3-(1-Ethoxyethoxy)propylmagnesium Bromide

[86551-76-0]  · C7H15BrMgO2  · 3-(1-Ethoxyethoxy)propylmagnesium Bromide  · (MW 235.41)

(nucleophilic Grignard reagent used as synthetic equivalent of 3-hydroxypropyl anion)

Solubility: normally prepared in THF and used in situ.

Handling, Storage, and Precautions: Grignard reagent sensitive to moisture; must be prepared in the cold and used immediately; tends to rearrange even below room temperature.

Nucleophilic Additions.

This reagent (referred to below as EEOPrMgBr), like the analogous organolithium reagent, is normally used in synthetic chemistry as a synthon for the 3-hydroxypropyl anion. The reagent was first prepared by Eaton in ethereal solution for this purpose in 1972,1 but was indicated by him to be much less useful than the corresponding organolithium reagent. Following a 1976 report by Ponaras concerning preparation of another sensitive Grignard reagent oxygenated at the 3-position,2 the reagent is now normally prepared in THF solution by treatment of the bromide with an excess of Magnesium while maintaining the temperature strictly below 25-30 °C; 1,2-Dibromoethane is used to initiate the reaction if necessary. At room temperature the reagent tends to rearrange and is normally used at around 0 °C. The 3-(1-ethoxyethoxy)propyl bromide starting material may be prepared on a large scale by the dichloroacetic acid-catalyzed solvent-free addition of acid-free 3-bromopropanol to Ethyl Vinyl Ether.1 The value of the ethoxyethoxy group over the possible alternative tetrahydropyran is readily seen: after reaction of the organometallic species, hydrolysis to liberate the free alcohol takes place more readily, and the byproducts ethanol and acetaldehyde are both volatile.

Unlike its organolithium counterpart,1 the reagent is not reported to add readily to ketones. The displacement of halides from primary bromides is, however, useful: in a report actually antedating that of Ponaras, the Grignard reagent is prepared at 0 °C in THF solution in 65% yield. Copper-catalyzed addition to 1-bromononane and subsequent hydrolysis of the acetal group using aqueous Trichloroacetic Acid gave 1-dodecanol in 52% isolated yield (eq 1).3 In a later example not requiring copper catalysis, Shea prepared a functionalized diene by displacement of bromide from 2-bromomethyl-1,3-butadiene in THF at -10 °C followed by hydrolysis using Pyridinium p-Toluenesulfonate (eq 2).4

The reagent is also reported to undergo efficient reaction with b-alkoxy-a,b-unsaturated ketones.5,6 For example, addition to 3-ethoxy-2-cyclohexenone in benzene-THF solution took place below 10 °C (eq 3). The authors comment that the corresponding organolithium reagent gives unsatisfactory yields. Very careful hydrolysis of the acetal to give the hydroxy ketone was necessary in order to avoid spirocyclization.5

Particularly interesting is the addition of the reagent to an enantiomerically pure N-acylpyridinium salt to give the N-acylpyridone, subsequently used in an asymmetric synthesis of (+)-elaeokanines A and C (eq 4).7

Related Reagents.

3-(1-Ethoxyethoxy)propyllithium; 2-(2-Bromoethyl)-1,3-dioxane; 3-Butenyl-1-magnesium Bromide.

1. Eaton, P. E.; Cooper, G. F.; Johnson, R. C.; Mueller, R. H. JOC 1972, 37, 1947.
2. Ponaras, A. A. TL 1976, 3105.
3. Anderson, R. J.; Henrick, C. A. JACS 1975, 97, 4327.
4. Shea, K. J.; Wise, S. TL 1979, 1011. Shea, K. J.; Wise, S.; Burke, L. D.; Davis, P. D.; Gilman, J. W.; Greeley, A. C. JACS 1982, 104, 5708.
5. Becker, D.; Harel, Z.; Nagler, M.; Gillon, A. JOC 1982, 47, 3297.
6. Sha, C.-K.; Ouyang, S.-L.; Hsieh, D.-Y.; Chang, R.-C.; Chang, S.-C. JOC 1986, 51, 1490.
7. Comins, D. L.; Myoung, Y. C. JOC 1990, 55, 292. Comins, D. L.; Hong, H. JACS 1991, 113, 6672.

Philip C. Bulman Page & Andrew Lund

University of Liverpool, UK

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