2- pyridylzinc bromide coupling reaction

Prior to the Pd-catalyzed coupling reaction with a variety of aryl halides, a preliminary test was performed using a Pd(0) catalyst to find any effect of substituents in the C—C bond forming reactions. Several different types of 2-pyridylzinc bromides (Table 3.32, P1-P6) were coupled with 3-iodothiophene in the presence of 1 mol% of Pd(PPhs)4 in THF at rt, and the results are summarized in Table 3.32. In general, good yields (Table 3.32, entries 1, 3, and 4) were obtained from using 2-pyridylzinc bromide (PI), 4-methyl-2-pyridylzinc bromide (P3), and 5-methyl-2-pyridylzinc bromide (P4). Reactions with 3-methyl-2-pyridylzinc bromide (P2), 6-methyl-2-pyridylzinc bromide (P5), and 6-methoxy-2-pyridylzinc bromide (P6) resulted in moderate yields (Table 3.32, entries 2, 5, and 6). 

Additionaly, less reactive atyl triflates react with arylzincs by method A furnishing the biaryls in excellent yields. Once again, the triflate involving reaction was accomplished in the presence of lithium chloride or bromide as mediators. These in situ generate appropriate more reactive aryl bromides or chlorides from the parent triflate, and thus accelerate the cross-coupling reaction with arylzinc. For instance, the reaction of 2-pyridylzinc chloride (145) with 3-methylpyridyl triflate (146) gave 3-methyl-2,2 -bipyridin (147) in 98% yield [51], respectively. Scheme 13. 

Table 3.30 Coupling reaction of 2-pyridylzinc bromide (PI) with benzoyl chlorides. ... 

Preparation and Cross-Coupling of2-Pyhdyl and 3-Pyridylzinc Bromides 83 Table 3.33 Steric effect on cross-coupling reaction. 

Preparation and Cross-Coupling of2-Pyridyl and 3-Pyridylzinc Bromides 85 Table 3.35 Coupling reactions of P2 P6 with heteroaryl halides. 

As described in many previous reports, bipyridine units are very important for many natural products as well as many molecules used in material chemistry [141]. Significantly, this structural moiety can be readily prepared utilizing 2-pyridylzinc bromides. As described in Table 3.36, not only symmetrical 2,2 -bipyridine (7a) but also several different types of unsymmetrical 2,2 -bipyri-dines (7b-7h) were prepared in moderate yields. Again, the coupling reaction was completed in the presence of lmol% Pd(PPh3)4 in THF at rt, and, in general, 3-methyl-2-pyridylzinc bromide (P2) and 6-methyl-2-pyridylzinc bromide (P6) produced 2,2 -bipyridines, 7e and 7h, in low yields (Table 3.36, entries 5 and 8). It should be emphasized that the preparation of bipyridines using readily available 2-pyridylzinc bromides (P1-P6) could be a very practical approach because considerable effort has been directed toward the preparation of unsymmetrical 2,2 -bipyridines. 

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... 

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. 

Interestingly, unsymmetrical amino-bipyridines were produced from the coupling reactions of 2-pyridylzinc bromides with halogenated aminopyri-dines under the conditions used previously. As shown in Scheme 3.11, 2-amino-5-iodopyridine reacted with PI to afford 2,3-bipyridine (s2a) in 59% isolated yield in the presence of lmol% of Pd(PPhs)4 catalyst (route A, Scheme 3.11). 

Table 3.39 Pd-catalyzed coupling reactions of 3-pyridylzinc bromide (P7).

The first approach included the reaction of 3-pyridylzinc bromide (P7) with iodoaniline in the presence of 1% of Pd(OAc)2 along with 2% of SPhos in THF (Table 3.42, entry 1). The coupling reaction was completed at rt in 30 min, affording 4-pyridin-3-yl-phenylamine (13a) in 80% isolated yield. Even though a little longer reaction time was required, the coupling product (13a) was also... 

We have demonstrated a practical synthetic route for the preparation of 2-pyridyl and 3-pyridyl derivatives. It has been accomplished by utilizing a simple coupling reaction of readily available 2-pyridylzinc bromides and 3-pyridylzinc bromides, which were prepared via the direct insertion of active zinc to the corresponding bromopyridines, or they can be purchased (Rieke... 

In 2010, Andreas Leitner and coworkers [174] at BASF reported the preparation of a very stable 2-pyridylzinc bromide (an sp organometallic nucleophile) on a multi-kilogram scale using Rieke technology and its application in the Negishi-Baba cross-coupling reaction. 

In a typical reaction (Scheme 69), 2- or 3-bromo-6-methoxypyridine is lithiated in THF with rerf-butyllithium in THF at - 78°C. Low temperature and a bulky lithiating reagent are used to limit (or avoid) the tendency for adduct formation between the 7r-deficient heterocycles and the reagent. The lithiated species is reacted in the cold with zinc chloride to form the zincated derivative (299). 3-Bromo-2,6-dimethylpyridine, a benzenoid bromide, is zincated by heating in THF with magnesium, and the metal-metal exchange is effected by zinc chloride (300). The pyridylzinc chlorides can be coupled with 3-bromo- or iodo-2-quinolines using Pd-... 

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