Cyclohexanone derivatives esters

Another concise route to 107 featured the facile construction of the cyclohexanone derivative 109 via the Michael addition of triply deprotonated methyl dioxohexanoate to the nitrostyrene (108 (Scheme 9) (115). Ketalization of 109 followed by hydrogenation of the nitro function and then cyclization of the resulting amino ester by thermolysis in refluxing xylene furnished the lactam 110, which was reduced LiAlH4 to the amine 111. All attempts to cyclize 111 via a Pictet-Spengler reaction led to complex mixtures of products. However, when the unstable enone 112, which was obtained by acid-catalyzed hydrolysis of 111,... 

A simultaneous reduction-oxidation sequence of hydroxy carbonyl substrates in the Meerwein-Ponndorf-Verley reduction can be accomplished by use of a catalytic amount of (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylaluminum) (8) [33], This is an efficient hydride transfer from the sec-alcohol moiety to the remote carbonyl group and, because of its insensitivity to other functionalities, should find vast potential in the synthesis of complex polyfunctional molecules, including natural and unnatural products. Thus, treatment of hydroxy aldehyde 18 with 8 (5 mol%) in CH2CI2 at 21 °C for 12 h resulted in formation of hydroxy ketone 19 in 78 % yield. As expected, the use of 25 mol% 8 enhanced the rate and the chemical yield was increased to 92 %. A similar tendency was observed with the cyclohexanone derivative. It should be noted that the present reduction-oxidation sequence is highly chemoselective, and can be utilized in the presence of other functionalities such as esters, amides, rert-alco-hols, nitriles and nitro compounds, as depicted in Sch. 10. 

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.. 

Scheme 7. Examples for Enantiomer Separations by Crystallization with TADDOLs. Besides the original TADDOL (from tartrate acetonide and PhMgX), Toda et al. [44] have often used the cyclopentanone- and cyclohexanone-derived analogs. The dynamic resolution (resolution with in-situ recychng) of 2-(2-methoxyethyl)cyclohexanone was reported by Tsunoda et al. The resolved compounds shown here are only a small selection from a large number of successful resolutions, which include alcohols, ethers, oxiranes, ketones, esters, lactones, anhydrides, imides, amines, aziridines, cyanohydrins, and sulfoxides. The yields given refer to the amount of guest compound isolated in the procedure given. Since we are not dealing with reactions (for which we use % es to indicate enantioselectivity with which the major enantiomer is formed), we use % ep (enantiomeric purity of the enantiomer isolated from the inclusion...

The synthesis of a series of a-aryl-P-keto allyl esters was accomplished by first preparing cyclopentanone- and cyclohexanone-derived P-keto allyl esters 3 and 4 (Scheme 6.1). This was achieved via Dieckmann condensation of commercially available diallyl adipate using NaH as the base to generate cyclopentanone P-keto allyl ester 3 in 73 % yield. Similarly, diallyl pimelate, prepared by transesterification... 

Fraga CAM, Teixeira LHP, Menezes CMOS et al (2004) Studies on diastereoselective reduction of cyclic J -keto esters with boron hydrides. Part 4 the reductive profile of functionalized cyclohexanone derivatives. Tetrahedron 60 2745-2755... 

The intramolecular variant of ester condensation is known as the Dieckmann reaction and preferred for construction of thermodynamically favored medium rings without steric strain, in particular cyclopentanone and cyclohexanone derivatives. 

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

Hydrocarbon Oxidation. The oxidation of hydrocarbons (qv) and hydrocarbon derivatives can be significantly altered by boron compounds. Several large-scale commercial processes, such as the oxidation of cyclohexane to a cyclohexanol—cyclohexanone mixture in nylon manufacture, are based on boron compounds (see Cylcohexanoland cyclohexanone Eibers, polyamide). A number of patents have been issued on the use of borate esters and boroxines in hydrocarbon oxidation reactions, but commercial processes apparently use boric acid as the preferred boron source. The Hterature in this field has been covered through 1967 (47). Since that time the Hterature consists of foreign patents, but no significant appHcations have been reported for borate esters. 

