E
P. Lei et al.
PSP
Synthesis
1H NMR (500 MHz, CDCl3): = 7.82 (d, J = 8.9 Hz, 2 H), 7.75 (d, J = 7.0
Hz, 2 H), 7.55 (t, J = 7.4 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 2 H), 6.95 (d, J = 8.9
Hz, 2 H), 3.87 (s, 3 H).
13C NMR (125 MHz, CDCl3): = 195.6, 163.3, 138.3, 132.6, 131.9,
130.2, 129.7, 128.2, 113.6, 55.5.
References
(1) Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Link-
age: Structural Significance in Chemistry, Biochemistry and
Materials Science; Wiley-VCH: New York, 2003.
(2) For selected reviews on amide N–C(O) bond activation, see:
(a) Meng, G.; Szostak, M. Eur. J. Org. Chem. 2018, 2352. (b) Liu,
C.; Szostak, M. Org. Biomol. Chem. 2018, 16, 7998. (c) Dander, J.
E.; Garg, N. K. ACS Catal. 2017, 7, 1413. (d) Takise, R.; Muto, K.;
Yamaguchi, J. Chem. Soc. Rev. 2017, 46, 5864. (e) Bourne Bran-
chu, Y.; Gosmini, C.; Danoun, G. Chem. Eur. J. 2019, 25, 2663.
(f) Chaudhari, M. B.; Gnanaprakasam, B. Chem. Asian J. 2019, 14,
76.
Methyl 4-Benzoylbenzoate (3d)
White solid (EtOAc/hexanes 1:20); yield: 96.4 mg (80%).
1H NMR (500 MHz, CDCl3): = 8.14 (d, J = 8.2 Hz, 2 H), 7.84 (d, J = 8.2
Hz, 2 H), 7.80 (d, J = 7.5 Hz, 2 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.50 (t, J = 7.7
Hz, 2 H), 3.96 (s, 3 H).
13C NMR (125 MHz, CDCl3): = 196.0, 166.3, 141.3, 137.0, 133.2,
133.0, 130.1, 129.8, 129.5, 128.5, 52.5.
(3) For a review on acyl-cross-coupling, see: Buchspies, J.; Szostak,
M. Catalysts 2019, 9, 53.
(4) For studies on amide bond destabilization, see: Liu, C.; Shi, S.;
Liu, Y.; Liu, R.; Lalancette, R.; Szostak, R.; Szostak, M. Org. Lett.
2018, 20, 7771.
Phenyl(o-tolyl)methanone (3b′)
Colorless oil (EtOAc/hexanes 1:20); yield: 60.9 mg (62%)
1H NMR (500 MHz, CDCl3): = 7.81 (d, J = 7.7 Hz, 2 H), 7.57 (t, J = 7.4
Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.5 Hz, 1 H), 7.30 (dd, J =
12.4, 7.6 Hz, 2 H), 7.25 (t, J = 7.4 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (125 MHz, CDCl3): = 198.6, 138.7, 137.8, 136.8, 133.2,
131.0, 130.3, 130.2, 128.5, 128.5, 125.2, 20.0.
(5) For lead references on amide bonds in drug discovery and
polymer chemistry, see: (a) Roughley, S. D.; Jordan, A. M. J. Med.
Chem. 2011, 54, 3451. (b) Kaspar, A. A.; Reichert, J. M. Drug
Discov. Today 2013, 18, 807. (c) Marchildon, K. Macromol. React.
Eng. 2011, 5, 22. (d) Brunton, L.; Chabner, B.; Knollman, B.
Goodman and Gilman’s The Pharmacological Basis of Therapeu-
tics; MacGraw-Hill: New York, 2010. For selected recent exam-
ples of amide bonds in synthetic chemistry, see: (e) Barger, C. J.;
Dicken, R. D.; Weidner, V. L.; Motta, A.; Lohr, T. L.; Marks, T. J.
J. Am. Chem. Soc. 2020, 142, 8019. (f) Wei, T.; Lu, S.; Sun, J.; Xu,
Z.; Yang, X.; Wang, F.; Ma, Y.; Shi, Y. S.; Chen, X. J. Am. Chem. Soc.
2020, 142, 3806. (g) Gonçalves, C. R.; Lemmerer, M.; Teskey, C. J.;
Adler, P.; Kaiser, D.; Maryasin, B.; González, L.; Maulide, N.
J. Am. Chem. Soc. 2019, 141, 18437. (h) Derosa, J.; Kleinmans, R.;
Tran, V. T.; Karunananda, M. K.; Wisniewski, S. R.; Eastgate, M.
