Diiodine-Mediated Oxidative Reaction for the Construction of Imidazo[1,5- a ]pyridines under Metal-Free Conditions

Article abstract of DOI:10.1055/s-0039-1691587

An efficient and general protocol has been developed for preparing imidazo[1,5- a ]pyridines in moderate to excellent yields by an I ₂ -mediated sequential dual oxidative C(sp ³)-H amination of ethyl pyridin-2-ylacetates with benzylamines. The metal- and peroxide-free reaction involves oxidative dehydrogenation and two C-N couplings.

Full text of DOI:10.1055/s-0039-1691587

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
de
K. Su et al.
Letter
Synlett
Diiodine-Mediated Oxidative Reaction for the Construction of
Imidazo[1,5-a]pyridines under Metal-Free Conditions
Kexin Sua
Mingda Qina
Yongxin Chenb
Yafeng Liua
Yuan Tiana
Baohua Chen*a
R1
N
NH2
I2
R2
N
R1
+
N
CH2Cl2, 8 h
100 °C
metal-free
R2
0
0
0
0-0
0
0
1-6
4
4
6-4
1
0
1
peroxide-free
12 examples
up to 90% yield
no additives
a State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Gansu Lanzhou, 730000, P. R. of China
chenbh@lzu.edu.cn
b Key Laboratory of Petroleum Resources, Gansu Lanzhou,
730000, P. R. of China
chenyongxin@lzb.ac.cn
Received: 21.11.20219
Accepted after revision: 05.01.2020
Published online: 04.02.2019
pyridotriazoles with benzylamines and amino acids.7 Al-
though imidazo[1,5-a]pyridines are obtainable in good
yields by using these methods, the use of expensive transi-
tion metals restricts their application in organic synthesis
and in the pharmaceutical industries. Therefore, an effi-
cient and economical catalyst for the oxidative C(sp3)–H
amination/cyclization is urgently required.
DOI: 10.1055/s-0039-1691587; Art ID: st-2019-u0627-l
Abstract An efficient and general protocol has been developed for
preparing imidazo[1,5-a]pyridines in moderate to excellent yields by an
I2-mediated sequential dual oxidative C(sp3)–H amination of ethyl pyri-
din-2-ylacetates with benzylamines. The metal- and peroxide-free reac-
tion involves oxidative dehydrogenation and two C–N couplings.
Previous work
Key words imidazopyridines, metal-free synthesis, amination, benzyl-
ic amines, ethyl pyridinylacetates
R1
N
R1
N
[Rh2(esp)2]
(1 mol%)
O
+
a)
b)
N
H2N
R2
N
TsOH•H2O
(1 equiv)
N
R2
Nitrogen-containing heterocycles, which are widely
present in natural products, play a vital role in organic
chemistry.1 Imidazo[1,5-a]pyridines, as one of the most im-
portant groups of N-heterocyclic compounds, have attract-
ed much attention because of their prominent role in the
pharmaceutical, agrochemical, and materials industries.2
Furthermore, because of their photophysical properties,
imidazo[1,5-a]pyridines also have a range of prospective
uses in organic light-emitting diodes and organic thin-layer
field-effect transistors.3
Because of their excellent properties, considerable at-
tention has been paid to the synthesis of imidazo[1,5-
a]pyridines and their derivatives. However, the reported
methods typically involve conventional Vilsmeier-type cy-
clizations4 or transition-metal-catalyzed direct C–H amina-
tion/cyclization (Scheme 1).5 For instance, in 2014 Gevorg-
yan and co-workers published a protocol for accessing im-
idazo[1,5-a]pyridines through rhodium-catalyzed NH
insertions of pyridyl carbene intermediates (Scheme 1a).6
Later, Adimurthy and co-workers developed a copper-cata-
lyzed aerobic oxidative synthesis of imidazo[1,5-a]pyri-
dines through a denitrogenative transannulation reaction of
Ts
NH
N
I2 (20 mol%)
TBHP (2 equiv)
N
N
H
CH2Cl2, rt
N
N
+
NIS
TBHP
CO2R
N
R1
NH2
+
c)
d)
CO2R
DMA
N
R1
N
NH4I
(1 equiv)
CH3CN/H2O
(5:1)
CO2Et
N
N
R
NH2
+
CO2Et
Pt/Pt 15mA/cm2
N
N
N
R
rt
This work
N
R1
I2
NH2
R2
+
R1
CH2Cl2, 8 h
100 °C
R2
Scheme 1 Syntheses of imidazo[1,5-a]pyridines by direct C–H amination
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. Su et al.
