Morpholine, 4-acetyl

More recently the acylation of aldehyde enamines has been reinvestigated (75) and shown to proceed normally when the enamine is added to the acid chloride. The morpholine enamine of isobutyraldehyde (98), on being added to an ether solution of acetyl chloride, afforded the iminium salt (99), from which the ketoaldehyde (100) was obtained in 66% yield by hydrolysis (75). 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

Treatment of 3-acetyl-4-methylfurazan with sulfur in morpholine resulted in a Willgerodt-Kindler transformation into the corresponding thioamide (Scheme 74). On further treatment with sulfuric acid 3-methylfurazan-4-acetic acid is obtained (96ROC734, 96ZOR766). 

Isobutylbenzene is first acetylated to give isobutylacetophenone. 4-i-butylacetophenone (40 g), sulfur (11 g) and morpholine (30 ml) were refluxed for 16 hours, cooled, acetic acid (170 ml) and concentrated hydrochloric acid (280 ml) were added and the mixture was refluxed for a further 7 hours. The mixture was concentrated in vacuo to remove acetic acid and the concentrate was diluted with water. 

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. 

Benzoxadiazole 1-oxide (481) with 3-acetyltetrahydro-2-furanone (2-acetyl-butyrolactone 482) gave 2-(2-hydroxyethyl)-3-methylquinoxaline 1,4-diox-ide (483) (KOH, MeOH-HaO, 20°C, 24 h 50%) but with 2-acetylacetaldehyde dimethyl acetal (484), in the presence of morpholine as base, it gave 2-(2-morpholinovinyl)quinoxaline 1,4-dioxide (485) (PhH, reflux, water separation, 9 h 47%) ... 

Fenclofenac Fenclofenac, o-[2,4-dichlorophenoxy)phenyl]acetic acid (3.2.45), is synthesized from 2,4-dichlorophenol and 2-chloroacetophenone, the reaction of which in the presence of sodinm hydroxide and powdered copper forms the corresponding 2-acetyl-2, 4 -dichloro-diphenyl ester (3.2.43). The resulting product is reacted with sulfur and morpholine according to Willgerodt method, giving thioamide (3.2.44), which is further hydrolyzed to the desired fenclofenac [109,110]. 

The A-acetyl derivatives of the 2-alkylthio-l,3-thiadiazol-4-imines (124, R = SR, R = Ac) undergo nucleophilic displacement reaction with amines (benzylamine, cyclohexylamine, morpholine, or aniline) giving the 2-amino derivatives (124, R = NRj, R = Ac). The salt (126, R = R = Ph, R = R = H, X = Cl) reacts with aniline at room temperature giving 4-anilino-2-phenyl-l,3-thiazole (128), presumably by a mechanism involving cleavage of the heterocyclic ring. ... 

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>. 

Displacement of the methylthio group in thiopyrano[2,3-,7 pyrimidine 219 with pyrrolidine, morpholine, and hydrazine gave the 2-substituted derivatives 220. Diazotization of 219 with NaN02 in AcOH followed by hydrolysis of the resulting diazonium salt gave the acetyl derivative 221 <1977JHC361>. 

The prototype for this class of compounds is ibufenac (42-3), developed by a group at Boots in the UK. This drug was to be quickly superseded by its a-methylated congener, ibuprofen, from the same laboratory [43]. The mechanistically very complex Wilgerodt reaction constitutes the key to the preparation of ibufenac. Thus, reaction of the acetylation product (42-1) from isobutyl benzene and acetyl chloride with sulfur and morpholine leads to the transposition of the oxidized function to the terminal carbon and formation of thiomorpholide (42-2). Hydrolysis of the thioamide... 

Yet a further increase in potency is observed when the para-isobutyl group is replaced by a benzene ring. One published synthesis for that compound is quite analogous to the malonate route to the parent drug. The acetyl biphenyl (50-1) is thus converted to the corresponding arylacetic acid by reaction with sulfur and morpholine, followed by hydrolysis of the first-obtained thiomorpholide. This is then esterified and converted to malonate anion (50-2) with sodium ethoxide and ethyl formate. The anion is quenched with methyl iodide hydrolysis of the esters followed by decarboxylation yields the NSAID flubiprofen (50-3) [51]. 

A simple synthesis of the novel hydroxylase inhibitor oudenone (76) has been reported which utilizes the furan ring as a masked hydroxybutyl unit (71JA1285). 2-Acetyl-l,3-cyclopentanedione was condensed with furfural in the presence of morpholine to yield (75). Hydrogenation of this product over platinum in the presence of sodium hydroxide followed by neutralization with hydrochloric acid yielded ( )-oudenone plus the side product (77 Scheme 18). It is interesting to note that hydrolysis of (76) at 150 °C in a sealed tube splits it into 1,3-cyclopentanedione and y-propyl-y-butyrolactone, a reaction which is the reversal of the foregoing synthetic process. 

TH-0-acetyl-2-azido-2-deoxy-a-D-galactopyranosyl)-L-threonine tert-Butyl Ester 22. A solution of Fmoc-Thr(aAc3GalN3)-OtBu 20 (215 mg, 0.3 mmol) in freshly distilled morpholine (2 mL) is stirred at room temperature for 20 min. After concentration in vacuo and codistillation with toluene (twice 3 mL) in vacuo, 22 is obtained quantitatively. It is immediately used in the following reaction. 

Acetyl chloride Morpholine Acetic acid Sodium hydoxide Sulfuric acid Crotyl bromide... 

Starting from 2-amino-3-cyano-4,5-dihydrothiophenes 60 the derived 2-benzamido derivatives 61 were treated with cyclohexylamine, morpholine, piperidine, or pyrrolidine to yield the respective 5,6-dihydro-2-phenyl 4-substituted aminothieno[2,3-d]pyrimidines 62a-d (83CPB401). In the presence of tin(IV) chloride, benzamides 61 reacted with acetic (or propionic) anhydride to give the corresponding 3-acetyl(or propionyl)thieno[2,3-[Pg.206]

EUP161917,85EUP164247 91JMC19). l,3,4,6,7,116-Hexahydro[l,4]ox-azino[3,4-a]isoquinoline and its 4-oxo derivative were obtained by cycliza-tion of 3-[o-(2-chloroethyl)phenyl]morpholine and l-[(2-chloroethoxy)-methyl]-l,2,3,4-tetrahydroisoquinoline on the action of ferf-BuOK, and by cyclization of 2-[o-(3-morpholinyl)phenyl]acetyl chloride on the action of NEt3 (67BRP1094470,67NEP6611733). 

Acetyl chloride acephate, azaconazole, chlorfenvinphos, cyhalotrin, dimethomorph, dinoseb acetate, fenitropan, fluxofenim, furconazole, mefluidide, propiconazole Acetyl chloride (dichloro) see dichloro Acetyl chloride phenyl carbinol bromadiolone Acetylene aldrin, 2,4 DB Acetyl hydrazine metamitron Acetylide (sodium) pronamide Acetyl magnesiun bromide empenthrin Acetyl morpholine dimethomorph Acetyloxy propionaldehyde furmecyclox Acrolein 8 hydroxy quinoline sulfate Acrylic acid propaquizafop Acryloyl chloride propaquizafop Acrylonitrile fenpiclonil, fludioxonil, nipyraclofen Aldrin dieldrin, endrin... 

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