Content Detail

• Content META

  Title	Iron/Rhodium Bimetallic Lewis Acid/Transition Metal Relay Catalysis for Alkynylation/Cyclotrimerization Sequential Reactions Toward Isoindolinone Derivatives from N,O -Cyclic Acetals
  ID	6636095
  External ID	7527941564
  Author	Sidi Mohamed, Ewies Fawzy, Ata Martin
  Published Date	Feb. 6, 2025, 2:18 a.m.
  Summary	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 (
  Tags	None
  URL	https://www.mdpi.com/2073-4344/15/2/151
  Sentiment	Negative: 0.00966    Neutral: 0.81987    Positive: 0.17047
  Relevance	0.00000

• Content Details

  Content ID	4116087
  Key	81f664e1-e624-4be1-ab65-77ec9d02b105
  Content	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 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 Département de Chimie, Faculté des Sciences, Université de Nouakchott Al-Aasriya, Nouakchott BP 5026, Mauritania Organometallic and Organometalloid, Chemistry Department, National Research Centre, 33 ElBohouth St., Cairo 12622, Egypt Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity, Cairo 11566, Egypt Author to whom correspondence should be addressed. 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 [ ]. 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 [ ], MDM2-p53 inhibitory [ ], antimicrobial [ ], antiviral [ ], PARP-1-inhibitory [ ], histone deacetylase inhibitory [ ], antihyperglycemic [ ], antioxidant [ ], anti-inflammatory [ ], antifungal [ ], antiparkinsonian [ ], selective NaV1.7 blocking [ ], antipsychotic [ ], antihypertensive [ ], anticancer [ ], anesthetic [ ], vasodilatory [ ], and survival motor neuron protein-production-regulating activities ( Figure 1 ) [ ]. Owing to the wide spectrum of isoindolinone core biological activities, substantial efforts have been devoted to preparing this heterocyclic skeleton [ ]. Among them are the functionalization of phthalimides or phthalimidines, and transition-metal-catalyzed C-C-bond-forming reactions involving, for example, C-H activation [ ], cyclotrimerization [ ], cross-coupling [ ], and carbonylation [ ] strategies. Despite the development of a plethora of methods, isoindolines [ ]- and pyrrolopyridine [ ]-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) [ ]. 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 [ ]. Since Reppe's pioneering cyclotrimerization of alkynes in 1948, a myriad of efficient catalytic species (e.g., Rh [ ], Ru [ ], Ir [ ], Co [ ], Ni [ ], Mo [ ], Nb [ ], Au [ ], Pd [ ], and Fe [ ]) 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 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 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 ( :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 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' = 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' 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 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 , such as p -methoxy or p -nitro, were well accommodated in this relay catalysis, delivering the isoindolinones 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 [ ]. 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 [ ], we also evaluated the one-pot alkynylation/cyclotrimerization reaction in the construction of novel pyridine-fused isoindolinones [ ]. 