Aryl halides, amination reactions

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

The reaction of amines with aryl halides requires a catalyst in most cases to initiate the reaction. There are several approaches that result in N-aryl amines. Treatment of cyclohexylamine with p-MeC6H4B(OH)2 and Cu(OAc)2 gave the N-aryl amide in 63% yield. Aryl halides react with amines in the presence of palladium... 

Complexes ligated by alkylphosphines had been used rarely as catalysts in cross-coupling chemistry, but several studies suggested that they could catalyze the amination of aryl halides with higher selectivity and activity than catalysts of arylphosphines. Steric hindrance promotes reductive elimination at the expense of /3-hydrogen elimination.54 Therefore, reactions of primary amines and, in... 

Recently, Taillefer et al. reported an Fe/Cu cooperative catalysis in the assembly of N-aryl heterocycles by C—N bond formation [90]. Similarly, Wakharkar and coworkers described the N-arylation of various amines with aryl halides in the presence of Cu—Fe hydrotalcite [91]. Interestingly, Correa and Bolm developed a novel and promising ligand-assisted iron-catalyzed N-arylation of nitrogen nucleophiles without any Cu co-catalysts (Scheme 6.19) [92]. Differently substituted aryl iodides and bromides react with various amides and N-heterocycles. The new catalyst system consists of a mixture of inexpensive FeCl3 and N,N -dimethylethylenediamine (dmeda). Clearly, this research established a useful starting point for numerous future applications of iron-catalyzed arylation reactions. 

In 1995, Hartwig and Buchwald published concurrently their two groups results on tin-free amination of aryl halides [79,80], Instead of isolating or generating a tin amide in situ, the amination reactions were conducted by reacting an aryl halide with the combination of an amine and either an alkoxide or silylamide base (Eq. (5)). These reactions were typically conducted between 80 and 100 °C in toluene solvent. The catalysts used initially were 1, 3, or a combination of [Pd2(dba)3] (Sa) (dba = trans, trans-dibenzylidene acetone) and P(o-C6H4Me)3. Catalysts used subsequently will be described below. As shown in Table 7.1, secondary amines were viable substrates, but primary amines gave substantial yields with... 

The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many substrates will produce high yields of mixed arylamines with one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, imidazoles and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction conditions have been developed for many substrates, the harsh conditions used in many of the applications indicate that continued studies on developing mild condi-... 

In 1995, Hartwig and Buchwald published concurrently their respective groups results on tin-free amination of aryl halides [98, 99]. Instead of isolating or generating a tin amide in situ, the amination reactions were conducted by allowing an aryl halide to react with a combination of an amine and either an alkoxide or silylamide base (Eq. (5)). 

Two groups [127, 128] have reported results on the solid-phase amination of aryl halides using both P(o-C6H4Me)3 and chelating ligands. It has been shown that Stille and Suzuki reactions are reliable, high-yielding processes for substrates loaded on solid supports [129]. Thus, supported aryl halides can now be used to form new C C and C-N bonds, and presumably C S, CP, and CO bonds as well. 

The use of a strong base in the palladium-catalyzed amination of aryl halides precludes the use of many substrates, such as those with aromatic nitro groups or enolizable hydrogens, esters other than tert-butyl esters, and many substrates with base-sensitive stereochemistry such as some protected amino acids and heterocyclic substrates [191]. Thus, conditions that employ milder bases are required. A solution that involves reaction temperatures as low as those used for reactions conducted with sodium tert-butoxide has not been developed. However, carbonate and phosphate bases can be used with certain catalysts at reaction temperatures comparable to those of reactions involving the first- and second-generation catalysts. 

The amine-ligated aryl halide complexes react with alkoxide or silylamide bases to form arylamine products (Eq. (48)) [279]. The reaction of Pd[P(o-C6H4Me)3](HNEt2)(p-Bu, )(Br) and LiN(SiMe3)2 occurred immediately at room temperature to form the arylamine in greater than 90 % yield. Low-temperature reactions conducted in the NMR spectrometer probe allowed direct observation of the anionic halo amido complex Pd[P(o-C6H4Me)3](NEt2)(Ar)(Br) [279]. Thus, one experimentally supported mechanism for gen-... 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

J. F. Hartwig, Palladium-Catalyzed Amination of Aryl Halides and Related Reactions, in Handbook of Organopalladium Chemistry for Organic Synthesis , ed. E. Negishi, John Wiley Sons, Hoboken, NJ, 2002, p. 1051. 

NaNHR, or NaNR2. Lithium dialkylamides also react with aryl halides to give the A-arylamine. With these reagents, the benzyne mechanism generally operates, so cine substitution is often found. The reaction of an amine, an aryl halide, and potassium tert-butoxide generates the A -aryl amine. A -Arylation was accomplished with butyllithium and a secondary amine using Ni/C-diphenylpho-sphinoferrocene (dppf). Ring closure has been effected by this type of reaction, as in the conversion of 16 to the tetrahydroquinoline. 

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