Non-nucleophilic Grignard Synthesis of Bridged Pyridine–Oxazoline Ligands and Evaluation in Palladium-Catalysed Allylic Alkylation

Abstract

The synthesis of eight pyridine-oxazoline ligands, five of which have never been reported previously, is described. The ligands were prepared in two efficient steps, initially preparing 2-pyridyl alkylnitriles, followed by their conversion into oxazolines ligands using chiral amino alcohols and zinc chloride. The 2-pyridyl nitriles are prepared via a novel S_NAr alkylation reaction of 2-bromopyridine with alkyl nitriles using methylmagnesium chloride as a non-nucleophilic base in conjunction with an amine mediator. This methodology allows preparation of the existing gem-dimethyl motif and its elaboration beyond previously prepared ligands in fewer steps with simplicity and scalability. The toleration of variation in the nitrile, halopyridine, and amino alcohol starting materials allows for other novel bridging substitution which gives new ligands with enhanced reactivity. The library of bridging ligands was applied to the Pd-catalysed allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate and afforded conversions of up to 100% and enantioselectivities of up to 68%.

Key words

nitriles - S_NAr alkylation - Grignard reaction - pyridine oxazoline - zinc chloride

Publication History

Received: 07 March 2023

Accepted after revision: 25 April 2023

Accepted Manuscript online:
25 April 2023

Article published online:
30 May 2023

• References and Notes

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• 9 1-(Pyridin-2-yl)cyclohexanecarbonitrile (8) – General 2-Pyridyl Nitrile Synthesis A three-neck round-bottom flask was fitted with a magnetic stirrer, reflux condenser, and anhydrous THF (25 mL). Diethylamine (180 μL, 1.8 mmol), cyclohexanecarbonitrile (6.4 mL, 54 mmol), and 2-bromopyridine (3.4 mL, 36 mmol) were added. MeMgCl (18 mL, 3 M in THF, 54 mmol) was added dropwise over a minute, and the reaction mixture was allowed to stir overnight at rt. The reaction mixture was quenched with saturated aqueous NH₄Cl followed by addition of Et₂O (2 × 20 mL). The organic layer was separated and washed using H₂O (2 × 10 mL) and brine (10 mL). The organic solution was dried over Na₂SO₄, filtered, and concentrated. The crude product was purified via bulb-to-bulb distillation at 100 °C at 2.0 mmHg to afford the title compound as an orange solid (4.0 g, 61%); mp 51–54 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.58 (ddd, J = 4.8, 1.7, 0.9 Hz, 1 H), 7.71 (td, J = 7.7, 1.8 Hz, 1 H), 7.58 (dt, J = 7.9, 1.1 Hz, 1 H), 7.22 (ddd, J = 7.5, 4.8, 1.1 Hz, 1 H), 2.14–2.06 (m, 2 H), 2.00 (td, J = 13.4, 12.9, 3.8 Hz, 2 H), 1.90–1.74 (m, 5 H), 1.34–1.25 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 159.7, 149.6, 137.3, 122.9, 122.7, 120.7, 46.9, 36.0, 25.0, 23.5. IR: 2933, 2861, 2228 (CN), 1587, 1469, 1443, 1432, 1148, 1023, 995 cm^–1.
• 10 2-{2-[(4S)-4-(propan-2-yl)-4,5-dihydro-1,3-oxazol-2-yl]propan-2-yl}pyridine (L1) – General PYOX Synthesis In a 50 mL Schlenk flask, ZnCl₂ (1.22 g, 9 mmol) was dried under vacuum and cooled under nitrogen. Once cooled, the ZnCl₂ was crushed. 2-Methyl-2-(pyridin-2-yl)propanenitrile (0.45 mL, 3 mmol) and (S)-valinol (0.37 mL, 3.3 mmol) were added to the flask with PhCl (3 mL). The mixture was stirred vigorously and allowed to reflux for 3 days under nitrogen. After cooling to rt, saturated aqueous NH₄Cl was added to the mixture and allowed to stir overnight. The organic phase was extracted with EtOAc (2 × 10 mL) and washed with H₂O (2 × 10 mL) and brine (2 × 10 mL). The organic phase was dried using anhydrous Na₂SO₄ and concentrated in vacuo to afford the product. The crude product was purified by column chromatography (cyclohexane–EtOAc, 8:2) and collected as a colourless (0.30 g, 43% yield); [α]_D –21.2 (c 0.08, EtOH, 20 °C). ¹H NMR (500 MHz, CHCl₃-d): δ = 8.52 (dd, J = 4.5, 2.3 Hz, 1 H), 7.61–7.54 (td, J = 7.4, 1.6 Hz, 1 H), 7.27 (dt, J = 7.8, 1.3 Hz, 1 H), 7.11–7.05 (ddd, 6.3, 2.1, 1.6 Hz, 1 H) 4.13 (m, 1 H), 3.98–3.90 (m, 2 H), 1.84–1.78 (m, 1 H), 1.61 (s, 6 H), 0.91 (d, J = 6.7 Hz, 3 H), 0.84 (d, J = 6.8 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 171.7, 164.1, 149.0, 136.5, 121.7, 120.4, 71.7, 69.9, 43.8, 32.4, 26.9, 26.4, 18.9, 17.6. IR: 2960, 2931, 2873, 1658, 1588, 1470, 1384, 1246, 1112, 981, 790 cm^–1. R_f = 0.45 (PE– EtOAc, 8:2).
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• 12 General Procedure for the Pd-Catalysed Allylic Alkylation To a flame-dried Schlenk tube were added a solution of the ligand (0.024 mmol) and [(η₃-C₃H₅)PdCl]₂ (0.01 mmol) in CH₂Cl₂ (1 mL), and the mixture was stirred for 30 min at rt. The solution was transferred through a cotton plug to a round-bottom flask. rac-(E)-1,3-Diphenyl-3-acetoxyprop-1-ene (0.40 mmol) in CH₂Cl₂ (2 mL), dimethyl malonate (1.2 mmol), bis(trimethylsilyl)acetamide (1.2 mmol), and potassium acetate (0.014 mmol) were added successively, and the resulting mixture was allowed to stir at rt for 36 h. Saturated NH₄Cl solution (5 mL) was added, and the organic layer was extracted with diethyl ether (3 × 5 mL). The combined organics were washed with brine (10 mL), dried, filtered, and concentrated in vacuo, affording the crude product. The crude product was then purified by flash column chromatography (PE– EtOAc, 9:1) yielding the product as a colourless oil, which solidified on standing. ¹H NMR (500 MHz, CDCl₃): δ = 7.36–7.07 (m, 10 H), 6.44 (d, J = 15.7 Hz, 1 H), 6.29 (dd, J = 15.7, 8.6 Hz, 1 H), 4.23 (dd, J = 10.9, 8.6 Hz, 1 H), 3.92 (d, J = 10.9 Hz, 1 H), 3.66 (s, 3 H), 3.47 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 168.2, 167.8, 140.2, 136.8, 131.8, 129.1, 128.7, 128.5, 127.9, 127.6, 127.2, 126.4, 57.7, 52.6, 52.5, 49.2. IR: 1749, 1730, 1494, 1227, 1210, 1142 cm^–1. Enantioselectivity was determined by HPLC using a chiral column, Daicel Chiralcel OD 25 cm × 4.6 mm, 5 µm, 254 nm, hexane–IPA, 98:2, 0.5 mL/min.
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