Chiral-at-Ru Catalyst with Cyclometalated Imidazo[1,5-a]pyridin­ylidene for Enantioselective Intramolecular Cyclopropanations

Dedicated to Prof. Masahiro Murakami’s impressive career accomplishments

Abstract

A chiral ruthenium catalyst is introduced which contains a cyclometalated N-(3-nitrophenyl)-imidazo[1,5-a]pyridinylidene ligand in addition to a bidentate 4-mesityl-2-(pyridin-2-yl)thiazole and two acetonitriles to complement the octahedral coordination sphere of the monocationic complex. Tetrafluoroborate serves as the counterion. Since all coordinated ligands are achiral, the overall chirality is formally due to a stereogenic metal center generating either a left-handed (Λ) or right-handed (Δ) helical topology of this chiral-at-metal complex. Nonracemic Λ and Δ complexes were synthesized using (R)- and (S)-N-benzoyl-tert-butanesulfinamide as chiral auxiliary ligands, respectively. The position of the nitro group in the metalated phenyl moiety is of crucial importance for the generation of enantiomerically pure complexes. The catalytic activity of the cycloruthenated chiral-at-metal catalyst was demonstrated for the enantioselective intramolecular cyclopropanation of trans-cinnamyl diazoacetate and an alkenyl diazoketone to generate bicyclic cyclopropanes in high yields (96–97%) and with satisfactory enantioselectivity (93% ee).

Key words

cyclometalation - imidazo[1,5-a]pyridinylidene - chiral-at-metal - stereogenic metal - ruthenium - asymmetric catalysis - cyclopropanation

