Cyclohexanone lithium enolate

Compare the geometries of the cyclohexanone enolate and the cyclohexanone lithium enolate. Do both molecules show delocalized structures, or is the bonding in one of them more localized For comparison, examine the geometries of 1-hydroxycyclohexene md cyclohexanone. 

Electrostatic potential map for cyclohexanone lithium enolate shows negatively-charged regions (in red) and positively-charged regions (in blue). 

HOMO of cyclohexanone lithium enolate reveals the most nucleophilic sites. 

Electrostatic and orbital interactions may steer reaction toward either carbon or oxygen. First, examine the electrostatic potential map for cyclohexanone lithium enolate. Which atom is more negatively charged, carbon or oxygen Is the difference significant If it is, what would be the favored mode of addition Does either methylation or silylation appear to be guided by electrostatics Explain. 

Now, examine the orbital on cyclohexanone lithium enolate most able to donate electrons. This is the highest-occupied molecular orbital (HOMO). Identify where the best HOMO-electrophile overlap can occur. Is this also the most electron-rich site An electrophile will choose the best HOMO overlap site if it is not strongly affected by electrostatic effects, and if it contains a good electron-acceptor orbital (this is the lowest-unoccupied molecular orbital or LUMO). Examine the LUMO of methyl iodide and trimethylsilyl chloride. Is backside overlap likely to be successful for each The LUMO energies of methyl iodide and trimethylsilyl chloride are 0.11 and 0.21 au, respectively. Assuming that the lower the LUMO energy the more effective the interaction, which reaction, methylation or silylation, appears to be guided by favorable orbital interactions Explain. 

SCHEME 73. Catalytic cycle in the protonation of 2-isopropyl-5-methyl cyclohexanone lithium enolate using Kemp s acid imide derivative as a catalyst357,358... 

Scheme 5.40. (a) Wynberg s early example of interligand asymmetric induction in the Michael reaction [201]. (b) Seebach s investigation of cyclohexanone lithium enolate complexed to chiral diamines with extra lithium [3]. (c) Mukaiyama s imide tin enolate and chiral diamine [202]. (d) Mukaiyama s catalytic tin dithioenolate Michael addition [203]. 

Regiospecific alkylation of ketones. This salt converts trimethylsHyl enol ethers into quaternary ammonium enolates that undergo regiospecific monoalkylation. This method is especially useful for alkylation at the less substituted position of a cyclohexanone lithium enolates are more useful for alkylation at... 

Reaction of cyclopropanone ethyl hemiacetal with methylmagnesium bromide and two equivalents of cyclohexanone lithium enolate provides a very interesting and highly stereospecific synthesis of tricyclic cycloheptanones a serendipitous reaction... 

A new procedure for the conversion of a y-lactone into the corresponding a-methylene-y-lactone has been developed during a total synthesis of the pseudoguaianolide ( )-aromatin (Scheme 48). The readily-prepared complex cation (97) functions as an a-acrylic ester cation equivalent, converting cyclohexanone lithium enolate into the cis- and trans-a-methylene-y-lactones (98). ... 

Kosugi and co-workers described the stoichiometric use of chiral sulfoxyde G as a proton source in the course of protonation of 2-substituted cyclohexanone lithium enolate Li -39. This methodology was extended to the synthesis of (—)-epibatidine 40, a potent antinociceptive agent. 

Common reagents such as lithium diisopropylamide (LDA see Chapter 11, Problem 5) react with carbonyl compounds to yield lithium enolate salts and diisopropylamine, e.g., for reaction with cyclohexanone. 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

In this way cyclohexanones with two or three contiguous stereogenic centers are obtained under mild conditions, as compared to the Diels-Alder conditions or the strongly basic conditions of the lithium enolate MIMIRC reaction. 

The stereochemical outcome of the addition of lithium enolates of aldehydes and ketones to nitroalkenes is dependent upon the geometry of the nitroalkene and the enolate anion. The synjanti selectivity in the reaction of the lithium enolates of propanal, eyelopentanone and cyclohexanone with ( )- and (Z)-l-nitropropene has been reported1. 

