Iodine-Promoted Synthesis of Dipyrazolo/Diuracil-Fused Pyridines and o-Amino Diheteroaryl ketones via Oxidative Domino Annulation of 2/4-Methylazaarenes

Article abstract of DOI:10.1002/adsc.202100839

The iodine-promoted oxidative domino annulation and carbonylation process has been developed for the synthesis of biologically important azaarene-substituted bis-pyrazolo[3,4-b:4′,3′-e]pyridines (BPPs), diuracilpyridines and o-amino diheteroaryl ketones. The domino procedure proceeded with easily available methyl azaarenes, 5-aminouracils and substituted 5-aminopyrazoles. This protocol is a simple and metal-free approach which exhibits high functional group compatibility and broad substrates scope. Moreover, this transformation can be applied for the preparation of dipyrazolo/diuracil-fused pyridines on a gram scale. (Figure presented.).

Full text of DOI:10.1002/adsc.202100839

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Iodine-Promoted Synthesis of Dipyrazolo/Diuracil-Fused
Pyridines and o-Amino Diheteroaryl ketones via Oxidative
Domino Annulation of 2/4-Methylazaarenes
Xin-Ke Zhang,+a Xiao-Yu Miao,+a Hui-Ru Jiang,+a Fei Ge,+a Jia-Chen Sun,a
Rui-Ying Zhang,a Qin Ouyang,a Wei-Yu Fan,a Yan-Ping Zthu,a,* and
Yuan-Yuan Suna,*
a
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative
Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University,
Shandong, Yantai, 264005, People’s Republic of China
E-mail: chemzyp@foxmail.com; 252825190@qq.com
+
These authors contributed equally to this work.
Manuscript received: July 6, 2021; Revised manuscript received: August 19, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100839
activities, they also have been utilized as versatile
Abstract: The iodine-promoted oxidative domino
building blocks for the synthesis of useful molecules.[3]
annulation and carbonylation process has been
Given their important activities and fascinating
developed for the synthesis of biologically impor-
research prospects, the construction of pyridine and its
tant azaarene-substituted bis-pyrazolo[3,4-b:4’,3’-e]
pyridines (BPPs), diuracilpyridines and o-amino
diheteroaryl ketones. The domino procedure pro-
derivatives has attracted considerable attention in
recent times. Several efficient methods for their syn-
thesis have been reported.[4] Among all methods, the
ceeded with easily available methyl azaarenes, 5-
direct functionalization of CÀ H bond from simple and
aminouracils and substituted 5-aminopyrazoles.
easily available feedstocks represents the most straight-
This protocol is a simple and metal-free approach
forward approach to construct a pyridine motif
which exhibits high functional group compatibility
(Scheme 1a). For instance, oxime acetates have
and broad substrates scope. Moreover, this trans-
emerged as meritorious starting materials for the
formation can be applied for the preparation of
synthesis of substituted pyridines. They can react with
dipyrazolo/diuracil-fused pyridines on a gram scale.
various coupling partners, such as aldehydes, N,N-
dialkylanilines, N,N-dimethylformamide, acroleins,
enals, α,β-unsaturated imines, β-CF3 enones, isatin,
Keywords: Dipyrazolo/diuracil-fused
pyridines;
activated methylenes with aldehydes, cyclopropanols,
toluene, benzylamine, and p-toluenesulfonylhydrazone
derivatives to afford the corresponding functionalized
pyridine derivatives. Generally, these strategies can
proceed with metal catalysis, in metal-free conditions
or via oxidation-reduction (redox) processes.[5] Be-
sides, the coupling of α,β-unsaturated ketoximes with
1,3-dicarbonyl compounds or N-acetyl enamides is
Methyl-azaarenes; Oxidative domino cyclization;
Oxidative carbonylation; Iodine
Introduction
As privileged scaffolds, pyridines is prevalent in also an efficient method for the synthesis of
natural products, top-selling drugs, and ligands for pyridines.[6] Another efficient approach is the coupling
catalytic reactions.[1] In addition, pyridine-fused bicy- of simple methyl ketones with different nitrogen
clic and tricyclic skeletons, such as pyrazolopyridine, sources, such as aromatic methylamines, ammonium
carboline, and dipyrazolo/diuracil-fused pyridines, are formate, and natural amino acids.[7] Wu et al. devel-
also widely applied as pharmaceutical intermediates, oped an elegant approach which involved the oxidative
agricultural chemicals, and functional materials.[2] Due trimerization of amino acids for the synthesis of
to their excellent biological and pharmacological diverse multi-substituted pyridines from very simple
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reported a switchable approach for the synthesis of
azaarene-substituted dipyrazolo/diuracil-fused pyri-
dines and o-amino diheteroaryl ketones from methyl
azaarenes. This method allows a switchable oxidative
functionalization and carbonylation of methyl azaar-
enes to afford different products via a metal-free
manner (Scheme 1c).
