The synthesis of substituted benzenes

Activating groups donate electron density toward the benzene ring (Section 7.3.1) 

An alkyl group is an ortho-ipara-directing activator 

The mechanism of Friedel-Crafts alkylation is discussed in Section 

The following points should be borne in mind when planning an efficient synthesis of a substituted benzene. 

The introduction of an activating group on to a benzene ring makes the product more reactive than the starting material. It is therefore difficult to stop after the first substitution. This is observed for Friedel-Crafts alkylations. 

If the bromine atom had been introduced first then a mixture of 2- and 4-bromo-nitrobenzene would have been formed 

Amine group is removed leaving Br groups meta-to one another 

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More recently, Murakami and co-workers have developed a highly regioselechve method for the synthesis of substituted benzenes, which employs vinylallene derivatives and monosubshtuted alkynes (Eq. 2) [8]. Simple olefins, such as ethylene, are also applicable as dieneophile components, albeit with decreased efficiency (Eq. 3). A mechanistic raho-nale was presented for the proposed catalyhc cycle, which nicely explains the observed regioselectivity (Scheme 12.1). The regiochemical outcome was attributed to steric repulsion between the highly hindered metal center and the alkynyl substituent (20 versus 18). 

The Sandmeyer reaction allows the synthesis of substituted benzenes that can t be formed by electrophilic aromatic substitution reactions. These reactions succeed because N2 is a very good leaving group. 

Bicyclic unsaturated /1-lactones (e.g., 5) can be considered masked arenes8, and are utilized in the synthesis of substituted benzenes via a simple sequence of reactions. 

SCHEME 17.4 Furtha- examples of the synthesis of substituted benzenes from acyclic precursors. (Reprinted with permission from Ref. [10]. Copyright (2009) American Chemical Society). 

Of course, challenges exist in the use of aUcene and enyne RCM for the assembly of aromatic rings. Firstly, while the methodology may not rely on the use of preformed aromatic rings, the metathesis precursors still need to be synthesized, and this synthesis can still be particularly challenging. Secondly, the experimental procedures, yields associated with the reactions, and the costs associated with the use of precious metal catalysts for the metathesis reaction may limit their use, particularly in an industrial setting. However, if cheaper, more air- and water-tolerant catalysts can be developed, this method for the synthesis of substituted benzene rings may find wider application. 

For examples of steric hindrance in the synthesis of substituted benzenes, see Section 7.8... 

The [2+2+2] cycloaddition or cyclotrimerization is a very useful atom economical transformation, which allows the synthesis of substituted benzenes from monoalkynes. Various reviews have been published on this topic [1], Historically, it was discovered (or invented) by Reppe and Sweckendiek... 

Rh has in fact been the most actively used catalyst for this transformation to date. This metal catalysis has been comprehensively reviewed by Shibata and Tanaka until 2011 [ Id]. Pioneering work was made by Miiller [3] in 1974. Miiller reported the synthesis of substituted benzenes through the reaction of... 

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 474 Substituent Effects in Electrophilic Aromatic Substitution Activating Substituents 476 Substituent Effects in Electrophilic Aromatic Substitution Strongly Deactivating Substituents 480 Substituent Effects in Electrophilic Aromatic Substitution Halogens 482 Multiple Substituent Effects 484 Retrosynthetic Analysis and the Synthesis of Substituted Benzenes 486 Substitution in Naphthalene 488 Substitution in Heterocyclic Aromatic Compounds 489... 

The Synthesis of Substituted Benzenes Using Arenediazonium Salts 947... 

THE SYNTHESIS OF SUBSTITUTED BENZENES USING ARENEDIAZONIUM SALTS... 

Intermolecular cyclization of diyne with monoynes or intermolecular cyclization of triynes is a general method for the synthesis of substituted benzenes [51]. But a serious drawback of this reaction is the presence of a secondary process of diyne dimerization or monoyne trimerization. The selectivity and yield of the cyclic products strongly depend on the structure of the reactants, solvent, catalyst, etc. A highly efficient and selective [2-I-2-I-2] cyclization of diynes and monoynes was described. A rhodium catalyst allowed the reaction to proceed at room... 

Wakatsuki, Y., Kuramitsu, T. and Yamazaki, H. (1974) Cobaltacyclopentadiene complexes as starting materials in the synthesis of substituted benzenes, cyclo-hexadienes, thiophenes, selenophenes and pyrroles. Tetrahedron Letters, 15(51), 4549-4552. 

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