Ethyl Vinyl Ether1

(R = Et)

[109-92-2]  · C4H8O  · Ethyl Vinyl Ether  · (MW 72.12) (R = Me)

[107-25-5]  · C3H6O  · Methyl Vinyl Ether  · (MW 58.09) (R = n-Bu)

[111-34-2]  · C6H12O  · Butyl Vinyl Ether  · (MW 100.18)

(protection of hydroxyl group; transvinylation, particularly to prepare allyl vinyl ethers for use in the Claisen rearrangement; condensation reactions; cycloaddition reactions)

Physical Data: R = Et, mp -115.8 °C, bp 35-36 °C, d 0.7589 g cm-3; R = Me, mp -123 °C, bp 12 °C, d 0.7725 g cm-3 at 0 °C; R = n-Bu, mp -92 °C, bp 94 °C, d 0.7888 g cm-3.2

Solubility: sol all common organic solvents; slightly sol water.

Form Supplied in: ethyl vinyl ether and n-butyl vinyl ether are colorless, extremely flammable liquids, while methyl vinyl ether is a colorless, extremely flammable gas. Ethyl vinyl ether is supplied stabilized with triethanolamine and methyl vinyl ether is supplied in stainless steel cylinders.

Purification: ethyl vinyl ether and n-butyl vinyl ether may be distilled from K2CO3 or Na if purification of the commercial materials is desirable.

Handling, Storage, and Precautions: all three compounds react violently with halogens and with strong oxidizing agents, and undergo rapid polymerization in the presence of acids. These vinyl ethers are lachrymatory and irritate the respiratory system; in particular, methyl vinyl ether can cause rapid suffocation if inhaled. Use in a fume hood.

Protection of the Hydroxyl Group.3

Acid-catalyzed reaction of primary and secondary alcohols with ethyl vinyl ether gives the a-ethoxyethyl (EE) group. Acids commonly used in the formation of the EE group include Trifluoroacetic Acid (eq 1),4 anhyd Hydrogen Chloride (eq 2),5 p-Toluenesulfonic Acid,6 and Pyridinium p-Toluenesulfonate (PPTS) (eq 3).7 Whereas attempts to form the methyl or benzyl ether of the hemiacetal (eq 3), and reaction with DHP, result in decomposition, the hemiacetal is successfully converted into the EE group with ethyl vinyl ether in the presence of PPTS (but not p-TsOH).7 For extremely acid-sensitive substrates, ethyl vinyl ether generated in situ from 1-chloroethyl ethyl ether (MeCH(Cl)OEt) with PhNMe2 in CH2Cl2 at 0 °C gives EE derivatives of primary, secondary, and some tertiary alcohols in excellent yields (eq 4).8 Selective protection of a primary alcohol in the presence of a secondary alcohol with ethyl vinyl ether may be achieved at low temperatures (eq 5).9 The EE group is more readily cleaved by acid hydrolysis than the THP ether, but is more stable than the 1-methyl-1-methoxyethyl ether.3 In the case of the nucleoside (eq 2), which is subsequently converted into a nucleotide, the ethoxyethyl group is preferred to the THP group because of its ease of removal (5% HOAc, 2 h, 20 °C), with no detectable isomerization of the 3-5 nucleotide linkage.5 Other methods of cleaving the EE group include 0.5N HCl in THF at 0 °C,6 and PPTS in n-PrOH, where cleavage is possible in the presence of an acetonide group (eq 6).10

Augmenting its role as a protecting group, the EE group has been used to direct ortho-lithiation in suitably substituted aromatic ethers, yielding lithiated species that react rapidly with a variety of electrophiles, such as Carbon Dioxide, to give the phthalide (eq 7).11


Acid-catalyzed transvinylation of allylic alcohols with ethyl vinyl ether gives allyl vinyl ethers, Claisen rearrangement12 of which affords g,d-unsaturated aldehydes of varying complexity (eqs 8-12).13,14,16-18 Mercury(II) Acetate (eq 8),13 Phosphoric Acid (eq 9),14 and p-TsOH15 are frequently used to catalyze the transvinylation reaction, and the allyl vinyl ethers produced need not be isolated but may be subjected directly to the Claisen rearrangement, typically at 145-200 °C. Hg(OAc)2, used in the transvinylation reaction, has been reported to effect the rearrangement at lower temperatures (eq 10).16 Other examples illustrating the stereoselectivity of the reaction are given in eqs 11 and 12.17,18

Condensation Reactions.

