Morpholine nitrile

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

Thiomorpholides have been obtained by the reaction of nitriles or ketones and elemental sulfur with morpholine under microwave irradiation (Scheme 5).21,22... 

Acyl nitroso compounds react with 1, 3-dienes as N-O heterodienophiles to produce cycloadducts, which have found use in the total synthesis of a number of nitrogen-containing natural products [21]. The cycloadducts of acyl nitroso compounds and 9,10-dimethylanthracene (4, Scheme 7.3) undergo thermal decomposition through retro-Diels-Alder reactions to produce acyl nitroso compounds under non-oxidative conditions and at relatively mild temperatures (40-100°C) [11-14]. Decomposition of these compounds provides a particularly clean method for the formation of acyl nitroso compounds. Photolysis or thermolysis of 3, 5-diphenyl-l, 2, 4-oxadiazole-4-oxide (5) generates the aromatic acyl nitroso compound (6) and ben-zonitrile (Scheme 7.3) [22, 23]. Other reactions that generate acyl nitroso compounds include the treatment of 5 with a nitrile oxide [24], the addition of N-methyl morpholine N-oxide to nitrile oxides and the decomposition of N, O-diacylated or alkylated N-hydroxyarylsulfonamides [25-29]. 

Nitrile 241 was reduced to the amine 242 with Red-Al in morpholine at —40 °C. However aluminium hydrides are mostly unsuitable if there is an A-acetyl group that is required to be conserved and this is discussed further in Section 8.06.8. Also, 240 could be prepared from the ester 243 by reaction with ammonia <1982AP538>. 

The 6//-l,3-thiazin-6-iminium hydroperchlorate salts 78-81 give interesting products when treated with nucleophiles <2003H(60)2273>. Hydrolysis of 6-imino-6//-l,3-thiazine hydroperchlorate 78 affords (2Z,4Z)-2-cyano-5-hydroxy-5-phenyM-azapenta-2,4-dienethioamide 82 in excellent yield, while treatment with morpholine gives 2-(morpholinomethylene)malononitrile 83 and thiobenzamide. The 5-(ethoxycarbonyl) -(methylthio)-2-aryl-6/7-l,3-thiazin-6-iminium salts 79 and 80 react with hydroxide or morpholine to afford ethyl 4-(methylthio)-2-aryl-6-thioxo-l,6-dihydropyrimidine-5-carboxylates 84 and 85. In the case of the 4-chloro analogue 80, the (Z)-ethyl 2-(5-(4-chlorophenyl)-37/-l,2,4-dithiazol-3-ylidene)-2-cyanoacetate 87 is also formed for the reaction with sodium hydroxide. The 1,2,4-dithiazoles 86 and 87 can be obtained as the sole product when 79 and 80 are treated with sodium acetate in DMSO. Benzoxazine 88 is isolated when the iminium salt 81 is treated with morpholine or triethylamine. Nitrile 89 is formed as a ( /Z)-mixture when 6-imino-67/-l,3-thiazine hydroperchlorate 79 is reacted with triethylamine and iodomethane in methanol <2003H(60)2273>. 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

Unsaturated nitro compound and nitriles do not usually suffer nucleophilic attack by enols or enolates and both are good at conjugate addition. The addition of the morpholine enamine 57 of cyclohexanone to 58 demonstrates that the nitro group is more effective than the ester at promoting conjugate addition.7... 

In the presence of morpholine and malononitrile, the initial reaction of cyclohex-3-enal with cyanothioacetamide is followed by a condensation with the dinitrile. Cyclization follows through attack of the thiol on a nitrile function and a penta-substituted 477-thiopyran is formed (Scheme 126) <1998RJ0557, 2005RJC1537>. 

Stork has used the addition of a,/ -unsaturated aldehydes, ketones, esters, and nitriles to enamines prepared from ketones and pyrrolidine, piperidine, or morpholine for the synthesis of a-substituted carbonyl compounds264 266 (Scheme 9). 

