Novel strategy for the preparation of 3-perfluoroalkylated-2H-indazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.03.051

A simple and novel methodology for the synthesis of 3-perfluoroalkylated-2H-indazole derivatives has been elaborated. The perfluoroalkylation of readily available 2-nitrobenzaldimines bearing electron donating groups was performed using the Ruppert-Prakas

Full text of DOI:10.1016/j.tetlet.2018.03.051

Accepted Manuscript
Novel strategy for the preparation of 3-perfluoroalkylated-2H-indazole deriva-
tives
Hassen Bel Abed, Nils Weißing, Jens Schoene, Jannik Paulus, Norbert Sewald,
Marc Nazaré
PII:
S0040-4039(18)30365-4
https://doi.org/10.1016/j.tetlet.2018.03.051
TETL 49820
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 January 2018
15 March 2018
19 March 2018
Please cite this article as: Abed, H.B., Weißing, N., Schoene, J., Paulus, J., Sewald, N., Nazaré, M., Novel strategy
for the preparation of 3-perfluoroalkylated-2H-indazole derivatives, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.03.051
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Novel strategy for the preparation of 3-
Leave this area blank for abstract info.
perfluoroalkylated-2H-indazole derivatives
Hassen Bel Abed, Nils Weißing, Jens Schoene, Jannik Paulus, Norbert Sewald and Marc Nazaré

1
Tetrahedron Letters
Novel strategy for the preparation of 3-perfluoroalkylated-2H-indazole derivatives
Hassen Bel Abed,a Nils Weißing,b Jens Schoene,a Jannik Paulus,b Norbert Sewaldb and Marc Nazaréac*
aLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany
bDepartment of Chemistry, Bielefeld University, P.O. Box 10 01 31, 33501 Bielefeld, Germany
cBerlin Institute of Health (BIH), Anna-Louisa-Karsch-Str. 2, 10178 Berlin, Germany
ARTICLE INFO
ABSTRACT
A simple and novel methodology for the synthesis of 3-perfluoroalkylated-2H-indazole
derivatives has been elaborated. The perfluoroalkylation of readily available 2-
nitrobenzaldimines bearing electron donating groups was performed using the Ruppert-Prakash
reagent and its analogues to afford -difluoromethylated, -trifluoromethylated and -
pentafluoroethylated benzylamines. A final reductive cyclization mediated by SnCl2•2H2O led to
2H-indazoles containing perfluoroalkyl groups via the generation of a new N−N bond in
moderate to good yields.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2H-Indazole
Perfluoroalkylation
N-N bond formation
Ruppert-Prakash reagent
Reductive cyclization
2012 Elsevier Ltd. All rights reserved.
* Tel.: +49 3094063083; E-mail address: nazare@fmp-berlin.de

