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Article

Iron/Rhodium Bimetallic Lewis Acid/Transition Metal Relay Catalysis for Alkynylation/Cyclotrimerization Sequential Reactions Toward Isoindolinone Derivatives from N,O-Cyclic Acetals

by
Sidi Mohamed Abdallahi
1,2,
Ewies Fawzy Ewies
1,3,
Mohamed El-Shazly
4,
Brahim Ould Elemine
2,
Abderrahmane Hadou
2,
Ata Martin Lawson
1,
Adam Daïch
1 and
Mohamed Othman
1,*
1
Normandie Univ, Université Le Havre Normandie, URCOM UR 3221, INC3M, FR CNRS 3038, 25 Rue Philippe Lebon, BP 1123, F-76063 Le Havre Cedex, France
2
Département de Chimie, Faculté des Sciences, Université de Nouakchott Al-Aasriya, Nouakchott BP 5026, Mauritania
3
Organometallic and Organometalloid, Chemistry Department, National Research Centre, 33 ElBohouth St., Cairo 12622, Egypt
4
Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity, Cairo 11566, Egypt
*
Author to whom correspondence should be addressed.
Catalysts 2025, 15(2), 151; https://doi.org/10.3390/catal15020151
Submission received: 10 December 2024 / Revised: 28 January 2025 / Accepted: 29 January 2025 / Published: 6 February 2025
(This article belongs to the Special Issue New Insights into Transition Metal Catalysts for Green Organic Synthesis)
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Versions Notes

Abstract

:
A novel sequential one-pot bimetallic catalytic system combining Fe(III)-catalyzed alkynylation and a Rh(I)-catalyzed [2+2+2] reaction was successfully developed. The σ-Lewis acid properties of iron (III) and the π-Lewis acid properties of rhodium (I) catalysts were unified in an unprecedented intermolecular alkynylation/cyclotrimerization one-pot process. Using this unique Fe/Rh bimetallic relay catalytic system, a variety of benzo and pyrridinoisoindolinone derivatives were obtained under mild conditions from easily available N-(propargyl) hydroxy aminals, as the simplest N-acyliminium ion precursors, and several alkynes.

1. Introduction

The development of novel methodologies that enable the rapid, practical, and economical construction of privileged small molecules in pharmaceutical sciences is highly desirable. In this context, sequential one-pot bimetallic catalysis is undoubtedly one of the most powerful strategies offering an efficient diversity-oriented, ecofriendly synthesis of these privileged scaffolds [1,2].
Isoindolinone frameworks, which are referred to as phthalimidines or benzo-fused γ-lactams, are common structural motifs in many synthetic and natural products that exhibit interesting biological activities. Many of these frameworks showed anxiolytic [3], MDM2-p53 inhibitory [4], antimicrobial [5], antiviral [6], PARP-1-inhibitory [7], histone deacetylase inhibitory [8], antihyperglycemic [9], antioxidant [10], anti-inflammatory [11], antifungal [12], antiparkinsonian [13], selective NaV1.7 blocking [14], antipsychotic [15], antihypertensive [16], anticancer [17], anesthetic [18], vasodilatory [19], and survival motor neuron protein-production-regulating activities (Figure 1) [20].
Owing to the wide spectrum of isoindolinone core biological activities, substantial efforts have been devoted to preparing this heterocyclic skeleton [21]. Among them are the functionalization of phthalimides or phthalimidines, and transition-metal-catalyzed C-C-bond-forming reactions involving, for example, C-H activation [22,23,24], cyclotrimerization [25], cross-coupling [26], and carbonylation [27] strategies. Despite the development of a plethora of methods, isoindolines [28]- and pyrrolopyridine [29]-fused isoindolinones were not yet reported.
Recently, our group developed an unprecedented (ligand-free) iron (III) tandem intermolecular amidoalkynylation/intramolecular hydration sequence of several isoindolic cyclic N,O-acetals (acetoxylactams), allowing expedient access to new functionalized isoindolinone ketone motifs. Unprotected hydroxy N,O-acetals (hydroxylactams), a more atom-economical source of electrophiles in comparison to the parent acetoxylactams, were used in these transformations (Scheme 1, eq. 1) [30].
Moreover, the transition-metal-catalyzed [2+2+2] cyclotrimerization reactions of alkynes constitute powerful methods for the synthesis of substituted six-membered aromatics in a one-step highly atom-economic process [31]. Since Reppe’s pioneering cyclotrimerization of alkynes in 1948, a myriad of efficient catalytic species (e.g., Rh [32], Ru [33], Ir [34], Co [35], Ni [36], Mo [37], Nb [38], Au [39], Pd [40], and Fe [41]) and coupling partners (e.g., olefins, nitriles, isocyanates, cyanamides, aldehydes, ketones, carbon dioxide, imines, and carbodiimides) were employed for this purpose.
Inspired by our results on iron (III) N,O-cyclic acetal alkynylation, the advances and elegance of transition-metal-catalyzed [2+2+2] cyclotrimerization reactions, and the biological and synthetic importance of isoindolinone scaffolds, we became interested in developing a one-step synthetic route to prepare novel isoindoline- and pyrrolopyridine-fused isoindolinones through bimetallic Fe(III) alkynylation/Rh(I) [2+2+2] cycloaddition relay catalysis (Scheme 1, eq. 2).

