1,3-Dibromobenzene → HCID 131730556, compound

HRID 1185347Notes

Reaction equation

Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:10]2)[CH:7]=[CH:6][CH:5]=1

Participants

Conditions

Temperature: 80 °C

Procedure

1,3-Dibromobenzene (0.2 g, 0.85 mmol), (R)-tert-butyl pyrrolidin-3-ylmethylcarbamate (0.17 g, 0.85 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), BINAP (40 mg, 0.06 mmol) and sodium tert-butoxide (98 mg, 1.02 mmol) were suspended in toluene (2 mL). The mixture was heated at 80° C. for 16 hr. The mixture was cooled and diluted with water and EtOAc. The organic layer was separated, passed through a phase separator cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (R)-tert-butyl (1-(3-bromophenyl)pyrrolidin-3-yl)methylcarbamate as a yellow oil (0.179 g, 59%). This oil (0.179 g, 0.5 mmol) was suspended in 1,4-dioxane (2 mL). Bis-pinacolato-diboron (0.166 g, 0.66 mmol), potassium acetate (65 mg, 0.66 mmol) and Pd(dppf)Cl2 (20 mg, 0.025 mmol) were added and the mixture was heated at 100° C. for 16 h. The solution was cooled, diluted with DCM and filtered through celite. The solvent was removed under reduced pressure to afford crude (R)-tert-butyl (1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methylcarbamate as a brown oil. A mixture of this oil (0.5 mmol), tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.177 g, 0.44 mmol), Na2CO3 (0.7 mL, 2M aq. solution, 1.32 mmol) in DME (4.3 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (72 mg, 0.09 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 40 min. The solvents were removed under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to yield (R)-tert-butyl 2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a yellow oil (86 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.90 (s, 1H), 7.98 (s, 1H), 7.58 (s, 1H), 7.00 (s, 1H), 6.63-6.57 (m, 1H), 4.71-4.69 (m, 1H), 3.92 (s, 3H), 3.59-3.36 (m, 5H), 2.67-2.46 (m, 1H), 2.14-2.13 (m, 1H), 1.84-1.80 (m, 1H), 1.55 (s, 9H), 1.54 (s, 9H). Three protons not seen

Workup

temperatureThe mixture was cooled
customThe organic layer was separated
concentrationconcentrated under reduced pressure
customPurification via silica gel column chromatography (0-100% EtOAc/isohexane)

Sources & evidence

ORD record: ord-a348c72a56a84598af49a4f65a8bb6ec
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08669361B2

Reaction notes

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