Regioselective synthesis of 2H-indazoles through Ga/Al- and Al-mediated direct alkylation reactions of indazoles

Article abstract of DOI:10.1039/c5ob01747e

A procedure has been developed for the regioselective, high yielding synthesis of 2H-indazoles that involves direct alkylation of indazoles with various allyl and benzyl bromides, and α-bromocarbonyl compounds.

Full text of DOI:10.1039/c5ob01747e

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Regioselective synthesis of 2H-indazoles through
Ga/Al- and Al-mediated direct alkylation reactions
of indazoles†
Cite this: DOI: 10.1039/c5ob01747e
Mei-Huey Lin,* Han-Jun Liu, Wei-Cheng Lin, Chung-Kai Kuo and
Tsung-Hsun Chuang
Received 20th August 2015,
Accepted 29th September 2015
DOI: 10.1039/c5ob01747e
A procedure has been developed for the regioselective, high yielding synthesis of 2H-indazoles that involves
direct alkylation of indazoles with various allyl and benzyl bromides, and α-bromocarbonyl compounds.
www.rsc.org/obc
Therefore, the development of methods to prepare 2H-ind-
azoles in a direct and highly regioselective manner through
Introduction
Numerous medicinal chemical studies have led to the identifi- the alkylation of indazoles remains a significant challenge in
cation of the indazole ring system as a highly effective heterocyclic chemistry.
pharmacophore. This ring system serves as a core component
of important nitrogen containing heterocycles that display a
broad range of biological properties, such as the inhibition of
nitric oxide1 and HIV protease,2 anti-inflammatory,3 anti-
tumor,4 and anti-cancer5 activities, and serotonin 5-HT3 recep-
tor antagonist behavior.6
Recently, the 2H-indazole ring system has been utilized as
ð1Þ
an important pharmacophore in drug discovery efforts.7 Com-
pared with their 1H analogs, 2H-indazoles have been much
less studied owing partly to difficulties associated with their
preparation. One of the synthetic strategies used to prepare
members of the 2H-indazole family utilizes the cyclization
reaction of properly tethered substrates such as iminonitro-
aromatics derived from 2-nitrobenzaldehyde and amines,
2-azidoimines derived from 2-azidobenzaldehyde and amine,
and the [3 + 2] dipolar cycloaddition of sydnone and benzyne.8
Perhaps the most straightforward route to the construction of
2H-indazoles utilizes direct alkylation reactions of the corres-
ponding 1H-indazoles. However, only very few reactions of
this type produce 2H-indazoles with high levels of regio-
selectivity.9 For example, Cheung et al. reported the highly
regioselective synthesis of 2-methyl and 2-ethyl 2H-indazoles
from the reaction of indazoles with Meerwein’s salts under
kinetic control conditions.9 Normally, direct alkylation of ind-
azoles in the presence of a base generally provides a mixture of
N-1 and N-2 alkylation products (eqn (1)) or the thermo-
dynamically favored N-1 alkylated product predominantly.10
It has been suggested that the N-2 lone pair electrons in
indazoles participate in kinetically controlled reactions that
lead to N-protected products (e.g., THP derivatives) when
carried out under mildly acidic conditions.11 Moreover, it has
been reported that indazole serves as a chelating ligand for
aluminum and gallium cations through coordination utilizing
its N-2 lone pair.12 In a related effort, it has been shown that
gallium and allyl bromide participate in nucleophilic substi-
tution reactions in aqueous media, as is exemplified by C-3
allylation reactions of indoles.13 These observations led us to
propose a new method for the regioselective synthesis of 2-sub-
stituted 2H-indazoles that involves gallium-mediated N-2 ally-
lation reactions with allyl bromide. We envisaged that an
allylgallium/allylaluminium cation would be generated in this
process by the reaction of gallium/aluminium metal and allyl
bromide and that enables allylation of indazole at the kineti-
cally more reactive N-2 position.
Results and discussion
Department of Chemistry, National Changhua University of Education, Changhua,
Taiwan 50007. E-mail: mhlin@cc.ncue.edu.tw
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob01747e
The effort designed to evaluate this proposal began with an
investigation of the gallium-mediated allylation reaction
between indazole and allyl bromide (Table 1). As anticipated,
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Table 1 Metal mediated regioselective N-2 allylation of indazolea
Table 2 Scope of reaction with various alkylating agentsa
Entry
RX
2; Yieldb (%)
Entry
Metal/additive (equiv.)
