Enantioselective Alkynylation of Aromatic Aldehydes: Pyridyl Phenylene Terpeneol Catalysts with Flexible Biaryl Axes

Abstract

Free rotating biaryl axes of pyridyl phenylene terpenols are fixed by zinc cations to give conformationally pure zinc complexes. These zinc alkoxide catalysts provide yields up to 99% and ee values up to 86% in the enantioselective addition of phenylacetylene to aromatic aldehydes.

Key words

enantioselectivity - biaryls - organometallic reagents - zinc - alkynes

References and Notes

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  No HPLC reference data available in the literature;

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10

All reactions were carried out under an argon atmosphere using Schlenk techniques. Solvents used in chemical conversions were dried by standard methods and distilled under argon prior to use. The enantiomeric excesses of the chiral propargylic alcohols were determined by chiral HPLC. A La Chrome elite unit from Hitachi was employed together with a 25 cm Chiracel OD-H chiral column (flow: 0.8 mL/min; pressure: 32 bar; detection λ = 240 nm; eluent: 90% n-hexanes and 10% i-propanol). The enantiomers of the alcohols were identified by comparison to reference spectra.^¹¹
NMR spectroscopy. Deuterated solvents where purchased from Acros Organics. Toluene-d ₈ was stored over sodium-lead alloy. NMR spectra for characterization of compounds where recorded with a Bruker DPX 300 spectrometer (^¹H frequency 300.13 MHz). 2D NMR and one-dimensional high resolution spectra for analysis of the catalytically active system were recorded with a Bruker AVANCE II 600 spectrometer (^¹H frequency 600.20 MHz) using a triple resonance Z gradient probe and processed using TopSpin 2.1 software (Bruker inc.). The temperature was calibrated with a 100% MeOH sample. 600 MHz 1D and 2D NMR experiments were carried out according to the following procedures.
Characterization of the methyl zinc alkoxide based on ligand 1: Ligand 1 (0.026 mmol, 10 mg) was charged into
a NMR tube and degassed in vacuo for 10 min. absolute toluene-d ₈ (0.30 mL) was added prior to addition of dimethyl zinc (2 M in toluene, 0.8 mL, 0.156 mmol). The constitution of the formed methyl zinc complex was confirmed by H,C-HMQC, H,N-HMQC and H,H-NOESY spectroscopic analysis at a temperature of 295 K. The conformation of the chiral biaryl axis was determined by characteristic NOE contacts.
In situ study of the reaction of the methyl zinc alkoxide based on 1 with phenylacetylene: A sample was prepared as described above. The mixture was equilibrated over a period of 30 min and phenylacetylene (0.02 mL, 0.156 mmol) was added. The mixture was equilibrated for 1 h
prior to use for measurements. The methylzinc alkoxide derivative of 1 was shown to be almost completely converted into a new species, which was analyzed by H,C-HMQC, H,C-HMBC, H,N-HMQC, and H,H-NOESY spectroscopy at a temperature of 295 K.
Procedure A: Pyridyl phenylene terpenol (0.074 mmol;
