A novel and efficient synthesis of 3-aryl and 3-heteroaryl substituted-1H-indazoles and their Mannich derivatives

Article abstract of DOI:10.1081/SCC-120014767

A general and highly convenient procedure for the synthesis of 3-heteroaryl and 3-aryl substituted-1H-indazoles has been developed. These compounds (3a-f) were synthesized in good yield by refluxing the NaHSO₃ adduct of heteroaromatic and aromatic aldehyde and phenyl hydrazine in DMF. This procedure is more general and shorter than earlier methods. Five new 3-hetero-aryl substituted-1H-indazoles were synthesized and characterized. New Mannich derivatives of 3-(1H-pyrrol-2-yl)-1H-indazole (3a) and 3-(1H-indol-3-yl)-1H-indazole (3b) were prepared from morpholine and formaldehyde.

Full text of DOI:10.1081/SCC-120014767

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A NOVEL AND EFFICIENT SYNTHESIS OF 3-ARYL AND 3-
HETEROARYL SUBSTITUTED-1H-INDAZOLES AND THEIR
MANNICH DERIVATIVES
Süleyman Servi a & Z. Rüstem Akgün a
a Department of Chemistry, Firat University, Elaziğ, 23169, Turkey
Published online: 22 May 2009.
To cite this article: Süleyman Servi & Z. Rüstem Akgün (2002): A NOVEL AND EFFICIENT SYNTHESIS OF 3-ARYL AND 3-
HETEROARYL SUBSTITUTED-1H-INDAZOLES AND THEIR MANNICH DERIVATIVES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:22, 3399-3405
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 22, pp. 3399–3405, 2002
A NOVEL AND EFFICIENT SYNTHESIS
OF 3-ARYL AND 3-HETEROARYL
SUBSTITUTED-1H-INDAZOLES AND
THEIR MANNICH DERIVATIVES
*
Suleyman Servi and Z. Rustem Akgun
Firat University, Department of Chemistry,
23169, Elazig, Turkey
ABSTRACT
A general and highly convenient procedure for the synthesis
of 3-heteroaryl and 3-aryl substituted-1H-indazoles has been
developed. These compounds (3a–f ) were synthesized in good
yield by refluxing the NaHSO3 adduct of heteroaromatic and
aromatic aldehyde and phenyl hydrazine in DMF. This
procedure is more general and shorter than earlier methods.
Five new 3-hetero-aryl substituted-1H-indazoles were syn-
thesized and characterized. New Mannich derivatives of
3-(1H-pyrrol-2-yl)-1H-indazole (3a) and 3-(1H-indol-3-yl)-
1H-indazole (3b) were prepared from morpholine and
formaldehyde.
*Corresponding author. Fax: 0424 2330062; E-mail: sservi@firat.edu.tr
3399
DOI: 10.1081/SCC-120014767
Copyright & 2002 by Marcel Dekker, Inc.
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3400
SERVI AND AKGUN
INTRODUCTION
The synthesis of 3-substituted-1H-indazole derivatives has become of
interest recently to medicinal chemists due to its pharmacophoric relation-
ship to the hetero-aromatic rings.[1–3] Heteroaromatic rings such as pyrrole,
thiophene, furan, pyridine, indole, pyridazine, 1,2-benzisooxazole, indole,
quinoline, and isoquinoline rings showed weak 5-HT3 receptor antagonistic
activity. Within this series, use of the 1H-indazole ring as an aromatic
moiety led to substantial increase of the activity.[4]
A review of the methods available for the synthesis of 3-heteroaryl
substituted-1H-indazoles derivatives was not encouraging. The reported
synthetic routes are generally laborious, multistep procedures requiring
the synthesis of relatively complicated starting materials and in addition,
several of these results in the preparation of 3-heteroaryl substituted-
1(2)H-indazoles derivatives were limited interest to us.[5,6]
In this study, a series of 3-heteroaryl and aromatic substituted-
1H-indazoles were easily prepared in good yield by refluxing the bisulfide
adduct of hetero-aromatic aldehydes and phenyl hydrazine in dimethyl-
formamide for 4 to 5 h.
RESULTS AND DISCUSSION
One of the formerly utilized general routes to indazoles involves the
reaction of aldehyde and ketones with nitro-phenyl-hydrazones.[7] Indazoles
can be synthesized by a number of methods, usually involving formation
of the N–N bond as the key step. One of the new classical methods for
3-aromatic substituted-1H-indazoles synthesis is the reaction of carboxylic
acids with phenyl hydrazines. In classic method, the excess of carboxylic
acid is used to close the ring (ncarboxylic acid/nphenyl hydrazine: 10/1). Reaction
yields very much depend on the amount of the carboxylic acid used in this
method.
Although there are studies related to 3d and 3e in the literature,
no studies were found about the other hetero-aromatic substituted
indazoles.[8–10] (Fig. 1).
Pyrrole, indole, thiophen, strenyl substituted 1H-indazoles and their
Mannich derivatives have been synthesized for the first time with this
method. This method can easily be applied to aliphatic aldehydes, too.
1H,10H-[3,30] Biindazolyl (4) was obtained at the end of the reaction of
the products of the glyoxal addition to NaHSO3 and phenyl hydrazine in
a high yield (Fig. 2).

