A Grignard-Type Phase-Vanishing Method: Generation of Organomagnesium Reagent and Its Subsequent Addition to Carbonyl Compounds

Abstract

A quadraphasic phase-vanishing system comprised of diethyl ether, magnesium, perfluoropolyether, and iodoalkane efficiently generated the corresponding Grignard reagents, which subsequently added to carbonyl compounds in the ether layer to afford alkylated alcohols in good yields.

Key words

fluorous solvent - phase-vanishing - Grignard reaction - ­Barbier reaction - magnesium - perfluoropolyether

• References and Notes

• 1 For a general review on fluorous chemistry, see: Handbook of ­Fluorous Chemistry . Gladysz JA, Curran DP, Horváth IT. Wiley-VCH; Weinheim: 2004

For reviews on the ‘Phase-vanishing’ method, see:
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• 6 Galden HT135 and HT 200 are polyether-type perfluorinated solvents, which is commercially available from Solvay Solexis Inc. The general structure of the solvents is shown in Figure 2. Kinetic viscosity of Galden HT135 and HT200 at 25 °C are 1.0 and 2.4 cSt, respectively.

For example, see:
• 7a Eicher T. The Chemistry of Carbonyl Group . Patai S. Wiley; New York: 1966. Part 1 621
• 7b Fieser LF, Fieser M. Reagents for Organic Synthesis, Coll. Vol. 1 . Wiley; New York: 1967: 415
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• 7d Raston CL, Salem G. The Chemistry of the Carbon–Metal Bond . Vol. 4. Hartley FR, Patai S. Wiley; New York: 1987: 159
• 7e Wakefield BJ. Organomagnesium Method in Organic Synthesis . Academic Press; San Diego: 1996: 21
• 8 Grignard-Type Phase-Vanishing Alkylation of Carbonyl Compounds; Typical Procedure (Table 1, entry 1): Galden HT135/200 = 1:1 (2 mL) was placed in a test tube (13 mm Φ × 105 mm), to which MeI (571 mg, 4.0 mmol) was added slowly using a glass pipette under argon. Anhydrous Et₂O (1 mL) was added slowly, whereupon three layers formed. Mg powder (98 mg, 4.0 mmol) was then added slowly, and floated between the Galden and ether layers, whereupon four layers formed. Subsequently, a solution of 2-decanone (1a, 313 mg, 2.0 mmol) in anhydrous Et₂O (3 mL) was added to the ether layer. The bottom layer was stirred slowly at 25 °C for 2 d, taking care not to mix the four layers. The ether solution and Mg salt were taken into a flask, to which hydrochloric acid (2 M) was added to quench the reaction, while cooling in an ice bath. The organic layer was separated, and the aqueous layer was extracted with Et₂O. The organic layer was collected, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (hexane–Et₂O, 3:1) to give 2-methyl-2-decanol (2a)13 (320 mg, 93%) as a colorless oil; ¹H NMR (500 MHz, CDCl₃): δ = 1.47–1.43 (m, 2 H, C-CH₂), 1.34–1.28 (m, 12 H, alkyl), 1.21 (s, 6 H, 2 × C-CH₃), 0.88 (t, J = 7.1 Hz, 3 H, CH₂-CH ₃); ¹³C NMR (126 MHz, CDCl₃): δ = 70.97, 43.95, 31.81, 30.12, 29.53, 29.20, 29.13, 24.28, 22.58, 14.01.
• 9 For example, see: Kürti L, Czakó B. Strategic Applications of Named Reactions in Organic Synthesis . Elsevier Academic Press; Burlington: 2005: 38
• 10 For example, see: Blagoev B, Ivanov D. Synthesis 1970; 615
