BF3@K10: An Efficient Heterogeneous Montmorillonite Catalyst for the Halogenation of N-Heterocycles

Az-eddine El Mansouri; Saida Lachhab; Ahmad Mehdi; Mustapha Ait-Ali; Yogesh S. Sanghvi; M. Zahouily; Hassan B. Lazrek

doi:10.1055/a-2212-7627

Synlett, Table of Contents

Synlett 2024; 35(06): 665-671
DOI: 10.1055/a-2212-7627

cluster

Special Issue to Celebrate the Centenary Year of Prof. Har Gobind Khorana

BF₃@K10: An Efficient Heterogeneous Montmorillonite Catalyst for the Halogenation of N-Heterocycles

Az-eddine El Mansouri

^aChemistry Department, University of the Free State, P.O. Box 339, Bloemfontein 9300, South Africa

,

Saida Lachhab

^bLaboratory of Molecular Chemistry, Faculty of Science Semlalia, Cadi Ayyad University, Marrakesh, Morocco

,

Ahmad Mehdi

^cICGM, ICGM, UMR5253 1919, Route de Mende 34293 Montpellier cedex 5, France

,

Mustapha Ait-Ali

^bLaboratory of Molecular Chemistry, Faculty of Science Semlalia, Cadi Ayyad University, Marrakesh, Morocco

,

Yogesh S. Sanghvi

^dRasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, USA

,

M. Zahouily

^eLaboratoire de Matériaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculté des Sciences et Techniques, Université Hassan II, Casablanca 20650, Morocco

,

Hassan B. Lazrek∗

^bLaboratory of Molecular Chemistry, Faculty of Science Semlalia, Cadi Ayyad University, Marrakesh, Morocco

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Abstract

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Honoring the contributions of the late Har Gobind Khorana in nucleic acid chemistry.

Abstract

Halogenated N-heterocycles are an essential structural building block in medicinal chemistry. Herein, we describe an economical and efficient protocol for the regioselective halogenation of several N-heterocycles (pyrimidines, a pyrazole, 2-aminopyridine, theophylline, and an imidazo[1,2-a]pyridine) with BF₃-doped montmorillonite (BF₃@K10). The new catalyst was characterized by FTIR and ¹¹B NMR spectroscopy, XRD, SEM, and EDS. The developed strategy provides easy and fast access to iodo-, bromo-, and chloro-N-heterocycles under mild conditions. This method was used to synthesize nine new halogenated pyrimidine derivatives. The reaction is simple and general, affording good to excellent yields of products under conventional heating or microwave conditions in the presence of BF₃@K10 as an ecofriendly, inexpensive, and efficient catalyst. This protocol is clearly superior to the conventional route because it offers short reaction times, high yields, and easy workup.

Key words

halogenation - heterogeneous catalysis - solid catalysts - montmorillonite K10 - nitrogen heterocycles

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References

References and Notes

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25 Synthesis of BF₃@K10: K10 clay (1.2 g) was dispersed in dichloromethane (10 mL). Subsequently, BF₃OEt₂ (400 mg) was added dropwise to the mixture at 0 °C under stirring. The mixture was then stirred at room temperature for 1 h, at the end of which the dichloromethane was evaporated under reduced pressure to obtain BF₃@K10. Typical procedure for the transformation of 2-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (1b) with conventional heating: A mixture of pyrimidine 1b (0.2 mmol), N-halosuccinimide (0.22 mmol), and BF₃@K10 (60 mg) in acetonitrile (3 mL) was heated at 60 °C for 4 h. The mixture was then cooled, the catalyst was recovered by filtration and washed with acetone and dichloromethane, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography with a methanol/dichloromethane mixture as the eluent to obtain the corresponding halogenated product 3b. Typical procedure for the transformation of 2-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (1b) with microwave activation: A mixture of pyrimidine 1b (0.2 mmol), N-halosuccinimide (0.22 mmol), and BF₃@K10 (60 mg) in acetonitrile (3 mL) was placed in a closed pressure vessel and heated to 100 °C (400 W) for 10 min in a microwave. The mixture was then cooled, the catalyst was recovered by filtration and washed with acetone and dichloromethane, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography with a methanol/dichloromethane mixture as the eluent to obtain the corresponding halogenated product 3b: R_f = 0.34 (CH₂Cl₂/MeOH, 9.9:0.1); mp 235–237 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.107 (s, 2 H, CH₂), 7.43 (d, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.50 (t, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.83 (t, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.87 (d, ³ J _H-H = 7.6 Hz, 1 H, H_Ph), 8.17 (s, 1 H, H-6), 11.68 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 50.53 (CH₂), 107.62 (C-5), 111.03 (C_Ph), 117.59 (CN), 128.51 (C_Ph), 128.97 (C_Ph), 133.77 (C_Ph), 134.04 (C_Ph), 142.25 (C_Ph), 143.36 (C-6), 150.66 (C-2), 159.92 (C-4). IR (KBr): 3420 (NH), 3041 (Csp2H), 2829 (Csp3H), 2232 (CN), 1694 (C=O), 1243 (Csp2-Cl) cm^–1. HRMS: m/z calcd [M + H]⁺: 262.0383; found: 262.0391.
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