2. Results

Cyclotrimerization of Dialkyne 2: Optimization Study

Based on our previous work on iron-catalyzed alkynylation and before exploring the one-pot procedure, we decided to test the feasibility of the cyclotrimerization reaction. We performed a catalyst screening for the [2+2+2] cycloaddition reaction. Based on recent successes in constructing highly substituted benzenes and pyridines via an iron cyclotrimerization reaction, we first applied a similar approach to diynes 2a,b, and phenylacetylene 3a as a model substrate. Unfortunately, all efforts to obtain the isoindolinones 4 using Fe(OTf)3, FeI2, or Fe(OAc)2 as precatalysts along with various ligands in the presence of Zn metal as a reducer were unsuccessful, and diynes 2a,b were invariably partially regenerated (Table 1, entries 1–3). To overcome these limitations, we decided to move from a monometallic-iron-based catalyst to a bimetallic sequence, using a hard Lewis acid (FeIII) catalyst for alkynylation and Rh or Ru catalyst for the [2+2+2] cycloaddition step (Table 1, entries 4–11).
The results showed that 2b and RhCl(PPh3)3 were the best substrate and the most effective catalyst for this reaction, respectively (Table 1, entries 4–8). Further assessment of the solvent effect indicated that PhMe was the best solvent for this cyclotrimerization reaction, providing a higher yield than other commonly used solvents (entry 5 vs. 7–8). Grubbs catalysts resulted in inferior results. The use of the Grubbs first-generation (Grubbs-I) catalyst (Table 1, entry 10) under Wilkinson conditions (3a (10 equiv.), PhMe reflux, argon) gave 4 in only 10% yield along with several side-products. Under the Grubbs second-generation (Grubbs-II) catalyst (Table 1, entry 11), the same profile of the reaction was observed (4:15%; several side-products) even after a prolonged reaction time (24 h). These findings highlighted the advantage of using Rhodium (I) in the cyclotrimerization reaction.
Encouraged by these results, we moved forward to optimizing the reaction conditions (Table 2). Different temperatures, addition rates, numbers of equivalents of alkyne 3a, and reaction times were examined. We found that the slow addition of alkyne 2b to the reaction media for 2 h and then refluxing in PhMe for 1 h afforded the expected isoindolinones 4a/4a’ (4a:4a’ = 60:40) in the highest yield (76%, entry 6).
The use of the Grubbs instead of Wilkinson catalyst under the above-optimized conditions did not improve the yield; isoindolinones 4 were obtained in 20% and 30% isolated yields, respectively, with Grubbs first-generation (Grubbs-I) and Grubbs second-generation (Grubbs-II) catalysts (Table 2, entries 12 and 14). Switching the solvent from PhMe to other solvents such as THF or DCE resulted in inferior results. For example, RhCl(PPh3)3 in DCE produced 4a/4a’ in 52% yield (Table 2, entry 10).
With the establishment of the optimized conditions, the substrate scope was examined (Table 3). The [2+2+2] cyclotrimerization proved to be quite general; a broad range of terminal aromatic alkynes served as suitable substrates for this reaction, leading to the desired isoindolinones in moderate to excellent yields (Table 3, entries 1−8). The reactions of alkynes bearing an electron-donating group such as m- or p-methyl on aryl rings resulted in high yields of isoindolinones 4b/4b’ (69% yield, 4b:4b’ = 54:46) and 4c/4c’(68% yield, 4c:4c’ = 60:40) (Table 3, entries 2 and 3). Substrates with an electron-withdrawing substituent on the aryl ring, such as p-NO2 and p-Br, proved to also be suitable, furnishing 4d/4d’and 4e/4e’ in 58% (4d:4d’ = 61:39) and 75% (4e:4e’ = 58:42) yields (Table 3, entries 4 and 5).
Interestingly, with the ortho-substituted alkynes 3f and 3g, the reaction proceeded with complete regioselectivity. Isoindolinones 4f and 4g were obtained in 59% and 83% isolated yields, respectively (Table 3, entries 6 and 7). Heteroaryl-substituted alkyne (e.g., 2-thienyl-substituted) transformed to 4h/4h’ (4h:4h’ = 54:46) successfully in 71% yield (Table 3, entry 8). The reaction was also applicable to internal aromatic alkynes, as exemplified by the synthesis of 4i/4i’ isoindolinone derivatives in 43% (4i:4i’ = 63:37) isolated yield (Table 3, entry 9).