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. H 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. C 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 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' 5.1.1. 2-((1-Methyl-7- oxo -7,11b-dihydro-5 H -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 ( ν max cm H NMR (300 MHz, CDCl3): δ H 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. C NMR (75 MHz, CDCl3): δ C 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 ( ν max cm H NMR (300 MHz, CDCl3): δ H 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. C NMR (75 MHz, CDCl3): δ C 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 (0.5 mmol) and propyne-TMS (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' 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 ( ν max cm H NMR (300 MHz, CDCl3): δ H 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. C NMR (75 MHz, CDCl3): δ C 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 ( ν max cm H NMR (300 MHz, CDCl3): δ H 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. C NMR (75 MHz, CDCl3): δ C 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 ( ν max cm H NMR (300 MHz, CDCl3): δ H 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. C NMR (75 MHz, CDCl3): δ C 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. References Malakar, C.C.; Dell'Amico, L.; Zhang, W. Dual catalysis in organic synthesis: Current challenges and new trends. Eur. J. Org. Chem. , e202201114. [ Google Scholar ] [ CrossRef ] Fu, C.; He, L.; Chang, X.; Cheng, X.; Wang, Z.-F.; Zhang, Z.; Larionov, V.A.; Dong, X.-Q.; Wang, C.-J. Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides. Angew. Chem. Int. Ed. , e202315325. [ Google Scholar ] [ CrossRef ] [ PubMed ] Takahashi, I.; Kawakami, T.; Hirano, E.; Yokota, H.; Kitajima, H. Novel phthalimidine synthesis. Mannich condensation of o-phthalaldehyde with primary amines using 1, 2, 3-1H-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries. Synlett , 353–355. [ Google Scholar ] [ CrossRef ] Hardcastle, I.R.; Liu, J.; Valeur, E.; Watson, A.; Ahmed, S.U.; Blackburn, T.J.; Bennaceur, K.; Clegg, W.; Drummond, C.; Endicott, J.A.; et al. Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein− protein interaction: Structure− activity studies leading to improved potency. Med. Chem. , 1233–1243. [ Google Scholar ] [ CrossRef ] [ PubMed ] Csende, F.; Porkoláb, A. A review on antibacterial activity of some isoindole derivatives. Pharma Chem. , 43–50. [ Google Scholar ] Mertens, A.; Zilch, J.H.; Konig, B.; Schafer, W.; Poll, T.; Kampe, W.; Seidel, S.; Leser, U.; Leinert, H.J. Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2, 3-dihydrothiazolo [2, 3-a] isoindol-5 (9bH)-ones and related compounds with anti-HIV-1 activity. Med. Chem. , 2526–2535. [ Google Scholar ] [ CrossRef ] [ PubMed ] Papeo, G.; Orsini, P.; Avanzi, N.R.; Borghi, D.; Casale, E.; Ciomei, M.; Cirla, A.; Desperati, V.; Donati, D.; Felder, E.R.; et al. Discovery of stereospecific PARP-1 inhibitor isoindolinone NMS-P515. ACS Med. Chem. Lett. , 534–538. [ Google Scholar ] [ CrossRef ] Lee, S.; Shinji, C.; Ogura, K.; Shimizu, M.; Maeda, S.; Sato, M.; Yoshida, M.; Hashimoto, Y.; Miyachi, H. Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Bioorg. Med. Chem. Lett. , 4895–4900. [ Google Scholar ] [ CrossRef ] Pascale, R.; Carocci, A.; Catalano, A.; Lentini, G.; Spagnoletta, A.; Maddalena Cavalluzzi, M.; De Santis, F.; De Palma, A.; Scalera, V.; Franchini, C. New N-(phenoxydecyl) phthalimide derivatives displaying potent inhibition activity towards α-glucosidase. Bioorg. Med. Chem. , 5903–5914. [ Google Scholar ] [ CrossRef ] Lee, I.