[6780-49-0]  · C9H11NO  · N-Ethoxymethyleneaniline  · (MW 149.19)

(preparation of aldehydes from Grignard reagents2,3)

Alternate Name: ethyl N-phenylformimidate.

Physical Data: bp 87-88 °C/10 mmHg.

Form Supplied in: liquid, commercially available; best preparation is from Triethyl Orthoformate and aniline.4

Handling, Storage, and Precautions: store refrigerated under dry nitrogen.

Formylation Reagent.

Of the various older methods reviewed1 for the synthesis of aldehydes from Grignard reagents, use of this imidate reagent was considered one of the best,2 giving higher yields than Triethyl Orthoformate.1a However, newer procedures have been developed that may yield superior results, e.g. treatment of Grignard reagents with Pentacarbonyliron.5 The reaction proceeds through the formation of the imine which is hydrolyzed to the aldehyde (eq 1).2 Cyclohexane-1,3-dione also adds to the imidate, and upon hydrolysis of the intermediate 2-(phenylamino)methylene gives the 2-formylcyclohexane-1,3-dione.6,7

Formation of Ketones.

Recent reinvestigation of the above reaction has demonstrated that the reagent can also be utilized for the synthesis of a variety of ketones, by using 2 equiv of a Grignard reagent (80 °C) or alkyllithium (-30 °C).8 This involves the addition of a second Grignard reagent or, preferably, an alkyllithium to the first-formed imine. Aqueous hydrolysis gives N-disubstituted methylaniline (ca. 100% yield) which is oxidized with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone to the Schiff's base; hydrolysis gives the ketone (eq 2).8 This is not applicable to aliphatic ketones.

a,b-Unsaturated a-Substituted Aldehydes.

Condensation of ethoxymethyleneaniline with a-lithioalkylphosphonates gives, after treatment with Lithium Diisopropylamide, lithio enaminoalkylphosphonates, which condense with aldehydes to give a,b-unsaturated a-substituted aldehydes in moderate yield (eq 3).9


Treatment of a-substituted aliphatic acid chlorides with ethoxymethyleneaniline in the presence of Triethylamine generates only trans 1-phenyl-3-substituted 4-ethoxy-b-lactams in moderate to good yield.10,11 The chromium carbene complex in eq 4 photochemically cyclizes with the imidate to give the same azetidinone (X = NBz2) in good yield.12

Related Reagents.

N,N-Dimethylformamide; N-Methyl-N-(2-pyridyl)formamide.

1. (a) Roger, R.; Neilson, D. G. CRV 1961, 61, 179. (b) Kharasch, M. S., Reinmuth, O.; Grignard Reactions of Nonmetallic Substances; Prentice Hall: Engelwood Cliffs, NJ, 1954. (c) Carnduff, J. QR 1966, 20, 169.
2. Smith, L. I.; Nichols, J. JOC 1941, 6, 489.
3. Monier-Williams, G. W. JCS 1906, 89, 273.
4. Roberts, R. M.; Vogt, P. J. OS 1955, 35, 65.
5. Yamashita, M.; Miyoshi, K.; Nakazono, Y.; Suemitsu, R. BCJ 1982, 55, 1663.
6. Rogers, N. A.; Smith, H. JCS 1955, 341.
7. Macmillan, J. G.; Browne, J. L. JOC 1977, 42, 2526.
8. Strekowski, L.; Wydra, R. L.; Cegla, M. T.; Czarny, A.; Patterson, S. JOC 1989, 54, 6120.
9. Tay, M. K.; Aboujaoude, E. E.; Collignon, N.; Savignac, P. TL 1987, 28, 1263.
10. Cardellini, M.; Claudi, F.; Micheletti Moracci, F. S 1984, 1070.
11. Bose, A. J.; Chiang, Y. H.; Manhas, M. S. TL 1972, 4091.
12. Borel, C.; Hegedus, L. S.; Krebs, J.; Satoh, Y. JACS 1987, 109, 1101.

Steven J. Brickner

The Upjohn Company, Kalamazoo, MI, USA

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