Synthesis and Selective Functionalization of [1,2,4]Triazolo-[4,3-a]pyrazines

Abstract

A new tactic for the synthesis and selective functionalization of [1,2,4]triazolo[4,3-a]pyrazines has been developed using an oxidative cyclization as key step. Furthermore, novel strategies for introducing diverse substituents in all positions of the heterocycle were identified.

Key words

heterocyclic chemistry - cyclization - lithiation - cross-coupling - PhI(OAc)₂

• References and Notes

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• 44 General Conditions for the Oxidative Intramolecular Cyclization To a solution of 2-chloro-3-hydrazinylpyrazine (1, 1.00 equiv) in CH₂Cl₂ (0.22 M) was added the corresponding aldehyde (1.05 equiv) and the reaction mixture was refluxed for 2 h. The solution was cooled to 0 °C (ice bath), and iodobenzene diacetate (1.15 equiv) was added portionwise before the ice bath was removed. The reaction mixture was stirred at r.t. until completion (usually 2 h as judged by LC–MS). Then, aq sat. Na₂CO₃ (1/3 of the volume of CH₂Cl₂) was slowly added, and the reaction mixture was stirred for 10 min. The organic phase was separated and washed with brine, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient of EtOAc and heptane. 8-Chloro-3-methyl[1,2,4]triazolo[4,3-a]pyrazine (2a) Prepared from 1 and acetaldehyde. The product was isolated as a white solid 60 mg (51%); mp 218.8–220.2 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.81 (d, J = 4.7 Hz, 1 H), 7.71 (d, J = 4.7 Hz, 1 H), 2.82 (s, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 146.42, 144.36, 143.9, 128.7, 114.8, 10.6. HRMS: m/z calcd for C₆H₄ClN₄ [M – H]^–: 167.0130; found: 167.0122. Example of Sonogashira Coupling (for further details see Supporting Information): 3-Phenyl-8-(phenylethynyl)-[1,2,4]triazolo[4,3-a]pyrazine (3) To a mixture of 8-chloro-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (2c, 100 mg, 0.43 mmol) and ethynylbenzene (106 mg, 0.114 mL, 1.04 mmol) in Et₃N (2 mL) was added bis(triphenylphosphine)palladium(II) chloride (30 mg, 0.043 mmol) and CuI (3.0 mg, 0.020 mmol) under an atmosphere of argon and stirred at 70 °C for 2 h. The reaction was cooled to r.t., poured into H₂O (15 mL), and extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography using a gradient of EtOAc and heptane to yield 73 mg (57%) of 3-phenyl-8-(phenylethynyl)-[1,2,4]triazolo[4,3-a]pyrazine as a yellow solid; mp 195.1–197.3 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.16 (d, J = 4.8 Hz, 1 H), 7.94 (d, J = 4.8 Hz, 1 H), 7.89–7.86 (m, 2 H), 7.82–7.78 (m, 2 H), 7.66–7.60 (m, 3 H), 7.48–7.41 (m, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 148.0, 146.3, 138.5, 133.0, 131.0, 130.8, 130.4, 129.6, 128.6, 128.5, 128.3, 125.6, 121.0, 114.4, 99.3, 84.1. HRMS: m/z calcd for C₁₉H₁₃N₄ [M + H]⁺: 297.1135; found: 297.1125. Example of Suzuki Coupling (for further details see Supporting Information): 3,8-Diphenyl[1,2,4]triazolo[4,3-a]pyrazine (4) To a mixture of 8-chloro-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (2c, 100 mg, 0.434 mmol), phenylboronic acid (159 mg, 1.30 mmol), and KF (101 mg, 1.73 mmol) in 1,4-dioxane (4.0 mL) was added bis(tri-tert-butylphosphine)palladium (22.0 mg, 0.043 mmol) under an atmosphere of argon. The reaction was heated for 19 h at 80 °C and then cooled to r.t. The reaction mixture was mixed with H₂O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc and heptane to yield 104 mg (88%) of 3,8-diphenyl[1,2,4]triazolo[4,3-a]pyrazine as a white solid; mp 145.6–147.2 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.97–8.78 (m, 2 H), 8.16 (d, J = 4.7 Hz, 1 H), 8.02 (d, J = 4.7 Hz, 1 H), 7.91–7.87 (m, 2 H), 7.67–7.58 (m, 6 H). ¹³C NMR (151 MHz, CDCl₃): δ = 151.57, 147.73, 145.33, 134.98, 131.80, 131.04, 130.48, 129.98, 129.74, 128.88, 128.63, 126.08, 113.90. HRMS: m/z calcd for C₁₈H₁₃N₄ [M + H]⁺: 273.1135; found: 273.1128. Representative Procedure for the Conversion of 2c into 5 and 8 to 9: 8-Methoxy-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (5) To a solution of 8-chloro-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (2c, 3.95 g, 17.1 mmol) in MeOH (50 mL) was added a freshly prepared 1.0 M solution of NaOMe in MeOH (22.2 mL, 22.2 mmol), and the reaction mixture was stirred at r.t. until full conversion as judged by TLC (1 h). To the reaction was added sat. aqueous NH₄Cl (20 mL) and H₂O (50 mL). The reaction was extracted with EtOAc (3 × 150 mL), the combined organic phases were washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc and heptane as solvents to yield 3.53 g (99%) of 8-methoxy-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (5) as a yellow solid; mp 193.8–194.2 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.86–7.82 (m, 3 H), 7.62–7.55 (m, 3 H), 7.41 (d, J = 4.9 Hz, 1 H), 4.22 (s, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 154.8, 148.8, 140.6, 131.0, 129.6, 128.4, 128.2, 126.1, 110.9, 54.9. HRMS: m/z calcd for C₁₂H₁₁N₄O [M + H]⁺: 227.0927; found: 227.0939. General Procedure for the Metalation with LDA of 8-Methoxy-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (5) A 0.27 M freshly prepared solution of lithium diisopropylamide in THF was added dropwise to a suspension of 8-methoxy-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (5, 2.00 g, 8.84 mmol) in dry THF (60 mL) cooled at –78 °C (temperature did not exceed –75 °C). The solution was allowed to warm up to –20 °C (very thick brown solution) after which it was recooled to –78 °C. A solution of the corresponding electrophile (1.2 equiv) in dry THF (5 mL) was added dropwise (temperature did not exceed –73 °C). The reaction mixture was stirred at –78 °C for 2 h before it was quenched with sat. aqueous NH₄Cl (50 mL) and H₂O (50 mL). The reaction was warmed to r.t. and then extracted with EtOAc (3 × 100 mL), and the combined organic phases were washed with brine (300 mL) and dried over Na₂SO₄, concentrated under reduced pressure, and purified by flash chromatography using a gradient of EtOAc and heptane. 5-Chloro-8-methoxy-3-phenyl[1,2,4]triazolo[4,3-a]pyrazine (6a) Hexachloroethane was used as the electrophile. The product was isolated as a light yellow solid 150 mg (65%); mp 152.6–154.2 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.71–7.66 (m, 2 H), 7.65–7.60 (m, 1 H), 7.59–7.52 (m, 3 H), 4.14 (s, 3 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 153.8, 149.8, 141.5, 132.1, 131.3, 128.6, 128.0, 126.9, 116.2, 55.5. HRMS: m/z calcd for C₁₂H₁₀ClN₄O [M + H]⁺: 261.0538; found: 261.0533.
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