One-pot regiospecific synthesis of imidazo[1,2-A ]pyridines: A novel, metal-free, three-component reaction for the formation of C-N, C-O, and C-S Bonds

Article abstract of DOI:10.1021/ol4031414

A novel transition-metal-free three-component reaction for the construction of imidazo[1,2-a]pyridines has been developed. It represents a facile approach for the formation of C-N, C-O, and C-S bonds from ynals, pyridin-2-amines, and alcohols or thiols.

Full text of DOI:10.1021/ol4031414

Letter
pubs.acs.org/OrgLett
One-Pot Regiospecific Synthesis of Imidazo[1,2‑a]pyridines: A Novel,
Metal-Free, Three-Component Reaction for the Formation of C−N,
C−O, and C−S Bonds
Hua Cao,*,† Xiaohang Liu,‡ Limin Zhao,† Jinghe Cen,† Jingxin Lin,† Qiuxia Zhu,† and Minling Fu†
†School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P.R. of China
‡BASF Catalyst, 23800 Mercantile Road, Beachwood, Ohio 44124, United States
S
* Supporting Information
ABSTRACT: A novel transition-metal-free three-component
reaction for the construction of imidazo[1,2-a]pyridines has
been developed. It represents a facile approach for the
formation of C−N, C−O, and C−S bonds from ynals,
pyridin-2-amines, and alcohols or thiols.
he imidazo[1,2-a]pyridines are an important target in
adding catalysts. As shown in Table 1, the reaction could be
catalyzed by AcOH (entry 10). But, the product 4a was formed
with low yield or not detected in the presence of DABCO,
DBU, THT, PPh3, K2CO3, Na2CO3, NaHCO3, or L-proline
(entries 2−9, 11). Lewis acids, such as ZnCl2, FeCl3, and AlCl3,
were also examined, which failed to produce the desired
products (entries 12−14). The addition of Lewis acid also led
to zero recovery of substrates. Interestingly, the corresponding
product 4a was obtained in 76% and 83% yields when the
reactions were carried out at 50 and 80 °C, respectively (entries
15−17). The result clearly indicated that the transformation
was sensitive to temperature variations. The effects of solvents
were next examined (entries 18−21). Among the solvents, we
were delighted to find that the product 4a was readily formed in
87% or 89% yields in CH3CN or C2H5OH, respectively. Other
solvents, such as DMF, DMSO, and toluene, were also afforded
in moderate to good yields. Finally, the optimization of reaction
time showed that 8 h was optimal (entries 22 and 23).
In order to explore the scope of this transformation, a variety
of pyridin-2-amines, ynals, and alcohols, or thiols were
evaluated under the optimized reaction conditions. First, 1a
and 3a were fixed as substrates to test various substituted
pyridin-2-amines. The results are described in Scheme 1.
Various substituted pyridin-2-amines reacted well with 1a, 3a
and led to the desired product 4a−l in good to high yields.
Different substituents on the pyridine ring, such as CH3, F, Cl,
Br, I, and CF3, led to a beneficial effect on the reaction
outcome. For the reaction of 1a, 2, and 3a, pyridin-2-amines
substituted with both electron-rich groups and electron-poor
groups were suitable partners and gave the desired products in
good yields. It is also worth noting that multisubstituted
pyridin-2-amine, 5-chloro-3-iodopyridin-2-amine, and 3,5-di-
bromo-4-chloropyridin-2-amine reacted with 1a and 3a more
smoothly under the optimized conditions. However, when 2-
T
organic synthetic chemistry1 and have attracted critical
attention of chemists for their application value. They are found
in a large number of natural products and bioactive molecules,
many of which exhibit a broad range of biological activities,
such as antiviral,2 antiprotozoal,3 antiherpes,4 and antiapop-
totic.5 The core structure of imidazo[1,2-a]pyridines has also
been found in many drugs such as zolpidem, alpidem,
zolimidine, olprinone, saripidem, and necopidem.6 It is not
surprising, therefore, that great efforts have been directed
toward developing synthetic approaches for the construction of
this privileged structure.7 Recently, a variety of significant and
elegant metal-catalyzed methods8 have been developed for the
synthesis of imidazo[1,2-a]pyridine derivatives. However, most
of the metal catalysts are costly and toxic to some degree, which
limit their applications. Therefore, the development of a metal-
free strategy9 to form C−N, C−O, and C−S bonds represents
an attractive area of research for the construction of those
heterocycles.10 On the other hand, metal-free, three-component
reactions (MCRs) represent powerful tools for the rapid
preparation of diverse and complex molecules with an optimal
number of new bonds and functionalities from readily
accessible starting materials in a single operation under mild
conditions.11
Very recently, we have developed an efficient transformation
to construct functionalized furans and imidazo[1,2-a]-
pyridine.12 In this context, we described a novel transformation
to prepare3- heteroatom substituted (O, N, S)-substituted
imidazo[1,2-a]pyridines which appeared as key structural units
in many important bioactive compounds.13
Initially, 3-phenylpropiolaldehyde 1a, pyridin-2-amine 2a,
and ethanol 3a were chosen as model substrates. The results of
the optimization study for the MCRs synthesis of 4a are
summarized in Table 1. A variety of catalysts in conjunction
with different temperatures, solvents, and time were screened.
