Electrochemical oxidative C(sp3)-H azolation of lactams under mild conditions

Article abstract of DOI:10.1039/d0gc00687d

Lactam-containing structural compounds are ubiquitous in drugs and biomolecules. An electrochemical oxidative direct C(sp3)-H azolation of lactams has been reported under metal catalyst-free and external chemical oxidant-free conditions. This electrochemical C(sp3)-H/N-H coupling is characterized by its broad substrate scope of azoles and lactams under mild conditions at room temperature. Mechanistic studies suggested that the reaction possibly involves a radical process. Moreover, the site selectivity can be explained by DFT calculations. More meaningfully, a gram-scale synthesis method of flow electrochemistry was employed to show the scaled-up applicability of this transformation.

Full text of DOI:10.1039/d0gc00687d

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DOI: 10.1039/D0GC00687D
COMMUNICATION
Electrochemical Oxidative C(sp3)-H Azolation of Lactams Under
Mild Conditions
Zhaohua Wan, Dan Wang, Zixuan Yang, Heng Zhang, Shengchun Wang and Aiwen Lei*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Lactam-containing structural compounds are ubiquitous in drugs
and biomolecules. An electrochemical oxidative direct C(sp3)-H
azolation of lactams has been reported under metal catalyst free
and external oxidant free conditions. This electrochemical C(sp3)-
H/N-H coupling is characterized by its broad substrate scope of
azoles and lactams, mild conditions at room temperature.
Mechanistic studies suggested that the reaction possibly involves a
radical process. Moreover, the site selectivity can be explained by
DFT calculations. More meaningfully, a gram-scale synthesis
method of flow electrochemistry was performed to demonstrate
the scaled-up applicability of this transformation.
a) Oxidative-induced cross-dehydrogenation coupling
R
X
[O]
[OH]
X
X
R
NH
H
X
X
SET
X
N
R2
R2
R1
X
R1
X
R2
R1
X
H+
X=O, N, S
b) Our design: Electrochemical oxidative C(sp3)-H azolation
H
R1
X
N
R1
X
O
R1
X
electricity
R2
N
N
N
H
X
oxidant-free
catalyst-free
X
X
N
N
H+
N
N
O
e-
R2
X=C, N
Scheme 1. Methods for C(sp3)-H azolation with azoles.
Lactam compounds have proven to be used in medical and
biological science,1 being used antibiotic and drug. Among
them, γ-lactam with a variety of biological activities have
been utilized in a large number of drugs.2 Not surprisingly,
the C–H functionalization of lactam is of great significance to
bio-pharmaceuticals. Azoles are an important class of
heterocyclic structures, which are rich in electrons with
strong, π-π stacking interaction, easy to form hydrogen
bonds.3 The presence of azole group provides a number of
bio-chemicals that function effectively, such as ligands, ionic
liquids, and azole affinity drugs4. Based on these, direct C-H
azolation of lactams with azoles shows potential
applications for seeking novel drugs. In recent years, the
C(sp3)-H azolation method has been reported using
transition metal catalysis,5 photochemistry6 and other
methods. Particularly under metal-free reaction, these
research advances have greatly promoted the development
of C(sp3)-N bond formation and many chemicals have been
created. However, stoichiometric oxidants need be used to
achieve this transform, including tert-butyl hydroperoxide
(TBHP),7 PhI(OAc)2,8 K2S2O8,9 etc.10 Therefore, developing an
electrolysis
DMPO
N
NH
N
N
N
Ph
Ph
O
result
fitting
3450 3460 3470 3480 3490 3500 3510 3520 3530 3540
H/G
Scheme 2. The electron paramagnetic resonance
experiment of 3-phenyl-1H-pyrazole.
efficient and environmentally friendly C(sp3)-H azolation
might be highly desirable.