2a′ : 2ab
2ac (%)
1
2
3
4
5
6
7
Allyl bromide
Allyl chloride
Propargyl bromide
PhCH2Br
PhCH2Cl
PhCH2OAc
2a; 54 (0 : 100)c
0
1
2
3
Ga (1)
Ga (2)
Ga (1)/ln (1)
0 : 100
0 : 100
0 : 100
0 : 100
0 : 100
0 : 100
0 : 100
0 : 100
50 : 50
0 : 100
42
44
22
14
20
54
48
33
42
42
<5
2h; 70 (0 : 100)c
0
0
0
4
5
6
Ga (1)/Cu (1)
Ga (1)/Zn (1)
Ga (1)/Al (1)
PhCH2OCOCF3
7
8
9
10
Al (2)
8
<5
Ga (1)/Al (1)/Bu4NBr (1)
Ga (1)/Al (1)/K2CO3 (2)
Ga (1)/Al (1)/HBr (0.1 mL)
a Conditions: indazole (1.0 mmol), allyl bromide (2.0 mmol), and
indicated metal in DMF (1.5 mL)/water (0.5 mL) at rt. b Ratio was
determined by 1H NMR. c Isolated yield.
9
0
0
10
11
12
0
we observed that the process produces the N-2 regioisomer 2a
exclusively with a moderate isolated yield and unreacted ind-
azole starting material (Table 1, entry 1).14 Screening other
metals led to the observation that the use of a combination of
gallium and aluminum is optimal for promotion of the alkyl-
ation reaction (Table 1, entry 6) and that the efficiency of the
process is not increased when a phase transfer reagent such as
tetrabutylammonium bromide is present in the reaction
mixture (Table 1, entry 8). In addition, when the reaction is
performed in the presence of a base such as potassium carb-
onate (2 equiv., pH of the resulting solution is 10), a mixture
of N-1 and N-2 allylation products is formed (Table 1, entry 9).
Finally, adding aqueous hydrobromic acid does not lead to an
improvement in the yield of the N-2 regioisomer (Table 1,
entry 10 versus 6).
The scope of the Ga/Al-mediated reaction of indazole was
explored using a variety of electrophiles (Table 2). The results
show that allyl bromide, benzyl bromide and α-bromoaceto-
phenone react with indazole in a highly regioselective and
efficient manner (Table 2, entries 1, 4, and 12). In the Ga/Al-
mediated reaction of benzyl bromide, benzyl alcohol is also
produced. Therefore, an acetylation procedure was employed
to chromatographically remove this hydrolysis product and
obtain pure 2-substituted 2H-indazole 2h. Importantly, alkyl
chlorides (Table 2, entries 2, 5 and 13), benzyl acetate (Table 2,
entry 6), benzyl trifluoroacetate (Table 2, entry 7) and aliphatic
bromides (Table 2, entries 9–11) do not participate in the alkyl-
ation reaction. Finally, propargyl bromide and secondary alkyl
bromides do serve as substrates but the yields of the processes
are low (Table 2, entry 3, 8 versus 4).
2k; 76 (2 : 98)c
13
0
a Conditions: indazole (1.0 mmol), RX (2.0 mmol), Ga (1.0 mmol), and
Al (1.0 mmol) in DMF (1.5 mL)/water (0.5 mL) at rt. b Isolated yield.
c N-1 : N-2, ratio was determined by 1H NMR.
substituted 2H-indazole forming reactions (Table 3, entries
4–7). Moreover, in each case, the C–N bond forming reaction
occurs at the least substituted carbon of the allylic framework.
These observations might suggest that the reaction does not
involve π-allyl chemistry, and the Lewis acid mediated substi-
tution reaction could be the scenario. In addition, a variety of
α-bromocarbonyl compounds, including arylacyl bromides,
1-bromopinacolone and ethyl bromoacetate, also participate in
this process (Table 4, entries 7 and 8). Due to the poor solubi-
lity of some arylacyl bromides under Ga/Al-mediated reaction
conditions at ambient temperature, heating was employed to
solve the solubility problem (Table 4, entries 2–6). As can be
seen in Tables 3 and 4, yields of the N-2 alkylation can be dra-
matically improved at a higher reaction temperature and in a
more concentrated reaction solution (yields are shown in par-
entheses). The advantage of using a combination of gallium
and aluminum over aluminum seems not obviously necessary
at ambient temperature (Table 1, entry 6 versus 7). Therefore,
the Al-mediated reaction of indazole was also explored using a
variety of electrophiles (Tables 3 and 4) and the Al-mediated
reaction is applicable to indazoles, which possess a variety of
aryl ring substituents (Table 5). However, when the nucleo-
Based on the results summarized in Table 2, the reactions
of a variety of functionalized allyl and benzyl bromides with
indazole were examined (Table 3). The results show that the
π-bond stereochemistry of allylic bromides is retained in N-2
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Table 3 Scope of the allylation and benzylation reactions
Entry
1
RX
Product
2; Yielda (%) from Ga/Al
2; Yielda (%) from Al
54 (88)b
48 (87)b
2
3
45 (84)b
82
92
4c
54 (71)c
49 (90)b
(68)c
5
6
7
50 (69)b
58 (83)b
(68)b
8
70 (81)d
66 (90)d
64 (76)d
(91)d
9
10
a Conditions: indazole (1.0 mmol), RX (2.0 mmol), Ga/Al (1.0 mmol, each) or Al (2.0 mmol) in DMF/H2O (2.0 mL) at rt. b Conditions: indazole
(1.0 mmol), RX (3.0 mmol), Ga/Al (1.5 mmol, each) or Al (3.0 mmol) in DMF/H2O (1.0 mL) at 55 °C. c Conditions: indazole (1.0 mmol), crotyl
bromide (85%, 4.0 mmol), Ga/Al (1.5 mmol, each) or Al (3.0 mmol) in DMF/H2O (1.0 mL) at 55 °C. d Conditions: indazole (1.0 mmol), RX
(2.0 mmol) Ga/Al (1.0 mmol, each) or Al (2.0 mmol) in DMF/H2O (1.0 mL) at 55 °C.