Publication History

Received: 07 August 2022

Accepted: 06 September 2022

Article published online:
19 October 2022

• References and Notes

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• 15 Ru1b To a 10 mL Schlenk tube was added ligand 1b (275 mg, 1 mmol, 2.0 equiv), [Ru(η⁶-C₆H₆)Cl₂]₂ (305 mg, 0.5 mmol, 1.0 equiv), KPF₆ (368 mg, 2 mmol, 4.0 equiv), NaOAc (82 mg, 1 mmol, 2.0 equiv), Ag₂O (231 mg, 1 mmol, 2.0 equiv), and MeCN (10 mL). The resulting solution was heated at 85 °C overnight. Afterwards, the liquid phase was removed by filtration, and the resulting residue was dried under high vacuum to provide the crude product which was purified by silica gel column chromatography (CH₂Cl₂–MeCN, 50:1). The ruthenium complex Ru1b was obtained as a red solid (305 mg, 0.47 mmol, 94% yield). ¹H NMR (300 MHz, CD₃CN): δ = 8.61 (dq, J = 7.4, 0.9 Hz, 1 H), 8.29 (d, J = 8.3 Hz, 1 H), 8.22–8.20 (m, 2 H), 7.82 (dd, J = 8.4, 2.4 Hz, 1 H), 7.39 (dt, J = 9.3, 1.1 Hz, 1 H), 6.88 (dd, J = 9.3, 6.2 Hz, 1 H), 6.73–6.68 (m, 1 H), 2.00 (s, 6 H), 1.97 (s, 6 H) ppm. ¹³C NMR (75 MHz, CD₃CN): δ = 193.6, 183.9, 150.1, 143.7, 139.5, 132.3, 127.3, 122.6, 118.6, 117.5, 113.3, 106.3, 105.0, 3.2, 1.5, 1.1, 0.8 ppm. ¹⁹F NMR (282 MHz, CD₃CN): δ = –72.9 (d, J _P–F = 707 Hz, 6 F) ppm. IR (neat): ν = 3507, 3117, 3080, 2917, 1775, 1685, 1503, 1168, 1003, 956, 895, 665, 641, 608 cm^–1. HRMS (APCI): m/z calcd for [C₂₁H₂₀N₇O₂Ru]⁺ [(M – PF₆)⁺]: 504.0716; found: 504.0756.
• 16 rac-Ru2b To a 10 mL Schlenk tube was added precursor Ru1b (259 mg, 0.4 mmol, 1.0 equiv) and 2 (140 mg, 0.5 mmol, 1.2 equiv). CH₂Cl₂ (10 mL, 0.04 M) was added, and the resulting solution was stirred at 40 ℃ overnight. Afterwards, the liquid phase was removed by filtration. The residue was dried under reduced pressure and purified by silica gel column chromatography (CH₂Cl₂–MeCN, 100:1 → 50:1) to afford rac-Ru2b as a purple solid (324 mg, 0.38 mmol, 96%). TLC (CH₂Cl₂–MeCN, 4:1): R_f = 0.4. ¹H NMR (500 MHz, CDCl₃): δ = 10.9 (d, J = 5.7 Hz, 1 H), 8.24–8.20 (m, 2 H), 7.93 (td, J = 7.4, 1.2 Hz, 1 H), 7.68–7.65 (m, 2 H), 7.60–7.57 (m, 1 H), 7.54 (s, 1 H), 7.43–7.38 (m, 2 H), 7.36–7.32 (m, 2 H), 7.12 (d, J = 8.7 Hz, 1 H), 6.89 (s, 1 H), 6.85 (d, J = 9.3 Hz, 1 H), 6.50 (dd, J = 8.6, 5.8 Hz, 1 H), 6.47 (s, 1 H), 6.41 (s, 1 H), 6.01 (ddd, J = 6.9, 6.0, 1.2 Hz, 1 H), 2.25 (s, 3 H), 2.10 (s, 3 H), 1.31 (s, 3 H), 0.41 (s, 9 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 186.4, 178.6, 173.2, 165.7, 158.7, 156.6, 152.1, 144.6, 137.2, 155.0, 137.0, 136.1, 135.4, 135.3, 133.2, 133.15, 132.9, 130.4, 129.8, 129.7, 129.1, 128.9, 128.3, 127.8, 127.7, 126.0, 122.3, 122.2, 118.1, 117.5, 117.0, 111.8, 110.3, 104.6, 66.4, 23.3, 22.2, 21.7, 21.0, 20.7 ppm. ¹⁹F NMR (282 MHz, CD₃CN): δ = –72.9 (d, J _P–F = 707 Hz, 6 F) ppm. IR (neat): ν = 3120. 2920, 2263, 2053, 1600, 1571, 1345, 1298, 1002, 831, 777, 665 cm^–1. HRMS (APCI): m/z calcd for [C₃₄H₃₀N₇O₂RuS]⁺ [(M – PF₆)⁺]: 702.1228; found: 702.1197.
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• 18 Λ-(S)-Ru3bTo a 10 mL Schlenk tube was added rac-Ru2b (see the Supporting Information for the synthesis) (169 mg, 0.2 mmol, 1 equiv), (R)-N-(phenylsulfinyl)benzamide (90 mg, 0.4 mmol, 4 equiv), and K₂CO₃ (82 mg, 0.6 mmol, 3 equiv). EtOH (2 mL, 0.1 M) was added, and the resulting solution was stirred at 100 °C in a sealed Schlenk tube for 4 h. Afterwards, the liquid phase was removed by filtration. The residue was dried under reduced pressure and was purified by column chromatography (CH₂Cl₂–EtOAc, 10:1 → 1:1) to afford Λ-(S)-Ru3b as a purple solid (39 mg, 0.046 mmol, 46%). TLC (CH₂Cl₂–EtOAc, 1:1): R_f = 0.5. ¹H NMR (300 MHz, CDCl₃): δ = 10.8 (d, J = 5.7 Hz, 1 H), 8.24–8.20 (m, 2 H), 8.02 (d, J = 7.4 Hz, 1 H), 7.91 (td, J = 7.4, 1.4 Hz, 1 H), 7.90 (d, J = 2.2 Hz, 1 H), 7.65 (dd, J = 7.3, 0.8 Hz, 1 H), 7.62 (s, 1 H), 7.55 (ddd, J = 7.4, 5.8, 1.4 Hz, 1 H), 7.50–7.49 (m, 1 H), 7.48 (dd, J = 8.3, 2.2 Hz, 1 H), 7.43–7.38 (m, 1 H), 7.36–7.32 (m, 1 H), 6.91 (s, 1 H), 6.88 (dt, J = 9.3, 1.0 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 6.52 (dd, J = 9.3, 6.2 Hz, 1 H), 6.48 (s, 1 H), 6.40 (s, 1 H), 6.03 (ddd, J = 6.7, 