Letter
Synlett
Some organic chemists have tried to replace transition
metals with other chemicals as catalysts for the oxidation.8
Kalita and Ahamed reported a I2–TBHP-catalyzed method
that affords 4,3-fused 1,2,4-triazoles in excellent yields
from azomethine imines and aromatic N-heterocycles
(Scheme 1b).9 This method requires a lower temperature,
but uses a hydroperoxide as oxidant. Wang and co-workers
reported a new protocol in which they prepared imid-
azo[1,5-a]pyridines in excellent yields by oxidation of ethyl
pyridin-2-ylacetate and benzylamine with N-iodosuccinim-
ide (NIS) and tert-butyl hydroperoxide (Scheme 1c).9,10 This
protocol gives excellent product yields, but the presence of
a hypervalent iodine(III) reagent and a hydroperoxide inev-
itably leads to waste, undesired side-reactions, and low
atom economy. When the hydroperoxide was replaced with
oxygen, the yield dropped drastically. Later, in 2019, Wang
and co-workers continued exploring this topic and reported
a tandem electrosynthesis of imidazo[1,5-a]quinolines me-
diated by NH4I in the absence of external chemical oxi-
dants.11 This method was metal- and hydroperoxide-free,
and electricity was used to promote a strong redox reac-
tion, maintaining excellent yields (Scheme 1d). However,
the use of electricity also led to the need for complex reac-
tors. Encouraged by these precedents, we have developed
an I2-mediated metal- and hydroperoxide-free oxidative
C(sp3)–H amination/cyclization of ethyl pyridin-2-ylace-
tates and benzylamines to give imidazo[1,5-a]pyridines.
Initially, we examined the model reaction of 0.2 mmol
of ethyl pyridin-2-ylacetate (1a) with 1.1 equivalents of
benzylamine (2a) in the presence of 1.0 equivalent of diio-
dine as the oxidant. When the mixture was stirred in CH2Cl2
(2 mL) under air at 100 ℃ for eight hours, the desired ethyl
3-phenylimidazo[1,5-a]pyridine-1-carboxylate (3aa) was
obtained in 72% isolated yield (Table 1, entry 1). We then
assessed the effect of iodine on this reaction; none of the
desired product 3aa was detected in the absence of iodine,
indicating that iodine is essential for this reaction (entry 2).
In addition, we tested various other solvents (DMF, DMSO,
1,4-dioxane, toluene), but found that CH2Cl2 gave the best
yield of 3aa (Table 1, entries 3–6). We then examined the
effects of various additives (PivOH, AcOH, TFA, Cs2CO3, Et3N,
and NaOAc) and found that either the yield of 3aa was not
markedly improved or that none of the desired product was
detected (entries 7–12). We also examined the effect of the
temperature on this reaction and found that a temperature
of 100 ℃ gave better results than did 60 ℃ or 80 ℃ (entries
13 and 14). Therefore the optimal conditions for this reac-
tion were 1a (0.2 mmol), 2a (1.1 equiv), and I2 (1.0 equiv) in
CH2Cl2 (2 mL) under air in 100 ℃.
Table 1 Optimization of the Reaction Conditionsa
N
conditions
NH2
CO2Et
+
CO2Et
N
N
1a
2a
3aa
Entry
Oxidant
Additive
Solvent
Temp (°C)
Yieldb (%)
1
2
I2
–
–
CH2Cl2
CH2Cl2
DMF
80
80
80
80
80
80
80
80
80
80
80
80
60
100
72
–
NDc
65
3
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
–
4
–
DMSO
1,4-dioxane
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ND
ND
ND
70
5
–
6
–
7
PivOH
AcOH
TFA
Cs2CO3
Et3N
NaOAc
–
8
65
9
30
10
11
12
13
14
27
36
ND
62
–
88
a Reaction conditions: 1a (0.2 mmol), 2a (1.1 equiv), I2 (0.2 mmol), CH2Cl2
(2 mL), 100 °C, in air.
b Isolated yield.
c ND = not detected.
smoothly to give the corresponding products 3ab–aj in
modest to excellent yields. No steric hindrance was ob-
served in the reaction; for example, 4-methylbenzylamine
gave the product 3ad in a similar yield to those of products
3ab and 3ac obtained from benzylamines 1 bearing o- or
m-methyl groups, respectively. Furan-2-amine was also tol-
erated, giving the desired product 3ak in moderate yield.