First, the desired product 4a was formed in 7% yield without
any catalysts in DMF at room temperature (entry 1). The result
encouraged us to improve the yield of this novel MCRs by
Received: October 31, 2013
Published: December 9, 2013
© 2013 American Chemical Society
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Letter
a
a
Table 1. Optimization of Reaction Conditions.
Scheme 2. Construction of Imidazo[1,2-a]pyridines
b
entry
catalyst
temp (°C)
solvent
time (h) yield (%)
1
rt
rt
DMF
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
12
4
7
<5
2
DABCO
DBU
DMF
3
rt
DMF
<5
4
Py
rt
DMF
<5
5
THT
rt
DMF
trace
trace
6
PPh3
rt
DMF
7
K2CO3
Na2CO3
NaHCO3
AcOH
L-proline
ZnCl2
FeCl3
rt
DMF
8
rt
DMF
9
rt
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
rt
DMF
32
<5
rt
DMF
rt
DMF
rt
DMF
AlCl3
rt
DMF
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
50
80
100
80
80
80
80
80
80
DMF
76
83
81
58
87
89
36
87
65
DMF
DMF
DMSO
CH3CN
C2H5OH
toluene
CH3CN
CH3CN
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (2.5
b
mmol %), solvents 2 mL. GC yield.
a
Scheme 1. Synthesis of Imidazo[1,2-a]pyridine Derivatives
a
Isolated yields.
found that the reaction conditions were useful for a variety of
alcohols and in most cases afforded the corresponding products
in good to excellent yields. Saturated aliphatic alcohol,
methanol, butan-1-ol, cyclohexanol, or propan-2-ol reacted
with 1a and substituted pyridin-2-amine smoothly and afforded
products in good yields. Notably, unsaturated alcohols, such as
prop-2-yn-1-ol and (E)-but-2-en-1-ol, also provided similar
isolated yields for this MCR for synthesis of functionalized
imidazo[1,2-a]pyridines. It was pleasing to find that the
corresponding products 5y−5b′ were obtained in 79−82%
yields when phenylmethanol was employed in the reaction.
However, the product was not detected when the reaction was
carried out under the optimized conditions using substrates 1a,
2a, and phenol. Those results clearly indicated that this
protocol is general and applicable for reactions of a wide variety
of alcohols.
a
Isolated yields.
aminopyridin-3-ol was tested as substrate, the corresponding
product 4m was not detected. All those results clearly indicated
that the most of substituted pyridin-2-amines have different
substituent groups on the ring could react smoothly and the
corresponding products were obtained in good yields.
Subsequently, a variety of alcohols were also tested as the
substrate with various substituted pyridin-2-amines and 1a. The
results are outlined in Scheme 2. As shown in Scheme 3, it was
For further investigation, commercially available oct-2-ynal
1b was employed to explore the scope of the MCRs, and the
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Letter
a
presence of AcOH at 80 °C in CH3CN. To our delight, both
substituted pyridin-2-amines and thiols as electrophile were
suitable for this transformation, and the corresponding
products 7a−i were obtained in good yield. It represents a
new approach for the construction of C−N and C−S bonds.
The plausible mechanism of the MCR has been described in
Scheme 5. AcOH-promoted intermolecular dehydration of 1a
Scheme 3. Formation of Imidazo[1,2-a]pyridines
Scheme 5. Possible Mechanism
a
Isolated yields.
and 2a occurs to give product A, which underwent Michael
type addition of EtOH to genernate the intermediate C.
Subsequently, the desired product was formed by sequential
proton transfer with the help of AcOH.
results are presented in Scheme 3. Interestingly, this strategy
proceeded perfectly when 1b, 2, and 3b in the presence of
AcOH at 80 °C in CH3OH. We were also pleased to find that
the three-component reaction would be successfully extended
to aliphatic ynals under the optimal conditions and afforded the
corresponding products 6a−i in good yields. All those results
showed that the MCRs allowed the formation of the
corresponding imidazo[1,2-a]pyridines, which represents an
efficient approach to the construction of C−N and C−O bonds
via transition-metal-free MCRs.
Extending the investigation further, the scope of electrophile
was also tested, and the results are summarized in Scheme 4.
