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Synthesis of Diastereomeric 2,6-bis{[3-(2-Hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substituted Phenols (R = Me, OMe) by Mannich-Type Tandem Reactions

1
Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Cajicá 250247, Colombia
2
Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Sede Bogotá, Carrera 30 No. 45-03, Bogotá 111321, Colombia
*
Author to whom correspondence should be addressed.
Molbank 2024, 2024(3), M1876; https://doi.org/10.3390/M1876
Submission received: 1 August 2024 / Revised: 22 August 2024 / Accepted: 26 August 2024 / Published: 28 August 2024
(This article belongs to the Section Organic Synthesis)

Abstract

:
The synthesis and characterization of two novel diastereomeric Mannich bases was carried out from the reaction of the cyclic aminal (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,70.11,16]icosane 1 and p-cresol 2a and 4-methoxyphenol 2b in a water/dioxane mixture. The title compounds (4ab) are interesting because bearing two 3-(2-hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl} substituents joined to an arenol ring. The formation of these new Mannich bases in the reaction mixture can be explained by aminomethylation of previously reported di-Mannich base 2,2′-((hexahydro-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(methylene))bis(4-substituentphenol) 3ab. NMR analysis demonstrated that compounds 4ab were formed as diastereomeric mixtures. Subsequent experiments revealed that at longer reaction times, the percentage yield of these new products increased considerably (yield percentages up to 22–27%), suggesting a nucleophilic competition between the p-substituted phenols and Mannich bases of type 3 for aminal 1.

