Phosphonate anions generation

The copper-catalyzed cross-coupling of vinyl bromides with secondary phosphites has been reported (Scheme 4.334) [497]. Copper iodide was an effective catalyst for this reaction however, three equivalents of Cul were needed for each vinyl bromide. The authors were pleased to find that the stereochemistry of the vinylphosphonate mirrored the starting vinyl bromide. Although HMPA was a superior solvent for the reaction chemistry, the authors successfully used other solvents snch as DMF and tetramethylurea due to the potential carcinogenicity of HMPA. The overall reaction was carried out in two stages with the phosphonate anion generated in the first step, while the cross-coupling reaction was carried out in the second step. 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

Olefination Reactions Involving Phosphonate Anions. An important complement to the Wittig reaction involves the reaction of phosphonate carbanions with carbonyl compounds 253 The alkylphosphonic acid esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are generated by treating alkylphosphonate esters with a base such as sodium hydride, n-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.254... 

Potassium hydride (KH) is a reactive base possessing a potassium cation and a hydrogen anion (hydride ion). The hydride ion reacts as any other base mentioned thus far and extracts acidic protons generating hydrogen gas and leaving behind anions with associated potassium cations. In this case, the dimethyl cyanomethyl-phosphonate anion, F, is formed. 

The better defined participation of carbonyl radical anions is evident [56] in the electrocatalyzed reaction between aromatic carbonyl compounds (or other easily reduced carbonyl compounds) and dialkyl phosphonates (Scheme 18). In similar vein, and also in Scheme 18, radical anions generated from aromatic aldehydes may abstract a proton from an added acidic hydrocarbon such as fluorene (pXa22.6) or indene (pXa20.1), and the resulting carbanion adds to unreduced aldehyde. The chain reaction is propagated by protonation of the addition product by another molecule of hydrocarbon [57]. Reaction is by controlled potential coelectrolysis in THE, at the aldehyde reduction potential, and substantial yields are only obtained with 2,6-dichlorobenzaldehyde. 

Another variation of the Wittig reaction is the Wittig-Horner reaction, in which the anion generated ot- to phosphine oxide is used as a nucleophile to react with carbonyl compounds. The intermediate formed in this reaction, -hydroxyphosphine oxide, is isolable particularly when bases with lithium counterion are used for deprotonation. Since the j6-hydroxyphosphine oxides are diastereomers, they can be separated and subjected to elimination to form the corresponding alkenes. Since the elimination of phosphonate moiety is syn, stereospecific alkenes are obtained from the elimination step. As expected, the generation of erythro and threo isomers is dependent on the solvent and the reaction conditions. 

General.—The factors affecting the cisUrans ratios of alkenes obtained by the condensation of anions generated from cyclic phosphonates have been studied. Larger amounts of cu-alkenes are obtained, particularly when using phosphonate (96). 

The Masamune-Roush modification of the HWE is a very mild variant that does not require the use of a strong base (i.e., NaH or n-BuLi) to generate the phosphonate anion. Instead, in the presence of LiCl, a lithium chelate fonns which enhances the acidity of the a-protons. Hence, DBU is sufficiently basic to cany out the deprotonation of the phosphonate. 

Renewed efforts have been made to sterically control the Michael addition of allylic phosphonate carbanions to cyclic enones. The anions generated by the... 

In a recent approach [66], 2,4,6-trisubstituted or 2-aminosubstituted pyridines 173/174 can be prepared in a one-pot cyclocondensation of methyl phosphonate anion with nitriles, aldehydes and enolates of methyl ketones or nitrile a-carbanions (followed by dehydrogenation) via in-situ generated a,p-unsaturated imines 172. 

Generation of Phosphorus Ylides and Phosphonate Anions. NaHMDS isthemostutiUzedbaseforthedeprotonation of a variety of phosphonium salts to generate the corresponding ylides, which then undergo Wittig reaction with a carbonyl compound. More recently, it was shown that such a base is compatible with a variety of other systems. For instance, it was shown that allenes and dienes could be prepared, respectively, from aromatic and alicyclic aldehydes when reacted with (Me2N)3P=CH2 in the presence of 4 equiv of NaHMDS and titanium trichloride iso-propoxide (eqs 30 and 31). ... 

