Covalently anchored carboxylic acid on uniform spherical silica nanoparticles with narrow slit like mesopores for the synthesis of pyrroloacridinones: CuI-catalyzed further C(sp³)–H oxyfunctionalization for C=O formation

Abstract

A new organic–inorganic hybrid catalyst (SMSNP-CA) was prepared by post synthesis grafting of –COOH functionalized organosilane on uniform spherical silica nanoparticles of 600 nm size with narrow slit like mesopores by using surface hydroxyl groups as anchor points. It was characterized by N₂ adsorption analysis, HRTEM, CHN analysis, ¹³C CP MAS, ²⁹Si MAS NMR and FTIR spectroscopy. The nanosilica particles possess unique morphological features. The broad applicability of SMSNP-CA was probed through a library synthesis of highly decorated pyrroloacridinone derivatives in the eco-friendly solvent ethanol. CuI-catalyzed further C (sp³)–H oxyfunctionalization leading to C=O formation was carried out using O₂ as an environmentally benign and ideal oxidant since water is the only byproduct in these reactions.

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1. Introduction

Heterogenization of catalysts by synthesizing inorganic–organic hybrid materials has been an interesting approach during the past years for the development of catalytic chemical technology. Ordered mesoporous silica (OMS) is often at the centre of catalytically active composite design because of a combination of interesting properties such as a high surface area with a robust yet flexible (e.g. in pore size and functionalisation) structure, and a wide range of compositional variations.¹ Therefore, design and synthesis of surface functionalized ordered mesoporous silica materials have attracted particular attention for their application in catalysis, adsorption, ion-exchange, sensing and so on.² Furthermore the diversity of organic groups that can be anchored onto mesoporous silicas and the potential applications of thus obtained materials, have stimulated widespread research interest for the synthesis of novel hybrid mesoporous materials with well-defined structure and morphology.³

Pyrroloacridines and pyrroloacridones are of immense interest because they have a variety of interesting biological activities. Significantly, members of this family are active in assays for antihelmintic, antitumor, antifungal, and DNA binding.⁴ Their abilities to intercalate into DNA are specifically important in inhibiting the growth of cancerous cells, making these compounds ideal for developing novel anticancer drugs.⁵ Three pentacyclic alkaloids, Plakinidines A, B, and C (Fig. 1), isolated from a Plakortis sponge possess the pyrrolo[2,3,4-kl]acridine parent ring system.^4b,6 Plakinidines A and B exhibited in vitro activity against Nippostrongylus brasiliensis.^6a Only a few reports are available for the synthesis of these molecules.^{4a,4h,6a,6c,7} Moreover, most of these methods associated with multistep syntheses,^4h,7 use of toxic solvents, homogeneous catalysts and difficulties in separating the product from reaction mixture. Thus, there is a need for the development of concise and efficient methods for the construction of this heterocyclic skeleton and its analogues.

Fig. 1 Biologically active pyrrolo[2,3,4-kl]acridine parent ring containing alkaloids.

Recently oxidations of aliphatic C–H bonds have attracted considerable research scrutiny for achieving various oxygen functionalities.⁸ There is no doubt that dehydrogenation of aliphatic C–H bonds by oxygen (O₂) as stoichiometric oxidant offers one of the most environmentally benign and ideal oxidation processes in organic synthesis.⁹ However, all reactions of O₂ in chemistry & biology require initial activation of [³Σ_g(Ö₂)] (S = 1) to singlet state [¹Δ_g(Ö₂)] (S = 0). This activation requires 23 kcal mol⁻¹ of energy which is not available biologically. Therefore the biological systems use metalloenzymes having transition metals in the active sites. Thus, for the activation of di-oxygen without much expenditure of energy, the use of transition metal catalysts becomes inevitable in chemistry also. Copper is a very important catalyst, especially in recent copper-catalyzed oxidative C–H bond activation, because of its low price and environmentally benign features among transition metals.^9,10 Although magnificent copper-catalyzed oxidations have been achieved,¹¹ there is still space for further modernization which mostly put emphasis on: (i) ligand and additive-free catalyst systems; (ii) mild conditions and high efficiency; (iii) use of air or O₂ as stoichiometric oxidant.^12,8f

Therefore report of synthetic protocol which implements oxidizing method requiring only a catalytic amount of metal reagent in combination with air or O₂ as stoichiometric oxidant is warranted.

