Regioselective methylation of indazoles using methyl 2,2,2- trichloromethylacetimidate

Article abstract of DOI:10.1016/j.tetlet.2013.01.030

An efficient and regio selective synthesis of substituted 2-methyl-2H-indazoles using a methyl 2,2,2-trichloroacetimidate is described.

Full text of DOI:10.1016/j.tetlet.2013.01.030

Tetrahedron Letters 54 (2013) 1661–1663
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective methylation of indazoles using methyl
2,2,2-trichloromethylacetimidate
Sudhakar Reddy Baddam a, N. Uday Kumar a, A. Panasa Reddy b, Rakeshwar Bandichhor a,
⇑
a Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupalli, Qutubullapur, R.R. Dist. 500072, Andhra Pradesh, India
b Department of Chemistry, Osmania University, Hyderabad 5000007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and regio selective synthesis of substituted 2-methyl-2H-indazoles using a methyl 2,2,2-tri-
chloroacetimidate is described.
Received 15 November 2012
Revised 6 January 2013
Accepted 8 January 2013
Available online 21 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Regio selective methylation
Methyl 2,2,2-trichloroacetimidate
Trifluoromethanesulfonic acid
The indazole ring is one of the intensively exploited templates
in the medicinal chemistry.1 In addition to this, the indazole ring
and its derivatives are found to exhibit analgesic,2 antitumor,3 anti-
cancer,4 anti-inflammatory,5 and anti-fertility activities.6 Surpris-
ingly, 2H-indazoles are much less explored than 1H-indazoles.7
Considering therapeutic potential of this class of the molecules,
it becomes extremely important to devise an efficient regioselec-
tive methylation of substituted 2-methyl-2H-indazoles. Indazoles
are found to undergo unselective alkylation under basic conditions
to afford corresponding mixture of N-1 and N-2 products, respec-
tively whereas, under mild acidic conditions, regio selective alkyl-
ation at N-2 position takes place. N-1 alkylated products are
thermodynamically controlled and the N-2 was favored under ki-
netic conditions. Cheung8 and Luo9 suggest that the N-2 lone pair
is more kinetically accessible than the N-1 lone pair for neutral
indazoles. Cheung’s work features one of the best methods for reg-
ioselective methylation by employing trimethyloxonium tetrafluo-
roborate (Meerwein’s reagent).8 In general, Catalan10 showed that
the 1H tautomer is more stable than the 2H tautomer of indazoles.
Morel et al.11a and Boyer et al.11b reported that the methylation
of 6-nitro-1H-indazole 1 by employing dimethyl sulfate in the
presence of potassium hydroxide at 45 °C affords the products
approximately in 1:1 mixture of 1-methyl-6-nitro-1H-indazole
(42% yield) and 2-methyl-6-nitro-2H-indazole (44% yield). Auwers
et al.12 reported a regioselective methylation at N-2 position of 6-
nitro-1H-indazole by heating with methyl iodide (4 equiv) at
100 °C in a sealed tube for 4 h; however, no yield was mentioned
in the report. Jaffari et al.13a also reported the regioselective meth-
ylation of 6-nitro-1H-indazole using alkylating agents such as
methyl iodide, methyl toluene-p-sulfonate, or diazomethane. Re-
cently, Bernard et al.13b reported regioselective N-ethylation by
using K2CO3/DMF/EtBr.
Interestingly, the regioselectivity of the indazoles was highly
dependent on the nature of the methylating agents. For example,
methylation of 1 (Scheme 1) using methyl iodide resulted in
mixtures of 2-methyl-6-nitro-2H-indazole 2 in 50%, 1-methyl-6-
nitro-1H-indazole 3 10%, and dimethylated product in 17% yields.
Methylation of 6-nitro-1H-indazole using methyl toluene-p-sulfo-
nate resulted in 50% yield of 2-methylated product with 25% yield
of recovered starting material. On the contrary, methylation of
6-nitro-1H-indazole using diazomethane in the presence of BF3
(CH2N2, BF3ÁEt2O, 70 °C, 6 h) resulted in a product with 75% yield
of 1-methylated product. In order to develop a methylating reagent
that has potential to afford regioselective product, we employed
methyl 2,2,2-trichloroacetimidate for the series of indazoles bear-
ing electron donating and electron with drawing groups.
It is well understood that there are many reagents that have
been shown to afford N-1 and N-2 alkylated products in moderate
to good yields but poor regioselectivity has always been observed.
In our endeavor, we attempted to develop a reliable method
that may address regioselectivity issue in indazole class of mole-
cules. In our initial exploration of the synthesis of substituted
2-methyl-2H-indazoles by using literature procedures, the N-alkyl-
ation afforded products with poor N-regioselectivity in minuscule
yields. We understood that the regioselectivity of the indazoles is
highly dependent on the nature of the alkylating agents thus we
turned our attention to other unexplored alkylating agents.
⇑
Corresponding author.
E-mail address: rakeshwarb@drreddys.com (R. Bandichhor).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.030

