Synlett 2023; 34(20): 2508-2514
DOI: 10.1055/s-0042-1752738
Special Issue Dedicated to Prof. Hisashi Yamamoto

2,2′-Biphenol-Derived Phosphoric Acid Catalyst for the Dehydrative Esterification of Carboxylic Acids with Alcohols

Manabu Hatano
a   Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
Chiaki Nishioka
a   Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
Ayaka Mimura
a   Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
Risa Kimura
a   Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
Yuki Okuda
a   Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
a   Faculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
Ken Sakata
b   Faculty of Pharmaceutical Sciences, Toho University, Miyama, Funabashi, Chiba 274-8510, Japan
› Author Affiliations
Financial support was partially provided by Japan Society for the Promotion of Science (JSPS) KAKENHI (grant JP20H02735 to M.H., JP23K04758 to T.Y.), and by the Hyogo Science and Technology Association (to M.H.).

Dedicated to Professor Hisashi Yamamoto on the occasion of his 80th birthday


A dehydrative esterification from an equimolar mixture of carboxylic acids and primary or secondary alcohols in toluene at 100 °C was promoted without the necessity to remove water by using a simple 2,2′-biphenol-derived phosphoric acid catalyst (2.5–10 mol%). This reaction was also successfully conducted at the gram scale. To demonstrate the synthetic utility of this catalytic system, pharmaceutically useful substrates and acid-sensitive substrates were examined using these acid–base cooperative phosphoric acid catalysts, which exhibit relatively weak Brønsted acidity.

Supporting Information

Publication History

Received: 21 April 2023

Accepted after revision: 23 May 2023

Article published online:
10 July 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

    • For reviews on esterifications, see:
    • 1a Otera J. Acc. Chem. Res. 2004; 37: 288
    • 1b Grasa GA, Singh R, Nolan SP. Synthesis 2004; 971
    • 1c Hoydonckx HE, De Vos DE, Chavan SA, Jacobs PA. Top. Catal. 2004; 27: 83
    • 1d Enders D, Niemeier O, Henseler A. Chem. Rev. 2007; 107: 5606
    • 1e Science of Synthesis, Vol. 20b. Panek JS. Thieme; Stuttgart: 2007
    • 1f Ishihara K. Tetrahedron 2009; 65: 1085
    • 1g Otera J. Esterification: Methods, Reactions, and Applications, 2nd Ed. Wiley-VCH; Weinheim: 2010
    • 1h Tang S, Yuan J, Liu C, Lei A. Dalton Trans. 2014; 13460
    • 1i Khusnutdinov RI, Baiguzina AR, Dzhemilev UM. Russ. J. Org. Chem. 2017; 53: 1113

      For selected examples of Brønsted acid catalysts, see:
    • 2a Wakasugi K, Misaki T, Yamada K, Tanabe Y. Tetrahedron Lett. 2000; 41: 5249
    • 2b Manabe K, Sun X.-M, Kobayashi S. J. Am. Chem. Soc. 2001; 123: 10101
    • 2c Manabe K, Iimura S, Sun X.-M, Kobayashi S. J. Am. Chem. Soc. 2002; 124: 11971
    • 2d Ishihara K, Nakagawa S, Sakakura A. J. Am. Chem. Soc. 2005; 127: 4168
    • 2e Maki T, Ishihara K, Yamamoto H. Org. Lett. 2005; 7: 5047
    • 2f Sakakura A, Nakagawa S, Ishihara K. Tetrahedron 2006; 62: 422
    • 2g Funatomi T, Wakasugi K, Misaki T, Tanabe Y. Green Chem. 2006; 8: 1022
    • 2h Mercs L, Pozzi G, Quici S. Tetrahedron Lett. 2007; 48: 3053
    • 2i Maki T, Ishihara K, Yamamoto H. Tetrahedron 2007; 63: 8645
    • 2j Sakakura A, Nakagawa S, Ishihara K. Nat. Protoc. 2007; 2: 1746
    • 2k Sakakura A, Koshikari Y, Akakura M, Ishihara K. Org. Lett. 2012; 14: 30
    • 2l Igarashi T, Yagyu D, Naito T, Okumura Y, Nakajo T, Mori Y, Kobayashi S. Appl. Catal. B: Environ. 2012; 119–120: 304
    • 2m Minakawa M, Baek H, Yamada YM. A, Han JW, Uozumi Y. Org. Lett. 2013; 15: 5798
    • 2n Kim Y.-H, Han J, Jung BY, Baek H, Yamada YM. A, Uozumi Y, Lee Y.-S. Synlett 2016; 27: 29
    • 2o Kumar M, Thakur K, Sharma S, Nayal OS, Kumar N, Singh B, Sharma U. Asian J. Org. Chem. 2018; 7: 227
    • 2p Hu H, Ota H, Baek H, Shinohara K, Mase T, Uozumi Y, Yamada YM. A. Org. Lett. 2020; 22: 160

