Palladium-catalyzed amination reactions

Reactions of heterocyclic amines 208 with 2-chloro-3-iodopyridine 209 in the presence of a palladium catalyst provide dipyridoimidazole and its benzo- and aza-analogues 210. The synthesis represents the first tandem double palladium-catalyzed amination reaction (Equation 23) <2004CC2466>. 

Scheme 6.58 Palladium-catalyzed amination reactions (Buchwald-Hartwig).

Scheme 6.59 Inter- and intramolecular palladium-catalyzed amination reactions of aryl bromides and triflates.

A structure similar to 104 has been constructed. This alkene 105 undergoes an intramolecular palladium-catalyzed amination reaction to provide the 5,6-disubstituted compounds 1021 and 102m <1998SC3885>. 

The palladium-catalyzed amination reaction with a monofunctional primary amine 167 effects i / -diarylation to afford the tertiary amine polymers 168. Hence, polycondensation of 167 with bifunctional arylene dihalides leads to 168 (Equation (81)). Polycondensation of a primary amine bearing an azobenzene moiety with dibromides in the presence of Pd2(dba)3 (2.5mol%)- Bu3P (P/Pd = 3 l) and NaO Bu at 100°G for 24h in toluene gives 168 in 81-93% yields, as reported by Kanbara. 

Non-Palladium-Catalyzed Amination Reaction without Base (Fig. 2)15... 

Transition metal catalyzed processes are useful tools for the synthesis of functionalized thiophenes. Thus for instance, a phosphine-free, palladium catalyzed coupling protocol for the synthesis of 2-arylbenzo[d]thiophenes from various 3-substituted benzo[6]thiophenes and aryl bromides or iodides has been reported <04T3221>. Likewise, 2,2 -bithiophenes have been 5,5 -diarylated directly with aryl bromides in the presence of Pd(OAc)2, bulky phosphine ligands and CS2CO3 <04T6757>. A series of electron-deficient and relatively electron-rich benzo[6]thienyl bromides have been shown to participate in palladium catalyzed amination reactions, as exemplified by the interesting conversion of 63 to the tetracyclic system 64 upon reaction with 2-aminopyridine 65 <04EJO3679>. 

The palladium-catalyzed amination reaction is developed for the preparation of fluoroanilines from fluorohaloarenes (82 - 98 % yields) and the synthesis of fluoroquinolone antibaeterials including Norfloxacin (58 — 75 % yields). For both sets of substrates, the fluoro-substituent remains intact, thus, the chemoselectivity is quantitative. 

This model study demonstrates the excellent chemoselectivity that the palladium-catalyzed amination reaction provides due to the inability of the catalyst to activate the C-F bond. Furthermore, since nucleophilic substitution is not a viable pathway for the synthesis of these non-flinctionalized substrates, this procedure represents the most general route yet available to simple fluoroanilines. 

The synthesis of fluoroquinoline antibacterials almost invariably involves substitution of the chlorofluoroquinolone with an amine as the final step (Scheme 1). Thus, the above model studies indicate excellent potential for the palladium-catalyzed amination reaction to succeed. However, initial attempts to couple the chlorofluoroquinolone derivative 2 with piperazine using the Pd2dba3/binap catalyst system and NaOtBu in toluene solvent resulted only in the recovery of unreacted starting material. Changing to more polar solvents (DMSO, DMF) or the addition of iodide salts (in an attempt to generate the iodo derivative) had no effect. It was believed that the insolubility of the carboxylic acid 2 played a role in its failure to react and that the ethyl ester would be a more productive substrate. Conveniently, the ethyl ester of 2 is an intermediate in the standard synthesis of Norfloxacin, thus, the synthesis of 13 was readily accomplished (eq 2). ... 

Very few examples of C2-lithiation reactions involving V-aryUndoles are known [258]. In the search for new indolyl phosphine ligands (e.g., 72) for palladium-catalyzed amination reactions, mono-lithiation and di-lithiation reactions involving V-arylindoles have been used (Scheme 15). Beller reported the synthesis of indolyl ligand 72a using a mono-lithiation of V-phenylindole (71a) [277], whereas Nifant ev used a dilithiation of 71b under much colder conditions to give bis (phosphine)indole 72b [278]. 

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. 

The sensitivity of palladium-catalyzed amination reactions towards air is heavily dependent on the properties of the phosphine Ugand. The degassing of solvents is of utmost importance when employing electron-rich phosphines, such as Pt-Bu3, although for some other Ugands the reactions can even be conducted under air, without any significant loss of efficacy. The presence of water is detrimental for only a few selected applications, as evidenced by several reports on C—N bond formation in aqueous media. 

Another route investigated employed a convergent palladium-catalyzed amination reaction (Scheme 8). Compound 25 was readily available via reaction of 21 (Scheme 7) with a methanol solution of ammonia. Unlike compound 21, the amino compound 25 readily undergoes a Heck reaction to produce enol ether 26. Compounds 26 and 27 conld then be combined and exposed to palladium-catalyzed amination conditions, resulting in the formation of the desired compound 23. While the reactions in this approach were efficient and the expectation was that they could be optimized further, the use of two palladium-catalyzed steps was undesirable from a cost/waste perspective, and would presumably increase the challenges associated with removal of residual metals from the process. For this reason, the ronte shown in Scheme 8 was not developed further. 

Table 13.1 briefly summarizes the advantages and disadvantages of commonly used bases for palladium-catalyzed amination reactions. 

This reaction corresponds, in fact, to the application of the classical palladium catalyzed amination reaction of olefins. The above example is of particular interest as it offers a novel entry to bromoindole, a synthon of particular importance for ergot alkaloid and tryptophanes synthesis. 

The application of palladium-catalyzed A -arylation reactions to the synthesis of polymers has attracted considerable attention due to the interesting electronic properties of these materials [6, 8, 11], For example, polyaniline has been utilized in anti-static materials, flexible electronics, and as electromagnetic shielding material. The first application of palladium-catalyzed amination reactions in polymer... 

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