Oxidant-Mediated Nitrogenation and Recyclization of Imidazo[1,2-a]pyridines with Sodium Azide: Synthesis of 4H-Pyrido[1,2-a][1,3,5]triazin-4-ones

Article abstract of DOI:10.1002/adsc.201701480

An expeditious and straightforward approach for the synthesis of 4H-pyrido[1,2-a][1,3,5]triazin-4-ones starting from readily available imidazo[1,2-a]pyridines and sodium azide has been presented under aerobic oxidative conditions. The reaction proceeded well with the promotion of potassium persulfate/potassium permanganate with good functional group tolerance. A wide range of biologically valuable 4H-pyrido[1,2-a][1,3,5]triazin-4-one scaffolds were assembled by this methodology. The gram-scale reaction was also achieved. A cascade nitrogenation and oxidative recyclization sequence could be involved in the reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.201701480

Title: Oxidant-Mediated Nitrogenation and Recyclization of
Imidazo[1,2-a]pyridines with Sodium Azide: Synthesis of 4H-
Pyrido[1,2-a][1,3,5]triazin-4-ones
Authors: Gangjian Cao, Zhengkai Chen, Jinyu Song, Jianfeng Xu,
Maozhong Miao, and Hongjun Ren
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701480
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10.1002/adsc.201701480
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Gangjian Cao, a Zhengkai Chen, a, * Jinyu Song, a Jianfeng Xu, a Maozhong Miao, a and
Hongjun Ren a, *
a Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China
Fax: (+86)-571-8684-3655; e-mail: zkchen@zstu.edu.cn, renhj@zstu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An expeditious and straightforward approach for
the synthesis of 4H-pyrido[1,2-a][1,3,5]triazin-4-ones
starting from readily available imidazo[1,2-a]pyridines and
sodium azide has been presented under aerobic oxidative
conditions. The reaction proceeded well with the promotion
of potassium persulfate/potassium permanganate with good
functional group tolerance. A wide range of biologically
valuable 4H-pyrido[1,2-a][1,3,5]triazin-4-one scaffolds were
assembled by this methodology. The gram-scale reaction
was also achieved. A cascade nitrogenation and oxidative
recyclization sequence could be involved in the reaction.
Keywords:
nitrogenation;
oxidative
recyclization;
imidazo[1,2-a]pyridines; 4H-pyrido[1,2-a][1,3,5]triazin-4-
ones; N-heterocyclic compounds
[1,3,5]Triazin-4-ones have been recognized as a class
of privileged heterocyclic scaffolds and have found
wide applications in organic synthesis, biological and
pharmaceutical fields.[1] They have been usually
applied as the important skeletons or precursors for
artificial C-deoxyribonucleoside, CRHR-1/5-HT2
antagonists, eosinophilia inhibitors and potential
antiviral medicines, which have attracted tremendous
more general and straightforward routes to access to
pyrido[1,2-a]-1,3,5-triazin-4-one structure is still
highly desirable.
1h-i]
attention over the past decades (Figure 1).[1d,
Among various derivatives of [1,3,5]triazin-4-ones,
pyrido[1,2-a]-1,3,5-triazin-4-ones have been rarely
studied and only a few relevant reports were
documented, whereas they were used as key
structures in DNA oligomers.[1d] The traditional
methods for the synthesis of diversely substituted
pyrido[1,2-a]-1,3,5-triazin-4-ones constituted the
reaction of N-fluoropyridinium salts with cyanate ion
and carbonitriles,[2] the reaction of 2-amino-pyridine
with ortho-ester and trimethylsilyl isocynante or with
ethoxycarbonyl isothiocyanate and mercury(II) salt,[1d,
3]
and the reaction of 2-amino-pyridine with N-
Benzyloxycarbonyl-2,2,2-trifluoroacetimidoyl
Figure 1. Representative Compounds Containing
[1,3,5]Triazin-4-one Unit.
