Haloarene amination

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

Selected examples of the reaction of Jt-deficient haloarenes with amines... 

Reaction of jr-deficient haloarenes with ammonia and amines... 

Method C Aqueous NaOH (53%, 4 ml) is added to the haloarene (2.27 mmol), amine (5.11 mmol) and TBA-Br (0.1 g, 0.32 mmol) in MeCN (5 ml) and the mixture is stirred at 40°C for 6 h. The solution is neutralized with aqueous NH4C1 and extracted with CH2C12 (3x10 ml). The dried (MgS04) extracts are evaporated to yield the diarylamine, which is purified by chromatography. 

DPPF-ligated palladium provided nearly quantitative yields for amination of aryl halides with anilines (Eq. (7)). Electron-rich, electron-poor, hindered or unhindered aryl bromides or iodides all participated in the amination chemistry, with only a few exceptions. Nitro haloarenes gave no amination product with aniline substrates,... 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules of biological relevance. The ability to prepare haloarenes selectively by an ortfio-metalation-halogenation sequence allows the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metalation to form aryl halides that were subsequently allowed to react with anilines to form diarylamines (Eq. (34)) [209]. Frost and Mendonqa have reported an iterative strategy to prepare, by the palladium-catalyzed chemistry, amides and sulfonamides that may act as peptidomimetics. Diaryl-amine units were constructed using the DPPF-ligated palladium catalysts, and the products were then acylated or sulfonated with 4-bromobenzoyl or arylsulfonyl chlorides [210]. Le-miere has coupled primary arylamines with 4-chloro-3(2H)-pyridazinones to form compounds with possible analgesic and antiinflammatory properties. 

Aromatic amines are found in biologically active natural products, common pharmaceuticals, dyestuffs, materials with conductive and emissive properties, and ligands for transition-metal-catalyzed reactions. For these reasons much effort has been spent for more than a century on methods to prepare aromatic amines. The synthetic methods to obtain these materials range from classical methods, such as nitration and reduction of arenes, direct displacement of the halogens in haloarenes at high temperatures, or copper-mediated chemistry, as well as modem transition-metal-catalyzed processes and improved copper-catalyzed processes. The following sections describe each of these synthetic routes to aromatic amines, including information on the scope and mechanism of most of these routes to anilines and aniline derivatives. 

The arylation reaction of primary and secondary amines has been investigated using nickel or palladium complexes as catalysts, and bromo- or chloroarenes as arylating agents. Among the complexes tested, the more efficient catalyst is the bis (bipyridyl) nickel (II) bromide, bipy2NiBr2, which affords for example high yields in the arylation of allylamine with /n-bromotrifluoromethylbenzene. The reduction of the haloarene, sometimes observed with the nickel complexes, becomes predominant with palladium catalysts whatever the complex used. 

As previously pointed out, till now few works have been done in the field of arylation using nickel or palladium systems (refs. 5, 7). Only one detailed study (ref. 7) concerns the arylation of amines by haloarenes using nickel (0) or nickel (II) complexes as catalysts with bromobenzene, ammonia does not react and usually the arylation yields (indeed the GC-conversion rates of a tenfold excess of amine into arylamine) are rather low (12-38 %), even if the best results mentionned for dimethylamine and piperidine reach 57-85 % yield. 

The mechanism which can be proposed for the observed reduction is similar to the one indicated for the reduction of a haloarene by an alcohol, catalyzed by the palladium (ref. 12). In the case of a palladium(O) catalysis, the different steps of this mechanism are shown in the following Scheme 3, involving in particular the dehydrogenation of the amine [the same reactions performed without any amine leads to exclusive formation of the reduction product 7 in a very low yield (< 5%). 

The mechanism would proceed through an oxidative addition of the haloarene on a palladium(O) moiety (step a). The palladium(II) species formed in this way reacts with an amine equivalent to lead to an aminopalladiated entity (step b). This last one, after P elimination (step c) (ref. 13) and dissociation of an imine (step d) (ref. 14), leads by reductive elimination (step e) to the in situ reduced aromatic product with regeneration of the catalytically active species (Scheme 3). 

The mechanism of the amines or alcohols arylation catalyzed by nickel(II) complexes has not been elucidated until now (refs. 7, 17), even though the arylation of nucleophiles catalyzed by nickel(0) complexes is better understood. In this last case it is generally admitted that the reaction proceeds by an oxidative addition step, followed by a nucleophilic substitution, and then a reductive elimination of the arylation product (Scheme 4). According to the work of Kochi (ref. 18), the oxidative addition of the haloarene on a nickel(O) complex takes place through a monoelectronic transfer from the metal to the aryl halide with simultaneous formation of a nickel(I) intermediate, the actual catalyst of the reaction (ref. 6). 

Irradiation of haloarenes in the presence of amines in polar solvents promotes electron transfer from the eunine to the excited arene this can be followed by loss of halide from the resulting arene radical anion. Ultimately dehalogenated arenes are obtained. Two new reports of this process have been published, one for 9,10-dlchloroanthracene and the other for hexabromobenzene. ... 

