Oximino

C. N-Hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione. O-Ethyl S-[2-oximino-2-(p-chlorophenyl)ethyl]dithiocarbonate (56.0 g, 0.19 mol) is placed in a 500-mL round-bottomed flask that is equipped with a magnetic stir bar. Diethyl ether (120 mL) is added and the slurry is treated at 0°C in small portions with solid anhydrous zinc chloride, ZnClj, 79.1 g, 0.58 mol) at such a rate that the solvent does not boil constantly (Note 8). After the addition is complete, the flask is stoppered with a drying tube (CaCl2) and stirring is continued for 48 hr at 20°C. The reaction mixture turns into a dear, dark brown solution that solidifies toward the end of the reaction. The flask is immersed in an ice bath and treated dropwise with 5.5 M hydrochloric add (140 mL, Note 9). The precipitate dissolves immediately. Stirring is continued for 30 min at 0°C whereupon a tan-colored solid separates. This material is collected by filtration. It is washed with small portions of diethyl ether (total of 110 mL) and dried to afford 39.8 g (86%) of N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione (Note 10). The crude material is transferred to a 2-L, round-bottomed flask equipped with a reflux condenser. 2-Propanol (760 mL) is added and the reaction mixture is heated to reflux. Once a dear solution is obtained the heat source is immediately removed (Note 11). The solution is allowed to cool to room temperature. Precipitation of N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione is completed by immersing the flask for 30 min in an acetone-dry ice bath (-78°C). The product is collected by filtration and dried to afford 21.9 g (53.5%) of N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione as tan crystals (Notes 12,13). 

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

In the present preparation, ethyl acetoacetate is treated with sufficient nitrous acid to convert half into the a-nitroso (or a-oximino) ester, which is reduced by zinc and acetic acid to the a-amino ester (I). The latter then condenses with... 

If the oximino intermediates are O-alkylated and then reduced with BHj-N(CH3)3, N-alkoxy tryptophans can be obtained[6]. 

Analogously, l-brcano-3-oxiininobutan-2-one yields the 4-oximino-ethyl compound (67), while chloromalonic dialdehyde gives rise to the S-formylthiazole (68) (Scheme 31) (618). 

Because the a-aminoketone is subject to self-condensation, the condensation with a P-dicarbonyl derivative (6) is usually carried out by generating the a-aminoketone in situ through reduction of an oximino derivative (7) 2iac ia glacial acetic acid is used as the reductant. For example, Knorr s pyrrole... 

The nitrosation of pyrroles and indoles is not a simple process. The 3-nitroso derivatives (84) obtained from indoles exist largely in oximino forms (85) (80IJC(B)767). Nitrosation of pyrrole or alkylpyrroles may result in ring opening or oxidation of the ring and removal of the alkyl groups. This is illustrated by the formation of the maleimide (86) from 2,3,4 -trime thylpyrrole. 

Methyl isothiazole-4-acetate is nitrosated by pentyl nitrite, and the oximino ester formed can be hydrolyzed to the a-keto ester (78GEP2745246). Secondary alcohols (94) can be oxidized to the ketones (72GEP2223648). 

H-Indole, 3,3-dichloro-synthesis, 4, 369 3H-Indole, 3,3-dimethyl-synthesis, 4, 224 3H-Indole, 3-hydroperoxy-autoxidation, 4, 247 rearrangement, 4, 249 3H-Indole, 3-oximino-synthesis, 4, 209, 210 3H-Indole, 3-oximino-2-phenyl Beckmann rearrangement, 4, 210 Indoleacetic acid synthesis, 4, 337 Indole-3-acetic acid as growth regulator, 4, 372 synthesis, 4, 346 Indole alkaloids, 4, 373 synthesis, 4, 276... 

Snyder and Smith prepared diethyl acetamidomalonate in 40% yield by reduction of diethyl isonitrosomalonate in ethanol over palladium on charcoal followed by direct acetylation of diethyl aminomalonate in the filtrate with acetic anhydride. Ghosh and Dutta used zinc dust instead of palladium. A modification using Raney nickel is described by Akabori et al. Shaw and Nolan reported a 98% yield by conversion of diethyl oximino-malonate-sodium acetate complex. 

