Similarity morpholines

Similarly, morpholine and piperidine reacted with tricyclo[2.2.1.0 ]heptan-3-one (10) to yield bicyclo[2.2.1]heptane-2-one derivatives 11 and 12. The reactions were catalyzed by acids such as /7-toluenesulfonic acid. 

The mechanism of the reaction la not known with certainty. It is known from studies utilising as tracer that no change in the carbon skeleton occurs during the reaction, and also that unsaturated hydrocarbons can undergo reactions very similar to those of ketones thus both styiene and phenyl-acetylene can react with sulphur and morpholine to produce phenylaceto-thiomorphoUde, hydrolysis of which yields phenylacetic acid ... 

The results of more recent investigations by Blicke with Maxwell and with Kaplan covering a wide range of basic components and of acyl residues, do not lend themselves to a simple generalisation. The basic components were mainly dialkylamino-derivatives of aliphatic hydrocarbons from ethane to pentane, e.g.,. CHj. CHj. NMcj to. CHj. CMcj. CHj. NEtj, and similar but shorter series of derivatives of piperidine (CgHjoN), morpholine, e.g.,. CHj. CHj. NC HgO, and methylcj/clohexylamine... 

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). 

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. 

Similar results were encountered by Bianchetti et al. (i52), who found that e ketal derivatives of //-alkyl methyl ketones with morpholine led to the enamines of the condensation products of these ketones. The authors have Suggested the following probable mechanism for the dienamine formation. 

Trichloroacetic acid behaves somewhat similarly in that protonation of the enamine occurs l7J7d). Subsequent decarboxylation of the trichloro-acetate gives trichloromethyl anion, which adds to the iminium cation to give the trichloromethyl amine derivative. Thus the enamine (113) undergoes reaction with trichloroacetic acid to give N-[l-(trichloromethyl)cyclo-hexyl]-morpholine (8). The latter compound undergoes rearrangement on... 

A similar sequence of reactions has been shown to take place with the dienamine derived from isophorone and morpholine (77). Reaction of this enamine with trichloroacetic acid gave a trichloromethyl derivative which was not isolated but which undergoes rearrangement and hydrolysis with base to give the diene acid (210). 

The vinylogous 3,5-hexadien-2-one (16) adds in a 1,4 cycloaddition with zl -dehydroquinolizidine (17) to form compound 18 (26). A similar 1,4-cycloaddition reaction takes place between pyrylium salts and the pyrrolidine or morpholine enamines of cycloalkanones (26a). 

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). 

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. 

Treatment of an epimeric mixture of 4-substituted 2-(trimethylsilyloxy)-5-phenyl-3-phenylthio-l,4-oxazine 264 with ZnBr2 led to the stereoselective formation of perhydropyrido[2,l-c][l,4]oxazine 266 via the iminium ion 265 by the phenyl bearing stereocenter directed addition of the olefinic double bond from the /S-face of the cyclic moiety (97SL799, 98T10309). Similarly, an epimeric mixture of (45,9aS)-l-trimethylsilyloxy-4-phenyl-3,4,6,7-tetra-hydropyrido[2,l-c][l,4]oxazine was prepared by cyclization of (Z)-5(S)-phenyl-3-phenvlsulfanyl-2-trimethylsilyloxy-4-[4-(trimethylsilyl)but-3-enyll morpholine (OOSC2565). 

Alkylation of that amine with p-(2-chloroethyl)aniline affords anileridine (82), an analgesic similar to the parent compound but somewhat more potent. In similar fashion alkylation by means of w-(2-chloroethyl)morpholine gives morpheridine (83), while the use of 2-(chloroethyl)-ethanol yields carbethl-... 

The thermolysis of 4-azidophenyl methyl ketone in morpholine at 170°C yields a mixture of the expected 5-acetyl-2-morpholino-3f/-azepine (33) and 6-acetyl-2-morpholino-3//-azepine (34), the product of a unique and totally unexpected thermal rearrangement of the 5-acetyl derivative.119 Similar results can be obtained in hot piperidine, whereas thermolysis of 4-azido-diphenyl ketone under similar conditions yields only the 6-benzoyl-2-(cycloalkylamino)-3//-azepines (7-18%) accompanied by much tar. 

Formulated products tend to use a 10 to 20% neutralized erythorbate, buffered to pH of 5 to 6 with ammonia, morpholine, cyclohexy-lamine, diethanolamine (DEA), or triethanolamine (TEA) to reduce the acidity of erythorbic acid. Similarly, amines are used with sodium erythorbate to improve the reaction rate. 