2
Tetrahedron
Fluorine substitution in bioactive molecules is considered
(fluorosulfonyl)acetate as trifluoromethide precursor from 3-
essential in several research fields such as agrochemical,
molecular imaging and medicinal chemistry. Around 20 % to 30
% of all newly approved drugs contain at least one fluorine.1 The
fluorine atom and its alkyl analogues have displayed unique
properties to develop improved biologically active molecules
with enhanced target affinity and metabolic stability.2 The
incorporation of perfluoroalkyl groups such as CF2H, CF3 and
CF2CF3 into bioactive compounds has been extensively
investigated3 in the past decades and has resulted in the approval
of diverse substances i.e. Celecoxib 1, an anti-inflammatory drug
containing a trifluoromethyl group4 and Bixafen 2, a cereal
fungicide5 bearing a difluoromethyl moiety. The pentafluoroethyl
group has been introduced recently as a superior lipophilic
analogue and its use in the synthesis of the selective estrogen
receptor degrader (SERD) Fulvestrant 3 has prevented metabolic
oxidation6 (Figure 1). It is interesting to note the relevance of
perfluoroalkylated pyrazole derivatives in the design of
promising pharmacophores.
bromo-2H-indazole10 9 (Scheme 1c).
Considering the limited number of existing methods, the
elaboration of a step-economical strategy starting from readily
available substrates to access 2H-indazoles bearing
perfluoroalkylated groups by an alternative approach is highly
required. As part of our ongoing efforts in the synthesis of
privileged structures11 and 2H-indazole derivatives,12 we report
herein a simple and novel methodology for the preparation of 3-
perfluoroalkylated-2H-indazoles from 2-nitrobenzaldehydes
through
a
sequential
imine
formation/perfluoroalkylation/reductive cyclization.
The work started with the straightforward access to the 2-
nitrobenzaldimines 13 by the reaction of 2-nitrobenzaldehydes 11
with aniline derivatives 12 in refluxing ethanol. 13 was then
subjected to different described perfluoroalkylation conditions13
which did not lead to the desired 2-nitro--perfluoroalkylated
benzylamine substrates 14 or in traces amounts. The full
conversion of the aldimine 13 into 14 was finally achieved by
using the procedure developed by Prakash et al.14 with 5
equivalents of perfluoroalkylating reagents instead of the initially
described 1.5 equivalents which resulted in no or only partial
conversion.
A
catalytic amount of tetrabutylammonium
difluorotriphenylsilicate (TBAT)15 was used to initiate the
reaction performed in THF at room temperature.
Table 1. Synthesis of perfluoroalkylated benzylamine derivatives.a
Figure 1. Perfluoroalkylated bioactive molecules.
Nevertheless, limited success has been reported towards the
synthesis of perfluoroalkylated fused pyrazole analogues and
especially for 2H-indazoles which have been recognized as novel
privileged structures for the bioisosteric replacement of indoles
and benzimidazoles.7
14a (75 %)
14b (18 %)
14c (41 %)
14d (25 %)
14g (31 %)
14e (63 %)
14h (49 %)
14f (54 %)
14i (32 %)
14j (14 %)b
14k (45 %)
aYields of isolated product over two steps and represent the average
b
Scheme 1. Synthesis of perfluoroalkylated 2H-indazole analogues.
over at least two experiments. Perfluoroalkylation was performed for
24 h.
To the best of our knowledge, only the Okada group through
the hydrazinolysis of trifluoromethyl ketones8 4 (Scheme 1a) and
the Langer group via the cyclization of hydrazone dianions 6
with ethyl trifluoroacetate9 (Scheme 1b) have addressed the
synthetic accessibility to this scaffold. Additionally,
Katzenellenbogen et al. have synthesized one single example of
These modified perfluoroalkylation conditions permitted the
synthesis of nine -trifluoromethylated benzylamines (14a-14i)
with the Ruppert-Prakash reagent as well as one -
pentafluoroethylated derivative 14k with C2F5TMS in moderate
to good yields. It is noteworthy to mention that the possible
introduction of a difluoromethyl group 14j via the use of
difluoromethyltrimethylsilane in extended reaction time i.e. 24
3-trifluoromethyl-2H-indazole 10 using
a
copper-mediated
coupling reaction with methyl
2,2-difluoro-2-

