Oxidative C(sp3)-H functionalization of methyl-azaheteroarenes: a facile route to 1,2,4-triazolo[4,3-a]pyridines

Article abstract of DOI:10.1039/c9ob00033j

We herein describe an oxidative [4 + 1] annulation used to prepare 1,2,4-triazolo[4,3-a]pyridines in the presence of I₂-DMSO. This protocol enables synthesis of triazolo[4,3-a]pyridine-quinoline linked diheterocycles via a direct oxidative functionalization of sp³ C-H bonds of 2-methyl-azaheteroarenes. The reaction shows a wide substrate scope and good functional group tolerance.

Full text of DOI:10.1039/c9ob00033j

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Takeharu Haino et al.
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DOI: 10.1039/C9OB00033J
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COMMUNICATION
Oxidative C(sp3)–H functionalization of methyl-azaheteroarenes:
a facile route to 1,2,4-triazolo[4,3-a]pyridines
Received 00th January 20xx,
Accepted 00th January 20xx
Wei-Zhao Weng,‡a Yin-He Gao,‡a Xue Zhang,‡a Yan-Hua Liu,‡a Ying-Jie Shen,‡a Yan-Ping Zhu,*a
Yuan-Yuan Sun,a Qing-Guo Menga and An-Xin Wu*b
DOI: 10.1039/x0xx00000x
www.rsc.org/
We herein describe an oxidative [4+1] annulation to prepare 1,2,4- anticonvulsant, antibacterial and antiproliferative.[11] Giving
triazolo[4,3-a]pyridines in the presence of I2-DMSO. This protocol their biological and pharmaceutical activities, extensive
enables to triazolo[4,3-a]pyridine and quinoline linked synthetic protocols have been reported for triazolopyridine
diheterocycles via a direct oxidative functionalization of sp3 C-H synthesis.
bond of 2-methyl-azaheteroarenes. The reaction shows a wide
The classical approach is coupling of aldehydes/carboxylic
substrate scope and good functional group tolerance for acids with 2-hydrazinylpyridines or hydrazones/acylhydrazine
substrates.
with 2-halo pyridines via multi-step manner, usually with
strong acids, high temperatures and transition metal catalysts
(Figure 1a).[12] As an alternative, the annulation of 2-
hydrazinylpyridines and isothiocyanates with TBAF or iodine is
a facile protocol, which can efficiently afford 3-amino-[1,2,4]-
triazolo pyridines in good yields with excellent substrate
tolerance (Figure 1b).[13] In 2016, Siddaiah and co-workers
disclosed a convenient and efficient protocol for carbonylation
of aryl iodides and 2-hydrazinylpyridines with molybdenum
hexacarbonyl to access [1,2,4]triazolo[4,3-a]pyridines in
excellent yields without CO gas and palladium catalyst (Figure
1c).[14] Multiform substrates coupling domino reaction is an
efficient strategy, which was widely utilized in organic
synthesis.[15] Very recently, Subba Reddy and co-workers also
developed a graceful multiform substrates approach for 1,2,4-
triazolo[4,3-a]pyridines synthesis in the presence of iodine/IBX
and DMSO from aryl methyl ketones, ethyl benzoylacetate,
styrenes, phenylacetylenes and 2-hydrazinylpyridines
In recent years, the direct oxidative functionalization of C-H
bond has drawn considerable attention from chemical
community and industries.[1] It has become one of the most
significant and powerful synthetic tools for C-C and
C−heteroatom bonds construction. Despite the significant
development, the oxidative functionalization of sp3 C–H bond
still has many challenges. [2] The combination of metal catalysts
with dioxygen or peroxide, such as copper or iron/O2,[3]
cobalt/O2[4]and copper/peroxide,[5] is a good catalytic system
for direct oxidative functionalization of sp3 C–H bond. Another
efficient approach is using iodine reagents and S8 with oxidant,
such as I2-DMSO,[6] iodine reagents/peroxide,[7] hypervalent
iodine/azide[8] and S8/oxidant[9]. However, these systems
usually were restrained to special substrates (e.g. aryl methyl
ketones and symmetric alkanes). Thus, developing efficient
method for oxidative functionalization of diversity sp3 C-H
bond is still challenging and also very desirable.