Graphical Abstract

1. Introduction

Mannich bases are compounds widely known for their affordable preparation and application versatility [1]. It is known that this class of compounds has demonstrated numerous biological activities [2,3]. Although they are highly explored compounds, multiple investigations continue to be carried out for their application. Recently, four series of Mannich bases were synthesized, incorporating phenothiazines, a pharmacophore used to treat severe mental and emotional disorders and reduce nausea [4]. The reaction of 10-methyl-10H-phenothiazine-3-sulfonamide with some secondary amines and formaldehyde afforded the respective Mannich bases, which showed inhibition of growth in vitro against P. aeruginosa, E. coli, and S. aureus (MIC between 3.125–12.5 μg/mL) [5]. The synthesis of Mannich bases of the benzimidazole type was carried out, and the in vitro evaluation of their antituberculous activity was performed [6]. These compounds were synthesized by condensation reaction between 1-(1H-benzo[d]imidazol-1-yl)ethanone and some amines, showing significant antituberculosis activity against the cell wall enzyme of Mycobacterium tuberculosis (M.tb), enoyl acyl reductase carrier protein (InhA), and regulatory protein of EthR in strain H73Rv. Functionalized bicyclo[3.1.1]heptane-type Mannich bases showed behavior as a human ornithine aminotransferase inhibitor [7], and isatin-containing N-Mannich base derivatives of primaquine with heterocyclic scaffolds were able to act against the dihydrofolate reductase receptor (DHFR) [8]. Protein kinase C (PKC)-epsilon inhibitors to treat alcohol disorders were also obtained through a highly enantioselective nitro-Mannich reaction using a dual-reactant catalysis system [9]. The synthesis of the Mannich bases of the N,N′-bis(3-oxo-3-phenylpropyl)ethane-1,2-diamine dihydrochloride type has been reported to afford corrosion inhibitors of N80 steel. This report demonstrated that the inhibition performance was significantly improved by combining these Mannich bases and allicin [10].
Although the Mannich reaction has been widely explored, numerous modifications and improvements have been reported trying to improve yields and stereoselectivity [11]. An example is the chemical synthesis of chiral compounds of the β-aminocarbonyl type, which are usually used as synthetic precursors [12]. These compounds have been obtained through Mannich-type organocatalytic reactions of glyoxylate imines using organocatalysts that operate through covalent activation of enamines, such as catalysts derived from pyrrolidine, as well as in the catalysts based on other structural motifs, and non-covalent organocatalysts, such as thioureas, squaramides, and chiral Brønsted acids [13]. An enantioselective vinylogenic Mannich reaction was carried out using 2-methoxyfuran under chiral catalysis with spirophosphoric acid, involving 4-isoxazoline derivatives as cyclic ketimine substitutes and providing γ-butenolide structures [14]. Additionally, the enantioselective Mannich reaction of α-fluoroindanones with N-Boc-ketimines derived from isatin, catalyzed by a phase transfer catalyst based on quinine, yielded 3-substituted 3-amino-2-oxindole compounds featuring vicinal tetrasubstituted stereocenters. This reaction achieved high yields (83–95%), moderate to excellent enantioselectivities (66–91%), and high diastereoselectivities (up to >99:1) [15]. Moreover, the use of trypsin or α-chymotrypsin immobilized on titanate nanotubes to synthesize β-amino carbonylated compounds, specifically 2-[phenyl(phenylamino)methyl] cyclohexanone, has also been reported, indicating that the use of this system allowed high conversions and diastereomeric ratios [16]. The synthesis of bicyclic γ-ureasultams, possible analogs of biotin and containing two consecutive chiral centers, was carried out through an intramolecular cascade of Mannich addition and aza-Michael of alkenyl sulfonamides [17]. Moreover, the use of a photochemical synthetic protocol to afford polyfunctionalized dihydro-2-oxypyrroles using Michael–Mannich cyclocondensation of amines, dialkyl acetylenedicarboxylates, and formaldehyde was recently reported. This methodology adopted a photocatalyst as a single-electron redox mediator in an ethanol solution under exposure to blue light of the perovskite halide type [18]
One of our research lines mainly uses cyclic aminals with asymmetric centers as preformed Mannich reagents in reactions with phenols in basic media [19,20]. This reaction between these interesting precursors and active-hydrogen compounds continues to be studied, and it is considered a potential synthetic route. The cyclic aminal 4,9-dimethyl-1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane, synthesized by the reaction of rac-1,2-propanediamine with paraformaldehyde, was used in a Mannich-type reaction against p-chlorophenol, resulting in 2,2′-[(4-methylimidazolidine-1,3-diyl)dimethanediyl]bis(4-chlorophenol) as a racemic mixture in moderate yields [19]. Another well-explored aminal, with the presence of chiral centers, corresponds to (2S,7R,11S,16R)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,7011,16]icosane, derived from cis-(meso)-1,2-diaminocyclohexane and formaldehyde. Its use as a suitable substrate for the preparation of a series of cis-meso Mannich bases of the 4,4′-disubstituted-2,2’-{[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazol-1,3-diyl]bis(methylene)}diphenols type was demonstrated [20]. Its diastereoisomer, the aminal (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,7011,16]icosane 1, has also been proven to be a potential precursor of di-Mannich bases. Notably, the reaction against p-cresol 2a and 4-methoxyphenol 2b apparently only led to the formation of the racemic bases di-Mannich 4,4′-dimethyl-2,2′-{[(3aRS,7aRS)-2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diyl]bis(methylene)}diphenol 3a and 4,4′-dimethoxy-2,2′-{[(3aRS,7aRS)-2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diyl]bis(methylene)}diphenol 3b, respectively [21,22]. However, subsequent studies have shown that the reaction between the Mannich phenolic bases 1,3-bis[2′-hydroxybenzyl]imidazolidines and the cyclic aminal 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD), in addition to allowing the formation of heterocalixarene-type Mannich bases, leads to the formation of linear benzylimidazolidine oligomers as minority products [23]. Performing experiments between aminal 1 and phenols 2ab, we observed that in addition to 3ab, other very minor products were formed based on what was reported. Then, we hypothesized that in our reaction, the same thing would occur in situ, and once 3ab were formed, they would react with aminal 1 in competition with phenols 2ab. For this reason, we decided to study the variables that govern this reaction, seeking to improve the yields of these minor products, to know them, characterize them, and understand their formation mechanism. Continuing this deep exploration, this manuscript presents the study of the reaction between aminal 1 and the active phenols 2ab, identifying that depending on the conditions of the reaction, oligomers of type 2,6-bis{[3-(2-hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substituted phenols 4ab can also be obtained as diastereomeric mixtures (Scheme 1). The results obtained are described below.

