1,4-Addition reaction conjugated kinetic control

In order to determine if the oxa-conjugate addition is kineticaUy or thermodynamically controlled, the trans isomer 2.6b was independently synthesized and subjected to tandem reaction conditions. Since it has been very well documented that 2,6-cji-tetrahydropyrans are thermodynamically more favorable than 2,6-trans- tetrahydropyrans in equilibrium [36-38], thermodynamic control would result in the isomerization of the compound. The complete lack of formation of the cis isomer 2.6a led us to conclude that the formation of the 2,6-cw-tetrahydro-pyrans 2.6a through tandem oxidation/oxa-conjugate addition is under kinetic control. 

Conjugated dienes undergo several reactions not observed for nonconjugated dienes. One is the 1,4-addition of electrophiles. When a conjugated diene is treated with an electrophile such as HCl, 1,2- and 1,4-addition products are formed. Both are formed from the same resonance-stabilized allylic carbocation intermediate and are produced in varying amounts depending on the reaction conditions. The L,2 adduct is usually formed faster and is said to be the product of kinetic control. The 1,4 adduct is usually more stable and is said to be the product of thermodynamic control. 

Both primary and secondary amines add to a /S-unsaturated aldehydes and ketones to yield /3-amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control (Section 14.3), so the more stable conjugate addition product is often obtained to the complete exclusion of the less stable direct addition product. 

It was recognized in early examples of nucleophilic addition to acceptor-substituted allenes that formation of the non-conjugated product 158 is a kinetically controlled reaction. On the other hand, the conjugated product 159 is the result of a thermodynamically controlled reaction [205, 215]. Apparently, after the attack of the nucleophile on the central carbon atom of the allene 155, the intermediate 156 is formed first. This has to execute a torsion of 90° to merge into the allylic carbanion 157. Whereas 156 can only yield the product 158 by proton transfer, the protonation of 157 leads to both 158 and 159. 

Such equilibria are governed by thermodynamics, and so the abundances of the different species in solution are dependent on their relative thermodynamic stabilities. If, however, such a mixture of species is applied in, for example, a conjugate addition reaction, the product formation will be controlled by kinetics, and it is most likely that Cu2Li2Mc4 would be kinetically the most active species present. 

Stereoelectronic effects should also play an important role in the nucleophilic 1,4-additions of anions to conjugated systems. These effects should therefore influence the Michael reaction as well as the hydrocyanation of a,6-unsaturated ketones. Studies on these reactions provided evidence that the kinetically controlled addition of a nucleophile to a cyclohexenone derivative is indeed subject to stereoelectronic effects. 

How can the Z selectivity in Wittig reactions of unstabilized ylids be explained We have a more complex situation in this reaction than we had for the other eliminations we considered, because we have two separate processes to consider formation of the oxaphosphetane and decomposition of the oxaphosphetane to the alkene. The elimination step is the easier one to explain—it is stereospecific, with the oxygen and phosphorus departing in a syn-periplanar transition state (as in the base-catalysed Peterson reaction). Addition of the ylid to the aldehyde can, in principle, produce two diastere-omers of the intermediate oxaphosphetane. Provided that this step is irreversible, then the stereospecificity of the elimination step means that the ratio of the final alkene geometrical isomers will reflect the stereoselectivity of this addition step. This is almost certainly the case when R is not conjugating or anion-stabilizing the syn diastereoisomer of the oxaphosphetane is formed preferentially, and the predominantly Z-alkene that results reflects this. The Z selective Wittig reaction therefore consists of a kinetically controlled stereoselective first step followed by a stereospecific elimination from this intermediate. 

The 1,4 conjugate addition of HCN to a, d-unsaturated ketones has received partictUar attention, because of its selectivity in the steroid field [2S). Alkyl aluminum cyanides are used as catalysts in these reactions. Two methods have been developed which allow either thermodynamic (Equation (39 or kinetic control (Equation (40)) of the addition stereochemistry (Nagata reaction). 

The intramolecular conjugate addition of in situ, chemoselectively generated amines 2 bearing an electrophilic double bond in the cu-position leads to functionalized pyrrolidines and piperidines 3 under very mild conditions34. The cyclization step occurs smoothly and the piperidine and pyrrolidine derivatives are obtained as a mixture of diastereomers with good diastereose-lection in most cases. The reactions are under kinetic control and the geometry of the starting alkene does not seem to have an influence on the stereochemical outcome of the cyclization step. 

Reaction of an a-(phenylthio)nitrile with base, such as LDA, followed by an aldehyde or a ketone gives a 1,2-addition product in good yield, while the use of a, -unsaturated aldehy s and ketones usually leads to the 1,4-addition product. Conjugate addition of the a-(phenylthio)acetonitrile anions to 2-methyl- or 2-phenyl-2-cyclohexenones or 2-methyl-2-cyclopentenones, followed by acid quenching under kinetic control, leads to different ratios of cis and rr[Pg.561]

The thiolate anion (RS /ArS ) does not react with oc,p-unsaturated esters to give or, p-unsaturated thioesters 98 because the equilibrium favors the ester. However, reaction with esters gives the products of conjugate addition 99 exclusively. The relative rate of attack at both the sites can, therefore, not be measured. It is likely that the conjugate attack is kinetically controlled. 

---