Bromomagnesium Diisopropylamide

[50715-01-0]  · C6H14BrMgN  · Bromomagnesium Diisopropylamide  · (MW 204.39)

(thermodynamic enolate generation; aldol condensation; Claisen ester condensation)

Alternate Names: diisopropylaminomagnesium bromide; BMDA.

Preparative Methods: prepared from Diisopropylamine and Methylmagnesium Bromide or Ethylmagnesium Bromide using either THF or ether as the solvent. In THF a 1.5 M solution was prepared at 80 °C and stored at 50 °C (presumably to prevent precipitation).1 A refluxing 0.5 M THF solution of BMDA was reported to be stable for several hours.2 In ether, preparations have been reported at rt; however, BMDA is practically insoluble in ether and was used as a slurry.3,4

Handling, Storage, and Precautions: use in a fume hood.

Ester Condensations.

BMDA has been examined as a base for the Claisen ester condensation3,5-7 and was found to be an excellent condensing agent for mixed condensations of methyl benzoate and methyl 2-furoate with aliphatic esters.5 A small study of BMDA's use in the Dieckmann cyclization of diesters seemed to show no obvious advantage over other bases.7 Intramolecular condensations using BMDA have been reported (eqs 1 and 2).8,9 Thiolactones have been condensed with Diethyl Oxalate (eq 3).10

Nitrile Condensations.

The condensation of nitriles using BMDA has been investigated. Although acetonitrile gave very poor yields, reactions of propio-, valero-, and phenylacetonitriles proceeded in 65-80% yields (eq 4). The reactions were carried out in refluxing ether. When the reactions were carried out in refluxing n-butyl ether, they were more complex and cyclic trimers of the pyrimidine and pyridine classes were formed.11

Aldol Condensations.

BMDA has found utility in a number of aldol condensations where other bases have failed. In Kishi's synthesis of monensin, BMDA was used to couple the left and right halves of the molecule (eq 5).1

In a synthesis of the taxane ring system, Holton used BMDA to effect the intramolecular condensation to give (2) in 90% yield (eq 6).12 Other reagents resulted in a retro Michael reaction.

Annunziata et al. found magnesium bases such as BMDA superior in diastereoselectivity to lithium bases for the aldol condensation of the enantiomerically pure 3-p-tolylsulfinylmethyl-4,5-dihydroisoxazoles (eq 7).13

Similarly, Nokami et al. reported the condensation of another p-tolylsulfinyl compound with propargyl aldehyde (eq 8).14

Enolate Generation.

Krafft and Holton reported the examination of a number of bases for the preparation of enolates. This examination showed that BMDA was the best base for the preparation of thermodynamic enolates. The enolate was trapped with Chlorotrimethylsilane and the product obtained in 85-95% yields with ratios of thermodynamic:kinetic product (4:5) of ca. 97:3 (eq 9).4 Lithium Diisopropylamide gave a 1:99 ratio of (4:5). Other bases examined gave predominately (4); however, the ratios of (4:5) were inferior to BMDA. This procedure has been used in the synthesis of the taxane ring system,12 intermediates for reserpine (trapped with t-Butyldimethylchlorosilane),15 dihydropallescensin D,16 and other systems.17 Thermodynamic enolates have also been trapped with N-Phenyltrifluoromethanesulfonimide to give vinyl triflates.18,19 Scott and Stille observed that the use of excess BMDA with 2-methylcyclohexanone led to lower ratios of thermodynamic:kinetic product when the enolate was trapped with either TMSCl or N-phenyltriflimide.19

Carey and Helquist used BMDA to generate enolates in their synthesis of fused cyclopentanones (eq 10).20

It should be noted that since BMDA can also promote aldol condensations, the use of BMDA to form enolates of ketones that are not relatively sterically hindered can lead to aldol products as the only reaction.12,21

Chiral Sulfoxides.