3
hours is due to the shorter length of the Si−CF2H bond compared
to Si−CF3 bond.16
The nucleophilicity of the -perfluoroalkylated benzylamine
14 was critical to perform the reductive cyclization step. The
presence of electron-donating groups attached to the aniline
derivatives 12 was necessary to promote the formation of 15 and
could be explained by the strong electron-withdrawing nature of
the perfluoroalkyl groups at the  position lowering the
nucleophilic behaviour of the benzylamine 14.
The second part of the investigation consisted in identifying
suitable conditions for the formation of 2H-indazole 15a through
the deoxygenation of the nitroarene derivative 14a. The use of
organophosphorus reagents such as P(n-Bu)3 did not lead to the
desired heterocycle 15a (Table 2, entry 1-2) while P(OEt)3
afforded the 2H-indazole 15a in only 16 % yield under neat
conditions (Table 2, entry 3). The optimization was then directed
Table 3. Synthesis of 3-perfluoroalkylated-2H-indazoles.a
17
towards Lewis acid-mediated reductive cyclization but ZnCl2
did not improve the previous results (Table 2, entry 4). To our
delight, SnCl2•2H2O18 in ethanol at 75 °C resulted in 44 % yield
(Table 2, entry 5) and the increase of equivalents of this reagent
as well as a shorter reaction time allowed the synthesis of 15a in
65 % yield (Table 2, entry 6). The replacement of ethanol by
2,2,2-trifluoroethanol
(TFE)
and
ethylene
glycol
monomethylether (EGMM) did not provide better yields (Table
2, entry 7-8).
15a (65 %)
15d (82 %)
15g (60 %)
15b (97 %)
15e (63 %)b
15h (55 %)
15c (58 %)
15f (59 %)b
15i (traces)
Table 2. Optimization of the reductive cyclization.a
Time
(h)
18
Yield
(%)b
0
Entry
Reagent
P(n-Bu)3
X eq.
Solvent
Toluenec
DMFc
1
2
3
4
5
6
7
8
3
3
P(n-Bu)3
18
18
18
18
5
0
c
P(OEt)3
3
−
16
0
ZnCl2
5
Toluenec
Ethanold
Ethanold
TFEd
SnCl2•2H2O
SnCl2•2H2O
SnCl2•2H2O
SnCl2•2H2O
1.5
3
44
65
63
52
15j (61 %)b
15k (44 %)
3
5
aSee supporting information for details, yields of isolated product
represent the average over at least two experiments. bReaction was
performed for 24 h.
3
5
EGMMd
aSee supporting information for details. bYield of isolated product.
cReaction was performed at 120 °C. dReaction was performed at 75 °C.
In conclusion, we have elaborated a novel strategy to
synthesize 3-perfluoroalkylated-2H-indazoles 15 through
perfluorolkylation of readily available benzaldimines 13 followed
by a reductive cyclization mediated by SnCl2•2H2O. The
application of this methodology led to the synthesis of eight
trifluoromethylated 2H-indazole analogues substituted by halides
or sterically hindered groups on the 2-nitrobenzaldehyde 11
component. However, the reductive cyclization step required the
use of anilines 12 bearing electron-donating groups in order to
assist the generation of the new N−N bond. It is also the first
report describing the preparation of the novel difluoromethylated
2H-indazole 15j and pentafluoroethylated 2H-indazole 15k
derivatives. This approach represents a simple and novel
alternative for the rapid access to 3-perfluoroalkylated-2H-
indazoles and their evaluation as promising pharmacophores.
The synthesis of a small library of perfluoroalkylated 2H-
indazole analogues was then initiated using the optimized
reductive cyclization conditions. The investigation of the
substrate scope focused at first on the nature of the 2-
nitrobenzaldehydes and the incorporation of an additional
fluorine delivered the trifluoromethylated heterocycle 15b in
excellent yield (97 %). The congener bearing a chlorine
substituent 15c was obtained in 58 % yield and could be used for
further derivatization of the 2H-indazole. The attachment of a
second trifluoromethyl group did not affect the deoxygenation
and subsequent cyclization leading to 15d in 82 % yield.
Sterically hindered benzylamines were also tolerated such as 14e
and the quinoline substrate 14f affording their corresponding 2H-
indazole in good yields. We observed that variation on the aniline
component was limited due to the reductive cyclization step,
hence only anilines bearing electron-donating groups such as
methoxy 15a, thiomethyl 15g and aliphatic group 15h allowed
the generation of the new N−N bond to form the expected
heterocycle. The use of anilines possessing non-electron-donating
groups did not give access to the 2H-indazole ring 15 but led to a
full reduction of the nitro substituent to the corresponding acyclic
amine. However, it was possible to observe traces of the
brominated derivative 15i. Finally, this approach facilitated the
synthesis of hitherto unknown difluoromethylated 15j and
pentafluoroethylated 15k structures.
Acknowledgements
This Letter is dedicated to Mongi Bel Abed, an exceptional
father (10/08/1951-16/01/2017). The authors thank Edgar
Specker for recording the HRMS spectra, Peter Schmieder and
Nils Trieloff for NMR assistance. We thank the Berlin Institute
of Health (BIH) and the Helmholtz Drug Research for financial
support.
References and notes

