Synthesis of 1H-indazole: A combination of experimental and theoretical studies

Article abstract of DOI:10.1007/s11164-012-0488-y

A new practical synthesis of 1H-indazole is presented. A previous mechanism for the cyclization step is proved to be nonfeasible and a hydrogen bond propelled mechanism is proposed. The new mechanism is suitable for similar cyclization, and a new reaction is predicted. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0488-y

Res Chem Intermed (2012) 38:1619–1628
DOI 10.1007/s11164-012-0488-y
Synthesis of 1H-indazole: a combination
of experimental and theoretical studies
Xinzhi Chen
Chaohong He
•
Shaodong Zhou
•
Chao Qian
•
Received: 23 November 2011 / Accepted: 11 January 2012 / Published online: 26 January 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A new practical synthesis of 1H-indazole is presented. A previous
mechanism for the cyclization step is proved to be nonfeasible and a hydrogen bond
propelled mechanism is proposed. The new mechanism is suitable for similar
cyclization, and a new reaction is predicted.
Keywords Cyclization ꢀ 1H-indazole ꢀ DFT study
Introduction
Biologically active compounds containing an indazole fragment have been
investigated and applied in producing HIV protease inhibitors, serotonin receptor
antagonists, aldol reductase inhibitors, and acetylcholinesterase inhibitors [1, 2].
Various routes have been explored to synthesize indazole [3–8]. Among all these
methods, cyclization of ortho-substituted benzylidenehydrazine using ortho-substi-
tuted benzaldehyde as starting material is a useful way. As shown in Eq. 1, utilizing
nitro as a leaving group was first reported more than a century ago; then this method
was developed by using 2-fluoro and 2-hydroxyl benzaldehyde. Lukin et al. [6]
reported synthesis of indazole from 2-fluorobenzaldehyde and hydrazine, and
Lokhande et al. [5] found that the reaction between 2-hydroxylbenzaldehyde and
hydrazine can also produce indazole.
X. Chen ꢀ S. Zhou ꢀ C. Qian (&) ꢀ C. He
State Key Laboratory of Chemical Engineering,
Department of Chemical and Biological Engineering,
Zhejiang University, Hangzhou 310027, China
e-mail: supmoney@163.com
123

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X. Chen et al.
O
Z
R
N H
2 4
R
X
X
N
N
ð1Þ
H
1
1
1
a. Z=NO2
b. Z=F
c. Z=OH
2
In our recent study, we found that the reaction between benzonitrile and hydrazine
under certain conditions produces benzylidenehydrazine. This approach was
expanded to the derivatives of benzonitrile with substitution on the benzene ring.
We further investigated cyclization of various ortho-substituted benzylidenehydr-
azines and found that some of our experimental results indicate a different
mechanism from that previously proposed by Lukin et al. [6]. To figure out the
reaction details, we performed theoretical calculations using density functional
theory (DFT). The results of our investigation led to a novel mechanism related to the
synthesis of indazole.
Calculation method
All the calculations were performed using the GAUSSIAN 03 software [9]. Hybrid
DFT theory is applied to this problem with B3LYP method, which uses Becke’s
three-parameter hybrid functional [10], together with the non-local correlation
provided by the LYP expression [11, 12], and VWN functional III [13] for local
correlation. The basis set 6-311??G(d,p) was used. The polarized continuum
(
overlapping spheres) model (PCM) [14–16], which is based on a description of the
solvent as a macroscopic continuum medium, was employed to estimate the solvent
effect in aqueous reaction. Geometries of transition states (TS) were searched and
optimized. Subsequent calculations, such as frequency calculation and the intrinsic
reaction coordinates (IRC) [17, 18] calculation, were performed to confirm the TS.
Frequency calculations on the optimized geometries were also used for the zero
point energy (ZPE) corrections.
Results and discussion
Synthesis of ortho-substituted benzylidenehydrazine
Our initial investigation on the synthesis of ortho-substituted benzylidenehydrazine
from ortho-substituted benzonitrile gave surprising results. The reactions were
carried out at temperatures between 0 and 20 °C, and completed in 5 h with high
yields of corresponding benzylidenehydrazine (higher than 85% of GC yields) under
catalysis by Raney nickel (Eq. 2). In employing hydrazine hydrate, a dose of more
than 2 eqv. per mole of 3 is needed. Organic solvent is not indispensable in this
1
23

