Synthesis of indazoles from 2-formylphenylboronic acids

Article abstract of DOI:10.1039/d1ra04056a

A method for the synthesis of indazoles was developed which involves a copper(ii) acetate catalysed reaction of 2-formylboronic acids with diazadicaboxylates followed by acid or base induced ring closure. Hydrazine dicarboxylates were also shown as competent reaction partners for the synthesis of indazoles, however, they required a stoichiometric amount of copper(ii) acetate for the C-N bond formation step. The transformation can be efficiently performed as a two step-one pot procedure to give a range of 1N-alkoxycarbonyl indazoles.

Full text of DOI:10.1039/d1ra04056a

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Synthesis of indazoles from 2-formylphenylboronic
acids†
Cite this: RSC Adv., 2021, 11, 22710
ab
Vitalii V. Solomin,ab Alberts Seinsab and Aigars Jirgensons
*
A method for the synthesis of indazoles was developed which involves a copper(II) acetate catalysed
reaction of 2-formylboronic acids with diazadicaboxylates followed by acid or base induced ring closure.
Hydrazine dicarboxylates were also shown as competent reaction partners for the synthesis of indazoles,
however, they required a stoichiometric amount of copper(II) acetate for the C–N bond formation step.
The transformation can be efficiently performed as a two step-one pot procedure to give a range of 1N-
alkoxycarbonyl indazoles.
Received 24th May 2021
Accepted 22nd June 2021
DOI: 10.1039/d1ra04056a
rsc.li/rsc-advances
diethylazodicarboxylate (DEAD, 2a) using Cu(OAc)2 as a catalyst
in a range of solvents (Table 1, entries 1–9). Solvents such as
Introduction
MeCN, DMF and DMA were found to be appropriate to obtain
the product 3a together with its cyclic tautomer 6a in a good
yield (Table 1, entries 5 and 6). Decreased catalyst loading was
also possible using DMA as a solvent without affecting the
product 6a yield (Table 1, entries 7–9). Range of other copper
sources was investigated (Table 1, entries 10–14). CuCl2
Cu(OTf)2 Cu(acac)2 performed as efficient catalysts for C–N
bond formation giving the product 3a in high yield (Table 1,
entries 10–12). Copper(I) source such as CuCl proved to be
ineffective catalyst, while catalytic amount of CuI enabled
product 3a formation in good yield (Table 1, entries 13 and 14).
Next, the conditions were investigated for the indazole ring
closure using arylhydrazine 3a (Table 2). Acidic reaction
conditions enabled the condensation of arylhydrazine 3a to 1N-
etoxycarbonyl indazole (4a) (Table 2, entries 1–5). TFA in DCM
and in MeCN gave the expected product 4a in good yield (Table
2, entries 1 and 2). Neat AcOH at r. t. did not enable the cycli-
zation of arylhydrazine 3a, while heating in a solution of MeCN
induced formation of indazole 4a (Table 2, entries 3 and 4).
The indazole motif plays an important role in pharmaceutically
relevant compounds including drugs and candidate drugs e.g.
Lonidamine, Gamendazole, Bendazac, Pazopanib, Axitinib
(Fig. 1).1–4 A number of approaches have been developed to
assemble indazole from 2-aminotoluenes,5 2-acyl-halobenzenes,6–8
2-aminophenyloximes,9 and 2-nitrobenzaldehydes,10,11 and by [3 +
2] annulations of in situ generated arynes.12–14 Most of the above
mentioned methods lead to the dened 1N or 2N indazole
substitution pattern, however, they require harsh conditions or
long routes to the key intermediates limiting their application.
Selective N-functionalization of indazoles has been reported for
alkylation reactions15–17 and few reports can be found on selective
N-acylation of indazoles.18
Previously, we demonstrated the construction of amino-
quinazolines from 2-formylphenylboronic acids.19 This method
involved the Chan–Evans–Lam reaction for the C–N bond
formation. To extend this approach for the synthesis of inda-
zoles, we turned our attention to copper catalysed addition of
phenyl boronic acids to azodicarboxylates reported by Uemura
and Chatani.20 Using 2-formylphenylboronic acids
1 as
substrates, the addition to N]N bond in azadicarboxylates 2
would give N-arylhydrazine intermediates 3 which could be
further transformed to indazoles 4 and 5 (Scheme 1).
Results and discussion
The initial investigation of the arylation conditions was per-
formed for the reaction of 2-formylphenylboronic acid (1a) with
aLatvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia. E-mail:
aigars@osi.lv
bFaculty of Materials Science and Applied Chemistry, Riga Technical University, P.
Valdena Str. 3, Riga, LV-1048, Latvia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra04056a
Fig. 1 Indazole containing drugs (Lonidamine, Gamendazole, Bend-
azac, Pazopanib) and candidate drug (Axitinib).
