· (MW 148.2)
(reagent for the protection of ketones and aldehydes under mild conditions1)
Alternate Name: cyclo-SEM.
Physical Data: mp 36-38 °C; bp 110-130 °C/2 mmHg.
Solubility: soluble in organic solvents, insoluble in water.
Form Supplied in: white, crystalline solid.
Analysis of Reagent Purity: 1H NMR, capillary GC.
Preparative Methods: preparation (1) is performed by lithium-halogen exchange of 1-(bromovinyl)trimethylsilane (1),2 with 2.1 equiv of t-BuLi in diethyl ether at -78 °C for 0.5 h followed by cold cannulation into a slurry of paraformaldehyde in diethyl ether and warming to room temperature over 5 h.3 The crude 2-trimethylsilyl-2-propenol (2) is purified, after water work-up and extraction, by column chromatography (5% EtOAc/petroleum ether) followed by bulb-to-bulb distillation (110-114 °C/60 mmHg). Treatment of 2 with 2.1 equiv of freshly prepared thexylborane4 at -10 °C followed by 18 h at room temperature generates the boronate ester which is subsequently hydrolyzed by treatment with two equiv of methanol followed by a standard H2O2/NaOH work-up. Column chromatography on base-treated silica gel with 50% EtOAc/petroleum ether yields 2-trimethylsilyl-1,3-propanediol (3), as a white crystalline solid.
Purification: column chromatography using silica gel as the stationary phase and a mobile phase consisting of 50% EtOAc/petroleum ether will provide reagent of excellent quality. Recrystallization from either petroleum ether or hexanes, or bulb-to-bulb distillation (110-130 °C/2 mmHg) may also be used to purify the cyclo-SEM diol (3).
Handling, Storage, and Precautions: store in a closed container. No noticeable degradation after 12 months on the bench top.
Protection of Ketones and Aldehydes
The protection of ketones and aldehydes (eqs 2-6) may be accomplished upon treatment with 2-5 equiv of cyclo-SEM diol 3 and 0.25 equiv of an acid source, either camphorsulfonic acid or p-toluenesulfonic acid in methylene chloride. Activated, powdered molecular sieves are used as a water scavenger and methylene chloride is the solvent of choice, although toluene may be used instead. Reactions take between 2 and 36 h, depending on the amount of diol 3 used, the reaction concentration, and the extent of steric hindrance around the carbonyl group.
The conditions for the formation of cyclo-SEM ketals are considerably milder than are those for the corresponding 1,3-dioxanes or 1,2-dioxolanes, which often require larger excess of diol and extended reflux times in benzene or toluene.5 Attempts at installation of a cyclo-SEM ketal under refluxing toluene or benzene conditions were unsuccessful, leading to decomposition of cyclo-SEM diol 3.
Saturated ketones and aldehydes react quickly and in high yields, even with a-substitution. Electronically deactivated ketones (cyclohexenone, acetophenone) and aldehydes (benzaldehyde), on the other hand, react poorly. Ketones and aldehydes with steric hindrance require a larger excess of cyclo-SEM diol to proceed to satisfactory levels of completion (eqs 4 and 5). Excess cyclo-SEM diol 3 may be recovered during product isolation by column chromatography, eluting with 50% EtOAc/petroleum ether. Recovery of 80-90% of the unreacted cyclo-SEM diol 3 is typical.
Unsymmetrical ketones and aldehydes protected as cyclo-SEM ketals or acetals form two distinct cis- and trans-isomers (7). The two isomers are individually separable and are uniquely identifiable by 1H and 13C NMR. This added complexity limits the utility of cyclo-SEM as a protecting group.
Deprotection of cyclo-SEM Ketals and Acetals
Removal of the cyclo-SEM ketal is performed by heating at reflux in the presence of one equiv of LiBF4 in THF (eqs 8-12).1 Use of a larger excess of LiBF4 decreases the deprotection time, and acetonitrile may be substituted for THF. These mild, non-reductive, non-oxidative conditions of removal provide significant advantage over other carbonyl protecting groups.5
LiBF4 removes cyclo-SEM ketals in refluxing THF (13) at rates that exceed those observed for 1,3-dioxanes (14) or 1,3-dioxolanes (15) under these conditions, thereby allowing selective deprotection of cyclo-SEM ketals.
TBAF fails to remove the cyclo-SEM ketal and facilitates protiodesilylation, returning a 1,3-dioxlane.
- 1. Lipshutz, B. H.; Mollard, P.; Lindsley, C. L.; Chang, V., Tetrahedron Lett. 1997, 38, 1873.
- 2. (a) Boeckmann, R. K., Jr; Blum, D. M.; Ganem, B.; Haley, N., Org. Syn. Coll. Vol. VI, 1988, 1033. (b) Boeckmann, R. K.; Blum, D. M.; Ganem, B.; Halvey, N., Org. Synth. 1978, 58, 152.
- 3. Overman, L. E.; Renhowe, P. A., J. Org. Chem. 1994, 59, 4138.
- 4. Brown, H. C.; Negishi, E. J., Am. Chem. Soc. 1972, 94, 3567.
- 5. Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 2nd edn. Chichester: Wiley, 1991, pp 119, 175.
- 6. Lillie, B. M.; Avery, M. A., Tetrahedron Lett. 1994, 35, 969.
Bruce H. Lipshutz & Paul Mollard
University of California, Santa Barbara, California, USA
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