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3-ARYL AND 3-HETEROARYL SUBSTITUTED-1H-INDAZOLES
3401
Figure 1. Synthetic route for synthesis of 3-aryl and 3-heteroaryl and aromatic
substituted-1H-indazole.
Figure 2. Synthesis of 1H,10H-[3,30]Biindazolyl (4).
Mannich derivatives of 3-(1H-pyrrol-2-yl)-1H-indazole (3a) and
3-(1H-indol-3-yl)-1H-indazole (3b) were prepared from morpholine and
35% formaldehyde. 3a and 3b compounds possess two different active
N–H hydrogenes, which can create Mannich reaction. The N–H hydrogenes
in indole and pyrrole rings are more active than those in the indazole.
Therefore, the Mannich reaction which is conducted with 1 equivalent reac-
tive is carried through the N–H hydrogenes in the pyrrole or indole ring
(Fig. 3).
Indazoles, pyrrole and indole N–H disappeared upon addition of D2O
1
to the solution, indicating that there are acidic protons in the H-NMR
spectra. The chemical shift values of protons in the 3-heteroaryl
1H-indazole are slightly shifted upfield compared to those of indazole
1
itself in the H-NMR spectra. Pyrrole, indole, furyl, thienyl, and phenyl
substituents have very small and similar effects on the chemical shifts of
protons in the indazole ring.
1,2-Disubstituted benzene ring (Indazole) showed C–H out-of-plane
deformation vibrations (very strong) at 750 or 740 cmÀ1 and the indazoles
(3386–3312 cmÀ1), pyrrole (3420 cmÀ1) and indole (3424 cmÀ1) N–H band
is sharp in the IR spectra.

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3402
SERVI AND AKGUN
Figure 3. Synthetic route for synthesis of Mannich derivatives.
EXPERIMENT
Melting points were determined on a Gallenkamp apparatus and
are uncorrected. IR spectra were measured on a Mattson model FT-IR
spectrometer and 1H, 13C-NMR spectra were measured on a FX-90 Q
JEOL model instrument. ꢀ shift values were reported in ppm relative to
TMS. Elemental analysis was determined in the Firat University,
Department of Chemistry.
The Bisulfide Addition of Hetero-Aromatic Aldehyde
0.01 mole of the appropriate hetero-aromatic aldehyde was dissolved
in 10 mL of ethanol and 0.01 mole of sodium bisulfide dissolved in 10 mL
of water. The latter solution was added to the former in small portions
within 10 min in an ice bath. The precipitate which occurred in the reaction
mixture was separated by filtration and dried under diminished pressure.
Synthesis of 3-Heteroaryl Substituted-1H-indazoles
The bisulfide adduct of hetero-aromatic aldehyde prepared was
refluxed with 0.011 mole of phenyl hydrazine in 30 mL of DMF for 4–5 h.
The reaction mixture was poured into 250 mL of ice water. The precipitate
formed was collected on filter and crystallized from ethanol.