-K.; Kim, S.-E.; Yeom, J.-H.; Ki, D.W.; Lee, M.-S.; Song, J.-G.; Kim, Y.-S.; Seok, S.-J.; Yun, B.-S. Daldinan A, a novel isoindolinone antioxidant from the ascomycete Daldinia concentrica. J. Antibiot. , 95–97. [ Google Scholar ] [ CrossRef ] [ PubMed ] Buttinoni, A.; Ferrari, M.; Colombo, M.; Ceserani, R.J. Biological activity of indoprofen and its optical isomers. Pharm. Pharmacol. , 603–604. [ Google Scholar ] [ CrossRef ] [ PubMed ] Tejesvi, M.V.; Pirttilä, A.M. Endophytes of Forest Trees: Biology and Applications ; Forestry Sciences; Pirttilä, A.M., Frank, A.C., Eds.; Springer: Berlin, Germany, 2011; Volume 80, p. 302. [ Google Scholar ] Chen, Z.-L.; Zhu, D.-Y. The Alkaloids: Chemistry and Pharmacology ; Brossi, A., Ed.; Academic Press: New York, NY, USA, 1987; Volume 31, pp. 29–62. [ Google Scholar ] Macsari, I.; Besidski, Y.; Csjernyik, G.; Nilsson, L.I.; Sandberg, L.; Yngve, U.; Åhlin, K.; Bueters, T.; Eriksson, A.B.; Lund, P.-E.; et al. 3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel NaV1.7 with Efficacy in Rat Pain Models. Med. Chem. , 6866–6880. [ Google Scholar ] [ CrossRef ] [ PubMed ] Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H.F.J. Isoindol-1-one Analogues of 4-(2'-methoxyphenyl)-1-[2'-[ N -(2''-pyridyl)- p -iodobenzamido]ethyl]piperazine ( p -MPPI) as 5-HT1A Receptor Ligands. Med. Chem. , 157–166. [ Google Scholar ] [ CrossRef ] [ PubMed ] Ferland, J.-M.; Demerson, C.A.; Humber, L.G. Synthesis of derivatives of isoindole and of pyrazino[2,1- a ]isoindole. Can. J. Chem. , 361–365. [ Google Scholar ] [ CrossRef ] Kim, K.H.; Noh, H.J.; Choi, S.U.; Lee, K.R.J. Isohericenone, a new cytotoxic isoindolinone alkaloid from Hericium erinaceum. Antibiot. , 575–577. [ Google Scholar ] [ CrossRef ] [ PubMed ] Laboratori Baldacci, S.P.A. Japanese Patent 5,946,268, Chem. Abstr. , 54922. [ Google Scholar ] Achinami, K.; Ashizawa, N.; Kobayasui, F. Japanese Patent 03,133,955, Chem. Abstr. , 255977j. [ Google Scholar ] Lunn, M.R.; Root, D.E.; Martino, A.M.; Flaherty, S.P.; Kelley, B.P.; Coovert, D.D.; Burghes, A.H.; thi Man, N.; Morris, G.E.; Zhou, J.; et al. Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism. Chem. Biol. , 1489–1493. [ Google Scholar ] [ CrossRef ] [ PubMed ] Gao, W.; Chen, M.-W.; Ding, Q.; Peng, Y. Catalytic asymmetric synthesis of isoindolinones. Chem. Asian, J. , 1306–1322. [ Google Scholar ] [ CrossRef ] Youn, S.W.; Ko, T.Y.; Kim, Y.H.; Kim, Y.A. Pd(II)/Cu(II)-Catalyzed Regio- and Stereoselective Synthesis of (E)-3-Arylmethyleneisoindolin-1-ones Using Air as the Terminal Oxidant. Org Lett. , 7869–7874. [ Google Scholar ] [ CrossRef ] Patureau, F.W.; Besset, T.; Glorius, F. Rhodium-catalyzed oxidative olefination of C-H bonds in acetophenones and benzamides. Angew. Chem. Int. Ed. , 1064–1067. [ Google Scholar ] [ CrossRef ] [ PubMed ] Wang, H.-L.; Shang, M.; Sun, S.-Z.; Zhou, Z.-L.; Laforteza, B.N.; Yu, J.