Synlett 2019; 30(09): 1057-1060
DOI: 10.1055/s-0037-1611815
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 6-Chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile: A Novel, Versatile Intermediate for the Synthesis of Trifluoromethylated Azaindazole Derivatives

Manjunath B. Channapur
a  Syngenta Biosciences Private Limited, Santa Monica Works, Corlim, Goa 403110, India   Email: [email protected]
,
Roger G. Hall
b  Syngenta Crop Protection AG, Schaffhauserstrasse, CH-4332 Stein
,
Jilali Kessabi
b  Syngenta Crop Protection AG, Schaffhauserstrasse, CH-4332 Stein
,
Mark Montgomery
c  Syngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK
,
Ashok S. Shyadligeri*
a  Syngenta Biosciences Private Limited, Santa Monica Works, Corlim, Goa 403110, India   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 19 March 2019

Accepted after revision: 12 April 2019

Publication Date:
02 May 2019 (online)


Abstract

A synthesis of 6-chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile, a versatile building block for the synthesis of trifluoromethylated N-heterocycles, is described. The reactions of 6-chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile with 1,2- and 1,3-bisnucleophiles were investigated.

Supporting Information

 
  • References and Notes

  • 1 Gaikwad DD, Chapolikar AP, Devkate CG, Warad KD, Tayade AP, Pawar RP, Domb AJ. Eur. J. Med. Chem. 2015; 90: 707
  • 2 Patel JB, Malick JB, Salama AI, Goldberg ME. Pharmacol. Biochem. Behav. 1985; 23: 675
  • 3 Harcken C, Kuzmich D, Cook B, Mao C, Disalvo D, Razavi H, Swinamer A, Liu P, Zhang Q, Kulkalka A, Skow D, Patel M, Patel M, Fletcher K, Sherry T, Joseph D, Smith D, Canfield M, Souza D, Bogdanffy M, Berg K, Brown M. Bioorg. Med. Chem. Lett. 2019; 29: 441
    • 4a Wang J, Sánchez-Roselló M, Aceña J.-L, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
    • 4b Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña J.-L, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
    • 4c Maienfisch P, Hall RG. Chimia 2004; 58: 93
  • 5 Clemens JJ, Coon T, Busch BB, Asgian JL, Hudson S, Termin A, Flores TB, Tran D, Chiang P, Sperry S, Gross R, Abt J, Heim R, Lechner S, Twin H, Studley J, Brenchley G, Collier PN, Pierard F, Miller A, Mak C, Dvornikovs V, Jimenez J.-M. Bioorg. Med. Chem. Lett. 2014; 24: 3398
  • 6 Kitade M, Ohkubo S, Yoshimura C, Yamashita S, Oshiumi H, Uno T, Kawai Y. WO 2011004610, 2011
  • 7 Hall RG. Synth. Commun. 2014; 23: 3456
  • 8 Kraus H, Traenckner H.-J. DE 4308152, 1994
  • 9 Arnott EA, Chan LC, Cox BG, Meyrick B, Phillips A. J. Org. Chem. 2011; 76: 1653
    • 10a Kremlev MM, Mushta AI, Tyrra W, Naumann D, Fischer HT. M, Yagupolskii YL. J. Fluorine Chem. 2007; 128: 1385
    • 10b Salvador RL, Saucier M, Simon D, Goyer R. J. Med. Chem. 1972; 15: 646
  • 11 Full data for the X-ray crystal-structure analysis can be found in the Supporting Information. CCDC 1895610, 1895609, and 1895614 contain the supplementary crystallographic data for compounds 4a, 4c, and 5f, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 12 Su D.-S, Lim JJ, Tinney E, Wan B.-L, Young MB, Anderson KD, Rudd D, Munshi V, Bahnck C, Felock PJ, Lu M, Lai M.-T, Touch S, Moyer G, DiStefeno DJ, Flynn JA, Liang Y, Sanchez R, Perlow-Poehnelt R, Miller M, Vacca JP, Williams TM, Anthony NJ. J. Med. Chem. 2009; 52: 7163
  • 13 Dar’in DV, Selivanov SI, Lobanov PS, Potekhin AA. Chem. Heterocycl. Compd. (N. Y., NY U. S.) 2004; 40: 888
  • 14 6-Chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile Hydrate (2.H2O) POCl3 (9.6 mL, 102.7 mmol, 2.5 equiv) was added over 15–20 min to a cooled (10 °C) slurry of enamine derivative 1 (10.0 g, 41.1 mmol, 1.0 equiv) and DIPEA (4.3 mL, 53.4 mmol, 1.3 equiv) in PhCl (70 mL), keeping the reaction temperature below 20 °C. The resulting suspension was stirred at 20 °C for 1 h, then heated to 100 °C and stirred for 24 h. The mixture was analyzed by TLC and GC–MS. (An aliquot of the mixture was sampled for reaction completion by quenching with sat. aq NaHCO3 and extracting with EtOAc). The mixture was then allowed to cool to 25 °C, concentrated, and neutralized with sat. aq NaHCO3. The resulting aqueous phase was extracted with EtOAc (3 × 60.0 mL). The combined organic layers were washed sequentially with H2O (20.0 mL) and brine (10.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography [silica gel, cyclohexane–EtOAc, (7:3)] to give a white solid; yield: 4.70 g (46%); mp 118–120 °C. IR (KBr): 3369, 3096, 2359, 2339, 1589, 1417, 1199, 850, 699 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 8.98 (d, J = 2.2 Hz, 1 H), 8.58 (d, J = 2.2 Hz, 1 H), 8.27 (s, 2 H). 13C NMR (101 MHz, DMSO-d6): δ = 153.7, 153.6, 144.1, 133.6, 123.4 (q, J = 290.9 Hz), 116.3, 108.6, 92.4 (q, J = 33.0 Hz). 19F NMR (377 MHz, DMSO-d 6): δ = –81.5 (s, 3 F). HRMS (ESI): m/z [M + H]+ calcd for C8H5ClF3N2O2: 251.9913; found: 251.9925. Full details of other preparations are given in the Supplementary Information.