AlCl3-promoted reaction of cycloalkanones with hydrazones: a convenient direct synthesis of 4,5,6,7-tetrahydro-1H-indazoles and their analogues

Article abstract of DOI:10.1016/j.tetlet.2019.150988

The AlCl₃-promoted reactions of cycloalkanones with hydrazones are described. This approach represents a mild and operationally simple method to access 2,3-diaryl-4,5,6,7-tetrahydro-1H-indazoles and their analogues in good to moderate yields.

Full text of DOI:10.1016/j.tetlet.2019.150988

Journal Pre-Proof
AlCl3-promoted reaction of cycloalkanones with hydrazones: a convenient di-
rect synthesis of 4,5,6,7-tetrahydro-1H-indazoles and their analogues
Rima Laroum, Fabienne Berrée, Thierry Roisnel, Vincent Dorcet, Bertrand
Carboni, Abdelmadjid Debache
PII:
S0040-4039(19)30743-9
DOI:
https://doi.org/10.1016/j.tetlet.2019.150988
TETL 150988
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 June 2019
19 July 2019
26 July 2019
Please cite this article as: Laroum, R., Berrée, F., Roisnel, T., Dorcet, V., Carboni, B., Debache, A., AlCl3-promoted
reaction of cycloalkanones with hydrazones: a convenient direct synthesis of 4,5,6,7-tetrahydro-1H-indazoles and
their analogues, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.150988
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. 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.
© 2019 Published by Elsevier Ltd.

JOURNAL PRE-PROOF
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.
AlCl3-promoted reaction of cycloalkanones with Leave this area blank for abstract info.
arylhydrazones: a convenient direct synthesis of
4,5,6,7-tetrahydro-1H-indazoles and their analogues
Rima Laroum, Fabienne Berrée, Thierry Roisnel, Vincent Dorcet, Bertrand Carboni and Abdelmadjid Debache
Ar1
O
N
N
H
N
Ar2
R
R
N Ar2
AlCl3
14 examples
31-65%
+
( )n
( )n
Ar1
R'
DCE, 80 °C, 16 h
R'
1
2
3

JOURNAL PRE-PROOF
1
Tetrahedron Letters
journal homepage: www.elsevier.com
AlCl3-promoted reaction of cycloalkanones with hydrazones: a convenient direct
synthesis of 4,5,6,7-tetrahydro-1H-indazoles and their analogues
Rima Laroum,a Fabienne Berrée,b Thierry Roisnel,b Vincent Dorcet, b Bertrand Carbonib* and Abdelmadjid
Debache a*
a Laboratoire de Synthèse des Molécules d’Intérêts Biologiques, Université des Frères Mentouri-Constantine, 25000 Constantine, Algérie
b Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000 Rennes, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The AlCl3-promoted reactions of cycloalkanones with hydrazones are described. This approach
represents a mild and operationally simple method to access 2,3-diaryl-4,5,6,7-tetrahydro-1H-
indazoles and their analogues in good to moderate yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Cycloalkanones
Hydrazones
Tetrahydroindazoles
Aluminium chloride
Introduction
4,5,6,7-Tetrahydro-1H-indazoles are generally prepared via the
2b,4c,11
reaction of aryl hydrazines with 1,3-diketones
or -
Nitrogen-containing heterocycles represent one of the most
important classes of organic compounds. They are abundant in
natural products and are also the major constituents of a variety
of drugs.1 Among the vast number of pharmacologically active
heterocyclic compounds, 4,5,6,7-tetrahydro-1H-indazoles and
their analogues are of particular interest since they possess anti-
unsaturated ketones,12 an approach that is often affected by
regioisomer formation. Other important strategies for the
construction of the tetrahydro-indazole ring consist of base-
mediated addition of hydrazones to nitroolefins13 metal-catalyzed
cyclization
of
-bromo--unsaturated
ketones
with
arylhydrazines,14 aminohydroxylation of allylic hydrazones,15
nitrilimine cycloaddition to enamines,16 or iodine-mediated
intramolecular amination.17 Alternative approaches include
modification of a prebuilt bicyclic subunit via oxidation of
dihydroindazoles,2a,18 partial reduction of indazoles,8 Pd(II)- or
photoredox-catalyzed C-3 arylation,19 or N-arylation reactions in
the presence of Cu(I).20
inflammatory,2
antituberculosis,3
and
antiproliferative
properties,4 or are sigma-1 receptor ligands,5 ER agonist/ER
antagonists,6 cannabinoid-1 receptor inverse agonists,7 gamma
secretase modulators8 or interleukin-2 inducible T-cell kinase
inhibitors9 (Fig. 1). In parallel, they are also used as ligands in
gold, uranium, rhodium, iridium and palladium complexes.10
F
O
N
N
F
N
N
N
H
N
H
N
N
N
N
N
N
O
N
N
N
N
N
O
H
N
4
DHODH inhibitor
Ar
N
N
8
H
-Secretase modulator
Cl
Cl
F
2a
Sigma-1 receptor
ligand 5
CoX-2 inhibitor
HO
H
N
N
O
N
N
N
H
N
H
N
N
N
OCF3
F
F
CB1 receptor
inverse agonist 7
N
O
N
O
O
OH
F
N
3
O S
Antituberculosis agent
9
ITK inhibitor
ER agonist / ER antagonist 6

