Multicomponent Synthesis of 4-Aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines Using L-Proline as a Catalyst—Does It Really Proceed?

Looking for effective synthetic methods for 1H-pyrazolo[3,4-b]quinolines preparation, we came across a procedure where, in a three-component reaction catalysed by L-proline, 4-aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines are formed. These compounds can be easily oxidised to a fully aromatic system, which gives hope for a synthetic method that could replace, e.g., Friedländer condensation, often used for this purpose, even though severely limited by the availability of suitable substrates. However, after careful repetition of the procedures described in the publication, it turned out that the compounds described therein do not form at all. The actual compounds turned out to be 4,4-(phenyl-methylene)-bis-(3-methyl-1-phenylpyrazol-5-oles). Therefore, 4-Aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines were prepared by another method and used as standards to compare the products formed in the original procedure.


Introduction
In 1901, Willstätter synthesised tropinone, a precursor to the tropane alkaloid atropine.This compound was obtained by a 21-step synthesis from cyclopentanone with an overall yield of 0.75% [1].The opposite of this synthesis is shown in the work published in 1917 by Robinson, who obtained the mentioned tropinone in a one-step, three-component reaction with a yield of 17% [2].This synthesis is one of the pioneering multi-component chemical reactions.Earlier reactions of this type include Strecker's synthesis of amino acids from aldehydes, NH 3 and HCN published in 1854, or the slightly later Mannich reaction [3,4].The subject of multi-component syntheses has been discussed in numerous reviews and is also presented in many monographs [5][6][7][8].The 1H-pyrazolo [3,4-b]quinoline, which is the focus of the research in the current publication, can also be obtained using multi-component reactions.Only some of these will be mentioned, because an exhaustive discussion of this topic was made in our recent review [9].The first reaction of this kind was described in 1998 by Hormanza et al. (Scheme 1) [10].
They used 5-aminopyrazole 1, aromatic aldehyde 2, and dimedone 3 for this purpose.During boiling in ethanol, the formation of the corresponding 1H-pyrazolo [3,4-b]quinoline 4 was observed, in which both the carbocyclic and the middle rings were not aromatic.Another important reaction leading to 4-aryl-1H-pyrazolo [3,4-b]quinolines 7 is the procedure described by Tomasik et al. [11].They reacted substituted anilines 5, aromatic aldehydes 2 and 2,5-diphenyl-2,4-dihydro-3H-pyrazol-5-one (6a, R 1,3 = Ph) or 2-phenyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one (6b, R 1 = Ph, R 2 = Me) (Scheme 2).In this case a fully aromatic product 7 is obtained and benzal derivative 8 was also isolated.The reaction yields of 7 ranged from 2-33%.At present, this is the only example of this type of multi-component reaction where a 1H-pyrazolo[3,4-b]quinoline 7 system is formed.In other cases, compounds with an aromatic pyridine ring and a saturated carbocyclic system are obtained.An example of such a reaction is shown in Scheme 3, where 5amino-3-methyl-1-phenylpyrazole 9, 2-hydroxy-1,4-naphthalenedione 10 and aromatic aldehyde 2 were used.The reaction was carried out in the presence of an ionic liquid and PEG1000 and led to the formation of derivatives 11 [12,13].In this case a fully aromatic product 7 is obtained and benzal derivative 8 was also isolated.The reaction yields of 7 ranged from 2-33%.At present, this is the only example of this type of multi-component reaction where a 1H-pyrazolo[3,4-b]quinoline 7 system is formed.In other cases, compounds with an aromatic pyridine ring and a saturated carbocyclic system are obtained.An example of such a reaction is shown in Scheme 3, where 5-amino-3-methyl-1-phenylpyrazole 9, 2-hydroxy-1,4-naphthalenedione 10 and aromatic aldehyde 2 were used.The reaction was carried out in the presence of an ionic liquid and PEG 1000 and led to the formation of derivatives 11 [12,13].In this case a fully aromatic product 7 is obtained and benzal derivative 8 was also isolated.The reaction yields of 7 ranged from 2-33%.At present, this is the only example of this type of multi-component reaction where a 1H-pyrazolo[3,4-b]quinoline 7 system is formed.In other cases, compounds with an aromatic pyridine ring and a saturated carbocyclic system are obtained.An example of such a reaction is shown in Scheme 3, where 5amino-3-methyl-1-phenylpyrazole 9, 2-hydroxy-1,4-naphthalenedione 10 and aromatic aldehyde 2 were used.The reaction was carried out in the presence of an ionic liquid and PEG1000 and led to the formation of derivatives 11 [12,13].In recent years, many multi-component reactions using L-proline as a catalyst have been mentioned for the synthesis of heterocyclic systems [14][15][16][17].In 2017, Hegde and Shetty used aniline 5a, aromatic aldehyde 2/12, 2-phenyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one 6b and L-proline as a catalyst in a reaction leading to pyrazolo [3,4-b]quinolines 13 (Scheme 4) [18].

