Abstract
Isoquinoline derivatives hold significant importance in the fields of natural product chemistry, medicinal chemistry, and biological sciences. Currently, researchers are actively exploring efficient and general synthetic methodologies for these compounds. Herein, we report the use of hydroxylamine-O-sulfonic acid (HOSA) as a novel transient directing group (TDG) to enable the selective ortho–C-H functionalization/cyclization of acetophenones with methyl propiolate. This strategy allows for the one-pot synthesis of isoquinoline derivatives under mild and easily tunable conditions. The type of transient directing group, solvent, and oxidant are key factors dictating the reaction pathway, enabling precise control over the product selectivity. The established protocol exhibits a broad substrate scope and excellent functional group tolerance. This study demonstrates that HOSA can serve as a catalytic transient directing group with high conversion efficiency and wide applicability for selective C–H cyclization reactions, and this method holds broad synthetic utility.
1. Introduction
Isoquinoline derivatives represent a class of nitrogen-containing heterocycles that are of paramount importance in medicinal chemistry and organic chemistry. − They are pervasive in a multitude of bioactive natural products and pharmaceutical agents, including anticancer compounds, antimicrobial drugs, and modulators of the central nervous system. Furthermore, these derivatives act as versatile building blocks in synthetic chemistry and crucial intermediates in materials science. Due to their substantial biological and chemical value, the development of efficient, atom-economical, and selective synthetic approaches for isoquinoline derivatives has been a persistent research focus in organic synthesis.
In the pursuit of constructing isoquinoline frameworks, significant endeavors have been directed toward transition-metal-catalyzed C–H activation strategies, which provided more step-economical routes than conventional methods. , As depicted in the previous work (Figure a), ruthenium-catalyzed annulation reactions that utilized preinstalled directing groups (for instance, acetamide moieties on aryl rings) have been documented for the synthesis of isoquinolines using alkynes. - Nevertheless, these methods frequently depended on substrates with prefunctionalized directing groups, which required additional synthetic steps, thus decreasing atom economy and practicality. , Moreover, the scope of alkynes and arenes is sometimes restricted, impeding the diversity-oriented synthesis of isoquinoline derivatives. ,
1.
Synthesis of isoquinoline derivatives in previous work (a) and this work (b).
To overcome these limitations and develop a more efficient synthetic protocol, we herein report a rhodium-catalyzed, atom-economical cyclization reaction for the direct synthesis of isoquinoline derivatives from easily accessible acetophenones and methyl propiolate (Figure b). The crucial innovation was the use of hydroxylamine-O-sulfonic acid (HOSA) as a transient directing group (TDG), which allowed for the in situ formation of a reactive imine intermediate with acetophenones. This TDG strategy eliminated the need for prefunctionalized substrates, enabling a one-step transformation. By utilizing Rh catalysis, this protocol achieved selective ortho −C–H functionalization and subsequent cyclization with methyl propiolate, yielding isoquinoline products in an atom-economical fashion. Notably, this method possessed a broad substrate scope, excellent functional group tolerance, and mild reaction conditions, thereby offering a versatile platform for accessing diverse isoquinoline derivatives with potential applications in drug discovery and organic synthesis. Roxadustat stands as the first-in-class, orally bioavailable small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) approved for the treatment of anemia associated with chronic kidney disease. The synthetic methodology developed in this study allowed for the direct preparation of a key intermediate of roxadustat, thereby streamlining its synthetic route.
2. Results and Discussion
2.1. Reaction Condition Optimization
Starting from acetophenone and methyl propiolate, with HOSA serving as both a TDG and a nitrogen source, we optimized reaction parameters, including solvent, oxidant, and temperature (Table ). Initial experiments employed a catalytic system consisting of a commercially available dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer ([Cp*RhCl2]2) and silver hexafluoroantimonate (AgSbF6) to mediate the cyclization of acetophenone with methyl propiolate, affording product 3a.