Acetal Condensations.

The acid-catalyzed condensation of ethyl vinyl ether with acetals derived from a,b-unsaturated aldehydes and ketones is an excellent method to lengthen a carbon chain by two carbon atoms, particularly of polyenals. In an industrial process for the manufacture of the C16 aldehyde (eq 13), the C14 acetal is reacted with ethyl vinyl ether in the presence of Zinc Chloride to give an alkoxy acetal, which, without isolation, is then hydrolyzed with moist acetic acid.19 Longer conjugated carotenals have been synthesized by this method,20 and montmorillonite K-10 clay (see Montmorillonite K10) has been reported to be an excellent replacement for the Lewis acids normally used in the condensation.21

Acyl Anion Equivalents.22

The a-H of simple vinyl ethers can be deprotonated with strong bases, such as t-Butyllithium, to give highly reactive a-alkoxyvinyllithium reagents (see also 1-Ethoxyvinyllithium and 1-Methoxyvinyllithium). These react rapidly with various electrophiles, including aldehydes and ketones (eq 14),23 and can undergo conjugate addition to a,b-unsaturated carbonyl compounds via the corresponding cuprates (eq 15).24

Cycloaddition Reactions.

Diels-Alder and Related Reactions.

Owing to their electron-rich nature, vinyl ethers participate in a number of inverse electron demand Diels-Alder reactions.25 a,b-Unsaturated aldehydes and ketones react rapidly with vinyl ethers to give dihydropyrans (eq 16),26 with high endo selectivity (eq 17),27 the proportion of endo adduct being increased by conducting the reaction at low temperatures under pressure (eq 18).28 Lewis acids can also catalyze these reactions and control the stereochemistry of cycloaddition.25b,29 o-Quinone methides yield chromans (eq 19),30 and imines give tetrahydroquinolines (eq 20).31 Vinyl ethers react regio- and stereoselectively with isoquinolinium salts giving cycloadducts, which on hydrolysis afford tetralins in excellent yields (eq 21).32 The cycloaddition of vinyl ethers with nitrones proceeds smoothly, giving, where relevant, isoxazolines with extremely high diastereoselectivity (eq 22).33 Vinyl ethers react with nitroalkenes to give nitronate esters in moderate yields (eq 23),34 but excellent yields of cyclobutane derivatives are obtained with tetracyanoethylene (eq 24).35


Vinyl ethers undergo the Paterno-Büchi reaction with simple aliphatic and aromatic carbonyl compounds to give regioisomeric mixtures of alkoxyoxetanes, with a preponderance of the 3-alkoxy regioisomer (eq 25).36 Photoaddition of vinyl ethers to enones produces alkoxycyclobutanes in excellent yields, with the alkoxy group orientated predominantly away from the carbonyl group (eq 26).36 Vinyl ethers also undergo photoaddition to arenes, giving, with benzene, a mixture of ortho- and meta-cycloadducts in low yields; only the exo isomer is produced in the ortho-cycloaddition, whereas the meta-cycloaddition gives a mixture of regio- and stereoisomers (eq 27).37

Related Reagents.

Acetaldehyde; Acetaldehyde N-t-Butylimine; 1-Ethoxy-1-propene; 2-Methoxy-1,3-butadiene; Vinyl Acetate.