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3-ARYL AND 3-HETEROARYL SUBSTITUTED-1H-INDAZOLES
Table 1. Physical and Spectroscopic Data for Compound 3
3403
Characteristic
IR (KBr, cmÀ1
)
Compound Yields
No.
M.P. (ꢀC) Molecular
Ethanol
(%)
Colours
Black
Light brown
Dark brown
Brown
Formulaea
N–Hb
C¼Nb
3a
3b
3c
3d
3e
3f
76
73
78
74
81
85
148
151
C11H9N3
3316
3386
3318
3320
3312
3313
1598
1660
1606
1605
1601
1603
C15H11N3
C11H8N2O
C11H8N2S
C13H10N2
C15H12N2
165c
137
Light pinkish
Light yellow
109d
170
aThe errors in elemental analysis are between Æ 0.03 and Æ 0.05; bRelated to indazole
rings; Lit.[10] 165–166ꢀC; Lit.[10] 107–108ꢀC.
c
d
3-(1H-Pyrrol-2-yl)-1H-indazole (3a): 1H-NMR (90 MHz) ꢀ: 6.217–
6.991 (m, 3H, pyrrol ring protons), 7.202–7.577 (m, 4H, indazole ring
protons), 9.86 (s, indazole N–H), 11.1 (s, indole N–H). 13C-NMR: ꢀ 108.0,
108.7, 113.8, 118.0, 120.15, 129.0, 130.7, 145.9.
3-(1H-Indol-2-yl-1H-indazole (3b): 1H-NMR (90 MHz, DMSO-d6,
ppm) ꢀ: 6.80–7.45 (m, 5H, indazole ring protons), 7.94–8.47 (5H, indole
ring protons), 9.81 (s, indazole N–H), 11.3 (s, indole N-H). 13C-NMR: ꢀ
111.1, 112.3, 117.2, 119.3, 121.7, 123.8, 126.02, 128.3, 134.4, 136.4, 145.6, 161.0.
3-Furan-2-yl-1H-indazole (3c): 1H-NMR (90 MHz, DMSO-d6, ppm) ꢀ:
6.447–6.913 (m, 3H, furan protons), 7.066–7.599 (m, 4H, aromatic protons),
10.3 (s, 1H, indazole N–H proton).
3-Thiophen-2-yl-1H-indazole (3d): 1H-NMR (90 MHz, DMSO-d6,
ppm) ꢀ: 7.21–7.85 (m, 7H, aromatic protons), 12.9 (s, 1H, indazole N–H
proton).
3-Phenyl-1H-indazole (3e): 1H-NMR (90 MHz, DMSO-d6, ppm) ꢀ:
6.852–7.669 (m, 9H, aromatic protons), 10.2 (s, 1H, indazole N–H protons).
3-Styryl-1H-indazole (3f ): 1H-NMR (90 MHz, DMSO-d6, ppm) ꢀ:
6.695–6.725 (m, 2H, CH¼CH protons), 7.010–7.563 (m, 9H, aromatic
protons), 10.39 (s, 1H, indazole N–H proton).
1H,10H-[3,30] Biindazolyl (4): Yield % 78, melting point: 166ꢀC, IR
(KBr) cmÀ1: 3305 indazole N–H stretching (sharp band), 1598 C¼N
stretching (very strong), 1122 C–N stretching (strong), 750 disubstituted
1
benzene. H-NMR (90 MHz, DMSO-d6, ppm) ꢀ: 6.58–7.68 (m, 8H, aro-
matic protons), 12.4 (s, 2H, indazole N–H proton). Elemental analysis,
C14H10N4, calculated C (71.78), H (4.30), N (23.92) found: C (69.48), H
(4.15), N (23.32).

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3404
SERVI AND AKGUN
Synthesis of Mannich Derivatives (General Method)
0.01 mole of 3-heteroaryl substituted-1H-indazoles in 20 mL of
methanol was stirred at room temperature for 2 h with 0.03 mole of 35%
formaldehyde and 0.02 mole of secondary amine such as morpholine at low
temperature. The solvent of the reaction mixture was removed with a rotary
evaporator. The residue was mixed with methanol and the precipitate
formed was filtered and then crystallized with methanol.
3-(1-Morpholin-4-yl methyl-1H-pyrrol-3-yl)-1H-indazole (5a): Yield %
63, melting point: 195ꢀC. IR (KBr) cmÀ1: 3318 Indazole N–H stretching
(sharp band), 1600 C¼N stretching, 1155 alifatic C–N stretching, 1112
cyclic ether C–O–C stretching, 745 disubsituted benzene. 1H-NMR
(90 MHz, DMSO-d6, ppm) ꢀ: 2.484 (t, 4H, morph. CH2–N–CH2), 3.472
(s, 2H, N–CH2–N), 3.734 (t, 4H, CH2–O–CH2), 6.816–7.783 (m, 7H,
aromatic protons), 9.75 (s, 1H, Indazole N–H proton).
Anal. calcd. for C16H18N4O: C, 68.06; H, 6.43; N, 19.84. Found: C,
65.68; H, 6.24; N, 19.34.
1-Morpholin-4-yl methyl-3-(1-morpholin-4-yl methyl-1H-indol-3-yl)-
1H-indazole (6b): Yield % 53, IR (KBr) cmÀ1: 1600 C¼N stretching (very
strong), 1155 alifatik C–N stretching (strong), 1114 C–O stretching, 750
1
disubstituted benzene. H-NMR (90 MHz, DMSO-d6, ppm) ꢀ: 2.53 (t, 8H,
morph. CH2–N–CH2), 3.36 (s, 4H, N–CH2–N), 3.58 (t, 8H, CH2–O–CH2),
7.29–8.30 (m, 9H, aromatic protons). 13C-NMR: 50.3, 66.1, 110.7, 111.5,
115.2, 120.3, 121.6, 122.4, 128.9, 130.4, 134.2, 138.8.
Anal. calcd. for C25H29N5O, calculated: C, 69.58; H, 6.77; N, 16.23.
Found: C, 67.61; H, 6.48; N, 15.56.
ACKNOWLEDGMENTS
We are indebted to the Firat University Research Foundation
(FUNAF) for financial support of this work (Project number: 343).
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3405
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Received in the Netherlands November 11, 2001

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