3-Hydroxy-2-(trialkylsilyl)phenyl triflates are presented as new versatile hydroxyaryne precursors. These are base-activated aryne precursors induced via a C-sp-to-O 1,3-Brook rearrangement. The reaction of various arynophiles and 3-trialkylsiloxybenzyne generated from 3-hydroxy-2-(trialkylsilyl)phenyl triflate efficiently afforded highly regioselective phenol derivatives. Furthermore, through crossover experiments, the intramolecular mechanism of silyl migration was demonstrated.
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.
The regioselective ortho arylation of polyhalo‐substituted (hetero)aryl tosylates has been investigated employing an integrated continuous flow/batch protocol. The regioselective ortho metalation of (hetero)aryl tosylates using n‐BuLi and ZnCl2 was effectively achieved using continuous flow chemistry in a short residence time of 10.92 s, without removal of the tosyloxy group. The Pd‐catalyzed Negishi coupling reactions of various (hetero)aryl iodides with the resulting arylzinc species proceeded readily at room temperature in 31% to 98% yields. Finally, the method was applied to the synthesis of perampanel in four linear steps, with an overall yield of 43%.
The continuous flow synthesis of N-sulfonyl-1,2,3-triazoles,
which are convenient reactive azavinyl carbene precursors, for tandem
relay Cu/Rh dual catalysis has been developed. Most reactions readily
proceeded at 75 °C in a short residence time of 13.09 min in
the presence of 2.5 mol % of CuTC. The scope of the reactions was
explored by synthesizing diversely functionalized N-sulfonyl and sulfamoyl triazoles in yields ranging from 92 to 98%.
To demonstrate the scalability of the process, the reaction was conducted
on a 5.4 mmol scale with residence and collection times of 13.09 and
60 min, respectively. Furthermore, a series of controlled experiments
were performed to investigate the compatibility of Cu and Rh in a
batch or a continuous flow system. Finally, the first integrated flow
system using the azavinyl carbene intermediate under the tandem relay
Cu/Rh dual catalysis was developed for the synthesis of various cis-diamino enones from alkynes and sulfonyl azides.
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