Synthesis of Diastereomeric Bis(oxazoline) Ligands Derived from (S,S)-1,1′-Bis(4-isopropyloxazolin-2-yl)ferrocene

Abstract

Starting from (S,S)-1,1′-bis(4-isopropyloxazolin-2-yl)ferrocene, all possible 2-trimethylsilyl- and 2,2′-di(trimethylsilyl)-substituted diastereoisomers, potential bisoxazoline ligands for use in asymmetric catalysis, were synthesised by selective lithiation followed by addition of trimethylsilyl chloride. Access to the (S,S,R _p,R _p)-diastereoisomer was achieved following diastereoselective introduction of two deuterium-blocking groups and utilisation of the high k _H/k _D value for lithiation, methodology that was also applied to the synthesis of a related 2,2′-di(diphenylmethanol)bisoxazoline ligand.

Key words

bisoxazoline - ligands - ferrocene - lithiation - deuterium - ­kinetic isotope effect - diastereoisomers

• References and Notes

• 1 Muñiz K. Bolm C. Chem. Eur. J. 2000; 6: 2309
• 2 Richards CJ. Arthurs RA. Chem. Eur. J. 2017; 48: 11460
• 3a Evan DA. Woerpel KA. Hinman MM. Faul MM. J. Am. Chem. Soc. 1991; 113: 726
• 3b Desimoni G. Faita G. Jørgensen KA. Chem. Rev. 2006; 106: 3561
• 4a Hartinger CG. Nazarov AA. Arion VB. Giester G. Kuznetsov ML. Galanski M. Keppler BK. Eur. J. Inorg. Chem. 2005; 1589
• 4b Lee S. J. Organomet. Chem. 2006; 691: 1347
• 5a Park J. Lee S. Ahn KH. Cho C.-W. Tetrahedron: Asymmetry 1995; 36: 7263
• 5b Zhang W. Adachi Y. Hirao T. Ikeda I. Tetrahedron: Asymmetry 1996; 7: 451
• 5c Park J. Lee S. Cho C.-W. Tetrahedron Lett. 1996; 37: 6137
• 5d Locke AJ. Pickett TE. Richards CJ. Synlett 2001; 141
• 5e Wu H. An Q. Liu D. Zhang W. Tetrahedron 2015; 71: 5112
• 6 Arthurs RA. Richards CJ. Org. Lett. 2017; 19: 702
• 7 The configuration of this monophosphine was initially incorrectly assigned as (S,S,S _p), see ref. 5a.
• 8 In our hands the use of 1.3 equivalents of n-BuLi resulted only in the recovery of starting material such that 2.6 equivalents were required to give the product.
• 9 For all lithiation/silylation reactions the identity and ratio (where possible) of the byproducts is given in the Supporting Information. All silylated bisoxazolines were obtained diastereomerically pure by colum chromatography.
• 10 Sammakia T. Latham HA. J. Org. Chem. 1995; 60: 6002
• 11 Richards CJ. Damalidis T. Hibbs DE. Hursthouse MB. Synlett 1995; 74
• 12 Sammakia T. Latham HA. J. Org. Chem. 1996; 61: 1629
• 13a Collum DB. Acc. Chem. Res. 1992; 25: 448
• 13b Reich HJ. Chem. Rev. 2013; 113: 7130
• 14 The diastereoselectivity of monolithiation of (S,S)-2 with n-BuLi can also be reversed by use of THF as solvent, see ref. 5c.
• 15 The electrophiles used in these studies are MeI, C₂Cl₆, C₂Br₂Cl₄, and ClPPh₂. The discussion of the resulting planar chiral configurations (R _p or S _p) is on the basis that the priority of the group introduced is higher than that of the oxazoline substituent (which is the case for Cl, Br, PPh₂, and SiMe₃, with CPh₂OH having a lower priority).
• 16 Lithiation under these conditions followed by the addition of benzophenone has been reported to result in a 3.5:1 ratio of (S,S,R _p,R _p) and (S,S,R _p,S _p) diastereoisomers, respectively. See: Zhang W., Yoshinaga H., Imai Y., Kida T., Nakatsuji Y., Ikeda I.; Synlett; 2000, 1512

