The Synthesis of Novel P,N-Ferrocenylpyrrolidine-Containing Ligands and Their Application in Pd-Catalyzed Allylic Alkylation – A Synthetic and Mechanistic Investigation

Abstract

The synthesis of a series of planar chiral P,N-ferrocenylpyrrolidine-containing ligands, with varying substituents at the phosphorus donor atom, is described. The phosphorus donor atom was introduced via a diastereoselective ortho-directed metalation of N-methylpyrrolidinyl ferrocene followed by a quench with various chlorophosphines. These P,N systems are very active in Pd-catalyzed allylic alkylation of 1,3-diphenylpropenyl acetate with dimethylmalonate (conversions of up to 100%) and demonstrated good levels of enantioselectivity (up to 85% ees). Good selectivity for the (R)-enantiomer was observed and mechanistic studies, involving X-ray crystallography and NMR spectroscopic experiments, were employed to help rationalize the observed stereochemical outcome of the reaction.

Key words

ferrocene - chiral ligand - pyrrolidine - asymmetric catalysis - Pd-catalyzed allylic alkylation

Publication History

Received: 23 August 2022

Accepted after revision: 06 September 2022

Article published online:
12 October 2022

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• 39 Preparation of 2-[(2R)-N-Methylpyrrolidin-2′yl]-(1R)-ferrocenyldi(aryl/alkyl)-phosphines 8a–c To a solution of (R)-1-ferrocenyl-2-methylpyrrolidine (7, 0.63 g, 2.12 mmol) in dry diethyl ether (7 mL) at –78 °C, sec-butyllithium (1.97 mL, 1.4 M, 2.76 mmol) was added dropwise. The orange suspension was stirred for 3 h at this temperature and at 0 °C for 90 min to ensure complete lithiation. The relevant chlorophosphine (2.76 mmol) was added as a solution in diethyl ether (3 mL) at 0 °C, and the reaction was stirred at room temperature for a further hour. The reaction was quenched with 10 % ammonium chloride (5 mL) and extracted with diethyl ether (3 × 8 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na₂SO₄), and concentrated to give the crude product as an orange oil. The crude product contained a mixture of diastereomers (80–85% de), which were separated by column chromatography. Analytical Data of Compound (R,R _p)-8a Isolated as an orange sticky solid in 51% yield; R_f = 0.64 (Al, 5:1 pentane/ethyl acetate); [α]_D +184.0 (c = 0.5, CHCl₃). IR (KBr disc): ν_max = 3020, 2926, 2400, 1216 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 1.15–1.50 (m, 9 H, Cy), 1.55–1.75 (m, 8 H, Cy, H_4′b), 1.85–1.90 (m, 3 H, Cy, H_4′a), 1.95–2.10 (m, 3 H, Cy), 2.18–2.25 (m, 2 H, H_3′b, H_5′b), 2.27 (s, 3 H, N–Me), 2.32–2.38 (m, 1 H, Cy), 2.40–2.48 (m, 1 H, H_3′a), 2.97 (app t, J = 8.0 Hz, 1 H, H_2′), 3.07 (app t, J = 8.0 Hz, 1 H, H_5′a), 4.10 (br s, 1 H, CpH₅), 4.13 (s, 5 H, unsub. Cp), 4.21 (br s, 1 H, CpH₃), 4.23 (app t, J = 2.1 Hz, 1 H, CpH₄). ¹³C NMR (151 MHz, CDCl₃): δ = 23.0 (d, ⁵ J _P,_C = 1.0 Hz, C_4′), 26.5 (d, ⁴ J _P,_C = 1.0 Hz, Cy), 26.6 (d, ⁴ J _P,_C = 1.0 Hz, Cy), 27.3 (d, ³ J _P,_C = 7.5 Hz, Cy), 27.6 (d, ³ J _P,_C = 7.4 Hz, Cy), 27.7 (d, ² J _P,_C = 13.2 Hz, Cy), 28.2 (d, ² J _P,_C = 12.3 Hz, Cy), 29.1 (d, ³ J _P,_C = 7.5 Hz, Cy), 30.1 (d, ³ J _P._C = 8.8 Hz, Cy), 32.1 (d, ² J _P,_C = 16.4 Hz, Cy), 32.7 (d, ² J _P,_C = 20.2 Hz, Cy), 33.6 (d, ⁴ J _P,_C = 12.1 Hz, C_3’), 35.0 (d, ¹ J _P,_C = 12.5 Hz, Cy), 36.3 (d, ¹ J _P,_C = 13.0 Hz, Cy), 40.9 (N–Me), 58.1 (C_5′), 66.0 (d, ³ J _P,_C = 1.7 Hz, C_2′), 67.5 (CpC₄), 69.5 (Cp), 70.8 (d, ³ J _P,_C = 3.0 Hz, CpC₃), 71.0 (d, ² J _P,_C = 2.5 Hz, CpC₅), 77.7 (d, ¹ J _P,_C = 22.7 Hz, CpC₁), 94.2 (d, ² J _P,_C = 16.7 Hz, CpC₂). ³¹P NMR (243 MHz, CDCl₃): δ = –11.0. Anal. Calcd for C₂₇H₄₀FeNP: C, 69.67; H, 8.66; N, 3.01. Found: C, 70.07; H, 8.75; N, 2.74. ESI-HRMS: m/z calcd for C₂₇H₄₀FeNP [M + H]: 466.2326; found: 466.2343.