Mangana(iii/iv)electro-catalyzed C(sp3)-H azidation

Article abstract of DOI:10.1039/d0sc05924b

Manganaelectro-catalyzed azidation of otherwise inert C(sp³)-H bonds was accomplished using most user-friendly sodium azide as the nitrogen-source. The operationally simple, resource-economic C-H azidation strategy was characterized by mild reaction conditions, no directing group, traceless electrons as the sole redox-reagent, Earth-abundant manganese as the catalyst, high functional-group compatibility and high chemoselectivity, setting the stage for late-stage azidation of bioactive compounds. Detailed mechanistic studies by experiment, spectrophotometry and cyclic voltammetry provided strong support for metal-catalyzed aliphatic radical formation, along with subsequent azidyl radical transfer within a manganese(iii/iv) manifold.

Full text of DOI:10.1039/d0sc05924b

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Mangana(III/IV)electro-catalyzed C(sp3)–H
azidation†
Cite this: Chem. Sci., 2021, 12, 2890
ab
ab
a
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Tjark H. Meyer,
‡
Ramesh C. Samanta,
*
‡
Antonio Del Vecchio
ab
and Lutz Ackermann
Manganaelectro-catalyzed azidation of otherwise inert C(sp3)–H bonds was accomplished using most
user-friendly sodium azide as the nitrogen-source. The operationally simple, resource-economic C–H
azidation strategy was characterized by mild reaction conditions, no directing group, traceless electrons
as the sole redox-reagent, Earth-abundant manganese as the catalyst, high functional-group
compatibility and high chemoselectivity, setting the stage for late-stage azidation of bioactive
compounds. Detailed mechanistic studies by experiment, spectrophotometry and cyclic voltammetry
provided strong support for metal-catalyzed aliphatic radical formation, along with subsequent azidyl
radical transfer within a manganese(III/IV) manifold.
Received 27th October 2020
Accepted 28th December 2020
DOI: 10.1039/d0sc05924b
rsc.li/chemical-science
Introduction
The development of selective, resource-economic methods for
the direct conversion of otherwise unreactive C(sp3)–H bonds is
one of the most demanding challenges in molecular sciences.1
Advances in this eld will not only be of direct importance to
petrochemical and polymer technologies,2 but will also enable
step-economical syntheses of pharmaceutical relevant
compounds3 by ideally late-stage drug diversication.4 Within
this topical research arena, concepts for direct C(sp3)–H ami-
nations are particularly prominent.5 Organic azides6 are key
structural motifs, that are oen key-intermediates in numerous
molecules of interest to medicinal chemistry,7 materials
sciences,8 peptide chemistry or molecular biology.9 Due to this
key importance,10 a plethora of functional group interconver-
sion strategies have been developed, exploiting inter alia
organic halides, alcohols, epoxides, and aldehydes. However,
more step-economical methods that directly install the azido-
group into otherwise inert C(sp3)–H bonds continue to be
scarce11 and generally require stoichiometric amounts of strong
indiscriminate chemical oxidants, such as persulfates,12 N-u-
orobenzenesulfonimide (NFSI),13 hypervalent iodine reagents14
or photochemical15 irradiation.16 In previous reports on selec-
tive electrochemical vicinal diazidation of olens, a metal-free
17
¨
approach was introduced by Schafer in 1970 (Scheme 1a).
Subsequently, Lin signicantly improved the efficacy and
aInstitut fur Organische und Biomolekulare Chemie, Georg-August-Universitat
¨
¨
¨
¨
Gottingen, Tammannstraße 2, 37077 Gottingen, Germany
bWoehler Research Institute for Sustainable Chemistry (WISCh), Georg-August-
¨
¨
¨
Universitat Gottingen, Tammannstraße 2, 37077 Gottingen, Germany
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0sc05924b
Scheme 1 Manganaelectro-catalyzed azidation.
‡ These authors contributed equally.
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selectivities upon the addition of a metal catalyst, that is able to the desired organo-azide 2a was formed in 15% yield, motivated
mediate the transfer of an azidyl radical to the double bond.18 us to study envisioned electrochemical C(sp3)–H azidation in
Here, particularly a manganese(II) pre-catalyst served as an further detail.29
efficient azide transfer reagent via a manganese(II/III) manifold.
