Synthesis of a Novel Unsymmetrical Bisoxazoline Ligand with sp^² Bridging Carbon

Abstract

A novel unsymmetrical bisoxazoline ligand was synthesized in one step by the Knoevenagel condensation of aldehydes with a C ₂-symmetric indane-derived bisoxazoline having two acidic hydrogens connected to the bridging carbon. The electronic properties of incorporated bridge substituent due to π-π conjugation with oxazoline rings can affect the catalytic performance of the ligand in asymmetric syntheses, as was shown for the Henry reaction between benzaldehyde and nitromethane.

Key words

bisoxazoline ligands - asymmetric catalysis - asymmetric synthesis - transition-metal complexes - Henry reaction

References and Notes

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• HPLC conditions used
• 16a

  for quantification of 2-nitro-1-phenylethanol and benzaldehyde: RP-8 column (Merck), 30 ˚C, 67 mM KH₂PO₄-MeOH (65:35), 2 mL/min, 225 nm;

• 16b

  for determination of ee of 2-nitro-1-phenylethanol: OD-RH column (Chiralcel), 5 ˚C, MeOH-H₂O (65:35), 0.2 mL/min, 225 nm.

• For discussion on the influence of ligand bite angle on the enantioselectivity in the Diels-Alder reaction, see:
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7

Representative Procedure for the Synthesis of Ligands 1-7
IndaBOX (1 mmol), aldehyde (1 mmol), and piperidinium acetate (0.2 mmol) were dissolved in pyridine (5 mL) at 65 ˚C while stirring. The obtained solution was maintained at the same temperature for 24 h. At the end the solvent is evaporated in vacuo and the solid residue purified by column chromatography on silica using EtOAc as an eluent. For the synthesis of ligand 7 only 0.05 mmol of aldehyde was added, and a EtOAc-MeOH mixture (10:1) was used as an eluent. Ligand 6 was isolated by pouring the reaction mixture into H₂O (50 mL), filtering the precipitate, and washing it on the filter with i-PrOH (25 mL) and CH₂Cl₂ (25 mL).

