Abstract
Highly efficient synthesis of isoquinolones is achieved by a Rh(III)-catalyzed C–H activation/annulation of N-chlorobenzamide derivatives with alkynes. This transformation leverages the N-Cl moiety as a highly effective internal oxidant, enabling the reaction to proceed smoothly under mild conditions and delivering the target products in excellent yields (up to 98% yield). Control experiments further reveal the superior oxidizing ability of the N-Cl benzamide relative to its N-OMe and N-OPiv analogues. Notably, the reaction proceeds with 85% yield even at an exceptionally low catalyst loading of 0.05 mol %.
Introduction
Over the past decades, research on efficient and convenient methods for synthesizing heterocyclic compounds has increased significantly. Among these, nitrogen-containing heterocyclic aromatic hydrocarbons, especially isoquinolinone and its derivatives, have attracted significant attention due to their notable pharmacological importance ranging from anticancer to antihypertensive (Scheme a). However, traditional methods for constructing isoquinolones frequently suffer from harsh conditions. This limitation has spurred the development of transition-metal-catalyzed C–H activation/annulation as a more efficient and concise synthetic strategy.
1. Synthesis of Isoquinolones via C–H Functionalization.
Building on this, oxidative transition-metal-catalyzed annulations of alkyne through C–H bond activation have been developed into powerful tools for atom- and step-economical construction of heterocycles. However, these methods typically rely on stoichiometric amounts of external metallic oxidants, resulting in the production of undesired waste. Since the pioneering contributions of Fagnou/Guimond, Ackermann, Glorius, and others, the application of oxidizing directing groups has grown significantly. In this strategy, the directing group plays the role of an internal oxidant besides anchoring the metal to the specific site for performing C–H activation. This allows the reaction to proceed under redox-neutral conditions, thereby eliminating the need for an external oxidant. Typical internal oxidants employed in such systems include N–O, N–N, N–S, and N–Cl substituted amides. Among these, N–Cl amides have drawn particular interest, as the N–Cl moiety efficiently promotes the desired reaction pathway and sustains redox-neutral catalytic cycles under mild conditions. Despite these advantages, current methods predominantly rely on cobalt or ruthenium catalysts, which typically require high catalyst loadings (2.5–10 mol %) and exhibit poor substrate compatibility. Meanwhile, the use of N–Cl amides in rhodium-catalyzed systems remains unreported (Scheme b).
In this work, we present a Rh(III)-catalyzed C–H activation/annulation between N-chlorobenzamides and alkynes (Scheme c). Notably, the reaction demonstrates a broad substrate scope and proceeds under mild conditions. Moreover, it can be scaled up to the gram scale with an exceptionally low catalyst loading of 0.05 mol %, affording the product in excellent yield. Further control experiments confirm that the N–Cl moiety exhibits superior oxidizing capability compared to the N–OMe and N–OPiv groups. The details of this study are outlined below.
Results and Discussion
Our study commenced by evaluating the reaction conditions with N-chlorobenzamide 1a (0.20 mmol) and 1-phenyl-1-propyne 2a (3.0 equiv) as the model substrates (Table ). The C–H activation/annulation proceeded in the presence of [Cp*RhCl2]2 (5 mol %) as the catalyst, along with sodium carbonate (2.0 equiv) as the base, and 2,2,2-trifluoroethanol (TFE) as the solvent at room temperature for 6 h. Good NMR yield (82%) was achieved for 3aa (entry 1). Control experiments demonstrated that the absence of a base (entry 2) resulted in a marked reduction of the target product (13% yield), indicating that the base probably promotes the C–H bond activation via a base-assisted concerted metalation deprotonation (CMD) mechanism. Moreover, when the rhodium catalyst was omitted (entry 3), no target product was detected, confirming its essential role in the reaction. Then, the effects of solvent were investigated (entries 4–7), and the polar protic solvents were found to be beneficial for the reaction (38–56% NMR yields, entries 4–5), while only a trace amount of the target product was obtained in aprotic solvents (11–15% NMR yields, entries 6–7). Among the solvents screened, 2,2,2-trifluoroethanol (TFE) was identified as the optimal solvent (82% NMR yield, entry 1). Next, various bases were tested in the reaction. Replacing Na2CO3 with NaOPiv·H2O or KOAc could give comparable results (entries 8–9). However, the yield decreased to 75% when NaO t Bu was employed (entry 10). Notably, the optimal result was achieved with NaOAc as the base, affording product 3aa in a slightly higher yield (95% yield, entry 11). We further proceeded to reduce the catalyst loading to 0.1 mol % while extending the reaction time to 24 h. Under these conditions, the reaction proceeded smoothly and afforded the target product 3aa in excellent yield (entry 12, 95% NMR yield). Further reduction of the catalyst loading to 0.05 and 0.03 mol % still provided 3aa in moderate to good yields (entries 13–14, 61–85% NMR yield). Remarkably, even at an ultralow catalyst loading of 0.01 mol %, the target product 3aa was still obtained in 15% NMR yield (entry 15). Of note, reducing the alkyne loading to 1.2–1.5 equiv still afforded the desired product in 90–92% isolated yield (see the SI, Table S4 for more details). Considering that excess alkyne can promote complete substrate conversion and achieve a higher yield, the optimal reaction conditions were finally determined as described in entry 12, Table , and the desired product 3aa was delivered in 94% isolated yield on a 0.3 mmol-scale reaction.