2. Results and discussion

Considering the growing interest on pyrroloacridone compounds as well as difficulties encountered in attempts to prepare these compounds and in continuation of our prior investigation on heterogeneous catalysis for heterocycle synthesis¹³ we were further interested to design and synthesize novel silica supported organic–inorganic hybrid catalyst (SMSNP-CA) (3) of 600 nm size by post synthesis grafting of carboxylic acid (–COOH) functionalized organosilane on uniform spherical mesoporous silica nano particle by using surface hydroxyl groups as anchor point (Scheme 1). The nanosilica particle has narrow slit-like mesopores with diameters of 2.5 nm. The leaching of the active site can also be avoided as the organic moieties are covalently attached to the inorganic support.

Scheme 1 Preparation of surface –CO₂H functionalized SMSNP.

This is the first example of organocatalysis promoted by a –COOH functionalized spherical mesoporous silica nano particle for an unprecedented coupling of cyclic-1,3-diketone (4), isatin (5) and amine (6) (N-centered nucleophile) to create 4,5-dihydropyrrolo[2,3,4-kl]acridinones (7) in ecofriendly solvent ethanol (Scheme 2). Further oxidation of these 4,5-dihydropyrrolo[2,3,4-kl]acridinones were carried out with CuI catalyst using O₂ as stoichiometric oxidant to afford the compound 8 (Scheme 2). The CuI/O₂ system has been proven to be a powerful promoter for the aerobic oxidation of pyrroloacridones.

Scheme 2 Synthesis of pyrrolo[2,3,4-kl]acridones and their oxidation by CuI/O₂.

2.1. Characterization of the catalyst

2.1.1. ¹³C CP MAS NMR spectrum. The solid state ¹³C CP MAS NMR spectrum of mercaptopropyl silica (1) (Fig. 2, panel a) showed peaks at δ 27.2 corresponding to (b and c) and at δ 11.0 for (a). The prepared SMSNP supported –COOH catalyst (3) was characterized by comparing the solid state ¹³C CP MAS NMR spectrum of the prepared catalyst (3) (panel b) with that of 1 and the normal solution phase ¹³C NMR spectrum of bromo-acetic acid (2).^13c–g The normal solution phase carbon-13 NMR spectrum of bromo-acetic acid (2) showed peaks corresponding to δ 40.4 (d), 173.3 (e). When the catalyst was prepared, the peak at δ 40.4 corresponding to (d) of bromo-acetic acid vanished and appeared at δ 35.4 as (d′). This indicates that bond formation has taken place through carbon (d) and S atom. The remaining peaks for carbons showed slight deviations and appeared at δ 11.3 for (a′), 22.6 for (b′ and c′), and the –COOH carbon appeared at more or less in the same position at δ 173.0. This confirms the structure of the prepared surface –COOH functionalized silica catalyst (3).

Fig. 2 ¹³C CP MAS NMR spectra of (a) mercaptopropyl silica (1) and (b) SMSNP-CA (3).

2.1.2. CHN analysis. In addition to structural confirmation, quantitative determination of covalently anchored –COOH group onto the surface of catalyst was performed by elemental analysis.^13c–g The elemental analysis of mercaptopropyl silica (1) showed the carbon and hydrogen content to be 1.58% and 0.31% respectively. From this 0.44 mmol g⁻¹ loading of the mercaptopropyl group on the silica surface is obtained. In the silica supported –COOH catalyst (3) the carbon and hydrogen content was found to be 2.52%, and 0.38% respectively which corresponds to a loading of 0.42 mmol g⁻¹. Therefore 95.5% conversion of the mercapto group to the S-substituted carboxylic acid is achieved.

2.1.3. ²⁹Si MAS NMR spectra. The ²⁹Si MAS NMR spectral pattern of SMSNP-CA is shown in Fig. 3. Three up resonance peaks assigned to tetrahedral Q² (−94 ppm), Q³ (−102 ppm) and Q⁴ (−113 ppm) silica species respectively where Qⁿ = Si(OSi)_n(OH)_4−n, n = 2–4.¹⁴ The down field peaks at −51 ppm assigned to Si–OH of RSi(OSi)₂(OH) group (T²) and −62 ppm assigned to R–Si(OSi)₃ group (T³) provide direct evidence that the hybrid catalyst (3) consists of a highly condensed siloxane network with an organic group covalently bonded to the silica gel as a part of the silica wall structure.¹⁴

Fig. 3 ²⁹Si MAS NMR spectrum of silica supported carboxylic acid catalyst (SMSNP-CA).

