Triethylamine

Et3N

[121-44-8]  · C6H15N  · Triethylamine  · (MW 101.22)

(tertiary amine base used in oxidation, dehydrohalogenation, and substitution reactions)

Alternate Name: TEA.

Physical Data: bp 88.8 °C; mp -115 °C; d 0.726 g cm-3.

Solubility: sol most organic solvents.

Purification: dried over CaSO4, LiAlH4, 4&AAring; sieves, CaH2, KOH, or K2CO3, then distilled from BaO, sodium, P2O5 or CaH2.1

Handling, Storage, and Precautions: is a corrosive and flammable liquid. Bottles of triethylamine 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.

Introduction.

The most widely used organic amine base in synthetic organic chemistry is probably triethylamine. Its popularity stems from availability and low cost, along with ease of removal by distillation due to a mid-range boiling point (88.8 °C). Also, the hydrochloride and hydrobromide salts are somewhat insoluble in organic solvents, such as diethyl ether, and may be removed by simple filtration. Triethylamine finds wide use in oxidations, reductions, eliminations, substitutions, and addition reactions. There follows a brief compilation of the uses of triethylamine.

Oxidations.

The addition of triethylamine and Acetic Anhydride during the workup of the ozonolysis of cycloalkenes allows for the selective differentiation of the oxidized termini.2 Ozonolysis of cycloalkenes in MeOH buffered with NaHCO3 generates the intermediate a-methoxy hydroperoxide aldehyde which dehydrates upon exposure to acetic anhydride and triethylamine to produce aldehyde esters (eq 1). Intermediate peroxy acetals are produced with the addition of p-Toluenesulfonic Acid to the ozonolysis reaction and similarly dehydrate with triethylamine and acetic anhydride to afford acetal esters. Omitting the acetic anhydride and triethylamine leads to acetal aldehydes under reduction conditions (eq 2).

In the Swern oxidation3 of alcohols to ketones and aldehydes, employing Dimethyl Sulfoxide-Oxalyl Chloride, triethylamine is usually the amine base utilized in the basification step of the reaction. Mechanistically, the basification step includes deprotonation of the methyl group of the alkoxysulfonium salt intermediate to form an ylide which then yields the carbonyl compound via an intramolecular proton transfer (eq 3).3b A similar mechanism is encountered with N-Chlorosuccinimide-Dimethyl Sulfide and TEA.4

The steric nature of the amine affects the overall performance of the oxidations. In comparative studies involving oxidations with Dimethyl Sulfoxide-Trifluoroacetic Anhydride5 and Dimethyl Sulfoxide-Methanesulfonic Anhydride6 the sterically hindered Diisopropylethylamine was found to be superior to TEA (eq 4).3b

The treatment of vicinal diols with an excess of DMSO/trifluoroacetic anhydride followed by basification with TEA results in complete oxidation to a-diketones in good yields (eq 5).7

Eliminations.

Dehydrohalogenation of alkyl halides to generate alkenes is normally carried out using alcoholic Potassium Hydroxide; however triethylamine has some utility.8 For example, bridgehead enones are produced efficiently by treatment of b-bromo ketones with 2 equiv of TEA at 0 °C. The highly reactive enones are not isolated (due to their instability) but can be subsequently trapped with a variety of dienes in a Diels-Alder reaction (eq 6).9

Triethylamine accomplishes the dehydrobromination of a,a-dibromo sulfones using TEA in CH2Cl2 to afford a,b-unsaturated bromomethyl sulfones in good yields. Further treatment of the sulfones with Potassium t-Butoxide induces a Ramberg-Bäcklund-like reaction and leads to 1,3-dienes in moderate to good yields (eq 7).10

Chloroalkylidene malonates are converted via a decarboxylation-elimination reaction to alkynic esters by treatment with triethylamine at 90 °C (eq 8).11 Likewise, triethylamine is the preferred base for the conversion of erythro-2,3-dibromobutanoic acid to cis-1-bromopropene (eq 9). Pyridine, Na2CO3, or NaHCO3 in DMF lead to poor yields of the bromopropene.12

Exposure of 2,3-dibromo-3,3-difluoropropionyl chloride to ca. 1 equiv of triethylamine in CH2Cl2 at 0 °C induces dehydrobromination and leads to 2-bromo-3,3-difluoroacryloyl chloride in 63% yield (eq 10).13 Under these reaction conditions, the ketene product of dehydrochlorination is not observed.