Boron trifluoride etherate in benzene converts A -20-acetoximinosteroids to the 17-ketones in somewhat lower yield, but the reaction of A -20-oximino steroids with this catalyst in the presence of acetic anhydride does not give the expected product two different compounds have been isolated and identified. ... 

All rearrangements of 20-oximino steroids have thus far given only the product arising from migration of the large steroid residue rather than the smaller C-21 methyl group. This is a consequence of the fact that only the oxime with the hydroxyl furthest removed, and therefore trans, to the bulk of the steroid, is formed. 

The initial observation that menthone reacts with amyl nitrite in the presence of base to give a good yield of an open-chain oximino ester was not expanded for synthetic purposes until Woodward almost forty years later utilized this reaction for the cleavage of a 7-keto-decahydroisoquinoline in the course of his total synthesis of quinine. 

Oximino steroids have been prepared starting from 2 -nitrites ... 

The yield of 18-oximino compounds from 20jS-nitrites varies from 15 to 36% whereas with a 20oc-nitrite a 60-65% yield is reported. This difference has been ascribed to steric hindrance in the transition state for hydrogen abstraction in the case of the 20j3 derivative. Similar differences... 

Ai -A-homo-4-ketones by reaction with lithium and biphenyl at The resulting dienone is transformed into the corresponding tropone by treatment with bromine. The Swiss chemists also found that base treatment of 19-mesyloxy-A " -3-oximes gives directly 4-oximino-A-homo-estra-l(10),2,4a-trienes in moderate yield. ... 

During 1961-2 four independent groups almost simultaneously reported the first syntheses of D-norsteroids, based on the photolysis of 16-diazo-17-ketones. In a typical procedure. Cava and Moroz ° convert the 16-oximino-17-one (93) derived from estrone methyl ether (92) to the diazoketone (94)... 

Hydroxy- 6-diazoandrost-5-en- l-one (96) To a stirred solution of 750 ml of methanol and 144 ml of 5 A sodium hydroxide is added 36 g (0.114 mole) of oximino ketone. Concentrated aqueous ammonia (56.6 ml, 0.850 mole) is then added followed by dropwise addition of 265 ml of cold 3 M sodium hypochlorite at a rate sufficient to maintain the temperature of the exothermic reaction mixture at 20 + 1° while cooling with an external ice bath. At temperatures below 20° appreciable amounts of a-mono- and a-dichloro ketones are obtained above 20° the chloramine decomposes before reacting with the oximino ketone. As soon as all of the sodium hypochlorite has been added, the ice bath is removed and the reaction mixture is allowed to warm to room temperature with continued stirring for 6 hr. The reaction mixture is diluted with an equal volume of water and extracted twice with... 

An a-oximino enamine was formed by the reaction of nitrosyl chloride and triethylamine with morpholinocyclohexene 494). Oxime functions have also been introduced into carbonyl conjugated enamines with isoamyl nitrite or NjOj 495). 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone 1 and a second carbonyl compound 2, having a reactive a-methylene group, to give a pyrrole 3. The amine 1 is often generated in situ by reduction of an oximino group. 

There are other Diels-Alder approaches to pyridines but they do not proceed in one step. For example, Weinreb reported the intramolecular Diels-Alder of oximino malonates tethered to a diene. Thermolysis of 102 produced 103 that upon treatment with base afforded pyridine 104. 

An interesting comparison between a catalytic hydrogenation and a zinc and acetic acid reduction is observed in the case of the oximino acid (49). The cw-fused hydroxamic acid (50) was the sole... 

The same oximino acid (49) underwent a cyclodehydration on treatment with dicyclohexyl carbodiimide to form the unsaturated hydroxamic acid (52) in almost quantitative yield. 

In 1898, Lowry observed that a-nitrocamphor (81) under Nef conditions did not give the expected a-diketone, but instead a compound to which he assigned, with little evidence, the oximino anhydride structure (85). This structure was recently corrected by Larson and Wat to the W-hydroxyimide (84). 

The interposition of a syn-oximino ether moiety between the amide carbonyl and the aromatic ring has proved richly... 

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