JOURNAL PRE-PROOF
Tetrahedron Letters
2
Figure 1. Selected examples of bioactive 4,5,6,7-tetrahydro-1H-indazoles and their analogues.
In this context, it is still relevant to develop simple and direct
yield (3aa versus 3ab) and no product was observed with a more
approaches for the synthesis of this class of heterocycles.
Inspired by the work of Minunni21 and Cecchi22 and co-workers
regarding the reaction of aldohydrazones with benzoylacetic
esters, we hypothesized that a similar approach could constitute a
direct access to 2,3-diaryl-4,5,6,7-tetrahydro-1H-indazoles and
their analogues starting from cycloalkanones and aryl hydrazones
via an acid-catalyzed process (Scheme 1).
hindered substrate such as menthone. In contrast, cycloheptanone
and
cyclooctanone
gave
4,5,6,7-tetrahydro-1H-indazole
analogues, as - and -tetralones, which afforded 3ae and 3af,
respectively. In the latter case, a single regioisomer was formed.
Finally, similar yields were obtained with hydrazones prepared
from 4-methyl and chloro-substituted benzaldehydes. It is worth
noting that this approach can be extended to a dialkylketone,
such as 3-pentanone, while the reaction inexplicably failed with
cyclopentanone.
Ar1
N
O
H
Ar2
N
R
R
Ar2
Table 2. Scope of the AlCl3-catalyzed reaction of alkanones with hydrazones.
N
AlCl3
Me
N
+
( )n
( )n
Ar1
DCE, 80°C, 15h
R'
R'
Me
2y
1x
3xy
N
N
N
Scheme 1. Synthesis of 2,3-diaryl-4,5,6,7-tetrahydro-1H-indazoles.
N
N
N
Results and Discussion
3ba (48%)
3aa (65%)
3ca (53%)
Our investigations were initiated with phenylhydrazone 1a
and cyclohexanone 2a as model substrates to develop optimal
conditions for the formation of 3aa, as depicted in Table 1. In the
presence of AlCl3 in 1,2-dichloroethane, no reaction occurred at
room temperature; however, the desired product was obtained in
49% yield after heating for 15 h at 80 °C (Table 1, entry 1).
Lower yields were observed with FeCl3 and Yb(OTf)3; the latter
had the advantage of requiring only 0.1 equivalents of catalyst
(Entries 2-3). The reaction failed with TsOH or PhB(OH)2
(Entries 4-5). A short study of the influence of the relative
amounts of 1a, 2a and AlCl3 showed that the highest yield was
obtained with a 1/1.5/2 ratio (Entries 1, 6-8).
Me
Cl
Br
N
N
N
N
N
N
3da (52%)
3ea (54%)
3fa (50%)
MeO
N
N
N
N
N
N
Table 1. Optimization of the reaction conditions.
Me
Ph
O
3ga (35%)
3ab (31%)
3ac (59%)
H
N
N
Lewis or Brønsted
acid
N
Ph
N
Ph
+
DCE, 80 °C, 16 h
Ph
N
N
N
N
N
N
1a
2a
3aa
Entry
1
Acid
2a (equiv.)a Acid (equiv.)a Yield 3aa (%)b
1
1
1
1
AlCl3
49
45
35
0
3ad
(65%)
3ae
(54%)
3af (41%)
2
3
4
5
6
7
8
FeCl3
N
N
1
0.1
1
N
N
Yb(OTf)3
PhB(OH)2
TosOH
AlCl3
N
N
1
3ja (61%)
3ia (56%)
Me
3ha (54%)
Me
Cl
1
1
0
a Reagents and conditions: 1a (1 mmol), alkanone 2a (1.5 mmol), AlCl3 (2
mmol), 1,2-dichloroethane (5 mL), 80 °C, 16 h. Yield was calculated
using the H NMR of the crude product with 1,3,5-trimethoxybenzene as
an internal standard.
1.5
1
2
72
53
45
b
1
AlCl3
2
AlCl3
2
2
Compounds 3 were fully characterized by 1H NMR, 13C
NMR, IR, and mass spectroscopy with experimental data in full
agreement with the proposed formula (see ESI). Additionally, the
structures of compounds 3ae and 3af were confirmed by single
crystal X-ray analysis (Fig. 2).23
The scope of the reaction was then evaluated under the
optimized conditions. A range of arylhydrazones 1 derived from
phenylhydrazine and aromatic aldehydes were first engaged in
this process using cyclohexanone 2a as a model partner (Scheme
1, Table 2). Various electron-donating or withdrawing
substituents on the aromatic moiety were tolerated with no
significant influence of their nature or location. The lower yield
observed for 3ga was attributed to partial demethylation due to
the presence of the Lewis acid. The introduction of a substituent
at the C-2 position of the cyclohexanone notably decreased the

