Metal-free synthesis of imidazo[1,5- a] pyridines via elemental sulfur mediated sequential dual oxidative Csp3-H amination

Article abstract of DOI:10.1039/c8ob01391h

A simple and efficient approach has been developed for the synthesis of imidazo[1,5-a]pyridines using the elemental sulfur mediated sequential dual oxidative Csp³-H amination of 2-pyridyl acetates and amines under metal- and peroxide-free conditions. Broad substrate scope, operational simplicity and gram-scale ability make this chemistry very practical.

Full text of DOI:10.1039/c8ob01391h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Metal‐free synthesis of imidazo[1,5‐a]pyridines via elemental
sulfur mediated sequential dual oxidative Csp3‐H amination
Jie Sheng,a Jidan Liu,*a,b He Zhao,a Liyao Zhenga and Xingchuan Wei*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple and efficient approach has been developed for the
synthesis of imidazo[1,5‐a]pyridines using elemental sulfur
mediated sequential dual oxidative Csp3‐H amination of 2‐pyridyl
acetates and amines under metal‐ and peroxide‐free conditions.
Broad substrate scope, operational simplicity and gram‐scale
ability make this chemistry very practical.
or ketones with alkylamines, respectively.8 Later, Adimurty and
co‐workers developed a copper‐catalyzed aerobic oxidative
Fused nitrogen heterocycles occur widely in natural products
and biologically active molecules which are important building
blocks in both material chemistry and pharmaceutical
synthesis of imidazo[1,5‐a]pyridines employing either
industry.1 In particular, the imidazo[1,5‐
a]pyridines are a class
pyridotriazoles or 2‐pyridyl acetates as substrates.9 Among the
mentioned methods and others,10 most of them require the
use of a copper catalyst or peroxide as an oxidant, in view of
the concerns about the influences of trace metals on human
consumption drugs and the efficiency of organic electronic
devices. Therefore, to explore a new protocol for the synthesis
of aza‐fused heterocyclic skeletons found in many
pharmacologically important compounds.2 Meanwhile, the
imidazo[1,5‐a]pyridines skeleton (2‐azaindolizines) has
potential applications in organic light‐emitting diodes (OLEDs)3
and organic thin‐layer field effect transistors (FETs).4 In
addition, the 2‐azaindolizine structure could also be
of imidazo[1,5‐a]pyridines from simple and readily available
starting materials under metal‐ and peroxide‐free conditions is
highly desirable.
considered as a precursor for N
‐heterocyclic carbene.5
Due to the great value in pharmaceuticals and material
chemistry, considerable attention has been paid to the
development of general and efficient methods for the
synthesis of imidazo[1,5‐a]pyridines and their derivatives.
Traditionally, the synthesis of molecules with such a scaffold
Elemental sulfur widely exists in nature which is nontoxic,
stable, odorless and easy handling under normal conditions,
and exists in numerous oxidation states, ranging from ‐2 to
+6.11 It is an inexpensive raw material for sulfur chemistry
which is employed for the vulcanization of rubber, the
synthesis of sulfuric acid, as well as other sulfur‐containing
compounds.12,13 Moreover, elemental sulfur could also serve
as a highly efficient and traceless oxidizing agent in oxidative
coupling reactions to form a variety of nitrogen‐containing
heterocycles.14 As our continuing interest in the synthesis of
fused nitrogen heterocycles,15 we herein disclose a metal‐free
and peroxide‐free oxidative cyclization reaction of 2‐pyridyl
acetates with alkylamines to construct various imidazo[1,5‐
involves
the
Vilsmeier‐type
cyclization
of
N‐2‐
pyridylmethylamides.6 Another attractive tool is the direct C‐H
amination/cyclization strategy. For instance, in 2013, Wang
reported a novel protocol to form imidazo[1,5‐
sequential dual oxidative amination of C(sp3)‐H bonds with
stoichiometric amount of
‐iodobutanimide and oxidant.7
Zeng and Xu group have independently investigated the
efficient synthesis of imidazo[1,5‐ ]pyridines through copper‐
catalyzed aerobic oxidative reaction of ‐heteroaryl aldehydes
a]pyridines via
N
a
N
a
]pyridine skeletons, in which elemental sulfur was found to
be the key for the success of this oxidative annulation process
(Scheme 1).
