Sodium Carbonate → 5-Methyl-3-(3-nitro-4-pyridinyl)-2-cyclohexen-1-one

Temperature

110 °C

To a solution of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane (0.5 M) and 2M Na2CO3 (2 equiv.) was added 4-chloro-3-nitropyridine (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.). The reaction was placed under a reflux condenser and heated in an oil bath to 110° C. for 1 h. Cooled to room temperature, filtered through a pad of Celite, washed the pad with ethyl acetate and concentrated the filtrate under vacuo. The residue was further pumped at 80° C. on a rotary evaporator for one hour to remove boronate by-products (M+H=101) via sublimation. The residue was partitioned between brine and ethyl acetate, and the layers were separated, the aqueous phase was further extracted with ethyl acetate (4×), the organics were combined, dried over sodium sulfate, filtered, and concentrated. The crude was purified via silica gel chromatography loading in DCM and eluting with 2-50% ethyl acetate and hexanes. The pure fractions were concentrated in vacuo to yield an orange oil. The oil was placed under high vacuum (˜500 mtorr) with seed crystals overnight to yield an orange solid. The solid was further purified via trituration in hexanes to yield 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (48% 2 steps). LC/MS=233.2 (M+H); Rt=0.69 min, LC=2.70 min. 1H-NMR (400 MHz, CdCl3) δ ppm: 9.31 (s, 1H), 8.88 (d, J=5.1, 1H), 7.30 (d, J=5.1, 1H), 6.00 (d, J=2.4, 1H), 2.62 (dd, J=16.4, 3.5, 1H), 2.53-2.34 (m, 3H), 2.23 (dd, J=16.1, 11.7, 1H), 1.16 (d, J=6.3, 3H).

1. customThe reaction was placed under a reflux condenser
2. temperatureCooled to room temperature
3. filtrationfiltered through a pad of Celite
4. washwashed the pad with ethyl acetate
5. concentrationconcentrated the filtrate under vacuo
6. customThe residue was further pumped at 80° C. on a rotary evaporator for one hour
7. customto remove boronate by-products (M+H=101) via sublimation
8. customThe residue was partitioned between brine and ethyl acetate
9. customthe layers were separated
10. extractionthe aqueous phase was further extracted with ethyl acetate (4×)
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated
14. customThe crude was purified via silica gel chromatography loading in DCM
15. washeluting with 2-50% ethyl acetate and hexanes
16. concentrationThe pure fractions were concentrated in vacuo
17. customto yield an orange oil
18. customwas placed under high vacuum (˜500 mtorr) with seed crystals overnight
19. customto yield an orange solid
20. customThe solid was further purified via trituration in hexanes

ORD record

ord-c7582a006d034447a7ce606aaae2f997

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09173883B2