Encouraged by the results with aromatic alkynes, we examined the [2+2+2] cyclotrimerization reaction with aliphatic alkynes. A wide range of aliphatic alkynes were used for our cycloaddition. The results are summarized in Table 4.
The reaction with benzylacetylene 3j provided isoindolinones 4j/4j’ in 51% (4j:4j’ = 60:40) yield (Table 4, entry 1). Similarly, diyne 2b reacted with tert-butylacetylene 3k to produce 4k/4k’ (4k:4k’ = 73:27) in 40% yield (Table 4, entry 2). Activated aliphatic alkynes were also good substrates for the reaction; diyne 2b reacted smoothly with methyl propiolate 3l to provide 4l/4l’ (4l:4l’ = 55:45) in 54% yield (Table 4, entry 3). The reaction with dimethyl acetylenedicarboxylate (DMAD) 3m gave isoindolinone 4m in 45% yield (Table 4, entry 5). An isoindole moiety was also introduced at the side-chain of the benzene ring. When diyne 2b was reacted with N-propargyl phthalimide 3n, isoindolinones 4n/4n’ were obtained in an excellent yield of 88% (4n:4n’ = 60:40) (Table 4, entry 5).
Having established the conditions for the two distinct catalytic (Fe(III)-catalyzed alkynylation and Rh(I)-catalyzed cycloaddition) reactions, we tried combining both catalytic systems into a one-pot bimetallic tandem alkynylation/[2+2+2] cycloaddition sequences to save time, labor, and resources and to avoid yield losses associated with the purification of dialkynes 2.
When the one-pot/sequential procedure was carried out in DCE (hydroxylactam 1a (1 equiv.), propyne-TMS (1 equiv.), Fe(OTf)3 10 mol%, 4 h at reflux (monitored by TLC)) followed by a portion-wise addition of a solution of alkyne 3b (10 equiv.) and 10 mol% of RhCl(PPh3)3 in DCE (2 mL) for 2 h, isoindolinones 4a/4a’ were isolated after 1 h of reflux (monitored by TLC) in a 20% yield. Although the desired products were isolated in moderate yield after purification, this result validates our initial design plan. The choice of solvent was found to be critical. Switching from DCE to a mixture of solvents DCE/PhMe (2:1) gave the desired isoindolinones in a 27% yield. Increasing the ratio of PhMe to 50% (DCE:PhMe (1:1)) delivered 4a/4a’ in a 36% isolated yield.
The replacement of DCE (removed under vacuum) after completion of the alkynylation step by PhMe, in the same above conditions (Fe(OTf)3 10 mol%, DCE (2 mL), 4 h under reflux (monitored by TLC), solvent removed in vacuo, a portion-wise addition of alkyne 2b solution (10 equiv.) and 10 mol% of RhCl(PPh3)3 in 2 mL of PhMe (for 2 h), under reflux 1 h), produced isoindolinones 4a/4a’ in a 60% yield (Table 5, entry 1).
Having established the optimal reaction conditions, we inspected the scope of the one-pot bimetallic sequence. As depicted in Table 5, electron-neutral (3a, 3o, 3p), electron-rich (3q), and electron-withdrawing (3d) substituents on the phenyl ring of alkyne 3, such as p-methoxy or p-nitro, were well accommodated in this relay catalysis, delivering the isoindolinones 4 in moderate to high yields (51–70% yields, Table 5, entries 1–5). The ortho-bromo and ortho-methoxy-substituted alkynes 3f and 3g were also favorable for this one-pot bimetallic transformation, generating the corresponding products 4f and 4g in 51 and 73% yields, respectively, and in total regioselectivity (Table 5, entries 6 and 7). Similarly, the reaction of 2b with DMAD 3m afforded the cyclotrimerization product 4m in a moderate yield of 35% (Table 5, entry 10).
Isoindolic substrates alkynes 3n and 3t and their non-aromatic analog succinimide 3u were suitable substrates in producing isoindolinones 4n/4n’, 4t/4t’, and 4u/4u’ in good yields of 70%, 82%, and 72%, respectively (Table 5, entries 11–13). It is worth mentioning that all the regiochemical profiles obtained throughout this exemplification study are in good agreement with the preliminary experiments obtained during the cyclotrimerization reactions (Table 3 and Table 4), demonstrating the formation of mixtures of ortho and meta isoindolinones in varying ratios.

