Peroxide-mediated site-specific C-H methylation of imidazo[1,2-: A] pyridines and quinoxalin-2(1 H)-ones under metal-free conditions

Article abstract of DOI:10.1039/c9ob02328c

An effective approach to realize the direct methylation of imidazo[1,2-a]pyridines and quinoxalin-2(1H)-ones with peroxides under metal-free conditions is described. In this protocol, peroxides serve as both the radical initiator and methyl source. Methylated imidazopyridines and quinoxalin-2(1H)-ones were smoothly synthesized in moderate to good yields. A free radical reaction mechanism was proposed to describe the methylation process.

Full text of DOI:10.1039/c9ob02328c

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Peroxide-mediated site-specific C–H methylation
of imidazo[1,2-a]pyridines and quinoxalin-2(1H)-
ones under metal-free conditions†
Cite this: Org. Biomol. Chem., 2020,
18, 205
Received 28th October 2019,
Accepted 28th November 2019
Shengzhou Jin, Hua Yao, Sen Lin, * Xiaoqing You, Yao Yang and Zhaohua Yan*
DOI: 10.1039/c9ob02328c
rsc.li/obc
An effective approach to realize the direct methylation of imidazo
Imidazo[1,2-a]pyridines have been recognized as a privi-
[1,2-a]pyridines and quinoxalin-2(1H)-ones with peroxides under leged scaffold and attracted great attention from chemists.9
metal-free conditions is described. In this protocol, peroxides There are several marketed drugs possessing imidazo[1,2-a]
serve as both the radical initiator and methyl source. Methylated pyridine moieties such as alpidem, zolpidem, and necopi-
imidazopyridines and quinoxalin-2(1H)-ones were smoothly syn- dem.10 Numerous methods have been developed for the syn-
thesized in moderate to good yields. A free radical reaction mecha- thesis of imidazo[1,2-a]pyridines, and especially for the con-
nism was proposed to describe the methylation process.
struction of C–X (X = C, N, O, F, and S) bonds at the C-3 posi-
tion of the imidazopyridine ring.11 It is worth mentioning that
our group recently reported for the first time a method for the
direct hydroxyalkylation of imidazo[1,2-a]pyridines at the C-5
position.12 Inspired by the result, we wonder whether it is
possible to functionalize imidazopyridine at the C-5 position
using other alkyl sources? Herein, we report an effective, non-
metal-catalyzed, and direct methylation using peroxides as
methyl sources at the C-5 position of imidazo[1,2-a]pyridine
(Scheme 1c).
Over the past decades, much effort has been devoted to the
C–C bond formation by C–H bond activation.1 In this regard,
direct methylation of C–H bonds has become one of the hot
research fields.2 Methyl halide,3 organometals4 and other
reagents5 have been widely used as traditional methylation
reagents in organic synthesis. Very recently, the pioneering
work of Li’s group6 has revealed the efficiency of palladium-
catalyzed methylation of aryl C–H bonds by using peroxides as
the methylating reagent (Scheme 1a). In 2016, similar studies
on methylation reactions of heterocycles under metal catalysis
were carried out by Chatani7 (Scheme 1b). And during the
period, a series of peroxide-promoted radical methylation
reactions with dicumyl peroxide (DCP), di-tert-butyl peroxide
(DTBP), cumyl hydroperoxide (CHP), and tert-butyl hydroperox-
ide (TBHP) have been developed for the functionalization of
C(sp2)–H bonds.6–8 However, most of these methylation
methods rely on metal catalysis to produce the methyl radical.
To the best of our knowledge, transition-metal catalysts will
undoubtedly bring about some limitations, such as toxicity
and metal contamination. Therefore, the strategy of direct
methylation of biologically active nonprefunctionalized hetero-
cycles via radical reactions by using peroxides as methyl
sources under non-metallic catalysis or greener conditions is
still a challenging and fascinating project.
