[102-82-9]  · C12H27N  · Tri-n-butylamine  · (MW 185.40)

(high boiling tertiary amine, used as a base in intramolecular Diels-Alder reactions,1 metal-catalyzed couplings and reductions, ketene generation, and hydrogenations)

Physical Data: bp 216 °C; mp -70 °C; d 0.778 g cm-3.

Solubility: sparingly sol H2O; very sol alcohols and ethers; sol acetone, benzene.

Form Supplied in: liquid; commercially available.

Handling, Storage, and Precautions: a corrosive and toxic liquid. Bottles of tri-n-butylamine should be flushed with nitrogen or argon to prevent exposure to carbon dioxide. The vapors are harmful and care should be taken to avoid absorption through the skin. Use in a fume hood.

Intramolecular Diels-Alder Reactions.

The addition of tri-n-butylamine to high-temperature intramolecular Diels-Alder reactions1 tends to reduce unwanted acid-catalyzed side reactions involving the reaction substrates and/or the Diels-Alder adducts. For example, heating the trienol (1) at 185 °C in chlorobenzene containing a catalytic amount of tri-n-butylamine leads to the four possible isomeric Diels-Alder products (2) in nearly quantitative yield (eq 1).2 Omitting the tri-n-butylamine results in only a 14% yield of the desired adducts. A major byproduct is the tetraene (3), the product of an acid-promoted dehydration.

Similarly, heating the mixture of the substituted 1,3-cyclopentadienes (4) in tri-n-butylamine at 190 °C for 10 h leads to the norbornadiene (5) in a distilled yield of 78% (eq 2).3 In contrast, use of HMPA as solvent at 220 °C generates the double bond isomer (6), the product of either an allene/alkyne equilibration of (4) prior to the intramolecular Diels-Alder reaction or an acid-catalyzed rearrangement of the Diels-Alder product (5). An acid-catalyzed isomerization of (5) to (6) has been observed using dilute sulfuric acid at room temperature.3

Metal-Catalyzed Reactions.

o-Bromoacetanilides and related substrates undergo palladium-catalyzed carbonylations using palladium catalysts and gaseous CO in tri-n-butylamine and water to generate anthranilic acid derivatives (eq 3).4 The method finds use in the carbonylative cyclization of substituted aminopyridines to prepare pyrido[2,1-b]quinazolines (eq 4).5

Enol trifluoromethanesulfonates (triflates) and aryl triflates undergo efficient Pd-catalyzed couplings with olefinic substrates to afford dienes,6 carbonylations with CO to afford carboxylic acids,7 and reductions with trialkylammonium formates to afford alkenes.8 b-Hydroxy enol triflates undergo a carbonylative cyclization with Tetrakis(triphenylphosphine)palladium(0) and tri-n-butylamine under a CO atmosphere to generate a,b-butenolides in good yields (eq 5).9 Likewise, treatment of the enol triflate (7) with tri-n-butylamine, Palladium(II) Acetate, and 1,1-Bis(diphenylphosphino)ferrocene (dppf) under a CO atmosphere in aqueous DMF leads to the diacid (8) in 42% isolated yield (eq 6).10

Enol triflates, as well as aryl triflates and aryl fluoroalkanesulfonates,11 are selectively deoxygenated to the corresponding alkenes and arenes using the combination of Formic Acid and tri-n-butylamine in the presence of a catalytic amount of Bis(triphenylphosphine)palladium(II) Acetate in DMF (eq 7).8,12 In the case of highly hindered aryl triflates, use of 1,3-Bis(diphenylphosphino)propane (dppp) as a ligand tends to increase the yields of the desired arenes (eq 8).13

Aryl iodides react with 4-hydroxy-2-alkynoates in the presence of formic acid, tri-n-butylamine, and a palladium(II) catalyst in DMF to generate highly substituted a,b-butenolides via a one-pot hydroarylation/cyclization sequence (eq 9).14 The regioselectivity is controlled by steric constraints and metal-coordination factors involved during the Pd-C bond forming step. 4-Hydroxy-2-alkynoates undergo a reductive cyclization under similar conditions to afford butenolides in high yields (eq 10). Use of a large excess of formic acid leads to fully saturated lactones.

Heck-type reactions,15 involving the coupling of aryl halides and substituted alkenes to produce arylated alkene derivatives, can be accomplished using tri-n-butylamine as a base and a variety of palladium catalysts. The arylation of conjugated alkenes is catalyzed efficiently using the clay-anchored catalyst montmorillonite-ethylsilyldiphenylphosphinepalladium(II) chloride, in tri-n-butylamine at 100 °C to produce the trans-alkenic products selectively in excellent yields (eq 11).16 The cross coupling between aryl iodides and vinyl acetates to generate trans-stilbene derivatives is made possible with the use of the clay-anchored catalyst and tri-n-butylamine (eq 12).17

C-Glycosides are assembled using a palladium-mediated glycal-aglycon coupling sequence.18 Reaction of furanoid glycals with aryl halides in the presence of a catalytic amount of palladium acetate and tri-n-butylamine in DMF at room temperature results in high yields of C-furanosyl products, usually with a high degree of regio- and stereocontrol (eq 13).19 Good regio- and stereocontrol is found with 3-deoxypyranoid glycals under similar reaction conditions.20

The reduction of enantiomerically enriched phosphine oxides is accomplished using an excess of Trichlorosilane to afford phosphines with retention of configuration. However, the use of strong organic amine bases (pKb < ca. 5), such as Triethylamine, leads to phosphines with inversion of configuration, while the use of weak amine bases (pKb > ca. 7) results in retention of configuration.21 Treatment of enantiomerically enriched bisphosphine oxides with trichlorosilane and tri-n-butylamine22 (or triethylamine)23 in acetonitrile at 70 °C affords enantiopure phosphines in high yields (eq 14).21 The combination of tri-n-butylamine and acetonitrile ensures a homogeneous reaction mixture and prevents incomplete reduction and the production of meso-bisphosphines.

