Hydroxy cyclohexanones, synthesis

The Fischer indole synthesis is quite tolerant of additional functional groups in the starting material. Thus reaction of 4-dimethylaminocyclohexanone (18-2) with phe-nylhydrazine (18-1) in acetic acid leads directly to cyclindole (18-3) [18], a compound described as an antidepressant. A shghtly different approach is used to prepare the fluorinated analogue. The tricyhc indole (18-5), in this case, is obtained by reaction of 2,4-diiluorophenylhydrazine (18-4) with 4-hydroxy-cyclohexanone. The hydroxyl... 

H Putter, H Hannebaum, D Hermeling. Electrochemical Synthesis of 2-Hydroxy-Cyclohexanone Dimethyl Ketal, Conference, Electrochemical Processing, The Versatile . ICI Chemicals Polymers, EA Technology, Barcelona, April 14-18, 1997. 

Kleinpeter, E., Heydenreich, M., Koch, A., Linker, T. (2012). Synthesis and NMR spectroscopic conformational analysis of esters of 4-hydroxy-cyclohexanone-the more polar the molecule the more stable the axial eonformer. Tetrahedron, 68(10), 2363-2373. 

A Methylamino)phenol. This derivative, also named 4-hydroxy-/V-methy1ani1ine (19), forms needles from benzene which are slightly soluble in ethanol andinsoluble in diethyl ether. Industrial synthesis involves decarboxylation of A/-(4-hydroxyphenyl)glycine [122-87-2] at elevated temperature in such solvents as chlorobenzene—cyclohexanone (184,185). It also can be prepared by the methylation of 4-aminophenol, or from methylamiae [74-89-5] by heating with 4-chlorophenol [106-48-9] and copper sulfate at 135°C in aqueous solution, or with hydroquinone [123-31 -9] 2l. 200—250°C in alcohoHc solution (186). 

The application of this addition to aminomethylene ketones provides a convenient synthesis of monoamides of pimelic acid (508). It should be noted that the corresponding oxidation of hydroxy methylene cyclohexanone leads to ring contraction and formation of cyclopentanoic acid. 

Stereoselective Synthesis of )0-Hydroxy Sulfoxides Catalyzed by Cyclohexanone Monooxygenase... 

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

The promising analgesic activity of 3-hydroxy-17-methylmorphinan stimulated Schnider and Hellerbach(11,12) to seek a commercial synthesis of it via 8. Bromoacetic ester reacted with cyclohexanone to give 10, which was converted rather laboriously to 8 (Scheme 3.2), Cyanoacetic ester afforded a more fluent route by way of cyclohexenylacetonitrile (11). In the presence of... 

Syndiesis of aldehydes. Meyers ei al. have described a method for synthesis of aldehydes similar to one using 2,4-dimethylthiazole (this volume). It is illustrated here for the synthesis of 2-(l-hydroxy)cyclohcxylacctaldehyde (5). The thiazoline (1) is treated in THF under nitrogen at —78° with a slight excess of n-butyllithium. The resulting lithiothiazoline is then treated with cyclohexanone first at —78° and then at... 

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. 

A serious obstacle to the use of the Julia alkenation for the synthesis of trisubstituted alkenes is illustrated in Scheme 31. Addition of cyclohexanone to the lithiated sulfone (86) gave intermediate (87), which could not be acylated under the reaction conditions because of the sterically hindered tertiary alk-oxide. Owing to an unfavorable equilibrium, (87) reverted back to starting materials. However, by reversing the functionality of the fragments a stable adduct (88) was formed in which the less hindered secondary alkoxide was acylated and the resultant -benzoyloxy sulfone (89) reductively eliminated to the alkene (90) in 54% overall yield. Trisubstimted alkenes have been generated by reductive elimination of 3-hydroxy sulfones ° but, in general, retroaldol reactions compete. 

An interesting example of the application of NHPI is the synthesis of lactones with the in situ generation of HP. Ishii et al. [31g] have reported that in the oxidation of the KA Oil mixture with air, in the presence of both NHPI and small amounts of initiator AIBN, the alcohol was converted into a mixture of cyclohexanone and HP via the intermediate formation of 1-hydroxy-1-hydroperoxycyclohexane the reaction was performed in an acetonitrile solvent at 70°C. The addition of catalytic amounts of InCla in the second step led to the reaction between cyclohexanone and HP, with the formation of 8-caprolactone, at 25 °C. The conversion was 23%, and the selectivity to the lactone was 57% (Scheme 7.8). 

Lewis acid catalyzed aldol coupling of silyl enol ethers with substituted cyclohexanone acetals showed an excellent preference for equatorial attack (95-l(X)%). In accord with this general rule, additions of a silyl enol ether to equatorially or axially substituted chiral spiroketals derived from -menthone gave 00% equatorial attack and formation of a single one of the four possible diastereoisomers (Scheme 9) 3, 4 -pjjjg methodology, followed by protection of the hydroxy group (X = OTHP, (XIPh.i) and alkaline removal of the chiral auxiliary was used for the synthesis of several natural products. ... 

In a three-step synthesis of a chiral, conformationally locked 1,3-hydroxy thiol from ( + )-pule-gone, 2-(l-benzylthio-l-methylethyl)-5-methyl-l-cyclohexanone was stereoselectively reduced by sodium/ammonia/methanol to the corresponding cyclohexanol9. The diastereomerie ratio (equatorial/axial 78 22) was determined by H NMR. 

If the substituent R contains an a-CH2 group, an intramolecular aldol condensation to give cyclohexanone derivatives 158 competes with 1,4-dihydropyridine formation. This can be avoided by using hydroxylamine for the cyclocondensation moreover, the dehydrogenation becomes superfluous, because the A -hydroxy intermediate 159 allows H2O elimination, yielding the pyridine derivative 157 directly. The synthesis of the dihydrocyclopenta[b]pyridine 160 provides an example ... 

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