Addition of phosphonyl

Addition of phosphonyl radicals onto alkenes or alkynes has been known since the sixties [14]. Nevertheless, because of the interest in organic synthesis and in the initiation of free radical polymerizations [15], the modes of generation of phosphonyl radicals [16] and their addition rate constants onto alkenes [9,12,17] has continued to be intensively studied over the last decade. Narasaka et al. [18] and Romakhin et al. [19] showed that phosphonyl radicals, generated either in the presence of manganese salts or anodically, add to alkenes with good yields. 

Scheme 16 1,4-Addition of phosphonyl radical to enones triggered by a SET...

In another series of experiments, addition of phosphonyl radicals to carbohydrate gem-difluoroenol ethers was investigated as a route to new anomeric carbohydrate difluoromethylene phosphonates 261,262 Phosphonyl radicals could be produced from either diethyl phosphite in the presence of di-ferf-butyl peroxide in refluxing octane, or diethyl(phenylselenyl)phosphonate, on treatment with n-Bu3SnH (plus AIBN) added slowly to a benzene solution under reflux. With the first method,... 

Addition of phosphonylated Schiff base to ethyl acrylate, under phase-transfer catalytic conditions in the presence of Aliquat 336 and KOH at room temperature, leads to the 1 1 Michael adduct with 60% yield (Scheme 8.57). The tert-butyl and ketimine protecting groups are eliminated under mild conditions (1 M HCl, room temperature) to provide the phosphonic analogue of glutamic acid. 

Electrophilic reaction can account for the additions of morpholine or phosphonyl (Scheme 14), or... 

An alternative approach is to have the chiral auxiliary on the enolate. Sweeney has reported the addition of bromoacyl sultam 102 to phosphonyl imines 103, which afforded the cis- or trans-aziridines with high levels of diastereoselectivity depending on the imine substituent (Scheme 1.30) [55]. 

The reactivity of electrochemically generated phosphonyl radicals has been recently reviewed by Kargin and Budnikova [8] and will not be considered here. The reactivity of phosphonyl radicals is mainly accounted for by the three processes [9] shown in Scheme 2 radical addition (1), atom transfer (2 and 3), and electron transfer (4). 

The phosphonyl adduct 300 reacted with a dilute solution of anhydrous hydrogen chloride in ethanol or with sodium ethoxide to afford an essentially quantitative yield of the P-N cleaved product 304 with inversion of configuration. Addition of sodium ethoxide to a solution of 304 in methanol resulted in the formation of enantiomerically pure (+)-(.V)-ethyl methyl phenylphosphonate (305). It also reacted quantitatively with methylmagnesium iodide at room temperature to give the product of P-S bond cleavage 306, which upon acid catalyzed methanolysis afforded enantiomerically pure (+)-(R)- methyl methylphenylphosphinate (307) (Scheme 72) [108],... 

More recently, 2-thioxo-4-thiazolidinones 415 were reported to undergo facile thiophilic addition of a-phosphonyl carbanions and subsequent lactamization to generate bicyclic thiazolo [2,3-A thiazole-3,5-diones 416 (Equation 189) <2004PS1307>. 

The authors have also observed that reverse addition of a carboxylic acid to a mixture of PPAA, hydroxylamine and TEA gave a lower hydroxamate yield (16% with oleic acid) compared to the direct addition, suggesting a certain competition between carboxylate and hydroxylamine for phosphonylation. 

The light-induced addition elimination reaction of diethyl phosphite to both 1,3,3,4,4-penta-fluorocyclobutene and l-chloro-3,3,4,4-tetrafluorocyclobutene afforded a mixture of diethyl 3,3,4,4-letrafluorocyclobutene-l-phosphonate (11) and tetraethyl 3,3,4,4-tetrafluorocyclobutane-1,2-diphosphonate (12). The postulated mechanism of addition involves phosphonyl radical attack at the cyclobutene moiety.17... 

As may be seen from Table n, the stereochemistry found for the products resulting from the addition of a phosphonyl radical to a difluoroenol ether double... 

