A Novel Synthetic Approach towards Chiral QUINAP via Diastereomeric Sulfoxide Intermediates

Tobias Thaler; Florian Geittner; Paul Knochel

doi:10.1055/s-2007-991047

LETTER

A Novel Synthetic Approach towards Chiral QUINAP via Diastereomeric Sulfoxide Intermediates

Tobias Thaler, Florian Geittner, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus F, 81377 München, Germany
Fax: +49(89)218077680; e-Mail: Paul.Knochel@cup.uni-muenchen.de;

Abstract

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Abstract

A novel enantioselective synthesis of chiral QUINAP is described. Hereby, the separation of the diastereomers was achieved by the preparation and simple chromatographic separation of chiral sulfoxide intermediates. Subsequent sulfoxide-lithium exchange, quenching with Ph₂PCl and sulfur, then desulfurisation with Raney-Ni provided (R)- and (S)-QUINAP in 54-56% overall yield.

Key words

asymmetric synthesis - ligand synthesis - resolution - sulfoxide-lithium exchange

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References

References and Notes

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Preparation of 1-(2-Bromo-1-naphthyl)isoquinoline (3) A 0.5 M solution of 2-bromo-1-iodonaphthalene (2.93 g, 8.8 mmol) in THF was placed in a flame-dried flask equipped with a magnetic stirring bar under Ar atmosphere. It was cooled to -78 °C and a 1.2 M solution of i-PrMgCl·LiCl (7.40 mL, 8.8 mmol) was slowly added. The reaction was allowed to proceed for 45 min at the same temperature before a 1.0 M solution of ZnCl₂ in THF (8.80 mL, 8.8 mmol) was slowly dropped to the orange mixture. After stirring for 30 min the reaction mixture was allowed to warm to 0 °C and was then cannulated into a solution of 1-iodo-isoquinoline (2.04 g, 8.0 mmol), Pd(dba)₂ (0.230 g, 0.4 mmol) and tri(2-furyl)phosphine (tfp) in 16 mL anhyd THF. The resulting mixture was subsequently heated to 60 °C and left to stir overnight at that temperature. After completion of the cross-coupling reaction (checked by GC-MS) the reaction was cooled to r.t. and 20 mL of a sat. NH₄Cl solution were added. The layers were separated in a separatory funnel. The aqueous phase was extracted with 4 × 20 mL CH₂Cl₂ and the combined organic layers were first washed with brine (20 mL) and then dried over MgSO₄. The solvents were removed in vacuo. The blackish crude product was subjected to column chromatography yielding 1-(2-bromo-1-naphthyl)isoquinoline as slightly yellow powder (1.98 g, 74%). Mp 164-166 °C. ¹H NMR (600 MHz, CDCl₃, 25 °C): δ = 8.7 (d, J = 5.7 Hz, 1 H), 8.0 (d, J = 8.2 Hz, 1 H), 7.9 (d, J = 8.2 Hz, 1 H), 7.9 (d, J = 8.8 Hz, 1 H), 7.8 (d, J = 5.7 Hz, 2 H), 7.8 (d, J = 8.8 Hz, 1 H), 7.5 (m, 1 H), 7.4 (m, 2 H), 7.3 (m, 1 H), 7.0 (d, J = 8.6 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃, 25 °C): δ = 159.4, 142.6, 136.7, 136.3, 133.9, 132.3, 130.4, 130.0, 129.8, 128.1, 127.8, 127.6, 127.2, 127.0, 126.8, 126.2, 125.9, 121.5, 120.6 ppm. HRMS (EI): m/z calcd for C₁₉H₁₂BrN: 333.0153; found: 333.0129. IR (neat): ν = 3065, 3052, 2916, 1988, 1955, 1924, 1840, 1788, 1714, 1620, 1581, 1557, 1502, 1498, 1449, 1426, 1418, 1406, 1377, 1340, 1319, 1310, 1275, 1258, 1239, 1205, 1159, 1135, 1114, 1070, 1044, 1024, 1012, 994, 974, 963, 951, 879, 864, 838, 828, 818, 798, 790, 774, 756, 744, 692, 678, 665, 633, 618, 602, 577 cm^-1.