1. Reaction Condition Optimization .
| Entry | Solvent | Oxidant | T (oC) | Additive | Yield (%) |
|---|---|---|---|---|---|
| 1 | MeOH | AgSbF6 | 80 | NaOAc | 31 |
| 2 | MeOH:DCE = 1:1 | AgSbF6 | 80 | NaOAc | 45 |
| 3 | MeOH:MeCN = 1:1 | AgSbF6 | 80 | NaOAc | 17 |
| 4 | MeOH:THF = 1:1 | AgSbF6 | 80 | NaOAc | NR |
| 5 | MeCN:DCE = 1:1 | AgSbF6 | 80 | NaOAc | NR |
| 6 | MeOH:DCE = 1:1 | Ag2O | 80 | NaOAc | NR |
| 7 | MeOH:DCE = 1:1 | Ag2CO3 | 80 | NaOAc | 56 |
| 8 | MeOH:DCE = 1:1 | Ag2CO3 | 60 | NaOAc | 36 |
| 9 | MeOH:DCE = 1:1 | Ag2CO3 | 100 | NaOAc | 53 |
| 10 | MeOH:DCE = 1:1 | Ag2CO3 | 120 | NaOAc | 39 |
| 11 | MeOH:DCE = 1:1 | Ag 2 CO 3 | 80 | AcOH | 85 |
| 12 | MeOH:DCE = 1:1 | Ag2CO3 | 80 | CsOAc | 59 |
| 13 | MeOH:DCE = 1:1 | Ag2CO3 | 80 | Cu(OAc)2 | 44 |
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), catalyst (5.0 mol %), oxidant (1.0 mmol), additive (2 mmol), in the solvent (3.0 mL) for 24 h.
Yields of isolated products.
First, the solvents were screened. Using methanol (MeOH) as the solvent at 80 °C, the reaction proceeded to form a new pyridine ring, affording 3a in 31% yield (Table , Entry 1). Switching to a mixed solvent system of MeOH:DCE = 1:1 (DCE = 1,2-dichloroethane) improved the yield to 45% (Table , Entry 2). In contrast, using MeOH:MeCN = 1:1 (MeCN = acetonitrile) lowered the yield to 17% (Table , Entry 3). Neither MeOH:THF = 1:1 (THF = tetrahydrofuran) nor MeCN:DCE = 1:1 yielded 3a (Table , Entries 4–5), indicating MeOH:DCE = 1:1 as a promising solvent system. Next, we evaluated the oxidants. Switching the oxidant to silver oxide (Ag2O) resulted in no reaction (Table , Entry 6). Using silver carbonate (Ag2CO3) as the oxidant, however, significantly improved the yield of 3a to 56% (Table , Entry 7). Further screening of reaction temperature showed that elevating or lowering the temperature both led to decreased yields (Table , Entries 8–10), indicating 80 °C as the optimal temperature. Notably, replacing sodium acetate (NaOAc) with acetic acid (AcOH) as the additive increased the yield of 3a to 85% (Table , Entry 11). In contrast, using cesium acetate (CsOAc) or copper(II) acetate (Cu(OAc)2) instead of NaOAc afforded no significant improvement in yield (Table , Entries 12–13). Thus, the optimized conditions for the formation of 3a were determined as follows: [Cp*RhCl2]2 as the catalyst, Ag2CO3 as the oxidant, and AcOH as the additive, with reaction at 80 °C for 24 h in MeOH:DCE (1:1).
