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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
substituents on the lactam nitrogen, as well as remote
Chem., 2015, 15, 988-1001.
functionality such as halogen, alkyl, and alkoxy. Benzylic
substituents are less well tolerated. Analysis of the reaction
kinetics with succinic acid revealed an almost second-order
(1.73 ± 0.15) dependency of the reaction rate on palladium,
indicative of an equilibrium between active monomeric and
dimeric palladium species, mediated by succinic acid. Divergent
aziridination and acetoxylation are possible by controlling the
nature of the acid additive in the reaction. Furthermore, the
aziridine products can further be derivatised through acid-
mediated nucleophilic ring-opening with a range of halogen, N,
O and S-nucleophiles. We anticipate that the use of diacids
could be a useful additive to suppress competitive acetoxylation
in similar C-H functionalisation processes, as well as a start point
to introduce a chiral coordination sphere on the catalytic
centers to develop enantioselective aziridination processes.
8
9
>100 marketed drugs contain a piDpOerI:a1z0in.1e039m/Co7iOetBy0.24S8e6eJ
DrugBank 5.0, Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu
A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N,
Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L,
Cummings R, Le D, Pon A, Knox C, Wilson M, Nucleic Acids
Res., 2017, gkx1037.
Small amounts of 2i were also detected.
10 The use of di-(pivaloyloxy)iodobenzene led to the detection of
some 2a, albeit in low amounts.
11 Evidence for polynuclear species may be inferred from
reported x-ray structures of cyclopalladated morpholinones in
reference 6a and computational data in reference 6b, as well
as precedented in: (a) Powers, D. C.; Ritter, T., Nat. Chem.,
2009, 1, 302-309. (b) Deprez, N. R.; Sanford, M. S., J. Am.
Chem. Soc., 2009, 131, 11234-11241. (c) Cotton, F. A.; Gu, J.;
Murillo, C. A.; Timmons, D. J., J. Am. Chem. Soc., 1998, 120,
13280-13281. (d) Dick, A. R.; Kampf, J. W.; Sanford, M. S.,
Organometallics, 2005, 24, 482-485. (e) Muñiz, K., Angew.
Chem., Int. Ed., 2009, 48, 9412-9423.
12 He, G.; Lu, G.; Guo, Z.; Liu, P.; Chen, G., Nat Chem, 2016, 8,
1131-1136.
13 We also investigated the aziridination of a 3-pyridyl analogue
of 1a however this gave erratic results variable with the
reaction scale.
14 In the case of benzylic substrates, aldehyde signals were
observed by 1H NMR in the crude reactions, suggesting these
substrates undergo competitive benzylic oxidation processes.
A 2-chlorobenzyl substituent and a 2-thiophenyl failed to give
satisfactory amounts of aziridine due to competitive oxidative
debenzylation.
15 Watson, I. D. G.; Yudin, A. K., J. Org. Chem., 2003, 68, 5160-
5167.
16 The reaction also produced higher-order acetoxylation
products (tetra- and penta- acetoxylation) in trace amounts,
detectable by mass spectrometry.
Acknowledgements
The authors would like to thank Oncology iMed, AstraZeneca for
the post-doctoral funding and Professor Matthew Gaunt
(University of Cambridge) for valuable discussions and insights.
We also thank Paul Davey, Becky Burton and Joshua Hill
(Oncology iMed, AstraZeneca) for purification and MS support
and Eva Lenz (Oncology iMed, AstraZeneca) for NMR support.
Notes and references
1
For a recent review on piperazine moieties in drug discovery,
see V. Patel, R.; Won Park, S., Mini-Rev. Med. Chem. 2013, 13,
1579-1601.
2
A Scifinder substance search (April 2016) reveals >4 000 000
hits for the piperazine scaffold, >180 000 hits for 2,2-
disubstituted piperazines and only ~1600 hits for 2,2,6,6-
tetrasubstituted piperazines.
17 See reference 6a; acetoxylation (not aziridination) was
observed in cases where there was no carbonyl moiety in the
substrate. We presume a similar process occurs on
methyl groups distal to the carbonyl.
6 on the
3
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(a) Olofson, R. A.; Dougherty, C. M., J. Am. Chem. Soc., 1973,
95, 582-584. (b) Krinninger, C., Spec. Chem. Mag., 2010, 30,
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(a) Zhou, Z.; Liu, L., Curr. Org. Chem., 2014, 18, 459-474. (b)
Ciriminna, R.; Pagliaro, M., Org. Process Res. Dev., 2010, 14,
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6
For selected recent reviews, see (a) Dastbaravardeh, N.;
Christakakou, M.; Haider, M.; Schnuerch, M., Synthesis, 2014,
46, 1421-1439. (b) Li, H.; Li, B.-J.; Shi, Z.-J., Catal. Sci. Technol.,
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(a) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J.,
Nature, 2014, 510, 129-133. (b) Smalley, A. P.; Gaunt, M. J., J.
Am. Chem. Soc., 2015, 137, 10632-10641. (c) Calleja, J.; Pla,
D.; Gorman, T. W.; Domingo, V.; Haffemayer, B.; Gaunt, M. J.,
Nat. Chem., 2015, 7, 1009-1016. (d) He, C.; Gaunt, M. J.,
Angew. Chem., Int. Ed., 2015, 54 (52), 15840-15844.
For selected examples, see: (a) Oh, S.; Ha, H.-J.; Chi, D.; Lee,
H., Curr. Med. Chem., 2001, 8, 999-1034. (b) Kowalski, P.;
Kowalska, T.; Mokrosz, M.; Bojarski, A.; Charakchieva-Minol,
S., Molecules, 2001, 6, 784-795. (c) Zhou, Y.; Manka, J. T.;
Rodriguez, A. L.; Weaver, C. D.; Days, E. L.; Vinson, P. N.;
Jadhav, S.; Hermann, E. J.; Jones, C. K.; Conn, P. J.; Lindsley, C.
W.; Stauffer, S. R., ACS Med. Chem. Lett., 2010, 1, 433-438. (d)
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