5 mol%; 1: 28 mg; 2: 29 mg; 3: 28 mg) was degassed in vacuum for 10 min, then dissolved in toluene (6 mL) and a solution of dimethyl zinc (2.0 M in toluene, 1.80 mL 3.6 mmol) was added at 0 ˚C. The ice bath was removed and the catalyst was equilibrated for 30 min at r.t. Phenylacetylene (3 mmol, 0.33 mL) was added at r.t. and the mixture was further stirred for 45 min. The mixture was cooled on the ice bath again and aldehyde (1.0 mmol) was added. The colorless solution was kept at 0 ˚C for 3 days and the reaction was subsequently quenched with saturated NaHSO₄ (5 mL). The organic phase was separated, the aqueous phase was extracted with MTBE (3 × 5 mL), and the combined organic phases were evaporated. The resulting oil was purified by column chromatography (n-hexanes-ethyl acetate, 4:1; 70 g SiO₂) to give the pure product.
Procedure B: See procedure A, with 5 min reaction time after adding phenylacetylene.
Procedure C: See procedure A, with 5 min reaction time after adding phenylacetylene and the solvent was replaced by a mixture of toluene and n-hexanes (1:1).
Procedure D: See procedure A, the precatalyst was stirred with dimethyl zinc (0.6 mmol) in toluene (3 mL) for 45 min and, separately, a mixture of dimethyl zinc (3.0 mmol) and phenylacetylene (3.0 mmol) in toluene (3 mL) was stirred for 30 min, then added to the catalyst complex at 0 ˚C.
1,3-Diphenylprop-2-yn-1-ol:^{¹¹b ¹}H NMR (300 MHz, CDCl₃): δ = 2.36 (s, 1 H), 5.72 (s, 1 H), 7.34-7.64 (m, 10 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 42.0, 118.1, 123.0, 128.9, 140.0. HPLC [Daicel Chiracel OD-H; λ = 254 nm; hexane-IPA = 90:10; 0.8 mL/min]: t _R = 10.7 (R), 17.4 (S) min.
1-(3-Fluorophenyl)-3-phenylprop-2-yn-1-ol:^{¹¹c ¹}H NMR (300 MHz, CDCl₃): δ = 1.28 (s, 1 H), 5.71 (s, 1 H), 7.28-7.50 (m, 9 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 64.3, 86.6, 88.2, 113.7, 115.3, 122.0, 122.0, 122.3, 128.4, 128.8, 130.2, 131.8, 143.2, 164.5. HPLC [Daicel Chiracel OD-H; λ = 254 nm; hexane-IPA = 90:10; 0.8 mL/min]: t _R = 9.4, 21.8 min.
( E )-1,5-Diphenylpent-1-en-4-yn-3-ol:^{¹¹a ¹}H NMR (300 MHz, CDCl₃): δ = 5.31 (t, J = 6.0 Hz, 1 H), 6.38 (m, 1 H), 6.90 (d, 1 H), 7.28-7.49 (m, 10 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 63.5, 86.5, 87.9, 122.4, 126.8, 128.1, 128.2, 128.4, 128.7, 131.9, 132.1, 136.0. HPLC [Daicel Chiracel OD-H; λ = 254 nm; hexane-IPA = 90:10; 0.8 mL/min]: t _R = 14.1 (R), 39.8 (S) min.
1-(Naphthalen-1-yl)-3-phenylprop-2-yn-1-ol:^{¹¹a ¹}H NMR (300 MHz, CDCl₃): δ = 2.40 (d, J = 6.0 Hz, 1 H), 6.38 (d, J = 5.9 Hz, 1 H), 7.40-7.80 (m, 8 H), 7.95 (d, J = 10.1 Hz, 1 H), 8.12 (d, J = 8.2 Hz, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 9.27 (d, J = 8.5 Hz, 1 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 63.3, 87.2, 89.0, 122.4, 124.9, 127.0, 128.4, 128.8, 130.7, 131.3, 131.8, 134.1, 135.4, 135.5, 138.0. HPLC [Daicel Chiracel OD-H; λ = 254 nm; hexane-IPA = 90:10; 0.8 mL/min]: t _R = 15.2 (R), 28.6 (S) min.
4,4-Dimethyl-1-phenylpent-1-yn-3-ol:^{¹¹d ¹}H NMR (300 MHz, CDCl₃): δ = 1.09 (s, 9 H), 1.95 (1 H), 4.26 (d, J = 5.9 Hz, 1 H), 7.28-7.46 (m, 5 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 25.4, 36.0, 71.9, 85.7, 89.0, 122.8, 128.3, 128.6, 131.7. HPLC [Daicel Chiracel OD-H; λ = 254 nm; hexane-IPA = 90:10; 0.8 mL/min]: t _R = 8.0 (R), 10.7 (S) min.