Rh(III)-catalyzed oxidative C–H annulation of 6-arylpyridazin-3(2H)-ones: direct access to diarylpyridazino[6,1-a]isoquinolin-5-ium-3-olates

Abstract

A novel strategy has been developed for the synthesis of diarylpyridazino[6,1-a]isoquinolin-5-ium-3-olate frameworks through a Rh(III)-catalyzed C–H annulation of 6-arylpyridazin-3(2H)-ones with internal alkynes by means of C–H bond activation. This is the first report on ortho-C–H bond annulation of 6-arylpyridazin-3(2H)-ones with alkynes to afford angularly fused heterocycles in good yields with high functional group tolerance. This method offers a facile and practical approach to structurally diverse mesoionic scaffolds of pharmaceutical relevance.d6ra01670g-s

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Introduction

In recent years, transition metal-catalyzed ortho-C–H bond functionalization has emerged as a powerful synthetic strategy in organic synthesis, enabling the formation of C–C, C–N, and C–X bonds without the need of pre-functionalization of the substrate.¹ For instance, substrate-directed C–H functionalization offers significant advantages by providing direct access to diverse substitution patterns and thus facilitating the construction of N-containing heterocycles, which are key components of many biologically active molecules. This method overcomes significant challenges associated with conventional approaches.²

In particular, Rh(III)-catalyzed directed C–H bond activation of aromatic rings with alkynes has received special attention due to its high atom efficiency in constructing a diverse range of fused polycyclic aromatic frameworks.^3,4 On the other hand, isoquinolinium salts are an important class of compounds that are widely utilized for the synthesis of several biologically active compounds.⁵ As a result, many efforts have been made to develop efficient methods for the synthesis of these compounds (Scheme 1).^6,7

Scheme 1 Previous reports on the synthesis of isoquinolinium salts.

In particular, transition metal-catalyzed annulation of aryl halides with alkynes is a commonly used strategy for the synthesis of isoquinolinium salts.^8,9 Furthermore, mesoionic compounds are distinct types of heterocycles, which belong to the class of non-benzenoid aromatics such as sydnones and munchnone etc (Fig. 1).¹⁰

Fig. 1 Examples of bioactive mesoionic compounds.

Interestingly, these mesoionic compounds are key building blocks for many biologically active compounds, which possess wide applications such as dyes, insecticides, pharmaceuticals.¹¹ Recently, ruthenium-catalyzed alkenylation of 6-aryl(dihydro)pyridazin-3(2H)-ones with alkynes has been reported to give N-alkenylated products (I) and C-alkenylated products (II) under different atmospheric conditions (Scheme 2).¹²

Scheme 2 Previous and present work.

However, there are no reports on the annulation of 6-arylpyridazin-3(2H)-ones with internal alkynes to generate a novel class of mesoionic compounds. Interestingly, these mesoionic compounds are used as precursors for dyes, insecticides and pharmaceuticals.¹³

Results and discussion

Following our interest on C–H functionalization of aza-aromatic systems,¹⁴ we herein report a novel strategy for the oxidative annulation of 6-arylpyridazin-3-oneswith internal alkynes using a catalytic system comprising of [Cp*RhCl₂]₂, AgSbF₆ & Cu(OAc)₂·H₂O to afford a novel class of mesoionic isoquinolinium derivatives. A model reaction between 6-phenylpyridazin-3(2H)-one (1a) and 1,2-diphenylethyne (2a) was performed under different experimental conditions (Table 1).

