5.5.2. Reductive Removal of Functional Groups

1. 5.5.2. Reductive Removal of Functional Groups An important synthetic application of this reaction is in dehalogenation of dichloro- and dibromocyclopropanes. The dihalocyclopropanes are accessible via carbene addition reactions. Reductive dehalogenation can also be used to introduce deuterium at a specific site. • The mechanism of the reaction presumably involves electron transfer to form a radical anion, which then fragments with loss of a halide ion. The resulting radical is reduced to a carbanion by a second electron transfer and subsequently protonated.

2. Phosphate groups can also be removed by dissolving-metal reduction. Reductive removal of vinyl phosphate groups is one of the better methods for conversion of a carbonyl compound to an alkene. • The required vinyl phosphate esters are obtained by phosphorylation of the enolate with diethyl phosphorochloridate or N,N,N’,N’-tetramethyldiamido phosphorochloridate. Reductive removal of oxygen from aromatic rings can also be achieved by reductive cleavage of aryl diethyl phosphate esters.

3. There are also examples where phosphate esters of saturated alcohols are reductively deoxygenate. Mechanistic studies of the cleavage of aryl dialkyl phosphates have indicated that the crucial C-O cleavage occurs after transfer of two electrons. For preparative purposes, titanium metal can be used in place of sodium or lithium in liquid ammonia for both the vinyl phosphate and aryl phosphate cleavages. The titanium metal is generated in situ from TiCl3 by reduction with potassium metal in THF.

4. Both metallic zinc and aluminum amalgam are milder reducing agents than the alkali metals. • These reductants selectively remove oxygen and sulfur functional groups a to carbonyl groups. • The mechanism that seems most generally applicable is a net two-electron reduction with expulsion of the oxygen or sulfur substituent as an anion. • The reaction seems to be a concerted process because the isolated functional groups are not reduced under these conditions. Substituents in vinylogous position undergo to the same elimination mechanism, too.

5. 5.5.3. Reductive Carbon-Carbon Bond Formation Because reductions by metals often occur as one-electron processes, radicals are involved as intermediates. • When the reaction conditions are adjusted so that coupling competes favorably with other processes, the formation of a carbon-carbon bond can occur. • The reductive coupling of acetone to form 2,3-dimethyl-2,3-butanediol (pinacol) is an example of such a process.

6. Reduced forms of titanium are currently the most versatile and dependable reagents for reductive coupling of carbonyl compounds. • Depending on the reagent used, either diols or alkenes can be formed. • One reagent for effecting diol formation is a combination of TiCl4, and magnesium amalgam. The active reductant is presumably titanium metal formed by reduction of TiCl4.

7. Good yields of pinacols from aromatic aldehydes and ketones are obtained by adding catechol to the TiCl3-Mg reagent prior to the coupling. • Pinacols are also obtained using TiCl3 in the presence of Zn-Cu as the reductant. • This reagent is capable of forming normal, medium, and large rings with comparable efficiency. • The macrocyclization has proven useful in the formation of a number of natural products.

8. Titanium metal generated by stronger reducing agents, such as LiAlH4, or lithium or potassium metal, results in complete removal of oxygen with formation of an alkene. • A particularly active form of Ti is obtained by reducing TiCl3 with lithium metal and then treating the reagent with 25mol% of I2. This reagent is especially reliable when prepared form TiCl3 purified as a DME complex. • A version of titanium-mediated reductive coupling in which TiCl3,-Zn-Cu serves as the reductant is efficient in closing large rings.

9. The mechanism of the titanium-mediated reductive couplings is presumably similar to that of reduction by other metals, but titanium is uniquely effective in reductive coupling of carbonyl compounds. The strength of Ti-O bonds is probably the basis for this efficiency. • Titanium-mediated reductive couplings are normally heterogeneous, and it is likely that the reaction takes place at the metal surface. • The partially reduced intermediates are probably bound to the metal surface, and this may account for the effectiveness of the reaction in forming medium and large rings.

10. Good results have also been reported for sodium metal dispersed on solid supports. • Diesters undergo intramolecular reactions, and this is also an important method for preparation of medium and large carbocyclic rings. There has been considerable discussion of the mechanism of the acyloin condensation. A simple formulation of the mechanism envisages coupling of radicals generated by one-electron transfer.

11. An alternative mechanism bypasses the postulated a-diketone intermediate since its involvement is doubtful.

12. Regardless of the details of the mechanism, the product prior to neutralization is the dianion of the final a-hydroxy ketone, namely, an enediolate. • It has been found that the overall yields are greatly improved if trimethylsilyl chloride is present during the reduction to trap these dianions as trimethylsilyl ethers. • These derivatives are much more stable under the reaction conditions than the enediolates. Hydrolysis during workup gives the acyloin product. This modified version of the reaction has been applied to cyclizations leading to small, medium, and large rings, as well as to intermolecular couplings.