Isotope‐Labeled Methanol‐Derived <i>O</i> ‐Alkylisoureas as Versatile and Practical Agents for d ₃ ‐Methylation, ¹³ C‐Methylation, and ¹³ CD ₃ ‐Methylation

ABSTRACT The development of highly efficient and practical methods for the incorporation of stable isotopes into organic molecules are valuable for the pharmaceutical industry. The introduction of deuterium or 13 C atoms can enable the direct tracing of the drug molecule without substantially altering its structure or function, and the introduction of CD 3 ‐ or 13 C‐labeled methyl into drug molecules is one of the most commonly employed methodology. However, the key issue that plagues the current research area is the lack of highly efficient, cheap and practical reagent. Herein, methyl‐d 3 ‐ N,N' ‐diisopropylcarbamimidate (MDIC‐d 3 ), methyl‐ 13 C‐ N,N' ‐diisopropylcarbamimidate (MDIC‐ 13 C) and methyl‐ 13 C‐d 3 ‐ N,N' ‐diisopropylcarbamimidate (MDIC‐ 13 CD 3 ), synthesized via reaction of diisopropylcarbodiimide with the corresponding stable isotope labelled methanols, have been developed for the efficient d 3 ‐methylation, 13 C‐methylation and 13 CD 3 ‐methylation of complex molecules bearing several possible reactive sites with good selectivity, high‐level deuterium and 13 C incorporation, and good functional group tolerance under external base‐free conditions. Additionally, these reagents can also be employed for the highly efficient isotope‐labeled methylation of arenes via palladium‐catalyzed Suzuki–Miyaura type cross‐coupling.