Table 1 Optimization of reaction conditions^a,b

Entry	Catalyst	Activator	Oxidant	Solvent	Temp.(°C)	Yield (%)^b
a Reaction conditions: 1a (1.0 equiv), 2a (1.2 equiv.), [Cp*RhCl2]2 (5 mol%), AgSbF6 (30 mol%), Cu(OAc)2 (0.5 equiv.), DCE (5.0 mL) at 120 °C for 8–10 h in a sealed tube.b Isolated yield after purification.
1	[RhCp*Cl2]2	AgSbF6	AgOAc	DCE	80	55
2	[RhCp*Cl2]2	AgSbF6	AgOAc	DCE	100	70
3	[RhCp*Cl2]2	AgSbF6	AgOAc	DCE	120	75
4	[RhCp*Cl2]2	AgSbF6	Cu(OAc)2.H2O	DCE	120	92
5	[RhCp*Cl2]2	—	Cu(OAc)2.H2O	DCE	120	Trace
6	[RhCp*Cl2]2	AgSbF6	—	DCE	120	40
7	[RhCp*Cl2]2	AgSbF6	Cu(OAc)2.H2O	MeOH	120	75
8	[RhCp*Cl2]2	AgSbF6	Cu(OAc)2.H2O	EtOH	120	70
9	[RhCp*Cl2]2	AgSbF6	Cu(OAc)2.H2O	Toluene	120	65
10	[RhCp*Cl2]2	AgSbF6	Cu(OAc)2.H2O	ACN	120	62
11	[Ru(p-cym)Cl2]2	AgSbF6	Cu(OAc)2.H2O	DCE	120	75
12	Pd(OAc)2	AgSbF6	Cu(OAc)2.H2O	DCE	120	—

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Initially, the annulation was carried out using a 5 mol% of [Cp*RhCl₂]_2, 30 mol% of AgSbF₆ and 0.5 equiv. of AgOAc in DCE at 80 °C under inert conditions. Interestingly, a novel mesoionic compound, i.e. 6,7-diphenylpyridazino[6,1-a]isoquinolin-5-ium-3-olate 3a was isolated in 55% yield (entry 1, Table 1). To improve the yield, the temperature was increased ranging from 80° to 120 °C. To our delight, the yield was enhanced from 55% to 75% respectively (entries 1, 2 and 3, Table 1). To optimize the role of additive, the reaction was further carried out using Cu(OAc)₂·H₂O under similar conditions. Remarkably, the product 3a was obtained in 92% yield (entry 4, Table 1). The use of either AgSbF₆ or Cu(OAc)₂.H₂O alone was found to be less effective (entries 5 & 6, Table 1). To realize the effect of solvent, the reaction was conducted in different solvents (entries 7–10, Table 1). Among them, DCE gave the best result. To understand the role of catalyst, the reaction was performed using other metal catalysts such as [Ru(p-cym)Cl₂]₂ & Pd(OAc)₂ (entries 11 and 12, Table 1). However, the use of [Ru(p-cym)Cl₂]₂ gave the product 3a in low yield compared to [RhCp*Cl₂]₂, whereas Pd(OAc)₂ failed to give the desired product under similar conditions.

Having the optimized reaction conditions in hand, we examined the scope and generality of this process. The reaction between various internal alkynes 2a–i and different pyridazinones was studied systematically. The results are summarized in Table 2. A variety of diaryl acetylenes bearing an electron withdrawing and donating substituents at the para-position of phenyl ring afforded the corresponding products in good to excellent yields (entries 3b, 3c, 3d & 3e, Table 2). The structure of 3d was confirmed by NMR spectroscopy and single crystal X-ray crystallography (Fig. 2a).¹⁵

Table 2 Annulation of arylpyridazin-3(2H)-ones with alkynes^a,b

a Reaction conditions: 1a (1.0 equiv.), 2a (1.2 equiv), [Cp*RhCl₂]₂(5 mol%), AgSbF₆(30 mol%), Cu(OAc)₂ (0.5 equiv.), DCE (5.0 mL) at 120 °C for 8–10 h in a sealed tube.b Isolated yield after purification.c No reaction.

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Fig. 2 (a) ORTEP diagram of 3d; (b) ORTEP diagram of 3h; (c) ORTEP diagram of 3t.

