Large screening of DNA-compatible reaction conditions for Suzuki and Sonogashira cross-coupling reactions and for reverse amide bond formation

Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries

“…A number of these results indicate that the method is superior to previously published methods, for example, 3-pyridylmethylamine, which gave 98% product ( Table 3 , entry 27), was shown to fail completely using optimised literature conditions. 26 The observation of the methylamide as the only by-product is also advantageous in DEL synthesis as it results in an in situ capping, thus preventing reaction of the carboxylate in subsequent steps. In the event that higher conversions for electron deficient heteroarylamines alone were required, the couplings could be carried out at higher temperature (52 °C), as suggested by the FED.…”

“…A recent study showed that for a range of amines, on-DNA N-to-C amide couplings only gave >70% conversion in 30% of cases. 26 Accordingly, we selected amide couplings between DNA-tagged acids and amine monomers as a highly desirable but suitably challenging application of micelle-promoted DEL synthesis.…”

Functional Group Tolerance of a Micellar on-DNA Suzuki–Miyaura Cross-Coupling Reaction for DNA-Encoded Library Design

“…Crucially, the reaction tolerates all of the functionality that would be desirable in a drug-like DEL, including strong hydrogen bond donors and acceptors, carboxylic acids and their isosteres, amine bases, and a wide variety of heterocyclic systems in both coupling partners. This type of polar functionality has been shown to be problematic in library synthesis previously including in DEL chemistry . We have already demonstrated the scope of the reaction with respect to the off-DNA boronates and the compatibility with encoded library synthesis .…”

DNA-Compatible Suzuki-Miyaura Cross-Coupling Reaction of Aryl Iodides With (Hetero)Aryl Boronic Acids for DNA-Encoded Libraries

“…Due to mild reaction conditions, commercial availability of coupling partners and high chemo-selectivity, the Suzuki–Miyaura cross-coupling reaction is now the second most utilized reaction in the field of medicinal chemistry ( Brown and Bostrom 2016 ), after the amide bond formation reaction. While methods for the Suzuki-Miyaura cross-coupling reaction were reported in the context of DNA-Encoded Library synthesis ( Scheme 1 ) ( Omumi et al, 2011 ; Deng et al, 2015 ; Ding and Clark 2015 ; Litovchick et al, 2015 ; Ding et al, 2016a ; Ding et al, 2016b ; Li and Huang 2018 ; Nicholas et al, 2019 ; Xu et al, 2019 ; Qu et al, 2020 ; Favalli et al, 2021 ), there is a great need to further develop this reaction.…”

“…Very recently Qu et al developed a Pd-mediated Suzuki-Miyaura cross-coupling of DNA-conjugated aryl bromides with potassium Boc-protected aminomethyltrifluoroborate at 95°C ( Qu et al, 2020 ). Most recently Favalli et al reported the Suzuki-Miyaura cross-coupling reaction of DNA-conjugated aryl iodides with (het)aryl boronic acids at 70°C using Pd(OAc) 2 and TPPTS ( Favalli et al, 2021 ).…”