6734
J . Org. Chem. 2001, 66, 6734-6737
Efficien t O-Tr im eth ylsilyla tion of Alcoh ols a n d P h en ols w ith
Tr im eth ylsilyl Azid e Ca ta lyzed by Tetr a bu tyla m m on iu m Br om id e
u n d er Nea t Con d ition s
David Amantini, Francesco Fringuelli, Ferdinando Pizzo,* and Luigi Vaccaro
Dipartimento di Chimica, Universita` di Perugia Via Elce di Sotto 8, I-06123 Perugia, Italy
pizzo@unipg.it
Received J une 4, 2001
A very efficient procedure for the trimethylsilylation of a wide variety of alcohols, including primary,
allylic, benzylic, secondary, hindered secondary, tertiary, and phenols is reported. The reactions
were carried out under neat conditions with trimethylsilyl azide (TMSN3) and, when necessary, in
the presence of a catalytic amount (20 mol %) of tetrabutylammonium bromide (TBABr) at 30 or
70 °C. Under catalytic conditions, the yields of the corresponding trimethylsilyl ethers were greater
than 91%. This procedure also allows the selective protection of primary and secondary alcohols in
the presence of tertiary ones.
In tr od u ction
trimethylsilyl acetate,10 N,N-bis(trimethylsilylurea),11
and methyl 3-(trimethylsilyloxy)crotonate.12 Hexameth-
yldisilazane has been used in the presence of a variety
of catalysts (Me3SiCl,13 sulfonic acids,14 ZnCl2,15 nitrogen
ligand complexes of metal chlorides,16 zirconium sul-
fophenyl phosphonate,17 K-10 montmorillonite,18 R1R2NH
compounds in which R1 and R2 are ester or amide
groups,19 I220). N-Trimethylsilyl-2-oxazolidinone21 and
N,O-bis(trimethylsilyl)acetamide22 were used in the pres-
ence of Me3SiCl and tetrabutylammonium fluoride, re-
spectively.
As a consequence of serious pollution problems, the
adoption of “cleaner production” methods is an urgent
priority. Four main approaches have recently been
developed to synthesize compounds in an environmen-
tally friendly manner: (i) use water or supercritical fluids
instead of organic solvent, (ii) use no solvent at all, (iii)
use catalytic amounts of metal instead of stoichiometric
amounts, and (iv) use biosynthetic processes.1
For several years, we have been investigating organic
processes in an exclusively aqueous medium,2 and re-
cently we discovered that even Lewis acids, such as AlCl3,
recommended for use under anhydrous conditions, are
excellent catalysts in aqueous medium.3 Here, we report
an efficient protocol to silylate primary, secondary, and
tertiary alcohols and phenols under neat conditions.
The use of a silyl ether function as a protecting group
of the hydroxy functionality is well documented in organic
synthesis.4 Among the most efficient reagents to intro-
duce the trimethylsilyl group we can recall: trimethyl-
silyl chloride in the presence of a base,5 Li2S,6 or Mg,7
ketene methyltrialkylsilyl acetals,8 allyl silanes,9 ethyl
With some exceptions,5a,7,20,22 these reagents are not
able to silylate, or only partly silylate, secondary hindered
(5) (a) Visser, R. G.; Boss, H. J . T.; Brandsma, L. Recl. Trav. Chim.
Pays-Bas 1980, 99, 70. (b) Lissel, M.; Weiffen, J . Synth. Commun. 1981,
11, 545-549.
(6) Olah, G. A.; Gupta, B. G. B.; Narang, S. C.; Malhotra, R. J . Org.
Chem. 1979, 44, 4272-4275.
(7) Nishiguchi, I.; Kita, Y.; Watanabe, M.; Ishino, Y.; Ohno, T.;
Maekawa, H. Synlett 2000, 1025-1027.
(8) Kita, Y.; Haruta, J .; Segawa, J .; Tamura, Y. Tetrahedron Lett.