To evaluate the generality of the Rh-catalyzed cyclization protocol, a diverse range of substrates was explored under the optimized conditions (1 (0.5 mmol), 2 (0.75 mmol), [Cp*RhCl2]2 (5.0 mol %), Ag2CO3 (1.0 mmol), AcOH (2 mmol), in MeOH:DCE (1:1, 3.0 mL) at 80 °C for 24 h), with all reported yields corresponding to isolated products (Figure , 3a–3ad, 3aa–3az as depicted). Starting with acetophenone derivatives, para-substituted analogues showed excellent reactivity: those bearing electron-donating groups (EDGs) such as methyl (3b, 84%), ethyl (3c, 85%), methoxy (3e, 82%), phenoxy (3f, 80%), and even bulky tert-butyl (3d, 79%) afforded high yields, while electron-withdrawing groups (EWGs) including fluoro (3g, 85%), chloro (3h, 83%), and bromo (3i, 79%) were well-tolerated, though para-cyano (3j, 38%) gave a moderate yield, likely due to strong electron withdrawal. Meta-substituted acetophenones also reacted efficiently, with EDGs like methoxy (3m, 69%) and phenoxy (3n, 81%) and EWGs such as fluoro (3o, 60%) yielding products in moderate to good yields, indicating minimal hindrance from meta substitution. Ortho-substituted derivatives, despite potential steric effects, maintained high reactivity: EDGs (methyl, 3l, 83%; methoxy, 3q, 72%) and EWGs (fluoro, 3r, 70%) afforded the target isoquinolines smoothly. Multisubstituted acetophenones were also viable substrates: 3,4-disubstituted analogues (3,4-methylenedioxy, 3t, 48%) and 3,5-disubstituted derivatives (3,5-dimethyl, 3w, 72%) underwent cyclization, highlighting tolerance for multiple ring substituents. Expanding to other aryl ethyl ketones, heteroaromatic and polycyclic variants showed varied reactivity: pyridyl ethyl ketone (3z, 71%) performed well, while 1-naphthyl (3y, NR) and quinolinyl (3aa, 10%) analogues gave lower yields, reflecting substrate specificity. Finally, extending to alkynyl compounds beyond methyl propiolate, esters with isopropyl (3ab, 32%), aldehyde (3ac, 34%), and ethyl (3ad, 55%) substituents participated in the reaction, expanding the structural diversity. However, 3ae and 3af were not detected, indicating that the corresponding reactions did not proceed. When phenyl acrylate was employed as the substrate, the absence of 3ae may be attributed to the lability of the ester moiety, which likely decomposed under the reaction conditions. In contrast, the considerable steric hindrance of benzophenone impeded the formation of a key intermediate and the subsequent C–H activation step, leading to the failed synthesis of 3af. All products were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) in the Supporting Information.
2.
Synthesis of Product 3. Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), [Cp*RhCl2]2(5.0 mol %), Ag2CO3 (1.0 mmol), AcOH (2 mmol), in the solvent (MeCN:DCE = 1:2) (3.0 mL) for 24 h. Yields of the isolated products.
Scale-up synthesis of 3a using this method afforded 3a in a 77% yield (Figure ). Compound 3a is a potentially versatile molecule bridging medicinal and materials science. In medicinal chemistry, it served primarily as a privileged scaffold with significant derivatization potential, paving the way for the development of novel antimicrobial and anticancer agents. We synthesized the key intermediate 4n for roxadustat from compound 3n, a notably typical example (Figure ). For specific experimental details, refer to the Supporting Information. In materials science, leveraging its prominent optical properties, it held promise for applications in next-generation organic optoelectronic materials and devices.
3.
Synthesis of 3a on a 5.0 mmol scale.
4.
Derivatization of 3n to prepare the roxadustat intermediate 4n.
To elucidate the reaction mechanism, we performed competition experiments to assess the reactivity of different directing groups and electronic effects. First, to compare the reactivity of HOSA versus conventional hydroxylamine hydrochloride as directing groups (Figure a), acetophenone (1a) was reacted with hydroxylamine hydrochloride to afford acetophenone oxime (4a), while 4-methylacetophenone (1b) was treated with HOSA to generate 4b. A 1:1 mixture of 4a and 4b was then subjected to a directing group competition experiment with compound 2a. The product ratio of 3a to 3b was determined to be 17%:64%, unequivocally demonstrating that HOSA exhibited significantly higher reactivity as a transient directing group compared to traditional hydroxylamine hydrochloride. This result highlighted the superior efficacy of HOSA in the reaction system. Additionally, to investigate the electronic effect on reactivity, a competition reaction was conducted between 1-(4-chlorophenyl)ethan-1-one (1e, electron-withdrawing substituent) and 1-(4-methoxyphenyl)ethan-1-one (1h, electron-donating substituent) with compound 2a (Figure b). The product ratio of 3h to 3e was found to be 76%:0, indicating that the electron-withdrawing chloro substituent markedly enhanced the reactivity relative to the electron-donating methoxy group. This outcome underscored the electronic sensitivity of the HOSA-assisted reaction pathway.
