Morpholine 4-chloro

Amines normally have no effect on the isothiazole ring, but 3-chloro-4-nitroisothiazole (49) reacts with cyclic amines such as morpholine at 0 °C to give the enamine (50) (75JOC955). The mechanism may involve attack either at sulfur or at the 5-position (Scheme 6). 

Reaction of the morpholine or piperidine enamine of cyclopentanone, however, gives an unstable adduct which rearranges under the reaction conditions and an aqueous work-up to give the ring expanded ketone 2-chloro-2-cyclohexen-l-one (203) (138,139). 

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). 

A one-step transformation of the C5-OH in 86 to the 5-(piperid-l-y)- or 5-(morpholin-4-yl) derivatives 168 was carried out by heating with the respective amines 166 in the presence of titanium tetrachloride. Tlie reaction probably involved formation of the unisolable 5-chloro compounds 167 (93JHC11) (Scheme 64). 

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. 

Chloro-4-methyl-6-phenylpyridazine N-(2-Aminoethyl)morpholine Hydrogen chloride... 

Carr and England211 investigated the kinetics of the hydrochloric acid-catalysed chlorination of phenol by N-chloro-succinimide, -acetamide, and -morpholine, and found that the latter compound gave third-order kinetics, viz. 

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. 

C,7H2oN20, 58027-51-3) see Epanolol 4-[7V-(2-aminoethyl)carbamoyl]morpholine (C7H]5Nj02 69630-16-6) see Xamoterol 7V-(2-aminoethyl)-lV-(5-chloro-2,l>3"benzothiadiazol-4-yl)thiourea... 

On page T 54 we use disconnection (a) to devise a synthesis of morpholines e.g. 14), Since cyclisation is so easy, we might consider the alternative double C-N disconnection (b) and use the bis-chloro ether (15), made on page... 

Halogenalkyl-substituted furazanes were also used for functionalization of the compounds. Thus, 3,4-bis(chloro-methyl)-l,2,5-oxadiazole 92 and 2(R)- fS>[ 3,5-bis(trifluoromethyl)pheny I ethoxy -3f.V,)-pheny I morpholine 93 gave 2W-[lW-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-dimethylaminomethyl-l,2,5-oxadiazol-3-yl)methyl-3( 3 Tphenyl-morpholine 94 (Equation 21) <1996W09629328>. 

The c-fused chloro benzimidazo[l,2-c][l,2,3]thiadiazole 9 can undergo nucleophilic displacements with secondary amines heating compound 9 with morpholine affords the adduct 42 (Equation 10) <2003TL6635>. 

Support for this mechanism has been obtained from the study of the effect of twelve hydrogen-bond acceptors on the reactions of 1-chloro- and l-fluoro-2,4-dinitrobenzenes with morpholine in benzene162. The reaction of l-chloro-2,4-dinitrobenzene is not catalysed by either morpholine or DABCO, i.e. kA = h the first stage of the reaction is rate-determining and the various additives have no effect on the rate constant. On the other hand, Table 22 shows that the reaction of the fluoro-substrate is highly sensitive to the presence of the various additives and it is base-catalysed while for ten additives there was a linear dependence of kA on either their concentration, [P], or on the square... 

Miyata N, Seki T, Tanaka Y, Omura T, Taniguchi K, et al. 2005. Beneficial effects of a new 20-hydroxyeicosatetrae-noic acid synthesis inhibitor, TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N -hydroxyimido formamide], on hemorrhagic and ischemic stroke. J Pharmacol Exp Ther 314 77-85. 

