H‑Bonding Activation in Highly Regioselective Acetylation of Diols Yixuan Zhou, † Martin Rahm, ‡ Bin Wu, † Xiaoling Zhang, † Bo Ren, † and Hai Dong* ,† † School of Chemistry & Chemical Engineering, Huazhong University of Science & Technology, Luoyu Road 1037, Wuhan 430074, P. R. China ‡ Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States * S Supporting Information ABSTRACT: H-bonding activation in the regioselective acetylation of vicinal and 1,3-diols is presented. Herein, the acetylation of the hydroxyl group with acetic anhydride can be activated by the formation of H-bonds between the hydroxyl group and anions. The reaction exhibits high regioselectivity when a catalytic amount of tetrabutylammonium acetate is employed. Mechanistic studies indicated that acetate anion forms dual H-bonding complexes with the diol, which facilitates the subsequent regioselective monoacetylation. R egioselective protection of carbohydrates under mild and environmentally sustainable conditions is necessary in order to meet the requirements for preparation of value-added intermediates and building blocks in efficient protecting group strategies, and it remains a prominent challenge in synthetic carbohydrate chemistry. 1,2 Several protection methods have been developed to this end by making use of certain reagents to enlarge small differences in reactivity of hydroxyl groups for diols and polyols. For example, methods employing organo- tin, 3-8 organoboron, 9-11 organosilicon, 12-15 and metal salts, 16-18 organo-catalytic methods, 19-21 and enzymatic methods 22-24 have been exemplified, all with their respective advantages and shortcomings. In the present study, we report on the application of H-bonding activation principles in a highly regioselective carbohydrate acetylation. Herein, a catalytic amount of tetrabutylammonium acetate was employed to promote the regioselective acylation of diols by acetic anhydride under mild conditions without the assistance of any other reagents. Different from the general pyridine-catalyzed acylation, 25-30 our mechanistic studies suggest that the catalytic acetylation owes its increased reactivity to hydroxyl groups engaged in H-bonding. In our earlier studies, we found that new and improved reaction routes may be found by the application of intermolecular non-covalent forces. 31-33 For example, in intramolecular acetyl group migration with anions in aprotic solvents under mild conditions, which was recently reported by us, the leading cause for this process was found to be the formation of hydrogen bonds between the neighboring hydroxyl group and anions. 33 The catalytic effect of anions follows the corresponding H-bond formation tendencies, where more basic anions lead to faster migration. These results inspired us to think that H-bonds between hydroxyl groups and anions might also be able to activate the acylation of hydroxyl groups. We have found this H-bond activation principle to be supported by experiments and preliminary quantum-chemical studies. First, acetylation of the diol methyl 4,6-O-benzylidene-α-D- glucoside (1) by the addition of anions was examined using 1.1 equiv of acetic anhydride (Table 1). Without the addition of anions, the acetylation of 1 did not proceed, even at 80 °C. With the addition of 0.6 equiv of tetrabutylammonium bromide (TBAB), the acetylation of 1 was very slow at 80 °C. However, when 0.6 equiv of tetrabutylammonium acetate (TBAOAc) was used, the reaction proceeded at room temperature, and the 2- hydroxyl group of diol 1 was regioselectively acetylated after 12 h, leading to a 90% isolated yield of methyl 2-O-acetyl-4,6-O- benzylidene-α-D-glucoside (2a). There no acetyl group migration occurred, since compound 2b is the migration product. The reason must be that only a catalytic amount of TBAOAc was used in this case. The reaction showed higher Received: September 13, 2013 Table 1. Acetylation of Methyl 4,6-O-Benzylidene-α-D- glucoside (1) upon the Addition of Anions a entry reagent T (°C) conversion 1 - 80 no reaction 2 HOAc 80 no reaction 3 TBAB 80 low conversion 4 TBAOAc r.t. 2a (90%) b 5 TBAF r.t. 2a/2b (68/32) c a Reaction conditions: reactant (100 mg), Ac 2 O (1.1 equiv), TBAX (0.3-0.6 equiv), 8-12 h. b Isolated yield. c NMR ratio. Note pubs.acs.org/joc © XXXX American Chemical Society A dx.doi.org/10.1021/jo402036u | J. Org. Chem. XXXX, XXX, XXX-XXX