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Synthesis of indazoles from 2-formylphenylboronic acids

Vitalii V. Solominab, Alberts Seinsab and Aigars Jirgensons*ab
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

Received 24th May 2021 , Accepted 22nd June 2021

First published on 28th June 2021


Abstract

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.


Introduction

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 defined 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
image file: d1ra04056a-f1.tif
Fig. 1 Indazole containing drugs (Lonidamine, Gamendazole, Bendazac, Pazopanib) and candidate drug (Axitinib).

Previously, we demonstrated the construction of aminoquinazolines 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 indazoles, 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[double bond, length as m-dash]N bond in azadicarboxylates 2 would give N-arylhydrazine intermediates 3 which could be further transformed to indazoles 4 and 5 (Scheme 1).


image file: d1ra04056a-s1.tif
Scheme 1 Indazole synthesis from 2-formylphenylboronic acids.

Results and discussion

The initial investigation of the arylation conditions was performed for the reaction of 2-formylphenylboronic acid (1a) with diethylazodicarboxylate (DEAD, 2a) using Cu(OAc)2 as a catalyst in a range of solvents (Table 1, entries 1–9). Solvents such as 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).
Table 1 Conditions for the arylation of DEAD (2a)

image file: d1ra04056a-u1.tif

Entry Copper catalyst Solvent Isolated yield
a Violent DEAD decomposition observed.b N,N-Dimethylformamide.c N,N-Dimethylacetamide.
1 20 mol% Cu(OAc)2 MeOHa 0%
2 20 mol% Cu(OAc)2 PhMe 0%
3 20 mol% Cu(OAc)2 THF 64%
4 20 mol% Cu(OAc)2 MeCN 80%
5 20 mol% Cu(OAc)2 DMFb 83%
6 20 mol% Cu(OAc)2 DMAc 98%
7 15 mol% Cu(OAc)2 DMAc 98%
8 10 mol% Cu(OAc)2 DMAc 98%
9 5 mol% Cu(OAc)2 DMAc 96%
10 10 mol% CuCl2 DMAc 94%
11 10 mol% Cu(OTf)2 DMAc 99%
12 10 mol% Cu(acac)2 DMAc 97%
13 10 mol% CuCl DMAc 25%
14 10 mol% CuI DMAc 93%


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 cyclization of arylhydrazine 3a, while heating in a solution of MeCN induced formation of indazole 4a (Table 2, entries 3 and 4). Formic acid was strong enough to enable the formation of indazole 4a at room temperature in a solution of MeCN (Table 2, entry 5).

Table 2 Cyclization of arylhydrazone 3a to indazoles 4a and 5a

image file: d1ra04056a-u2.tif

Entry Reagent Solvent Temp., time Product Yield
1 5 equiv. TFA DCM 25 °C, 12 h 4a 63%
2 5 equiv. TFA MeCN 25 °C, 12 h 4a 64%
3 AcOH Neat r. t., 12 h 4a 0%
4 30 equiv. AcOH MeCN 70 °C, 12 h 4a 56%
5 30 equiv HCOOH MeCN r. t., 12 h 4a 56%
6 3 equiv. K2CO3 MeOH 70 °C, 1 h 5a 67%
7 3 equiv. K2CO3 MeOH 25 °C, 12 h 5a 67%
8 4 equiv. KOH EtOH r. t., 12 h 5a 59%


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.

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).

Table 3 One-pot conversion of boronic acid 1a to indazole 4a

image file: d1ra04056a-u3.tif

Entry Solvent Conditions, step 2 3a, isolated yield
a 3 mL of TFA/DCM mixture added per 1 mL of DMA.
1 DMA 10 equiv. TFA, 25 °C, 2 h 0%
2 DMA TFA[thin space (1/6-em)]:[thin space (1/6-em)]DCM 1[thin space (1/6-em)]:[thin space (1/6-em)]4a, 25 °C, 2 h 73%
3 DCM 5 equiv. TFA, 25 °C, 1 h 48%
4 MeCN 5 equiv. TFA, 25 °C, 1 h 78%


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 azodicarboxylate (DIAD, 2b, Table 4, entry 1).

Table 4 Azodicarboxylate 2 scope for the synthesis of indazoles 4

image file: d1ra04056a-u4.tif

Entry R 4, isolated yield
1 i-Pr 4b, 86%
2 Bn 4c, 60%
3 i-Bu 4d, 45%


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.


image file: d1ra04056a-s2.tif
Scheme 2 The reaction of substituted formylboronic acids with DIAD (2b).

