Amines from nitroarenes

Diethyl methylphosphonite in refluxing dialkylamine is the favored method for the formation of 37/-azepines from nitroarenes,75,176,207 although tributylphosphane and tri-piperidinophosphane are recommended for the deoxygenation of nitrobenzene in piperidine.79 Deoxygenation of nitrobenzene in diethylamine furnishes Ar,Ar-diethyl-3/f-azepin-2-amine, and a range of 5-substituted 3//-azepines 97 have been prepared in a similar manner from 4-sub-stituted nitroarenes.79,176 Curiously, the corresponding 2-substituted nitroarenes, with the exception of 2-nitrotoluene, yield only tarry products. 

V,/V-Diethyl-3//-azepin-2-amines 97 from Nitroarenes General Procedure 176... 

Tin-mediated-radical cyclization of isonitriles provides a useful strategy for the preparation of indoles (Fukuyama reaction).90 This radical cyclization is used for synthesis of 6-hydroxy-indole-3-acetic acid, which is the aromatic subunit of Nephilatoxin. The requisite isonitriles are prepared from nitroarenes via amines (Eq. 10.66).91... 

The synthesis of quinoline derivatives using metal catalyzed processes continues to be of interest. A modified preparation of 2,3-dialkylquinolines was reported <04JHC423> from nitroarenes and tetraalkylammonium halides via an in situ ruthenium-catalyzed reduction followed by an intrinsic amine exchange reaction using tin(ll) chloride. One of the examples reported is shown below in Scheme 25. 

Amination of nitroarenes with hydroxylamine, known for over 100 years [43], proceeds undoubtedly according to the VNS mechanism. Modem aminating agents, such as 4-amino-1,2,4-triazole [44—46], sulfenamides [47, 48], and 0-methyl hydroxylamine [49, 50], are more versatile and efficient than hydroxylamine. 1,1,1-Trimethyl hydrazinium iodide proved to be particularly useful for this purpose [51-53]. Amination with this reagent proceeds via addition of the hydrazino moiety followed by a base-induced p-elimination of trimethylamine from the corresponding adducts. 

Feng C, Deng G, Li C-J et al (2010) Ruthenium-catalyzed tertiary amine formation from nitroarenes and alcohols. Org Lett 12(21) 4888—4891... 

From a practical point of view, isocyanates, together with carbamates and ureas (Chapter 3), are the most important organic products discussed in this book. Their synthesis from nitroarenes has indeed been the subject of many patents. There are also limited examples of aliphatic isocyanates obtained by this route. Organic mono- and diisocyanates may be prepared in a continues liquid phase method by treating the appropriate amine with phosgene. However, the reaction is rather complex [6] and, besides the use of the dangerous phosgene, the formation of the corrosive hydrochloric acid creates several problems. Aliphatic isocyanates can also be obtained from olefins with isocyanate ion in the presence of a salt of a coordination compound of palladium or platinum [7], from olefins with isocyanic acid in the vapour phase over Pt/ALOs [8], and from formamides, by oxidation over a silver catalyst [9]. Apparently only the last reaction seems to have some potential practical applications [10]. 

For the formation of 45, nitrobenzene would be reduced to aniline by CO/H2O (see Chapter 4.2.). By aldol condensation, an a,p-unsaturated aldehyde is formed. Michael addition of aniline to the unsaturated aldehyde followed by ring closure with dehydration would form 1,2-dihydroquinoline. Oxidation of this last product by nitrobenzene would yield 45. This sequence of reactions is similar to what proposed in Scheme 15. For the formation of 46, an intermediate nitrene was suggested (Scheme 16). Addition of the nitrene to the aldehyde would give an oxaziridine and, correspondingly, an isomeric nitrone. The nitrone would then be reduced by CO to the Schiff base and this, in turn, would be reduced to the amine. Final reaction with one more molecule of aldehyde would lead to 46. Some previously made comments on the formation of Schiff bases from nitroarenes and aldehydes vide supra and Chapter 4.5.) also apply to the first part of this scheme. 

As expected, similar treatment of 3-nitroarenes furnishes mixtures of 4- and 6-substituted 3H-azepines, 54 and 55, respectively.176 Comparable yields of mixed azepines were also obtained by deoxygenation of 3-nitroarenes with alkylphophorous triamides, formed in situ from hexa-methylphosphorous triamide and excess of a secondary amine.66 In a few cases the 3//-azepines were separated by fractional crystallization of their oxalate salts66 but, in general, pure isomers were not isolated and the yields cited in the table were determined by HNMR spectroscopy. 

The deoxygeneration of nitroarenes by trivalent phosphorus compounds in the presence of amines is a useful route to 3/f-azepin-2-amines (cf. compounds 32, Section 3.1.1.4.2.2.). Subsequently, it has been shown, by carrying out the reaction in strongly basic solution, that the process can be extended to the synthesis of 1H-. 3H- and 5//-2-benzazepines from nitronaph-thalenes 43 For example, 1-nitronaphthalenes 3 with dimethyl phosphite in the presence of sodium methoxide and a primary or secondary aliphatic amine, yield the dimethyl 5//-2-ben-zazepin-3-yl phosphonates 4 accompanied, in some cases, by the isomeric 3//-2-bcnzazepin-3-yl phosphonates 5. 

Table 2 shows some Kc values of equilibria like 29 between nitroarenes and aliphatic amines. Even if differences in the mechanism of interactions (as well as differences in experimental conditions, in particular solvents and temperature) make a full comparison difficult, some main points from data of Table 2 are worthy of consideration. 

