FULL PAPER DOI: 10.1002/ejoc.200500824 Unexpected Selectivity in Sodium Borohydride Reductions of α-Substituted Esters: Experimental and Theoretical Studies Liang-Chun Li, [a,d] Ju-Xing Jiang, [a,d] Jie Ren, [a] Yi Ren, [c] Charles U. Pittman Jr., [b] and Hua-Jie Zhu* [a] Keywords: Borohydrides / Chemoselectivity / Density functional calculations / Esters / Reduction The propensity of sodium borohydride to reduce the carbonyl group in eleven α-substituted and two aromatic esters has been investigated by experiments and at the B3LYP/6- 31++G(d,p)//HF/6-31G(d,p) level of theory. The chemoselec- tivities in nine of these reductions have been examined by experiments. Experimental results agree well with the calcu- Introduction Sodium borohydride reductions have been well studied, [1–5] and reductions of esters or keto esters have been studied by Brown and others. [6–8] Semi-empirical theo- retical studies of aldehyde reductions with sodium borohyd- ride have been reported, [9] and HF theoretical studies of sodium borohydride itself have also appeared. [10–12] Almost all of the selective reductions with sodium borohydride have been conducted on compounds containing two very dif- ferent functional groups, e.g. C=C vs. C=NH, [13] C=C vs. –CHO, [14] or –CO 2 Me vs. –CO 2 H, [1,6a,15] whose reduction activities are widely different. However, experi- mental and quantum (e.g. HF or DFT method) studies of chemoselective α-substituted ester reductions have never been reported (or compared) where the carbonyl groups may have similar reduction reactivities towards sodium borohydride. The experimental and computational studies of different reactivities would be a valuable contribution because α-sub- stituted alcohols derived from their corresponding esters are important intermediates in organic syntheses and as me- dicinal intermediates. The dramatic increase of new drug targets arising from genomics and proteomics has generated a need for efficient methods to assemble small molecules that exhibit an ever-increasing level of structural complex- [a] Organic Synthesis and Natural Product Laboratory, Kunming Institute of Botany, CAS, Kunming, 650204, China, hjzhu@mail.kib.ac.cn [b] Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA [c] Colleague of Chemistry, Sichuan University, Chengdu, 610064, China [d] Graduate school of the Chinese Academy of Sciences, Beijing, 100039, China Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2006, 1981–1990 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1981 lated order of activation energies for hydride transfer to the ester carbonyl group. Methyl α-bromoacetate reduces faster than methyl α-fluoroacetate. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) ity. Successful chemoselective reductions of various α-sub- stituted esters could provide a useful tool for the syntheses of many poly-functional chiral compounds. Structurally complex natural products often have two or more carbonyl groups with similar, but different, reactivities, and the selec- tive reduction of one carbonyl function would be especially valuable. Herein, we report some chemoselective α-substi- tuted ester reductions with sodium borohydride where some unexpected chemoselectivities are observed. It has been traditionally accepted that higher electrone- gativity values, χ, of the substituent at the α-carbon in es- ters, in the absence of steric effects and conjugation, in- crease the rate of NaBH 4 reduction. We now report that this is not correct for the α-halogenated esters based both on experimental and computational findings. Furthermore, a wide range of reactivities are demonstrated based on the nature of the α-substituent or the nature of the α-carbon. Results and Discussion Nine esters were reduced by sodium borohydride in di- glyme solution. The conversions of esters 1, 7 and 12–14 were determined by HPLC after 3 h. For esters 1 and 7, toluene was used as the internal standard, for esters 12–14, PhCO 2 Me was used. The temperature required for the first appearance of alcohol (on-set temperature) was employed for compounds 1, 7, and 12–14. The other on-set tempera- tures were determined by the initial appearance of the prod- ucts on a TLC plate where the products were sensitive to detection when exposed to I 2 or H 2 SO 4 . These results are summarized in Table 1. The differences of on-set tempera- tures among these α-substituted esters are substantial and some of the observed selectivities are unexpected. For ex- ample, the on-set temperature for methyl α-hydroxyacetate