2. Results

The study of the reactivity of cyclic aminal 1 against p-cresol 2a and 4-methoxyphenol 2b has been previously addressed [21,22]. The reaction between aminal 1, 2a, and 2b was carried out under conventional heating conditions and in the presence of a dioxane: water mixture as solvent. The main products corresponded to the previously reported di-Mannich base 2,2′-((hexahydro-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(methylene))bis(4-substituentphenol) 3ab (yield percentages 45 and 34%, respectively) [21,22]; however, a close inspection of the crude reaction mixture by NMR made evident the formation of the entitled compounds as diastereomeric mixtures 4ab. Considering the main variables that affect the reaction, such as temperature, concentration, and polarity of the solvent, a series of experiments was carried out to optimize these conditions towards the total consumption of the respective aminal 1 and to increase the yields of oligomeric products 4ab (Table 1). Solvents of varying polarities—low (benzene, toluene, 1,4-dioxane), medium (ethyl acetate, chloroform), and high (methanol, ethanol)—were tested. Based on the background information on chemical reactivity reported by Rivera [23], the reactions were carried out with a stoichiometric ratio of 1:2 of aminal 1 to phenol 2 to allow the formation of di-Mannich bases via double-aminomethylation reaction. Temperatures between 20 °C and 30 °C with constant stirring were evaluated for up to 40 h until the reagent concentrations were stabilized or the reagents were consumed entirely. Initial tests showed that both aminal 1 and phenol 2 were mostly recovered unchanged at temperatures between 20 °C and 40 °C. Therefore, further tests were conducted by varying the temperature. It was found that, using medium- to high-polarity solvents, the concentrations of the reactants decreased over 40 h of heating and stirring, indicating the formation of product 3. However, complete conversion was not achieved. In 1,4-dioxane, 65% of the starting aminal 1 was recovered despite its low polarity, suggesting some reaction occurred. Polar solvents were expected to enhance reaction kinetics. In ethanol, 45% of aminal 1 was recovered after 40 h at optimal temperatures, indicating partial conversion. This suggests that the reaction depends significantly on both temperature and solvent polarity. It was proposed that increasing these factors would enhance reactant conversion. Further tests involved using mixtures of ethanol and 1,4-dioxane with water to vary polarity and temperature. 1,4-Dioxane is miscible with water, which allows for manipulation of the dielectric constant, while ethanol–water mixtures create a highly polar medium through hydrogen bonding. Reactions were performed at 90 °C for 40 h using these solvent mixtures. The results showed that increasing the proportion of water in the solvent mixtures decreased the recovery percentage of aminal 1. Using mixtures of 1,4-dioxane and water, in addition to increasing the polarity of the medium, allowed the reaction temperature given by the medium under reflux conditions to be higher, increasing the reaction rate and ensuring that 1 was consumed entirely. The hypothesis was supported by a high conversion of the reagents employing a 60:40 1,4-dioxane-water mixture, with conversion rates enhanced by higher temperatures. Thus, the reactions between aminal 1 and phenol 2 were carried out in a prolonged reaction time of 72 h. Although the main products corresponded to 3ab, a decrease in yields of 15–30% was observed, and the concentration of the new products increased progressively (22–27% yield), identified as the titled compounds. The results of the characterization by NMR and HR-ESI-MS are presented in the Supplementary Materials.
The 1H NMR spectrum of compound 4a (Figure S1a) is characterized by several multiplet signals between 1.00 and 2.50 ppm, integrating 40 hydrogen atoms. These signals are similar to those observed for compounds 3a and were assigned to the diastereotopic hydrogens of two cyclohexane rings in the meso-(3aR,7aR,3a’S,7a’S) and enantiomers (3aS,7aS,3a’S,7a’S) and (3aR,7aR,3a’R,7a’R). The meso-(3aR,7aR,3a’S,7a’S) stereoisomers present a plane of symmetry through the central aromatic ring, to which the (methylene)-(1H-benzo[d]imidazole-3,1-(2H,3H,3aH,4H,5H,6H,7H,7aH)-diyl))-bis-(methylene)-4-substituted aryl groups are attached in positions 2 and 6. Enantiomers (3aS,7aS,3a’S,7a’S) and (3aR,7aR,3a’R,7a’R) possess a C2 symmetry axis, also through the central aromatic ring, but without a plane of symmetry. These symmetry elements influence the simplicity of the spectrum concerning the signals of the diastereotopic cyclohexane rings (Figure 1).
The integration of the signals between 3.20 and 4.20 ppm suggests the presence of 24 hydrogen atoms grouped in two signals of 12 hydrogens corresponding to the pairs of stereoisomers of compound 4a. The observed multiplicity seems complex and unexpected compared to trans-1,2-diaminocyclohexane-derived compound 3. Around these chemical shift values, the signals from the benzylic hydrogens ArCH2 and the hydrogens on the amino carbon N-CH2-N were expected. However, the apparent multiplicity of these signals and the difficulty in calculating the coupling constants complicated the analysis. Through two-dimensional COSY, HMQC, and HMBC experiments (Figure 2), the nature of these signals was clarified so that eight signals appeared, each integrating two hydrogens, with doublet multiplicity and a geminal coupling constant of 14.0 Hz, overlapping each other, and with a molar ratio of 1:1 between the enantiomer mixture and meso compounds. The signals were grouped into two sets of four and were assigned to the hydrogens of the ArCH₂N group, which acted as a bridge between the aromatic rings and the perhydrobenzimidazolidin system. For the meso-(3aR,7aR,3a’S,7a’S) compounds, the signals at 4.16 ppm and 4.07 ppm appeared as doublets, with a geminal coupling constant of 14.0 Hz. These doublets coupled with the signals at 3.52 ppm and 3.47 ppm, which had the same multiplicity, and were assigned to the benzylic protons. In the 13C NMR spectrum (Figure S1b), the benzylic carbons were identified by signals around 56.7 ppm, indicating that these hydrogens behaved as diastereotopic protons. For the enantiomers (3aS,7aS,3a’S,7a’S) and (3aR,7aR,3a’R,7a’R), a similar pattern was observed. The doublet signals at 4.14 ppm and 3.97 ppm coupled with the signals at 3.51 ppm and 3.41 ppm, correlating with the signals from the benzylic carbons around 56.7 ppm. Additionally, hydrogens were observed on the amino carbon at 3.60 ppm and 3.59 ppm with singlet multiplicity, correlating with the carbons around 76.3 ppm. The 1H NMR spectrum of compound 4a showed signals above 6.50 ppm, indicating the presence of aromatic ring systems as ABX coupling systems (with doublets and a singlet at 6.72 ppm, 7.09 ppm, and 6.92 ppm). The two-dimensional HMBC experiment (Figure 2) confirms the assignment of these aromatic hydrogens and their correlation with the signals of the benzylic hydrogens. The proposed structure for compound 4a was confirmed by the HR-ESI-MS mass spectrum in its positive mode (Figure S3), which showed a signal with m/z of 625.4086 for [M + H]+ (calculated for C39H53N4O3: 625.4112). The results of the spectroscopic characterization using uni- and two-dimensional NMR experiments of compound 4b reflected a similar behavior for the signals of both the 1H and 13C nuclei, as previously discussed for the results for compound 4a. As expected, CH3O groups attached to the aromatic rings appeared as singlet signals around 3.69 ppm in the 1H NMR spectrum and around 56.0 ppm in the 13C NMR spectrum (Figure S3). These results confirm the formation of the title compounds 4ab from the synthetic route described in this report.