8

Characterization Data for Ligands 1-7
2,2′-(2-Cyclohexylethene-1,1-diyl)bis(8,8a-dihydro-3a H -indeno[1,2- d ]oxazole) (1)
^¹H NMR (400 MHz, CDCl₃): δ = 7.47-7.37 (m, 2 H), 7.21-7.11 (m, 6 H), 6.43 (d, J = 10.0 Hz, 1 H), 5.65 (d, J = 7.6 Hz, 1 H), 5.59 (d, J = 7.9 Hz, 1 H), 5.32 (ddd, J = 7.6, 6.5, 1.2 Hz, 1 H), 5.24 (ddd, J = 7.9, 6.7, 1.6 Hz, 1 H), 3.35 (dd, J = 18.0, 6.5 Hz, 1 H), 3.32 (dd, J = 18.3, 6.7 Hz, 1 H), 3.23-3.13 (m, 2 H), 1.89-1.74 (m, 1 H), 1.47-1.24 (m, 5 H), 0.99-0.58 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.8, 161.1, 151.9, 142.1, 141.8, 139.8, 139.5, 128.4, 128.3, 127.4, 127.3, 125.8, 125.6, 125.2, 125.1, 118.4, 83.2, 83.0, 77.1, 76.7, 39.7, 39.5, 38.6, 31.9, 31.6, 25.6, 25.3, 25.1. MS (EI): m/z = 424 [M].
2,2′-[2-(4-Methoxyphenyl)ethene-1,1-diyl]bis(8,8a-dihydro-3a H -indeno[1,2- d ]oxazole) (2)
^¹H NMR (400 MHz, CDCl₃): δ = 7.45-7.07 (m, 9 H), 6.83-6.67 (m, 2 H), 6.28-6.22 (m, 2 H), 5.75 (d, J = 7.7 Hz, 1 H), 5.64 (d, J = 7.8 Hz, 1 H), 5.40-5.30 (m, 2 H), 3.63 (s, 3 H), 3.39 (dd, J = 18.1, 6.7 Hz, 1 H), 3.36 (dd, J = 18.1, 6.7 Hz, 1 H), 3.25 (d, J = 17.9 Hz, 1 H), 3.16 (d, J = 18.1 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.2, 160.4, 159.7, 141.0, 139.9, 139.2, 138.8, 130.4, 127.6, 126.8, 126.4, 124.9, 124.8, 124.4, 114.5, 112.6, 82.5, 82.2, 76.3, 76.0, 54.3, 38.6, 38.3. MS (EI): m/z = 447 [M - H].
2,2′-[2-(4-Chlorophenyl)ethene-1,1-diyl]bis(8,8a-dihydro-3a H -indeno[1,2- d ]oxazole) (3)
^¹H NMR (400 MHz, CDCl₃): δ = 7.49-7.16 (m, 9 H), 6.80-6.65 (m, 4 H), 5.75 (d, J = 7.6 Hz, 1 H), 5.68 (d, J = 7.8 Hz, 1 H), 5.36 (ddd, J = 7.2, 6.4, 0.9 Hz, 1 H), 5.33 (ddd, J = 7.2, 6.4, 1.7 Hz, 1 H), 3.38 (dd, J = 17.9, 6.7 Hz, 1 H), 3.32 (dd, J = 17.0, 6.1 Hz, 1 H), 3.26 (dd, J = 17.4, 1.0 Hz, 1 H), 3.10 (d, J = 18.0 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 162.2, 160.9, 141.6, 140.7, 140.0, 139.9, 139.7, 135.2, 132.0, 130.5, 128.7, 128.5, 128.3, 127.8, 127.5, 125.9, 125.2, 125.1, 118.9, 83.7, 83.4, 77.3, 76.9, 39.5, 39.1. MS (EI): m/z = 451 [M - H].
4-{2,2-Bis(8,8a-dihydro-3a H -indeno[1,2- d ]oxazol-2-yl)vinyl}benzonitrile (4)
^¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.16 (m, 9 H), 6.98-6.87 (m, 4 H), 5.72 (d, J = 7.6 Hz, 1 H), 5.70 (d, J = 7.9 Hz, 1 H), 5.38-5.31 (m, 2 H), 3.39 (dd, J = 18.0, 6.7 Hz, 1 H), 3.31 (dd, J = 16.6, 6.5 Hz, 1 H), 3.26 (dd, J = 17.0, 1.1 Hz, 1 H), 3.05 (d, J = 18.2 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.7, 160.4, 141.4, 140.4, 139.9, 139.6, 139.0, 137.9, 131.7, 129.4, 128.9, 128.6, 127.9, 127.5, 125.9, 125.3, 125.2, 121.8, 118.5, 112.2, 84.0, 83.6, 77.4, 76.9, 39.5, 39.1. MS (EI): m/z = 442 [M - H].
2,2′-[2-(4-Nitrophenyl)ethene-1,1-diyl]bis(8,8a-dihydro-3a H -indeno[1,2- d ]oxazole) (5)
^¹H NMR (400 MHz, CDCl₃): δ = 7.53-7.15 (m, 11 H), 6.98-6.92 (m, 2 H), 5.72 (d, J = 6.4 Hz, 1 H), 5.70 (d, J = 6.4 Hz, 1 H), 5.38-5.32 (m, 2 H), 3.39 (dd, J = 18.0, 6.7 Hz, 1 H), 3.31 (dd, J = 17.9, 6.5 Hz, 1 H), 3.27 (dd, J = 18.0, 1.0 Hz, 1 H), 3.06 (d, J = 18.2 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.6, 160.3, 147.4, 141.4, 140.4, 139.9, 139.8, 139.6, 138.7, 129.6, 129.0, 128.7, 127.9, 127.5, 125.9, 125.8, 125.3, 125.2, 123.2, 122.4, 84.1, 83.6, 77.5, 76.9, 39.5, 39.1. MS (EI): m/z = 462 [M - H].
4-{2,2-Bis(8,8a-dihydro-3a H -indeno[1,2- d ]oxazol-2-yl)vinyl}phenol (6)
^¹H NMR (400 MHz, DMSO-d ₆): δ = 10.7 (s, 1 H), 7.38-7.16 (m, 9 H), 6.82-6.75 (m, 2 H), 6.40-6.33 (m, 2 H), 5.65 (d, J = 7.7 Hz, 1 H), 5.56 (d, J = 7.9 Hz, 1 H), 5.43-5.31 (m, 2 H), 3.40 (dd, J = 18.1, 7.0 Hz, 1 H), 3.37 (dd, J = 18.0, 6.7 Hz, 1 H), 3.09 (d, J = 17.4 Hz, 1 H), 3.05 (d, J = 17.8 Hz, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.6, 160.1, 159.8, 141.8, 140.6, 140.1, 139.8, 139.6, 131.4, 128.4, 128.2, 127.2, 127.1, 125.4, 125.3, 125.2, 125.1, 123.3, 115.2, 113.5, 82.8, 82.5, 76.3, 76.2, 39.1, 38.8. MS (EI): m/z = 433 [M - H].
1,4-Bis{2,2-bis(8,8a-dihydro-3a H -indeno[1,2- d ]oxazol-2-yl)vinyl}benzene (7)
^¹H NMR (400 MHz, CDCl₃): δ = 7.49-7.14 (m, 18 H), 6.35 (s, 4 H), 5.71 (d, J = 7.7 Hz, 2 H), 5.68 (d, J = 7.9 Hz, 2 H), 5.36-5.28 (m, 4 H), 3.39 (dd, J = 18.0, 6.6 Hz, 2 H), 3.32-3.22 (m, 4 H), 3.03 (d, J = 18.1 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 162.3, 160.8, 141.7, 140.7, 140.4, 139.9, 139.7, 134.4, 129.0, 128.6, 128.5, 127.7, 127.5, 125.9, 125.8, 125.2, 125.0, 119.0, 83.6, 83.4, 77.3, 76.9, 39.6, 39.1. MS-FAB: m/z = 759 [M + H].

14

The ligands (1 equiv) were mixed with Cu(OAc)₂ (1.5 equiv) in CH₂Cl₂ at r.t. overnight. The uncomplexed salt was removed from the resulting solutions by extraction with H₂O (3×). The organic phases were dried over anhyd Na₂SO₄, the solvent was evaporated in vacuo yielding the complexes as dark solids.