Hartwig-Buchwald amination amines

Amines are generally prepared by nucleophilic amination, which is a coupling of carbon electrophiles with a nucleophilic amination reagent, NR2, and Ni and Pd catalyzed reaction of aryl halides with arylamines (Hartwig-Buchwald amination) . Thus, the direct C—N bond formation between carbon nucleophiles and electrophilic nitrogen functionality R2N+ constitutes an example of the umpolung methodology. 

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

Recently, Lautens engineered a silver-promoted domino Hartwig-Buchwald amination/direct arylation access to polycyclic heteroaromatics [195], From substrate 130, a unique a hetero-pentacycle 131 was assembled with a seven-membered ring as its core. 

This section deals with catalyzed aminations in aqueous phases, so the developments discussed here must have some water in the reaction mixture. AH reactions known to synthesize amines via catalysts in the presence of water can be divided into four categories and are discussed in the following order Hartwig—Buchwald aminations, telomerization to yield amines, reductive aminations/hydroamino-methylations, and aUyhc aminations. 

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). 

The mechanism of the Hartwig-Buchwald amination involves three basic steps oxidative addition of the aryl halide to a palladium(O) species, coordination ofa nitrogen atom to the palladium or transmetaUation, and finally, reductive elimination (Scheme 13.1). 

Scheme 13.5 Conformations for monophosphine-Pd complexes in the Hartwig-Buchwald amination [28].

K2CO3 in tBuOH is also a suitable base for substrates bearing ester moieties [54a]. When using liHMDS as base, electrophiles with acidic moieties, such as alcohols, carboxylic acids, and amides, can readily be subjected to the Hartwig-Buchwald aminations with primary amines (Scheme 13.38). 

Most of the catalysts reported for the Hartwig-Buchwald amination with primary amines also work well for cychc secondary amines. Generally, bulky mono- and bisphosphines such as P(oTol)j (29) [16], DPPF (9) [38c], or BINAP (1) [39] have been discovered as viable ligands for such aminations. Similar to the coupling of primary amines, NaOtBu is most often employed as a base, and the same considerations with regard to functional group tolerance need to be taken into account. 

Scheme 13.71 The Hartwig-Buchwald amination for the synthesis of polyaniline derivatives [119],...

Hartwig-Buchwald (amination) LnPd (cal), base Sonogashira... 

The powerful Buchwald-Hartwig aryl amination methodology [135-141] has been applied by Hartwig to the synthesis of N-arylpyrroles (196) [142,143]. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

The Buchwald-Hartwig aryl amination methodology cited above in this section was engaged by Hartwig and others to synthesize N-arylindoles 377 [469]. Carbazole can be N-arylaied under these same conditions with p-cyanobromobenzene (97% yield). Aryl chlorides also function in this reaction. The power of this amination method is seen by the facile synthesis of tris-carbazole 378 [469c]. 

Concurrently with this report from Hartwig, Buchwald and co-workers reported that the system based on commercially available ligand 4 is an excellent catalyst for the coupling of aryl chlorides and primary aliphatic amines, Eq.(103) [42]. 

Despite the success of the original Hartwig-Buchwald protocol, this procedure was not without its drawbacks. The scope was limited to aryl bromide substrates and secondary amine coupling partners, and the requirement of a strong rert-butoxide or amide base meant that substrates with base-sensitive fimctional groups would not be compatible. While this latter constraint has since been obviated by the discovery that weaker bases such as CS2CO3 can promote the reaction, the extension of the scope has required some sophisticated catalyst development (vide infra). 

The Buchwald-Hartwig aryl amination methodology cited above in this section was... 

Several tandem reaction sequences have been developed for indole synthesis featuring a Buchwald-Hartwig aryl amination as one component. For instance, a tandem double JV-arylation of substrate 5 leads to indoles 6 through a cascade of C-N bond forming reactions. A range of structurally and electronically diverse amines can be used successfully in this transformation. 

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