3. Mechanistic Study

The use of Fe(OTf)3 and the 1-TMS-propyne in the alkynylation reactions may generate TMSOTf, TMSOH, or TfOH (generated by Fe(OTf)3 hydrolysis) (Scheme 2), highlighting the possibility that the in situ-generated TMSOTf, TMSOH, and TfOH may catalyze or co-catalyze the [2+2+2] reaction [42,43,44]. The following control experiments were performed. When 10 mol% of TMSOH was used as the catalyst under the described conditions for 2b, no cyclotrimerization product was observed even after a prolonged reaction time (24 h). Only dialkyne 2b was partially regenerated along with several side-products resulting from the hydration of alkyne functions, thus ruling out the possibility of TMSOH catalysis.
The reaction of 2b with 3a catalyzed by 10 mol% of TMSOTf afforded 4a/4a’ in trace amounts (<10%). However, the addition of 10 mol% of RhCl(PPh3)3 to the reaction mixture led to the formation of 4a/4a’ in 67% yield. These results suggested that the cyclotrimerization reaction proceeded through rhodium catalysis. These observations were confirmed by experiments performed with TMSOTf + RhCl(PPh3)3. The treatment of 2b with 3d or 3g under a mixture of 10 mol% of (TMSOTf + RhCl(PPh3)3) provided isoindolinones 4d/4d’ and 4g in 55% and 81% isolated yields, respectively, and in shorter reaction times (4 h for 4d/4d’ and 2 h for 4g). Considering the cyclotrimerization reactions, the yields were not diminished (55% vs. 58% (Table 3, entry 4) for 4d/4d’ and 81% vs. 83% (Scheme 2, entry 7) for 4g), and combined with the fact that the higher rates were observed (4 h vs. 6 h for 4d/4d’ and 2 h versus 3 h for 4g), we believe that the reaction proceeded through rhodium catalysis, although RhCl(PPh3)3/TMSOTf co-catalysis should not be excluded.
Encouraged by the efficiency and robustness of the current protocol in the construction of novel isoindolinone products and inspired by the fact that pyridines are privileged structures widely available in natural products, pharmaceuticals, and agrochemicals [45], we also evaluated the one-pot alkynylation/cyclotrimerization reaction in the construction of novel pyridine-fused isoindolinones [46,47,48,49,50,51,52]. A nitrile derivative 5a was subjected to our protocol under the standard reaction conditions (Scheme 3). The pyridine derivative 6a was obtained as a single regioisomer and isolated in an acceptable yield of 40%.

4. Conclusions

In conclusion, we took advantage of the different reactivities of iron and rhodium, and of their compatibility to develop an efficient sequential one-pot bimetallic iron–rhodium alkynylation/cyclotrimerization sequential reactions to synthesize novel fused benzene and pyridine isoindolinone derivatives from trivial starting materials. The σ-Lewis acid properties of iron (III) were implemented to promote the alkynylation step, and then, in a one-pot procedure, rhodium (I) was used to ensure the [2+2+2] cycloaddition reaction. Additional studies are currently under development in our laboratory to extend the scope and utility of this Fe/Rh-catalyzed cascade reaction.

5. Experimental Section

General Information. 1H NMR spectra were recorded at 300 MHz with a Bruker AvanceTM 300 spectrometer and data are reported as chemical shift (δ) in ppm, multiplicity (s = singlet, d = doublet, t = triplet, b = broad, m = multiplet), and coupling constants J in Hz. 13C NMR spectra were recorded at 75 MHz using broadband proton decoupling and the data are reported as chemical shift (δ) in ppm. High-resolution mass spectra (HRMS) were measured on the Agilent 6530 Q-Tof MS system (Les Ulis, France). FTIR spectra were recorded with a PerkinElmer Frontier (Waltham, MA, USA). The starting materials were purchased from commercial sources such as Sigma-Aldrich (Saint Louis MO, USA), Fisher scientific (Waltham, MA, USA), and TCI (Palo Alto, CA, USA). All solvents were dried and freshly distilled by refluxing over CaH2. Flash chromatography purifications were performed on an Interchim Puriflash (Puriflash columns 50 μ) (Montluçon, France) using a cyclohexane/ethyl acetate eluent system.
Representative Procedure for the Rhodium(I)-Catalyzed Cyclotrimerization of Dialkynes: To a solution of alkynes 3a–w (2.3 mmol, 10 eq) and RhCl(PPh3)3 (0.023 mmol, 0.1 eq) in toluene (4 mL), we slowly added the substrate 2b (0.23 mmol, 1 equiv.), for 2 h, under argon. The reaction mixture was heated under reflux and monitored by TLC. After the total conversion of the starting material, the solvent was removed under reduced pressure. The crude product was then purified by flash chromatography on a silica gel column using a mixture of cyclohexane/AcOEt as the eluent or DCM/AcOEt to give the desired compounds 4.

