Microwave-Assisted Synthesis of 1-(5-Substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-ones from 2-Amino Acid-Derived Enamine-Type Schiff Bases

Abstract

Pyrrole-type compounds are widely known for their potential biological activity. However, methods for synthesizing 2,3,4,5-tetrasubstituted pyrroles remain limited. This study explores an intramolecular cyclocondensation of 2-amino acid-derived enamines to yield novel 1-(5-substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-ones. Using ʟ-alanine, ʟ-tyrosine, ʟ-phenylalanine, and ʟ-tryptophan, the corresponding 2-amino esters were synthesized, converted into enamines, and cyclized under microwave irradiation (55–86% yield). The highest yield was obtained from methyl ʟ-phenylalaninate (R¹ = CH₂Ph, R⁴ = Me). Steric hindrance from bulkier groups reduced yields, while the electronic nature of R¹ influenced reactivity. Structural analysis (NMR, HR-ESI-MS) confirmed product identities, and a 5-exo-trig cyclization mechanism explained base-mediated deprotonation and steric effects. These findings highlight steric and electronic factors in this cyclocondensation, guiding reaction optimization for valuable heterocycles.

1. Introduction

Pyrrole-type compounds constitute a broad family of biologically active molecules [1]. Many reports have demonstrated this family’s importance for medicinal chemistry [1,2,3,4] due to their exceptional pharmacological properties. These compounds with a nitrogenous heterocyclic structure have been prominent in drug discovery, especially in therapeutic areas such as oncology, microbiology, and virology. The pyrrole nucleus, known for its biological versatility, is a key structure in the synthesis of bioactive compounds. Its most notable applications include anticancer, antimicrobial, and antiviral activities, with numerous pyrrole derivatives showing remarkable efficacy in fighting diseases such as cancer, bacterial, fungal, and viral infections [5]. Furthermore, the development of pyrrole analogs has enabled the creation of drugs with broad therapeutic properties, such as antipsychotics, anxiolytics, and antimalarials, standing out in the treatment of conditions such as leukemia, lymphoma, and myeloid fibrosis [6]. The continued study of pyrrole derivatives through conventional and modern synthetic approaches remains a promise in pharmaceutical research, driving the search for new routes of development of more effective drugs in the treatment of infectious and non-infectious diseases such as cancer and neurodegenerative disorders [7].

Although there are many reports related to synthesizing substituted pyrroles, few involve obtaining 2,3,4,5-tetrasubstituted systems. The most widely used methodology involves the use of photochemical reactions, such as the study of the reaction of 1,1′-bis-(methoxycarbonyl) divinylamine (BDA) with acetylenedicarboxylates, which has led to the obtaining of 7-azabicyclo[2.2.1]hept-2-ene-1,2,3,4-tetracarboxylates, which were thermally transformed into 1H-pyrrole-2,3,4,5-tetracarboxylates at a high yield [8]. This reaction provided an efficient route for the synthesis of pyrrolotetracarboxylates. On the other hand, an efficient [3 + 2] cyclization reaction between isocyanides and 4-(arylidene)-2-substituted oxazol-5(4H)-ones has been developed [9], which allows the formation of tri- and tetrasubstituted pyrrole derivatives (Scheme 1). This base-catalyzed process is carried out at room temperature under environmentally friendly conditions, without transition metals, and is compatible with water and air. This methodology promises to be helpful for the synthesis of more complex molecules containing pyrroles.

Cyclocondensation reactions have also been reported for this purpose (Scheme 2). Simple methods for the synthesis of 2,4- and 3,5-disubstituted pyrroles by the cyclocondensation of enones with aminoacetonitrile, followed by microwave-assisted dehydrocyanation or dehydrogenation with DDQ have been described, constituting a simple and efficient entry for useful pyrrole compounds [10]. A strategy to synthesize 2,3,4,5-tetrasubstituted pyrroles from oxime-dienedioates and nitroolefins [11] has inspired the present manuscript. This reaction, which involves a double Michael addition followed by a dehydrative aromatization, utilizes a strong base and could have applications in the preparation of heterocyclic compounds of biological interest and organic materials.

