Diethyl formylmethylphosphonate

B. Diethyl Formylmethylphosphonate (Note 5). A mixture of 192 g. (0.755 mole) of diethyl 2,2-diethoxyethylphosphonate and 670 ml. of 2% aqueous hydrochloric acid is refluxed for 10 minutes under a nitrogen atmosphere. 

Walz, A.J., and Sundberg, R.J., Diethyl formylmethylphosphonate as an acetaldehyde synthon for quinoline synthesis, Synlett, 75, 2001. 

The reagent is prepared1 by reaction of diethyl formylmethylphosphonate (l)2 with an equimolecular amount of cyclohexylaminc in methanol followed by distillation of the crude product in the presence of potassium carbonate. 

Possibly the most frequently used and most widely known phosphonylated aldehyde is diethyl l-formylmethyIphosphonate. A vaiiety of methods for the preparation of this aldehyde are reported in the literature. The oldest employs tlie Michaelis-Arbuzov reaction between triethyl phosphite and bromoacetaldehyde diethyl acetal, which yields diethyl 2,2-diethoxyethylphosphonate on heating to 160°C (Scheme 5.5). Subsequent acid hydrolysis gives diethyl 1-formylmethylphosphonate. The aldehyde function requires protection because it is known that a-haloaldehydcs react with trialkyl phosphites in a Perkow reaction affording dialkyl vinylphosphates isomeric with the expected phosphonates. " ... 

The use of an appropriate hydrolytic procedure for the conversion of diethyl 2,2-diethoxyeth-ylphosphonate into diethyl 1-formylmethylphosphonate is an important step in the reaction sequence. A high concentration and a large excess of acid should be avoided to prevent hydrolysis of the acid-sensitive ester groups attached at phosphorus. The use of drastic conditions may provoke undesired side reactions, resulting in loss of the expected product. In the case of diethyl 1-fonnyhnethylphosphonate, a variety of acids have been used H2SO4, H2SO4-... 

In some cases, diethyl 1,2-epoxyalkylphosphonates undergo thermal phosphoryl group migration at high temperatures (170-300°C) to produce 1-substituted l-formylmethylphosphonates. However, this method has only limited utility because the rearrangement products themselves can be thermally labile with respect to dephosphorylation. >37,143,144... 

The palladium-catalyzed Michaelis-Arbuzov reaction of allyl acetates with triethyl phosphite provides reasonable yield (65%) of diethyl allylphosphonates. The reaction has been employed in the synthesis of diethyl 1-formylmethylphosphonate on a preparative scale (52%) by reductive ozonolysis of diethyl allylphosphonate in CH2CI2 at low temperature (Scheme 5.17). 5°... 

The reaction of diethyl 1-formylmethylphosphonate with dimethyl W(benzyloxycarbonyl)-1-amino-l-(methoxycarbonyl)methylphosphonate to give the p.y-unsalurated phosphonate is promoted by a variety of bases (n-BuLi, NaH, t-BuOK). Under these conditions, t-BuOK gives the best results in terms of selectivity (Z/E = 33/1) and yield (78%, Scheme 5.68). ... 

Similarly, the reaction of diethyl 1-formyletliylphosphonate witli diethyl 1-methoxy-l-(meth-oxycarbonyl)methylphosphonate in the presence of NaHMDS in THF at room temperature affords the expected Y-methoxy-P,Y-unsaturated phosphonate in 39% yield. Diethyl 1,1-difluoro-l-formylmethylphosphonate hydrate undergoes an olefination reaction with stabilized methylphosphonate carbanions under a variety of conditions to give 3-substituted diethyl l,l-difluoro-2-propenylphosphonates in 45-78% yields. ... 

The chlorination process is extended to the preparation of 1-substimted-1-fonnyhnethylphos-phonates with comparable yields (53-92%). 5-3°8 Contrary to the previously reported results, the reaction of triethyl phosphite with trichloroacetaldehyde does not give diethyl 1,1-dichloro-1-formylmethylphosphonate (Michaelis-Arbuzov product) instead, the isomeric diethyl 2,2-dichlo-rovinylphosphate (Perkow product) is formed in 98% yield. However, protection of the formyl group before reaction with triethyl phosphite provides the expected diethyl 1,1-dichloro-l-formyl-methylphosphonate selectively in high yield (80%). ... 

Under carefnlly optimized experimental conditions, dialkyl 2,2-diethoxyethylphosphonates react with chlorine in reflnxing CCI4 under UV irradiation to provide dialkyl l,l-dichloro-2,2-diethoxyethylphosphonates. 5 These products can also be prepared in quantitative yield by reaction of diethyl 1,1-dichloro-1-formylmethylphosphonate with orthoformic esters in the presence of sulfuric acid. However, subsequent hydrolysis of these acetals gives modest yields of the corresponding aldehydes (30-40%). ... 

The first example of preparation of an a,P-unsaturated aldehyde from unprotected 1-formylmethylphosphonate involved the rather reactive substrate hexafluoroacetone. Thus, diethyl 1-formyhnethylphosphonate reacts with hexafluoroacetone in n-BujO at room temperature in the presence of t-BuOK to give the 3,3-Z /i(trifluoromethyl)propenal in 54% yield. " " Another example describes the formation of an aji-unsaturated aldehyde in 62% yield from unprotected 1-formyhnethylphosphonate under Masamune conditions (LiCl, DIE A, MeCN, room temperature).3" ... 

The dimethylhydrazine derivative of diethyl 1-formylmethylphosphonate, on reaction with 0-propargyl-2-hydroxybenzaldehyde, gives an azadiene that, on heating in mesitylene at 138-162°C for several hours, participates directly in an intramolecular [4 -i- 2] cycloaddition (Scheme 5.82). ... 

The preparation of AEP via the reduction of oxime of diethyl 1-formylmethylphosphonate is of synthetic importance. The oxime is prepared from diethyl 1-formylmethylphosphonate and hydroxylamine hydrochloride in EtOH/Py, treated with (AcO)2O in AcOH, and then hydrogenated using 5% Pd/C. After acid hydrolysis using 6 M HCl and purification with ion-exchange resin (Dowex 50W), AEP is isolated in 43% yield. ... 

It was shown that diethyl 2,2-disubstituted -1,2-epoxyethylphosphonates undergo thermal rearrangement to yield diethyl 1,1-disubstituted -1-formylmethylphosphonate [266]. 

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