Thiophene boronic acid 8 was found a suitable substrate to obtain thienopyrazole derivative 9 in a good yield (Scheme 3).


image file: d1ra04056a-s3.tif
Scheme 3 The reaction of substituted formylboronic acids with DIAD (2b).

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 reaction with diethyl hydrazine dicarboxylate (7a) using the two-step one-pot procedure for the formation of indazole 4a. The catalytic 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 excess of triethylamine for the first 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 3). The transformation of 2-formylphenylboronic (1a) to indazole 4a was not efficient in the absence of base for the first step, however, TEA could be replaced by TMEDA and DIPEA without significantly reducing the product 4b yield (Table 5, entries 5 and 6). Several other Cu salts were tried for the first 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 hydrazine 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

Table 5 Synthesis of indazole using of hydrazine dicarboxylate 7a

image file: d1ra04056a-u5.tif

Entry Catalyst Solvent Additive NMR yielda
a NMR yield, using 1,3,5-trimethoxybenzene as internal standard.
1 20 mol% Cu(OAc)2 MeCN 3 equiv. TEA 25%
2 1 equiv. Cu(OAc)2 MeCN 3 equiv. TEA 66%
3 1.5 equiv. Cu(OAc)2 MeCN 3 equiv. TEA 50%
4 1 equiv. Cu(OAc)2 MeCN None 26%
5 1 equiv. Cu(OAc)2 MeCN 2 equiv. TMEDA 67%
6 1 equiv. Cu(OAc)2 MeCN 3 equiv. DIPEA 60%
7 1 equiv. CuCl MeCN 3 equiv. TEA 35%
8 1 equiv. CuCl2 MeCN 3 equiv. TEA 25%



image file: d1ra04056a-s4.tif
Scheme 4 Scope of boronic acids 1 in the reaction with diazadicarboxylate 7g.

image file: d1ra04056a-s5.tif
Scheme 5 Proposed mechanism for the C–N bond forming step.

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).

Table 6 Hydrazine dicarboxylate 7 scope for the synthesis of indazoles 4

image file: d1ra04056a-u6.tif

Entry 7, R Acid 4, isolated yield
1 7a, Et TFA 4a, 63%
2 7b, i-Pr TFA 4b, 47%
3 7c, Bn TFA 4c, 46%
4 7d, i-Bu TFA 4d, 61%
5 7e, Me TFA 4j, 63%
6 7f, allyl TFA 4k, 40%
7 7g, t-Bu AcOH 4l, 73%


The scope of phenyl boronic acids 1b–i was explored with di-tert-butyl hydrazine dicarboxylate 7g as a reaction component for the synthesis of 1N-Boc indazoles 4m–t (Scheme 4). The major reason for reduction was formation of N-acetyl indazoles 10 as by-products (see ESI for the characterization of 10a, R = H).

The mechanism for the C–N bond formation in the copper catalysed reaction of arylboronic acids with diazadicarboxylates has been proposed by Uemura and Chatani.20 According to this, the transmetalation reaction of arylboronic acid 1a with a copper catalyst would form an arylcopper species 10 (Scheme 5). Addition of intermediate 10 to N[double bond, length as m-dash]N double bond gives an arylhydrazine 11 which undergoes the transmetalation with boronic acid 1a to give intermediate 12 and return arylcopper species 10 into catalytic cycle. Work-up would produce arylhydrazine 3a. Noteworthy, it was shown by Uemura and Chatani that dialkoxycarbonyl hydrazines are not competent substrates for this reaction unless additional oxidant is added.20 This implies that hydrazine 7a is likely oxidised to diazadicarboxylate 2a by stoichiometric amount of copper source.

The proposed mechanism for the condensation of arylhydrazine intermediate into indazole is given in Scheme 6. In the presence of acid, N-acyliminium ion 13 is formed. Selective hydrolytic cleavage of one ethoxycarbonyl group in intermediate 13 gives 1N-ethoxycarbonyl indazole 4a. In turn, basic conditions would enable cleavage of both ethoxycarbonyl groups leading to intermediate 14 which eliminates water to give indazole 5a.


image file: d1ra04056a-s6.tif
Scheme 6 Proposed mechanism for the condensation step.

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-alkoxycarbonyl indazole derivatives. The indazole synthesis can also be performed using hydrazine dicarboxylates as reaction partners for the synthesis of indazoles, however, required a stoichiometric 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.

Author contributions

V. S. and A. S performed the synthesis. A. J. wrote the paper.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Funding from H2020 MSC-ITN project CARTNET “Combating Antimicrobial Resistance Training Network”, grant agreement ID: 765147 is acknowledged.

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra04056a

This journal is © The Royal Society of Chemistry 2021