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DOI: 10.1055/a-2316-5200
One-Pot Expeditious Synthesis of Pyrazoloindolones via Base-Promoted Electrocyclization, C–N Coupling and Intramolecular Oxidative Cyclization
Research grants from Council of Scientific and Industrial Research (Grant No. 02(0346)/19/EMR-II) and Science and Engineering Research Board, New Delhi (Grant No. CRG/2023/000021 and CRG/2023/000121), and the Institute of Eminence, Banaras Hindu University (IoE-BHU, Seed Grant 6031) are gratefully acknowledged.
Abstract
Pyrazoloindolones are synthesized from N-tosylhydrazones in a one-pot multistep process which include base-promoted (i) electrocyclization reaction of N-tosylhydrazones derived from α,β-unsaturated aldehydes, (ii) aromatic nucleophilic substitution, and (iii) a domino cyclization–oxidation process under aerobic conditions.
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Key words
N-tosylhydrazone - electrocyclization - aromatic nucleophilic substitution - oxidative cyclization - pyrazoloindolonesPyrazole-fused heterocyclic compounds such as pyrazolopyrimidines, pyrazolopyridines, and pyrazolopyrroles occur in many biologically and medicinally important compounds.[1] [2] [3] [4] Pyrazole-fused compounds act as inhibitors of phosphoinositide 3-kinase γ (PI3Kγ) and have been evaluated for antileishmanial efficacy.[5] They are also considered as potential candidates for the treatment of Alzheimer’s and Parkinson’s diseases.[6] On the other hand, indole-fused heterocyclic compounds are found in many natural products and medicinally important compounds.[7]
Figure [1] depicts a few selected examples of biologically active pyrazole- and indole-fused heterocyclic compounds. Due to the widespread pharmacological and medicinal importance, development of novel methods for the synthesis of pyrazole- and indole-fused compounds have gained significant research interest.[8] One-pot multistep synthesis is an important topic in organic chemistry owing to its intrinsic advantages such as operational simplicity, low cost, shorter synthesis time, and less amount of waste disposal. These aspects render practicality to the process and contribute to green chemistry.
N-Tosylhydrazones derived from α,β-unsaturated aldehydes undergo base-promoted intramolecular cyclization (likely an electrocyclization) generating substituted pyrazoles.[9] Recently, Kang et al. demonstrated aromatic nucleophilic substitution reaction of halogenated heteroaryl compounds with pyrazoles in situ.[10] Inspired by these literature reports,[9] [10] and a report by Yang, Chen, and co-workers,[11] we envisioned for the synthesis of pyrazoloindolone from pyrazole 2 in two steps (i) coupling with 2-fluorobenzaldehyde to obtain aldehyde 4 and (ii) intramolecular dehydrogenative coupling to access pyrazoloindolone 5 (Scheme [1]).
Our work began with N-tosylhydrazone 1a which underwent smooth intramolecular cyclization when treated with K2CO3 (2.5 equiv) in DMF at 110 °C (Scheme [2]). The reaction profile was clean and therefore, we added 1.0 equiv of 2-fluorobenzaldehyde to the reaction mixture to carry out the aromatic nucleophilic substitution reaction in one pot. At 110 °C, the coupling of pyrazole with 2-fluorobenzaldehyde required 6 h for completion giving rise to compound 4a in 67% yield along with formation of alcohol 5a′ and pyrazoloindolone 5a.
Encouraged by these results, we planned to study the intramolecular oxidative cyclization reaction of isolated aldehyde 4a. Initially, using 1.5 equiv of K2CO3 as the base, the intramolecular cyclization reaction was tested in various solvents. The oxidative cyclization reaction was ineffective in nonpolar (toluene) and moderately polar solvents (THF, CH3CN, 1,4-dioxane; entries 1–4, Table [1]). Among the polar-aprotic solvents, DMSO provided better results (53% yield) under aerobic conditions (flask open to air; entry 6, Table [1]). Carrying out the reaction in a closed vial under oxygen atmosphere provided improved yield (62%, entry 7, Table [1]). It is noteworthy that no reaction was observed in the absence of K2CO3. Screening of other bases in DMSO revealed that Li2CO3 and Na2CO3 were ineffective as the base (entries 10 and 11, Table [1]). Cs2CO3 gave superior yield among the alkali metal carbonates. KOt-Bu as a base produced low yield of the product along with the formation of unidentified byproducts (entry 13, Table [1]). Interestingly, commercially available phosphazene base[12] (P1-t-Bu, 1.5 equiv) yielded the desired product, albeit in moderate yield (entry 14, Table [1]). Use of 10 mol% Cu2O did not provide improved yield (entry 15, Table [1]). Use of 2.0 equiv of Cu2O in the absence of oxygen led to the formation identified product (entry 16, Table [1]). TBHP alone or in the presence of catalyst (I2 or CuI) in CH3CN generated unidentified products and did not yield the desired oxidative cyclization product (entries 17 and 18, Table [1]). Similarly, catalytic amount of AgOTf in the presence of Oxone® as the oxidant[13] also did not give the desired product (entry 20, Table [1]).