Triazolopyridines are important heterocycles which are
widely present in natural products, synthetic drugs and
materials.[10] Many triazolopyridines show significant biological
activities and pharmaceutical activities, including antifungal,
(a) Classical approachs
O
(d) Multiform substrates approach
O
Ar
Ar
X
N
I2/DMSO
N
NHNH2
Ar
X= H or OH
O
N
N
O
CO2Et
N
Ar
N
NHNH2
Ar
N
X
Ar
NHNH2
N
N
Subba's work
OH
COAr
I2/IBX/DMSO
(b) Coupling of thiosemicarbazides with 2-hydrazinylpyridines
N
Ar
Ar
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, P. R. China.
NCS
N
Ar
N
N
NHNH2
NHAr
(e) This work
N
N
N
NHNH2
(c) Three components condensation
Co(CO)8
I2-DMSO
N
E-mail: chemzyp@foxmail.com
N
N
N
I
N
CH3
b. Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Hubei, Wuhan, 430079, P. R. China.
E-mail: chwuax@mail.ccnu.edu.cn
Ar
N
N
NHNH2
Ar
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
‡ These authors contributed equally to this work.
Figure 1. The protocols for 1,2,4-triazolo[4,3-a]pyridines
synthesis
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Table 1. Optimization of the reaction conditions for the preparation
of 3aa.
N
N
H
N
View Article Online
N
DOI: 1N0.1039/C9ORB00033J
I2 (1.5 equiv.)
DMSO, 110 o
NH2
R
N
C
N
N
2a
1
H
3
N
N
Conditions
N
NH2
N
OMe
N
N
N
OEt
N
N
N
N
Me
N
N
N
N
N
N
N
N
N
N
N
1a
2a
3a
3aa:
3ba:
3ca:
3da:
72%
71%
65%
73%
75%
67%
Cl
N
Br
N
N
Temp.
(oC)
N
F
N
N
N
Cl
N
N
N
N
N
Yield (%)b
N
N
Entry
I2 (equiv)
Base
N
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15c
16d
17 e
18 f
1.0
1.5
2.0
0.8
0.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0
-
100
100
100
100
100
110
120
90
58
65
62
48
35
71
60
54
20
68
69
40
15
0
3ea:
3fa:
3ga:
3ha:
70%
61%
82%
F
N
N
N
N
N
S
N
N
N
N
N
N
N
N
N
N
N
N
3ia:
3ja:
3ka:
3la:
64%
57%
46%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
70
a
3na:
n.r.
3oa:
3pa:
25%
n.r.
3ma:
64%
Na2CO3
K2CO3
Cs2CO3
KOH
110
110
110
110
110
110
110
110
110
N
N
N
N
N
N
N
N
N
N
N
N
3qa:
n.r.
3ra:
n.r.
3sa:
n.r.
Scheme 1. Scope of substituted methyl quinolines and derivatives.
Reaction conditions: 1 (0.5 mmol), I2 (0.75 mmol) in DMSO (3 mL) at
110 C for 4-6 h, then added 2a (0.6 mmol) and stirred at 110 C
until the disappearance of Isolated yields provided. n.r. = no
reaction. a The reaction was performed for 48 hours.
1.5
1.5
1.5
1.5
-
-
-
-
Trace
0
0
o
o
0
a
Reaction conditions: 2-methyl quinoline 1a (0.5 mmol), 2-
hydrazinylpyridine 2a (0.6 mmol ) and I2 were heated in DMSO
binding agent would probably improve the yield. Next, a series
of base such as Na2CO3, K2CO3, Cs2CO3 and KOH, were
screened for the reaction. The base Na2CO3 and K2CO3 did not
show an influence for the yield. But the yield was significantly
decreased when Cs2CO3 and KOH were added. In addition, a
blank experiment was conducted without any iodine, the
reaction did not give the desired product. This result indicated
that iodine is essential for this transformation. Reaction
solvents were also investigated. The reaction can not perform
in other solvents, such as MeOH, Dioxane, MeCN and toluene.
