Regioselectivity electron-withdrawing substituents

The coupling of bromo- or iodobenzene to styrene yields regioselectively a mixture of E- and Z-stilbenes 12 and 13. An electron-withdrawing substituent at the olefinic double bond often improves the regioselectivity, while an electron-donor-substituted alkene gives rise to the formation of regioisomers. 

When strong electron-withdrawing substituents were introduced at the a-or )S-carbon of the vinyl group, the styrenes acted as dienophiles. Thus cycloaddition of a-trifluoromethyl styrene (58) with Danishefsky s diene 59 afforded regioselectively a 1 1 mixture of cycloadducts which were then converted (Equation 2.20) into 4-phenyl-4-trifluoromethyl-2-cyclohexen-l-one [54]. 

Albeit nitrile oxides are more regioselective than nitrones towards MCP, in cycloadditions with alkylidenecyclopropanes they show a lower regiocontrol than nitrones. The same trend, however, on passing from electron-donating to electron-withdrawing substituents is observed. Benzylidenecyclopropane (156) gives (entry 1, Table 28) only a 1 4 mixture (compared with 1 19 with nitrone... 

As in benzene, the substituents in ortho and para will be better conjugated than those in meta. These qualitative aspects of regioselectivity have been studied quantitatively by quantum mechanical studies. Further the molecular orbital considerations have shown that the favoured transition state will be that in which there is strongest interaction between the HOMO of the diene and LUMO of the dienophile. In the most common cases the dienophile bears an electron withdrawing substituent and the diene an electron releasing one. Here the interation is between the LUMO of the dienophile and the HOMO of diene. 

Oxathiazoles are produced from sulfines in 1,3-cycloaddition reactions with nitrones <84CHEC-I(6)934>. With nitrile oxides only those sulfines which have sufficiently strong electron-withdrawing substituents such as CF3 (115) display the desired regioselectivity otherwise 1,3-... 

The regioselectivity for the ene pathway, in the photooxidation of several para substituted /3,/3-dimethylstyrenes, was recently found to depend on the electronic nature of the aryl substituents . Electron-withdrawing substituents, such as p-CFs or p-F,... 

In addition to the regioselectivity of the cycloaddition, there also exists a question of stereoselectivity. This issue involves the location of the substituent X on the dipolarophile in either an exo or endo fashion (Scheme 2.3). In the case of simple alkyl nitronates bearing an electron-withdrawing substituent, the stereoselectivity is highly dependent on both the nature of the dipolarophile and the configuration of the nitronate (Scheme 2.5) (96). In the case of nitronate 47, either a mixture of diastereomers or only the exo adduct is observed. However, the cycloaddition of maleic anhydride with 47 provides only the endo stereoisomer (97). 

Regioselective substitutions in di- and tri-halogenopyrimidine derivatives can in many cases be achieved. Chloro, bromo, and iodo substituents undergo aminolysis at approximately the same rates whereas a fluoro substituent reacts 60-200 times faster. 4(6)-Halo substituents react up to 10 times faster than 2-halo substituents. Electron-donating substituents (e.g., Me, Ph, OMe, NMe2) decrease the rate of aminolysis whereas electron-withdrawing substituents (Cl, CF3, N02) have the opposite effect (B-94MI602-01). 

Fluoro-l,l-dimethoxy-3-methylbut-2-ene reacts smoothly with a number of phenols. Monohydric phenols containing either electron-releasing or electron-withdrawing substituents afford satisfactory yields of 3-fluoro-2,2-dimethylchromenes. The regioselectivity of this synthon appears to parallel that described above (80JHC1377). 

An exciting development has come from work with an iridium catalyst. The use of the complex derived from phosphinoaryloxazoline ligand 149 leads to an efficient alkylation of E-cinnamyl acetate (Eq. 8E.32) [217], It is of note that electron-withdrawing substituents on the phosphorus atom, which are known to be required to give a good regioselectivity in general [218], also increased the enantioselectivity dramatically. 

In benzene derivatives, electron-donating substituents direct into the ortho-and para-positions, while in the case of the electron-withdrawing substituents considerable meta-addition is observed (Table 3.1) otherwise a more equal distribution is established [reactions (6)-(9) and Table 3.1]. In agreement with the pronounced regioselectivity, ipso-addition at a bulky substituent such as the chlorine substituent in chlorobenzene is disfavored. Evidence for this is the low HC1 yield in the case of chlorobenzene, the low yield of para adduct in 4-methyl-phenol (Table 3.1), or the decarboxylation in the case of benzoic acid [reactions (6) and (10)]. 

The presence of an electron-withdrawing substituent at the (3-position with respect to the double bond causes various trends in the ene regioselectivity [106] (Table... 

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