Ugi reaction - one-pot reaction for the synthesis of polyamides polymers

study was performed using p-TSA^.H²O, and the desired amide (3.5.1) was achieved with 55%

yield.

5-HMF (1.4), a biomass-derived compound was also investigated. Once again, we ob-served the formation of humins leading to low yield. When the reaction was performed in the presence of Na²S²O⁴ (additive), the corresponding amide (3.4.1) was achieved in 28% yield, along with the polymer, however in a much lower amount. The 2-hydroxymethylpyridine substrate (1.6) was not consumed under these conditions to achieve the target molecule (3.6.1), probably protonation of the pyridine might occur. Next, methoxybenzyl alcohol (1.7) and 4-(trifluoromethyl)benzylic alcohol (1.8) were studied. From what was possible to observe by TLC for both substrates, a complex mixture was detected, but no amide (3.7.1 and 3.8.1) was found. In similar manner, vanillin (1.9), another biomass derived substrate, generate a com-plex mixture making the amide (3.9.1) detention more difficult. Finally, BHMF (1.10) was also investigated, unfortunately there was no detection of the corresponding amide (3.10.1).

It is important to reference some key aspects. MWCNT-CSP has emerged to be a prom-ising catalytic activity in Ritter reaction bearing the amide formation from simple molecules with low steric hindrance. However, when the reaction with biomass derived compounds were performed, it was not possible to recover the catalyst. Despite the great reactivity, most part of nitriles are associated to high melting points. Consequently, the recovery step became very difficult, and the reusability of the catalyst becomes unfeasible.

2.3 Ugi reaction - one-pot reaction for the synthesis of

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reaction was next considered. The Ugi reaction is compatible with the use of biomass-derived compounds, as previously described by Shade et al., in 2019,⁶⁹ that used FDCA (a 5-HMF de-rived) in a Ugi reaction to produce the polymer of polyamides. In 2016, Hartweg and cowork-ers⁶⁸ also reported a polymer of polyamides by employing levulinic acid in Ugi reaction. Thus, this reaction became extremely attractive for a more sustainable production of the desired pol-yamides.

In the first attempts conditions previously reported by Xiaojie Zhang et al., in 2016, for the synthesis of polymer, were considered (Scheme 32, A).¹⁵⁰ The first experiments aimed to investigate the behavior of biomass compounds, in particular furfural (6), under the reported reaction conditions to synthesize only the monomer 14 (Scheme 32, B).

Scheme 32. A) Protocol adopted by Zhang et al.; B) Protocol adopted for the synthesis of monomer in this thesis.

Reaction conditions: 11.1 (1.0 mmol), 12 (1.0 mmol), 6.1 (1.0 mmol), 13 (1.0 mmol) and methanol (solvent, 2 mL) at room temperature.

Our initial screening, focused on varying different carboxylic acids, including trifluoro-acetic acid (12.1) and trifluoro-acetic acid (12.2). This is an important step since the imine is protonated by the carboxylic acid and previously attacked by the carboxylate generated (Scheme 33).

Scheme 33. Proposed mechanism for monomer synthesis via Ugi reaction.

The acetic acid (12.2) and trifluoroacetic acid (12.1) were selected due to their different acidity (pKa=4.76 acetic acid; pKa=0.52 trifluoroacetic acid). The fact that the trifluoromethyl group has an electron-withdrawing effect, stabilizes the conjugated base, making TFA a stronger acid.

The model reaction was performed using furfural (6.1) as aldehyde substrate, propyla-mine (11.1), and tert-butyl isocyanide (13) in methanol at room temperature (Scheme 34).

Scheme 34. Results obtained for monomer synthesis by differ the carboxylic acid source via Ugi reaction proce-dure. Reaction conditions: Furfural 6.1 (1.0 mmol), propylamine 11.1 (1.0 mmol), tert-butyl isocyanide 13 (1.0

mmol), carboxylic acid 12 (1.0 mmol), in methanol (solvent, 2 mL) at room temperature.

As can be seen, using trifluoroacetic acid, the monomer was not detected by TLC. In contrast, with acetic acid, after 2 hours, the reaction crude revealed on the TLC a remarkable dragging spot at R^f 0.18, that stained with phosphomolybdic acid. After purification by column chromatography, the isolated product was analyzed by ¹H NMR (Spectrum 4).

