Synlett 2019; 30(11): 1308-1312
DOI: 10.1055/s-0037-1611551
© Georg Thieme Verlag Stuttgart · New York

A Simple Method for the Preparation of Stainless and Highly Pure Trichloroacetimidates

a  School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan   Email: [email protected]
b  Department of Chemistry, Faculty of Science, Hokkaido University, West 8, North 10, Kita-ku, Sapporo 060-0810, Japan   Email: [email protected]
Kentaro Murasawa
a  School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan   Email: [email protected]
a  School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan   Email: [email protected]
› Author Affiliations
The Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan supported the program for the Strategic Research Foundation at Private Universities (Grant No. S1311046), and the Japan Society for the Promotion of Science (JSPS) (KAKENHI) (Grant No. JP16H01163 in Middle Molecular Strategy, and Grant No. JP16KT0061) partly supported this work.
Further Information

Publication History

Received: 10 April 2019

Accepted after revision: 29 April 2019

Publication Date:
15 May 2019 (online)


We describe a method for obtaining various allylic, benzylic, and glucosyl 2,2,2-trichloroacetimidates (TCAIs) as stainless liquids or solids at the crude stage. The general synthetic method for the preparation of TCAIs often leads to stained products, and further purification of crude TCAIs causes decomposition due to their instability. In the described method, we use a solvent that barely dissolves the reactant, providing stainless and sufficiently pure TCAIs without requiring a purification step. Furthermore, the reaction mixture is turbid at the beginning and clear at the end, allowing us to monitor the progress of the reaction visually.

Supporting Information

  • References and Notes

  • 3 Comprehensive Organic Name Reactions and Reagents, Vol. 3. Wang Z. John Wiley & Sons; New York: 2009: 3026
  • 4 Overman LE, Carpenter NE. Org. React. 2005; 66: 1
  • 5 Fernandes RA, Kattanguru P, Gholap SP, Chaudhari DA. Org. Biomol. Chem. 2017; 15: 2672
    • 6a Schmidt RR, Michel J. Angew. Chem. Int. Ed. 1980; 19: 731
    • 6b Zhu X, Schmidt RR. Angew. Chem. Int. Ed. 2009; 48: 1900

      For examples of the preparation of Bn-TCAI, see:
    • 7a Lonca GH, Ong DY, Tran MT. H, Tejo C, Chiba S, Gagosz F. Angew. Chem. Int. Ed. 2017; 56: 11440
    • 7b Li C, Li W, Wang J. Tetrahedron Lett. 2009; 50: 2533
    • 7c Trappeniers M, Goormans S, Van Beneden K, Decruy T, Linclau B, Al-Shamkhani A, Elliott T, Ottensmeier C, Werner JM, Elewaut D, Van Calenbergh S. ChemMedChem 2008; 3: 1061
    • 7d Wessel H.-P, Iversen T, Bundle DR. J. Chem. Soc., Perkin Trans. 1 1985; 2247

      For examples of the preparation of PMB-TCAI, see:
    • 8a Green RA, Jolley KE, Al-Hadedi AA. M, Pletcher D, Harrowven DC, Frutos OD, Mateos C, Klauber DJ, Rincoń JA, Brown RC. D. Org. Lett. 2017; 19: 2050
    • 8b Kumar R, Rej RK, Halder J, Mandal H, Nanda S. Tetrahedron: Asymmetry 2016; 27: 498
    • 8c Wadavrao SB, Ghogare RS, Narsaiah AV. Synthesis 2015; 47: 2129
    • 8d Chen T, Altmann K.-H. Chem. Eur. J. 2015; 21: 8403

      For examples of the preparation of allylic TCAIs, see:
    • 9a Debbarma S, Bera SS, Maji MS. J. Org. Chem. 2016; 81: 11716
    • 9b Das D, Halder J, Bhuniya R, Nanda S. Eur. J. Org. Chem. 2014; 5229
    • 9c Ghosh AK, Cheng X, Bai R, Hamel E. Eur. J. Org. Chem. 2012; 4130
    • 9d Cui Y, Tu W, Floreancig PE. Tetrahedron 2010; 66: 4867

      In the case of preparing glycosyl TCAIs, the mainly used base/solvent combination is NaH/CH2Cl2. For examples, see:
    • 10a Lee AM. M, Painter GF, Compton BJ, Larsen DS. J. Org. Chem. 2014; 79: 10916
    • 10b Ganesh NV, Fujikawa K, Tan YH, Stine KJ, Demchenko AV. Org. Lett. 2012; 14: 3036
    • 10c Dieskau AP, Plietker B. Org. Lett. 2011; 13: 5544
    • 10d Boonyarattanakalin S, Liu X, Michieletti M, Lepenies B, Seeberger PH. J. Am. Chem. Soc. 2008; 130: 16791

