Manganese-Catalyzed Oxidative Azidation of C(sp3)-H Bonds under Electrophotocatalytic Conditions

Article abstract of DOI:10.1021/jacs.0c08437

The selective installation of azide groups into C(sp3)-H bonds is a priority research topic in organic synthesis, particularly in pharmaceutical discovery and late-stage diversification. Herein, we demonstrate a generalized manganese-catalyzed oxidative azidation methodology of C(sp3)-H bonds using nucleophilic NaN3 as an azide source under electrophotocatalytic conditions. This approach allows us to perform the reaction without the necessity of adding an excess of the substrate and successfully avoiding the use of stoichiometric chemical oxidants such as iodine(III) reagent or NFSI. A series of tertiary and secondary benzylic C(sp3)-H, aliphatic C(sp3)-H, and drug-molecule-based C(sp3)-H bonds in substrates are well tolerated under our protocol. The simultaneous gram-scale synthesis and the ease of transformation of azide to amine collectively advocate for the potential application in the preparative synthesis. Good reactivity of the tertiary benzylic C(sp3)-H bond and selectivity of the tertiary aliphatic C(sp3)-H bond in substrates to incorporate nitrogen-based functionality at the tertiary alkyl group also provide opportunities to manipulate numerous potential medicinal candidates. We anticipate our synthetic protocol, consisting of metal catalysis, electrochemistry, and photochemistry, would provide a new sustainable option to execute challenging organic synthetic transformations.

Full text of DOI:10.1021/jacs.0c08437

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Article
Manganese-Catalyzed Oxidative Azidation of C(sp3)-
H Bonds under Electrophotocatalytic Conditions
Linbin Niu, Chongyu Jiang, Yuwei Liang, Dingdong Liu, Faxiang Bu,
Renyi Shi, Hong Chen, Abhishek Dutta Chowdhury, and Aiwen Lei
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c08437 • Publication Date (Web): 17 Sep 2020
Downloaded from pubs.acs.org on September 18, 2020
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Manganese-Catalyzed Oxidative Azidation of C(sp3)-H Bonds
under Electrophotocatalytic Conditions
Linbin Niu,a Chongyu Jiang,a Yuwei Liang,a Dingdong Liu,a Faxiang Bu,a Renyi Shi,a Hong Chen,a
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Abhishek Dutta Chowdhury,a and Aiwen Lei*a,b
a
College of Chemistry and Molecular Sciences, the Institute for Advanced Studies (IAS), Wuhan University, Wuhan
430072, P. R. China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China
Supporting Information Placeholder
electrochemical conditions usually follows the CDC (cross-
dehydrogenative coupling) reaction mode: the carbon cation is
attacked by a nucleophile,4 while the reported substrates for
electrochemical intermolecular C(sp3)-H amination are mainly
concentrated on the C(sp3)-H bonds adjacent to N and O atom or
special benzyl C(sp3)-H bonds, and thus, arguably limiting its
application in biomedicine.
ABSTRACT: The selective installation of azide groups into
C(sp3)-H bonds is a priority research topic in organic synthesis,
particularly in pharmaceutical discovery and late-stage
diversification. Herein, we demonstrate a generalized manganese-
catalyzed oxidative azidation methodology of C(sp3)-H bonds
using nucleophilic NaN3 as an azide source under
electrophotocatalytic conditions. This approach allows us to
perform the reaction without the necessity of adding an excess of
the substrate and successfully avoiding the use of stoichiometric
chemical oxidants such as iodine(III) reagent or NFSI. A series of
tertiary and secondary benzylic C(sp3)-H, aliphatic C(sp3)-H, and
drug-molecules-based C(sp3)-H bonds containing in substrates are
well tolerated under our protocol. The simultaneous gram-scale
synthesis and the ease of transformation of azide to amine
collectively advocate for the potential application in the
preparative synthesis. Good reactivity of tertiary benzylic C(sp3)-
H bond and selectivity of tertiary aliphatic C(sp3)-H bond
containing in substrates to incorporate nitrogen-based
functionality at tertiary alkyl group also provide opportunities to
manipulate numerous potential medicinal candidates. We
anticipate our synthetic protocol, consisting of metal catalysis,
electrochemistry and photochemistry, would provide a new
sustainable option to execute challenging organic synthetic
transformations.
