(R = Me)

[696-59-3]  · C6H12O3  · 2,5-Dimethoxytetrahydrofuran  · (MW 132.16) (R = Et)

[3320-90-9]  · C8H16O3  · 2,5-Diethoxytetrahydrofuran  · (MW 160.21)

(1,4-butanedial equivalents; useful for constructing heterocycles; the methoxy derivative is more commonly used)

Alternate Name: DMTHF.

Physical Data: R = Me: bp 145-147 °C; d 1.020 g cm-3. R = Et: bp 167-174 °C; d 0.967 g cm-3.

Solubility: practically insol H2O; sol MeOH, Et2O, THF.

Form Supplied in: colorless liquids; commercially available as a mixture of cis and trans isomers.

Preparative Method: by catalytic hydrogenation of 2,5-dialkoxy-2,5-dihydrofurans.1

Handling, Storage, and Precautions: flammable liquids; must be stored in a cool ventilated place. Noxious by inhalation, ingestion, or by contact with skin. Use in a fume hood.

Synthesis of Pyrroles, Pyrrolidines, Carbazoles, and Dihydropyridazines.

2,5-Dimethoxytetrahydrofuran1 is a stable compound which liberates 1,4-butanedial (Succindialdehyde) in acid medium. The latter reacts with primary amines and hydrazines to give pyrrole derivatives according to the Paal-Knorr reaction of 1,4-dicarbonyl compounds (eq 1).2

Thus a large variety of polyfunctionalized aliphatic, aromatic, or heterocyclic derivatives bearing a primary amine function give pyrroles by heating in acetic acid3 in the presence of DMTHF. Interestingly, the same reaction performed in refluxing benzene affords 9-substituted carbazoles4 in a one-pot synthesis (eq 2).

When the reaction with unsubstituted hydrazines is conducted in a saturated solution of HCl in ethanol, formation of either pyrrole (X = NO2) or dihydropyridazine (X = H) (eq 3) occurs.5 A mixture of both heterocyclic compounds6 has also been observed.

The Robinson-Schopf condensation of DMTHF with R-(-)-phenylglycinol in the presence of Potassium Cyanide affords 2-cyano-5-oxazolopyrrolidine (eq 4).7 This synthon constitutes the basis of a general method for the synthesis of enantiomerically pure pyrrolidine8 and pyrrolizidine9 alkaloids.

Substituted Furans.

Either 2- or 2,5-substituted tetrahydrofuran derivatives can be formed by nucleophilic addition of benzotriazole,10 Chlorodiphenylphosphine,11 silyl ethers,12 or Cyanotrimethylsilane13 (eq 5). However, halotrimethylsilanes induce acetal cleavage to give 1,4-dihalo-1,4-dimethoxybutane and not 2,5-dibromotetrahydrofuran (eq 6).14

Acyclic Derivatives.

DMTHF also reacts as a dialdehyde in the presence of acid, without recyclization to a five-membered ring system. Thus condensation with dithiols affords bisdithioacetals,15 reaction with b-naphthol leads to dibenzoxanthene derivatives (eq 7),16 and aldolization reaction with aromatic aldehydes gives diaryl-2,3-diformylbutadienes.17

Related Reagents.

2,5-Dihydro-2,5-dimethoxyfuran; Furan; Glutaraldehyde; Succindialdehyde; 2-Trimethylsilyloxyfuran.

1. Fakstorp, J.; Raleigh, D.; Schniepp, L. E. JACS 1950, 72, 869.
2. (a) Clauson-Kaas, N.; Tyle, Z. ACS 1952, 6, 667. (b) Baltazzi, E.; Krimen, L. I. CRV 1963, 63, 511.
3. (a) Massa, S.; Mai, A.; Artico, M.; Corelli, F. JHC 1990, 27, 1805. (b) Gmeiner, P.; Lerche, H. H 1990, 31, 9.
4. Kashima, C.; Hibi, S.; Maruyama, T.; Omote, Y. TL 1986, 27, 2131.
5. Stefancich, G.; Artico, M.; Corelli, F.; Massa, S. S. 1983, 757.
6. Bellasio, E.; Campi, A.; Di Mola, N.; Baldoli, E. JMC 1984, 27, 1077.
7. Royer, J.; Husson, H.-P. TL 1987, 28, 6175.
8. Arseniyadis, S.; Huang, P. Q.; Piveteau, D.; Husson, H.-P. T 1988, 44, 2457.
9. Arseniyadis, S.; Huang, P. Q.; Husson, H.-P. TL 1988, 29, 1391.
10. Katritzky, A.; Rachwal, S.; Rachwal, B. JCS(P1) 1990, 1717.
11. Maleki, M.; Miller, A.; Lever, O. W., Jr. TL 1981, 22, 365.
12. (a) Brownbridge, P.; Chan, T.-H. TL 1979, 4437. (b) Lee, S. D.; Chan, T. H. T 1984, 40, 3611.
13. Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama, Y.; Obayashi, M.; Nozaki, H. T 1983, 39, 967.
14. Chan, T. H.; Lee, S. D. TL 1983, 24, 1225.
15. Kawase, T.; Awaji, H.; Yoneda, S.; Yoshida, Z. H 1982, 18, 123.
16. Van Allan, J. A.; Giannini, D. D.; Whitesides, T. H. JOC 1982, 47, 820.
17. El Gendy, A. M.; Mallouli, A.; Lepage, Y. S 1980, 898.

Henri-Philippe Husson

Université René Descartes, Paris, France

Jacques Royer

CNRS, Gif-sur-Yvette, France

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