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Synlett 2021; 32(01): 51-56
DOI: 10.1055/s-0040-1705944
letter

Reductive Deuteration of Aromatic Esters for the Synthesis of α,α-Dideuterio Benzyl Alcohols Using D2O as Deuterium Source

Shihui Luo
a   Department of Chemistry and Innovation Center of Pesticide Research, China Agricultural University, Beijing 100193, P. R. of China
,
Chaoqun Weng
a   Department of Chemistry and Innovation Center of Pesticide Research, China Agricultural University, Beijing 100193, P. R. of China
,
Yuxuan Ding
a   Department of Chemistry and Innovation Center of Pesticide Research, China Agricultural University, Beijing 100193, P. R. of China
,
Chen Ling
b   Department of Nutrition and Health, China Agricultural University, Beijing 100193, P. R. of China   Email: jie_an@cau.edu.cn
,
Michal Szostak 
c   Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, USA
,
Xiaodong Ma  ∗
d   College of Science, China Agricultural University, Beijing 100083, P. R. of China   Email: maxiaodong@cau.edu.cn
,
Jie An  ∗
b   Department of Nutrition and Health, China Agricultural University, Beijing 100193, P. R. of China   Email: jie_an@cau.edu.cn
› Author AffiliationsWe thank the National Key Research and Development Plan of China (2017YFD0200504), the National Natural Science Foundation of China (NSFC; 11801558), the Natural Science Foundation of Beijing Municipality (2192026), and Tianjin Haiyi Tech. Ltd. for financial support.
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Abstract

α,α-Dideuterio benzyl alcohols are important building blocks for the synthesis of deuterium-labeled medicines and agrochemicals. We have developed the first general single-electron transfer reductive deuteration of readily commercially available aromatic esters for the synthesis of α,α-dideuterio benzyl alcohols using benign D2O and a mild single-electron donor SmI2. This operationally convenient method features very good functional group tolerance and high deuterium incorporations (>95% D2). The potential impact has been exemplified by the synthesis of numerous deuterium labeled building blocks of important bioactive compounds. Most crucially, the method represents the first example of selective reductive deuteration of benzylic-type ketyl radicals using mild and highly chemoselective lanthanide(II) reagents.

Key words

reductive deuteration - α,α-dideuterio benzyl alcohol - single-electron transfer - reduction - D2O

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1705944.
  • Supporting Information


Publication History

Received: 28 August 2020

Accepted after revision: 17 September 2020

Article published online:
16 October 2020

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  • References and Notes

  • 1 For a recent review, see: Atzrodt J, Derdau V, Kerr WJ, Reid M. Angew. Chem. Int. Ed. 2018; 57: 1758
    CrossrefPubMed
  • 2 Simmons EM, Hartwig JF. Angew. Chem. Int. Ed. 2012; 51: 3066
    CrossrefPubMed

      • For recent reviews, see:
    • 3a Pirali T, Sera M, Cargnin S, Genazzani AA. J. Med. Chem. 2019; 62: 5276
      CrossrefPubMed
    • 3b Gant TG. J. Med. Chem. 2014; 57: 3595
      CrossrefPubMed