A. Azides' diverse chemical-biology applications
R
R1
N
N
Cu(I)
R2
Reduction
NH2
N3
R
N
N
N
R1 R2
R1 R2
N
Click Chemistry
Biopolymer
R
Bioorthogonal Labeling
3-Pyridine
HO
O
N
OH Bn
H
H
OH
O
N
O
N
N
Ph
N
N
N
N
tBu
O
N
S
O
O
N
H
O
O
H
Mephenytoin
anti-epilepsy drug
Indinavir
inhibition against protease
(
Tazobactam
-lactum antibiotic
(
)
(
)
and Anti-HIV
)
B. Current strategies for C(sp3)-H bonds azidation
Strategies:BzOOBz, [Fe], [Cu], [hv]
With electrophilic azide reagent
N3
INTRODUCTION
O
I
The development of new and selective catalytic functionalization
of readily available and abundant hydrocarbons remains a crucial
goal in the organic synthesis due to their relatively lower intrinsic
reactivity. The functionalization of C(sp3)-H bonds, widespread in
the most abundant and inexpensive chemical feedstock, to
produce the value-added chemicals is not only significant in
organic chemistry but also yet to be fully explored. Among all, the
development of efficient strategies to install N-functional group
on C(sp3)-H bonds,1 is crucial in pharma-industry, whose late-
stage functionalization to gain rapid access to complex molecules
from the simplest feedstock highlights the significance. For
instance, typical C(sp3)-H amination reactions are vastly
dominated by ‘nitrene insertion’ strategy, which usually relies
upon the use of stoichiometric (thus, waste generating) iodine(III)
reagent.2 To overcome this limitation, electroorganic synthesis is
an ideal approach to deal with ‘intractable’ synthetic challenges
with lesser waste generation via the utilization of electron as an
oxidant or reductant.3 However, C(sp3)-H amination under
IN3
O
R
S
N3
O
H
N3
R
R
R1 R2
R1 R2
Strategies: [Mn]/Iodine(III), [Cu]/NFSI
With nucleophilic azide reagent
NaN3, TMSN3
C. Our designed strategy for C(sp3)-H bonds azidation
Mn hv
H
e-
e-
N3
+
NaN3
R1 R2
Constant current/Blue LEDs
R1 R2
Figure 1. Azidation of C(sp3)-H bonds for valuable N-
scaffolds: (a) representative applications; (b) reported strategies
and (c) our designed azidation of C(sp3)-H bonds without
involving chemical oxidants.
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Page 2 of 9
The photocatalytic strategy has also been recognized as a
that the coordination of bidentate nitrogen ligand L1 for
manganese catalyst indeed played crucial role for this
1
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5
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8
powerful tool for the functionalizing of C(sp3)-H bonds,5 due to
natural abundance, lower cost, and fascinating application
prospects. Recently, the electrophotocatalytic method is more
intriguing owing to the combining advantages of electrochemistry
and photochemistry, which further enriches catalytic strategies to
explore more challenging chemical transformations.6 In this work,
we intended to develop a manganese-catalyzed electrochemical
oxidative azidation of C(sp3)-H bonds protocol under
electrophotocatalytic conditions to deliver various alkyl azides.
Given the ubiquitous nature of the azide motifs, a well-known
and versatile reactive intermediate that can be readily transformed
to amines, imines, amides, aziridines, and triazoles,7 there is a
constant need for the development of sustainable and selective
methods to form C(sp3)–N3 bonds in synthetic organic chemistry,
chemical biology, and drug discovery (e.g., azide-alkyne Huisgen
cycloaddition and Staudinger ligation in the “click” chemistry, see
Figure 1A).8 Notably, their swift reduction to alkyl amine,
especially for generating tertiary amine, further highlights the
significance, as such nitrogen-containing molecules are often
crucial in pharma-industry.9 Azidation from the C(sp3)-H bonds
via radical C-H activation is an economical way to avoid the pre-
functionalization steps. However, the real fact is that current
catalytic methods for the azidation of C(sp3)-H bonds via radical
C-H activation, usually require electrophilic azidation reagents
(IN3, Zhdankin's aziodoiodinanes, TsN3, etc.)9,10 to capture the
nucleophilic C(sp3) radical.11 For the current catalytic strategies
that utilize nucleophilic azide reagents (TMSN3, NaN3, etc.), the
utilization of (undesired) stoichiometric chemical oxidants such as
iodine(III) and NFSI reagent is unavoidable (Figure 1B).12
Therefore, under the external chemical oxidants-free conditions
and to achieve oxidative azidation of C(sp3)-H bonds, using NaN3
as an azide source is the most atom-economical strategy.
a
electrophotocatalytic azidation protocol. In contrast, electron-rich
L4 (triphenylphosphine) could not be utilized as an effective
ligand for the C(sp3)-H azidation (entry 9).
