# Does the synthesis of beta-keto phosphonates from esters have a name?

Consider the Horner–Wadsworth–Emmons reaction; one of its reactants is a phosphonate, usually stabilised by a β-carbonyl group which is then deprotonated in α position (figure 1). These phosphonate esters can be synthesised in a Michaelis–Arbuzov reaction from a phosphorous acid triester and an alkyl halide (figure 2). Another viable way is to start from diethyl ethylphosphonate, deprotonate that (e.g. with n-BuLi) and let it attack a carboxylic ester much like a Grignard reagent would (figure 3).

Figure 1: Horner–Wadsworth–Emmons reaction. Image taken from Wikipedia, originally created by Wikipedia user ~K.

Figure 2: Michaelis–Arbuzov reaction. Image taken from Wikipedia, originally created by Wikipedia user ~K.

Figure 3: Alternative synthesis of HWE phosphonates. Image self-drawn.

Since about every reaction in organic chemistry has a name of some kind, is the reaction in figure 3 also a named reaction, and if so, what is the reaction’s name?

• I might call this reaction in scheme 3 a Claisen reaction/condensation, but the purist might contend that the Claisen condensation is for ester nucleophiles and other carbonyl electrophiles and not for other carbon nucleophiles with ester electrophiles. – Ben Norris Mar 21 '16 at 0:44
• @BenNorris We'll just call it a phosphonate ester and be happy! – SendersReagent Mar 21 '16 at 4:05
• @Jan Does reaction 3 actually stop after the first addition? (Sorry, I don't have access to general chem lit searches any more.) – Zhe Nov 2 '16 at 21:41
• @Zhe Yes. I used 3 equivalents of diethyl ethylphosphonate and BuLi and yet good pretty good yields of the ketophosphonate. – Jan Nov 2 '16 at 21:44

My inclination is to call this reaction a "phosphono-Claisen condensation." A Claisen condensation is the alpha-acylation of an ester with another ester. In this case, the typical carbon-centered ester is replaced with a phosphonate, so phosphono-Claisen condensation specifies that difference. Avoiding the proper name, "alpha-acylation of a phosphonate" is a suitable description of the reaction.

Montchamp and coworkers published a paper describing the "phospha-Claisen condensation" reaction, which they limit to the condensation of two phosphonates to give a 1,1-diphosphono compound.

The website maintained by the venerable Hans Reich describes this reaction as "Claisen-like":

(MeO)2P(O)CH2Li will also react with carboxylic acid derivatives like esters, lactones and amides in a Claisen-like reaction to form keto phosphonates.

The Organic Chemistry Portal describes the reaction as "the condensation of esters and phosphonates."

A brief survey of the literature featuring this reaction type (Thanks SciFinder!) doesn't show any convention for naming this reaction beyond calling it the acylation of a phosphonate. In my SciFinder searching, the earliest usage of this reaction is from 1970, and that paper cites a Corey paper from 1966. The latter paper doesn't have a proper experimental on the reaction but contains the note:

Anions derived from 1 (X = H or alkyl) are of value in the synthesis of keto phosphonates 1 (X = RCO) by reaction with esters. The preparation of these intermediates, which are of value in olefin synthesis [see H. Takahashi, K. Fujiwara, and M. Ohta, Bull. Chem. Soc. Japan, 35, 1498 (1962)], is usually impractical by the Michaelis-Arbusov reaction.

It's a little nebulous who performed this chemistry first, but perhaps someone could have christened it the "Corey-Claisen condensation" or the "Corey variant of the Claisen condensation". Of course there is already a Corey-Claisen rearrangement so this would be really confusing.

Two separate papers I found containing this paritcular type of reaction had the following wording:

Protection of the ketoester as the dioxolan followed by reaction with lithium diethylmethylphosphonate and hydrolysis of the intermediate dioxolanphosphate led to the diketophosphonate.$^{[1]}$

and

"... treatment with lithiated ethylphosphonate furnished the target phosphonate."$^{[2]}$

The lack of results online and the wording in these papers leads me to believe that there isn't any particular name for this reaction. You might say that this is a Claisen-type reaction, though instead of an ester enolate nucleophile, it is a lithium phosphonate nucleophile.

Yesterday I chanced upon a rather obscure name for it: the "Corey–Kwiatkowski condensation".

The reaction between lithium phosphonamide or phosphonate and ester to give β-keto phosphonamide or phosphonate is called the Corey–Kwiatkowski condensation.

Wang, Z. Corey-Kwiatkowski Reaction. Comprehensive Organic Name Reactions and Reagents [Online]; Wiley: 2010, 160, 730–733. DOI: 10.1002/9780470638859.conrr160.

This cites Ciufolini's synthesis of (+)-camptothecin:

Radical bromination and methanolysis advanced 13 to 14, which delivered phosphonate 4 upon Corey–Kwiatkowski reaction.

Ciufolini, M. A.; Roschangar, F. Total Synthesis of (+)-Camptothecin. Angew. Chem. Int. Ed. 1996, 35 (15), 1692–1694. DOI: 10.1002/anie.199616921.

In turn Ciufolini cites a 1966 paper by Corey and Kwiatkowski. Oddly enough, that paper makes no mention of any such reaction, except in footnote 6. This was already mentioned in jerepierre's answer, but it is reproduced here:

Anions derived from 1 (X = H or alkyl) are of value in the synthesis of keto phosphonates 1 (X = RCO) by reaction with esters. The preparation of these intermediates, which are of value in olefin synthesis [see H. Takahashi, K. Fujiwara, and M. Ohta, Bull. Chem. Soc. Japan, 35, 1498 (1962)], is usually impractical by the Michaelis-Arbusov reaction.

Corey, E. J.; Kwiatkowski, G. T. The Synthesis of Olefins from O,O'-Dialkyl β-Lithioalkylphosphonothioate Esters. J. Am. Chem. Soc. 1966, 88 (23), 5654–5656. DOI: 10.1021/ja00975a057.

Anyway, I wouldn't really recommend using this name, as (1) it is not well-known (2) there is potential for confusion.

The name "Corey–Kwiatkowski _____" is also sometimes used to describe the reaction of a lithium phosphonamide with an aldehyde to give an olefin directly (this is what Corey's 1966 paper was actually talking about). In the very first book cited, Comprehensive Organic Name Reactions and Reagents by Wang, the "Corey–Kwiatkowski reaction" refers to precisely that. Also, in Kürti and Czakó's section on HWE olefination,

The Corey–Kwiatkowski modification uses phosphoric acid bisamides to prepare (Z)-alkenes stereoselectively, $\ce{(Me2N)2P(O)CH2R}$, where R = aryl.

Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier: Amsterdam, 2005; pp 212–213.

In turn they cite two papers by Corey and Kwiatkowski, different from the one already quoted above:

• Corey, E. J.; Kwiatkowski, G. T. The Synthesis of Olefins from Carbonyl Compounds and Phosphonic Acid Bisamides. J. Am. Chem. Soc. 1966, 88 (23), 5652–5653. DOI: 10.1021/ja00975a055.
• Corey, E. J.; Kwiatkowski, G. T. Synthesis of olefins from carbonyl compounds and phosphonic acid bis amides. J. Am. Chem. Soc. 1968, 90 (24), 6816–6821. DOI: 10.1021/ja01026a045.
• If Kürti-Czakó says that the Corey-Kwiatkowski is that, it is that. We might still call it Corey-Kwiatkowski phophonylation or something … I have been calling it phosphono Claisen long enough ;) – Jan Sep 17 '17 at 11:30