Reagents for Condensation Reactions (HATU) (HPMC encapsulated)

• 4-Bromobenzoic Acid [B0553]
• Morpholine [M0465]
• Reagents for Condensation Reactions (HPMC encapsulated) (HATU) [R0295]
• N,N-Diisopropylethylamine (= DIPEA) [D1599]
• DMF

Reagents for condensation capsule (HATU) (one capsule) was added to a solution of 4-bromobenzoic acid (80 mg, 0.40 mmol, 1.0 eq.), morpholine (37 μL, 0.42 mmol, 1.05 eq.) and N,N-diisopropylethylamine (100 μL, 0.60mmol, 1.5 eq.) in DMF (2 mL) at r.t. and the mixture was stirred at 30 °C for 1 hour.　The reaction solution was diluted with sat. Na₂SO₄ aq. (15 mL) and extracted with ethyl acetate (15 mL x 2). The organic layer was washed with 2 mol/L HCl aq. (15 mL), sat. NaHCO₃ aq. (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexane:ethylacetate = 2:1 - 1:1) to afford (4-bromophenyl)(morpholino)methanone (95 mg, 88% yield) as a white solid.

The reaction mixture was monitored by UPLC.
The shape of the capsule is like below image and each capsule includes HATU (ca. 0.40 mmol).
The material of the capsule is water-soluble HPMC (hydroxypropyl methylcellulose).
HPMC was removed with a saturated sodium sulfate solution, but during the separation, the separating funnel was clogged due to the precipitation of sodium sulfate. Therefore, the precipitated sodium sulfate was filtered off, and ethyl acetate was added to the filtrate for extraction. Use of a more dilute sodium sulfate solution may reduce clogging problems.

(4-Bromophenyl)(morpholino)methanone

¹H NMR (400 MHz, CDCl₃); δ 7.57 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 3.74-3.44 (m, 8H).

• Hydrophobic Pockets of HPMC Enable Extremely Short Reaction Times in Water
  • D. Petkova, N. Borlinghaus, S. Sharma, J. Kaschel, T. Lindner, J. Klee, A. Jolit, V. Haller, S. Heitz, K. Britze, J. Dietrich, W. M. Braje, S. Handa, ACS Sustainable Chem. Eng. 2020, 8, 12612.

• 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.