[18297-67-7]  · C7H20N2OSi2  · N,N-Bis(trimethylsilyl)urea  · (MW 204.42)

(large-scale silylating reagent for alcohols and carboxylic acids;1b does not require acid or base catalysis and the urea byproduct is insoluble in CH2Cl2, which aids in the reaction workup)

Alternate Name: BSU.

Physical Data: mp 232 °C (dec).

Form Supplied in: white powder.

Handling, Storage, and Precautions: when using, wear protective clothing to prevent contact with eyes and skin. May cause irritation if inhaled, ingested, or comes in contact with skin. Toxicological properties have not been thoroughly investigated. Store in a cool dry place, under an inert atmosphere to prevent hydrolysis.

The use of a trimethylsilyl group as a protecting group in organic synthesis has become a widely used procedure, due to the fact that it may be easily removed under mild conditions.1 The reagents which have been developed for its introduction are Chlorotrimethylsilane,2 Hexamethyldisiloxane,3,4 ketene methyl trialkylsilyl acetals,5 Triethylsilyl Perchlorate,6 and allylsilanes.7 However, problems exist with the above procedures, which include the necessity for acid3,4,7 or base2,6 catalysis, the silylating agent is not readily accessible,5 or a gas is produced during the reaction which may cause problems when working on a large scale.7

As a silylating agent, N,N-bis(trimethylsilyl)urea has primarily been used in industry for large-scale production of pharmaceuticals such as prostaglandins and semisynthetic penicillins and cephalosporins.1b Not until recently has this reagent been utilized in the laboratory as a silylating agent for smaller-scale organic transformations. Researchers have found that N,N-bis(trimethylsilyl)urea can be generally used for the O-silylation of alcohols and carboxylic acids.8

The use of N,N-bis(trimethylsilyl)urea as a silylating agent has many advantages over other reagents which perform the same purpose. The reaction conditions that are employed are very mild (0-40 °C, CH2Cl2). The urea byproduct formed is neutral and also precipitates out of solution, lending to easy reaction workups, and the reactions generally proceed in excellent yields (>85%). The generality of this reagent is demonstrated in the following transformations of primary, secondary, and tertiary alcohols and carboxylic acids (eqs 1-4). This transformation is not limited to just alkanols, as aryl alcohols can also be transformed to their TMS ethers easily in high yields.

As a silylating agent N,N-bis(trimethylsilyl)urea has been employed in the derivatization of carboxylic acids in peptide synthesis due to the solubility properties of the silylating agent and the urea byproduct.9

N,N-Bis(trimethylsilyl)urea has also been employed in the silylation of primary amines, which are generated in situ and will readily add to arylethylene oxides to give b-hydroxyamines in good to excellent yields (eq 5).10

Related Reagents.

N,O-Bis(trimethylsilyl)acetamide; N-(Trimethylsilyl)imidazole; Trimethylsilyl Nonaflate; Trimethylsilyl Perchlorate; Trimethylsilyl Trifluoromethanesulfonate.

1. For reviews on silylations see: (a) Klebe, J. F. ACR 1970, 3, 299. (b) Cooper, B. E. CI(L) 1978, 794.
2. Birkofer, L.; Ritter, A. AG(E) 1965, 4, 417.
3. Pinnick, H. W.; Bal, B. S.; Lajis, N. H. TL 1978, 10, 4261.
4. Matsumoto, H.; Hoshino, Y.; Nakabajashi, J.; Nakano, T.; Nagai, Y. CL 1980, 1475.
5. Kita, Y.; Haruta, J.; Segawa, J.; Tamura, Y. TL 1979, 11, 4311.
6. Collum, D. B.; McDonald, J. H.; Still, W. C. JACS 1980, 102, 2117.
7. Morita, T.; Okamoto, Y.; Sakurai, H. TL 1980, 21, 835.
8. Verboom, M.; Visser, C. W.; Reinhoudt, D. N. S 1981, 899.
9. Zalipsky, S.; Albericio, F.; Slomczyñska, U.; Barney, G. Int. J. Pept. Res. 1987, 30, 740.
10. Atkins, R.; Frazier, J.; Moore, L. W.; Weigel, L. TL 1986, 27, 2451.

Janet Wisniewski Grissom

University of Utah, Salt Lake City, UT, USA

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