5.1. Synthesis and Characterization of Compounds 4n/4n′

These products were obtained as a mixture of separable two regioisomers in 88% global yield, with a ratio of 4n/4n’: 60/40.

5.1.1. 2-((1-Methyl-7-oxo-7,11b-dihydro-5H-isoindolo[1,2-a]isoindol-3-yl)methyl)isoindoline-1,3-dione (4n)

Major regioisomer-4n: This product was isolated as a white solid, Rf (DCM/AcOEt: 9/1) = 0.24; m.p. = 174–176 °C; IR (νmax cm−1): 1687; 1H NMR (300 MHz, CDCl3): δH 7.89–7.80 (m, 4H, Haro), 7.73–7.68 (m, 2H, Haro), 7.58 (t, J = 7.5 Hz, 1H, Haro), 7.46 (t, J = 7.4 Hz, 1H, Haro), 7.18 (s, 1H, Haro), 7.14 (s, 1H, Haro), 6.03 (s, 1H, CH), 5.18 (d, J = 15.1 Hz, 1H, CH2), 4.79 (s, 2H, CH2), 4.41 (d, J = 15.1 Hz, 1H, CH2), 2.63 (s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δC 174.0, 168.1, 145.0, 142.6, 137.1, 136.5, 134.2, 133.9, 133.6, 132.2, 132.1, 130.0, 128.8, 125.1, 124.7, 123.5, 121.2, 69.4, 49.3, 41.3, 21.6 ppm. HRMS (+ESI) calculated for C25H18N2O3 [M + H]+: 395.1390, found 395.1395.

5.1.2. 2-((1-Methyl-7-oxo-7,11b-dihydro-5H-isoindolo[1,2-a]isoindol-2-yl)methyl)isoindoline-1,3-dione (4n′)

Minor regioisomer-4n’: This product was isolated as a white solid, Rf (DCM/AcOEt: 9/1) = 0.19; m.p. = 208–210 °C; IR (νmax cm−1): 1687; 1H NMR (300 MHz, CDCl3): δH 7.95 (d, J = 7.8 Hz, 1H, Haro), 7.88–7.79 (m, 3H, Haro), 7.74–7.69 (m, 2H, Haro), 7.59 (t, J = 7.4 Hz, 1H, Haro), 7.47 (t, J = 7.5 Hz, 1H, Haro), 7.32 (d, J = 7.8 Hz, 1H, Haro), 7.07 (d, J = 7.8 Hz, 1H, Haro), 6.13 (s, 1H, CH), 5.19 (d, J = 15.1 Hz, 1H, CH2), 4.98–4.75 (m, 2H, CH2), 4.41 (d, J = 15.0 Hz, 1H, CH2), 2.82 (s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δC 174.1, 168.2, 145.5, 141.3, 138.1, 134.2, 134.2, 134.1, 133.6, 132.2, 132.2, 132.1, 129.9, 128.8, 125.2, 124.7, 123.5, 121.0, 69.8, 49.5, 39.3, 18.5 ppm. HRMS (+ESI) calculated for C25H18N2O3 [M + H]+: 395.1390, found 395.1395.
Representative Procedure for the Iron(III)/Rhodium(I)-Catalyzed One-Pot Alkynylation/Cyclotrimerization of N,O-Acetals: Commercially available Fe(OTf)3 (Aldrich, 5 mol%) was added to a solution of hydroxylactam 1 (0.5 mmol) and propyne-TMS 2 (1.1 equiv.) in 1,2-dichloroethane (2 mL) under argon. The mixture was placed in a pre-heated oil bath at reflux and magnetically stirred. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure. The intermediate 2b was solubilized without purification in 2 mL of toluene and was added dropwise over 2 h to a solution of 3a–t alkynes (10 equiv.) and RhCl(PPh3)3 (10 mol%) in toluene (4 mL). The reaction mixture was heated under reflux. After the total conversion of the starting material as monitored by TLC, the solvent was removed under reduced pressure. The crude products were purified by flash chromatography (silica gel column, cyclohexane/AcOEt, or DCM/AcOEt as eluents).

5.2. Synthesis and Characterization of Compounds 4o/4o′

These products were obtained as a mixture of two separable regioisomers in 59% global yield, with a ratio of 4o/4o’: 58/42.

