Diethyl Chloromethylphosphonate

[3167-63-3]  · C5H12ClO3P  · Diethyl Chloromethylphosphonate  · (MW 186.58)

((diethylphosphono)- or chloro(diethylphosphono)methylating agent for different functional groups; reacts mainly via the corresponding derived lithiated anion as an organometallic reagent;1 can function as an electrophile2)

Physical Data: bp 109-111 °C/10 mmHg; d 1.200 g cm-3; n20D 1.439; d 31P 18 ppm (from 85% H3PO4); on a comparative scale of different phosphonates and reference compounds, the acidity of (EtO)2P(O)CH2Cl is 1.74 pKa units superior to that of phenylacetylene and 1 pKa unit inferior to that of acetonitrile. Relative to other phosphonates, (EtO)2P(O)CH2Cl is more acidic than (EtO)2P(O)Me, by approximately 3 pKa units and less acidic than (EtO)2P(O)CH2Ph by 1.74 pKa units.3

Solubility: sol THF, ether, dichloromethane, chloroform.

Form Supplied in: colorless liquid.

Preparative Methods: synthesis on a preparative scale of (EtO)2P(O)CH2Cl and other (1-chloroalkyl)phosphonates is relatively difficult.5-8 Ethanolysis of (chloromethyl)phosphonic dichloride is the most general and useful procedure (eq 1).6 However, (chloromethyl)phosphonic dichloride is expensive and only commercially available in small amounts. Its preparation has been realized by reaction of Phosphorus(III) Chloride with dichloromethane in a closed metallic vessel heated at 100 °C for 24 h (eq 2).7

Other preparations using classical glass vessel apparatus can be used to obtain (EtO)2P(O)CH2Cl on a small scale (up to 10 g) from diethyl (hydroxymethyl)phosphonate (eq 3).8

Analysis of Reagent Purity: the methyl hexyl ketone-acetone-heptane (4:1:5) system ensures effective thin-layer chromatographic separation on silufol plates of normal esters of methylphosphonic and (chloromethyl)phosphonic acids and a procedure has been developed for the identification of 32P-labeled (chloromethyl)phosphonic acid esters in CCl4 and CHCl3.4

(Diethylphosphono)- or Chloro(diethylphosphono)methylation.

(EtO)2P(O)CH2Cl (1) reacts with n-Butyllithium at low temperature in THF to give a lithiated anion which can be used as a (diethylphosphono)- or chloro(diethylphosphono)methylating agent for electrophilic compounds. As this carbanion degrades at temperatures above -30 °C to give unidentified oligomeric products,3 it is advantageous to metalate (1) with an excess of Lithium Diisopropylamide (2 equiv) in THF. Under these conditions a stoichiometric amide-carbanion (1:1) association stabilizes the carbanion at 0 °C for at least 1 h (eq 4).9

The Grignard reagent of (1) is known, but it has to be prepared by an exchange reaction between diethyl(iodomethy)phosphonate and isopropylmagnesium chloride. It reacts with some electrophiles such as Bromine, Benzeneselenenyl Chloride, and Benzeneselenenyl Bromide better than the corresponding lithiated anion (eq 5).10

Chloro(diethylphosphono)methylation of various electrophiles such as carboxylic acid esters, diethyl carbonate, diethyl oxalate,1 and chlorophosphates or -phosphinates11 using the lithiated anion of (1) gives direct access to chloro(diethylphosphono)methyl-substituted ketones, carboxylic acid esters, and a-ketocarboxylic acid esters,1 and chloromethylenediphosphonates or chloromethylphosphinophosphonates.11 The reaction can be adjusted to deliver chloro(diethylphosphono)acetaldehyde (eq 6).1

In these reactions, only the intermediate lithiated enolate prepared from ethyl carbonate1 or ethyl chloroformate,12 or the intermediate lithiated anions prepared from chlorophosphates13 or -phosphinates14 in the presence of excess LDA, can react with aldehydes or ketones in a Horner-Emmons type reaction. The reaction leads to diethyl a-chlorinated a,b-unsaturated phosphonates when diethyl chlorophosphate is used in the initial phosphorus acyl chloride phosphonomethylation (eq 7).13 This carbonyl alkenation reaction has been extended to the preparation of diphenyl(chlorovinyl)phosphine oxides by use of chlorodiphenylphosphine oxide as phosphonoalkylating reagent.14 It is worth noting that (chlorovinyl)phosphonates or (chlorovinyl)phosphine oxides are obtained with predominant (Z) stereoselectivity.