1. Optimization of Reaction Conditions .
| entry | base | solvent | catalyst loading (x mol %) | yield (%) |
|---|---|---|---|---|
| 1 | Na2CO3 | CF3CH2OH | 5 | 82 |
| 2 | CF3CH2OH | 5 | 13 | |
| 3 | Na2CO3 | CF3CH2OH | no T.M. | |
| 4 | Na2CO3 | HFIP | 5 | 56 |
| 5 | Na2CO3 | MeOH | 5 | 38 |
| 6 | Na2CO3 | CH3CN | 5 | 11 |
| 7 | Na2CO3 | DCM | 5 | 15 |
| 8 | NaOPiv·H2O | CF3CH2OH | 5 | 82 |
| 9 | KOAc | CF3CH2OH | 5 | 82 |
| 10 | NaO t Bu | CF3CH2OH | 5 | 75 |
| 11 | NaOAc | CF3CH2OH | 5 | 95 |
| 12 | NaOAc | CF3CH2OH | 0.1 | 95 (94) |
| 13 | NaOAc | CF3CH2OH | 0.05 | 85 |
| 14 | NaOAc | CF3CH2OH | 0.03 | 61 |
| 15 | NaOAc | CF3CH2OH | 0.01 | 15 |
The reaction was carried out with 1a (0.20 mmol), 2a (0.60 mmol), [Cp*RhCl2]2 (x mol %), and base (0.40 mmol) in different solvents (5 mL) at room temperature under air for 6 h.
Determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.
Isolated yield on a 0.3 mmol-scale reaction: 24 h.
48 h.
62 h.
Having established the optimal reaction conditions (entry 12, Table ), the substrate scope of the Rh-catalyzed C–H activation/annulation reaction was explored with respect to various alkynes (Table ). The investigation commenced by examining the coupling of various unsymmetrical alkynes 2 with 1a. It was found that 1-arylprop-1-yne derivatives displayed excellent compatibility, accommodating a diverse array of para-substituents on the phenyl ring. This encompassed electron-donating groups (Me, OMe, t Bu, Ph), halogens (F, Cl, Br), and strong electron-withdrawing groups (CF3, CO2Et), affording the corresponding products 3ab–3aj in excellent yields (92–96%). We next explored the effect of meta-substituted phenyl rings. Similarly, excellent yields were achieved with both an electron-donating group (OMe) and an electron-withdrawing group (F), affording products 3ak and 3al in 85–92% yield. Gratifyingly, ortho-chloro and ortho-methoxy substituted phenyl substrates were also well compatible, delivering the desired products 3am–3an in good yields (75–78%). Moreover, thiophene-based alkynes with substitution at the C2 or C3 position of the heteroaromatic ring were also viable reaction partners, providing the corresponding functionalized products 3ao–3ap in good to excellent yields (83–84%). Next, the scope was extended to alkynes with longer linear alkyl chains (ethyl, n-propyl, n-butyl), all of which reacted efficiently to give products 3aq–3as in 98% yield. In contrast, an alkyne bearing an electron-withdrawing ester group (CO2Et) afforded product 3at in only 28% yield, likely due to poorer coordination resulting from its lower electron density. Furthermore, the reaction was also effective for symmetrical diarylalkynes bearing either electron-donating or -withdrawing groups, furnishing products 3au–3aw in 90–95% yield. Besides, the more challenging dialkyl-substituted alkyne 2x was also tolerated, albeit affording product 3ax in a moderate yield (37% yield).
2. Substrate Scope: Alkynes ,
The reaction was carried out with 1a (0.30 mmol), 2 (0.90 mmol), [Cp*RhCl2]2 (0.1 mol %), and NaOAc (0.60 mmol) in 2,2,2-trifluoroethanol (7.5 mL) at room temperature under air for 24 h.
Isolated yields.
30 h.