Herein, we report the manganaelectro-catalyzed C(sp3)–H
Despite numerous reports on C(sp2)–H transformations azidation of unactivated secondary, tertiary and benzylic C–H
catalyzed by manganese,19 reports on manganese-catalyzed bonds. Key features of our ndings include (a) C(sp3)–H azi-
C(sp3)–H functionalization remain underdeveloped.20 For the dation via synergistic electrosynthesis and an Earth-abundant
direct azidation of unactivated C(sp3)–H bonds, early reports by manganese catalyst, (b) mild and chemical oxidant-free reac-
Hill and Groves indeed employed manganese complexes tion conditions, (c) high regio- and chemoselectivity, (d) and
derived from porphyrin or a Schiff-base (Scheme 1b).21 Here, late-stage azidation of bioactive compounds. It is noteworthy
polymeric and potentially explosive iodosylbenzene was that efficient manganese-catalyzed electro-azidation occurred in
however used as the chemical oxidant to generate high-valent the absence of photochemical irradiation,15 with detailed
manganese(V)-oxo intermediates, which have been reported to
undergo hydrogen-abstraction of aliphatic C(sp3)–H bonds to
form the desired alkyl radical.22 Thereaer, the thus formed
aliphatic radical is proposed to be captured by the Mn(IV)–X
intermediate to form either azidated or undesired oxygenated
products. Unfortunately, depending on the substrate, the re-
ported azide to oxygen incorporation ratio was relatively low (2–
4 : 1).21a
Table 1 Optimization of the reaction conditionsa
Results and discussion
Within our program on sustainable organic electrosynthesis23
for strong bond activation,24 we envisioned the direct azidation
of activated C(sp3)–H bonds via anodically formed azidyl-
radicals in aqueous acidic media (Scheme 2).23g,25 The genera-
tion of transient azidyl-radicals by anodic oxidation was re-
ported earlier,26 yet, direct electrochemical C(sp3)–H azidations
are thus far unprecedented. The azide anion is thus proposed to
be oxidized at the graphite-felt (GF) anode and hence results in
nitrogen gas formation, while hydrogen gas is formed on the
platinum cathode (Scheme 2a). Unfortunately, the direct
Yield [%]
(ratio 2b/3b)
Entry
[Mn]
Solvent
Additive (equiv.)
oxidation of activated benzylic C(sp3)–H (BDE C–H ¼ 82.9 ꢀ
1b
2b
3b
4b
5c,d
6d
[Mn1]
[Mn2]
[Mn2]
[Mn2]
[Mn2]
[Mn2]
AcOH/H2O
AcOH/H2O
AcOH/H2O
AcOH/MeCN
AcOH/MeCN
AcOH/MeCN
PhI (0.2)
PhI (0.2)
—
LiClO4 (1.0)
LiClO4 (1.0)
LiClO4 (1.0)
25 (2.6 : 1.0)
33 (2.0 : 1.0)
30 (2.8 : 1.0)
31 (5.2 : 1.0)
40 (12.3 : 1.0)
45 (10.0 : 1.0)
1.2 kcal molꢁ1
,
E
¼ 2.1 V vs. SCE28) occurred with only poor
27
p,a
chemoselectivity, yet with high conversion of 1a (Scheme 2b).
This unsatisfactory outcome, was however very promising since
Deviation from entry 6
7
8
9
[Mn1] instead of [Mn2]
44 (1.6 : 1.0)
10 (4.0 : 1.0)
39 (12.0 : 1.0)
47 (8.4 : 1.0)
44 (5.3 : 1.0)
30 (8.0 : 1.0)
0
[Mn3] instead of [Mn2]
[Mn4] instead of [Mn2]
[Mn5] instead of [Mn2]
KN3 instead of NaN3
TMSN3 (4.0 equiv.) instead of NaN3
TsN3 (4.0 equiv.) instead of NaN3
No current: under a N2 or air atmosphere
No [Mn]
10
11
12
13
14
15
16
17
0
10 (2.0 : 1.0)
30 (1.0 : 1.0)
42 (10.0 : 1.0)