Chloro-3-phenylethynylquinoxaline gave 2,3-dipiperidinoquinoxaline (piperidine, reflux, 5h 90%), 2,3-dimorpholinoquinoxaline (morpholine, similarly 95%), or 2,3-bis(2-hydroxyethylamino)quinoxaline (ethanolamine, PhH-EtOH, reflux, 15 h 74%). For an example of amine addition to the triple bond, see Section 4.2.1. 

An alternative sequence utilized 2-oxazolidone, which was readily synthesized from urea and ethanolamine, as the glycine equivalent. Subsequent treatment with phosphorous acid and formaldehyde produced iV-phosphonomethyl-2-oxazolidone 12 (16). Upon hydrolysis, and loss of CO2,12 provided the related derivative, iV-phosphonomethylethanolamine 13, which was oxidized at high temperature with a variety of metal catalysts including cadmium oxide (16) or Raney copper (17) to give GLYH3, after acidification. A similar oxidation route has also been reported starting from iV-phosphonomethy 1-morpholine (18). 

In a similar study, Gray et al. (60) investigated the possible formation of N-nitrosamines in heated chicken frankfurters which been prepared with various levels of nitrite (0-156 mg/kg). As expected, apparent N-nitrosamine levels increased with increasing concentrations of nitrite, but did not exceed 4 yg/kg except for two samples which contained 8 and II yg/kg of NMOR. The presence of these relatively high levels of NMOR was confirmed by mass spectrometry and raised the question as to its mode of formation. It was shown to be due to the morpholine present in the steam entering the smokehouse, as this amine is commonly used as a corrosion inhibitor in steam process equipment ( ). The detectable levels of NMOR in the Canadian study ( ) were also attributed in part to the use of morpholine as an anti-corrosion agent in the steam supply (62). 

DMM was chosen for detecting nitrosation during the workup because of its similarity to morpholine. DMM is a good model because, in a kinetic experiment [lO mM DMM from Aldrich Chem. 

Co. and 20 mM nitrite in water, pH 3, 25 C, 60 min reaction], it was nitrosated to yield 3.62 mM 2,6-dimethyl-N-nitrosomorpho-line (DMNM), which was a 10% greater yield than that for a similar nitrosation of morpholine to give NMOR. This indicated a slightly larger rate constant for DMNM than for NMOR formation (3). Crude DMM is a 2 1 mixture of the cis and trans isomers ( 0). GC analysis of the product of the kinetic run showed that the 2 isomers were nitrosated at similar rates. Cis-DMNM [retention time (RT), 320 sec] was well separated from NMOR (RT, 430 sec), but trans-DMNM (RT, 405 sec) was not. Accordingly, we prepared pure cis-DMM, b.p. 133 C, by spinning-band fractional distillation of crude DMM and used it in the analytical procedure. The RT of N-nitrosopyrrolidine (NPYR) was 390 sec. 

Figure 1, Two GC-TEA tracings of experiments with analysis by our method. The left tracing shows the results of an experiment, similar to that in Table /, Experiment 4, in which nitrite was added to the diet and the hexane wash of the column (which reduced the solvent-front peak) was omitted. The right tracing shows one of the positive experiments (including the hexane wash) on the homogenate of a mouse exposed to morpholine and NOt (Table II, Experiment 3),...

To check that the NO exposure was necessary for nitrosamine formation, morpholine was gavaged to mice as usual, but the NO exposure was omitted. Five g mouse homogenate was worked up by the Iqbal method (after addition of 11 mg cis-DMM) and yielded neither NMOR nor cis-DMNM. Similarly, when 10 mg morpholine was added to 5 g homogenate prepared from an untreated mouse and... 

When mice were gavaged with morpholine and exposed to NO j the NMOR yield of 140 ng/g (4.2 yg/30 g mouse) obtained by the Iqbal method (Table II, exp. 1) was similar to that of 2.23 yg/mouse previously reported by Iqbal et a l. hence confirms these results. However, the finding that similar homogenates, when worked up by our method, did not yield a significant amount of NMOR demonstrated that the NMOR formation occurred during the workup, i.e., was an artifact. This confirmed our negative results with rat stomach contents and blood (Table I). 

In a similar vein, alkylation of 4-(5)-nitro-imidazole with N-(2-chloroethyl)morpholine affords a mixture of N-alkylated imidazoles (61 and 62). The compound containing the adjacent ring substituents (61) is the antitrichomonal agent nimorazole.15... 

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