Chlorinating and Brominating Reagents Suitable for Medicinal Chemistry

The electrophilic halogenation reaction is one of the most used reactions in organic synthesis and pharmaceutical chemistry.¹⁾ Halogen groups not only serve as starting points for coupling reactions but also significantly impact biological activity.²⁾ Along with fluorination, the effect of the chloro group, known as the "magic chloro effect",²⁾ has gathered considerable attentions in recent years.
Conventional halogenation methods have relied on reagents such as elemental halogens, NBS, NCS, TCCA and activation by Lewis acids. However, these methods face challenges in terms of operability and reactivity, particularly when applied to complex compounds or late-stage functionalization, such as pharmaceuticals.
1 is a chlorinating reagent with a guanidine framework and allows for regioselective chlorination under mild conditions.³⁾ Additionally, 2 and 3 are chlorinating and brominating agents respectively with an anomeric amide scaffold.⁴⁾ There are specific advantages for 1 and 2 in that 1 is more affordable than 2, but 2 shows higher reactivity than 1 in most cases. Furthermore, extra additives are not required, so the procedure is just mixing and stirring. So, these reagents enable halogenation of complex bioactive compounds with excellent regioselectivity and yields.

References

• 1) Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
  • D. G. Brown, J. Boström, J. Med. Chem. 2016, 59, 4443.
• 2) “Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery
  • D. Chiodi, Y. Ishihara, J. Med. Chem. 2023, 66, 5305.
• 3) Palau'chlor: A Practical and Reactive Chlorinating Reagent
  • R. A. Rodriguez, C.-M. Pan, Y. Yabe, Y. Kawamata, M. D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 6908.
• 4) Discovery of N-X anomeric amides as electrophilic halogenation reagents
  • Y. Wang, P. S. Baran, et al., Nat. Chem. 2024, 16, 1539.

Related Products

B2414

Bromine

B0656

N-Bromosuccinimide (= NBS)

D1265

1,3-Dibromo-5,5-dimethylhydantoin

C0291

N-Chlorosuccinimide (= NCS)

T0620

Trichloroisocyanuric Acid (= TCCA)

D1783

1,3-Dichloro-5,5-dimethylhydantoin

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