Perimidine directed Rh(III)-catalyzed [4 + 1] and [4 + 2] annulations: synthesis of perimidine linked spiro-succinimides and isoquinolines

Abstract

We report a novel Rh(III)-catalyzed perimidine-directed C–H activation strategy for the synthesis of perimidine-fused heterocycles using various types of alkenes. The reaction of 2-aryl perimidines with maleimides in the presence of the [RhCp*Cl₂]₂ catalyst facilitates a cascade [4 + 1] spiro-annulation, affording perimidine-linked isoindoles spiro-fused with succinimides. Conversely, vinylene carbonates provided a fused six-membered ring via a [4 + 2] cyclization, yielding perimidine-fused isoquinolines. This methodology is useful for synthesizing a library of polycyclic perimidine-fused heterocycles.

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Introduction

In modern organic synthesis, site-selective C–H activation is considered an efficient strategy for the synthesis of complex molecules. Utilizing biologically relevant scaffolds as intrinsic directing groups has gained considerable interest as it circumvents the need for installing and removing external auxiliaries, thereby providing an efficient synthetic route.¹

Perimidine, a unique fused pyrimidine derivative, holds significant promise across diverse fields including medicine, life sciences, and industrial chemistry.² Perimidine derivatives demonstrate a wide spectrum of biological activities, exhibiting antimicrobial,³ antibacterial,⁴ anticancer,⁵ antitumor,⁶ and anti-inflammatory⁷ properties, as well as being useful chemosensors⁸ and coloring agents.⁹ Perimidine exhibits distinctive electronic features arising from delocalization of the nitrogen lone pair into the naphthalene ring, imparting a unique combination of π-rich and π-deficient character that enhances its reactivity in diverse transformations.² This characteristic electronic structure enables perimidine to coordinate with metals by accepting electrons into its low-lying vacant π-orbitals. This coordination also enhances the electropositive character of the metal centre, thereby promoting the coordination of alkenes.¹⁰

In recent years, pyrimidine has been extensively utilized as a removable auxiliary and transient directing group for directed C–H activation.^10–13 In 2022, Chatani and co-workers reported the activation of the ortho-C–H bond of pyrimidine-protected aniline for the oxidative ortho-alkylation with secondary allyl alcohols to synthesize β-aryl ketones (eqn (a), Scheme 1).¹² Similarly, in 2021, Maiti and co-workers reported meta-olefination of complex biaryls using a palladium catalyst and pyrimidine as a transient directing group via reversible imine formation (eqn (b), Scheme 1).¹³ Despite the enormous applications in drugs and the synthetic utility of pyrimidines, using it as an intrinsic directing group is still limited. On the other hand, to the best of our knowledge, perimidine-directed C–H activation remains largely unexplored. The only related studies were reported by Li and co-workers, in which 2-aryl-2,3-dihydro-1H-perimidines underwent Rh(III)-catalyzed annulation to furnish cationic azaperylene derivatives (eqn (c), Scheme 1).¹⁴

Scheme 1 Comparison of the present work with some previously reported methods.

Furthermore, intrinsic group directed C–H annulation and spiro-annulation have gathered considerable attention recently.^15–20 Motivated by the directing properties of pyrimidine and the growing interest in intrinsic group-directed annulation and spiro-annulation, and in continuation of our work on C–H functionalization of heterocycles,²¹ we turned our attention towards C–H activation using perimidine as an intrinsic directing group (eqn (d), Scheme 1). Herein, we report for the first time an efficient Rh(III)-catalyzed C–H activation strategy utilizing 2-aryl-1H-perimidine as an intrinsic directing group for the synthesis of structurally diverse polycyclic spiro-succinimides and isoquinoline-fused perimidines.