Conversely, the substrate bearing –CF₃ group at the para-position and dialkylacetylene also gave the desired product relatively in low yield (entries 3f & 3g, Table 2). Interestingly, the reaction was quite successful with 1,4-diphenylbutadiyne furnishing the required product in good yield (entry 3i, Table 2). Nevertheless, the substrate derived from thiophene afforded the respective product in good yield (entry 3j, Table 2). Furthermore, we evaluated the scope of this process with various pyridazinones bearing different substituents such as methyl, methoxy, fluoro and chloro on benzene ring. It is noteworthy to mention that these groups are well tolerated under the reaction conditions and the corresponding products were isolated in excellent yields (entries 3k, 3l, 3m & 3n, Table 2). However, a few unsymmetrical alkynes gave the product as a mixture of regioisomers in different ratio (3r in 1 : 1 ratio, 3s in 1 : 1.8 ratio). Where as the unsymmetrical alkyne bearing substituents like 4-chlorophenyl, 4-fluorophenyl and methyl furnished the desired product with high regioselectivity due to electronic effects (entries 3h, 3i, 3t, & 3u, Table 2). The structures of compounds 3i and 3u were confirmed through extensive 2D NMR analysis. For compound 3i, NOE correlations between H12 ↔ H25, 29 and H15 ↔ H8, along with HMBC correlations between H25, 29 ↔ C23, established the structure of 3i. Similarly, for compound 3u, NOE correlations between 23-methyl ↔ H12, 23-methyl ↔ H18, 22, and H15 ↔ H8 confirmed the regioisomer. The spectral data and interpretation of nOes are presented as Fig. Sx–Sy and Tables S1 and S2 in SI. In addition to this, the structures of 3h and 3t were established by single crystal X-ray crystallographic studies (Fig. 2b and 2c).¹⁵ It was observed that the reaction did not proceed either with diethyl or with dimethyl acetylene carboxylate (entries 3p and 3q, Table 2).

Based on experimental results and previous reports,^16,17 a plausible reaction mechanism is proposed in Scheme 3. The catalyst, [RhCp*Cl₂]₂ is activated by AgSbF₆ to generate a highly reactive monomeric Rh(III) species, which coordinates with a nitrogen atom of the substate 1a along with ortho-C–H bond cleavage to form a five-membered rhodacycle (I). In the second step, the alkyne 2a coordinates with a rhodacycle (I) to form a ternary complex (II). Then, a migratory insertion of alkyne into Rh–C bond generates a seven-membered rhodacycle (III). Finally, the reductive elimination occurs to give the intermediate IV along with Rh(I) species, which can undergo oxidation by Cu(II) to complete the catalytic cycle, while Cu(II) is reduced to Cu(I) or Cu(0). Finally, the anion (acetate) abstracts the proton from hydroxyl group, probably due to its basicity to produce the mesoionicisoquinoline3a (Scheme 3).

Scheme 3 A plausible reaction mechanism.

Conclusions

We have successfully developed a novel approach to the synthesis of mesoionic isoquinolin-5-ium-3-olate frameworks through a transition metal catalyzed oxidative C–H annulation of 6-arylpyridazin-3(2H)-ones with diarylacetylenes. The catalytic system comprises 5 mol% Rh(III), 30 mol% AgSbF₆ and 0.5 equiv of Cu(OAc)₂·H₂O and acts as a trifunctional catalyst. This approach offers several advantages including operational simplicity, broad substrate scope, and excellent functional group tolerance. The end products are more relevant to pharmaceuticals and agrochemicals and also serve as versatile precursors for novel heterocycles through dipolar cycloadditions.