Light irradiation with blue LEDs
In the dark
a
Reaction conditions: undivided cell, 1b (0.5 mmol), [Mn] (5.0 mol%),
NaN3 (8.0 equiv.), an additive (xx equiv.), solvent (1 : 1, 5 mL), 25 ꢂC,
constant current electrolysis (CCE) at 8 mA, a graphite felt (GF) anode,
and a Pt-plate cathode. Yields are determined by GC-FID with n-
b
c
dodecane as the internal standard. 5 h, 6 mA, 2.24 F. 10 h, 6 mA,
d
4.48 F. Under nitrogen atmosphere.
Scheme 2 Proof of concept electro C(sp3)–H azidation.
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Scheme 3 Reaction scope of manganaelectro-catalyzed C(sp3)–H azidation. [a] Standard conditions: substrate (0.5 mmol), NaN3 (4.0 mmol),
[Mn2] (2.5 or 5.0 mol%), LiClO4 (0.5 mmol), MeCN/AcOH (5 mL, 1 : 1), a nitrogen atmosphere, 10 h, 25 ꢂC, and constant current electrolysis at
8.0 mA in an undivided cell. All yields are isolated products; ratios for site-selectivity are determined by 1H-NMR of the crude mixture. [b] At 50 ꢂC.
1
[c] 3,4-Dihydronaphthalen-1(2H)-one 3 was detected in 10% from crude H-NMR with 1,3,5-trimethoxy benzene as the internal standard. [d]
Standard conditions for 20 h.32
mechanistic studies being supportive of a manganaelectro(III/IV) C(sp3)–H azidation of unactivated alkane 1b (BDE C–H:
regime. We initiated our studies by probing various reaction 95.7 kcal molꢁ1
parameters for the envisioned manganaelectro-catalyzed ESI†).32
,
Eox $ 2.5 V 31) (Tables 1 and S-2–S-5 in the
30
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Preliminary optimization demonstrated that C–H azidation
to afford 2b could indeed be achieved with a manganese(III)
porphyrin33 or salen complex at 25 ꢂC in acetic acid/H2O
mixtures, under air, albeit with signicant amounts of over-
oxidized ketone 3b as the side product (entries 1–3). Aer
considerable experimentation, we found that the desired elec-
trochemical C–H azidation was accomplished with high che-
moselectivity and efficacy (5.97 F per mole 1b) when a mixture of
MeCN/AcOH was used as the reaction medium under a N2
atmosphere (entries 4–6). Variation of the manganese catalyst
did not improve the catalytic performance (entries 7–10).
Nucleophilic azide sources proved to be benecial (entries 11–
13). Likewise, control experiments revealed the key role of
electricity, as well as the importance of the high surface area of
a carbon-based anode material (entry 14).32 The absence of the
manganese catalyst resulted in a major nitrogen gas formation
at the anode, translating into signicantly reduced yield and
chemoselectivity (entry 15). Light irradiation resulted in rather
unselective product mixtures and a diminished yield (entry 16).
However, the reaction efficacy remained unaffected under dark
conditions (17).32
With the optimized manganese catalyst in hand, we evalu-
ated manganaelectro-catalyzed C(sp3)–H azidation for benzylic,
secondary and tertiary C–H bonds (Scheme 3). Azidation
occurred in moderate to excellent yields with high selectivity for
tertiary over secondary or primary C–H bonds. We also observed
an unprecedented chemoselectivity for manganese-catalyzed
C(sp3)–H azidation in terms of the azidation to oxygenation
ratio. Functional groups including silyloxy, amides, ethers,
esters, enolizable ketones and nitriles, were well tolerated, while
the mass balance accounted for unreacted substrates 1. Cyclic,
secondary hydrocarbons provided the organic azide in
moderate yields 2b and 2c (32–40%). When multiple reactive
sites were present, C–H azidation inherently took place at the
tertiary C–H bond over secondary or primary C–H scission.