-Q. Cu (II)-catalyzed coupling of aromatic C–H bonds with malonates. Org. Lett. , 1228–1231. [ Google Scholar ] [ CrossRef ] Foster, R.W.; Tame, C.J.; Hailes, H.C.; Sheppard, T.D. Highly Regioselective Synthesis of Substituted Isoindolinones via Ruthenium-Catalyzed Alkyne Cyclotrimerizations. Adv. Synth. Catal. , 2353–2360. [ Google Scholar ] [ CrossRef ] [ PubMed ] Saini, H.K.; Nandwana, N.K.; Dhiman, S.; Rangan, K.; Kumar, A. Sequential Copper-Catalyzed Sonogashira Coupling, Hydroamination and Palladium-Catalyzed Intramolecular Direct Arylation: Synthesis of Azepino-Fused Isoindolinones. Eur. J. Org. Chem. , 7277–7282. [ Google Scholar ] [ CrossRef ] Guo, S.; Wang, F.; Sun, L.; Zhang, X.; Fan, X. Palladium-Catalyzed Oxidative Cyclocarbonylation of Isoquinolones with CO via C− H/N− H Bond Cleavage: Easy Access to Isoindolo [2, 1- b ] isoquinoline-5, 7-dione Derivatives. Adv. Synth. Catal. , 2537–3545. [ Google Scholar ] [ CrossRef ] Soto, Y.; Nishimata, T.; Kori, M.J. Asymmetric synthesis of isoindoline and isoquinoline derivatives using nickel (0)-catalyzed [2+ 2+ 2] cocyclization. Org. Chem. , 6133–6135. [ Google Scholar ] [ CrossRef ] Wójcicka, A.; Redzicka, A. An Overview of the Biological Activity of Pyrrolo[3,4-c]pyridine Derivatives. Pharmaceuticals , 354. [ Google Scholar ] [ CrossRef ] [ PubMed ] Abdallahi, S.M.; Ewies, E.F.; El-Shazly, M.; Ould Elemine, B.; Hadou, A.; Moncol, J.; Lawson, A.M.; Daïch, A.; Othman, M. Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry. Chem. Eur. J. , 15440–15449. [ Google Scholar ] [ CrossRef ] Chopade, P.R.; Louie, J. [2+2+2] Cycloaddition reactions catalyzed by transition metal complexes. Adv. Synth. Catal. , 2307–2327. [ Google Scholar ] [ CrossRef ] Ramana, C.V.; Dushing, M.P.; Mohapatra, S.; Mallik, R.; Gonnade, R.G. Target cum flexibility: An alkyne [2+2+2]-cyclotrimerization strategy for synthesis of trinem library. Tetrahedron Letters , 38–41. [ Google Scholar ] [ CrossRef ] Witulski, B.; Stengel, T.; Fernández-Hernández, J.M. Chemo- and regioselective crossed alkyne cyclotrimerisation of 1,6-diynes with terminal monoalkynes mediated by Grubbs' catalyst or Wilkinson's catalyst. Chem. Commun. , 1965–1966. [ Google Scholar ] [ CrossRef ] Kezuka, S.; Tanaka, S.; Ohe, T.; Nakaya, Y.; Takeuchi, R.J. Iridium complex-catalyzed [2+2+2] cycloaddition of α, ω-diynes with monoynes and monoenes. Org. Chem. , 543–552. [ Google Scholar ] [ CrossRef ] Saino, N.; Amemiya, F.; Tanabe, E.; Kase, K.; Okamoto, S.A. Highly Practical Instant Catalyst for Cyclotrimerization of Alkynes to Substituted Benzenes. Org. Lett. , 1439–1442. [ Google Scholar ] [ CrossRef ] [ PubMed ] Reppe, W.; Schweckendiek, W.J. * CYCLISIERENDE POLYMERISATION VON ACETYLEN. 3. BENZOL, BENZOLDERIVATE UND HYDROAROMATISCHE VERBINDUNGEN. Justus Liebigs Ann. Chem. , 104–116. [ Google Scholar ] Kotha, S.; Sreevani, G. Synthesis of Spiro Barbiturates and Meldrum's Acid Derivatives via a [2+2+2] Cyclotrimerization. Synthesis , 4883–4888. [ Google Scholar ] [ CrossRef ] YWatanabe, K.; Satoh, Y.; Kamei, M.; Furukawa, H.; Fuji, M.; Obora, Y. NbCl5/Zn/PCy3-System-Catalyzed Intramolecular [2+2+2] Cycloadditions of Diynes and Alkenes To Form Bicyclic Cyclohexadienes. Org. Lett. , 5398–5401. [ Google Scholar ] [ CrossRef ] Jónsson, H.F.; Evjen, S.; Fiksdahl, A. Gold (i)-catalyzed [2+ 2+ 2] cyclotrimerization of 1, 3-diarylpropargyl acetals. Org. Lett. , 2202–2205. [ Google Scholar ] [ CrossRef ] Zhao, W.-C.; Wang, X.; Feng, J.; Tian, P.; He, Z.