Reduction nitroarenes

Nitroarenes reduction to arenamines, 253 reductive V,.V-coupling, 305 Nitrofurantoin, 308... 

Reductions of aromatic nitro compounds provide a simple and general access to various heterocyclic compounds through the domino process (Scheme 9.23). Quinolines are important skeletal moieties present in various natural products and biologically active compounds [58]. Most common methods of their preparation involve condensation of o-amino benzaldehydes with an enolizable carbonyl compound (Friedlander synthesis) [59]. Miller et al. [60] reported an efficient synthesis of quinolines 109, in which a reduction of o-nitroaryl carbaldehyde by SnCl2 followed by condensation with an enolizable carbonyl compound in the presence of ZnCl2 yielded 109 through a domino process. In 2001, Bunce et al. [61] reported a domino nitroarene reduction/reductive amination sequence for the preparation of tetrahydroquinoline-4-carboxylic ester 110 with excellent yields. 

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... 

Scheme 9.23 Nitroarene reduction initiated domino process in various heterocycles synthesis.

Additionally, Tomkinson and coworkers have shown that traditional nitroarene reduction is equally effective for the preparation of similar compounds. 

The reaction described in eq. 8 is promoted by bases, with tertiary amines being often used [220]. Since some base is always added in all catalytic reactions, it has also been suggested that H2Se is in equilibrium with the deprotonated forms HSe and Se and that these last species may be the ones responsible for nitroarene reduction [213], Since no mechanistic study has been conducted on the selenium-catalysed reductive carbonylation of nitroarenes, we will not discuss the details of the mechanistic pathway. However, the occurrence of the reactions described by eqs. 7-10 appears to be well based. The reduction of nitroarenes by CO/H2O (see Chapter 4) and the oxidative carbonylation of amines by CO/O2 [218] have both been reported to be catalysed by selenium under conditions similar to those employed in the reactions here discussed. 

However, whereas the reaction of the anionic hydride is probably a correct description for the reactivity of Fe(CO)s (see Chapter 6), the dihydride is unlikely to react with nitroarenes and the generality of the role of hydride reagents as the active species for nitroarene reduction is highly questionable (see Chapter 6). 

The activity of this catalytic system is very high. Although comparisons between data collected in different laboratories should be made with caution, it appears that [PPN][Rh(CO)4] is the most active homogeneous catalyst ever reported for the reduction of nitrobenzene to aniline. In the paper, only forcing conditions were used, in order to reach the highest turnover frequencies. However, we have observed in model studies that nitroarenes reduction to anilines with this catalyst can occur even at room temperature and atmospheric CO pressure. So the reaction appears to be very versatile and easily tuneable depending on the activities required and the apparatus available. 

Nitroarene reductases catalyze the reduction of nitroarenes. They are flavoprotein (FMN) enzymes (Blehert et al. 1999) and are of two types ... 

Type 1 are 02-insensitive six-electron reductases that catalyze the sequential reduction of nitroarenes to nitroso, hydroxylamino, and amino arenes. They are encoded in E. coli by NfsA for the major enzyme and NfsB for the minor (Rau and Stolz 2003), and are also important in establishing resistance to nitrofuran drugs (Koziarz et al. 1998). 

Nitrotoluenes including 2,4,6-trinitrotoluene (TNT) are important components of explosives and several nitroarenes including the antibacterial nitrofurans have established mntagenicity (Purohit and Basu 2000). Substantial effort has been directed to the degradation of nitroarenes, and to their reduction to amines. Although nitroarene reductases, noted in Chapter 3, Part 3, are distribnted in a range of biota, the products may not necessarily represent intermediates in the degradation... 

Reduction of nitroarenes has been demonstrated in species of Clostridium and Eubacte-rium, and was associated with the reduction in the mutagenic activity of 1-nitropyrene, and... 

Partial reduction to hydroxylamines may also be involved in the degradation of nitroarenes ... 

Scheme 2.5 Products formed in the transfer hydrogenation reduction of nitroarenes by complex 35...

The Bunce group disclosed a straightforward domino process for the construction of aryl-fused nitrogen heterocycles by employing a combination of a reduction and a Michael addition [20]. The transformation involves an initial Fe-mediated reduction of nitroarenes 7-38, furnishing an aniline which undergoes a subsequent... 

