Synthesis of Axially Chiral Cyclic Amine-Substituted 2-(Oxazolinyl)pyridine Ligands for Catalytic Asymmetric Fluorination of β-Keto Esters

Abstract

Novel optically active N,N,N-tridentate ligands, which possess both binaphthyl axial chirality and carbon-centered chirality, were prepared and successfully used in the catalytic asymmetric α-fluorination of β-keto esters giving ee values up to 94%.

Key words

asymmetric fluorination - chiral ligand - Lewis acid ­catalysis - β-keto esters - nickel catalyst

References and Notes

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• Very recently, the development of new chiral P,N,N-tridentate ligands having both axial chirality and a centered chiral oxazoline subunit was reported, see:
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• 5b

  For other hybrid chiral ligands, see ref. 4c.

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7

1a: [α]_D ²⁵ +119.1 (c 0.49, CHCl₃); ¹H NMR (400 MHz, CD₂Cl₂-Me₄Si): δ = 0.98 (d, J = 6.8 Hz, 3 H), 1.09 (d, J = 6.8 Hz, 3 H), 1.89 (m, 1 H), 3.30 (d, J = 12.3 Hz, 2 H), 3.74 (d, J = 12.3 Hz, 2 H), 3.79 (d, J = 13.8 Hz, 1 H), 3.97 (d, J = 13.8 Hz, 1 H), 4.15 (ddd, J = 9.6, 8.4, 6.4 Hz, 1 H), 4.23 (dd, J = 8.4, 8.0 Hz, 1 H), 4.52 (dd, J = 9.6 Hz, 8.0 Hz, 1 H), 7.28-7.32 (m, 2 H), 7.47-7.53 (m, 4 H), 7.66 (d, J = 8.3 Hz, 2 H), 7.73 (br d, J = 8.0 Hz, 1 H), 7.84 (dd, J = 7.8, 7.6 Hz, 1 H), 7.98-8.05 (m, 5 H); ¹³C NMR (100 MHz, CD₂Cl₂-Me₄Si): δ = 162.8, 146.9, 137.3, 135.3, 133.6, 131.7, 128.6, 128.1, 127.6, 126.0, 125.7, 125.5, 122.8, 73.3, 71.1, 61.2, 55.3, 33.2, 31.8, 22.9, 19.0, 18.4, 14.1; Anal. Calcd for C₃₄H₃₁N₃O·0.5H₂O: C, 80.60; H, 6.37; N, 8.29. Found: C, 80.67; H, 6.69; N, 7.91.

8

Mg-catalyzed efficient asymmetric fluorination of carbonyl compound has not been reported to the best of our knowledge, although the efficient catalyst system using a chiral Ni(II) complex has been reported by Shibata (see ref. 3h and 3i).

9

General experimental procedure for Ni(II)-1 catalyzed asymmetric fluorination: The catalysts were prepared by refluxing (S,S)-1a (0.05 mmol) with Ni(ClO₄)₂·6H₂O (0.25 mmol) for 2 h in CH₂Cl₂ in the presence of MS 4 Å (100 mg). After the complex had formed, the MS and extra Ni(ClO₄)₂ were filtered off to give a clear solution which was filtered again using a membrane filter. The catalyst solution was added to pre-activated MS 4 Å (100 mg) at r.t. followed by addition of 2-tert-butoxycarbonyl-1-indanone (8a, 1.0 mmol) and NFSI (1.1 mmol). The resulting suspension was stirred at r.t. for 0.5 h. At the end of the reaction, the mixture was extracted into EtOAc and the organic layer was concentrated in vacuo. The crude mixture was purified by flash column chromatography on silica gel to give (R)-2-tert-butoxycarbonyl-2-fluoro-1-indanone (9a) (0.99 mmol, 94% ee).

11

1e was synthesized using (S)-3,3′-diphenyl-2,2′-bis(bromo-methyl)-1,1′-binaphthyl (ref. 6) as a synthon instead of (S)-6.