Synthesis of 1H-indazole
1621
process, and any strong base must be excluded from the reaction system. The yields
of 4 are diminished even if a little strong base, such as NaOH, is added, and the
resulting byproducts are substituted benzylamines. Though prolonging the reaction
time gives a higher conversion of 3, a too-long reaction time (longer than 10 h)
causes the formation of dibenzylidenehydrazines 5. The compound 4 can be
separated from water through extraction by organic solvents. It is important that
acid should be excluded from 4, otherwise it can be fully converted to 5 (Eq. 3). The
benzylidenehydrazines should be used for subsequent reactions shortly after they
are prepared. The reaction mixtures are filtered and the filtrates are used for
intramolecular cyclization.
Z
N
NH2
N H
N
2
4
N
+
N
Ni
Z
Z
Z
ð2Þ
3
3
3
3
a. Z=F
b. Z=Cl
c. Z=OH
d. Z=NH3
4a. Z=F
4b. Z=Cl
4c. Z=OH
4d. Z=NH3
5a. Z=F
5b. Z=Cl
5c. Z=OH
5d. Z=NH3
Cyclization of ortho-substituted benzylidenehydrazines
Heating the filtrates containing 4a or 4c to 100 °C results in 1H-indazole 7 (less than
0% yield), as well as the side products 5a, 6a and 5c, 6c, respectively. However,
3
heating 4b and 4d only resulted in dibenzylidenehydrazines 5b, 5d and ortho-
substituted toluene 6b, 6d. We decided to optimize the reaction conditions for
intramolecular cyclization of the isolated benzylidenehydrazine 4a and 4c to
indazole. Selection of the base used in the process is critical to minimizing the side
products. Considerable amounts of ortho-substituted toluene 6a and 6c were
observed in the presence of strong bases (e.g., sodium hydroxide and potassium
carbonate), while the yield of 5a and 5c increased when a too-weak base was used.
Actually, formation of the Wolff–Kishner reaction products 6b and 6d were
inevitable. Only when ammonia or excess hydrazine was present could indazole be
obtained with higher yields (see Table 1).
Z
NH2
N
N
+
+
N
N
N
H
Z
Z
Z
ð3Þ
4
4
4
4
a. Z=F
5
5
5
5
a. Z=F
6a. Z=F
6b. Z=Cl
6c. Z=OH
6d. Z=NH3
7
b. Z=Cl
c. Z=OH
d. Z=NH3
b. Z=Cl
c. Z=OH
d. Z=NH3
Lukin et al. [6] proposed that the formation of 4-bromo-1H-indazole 11 in the
reaction of 2-bromo-6-fluorobenzaldehyde with hydrazine does not proceed via an
intramolecular cyclization of 2-bromo-6-fluorobenzylidenehydrazine 8. Instead,
123

