The effects of CO₂pressure and pH on the Suzuki coupling of basic nitrogen containing substrates

Abstract

The Suzuki coupling reaction of basic nitrogen containing substrates (2-bromo- and 2-chloro-4-aminopyridine, and 2-bromo and 2-chloropyridine) with phenylboronic acid using Pd(TPP)2Cl2/K3PO4 in acetonitrile-water biphasic solvent systems under a CO2 or a N2 atmosphere is discussed. It was observed that 2-halo-4-aminopyridine produced quantitative yields of coupled products under a CO2 atmosphere while the yields for the 2-halopyridines were poor. In contrast, the yields of coupled products for the 2-halopyridines substrates were quantitative under a N2 atmosphere while only poor yields were realized for the 2-halo-4-aminopyridines under the same conditions. Evidence is presented which suggests that the presence of CO2 alters the pH of the aqueous phase of the reaction system and the accompanying efficiency of the coupling process. Using a series of buffers to adjust the pH of the aqueous phase, the pH dependence associated with the efficiency of the coupling process is illustrated.

Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate Structure

“…It appears that when the pH is allowed to ultimately reach a value of approximately 8.4 during the course of reaction, the highest yields were achieved (Entries 4, 5, 7, and 8, Table ). These observations are consistent with those reported by Senter et al who showed that in an acetonitrile–water solvent system the best yield for this reaction was realized at an aqueous pH of approximately 8.…”

“…These observations are consistent with those reported by Senter et al 71 who showed that in an acetonitrilewater solvent system the best yield for this reaction was realized at an aqueous pH of approximately 8. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Table 9.…”

“…The difference between the yield and conversion was partially due to the formation of 2,2′-bipyridine formed via the homocoupling of 2-bromopyridine (Table S1, SI). Our previous report indicated that the cross-coupling of 2-bromopyridine ( 4 ) with PhB­(OH) 2 using Pd­(TPP) 2 Cl 2 /K 3 PO 4 in acetonitrile–water required a pH of 12 or greater in the aqueous phase to reach the quantitative yield . However, this reaction did not perform as well with the present catalytic system (Pd­(OAc) 2 /K 3 PO 4 /H 2 O) when the initial pH was greater than 12 (Entries 5 and 6, Table ).…”

“…Our previous report indicated that the cross-coupling of 2-bromopyridine (4) with PhB(OH) 2 using Pd(TPP) 2 Cl 2 /K 3 PO 4 in acetonitrile-water required a pH of 12 or greater in the aqueous phase to reach the quantitative yield. 71 However, this reaction did not perform as well with the present catalytic system (Pd(OAc) 2 /K 3 PO 4 /H 2 O) when the initial pH was greater than 12 (Entries 5 and 6, Table 10). The best yields at 50 mL-scale reactions were observed at the initial pH range of 11 -12, when 1.1 or 1.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 19 equivalents of K 3 PO 4 were used.…”

“…The combined organic phase was dried over anhydrous MgSO 4 , filtered, and then concentrated in vacuo. The crude product was analyzed by GC and 1 H NMR following the published methods . The pure product was isolated from a chromatography column packed with silica gel (for the reaction of 4-bromoanisole) or neutral alumina (for reactions containing basic nitrogen centers) using CH 2 Cl 2 –hexane as eluent.…”