chloride.[4] However, the above synthetic approaches
suffered from multistep reaction procedures, low
efficiency and poor regioselectivity, or the necessity
of pre-functionalized starting materials. Recently,
Cheng and coworkers demonstrated a base-promoted
dearomative annulation reaction between N-2-
pyridylamidine and atmospheric CO2 for the rapid
construction of a variety of pyrido[1,2-a]-1,3,5-
triazin-4-ones.[5] Nevertheless, the development of
Functionalized
imidazo[1,2-a]pyridine
derivatives are significant heterocyclic scaffolds
possessing a number of biological activities and act
as versatile building blocks for
several
pharmaceutically useful compounds.[6] Some
imidazo[1,2-a]pyridine motifs have been applied as
commercially available clinical drugs, including
1
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10.1002/adsc.201701480
Advanced Synthesis & Catalysis
necopidem,
saripidem,
zolpidem,
alpidem,
[b] Isolated yields.
mosapramine, and olprinone.[7] In the past few years,
substantial efforts toward the regioselective
functionalization of imidazo[1,2-a]pyridines were
largely focused on the C3 position, such as arylation,
alkenylation, carbonylation, sulfenylation, cyanation,
thiocyanation, phosphonation, trifluoromethylation,
trifluoroethylation and so on.[8] On the other hand, the
transformation based on the ring-opening of
imidazo[1,2-a]pyridines into other valuable synthetic
intermediates or more complicated heterocycles has
been scarcely reported.[9] In recent years, the N-atom
incorporation process using readily available nitrogen
sources enabled the formation the useful target
products with enriched structural diversity.[10]
Additionally, the selective oxidation based on the
specific reactive site was identified as one of the most
[c] K2S2O8 (5.0 equiv).
[d] The reaction was performed in the absence of K2S2O8
under air or O2 atmosphere.
[e] KMnO4 (1.0 equiv).
[f]
Under N2 atmosphere. NR = No reaction. TCP = 1,2,3-
Trichloropropane, Oxone
TBHP = 70% t-BuOOH in water.
=
2KHSO5•KHSO4•K2SO4,
We started our investigation by choosing 2-(p-
tolyl)imidazo[1,2-a]pyridine 1b and sodium azide
(NaN3) as model substrates to optimize the reaction
conditions. The reaction between 1b and NaN3 in the
presence of 3.0 equiv of K2S2O8 in CH3CN at 120 oC
under air atmosphere was initially examined.
Unfortunately, the desired product was not detected
(Table 1, entry 1). Then, a variety of different
solvents were screened and the results revealed that
toluene and DCE could afford the 4H-pyrido[1,2-
a][1,3,5]triazin-4(3H)-one product 2b in 15% and
21% yield, respectively (Table 1, entries 2-5).
Considering the unique role of polychlorinated
solvent in K2S2O8 promoted oxidation reactions,[12]
the high boiling TCP (1,2,3-trichloropropane) was
applied as solvent to the reaction, and to our delight,
the reaction yield obviously increased to 51% (Table
1, entry 6). Further increasing the amount of K2S2O8
to 5.0 equivlents led to the lower yield of the reaction
(Table 1, entry 7). Replacing the oxidant K2S2O8 with
air or O2 did not enable the occurrence of the reaction
(Table 1, entry 8). In order to further improve the
conversion of the oxidation reaction, diverse
oxidative additives were tested herein. Among these
additives, including Oxone, TBHP, KMnO4,
(NH4)2S2O8, PhI(OAc)2, H2O2, and O2, KMnO4 was
identified as the optimal candidate to lead to the
target product 2b in 60% yield (Table 1, entries 9-15).
frequently-used
reactions
for
the
organic
transformation.[11] Therefore, we combine the two
versatile strategies into one procedure to convert
imidazo[1,2-a]pyridine molecules into a plethora of
pyrido[1,2-a]-1,3,5-triazin-4-ones
K2S2O8/KMnO4 as oxidant under aerobic conditions.
Table 1. Optimization of reaction conditions.[a]
employing
Entry Additive. Solvent Temperature Yield[b]
(equiv)
(mL)
(oC)
(%)
1
2
--
--
CH3CN
DMF
DMSO
toluene
DCE
TCP
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
130
140
130
130
NR
trace
trace
15
3
--
4
--
5
--
21
o
Reducing the reaction temperature to 100 C resulted
in the slight decrease in the efficiency of the
transformation (Table 1, entry 16). Of note, when the
6
--
51
7
--
TCP
43[c]
trace[d]
27
8
--
TCP
o
reaction was performed at 130 C, the product 2b
9
Oxone
TBHP
KMnO4
(NH4)2S2O8
PhI(OAc)2
H2O2
O2
TCP
could be isolated in the highest yield (68%) (Table 1,
entry 17). Further elevating the temperature to 140 oC
clearly inhibited the reaction (Table 1, entry 18). The
diminished yield of the reaction was observed upon
employing a stoichiometric amount of KMnO4 (Table
1, entry 19). It is worth mentioning that an inert
atmosphere could enable the decline of the reaction
conversion (Table 1, entry 20).
