Cyanohydrins oxidation

Unsaturated chiral cyanohydrins bear another synthetically interesting functionality, the C-C double bond. Among the opportunities of transforming unsaturated cyanohydrins, oxidative cleavage [208, 215], epoxidation [209, 210], iodolactonisation [209], addition reactions [211, 212, 216] and metal assisted... 

Cyanohydrin-oxidation-substitution sequence (Corey method) [1] ... 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

In the early versions, ethylene cyanohydrin was obtained from ethylene chlorohydrin and sodium cyanide. In later versions, ethylene oxide (from the dkect catalytic oxidation of ethylene) reacted with hydrogen cyanide in the presence of a base catalyst to give ethylene cyanohydrin. This was hydrolyzed and converted to acryhc acid and by-product ammonium acid sulfate by treatment with about 85% sulfuric acid. 

Processes rendered obsolete by the propylene ammoxidation process (51) include the ethylene cyanohydrin process (52—54) practiced commercially by American Cyanamid and Union Carbide in the United States and by I. G. Farben in Germany. The process involved the production of ethylene cyanohydrin by the base-cataly2ed addition of HCN to ethylene oxide in the liquid phase at about 60°C. A typical base catalyst used in this step was diethylamine. This was followed by liquid-phase or vapor-phase dehydration of the cyanohydrin. The Hquid-phase dehydration was performed at about 200°C using alkah metal or alkaline earth metal salts of organic acids, primarily formates and magnesium carbonate. Vapor-phase dehydration was accomphshed over alumina at about 250°C. 

The handling of toxic materials and disposal of ammonium bisulfate have led to the development of alternative methods to produce this acid and the methyl ester. There are two technologies for production from isobutylene now available ammoxidation to methyl methacrylate (the Sohio process), which is then solvolyzed, similar to acetone cyanohydrin, to methyl methacrylate and direct oxidation of isobutylene in two stages via methacrolein [78-85-3] to methacryhc acid, which is then esterified (125). Since direct oxidation avoids the need for HCN and NH, and thus toxic wastes, all new plants have elected to use this technology. Two plants, Oxirane and Rohm and Haas (126), came on-stream in the early 1980s. The Oxirane plant uses the coproduct tert-huty alcohol direcdy rather than dehydrating it first to isobutylene (see Methacrylic acid). 

Reaction of hydra2ine with acetone cyanohydrin gives a disubstituted hydra2ine, which upon oxidation with chlorine water gives 2,2 -a2obisisobutyronitrile [78-67-1] (AIBN), a stable, colorless, crystalline material at room temperature. 

Ethylene Cyanohydrin. This cyanohydrin, also known as hydracrylonitnle or glycocyanohydrin [109-78-4] is a straw-colored Hquid miscible with water, acetone, methyl ethyl ketone, and ethanol, and is insoluble in benzene, carbon disulfide, and carbon tetrachloride. Ethylene cyanohydrin differs from the other cyanohydrins discussed here in that it is a P-cyanohydrin. It is formed by the reaction of ethylene oxide with hydrogen cyanide. 

Other Derivatives. Ethylene carbonate, made from the reaction of ethylene oxide and carbon dioxide, is used as a solvent. Acrylonitrile (qv) can be made from ethylene oxide via ethylene cyanohydrin however, this route has been entirely supplanted by more economic processes. Urethane intermediates can be produced using both ethylene oxide and propylene oxide in their stmctures (281) (see Urethane polymers). 

Cyanides are dangerously toxic materials that can cause instantaneous death. They occur in a number of industrial situations but are commonly associated with plating operations, and sludges and baths from such sources. Cyanide is extremely soluble and many cyanide compounds, when mixed with acid, release deadly hydrogen cyanide gas. Cyanide is sometimes formed during the combustion of various nitrile, cyanohydrin, and methacrylate compounds. Cyanides (CN ) are commonly treated by chlorine oxidation to the less toxic cyanate (CNO ) form, then acid hydrolyzed to COj and N. Obviously, care should be taken that the cyanide oxidation is complete prior to acid hydrolysis of the cyanate. 

