Synlett 2017; 28(20): 2817-2822
DOI: 10.1055/s-0036-1588837
letter
© Georg Thieme Verlag Stuttgart · New York

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

Marthe Ketels ‡, Dorothée S. Ziegler ‡, Paul Knochel*
  • Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus F, 81377 München, Germany   Email: paul.knochel@cup.uni-muenchen.de
Further Information

Publication History

Received: 10 April 2017

Accepted after revision: 26 April 2017

Publication Date:
06 June 2017 (eFirst)

Dedicated to Professor Victor Snieckus on the occasion of his 80th 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.

Supporting Information

 
  • References and Notes

    • 1a Zhao Y. Snieckus V. Chem. Commun. 2016; 52: 11224
    • 1b Fuentes MA. Kennedy AR. Mulvey RE. Parkinson JA. Rantanen T. Robertson SD. Snieckus V. Chem. Eur. J. 2015; 21: 14812
    • 1c Zhao Y. Snieckus V. J. Am. Chem. Soc. 2014; 136: 11224
    • 1d Schneider C. David E. Toutov AA. Snieckus V. Angew. Chem. Int. Ed. 2012; 11: 2722
    • 1e Chauder BA. Kalinin AV. Snieckus V. Synthesis 2001; 140
    • 1f Beaulieu F. Snieckus V. Synthesis 1991; 112
    • 1g Snieckus V. Chem. Rev. 1990; 90: 879
    • 1h Beak P. Snieckus V. Acc. Chem. Res. 1982; 15: 306
    • 1i Snieckus V. Heterocycles 1980; 14: 1649
    • 1j Watanabe M. Snieckus V. J. Am. Chem. Soc. 1980; 102: 1457
    • 2a Nicolaou KC. Chen JS. Edmonds DJ. Estrada AA. Angew. Chem. Int. Ed. 2009; 48: 660
    • 2b Chinchilla R. Nájera C. Yus M. Tetrahedron 2005; 61: 3139
    • 2c Nicolaou KC. Sorensen EJ. In Classics in Total Synthesis . Wiley-VCH; Weinheim; 1996
    • 2d Nafe J. Knochel P. Synthesis 2016; 48: 103
    • 2e Nicolaou KC. Snyder SA. In Classics in Total Synthesis II . Wiley-VCH; Weinheim; 2003
    • 2f Lima F. Kabeshov MA. Tran DN. Battilocchio C. Sedelmeier J. Sedelmeier G. Schenkel B. Ley SV. Angew. Chem. Int. Ed. 2016; 55: 14085
    • 2g Kim JY. Lee K. Coates NE. Moses D. Nguyen T.-Q. Dante M. Heeger AJ. Science 2007; 317: 222
    • 2h Kohei M. Schwaerzer K. Karaghiosoff K. Knochel P. Synthesis 2016; 48: 3141
    • 2i Clarke T. Ballantyne A. Jamieson F. Brabec C. Nelson J. Durrant J. Chem. Commun. 2009; 89
    • 2j Bellan B. Kuzmina OM. Vetsova VA. Knochel P. Synthesis 2017; 49: 188
    • 3a Tejerina L. Martínez-Díaz MV. Nazeeruddin MK. Torres T. Chem. Eur. J. 2016; 22: 4369
    • 3b Yamamoto S. Zhang A. Stillmann MJ. Kobayashi N. Kimura M. Chem. Eur. J. 2016; 22: 18760
    • 3c Xu H. Chan W.-K. Ng DK. P. Synthesis 2009; 1791
    • 3d Senge MO. Sergeeva NN. In The Chemistry of Organozinc Compounds . Rappoport Z. Marek I. John Wiley & Sons., Ltd; Chichester; 2006: 395
  • 4 Frischmuth A. Fernández M. Barl NM. Achrainer F. Zipse H. Berionni G. Mayr H. Karaghiosoff K. Knochel P. Angew. Chem. Int. Ed. 2014; 53: 7928
  • 5 Krasovskiy A. Kopp F. Knochel P. Angew. Chem. Int. Ed. 2006; 45: 497
    • 6a Uzelac M. Kennedy AR. Hevia E. Mulvey RE. Angew. Chem. Int. Ed. 2016; 55: 13147
    • 6b Kissel CL. Rickborn B. J. Org. Chem. 1972; 37: 2060
    • 6c Rathke MW. Kow R. J. Am. Chem. Soc. 1972; 49: 6854
    • 6d Olofson RA. Dougherty CM. J. Am. Chem. Soc. 1973; 95: 581
    • 6e Olofson RA. Dougherty CM. J. Am. Chem. Soc. 1973; 95: 582
    • 7a Ketels M. Konrad DB. Karaghiosoff K. Trauner D. Knochel P. Org. Lett. 2017; 19: 1666
    • 7b Becker MR. Knochel P. Angew. Chem. Int. Ed. 2015; 54: 1
    • 7c Ganiek MA. Becker MR. Ketels M. Knochel P. Org. Lett. 2016; 18: 828
    • 7d Petersen TP. Becker MR. Knochel P. Angew. Chem. Int. Ed. 2014; 53: 7933
  • 8 Flow reactions were performed with commercially available equipment from Uniqsis Ltd (FlowSyn; http://www.uniqsis.com).
  • 9 Using the same stoichiometry in a batch reaction leads to a lower conversion and poorer yields are obtained.
  • 10 Knochel P. Yeh MC. P. Berk SC. Talbert J. J. Org. Chem. 1988; 53: 2390
    • 11a Negishi E. Valente LF. Kobayashi M. J. Am. Chem. Soc. 1980; 102: 3298
    • 11b Negishi E. Acc. Chem. Res. 1982; 15: 340
  • 12 Martin R. Buchwald SL. Acc. Chem. Res. 2008; 41: 1461
  • 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.
    • 14a Krasovskiy A. Straub BF. Knochel P. Angew. Chem. Int. Ed. 2006; 45: 159
    • 14b i-PrMgCl·LiCl in THF is available from Albermale (Frankfurt/Höchst, Germany).
    • 15a Leznoff CC. Dre DM. Can. J. Chem. 1996; 74: 307
    • 15b Drew M. Leznoff CC. Synlett 1994; 623