• 11 Alkynylation of Carbonyl Compounds by the Grignard-Type Phase-Vanishing Method; Typical Procedure (Table 3, entry 2): Galden HT135/200 = 1:1 (2 mL) was placed in a test tube (13 mm φ × 105 mm), to which MeI (391 mg, 2.7 mmol) was added slowly using a glass pipette under argon. Anhydrous Et₂O (1 mL) was added slowly, whereupon three layers formed. Mg powder (61 mg, 2.5 mmol) was then added slowly, which floated between the Galden and ether layers, whereupon four layers formed. Subsequently, a solution of 1-octyne (221 mg, 2.0 mmol) in anhydrous Et₂O (3 mL) was added to the ether layer. The bottom layer was stirred slowly at 25 °C for 2 d, taking care not to mix the four layers. After confirming that the MeI layer vanished and Mg was consumed, a solution of dipentyl ketone (1b, 341 mg, 2 mmol) anhydrous Et₂O (1 mL) was slowly added to the organic layer. The mixture was then stirred at 25 °C for 1 d. The ether solution and Mg salt were taken into a flask, to which hydrochloric acid (2 M) was added to quench the reaction, while cooling in an ice bath. The organic layer was separated, and the aqueous layer was extracted with ether. The organic layer was collected, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (hexane–Et₂O, 9:1) to give 6-(1-octynyl)undecan-6-ol (4b; 466 mg, 83%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 2.19 (t, J = 7.1 Hz, 2 H, -CH₂C≡), 1.82 (s, 1 H, OH), 1.61–1.57 (m, 6 H, 2 × -CH₂CO + -CH ₂CH₂C≡), 1.51–1.46 (m, 6 H, alkyl), 1.38–1.26 (m, 12 H, alkyl), 0.91–0.86 (m, 9 H, 3 × CH₃); ¹³C NMR (126 MHz, CDCl₃): δ = 84.62, 83.19, 71.31, 42.24, 32.00, 31.50, 31.24, 28.66, 28.38, 23.93, 22.53, 18.54, 13.94; MS (EI, 70 eV): m/z (%) = 280 (0.07), 262 (3), 209 (100), 195 (1), 177 (3), 163 (1), 135 (5); HRMS (EI, 70 eV): m/z calcd for C₁₉H₃₆O: 280.2766; found: 280.2764; IR (neat): 3424, 2932, 2238, 1378, 1342, 1140, 1025 cm^–1 .
• 12 Spectroscopic data for new compounds: Compound 4a: ¹H NMR (500 MHz, CDCl₃): δ = 2.18 (t, J = 6.9 Hz, 2 H, CH₂C≡), 1.86 (s, 1 H, OH), 1.63–1.59 (m, 2 H, CH₂CO), 1.50–1.40 (m, 5 H, CH ₂CH₂C≡ + CH₃C), 1.38–1.24 (m, 18 H, alkyl), 0.90–0.86 (m, 6 H, 2 × CH ₃CH₂); ¹³C NMR (126 MHz, CDCl₃): δ = 84.10, 83.75, 68.36, 44.01, 31.88, 31.31, 30.13, 29.75, 29.55, 29.25, 28.68, 28.47, 24.79, 22.66, 22.54, 18.59, 14.10; MS (EI, 70 eV): m/z (%) = 266 (0.3), 251 (35), 181 (2), 165 (3), 157 (5), 153 (100), 137 (6); HRMS (EI, 70 eV): m/z [M – H]⁺ calcd for C₁₈H₃₃O: 265.2531; found: 265.2532; IR (neat): 3364, 2928, 2240, 1630, 1466, 1370, 1131, 930 cm^–1. Compound 4d: ¹H NMR (500 MHz, CDCl₃): δ = 7.63 (d, J = 7.3 Hz, 2 H, PhH), 7.35 (t, J = 7.6 Hz, 2 H, PhH), 7.27 (t, J = 7.3 Hz, 1 H, PhH), 2.30 (t, J = 7.1 Hz, 2 H, CH₂C≡), 2.17 (s, 1 H, OH), 1.98–1.85 (m, 2 H, CH₂CO), 1.54–1.42 (m, 4 H, alkyl), 1.34–1.27 (m, 4 H, alkyl), 0.95–0.89 (m, 6 H, 2 × CH₃); ¹³C NMR (126 MHz, CDCl₃): δ = 145.08, 127.95, 127.39, 125.56, 86.86, 82.38, 73.96, 38.49, 31.28, 28.66, 28.54, 22.53, 18.73, 14.01, 9.13; MS (EI, 70 eV): m/z (%) = 244 (0.5), 227 (29), 215 (100), 185 (2), 167 (3), 157 (6), 144 (13); HRMS: m/z calcd for C₁₇H₂₄O: 244.1827; found: 244.1820; IR (neat): 3424, 3060, 3028, 2932, 2243, 1666, 1600, 1448, 1329, 1213, 1051, 973, 758, 700 cm^–1. Compound 4f: ¹H NMR (500 MHz, CDCl₃): δ = 4.34 (t, J = 5.6 Hz, 1 H, CHO), 2.19 (m, 2 H, CH₂C≡), 1.67–1.64 (m, 2 H, CH ₂CHO), 1.50–1.25 (m, 26 H, alkyl), 0.90–0.86 (m, 6 H, 2 × CH₃); ¹³C NMR (126 MHz, CDCl₃): δ = 85.52, 81.33, 62.79, 38.22, 31.91, 31.32, 29.63, 29.56, 29.34, 28.63, 28.50, 25.20, 22.68, 22.54, 18.67, 14.10, 14.03; MS (EI, 70 eV): m/z (%) = 294 (2), 237 (9), 209 (47), 181 (5), 167 (7), 153 (25), 139 (100); HRMS (EI, 70 eV): m/z (%) calcd for C₂₀H₃₈O: 294.2923; found: 294.2917; IR (neat): 3357, 2925, 2234, 1701, 1465, 1033 cm^–1.
• 13 Dragovich PS, Prins TJ, Zhou R. J. Org. Chem. 1995; 60: 4922