1622
X. Chen et al.
Table 1 Cyclization of ortho-
substituted
benzylidenehydrazines in the
presence of different bases
Entry
Reactant
Base added
NaOH
GC of 7 (%)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4c
4c
4c
4c
4c
4
8
Na
KOH
NH
ꢀH
ꢀH
NaOH
Na CO
KOH
NH
ꢀH
ꢀH
2 3
CO
\1
19
25
5
3
2
O
N
2
H
4
2
O
2
3
10
\1
54
61
3
2
O
1
0
N
2
H
4
2
O
they proposed a mechanism that the reaction proceeds by substitution of the aryl
fluoride of 2-bromo-6-fluorobenzylidenehydrazine with another molecule of
hydrazine, followed by the cyclization of 3-bromo-2-(hydrazonomethyl)phen-
ylhydrazine 9, as shown in Eq. 4. To support the conclusion, they prepared benzyl-
substituted benzylidenehydrazine and subjected it to the cyclization with hydrazine
(
Eq. 5). The major product, 4-bromo-1H-indazole 11, seems to be proof of the
fluoride-substitution mechanism. However, the singular result that no 4-fluoro-1H-
indazole was formed made us doubt the proposed mechanism. As substitution of the
bromo on benzene ring by hydrazine is more favorable than that of fluoro, the yield
of 4-fluoro-1H-indazole should have been higher than that of 4-bromo-1H-indazole
according to Lukin et al. We carried out comparative reactions between different
benzene halides (fluoro-, chloro-, bromo- and iodo-benzenes) and hydrazine
hydrate. For all four reactions, only a little phenylhydrazine was produced after 3 h
under reflux; no obvious higher yield was detected in the reaction between
fluorobenzene and hydrazine hydrate.
Br
Br
Br
NH2
HN
Br
NH2
NH2
N
hydrazine
N
NH
N
ð4Þ
ð5Þ
N
H
F
NH
NH2
N
H
8
9
10
11
Br
Br
Br
Ph
NH hydrazine
N
N
+
N
N
H
N
F
Ph
1
0
:
1
1
2
11
13
Considering the reaction result shown in Eq. 5, we proposed a reaction route
which can give a reasonable explanation, as shown in Eq. 6. Reaction between
1
23

Synthesis of 1H-indazole
1623
benzyl-substituted benzylidenehydrazine 12 and hydrazine yields 2-bromo-6-
fluorobenzylidenehydrazine directly, while subsequent cyclization gives
-bromo-1H-indazole 11. To prove our assumption, another reaction between
8
4
benzyl-substituted benzylidenehydrazine 15 and hydrazine was carried out, and
hydrazone 16 was obtained after reflux for 2 h. Carmeli et al. [19] have also
reported a similar result. Thus, it can be concluded that the conversion from ortho-
substituted benzylidenehydrazine to indazole does not follow the substitution–
cyclization route (Eq. 4). It remains unknown why cyclization of hydrazone 4a and
4c occurs while the reactants 4b and 4d give no indazole at all. DFT investigation
was further performed.
NH2
Br
Br
Ph
Br HN
Br
H
N
NH
NH2
-
phenylhydrazine
hydrazine
N
N
Ph
N
N
H
N
F
F
14
F
H
1
2
8
11
ð6Þ
ð7Þ
H
N
NH2
hydrazine
N
N
15
16
Geometries of ortho-substituted benzylidenehydrazine
Six ortho-substituted benzylidenehydrazines, 2-nitrobenzylidenehydrazine, 2-fluor-
obenzylidenehydrazine, 2-chlorobenzylidenehydrazine, 2-bromobenzylidenehydr-
azine, 2-hydroxylbenzylidenehydrazine and 2-aminobenzylidenehydrazine, were
optimized. Each ortho-substituted benzylidenehydrazine has cis-(E)-, cis-(Z), anti-
(E)- and anti-(Z) configurations related to different energies; only the cis-
configurations are ready for intramolecular cyclization while the anti-ben-
zylidenehydrazines need transition of configuration. The calculation results indicate
that
mobenzylidenehydrazine, and 2-aminobenzylidenehydrazine have lower energies
cis-(E)-configurations
of
2-chlorobenzylidenehydrazine,
2-bro-
than the corresponding cis-(Z)-configurations, while cis-(Z)-configurations of
2
-nitrobenzylidenehydrazine, 2-fluorobenzylidenehydrazine, and 2-hydroxylbenzy-
lidenehydrazine have slightly higher energies than the corresponding cis-(E)-
configurations. On comparing the cis-(Z)-configuration of each ortho-substituted
benzylidenehydrazine, we found that a hydrogen bond forms between the terminal
H atom and the ortho-group in 2-nitrobenzylidenehydrazine, 2-fluorobenzylidene-
hydrazine, and 2-hydroxylbenzylidenehydrazine (as shown in Fig. 1), so that the
cis-(Z)-configuration is stabilized. We believe that the cyclization process is greatly
affected by the hydrogen bond.
123

