Stereoselective Preparation of Cyclopropylmagnesium Reagents via a Br-Mg Exchange Using i-PrMgCl×LiCl in the Presence of Dioxane

Abstract

The reaction of various cyclopropyl bromides with i-PrMgCl˙LiCl in THF-dioxane provides the corresponding magnesiated cyclopropane reagents with complete retention of configuration.

Key words

Grignard reactions - organometallic reagents - stereo­selectivity - copper - carbocycles

References and Notes

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12

i-PrMgCl˙LiCl is commercially available from Chemetall GmbH (Frankfurt).

16

Typical Procedure for the Preparation of trans -(2-Allylcyclopropyl)benzene (3a) and cis -(2-Allylcyclo-propyl)benzene (3b): A dry and argon-flushed 10-mL flask, equipped with a magnetic stirrer and a septum, was charged with i-PrMgCl˙LiCl (1.1 M in THF, 1.1 mmol, 1.1 equiv) and 1,4-dioxane (0.1 mL). The cis- or trans-(2-bromocyclo-propyl)benzene (1a or 1b, 197 mg, 1.0 mmol, 1.0 equiv) was added neat at 25 ˚C. The resulting mixture was stirred at 25 ˚C for 8 h to complete the Br-Mg exchange (checked by GC-MS analysis of reaction aliquots). Allyl bromide (145 mg, 1.2 mmol, 1.2 equiv) followed by CuCN˙2LiCl (1.0 M in THF, 0.01 mmol, 1.0 mol%) was added at 0 ˚C. The mixture was warmed to 25 ˚C and was quenched with a sat. aq NH₄Cl solution (10 mL). The aqueous phase was extracted with Et₂O (3 × 20 mL). The combined organic fractions were dried (MgSO₄) and after filtration the solvent was removed in vacuo. Purification by flash chromatography (pentane, silica gel) yielded 3a as a colorless oil [117 mg, 74% or 3d (117 mg, 74%)]. Spectroscopic data for 3a: ^¹H NMR (300 MHz, CDCl₃): δ = 7.09-7.32 (m, 5 H), 5.96 (ddt, J = 16.6, 10.2, 6.3 Hz, 1 H), 5.02-5.17 (m, 2 H), 2.18-2.23 (m, 2 H), 1.70-1.73 (m, 1 H), 1.12-1.23 (m, 1 H), 0.83-1.00 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 144.0, 137.7, 128.6, 126.1, 125.7, 115.4, 38.4, 23.2, 22.8, 16.1. IR (film): 3066 (m), 3002 (m), 1640 (m), 1607 (m), 1497 (m), 1030 (w), 996 (w), 912 (s), 753 (m), 696 (vs) cm^-¹. MS (EI, 70 eV): m/z (%) = 158 (6), 118 (9), 117 (100), 116 (11), 115 (42), 104 (31), 103 (6), 91 (25), 78 (6), 77 (6). HRMS (EI, 70 eV): m/z calcd for C₁₂H₁₄: 158.1096; found: 158.1082. Spectroscopic data for 3d: ^¹H NMR (300 MHz, CDCl₃): δ = 7.21-7.33 (m, 5 H), 5.80 (ddt, J = 16.5, 10.2, 6.3 Hz, 1 H), 4.91-5.03 (m, 2 H), 2.22 (ddd, J = 8.6, 8.6, 6.1 Hz, 1 H), 1.86-1.96 (m, 1 H), 1.69 (dddt, J = 15.5, 7.8, 6.4, 1.5 Hz, 1 H), 1.15-1.27 (m, 1 H), 1.01-1.09 (m, 1 H), 0.71-0.77 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 139.6, 138.4, 129.6, 128.2, 126.0, 114.7, 33.2, 21.4, 18.3, 9.7. IR (film): 3066 (m), 3002 (m), 2908 (w), 1640 (m), 1604 (w), 1498 (m), 1028 (w), 911 (s), 769 (m), 727 (w), 698 (vs) cm^-¹. MS (EI, 70 eV): m/z (%) = 158 (3) [M⁺], 129 (11), 128 (10), 118 (10), 117 (100), 116 (11), 115 (41), 104 (37), 103 (9), 91 (24), 78 (8), 77 (8), 65 (5), 51 (5). HRMS (EI, 70 eV): m/z calcd for C₁₂H₁₄: 158.1096; found: 158.1066.