Catalysed oxidation of primary and secondary amines generally has little synthetic value. Primary amines yield either a mixture of nitriles and amides (ca. 30%) or, in the case of arylamines, the azo derivatives (42-99%) [39], Symmetrical and non-symmetrical azoarenes are also produced in good yields ( 60%) from the reaction of acetanilides with nitroarenes under basic solidtliquid conditions, although higher yields are obtained using TDA-1 [40],... 

Magnesium oxide exhibited high activity and high selectivity in the hydrogen transfer from alcohols to studied nitroarenes. Because of the limited space of the paper the complete amine yield - temperature dependence was shown only for nitrobenzene reduction (Table 1). However, also for other reactants the yield of the aminic product increased continously between the values obtained at the lowest (350°C) and the highest (450°C) reaction temperatures. Below 350°C the complete lack of activity of MgO in the studied transformation was noted. The same was observed by us earlier (ref. 2) in the case the catalytic transfer reduction of other functional groups. 

Selective reduction to hydroxylamine can be achieved in a variety of ways the most widely applicable systems utilize zinc and ammonium chloride in an aqueous or alcoholic medium. The overreduction to amines can be prevented by using a two-phase solvent system. Hydroxylamines have also been obtained from nitro compounds using molecular hydrogen and iridium catalysts. A rapid metal-catalyzed transfer reduction of aromatic nitroarenes to N-substituted hydroxylamines has also been developed the method employs palladium and rhodium on charcoal as catalyst and a variety of hydrogen donors such as cyclohexene, hydrazine, formic acid and phosphinic acid. The reduction of nitroarenes to arylhydroxyl-amines can also be achieved using hydrazine in the presence of Raney nickel or iron(III) oxide. ... 

Various modern products may serve as sources for trace amounts of PAA. The origins, known hazards, release restrictions and environmental fate of PAA derived from azo dyes have been reviewed2. The metabolism of nitroarenes is closely linked to that of aromatic amines, as shown in a simplified way in equation 369. Gloeophyllum trabeum cultures spiked with TNT show formation of nitroaromatic amines such as 2-ami no-4,6-dinitrotoluene, 4-amino-2,6-dinitrotoluene and 2,4-diamino-6-nitrotoluene. Also, autoxi-dation of the methyl group of TNT or its metabolites may take part in the degradation process, as shown by the presence of Schiff bases and oligomeric and polymeric species detection and determination of the analytes after LLE and concentration were by HPLC-UVD or GC-MS70. 

A similarly selective reduction of nitroarenes was achieved under WGS conditions by using [ Ru3(CO)12] in the presence of certain amines, such as diisopropylamine, piperidine, dibutylamine, and triethylamine [146]. Importantly, the latter reaction yielded no unwanted H2 as by-product from a concomitant WGS reaction. 

The reaction of nitroarenes with an excess of nucleophile (RNH2) (without a base) begins with the formation of a zwitterionic complex at the first step. In the presence of nucleophile (RNH2) and base the o-complexes are formed directly. The ratio of or o -complexes depends on the nature of substituents. The complexes, as the key intermediates, can eliminate two electrons and a proton to give rise to the products, while the o -complexes, by loss of an electron and X, can be transformed into the Sn product. The Sn products are formed through selective electrochemical oxidation (lower oxidation potential of the intermediates) or from the compounds. An excess of amine present in the reaction mixture is not oxidized because the oxidation potentials for primary amines are about 1.50 V. The oxidation potential peaks for o-complexes are lower in all cases. Finally, a comparison of chemical [42, 43] and electrochemical oxidation reactions shows that the electro-oxidation is a more convenient process in those cases when the oxidation peak potentials for o -complexes are more positive than 0.6 V. 

In this domino process, first, the nitro group gets reduced to give an amine moiety, which then undergoes a Michael addition to afford an unsaturated ester the final step is the elimination of water to yield 117 [69]. Recently, Banwell et al. applied a domino nitroarene reduction protocol for the total synthesis of 1,5-methanoazocino[4,3-f)]indole 118 framework of the uleine and strychnos alkaloids (Scheme 9.24). Pd/C reduction of nitroarene 119 in methanolic solution afforded annulated indole 120, which presumably arose from the reduction of both nitro and the carbon-carbon double bond. Raney-nickel reduction produced the amine analog 121. However, Raney-cobalt reduction resulted in the tetracyclic compound... 

The only reliable method of introducing a fluoro substituent into an aromatic system is through the diazotisation and subsequent fluorination (Scheme 12) of the appropriate aromatic amine (40), which is in turn generated from the reduction of the nitroarene (39) generated from the nitration of the basic aryl unit (1). However, there are maity simple fluoro-substituted materials that are coimnercially available and so generally the synthesis of most fluoro-substituted target molecules can begin with the fluoro substituents already present. 

Nitroarenes and nitriles could also be employed as amine precursors. In 2010, Li and co-workers reported a ruthenium complex-catalyzed synthesis of tertiary amines by A -alkylation of nitroarenes with alcohols (Eq. 14) [87], In this method, large excess amounts of the alcohols (mostly 7.5 equiv.) are necessary to reduce the nitroarenes to anilines prior to A -alkylation. In 2011, Shi and co-workers also developed an amination reaction for secondary amine synthesis from nitro or nitrile compounds (Eq. 15) [88]. In the same year, Deng and co-workers reported a ruthenium-catalyzed method for tertiary-amine synthesis from nitriles and primary alcohols [89]. In 2013, Beller and co-workers reported another A -alkylation reaction of nitrile compounds with secondary alcohols [90]. 

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