N-chlorobenzamide derivatives 1 possessing varied substituents were next tested in this Rh-catalyzed C–H activation/annulation with 2b as the coupling partner (Table ). In general, the reaction tolerated a range of para-substituents on the phenyl ring of the N-chlorobenzamide. Both electron-donating groups (Me, t Bu) and halogens (F, Cl, Br) were well tolerated, affording products 3ba–3fa in excellent yields (89–93%). Notably, strong electron-withdrawing groups (CF3, CN, NO2) at the para position were also compatible, delivering products 3ga–3ia in similarly high yields (91–93%). It was observed that substrates with methyl, fluorine, or bromine substituents at the meta position were also compatible, affording products 3ja–3la in slightly lower yields (72–76%) than their para-substituted analogues, likely owing to competing regioselectivity. Likewise, ortho-substitution led to diminished reactivity, affording products 3ma–3oa in 72–83% yields. This decrease can be attributed to steric hindrance at the ortho position. To further demonstrate the generality of this transformation, we examined a series of N-chlorobenzamide derivatives derived from bioactive compounds. Gratifyingly, substrates prepared from (−)-borneol, l-menthol, and geraniol (2p–2r) were efficiently converted under the standard conditions, delivering products 3pa–3ra in excellent yields (86–90%).
3. Substrate Scope: N-Chlorobenzamide Derivatives ,
The reaction was carried out with 1 (0.30 mmol), 2a (0.90 mmol), [Cp*RhCl2]2 (0.1 mol %), and NaOAc (0.60 mmol) in 2,2,2-trifluoroethanol (7.5 mL) at room temperature under air for 24 h.
Isolated yields are reported.
30 h.
To demonstrate the practical utility of this methodology, a gram-scale synthesis was successfully conducted with the catalyst loading reduced to 0.05 mol %, affording the desired product 3aa (999.8 mg) in 85% yield. This result confirms the robustness and scalability of the process, even under significantly reduced catalyst loading. Subsequently, a series of functional group transformations were efficiently performed on 3aa. Oxidative rearrangement with m-CPBA in 1,2-dichloroethane yielded the structurally reconfigured compound 4 in 75% yield. O-methylation using iodomethane and Ag2CO3 in toluene gave product 5 in 88% yield. Additionally, chlorination with POCl3 afforded key intermediate 6 in 87% yield, which was further elaborated via nucleophilic substitution with N-ethylpiperazine to provide target derivative 7 in 90% yield. This series of efficient transformations successfully constructed a library of structurally diverse isoquinolone and isoindolinone derivatives (Scheme ), thereby offering valuable building blocks for drug discovery and screening initiatives.
2. Gram-Scale Synthesis and Transformation of 3aa .
Control experiments were next conducted to compare the reactivity of N–Cl benzamides with N-pivaloyl- and N-methoxy-substituted analogues in this rhodium-catalyzed C–H activation/annulation (Scheme a). Under standard conditions with 0.05 mol % [Cp*RhCl2]2, the N–Cl benzamide provided significantly higher yields than its N-pivaloyl analogue, while the N-methoxy substrate remained largely unreacted. These results indicate that the N–Cl moiety functions as both an efficient directing group and a superior internal oxidant, thereby enabling the targeted C–H activation/annulation to proceed under milder conditions with ultralow catalyst loading.
3. Control Experiments and Proposed Catalytic Cycle.
On the basis of our mechanistic studies and literature precedents, , a plausible catalytic cycle was proposed for the reaction of 1a and 2a as an example (Scheme b). The cycle begins with coordination of 1a to Cp*Rh(OAc)2, accompanied by acetate dissociation. Subsequent C–H activation via a concerted metalation–deprotonation (CMD) transition state affords the five-membered rhodacyclic I. Coordination of 1-phenyl-1-propyne (2a) followed by migratory insertion into the Rh–C bond then yields the seven-membered rhodacyclic II. Notably, intermediate II may undergo two possible reaction pathways to form intermediate IV. In Path a, intermediate II undergoes reductive elimination with concomitant N–Cl bond cleavage to directly deliver intermediate IV. Alternatively, in Path b, intermediate II is first oxidized to generate a Rh(V) intermediate III′, which then undergoes reductive elimination to afford intermediate IV. Finally, protonation of intermediate IV furnishes product 3aa and regenerates the active Rh(III) species.
Conclusion
In conclusion, we have successfully developed a Rh-catalyzed C–H activation/annulation of N-chlorobenzamides and alkynes. This strategy utilizes the N–Cl moiety as an effective internal oxidant in the Rh catalytic system, allowing the transformation to proceed smoothly under mild conditions and delivering the products in high yields. Control experiments confirm the superior oxidizing capacity of the N–Cl motif compared to its N–OMe and N–OPiv analogues. Notably, the reaction remains efficient even at an extremely low catalyst loading of 0.05 mol %, affording the target isoquinolone in 85% yield. Accordingly, this work offers a viable and chemoselective approach to access functionalized isoquinolones via C–H activation from readily available starting materials.
Supplementary Material
Acknowledgments
Financial support for this work was provided by the National Natural Science Foundation of China (22401293 and 82473778).
The data underlying this study are available in the published article and its Supporting Information.
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c02975.
Detailed experimental procedures, characterization of synthesized compounds, copies of 1H, 13C, and 19F NMR spectra (PDF)
§.
Q.-X.J. and J.-C.H. contributed equally to this work.
The authors declare no competing financial interest.
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Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.