10.1002/anie.201813631
Angewandte Chemie International Edition
COMMUNICATION
a) reaction with deuterated indole
performed the YfeX mutagenesis and Gerd Balcke for ESI-ToF
MS analysis of the deuterium experiments. J.H. thanks the
Australian Research Council for financial support (Grant
DE160100807).
D
73% yield
55% deuterium content
FeTPPCl
D
N
N
N
N
700 µM (TON = 35, conv. <3%)
35% deuterium content
YfeX I230A
N
N
N
deutero-1
2a
3a
b) competition experiments
Keywords: iron • C-H functionalization • diazoalkanes • indole •
H/D
H/D
N
FeTPPCl
35% yield
5 : 1 H/D ratio
biocatalysis
N
N
N
YfeX I230A 1080 µM (TON = 54, conv. <3%)
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N
5 : 1 H/D ratio
deutero-1 : 1
3a
2a
(1:1)
c) reaction in the presence of radical scavenger
H
N
H
N
FeTPPCl
radical
N
scavenger
(TEMPO)
X
N
N
N
1
[2]
[3]
2a
no product formation
Scheme 3. Mechanistic studies: a) reaction with deutero-1; b) competition
experiment; c) reaction in the presence of TEMPO as radical scavenger.
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We thus set out to investigate a potential radical mechanism of
this transformation and conducted the reaction in the presence
of TEMPO as radical scavenger (Scheme 3c). Surprisingly, a
complete inhibition of the C—H functionalization reaction was
observed. This observation is in accordance with a report by the
Driver group, who reported on a complete inhibition of iron-
porphyrin catalyzed nitrene transfer reactions, if radical
quenchers were added.[22]
Based on our data and the previous reports, we thus
hypothesize that the mechanism of this iron-catalyzed C—H
functionalization reaction of indole with diazoacetonitrile might
proceed via radical intermediates.[23] Yet, at this point it remains
unclear, in which particular step radicals are involved.
In summary, we have discovered a novel reactivity of iron-
porphyrin catalysts, which enables C—H functionalization
reactions of N-heterocycles with diazoacetonitrile. A focused
mutant library of the heme-protein YfeX was used to perform
biocatalytic C—H functionalizations with conversions of up 29%.
The organometallic FeTPPCl complex proved highly efficient in
this reaction (37 examples, up to 99% yield, down to 0.1 mol-%
catalyst loading) and exhibits broad functional group tolerance,
operational simplicity and can be used in gram-scale synthesis.
Mechanistic investigations show the participation of radicals in
this transformation. This C—H functionalization reaction thus
opens up new and highly efficient pathways for the synthesis of
tryptamine and applications in total synthesis, medicinal
chemistry and agrochemistry.
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[6]
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During the preparation of this manuscript, the Fasan group reported on
a similar reaction with ethyl diazoacetate and an enzymatic reaction of
diazoacetonitrile: g) D. A. Vargas, A. Tinoco, V. Tyagi, R. Fasan,
Angew. Chem. Int. Ed. 2018, 57, 9911-9915; Angew. Chem. 2018, 130,
10059-10063; h) A. L. Chandgude, R. Fasan, Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201810059.
Acknowledgements
R.M.K. thanks for support from the Excellence Initiative of the
German federal and state governments and the Fonds der
Chemischen Industrie (Sachkostenbeihilfe) for financial support.
M.J.W and A.K. thank the BMBF („Biotechnologie 2020+
Strukturvorhaben: Leibniz Research Cluster“, 031A360B) for
generous funding. The authors thank Niels Borlinghaus who
[7]
a) T. Curtius, Ber. Dtsch. Chem. Ges. 1898, 31, 2489-2492; b) D. D.
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