<A NAME="RG25507ST-17">17</A> Krasovskiy A. Krasovskaya V. Knochel P. Angew.Chem. Int. Ed. 2006, 45: 2958

<A NAME="RG25507ST-18A">18a</A> Andersen KK. Tetrahedron Lett. 1962, 3: 93

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<A NAME="RG25507ST-18C">18c</A> Watanabe Y. Mase N. Moto-aki T. Toru T. Tetrahedron: Asymmetry 1999, 10: 737

Preparation and Separation of the Sulfoxide Intermediates 5 and 6 A 0.2 M solution of 1-(2-bromo-1-naphthyl)isoquinoline (3, 3.34 g, 10 mmol) in anhyd Et₂O was placed in a flame-dried flask equipped with a magnetic stirring bar under Ar atmosphere. The solution was cooled to -78 °C and t-BuLi (1.5 M in n-pentane; 13.4 mL, 20 mmol) was added dropwise. The reaction was left to stir for additional 30 min at -78 °C before it was allowed to warm to r.t.
The reaction mixture was then slowly and very carefully added to a 0.5 M solution of (-)-menthyl (S)-p-toluene-sulfinate (3.53 g, 12 mmol) in THF which was kept -78 °C under Ar atmosphere. The reaction was left to proceed overnight at -78 °C. The reaction was then quenched with 2 M NaOH (10 mL) at -78 °C. It was then allowed to warm to r.t. and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with 3 × 10 mL CH₂Cl₂. The combined organic layers were washed with 5 mL brine, dried over MgSO₄, and the solvents were removed in vacuo. For purification and separation of the two sulfoxide diastereomers, the crude product was subjected to column chromatography with Florisil^® (60-100 mesh). Compound 6 was eluated with a Et₂O-n-pentane mixture of 4:1. Compound 5 was eluated with a Et₂O-acetone mixture of 2:1. The two diastereomers were obtained as slightly yellow crystals yielding 1.89 g (47%) of 5 and 1.89 g (47%) of 6.
Compound 5: mp 99-101 °C. ¹H NMR (600 MHz, CDCl₃, 25 °C): δ = 8.7 (d, J = 5.7 Hz, 1 H), 8.1 (d, J = 8.8 Hz, 1 H), 8.0-7.9 (m, 2 H), 7.9 (d, J = 8.2 Hz, 1 H), 7.8 (d, J = 5.7 Hz, 1 H), 7.7 (m, 1 H), 7.6 (d, J = 8.2 Hz, 2 H), 7.6 (d, J = 8.4 Hz, 1 H), 7.5 (m, 1 H), 7.5 (m, 1 H), 7.3 (m, 1 H), 7.2 (t, J = 7.7 Hz, 3 H), 2.3 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃, 25 °C): δ = 156.9, 143.1, 142.0, 141.9, 140.6, 136.2, 136.2, 134.5, 131.9, 130.9, 130.8, 129.7, 128.7, 128.3, 128.3, 127.9, 127.5, 127.0, 126.9, 126.8, 124.8, 121.2, 120.5, 21.3 ppm. HRMS (EI): m/z calcd for C₂₆H₁₉NOS: 393.1187; found: 393.1197. IR (neat): ν = 3052, 2921, 2858, 1920, 1725, 1620, 1583, 1556, 1495, 1450, 1425, 1404, 1376, 1342, 1315, 1274, 1258, 1237, 1205, 1179, 1165, 1140, 1120, 1082, 1041, 1016, 954, 876, 810, 780, 746, 704, 694, 680, 670, 638, 621, 608, 574 cm^-1. Enantiomeric excess: HPLC (Gynkotec XX); Chiralcel AD; n-heptane-i-PrOH (80:20); flow rate: 0.5 mL/min: 99% ee.
Compound 6: mp 148-150 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.8 (d, J = 5.7 Hz, 1 H), 8.4 (d, J = 8.8 Hz, 1 H), 8.2 (d, J = 8.8 Hz, 2 H), 8.0 (d, J = 8.2 Hz, 1 H), 7.8 (d, J = 8.2 Hz, 1 H), 7.8 (d, J = 5.7 Hz, 1 H), 7.5 (t, J = 7.5 Hz, 1 H), 7.5 (m, 1 H), 7.3 (m, 1 H), 7.0 (m, 2 H), 6.8 (d, J = 8.2 Hz, 2 H), 6.7 (m, 2 H), 2.1 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 156.2, 142.8, 142.7, 141.3, 141.2, 135.9, 135.4, 134.0, 132.1, 130.1, 129.8, 129.2, 128.5, 128.3, 127.4, 127.2, 127.0, 127.0, 126.8, 126.3, 125.7, 121.2, 120.3, 21.1 ppm. HRMS: m/z calcd for C₂₆H₁₉NOS: 393.1187; found: 393.1175. IR (neat): ν = 3052, 2921, 2856, 1914, 1731, 1620, 1595, 1582, 1556, 1494, 1450, 1437, 1401, 1372, 1338, 1318, 1257, 1237, 1194, 1178, 1164, 1140, 1118, 1082, 1045, 1038, 1014, 954, 869, 824, 806, 779, 746, 720, 695, 670, 637, 622, 608, 586, 569 cm^-1. Enantiomeric excess: HPLC; Chiralcel AD; n-heptane-i-PrOH (8:2); flow rate: 1.0 mL/min: 99% ee.