Merck and Maeder have patented the manufacture of arecaidine by loss of water from l-methyl-4-hydroxypiperidine-3-carboxylic acid. A method of producing the latter has been describd by Mannich and Veit and has been developed by Ugriumov for the production of arecaidine and arecoline. With the same objective, Dankova, Sidorova and Preobrachenski use what is substantially McElvain s process,but start by converting ethylene oxide, via the chlorohydrin and the cyanohydrin, into -chloropropionic acid. The ethyl ester of this with methylamine in benzene at 140° furnishes methylbis(2-carbethoxyethyl) amine (I) which on refluxing with sodium or sodium Moamyloxide in xylene yields l-methyl-3-carbethoxy-4-piperidone (II). The latter is reduced by sodium amalgam in dilute hydrochloric acid at 0° to l-methyl-3-carbethoxy-4-hydroxypiperidine (III) which on dehydration, and hydrolysis, yields arecaidine (IV R = H), convertible by methylation into arecoline (IV R = CH3). 

Steroids possessing an epoxide grouping in the side chain have likewise been converted to fluorohydrins. Thus, 20-cyano-17,20-epoxides of structure (19) furnish the 17a-fluoro-20-ketones (20) after treatment of the intermediate cyanohydrins with boiling collidine. The epimeric 5a,6a 20,21-oxides (21) afford the expected bis-fluorohydrins (22). The reaction of the allylic... 

Steroidal 17-cyanohydrins are relatively stable towards chromium trioxide in acetic acid (thus permitting oxidation of a 3-hydroxyl group ) and towards ethyl orthoformate in ethanolic hydrogen chloride (thus permitting enol ether formation of a 3-keto-A system ). Sodium and K-propanol reduction produces the 17j -hydroxy steroid, presumably by formation of the 17-ketone prior to reduction. ... 

Generally, the successful conversion of 20-ketopregnanes to 17-hydroxy-androstanes with peracids requires the protection of other ketones, with the exception of those at C-11, and possibly C-12 e.g., as ketals or cyanohydrins ) and isolated double bonds e.g., as dibromides). Unprotected hydroxyl groups do not interfere, except, as expected, a 17a-hydroxy-20-keto steroid is oxidized to the 17-ketone. The use of nitrate esters to protect... 

Hydroxy-20-cyanohydrins can be oxidized to 3-ketones in good yield with chromic acid, and the osmate ester of the unsaturated nitrile is also stable to this oxidant. " After hydrolysis of the osmate ester, the new 17-hydroxy-20-cyanohydrin which is presumably formed cannot be isolated, but loses hydrogen cyanide during the hydrolysis, and only the 17a-hydroxy-20-ketone is obtained. 

Cholestane-3/3,5a-diol 3-acetate, 397 Cholestane-4a,5a-diol 4-tosylate, 398 Cholestane-5a,6a-diol 6-tosylate,394 5a-Cholestan-2-one, 57, 88, 427 10(5 4 H)ijAeo-Cholestan-5-one, 398 10(5 6)ij ieo-Cholestan-5-one, 392, 394 5a-Cholestan-3-one cyanohydrin, 359 5a-Cholestan-3-one cyanohydrin acetate, 360 5a-Cholestan-2a,3a-oxide, 42 5a-Cholestan-2/3,3/3-thiirane, 43 Cholest-5-ene-3, 19-diol, 268 Cholest-5-ene-3, 25-diol, 71 5(10->l/3H)flfc eo-cholest- 10(19)-ene-3/8,5a-diol 3-acetate, 397, 398 Cholest-4-ene-3,6-dione, 105 Cholest-4-en-3-one, 318 Chromium trioxide, 147, 150 5a-Conanine-3/3-ol-ll-one 3-acetate, 259 Cupric bromide, 210, 211 Cuprous chloride-catalyzed conjugate addition, 76, 80... 

J-Chloropropionic acid has been prepared by the hydrolysis of ethylene cyanohydrin with hydrochloric acid,1 and by the oxidation of /S-chloropropionaldehyde2 or of trimethylene chlorohydrin 3 by nitric acid. 

