One-pot synthesis of new 6-pyrrolyl-N-alkyl-indazoles from reductive coupling of N-alkyl-6-nitroindazoles and 2,5-hexadione

Article abstract of DOI:10.1016/j.tetlet.2015.11.071

One-pot synthesis of 6-pyrrolyl-N-alkyl-indazoles by the reductive coupling of N-alkyl-6-nitroindazoles and 2,5-hexadione was investigated in the presence of different reducing agents (SnCl₂/AcOH and In/AcOH in THF). Indazoles 5a-h and 6a-h wer

Full text of DOI:10.1016/j.tetlet.2015.11.071

Accepted Manuscript
One-pot synthesis of new 6-pyrrolyl-N-alkyl-indazoles from reductive coupling
of N-alkyl-6-nitroindazoles and 2,5-hexadione
Mohamed El Ghozlani, Hakima Chicha, Najat Abbassi, Mohamed Chigr,
Lahcen El Ammari, Mohamed Saadi, Domenico Spinelli, El Mostapha Rakib
PII:
S0040-4039(15)30379-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.071
TETL 47011
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 July 2015
26 October 2015
24 November 2015
Please cite this article as: Ghozlani, M.E., Chicha, H., Abbassi, N., Chigr, M., Ammari, L.E., Saadi, M., Spinelli,
D., Rakib, E.M., One-pot synthesis of new 6-pyrrolyl-N-alkyl-indazoles from reductive coupling of N-alkyl-6-
nitroindazoles and 2,5-hexadione, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.071
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Tetrahedron Letters
One-pot synthesis of new 6-pyrrolyl-N-alkyl-indazoles from reductive coupling
of N-alkyl-6-nitroindazoles and 2,5-hexadione
Mohamed El Ghozlania, Hakima Chichaa, Najat Abbassia, Mohamed Chigra, Lahcen El Ammarib,
Mohamed Saadib, Domenico Spinellic, El Mostapha Rakiba,*
aLaboratoire de Chimie Organique et Analytiques, Faculté des Sciences et Techniques, Université Sultan Moulay Slimane, B.P. 523, Béni-Mellal, Morocco
bLaboratoire de Chimie du Solide Appliquée, Faculté des Sciences, Université Mohammed V, Avenue Ibn Battouta, B.P. 1014, Rabat, Morocco
cDepartment of Chemistry ‘G. Ciamician’ Alma Mater Studiorum – University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
One-pot synthesis of 6-pyrrolyl-N-alkyl-indazoles by the reductive coupling of N-alkyl-6-
nitroindazoles and 2,5-hexadione was investigated in the presence of different reducing agents
(SnCl2/AcOH and In/AcOH in THF). Indazoles 5a–h and 6a–h were obtained with good to
excellent yields (74–95%) and characterized by elemental analysis, NMR and single crystal X-
ray diffraction. The same synthetic approach was also used to obtain 5-pyrrolyl-N-alkyl-
indazoles.
Available online
Keywords:
N-alkyl-6-nitroindazoles
N-alkyl-5-nitroindazoles
Reduction (SnCl2 or Indium)
6-pyrrolyl-N-alkyl-indazoles
5-pyrrolyl-N-alkyl-indazoles
2015 Elsevier Ltd. All rights reserved.
1. Introduction
and 2,5-hexadione using indium or stannous chloride in THF in
the presence of acetic acid.
Because of their presence in several life processes, e.g.
hemoglobin, chlorophyll, DNA, RNA and nucleic acids,
nitrogen-containing heterocycles have attracted the attention of
organic and pharmaceutical researchers.1 Thus, benzoannulated
nitrogen heterocycles offer a high degree of structural diversity
and have proven to be broadly useful as therapeutic agents.2
2. Results and discussions
6-Nitroindazoles (1a,b) are themselves interesting substrates,
and their heterocyclic skeletons are decorated with functional
groups which are able to undergo modification. They are able to
react with alkylating agents at the N-1 and N-2 atoms. Moreover
the nitro group can be modified by reducing agents or by
ONSH7,8 and SNH17 processes.
Among these heterocyclic frameworks, indazole (aromaticity
index 144)3 derivatives have been widely used in medicinal
chemistry4 and drug discovery,5 Following this line of research
we have reported a series of indazoles bearing a sulfonamide
moiety possessing good antiproliferative activities.6-8
Recently Moreau and Coworkers have reviewed synthetic
approaches to indazole derivatives and examined their kinase
inhibitory potency.9 Indazoles substituted with azolyl nuclei also
have profound interest in medicinal chemistry due to their wide
range of biological activities.4,10 Only a few examples of
syntheses for joining indazoles with heterocyclic moieties such as
furan, thiophene, pyridine, pyrrole and thiazole moieties have
been reported.11-16 Generally, the cross-coupling procedures were
applied for the synthesis of heteroaryl substituted indazoles.13-16
Due to our ongoing interest in developing simple and low-
cost procedures for obtaining heterocyclic compounds that may
be of interest for medicinal purposes, herein, we present a simple
and efficient procedure for the synthesis of 6-pyrrolyl-N-alkyl-
indazoles by reductive coupling of N-alkyl-6-nitroindazoles
Scheme 1.Synthesis of N-alkyl-6-nitroindazoles
By exploiting this different possible reactivity we firstly
describe the synthesis of N-alkyl-6-nitroindazoles (2a-d and 3a-
d) and N-alkyl-3-chloro-6-nitroindazoles (2e–h and 3e–h) by
alkylation of 6-nitroindazoles (1a,b) with methyl iodide, ethyl
iodide, allyl bromide and 4-methylbenzyl bromide using
conditions previously developed by our group.18 The
 Corresponding author. Tel.: +212 523485182; fax: +212
523485201. E-mail: elmostapha1@ymail.com (E.M. Rakib).

