C-alkylation, of enolates

The heats of reaction for O-alkylation and C-alkylation of enolate anions clearly show that the latter reactions lead to the thermodynamically more stable products 12). 

The concept of memory of chirality —in which the chirality of the starting material is preserved in a reactive intermediate for a limited time—is discussed with particular reference to the C-alkylation of enolates of chiral ketones. ... 

In the aliphatic series, the C-alkylation of enolates 17 is achieved through their O-silylated derivatives 66. In the presence of a catalytic amount of ZnBr2, the silyl enol ether 66 reacted with CICH2OCH3 to give only the C-alkylated a-ketoester 67. The alkylation is regiospecific but the ketoesters (67a, c) are obtained with modest yields (about 50% yield). 

As mentioned on p. 99, gas-phase reactions are under charge control and, therefore, almost by definition, FO theory is inappropriate for their study. Such a conclusion would be precipitous. Note to begin with that only the anion behaves in an unusual manner, the comportment of its partner being normal. An FO study of gas-phase SN2 reactions (X- + RY —> XR + Y ) is therefore perfectly possible. We can also study the competition of electrophilic sites. On the other hand, FO theory will give questionable conclusions for the regioselectivity of anions (e.g. O-alkylation versus C-alkylation of enolates). For these problems, a more thorough study, requiring in particular transition states determination, is necessary. 

Can FO theory confirm that the percentage of C-alkylation of enolates increases steadily in the series RI < RBr < RC1 Table 5.2 shows the LUMO energies of MeBr, EtBr and PrBr, according to AMI, PM3, STO-3G and 3-21G calculations. 

When the cation remains coordinated to the nucleophile, the reaction is under association control. Association-controlled reactions are usually slow, because the substrate is not activated and the nucleophile is deactivated. This general class can be subdivided into two groups. In the first (which occurs in the C-alkylation of enolates), the metal is not directly bound to the reactive site. If the transition state is acyclic, conjugate additions will dominate because there is no electrophilic assistance. If it is cyclic, chelation favors addition to the carbonyl ... 

Fig. 3.37. Differential reaction energy profiles for O versus C alkylation of enolates. (a) O-Alkylation is characterized by an early transition state, weak O-solvation, high anion reactivity, and relatively large electrostatic effects, (b) C-Alkylation is characterized by a later transition state with more C—C bond formation and more diffuse charge distribution.

Within each of the groups there are marked differences. For example, lithium alkynylides, RC=CLi, dissolved in mixtures of THF and HMPT (20 vol%) do not react below — 50 °C with ethyl bromide and higher homologues in the presence of HMPT the carbenoids LiCCl3 and LiCBr3, much weaker bases than acetylides, can be alkylated with good results within one hour at — 100 °C. Alkylation of enolates under these extreme conditions proceeds sluggishly. 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

Carbon is alkylated ia the form of enolates or as carbanions. The enolates are ambident ia activity and can react at an oxygen or a carbon. For example, refluxing equimolar amounts of dimethyl sulfate and ethyl acetoacetate with potassium carbonate gives a 36% yield of the 0-methylation product, ie, ethyl 3-methoxy-2-butenoate, and 30% of the C-methylation product, ie, ethyl 2-methyl-3-oxobutanoate (26). Generally, only one alkyl group of the sulfate reacts with beta-diketones, beta-ketoesters, or malonates (27). Factors affecting the 0 C alkylation ratio have been extensively studied (28). Reaction ia the presence of soHd Al O results mosdy ia C-alkylation of ethyl acetoacetate (29). 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

It is important to perform both the Birch reduction of 5 and the alkylation of enolate 6 at —78 °C. Enolate 6 obtained directly from 5 at low temperatures is considered to be a kinetic enolate . A thermodynamic enolate obtained from 6 by equilibration techniques has been shown to give an opposite sense of stereoselection on alkylation. Although a comprehensive study of this modification has not been carried out, diastereoselectivities for formation of 8 were found to be greater than 99 1 for alkylations with Mel, EtI, and PhCH2Br. Thus, it should be possible to obtain both enantiomers of a target structure by utilization of a single chiral benzamide. SE... 

Intramolecular alkylation of enolates leads to formation of cyclic products. In addition to the other factors that govern C/O-alkylation ratios, the element of stereo elec -tronic control comes into play in such cases. The following reactions illustrate this point.51... 

Alkylation of enolates, such as 4, produces products that are consistent with the preferred approach of the electrophile from either the least hindered face of an T -cnolate of conformation C or the least hindered face of a Z-enolate of conformation D88. Steric factors influencing approach of the electrophile appear to be similar in both of these models since the steric bulk of the hydridotris(3,5-dimethyl-l-pyrazolyl)borate ligand and the phosphite are both considerable any stereoelectronic and dipolar factors due to interaction of the enolate ligand with the carbon monoxide ligand would likely be similar for both geometries. The is-enolate geometry C appears to benefit from reduced steric interactions between the R substituent and the metal ligands. 

The possibility of the enolate anion acting as if its charge were effectively concentrated on carbon or on oxygen was discussed previously in connection with aldol addition (Section 17-3B). However, the situation there was quite different from the one here, because aldol addition is easily reversible, whereas alkylation is not. Furthermore, while the aldol reaction involving C-O bond formation is unfavorable (AH° = + 20 kcal mole-1) compared to C-C bond formation (AHn = —4 kcal mole-1), both O- and C-alkylation of the anion have AH° < 0 (see Exercise 17-64). 

Exercise 18-31 Arguing from the factors that appear to regulate the ratio of C- to O-alkylation of enolate anions (Section 17-4), show how you could decide whether the reaction of the sodium enolate salt of ethyl 3-oxobutanoate with a strong acid would give, as the initial product, mostly the enol form, mostly the keto form, or the equilibrium mixture. 

N-Acetyl-L-phenylalanylsarcosine amide, 348 O-Acetylserine, 148 N-0 Acyl migrations, 157 Acyl-enzyme, 342-350 Z-0-Acylisoamide, 295 1,4-Addition, 221-242 1,6-Addition, 231 L-Ala-L-Ala-pNA,350 f-Ala-T-Pro-pNA, 350 AicohoT dehydrogenase, 340-341 Aldehydes, 209-211 Aldol condensation, 304-306 2-Alkoxytetrahydrofuran, 86 2-Alkoxytetrahydropyran, 18, 85-90 Alkylation of enamine, 282 Alkylation of enolate, 280 C and 0-Alkylation, 240 O-Alkylbenzohydroximoyl chloride, 155... 

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