Access to 3‑Acyl-(2H)‑indazoles via Rh(III)-Catalyzed C−H Additionand Cyclization of Azobenzenes with α‑Keto AldehydesTaejoo Jeong,†,§ Sang Hoon Han,†,§ Sangil Han,† Satyasheel Sharma,† Jihye Park,† Jong Suk Lee,‡

Jong Hwan Kwak,† Young Hoon Jung,† and In Su Kim*,†

†School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea‡Biocenter, Gyeonggi Institute of Science & Technology Promotion, Suwon 443-270, Republic of Korea

*S Supporting Information

ABSTRACT: The rhodium(III)-catalyzed direct C−H func-tionalization of azobenzenes with ethyl glyoxalate and arylglyoxals is described. This protocol provides the facile andefficient formation of various C3-acylated-(2H)-indazoles inmoderate to high yields.

The indazole heterocycle has been recognized as a crucialstructural core found in natural products and pharmaceut-

icals with a broad spectrum of medicinal applications.1 Inparticular, the 3-acyl indazole motif is present in molecules thatpossess anticancer, antiemetic, viral polymerase inhibition, andanti-inflammatory activities (Figure 1).2 The classical routes to 3-

acyl indazoles involve (1) N-nitrosation of acetanilides followedby intramolecular cyclization onto the ortho-methylene group,(2) multistep synthesis from isatins via hydrolysis of the amideunit, diazotization and reduction, and (3) direct lithiation at theC3-position followed by the addition of electrophiles.3

Surprisingly, however, the catalytic preparation of 3-acyl indazolescaffolds remains virtually unexplored.With advances in transition-metal-catalyzed C−H bond

functionalization, great effort has been devoted to the formationof various heterocycles.4 In this area, recent progress has beenfocused on the preparation of indazoles via the oxidativeannulation process of hydrazones under palladium, copper, andiron catalysis.5 Lavis and Ellman disclosed beautiful works on thesynthesis of 2,3-diaryl-2H-indazoles via the Rh(III)- or Co(III)-catalyzed redox-neutral coupling of azobenzenes with arylaldehydes (Scheme 1).6

In addition, Glorius demonstrated the Rh- and Cu-catalyzedtandem C−N and N−N bond formations between arylimidatesand sulfonyl azides providing 3-oxo-(1H)-indazoles.7 Recently,our group reported a new strategy for the construction of 2,3-dihydro-(1H)-indazoles from arylhydrazines with various olefinsunder Rh(III) catalysis.8 Moreover, Wang reported therecatalyzed annulation of azobenzenes and aldehydes affording2,3-diaryl-(2H)-indazoles.9 In continuation of our recent studieson the rhodium-catalyzed C−H functionalization and hetero-cycle synthesis,10 we herein present the Rh(III)-catalyzed directC−H addition followed by intramolecular cyclization ofazobenzenes with α-keto aldehydes, such as ethyl glyoxalateand aryl glyoxals, affording 3-acyl-(2H)-indazoles.The optimization of reaction conditions was initiated by

examining the coupling of azobenzene (1a) and ethyl glyoxalate(2a) under rhodium catalysis (Table 1). To our delight, thecationic rhodium complex, derived from [Cp*RhCl2]2 andAgSbF6, was found to promote the coupling of 1a and 2a in DCEat 60 °C to provide the monoalkylated compound 3aa in

Received: November 24, 2015Published: January 7, 2016

Figure 1. Bioactive 3-acyl indazole compounds.

Scheme 1. Indazole Synthesis via C−H Functionalization

Letter

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© 2016 American Chemical Society 232 DOI: 10.1021/acs.orglett.5b03368Org. Lett. 2016, 18, 232−235

concomitant with indazole compounds 3ab and 3ac (Table 1,entry 1). Screening of solvents such asMeOH, t-AmOH, toluene,and 1,4-dioxane did not provide the coupling products in asatisfactory yield (Table 1, entries 2−5). However, the additionof NaOAc as an additive showed an increment of the formationof coupling products in 60% combined yield (Table 1, entry 6).This reaction was found to be comparable with KOAc andAgOAc additives, but Cu(OAc)2 was less effective in thiscoupling reaction (Table 1, entries 7−9). In all cases, we couldnot control the formation of alkylated azobenzene 3aa andindazoles 3ab and 3ac. However, increasing the amount of ethylglyoxalate (2a) to 3 equiv, indazole 3acwas exclusively formed inhigh yield (Table 1, entry 10).To evaluate the scope of this process, the optimal reaction