The reverse trend is observed with (Z)-enolates. The reaction of the lithium enolate of cyclohexanone with ( )-(2-nitroethenyl)benzene gives a 75 25 mixture of the syn- and anti-adducts. In contrast, the same enolate undergoes addition of ( )-5-(2-nitroethenyl)-l,3-benzo-dioxole to give exclusively the yymaddition product in 93% yield2. 

The lithium enolates of cyclopentanone and cyclohexanone undergo addition-elimination to the 2,2-dimethylpropanoic acid ester of ( )-2-nitro-2-hepten-l-ol to give 2-(l-butyl-2-nitro-2-propenyl)cycloalkanones with modest diastereoselection. An analogous reaction of the enolate ion of cyclohexanone with the 2,2-dimethylpropanoic acid ester of (Z)-2-nitro-3-phenyl-2-propenol to give 2-(2-nitro-l-phenyl-2-propenyl)cyclohexanones was also reported. The relative configuration of these products was not however determined6. 

The initial addition step is reversible allowing isomerization of the ( )- and (Z)-nitroalkenes and equilibration between the initially formed syn- and ann -imminium ion adducts. The spn-ad-duct is identical to that obtained from the lithium enolate of cyclohexanone and ( >(2-nitro-cthenyl)benzenc. The preference for the. yyu-adduct can be rationalized by inferring the transition state 1 which is similar to that proposed for the reaction of (-E)-nitroalkcnes with ( )-eno-lates11, l2. 

The reaction of the enamines of cyclohexanones with a,ft-unsaluraled sulfones gives mixtures resulting from attack of the enamine at the a- and /(-carbons of the oc,/ -unsaturated sulfone. The ratio of x- and /1-adducts is dependent upon the reaction solvent, the geometry and structure of the sulfone1 4. The diastereoselectivity of these reactions is also poor. The reaction of lithium enolates of cyclic ketones with ( )-[2-(methylsulfonyl)ethenyl]benzene, however, gives bicyclic alcohols, as single diastereomers, that result from initial -attack on the oc,/ -unsaturated sulfone5. 

From the readily available benzotriazole derivative 76, Katritzky and Harris (90T987) prepared a diastereomeric mixture of the /3-amino ketone 77 with the lithium enolate of cyclohexanone. In the reduction of 77 with lithium aluminium hydride, a reductive cyclization took place, resulting in the two diastereomeric oxazinones 78 in a ratio of 5 2. This cyclization can be regarded as a variation of the chloroformate cyclization under alkaline conditions. 

Table 2. Enantioselective Dcprotonation of 4-Substituted Cyclohexanones 1 in THF with in situ Trapping of the Intermediate Lithium Enolate with (CH3)3SiCl at — 78°Ca-b 13-14-24-2g-3S-37-55-55a...

The feasibility of a deprotonation of cyclohexanone derivatives bearing a chiral heterocyclic substituent in the 4-position with the C2-symmetric base lithium bis[(/f)-l-phenylethyl]amide with internal quenching of the lithium enolate formed with chlorotrimethylsilane is shown in entries 32 and 33 of Table 229,25a. The silyl enol ethers are obtained in a diastereomeric ratio of 79.5 20.5. By using lithium bis[(1S)-l-phenylethyl]amide the two diastereomers are formed in a ratio of 20 80 indicating that the influence of the chirality of the substituent is negligible. 

Homologation reaction of lithium enolates with bis(iodomethyl)zinc (58) yields a homoenolate, namely the organozinc derivatives bearing a carbonyl group at the /3 position (Scheme 6)55. Treatment of the lithium enolate of cyclohexanone, generated from the silyl... 

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). 

Phenol annelation.1 This modified methyl vinyl ketone can be used for synthesis of 5,6,7,8-tetrahydro-2-naphthol or 5-indanol by reaction with the lithium enolate of cyclohexanone or cyclopentanone, respectively. The former reaction is formulated in equation (I). 

We have already established that RCHO and RCOC1 are poor at conjugate addition while ketones and esters are better. An extreme example is the amide 61 that does conjugate addition even with the lithium enolate 60 of cyclohexanone.8... 

To test this idea, the chloro-diketone must be made and the route chosen was to react the lithium enolate of 4-f-butyl cyclohexanone with the correct acid chloride. 

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