JOURNAL PRE-PROOF
3
Acknowledgments
This work was supported by the University of Rennes 1 and
the Centre National de la Recherche Scientifique (CNRS). RL
gratefully acknowledges le Ministère de l’Enseignement
Supérieur et de la Recherche Scientifique (Algeria) for financial
support (Profas program).
Appendix A. Supplementary data
Experimental procedures for the preparation of compounds 3
and the copies of their 1H/13C NMR spectra) can be found online
at ……..
References and notes
1. (a) E. Vitaku, D.T. Smith, J.T. Njardarson, J. Med. Chem. 57 (2014)
10257–10274. (b) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med.
Chem. 57 (2014) 5845-5859.
2. (a) Z. Sui, J. Guan, M.P. Ferro, K. McCoy, M.P. Wachter, W.V. Murray,
M. Singer, M. Steber, D.M. Ritchie, D.C. Argentieri, Bioorg. Med.
Chem. Lett. 10 (2000) 601–604. (b) H.H. Kim, J.G. Park, T.C. Moon,
H.W. Chang, Y. Jahng, Arch. Pharm. Res. 22 (1999) 372–379. (c) M.
Nagakura, T. Ota, N. Shimidzu, K. Kawamura, Y. Eto, Y. Wada, J. Med.
Chem. 22 (1979) 48–52. (d) V.B. Anderson, M.N. Agnew, R.C. Allen,
J.C. Wilker, H.B. Lassman, W.J. Novick Jr., J. Med. Chem. 19 (1976)
318–325.
Figure 2. X-Ray crystallographic structures of 4,5,6,7-tetrahydro-1H-
indazoles 3ae and 3af.
A plausible mechanism was proposed using 1-benzylidene-2-
phenylhydrazine 1a and cyclohexanone 2a as model reactants
(Scheme 2). The formation of aluminum enolate 4 is followed by
the addition of hydrazone to afford hydrazinoketone 5.24
Cyclization provides the corresponding 2,3,4,5,6,7-tetrahydro-
1H-indazole via the elimination of water. The final aromatization
step results from oxidation by atmospheric oxygen, either during
the reaction or upon workup.13,25 This proposal is in agreement
with the observed regioselectivity in the case of -tetralone 3af
resulting from the more stable enolate.
3. S. Guo, Y. Song, Q. Huang, H. Yuan, B. Wan, Y. Wang, R. He, M.G.
Beconi, S.G. Franzblau, A.P. Kozikowski, J. Med. Chem. 53 (2010) 649–
659.
4. (a) M.J. Ladds, I.M. van Leeuwen, C.J. Drummond, S. Chu, A.R. Healy,
G. Popova, A. Pastor Fernandez, T. Mollick, S. Darekar, S.K. Sedimbi,
M. Nekulova, M.C. Sachweh, J. Campbell, M. Higgins, C. Tuck, M.
Popa, M.M. Safont, P. Gelebart, Z. Fandalyuk, A.M. Thompson, R.
Svensson, A.-L. Gustavsson, L. Johansson, K. Faernegaardh, U. Yngve,
A. Saleh, M. Haraldsson, A.C. D’Hollander, M. Franco, Y. Zhao, M.
Haakansson, B. Walse, K. Larsson, E.M. Peat, V. Pelechano, J. Lunec, B.
Vojtesek, M. Carmena, W.C. Earnshaw, A.R. McCarthy, N.J. Westwood,
