New Preparation of Benzylic Manganese Chlorides by the Direct Insertion of Magnesium into Benzylic Chlorides in the Presence of MnCl₂·2LiCl

Dedicated to Dr. Klaus Römer on the occasion of his 75^th birthday

Abstract

Functionalized benzylic manganese chlorides were smoothly prepared by the direct insertion of magnesium into benzylic chlorides in the presence of MnCl₂·2LiCl. Reactions with acid chlorides, aldehydes, an allyl bromide, and an enone proceed without any additional transition metal.

Key words

manganese - magnesium - insertion - addition - cross-coupling

• References and Notes

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• 12 Procedures All reactions were carried out under an argon atmosphere in flame-dried glassware. Syringes which were used to transfer anhydrous solvents or reagents were purged with argon prior to use. THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen. Methyl tert-butyl ether (MTBE) was freshly distilled from sodium benzophenone ketyl under nitrogen. Yields refer to isolated yields of compounds estimated to be >95% pure as determined by ¹H NMR (25 °C) and capillary GC analysis. Solution of MnCl₂·2LiCl (1.0 M in THF) A dry and argon-flushed 250 mL Schlenk flask, equipped with a magnetic stirring bar and a glass stopper, was charged with LiCl (6.8 g, 160 mmol) and heated up to 150 °C under high vacuum for 3 h. After cooling to r.t. under argon, MnCl₂ (10.1 g, 80 mmol, 99% pure) was added under inert atmosphere. The Schlenk flask was further heated to 130 °C for 3 h under high vacuum, cooled to r.t. and charged with freshly distilled THF (80 mL) under argon with vigorous stirring. The mixture was stirred for at least 24 h at 25 °C. The reagent MnCl₂·2LiCl (1.0 M in THF) appears as a yellow solution. Preparation of Benzyl Manganese Chlorides 1a–f A dry and argon flushed Schlenk flask, equipped with a magnetic stirring bar and a rubber septum, was charged with magnesium (175 mg, 2.40 equiv), followed by dry THF (1 mL) or MTBE (1.9 mL) and a solution of MnCl₂·2LiCl (3.75 mL, 1.25 equiv; 1.0 M in THF). The mixture was cooled to 0 °C, the benzyl chloride (3.0 mmol, 1.0 equiv) was added at once and the reaction was maintained at 0 °C still complete conversion of the starting material was observed (reaction of aliquots with iodine followed by GC analysis). When the insertion reaction was complete, the solution of benzyl manganese chloride was separated from the resulting salts via a syringe equipped with a filter and transferred to another Schlenk flask, dry and argon flushed, before being titrated against iodine. Reaction of Benzyl Manganese Chlorides with Electrophiles; Typical Procedure A dry and argon flushed Schlenk flask, equipped with a magnetic stirring bar and a rubber septum, was charged with the electrophile (1.0 equiv), followed by dry THF. The benzyl manganese chloride solution (1.05–1.10 equiv) was added dropwise at 0 °C, and the reaction mixture was slowly warmed up to 25 °C and stirred overnight. Sat. aq NH₄Cl (4 mL) and H₂O (2 mL) were added and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na₂SO₄ and filtered. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products. 