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. 2024 Apr 23;14(19):13095-13099.
doi: 10.1039/d4ra02090a. eCollection 2024 Apr 22.

Regioselective C(sp2)-H halogenation of pyrazolo[1,5- a]pyrimidines facilitated by hypervalent iodine(iii) under aqueous and ambient conditions

Abhinay S Chillal  1 , Rajesh T Bhawale  1 , Umesh A Kshirsagar  1
Affiliations

Regioselective C(sp2)-H halogenation of pyrazolo[1,5- a]pyrimidines facilitated by hypervalent iodine(iii) under aqueous and ambient conditions

Abhinay S Chillal et al. RSC Adv. .

Abstract

An efficient and mild approach has been developed for the regio-selective direct C3 halogenation of pyrazolo[1,5-a]pyrimidines employing readily available potassium halide salts and a hypervalent iodine(iii) reagent at ambient temperature. The protocol is both practical and environmentally friendly, utilizing water as a green solvent, potassium halides as an inexpensive and bench stable halogen source and PIDA as a non-toxic reagent, enabling clean and efficient halogenation at room temperature. The procedure yields a range of C3 halogenated pyrazolo[1,5-a]pyrimidines in good to excellent yields. Mechanistic studies suggest the involvement of electrophilic substitution mechanism in the halogenation process.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Bioactive compounds with pyrazolo[1,5-a]pyrimidine scaffold.
Scheme 1
Scheme 1. Previous work on halogenation of pyrazolo[1,5-a]pyrimidines.
Scheme 2
Scheme 2. Substrate scope for the regioselective halogenation of pyrazolo[1,5-a]pyrimidines and other N-heterocycles. Reaction conditions: 1 (0.2 mmol), KX (0.3 mmol), PIDA (1.0 equiv.), H2O (3.0 mL), rt (25–27 °C), 3 h. Yields are isolated yields. aReactions were carried out in MeOH.
Scheme 3
Scheme 3. Gram scale synthesis.
Scheme 4
Scheme 4. Synthetic application in cross coupling reactions.
Scheme 5
Scheme 5. Control experiments.
Scheme 6
Scheme 6. Plausible reaction mechanism.
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