An Improved Scalable Process for the Synthesis of (S,S)-DACH-Ph Trost Ligand

Abstract

An improved chemical process has been developed for the synthesis of (S,S)-DACH-Ph Trost ligand. The amidation of 2-diphenylphosphinylbenzoic acid and (S,S)-diaminocyclohexane is promoted by stoichiometric CDI and catalytic imidazole hydrochloride. The resulting product, (S,S)-DACH-Ph Trost ligand, is isolated as a white solid in 80% yield with >99% ee by simple filtration without column chromatography. The current facile process is also demonstrated on kilogram scale.

Key words

Trost ligand - DACH-Ph - coupling - 2-diphenylphosphinylbenzoic acid - chiral diaminocyclohexane - CDI - imidazole hydrochloride - kilogram

Publication History

Received: 06 April 2022

Accepted after revision: 03 May 2022

Article published online:
23 May 2022

• References and Notes

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• 2a Trost BM, Van Vranken DL, Bunt RC. US Patent US5739396, 1998
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• 4 Current market price: 6000–7000 $/kg on 5 kg scale.
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• 9a (S,S)-DACH-Ph Trost Ligand (1) Under nitrogen, 2-diphenylphosphinylbenzoic acid (2) (1.0 kg, 3.26 mol) and CDI (557.2 g, 3.33 mol) were charged into a clean and dry Reactor. After CH₃CN (2 L) had been added to give a slurry, the resulting mixture was agitated for 1 h at 20–25 °C to afford a clear and homogenous solution. The solution was transferred to a Reactor containing (S,S)-diaminocyclohexane (3) (186.4 g, 1.63 mol) and imidazole hydrochloride (170.6 g, 1.63 mol), rinsed with CH₃CN (0.60 L). The resulting mixture was then heated at 80–82 °C for 8 h. After the solution was cooled to 60 °C, a slurry was obtained. Water (1.3 L) was added over 0.5 h at 55–60 °C. After 0.5 h, the obtained slurry was cooled to 23 °C over 0.5 h. After 0.5 h, the solid was collected by filtration and then washed with CH₃CN/H₂O (2:1, 3 L) and H₂O (2 L) successively. After being dried under vacuum at 55 °C, the (S,S)-DACH-Ph Trost ligand (1) was obtained as a white solid (902.1 g, 80%) in sufficient quality for asymmetric allylic alkylation. The NMR spectroscopic data are in accordance with the literature.³ Mp 141.9–143.9 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.22 (s, 1 H), 8.20 (s, 1 H), 7.54–7.52 (m, 2 H), 7.32–7.29 (m, 14 H), 7.27 (t, J = 7.44 Hz, 2 H), 7.14–7.09 (m, 8 H), 6.83–6.81 (m, 2 H), 3.74 (br s, 2 H), 1.70 (d, J = 12.6 Hz, 2 H), 1.65 (d, J = 7.74 Hz, 2 H), 1.33 (m, 2 H), 1.18 (m, 2 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 167.7, 141.6, 141.4, 138.6, 138.5, 138.5, 138.5, 136.5, 136.3, 133.6, 133.3, 133.2, 133.2, 133.1, 129.7, 128.3, 128.3, 128.3, 128.2, 128.2, 128.2, 127.7, 127.7, 52.6, 31.4, 24.5. ³¹P NMR (243 MHz, DMSO-d ₆): δ = –9.04
• 9b HPLC: ChiralPak AY-H 4.6 × 250 mm, flow rate = 0.50 mL/min, column temperature = 35 °C, heptane:[MeOH/ethanol (1:1) with 0.4% Et₃N] = 75:25, detection at 220 nm; t _R = 7.7 min (S,S), t _R = 8.3 min (R,R).
• 10 CCDC 2152627 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.