Morpholine phenols

The supported aqueous phase methodology was applied to the system Pd(OAc)2/5 TPPTS, a catalytic precursor for the Trost-Tsuji reaction. The characterization of the solid by 31P MAS NMR confirms the presence of Pd°(TPPTS)3 as the main surface species. The catalytic properties of the solid were tested for the allylic substitution of E-cinnamylethylcarbonate by different nucleophiles such as ethyl acetoacetate, dimethyl malonate, morpholine, phenol, and 2-mercapto-pyridine. The absence of palladium leaching was demonstrated, and having solved the problem of water leaching from the solid to the organic phase, the SAP-Pd catalyst was successfully recycled several times without loss in its activity. It was used in a continuous flow experiment which... 

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

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. 

The oxidation of phenol in alcoholic media by a morpholine complex of Cu(II) (as a model for tyrosinase) to give 4,5-dimorpholino-orr/jo-benzoquinone in 64 %... 

The addition of morpholine to 2,3-dihydrofuran in the presence of palladium(II) thiocyanate-bis(triphenylphosphine) yields 2-(morpholin-4-yl)tetrahydrofuran (276)303. Irradiation of mixtures of 2-(2-methylpropenyl)phenol (277) and alkylamines yields adducts, e.g. 278 with isopropylamine304. 

EINECS 203-468-6, see Ethylenediamine EINECS 203-470-7, see Allyl alcohol EINECS 203-472-8, see Chloroacetaldehyde EINECS 203-481-7, see Methyl formate EINECS 203-523-4, see 2-Methylpentane EINECS 203-528-1, see 2-Pentanone EINECS 203-544-9, see 1-Nitropropane EINECS 203-545-4, see Vinyl acetate EINECS 203-548-0, see 2,4-Dimethylpentane EINECS 203-550-1, see 4-Methyl-2-pentanone EINECS 203-558-5, see Diisopropylamine EINECS 203-560-6, see Isopropyl ether EINECS 203-561-1, see Isopropyl acetate EINECS 203-564-8, see Acetic anhydride EINECS 203-571-6, see Maleic anhydride EINECS 203-576-3, see m-Xylene EINECS 203-598-3, see Bis(2-chloroisopropyl) ether EINECS 203-604-4, see 1,3,5-Trimethylbenzene EINECS 203-608-6, see 1,3,5-Trichlorobenzene EINECS 203-620-1, see Diisobutyl ketone EINECS 203-621-7, see sec-Hexyl acetate EINECS 203-623-8, see Bromobenzene EINECS 203-624-3, see Methylcyclohexane EINECS 203-625-9, see Toluene EINECS 203-628-5, see Chlorobenzene EINECS 203-630-6, see Cyclohexanol EINECS 203-632-7, see Phenol EINECS 203-686-1, see Propyl acetate EINECS 203-692-4, see Pentane EINECS 203-694-5, see 1-Pentene EINECS 203-695-0, see cis-2-Pentene EINECS 203-699-2, see Butylamine EINECS 203-713-7, see Methyl cellosolve EINECS 203-714-2, see Methylal EINECS 203-716-3, see Diethylamine EINECS 203-721-0, see Ethyl formate EINECS 203-726-8, see Tetrahydrofuran EINECS 203-729-4, see Thiophene EINECS 203-767-1, see 2-Heptanone EINECS 203-772-9, see Methyl cellosolve acetate EINECS 203-777-6, see Hexane EINECS 203-799-6, see 2-Chloroethyl vinyl ether EINECS 203-804-1, see 2-Ethoxyethanol EINECS 203-806-2, see Cyclohexane EINECS 203-807-8, see Cyclohexene EINECS 203-809-9, see Pyridine EINECS 203-815-1, see Morpholine EINECS 203-839-2, see 2-Ethoxyethyl acetate EINECS 203-870-1, see Bis(2-chloroethyl) ether EINECS 203-892-1, see Octane EINECS 203-893-7, see 1-Octene EINECS 203-905-0, see 2-Butoxyethanol EINECS 203-913-4, see Nonane EINECS 203-920-2, see Bis(2-chloroethoxy)methane EINECS 203-967-9, see Dodecane EINECS 204-066-3, see 2-Methylpropene EINECS 204-112-2, see Triphenyl phosphate EINECS 204-211-0, see Bis(2-ethylhexyl) phthalate EINECS 204-258-7, see l,3-Dichloro-5,5-dimethylhydantoin... 

