Chloral hydrate-hydroxylamine

Sandmeyer isonitrosoacetanilide isatin synthesis. Formation of isonitrosoacetodi-phenylamidine by condensation of chloral hydrate, hydroxylamine, and aniline cyclization with concentrated sulfuric acid and quantitative hydrolysis to isatin on dilution. 

Reaction of o-toluidine with chloral hydrate in presence of hydroxylamine hydrochloride and subsequent treatment with H2SO4 gave the isatin derivative 337. Bromination of 337 followed by reaction with sodium diethyl malonate gave 338. Catalytic reduction with Pd/C gave the oxoindole derivative 339 that upon hydrolysis with aqueous NaOH followed by... 

Following a published procedure for converting substituted anilines to isatins by reaction with chloral hydrate and hydroxylamine [1], it was noticed that at the end of the first stage (formation of an isonitrosoacetanilide), the odour of hydrogen cyanide was present, and this was confirmed by a Prussian blue test [2], In related work, concentrations of 100-200 ppm of hydrogren cyanide were found [3]. A mechanism for its formation from chloral hydrate and hydroxylamine was proposed [2], and the need for appropriate precautions was stressed [2,3],... 

The most frequently used synthesis of isatins is the Sandmeyer procedure, which involves the formation of an isonitrosoacetanilide (3) from an aniline (2), chloral hydrate, and hydroxylamine. The isonitroso-... 

There are only two practical laboratory methods lor the production of isatin, viz. the oxidation of indigo,1 and the condensation of aniline, chloral hydrate, and hydroxylamine salts, followed by the action of sulfuric acid.2... 

Of these methods, that of Sandmeyer 2 using aniline, chloral hydrate, and hydroxylamine salts, seemed most promising and has been studied in detail. The present method differs from that described by Sandmeyer in the use of hydroxylamine hydrochloride instead of a crude solution of hydroxylamine sulfate, and in the use of sodium sulfate to salt out the isonitroso compound. 

So now we start the synthesis. Available 46 was converted in two steps into 45 and an interesting reaction with chloral hydrate and hydroxylamine gave the amido-oxime 47, cyclised to 48 with polyphosphoric acid.5... 

It has long been known16 that primary aromatic amines react with chloral hydrate and hydroxylamine hydrochloride (or preformed chloral oxime) in aqueous solution to give isonitrosoacetanilides (e.g, 40). The reaction is improved by addition of certain inorganic ions (e.g., sulfate16) and is of value as a route to isatins obtained by... 

The method developed by Sandmeyer is the oldest and the most frequently used for the synthesis of isatin. It consists in the reaction of aniline with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulfate to form an isonitrosoacetanilide, which after isolation, when treated with concentrated sulfuric acid, furnishes isatin in >75% overall yield17. The method applies well to anilines with electron-withdrawing substituents, such as 2-fluoroaniline18, and to some heterocyclic amines, such as 2-aminophenoxathine19 (Scheme 1). 

Synthesis of isatin. This synthesis originated with Sandmeyer and was further improved by Marvel and Hiers. " The first step, in which aniline is condensed with chloral hydrate and hydroxylamine hydrochloride to form isonitrosoacetanilide (I) is represented schematically as follows ... 

An anhydride [2309, 2323] (catalysed by mineral acid) or ethyl hippurate (ethyl 2-benzoylglycinate) [2186] cyclizes an o-aminophenol on prolonged refluxing. Chloral hydrate and hydroxylamine convert an aminophenol into a benzoxazole-2-carboxaldehyde oxime [2104]. 

In Anlehnung an die 2,3-Dioxo-2,3-dihydro-indol-Synthese kann aus 5-Amino-1 H-indazol durch Reaktion mit Chloral-Hydrat und Hydroxylamin-Hydrochlorid N-(l-Hydroximino-ethyl)-lH-indazol erhalten werden, das mit Schwefelsaure zu 4,5-Dioxo-l,4,5,6-tetrahydro- 330° (Eisessig)] cyclisiert ... 

