Rh-Catalyzed Cascade C-H Activation/Annulation of N-Hydroxybenzamides and Propargylic Acetates for Modular Access to Isoquinolones

A sequential Rh(III)-catalyzed C-H activation/annulation of N-hydroxybenzamides with propargylic acetates leading to the formation of NH-free isoquinolones is described. This reaction proceeds through a sequential C-H activation/alkyne insertion/intramolecular annulation/N-O bond cleavage procedure, affording a broad spectrum of products with diverse substituents in moderate-to-excellent yields. Notably, this protocol features the simultaneous formation of two new C-C/C-N bonds and one heterocycle in one pot with the release of water as the sole byproduct.


Introduction
Isoquinolone is a ubiquitous, structural motif that presents in various natural products, conjugated materials, and pharmaceuticals with a wide range of biological activities [1][2][3][4]. Meanwhile, isoquinolone derivatives, as versatile intermediates, provide wide access to a large variety of chemical molecules and drug structures in various organic transformations [5][6][7]. In this regard, the formation of isoquinolone derivatives has gained significant attention among synthetic and medicinal chemists [8][9][10][11][12][13][14]. Traditional methods to access these valuable derivatives involve the Bischler-Napieralski and Pictet-Spengler reactions [15,16], but they often suffer from the need for pre-activated substrates and harsh reaction conditions, which restrict their regioselectivity. Consequently, the development of efficient and atom/step-economical synthetic methods to construct these structures has attracted considerable attention from synthetic chemists.
In the last few decades, transition-metal-catalyzed C-H activation/annulations have been recognized as a powerful and straightforward approach for the synthesis of N-heterocycles and, therefore, have attracted increasing attention [17][18][19][20]. Recently, the transition-metalcatalyzed oxidative cyclization of N-substituted benzamides with symmetrical alkynes or diazos via C-H bond activation has been an efficient method for constructing N-protected isoquinolone derivatives [21][22][23][24][25][26][27][28]. Meanwhile, many other substrates bearing the N-directing group have also been used to construct an isoquinolone scaffold through the C-H activation/annulation strategy [29][30][31]. Despite these achievements, directing access to NHfree isoquinolone scaffolds via cascade C-H activation/annulation has attracted our great interest [32]. Ackermann reported the preparations of isoquinolone derivatives by Ru-catalyzed C-H functionalization/annulation of N-methoxybenzamides or N-hydroxybenzamides with Molecules 2022, 27, 8553 2 of 13 alkynes in water in the presence of MesCO 2 K or 3-(CF 3 )C 6 H 4 CO 2 K as the cocatalytic additive (Scheme 1a) [33,34]. Later, a Rh(III)-catalyzed synthesis of isoquinolones via C-H activation/annulation of benzoylhydrazines and alkynes was further developed (Scheme 1b) [35]. In addition, Li described a highly efficient synthesis pathway by the reaction of iminopyridinium ylides with alkynes for the formation of an isoquinolone skeleton (Scheme 1c) [36]. Very recently, Wu disclosed a robust and convenient rhodium-catalyzed regioselective C-H activation/ [4 + 2] annulation using propargyl alcohols as two-carbon synthons to construct 3-methylisoquinolones (Scheme 1d) [37]. Among the limited successful procedures with unsymmetric alkynes serving as the coupling partners, it is desirable to explore a new pathway for furnishing greater structural diversity of NH-free isoquinolone derivatives. We herein describe a novel rhodium(III)-catalyzed cascade C-H activation/annulation of N-hydroxybenzamides and propargylic acetates to generate NH-free 3-aryisoquinolones, releasing H 2 O as the sole byproduct (Scheme 1e).
Molecules 2022, 27, x FOR PEER REVIEW 2 of 13 tracted our great interest [32]. Ackermann reported the preparations of isoquinolone derivatives by Ru-catalyzed C-H functionalization/annulation of N-methoxybenzamides or N-hydroxybenzamides with alkynes in water in the presence of MesCO2K or 3-(CF3)C6H4CO2K as the cocatalytic additive (Scheme 1a) [33,34]. Later, a Rh(III)-catalyzed synthesis of isoquinolones via C-H activation/annulation of benzoylhydrazines and alkynes was further developed (Scheme 1b) [35]. In addition, Li described a highly efficient synthesis pathway by the reaction of iminopyridinium ylides with alkynes for the formation of an isoquinolone skeleton (Scheme 1c) [36]. Very recently, Wu disclosed a robust and convenient rhodium-catalyzed regioselective C-H activation/ [4 + 2] annulation using propargyl alcohols as two-carbon synthons to construct 3-methylisoquinolones (Scheme 1d) [37]. Among the limited successful procedures with unsymmetric alkynes serving as the coupling partners, it is desirable to explore a new pathway for furnishing greater structural diversity of NH-free isoquinolone derivatives. We herein describe a novel rhodium(III)-catalyzed cascade C-H activation/annulation of N-hydroxybenzamides and propargylic acetates to generate NH-free 3-aryisoquinolones, releasing H2O as the sole byproduct (Scheme 1e).

