Enol Phosphorus Compounds

In this paper Speziale and Smith 109) described experiments which led them to modify the mechanism proposed earlier 108) for the reaction of trivalent phosphorus compounds with haloamides. The first step is considered to be attack of the trivalent phosphorus compound on a chlorine atom of the halo amide (132) to produce a resonance-stabilized enolate ion (133). This is reasonable since under conditions where the trichloroamide... 

A reaction involving phosphorus trichloride providing a free phosphonic acid apparently involves an enolized carbonyl compound as the species attacking the phosphorus.96 Methyl aromatic ketones thus provide access to the vinylicphosphonic acids (Figure 6.26). 

Many examples exist where the open chain betaine may be quenched by reagents, giving stable phosphorus compounds with P-C1V = 3. When (180) is reacted with acetyl chloride the open chain enol phosphate (181) is formed. Many interesting O- and N-phosphaspirans are also mentioned in (75BSF407). 

Gent-dichlorides can be obtained from ketones that are not capable of conversion into an enol form by using phosgene in the presence of an organic phosphorus compound [316], For example, PhjC=0 was converted into PhjCClj in the presence of one of a wide variety of phosphine or phosphine oxide catalysts between 100 and 190 C. Further, PhC(0)C(0)Ph, when treated with COClj in the presence of PPhjO at 130-140 C, resulted in the conversion of one of the CO groups into a CClj moiety. PhC(0)-4-C 4C(0)Ph reacted in the... 

Borowitz and his co-workers have carried out a detailed comparative study of the reactions of phosphinites, phosphonites, and phosphites with -halogenoketones. The balance between keto-phosphorylation and enol-phosphorylation favours the former with increasing oxygen content of the phosphorus compound, higher temperature, more polar solvents, and bromo-rather than chloro-ketones. a -Dibromobiacetyl reacts with two moles of phosphite to give the double Perkow product (43) and no trace of the alternative Arbusov product or of the phosphorane (45). The rate of the first Perkow... 

When the phosphorus compound is a phosphite ester the stable product is an enol phosphate. 

Enolates of aldehydes, ketones, and esters and the carbanions of nitriles and nitro compounds, as well as phosphorus- and sulfur-stabilized carbanions and ylides, undergo the reaction. The synthetic applications of this group of reactions will be discussed in detail in Chapter 2 of Part B. In this section, we will discuss the fundamental mechanistic aspects of the reaction of ketone enolates with aldehydes md ketones. 

In further modifications of these norprogestins, reaction of norethindrone with acetic anhydride in the presence of p-toluene-sulfonic acid, followed by hydrolysis of the first-formed enol acetate, affords norethindrone acetate (41). This in turn affords, on reaction with excess cyclopentanol in the presence of phosphorus pentoxide, the 3-cyclopentyl enol ether (42) the progestational component of Riglovic . Reduction of norethindrone affords the 3,17-diol. The 33-hydroxy compound is the desired product since reactions at 3 do not show nearly the stereoselectivity of those at 17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium aluminum-tri-t-butoxide. Acetylation of the 33,173-diol iffords ethynodiol diacetate, one of the most potent oral proves tins (44). ... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

An alternate scheme for preparing these compounds starts with a prefabricated pyrimidone ring. Aldol condensation of that compound (95), which contains an eneamide function, with pyridine-3-aldehyde (80), gives the product 96. Catalytic hydrogenation gives the product of 1,4 reduction. The resulting pyrimidinedione, of course exists in the usual tautomeric keto (97a) and enol (97b) forms. Reaction with phosphorus oxyxchloride leads to the chloro derivative 98. Displacement with methoxide gives 99. Reaction of this last intermediate with the furylalkylamine derivative 92 leads to the H-2 blocker lupitidine (100) [22]. 

The particularly good activity against protein kinases of a-aminoquinazoline derivatives is borne out by their activity against both in vitro and in vivo models of human tumors. The examples that follow are but two of a number of compounds from this structural class that have emerged from the focus that has been devoted to this stmctural class. Nitration of the benzoate (78-1) with nitric acid affords the nitro derivative. Hydrogenation converts this to the anthrandate (78-2). In one of the standard conditions for forming quinazolones, that intermediate is then treated with ammonium formate to yield the heterocycle (78-3). Reaction of this last product with phosphorus oxychloride leads to the corresponding enol chloride (78-4). Condensation of this last intermediate with meta-iodoanUine (78-5) leads to displacement of chlorine and the consequent formation of the aminoquinazoline... 

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