Cyclohexanone morpholine

Preparation from a mixture of cyclohexanone, morpholine, toluene, and a trace of p-toluenesulfonic acid is described on page 706. 

Cyclopentanone and cyclohexanone morpholine enamines underwent oxidation in methanol-sodium methoxide solution to yield 2-methoxycycloalkanones (Scheme 75). The enamine intermediates were also identified . ... 

Addition of Nitrostyrenes to Substituted Cyclohexanone Morpholine Enamines (Eq. [1], Scheme 19)... 

Thallium triacetate added to a soln. of cyclohexanone morpholine enamine in dry acetic acid, stirred 2 days at room temp, under Ng, then most of the acetic acid... 

ILs have been used in bulk membranes (nonsupported) for the selective transport of 1,4-dioxane, propan-l-ol, butan-l-ol, cyclohexanol, cyclohexanone, morpholine, and methylmor-pholine by Branco et al. [32], They have also studied the transport of the aforementioned organic compounds in supported ILM and in IL immobilized in a porous membrane to improve the selectivity in the transport of the target compounds. Another advantage of SLMs versus bulk membranes is the less amounts of liquid phase needed and their easiest implementation in chemical processes. 

One of the most studied applications of SILMs is the selective separation of organic compounds. The first example was reported by Branco et al. [71], who studied the selective transport of 1,4-dioxane, 1-propanol, 1-butanol, cyclohexa-nol, cyclohexanone, morpholine, and methyhnorpholine as a model of seven-component mixture of representative organic compounds. For that, four ILs based on the l- -alkyl-3 methylimidazolium combined with the anion hexafluoro-phosphate or tetrafluoroborate, immobilized in different organic polymeric membranes, were used. The use of the IL [bmim+][PFg ] immobilized in a PVDF membrane allowed an extremely highly selective transport of secondary amines over tertiary amines (up to a 55 1 ratio). 

A soln. of cyclohexanone morpholine enamine in dioxane added to an aq. soln. of tropylium fluoroborate, and stirred 0.5 hr. at room temp. 2-tropylcyclo-... 

Chloral forms well-crystallized adducts (126) with diaziridines containing at least one NH group (B-67MI50800). Carbonyl addition products to formaldehyde or cyclohexanone were also described. Mixtures of aldehydes and ammonia react with unsubstituted diaziridines with formation of a triazolidine ring (128). Fused diaziridines like (128) are always obtained in ring synthesis of diaziridines (127) from aldehyde, ammonia and chloramine. The existence of three stereoisomers of compounds (128) was demonstrated (76JOC3221). Diaziridines form Mannich bases with morpholine and formaldehyde (64JMC626), e.g. (129). 

The tetrasubstituted isomer of the morpholine enamine of 2-methyl-cyclohexanone (20) because cf the diminished electronic overlap should be expected to exhibit lower degree of enamine-type reactivity toward electrophilic agents than the trisubstituted isomer. This was demonstrated to be the case when the treatment of the enamine with dilute acetic acid at room temperature resulted in the completely selective hydrolysis of the trisubstituted isomer within 5 min. The tetrasubstituted isomer was rather slow to react and was 96% hydrolyzed after 22 hr (77). The slowness might also be due to the intermediacy of quaternary iminium ion 23, which suffers from a severe. 4< strain 7,7a) between the equatorial C-2 methyl group and the methylene group adjacent to the nitrogen atom, 23 being formed by the stereoelectronically controlled axial protonation of 20. 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

In a similar manner the addition of ethyl azodicarboxylate to the morpholine enamine of cyclohexanone furnished the less substituted isomer (34) with the substituent in the axial orientation (2, 26). 

However, when the bulky substituent is no longer present at the electrophilic carbon atom, the addition of the olefin to the morpholine enamine of cyclohexanone leads largely to the tetrasubstituted isomer. For instance the reaction of this enamine with phenyl vinyl sulfone gave a 1 3 mixture of... 

Risaliti et al. (2J) have also studied the addition of 2-nitropropene, which also lacks any substituent at the electrophilic carbon atom, to the morpholine enamine of cyclohexanone. The product, as expected, was the tetrasubstituted isomer, the formation of which may be envisioned via the transition state (42). 

