Enol phosphates coupling reactions

The coupling reaction between lithium dimethylcuprate and acyclic enol phosphates must be carried out between -47 and -98 C for stereoselective formation of g-methyl-a,g-unsaturated esters. 

This procedure illustrates a new method for the preparation of 6-alkyl-a,g-unsaturated esters by coupling lithium dialkylcuprates with enol phosphates of g-keto esters. The procedure for the preparation of methyl 2-oxocyclohexanecarboxylate described in Part A Is based on one reported by Ruest, Blouin, and Deslongcharaps. Methyl 2-methyl-l-cyc1ohexene-l-carboxylate has been prepared by esterification of the corresponding acid with dlazomethane - and by reaction of methyl 2-chloro-l-cyclohexene-l-carboxyl ate with lithium dimethylcuprate. -... 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

Cahiez and Avedissian further reported the cross-coupling reaction of cheap and easily available enol phosphates [10]. These substrates are less reactive, which explains the higher catalyst loadings and 2 equiv. of Grignard reagent are required (Scheme 5.5). 

Scheme 5.5 Iron-catalyzed cross-coupling reaction of an enol phosphate reported by Cahiez and Avedissian.

The aryl and enol triflates 306 and 307 couple with Me3Al, Et3Al and BU3AI [136], The enol phosphate 309, derived from ketone 308, is displaced with methyl group of Me3Al using Pd catalyst in dichloroethane. Based on this reaction, 4-tert-butylcyclohexanone (308) is converted to 2-methyl-5-tert-butylcyclohexanone (311) via 310 [137],... 

A new cyclising reagent is proposed for the synthesis of 5-unsubstituted 1,3,4-thiadiazoles (133). The latter are formed in good yield by the reaction of thiohydrazides (134) with diethyl chlorophosphate (Scheme 39). A useful, one-pot protocol has been developed for the conversion of enolizable ketones (135) to alkylated or arylated olefins (136) by Pd-catalysed cross coupling of in-situ generated enol phosphates (137) with Grignard reagents (Scheme 40). ... 

Because of the very high price of ATP, reaction (5.7) must be coupled with a regenerating system, the transfer of phosphate to ADP starting from the enol phosphate of pyruvic acid (an easily accessible and inexpensive phosphate), catalysed by the enzyme pyruvate kinase (reaction (5.8). In the same flask are mixed glucose, phosphoenolpyruvate, hexokinase, pyruvate kinase, and a catalytic quantity of ATP (about 1% mol) and the system produces D-glucose 6-phosphate until the phosphoenolpyruvate runs out. The kinases are easily accessible and, if they are immobilized on an insoluble support (see Section 10.4.1), they are reusable a certain number of times. In this way glucose 6-phosphate can be easily prepared on a 250 g scale (Poliak et al. 1977). 

Two further complicating features may be noted. The first is of little, if any, practical consequence with regard to the formation of oxoalkyl phosphonates, but is to be found in the formation of enol phosphates from a-polyhaloketones, when the latter may be accompanied by simple dehalogenation of the carbonyl reactant when treated with phospho-rus(III) esters particularly when reactions are carried out in protic solvents This is coupled with the second feature, which consists in the formation of (1-hydroxyalkyl)phos-phonic acid esters from a trialkyl phosphite and the substituted a-monohaloacetophenone also in the presence of a protic solvenr . ... 

Coupling with enol diphenylphosphate esters. Ketones can be converted into nlefins by conversion into the enol diphenylphosphate esters followed by treatment of a dialkylcopperlithium. Dimethylcopperlithium does not undergo this reaction, nor do hindered enol phosphates. ... 

Hydroboration of exocyclic enol ether 111 with 9-BBN and following Suzuki-Miyaura reaction with enol triflate 128 proceeded smoothly to generate the cross-coupled product 129 in 81% yield (Scheme 17). Not unexpectedly, the corresponding enol phosphate of 128 proved to be a poor substrate for this complex fragment coupling. Given the structural complexity and sheer size of the respective fragments, this remarkable yield (81%) represents... 

Opening to the -rr-allyl complex 9.214, which was reduced by hydride transfer from formate. Unlike most other nucleophiles (see Schemes 9.32 and 9.34), formate transfers hydrogen with retention, giving the required stereochemistry for the natural product. Completion of the synthesis included a nickel-catalysed Kumada coupling to convert the ketone, via an enol phosphate 9.216, into a methyl group and a McMurry reaction to close the seven-membered ring. 

Specific phosphate reagents have involved enol phosphates and ketene acetal phosphates that have been utilized in the Suzuki-Miyaura and Stille cross-coupling carbon-carbon bond formation reactions as well as tetra-benzylpyrophosphate, used for the first time as a dehydrating agent for synthesis of carboxamides. 

The coupling reactions of organoaluminium reagents have again received attention, and have been extended to cover for example the substituted enol phosphates (104), which react with R3AI [catalysed by Pd(0)] to give, after hydrolysis, ketones (105). Similar methodology has been used to effect 1,2- and 1,3-carbonyl transpositions with concomitant alkylation. The scope of... 

Coupling with Allylic and Enol Phosphates. The reagent converts allylic phosphates into allylsUanes (eq 3). Reaction with (2-vinyl-1,1-cyclopropanedicarboxylate gives the 1,7-homo-conjugate addition product (eq 4). In the presence of a Pd catalyst, PhMc2SiAlEt2 converts enol phosphates into vinylsilanes (eq 5). Higher yields are usually obtained with PhMe2SiMgMe. 

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