Oxidative-induced cross-dehydrogenation coupling is
undoubtedly a powerful strategy for C(sp3)-H azolation
(Scheme 1, a). During the course of the reaction, the C(sp3)-
H bond adjacent to the heteroatom gives a carbenium ion by
single-electron transfer (SET) and deprotonation, which is
trapped by azole to give the azolated product. It is worth
noting that the method of oxidative induction is azolation by
College of Chemistry and Molecular Sciences, The Institute for Advanced Studies
(IAS), Wuhan University, Wuhan 430072, China.
E-mail: aiwenlei@whu.edu.cn
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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direct oxidation of the sp3 C-H bond. We envisage whether mA for 4 h at room temperature, the product 1 was obtained
View Article Online
DOI: 10.1039/D0GC00687D
the azole can be anodized in the electrolytic cell to obtain a in 88% yield (SI, Entry 1). While keeping the electric quantity
nitrogen radical, which is then used directly to formation of constant (4.97 F), properly increasing or decreasing the
C-N bond with lactam (Scheme 1, b). Actually, the method constant current, lower reaction yields were obtained (SI,
for achieving C-H/N-H cross coupling by anodizing strategies Entries 2 and 3). The electrosynthesis of 1 could also
has been reported, and C(sp2)-N bond formation is becoming beconducted with cheaper nickel plate as cathode, the
more and more mature.11 However, the activation of C(sp3)- nickel plate was slightly less effective than the platinum
H is still challenging with only a few reported cases,12 which plate (SI, Entry 4). Further screening of the electrolyte
may be due to the poor chemical activation energy of the sp3 showed that nBu4NBF4 was the best one (SI, Entries 6-8). To
C-H bond.
understand effect of solvent on the reaction, several
solvents were examined (SI, Entry 9-11), attempts using
MeOH or N,N-dimethylformamide (DMF) was not
successful, and when dichloroethane (DCE) was used instead
of MeCN, just 29% of yield was obtained. In addition, 52%
yield was obtained when conducted under air, and some N-
methylsuccinimide are detected by GC-MS (SI, Entry 12).
Finally, this conversion cannot occur without current (SI,
Entry 13).
Electrochemical oxidation has emerged one of the most
promising organic synthesis.13 Our group has long been to
the development of green organic synthesis methods while
interest in mechanism studies. We have demonstrated
through experiment of electron paramagnetic resonance
(EPR) that azole can be oxidized to give a nitrogen radical
during electrolysis (Scheme 2). Encouraged by this result, we
sought to develop an azolation reaction of organic
compounds. Herein, we report a direct electrochemical
With the optimal reaction conditions in hand, to verify the
oxidation reaction to achieve C(sp3)-H azolation, using a universality of lactam azolation, pyrrolidin-2-one was first
broad range of azole and lactams substrates under mild used for investigation (Scheme 3), gave corresponding the
reaction conditions.
product in 84% yield (2). The six- and seven-membered
lactams provide the products in moderate to good yields (3,
4). The reaction can also tolerate lactams with oxygen atom,
gave corresponding products in 65% and 85% yields (5, 6).
The substrate with a large steric effect, gabapentin-lactam
provided the product in 44% yield (7). Next, we started using
amides as a coupling partner with azole, N-acetylpiperazine
gave the corresponding azolation product 8. We also
investigated the chain amides, N-methylacetamide, DMF,
Initially, 3-phenyl-1H-pyrazole
and
1-methyl-2-
pyrrolidinone were used to identify the optimal condition
for the C-N coupling product. After painstaking efforts, we
discovered that using a carbon cloth anode and a platinum
plate cathode, under the constant-current electrolysis at 10
Scheme 3. Electrochemical oxidative C(sp3)-H azolation with
different amides.
N,N-dimethylacetamide,
N,N-diethylpropionamide
to
provide the products in yields of 41%-91% (9-12). A variety
of ureas, including 1,1,3,3-tetramethylurea, 1,1-
dimethylurea, N,N'-dimethylurea were also compatible with
the reaction (13-15).