10
11
12
13
14
15
16
17
18
19
20
TCP
17
TCP
60
TCP
40
TCP
10
TCP
30
TCP
37
KMnO4
KMnO4
KMnO4
KMnO4
KMnO4
TCP
54
After the establishment of the optimized reaction
conditions, we evaluated the generality and limitation
of this new oxidative protocol. A range of diverse
substituents on the imidazole ring were investigated
(Table 2). Gratifyingly, most of substituents and
functional groups on the aryl ring could be well
compatible with the current reaction conditions,
TCP
TCP
68
31
TCP
59[e]
51[f]
TCP
[a]
Reaction conditions: 1b (0.3 mmol), NaN3 (0.6 mmol),
K2S2O8 (3.0 equiv) and additive (0.5 equiv) in TCP (2.0
affording
the
corresponding
4H-pyrido[1,2-
mL) under air at 130 oC for 12 h.
a][1,3,5]triazin-4(3H)-one products 2a-l in moderate
2
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10.1002/adsc.201701480
Advanced Synthesis & Catalysis
Table 2. Synthesis of 4H-Pyrido[1,2-a][1,3,5]triazin-4-
ones from Imidazo[1,2-a]pyridines.[a,b]
Table 3. Scope of Imidazo[1,2-a]pyridines with
Modifications of the Pyridine Core.[a,b]
[a]
Reaction conditions: 1 (0.3 mmol), NaN3 (0.6 mmol),
K2S2O8 (3.0 equiv) and KMnO4 (0.5 equiv) in TCP (2.0
mL) under air at 130 oC for 12 h.
[b] Isolated yields.
yield. Noteworthy was that the steric hindrance in the
aryl ring exerted an obvious effect on the reaction, as
exemplified that lower yields were observed with
regard to ortho- and meta-methyl substituted
substrates (2d-c). The low yield of product 2c was
presumably due to the partially oxidation of meta-
methyl group under the oxidative conditons. Overall,
the electronic nature of the aryl ring had a marginal
influence on the reaction. Apart from halogen groups,
some strongly electron-withdrawing groups attached
in the imidazo[1,2-a]pyridines, including cyano,
trifluoromethyl and sulfonyl, were tolerated under the
optimized conditions (2e-h, 2k-l), underscoring the
good functional-group compatibility of the
methodology. Furthermore, the naphthalene ring and
thiophene ring could also be incorporated into the
target [1,3,5]triazin-4(3H)-one molecules, albeit in
lower yields (2m-n). Although a low yield with
regard to some substrates was observed, the result
indicated the feasibility of the present protocol. We
also performed the reaction by using 2-tert-butyl-
imidazo[1,2-a]pyridine or imidazo[1,2-a]pyridine,
but unfortunately, trace amounts of product (2o-p)
was observed. It was speculated that the existence of
aryl group in C-2 position of imidazoheterocycles
was necessary for improving the stability of the
intermediates in the reaction process.
[a]
Reaction conditions: 1 (0.3 mmol), NaN3 (0.6 mmol),
K2S2O8 (3.0 equiv) and KMnO4 (0.5 equiv) in TCP (2.0
mL) under air at 130 oC for 12 h.
[b] Isolated yields.
[c] The reaction was performed on 10 mmol scale.
