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. 2022 Jun 27;12(29):18722-18727.
doi: 10.1039/d2ra00241h. eCollection 2022 Jun 22.

Transient directing group enabled Pd-catalyzed C-H oxygenation of benzaldehydes and benzylic amines

Mixiang Tian  1 , Lidong Shao  1 , Xiaosan Su  1 , Xuhong Zhou  1 , Honglei Zhang  1 , Kun Wei  2 , Ruifen Sun  1 , Junliang Wang  1
Affiliations

Transient directing group enabled Pd-catalyzed C-H oxygenation of benzaldehydes and benzylic amines

Mixiang Tian et al. RSC Adv. .

Abstract

We report a general protocol for ortho-C-H fluoroalkoxylation of benzaldehydes and benzylic amines utilizing an inexpensive amino amide as a transient directing group. In the presence of an electrophilic fluorinating bystanding oxidant and fluorinated alcohols, a wide range of benzaldehydes and benzylic amines could be oxygenated selectively at the ortho positions to afford fluoroalkyl aryl ethers. This elegant approach would provide appealing strategies for synthesis of drug molecules and natural products.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Controlled site-selective C–H bond oxygenation.
Scheme 2
Scheme 2. Scope of aldehydes and fluorinated alcohols.a a Reaction conditions: 1 (0.2 mmol), fluorinated alcohols (2 mL), Pd(OAc)2 (10 mol%), A9 (50 mol%), F1 (0.4 mmol), TFA (2 equiv.) and stirred at 80 °C for 12 h. All yields given are those for the isolated products.
Scheme 3
Scheme 3. Scope of benzylic amines.a a Reaction conditions: 4 (0.2 mmol), TFE (2 mL), Pd(OAc)2 (10 mol%), A9 (50 mol%), F1 (0.2 mmol), F4 (0.2 mmol), TFA (2 equiv.) and stirred at 80 °C for 12 h. All yields given are those for the isolated products.
Scheme 4
Scheme 4. Proposed mechanism.
See this image and copyright information in PMC

References

    1. For examples on functionalization of C-H bond:

    2. Whisler M. C. MacNeil S. Snieckus V. Beak P. Angew. Chem., Int. Ed. 2004;43:2206–2225. doi: 10.1002/anie.200300590. - DOI - PubMed
    3. Daugulis O. Do H. Q. Shabashov D. Acc. Chem. Res. 2009;42:1074–1086. doi: 10.1021/ar9000058. - DOI - PMC - PubMed
    4. Engle K. M. Mei T. S. Wasa M. Yu J. Q. Acc. Chem. Res. 2012;45:788–802. doi: 10.1021/ar200185g. - DOI - PMC - PubMed
    5. Chen X. Engle K. Wang D. Yu J. Angew. Chem., Int. Ed. 2009;48:5094–5115. doi: 10.1002/anie.200806273. - DOI - PMC - PubMed
    6. Colby D. Bergman R. Ellman J. Chem. Rev. 2010;110:624–655. doi: 10.1021/cr900005n. - DOI - PMC - PubMed
    7. Lyons T. Sanford M. Chem. Rev. 2010;110:1147–1169. doi: 10.1021/cr900184e. - DOI - PMC - PubMed
    8. Rouquet G. Chatani N. Angew. Chem., Int. Ed. 2013;52:11726–11743. doi: 10.1002/anie.201301451. - DOI - PubMed
    9. Zhang F. L. Hong K. Li T. J. Park H. Yu J. Q. Science. 2016;351:252. doi: 10.1126/science.aad7893. - DOI - PMC - PubMed
    10. Tiwari V. K. Kapur M. Org. Biomol. Chem. 2019;17:1007–1026. doi: 10.1039/C8OB02272K. - DOI - PubMed
    11. Bisht R. Chattopadhyay B. J. Am. Chem. Soc. 2016;138:84–87. doi: 10.1021/jacs.5b11683. - DOI - PubMed
    12. He J. Wasa M. Chan K. S. L. Shao Q. Yu J. Q. Chem. Rev. 2017;117:8754. doi: 10.1021/acs.chemrev.6b00622. - DOI - PMC - PubMed
    13. Chen Y.-Q. Singh S. Wu Y. Wang Z. Hao W. Verma P. Qiao J. X. Sunoj R. B. Yu J. Q. J. Am. Chem. Soc. 2020;142:9966. doi: 10.1021/jacs.9b13537. - DOI - PMC - PubMed
    14. Xiao L. J. Hong K. Luo F. Hu L. Ewing W. R. Yeung K. S. Yu J. Q. Angew. Chem., Int. Ed. 2020;59:9594. doi: 10.1002/anie.202000532. - DOI - PMC - PubMed
    15. Provencher P. A. Hoskin J. F. Wong J. J. Chen X. Yu J. Q. Houk K. N. Sorensen E. J. J. Am. Chem. Soc. 2021;143:20035. doi: 10.1021/jacs.1c09368. - DOI - PubMed
    16. Provencher P. A. Bay K. L. Hoskin J. F. Houk K. N. Yu J. Q. Sorensen E. J. ACS Catal. 2021;11:3115. doi: 10.1021/acscatal.0c05081. - DOI - PubMed
    17. Li Y.-H. Ouyang Y. Chekshin N. Yu J. Q. J. Am. Chem. Soc. 2022;144:4727. doi: 10.1021/jacs.1c13586. - DOI - PMC - PubMed
    18. Higham I. Bull J. A. Angew. Chem., Int. Ed. 2022:e202202933. - PMC - PubMed
    19. Cheng J.-T. Xiao L.-J. Qian S.-Q. Zhuang Z. Liu A. Yu J.-Q. Angew. Chem., Int. Ed. 2022;61:e202117233. - PMC - PubMed

