Acylphosphonates reactions

Takamizawa et al. developed a general ring-expansion reaction of heterocycles that, applied to thiazolium salts, yields 1,4-thiazines (496, 497) thiamine (220) reacts with dialkyl acylphosphonates (221) to give the tricyclic 1,4-thiazine (222) (498), which is easily hydrolyzed to dihydro-1,4-thiazinone (223) (499) (Scheme 106). In the case of thiazolium slats containing no functional groups (224), 1,4-thiazine derivatives (226) were directly obtained in fairly good yields (Scheme 107). 

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

Figure 26. Proposed stereochemical model for the hetero-Diels-Alder reaction of ethyl vinyl ether and acylphosphonate catalyzed by 55c-Cu(II) complex.

The hetero-Diels-Alder reaction between a,p-unsaturatcd ketoesters and nucleophilic alkenes has been described in two concurrent and independent reports (220, 222). As with acylphosphonates, these proved to be excellent substrates for catalyst 269c. The reaction proceeds efficiently in THF at low temperatures providing the cycloadduct in >99% ee at -78°C. Indeed, the impressive selectivity exhibited under these conditions allows the reaction to be conducted at a convenient temperature of 0°C, using the hydrated catalyst 266c in the presence of molecular sieves, Eq. 181. Observed diastereoselectivities... 

Reaction of Azolium Ylides with Dialkyl Acylphosphonate New Synthesis of Heterocyclic Compounds A. Takamizawa et al., Heterocycles, 1974, 2, 521-554. 

The oxazoliumcarboxylic acid (147) is easily decarboxylated via the ylide (148) the neutral compound (149) is much more stable due to the low equilibrium concentration of the zwitterionic tautomer (150 Scheme 7). Oxazolium salts lacking substituents at the 2-position react with dialkyl acylphosphonates in the presence of triethylamine to give mixtures of l,4-oxazin-3-ones and 2-azetidinones the reaction (see Scheme 8) proceeds by electrophilic attack of the phosphonate on an oxazolium ylide, e.g. (151), followed by insertion of oxygen into the carbon-phosphorus bond, ring-opening, and formation of the enolate anion (152) which can cyclize in two alternative ways with expulsion of the phosphonate group. 

The reaction is also facile (no external heating) and proceeds in high yield when the snbstrate is an acyl halide or related material. Snch reactions, producing acylphosphonate derivatives (eqnation 28), are of nse for the preparation of componnds for a variety of practical applications. ... 

The first examples of the Pd-promoted decarbonylation and metathesis reactions of acylphosphonic diesters have been reported. 

An alternative approach to preparation of a-ketophosphonates is indicated in a report that acylphosphonates can be obtained by heating the silyl diester of the corresponding hemiacetal above 140°C [20]. However, the spectroscopic data presented in this paper (IR, 31P-, 13C-NMR) do not appear to fully support the acylphosphonate structure assigned to the reaction product. 

The utility of Sm in deoxygenative coupling of carbonyl compounds has already been discussed [38]. One study has been published on the reaction of acylphos-phonates with another lanthanide metal, Yb [46]. Ytterbium converted a substituted acylphosphonate under mild conditions (THF, HMPA, rt) to 1,2-diphenyl-2-oxoethyl phosphate and l-(phosphoryloxy)-l-phenylmethylphosphonate. The reactivity of Yb was explained in terms of its oxophilicity, leading initially to an acylytterbium complex. 

Hanis. R.L.N., and McFadden, H.G., Acylphosphonates as substrates for Wittig and Homer-Wittig reactions. Unusual stereoselectivity in the synthesis of P-phosphinoylacrylates, Aust. J. Chem., 37, 417. 1984. 

Dialkyl acylphosphonates were obtained for the first time by Kabachnik and Rossiiskaya in 1945 by the reaction of acyl chlorides with trialkyl phosphites. The reaction proceeds readily at room temperature and even on cooling by slowly adding trialkyl phosphite to acyl chlorides. Improvements have been made, especially by controlling the temperature of the reaction. The different versions of this reaction, which are distinguished by the nature of the acylating agent and the structure of the phosphite, have been covered by the reviews of Zhdanov et al. in 1980, Breuer in 1996," and McKenna and Kashemirov in 2002. ... 

Reaction between equimolar amounts of dialkyl chlorophosphites and acyclic acid anhydrides at 50°C has been reported to produce the corresponding dialkyl acylphosphonates in satisfactory yields (70-75%), but the general utility of this procedure remains to be demonstrated. On pyrolysis, diethyl 1-oxoethyIphosphonate produces ketene and diethyl phosphite. ... 

The previous reactions suggest that trialkyl phosphites are able to react with acylphosphonates. Effectively, it has been shown that the reaction of trimethyl phosphite with dimethyl aroylphos-phonates under appropriate conditions leads to the formation of anionic adducts that decompose to give phosphonyl carbenes and trimethyl phosphate. These carbene intermediates can react with further trimethyl phosphite to give ylidic phosphonates, or, when suitable < rt/z<9-substituents are present on the aromatic ring, intramolecular carbene insertion reactions can occur to give cychc systems (Scheme 7.4).38.4o,56,58-65... 

The Michaelis-Arbuzov reaction has been applied to t/7.v(trialkylsilyl) phosphites, which, on reaction with aliphatic or aromatic acyl halides in Et2O or CgHg at room temperature, undergo the rearrangement in mild conditions to produce the valuable fczXtrialkylsilyl) 1-oxoalkyl- or 1-oxoarylphosphonates in good yields (50-77%, Scheme 7.6). - Free acylphosphonic acids are obtained by treatment of the trimethylsilyl) esters with EtOH or by exposure to air for several hours. 