1624
X. Chen et al.
Fig. 1 Geometries
2
of
-fluorobenzylidenehydrazine (b), and 2-hydroxylbenzylidenehydrazine (c)
the
cis-(Z)-configurations
of
2-nitrobenzylidenehydrazine
(a),
Calculation results for cyclization of ortho-substituted benzylidenehydrazine
Direct cyclization of ortho-substituted benzylidenehydrazines via substitution of the
ortho-group by the terminal N atom was investigated. The reactants, products, and
TS were located and optimized, and the corresponding reaction energies and
barriers are shown in Table 2. It is clear in Table 2 that cyclization of
2
-nitrobenzylidenehydrazine, 2-fluorobenzylidenehydrazine, and 2-hydroxylbenzy-
lidenehydrazine have obviously lower barriers than those of the other ortho-
substituted benzylidenehydrazines. The calculation results are in good agreement
with our experiment. Relative TS structures are shown in Fig. 2.
The lower barriers of reactions 1, 5, and 6 can be attributed to electron
withdrawing from the ortho group to the terminal H atom. Effective electron
attraction results in obvious increase of electron density around the ortho group and
the terminal N atom, so both ionization of the ortho group and nucleophilic attack
by the terminal N are favored. The question arises as to which group can give
effective attraction? Comparative calculation on different ortho substituted
benzylidenehydrazines indicates that only the hydrogen bond forms between the
terminal H and the ortho group. Can the group give effective attraction? In other
words, the ortho group must contain at least one atom of sufficient electronegativity.
Considering the electron withdrawing effect of benzene ring, which decreases the
electronegativity of the ortho amino, only 2-fluoro and 2-hydroxyl are available to
form a hydrogen bond. We further calculated substitution of the fluorine in
2
-fluorobenzylidenehydrazine by hydrazine, and compared it with direct cycliza-
tion. The calculated barrier of the substitution is 35.4 kJ/mol, considerably higher
than that of direct cyclization. This can be further proof that the substitution–
cyclization route is nonfeasible. Therefore, it can be concluded that cyclization of
ortho-substituted benzylidenehydrazines is propelled by the hydrogen bond.
If the above approach is suitable for compounds of similar structures, ortho-
substituted benzaldehyde oxime 17 can proceed via intramolecular cyclization when
the ortho group is –F or –OH, as shown in Eq. 8. Strupczewski et al. [20] have
reported intramolecular cyclization of 2-fluorobenzaldehyde oxime 17a, and
cyclization of 2-hydroxylbenzaldehyde oxime 17b [21–23], with the same product
benzo[d]isoxazole 18. Other ortho-substituted benzaldehyde oximes, such as
2
-chloro, 2-bromo, and 2-amino, have not been shown to be amenable for
1
23