Results and Discussion
Initially, we chose 2-methyl quinoline (1a, 0.3 mmol)
and
3-methyl-1-phenyl-1H-pyrazol-5-amine
(2a,
2.0 equiv., 0.6 mmol) as the model substrates to
optimize the reaction parameters (see Table 1). With
°
1.0 equivalent of I2 the reaction in DMSO at 110 C
produced the expected product 3aa in 56% yield and
trace mount of o-amino diheteroaryl ketone product
6aa (entry 1). Subsequently, the effect of the varying
amounts of I2 was investigated, and the optimum result
was obtained with 1.5 equivalent of I2. The yield of
3aa was increased to 70% at the same time (Table 1,
entries 2–4). Next, an evaluation of various solvents,
such as DMF, 1,4-dioxane and DMAc, revealed that
Scheme 1. The methods for pyridines synthesis and methyl
group oxidative carbonylation.
starting materials.[8] Moreover, Wan et al. discovered the reaction can be carried out in different solvents, but
some domino reactions involving enaminones with
aldehydes and ammonium chloride for the synthesis of
Table 1. Optimization of the reaction conditions[a]
substituted pyridines.[9]
Methyl azaarenes are important bioactive structural
motifs and versatile building blocks for organic
synthesis.[10] In recent years, many effective methods
have been established for the synthesis of heterocycles
via a direct functionalization of the sp3 CÀ H bond of
methyl azaarenes.[11] However, as far as we know, no
method has been reported for the synthesis of
azaarenes-substituted dipyrazolo/diuracil-fused pyri-
dines via a direct functionalization of the sp3 CÀ H
bond of methyl azaarenes by a metal-free approach.
Meanwhile, it is very difficult to synthesize dipyrazo-
lo/diuracil-fused pyridines containing heterocyclic
fragments, such as quinoline, quinoxaline, benzo[f]
quinoline, benzothiazole, benzoxazole, and pyridine.
The existing methods have only been successful in
introducing aryl and alkyl groups to dipyrazolo/
dipyrimidine-fused pyridines. Moreover, it is very
challenging to achieve the oxidative methyl azaarenes
to form o-amino diheteroaryl ketones. Presently, the
oxidative carbonylation of methyl groups is limited to
aryl methyl ketones (Scheme 1b). For example, studies
exist on the oxidative carbonylation of aryl methyl
ketones with aryl amines, aryl phenol, indoles, imidazo
[1,2-a]pyridines, benzo[d]imidazo[2,1-b]thiazole and
2-naphthol..[12] Also, the oxidative carbonylation of
methyl aryl ketones with acetamides, formamidine,
secondary amines, and alcohols was investigated for
the synthesis of α-carbonylamides and α-ketoesters.[13]
As part of our ongoing interest in the synthesis of
heterocycles from methyl azaarenes,[14] we herein
°
Entry I2 (equiv.) Solvent
Temp ( C) 3aa yield[b] (%)
1
2
3
4
5
6
7
8
9
1.0
0.5
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
DMSO
DMSO
DMSO
DMSO
DMF
110
110
110
110
110
56 (trace)[d]
48 (trace) [d]
70 (15) [d]
58 (11) [d]
51 (trace) [d]
54 (10) [d]
59 (trace) [d]
63 (16) [d]
77 (13) [d]
74 (10) [d]
83 (11) [d]
78 (11) [d]
52 (18) [d]
71 (14) [d]
1,4-dioxane 110
DMAc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
110
100
120
130
120
120
120
120
10
11 [c] 1.5
12 [e] 1.5
13 [f] 1.5
14 [g] 1.5
[a] Reaction conditions: 2-methyl quinoline 1a (0.3 mmol), 3-
methyl-1-phenyl-1H-pyrazol-5-amine 2a (0.6 mmol) and I2
in solvent (3.0 mL) at different temperatures for 6 hours.