As discussed in Chapter 9, various nucleophiles can be introduced at the ortho position of nitroarenes via the VNS process. This provides a useful strategy for the synthesis of indoles. One of the most attractive and general methods of indoles and indolinones would be the reductive cyclization of a-nitroaryl carbonyl compounds (Eq. 10.54). The VNS and related reactions afford a-nitroaryl carbonyl compounds by a simple procedure. For example, alkylation of 4-fluoronitrobenzene with a lactone silyl enol ether followed by reductive cyclization leads to tryptophols (Eq. 10.55).73... 

The cyanomethylation of nitroarenes followed by alkylation and reductive cyclization yields indoles (see Chapter 9, which discusses the VNS reactions) (Eq. 10.56).74... 

Tandem reduction-Michael addition using suitably substituted nitroarenes provides a general route to aryl-fused nitrogen heterocycles (Eq. 10.79).135... 

Nitrosoarenes are readily formed by the oxidation of primary N-hydroxy arylamines and several mechanisms appear to be involved. These include 1) the metal-catalyzed oxidation/reduction to nitrosoarenes, azoxyarenes and arylamines (144) 2) the 02-dependent, metal-catalyzed oxidation to nitrosoarenes (145) 3) the 02-dependent, hemoglobin-mediated co-oxidation to nitrosoarenes and methe-moglobin (146) and 4) the 0 2-dependent conversion of N-hydroxy arylamines to nitrosoarenes, nitrosophenols and nitroarenes (147,148). Each of these processes can involve intermediate nitroxide radicals, superoxide anion radicals, hydrogen peroxide and hydroxyl radicals, all of which have been observed in model systems (149,151). Although these radicals are electrophilic and have been suggested to result in DNA damage (151,152), a causal relationship has not yet been established. Nitrosoarenes, on the other hand, are readily formed in in vitro metabolic incubations (2,153) and have been shown to react covalently with lipids (154), proteins (28,155) and GSH (17,156-159). Nitrosoarenes are also readily reduced to N-hydroxy arylamines by ascorbic acid (17,160) and by reduced pyridine nucleotides (9,161). 

The reduction of nitroarenes to azoxy compounds ArN=N(0)Ar is promoted by bismuth trichloride/powdered zinc427. Aromatic amines are formed in excellent yields in the reduction of nitroarenes with BH3/NiCl2428 or nickel boride429. Acyl, ester, amide and cyano groups are not affected. Reaction of the nitro compounds RCH2N02 (R = Ph, Bz... 

Interestingly, the photoreaction of indene with nitroarenes gives good yields of coupling products as shown in equation 62 (66% from 2-nitrothiophene and 52% from 2-nitrofurane). Nitrobenzene gives the reduction product. Strangely there is no reaction for p-nitrotoluene with indene. 

Nitroarenes are reduced to anilines (>85%) under the influence of metal carbonyl complexes. In a two-phase system, the complex hydridoiron complex [HFe,(CO)u]2-is produced from tri-iron dodecacarbonyl at the interface between the organic phase and the basic aqueous phase [7], The generation of the active hydridoiron complex is catalysed by a range of quaternary ammonium salts and an analogous hydrido-manganese complex is obtained from dimanganese decacarbonyl under similar conditions [8], Virtually no reduction occurs in the absence of the quaternary ammonium salt, and the reduction is also suppressed by the presence of carbon monoxide [9], In contrast, dicobalt octacarbonyl reacts with quaternary ammonium fluorides to form complexes which do not reduce nitroarenes. 

In many respects the apparently analogous reduction of nitroarenes with triruthenium dodecacarbonyl under basic phase-transfer conditions is superior to that of the iron carbonyl-mediated reductions. However, the difference in the dependence of the two processes on the concentration of the aqueous sodium hydroxide and the pressure of the carbon monoxide suggests that they may proceed by different mechanisms. Although the iron-based system is most effective under dilute alkaline conditions in the absence of carbon monoxide, the use of 5M sodium hydroxide is critical for the ruthenium-based system, which also requires an atmosphere of carbon monoxide [11]. The ruthenium-based reduction has been extended to the... 

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