Green Chemistry
Paper
lowed by oxidation to obtain 2-oxopropanoic acid; and (3)
radical addition of protonated heteroarenes. The Minisci reac-
Acknowledgements
tion is well known in the alkyl and acyl functionalization of The authors gratefully acknowledge funding from the Ministry
the electron-deficient heteroaromatic moiety.7
of Science and Technology (MOST), Taiwan, and the Centre for
Based on previous literature,19 the possible mechanism Research and Development of Kaohsiung Medical University
for the methylation and acetylation of heteroarenes is pro- for 400 MHz NMR analyses, LC-MS and GC-MS analysis.
posed in Scheme 6. Initially, PEG-400 first reacts with oxygen
to form α-hydroperoxide (A). Further, the thermal breakdown
of (A) forms O-centered alkoxy radical (B), which undergoes
double β-scission followed by 1,2 HAT to obtain intermediate
Notes and references
(E). This intermediate again reacts with O2 and undergoes
subsequent decomposition to acquire acetaldehyde (2). The
acetyl radical generated under the oxidative condition from
intermediates 6 or 7 (in situ formed from 5) reacts with the
protonated electron deficient heteroarene, quinoline 3a, via
the Minisci-type route to afford the aminyl radical cation.
Due to the sufficient acidity of the α-C–H bond, this inter-
mediate undergoes further deprotonation to form an α-amino
radical20 followed by oxidation to acquire the acetylated
quinoline (4a).
Brief literature survey revealed that due to the less aromati-
city of the pyrimidin-4-one ring of 3-phenylquinazolin-4(3H)-
one,18e it preserved higher reactivity which reacts with initially
formed alkoxymethyl radical intermediate (C) via a Minisci-
type reaction. Further, the deprotonation of methine proton
forming more stable α-amino radical20 intermediate (I) fol-
lowed by oxidative cleavage to acquire methylated product via
1,3-H shift. But quinoline or other heterocycles (like pyridine,
benzothiophene, quinazoline, and quinoxaline), due to aro-
matic, are less reactive as compared to 3-phenylquinazolin-4
(3H)-one so they will react directly with insitu generated acyl
radical for the C–H functionalization.
1 (a) E. J. Barreiro, A. E. Kümmerle and C. A. M. Fraga, Chem.
Rev., 2011, 111, 5215–5246; (b) G. Yan, A. J. Borah, L. Wang
and M. Yang, Adv. Synth. Catal., 2015, 357, 1333.
2 (a) S.-Y. Zhang, G. He, W. A. Nack, Y. Zhao, Q. Li and
G. Chen, J. Am. Chem. Soc., 2013, 135, 2124–2127;
(b) S.-Y. Zhang, Q. Li, G. He, W. A. Nack and G. Chen, J. Am.
Chem. Soc., 2013, 135, 12135–12141.
3 (a) X. Chen, J.-J. Li, X.-S. Hao, C. E. Goodhue and J.-Q. Yu,
J. Am. Chem. Soc., 2006, 128, 78–79.
4 (a) B. R. Rosen, L. R. Simke, P. S. Thuy-Boun, D. D. Dixon,
J.-Q. Yu and P. S. Baran, Angew. Chem., Int. Ed., 2013, 52,
7317–7320; (b) S. R. Neufeldt, C. K. Seigerman and
M. S. Sanford, Org. Lett., 2013, 15, 2302–2305.
5 (a) Y. Zhang, J. Feng and C.-J. Li, J. Am. Chem. Soc., 2008,
130, 2900–2901; (b) Q. Dai, J. Yu, Y. Jiang, S. Guo, H. Yang
and J. Cheng, Chem. Commun., 2014, 50, 3865–3867;
(c) Z. Xu, C. Yan and Z.-Q. Liu, Org. Lett., 2014, 16, 5670–
5673; (d) P.-Z. Zhang, J.-A. Li, L. Zhang, A. Shoberu,
J.-P. Zou and W. Zhang, Green Chem., 2017, 19, 919–923.
6 (a) J. Wang, J. Zhao and H. Gong, Chem. Commun., 2017,
53, 10180–10183; (b) T. Uemura, M. Yamaguchi and
N. Chatani, Angew. Chem., Int. Ed., 2016, 55, 3162–3165;
(c) T. Uemura, M. Yamaguchi and N. Chatani, Angew.
Chem., Int. Ed., 2016, 55, 3162–3165.
7 (a) F. Minisci, R. Bernardi, F. Bertini, R. Galli and
M. Perchinummo, Tetrahedron, 1971, 27, 3575–3580;
Conclusions
We developed a new methodology for the methylation and
acetylation of heteroarenes under metal-free conditions using
PEG-400 as methyl and acetyl surrogates, thereby substituting
conventional methylation sources that require costly metal
catalysts and harmful oxidants. To highlight the applicability
of the protocol, we performed a one-pot strategy for the syn-
thesis of sedative drug molecules from the readily available
starting material. This work demonstrated for the first time
that PEG-400 can be used as a carbon source. We hope that
these new findings for the generation of a carbon source
from a sustainable solvent will be further explored in up-
coming research. Further, extension of this strategy to other
cyclic/acyclic and aromatics compounds is ongoing in our
laboratory, and the results of which will be conveyed in due
course.
(b) Y. Chen, Chem. – Eur. J., 2019, 25, 3405–3439;
(c) R. S. J. Proctor and R. J. Phipps, Angew. Chem., Int. Ed.,
2019, 58, 13666–13699.
8 (a) J. Jin and D. W. MacMillan, Nature, 2015, 525, 87–90;
(b) L. K. M. Chan, D. L. Poole, D. Shen, M. P. Healy and
T. J. Donohoe, Angew. Chem., Int. Ed., 2014, 53, 761–765;
(c) J. Sklyaruk, J. C. Borghs, O. El-Sepelgy and M. Rueping,
Angew. Chem., Int. Ed., 2019, 58, 775–779; (d) K. Natte,
H. Neumann, M. Beller and R. V. Jagadeesh, Angew. Chem.,
Int. Ed., 2017, 56, 6384–6394; (e) W. Liu, X. Yang, Z.-Z. Zhou
and C.-J. Li, Chem, 2017, 2, 688–702; (f) A. Bruneau-
Voisine, L. Pallova, S. Bastin, V. Cesar and J.-B. Sortais,
Chem. Commun., 2019, 55, 314–317; (g) T. McCallum,
S. P. Pitre, M. Morin, J. C. Scaiano and L. Barriault, Chem.
Sci., 2017, 8, 7412–7418.
9 (a) Y. Li, D. Xue, W. Lu, C. Wang, Z.-T. Liu and J. Xiao, Org.
Lett., 2014, 16, 66–69; (b) H.-M. Xia, F.-L. Zhang, T. Ye and
Y.-F. Wang, Angew. Chem., Int. Ed., 2018, 57, 11770–11775.
10 (a) B. Yao, R.-J. Song, Y. Liu, Y.-X. Xie, J.-H. Li, M.-K. Wang,
R.-Y. Tang, X.-G. Zhang and C.-L. Deng, Adv. Synth. Catal.,
Conflicts of interest
Author claim no conflicts of interest.
This journal is © The Royal Society of Chemistry 2020
Green Chem.