Regioselectivity substituted benzenes

Perfluoroalkylation of substituted benzenes and heterocyclic substrates has been accomplished through thermolysis of perfluoroalkyl iodides in the presence of the appropriate aromatic compound Isomeric mixtures are often obtained W-Methylpyrrole [143] and furan [148] yield only the a-substituted products (equation 128) Imidazoles are perfluoroalkylated under LTV irradiation [149] (equation 129). 4-Perfluoroalkylimidazoles are obtained regioselectively by SET reactions of an imidazole anion with fluoroalkyl iodides or bromides under mild conditions [150] (equation 130) (for the SET mechanism, see equation 57)... 

There are only a few reactions in which substituted benzenes are constructed in one step and with predictable regioselectivity. Carbene-complex-mediated benzannulations are one of these. Because of the scarcity of reliable benzannulation reactions, the use of carbene complexes for this purpose has become one of the most valuable synthetic applications of these organometallic reagents. 

Regioselective syntheses of 1,3,5-unsymmetrically substituted benzenes (309) are catalyzed by Pd(dba)2/PPh3 mixed alkyne/diyne reactants give mixtures containing homocoupled and mixed products (24 21 from HC CPh + HC=CC= CC Hn). The probable mechanism involves oxidative addition to the Pd(0) center, insertion of the second diyne into the Pd—H bond, reductive coupling and subsequent jr-complexation of this product to Pd(0), followed by Diels-Alder cycloaddition of the third diyne and elimination of product. 

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). 

Perhaps it should be mentioned also the orientation of the Birch reduction which is strongly dependent on the nature of the aromatic substituents. Donor-substituted benzenes furnish predominantly 1-substituted 1,4-cyclohexadienes while acceptor-substituted analogues give 3-substituted 1,4-cyclohexadienes. The regioselectivities can be explained by the destabilizing d-d pairing in the intermediates from d-substi-tuted cyclohexadienyl radical anions leading to the 3-substituted products, and the... 

The solid acid catalyzed adamantylation of substituted benzene derivatives was studied with the aim to achieve high para regioselectivities. Of various acidic resins, zeolite HY, sulfated zirconia, perfluorolkanesulfonic acids, and phosphotungstic acid, Amberlyst XN-1010 was found to be the catalyst of choice to afford para-substituted alkylbenzenes with selectivities exceeding 70%.398 In further systematic studies with a Nafion-H-silica nanocomposite catalyst,399 and various... 

Cyclotrimerization of acetylenes to form benzene derivatives is studied intensively mainly because of the challenge of chemo- and regioselectivities. A regiose-lective and highly chemoselective method for preparing substituted benzenes was described via PdCl2-catalyzed cyclotrimerization in the presence of CuCl2 537... 

A second major mode of photocydoaddition involves 1.2-addition to the aromatic ring, and this predominates if there is a large difference in electron-donor/acceptor capacity between the aromatic compound and the alkene. It is therefore the major reaction pathway when benzene reacts with an electron-rich alkene such as 1,1-dimethoxyethylene (3.43) or with an electron-deficient alkene such as acrylonitrile (3.441. When substituted benzenes are involved, such as anisole with acrylonitrile (3.45), or benzonitrile with vinyl acetate (3.46), reaction can be quite efficient and regioselective to give products in which the two substituents are on adjacent carbon atoms. 

Bis(trifluoromethyl)-l,2,4,5-tetrazine (426) cycloadds to benzyne giving a quantitative yield of l,4-bis(trifluoromethyl)phthalazine (427). Cycloaddition of (426) to benzene also forms (427) in good yield by oxidation of the initial dihydro derivative. Reasonable yields of l,4-bis(trifluoromethyl)-6-substituted phthalazines are obtained when electron donor-substituted benzenes are used in this reaction, and the regioselectivity is in agreement with calculations (87AG(E)332). 

With substituted benzenes the regioselectivity and the rate of the reduction are crucially dependent on the electron-donating or electron-withdrawing characteristics of the substituent. Thus with anisole, the rate of reaction is decreased and the product is 1-methoxycyclohexa- 1,4-diene (2,5-dihydroanisole) (42) with benzoic acid the rate of reaction is increased and the product is cyclohexa-2,5-dienecarboxylic acid (1,4-dihydrobenzoic acid) (43). 

The 1,3-diyne 160 undergoes an interesting regioselective cyclotrimerization to afford unsymmetrically 1,3,5-substituted benzene 162. In this reaction the enetriyne 161 is formed at first by the Pd-catalysed dimerization of 160, and the reaction... 

Fig. 5.5. De-tert-butylation via Ar—SE reaction. The sequence consisting of tert-butylation and de-tert-butyla-tion can in terms of a protecting group strategy be employed in the regioselective synthesis of a multiply substituted benzene derivative (cf. Figures 5.28 and 5.33).

Kinetic Aspects of Ar-SE Reactions Reactivity and Regioselectivity in Reactions of Electrophiles with Substituted Benzenes... 

Therefore, the reactivity and the regioselectivity of Ar-SE reactions with substituted benzenes can be predicted rehably. According to what has been stated above, one only has to iden-... 

Fig. 5.10. Ar-SE reactions with donor-substituted benzenes (Do, donor substituent) comparing the regioselectivity and the reactivity with benzene. The thicknesses of the initial arrows show qualitatively to what extent the reaction takes place via the corresponding transition state.

One of the solvated electrons is transferred into an antibonding 7t -orbital of the aromatic compound, and a radical anion of type C is formed (Figure 17.82). The alcohol protonates this radical anion in the rate-determining step with high regioselectivity. In the case under scrutiny, and starting from other donor-substituted benzenes as well, the protonation occurs in the ortho position relative to the donor substituent. On the other hand, the protonation of the radical anion intermediate of the Birch reduction of acceptor-substituted benzenes occurs in the para-position relative to the acceptor substituent. 

Recent results revealed that the ortho photocycloaddition frequently occurs concomitantly with the meta photocycloaddition even in cases where only meta derivatives are obtained. Especially in the case or electron-donor substituted benzene derivatives, the competitive ortho cycloaddition is less stereo- or regioselective and the resulting products are less stable. Aside the meta adducts as main products, complex mixtures of ortho products or products resulting from rearrangements of these primary photoproducts have been obtained [15,16], Improved separation techniques recently enabled a better characterization of these products. Furthermore, using particular conditions like an acidic reaction medium, the intermediates resulting from ortho photocycloaddition could be transformed selectively in more stable final products [17]. 

Therefore, the reactivity and the regioselectivity of Ar-SE reactions with substituted benzenes can be predicted reliably. According to what has been stated above, one only has to identify the electron donating and withdrawing substituents in the substrate. The electronic effects of the most important functional groups are listed in Table 5.3, where they are ordered semiquantitatively the best electron donors are on top and the best... 

Regioselectivity in the meta cycloaddition to substituted benzenes has been assumed to depend on charge polarization in the biradical intermediate shown in Scheme 21 (van der Hart et al., 1987). The theoretical calculations mentioned earlier, however, point out that in the early stage of the reaction the excited state has appreciable polar character that disappears as the reaction proceeds the biradical itself does not have any particular polarity. 

---