The results showed that MCRs delivered other imidazo[1,2-
a]pyridines derivatives which can be easily functionalized. This
strategy was achieved perfectly by treatment of substrates in the
In summary, we have reported an unprecedented and
efficient transition-metal-free three-component reaction syn-
thesis of substituted imidazo[1,2-a]pyridine derivatives. It
represents a simple process for the formation of C−N, C−O,
and C−S bonds via one-pot, three-component reaction of
pyridin-2-amines, ynals and alcohols or thiols. The features of
transformation are metal-free, environmentally benign and
inexpensive. It provided a wide range of substrates to form
highly decorated imidazo[1,2-a]pyridines in good yields.
Furthermore, our findings open a novel synthetic route to a
variety of substituted imidazo[1,2-a]pyridines which are useful
structural motif in pharmaceuticals and natural compounds.
Scheme 4. Formation of C−N and C−S Bonds To Prepare
a
ASSOCIATED CONTENT
* Supporting Information
Imidazo[1,2-a]pyridines
■
S
Experimental procedure and characterization of compounds
4a−l, 5a−z, 5a′,b′, 6a−i, and 7a−i. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: caohua@gdpu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially Supported by Foundation for
National Natural Science Foundation of China (21302023
and 21272044).
REFERENCES
■
(1) (a) Hand, E. S.; Paudler, W. W. J. Org. Chem. 1978, 43, 2900−
2906. (b) Hand, E. S.; Paudler, W. W. J. Org. Chem. 1978, 43, 658−
663. (c) Dai, W. X.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2005, 70,
a
b
Isolated yields. Reaction condition for the synthesis of 7a−d: 1a
(0.5 mmol), 2a (1.2 mmol), AcOH (2.5 mol %), CH3CN 3 mL.
148
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Letter
6647−6652. (d) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. J.
Org. Chem. 1997, 62, 3453−3459. (e) Marson, C. M. Chem. Soc. Rev.
2011, 40, 5514−5533.
Mai, R. H.; Zhu, S. F.; Qi, C. R. Adv. Synth. Catal. 2010, 352, 143−152.
(e) Cao, H.; Jiang, H. F.; Yuan, G. Q.; Chen, Z. W.; Qi, C. R. Chem.
Eur. J. 2010, 16, 10553−10559. (f) Cao, H.; Zhan, H. Y.; Lin, Y. G.;
Lin, X. L.; Du, Z. D.; Jiang, H. F. Org. Lett. 2012, 14, 1688−1691.
(13) (a) Al-Tel, T. H; Al-Qawasmeh, R. A. Eur. J. Med. Chem. 2010,
45, 5848−5855. (b) Odell, L. R.; Nilsson, M. T.; Gising, J.; Lagerlund,
(2) Puerstinger, G.; Paeshuyse, J.; Declercq, E.; Neyts, J. Bioorg. Med.
Chem. Lett. 2007, 17, 390−393.
(3) (a) Ismail, M. A.; Arafa, R. K.; Wenzler, T.; Brun, R.; Tanious, F.
A.; Wilson, W. D.; Boykin, D. W. Bioorg. Med. Chem. 2008, 16, 681−
685.
(4) Gudmundsson, K. S.; Johns, B. A. Bioorg. Med. Chem. Lett. 2007,
17, 2735−2739.
(5) Enguehard-Gueiffier, C.; Fauvelle, F.; Debouzy, J. C.; Peinnequin,
A.; Thery, I.; Dabouis, V.; Gueiffier, A. Eur. J. Pharm. Sci. 2005, 24,
219−227.
́
O.; Muthas, D.; Nordqvist, A.; Karlen, A.; Larhed, M. Bioorg. Med.
Chem. Lett. 2009, 19, 4790−4793. (c) Mareev, A. V.; Medvedeva, A.
S.; Mitroshina, I. V.; Afonin, A. V.; Ushakov, I. A.; Romanenko, G. V.;
Tret’yakov, E. V. Russ. J. Org. Chem. 2008, 44, 1718−1720.
(6) Harrison, T. S.; Keating, G. M. CNS Drugs 2005, 19, 65−89.
(7) (a) Wen, L. R.; Li, Z. R.; Li, M.; Cao, H. Green Chem 2012, 14,
707−716. (b) Ma, L.; Wang, X.; Yu, W.; Han, B. Chem. Commun.
2011, 47, 11333−11335. (c) Pericherla, K.; Khedar, P.; Khungara, B.;
Kumar, A. Chem. Commun. 2013, 49, 2924−2926. (d) Maiti, B.;
Chanda, K.; Selvaraju, M.; Tseng, C. C.; Sun, C. M. ACS Comb. Sci.