5.2.1. 11-Methyl-9-(thiophen-3-yl)-7,11b-dihydro-5H-isoindolo[1,2-a]isoindol-5-one (4o)

Major regioisomer-4o: This compound was isolated as a white solid, Rf (cyclohexane/AcOEt: 8/2) = 0.21; m.p. = 193–195 °C; IR (νmax cm−1): 1683; 1H NMR (300 MHz, CDCl3): δH 7.95–7.85 (m, 2H, Haro), 7.68-7.57 (m, 1H, Haro), 7.55–7.44 (m, 1H, Haro), 7.41 (s, 1H, Haro), 7.39–7.32 (m, 3H, Haro), 7.31 (s, 1H, Haro), 6.11 (s, 1H, CH), 5.27 (d, J = 15.7 Hz, 1H, CH2), 4.49 (d, J = 15.0 Hz, 1H, CH2), 2.70 (s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δC 174.0, 145.2, 142.7, 141.7, 136.5, 135.7, 133.9, 133.7, 132.2, 128.8, 128.0, 126.5, 126.4, 125.2, 124.7, 120.8, 119.0, 69.5, 49.4, 21.8 ppm. HRMS (+ESI) calculated for C20H15NOS [M + H]+: 318.0947, found 318.0947.

5.2.2. 11-Methyl-10-(thiophen-3-yl)-7,11b-dihydro-5H-isoindolo[1,2-a]isoindol-5-one (4o′)

Minor regioisomer-4o’: This compound was isolated as a white solid, Rf (cyclohexane/AcOEt: 8/2) = 0.18; m.p. = 191–193 °C; IR (νmax cm−1): 1696; 1H NMR (300 MHz, CDCl3): δH 7.96 (d, J = 7.7 Hz, 1H, Haro), 7.90 (d, J = 7.6 Hz, 1H, Haro), 7.62 (t, J = 7.1 Hz, 1H, Haro), 7.50 (t, J = 7.4 Hz, 1H, Haro), 7.42–7.33 (m, 1H, Haro), 7.27–7.25 (m, 1H, Haro), 7.20–7.10 (m, 2H, Haro), 7.12–7.04 (m, 1H, Haro), 6.16 (s, 1H, CH), 5.27 (d, J = 15.2 Hz, 1H, CH2), 4.50 (d, J = 15.0 Hz, 1H, CH2), 2.63 (s, 2H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δC 174.1, 145.5, 141.5, 140.9, 138.1, 136.9, 133.7, 132.2, 131.7, 130.4, 129.1, 128.8, 125.4, 125.3, 124.7, 123.2, 120.8, 69.9, 49.5, 20.2 ppm. HRMS (+ESI) calculated for C20H15NOS [M + H]+: 318.0947, found 318.0947.

5.3. Synthesis and Characterization of Compound 6a

3-(Dimethylamino)-1-methyl-5,11b-dihydro-7H-pyrido[3′,4′:3,4]pyrrolo[2,1-a]isoindol-7-one (6a)

This product was isolated as a yellow oil in 40% yield, Rf (cyclohexane/AcOEt: 7/3) = 0.5; IR (νmax cm−1): 1695; 1H NMR (300 MHz, CDCl3): δH 7.92–7.80 (m, 2H, Haro), 7.61 (td, J = 7.5 and 1.4 Hz, 1H, Haro), 7.48 (t, J = 7.4 Hz, 1H, Haro), 6.23 (s, 1H, Haro), 5.96 (s, 1H, CH), 5.12 (d, J = 15.6 Hz, 1H, CH2), 4.34 (d, J = 15.5 Hz, 1H, CH2), 3.05 (s, 6H, 2× CH3), 2.68 (s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δC 174.2, 159.1, 152.8, 151.2, 145.9, 133.3, 132.3, 128.7, 124.7, 124.6, 120.1, 97.3, 67.8, 49.3, 38.3, 24.7 ppm. HRMS (+ESI) calculated for C17H17N3O [M + H]+: 280,1450, found 280.1448.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal15020151/s1.

Author Contributions

Conceptualization, methodology, and data curation, S.M.A. and E.F.E.; writing—original draft preparation, S.M.A., B.O.E. and E.F.E.; supervision, A.H., A.M.L. and A.D.; writing—reviewing and editing, M.O. and M.E.-S. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful for the financial support from Institut Français d'Égypte (IFE); Campus France; Ministry of Education of Mauritania; and Le Havre Normandie University, France.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this work are available in this article.

Acknowledgments

We are grateful to the financial support from Institut Français d'Égypte (IFE); Campus France; National Research Centre (NRC) and Science and Technology Development Fund (STDF), Egypt; Ministry of Education of Mauritania; and Le Havre Normandie University, France.

Conflicts of Interest

The authors declare no conflicts of interest.