Starting from this background, the present study describes the intramolecular cyclocondensation of 2-aminoacid-derived enamine-type Schiff bases, as previously reported in the literature [11,12], towards the formation of novel compounds of the type 1-(5-substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-one (Scheme 2c). The optimization of the synthetic method, the substituent effect, the characterization of the compounds, and the possible reaction mechanism are discussed below.

2. Results and Discussion

The synthetic route was started by converting ʟ-alanine, ʟ-tyrosine, ʟ-phenylalanine, and ʟ-tryptophan to the respective esters through a previously reported procedure [13]. Thus, alkyl 2-aminoesters were separately obtained in excellent yields (93–98%) from aliphatic alcohol. Therefore, the reactions of 2-aminoesters with dicarbonyl compounds (e.g., acetylacetone, ethyl acetoacetate, and cyclohexane-1,3-dione) were conducted to afford enamine-type compounds using the one-pot-based synthetic method proposed by Borrego-Muñoz et al. [12,14]. Two methodologies were evaluated with the aim of improving the yield of the desired compounds. First, enamine-type compounds were mixed with sodium ethoxide in ethanol, and then each mixture was heated over reflux conditions for 48 h. Second, each enamine-type compound was treated with sodium ethoxide in ethanol under microwave irradiation for 30 min. Both methodologies afforded pyrrole-oriented cyclocondensation (Scheme 3,

Table 1. Yields for synthesized compounds employing two methodologies: conventional conditions vs. the MW-assisted method.

Enamine a	R1	R4	Product b	Conventional Conditions c	MW-Assisted Method
				Yield (%)	Yield (%)
2a	CH2Ph	Me	1a	23	86
2b	CH2Ph	Et		24	83
2c	CH2Ph	i-Pr		17	61
2d	CH2Ph	n-Bu		16	57
2e	CH2(4-PhOH)	Me	1b	24	82
2f	CH2(4-PhOH)	Et		25	79
2g	CH2(4-PhOH)	i-Pr		19	62
2h	CH2(4-PhOH)	n-Bu		17	55
2i	CH2(3-1H-indolyl)	Me	1c	22	77
2j	CH2(3-1H-indolyl)	Et		24	72
2k	CH2(3-1H-indolyl)	i-Pr		19	67
2l	CH2(3-1H-indolyl)	n-Bu		17	56
2m	Me	Me	1d	26	85
2n	Me	Et		27	81
2o	Me	i-Pr		19	65
2p	Me	n-Bu		17	57

^a Enamine precursors 2a-p illustrated in Scheme 2. ^b Target 2,3,4,5-tetrasubstituted 1a-d pyrroles illustrated in Scheme 2. ^c Reflux during 48 h.

). Next, diluted hydrochloric acid was added to neutralize, and ethyl acetate was used to extract the crude product. The main product of each reaction was finally purified through conventional column chromatography (CC). When enamines derived from ethyl acetoacetate were used as precursors, thin-layer chromatography (TLC) analysis revealed the formation of multiple by-products.