2.1.4. HR TEM image of SMSNP-CA. Representative HR TEM images of material SMSNP-CA (3) are shown in Fig. 4. As seen from the TEM images the material is composed of uniform spherical particles of dimension ca. 600 nm throughout the specimen (Panel a); and on magnification of a particular spherical nanoparticle the pores (low density spots) of dimension ca. 2.6 nm are observable (panel b and c). Therefore, the mesoporous structure of the host silica material (panel d) remains intact after modification with organic functional group.

Fig. 4 HRTEM images of SMSNP-CA (panel a, b and c) and SMSNP (panel d).

2.1.5. Nitrogen adsorption analysis. The N₂ adsorption/desorption isotherms and corresponding pore size distribution of pure silica (Fig. 5, panel a and b) and silica supported carboxylic acid catalyst (3) (Fig. 5, panel c and d) are shown. Brunauer–Emmett–Telller (BET) surface area, average pore diameter and pore volume of SMSNP-CA (3) are estimated from the adsorption/desorption isotherms. The isotherm can be classified into typical type IV characteristic (panel c) of mesoporous materials together with a H3 type hysteresis loop, indicating substantial textural mesoporosity with narrow slit-like pores. The BET surface area for SMSNP-CA (3) is 349 m² gm⁻¹ and pore volume 0.22 cm³ gm⁻¹. Corresponding pore size distribution employing non-local density functional theory (NLDFT) model is shown in the panel d. The pore size distribution shows peaks at 2.6 nm for SMSNP-CA (3). We can find that the surface area of the SMSNP-CA (3) (349 m² g⁻¹) decreases when compared to pure silica (600 m² g⁻¹) and pore volume also decreases. It is expected for organic-functionalized porous silica due to blockage of narrow pore openings with the covalently anchored large organic groups and thereby the access to these pores is restricted. Therefore, the organic acid functionality is grafted compactly and securely inside the pores while not fully occupying the total available space, therefore still leaving room for N₂ adsorption and molecular transport.^13c

Fig. 5 (a) N₂ adsorption isotherm and (b) pore size distribution of SMSNP; (c) N₂ adsorption isotherm and (d) pore size distribution of SMSNP-CA (3).

2.1.6. IR analysis. The chemical structure of SMSNP-CA (3) was studied using FT-IR spectroscopy (Figure given in ESI†). Within 2800–3000 cm⁻¹ range, ν(C–H) vibrations of the –CH₂-groups are evidenced.^13e,15 The strong and broad band in the range 3500–3400 cm⁻¹ corresponds to the hydrogen bonded Si–OH groups and adsorbed water.^16,17 The thio-propyl groups which are attached to the silicon framework are identified by the methylene C–H stretching bands at roughly 2940–2875 cm⁻¹ and another broad at 1645 cm⁻¹ is also due to O–H vibration of adsorbed water. The weak signal between 1580–1450 is due to –CH₂-bending. The band at 1222 cm⁻¹ corresponds to the vibration of Si–C bond and the sharp features around 1092 cm⁻¹ indicated Si–O–Si stretching vibrations.^13e,16,17 The most convincing infra red data for the carboxylic acid moiety appeared at 1738 cm⁻¹ is due to C=O stretching. These results showed that the silica surface has been immobilized by covalent bonded organic molecules.

2.1.7. Ion exchange pH analysis. The amounts of acid groups in SMSNP-CA (3) catalyst were measured by means of pH measurement. Ion-exchange capacities of the carboxylic acid group were determined using aqueous solution of sodium chloride as exchange agents. In a typical experiment 1.0 g of the catalyst was added to 100 ml saturated solution of NaCl. The resulting suspension was allowed to equilibrate for 48 h and then pH of the solution dropped to 3.40 since ion exchange occurred between sodium ions and protons. From this ion-exchange pH analysis a loading of –COOH of 0.40 mmol g⁻¹ on silica surface was obtained.

