Pinacolones enolates

In this study, benzaldehyde and benzaldehyde-methyllithium adduct were fully optimized at HF/6-31G and their vibrational frequencies were calculated. The authors used MeLi instead of lithium pinacolone enolate, since it was assumed that the equilibrium IBs are not much different for the MeLi addition and lithium enolate addition. Dehalogena-tion and enone-isomerization probe experiments detected no evidence of a single electron transfer to occur during the course of the reaction. The primary carbonyl carbon kinetic isotope effects and chemical probe experiments led them to conclude that the reaction of lithium pinacolone enolate with benzaldehyde proceeds via a polar mechanism. 

FIGURE 27. The polar addition mechanism and electron transfer-radical coupling sequence in the addition of lithium pinacolone enolate to benzaldehyde. Reprinted with permission from Reference 28. Copyright 1997 American Chemical Society... 

Reactivities of lithium pinacolone enolate with various ketones were determined by competition experiments in diethyl ether at —78 °C. For a series of substrates, MeCOCH2X and PhCOCH2X, pi(X) = 6.62 and 7.61, indicating a large electronic field effect. ... 

Aldol reactions have continued to attract attention.28-39 hi order to determine the mechanism of addition of lithium pinacolone enolate [CH2=C(OLi)C(Me)3] to benzaldehyde the carbonyl-carbon KIE (xlk/nk = 1.019) and the substituent effects (p = 1.16 0.31) have been compared with those for other lithium reagents.28,29 The small positive KIE, which is larger than the equilibrium IE (nK/nK = 1.006) determined by ab initio MO calculations (HF/6—31 + G ), is in contrast with nk/l4k = 1.000 for MeLi addition which proceeds by the rate-determining ET mechanism, characterized by a much smaller p value. Since probe experiments showed no evidence of single electron transfer, it has been concluded that the significant isotope effect for reaction of lithium pinacolone enolate is indicative of rate-determining polar attack (PL) rather than radical coupling (RC) (Scheme 2). 

In 1994, it was found that several reactions thought to proceed via the vinylic SflArl mechanism were contaminated by a nonradical, a, /t-ehrninalion/addition pathway (equation 40)178. However, this elimination/addition pathway becomes inaccessible when substrates without ft (or ft1) hydrogens are utilized. Thus, the reaction of pinacolone enolate (f-Bu(CO)CH2) with l-bromo-l,2,2-triphenylethylene was touted to be the first unequivocal example of vinylic substitution exclusively by the S l pathway. 

The mechanism of addition of lithium pinacolone enolate, H2C=C(OLi)Bff, to benzaldehyde has been investigated by the determination of kinetic isotope effects69 (phenyl-t/s and carbonyl-13C) C—C bond formation occurs in the rate-determining step (a result supported by MO calculations), in contrast to addition of MeLi or PhLi, which proceed via electron transfer. Further carbonyl-13 C isotopic studies on substituted benzaldehydes (including equilibrium effects) by the same authors confirmed these conclusions.70... 

For a given aryl moiety, there is a rough correlation between the reduction potential and its reactivity in SRN1 reactions [12]. The order of reduction potential in liquid ammonia, Phi >PhBr >PhNMe3I >PhSPh > PhCl >PhF >PhOPh coincides with the reactivity order determined under photoinitiation. By competition experiments of pairs of halobenzenes toward pinacolone enolate ions under photoinitiation, the span in reactivity from PhF to Phi was found to be about 100,000 [13]. 

When the photoinduced reaction of pinacolone enolate ion with bromobenzene is carried out in DMF as solvent, it leads to the formation of benzene (28%), while in liquid ammonia this byproduct is almost precluded. The reaction in DMSO produces little benzene. On the other hand, THF... 

The photostimulated reactions of vie aminohalo pyridines with acetone or pinacolone enolate ions lead to azaindoles in high yields (75-95%) [67]. When the amino group is protected as pivaloylamino derivative, (as in 17, Sch. 20), the analogs of substitution compounds 18 obtained by the photoinduced reaction of 2-amino-3-iodo-, 3-amino-4-iodo- and 4-amino-3-iodopyridines with acetone or pinacolone enolate ions, afford 5-, 6- and 7-azaindoles in almost quantitative yields by cyclization upon deprotection of the amino group and dehydration under acidic conditions (for example, see Sch. 20) [67]. 

The factors affecting the relative reactivity of aryl halides in SrnI reactions have been analysed and compared645. Competition experiments of pairs of substrates, in photo-stimulated reactions with pinacolone enolate ion in liquid ammonia, reveal a spread of reactivity exceeding three powers of ten. The ease of formation of the radical anion of the substrate appears to dominate the overall reactivity. The rate of dehalogenation of the radical anion may become important when its stability exceeds a certain threshold. When the fragmentation rate of the radical anion intermediate is fairly slow, the overall reactivity diminishes. 

Acetone enolate ion did not react with 66, whereas pinacolone enolate ion reacted to give 18% of 67d145. However, good yields of the substitution product were obtained in the photostimulated reaction of 7-iodonorcarane (68) with acetophenone enolate ion in DM SO (87%). This reaction is inhibited by p-D NB and it is sluggish in the dark (equation... 

Disubstitution product (46%) was the only product obtained in the photostimulated reaction of 70 with pinacolone enolate ion while n-butanethiolate ion led to the monosubstitution product in a relatively low yield (22%) 145. 

The dark reaction of pinacolone enolate ion and Phi in DMSO was described167. The same reaction is stimulated by light and inhibited by radical scavengers. This system was used to study the reactivity of different ketone enolate ions with Phi. In competition experiments, the following reactivity order was determined 2-acetylcyclohexanone (unreactive) < phenylacetone (0.39) < cyclohexanone (0.67) < pinacolone (1.00) < acetone (1.09) < 2-butanone (1.10) < 3-pentanone (1.40)168. 