3. Materials and Methods

3.1. General

All reagents and chemicals were commercially acquired (Merck KGaA and/or Sigma-Aldrich, Darmstadt, Germany). They were employed without additional refinement. As a result, the purity of dry solvents was sufficiently defined during purchase. The products’ progression of reaction and purification were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 plates (Merck KGaA) under detection at 254 nm. Nuclear magnetic resonance (NMR) experiments were conducted using a Bruker Avance AV-400 MHz spectrometer. TMS was used as a reference to give chemical shifts in δ (ppm). Typical splitting patterns were implemented to define the signal multiplicity (i.e., s, singlet; d, doublet; t, triplet; m, multiplet).

3.2. General Procedure: Reaction between Aminal and p-Substituted Phenols

To a solution of aminal 1 (1.00 mmol, 0.276 g) in 1,4-dioxane (3.0 mL), the respective p-substituted phenol 2ab (2.00 mmol; p-cresol and 4-methoxyphenol) dissolved in 1,4-dioxane (3.0 mL) was slowly added. The reaction mixture was kept at room temperature for 10 min. Water (4.0 mL) was added and heated to reflux with constant stirring for 72 h. Once the reaction was completed, the solvent was removed under reduced pressure, and products 3ab and 4ab were purified by column chromatography (silica gel), eluting with mixtures of hexanes: ethyl acetate in a polarity gradient. 1H and 13C NMR spectroscopy, HR-ESI-MS, and FT-IR spectroscopy were used to characterize compounds 4ab. The results are presented in the Supplementary Materials (Figures S1–S3).

