Communication
Green Chemistry
To showcase late-stage drug modifications and to research putational resources. We also thank Prof. Ruibo Wu at SYSU
the putative biosynthetic approach of natural products, linezo- for his help in mechanism analysis and QM computation.
lid (39a) which is an antimicrobial, momelotinib (40a) which
is an antineoplastic, and two natural products (41a and 42a)
were employed to perform our reaction. To our delight, the
desired exclusive oxidative cleavage products of morpholine
Notes and references
rings were formed in good yields with excellent selectivities
(60–73% yields for 39b–42b). Notably, in the case of 42a,
although there were two CvC double bonds that were more
sensitive to O2, our oxidative cleavage still selected the C–C
single bond of the morpholine ring. As shown in Scheme 3, 9
different piperazine arylamines also provided the desired
exclusive oxidative cleavage products and H2O2. For the pheny-
lamine containing piperazine ring, N-substituents, such as
phenyl (43a), tolyl (44a and 45a), 4-formyl phenyl (46a),
4-acetyl phenyl (47a), 4-methoxycarbonyl phenyl (48a),
4-benzoyl phenyl (49a) and acetyl (50a), gave the expected oxi-
dative cleavage products 43b–50b in excellent yields of
68–84%. Meanwhile, other arylamines, such as pyrilamine
51a, also provided the oxidative cleavage product 51b in a good
yield of 65%.
1 (a) P. Liu, S. Zou, B. Yu, L. Li and H. Huang, Org. Lett.,
2018, 20, 3601; (b) F. P. Guengerich and F. K. Yoshimoto,
Chem. Rev., 2018, 118, 6573; (c) Y. Xia, J. Wang and
G. Dong, Angew. Chem., Int. Ed., 2017, 56, 2376; (d) X. Li,
J. Pan, H. Wu and N. Jiao, Chem. Sci., 2017, 8, 6266;
(e) D.-S. Kim, W.-J. Park and C.-H. Jun, Chem. Rev., 2017,
117, 8977; (f) G. Fumagalli, S. Stanton and J. F. Bower,
Chem. Rev., 2017, 117, 9404; (g) F. Chen, T. Wang and
N. Jiao, Chem. Rev., 2014, 114, 8613; (h) T. Wang and
N. Jiao, J. Am. Chem. Soc., 2013, 135, 11692.
2 (a) E. Ota, H. Wang, N. L. Frye and R. R. Knowles, J. Am.
Chem. Soc., 2019, 141, 1457; (b) J. Liu, X. Qiu, X. Huang,
X. Luo, C. Zhang, J. Wei, J. Pan, Y. Liang, Y. Zhu, Q. Qin,
S. Song, et al., Nat. Chem., 2019, 11, 71; (c) K. V. N. Esguerra
and J.-P. Lumb, Angew. Chem., Int. Ed., 2018, 57, 1514;
(d) M. Murakami and N. Ishida, Nat. Chem., 2017, 9, 298;
(e) J. He, M. Wasa, K. S. L. Chan, Q. Shao and J.-Q. Yu,
Chem. Rev., 2017, 117, 8754; (f) C. E. Elwell, N. L. Gagnon,
B. D. Neisen, D. Dhar, A. D. Spaeth, G. M. Yee and
W. B. Tolman, Chem. Rev., 2017, 117, 2059; (g) Y. Xia, G. Lu,
P. Liu and G. Dong, Nature, 2016, 539, 546;
(h) M. Murakami and N. Ishida, J. Am. Chem. Soc., 2016,
138, 13759.
3 (a) F. Wang, X. Zhang, Y. He and X. Fan, Org. Biomol.
Chem., 2019, 17, 156; (b) S. Wang, X.-D. An, S.-S. Li, X. Liu,
Q. Liu and J. Xiao, Chem. Commun., 2018, 54, 13833;
(c) C. Yu, M. A. Shoaib, N. Iqbal, J. S. Kim, H.-J. Ha and
E. J. Cho, J. Org. Chem., 2017, 82, 6615; (d) T. J. Osberger,
D. C. Rogness, J. T. Kohrt, A. F. Stepan and M. C. White,
Nature, 2016, 537, 214.
4 (a) R. Suarez-Bertoa, F. Saliu, M. Bruschi and B. Rindone,
Tetrahedron, 2012, 68, 8267; (b) F. Saliu, M. Orlandi and
M. Bruschi, ISRN Org. Chem., 2012, 2012, 281642;
(c) C. M. Binder, D. D. Dixon, E. Almaraz, M. A. Tius and
B. Singaram, Tetrahedron Lett., 2008, 49, 2764;
(d) R. Criegee, Ber. chem. Ges., 1931, 64, 260.
Conclusions
In conclusion, complementary to the oxidation mechanism of
arylamines, especially to the detailed oxidative cleavage
mechanism of the C(sp3)–C(sp3) bond, we extended a photo-
induced oxidative cleavage mechanism of the C–C single bond
based on the previous state-of-the-art oxidation mechanism of
arylamines. Both well-designed experiments and QM compu-
tations to some extent confirmed this extended mechanism
that once a polar atom is introduced at the γ-position of a ter-
tiary arylamine, it will avoid other oxidation reactions
(carbonylation and N-dealkylation) and exclusively undergo
the selective oxidative Cα(sp3)–Cβ(sp3) bond cleavage through
SET, proton transfer, radical–radical coupling, dehydroperox-
ide and 1,2-addition reactions under simple O2 and catalyst-
free conditions. Notably, our protocol is not only effective for
the tolerance of a diverse array of functional groups, but also
practical for the late-stage modification of clinical drugs and
scalable functionalization of natural products. Meanwhile,
studies on the C(sp3)–C(sp3) bond cleavage in arylamines
without polar atom substitution at the γ-position are ongoing
in our labs.
5 (a) N. García, R. Rubio-Presa, P. García-García,
M. A. Fernández-Rodríguez, M. R. Pedrosa, F. J. Arnáiza
and R. Sanz, Green Chem., 2016, 18, 2335; (b) Z.-Z. Zhou,
M. Liu, L. Lv and C.-J. Li, Angew. Chem., Int. Ed., 2018, 57,
2616; (c) E. Amadio, J. González-Fabra, D. Carraro,
W. Denis, B. Gjoka, C. Zonta, K. Bartik, F. Cavani, S. Solmi,
C. Bo and G. Licini, Adv. Synth. Catal., 2018, 360, 3286;
(d) E. Amadio, R. D. Lorenzo, C. Zonta and G. Licini, Coord.
Chem. Rev., 2015, 301–302, 147; (e) A. Wang and H. Jiang,
J. Org. Chem., 2010, 75, 2321; (f) M. Kirihara, K. Yoshida,
T. Noguchi, S. Naito, N. Matsumoto, Y. Ema, M. Torii,
Y. Ishizuka and I. Souta, Tetrahedron Lett., 2010, 51, 3619;
(g) C. Klein-Koerkamp, R. Granet, R. Zerrouki,
N. Villandier, F. Jérôme, J. Barrault and P. Krausz,
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Science Foundation
of China (81803436 and 21702236). We thank the National
Supercomputing Center in Guangzhou for providing the com-
3266 | Green Chem., 2021, 23, 3261–3267
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