Results and Discussion
The reactions published in the paper by Hedge and Shetty seemed very interesting because the obtained compounds 13 can be oxidised to give fully aromatic systems 7 (Scheme 5).An example of such a reaction is the oxidation of pyrazolines to pyrazoles, which can be performed, e.g., with oxygen in acetic acid, MnO2, DDQ or other oxidants [19][20][21].Moreover, it can be expected that the overall yield could be greater than 33%, which is a serious shortcoming of the previous reaction described by Tomasik et   They obtained a series of eight 4-aryl-4,9-dihydro-3-methyl-1-phenyl-1H-pyrazolo [3,4b]quinolines 13a-f, h, i with an aromatic carbocyclic ring and two with a heterocyclic 13g,j in the 4-position, which has not been found in the reactions reported so far.The final yields were relatively high, reaching 78-89%.

Results and Discussion
The reactions published in the paper by Hedge and Shetty seemed very interesting because the obtained compounds 13 can be oxidised to give fully aromatic systems 7 (Scheme 5).

Results and Discussion
The reactions published in the paper by Hedge and Shetty seemed very interesting because the obtained compounds 13 can be oxidised to give fully aromatic systems 7 (Scheme 5).An example of such a reaction is the oxidation of pyrazolines to pyrazoles, which can be performed, e.g., with oxygen in acetic acid, MnO2, DDQ or other oxidants [19][20][21].Moreover, it can be expected that the overall yield could be greater than 33%, which is a serious shortcoming of the previous reaction described by Tomasik  An example of such a reaction is the oxidation of pyrazolines to pyrazoles, which can be performed, e.g., with oxygen in acetic acid, MnO 2 , DDQ or other oxidants [19][20][21].Moreover, it can be expected that the overall yield could be greater than 33%, which is a serious shortcoming of the previous reaction described by Tomasik et al.For this reason, the reactions presented in Scheme 4 were very interesting and we decided to use their potential when it comes to the synthesis of fully aromatic 1H-pyrazolo [3,4-b]quinolines [22,23].At first, we decided to test some of the procedures described by Hegde and Shetty and p-tolualdehyde 2a, p-chlorobenzaldehyde 2b and 2,4-dichlorobenzaldehyde 2e were selected for the experiments.We chose these three compounds, among others, because the authors included the spectra data of resulted 4,9-dihydro-1H-pyrazolo [3,4-b]quinolines 13a,b,e in Supplementary Materials in the form of graphics.In the original publication, the reaction was carried out on a scale of 1 mmol, which we increased to 5 mmol to facilitate the isolation of the product, which in most cases precipitated after a few minutes of heating.The yields resulted in three products that were really high, and standard 1 H NMR and 13 C NMR analyses were performed.Unfortunately, it turned out that the obtained compounds were not the expected 4-aryl-4,9-dihydro-1H-pyrazolo [3,4- When we used 2-furylaldehyde, we were unable to isolate any products from the post-reaction mixture due to its tarnation, even though we used freshly purified aldehyde.However 14j was detected with TLC in the reaction mixture using an authentic sample prepared by another method.In addition, in the case of p-tolu-aldehyde, Schiff's base 15 (Ar = C 6 H 4 Me) was isolated from the post-reaction mixture.The compound was identified by comparison with a separately synthesised Schiff base, prepared from aniline and p-tolu-aldehyde and with 1 H NMR spectrum [24].Appropriate Schiff bases were also detected with TLC in the post-reaction mixtures in the other two cases.Extending the reaction time from 5-6 h up to 24 h did not cause any changes as far as the final product was concerned.What is particularly surprising is that, when we removed L-proline from the reaction medium, we also obtained only compounds 14 and traces of Schiff bases 15.So there is a clear conclusion that L-proline has no part in this reaction at all in spite of the fact that, in the original publication, the authors proposed a potential mechanism for this reaction, with an emphasis on the role of this amino acid.Our results are in part supported by the work of Hennig and colleagues who studied the reactions of azomethines with CH-acids.Among the entire series of the latter, they tested the reaction of pyrazolone 6b, aniline 5a and aromatic aldehydes 2. Depending on the reaction conditions, 14, 16 and 15 were formed and the potential formation of 13 was not mentioned at all [25].