As a kind of nitrogen-containing fused heterocycle, quinox-
alin-2(1H)-ones, especially 3-substituted ones, have a wide
array of potent biological properties, such as antitumor,13 anti-
cancer,14 and aldose reductase inhibitor properties.15 Recently,
Department of Chemistry, Nanchang University, No. 999, Xuefu Rd., Nanchang,
330031, P. R. China. E-mail: senlin@ncu.edu.cn, yanzh@ncu.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02328c
Scheme 1 Representative examples of direct methylation of aromatic
rings.
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several significant developments have been reported including the reaction can also take place under an atmosphere of air
radical C3–H arylation, phosphonation, amination, acylation, and produce 3a in 70% yield (Table 1, entry 15). Finally, the
and cyanoalkylation of quinoxalin-2(1H)-ones.16 However, the best yield (74%) was obtained using DCP as the methylating
direct methylation of quinoxalin-2(1H)-ones has not been reagent in HOAc under N2 at 120 °C for 24 h.
reported yet. To expand the application scope of quinoxalin-2
(1H)-ones, we investigated the direct methylation of quinoxa- substrate scope of 2-arylimidazo[1,2-a]pyridines (Scheme 2).
lin-2(1H)-ones (Scheme 1d). Initially, the C2-substituted imidazo[1,2-a]pyridines 1a–1c were
Under the optimized reaction conditions, we examined the
To realize the methylation of N-heteroaromatic compounds, investigated. It is noteworthy that both electron-donating
we initially selected the combination of 2-phenylimidazo (–OMe) and electron-withdrawing groups (–Br) could survive
[1,2-a]pyridine (1a, 0.3 mmol), and di-tert-butyl peroxide well to produce the desired products 3a–3c in moderate to
(DTBP) (2 equiv.) in HOAc (2 mL) at 120 °C as the model reac- good yields. Next, substrates 1d–1g bearing substituents at the
tion, and to our surprise, the desired product (3a) was isolated C-6, C-7 and C-8 positions of imidazo[1,2-a]pyridines were also
in 38% (Table 1, entry 1). Inspired by the initial result, the evaluated and also successfully afforded the desired products
effect of different solvents such as PhCl, DMSO, and acetone with good yields (3d–3g). Regretfully, when C-6 is a methyl
was screened, but unfortunately they displayed worse effects group, we did not obtain the ideal product (3h). Moreover, di-
than HOAc (Table 1, entries 2–4). To improve the reactivity, a substituted imidazo[1,2-a]pyridines were employed under the
series of peroxides, including CHP, TBHP (70% in water), and optimal conditions producing a moderate yield of products
DCP, were tested in this reaction (Table 1, entries 5–7), and (3i–3j). However disappointingly, substrates with methyl groups
among them DCP was found to be a much more suitable at the C-3 position of imidazo[1,2-a]pyridine or tert-butyl groups
methylation source generating 3a in 45% yield (Table 1, at the C-2 position were not suitable for this transformation.
entry 7). Next, we explored the influence of catalysts such as The extension of our protocol to the 2-thiophene substituted
Ni(OAc)2·4H2O, Pd(OAc)2, and CuCl2 on the yield of 3a, and all imidazo[1,2-a]pyridine was also explored, but the result showed
of them resulted in lower yields (Table 1, entries 8–10). that the reaction was not ideal, and only a small number of
Furthermore, we screened the amount of DCP (Table 1, entries methylated products were detected by GC-MS (3k).
11 and 12), and surprisingly, 3a could be obtained in 74%
After screening the direct methylation of imidazo[1,2-a]pyri-
yield when 3 equiv. of DCP were used (Table 1, entry 11). dines, we next sought to expand the methylation of quinoxa-
Screening of the reaction time revealed that 24 h was the best lin-2(1H)-ones. First, the methylation conditions for the reac-
(Table 1, entries 13 and 14). The further experiments showed tion of quinoxaline-2(1H)-one 4a and dicumyl peroxide (DCP)
that the yield of 3a did not increase when the temperature was were optimized (Table 2). After screening various solvents
increased or decreased (Table 1, entries 16 and 17). Notably, (Table 2, entries 1–4), HOAc was found to be the best choice to
Table 1 Optimization of reaction conditionsa
Temp. Time Yieldb
Entry 2 (equiv.)
