The Preparation of a Bridgehead Organolithium Reagent

Abstract

The reaction of the THP-protected compound 5 with t-BuLi at -78 °C in THF/DME affords a new tertiary organolithium species that reacts with a variety of electrophiles in good yield. As an example of the utility of the adducts of such reactions, treatment of 13 with a metathesis catalyst afforded 21 in excellent yield.

Key words

cycloadditions - electrophilic additions - lithium - metalations - metathesis

References

• For examples, see:
• 1a Wieringa JH. Strating J. Wynberg H. Synth. Commun.  1972,  2:  191 
• 1b Molle G. Bauer P. Dubois JE. J. Org. Chem.  1983,  48:  2975 
• 1c Kraus GA. Siclovan TM. J. Org. Chem.  1994,  59:  922 
• 1d Wender PA. Wesjohann LA. Peschke B. Rawlins DB. Tetrehedron Lett.  1995,  36:  7181 
• 2 Harmata M. Shao L. Synthesis  1999,  1534 
• 3a Harmata M. Shao L. Kürti L. Abeywardane A. Tetrahedron Lett.  1999,  40:  1075 
• 3b Harmata M. Rashatasakhon P. Tetrahedron Lett.  2001,  42:  5593 
• 3c Harmata M. Rashatasakhon P. Org. Lett.  2001,  3:  2533 
• 3d Harmata M. Bohnert G. Kürti L. Barnes CL. Tetrahedron Lett.  2002,  43:  2347 
• 4a Calton GJ. Ranieri RL. Espenshade MA. J. Antibiot.  1978,  31:  38 
• 4b Ranieri RL. Calton GJ. Tetrahedron Lett.  1978,  6:  499 
• 5 Bokesch HR. McKee TC. Cardellina JH. Boyd MR. Tetrahedron Lett.  1996,  37:  3259 
• 7 For examples of the metathesis chemistry of [4+3] cycloaddition products, see ref. and: Wright DL. Usher LC. Estrella-Jimenez M. Org. Lett.  2001,  3:  4275 
• 9 For the formation of 1 see: Folkins PL. Harpp DN. J. Org. Chem.  1992,  57:  2013 

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CCDC 200258 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: [phone]; e-mail: [e-mail]].

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All new compounds exhibited satisfactory ¹H and ¹³C and IR spectral data as well as satisfactory combustion analysis.

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Procedure for Making Protected Cycloadducts 4 and 5: Dibromide 1 (3 g, 12.4 mmol) was dissolved in a mixture of trifluoroethanol/Et₂O (1:1, 90 mL), to which freshly distilled cyclopentadiene (8.2 g, 124 mmol) was added at -78 °C. Freshly distilled Et₃N (5.18 mL, 37.2 mmol) was added via syringe pump over 15 min. The mixture was slowly warmed to r.t. over 2 h, quenched with H₂O, extracted with Et₂O (3 × 20 mL), washed with H₂O (2 × 10 mL), washed with brine (1 × 10 mL), dried over MgSO₄, filtered, concentrated, and dried under full vacuum. The crude product was dissolved in EtOH (60 mL) and treated with NaBH₄ (1.7 g, 37.83 mmol) at 0 °C for 5 h. The reaction was quenched with sat. aq NH₄Cl (10 mL), extracted with Et₂O (3 × 20 mL), washed with H₂O (2 × 10 mL), brine (1 × 10 mL), dried over MgSO₄, filtered, and concentrated. The residual was subjected to column chromatography (10% EtOAc-hexanes) to give pure alcohol as a white solid. A solution of the alcohol (1.6 g, 6.98 mmol) in CH₂Cl₂ (35 mL) cooled to 0 °C, was treated with dihydropyran (3.19 mL, 34.92 mmol) and TsOH·H₂O (13.3 mg, 0.07 mmol) for 10 min. The reaction was warmed to r.t. and stirred for 1.75 h. The reaction was quenched with a mixture of brine:sat. NaHCO₃:H₂O (1:1:2, 5 mL), diluted with Et₂O (25 mL), washed with brine (2 × 10 mL), dried over MgSO₄, filtered, and concentrated. The crude yellow oil was purified by column chromatography (5% EtOAc-hexanes) to give separable 4 and 5 (2.18 g, 86% for 2 steps) as a crystalline solid.