Other methods for the preparation of cyclohexanecarboxaldehyde include the catalytic hydrogenation of 3-cyclohexene-1-carboxaldehyde, available from the Diels-Alder reaction of butadiene and acrolein, the reduction of cyclohexanecarbonyl chloride by lithium tri-tcrt-butoxy-aluminum hydride,the reduction of iV,A -dimethylcyclohexane-carboxamide with lithium diethoxyaluminum hydride, and the oxidation of the methane-sulfonate of cyclohexylmethanol with dimethyl sulfoxide. The hydrolysis, with simultaneous decarboxylation and rearrangement, of glycidic esters derived from cyclohexanone gives cyclohexanecarboxaldehyde. 

The enamines derived from cyclic ketones give the normal alkylated products, although there is some evidence that unstable cycloadducts are initially formed (55b). Thus the enamine (28) derived from cyclohexanone and pyrrolidine on reaction with acrylonitrile, acrylate esters, or phenyl vinyl sulfone gave the 2-alkylated cyclohexanones (63) on hydrolysis of the intermediates (31,32,55,56). These additions are sensitive to the polarity of the solvent. Thus (28) in benzene or dioxane gave an 80% yield of the... 

Recendy, Darzens reaction was investigated for its synthetic applicability to the condensation of substituted cyclohexanes and optically active a-chloroesters (derived from (-)-phenylmenthol). In this report, it was found that reaction between chloroester 44 and cyclohexanone 43 provided an 84% yield with 78 22 selectivity for the axial glycidic ester 45 over equatorial glycidic ester 46 both having the R configuration at the epoxide stereocenter. 

Ethynyl derivatives of 2-aryl-4,5,6,7-tetrahydroindazole were prepared from the p-chlorophenyl hydrazone of cyclohexanone. The hydrazone was treated with two equivalents of -butyllithium at —78°C to generate the dianion, which was then quenched with the appropriate substituted ethyl ester (94MT29). 

The preparation of Pans-1,2-cyclohexanediol by oxidation of cyclohexene with peroxyformic acid and subsequent hydrolysis of the diol monoformate has been described, and other methods for the preparation of both cis- and trans-l,2-cyclohexanediols were cited. Subsequently the trans diol has been prepared by oxidation of cyclohexene with various peroxy acids, with hydrogen peroxide and selenium dioxide, and with iodine and silver acetate by the Prevost reaction. Alternative methods for preparing the trans isomer are hydroboration of various enol derivatives of cyclohexanone and reduction of Pans-2-cyclohexen-l-ol epoxide with lithium aluminum hydride. cis-1,2-Cyclohexanediol has been prepared by cis hydroxylation of cyclohexene with various reagents or catalysts derived from osmium tetroxide, by solvolysis of Pans-2-halocyclohexanol esters in a manner similar to the Woodward-Prevost reaction, by reduction of cis-2-cyclohexen-l-ol epoxide with lithium aluminum hydride, and by oxymercuration of 2-cyclohexen-l-ol with mercury(II) trifluoro-acetate in the presence of ehloral and subsequent reduction. ... 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

Camell, A.J., Barkely, J. and Singh, A., Desymmetrisation of prochiral ketones by catal3ftic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997, 38, 7781-7784 Allan, G.R., Carnell, A.J. and Kroutil, W., One-pot deracemisation of an enol acetate derived from a prochiral cyclohexanone. Tetrahedron Lett., 2001, 42, 5959-5962. 

Apart from the reaction of cyclohexanecarboxylic acid with methyllithium, cyclohexyl methyl ketone has been prepared by the reaction of cyclohexylmagnesium halides with acetyl chloride or acetic anhydride and by the reaction of methylmagnesium iodide with cyclohexanecarboxylic acid chloride. Other preparative methods include the aluminum chloride-catalyzed acetylation of cyclohexene in the presence of cyclohexane, the oxidation of cyclohexylmethylcarbinol, " the decarboxylation and rearrangement of the glycidic ester derived from cyclohexanone and M)utyl a-chloroj)ropionate, and the catalytic hydrogenation of 1-acetylcycIohexene. "... 

This process (also known as the Ferrier II Reaction ) has proved to be of considerable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex compounds of interest in biological and medicinal chemistry. ... 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

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