Combination of aza-Friedel Crafts MCR with Other MCRs Under Heterogeneous Conditions

Abstract

Multicomponent reactions (MCRs) enable the efficient assembly of complex small molecules via multiple bond-forming events in a single step. However, individual MCRs typically yield products with similar core structures, limiting access to larger, more intricate scaffolds. Strategic selection of reactants allows the combination of distinct MCRs, thus facilitating the synthesis of advanced molecular architectures with potential biological significance. Using our previously reported method for performing the aza-Friedel Crafts multicomponent reaction under green heterogeneous conditions, we have incorporated some of the obtained products into diverse multicomponent reactions to generate, in an unprecedent approach, eight novel products, some of which were also characterized by two-dimensional NMR techniques. The biological properties of such products are under investigation.

1. Introduction

Multicomponent reactions (MCRs) are able to generate libraries of relatively small molecules by the simultaneous combination of three or more reactants in one-pot. In such atom economic processes, intermediate purification is not necessary, hence resulting in less solvent waste generation [1,2,3,4,5,6]. Simultaneously, the combination of reactants in the same pot allows for the concomitant formation of new bonds to result in complex final products. Albeit this, specific MCRs are limited because they can generate different versions of the same product molecular scaffold. In order to increase diversity in the synthesized scaffolds, post MCR modification can be performed by carrying out reactions on the final product such as Diels-Alder cyclisation reactions, cross-coupling reactions, click chemistry etc. [7,8].

An alternative way of increasing end-product complexity and to widen the molecular space is by combining multicomponent reactions together. The latter, defined union of MCRs, was originally put forward by Ugi and Dömling, who performed a one-pot Asinger-Ugi seven-component reaction [9]. MCR combinations are brought about either because the starting material has orthogonal groups, which can react separately via different MCRs or because during the first MCR, a reactive group is created that can then react further [7,10]. For instance, the Orru group in 2009 unified three separate multicomponent reactions by combining the products of two separate 3-component reactions with two other reactants to ultimately result in an 8-component reaction [11]. Another successful attempt was reported by Al-Tel, who combined the Groebke-Bienayme-Blackburn reaction with the Ugi or Passerini reaction to generate complex products with up to 10 points of diversity, ergo there are 10 positions on the main polycyclic skeleton that can be varied [12]. Other literature examples include the seven-component Ugi-Mumm/Ugi-Smiles reaction (Scheme 1) [13]. Meanwhile, recent examples of post-MCR modification include the KA²-Pauson-Khand reaction (Scheme 2), the post-Ugi dearomatization/ipso-cyclization/Michael reaction developed by Van der Eycken et al. and the Ugi/intramolecular aza-Michael reaction studied by Halimehjani et al. [14,15,16].

Our research group has recently reported novel multicomponent combinations in the synthesis of tetrahydronaphthalenes via the use of orthogonal reactants, namely p-terephthaldehyde that could react with two equivalents of malononitrile and cyclohexanone on one end and with 1 or 2-naphthol and another equivalent of malononitrile on the other carbonyl group [17]. In addition, in another study, we have also reported the use of an aza-Friedel-Crafts (AFC) MCR product as a reactant for the 4-arylsubstituted dihydropyridine (DHP) MCR [18]. Hereunder, further investigations in the union of different MCRs and novel examples are presented, expanding the use of the AFC products as reactants in other MCRs.

2. Results and Discussion

2.1. Synthesis of MCR Products Using an aza-Friedel Crafts Product with a Free Aldehyde Group

In order to carry out post MCR modification, a previously established method by our research group for the synthesis of aza-Friedel Crafts (AFC) products was adopted to synthesize the 3-substituted indole (4a) from indole (1), N-methylaniline (2a) and p-terephthaldehyde (3a) under heterogeneous, quasi-neat conditions using the Amberlyst^® 15-supported silicotungstic acid, WSi-A15, an example of a heteropoly acid [19]. Owing to the catalyst’s satisfactory selectivity, one of the aldehyde groups of the aldehyde (3a) remained unreacted to furnish the final product (4a) (Scheme 3).

Thereafter, the latter product (4a) was inserted into two separate pathways (Scheme 4), yielding, respectively, the tetrahydronaphthalene (8) and tetrahydroquinoline (9) by MCR combinations using the heterogeneous catalyst DABCO supported on Amberlyst^® 15 (DABCO-A15). The latter had already been deemed an easily recoverable, recyclable and inexpensive catalyst in a previous study by our research group involving the separate combinations of simple aldehydes (3), malononitrile (5) and c-hexanone (6) (to yield tetrahydronaphthalenes) or aldehydes (3), malononitrile (5), c-hexanone (6) and ammonium acetate (7) [17]. Henceforth, in this post-MCR modification study, the commercially available aldehydes (3) were replaced by 4a.