[b] Isolated yields of 3aa based on 1a.
[c] 2.2 equivalent of 2a was added.
[d] The yield of compound 6aa.
[e] 2.5 equivalent of 2a was added.
[f] Reaction time for 3 h.
[g] Reaction time for 9 h.
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DMSO proved to be the most efficient solvent for the 6-OEt), and electron-withdrawing (eg. 6-F, 6-Cl, and
reaction as it afforded the best yield of the desired 6-Br) groups. All the substrates proceeded smoothly to
product (Table 1, entries 5–7). The reaction was further afford the desired products in moderate to good yields
tested under different temperature, ranging from 100 to (3ba–3ga, 40–77%). Furthermore, various methyl N-
°
130 C, and the results showed that the optimum heterocycles, such as 2-methyl-1,8-naphthyridine (1h)
°
reaction temperature was 120 C (Table 1, entries 8– and 4-methyl quinoline (1i) participated satisfactorily
10). Additionally, the effect of varying substrates ratio in the reaction, affording the desired products, 3ha and
was evaluated to determine the best ratio for the 3ia, in 62% and 42% yields, respectively. Further
reaction, and the highest yield was recorded for 2- investigations were carried out on several methyl
methyl quinoline (1a) and 3-methyl-1-phenyl-1H- azaarenes, such as 2-methylbenzothiazole (1j) and 2-
pyrazol-5-amine (2a) ratio of 1:2.2 (Table 1, en- methylbenzoxazole (1k), and they produced the
tries 11–12). Furthermore, the influence of time on the desired products, 3ja and 3ka, in moderate yields.
reaction was investigated, and the results revealed that However, 2-methylbenzimidazole (1l) proved unsuit-
the maximum yield was obtained after 6 hours reaction able for the reaction. Interestingly, some methyl
time. Consequently, lower yields were recorded below pyridines, namely 2-methylpyridine (1m), 4-meth-
and above this optimum reaction time (Table 1, ylpyridine (1n) and 4-ethyl-2-methylpyridine (1o),
entries 13–14).
proved feasible for the reaction by affording the
With the optimal reaction conditions in hand, we corresponding products, 3ma–3oa, in 36–76% yields.
next explored the generality of this domio annulation 2-Methylquinazolin-4(3H)-one (1p) also proved suit-
reaction for substituted methyl azaarenes and various able for the reaction as it afforded the desired product,
aminopyrazoles (Table 2). The protocol showed an 3pa, in a moderate yield.
excellent tolerance for the substituted methyl quino-
A variety of substituted amino pyrazoles were
lines bearing electron-donating (eg. 6-Me, 6-OMe, and subsequently investigated. Herein, 4-phenyl-1H-pyrrol-
2-amine (2b) reacted with 2-methyl quinoline (1a) to
give 46% yield of the desired product, 3ab. Amino
pyrazoles containing substituted groups, such as
phenyl, 6-F-phenyl and tert-butyl, were also suitable
for the reaction, producing moderate yields of the
desired products, 3ac, 3ad, and 3af. In addition, 3-
amino-3-phenyl-2-propenoic acid ethyl ester (2g) and
3-amino-3-(3-methoxyphenyl)-2-propenoic acid ethyl
ester (2h) reacted with 2-methyl quinoline to afford
27% and 24% yields of 3ag and 3ah, respectively.
