Diethyl phosphonate esters

In a study by Hansch, five mete-substituted diethyl phosphonate esters (12.14) showed cholinesterase inhibition in fruit flies. Correlations between cr-values, ),-values, and both parameters together were explored. The relevant data are included in Table 12.5. 

Among the early attempts of amination of lithium and copper enolates were those which involved formation of a-A-(Boc)- or A-(Alloc)amino-substituted carboxylic esters, A-acyloxazolidinones and diethyl phosphonates (Scheme 33) ° . a-Lithum or a-copper derivatives of these enolates were aminated using A-lithium derivatives of A-Alloc O-(mesitylenesulfonyl)hydroxylamine 3j, NHBocOTos 31 and NHAllocOTos 3m. 

Diethyl phosphonate Phosphonic acid, diethyl ester (8,9) (762-04-9)... 

The methanolyses of several phosphate/phosphonate esters and their thio analogues [e.g. 0,0-diethyl 0-(4-nitrophenyl) phosphate, paraoxon (101 X = O, Z = 4-N02), 0,0-diethyl S- S-dichlorophenyl) phosphorothioate, (102 R = OEt), and 0-ethyl S-OA-dichlorophenyl) methylphosphonothioate (102 R = Me)] catalysed by methoxide and the complex of Zn2+ (MeO-) with 1,5,9-triazacyclododecane (79 M = Zn) were studied in methanol at 25 °C. The reaction of methoxide and (79 M = Zn) with the entire series of esters appears to adhere to a common mechanism that involves pre-equilibrium binding of the substrate, followed by intramolecular attack of the coordinated methoxide concerted with OAr or SAr leaving group departure.79... 

Finally, ortho- 2,2-dibromovinyl)-aniline or -acetanilide can successfully be applied in a sequential cyclizing amination-cross coupling reaction with diethyl phosphonate to furnish the indolyl phosphonic ester 136 or the N-acetyl 2-aryl indole 137 as recently shown by Bisseret and coworkers [ 105] (Scheme 50). This sequence can be also performed with corresponding phenol derivatives furnishing benzofurans. For the N-acetyl 2-aryl indole 137 it can be shown that the Suzuki coupling occurs prior to the intramolecular animation as a consequence of the gradual difference in reactivity between trans-and czs-carbon-bromine bonds. 

In the presence of [PdMe2(PMePh2)3] diethyl benzoylphosphonate is degraded during minutes and with quantitative yield, into diethyl phenylphosphonate (l-oxoalkyl)phosphonic esters suffer a similar fate but the process may take several hours under the same conditions. When mixtures of aroylphosphonic diesters and esters of (l-oxoalkyl)phosphonic acids are brought into contact with the... 

Reduction of phenols [1, 252, after citation of ref. 3]. In achieving the synthesis of triptindane (11), Thompson obtained the methyl ether (8a) as an intermediate, demethylated it to (9), and effected deoxygenation to (11) by the method of Kenner and Williams consisting in reaction with diethyl phosphonate or mesyl chloride and reduction of the diethyl phosphate or the mesylate ester with sodium in liquid ammonia yields, first procedure 58% second procedure 36%. 

Diethyl (3-oxobutyl)phosphonate 354 The methiodide obtained from 4-(diethylamino)-2-butanone (7.15 g, 0.05 mole) and methyl iodide (7.15 g) is heated with triethyl phosphite (0.25 mole, 41.5 g) for 1 h at 130°. After cooling, the triethylmethylammonium iodide formed (10.6 g, 87%) is filtered off and washed with benzene. On evaporation the filtrate and wash-benzene leave a pale yellow oil which is distilled in a vacuum (yield 8.4 g, 81 % b.p. 89-97°/ 0.08 mm) and on redistillation gives the phosphonic ester (7.5 g, 72%), b.p. 96-98°/0.14 mm, nD25 1.4352. 

One route to (l-alkynyl)phosphonic esters depends on the base-catalysed destruction of enol phosphates (123) obtained in situ from (2-oxoalkyl)phos-phonates in the case of (123) (R = Et), a mixture of (1-butynyl)- and (2-butynyl)-phosphonic esters was obtained, but in all other quoted cases only the acetylenic compound was obtained. A second route starts with diethyl (trichloromethyl)-phosphonate (a reagent of increasing synthetic importance) followed by sequential reaction in one-pot with BuLi (two equivalents), an aldehyde (RCHO), and a lithiumdialkylamide, and gives the products (Et0)2P(0)CsCR in very high yields. ... 

A new route to (a,a,-difluorobenzyl)phosphonic esters which does not use the DAST reagent, employs 4,4-dimethoxy-2,5-cyclohexadienone and its reaction with diethyl (lithiodifluoromethyl)-phosphonate (Scheme 7). ... 