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Table 2 Cyclization of arylhydrazone 3a to indazoles 4a and 5a
Scheme 1 Indazole synthesis from 2-formylphenylboronic acids.
Entry Reagent
Solvent Temp., time Product Yield
1
2
3
4
5
6
7
8
5 equiv. TFA
5 equiv. TFA
AcOH
30 equiv. AcOH
30 equiv HCOOH MeCN
3 equiv. K2CO3
3 equiv. K2CO3
4 equiv. KOH
DCM
MeCN
Neat
25 ꢀC, 12 h
25 ꢀC, 12 h
r. t., 12 h
4a
4a
4a
4a
4a
5a
5a
5a
63%
64%
0%
56%
56%
67%
67%
59%
Formic acid was strong enough to enable the formation of
indazole 4a at room temperature in a solution of MeCN (Table 2,
entry 5).
The use of a base in alcoholic solvent provided unprotected
indazole 5a (Table 2, entries 6–8). Both K2CO3 and KOH could
be efficiently used for the ring closure – deacylation reaction of
arylhydrazine 3a.
MeCN
70 ꢀC, 12 h
r. t., 12 h
MeOH
MeOH
EtOH
70 ꢀC, 1 h
25 ꢀC, 12 h
r. t., 12 h
Next, the one pot formation of 1N-etoxycarbonyl indazole
(4a) from 2-formylphenylboronic acid (1a) was investigated
(Table 3). Unfortunately, DMA which was the solvent of choice
for high yielding arylation of DEAD was not suitable for the ring
closure step in the presence of TFA (Table 3, entry 1). In this
case, the arylhydrazine 3a intermediate was not transformed to
product 4a, according to LC-MS. In turn, the addition of TFA in
DCM in an amount to sufficiently dilute DMA, enabled the
formation of expected product 4a in a good yield (Table 3, entry
2). The use of DCM as a solvent for both steps was less
productive (Table 3, entry 3). However, MeCN was found as an
appropriate solvent for both arylation and ring closure in the
presence of TFA to give 1N-protected indazole 4a in a good
overall yield (Table 3, entry 4).
With one-pot conditions in hand, the synthesis of other
alkoxycarbonylindazoles 4b–d was performed by the reaction of
boronic acid 1a with azodicarboxylates 2b–d (Table 4). The best
yield of product 4b was obtained with diisopropyl azodi-
carboxylate (DIAD, 2b, Table 4, entry 1).
The scope of boronic acid substitution was investigated in the
reaction of a range of formylboronic acids 1b–f with DIAD (2b)
followed by cyclization (Scheme 2). Substrates 1b–d bearing
methoxy and benzyloxy groups provided indazoles 4e–g in a good
to moderate yield. In the case of substrates 1e,f bearing electron-
withdrawing substituents, yields of products 4h, i were decreased.
Thiophene boronic acid 8 was found a suitable substrate to
obtain thienopyrazole derivative 9 in a good yield (Scheme 3).
Hydrazine dicarboxylate 7a was also explored as a reagent for
the synthesis of indazoles instead of azodicarboxylate 2a (Table
5). 2-Formylphenylboronic acid (1a) was subjected to the reac-
tion with diethyl hydrazine dicarboxylate (7a) using the two-step
one-pot procedure for the formation of indazole 4a. The cata-
lytic amount of Cu(OAc)2 and excess of triethylamine was not
sufficient to achieve good yield of product 4a formation (Table
5, entry 1). The use of equimolar amount of Cu(OAc)2 and an
Table 1 Conditions for the arylation of DEAD (2a)
Entry
Copper catalyst
Solvent
Isolated yield
Table 3 One-pot conversion of boronic acid 1a to indazole 4a
1
2
3
4
5
6
7
8
20 mol% Cu(OAc)2
20 mol% Cu(OAc)2
20 mol% Cu(OAc)2
20 mol% Cu(OAc)2
20 mol% Cu(OAc)2
20 mol% Cu(OAc)2
15 mol% Cu(OAc)2
10 mol% Cu(OAc)2
5 mol% Cu(OAc)2
10 mol% CuCl2
MeOHa
PhMe
THF
0%
0%
64%
80%
83%
98%
98%
98%
96%
94%
99%
97%
25%
93%
MeCN
DMFb
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
Entry
Solvent
Conditions, step 2
3a, isolated yield
9
10
11
12
13
14
1
2
3
4
DMA
DMA
DCM
MeCN
10 equiv. TFA, 25 ꢀC, 2 h
TFA : DCM 1 : 4a, 25 ꢀC, 2 h
5 equiv. TFA, 25 ꢀC, 1 h
5 equiv. TFA, 25 ꢀC, 1 h
0%
10 mol% Cu(OTf)2
10 mol% Cu(acac)2
10 mol% CuCl
73%
48%
78%
10 mol% CuI
a
a
b
3 mL of TFA/DCM mixture added per 1 mL of DMA.
Violent DEAD decomposition observed. N,N-Dimethylformamide.