NH
N
+
N
N
N
N
undivided cell
O
O
Ph
Ph
R
R
Lactam/Amide
We next explored the regioselectivity by using 1-ethyl-2-
pyrrolidone (NEP) (Scheme 4). 3-Phenyl-1H-pyrazole
coupling with NEP regio-isomers 16 and 16’ in a ratio of 5:1
with an overall overall yield of 78%. The nitrogen atom of
pyrrolidone could be substituted with cyclohexyl (17) and
octyl (18), in which case delivering predominantly the
specific selection products, and the steric hindrance reduced
N
N
N
N
N
N
HN
HN
N
N
N
N
Ph
Ph
Ph
O
Ph
Ph
O
O
Ph
H
O
O
1
2
3
4
, 88%
, 84%
, 65%
, 39%
O
O
N
N
N
N
N
N
HN
N
N
H
N
Ph
O
O
N
N
O
Ph
Ph
H
the
overall
yield.
When
N,N'-dimethyl-
N,N'-
5
6,
7
8
, 65%
85%
, 44%
, 65%
trimethyleneurea was used in the reaction as cyclic amide
substrate, the ratio of the N-methyl regioselective is close to
half of the total yield. Interestingly, the reaction of N-
methylcaprolactam was the N-methyl regioselective,
provide product in 41% yield. The regioselectivity seem to be
affected by the number of ring atoms. The C-H azolation of
1-methyl-2-pyrrolidinone with various types of azoles shown
that more N-CH2 explored the regioselectivity by changing
the substituents of azoles. As summarized in Scheme 4, the
pyrazole ring could be substituted with phenyl (1), methyl
(22), Trifluoromethyl (24), and Nitro (25) at position 3, and
N-CH2 regioselective coupling is the main product
(ratio>20:1). Importantly, we have found that when pyrazole
ring at position 4 with a high electron withdrawing group,
the proportion of N-methyl regioselective coupling products
O
O
N
N
O
N
O
N
N
N
N
N
Ph
N
N
HN
N
Ph
Ph
9
10
11
12
, 41%
, 62%
, 78%
, 91%
O
N
O
N
O
N
N
N
N
Ph
N
N
HN
Ph
Ph
N
NH2
HN
13
14
15
, 70%
, 81%
, 80%
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), carbon
cloth anode (15 mm*15 mm*0.36 mm), Pt plate cathode (15
mm*15 mm*0.3 mm), constant current=10 mA, Bu4NBF4 (0.5
mmol), MeCN (10 mL), room temperature, 4 h, undivided cell
(4.97 F).
n
2 | J. Name., 2012, 00, 1-3
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increases (30-32). Further, the 3, 5 position of pyrazole was various azoles, such as indazole (40), 1H-benzotriazole (41),
View Article Online
DOI: 10.1039/D0GC00687D
substituted by an iodine atom, the proportion of the N- triazole (42-44, 46), and tetrazole (45) were also compatible
methyl coupling product was increased, 3-iodopyrazole, 5- with the process, producing the corresponding products in
iodopyrazole, afforded products consisting of regioisomers 39%-96% yields.
in the ratio of 2.7:1(23) and 4:1 (33). The azolation of lactams
To further demonstrate the applicability of this reaction
is also effectively using substrates with a multisubstituted
protocol, clinical drugs have been explored, like Piracetam
pyrazole ring, when the 3, 5 position of pyrazole was
and Levetiracetam, and the drug bearing electron-
substituted with the electron-rich Me group, the reaction
withdrawing amide group was compatible with
corresponding azolation products obtained in 75% and 55%
yields (Scheme 5).
proceeded with good to excellent regioselectivity (34, 37,
38). The directing effect of the N-methyl regioselective was
enhanced when the electron withdrawing CO2Et (35, 36),
Furthermore, we attempted N-vinyl amides (Scheme 6). It
NO2 (39) was introduced. Finally,
is worth noting that C(sp3) of N-vinyl-2-pyrrolidinone carbon
Scheme 4. The regioselectivity of electrochemical oxidative was unreactive in this transformation. Under our standard
C(sp3)-H azolation between lactams and azoles.
