Morpholine enamines from

Tosyl azide reacts differently to give sulfonamide derivatives 134). The morpholine enamine from dibenzylketone (196) for instance reacted with tosylazide to give 197 and phenyldiazomethane (198), which was trapped with acetic acid giving benzyl acetate 134). 

The conditions for optimal synthesis of morpholine enamines from alkyl methyl ketones (alkyl = isopropyl, isobutyl, t-butyl) were studied by using molecular sieves or titanium tetrachloride as the water scavengers56. 

In contrast, morpholine enamines from higher alkyl ketones do not dimerise but undergo disproportionation to the reduced enamine and various oxidation products. Aldehyde enamines dimerise, but with more difficulty at higher temperatures544. Cross-conjugated545 and linear dienamines (e.g. 132)546 have been prepared by condensation of amide acetals with alkynyl alcohols (equation 37). 

Enamines can be reduced to the corresponding saturated amines by treatment with formic acid. A very simple experimental procedure can be used in which formic acid is added to the neat enamine at such a rate that foaming due to evolution of carbon dioxide can be kept under control. The reduction of the morpholine enamine from camphor was studied in a two-level factorial design in order to determine whether or not an excess of formic acid should be used and at which temperature the reaction should be run. 

Euamines. Tn preparing the morpholine enamine from cyclohexanone, Hiinig and co-workers carried out the azeotropic distillation with a water separator... 

Synthesis of bromomethyl ketones can be accomplished by treating the morpholine enamine from the parent ketone with elemental bromine followed by hydrolysis. 

For the modified procedure, it was found that the relative amounts of TiCl4/ketone and amine /ketone which should be used to achieve a rapid conversion were highly dependent on the structure of the ketone.[7,8] In the example below, the formation of the morpholine enamine from methyl isobutyl ketone was studied. 

Synthesis of the morpholine enamine from pinacolone (3,3-dimethyl-2-butanone) by the modified TiC -method discussed above was complicated by considerable self-condensation of the ketone. 

The synthesis of enamines by the modified titanium tetrachloride method was discussed in Chapter 12. The final yield and the rate of enamine formation depend on the molar ratios of TiCl4/substrate and amine/substrate. The optimum conditions with regard to these variables were determined by response surface technique and/or simplex technique for a series of carbonyl compounds. The results obtained for the morpholine enamines are summarized in Fig. 14.2. It is seen that the more crowded substrates require an excess of the reagents. The use of standardized conditions would have led to the wrong conclusions as to the utility of the method. For instance, when the optimum conditions for synthesis of the morpholine enamine from methyl isobutyl ketone were applied to diisopropyl ketone a yield of 12 % was obtained after 4 h. Under optimized conditions yields > 70 % could be obtained. 

Fig. 14.2 Variation in the conditions affording the maximum yield in the synthesis of morpholine enamines from a series of carbonyl compounds (1) methyl isopropyl ketone, (2) pinacolone, (3) methyl isobutyl ketone, (4) methyl neopentyl ketone, (5) diethyl ketone, (6) diisopropyl ketone, (7) ethyl isobutyl ketone, (8) diisobutyl ketone, (9) isobutyraldehyde,...

The reduction of the morpholine enamine from camphor by the reaction with formic acid was discussed in Chapter 5. In the example below, this reaction was applied to the reduction of the corresponding pyrrolidine enamine. The reaction was conducted without any solvent present, i.e. by adding formic acid dropwise to the hot enamine, and afforded an almost quantitative conversion to the corresponding bornyl pyrrolidine. However, the reaction was not stereoselective and a mixture of endo and exo isomers was formed. The proportions were endo isomer (85 %), exo isomer (15 %). This was regarded as a promising result. 

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. 

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). 

Lochte and Pitman (44) have reported the cyanoethylation of the pyrrolidine enamine of 3-methylcycIopentanone (84), the product being a mixture of C-2 and C-5 cyanoethylated ketones (85 and 86). Hunig and Salzwedel 20) have obtained a mixture of C2- and C5-acylated products from the reaction of morpholine enamine of 3-methylcyclopentanone with propionyl chloride. 

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

Information regarding the position of the substituents can be obtained from the mass spectra of the enamines of cyclic ketones. For instance in the case of the morpholine enamine of 3-methylcyclohexanone, which is shown to be a 2 1 mixture of/ and isomers by NMR spectroscopy, the fragmentation of the radical ion from the /) isomer results in the loss of a methyl radical from the C-3 position. The d isomer gives a complicated spectrum due to the loss of the hydrogen radical. 