5.
Competitive experiments.
2.2. Proposed Mechanism
We conducted detailed studies based on the experimental observations and proposed the following catalytic cycle (Figure ). Initially, acetophenone (1a) reacts with hydroxylamine-O-sulfonic acid (HOSA) to form intermediate IN1 via a condensation process, with water as a byproduct. Simultaneously, the precatalyst [CpRhCl2]2 is activated by acetic acid (AcOH) to generate active species Cp*Rh(OAc)2, with HCl released as a byproduct. Subsequently, IN1 undergoes site-selective ortho C(sp2)–H activation by Cp*Rh(OAc)2, leading to the formation of a six-membered rhodacycle IN2. Next, methyl propiolate (2a) coordinates to the Rh center in IN2, affording intermediate IN3. This is followed by double-bond insertion of the alkyne into the Rh–C bond, yielding the seven-membered rhodacycle IN4. Finally, intermediate IN4 undergoes reductive elimination, releasing the target isoquinoline product 3a and generating a Rh(I) species. The Rh(I) species is then reoxidized to the active Rh(III) species Cp*Rh(OAc)2 by Ag2CO3 (with Ag, H2O, and CO2 as byproducts), thus completing the catalytic cycle. This mechanistic proposal highlights the key roles of HOSA as a transient directing group for C–H activation, the Rh(III)/Rh(I) redox cycle, and the sequential alkyne coordination–insertion process in enabling the efficient construction of the isoquinoline scaffold.
6.
Proposed mechanism.
3. Conclusion
In summary, we have developed a one-step Rh-catalyzed atom-economical cyclization reaction for the synthesis of isoquinoline derivatives from acetophenones and methyl propiolate. The key to this success lay in the employment of HOSA as a novel catalytic TDG, which enabled the selective ortho −C–H functionalization and subsequent cyclization in a one-pot manner under mild and easily modifiable conditions. This methodology exhibited several notable advantages. First, it obviated the need for prefunctionalized substrates, thus enhancing atom economy and synthetic efficiency. Second, the reaction parameters, including the type of TDG, solvent, and oxidant, could be finely tuned to achieve precise control over product selectivity. Moreover, the protocol demonstrated a broad substrate scope and excellent functional group tolerance, making it applicable to a wide range of acetophenone and alkyne derivatives. Importantly, this study validated HOSA as a highly efficient and versatile catalytic TDG for selective C–H cyclization reactions, expanding the toolbox of transient directing group strategies in C–H activation chemistry. Given the significant role of isoquinoline derivatives in natural product chemistry, medicinal chemistry, and biological sciences, this atom-economical and operationally simple synthetic approach was anticipated to find extensive applications in the construction of bioactive molecules and complex heterocyclic scaffolds. Furthermore, the successful implementation of HOSA as a catalytic TDG may inspire the development of other novel transient directing groups for diverse C–H functionalization reactions, paving the way for more efficient and sustainable synthetic methodologies in organic chemistry.
Supplementary Material
Acknowledgments
Thanks to my supervisor, lab team, family, anonymous reviewers, and journal editors for their invaluable guidance, support, and contributions.
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.5c13645.
1H and 13C NMR spectra of all newly synthesized compounds (PDF)
The authors declare no competing financial interest.
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Associated Data
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Supplementary Materials
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.