Catalyst (equiv.) Solvent (oC)
(h)
(%)
1
2
3
4
5
6
7
8
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
CHP (2.0)
TBHP (2.0)
DCP (2.0)
DCP (2.0)
—
—
—
—
—
—
—
HOAc
PhCl
DMSO
120
120
120
24
24
24
24
24
24
24
24
38
29
20
34
Trace
30
45
Acetone 120
HOAc
HOAc
HOAc
HOAc
120
120
120
120
Ni(OAc)2·4H2O
(0.1)
31
9
DCP (2.0)
DCP (2.0)
DCP (3.0)
DCP (4.0)
DCP (3.0)
DCP (3.0)
DCP (3.0)
DCP (3.0)
DCP (3.0)
Pd(OAc)2 (0.1)
CuCl2 (0.1)
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
120
120
120
120
120
120
120
100
130
24
24
24
24
16
30
24
24
24
42
16
74
71
48
69
70
44
72
10
11
12
13
14
15c
16
17
—
—
—
—
—
—
—
a Reaction conditions: 1a (0.30 mmol), 2 (3.0 equiv.), solvent (2 mL),
120 °C, N2, 24 h, sealed tube. b Isolated yields. c Under an air
atmosphere.
Scheme 2 C-5 methylation of i̲midazopyridines with dicumyl peroxide.
Reaction conditions: 1 (0.3 mmol), HOAc (2 mL), DCP (3 equiv.) 120 °C
under N2, 24 h, sealed tube, isolated yields.
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Table 2 Optimization of reaction conditionsa
Temp. Time Yieldb
Entry 5 (equiv.) Catalyst (equiv.)
Solvent (°C)
(h)
(%)
1
2
3
4
5
6
7
8
DCP (3.0)
DCP (3.0)
DCP (3.0)
DCP (3.0)
CHP (3.0)
TBHP (3.0)
DTBP (3.0)
TBHP (3.0) Ni(OAc)2·4H2O (0.1) HOAc
TBHP (3.0) Pd(OAc)2 (0.1)
TBHP (3.0) CuCl2 (0.1)
TBHP (4.0)
TBHP (2.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
—
—
—
—
—
—
—
HOAc
PhCl
DMSO 120
Acetone 120
HOAc
HOAc
HOAc
120
120
24
24
24
24
24
24
24
24
24
24
24
24
12
15
24
24
24
74
52
46
48
76
80
75
62
74
53
78
73
81
85
36
75
83
120
120
120
120
120
120
120
120
120
120
120
100
130
9
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
10
11
12
13
14
15c
16
17
—
—
—
—
—
—
—
a Reaction conditions: 4a (0.30 mmol), 5 (3.0 equiv.), solvent (2 mL),
120 °C, N2, 15 h, sealed tube. b Isolated yields. c Under an air
atmosphere.
Scheme 3 C-3 methylation of quinoxalin-2(1H)-ones. Reaction con-
ditions: 4 (0.3 mmol), TBHP (70% in water) (3 equiv.), HOAc (2 mL),
120 °C under N2, 15 h, sealed tube. Isolated yields.
provide the desired product in 74% yield (Table 2, entry 1).
Subsequently, other peroxides such as CHP, TBHP (70% in
water), and DTBP were tested (Table 2, entries 5–7), and TBHP yields (6d–6h). However, the reaction with 4i failed to provide
(70% in water) turned out to be the most effective and the the corresponding product. Next, quinoxalin-2(1H)-ones with
yield of 6a was 80% (Table 2, entry 6). However, the yield of 6a electron-donating groups or electron-withdrawing substituents
could not be improved when the catalysts were used (Table 2, could proceed smoothly (6j–6n). A mixture of 6-Me and 7-Me
entries 8–10). We then switched our attention toward the role substituted quinoxalin-2(1H)-ones reacted with TBHP (70% in
of the amount of TBHP (70% in water), but to our regret, the water) and gave the products (6o and 6o′) in 76% yields. To our
yield of 6a did not increase when the amount of TBHP (70% in surprise, N-unsubstituted quinoxalin-2(1H)-one was well compa-
water) was increased or decreased (Table 2, entries 11 and 12). tible with these reaction conditions (6p). Finally, a gram-scale
Moreover, a better yield (85%) was achieved when the reaction reaction of 4a (5 mmol) with TBHP (70% in water) (3 equiv.) was
time was 15 hours (Table 2, entries 13 and 14). Meanwhile, we explored, and the product 6a could be produced in 61% yield.
