Direct Acyl Radical Addition to 2H

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Direct Acyl Radical Addition to 2H‑Indazoles Using Ag-Catalyzed Decarboxylative Cross-Coupling of α‑Keto Acids Ganganna Bogonda, Hun Young Kim, and Kyungsoo Oh* Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic of Korea S Supporting Information *

ABSTRACT: A direct acyl radical addition to 2H-indazoles has been achieved for the first time, where the less-aromatic quinonoid 2H-indazoles readily accepted radical species to the C-3 position. Motivated by the lack of direct acylation strategy for 2Hindazoles, the current method utilizes the radical acceptability of 2H-indazoles, discovering an ambient temperature reaction to provide facile access to a diverse array of 3-acyl-2H-indazoles with three points of structural diversification in 25%−83% yields.

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Scheme 1. Synthetic Approaches to 2H-Indazoles

s an isostere of indoles and purines, indazoles have found therapeutic applications across a broad spectrum of human diseases.1 In particular, 2H-indazoles have recently emerged as promising anticancer agents,2 in addition to having excellent anti-inflammatory activities.3 While there exist numerous synthetic methods to substituted 1H-indazoles,4 the synthetic routes to 2H-indazoles are less prevalent and include the Pd-catalyzed reductive cyclization of nitroarenes,5 aryne [3 + 2] cycloaddition reaction,6 metal-catalyzed azide addition to 2-bromobenzyl imines,7 Sn-mediated cyclization of 2-nitrobenzyl amines,8 phosphine-mediated reductive cyclization of 2-nitrobenzyl imines,9 and Co(III)-catalyzed C−H arylation of diazo compounds followed by cyclization.10 In contrast to the assembly methods for 2H-indazoles from the acyclic synthetic precursors, the direct 3-aryl introduction to 2H-indazoles includes the Pd-catalyzed arylation,11 direct metalation followed by Negishi coupling,12 and Cu-catalyzed C−H arylation (Scheme 1a).13 At the present time, however, direct acylation of 2H-indazoles has not been achieved, while access to 3-acyl-2H-indazoles is limited to the cycloaddition between arynes and diazocarbonyl compounds,14 and the Rh(II)-catalyzed C−H addition and cyclization of azobenzene derivatives (Scheme 1b).15 With the lack of direct acylation methods for 2H-indazoles,16 combined with the symmetric substrate nature of benzyne and azobenzene approaches, there are critical synthetic and medicinal needs for the development of direct acylation of diversely substituted 2H-indazoles under mild reaction conditions. Herein, we report the development of direct radical addition reactions to 2H-indazoles through the AgNO3catalyzed decarboxylative cross-coupling of α-keto acids, where the regioselective synthesis of 3-acyl-2H-indazoles has been achieved at ambient temperature. The current direct acyl radical addition to 2H-indazoles significantly differs from the previous direct C−H activation approach where the anionic character of the 3-carbon of 2H-indazoles was utilized. The use of radical acceptor character of 2H-indazoles allows facile access © XXXX American Chemical Society

to a diverse array of 3-acyl-2H-indazoles with different substitution patterns under much milder reaction conditions. Given the previous successes of metal-catalyzed C−H activation strategies,17 we initially examined the direct acylation of 2H-indazole via C−H activation using palladium and copper catalysts in the presence of acyl radical precursors, such as toluene, benzaldehyde, and benzoic acid.18 Without much success, we turned our attention to silver-catalyzed decarboxylative acyl radical generation from α-keto acids.19 Table 1 Received: March 21, 2018

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DOI: 10.1021/acs.orglett.8b00920 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 2. Scope of α-Keto Acids in the AgNO3-Catalyzed Radical Addition to 2H-Indazole

Table 1. Silver-Catalyzed Decarboxylative Cross-Coupling of α-Keto Acid with 2H-Indazolea

entry

Ag (mol %)

oxidant (equiv)

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e 16f

AgOAc (20) Ag2CO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (40) AgNO3 (10) AgNO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (20) AgNO3 (20)

Na2S2O8 (2) Na2S2O8 (2) Na2S2O8 (2) K2S2O8 (2) (NH4)2S2O8 (2) Na2S2O8 (3) K2S2O8 (3) Na2S2O8 (2) Na2S2O8 (2) Na2S2O8 (3) Na2S2O8 (3) Na2S2O8 (3) Na2S2O8 (3) Na2S2O8 (3) Na2S2O8 (3) Na2S2O8 (3)