<A NAME="RG25507ST-20">20</A> Kloetzing RJ. Knochel P. Tetrahedron: Asymmetry 2006, 17: 116

Preparation of ( R )- and ( S )-QUINAP In a flame-dried flask equipped with a stirring bar iodobenzene (0.337 g, 1.65 mmol) was diluted in 3 mL Et₂O under Ar atmosphere. The solution was then cooled to -78 °C and t-BuLi (1.5 M in n-pentane, 2.2 mL, 3.3 mmol) was added dropwise. The reaction was stirred for 10 min at -78 °C before it was allowed to warm to r.t. The solvents were subsequently removed in vacuo until a white precipitate remained. The flask was then flushed with Ar and cooled to -78 °C. Then, 3 mL THF were carefully added and the mixture was then allowed to warm to 0 °C in order to produce a homogeneous solution. The solution was then again cooled to -78 °C. A 0.5 M solution of 5 or 6 (0.590 g, 1.50 mmol) was added dropwise. The reaction was left to stir for 15 min at -78 °C before a 1.0 M solution of Ph₂PCl (0.397 g, 1.80 mmol) was slowly added. The reaction mixture was then additionally stirred for 15 min at -78 °C before sulfur (0.063 g, 1.95 mmol) was added. The reaction mixture was then heated to 45 °C and left to stir overnight at that temperature. The reaction mixture was then cooled to r.t. and quenched with 10 mL of a sat. NH₄Cl solution before it was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with 3 × 10 mL CH₂Cl₂. The combined organic layers were washed with brine (5 mL) and dried over MgSO₄. The solvents were removed in vacuo and the crude product was subjected to column chromatography with SiO₂. After column chromatography, the product was redissolved in CH₂Cl₂ and 0.3 mL MeSO₃H was added. The product was then filtrated over SiO₂ using pure Et₂O in order to remove the impurities and 5 mL Et₃N in Et₂O in order to wash down the product. After removal of the solvents the product was redissolved in CH₂Cl₂ and transferred to a separatory funnel. The organic phase was washed with 5 mL of a sat. NH₄Cl solution. The aqueous phase was extracted with 3 × 10 mL CH₂Cl₂. The combined organic layers were dried over MgSO₄. The solvent was evaporated. Then, (R)- and (S)-7 were subjected to desulfurisation with Raney-Ni. To this end, Raney-Ni (30 equiv) was placed in a N₂-flushed flask. It was washed five times with MeOH and finally suspended in MeOH. A solution of (R)-7 or (S)-7 in MeOH-THF was then dropped to the Raney-Ni suspension. The reaction was left to stir overnight at r.t. Filtration and removal of the solvent yielded (S)-QUINAP (0.395 g, 60%, 99% ee) and (R)-QUINAP (0.376 g, 57%, 99% ee) as white solids [the ee was determined after resulfurisation: HPLC Chiralcel OD-H; n-heptane-i-PrOH (9:1); flow rate: 0.5 mL/min].

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