hoped to increase the reaction rate by raising or reducing the
To understand the mechanistic pathway of the two reac-
temperature. Unfortunately, we did not obtain a positive result tions, a few control experiments were carried out (Scheme 4).
(Table 2, entries 16 and 17). Furthermore, no substantial The methylation of imidazo[1,2-a]pyridines and quinoxalin-2
increase in the yield was obtained under an air atmosphere (1H)-ones did not proceed at all in the presence of radical sca-
(Table 2, entry 15). According to the above experimental venger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, 3 equiv.),
results, the optimal reaction conditions were obtained as which signifies that the reaction proceeds through a radical
follows: 3 equiv. TBHP (70% in water) at 120 °C under N2 for pathway (Scheme 4a and d). The addition of BHT (butylated
15 h.
hydroxytoluene, 3 equiv.) could also suppress the two reactions
With the optimized reaction conditions in hand, we further obviously, together with the formation of the compound 7
turned our attention to explore the scope of quinoxalin-2(1H)- detected by GC-MS (Scheme 4b and e). Furthermore, when 3.0
ones (Scheme 3). Most reactions smoothly occurred to afford equiv. of radical scavenger ethene-1,1-diyldibenzene were
the corresponding C-3 methylated products. A variety of qui- added under optimized conditions, the methylation of
noxalin-2(1H)-ones bearing N-methyl, N-ethyl, and N-propynyl imidazo[1,2-a]pyridines was completely inhibited and the
engaged in this reaction efficiently, affording the corres- methylation of quinoxalin-2(1H)-ones was inhibited signifi-
ponding products (6a–6c) in moderate to good yields. Notably, cantly. Meanwhile, the methyl radical was captured (com-
N-benzyl substrates with electron-rich groups (–OCH3, –CH3) pound 8, detected by GC-MS) by ethene-1,1-diyldibenzene
and electron-poor groups (–NO2) were compatible with the (Scheme 4c and f). These results suggest that the methylation
reaction generating the corresponding products with good proceeds via a radical pathway.
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ones with peroxides. This transformation possesses the advan-
tage of the use of green and low toxic solvent HOAc under
non-metal conditions. Most of the reported functionalization
reactions of imidazo[1,2-a]pyridines occurred at the C-3 posi-
tion, and we successfully achieved methylation at the C-5 posi-
tion. Multisubstituted imidazo[1,2-a]pyridines and quinoxalin-
2(1H)-one derivatives can be smoothly synthesized in moderate
to good yields.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 21362022) and the Natural Science Foundation of Jiangxi
Province (No. 20192BAB203006) for financial support.
Scheme 4 Mechanistic studies.
Notes and references
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Scheme 5 Proposed mechanism of the methylation.
On the basis of the control experiments and previous
studies, a plausible mechanism for the radical methylation is
outlined in Scheme 5. At first, the reaction is initiated by
homolysis of peroxides under heating conditions, affording
alkoxy radicals A and D. β-Scission of the alkoxy radical gener-
ated a methyl radical B and the corresponding ketones. For
the methylation of imidazo[1,2-a]pyridines, the methyl radical
B reacts at the C-5 position of 2-phenylimidazo [1,2-a]pyridine
1a to form C–C bonded intermediate C. Next, the reaction
between C and the 2-phenyl-propanoxy radical led to the
product 3a. For the methylation of quinoxalin-2(1H)-ones, the
methyl radical B reacted with 4a to form the radical intermedi-
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