Reagents for Suzuki-Miyaura Cross-Coupling Reactions [Pd(dppf)Cl₂·CH₂Cl₂, Cs₂CO₃] (HPMC encapsulated)

• 2-Acetamido-5-bromo-4-methylpyridine [A2823]
• Phenylboronic Acid [B0857]
• Reagents for Suzuki-Miyaura Cross-Coupling Reactions (HPMC encapsulated) (Pd(dppf)Cl₂·CH₂Cl₂, Cs₂CO₃) [R0275]
• THF

Reagents for Suzuki-Miyaura Cross-Coupling Reactions (one capsule) was added to a solution of 2-acetamido-5-bromo-4-methylpyridine (137 mg, 0.60 mmol) and phenylboronic acid (110 mg, 0.90 mmol, 1.5 eq.) in THF/H₂O (4:1, 2 mL) at r.t. and the reaction mixture was stirred at 100 °C for 2 hours. The solution was then filtered through Celite pad and the filtrate was diluted with sat. Na₂SO₄ aq. (15 mL). The aqueous layer was extracted with ethyl acetate (15 mL x 2) and the organic layer was washed with water (15 mL) and brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate:hexane = 2:1 - 1:4) and then further purified by reversed-phase silica gel chromatography (water:acetonitrile = 95:5 - 40:60) to afford 2-acetamido-4-methyl-5-phenylpyridine (122 mg, 90% yield) as a white solid.

The reaction mixture was monitored by GC.
The shape of the capsule is like below image and Pd(dppf)Cl₂·CH₂Cl₂ (ca. 0.03 mmol) and Cs₂CO₃ (ca. 0.7 mmol) are encapsulated in each capsule.
The material of the capsule is water-soluble HPMC (hydroxypropyl methylcellulose).
Since it was difficult to remove the starting material by the normal phase silica gel column purification, so the reverse-phase column purification was performed.

2-Acetamido-4-methyl-5-phenylpyridine

¹H NMR (400 MHz, CDCl₃); δ 9.24-9.06 (brs, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.46-7.36 (m, 3H), 7.30-7.29 (m, 2H), 2.32 (s, 3H), 2.21 (s, 3H).

• Reagent and Catalyst Capsules: A Chemical Delivery System for Reaction Screening and Parallel Synthesis
• N. Borlinghaus, B. Schönfeld, S, Heitz, J. Klee, S. Vukelić, W. M. Braje, A. Jolit, J. Org. Chem. 2021, 86, 1357.

• HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water
• S. Sharma, T. N. Ansari, S. Handa, ACS Sustainable Chem. Eng. 2021, 9, 12719.