Ketyl Addition Reactions

Finally, isocyanates have been dimerized to form oxamides in good yields with Sml2 in THF/HMPA [50], and amides can be coupled with a combination of Sml2 and Sm(0) to afford vicinal diaminoalkenes [51], 

By far the most useful and highly utilized radical reactions promoted by Sml2 are couplings between ketyls and alkenes or alkynes. The selectivity that can be achieved in these transformations, combined with the versatility of the method for the construction of diverse targets, makes it an extremely attractive means to form carbon-carbon bonds. 

The utility of SmT-generated ketyl radicals in selective organic synthesis can be ascribed in part to their persistence. Thus ketyl radical anions have been postulated to form reversibly in the presence of Sml2 [9]. With the possible exception of aromatic carbonyls, the radical anions are not further reduced under the reaction conditions to the corresponding dianions. In addition, ketyls are not particularly prone to quenching by hydrogen atom abstraction from the solvent, from disproportionation, or related processes [52], 

Several contributions have appeared in which intermolecular reductive couplings between ketones or aldehydes and electron-deficient alkenes have been described [30h, 53]. Reactions of aldehydes and ketones with unsaturated esters result in the formation of lactones. Diastereoselectivities are normally modest in these cases, but can be quite high for certain substitution patterns (Eq. 45). 

Chelation control has been utilized as one means to effect high diastereoselec-tivity in the intermolecular ketyl coupling reactions [54], Examples of both 1,2- and 

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Sml2 has also been used to form cyclooctanols by cyclization of 7,8-enones.262 These alkene addition reactions presumably proceed by addition of the ketyl radical to the double bond, followed by a second electron transfer. 

The comparison of the values of Ee0 for reactions of ketyl radicals with peroxides with those for reactions R1R2C 0H + R2C(0) show that the reaction of the ketyl radical with peroxide occurs with sufficiently higher Ee0 (see Table 6.30). Obviously, this is the result of strong additional repulsion in the nonlinear polyatomic transition state of the ketyl radical reaction with peroxide... 

Practically one reaction of alkyl radicals with dioxygen is known, namely addition reaction (see Chapter 2). Ketyl radicals having a free valence on the carbon atom add dioxygen also. However, they possess high reducing activity and easily react with dioxygen by the abstraction reaction. 

Since products from the 1,6-addition reactions are formed in much larger amounts than those from the 1,2-addition reaction (38 72), and since no cyclization takes place in the latter reaction, the conclusion was made that the 1,2-addition reaction product results from a collapse of a radical anion (ketyl)-radical cation (RMgX pair in which the group R of the Grignard is still tightly bound to the magnesium. 

However, how free, is the radical anion in reactions of benzophenone In the presence of a radical anion scavenger, such as p-dinitrobenzene [48], pinacol formation is totally suppressed in reactions of CHjMgBr and f-C4H9MgCl [49] with 2-methylbenzophenone, but the same scavenger had no effect on the ratio or the rate of 1,2- and 1,6-addition reaction products. Thus, the formation of these products does not involve a free ketyl. A single-electron transfer (SET) intermediate, I, was proposed (Scheme 12)... 

The most feasible pathway to coupled products is intramolecular ketyl addition to the Sm -coordi-nated ketone (see Scheme 6). Several examples of ketyl addition to Lewis acid activated carbonyls have been reported in the literature. Clerici and Porta have demonstrated in detailed experiments that intermolecular addition of ketyls to carbonyls can be a rapid process. Generally, ketyl addition to carbonyls is a reversible reaction. However, reversibility can be greatly affected by Lewis acid chelation of the complex, and further reduction of the radical intermediate (8) by the second equivalent of Smh would serve to make the process irreversible. ... 

Reaction of ketyls. The carbonyl group reacts with Smlj to generate ketyl species which may be reduced further. Capture of the ketyls with suitable reactants expands the utility of the samarium chemistry. Important reactions include butyrolactone synthesis that is amenable to asymmetric induction when chiral acrylic esters are employed. The reagent system (catalytic in Smij) generated in situ from Smij and Zn-Hg is more economical. The system also contains Lil and MCjSiOTf, and in practice MejSiOTf is added to the mixture of the other components at just the rate to maintain a light blue color (indicating the presence of Smij). When Nilj is added as a catalyst, p-propiolactone instead of acrylic esters can be used. Sometimes steric factors preclude cyclization, and 7-hydroxy esters result. Ketyl addition to acrylamides opens a route to 1,4-amino alcohols. ... 

The high preference for reaction at the exo-face is, however, strongly influenced by substituents at C-7 and only endo attack is found in pinacol formation of camphor57. The intermediate ketyl radicals recombine exclusively to form the endo-endo-addition product. Furthermore, the reaction also shows high enantioselectivity as the ketyl radicals derived from (+)-camphor recombine much faster with a second ( + )- instead of a (-)-camphor ketyl radical. Reaction of a racemic mixture, therefore, proceeds to yield only one racemic product. 

In addition to alkenes and allenes, alkynes have also served as acceptors in a variety of ketyl cyclization reactions [36b, 83, 90]. Activated alkynes in general appear to work most favorably in the 5-exo and 6-exo cyclization processes, permitting the synthesis of carbocycles as well as oxygen and nitrogen heterocycles in reasonable yields, albeit as mixtures of diastereomers (Eqs. 77-79). 

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