Acetophenone lithium enolate

The leaving group in the alkylating reagent has a major effect on whether C- or O-alkylation occurs. In the case of the lithium enolate of acetophenone, for example, C-alkylation is predominant with methyl iodide, but C- and O-alkylation occur to approximately equal extents with dimethyl sulfate. The C- versus O-alkylation ratio has also been studied for the potassium salt of ethyl acetoacetate as a function of both solvent and leaving group. ... 

Although enolates, their equivalents, and otherwise stabilized carbanions would be interesting candidates for ARO of weso-epoxides, no efficient catalytic method has been developed to date. Crotti reported that 20 mol% of (salen)Cr-Cl complex 2 promoted the addition of the lithium enolate of acetophenone to cyclohexene oxide with moderate ees (Scheme 7.26) [50], However, the very low yields obtained... 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Initial reports on the use of simple enolates as nucleophiles in TT-allylpalladium chemistry met with only limited success.77 106 The enolate of acetophenone reacted with allyl acetate in the presence of Pd(PPh3)4, but gave predominantly dialkylated product.106 The use of the enol silyl ether of acetophenone gave only monoalkylated product with allyl acetate and Pd° catalysis, but substituted allyl acetates did not function in this reaction.106 Enol stannanes, however, have been found to give monoalkylated products with a wide variety of allyl acetates (equation 19).106 In situ generation of enol stannanes from lithium enolates and trialkylstannyl trifluoroacetates followed by Pd°-catalyzed allylation has been demonstrated.107... 

The following is a typical example of a process described by Russian workers as "anionic activation", and used for the rapid construction of fluoro-substituted heterocycles Treatment of 2-(trifluoromethyl)aniline with either lithium phenylacetylide or the lithium enolate of acetophenone in THF at -60°C gave 4-fluoro-2-phenylquinoline in 25-40% yield. 

AUylic alkylation. In the presence of this Pd(0) complex and hls(tl iphcnylphosphine)ethane, allylic acetates can be alkylated by lithium enolates of cyclohexanone, 3-pentanone, acetophenone, and mesityl oxide in 40-80% yield. The i I m I ion was shown to occur with overall retention of configuration in the case of the lithium enolate of acetone (equation I). 

Evans and co-workers have reported successful diazo transfer from p-nitrobenzenesulfonyl azide (PNBSA) to the enolate derivatives of an N-acyloxazolidinone and a benzyl ester (a) Evans, D. A. Britton, T. C. Ellman, J. A. Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. However, we have not been able to achieve efficient diazo transfer to ketone enolates employing these conditions. For example, exposure of the lithium enolate of acetophenone to 1.2 equiv of PNBSA in THF at -TS C for 15 min gave a-diazoacetophenone in only 21% yield. 

Evans and Leahy reported on a method for the rhodium-catalyzed allylic alkylation using copper enolates, generated by transmetalation of the corresponding lithium enolates (equation 19). These enolates are softer and less basic nucleophiles than lithium enolates and therefore problems typically associated with enolate nncleophiles in metal-allyl chemistry can be avoided. A copper(I) enolate, derived from acetophenone derivative 63, was used as nucleophile in a regio- and stereoselective rhodinm-catalyzed alkylation of the in situ activated allylic alcohol 62. Thereby, the synthesized ketone 64, a key intermediate in the total synthesis of (—)-sugiresinol dimethyl ether (65), was produced as the only detectable regioisomer with complete conservation of enantiomeric excess. 

A difficult challenge in developing ARO reactions with carbon nucleophiles is identifying a reagent that is sufficiently reactive to open epoxides but at the same time innocuous to chiral metal catalysts. A recent contribution by Crotti clearly illustrates this dehcate reactivity balance. The lithium enolate of acetophenone added in the presence of 20 mol % of the chiral Cr(salen) complex 1 to cyclohexene oxide in very low yield but in 84% ee (Scheme 10) [23]. That less than one turnover of the catalyst was observed strongly suggests that the lithium enolate and the Schiff base catalyst are not compatible under the reaction conditions. 

The aldol reaction in carbonyl compounds has its equivalents in 7i-electron deficient heterocycles. In the carbanion approach, lithiated acetophenone added rapidly and regioselectively to 1-substituted 2-pyrimidinones to form the 3,4-dihydro isomer (279) (Scheme 45) <85ACS(B)195>. The adducts are readily oxidized to their aromatic equivalents (280) by DDQ. With the lithium enolate of mesityl oxide, however, equal amounts of the two dihydro isomers were formed <88JOM(338)34l>. In highly 7i-electron deficient heterocyclic systems, aldol reactions will also take place under the influence of acid catalysis such as in the addition of acetone to the pyrimidinone (281) the product is fully conjugated (282) after DDQ dehydrogenation <79ACS(B)150>. 

Quinoline, Isoquinoline, and their Benzo- and Hydro- derivatives 6- and 7- Substituted quinolines have been prepared by reaction of the appropriately substituted anilinobutenoate with the Vilsmeier reagent (Scheme 16).92 Reaction of a N-methylisatoic anhydride (70) with the lithium enolate of an acetophenone gives good yields of 2-aryl-4-quinolones (71). 93... 

Diketones. Saegusa et al have reported the synthesis of 1,4-diketones by treatment of lithium enolates of methyl ketones with cupric chloride (1 eq.) in DMF at -78°, Yields of coupled products are high in the case of ketones with only one enohzable hydrogen (pinacolone and acetophenone) ... 