Reaction of aldehydes or ketones with the lithiated derivative of (1) in a mixture of THF and hexane at low temperature results in the almost immediate formation of lithiated (1-chloro-2-hydroxyalkyl)phosphonate alkoxides, which afford epoxy phosphonates on warming.15 Under these conditions, (1) undergoes a Darzens-type reaction instead of a Horner-Emmons reaction. With aldehydes, this (diethylphosphono)methylation reaction can take a different course leading to (2-oxoalkyl)phosphonates, if the intermediate alkoxide anion is treated at low temperature with LDA (eq 8).16

In an analogous reaction, the lithiated derivative of (1) reacts with aromatic imines to give aziridinylphosphonates with high stereoselectivity (eq 9).17

The carbanion (EtO)2P(O)CHClLi can be also carbonated,18 chlorinated,19 or silylated.20 The (carboxychloromethyl)phosphonate and (dichloromethyl)phosphonate obtained serve further as reagents in Horner-Emmons alkenation reactions.18,22-24 (Trimethylsilylchloromethyl)phosphonate can be used for the preparation of a-bromo- and a-iodophosphonates20 and chloro(diethylphosphono)sulfine.21

Often these reactions can be carried out using an efficient and simple one-pot procedure. For instance, the carboxychloroalkenation takes place in two independent steps, leading to a-chloro-a,b-unsaturated acids.18 The one-step a-chlorination or a-bromination Horner-Emmons procedure allows the preparation of dichloro-22,23 or dibromoalkenes,24 respectively. The method can be applied to sterically hindered cyclic ketones as an alternative to the Corey procedure,25 with the lithium phosphate byproduct being soluble in aqueous media. It is important to note that the stabilization of the lithiated anion derived from the (dichloromethyl)phosphonate formed in situ requires the presence of the lithium salts Lithium Bromide and Lithium Chloride (eqs 10 and 11).26

Diethyl Chloromethylphosphonate as an Electrophilic Reagent.

(EtO)2P(O)CH2Cl can function as an electrophilic reagent to introduce a (diethylphosphono)methyl moiety to a nucleophilic substrate. The chlorine atom can be substituted by dimethyl sulfide,27 phosphites,28 arylcopper,2 and phenolic compounds29 to afford the corresponding (diethylphosphono)methylated products. For example, copper reagents prepared from aryl bromides react with (1) to yield diethyl (arylmethyl)phosphonates. In certain cases this method is better than the classical Michaelis-Arbuzov reaction30 applied to arylmethyl halides because the synthesis of these last compounds by benzylic bromination is often not selective and requires a number of steps (eq 12).2 Thiolates react with (1) partially by chlorine substitution and dealkylation.31 The ethoxy group in (1) can also be substituted. As a specific case of the preparation of an a-functionalized chlorophosphonic acid monoester by a selective chlorination of the corresponding phosphonic acid diesters, ethyl (chloromethyl)chlorophosphonic acid ester was obtained by the reaction between (1) and Phosphorus Oxychloride (eq 13).32

Reduction of diethyl (chloromethyl)phosphonate and other (chloroalkyl)phosphonates with different hydride reagents has been studied. Whereas Lithium Aluminum Hydride gives primary phosphines without chemoselectivity when a C-Cl bond is in an a-position to the phosphoryl group, reduction of (1) with AlH3 affords (chloromethyl)phosphine with good chemoselectivity (eq 14).33


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Philippe Coutrot & Claude Grison

Université de Nancy I, Vandoeuvre-les-Nancy, France



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