C(+)|Pt(-)
nBu4NBF4(0.05 M)
O
O
NH2
NH2
MeCN (10 mL)
NH
+
O
O
10 mA, 4 h
N2, r.t.
undivided cell
N
R1
N
N
R1
Ph
X
X
N
X
X
N
NH
+
N
N
Ph
undivided cell
N
N
O
N
O
Piracetam
0.6 mmol
R2
47
0.3 mmol
, 75%
R2
Azole
Lactam
R=Alkyl
C(+)|Pt(-)
O
N
O
N
nBu4NBF4(0.05 M)
N
N
N
N
O
NH2
O
N
N
NH2
N
N
N
O
N
Ph
MeCN (10 mL)
N
O
Ph
Ph
NH
O
Ph
+
Cy
O
10 mA, 4 h
N2, r.t.
undivided cell
N
N
Ph
7
N
16, 65%
16', 13%
17
18
, 53%
, 29%
N
Ph
Levetiracetam
0.6 mmol
48
0.3 mmol
, 55%
O
N
N
N
N
Scheme 5. Electrochemical oxidative C(sp3)-H azolation with
drugs.
N
N
N
N
Ph
N
N
N
N
Ph
Ph
O
N
O
O
N
Ph
19
19'
20, trace
20', 41%
N
19 19'
: =1.16:1)
94%(
standard conditions
O
NH
N
+
N
N
O
Ph
N
I
Ph
a
a
N
21
22
23
24
25
, R=H, 67%(a:b=15:1)
, R=Me, 69%(a:b>20:1)
, R=I, 79%(a:b=2.7:1)
, R=CF3, 91%(a:b>20:1)
, R=NO2, 37%(a:b>20:1)
N
0.3 mmol
0.6 mmol
O
16'
, 74 %
a
N
N
N
N
N
O
O
N
N
O
R
R
b
b
standard conditions
N
O
H
NH
b
+
33,
34
70%(a:b=4:1)
COOEt
, 78%(a:b>20:1)
COOEt
N
HN
N
H
H
Ph
N
Ph
0.3 mmol
49
0.6 mmol
, 59 %
26
27
28
29
30
31
32
, R=Me, 85%(a:b=20:1)
, R=Cl, 68%(a:b=12.5:1)
, R=Br, 70%(a:b=5:1)
, R=I, 58%(a:b=10:1)
, R=CN, 69%(a:b=2.2:1)
a
Scheme 6. Electrochemical oxidative 3-phenyl-1H-pyrazole
with N-vinyl amide.
N
a
a
N
N
N
N
b
O
N
N
N
N
O
O
EtOOC
b
b
-
, R=COOEt, 69%(a:b=2.6:1)
, R=NO2, 50%(a:b=5.6:1)
35
36
, 49%(a:b=2:1)
, 76%(a:b=3.6:1)
carbon paper(+)|carbon paper(-)
N
NH
+
N
N
N
MeCN, 20 mA, 33 h
N2, r.t.
N
O
O
Ph
Ph
I
R
a
a
N
1
10 mmol
20 mmol
a
N
a
N
N
N
N
1.61 g, 67%
N
N
O
N
N
O
N
N
N
O
O
b
b
b
b
Scheme 7. Gram-scale synthesis in flow cell.