On the other hand, the relative reactivity of different aryl bromides toward pinacolone enolate ion170 is given in Table 1. 

Carbanions occasionally react with aryl halides spontaneously, mostly under irradiation, or by supplying electrons either from dissolved metals or from a cathode. However, certain Fe+2 salts catalyse the S l reactions with carbanions. That was the case for the reaction of PhBr or Phi with acetone or pinacolone enolate ions in liquid ammonia or DMS0172a, as well as for the reaction of the enolate ion of several carbanions with several aryl and hetaryl halides in DMS0172b. Since these reactions are inhibited byp-DNB andp-cymene, and the relative reactivity of nucleophiles is similar to that determined in photo-stimulated or spontaneous reactions, it seems that FeCl2 initiates the S l process. 

The reaction of carbanions with hetaryl halides has been reported. Thus, pinacolone enolate ion reacts with 2-halothiazoles (127) affording the substitution product 128 in good yields (44-67%) (equation 87)176. 

Ethyl phenylacetate and even the tertiary carbanion methyl diphenylacetate gave 84 and 42%, respectively, of the disubstitution product in their reaction with 2,6-dibromopy-ridine179. However, only monosubstitution product at position 4,134 was obtained in 70% yield in the reaction of 4,7-dichloroquinoline (133) with pinacolone enolate ion (equation 90)179. 

The substitution reaction of o-iodonitrobenzene (135) with pinacolone enolate ion in liquid ammonia has been reported to afford 136 (66%) (equation 91). 

An interesting approach to the synthesis of indoles is the combination of directed orr/w-lithiation followed by an S l reaction324. Thus, the selective or o-lithiation of 2-fluoropyridine (262) by LDA followed by iodination afforded 2-fluoro-3-iodopyridine (263) in high yield (75%). Substitution of the 2-fluorine atom under S Ar conditions is a convenient synthesis of 2-substituted 3-iodopyridines (264) (equation 169), which can react with acetone or pinacolone enolate ions in liquid ammonia, followed by acidic treatment, to give the corresponding substituted 7-azaindoles (265) [R = H, R = Me (75%), R = t-Bu (78%) R = Me, R = f-Bu (70%), R = Me (95%)] (equation 170). 

These iodo(pivaloylamino)pyridines underwent photostimulated S l reaction with acetone or pinacolone enolate ions in liquid ammonia to give, after acidic treatment, the azaindoles 269-271 in good yields324. 

It is interesting to note that the chlorine atom in position 5 did not react under these conditions. Also, 5,7-dichloro-8-/-propoxyquinoline gave only 276 (R = f-Bu) when irradiated with pinacolone enolate ion. However, 5,7-dibromo-8-methoxyquinoline gave the disubstitution product (60%)326. 

The substitution products, formed in the reaction of acetone or pinacolone enolate ions with aromatic substrates bearing a F3C group either ortho or para to the halogen, undergo reactions in which fluoride ions are eliminated. In the case of the ortho-isomer 310, a ring closure product 311 is formed by intramolecular reaction (equation 186)334. 

Recently, evidence for the vinylic nucleophilic substitutions suggests the occurrence of an ionic elimination-addition along with the originally proposed S l route352. Thus, the reaction of /Lbromostyrene with pinacolone enolate ions and FeCl2 as catalyst in DMSO gave a mixture of products 362-366 in yields that depend on the reaction time, 10 min or (3 h). 

Seebach, Dunitz and coworkers reported, in 1981226, the first crystal structures of lithium enolates of simple ketones, obtained in THF from pinacolone (3,3-dimethyl-2-butanone) and cyclopentanone. Both were arranged as tetrasolvated cubic tetramers, one THF molecule capping each lithium cation (Scheme 58A). Note that pinacolone enolate can also be crystallized, from heptane at — 20 °C, as a prismatic unsolvated hexamer exhibiting an approximate S6 symmetry and six slight it-cation interactions227,228 (Scheme 58B) or as a dimer in the presence of 2 molecules of TriMEDA29. Similarly,... 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

Examples are the reaction of the nitronate anion 4.14 with p-nitrobcnzyl chloride 4.15, and the reaction of the pinacolone enolate 4.16 with bromo-benzene 4.17. The former might have been a straightforward SN2 reaction, but actually takes the SrnI pathway because the nitro groups make the electron transfer exceptionally easy. The latter cannot take place by a conventional Sk2 reaction, because aryl (and vinyl) halides are not susceptible to direct displacement, and the SrnI pathway overcomes this difficulty. 

The carbonyl-carbon kinetic isotope effect (KIE) and the substituent effects for the reaction of lithium pinacolone enolate (112) with benzaldehyde (equation 31) were analyzed by Yamataka, Mishima and coworkers ° and the results were compared with those for other lithium reagents such as MeLi, PhLi and AllLi. Ab initio (HF/6-31-I-G ) calculations were carried out to estimate the equilibrium isotope effect (EIE) on the addition to benzaldehyde. In general, a carbonyl addition reaction (equation 32) proceeds by way of either a direct one-step polar nucleophilic attack (PL) or a two-step process involving electron transfer (ET) and a radical ion intermediate. The carbonyl-carbon KIE was of primary nature for the PL or the radical coupling (RC) rate-determining ET mechanism, while it was considered to be less important for the ET rate-determining mechanism. The reaction of 112 with benzaldehyde gave a small positive KIE = 1.019),... 

Aldol reactions have continued to attract attention. In order to determine the mechanism of addition of lithium pinacolone enolate [CH2=C(OLi)C(Me)3] to benzaldehyde the carbonyl-carbon KIE 1.019) and the substituent effects... 

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