Table 1. Optimization of the reaction conditionsα
C cloth (+) Pt (-) 4.5 mA, 15 h
5.5 mol% 9-fluorenone
10 mol% MnF2
H
N3
20 mol% 1,10-phen
NaN3
+
40 mol% KBr, 4 eq. TFA, 2 eq. LiClO4
CH3CN/HOAc, Blue LEDs
9
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12
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17
, 61%
Entry
1
Variation from the standard conditions
None
Yield (%)b
61
2
3
6.5 mA instead of 4.5 mA, 10.4 h
8.5 mA instead of 4.5 mA, 10.4 h
MnBr2·4H2O instead of MnF2
MnCl2 instead of MnF2
MnSO4 instead of MnF2
L2 instead of L1
44
40
4
54
5
60
6
55
7
9
8
L3 instead of L1
3
9
L4 instead of L1
n.d.
27
10
11
12
13
14
15
16
17
18
19
20
1.5 mmol NaN3 were used
TMSN3 instead of NaN3
In order to achieve a universal and sustainable C(sp3)-H
azidation protocol and, to avoid the utilization of stoichiometric
chemical oxidants, we designed to merge the sustainability of
electrochemical synthetic method, the assisting effect of
manganese catalyst towards azide radical,13 and the ability of
visible-light catalysts to abstract H atom of C(sp3)-H bond
altogether to generate C(sp3) radical14 under electrophotocatalytic
conditions (Figure 1C). Herein, we demonstrated that the
combination of the metal catalyst, visible-light and
electrosynthesis, has successfully accomplished azidation of C(sp3)-
H bonds, which would have immense implications for a diverse
array of C(sp3)-H bonds functionalization.
33
Bis(4-methoxyphenyl)methanone
instead of 9-fluorenone
Xanthone instead of 9-fluorenone
61
61 (27)c
55 (24)c
28
DDQ instead of 9-fluorenone
No blue LEDs
No Mn catalyst
12
No 1,10-phen
25
RESULTS AND DISCUSSION
No 9-fluorenone
43
With all these research developments in mind, we first decided
to investigate the azidation of benzyl C(sp3)-H bond under our
manganese-based electro-catalytic conditions in combination with
the visible-light-catalysis. The model reaction between 1-
ethylnaphthalene and NaN3 has been performed in the presence of
manganese catalyst, ligand, photocatalyst, additive, acids and
electrolyte under blue LEDs irradiation and constant current
electrolysis (Table 1, entry 1). For the electric current, we
observed that the higher value of constant current (>4.5 mA)
could result in the decline of yields (entries 2 and 3). All other
manganese (II) salts all displayed satisfying azidation reactivity
(entries 4- 6). Ligands could significantly affect the efficiency of
azidation. Notably, when L2 (1,10-phenanthroline-5,6-dione) that
equipped with electron-withdrawing group (carbonyl) and L3
(bathocuproine) with steric hindrance effect was employed to
replace L1 (1,10-phenanthroline), only 9 % and 3 % yield of
desired benzyl azides were isolated (entries 7 and 8), indicating
No 9-fluorenone, and 50 oC heating
instead of blue LEDs
No 9-fluorenone and blue LEDs
44
45
O
O
Ph
Ph
Ph
Ph
P
Ph
N
N
N
N
N
N
L1
L2
L3
L4
αReaction conditions: 1-ethylnaphthalene (0.5 mmol), NaN3 (2.5
mmol), 9-fluorenone (5.5 mol%), MnF2 (10 mol%), 1,10-Phen (20
mol%), KBr (40 mol%),TFA (2.0 mmol) and LiClO4 (1.0 mmol)
in CH3CN (9.5 mL)/HOAc (0.5 mL) stirring under nitrogen
atmosphere was electrolyzed at a constant current of 4.5 mA and
irradiated by blue LEDs at 35 ˚C for 15 h. bIsolated yields. cYields
under darkness in parenthesis.
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Then, we found that reducing the amount of sodium azide could
azidation product in a moderate yield (13). Next, we turned our
attention to the azidation of secondary benzyl C(sp3)-H bonds.
Ethylbenzene derivatives in this synthetic protocol proved to be
competent substrates (14-19), while the primary benzyl C(sp3)-H
bond is unaffected (15). For heteroaromatic-based secondary
benzyl C(sp3)-H bond, like alkyl-substituted thiophenes, were
compatible substrate, but with the lower yield (20). A valuable
medical intermediate,16 2,3- dihydrobenzofuran, selectively
provided the expected benzylic azidation product (21). The decent
reactivity was observed from indan as well (22). Long-chain
alkyl-substituted benzenes were also well-treated in our protocol,
yielding the azidation products of benzyl C(sp3)-H bond with
moderated yields (23-25). We could summarize that the azidation
reactivities of tertiary benzyl C(sp3) -H bonds are generally better
than secondary benzyl C(sp3)-H bonds, which could be explained
by the fact that the tertiary benzyl radical is more stable than the
secondary benzyl radical.