Scheme 1.
Synthesis of NH-free isoquinolones via C-H activation/annulation strategy.

Results and Discussion
Our study commenced with the reaction between N-hydroxybenzamide (1a) and 3phenylprop-2-yn-

Results and Discussion
Our study commenced with the reaction between N-hydroxybenzamide (1a) and 3-phenylprop-2-yn- With the establishment of the optimum conditions, we first investigated the scope and generality of N-hydroxybenzamide substrates (Scheme 2a). It was found that a variety of substituted N-hydroxybenzamides reacted smoothly with 3-phenylprop-2-yn-1-yl acetate 2a to produce the corresponding isoquinolones in 41-89% yields. In general, N-hydroxybenzamides with either electron-donating (e.g., -Me, -Et, -t Bu, -OMe) or electron-withdrawing (e.g., -F, -Cl, -Br) groups at the para position of the benzene ring worked well with 2a to afford the corresponding products 3ba-3ha in 53-87% yields. Notably, various functional groups, including phenyl and even strong electron-withdrawing substituents -CN, -NO 2 , and -CF 3 , were tolerated well to supply the desired products 3ia-3la in 69-89% yields. Furthermore, metaand ortho-substituted substrates were also tolerated regardless of the electronic property on the benzene ring, providing the desired isoquinolones 3ma-3ra in 41-78% yields. In addition, disubstituted N-hydroxybenzamides were also reactive to produce the corresponding products in 71-79% yields (products 3sa-3wa). Moreover, this transformation was further extended to N-hydroxy-2-naphthamide and N-hydroxythiophene-2-carboxamide substrates, giving the corresponding products 3xa and 3ya in 63% and 51% yields, respectively. Subsequently, we probed the scope of this transformation, employing propargylic acetates 2 bearing diverse substituents at the para position of the benzene ring and leading to the corresponding products 3ab-3ai in 49-89% yields (Scheme 2b). Encouragingly, the halo groups on either benzamide, as well as on the propargylic acetates moiety, were well tolerated to produce the target products, which may have potential applications in organic synthesis by further functionalization through Pd-catalyzed coupling reactions.
droxybenzamides with either electron-donating (e.g., -Me, -Et,t Bu, -OMe) or electronwithdrawing (e.g., -F, -Cl, -Br) groups at the para position of the benzene ring worked well with 2a to afford the corresponding products 3ba-3ha in 53-87% yields. Notably, various functional groups, including phenyl and even strong electron-withdrawing substituents -CN, -NO2, and -CF3, were tolerated well to supply the desired products 3ia-3la in 69-89% yields. Furthermore, meta-and ortho-substituted substrates were also tolerated regardless of the electronic property on the benzene ring, providing the desired isoquinolones 3ma-3ra in 41-78% yields. In addition, disubstituted N-hydroxybenzamides were also reactive to produce the corresponding products in 71-79% yields (products 3sa-3wa). Moreover, this transformation was further extended to N-hydroxy-2-naphthamide and N-hydroxythiophene-2-carboxamide substrates, giving the corresponding products 3xa and 3ya in 63% and 51% yields, respectively. Subsequently, we probed the scope of this transformation, employing propargylic acetates 2 bearing diverse substituents at the para position of the benzene ring and leading to the corresponding products 3ab-3ai in 49-89% yields (Scheme 2b). Encouragingly, the halo groups on either benzamide, as well as on the propargylic acetates moiety, were well tolerated to produce the target products, which may have potential applications in organic synthesis by further functionalization through Pdcatalyzed coupling reactions. To further prove the robustness and the general utility of this