17

Typical Procedure for the Preparation of 1-(2-Bromo-cyclopropyl)-4-fluorobenzene (1c): [¹5] [¹8] A round-bottomed flask equipped with a magnetic stirrer was charged with 1-fluoro-4-vinylbenzene (6.11 g, 50.0 mmol), CHBr₃ (50.5 g, 0.20 mol), pinacol (0.768 g, 6.50 mmol) and triethylbenzyl-ammonium chloride (0.569 g, 2.50 mmol). NaOH (8.00 g, 0.20 mol in 8 mL H₂O) was added dropwise and the reaction mixture was stirred vigorously for 16 h. Then, the solids were filtered off and washed with CH₂Cl₂ (50 mL). The aqueous layer was extracted with CH₂Cl₂ (50 mL) and the combined organic phases were dried (MgSO₄). After filtration the solvent was removed under reduced pressure and the crude product was purified by distillation (100 ˚C, 2.5 mbar), furnishing 1-(2,2-dibromocyclopropyl)-4-fluorobenzene as a colorless liquid (10.2 g, 70%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.98 (t, J = 8.0 Hz, 1 H), 2.16 (dd, J = 10.5, 7.8 Hz, 1 H), 2.94 (dd, J = 10.2, 8.6 Hz, 1 H), 7.04-7.11 (m, 2 H), 7.22-7.28 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 27.9 (CH₂), 28.5, 35.6 (CH), 115.7 (d, J = 21.6 Hz, CH), 130.9 (d, J = 8.2 Hz, CH), 132.2 (d, J = 3.1 Hz), 162.6 (d, J = 246.7 Hz, CF). IR (film): 1606 (m), 1510 (vs), 1434 (w), 1228 (s), 1220 (s), 1158 (m), 1102 (m), 1052 (m), 1038 (m), 1014 (w), 926 (w), 860 (m), 830 (vs), 818 (s), 730 (m), 676 (s), 634 (w) cm^-¹. MS (EI, 70 eV): m/z (%) = 215 (24), 213 (26), 135 (8), 134 (100), 133 (88), 107 (7), 67 (12), 57 (6). HRMS (EI, 70 eV): m/z calcd for C₉H₇ ⁷⁹Br₂F: 291.8899; found: 291.8898.
A dry and argon-flushed two-necked Schlenk flask, equipped with a magnetic stirrer and a septum was charged with LiBr (3.02 g, 34.8 mmol). The salt was dried (0.01 mbar, 5 h, 150 ˚C) and then dissolved in THF (30 mL) and Et₂O (30 mL). The solution was cooled to -80 ˚C and
n-BuLi (14.4 mL, 34.8 mmol, 2.42 M in hexane) was added, and the reaction mixture was cooled to -110 ˚C. 1-(2,2-Dibromocyclopropyl)-4-fluorobenzene (9.23 g, 31.6 mmol) was added dropwise and the reaction mixture was stirred for 1 h at -100 ˚C. Then, ethanol (15 mL) was added and the reaction mixture was warmed to 25 ˚C and was quenched with a sat. aq NH₄Cl solution (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (MgSO₄) and after filtration the solvent was removed under reduced pressure. Flash chromatographic purification (pentane, silica gel) furnished 1c a colorless liquid (3.37 g, 50%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.37-1.55 (m, 2 H), 2.34-2.41 (m, 1 H), 2.94-2.99 (m, 1 H), 6.94-7.05 (m, 4 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 18.7 (CH₂), 21.3 (CH), 26.2 (CH), 115.3 (d, J = 21.3 Hz, CH), 127.5 (d, J = 8.3 Hz, CH), 135.3 (d, J = 3.2 Hz), 161.5 (d, J = 244.3 Hz, CF). IR (film): 1608 (w), 1600 (w), 1510 (vs), 1444 (w), 1226 (vs), 1180 (w), 1160 (m), 1104 (m), 1070 (w), 1042 (w), 1014 (w), 982 (w), 934 (m), 890 (m), 860 (m), 818 (vs), 718 (m), 702 (m), 634 (w), 612 (s) cm^-¹. MS (EI, 70 eV): m/z (%) = 136 (8), 135 (100), 134 (7), 133 (26), 115 (13), 109 (14), 107 (4), 83 (4), 67 (2), 56 (3). HRMS (EI, 70 eV): m/z calcd for C₉H₈ ⁷⁹BrF: 213.9793; found: 213.9777.