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Catalysts 15 00151 g001
Figure 1. Examples of biologically active isoindolinone derivatives.
Figure 1. Examples of biologically active isoindolinone derivatives.
Catalysts 15 00151 g001
Catalysts 15 00151 sch001
Scheme 1. Current state-of-the-art C-alkynylation of N-acyliminium reactions (a, eq. 1) and this work (b, eq. 2).
Scheme 1. Current state-of-the-art C-alkynylation of N-acyliminium reactions (a, eq. 1) and this work (b, eq. 2).
Catalysts 15 00151 sch001
Catalysts 15 00151 sch002
Scheme 2. Mechanistic study to reveal the identity of the catalytic species.
Scheme 2. Mechanistic study to reveal the identity of the catalytic species.
Catalysts 15 00151 sch002
Catalysts 15 00151 sch003
Scheme 3. Cyclotrimerization of nitriles and preparation of pyridine 6a.
Scheme 3. Cyclotrimerization of nitriles and preparation of pyridine 6a.
Catalysts 15 00151 sch003
Table 1. Identification of the best cyclotrimerization catalyst [a].
Table 1. Identification of the best cyclotrimerization catalyst [a].
Catalysts 15 00151 i001
EntryR1CatalystSolventProductYield [b]
1Ph/MeFe(OTf)3- [c,d]-ND
2Ph/MeFe(OAc)2/L/Zn- [c,d]-ND
3Ph/MeFeI2/dppp/Zn- [c,d]-ND
4PhRhCl(PPh3)3PhMe- [d]ND
5MeRhCl(PPh3)3PhMe435
6MeRhCl(PPh3)3PhMe415
7MeRhCl(PPh3)3THF417
8MeRhCl(PPh3)3DCE425
9PhGrubbs-I/II- [c,d]- [d]ND
10MeGrubbs-IPhMe410
11MeGrubbs-IIPhMe415
[a] Standard reaction conditions: All reactions were carried out using 2 (0.5 mmol), 3a (5 mmol), 10 mol% catalyst, and 2 mL of solvent under N2. [b] Isolated yield. [c] The reaction was tested in DCM, DCE, PhMe, or THF. [d] The reaction was tested at room temperature and under reflux. ND = not determined.
Table 2. Optimization of cyclotrimerization of di-alkyne 2b [a].
Table 2. Optimization of cyclotrimerization of di-alkyne 2b [a].
Catalysts 15 00151 i002
EntryCatalystAdd of 3a (h)t (h)T (°C)Yield (%) [b]4a:4a’ [c]
1RhCl(PPh3)30.548rt2955:45
2RhCl(PPh3)30.50.3reflux4760:40
3RhCl(PPh3)310.5reflux5558:42
4RhCl(PPh3)322reflux6860:40
5RhCl(PPh3)332reflux6057:43
6RhCl(PPh3)321reflux7660:40
7RhCl(PPh3)321806457:43
8 [d]RhCl(PPh3)321reflux2060:40
9 [e]RhCl(PPh3)321reflux4360:40
10 [f]RhCl(PPh3)321reflux5558:42
11 [g]RhCl(PPh3)321reflux6056:44
12 [h]RhCl(PPh3)321reflux5257:43
13 [i]RhCl(PPh3)321reflux4557:43
14Grubbs-I21reflux2060:40
15 [j]Grubbs-I21reflux1558:42
16Grubbs-II21reflux3060:40
17 [k]Grubbs-II21reflux1260:40
[a] Standard reaction conditions: all reactions were carried out using 2b (0.5 mmol), 3a (5 mmol, 10 equiv.), 10 mol% catalyst, and 2 mL of solvent under N2. [b] Isolated yield. [c] Ratio was determined by 1H NMR of the crude materials (see Supplementary Materials). [d] Reaction was performed using 2 equiv. of alkyne 3a. [e] Reaction was performed using 5 equiv. of alkyne 3a. [f] Reaction was performed using 8 equiv. of alkyne 3a. [g] Reaction was performed using 5 mmol% of the catalyst. [h] The reaction was tested in DCE. [i] The reaction was tested with RhCl(PPh3)3 in THF. [j] The reaction was tested with Grubbs-I in THF. [k] The reaction was tested with Grubbs-II in THF.
Table 3. Reaction scope of aromatic alkynes [a,b]
Table 3. Reaction scope of aromatic alkynes [a,b]
Catalysts 15 00151 i003
EntryAlkynet (h)4:4′ [b]Yield (%) [c] of 4 + 4′
1Catalysts 15 00151 i004157:4376
2Catalysts 15 00151 i005454:4669
3Catalysts 15 00151 i006160:4068
4Catalysts 15 00151 i007661:3958
5Catalysts 15 00151 i008158:4275
6Catalysts 15 00151 i0095100:0059
7Catalysts 15 00151 i0103100:0083
8Catalysts 15 00151 i011657:4371 [d]
9Catalysts 15 00151 i012863:3743 [d]
[a] Standard reaction conditions: 2b (0.5 mmol) in PhMe (1 mL), a portion-wise addition of a mixture of alkyne 3 (5 mmol) and RhCl(PPh3)3 (10 mol%) in PhMe (2 mL) for 2 h, and under reflux (monitored by TLC). [b] Ratio was determined by 1H NMR of the crude materials (see Supplementary Materials). [c] Isolated product yield. [d] Separable through column chromatography.
Table 4. Reaction scope of non-aromatic alkynes [a].
Table 4. Reaction scope of non-aromatic alkynes [a].
Catalysts 15 00151 i013
EntryAlkynet (h)4:4′ [b]Yield (%) [c] of 4 + 4′
1Catalysts 15 00151 i0142460:4051
2Catalysts 15 00151 i015273:2740
3Catalysts 15 00151 i016855:4554 [d]
4Catalysts 15 00151 i01710100:0045
5Catalysts 15 00151 i018360:4088 [d]
[a] Standard reaction conditions: 2b (0.5 mmol) in PhMe (1 mL), a portion-wise addition of a mixture of alkyne 3 (5 mmol) and RhCl(PPh3)3 (10 mol%) in PhMe (2 mL) for 2 h, and under reflux (monitored by TLC). [b] Ratio was determined by 1H NMR of the crude materials (see Supplementary Materials). [c] Isolated product yield. [d] Separable through column chromatography.
Table 5. The scope of one-pot [Fe]/[Rh]-catalyzed alkynylation/cyclotrimerization reaction [a].
Table 5. The scope of one-pot [Fe]/[Rh]-catalyzed alkynylation/cyclotrimerization reaction [a].
Catalysts 15 00151 i019
EntryAlkyneTime (h)4:4′ [b]Yield (%) [c] of 4 + 4′
1Catalysts 15 00151 i020160:4060
2Catalysts 15 00151 i021458:4259 [d]
3Catalysts 15 00151 i022351:4170
4Catalysts 15 00151 i023353:4768 [d]
5Catalysts 15 00151 i024461:3951
6Catalysts 15 00151 i0253100:0051
7Catalysts 15 00151 i0262100:0073
8Catalysts 15 00151 i027170:3069
9Catalysts 15 00151 i028263:3755
10Catalysts 15 00151 i0298100:0035
11Catalysts 15 00151 i030260:4070 [d]
12Catalysts 15 00151 i031358:4282 [d]
13Catalysts 15 00151 i032767:3372 [d]
[a] Standard reaction conditions: hydroxylactam 1a (0.5 mmol), propyne-TMS (0.5 mmol), Fe(OTf)3 (10 mmol%), DCE (2 mL), under reflux, 4 h, a portion-wise addition of a mixture of alkyne 3 (5 mmol) and RhCl(PPh3)3 (10 mol%) in PhMe (2 mL) for 2 h and refluxed (monitored by TLC). [b] The ratio was determined by 1H NMR of the crude materials (see Supplementary Materials) [c] Isolated product yield. [d] Separable through column chromatography.
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Abdallahi, S.M.; Ewies, E.F.; El-Shazly, M.; Ould Elemine, B.; Hadou, A.; Lawson, A.M.; Daïch, A.; Othman, M. Iron/Rhodium Bimetallic Lewis Acid/Transition Metal Relay Catalysis for Alkynylation/Cyclotrimerization Sequential Reactions Toward Isoindolinone Derivatives from N,O-Cyclic Acetals. Catalysts 2025, 15, 151. https://doi.org/10.3390/catal15020151

