Download PDF
Synlett 2007(17): 2655-2658  
DOI: 10.1055/s-2007-991047
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 14 August 2007
Publication Date:
25 September 2007 (online)

    Permissions and Reprints All articles of this category

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

16

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.

19

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.

21

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].