Dehydrohalogenation of acid chlorides with a tertiary amine is the typical method for the preparation of ketenes,14 most likely involving an acylammonium intermediate.15 Other methods are available which involve carboxyl group-activating agents and tertiary amine bases. TEA-generated ketenes find wide application in organic synthesis, in particular in the synthesis of b-lactams16 using stereo- and enantioselective ketene-imine cycloaddition methodology. For example, the diastereoselective Staudinger [2 + 2] ketene-imine cycloaddition reaction17 between chiral nonracemic oxazolidinone-N-acetyl chlorides and imines18 generates b-lactams in high yields and with good stereocontrol (eq 11).19

The dehydration of primary nitroalkanes and the dehydrochlorination of chloroximes allows for the preparation of highly reactive nitrile oxides (eq 12). The nitrile oxides, which are not isolated, undergo facile [3 + 2] cycloaddition reactions20 with a variety of trapping agents. Subjecting nitroalkanes to 2 equiv of Phenyl Isocyanate and a catalytic amount of triethylamine21 effects dehydration to form nitrile oxides (eq 13).22 Alternatively, treatment of oximes with aqueous Sodium Hypochlorite and triethylamine in CH2Cl2 efficiently produces the nitrile oxides (eq 14).23

Substitutions.

Triethylamine finds use as a proton scavenger in palladium-catalyzed coupling reactions involving aryl, alkenyl, allyl, and alkyl derivatives.24 The palladium-catalyzed coupling of vinyl halides with alkenes (Heck reaction) is an invaluable method for forming carbon-carbon bonds.25 The elements of an intramolecular Heck reaction and the coupling of allylic alcohols with vinyl halides to afford aldehydes or ketones have been combined to generate moderate to excellent yields of cyclized products (eq 15).26

In an asymmetric variation of the Heck reaction, triethylamine is used in combination with (R)-2,2-Bis(diphenylphosphino)-1,1-binaphthyl ((R)-BINAP) for preparing enantiomerically enriched 2-aryl-2,3-dihydrofurans from aryl triflates.27 Though TEA resulted in the highest degree of diastereoselectivity, the base 1,8-Bis(dimethylamino)naphthalene (proton sponge) was found to be superior in regards to enantiomeric purity (eq 16).28,29

Triethylamine also finds use in the enolboronation of various carbonyl compounds using dialkylboron halides.30 These boron enolates are valuable in the stereocontrolled aldol reaction. Proper choice of boron reagent, reaction solvent, reaction temperature, and tertiary amine base influences the enolate geometry of ketones31 and esters.32 The use of the sterically demanding dialkylboron halides, such as dicyclohexylboron chloride (Chx2BCl), with triethylamine favors formation of the (E)-enol borinates, while dialkylboron triflates or dialkylboron halides, such as B-chloro-9-BBN, with diisopropylethylamine in ether at -78 °C favor the (Z)-enol borinates (eq 17).31a,b For similar complementary methodologies for generating both the (E)- and (Z)-boron enolates of esters, see Diisopropylethylamine.

The asymmetric aldol addition involving N-acyloxazolidinones and aldehydes can be carried out with high stereoselectivity utilizing Tin(II) Trifluoromethanesulfonate and triethylamine. Treatment of N-(isothiocyanoacetyl)-2-oxazolidinones and aldehydes with tin(II) triflate and TEA at -78 °C in THF leads to high yields of aldol products with high diastereoselectivity (eq 18).33

The regioselective synthesis of silyl enol ethers involves the trapping of the enolate anion of ketones and esters under kinetic or thermodynamic conditions.34 Treatment of the unsymmetrical ketone 2-methylcyclohexanone with TEA and Chlorotrimethylsilane in DMF affords a 22:78 mixture of the kinetic and thermodynamic trimethylsilyl enol ethers. Using Lithium Diisopropylamide in DME under kinetic control leads to a >99:1 mixture of the kinetic and thermodynamic silyl enol ethers in 74% yield (eq 19).35 Likewise, treatment of acetone with chlorotrimethylsilane, TEA, and anhydrous Sodium Iodide in acetonitrile leads to acetone trimethylsilyl enol ether in good yield.36