Free radical cyclization of 1,6-diene (120) using diethyl phosphite or diphenylpho-sphine oxide initiated by peroxide, produces an organophosphorus compound (121) via the addition of a phosphonyl radical to an olefinic group (eq. 4.42a). Radical addition of PH3 to limonene (122) results in the formation of 4,8-dimethyl-2-phosphabicyclo[3.3.1]-nonane (123) (eq. 4.42b) [121, 122]. 

Binding of sarin and soman to a tyrosine residue present in blood has been observed by Black et al. (51) When sarin or soman was incubated with human plasma, phosphonylated tyrosine was observed by LC/MS after Pronase digestion, in addition to phosphonylated serine. The precise site of this residue has not yet been confirmed but it is associated with the albumin fraction. A phosphonylated tryptic peptide [/-PrO(CH3)P(0)]-Tyr-Thr-Lys, consistent with albumin, has been identified but this sequence is also present in other proteins. Before the advent of modem mass spectrometry, diisopropyl fluorophosphate was reported to bind... 

Free radical promoted, cationic polymerization also occurs upon irradiation of pyridinium salts in the presence of acylphosphine oxides. But phosphonyl radicals formed are not oxidized even by much stronger oxidants such as iodonium ions as was demonstrated by laser flash photolysis studies [51, 52]. The electron donor radical generating process involves either hydrogen abstraction or the addition of phosphorus centered or benzoyl radicals to vinyl ether monomers [53]. Typical reactions for the photoinitiated cationic polymerization of butyl vinyl ether by using acylphosphine oxide-pyridinium salt combination are shown in Scheme 10. 

Addition of diethyl phosphite to aldimines bearing less bulky substituents (e.g., CH3 or Et)39 proceeds with very low stereoselectivity and leads to the various diastereomeric products in comparable amounts. For this reason a new phosphonylating agent was introduced, trisftri-methylsilyl) phosphite40. However, the stereoselectivity with this reagent is not much improved, although yields increased by ca. 20 %. 

Notable were highly enantioselective additions of N-phosphonyl imines with dialkyl zinc or hydroxyketones and a one-pot reaction of alkynylzirconocenes with alkynyl phosphazenes and zinc carbenoids to give single isomer cyclopropylphosphonamides. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. Other interesting reports cover the use of phosphoramidates for the synthesis of allylic amines as well as the first example of C-P cleavage of a-aminophosphono acids using periodate. 

Treatment of diethyl 2-chloroethynylphosphonate with binucleophilic reagents such as ort/zo-phe-nylenediamine, ort/zo-aminophenol, or 2-aminoethanol leads to phosphonylated benzimidazoles, ben-zoxazoles, and 4,5-dihydroxazoles by a mechanism involving initial substitution of the halogen followed by addition of the second nucleophilic center at the same carbon atom (Scheme 1.36). ... 

More recently, another example involving the intermediacy of phosphonylated sul fines has been reported. Treatment of diethyl 3-methyl-l,2-butadienylphosphonate with LDA at low temperature followed by reaction with MejSiCl leads to the desired diethyl l-(trimethylsilyl)-3-methyl-l,2-butadienylphosphonate. The addition of alkyllithiums to the a,P-doublc bond of this very unstable compound gives the a-phosphonylated carbanions, which are allowed to react with an excess of SO2. The resulting sulfines are stirred overnight, and only low yields of diethyl 2-thienylphospho-nates (12-25%) are obtained, contaminated with protonated anion (Scheme 2.23). The separation of these two compounds proved to be problematic. The major disadvantage of the method is the incomplete reaction of the anion with S02. ... 

HCl at room temperature produces optically active l-ctiloroalkylpliosphonic acids in 65-86% overall yields. -" The Michael addition of the same chloromethylphosphonamide to P-substituted tert-butyl acrylates gives, after cyclization, the corresponding phosphonylated cyclopropanes in 46-80% yields. The high selectivities observed in some cases seem to result from a combination of steric and electronic tacioi s. - ... 