It is worth considering on what basis the authors assigned the structure of 13 to compounds 14.In our opinion, there was an incorrect interpretation of the 1 H NMR spectra of To finally remove any doubts about the product obtained by Hegde and Shetty, we performed additional syntheses by heating the pyrazolone 6b and a few aldehydes, namely 2a, 2i and 2j, in a 2:1 molar ratio.The obtained compounds 14 are known and described in the literature, hence there are no doubts about their structure.When we compared the R f values of these products with compounds obtained in the three-component reaction with L-proline and without L-proline using TLC chromatography, it turned out that they were identical.
Our results are in part supported by the work of Hennig and colleagues who studied the reactions of azomethines with CH-acids.Among the entire series of the latter, they tested the reaction of pyrazolone 6b, aniline 5a and aromatic aldehydes 2. Depending on the reaction conditions, 14, 16 and 15 were formed and the potential formation of 13 was not mentioned at all [25].
It is worth considering on what basis the authors assigned the structure of 13 to compounds 14.In our opinion, there was an incorrect interpretation of the 1 H NMR spectra of 13a-j (Scheme 4).If we analyse these spectra included in the publication they have a common element, namely peaks in the range of 14.00-13.00ppm and occasionally at 5 ppm.The authors attribute the first of these to the proton bounded to nitrogen in position 9 of 13 and the second to the methine proton at carbon C-4 of the parent skeleton.The collected data are included in the first and second column (Table 1).
Table 1. 1   In the table we have included the value of 1 H NMR shifts of the protons associated with oxygen and the methine protons of 14 (the third and fourth column), which correspond to the alleged 13 obtained by Hedge and Shetty, collected on the basis of some literature resources [27,29,30].An example of such a publication is the work of Mohammadi and Ghorbani-Choghamarani, who synthesised 14 (R = 4-Me, 4-Cl) using magnetic nanocomposites modified with sulfone groups [26].If we take into account the 1 H NMR shift values of protons attached to nitrogen in position 9 for p-tolu-benzaldehyde and p-chlorobenzaldehyde derivatives 13 in the Hedge and Shetty paper, they are 14.00 and 13.90 ppm, respectively [18].The corresponding shift values of the methine protons at the C-4 position are 4.89 ppm and 4.96 ppm.When we compare these values with the data published in the Mohammadi and Ghorani-Choghamarani paper, we notice that they are almost identical, except that the values at the 13.94 ppm and 13.89 ppm correspond to protons attached to oxygen atoms of 14 and not nitrogen N-9 atoms in 13.In the 1 H NMR spectra included in the work by Hegde and Shetty, one can also notice very weak broad peaks in the region of 12-13 ppm, which are identical to the peaks at 12.44 and 12.53 ppm coming from hydrogens associated with oxygen.In some derivatives 14, these peaks are not always visible.
protons attached to oxygen atoms of 14 and not nitrogen N-9 atoms in 13.In the 1 H NMR spectra included in the work by Hegde and Shetty, one can also notice very weak broad peaks in the region of 12-13 ppm, which are identical to the peaks at 12.44 and 12.53 ppm coming from hydrogens associated with oxygen.In some derivatives 14, these peaks are not always visible.
In Figure 1 we included a 1 H NMR spectrum of 4,4′-(4-chlorophenylmethylene)-bis-(3-methyl-1-phenyl-pyrazol-5-ole) 14b and these two peaks can be seen.In the case of the derivative obtained from p-chlorobenzaldehyde, the authors included the measurement result of a mass spectrum (ESI) of the sample, obtaining values for [M + ] 371 (100%), which corresponds to the structure of 4,9-dihydro-1-H-pyrazolo [3,4b]quinoline 13b (R = Cl).Elemental analysis also confirms this structure.However, the 1 H NMR spectrum indicates that in fact product 14b was formed.Unfortunately, we do not know where this inaccuracy came from.In the case of the derivative obtained from p-chlorobenzaldehyde, the authors included the measurement result of a mass spectrum (ESI) of the sample, obtaining values for [M + ] 371 (100%), which corresponds to the structure of 4,9-dihydro-1-H-pyrazolo [3,4-b]quinoline 13b (R = Cl).Elemental analysis also confirms this structure.However, the 1 H NMR spectrum indicates that in fact product 14b was formed.Unfortunately, we do not know where this inaccuracy came from.