N,N-Dimethylacetamide.
c
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Table 4 Azodicarboxylate 2 scope for the synthesis of indazoles 4
Entry
R
4, isolated yield
1
2
3
i-Pr
Bn
i-Bu
4b, 86%
4c, 60%
4d, 45%
Scheme
4
Scope of boronic acids 1 in the reaction with dia-
zadicarboxylate 7g.
3). The transformation of 2-formylphenylboronic (1a) to inda-
zole 4a was not efficient in the absence of base for the rst step,
however, TEA could be replaced by TMEDA and DIPEA without
signicantly reducing the product 4b yield (Table 5, entries 5
and 6). Several other Cu salts were tried for the rst step of
indazole 4b formation, however, were found to be ineffective
(Table 5, entries 7 and 8). The need for an equimolar amount of
Cu (OAc)2 for successful synthesis of indazole 4a using hydra-
zine dicarboxylate 7a implies in situ oxidation of reagent 7a to
azodicarboxylate 2a (see also Scheme 5). However, C–N bond
formation with hydrazine dicarboxylate 7a in the Chan–Evans–
Lam reaction cannot be excluded.21
Scheme 2 The reaction of substituted formylboronic acids with DIAD
(2b).
Scheme 3 The reaction of substituted formylboronic acids with DIAD
(2b).
Next, a range of hydrazine dicarboxylates 7a–g was explored
as reaction components for a one-pot two-step synthesis of
indazoles 4a–d, j–l (Table 6). TFA was a suitable acid for the
cyclization step to give the corresponding products 4a–d, j, k from
the reaction of boronic acid 1a with hydrazine dicarboxylates 7a–f
(Table 6, entries 1–6). For the synthesis of product 4l bearing acid
labile t-Bu group, acetic acid at elevated temperature was used
instead of TFA (Table 6, entry 7). This approach successfully
provided product 4l in a very good yield (Table 6, entry 8).
The scope of phenyl boronic acids 1b–i was explored with di-
tert-butyl hydrazine dicarboxylate 7g as a reaction component
excess of triethylamine for the rst step enabled good yield of
product 4a over two steps, while increasing the amount of
Cu(OAc)2 reduced the yield of product 4a (Table 5, entries 2 and
Table 5 Synthesis of indazole using of hydrazine dicarboxylate 7a
Entry Catalyst
Solvent Additive
NMR yielda
1
2
3
4
5
6
7
8
20 mol% Cu(OAc)2
1 equiv. Cu(OAc)2
1.5 equiv. Cu(OAc)2 MeCN
1 equiv. Cu(OAc)2
1 equiv. Cu(OAc)2
1 equiv. Cu(OAc)2
1 equiv. CuCl
MeCN
MeCN
3 equiv. TEA
25%
66%
50%
26%
3 equiv. TEA
3 equiv. TEA
None
MeCN
MeCN
MeCN
MeCN
MeCN
2 equiv. TMEDA 67%
3 equiv. DIPEA
3 equiv. TEA
3 equiv. TEA
60%
35%
25%
1 equiv. CuCl2
a
NMR yield, using 1,3,5-trimethoxybenzene as internal standard.
Scheme 5 Proposed mechanism for the C–N bond forming step.
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Table 6 Hydrazine dicarboxylate 7 scope for the synthesis of inda-
zoles 4
Conclusions
In summary, copper catalysed reaction of 2-formylboronic acids
with diazadicaboxylates followed by acid or base induced ring
closure is a convenient method for the synthesis of 1N-alkox-
ycarbonyl indazole derivatives. The indazole synthesis can also
be performed using hydrazine dicarboxylates as reaction part-
ners for the synthesis of indazoles, however, required a stoi-
chiometric amount of copper(II) acetate for the C–N bond
formation step. The method is based on readily available
building blocks and can be performed at relatively mild reaction
conditions which enables its application for the synthesis of
indazole motif containing compounds.
Entry
7, R
Acid
4, isolated yield
1
2
3
4
5
6
7
7a, Et
7b, i-Pr
7c, Bn
7d, i-Bu
7e, Me
7f, allyl
7g, t-Bu
TFA
TFA
TFA
TFA
TFA
TFA
AcOH
4a, 63%
4b, 47%
4c, 46%
4d, 61%
4j, 63%
4k, 40%
4l, 73%
Author contributions
V. S. and A. S performed the synthesis. A. J. wrote the paper.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Funding from H2020 MSC-ITN project CARTNET “Combating
Antimicrobial Resistance Training Network”, grant agreement
ID: 765147 is acknowledged.
Scheme 6 Proposed mechanism for the condensation step.
Notes and references
for the synthesis of 1N-Boc indazoles 4m–t (Scheme 4). The
major reason for reduction was formation of N-acetyl inda-
zoles 10 as by-products (see ESI† for the characterization of
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22714 | RSC Adv., 2021, 11, 22710–22714
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