2.2. Synthetic application of the catalyst

In order to synthesize the desired compounds selectively, it is extremely important to control the reactions by appropriate choice of the reaction conditions (particularly solvents and catalysts). For this reason, we have optimized the reaction condition (Table 1) and therefore, a series of experiments were conducted with a representative reaction of dimedone (1 mmol), isatin (1 mmol) and 3,4-dimethylaniline (1 mmol) with variation of reaction parameters, such as catalyst, reaction temperature, etc. Screening of the reaction conditions established that the nature of the catalyst and the temperature of the reaction medium had a significant effect on the yield of the pyrrolo[2,3,4-kl]acridinones. Good to excellent conversion was achieved with different strong homogeneous acids like HCl, H₂SO₄, HClO₄, TfOH, PTS, etc. However, they required repeated work-up, neutralization of strong acids and extensive chromatographic purification. Ultimately the isolated yields were not good (Table 1, entries 1–5). However mildly acidic AcOH afforded better yield among the homogeneous acids because of less extensive work up with weak acid AcOH (entry 6). Again since green chemistry not only prioritizes the product yields but also the use of reusable catalysts, we therefore designed and synthesized a new –COOH anchored silica catalyst according to Scheme 1. Thus the best yield, cleanest reaction, and most facile work-up were achieved employing 1.0 equiv. of each of dimedone (1 mmol), isatin (1 mmol), and 3,4-dimethylaniline (1 mmol) employing 20 mg of silica supported –COOH (4) as the right choice of catalyst and was demonstrated to be the key to obtain good to excellent yields of pyrrolo[2,3,4-kl]acridinones (entry 7). Several common solvents, viz. DCE, DCM, toluene, THF, EtOH, MeOH and water were tested (Table 1, entries 9–15). Though the yield of the reaction increased in high boiling and polar-protic solvent than low boiling, aprotic and non polar solvent, the reaction was better in EtOH than in water, possibly due to less homogeneity of the reaction mixture. Therefore ethanol (2 ml) came out as a best choice of solvent. Similarly, temperature appears to play a significant role because there was only 55% pyrroloacridinone formation after stirring the reaction mixture at 50–60 °C for 8 h (Table 1, entry 8) in ethanol instead of 95% yield at 70–80 °C (Table 1, entry 9).

Table 1 Optimization of reaction condition^a

Entry	Catalyst	Temp. (°C)	Solvents (4 ml)	Time (h)	Yield of 7c^b (%)
a Reaction conditions: dimedone (1 mmol), isatin (1 mmol), 3,4-dimethylaniline, different catalysts (0.1 mmol for homogeneous catalysts and 20 mg for heterogeneous catalysts), different solvents, different time, different temperature.b Isolated yields.
1	HCl	70–80	EtOH	4.0	74
2	H2SO4	70–80	EtOH	4.0	70
3	HClO4	70–80	EtOH	4.0	69
4	TfOH	70–80	EtOH	4.5	79
5	PTS	70–80	EtOH	5.0	83
6	AcOH	70–80	EtOH	5.5	85
7	SMSNP-CA	70–80	EtOH	6.0	95
8	SMSNP-CA	50–60	EtOH	10.0	55
9	SMSNP-CA	25–30	DCM	12.0	12
10	SMSNP-CA	80–85	DCE	6	65
11	SMSNP-CA	100–110	Toluene	6	80
12	SMSNP-CA	50–55	Acetone	10	15
13	SMSNP-CA	60–65	THF	10	55
14	SMSNP-CA	60–65	MeOH	8	60
15	SMSNP-CA	100	H2O	6	87

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With the optimized conditions in hand, to delineate this approach, the scope and generality of this protocol was next examined by employing various amines and isatins. An assembly of 14 compounds was synthesized using this protocol (Scheme 3). For precursors 6 bearing either electron-donating or electron-withdrawing substituents on the aromatic ring, the reactions all proceeded very smoothly to provide the corresponding pyrrolo[2,3,4-kl]acridinones. Acid-sensitive methoxy-substituted aryl amines as well as aliphatic amine reacted very efficiently with no side reactions. Therefore, the present silica-carboxylic acid catalyzed protocol has a general applicability accommodating a variety of substitution patterns. Aromatic amine having substituents in ortho, meta and para positions reacted well to give the corresponding product in excellent yields. The synthetic route is facile, convergent, and allows easy placement of a variety of substituents around the periphery of the heterocyclic ring system. Worth mentioning the product structure was unambiguously proved by X-ray single crystal analysis of 7b (Fig. 6) and 7n (ORTEP diagram given in ESI†).

Scheme 3 Structures of the synthesized 4,5-dihydropyrrolo[2,3,4-kl]acridinones.

Fig. 6 X-ray single crystal structure of 7b.

