Arylamine is a ubiquitous structural element in natural products and synthetic substances. The traditional synthetic methods for construction of the arene-nitrogen linkage of arylamines are abundant albeit with many limitations. Encouraging results on preparation and synthetic application of arylamines have emerged during the last decade. The metal-catalyzed amination and microwave-assisted metal-free amination are most promising....[ Read more ]

Arylamine is a ubiquitous structural element in natural products and synthetic substances. The traditional synthetic methods for construction of the arene-nitrogen linkage of arylamines are abundant albeit with many limitations. Encouraging results on preparation and synthetic application of arylamines have emerged during the last decade. The metal-catalyzed amination and microwave-assisted metal-free amination are most promising.

Following a brief overview on different approaches toward amination on aromatic rings in Chapter 1, the Pd-catalyzed amination of aryl chlorides with anilines by the simple amide-derived P,O-ligands (Aphos ligands) is presented in Chapter 2. The Aphos ligands were recently developed by our group and demonstrated excellent catalytic efficiency in the Pd-catalyzed Suzuki cross-coupling of aryl bromides and chlorides. The Aphos ligands were synthesized via a one-pot process in good yields by conventional purification procedures in open air. It was found that efficiency of the Aphos ligands in the Pd-catalyzed amination of 1-chloro-2-nitrobenzene with substituted anilines correlated both with the amide scaffold and the phosphorus substituent. Balanced steric and electronic effects were essential since the benzamide-derived t-Bu-Aphos 42b afforded the best results. By using the Pd-42b catalyst system, aminations of both electron-rich and electron-deficient anilines with a series of aryl chlorides possessing -NO₂, -CN, -C(O)Me, -CO₂Me, and -SO₂Me group(s) were examined, providing the desired amination products in good to excellent yields except for the case of 1-chloro-3-nitrobenzene. Efforts were also made for selective amination of activated aryl chlorides with 2-, 3-, and 4-aminophenols in the presence of Pd-42b with success to some extent. The major remained issues are the low conversion and, in some cases, formation of the O-arylation by-products of the aminophenols. As a demonstration of synthetic applications of the amination products, the diarylamines containing a 2-nitro group were transfomed into benzimidazoles, capable of introducing three points of diversity, by NO₂ reduction and subsequent condensation with acyl chlorides.

In Chapter 3, design and synthesis of a novel series of N,N'-tethered aniline dimers are described in connection with development of NMDA receptor antagonists. The synthesis was based on the Pd-catalyzed amination of aryl bromides and chlorides with α,ω-diamines of 3-10 methylene groups. However, it was found that the desired aniline dimers could not be formed under conventional themal heating. In contrast, acceptable yields of 45-60% were obtained for the Pd-catalyzed aminations of 1-bromo-2,4-dimethoxybenzene with α,ω-diamines of 3-10 methylene groups under controlled microwave heating at 180 ℃ for 3 min. Variation in the amination yields was observed for various aryl bromides and chlorides but the microwave-heated Pd-catalyzed amination reliably provided the N,N'-tethered aniline dimers for biological assay. Several promising candidates of NMDA receptor antagonists were identified as a result of the synthetic efforts.

The last two chapters involve applications of microwave-assisted organic synthesis (MAOS). In Chapter 4, the microwave-assisted nucleophilic aromatic amination was studied in order to establish the nature of the activation group enabling metal-free amination of aryl chlorides. It was found that aryl chlorides possessing 2- or 4-NO₂, 4-CN, 4-SO₂Me, 4-SO₂Ph, 4-C(O)Me, and 4-CHO underwent amination with secondary alkyl amines such as piperidine under microwave irradiation at 200-250 ℃ to afford the products in 66-99% yields. Amination on chlorinated heterocycles, including pyridine, pyrimidine, quinoline, benzoxazine, and acridine was also possible. However, metal-free amination of both electron-rich and electron-deficient anilines with 1-chloro-2-nitrobenzene failed under controlled microwave heating even at 250 ℃. Finally, as an extension of microwave-assisted synthesis, a one-pot regioselective synthesis of a small library of 2-alkyl-3,4-dihydro-3-oxo-2H-1, 4-benzoxazines was developed, starting from 17 commercially available 2-amininophenols. The synthesis was carried out in NMP in the presence of DBU and under controlled microwave heating at 180 ℃ for 3 min to furnish the targeted products in 44-82% yields.