protocol, we carried out the reaction of N-hydroxybenzamide 1a and 3-phenylprop-2-yn-1-yl acetate 2a in gramscale synthesis under the standard condition. This transformation was easily scaled up to 6 mmol (scaled up to 30 times), producing the desired product 3aa in 69% yield (Scheme 3a). Subsequently, insights into this cascade C-H activation/annulation were gained by performing control experiments to clarify the reaction mechanism. Treating N-hydroxybenzamide 1a with methanol-d 4 under standard conditions for 2 h, a 74% deuterium was detected on the ortho C-H bond (Scheme 3b(i)), which indicated that the C-H activation process might be the reversible step. Next, a kinetic isotope effect (KIE) value of 1.08 was measured from two parallel reactions of N-hydroxybenzamide 1a or 1a-d 5 with propargylic acetate 2a for 2 h under the standard conditions (Scheme 3b(ii)). The intermolecular competitive experiment of para-methoxyland para-trifluoromethyl-substituted N-hydroxybenzamide showed that the electron-donating group facilitated the reaction step, implying that C(sp 2 )-H bond cleavage might be the limiting step (Scheme 3b(iii)). As for the distinct propargylic acetates 2b and 2g, the electron-deficient propargylic acetate 2g delivered the product in a higher yield.
gained by performing control experiments to clarify the reaction mechanism. Tre hydroxybenzamide 1a with methanol-d4 under standard conditions for 2 h, a 74% ium was detected on the ortho C-H bond (Scheme 3b(i)), which indicated that activation process might be the reversible step. Next, a kinetic isotope effect (KI of 1.08 was measured from two parallel reactions of N-hydroxybenzamide 1a or 1a propargylic acetate 2a for 2 h under the standard conditions (Scheme 3b(ii)). The i lecular competitive experiment of para-methoxyl-and para-trifluoromethyl-substi hydroxybenzamide showed that the electron-donating group facilitated the react implying that C(sp 2 )-H bond cleavage might be the limiting step (Scheme 3b(iii) the distinct propargylic acetates 2b and 2g, the electron-deficient propargylic ac delivered the product in a higher yield. On the basis of the above control experiments and relevant reports [33,36,38] sible mechanism for the Rh-catalyzed cascade C-H activation/annulation for the fo of NH-free isoquinolones is proposed in Scheme 4. Initially, the active catalyst wa ated via ligand exchange, which mediated a facile C-H metalation process to give membered rhodacycle A. Subsequent coordination of the alkyne to the rhodium followed by the 1,2-insertion of the alkyne afforded the seven-membered rhoda On the basis of the above control experiments and relevant reports [33,36,38], a plausible mechanism for the Rh-catalyzed cascade C-H activation/annulation for the formation of NH-free isoquinolones is proposed in Scheme 4. Initially, the active catalyst was generated via ligand exchange, which mediated a facile C-H metalation process to give the five-membered rhodacycle A. Subsequent coordination of the alkyne to the rhodium center followed by the 1,2-insertion of the alkyne afforded the seven-membered rhodacycle C. Then, the metal migration and C-N bond formation of intermediate C afforded the intermediate D, which underwent the protonation to generate the desired product 3aa along with the release of a molecule of water. Then, the metal migration and C-N bond formation of intermediate C afforded the intermediate D, which underwent the protonation to generate the desired product 3aa along with the release of a molecule of water.

Scheme 4.
Proposed mechanism for the formation of NH-free isoquinolones.

Materials and Methods
The detailed procedures for the synthesis and characterization of the products are given in Appendix A.

