10.1002/chem.201903505
Chemistry - A European Journal
COMMUNICATION
solution and its aqueous solution fed as a third stream (see
supporting information), the corresponding oxygenated products
20 and 22 were obtained in 40% and 48% yield, respectively.
method represents a reliable alternative and complementary
protocol for the well-known photochemical protocols of generating
singlet oxygen. The developed generator was applied to various
substrates and the expected products were obtained in good to
excellent yields in sufficiently pure form so that purification was
not needed in most cases. Moreover, this protocol was
successfully applied to the synthesis of the anti-malarial drug
artemisinin. In addition, the developed flow protocol provides a
solution to some intrinsic problems of the chemical generation of
Table 3. Oxidation of pinenes using ‘dark’ 1O2 in flow[a]
Entry
Substrate
Product
Yield [%]
40[b]
OOH
1
2–
1O2 using H2O2 / MoO4 system in batch, such as solvent and
19
20
substrate limitations.
OH
2
48[b,c]
21
22
Experimental Section
[a] Reactions setup and conditions (See supporting information). [b] Performing
the reaction in batch using methanol or acetonitrile led to the formation of the
products in a very poor yield (< 3%). [c] Obtained after reduction of the initially
formed hydroperoxide using PPh3.
Using the reaction setup shown in Figure 1, a solution of substrate (0.1 M)
and Li2MoO4 (0.025 M) in MeOH/H2O (96:4) was pumped using a syringe
pump (0.25 mL/min) and combined with a stream of 50% (wt/wt) H2O2 (7.8
μL/min) using a T-mixer and pumped in a PTFE coil reactor (4 mL, 1 mm
i.d.) at 40 ºC. The first two reactor volumes (8 mL) were discarded and the
next 20 mL (2.0 mmol of substrate) were collected. Quenching the reaction
immediately by a reducing agent did not led to any change in yields. Hence,
the reactions were collected without quenching to simplify the workup
procedure. The reaction mixture was concentrated under reduced
pressure, then diluted with water (10 mL) and extracted with CHCl3 (3 x 10
mL). The combined organic layers were evaporated under reduced
pressure to give the crude reaction product.
Finally, the applicability of the developed ‘dark’ 1O2 generator
was confirmed by its successful application in the synthesis of the
anti-malarial drug artemisinin.[
However, under modified
20
]
reaction conditions, 60 mol% of the molybdate catalyst and
adjusting the H2O2 flow rate to 18.7 μL/min were necessary to
achieve full conversion of the dihydroartemisinc methyl ester
23.[15] Treatment of the crude hydroperoxide 24 with trifluoroacetic
acid (20 mol%) while bubbling oxygen into the reaction mixture in
dichloromethane led to the formation of artemisinin 25 (Scheme
3) in 35% yield, which is comparable to established
photochemical methods.[15,21]
Acknowledgements
3O2
TFA (20 mol%)
H
H
H
"dark" 1O2
in flow
O
The authors are grateful to the Bill and Melinda Gates foundation
for the generous funding (Grant no: OPP1190186). We also thank
Drs Alice Dunbabin and Donya Valikhani and Ms Florence Huynh,
Cardiff University, for helpful discussions and assistance.
O
OOH
O
CH2Cl2
H
H
H
H
O
H
CO2Me
CO2Me
O
23
24
25 (35%)
Scheme 3. Application of the ‘dark’ 1O2 generator in the synthesis of artemisinin
(25).
Keywords: Artemisinin • Flow Chemistry • Hydroperoxides •
Oxidation • Singlet Oxygen
In conclusion,
a simple and practical continuous-flow
generator of ‘dark’ singlet oxygen has been developed. This
[1] Z. Guo, B. Liu, Q. Zhang, W. Deng, Y. Wang, Y. Yang, Chem. Soc. Rev.
2014, 43, 3480–3524.
[9] D. S. Lee, Z. Amara, C. A. Clark, Z. Xu, B. Kakimpa, H. P. Morvan, S. J.
Pickering, M. Poliakoff, M. W. George, Org. Process Res. Dev. 2017, 21,
1042–1050.
[2] Modern Oxidation Methods, Ed. J.-E. Bäckvall, Wiley-VCH, Weinheim,
2010.
[10] a) Y. You, Org. Biomol. Chem. 2018, 16, 4044–4060; b) V. Nardello, J.
Marko, G. Vermeersch, J. M. Aubry, Inorg. Chem. 1995, 34, 4950–4957; c)
R. W. Murray, M. L. Kaplan, J. Am. Chem. Soc. 1969, 91, 5358–5364.
[11] a) W. Fudickar, T. Linker, Angew. Chem. Int. Ed. 2018, 57, 12971–12975;
Angew. Chem. 2018, 130, 13153–13157; b) M. Bauch, A. Krtitschka, T.
Linker, J. Phys. Org. Chem. 2017, 30, e3734.
[3] a) Y.-F. Liang, N. Jiao, Acc. Chem. Res. 2017, 50, 1640–1653; b) L.
Vanoye, J. Wang, M. Pablos, C. de Bellefon, A. Favre-Réguillon, Catal. Sci.
Technol. 2016, 6, 4724–4732.
[4] C. A. Hone, C. O. Kappe, Top. Curr. Chem. 2019, 377, 1–44.
[5] P. E. Correa, G. Hardy, D. P. Riley, J. Org. Chem. 1988, 53, 1695–1702.
[6] N. Emmanuel, C. Mendoza, M. Winter, C. R. Horn, A. Vizza, L. Dreesen, B.
Heinrichs, J.-C. M. Monbaliu, Org. Process Res. Dev. 2017, 21, 1435–1438.
[7] a) A. A. Ghogare, A. Greer, Chem. Rev. 2016, 116, 9994–10034; b) H. H.
Wasserman, R. W. DeSimone, K. R. X. Chia, M. G. Banwell, in Encycl.
Reag. Org. Synth., Wiley, Chichester, 2013; E. L. Clennan, A. Pace,
Tetrahedron 2005, 61, 6665–6691.
[12] V. Nardello, S. Bogaert, P. L. Alsters, J.-M. Aubry, Tetrahedron Lett. 2002,
43, 8731–8734.
[13] a) P. L. Alsters, W. Jary, V. Nardello-Rataj, J.-M. Aubry, Org. Process Res.
Dev. 2010, 14, 259–262; b) B. F. Sels, D. E. De Vos, P. J. Grobet, P. A.
Jacobs, Chem. Eur. J. 2001, 7, 2547–56; c) F. van Laar, D. De Vos, D.
Vanoppen, B. Sels, P. A. Jacobs, Chem. Commun. 1998, 267–268.
[14] X. Tang, M. Demiray, T. Wirth, R. K. Allemann, Bioorg. Med. Chem. 2018,
26, 1314–1319.
[8] a) E. N. DeLaney, D. S. Lee, L. D. Elliott, J. Jin, K. I. Booker-Milburn, M.
Poliakoff, M. W. George, Green Chem. 2017, 19, 1431–1438; b) F.
Lévesque, P. H. Seeberger, Org. Lett. 2011, 13, 5008–5011.
This article is protected by copyright. All rights reserved.