Considering the ample possibilities of reactivity that an aldehyde group has, the indole (4a) was then used in two other separate pathways, one of which involved the generation of the novel (2H)-pyridone (13) via the use of dimedone (10), Meldrum’s acid (11) and ammonium acetate (12) (Scheme 5). In an earlier study by our research group, it had been discovered that piperazine-infused agar gel could be used to synthesize 4-aryl-substituted dihydropyridines (DHPs) from aldehydes, aryl amines, malononitrile and dimedone [18]. The physical nature of the catalyst (fragment-like) allowed it to be recovered easily and reused in subsequent recyclability trials. Considering its advantages and the fact that it was biologically derived, the same catalyst was then employed to synthesize compound (13), whose preparation involved the replacement of malononitrile with Meldrum’s acid, in comparison to the trials in [18]. This was done systematically as a series of pre-trials found out that the products derived from malononitrile were much more difficult to obtain in pure form than those from Meldrum’s acid. The procedure followed was similar to that adopted in [18], which entailed refluxing 10 and 12 in ethanol for 8 h before adding the catalyst, 4a and 11, to collect the product (13) at a yield of 31%.

An alternative union of MCRs was based on the incorporation of 4a into the A³ coupling reaction (Scheme 6). Previous research conducted in our labs had already delved into the synthesis of simple A³ products from aldehydes, alkynes and amines under neat conditions using copper (I) iodide supported on the tertiary-amine-containing Amberlyst^® A21 beads (CuI-A21) as a heterogeneous catalyst [20]. Despite this, in a couple of optimization steps, it was established that CuI-A21 resulted in a significant number of side products and could not allow the pure isolation of the required product. Subsequently, copper (I) iodide supported on aminopropyl-terminated microcrystalline cellulose (CuI-CellNH₂) was identified to be a better alternative to furnish the complex product (16) in a higher yield and purity than when CuI-A21 was employed. A possible reason for this is that CuI-CellNH₂ had a higher surface area than CuI-A21, in addition to having a lower copper (I) loading (0.21 mmol/g for CuI-CellNH₂ as opposed to 1.3 mmol/g for CuI-A21 as determined by XRF spectroscopy). Consequently, this probably resulted in less random copper (I) aggregates on the surface of the catalyst which potentially contributed to less side reactions such as the Glaser coupling reaction [21]. Further to the above, it is important to note that the preparation of CuI-CellNH₂ required the modification of a method available in the literature [22] by omitting the incorporation of magnetite in the final catalyst so as to allow it to be recovered by simple filtration.

2.2. Synthesis of MCR Products Using an aza-Friedel Crafts Product with a Terminal Amino Group

As mentioned earlier, WSi-A15 had been determined to be ideal as a heterogeneous catalyst in the synthesis of aza-Friedel Crafts products including those derived from primary aryl amines. Interestingly, the latter underwent substitution at their para position rather than reacting from their nitrogen moiety. This meant that the final 3-substituted indoles (4) had a free amino group [19]. Such a discovery was then taken advantage of in the below study by incorporating the aza-Friedel Crafts products with terminal amino groups (4b–d) in other MCRs such as in the synthesis of N-aryl-substituted DHPs using the catalyst Pip-Agar similar to the reaction described earlier (Scheme 5) [18]. The amine-terminated indoles which were synthesized are summarized in Scheme 7.

The pure isolated indoles (4b–d) were then incorporated into DHP moieties by adapting the method reported in [18], ergo refluxing the amine-terminated indole (4) with dimedone (10) in ethanol for 8–10 h before adding the catalyst (Pip-Agar), the aldehyde (3) or isatin (18) and either one of malononitrile (5) or Meldrum’s acid (10) and refluxing for 8–10 further hours as schematized in Scheme 8, Scheme 9, and Scheme 10. In all of these reactions, catalyst recovery was relatively easy because of its physical nature.

2.3. Advanced Product Characterization

Considering the complexity of the final products, apart from the usual IR, ¹H-NMR, ¹³C-NMR spectroscopies and MS spectrometry, 2-dimensional NMR experiments were run on some of the products to confirm their structure beyond reasonable doubt. These experiments include ¹H-¹H-COSY, ¹H-¹³C-HSQC and ¹H-¹³C-HMBC. Herein below is an in-depth characterization of the product denoted as 20a, that was studied in more detail [18].

¹H-NMR spectrum of 20a

In the ¹H-NMR spectrum of the product (20a), the most downfield peak is a triplet at 8.16 (J = 2.1 Hz), which can be attributed to the electron-poor hydrogen H2 (ortho to the nitro group). This is undergoing long-range coupling (common J constant of 2.1 Hz) with H3 at 8.11 ppm (ddt, J = 8.3, 2.1, 0.9 Hz). H42 of the indole moiety is deshielded because the nitrogen’s electrons are being contributed to ensure ring aromaticity, and it appears as a broad peak at 8.08 ppm. At 7.67 ppm, there is a doublet (J = 7.7 Hz) caused by H6 which are rendered electron poor by -M of the nitro group. The apparent triplet at 7.48 ppm (J = 7.9 Hz) is likely to be caused by H5 as will be confirmed below by ¹H-¹H-COSY NMR. At 7.40 ppm, there is a doublet (J = 8.3 Hz) caused most likely by H34,35, whereas at 7.35 ppm (J = 8.0 Hz), there is a doublet possibly caused by the least shielded hydrogens of the aniline moiety H27,28 (see ¹H-¹H-COSY analysis below). At 7.24–7.14, there are overlapping peaks likely caused by H46, H32,33 and H43 as the below ¹H-¹H-COSY analysis shows. A broad peak at 7.04–7.05 would be caused by H25,26 while the dddd at 7.03 ppm (J = 8.0, 6.9, 3.5, 1.0 Hz) should be caused by H44.

