Microwave-assisted synthesis of 2-pyridinylethyl indazoles

Article abstract of DOI:10.1016/j.tetlet.2015.06.065

An atom-economic pathway to obtain N-alkyl indazoles bearing pyridine from indazoles and vinylpyridines in water is reported. Assisted with microwave irradiation, the reaction could be completed within 20 min, affording N1 or N2 alkylation indazoles in high yields. 4-Vinylpyridine gave N1 alkylated products exclusively.

Full text of DOI:10.1016/j.tetlet.2015.06.065

Accepted Manuscript
Microwave-Assisted Synthesis of 2-Pyridinylethyl Indazoles
Dao-Liang Ge, Xiao-Zhuan Zhang, Shan-Yong Chen, Lin Pu, Xiao-Qi Yu
PII:
S0040-4039(15)01084-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.065
TETL 46457
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 May 2015
19 June 2015
22 June 2015
Please cite this article as: Ge, D-L., Zhang, X-Z., Chen, S-Y., Pu, L., Yu, X-Q., Microwave-Assisted Synthesis of
2-Pyridinylethyl Indazoles, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.065
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Microwave-Assisted Synthesis of 2-Pyridinylethyl Indazoles
Dao-Liang Ge, Xiao-Zhuan Zhang, Shan-Yong Chen,* Lin Pu, and Xiao-Qi Yu*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu, Sichuan 610064, P. R. China
E-mail: chensy@scu.edu.cn, xqyu@scu.edu.cn; Fax: + (86)-28-85415886; Tel: + (86)-28-85415886
1

Abstract
An atom-economic pathway to obtain N-alkyl indazoles bearing pyridine from indazoles and vinylpyridines in
water is reported. Assisted with microwave irradiation, the reaction could be completed within 20 minutes, affording
N1 or N2 alkylation indazoles in high yields. 4-Vinylpyridines gave N1 alkylated products exclusively.
Key Words: Alkyl indazole, microwave, pyridine, alkylation
2

Introduction
The indazole ring is a commonly used motif in the discovery of biologically active
1
molecules.
The manipulation of substitution pattern is crucial for designing
pharmaceutical molecules bearing indazoles. We are interested in the introduction of a
pyridinyl alkyl group into indazoles because some pyridinyl alkyl indazoles have shown
important biological properties. For example, Compounds A are inhibitors for type III
receptor tyrosine kinase (Figure 1). 2 Compounds B are thrombin inhibitors, which could
3
be used for the treatment of thromboembolic diseases. The general method to
synthesize alkyl indazoles is nucleophilic substitution between indazoles and alkyl
halides (Figure 2, eq 1). 4 However, it is still a challenge for the reaction of an alkyl
halide bearing a nitrogen-containing heterocycle. For example, the reaction of
2-bromo-ethyl pyridine with indazoles is very sluggish (Eq 2). 3 The reason is that these
halides would rather react with themselves to form pyridium salts than react with
indazoles. We envisioned that using vinylpyridines as the alkylation reagent would avoid
this side reaction, thus increasing the alkylation efficiency.
Figure 1. Biologically active N pyridinyl alkyl indazoles
Microwave as a green energy becomes more and more popular in the modern
organic synthesis. Microwave can not only reduce energy consumption, but also shorten
4
the reaction time, thereby increasing efficiency. Using water as solvent provides
5
opportunities for clean processing and pollution prevention. However, most organic
compounds hardly dissolve in water at ambient condition, which limit the application of
3

water. The supposed near-critical region of water at temperatures between 150 and
300 is of great importance to organic synthesis. 6 Organic compounds become more
soluble in near-critical region of water. With the help of commercial microwave
equipment, it is easy to use near-critical water as the solvent. Herein, we reported a
microwave assisted synthesis of pyridinyl alkyl indazoles in water (Figure 2, eq 3).
R
R
N
N
+
+
X
EWG
R
R
N
N
(1)
(2)
N
H
DMF, 16 h
DMF, 72 h
N
N
X = Cl Br
、
EWG
X
N
H
N
N
X = Br
<15%
MW
R
N
N
+
R
N
N
(3)
N
N
H2O, 20 min
H
this work
up to 96%
Figure 2. Methods for alkylation of indazoles
Assisted with microwave irradiation for 20 min at 180 ℃, the reaction of
2-vinylpyridine with indazole was completed. Two products 3a (Rf =0.4) and 3a′ (Rf
=0.2) were isolated by chromatograph in 1:1 ratio (Table 1).7 Then a variety of
substituted indazoles were tested (Table 1). All of substituted indazoles afforded
pyridinyl alkyl indazoles in high yields except 6-nitroindazole (3c and 3c′).
C3-substituted indazoles provided N1 alkylation products exclusively in high yields
(3e-3h). Generally, the selective alkylation of C3-unsubstituted indazoles at the N1
8
position is difficult. Fortunately, when 4-vinylpyridine was used as the alkylation
reagent, we found that only N1 alkylated products were isolated in high yields (Table 2).
9
The mechanism of this reaction should be the classic Michael addition mechanism.
The reason why 4-vinylpyridine affords high regioselectivity products is uncertain.
4