1662
S. R. Baddam et al. / Tetrahedron Letters 54 (2013) 1661–1663
Table 2
"Me
N
Screening of acid for synthesis of 2
N
source"
N
+
N
N
H
O2N
N
O2N
O2N
Entry
Acid reagent
Yield %
3
1
2
1
2
3
Trifluoromethanesulfonic acid
Sulfuric acid
Pyridinium p-toluenesulfonate
87
48
35
N-2 product
N-1 product
2H-indazole
1H-indazole
Scheme 1. N-Alkylated, N-1, and N-2 indazoles.
H
N
N
2.5 eq.CCl3CNHOMe
R
N
R
N
1.0 eq. CF3SO3H
R1
R1
N-2 product
N
R= NO2, CO2Me, Cl, I, H, OMe
( )
R1= H,Me
7 a-k
N
N
5
(a-k)
N
N
N
H
N
O2N
O2N
N
NH
2
N
O2N
N
N
H
HCl
S
N
N
N
N
O
O
N
O2N
4
5a
6
NO2
96%
87%
5a
97%
5c
Figure 1. Retro synthetic analysis of Pazopanib hydrochloride.
5b
NO2
O2N
MeO2C
N
N
N
N
N
Table 1
Screening of solvents for the synthesis of 2
N
95%
5d
94%
5e
87%
5f
Entry Screening solvents Yield %
Remarks
1
2
3
Dichloromethane
Ethyl acetate
Acetonitrile
87
80
52
Reaction completed in 16–18 h
Reaction completed in 12–13 h
20–30% of starting material
were unreacted
Cl
I
N
N
N
N
N
N
4
Tetrahydrofuran
—
Reaction did not proceed
85%
83%
79%
5g
5h
5i
N
MeO
N
N
N
Considering the requirement of sterically hindered methyl source
which would provide regioselective product we employed methyl
2,2,2-trichloroacetimidate. This reagent is used for alkylation of
other functional group other than amines.14
MeO
90%
5j
78%
5k
We exploited the potential of this reagent to synthesize one of
the key starting materials 5a of Pazopanib hydrochloride 4 as
shown in Figure 1 (Votrient™, made by GlaxoSmithKline). This
compound 4 is a tyrosine kinase inhibitor (TKI). It has been ap-
proved for renal cell carcinoma by the US Food and Drug Adminis-
tration (FDA).
As part of a process development program, it is required to pre-
pare a large quantity of 2,3-dimethyl-6-nitro-2H-indazole 5a for
the synthesis of Pazopanib hydrochloride 4.
Regioselective methylation on 3-methyl-6-nitro-1H-indazole 6
was extensively optimized with regard to combinations of reagent,
solvent, time, temperature as well as stoichiometry of reagent. In
our approach, the regioselective methylation on 3-methyl-6-ni-
tro-1H-indazole 6 was carried out in the following selected sol-
vents such as dichloromethane, ethyl acetate, acetonitrile, and
tetrahydrofuran. Among these, dichloromethane and ethyl acetate
were found to be effective solvents of choice in terms of complete
reaction conversion; in ethyl acetate rate of reaction was faster
than the dichloromethane but there were a few impurities that
have been observed and incomplete reaction conversion was ob-
served in acetonitrile. Attempts to perform this reaction in tetrahy-
drofuran solvent were futile. Eventually, dichloromethane was
opted as choice of solvent as shown in Table 1.
Thereafter, a systematic approach was adopted toward optimi-
zation of reaction conditions that involve mole equivalence of acid
reagent and methyl 2,2,2-trichloroacetimidate, reaction time, and
temperature. We were able to identify the optimum conditions
featuring dichloromethane as a solvent, temperature; 25–35 °C
and time about 16–18 h.
Scheme 2. Synthesis of 2-alkyl-substituted 2H-indazole.
Different acid reagents were screened for methylation on indoz-
ole moiety; for example, sulfuric acid (H2SO4), trifluoromethane-
sulfonic acid (CF3SO3H), and pyridinium p-toluenesulfonate.
Among these, trifluoromethanesulfonic acid afforded best results.
Finally, optimum mole equivalent of trifluoromethanesulfonic acid
was found to be 1.0 equiv for methylation of 7 (a–k) as shown in
Table 2.
Initial experiments were begun with 1.25, 1.75, 2.1, and 2.5 mo-
l equiv of methyl 2,2,2-trichloroacetimidate. These screening efforts
reveal that 2.5 equiv is the optimum quantity for regioselective
methylation of 7 (a–k). The quantity of solvent, dichloromethane
was adjudged to be 25 vol with respect to starting material.
The electronic effects on the methylation of indazoles were
studied. In general, the electron withdrawing group favors the for-
mation of N-1 product whereas the electron donating group helps
to afford N-2 selective product. In our endeavor, regioselective
methylation was explored by using different types of indazoles 7
(a–k), containing either electron donating (e.g., methoxy, etc.) or
electron withdrawing (e.g., nitro, ester, etc.) groups and without
substituent in the aromatic system (7i). As shown in Scheme 2,
irrespective of substituent in the reactant, 2-alkyl-substituted
2H-indazole (N-2-methyl) compounds 5 (a–k) were preferentially
isolated in the range of 75–97% yields.15
In conclusion, we have developed an efficient and regio
selective synthesis of substituted 2-methyl-2H-indazoles using
methyl 2,2,2-trichloroacetimidate as a methylating agent. This