-T. Palladium-catalyzed desymmetric [2+2+2] cycloaddition of 1,6-enyne and alkyne. Tetrahedron , 131862. [ Google Scholar ] [ CrossRef ] Liu, Y.; Yan, X.; Yang, N.; Xi, C. Highly regioselective cyclotrimerization of terminal alkynes catalyzed by Fe (II) complexes bearing 2-(benzimidazolyl)-6-(1-(arylimino) ethyl) pyridines. Catal. Commun. , 489–492. [ Google Scholar ] [ CrossRef ] Zhang, J.; Guo, M.; Chen, Y.; Zhang, S.; Wang, X.-N.; Chang, J. Synthesis of amino-substituted α-and δ-carbolines via metal-free [2+2+2] cycloaddition of functionalized alkyne-nitriles with ynamides. Org. Lett. , 1331–1336. [ Google Scholar ] [ CrossRef ] [ PubMed ] Wen, H.; Cao, W.; Liu, Y.; Wang, L.; Chen, P.; Tang, Y.J. Metal-Free [2+2+2] Cycloaddition of Ynamide–Nitriles with Ynamides: A Highly Regio-and Chemoselective Synthesis of δ-Carboline Derivatives. Org. Chem. , 13308–13324. [ Google Scholar ] [ CrossRef ] [ PubMed ] You, X.; Xie, X.; Wang, G.; Xiong, M.; Sun, R.; Chen, H.; Liu, Y. Nickel-Catalyzed [2+2+2] Cycloaddition of Alkyne-Nitriles with Alkynes Assisted by Lewis Acids: Efficient Synthesis of Fused Pyridines. Chem. Eur. J. , 16765–16769. [ Google Scholar ] [ CrossRef ] [ PubMed ] Islam, M.B.; Islam, M.I.; Nath, N.; Emran, T.B.; Rahman, M.R.; Sharma, R.; Martin, M.M. Recent advances in pyridine scaffold: Focus on chemistry, synthesis, and antibacterial activities. Biomed Res. Int. , 9967591. [ Google Scholar ] [ CrossRef ] Sugiyama, Y.; Amo, M.; Ibe, K.; Okamoto, S. Synthesis of 2-Aminopyridines via Cobalt-Catalyzed Cycloaddition of Diynes with N -Substituted and N -Unsubstituted Cyanamides. Adv. Synth. Catal. , 3897–3901. [ Google Scholar ] [ CrossRef ] Ipouck, M.; Merel, D.S.; Gaillard, S.; Whitby, R.J.; Witulski, B.; Renaud, J.L. Iron (II)-catalysed [2+2+2] cycloaddition for pyridine ring construction. Chem. Commun. , 593–595. [ Google Scholar ] Chen, Y.L.; Sharma, P.; Liu, R.S. Sulfonamide-directed gold-catalyzed [2+2+2]-cycloadditions of nitriles with two discrete ynamides to construct 2, 4-diaminopyridine cores. Chem. Commun. , 3187–3190. [ Google Scholar ] [ CrossRef ] [ PubMed ] Sheng, J.; Wang, Y.; Su, X.; He, R.; Chen, C. Copper-catalyzed [2+2+2] modular synthesis of multisubstituted pyridines: Alkenylation of nitriles with vinyliodonium salts. Angew. Chem. Int. Ed. , 4824–4828. [ Google Scholar ] [ CrossRef ] [ PubMed ] Kumar, P.; Prescher, S.; Louie, J. A Serendipitous Discovery of a Nickel-Catalyst for Cycloaddition of Diynes with Unactivated Nitriles. Angew. Chem. Int. Ed. , 10694–10698. [ Google Scholar ] [ CrossRef ] Medina, S.; Domínguez, G.; Pérez-Castells, J. Efficient Generation of Pyridines by Ruthenium Carbene Mediated [2+2+2] Cyclotrimerization. Org. Lett. , 4982–4985. [ Google Scholar ] [ CrossRef ] Komine, Y.; Tanaka, K. Rhodium-catalyzed complete regioselective intermolecular cross-cyclotrimerization of aryl ethynyl ethers and nitriles or isocyanates at room temperature. Org. Lett. , 1312–1315. [ Google Scholar ] [ CrossRef ] © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/
  Content Reference URL	None

• Publisher

  Publisher Name	International Journal of Molecular Sciences (#6058)
  Publisher URL	https://www.mdpi.com/
  Description	None
  Trust Flow Score	67
  Citation Flow Score	53

• Data Source

  Data Source Name	Quantexa News (#5)
  Data Source Type	news
  Data Source URL	https://app.aylien.com/dashboard
  Description	Welcome to Quantexa News API — the most powerful way to aggregate, filter, and integrate global news data into your apps and models.
  Weight	10