4. Conclusions

The study on the reactivity of cyclic aminal 1 with p-cresol 2a and 4-methoxyphenol 2b showed that under specific conditions, the formation of di-Mannich bases 3ab or oligomers 4ab could be favored. Variables such as the polarity of the medium, the temperature, and the time of reaction presumably determined the mechanism pathway. These reaction conditions influence the competition between 2 and 3 to attack the aminal 1. Structural characterization of 4a via NMR and HRMS confirmed the proposed structures, underscoring the importance of reaction conditions in product yield and conversion.

Supplementary Materials

Figure S1: 1H and 13C NMR spectra of compound 4a; Figure S2: HR-ESI-MS spectrum of compound 4a; Figure S3: 1H and 13C NMR spectra of compound 4b.

Author Contributions

Conceptualization, D.Q., J.R.-M. and A.R.; methodology, D.Q.; software, D.Q. and A.R.; chemical synthesis and structural elucidation, D.Q., J.R.-M. and A.R.; writing—original draft preparation, D.Q., J.R.-M. and A.R.; writing—review and editing, D.Q., J.R.-M. and A.R.; project administration, D.Q.; funding acquisition, D.Q. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

The present work is a product derived from the project INV-CIAS-3954 funded by Vicerrectoría de Investigaciones at UMNG—Validity 2024.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Ganjoo, R.; Verma, C.; Thakur, A.; AlFantazi, A.; Assad, H.; Sharma, S.; Dubey, S.; Kumar, A. Mannich Bases: Chemical Structure, Chemistry, Coordination Bonding and Application in Aqueous Phase Corrosion Protection. J. Ind. Eng. Chem. 2024, 131, 136–166. [Google Scholar] [CrossRef]
  2. Bala, S.; Sharma, N.; Kajal, A.; Kamboj, S.; Saini, V. Mannich Bases: An Important Pharmacophore in Present Scenario. Int. J. Med. Chem. 2014, 2014, 191072. [Google Scholar] [CrossRef] [PubMed]
  3. Roman, G. Mannich Bases in Medicinal Chemistry and Drug Design. Eur. J. Med. Chem. 2015, 89, 743–816. [Google Scholar] [CrossRef] [PubMed]
  4. Csonka, A.; Varga, B.; Csonka, A.; Molnar, J.; Amaral, L.; Spengler, G. Possible Biological and Clinical Applications of Phenothiazines. Anticancer. Res. 2017, 37, 5983–5993. [Google Scholar]
  5. Abdula, A.M.; Qarah, A.F.; Alatawi, K.; Qurban, J.; Abualnaja, M.M.; Katuah, H.A.; El-Metwaly, N.M. Design, Synthesis, and Molecular Docking of New Phenothiazine Incorporated N-Mannich Bases as Promising Antimicrobial Agents. Heliyon 2024, 10, e28573. [Google Scholar] [CrossRef]
  6. Gopi, C.; Dhanaraju, M.D.; Pranusha, K.; Deepan, T.; Magesh, A.; Kavitha, D. Design, Synthesis, Characterization and Antitubercular Activity of Novel Benzimidazole Mannich Base Derivatives: Anti-Tubercular Activity of Novel Benzimidazole Mannich Base Derivatives. Asian J. Chem. 2024, 36, 969–973. [Google Scholar] [CrossRef]
  7. Dukes, A.O.; Weerawarna, P.M.; Devitt, A.N.; Silverman, R.B. Synthesis of (2R, 4S)-4-Amino-5-Hydroxybicyclo [3.1.1]Heptane-2-Carboxylic Acid via an Asymmetric Intramolecular Mannich Reaction. J. Org. Chem. 2024, 89, 9110–9117. [Google Scholar] [CrossRef]
  8. Kumar, S.; Arora, D.; Bhardwaj, T.R.; Dhingra, N. Design, Synthesis and Studies on Novel N-Mannich Base Derivatives of Isatin Targeting Dihydrofolate Reductase Receptor. J. Mol. Struct. 2024, 1311, 138385. [Google Scholar] [CrossRef]