Synthesis of 1H-indazole
1625
Table 2 Reaction energies and barriers for direct cyclization of various ortho-substituted ben-
zylidenehydrazines; both the barriers and the reaction energies, which have been corrected with ZPVE,
are in kJ/mol
Reaction
Barrier
Reaction energy
1
3
3
3
9.5
6.7
0.0
6.1
-29.5
N
N
N
N
+
+
+
HF
1
2
3
.
.
.
NH2
N
H
F
-27.1
-26.4
20.7
N
HCl
HBr
NH2
N
H
Cl
Br
N
NH2
N
H
N
N
4a.
4b.
5a.
NH2
NH2
N
H
H2N
H
2
1
1
2
3.6
8.6
1.4
0.1
-50.2
17.5
N
N
+
NH3
N
N
H
H
H2N
H
N
N
NH2
OH
N
H
HO
H
-34.1
-25.3
N
N
+
H O
2
5
b.
.
N
N
H
H
HO
H
N
N
+
HNO2
6
NH
2
N
H
NO
2
intramolecular cyclization. Thus, the cyclization of ortho-substituted benzaldehyde
oxime 17 lends support to the hydrogen bond propelling mechanism.
N
N
+
XH
OH
O
X
ð8Þ
1
7a. X=F
18
17b. X=OH
It should be noticed that the N–O bond in ortho-substituted benzaldehyde oxime is
active and easy to rupture. So the cyclization may proceed via dehydration if a
hydrogen bond can form between the terminal O and an active H in the ortho group.
Then, we speculated that cyclization of 2-aminobenzaldehyde oxime 17c will give
1
H-Indazole 7 (Eq. 9), although this reaction has not been reported. Full calculation
was performed on this cyclization using the aforementioned methods. The calculated
barrier for direct cyclization of cis-(Z)-2-aminobenzaldehyde oxime is 20.5 kJ/mol,
which is comparable with that for cyclization of 2-nitrobenzylidenehydrazine, and
123

1626
X. Chen et al.
Fig. 2 TS structures of reactions 1–6 in Table 2
the reaction is also energetically favorable. Judging from the calculation results, we
can conclude that synthesis of 1H-Indazole via cyclization of 2-aminobenzaldehyde
oxime is probably feasible, but there is as yet no report on this and similar reactions.
N
N
+
H O
2
OH
NH2
N
H
ð9Þ
17c
7
Conclusion
We have presented a new practical synthesis of 1H-indazole. The intermediate
ortho-substituted benzylidenehydrazines were obtained in high yields via reaction
of ortho-substituted benzonitrile with hydrazine catalyzed by Raney nickel. The
introduction of even a little acid or base into the reaction system can decrease the
yield of ortho-substituted benzylidenehydrazine dramatically. Cyclization of
2
-fluorobenzylidenehydrazine and 2-hydroxylbenzylidenehydrazine gave the final
product, 1H-indazole; a previously proposed mechanism for the cyclization step was
proved to be nonfeasible according to other literature and our experiment. To
determine the details of cyclization, theoretical calculations using DFT were
performed. The calculation results indicated that cyclization of ortho-substituted
benzylidenehydrazine is propelled by the hydrogen bond between the terminal H on
N and the ortho group. The reported cyclization of ortho-substituted benzaldehyde
oxime proved that the hydrogen bond propelled mechanism is also suitable for
cyclization of compounds with similar structures. Finally, we proposed the
cyclization of 2-aminobenzaldehyde oxime to synthsize 1H-indazole, and theoret-
ical calculation indicated that it is feasible. Further study is in progress.
1
23

Synthesis of 1H-indazole
1627
Experimental section
Typical procedure for synthesis of ortho-substituted benzylidenehydrazine
Hydrazine (85%, 10 mL) was added into a solution of 2-fluorobenzonitrile (5 mmol)
in toluene (10 mL). Raney nickel (0.2 g) was added. Then, the mixture was stirred
for 3 h at 10–15 °C, giving 90% GC yield of 2-fluorobenzylidenehydrazine.
Typical procedure for cyclization of ortho-substituted benzylidenehydrazines
Hydrazine (85%, 5 mL) was added into the concentrated 2-fluorobenzylidenehy-
drazine solution (5 mmol). The mixture was refluxed for 5 h, giving 25% GC yield
of 1H-Indazole.
1
H-indazole (7)
1
H NMR (DMSO-d , 400 MHz, ppm): d = 7.11 (t, 1H, J = 7.6 Hz), 7.35 (t, 1H,
6
J = 7.6 Hz), 7.55 (d, 1H, J = 8.3 Hz), 7.79 (d, 1H, J = 8.2 Hz), 8.07 (s, 1H),
1
3
1
3.09 (s, 1H, NH); C NMR (DMSO-d , 100 MHz, ppm): d = 111.2, 121.0, 121.4,
6
1
22.5, 126.6, 135.2, 141.3.
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