It is important to note that the main basis for making specific assignments lies in the results obtained by ¹H-¹³C-HMBC experiments (see below). At 4.9 ppm, there is a characteristic d (J = 7.5 Hz) which is caused by H10 whereas H30 appears as a singlet at 5.71 ppm. At 3.17 and 2.99 ppm, there are two dds which are undergoing geminal coupling (J = 16.3 Hz). One of them is coupling with H10 while the other is not. This can be explained as follows: in rigid rings, the dihedral angle between vicinal hydrogens determines the coupling constant of vicinal hydrogens. Hydrogens which are at 90^o to each other may have coupling constants of 0–1 Hz (hence not detected) while those which are at 0 or 180⁰ have the largest coupling constants. In this case, it can be stated that H10 is at 0 or 180⁰ with the hydrogen giving a peak at 3.17 ppm because it has a common coupling constant of 7.5 Hz. Meanwhile, the H18s appear as one singlet at 2.34 ppm. H19s also appear in two coupled doublets at 2.22 and 2.12 ppm with a common J constant of 17.6 Hz (geminal coupling). Ultimately, H22 and H23 appear as two doublets because the compound is present in the form of a pair of diastereomers.

¹H-¹H-COSY spectrum of 20a

In the ¹H-¹H-COSY spectrum, the following correlations can be extracted, which confirm further the above assignments. Note that since a more concentrated sample (25 mg/800 μL) was used for the ¹H-¹H-COSY and for the parent ¹H-NMR spectrum on which it was based, the peak caused by H42 shifted to a slightly higher chemical shift compared to that of the earlier ¹H-NMR spectrum (lower concentration–5 mg/800 μL).

(1) H2 does not give any cross peaks

(2) H42 gives a weak cross peak with H40 (indole moiety)

(3) H3 gives a cross peak with the peak labelled as H5 (ortho coupling in the 3-nitrophenyl moiety)

(4) H6 gives a strong cross peak with the peak labelled as H5 (ortho coupling) and a weak cross peak with H2 (meta coupling)

(5) H5 gives a separate strong cross peak with H6 and H3 (both ortho)

(6) H34,35 give a cross peak with the multiplet in which there are supposedly the peaks of H32,33

(7) H45 (although not clear) gives a cross peak with the multiplet in which there is H46 (ortho relationship)

(8) H46 and H43 (within a multiplet) are giving cross peak with H44 and with H45 (ortho relationships). Simultaneously, H44 is giving a cross peak with H43 and H46 but not with H45 (no ortho relationship)

¹³C-NMR spectrum of 20a

The most downfield peak in ¹³C-NMR spectrum is undeniably caused by C17 at 195.67 ppm and the other carbonyl-carbon C13 at 169.14 ppm. At 154.48 ppm, there is a peak that should be the result of the electron-deficient (by -I and by -M) C14 (bonded to the nitrogen and beta to the carbonyl). C1 is also neighboring a nitrogen (of the nitro group) but is not deshielded by a -M effect and hence appears at 148.58 ppm. All of these peaks are absent in the DEPT135 spectrum.

As will be explained below in the ¹H-¹³C-HMBC spectral analysis, the peaks at 144.49, 143.44 and 142.14 ppm are caused by C29, C4 and C31, respectively; which atoms are relatively similar because they pertain to quaternary carbons of phenyl rings. Further upfield, C41 and C24 appear at 136.75 and 134.83 ppm; which carbons are both directly bonded to an sp²-hybridized nitrogen atom, hence their similar chemical shift value. All carbon atoms mentioned thus far do not give rise to any peaks in the DEPT135 spectrum.

Using the ¹H-¹³C-HSQC spectrum, it could be understood that C6 appears at 133.71 ppm while the large peak at 131.60 is caused by C34,35. Close by, the peak at 130.77 ppm is caused by the similar carbon atoms C32,33. At 130.58–130.41 ppm and at 129.18 and 128.06 ppm, there are broad peaks representing C25, 26, 27, 28, as could be understood from the correlation to the wide peaks of the proton component of the ¹H-¹³C-HSQC spectrum. Such band broadening is caused by the presence of rotamers that are interchanging at a reasonable rate at the experimental temperature. Such results cause C27/28 and C25/26 to no longer be magnetically and chemically equivalent.

At 130.06 ppm, as per ¹H-¹³C-HSQC spectrum, there is a peak caused by C5 while at 126.60 ppm (absent in DEPT135) there is a peak which is due to C39, as the ¹H-¹³C-HMBC spectrum will attest. C40 then appears at 124.16 ppm (such peak has been noted in all indole-containing products and is confirmed as per ¹H-¹³C-HMBC) while C3 is present at 122.40/122.29 ppm (using ¹H-¹³C-HSQC spectrum for cross peak identification). C2 is located close by at 121.26 ppm (this correlates to H2 in ¹H-¹³C-HSQC). C36 is relatively shielded and appears at 120.51 ppm because of the heavy atom effect induced by the attached bromine atom.

At 119.60/119.59 ppm and 119.55 ppm, there are two peaks caused by C43,44 as understood from the ¹H-¹³C-HSQC. C38, as per DEPT135 (it is absent in it) appears at 118.65/118.61 ppm while C45, being close to the electron rich pyrrole ring is significantly shielded and appears at 111.33 ppm (cross peak with H45 in ¹H-¹³C-HSQC). C12, whose identity was confirmed by ¹H-¹³C HMBC appears at 116.19 ppm.

