Conjugate addition regioselectivity

When ene-nitrile oxidoisoquinolium betaine 131 was heated as a dilute solution in toluene to 120 °C (Scheme 1.15), near quantitative conversion to the cycloadduct 133, resulting from the undesired regioselectivity, was observed. While the near complete conversion to cycloadduct 133 of oxidoisoquinolinium betaine 131 indeed demonstrated complete avoidance of the conjugate addition pathway in favor of cycloaddition, initial production of undesired isomeric cycloadduct 133 (instead of 136) was disappointing. Notably, cycloadduct 133 is expected to be less kinetically favored based on frontier molecular orbital (FMO) analysis (assuming dipole HOMO-controlled cycloaddition) of the putative transition state. This result stands in contrast to the cycloaddition of nitroalkene oxidoisoquinolinium betaine... 

Pentadienyltrimethylstannanes undergo regioselective conjugate additions to aldehydes, catalysed by Lewis acids. The dominant product obtained depends on the catalyst used, as shown in reaction 46. In the case of titanium tetrachloride catalysis the reaction is also stereoselective and only one diasteroisomer is obtained297. Reaction with chiral aldehydes leads to asymmetric induction with similar organotin compounds298. 

Scheme 2.21 Regioselectivity in conjugate addition reactions to acceptor-substituted enynes 58.

One exception is the reaction of acetone oxime with divinyl ketone in the presence of an equimolar amount of zinc(II) bromide (162). Acetone oxime reacts with divinyl ketone on heating in THE at reflux, leading to both conjugate addition and nitrone cycloaddition, producing a 5 1 mixture of regioisomers with 8-oxa-l-azabicyclo[3.2.1]octan-4-one as the major isomer (Scheme 11.42). On the other hand, in the presence of an equimolar amount of zinc(II) bromide, 7-oxa-l-azabicyclo[3.2.1]octan-4-one is the major isomer (97 3) in a total yield of 97%, indicating that the Lewis acid has controlled the regioselectivity of the second step, namely, the cycloaddition. 

Hosokawa, Murahashi, and coworkers demonstrated the ability of Pd" to catalyze the oxidative conjugate addition of amide and carbamate nucleophiles to electron-deficient alkenes (Eq. 42) [177]. Approximately 10 years later, Stahl and coworkers discovered that Pd-catalyzed oxidative amination of styrene proceeds with either Markovnikov or anti-Markovnikov regioselectivity. The preferred isomer is dictated by the presence or absence of a Bronsted base (e.g., triethylamine or acetate), respectively (Scheme 12) [178,179]. Both of these reaction classes employ O2 as the stoichiometric oxidant, but optimal conditions include a copper cocatalyst. More recently, Stahl and coworkers found that the oxidative amination of unactivated alkyl olefins proceeds most effectively in the absence of a copper cocatalyst (Eq. 43) [180]. In the presence of 5mol% CUCI2, significant alkene amination is observed, but the product consists of a complicated isomeric mixture arising from migration of the double bond into thermodynamically more stable internal positions. 

Regioselective alkylative opening of a,(1-epoxy ketone oxime [40] and tosylhydra-zones [41] with organocopper reagents is initiated by the generation of unsaturated azo compounds which undergo conjugate addition. 

The first examples of nitrofluorination of alkenes were demonstrated by the reaction in a solution of 10% nitric acid in hydrogen fluoride at — 10 C.204 Further investigation has shown that the rate of this conjugate addition is determined predominantly by the nature of the tr-bond (electron density, polarity).205 As a rule, the reaction is carried out at temperatures between - 60 C (i.e., 1,1-dichloro-or 1,1-difluoroethene) and + 20 C. However, nitrofluorination of hexafluoropropene is only successful at higher pressure and temperature, i.e. if the alkene rc-bond is less polar the regioselectivity of the addition is also unsatisfactory,205 e.g. reaction of 1 and 2.206... 

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