Experimental section

All solvents were dried by a standard literature procedure. Crude products were purified by column chromatography on silica gel of 60–120 or 100–200 mesh. Thin layer chromatography (TLC) plates were visualized by exposure to ultraviolet light at 254 nm, and by exposure to iodine vapors and/or by exposure to methanolic acidic solution of p-anisaldehyde followed by heating (<1 min) on a hot plate (∼250 °C). Organic solvents were concentrated on rotary evaporator at 35–40 °C. Melting points (mp) were measured on Buchi B-540. ¹H & ¹³C NMR (proton-decoupled) spectra were recorded in CDCl₃ solvent on 300, 400 or 500 MHz NMR spectrometer. Chemical shifts (δ) were reported in parts per million (ppm) with respect to TMS as an internal standard. Coupling constants (J) are quoted in hertz (Hz). ORBITRAP and ESI mass spectrometer were used for recording the HRMS.

Experimental procedure for the synthesis of 3a

To an oven dried sealed tube equipped with a stir bar were charged with 6-phenylpyridazin-3(2H)-one (1a, 1.0 equiv.), biphenyl acetylene (2a, 1.2 equiv.) in 3 mL of DCE, followed by addition of [Cp*RhCl2]2catalyst (5 mol%), AgSbF6(30 mol%) and Cu(OAc)2.H2O (0.5 equiv.) at room temperature. The resulting mixture was stirred at 120 °C for 8–10 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH/Chloroform) to afford the pure product 3a.

Conflicts of interest

The authors declare that no conflict of interest.

Data availability

CCDC 2480463 (3d), 2548013 (3h), and 2548012 (3t) contain the supplementary crystallographic data for this paper.^15a,b,c

Data is available in the supplementary information (SI) file along with this article. Supplementary information: copies of ¹H &¹³C NMR spectra of products are provided in the supplementary information. See DOI: https://doi.org/10.1039/d6ra01670g.

Acknowledgements

The authors would like to thank Dr. Ravi S. Ampapathi for helpful discussions regarding the NMR studies.

