Alkylation of cyclohexanone

Bicyclic keto ester (22) was needed for conformational studies. The common atoms are marked ( ) and the obvious disconnections of this symmetrical molecule require double alkylation of cyclohexanone with a reagent such as (23), Double 1,5-diCO disconnection of (22) is impossible as you will discover if you attempt it. 

The double alkylation of cyclohexanone with (23) is easily carried out in one step via an enamlne. The first alkylation is unambiguous and the second is a cycllsation so occurs very easily. 

Another approach to (R)-(-)-phoracantholide I (245) used a ring enlargement of cyclohexanone (255) which had been alkylated with chiral synthon 256 (Scheme 14) [206]. Thus, compound 257 was prepared in 35% yield on a 7-g scale by alkylation of cyclohexanone with chiral 256. Cyclization with Am-berlyst A-15 provided enol ether 258 that was directly submitted to ruthenium tetroxide oxidation to give oxolactone 259 in a 47% yield. Reduction of the latter with catecholborane via its tosylhydrazone afforded (R)-(-)-phoracan-tholide I (245) in 31% yield. 

Alkylation of cyclohexanone imines derived from /i-methoxy-a-phenylbenzeneethanamine depends on the metal and the temperature. In order to generate zinc azaenolates, deprotonation is performed under optimized conditions (LDA, THF. —23 "C, 1 h) followed by the addition of zinc bromide and refluxing for 0.5 hours16. Alkylation of these azaenolates proceeds best at 0 C at lower temperatures ( — 78 C) yields are drastically decreased. 

Enol alkylation of cyclohexanone by oxetane has been achieved by the reaction of oxetane with an enamine salt, bromomagnesium Af-cyclohexyliminocyclohexane, in THF. An 80%... 

Enolate anions generated from ketones, esters, and nitriles can be used as nucleophiles in Sn2 reactions. This results in the attachment of an alkyl group to the a-carbon in a process termed alkylation. Aldehydes are too reactive and cannot usually be alkylated in this manner. Alkylation of cyclohexanone is illustrated in the following equation ... 

Alkylation of cyclohexanone enamines with methyl chloro(methoxy)acetate, followed by alkaline hydrolysis, affords the y-keto acid 30, which readily cyclizes to the unsaturated lactone 31 on treatment with hydrogen chloride in acetic acid (equation 20)40. 

Asymmetric synthesis of ketones (7, 17). Meyers and Williams have extended the asymmetric alkylation of cyclohexanones via the imines formed from 1 to acyclic ketones. Initially optical yields were only 3-44%, but they can be increased to 20-98% by heating the lithioenamines to reflux (THF) prior to alkylation at -78°. Evidently the lithioenamines formed at —20° are mixtures of (E)- and (Z)-isomers. The optical yields are lowered as the size of substituents on the ketone increases. Example ... 

Enantiosekctive a-alkylation of cyclohexanone. A polymeric form of this chiral amine (1) has been prepared as shown in equation (I). The reaction of 1 with cyclohexanone leads to the polymer-bound chiral alkoxyimine (2). Alkylation of the anion of 2 followed by mild acid cleavage results in an (S)-2-alkylcyclohexanone (4). When methyl iodide is the alkylating reagent, the optical yield is 95% it is somewhat less when isopropyl iodide is used. These results compare favorably with those obtained by Enders and Eichenauer by alkylation of a chiral hydrazone of cyclohexanone (7, 10-11). For a related reaction, see Benzyl(methoxymethyl)methyl-amine, this volume. 

Alkylations and Allylations. The asymmetric alkylation of chiral enamines derived from (S)-proline esters has been disclosed. The a-alkylation of cyclohexanone proceeds with an optical purity of 59%. (5)-Proline catalyzes the alkylation of xanthopurpurin (34) by 2-hydroxytetrahydropyran yielding... 

Cleavage of tkhkeuds. Protection of ketones and aldehydes by conversion to thioketals is rarely u.sed because thioketals are resistant to both acid- and base-catalyzed hydrolysis. Use of mercuric salts has been the most useful procedure known (1, 654 2, 182 3, 136). Japanese chemists now report that cleavage can be effected readily through alkylation with triethyloxonium fluoroborate. Thus alkylation of cyclohexanone ethylenethioketal (I) with the reagent affords the salt (2). Alkaline hydrolysis of (2) gives cyclohexanone in only 36% yield. However, if the salt (2) is shaken with 3% CUSO4 solution in methylene chloride, cyclohexanone is obtained in 81 % yield. 

Enantioselective alkylation of cyclohexanones can be accomplished via a chiral lithio-chelated enamine.30... 

Alkylations of lithium enolates of ketones in the presence of chiral bases has been widely studied [77, 559, 1008], but disappointing results were often obtained. However, Koga and coworkers performed asymmetric alkylations of cyclohexanone and tetralone lithium enolates in toluene at low temperatures [108, 1017]. The enolates are generated from the Li amide of chiral diamine 2.4 (X = CH2. R = MeOCH2CH2OCH2CH2). The presence of LiBr is essential to observe a high enantioselectivity (Figure 5.8), and the involvment of mixed aggregates is implied. 

A further extension of these concepts is the alkylation of enolate / secondary amine complexes. Following several early observations [141-143]/ systematic investigations were undertaken by the Koga group [24,25,147-149]. These efforts have resulted in a very selective asymmetric alkylation of cyclohexanone and a-tetralone with activated alkyl halides (Scheme 3.25). As listed in Table 3.10, alkylation of these ketones affords up to 96% enantioselectivity. During the optimization studies, Koga observed an increase in enantioselectivity and chemical yield as the reaction time increased, and ascribed the phenomenon to the formation of a mixed aggregate that includes the lithium bromide formed as the reaction proceeds. Further experiments revealed that addition of one equivalent of lithium... 

