Morpholine, addition reactions

Although the enamine (30) underwent addition reaction with ethyl azido-dicarboxylate, it failed to add another mole of jS-nitrostyrene. In a similar manner the morpholine enamine of 2-methylcyclohexanone also failed to react with this olefin, i.e., jS-nitrostyrene, which is undoubtedly due to the 1,3-diaxial interaction between the methyl group and the incoming electrophile in the transition state. 

With some secondary amines, especially morpholine, the reaction leads to a mixture of the oxidative amination product and of the hydroamination product, both corresponding to an anh-Markovnikov addition (Eq. 4.39) [166]. 

Cyclic ketone with exo cyclic methylenes can be prepared in just the same way and used in situ. Morpholine is often used as a convenient secondary amine for the Mannich reaction and the resulting amino-ketones can be methylated and undergo elimination-addition reactions with stabilized enoUtes such as that derived from ethyl acetoacetate. This starting material wias prepared from natural menthone and the mixture of diastereoisomers produced is unimportant because the product is to be used in a Robinson annelation (see below). 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

The a- and p-L-fucosyl esters of UMP and dTMP have been prepared as anomeric mixtures by treating the nucleotides with orthoester (15) in DMF. In the absence of methylenetetrahydrofolate cofactor, thymidylate synthetase has been observed to catalyse nucleophilic addition reactions at the ethynyl moiety of 5-ethynyl-2 -deoxyuridylate. On the basis of isotope effects and other kinetic studies, it has been suggested that addition of a thiol group of the enzyme at C-6 of the nucleotides results in formation of the allenic intermediate (16), followed by addition of 2-mercaptoethanol, morpholine, or other nucleophiles at the jp-hybridized carbon of the allene, and subsequent elimination of the enzyme. 

Crotonic acid esters of cellulose undergo addition reaction with cycloaliphatic amines, like morpholine or piperidine and with aliphatic primary amines. Unsaturated polymers can also undergo Diels-Alder reactions. One example is a reaction of hexachlorocyclopentadiene with polycyclopentadiene ... 

The action of diethyl ethoxymethylenemalonate on 3-amino-l,2-benzisothiazole 1,1-dioxide affords low yields of the 3-aminomethylene-malonate derivative (163), which is converted into (164) by the action of morpholine. The reaction may proceed by the addition of the base to the C=N bond, followed by elimination of diethyl aminomethylenemalonate. ... 

The morpholine-promoted reaction of Af-alkyl piperi-dine-4-one with malonodinitrile and p-nitrostyrene derivatives in refluxing EtOH directly led to substituted tetrahydroisoquinoline derivatives in moderate to good yields [121], The reaction is initiated by a Knoevenagel condensation, in which a Michael addition/Thorpe-Ziegler sequence follows. Oxidation by air is the last step to occur providing the desired products. 

Electrophilic reaction can account for the additions of morpholine or phosphonyl (Scheme 14), or... 

Significant quantities of amine and amide esters are formed by side reactions (9). In addition, with dialkanolamines, amide diesters, morpholines, and piperazines can be obtained, depending on the starting material. Reaction of dialkanolamines with fatty acids in a 2 1 ratio, at 140—160°C, produces a second major type of alkanolamide. These products, in contrast to the 1 1 alkanolamides, are water soluble they are complex mixtures of AJ-alkanolamides, amine esters, and diesters, and still contain a considerable amount of unreacted dialkanolamine, accounting for the water solubiUty of the product. Both the 1 1 and the 2 1 alkanolamides are of commercial importance in detergents. 

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). 

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... 

Additional evidence that a dynamic equilibrium exists between an enamine, N-hemiacetal, and aminal has been presented by Marchese (41). It should be noted that no acid catalysts were used in the reactions of aldehydes and amines discussed thus far. The piperidino enamine of 2-ethylhexanal (0.125 mole), morpholine (0.375 mole), and p-toluene-sulfonic acid (1.25 x 10 mole) diluted with benzene to 500 ml were refluxed for 5 hr. At the end of this time the enamine mixture was analyzed by vapor-phase chromatography, which revealed that exchange of the amino residue had occurred in a ratio of eight morpholine to one piperidine. Marchese proposed a scheme [Eqs. (4), (5) and (6)] to account for these... 

The reactions of dichlorocarbene with morpholine and piperidine enamines derived from cyclopentanone and cyclohexanone have been reported to lead to ring expanded and a-chloromethylene ketone products (355,356). Similarly a-chloro-a, -unsaturated aldehydes were obtained from aldehyde derived enamines (357). Synthesis of aminocyclopropanes (353,359) could be realized by the addition of diphenyldiazomethane (360) and the methylene iodide-zinc reagent to enamines (367). 

The Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

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