In this new scheme, the initial step is the reaction of the amine with dialkyl H-phosphonate to form the corresponding monoalkyl phosphonium salt. The subsequent three steps form the catalytic cycle that leads to product formation. The anion of the monoalkyl H-phosphonate, acting as a base, first deprotonates the dialkyl H-phosphonate to generate the reactive diaUcyl phosphite anion. In the subsequent step, which is the same as in the originally proposed mechanism of that reaction, dialkyl chlorophosphate is formed along... 

Sodium hydride Is a strong base deprotonatlon of the a-protons proceeds easily, generating a phosphonate anion, which reacts with the added ketone by nucleophilic addition. Cycllsatlon to form an oxaphosphetane Intermediate Is followed by collapse with formation of a P=0 bond giving the product alkene. 

An attempt was made to synthesize the bicyclic retinoids (247) directly by Simmons-Smith cyclopropanation of ethyl retinoate (24). Only isomerized starting material was obtained (Dawson et aL, 1981b). It was therefore necessary to develop a separate, multistage procedure for the synthesis of (247). Initially, cyclopropanated p-cyclocitral (243) was reacted with the weakly nucleophilic anion of the phosphonate (244), generated by means of sodium hydride in di-methylsulfoxide. This procedure, too, failed to give the desired molecule (247), and the product obtained was merely the derivative (245) containing an expanded ring. 

The benzoates (648) and (649), which can be regarded as modified structures of (all- )-retinoic acid (3) and (9Z)-retinoic acid (348), were synthesized by both nonstereoselective and stereoselective routes. The stereoselective route, which dispenses with the extremely difficult separation of the E and Z esters (648) and (649), is more productive. P-Ionone (125) reacted with the PO-stabilized anion generated from the phosphonate (646) to give a mixture of the isomeric ethyl esters (648a) and (649a), which was difficult to separate into the pure components, even by HPLC. 

The formation of phosphonate anions has also been achieved using LHMDS to generate Horner-Wadsworth-Emmons reagents. For instance, the final coupling step in the synthesis of leukotriene B4 involving phosphonate 16 and aldehyde 17, in the presence of LHMDS, leads to -alkene 18 in 77% yield (eq 53). ... 

The report on the synthesis of the phosphonate isostere of AZT 5 -phosphate by a BF3-Et20-catalyzed nucleophilic addition of diethyl methanephosphonate to an oxetane prompted us to apply the same reaction conditions to the opening of epoxides. Indeed, when the anion of the same phosphonate was generated with BuLi in THF, followed by the sequential addition of epoxide 10a or 10b and BF3-Et20 at -78°, the corresponding P-hydroxyphosphonates 20 (a and c) were obtained in quantitative yield.26 Extension of this reaction to a phosphorus nucleophile proved to be equally effective. Thus, when diethyl phosphite was condensed with the same epoxides under identical reaction conditions, the corresponding P-hydroxyphosphonates 20 (b and d) were isolated in... 

Because dialkyl phosphonates undergo phosphite-phosphonate tautomerism, a simple strategy to accelerate the phosphite-phosphonate tautomerization is the deprotonation of phosphonates using a base. Inorganic bases, such as potassium carbonate, which have relatively weak basicity and low solubility in organic solvents, could made the dialkyl phosphonate to generate an active phosphite anion at... 

The phosphonate (176) has been used for the addition to aldehydes of a masked jS-keto-ester function and applied in the synthesis of ( )-7(f),9(t)-trisporic acid B methyl ester. The isomerically pure phosphonate (177) has been used in a synthesis of dehydro-Cig juvenile hormone," the anion being generated by treatment with lithium di-isopro-pylamide in THF-HMPT at - 65 °C for 1 min. 

Most of these reactions have been extended to ethyl bromodifluoromethyl phos-phonate (Figure 2.15). ° However, conversely to the anions of difluoroacetate, lithiated anions of diethyl difluoromethylphosphonate are easily generated through the deprotonation of ethyl difluoromethyl phosphonate. They are frequently used for the synthesis of difluorophosphonates (cf. Chapter 7)." ° ... 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

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