-[1,2-a]pyridines with a number of electron-donating
or electron-withdrawing groups located at different
positions of the pyridine ring, were applicable under
the standard conditions, leading to the desired
products in moderated to good yields (3a-n). It
should be notable that halogenated substituents
survived smoothly in the reaction, providing the
potential of further derivatization of the relevant
products (3d-h, 3n). The substrates decorating
trifluoromethyl groups showed good reactivity and
the corresponding 4H-pyrido[1,2-a][1,3,5]triazin-
4(3H)-one products could be furnished in reasonable
yield (3i-m). More significantly, the reaction could be
reproducible on a gram scale and the product 3m was
obtained in 76% yield. With respect to the
imidazo[1,2-a]pyridine derived from quinolin-2-
amine, the reaction proceeded well to afford the
product 3o in relatively lower yield. It was observed
that a structurally complicated imidazoheterocycles
proved to be effective in the reaction, delivering the
4H-benzo[4,5]thiazolo[3,2-a][1,3,5]triazin-4-one (3p)
in satisfactory yield and 2-phenyl-4H-thiazolo[3,2-
a][1,3,5]triazin-4-one (3q) in relatively lower yield.
The exact structure of the obtained product 3f was
unambiguously determined by single X-ray
The compatibility of the present oxidative
protocol was further explored by the investigation of
imidazo[1,2-a]pyridines with various substituents on
the pyridine ring (Table 3). As expected, imidazo-
diffraction analysis[13] (Figure 2)
.
3
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10.1002/adsc.201701480
Advanced Synthesis & Catalysis
(imidazo[1,2-a]pyridin-3-one) and B (pyrido[1,2-
c][1,3,5]oxadiazin-4-one) were detected by LC-
HRMS. There results indicated that the oxidation
process could occur upon the substrate 1a.
Subsequently, 2 equiv of NaN3 was added into the
reaction. After 2 hours, except for intermediate A and
B, the species C (3-azidoimidazo-[1,2-a]pyridine), D
(strained azirine) and product 2a all could be detected.
After 4 hours, the species C, D disappeared, which
demonstrated that the intermediacy of the species C
and D. On the other hand, the standard reaction was
also monitored by LC-HRMS based on different
reaction time intervals (Scheme 2, eq 2). It was
observed that all the possible intermediates and
product could be initially detected and the species C
and D disappeared along with the time elapsed. It was
speculated that the intermediates C and D was
presumably involved in the reaction process. We also
attempt to isolate the intermediates C and D to verify
the assumption, but unfortunately, these active
Figure 2. The X-ray Structure of Product 3f.
intermediates were very unstable and could not be
Scheme 1. Radical trapping experiments.
[14]
isolated during the reaction
.
Furthermore, a radical trapping experiment was
conducted to shed light on the nature of the reaction
(Scheme 1). It is noteworthy that the addition of
radical scavenger of 2 equiv of TEMPO (2,2,6,6-
tetramethylpiperidine 1-oxyl), BHT (2,4-di-tert-
butyl-4-methylphenol), BQ (benzoquinone) or 1,1-
diphenylethylene resulted in the decrease of the
reaction yield. In the meantime, the radical coupling
product between BHT and imidazo[1,2-a]pyridine
was successfully detected by LC-HRMS (see the
Supporting Information). The observation data
suggested that a single electron transfer (SET)
process might be involved in the reaction, but other
possible reaction pathway could not be entirely ruled
out.
Scheme 3. Plausible Reaction Mechanism.
Base
on
the
preliminary
mechanistic
investigation and the previous reported literatures,[9, 11]
a plausible reaction mechanism was proposed as
depicted in Scheme 3. First, 3-azidoimidazo-[1,2-
a]pyridine C was formed between 1a and NaN3 in the
presence of K2S2O8/KMnO4. This azidation process
possibly involved a radical pathway[10a] or an oxidant-
mediated pathway,[9] as also evidenced by the results
of control experiment. The aryl azide C could
undergo thermal decomposition to afford nitrene
intermediate E with the exclusion of N2, which
occurred intramolecular cyclization for the formation
of strained azirine D.[10a, 15] With the promotion of
K2S2O8, the intermediate F was generated, followed
by a similar Aza-Baeyer-Villiger oxidation process to
furnish the final product 2a. The role of KMnO4 was
presumably defined as co-oxidant in the reaction,
because MnO2 was obviously detected through the
XRD analysis of the reaction residue (see the
Scheme 2. Control Experiments.
To gain more insight into the reaction mechanism, Supporting Information).
several control experiments were implemented as
In summary, we have developed an attractive
shown in Scheme 2. Initially, a series of possible
intermediates were proposed on the basis of previous
reported literatures.[9,11] Then, the substrate 1a was
subjected into the standard reaction conditions
without the addition of NaN3, and the reaction
process was monitored by LC-HRMS (Scheme 2, eq
1). After 2 hours and 4 hours, the intermediate A
pathway for the rapid synthesis of 4H-pyrido[1,2-
a][1,3,5]triazin-4-ones from imidazo[1,2-a]pyridines
and NaN3 under aerobic oxidative conditions.