38
39
, R=Br, 48%(a:b=18.2:1)
, R=NO2, 48%(a:b=4.3:1)
37
40
41
, 47%(a:b=7.1:1)
, 24%(a:b=10:1)
, 77%(a:b>20:1)
OH
R
Ph
N
N
N
N
a
a
standard conditions
NH
N
N
1
+
N
N
a
N
N
N
O
BHT (1.2 eq)
N
O
N
O
N
N
Ph
b
N
N
Ph
b
O
0.3 mmol
0.6 mmol
trace
b
Detected by HRMS
[M+H+]: 363.2429
45
46
, 96%(a:b>20:1)
, 39%(a:b>20:1)
42
, R=F, 41%(a:b=6.7:1)
43
44
, R=Me, 51%(a:b>20:1)
t
, R= Bu, 46%(a:b>20:1)
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), carbon
N
O
standard conditions
TEMPO (1.2 eq)
NH
1
+
cloth anode (15 mm*15 mm*0.36 mm), Pt plate cathode (15
N
O
N
Ph
n
N
O
mm*15 mm*0.3 mm), constant current=10 mA, Bu4NBF4 (0.5
mmol), MeCN (10 mL), room temperature, 4 h, undivided cell
(4.97 F).
Detected by HRMS
[M+H+]: 255.2068
0.3 mmol
0.6 mmol
trace
Scheme 8. Control experiments.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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(a)
(b)
conditions, N-vinylpyrrolidone undergoes an addition
reaction with 3-phenylpyrazole. A similar reaction occurs in
N-vinylformamide and obtain a carbon-carbon double bond
addition product, which indicates that coupling products
may involve a nucleophilic attack process.14
View Article Online
DOI: 10.1039/D0GC00687D
22.5
H
22.5
H
H
NC
N
N
H
17.2
7.4
N
N
O
O
N
N
Ph
H2C
H2C
H
H
7.8
18.4
To further explore the practicality of our approach, we
expanded synthesis of 1 in gram scale (Scheme 7).15 When
the reaction was carried out under 20 mA constant current
for 33 hours using carbon paper anode and carbon paper
cathode in a flow cell, the desired product (1) could be
obtained in 67% yield in the presence of 10 mmol 3-phenyl-
1H-pyrazole and 20 mmol 1-methyl-2-pyrrolidinone in 60 mL
CH3CN.
Scheme 10. Free energy barrier of the hydrogen atom
abstraction at different site of 1-methylpyrrolidin-2-one
using (a) 3-phenyl-1H-pyrazole N radical; (b) 1H-pyrazole-4-
carbonitrile N radical. The energies are in kcal/mol.
e-
e-
anode
H+
Ph
To ascertain the mechanism involved, we carried out
several control experiments (Scheme 8). 2,2,6,6-
Tetramethylpiperidin-1-oxyl (TEMPO) and 2,6-di-tert-
butylphenol (BHT) were added to the electrochemical
oxidative reaction respectively, which can inhibit the
formation of coupled product 1 significantly. At the same
time, two capture products were detected by HRMS. These
results demonstrate that there may be a mechanism of
radical processes in the transformation.
NH
N
N
N
N
A
N
O
O
Ph
B
C
D
A
A
H+
N
O
N
N
N
Ph
O
H+
2
H
1/2
-
1
In order to further the details of the mechanism, we
studied the electrochemical oxidation step of substrates by
performing cyclic voltammetry (CV) experiments (Scheme
9). The oxidation peak of the substrate 3-phenyl-1H-pyrazole
(2.04 V, red line) was observed to be smaller than the
oxidation potential of the substrate 1-methyl-2-
pyrrolidinone (2.39 V, blue line) Therefore, we conjecture
that 3-phenyl-1H-pyrazole is the first substrate to be
oxidized during the reaction. To confirm the oxidation of the
two coupling substrates of the reaction, electron
paramagnetic resonance (EPR) experiments were carried
out to determine the radical intermediates (see Supporting
Information). No radical signal was detected in the presence
of 1-methyl-2-pyrrolidinone. These results proved that 3-
phenyl-1H-pyrazole is the first substrate to be oxidized by
the carbon anode under the electrolytic conditions.
cathode
e-
Scheme 11. Possible mechanism.
phenyl-1H-pyrazole N radical, 1H-pyrazole-4-carbonitrile N
radical and 1-methyl-2-pyrrolidinone were calculated. When
3-phenyl-1H-pyrazole was employed as substrate, the
lowest two energy barrier occurred at the sites of C3-H and
N-CH2-H, which fitted well with the observed selectivity
(Scheme 3, 1). The same trend could be observed for the
selectivity when 1H-pyrazole-4-carbonitrile was used as
substrate (Scheme 4, 30).
