Phosphonates addition reaction with enolates

A relatively general procedure for the preparation of dialkyl 2-oxoalkylphosphonates by direct acylation of dialkyl 1-lithioalkylphosphonates has been introduced by Corey and Kwiatkowski in 1966. The use of phosphonate carbanions as nucleophiles in reaction with carboxylic esters avoids the problems associated with the Michaelis-Arbuzov reaction. The reaction sequence is initiated by the addition at low temperature of dimethyl 1-lithiomethylphosphonate (2 eq and frequently more) to a carboxylic ester (1 eq) to give the transient lithium phosphonoenolate. The dimethyl methylphosphonate, being readily available and easy to eliminate, is the most frequently used phosphonate, but other phosphonates such as diethyl and diisopropyl methylphosphonates can be used. When the resulting enolate is treated with acid, dimethyl 2-oxoalkylphosphonate is produced in moderate to good yields (45-95%, Scheme 7.20). The reaction has been achieved with... 

The conjugate Michael addition of phosphonate-stabilized anions with dimethyl acetylenedicarboxylate has been described. For example, when the sodium salt of dimethyl l-(methoxycarbo-nyljmethylphosphonate is treated with dimethyl acetylenedicarboxylate, an (fij/CZ) mixture of two isomeric P.y-unsaturated phosphonates is isolated in modest yield (37%). ° Addition of enolates derived from diethyl 2-oxocycloalkylphosphonates to dimethyl acetylenedicarboxylate in aprotic conditions results in [n + 2] ring-expanded products in reasonable yields (Scheme 8.50). The reaction proceeds via a tandem Michael-aldol-fragmentation mechanism to give the ring enlarged products. 

Phosphorus-based synthons for acetoacetic ester and acetylacetone derivatives are described the phosphonate (78) has been used in the preparation of the /S-ketoester (79), a key intermediate in a synthesis of the fungal sex hormone, trisporic acid B methyl ester (80). Michael addition of an a-methylene ketone to 2,2-diethoxyvinylidenetriphenylphosphorane followed by loss of ethanol gives a valuable reagent (81) for the preparation of 1,3-dioxopent-4-enes by Wittig reaction with aldehydes the intermediate enol ethers (82) can be isolated if desired. 

The highly electrophilic cationic bis(8-quinolinolato)aluminum complex 407 enabled Yamamoto and coworkers to perform Mukaiyama-Michael additions of silyl enol ethers to crotonylphosphonates 406. The procedure was not only applicable to enol silanes derived from aryl methyl and alkyl methyl ketones (a-unsubstituted silicon enolates) but also to several cycfic a-disubstituted silyl enol ethers, as illustrated for the derivatives of a-methyl tetralone and indanone 405 in Scheme 5.105. Despite the steric demand of that substitution pattern, the reaction occurred in relatively high chemical yield with varying diastereoselectivity and excellent enantiomeric excess of the major diastereomer. The phosphonate residue was replaced in the course of the workup procedure to give the methyl esters 408. The protocol was extended inter alia to the silyl enol ether of 2,6,6-tetramethylcyclohexanone. The relative and absolute configuration of the products 408 was not elucidated [200]. 

The structure of catalyst 428 was proposed as a result of the several experiments shown in Sch. 60 and discussed below [89]. Firstly, it was observed that treatment of ALB catalyst 394 (Sch. 51) with methyllithium produced a solution from which the hexacoordinate aluminum species 434 (M = Li) could be crystallized in 43 % yield. The same compound could also be obtained from solutions prepared from 394 and nBuLi, and the sodium enolate of 425. Solid-state X-ray analysis of this compound revealed that it has the same structiu-e as the species 417 (Sch. 56) isolated by Feringa and coworkers during the preparation of ALB with excess BINOL (Sch. 55) [86]. The tris-BINOL(tris-lithium) alimunum complex 434 is not the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone because the use of this material as catalyst gave the Michael adduct 426 in 28 % yield and 57 % ee which is dramatically lower than obtained by use of catalyst 428 (Sch. 59). In addition, the use of catalyst 434 (M = Li) gave the alkene product 429 in 13 % yield, a product that was not seen with catalyst 428. Additional evidence comes from the reaction between 425 and cyclopentenone with catalyst 434 (M = Li) which gives the adduct 427 in 78 % yield and 12 % ee. 

Table 5) [28], and heteroatom Diels-Alder reactions (Sch. 50) [79,80] but no X-ray structure had ever been reported for it or for the 3,3 -disubstituted derivatives which were first introduced as an asymmetric Claisen catalyst [24-27]. Although compound 435 was found not to induce any reaction between cyclohexenone and phosphonate 425 under the standard conditions for catalyst 428, consistent with the proposed equilibrium of species 394, 431, 432, 433, and 434 is the finding that catalysis of the reactions between cyclohexenone or cyclopentenone and phosphonate 425 with a 2 1 mixture of 434 (M = Li) and 435 gave only the Michael adducts 426 and 427 in 96 % ee and 92 % ee, respectively. Because 394 and 432 are inactive catalysts and 434 results in much lower induction and some 1,2-adduct, it was proposed that the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone was the species 431 resulting from association of ALB catalyst with a metal alkoxide. It was proposed that the stereochemical determining step involved intramolecular transfer of the enolate of 425 to the coordinated cyclohexenone in species 436. 

Kim, D.Y, Mang, J.Y, and Oh, D.Y, Reaction of silyl enol ethers with phosphite using hypervalent iodine compound. A new synthesis of 2-aryl-2-oxoalkylphosphonates, Synth. Commun., 24, 629, 1994. Hohnquist, C.R., and Roskamp, E.J., Tin(II) chloride catalyzed addition of diazo sulfones, diazo phosphine oxides, and diazo phosphonates to aldehydes. Tetrahedron Lett., 33, 1131, 1992. 

Dual pathways are available for the reaction of phosphonate anions with a,/ -enones (55). The Michael addition is frontier orbital-controlled and is favored by the presence of proton sources, which quickly neutralize the charge on the enolate anions. These products decrease with time because they are gradually channeled into the charge-controlled Horner-Emmons olefination. 

In 1991, Pattenden exploited the inherent regioselectivity of nucleophilic additions on P-methoxy maleic anhydrides to prepare gomphidic acid (30) by two different routes (Scheme 1.10) [63]. The first one involves an HWE reaction between phosphonate 80 and aryl pyruvate 81 [63b], and the second one is based on a Reformatsky-type reaction of 77 with zinc enolates derived from aryl acetate 79 [63cj. 

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