We started our investigation by taking readily available
ethyl 2‐(pyridin‐2‐yl)acetate 1a and benzylamine 2a as the
model substrates to optimize the reaction conditions (Table 1).
a. School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou
510006, P. R. China. E‐mail: xing6363@126.com, jdliu@gzhu.edu.cn
b. Key Laboratory of Functional Molecular Engineering of Guangdong Province,
South China University of Technology, Guangzhou 510640, P. R. China
Electronic Supplementary Information (ESI) available: Detail experimental
procedures, analytical data. See DOI: 10.1039/b000000x
This journal is © The Royal Society of Chemistry 20xx
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a
DOI: 10.1039/C8OB01391H
Table 1
Screening of optimal conditions
COOEt
conditions
N
N
COOEt
+
Ph
NH2
N
Ph
1a
2a
3a
Entry
S
T (oC)
Yieldb (%)
Solvent
1
2
S (0.6 mmol)
S (0.6 mmol)
NMP
DMF
110
110
56
70
3
4
5
6
7
8
9
S (0.6 mmol)
S (0.6 mmol)
S (0.6 mmol)
S (0.6 mmol)
S (0.6 mmol)
S (0.6 mmol)
S (0.6 mmol)
DMSO
Dioxane
CH3CN
Toluene
DCE
110
110
110
110
110
110
120
88
0
0
0
0
0
85
H2O
DMSO
10
11
12
S (0.6 mmol)
S (0.6 mmol)
S (0.6 mmol)
DMSO
DMSO
DMSO
100
110
110
76
78c
64d
73
13
14
15
S (0.4 mmol)
S (0.8 mmol)
S (0.6 mmol)
DMSO
110
DMSO
DMSO
DMSO
110
110
110
86
85e
0
16
a
1a
2a
(0.24 mmol), sulfur (0.6 mmol),
Reaction conditions:
(0.2 mmol),
solvent (1.0 mL), 110 oC, under air for 2 h. b Isolated yield. c 2a (0.2 mmol,
1 equiv.). d 2a (0.3 mmol, 1.5 equiv.). e Under N2.
To our utmost delight, the desired ethyl 3‐phenylimidazo[1,5‐
a
]pyridine‐1‐carboxylate 3a was successfully isolated in 56%
yield in the presence of elemental sulfur (3.0 equiv.) in NMP at
110 °C for 2 h (Table 1, entry 1). Encouraged by this result,
various solvents were tested for this transformation to
improve the yield (Table 1, entries 1‐8), and DMSO was found
to be the best, and the desired product 3a was afforded in 88%
yield (Table 1, entry 3). It is found that increasing the reaction
temperature to 120 °C, or reducing the reaction temperature
to 100 °C, did not further increase the yield of the target
product (Table 1, entries 9 and 10). Furthermore, changing the
equivalent of elemental sulfur and benzylamine 2a did not
further improve the reaction either (Table 1, entries 11‐14). A
similar yield was achieved when the reaction was carried out
under nitrogen atmosphere which indicates that elemental
sulfur is the only oxidant (Table 1, entries 15). Finally, the
control experiment revealed that no desired product 3a was
formed in the absence of elemental sulfur (Table 1, entry 16).
reaction efficiency. Notable, hetero amines including furan and
With the aforementioned optimized reaction conditions thiophene derivatives also were found to be suitable
in hand (Table 1, entry 3), we next set out to examine the substrates to afford the desired products (Table 2, 3o and 3p).
scope of the present oxidative annulations. First, a wide range Additionally, the present system is also applicable to simple
of alkylamines were tested with ethyl 2‐(pyridin‐2‐yl)acetate aliphatic amines, and the corresponding imidazo[1,5‐
1a. As can be seen from the results of Table 2, the reactions of
aromatic benzylamines bearing either electron‐donating
a
]pyridine derivatives 3q‐3t were obtained in moderate yields.
