Direct Access to Fluorinated Thiadiazolo[3,2-a]pyrimidin-7-one Systems

Abstract

A mild, simple method for the regioselective synthesis of thiadiazolo[3,2-a]pyrimidin-7-ones bearing a perfluoroalkyl group is reported. In order to study the core reactivity, various nucleophile substitutions were performed involving the reactive carbon–bromide bond via a one-pot strategy.

Key words

regioselectivity - one-pot synthesis - fluorinated thiadiazo[3,2-a]pyrimidin-7-ones - nucleophile substitution

• References and Notes

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• 15 Typical Experimental Procedure for the Preparation of 6b Ethyl 4,4,4-trifluorobutynoate (5a, 980 mg, 5.80 mmol) was added dropwise to a solution of 4b (700 mg, 3.88 mmol) in MeOH (40 mL) at r.t. The mixture was stirred vigorously overnight before adding an extra 0.4 equiv of 5a. The mixture was allowed to stir for 24 h at r.t. The solvent was evaporated under reduced pressure, and the solid was washed with Et₂O affording 520 mg (44%) of 6b as a brown solid; mp 186–188 °C. IR (neat): 3065, 2059, 1642, 1519–1447 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.670 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 111.2 (q, J = 3.6 Hz), 118.1 (q, J = 273.3 Hz), 133.5, 136.4 (q, J = 38.5 Hz), 164.5, 165.1. ¹⁹F NMR (282 MHz, CDCl₃): δ = –67.70 (s). ESI-HRMS: m/z calcd for C₆H₂BrF₃N₃OS [M + H]⁺: 299.90540; found: 299.90486.
• 16 Typical Experimental Procedure for the Preparation of 7a To a solution of compound 4b (200 mg, 1.1 mmol) in MeOH (20 mL) was gradually added the activated alkyne 5a (237 mg, 1.43 mmol). The solution was stirred at r.t. overnight before incorporating another 0.3 equiv of 5. The mixture was allowed to stand at r.t. for 24 h. Once the reaction was complete, allylamine (130 mg, 2.2 mmol) was then added dropwise. The mixture was vigorously stirred and monitored using TLC (SiO₂, EtOAc–PE = 6:4) until the reaction was complete. MeOH was removed in vacuo. The solid was washed with Et₂O, then filtered to provide 97 mg (32%) of 7a as a white solid; mp 260 °C. IR (neat): 3065, 2059, 1640, 1573, 1518–1447 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.87 (d, J = 5.1 Hz, 2 H), 5.16–5.30 (m, 2 H), 5.84–5.93 (m, 1 H), 6.59 (s, 1 H), 8.48 (br s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 46.0, 109.6, 117.6, 119.0 (q, J = 272.4 Hz), 133.3, 135.5 (q, J = 36.7 Hz), 157.0, 162.8, 166.1. ¹⁹F NMR (282 MHz, DMSO-d ₆): δ = –67.12. ESI-HRMS: m/z calcd for C₉H₈F₃N₄OS [M + H]⁺: 277.03709; found: 277.03626.