Results and discussion

We initiated our study with the reaction between 2-phenyl-1H-perimidine (1a) and N-phenylmaleimide (2a) in the presence of [RhCp*Cl₂]₂ (5 mol%), NaOAc (1 equiv.), and AcOH (2 equiv.) in 1 mL of MeOH at 80 °C, which afforded the desired product 3a in 84% yield (Table 1, entry 1). Notably, alternative C–H activation catalysts such as [Ru(p-cymene)Cl₂]₂, Pd(OAc)₂, and [CoCp*(CO)I₂] failed to afford the desired product (Table 1, entries 2–4). Other additives such as AgOAc and Cu(OAc)₂·H₂O were ineffective, with no improvement in yield (Table 1, entry 5). Subsequently, various solvents (e.g., 1,2-DCE, ACN, THF, and acetone) were screened to optimize the yield (Table 1, entry 6). These results established MeOH as the most suitable solvent. Substituting AcOH with Na₂CO₃ resulted in a decreased yield of 3a (52%) (Table 1, entry 7). Similarly, altering the acid source was ineffective, affording a comparable yield (Table 1, entry 8). Conducting the reaction under a N₂ atmosphere resulted in no improvement in yield, with 24% of the starting material remaining, suggesting that air serves as a key oxidant (Table 1, entry 9). No product formation was observed without [RhCp*Cl₂]₂ or NaOAc, while omission of AcOH led to a moderate 47% yield (Table 1, entries 10–12).

Table 1 Optimization of reaction conditions^a,b

Entry	Deviation from standard conditions	Yield^b
a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), catalyst (5 mol%), additive 1 (1.0 equiv.), and additive 2 (2.0 equiv.) in solvent (1.0 mL) at 80 °C for 1 h. b Isolated yield. c Under a N2 atmosphere; 24% of 1a was recovered; NR = no reaction.
1	None	84
2	[Ru(p-cymene)Cl2]2 instead of [RhCp*Cl2]2	NR
3	Pd(OAc)2 instead of [RhCp*Cl2]2	NR
4	[CoCp*(CO)I2] instead of [RhCp*Cl2]2	NR
5	AgOAc/Cu(OAc)2·H2O instead of NaOAc	65/45
6	1,2-DCE/ACN/THF/acetone instead of MeOH	43/27/NR/55
7	Na2CO3 instead of AcOH	52
8	PivOH instead of AcOH	71
9	Under N2 gas	43^c
10	No [RhCp*Cl2]2	NR
11	No NaOAc	NR
12	No AcOH	47

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With the optimized reaction conditions established, we next explored the substrate scope by varying perimidine derivatives while keeping N-phenylmaleimide (2a) constant (Scheme 2). Under standard conditions, unsubstituted 2-phenyl-1H-perimidine (1a) reacted with N-phenylmaleimide (2a) to afford polycyclic fused succinimide 3a in 84% yield. We then examined the effect of para-substitution on the phenyl ring of perimidine. Electron-donating (1b, 1f) and halogen-substituted (1c, 1d) compounds reacted efficiently with 2a, affording the corresponding products in yields of 80–88%. In contrast, the fluoro-substituted derivative (1e) gave a reduced yield of 62%, while the strongly electron-withdrawing cyano-substituted perimidine (1g), i.e., 4-(2,3-dihydro-1H-perimidin-2-yl) benzonitrile, failed to produce the desired product. So, we performed the reaction under the modified conditions using 20 mol% AgOAc instead of NaOAc; the reaction proceeded slowly to provide a low yield of the product 3g in 24 h. The 4-phenyl-substituted perimidine (1h) afforded spirocyclic product 3h in 79% yield, while naphthyl perimidine (1i) delivered 3i in 77% yield. Notably, ortho-substituted derivatives (1j and 1k) were also tolerated, furnishing 3j and 3k in moderate yields. All the products were fully characterized by recording ¹H, ¹³C NMR and HRMS spectra. For unambiguous confirmation of the structures, the single crystal X-ray structure of the product 3b (CCDC no. 2279344) was obtained. The crystal was grown in EtOAc as a solvent by a slow evaporation method. The details of the XRD structure of 3b are available in the SI. In the case of meta-substituted perimidine 1l, selective activation of the less hindered ortho C–H bond afforded product 3l in 76% yield.^15,17 The structure was further confirmed by performing single crystal-XRD of 3l (CCDC no. 2495811). The crystal was grown in EtOAc as a solvent by a slow evaporation method (for crystal details, please see the SI). The carbazole-linked perimidine 1m also underwent smooth transformation with 2a, delivering 3m in 62% yield, demonstrating the protocol's compatibility with heterocycle-linked frameworks. Next, we performed the reaction with 2-(thiophen-2-yl)-1H-perimidine 1n with N-phenylmaleimide 2a under the standard reaction conditions. Interestingly, this reaction did not provide the desired spiro-succinimides, instead it provided the [4 + 2] annulated product 3n in only 38% yield even after a longer reaction time (3 h), and the structure was confirmed by recording ¹H, ¹³C NMR and HRMS spectra. This could be due to the slow reactivity of the 2-(thiophen-2-yl)-1H-perimidine 1n towards the aza-Michael addition step. On the other hand, 2-(pyridin-4-yl)-1H-perimidine 1o was found to be not suitable for this reaction and the corresponding expected product 3o could not be prepared using this methodology.

