Combiflash rf unit

A mixture of (±)-(3aR,6aS)-tert-butyl 5-(2-(trifluoromethyl)-phenyl)-3,3a,6,6a–tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate ((±)-24, 8.63 g, 24.41 mmol) and 10% Pd/C (1.57 g, wet, 10% w/w) in CH₃OH (50 mL) was subjected to an atmosphere of H₂ gas (40 psi) using a Parr Shaker apparatus at rt for 16 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (Isco CombiFlash Rf unit, 40 g RediSep column, 0%-30% EtOAc in hexanes) to give (3aR,5r,6aS)-tert-butyl 5-(2-(trifluoromethyl)-phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (25) as a clear, viscous oil (0.910 g, 85%): ¹H NMR (500 MHz, CDCl₃) δ 7.69 (m, 1H), 7.51 (m, 2H), 7.25 (m, 1H), 3.49 (m, 5H), 2.75 (m, 2H), 2.92 (m, 2H), 1.52 (m, 2H), 1.48 (s, 9H).

To a mixture of (3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydro-cyclopenta[c]pyrrole hydrochloride (26, 0.153 g, 0.524 mmol), methyl 5-bromonicotinate (0.103 g, 0.477 mmol), XantPhos (0.083 g, 0.140 mmol), and Cs₂CO₃ (0.465 g, 1.43 mmol) in 1,4-dioxane (8 mL) was added Pd₂(dba)₃ (0.043 g, 0.047 mmol). The mixture was heated at reflux for 16 h, then allowed to cool to rt. The mixture was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (Isco CombiFlash Rf unit, 40 g Gold RediSep column, 0%-25% CH₃OH in CH₂Cl₂) to give methyl 5-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-nicotinate as a yellow film (0.077 g, 41%): ¹H NMR (500 MHz, CDCl₃) δ 8.59 (s, 1H), 7.62 (s, 1H), 7.53 (m, 1H), 7.48 (m, 3H), 7.29 (m, 1H), 3.94 (s, 3H), 3.52 (m, 1H), 3.43 (m, 4H), 2.98 (m, 2H), 2.45 (m, 2H), 1.67 (m, 2H); MS (ESI+) m/z 391 [M + H]⁺.

To a mixture of (3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydro-cyclopenta[c]pyrrole hydrochloride (26, 0.400 g, 1.37 mmol), 6-chloro-3-methylpicolinic acid (0.254 g, 1.37 mmol), JohnPhos (0.048 g, 0.137 mmol), and Cs₂CO₃ (1.34 g, 4.11 mmol) in toluene (7 mL) was added Pd(OAc)₂ (0.015 g, 0.068 mmol). The mixture was heated at reflux for 14 h then allowed to cool to rt. The mixture was filtered over Celite, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (Isco CombiFlash Rf unit, 40 g Gold RediSep column, 0%-15% EtOAc in hexanes) to give methyl 3-methyl-6-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)picolinate as a white solid (0.366 g, 66%): MS (ESI+) m/z 405 [M + H]⁺.

To a suspension of 2,2′-((3S,4R)-1-(tert-butoxycarbonyl)-pyrrolidine-3,4-diyl)diacetic acid (21, 6.97 g, 24.31 mmol) in Ac₂O (50 mL) was added NaOAc (1.99 g, 24.31 mmol), and the mixture was heated at 120 °C for 3 h. The mixture was allowed to cool to rt and filtered through Celite. The filter cake was washed with Et₂O (5 × 50 mL), and the mother liquor was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (Isco CombiFlash Rf unit, 120 g RediSep column, 0%-30% EtOAc in hexanes) to give (3aR,6aS)-tert-butyl 5-oxohexahydro-cyclopenta[c]pyrrole-2(1H)-carboxylate (22) as a white foam (2.17 g, 40%): ¹H NMR (500 MHz, CDCl₃) δ 3.69 (m, 2H), 3.22 (m, 2H), 2.91 (m, 2H), 2.50 (m, 2H), 2.17 (m, 2H), 1.46 (s, 9H).

To a mixture of (3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]-pyrrole hydrochloride (26, 0.250 g, 0.86 mmol), NaOt-Bu (0.180 g, 0.89 mmol), and BINAP (0.105 g, 0.17 mmol) in toluene (10 mL) was added Pd(OAc)₂ (0.020 g, 0.089 mmol). The mixture was heated at 110 °C for 16 h, then allowed to cool to rt. The mixture was filtered over Celite, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (Isco CombiFlash Rf unit, 40 g Gold RediSep column, 0%-15% EtOAc in hexanes) to give methyl 3-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydro-cyclopenta[c]pyrrol-2(1H)-yl)benzoate as a white solid (0.132 g, 63%): MS (ESI+) m/z 390 [M + H]⁺.

To a solution of (3aR,5r,6aS)-5-(2-(trifluoromethyl)-phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carbonyl chloride (0.300 g, 1.03 mmol) in DMSO (8 mL) and ethyl 2-chloro-5-methyl-thiazole-4-carboxylate (0.211 g, 1.03 mmol) was added i-Pr₂NEt (0.40 g, 3.09 mmol). The resulting solution was heated at 110 °C for 24 h. The reaction was allowed to cooled to rt and diluted with H₂O (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (2 × 30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was chro-matographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0–30% EtOAc in hexanes) to give ethyl 5-methyl-2-((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]-pyrrol-2(1H)-yl)thiazole-4-carboxylate as an off-white solid (0.042 g, 9%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.76–7.70 (m, 1H), 7.68–7.54 (m, 2H), 7.42–7.35 (m, 1H), 4.22 (q, J = 6.9 Hz, 2H), 3.55–3.42 (m, 2H), 3.42–3.35 (m, 2H), 2.97–2.83 (m, J = 2H), 2.55 (s, 3H), 2.32–2.18 (m, 3H), 1.74–1.53 (m, 2H), 1.27 (t, J = 6.9 Hz, 3H); MS (ESI+) m/z 425 [M + H]⁺.

To a mixture of tert-butyl piperazine-1-carboxylate (1.0 g, 5.37 mmol), 1-bromo-2-(trifluoromethyl)-benzene (5, 1.0 mL, 7.34 mmol), BINAP (0.135 g, 0.22 mmol), and NaOt-Bu (0.670 g, 6.57 mmol) in toluene (20 mL) was added Pd(OAc)₂ (0.024 g, 0.11 mmol). The mixture was heated at 110 °C for 16 h then allowed to cool to rt. The mixture was filtered over Celite, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (Isco CombiFlash Rf unit, 40 g Gold RediSep column, 0%-100% EtOAc in hexanes) to give tert-butyl 4-(2-(trifluoromethyl)-phenyl)piperazine-1-carboxylate (11) as an off-white solid (1.63 g, 92%): ¹H NMR (300 MHz, CDCl₃) δ 7.64 (m, 1H), 7.55 (m, 1H), 7.33 (m, 1H), 7.21 (m, 1H), 3.57 (m, 4H), 2.88 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 331 [M + H]⁺.