TY - JOUR
T1 - Iridium-catalysed C(sp3)−H activation and hydrogen isotope exchange via nitrogen-based carbonyl directing groups
AU - Knight, Nathan M. L.
AU - Thompson, James D. F.
AU - Parkinson, John A.
AU - Lindsay, David
AU - Tuttle, Tell
AU - Kerr, William J.
PY - 2024/6/10
Y1 - 2024/6/10
N2 - Growing interest in improved structural diversity within the pharmaceutical industry has led to a focus on more sp
3-rich drug frameworks. Meanwhile, spiralling pharmaceutical research and development costs continue to require expedited adsorption, distribution, metabolism, excretion, and toxicity studies, which are heavily reliant on the use of molecules incorporating deuterium and tritium. Herein, we report an iridium catalyzed C(sp
3)−H activation and hydrogen isotope exchange (HIE) methodology capable of utilizing pharmaceutically ubiquitous nitrogen-based carbonyl directing groups. High levels of deuterium incorporation (>80% in 37 of the examples) are demonstrated across a range of substrates (5-, 6-, and 7-membered lactams, cyclic carbamates and ureas, acyclic amides), with tolerance of a range of common functional groups (aryl, alkoxy, halogen, ester, alcohol, sulfonamide) and predictable regioselectivity. The applicability of this methodology was demonstrated with up to 98% deuterium incorporation observed in a range of challenging bioactive molecules such as Nefiracetam, Praziquantel, and Unifiram. Density functional theory has provided mechanistic insight into the C−H activation and HIE at both the expected site of incorporation and an unexpected aryl labelling via a 7-membered metallocyclic intermediate.
AB - Growing interest in improved structural diversity within the pharmaceutical industry has led to a focus on more sp
3-rich drug frameworks. Meanwhile, spiralling pharmaceutical research and development costs continue to require expedited adsorption, distribution, metabolism, excretion, and toxicity studies, which are heavily reliant on the use of molecules incorporating deuterium and tritium. Herein, we report an iridium catalyzed C(sp
3)−H activation and hydrogen isotope exchange (HIE) methodology capable of utilizing pharmaceutically ubiquitous nitrogen-based carbonyl directing groups. High levels of deuterium incorporation (>80% in 37 of the examples) are demonstrated across a range of substrates (5-, 6-, and 7-membered lactams, cyclic carbamates and ureas, acyclic amides), with tolerance of a range of common functional groups (aryl, alkoxy, halogen, ester, alcohol, sulfonamide) and predictable regioselectivity. The applicability of this methodology was demonstrated with up to 98% deuterium incorporation observed in a range of challenging bioactive molecules such as Nefiracetam, Praziquantel, and Unifiram. Density functional theory has provided mechanistic insight into the C−H activation and HIE at both the expected site of incorporation and an unexpected aryl labelling via a 7-membered metallocyclic intermediate.
KW - C−H activation
KW - hydrogen isotope exchange
KW - iridium
KW - lactams
KW - amides
KW - pharmaceuticals
UR - https://onlinelibrary.wiley.com/journal/16154169
U2 - 10.1002/adsc.202400156
DO - 10.1002/adsc.202400156
M3 - Article
SN - 1615-4150
VL - 366
SP - 2577
EP - 2586
JO - Advanced Synthesis and Catalysis
JF - Advanced Synthesis and Catalysis
IS - 11
ER -