Chloral is an oily liquid, which has a penetrating odor it boils at 97° and has the specific gravity 1.512 at It reacts with water with the evolution of heat, and forms chloral hydrate, a compound which crystallizes well from water and melts at 57°. Chloral hydrate is much used as a soporific. The formula usually assigned to chloral hydrate is CCl3.CH(OH)2. There is in this case the same uncertainty as to structure as in the case of glyoxylic acid (321). Chloral hydrate shows most of the reactions of aldehydes it reduces an ammoniacal solution of silver nitrate, and reacts with hydroxylamine. It does not, however, affect Schiff s reagent (188). Concentrated sulphuric acid converts it into chloral. 

In this reaction chloral hydrate is quantitatively converted to chloral oxime with hydroxylamine hydrochloride. The chloral oxime is then condensed with 2,6-diaminopyridine in N hydrochloric acid to give a cherry-red pyri-isatTn dye (X max. 530my). Archer and Haugasl77 developed a colorimetric procedure for the specific determination of chloral hydrate (up to 150yg/10ml sample solution). This procedure uses the color (605my) produced by chloral hydrate on reaction with quin-aldine ethiodide in alkaline (ethanolamine) isopropanol. ... 

An aq. soln. of chloral hydrate and hydroxylamine hydrochloride added to a soln. of N-o-aminophenylpiperidine in M HCl, and stirred 2 weeks at room temp. 

After a mixture of 1.68 g chloral hydrate (10.2 mmol), 2.03 g hydroxylamine hydrochloride (29.2 mmol), 13.4 g anhydrous Na2S04, and 45 mL water was stirred at 45-50°C for 15 min, a 7.0 mL solution prepared from 1.517 g aniline, 0.75 mL cone. HCl, and water was added. The resulting mixture was heated for 1 h each at 45-50°C, 55-60°C and 65-70°C. An additional 0.45 g chloral hydrate and 4.1 g hydroxylamine hydrochloride were added, and the reaction mixture was heated at 75-80°C for another hour. When the mixture was cooled in ice water, a light brown precipitate formed, which was filtered to afford 1.58 g A-(2,3-dimethoxy-4-methylphenyl)-2-(hydroxyimino)-acetamide of sufficient purity, in a yield of 73%. To 20 mL polyphosphoric acid at 100°C was added 2.0 g M-(2,3-dimethoxy-4-methylphenyl)-2-(hydroxyimino)-acetamide (8.39 mmol) over a period of 5 min. After 20 min, the reaction mixture was cooled, and 40 mL water was carefully added to yield an orange precipitate, which was filtered to give 1.30 g 6,7-dimethoxy-5-methyl-lH-indole-2,3-dione, in a yield of 70%. This compound could be further purified by recrystallization in methanol, m.p. 180.5-181.5°C. 

Bromo-5-fluoroisatiii (4-9). To a solution of chloral hydrate (12.9 g, 78 mmol) in deionized water (180 mL), Na2S04 (142 g, 923 mmol), 3-bromo-4-fluoroaniline (13.5 g, 71 mmol), H2SO4 (45 mL, 1 M) and hydroxylamine hydrochloride (14.8 g, 213 mmol) were added. The mixture was heated to 130 °C and refluxed for 30 min. The mixture was then cooled to 80 °C and filtered to collect the product. The product was washed with deionized water and dried in vacuum to afford 4-8 as a yellowish solid, which was directly used for the next step without further purification. 

Indole-2,3-dione (isatin), red crystals, mp 204°C, is formed inter alia (cf p. 146) by the oxidation of indigo. A generally applicable synthesis of isatins 126 is the Sandmeyer synthesis, in which isonitrosoacetanilides 125 (easily accessible from primary arylamines, chloral hydrate, and hydroxylamine hydrochloride) are cyclized in acidic medium [195] ... 

Reaction of chloral (7, or hydrate) with hydroxylamine (8) produces chloral oxime (10) after dehydration. Aniline then displaces one of the chlorides to form the dichloroamine 11, which undergoes hydrolysis to yield the desired isonitrosoacetanilide 6. 

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