1
2
3
4
5
6
7
8
lead to decrease of yield (entry 10), and a similar result was
observed while TMSN3 was utilized as azide source (entry 11).
For the investigation of HAT photocatalyst, we mainly focus on
the cheap and readily available aryl ketones and DDQ to improve
the practicability of our method, while almost the same results
were detected (entries 12- 14). Finally, several important control
experiments were conducted to demonstrate the necessity of blue
LEDs irradiation (entries 13-15), manganese catalyst, l,10-Phen,
and HAT photocatalyst for this external chemical oxidant-free
azidation protocol (entries 16- 20), which was consistent with our
hypothesis that constructively merging the manganese-catalysis,
electrosynthesis and visible light catalysis could achieve the
azidation of C(sp3)-H bonds under the metal-catalyzed
electrophotocatalytic conditions.
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Next, we examined the scope of benzyl C(sp3)-H bonds under
our optimized reaction condition (Figure 2). It is noteworthy that
an excellent yield of 99% (4) was isolated when the
triphenylmethane was examined, probably owning to the
stabilization of phenyl groups for the benzyl radical. Then, a
range of tertiary benzyl C(sp3)-H bonds were further investigated
and delivered the desired azidation products (5-8) in good yields.
Interestingly, in the presence of multiple tertiary benzyl C(sp3)-H
groups, the usual mono-azidation products have been isolated in
moderated yields, accompanying with the formation of minor
diazidation products (9 and 10). Another tertiary benzyl C(sp3)-H
bond containing in an important framework, oxothioxanthene, that
has broad application in pharmaceuticals15 and photochemistry,14d
also successfully provided the organic azide (11). Halogen atom
(e.g. Br) was tolerated as well, allowing an additional opportunity
for further synthetic manipulations/transformations (12). For the
azidation of sec-butylbenzene, we could isolate the desired
Compared to the benzyl C(sp3)-H bonds, the selective azidation
of conventional alkyl and remote C(sp3)-H bonds are indeed more
challenging (Figure 3). Under the oxidant-free azidation strategy,
both cyclooctane and cyclododecane provided the corresponding
cycloalkyl azides in moderate yields (26 and 27). Considering the
weaker bond dissociation energy (BDE) of the tertiary aliphatic
C(sp3)-H bond,10h selective azidation of tertiary C(sp3)-H bonds
could be achieved in the presence of multiple C(sp3)-H bonds.
Isopropylcyclohexane, decahydronaphthalene, and bicyclohexyl
were also competent substrates (28-30), delivering the tertiary
C(sp3)-H azidation products. Similarly, the mono-selectivity and
satisfactory yields were obtained too from adamantanes (31 and
32). Notably, benzoate esters and analogous protected primary
amine could also selectively produce remote tertiary C(sp3)-H
bonds azidation products under this protocol (33-35).
(+)C | Pt(-), constant current
R2
R2
1
O
N3
R3
Mn/1.10-Phen
:
,
9-Fluorenone DQQ or
+
NaN3
R3
bis(4-methoxyphenyl)methanone
R1
R1
KBr, LiClO4, TFA
CH3CN/HOAc
Blue LEDs
1
Azidation of tertiary benzyl C(sp3)-H
N3 N3
Ph
N3
N3
N3
MeO
TBSO
4
5
6
7
8
, 69%
, 99%
, 96%
N3
, 80%
, 65%
N3
O
N3
N3
N3
Br
H
S
H
b
9
10
11
, 50%
, 57% (+35% diazidation)
, 63% (+22% diazidation)
12
, 63%
13
, 46%
Azidation of secondary benzyl C(sp3)-H
N3
N3
N3
N3
N3
N3
Ph
Ph
O
c
14
15
16
17
19
, 41%
, 43%
S
, 51%
, 45%
, 61%
18
, 55%
N3
N3
N3
N3
N3
OMe
N3
3
3
O
c
20
, 32%
21
25
, 39%
, 55%
22
23
24
, 52%
, 50%
, 51%
Figure 2. Substrate scope for benzyl C(sp3)-H bonds. αReaction conditions: carbon cloth as anode, platinum as cathode, substrate (0.5
mmol), NaN3 (2.5 mmol), HAT photocatalyst 1 (5.5 mol% or 11 mol%), MnF2 or MnBr2·4H2O (10 mol%), 1,10-Phen (20 mol%), KBr (40
mol%), TFA (2.0 mmol) and LiClO4 (1.0 mmol) in CH3CN (9.5 mL)/HOAc (0.5 mL) stirring under nitrogen atmosphere was electrolyzed
at a constant current of 4.5 mA and irradiated by blue LEDs at 35 ˚C for 15 h, isolated yields. bCarbon felt as anode, substrate (1.0 mmol),
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NaN3 (4.0 mmol), DDQ (5.5 mol%), MnF2 (5 mol%), 1,10-Phen (10 mol%), without KBr, CH3CN (3.0 mL), DCE (2.5 mL), i= 8.0 mA, 21
1
2
h. cCarbon felt as anode, substrate (1.0 mmol), NaN3 (4.0 mmol), DDQ (5.5 mol%), MnF2 (2.5 mol%), 1,10-Phen (10 mol%), without KBr,
CH3CN (3.0 mL), DCE (2.5 mL), i= 4.5 mA, 24 h. See Supporting Information for further details.
