Sodium Metabisulfite Mediated Synthesis of Bis(pyrazolo[1,5-a] pyrimidin-3-yl)methanes from Pyrazolo[1,5-a]pyrimidines with Dimethyl Sulfoxide as a C1 Synthon

Dedicated to Professor Brindaban C. Ranu on the occasion of his 75^th birthday.

Abstract

We report an unprecedented synthesis of bis(pyrazolo[1,5-a]pyrimidin-3-yl)methanes, a new class of di(hetaryl)methanes, from pyrazolo[1,5-a]pyrimidines by using DMSO as a C1 synthon (methylene source). The transformation is mediated by sodium metabisulfite (Na₂S₂O₅), which plays a crucial role in the presence of acetic acid as a promoter. A wide variety of bis(pyrazolo[1,5-a]pyrimidin-3-yl)methanes were synthesized in moderate to good yields of up to 90%. Mechanistic studies suggested that the reaction follows an ionic pathway, probably involving a methyl(methylene)sulfonium ion as an active electrophilic species formed in situ by the reaction of DMSO with Na₂S₂O₅.

Key words

sodium metabisulfite - pyrazolopyrimidines - bispyrazolopyrimidinylmethanes - C1 synthons - DMSO - metal-free reaction

Publication History

Received: 31 August 2024

Accepted after revision: 25 September 2024

Accepted Manuscript online:
25 September 2024

Article published online:
18 October 2024

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• 31 3,3′-Methylenebis(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidine) (2c); Typical Procedure An oven-dried round-bottomed flask was charged with 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidine (1c; 0.5 mmol, 105 mg), Na₂S₂O₅ (284.7 mg, 1.5 mmol, 3 equiv), and AcOH (6 μL, 0.1 mmol, 0.2 equiv). DMSO (5 mL) was added, and the mixture was stirred at 120 °C for 16 h until the reaction was complete (TLC). The resulting solution was extracted with EtOAc (3 × 10 mL), and the combined organic layer was washed with ice-cold water (3 × 10 mL). The organic layer was dried (Na₂SO₄), and the solvent was evaporated under reduced pressure to afford a crude product that was purified by column chromatography (silica gel, 20% EtOAc–hexane) to give a yellow solid; yield: 0.092 g (85%); mp 190–192 °C. IR (neat): 2921.28, 2851.43 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.47 (d, J = 4.3 Hz, 2 H), 8.08–8.01 (m, 4 H), 7.56–7.50 (m, 6 H), 6.76 (d, J = 4.3 Hz, 2 H), 4.40 (s, 2 H), 2.40 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 153.96, 147.83, 147.69, 145.77, 131.33, 130.80, 129.17, 128.59, 106.74, 106.17, 77.00, 15.63, 13.39. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₃N₆: 431.1984; found: 431.2000.