2.3. Mechanism

A mechanism portraying the probable sequence of events for the synthesis of 4,5-dihydropyrrolo[2,3,4-kl]acridinones is shown in Scheme 4. It is thought that, the reaction proceeds via a cascade of condensation reactions. Condensation of amine with cyclic-1,3-diketone formed enaminoketone (9) which in turn condensed with isatin to give intermediate 10. Translactamization of 10 affords intermediate 11 which undergoes cyclocondensation to afford the desired product (7).^4a Compound 9 was also formed by the reaction of dimedone with amine in presence of SMSNP-CA catalyst in ethanol under reflux. This compound on reaction with isatin produced the target molecule (7). Thus the intermediacy of enaminoketone (9) in this reaction is established.

Scheme 4 Probable mechanistic pathway to explain the catalytic formation of 4,5-dihydropyrrolo[2,3,4-kl]acridinones.

Being inspired by the above results, it was thought worthwhile to replace dimedone with cycloxexane-1,3-dione or 5-phenyl-cyclohexane-1,3-dione (12) in order to get some newly substituted pyrroloacridinones and to show the versatility of this protocol. With these reagents under the above optimized conditions, instead of the desired 4,5-dihydropyrrolo[2,3,4-kl]acridinones the corresponding fully oxidized products, i.e., the pyrrolo[2,3,4-kl]acridinone derivatives 13 were produced (Scheme 5). The reason is that when there is no substituent or only one substituent (phenyl) on the C5 position of cyclohexane-1,3-dione or 5-phenyl-cyclohexane-1,3-dione, the 4,5-dihydropyrrolo[2,3,4-kl]acridinone derivatives would be oxidized by oxygen in the air to give pyrrolo[2,3,4-kl]acridinones. The driving forces being the stability of the final product through extensive conjugation since all the three 6-membered fused rings gain aromaticity after oxidation. However since dimedone has two methyl substituents at C5 position, therefore, for the 4,5-dihydropyrrolo[2,3,4-kl]acridinone compounds, the aromatization of the 3^rd ring is not possible. Therefore no such aerial oxidation occurs in case of the compounds obtained from dimedone. The structure of the pyrrolo[2,3,4-kl]acridinone (13) was confirmed indisputably by X-ray single crystal structure of 13a (Fig. 7).

Scheme 5 Structures of the synthesized fully oxidized pyrrolo[2,3,4-kl]acridinones.

Fig. 7 X-ray single crystal structure of 13a.

After synthesizing both 4,5-dihydropyrrolo[2,3,4-kl]acridinone (7) and pyrrolo[2,3,4-kl]acridinone (13), we next attempted to further oxidize the 4,5-dihydropyrrolo[2,3,4-kl]acridinones in a mild condition using 10 mol% CuI as catalyst and O₂ as stoichiometric and green oxidant (Scheme 6). To discuss the scope and limitation of this reported protocol we envisioned that a wide range of R² groups (aliphatic, aromatic and hetero-aromatic) were well tolerated and incorporated providing a functional handle for further manipulation. Finally we confirmed the structure of the products indisputably by X-ray single crystal analysis of two distinct compounds 8f (Fig. 8) and 8p (ORTEP diagram given in ESI†).

Scheme 6 Structure of the 4,5-dihydropyrrolo[2,3,4-kl]acridinones after oxidation with CuI/O₂.

Fig. 8 X-ray single crystal structure of 8f.

The CuI catalyst was heterogeneous in the present reaction condition since organic solvent (ethanol) was used as the reaction medium. Therefore CuI could be recovered from the reaction mixture and reused at least up to 5 cycles without significant loss of catalytic activity. Therefore, this aforementioned oxidizing methodology at least satisfies the core principles of green chemistry i.e., the use of reusable catalyst, environmentally benevolent solvent and also the product yields. The protocol was proficient enough to synthesize an assembly of 19 compounds without facing any difficulty. The nature of the substituents on the aromatic ring of the amine did not assert any obvious effect on the product yield. The excellent conversions show that the O₂ in combination with CuI catalyst has very good activity for oxidation of 4,5-dihydropyrrolo[2,3,4-kl]acridinones.

We have also carried out the reaction of dimedone, isatin and amine in presence of both silica-carboxylic acid catalyst and CuI in oxygen atmosphere according to Scheme 7. In this case the compound 8 was solely formed in slightly better yield without formation of compound 7. Therefore when compound 8 is the desired molecule then Scheme 7 can also be followed.

Scheme 7 Reaction of dimedone, isatin and amine in presence of both SMSNP-CA and CuI catalyst in O₂ atmosphere.