1. Mundy, B. P.; Ellerd, M. G. Name Reactions and Reagents in Organic Synthesis; Wiley: New York, 1988; p 354.
2. (a) CRC Handbook of Chemistry and Physics, 73rd ed.; CRC: Boca Raton, FL, 1992; pp 3-241. (b) Dictionary of Organic Compounds, 5th ed.; Chapman & Hall: New York, 1982; Vol. 3, p 2571. (c) Sax's Dangerous Properties of Industrial Materials, 8th ed.; Lewis, R. J., Ed.; van Nostrand Rheinhold: New York 1992; Vol. 2, p 1668.
3. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991; p 38.
4. Manchand, P. S.; Schwartz, A.; Wolff, S.; Belica, P. S.; Madan, P.; Patel, P.; Saposnik, S. J. H 1993, 35, 1351.
5. (a) Smrt, J.; Chladek, S. CCC 1966, 31, 2978. (CA 1966, 65, 10 648c). (b) Young, S. D.; Buse, C. T.; Heathcock, C. H. OSC 1990, 7, 381.
6. Meyers, A. I.; Comins, D. L.; Roland, D. M.; Henning, R.; Shimizu, K. JACS 1979, 101, 7104.
7. Anderson, R. C.; Fraser-Reid, B. TL 1978, 3233.
8. Still, W. C. JACS 1978, 100, 1481.
9. Semmelhack, M. F.; Tomoda, S. JACS 1981, 103, 2427.
10. Tius, M. A.; Fauq, A. H. JACS 1986, 108, 1035.
11. Napolitano, E.; Giannone, E.; Fiaschi.; Marsili, A. JOC 1983, 48, 3653.
12. (a) Rhoads, S. J.; Raulins, N. R. OR 1975, 22, 1. (b) Ziegler, F. E. CRV 1988, 88, 1423; (c) Wipf, P. COS 1991, 5, 827.
13. Dauben, G.; Dietsche, T. J. JOC 1972, 37, 1212.
14. Marbet, R.; Saucy, G. HCA 1967, 50, 2095.
15. Saucy, G.; Marbet, R. HCA 1967, 50, 1158.
16. Reed, S. F. JOC 1965, 30, 1663.
17. Grieco, P. A.; Takigawa, T.; Moore, D. R. JACS 1979, 101, 4380.
18. (a) Paquette, L. A.; Annis, G. D.; Schostarez, H. JACS 1981, 103, 6526. (b) Paquette, L. A.; Annis, G. D.; Schostarez, H.; Blount, J. F. JOC 1981, 46, 3768.
19. Isler, O.; Lindlar, H.; Montavon, M.; Rüegg, R.; Zeller, P. HCA 1956, 39, 249.
20. (a) Isler, O.; Schudel, P. Adv. Org. Chem. Methods Results 1963, 4, 115. (b) Effenberger, F. AG(E) 1969, 8, 295. (c) Carotenoids; Isler, O., Ed.; Birkhauser: Basel, Switzerland, 1971. (d) Makin, S. M. PAC 1976, 47, 173.
21. Fishman, D.; Klug, J. T.; Shani, A. S 1981, 137.
22. Umpoled Synthons; Hase, T. A. Ed.; Wiley: New York, 1987.
23. (a) Kraus, G. A.; Krolski, M. E. SC 1982, 521. (b) Baldwin, J. E.; Höfle, G. A.; Lever, O. W. JACS 1974, 96, 7125.
24. Boeckman, R. K.; Bruza, K. J. JOC 1979, 44, 4781.
25. (a) Desimoni, G.; Tacconi, G. CRV 1975, 75, 651. (b) Boger, D. L. COS 1991, 5 451. (c) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon: New York, 1990. (d) Boger, D. L.; Weinreb. S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic: San Diego, 1987.
26. Longley, R. I.; Emerson, W. J.; Blardinelli, A. J. OSC 1963, 4, 311.
27. (a) Apparao, S.; Maier, M. E.; Schmidt, R. R. S 1987, 900. (b) Schmidt, R. R. ACR 1986, 19, 250.
28. Tietze, L. F.; Hübsch, T.; Voss, E.; Buback, M.; Tost, W. JACS 1988, 110, 4065.
29. Chapleur, Y.; Envrard, M.-N. CC 1987, 884.
30. Inoue, T.; Inoue, S.; Sato, K. CL 1989, 653.
31. Cabral, J.; Laszlo, P.; Montaufier, M. T. TL 1988, 29, 547.
32. Gupta, R. B.; Franck, R. W. JACS 1987, 109, 5393.
33. (a) Advances in Cycloadditions; Curran, D. P., Ed.; Jai: Greenwich, CT, 1988; Vol. 1. (b) DeShong, P.; Leginus, J. M. JACS 1983, 105, 1686. (c) Confalone, P. N.; Huie, E. M. OR 1988, 36, 1.
34. Backvall, J. E.; Karlsson, U.; Chinchilla, R. TL 1991, 32, 5607.
35. (a) Fatiadi, A. J. S 1987, 749. (b) Baldwin, J. E. COS 1991, 5, 63.
36. Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum: New York, 1984.
37. Gilbert, A.; Taylor, G. N.; binSamsudi, M. W. JCS(P1) 1980, 869.

Percy S. Manchand

Hoffmann-La Roche, Nutley, NJ, USA

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