Morpholines, conformation

The preferred formation of the tetrasubstituted isomer with the olefin without any bulky substituent at the electrophilic carbon atom is undoubtedly due to the preponderance of that conformation of the dipolar intermediate in which the substituent is syn to the morpholine group, as shown in (41). The situation is, however, reversed in case of the olefin with... 

The conformationally locked racemic enamine, 4-(4-rOT-butyl-1-cyclohexenyl)morpholine, reacts with (l-nitroethenyl)benzene to give a mixture of diastereomeric 1,2-oxazine 2-oxides 1 and 2 (ratio 1/2 75 25). Whether these arise via an ionic or a cycloaddition mechanism is unclear. Hydrolysis of 1 and 2 with dilute acid gave a 80 20 mixture of trans- and cis-ketones, 3 and 414. 

Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = 0(CH2)3NR r2 where NR r2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. 

Barker and Cromwell78 have measured the rate of reaction ol morpholine with benzalocetophenono oxide. Second-order kinetics wore observed, in conformity with a bimoleoular process. 

A number of solid state structures of N-substituted morpholines show (cf. Table XX) the substituents prefer exclusively the equatorial position on the chair conformer of the saturated 6-membered ring, as in a number of 2,2-spiro compounds (02JMC11). 

Table XX. Preferred Conformers of Substituted Morpholines in the Solid State...

The stereochemical course of the annulation process has been determined by reaction of acryloyl chloride with the morpholine enamine of 4-f-butyl-2-methylcyclohexanone. The bicyclic dione was obtained in 76% yield as a 4 1 mixture of two isomers (Scheme 150). X-ray analysis of the main isomer showed that reaction had occurred by axial attack from the same side as the C-2 methyl group. In order for regeneration of the enamine system to occur under conditions of stereoelectronic control, the intermediate ketene-iminium salt presumably adopts a twist conformation. Cyclization of the ketene... 

As already discussed, like the crystalline adduct of bzs(diethyldithio carbamato)zinc(II) with pyridine, [Zn C5H5N S2CN(C2H5)2 2] (34), a corresponding adduct with a non-planar N-donor morpholine molecule, [Zn 0(CH2)4NH S2CN(C2H5)2 2] (35), exists as two conformers which are cor-... 

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