    1. For examples on directing groups:

    2. Zaitsev V. G. Shabashov D. Daugulis O. J. Am. Chem. Soc. 2005;127:13154–13155. doi: 10.1021/ja054549f. - DOI - PubMed
    3. Desai L. V. Malik H. A. Sanford M. S. Org. Lett. 2006;8:1141–1144. doi: 10.1021/ol0530272. - DOI - PubMed
    4. Cabrera P. J. Lee M. Sanford M. S. J. Am. Chem. Soc. 2018;140:5599–5606. doi: 10.1021/jacs.8b02142. - DOI - PMC - PubMed
    5. Deprez N. R. Sanford M. S. J. Am. Chem. Soc. 2009;131:11234–11241. doi: 10.1021/ja904116k. - DOI - PMC - PubMed
    6. Neufeldt S. R. Sanford M. S. Acc. Chem. Res. 2012;45:936–946. doi: 10.1021/ar300014f. - DOI - PMC - PubMed
    7. Xu Y. Young M. C. Wang C. Magness D. M. Dong G. Angew. Chem., Int. Ed. 2016;55:9084–9087. doi: 10.1002/anie.201604268. - DOI - PubMed
    8. Wang J. Li R. Dong Z. Liu P. Dong G. Nat. Chem. 2018;10:866–872. doi: 10.1038/s41557-018-0074-z. - DOI - PubMed

    9. . For selected reviews on transient directing groups:

    10. Goswami N. Bhattacharya T. Maiti D. Nat. Rev. Chem. 2021;5:646–659. doi: 10.1038/s41570-021-00311-3. - DOI - PubMed
    11. Jacob C. Maes B. U. W. Evano G. Chem. - Eur. J. 2021;27:13899–13952. doi: 10.1002/chem.202101598. - DOI - PubMed
    12. Zu B. Guo Y. Ke J. He C. Synthesis. 2021;53:2029–2042. doi: 10.1055/a-1372-6627. - DOI
    13. Lapuh M. I. Mazeh S. Besset T. ACS Catal. 2020;10:12898–12919. doi: 10.1021/acscatal.0c03317. - DOI
    14. Das J. Guin S. Maiti D. Chem. Sci. 2020;11:10887–10909. doi: 10.1039/D0SC04676K. - DOI - PMC - PubMed
    15. Higham J. I. Bull J. A. Org. Biomol. Chem. 2020;18:7291–7315. doi: 10.1039/D0OB01587C. - DOI - PubMed
    16. Bag D. Verma P. K. Sawant S. D. Chem.–Asian J. 2020;15:3225–3238. doi: 10.1002/asia.202000657. - DOI - PubMed
    17. Liao G. Zhang T. Lin Z. K. Shi B.-F. Angew. Chem., Int. Ed. 2020;59:19773–19786. doi: 10.1002/anie.202008437. - DOI - PubMed
    18. Niu B. Yang K. Lawrence B. Ge H. ChemSusChem. 2019;12:2955–2969. doi: 10.1002/cssc.201900151. - DOI - PubMed
    19. Rasheed O. K. Sun B. ChemistrySelect. 2018;3:5689–5708. doi: 10.1002/slct.201801097. - DOI
    20. St John-Campbell S. Bull J. Org. Biomol. Chem. 2018;16:4582–4595. doi: 10.1039/C8OB00926K. - DOI - PubMed
    21. Gandeepan P. Ackermann L. Chem. 2018;4:199–222. doi: 10.1016/j.chempr.2017.11.002. - DOI
    22. Qun Z. Thomas P. Xavier P. Tatiana B. Synthesis. 2017;49:4808–4826. doi: 10.1055/s-0036-1590878. - DOI