DMSO:H2O DMSO:H2O DMSO:H2O DMSO:H2O DMSO:H2O DMSO:H2O DMSO:H2O DMSO:H2O DMSO:H2O CH3CN:H2O THF:H2O acetone:H2O acetone:H2O acetone:H2O acetone:H2O acetone:H2O

58 60 60 69 71 78 72 62 46 NR 29 81 76 68 75 0

a

Reaction conditions: 1a (0.10 mmol) and 2a (0.30 mmol) in solvents (v/v = 1:1, 0.05 M) under Ar. bIsolated yields after column chromatography. cUse of 2a (0.2 mmol). dReaction at 40 °C. e Reaction at 50 °C. fReaction under air (no 1a and 2a left).

summarizes the optimization conditions for the direct acylation of 2H-indazole 1a with 2-oxo-2-phenylacetic acid 2a. First, from the screening of silver salts, AgNO3 was identified as a suitable water-tolerant silver source, where the formation of 3-acyl-2Hindazole 3a was observed in 58%−60% yields (entries 1−3 in Table 1). While the use of other persulfate salts improved the isolated yields of 3a (entries 4 and 5 in Table 1), the employment of 3 equiv of persulfates consistently provided 3acyl-2H-indazole 3a in 72%−78% yields (entries 6 and 7 in Table 1). After confirming the optimal loading of AgNO3 as 20 mol % (entries 8 and 9 in Table 1), we investigated other solvent mixtures (entries 10−12 in Table 1) since water is essential in dissolving AgNO3, 2-oxo-2-phenylacetic acid 2a, and persulfates.20 The reaction in an acetonitrile−water mixture did not proceed (entry 10 in Table 1), and only 29% of 3a was obtained upon using a mixture of THF−water (entry 11 in Table 1). Gratifyingly, a mixture of acetone−water turned out to be the optimal solvent mixture, providing the desired 3-acyl2H-indazole 3a in 81% yield (entry 12 in Table 1). Further control experiments (1) using 2 equiv of α-keto acid 2a, (2) at a higher temperature of 40−50 °C, and (3) under an oxygen atmosphere confirmed our optimized conditions as 20 mol % of AgNO3 and 3 equiv of Na2S2O8 in acetone−water at ambient temperature (entry 12). Scheme 2 illustrates the substrate scope of α-keto acids in the radical addition reaction to 2H-indazole 1a. The investigation into the electronic effect of α-keto acids 2 revealed that electron-donating groups are preferred at the para-position of the phenyl group (3b and 3c, 66%−81% yields), as opposed to the meta-position (3d and 3e, 60%−65% yields). The presence of electron-withdrawing groups also reduced the reaction efficiency somewhat, as evidenced by 3-acyl-2H-indazoles 3f−

a

Reaction at 50 °C.

3h in 44%−66% yields. However, the presence of a halogen atom at the para-position reinstated the reaction efficiency to 74%−81% yields for 3i and 3j, because of the electron-donating effect of heavier halogen atoms. Similarly, the benzodioxole subunit acted as an electron-donating group to give 81% yield of 3-acyl-2H-indazole 3k. Other aryl-substituted α-keto acids either gave the reduced reactivity, only leading to 53% yield for a naphthyl-substituted 3-acyl-2H-indazole 3l, or required the higher reaction temperature of 50 °C to give 40% yield of a thiophenyl-substituted 3-acyl-2H-indazole 3m. The use of alkyl α-keto acids also required the higher reaction temperature of 50 °C to give 40%−45% yields of 3-acyl-2H-indazoles 3n and 3o. A limitation of the current method exists for tert-butyl acyl radical, where further decarbonylation led to 3-tert-butyl-2Hindazole 3p in 55% yield. In addition, the use of benzyl and indolyl α-keto acids failed to undergo the desired reactions, possibly due to the facile decarbonylation of the corresponding acyl radicals to more stable radical species.21 Further substrate scope in the Ag-catalyzed decarboxylative cross-coupling of α-keto acids with 2H-indazoles is presented in Scheme 3. Since a diverse array of 2H-indazoles is readily accessible by the copper-catalyzed one-pot reactions of 2bromobenzaldehydes, amines, and sodium azide originally developed by the Lee group,7b we first examined the electronic B