Another interesting example is found in the morpholine enamine of 2- -propylcyclohexanone (138), which consists of a 2 3 mixture of tri- and tetrasubstituted isomers. The radical ion from the tetrasubstituted isomer loses an ethyl radical, giving the base peak at m/e 180. 

The basicity of the enamine has an overriding influence on the yield of product. Good yields are obtained from the pyrrolidine enamines, poor yields from the piperidine enamines, and the morpholine enamines fail to... 

More recently the acylation of aldehyde enamines has been reinvestigated (75) and shown to proceed normally when the enamine is added to the acid chloride. The morpholine enamine of isobutyraldehyde (98), on being added to an ether solution of acetyl chloride, afforded the iminium salt (99), from which the ketoaldehyde (100) was obtained in 66% yield by hydrolysis (75). 

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... 

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). 

Enamines formed in this way may be distilled or used in situ. The ease of formation of the enamine depends on the structure of the secondary amine as well as the structure of the ketone. Thus pyrrolidine reacts faster than morpholine or piperidine, as expected from a rate-controlling transition state with imonium character. Six-membered ring ketones without a substituents form pyrrolidine enamines even at room temperature in methanol (20), and morpholine enamines are generated in cold acetic acid (21), but a-alkylcyclohexanones, cycloheptanone, and linear ketones react less readily. In such examples acid catalysis with p-toluenesulfonic acid or... 

Similarly, a-trichloromethylamines (522) were obtained by decomposition of trichloroacetic acid in morpholine enamines, but an amide ester was formed from sodium trichloroacetate and the imonium salt of pyrrolidino-cyclohexene (523). The product is presumably derived from opening of an intermediate dichloroaziridinium salt. 

Treated with ZnBr2 followed by enamines, phenyl thioethers 829 derived from aryl aldehydes are converted to (l-(phenylthio)alkyl ketones or aldehydes 830 in moderate to good yields (Equation 19). Enamines used in these syntheses are (1) morpholine enamine derived from diethyl ketone, (2) diethylamine enamine of propiophenone, (3) piperidine enamine derived from isovaleraldehyde, and (4) pyrrolidine enamine of cyclohexanone <2000H(53)331>. 

The racemic polyzonimine (19) is prepared as shown in Scheme 33. The expoxide (314) is rearranged to the aldehyde (315) by refluxing with LiBr-HMPA in benzene. Morpholine enamine (316) derived from 315 is condensed with nitroethylene, generated in situ from 2-acetoxynitroethane, to afford the nitroaldehyde (317). Ethylene acetalization, reduction over Raney nickel, and subsequent deacetalization give ( )-polyzonimine (19) in 22% overall yield from the epoxide (314) 113). 

Scheme 6.94 Typical products obtained from the 86-catalyzed Michael addition of aryl methyl-ketone-derived morpholine enamines to various aromatic nitroalkenes and subsequent acidic hydrolysis.

Both tetrahydro-l,4-oxazine (morpholine) and its thia analogue (thiomorpholine) find application as solvents and bases, morpholine having particular value in synthesis as it is often used to prepare enamines from ketones with a free a-hydrogen atom. TV-Acylation and -alkylation are readily accomplished and a great diversity of TV-substituted morpholines and thiomorpholines are encountered in the patent literature, some having biological activity. 

As with imines, enamine formation may be achieved using azeotropic distillation,219 or with the aid of molecular sieves. The procedure described in Expt 5.201 for the preparation of the enamine from morpholine and diisobutyl ketone utilises titanium(iv) chloride as a catalyst and water scavenger.220... 

From a preparative point of view, the acylation of ketones via enamines is of particular interest. In comparison with pyrrolidine and piperidine enamines, the less reactive morpholine enamines give better yields, as found by Hiinig et al.2iZ j8-Diketones are the products of acylation with an acyl halide followed by acid hydrolysis, whereas with ethyl chloroformate, /J-ketoesters are obtained.212 Hiinig and his collaborators242-247 have used the acylation of 1-morpholino-l-cyclopentene and 1-morpholino-l-cyclohexene to lengthen the chains of acids by five and six carbon atoms, respectively. The reaction may... 

The Swiss chemist Oppolzer used just such a reaction. He first prepared an acid chloride from cyclopentadiene, and the enamine from cyclopentanone and the secondary amine morpholine. 

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