Amide 1d and dihydrocitronellol derivatives 1e and 1f afforded
the desired azidated products 2d–2f likewise, with good selec-
tivity for the tertiary C–H bond. Leucine derivative 1g reacted
efficiently under exceedingly mild reaction conditions. Similar
to aliphatic substrates, the manganaelectro-catalyzed C(sp3)–H
azidation of benzylic substrates preferentially selected tertiary
over primary or secondary C–H bonds. Generally, electron-
donating substituents facilitated C–H azidation; however,
longer reaction times proved viable to convert electron-decient
substrates. Isobutylbenzene 1x and isopentylbenzene 1y con-
taining both secondary benzylic and tertiary C–H bonds were
next selected to examine site selectivity. Here, a preference for
the benzylic C–H bond was detected, with a benzylic to tertiary
ratio of about 3 : 1. The reaction of p-cymene 1z almost exclu-
sively delivered azidation of tertiary C–H, highlighting the
strong inuence of C–H bond dissociation energies (BDE) over
steric effects (2x–2z). Subsequently, we probed the
manganaelectro-catalyzed C–H azidation of complex molecules
and for late-stage functionalization of pharmaceutically active
molecules 5.14a Biaryl 5a, an analogue of a retinoic acid receptor
agonist34 was effectively converted into the corresponding azide
6a. Ibuprofen methyl ester 5b preferentially reacted at the
Scheme
(4.30 F).
4
Gram-scale manganaelectro-catalyzed C–H azidation
secondary benzylic position (2.3 : 1, 42% yield), surprisingly
without azidation of the tertiary C–H bond adjacent to the ester
group. Azidation of celestolide 5c proceeded efficiently and
afforded 6c in high yield (65%). Functionalization of acetyl(ꢁ)-
menthol 5d, containing four tertiary C(sp3)–H bonds, afforded
azide 6d, favoring the sterically more accessible isopropyl
sidechain. Estrone acetate 5e was transformed into the desired
azide 6e in 75% yield as a diastereomeric mixture. This result is
supportive of a radical pathway, compared to previous reports
where the proposed formation of benzylic carbocation resulted
in different diastereomeric ratios.14a The user-friendly nature of
our manganaelectro-catalyzed C(sp3)–H azidation was further
illustrated by a gram-scale preparation of azidated product 2n
with similar levels of efficiency (Scheme 4).
Given the versatility of manganaelectro-catalyzed C–H azi-
dation, we became attracted to probe its mode of action
(Scheme 5). Upon the addition of persistent radical sources,
such as TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) or BHT
(2,6-di-tert-butyl-4-methylphenol) the reaction was completely
inhibited and no desired product 2r could be detected (Scheme
5a). Intermolecular competition reactions of 1o and 1q
conrmed the general trend that electron-rich substrates reac-
ted preferentially (Scheme 5b). Independent rate measurements
revealed a signicant kinetic isotope effect (KIE) of kH/kD ¼ 3.0
(Scheme 5c). To unambiguously identify the involvement of
a trans-diazidomanganese(IV) complex as the active catalyst for
manganaelectro-catalyzed C–H azidation, the novel complexes
Mn5(III)–N3 and Mn5(IV)–(N3)2 were prepared and fully charac-
terized.32 Initially, Mn5(III)–N3 was synthesized by treating the
corresponding chloride complex [Mn5] with sodium azide.
Subsequently, the thus derived manganese(III) complex was
oxidized to manganese(IV) in the presence of an excess of
sodium azide to afford Mn5(IV)–(N3)2 (Scheme 5e). With the
well-dened complexes in hand, spectrophotometric and elec-
troanalytic studies were performed (Schemes 5f, 6 and Fig. S-2–
S-17†).32 UV-vis spectroscopy of [Mn5], a mixture of [Mn5] and
sodium azide, and the well-dened Mn5(III)–N3 complex resul-
ted in similar spectra with characteristic absorption maxima at
244, 328, and 440 nm (Scheme 5f(i)). In comparison, Mn5(IV)–
(N3)2 revealed signicantly different absorption properties with
maxima at 277, 342, 442, and 642 nm. The strong increased
absorption at 442 nm can be assigned to the charge transfer
bands from coordinating azide to the manganese(IV) metal
center.35
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Scheme 5 Mechanistic investigation of manganaelectro-catalyzed azidation of unactivated C(sp3)–H bonds. (a) Radical trap experiments. (b)
Competition experiment. (c) Kinetic experiments. (d) Chronoamperometric studies at 0.8 V vs. Ag/Ag+. (e) Stoichiometric synthesis of well-
defined manganese(III) azide and manganese(IV) diazide complexes. (f) UV-vis spectroscopic studies: (i) MeCN (0.04 mM) was used as the solvent
at 25 ꢂC. (ii) MeCN/AcOH (1 : 1, 0.05 mM) was used as the solvent at 25 ꢂC.
