Haloaromatic coupling reaction amines

Since Pd(ll) catalysts along with an appropriate ligand have been used in the coupling reactions of organozinc reagents with haloaromatic amines and alcohols [142], it seemed reasonable to try these conditions. The coupling reactions worked well with 2-pyridylzinc bromide (la), and the results are summarized in Table 3.37. The reaction of PI with 4-iodoaniline in the presence... 

Preparation and Cross-Coupling of2-Pyridyl and 3-Pyridylzinc Bromides 89 Table 3.37 Coupling reaction with haloaromatic amines. 

The reaction of PI with 4-iodoaniline in the presence of lmol% Pd(PPhs)4 provided 2-(4-aminophenyl)pyridine (8a) with similar results (89% isolated yield, Table 3.37, entry 6). 3-lodoaniline and 2-iodoaniline were also coupled with PI under the same conditions (Table 3.37, condition C), affording the aminophenyl pyridines (8d and 8e) in 64% and 74% isolated yields, respectively (Table 3.37, entries 7 and 8). Another successful coupling reaction (Table 3.37, entry 9) was achieved from a sterically hindered 3-methyl-2-pyridylzinc bromide (P2), resulting in 68% isolated yield with the formation of 8f. Unfortunately, no satisfactory coupling reaction occurred with 4-bromoaniline using the Pd(0) catalyst (Table 3.37, entry 10). With the results obtained from the coupling reactions with haloaromatic amines, it can be concluded that the Pd(0)-catalyzed reaction of 2-pyridylzinc bromides works effectively with iodoaromatic amines and also the relatively more reactive bromoaromatic amines. 

Many pharmacologically active compounds have been synthesized using 5-bromoisoquinoline or 5-bromo-8-nitroisoquinoline as building blocks.6 7 8 9 10 11 The haloaromatics participate in transition-metal couplings 81012 and Grignard reactions. The readily reduced nitro group of 5-bromo-8-nitroisoquinoline provides access to an aromatic amine, one of the most versatile functional groups. In addition to N-alkylation, TV-acylation and diazotiation, the amine may be utilized to direct electrophiles into the orthoposition. 

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