· (MW 166.73)
(the Grignard reagent is a nucleophilic hydroxymethylating agent for aldehydes, ketones, epoxides, organic halides, and sulfoximines)
Physical Data: bp 64-66 °C/54 mmHg; n20D 1.4160; d 0.926 g cm-3.
Solubility: sol common organic solvents.
Form Supplied in: neat liquid.
Handling, Storage, and Precautions: moisture sensitive, but no special precautions are necessary for handling in the air for a short period of time. May be stored under nitrogen in a tightly capped bottle in a refrigerator.
The Grignard Reagent.1,2
The Grignard reagent, (i-PrO)Me2SiCH2MgCl, is readily prepared from (i-PrO)Me2SiCH2Cl by the reaction with Magnesium activated with 1,2-Dibromoethane in THF in greater than 90% yield. It is sufficiently stable to be stored at room temperature for at least two days with little decrease in activity. The reagent is a versatile nucleophilic hydroxymethyl anion equivalent, in combination with Hydrogen Peroxide oxidation of the silicon-carbon bond (see also the diisopropoxy counterpart, (Diisopropoxymethylsilyl)methylmagnesium Chloride) (eq 1).3 The primary products, (i-PrO)Me2SiCH2E, are stable to weakly basic and acidic aqueous workup and silica gel chromatography. Caution: transition metal catalysts such as copper, nickel, and palladium, if used for any
reactions with this reagent, should be removed prior to the subsequent oxidation, otherwise vigorous decomposition of hydrogen peroxide may occur.
The nucleophilic hydroxymethylation is applicable to aldehydes, including a,b-unsaturated aldehydes (eq 2)4 and protected sugar derivatives (eq 3),5 and ketones (eqs 4 and 5).1,6 Following H2O2 oxidation, the corresponding 1,2-diols are obtained in high overall yields. It should be noted that the b-hydroxysilanes do not undergo b-elimination (Peterson alkenation) even under oxidation conditions which contain fluoride ion (eq 4).1 A highly stereoselective hydroxymethylation of a-hydroxy ketones is also noted (eq 5).6
Epoxides are converted into 1,3-diols by a sequence involving copper-catalyzed Grignard addition, followed by oxidation of the five-membered cyclic alkoxysilane intermediates (eq 6).7 Similarly, primary alcohols are homologated via the tosylates (eq 7).7 Allylic halides are hydroxymethylated without isomerization or migration of the double bond (eq 8).8 Alkenyl sulfoximines are also hydroxymethylated with retention of the alkene geometry, via nickel-catalyzed cross-coupling with the corresponding diorganozinc reagent in the presence of Magnesium Bromide as a co-catalyst, followed by oxidation (eq 9).9
- 1. Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. OS 1990, 69, 96.
- 2. Tamao, K.; Ishida, N. TL 1984, 25, 4245.
- 3. Tamao, K.; Ishida, N.; Kumada, M. JOC 1983, 48, 2122.
- 4. Joyce, R. P.; Parvez, M.; Weinreb, S. M. TL 1986, 27, 4885.
- 5. Boons, G. J. P. H.; van der Klein, P. A. M.; van der Marel, G. A.; van Boom, J. H. RTC 1988, 107, 507.
- 6. Konosu, T.; Tajima, Y.; Takeda, N.; Miyaoka, T.; Kasahara, M.; Yasuda, H.; Oida, S. CPB 1990, 38, 2476.
- 7. Tamao, K.; Ishida, N. Unpublished results.
- 8. McMurry, J. E.; Bosch, G. K. JOC 1987, 52, 4885.
- 9. Gais, H.-J.; Bülow, G. TL 1992, 33, 461 and 465.
Kyoto University, Japan
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