Aiming towards the development of one-pot synthesis of novel pyrazoloindolones from N-tosylhydrazones, intramolecular cyclization reaction and aromatic nucleophilic substitution reaction with 2-fluorobenzaldehydes was carried out in dry DMSO using Cs2CO3 in one pot under nitrogen atmosphere. The resulting aldehyde 4 underwent Cs2CO3-mediated oxidative cyclization in the presence of molecular oxygen to furnish the desired compound 5 in satisfactory yields. For example, pyrazoloindolone 5a was obtained in 65% yield in a one-pot synthesis (Scheme [2]). N-Tosylhydrazones generated from a variety of α,β-unsaturated aldehydes were subjected to this one-pot multistep process. The synthetic results are summarized in Scheme [2].
aAll reactions were carried out in 0.20 mmol scale using 0.30 mmol base in appropriate solvent (0.50 M); NR = no reaction.
As listed in Scheme [2], pyrazoloindolones bearing aryl and heteroaryl substituents at 3-position can be obtained in moderate to good yields in one pot under the optimized reaction conditions. Pyrazoloindolone 5b bearing a naphthyl substituent at the 3-position was obtained in 62% yield. Pyrazoloindolones 5c–e containing electron-rich phenyl groups were obtained in 58–68% yields. Similarly, pyrazoloindolones 5f–h having electron-deficient phenyl groups were obtained in 57–66% yields. Among the heteroaryl substituents, pyrazoloindolones 5i and 5j having pyridine and quinoline ring were obtained in 45% and 42% yields, respectively. On the other hand, pyrazoloindolones 5k–n having a thiophene, benzothiophene, furan, and benzofuran ring at the 3-position were obtained in 62%, 67%, 64% and 61% yield, respectively. Notably, halogenated (Cl, Br) fluorobenzaldehydes underwent aromatic nucleophilic substitution with pyrazoles at room temperature to generate the corresponding C–N coupling products (aldehyde intermediates) which subsequently generated the corresponding pyrazoloindoles 5o–q at 130 °C in modest (42–51%) yields. Gratifyingly, this one-pot method was also found to be efficient for the synthesis of 3,4-disubstituted pyrazoloindolones 5r–t in good yields (58–62%). However, N-Boc-protected indole containing compound 5u could not be obtained in synthetically useful yield under the oxidative cyclization condition possibly due to the oxidation of indole ring. Similarly, compounds 5v and 5w having a pyridyl and quinoline moiety could not be obtained as the oxidative cyclization of intermediate aldehydes under the optimized conditions were not successful.
The plausible mechanism of the oxidative cyclization of 4a is outlined in Scheme [3]. Deprotonation of 1a by Cs2CO3 leads to the formation of the diazo intermediate A which undergoes rapid intramolecular electrocyclization to give intermediate B. 1,3-Proton shift converts intermediate B into pyrazole 2a which on aromatic nucleophilic substitution reaction with 2-fluorobenzaldehyde generates aldehyde 4a. Deprotonation of pyrazole proton at C-5 position followed by 5-exo-trig cyclization and protonation leads to intermediate 5a′ which rapidly undergoes aerial oxidation[14] to generate pyrazoloindolone 5a. In a control experiment, we observed rapid conversion of 5a′ into 5a under aerobic conditions in the presence of 1.2 equiv of Cs2CO3 indicating that the intramolecular cyclization is the slowest step (rate-determining step).
A few selected synthetic modifications of halogenated pyrazoloindolone 5f have been depicted in Scheme [4]. The Suzuki reaction with phenylboronic acid, Heck reaction with ethyl acrylate, and Sonogashira coupling with phenyl acetylene on the bromine-containing phenyl ring of pyrazoloindolone 5f occurred smoothly under standard reaction conditions to generate functionalized pyrazoloindolones 6–8 in high yields. Pyrazoloindolone 5f was also converted into its hydrazone derivative 9 in quantitative yield by treating with benzenesulfonyl hydrazide in MeOH at 60 °C. It would be interesting to explore the chemistry of hydrazone derivative 9.
In summary, an efficient one-pot protocol for the expeditious synthesis of 3,4-disubstituted pyrazoloindolones has been developed.[15] The synthesis relies upon Cs2CO3-promoted intramolecular electrocyclization, aromatic nucleophilic substitution reaction with 2-fluorobenzaldehydes, and crucial intramolecular oxidative cyclization reaction under aerobic conditions. Our method provides straightforward access to variety of novel pyrazoloindolones which might be useful in medicinal chemistry research. The synthesized pyrazoloindolones can be further functionalized under standard reaction conditions.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
HSK thanks UGC New Delhi for research fellowship. MKS and KP are grateful to CSIR, New Delhi for research fellowship. We thank SATHI BHU for analytical support.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2316-5200.
