Rapid Generation of Molecular Complexity: Synthesis of α-Hydroxyallenes Using Functionalized Grignard Reagents

Abstract

The use of functionalized aryl-Grignard reagents in the copper-mediated S_N2′ substitution of propargylic oxiranes leads to structurally complex α-hydroxyallenes, usually with high yield and diastereoselectivity. Further transformations, such as gold-catalyzed cycloisomerization to 2,5-dihydrofurans and palladium-catalyzed coupling reactions, demonstrate the high potential of these compounds for the rapid generation of molecular complexity.

allenes - chirality transfer - functionalized Grignard ­reagents - organocopper reagents - S_N2′ substitution

References and Notes

1

New address: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.

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12

Representative Procedure and Spectroscopic Data - Synthesis of 1-( tert -Butyldimethylsilyloxy)-5-(4-fluoro-phenyl)-3-methylpenta-3,4-dien-2-ol (2a).
To a stirred solution of 4-fluoroiodobenzene (706 mg, 3.2 mmol) in anhyd THF (15 mL) was added i-PrMgCl (2.1 mL, 3.4 mmol; 1.7 M in Et₂O) at -40 °C. After 1 h at this temperature, the Grignard reagent was added via cannula to a cold (-30 °C), freshly prepared solution of copper(I) cyanide (142 mg, 1.6 mmol) and tri-n-butylphosphine (322 mg, 1.6 mmol) in anhyd THF (20 mL). The resulting cuprate solution was stirred for 30 min at -30 °C, followed by addition of cis-1-(tert-butyldimethylsilyloxy)-2,3-epoxy-3-methylpent-4-yne (1, 300 mg, 1.3 mmol) in anhyd THF (3 mL). After stirring for 16 h under warming to r.t., quenching with 3 mL of a sat. NH₄Cl solution, washing with 3 × 10 mL of a 2% H₂O₂ solution, filtration through a pad of Celite^®, evaporation of the solvent and column chromatography (SiO₂, EtOAc-cyclohexane = 10:1) furnished 287 mg (68%) of 2a as a yellow oil (dr = 94:6 according to NMR analysis).
¹H NMR (500 MHz, C₆D₆): δ = 7.14-7.09 (m, 2 H), 6.87-6.83 (m, 2 H), 6.10 (m, 1 H), 4.21 (m, 1 H), 3.73 (dd, ^² J _HH = 10.0 Hz, ^³ J _HH = 4.0 Hz, 1 H), 3.66 (dd, ^² J _HH = 10.0 Hz, ^³ J _HH = 4.0 Hz, 1 H), 2.41 (br s, 1 H), 1.88 (m, 3 H), 0.95 (s, 9 H), 0.04 and 0.03 (2 s, 6 H) ppm. ¹³C NMR (125 MHz, C₆D₆): δ = 202.0, 163.4 (d, ¹ J _CF = 241 Hz), 132.3, 128.7 (d, ³ J _CF = 10 Hz), 115.9 (d, ² J _CF = 21 Hz), 105.2, 95.6, 72.8, 66.2, 26.0, 18.4, 15.3, -5.3 ppm.
Spectroscopic Data of 2-(4-Methoxycarbonylphenyl-ethenylidene)cyclohexan-1-ol (4a).
¹H NMR (400 MHz, C₆D₆): δ = 8.18 (d, ^³ J _HH = 8.2 Hz, 2 H), 7.26 (d, ^³ J _HH = 8.2 Hz, 2 H), 6.13 (s, 1 H), 4.04 (m, 2 H), 3.49 (s, 3 H), 2.43 (m, 1 H), 1.99 (m, 3 H), 1.65 (m, 1 H), 1.56 (m, 1 H), 1.44 (m, 1 H), 1.36 (m, 1 H) ppm. ¹³C NMR (100 MHz, C₆D₆): δ = 199.1, 166.6, 140.7, 130.5, 127.0, 112.3, 97.0, 69.2, 51.6, 36.3, 29.3, 27.0, 23.3 ppm.
Spectroscopic Data of cis -2-( tert -Butyldimethylsilyloxy-methyl)-3-methyl-5-(4-trimethylsilylethynylphenyl)-2,5-dihydrofuran (10). ¹H NMR (400 MHz, C₆D₆): δ = 7.43 (d, ^³ J _HH = 8.3 Hz, 2 H), 7.21 (d, ^³ J _HH = 8.3 Hz, 2 H), 5.58 (br s, 1 H), 5.21 (s, 1 H), 4.68 (br s, 1 H), 3.79 (dd, ^² J _HH = 10.0 Hz, ^³ J _HH = 4.0 Hz, 1 H), 3.66 (dd, ^² J _HH = 10.0 Hz, ^³ J _HH = 4.0 Hz, 1 H), 1.62 (s, 3 H), 0.95 (s, 9 H), 0.10 (s, 9 H), 0.05 (s, 6 H) ppm. ¹³C NMR (100 MHz, C₆D₆): δ = 142.2, 137.6, 131.4, 129.0, 125.7, 121.5, 88.7, 86.1, 65.1, 25.9, 18.3, 12.4, -0.8, -5.5 ppm.