Potassium Hydride-s-Butyllithium-N,N,N,N-Tetramethylethylenediamine


[7693-26-7]  · HK  · Potassium Hydride-s-Butyllithium-N,N,N,N-Tetramethylethylenediamine  · (MW 40.11) (s-BuLi)

[598-30-1]  · C4H9Li  · Potassium Hydride-s-Butyllithium-N,N,N,N-Tetramethylethylenediamine  · (MW 64.07) (TMEDA)

[110-18-9]  · C6H16N2  · Potassium Hydride-s-Butyllithium-N,N,N,N-Tetramethylethylenediamine  · (MW 116.24)

(a,b-dideprotonation of g,d-unsaturated ketones1,2 and their analogs,1,3,4 producing dianions, d5-synthons,5 which react with electrophiles exclusively at the d-position2,3)

Physical Data: see entries for Potassium Hydride, s-Butyllithium, and N,N,N,N-Tetramethylethylenediamine.

a,b-Dideprotonation of Unsaturated Ketones.

This combination of reagents is used to dideprotonate g,d-enones in two steps. The relatively acidic a-proton is abstracted with 1 equiv of KH in THF (eq 1) and the less acidic b-proton is removed with 1 equiv of s-BuLi and 1 equiv of TMEDA (eq 2).1,3 These last two reagents are simply added to the solution of the enolate. The resulting dianions, (1) (eq 3) and (2) (eq 4), react with suitable electrophiles exclusively at the d-position2,3 and are thus d5-synthons.5

Analogous a,b-dideprotonation of g,d;ε,ζ-dienones yields dianions which also react with electrophiles exclusively at the terminal position. Higher yields are generally obtained when the nucleophile lacks any readily enolizable a-protons.1 Aldehydes, ketones (eq 4), and alkyl halides (eq 5) are all suitable electrophiles.1,2

Acylation of dianions (1) and (2) does not give good yields.1 Isolated double bonds in the electrophile (eq 6) are usually not affected, and conjugated double bonds (eq 7) give Michael adducts.1

Alkylations and carbonyl condensations using dianions (1) and (2) are not very diastereoselective.1 Excellent stereoselectivity can, however, be obtained with the use of epoxides as the electrophiles (eq 8).1

Enols such as the products of eq 4 and eq 8 cyclize, when treated with Sodium Methoxide in methanol, into THF (eq 9) and THP (eq 10) derivatives, respectively.1,2

a,b-Dideprotonation of Ketone Analogs.

While carboxylic acids, esters, and amides do not undergo this reaction,3 other ketone analogs do.1,3,4 a-Hydroxy ketones work well (eq 11),1 but the trianion, instead of the dianion, derivative must first be made. This is accomplished by using an extra equivalent of KH in the first step. The resulting ketones are very useful products, since they may be reacted with glycol cleaving agents to yield carboxylic acids which are then amenable to many useful transformations.1

Dideprotonation of dithioesters yields dianions of type (3) that react with electrophiles in the same fashion (eq 12).1,4 Alternatively, the adduct (4) can be quenched with methyl iodide to give ketene thioacetals (eq 13).1,4

These ketene thioacetals can be deprotonated using excess Lithium Diisopropylamide and protonated with acid or alkylated with an alkyl halide at the acetal carbon to give products of type (5) which can then be hydrolyzed to the ketone (eq 14).1

Most of the reaction products illustrated here can undergo further functional group transformations, furnishing a variety of useful synthetic intermediates.1 There are a variety of other d5-synthons5 reported in the literature, some similar to those presented here. They range from Wittig reagents derived from carboxylic acid salts6 or protected ketones,7 to nitro compounds,8 alkynes,9 Grignard reagents,10 thio-Claisen substrates,11 and others.12 A similar combination of reagents has also been used to dideprotonate b-carboline formamidine to produce a dianion that alkylates at C-1 (eq 15).13

1. Seebach, D.; Pohmakotr, M.; Schregenberger, C.; Weidmann, B.; Mali, R. S.; Pohmakotr, S. HCA 1982, 65, 419.
2. Pohmakotr, M.; Seebach, D. AG(E) 1977, 16, 320.
3. Seebach, D.; Pohmakotr, M. T 1981, 37, 4047.
4. Pohmakotr, M.; Seebach, D. TL 1979, 2271.
5. For an explanation of this nomenclature, see: Seebach, D. AG(E) 1979, 18, 239.
6. (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. JACS 1969, 91, 5675. (b) Bindra, J. S.; Bindra, R. Prostaglandin Synthesis; Academic: New York, 1977; p 210.
7. (a) Fleming, I.; Long, W. E. SC 1975, 5, 177. (b) Groen, M. B.; Zeelen, F. J. RTC 1978, 97, 301.
8. (a) Tufariello, J. J.; Tegeler, J. J.; Wong, S. C.; Asrof Ali, Sk. TL 1978, 1733. (b) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski, E. J.; Wong, S. C.; Asrof Ali, Sk. JACS 1979, 101, 2435.
9. (a) Gerlach, H.; Künzler, P.; Oertle, K. HCA 1978, 61, 1226. (b) Seidel, W.; Seebach, D. TL 1982, 23, 159. (c) Stork, G.; Borch, R. JACS 1964, 86, 935.
10. Barluenga, J.; Rubiera, C.; Fernández, J. R.; Flórez, J.; Yus, M. S 1987, 819.
11. (a) Oshima, K.; Takahashi, H.; Yamamoto, H.; Nozaki, H. JACS 1973, 95, 2693. (b) Oshima, K.; Yamamoto, H.; Nozaki, H. JACS 1973, 95, 4446. (c) Takahashi, H.; Oshima, K.; Yamamoto, H.; Nozaki, H. JACS 1973, 95, 5803. (d) Beslin, P.; Perrio, S. T 1992, 48, 4135.
12. Alexakis, A.; Chapdelaine, M. J.; Posner, G. H.; Runquist, A. W. TL 1978, 4205.
13. Meyers, A. I.; Loewe, M. F. TL 1984, 25, 2641.

René Castro & Robert E. Gawley

University of Miami, Coral Gables, FL, USA

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