- Supporting Information
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References and Notes
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- 15 Experimental Procedure for the One-Pot Synthesis of Pyrazoloindolone 5a A round-bottomed flask (10 mL) fitted with a magnetic stir bar and nitrogen inlet was charged with cinnamaldehyDe (26.2 mg, 0.20 mmol) and MeOH (0.40 mL) at rt. Then TsNHNH2 (37.2 mg, 0.20 mmol) was added, and the mixture was stirred at rt for 3 h. During this time TLC analysis indicated complete conversion. Then, MeOH was evaporated, the residue was dissolved in dry DMSO (0.40 mL), and Cs2CO3 (81.5 mg, 0.25 mmol) was added under nitrogen atmosphere. The resulting mixture was placed in a pre-heated oil bath at 110 °C and stirred for 15 min. Then, 2-fluorobenzaldehyde 3a (24.8 mg, 0.20 mmol) and Cs2CO3 (146.6 mg, 0.45 mmol) were added, and the reaction mixture was stirred at 110 °C for 5 h. Then, the reaction mixture was purged with oxygen and heated at 130 °C under oxygen atmosphere (balloon) for 10 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (25 mL), extracted with brine (3 × 10 mL), dried over Na2SO4, and evaporated. The crude product was purified by silica gel column chromatography using 5% ethyl acetate in hexanes as eluent to obtain pyrazoloindolone 5a (32.1 mg, 65% yield) as a yellow-brown solid; mp 150–152 °C; Rf = 0.75 (0.5:9.5 ethyl acetate/hexane); purified using 2% ethyl acetate in hexanes as eluent. 1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 6.5 Hz, 2 H), 7.53 (d, J = 6.5 Hz, 1 H), 7.45 (apt, J = 7.5 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.29 (apt, J = 8.0 Hz, 1 H), 7.12 (apt, J = 8.0 Hz, 1 H), 6.86 (s, 1 H). 13C{1H} NMR (126 MHz, CDCl3): δ = 179.5, 157.9, 144.0, 139.7, 135.6, 132.0, 128.8, 128.7, 128.0, 126.3, 125.6, 124.9, 110.7, 103.3. HRMS (ESI-TOF): m/z calcd for C16H11N2O [M + H]+: 247.0871; found: 247.0842.
For pyrrolo[1,2-a]indole-based natural products and bioactive molecules, see:
Corresponding Authors
Publication History
Received: 28 March 2024
Accepted after revision: 29 April 2024
Accepted Manuscript online:
29 April 2024
Article published online:
14 May 2024
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References and Notes
- 1a Cherukupalli S, Karpoormath R, Chandrasekaran B, Hampannavar GA, Thapliyal N, Palakollu VN. Eur. J. Med. Chem. 2017; 126: 298
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- 15 Experimental Procedure for the One-Pot Synthesis of Pyrazoloindolone 5a A round-bottomed flask (10 mL) fitted with a magnetic stir bar and nitrogen inlet was charged with cinnamaldehyDe (26.2 mg, 0.20 mmol) and MeOH (0.40 mL) at rt. Then TsNHNH2 (37.2 mg, 0.20 mmol) was added, and the mixture was stirred at rt for 3 h. During this time TLC analysis indicated complete conversion. Then, MeOH was evaporated, the residue was dissolved in dry DMSO (0.40 mL), and Cs2CO3 (81.5 mg, 0.25 mmol) was added under nitrogen atmosphere. The resulting mixture was placed in a pre-heated oil bath at 110 °C and stirred for 15 min. Then, 2-fluorobenzaldehyde 3a (24.8 mg, 0.20 mmol) and Cs2CO3 (146.6 mg, 0.45 mmol) were added, and the reaction mixture was stirred at 110 °C for 5 h. Then, the reaction mixture was purged with oxygen and heated at 130 °C under oxygen atmosphere (balloon) for 10 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (25 mL), extracted with brine (3 × 10 mL), dried over Na2SO4, and evaporated. The crude product was purified by silica gel column chromatography using 5% ethyl acetate in hexanes as eluent to obtain pyrazoloindolone 5a (32.1 mg, 65% yield) as a yellow-brown solid; mp 150–152 °C; Rf = 0.75 (0.5:9.5 ethyl acetate/hexane); purified using 2% ethyl acetate in hexanes as eluent. 1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 6.5 Hz, 2 H), 7.53 (d, J = 6.5 Hz, 1 H), 7.45 (apt, J = 7.5 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.29 (apt, J = 8.0 Hz, 1 H), 7.12 (apt, J = 8.0 Hz, 1 H), 6.86 (s, 1 H). 13C{1H} NMR (126 MHz, CDCl3): δ = 179.5, 157.9, 144.0, 139.7, 135.6, 132.0, 128.8, 128.7, 128.0, 126.3, 125.6, 124.9, 110.7, 103.3. HRMS (ESI-TOF): m/z calcd for C16H11N2O [M + H]+: 247.0871; found: 247.0842.
For pyrrolo[1,2-a]indole-based natural products and bioactive molecules, see:
