Protecting Group‐Controlled Regioselective Synthesis for Unsymmetrical 3,5‐Disubstituted Pyridones

Abstract

Protecting group‐controlled regioselective functionalization of 3,5‐dibromo‐2‐pyridones has been studied for preparation of unsymmetrical 3,5‐disubstituted 2‐pyridones. A bulky di‐tert‐butyl(isobutyl)silyl (BIBS) group was utilized for C5 regioselective arylation in Suzuki‐Miyaura reactions. Meanwhile, the p‐toluenesulfonyl (Ts) group was used to maximize C3 selective halogen‐lithium exchange employing flow chemistry. Most of the reactions proceeded well, with yields of 76 to 95% and excellent regioselectivity. A one‐pot synthesis of unsymmetrical 3,5‐diaryl‐2‐pyridones starting from 3,5‐dibromo‐2‐silyloxypyridine was conducted to demonstrate the practical convenience. Further functionalization onto the remaining bromine group, such as transition metal‐catalyzed C−C and C−N bond‐forming reactions and retro‐Brook rearrangement for C−Si bond formation, was accomplished for synthesis of biologically relevant 3,5‐disubstituted 2‐pyridones. Finally, amrinone and milrinone, commonly used for congestive heart failure, were synthesized in three steps from 3,5‐dibromo‐2‐pyridones in 41% and 56% overall yields, respectively.

Regioselective Ortho‐Arylation of Polyhalo‐Substituted (Hetero)Aryl Tosylates Using an Integrated Continuous Flow/Batch Protocol

“…Recently, we have successfully demonstrated protecting group‐controlled regioselective functionalization of 3,5‐dibromo‐2‐pyridones [15] . The p ‐toluenesulfonyl (Ts) group was employed for the continuous‐flow regioselective C3 functionalization of 3,5‐dibromo‐2‐pyridones.…”

“…We began our study by using 1‐iodo‐4‐methoxybenzene 1 with 3,5‐dibromo‐2‐tosyloxypyridine 2 as a test substrate, given that it contains two competitive bromines in the lithium‐halogen exchange stage (Table 1). Initially, the target lithium‐halogen exchange reaction was attempted by modifying the reaction conditions previously established by our group [15,17] . Then, the subsequent zincation of the resulting organolithium reagent and Negishi coupling reaction was performed using an integrated continuous flow/batch protocol.…”

“…Recently, we have successfully demonstrated protecting group-controlled regioselective functionalization of 3,5-dibromo-2-pyridones. [15] The p-toluenesulfonyl (Ts) group was employed for the continuousflow regioselective C3 functionalization of 3,5-dibromo-2-pyridones. After regioselective halogen-lithium exchange (HLE) of 3,5-dibromo-2-tosyloxypyridine, various electrophiles such as N,N-dimethylformamide (DMF), weinreb amide, aldehydes, ketone, chlorotrimethylsilane, and p-toluenesulfonyl cyande (TsCN) were used to quench the resulting orgnolithium reagent.…”

“…Initially, the target lithium-halogen exchange reaction was attempted by modifying the reaction conditions previously established by our group. [15,17] Then, the subsequent zincation of the resulting organolithium reagent and Negishi coupling reaction was performed using an integrated continuous flow/batch protocol. The use of zinc chloride (2.66 equiv.)…”

“…As part of our ongoing efforts toward regioselective functionalization of (hetero)aryl polyhalides, [15,16] we hypothesized that employing continuous flow chemistry for ortho-zincation of (hetero)aryl tosylates would be the ideal way to achieve the reproducible and rapid preparation of arylzinc reagents and the safe handling of these unstable intermediates. In addition, performing the Negishi coupling reaction under batch conditions at room temperature using the resulting arylzinc reagent would be an effective approach, because it would facilitate setting up and carrying out multiple reactions at once.…”