Phosphonate reagent

The title phosphonate and related substances undergo thermal decomposition to B-acyl ketenes at temperatures in excess of 50°C. Thus thermolysis in the presence of alcohols, amines, a-hydroxy esters, and a-amino esters affords the corresponding g-keto esters and amides the latter two classes can be cyclized upon subsequent base treatment to unsaturated tetronic and tetramic acids and the related phosphonate reagents. ... 

The resulting tetramic and tetronic acid phosphonate reagents undergo the... 

The resulting tetramic and tetronic acid phosphonate reagents undergo the Wadsworth-Emmons olefination with a variety of aldehydes to afford (E)-a.B-unsaturated and diene acyl tetramic and tetronic acids in good to excellent yields upon treatment with potassium tert-butoxide (2 equiv) in tetrahydrofuran. For readily enolizable substrates use of the N-protected systems is generally required. The following compounds have been prepared, in the indicated yields, in this manner... 

IMmethyl phosphite-Chloroaceticacid, (CH30),P(0)H-C1CH2C00H. In the presence ol a base, this combination of reagents results in the phosphonate reagent (nUD.WHC HjCO, M (l)... 

Step 3 HWE-modification of the Wittig reaction tetramethylguanidine is a mild, non-nucleophilic base (much like DBU) that deprotonates the phosphonate reagent. 

Figure 19.1 Synthetic scheme for example pheromone components. Abbreviations al and a2 = Wittig-Homer condensations with triethyl 2-phosphonopropionate and triethyl 2-phosphonobutyrate, respectively b = reduction of ester with lithium aluminum hydride c = partial oxidation of alcohol with manganese dioxide to aldehyde dl and d2 = Wittig condensations with ethyltriphenylphosphonium bromide and propyltriphenylphosphonium bromide, respectively e = condensation with dimethylhydrazone phosphonate reagent f = hydrolysis under acidic conditions. Compound numbers are as in Table 19.1.

An attractive alternative to the direct preparation of enamines from mono-substituted phosphonate reagents is the use of dimethyl diazomethylphosphonate (Me0)2P(0)CH= N2. Treatment of this diazo compound with t-BuOK (or with LiOH or K2C03), followed by various ketones in the presence of secondary amines, delivered the corresponding enamines251-253 (equation 17). In the presence of amines, (MeO)2P(0)CH= N2 and RCHO afforded the terminal acetylenes RC=CH. 

In the reaction outlined in Section II.A.2.b, the desired cross-coupled product is sometimes contaminated with small amounts of symmetrical TTFs. The contaminants are believed [61] to arise because of the instability of the phosphonium salt intermediate (25). Lerstrup has reported an improved synthesis utilizing phosphonate reagents (27) that presumably circumvents this problem [62]. Dimethyltetrathiafulvalene can be synthesized in good yield with no contaminating TTF by products following the sequence in Scheme 10. 

The HWE reaction can be carried out on a ketone, but often the stereoselectivity is not as good as the reaction of a substituted phosphonate carbanion with the corresponding aldehyde. Because of the greater reactivity of the phosphonate reagent relative to the phosphonium carbanion, the HWE reaction has proven to be effective with hindered ketones that were unreactive toward classical Wittig ylides. 

Several examples are presented in Table 15 which indicate that a-heteroatom substitution is compatible with this reagent. The tremendous advantage of the trifluoroethyl phosphonate reagent is the selective formation of (Z>alkene with aromatic aldehydes, while the trimethyl phosphonate gives the normal selectivity. 

A number of methods are available for the preparation of phosphonate reagents. For example, treatment of triethylphosphite with ethyl bromoacetate Arbuzov reaction) produces the phosphonoacetate A. Its reaction with a suitable base such as NaH gives the carbanion B, which, on treatment with cyclohexanone, furnishes cyclo-hexylideneacetate C in 70% yield. This compares favorably to the 25% yield obtained when using the triphenylphosphorane Ph3P=CHC02Et. 

Relatively strong bases are used for the deprotonation of phosphonate reagents, and the phosphonate-stabilized carbanions formed are more basic than the corresponding phosphorane reagents. Such conditions may be incompatible with base-sensitive aldehydes and ketones, causing epimerization of chiral compounds or... 

By proper choice of the phosphonate reagent, the HWE reaction shows great flexibility in controlling the stereochemistry of the double bond of vinylic esters. Whereas condensation of dialkylphosphonoacetates with aldehydes gives preferentially the more stable ( )-unsaturated esters, the reaction of methyl bis(trifluoroethyl)phospho-noacetate with aliphatic and aromatic aldehydes in the presence of a mixture of KHMDS (potassium hexamethyldisilazide) and 18-crown-6 produces (Z)-a, (3-unsat-urated esters stereoselectively. ... 

A different strategy has been adopted for the transformation of 21a into 335 and 336. In these cases, one carbon atom of the final benzene ring comes from an external phosphonate reagent by means of intramolecular Wadsworth-Emmons reactions. The overall transformations can be classified as C2/C/C6 [84JCS(PI)1035]. 

Hammond, G.B.. and Zapata. A.J., Preparation and applications of fluorinated propargyl phosphonate reagents, University of Massachusetts, Int. Patent Appl. WO 9918138, 1999 Chem. Abstr, 130, 296825, 1999. 

This reaction is cnrrently nsed for the preparation of synthetically nsefnl phosphonate reagents employed in modi lied retinal stndies. Thns, dietliyl 3-alkoxycarbonyl-2-propenylphosphonates are prepared in 72-91 % yields by the reaction of metiiyT or ethyP28,729 4 bromocrotonates with triethyl phosphite at 150-160°C. Similarly, diethyl 3-(etiioxycarbonyl)-2-methyl-2-propenylphosphonate is prepared in 81% yield from triethyl phosphite and ethyl 3-methyl-4-chlorocrotonate by heating at 180-200°C7 The diethyl (E)- and (Z)-3-ethoxycarbonyl-3-flnoro-2-methyl-2-propenylphospho-nates are respectively obtained from triethyl phospliite and ( )- or (Z)-4-bromo-2-flnoro-3-methyl-2-bntenoates at 140°C%°... 

Formylolefination.1 In the presence of sodium hydride this phosphonate reagent reacts with aldehyde or ketones, for example cyclohexanone, in THF to give an a -unsaturated aldimine (3), which on hydrolysis (oxalic acid or buffered acetic acid) gives the formylolefin (4). 

The reagent is useful because the Wittig reagent (C6H5)3P=CHCHO and the usual phosphonate reagent (C2 H 5 0)2 P OCH 2 C H (O C2 H.-,), do not react with ketones. Moreover, the reaction proceeds stereoselectively to give the trans olefin thus benzaldehyde affords cinnamaldehyde in 11% yield. 

The transformation outlined in Scheme 14 nicely illustrates some of the advantages associated with the Peterson alkenation relative to the Homer-Emmons reaction for the conversion of the aldehyde (31) into the a,3-unsaturated aldehyde (32). When the corresponding phosphonate reagent is used, only the 3-hy-droxy phosphonate (33) is isolated elimination to form the a,3-unsaturated imine from (33) could not be induced under a variety of conditions. ... 

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