Cyclohexanone activation

Olmstead, K. K., Nickon, A. 1,2-Hydrogen shifts in thermal and photic Bamford-Stevens reactions of cyclohexanones. Activation by an endocyclic oxygen. Tetrahedron 1998, 54,12161-12172. 

AA is probably generated via the intermediate formation of 2-hydroxycyclohexanone and 6-oxohexanoic acid. The mechanism may potentially include the formation of the enol tautomer of cyclohexanone, favored by the presence of an acid (Scheme 7.4 this may also be an alternative mechanism for cyclohexanone activation). The cyclohexen-l-ol formed is then oxidized to 2-hydroperoxycyclohexanone. The hydroperoxide generates 2-hydroxycyclohexanone, which is then cleaved to 6-oxohexanoic acid. The latter is then converted into AA via monoperoxyadipic acid this step is eventually catalyzed by cobalt. Scheme 7.5 shows the steps in the mechanism of reaction. 

Scheme 7.4 One possible mechanism of cyclohexanone activation via enol tautomer.

Synthetically useful stereoselective reductions have been possible with cyclic carbonyl compounds of rigid conformation. Reduction of substituted cyclohexanone and cyclopentan-one rings by hydrides of moderate activity, e.g. NaBH (J.-L. Luche, 1978), leads to alcohols via hydride addition to the less hindered side of the carbonyl group. Hydrides with bulky substituents 3IQ especially useful for such regio- and stereoselective reductions, e.g. lithium hydrotri-t-butoxyaluminate (C.H. Kuo, 1968) and lithium or potassium tri-sec-butylhydro-borates or hydrotri-sec-isoamylborates (=L-, K-, LS- and KS-Selectrides ) (H.C. Brown, 1972 B C.A. Brown, 1973 S. Krishnamurthy, 1976). 

Enamines as nucleophiles react with butadiene, and a-octadienyl ketones or aldehydes are obtained after hydrolysis[57]. This is a good way of introducing an octadienyl group at the o-position of ketones or aldehydes, because butadiene does not react with ketones or aldehydes directly. The reaction of the pyrrolidine enamine of cyclohexanone gives, after hydrolysis, 2-(2,7-octadie-nyOcyclohe.xanone (58) as the main product, accompanied by a small amount of 2,6-di(2,7-octadienyl)cyclohexanone. The reaction of the optically active enamine 59 with butadiene gave 2-(2,7-octadienyl)cyclohexanone (60) in 72% ce[58]. 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Also due to the high barrier of inversion, optically active oxaziridines are stable and were prepared repeatedly. To avoid additional centres of asymmetry in the molecule, symmetrical ketones were used as starting materials and converted to oxaziridines by optically active peroxyacids via their ketimines (69CC1086, 69JCS(C)2648). In optically active oxaziridines, made from benzophenone, cyclohexanone and adamantanone, the order of magnitude of the inversion barriers was determined by racemization experiments and was found to be identical with former results of NMR study. Inversion barriers of 128-132 kJ moF were found in the A-isopropyl compounds of the ketones mentioned inversion barriers of the A-t-butyl compounds lie markedly lower (104-110 kJ moF ). Thus, the A-t-butyloxaziridine derived from adamantanone loses half of its chirality within 2.3 days at 20 C (73JCS(P2)1575). 

Aryl halides with a halogen activated by electron-withdrawing groups react with pyrrolidine enamines of cyclic ketones (68) to give the a-arylated ketones after hydrolysis. The enamine (28) with 2,4-dinitrochlorobenzene gave an excellent yield of 2(2,4-dinitrophenyl)cyclohexanone (88). 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. 

Fusion of an all cyclic ring onto the piperidine so as to form a perhydroisoquinoline is apparently consistent with analgesic activity. Synthesis of this agent, ciprefadol (68), starts with the Michael addition of the anion from cyclohexanone 56 onto acrylonitrile (57). Saponification of the nitrile to the corresponding acid ( ) followed by Curtius rearrangement leads to isocyanate Acid... 

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functionalized cyclohexanone 0 with phenyl hydrazine (19). The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenyl hydrazine with 4-hydroxycyclohexanone (23). The resulting alcohol (24) is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26). ... 

Changing the functionality on the alicyclic ring from an amine to a carboxylic acid leads to a compound that shows antiallergic activity, acting possibly by means of inhibition of the release of allergic mediators. Thus, condensation of acylated indole with cyclohexanone carboxylic acid affords directly oxarbazole (29). ... 