The high boiling point of tri-n-butylamine makes it an attractive base in reactions requiring high temperatures. For example, intramolecular ketene-alkene [2 + 2] cycloaddition is accomplished by slowly adding the acid chloride (9) to an excess of tri-n-butylamine in refluxing toluene to afford the tricyclic ketone (10) in 71-87% yield (eq 15).24 The elimination of the anomeric methoxy group is catalyzed by the tri-n-butylammonium chloride produced in the reaction.

Thermolysis of ethyl alkynyl ethers in the presence of 10 equiv of tri-n-butylamine in refluxing xylenes (137-144 °C) leads to good yields of macrocyclic lactones. The tri-n-butylamine facilitates the cyclization step involving the ketene intermediate produced by a retro-ene reaction (eq 16).25


The enantioselective hydrodechlorination of L-5,5-dichloro-1-(chlorocarbonyl)proline esters (11) to afford L-proline in 78% yield is achieved using a 10% Palladium on Carbon catalyst and 180 bar of H2 pressure in tri-n-butylamine at 50 °C. The tri-n-butylammonium chloride produced in the reaction remains in solution and the catalyst retains its full activity (eq 17).26 When other tertiary amine bases such as triethylamine are used, the trialkylammonium salt produced tends to precipitate onto the catalyst surface. As a result, the catalyst becomes deactivated and the overall yield is reduced.

1. (a) Roush, W. R. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich, CT, 1990; Vol. 2, pp 91-146. (b) Taber, D. F. Intramolecular Diels-Alder and Alder Ene Reactions; Springer: New York, 1984. (c) Brieger, G.; Bennett, J. N. CRV 1980, 80, 63.
2. Kozikowski, A. P.; Tuckmantel, W. JOC 1991, 56, 2826.
3. (a) Nystrom, J.-E.; McCanna, T. D.; Helquist, P.; Iyer, R. S. TL 1985, 26, 5393; Nystrom, J.-E.; Helquist, P. JOC 1989, 54, 4695. (b) See also: Corey, E. J.; Glass, R. S. JACS 1967, 89, 2600.
4. Valentine, D., Jr.; Tilley, J. W.; LeMahieu, R. A. JOC 1981, 46, 4614.
5. Tilley, J. W.; Coffen, D. L.; Schaer, B. H.; Lind, J. JOC 1987, 52, 2469.
6. Cacchi, S.; Morera, E.; Ortar, G. TL 1984, 25, 2271.
7. Cacchi, S.; Morera, E.; Ortar, G. TL 1985, 26, 1109.
8. Cacchi, S.; Morera, E.; Ortar, G. TL 1984, 25, 4821.
9. Crisp, G. T.; Meyer, A. G. JOC 1992, 57, 6972.
10. Murai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. JACS 1988, 110, 1985.
11. Chen, Q.-Y.; He, Y.-B.; Yang, Z.-Y. CC 1986, 1452.
12. Dolle, R. E.; Schmidt, S. J.; Kruse, L. I. TL 1988, 29, 1581.
13. Saa, J. M.; Dopico, M.; Martorell, G.; Garcia-Raso, A. JOC 1990, 55, 991.
14. (a) Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.; Pietroni, B. T 1988, 44, 481. (b) Arcadi, A.; Cacchi, S.; Marinelli, F.; Misiti, D. TL 1988, 29, 1457.
15. (a) Daves, G. D., Jr.; Hallberg, A. CRV 1989, 89, 1433. (b) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic: New York, 1985.
16. (a) Choudary, B. M.; Sarma, R. M.; Rao, K. K. T 1992, 48, 719. (b) Choudary, B. M.; Sarma, R. M.; Rao, K. K. TL 1990, 31, 5781. (c) For a palladium-graphite catalyst, see: Savoia, D.; Trombini, C.; Umani-Ronchi, A.; Verardo, G. CC 1981, 541.
17. Choudary, B. M.; Sarma, R. M. TL 1990, 31, 1495.
18. For a review, see: Daves, G. D., Jr. ACR 1990, 23, 201.
19. Farr, R. N.; Outten, R. A.; Cheng, J. C.-Y.; Daves, G. D., Jr. OM 1990, 9, 3151, and references cited within.
20. Kwok, D.-I.; Farr, R. N.; Daves, G. D., Jr. JOC 1991, 56, 3711.
21. Naumann, K.; Zon, G.; Mislow, K. JACS 1969, 91, 7012.
22. (a) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J. JACS 1977, 99, 5946. (b) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D.; Weinkauff, D. J. JACS 1975, 97, 2567.
23. (a) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori, R. JOC 1986, 51, 629. (b) Takaya, H.; Akutagawa, S.; Noyori, R. OSC 1993, 8, 57. (c) For other examples, see; Juge, S.; Genet, J. P. TL 1989, 30, 2783; Schmid, R.; Foricher, J.; Cereghetti, M.; Schonholzer, P. HCA 1991, 74, 370, and references cited within.
24. (a) Corey, E. J.; Kang, M.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. JACS 1988, 110, 649. (b) Corey, E. J.; Gavai, A. V. TL 1988, 29, 3201.
25. Liang, L.; Ramaseshan, M.; MaGee, D. I. T 1993, 49, 2159.
26. Drauz, K.; Kleemann, A.; Martens, J.; Scherberich, P.; Effenberger, F. JOC 1986, 51, 3494; see also: Blaser, H.-U.; Boyer, S. K.; Pittelkow, U. TA 1991, 2, 721.

Kirk L. Sorgi

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA

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