Regiochemistry regioselective reactions

The most synthetically valuable method for converting alkynes to ketones is by mercuric ion-catalyzed hydration. Terminal alkynes give methyl ketones, in accordance with the Markovnikov rule. Internal alkynes give mixtures of ketones unless some structural feature promotes regioselectivity. Reactions with Hg(OAc)2 in other nucleophilic solvents such as acetic acid or methanol proceed to (3-acetoxy- or (3-methoxyalkenylmercury intermediates,152 which can be reduced or solvolyzed to ketones. The regiochemistry is indicative of a mercurinium ion intermediate that is opened by nucleophilic attack at the more positive carbon, that is, the additions follow the Markovnikov rule. Scheme 4.8 gives some examples of alkyne hydration reactions. 

The regiochemistry can be controlled by the nature of the substituents. With a tri-methylsilyl-substituted acetylene, the trimethylsilyl groups are placed in a positions of zirconacyclopentadienes with excellent selectivity (Eq. 2.8) [20]. With a phenyl-substituted alkyne, regioselective reactions are usually observed, although in some cases a mixture of two isomers may be formed. 

Regioselective reaction (Section 11.2) A reaction that produces predominantly one possible orientation (regiochemistry) in a reaction but does form some of the product with the other orientation. 

For unsymmetrical alkenes, the placement of the halogen represents an issue of regiochemistry. Hydrohalogenation reactions are regioselective, because the halogen is generally placed at the more substituted position, called Markovnikov addition. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

The regiochcmistry for stoichiometric alkylation with butyl(cyano)copper magnesium bromide is the same as that for the copper cyanide catalyzed reaction. The regiochemistry with dibutyl-copper magnesium bromide is also very similar to that of the copper(I) bromide catalyzed reaction. Lithium cuprates do not exhibit y regioselectivity in this biased system. 

An unexpected varying regiochemistry in intramolecular benzannulation has also been observed in the synthesis of cyclophanes. As mentioned above, there are only two possible regiochemical outcomes in the benzannulation reaction, which differ in the direction of alkyne incorporation. / -Tethered vinyl-carbene chromium complexes undergo an intramolecular benzannulation reaction with incorporation of the tethered alkyne with normal regioselectivity to give meta-cyclophanes [28]. 

The regiochemistry of Al-H addition to unsymmetrically substituted alkynes can be significantly altered by the presence of a catalyst. This was first shown by Eisch and Foxton in the nickel-catalyzed hydroalumination of several disubstituted acetylenes [26, 32]. For example, the product of the uncatalyzed reaction of 1-phenyl-propyne (75) with BujAlH was exclusively ds-[3-methylstyrene (76). Quenching the intermediate organoaluminum compounds with DjO revealed a regioselectivity of 82 18. In the nickel-catalyzed reaction, cis-P-methylstyrene was also the major product (66%), but it was accompanied by 22% of n-propylbenzene (78) and 6% of (E,E)-2,3-dimethyl-l,4-diphenyl-l,3-butadiene (77). The selectivity of Al-H addition was again studied by deuterolytic workup a ratio of 76a 76b = 56 44 was found in this case. Hydroalumination of other unsymmetrical alkynes also showed a decrease in the regioselectivity in the presence of a nickel catalyst (Scheme 2-22). 

With trisubstituted benzoquinones and use of the cationic oxazaborolidinium catalyst B, 2-[tra-(isopropyl)silyloxy]-l,3-butadiene reacts at the monosubstituted quinone double bond. The reactions exhibit high regioselectivity and more than 95% e.e. With 2-mono- and 2,3-disubstimted quinones, reaction occurs at the unsubstituted double bond. The regiochemistry is directed by coordination to the catalyst at the more basic carbonyl oxygen. 

Mesitonitrile oxide and acridine (1 2 ratio) react site- and regioselectively to give mono-cycloadduct 127. The reaction of the same reagents in a 10 1 ratio afforded the mono-cycloadduct 127, and the bis-cycloadduct 128 with the opposite regiochemistry to that of the mono-cycloadduct (288). 

The reaction proceeds via electrogenerated cationic species as its seen with the nonfluorinated amines, carbamates, and amides (Scheme 6.14). However, the regiochemistry of this anodic methoxylation is not governed by the stability of the cationic intermediates B and B (thermodynamic control) since the main products are formed via the less stable intermediates B. Indeed, this remarkable promotion effect and unique regioselectivity can be explained mainly in terms of a-CH kinetic acidities of the cation radicals formed by one-electron oxidation of the amines since the stronger the acidity of the methylene hydrogen, the easier the deprotonation. 

The reactions of 521 with 1,3-dienes were found to proceed exclusively in an [8 + 2] addition mode. The reactions were completely site and regioselective, as exemplified by the reaction between 521 and 2-methyl-l,3-pentadiene (525) which gave 526 after loss of CO2 (equation 152). The regiochemistry observed was in agreement with the frontier orbital coefficients calculated with semi-empirical methods. 

In a context of industrial interest, the copper-catalyzed addition of acetic acid36 to 1 (hydroacetoxylation) in the absence of oxygen was shown to be non-regioselective, a 1 0.5 mixture of 1,2- and 1,4-addition products being obtained in a yield of 60% based on butadiene. The effect of various additives on the regiochemistry and the yield has been carefully studied. The butadiene conversion was mainly efficient with the CuBr-LiBr catalytic system (equation 12). The role of the catalyst in the reaction mechanism has been discussed but not fully understood. It has been shown that the dominant formation... 

The similarities and differences between copper-catalyzed oxycyanation and diacetoxy-lation (vide supra), which are summarized in Figure 3, have been discussed. The main difference in the regiochemistry of the two reactions, i.e. an almost exclusive 1,4-addition in the cyanation and a non-regioselective acetoxylation, has been emphasized but was not interpreted in mechanistic terms. 

However, the reaction of 1,3-cycloheptadiene is less regioselective. Isoprene and E,E-2,4-hexadiene afford 1,2-/1,4-adducts in ratios of 87 13 and 83 17, respectively. The high selectivity for 1,2-addition (>95%) to 1,3-pentadiene is opposite to the corresponding oxymercuration of the same diene, which has been reported159 to give mainly 1,4-adducts. The different regiochemistry has therefore been explained by assuming that sulfomercu-ration occurs under kinetic control whereas oxymercuration occurs under thermodynamic control. 

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