Notes and references

1. (a) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz and L. Ackermann, Chem. Rev., 2019, 119, 2192–2452; (b) J. H. Docherty, T. M. Lister, G. Mcarthur, M. T. Findlay, P. Domingo-Legarda, J. Kenyon, S. Choudhary and I. Larrosa, Chem. Rev., 2023, 123, 7692–7760; (c) A. Bera, L. M. Kabadwal, S. Bera and D. Banerjee, Chem. Commun., 2022, 58, 10–28; (d) S. Rej, Y. Ano and N. Chatani, Chem. Rev., 2020, 120, 1788–1887; (e) H. M. Davies and D. Morton, J. Org. Chem., 2016, 81, 343–350.
2. (a) H. M. Davies and D. Morton, J. Org. Chem., 2016, 81, 343–350; (b) L. Monsigny, F. Doche and T. Besset, Beilstein J. Org. Chem., 2023, 19, 448–473; (c) U. Dhawa, N. Kaplaneris and L. Ackermann, Org. Chem. Front., 2021, 8, 4886–4913; (d) T. Swamy, B. V. S. Reddy, R. Grée and V. Ravinder, ChemistrySelect, 2018, 3, 47–70; (e) N. Umadevi, G. Kumar, N. C. G. Reddy and B. V. S. Reddy, Curr. Org. Chem., 2021, 25, 601–634; (f) M. V. K. Rao, S. Kareem, S. R. Vali and B. V. S. Reddy, Org. Biomol. Chem., 2023, 21, 8426–8462.
3. S. Mochida, N. Umeda, K. Hirano, T. Satoh and M. Miura, Chem. Lett., 2010, 39, 744–774.
4. C. Ajay, B. Sridhar and B. V. S. Reddy, Chem. Asian J., 2024, 19, e202400723.
5. (a) R. M. Scarborough, K. A. Kane-Maguire, C. K. Marlowe, M. S. Smyth, X. Zhang, US pat., US 0113399A1, 2005; (b) L. J. Adams, WO 108682A2, 2004; (c) R. B. Gupta, R. W. Franck, K. D. Onan and C. E. Soll, J. Org. Chem., 1989, 54, 1097; (d) O. Tsuge, S. Kanemasa, K. Sakamoto and S. Takenaka, Bull. Chem. Soc. Jpn., 1988, 61, 2513; (e) S. Su and J. A. P. Jr, J. Am. Chem. Soc., 2007, 129, 7744.
6. (a) R. P. Korivi, W.-C. Wu and C.-H. Cheng, Chem. Eur J., 2009, 15, 10727; (b) R. P. Korivi and C.-H. Cheng, Chem. Eur J., 2010, 16, 282; (c) K. R. Roesch, H. Zhang and R. C. Larock, J. Org. Chem., 2001, 66, 8042; (d) R. P. Korivi and C.-H. Cheng, Org. Lett., 2005, 7, 5179.
7. (a) K. Parthasarathy, N. Senthilkumar, J. Jayakumar and C.-H. Cheng, Org. Lett., 2012, 14, 3481; (b) G. Zhang, L. Yang, Y. Wang, Y. Xie and H. Huang, J. Am. Chem. Soc., 2013, 135, 8850–8853; (c) N. Senthilkumar, P. Gandeepan, J. Jayakumar and C.-H. Cheng, Chem. Commun., 2014, 50, 3106.
8. N. Asao, S. Y. S. T. Nogami and Y. Yamamoto, Angew. Chem., Int. Ed., 2005, 44, 5526–5528.
9. (a) R. B. Gupta and R. W. Franck, J. Am. Chem. Soc., 1987, 109, 5393; (b) K. Akiba, M. Nakatani, M. Wada and Y. Yamamoto, J. Org. Chem., 1985, 50, 63.
10. (a) Y. Kuroda, M. Krell, K. Kurokawa and K. Takasu, Chem. Commun., 2024, 60, 1719–1722; (b) S. Zhao, R. Yu, W. Chen, M. Liu and H. Wu, Org. Lett., 2015, 17, 2828–2831.
11. K. Porte, M. Riomet, C. Figliola, D. Audisio and F. Taran, Chem. Rev., 2021, 12, 6718–6743.
12. W. Wang, L. Liang, F. Xu, W. Huang, Y. Niu, Q. Sun and P. Xu, Eur. J. Org Chem., 2014, 6863–6867.
13. (a) M. Komloova, A. Horovac, M. Hrabinova, D. Junc, M. Dolezal, J. Vinsova, K. Kuca and K. Musilek, Bioorg. Med. Chem. Lett., 2013, 23, 6663; (b) J. Zhao, X. Yang, Y. Hao, M. Cheng, J. Tian and L. Sun, ACS Appl. Mater. Interfaces, 2014, 6, 3907; (c) M. Jayaraman, B. M. Fox, M. Hollingshead, G. Kohlhagen, Y. Pommier and M. Cushman, J. Med. Chem., 2002, 45, 242.
14. (a) D. Y. Chary, I. Chaitanya, B. Sridhar and B. V. S. Reddy, Eur. J. Org Chem., 2021, 21, 3083–3090; (b) C. Ajay, D. Y. Chary, B. Sridhar and B. V. S. Reddy, ChemistrySelect, 2021, 6, 13046–13050; (c) I. Chaitanya, D. Y. Chary, B. Sridhar and B. V. S. Reddy, Eur. J. Org Chem., 2023, 27, e202300983; (d) C. Ajay, B. Sridhar and B. V. S. Reddy, Org. Biomol. Chem., 2025, 23, 4206.
15. (a) CCDC 2480463: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2p83y1; (b) CCDC 2548013: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2rjdzp; (c) CCDC 2548012: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2rjdyn.
16. W. Zhang, C.-Q. Wang, H. Lin, L. Dong and Y.-J. Xu, Chem. Eur J., 2016, 22, 907.
17. K. Ueura, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2010, 12, 2068.

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