The second method is based on the optically active enamine formed from (S)-prolinol methyl ether and cyclohexanone. This enamine reacts spontaneously with 2-(arylmethylcnc)propane-dioates to give, after hydrolysis, the 2- (.S )-aryl[(,S )-2-oxocyclohexyllmethyl propanedioates 4 in 35-76% yield with d.r. 94 6 > 97 361. 

For example, using (/ )-5-trimethylsilyl-2-cyclohexenone as the chiral Michael acceptor, optically active m // .v-3.5-disubstituied cyclohexanones 1 are obtained via a Lewis acid catalyzed addition of silylenol ethers or ketene acetals. 

Optically pure (S)-benzyl methyl sulfoxide 139 can be converted to the corresponding a-lithio-derivative, which upon reaction with acetone gave a diastereomeric mixture (15 1) of the /S-hydroxysulfoxide 140. This addition reaction gave preferentially the product in which the configuration of the original carbanion is maintained. By this reaction, an optically active epoxy compound 142 was prepared from the cyclohexanone adduct 141181. Johnson and Schroeck188,189 succeeded in obtaining optically active styrene oxide by recrystallization of the condensation product of (+ )-(S)-n-butyl methyl sulfoxide 143 with benzaldehyde. 

For a number of applications curing at room temperature is desirable. This so-called cold cure is brought about by using a peroxy initiator in conjunction with some kind of activator substance. The peroxy compounds in these cases are substances such as methyl ethyl ketone peroxide and cyclohexanone peroxide, which as used in commercial systems tend not to be particularly pure, but instead are usually mixtures of peroxides and hydroperoxides corresponding in composition approximately to that of the respective nominal compounds. Activators are generally salts of metals capable of undergoing oxidation/reduction reactions very readily. A typical salt for this purpose is cobalt naphthenate, which undergoes the kind of reactions illustrated in Reactions 4.6 and 4.7. 

The problem arises in controlling the reaction. Cyclohexanone enolises easily but attacks Itself easily too. Direct acylation with RC02Jit and EtO catalyst gives poor yields. " Clearly a specific enol is needed. An activating group could easily be added, as in (72), but acylation of this, to replace the last remaining proton, is not a good idea (cf p 211 ),... 

Because of the many examples of such activation of metal powders by TCS 14 only a limited and arbitrary number will be discussed here. The Clemmensen-type reduction of ketones such as cyclohexanone with Zn powder in the presence of TCS 14 affords, via 2082, 2084, and 2085, cyclohexene and, via 2082, O-silylated pinacol 2083 [19, 20]. Ketones such as 5a-cholestan-3-one 2086 are reduced by Zn dust-TCS 14 in TFIF, in ca 65-70% yield, to give 5a-cholest-2-ene 2087 and ca 5% 5a-cholest-3-ene [21] (Scheme 13.8). 

Table 3 summarizes the scope and limitation of substrates for this hydrogenation. Complex 5 acts as a highly effective catalyst for functionalized olefins with unprotected amines (the order of activity tertiary > secondary primary), ethers, esters, fluorinated aryl groups, and others [27, 30]. However, in contrast to the reduction of a,p-unsaturated esters decomposition of 5 was observed when a,p-unsaturated ketones (e.g., trans-chalcone, trans-4-hexen-3-one, tra s-4-phenyl-3-buten-2-one, 2-cyclohexanone, carvone) were used (Fig. 3) [30],... 

TS-1 is a material that perfectly fits the definition of single-site catalyst discussed in the previous Section. It is an active and selective catalyst in a number of low-temperature oxidation reactions with aqueous H2O2 as the oxidant. Such reactions include phenol hydroxylation [9,17], olefin epoxida-tion [9,10,14,17,40], alkane oxidation [11,17,20], oxidation of ammonia to hydroxylamine [14,17,18], cyclohexanone ammoximation [8,17,18,41], conversion of secondary amines to dialkylhydroxylamines [8,17], and conversion of secondary alcohols to ketones [9,17], (see Fig. 1). Few oxidation reactions with ozone and oxygen as oxidants have been investigated. 

Stereoselective oxygen transfer to the sulphur atom of alkyl aryl sulphides catalyzed by 2-flavoenzyme monooxygenases afforded optically active sulphoxides in high optical yields . For instance, with ethyl p-tolyl sulphide as substrate cyclohexanone monooxygenase from Actinetobacter produces predominantly (— )-(S)-sulphoxide with 64% e.e. In contrast, FAD-containing dimethylaniline monooxygenase purified from hog liver microsomes affords (+ )-(i )-enantiomer of this sulphoxide with 90% optical purity . ... 

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