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Synlett 2006(18): 3150-3154  
DOI: 10.1055/s-2006-951500
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Application of HETPHOX Ligands to the Intramolecular Asymmetric Heck Reaction

Martin O. Fitzpatrick, Anthony G. Coyne, Patrick J. Guiry*
Centre for Synthesis and Chemical Biology, Conway Institute for Biomolecular and Biomedical Research, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
e-Mail: p.guiry@ucd.ie;
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Publication History

Received 10 April 2006
Publication Date:
25 October 2006 (online)

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Abstract

A new thiophene-oxazoline P,N ligand derived from cis-aminoindanol was prepared and a range of analogous HETPHOX ligands were applied to the intramolecular Heck reaction. The enantioselectivity obtained was 76% employing the tert-butyl-substituted HETPHOX ligand with an aryl triflate spirooxindole precursor. The isomer distribution of the product spirooxindoles was high (up to 99:1).

Key words

Heck reaction - asymmetric catalysis - ligands - oxazolines - palladium

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Typical Experimental Procedure for the Synthesis of (3a R ,8b S )-2-(thiophen-2-yl)-4,8b-dihydro-3a H -indeno[2,1- d ]oxazole ( 10). Thiophene-2-carbonitrile (1.20 g, 10.9 mmol), (1S,2R)-cis-aminoindanol (2.13 g, 14.2 mmol) and chlorobenzene (20 mL) were placed into an oven-dried Schlenk tube. The solution was treated with anhyd ZnCl2 (1.95 g, 14.2 mmol) and was stirred under reflux for 16 h. Then, CH2Cl2 (5 mL) was added to the off-white solution. This was followed by H2O (10 mL), which caused a white precipitate to form. The precipitate was filtered off and the filtrate washed with CH2Cl2 (5 mL). The phases were separated and the aqueous phase extracted with CH2Cl2 (2 × 5 mL) and the organic layers were combined and dried over MgSO4. The solvent was removed under reduced pressure to give an oil which was purified by column chromatography (CH2Cl2) to give a white solid. Yield 79%; mp 125-126 °C; [α]D -7.0 (c 0.1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.29 (dd, J = 1.6, 18.0 Hz, 1 H), 3.42 (dd, J = 6.7, 18.0 Hz, 1 H), 5.41 (m, 1 H), 5.65 (d, J = 7.7 Hz, 1 H), 6.96 (dd, J = 3.8, 5.0 Hz, 1 H), 7.18-7.22 (m, 3 H), 7.34 (dd, J = 1.2, 5.0 Hz, 1 H), 7.48-7.53 (m, 2 H). 13C NMR (400 MHz, CDCl3): δ = 39.8 (CH2), 83.9, 125.4, 125.9, 127.7, 127.8, 128.8, 130.1, 130.7, 139.8, 141.9, 160.0. MS (EI): m/z (%) = 241 (100), 115 (2), 111 (9).
Typical Experimental Procedure for the Synthesis of (3a R ,8b S )-2-[3-(diphenylphosphino)thiophenyl-2-yl]-4,8b-dihydro-3a H -indeno[2,1- d ]oxazole ( 9). Thiophene-2-oxazoline 10 (0.365 g, 1.51 mmol) was dissolved in dry Et2O (15 mL) and the resultant solution was cooled to -78 °C. A solution of 2.5 M n-BuLi in hexane (1.20 mL, 3.0 mmol) was added dropwise and the orange solution was stirred at -78 °C for 30 min. The reaction was warmed up to 0 °C and stirred at this temperature for 30 min. The orange solution was then cooled to -78 °C then ClPPh2 (0.54 mL, 3.0 mmol) was added. The reaction was allowed to warm to r.t. over 20 h and quenched with H2O (10 mL). The phases were separated and the aqueous phase extracted with Et2O (2 × 5 mL) then the organic layers were combined, dried over Na2SO4 and evaporated under reduced pressure to give an oil which was purified by column chromatography (Et2O-pentane, 1:1) to give a solid. Yield 24%; mp 99-101 °C; [α]D -13.0 (c 0.3, CHCl3).1H NMR (300 MHz, CDCl3): δ = 2.85 (d, J = 18.0 Hz, 1 H), 3.48 (dd, J = 6.9, 18.0 Hz, 1 H), 5.27 (d, J = 9.6 Hz, 1 H), 5.59 (d, J = 7.7 Hz, 1 H), 6.29 (d, J = 4.9 Hz, 1 H), 7.08-7.57 (m, 14 H). 13C NMR (75 MHz, CDCl3): δ = 42.3 (CH2), 85.8, 128.2, 128.8, 130.8, 131.6, 131.9, 132.2, 136.9, 137.2, 158.2 (some overlap occurred in the aromatic region). 31P NMR (122 MHz, CDCl3): δ = -13.06. MS (EI): m/z (%) = 425.0 (100), 331 (2), 242 (9), 111 (2).

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Typical Experimental Procedure for Asymmetric Intramolecular Heck Reaction. Pd2(dba)3 (0.002 mmol), ligand (0.008 mmol) and solvent (0.5 mL) were charged to a 10 mL Schlenk tube and stirred for 1 h. A 0.5-mL solution of the triflate 12 (0.08 mmol) and base (0.4 mmol) was added and the reaction was stirred for 5 min. The reaction was degassed, sealed and heated for up to 168 h at 110 °C. The reaction was the quenched with sat. aq NaHCO3 (5 mL), diluted with H2O (5 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (3:1 pentane-EtOAc).
Spectral data for compounds 13 and 14: Δ2,3 13: 1H NMR (300 MHz, CDCl3): δ = 7.30-7.20 (m, 2 H, H5 ′ ,6 ′), 7.00 (m, 1 H, H4 ′), 6.83 (d, J = 7.6 Hz, 1 H, H3 ′), 6.13 (dt, J = 9.8, 4.0 Hz, 1 H, H2), 5.28 (d, J = 9.9 Hz, 1 H, H3), 3.21 (s, 3 H, NMe), 2.25-2.20 (m, 2 H, H4a,b), 2.05-2.00 (m, 2 H, H6a,b), 1.65-1.95 (m, 2 H, H5a,b). Δ3,4 14: 1H NMR (300 MHz, CDCl3): δ = 7.31 (t, 1 H, J = 7.3 Hz, H6 ′) 7.27-7.25 (m, 1 H, H5 ′), 7.04 (t, 1 H, J = 7.5 Hz, H4 ′), 6.86 (d, 1 H, J = 7.7 Hz, H3 ′), 5.84-5.95 (m, 2 H, H3,4), 3.23 (s, 3 H, NMe), 2.61-2.70 (m, 1 H, H2a), 2.30-2.36 (m, 2 H, H5a,b), 1.91-2.00 (m, 2 H, H6), 1.49-1.58 (m, 1 H, H2b).