To confirm the structures of N1 or N2 substituted indazoles, several NOESY
experiments were carried out. As shown in Figure 3, the spectrum of compound 3d
displayed a cross-peak between H-7 and H-6, while compound 3d′ displayed the dipolar
correlation between H-10 and H-6.
Table 1. Microwave-assisted alkylation of indazoles with 2-vinylpyridine[a]
[a] Reaction conditions:1 (0.5 mmol), 2 (1.5 mmol), K3PO4 (1 mmol), TBAB (20 mol%), H2O (2 mL), 180℃
under microwave irradiation for 20 min. TBAB = Tetrabutyl ammonium bromide. Isolated Yields
5

Table 2. Selective alkylation of indazole with 4-vinylpyridie[a]
Cl
N
N
N
5e
89.3%
[a] Reaction conditions:1 (0.5 mmol), 4 (1.5 mmol), K3PO4 (1 mmol), TBAB (20 mol%),
H2O (2 mL), 180℃ under microwave irradiation for 20 min. TBAB = Tetrabutyl
ammonium bromide. Isolated yields.
Figure 3. H-H NOESY of 3d and 3d′
6

Conclusion
We have reported a transition-metal-free hydroamination reaction to obtain N
pyridinyl alkyl indazoles. It is possible to isolate the pure N1 substituted and N2
substituted indazole products respectively. These compounds may have potential
application in the discovery of new biologically active compounds. This reaction meets
some requirements of green chemistry 10 with atom economy, the utility of water as
reaction medium, the absence of toxic catalysts and additives, while microwave is
applied as clean and efficient energy to shorten reaction time.
Acknowledgements
This work was supported financially by the National Program on Key Basic Research
Project of China (973 Program, 2013CB328900) and the National Science Foundation of
China (grant no. 21202107).
Supplementary data:
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/
7

References
1. Thangadurai, A.; Minu, M.; Wakode, S.; Agrawal, S.; Narasimhan, B. Med. Chem. Res. 2012, 21,
1509.
2. Boys, M. L.; Delisle, R. K.; Hicken, E. J. WO2012082689A1, Jun 21, 2012.
3. Siegel, S.; Schneider, D.; Buchmueller, A. WO2008006479A1, Jan 17, 2008.
4. Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
5. Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563.
6. (a) Bröll, D.; Kaul, C.; Krämer, A.; Krammer, P.; Richter, T.; Jung, M.; Vogel, H.; Zehner, P.
Angew. Chem. Int. Ed. 1999, 38, 2998. (b) Savage, P. E. Chem. Rev. 1999, 99, 603. (c) Siskin, M.;
Katritzky, A. R. Chem. Rev. 2001, 101, 825. (d) Katritzky, A. R.; Nichols, D. A.; Siskin, M.;
Murugan, R.; Balasubramanian, M. Chem. Rev. 2001, 101, 837. (e) Watanabe, M.; Sato, T.;
Inomata, H.; Smith, R. L., Jr.; Arai, K.; Kruse, A.; Dinjus, E. Chem. Rev. 2004, 104, 5803. (f)
Akiya, N.; Savage, P. E. Chem. Rev. 2002, 102, 2725. (g) Weingärtner, H.; Franck, E. U. Angew.
Chem. Int. Ed. 2005, 44, 2672.
7. General procedure for alkylation of indazoles: To a 10 mL glass microwave vial equipped with a
magnetic stir bar was charged with a mixture of 1H-indazoles (0.5 mmol, 1 equiv),
2-vinylpyridine or 4-vinylpyridine (1.5 mmol, 3 equiv), Potassium phosphate (1mmol, 2equiv)
and TBAB (20 mol%, 0.1 mmol) in water (2 mL). The mixture was heated to 180 ℃ as fast as
possible in microwave oven, and stirred for 20 min at 180 ℃. The resulting solution was cooled
to temperature and extracted with EtOAc twice. The combined organic layer was washed with
saturated salt water, dried over Na2SO4 and concentrated under reduced pressure. The residue was
purified by gradient elution (PE/AcOEt for starting materials, PE/AcOEt/TEA=100/50/3 for the
pure N1 substituted products and PE/AcOEt/TEA=20/20/1 for N2 substituted products).
8. Saenz, J.; Mitchell, M.; Bahmanyar, S.; Stankovic, N.; Perry, M.; CraigWoods, B.; Kline, B.; Yu,
S.; Albizati, K. Org. Process Res. Dev. 2007,11, 30.
9. Klumpp, D. A. Synlett 2012, 23, 1590.
10.The 12 principles of green chemistry are as follows: prevention, atom economy, less hazardous
chemical synthesis, designing safer chemicals, safer solvents, design for energy efficiency, use of
renewable feedstocks, reduce derivatives, catalysis, design for degradation, real-time analysis for
pollution prevention, inherently safer chemistry for accident prevention.
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Graphical Abstract
Microwave-Assisted Synthesis of 2-Pyridinylethyl Indazoles
Dao-Liang Ge, Xiao-Zhuan Zhang, Shan-Yong Chen,* Lin Pu, and Xiao-Qi Yu*
9