The mixture of TEA and Zinc Chloride is effective for converting a,b-unsaturated ketones and aldehydes into the corresponding silyl enol ethers. The Danishefsky-Kitahara diene is prepared in 68% yield by treatment of 4-methoxy-3-buten-2-one with an excess of TEA and TMSCl in the presence of a catalytic amount of anhydrous ZnCl2 in benzene (eq 20).37 Under similar reaction conditions, crotonaldehyde and 3-methylcrotonaldehyde are also converted into their corresponding enol ethers. 3-Methylcrotonaldehyde leads to an 80/20 mixture of (E/Z) dienes, while crotonaldehyde yields the (E)-silyl enol ether exclusively (eq 21).38

Triethylamine in combination with Triethylsilyl Perchlorate is somewhat selective in the generation of the (Z)-silylketene acetal of isopropyl propionate (eq 22)39 (see 2,2,6,6-Tetramethylpiperidine for a comparison of other bases). Triethylamine and t-Butyldimethylsilyl Trifluoromethanesulfonate (TBDMSOTf) are quite effective in preparing silyl enol ethers from sterically hindered ketones and lactones (eq 23).40

Triethylamine is the base of choice in neutralizing the acids liberated in preparing (1) diazo ketones from acid chlorides and Diazomethane, (2) mixed anhydrides from carboxylic acids and alkyl haloformates, and (3) esters from carboxylic acids and alkyl halides, such as phenacyl bromide.41

Triethylamine is particularly useful as a proton scavenger in the field of protective group chemistry.42 For just a few examples: alcohols have been protected as substituted methyl ethers with such alkylating agents as Chloromethyl Methyl Sulfide43 and t-Butyl Chloromethyl Ether44 using TEA as a base. Primary alcohols can be selectively silylated in the presence of secondary and tertiary alcohols using t-Butyldiphenylchlorosilane with TEA and a catalytic amount of 4-Dimethylaminopyridine (eq 24).45 The selective benzoylation of diols can be achieved using 1-(benzoyloxy)benzotriazole (BOBT) and TEA in CH2Cl2 at room temperature (eq 25).46 Diols, in particular 1,2- and 1,3-diols, react with Di-t-butyldichlorosilane in the presence of TEA and a variety of silyl transfer agents to afford the di-t-butylsilylene derivatives in good yields (eq 26).47

Carbamates are cleaved easily to alcohols upon exposure to Trichlorosilane and TEA48 and carboxylic acids are conveniently esterified using equimolar amounts of alkyl chloroformates with triethylamine and a catalytic amount of 4-Dimethylaminopyridine.49 TEA is an effective base for the alkylation (protection) of carboxylic acids with Chloroacetonitrile to produce cyanomethyl esters.50 Primary amines with pKa values of 10-11 react with 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene in the presence of TEA at rt to afford the disilylazacyclopentane derivatives in high yields (eq 27).51 Amines with lower pKa values require n-Butyllithium as the base or can be protected via a Zinc Iodide-catalyzed trans-silylation with 1,1,4,4-tetramethyl-1,4-bis(N,N-dimethylamino)disilethylene (eq 28).52

Triethylamine and other tertiary amines find utility in the derivatization of amino acids as well as coupling reactions to prepare peptides.53 The basicity and steric nature of the tertiary amine utilized during the coupling reaction influences the degree of racemization.54

Related Reagents.

Palladium-Triethylamine-Formic Acid.


1. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988; p 296.
2. (a) Schreiber, S. L.; Claus, R. E.; Reagan, J. TL 1982, 23, 3867. (b) Claus, R. E.; Schreiber, S. L. OSC 1990, 7, 168. (c) See also: Bailey, P. S. Ozonation in Organic Chemistry; Academic: New York, 1978; Vol. 1.
3. (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. JOC 1978, 43, 2480. (b) Omura, K.; Swern, D. T 1978, 34, 1651. (c) Mancuso, A. J.; Swern, D. S 1981, 165. (d) For other examples of Swern-like oxidations, see: Hudlicky, M. Oxidations in Organic Chemistry; American Chemical Society: Washington, 1990.
4. Corey, E. J.; Kim, C. U. JACS 1972, 94, 7586.
5. Huang, S. L.; Omura, K.; Swern, D. S 1978, 297.
6. Albright, J. D. JOC 1974, 39, 1977.
7. Amon, C. M.; Banwell, M. G.; Gravatt, G. L. JOC 1987, 52, 4851.
8. For examples, see: Fieser, L. F.; Fieser, M. FF 1967, 1, 1201.
9. See (a) Kraus, G. A.; Hon, Y.-S. JOC 1986, 51, 116. (b) Kraus, G. A.; Hon, Y.-S.; Sy, J.; Raggon, J. JOC 1988, 53, 1397, and references cited therein.
10. Block, E.; Aslam, M. JACS 1983, 105, 6164 and 6165.
11. Hormi, O. OSC 1993, 8, 247.
12. Fuller, C. E.; Walker, D. G. JOC 1991, 56, 4066.
13. Brahms, J. C.; Dailey, W. P. JOC 1991, 56, 900.
14. Koppel, G. A. In Small Ring Heterocycles; Hassner, A., Ed.; Wiley: New York, 1983.
15. Wasserman, H. H.; Piper, J. U.; Dehmlow, E. V. JOC 1973, 38, 1451 and references cited therein.
16. Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of b-Lactams; Georg, G. I. Ed.; VCH: New York, 1992; pp 295-368.
17. (a) Thomas, R. C. TL 1989, 30, 5239. (b) Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. PAC 1987, 59, 485.
18. (a) Evans, D. A.; Sjogren, E. B. TL 1985, 26, 3783. (b) Evans, D. A.; Sjogren, E. B. TL 1985, 26, 3787. (c) Bodurow, C. C.; Boyer, B. D.; Brennan, J.; Bunnell, C. A.; Burks, J. E.; Carr, M. A.; Doecke, C. W.; Eckrich, T. M.; Fisher, J. W.; Gardner, J. P.; Graves, B. J.; Hines, P.; Hoying, R. C.; Jackson, B. G.; Kinnick, M. D.; Kochert, C. D.; Lewis, J. S.; Luke, W. D.; Moore, L. L.; Morin, J. M., Jr.; Nist, R. L.; Prather, D. E.; Sparks, D. L.; Vladuchick, W. C. TL 1989, 30, 2321.
19. Boger, D. L.; Myers, J. B., Jr. JOC 1991, 56, 5385.
20. Curran, D. P. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich, CT, 1988; Vol. 1, pp 129-189.
21. Mukaiyama, T.; Hoshino, T. JACS 1960, 82, 5339.
22. (a) Kozikowski, A. P.; Stein, P. D. JACS 1982, 104, 4023. (b) Kozikowski, A. P. ACR 1984, 17, 410.
23. Lee, G. A. S 1982, 508.
24. (a) Daves, G. D., Jr.; Hallberg, A. CRV 1989, 89, 1433. (b) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic: New York, 1985.
25. Heck, R. F. OR 1982, 27, 345.
26. (a) Gaudin, J.-M. TL 1991, 32, 6113, and references cited therein. (b) See also: Shi, L.; Narula, C. K.; Mak, K. T.; Kao, L.; Xu, Y.; Heck, R. F. JOC 1983, 48, 3894.
27. Ozawa, F.; Kubo, A.; Hayashi, T. JACS 1991, 113, 1417.
28. Ozawa, F.; Kubo, A.; Hayashi, T. TL 1992, 33, 1485.
29. For an intramolecular Heck-type reaction, see: (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. JOC 1989, 54, 4738. (b) Mori, M.; Kaneta, N.; Shibasaki, M. JOC 1991, 56, 3486.
30. Brown, H. C.; Ganesan, K.; Dhar, R. K. JOC 1992, 57, 3767.
