Hartwig-Buchwald aromatic amination

Palladium-catalyzed amination of aromatic halides, developed independently by Buchwald and Hartwig, is a useful tool for the construction of C—N bonds. Caravieilhes and coworkers reported using a microreador for aromatic amination [35]. With the use of CPC CYTOS Lab System, the reaction of p-bromotoluene with piperidine gave the desired coupling produd in quantitative yields with a residence time of 7.5 min (Scheme 4.24). 

MAP and its analogues considerably accelerate the Hartwig-Buchwald amination of aromatic and heteroaromatic halides and triflates (eq simiiai- acceleration is observed for Suzuki-... 

The synthesis of 7-azaindoles is a challenging task and there are few efficient routes to substituted derivatives. In the laboratory of C. Thibault, the concise and efficient synthesis of 4-fluoro-1/-/-pyrrolo[2,3-jb]pyridine was achieved. The fluorination was carried out using the Balz-Schiemann reaction. The aromatic amine precursor was prepared via the Buchwald-Hartwig coupling of the aryl chloride with A/-allylamine followed by deallylation. The diazonium tetrafluoroborate intermediate was generated at 0 C and it decomposed spontaneously in 48% HBF4 solution to afford the desired aromatic fluoride. 

The Buchwald-Hartwig amination is an exceedingly general method for generating any type of aromatic amine from an aryl halide or aryl sulfonates.1,2 The key feature of this methodology is the use of catalytic palladium modulated by various electron-rich ligands. Strong bases, such as sodium ferf-butoxide, are essential for catalyst turnover. 

The palladium-catalyzed amination of aryl halides and sulfonates has emerged as a valuable method for the preparation of aromatic amines [2], Numerous ligands and catalysts have been reported to effect this type of cross-coupling. This reaction, known as the Hartwig-Buchwald amination, is shown in Eq. (1). 

You ye seen that palladium catalysis helps form carbon-carbon bonds that are difficult to make using conventional reactions. It can also help form carbon-heteroatom bonds that are difficult to make, and you have already seen some examples in the reactions of re-allyl complexes. Work starting in the 1990s by Buchwald and Hartwig has shown that Pd can be used to promote nucleophilic substitution at a vinylic or aromatic centre—a reaction which would not normally be possible. For example, aromatic amines can be prepared directly from the corresponding bromides, iodides, or triflates and the required amine in the presence of pal-ladium(0) and a strong alkoxide base. 

Transition-metal-catalyzed synthesis of poly(arylene)s via carbon-carbon coupling reactions was started by Yamamoto et al. three decades ago [52,53] since then various carbon-carbon bond formation processes with transition-metal catalysts have been applied to polycondensation [54-57]. In recent years, Buchwald et al. and Hartwig et al. developed Pd-catalyzed amination and etherification of aromatic halides by using bulky, electron-rich phosphine ligands [58-60], and this chemistry has been applied to polycondensation for... 

The synthesis of cyclophane 17 (9,10,ll,12,26,27,28,29-octahydro-3H,8H,16H,20H,25H, 33H-4,7 21,24- dimetheno -13,19,15 30,2,32-di[ 1 ]propane[ 1 ]yl[3Jylidine- 1H, 18H-dipyrimidino [l,2-a l ,6 -o] [l,8,15,22]tetraazacyclo-octacosine) is described. Both isomers of cyclophane 17 were synthesized over nine steps in 46 % overall yield from readily available starting materials. We designed and synthesized a side group for attachment to cyclophane 17, which we wish to use for the directed-complexation of the cyclophane with a specified aromatic guest. We had hoped to use the Buchwald-Hartwig reaction to attach this side arm to the secondary amines of 17, but despite our many efforts we were unable to achieve this goal in a reproducible manner. 

The workers at Sepracor then added the left-hand end of the molecule (we shall call this R ) to the free OH group. The other aromatic ring, already functionalized with the right-hand end of the molecule (we shall call this R ) was coupled as its bromide to the free NH group by a second Buchwald—Hartwig amination reaction process. It s easy to see how this chemistry simplifies the assembly of such a large and complex molecule. 

Nucleophilic aromatic substitution reactions were employed to place amines on pyrimidine and pyrimidinone rings. As a more economical substitute for Buchwald-Hartwig cross-coupling reaction conditions GeUis and collaborators developed a DMAP-catalyzed, microwave-assisted method to form 4-hetero-arylamino-substituted quinazolines (Scheme 33) (14T8257). Treatment of... 

The reaction conditions are similar to the palladium-catalyzed Buchwald-Hartwig amination (see Chapter 3) with one distinct advantage when the base NaOt-Bu used in the Buchwald-Hartwig procedure is replaced with KOt-Bu, the reaction proceeds without the need for a palladium catalyst. Primary and secondary amines, as well as aromatic and aliphatic amines, undergo the amination smoothly however, only meto-substituted aniUnes can be obtained. 

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