  9. De Kraker, H.; Wang, H.-Y.L.; Arman, H.D.; Renteria, R.N.; Fleischer, C.N.; Messing, R.O.; McHardy, S.F. Asymmetric Synthesis of CIDD-0072424 via an Enantioselective Nitro-Mannich Reaction: A Central Nervous System Penetrant, Selective Small Molecule Inhibitor of Protein Kinase C Epsilon. J. Org. Chem. 2024, 89, 5134–5141. [Google Scholar] [CrossRef]
  10. Zhang, X.; Zhang, Y.; Su, Y.; Guan, S. Enhancing the Corrosion Inhibition Performance of Mannich Base on Mild Steel in Lactic Acid Solution through Synergistic Effect of Allicin: Experimental and Theoretical Study. J. Mol. Struct. 2024, 1304, 137658. [Google Scholar] [CrossRef]
  11. Afsah, E.M. Double Mannich Reaction with Ketones as a Route to Heterocyclic Systems: A Mini Review. J. Heterocycl. Chem. 2024, 61, 805–817. [Google Scholar] [CrossRef]
  12. Singh, R.; Bhasin, G.; Srivastava, R.; Geetanjali, B.S.P. β-Aminocarbonyl Compounds: Chemistry and Biological Activities. Mini-Rev. Org. Chem. 2016, 13, 143–153. [Google Scholar] [CrossRef]
  13. Šramel, P.; Šebesta, R. Organocatalytic Mannich Type Reactions of Glyoxylate Imines and Related Compounds. Tetrahedron Lett. 2024, 143, 155129. [Google Scholar] [CrossRef]
  14. Chao, Y.-H.; Jamwal, P.; Ananda Rao, G.; Gurubrahamam, R.; Chen, K. Chiral Spirophosphoric-Acid-Catalyzed Divergent Vinylogous Mannich and Aza -Friedel–Crafts Reactions of 2-Methoxyfuran. Org. Lett. 2024, 26, 4938–4944. [Google Scholar] [CrossRef] [PubMed]
  15. Zhao, M.; Zhao, Z.; Wei, Z.; Cao, J.; Liang, D.; Lin, Y.; Duan, H. Asymmetric Mannich Reaction of Isatin-Derived Ketimines with α-Fluoroindanones Catalyzed by a Chiral Phase-Transfer Catalyst. J. Org. Chem. 2024, 89, 4474–4483. [Google Scholar] [CrossRef] [PubMed]
  16. Bessoni Kosctiuk, J.; Ribeiro Neto, M.E.; Alcoforado Pereira, G.; Krieger, N.; Zambelli Mezalira, D.; Pilissão, C. A Multicomponent Mannich Reaction Catalyzed by Hydrolases Immobilized on Titanate Nanotubes. ChemPlusChem 2024, 89, e202300698. [Google Scholar] [CrossRef] [PubMed]
  17. Yin, F.; Qu, L.; Chen, Y.; Luo, Z.; Kong, L.; Wang, X. Stereoselective Synthesis of β, Γ-Fused Bicyclic γ-Ureasultams via an Intramolecular Mannich and Aza-Michael Addition Cascade. Chem.—Eur. J. 2024, 30, e202400438. [Google Scholar] [CrossRef]
  18. Mohamadpour, F.; Kamyab, H.; Chelliapan, S.; Mohammad Amani, A. Light-Induced Access to Gram-Scale Photosynthesis of Polyfunctionalized Dihydro-2-Oxypyrroles: A Recyclable Halide Perovskite Photocatalyst as a Single-Electron Redox Mediator for Radical-Initiated Michael-Mannich Cyclocondensation in Air Atmosphere. Inorg. Chem. Commun. 2024, 167, 112807. [Google Scholar] [CrossRef]
  19. Rivera, A.; Pacheco, D.J.; Ríos-Motta, J.; Fejfarová, K.; Dušek, M. Synthesis of a New Chiral Cyclic Aminal Derived from Rac-1,2-Propanediamine. Tetrahedron Lett. 2012, 53, 6132–6135. [Google Scholar] [CrossRef]
  20. Rivera, A.; Quiroga, D.; Ríos-Motta, J.; Eigner, V.; Dušek, M. Single-Step Synthesis of a New Series of Meso Di-Mannich Bases from the Cyclic Aminal (2S,7R,11S,16R)-1,8,10,17-Tetraazapentacyclo [8.8.1.1.8,170.2,7011,16]Icosane and p-Substituted Phenols. Chem. Cent. J. 2013, 7, 100. [Google Scholar] [CrossRef]
