Synthesis nitroarene reduction

A few type la reductive cycUzations leading to indoles have been reported. A palladium (II) trifluoroacetate catalyst was effective in the reductive cyclization of orfho-nitrostyrenes to 2-substituted indoles <05T6425>. The Batcho-Leimgruber indole synthesis, the reductive cyclization of p-amino-2-nitrostyrenes, was utilized in a synthesis of 5-formylindole <05JHC137>. A partial reduction of a nitroarene provided a route to iV-hydroxyindoles <05AG(E)3736>. Treatment of nitro ketoester 90 with tin chloride in the presence of a primary alcohol nucleophile provided Al-hydroxyindole 93 via hydroxylamine intermediate 91. 

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.

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... 

Stilbenes, photocyclization of, 30, 1 StiUe reaction, 50, 1 Stobbe condensation, 6, 1 Substitution reactions using organocopper reagents, 22, 2 41, 2 Sugars, synthesis by glycosylation with sulfoxides and sulfinates, 64, 2 Sulfide reduction of nitroarenes, 20, 4 Sulfonation of aromatic hydrocarbons and aryl halides, 3, 4 Swem oxidation, 39, 3 53, 1... 

Dohle, W. Staubitz, A. Knochel, P. Mild synthesis of polyfunctional benzimidazoles and indoles by the reduction of functionalized nitroarenes with PhMgCl. Chem. Eur. J. 2003, 9, 5323-5331. 

Tsukinoki, T. Hirohisa, Tsuzuki. Organic Reaction in Water. Part 5. Novel Synthesis of Anilines by Zinc Metal-Mediated Chemoselective Reduction of Nitroarenes, Green Chem. 2001, 3, 37-38. 

Miyake and co-workers (40) have published a synthesis of ellipticine that features a novel reductive phenylation of nitroarenes (41) (Scheme 4). Nitration of 5,8-dimethyl-l, 2,3,4-tetrahydroisoquinoline (22) gave an inseparable mixture of nitro compounds 23. Treatment of this mixture with iron pentacarbonyl and triflic acid in the presence of benzene gave a 2 1 mixture of amines 24 and 25. Separation of these isomers and diazotization of each with nitrous acid, conversion to the azide, and thermolysis yielded ellipticine (1) and isoellipticine (27) (5,11-dimethyl-10f/-pyrido[3,4- )]carbazole), respectively, following Pd/C dehydrogenation of the initially formed nitrene insertion product (e.g., 26). The overall yield of ellipticine is 9%. 

A series of reactions of nitroarenes with triallyl-, trimethallyl- and tricrotylborane have been studied. It has been established that the major process is reductive allylboration of nitro-groups accompanied by an allylic rearrangement. As a result, a new convenient method of the synthesis of N-allylanilines has been elaborated. 

In their quest to synthesize quinolines without the need to involve metalated species as cross-coupling partners, Banwell and coworkers have devised a two-step procedure wherein the first step is the palladium[0]-mediated Ullmann cross-coupling of 1-bromo-2-nitroarenes (e.g. 173) with p-halo-cnals [74]. The resulting p-nitroaryl enal undergoes reductive cyclization, in the style of the Friedlander quinoline synthesis, to give the corresponding quinoline. A wide range of quinolines can be accessed by this method since many l-halo-2-nitroarenes are commercially available and p-halo-cnals such as 174 can be easily prepared by Vilsmeier haloformylation of the appropriate ketones. 

SAMPLE SOLUTION (a) The last step in the synthesis of o-isopropylaniline, the reduction of the corresponding nitro compound by catalytic hydrogenation, is given as one of the three preceding examples. The necessary nitroarene is obtained by fractional distillation of the ortho-para mixture formed during nitration of isopropylbenzene. 

The main synthesis of oxindoles is simple and direct and involves an intramolecular Friedel-Crafts alkylation reaction as the cyclising step. Also straightforward in concept is the displacement of halogen from an ort/to-halo-nitroarene with malonate, this leading to an oxindole after decarboxylation and reduction of the nitro group with spontaneous lactamisation. ... 

Synthesis of ortho alkyl anilines (Rosini) by reductive C-alkylation of nitroarenes. Also synthesis of indoles (Bartoli) by reaction of 2-substituted nitroarenes with vinyl Grignard reagents. 

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. 

Although Nenitzescu is best known for his 5-hydroxyindole synthesis (Chapter 15), he and his colleagues pioneered the reduction and cyclization of ort/jo-p-dinitrostyrenes to indoles. This classic reaction paved the way for other indole ring syntheses involving the reduction of nitroarenes. Nenitzescu described the inaugural reaction in 1925 as shown in Scheme 1, equation 1 [1], The o,p-dinitrostyrene was prepared by the base-catalyzed condensation of... 

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. 

Following the isolation of these complexes, all of the mechanistic studies on the carbonylation and reduction reactions of nitroarenes catalysed by Ru3(CO)i2, even in the presence of several promoters, have focused on the reactivity of these or related clusters [157-164]. Moreover, many studies have been also conducted on analogous osmium [165-172] and iron (see paragraph 6.6.) clusters, including insertion reactions of isocyanates, which yield potential intermediates in the carbonylation reaction (Insertion reaction of other cumulenes into the Ru-N bond will not be discussed here. However, see the paragraph of the synthesis of heterocycles later in this chapter). Although not all of the previously mentioned studies were intended to be a basis for a mechanistic understanding of the reactions here discussed, they still contain a lot of information on the possible transformations of amido or imido moieties on a trinuclear cluster. 

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