The efficiency of Lewis acid activation depends not only on the reactivity of the bound substrate but also on the equilibrium constant for coordination of the substrate. The equilibrium constants for binding of an amide, a nitrile and phosphates to Co(m) complexes have been measured (Figure 6.5). Formyl morpholine binds to 6 with an equilibrium constant of 0.4 m-1 [35]. Binding of acetamide to 6 could not be detected. The steric effect of the methyl group is expected to significantly lower the binding of acetamide compared with that of formyl morpholine. 

Treatment of ethyl l- 2-[(tm-butyl, dimethylsilyl)oxy]-l-phenylethyl -6-alkylpiperidine-2-carboxylates with 10% HF in MeCN afforded diastereo-meric mixtures of 4-phenyl-6-substituted perhydropyrido[2,l-c][l,4]oxazin-1-ones (94JOC3769). Dieckmann cyclization of ethyl 4-(3-ethoxy-carbonylpropyl)morpholine-3-carboxylate with ferf-BuOK in Et20 and subsequent ester hydrolysis and decarboxylation furnished perhydropy-rido[2,l-c][l,4]-oxazin-9-one (82EUP57536 92BMC1293). Mild acidic hydrolysis of the nitrile moiety of amino nitrile 185 gave pyrido[2,l-c][l,4]ox-azin-l-one 60 (96TL4001). 

Subtle reactivity differences are also found in the reaction of 6-bromo[l,2,5]thia- (or selena) diazolo[3,4-/)]pyridines (92) with morpholine and cuprous cyanide which afford the C(7)-amine (94) and C(6)-nitrile (95), respectively (Scheme 15). Under identical reaction conditions, 6-bromo-benzo[l,2,5]thiadiazole affords exclusive C(6)-amination and C(6)-cyanation. The anomalous regio-chemistry in the formation of (94) is attributed to initial formation of a hetaryne intermediate (93), which adds morpholine at the more electron-deficient C-7 position <79IJC(B)13,86IJC(B)500>. 

Various p-aminonitriles, which are best prepared by the addition of ammonia, primary amines, or secondary amines to acrylonitrile,101 were successfully hydrogenated with Raney Ni at temperatures of 90-130°C and 6.7-27 MPa H2.102 A typical hydrogenation is shown in eq. 7.50 for P-morpholinopropionitrile. Hydrogenation of the nitrile at 190°C decreased the yield of y-morpholinopropylamine to 45%. The decrease in the yield may be explained by a reversal of the morpholine-acrylonitrile-... 

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. 

Synthesis of 2-aminoquinoline-3-carboxylic acids 165 from 2-tosylami-nobenzaldehyde or its morpholine 164 and nitrile analogs has been reported (08RCB418) (Scheme 32). 

Finally, a facile and regioselective synthesis of rimonabant was accomplished through an enamine-directed 1,3-dipolar cycloaddition." In the presence of triethylamine, hydrazonoyl iodide was converted into the nitrile imine in situ. The subsequent 1,3-dipolar cycloaddition with the morpholine enamine provided the 1,5-diarylpyrazole, which was transformed into rimonabant. 

The problem is apparently due to some residual aluminum that is hard to remove. If, however, the reduction is carried out in a iV-methylmorpholine solution, followed by addition of potassium tartrate, a pure product can be isolated. A -Methylmorpholine is a good solvent for reductions of various macromolecules with metal hydrides.In addition, the solvent permits the use of strong NaOH solutions to hydrolyze the addition complexes that form. Other polymers that can be reduced in it are those bearing nitrile, amide, imide, lactam, and oxime pendant groups. Reduction of polymethacrylonitrile, however, yields a product with only 70% of primary amine groups. Complete reductions of pendant carbonyl groups with LiAlH4 in solvents other than A -methyl-morpholine, however, were reported. Thus, a copolymer of methyl vinyl ketone with styrene was fully reduced in tetrahydrofuran. ... 

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