The scope of pyridyl ester derivatives in this reaction was
also investigated under the optimal conditions, and 1 (R1 =
CO2Me) gave product 3ba in excellent yield; however, 1 (R1
= CN) failed to give any of the desired product 3ca.
To gain insight into the mechanism, we carried out sev-
eral control experiments. The reaction was not restrained
in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT)
(Scheme 3a), suggesting that the reaction might not pro-
ceed by a radical pathway. When the reaction was conduct-
ed under N2 instead of air, 3aa was isolated in 44% yield
(Scheme 3b). It was therefore apparent that HI is oxidized
by O2 to complete the catalytic cycle of I2.
Having determined the optimal reaction conditions, we
investigated the substrate scope of the ethyl pyridin-2-ylac-
etate 1 and benzylamine 2 in this reaction (Scheme 2). Vari-
ous substituents on the aromatic ring of the benzylamine
were well tolerated; benzylamines bearing electron-donat-
ing groups or electron-withdrawing groups both reacted
On the basis of the experiments described above and
previous reports in the literature,12 a plausible mechanism
is proposed (Scheme 4). Ethyl pyridin-2-ylacetate (1a) is
first iodinated.13 Then, a nucleophilic attack of intermediate
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
K. Su et al.
Letter
Synlett
R1
N
I2
NH2
+
R2
N
R1
CH2Cl2, 8 h
100 °C
N
R2
1
3
2
CO2Et
N
CO2Et
N
CO2Et
CO2Et
N
N
N
CO2Et
N
CO2Et
N
N
N
N
N
N
OCH3
H3CO
3aa, 88%
3ab, 80%
3ac, 78%
3ad, 83%
3ae, 58%
3af, 62%
CO2Et
N
CO2Et
N
N
CO2Et
N
CO2Et
CO2Me
N
N
CO2Et
N
N
CN
N
N
N
N
N
N
O
F
F
Br
Cl
3ag, 55%
3ah, 65%
3ai, 68%
3aj, 54%
3ak, 58%
3ba, 90%
3ca, ND
Scheme 2 I2-mediated one-pot synthesis of arylimidazo[1,5-a]pyridines. Reagents and conditions: 1 (0.2 mmol), 2 (0.22 mmol), I2 (0.2 mmol), CH2Cl2
(2 mL), 100 °C, 8 h. Isolated yields are reported. ND = not detected.
A with benzylamine (2a) occurs with elimination of HI to
give intermediate B, which is transformed into intermedi-
ate C by a second iodination. Intermediate C undergoes de-
Funding Information
hydroiodination to give intermediate D, which undergoes a
Financial support for this study from the Key Laboratory Project of
third iodination and deiodination to form carbocation F.
This cyclizes by intramolecular nucleophilic addition to
give intermediate G.6 Finally, intermediate G undergoes de-
hydrogenation to give the desired product 3aa.14
Gansu Province (Grant No. 1309RTSA041).()
O2
I2
In summary, we have developed a unique protocol for
the synthesis of imidazo[1,5-a]pyridines in moderate to ex-
cellent yields.15 This strategy avoids the need for expensive
transition metals by using I2 as an oxidant, and efficiently
gives imidazo[1,5-a]pyridines from ethyl pyridin-2-ylace-
tates and benzylamines, without the use of extra additives.
The reaction is therefore sufficiently valuable to induce us
to explore it in more depth.
HI
Ph
NH2
CO2Et
2a
CO2Et
N
N
CO2Et
NH
HI
N
I
B
A
1a
Ph
I2
I
CO2Et
CO2Et
CO2Et
N
I
N
N
I2
N
N
NH
– HI
standard conditions
C
Ph
Ph
a)
Ph
Ph
NH2
CO2Et
CO2Et
+
N
N
D
E
radical inhibitors
N
2a
1a
(1.0 equiv)
Ph
3aa
I–
TEMPO
BHT
85%
81%
CO2Et
Ph
+
N
CO2Et
N
CO2Et
N
– H+
Ph
I2
N
N
N
b)
H
Ph
NH2
CO2Et
+
Ph
3aa
N
CH2Cl2,
N2, 100 °C, 8 h
2a
F
1a
44%
G
3aa
Scheme 3 Control experiments for mechanistic studies
Scheme 4 Plausible reaction mechanism
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
K. Su et al.
Letter
Synlett
Supporting Information
(8) (a) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2011,
133, 16382. (b) Souto, J. A.; Zian, D.; Muñiz, K. J. Am. Chem. Soc.