conditions were subjected to a range of azobenzenes 1a−1n(Scheme 2). In case of para-substituted azobenzenes 1b and 1cwith electron-rich groups, high yields of C7-alkylated indazolecompounds 3bc and 3cc were obtained. However, electron-deficient azobenzenes 1d−1f underwent the formation ofindazole products 3db−3fb and 3dc−3fc at elevated temper-ature (100 °C) in good to high yields, but lower ratio betweenindazoles 3db−3fb and C7-alkylated indazoles 3dc−3fc wasdetected. Thus, with the increased loading of 2a (5 equiv), a goodlevel of ratio and improved yields of indazole products wereobtained. Interestingly, meta-substituted azobenzenes 1g and 1hwith OMe and F groups, respectively, provided good to highyields of C7-alkylated indazoles 3gc and 3hc. In contrast,azobenzenes 1i and 1j containing halogen groups (Cl and Br) atthemeta-position, provided indazoles 3ib and 3jb along with C7-alkylated indazoles 3ic and 3jc in high yields. However, stericallycongestedmeta-acetyl azobenzene 1k provided only C3-acylatedindazole 3kb. Additionally, ortho-substituted azobenzenes 1l−1nproved to be good substrates for the formation of indazoles 3lb−3nb.

To further explore the scope and limitation of this trans-formation, various glyoxals 2b−2k were screened, as shown inScheme 3. Initially, ortho-substituted azobenzene 1m wascoupled with phenyl glyoxal (2b) under the optimized reactionconditions to afford the desired indazole 4b in 46% yield.However, the addition of AgOAc instead of NaOAc provided animproved yield (56%) of 4b. Other reaction conditions werefound to be inferior for the coupling of 1m and 2b. The modifiedconditions were applied to various aryl glyoxals 2c−2i to give thecorresponding products 4c−4i in moderate yields. To ourdelight, heteroaryl glyoxal 2j and alkyl glyoxal 2k alsoparticipated in the coupling reaction to furnish indazoles 4jand 4k, respectively. In addition, in the case of para- and meta-substituted azobenzenes 1b and 1j, C3-acylated indazoles 4l and4mwere exclusively formed, and C7-alkylated indazoles were notobserved presumably due to fast intramolecular cyclization ofmonoalkylated intermediates.Further investigation of unsymmetrical azobenzenes 1o and

1p with 2a revealed that this transformation can predominantlyoccur at the ortho-C−H bonds on the electron-rich aromatic ringto provide the corresponding indazoles (5a and 6a′) as major

Table 1. Selected Optimization for Reaction Conditionsa

entry additive (mol %) solvent yield (%),b ratioc

1 AgSbF6 (10) DCE 30 (8:1:1)2 AgSbF6 (10) MeOH N.R.3 AgSbF6 (10) t-AmOH trace4 AgSbF6 (10) toluene trace5 AgSbF6 (10) dioxane 12 (1:0:1)6 AgSbF6 (10), NaOAc (30) DCE 60 (5:1:4)7 AgSbF6 (10), KOAc (30) DCE 55 (6:1:3)8 AgSbF6 (10), AgOAc (30) DCE 56 (5:1:4)9 AgSbF6 (10), Cu(OAc)2 (30) DCE 20 (1:2:1)10d AgSbF6 (10), NaOAc (30) DCE 95 (0:1:48)

aReaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [RhCp*Cl2]2(2.5 mol %), additive (quantity noted), solvent (1 mL) at 60 °C for 20h under air in reaction tubes. bIsolated yield by columnchromatography. cParentheses shows ratio of 3aa/3ab/3ac. dCom-pound 2a (0.6 mmol) was used.

Scheme 2. Scope of Azobenzenesa

aReaction conditions: 1a−1n (0.2 mmol), 2a (0.6 mmol),[RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), NaOAc (30 mol%), DCE (1 mL) at 60 °C for 20 h under air in reaction tubes.bIsolated yield by flash column chromatography. cReactions wereperformed at 100 °C for 20 h. dReactions were performed with 2a (1.0mmol) at 100 °C for 20 h.