With the optimized conditions in hand, we firstly investigated the
scope of substituted substituted methyl quinolines and methyl
azaheterocycles (Scheme 1). The results showed that various
substituted methyl quinolines and derivatives 2 were tolerant in the
reaction. For example, the aryl rings of 2- methyl quinolines bearing
electron-rich substituents (e.g. 6-Me, 6-OMe, 6-OEt) did not affect
the reaction efficiency, the desired products 3ba-3da could be
obtained in 73%, 75% and 72% yields, respectively. While the aryl
rings were substituted with halogen atoms (e.g., 6-Cl, 7-Cl, 6-Br, 6-F,
7-F), the reactions could proceed smoothly to give the
corresponding products 3ea–3ia in moderate to good yields, which
could be used for further transformations. Moreover, two
heteroatoms containing substrates 2-methylquinoxaline 1k and 2-
methylbenzo[d]thiazole 1l were also suitable for this reaction,
affording the corresponding products 3ka and 3la in 57% and 46%
yields, respectively. It is noteworthy that 4-methyl quinoline 1m
was also tolerant for this reaction to generate the desired product
3ma (64% yield). Unfortunately, 3-methyl quinoline 1n and 8-
methyl quinoline 1o did not work under the standard conditions. In
addition, 2-picoline could proceed this reaction to afford the
(3 mL). Isolated yields. MeOH instead of DMSO, d) Dioxane
instead of DMSO, MeCN instead of DMSO, Toluene instead
of DMSO.
b
c
e
f
(Figure 1d).[16] This reaction can efficiently afford the products
in good yields from diversity substrates via different pathways.
Although many useful methods have been reported, the
protocol for direct oxidative functionalization of sp3 C-H bond
of methyl group to construct 1,2,4-triazolo[4,3-a]pyridines is
still very limited. In addition, the development of a one-pot
and metal-free protocol to triazolo[4,3-a]pyridines containing
diheterocycles remains very desirable. Herein, we report an
efficient direct oxidative functionalization of sp3 C-H bond of
methyl-azaheteroarenes to triazolo[4,3-a]pyridines in the
presence of I2-DMSO under mild conditions.
Initially, we evaluated various reaction conditions using 2-
methyl quinoline (1a) and 2-hydrazinylpyridine (2a) as model
substrates (Table 1). Gratifyingly, the reaction of 1a with 2a
performed smoothly with 1.0 equivalent of iodine at 100 oC to
afford the product 3aa in 58% yield. When increasing the
amount of iodine to 1.5 and 2.0 equivalents, the reaction yield
was increased to 65% and 62%, respectively. However, the
yield was significantly decreased when the amount of iodine
reduced to 0.8 and 0.5 equivalent. Subsequently, we
investigated the influence of temperature to the reaction, the
results showed that the reaction worked fine at 110 oC. High or
low temperature would lead low yield. Because acid HI would
generate from I2 and DMSO in this reaction. Base as acid
2 | J. Name., 2012, 00, 1-3
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N
N
H
N
R
View Article Online
DOI: 10.1039/C9OB00033J
I2 (1.5 equiv.)
