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Green Chemistry
Journal Name
COMMUNICATION
CO2
DOI: 10.1039/D0GC02618B
O
R
N
base
Mes-Acr+*
1
h
SBn
Notes and references
A
Mes-Acr+
1
(a) F. Zani and P. Vicini, Arch. Pharm. Pharm. Med. Chem.,
1998, 331, 219; (b) P. Vicini, A. Geronikaki, M. Incerti, B.
Busonera, G. Poni, C. A. Cabras and P. La Colla, Bioorg. Med.
Chem., 2003, 11, 4785; (c) G. Morini, E. Poli, M. Comini, A.
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A. Geronikaki, P. Eleftheriou, P. Vicini, I. Alam, A. Dixit and A.
K. Saxena, J. Med. Chem., 2008, 51, 5221.
SET
CO2
SET
O2
O2
O
N
Mes-Acr
O
R
[O]
H
Bn
SBn
B
N
R
2
(a) T. F. Seeger, P. A. Seymour, A. W. Schmidt, S. H. Zorn, D.
W. Schulz, L. A. Lebel, S. McLean, V. Guanowsky, H. R. Howard,
J. A. Lowe III and J. Heym, J. Pharmacol. Exp. Ther., 1995, 275,
101; (b) C. Prakash, A. Kamel, D. Cui, Drug Metab. Dispos.,
1997, 25, 897.
CO2
+
(CH3)2CO
R
N
cyclization
SBn
S
C
2
3
4
(a) M. George, R. Amrutheshwar, R.P. Rajkumar, S. Kattimani
and S. A. Dkhar, Eur. J. Clin. Pharmacol., 2013, 69, 1497; (b) M.
Sanford and S. Dhillon, CNS Drugs, 2015, 29, 253.
1d
1d + NaOAc
NaOAc
S. Kovackova, L. Chang, E. Bekerman, G. Neveu, R. Barouch-
Bentov, A. Chaikuad, C. Heroven, M. Šála, S. De Jonghe, S.
Knapp, S. Einav and Piet Herdewijn, J. Med. Chem., 2015, 58,
3393.
3.0x108
2.8x108
2.6x108
5
6
De. Pat., DE3837578A1, 1990.
For selected reviews on synthesis of isothiazoles, see: (a) D.
W. Brown and M. Sainsbury, in Science of Synthesis, ed. E.
Schaumann, Thieme, Stuttgart, 2002, vol. 11, pp. 573-623; (b)
R. V. Kaberdin and V. I. Potkin, Russ. Chem. Rev., 2002, 71,
673; (c) A.-S. S. Hamad Elgazwy, Tetrahedron, 2003, 59, 7445;
(d) A. De Oliveira Silva, J. McQuade and M. Szostak, Adv.
Synth. Catal., 2019, 361, 3050; (e) A. V. Kletskov, N. A.
Bumagin, F. I. Zubkov, D. G. Grudinin and V. I. Potkin,
Synthesis, 2020, 52, 159.
3.0x10-3
6.0x10-3
0.0
Concentration (M)
7
For selected references on the synthesis of benzoisothiazoles,
see: (a) R. Leardini, H. McNab, M. Minozzi and D. Nanni, J.
Chem. Soc., Perkin Trans. 1, 2001, 1072; (b) T. Creed, R.
Leardini, H. McNab, D. Nanni, I. S. Nicolson and D. Reed, J.
Chem. Soc., Perkin Trans. 1, 2001, 1079; (c) N. O. Devarie-Baez
and M. Xian, Org. Lett., 2010, 12, 752; (d) Y. Chen and M. C.
Willis, Org. Lett., 2015, 17, 4786; (e) F. Xu, Y. Chen, E. Fan and
Z. Sun, Org. Lett., 2016, 18, 2777; (f) H. Xie, G. Li, F. Zhang, F.
Xiao and G.-J. Deng, Green Chem., 2018, 20, 827; (g) R. Zhu, Z.
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Huang, Org. Lett., 2018, 20, 3161; (h) H. Yuan and Z. Sun,
Synlett, 2019; 30, 1904.
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Stephenson, Chem. Soc. Rev., 2011, 40, 102. (b) C. K. Prier, D.
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Rev., 2016, 116, 10075; (e) Visible Light Photocatalysis in
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W. C. MacMillan, Wiley-VCH, Weinheim, 2018; (f) L. Marzo, S.
K. Pagire, O. Reiser and B. König, Angew. Chem. Int. Ed., 2018,
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Stephenson, Trends Chem., 2019, 1, 111; (h) A. F. Garrido-
Castro, M. C. Maestro and J. Alemán, Tetrahedron Lett., 2018,
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Catalysts, 2020, 10, 562.
Scheme 6. Proposed mechanism based on time resolved fluorescence
quenching studies
In summary, we have developed an efficient and scalable
method to synthesize isothiazoles using readily accessible
oximes derivatives and visible light. The described protocol
involves an organo-photoredox generation of iminyl radicals by
oxidative SET followed by a cyclization, which represents an
effective approach to create N−S bonds under mild conditions.
Moreover, the preparation of a valuable molecule and the
implementation of the reaction in a flow setup highlighted the
broad applicability of the strategy.
8
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
We acknowledge the financial support by the Spanish
Government (RTI2018-095038-B-I00) and ERC (ERC-CG,
647550). S.C. thanks the Ministerio de Ciencia e Innovación for
a Juan de la Cierva contract. M. J. C. thanks the Comunidad
Autónoma de Madrid for a postdoctoral contract (PEJD-2018-
POST/AMB-8938). L. M. thanks the Comunidad Autónoma de
Madrid for a postdoctoral contract (PEJD-2018-POST/AMB-8938)
and for an Atracción de Talento Investigador contract (2017-
T2/AMB-5037). The authors also wish to thank the Comunidad
9
For reviews on iminyl radicals, see: (a) S. Z. Zard, Synlett, 1996;
12, 1148; (b) J. C. Walton, Molecules, 2016, 21, 1690; (c) M.
M. Jackman, Y. Cai and S. L. Castle, Synthesis, 2017, 49, 1785;
(d) J. Lei, D. Li and Q. Zhu, Top. Heterocycl. Chem., 2018, 54,
285; (e) W. Yin and X. Wang, New J. Chem., 2019, 43, 3254. (f)
S. P. Morcillo, Angew. Chem. Int. Ed., 2019, 58, 14044.
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