2
Tetrahedron Letters
regioisomeric 1-alkyl-6-nitroindazoles (2a–d and 2e–h) and 2-
alkyl-6-nitroindazoles (3a–d and 3e–h) could be separated by
column chromatography and identified by comparison of their
spectral data (Scheme 1).
As shown in Table 1, alkylation of 6-nitroindazoles 1a,b with
alkyl halides provided the expected mixture of N1 and N2
alkylation products with moderate selectivity in favor of
compounds 2 with respect to 3. In our previous work,18 and in the
literature19-21 it has been shown that the nature of alkylating agent
and the experimental conditions used (solvent, base and
temperature) significantly affect the alkylation regioselectivity at
N-1 or N-2 of the indazole ring.
5a
Table 1: Yields for N-alkyl-6-nitroindazoles 2a-h and 3a-h
Entry
X
R
Yield of 2a–h
2a (55%)
2b (53%)
2c (65%)
2d (45%)
2e (56%)
2f (64%)
Yield of 3a–h
3a (44%)
3b (46%)
3c (34%)
3d (31%)
3e (42%)
3f (32%)
1
2
3
4
5
6
7
8
H
CH3
H
CH3CH2
Allyl
H
H
4-Me-benzyl
CH3
Cl
Cl
Cl
Cl
CH3CH2
Allyl
6e
2g (62%)
2h (65%)
3g (36%)
3h (31%)
Figure 1. X-ray crystal structures of 5a and 6e.23
4-Me-benzyl
Looking at the influence that the structure of the starting 6-
nitro-N-alkyl-indazole had on the reduction/cyclization yields in
the presence of SnCl2 we observed that indazoles 2a–h (alkylated
at N-1) gave higher yields than indazoles 3a–h (alkylated at N-2)
(mean yield 85% vs 78%). We also noted that 2g and 2h
(substituted at C-3 with a chlorine atom and at N-1 with an allyl
or a 4-methylbenzyl group) gave the 6-pyrrolyl-1-alkyl-indazoles
5g,h with the highest yields (95% and 90%, respectively).
We initially examined the reactivity of N-alkyl-6-
nitroindazoles 2a–h and 3a–h with 2,5-hexadione in the presence
of In/AcOH in THF. In all cases, N-alkyl-6-(2,5-dimethyl-1H-
pyrrol-1-yl)-1H-indazoles 5a–h and 6a–h were obtained in
moderate to good yields (64-88%, Table 2, Scheme 2).
Searching for improved experimental conditions in order to
maximize the yields, we investigated the reductive
heterocyclisation of 6-nitroindazoles with 2,5-hexadione in the
presence of SnCl2/AcOH in THF at 80 °C, obtaining compounds
5a–h and 6a–h in high purity, with good to excellent yields (74–
95%, mean yield 82%, Table 2, scheme 2).22
Regarding the possible mechanism, it is likely that the 1- or
2-alkyl-6-nitroindazoles (2a–h or 3a–h, respectively) were first
transformed into the corresponding amine by the reducing agents
and then undergo reaction in situ with 2,5-hexadione according to
the well known Paal-Knorr pyrrole synthesis mechanism.24
Encouraged by these results, we decided to expand the scope
of this methodology to the synthesis of other substituted
indazoles. Selected N-alkyl-5-nitroindazoles 7a–c were reacted
with 2,5-hexadione 4 using the optimized reaction conditions
(Scheme 3). As expected, the corresponding N-alkyl-5-
pyrrolylindazoles 8a,b and 8c were formed in 78%, 84% and
72% yields, respectively.
Scheme 2.
All structures were determined by examination of their NMR
data. Furthermore, the structures of products 5a and 6e were
unambiguously confirmed through single crystal X-ray
crystallographic analysis (Fig. 1).23
Scheme 3.