The Michaelis-Arbuzov reaction works well for the less complex aroyl and alkanoyl chlorides, where purification by distillation is possible. Moreover, there has been less success in the preparation of oc,P-unsaturated acylphosphonates, where multiple addition products are often observed. Recourse has been found in an attractive route that entails oxidation of dialkyl 1-hydroxyalkyl- or 1-hydroxyaryIphosphonates produced by nucleophilic addition of dialkyl phosphites to carbonyl compounds under basic conditions (Pudovik reaction). Alkali metal salts of dialkyl phosphites are currently used in the Pudovik reaction, and the more common procedure of generating the anion involves the addition of a small amount of alcoholic alkoxide ion to the reaction mixture. Neutral amines represent an alternative to the use of anionic bases. In recent years, the use of solid-phase materials as basic catalysts has been successfully developed (Scheme 7.7). One system involves the addition of basic alumina to the carbonyl compound and dialkyl phosphite the other involves the addition of KF or CsF to the mixture of carbonyl compound and dialkyl phosphite. - Such a process for generating dialkyl 1-hydroxyalkyIphosphonates is very flexible and accommodates a large variety of carbonyl compounds. 

One example of reductive amination of acylphosphonates has been reported. Thus, reaction of dimethyl 1-oxoalkylphosphonates with benzhydrylamine results in the formation of an imine reduced in situ with NalllKOAc),. The reaction is independent of the solvent, and THF, CIFCh and CHCI3 give similar results - After selective removal of the benzhydrylic group by catalytic hydrogenation and hydrolysis with concentrated HCl, the 1 -aminoalkylphosphonic acids are isolated in satisfactory yields (30-60%, Scheme 7.66) ... 

Hydroxylamine reacts with acylphosphonates to give the corresponding oximes. The reactions are usually carried out by reacting hydroxylamine hydrochloride with dialkyl acylphosphonates in the presence of Py in absolute EtOH (Scheme Yields are generally near quantitative, and... 

Activated methylene compounds such as malononitrile and isocyimoacetates - react with acylphosphonates in the presence of bases, piperidine, or Nall to give p-functionalized-ot-hydrox-yphosphonates. These adducts undergo successive dehydration to the vinyl analogue followed by hydration of either the cyano (Scheme 7.73)" or the isocyano groups." In the case of isocyanoac-etate, the same result is obtained by conducting the reaction between acylphosphonates and isocy-anoacetate in refluxing THF in the presence of ( ibO. ... 

The course of the reaction between acylphosphonates and 1-nitroalkane carbanions depends on the nature of the acyl group. Thus, nucleophilic addition of nitromethane to acetylphosphonates in the presence of di- or triethylamine results in the formation of dialkyl 1-hydroxy-l-methyl-2-nitro-ethylphosphonates (R = Me, = H, Scheme 7.75)." " However, the procedure is not applicable to the synthesis of dialkyl 1 -hydroxy-l-pheny 1-2-nitrocthyIphosphonate because the electron-with-drawing ability of the benzene ring destabilizes the molecule toward alkali and results in C-P or C-C bond cleavage. The fact that diisopropyl 1-hydroxy-l-phenyl-2-nitroethylphosphonate was... 

Diethyl acylphosphonates, on treatment with diethyl trimethylsilyl phosphite at room temperature, produce high yields of symmetric diethyl (l-trimethylsilyloxy)alkylidenediphosphonates (Scheme The same reaction has been applied to diphcnyl(trimethylsilyl)phosphine. "... 

Acylphosphonates are suilable carbonyl substrates for Wittig and Homer-Wadsworth-Emmons reactions, but with certain limitations. 5° These limitations are the result of competing side reactions involving proton iransfer or acylation. Homer-Wadsworth-Emmons reactions fail with... 

It has been shown qnite recently that oc,P-unsaturated acylphosphonates participate in hetero-Diels-Alder reactions with electron-rich olefins. The heterocycloaddition reactions between dimethyl 1-0x0-2,4-hexadienephosphonate (10 1 mixture of E,E- and E.Z-dienes) and 2-aIkylidene-... 

The enantioselective hetero-Diels-Alder reactions of a,p-unsaturated acylphosphonates with enol ethers catalyzed by Cu(II)bzT(oxazoline) complexes have been investigated in depth. It was found that Cu(II)bA(oxazoline) complexes activate a,p-unsaturated acylphosphonates to the extent that they undergo facile cycloaddition reactions at low temperature with electron-rich alkenes. For example, dimethyl ( )-l-oxo-2-butenylphosphonate reacts with ethyl vinyl ether in the presence of Cu[(S,5)-t-Bu-box] (OTf)2 complex (10 mol% catalyst) to generate the cycloadduct in 89% yield (Scheme 7.86) with exceptional stereoselectivity (endo/exo = 99/1, 99% ee). Cyclic enol ethers also undergo stereoselective reactions with dimethyl ( )-l-oxo-2-butenylphosphonate. It specifically reacts with 2,3-dihydrofuran in the presence of Cu[(5,5)-t-Bu-box] (OTf)2 to deliver the bicyclic enolphosphonate. Of particular merit is the fact that a large variety of p.y-unsaturated acylphosphonates may be tolerated with no loss in selectivity for the derived cycloadducts. ... 

NaBH3CN,5" BH3 MciS,-" calecholhorane," Al(O/ -Pr)3, ° or activated Zn in AcOH.5°5 Reduction of acylphosphonates using NaBH4 needs careful control of the reaction conditions (H2O or MeOH, KH2PO4, 0-5°C, pH = 6-7) to avoid hydrolysis of both starting acylphosphonates and reaction... 

Brittelli, D.R., A study of the reaction of 2-haloacyl halides with trialkyl phosphites. Synthesis of 2-siibsliliilcd acylphosphonates, J. Org. Chem.. 50. 1845, 1985. 

---