However, when the substrate was converted to either
1-methyl-1H-pyrazol-5-amine (2i), 1,3-dimethyl-1H-
pyrazol-5-amine (2j) or 1-ethyl-1H-pyrazol-5-amine
(2k), the main product changed to o-aminoaromatic
ketones (see Table 4).
Table 2. Scope of bis-pyrazolopyridines.[a,b]
After the synthesis of a series of azaarene
substituted dipyrazolo-fused pyridines, we next ex-
plored the scope of substituted quinolines and 6-
amino-1,3-dimethylpyrimidine-2,4-dione (4a) under
the standard conditions (see Table 3). Generally, most
of the 2-methyl quinolines containing different sub-
stituents were employed in this protocol. For instance,
several 2-methyl quinolines bearing electron-rich sub-
stituents (e.g. 6-Me, 6-OMe, and 6-OEt) were inves-
tigated, and their corresponding products, 5ba–5da,
were obtained in 97%, 78% and 76% yields, respec-
tively. Moreover, the reactions afforded the corre-
sponding products in moderate to good yields when
halogen atoms were attached to the aryl rings (e.g. 6-F,
6-Cl, 6-Br 7-F, 7-Cl). Besides, 99% yield of 5ha was
obtained for the test with methylbenzo[f]quinoline
(1h). 2-Methyl-1,8-naphthyridine (1s), 4-meth-
ylquinoline (1i), and 1-methyl isoquinoline (1t) were
also suitable for the reaction, and their corresponding
[a] Reaction conditions: 1 (0.30 mmol), 2 (0.66 mmol), I2
°
(0.45 mmol) in DMSO (3 mL) at 120 C for 6 h.
[b] Isolated yields.
[c] N.D.=Not detected.
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Table 3. Scope of dipyrimidine-2,4(1H,3H)-dione pyridines.[a,b]
Table 4. Scope of o-amino diheteroaryl ketones.[a,b]
[a] Reaction conditions:
1
(0.30 mmol, 1.0 equiv.),
2
(0.54 mmol, 1.8 equiv.), I2 (0.54 mmol, 1.8 equiv.) in DMSO
°
(3 mL) at 130 C for 6 h.
[b] Isolated yields.
[c] Reaction conditions:
1
(0.30 mmol, 1.0 equiv.),
2
[a] Reaction conditions: 1 (0.30 mmol), 2 (0.66 mmol), I2
°
(0.66 mmol, 2.2 equiv.), I2 (0.45 mmol, 1.5 equiv.) in DMSO
(0.45 mmol) in DMSO (3 mL) at 120 C for 6 h.
[b] Isolated yields.
°
(3 mL) at 120 C for 6 h.
products were obtained in moderate yields. Further- although not specific (see SI details in Table 4).
more, 2-methylbenzothiazole (1j) and 2-meth- Furthermore, 1-ethyl-1H-pyrazol-5-amine (2k) was
ylbenzoxazole (1k) reacted with 6-amino-1,3-dimeth- also tested in this reaction. Unfortunately, when 3-
ylpyrimidine-2,4-dione (4a) under the optimal methyl-1-phenyl-1H-pyrazol-5-amine (2a) was applied
conditions to afford their corresponding products, 5ja as a substrate, the reaction mainly transformed towards
and 5ka, in 15% and 26% yields, respectively. Mean- the structure of bis-pyrazolopyridines instead of o-
while, methyl pyridines, such as 2-methyl pyridine amino diheteroaryl ketones. The distinctively different
(1m) and 4-methyl pyridine (1n) showed excellent behaviour of the above-mentioned substrates may have
reactivities as substrates, affording the desired prod- resulted from the low electron density on the amino-
ucts, 5ma and 5na, in good yields.
pyrazole ring when the 1-position was substituted by
Several o-amino diheteroaryl ketones were obtained an alkyl group, which reduced the ability of the second
under the I2/DMSO system (see Table 4). At the outset, molecule of the aminopyrazole substrate to attack the
2,6-dimethylquinoline and 1-methyl-1H-pyrazol-5- intermediate B (see Scheme 3).
