Micellar Buchwald–Hartwig Coupling of Aryl and Heteroarylamines for the Synthesis of DNA-Encoded Libraries

Abstract

DNA-encoded libraries are a very efficient means of identifying ligands for protein targets in high throughput. To fully maximize their use, it is essential to be able to carry out efficient reactions on DNA-conjugated substrates. Arylamines are privileged motifs in druglike molecules, and methods for their incorporation into DNA-encoded libraries are highly desirable. One of the preferred methods for their preparation, the Buchwald–Hartwig coupling, does not perform well on DNA conjugates using current approaches. We report the application of our recently developed micellar technology for on-DNA chemistry to the Buchwald–Hartwig reaction. Optimization of conditions led to a robust, high-yielding method for the synthesis of DNA-conjugated aryl and heteroarylamines, which is broad in substrate scope for both the arylamine and the DNA-conjugated aryl halide and is fully compatible with DNA-encoding and decoding procedures. This method will enable the preparation of diverse, high-fidelity libraries of biarylamines.

The Potential of Micellar Media in the Synthesis of DNA‐Encoded Libraries

“…[27,50] Very recently, Waring and co-workers developed a micelle-aided Buchwald-Hartwig amination reaction using [(cinnamyl)PdCl] 2 precatalyst, cBRIDP ligand and tBuOK base (Scheme 7). [28] Initial experiments revealed that the addition of a cosolvent increased the amount of product formed and suppressed dehalogenation of the starting material (similarly to their Suzuki-coupling). The best results were achieved with 5 % DMPU.…”

“…Palladium‐catalyzed cross‐coupling reactions have been widely investigated for the synthesis of DNA‐tagged molecules, however, the demanding reaction conditions often lead to DNA damage [24] . As discussed earlier, DEL compatible micellar Suzuki and Buchwald–Hartwig conditions have been developed by the Waring group [25,28] . Below we discuss the state of the art of other types of prominent cross‐couplings under micellar conditions.…”

“…[ 27 , 50 ] Very recently, Waring and co‐workers developed a micelle‐aided Buchwald–Hartwig amination reaction using [(cinnamyl)PdCl] 2 precatalyst, cBRIDP ligand and t BuOK base (Scheme 7 ). [28] …”

“… [24] As discussed earlier, DEL compatible micellar Suzuki and Buchwald–Hartwig conditions have been developed by the Waring group. [ 25 , 28 ] Below we discuss the state of the art of other types of prominent cross‐couplings under micellar conditions.…”

“…The transition‐metal‐catalyzed carbon‐nitrogen bond formation reactions are also powerful tools to access aromatic amines, [49] and the DEL community have showed significant interest in this transformation as well. [50] Very recently even a micellar example was published, [28] nevertheless, the scope of on‐DNA transition‐metal catalyzed C−N coupling reactions is still limited.…”