Reaction with cyclohexanone reductions

A related reductive cyclisation has been developed by Schafer et al. in which the cathodic cyclisation of A-(oxoalkyl)pyridinium salts led to indolizidine and quinolizidine derivatives <95AG(E)2007, 03EJO2919>. Electrolyses of the pyridinium salts were carried out in a divided beaker-t5q)e cell at a mercury pool cathode under constant current, using 1 M aqueous sulfuric acid as the electrolyte. In this way, cyclisation of cyclopentanone 129 to the isomeric quinolizidines 130 and 131 was achieved in high yield and with excellent diastereoselectivity (Scheme 38). The stereochemical course of the reaction with cyclohexanone 133 was not as well defined, with three of the four possible diastereoisomers being given in a ratio of 10 21 26 (for 134,135 and 136 respectively). 

A year later Rodriguez and Bohn [33] reported the asymmetric direct Mannich reaction with cyclohexanone, formaldehyde, and aniline using only lmol% of L-proline as catalyst (Scheme 21.11). After carrying out the reaction at 45-50°C for 23 h and a subsequent reduction the corresponding aminoalcohol was obtained in... 

Other secondary amines such as pyrrolidine, di- -butylamine, tetrahydro-quinoline, n-benzylamine, and piperidine were also found to be capable of effecting this reduction. Interestingly, morpholine does not reduce enamines as readily (47) and its acid-catalyzed reaction with norbornanone was reported (45) to give only the corresponding enamine (93), although trace amounts of the reduction product were detected when cyclohexanone was treated with morpholine under these conditions (47a). The yield of morpholine reduction product was increased by using higher temperatures. 

In an analogous sequence, reductive alkylation of aminoalcohol, 46, with cyclohexanone affords the secondary amine (47). Acylation with benzoyl chloride affords hexylcaine (48) in a reaction that may again involve acyl migration. 

With less hindered hydride donors, particularly NaBH4 and LiAlH4, confor-mationally biased cyclohexanones give predominantly the equatorial alcohol, which is normally the more stable of the two isomers. However, hydride reductions are exothermic reactions with low activation energies. The TS should resemble starting ketone, so product stability should not control the stereoselectivity. A major factor in the preference for the equatorial isomer is the torsional strain that develops in the formation of the axial alcohol.117... 

The organosilane reduction of ketones in the presence of alcohols provides an excellent route to unsymmetrical ethers. The reaction of cyclohexanone with ethanol and Et3SiH/TFA gives cyclohexyl ethyl ether in good yield.327,328 The... 

Triisobutylaluminum (TIBA) is an effective reducing agent for ketones. However, in most cases only one isobutyl group is available for reduction. Enolization occurs after a rapid reduction involving the first isobutyl group (143,147). For example, an enolate is formed in the reaction of TIBA with cyclohexanone (143) (eq. [31]). 

A linear phenylene-ethylene copolymer is obtained by a Wurtz-type condensation of 1,2-dibromoethane and 1,4-dibromobenzene. A cross-linked variation can be obtained on addition of 1,3,5-tribromobenzene to the reaction mixture. Equation 119 illustrates the reductive scission of a cyclic ether, catalyzed by such polymers in the presence of lithium, followed by quenching with cyclohexanone . 

In analogy to 23, the chiralities of [2.2]meta- and [10]paracyclophanecarboxylic acids were also deduced from the results of kinetic resolutions 40-77>. For the application of Horeau s method, (—)-[10]paracyclophanecarboxylic acid (14) was transformed by stereoselective hydrogenation and subsequent sodium borohydride reduction of an intermediate cyclohexanone into the (—)-cis-cyclohexanol 94 which on reaction with racemic 2-phenylbutanoic anhydride afforded a 15% excess of the Ievorotatory acid thereby proving (in agreement with the kinetic resolution of the anhydride of 14, vide supra) the chirality (5) for (—)-14 and all its derivatives 40). Optical comparison with dioxa[10]paracyclophanecarboxylic acid (16) confirmed this result63,108). 

Methyl- or 2-ethyl-benzo[Z> ]thiophenes are conveniently prepared by treatment of 2-benzo[6]thienyllithium with the appropriate alkyl sulfate <70AHC(11)177). Clemmensen or Wolff-Kishner reductions of the 2-acylbenzo[Z>]thiophenes are useful, but since acylation produces a mixture of the 2- and 3-acyl isomers (Section 3.14.2.4), these must be separated. Cyclization of phenyl phenacyl sulfide with hydrofluoric acid leads exclusively to 2-phenyl-benzo[6]thiophene, and 3-phenylbenzo[6]thiophene can be rearranged to the 2-isomer in hydrofluoric acid (Section 3.15.2.3.2). Aromatization of 2-cycIohexenylbenzo[6]thiophene, obtained by condensation of the 2-lithio reagent with cyclohexanone, gives 2-phenyl-benzo[6]thiophene, and the reaction is adaptable to the 2-(l-naphthyl) derivative also. 

Platinum sulfide appeared superior to palladium for the reductive alkylation of piperidine with acetone. A more carefully controlled comparison of platinum sulfide with palladium and with platinum is shown in Table 2 for the reaction of N-ethylcyclohexylamine with cyclohexanone. Platinum gave a very poor conversion of the starting secondary amine (27%) and a correspondingly low yield of the tertiary amine product (22%), although the yield based on conversion was good (81%). The... 