S. R. Baddam et al. / Tetrahedron Letters 54 (2013) 1661–1663
1663
8. Cheung, M.; Boloor, A.; Stafford, J. A. J. Org. Chem. 2003, 68, 4093.
9. Luo, G.; Chen, L.; Dubowchik, G. J. Org. Chem. 2006, 71, 5392.
10. Catalan, J.; del Valle, J. C.; Claramunt, R. M.; Boyer, G.; Laynez, J.; Gomez, J.;
Jimenez, P.; Tomas, F.; Elguero, J. J. Phys. Chem. 1994, 98, 10606.
11. (a) Morel, S.; Boyer, G.; Coullet, F.; Galy, J.-P. Synth. Commun. 1996, 26, 2443;
(b) Boyer, G.; Galy, J. P.; Barbe, J. Heterocycles 1995, 41, 487.
methodology can be applied to one of the key intermediates of Paz-
opanib hydrochloride and various substituted indozole ring sys-
tems of pharmaceutical significance.
Acknowledgements
12. (a) Auwers, K. V.; Schwegler, K. Chem. Ber. 1920, 53, 1211; (b) Witt, O. N.;
Nolting, E.; Grandmougin, E. Chem. Ber. 1890, 23, 3635.
13. (a) Jaffari, G. A.; Nunn, A. J. J. Chem. Soc., Perkin Trans. 1 1973, 2371; (b) Bernard,
M. K.; Kujawski, J.; Skierska, U.; Gzella, A. K.; Jankowski, W. ARKIVOC 2012, 8,
1–18.
14. Stahl, I. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
John Wiley & Sons: Chichester, 1995; Vol. 7, pp 5213–5216.
We thank the management of IPDO-API, Dr. Reddy’s laborato-
ries Ltd. for supporting this work. Support from the colleagues at
analytical research and development team is highly appreciated.
DRL IP Communication number: 00356.
15. Regiochemistry of the products was determined by observing a correlation
between H-1 and H-3 from the 1D-NOE- NMR spectroscopic experiments.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
030.
H
4
3
H
5
6
N
R
1
2
N
1
7
References and notes
5
(a-k)
1. Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; de Ocarizi, C. O. Mini-Rev.
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2. Fletcher, S. R.; Mclver, E.; Lewis, S.; Burkamp, F.; Leach, C.; Mason, G.; Boyce, S.;
Morrison, D.; Richards, G.; Sutton, K.; Jones, A. B. Bioorg. Med. Chem. Lett. 2006,
16, 2872.
3. Wang, H.; Han, H.; Von Hoff, D. D. Cancer Res. 2006, 66, 9722.
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6. Silvestrini, B.; Cheng, C. Y. US Patent Appl. 99-304042, 1999.
7. (a) Halland, N.; Nazare, M.; R’kyek, O.; Alonso, J.; Urmann, M.; Lindenschmidt,
A. Angew. Chem., Int. Ed. 2009, 48, 6879–6882; (b) Vina, D.; Olmo, E. D.; Lopez-
Perez, J. L.; Feliciano, A. S. Org. Lett. 2007, 9, 525–528; (c) Stadlbauer, W.; Camp,
N. In Science of Synthesis: Houben–Weyl Methods of Molecular Transformations;
Bellus, D., Ley, S. V., Noyori, R., Regitz, M., Schaumann, E., Shinkai, E., Thomas, E.
J., Trost, B. M., Reider, P. J., Eds.; Thieme: Stuttgart, 2002; Vol. 12, p 227.
General procedure for the synthesis of 2-methylsubstituted 2H-indazoles: Preparation of
2-methyl-6-nitro-2H-indazole (5d). To a stirred mixture of 6-nitro-1H-indazole (1.0 g,
0.0061 mmol) in dichloromethane (25.0 mL) was added trifluoromethanesulfonic
acid (0.54 mL, 0.0061 mmol), stirred for 5–10 min at 25–35 °C. To this mixture
was added methyl 2,2,2,-trichlroacetimidate (2.69 g, 0.015 mmol) at room tempera-
ture. The reaction mixture was stirred at room temperature for 16–18 h under N2.
After reaction completion, chilled saturated NaHCO3 solution was added. The aque-
ous and organic phases were separated. Aqueous phase was extracted with dichlo-
romethane 10 mL. Combined organic layers were washed with DM water
(2 Â 10 mL). Organic layer was dried over anhydrous Na2SO4, filtered, and evapo-
rated completely under vacuum to obtain 2-methyl-6-nitro-2H-indazole (1.03 g,
95.0%) as a yellow solid. 1H NMR (400 MHz, CDCl3) d 8.683 (s, 1H), 8.03 (s, 1H),
7.91 (d, 1H), 7.89 (d, 1H), 4.31 (s, 3H); 13C NMR (400 MHz, CDCl3) 146.93, 146.46,
124.52, 121.24, 115.70, 115.27, 41.06; MS (+ve ES) 178 (M+H).