31. (a) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. JACS 1989, 111, 3441. (b) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. JOC 1992, 57, 499 and 2716. (c) Enders, D.; Lohray, B. B. AG(E) 1988, 27, 581. (d) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. JACS 1981, 103, 3099. (e) Van Horn, D. E.; Masamune, S. TL 1979, 2229. (f) Evans, D. A.; Vogel, E.; Nelson, J. V. JACS 1979, 101, 6120. (g) Paterson, I.; Osborne, S. TL 1990, 31, 2213. (h) For sulfenylation and selenenylation of enol borinates, see: Paterson, I.; Osborne, S. SL 1991, 145.
32. (a) Corey, E. J.; Lee, D.-H. JACS 1991, 113, 4026. (b) Corey, E. J.; Kim, S. S. JACS 1990, 112, 4976. (c) Hirama, M.; Masamune, S. TL 1979, 2225. (d) Gennari, C.; Bernardi, A.; Cardani, S.; Scolastico, C. T 1984, 40, 4059. (e) Otsuka, M.; Yoshida, M.; Kobayashi, S.; Ohno, M. TL 1981, 22, 2109.
33. (a) Lago, M. A.; Samanen, J.; Elliott, J. D. JOC 1992, 57, 3493. (b) Evans, D. A.; Weber, A. E. JACS 1986, 108, 6757. (c) See also: Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. TL 1987, 28, 39 and Iseki, K.; Oishi, S.; Taguchi, T.; Kobayashi, Y. TL 1993, 34, 8147.
34. (a) Colvin, E. W. Silicon in Organic Synthesis; Butterworths: London, 1981; Chapter 17. (b) Rasmussen, J. K. S 1977, 91. (c) Fleming, I. C 1980, 34, 265. (d) Brownbridge, P. S 1983, 1 and 85. (e) Taylor, R. J. K. S 1985, 364.
35. (a) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. JOC 1969, 34, 2324. (b) Fleming, I.; Paterson, I. S 1979, 736. (c) Reetz, M. T.; Chatzhosifidis, I.; Hubner, F.; Heimbach, H. OSC 1990, 7, 424. (d) Jung, M. E.; McCombs, C. A. OS 1978, 58, 163; OSC 1988, 6, 445.
36. Walshe, N. D. A.; Goodwin, G. B. T.; Smith, G. C.; Woodward, F. E. OS 1987, 65, 1; OSC 1993, 8, 1.
37. (a) Danishefsky, S.; Kitahara, T. JACS 1974, 96, 7807. (b) Danishefsky, S.; Kitahara, T.; Schuda, P. F. OSC 1990, 7, 312.
38. Gaonac'h, O.; Maddaluno, J.; Chauvin, J.; Duhamel, L. JOC 1991, 56, 4045.
39. Wilcox, C. S.; Babston, R. E. TL 1984, 25, 699.
40. Mander, L. N.; Sethi, S. P. TL 1984, 25, 5953.
41. For examples, see: Fieser, L. F.; Fieser, M. FF 1967, 1, 1198.
42. For numerous references, see: Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
43. Suzuki, K.; Inanaga, J.; Yamaguchi, M. CL 1979, 1277.
44. Pinnick, H. W.; Lajis, N. H. JOC 1978, 43, 3964.
45. (a) Chaudhary, S. K.; Hernandez, O. TL 1979, 99. (b) See also: Guindon, Y.; Yoakim, C.; Bernstein, M. A.; Morton, H. E. TL 1985, 26, 1185. (c) Hanessian, S.; Lavallee, P. CJC 1975, 53, 2975.
46. (a) Soll, R. M.; Seitz, S. P. TL 1987, 28, 5457. (b) See also: Kim, S.; Chang, H.; Kim, W. J. JOC 1985, 50, 1751.
47. Trost, B. M.; Caldwell, C. G.; Murayama, E.; Heissler, D. JOC 1983, 48, 3252.
48. Pirkle, W. H.; Hauske, J. R. JOC 1977, 42, 2781.
49. Kim, S.; Kim, Y. C.; Lee, J. I. TL 1983, 24, 3365.
50. Hugel, H. M.; Bhaskar, K. V.; Longmore, R. W. SC 1992, 22, 693.
51. Djuric, S.; Venit, J.; Magnus, P. TL 1981, 22, 1787.
52. Guggenheim, T. L. TL 1984, 25, 1253.
53. See: (a) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis, 2nd ed.; Springer: Berlin, 1994. (b) Bodanszky, M.; Klausner, Y. S.; Ondetti, M. A. Peptide Synthesis, 2nd ed.; Wiley: New York, 1976.
54. (a) Bodanszky, M.; Bodanszky, A. CC 1967, 591. (b) Williams, A. W.; Young, G. T. JCS(P1) 1972, 1194. (c) Chen, F. M. F.; Lee, Y.; Steinauer, R.; Benoiton, N. L. CJC 1987, 65, 613. (d) Slebioda, M.; St-Amand, M. A.; Chen, F. M. F.; Benoiton, N. L. CJC 1988, 66, 2540.

Kirk L. Sorgi

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



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