Scheme 2 Substrate scope for 2-aryl-1H-perimidines. Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), 5 mol% (3 mg) [RhCp*Cl₂]₂, 1.0 equiv. (8 mg) NaOAc, and 2.0 equiv. (11 μL) AcOH in 1.0 mL MeOH at 80 °C for 1 h; isolated yield; ^a 20 mol% (3 mg) AgOAc instead of 1 equiv. NaOAc for 24 h; ^b 6 h; ^c 3 h.

Encouraged by these results, next, we explored the substrate scope with diverse maleimides and alkenes as summarized in Scheme 3. Perimidine 1b reacted with N-benzyl (2b) and N-cyclohexyl maleimide (2c) to afford spirocycles 4a and 4b in excellent yields (86% and 90%, respectively). The 4-bromo-substituted maleimide 2d provided 4c in 69% yield, while the strongly electron-withdrawing 4-nitro derivative 2e gave 4d in a good yield of 78%. The meta-substituted maleimide 2f reacted efficiently with perimidine 1b to afford spirocycle 4e in a good yield of 71%. Similarly, 3,4-dimethoxy-substituted maleimide 2g gave 4f in 72% yield. Notably, the heteroaryl-linked N-methyl thiophene maleimide 2h also reacted smoothly, furnishing 4g in 80% yield. The applicability of this methodology was further demonstrated with N-alkyl-substituted maleimides 2i and 2j, which reacted efficiently with perimidine 1b to afford 4h and 4i in 76% and 84% yields, respectively. Likewise, N-oleyl maleimide 2k reacted with perimidine 1b to afford the spirocyclized product 4j in 76% yield. The unsubstituted maleimide 2l also reacted with 1b, furnishing 4k in a moderate yield of 62%. Reaction of 1b with carbazole-linked maleimide 2m provided product 4l in 77% yield. Naphthoquinone 2n, a cyclic electron-deficient alkene, also afforded the [4 + 1] spirocyclized product 4m in 82% yield. Acyclic electron-deficient alkenes like ethyl acrylate 2o and acrylonitrile 2p reacted with 1b to provide [4 + 1] annulated perimidines 4n and 4o in excellent yields of 93% and 84%, respectively. In contrast, symmetric alkene trans-stilbene 2q remained unreactive under the optimized conditions. Subsequently, 4-chlorophenyl perimidine 1c was reacted with various maleimides, including N-benzyl 2b, N-cyclohexyl 2c, and N-ethyl 2i. In all instances, the reaction proceeded efficiently, demonstrating the broad scope of this methodology.

Scheme 3 Substrate scope for maleimides/alkenes. Reaction condition: 1 (0.1 mmol), 2 (0.1 mmol), 5 mol% (3 mg) [RhCp*Cl₂]₂, 1.0 equiv. (8 mg) NaOAc, and 2.0 equiv. (11 μL) AcOH in 1.0 mL MeOH at 80 °C for 1 h; Isolated Yield.