Notable features of the methodology include the
usage of readily available materials, a broad substrate
scope and easy scalability. Considering the present
4
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10.1002/adsc.201701480
Advanced Synthesis & Catalysis
convenient methods for achieving 4H-pyrido[1,2-
a][1,3,5]triazin-4-ones were scarce, we provide an
alternative approach for the construction of these
[2] A. S. Kiselyov, L. Strekowski, Tetrahedron Letters
1994, 35, 207-210.
[3] M. Kopp, J.-C. Lancelot, S. Dagdag, H. Miel, S. Rault,
valuable
heterocyclic
compounds.
Further
J. Heterocyclic Chem. 2002, 39, 1061-1064.
investigation towards the reaction mechanism and
practical application are ongoing in our laboratory.
[4] N. V. Mel’nichenko, V. N. Tkachuk, E. B. Rusanov, V.
A. Sukach, V. I. Boiko, M. V. Vovk, Russian Journal of
Organic Chemistry, 2013, 49, 119-122.
Experimental Section
[5] M. Xia, W. Hu, S. Sun, J.-T. Yu, J. Cheng, Org. Biomol.
Chem. 2017, 15, 4064–4067.
Typical Procedure for the Synthesis of 4H-
Pyrido[1,2-a][1,3,5]triazin-4-ones
[6] a) C. Hamdouchi, J. de Blas, M. del Prado, J. Gruber, B.
A. Heinz, L. Vance, J. Med. Chem. 1999, 42, 50-59; b)
K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth,
D. E. Cavender, G. C. Olini, B. Fahmy, J. J. Siekierka,
Bioorg. Med. Chem. Lett. 2003, 13, 347-350; c) K. S.
Gudmundsson, J. D. Williams, J. C. Drach, L. B.
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Enguehard-Gueiffier, A. Gueiffier, Mini-Rev. Med.
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Morlock, K. A. Satyshur, C. Czajkowski, J. Med. Chem.
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S. E. Kazzouli, M. Bousmina, G. Guillaumet, Eur. J.
Org. Chem. 2014, 5119-5138.
K2S2O8 (243 mg, 0.9 mmol) and KMnO4 (23.7
mg, 0.15 mmol) were added to a solution of substrate
1 (0.3 mmol) and NaN3 (39 mg, 0.6 mmol) in TCP (2
mL). The mixture was stirred at 130 °C under air for
12 h. After the completion of the reaction (monitored
by TLC), the reaction mixture was cooled to ambient
temperature, quenched by water and extracted with
ethyl acetate (3 x 15 mL). The extract was dried over
anhydrous Na2SO4 and the solvent was removed in
vacuo to provide a crude product, which was purified
by column chromatography on silica gel with
petroleum ether/EtOAc as eluent to afford the product
2 or 3.
Acknowledgements
[7] a) H. Depoortere, P. George, US 5064836, 1991. b) A.
Berson, V. Descatoire, A. Sutton, D. Fau, B. Maulny, N.
Vadrot, G. Feldmann, B. Berthon, T. Tordjmann, D.
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We thank the financial support from the National Nature Science
Foundation of China (Grant No. 21602202), the Science
Foundation of Zhejiang Sci-Tech University (Grant Nos.
15062092-Y) as well as the Zhejiang Provincial Top Key
Academic Discipline of Chemical Engineering and Technology of
Zhejiang Sci-Tech University.
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Advanced Synthesis & Catalysis
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10.1002/adsc.201701480
Advanced Synthesis & Catalysis
COMMUNICATION
Oxidant-Mediated Nitrogenation and Recyclization
of Imidazo[1,2-a]pyridines with Sodium Azide:
Synthesis of 4H-Pyrido[1,2-a][1,3,5]triazin-4-ones
Adv. Synth. Catal. 2017, Volume, Page – Page
Gangjian Cao, a Zhengkai Chen, a, * Jinyu Song, a
Jianfeng Xu, a Maozhong Miao, a Hongjun Ren a, *
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