The copper-catalyzed reaction of aryl aldehydes with 2-iodobenzylcyanides afforded 2-aryl-3-cyanobenzofurans in isolated yields of up to 74% in a cascade manner, which involves Knoevenagel condensation, aryl hydroxylation, oxa-Michael addition, and aromatization reactions. Conversely, 2-halo benzaldehydes as reacting partners with 2-iodobenzylcyanide regioselectively furnished dibenzo[ b,f]oxepine-10-carbonitrile derivatives up to 85% isolated yields via tandem Knoevenagel condensation, aryl hydroxylation, and Ullmann coupling reactions.
Remdesivir, an inhibitor of RNA-dependent
RNA polymerase developed
by Gilead Sciences, has been used for the treatment of COVID-19. The
synthesis of remdesivir is, however, challenging, and the overall
cost is relatively high. Particularly, the stereoselective assembly
of the P-chirogenic center requires recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate mixture several times to obtain
the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety
of chiral bicyclic imidazoles were synthesized as organocatalysts
for stereoselective (S)-P-phosphoramidation employing
a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the
coupling reagent to avoid a waste of the other diastereomer. Through
a systematic study of different catalysts at different temperatures
and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9
ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived
carbamate was utilized in the reaction at −20 °C. A 10-g
scale one-pot synthesis via a combination of (S)-P-phosphoramidation
and protecting group removal followed by one-step recrystallization
gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst
was recovered in 83% yield for reuse, and similar results were obtained.
This one-pot process offers an excellent opportunity for industrial
production of remdesivir.
The synthesis of some dibenzo[b,f]‐[1,8]naphthyridine derivatives in a cascade manner is reported. The reaction includes a Knovenagel condensation, the insertion of a nitrile and an alkyne into an N–H bond and an oxidation/oxidative C–C bond cleavage sequence in the presence of copper iodide. The key 1,8‐naphthyridine core was constructed in a cascade manner during the course of the reaction itself which allows diverse dibenzo[b,f]‐[1,8]naphthyridine derivatives to be readily prepared.magnified image
An approach for the synthesis of functionalized unsymmetrical 1,3-butadiene-3-yne derivatives is reported starting from b-halo styrene and phenyl acetylene derivatives in the presence of PdCl 2 and CuI catalysts.Functional groups such as aldehyde, cyano and ester groups are well tolerated and afford the desired functionalized dienynes. Further, these 1,3-buta-diene-3-yne derivatives are utilized for the synthesis of novel trisubstituted pyridine derivatives.
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