Amines such as diethylamine, morpholine, pyridine, and /V, /V, /V, /V -tetramethylethylene-diamine are used to solubilize the metal salt and increase the pH of the reaction system so as to lower the oxidation potential of the phenol reactant. The polymerization does not proceed if one uses an amine that forms an insoluble metal complex. Some copper-amine catalysts are inactivated by hydrolysis via the water formed as a by-product of polymerization. The presence of a desiccant such as anhydrous magnesium sulfate or 4-A molecular sieve in the reaction mixture prevents this inactivation. Polymerization is terminated by sweeping the reaction system with nitrogen and the catalyst is inactivated and removed by using an aqueous chelating agent. 

The above mentioned reactions are widely used in alkaloid modification. A good example of alkaloid modifications for clinical curation purposes are opioides. Morphine and codeine are natural products of Papaver somniferum. However, the codeine is naturally produced in small amounts. This is one reason why it is produced synthetically from morphine by modification. As codeine is the 3-0-methyl ether of morphine, the mono-O-methylation occurs in the acidic phenolic hydroxyl. Pholcodine is obtained by modification of morphine through alkylation with A-(chloroethyl)morpholine. Moreover, dihydrocodeine, hydro-morphone and heroine are also obtained from morphine through modifications. 

It is worthwhile to cite the pioneering work of Brackman and Havinga, carried out in the 1950s and considered as early tyrosinase models [1,2,179], Here, conditions were found to effect the straightforward catalytic o-hydroxyla-tion of phenols to give substituted o-quinones. A most interesting case occurs when copper salts are reacted with phenol, 02, and morpholine (mp) in methanol, giving insoluble morpholino-substituted o-benzoquinone. The reaction is complicated, but a Cu(II)-peroxo-phenol-mp species is seen to be an important intermediate (Scheme 17). 

The electron-withdrawing S=0 group helps the nucleophilic substitution of bromide with sodium phenolate in 3-bromobenzoMthiophene 1-oxide (Scheme 26). Nucleophilic substitution of bromine could also be carried out using secondary amines such as piperidine and morpholine <2005JOC3569>. 

Interception of the ji-allyl palladium intermediate with soft nucleophiles such as morpholine and dimedone is attractive on the grounds of efficacy, economy, safety and scope. Deprotection of a phenol allyl ether in a synthesis of the antibiotic Vancomycin demonstrates that aryl iodides and chlorides remain intact [Scheme 4.227],429... 

Alkylation of the enolate from treatment of the phenol with base with the chloropropyl morpholine (161) then affords gefitinib (162). " ... 

Fig. 5. Rates of proton transfer for cyanocarbon acids. Open and closed points represent forward (log10 k, ) and reverse (logI0 -i ) rate coefficients, respectively, and ApK is the statistically corrected difference in acidities between the cyanocarbon acid and base (B). Points are o and for f-butylmalononitrile reacting with carboxylate ions and H20 a and for malononitrile with formate ion and H20 and for bromomalononitrile with phosphate ion and morpholine x for 1,4-dicyano-2-butene with phenolate ions. Redrawn with permission from F. Hibbert and F. A. Long, J. Am. Chem. Soc., 94 (1972) 2647. Copyright by the American Chemical Society.

Chabrier et al. found that phenols and arylamines can be iodinated in good yield by reaction of the substrate, iodine, and morpholine in the molecular ratio 1 1 3 in an anhydrous solvent (ethanol, ether, benzene). For example, phenol afforded 2,4,6-triiodophenol in 90% yield. 

Morpholine, TBDMSCl, THF, 2 min, 20 C, >80% yield. In this case the ester was formed in the presence of a phenol. The functionally and sterically similar thexyldimethylsilyl ester is also formed under these conditions. ... 

Addition of fiirther bases like triethylamine or N-ethyl morpholine allowed the reduction of the level of alkylcyclohexanols (see Table 2). Whereas small amounts of the tertiary amine yielded a cis/trans ratio of about 3, a higher ratio was obtained at a N-ethyl morpholine concentration of 0.2 mol/mol phenol However, under the latter conditions the formation of alkylcyclohexanols was increased in fiivor of the desired alkylcyclohexylamines. As in the case of the inorganic bases, larger amounts of tertiary amines added to the reaction led to a decrease of the catalyst activity. 

Run N-ethyl morpholine fmol/mol phenoll Reaction time fminl Conversion [%] Selectivity to amines f%l cis/trans ratio amines... 

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