      For the preparation of Bn-TCAI, see:
    • 11a Ionescu C, Sippelli S, Toupet L, Barragan-Montero V. Bioorg. Med. Chem. Lett. 2016; 26: 636
    • 11b Wallach DR, Stege PC, Shah JP, Chisholm JD. J. Org. Chem. 2015; 80: 1993
    • 11c Kato D, Mitsuda S, Ohta H. J. Org. Chem. 2003; 68: 7234

      For the preparation of PMB-TCAI, see:
    • 12a Kuroda Y, Harada S, Oonishi A, Kiyama H, Yamaoka Y, Yamada K, Takasu K. Angew. Chem. Int. Ed. 2016; 55: 13137
    • 12b Liu C, Richards MR, Lowary TL. Org. Biomol. Chem. 2011; 9: 165

      For examples of the preparation of allylic TCAIs, see:
    • 13a Porter MR, Shaker RM, Calcanas C, Topczewski JJ. J. Am. Chem. Soc. 2018; 140: 1211
    • 13b Martinez-Alsina LA, Murray JC, Buzon LM, Bundesmann MW, Young JM, O’Neill BT. J. Org. Chem. 2017; 82: 12246
    • 13c Mwenda ET, Nguyen HM. Org. Lett. 2017; 19: 4814
    • 13d Sharif SA. I, Calder ED. D, Delolo FG, Sutherland A. J. Org. Chem. 2016; 81: 6697

      For examples of the preparation of glycosyl TCAIs, see:
    • 14a Lu Y.-J, Lai Y.-H, Lin Y.-Y, Wang Y.-C, Liang P.-H. J. Org. Chem. 2018; 83: 3688
    • 14b Mukherjee MM, Ghosh R. J. Org. Chem. 2017; 82: 5751
    • 14c Goto K, Sawa M, Tamai H, Imamura A, Ando H, Ishida H, Kiso M. Chem. Eur. J. 2016; 22: 8323
    • 14d Kong L, Almond A, Bayley H, Davis BG. Nat. Chem. 2016; 8: 461
  • 15 Yamada K, Fujita H, Kitamura M, Kunishima M. Synthesis 2013; 45: 2989
  • 16 We also examined the use of cyclohexane and petroleum ether as reaction solvents. However, both results were inferior to that using hexane. For more details, see pages S17–18 of the Supporting Information.
    • 17a Takeuchi Y, Ono Y, Hisanaga N, Kitoh J, Sugiura Y. Br. J. Ind. Med. 1980; 37: 241
    • 17b Takeuchi Y, Ono Y, Hisanaga N. Clin. Toxicol. 1981; 18: 1395
  • 18 Dixon N. Filtr. Sep. 2007; 44: 18
    • 19a Eastman HE, Jamieson C, Watson AJ. B. Aldrichimica Acta 2015; 48: 51
    • 19b Prat D, Hayler J, Wells A. Green Chem. 2014; 16: 4546
  • 20 p-Methoxybenzyl 2,2,2-Trichloroacetimidate [PMB-TCAI (2)]; Typical Procedure To a suspension of PMBOH (1.00 g, 7.24 mmol) and Cl3CCN (1.15 g, 7.97 mmol) in heptane (18 mL) was added DBU (110 mg, 723 μmol) at 0 °C. After the suspension became a solution (actual reaction time = 25 min), heptane (18 mL) and saturated aq NH4Cl (18 mL) were added to the reaction mixture. The separated heptane layer was washed with saturated aq NH4Cl (18 mL) and dried over Na2SO4. Filtration of the Na2SO4 and concentration of the filtrate under reduced pressure gave PMB-TCAI (2) (2.01 g, 99%) as a colorless oil. The 1H and 13C NMR spectra of 2 were in good agreement with the literature data.22 1H NMR (400 MHz, CDCl3, 24 °C): δ = 8.36 (br s, 1 H), 7.37 (d, J = 8.7 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 5.28 (s, 2 H), 3.82 (s, 3 H). 13C NMR (101 MHz, CDCl3, 24 °C): δ = 162.8, 159.9, 129.9 (2 C), 127.7, 114.1 (2 C), 91.6, 70.8, 55.4.
  • 21 As in the syntheses of 1 and 2, the reaction mixtures for 4af, 5, 6 and 7 were initially suspensions, and then gradually became clear solutions (see pages S29–39 of the Supporting Information). All obtained products were stainless. We also confirmed that 4a, 4e, and 6 could also be preserved at –10 °C for more than one month.
  • 22 Tokuyama H, Okano K, Fujiwara H, Noji T, Fukuyama T. Chem. Asian J. 2011; 6: 560