Potassium Diisopropylamide


[67459-71-6]  · C6H14KN  · Potassium Diisopropylamide  · (MW 139.31)

(non-nucleophilic strong base)

Alternate Name: KDA.

Solubility: sol THF; insol benzene.

Analysis of Reagent Purity: amide bases can be titrated utilizing 1,6-dihydro-6-butyl-2,2-bipyridine.1 This indicator is able to determine the concentration of amide base solutions even in the presence of alkoxide.

Preparative Methods: KDA is prepared in situ immediately prior to use. In the original paper, the reagent was prepared either by the addition of diisopropylamine to a mixture of n-butylpotassium-lithium t-butoxide in hexane at 0 °C, or by the addition of n-Butyllithium to a solution of Potassium t-Butoxide and Diisopropylamine in THF at -78 °C.2 It is also common to treat a solution of Lithium Diisopropylamide with potassium t-butoxide.3 This reagent has been referred to in the literature as KDA, KDA-lithium t-butoxide, and LIDAKOR (lithium diorganylamide potassium alcoholate), but an examination of the experimental procedures indicates that all of the authors are, for practical purposes, referring to the same reagent. The exchange of lithium for potassium between organolithium compounds and potassium alkoxides is well established and has been reviewed.4

Handling, Storage, and Precautions: moisture sensitive. Use in a fume hood.

Deprotonation Reactions.

KDA is used to effect deprotonations when a strong, non-nucleophilic base is required. It is considerably more reactive than its lithium counterpart and thus it is often used in situations where Lithium Diisopropylamide (LDA) has been tried and shown to be ineffective. Even in cases where LDA is effective for deprotonation, KDA can be used advantageously to promote anion generation more rapidly and at lower temperatures and to provide a more reactive derivative. KDA is also used when the potassium counterion is important for the outcome of a reaction. For example, it is well recognized that, in contrast to lithium enolates, when potassium enolates are employed, enolate equilibration is normally faster than alkylation, resulting in predominant alkylation of the thermodynamically more stable enolate.5 The examples outlined below have been selected to illustrate these types of situations in which the unique properties of KDA are exploited.

KDA is used periodically for the generation of enolates. In a recent example, an oxindole system was successfully alkylated with an aziridine via the dianion formed by treatment with 2 equiv of KDA in THF at -78 °C (eq 1).6 KDA can also be used to generate the dianions of carboxylic acids which then add predominantly 1,2 to a,b-unsaturated carbonyl compounds.7 The counterion in this reaction has a pronounced effect on the ratio of 1,2- to 1,4-addition. The heightened reactivity of KDA has proved useful when enolate stability is a concern. In one example it was determined that the enolate of a particular pyrrolidinone was unstable above -70 °C, but the compound was successfully deprotonated at -90 °C within 20 min using KDA.8 KDA has also been used when greater reactivity is required in the generated enolate. Potassium enolates have been shown to undergo a conjugate addition to a vinyl sulfone in cases where the lithium enolate was completely unreactive.9

In one of the first reports of this reagent, it was shown that KDA can be used for the metalation of nitrosamines (eq 2).10 The reaction takes place more rapidly than with LDA and gives a more reactive intermediate toward alkylation. KDA is also preferred over LDA for the generation of alkyl phosphonate anions prior to mono- or difluorination using N-fluorobenzenesulfonimide.11 In the deprotonation of alkoxyalkyl phenyl sulfones (acyl anion equivalents), KDA must be used if the anion is to be added to a ketone rather than simply alkylated.12

KDA has been used for the deprotonation of dimethylhydrazones and oxime ethers.13 In most cases, deprotonation is complete in THF at -78 °C within 15 min. By contrast, the conditions for successful deprotonations using n-butyllithium or LDA are substrate dependent, requiring more time for optimization on a case by case basis. The anion of acetone dimethylhydrazone, generated by treatment with KDA, has been added to a vinyl sulfone and the resulting a-sulfonyl anion further alkylated (eq 3).14

KDA appears to be the base of choice for the generation of selenium-stabilized carbanions. It has been used to effect the deprotonation of 1-(phenylseleno)alkenes and bis(phenylseleno)acetals to give carbanions which react rapidly with a variety of electrophiles (eq 4).15 Carbonyl compounds which contain an a-hydrogen undergo carbonyl addition rather than enolate formation. By comparison, LDA does not deprotonate these systems at an appreciable rate. In the case of a-aryl bis(phenylseleno)-acetals, the use of LDA results in the recovery of a significant amount of starting material while the use of KDA produces only the desired product (eq 4).16 KDA will also successfully deprotonate simple benzyl selenides and 1,1,1-tris(trifluoromethylseleno)methane.16,17 However, when dibenzyl diselenide is treated with KDA, cleavage of the Se-Se bond is the predominant reaction in a rare example of KDA acting as a nucleophile.18

KDA has been used for the deprotonation of phenylthiotributylstannyltrimethylsilylmethane (eq 5).19 The potassium anion is formed in 15 min and readily alkylated, whereas the analogous lithium anion is formed in only 80% after 1 h and requires a complexing agent like TMEDA to achieve good yields of alkylated product. Transmetalation of the tributylstannyl group with n-butyllithium followed by alkylation provides a-silyl sulfides which can be subsequently converted to ketones. If, instead of an alkyl halide, the potassium anion is reacted with a nonenolizable carbonyl compound, a vinylstannane is obtained via a Peterson reaction (eq 5).20 No control over alkene geometry was observed in this case. However, cation dependent geometric control has been shown to occur in the Peterson reaction between bistrimethylsilyl acetate enolates and aldehydes (eq 6).21 Employing the potassium enolate generated with KDA gives significant selectivity for the (E)-isomer, suggesting that elimination occurs largely from a nonchelated intermediate.

