Endocyclic reactions regioselectivity

If there are several nonequivalent endocyclic reaction centers in the aminoazole molecule, a question arises about regioselectivity of the condensation. Some difficulties in the determination of the isomer structures in these cases are illustrated, for example, in [165, 166] the product of the reaction of 2-aminoindole 162 with chalcone initially was assigned the structure of a pyrimidoindole 163 [165], but in a subsequent publication another arrangement of a-carboline 165 was proven (Scheme 3.48). 

Remarkably, a change of solvent from DCM to tetrahydrofuran (THF) resulted in an unprecedented switch of reaction regioselectivity, leading to the formation of 2,3-substituted styrenes 8. A variety of 4-aryl- or heteroaryl-substituted enynes was shown to react with good efficiency (Table 14.2, entries 1 to 8). Notably, in the case of bromo-substituted enyne, a clean reaction without protodebromination or formation of crosscoupling products occurred (entry 4). For a dienyne substrate, having both terminal and endocyclic double bonds, the former double bond reacted regioselectively, while the double bond of the cyclohexene subunit remained untouched (entry 9). 

The N-(bicycloalkenyl)nitrone (37) afforded the tetracyclic isoxazolidine (38) in 67% yield none of the regioisomeric isoxazolidine was observed (Scheme 9).17 The authors attributed this to non-bonded C—H interactions as shown, but the observed isoxazolidine was also entropically favored, forming via a six-membered, as opposed to a seven-membered, carbocyclic transition state. The N-(bicycloalkenyl)ni-trone formed from (39) and furfural cyclized in 45% yield predominantly to the tetracyclic product (40b), but some (41b) was also produced (95 5 ratio).18 Reaction of (39) and formaldehyde gave a mixture of (40a) and (41a) (62 38 ratio). The authors attribute the somewhat higher regioselectivity for (40b) in part to non-bonded interaction of the 2-furyl substituted methylene with the C-8 endocyclic C—H bond. 

The rhodium-catalysed enantioselective 1,4-addition of arylboronic acids to the bifunctional Michael acceptors (192) in the presence of phosphoramidites (194) occurs regioselectively at the endocyclic C=C bond and in up to 95% ee. The presence of KOH is required to increase the reactivity so that less boronic acid and lower reaction temperatures can be used.241... 

In related work, carbohydrate 1,2-diol dibutylstannylene acetals have been regiospecifically oxidized by IV-bromosuccinimide to give a-hydroxy-ketones. The reaction is illustrated for the preparation of 3-deoxy-l,2-O-isopropylidene-a-D-eryt/zro-hexofuranos-5-ulose (223) in Scheme 24. The endocyclic diol is also regioselectively oxidized to one product (224) in 44% yield, although 55% of the starting compound was recovered. (Scheme 24).439a... 

A simple relation between regioselectivity of maleic anhydride addition to benzenoid hydrocarbons and Claris n sextet formulae has already previously been observed [65]. In cases where the addition can lead to several isomeric adducts, the adduct whose Clar formula has the largest number of inherent it sextets is always the only one to be formed. Scheme 6 gives some examples. A necessary and, usually, also adequate condition for the endocyclic Diels-Alder reaction of benzenoid hydrocarbons with maleic anhydride is that at least one n sextet be gained by the addition, i.e. that the number of sextets in the product be at least one more than in the reactant. 

The results in the diazomethane reactions involving zinc(II) chloride catalysis have been explained by invoking a carbenoid intermediate. The properties of such a species will, of course, be sensitive to the nature of the metal and this might explain the different regioselectivity observed when diphenyldiazomethane is decomposed with rhodium and palladium salts in the presence of 5-methylenebicyclo[2.2.1]hept-2-ene (9). With rhodium(II) acetate as catalyst the exocyclic double bond is attacked exclusively, whereas palladium(II) chloride catalysis directs cyclopropanation to the endocyclic double bond. ... 

Intermolecular direct arylations of heteroarenes with aryl halides were thus far predominantly accomplished with palladium or rhodium complexes [31, 39,75, 76], Hence rhodium catalysts proved applicable to various electron-rich heteroarenes. In contrast, less expensive and more versatile palladium catalysts allowed for direct arylations of both electron-rich and electron-deficient substrates. Generally, the problem of achieving regioselectivities in direct arylation reactions of heteroarenes is less pronounced than it is for simple arenes, since in many cases the heteroatom can be considered as an endocyclic directing group. 

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