Sandmeyer hydrolysis

By Sandmeyer hydrolysis (ref. 3a - 3e) (diazotisation, acidic hydrolysis without copper salts) the target specification (Table 1) is reached without difficulty but the process has two major drawbacks for industrialisation, as underlined in the recent patent from Octel Chemicals (ref. 3c) safety and corrosion on using convention equipment. 

By the hydrolysis of nitriles. The nitriles may be easily prepared either from amines by the Sandmeyer reaction (Section IV,66) or by the action of cuprous cyanide upon aryl halides (compare Section IV,163). Benzyl cyanide... 

Physical properties for naphthalene mono-, di-, tri-, and tetracarboxyhc acids are summari2ed in Table 9. Most of the naphthalene di- or polycarboxyLic acids have been made by simple routes such as the oxidation of the appropriate dior polymethylnaphthalenes, or by complex routes, eg, the Sandmeyer reaction of the selected antinonaphthalenesulfonic acid, to give a cyanonaphthalenesulfonic acid followed by fusion of the latter with an alkah cyanide, with simultaneous or subsequent hydrolysis of the nitrile groups. 

Tetrachlorotoluene, C H Cl (mol wt 229.93) (1,2,3,5-tetrachloro-4-methylben2ene), is prepared from the Sandmeyer reaction on 3-arnino-2,4,6-trichlorotoluene. 2,3,4,5-Tetrachlorotoluene (l,2,3,4-tetrachloro-5-methylben2ene) is the principal isomer in the further chlorination of 2,4,5-trichlorotoluene. Exhaustive chlorination of -toluenesulfonyl chloride, followed by hydrolysis to remove the sulfonic acid group yields... 

Because cyano groups may be hydrolyzed to carboxylic acids (Section 20.19), the Sandmeyer preparation of aryl nitriles is a key step in the conversion of arylarnines to substituted benzoic acids. In the example just cited, the o-rnethylbenzonitrile that was formed was subsequently subjected to acid-catalyzed hydrolysis and gave o-rnethylbenzoic acid in 80-89% yield. 

Substituted thioindigoid dyes are usually obtained via the appropriate benzenethiol in a Heumann-type synthesis. The final cyclisation of the phenylthioglycolic acid derivative can often be achieved in concentrated sulphuric acid or by using chlorosulphonic acid. Several routes make use of the Herz reaction (Scheme 6.22), in which a substituted aniline is converted into the corresponding o-aminothiophenol by reaction with sulphur monochloride followed by hydrolysis of the intermediate dithiazolium salt [47]. After reaction between the thiol and chloroacetic acid, the amino group is converted into a nitrile group by a Sandmeyer reaction. Hydrolysis of the nitrile leads to the formation of the required thioindoxyl derivative. 

There are more routes to cyclization. Phenylmercaptoacetic acid may be replaced by its o-carboxy or o-amino derivative to form the thionaphthenone-3. The first reaction is performed in molten alkali, the second proceeds via diazotization, Sandmeyer reaction with sodiumcyanide/copper cyanide, alkaline hydrolysis, and acid treatment. 

Sandmeyer s valuable isatin synthesis involves the removal of sulphur from diphenylthiourea (I) (p. 169) with basic lead carbonate. Hydrogen cyanide is combined with the reactive diphenylcarbodiimide (II) so obtained, and the nitrile (III) produced is converted by means of hydrogen sulphide into tbe thioamide (IV). Concentrated sulphuric acid brings about ring closure and the product is the a-anil of isatin (V). Then, by hydrolysis with dilute sulphuric acid, aniline is removed ... 

The Sandmeyer method has been used with di- and trisubstituted anilines to prepare di-4,6,13,14,19,32,38-55 and tri-5,13,19,30,56 substituted isatins. Although -acetamidoaniline and 5-acetamido-2-aminotoluene gave 5-acetamido- and 5-acetamido-7-methylisatin, respectively,30 the use of 4-acetamido-2-aminotoluene and 5-acetamido-2,4-dimethyl-aniline gave the appropriate aminoisatins.30,52 Other examples of hydrolysis during this cyclization are in the conversion of diethyl 5-aminoisophthalate to isatin-4,6-dicarboxylic acid53 and 2-methyl-5-... 

