Diethyl cyanomethylphosphonate

The synthetic 31 was converted to the cyanoglucoside osmaronin (41a) which was isolated from a methanolic extract of the leaves of Osmaronia cerasi-formis. Acetylation of 31 gave an acetate (99% yield) which was subjected to ozonolysis to afford a ketone 42. The Horner-Emmons reaction of 42 using diethyl cyanomethylphosphonate furnished (Z)-43a (22% yield from the acetate of 31) and ( )-43b (10% yield from the acetate of 31). Deprotection of (Z)-43a and ( )-43b gave the (3-D-glucosides 41a (83% yield) and 41b (94% yield), respectively. The spectral data of the synthetic 41a were identical with those ( H- and C-NMR) of the natural osmaronin (41a) (Fig. 5). 

Then the synthetic 32 was converted to the cyanoglucoside sutherlandin (44) which was isolated from leaves of Acacia sutherlandii. Acetylation of a diastereomeric mixture of 32 gave the corresponding acetate which was subjected to the hydrogenation and the subsequent oxidation to yield the a-acetoxyl ketone (45, 84% overall yield from the acetate of 32). The Homer-Emmons reaction of 45 using diethyl cyanomethylphosphonate furnished (Z)-46a (33% yield from 45) and ( )-46b (31% yield from 45). Deprotection of the presumably desired (Z)-46a afforded (Z)-44 (76% yield), whose C-NMR spectra were identical with those of the natural sutherlandin (44) (Fig. 6). 

The reaction of diethyl cyanomethylphosphonate in the presence of A1203 with aliphatic or aromatic aldehydes in the absence of solvent results mainly in the product of Knoevenagel reaction (equation II). 

Hachemi, M., Puciova-Sebova, M., Toma, S. and Villemin, D. Dry reaction of diethyl cyanomethylphosphonate and tetraethyl methylenediphosphonate with benzaldehyde on solid bases, Phosphorus, Sulfur Silicon Relat. Elem, 1996, 113, 131-136. 

L-proline followed by reaction of the product with diethyl cyanomethylphosphonate (1, 250 2, 130-131) gives 2 and 3 in a 1 1 ratio (18.3% total yield). Use of piperidine acetate gives 2 and 3 in a 1 22 ratio (50.3% total yield). Dibenzylam-monium trifluoroacetate shows similar selectivity 2/3 = 1 19 (76.4% total yield). However, use of morpholine-camphoric acid in ether-HMPT favors formation of 2. With this catalyst 2 and 3,are obtained in 37.5% and 1.5% yield, respectively. ... 

An important step in a synthesis of 3/i-acetoxy-5/i,14c -bufa-20,22-dicnolide from dchydroepiandrostene includes ihe condensation of the carbanion derived from diethyl cyanomethylphosphonate with the ketone (1), ... 

Diethyl cyanomethylphosphonate, (CjH50)2P CH2CN. Mol. wt. 177.17. Supplier Aldrich. 

Cyclopropanes Diborane. Diethylaluminum iodide. Diethyl cyanomethylphosphonate. Dlphenyldiazomethane. Lithium ahitninum hydride. Simmona-Smith reaction. Sodium hydride. Triethylphoiphoenol pyruvate. 

While the diethyl benzylphosphonate anion did not react with phenyloxirane, even though the anion was prepared in situ, the diethyl cyanomethylphosphonate anion gave 2-phenylcy-clopropane carbonitrile in 51% yield. ... 

A -FluorohiXtrifluoromethanesulfonyl)imide is one of the most powerful electrophilic fluori-nating agents. It was successfully used to fluorinate diethyl cyanomethylphosphonate in the presence of w-BuLi (1 eq), and the resulting diethyl 1-fluoro-1-cyanomethylphosphonate can be isolated (51% yield) or metallated in situ and reacted with carbonyl compounds in a Homer-Wadsworth-Emmons reaction to give a-fluoroacrylonitriles in 30-58% overall yields (Scheme 3.21). 2 These results aie especially noteworthy because the fluorination of diethyl cyanomethylphosphonate with NFBS in the presence of LiHMDS (2 eq) produces the A -fluoro and not the expected C-fluoro phosphonate. 

Dawson and Burger first demonstrated that the Michaelis-Arbuzov reaction of chloroacetonitrile and triethyl phosphite furnishes diethyl cyanomethylphosphonate. In its most general form, it involves the addition of triethyl phosphite to chloroacetonitrile at 150-170°C to give diethyl cyanomethylphosphonate in up to 80% yields (Scheme 6.2). ° This procedure has been developed on an industrial scale The use of bromo- or iodoacetonitrile (X = Br, I, Scheme 6.2) was also reported. The reaction may be used to prepare any dialkyl cyanomethylphosphonate, and a variety of trialkyl phosphites have produced the corresponding phosphonates in reasonable to good yields (29-90%, Scheme 6.2). " Cyclic phosphites, 4,5-dimethyl-2-methoxy-l,3,2-dioxaphos-pholane (meso and racemic) and 5,5-dimethyl-2-methoxy-l,3,2-dioxaphosphorinane, react with chloroacetonitrile to produce 5- and 6-membered cyclic phosphonates in 50% and 72% yields, respectively. ... 