DOI: 10.1021/acs.orglett.8b00920 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Further Substrate Scope for Silver-Catalyzed Decarboxylative Cross-Coupling of α-Keto Acids with 2HIndazoles

a

Scheme 4. Control Experiments and Proposed Reaction Mechanism

acetone−water solvent system only led to the formation of acetone-captured TEMPO 4a in 85% yield with benzoic acid and 3-acyl-2H-indazole 3a in 72% and 43% yields, respectively. The acetone-captured TEMPO 4a may have originated from the oxidation TEMPO under the reaction condition to the Noxoammonium salt, followed by the attack from the enol form of acetone.22 Nevertheless, the same TEMPO reaction in the dimethyl sulfoxide (DMSO)−water solvent system provided the acyl-captured TEMPO 4b in 17%−53% yields, demonstrating the involvement of radical species in the current synthetic route to 3-acyl-2H-indazoles. The radical addition reaction was unique to 2H-indazoles, since benzonoid 1H-indazoles 5a and 5b did not undergo the radical addition reactions. Based on our experimental data, a plausible reaction mechanism is proposed that utilizes the sequence of Ag-initiated decarboxylative radical generation from α-keto acids, followed by another Ag-mediated oxidation of the radical intermediate species to the cationic species that, in turn, rearomatizes to 3-acyl-2H-indazoles (Scheme 4b). While the Ag-mediated oxidation of the radical intermediate to the cationic species may prevail, the formation of benzoic acid as byproduct from the reaction mixture strongly indicates the active involvement of an acyl radical to acyl cationic species in a secondary radical pathway. Thus, by utilizing the electronic feature of α-keto acids, combined with the less-aromatic quinonoid character of 2H-indazoles,23 it may be possible to design better Ag-catalyzed decarboxylative crosscoupling reactions. In summary, we have developed the first direct acylation method for 2H-indazoles using the Ag-catalyzed decarboxylative cross-coupling of α-keto acids. The developed synthetic method for 3-acyl-2H-indazoles employs a mild reaction

Reaction at 50 °C.

effect of the N-2 substituent of 2H-indazoles. While no particular electronic pattern was found, the presence of phenyl groups with para-carbon-based subsitutents required the higher reaction temperature of 50 °C (3q, 3t, and 3v), and the halogen substituents resulted in better yields of 74%−75% (3s and 3u). The phenyl group with an ortho-substitution significantly exerted a steric effect to give 3-acyl-2H-indazole 3w in 45% at 50 °C. Alkyl 2H-indazoles could be employed (3x−3z), but the observed yields remained 25%−38%, because of the facile decarbonylation of alkyl-substituted acyl radicals.21 Next, the electronic effect of the arene part of 2H-indazoles was studied. Fluorine-substituted 2H-indazole at C-5 provided the desired product 3aa in 75% yield; however, the benzodioxolesubstituted 2H-indazole required higher reaction temperature to give product 3ab in 40% yield. The use of 6-methyl-2Hindazole provided product 3ac in 63% yield. Once again, it is likely that the fluorine substituent acts as an electronwithdrawing group, whereas the benzodioxole/methyl substituents act as electron-donating groups. Based on the observed electronic as well as steric effects of α-keto acids and 2H-indazoles, a diverse array of 3-acyl-2H-indazoles 3ad− 3aj was prepared in 49%−83% yields. To better understand the radical addition to 2H-indazoles, control experiments were conducted in the absence of oxidant or silver salt (Scheme 4a). The experimental results confirmed the necessity of both reagents, Na2S2O8 and AgNO3, where no product formation was observed in the absence of either reagent. Attempts to capture the radical species with the C

DOI: 10.1021/acs.orglett.8b00920 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters condition, where a diverse array of α-keto acids and 2Hindazoles are used as a tool for the structural diversification of 3-acyl-2H-indazoles. Our three-point structural variation studies map out the importance of electronic features in the α-keto acids and 2H-indazoles. With direct synthetic access to 3-acyl2H-indazoles, the medicinal chemistry aspect of 3-acyl-2Hindazoles can be now examined. Additional biological studies of thus-prepared 2H-indazole derivatives, as well as the extension of radical addition reactions to other heteroaromatic compounds, are currently underway, and our results will be reported in due course.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00920. Experimental procedures and characterization data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kyungsoo Oh: 0000-0002-4566-6573 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Dr. Yogesh Goriya (Chung-Ang University) for a preliminary investigation. This research was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (Nos. NRF2015R1A5A1008958 and NRF-2015R1C1A2A01053504).

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Organic Letters

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DOI: 10.1021/acs.orglett.8b00920 Org. Lett. XXXX, XXX, XXX−XXX