Hartwig was able to show that LiHMDS could serve as both an ammonia equivalent and as the stoichiometric base for the amination reaction catalyzed by Pd(f-Bu)3P.94 The reaction conditions tolerate many aryl bromides and chlorides, but due to the size of LiHMDS, or/Ao-substituted haloarenes are not acceptable. As before, acidic workup reveals the aniline by cleavage of the N-Si bond. 

It is used for making NHCs for metal catalysed a-arylation of acychc ketones, e.g. propiophenones, and amination of haloarenes [Matsubara et al. J Org Chem 72 5069 2007], It has been sirlfonated for making sulfonated anilines, and consequently sulfonated NHCs, which provide water soluble Pd-NHCs used for Suzuki coupling of arylhalides with arylboronic acids in aqueous medium [Fleckenstein et al. Chem Commun 2870 2007],... 

Gattermann reaction A variation of the Sandmeyer reaction for preparing chloro-or bromoarenes by reaction of the diazo-nium compound. In the Gattermann reaction the aromatic amine is added to sodium nitrite and the halogen acid (10°C), then fresh copper powder (e.g. from Zn + CuSOJ is added and the solution warmed. The dia-zonium salt then forms the haloarene, e.g. 

In the 1990s, a breakthrough was independently accomplished by Buchwald [105] (Scheme 1.31) and Hartwig [106] (Scheme 1.32), establishing broadly appU-cable palladium-catalyzed Ullmann-type aminations of haloarenes, employing amines directly as nucleophiles. Thereby, the preparation and use of tin amides could be circumvented, and intramolecular [105] aminations of haloarenes were shown also to occur efficiently. 

These palladium-catalyzed amination reactions of haloarenes are among the most popular modern methodologies for C(sp )-N bond formations. A detailed summary on the state of the art of these (also industrially relevant) reactions, as well as of related arylation reactions of a-C—H acidic compounds, is provided in Chapter 3 by Bjorn Schlummer and Ulrich Scholz. 

For selected recent examples of nickel-catalyzed aminations of haloarenes, see ... 

In many cases, complexes of hindered monodentate alkylphosphines and N-heterocy-clic carbenes are less stable as catalysts for reactions of primary amines than for reactions of secondary amines and are less stable for coupling of halogenated heterocycles, such as pyridines, than they are for coupling of haloarenes. " One factor that could lead to this reduced activity is the displacement of the ligand by the primary amine and the basic heterocycle. This point has been debated, but turnover numbers for coupling of these two classes of substrate have tended to be higher for reactions catalyzed by complexes of bisphosphines. ... 

Indoles can be synthesized via a palladium-mediated intramolecular amination reaction of an appropriately substituted haloarene. This is a specific application of the Buchwald-Hartwig amination reaction that has found use in the synthesis of biologically active natural products. 

The base used is not innocent in the catalytic cycle. Hartwig and Shekhar [390] studied the effects of the anions on the rates of amination reactions catalyzed by Pd(PtBu3)2. Chloroarenes bearing electron-neutral and electron-donating substituents were independent of the concentration of bulky bases, but were dependent on the concentration of less sterically demanding or weaker bases. This fact is explained by the simultaneous oxidative addition to (Pd(PtBu3)] and [(PtBu3)Pd(OR)] observed. On the contrary, electron-poor chloroarenes and bro-moarenes are independent of the concentration of the base. Thus, both the concentration and the type of base used are dependent on the electronic properties of the haloarenes. 

The heterofunctionalization of haloarenes on a solid support is a versatile method to create smaU-molecule libraries of high diversity. Starting with simple resins, aryl amines can be prepared in good to excellent yield by amination of polymer-bound aryl halides employing either the Hartwig or the Buchwald protocol (BINAP or P(o-Tol)3, t-BuONa (Scheme 16) for a review see Ref. Primary and secondary alkylamines... 

For l-carbon-2-haloarenes, such as 2-bromoacetophenone, 2-bromotoluene, 2-bromobenzyl amine, 2-bromobenzaldehyde and so on, in general, they can all be prepared by the halogenation of their parent molecules. 

Nucleophilic aromatic substitution reactions of haloarenes complexed to transition metal moieties with oxygen-, sulfin-, and nitrogen-containing nucleophiles allows for the synthesis of a wide variety of aryl ethers, thioethers, and amines. These metal-mediated reactions proceed under very mild conditions and allow for the incorporation of a number of different functional groups. Nucleophilic substitution reactions of chloroarenes complexed to the cyclopentadienyliron moiety have been the focus of many studies directed toward the design of functionalized organic monomers. ... 

Metal-catalyzed N-arylation of amines with haloarenes (Buchwald-Hartwig coupling) has been developed since the 1990s and provided more efficient access to carbazoles. Nozaki et al. reported the palladium-catalyzed double N-arylation of primary amines with 2,2 -dihalobiphenyls [8], A variety of dihalobiphenyls 10 and anilines 11 with electron-donating or electron-withdrawing substituent(s) are applicable to give multisubstituted carbazoles 12 in moderate to high yields (Scheme 23.4). 

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