[75-50-3]  · C3H9N  · Trimethylamine  · (MW 59.13)

(low boiling tertiary amine used as base in dehydrochlorinations, nucleophilic substitutions, 1,4-additions, and aldol-type condensations)

Physical Data: bp 2.9 °C; mp -117 °C; d 0.656 g cm-3.

Solubility: sol alcohols, H2O, ethers, benzene, toluene, xylene, ethylbenzene, CHCl3.

Form Supplied in: anhydrous trimethylamine is supplied as liquefied gas in steel cylinders; 23-25% aqueous solutions are available.

Handling, Storage, and Precautions: corrosive; toxic; lachrymator. The vapors are harmful and care should be taken to avoid absorption through the skin. Use in a fume hood.

Dehydrochlorinations: Ketene Generation.

The use of trimethylamine as the base in generating ketenes from 2-arylpropionic acid chlorides allows for selective asymmetric esterifications with a variety of chiral non-racemic a-hydroxy esters.1 Treatment of the acid chloride of racemic ibuprofen with a large excess of trimethylamine in heptane at rt generates the unisolated ketene, which is further reacted with ethyl (S)-lactate at -78 °C to afford, in high diastereo- and enantioselectivity, the corresponding (S,S)-2-arylpropionate (eq 1). The more sterically demanding tertiary amines, such as Triethylamine or Diisopropylethylamine, lead to much lower diastereoselectivities.

Nucleophilic Substitutions.

2-Amino-6-chloropurines react with trimethylamine and b-hydroxypropionitrile in the presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) to generate the corresponding guanines in high yields.2 The mechanism of the overall hydrolysis consists of a series of nucleophilic displacements involving the intermediacy of the 6-trimethylammonium salt and 6-(2-cyanoethoxy) derivatives. Base-induced b-elimination of acrylonitrile from the cyanoethoxy intermediate completes the reaction sequence and leads to guanines in good overall yields (eq 2). Similarly, treatment of O-6-sulfonated guanosines with trimethylamine and alcohols leads to the O-alkylated guanosine derivatives in good yield (eq 3).3 In related chemistry, treatment of triacetyl-2-chloroadenosine with trimethylamine in MeCN at an elevated temperature leads to the 2-(N,N-dimethylamino)adenosine derivative in a near quantitative yield (eq 4). The reaction mechanism involves a chloride ion induced dealkylation of the trimethylammonium salt intermediate.4

Trimethylammonium salt intermediates prepared from chloropyrimidines and chloroquinazolines react efficiently with Tetraethylammonium Cyanide to produce the heterocyclic nitriles in excellent yields.5 Trimethylamine in ether (or toluene) reacts with 3-chloro-2-cyclopentenone to produce the trimethylammonium salt derivative in 90% yield. Subsequent treatment with an aqueous solution of Potassium Cyanide generates the 3-cyanocyclopentenone derivative in 79% yield (eq 5).6

Treatment of cyclic phosphotriesters with an amine, for example anhydrous trimethylamine, and a slight excess of Trimethylsilyl Trifluoromethanesulfonate at 0 °C effects nucleophilic ring opening to afford phosphate diesters in good yields (eq 6).7


Trimethylamine (25% aqueous solution) adds in a 1,4-fashion to alkyl propiolates with accompanying hydrolysis of the ester group to generate the (E)-(carboxyvinyl)trimethylammonium betaine as the sole isomer (eq 7).8 In contrast, addition of trimethylammonium tetrafluoroborate to methyl propiolate in refluxing MeOH results in a 57:43 ratio of (E)- and (Z)-b-trimethylammonium acrylate esters (eq 8).9 Remarkable stereochemical control is encountered with other alkynes containing electron-withdrawing groups. Trimethylammonium tetrafluoroborate adds selectively to 3-butyn-2-one to generate the (E)-isomer exclusively, while propiolonitrile, under identical reaction conditions, affords only the (Z)-isomer (eq 9).9

Aldol-Type Condensations.

a-Ketoaldehyde hemiacetals combine with nitroalkanes in the presence of methanolic trimethylamine to produce a-diketones in high yields. This variation of the Henry nitro-aldol reaction involves the addition of the nitroalkane to the aldehyde followed by base-induced b-elimination of nitrite (eq 10).10

Conversions of Hydrazones to Vinyl Halides.

Treatment of hydrazones with iodine in the presence of a tertiary amine leads to vinyl iodides in good yields.11 In reactions where isomeric vinyl iodides may be produced, the steric nature of the tertiary amine seems to exert a minor influence on the regiochemical outcome (eq 11).12

1. Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grabowski, E. J. J. JACS 1989, 111, 7650.
2. (a) Ashwell, M.; Bleasdale, C.; Golding, B. T.; O'Neill, I. K. CC 1990, 955. (b) See also: Reitz, A. B.; Rebarchak, M. C. Nucleosides Nucleotides 1992, 11, 1115.
3. Gaffney, B. L.; Jones, R. A. TL 1982, 23, 2253.
4. Robins, M. J.; Uznanski, B. CJC 1981, 59, 2601.
5. Hermann, K.; Simchen, G. LA 1981, 333.
6. Zimmerman, H. E.; Pasteris, R. J. JOC 1980, 45, 4864.
7. (a) Gadek, T. R. TL 1989, 30, 915. (b) See also: Chandrakamur, N. S.; Hajdu, J. JOC 1982, 47, 2144.
8. (a) Vogel, D. E.; Buchi, G. H. OS 1987, 66, 29; OSC 1993, 8, 536. (b) Buchi, G. H.; Vogel, D. E. JOC 1983, 48, 5406.
9. Jung, M. E.; Buszek, K. R. JACS 1988, 110, 3965.
10. Petrakis, K. S.; Batu, G.; Fried, J. TL 1983, 24, 3063.
11. Barton, D. H. R.; O'Brien, R. E.; Sternhell, S. JCS 1962, 470.
12. (a) Paquette, L. A.; Annis, G. D.; Schostarez, H. JACS 1982, 104, 6646. (b) See also: Mori, K.; Tsuji, M. T 1988, 44, 2835.

Kirk L. Sorgi

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

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