amine were chosen as the model substrates and
To show the potential application of this synthetic
investigated under the optimal conditions. (see SI route, gram-scale reactions were conducted on the
optimization of the reaction conditions 2.) With 1- starting material 1a (5 mmol), with 2a and 4a under
methyl-1H-pyrazol-5-amine (2i), the reaction showed the standard conditions (see Table 5). To our delight,
broad substrate tolerance for the substituted 2-meth- the desired products, 3aa and 4aa, were obtained in
ylquinolines (e.g. 6-Me, 6-OMe, 6-OEt, 6-F, 6-Cl, 6- 67% (1.57 g) and 87% (1.87 g) yields, respectively
Br). These reactions proceeded successfully to produce (Table 4). These promising results present the possibil-
the corresponding products, 6bi-6gi, in good yields. ity for large-scale applications.
Similarly, when the substrate was changed to 1,3-
In order to obtain further insights into the reaction
dimethyl-1H-pyrazol-5-amine (2j), moderate to good mechanism, a series of control experiments were
yields of the products, 6aj–6gj, were obtained, conducted (Scheme 2). The conversion process of 2-
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Table 5. Scale-up of the reaction.[a,b]
me 2e). These results indicate that compounds 1aa and
1ab were the potential intermediates, while compound
6aa was an independent product in the oxidation
reaction.
Based on the aforementioned results, a plausible
mechanism for the oxidative domino cyclization was
proposed, as shown in Scheme 3. Initially, 2-methyl
quinoline (1a) was converted into the intermediate 2-
(iodomethyl)quinoline (1aa) with I2 via an iodination
reaction. Kornblum oxidation occurred subsequently in
the presence of DMSO to generate quinoline-2-
carbaldehyde (1ab), then the activated aldehyde group
of the quinoline-2-carbaldehyde (1ab) was attacked by
the C-nucleophilic center of 3-methyl-1-phenyl-1H-
pyrazol-5-amine (2a) to produce intermediate A. Since
intermediate B has a more stable conjugated structure
than intermediate A, the intermediate A would convert
to intermediate B after the loss of water. Furthermore,
intermediate A can also be oxidized by iodine or
DMSO to afford product 6aa. Intermediate B reacted
with another molecule of 2a to form intermediate C
via a Michael addition. Finally, intermediate C went
through a series of reactions, such as intramolecular
cyclization, deamination, and oxidative aromatization,
to afford the target product 3aa. Analogously, the
reaction between 2-methylquinoline (1a) and 6-amino-
1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4a) can be
explained with a similar mechanism (see SI).
[a] Reaction conditions: 1a (5 mmol, 1.0 equiv.), 2a or 4a
(11 mmol, 2.2 equiv.), I2 (7.5 mmol, 1.5 equiv.) in DMSO
°
(30 mL) at 130 C for 6 h.
[b] Isolated yields.
Scheme 2. Control experiments.
methylquinoline (1a) was initially explored under the
standard conditions. 2-(Iodomethyl)quinoline (1aa)
was obtained in 55% yield after the reaction proceeded
for 30 minutes, while quinolin-2-carboxaldehyde
(1ab) was obtained in 27% yield. With prolonged time
(after 4 hours), 2-(iodomethyl)quinoline (1aa) was
gradually converted to quinolin-2-carboxaldehyde
(1ab). Nevertheless, 2-(iodomethyl)quinoline (1aa)
and quinolin-2-carboxaldehyde (1ab) were not realized
in the absence of iodine (Scheme 2a). The reaction of
2-methylquinoline (1a) and 3-methyl-1-phenyl-1H-
pyrazol-5-amine (2a) did not proceed without molec-
ular iodine (Scheme 2b). Without and with iodine, 2-
(iodomethyl)quinoline (1aa) and quinolin-2-carboxal-
dehyde (1ab) each reacted with 5-aminopyrazole (2a)
to afford good yields of the desired product, 3aa
(Scheme 2c and 2d). Moreover, the product 6aa could
not react with 5-aminopyrazole (2a) to give the desired
product 3aa under the standard conditions (Sche-
Scheme 3. The plausible mechanism.
