Org. Synth. 1985, 63, 183
DOI: 10.15227/orgsyn.063.0183
[(E)-2-Butenedioic acid, ethyl 1,1-dimethylethyl ester]
Submitted by B. Neises and Wolfgang Steglich1.
Checked by Cheryl Stubbs and Robert V. Stevens.
1. Procedure
Caution! Dicyclohexylcarbodiimide is a potent allergen and should be handled with gloves.
A 500-mL, one-necked flask equipped with a calcium chloride drying tube is charged with 28.83 g (0.20 mol) of monoethyl fumarate (Note 1), 200 mL of dry dichloromethane (Note 2), 44.47 g (0.60 mol) of tert-butyl alcohol (Note 3), and 2.00 g (0.016 mol) of 4-dimethylaminopyridine (Note 4). The solution is stirred and cooled in an ice bath to 0°C while 45.59 g (0.22 mol) of dicyclohexylcarbodiimide (Note 5) is added over a 5-min period. After a further 5 min at 0°C the ice bath is removed and the dark-brown reaction mixture is stirred for 3 hr at room temperature. The dicyclohexylurea that has precipitated is removed by filtration through a fritted Büchner funnel (G3), and the filtrate is washed with two 50-mL portions of 0.5 N hydrochloric acid (Note 6) and two 50-mL portions of saturated sodium bicarbonate solution. During this procedure some additional dicyclohexylurea is precipitated, which is removed by filtration of both layers to facilitate their separation. The organic solution is dried over anhydrous sodium sulfate and concentrated with a rotary evaporator. The concentrate is distilled under reduced pressure, affording, after a small forerun, 30.5–32.5 (76–81%) of tert-butyl ethyl fumarate, bp 105–107°C (12 mm) (Note 7).
2. Notes
1. Monoethyl fumarate was purchased from Ega-Chemie, D-7924 Steinheim, Germany.
2. Dichloromethane was freshly distilled over P4O10.
3. tert-Butyl alcohol was purchased from E. Merck, D-6100 Darmstadt, Germany, and used without further purification.
4. 4-Dimethylaminopyridine was obtained from Schering AG, D-1000 Berlin, Germany. 4-Pyrrolidinopyridine, which is equally well suited as a catalyst in this reaction may be purchased from Ega-Chemie, D-7924 Steinheim, Germany.
5. Dicyclohexylcarbodiimide was freshly distilled with a Kugelrohr apparatus (Büchi GKR-50), bp 135–140°C (0.5 mm). It may be either added in crystalline form or dissolved in 50 mL of dry dichloromethane.
6. For esters more sensitive to acids, the use of concentrated aqueous citric acid solution is advisable.
7. The proton magnetic resonance spectrum of the product in chloroform-d shows the following absorptions: δ 1.30 [t, 3 H, J = 7.5, CH3CH2), 1.50 (s, 9 H, C(CH3)3], 4.23 (q, 2 H, J = 7.5, CH3CH2), 6.77 (s, 2 H, CH=CH). tert-Butyl ethyl fumarate may be easily converted into ethyl fumarate by alkaline hydrolysis.
3. Discussion
This procedure offers a convenient method for the esterification of carboxylic acids with alcohols2,3,4 and thiols2 under mild conditions. Its success depends on the high efficiency of 4-dialkylaminopyridines as nucleophilic catalysts in group transfer reactions.5 The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacidic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols, including polyols,2,4,6 α-hydroxycarboxylic acid esters,7 and even very acid labile alcohols such as vitamin A.8 It has also been used for the esterification of urethane-protected α-amino acids with polymeric supports carrying hydroxy groups.9 In this case, however, some racemization of the amino acid is observed because of 2-alkoxyoxazolin-5-one formation.10 Racemization can be decreased by shortening the coupling time10 or completely avoided by working with N-(p-nitrophenylsulfenyl)amino acids.11
With increasing steric hindrance, the rate of esterification is decreased and the formation of N-acylureas may become a serious side reaction. This is indicated by the decrease in yield in the esterification of 2,5-cyclohexadiene-1-carboxylic acid with different alcohols: MeOH (95%), EtOH (84%), i-PrOH (75%), c-C6H11OH (65%), t-BuOH (65%).12 Diminished acidity because of the influence of electron-donating substituents in aromatic carboxylic acids can also lead to low yields.
The dicyclohexylcarbodiimide/4-dialkylaminopyridine method is also well suited to the synthesis of a wide variety of thiol esters.2,13
4-Dimethylaminopyridine also catalyzes the formation of esters and thiol esters in the reaction of mixed carboxylic anhydrides14 or 2,4,6-trinitrophenyl esters15 with alcohols and thiols. 1-Acyl-4-benzylidene-1,4-dihydropyridines have been introduced recently as promising reagents for the synthesis of sterically hindered esters.16 The current methods available for ester and thiol ester formation have been reviewed recently by Haslam.17