      For selected examples of Lewis acid catalysts, see:
    • 3a Ishihara K, Ohara S, Yamamoto H. Science 2000; 290: 1140
    • 3b Xiang J, Orita A, Otera J. Angew. Chem. Int. Ed. 2002; 41: 4117
    • 3c Nakayama M, Sato A, Ishihara K, Yamamoto H. Adv. Synth. Catal. 2004; 346: 1275
    • 3d Hao X, Yoshida A, Nishikido J. Green Chem. 2004; 6: 566
    • 3e Bartoli G, Boeglin J, Bosco M, Locatelli M, Massaccesi M, Melchiorre P, Sambri L. Adv. Synth. Catal. 2005; 347: 33
    • 3f Sato A, Nakamura Y, Maki T, Ishihara K, Yamamoto H. Adv. Synth. Catal. 2005; 347: 1337
    • 3g Mantri K, Komura K, Sugi Y. Green Chem. 2005; 7: 677
    • 3h Chen C.-T, Munot YS. J. Org. Chem. 2005; 70: 8625
    • 3i Nakamura Y, Maki T, Wang X, Ishihara K, Yamamoto H. Adv. Synth. Catal. 2006; 348: 1505

      For reviews on cooperative acid–base chemistry, see:
    • 4a Kanai M, Kato N, Ichikawa E, Shibasaki M. Synlett 2005; 1491
    • 4b Ishihara K, Sakakura A, Hatano M. Synlett 2007; 686
    • 4c Ishihara K. Proc. Jpn. Acad., Ser. B 2009; 85: 290
    • 4d Shibasaki M, Kanai M, Matsunaga S, Kumagai N. Acc. Chem. Res. 2009; 42: 1117
    • 5a Hayashi H, Yasukochi S, Sakamoto T, Hatano M, Ishihara K. J. Org. Chem. 2021; 86: 5197

    • For relevant reports on our catalytic transesterification, see:
    • 5b Hatano M, Furuya Y, Shimmura T, Moriyama K, Kamiya S, Maki T, Ishihara K. Org. Lett. 2011; 13: 426
    • 5c Hatano M, Kamiya S, Moriyama K, Ishihara K. Org. Lett. 2011; 13: 430
    • 5d Hatano M, Kamiya S, Ishihara K. Chem. Commun. 2012; 48: 9465
    • 5e Hatano M, Tabata Y, Yoshida Y, Toh K, Yamashita K, Ogura Y, Ishihara K. Green Chem. 2018; 20: 1193
    • 5f Ng JQ, Arima H, Mochizuki T, Toh K, Matsui K, Ratanasak M, Hasegawa J.-Y, Hatano M, Ishihara K. ACS Catal. 2021; 11: 199
    • 6a Quin LD. A Guide to Organophosphorus Chemistry . John Wiley & Sons; New York: 2000
    • 6b Timperley CM. Best Synthetic Methods: Organophosphorus (V) Chemistry. Academic Press; Oxford: 2015

      For seminal studies of chiral BINOL-derived phosphoric acids as organocatalysts, see:
    • 7a Akiyama T, Itoh J, Yokota K, Fuchibe K. Angew. Chem. Int. Ed. 2004; 43: 1566
    • 7b Uraguchi D, Terada M. J. Am. Chem. Soc. 2004; 126: 5356