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°
was sealed and the resulting mixture was stirred at 130 C for
6 h under an air atmosphere. After the reaction was completed
(monitored by TLC), and added 50 mL water to the mixture,
then extracted with EtOAc 3 times (3×50 mL). The extract was
washed with 10% Na2S2O3 solution (w/w), dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel to yield the corresponding product 6ai as a yellow solid
(64% yield).
Conclusion
In summary, an iodine-promoted domino annulation
and oxidative carbonylation method was developed for
the synthesis of azaarene substituted dipyrazolo/diur-
acil-fused pyridines and o-amino diheteroaryl ketones
from easily available methyl azaarenes, 5-aminopyr-
azoles and 6-amino-pyrimidine-2,4-diones. This proto-
col is a simple and metal-free approach, that tolerates
high functional group and broad substrates scope, such
as methyl quinolines, methyl pyridines, 2-methyl
quinoxaline, 2-methyl benzothiazole, 2-methyl benzox-
azole and 2-methyl-4(3H)-quinazolinone. Moreover,
this transformation can be applied for the preparation
of dipyrazolo/diuracil-fused pyridines on a gram scale.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21702091), Science and Technology
Innovation Development Plan of Yantai (2020MSGY114) and
Yantai “Double Hundred Plan”. The authors also thank Talent
Induction Program for Youth Innovation Teams in Colleges and
Universities of Shandong Province.
Experimental Section
General Procedure for the Synthesis of Bis-Pyrazo-
lopyridines (3aa as an Example)
References
A 25 mL pressure vial was charged with 2-methylquinoline
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pyrazol-5-amine (2a) (114.3 mg, 0.66 mmol, 2.2 equiv.), I2
(114.2 mg, 0.45 mmol, 1.5 equiv.) and DMSO (3.0 mL). The
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°
vial was sealed and the resulting mixture was stirred at 120 C
for 6 h under an air atmosphere. After the reaction was
completed (monitored by TLC), and added 50 mL water to the
mixture, then extracted with EtOAc 3 times (3×50 mL). The
extract was washed with 10% Na2S2O3 solution (w/w), dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatog-
raphy on silica gel to yield the corresponding product 3aa as a
green solid (83% yield).
General Procedure for the Synthesis of Diuracilpyr-
idines (5aa as an Example)
A 25 mL pressure vial was charged with 2-methylquinoline
(1a) (43.0 mg, 0.30 mmol, 1.0 equiv.), 6-amino-1,3-dimeth-
ylpyrimidine-2,4(1H,3H)-dione (4a) (102.4 mg, 0.66 mmol,
2.2 equiv.), I2 (114.2 mg, 0.45 mmol, 1.5 equiv.) and DMSO
(3.0 mL). The vial was sealed and the resulting mixture was
°
stirred at 120 C for 6 h under an air atmosphere. After the
reaction was completed (monitored by TLC), and added 50 mL
water to the mixture, then extracted with EtOAc 3 times (3×
50 mL). The extract was washed with 10% Na2S2O3 solution
(w/w), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel to yield the corresponding product
5aa as a white solid (94% yield).
General Procedure for the Synthesis of o-Amino-
aromatic Ketones (6ai as an Example)
A 25 mL pressure vial was charged with 2-methylquinoline
(1a) (43.0 mg, 0.30 mmol, 1.0 equiv.), 3-methyl-1-phenyl-1H-
pyrazol-5-amine (2i) (52.4 mg, 0.54 mmol, 1.8 equiv.), I2
(137 mg, 0.54 mmol, 1.8 equiv.) and DMSO (3.0 mL). The vial
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UPDATES
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UPDATES
Iodine-Promoted Synthesis of Dipyrazolo/Diuracil-Fused
Pyridines and o-Amino Diheteroaryl ketones via Oxidative
Domino Annulation of 2/4-Methylazaarenes
Adv. Synth. Catal. 2021, 363, 1–8
X.-K. Zhang, X.-Y. Miao, H.-R. Jiang, F. Ge, J.-C. Sun, R.-Y.
Zhang, Q. Ouyang, W.-Y. Fan, Y.-P. Zthu*, Y.-Y. Sun*