M. Arsenian-Henriksson, D.P. Lane, R. Bhatia, E. McCormack, S. Lain,
Nat. Commun. 9 (2018) 1–14. (b) K.M. Kasiotis, E.N. Tzanetou, D.
Stagos, N. Fokialakis, E. Koutsotheodorou, D. Kouretas, S.A.
Haroutounian, Z. Naturforsch. 70 (2015) 677–690. (c) E. Tzanetou, S.
Liekens, K.M. Kasiotis, N. Fokialakis, S.A. Haroutounian, Arch. Pharm.
345 (2012) 804–811.
5. I. D. Iyamu, W. Lv, N. Malik, R. K. Mishra, G. E. Schiltz, Bioorg. Med.
Chem. 27 (2019), 1824-1835.
6. X. Alexia, K. M. Kasiotis, N. Fokialakis, G. Lambrinidis, A. K.
Meligova, E. Mikros, S. A. Haroutounian, M. N. Alexis, J. Steroid
Biochem. Mol. Biol. 117 (2009) 159-167.
7. J.M. Matthews, J.J. McNally, P.J. Connolly, M. Xia, B. Zhu, S. Black, C.
Chen, C. Hou, Y. Liang, Y. Tang, M.J. Macielag, Bioorg. Med. Chem.
Lett. 26 (2016) 5346–5349.
Ph
Cl
Al
H
Cl
Cl
O
Cl
N
Ph
N
Al
Al
O
O
Cl
AlCl3
O
1a
N
NHPh
Ph
Cl
N
NHPh
via
Ph
- HCl
4
2a
5
Ph
H
HNPh
NH
H
Ph
H
N
O
N
N
N
O
+HCl
- AlCl3
HO
Ph
Ph
Ph
Ph
H
Ph
N
N
N
N
O2
-H2
Ph
Ph
-H2O
8. K. Gerlach, S. Hobson, C. Eickmeier, U. Gross, C. Braun, P. Sieger, M.
Garneau, S. Hoerer, N. Heine, Bioorg. Med. Chem. 26 (2018) 3227–3241
9. J.D. Burch, K. Barrett, Y. Chen, J. DeVoss, C. Eigenbrot, R. Goldsmith,
M.H.A. Ismaili, K. Lau, Z. Lin, D.F. Ortwine, A.A. Zarrin, P.A.
McEwan, J.J. Barker, C. Ellebrandt, D. Kordt, D.B. Stein, X. Wang, Y.
Chen, B. Hu, X. Xu, P.-W. Yuen, Y. Zhang, Z. Pei, J. Med. Chem. 58
(2015) 3806–3816.
3aa
Scheme 2. Proposed mechanism for the formation of 3
Conclusion
10. (a) S. Radisavljevic, I. Bratsos, A. Scheurer, J. Korzekwa, R. Masnikosa,
A. Tot, N. Gligorijevic, S. Radulovic, A. Rilak Simovic, Dalton Trans.
47 (2018) 13696–13712. (b) J. Korzekwa, A. Scheurer, F.W. Heinemann,
K. Meyer, Dalton Trans. 46 (2017) 13811–13823. (c) A. Herrera, A.
Briceno, T. Gonzalez, A. Linden, F.W. Heinemann, G. Agrifoglio, J.
Pastran, R. Dorta, Tetrahedron: Asymmetry. 27 (2016) 759–767. (d) I.
Ilaldinov, D. Fatkulina, S. Bucharov, R. Jackstell, A. Spannenberg, M.
Beller, R. Kadyrov, Tetrahedron: Asymmetry. 22 (2011) 1936–1941. (e)
I.Z. Ilaldinov, D.A. Fatkulina, R. Kadyrov, Russ. J. Org. Chem. 47
A
series of 4,5,6,7-tetrahydro-1H-indazoles and their
analogues was synthesized via the reaction of cycloalkanones
with hydrazones promoted by the inexpensive aluminum
chloride. Although the yields are only moderate, this direct
approach offers the major advantage of using commercially
available or easily accessible starting materials with a wide range
of structural diversity.