As can be noted in the characterization data, some of the peaks are denoted as pairs (with a forward slash in between) and this is likely to be a result of the fact that two diastereomers are present in the sample (see the example in Figure 1). In fact, in a series of separate experiments, it was found out that the peak-pair separation occurred after the addition of traces of pure L-tartaric acid to a sample of one of the products.

Moving upfield, C11 should be the peak at 50.02 ppm (negative peak in DEPT135) as per ¹H-¹³C-HSQC spectrum (this spectral region is not shown). C30 appears at 47.94 ppm while C33 and C30 appear at 41.80 and 38.75 ppm, respectively (both give negative peak in DEPT135). By elimination, C10 appears at 33.25 ppm, C20 is at 33.12 ppm (absent in DEPT135) and C22/23 appear at 28.45 and 28.17 ppm.

It needs to be noted that in all other ¹³C-NMR spectra of these complex MCR products, (20a,b,c) most of the peaks corresponding to the indolyl and 4-bromophenyl moiety matched perfectly (in terms of chemical shift positions). Peaks pertaining to the central N-phenyl ring which appears to have restricted rotatory movement were also similarly broad and with very similar chemical shift values.

¹H-¹³C-HMBC spectrum of 20a

In the ¹H-¹³C-HMBC spectrum, the following correlations could be observed, which helped in making the above assignments. As can be noted, most of the correlations due to hydrogen/carbon atoms in aromatic rings are three-bond long, which correlations are caused by 5–8 Hz couplings. Those pertaining to two or four-bond correlations (in aromatic systems) have lower J constants, and they do not give strong cross peaks due to the specific parameters which were set in the NMR spectrophotometer pulse program.

(1) H42 is correlated strongly to C38 and C39 (three-bond correlations) and C41 (weakly, two-bond correlation), confirming that these atoms pertain to the same ring.

(2) Meanwhile, H2 is correlated to C1 and C6 (three-bond correlation) whereas H3 is also correlated to C1, C2 and C6 (all three-bond correlations). In so doing, the assignment of the nitro-bonded carbon C1 is verified. H6 is correlated strongly to C2 and C3 but weakly to C5 (two-bond correlations get partially suppressed along with single bond ones). In fact, H5 also gives a weak cross peak with C6 but stronger cross peaks with C4 and C1 (meta to 5).

(3) H34,35 give a strong cross peak with carbon atom labelled C36 (three-bond correlation) and with C34,35 itself due to coupling of H34 with C35 or H35 with C34. A similar effect is observed for H27,28 which gives a cross peak with C27,28 and with C24 (three-bond correlation once again).

(4) As noted in other spectra (see Supplementary Information), the peak assignments of the hydrogen/carbon atoms of the indolyl moiety follow the same correlation pattern observed in their respective ¹H-¹³C-HMBC spectra. The strongest peaks were caused by three-bond correlations. For instance, H45 is correlated to C44 and C39.

(5) The multiplet caused by the overlapping peaks of H32,33 and H43,46 gives relevant cross peaks as follows: it gives a cross peak with C36 (due to H32,33) and with C43 due to coupling with H46 (three-bond).

(6) The multiplet composed of H25,26 and 44 gives cross peaks with C45 (three-bond correlation with H44) and with C39 (three bond correlation with H44). It needs to be stressed that the above is the most reasonable peak assignment; otherwise, strong cross peaks would have been caused by 4-bond and 2-bond correlations (unlikely).

(7) H40 is coupled to C38 (a rare instance of two-bond correlations due to the pyrrole ring nature), C39 and C41, hence confirming the identity of the quaternary carbons even further.

(8) Ultimately, H30 is coupled to C38, C40, C39, C32,33, C31 and C29, confirming how it is occupying a location connecting various moieties to each other.

3. Methodology

3.1. Instrumentation

IR spectra were recorded on a Shimadzu IRAffinity-1 FTIR spectrometer (Shimadzu Corporation, Kyoto, Japan) calibrated against 1602 cm⁻¹ polystyrene absorbance spectra. After carrying out a background scan using KBr only, the samples were analyzed as KBr pellets. The pellets were prepared by grinding about 5–10 mg of each separate sample with 100 mg of oven-dried potassium bromide with a pestle and mortar, before subjecting the samples to pressure in a screwable die. The final spectra were given as % transmittance against wavenumber (cm⁻¹) and could be analyzed and processed by the software IRsolution^® ver. 1.10 before being exported as txt files and then opened in MS Office Excel^®.

The NMR spectra were recorded on a Bruker Avance III HD^® NMR spectrometer (Bruker, Billerica, MA, USA), equipped with an Ascend 500 11.75 Tesla superconducting magnet and operating at 500.13 MHz for 1H and 125.76 MHz for 13C, and a multinuclear 5 mm PABBO probe. Samples were dissolved in deuterated chloroform, DMSO, or acetone (with TMS). For ¹H-NMR, the product (3–5 mg) was dissolved in 0.8 mL of deuterated solvent, whilst for ¹³C-NMR, DEPT135, ¹H-¹³C-HSQC, ¹H-¹H-COSY, and ¹H-¹³C-HMBC spectra, the mass of product (dissolved in the same volume) was increased to 25–30 mg. The NMR spectra were analyzed and processed using Topspin^® Software, ver. 3.2, and MestreNova^®, v12.0.2.

