Selective Zincation of 1,2-Dicyanobenzene and Related Benzonitriles in Continuous Flow Using In Situ Trapping Metalations

Dedicated to Professor Victor Snieckus on the occasion of his 80^th birthday and in recognition of his pioneer contributions in organometallic chemistry

^‡ These authors contributed equally.

Abstract

A mild and general metalation procedure for the functionalization of 1,2-dicyanobenzene and related polyfunctionalized benzonitriles using a commercially available continuous flow setup is reported. The addition of TMPLi (TMP = 2,2,6,6-tetramethylpiperidyl) to a mixture of an aromatic substrate with a metallic salt such as ZnCl₂ under appropriate conditions (0 °C, 20 s) leads to fast in situ lithiation of the arene followed by transmetalation with ZnCl₂ to afford the corresponding functionalized arylzinc compound that were trapped with various electrophiles in high yields. The reaction scope of these in situ trapping metalations in flow is broader and needs less equivalents of the base and the metal salt than the corresponding batch procedure.

Key words

continuous flow - in situ trapping metalation - TMPLi, ZnCl₂ - 1,2-dicyanobenzene

• References and Notes

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• 13 General Procedure for the In situ Trapping Metalation of 1,2-Dicyanobenzene in Flow followed by the Reaction with an Electrophile in Batch: The flow system (FlowSyn, Uniqsis) was dried by flushing it with anhyd THF (flow rate of all pumps: 1.00 mL/min, run-time: 30 min). Injection loop A (1.0 mL) was loaded with TMPLi (0.60–0.66 M in anhyd THF; 1.5 equiv) and injection loop B (1.0 mL) was loaded with the reactant solution (0.40–0.43 M in anhyd THF containing 0.5 equiv ZnCl₂ additive). The solutions were simultaneously injected into separate THF streams (pump A and B, flow rates: 1.50 mL/min), which passed a pre-cooling loop (1 mL, residence time: 40 s, 0 °C) respectively, before they were mixed in a coiled reactor (1 mL; residence time: 20 s, 0 °C). The combined streams were collected in a flame-dried, argon flushed 25-mL flask equipped with a magnetic stirrer and a septum containing the electrophile (1.1 equiv) dissolved in anhyd THF (1 mL). Then, the reaction mixture was further stirred for the indicated time at the indicated temperature. 4′-Methoxy-[1,1′-biphenyl]-2,3-dicarbonitrile (3h): According to the typical procedure, injection loops A and B were loaded with solutions of 1,2-dicyanobenzene (1a; 0.44 M containing 0.5 equiv ZnCl₂, 1 mL) and TMPLi (0.66 M, 1 mL), respectively. After injection and in situ trapping metalation the combined streams were collected in a flask containing 4-iodoanisol (113 mg, 0.49 mmol, 1.1 equiv), Pd(OAc)₂ (2.0 mg, 2 mol%) and SPhos (7.2 mg, 4 mol%) dissolved in THF (1 mL) at r.t. The reaction mixture was stirred overnight before it was quenched with sat. NH₄Cl (15 mL). The aq. layer was extracted with EtOAc (3 × 15 mL), the combined organic fractions were dried over anhyd Mg₂SO₄, filtrated and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel; i-hexane–EtOAc, 9:1) afforded 3h as a pale brown solid (89 mg, 0.38 mmol, 87%; mp 200.3–201.5 °C). IR (Diamond-ATR, neat): 2225, 1608, 1580, 1523, 1514, 1460, 1442, 1308, 1298, 1249, 1178, 1117, 1082, 1026, 991, 861, 840, 820, 802, 783, 769, 743, 725, 683 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.72–7.76 (m, 3 H), 7.49–7.55 (m, 2 H), 7.02–7.06 (m, 2 H), 3.88 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 161.0, 147.2, 134.1, 133.0, 131.7, 130.2, 128.8, 117.5, 115.9, 115.7, 114.7, 114.2, 55.6. MS (EI, 70 eV): m/z (%) = 235 (18), 234 (100), 219 (6), 191 (28), 165 (10), 164 (10), 138 (5), 43 (6). HRMS (EI): m/z [M] calcd for C₁₅H₁₀N₂O: 234.0793; found: 234.0783. Ethyl 2-(2,3-Dicyanobenzyl)acrylate (3c): According to the typical procedure, injection loops A and B were loaded with solutions of 1,2-dicyanobenzene (1a; 0.42 M containing 0.5 equiv ZnCl₂, 1 mL) and TMPLi (0.63 M, 1 mL), respectively. After injection and in situ trapping metalation the combined streams were collected in a flask containing ethyl 2-(bromomethyl)acrylate (89 mg, 0.46 mmol, 1.1 equiv) and CuCN·2LiCl solution (0.04 mL, 10 mol%) dissolved in THF (1 mL) at 0 °C. The reaction mixture was stirred for further 2 h at 0 °C before it was quenched with sat. NH₄Cl (15 mL). The aq. layer was extracted with EtOAc (3 × 15 mL), the combined organic fractions were dried over anhyd Mg₂SO₄, filtrated and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel; i-hexane–EtOAc, 9:1) afforded 3c as a colorless liquid (77 mg; 0.32 mmol; 76%). IR (Diamond-ATR, neat): 3085, 2984, 2930, 2854, 2362, 2236, 1711, 1632, 1586, 1465, 1447, 1408, 1369, 1329, 1300, 1255, 1200, 1175, 1139, 1096, 1024, 959, 858, 809, 792, 753, 733, 715 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.62–7.69 (m, 3 H), 6.57 (s, 1 H), 5.72 (s, 1 H), 4.13–4.18 (q, J = 8 Hz, 2 H) 3.9 (s, 2 H), 1.22–1.26 (t, J = 8 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.8, 145.0, 137.0, 134.5, 132.9, 131.7, 128.8, 116.5, 116.1, 115.7, 114.7, 61.3, 37.0, 14.1. MS (EI, 70 eV): m/z (%) = 212 (37), 195 (20), 194 (12), 168 (14), 167 (31), 166 (100), 165 (12), 141 (13), 140 (21). HRMS (EI): m/z [M] calcd for C₁₄H₁₂N₂O₂: 240.0899; found: 240.0883.
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