The reaction of morpholine enamine of cyclohexanone with 1 mole of phenyl isocyanate has been reported (30,31) to give the monoadduet (49), consisting largely of the trisubstituted isomer, and with 2 moles of phenyl isocyanate, the bis adduct (50). That the bis adduct is a dicarboxyanilide rather than a urea derivative (32) such as 51 was shown by its mild hydrolysis to the ketone (52). Reaction of the morpholine enamine of 2-methylcyclo-... 

The reaction of the morpholine enamine of cyclohexanone with phenyl isothiocyanate led only to the tetrasubstituted isomer of the monoadduct (54), which failed to add any more of the phenyl isothiocyanate. The formation of only the tetrasubstituted isomer has been attributed by Hunig et al. (37) to the stronger conjugation of the C=S group with the enamine double bond than that of the C=0 group in the enamine (49). 

In their original communication on the alkylation and acylation of enamines, Stork et al. (3) had reported that the pyrrolidine enamine of cyclohexanone underwent monoacylation with acid chlorides. For example, the acylation with benzoyl chloride led to monobenzoylcyclohexanone. However, Hunig and Lendle (33) found that treatment of the morpholine enamine of cyclopentanone with 2 moles of propionyl chloride followed by acid hydrolysis gave the enol ester (56), which was proposed to have arisen from the intermediate (55). 

Campbell and Jung (34) have reported that the reaction of 2 moles of o-halo-substituted benzoyl chloride with the morpholine enamine of cyclohexanone gave the corresponding 2,2-dibenzoyI derivative (57). 

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. 

The piperidine, pyrrolidine, and morpholine enamines of cyclohexanone substituted in the 3-position by methyl, phenyl, and l-butyl have been prepared (49). The complexity of the NMR spectra in the ethylenic hydrogen region indicated a mixture of isomeric enamines. Estimation of the per cent of each isomer by examination of the NMR spectra was not possible, nor were the isomeric enamines separable by vapor-phase chromatography. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

The reaction of morpholine enamines of cyclic ketones with ethyl azodicarboxylate has also been demonstrated 56,136). The enamine (113) on reaction with ethyl azodicarboxylate can give the 2- or 2,6-bis(N,N di-carboxyhydrazino)cyclohexanones 199 and 200, respectively, on hydrolysis. 

The reaction of enamines derived from cyclohexanone with dichlorocarbene to give the 1 1 adducts is now well established (137-139). The morpholine enamine (113) reacted with dichlorocarbene at —10 to —20° in tetrahydrofuran to give the stable crystalline adduct (201). Thermal decomposition followed by an aqueous work-up gave an a,)3-unsaturated ketone identified as 2-chloromethylene-cyclohexan-l-one (202) (139). 

Nitroolefins also offer the possibilities of 1,2 cycloaddition (37,57) or simple alkylation (57-59) products when they are allowed to react with enamines. The reaction of nitroethylene with the morpholine enamine of cyclohexanone led primarily to a cyclobutane adduct in nonpolar solvents and to a simple alkylated product in polar solvents (57). These products are evidently formed from kinetically controlled reactions since they cannot be converted to the other product under the conditions in which the other... 

Cyanoallene, when treated with the morpholine enamine of cyclohexanone, undergoes a 1,3-cycloaddition reaction to form 72 (89). The reaction between cyanoallene and diendiamine 73a produces di-1,2-cycloaddition adduct 73 (i 9). The 4a-azonioanthracene ion (73b) readily undergoes a 1,4-cycloaddition reaction with nucleophilic dienophiles such as enamines (89a). The cycloaddition is stereoselective so that the a- and... 

Adduct 100 is formed from the 1,4 cycloaddition of o-quinone (99) with the morpholine enamine of cyclohexanone (125). Treatment of styrene oxide with cyclic enamines at elevated temperatures (about 230°C) produces O.N-ketals possessing a furan nucleus (125a). 

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

The reaction of isobenzofuroxan (131) with the morpholine enamine of cyclohexanone results in a 1,4 cycloaddition to form quinoxaline-di-N-oxide 132 (777). Quinone dibenzenesulfonimide has been found to undergo... 

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