Methylaluminum Bis(2,6-di-t-butyl-4-methylphenoxide)

[65260-44-8]  · C31H49AlO2  · Methylaluminum Bis(2,6-di-t-butyl-4-methylphenoxide)  · (MW 480.78)

(designer Lewis acid for amphiphilic alkylation,1,4,5 amphiphilic reduction,6 conjugate addition,7-10 discrimination of two different substrates (ethers and ketones),12-14 strereocontrolled cycloadditions,15-17 and polymerization18)

Alternate Name: MAD.

Physical Data: a crystal structure of a MAD-benzophenone complex has been reported.3

Solubility: sol CH2Cl2, toluene, hexane.

Form Supplied in: prepared from commercially available reagents and used in situ.

Preparative Method: prepared by reaction of a 1-2 M hexane solution of Trimethylaluminum with 2 equiv of 2,6-di-t-butyl-4-methylphenol in toluene or CH2Cl2 at rt for 1 h.1,2

Handling, Storage, and Precautions: the dry solid and solutions are highly flammable and must be handled in the absence of oxygen and moisture. The solution should be used as prepared for best results. Use in a fume hood.

Amphiphilic Alkylation.

The exceptionally bulky, oxygenophilic organoaluminum reagent methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide) has been developed for the stereoselective activation of carbonyl groups. Combination of MAD with Grignard reagents or organolithium reagents generates the amphiphilic alkylation systems, where substituted cyclohexanones and cyclopentanones afford equatorial alcohols with high stereoselectivity (eqs 1-3).1 The X-ray crystallographic determination of a benzophenone-MAD complex shows that the ketone coordinates such that the aluminum is in the nodal plane of the C=O p-bond.3

This methodology has been used in the final step of the stereocontrolled synthesis of a defense substance of the termite Nastitermes princeps, a secotrinervitane diterpene. Whereas Methyllithium adds exclusively to the b-face of the ketone to furnish the a-alcohol as the sole isolable product, attack of methyllithium occurs preferably at the a-face of the carbonyl in the amphiphilic alkylation system using MAD/MeLi to give the desired substance as a major product (eq 4).4

Alkylation of a-substituted aldehydes with the MAD/RMgX system provides anti-alcohols preferentially (eq 5).1 This amphiphilic system allows the chemoselective carbonyl alkylation and reduction of aldehydes in the presence of ketones (eq 6).5

Amphiphilic Reduction.

In contrast to the facile MAD-mediated alkylation of cyclic ketones with primary organolithiums or Grignard reagents, both alkylation and reduction take place with s-alkylmagnesium halides. When a bulky nucleophile such as t-BuMgCl is employed for the amphiphilic reaction system, substituted cyclohexanones afford equatorial alcohols exclusively as reduction products with high selectivity (eq 7).6

Conjugate Addition.

The MAD/RLi system can also be used for conjugate alkylation and reduction of a,b-unsaturated ketones with organolithiums and Lithium n-Butyl(diisobutyl)aluminum Hydride, respectively (eqs 8 and 9).7,8 This method is particularly effective for the conjugate alkylation and reduction of quinone monoacetals and their derivatives (eqs 10 and 11).9,10

Discrimination of Two Different Oxygen-Containing Substrates.

MAD can be used as a Lewis acidic receptor for the discrimination of two different oxygen-containing substrates based on selective Lewis acid-base complex formation.11 Indeed, in an equimolar mixture of methyl and ethyl ether substrates, MAD coordinates to the methyl ether exclusively (eq 12). This chemistry has been applied to a new type of coordination chromatography using polymeric, bulky organoaluminum compounds as a stationary phase that allows a surprisingly clean separation of structurally similar methyl ethers from ethyl ethers.12,13

Selective reduction of sterically more hindered ketones has been effected with the MAD/Diisobutylaluminum Hydride system by selective complexation of the less hindered ketones with MAD and subsequent attack of i-Bu2AlH at the free, more hindered ketones (eq 13).14

The selective binding behavior of Lewis acidic MAD for two different ester groups allows the regio- and stereocontrolled Diels-Alder reaction of unsymmetrical fumarates (eq 14).15


