Allyl toluidine

The next milestone in the development of organic synthesis was the preparation of the first synthetic dye, mauveine (aniline purple) by Perkin in 1856 Perkin, 1856, 1862). This is generally regarded as the first industrial organic synthesis. It is also a remarkable example of serendipity. Perkin s goal was the synthesis of the antimalarial drug quinine by oxidation of N-allyl toluidine (Fig. 2.4). 

One of the research projects that von Hoffman suggested to his students was an investigation of the possibility of producing quinine from coal tar. Quinine is a valuable drug for the treatment of malaria. Perkin decided to take on this task and tried to convert both allyl toluidine and aniline (coal tar derivatives) into quinine. His experiments failed, but he noticed that an ugly black sludge was left behind on the bottom of the reaction flask in the aniline experiment. Curious about the residue, he added ethanol (ethyl alcohol) to the flask. A beautiful, deep purple solution formed when the sludge dissolved in the alcohol. 

Organic synthesis followed a different line of evolution. A landmark was Perkin s serendipitous synthesis of mauveine (aniline purple) in 1856 [26] which marked the advent of the synthetic dyestuffs industry, based on coal tar as the raw material. The present day fine chemicals and pharmaceutical industries evolved largely as spin-offs of this activity. Coincidentally, Perkin was trying to synthesise the anti-malarial drug, quinine, by oxidation of a coal tar-based raw material, allyl toluidine, using stoichiometric amounts of potassium dichromate. Fine chemicals and pharmaceuticals have remained primarily the domain of... 

Among the first attempts to synthesise quinine, though unsuccessful, is the one by William Henry Perkin (1838-1907), an 18-year-old student at the Royal College of Chemistry in London. While the constitution of quinine was stiU rmknown, Perkin thought it would be possible to produce this alkaloid by oxidising N-allyl toluidine. Instead, he prepared accidentally aniline purple, which became better known as mauveine, the first industrial dyestuff and a cornerstone for the development of the chemical industry. 

Perkin prepared a compound of composition C10H13N (actually allyl toluidine). He hoped that by oxidation he might be able to produce the important drug quinine ... 

The structural formulae of the organic compounds concerned were, of course, unknown at this stage, and so Perkin s suggested method of synthesis was not unreasonable. Perkin later recalled what happened when he treated allyl toluidine with the oxidising agent potassium dichromate ... 

Tab. 10.6 summarizes the application of this transformation to a variety of racemic secondary allylic carbonates using the lithium anion of 4-methoxy-N-(p-toluidine)-benzene sulfonamide. The excellent regioselectivity obtained for this type of substitution provided an important advance in the synthesis of N-(arylsulfonyl)anihnes using the metal-catalyzed allyhc amination reaction. The allyhc alcohol derivatives examined... 

The bridging chlorine atoms in these ir-allylicpalladium complexes are readily replaced by bromine, iodine, or the thiocyanate group by treatment with the corresponding alkali metal salt in a suitable solvent such as acetone 105, 194). The chlorine bridge is split by amines for example, the ir-allyl complex [PdCl(7r-CsH6)]2, with p-toluidine, gives [PdCl(7r-C3H6) (p-tolui-dine)] as stable, pale yellow crystals (105). 

The Claiaen rearrangement in nitrogen heterocyclic systems has been carried out in many different solvents. The ease of allylic migration appears to vary considerably among the different systems. The solvent media commonly employed are diethylaniline, 1-methyl-naphthalene, and AjA-diethyl-m-toluidine (b.p., 231°). In other instances, where the allyl ethers are liquids, the rearrangement has also been effected without any solvent. Under these conditions, the results are not always the same as those observed with a solvent. 

Alkyl phosphates, preparation, 16, 9 Alkyl sulfates, preparation, 19, 27 Alkyl sulfides, preparation, 15, 72 Alkyl sulfites, preparation, 19, 29 Ai-AlkyW -toluidines, 18,42 Allanioin, 13,1 Allyl alcohol, 10, 107 16, 85 Allylamine, 18, 5 Allyl cyanide, 16, 85 Allyl isothiocyanate, 18, 5 Alumina, 17, 27... 

Under similar conditions, 2-allyl-4-toluidine (16) was converted to the seven-membered lactam 17 as the main product and the six-membered lactam 18 as the minor product under CO and H2 pressure in 95 % total yield [8]. 

Caminylidsn-p-toluidin 18.911. AUyl-o-tolyl-benzyl-amin 18,1033. Allyl-p-tolyl-benzyl-anun 18,1034. Allyl-dibemyl-sinin 18,1037. l-Athylanjlino-hjalrindsn 18II652. l-[Hethy. beDzyl-smino]-hydrindsn 18 n 653. 

A palladium 2-amino-substitutcd 77 -allylic complex [Pd( j -CH2(NHTol- )CH2)(PPh3)2](BF4) has been synthesized from [Pd2(/t-OH)2(PPh3)4](BF4)2 in acetone in the presence of -toluidine. It is the acetone that provides the building block of the allyl skeleton. " ... 

Methyl allyl chloride) see Dimethylvinyl chloride Methylamine (Monomethylamine) (2-(Methylamino)ethanol) see A-Methylethanolamine 3-Methylaminopropylamine (Methyl tert-amyl ether) see tert-Amyl methyl ether (Methyl amyl ketone) see Methyl pentyl ketone (2-Methylaniline) see o-Toluidine (3-Methylaniline) see m-Toluidine (Methylbenzene) see Toluene (a-Methylbenzyl alcohol) see 1-Phenylethanol Methyl bromide (Bromomethane)... 

Suitable mechanisms have been proposed following determination of the kinetic and activation parameters for oxidation of 2-naphthol and cyclic ketones by nicotinium dichromate some a-amino acids by tripropylammonium fluorochromate " distyryl ketone by quinaldinium fluorochromate methanol by benzyltriethylammonium chlorochromate catalysed by 1,10-phenanthroline substituted benzyl alcohols by tetraethylammonium bromochromate L-cysteine by pyridinium bromochromate lactic acid and 3,5-dimethyl-2,6-diaryl piperidin-4-one oximes by pyridinium chlorochromate allyl alcohol by IDC benzophenoxime by bispyridine silver(I) dichromate and alkyl phenyl sulfides by cetyltrimethylammonium dichromate. A non-linear Hammett plot obtained for the oxidation of substituted benzyl alcohols by IDC has been attributed to the operation of substituent effect on two steps of the proposed mechanism. " Kinetic and activation parameters for oxidation of o-toluidine and of A-methyl-2,6-diphenyl piperidin-4-one oxime and its 3-alkyl derivatives by sodium dichromate have been determined and suitable mechanisms have been suggested. Micellar catalysis in the 1,10-phenanthroline-promoted chromic acid oxidation of propanol... 

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