Polysubstituted aromatics

Snieckus, V. Directed ortho Metalation—Tertiary Amide and o-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics, Chem. Rev. 1990, 90, 879-933. 

Other examples of intramolecularly coordinated (by 0 as well as by N groups) organolithium compounds can be found in Setzer and Schleyer (2) and Seebach (4). Two recent reviews are also pertinent. Klumpp (34) deals with 0- and N-assisted lithiation and carbolithiation of nonaromatic compounds, and Snieckus (34a) deals with directed (by amide and carbamate groups) ortho metalation in polysubstituted aromatics. 

For the chemist practicing polysubstituted aromatic and heteroaromatic synthesis, methods steeped in classical electrophilic (1, Scheme 1) [1] and nucleophilic substitution [2] and SRN1 (2) [3] reactions have been joined and, not infrequently super-ceded, by vicarious substitution (3) [4] and by DoM (4) [5] processes. The Murai ortho CH activation (5) [6] is a recently evolving and potential competitive method to the DoM tactic. The 60 years since its discovery by Wittig and Gilman, and 40 years since its systematic study by the school of Hauser, the DoM reaction has advanced by the contributions of Christensen, Beak, Meyers, and many other... 

Victor Snieckus is well known for having developed powerful methodological tools for the synthesis of polysubstituted aromatics, in particular heteroaromatic directed ortho-metalation. Thus, in his chapter (No. 10), prepared with his co-author Christian Hartung, directed ortho-metalation is taken as a starting point for new synthetic aromatic chemistry. 

Other aminations of more substituted arene complexes allow the regiospedfic synthesis of polysubstituted aromatics. For example, p-fluoroanisoletricarbonylchromium complex can first be lithiated and quenched with chloroformate to give 33b (R = OMe, R = CChMe). After substitution of the fluoride by pyrrolidine, complex 31 is obtained in 89 % yield (Scheme 18) [29]. 

Beak, P., Snieckus, V. Directed lithiation of aromatic tertiary amides an evolving synthetic methodology for polysubstituted aromatics. Acc. Chem. Res. 1982,15, 306-312. 

Benzene. The earliest work in directed metalation was done on the benzene system in the early 1930s (3). That the benzene ring was the most promising system for the exploitation of this reaction appears logical since it was by far the most examined aromatic system at that time. Not only have the largest number of directing substituents been successfully demonstrated for this system, but in all probability the demand for a convenient route to a specific polysubstituted aromatic compound will be highest for this system. In all cases examined, directed metalation of a monosubstituted benzene has yielded almost exclusively ortho metalation, with only ortho-disubstituted products obtained (Reaction 1). With... 

Snieckus, V. 1990. Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics. Chem. Rev. 90 879-933. 

In the conversion of methanol to gasoline on ZSM-11, much less Ci-Cj products are observed than with ZSM5 while the Cg -aliphatics are more abundant. Whereas on ZSM-5 the aromatics fraction is mainly composed of xylenes, on ZSM-11 more aromatics are produced. Harrison et al. defined in this context product selectivity as the ratio of xylenes to trimethylbenzenes. The ratio varied from 2.5 to 0.5 for the conversion of methanol on ZSM-5 and ZSM-11, respectively. The difference in shape selectivity was also illustrated by the (m+p) o-xylene ratio, which was 13 on HZSM-5 but only 3 on HZSM-11. This was attributed to the relative dimensions of the channel intersections, 50% of which are 30% larger in ZSM-11, and to the difference in relative length of the straight (ZSM-5, ZSM-11) and tortuous channels (ZSM-5). Furthermore, since ZSM-11 contains only one type of channel, the molecular traffic control shape selectivity should, in principle, not occur in this catalyst. This provides a possible explanation for the higher yield of polysubstituted aromatics methanol reactant and aromatic products cannot avoid counterdiffusion as in ZSM-5 and this increases the probability of alkylation of the aromatics. 

It is shown that the MP2(/c)/6-31G7//fF/6-31G + ZPE (HF/6-31G ) model reproduces very well the experimental proton affinities in a large number of substituted benzenes and naphthalenes. Extensive applications of this model revealed that the proton affinity of polysubstituted aromatics followed a simple additivity rule, which have been rationalized by the ISA (independent substituent approximation) model. Performance of this model is surprisingly good. Applications of proton affinities, obtained by the transparent and intuitively appealing ISA model, in interpreting directional ability of substituents in the electrophilic substitution reactions of aromatics are briefly discussed. 

The benzannulation reaction is a versatile method for the formation of polysubstituted aromatic compounds such as naphthoquinones. This three-component coupling involves the reaction between an a. unsaturated Fischer carbene, an acetylene, and a CO ligand, and initially proceeds by cycloaddition of the alkyne with the carbene complex. The regioselectivity of this step is highly dependent on the substituents on the acetylene moiety and is usually low in the case of internal acetylenes. 

Heteroatom-facilitated lithiations , Gschwend, H. W. and Rodriguez, H. R., Org. React., 1979, 26, 1 Directed metallation of 7r-deficient azaaromatics strategies of functionalisation of pyridines, quinolines, and diazines , Queguiner, G., Marsais, F., Snieckus, V., and Epsztajn, J., Adv. Heterocycl. Chem., 1991, 52, 187 Metallation and metal-assisted bond formation in 7r-electron deficient heterocycles , Undheim, K. and Benneche, T., Heterocycles, 1990, 30, 1155 Directed ortho metallation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics , Snieckus, V., Chem. Rev., 1990, 90, 879. 

Secondary amides as ortho-directed metallation groups for arenes a useful construction way for polysubstituted aromatic and heteroaromatic systems 06COC1817. 

The formation of arenium ions from heteroatomic electrophilic reagents was observed by the NMR method for other polysubstituted aromatic compounds as... 

Another group of dielectrically interesting solids are the polysubstituted aromatics having at least four halogen, nitro or methyl group substituents. These molecules have the symmetry of circular discs and exhibit ready rotation about one axis. Two examples of such systems are presented in Table 4.1. 

Conveniently prepared from phenols, more readily available than the corresponding aryl halides, and recognized as the most powerful in the hierarchy of DMGs [63], the aryl O-carbamates are primed for synthetic application. One application is their use in the regioselective preparation of polysubstituted aromatics and then involvement as leaving groups in subsequent Suzuki-Miyaura or Kumada-Corriu (Section 14.3.1.2) cross-coupling reactions for the establishment of 1,2-disubstituted aromatics, illustrated by the conceptual 1,2-dipole synthetic equivalent, 35 36 = 37 (Scheme 14.10 and Scheme 14.11) [64]. 

Scheme 14.10 The combined Suzuki-Miyaura or Kumada-Corriu cross-coupling reactions for the synthesis of polysubstituted aromatics.

Orientation and activating/deactivating effects have a large practical significance, because in synthesizing polysubstituted aromatics, the order of addition of the substituents must be taken into account. 

Transition metal-catalyzed cyclotiimerizations [48] are a very important method for the synthesis of polysubstituted aromatic systems [49]. In this section, we will illustrate the use of this methodology for the de novo construction of a benzene ring, although the final products produced in many cases may be considered to be heteroaromatic. 

The reaction between benzene and SO3 is highly sensitive to the concentrations of the reagents and is, therefore, reversible. The reversibility of this process will be reexamined later in this chapter and will also be utilized heavily in the synthesis of polysubstituted aromatic compounds. 

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