Exposed to hydrolytic conditions at different pH (2, 6,10), tetraethyl oxiranylidene-l,l-diphos-phonate reacts very slowly with water. " The reaction of tetraethyl oxiranyhdene-l,l-diphosphonate with several primary amines, including -propylamine, cyclohexylamine, benzylamine, and ally-lamine, has been examined, and the phosphonyl phosphates were isolated as the major products in 40-63% yields (Scheme 4.38). It seems very likely that the formation of phosphonyl phosphates is the result of a rearrangement either in concert with (path a) or subsequent to (path b) the opening of the epoxide with amine and generation of an intermediate alkoxide ion. When di- -propylamine was used, a second product, ethenylidene-1-phosphonyl-1-phosphate, corresponding to the loss of amine by elimination, is formed (32%) in addition to aminoethyl-l-phosphonyl-1-phosphate (20%). ... 

An interesting approach to the central eight-membered ring of ceroplastol I is based on an intramo-lecnlar Homer-Wadsworth-Emmons reaction employing a diethyl 7-formylalkylphosphonate. The C-7 aldehyde, protected as a 1,3-dioxolane, is obtained in 20% yield by a Michael addition of an alkenyllithium to 2-(diethoxyphosphinyl)cyclopentenone in THF at -78°C. Hydrolysis of the acetal nsing HjO and TsOH in reflnxing acetone yields 89% of the phosphonylated ketoaldehyde (Scheme, 5.56). ... 

The same strategy has been used to prepare trans bicyclic enones. The protected C5 phosphonylated aldehyde is obtained in 84% yield by a CuBr SMe2-mediated Michael addition of the Grignard reagent derived from 4-chlorobutyraldehyde diethyl acetal to a 5-phosphonylated 2,3-dihydro-4-pyridone in THF. Subsequent room-temperature hydrolysis of the acetal using aqueous oxalic acid in THF affords a near-quantitative yield of the crude aldehyde, which undergoes an intramolecular Homer-Wadsworth-Emmons reaction under treatment with Et3N/LiCl in THF at room temperature (89%). ... 

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. ... 

The applicability of cyanation has been successfully demonstrated in several instances. Thus, a 2 -phosphonylated 3 -trifluoromethylsulfonyhiucleoside reacts smoothly with w-Bi Nf N in MeCN to give the cyanation product in 45% yield (Scheme 6.36). With halo derivatives, assistance is needed, and 3-bromo-3-(l-trityl-l,2,4-triazol-3-yl)propylphosphonate reacts with NaCN and 15-crown-5 in DMF at room temperature,2 295 whereas diethyl 4-(bromomethyl)benzylphosphonate reacts with KCN and Nal in AcjO/HgO.- The preparation of (3-cyanaziridiii-2-yl)methylphospho-nates by addition of McjSiCN to (2H-azirin-2-yl)metliylphosphonates has also been reported. ... 

With heating in the presence of aqueous HCl, alcohols add to the triple bond of phosphonylated nitriles to produce the corresponding iunidcs. - Several variations on the preparation of diethyl l-(thioacetamido)methylphosphonate by mercaptolysis of diethyl cyanomethylphosphonate have been reported. Best yields, up to 90%, are obtained by addition of H2S to a suspension of diethyl cyanomethylphosphonate, EtjN, and tetrabutylphosphonium bromide in toluene (Scheme 6.59). The early reported procedure using mercaptolysis at room temperature of a mixture of diethyl cyanomethylphosphonate, EtjN, and Py led to diethyl l-(thioacetamido)methylphosphonate in low to good yields (23-85%). The addition of cysteamine to the cyano group has also been reported. ... 

In the presence of DBU and MejSiCl in CH2CI2, the addition of diethyl phosphite to the readily available nitroalkenes gives transient a-phosphonyl nitronates, which are smoothly converted into P-ketophosphonates on treatment with MCPBA. The procedure is useful to prepare a variety of diethyl l-aryl-2-oxoaIkyIphosphonates (Scheme 7.53). ... 

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