Values for k _H/k _D in excess of 50 are known, see:
• 17a Hoppe D. Paetow M. Hintze F. Angew. Chem., Int. Ed. Engl. 1993; 32: 394
• 17b Clayden J. Pink JH. Westlund N. Wilson FX. Tetrahedron Lett. 1998; 39: 8377
• 18 Compounds that differ only by the presence or absence of deuterium have the same number. In all cases, position 1 of the substituted cyclopentadienyl ring is attached to the oxazoline substituent. A compound is designated deuterated if it contains >50% D incorporation at the position indicated [i.e., D rather than (D)].
• 19 Synthesis of (S,S,R _p,R _p)-2,2′-d ₂-2Bisoxazoline (S,S)-2 (0.524 g, 1.28 mmol) was added to an oven-dried Schlenk tube under an atmosphere of argon and dissolved in dry diethyl ether (40 mL). Tetramethylethylenediamine (0.52 mL, 3.49 mmol) was added, and the subsequent orange solution was cooled to –78 °C and stirred for 5 min after which s-butyllithium (1.4 M in cyclohexanehexane, 2.40 mL, 3.4 mmol) was slowly added. After stirring for 5 h at –78 °C the reaction was quenched with methanol-d ₄ (0.40 mL, 10 mmol). The reaction was allowed to warm to room temperature, and after an additional 10 min, was washed with water (3 × 40 mL) followed by brine (40 mL). The diethyl ether layer was further dried (MgSO₄), filtered, and evaporated to give the product as an orange oil that crystallised on standing (0.51 g, 97%). HRMS (AS): m/z calcd for C₂₂H₂₆D₂FeN₂O₂ + H⁺ [M + H]⁺: 411.1699; found: 411.1697. ¹H NMR (500 MHz, CDCl₃) essentially identical to that of (S,S)-2 ^5a except for 4.74 (1.74 H, br s, CpH) and 4.77 (0.4 H, br s, CpH).
• 20 Lithiation of (S,S)-2 with s-BuLi (2.2 equiv) in THF followed by the addition of PPh₂Cl has previously been reported to result in 2.9:1 ratio of (S,S,S _p,S _p) and (S,S,R _p,S _p) diastereoisomers.^5c An attempt to use diethyl ether as the reaction solvent in place of THF with (S,S,R _p,R _p)-2,2′-d ₂-2 resulted in only monosilylation.
• 21 Synthesis of (S,S,R _p,S _p)-5-d-6 and (S,S,R _p,R _p)-5,5′-d ₂-7Bisoxazoline (S,S,R _p,R _p)-2,2′-d ₂-2 (0.099 g, 0.24 mmol) was added to an oven-dried Schlenk tube under an atmosphere of argon and dissolved in dry THF (4 mL). The subsequent orange solution was cooled to –78 °C and stirred for 5 min after which s-butyllithium (1.4 M in cyclohexane, 0.45 mL, 0.63 mmol) was slowly added. After stirring at –78 °C for 3 h, the mixture was stirred at 0 °C (ice bath) for a further 1.5 h. The reaction was quenched with trimethylsilyl chloride (0.09 mL, 0.72 mmol), removed from the ice bath, and stirred at r.t. for 30 min. Following the addition of water (20 mL), the mixture was extracted with diethyl ether (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO₄), filtered, and the solvent removed in vacuo. Column chromatography (SiO₂, 7% EtOAc in hexane) gave initially (S,S,R _p,R _p)-5,5-d ₂-7 (0.048 g, 36%) as an orange solid that crystallised on standing. Increasing the solvent polarity (15% EtOAc in hexane) then gave (S,S,R _p,S _p)-5-d-6 (0.055 g, 41%) also as an orange solid that crystallised on standing.(S,S,R _p,R _p)-5,5-d ₂-7 R_f = 0.65 (20% EtOAc in hexane); mp 83–84 °C; [α]_D ²² = –75 (c 0.56, CHCl₃). HRMS (AS): m/z calcd for C₂₈H₄₂D₂FeN₂O₂Si₂ + H⁺ [M+H]⁺: 555.2495; found: 555.2496. IR (film): ν_max = 2960, 2894, 1656 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 4.95 (0.08 H, dd, J 2.3, 1.5 Hz CpH), 4.33–4.31 (4 H, m, CpH), 4.29 (2 H, dd, J = 9.5, 8.1 Hz, CHH), 3.99 (2 H, t, J = 8.1 Hz, CHH), 3.92 (2 H, ddd, J = 9.5, 8.1, 6.4 Hz, CH), 1.82–1.72 (2 H, m, CH(CH₃)₂), 1.02 (6 H, d, J = 6.7 Hz, CH₃), 0.95 (6 H, d, J = 6.7 Hz, CH₃), 0.29 (18 H, s, Si(CH ₃)₃). ¹³C NMR (125 MHz, CDCl₃): δ = 165.2, 78.5, 76.8, 74.3, 73.6, 73.0, 70.0, 32.9, 19.1, 18.7, 0.5.
• 22 Synthesis of (S,S,R _p,S _p)-5-d-8 and (S,S,S _p,S _p)-5,5′d ₂-9Prepared in essentially the same way as described²¹ starting from (S,S,R _p,R _p)-2,2′-d ₂-2 (0.100 g, 0.24 mmol) with the reaction quenched by the addition over approximately 1 min of a solution of benzophenone (0.137 g, 0.75 mmol) in THF (1 mL). Column chromatography (SiO₂, 3–5% EtOAc in hexane) gave initially (S,S,S _p,S _p)-5,5′-d ₂-9 (0.062 g, 33%) as an orange crystalline solid followed by (S,S,R _p,S _p)-5-d-8 (0.059 g, 31%) as an orange oil that solidified on standing.(S,S,S _p,S _p)-5,5-d ₂-9 R_f = 0.40 (5% EtOAc in hexane); mp 84–86 °C; [α]_D ²⁶ = +781 (c 0.52, CHCl₃). HRMS (AS): m/z calcd for C₄₈H₄₆D₂FeN₂O₄ + H⁺ [M + H]⁺: 775.3168; found: 775.3179. IR (film): ν_max = 3096, 2960, 2923, 1653 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.20 (2 H, br s, OH), 7.47–7.39 (4 H, m, o-PhH), 7.25–7.20 (4 H, m, o-PhH), 7.20–7.16 (2 H, m, p-PhH), 7.16–7.04 (10 H, m, m+p-PhH), 5.05 (0.08 H, br s, CpH), 4.38 (2 H, br s, CpH), 4.28 (2 H, br s, CHH), 3.94 (2 H, br s, CHH), 3.83 (2 H, br s, CH), 3.55 (2 H, br s, CpH), 1.20 (2 H, br s, CH(CH₃)₂), 0.54 (6 H, br s, CH₃), 0.33 (6 H, br s, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 166.2, 149.0, 146.0, 127.7, 127.6, 127.5, 127.2, 126.8, 126.6, 101.5, 77.0, 75.7, 72.2, 70.8, 70.1, 69.5, 32.6, 18.4, 17.1.