The steric effects of MAD on stereoselectivity in the Diels-Alder reactions of cyclic dienes and a,b-unsaturated aldehydes has been studied (eq 15).16 MAD promotes very mild and highly stereocontrolled [2 + 4] cycloaddition between a pyrone sulfone and an enantiomerically pure vinyl ether. After 12 h at -45 °C in 4:1 toluene/CH2Cl2 with 0.5 equiv of MAD and 2.5 equiv of the vinyl ether, cycloadducts are isolated in 93% yield as a 98:2 ratio of the endo diastereomers (eq 16).17


A novel, Lewis acid-induced Michael addition of an enolate complex to an a,b-unsaturated ester has been developed, where the unfavorable reaction between the nucleophile and Lewis acid is sterically suppressed.18 For example, the addition polymerization of methyl methacrylate (MMA) via an enolate complex of aluminum tetraphenylporphyrin (1) as the nucleophilic growing species has been effected in the presence of MAD, producing polymer molecules cleanly with a narrow molecular weight distribution (eq 17).

1. (a) Maruoka, K.; Itoh, T.; Yamamoto, H. JACS 1985, 107, 4573. (b) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. JACS 1988, 110, 3588.
2. (a) Starowieyski, K. B.; Pasynkiewicz, S.; Skowronska-Ptasinska, M. JOM 1975, 90, C43. (b) Skowronska-Ptasinska, M.; Starowieyski, K. B.; Pasynkiewicz, S. JOM 1977, 141, 149. (c) Skowronska-Ptasinska, M.; Starowieyski, K. B.; Pasynkiewicz, S.; Carewska, M. JOM 1978, 160, 403.
3. (a) Power, M. B.; Bott, S. G.; Atwood, J. L.; Barron, A. R. JACS 1990, 112, 3446. (b) Healy, M. D.; Ziller, J. W.; Barron, A. R. JACS 1990, 112, 2949.
4. (a) Kato, T.; Hirukawa, T.; Uyehara, T.; Yamamoto, Y. TL 1987, 28, 1439. (b) Hirukawa, T.; Shudo, T.; Kato, T. JCS(P1) 1993, 217.
5. Maruoka, K.; Araki, Y.; Yamamoto, H. TL 1988, 29, 3101.
6. Maruoka, K.; Sakurai, M.; Yamamoto, H. TL 1985, 26, 3853.
7. Maruoka, K.; Nonoshita, K.; Yamamoto, H. TL 1987, 28, 5723.
8. Nonoshita, K.; Maruoka, K.; Yamamoto, H. BCJ 1988, 61, 2241.
9. Stern, A. J.; Rohde, J. J.; Swenton, J. S. JOC 1989, 54, 4413.
10. Doty, B. J.; Morrow, G. W. TL 1990, 31, 6125.
11. Maruoka, K.; Nagahara, S.; Yamamoto, H. TL 1990, 31, 5475.
12. Maruoka, K.; Nagahara, S.; Yamamoto, H. JACS 1990, 112, 6115.
13. (a) Maruoka, K.; Nagahara, S.; Yamamoto, H. BCJ 1990, 63, 3354. (b) Healy, M. D.; Power, M. B.; Barron, A. R. J. Coord. Chem. 1990, 21, 363.
14. Maruoka, K.; Araki, Y.; Yamamoto, H. JACS 1988, 110, 2650.
15. Maruoka, K.; Saito, S.; Yamamoto, H. JACS 1992, 114, 1089.
16. Maruoka, K.; Nonoshita, K.; Yamamoto, H. SC 1988, 18, 1453.
17. Posner, G. H.; Kinter, C. M. JOC 1990, 55, 3967.
18. (a) Kuroki, M.; Watanabe, T.; Aida, T.; Inoue, S. JACS 1991, 113, 5903. (b) Adachi, T.; Sugimoto, H.; Aida, T.; Inoue, S. Macromolecules 1992, 25, 2280. (c) Adachi, T.; Sugimoto, H.; Aida, T.; Inoue, S. Macromolecules 1993, 26, 1238.

Keiji Maruoka & Hisashi Yamamoto

Nagoya University, Japan

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