KDA has been used for the metalation of imidazoles in cases where n-butyllithium and LDA were ineffective.22 In a synthesis of a dinucleating hexaimidazole ligand, both rings of a bis-imidazole system were metalated and derivatized using KDA.23

The high reactivity and kinetic basicity of KDA allow it to deprotonate even simple aromatic methyl groups. For this reason, toluene is not recommended as a solvent for KDA reactions. The deprotonation of dimethylnaphthalene, dimethylanthracene, and dimethyltriptycene systems have been studied using KDA.24 KDA has also been used for the direct metalation of isoprene.25

Elimination Reactions.

KDA has been used for the generation of dienols from homoallylic cyclic ethers (eq 7).26 KDA promotes the ring-opening elimination without reacting with the resulting diene. By contrast, the use of LDA decreases yields dramatically. In this system, KDA is generated from LDA in the presence of a catalytic amount (10 mol %) of potassium t-butoxide. Presumably the product potassium alkoxide that is formed reacts with remaining LDA to generate a constant, low level of KDA which helps to minimize undesirable side reactions.

KDA has also been used to promote the smooth ring opening of epoxides to generate allylic alcohols in good yields.27 It is felt that the combination of lithium and potassium bases used in the generation of KDA both play important roles in facilitating this reaction: the electrophilic lithium may help to open the epoxide while the heavier alkali metal potassium confers maximum basicity to its anion to facilitate deprotonation. Where possible, trans-alkenols are the preferred or exclusive product, probably arising via a syn-periplanar elimination route.

KDA has been cited in an improved procedure for the Wharton transposition.28 This multistep 1,3-transposition of oxygen proceeds through a base-induced rearrangement of an a,b-epoxyhydrazone. For stable epoxyhydrazones, yields are improved considerably by the use of KDA or potassium t-butoxide (eq 8).

Related Reagents.

Lithium Diisopropylamide; Potassium 3-Aminopropylamide.

1. Ireland, R. E.; Meissner, R. S. JOC 1991, 56, 4566.
2. Raucher, S.; Koolpe, G. A. JOC 1978, 43, 3794.
3. Lochmann, L.; Trekoval, J. JOM 1979, 179, 123.
4. Lochmann, L.; Trekoval, J. CCC 1988, 53, 76.
5. Caine, D. COS 1991, 3, 1.
6. Carroll, W. A.; Grieco, P. A. JACS 1993, 115, 1164.
7. Mulzer, J.; Brüntrup, G.; Hartz, G.; Kühl, U.; Blaschek, U.; Böhrer, G. CB 1981, 114, 3701.
8. Fray, M. J.; Bull, D. J.; James, K. SL 1992, 709.
9. Hamann, P. R.; Fuchs, P. L. JOC 1983, 48, 914.
10. Renger, B.; Hügel, H.; Wykypiel, W.; Seebach, D. CB 1978, 111, 2630.
11. Differding, E.; Duthaler, R. O.; Krieger, A.; Rüegg, G. M.; Schmit, C. SL 1991, 395.
12. Tanaka, K.; Matsui, S.; Kaji, A. BCJ 1980, 53, 3619.
13. Gawley, R. E.; Termine, E. J.; Aube, J. TL 1980, 21, 3115.
14. Pyne, S. G.; Spellmeyer, D. C.; Chen, S.; Fuchs, P. L. JACS 1982, 104, 5728.
15. Raucher, S.; Koolpe, G. A. JOC 1978, 43, 3794.
16. Clarembeau, M.; Krief, A. TL 1986, 27, 1723.
17. Haas, A.; Kempf, K. W. T 1984, 40, 4963.
18. Krief, A.; Trabelsi, M.; Dumont, W. SL 1992, 638.
19. Ager, D. JCS(P1) 1986, 195.
20. Ager, D. J.; Cooke, G. E.; East, M. B.; Mole, S. J.; Rampersaud, A.; Webb, V. J. OM 1986, 5, 1906.
21. Boeckman, R. K. Jr.; Chinn, R. L. TL 1985, 26, 5005.
22. Iddon, B.; Lim, B. L. CC 1981, 1095.
23. Tolman, W. B.; Rardin, R. L.; Lippard, S. J. JACS 1989, 111, 4532.
24. (a) Inagaki, S.; Imai, T.; Mori, Y. BCJ 1989, 62, 79. (b) Inagaki, S.; Imai, T.; Kawata, H. CL 1985, 1191.
25. Klusener, P. A. A.; Tip, L.; Brandsma, L. T 1991, 47, 2041.
26. Margot, C.; Schlosser, M. TL 1985, 26, 1035.
27. Mordini, A.; Ben Rayama, E.; Margot, C.; Schlosser, M. T 1990, 46, 2401.
28. Dupuy, C.; Luche, J. L. T 1989, 45, 3437.

Katherine S. Takaki

Bristol-Myers Squibb Co., Wallingford, CT, USA

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