(+)C | Pt(-), constant current
3
4
5
1
O
MnF2/1.10-Phen
R-H
+
NaN3
R-N3
:
DQQ
LiClO4,TFA
CH3CN/DCE/HOAc
Blue LEDs
1
C(sp3)-H
6
7
8
Azidation of simple C(sp3)-H
H
N3
N3
N3
N3
9
N3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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60
b
b
27
29
30
, 50%
, 31%
, 38%
26
28
, 51%
, 41%
2.4:1 site selectivity
Cl
O
N3
N3
N
O
(p-Me)BzO
N3
(p-Me)BzO
N3
N3
, 54%
c
31
32
33
34
35
, 35%
, 46%
, 35%
, 38%
Late-stage azidation of bioactive molecules
NPhth
O
MeO
N3
OMe
CO2Me
O
N3
N3
N3
N3
O
Br
e
d
d
37
, 43%
36
38
39
40
, 35%
, 51%
, 40%
N3-ibuprofen methyl ester
, 33%
N3-ioxoprofen methyl ester
N3-differin precursor
N3-N-Phth-memantine
N3-celestolide
Figure 3. Substrate scope for simple C(sp3)-H bonds and late-stage functionalization. Reaction conditions: carbon felt as anode,
platinum as cathode, substrate (1.0 mmol), NaN3 (4.0 equiv.), DDQ (5.5 mol%), MnF2 (5 mol%), 1,10-Phen (10 mol%), TFA (2.0 equiv.)
and LiClO4 (1.0 equiv.) in CH3CN (3.0 mL), DCE (2.5 mL)/HOAc (0.5 mL) stirring under nitrogen atmosphere was electrolyzed at a
α
b
constant current of 8.0 mA and irradiated by blue LEDs at 35 ˚C for 21 h, isolated yields. 0.5 mmol scale, NaN3 (5.0 equiv.), MnF2 (10
mol%), 1,10-Phen (20 mol%), TFA (4.0 equiv.) and LiClO4 (2.0 equiv.), 6.0 mA, 15 h. c0.5 mmol substrate, NaN3 (8.0 equiv.), DDQ (11.0
mol%), MnF2 (7.5 mol%), 1,10-Phen (20 mol%), TFA (4.0 equiv.) and LiClO4 (2.0 equiv.). dMnF2 (2.5 mol%). e0.5 mmol scale, NaN3 (5.0
equiv.), MnF2 (10 mol%), 1,10-Phen (20 mol%), TFA (4.0 equiv.) and LiClO4 (2.0 equiv.), 4.5 mA, 15 h. See Supporting Information for
further details.
In short, the selectivity of tertiary aliphatic C(sp3)-H bond
containing in substrates to incorporate nitrogen-based
functionality at the tertiary alkyl group provides opportunities to
manipulate numerous potential medicinal candidates.
Figure 4. Gram-scale experiment. PC: bis(4-
methoxyphenyl)methanone.
To demonstrate the feasibility of our protocol towards the
preparative synthesis, the upscaling of our methodology has also
been conducted in a 10 mmol scale (Figure 4). In this case, a good
isolated yield of 71% (5) was isolated. It provided the opportunity
for further synthetic manipulations and redeemed the few gram-
scale demonstrations of previous methods on the azidation of
benzylic and simple alkyl C(sp3)-H bonds.10e Considering alkyl
azides as versatile synthetic intermediates, and the significance of
alkyl amines, especially tertiary amines in organic chemistry,9 we
further reduced the azide 5, successfully to produce the
corresponding tertiary amine (41) with an excellent 93% yield
(Figure S1).