4
Tetrahedron
1. (a) Wang, J.; S - o , M , J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.
2014, 114, 2432-2506. (b) o S
, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev.
2016, 116, 422-518.
2.
(a) , K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881-1886.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320-330. (c) Gillis, E. P.; Eastman, K. J.; Hill, M. D.;
Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315-8359.
(d) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer,
H.; Kansy, M.; Zimmerli, D.; Carreira, , K. J. Med.
Chem. 2015, 58, 9041-9060.
3.
4.
(a) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1-PR43. (b)
Mykhailiuk, P. K. Chem. Eur. J. 2014, 20, 4942-4947. (c) Ni, C.; Hu,
M.; Hu, J. Chem. Rev. 2015, 115, 765-825. (d) Liu, X.; Xu, C.; Wang,
M.; Liu, Q. Chem. Rev. 2015, 115, 683-730. (e) Mykhailiuk, P. K.
Angew. Chem. Int. Ed. 2015, 54, 6558-6561.
Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins,
P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. J. Med. Chem. 1997, 40, 1347-1365.
5.
Dunkel, R.; Rieck, H.; Elbe, H.-L.; Wachendorff-Neumann, U.; Kuck,
K.-H. WO 2003/070705.
6.
7.
Croxtall, J. D.; McKeage, K. Drugs 2011, 71, 363-380.
Cerecetto, H.; Gerpe, A.; González, M.; Arán, V. J.; de Ocáriz, C. O.
Mini-Rev. Med. Chem. 2005, 5, 869-878.
8.
9.
(a) Okada, E.; Hatakenaka, M.; Sakaemura, T. Heterocycles, 2015, 90,
1072-1081. (b) Hatakenaka, M.; Adachi, S.; Okada, E. Heterocycles,
2016, 92, 936-943.
Ngo, T. N.; Ejas, S. A.; Hung, T. Q.; Dang, T. T.; Igbal, J.; Lecka, J.;
Svigny, J.; Langer, P. Org. Biomol. Chem. 2015, 13, 8277-8290.
10. Angelis, M. D.; Stossi, F.; Carlson, K. A.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. J. Med. Chem. 2005, 48, 1132-1144.
11. (a) Bel Abed, H.; Mammoliti, O.; Van Lommen, G.; Herdewijn, P.
Tetrahedron Lett. 2012, 53, 6489-6491. (b) Bel Abed, H.; Mammoliti,
O.; Van Lommen, G.; Herdewijn, P. Tetrahedron Lett. 2013, 54, 2612-
2614. (c) Bel Abed, H.; Mammoliti, O.; Bande, O.; Van Lommen, G.;
Herdewijn, P. J. Org. Chem. 2013, 78, 7845-7858. (d) Bel Abed, H.;
Bande, O.; Mammoliti, O.; Van Lommen, G.; Herdewijn, P.
Tetrahedron Lett. 2013, 54, 7056-7058. (e) Bel Abed, H.; Mammoliti,
O.; Bande, O.; Van Lommen, G.; Herdewijn, P. Org. Biomol. Chem.
2014, 12, 7159-7166. (f) Bel Abed, H.; Van Brandt, S. F. A.; Vega, J.
A.; Gijsen, H. J. M. Tetrahedron Lett. 2015, 56, 4028-4030.
12. (a) Halland, N.; Nazaré, M.; R'kyek, O.; Alonso, J.; Urmann, M.;
Lindenschmidt, A. Angew. Chem. Int. Ed. 2009, 48, 6879-6882. (b) Bel
Abed, H.; Schoene, J.; Christmann, M.; Nazaré, M. Org. Biomol.
Chem. 2016, 14, 8520-8528. (c) Schoene, J.; Bel Abed, H.;
Christmann, M.; Nazaré, M. Tetrahedron Lett. 2017, 58, 1633-1635.
13. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757-786. (b)
Pooput, C.; Dolbier, W. R., Jr.; Medebielle, M. J. Org. Chem. 2006,
71, 3564-3568. (c) Dilman, A. D.; Levin, V. V. Eur. J. Org. Chem.
2011, 2011, 831-841. (d) Beier, P.; Zibinsky, M.; Prakash, G. K. S.
Nucleophilic Additions of Perfluoroalkyl Groups. Organic Reactions.
2016, 1-492.
14. Prakash, G. K. S.; Mogi, R.; Olah, G. A. Org. Lett. 2006, 8, 3589-
3592.
15. Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901-6905.
16. Hagiwara, T.; Fuchikami, T. Synlett 1995, 717-718.
17. Shirtcliff, L. D.; Rivers, J.; Haley, M. M. J. Org. Chem. 2006, 71,
6619-6622.
18. (a) Yoo, C. L.; Fettinger, J. C.; Kurth, M. J. J. Org. Chem. 2005, 70,
6941-6943. (b) Sawant, D.; Kumar, R.; Maulik, P. R.; Kundu, B. Org.
Lett. 2006, 8, 1525-1528. (c) Shi, D.-Q.; Dou, G.-L.; Ni, S.-N.; Shi, J.-
W.; Li, X.-Y.; Wang, X.-S.; Wu, H.; Ji, S.-J. Synlett 2007, 2509-2512.
Supplementary Material
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online
version, at XXX.

5
Highlights
 A novel methodology for the synthesis of 3-
perfluoroalkylated-2H-indazoles
 Sequential imine formation,
perfluoroalkylation and SnCl2 mediated
cyclization
 Rapid generation of "drug-like” 3-
perfluoroalkylated indazole libraries.
3.
4.
3