Intermediate enols

The unconjugated ketone can be isolated if the enolate salt (59) is quenched with ammonium chloride 6-dehydrotestosterone affords androst-5-en-I7-ol-3-one in 74% yield under such conditions. If the intermediate enolate salt is quenched with water, the hydroxide ion so formed may isomerize the 5-en-3-one to the corresponding 4-en-3-one before the product can be isolated. 

Reductions of unsaturated ketones and a-acetoxy ketones usually are effected with an excess of reducing agent. For optimum yields of saturated ketones, the intermediate enolate salt obviously must not become protonated while... 

Weiss ° treated 16-dehydro- (6), 17a-acetoxy- (8), 17a-hydroxy- (9) and 17a-bromopregnan-20-one (11) with a solution of lithium, barium, calcium or sodium in liquid ammonia and reacted the intermediate enolate anion (7) with the appropriate alkyl halide. 

The methyl group of a methyl ketone is converted into an a ,a ,a -trihalomethyl group by three subsequent analogous halogenation steps, that involve formation of an intermediate enolate anion (4-6) by deprotonation in alkaline solution, and introduction of one halogen atom in each step by reaction with the halogen. A... 

Reaction of estrone methyl ether with methyl Grignard reagent followed by Birch reduction and hydrolysis of the intermediate enol ether affords the prototype orally active androgen in the 19-nor series, normethandrolone (69). ° (Note that here again the addition of the methyl group proceeded stereoselectively by approach from the least hindered side.) The preparation of the ethyl homolog starts by catalytic reduction of mestranol treatment of the intermediate, 70, under the conditions of the Birch reduction and subsequent hydrolysis of the intermediate enol ether yields norethandrolone (71). ... 

Figure 8.3 MECHANISM Mechanism of the mercury(II)-catalyzed hydration of an alkyne to yield a ketone. The reaction occurs through initial formation of an intermediate enol, which rapidly tautomerizes to the ketone.

The chemistry of alkynes is dominated by electrophilic addition reactions, similar to those of alkenes. Alkynes react with HBr and HC1 to yield vinylic halides and with Br2 and Cl2 to yield 1,2-dihalides (vicinal dihalides). Alkynes can be hydrated by reaction with aqueous sulfuric acid in the presence of mercury(ll) catalyst. The reaction leads to an intermediate enol that immediately isomerizes to yield a ketone tautomer. Since the addition reaction occurs with Markovnikov regiochemistry, a methyl ketone is produced from a terminal alkyne. Alternatively, hydroboration/oxidation of a terminal alkyne yields an aldehyde. 

The third major reaction of carbonyl compounds, alpha substitution, occurs at the position next to the carbonyl group—the alpha (a) position. This reaction, which takes place with all carbonyl compounds regardless of structure, results in the substitution of an a hydrogen by an electrophile through the formation of an intermediate enol or enolcite ion ... 

Carboxylic acids having a second carbonyl group two atoms away lose C02 (clecarboxylatc) through an intermediate enolate ion when treated with base. Write the mechanism of this decarboxylation reaction using curved arrows to show the electron flow in each step. 

Mechanism of base-catalyzed enol formation. The intermediate enolate ion, a resonance hybrid of two forms, can be protonated either on carbon to regenerate the starting keto tautomer or on oxygen to give an enol. 

Through a short sequence of functional group manipulations, compound 6 could be elaborated from allylic alcohol 7, the projected product of a Wharton fragmentation4 of epoxy ketone 8 (vide infra). In turn, compound 8 could be derived from enone 9. In the synthetic direction, a Michael addition5 of hydroperoxide anion to enone 9 would be expected to take place from the less hindered side of the molecule. Epoxy ketone 8 would fhen form upon collapse of the intermediate enolate with concomitant expulsion of hydroxide ion (see arrows, Scheme 2). 

Key features of the cyclopropanation include the ylide acting as a mild base to isomerize the 1,2-dioxines into cis-y-hydroxy enones, followed by Michael addition of the ylide and last by cyclization of the intermediate enolate [35]. It must be noted that the trans-y-hydroxyenones do not give the cyclopropanation. 

As shown above, the electronic properties have a serious effect on the rate of the reaction. It means that the aromatic ring should occupy the same plane with that of the estimated intermediate enol moiety. Then, it is supposed that the conformation of the substrate is already restricted when it binds to the active site of the enzyme. The evidence that supports this estimation is the inactiveness of a-methyl-o-cWorophenyl and a-naphthylmalonic acids. This is a marked difference with the fact that a-methyl-p-Cl-phenyl and methyl-(3-naphthylmalonic acids are... 

The reaction mechanism for glutamate racemase has been studied extensively. It has been proposed that the key for the racemization activity is that the two cysteine residues of the enzyme are located on both sides of the substrate bound to the active site. Thus, one cysteine residue abstracts the a-proton from the substrate, while the other detivers a proton from the opposite side of the intermediate enolate of the amino acid. In this way, the racemase catalyzes the racemization of glutamic acid via a so-called two-base mechanism (Fig. 15). 

If the proton-donating ability of the amino acid at 188 is weaker, then the enantioselectivity of the reaction will be reversed compared to that of native enzyme. As shown in Table 3, the absolute configuration of the products by this mutant is opposite to those of the products obtained by the native enzyme and the ee of the products dramatically increased to 94 and 96%, respectively. This inversion of the enantioselectivity of the reaction supports the reaction mechanism that the Cys 188 of the native enzyme is working as the proton donor to the intermediate enolate form of the product. ... 