      The asymmetric acylation of alcohols with acetyl chloride or acid anhydrides by using chiral BINOL-derived phosphoric acid catalysts has already been reported; for details, see:
    • 8a Mandai H, Murota K, Mitsudo K, Suga S. Org. Lett. 2012; 14: 3486
    • 8b Harada S, Kuwano S, Yamaoka Y, Yamada K.-i, Takasu K. Angew. Chem. Int. Ed. 2013; 52: 10227
    • 8c Mori K, Kishi H, Akiyama T. Synthesis 2017; 49: 365
  • 9 Handbook of Chemistry: Pure Chemistry, 6th Edition. Maruzen Publishing; Tokyo: 2021
  • 10 Shamir D, Zilbermann I, Maimon E, Shames AI, Cohen H, Meyerstein D. Inorg. Chim. Acta 2010; 363: 2819
  • 11 Krašovec F, Jan J. Croat. Chem. Acta 1963; 35: 183
  • 12 Gupta KK, Misra SK, Tripathi SC, Dakshinamoorthy A, Pandey AK, Reddy AV. R. J. Membr. Sci. 2008; 318: 452
    • 13a Yang C, Xue X.-S, Jin J.-L, Li X, Cheng J.-P. J. Org. Chem. 2013; 78: 7076
    • 13b Christ P, Lindsay AG, Vormittag SS, Neudörfl J.-M, Berkessel A, O’Donoghue AC. Chem. Eur. J. 2011; 17: 8524
  • 14 Compound 1e and its conjugate base can adopt various stable structures with relatively small energy differences. We estimated the pK a value by using both the structure of 1e with the lowest free energy (I) and the structure of the conjugated base with the lowest energy (XI); for details, see the Supporting Information.
  • 15 Monaco MR, Pupo G, List B. Synlett 2016; 27: 1027
  • 16 The difference in the dihedral angle of the biaryl moiety in catalysts 1h (43.5°) and 1i (53.2°) can be expected to partially affect the structural rigidity of 1h and 1i. The dihedral angle of the biaryl moiety in 1j is 53.1°. Therefore, the stronger Brønsted acidity (i.e., pK a) of 1j compared to that of 1i might be reflected in the catalytic activity; for details, see the Supporting Information.
  • 17 EtOAc does not react with alcohols under our catalytic conditions, and the source of the acetyl moiety of AcOBn (4aa) is AcOH (2a) in Scheme 1. Actually, in Scheme 4, when the reaction of 2l and 3a in EtOAc was performed, 4la was obtained in 90% yield and 4aa was not obtained.
    • 18a Normanly J, Bartel B. Curr. Opin. Plant Biol. 1999; 2: 207
    • 18b Zhang M.-Z, Chen Q, Yang G.-F. Eur. J. Med. Chem. 2015; 89: 421
  • 19 Nursing Drug Handbook . Lippincott Williams & Wilkins/Wolters Kluwer Health; Philadelphia: 2022
  • 20 Theodosis-Nobelos P, Kourti M, Tziona P, Kourounakis PN, Rekka EA. Bioorg. Med. Chem. Lett. 2015; 25: 5028
    • 21a Gryko D, Zimnicka M, Lipiński R. J. Org. Chem. 2007; 72: 964
    • 21b Kim H, Gao J, Burgess DJ. Int. J. Pharm. 2009; 377: 105
    • 22a Naumann EC, Göring S, Ogorek I, Weggen S, Schmidt B. Bioorg. Med. Chem. Lett. 2013; 23: 3852
    • 22b Serbinova EA, Packer L. Methods Enzymol. 1994; 234: 354
  • 23 Since catalysts 1e and 1h were soluble under our reaction conditions at 80–100 °C, the yields of the products in Scheme 6 might not simply depend on the solubility of the catalysts. At the present preliminary stage, we cannot clearly explain the observed results in Scheme 6, and pK a value, the basicity of the P=O moiety, homodimerization, and conformational flexibility of the catalysts and the instability of the starting materials and products might complicate the results.
  • 24 General Procedure: A thoroughly flame-dried, two-necked flask with a condenser was charged with catalyst 1h (12.4 mg, 0.050 mmol, 5 mol%) under an argon atmosphere. Toluene (2 mL), carboxylic acid 2 (1.0 mmol), and alcohol 3 (1.0 mmol) were added at room temperature. The mixture was then stirred at 100 °C (bath temperature) for the indicated reaction time (6–72 h), and the reaction was monitored by TLC. Subsequently, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (n-hexane/EtOAc, 20:1 to 5:1) to give 4. For characterization data and copies of NMR spectra, see the Supporting Information.