Novel and Efficient Method for the Silylation of Hydroxyl Groups with Hexamethyldisilazane (HMDS) under Solvent-Free and Neutral Conditions Najmedin Azizi and Mohammad R. Saidi* Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516, Tehran, Iran Received September 3, 2003 Summary: Various alcohols and phenols were silylated to trimethylsilyl ethers with hexamethyldisilazane in the presence of solid lithium perchlorate under very mild, neutral, and solvent-free conditions in good to excellent yields. Perhaps one the most important uses of trimethylsilyl groups in organic synthesis is for the protection of hydroxyl groups of alcohols, phenols, and carboxylic acids. Several chemical conversions and multiple- sequence syntheses often require protection of hydroxyl groups. The trimethylsilyl group is one of the most popular and widely used groups for protecting the hydroxyl function and often is used in analytical chem- istry to prepare silyl ethers as volatile derivatives of alcohols and phenols. 1 Several methods have been reported for this conver- sion, including the reaction of an alcohol with trimeth- ylsilyl halides in the presence of a stoichiometric amount of a tertiary amine, 2 with trimethylsilyl triflate, which is more reactive than the chloride, 3 with allylsilanes in the presence of a catalytic amount of p-toluenesulfonic acid, 3 with iodine, 4 with trifluoromethanesulfonic acid, 5 and with Sc(OTf) 3 . 6 Hexamethyldisilazane (HMDS) is frequently used for the trimethylsilylation of hydroxyl groups. HMDS is an inexpensive and commercially available reagent. Its handling does not require special precautions, and the workup is not time-consuming, because the byproduct of the reaction is ammonia, which is simple to remove from the reaction medium. The low silylation power of HMDS is the main drawback to its application; there- fore, there are a variety of catalysts for activating of this reagent, such as I 2 , 7 (CH 3 ) 3 SiCl, 8 and K-10 mont- morillionite. 9,10 However, in most of these cases a long reaction time, drastic reaction conditions, or tedious workup is needed. In addition, many of these reagents are moisture sensitive or expensive. The lack of a facile and general synthetic methodology for the silylation of hydroxyl groups (alcohols, phenols), under essentially neutral conditions, prompted us to develop an efficient, convenient, and practical procedure for the protection of hydroxyl groups under solvent-free conditions. In continuation of our interest in the application of solid LiClO 4 in organic synthesis, 11 we report here the use of readily available HMDS for silylation of hydroxyl groups in the presence of solid LiClO 4 under environ- mentally benign and natural conditions. We examined the potential of HMDS for silylation of alcohols in the presence of solid LiClO 4 without using a solvent. Upon addition of HMDS to an alcohol in the presence of solid LiClO 4 , the silylated product was formed in high yield and in a short time. The workup procedure is very simple. By addition of petroleum ether or CH 2 Cl 2 to the reaction mixture, LiClO 4 is recovered easily by filtration and the crude product can be obtained by distilling the solvent. To find out the best reaction conditions for the protection of alcohol in the presence of solid LiClO 4 , benzyl alcohol and HMDS were used with different amounts of solid LiClO 4 (Scheme 1). In the case of simple alcohols 20 mol % of solid LiClO 4 was sufficient for the completion of the reaction. How- ever, the optimal molar ratio of ROH, HMDS, and LiClO 4 is 1:0.7:0.5. With the mixture of HMDS and LiClO 4 , primary, allylic, benzylic, and hindered primary alcohols, unhindered secondary, tertiary, and acid- sensitive alcohols, and phenols were readily transformed into their corresponding trimethylsilyl ethers in high yield. The results are summarized in Table 1. To show the accelerating effect of solid LiClO 4 , the reactions of HMDS and various alcohols were examined in the absence of lithium perchlorate as catalyst. However, these reactions remained incomplete and low (1) Van Look, G.; Simchen, G.; Heberle, J. Silylation Agents; Fluka; Buchs, Switzerland, 1995. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999. (2) Brook, M. A. Silicon in Organic, Organometallic, and Polymer Chemistry; Wiley: New York, 2000. (3) (a) Morita, T.; Okamoto, Y.; Sakurai, H. Tetrahedron Lett. 1980, 21, 835. (b) Vesoglu, T.; Mitscher, L. A. Tetrahedron Lett. 1981, 22, 1299. (4) Hosomi, A.; Sakurai, H. Chem. Lett. 1981, 85, 880. (5) Olah, G. A.; Husain, A.; Gupta, B. G. B.; Salem, G. F.; Narang, S. C. J. Org. Chem. 1981, 46, 5212. (6) Suzuki, T.; Watahiki, T.; Oriyama, T. Tetrahedron Lett. 2000, 41, 8903. (7) Karimi, B.; Golshani, B. J. Org. Chem. 2000, 65, 7228. (8) (a) Langer, S. H.; Connell, S.; Wender, J. J. Org. Chem. 1958, 23, 50. (b) Gauuret, P.; El-Ghamarli, S.; Legrand, A.; Couirier, D.; Rigo, B. Synth. Commun. 1996, 26, 707. (9) Zhang, Z. H.; Li, T. S.; Yang, F.; Fu, C. G. Synth. Commun. 1998, 28, 3105. (10) Mojtahedi, M. M.; Saidi, M. R.; Bolourtchian, M.; Heravi, M. M. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 289. (11) (a) Saidi, M. R.; Azizi, N. Synlett 2002, 1347. (b) Saidi, M. R.; Azizi, N.; Zali-Boinee, H. Tetrahedron 2001, 57, 6829. (c) Saidi, M. R.; Azizi, N.; Naimi-Jamal, M. R. Tetrahedron Lett. 2001, 42, 8111 (d) Azizi, N.; Saidi, M. R. Tetrahedron Lett. 2002, 43, 4305. Scheme 1 2PhCH 2 OH 1.0 mol + (Me 3 Si) 2 NH 0.7 mol 9 8 LiClO 4 (solid) 0.5 mol, room temp 2PhCH 2 OSiMe 3 + NH 3 1457 Organometallics 2004, 23, 1457-1458 10.1021/om0341505 CCC: $27.50 © 2004 American Chemical Society Publication on Web 11/08/2003