Mass spectra were performed using a Waters Acquity^® TQD system (Waters, Milford, MA, USA), equipped with a tandem quadrupole mass spectrometer, and analyzed directly with a probe. The spectra were obtained in relative abundance compared to m/z and were generated by the software MassLynx^®, ver. 4.2.

The melting points of products were determined using a Griffin^® melting point determination apparatus (Gallenkamp Labs, Cambridge, UK) fitted with a mercury thermometer. Three separate readings were taken, and the mean average was then calculated to achieve better accuracy.

The XRF (X-ray fluorescence) analyses of the copper-containing catalysts were performed using a Bruker S2 Ranger^® XRF instrument (Bruker, Billerica, MA, USA). Catalysts were loaded in a polystyrene container and covered with a thin transparent film before placing in a rack in the XRF instrument.

3.2. Reaction Methods

3.2.1. Synthesis of aza-Friedel Crafts Products (4a–d)

The AFC products which were subsequently used as reactants in other MCRs were generally prepared, following the procedure reported in [19], by stirring the aldehyde (3) (2.5 mmol) and the amine (2) (5 mmol) in the presence of 30% w/w WSi/A15 catalyst (0.3 g) under neat conditions at room temperature/in an ice-bath in a nitrogen-dried 25 mL three-neck round bottomed flask. After 10 min, indole (1) (2.5 mmol, 0.293 g) was carefully added via a plastic funnel. The reaction was left to stir at the same conditions and TLCs were carried out at 30 min or 1 h intervals. During the course of the reaction, drops of ethyl acetate were added in cases when the stirring bar could no longer rotate. Upon completion, work up with cold dry acetone was conducted before filtering and concentrating the filtrate. The latter was purified using column chromatography with 8:2 → 7:3 mixtures of hexane/ethyl acetate serving as eluents. However, for the combination of p-terephthaldehyde (3a) with N-methylaniline (2a) and indole (1), the reaction was left to take place for 24 h at room temperature and during the course of the reaction, drops of ethanol had to be added to ensure stirring since ethyl acetate was not able to solubilize the reaction mixture (it caused clumping of the reaction mixture).

3.2.2. Synthesis of Product (8)

In the synthesis of 8, the procedure reported in [17] was followed. However, the final product could not be purified simply by recrystallization. Rather, it was purified by column chromatography using neutral silica (60–200 mesh) as the stationary phase and 6:4/5:5 mixtures of hexane/ethyl acetate as the eluent.

3.2.3. Synthesis of Product (9)

In the synthesis of 9, the procedure reported in [17] was followed except for the fact that the amount of catalyst used was increased to 10 mol% instead of 5 mol%. Furthermore, the final product was collected after performing column chromatography using neutral silica (60–200 mesh) as the stationary phase and 6:4/5:5 mixtures of hexane/ethyl acetate as the eluent.

3.2.4. Synthesis of Product (13)

In the synthesis of 13, an adaptation of the method reported in [18] was performed. To a nitrogen-flushed dry 25-mL-two-necked flask, dimedone (10) (1.25 mmol, 0.175 g) and ammonium acetate (7) (1.875 mmol) were added and stirred in ethanol (2 mL) at 85 °C for 8 h. Subsequently, the catalyst (25 mol% of Pip-Agar, 1.1 mmol/g, 0.28 g), Meldrum’s acid (11) (1.625 mmol, 0.234 g) and the AFC-derived aldehyde (4a) (1.25 mmol) were added in that order and the mixture was left to stir at 85 °C. The reaction was monitored using TLC every 1/2-h intervals and was stopped until complete consumption of the enaminone intermediate or until no further change was observed. Subsequently, the reaction mixture was dissolved in hot acetone, filtered using a G4 sintered funnel and then concentrated under vacuum by rotary evaporation. Purification was achieved by column chromatography using neutral silica gel (60–200 mesh) as the stationary phase and 6:4/5:5/4:6 hexane/ethyl acetate solvent mixtures.

3.2.5. Synthesis of Product (16)

For the synthesis of 16, piperidine (14) (3 mmol, 0.255 g), the AFC-derived aldehyde (4a) (2.5 mmol) and phenylacetylene (15) (3.75 mmol, 0.383 g) were stirred for 5 min at room temperature before adding the catalyst (0.2 g CuI-CellNH₂) and then heating to 80 °C. The reaction was monitored using TLC until the alkyne was consumed completely and the product spot was intense. Thereafter, the reaction mixture was dissolved in ethyl acetate, filtered and concentrated under vacuum to collect oil which was purified by column chromatography using 9:1 → 8:2 hexane/ethyl acetate as eluant.

3.2.6. Synthesis of Products (17), (19), (20)

In the synthesis of 17, 19, 20, the AFC-derived aniline (4b-d) (1.25 mmol) was stirred at 85 °C along with dimedone (10) (1.25 mmol, 0.175 g) in neat conditions (4–5 drops of ethanol added to aid stirring) for 7 h before adding the catalyst (25 mol% Pip-Agar, 1.1 mmol/g, 0.28 g), malononitrile (5) (1.625 mmol, 0.107 g) Meldrum’s acid (11) (1.625 mmol, 0.234 g) and the aldehyde (3) or isatin (18) (1.25 mmol, 0.184 g). The products of such reactions usually require purification by column chromatography (6:4 → 4:6 hexane/ethyl acetate) followed by recrystallization from ethanol/diethyl ether.