Next, we turned our attention to the scope of various
substituents (such as Me, OMe, and
t‐Bu) or electron‐ pyridyl ester derivatives and the results were summarized in
withdrawing substituents (such as F, Cl, Br, and CF3) on the Table 3. As expected, substrates with various common ester
benzene ring proceeded smoothly to deliver the desired groups, such as ‐COOMe, ‐COOiPr, ‐COOnBu and ‐COOtBu, were
products in moderate to good yields (Table 2, 3b‐3n). Halogen well tolerated to deliver the desired products 3u‐3x in good to
groups substituted at the aromatic ring of benzylamines, such excellent yields. In addition, ethyl 2‐(quinolin‐2‐yl)acetate
as fluro, chloro, and even bromo, were all well tolerated, could also participate in this transformation to give 3y in 90%
which provided the possibility for further synthetic elaboration. yield. Moreover, pyridyl acetates with methyl and chloro
It is worthwhile to mention that the presence of a variety of groups on the pyridine ring as well as pyridyl acetamide
electron‐donating/withdrawing groups in benzylamine produced the desired products 3z
−3ac in good yields. However,
moieties at either (o/m/p) position had almost no effect on the when R2 was a cyano or COPh group, no desired product 3ad
2 | J. Name., 2012, 00, 1‐3
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inhibited when 2,2,6,6‐tetramethyl‐1‐piperidinyloxy (TEMPO)
or 2,6‐di‐tert‐butyl‐4‐methylphenol (BHT), as radical
a
scavenger, was added to the reaction under the standard
conditions. This meant that a radical pathway might not be
involved in this reaction.
S
S2-
H+
Ph
NH2
COOEt
NH
2a
N
COOEt
COOEt
-H+
N
N
first
Ph
1a
8
amination
9
or 3ae was detected in the reaction mixture, presumably due
to the incompatibility of the two functional groups and amine
under elevated temperature.
H2S
S
S
S2-
H+
COOEt
COOEt
N
N
COOEt
N
To further demonstrate the practicability of this one‐pot
protocol, a gram‐scale reaction was also performed using 8
mmol of 1a (1.32 g) under the optimal conditions. This
transformation proceeded smoothly to afford the
corresponding 3a in 80% isolated yield without significant loss
of reaction efficiency (Scheme 2).
N
second
amination
oxidation
N
H
N
Ph
10
Ph
Ph
11
12
COOEt
N
-H+
N
Ph
3a
Plausible reaction mechanism
Scheme 4
Although the exact reaction mechanism is still unknown
at this stage, based on the results described above and
literature reports,7,9,16 a plausible mechanism was proposed
(Scheme 4). Initially, the substrate 1a undergoes oxidation to
give the corresponding carbocation
To elucidate the reaction mechanism, several control elemental sulfur as an oxidant.16b The nucleophilic addition of
experiments shown in scheme 3 were conducted. First, when 2a to generates an intermediate , intermediate undergoes
secondary amine, like dibenzylamine or ‐phenyl oxidative dehydrogenation to form imine intermediate 10 in
benzylamine was applied, respectively, in the system instead the presence of elemental sulfur. Subsequently, 10 undergoes
8 in the presence of
8
9
9
4
n
5
of benzylamine 2a, the desired product 3a was not produced further oxidation to provide the intermediate 11, which can be
efficiently which demonstrates that a free amine is necessary further attacked by the nitrogen of pyridine to deliver the
for the success of the tandem reaction. Moreover, when the intermediate 12. Finally, oxidative aromatization of 12 will
reaction of 1a with 1‐phenylethanamine
under the standard conditions, an imine product
isolated in 94% yield which indicates that a methyl group at mediated oxidative cyclization of 2‐pyridyl acetates and
the ‐position of benzylamine prevented the second amines leading to various imidazo[1,5‐ ]pyridines in moderate
6
was carried out afford the desired imidazo[1,5‐a]pyridine 3a.
7
was In summary, we have developed a novel elemental sulfur
α
a
amination process. Finally, the model reaction was not
to excellent yields. This procedure avoids the employment of
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DOI: 10.1039/C8OB01391H
8
(
a
A wide range of functional groups are proved to be compatible
with the standard conditions. Moreover, gram‐scale reaction
of 1a and 2a demonstrates the practicality of the protocol.
Deep studies into the detailed reaction mechanism and further
synthetic applications are ongoing in our laboratory.
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(a
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
11 For recent reviews on the application of elemental sulfur in
We thank the Natural Science Foundations of Guangdong
Province (Grant No. 2017A030310620), Science and
Technology Research Project of Guangzhou (Grant No.
201707010483), Scientific Research Project of Guangzhou
Municipal Colleges and Universities (Grant No. 1201630327)
and the Open Fund of the Key Laboratory of Functional
Molecular Engineering of Guangdong Province (No. 2017kf08,
South China University of Technology) for financial support.
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An efficient procedure for imidazo[1,5-a]pyridine formation via dual
oxidative Csp3-H amination using elemental sulfur is described.
Transition-metal-free
Peroxide-free
No additives
Broad substrate scope
R3
S
R3
R1
NH2
+
R2
N
R2
N
N
R1
63-92% yields
29 examples