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TCI Practical Example: Preparation of Unsymmetrical 1,2,4,5-Tetrazine

We are proud to introduce the successive amination-Suzuki-Miyaura coupling reaction of 3,6-dichlorotetrazine.

Used Chemicals

• 3,6-Dichloro-1,2,4,5-tetrazine [D5732]
• Butylamine [B0707]
• N,N-Diisopropylethylamine [D1599]
• tert-Butyl Methyl Ether (= MTBE) [B0991]
• 4-Methylphenylboronic Acid [M1126]
• [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) Dichloride Dichloromethane Adduct (= Pd(dppf)Cl₂·DCM) [B2064]
• Potassium Carbonate [P1748]
• Toluene

Procedure

To a solution of 3,6-dichloro-1,2,4,5-tetrazine (0.50 g, 3.2 mmol) in MTBE (15 mL) was added N,N-diisopropylethylamine (0.42 g, 3.2 mmol), followed by the dropwise addition of butylamine (0.24 g, 3.2 mmol) in MTBE (2 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. Additional N,N-diisopropylethylamine (0.42 g, 3.2 mmol) and butylamine (0.24 g, 3.2 mmol) in MTBE (2 mL) were added at room temperature and the mixture was further stirred for 1 hour. The solvent was removed under reduced pressure, and resulted crude product was purified by column chromatography (ethyl acetate:hexane = 1:15 on silica gel) to give compound 1 as an orange solid (0.45 g, 74% yield).
1 (0.20 g, 1.1 mmol), 4-methylphenylboronic acid (0.17 g, 1.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (44 mg, 0.053 mmol) and potassium carbonate (0.44 g, 3.2 mmol) were combined in a sealed vial which was purged with N₂. Toluene/H₂O solution (5:1, 3 mL, degassed) was then added via syringe. The reaction mixture was stirred overnight at room temperature, then diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane and the combined organic layer was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate:hexane = 1:10 on silica gel) to give compound 2 as a red powder (84 mg, 32% yield).

Experimenter’s Comments

Both the reaction mixtures were monitored by UPLC.

Analytical Data

N-Butyl-6-(p-tolyl)-1,2,4,5-tetrazin-3-amine (compound 2)

¹H NMR (400 MHz, CDCl₃); δ 8.28 (d, 2H, J = 7.8 Hz), 7.33 (d, 2H, J = 7.8 Hz), 5.80-5.66 (brs, 1H), 3.71-3.60 (m, 2H), 2.43 (s, 3H), 1.78-1.67 (m, 2H), 1.53-1.40 (m, 2H), 0.99 (t, 3H, J = 7.4 Hz).

¹³C NMR (101 MHz, CDCl₃); δ 161.5, 160.3, 130.2, 129.8, 126.3, 41.3, 31.4, 21.6, 20.2, 13.9.

Lead Reference

• Preparation of Unsymmetrical 1,2,4,5-Tetrazines via a Mild Suzuki Cross-Coupling Reaction
• A. M. Bender, T. C. Chopko, T. M. Bridges, C. W. Lingsley, Org. Lett. 2017, 19, 5693.