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Typical Procedure: A solution of (5), (25 mg, 0.08 mmol) in a 9:1 mixture of THF-DME (0.42 mL) was stirred at
-78 °C for 15 min. t-BuLi (0.16 mmol) was slowly added drop wise and the solution allowed to stir for 10 min. At that time p-methoxybenzaldehyde (0.029 mL, 0.24 mmol) was added drop wise. The reaction was allowed to warm slowly to r.t. (1.5 h) and quenched with H₂O (1 mL). The reaction mixture was extracted with Et₂O (2 × 5 mL), washed with brine (5 mL), dried with MgSO₄, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel with 5% EtOAc/hexanes to give a colorless oil (7) as inseparable diastereomers (25.7 mg, 87%). ¹H NMR (500 MHz, CDCl₃): δ = 7.38-7.23 (m, 4 H), 6.90-6.83 (m, 4 H), 6.24 (dd, J = 2.8, 5.5 Hz, 1 H), 6.12 (dd, J = 2.6, 5.5 Hz, 1 H), 6.03 (dd, J = 2.5, 5.5 Hz, 1 H), 5.94 (dd, J = 2.6, 5.5 Hz, 1 H), 4.75 (s, 1 H), 4.68-4.64 (m, 1 H), 4.62 (d, J = 4.0 Hz, 1 H), 4.52 (d, J = 4.1 Hz, 1 H), 4.46 (s, 1 H), 4.35-4.31 (m, 1 H), 4.00-3.94 (m, 1 H), 3.91 (d, J = 2.3 Hz, 1 H), 3.87-3.83 (m, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.77-3.73 (m, 1 H), 3.57-3.44 (m, 2 H), 2.60-2.58 (m, 1 H), 2.45-2.40 (m, 2 H), 2.35-2.31 (m, 1 H), 2.27-2.22 (m, 2 H), 2.02 (dt, J = 3.9, 11.0 Hz, 1 H), 1.85-1.46 (m, 20 H), 1.41-1.27 (m, 2H), 1.20-1.04 (m, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 158.6, 158.6, 137.7, 137.1, 135.2, 124.2, 133.9, 133.4, 129.0, 128.0, 113.0, 112.9, 101.6, 95.7, 85.5, 83.1, 81.5, 73.4, 65.6, 62.0, 55.2, 52.9, 51.1, 44.6, 42.9, 42.5, 41.8, 41.4, 41.2, 39.0, 35.6, 31.7, 31.5, 30.3, 29.7, 27.3, 26.8, 26.3, 25.2, 25.1, 21.6, 19.1. IR (film): 3465, 3052, 2938, 1511, 1246, 1131, 1025, 731 cm^-1; Anal. Calcd for C₂₃H₃₀O₄: C, 74.56; H, 8.16. Found: C, 74.56; H, 8.30.

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Typical Procedure for ROM/RCM: A r.t. solution bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (4 mg, 0.005 mmol) in CH₂Cl₂ (2 mL) was stirred in a stream of ethylene gas until the purple solution turned brown. After the ruthenium catalyst was stirred 10 additional min, a solution of (13), (14 mg, 0.048 mmol) in CH₂Cl₂ (1.5 mL) was added via syringe drop wise. After 2 h, the solvent was removed and the crude mixture purified by column chromatography with 10-50% EtOAc-hexanes to give a (1:1) ratio of the two isomers of (21) as an oil (13 mg, 93%). 21a: R_f = 0.11 (10% EtOAc-hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 5.83-5.76 (m, 2 H), 5.72-5.70 (m, 1 H), 4.93-4.89 (m, 1 H), 4.85-4.82 (m, 1 H), 4.72-4.69 (m, 1 H), 4.50 (dd, J = 2.4, 7.2 Hz, 1 H), 4.10 (d, J = 5.0 Hz, 1 H), 3.98 (d, J = 12.3 Hz, 1 H), 3.98-3.94 (m, 1 H), 3.48-3.43 (m, 1 H), 2.53-2.48 (m, 1 H), 2.21-2.16 (m, 1 H), 2.12 (t, J = 6.0 Hz, 1 H), 1.99-1.86 (m, 2 H), 1.81-1.75 (m, 2 H), 1.70-1.38 (m, 8 H). ¹³C NMR (125.75 MHz, CDCl₃): δ = 145.7, 135.4, 133.5, 111.4, 101.2, 82.3, 82.2, 65.1, 52.8, 52.3, 48.0, 39.1, 32.6, 31.4, 29.3, 28.2, 25.0, 21.1. IR (film): 3436, 3048, 2942, 1131, 1070, 1025 715 cm^-1. Anal. Calcd for C₁₈H₂₆O₃: C, 74.45; H, 9.02. Found: C, 74.55; H, 8.76. 21b: R_f = 0.26 (50% EtOAc-hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 5.92 (dd, J = 1.4, 5.7 Hz, 1 H), 5.86-5.84 (m, 1 H), 5.77 (ddd, J = 7.6, 10.2, 17.2 Hz, 1 H), 4.93 (dt, J = 1.1, 17.1 Hz, 1 H), 4.84 (d, J = 10.1 Hz, 1 H), 4.73 (d, J = 12.2 Hz, 1 H), 4.63 (t, J = 3.0 Hz, 1 H), 3.89 (d, J = 4.7 Hz, 1 H), 3.82-3.78 (m, 1 H), 3.50-3.46 (m, 1 H), 2.74-2.70 (m, 1 H), 2.27-2.22 (m, 1 H), 2.19 (dd, J = 4.8, 7.4 Hz, 1 H), 2.05-1.97 (m, 1 H), 1.89-1.84 (m, 1 H), 1.75-1.39 (m, 10 H), 1.24 (d, J = 8.3 Hz, 1 H). ¹³C NMR (125.75 MHz, CDCl₃): δ = 145.4, 140.2, 131.3, 111.6, 96.5, 83.0, 81.3, 61.7, 52.0, 51.8, 48.8, 38.5, 30.5, 28.6, 28.4, 28.3, 25.6, 18.9. IR (film): 3380, 3049, 2939, 1122, 1030, 973, 916 cm^-1. Anal. Calcd for C₁₈H₂₆O₃: C, 74.45; H, 9.02. Found: C, 74.59; H, 8.88.