JOURNAL PRE-PROOF
4
Tetrahedron
(2011) 952–953. (f) M.J. Spallek, S. Stockinger, R. Goddard, O. Trapp,
Adv. Synth. Catal. 354 (2012) 1466–1480.
18. G. A. Nishiguchi, A. L. Rodriguez, J. A. Katzenellenbogen, Bioorg.
Med. Chem. Lett. 12 (2002) 947–950.
11. (a) S.S. Rahmatzadeh, B. Karami, S. Khodabakhshi, J. Chin. Chem. Soc.
62 (2015) 17–20. (b) M. Curini, O. Rosati, V. Campagna, F. Montanari,
G. Cravotto, M. Boccalini, Synlett. (2005) 2927–2930. (c) D.V.
Sevenard, O.G. Khomutov, M.I. Kodess, K.I. Pashkevich, I. Loop, E.
Lork, G.-V. Roschenthaler, Can. J. Chem. 79 (2001) 183–194. (e) C.
Ainsworth, Org. Synth. 39 (1959), 27-30.
12. (a) M.M. Gar, A.V. Eremeev, K.Yu. Suponitsky, S.V. Popkov, Russ.
Chem. Bull. 63 (2014) 1142–1147. (b) A. Nakhai, J. Bergman,
Tetrahedron. 65 (2009) 2298–2306. (c) G.A. Nishiguchi, A.L. Rodriguez,
J.A. Katzenellenbogen, Bioorg. Med. Chem. Lett. 12 (2002) 947–950.
13. (a) X. Deng, N.S. Mani, J. Org. Chem. 73 (2008) 2412–2415. (b) X.
Deng, N.S. Mani, Org. Lett. 10 (2008) 1307–1310.
19. N.A. Romero, K.A. Margrey, N.E. Tay, D.A. Nicewicz, Science 349
(2015) 1326–1330.
20. S.E. Ward, M. Harries, L. Aldegheri, N.E. Austin, S. Ballantine, E.
Ballini, D.M. Bradley, B.D. Bax, B.P. Clarke, A.J. Harris, S.A. Harrison,
R.A. Melarange, C. Mookherjee, J. Mosley, G. Dal Negro, B. Oliosi, K.J.
Smith, K.M. Thewlis, P.M. Woollard, S.P. Yusaf, J. Med. Chem. 54
(2011) 78–94.
21. (a) G. Minunni, G. Lazzarini, S. D'Urso, Gazz. Chim. Ital. 55 (1925)
502-539. (b) G. Minunni, S. D'Urso, T.G. Troia, A. Carnevale, G. Arezzi,
C. Vizzini, Gazz. Chim. Ital. 58 (1928) 691-712.
22. L. Cecchi, F. Melani, G. Palazzino, G. Filacchioni, G. C. Porretta,
Farmaco 39 (1984) 888-900. (b) L. Cecchi, F. Melani, G. Palazzino, G.
Filacchioni, Farmaco 39 (1984) 953-962.
23. CCDC 1922242 and 1922243 contains the crystallographic data for
compounds 3ae and 3af, respectively. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac. uk/data_request/cif.
14. (a) H.K. Lee, C.S. Cho, Synth. Commun. 43 (2013) 915–921. (b) H.K.
Lee, C.S. Cho, Appl. Organomet. Chem. 26 (2012) 570–575.
15. Y.-C. Chen, M.-K. Zhu, T.-P. Loh, Org. Lett. 17 (2015) 2712–2715.
16. K. Tshiamala, S. Kitane, J. Vebrel, B. Laude, Bull. Soc. Chim. Belg. 95
(1986) 1083–1098. (b) S. Kitane, T. Kabula, J. Vebrel, B. Laude,
Tetrahedron Lett. 22 (1981) 1217–1218. (c) M.E. Kuehne, J. Weaver, P.
Franz, J. Org. Chem. 29 (1964) 1582–1586.
24. For a similar mechanistic hypothesis in the case of -ketoesters, see: K.
S. Hariprasad, K. V. Prasada, B. C. Raju, RSC Adv. 6 (2016) 108654-
108661.
25. A. Citterio, M. Ramperti, E. Vismara, J. Heterocyclic Chern. 18, (1981)
763-765
17. W. Wei, Z. Wang, X. Yang, W. Yu, J. Chang, Adv. Synth. Catal. 359
(2017) 3378–3387.

JOURNAL PRE-PROOF
5
Highlights
 Direct synthesis of 2,3-diaryl-4,5,6,7-
tetrahydro-1H-indazoles and analogues
 Pharmacologically active heterocyclic
compounds
 Commercially available or easily accessible
starting materials
 Inexpensive Lewis acid as reagent