After obtaining these encouraging results, we next explored vinylene carbonate as a reaction partner, replacing maleimide. Under the optimized conditions, no reaction occurred. Consequently, we optimized reaction conditions for the reaction of 2-phenyl-1H-perimidine 1a with vinylene carbonate 5a. After a series of reactions (summarized in Table 2), we found that vinylene carbonates can be reacted with 1a. Interestingly, the resulting product is a fused six-membered ring formed via a [4 + 2] annulation. Among all the screened conditions, entry 1 conditions in Table 2 provided the best result and were therefore considered the optimal reaction conditions.

Table 2 Optimization of reaction conditions^a,b

Entry	Deviation from standard conditions	Yield^b
a Reaction conditions: 1a (0.1 mmol), 5a (0.2 mmol), catalyst (5 mol%), additive 1 (1.0 equiv.), and additive 2 (2.0 equiv.) in solvent (1.0 mL) at 110 °C for 4 h under N2. b Isolated yield. c MeOH instead of 1,2-DCE; NR = no reaction.
1	None	60
2	AgSbF6/AgOTf/AgNTf2/KPF6/NaOAc^c Instead of Zn(OAc)2	45/45/41/30/trace
3	Toluene/DCM/ACN instead of 1,2-DCE	41/37/22
4	80 °C/130 °C instead of 110 °C	41/45
5	Air instead of N2 gas	Trace
6	No [RhCp*Cl2]2	NR
7	No Zn(OAc)2	NR
8	No AcOH	30

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After establishing the optimal conditions, next we studied the generality of this methodology, and the results are summarized in Scheme 4. We initially reacted 2-phenyl-1H-perimidine (1a) with vinylene carbonate (5a) under the optimal conditions, yielding product 6a in 60%. Subsequent reactions with para-substituted perimidines (1a–1f) generally gave good yields, except for the 4-fluoro derivative (1e), which produced 6e in only 42% yield under the standard conditions. We then treated naphthyl-1H-perimidine (1i) with vinylene carbonate (5a), yielding 50% of the [4 + 2] cyclized product 6g. The substituent at the ortho position of 2-phenyl-1H-perimidine provided 6h in a moderate yield of 50%, whereas the meta substituted perimidine resulted in the selective activation of the less hindered C–H bond, furnishing a 54% yield of 6i.^15,17 Next, we treated the heteroaromatic 2-(thiophen-2-yl)-1H-perimidine 1n. The reaction proceeded to furnish the [4 + 2] annulated product 6j in 6 h.

Scheme 4 Substrate scope of vinylene carbonates. Reaction conditions: 1 (0.1 mmol), 5a (0.2 mmol), 5 mol% (3 mg) of [RhCp*Cl₂]₂, 1.0 equiv. (18 mg) of Zn(OAc)₂, and 2.0 equiv. (11 μL) of AcOH in 1.0 mL of 1,2-DCE at 110 °C for 4 h under N₂; isolated yield; ^a 6 h.

To demonstrate scalability, the reaction was performed on a 1 mmol scale with perimidine (1a) and N-phenylmaleimide (2a), providing 68% yield of compound 3a under standard conditions as shown in Scheme 5.

Scheme 5 1 mmol scale synthesis of 3a.

Subsequently, to illustrate late-stage modifications, an additional reaction was carried out using the reported method as shown in Scheme 6.²² We conducted a ring-opening reaction of spiro-succinimide 3a with NaOMe, followed by acid work-up yielding product 7 in 85% yield.

Scheme 6 Late-stage modification of 3a.

