CC/NUMBER 17This Week’s Citation Classic APRIL 28, 1986r Stork G, Brizzolara A, LandesmanH, SzmuszkoviczI & Terrell R. The enaminealkylation andacylationof carbonylcompounds.J. Amer. Chem. Soc. 85:207-22, 1963.IChandlerLaboratories,ColumbiaUniversity, New York, NY]

This is a Comprehensive paper that put to-~gether our work on the enamine alkylation.a new method demonstrating that mono-alkylation of ketones and aldehydes couldbe achieved via reaction of the derived en-amines with electrophilic carbon species.[The Sd® indicates that this paper has beencited in over 945 publications.]

Gilbert StorkDepartment of Chemistry

Columbia UniversityNew York, NY 10027

February14, 1986

It is hard to realize today that, althoughthe carbonyl group had long been recog-nized as the preeminent function in organicsynthesis, there was by the mid-1940s nomethod available for the alkylation ofaldehydes. The monoalkylation of ketonescould be achieved, but only by previousconversion to a 13-ketoester, alkylation, anddecarboxylation.

I had often thought that there must bemilder ways of accomplishing such transfor-mations, and I imagined that, perhaps, theenamine tautomers of some sort of imine de-rived from the condensation of a carbonylgroup and an amino acid might be involvedin some biochemical alkylations. These mus-ings, which owed much to my biochemicalnaiveté, eventually led me to wonder if en-amines, whether biologically relevant ornot, might undergo alkylation on carbon.The evidence was discouraging. In the 20years or so that enamines of ketones and al-dehydes had been known, there had onlybeen scattered reports of “normal” alkyl-ation on the nitrogen atom.

This was the state of affairs when, a fewmonths after I moved to Columbia in Octo-ber 1953, luck intervened in the form of RossTerrell, a graduate student who was doing athesis with Layton McCoy, then an instruc-tor. Ross had been attempting to monometh-ylate a ketone, specifically 5-phthalimido-2-tetralone. As everyone who has worked with2-tetralones will appreciate, monomethyl-ation was—and still is—essentially unattain-able via the usual metal enolates; mixturescontaining mostly dimethylated productsarise. I suggested to Terrell that he find outwhat would happen if he were to treat thepyrrolidine enamine from his ketone withmethyl iodide. This was an extremely luckyfirst case, for although yields were onlymoderate at first, they soon reached around80 percent. This is a typical yield with2-tetralones, but is decidedly higher thancan be obtained from the methylation ofmost ketone enamines.’ Without this re-markable result, we might not have gone onto discover the general alkylation of alltypes of enamines with electrophilic olefins(with Hans Landesman

2)or the acylation re-

action of ketone enamines (with A. Briz-zolara, Jr.).

I have, of course, derived much satisfac-tion from the fact that while no reference tothe carbon alkylation of enamines (otherthan to our own work) could be found eitherin the 1954 or in the 1955 Chemical Ab-stracts index, the index for the first half of1985 (volume 102) not only has an entry for“enamines” in the Chemical Subjects index,but also has at least 40 references to reac-tions of specific enamines with carbon elec-trophiles.

In someways, I am surprised, but pleased,that the 1963 enamine paper is still beingquoted as much as it is, even though thereare now excellent comprehensive sum-maries of the chemistry of this fascinatingclass of substances.

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1. Stork G, Teirell B & SzmuszkovlezI. A new synthesis of 2.alkyl and 2’acyl ketones.I. Amer. Chem. Soc. 76:2029-30. 1954. Cited 195 times since 1955.(

2. Stork G & l.aadeainan H K. A new alkylanon of carbonyl compounds. II. I. Amer. Chem. Soc. 78:5128-9, 1956.(Cited 90 tames.)

3. Cook AG. Enamjnes. New York: Marcel Dekker, 1969. 515 p. ICiled 385 times.l4. Hk,kmots P W. Enamjnes: recent advances in synthetic. specsroscopic. mechanistic, and stereochemical aspects—I.

Tetrahedron 38:1975-2050, 1982.5. . Enasnines: recens advances in synthetic, spectroscopic. mechanistic, and stereochemical aspects—lI.

Tetrahedron 38:3363-446, 1982.6. .-—..-.- . Recent advances in the chemistry of conjugated enamines. Tetrahedron 40:2989-3051. 1984.

ET8LAS )~1986 by (SI® CURRENT CONTENTS®

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