2.4. Mechanism of oxidation by molecular oxygen

Di-oxygen (Ö₂) remains in spin free triple state, ³Σ_g(Ö₂), S = 1. However organic molecules are in spin paired singlet state, S = 0. Since the reaction between spin paired and spin free-state is forbidden, all reactions of O₂ in chemistry & biology require initial activation (23 kcal mol⁻¹) of O₂ from triplet [³Σ_g(Ö₂)] (S = 1) to singlet state [¹Δ_g(Ö₂)] (S = 0). Some transition metals like Cu (standard reduction potential for the Cu²⁺/Cu⁺ = 0.15 Volt), Fe etc. can easily swing between two possible oxidation states and thus they can donate one electron in one of the 2π_g anti-bonding molecular orbitals of oxygen molecule breaking their degeneracy (Fig. 9). The filled orbital becomes lower in energy than the half filled orbital and consequently when electron reverts back to the transition metal ion it is released from the other 2π_g (higher energy orbital) and a consequent conversion of di-oxygen from triplet state (S = 1) to singlet state (S = 0). Thus the oxidation of organic molecules by molecular O₂ becomes possible in presence of transition metal catalysts. A probable mechanism for the oxidation of 4,5-dihydropyrrolo[2,3,4-kl]acridinones by singlet molecular oxygen is depicted below in Scheme 8.

Fig. 9 Transformation of ³Σ_g(Ö₂) to ¹Δ_g(Ö₂).

Scheme 8 Probable mechanism for the oxidation of 4,5-dihydropyrrolo[2,3,4-kl]acridinones with CuI/O₂.

2.5. Stability of SMSNP-CA (3) catalyst and recycling

In the presence of silica-carboxylic acid catalyst (preheated at 80 °C for 4 hours) the reaction of dimedone, isatin and 3,4-dimethyl amine (Table 2) occurred with 92% yield of 7c without formation of any other side-products. The same reaction in the presence of silica-carboxylic acid after having it exposed to ambient atmosphere for 20 days produced similar observation. Obviously, there was no deteriorating effect of aerial oxygen or moisture towards the activity of the catalyst provided evidence for covalent anchoring.

Table 2 Recycling of SMSNP-CA (3) catalyst^a

Cycles^b	Time (h)	Yield^c (%)	C content (%)	H content (%)	[H^+] (mmol g^−1) of residual solid
a Reaction conditions: dimedone (1 mmol), isatin (1 mmol), 3,4-dimethylaniline (1 mmol), 20 mg SMSNP-CA (3) catalyst, refluxing in ethanol.b Reaction was carried with recovered catalyst.c Isolated yield.
1	6.0	95	2.52	0.38	0.42
2	6.2	93	2.52	0.38	0.42
3	6.4	91	2.46	0.37	0.41
4	6.5	90	2.46	0.37	0.41
5	7.0	89	2.34	0.35	0.39

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The CHN (carbon, hydrogen, nitrogen) analysis of the recovered catalyst after successive experiments were performed and furnished in Table 2. These results showed that that the organic carboxylic acid was not leached in the reaction medium. It implied that –COOH moiety was tightly anchored with the silica surface through a covalent linkage with the oxygen atoms of silica silanol. Therefore, this catalyst has potential of efficient recycling.

The recycled catalyst could be used at least six times with good efficiency without any further treatment. A slight decrease in yields and slightly extended reaction time with recovered catalyst were due to loss of some catalyst during filtration.

4. Conclusions

The present method utilized SMSNP-CA as a chemically robust, recyclable, organic–inorganic hybrid Bronsted acid catalyst for the synthesis of pyrroloacridinone derivatives in ecofriendly solvent ethanol. The aim of this protocol is to highlight the synergistic effects of the combined use of multi-component reactions in an environmentally benevolent solvent and the application of solid acid catalyst supported on silica with inherent properties like reusability and robustness for the development of new eco-compatible strategy for heterocyclic synthesis. Further CuI-catalyzed C(sp³)–H oxyfunctionalization leading to C=O formation was carried out using O₂ as environmentally benign and ideal oxidant since water is the only byproduct in such reactions. The developed ligand- and additive-free CuI-catalyzed oxidation unlocks a facile, atom-, step- and redox-economical and eco-friendly C=O formation. Given the simplicity of the reaction and the pharmaceutical importance of its products, it is hoped that this methodology will be embraced by the synthetic organic community at large.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: For experimental procedure, spectroscopic data. CCDC 972994, 972995, 972996, 972997, 972998. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra01287a

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