3.2.7. Catalyst Synthesis

DABCO-A15 was synthesized as described in [17] while Pip-Agar was synthesized by following the method already reported in [18].

CuI-CellNH₂ was synthesized by adapting the method in [22]. Cellulose (2.0 g) was mixed with aminopropyltriethoxysilane (APTES) (6.0 g) at room temperature in DMF (10 mL) for 24 h before filtering and then washing with DMF (5 mL), followed by ethanol (3 × 10 mL). The catalyst was then dried at 80 °C in an air-oven for 8 h. To the dried catalyst, copper (I) iodide (1.3 mmol) was added and the mixture stirred in methanol (30 mL) for 24 h at room temperature before filtering, washing with methanol (3 × 10 mL) and then leaving to dry in a vacuum desiccator for 48 h.

3.3. Selected Product Characterization

4-(4-((1H-indol-3-yl)(4-(methylamino)phenyl)methyl)phenyl)-2-amino-4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-tricarbonitrile (8). [NOVEL] White solid m.p. 174–176 °C. IR (KBr) (ν, cm⁻¹): 3418, 3345, 3256, 3219, 3044, 2980, 2932, 2903, 2862, 2832, 2810, 2208, 1732, 1647, 1636, 1614, 1518, 1506, 1456, 1373, 1269, 1250, 1182, 1152, 1096, 1043, 806, 746. ¹H-NMR (500 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.38 (dt, J = 8.2, 0.9 Hz, 4H), 7.26–7.12 (m, 3H), 7.12–7.05 (m, 2H), 7.01 (ddt, J = 8.1, 7.0, 1.1 Hz, 1H), 6.63–6.55 (m, 3H), 6.05 (dt, J = 5.2, 2.6 Hz, 1H), 5.62 (s, 1H), 4.86 (d, J = 9.7 Hz, 2H), 3.68 (s, 1H), 3.11–3.02 (m, 1H), 2.85 (d, J = 2.8 Hz, 4H), 2.35–2.25 (m, 1H), 2.21–2.11 (m, 1H), 1.82 (d, J = 13.2 Hz, 1H), 1.75–1.65 (m, 1H), 1.55–1.45 (m, 1H), 0.97 (q, J = 12.5 Hz, 1H). ¹³C-NMR (126 MHz, DMSO-d₆) δ 148.72, 146.49, 144.13, 137.14, 132.56, 132.49, 131.38, 129.50, 129.40, 129.25, 128.89, 127.06, 126.99, 124.29, 121.46, 120.75, 119.64, 119.07, 118.68, 116.67, 113.09, 112.86, 112.04, 111.92, 82.00, 50.87, 47.62, 43.40, 34.50, 30.32, 27.50, 25.36, 21.51. MS(ES+) m/z = 535.47 [M + H], 484.35, 428.38, 389.43, 283.16, 196.21, 78.80.

4-(4-((1H-indol-3-yl)(4-(methylamino)phenyl)methyl)phenyl-2-amino-5,6,7,8-tetrahydroquinoline-3-carbonitrile (9). [NOVEL] White solid m.p. 214–216 °C. IR (KBr) (ν, cm⁻¹): 3414, 3368, 3292, 3136, 3057, 2936, 2862, 2812, 2208, 1636, 1614, 1555, 1516, 1506, 1456, 1339, 1317, 1254, 1169, 1109, 1096, 1020, 1011, 791, 743. ¹H-NMR (500 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.41–7.31 (m, 3H), 7.29 (d, J = 1.0 Hz, 0H), 7.28 (d, J = 1.4 Hz, 0H), 7.22–7.14 (m, 3H), 7.10 (d, J = 7.8 Hz, 2H), 7.02 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.65–6.53 (m, 3H), 5.65 (s, 1H), 5.03 (s, 2H), 2.87–2.77 (m, 5H), 2.37 (t, J = 6.3 Hz, 2H), 1.90–1.80 (m, 2H), 1.72–1.64 (m, 2H). ¹³C-NMR (126 MHz, Chloroform-d) δ 161.30, 157.12, 154.70, 147.81, 145.59, 136.76, 133.77, 132.28, 129.82, 129.19, 128.00, 127.06, 124.10, 122.02, 121.05, 120.31, 120.05, 119.34, 116.78, 112.44, 111.04, 90.22, 47.81, 33.32, 30.88, 26.55, 22.90, 22.59. MS(ES+) m/z = 484.41 [M + H], 367.24, 313.31, 257.34, 237.26.

