a challenging target in the synthesis of polysubstituted benzenes. However, selectivity is a drawback, and the development of a highly selective catalyst is desired. 

The present method was applicable to the synthesis of polysubstituted benzene compounds. For example, treatment of 20 with 2 in the presence of 10 mol % Cu(OTf)2 and 1 equiv of H2O in a mixture of 1,2-dichloroethane and CFI3CN (3 1) gave the corresponding benzene derivative 21 in 71% yield as a sole product (Scheme 15.7). 

REACTIONS OF [4+2] CYCLOADDITION AND OTHER APPROACHES TO THE SYNTHESIS OF POLYSUBSTITUTED BENZENES... 

Xi, C., Chen, C., Ling, J. and Hong, X. (2005) Pd-catalyzed one-pot multicomponent coupling reaction for the highly regioselective synthesis of polysubstituted benzenes. Organic Letters, 7 2), 347-349. 

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