DMSO, 110 o
N
NH2
R
Conditions
DMSO, 110 o
N
C
N
N
I
(a)
C
N
N
N
CHO
2a
1
3
4a
5a
1a
Cl
4a
standard conditions, without I2: : not detected
N
N
N
N
N
standard conditions:
N
N
N
N
N
N
N
N
N
N
Cl
4a
5a
50 mins, : 38% yield, : 52%
: 86% yield, : not detected
Br
N
N
Br
N
4a 5a
4 h,
N
Cl
N
H
N
N
N
(b)
(c)
N
N
Standard
conditions
NH2
3ab:
62%
3ac:
65%
3ad:
69%
3ae:
3af:
61%
71%
I
N
F
Me
N
CF3
N
N
N
N
N
N
N
N
N
N
N
2a
1
N
N
3aa
N
: 67% yield
N
F3
C
Br
N
N
N
CF3
N
N
H
N
N
N
N
N
Conditions
DMSO, 110 o
NH2
C
3ag:
69%
3ai:
N
59%
3ah:
3aj:
61%
64%
3ak:
Me
57%
N
CHO
N
N
N
N
N
N
N
2a
1
N
N
N
N
N
N
3aa
Standard conditions:
: 87% yield
N
Me
O2
N
N
Br
3aa:
without I2:
not observed
N
N
Me
Me
Scheme 3. Control experiments.
N
N
N
a
3mg:
50%
3mn:
46%
Me
3mm:
3bl:
52%
41%
3am:
48%
H
N
NH2
N
N
N
N
DMS + HI
DMSO
I
N
N
I2
HI
N
2a
N
N
N
N
1a
N
N
N
N
N
Br
Br
N
N
N
CHO
N
Br
N
N
Br
I
I
H
1aa
1ab
N
1ac
H
N
N
1a'
Br
Br
3ge:
65%
3me:
3mf:
59%
63%
3gf:
71%
I2
N
N
N
N
N
H
N
N
Scheme 2. Scope of substituted 2-hydrazinylpyridine
and
N
N
-HI
HN
N
N
I
methylquinolines. Reaction conditions: 1 (0.5 mmol), I2 (0.75 mmol)
1ad
3aa
1ae
o
in DMSO (3 mL) at 110 C for 4-6 h, then added 2 (0.6 mmol) and
Scheme 4. A plausible reaction mechanism for the preparation of
1,2,4-triazolo[4,3-a]pyridines.
products 3me and 3mf in 59% and 63% yields, respectively.
To gain insight into the reaction mechanism, some control
experiments were performed (Scheme 3). When 2-
methylquinoline performed the reaction under standard
o
stirred at 110 C until the disappearance of 2a (monitored by TLC).
a
Isolated yields provided.
2-hydrazineyl-5-methylpyridine
hydrochloride (1.2 eqquiv.) and K2CO3 (2.0 equiv.) were used for
this reaction.
desired product 3pa in 25% yield. However, substrates 4-picoline,
2,6-dimethyl pyridine and 2,4,6-trimethyl pyridine could not
perform this reaction.
conditions for
4 hours without 2-hydrazinylpyridine, it
absolutely transferred to quinolin-2-carboxaldehyde in 86%
isolated yield, whereas this reaction could not proceed without
I2 (Scheme 3a). If the reaction of 2-methylquinoline with iodine
performed at 110 oC in DMSO for only 50 mins, 2-
(iodomethyl)quinoline and quinolin-2-carboxaldehyde could
be detected in 52% and 38% yields, respectively. The above
results indicate that 2-(iodomethyl)quinoline and quinolin-2-
carboxaldehyde are the potential intermediates in the reaction,
and I2 is very essential for this transformation. Giving the
potential intermediate of 2-(iodomethyl)quinoline, the
reactions of 2-methylquinoline with iodine were conducted in
MeOH, Dioxane, MeCN and Toluene. Interestingly, 2-
(iodomethyl)quinoline could be observed, and quinoline-2-
carbaldehyde was not detected in these reactions (See SI). 2-
Encouraged by the achieved results, we turned our attention to
the scope of 2-hydrazinylpyridines (Scheme 2). Agreeably, a variety
of substituted 2-hydrazinylpyridines were suitable for this reaction
to afford the corresponding products. For example, 2-
hydrazinylpyridines substituted with halogen atoms (e.g. 3-Cl, 5-Cl,
6-Cl, 5-Br, 6-Br, 2-Me-5-Br, 3-F) were tolerant for the reaction,
affording the corresponding products 3ab-3ah in 61-71% yields.