      • For selected recent examples, see:
    • 3c Mullard A. Nat. Rev. Drug Discovery 2016; 15: 219
      CrossrefPubMed
    • 3d Schmidt C. Nat. Biotechnol. 2017; 35: 493
      CrossrefPubMed
    • 3e Tong CC, Hwang KC. J. Phys. Chem. C 2007; 111: 3490
      Crossref
    • 3f Shao M, Keum J, Chen J, He Y, Chen W, Browning JF, Jakowski J, Sumpter BG, Ivanov IN, Ma Y.-Z, Rouleau CM, Smith SC, Geohegan DB, Hong K, Xiao K. Nat. Commun. 2014; 5: 3180
      CrossrefPubMed
  • 4 Zhang Z, Tang W. Acta Pharm. Sin. B 2018; 8: 721
    CrossrefPubMed
    • 5a Leonetti F, Capaldi C, Pisani L, Nicolotti O, Muncipinto G, Stefanachi A, Cellamare S, Caccia C, Carotti A. J. Med. Chem. 2007; 50: 4909
      CrossrefPubMed
    • 5b Pan X, Huang R, Zhang J, Ding L, Li W, Zhang Q, Liu F. Tetrahedron Lett. 2012; 53: 5364
      Crossref
    • 5c Li W, You XD, Wu J. CN104230809A, 2014
      PubMed
    • 5d Wipf P, Tzounopoulos A. WO 2016077724 2016
      PubMed
    • 5e Dong D, Tian X, Liu Q, Liang Y, Wang C, Liang F, Sun Z, Yu H, Ouyang Y. CN1775750A, 2006
      PubMed
    • 5f Lee LF, Schleppnik FM, Howe RK. J. Heterocycl. Chem. 1985; 22: 1621
      Crossref
    • 5g Cuevas Yañez E, Canul Sánchez A, Serrano Becerra JM, Muchowski J, Cruz Almanza R. Rev. Soc. Quim. Mex. 2004; 48: 49
    • 6a Ding Y, Luo S, Weng C, An J. J. Org. Chem. 2019; 84: 15098
      CrossrefPubMed
    • 6b Ding Y, Luo S, Adijiang A, Zhao H, An J. J. Org. Chem. 2018; 83: 12269
      CrossrefPubMed
    • 6c Han M, Ding Y, Yan Y, Li H, Luo S, Adijiang A, Ling Y, An J. Org. Lett. 2018; 20: 3010
      CrossrefPubMed
    • 6d Zhang B, Li H, Ding Y, Yan Y, An J. J. Org. Chem. 2018; 83: 6006
      CrossrefPubMed
    • 6e Han M, Ma X, Yao S, Ding Y, Yan Z, Adijiang A, Wu Y, Li H, Zhang Y, Lei P, Ling Y, An J. J. Org. Chem. 2017; 82: 1285
      CrossrefPubMed
    • 6f Li H, Zhang B, Dong Y, Liu T, Zhang Y, Nie H, Yang R, Ma X, Ling Y, An J. Tetrahedron Lett. 2017; 58: 2757
      Crossref
    • 7a Li H, Hou Y, Liu C, Lai Z, Ning L, Szostak R, Szostak M, An J. Org. Lett. 2020; 22: 1249
      CrossrefPubMed
    • 7b Szostak M, Spain M, Procter DJ. Org. Lett. 2014; 16: 5052
      CrossrefPubMed
    • 8a Shi S, Szostak M. Molecules 2017; 22: 2018
      CrossrefPubMed
    • 8b Szostak M, Fazakerley NJ, Parmar D, Procter DJ. Chem. Rev. 2014; 114: 5959
      CrossrefPubMed

      • For recent selected reviews on radical reactions, see:
    • 8c Prier CK, Rankic DA, MacMillan DW. C. Chem. Rev. 2013; 113: 5322
      CrossrefPubMed
    • 8d Romero NA, Nicewicz DA. Chem. Rev. 2016; 116: 10075
      CrossrefPubMed
    • 8e Skubi KL, Blum TR, Yoon TP. Chem. Rev. 2016; 116: 10035
      CrossrefPubMed
    • 8f Staveness D, Bosque I, Stephenson CR. J. Acc. Chem. Res. 2016; 49: 2295
      CrossrefPubMed
    • 8g Narayanam JM. R, Stephenson CR. J. Chem. Soc. Rev. 2011; 40: 102
      CrossrefPubMed
    • 8h Lang X, Chen X, Zhao J. Chem. Soc. Rev. 2014; 43: 473
      CrossrefPubMed
    • 8i Xuan J, Zhang ZG, Xiao WJ. Angew. Chem. Int. Ed. 2015; 54: 15632
      CrossrefPubMed
    • 8j Wang L, Lear JM, Rafferty SM, Fosu SC, Nagib DA. Science 2018; 362: 225
      CrossrefPubMed
    • 8k Boyington AJ, Riu ML, Jui NT. J. Am. Chem. Soc. 2017; 139: 6582
      CrossrefPubMed

