Amides, enolates, reaction with

By contrast, lithium enolates derived from tertiary amides do react with oxiranes The diastereoselectivity in the reaction of simple amide enolates with terminal oxiranes has been addressed and found to be low (Scheme 45). The chiral bicyclic amide enolate 99 reacts with a good diastereoselectivity with ethylene oxide . The reaction of the chiral amide enolate 100 with the chiral oxiranes 101 and 102 occurs with a good diastereoselectivity (in the matched case ) interestingly, the stereochemical course is opposite to the one observed with alkyl iodides. The same reversal is found in the reaction of the amide enolate 103. By contrast, this reversal in diastereoselectivity compared to alkyl iodides was not found in the reaction of the hthium enolate 104 with the chiral oxiranes 105 and 106 °. It should be noted that a strong matched/mismatched effect occurs for enolates 100 and 103 with chiral oxiranes, and excellent diastereoselec-tivities can be achieved. 

Camphorsulfonyl chlorides 45 readily form amides by reaction with amines. On reduction of the carbonyl group, alcohols, e.g., 46 and 47, are obtained which are extremely useful auxiliaries for many purposes. Thus, esters are formed with carboxylic acids which may then undergo enolate reactions (SectionsD.1.1.1.3.2., D.l.5.2.1., D.3. and D.7.1.) or act as dienophiles and dipolar-ophiles (Sections D.l.6.1.1.1.2.2.1. and D.l.6.1.2.1.). Enol ethers of these auxiliaries give [2 + 2] cycloadditions with dichloroketene (Section D.l.6.1.3.), while carbamate derivatives have been used in acyliminium reactions (Section D.l.4.5.). Generally, steric hindrance in the sulfonamide group improves the stereoselectivity of the reactions and, therefore, the amides with diisopropylamine and dicyclohexylamine are used as auxiliaries both enantiomers of the dicyclohexyl derivative are commercially available. 

Five- and six-membered ring enolates with an endocyclic double bond also react to deliver an electrophile from the sterically less hindered face. Enolate 498 was obtained by treatment of 497 with lithium amide. Subsequent reaction with an alkyl halide led to delivery of the halide from the face opposite the alkenyl group (path a) and the trans product shown (499) was isolated in 60% yield.-. Approach via path b would have serious steric consequences, and that transition state is destabilized. Similar effects are observed with 3-alkyl-cyclohexanone derivatives. 

Rossi, R. A. and Alonso, R. A., Photostimulated reactions of N,iV-disubstituted amide enolate anions with haloarenes by the Sr I mechanism in liquid ammonia, /. Org. Chem., 45,1239,1980. 

Lotz, G. A., Palacios, S. M., and Rossi, R. A., Stereoselective reaction of a chiral assisted amide enolate ion with 1-iodonaphthalene by the S jj mechanism. Tetrahedron Lett., 35, 7711, 1994. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

Thus, in the above reactions of cither enantiomer of chiral aldehydes with the ketone enolate, as well as with the amide enolate, the stereochemical outcome in each case is largely determined by the inherent selectivity of the chiral enolate reagent. 

For amide enolates (X = NR2), with Z geometry, model transition state D is intrinsically favored, but, again, large X substituents favor the formation of nt/-adducts via C. Factors that influence the diastereoselectivity include the solvent, the enolate counterion and the substituent pattern of enolate and enonc. In some cases either syn- or unh-products are obtained preferentially by varying the nature of the solvent, donor atom (enolate versus thioeno-late), or counterion. Most Michael additions listed in this section have not been examined systematically in terms of diastereoselectivity and coherent transition stale models are currently not available. Similar models to those shown in A-D can be used, however all the previously mentioned factors (among others) may be critical to the stereochemical outcome of the reaction. 

Although the methodology described so far produces <5-oxo esters via diastereoselective enolate additions to enones, the same product may be obtained via an alternate sequence, i.e., addition of ketone or aldehyde enolates to a,j3-unsaturated esters or amides. Enolates of ketones are known to react with a,/ -unsaturated esters to give the Michael adducts50, however, the study of simple diastcrcoselectivity has, so far, been limited to special cases (MIMIRC reactions, Section 1.5.2.4.4.). 

Ketones and carboxylic esters can be a hydroxylated by treatment of their enolate forms (prepared by adding the ketone or ester to LDA) with a molybdenum peroxide reagent (MoOs-pyridine-HMPA) in THF-hexane at -70°C. The enolate forms of amides and estersand the enamine derivatives of ketones can similarly be converted to their a hydroxy derivatives by reaction with molecular oxygen. The M0O5 method can also be applied to certain nitriles. Ketones have also been Qc hydroxylated by treating the corresponding silyl enol ethers with /n-chloroperoxy-... 

Besides ordinary esters (containing an a hydrogen), the reaction can also be carried out with lactones and, as in 16-38, with the y position of a,p-unsaturated esters (vinylogy). There are also cases, where the enolate anion of an amide was condensed with an aldehyde. ... 

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

Clear formation of ketene—zirconocene complexes upon treatment of acylzirconocene chlorides with a hindered amide base indicates that the carbonyl group of the acylzirconocene chloride possesses usual carbonyl polarization (Scheme 5.10). However, these zirconocene—ketene complexes are exceptionally inert due to the formation of strongly bound dimers [13a], Conversion of the dimer to zirconocene—ketene—alkylaluminum complexes by treating with alkylaluminum and reaction with excess acetylene in toluene at 25 °C has been reported to give a cyclic enolate in quantitative yield. Although the ketene—zirconocene—alkylaluminum complex reacts cleanly with acetylene, it does not react with ethylene or substituted acetylenes [13b]. Thus, the complex has met with limited success as a reagent in organic synthesis. 

Schulenberg (117) describes the material 55a, which is obtained from the amide 55c on reaction with a deficiency of sodium methoxide the white prisms of the product melt at 110 to 122°C (variable). These crystals give fairly stable solutions, enabling measurement of the NMR spectrum and observation that the material gives a positive FeCl3 reaction, in accord with the enol structure. After recrystallization a mixture of crystals of 55a and pale yellow prisms melting at... 

In the late 1960s, methods were developed for the synthesis of alkylated ketones, esters, and amides via the reaction of trialkyl-boranes with a-diazocarbonyl compounds (50,51), halogen-substituted enolates (52), and sulfur ylids (53) (eqs. [33]-[35]). Only one study has addressed the stereochemical aspects of these reactions in detail. Masamune (54) reported that diazoketones 56 (Ri = CH3, CH2Ph, Ph), upon reaction with tributylborane, afford almost exclusively the ( )-enolate, in qualitative agreement with an earlier report by Pasto (55). It was also found that E) - (Z)-enolate isomerization could be accomplished with a catalytic amount of lithium phenoxide (CgHg, 16 hr, 22°C) (54). 

---