After completing the investigation of substrates scopes and
synthetic applications, a series of designed experiments were
conducted to validate the mechanistic hypothesis. The radical
inhibition experiment was firstly carried out by adding
stoichiometric TEMPO (2,2,6,6-tetramethylpiperidinyloxy) into
our electrophotocatalytic condition. We observed that neither
desired benzyl azide nor the adduct of TEMPO and benzyl radical
was generated (Figure 5A). According to Lin et al.’s study on
electrochemical azidooxygenation of alkenes mediated by a
TEMPO−N3 charge-transfer complex,17 the electrochemically
generated oxoammonium ion (TEMPO+) can facilitate the
Based on these obtained results, the application to several
bioactive molecules with multiple C(sp3)−H bonds sites were
demonstrated (Figure 3). N-phthalimide-protected memantine, a
N-Methyl-D-aspartate (NMDA) receptor antagonist, utilized to
treat Alzheimer’s disease,10h afforded the tertiary C(sp3)-H bond
azidation product (36). In spite of the electron-rich arene on an
adapalene precursor, the azidation of the tertiary C(sp3)-H bond
could still be achieved in a reasonable yield (37). Subjecting the
celestolide spice under our methodology provided the benzylic
azidation product in a satisfying yield (38). For the complex
pharmaceutical molecule derivatives, which contain the multiple
tertiary C(sp3)-H bonds, like ibuprofen methyl ester (39) and
ioxoprofen methyl ester (40), selectively favored the formation of
secondary benzyl C(sp3)-H bond azidation products with modest
yields.
C cloth (+) | Pt(-) 8.0 mA
H
N3
5.5 mol% PC
10 mol% MnF2
20 mol% 1,10-Phen
+
NaN3
40 mol% KBr, 4 eq. TFA
2 eq. LiClO4
O
O
CH3CN/HOAc
Blue LEDs, 72 h
5
, 71%, 1.36 g
10 mmol
-
formation of azide radical from N3 , and TEMPO that has the
ability to capture the C(sp3) radical to deliver corresponding
radical adduct, was evidenced as well. Therefore, we propose that
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azide radicals were smoothly produced but the generation of
trapping reagent (Figure 5B-a), which indicated that the azide
radicals are indeed existing during this manganese catalyzed
electrophotocatalytic system. Notably, we also observed the
existence of carbon radical, while treating the 1-ethylnaphthalene
1
2
3
4
C(sp3) radical was restrained in the presence of TEMPO in our
system. Then, the EPR experiments were designed to detect
radical intermediates. Under the standard electrophotocatalytic
conditions, we successfully captured the azide radical by
employing DMPO (5,5-Dimethyl-1-pyrroline N-oxide) as radical
and
HAT
photocatalyst
under
the
blue
5
A. The radical inhibition experiment
B. The EPR experiments
6
N3
7
8
9
a
b
)
(
)
(
C cloth (+) I Pt(-) 4.5 mA, 15 h
5.5 mol% PC
10 mol% MnBr2 4H2O
20 mol% 1,10-Phen
17
, n.d.
+
NaN3
10
11
12
13
14
15
16
17
18
19
20
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22
23
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25
26
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40
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52
53
54
55
56
57
58
59
60
40 mol% KBr, 4 eq. TFA, 2 eq. LiClO4
CH3CN/HOAc
Blue LEDs
N
O
2 eq. TEMPO
n.d.
C. Accelerating effect of visible light irradiation
D. CV and UV-vis experiments
a
b
( )
(
)
C cloth (+) Pt (-) 4.5 mA, 15 h
N3
5.5 mol% PC
10 mol% MnF2
20 mol% 1,10-phen
H
O
NaN3
+
40 mol% KBr, 4 eq. TFA
2 eq. LiClO4
CH3CN/HOAc
Blue LEDs or Darkness
T h
O
c
(
)
d
(
)
Figure 5. Gram-scale experiment and mechanistic studies. PC: 9-fluorenone (Figure 5A) or bis(4-methoxyphenyl)methanone (Figure
5B and 5C). See Supporting Information for further details.