      • For an excellent review on acyl radicals, see:
    • 8l Banerjee A, Lei Z, Ngai MY. Synthesis 2019; 51: 303
      Article in Thieme ConnectPubMed
    • 9a Khaskin E, Milstein D. ACS Catal. 2013; 3: 448
      Crossref
    • 9b Balzarek C, Weakley TJ. R, Tyler DR. J. Am. Chem. Soc. 2000; 122: 9427
      Crossref
    • 9c Albrecht M, Lindner MM. Dalton Trans. 2011; 40: 8986
      CrossrefPubMed
    • 9d Bai W, Lee K.-H, Tse SK. S, Chan KW, Lin Z, Jia G. Organometallics 2015; 34: 3686
      Crossref
  • 10 Chatterjee B, Gunanathan C. Org. Lett. 2015; 17: 4794
    CrossrefPubMed
    • 11a Mo X, Yakiwchuk J, Dansereau J, McCubbin JA, Hall DG. J. Am. Chem. Soc. 2015; 137: 9694
      CrossrefPubMed

      • For a recent reductive deoxygenative deuteration reaction, see:
    • 11b Zhang M, Yuan X.-A, Zhu C, Xie J. Angew. Chem. Int. Ed. 2019; 58: 312
      CrossrefPubMed
  • 12 Bodnar BS, Vogt PF. J. Org. Chem. 2009; 74: 2598 ; and references cited therein
    CrossrefPubMed
  • 13 Ankner T, Hilmersson G. Tetrahedron 2009; 65: 10856
    Crossref
  • 14 Tsuruta H, Imamoto T, Yamaguchi K. Chem. Commun. 1999; 1703
    • 15a Denton RM, An J, Adeniran B. Chem. Commun. 2010; 46: 3025
      CrossrefPubMed
    • 15b Denton RM, An J, Adeniran B, Blake AJ, Lewis W, Poulton AM. J. Org. Chem. 2011; 76: 6749
      CrossrefPubMed
    • 15c Beddoe RH, Andrews KG, Magne V, Cuthbertson JD, Saska J, Shannon-Little AL, Shanahan SE, Sneddon HF, Denton RM. Science 2019; 365: 910
      CrossrefPubMed
  • 16 Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
    Crossref
  • 17 Stoochnoff BA, Benoiton NL. Tetrahedron Lett. 1973; 14: 21
    Crossref
  • 18 Roughley SD, Jordan AM. J. Med. Chem. 2011; 54: 3451
    CrossrefPubMed
  • 19 It should be noted that in addition to delivering as a mild single-electron donor that well-tolerates benign deuterium donor D2O, SmI2 is readily synthesized from Sm metal (<$1.00/g, Energy Chemical, Feb 8, 2020) and I2. See: Szostak M, Spain M, Procter DJ. J. Org. Chem. 2012; 77: 3049 DOI: ; and references cited therein.
    CrossrefPubMed
  • 20 Typical Procedure for the Preparation of Model Compound (4-Heptylphenyl)methan-d2 -ol (2a) To a solution of samarium(II) iodide (0.10 M in THF; 12 mL, 1.2 mmol, 6.0 equiv) a solution of methyl 4-heptylbenzoate (46.9 mg, 0.200 mmol) in THF (2.0 mL) was added, followed by Et3N (0.33 mL, 2.4 mmol) and D2O (0.261 mL, 14.4 mmol) under Ar at room temperature and stirred vigorously. After 15 min, the excess of SmI2 was oxidized by bubbling air through the reaction mixture. The reaction mixture was diluted with CH2Cl2 (10 mL) and NaOH (10 mL, 1 M, aq). The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), organic layers were combined, washed with Na2S2O3 (2 × 20 mL, sat., aq), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica, 15% EtOAc/hexane) to afford 2a (40.8 mg, 98%) as a colorless oil. Percentage of exchanged protons are determined by 1H NMR spectroscopy indicated in square brackets in Scheme 2. 1H NMR (300 MHz, CDCl3): δ = 7.26 (m, 2 H), 7.16 (m, 2 H), 2.59 (t, J = 7.7 Hz, 2 H), 1.86 (br, 1 H), 1.60 (m, 2 H), 1.38–1.19 (m, 8 H), 0.87 (t, J = 6.8 Hz, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 142.6, 138.1, 128.6, 127.2, 64.6 (m), 35.7, 31.9, 31.6, 29.3, 29.2, 22.7, 14.1.