Nitro Halides

The Fx ring is more susceptible to nucleophilic attack than it is to react with electrophiles. Nitro, halides, and suhbnyl groups, in position 3- and 4-, have been reported as moieties that suffer nucleophihc displacement [60,61 ]. Figure 7 depicts some recent examples. 

Only a few of the many aromatic diamino ethers used to prepare macrocycles will be mentioned here. A reduction process has been used to prepare aromatic diamines from nitro- and azide-containing ethers. The preparation of an aromatic diamine using known methods was reported by Glinka (1982), who treated an aromatic nitro halide with hexamethylenetetraamine followed by hydrolysis to give an aromatic nitro amine. The nitro amine was... 

General. Reduces most groups aldehydes, ketones, acids and acid derivatives, nitriles, aliphatic nitro, halides and propargyl alcohols... 

Systems are known which will reduce most of the organic functions (amides, carboxylic acids, nitriles, nitro, halides, double and triple bonds, aromatic rings, for instance). In most cases, the true catalyst is formed in situ by reduction of the metal with the hydride. Actually, very little is known of the mechanisms of those transition metal-assisted hydride reductions. Catalyzed reductions with NaBH4 have been reviewed [7]. 

Aliphatic nitro compounds. These are isomeric with the alkyl nitrites and may be prepared from the alkyl halide and silver nitrite, for example C,H,aBr + AgNOj — C Hj NO + AgBr... 

The diazonium salts 145 are another source of arylpalladium com-plexes[114]. They are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature. In addition, they can be used for alkene insertion in the absence of a phosphine ligand using Pd2(dba)3 as a catalyst. This reaction consists of the indirect substitution reaction of an aromatic nitro group with an alkene. The use of diazonium salts is more convenient and synthetically useful than the use of aryl halides, because many aryl halides are prepared from diazonium salts. Diazotization of the aniline derivative 146 in aqueous solution and subsequent insertion of acrylate catalyzed by Pd(OAc)2 by the addition of MeOH are carried out as a one-pot reaction, affording the cinnamate 147 in good yield[115]. The A-nitroso-jV-arylacetamide 148 is prepared from acetanilides and used as another precursor of arylpalladium intermediate. It is more reactive than aryl iodides and bromides and reacts with alkenes at 40 °C without addition of a phosphine ligandfl 16]. 

Amino-5-nitrothiazole, on treatment with arenesulfonyl halides and dimethylformamide at 140 C, gives (5-nitro-2-thiazolyl)amidme (274) (Scheme 168) (507, 508). The condensation products of the reaction of 2-aminothiazole derivatives with various aldehydes are grouped in Tables... 

Nucleophilic Substitution in Nitro Substituted Aryl Halides... 

NUCLEOPHILIC SUBSTITUTION IN NITRO-SUBSTITUTED ARYL HALIDES... 

One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen... 

In contrast to nucleophilic substitution m alkyl halides where alkyl fluorides are exceedingly unreactive aryl fluorides undergo nucleophilic substitution readily when the ring bears an o or a p nitro group... 

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

The most common types of aryl halides m nucleophilic aromatic substitutions are those that bear o ox p nitro substituents Among other classes of reactive aryl halides a few merit special consideration One class includes highly fluormated aromatic compounds such as hexafluorobenzene which undergoes substitution of one of its fluorines on reac tion with nucleophiles such as sodium methoxide... 

Nitro substituted aromatic compounds that do not bear halide leaving groups react with nucleophiles according to the equation... 

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

The common impurities found in amines are nitro compounds (if prepared by reduction), the corresponding halides (if prepared from them) and the corresponding carbamate salts. Amines are dissolved in aqueous acid, the pH of the solution being at least three units below the pKg value of the base to ensure almost complete formation of the cation. They are extracted with diethyl ether to remove neutral impurities and to decompose the carbamate salts. The solution is then made strongly alkaline and the amines that separate are extracted into a suitable solvent (ether or toluene) or steam distilled. The latter process removes coloured impurities. Note that chloroform cannot be used as a solvent for primary amines because, in the presence of alkali, poisonous carbylamines (isocyanides) are formed. However, chloroform is a useful solvent for the extraction of heterocyclic bases. In this case it has the added advantage that while the extract is being freed from the chloroform most of the moisture is removed with the solvent. 

A mechanism of this type permits substitution of certain aromatic and ahphatic nitro compounds by a variety of nucleophiles. These reactions were discovered as the result of efforts to explain the mechanistic basis for high-yield carbon alkylation of the 2-nitropropane anion by p-nitrobenzyl chloride. p-Nitrobenzyl bromide and iodide and benzyl halides that do not contain a nitro substituent give mainly the unstable oxygen alkylation product with this ambident anion ... 

Aryl bromides were also perfluoroethylated under these conditions [205] The key to improved yields was the azeotropic removal of water from the sodium perfluoroalkylcarboxylate [205] Partial success was achieved with sodium hepta-fluorobutyrate [204] Related work with halonaphthalene and anthracenes has been reported [206 207] The main limitation of this sodium perfluoroalkylcarboxylate methodology is the need for 2 to 4 equivalents of the salt to achieve reasonable yields A trifluoromethylcopper solution can be prepared by the reaction of bis(tri-fluoromethyl)mercury with copper powder in /V-methylpyrrolidone (NMP) at 140 °C [208] (equation 138) or by the reaction of N-trifluoromethyl-A-nitro-sotnfluoromethane sulfonamide with activated copper in dipolar aprotic solvents [209] This trifluoromethylcopper solution can be used to trifluoromethylate aro matic [209], benzylic [209], and heterocyclic halides [209]... 

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