  21. Rivera, A.; Quiroga, D.; Ríos-Motta, J.; Fejfarová, K.; Dušek, M. 4,4′-Dimethoxy-2,2′-{[(3a RS, 7a RS)-2,3,3a,4,5,6,7,7a-Octahydro-1 H -1,3-Benzimidazole-1,3-Diyl]Bis(Methylene)}diphenol. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, o2298–o2299. [Google Scholar] [CrossRef] [PubMed]
  22. Rivera, A.; Quiroga, D.; Ríos-Motta, J.; Carda, J.; Peris, G. Synthesis, Characterization and X-Ray Crystal Structure of the Di-Mannich Base 2,2′-(3aR,7aR/3aS,7aS)-Hexahydro-1H-Benzo[d]Imidazole-1,3(2H)-Diyl)Bis(Methylene)Bis(4-Methylphenol). J. Chem. Crystallogr. 2009, 39, 827–830. [Google Scholar] [CrossRef]
  23. Rivera, A.; Nerio, L.S.; Quevedo, R. Synthesis of Macrocyclic and Linear Benzylimidazolidine Oligomers from Solvent Free Aromatic Mannich-Type Reaction. Tetrahedron Lett. 2015, 56, 6059–6062. [Google Scholar] [CrossRef]
Scheme 1. Sequential synthesis of 4a–b.
Scheme 1. Sequential synthesis of 4a–b.
Molbank 2024 m1876 sch001
Figure 1. Labeled chemical structures of the formed diastereoisomers for the title compounds 4a–b.
Figure 1. Labeled chemical structures of the formed diastereoisomers for the title compounds 4a–b.
Molbank 2024 m1876 g001
Figure 2. Two-dimensional nuclear magnetic resonance experiments of compound 4a. (a) COSY, (b) HMQC, (c) HMBC, (d) schematic representation of the connectivity between resonances of 1H and 13C atoms in 4a.
Figure 2. Two-dimensional nuclear magnetic resonance experiments of compound 4a. (a) COSY, (b) HMQC, (c) HMBC, (d) schematic representation of the connectivity between resonances of 1H and 13C atoms in 4a.
Molbank 2024 m1876 g002
Table 1. Summary of the reactivity assays of aminal 1 vs. phenols 2a–b varying solvent, temperature, and reaction times to afford compounds 4ab.
Table 1. Summary of the reactivity assays of aminal 1 vs. phenols 2a–b varying solvent, temperature, and reaction times to afford compounds 4ab.
Tested Solvent SystemSolvent PolarityTemperature/°CReaction Time/hRecovery of Aminal 1/%Yield for Compounds 4a–b/%
Benzene or tolueneLow20–40 °CUp to 40>990
1,4-DioxaneIntermediate40 °C4065<2
EthanolHigh77 °C400,45<2
1,4-Dioxane/waterIntermediate–high90 °C400,113–15
1,4-Dioxane/waterIntermediate–high94–97 °C72022–27
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Quiroga, D.; Ríos-Motta, J.; Rivera, A. Synthesis of Diastereomeric 2,6-bis{[3-(2-Hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substituted Phenols (R = Me, OMe) by Mannich-Type Tandem Reactions. Molbank 2024, 2024, M1876. https://doi.org/10.3390/M1876

AMA Style

Quiroga D, Ríos-Motta J, Rivera A. Synthesis of Diastereomeric 2,6-bis{[3-(2-Hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substituted Phenols (R = Me, OMe) by Mannich-Type Tandem Reactions. Molbank. 2024; 2024(3):M1876. https://doi.org/10.3390/M1876

Chicago/Turabian Style

Quiroga, Diego, Jaime Ríos-Motta, and Augusto Rivera. 2024. "Synthesis of Diastereomeric 2,6-bis{[3-(2-Hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substituted Phenols (R = Me, OMe) by Mannich-Type Tandem Reactions" Molbank 2024, no. 3: M1876. https://doi.org/10.3390/M1876

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