2013, 15, 291−297. (e) Albrecht, L.; Albrecht, A.; Ransborg, L. K.;
Jørgensen, K. A. Chem. Sci. 2011, 2, 1273−1277. (f) Chernyak, N.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2743. (g) He, C.; Hao,
J.; Xu, H.; Mo, Y. P.; Liu, H. Y.; Han, J. J.; Lei, A. W. Chem. Commun.
2012, 48, 11073−11075.
(8) (a) Marhadour, S.; Bazin, M. A.; Marchand, P. Tetrahedron Lett.
2012, 53, 297−300. (b) Fu, H. Y.; Chen, L.; Doucet, H. J. Org. Chem.
2012, 77, 4473−4478. (c) Yang, H.; Yang, L.; Li, Y.; Zhang, F.; Liu,
H.; Yi, B. Catal. Commun. 2012, 11−14. (d) Stasyuk, A. J.;
́
Banasiewicz, M.; Cyranski, M. K.; Gryko, D. T. J. Org. Chem. 2012,
77, 5552−5558. (e) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q.
J. Am. Chem. Soc. 2010, 132, 13217−13219. (f) Masters, K. S.; Rauws,
T. R. M.; Yasav, A. K.; Herrebout, W. A.; Veken, B. V.; Mases, B. U. W.
Chem.Eur. J. 2011, 17, 6315−6320. (g) Wang, H.; Wang, Y.; Liang,
D.; Liu, L.; Zhang, J.; Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678−
5681. (h) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A.
Adv. Synth. Catal. 2013, 355, 1741−1747. (i) Santra, S.; Bagdi, A. K.;
Majee, A.; Hajra, A. Adv. Synth. Catal. 2013, 355, 1065−1070.
(j) Zeng, J.; Tan, Y. J.; Leow, M. L.; Liu, X. W. Org. Lett. 2012, 14,
4386−4389.
(9) (a) Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc. 2010, 132,
1249−1251. (b) Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.;
Dohi, T. J. Am. Chem. Soc. 2009, 131, 1668−1669. (c) Schmidt, V. A.;
Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 11402−11405. (d) Souto,
J. A.; Zian, D.; Muniz, K. J. Am. Chem. Soc. 2012, 134, 7242−7245.
̃
(e) Rahimi, A.; Azarpira, A.; Kim, H.; Ralph, J.; Stahl, S. S. J. Am.
Chem. Soc. 2013, 135, 6415−6418. (f) Souto, J. A.; Becker, P.; Iglesias,
́
A.; Muniz, K. J. Am. Chem. Soc. 2012, 134, 15505−15511. (g) Giglio,
̃
B. C.; Schmidt, V. A.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133,
13320−13322. (h) Dohi, T.; Ito, M.; Itani, I.; Yamaoka, N.; Morimoto,
K.; Fujioka, H.; Kita, Y. Org. Lett. 2011, 13, 6208−6211.
́
(10) (a) Escudie, J.; Ranaivonjatovo, H.; Rigon, L. Chem. Rev. 2000,
100, 3639−3696. (b) Turner, N. J. Chem. Rev. 2011, 111, 4073−4087.
(c) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem.
Rev. 2007, 107, 5318−5365.
(11) (a) Domling, A. Chem. Rev. 2006, 106, 17−89. (b) Gonzal
Lo
́
ez-
̈
́
pez, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164−189.
(c) Kozhevnikov, I. V. Chem. Rev. 1998, 98, 171−198. (d) Church,
T. L.; Byrne, C. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc.
2007, 129, 8156−8162. (e) Chen, Y. K.; Walsh, P. J. J. Am. Chem. Soc.
2004, 126, 3702−3703. (f) Kriis, K.; Ausmees, K.; Pehk, T. n.; Lopp,
M.; Kanger, T. N. Org. Lett. 2010, 12, 2230−2233. (g) Carballares, S.;
Espinosa, J. F. Org. Lett. 2005, 7, 2329−2331. (h) Fayol, A.; Zhu, J.
Org. Lett. 2004, 6, 115−118. (i) Rajarathinam, B.; Vasuki, G. Org. Lett.
2012, 14, 5204−5206.
(12) (a) Cao, H.; Zhan, H. Y.; Cen, J. H.; Lin, J. X.; Lin, Y. G.; Zhu,
Q. X.; Fu, M. L.; Jiang, H. F. Org. Lett. 2013, 15, 1080−1083. (b) Cao,
H.; Jiang, H. F.; Yao, W. J.; Liu, X. H. Org. Lett. 2009, 11, 1931−1933.
(c) Zhan, H. Y.; Lin, X. L.; Qiu, Y. Y.; Du, Z. D.; Li, P. X.; Li, Y. J.;
Cao, H. Eur. J. Org. Chem. 2013, 2284−2287. (d) Cao, H.; Jiang, H. F.;
149
dx.doi.org/10.1021/ol4031414 | Org. Lett. 2014, 16, 146−149