1979, 20, 4311-4314.
(9) (a) Morita, T.; Okamoto, Y.; Sakurai, H. Tetrahedron Lett. 1980,
21, 835-838. (b) Olah, G. A.; Husain, A.; Gupta, B. G. B.; Salem, G.
F.; Narang, S. C. J . Org. Chem. 1981, 46, 5212-5214.
(10) Nakamura, E.; Hashimoto, K.; Kuwajima, I. Bull. Chem. Soc.
J pn 1981, 54, 805-808.
* To whom correspondence should be addressed. Phone: +39 075
5855546. Fax: +39 075 5855560.
(1) (a) Stinson, S. C. Chem. Eng. 1996, 74, 39-44. (b) Tanaka, K.;
Toka, F. Chem. Rev. 2000, 100, 1025-1074.
(11) Verboom, W.; Visser, G. W.; Reinhoudt, D. N. Synthesis 1981,
807-809.
(12) Veysoglu, T.; Mitscher, L. A. Tetrahedron Lett. 1981, 22, 1303-
1306.
(13) Gautret, P.; El-Ghammarti, S.; Legrand, A.; Couturier, D.; Rigo,
B. Synth. Commun. 1996, 26, 707-713.
(14) Goldschmidt, A. G. German. Patent 2758884.
(15) Firouzabadi, H.; Karimi, B. Synth. Commun. 1993, 23, 1633-
1641.
(2) (a) Fringuelli, F.; Germani, R.; Pizzo, F.; Santinelli, F.; Savelli,
G. J . Org. Chem. 1992, 57, 1198-1202. (b) Fringuelli, F.; Pani, G.;
Piermatti, O.; Pizzo, F. Tetrahedron 1994, 50, 11499-11508. (c)
Fringuelli, F.; Piermatti, O.; Pizzo, F. Targets in Heterocyclic Systems.
Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; SCI:
Roma, 1997; Vol. 1, pp 57-73. (d) Fringuelli, F.; Piermatti, O.; Pizzo,
F. Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
and Professional-Thomson Science: London, 1998; 250-261. (e)
Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J . Org. Chem. 1999,
64, 6094-6096. (f) Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2000,
311-314. (g) Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synthesis 2000, 646-
650. (h) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Eur. J . Org.
Chem. 2001, 439-455.
(3) Fringuelli, F.; Pizzo, F.; Vaccaro, L. Tetrahedron Lett. 2001, 42,
1131-1133.
(4) (a) Greene, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley and Sons: New York, 1999. (b) Lalonde,
M.; Chan, T. H. Synthesis 1985, 817-845. (c) Kocienski, P. J . In
Protective Groups; Enders, R., Noyori, R., Trost, B. M., Eds.; Thieme:
Stuttgart, 1994. (d) Muzart, J . Synthesis 1993, 11-27.
(16) Firouzabadi, H.; Sardarian, A. R.; Khayat, Z.; Karimi, B.;
Tangestaninejad, S. Synth. Commun. 1997, 27, 2709-2719.
(17) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.; Costan-
tino, U. Synth. Commun. 1999, 29, 541-546.
(18) Zhang, Z.-H.; Li, T.-S.; Yang, F.; Fu, C.-G. Synth. Commun.
1998, 28, 3105-3114.
(19) Bruynes, C. A.; J urriens, T. K. J . Org. Chem. 1982, 47, 3966-
3969.
(20) Karimi, B.; Golshani, B. J . Org. Chem. 2000, 65, 7228-7230.
(21) Aizpurua, J . M.; Palomo, C. Bull. Soc. Chim. Fr. Mem. 1982,
II, 265-268.
(22) (a) J ohnson, D. A. Carbohydr. Res. 1992, 237, 313-318. (b)
Tanabe, Y.; Murakami, M.; Kitaichi, K.; Yoshida, Y. Tetrahedron Lett.
1994, 45, 8409-8412.
10.1021/jo015814s CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001