Synthesis of tetramethylchroman analogue (64) was similar to that of thiochroman (63) except that the key ethynyl intermediate (72) was prepared from acetophenone (70). Formation of a phosphoester from the lithium enolate salt of (70) was followed by elimination of the phosphate group to give acetylene (72). Coupling of (72) with ethyl 4-iodobenzoate proceeded as with (71) and gave (64). 

On the other hand, enolates almost always form trialkyl enol ethers on reaction with the hard chlorosilanes (144). Ethylation of 4-/er/-butylcyclo-hexanone lithium enolate (145) with iodoethane leads solely to a-ethylated ketones. However, up to 17% enol ether is obtained when the Meerwein reagent is used. Acetophenone anion is alkylated at oxygen and carbon in the following ratios—0.1, 3.5, and 4.9—depending on whether the reagent is EtI, Me2S04, or EtjO BF respectively (146). Amylation of butyrophenone enolate in dimethyl sulfoxide (DMSO) with reference to halide variation has also been studied (147). The lesser amount of enol ether formed corresponds to the softer halide. 

We mentioned that by mixing vinyl epoxides and zerovalent palladium, the alcoholate formed was usually sufficiently basic to deprotonate the pronucleophile entity. In some cases, especially with ketones, low reactivity and yields were reported (Table To overcome the problem of the weak basicity of the alcoholate, silyl enol ethers, keto adds, or preformed lithium enolates have successfully been employed.f f" f f /3-Keto acids are masked enolates via the decarboxylation of the intermediary Tr-allylpalladium ]3-ketocarboxylate complexes. The main limitation of the use of keto adds as pronucleophiles seems to be their low reactivity toward the hindered cyclic vinyl epoxides. In these cases, the cationic n-allylpalladium complex undergoes ]S-elimination. Indeed, the reaction between benzoyl acetic acid and cyclobutadiene monoxide in the presence of Pd(PPh3>4 gives only the corresponding cyclopentanone and acetophenone as the... 

Lithium enolates of ketones and esters undergo a coupling reaction with copper(II) halides to afford the corresponding 1,4-dicarhonyl compounds. Thus treating a 3 1 mixture of f-butyl methyl ketone and acetophenone with lithium diisopropylamide and CuCU gives a 60% yield of the cross-coupled product (eq 12). 

The probes (Z)-60 and ( )-65, both enantiomerically and diastereomerically pure allylic substrates [37], were submitted to the standard allylation protocol, however with the achiral ligand dppf, as the stereocontrol was left to the substrate. The results are shown in Schemes 5.21 and 5.22 for the lithium enolate of acetophenone with the additive lithium chloride. The reaction of (Z)-configured allylic acetate 60 led to the formation of the ketone 64 as a single diastereomer. This result is remarkable inasmuch as the new carbon-carbon bond had formed... 

The most direct route towards functionalized aliphatic polyesters is based on the functionalization of polyester chains. This approach is a very appealing because a wide range of functionalized aliphatic polyesters could then be made available from a single precursor. This approach was implemented by Vert and coworkers using a two-step process. Eirst, PCL was metallated by lithium diisopropylamide with formation of a poly(enolate). Second, the poly(enolate) was reacted with an electrophile such as naphthoyl chloride [101], benzylchloroformate [101] acetophenone [101], benzaldehyde [101], carbon dioxide [102] tritiated water [103], ot-bromoacetoxy-co-methoxy-poly(ethylene oxide) [104], or iodine [105] (Fig. 26). The implementation of this strategy is, however, difficult because of a severe competition between chain metallation and chain degradation. Moreover, the content of functionalization is quite low (<30%), even under optimized conditions. 

Not much is currently known concerning diastereoselective addition of metal enolates to ketones 48,108), but selectivities are expected to be lower. In case of titanium enolates, several examples have been studied 77). The reaction shown in Equation 67 involves an ester-enolate21 and proceeds strictly in a 1,2 manner with 90% diastereoselectivity. The observation is significant because similar reactions with aldehydes are essentially stereo-random77). Also, the lithium analog of 203 affords a 1 1 mixture of diastereomers. Diastereoface-selectivity in Equation 67 is not an exception, because 203 adds to acetophenone and pinacolone to afford 85 15 and >76 24 diastereomer mixtures, respectively 77). Although stereochemical assignments have not been made in all cases, the acetophenone adduct was converted stereospecifically into the p-lactone which was decarboxylated to yield an 85 15 mixture of Z- and E-2-phenyi-2-butene 77). 

Compounds with acidic hydrogen atoms react rapidly with cuprates. Phenylacetylene has been mentioned as one example (223). Another is diethyl phenylmalonate (144), which on addition to lithium dimethylcuprate gave a rapid evolution of methane and the formation of a methyl-copper-like precipitate which did not redissolve. Subsequent to the addition of benzoyl chloride and the customary work-up, only acetophenone and the phenylmalonate were isolated. The reaction may be summarized by Eq. (23). The failure to isolate the acylated product may be ascribed to the formation of the enolate, (II). 

A systematic study of the reductive alkylation of acetophenones revealed that the desired transformation (Scheme 30) required a careful selection of reagents and conditions. The best results were obtained from reduction by potassium in ammonia at -78 °C, with t-butyl alcohol as the proton source. Exchange of the potassium counterion of the enolate (152 M = K) for lithium then ensured regioselective alkylation at C-1 to give (153) in 80-90% yields (Scheme 30). Metals other than potassium as the reductant led to undesirable side reactions with the carbonyl group, which included simple reduction to the methylcar-binol and ethylbenzene (lithium or sodium), while the absence of a proton source or presence of a strong... 

---