4-[2-(2-Chlorophenyl)-1-hydroxyethyl]benzonitrile (3b) To a solution of 4-cyanobenzaldehyde (66 mg, 0.5 mmol) in THF (1 mL) was added dropwise a solution of benzyl manganese chloride 1b (0.37 M, 1.49 mL, 1.1 equiv) at 0 °C. The reaction mixture was slowly warmed up to 25 °C and stirred overnight. Purification by flash chromatography (SiO₂; i-hexane–EtOAc, 7:3 + Et₃N 1%) afforded the desired product 3b (122 mg, 95%) as a white solid; mp 90–92 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 8.00 Hz, 2 H), 7.49 (d, J = 8.20 Hz, 2 H), 7.40 (d, J = 7.22 Hz, 1 H), 7.26–7.12 (m, J = 7.22, 1.76 Hz, 3 H), 5.09 (dd, J = 8.49, 4.59, 3.90 Hz, 1 H), 3.23–3.00 (ddd, J = 13.66, 8.68, 4.49 Hz, 2 H), 2.18 (br s., 1 H, OH) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 149.3, 135.2, 134.6, 132.5 (2C), 132.3, 130.0, 128.8, 127.2, 126.7 (2 C), 119.1, 111.6, 73.0, 44.1 ppm. IR (diamond ATR, neat): ν = 3556, 3064, 2953, 2925, 2360, 2340, 2225, 1946, 1700, 1606, 1573, 1504, 1471, 1444, 1412, 1374, 1355, 1318, 1308, 1270, 1173, 1048 cm^–1. MS (70 eV, EI): m/z (%) = 77 (15), 89 (13), 91 (30), 102 (10), 104 (49), 125 (28), 126 (84), 127 (17), 128 (27), 132 (100), 239 (2). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₂NOCl: 257.0607; found: 239.0486 (– H₂O). 5-[3-(Trifluoromethyl)benzyl]benzo[d][1,3]dioxole (3l) To a solution of 5-bromo-1,3-benzodioxole (101 mg, 0.06 mL, 0.5 mmol) in THF (0.5 mL) was added 2% Pd(OAc)₂ (2.3 mg) and 4% S-Phos (8.2 mg). The benzyl manganese chloride solution 1c (0.44 M, 1.25 mL, 1.1 equiv) was added dropwise at 0 °C, and the reaction mixture was slowly warmed up to 25 °C and stirred overnight. Purification by flash chromatography (SiO₂; i-hexane–EtOAc, 98:2) afforded the desired product 3l (100 mg, 71%) as a colorless liquid. ¹H NMR (300 MHz, CDCl₃): δ = 7.51–7.33 (m, J = 23.50, 3.87 Hz, 4 H), 6.80–6.73 (dd, J = 0.83 Hz, 2 H), 6.67 (dd, J = 1.11, 0.55 Hz, 2 H), 5.94 (s, 3 H), 3.96 (s, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 147.9, 146.2, 142.2, 133.8, 132.1, 132.1, 130.8 [q, ²J(C,F) = 32 Hz], 128.9, 125.4 [q, ³J(C,F) = 4 Hz], 124.2 [q, ¹J(C,F) = 272 Hz], 123.0 [q, ³J(C,F) = 4 Hz], 109.3, 108.3, 101.0, 41.3 ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –62.6 ppm. IR (diamond ATR, neat): ν = 3017, 2896, 2778, 2361, 1846, 1714, 1610, 1597, 1503, 1488, 1442, 1360, 1329, 1244, 1160, 1120, 1092, 1072, 1038 cm^–1. MS (70 eV, EI): m/z (%) = 135 (33), 152 (18), 153 (11), 159 (11), 181 (26), 201 (10), 242 (24), 249 (11), 261 (11), 279 (23), 280 (100), 281 (15). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₁O₂F₃: 280.0711; found: 280.0704. 3-(3-Fluorobenzyl)cyclohexanone (5) To a solution of cyclohexenone (96 mg, 0.10 mL,1.0 mmol) in THF (1 mL) was added dropwise the benzyl manganese chloride solution 1d (0.44 M, 2.5 mL, 1.1 equiv) at –40 °C. The reaction mixture was slowly warmed up to 25 °C and stirred overnight. Sat. aq NH₄Cl (4 mL) and H₂O (2 mL) were added, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na₂SO₄ and filtered. Evaporation of the solvents in vacuo and purification by flash column chromatography (SiO₂; i-hexane–EtOAc, 9:1 + Et₃N 1%) afforded the desired product 5 (163 mg, 79%) as a yellowish oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.25–7.17 (m, J = 7.43, 1.37 Hz, 1 H), 6.90–6.83 (m, J = 5.87, 2.93 Hz, 2 H), 6.80 (dd, J = 9.98, 1.57 Hz, 1 H), 2.66–2.51 (m, J = 6.65 Hz, 2 H), 2.38–2.17 (m, 3 H), 2.07–1.95 (m, 3 H), 1.89–1.79 (m, 1 H), 1.66–1.55 (m, 1 H), 1.41–1.28 (m, 1 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 211.2, 162.8 [d, ¹J(C,F) = 246 Hz], 141.9 [d, ³J(C,F) = 7 Hz], 129.7 [d, ³J(C,F) = 8 Hz], 124.7 [d, ⁴J(C,F) = 3 Hz], 115.8 [d, ²J(C,F) = 21 Hz], 113.1 [d, ²J(C,F) = 21 Hz], 47.6, 42.6 [d, ⁴J(C,F) = 2 Hz], 41.3, 40.6, 30.8, 25.0 ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –113.6 ppm. IR (diamond ATR, neat): ν = 2933, 2866, 1708, 1614, 1587, 1486, 1448, 1346, 1311, 1249, 1225, 1139, 1056 cm^–1. MS (70 eV, EI): m/z (%) = 41 (54), 42 (10), 55 (41), 69 (38), 83 (33), 97 (42), 109 (100), 133 (19), 135 (20), 147 (33), 148 (94), 206 (9), 207 (5). HRMS (EI): m/z [M⁺] calcd for C₁₃H₁₅FO: 206.1107; found: 206.1102.