LEDs irradiation (Figure 5B-b), probably providing the direct
mechanistic evidence that the excited HAT photocatalyst can
abstract the C(sp3)-H to benzyl C(sp3) radical. To get a deeper
understanding of the role of visible light irradiation, we have
demonstrated the accelerating effect of blue LEDs irradiation for
the azidation of 4-isopropylanisole during the initial stage of the
reaction (Figure 5C). Without the blue LEDs irradiation, the
azidation of C(sp3)-H could still proceed, but the reaction rate was
slower than in the presence of blue LEDs irradiation. Combining
the results of EPR studies, we concluded that the azide radical is
also capable of abstracting the H atom of C(sp3)-H bond.18 Thus,
we considered that the generation of C(sp3) radical under the
electrophotocatalytic condition might derive from the
photocatalytic HAT process and the abstraction of N3 radical for
C(sp3)-H bonds.
What’s more, the CV (cyclic voltammetry) experiments were
designed to obtain details concerning the role of the manganese
catalyst under the electrophotocatalytic conditions. As shown in
Figure 5D-a and 5D-b, the oxidative potential of NaN3 was lower
than substrates and photocatalysts, even in the acidic solution
system existing the protonation of NaN3, suggesting that the
oxidation of NaN3 to azide radical on the anodic surface was
fairly easy. Moreover, we also measured the anodic oxidative
potential (constant current: 4.5 mA) ranges from 1.2~1.5 V (vs
Ag/AgCl) in the whole azidation process, evidencing that the
direct oxidation of substrates and photocatalysts was indeed
difficult. For the azidation of simple alkyl C(sp3)-H, the inert
alkyl C(sp3)-H bonds and DDQ were also not likely oxidized by
anodic oxidation (8.0 mA electric current) that the oxidative
potential is about 1.9~2.2 V (vs Ag/AgCl). Further, we found that
the oxidation peak of Mn(II)/1,10-Phen was at ~1.75 V (Figure
5D-c). By contrast, we observed a new oxidation peak at ~0.55 V
when Mn(II), 1,10-Phen and NaN3 were mixed under
electrochemical CV conditions, which was assigned as the
oxidation of Mn(II)/L-N3 to Mn(III)/L-N3. The similar result was
also noted after removing 1,10-Phen.13b Besides, the coordination
-
of N3 and 1,10-Phen to Mn(II) was evidenced by UV-vis
experiments (Figure 5D-d). Given that the excess amount of
sodium azide and the lower oxidative potential of Mn(II)/L-N3,
we proposed the direct oxidation of Mn(II)/L to Mn(III)/L is not
realistic even under the 8.0 mA electric current condition.
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Page 6 of 9
C cloth (+) | Pt(-) 4.5 mA, 2 h
5.5 mol% PC
10 mol% MnF2
20 mol% 1,10-Phen
1
2
3
4
X-
H+
2H+
H2
HX
N3
+
NaN3
40 mol% KBr, 4 eq. TFA
2 eq. LiClO4
N3
H
CH3CN/HOAc
Blue LEDs
R1 R2
8
R1 R2
HN3
, 10%
O*
5
6
7
8
KH : KD= 5.0
HAT
Mn(II)/L
C cloth (+) | Pt(-) 4.5 mA, 2 h
5.5 mol% PC
N3
2
-
N3
HAT
10 mol% MnF2
20 mol% 1,10-Phen
D
N3
R1 R2
+
NaN3
Mn catalysis
Visible light catalysis
40 mol% KBr, 4 eq. TFA
2 eq. LiClO4
9
Mn(II)/L
N3
Mn(III)/L
N3
OH
O
N3
CH3CN/HOAc
Blue LEDs
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
, 2%
NaN3
SET
-H+
1
3
Figure 6. Kinetic of isotopic effect experiments. PC: bis(4-
SET
SET
methoxyphenyl)methanone.
The cleavage of C(sp3)-H bonds, possibly involving the rate-
determining step was evidenced by the parallel KIE (kinetic
isotope effect) experiments (Figure 6). Next, the kinetic studies of
manganese catalyst, 1,10-phenanthroline, sodium azide, and 4-
isopropylanisole were also conducted for further understanding of
the reaction mechanism. According to the kinetic curves of the
manganese catalyst, 1,10-Phen and NaN3 (Figure S2, S3 and S4),
increasing the loading of Mn(II) catalyst could lead to the
decrease of the azidation rate, while the 1,10-Phen and NaN3
appeared to have the facilitating effects for azidation in the
reasonable concentration ranges. Considering the concentration of
1-isopropyl-4-methoxybenzene has little effect on the initial
reaction rate (Figure S5) and the cleavage of C(sp3)-H bonds
involving the rate-determining step, we proposed that the
concentrations of azide radical and Mn(III)/L-N3 have important
effects for our azidation reaction. It is due to the fact that azide
radicals were involved in the abstraction of C(sp3)-H step, which
also possibly react with Mn(II)/L-N3 to Mn(III)/L-N3, and
Mn(III)/L-N3 determines the capture of C(sp3) radical to deliver
the final product. Since the oxidative potential of Mn(II)/L-N3 is
Figure 7. Proposed mechanism for electrophotocatalytic
-
azidation of C(sp3)-H bonds. (X-: OAc-, CF3COO- or N3 ).