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Spectrum 4. ¹H NMR spectrum (CDCl³, at 400MHz) obtained with acetic acid, where the desired amide monomer can be observed.

This compound (14.2) is not described in literature, however similar compound which differs in thiophene ring instead of the furan ring, has been reported by Zidan et al., which facilitated the structural assignment.¹⁵¹ In this spectrum, the signals corresponding to reso-nance of protons from furan ring, such as the doublet at 7.41 ppm, the doublet at 6.64 ppm, and the doublet of doublets at 6.38 ppm, indicate that the furfural moiety is present. Other important signals are the singlet at 1.32 ppm, corresponding to the resonance of the protons from the tert-butyl group and the broad signal at 6.01 ppm corresponding to the resonance of NH proton, both from the isocyanide moiety. The diastereotopic protons signals from propyl-amine appear at 3.33 to 3.13ppm, and 1.50 to 0.96 ppm. Finally, the singlet at 2.16 ppm corre-sponds to the resonance of the 3 protons from methyl group of acetic acid. However, only 19%

yield were achieved.

Next, the influence of solvent was also considered under the same conditions, thus instead of methanol, water was used as solvent (Scheme 35).

Scheme 35. Results obtained for monomer synthesis via Ugi reaction procedure, by employing water as solvent.

Reaction conditions: 11.1 (1.0 mmol), 12.2 (1.0 mmol), 6.1 (1.0 mmol), 13 (1.0 mmol) and water (solvent, 2 mL) at room temperature.

Surprisingly, employing water as solvent afforded the target molecule 14.2 in 100%

yield, while with methanol only 19% yield of monomer was obtained. Literature reports on the use of the Ugi reaction to attain other monomers (with similar substrates) has been per-formed under water as solvent, and higher yields were obtained when compared to the reac-tions carried in methanol.^152,153 This discrepancy could be attributed to a higher solubility of the compounds in water.¹⁵⁴

It was important to know whether the procedure is compatible with a polymerization reaction. Following the outlined synthetic plan, an experiment was carried out in methanol, using diformylfuran (DFF, 6.2) and ethylenediamine (11.2), as polymerization partners (Scheme 32).

Scheme 36. Synthetic approach to synthesize the polymer using DFF and ethylenediamine as polymerization source. Reaction conditions: 11.2 (1.0 mmol), 12.2 (2.0 mmol), 6.2 (1.0 mmol), 13 (2.0 mmol) and methanol

(sol-vent, 2 mL) at room temperature.

Curiously, when the reaction mixture was dissolved in petroleum ether, it was ob-served the formation of a dark-brown thick mixture stuck to the bottom of flask. Attempts were performed to identify the compound formed by ¹H NMR (Spectrum 5). Due to the ap-parent low purity, it was complicated to analyse this sample. However, the signals at 6.67 and 6.44 ppm seem to correspond to protons from the furan ring, although it is not possible to confirm the presence of the desired polymer.

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Spectrum 5. ¹H NMR spectrum (CDCl³, at 400MHz) obtained for the dark-brown thick mixture.

Next, we tried a different approach. Herein, the polymerization source was ethylene-diamine (11.2) and malonic acid (12.3), instead of DFF (Scheme 37). In contrast with the pre-vious reaction, when the reaction mixture was dissolved in dichloromethane, some suspen-sions were observed, and the dark-brown thick mixture was not formed when dissolved with petroleum ether. Unfortunately, due to low solubility it was not possible to characterize the suspension by ¹H NMR.

Scheme 37. Synthetic approach to synthesize the polymer using malonic acid and ethylenediamine as polymeri-zation source. Reaction conditions: 11.2 (1.0 mmol), 12.3 (2.0 mmol), 6.1 (1.0 mmol), 13 (2.0 mmol) and methanol

(solvent, 2 mL) at room temperature.

Wang Xue and coworkers⁶⁶ adopted the same protocol but with a few modifications to achieve the polyamides polymer. The authors used furfural, FDCA, tert-butyl isocyanide and an amine with high carbon chain (between C⁵ and C¹⁰), affording the polymer with high yields (68-95%). With this information in hands, a possible explanation for our results may be the steric hindrance caused by furan ring.

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