The structure of the products is determined by the site of protonation of the radical anion intermediate formed after the first electron transfer step. In general, ERG substituents favor protonation at the ortho position, whereas EWGs favor protonation at the para position.215 Addition of a second electron gives a pentadienyl anion, which is protonated at the center carbon. As a result, 2,5-dihydro products are formed with alkyl or alkoxy substituents and 1,4-products are formed from EWG substituents. The preference for protonation of the central carbon of the pentadienyl anion is believed to be the result of the greater 1,2 and 4,5 bond order and a higher concentration of negative charge at C(3).216 The reduction of methoxybenzenes is of importance in the synthesis of cyclohexenones via hydrolysis of the intermediate enol ethers. 

The intermediate enolate or enol ether from the initial reduction of an enone may be alkylated in situ (Eq. 281).455 / -Substituted cyclopentenones may be asymmetrically reduced and alkylated459 (see section on asymmetric reductions of enones). Enolates may also be trapped with an aldehyde in a reductive aldol condensation of an enone with an aldehyde,455 permitting a regioselective aldol condensation to be carried out as shown in Eq. 282.455 This class of reductive aldol condensation reactions can also occur in a cyclic manner (Eq. 283).460... 

The sequence of chiral 1,4-reduction of a fi-substituted cyclopentenone followed by electrophilic trapping of the intermediate enolate provides an efficient route to chiral 2,3-disubstituted cyclopentanones that generates two chiral centers in the process (Eq. 352)459... 

Recently, it has been shown that Me3GeLi undergoes conjugate addition to cyclo-hexenones to give /J-Me3Ge cyclohexanones (Scheme 23)51. The intermediate enolate can be trapped with Mel to afford the trans methylated product. 

The intermediate enol silyl ether permits further regioselective substitutions such as bromination followed by dehydrobromination (Eq. 81)49> and alkylation (Eqs. 82 93) and 83 103)). Thus, in addition to activating the rearrangement, the oxygen substituent regioselectivity creates an enol silyl ether, a powerful enolate synthon. 

Intramolecular cyclizationlenolate trapping of allylsilanes (cf., 12,496-497).3 The intermediate enolate formed in the TiCl4-catalyzed cyclization of 1 can be trapped by chloromethyl methyl sulfide to give a decalone derivative with a potential methyl group on the angular position. Actually the reaction results in... 

The preferential -configuration of the enol esters, derived from p-dicarbonyl compounds under phase-transfer conditions, contrasts with the formation of the Z-enol esters when the reaction is carried out by classical procedures using alkali metal alkoxides. In the latter case, the U form of the intermediate enolate anion is stabilized by chelation with the alkali metal cation, thereby promoting the exclusive formation of the Z-enol ester (9) (Scheme 3.5), whereas the formation of the ion-pair with the quaternary ammonium cation allows the carbanion to adopt the thermodynamically more stable sickle or W forms, (7) and (8), which lead to the E-enol esters (10) [54],... 

The scope of the reaction has been successfully extended to a,p-ethylenic aldehydes,5 esters,6 and amides7 as well as to a,p-acetylenic ketones8 (see Table IV). With esters, the reaction must be performed in the presence of chlorotrimethylsilane (MeaSiCI) to avoid the Claisen reaction by trapping the intermediate enolate. In most cases the organomanganese procedure is simple and more efficient than the organocopper procedure. 

Substituted quinone ketals, prepared in this manner, serve nicely in annelation strategies leading to natural products. Two are illustrated, one in Scheme 20 leading to (+)-4-demethoxydaunomycinone (87) and (+)-daunomycinone (88) [46-48], the other in Scheme 21 serving as a pathway to a-citromycinone (94). The first calls for a Michael addition of (84) to quinone ketal (83) followed by capture of the intermediate enolate, and leads to annelated... 

Although unhindered enones and enoates work well, attempted 1,4-reduction of acrylonitrile afforded a-silylated product 9 (Scheme 5.4). Presumably this unexpected product results from a 1,4-reduction/a-anion trapping by the PhMe2SiCl present in solution. Curiously, there was no mention of any similar quenching of intermediate enolates on either carbon or oxygen when unsaturated ketones or esters were involved. 

The Birch reduction of derivatives of 2-methoxybenzoic acid followed by alkylation of the intermediate enolate is of even greater strategic value. The resulting chiral cyclohexa-... 

It is mentioned in an early paper on the effect of water on Heck vinylations [62] that 2,4-dimethoxy-5-iodopyrimidine reacted with 1-(ethoxyethenyl)-tri-n-butylstannane to afford an acylated pyrimidine derivative in 83 % yield (via in situ hydrolysis of the intermediate enol ether) (Scheme 6.28). 

Removal of the a-hydrogen in o-glucose leads to enolization (we have omitted the enolate anion in the mechanism). Reversal of this process allows epimerization at C-2, since the enol function is planar, and a proton can be acquired from either face, giving D-mannose as well as o-glucose. Alternatively, we can get isomerization to o-fmctose. This is because the intermediate enol is actually an enediol restoration of the carbonyl function can, therefore, provide either a C-1 carbonyl or a C-2 carbonyl. The equilibrium mixture using dilute aqueous sodium hydroxide at room temperature consists mainly of o-glucose and o-fructose, with smaller amounts of D-mannose. The same mixture would be obtained... 

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