With all these mechanistic studies taken together, the proposed
mechanism has been illustrated in Figure 7. On the anodic surface,
NaN3 could directly be oxidized to azide radical, while the Mn(II)
coordinated by N3 and ligand (1,10-Phen or OAc-, etc.) have
-
undergone the anodic oxidation to deliver Mn(III)/L-N3
intermediate.13b We considered that the addition of azide radical
to Mn(II)/L to Mn(III)/L-N3 was also possible. In the
photocatalytic cycle, the excitation of HAT photocatalyst by blue
LEDs irradiation14 induced the hydrogen atom transfer (HAT)
event on C(sp3)-H bond to generate the C(sp3) radical. The
regeneration of this visible-light catalyst could be accomplished
by anodic oxidations. At the same time, we could not exclude the
possibility that Mn(III)/L-N3 involving the turnover of the HAT
photocatalyst: oxidation of 3 back to 1. Notably, the azide radical
could also abstract H atom of C(sp3)-H bonds to offer alkyl
radical.18 The final formation of alkyl azide was accomplished by
the azide-transfer of Mn(III)/L-N3 to an alkyl radical,
simultaneously completing the turnover of the Mn(II) catalyst. On
the other hand, the acidic reaction system provided enough
protons for hydrogen evolution on the cathode, avoiding the
reduction of manganese catalyst.
In conclusion, we have successfully achieved manganese-
catalyzed electrochemical oxidative azidation of benzylic C(sp3)-
H, alkyl C(sp3)-H, and selective remote C(sp3)-H bonds
accelerated by visible light catalysis with nucleophilic sodium
azide as an azidation reagent (i.e., successfully avoiding the use of
stoichiometric chemical oxidants). The ability to install N3 group
successfully at the tertiary alkyl group indeed highlights the
significance of our protocol. The late-stage azidation of valuable
drug-like molecules and gram-scale synthesis demonstrate the
potential application in the preparative pharmaceutical synthesis.
The detailed mechanistic studies were also conducted for an in-
depth understanding of the reaction mechanism. The development
of more challenging N-scaffolds construction from C(sp3)-bonds
is underway in our laboratory. Inspiring from our work, we
anticipate that the scientific community will develop more
emerging technologies in organic synthesis in the near future.
-
lower than N3 , and in the presence of excess sodium azide, both
the oxidation of NaN3 to azide radical and Mn(II)/L-N3 to
Mn(III)/L-N3 might proceed at the same time and have a
competitive relationship. We have observed that the rate-
determining abstraction of C(sp3)-H step is probably driven by the
azide radical and the excited HAT photocatalyst. If the
concentration of Mn(II)/L-N3 was too high, then the concentration
of Mn(III)/L-N3 by the anodic oxidation of Mn(II)/L-N3 would
also increase, while the excited HAT photocatalyst might also
participate in the oxidation of Mn(II)/L-N3, and simultaneously,
the concentration of azide radical generated by the direct anodic
oxidation would decrease. These two possible facts might induce
the rate of abstraction of C(sp3)-H slowing down, causing a
decrease of azidation rate. On the other hand, if the concentration
of Mn(II)/L-N3 was too low, the generation of C(sp3) radical
would not be affected. However, a very small amount of
Mn(III)/L-N3 would influence the azide transfer to C(sp3) radical,
which could still decrease the efficiency of azidation. Therefore,
we proposed that the constructive combination of manganese
catalysis, electrosynthesis and visible light catalysis would
successfully achieve the transformation of C(sp3)-H bonds.
ASSOCIATED CONTENT
Supporting Information
The experimental procedure, characterization data, and copies of
1H and 13C spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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oxidation of organic molecules at lower overpotential: accessing broader
Corresponding Author
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*aiwenlei@whu.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21520102003, 21702152) and the Hubei
Province Natural Science Foundation of China (2017CFA010).
The Program of Introducing Talents of Discipline to Universities
of China (111 Program) is also appreciated.
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DEDICATION
This paper is dedicated to P.H. Dixneuf for his meaningful
contribution to organometallic chemistry and catalysis.
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