7,7-Dimethyl-4-4-{(1H-indol-3-yl)[4-(methylamino)phenyl]methyl}phenyl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione (13). [NOVEL] White solid m.p. 170–172 °C. IR (KBr) (ν, cm⁻¹): 3393, 3350, 3283, 3221, 3049, 2955, 2868, 2810, 1697, 1616, 1522, 1489, 1456, 1373, 1339, 1288, 1217, 1146, 1097, 1043, 1011, 976, 957, 810, 743, 600. ¹H-NMR (500 MHz, Chloroform-d) δ 7.89 (d, J = 14.4 Hz, 1H), 7.76 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23–7.18 (m, 1H), 7.17–7.03 (m, 5H), 7.02–6.91 (m, 3H), 6.56–6.43 (m, 3H), 5.48 (s, 1H), 4.31 (dd, J = 6.9, 1.7 Hz, 1H), 2.86 (ddd, J = 16.7, 7.9, 1.6 Hz, 1H), 2.77–2.79 (m, 4H), 2.40 (dd, J = 17.0, 1.3 Hz, 1H), 2.34–2.19 (m, 3H), 1.11 (s, 3H), 1.03 (s, 3H). ¹³C-NMR (126 MHz, Chloroform-d) δ 195.69, 172.07, 150.40, 147.62, 143.4, 139.45, 136.70, 132.83, 129.70, 129.26, 127.06, 126.43, 124.07, 121.86, 120.40, 120.04, 119.16, 114.79, 112.39, 111.03, 50.69, 47.54, 41.06, 38.06, 33.47, 32.83, 30.90, 28.91, 27.92. ES(+) m/z = 504.43 [M + H], 418.24, 369.54, 284.05, 282.01, 252.95, 194.11.

N-Methyl-4-[(1H-indol-3-yl)(4-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)phenyl)methyl]aniline (16). [NOVEL] Transparent thick oil. IR (KBr) (ν, cm⁻¹): 3414, 3055, 3021, 2976, 2932, 2851, 2804, 2749, 1616, 1516, 1506, 1489, 1456, 1418, 1317, 1248, 1153, 1092, 1045, 802, 758, 743, 692. ¹H-NMR (500 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.62–7.50 (m, 4H), 7.36–7.34 (m, 3H), 7.34–7.33 (m, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.29 (J = 6.8 ppm, 2H), 7.20 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.4 (t, J = 7.0 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 6.59 (d, J = 8.5 Hz, 2H), 5.63 (s, 1H), 4.83 (s, 1H), 2.85 (s, 3H), 2.68–2.61 ppm (m, 4H), 1.62–1.54 (m, 4H), 1.52–1.42 (m, 2H).¹³C-NMR (126 MHz, Chloroform-d) δ 147.70, 144.14, 136.80, 136.06, 132.99, 131.86, 129.78, 128.70, 128.46, 128.33, 128.06, 127.18, 124.08, 123.45, 121.91, 120.52, 120.11, 119.21, 112.44, 111.10, 87.71, 86.54, 62.30, 50.79, 47.78, 30.94, 26.24, 24.54. ES(+) m/z = 510.55 [M + H], 425.43, 369.34, 388.29.

2-Amino-1-[4-[(4-bromophenyl)(1H-indol-3-yl)methyl]phenyl]-7,7-dimethyl-5-oxo-4-(3-methylphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (17). [NOVEL] Yellow solid m.p. 170–174 °C. IR (KBr) (ν, cm⁻¹): 3377, 3355, 3219, 3055, 2957, 2868, 2181, 1636, 1562, 1485, 1456,1408, 1371, 1258, 1146, 1103, 1042, 1009, 837, 743, 702, 615. ¹H-NMR (500 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.45–7.39 (m, 3H), 7.28–7.22 (m, 4H), 7.21–7.19 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 7.09 (dt, J = 7.8, 1.8 Hz, 1H), 7.03 (ddt, J = 8.0, 6.9, 1.0 Hz, 1H), 6.68 (d, J = 1.2 Hz, 1H), 5.75 (s, 1H), 4.74 (s, 1H), 4.10 (d, J = 13.9 Hz, 2H), 2.35 (s, 3H), 2.25–2.14 (m, 2H), 2.06 (dd, J = 17.8, 7.5 Hz, 1H), 1.84 (d, J = 17.4, 1H), 0.99 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H). ¹³C-NMR (126 MHz, DMSO-d₆) δ 195.71, 150.52/150.50, 149.75/149.74, 147.01, 144.73, 138.28, 136.84, 133.89/133.86, 131.62, 131.16, 129.68, 129.42, 129.00, 128.99, 128.55, 127.66, 126.70/126.69, 125.96, 124.07/124.06, 122.38, 120.86, 120.47, 119.54/119.53, 119.45/119.42, 118.76/118.71, 112.84, 111.46, 62.61/62.59, 49.96/49.60, 47.71/47.70, 35.76, 32.40, 29.45/29.44, 27.03, 21.57. ES(+) m/z = 669.51 [M + H], 551.75, 481.40–479.43 (isotopes), 217.17, 307.17.

1′-(4-((1H-indol-3-yl)(phenyl)methyl)phenyl)-2′-amino-7′,7′-dimethyl-2,5′-dioxo-5′,6′,7′,8′-tetrahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (19). [NOVEL] White solid m.p. 254–256 °C. IR (KBr) (ν, cm⁻¹): 3460, 3318, 3215, 3053, 2955, 2868, 2185, 1717, 1647, 1616, 1562, 1560, 1468, 1456, 1362, 1339, 1312, 1260, 1219, 1150, 1053, 1016, 918, 880, 748, 704, 611. ¹H-NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H), 10.20 (s, 1H), 7.61–7.30 (m, 9H), 7.29–7.23 (m, 1H), 7.19–7.01 (m, 4H), 6.94–6.80 (m, 3H), 6.79–6.73 (m, 1H), 5.83 (s, 1H), 5.42 (s, 2H), 2.10 (dd, J = 16.5, 7.9 Hz, 2H), 1.93 (d, J = 15.9 Hz, 1H), 1.81 (d, J = 17.2 Hz, 1H), 0.89 (s, 3H), 0.82 (s, 3H). ¹³C-NMR (126 MHz, DMSO-d₆) δ 194.34, 179.95, 152.57, 151.63, 146.40, 144.07, 141.95, 137.23, 137.18, 134.34, 129.25, 128.86, 128.13, 126.88, 126.85, 124.97, 124.90, 123.59, 121.85, 121.63, 119.47, 119.45, 118.83, 118.03, 112.08, 110.89, 110.86, 109.31, 61.26, 49.75, 49.00, 48.24, 32.56, 28.70, 27.13. ES(+) m/z = 616.72 [M + H], 537.74, 499.37, 457.24, 397.42, 308.28, 237.35, 91.07.