AMA Style

Abdallahi SM, Ewies EF, El-Shazly M, Ould Elemine B, Hadou A, Lawson AM, Daïch A, Othman M. Iron/Rhodium Bimetallic Lewis Acid/Transition Metal Relay Catalysis for Alkynylation/Cyclotrimerization Sequential Reactions Toward Isoindolinone Derivatives from N,O-Cyclic Acetals. Catalysts. 2025; 15(2):151. https://doi.org/10.3390/catal15020151

Chicago/Turabian Style

Abdallahi, Sidi Mohamed, Ewies Fawzy Ewies, Mohamed El-Shazly, Brahim Ould Elemine, Abderrahmane Hadou, Ata Martin Lawson, Adam Daïch, and Mohamed Othman. 2025. "Iron/Rhodium Bimetallic Lewis Acid/Transition Metal Relay Catalysis for Alkynylation/Cyclotrimerization Sequential Reactions Toward Isoindolinone Derivatives from N,O-Cyclic Acetals" Catalysts 15, no. 2: 151. https://doi.org/10.3390/catal15020151

APA Style

Abdallahi, S. M., Ewies, E. F., El-Shazly, M., Ould Elemine, B., Hadou, A., Lawson, A. M., Daïch, A., & Othman, M. (2025). Iron/Rhodium Bimetallic Lewis Acid/Transition Metal Relay Catalysis for Alkynylation/Cyclotrimerization Sequential Reactions Toward Isoindolinone Derivatives from N,O-Cyclic Acetals. Catalysts, 15(2), 151. https://doi.org/10.3390/catal15020151

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