2012, 134, 7242. (c) Armstrong, A.; Collins, J. C. Angew. Chem.
Int. Ed. 2010, 49, 2282. (d) Pan, J.; Su, M.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2011, 50, 8647. (e) He, G.; Zhao, Y.; Zhang, S.; Lu,
C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (f) Nadres, E. T.;
Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691587.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
References and Notes
(9) Inturi, S. B.; Kalita, B.; Ahamed, A. J. Org. Biomol. Chem. 2016, 14,
11061.
(10) (a) Yan, Y.; Zhang, Y.; Zha, Z.; Wang, Z. Org. Lett. 2013, 15, 2274.
(b) Yan, Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang, Z. Angew. Chem.
Int. Ed. 2012, 51, 8077.
(1) (a) Chen, C.-Y.; Hu, W.-P.; Yan, P.-C.; Senadi, G.-C.; Wang, J.-J.
Org. Lett. 2013, 15, 6116. (b) Wang, H.; Wang, Y.; Peng, C.;
Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217.
(c) Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.;
Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453. (d) Wu, X. F.;
Neumann, H.; Beller, M. Chsem. Rev. 2013, 113, 1. (e) Vitaku, E.;
Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257.
(2) (a) Kim, D.; Wang, L.; Hale, J. J.; Lynch, C. L.; Budhu, R. J.;
MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino,
J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R.
C.; Carver, G.; Carella, A.; Henry, K.; Lineberger, J.; Schleif, W. A.;
Emini, E. A. Bioorg. Med. Chem. Lett. 2005, 15, 2129. (b) Alcarazo,
M.; Roseblade, S. J.; Cowley, A. R.; Fernández, R.; Brown, J. M.;
Lassaletta, J. M. J. Am. Chem. Soc. 2005, 127, 3290.
(3) (a) Hutt, J. T.; Jo, J.; Olasz, A.; Chen, C.-H.; Lee, D.; Aron, Z. D. Org.
Lett. 2012, 14, 3162. (b) Weber, M. D.; Garino, C.; Volpi, G.;
Casamassa, E.; Milanesio, M.; Barolo, C.; Costa, R. D. Dalton
Trans. 2016, 45, 8984. (c) Salassa, L.; Garino, C.; Albertino, A.;
Volpi, G.; Nervi, C.; Gobetto, R.; Hardcastle, K. I. Organometallics
2008, 27, 1427.
(4) (a) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett.
2006, 8, 5621. (b) Pelletier, G.; Charette, A. B. Org. Lett. 2013, 15,
2290. (c) Mphahlele, M. J.; Mmonwa, M. M. Org. Biomol. Chem.
2019, 17, 2204. (d) Sandoval, C.; Lim, N.-K.; Zhang, H. Org. Lett.
2018, 20, 1252.
(5) (a) Helan, V.; Gulevich, A. V.; Gevorgyan, V. Chem. Sci. 2015, 6,
1928. (b) Yang, Y.; Zhou, M.-B.; Ouyang, X.-H.; Pi, R.; Song, R.-J.;
Li, J.-H. Angew. Chem. Int. Ed. 2015, 54, 6595. (c) Wang, Y.; Lei,
X.; Tang, Y. Chem. Commun. 2015, 51, 4507. (d) Joshi, A.; Mohan,
D. C.; Adimurthy, S. J. Org. Chem. 2016, 81, 9461. (e) Gulevich, A.
V.; Gevorgyan, V. Angew. Chem. Int. Ed. 2013, 52, 1371. (f) Lei, X.;
Li, L.; He, Y.-P.; Tang, Y. Org. Lett. 2015, 17, 5224. (g) Miura, T.;
Tanaka, T.; Matsumoto, K.; Murakami, M. Chem. Eur. J. 2014, 20,
16078. (h) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117,
9247. (i) Li, M.; Xie, Y.; Ye, Y.; Zou, Y.; Jiang, H.; Zeng, W. Org.
