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TCI Practical Example: The Metallophotoredox Reaction Using a Capsule Reagent

We are proud to present the metallophotoredox C-N cross-coupling reaction of 5-bromopyrimidine and morpholine using the capsule reagent. This reagent can omit weighing the base and catalysts. 0.12 μmol of iridium catalyst, 0.03 mmol of nickel catalyst, and 1.1 mmol of DABCO are encapsulated in each capsule.

Used Chemicals

• 5-Bromopyrimidine [B2229]
• Morpholine [M0465]
• Reagents for Metallophotoredox Cross-Coupling Reactions (HPMC encapsulated) (NiBr₂(dme), [Ir[dF(CF₃)ppy]₂(dtbbpy)]PF₆, DABCO) [R0273]
• N,N-Dimethylacetamide (= DMAc)

Procedure

Reagents for metallophotoredox cross-coupling reactions (HPMC encapsulated) (one capsule) was added to a solution of 5-bromopyrimidine (95 mg, 0.60 mmol) and morpholine (78 μL, 0.90 mmol, 1.5 eq.) in DMAc (6 mL) at room temperature. The solution was placed at a distance of 3-5 cm from Blue LED lamp and stirred for 24 hours at 60 °C. The reaction mixture was then filtered through Celite^®. The filtrate was diluted with saturated Na₂SO₄ aq. (15 mL) and extracted with ethyl acetate (15 mL x 5). The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford 4-(pyrimidin-5-yl)morpholine (84 mg, 85% yield) as a pale brown solid.

Experimenter’s Comments

The reaction mixture was monitored by GC.
Irradiation of visible light was performed with Kessil A160WE Tuna Blue 40W x 2.
DMAc was degassed with nitrogen gas for 30 minutes before use.
The shape of the capsule is like below image and each capsule includes NiBr₂(dme) (ca. 0.03 mmol), [Ir[dF(CF₃)ppy]₂(dtbbpy)]PF₆ (ca. 0.12 μmol), and DABCO (ca. 1.1 mmol).
The material of the capsule is water-soluble HPMC (hydroxypropyl methylcellulose).

Analytical Data

4-(Pyrimidin-5-yl)morpholine

¹H NMR (400 MHz, CDCl₃); δ 8.74 (s, 1H), 8.37 (s, 2H), 3.91-3.88 (m, 4H), 3.25-3.22 (m, 4H).

Lead Reference

• 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.

Other Reference

• 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.