Another problem occurs in the case of a product obtained from p-tolu-aldehyde 2a.The 1 H NMR spectra of our compound is depicted in Figure 2.
In the case of the 1 H NMR spectrum of alleged 4-(p-methylphenyl)-4,9-dihydro-3methyl-1-phenyl-1H-pyrazolo [3,4-b]quinoline 13a (R = Me), the authors assigned (in their publication) each of the peaks located at 2.30 and 2.24 ppm, respectively, to three protons from the methyl groups in each case.In fact, if we look closer at the 1 H NMR spectrum for 14a, the ratio of the number of protons at 2.27 and 2.21 is 2:1, so it cannot be the compound 13a at all.The spectra from the publication of Hedge and Shetty are identical to those we obtained and the analysed compound cannot be 4-(p-methylphenyl)-1-phenyl-3-methyl-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline 13a (Scheme 4), though elemental analysis again confirmed the molecular structure of 13a.
In such a case, the question arises whether the previously mentioned structures 13 can be synthesised.A different approach was used to check this.In 1911, Michaelis described the synthesis of 4-benzylidene-5-N-phenylaminopyrazoles 20 by reacting aromatic aldehydes 2 with 5-N-phenyl-3-methyl-1-phenylpyrazole 19 (Scheme 7) [31].The author reported in the publication that he obtained two derivatives of this kind.However, later research by Tomasik et al. showed that the actual products formed in this reaction were 1H-pyrazolo[3,4-b]quinolines 7 [32].
Molecules 2023, 28, x FOR PEER REVIEW 7 of 17 Another problem occurs in the case of a product obtained from p-tolu-aldehyde 2a.The 1 H NMR spectra of our compound is depicted in Figure 2. In the case of the 1 H NMR spectrum of alleged 4-(p-methylphenyl)-4,9-dihydro-3methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline 13a (R = Me), the authors assigned (in their publication) each of the peaks located at 2.30 and 2.24 ppm, respectively, to three protons from the methyl groups in each case.In fact, if we look closer at the 1 H NMR spectrum for 14a, the ratio of the number of protons at 2.27 and 2.21 is 2:1, so it cannot be the compound 13a at all.The spectra from the publication of Hedge and Shetty are identical to those we obtained and the analysed compound cannot be 4-(p-methylphenyl)-1-phenyl-3-methyl-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline 13a (Scheme 4), though elemental analysis again confirmed the molecular structure of 13a.
In such a case, the question arises whether the previously mentioned structures 13 can be synthesised.A different approach was used to check this.In 1911, Michaelis described the synthesis of 4-benzylidene-5-N-phenylaminopyrazoles 20 by reacting aromatic aldehydes 2 with 5-N-phenyl-3-methyl-1-phenylpyrazole 19 (Scheme 7) [31].The author reported in the publication that he obtained two derivatives of this kind.Michaelis and the authors of the later publication did not study the course of the reaction, but it can be expected that, during it, intermediate products 13 can be formed and correspond to those described in the work of Hedge and Shetty.To test this hypothesis, the appropriate amino-pyrazole 19 was synthesised from phenyl-hydrazine 18 and 3-oxo-N-phenylbutanethioamide 17.Next, it was reacted with aldehydes 2a, 2b, 2e and 2g in the presence of anhydrous ZnCl 2 .Michaelis and Tomasik and their co-workers carried out a melting reaction of aromatic aldehyde 2 with 5-N-phenylpyrazole 19 in an open flask with the final yields of 7 in the order of 40-50%.This was slightly larger when using a microwave field.If it is assumed that the intermediate product in this reaction is the 4,9-dihydro-1H-pyrazolo [3,4-b]quinoline 13, it can be taken for granted that the oxygen present in the air plays a significant role in the oxidation of this compound.In order to eliminate its influence, the reaction was carried out in closed ampoules for 6 h.At the end of heating and analysis of the post-reaction mixture by TLC, the presence of three products was found, namely 4-aryl-1H-pyrazolo [3,4- Michaelis and the authors of the later publication did not study the course of the reaction, but it can be expected that, during it, intermediate products 13 can be formed and correspond to those described in the work of Hedge and Shetty.To test this hypothesis, the appropriate amino-pyrazole 19 was synthesised from phenyl-hydrazine 18 and 