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products (Scheme 4). In addition, when we performed thereaction of azobenzene 1q containing sterically different

aromatic rings, a single product 7a was obtained in 98% yield.This result indicates that the steric environment of azobenzene isalso crucial to tune the site-selectivity of this transformation.To gain mechanistic insight, we carried out an experiment of

3aa with aryl glyoxal 2c under the standard reaction conditions(Scheme 5). A trace amount of 3ab and no crossover product 4pwas observed. This result indicates irreversible addition of α-ketoaldehydes to the rhodacycle intermediate, which is in contrast tothose of the Rh(III)- and Co(III)-catalyzed reversible insertionof aldehydes, imines, and isocyanates.11 For an example onirreversible insertion of aldehydes, Li demonstrated the Rh(III)-catalyzed C−H addition of phenylpyridines to ethyl glyoxalate,12

which is thermodynamically favorable due to aldehydedestabilization as opposed to additions to standard aldehydes.

Thus, our reaction afforded C7-alkylated indazole 8a as a majorproduct in 56% yield, and no formation of 8b was detected,which shows that intramolecular cyclization of α-hydroxyketones generated from aryl glyoxals is faster than α-hydroxyesters generated from ethyl glyoxalate. The above results alsosupport the formation of indazoles 4l and 4m throughmonoalkylation followed by fast intramolecular cyclization. Insharp contrast, in the case of ethyl glyoxalate, the formation ofbis-alkylation took place faster than intramolecular cyclization togive C7-alkylated indazole products.Next, we envisioned the sequential C−H activation of our

products by assisting indazole and carbonyl directing groups.Thus, the deuterium-labeling experiment of 4c was performed,which resulted in H/D exchanges at all C−H bonds in theproximity of indazole and carbonyl directing groups (Scheme 6).However, the sequential C−H functionalization of 4c withacrylate 9a took place preferentially on the 4-methoxyphenyl ringto furnish mono-olefination product 10a in 32% yield.

Based on the precedent literatures on the C−H functionaliza-tion of azobenzenes with carbonyl compounds,6,9,10b,d a plausiblemechanistic pathway for the formation of ortho-alkylatedazobenzenes and indazoles is depicted in Scheme 7. First,coordination of an azo group in azobenzene 1a to a cationicRh(III) catalyst and subsequent C−H cleavage generates a five-membered rhodacycle species I.13 Then coordination of ethylglyoxalate 2a to I affords an intermediate II. An irreversibleinsertion of α-keto aldehydes to a Rh−carbonyl bond ofintermediate II forms the seven-membered rhodacycle III,12

which undergoes protonation to give the alkylated product 3aa

Scheme 3. Scope of Glyoxalsa

aReaction conditions: 1b, 1j, and 1m (0.2 mmol), 2b−2k (0.6 mmol),[RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), AgOAc (30 mol %),DCE (1 mL) at 100 °C for 20 h under air in reaction tubes. bIsolatedyield by flash column chromatography. cNaOAc (30 mol %) was used.

Scheme 4. Reactions of Unsymmetrical Azobenzenes

Scheme 5. Reversibility and Competition Experiment

Scheme 6. Deuterium-Labelling Experiment and SequentialC−H Functionalization of Indazole Product

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and an active Rh(III) catalyst. Further alkylation of 3aa affordsbis-alkylated intermediate IV, which on cyclization andsubsequent aromatization delivers indazole 3ac.In conclusion, we disclosed the rhodium(III)-catalyzed direct

insertion of ethyl glyoxalate and aryl glyoxals to azobenzenes C−H bonds followed by intramolecular cyclization affording highlysubstituted indazoles. This approach allows the generation of anarray of C3-carbonylated indazoles, which are known to becrucial scaffolds of biologically active compounds. Furthermechanistic investigations revealed that the insertion step of α-keto aldehydes to rhodacycle intermediate is irreversible, which isin sharp contrast to those of other π-unsaturates under Rh- andCo-catalysis.

■ ASSOCIATED CONTENT*S Supporting Information

The Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.orglett.5b03368.

Experimental procedures, characterization data, and 1Hand 13C NMR spectra for all compounds (PDF)X-ray crystallographic data (CIF)

■ AUTHOR INFORMATIONCorresponding Author

*E-mail: insukim@skku.edu.Author Contributions§These authors contributed equally to this work.Notes

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis work was supported by the National Research Foundationof Korea (NRF) funded by the Korea government (MSIP) (Nos.2015R1A2A1A15053033 and 2015H1D3A1058932).

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Scheme 7. Plausible Reaction Pathway

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