One synthetic route to optically active a-sulfinyl esters is the displacement of the O-menthyl group of an optically active sulfinate ester (eq 11).22-24 When R = Me the ratio of diastereomers was 1:1 and when R = Et the ratio was 3:7. A similar reaction with cyclic ketones has been reported (eq 12).21 When n = 1 the ratio of diastereomers was 3.0:1 and with n = 2 the ratio was 1.6:1.

Other Reactions.

BMDA has proven useful for the functionalization of cubanes. Treatment of (6) with BMDA in refluxing THF gave the diester (7) as the product,2 whereas at rt the monoester (8) is formed (eq 13).2,25

BMDA metalates (diphenylphosphinyl)ferrocene exclusively ortho to the diphenylphosphinyl group (eq 14).26

BMDA has been reported to be complementary to LDA in the acylation of 2-acyl-1,3-dithianes (9) (eq 15). When R = aryl, LDA gave predominately O-acylation (11), whereas BMDA gave exclusive C-acylation (10). When R = Me, LDA gave 100% O-acylation and BMDA gave 78% C-acylation.27

1. Fukuyama, T.; Akasaka, K.; Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. JACS 1979, 101, 262.
2. Eaton, P. E.; Lee, C.-H.; Xiong, Y. JACS 1989, 111, 8016.
3. Frostick, F. C.; Hauser, C. R. JACS 1949, 71, 1350.
4. Krafft, M. E.; Holton, R. A. TL 1983, 24, 1345.
5. Royals, E. E.; Turpin, D. G. JACS 1954, 76, 5452.
6. Sommer, L. H.; Pioch, R. P.; Marans, N. S.; Goldberg, G. M.; Rockett, J.; Kerlin, J. JACS 1953, 75, 2932.
7. Singh, P. K.; Rajeswari, K.; Ranganayakulu, K. IJC(B) 1980, 19B, 823.
8. Haynes, L. J.; Stanners, A. H. JCS 1956, 4103.
9. Eistert, v. B.; Heck, G. LA 1965, 681, 123.
10. Korte, F.; Büchel, K. H. CB 1960, 93, 1021.
11. Reynolds, G. A.; Humphlett, W. J.; Swamer, F. W.; Hauser, C. R. JOC 1951, 16, 165.
12. Holton, R. A. JACS 1984, 106, 5731.
13. Annunziata, R.; Cinquini, M.; Cozzi, F.; Restelli, A. JCS(P1) 1985, 2293.
14. Nokami, J.; Ohtsuki, H.; Sakamoto, Y.; Mitsuoka, M.; Kunieda, N. CL 1992, 1647.
15. Jung, M. E.; Light, L. A. JACS 1984, 106, 7614.
16. White, J. D.; Somers, T. C.; Yager, K. M. TL 1990, 31, 59.
17. Piers, E.; Friesen, R. W.; Keay, B. A. CC 1985, 809.
18. Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. JOC 1986, 51, 277.
19. Scott, W. J.; Stille, J. K. JACS 1986, 108, 3033.
20. Carey, J. T.; Helquist, P. TL 1988, 29, 1243.
21. Carreño, M. C.; Ruano, J. L. G.; Pedregal, C.; Rubio, A. JCS(P1) 1989, 1335.
22. Mioskowski, C.; Solladié, G. TL 1975, 3341.
23. Solladié, G. S 1981, 185.
24. Solladié, G.; Matloubi-Moghadam, F.; Luttmann, C.; Mioskowski, C. HCA 1982, 65, 1602.
25. Castaldi, G.; Colombo, R.; Allegrini, P. TL 1991, 32, 2173.
26. Sawamura, M.; Yamauchi, A.; Takegawa, T.; Ito, Y. CC 1991, 874.
27. Fétizon, M.; Goulaouic, P.; Hanna, I. SC 1989, 19, 2755.

Ronald H. Erickson

Scios Nova, Baltimore, MD, USA

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