This method of preparing alcohols is an adaptation of an oxymercuration procedure of Sand and Genssler2 and reduction methods of Henbest and Nicholls.3 Other methods for preparing 1-methylcyclohexanol are oxymercuration followed by reduction in tetrahydrofuran-water 4 reaction of cyclohexanone with... 

Not surprisingly, nowadays most Oppenauer oxidations are carried out employing cyclohexanone as oxidant because—for structural reasons— this ketone possesses an exceptionally high oxidation potential among ketones. Similarly, /V-methyI -4-pi peridone is used quite often because it possesses an oxidation potential close to cyclohexanone, while it is very easy to remove together with its reduction product from the reaction mixture by washing with aqueous acid.9... 

Malz, Jr. and Greenfield studied the preparation of tertiary amines by reductive alkylation of aliphatic secondary amines with ketones, using platinum metals and their sulfides as catalysts.40 Excellent yields of tertiary amines were obtained with unhindered ketones, such as cyclohexanone and acetone, and relatively unhindered secondary amines. In this study, 5% Pd-C and various transition metal sulfides were compared in the reductive alkylation of dibutylamine with cyclohexanone. By using the reaction conditions suitable to each catalyst, excellent yields of tertiary amines were obtained, as shown in Table 6.5. Approximately 5-15% of the excess cyclohex-... 

In the reductive alkylation of (V-ethylcyclohexylamine with cyclohexanone at 160°C and 4.1-5.2 MPa H2, platinum gave only a 27% conversion of the starting secondary amine and 22% yield of the corresponding tertiary amine, compared with 52% conversion and 42% yield of the tertiary amine with platinum sulfide. Thus, in general, platinum sulfide, or other platinum metal sulfides, have been shown to be the catalysts of choice when more hindered reagents require more severe reaction conditions. 

The reductive alkylation of /V-alkylarylamines and diarylamine with ketones to give tertiary amines has been investigated by Greenfield and Malz, Jr.42 with platinum metal sulfides that had been shown to be excellent catalysts for the reductive alkylation of primary arylamines with ketones37 (see eq. 6.15). Good conversions to tertiary amines were obtained with relatively unhindered secondary arylamines and less hindered ketones. The relative ease in the reductive alkylation of diarylamines with ketones was in the following order cyclohexanone > acetone > ethyl methyl ketone > isoamyl methyl ketone > isobutyl methyl ketone. For example, 58% of diphenylamine was converted to iV-alkyldiphenylamine with cyclohexanone over rhodium sulfide at 150°C and 3.4-5.5 MPa H2 (eq. 6.19), while with isobutyl methyl ketone, a conversion of only 28% was obtained even at 235°C with in the same reaction time. 

The proline-catalyzed asymmetric Mannich reaction between cyclohexanone, formaldehyde and an aniline has been described by Bolm and co-workers [182]. With only 0.5 mol% of homochiral catalyst, the Mannich products have been obtained with excellent ee s up to 98% after a short irradiation time using a constant low power of 10-15 W in conjunction with simultaneous cooling with compressed air. These reaction conditions allow achieving a high reaction rate and an excellent enantioselectivity. In situ reduction of the resulting ketones 129 afford the V-aryl amino alcohols 130 in high yield (syn/anti in ratio 1 5) (Scheme 101). 

Gtmnal alkylation af ketones. Coates and Sowerby have reported a new method for site-selective geminal alkylation of ketones which involves reduction of the n-butylthiomethylene derivative of the ketone by lithium-ammonia to give a methyl-substituted cnolatc anion which can be alkylated in situ. The ketone, for example cyclohexanone (I), is condensed with ethyl formate and then transformed into the n-butylthiomethylene derivative (2) by reaction with n-butyl mercaptan (2, 53-54). This is then reduced with excess lithium in liquid ammonia at -33° with 2 eq. of a proton donor (water is usually used to avoid ovcralkylation). The lithium cnolate is then... 

Thus reaction of cyclohexanone, n-propylamine, and sodium cyanoborohydride in methanol at pH 6-8 at 25° for 24 hr. gives n-propyleyelohexylamine in 85 % yield. The reaction is general for ammonia and primary and secondary amines aromatic amines are somewhat sluggish. All aldehydes and relatively unhindered ketones can be reduc-tively aminated. Yields are improved by use of 3A molecular sieves to absorb the water generated in the reaction. Note that reductive amination of substituted pyruvic acids with ammonia leads to oi-amino acids. Thus alanine can be obtained from pyruvic acid in 50 % yield. A pH of 7 is optimum for. synthesis of a-amino acids. 

The reduction of ferriin by cyclohexanone (484), Ag(bipy)2 by water (31), and CrOs by aldehyde in the presence of ligand (15) have been reported, while the reduction of Cu(phen) + by methanol catalyzed by (<-Bu)2NO is described as an example of a reaction with a memory (91). Several examples of electron transfer between two different complexes of these ligands are also known (25, 77, 279, 294). The effect of changes of wavelength, concentrations, and pH on several photochemical reactions has been examined. These studies include the reduction of complexes of Fe(III) (49, 303, 592) and of Ag(bipy) + (135), and the replacement of CN ligands on Fe(II) by bipy or phen (32, 33). 

The reaction may include a cyclopropanol intermediate derived from an anion radical, as seen in the reduction of cyclohexenones under Clemmensen conditions to afford ring-contracted cyclopentanones along with cyclohexanone derivatives.Thus the diastereomeric cyclopropanol acetates (12) and (13) can be obtained in different ratios from both (10) and (11) (12/13 = 3 from 10, 12/13 > 100 from 11 Scheme 6). ... 

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