Potassium Hydride-Hexamethylphosphoric Triamide1

KH/(Me2N)3PO
(KH)

[7693-26-7]  · HK  · Potassium Hydride-Hexamethylphosphoric Triamide  · (MW 40.11) (HMPA)

[680-31-9]  · C6H18N3OP  · Potassium Hydride-Hexamethylphosphoric Triamide  · (MW 179.24)

(strong base used for the deprotonation of alcohols, ketones, and silanes; HMPA appears to facilitate subsequent transformations such as fragmentations and sigmatropic rearrangements)

Physical Data: see entries for Potassium Hydride and Hexamethylphosphoric Triamide.

Oxygen Acids.

Potassium hydride is superior to both Sodium Hydride and lithium hydride in the deprotonation of a number of weak acids (see Potassium Hydride). In the presence of HMPA, alkoxides of several allylic alcohols may be induced to fragment to allyl anions and ketones. Subsequent deprotonation of the ketone by the allylpotassium liberates propene, and workup affords a mixture of unsaturated ketones (eqs 1 and 2).2

In the total synthesis of the antibiotic ionomycin, Evans used the asymmetric alkylation of a prolinol amide (eq 3). Deprotonation of the hydroxy group with KH, then deprotonation of the amide with Lithium Diisopropylamide, produced the dianion. Addition of HMPA and a primary alkyl iodide afforded the alkylation product in good yield and excellent stereoselectivity.3 Note that there are relatively few methods for the highly selective alkylation of enolates, since most enolates tend to be unreactive toward unactivated (nonallylic) alkyl halides at the low temperatures required for high selectivity.

When a-hydroxysilanes are treated with KH in HMPA, the alkoxide undergoes a stereospecific Brook rearrangement4 producing a silyl ether which, upon hydrolysis, affords the desilylated alcohol. This rearrangement has been observed for aryl-, alkyl-, and vinyl-substituted a-hydroxysilanes (eq 4).5

Potassium salts of 1-vinylcyclobutanols rearrange readily to form cyclohexanones when a sulfur substituent is present at the 2-position. This reaction proceeds by a fragmentation/Michael addition mechanism (eqs 5 and 6) and provides a synthetically useful route to cyclohexanones functionalized with a 4-phenylthio group.6

The KH/HMPA combination reagent also accelerates [1,3]- and [3,3]-sigmatropic rearrangements. For medium-sized ring 1-vinyl alcohols, [1,3]-sigmatropic shifts predominate at rt under the influence of KH and HMPA (eq 7).7 In contrast, thermal rearrangements of the corresponding trimethylsilyl ethers require temperatures of approximately 300 °C.

Evans found rate enhancements on the order of 1010 to 1017 for a [3,3]-sigmatropic rearrangement of an endo-vinyl-bicyclo[2.2.2]octene alkoxide (in the presence of HMPA or crown ether) vs. the alcohol (eq 8).8

Carbon Acids.

Potassium hydride may be used for the deprotonation of ketones, as illustrated by eq 9. In this example, attempts to alkylate the lithium enolate were unsuccessful.9

Deprotonation and alkylation of b-keto esters using KH/HMPA constitutes a key step in a cyclopentenone annulation strategy (eq 10).10 In the absence of HMPA, the yield of this one-pot annulation drops to 27%.

In an enantiodivergent synthesis of (+)- and (-)-nonactic acid, Bartlett employed a deprotonation and intramolecular O-alkylation of a carbonate to obtain a tetrahydrofuran in 90% yield (eq 11).11 It was noted that this intramolecular reaction was surprisingly facile due to the stereoelectronic effect of the syn-syn geometry of the carbonate. A diastereomeric furan was obtained by acid-catalyzed cyclization of the corresponding diol.

Deprotonation of a ketone with KH/HMPA may also be used in an enolate acylation process (eq 12).12

Rate accelerations of Claisen rearrangements were observed when aryl sulfones were deprotonated with KH/HMPA (eq 13);13 thus significant improvements in yield (from 40 to 78%) resulted. Note that the regiochemistry of the rearrangement is thermodynamically controlled, as the more stable anion is formed even though rearrangement takes place at the more hindered site.

Silicon Acids.

Finally, when triphenylsilane is treated with KH in 1:1 HMPA/DME, triphenylsilylpotassium is produced in high yield (eq 14).14


1. (a) Brown, C. A. JOC 1974, 39, 3913. (b) CRC Handbook of Chemistry and Physics, 73rd ed., 1992-1993; Lide, D. R., Ed.; CRC: Boca Raton, FL, 1992. (c) Lewis, R. J. Carcinogenically Active Chemicals, A Reference Guide; Van Nostrand Reinhold: New York, 1991. (d) Riddick, J. A.; Bunger, W. B. Organic Solvents: Physical Properties and Methods of Purification, 3rd ed.; Techniques of Chemistry, Vol. 2; Wiley: New York, 1970.
2. Snowden, R. L.; Muller, B. L.; Schulte-Elte, K. H. TL 1982, 23, 335.
3. Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. JACS 1990, 112, 5290.
4. Brook, A. G. ACR 1974, 7, 77.
5. Wilson, S. R.; Hague, M. S.; Misra, R. N. JOC 1982, 47, 747.
6. Cohen, T.; Yu, L.-C.; Daniewski, W. M. JOC 1985, 50, 4596.
7. Thies, R. W.; Seitz, E. P. CC 1976, 846.
8. Evans, D. A.; Golob, A. M. JACS 1975, 97, 4765.
9. Smith, A. B. III; Liverton, N. J.; Hrib, N. J.; Sivaramakrishnan, H.; Winzenberg, K. JACS 1986, 108, 3040.
10. Welch, S. C.; Assercq, J.-M.; Loh, J.-P.; Glase, S. A. JOC 1987, 52, 1440.
11. Bartlett, P. A.; Meadows, J. D.; Ottow, E. JACS 1984, 106, 5304.
12. Liu, H.-J.; Dieck-Abularach, T. H 1987, 25, 245.
13. Denmark, S. E.; Harmata, M. A. JACS 1982, 104, 4972.
14. Corriu, R. J. P.; Guérin, C.; Kolani, B. BSF 1985, 973 (CA 1990, 112, 198 473d).

Robert E. Gawley & Johnny E. Ramirez

University of Miami, Coral Gables, FL, USA



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