The hydrolysis of nitriles under either acidic or basic conditions, which has already been discussed in Section 5.11.2, p. 671, for alkyl and aralkyl nitriles, is equally applicable to the synthesis of aromatic carboxylic acids (Expt 6.153). The aromatic nitriles are readily obtained by the Sandmeyer reaction (see Section 6.7.1, p. 923). 

Nitroacetanilides, obtained by alkaline hydrolysis of l-arylamino-l-methylthio-2-nitroethenes, are readily cyclised to isatin-3-oximes by the use of concentrated sulfuric acid or trifluoromethanesulfonic acid at room temperature the latter giving somewhat higher yields. Although this methodology is related to the Sandmeyer methodology, it has no obvious benefit over the latter (Scheme 7). 

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. 

Examples of the three mechansims are, respectively (a) hydrolysis of aryl diazonium salts to phenols (b) reaction of aryl diazonium ions with Ns to give the aryl azides " and (c) the Sandmeyer reaction, involving cuprous chloride or bromide for synthesis of aryl halides. Specific synthetically important substitution processes are considered in the succeeding sections. 

The Sandmeyer diphenylurea isatin synthesis uses symmetrical diphenylthiourea 1 as a substrate for generation of cyanoformamidine 2, via treatment of 1 with potassium cyanide in the presence of lead carbonate. Reaction of formamidine 2 with ammonium sulfide leads to thioamide 3, which can undergo acid-induced cyclization and hydrolysis to produce isatin (4). Examples of the diphenylurea isatin synthesis in the literature are scarce. This is due to Sandmeyer developing the more practical isonitrosoacetanilide isatin synthesis 16 years later. 

The isatin products from the Sandmeyer synthesis can serve as a source of ortto-arylaminoacids through degradation. Hydrolysis of isatin 42, yielded aminoacid 43, which was converted to the anticancer compound DMXAA (44). ... 

Acetic acid dropped slowly into a cooled mixture of p-methoxybenzenediazo-nium fluoroborate and nickel carbonyl anisic acid. Y 74%.—This method may provide a useful single-step alternative to the Sandmeyer reaction, especially where the nitriles from the latter contain other groups susceptible to hydrolysis. F. e. s. J. C. Glark and R. G. Cookson, Soc. 1962, 686. 

Ruff degnulation a method used to shorten an aldose by one carbon. Sandmeyer reaction the reaction of an aryl diazonium salt with a cuprous salt, saponification hydrolysis of an ester (such as a fat) under basic conditions, saturated hydrocarbon a hydrocarbon that is completely saturated (i.e., contains no double or triple bonds) with hydrogen. 

A -oxide which is easily reduced to codeine with sulphur dioxide [303]. The 0-methylation of certain Erythrina alkaloids has been carried out in a similar manner [304]. A -Oxidation has also been used to protect tertiary ring nitrogen atoms in heteroaromatic compounds. Protonation of the ring nitrogen atom in 4- (and 2-) aminopyridines renders their diazonium salts very susceptible to hydrolysis, thus they cannot be converted into cyanides by the Sandmeyer reaction. The corresponding TV-oxides may, however, be used in the normal way and the oxide function removed at a later stage, as in the sequence (63) (64) used by Berson and Cohen in studies on ipecac... 

One more method for the preparation of 198 commenced from pyrazine derivative 207, which was transformed to dichloride 208 using Sandmeyer reaction (Schane 49) [ 166], Hydrolysis of the ester moiety in 208 followed by one-pot chlo-roanhydride formation, introduction of fluorine atom and amination gave derivative 209, which was transformed into 198 by diazotization and subsequent hydrolysis. 

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