To understand the mechanism, we conducted a few control experiments (Scheme 7). Reacting 1e and 1f (1 : 1) with N-phenyl maleimide 2a under standard conditions (eqn (a), Scheme 7) yielded 3e and 3f in a 1 : 1.3 ratio, suggesting an electrophilic cyclo-rhodation. The deuterium exchange with perimidine 1f under the optimum reaction conditions for [4 + 1] and [4 + 2] cyclizations resulted in 25% and 78% deuteration, respectively, at both the ortho positions, suggesting a reversible C–H activation (eqn (b), Scheme 7).^23,24 The radical trapping experiment with 2 equivalents of BHT under standard reaction conditions proceeded without any significant abatement of yield, i.e., 72% and 48%, respectively, ruling out the probability of any radical being involved in the reaction pathway (eqn (c), Scheme 7). The competitive kinetic isotope effect studies afforded k_H/k_D values of 2.70 and 5.25, respectively, in both cases. This delineates that C–H bond breaking is involved in the rate-determining step (eqn (d) and (e), Scheme 7).

Scheme 7 Control experiments.

On the basis of our control experiments and previously reported studies^25–32 and the obtained mass spectra, we have proposed a plausible mechanism accounting for the cascade annulations (Schemes 8 and 9). Initially, the [RhCp*Cl₂]₂ is activated upon reaction with NaOAc, resulting in the monomeric active catalyst [RhCp*(OAc)₂] A, which undergoes reversible C–H activation with 2-aryl-1H-perimidine, leading to the formation of intermediate B. The maleimide 2 then coordinates with B, yielding complex C, which, upon migratory insertion, forms the seven-membered rhodacycle D. A β-hydride elimination generates the alkenylated intermediate E along with regeneration of the active catalyst A. Intermediate E then undergoes a rapid aza-Michael addition to form the spiro-annulated product 3/4.

Scheme 8 Plausible reaction mechanism for 3/4.

Scheme 9 Plausible reaction mechanism for 6.

In the catalytic cycle with vinylene carbonate (Scheme 9), [RhCp*Cl₂]₂ is activated by Zn(OAc)₂ to form monomeric Rh(III) complex A followed by C–H activation with 2-aryl-1H-perimidine to form rhodacycle B′. Coordination with vinylene carbonate 5a forms complex C′, which undergoes migratory insertion to yield the seven-membered intermediate D′. A β-oxygen elimination and decarboxylation from D′ generates the eight-membered ring E′. The intermediate E′ undergoes protonation with AcOH, producing intermediate F′ and regenerates the active catalyst A. Intermediate F′ undergoes intramolecular cyclization and dehydration to afford the [4 + 2] cyclized product 6.

Conclusions

In conclusion, we have developed an operationally simple and efficient strategy involving cascade C–H activation of 1-aryl-1H-perimidines for the synthesis of perimidine-linked spiro-succinimides and isoquinolines. The use of various alkenes, including maleimides, naphthoquinones, ethyl acrylate, and acrylonitrile, predominantly led to the [4 + 1] annulated products via selective C–H activation. In contrast, vinylene carbonates exhibited divergent reactivity, furnishing [4 + 2] annulated products. This methodology demonstrates high regioselectivity, broad functional group tolerance, moderate to excellent yields, and scalability, thus offering a valuable approach for the synthesis of structurally diverse heterocycles.

Author contributions

Vidya Kumari: concept building, performing experiments, data acquisition, data analysis and manuscript writing. Lokman H. Choudhury: concept building, supervision, fund acquisition and manuscript writing.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

The data supporting this article have been included in the manuscript and its supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5qo01292a.

CCDC 2279344 and 2495811 contain the supplementary crystallographic data for this paper.^33a,b

Acknowledgements

L. H. C. gratefully acknowledges the financial support from the ANRF, Government of India (Sanction No. CRG/2021/003716). The authors also express their sincere gratitude to IIT Patna for providing essential research facilities, and to SAIF IIT Patna, IIT (ISM) Dhanbad and BHU, Varanasi, for NMR, HRMS and SC-XRD analyses. Special thanks are extended to Mr Kamlesh Satpute (IIT Ropar) for his assistance with single-crystal X-ray diffraction analysis.

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