Related reactions in the oxygen series were first observed only recently as complications in Michaelis-Arbuzov reactions. The 2-halo-alkyl phosphate and phosphonate esters which occur as intermediates in the Michaelis-Arbuzov reaction of certain cyclic phosphites and phos-phonites (cf. Section II-A-1) undergo an internal alkyl exchange reaction (eq. 4) (176). Although reaction of 8-bromoethyl acetate with triethyl phosphite is said to furnish the expected product, diethyl fi-acetoxyethylphosphonate, in 28% yield (220), reaction of this same alkyl halide with dimethyl phenylphosphonite (129) gave the expected methyl phenyl(/9-acetoxyethyl)phosphinate in not greater than 5% yield (eq. 6). Instead, the major products were d-acetoxyethyl phenyl-(methyl)phosphinate (60%) (12) and a mixture of ethylene bi [phenyl-(methyl)phosphinate], [CH20P(0)(Me)Ph]2, (13) and an, ester of... 

Methanesulfonate and p-toluenesulfonate esters have been employed for this purpose in our own laboratory. Since the relative reactivity of alkyl p-toluenesulfonates with other nucleophilic reagents, including sodium diethyl phosphonate (128), lies between those of chloride and bromide, a similar relationship would be expected to apply here also. 

A variation of this type of reaction involving interaction of tetraethyl pyrophosphite with an amino acid has been employed for peptide synthesis (12). In this instance, the initial product, an acyloxy phosphite (22), is sufficiently reactive to interact with an amino acid ester to yield a peptide and diethyl phosphonate. 

Michaelis-Becker reactions have been carried out in two-phase systems even under such mild conditions, isomerization of prop-2-ynylphosphonic diesters occurs to give a 90% combined yield consisting of a mixture of diethyl propadienylphosphonate and diethyl-propy-l-nylphosphonate (85 15). Some of the allylic halides furnish small amounts of phosphonic esters, but others, and also benzyl halides, only undergo reaction in the presence of a long-chain tertiary amine hydrochloride catalyst. Dialkyl hydrogenphospho-nates and tertiary benzylamines react together to give dialkyl benzylphosphonates ". ... 

The rearrangement of dialkyl 3-pyridinyl phosphates and thiophosphates under the influence of a base (Ida) at low temperatures has been shown to be remarkably regioselective. In the case of the diethyl phosphate ester, the sole product is diethyl (2-hydroxy-4-pyridinyl)phosphonate with the corresponding thiophosphate O, O, (9-triester, diethyl (3-hydroxy-2-pyridinyl)phosphonothioate is formed in a large excess over the (2-hydroxy-4-pyridinyl)phosphonothioic diester ... 

R = O-alkyl, n= 1) in the same way, diethyl phenylphosphonite affords 11 (R = Ph, R = Et, = 1, X = I). Bromoform and iodoform, although reactive to trialkyl phosphites, tend to yield alkyl halide, dialkyl hydrogenphosphonate and dialkyl phosphorohalidate, but (halomethyl)phosphonate esters are not obtained. With tetrahalomethanes, particularly those based on two or more different halogens, a more interesting picture is presented. Triethyl phosphite and tetrabromomethane are reported to yield EtBr quantitatively but... 

The reaction between lithiated diethyl propenylphosphonate and ethyl propenoate leads to carbon-carbon bond formation involving either C(i) or C(3) of the phosphonate ester. Thus, ethyl but-2-enoate or but-3-en-2-one yielded 481 and 482, respectively, and the esters 483 were obtained from coumarin, all by simple addition, but addition-elimination and multiple addition processes were also described. 

Rare examples of normal Michaelis-Becker reactions which involve co-chloroalkanal diethyl acetals are to be found, and although the formation of dialkyl acylphosphonates from sodium dialkyl phosphites and, for example, benzoyl chloride, is to be observed at -85 °C, the system is further complicated, even at -10 °C, by further addition steps followed by rearrangements which would seem to render the process of little value for the synthesis of oxoalkyl phosphonic esters On the other hand, in a more detailed and systematic study of reactions between sodium dialkyl phosphites, (RO)2PONa(R = Et or Bu), and the ketones R CO(CH2) Cl, Sturtz and others have observed the formation of epoxides when n = 1 and (1-hydroxy alk-2-enyl)phosphonic diesters when n = 2(R = Me or Pr ), according to the displacement in 532, and of derivatives of tetrahydrofuran or tetrahy-dropyran, according to 533 n = 3 or 4) when R = Et, the formation of the cyclic ethers was accompanied by low yields of the expected (oxoalkyl)phosphonic diester, but otherwise the latter were isolated as a single product only for R = Me, n = 5, and R = Et or Pr when n = 2. 

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