Table 2. Metal-mediated reductive heterocyclization of N-alkyl-6-nitroindazole with 2,5-hexadione under different experimental
conditions.
Reaction
time (h)
Yield using
In (%)
Yield using
SnCl2 (%)
Entry
Substrate
Product
1
3
3
4
4
4
4
76
70
64
68
76
73
84
76
80
75
80
78
2
3
4
5
6
7
8
5
5
76
74
84
80
9
4
4
3
3
4
4
75
70
75
67
88
64
84
80
85
74
95
76
10
11
12
13
14
15
4
83
90

4
Tetrahedron
16
4
79
88
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3. Conclusions
We have developed a simple and efficient synthesis of N-
alkyl-6-(2,5-dimethyl-pyrrol-1-yl)-indazoles using the reductive
heterocyclisation of N-alkyl-6-nitroindazole derivatives with 2,5-
hexadione in the presence of acetic acid. Using SnCl2/AcOH in
THF at 80°C we realized a methodology which provided high
yields, short reaction times, easy work-up, and clean reactions.
This represents
a
new strategy for obtaining N-fused
heterocycles, which promises to have wide application in organic
and medicinal chemistry. Biological evaluation of the obtained
compounds is currently underway in our laboratory.
Acknowledgments
We thank the University of Sultan Moulay Slimane, Beni-
Mellal for financial support and the National Centre for Scientific
and Technical Research (CNRST), Rabat, for providing the NMR
and X-ray crystallography of compounds.
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22. General procedure for the synthesis of compounds 5a–h and 6a–h.
N-alkyl-6-nitroindazoles (1.0 mmol) were added to a mixture of
anhydrous SnCl2 powder (460 mg, 4.0 mmol), and acetic acid
(0.572 mL, 10 mmol) in THF (10 mL), followed by the addition of
2,5-hexadione (1.0 mmol) in THF (15 mL). The reaction mixture
was stirred at 80 °C for 3 to 5 h. Upon reaction completion, the
mixture was diluted with EtOAc (30 mL), poured into 10%
NaHCO3 (30 mL), and extracted with EtOAc (50 mL x 3). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated. The residue was purified by column chromatography
on silica gel using EtOAc/hexane (3:7) to afford the N-alkyl-6-
pyrrolyl-indazoles. 1H NMR, 13C NMR and DEPT copies of
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Supplementary Material
Supplementary data (spectroscopic and X-ray data) associated
1
with this article - copies of H and 13C NMR Spectra can be
found, in the online version, at

Graphical abstract
One-pot synthesis of new 6-pyrrolyl-N-alkyl-indazoles
from reductive coupling of N-alkyl-6-nitroindazoles
and 2,5-hexadione
Leave this area blank for abstract info.
Mohamed El Ghozlania, Hakima Chichaa, Najat Abbassia, Mohamed Chigra, Lahcen El Ammarib,
Mohamed Saadib, Domenico Spinellic, El Mostapha Rakiba,*