On the basis the above results and literature reports,17
a
possible mechanism was proposed as show in Scheme 11.
First, 3-phenyl-1H-pyrazole with relatively low oxidation
potential was oxidized at anode, followed by hydrogen
transfer to form nitrogen radical B. Then, radical B and the
1-methyl-2-pyrrolidinone undergo an intermolecular
hydrogen atom transfer to obtain radical C and 3-phenyl-1H-
pyrazole. Next, radical B was oxidized on the anode and the
iminium cation D generated, D was trapped by 3-phenyl-1H-
pyrazole to give the product 1. Meanwhile, concomitant
cathodic reduction of proton-hydrogen would generate H2
during the reaction process.
The selectivity of the reaction can be rationalized using
DFT calculations.16 As show in Scheme 10, the free energy
barrier of hydrogen atom abstraction process between 3-
3.5
blank
3-Phenyl-1H-pyrazole
3.0
NMP
2.5
2.0
1.5
1.0
0.5
0.0
Conclusions
In summary, we have developed a method to activate azoles
and lactams to corresponding C(sp3)-H/N-H coupling products
under mild electrochemistry conditions. This transformation
accommodates pyrazoles with various substituents and other
types of azoles. Various types of amides can be used in this
process. Utilizing the flow cell, gram scale product with a good
conversion yield provide the possibility of industrial application.
Control experiments, cyclic voltammetry experiments, DFT
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Potential (V)
Scheme 9. Cyclic voltammetry of 3-phenyl-1H-pyrazole and
1-methyl-2-pyrrolidinone in MeCN (10 mL).
4 | J. Name., 2012, 00, 1-3
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Synlett, 2017, 28, 868-872; (g) H. Aruri, U. SinghV,ieMw.AKrtuicmle Oarn,linSe.
Sharma, S. K. Aithagani, V. K. GuDpOtaI:, 10S..10M39i/gDn0aGnCi,00R6.87AD.
Vishwakarma and P. P. Singh, J. Org. Chem., 2017, 82, 1000-
1012; (h) J. He, A. Dhakshinamoorthy, A. Primo and H. Garcia,
Chemcatchem, 2017, 9, 3003-3012; i) Z. Luo, Z. Jiang, W. Jiang
and D. Lin, J. Org. Chem., 2018, 83, 3710-3718.
W. Su, C. Jin, B. Sun and Z. Yan, Synlett, 2018, 29, 2432-2436.
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calculations and EPR experiments were conducted and a
reasonable reaction mechanism were proposed. Further
studies on the C(sp3)-H compound electrochemistry synthetic
applications is currently ongoing in our group.
8
9
Conflicts of interest
There are no conflicts to declare.
10 Z. Pan, Z. Fan, B. Lu and J. Cheng, Adv. Synth. Catal., 2018, 360,
1761-1767.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003, 21702150), the
Hubei Province Natural Science Foundation of China
(2017CFA010) and China Postdoctoral Science Foundation
(BX201600114, 2016M602340). The Program of Introducing
Talents of Discipline to Universities of China (111 Program) is
also appreciated. The numerical calculations in this paper have
been done on the supercomputing system in the
Supercomputing Center of Wuhan University.
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DOI: 10.1039/D0GC00687D
TOC graphic:
Electrochemical Oxidative C(sp3)-H Azolation of Lactams Under Mild
Conditions
R1
R1
X
X
H
H
H
H
N
N
X
X
N
R2
N
N
N
R2
O
O
· metal-free and oxidant-free
· wide substrate
· gram scale
· mild condition
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