1-[4-[(4-bromophenyl)(1H-indol-3-yl)methyl]phenyl]-4-(2,4-dichlorophenyl)-7,7-dimethyl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione (20b). [NOVEL] White solid m.p. 174–176 °C. IR (KBr) (ν, cm⁻¹): 3402, 3055, 2957, 2868, 1705, 1651, 1616, 1506, 1485, 1472, 1456, 1369, 1312, 1263, 1221, 1194, 1138, 1103, 1047, 1011, 824, 804, 766, 741. 1H-NMR (500 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.51–7.40 (m, 3H), 7.38 (d, J = 8.1 Hz, 1H), 7.35–7.28 (m, 2H), 7.22–7.16 (m, 2H), 7.16–7.07 (m, 4H), 7.04–6.93 (m, 3H), 6.59 (s, 1H), 5.69 (s, 1H), 4.78 (d, J = 7.7 Hz, 1H), 3.04 (dd, J = 16.2, 7.9 Hz, 1H), 2.97 (dd, J = 16.2, 2.0 Hz, 1H), 2.30 (s, 2H), 2.21 (dd, J = 17.7, 1.7 Hz, 1H), 2.10 (dt, J = 17.7, 1.8 Hz, 1H), 1.17–0.93 (m, 6H). ¹³C-NMR (126 MHz, DMSO-d₆) δ 195.32, 169.14/169.13, 155.92, 144.64/144.61, 143.80/143.70, 137.58/137.55, 137.20/137.18, 135.29, 134.04, 132.87, 131.74, 131.33/131.31, 130.01, 129.89, 129.74, 129.23, 128.85, 128.32, 126.73/126.70, 124.70/124.67, 121.75, 119.90/119.88, 119.41/119.38, 118.97/118.94, 117.56/117.46, 117.56/117.46, 114.74/114.69, 112.14, 49.71, 47.47/47.43, 41.58, 37.51, 33.24, 31.00, 29.45/29.43, 27.30. ES(+) m/z = 697.46–701.41 ([M + H], isotopes), 583.43–587.43, 377.21–380.27, 339.21–341.19, 286.21, 260.16, 158.07.

1-(4-((4-bromophenyl)(1H-indol-3-yl)methyl)phenyl)-4-(3-cyanophenyl)-7,7-dimethyl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione (20c). [NOVEL] White solid m.p. 178–180 °C. IR (KBr) (ν, cm⁻¹): 3447, 3341, 3053, 2963, 2870, 2232, 1692, 1647, 1624, 1506, 1379, 1337, 1300, 1267, 1221, 1202, 1142, 1009, 876, 851, 795, 743, 669. ¹H-NMR (500 MHz, DMSO-d₆) δ 10.99 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 57.8 Hz, 3H), 7.28–7.16 (m, 3H), 7.14–6.99 (m, 3H), 6.87 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 5.79 (s, 1H), 4.38 (d, J = 7.6 Hz, 1H), 3.32–3.23 (m, 3H), 2.74 (dd, J = 16.1, 1.8 Hz, 1H), 2.34 (d, J = 16.0 Hz, 1H), 2.24 (d, J = 17.4 Hz, 1H), 2.18 (d, J = 16.0 Hz, 1H), 1.99 (d, J = 17.4 Hz, 1H), 0.99 (s, 3H), 0.94 (s, 3H). ¹³C-NMR (126 MHz, DMSO-d₆) δ 195.56, 169.54, 154.93, 148.07, 144.58, 143.81, 137.18, 135.34, 133.18, 131.73, 131.30, 129.86 (d, J = 29.1 Hz), 128.67, 128.33, 126.73, 124.69, 121.73, 119.87, 119.37, 119.23, 118.96, 117.44, 115.49, 112.13, 110.11, 56.51, 49.78, 47.42, 41.51, 38.85, 33.60, 33.25, 29.12, 27.51, 19.04. ES(+) m/z = 656.52 [M + H], 551.75, 371.31, 342.28, 296.27, 254.19.

4. Conclusions

The scope of the aza-Fridel Crafts reaction was expanded in a union of MCR approach by incorporating its products into further diverse multicomponent reactions, also performed under green heterogeneous conditions. The resulting unions of MCRs were able to generate eight novel compounds. The authors believe that this could serve as a breakthrough in the application of MCRs under heterogeneous catalysis to synthesize densely-functionalized end products. Apart from the normally performed IR, MS and ¹H, ¹³C-NMR characterization experiments, some of the products were also analyzed by 2-dimensional NMR such as ¹H-¹H-COSY, ¹H-¹³C-HSQC and ¹H-¹³C-HMBC to confirm their structure completely.