Methylmagnesium N-Cyclohexylisopropylamide1

[102276-92-6]  · C10H21MgN  · Methylmagnesium N-Cyclohexylisopropylamide  · (MW 179.63)

(isomerization of epoxides to allylic alcohols1)

Alternate Name: MMA.

Solubility: sol toluene.

Form Supplied in: prepared and used in situ.

Preparative Methods: prepared by adding n-Butyllithium (1 equiv) to a 0 °C solution of N-cyclohexylisopropylamine in anhydrous toluene (0.85 M). After 15 min, Methylmagnesium Bromide (1 equiv, 3 M in Et2O) is introduced dropwise. Stirring is continued for another 30-45 min, during which time a white precipitate develops.1a

Handling, Storage, and Precautions: moisture sensitive; prepared and used in situ.

Isomerization of Epoxides to Allylic Alcohols.1

The isomerization of epoxides to allylic alcohols (eq 1) is a common and preparatively useful functional group interchange.2 Methylmagnesium N-cyclohexylisopropylamide is an efficient reagent for the isomerization of epoxides to allylic alcohols. Although the nature of the reagent and its state of aggregation are unknown, the formation of allylic alcohols from epoxides is assumed to proceed by a b-elimination pathway by analogy with related systems.2

The epoxide in toluene is added to a 3-4 fold excess of MMA (final MMA concentration 0.55 M) at 0 °C and the mixture is maintained under the conditions summarized in Table 1. Proton abstraction from a methyl group is greatly preferred over that from a methylene in acyclic3 (entry 1) and cyclic (entry 2) systems. However, in some cases such as a 1,1-disubstituted epoxide (entry 3) and a simple cyclic epoxide (entry 5), nucleophilic addition of methyl from MMA is the major result. In contrast, the more sterically biased pyranoside4 in entry 4 isomerizes exclusively to the allylic alcohol. It is noteworthy that, unlike lithium amides,5 MMA converts 5,6-epoxycyclooctene (entry 6) to 2,5-cyclooctadien-1-ol without significant ketone or conjugate diene formation. Exposure of 14,15-epoxyicosatrienoic acid (1) (entry 7) to MMA affords 15-hydroxyicosatetraenoic acid (15-HETE; 2). The yield of 15-HETE decreases dramatically if THF or toluene/HMPA (2:1) is the solvent.6,7 Abstraction of an allylic proton in a related bis-epoxide (3) (entry 8) also leads to a conjugated (E,Z)-dienol (4).

The epoxide (5) of oleic acid displays intermediate reactivity with respect to isomerization or nucleophilic addition. Treatment with MMA furnishes approximately equal amounts of allylic alcohols (6) and methyl addition product (7) (entry 9). The ethylmagnesium and isopropylmagnesium analogs of MMA behave similarly. On the other hand, phenylmagnesium N-cyclohexylisopropylamide gives rise to only allylic alcohol (6), albeit in low yield (~20%).

1. (a) Mosset, P.; Manna, S.; Viala, J.; Falck, J. R. TL 1986, 27, 299. (b) Moustakis, C. A.; Weerasinghe, D. K.; Mosset, P.; Falck, J. R.; Mioskowski, C. TL 1986, 27, 303.
2. (a) Reviews: Crandall, J. K.; Apparu, M. OR 1983, 29, 345. (b) Smith, J. G. S 1984, 629. (c) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. T 1983, 39, 2323.
3. Tananka, S.; Yasuda, A.; Yamamoto, H.; Nozaki, H. JACS 1975, 97, 3252.
4. Yang, Y.-L.; Falck, J. R. TL 1982, 23, 4305.
5. Crandall, J. K.; Chang, L. H. JOC 1967, 32, 532.
6. For a detailed study of the effect of HMPA on the reactivity of epoxides with lithium amides, see: Apparu, M.; Barrelle, M. T 1978, 34, 1817, and earlier papers.
7. Treatment of certain classes of epoxides with halomagnesium alkylamides in THF affords the corresponding b-amino alcohols: Carre, M. C.; Houmounou, J. P.; Caubere, P. TL 1985, 26, 3107.

K. Ishihara & H. Yamamoto

Nagoya University, Japan

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.