There are relatively few reports involving the Michael addition of cyanomethylphosphonate anions to unsaturated compounds. The reaction provides a methodology for the elaboration of new reagents but more frequently is used for the preparation of phosphonylated heterocycles. Under basic conditions, diethyl cyanomethylphosphonate adds to benzalacetophenone and 2-bcnzylidcne-3-methyl-4-nitro-3-thiolene-l,l-dioxide to give the addition products in modest yields.- - - " ... 

Michael addition of diethyl cyanomethylphosphonate to a-nitroalkenes in the presence of LDA (1 eq) followed by treatment with Mc,SiOI provides a one-pot synthesis of 2-isoxazoline derivatives. The reaction proceeds through a 1,3-dipolar cycloaddition of trimethylsilyl nitronate with an a-cyanovinylphosphonate. Similarly, the 1,4-addition of the sodium diethyl cyanomethylphosphonate to the azo-ene system of conjugated alkenes results in the formation of l,2-diamino-3-(dietlioxyphosphinyl)pyrroles in moderate to good yields via a hydrazonic intermediate. - In a route to phosphonylated pyrones, the sodium diethyl cyanomethylphosphonate reacts with 3-anilinometliylene derivatives of 4-hydroxycouinaiins in DMF with displacement of aniline. ... 

Other applications include the Knoevenagel reaction under microwave irradiation in a solvent-free reaction. With this technique, benzaldehyde reacts in a few minutes with diethyl cyanomethylphosphonate in the presence of carefully controlled amounts of piperidine to give diethyl 1-cyano-... 

The use of magnesium cyanomethylphosphonate, prepared from magnesium in liquid ammonia, was rather disappointing. Although the combination of potassiiun metal and diethyl cyanomethylphosphonate, on heating in Et2O-dioxane, gives fair yields of a-substituted cyanomethylphosphonate, ° the best results are obtained with the use of alkali metal hydrides (NaH, KH) in THF... 

Diethyl cyanomethylphosphonate anion undergoes halogenation, rendering it a convenient precursor of diethyl 1-cyano-l-fluoromethylphosphonate. Thus, treatment of an aqueous solution of sodium enolate of diethyl 1-cyano-1-formyhnethylphosphonate with fluorine gives diethyl 1-cyano-1-fluoromethylphosphonate in 61% yield after concomitant deformylation (Scheme 6.12)." "° In contrast, treatment of unprotected lithium diethyl cyanomethylphosphonate with (CF3SO2)2NF in THF at low temperature leads to 1-cyano-1-fluoromethylphosphonate in lower yield (51%). "... 

As anticipated, sodium diethyl cyanomethylphosphonate does not undergo arylation by condensation of halobenzenes on simple heating. In contrast, the Cu(I)-mediated reaction produces diethyl cyanobenzylphosphonate in moderate yield (50%). " The reaction occurs in DMF or HMPA in the presence of Cul (1 eq) at 100°C (Scheme 6.13). This approach has provided a novel route to... 

Arylation of diethyl cyanomethylphosphonate can also be efficiently catalyzed by Pd(0). 5 " When 4-substituted bromo- or iodobenzenes are heated with sodium diethyl cyanomethylphosphonate in the presence of a catalytic amount of Pd(PPh3)4 in refluxing DME, diethyl cyanobenzylphos-phonates are isolated in 69-86% yields (Scheme 6.13). By a similar procedure, 2- and 3-bromopy-ridines and 2-bromothiophene are phosphonylated in high yields (59-80%)." ... 

Nucleophilic aromatic substitution of activated substrates (pentafluoropyridine, octafluorotoluene, hexafluorobenzene, metal arene jc-complexes) by anions of diethyl cyanomethylphosphonate has been achieved. The reaction is carried out with satisfactory yields in DMF, MeCN, or THF at room temperature in the presence of NaH, CsF, KjtX), or CS2CO3." In a similar manner, 3,6-dihalopyridazines react with sodium diethyl cyanomethylphosphonate in refluxing THF to give phosphonosubstituted pyridazines in 22-68% yields. ... 

Acylation of dialkyl cyanomethylphosphonates was first accomplished using potassium metal in Et2O and acyl chlorides. The resulting a-cyano-3-kctoalkyIphosphonates were isolated in modest yields (24-36%), usually as a mixture of the keto and enol forms. The recently reported procedure using powdered NaOH or KOH in MeCN offers a more convenient route and better yields (17-90%, Scheme 6.14). 2-Chloroethyl chloroformate reacts with sodium diethyl cyanomethylphosphonate in THF to produce diethyl l-cyano-(l,3-dioxolan-2-ylidene)methylphosphonate in 83% yield by a C-acylation-O-alkylation sequence. 

The yields are not so good when the ester function serves as leaving group. Thus, diethyl 1-cyano-l-oxalyhnethylphosphonate is obtained in 55% yield from diethyl oxalate and hthium diethyl cyanomethylphosphonate in THF at low temperature and in 64% yield from the sodium salt in refluxing Et2O. - Acylation using TFA esters and TFAA has also been reported. ... 

An alternative procedure is the reaction of A,A-dimethylformamide dimethyl acetal with diethyl cyanomethylphosphonate. In this case, the reaction proceeds spontaneously at room temperature to give the corresponding enaminophosphonate in high yield (95%, Scheme 6.15). Hydrolysis under basic conditions (2 M NaOH) at room temperature leads to diethyl 1-cyano-l-formyl-methylphosphonate in 83% yield in the enolic form exclusively. "... 

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