3-oxo-N-phenylbutanethioamide 17.Next, it was reacted with aldehydes 2a, 2b, 2e and 2g in the presence of anhydrous ZnCl2.Michaelis and Tomasik and their co-workers carried out a melting reaction of aromatic aldehyde 2 with 5-N-phenylpyrazole 19 in an open flask with the final yields of 7 in the order of 40-50%.This was slightly larger when using a microwave field.If it is assumed that the intermediate product in this reaction is the 4,9dihydro-1H-pyrazolo [3,4-b]quinoline 13, it can be taken for granted that the oxygen present in the air plays a significant role in the oxidation of this compound.In order to eliminate its influence, the reaction was carried out in closed ampoules for 6 h.At the end of heating and analysis of the post-reaction mixture by TLC, the presence of three products was found, namely 4-aryl-1H-pyrazolo [3,4-   We performed the reaction on only four aldehydes 2a,b,e,g because, in the case of the others, we were not able to separate the final products 13 and 21 with a sufficient purity for analysis.In case of furfural 2j, the only result we received was a black tar. Figure 3 shows the 1 H NMR spectrum of 4-(4-methylphenyl)-1-phenyl-3-methyl-4,9-dihydro-1Hpyrazolo[3,4-b]quinoline 13a.The signals presented in the spectrum do not coincide at all with those that are included in the Supplementary Materials of Shetty and Gatta.The proton at N-9 is visible at 6.32 ppm instead of 14.00 ppm (compare with Table 1).Both protons at 6.32 ppm and 5.28 ppm disappear after oxidation of 13a when 1H-pyrazolo [3,4-b]quinoline 7a is formed (Figure 4).
After obtaining and establishing the structure, compounds 13a, 13b, 13e and 13g were used as TLC standards when the three-component reaction was repeated with L-proline as a catalyst.These products were not found even in trace amounts.Taking into account the experiments performed and the interpretation of the results, the issue of the synthesis of pure 4-aryl-4,9-dihydro-1H-pyrazolo [3,4-b]quinolines using a multi-component reaction remains a challenge.
shows the 1 H NMR spectrum of 4-(4-methylphenyl)-1-phenyl-3-methyl-4,9-dihydro-1Hpyrazolo [3,4-b]quinoline 13a.The signals presented in the spectrum do not coincide at all with those that are included in the Supplementary Materials of Shetty and Gatta.The proton at N-9 is visible at 6.32 ppm instead of 14.00 ppm (compare with Table 1).Both protons at 6.32 ppm and 5.28 ppm disappear after oxidation of 13a when 1H-pyrazolo [3,4-b]quinoline 7a is formed (Figure 4).After obtaining and establishing the structure, compounds 13a, 13b, 13e and 13g were used as TLC standards when the three-component reaction was repeated with L-

Chemicals and Instruments
Chemicals and solvent were purchased from Aldrich/Merck and POCh (Polish chemical company) respectively. 1H NMR and 13 C NMR spectra were recorded using the Bruker Advance III (400 MHz) and the Bruker Advance III (600 MHz) spectrometers (Jagiellonian University, Faculty of Chemistry, Kraków, Poland).Elemental analysis was performed using the CHNS Vario MICRO Cube analyser with electronic micro-balance.Melting points were measured using a MEL-TEMP II cryometer (Agricultural University, Faculty of Food Chemistry).TLC chromatograms were visualised using a dual-band (254 and 365 nm) Spectroline UV lamp model ENF-260/FE and 70-230 mesh ASTM silica gel purchased from Merck KGaA (Darmstadt, Germany) was used as the stationary phase in the column chromatographic methods.The 70-230 mesh ASTM (Activity Grade I) alumina was also purchased at Merck KGaA.The mass spectra were taken with a mass spectrometer coupled to a Shimadzu LCMS-8040 high performance liquid chromatograph (Jagiellonian University, Faculty of Chemistry).
Procedure (b): 5 mmoles of substrates without L-proline were used in the reaction.The filtrate was evaporated, and the resulting oil was dissolved in chloroform and dried with anhydrous MgSO 4 .The chloroform was evaporated and the oil obtained was dissolved in petroleum ether (40/60) and chromatographed on a silica gel column.The solution was evaporated and the light-yellow oil was left in the refrigerator to solidify.Pale yellow crystalline mass, 173 mg, yield 18%, mp.40-42 • C. Lit.40-41 • C [24].TLC testing (toluene:petroleum ether 40/60 ratio 1:1) showed the sample to have identical R f values to the original Schiff base synthesised from aniline and p-tolu-aldehyde.