Moreover, the strong electron-withdrawing group CF3 attached 2-
hydrazinylpyridines 2i-2k (3-CF3, 5-CF3, 6-CF3) could also proceed
the reaction smoothly to give products 3ai-3ak in 57-61% yields. 2-
Hydrazinyl-5-nitropyridine 2l was also tolerant. However, the
reaction yield was significantly decreased (41%). Moreover,
electron-donating groups attached 2-hydrazinylpyridines were also
investigated. 5-Bromo-2-hydrazineyl-3-methylpyridine 2g, 2-
hydrazineyl-6-methylpyridine
2m
and
2-hydrazineyl-5-
(Iodomethyl)quinoline
was
also
reacted
with
2-
methylpyridine 2n could coupling with 2-methyl quinoline and 4-
methyl quinoline to afford the corresponding products (3ag, 3mg,
3am, 3mm and 3mn) in moderate yields. Both 2-hydrazinylpyridines
and 2-methyl quinolines attached with bromo atoms were also
tolerant to afford 3ge and 3gf (65% and 71%), which could be used
for further functionalization. In addition, 4-methyl quinoline 1m
would also coupling with 5-bromo-2-hydrazinylpyridine 2e and 6-
bromo-2-hydrazinylpyridine 3f to deliver the corresponding
hydrazinylpyridine under standard conditions, the desired
product 3aa was obtained in 67% yield (Scheme 3b).
Subsequently, the reaction of quinolin-2-carboxaldehyde with
2-hydrazinylpyridine was conducted under standard conditions,
the product 3aa could be generated in excellent yield (Scheme
3c). However, the reaction could not give the desired product
without
I2.
These
results
uncovered
that
2-
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2
3
(a) R. Vanjari and K. N. Singh, Chem. Soc. Rev., 2V0ie1w5,Ar4tic4le, 8O0nl6in2e;
(b) J. Xie, C. Pan, A. Abdukader and CD. OZhI:u10, .C10h3e9m/C.9SOoBc0.0R0e3v3.J,
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(iodomethyl)quinoline and quinolin-2-carboxaldehyde are the
potential intermediates, I2 may play an important role in the
condensation step of quinolin-2-carboxaldehyde with 2-
hydrazinylpyridine.
On the basis of the above results and previous reports,[17]
a
plausible reaction mechanism was proposed in scheme 4.
Since the substrate 1a exists the equilibrium between 2-
methylpyridine 1a and its enamine counterpart 1a‘ bearing an
exocyclic double bond. Initial, enamine counterpart
1a‘ undergoes an iodination reaction with I2 to afford the
intermediate 2-(iodomethyl)quinoline (1aa), which is further
oxidized to quinolin-2-carboxaldehyde 1ab by a subsequent
Kornblum oxidation with DMSO. Subsequently, quinolin-2-
carboxaldehyde 1ab undergoes condensation and annulation
with 2-hydrazinylpyridine to generate intermediate 1ad.
Finally, intermediate 1ad performs oxidation and
aromatization process in the presence of I2 to finish the end
product 3aa.
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4
5
Conclusions
In summary, We have developed an oxidative [4+1] annulation
to prepare 1,2,4-triazolo[4,3-a]pyridines in the presence of I2-
DMSO. This protocol enabled to triazolo[4,3-a]pyridine and
quinoline linked diheterocycles via the direct oxidative
functionalization of sp3 C-H bond of methyl-azaheteroarenes
without any metal catalyst. The reaction underwent
a
sequential iodination, Kornblum oxidation, condensation,
oxidation and aromatization process. Mechanism investigation
uncovered that 2-(iodomethyl)quinoline and quinolin-2-
carboxaldehyde were the potential intermediates. The
reaction showed a wide substrate scope and good functional
group tolerance for methyl-azaheteroarenes and 2-
hydrazinylpyridine derivatives.
6
Conflicts of interest
There are no conflicts to declare
Acknowledgements
7
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This work was supported by the National Natural Science
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Key Research & Development Project of Shandong Province
(2018GGX109014). This work was also supported by Yantai
“Double Hundred Plan”. The National College Students
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