6.3, 1.0 Hz, 1 H), 2.23 (s, 3 H), 2.10 (s, 3 H), 1.36 (s, 3 H), 0.39 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 196.1, 183.8, 178.4, 165.8, 158.8, 156.5, 152.5, 149.5, 142.0, 138.5, 137.1, 137.0, 136.1, 135.3, 133.2, 133.0, 130.5, 129.9, 129.4, 129.1, 128.9, 128.5, 128.0, 127.9, 127.7, 125.9, 122.1, 122.0, 118.3, 118.2, 117.6, 111.9, 104.6, 104.2, 66.8, 23.2, 22.2, 21.7, 20.9, 20.8 ppm. IR (neat): ν = 3063, 2965, 2921, 1735, 1600, 1406, 1240, 1054, 1022, 707, 600 cm^–1. HRMS (APCI): m/z calcd for [C₄₁H₃₉N₆O₄RuS₂]⁺ [(M + H)⁺]: 845.1522; found: 845.1522. CD (CH₂Cl₂): λ, nm (Δε, M^–1 cm^–1): 255 (–9), 309 (+19), 340 (–4), 390 (+1), 450 (–5), 515 (+10).
• 19 Δ-(R)-Ru3b Following the same procedure as for Λ-(S)-Ru3b, the reaction of rac-Ru2b with (S)-N-(phenylsulfinyl) benzamide afforded Δ-(R)-Ru3b as a purple solid (38 mg, 0.045 mmol, 45% yield). Δ-(R)-Ru3b and Λ-(S)-Ru3b are enantiomers. CD (CH₂Cl₂): λ, nm (Δε, M^–1 cm^–1) 255 (+9), 309 (–19), 340 (+4), 390 (–1), 450 (+5), 515 (–10). All other spectroscopic data are in agreement with the enantiomer Λ-(S)-Ru3b.
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• 22 Λ-Ru2bTo a 10 mL Schlenk tube was added Λ-(S)-Ru3b (83 mg, 0.1 mmol, 1 equiv) and NH₄BF₄ (163 mg, 1 mmol, 10 equiv). MeCN (1 mL, 0.1 M) and H₂O (0.2 mL) were added, and the resulting solution was stirred at 60 °C for 16 h. Afterwards, the liquid phase was removed by filtration. The residue was dried under reduced pressure and purified by silica gel column chromatography. The chiral auxiliary (R)-N-(tert-butylsulfinyl)benzamide could be recovered as a colorless oil (21 mg, 0.093 mmol, 93%) using the eluent CH₂Cl₂–MeCN (200:1). Increasing the polarity to CH₂Cl₂–MeCN (20:1) then provided Λ-Ru2b as a red solid (82 mg, 0.095 mmol, 95%). ¹⁹F NMR (282 MHz, CD₃CN): δ = –151.0, –151.1 ppm. Enantiomeric excess was established by HPLC analysis using a Daicel Chiralpak IB-N5 column, ee = 99.1% (HPLC: 254 nm, H₂O + 0.1% TFA–MeCN = 50:50, flow rate 1 mL/min, 25 °C, t _R (Λ-Ru2b) = 16.9 min, t _R (Δ-Ru2b) = 19.3 min). CD (CH₃CN): λ, nm (Δε, M^–1 cm^–1) 265 (+30), 309 (+8), 318 (–16), 375 (+2), 450 (+12), 505 (–1). All other spectroscopic data are in agreement with rac-Ru2b.
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• 26 (1R,5S,6S)-6-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one (6) A pre-dried 10 mL Schlenk tube was charged with Λ-Ru2b (4.2 mg, 0.05 mmol, 1 mol%). The tube was evacuated and backfilled with nitrogen for three times. A solution of the diazo substrate 5 (101 mg, 0.5 mmol, 1 equiv.) dissolved in distilled CH₂Cl₂ (2.5 mL, 0.2 M) was added via syringe. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 min. Afterwards, the mixture was directly transferred to a silica gel column and purified by flash chromatography (EtOAc–n-hexane, 1:50 → 1:10) to afford analytical pure product 6 as a white solid (84.4 mg, 0.485 mmol, 97% isolated yield) with 93% ee as determined by GC analysis (Macherey-Nagel HYDRODEX β-TBDAc column, Agilent GC 7820A, oven temperature = 190 °C, H₂, FID; t _R (major) = 8.0 min, t _R (minor) = 9.8 min). [α]_D ²⁵ +127 (CH₂Cl₂, c 1.0). Spectroscopic data are in agreement with ref. 28.
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• 29 (1S,5S,6S)-6-Phenylbicyclo[3.1.0]hexan-2-one (8) A pre-dried 10 mL Schlenk tube was charged with Λ-Ru2b (4.2 mg, 0.05 mmol, 1 mol%). The tube was evacuated and backfilled with nitrogen for three times. A solution of the diazo substrate 7 (100 mg, 0.5 mmol, 1 equiv) dissolved in distilled CH₂Cl₂ (2.5 mL, 0.2 M) was added via syringe. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 min. Afterwards, the mixture was directly transferred to a column and purified by flash chromatography on silica gel (EtOAc–n-hexane, 1:50 → 1:10) to afford analytical pure product 8 that was obtained as a white solid (82.5 mg, 0.48 mmol, 96% yield) with 93% ee as determined by GC analysis (Macherey-Nagel HYDRODEX β-TBDAc column, Agilent GC 7820A, oven temperature = 140 °C, H₂, FID; t _R (major) = 16.9 min, t _R (minor) = 17.4 min). [α]_D ²⁵ +116 (CH₂Cl₂, c 1.0). Spectroscopic data are in agreement with ref. 28.