AI3-00040, see Cyclohexanol AI3-00041, see Cyclohexanone AI3-00045, see Diacetone alcohol AI3-00046, see Isophorone AI3-00050, see 1,4-Dichlorobenzene AI3-00052, see Trichloroethylene AI3-00053, see 1,2-Dichlorobenzene AI3-00054, see Acrylonitrile AI3-00072, see Hydroquinone AI3-00075, see p-Chloro-rrr-cresol AI3-00078, see 2,4-Dichlorophenol AI3-00085, see 1-Naphthylamine AI3-00100, see Nitroethane AI3-00105, see Anthracene AI3-00109, see 2-Nitropropane AI3-00111, see Nitromethane AI3-00118, see ferf-Butylbenzene AI3-00119, see Butylbenzene AI3-00121, see sec-Butylbenzene AI3-00124, see 4-Aminobiphenyl AI3-00128, see Acenaphthene AI3-00134, see Pentachlorophenol AI3-00137, see 2-Methylphenol AI3-00140, see Benzidine AI3-00142, see 2,4,6-Trichlorophenol AI3-00150, see 4-Methylphenol AI3-00154, see 4,6-Dinitro-o-cresol AI3-00262, see Dimethyl phthalate AI3-00278, see Naphthalene AI3-00283, see Di-rj-butyl phthalate AI3-00327, see Acetonitrile AI3-00329, see Diethyl phthalate AI3-00399, see Tributyl phosphate AI3-00404, see Ethyl acetate AI3-00405, see 1-Butanol AI3-00406, see Butyl acetate AI3-00407, see Ethyl formate AI3-00408, see Methyl formate AI3-00409, see Methanol AI3-00520, see Tri-ocresyl phosphate AI3-00576, see Isoamyl acetate AI3-00633, see Hexachloroethane AI3-00635, see 4-Nitrobiphenyl AI3-00698, see IV-Nitrosodiphenylamine AI3-00710, see p-Phenylenediamine AI3-00749, see Phenyl ether AI3-00790, see Phenanthrene AI3-00808, see Benzene AI3-00867, see Chrysene AI3-00987, see Thiram AI3-01021, see 4-Chlorophenyl phenyl ether AI3-01055, see 1.4-Dioxane AI3-01171, see Furfuryl alcohol AI3-01229, see 4-Methyl-2-pentanone AI3-01230, see 2-Heptanone AI3-01231, see Morpholine AI3-01236, see 2-Ethoxyethanol AI3-01238, see Acetone AI3-01239, see Nitrobenzene AI3-01240, see I idine AI3-01256, see Decahydronaphthalene AI3-01288, see ferf-Butyl alcohol AI3-01445, see Bis(2-chloroethoxy)methane AI3-01501, see 2,4-Toluene diisocyanate AI3-01506, see p,p -DDT AI3-01535, see 2,4-Dinitrophenol AI3-01537, see 2-Chloronaphthalene... 

Photolytic. Mathew and Khan (1996) studied the photolysis of metolachlor in water in the presence of kaolinite, montmorillonite, and goethite and fulvic acid under neutral and acidic conditions at 22 °C. Metolachlor degraded in all the treatments at both pH conditions. The rate of photolysis and degradation products formed was dependent on the duration of UV exposure, the initial pH of the solution, and the composition of the suspended/dissolved material. The following photoproducts identified included 2-hydroxy-A-(2-ethyl-6-methylphenyl)-A-(2-methoxy-l-meth-ylethyl)acetamide, 4-(2-ethyl-6-methylphenyl)-5-methyl-3-morpholine (major product forming at 74-84% yield), 8-ethyl-3-hydroxy-A-(2-methoxy-l-methylethyl)-2-oxo-l,2,3,4-tetrahydroquino-line, 2-chloro-A -(2-(l-hydroxyethyl)-6-methylphenyl)-7V-(2-hydroxy-l-methylethyl)acetamide, and 2-chloro-A -(2-ethyl-6-hydroxymethylphenyl)-A-(2-methoxy-l-methylethyl)acetamide. 

A detailed study of the conversion of 3,4-dichloro-l,2,5-thiadiazole into 3,4-diamino-l,2,5-thia-diazole has been carried out <76JHC13>. Reaction with lithium or sodium amide produces only 4% of the diamine together with cyano-containing by-products, a consequence of direct attack on sulfur. Use of a less powerful nucleophile, ammonia or potassium phthalimide, resulted in an increased attack on carbon and produced the diamine in 24% and 66% yields, respectively. Secondary amines, e.g. morpholine <76JOC3l2l> and dimethylamine <72JMC315>, produce the normal displacement products. The reaction of dichlorothiadiazole with potassium fluoride in sulfolane gives a mixture of 3-chloro-4-fluoro and 3,4-difluoro-l,2,5-thiadiazole <82CB2135>. 

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>. 

Similar dicholoro precursor 205 was utilized by Katoh and co-workers in the discovery of a new fluorescence derivatizing agent for fatty acids <99H299>. The conversion of 205 to fatty acid-coupled 206 proceeded through the displacement of both chloro groups with morpholine in several high-yielding steps. 

Chloro-l,3-dithiane (797) has been employed as a formyl cation equivalent . The morpholine enamines of a variety of aldehydes and ketones were shown to react with this dithiane to produce the a-(l,3-dithan-2-yl) aldehydes and ketones (798) in good yield (Scheme 186) (77TL2077). In direct analogy with this work, the reaction of enol silyl ethers with 2-ethoxy-l,3-dithiolane in the presence of zinc chloride has been reported to afford half-protected 1,3-dicarbonyl compounds (81TL3243). 

The structure of the bromo analogue also was determined and was found to be very similar to that of the chloro complex (Fe-Br, 2.42 A) (114). The XFe(R2Dtc)2 complexes were rediscovered in 1975 (527) and a series of these molecules were obtained with the piperidine, thiomorpholine, and morpholine dithiocarbamates. 

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