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Table 4 Scope of α-bromocarbonyl compounds
Entry
1
RCOCH2Br
Product
2; Yielda (%) from Ga/Al
2; Yielda (%) from Al
76b
97b
2
3
78
75
79
—
4
5
78
74
—
73
6
7
8
82
—
70b (94)c
74b (82)c
(89)c
—
a Conditions: indazole (1.0 mmol), ArCOCH2Br (2.0 mmol), Ga/Al (1.0 mmol, each) or Al (2.0 mmol) in DMF/H2O (2.0 mL) at 55 °C. b Conditions:
indazole (1.0 mmol), PhCOCH2Br (2.0 mmol), Ga/Al (1.0 mmol, each) or Al (2.0 mmol) in DMF/H2O (2.0 mL) at rt. c Conditions: indazole
(1.0 mmol), RCOCH2Br (3.0 mmol), Ga/Al (1.5 mmol, each) and Al (3.0 mmol) in DMF/H2O (1.0 mL) at 55 °C.
philicity of indazole is reduced by the presence of strong allyl complex, b: η3 π-allyl cation). Results of Table 3 show that
electron-withdrawing substituents (e.g., nitro) yields of the the π-bond stereochemistry of allylic bromides is retained in
processes are lower (Table 5, entries 1 and 2). Finally, the N-2 substituted 2H-indazole forming reactions (Table 3, entries
allylation reaction takes place in a normal fashion even in the 4–7). Moreover, in each case, the C–N bond forming reaction
case of an indazole substrate bearing an amino substituent occurs at the least substituted carbon of the allylic framework.
(Table 5, entry 4).
These observations might suggest that the reaction does not
A plausible mechanism is proposed in Scheme 1 (taking involve π-allyl chemistry. Meanwhile, it has been reported that
allyl bromide as an example). The reaction of gallium (alu- indazole serves as a chelating ligand for aluminum and
minium) metal and allyl bromide generates an allylgallium gallium cations through coordination utilizing its N-2 lone
(allylaluminium) cation complex. Highly regioselective syn- pair.12 Therefore, reaction of indazole with the η1-allyl
thesis of 2-alkyl 2H-indazoles via the reaction of indazole with complex could go through the chelation or non-chelation
a carbocation intermediate has been reported.9,11 Generation pathway, which enables the kinetically controlled reaction that
of the allylic cation would give two possible pathways (a: η1- leads to 2-allyl 2H-indazole.
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Table 5 Scope of indazoles
Entry
1
Substrate
Product
4, Yielda (%) from Ga/Al
4, Yielda (%) from Al
55
32
2
50
78
80
38
74
—
3
4b
a Conditions: indazole (1.0 mmol), allyl bromide (3.0 mmol), Ga/Al (1.5 mmol, each) or Al (3.0 mmol) in DMF (0.75 mL)/water (0.25 mL) at 55 °C.
b Conditions: indazole (1.0 mmol), allyl bromide (6.0 mmol), Ga/Al (3.0 mmol, each) in DMF/H2O (1.0 mL) at 55 °C.
Scheme 1 Plausible mechanism.
Conclusions
Notes and references
In the studies described above, we have developed a simple
and efficient method for the regioselective synthesis of 2-sub-
stituted alkyl 2H-indazole that utilizes Ga/Al- and Al-mediated
reactions of allyl and benzyl and α-bromo-carbonyl com-
pounds with indazoles. This method has been found to be
generally useful for the preparation of a wide variety of 2-alkyl
2H-indazoles some of which are difficult to make in such
high overall yields via the conventionally reported approaches.
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Acknowledgements
Financial support from the Ministry of Science and Technology
of the Republic of China, Taiwan (MOST 104-2113-M-018-005)
is gratefully acknowledged.
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