    1. For examples on TDG enabled C(sp2)–H (hetero)arylations:

    2. Liu X.-H. Park H. Hu J.-H. Hu Y. Zhang Q.-L. Wang B.-L. Sun B. Yeung K.-S. Zhang F.-L. Yu J.-Q. J. Am. Chem. Soc. 2017;139:888–896. doi: 10.1021/jacs.6b11188. - DOI - PubMed
    3. Xu J. Wang Y. Li Y. Xu X. Jin Z. Org. Lett. 2017;19:1562–1565. doi: 10.1021/acs.orglett.7b00363. - DOI - PubMed
    4. Thrimurtulu N. Dey A. Singh A. Pal K. Maiti D. Volla C. M. R. Adv. Synth. Catal. 2019;361:1441–1446. doi: 10.1002/adsc.201801378. - DOI
    5. Wang J. Dong C. Wu L. Xu M. Lin J. Wei K. Adv. Synth. Catal. 2018;360:3709–3715. doi: 10.1002/adsc.201800489. - DOI
    6. Cheng Y. Zheng J. Tian C. He Y. Zhang C. Tan Q. An G. Li G. Asian J. Org. Chem. 2019;8:526–531. doi: 10.1002/ajoc.201900037. - DOI
    7. Xu J. Liu Y. Zhang J. Xu X. Jin Z. Chem. Commun. 2018;54:689–692. doi: 10.1039/C7CC09273C. - DOI - PubMed
    8. Liao G. Chen H.-M. Xia Y.-N. Li B. Yao Q.-J. Shi B.-F. Angew. Chem., Int. Ed. 2019;58:11464–11468. doi: 10.1002/anie.201906700. - DOI - PubMed
    9. St John-Campbell S. Ou A. Bull J. Chem. 2018;24:17838–17843. doi: 10.1002/chem.201804515. - DOI - PMC - PubMed
    10. Li B. Seth K. Niu B. Pan L. Yang H. Ge H. Angew. Chem., Int. Ed. 2018;57:3401–3405. doi: 10.1002/anie.201713357. - DOI - PubMed
    11. Wang D.-Y. Guo S.-H. Pan G.-F. Zhu X.-Q. Gao Y.-R. Wang Y.-Q. Org. Lett. 2018;20:1794–1797. doi: 10.1021/acs.orglett.8b00292. - DOI - PubMed
    12. Wu L.-F. Yao J.-W. Zhang X. Liu S.-Y. Zhuang Z.-N. Wei K. Org. Lett. 2021;23:6237–6241. doi: 10.1021/acs.orglett.1c01933. - DOI - PubMed

    1. For examples on TDG enabled C(sp2)–H alkylations:

    2. Chen X.-Y. Sorensen E. J. J. Am. Chem. Soc. 2018;140:2789–2792. doi: 10.1021/jacs.8b00048. - DOI - PubMed
    3. Liao G. Li B. Chen H.-M. Yao Q.-J. Xia Y.-N. Luo J. Shi B.-F. Angew. Chem., Int. Ed. 2018;57:17151–17155. doi: 10.1002/anie.201811256. - DOI - PubMed
    4. Chen H.-M. Zhang S. Liao G. Yao Q.-J. Xu X.-T. Zhang K. Shi B.-F. Organometallics. 2019;38:4022–4028. doi: 10.1021/acs.organomet.9b00490. - DOI
    5. Tan P. W. Juwaini N. A. B. Seayad J. Org. Lett. 2013;15:5166–5169. doi: 10.1021/ol402145m. - DOI - PubMed
    6. Li G. Jijun J. Xie H. Wang J. Chem. - Eur. J. 2019;25:4688–4694. doi: 10.1002/chem.201900762. - DOI - PubMed
    7. Chen H.-M. Liao G. Xu C.-K. Yao Q.-J. Zhang S. Shi B.-F. CCS Chem. 2021;3:455–465. doi: 10.31635/ccschem.021.202000695. - DOI

    1. For examples on TDG enabled C(sp2)–H alkenylation:

    2. Engle K. M. Yu J.-Q. J. Org. Chem. 2013;78:8927–8955. doi: 10.1021/jo400159y. - DOI - PMC - PubMed
    3. Shao Q. Wu K. Zhuang Z. Qian S. Yu J.-Q. Acc. Chem. Res. 2020;53:833–851. doi: 10.1021/acs.accounts.9b00621. - DOI - PMC - PubMed
    4. Bag S. Jana S. Pradhan S. Bhowmick S. Goswami N. Sinha S. K. Maiti D. Nat. Commun. 2021;12:1393. doi: 10.1038/s41467-021-21633-2. - DOI - PMC - PubMed
    5. Yao Q.-J. Zhang S. Zhan B.-B. Shi B.-F. Angew. Chem., Int. Ed. 2017;56:6617–6621. doi: 10.1002/anie.201701849. - DOI - PubMed
    6. Dhawa U. Tian C. Wdowik T. Oliveira J. C. A. Hao J. Ackermann L. Angew. Chem., Int. Ed. 2020;59:13451–13457. doi: 10.1002/anie.202003826. - DOI - PMC - PubMed