Similar absorption maxima were detected when a mixture (328 nm) and manganese(IV) (277, and 440 nm), were detected,
of [Mn5], NaN3, and LiClO4 in a MeCN/AcOH mixture was giving strong support for the catalytic formation and
anodically oxidized for 30 min at 8 mA (Scheme 5f(ii), green consumption of Mn5(IV)–(N3)2 (Scheme 5f(ii), blue line). These
line). However, when the crude reaction mixture was analyzed, results were further supported by detailed cyclic voltammetric
mixed absorption maxima of both species, manganese(III) (CV) studies (Scheme 6). The well-dened complex Mn5(IV)–
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Fig. 1 Proposed mechanism for manganaelectro-catalyzed C(sp3)–H
azidation.
hydrogen-atom-transfer (HAT)37 with the substrate, thus
generating the aliphatic radical. Subsequently, the key C–N3
bond is formed via manganese-catalyzed azide radical
transfer, yet alternative azide transfer scenarios, such as
radical-polar crossover, can at this point not be fully ruled
out.
Scheme 6 Cyclic voltammetry: MeCN (0.3 mm) and LiClO4 (0.1 m)
was used as the electrolyte and Ag/AgCl (3 M) aꢁs1the reference elec-
trode, at 25 ꢂC and a scanning rate of 100 mV s
.
(N3)2 showed two characteristic redox-events at E1/2 ¼ ꢁ0.37 V
(vs. Ag/AgCl), which can be assigned to the Mn(II/III) redox
couple and E1/2 ¼ +0.37 V (vs. Ag/AgCl) for the formal Mn(III/IV)
oxidation (Scheme 6(i)).36 Complex Mn5(III)–N3 showed similar
values (Fig. S-5–S-7†).32 In stark contrast, a solution of the
Conclusions
In conclusion, we have reported the unprecedented
manganese-electrocatalyzed C–H azidation of otherwise inert
C(sp3)–H bonds devoid of chemical oxidants, hypervalent
iodine reagents or photochemical irradiation. Detailed
mechanistic studies by experiment, spectrophotometry and
cyclic voltammetry are supportive of an unique man-
ganese(III/IV) electrocatalysis, thus avoiding overoxidation to
the carbocation, while minimizing undesired side-reactions
to oxygenated products. The robustness and utility of the
most user-friendly method was highlighted by azidation of
bioactive and pharmaceutically-relevant compounds by late-
stage diversication.
azide anion in MeCN showed irreversible oxidation at Ep,a
¼
+0.89 V (vs. Ag/AgCl), which shied to Ep,a ¼ +1.45 V (vs. Ag/
AgCl) when AcOH was added (Fig. S-3†). This was likely due
to a protonation, which was substantially higher in poten-
tial, compared to the manganese-complexes. Mixtures of the
manganese chloride complex with tetra-n-butylammonium
azide showed comparable redox properties with the well-
dened manganese azide complexes (Scheme 6(ii)).32
Finally, chronoamperometric experiments revealed selective
product formations of tetralin 1a to the corresponding azide
product 2a, at potentials as low as 0.8 V vs. Ag/Ag+, without
the formation of oxygenated side-products 3a (Scheme 5d).
This gives strong support that the manganese catalyst is
involved in both steps of the reaction.
Conflicts of interest
There are no conicts to declare.
Based on our mechanistic studies, we propose the cata-
lytic cycle to be initiated by facile ligand-exchange to form the
active Mn(III)–N3 complex, followed by anodic oxidation to
generate the manganese(IV) diazide complex (Fig. 1). The
high-valent d3 manganese(IV) complex is prone35b to undergo
Acknowledgements
Generous support by the DFG (Gottfried-Wilhelm-Leibniz
award to L. A.) and the Alexander von Humboldt Foundation
(fellowship to R. C. S.) is gratefully acknowledged.
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