Potassium 3-Aminopropylamide


[56038-00-7]  · C3H9KN2  · Potassium 3-Aminopropylamide  · (MW 112.24)

(strong base1 used primarily for the isomerization of internal alkynes to terminal alkynes;2 can also be used to isomerize alkenes;3 also used to promote intramolecular transamidation reactions4)

Alternate Name: KAPA.

Solubility: highly sol (&egt;1.5 M) in excess 1,3-diaminopropane

Preparative Methods: usually prepared as a solution in excess, dry 1,3-diaminopropane.5 The most common preparation involves the direct, quantitative reaction of Potassium Hydride with excess amine at 20-25 °C.6 Alternative preparations have been developed to avoid the handling and purification of KH. The reagent has been prepared by the reaction of Potassium Amide and 1,3-diaminopropane followed by evaporation of excess Ammonia in vacuo.7 The reagent has also been prepared by heating Potassium and 1,3-diaminopropane under sonication.8 A trace of iron(III) nitrate increases the rate of reagent formation, although it is not essential. Addition of Potassium t-Butoxide to lithium 3-aminopropylamide (from Lithium and 1,3-diaminopropane) probably generates KAPA in situ via cation exchange.9

Handling, Storage, and Precautions: moisture sensitive. A solution of KAPA in 1,3-diaminopropane appears stable for at least 8 h at rt and possibly even for 2-3 days.2,10 Use in a fume hood.

Isomerization of Alkynes.

Potassium 3-aminopropylamide is best known for its use in the acetylene zipper reaction.2 This reagent induces a rapid migration of triple bonds from the interior of a carbon chain to the terminus. Previously reported isomerizations of alkynes required very strong bases (e.g. Sodium, Sodium Amide) and elevated temperatures to effect a one-position isomerization of a 2-alkyne to a 1-alkyne. Migrations over more than one position were reported to be generally unsatisfactory or very slow. By contrast, KAPA produces rapid, multiposition alkyne migrations to provide the terminal alkyne within seconds at 0 °C (eq 1). Although internal alkynes are favored thermodynamically, this isomerization is driven forward by the formation (possibly aided by precipitation) of the stable metal acetylide. Quenching of the acetylide with water provides the terminal alkyne in excellent yield. In nonlinear systems, migration is blocked by branching in the chain.

The reaction has also been studied in functionalized systems. In alkynic alcohols, KAPA-induced migration of the triple bond proceeds to the chain terminus which is remote from the OH function (eq 2).11 It is believed that the anionic intermediate in the migration of the triple bond is inhibited from migrating toward the similarly charged alkoxide.11a If the hydroxy group is attached to a chiral carbon, this phenomenon protects the configuration of that carbon during the migration process. Isomerization of chiral propargylic alcohols proceeds to give the terminal alkynic alcohols with no significant loss of enantiomeric purity (eq 3).12

Successful isomerizations have also been carried out with o-alkynylorganoboranes and propynyl ethers.13 Isomerizations of alkynic carboxylic acids generally lead to a mixture of products and poor yields of the terminal alkyne.14 However, if the carboxylic acid group is separated from the alkyne by an intervening carbinol, the carboxylate can be carried through the migration reaction without difficulty.15

KAPA can also be used for the in situ generation of an internal alkyne which then rapidly isomerizes to the terminal position. Allenes, vinyl sulfides, and cyclic ethers have been used as alkyne equivalents to provide terminal alkynes (eq 4).16

Isomerization of Exocyclic Alkenes.

Trace quantities of KAPA can be used in a two-phase reaction to effect the rapid, low-temperature isomerization of neat, exocyclic alkenes on a large scale.3 In particular, KAPA has been used for the isomerization of (-)-b-pinene to the less accessible (-)-a-pinene in high yield and without racemization (eq 5).17

Intramolecular Transamidation Reactions.

KAPA is recommended for use in the zip reaction for the ring enlargement of aminolactams (eq 6).4,18 It is believed that the reaction is driven in part by formation of the resonance-stabilized amide anion.

Related Reagents.

Lithium Amide; Lithium Diisopropylamide; Potassium Hexamethyldisilazide; Potassium Diisopropylamide.

1. KAPA has been reported to be over a million times more basic than the potassium salt of DMSO: Arnett, E. M.; Venkatasubramaniam, K. G. TL 1981, 22, 987.
2. Brown, C. A.; Yamashita, A. JACS 1975, 97, 891.
3. Brown, C. A. S 1978, 754.
4. Kramer, U.; Guggisberg, A.; Hesse, M.; Schmid, H. AG(E) 1977, 16, 861.
5. Burfield, D. R.; Smithers, R. H.; Tan, A. S.-C. JOC 1981, 46, 629.
6. Brown, C. A. CC 1975, 222.
7. Hommes, H.; Brandsma, L. RTC 1977, 96, 160.
8. (a) Kimmel, T.; Becker, D. JOC 1984, 49, 2494. (b) Theobald, P. G.; Okamura, W. H. JOC 1990, 55, 741.
9. Abrams, S. R. CJC 1984, 62, 1333.
10. No change in the NMR spectrum noted after 2-3 days: Arnett, E. M.; Venkatasubramaniam, K. G. JOC 1983, 48, 1569.
11. (a) Brown, C. A.; Yamashita, A. CC 1976, 959. (b) Lindhoudt, J. C.; van Mourik, G. L.; Pabon, H. J. J. TL 1976, 2565. (c) Abrams, S. R.; Shaw, A. C. OS 1988, 66, 127. (d) Abrams, S. R.; Shaw, A. C. OSC 1993, 8, 146.
12. (a) Midland, M. M.; Halterman, R. L; Brown, C. A.; Yamaichi, A. TL 1981, 22, 4171. (b) Maas, R. L.; Ingram, C. D.; Porter, A. T.; Oates, J. A.; Taber, D. F.; Brash, A. R. JBC 1985, 260, 4217. (c) Heathcock, C. H.; Stafford, J. A. JOC 1992, 57, 2566.
13. (a) Brown, C. A.; Negishi, E.-I. CC 1977, 318. (b) Almansa, C.; Moyano, A.; Pericàs, M. A.; Serratosa, F. S 1988, 707.
14. Conditions have been reported for the isomerization of the triple bond of stearolic acid to the terminal position in moderate yield: Augustin, K. E.; Schäfer, H. J. LA 1991, 1037.
15. Burger, A.; Clark, J. E.; Nishimoto, M.; Muerhoff, A. S.; Masters, B. S. S.; de Montellano, O. JMC 1993, 36, 1418.
16. (a) Brown, C. A. JOC 1978, 43, 3083. (b) Grattan, T. J.; Whitehurst, J. S. JCS(P1) 1990, 11. (c) Barajas, L.; Hernández, J. E.; Torres, S. SC 1990, 20, 2733.
17. (a) Brown, C. A.; Jadhav, P. K. OS 1987, 65, 224. (b) Brown, C. A.; Jadhav, P. K. OSC 1993, 8, 553.
18. Kramer, U.; Guggisberg, A.; Hesse, M.; Schmid, H. AG(E) 1978, 17, 200.

Katherine S. Takaki

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

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