(  A round-bottomed flask (50 mL) equipped with a reflux condenser and a magnetic stirring bar was charged with p-tolu-aldehyde (120 mg, 1 mmol), 5-methyl-2-phenyl-2,4dihydro-3H-pyrazole-3-one (340 mg, 2 mmol) and ethanol (10 mL).The content was boiled for five hours.After a few minutes, a formation of light pink precipitate was observed.After cooling, the precipitate was filtered off and crystallised from the ethanol/DMF mixture.

Conclusions
The aim of our research was to investigate the possibility of obtaining fully aromatic 4-aryl-1H-pyrazolo [3,4-b]quinolines by the oxidation of 4-aryl-4,9-dihydro-1H-pyrazolo [3,4b]quinolines.These last compounds, according to the paper published by Hegde and Shetty that we investigated some time ago, can be easily obtained in a three-component reaction from aromatic aldehyde, aniline, pyrazolone and a catalytic amount of L-proline.Unfortunately, after repeating the procedures described in the above-mentioned publication, we failed to obtain the expected compounds.The only compounds that we obtained were 4,4 -(arylenemethylene)-bis-(3-methyl-1-phenyl-pyrazol-5-ol)-oles, regardless of the modification of the reaction conditions.Their structure was confirmed beyond any doubt by 1 H NMR/ 13 C NMR and literature studies.The actual 4-aryl-4,9-dihydro-1H-pyrazolo [3,4b]quinolines were obtained by another synthetic method and used as standards in the original multi-component reaction.During tests, it turned out that they are not produced even in trace amounts.Therefore, we certainly disagree with the authors' final statement: "In conclusion, a simple and efficient protocol for one-pot multi-component synthesis of 1H-pyrazolo [3,4-b]quinolines using L-proline as a catalyst has been developed" [18].It seems to us that the authors simply misinterpreted the data they obtained.

Scheme 8 .
Scheme 8.The final products from the Michaelis protocol.The yield of 1H-pyrazolo[3,4-b]quinoline was definitely lower (5-8%) than in the case of the reaction carried out under air condensation (as in the original work by Michaelis).

Scheme 8 .
Scheme 8.The final products from the Michaelis protocol.The yield of 1H-pyrazolo[3,4-b]quinoline was definitely lower (5-8%) than in the case of the reaction carried out under air condensation (as in the original work by Michaelis).Separation of the products was very troublesome due to the almost identical starting values R f 19 and resulted in 4,9-dihydro-1H-pyrazolo[3,4-b]quinolines 13.The products were separated by pre-removal of 1H-pyrazolo[3,4-b]quinolines 7 with residual unreacted aldehyde after digesting of the reaction mixture with methanol, in which pyrazolo-quinolines are insoluble.The filtrate was subjected to column chromatography using a mixture of toluene and ethyl acetate in a ratio of 3:0.1 with a gradual increase in the amount of ethyl acetate to 3:0.4 to separate off unreacted 19, 13 and 21.We performed the reaction on only four aldehydes 2a,b,e,g because, in the case of the others, we were not able to separate the final products 13 and 21 with a sufficient purity for analysis.In case of furfural 2j, the only result we received was a black tar.Figure3shows the 1 H NMR spectrum of 4-(4-methylphenyl)-1-phenyl-3-methyl-4,9-dihydro-1Hpyrazolo[3,4-b]quinoline 13a.The signals presented in the spectrum do not coincide at all with those that are included in the Supplementary Materials of Shetty and Gatta.The proton at N-9 is visible at 6.32 ppm instead of 14.00 ppm (compare with Table1).Both protons at 6.32 ppm and 5.28 ppm disappear after oxidation of 13a when 1H-pyrazolo[3,4-b]quinoline 7a is formed (Figure4).After obtaining and establishing the structure, compounds 13a, 13b, 13e and 13g were used as TLC standards when the three-component reaction was repeated with L-proline as a catalyst.These products were not found even in trace amounts.Taking into account the experiments performed and the interpretation of the results, the issue of the synthesis of pure 4-aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines using a multi-component reaction remains a challenge.