Lett. 2014, 16, 6232.
(11) Qian, P.; Yan, Z.; Zhou, Z.; Hu, K.; Wang, J.; Li, Z.; Zha, Z.; Wang,
Z. J. Org. Chem. 2019, 84, 3148.
(12) (a) Song, L.; Tian, X.; Lv, Z.; Li, E.; Wu, J.; Liu, Y.; Yu, W.; Chang, J.
J. Org. Chem. 2015, 80, 7219. (b) Zhang, X.; Wang, P.; Yuan, X.;
Qin, M.; Chen, B. Asian J. Org. Chem. 2019, 8, 1332. (c) Wang, P.;
Zhang, X.; Liu, Y.; Chen, B. Asian J. Org. Chem. 2019, 8, 1122.
(d) Wang, Q.; Zhang, S.; Guo, F.; Zhang, B.; Hu, P.; Wang, Z. J. Org.
Chem. 2012, 77, 11161. (e) Wu, Y.-D.; Geng, X.; Gao, Q.; Zhang, J.;
Wu, X.; Wu, A.-X. Org. Chem. Front. 2016, 3, 1430. (f) Liu, X.;
Wang, D.; Chen, Y.; Tang, D.; Chen, B. Adv. Synth. Catal. 2013,
355, 2798.
(13) (a) Qin, M.; Tian, Y.; Guo, X.; Yuan, X.; Yang, X.; Chen, B. Asian J.
Org. Chem. 2018, 7, 1591. (b) Sheng, J.; Liu, J.; Zhao, H.; Zheng,
L.; Wei, X. Org. Biomol. Chem. 2018, 16, 5570. (c) Lamani, M.;
Prabhu, K. R. J. Org. Chem. 2011, 76, 7938; corrigendum: J. Org.
Chem. 2011, 76, 9552. (d) Tang, S.; Liu, K.; Long, Y.; Gao, X.; Gao,
M.; Lei, A. Org. Lett. 2015, 17, 2404. (e) Wu, X.; Gao, Q.; Liu, S.;
Wu, A. Org. Lett. 2014, 16, 2888. (f) Chen, Z.; Li, H.; Dong, W.;
Miao, M.; Ren, H. Org. Lett. 2016, 18, 1334.
(14) (a) Arai, T.; Yokoyama, N. Angew. Chem. Int. Ed. 2008, 47, 4989.
(b) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008,
130, 416. (c) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008,
10, 889.
(15) Ethyl 3-Phenylimidazo[1,5-a]pyridine-1-carboxylate (3aa);
Typical Procedure
A 10-mL Schlenk tube was charged with 1a (0.2 mmol), 2a (1.1
equiv, 0.22 mmol), and I2 (1 equiv, 0.2 mmol). CH2Cl2 (2 mL) was
then added and the mixture was stirred at 100 ℃ for 8 h under
air. The solvent was removed, and the mixture was filtered and
evaporated under vacuum. The residue was purified by column
chromatography [silica gel, EtOAc–PE (10:1)] to give a white
solid; yield: 88%; mp 127–130 °C.
(6) Shi, Y.; Gulevich, A. V.; Gevorgyan, V. Angew. Chem. Int. Ed. 2014,
53, 14191.
(7) (a) Mohan, D. C.; Rao, S. N.; Ravi, C.; Adimurthy, S. Org. Biomol.
Chem. 2015, 13, 5602. (b) Joshi, A.; Mohan, D. C.; Adimurthy, S.
Org. Lett. 2016, 18, 464.
1H NMR (300 MHz, CDCl3):  = 8.28 (dd, J = 16.6, 8.2 Hz, 2 H),
7.79 (d, J = 6.6 Hz, 2 H), 7.57–7.46 (m, 3 H), 7.13 (dd, J = 8.9, 6.7
Hz, 1 H), 6.78 (t, J = 6.8 Hz, 1 H), 4.50 (q, J = 7.1 Hz, 2 H), 1.47 (t,
J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3):  = 163.8, 139.4,
135.6, 129.8, 129.3, 129.2, 129.0, 124.5, 122.7, 121.9, 120.2,
114.7, 60.6, 14.9.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D