The role of proton donors, solvation, and additives in SmI2 mediated reduction of ketones

Date

2004-12

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Publisher

Texas Tech University

Abstract

Samarium diiodide is a versatile reducing reagent commonly utilized in organic synthesis. A variety of reduction, reductive coupling, and sequential reactions are mediated by SmI2 with optimum reaction outcomes. However, little is known about its mode of action. A systematic investigation was carried out to unravel the mechanism of this extremely useful reagent.

The first portion of this study deals with the role of commonly utilized proton donors such as alcohols and water in SmI2 mediated reduction reactions. A linear relationship between the acidity of the proton donor and the rate of acetophenone reduction was observed in the absence of complexation between a proton donor and SmI2. The proton source must be sufficiently acidic to protonate the carbanion intermediate formed upon initial reduction by SmI2. Water has a much higher affinity for SmI2 than the alcohols examined in this study. As a result, complexation between water and SmI2 was observed. Methanol was also found to complex to SmI2 at concentrations approaching 1 M. The unique reductants formed as a result of complexation between SmI2 and proton donor react with acetophenone through a mechanistically distinct pathway.

The second portion is related to the role of HMPA in reduction of β-alkoxyketones utilizing SmI2. Addition of HMPA was found to increase reaction rates and affect stereochemical outcome of these reactions. Syn-1,3-Diols were predominantly the major products, However, addition of HMPA and presence of a bulky protecting functionality such as SiMcg-, resulted in reversal of stereoselectivity and provided the anti-,3-diols as the major product due to inhibition of coordination. Chelation was found to play an important role in the stereoselectivity of these reduction reactions.

The third portion deals with the role of solvation in SmI2 mediated reduction reactions. The preparation and reactivity of SmI2 in different solvents such as THF, acetonitrile, and DME was studied. SmI2 in these solvents are distinct species and reduce βhydroxyketones via different mechanistic pathways. SmI2-THF and SmI2-DME solvates gave predominandy the syn-l,3-âiols in excellent yields and diastereoselectivity. Their reactions follow similar pathways. SmI2-acetonitrile solvates however, reduced βhydroxyketones via a different mechanism and provided anti-l,3-diols in modest stereoselectivity. The concentration of methanol utilÍ2ed as proton donors was shown to have significant impact on reaction outcome in acetonitrile.

Finally, the effect of triethylamine-water mixture on SmI2 mediated reduction of βhydroxyketones was studied. These reactions are usually completed in less than five minutes and quantitative yields of reduced products were obtained in high stereochemical control. The use of SmI2 in reduction of 1,4-hydroxyketones was also explored. Thus, mechanistic and synthetic aspects of SmI2 mediated reduction of ketones were studied.

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