Arylamine synthesis

Wolfe etal, US Patent 6,323,366 (November 27, 2001) Assignee Massachusetts Institute of Technology Utility Arylamine Synthetic Method 

A test tube was charged with tris(dibenzylideneacetone)dipalladium (0.005 mmol), bis[(phenylphosphino)phenyl] ether (0.015 mmol), benzophenone imine (1.05 mmol), 2-bromoanisole (1.0 mmol) and 2 ml toluene. The mixture stirred 5 minutes, t-BuONa (1.4 mmol) was added, and the mixture stirred an additional 23 minutes. Thereafter, it was heated to 80°C, stirred 2 hours 10 minutes, cooled and 1 ml diethylether added followed by 2 ml saturated aqueous NaCl. The product was purified by flash chromatography on silica gel EtOAc/hexanes, 1 10, and isolated in 75% yield. 

To a 0.3 M THE solution of product from Step 1 was added 2.0 M HCl and the mixture stirred 5 minutes to 20 minutes. Thereafter, it was partitioned between 0.5 M HCl and hexane/EtOAc, 2 1, and the aqueous layer made alkaline. The product was extracted with CH2CI2, dried, and isolated (Note 2). 

The two component catalyst consists of a 1 3 molar ratio of tris(dibenzylidene-acetone)dipalladium and bis(2-diphenylphosphino)phenyl)ether, respectively. 

The preparation of the co-catalyst, bis[(2-diphenylphosphino)-phenyl]ether, is described (1). 

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Aryl iodides, bromides, chlorides, triflates and some tosylates are used for the arylamine synthesis. Secondary (dialkyl, alicyclic, alkyl-aryl, and diarylamines) and primary amines (alkyl and arylamines) participate in the reaction with different reactivity. In general, more basic and less bulky amines react faster. 

Aryl diazonium ions prepared by nitrous acid diazotization of primary arylamines are substantially more stable than alkyl diazonium ions and are of enormous synthetic value Their use m the synthesis of substituted aromatic compounds is described m the following two sections... 

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

The classic syntheses of the antibacterial sulfonamides involve reaction of the appropriate arylamine with an acid addition salt of p-amino-benzenesulfonyl chloride, or p-nitrobenzenesulfonyl chloride followed by reduction. Chemical interest largely resides in preparation of the corresponding arylamines. For the synthesis of sulfacytine (134), N-ethyl uracil (131) was converted to its thioamide (132) by reaction with phosphorous pentasulfide. The newly introduced sulfur is then displaced with ammonia in methanol to give 133. Standard reactions complete... 

Biologically important arylamines, various kinds of heterocycles, and macrocyclic compounds have been prepared by using resin-bound nitro halo compounds via SNAr reactions. Such a process is very important for combinatorial synthesis of biologically important compounds. Typical examples are presented in Eqs. 9.13—9.21,22-31... 

A combination of organometallic procedures has been used in the design of a simple, efficient synthesis of 2-alkylindoles from o-bromoanilines.76 The arylamines are converted in reactions with 73-allylnickel dimers77 into 2-allylarylamines (36, Scheme 48) which can be cyclized in a separate step... 

The specific ortho functionalization of arylamines is obviously important in quinoline synthesis (cf. the rc-allyl procedure devised for the preparation of o-allylanilines used as indole and quinoline precursors).76 Recently acetanilides have been subjected to orthopalladation and the ensuing complexes converted into useful precursors of 2-substituted quinoline derivatives (Scheme 143).215... 

The Clauson-Kaas pyrrole synthesis was adapted to a soluble polyglycerol (PG) support <060L403>. Electrochemical oxidation of furan 33 in the presence of methanol followed by hydrogenation gave 2,5-dimethoxytetrahydrofuran 34. Cyclocondensation with primary arylamines gave A-arylpyrroles 35. Removal from the PG support was then accomplished by treatment of 35 with LiOH which gave 2-pyrrolepropanoic acids 36. 

The second method is advantageous over the Gould-Jacobs method with respect to (a) the cyclization step which proceeds smoothly under mild conditions (b) one-pot synthesis of the 1-substituted derivatives and bypassing the alkylation/arylation of the Ni-position of l,4-dihydro-4-oxoquinoline-3-carboxylate, which usually gives rise to mixed N1/O4-substituted products and (c) product versatility due to the ability to utilize a wide range of alkyl-and arylamines in the step before cyclization. 

Heavy metals are widely used as catalysts in the manufacture of anthraquinonoid dyes. Mercury is used when sulphonating anthraquinones and copper when reacting arylamines with bromoanthraquinones. Much effort has been devoted to minimising the trace metal content of such colorants and in effluents from dyemaking plants. Metal salts are used as reactants in dye synthesis, particularly in the ranges of premetallised acid, direct or reactive dyes, which usually contain copper, chromium, nickel or cobalt. These structures are described in detail in Chapter 5, where the implications in terms of environmental problems are also discussed. Certain basic dyes and stabilised azoic diazo components (Fast Salts) are marketed in the form of tetrachlorozincate complex salts. The environmental impact of the heavy metal salts used in dye application processes is dealt with in Volume 2. 

Although the synthesis is completed in very few steps, oxidation of 1,4-xylene to the corresponding terephthalic acid does not afford a uniform product. Partial dihalogenation gives rise to side products. The condensation reaction requires two equivalents of arylamine per halogen atom. One equivalent is needed to neutralize the generated hydrohalogen acid, which is subsequently separated as aryl-amine-hydrohalide and recycled as hydrohalide and arylamine. 

The hydroquinone process was developed by BASF [12]. Hydroquinone-2,5-di-carboxylic acid is prepared by a modified Kolbe-Schmidt synthesis from hydroquinone and carbon dioxide. Subsequent reaction with arylamine in an aqueous-methanolic suspension in the presence of an aqueous sodium chlorate solution and a vanadium salt affords the product in good yield ... 

The scheme shows that arylamine plays the role of nucleophilic catalyst reaction of direct condensation of monosaccharide with the ureido derivatives. That is why in order to simplify the synthesis of N-glycosylureas, one can go without N-arylglycozid and instead use the catalyst additions of arylamine [13, 14],... 

Organic Mediators Organic mediators are very useful in electroorganic chemistry since their structural modification may increase the selectivity of the oxidation. The first organic mediator exploited for oxidation in synthesis was thio-anisole. Since then, there appeared a variety of other organic mediators such as tris-arylamines, tetramethylpiperidinyl-1 -oxy (TEMPO), and Ai-hydroxyphthalimides (NHPIs). 

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