Alkylation of cyclohexanone under vigorous conditions gives (5), while (7) can be made from ketone (9) by elimination on the gem-dihalide (8). 

Asymmetric alkylation of cyclohexanone. Hashimoto and Koga have reported an asymmetric synthesis of a-alkylated cyclohexanones by conversion of cyclohexanone to the chiral imine 1 by reaction with the /-butyl ester of /-leucine. The imine is treated with LDA in THF at - 78°, and after 30 minutes the alkylating agent is added to the lithioenamine (a). a-Alkylated cyclohexanones (2) are obtained in chemical yields of 60-75% and in optical yields of 84-98 (four examples). 

Asymmetric alkylation of cyclohexanone, Yamada et al. have reported asymmetric induction in the alkylation of enamines derived from proline esters, but typical optical yields are somewhat low (10-30%). Optical yields of 80-93% have now been observed in alkylations of the enamine of cyclohexanone derived from 1. The higher yields obtained from enamines derived from 1 are attributed to the Ca-axis of symmetry in I.. 

Enantioulective alkylation of cyelokexanoue. M6a-Jacheet and Horeau nd Yamada et al. have reported enantioselective alkylation of cyclohexanones Via imines formed from chiral amines. Meyers et al. have since reported efficient Oantioselective alkylations of imines from (RHl). Thus the imine (2) is alkylated to give (3) the enantiomeric excess of the ketone is in the range of 82-95%. 

The utility of a series of different inorganic bases, including LHMDS, NaHMDS, KHMDS, f-BuONa, f-BuOK, f-BuOLi, LTMP, LDA, PhOLi, MeONa, and EtONa for the alkylation of cyclohexanone with benzyl bromide in a microreactor was studied. The microreactor employed a field-induced electro-kinetic flow acting as apump. To achieve a sufficient electrokinetic mobilization, the inorganic bases had to be solubilized by the addition of stoichiometric quantities of the appropriate crown ethers. With a single exception (LHMDS with 12-crown-4 ether), the desired electrokinetic mobility was reached with aU other bases under these conditions. 

Interactive mechanism for axial alkylation of cyclohexanone enamine... 

Ireland and co-workers used a Wichterle sequence in their stereoselective syntheses of diterpenoid resin acids when annulations with methyl vinyl ketone resulted in polymeric tars. Stereoselective alkylation of cyclohexanone 34 with Wichterle s reagent afforded 35 as a single stereoisomer. Studies performed on this system determined that alkylation was favored cis to the C2 methyl group. After hydrolysis of the vinylic chloride 35 to the diketone 36, cyclization proved difficult due to the large amount of steric hindrance present in the molecule. Base-catalyzed cyclization resulted in only partial conversion to the desired octalone 37. It was found that a significant portion of the material was cleaved to the starting material for this sequence, monoketone 34, via facile reverse Michael addition when the side chain adopted an equatorial confirmation. 

Disconnection (a) results in the a-methylenic derivative of cyclohexanone, an enone whose synthesis will be shown in Sect. 4.4.2, Scheme 4.43, and acetaldehyde. Disconnection (b) leads to the easily available raw materials cyclohexanone and acrolein. Acrolein is an industrial commodity produced by thermal oxygenation of propene with oxygen at 250 °C. Cyclohexanone is commercially produced by co-catalyzed oxidation of cyclohexane or by controlled hydrogenation of phenol [25]. The availability of both starting materials suggests a one-step synthesis of TM 4.8 workable on the large scale (Scheme 4.28). The molar ratio of reactants is controlled to avoid double a,a -alkylation of cyclohexanone. 

Baeyer-Villiger reactions of /8-silyl-ketones are highly regioselective, oxygen insertion occurring almost exclusively between carbonyl and silicon. When applied to cyclic /8-silyl-ketones, for example (52), which is easily prepared by alkylation of cyclohexanone, this reaction can be used as part of a sequence to generate acids and esters with a remote carbon-carbon double bond. ... 

C-alkylation of cyclohexanone enolate with 3-chloropropene (Section 18-1) is much fastothan the corresponding reaction with 1-chloropropane. Explain. (Hint See Section 14-3.) What product(s) would you expect from reaction of cyclohexanone enolate with (a) 2-bromopropane and (b) 2-bromo-2-methylpropane (Hint See Chapter 7.)... 

The first diastereoselective and enantioselective allylic alkylation of cyclohexanone (through the magnesium enolate 18a) with diphenylallyl acetate 19a was reported in 2000 by Braun and coworkers [16a]. (7J)-BINAP (23) served as the optimum chiral ligand, and the alkene 20 was obtained as an almost pure diastereomer with an enantiomeric excess of 99% ee. The relative configuration was proven by the crystal structure analysis the absolute configuration was assigned unambiguously by chemical correlation. A first diastereoselective and enantioselective Tsuji-Trost reaction of a lithium enolate derived from... 

Scheme 5.9 Diastereoselective and/or enantioselective palladium-catalyzed allylic alkylation of cyclohexanone through the magnesium or lithium enolate.

Meyers AI, Williams DR, Druelinger M. Enantioselective alkylation of cyclohexanone via chiral lithio-chelated enam-ines. J. Am. Chem. Soc. 1976 98 3032-3033. 

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