References and Notes
  1. Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Strasse 1. D-5300 Bonn, Germany.
  2. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522; Angew. Chem. 1978, 90, 556.
  3. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475.
  4. Ziegler, F. E.; Berger, G. D. Synth. Commun. 1979, 9, 539.
  5. Steglich, W.; Höfle, G. Angew. Chem., Inter. Ed. Engl. 1969, 8, 981; Angew. Chem. 1969, 81, 1001; Höfle, G.; Steglich, W. Synthesis 1972, 619; Höfle, G.; Steglich, W.; Vorbrüggen, H. Angew. Chem., Inter. Ed. Engl. 1978, 17, 569; Angew. Chem. 1978, 90, 602; Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34, 2069.
  6. Zinic, M.; Bosnic-Kasnar, B.; Kolbah, D. Tetrahedron Lett. 1980, 1365.
  7. Gilon, Ch.; Klausner, Y.; Hassner, A. Tetrahedron Lett. 1979, 3811.
  8. Niewöhner, U.; Steglich, W., unpublished results.
  9. Wang, S.-S.; Yang, C. C.; Kulesha, I. D.; Sonenberg, M.; Merrifield, R. B. Int. J. Pept. Protein Res. 1974, 6, 103; Wang, S.-S.; Kulesha, I. D. J. Org. Chem. 1975, 40, 1227; Chang, C.-D.; Meienhofer, J. Int. J. Pept. Protein Res. 1978, 11, 246.
  10. Atherton, E.; Benoiton, N. L.; Brown, E.; Sheppard, R. C.; Williams, B. J. J. Chem. Soc., Chem. Commun. 1981, 336.
  11. Neises, B.; Andries, Th.; Steglich, W., publication in preparation.
  12. Neises, B.; Steglich, W., unpublished results.
  13. Neises, B.; Steglich, W.; van Ree, T. S. Afr. J. Chem. 1981, 34, 58.
  14. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.; Bull. Chem. Soc. Jpn. 1979, 52, 1989; Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943.
  15. Kim, S.; Yang, S. Synth. Commun. 1981, 11, 121; Kim, S.; Yang, S. Chem. Lett. 1981, 133.
  16. Anders, E.; Will, W. Synthesis 1980, 485.
  17. Haslam, E. Tetrahedron 1980, 36, 2409.

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)


hydrochloric acid (7647-01-0)

diethyl ether (60-29-7)

acetonitrile (75-05-8)

citric acid (77-92-9)

sodium bicarbonate (144-55-8)

sodium sulfate (7757-82-6)

ethyl fumarate,
monoethyl fumarate (2459-05-4)

dichloromethane (75-09-2)

Tetrahydrofuran (109-99-9)

2,5-Cyclohexadiene-1-carboxylic acid (4794-04-1)

tert-butyl alcohol (75-65-0)

dicyclohexylcarbodiimide (538-75-0)

dicyclohexylurea (2387-23-7)

4-dimethylaminopyridine (1122-58-3)

4-Pyrrolidinopyridine (2456-81-7)

tert-Butyl ethyl fumarate,
(E)-2-Butenedioic acid, ethyl 1,1-dimethylethyl ester (100922-16-5)