Conclusions
In conclusion, we developed an efficient and practical method to construct NH-free isoquinolones via Rh(III)-catalyzed C-H activation/annulation of N-hydroxybenzamides and propargylic acetates. A variety of N-hydroxybenzamides with a diverse array of substituents, irrespective of their electronic and steric nature, were tolerated well under the optimal conditions. Generation of H2O as the only byproduct makes this 100% carbonefficient process attractive for the synthesis of isoquinolone derivatives. Moreover, the synthetic utility and practicability of the developed methodology in gram-scale synthesis were validated.

Supplementary Materials:
The following supporting information can be downloaded at: www.mdpi.com/xxx/s1, Characterization data for product 3, including 1 H-and 13 C-NMR spectroscopies, are available online. CCDC 2220211 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif or by emailing data_request@ccdc.cam.ac.uk or by contacting the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44-1223-336033.

Materials and Methods
The detailed procedures for the synthesis and characterization of the products are given in Appendix A.

Conclusions
In conclusion, we developed an efficient and practical method to construct NH-free isoquinolones via Rh(III)-catalyzed C-H activation/annulation of N-hydroxybenzamides and propargylic acetates. A variety of N-hydroxybenzamides with a diverse array of substituents, irrespective of their electronic and steric nature, were tolerated well under the optimal conditions. Generation of H 2 O as the only byproduct makes this 100% carbonefficient process attractive for the synthesis of isoquinolone derivatives. Moreover, the synthetic utility and practicability of the developed methodology in gram-scale synthesis were validated.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/molecules27238553/s1, Characterization data for product 3, including 1 H-and 13 C-NMR spectroscopies, are available online. CCDC 2220211 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif or by emailing data_request@ccdc.cam.ac.uk or by contacting the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44-1223-336033.  Data Availability Statement: The data presented in this study are available in this article.

Conflicts of Interest:
The authors declare no conflict of interest.

Appendix A. Experimental Section
Unless otherwise noted, all reagents were purchased from commercial suppliers and used without purification. All cascade reactions were performed in a resealable screwcapped Schlenk flask (approx. 15 mL volume) in the presence of a Teflon-coated magnetic stirrer bar (4 mm × 10 mm). Reactions were monitored by using thin-layer chromatography (TLC) on commercial silica gel plates (GF 254). Visualization of the developed plates was performed under UV lights (GF 254 nm). Flash column chromatography was performed on silica gel (200-300 mesh). 1 H NMR spectra were recorded on a 500 MHz spectrometer, and 13 C NMR spectra were recorded on a 125 MHz spectrometer (Supplementary Materials: 1 H NMR and 13 C NMR). Chemical shifts were expressed in parts per million (δ), and the signals were reported as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), and m (multiplet), and coupling constants (J) were given in Hz. Chemical shifts as internal standards were referenced to CDCl 3 (δ = 7.26 for 1 H and δ = 77.16 for 13 C NMR) as internal standard. HRMS analysis with a quadrupole time-of-flight mass spectrometer yielded ion mass/charge (m/z) ratios in atomic mass units. The melting points were measured using SGWX-4 melting point apparatus and were not corrected. The X-ray source used for the single-crystal X-ray diffraction analysis of compound 3aa was Mo Kα (λ = 0.71073 Å), and the thermal ellipsoid was drawn at the 30% probability level (Supplementary Materials: X-ray crystal data).
General procedure for the synthesis of isoquinolones 3 (product 3aa as an example). N-Hydroxybenzamides 1a (27.4 mg, 0.2 mmol), [Cp * RhCl 2 ] 2 (3.1 mg, 2.5 mol%), and NaOAc (16.4 mg, 0.2 mmol) were loaded into a Schlenk tube equipped with a Tefloncoated magnetic stir bar. The tube was evacuated and flushed with argon for three cycles. Propargylic acetates 2a (34.8 mg, 0.2 mmol) and toluene (2 mL) were then added, and the tube was placed into a preheated oil bath (100 • C) and stirred for 12 h. After the completion of the reaction, the reaction tube was allowed to cool to room temperature, extracted with CH 2 Cl 2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na 2 SO 4 , filtered, and then evaporated under vacuum. The residue was purified using flash column chromatography with a silica gel (200-300 mesh) and using ethyl acetate and petroleum ether as the elution solvent to give desired product 3.