Benzenediamine (199) and C-(2-chloro-2-phenylacetyl)formamide (200) gave 3-phenyl-3,4-dihydro-2-quinoxalinecarboxamide (201), formulated as its 1,4-dihydro tautomer (EtOH, reflux, 6 h 56%) in contrast, the same substrate (199) with methyl C-(2-chloro-2-phenylacetyl)formate cyanohydrin (202) gave methyl 3-phenyl-2-quinoxalinecarboxylate (203), presumably by aerial oxidation of a dihydro precursor (MeCN, reflux, 12 h 7%). ... 

The reaction is an important step in a method for the oxidative decyanation of nitriles containing an a hydrogen. The nitrile is first converted to the a-hydro-peroxy nitrile by treatment with base at — 78°C followed by O2. The hydroperoxy nitrile is then reduced to the cyanohydrin, which is cleaved (the reverse of 16-51) to the corresponding ketone. The method is not successful for the preparation of aldehydes (R =H). 

A 1,3-diol sometimes represents a more convenient precursor to cyanohydrin acetonides. For these instances, an alternate procedure has been developed. Selective oxidation of a 1,3-diol with TEMPO/NaOCl generates a sensitive -hydroxy aldehyde (see also Sect. 3.2). The neat -hydroxy aldehyde is prone to dimerization, but can be handled in solution without significant dimerization. Conversion to the cyanohydrin acetonide is accomplished in a manner similar... 

S (2)-hydroxy-3-butenenitrile from acrolein and HCN trans hydrocyanation using, for instance, acetone cyanohydrin Hydrolysis of nitriles to amides, e.g. acrylonitrile to acrylamide Isomerization of glucose to fructose Esterifications and transesterifications Interesterify positions 1 and 3 of natural glycerides Oxidation of glucose to gluconic acid, glycolic acid to glyoxalic acid... 

Cyanide and thiocyanate anions in aqueous solution can be determined as cyanogen bromide after reaction with bromine [686]. The thiocyanate anion can be quantitatively determined in the presence of cyanide by adding an excess of formaldehyde solution to the sample, which converts the cyanide ion to the unreactive cyanohydrin. The detection limits for the cyanide and thiocyanate anions were less than 0.01 ppm with an electron-capture detector. Iodine in acid solution reacts with acetone to form monoiodoacetone, which can be detected at high sensitivity with an electron-capture detector [687]. The reaction is specific for iodine, iodide being determined after oxidation with iodate. The nitrate anion can be determined in aqueous solution after conversion to nitrobenzene by reaction with benzene in the presence of sulfuric acid [688,689]. The detection limit for the nitrate anion was less than 0.1 ppm. The nitrite anion can be determined after oxidation to nitrate with potassium permanganate. Nitrite can be determined directly by alkylation with an alkaline solution of pentafluorobenzyl bromide [690]. The yield of derivative was about 80t.with a detection limit of 0.46 ng in 0.1 ml of aqueous sample. Pentafluorobenzyl p-toluenesulfonate has been used to derivatize carboxylate and phenolate anions and to simultaneously derivatize bromide, iodide, cyanide, thiocyanate, nitrite, nitrate and sulfide in a two-phase system using tetrapentylammonium cWoride as a phase transfer catalyst [691]. Detection limits wer Hi the ppm range. 

The reaction of aldehydes with MnOz in the presence of cyanide ion in an alcoholic solvent is a convenient method of converting aldehydes directly to esters.214 This reaction involves the cyanohydrin as an intermediate. The initial oxidation product is an acyl cyanide, which is solvolyzed under these reaction conditions. 

The first report on the reaction of D-pseudoephedrine 66 with phosphoryl chloride appeared as early as 1962 [49], More recently it was found that this condensation gave 2-chloro-l,3,2-oxazaphospholidine 2-oxides 67 as a single diastereomer which was subsequently esterified with racemic aldehyde cyanohydrins 68 without racemization at the phosphorus atom. The prepared diastereomeric esters 69 were used as substrates for the asymmetric synthesis of optically active cyanohydrins 72, which involves the intermediate formation of the tertiary esters 70, as shown in Scheme 22 [50],... 

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