D.; Engle, K. M. J. Am. Chem. Soc. 2018, 140, 17878. (i) Chen, J.;
Xia, Y.; Lee, S. Org. Lett. 2020, 22, 3504. (j) Sharma, S.;
Buchbinder, N. W.; Braje, W. M.; Handa, S. Org. Lett. 2020, 22,
5737.
(6) For selected studies on amide N–C(O) cross-coupling, see:
(a) Hie, L.; Nathel, N. F. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang,
Y. F.; Liu, P.; Houk, K. N.; Garg, N. K. Nature 2015, 524, 79.
(b) Meng, G.; Szostak, M. Org. Lett. 2015, 17, 4364. (c) Meng, G.;
Szostak, M. Angew. Chem. Int. Ed. 2015, 54, 14518. (d) Ni, S.;
Zhang, W.; Mei, H.; Han, J.; Pan, Y. Org. Lett. 2017, 19, 2536.
(e) Yue, H.; Guo, L.; Liao, H. H.; Cai, Y.; Zhu, C.; Rueping, M.
Angew. Chem. Int. Ed. 2017, 56, 4282. (f) For a comprehensive
list, refs. 2 and 3.
(4-Methoxyphenyl)(phenyl)methanone (3c′)
White solid (EtOAc/hexanes 1:20); yield: 91.5 mg (86%).
1H NMR (500 MHz, CDCl3): = 7.82 (d, J = 8.9 Hz, 2 H), 7.75 (d, J = 7.0
Hz, 2 H), 7.55 (t, J = 7.4 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 2 H), 6.95 (d, J = 8.9
Hz, 2 H), 3.87 (s, 3 H).
13C NMR (125 MHz, CDCl3): = 195.6, 163.3, 138.3, 132.6, 131.9,
130.2, 129.7, 128.2, 113.6, 55.5.
Methyl 4-Benzoylbenzoate (3d′)
White solid (EtOAc/hexanes 1:20); yield: 90.2 mg (75%).
1H NMR (500 MHz, CDCl3): = 8.14 (d, J = 8.2 Hz, 2 H), 7.84 (d, J = 8.2
Hz, 2 H), 7.80 (d, J = 7.5 Hz, 2 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.50 (t, J = 7.7
Hz, 2 H), 3.96 (s, 3 H).
13C NMR (125 MHz, CDCl3): = 196.0, 166.3, 141.3, 137.0, 133.2,
133.0, 130.1, 129.8, 129.5, 128.5, 52.5.
Funding Information
Rutgers University and the NSF (CAREER CHE-1650766) are gratefully
acknowledged for support. Supplement funding for this project was
provided by the Rutgers University – Newark Chancellor’s Research
Office. The Bruker 500 MHz spectrometer was supported by the NSF-
MRI grant (CHE-1229030). P.L. thanks Natural Science Basic Research
Program of Shaanxi (Program No. 2020JQ-238), the Young Talent
Fund of University Association for Science and Technology in Shaanxi
(Program No. 2019-02-02). We gratefully acknowledge VLAIO (SBO
project CO2PERATE), the Special Research Fund (BOF) of Ghent Uni-
versity is also acknowledged for starting and project grants to S.P.N.
We thank the National Natural Science Foundation of China (No.
(7) For reviews on Pd–NHCs in amide N–C(O) activation, see:
(a) Shi, S.; Nolan, S. P.; Szostak, M. Acc. Chem. Res. 2018, 51,
2589. (b) Vemula, S. R.; Chhoun, M. R.; Cook, G. R. Molecules
2019, 24, 215.
(8) For excellent reviews on the impact of synthetic chemistry on
medicinal chemistry, see: (a) Cernak, T.; Dykstra, K. D.;
Tyagarajan, S.; Vachal, P.; Krska, S. W. Chem. Soc. Rev. 2016, 45,
546. (b) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.;
Thomas, A. W.; Wilson, D. M.; Wood, A. Nat. Chem. 2018, 10,
383.
(9) For studies using different classes of [Pd–NHCs], see:
(a) [Pd(NHC)(allyl)Cl] complexes: Lei, P.; Meng, G.; Szostak, M.
ACS Catal. 2017, 7, 1960. (b) [Pd(NHC)(ind)Cl] complexes: Lei,
P.; Meng, G.; Shi, S.; Ling, Y.; An, J.; Szostak, R.; Szostak, M.
Chem. Sci. 2017, 8, 6525. (c) [Pd–PEPPSI] complexes: Lei, P.;
22077137, Y.L.).
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