FT-IR, ¹H and ¹³C NMR, HPLC-ESI-MS analysis, and HR-ESI-MS showed that 2,3,4,5-tetrasubstituted pyrroles 1a-d were effectively formed when the reaction employed enamines derived from acetylacetone 2a-p. Spectroscopic characterization data are consistent with those previously reported by Quiroga et al. [15]. For the synthesis of compounds 1a-d from enamines 2a-p by an intramolecular cyclization reaction, two methodologies were compared: conventional conditions and the microwave-assisted (MW) method. The results are depicted in Table 1 and show a significant improvement in yields when microwave irradiation (MW) is used. The yield for product 1a with group R¹ = CH₂Ph increased from 23% under conventional conditions to 86% under MW-assisted conditions. This trend was maintained in the other cases; for example, product 1b (with R¹ = CH₂(4-PhOH)) presented a yield of 24% under conventional conditions and 82% under microwave. Similarly, for product 1c (with R = CH₂(3-1H-indolyl)), the yield increased up from 22% to 77%. Although the difference in yields varied slightly between different substituent groups, overall, the MW-assisted methodology showed superior yields, with values generally above 70% compared to the lowest yields observed under conventional conditions. Furthermore, different variations in the R¹ groups seemed not to significantly affect the improvement in yields upon MW irradiation. However, the benzyl group likely offered a balance of moderate steric effects and resonance stabilization, enhancing reaction efficiency. When R¹ was substituted with CH₂(4−PhOH) (4-hydroxybenzyl) from ʟ-tyrosine, the yields were slightly lower than those for CH₂Ph across all R⁴ groups. This reduction can be attributed to electronic effects from the hydroxyl group on the benzyl ring, which may alter the reactivity of the enamine. Substituting R¹ with CH₂(3H-indol-3-yl) from ʟ-tryptophan introduced additional steric and electronic complexities, resulting in slightly lower yields compared to the benzyl and 4-hydroxybenzyl-derived series. This effect was likely due to the extended structure of the indole group, which increased steric interference during the reaction. The simplest substituent for the R¹, methyl group from ʟ-alanine, achieved relatively high yields across the board. Minimal steric interference and consistent reactivity made this group particularly effective. The electronic nature of R¹, particularly in functionalized groups like CH₂(4−PhOH) or CH₂(3H−indol-3-yl), further modulated reactivity and yield. These findings underline the critical interplay between steric and electronic effects in optimizing reaction outcomes to obtain these 2,3,4,5-tetrasubstituted pyrroles. A comparison between the use of different alkyl ester groups in enamines precursors 2a-p revealed significant influences from the substituents at R⁴ (Table 1). A clear trend was observed where the yields decreased consistently as the bulkiness of the R⁴ substituent increased. For instance, compounds with R⁴ = Me generally achieved the highest yields, while those with R⁴ = n-Bu consistently exhibited the lowest yields. This pattern strongly suggests that steric hindrance from larger R⁴ groups limits the efficiency of the reaction, likely by interfering with the approach or proper orientation of reactants during the key steps of the synthesis.

These results suggest that the MW-assisted method favored the intramolecular cyclization reaction, improving the efficiency and rate of the reaction by providing more uniform and controlled energy. The use of microwave (MW) irradiation in organic synthesis has proven to be highly beneficial, particularly in accelerating reactions, increasing yields under milder conditions, and improving the purity of the products obtained [16]. The thermal effects of MW irradiation derive from several factors, including the heating rate, localized overheating, and the formation of “hot spots”, as well as the selective absorption of radiation by polar compounds. MW irradiation not only reduces reaction times but also increases yields, resulting in a more efficient process compared to the evaluated conventional methodology, where heating is slower and less controlled. Furthermore, the use of MW in this type of reaction allowed us to operate under milder conditions, contributing to the reduction in energy consumption.

MW has proven to be a powerful tool in various organic synthesis methodologies, providing significant advantages in terms of reaction rate, yield, and product selectivity. The synthesis of macrocyclic Schiff bases via the condensation of dialdehydes with diamines has been explored using MW-assisted methodology [17]. Under conventional thermal conditions, the reaction generated a mixture of linear oligomers and macrocycles with moderate yields. However, MW irradiation has allowed the selective formation of the desired macrocycles with higher yields and shorter reaction times. The formation of oxazoles from oximes and acyl chlorides by MW irradiation demonstrated the effectiveness of this protocol since MW irradiation significantly accelerated the reaction and improved the efficiency of the process in comparison with traditional thermal methods [18]. MW irradiation has also been successfully applied in tandem cross-metathesis reactions with aza-Michael. In these transformations, the combination of the Hoveyda–Grubbs catalyst with BF₃∙OEt₂ and the use of microwaves has been shown to significantly accelerate the formation of β-aminocarbonyl units. Furthermore, a positive effect on the selectivity of the reaction has been reported, highlighting the influence of irradiation on the stereoelectronic configuration of the obtained products [19]. Finally, the synthesis of substituted aporphines, such as MW, has allowed for a significant improvement in yields and a reduction in reaction times compared to conventional methods. The enamine-type addition of dehydroaporphins with electrophiles presents limitations under conventional heating, such as long times and low conversions. However, the application of MWs has optimized this process, allowing the production of the desired products in reduced times and with better yields [20]. These antecedents support our results, allowing us to conclude that MW irradiation provided significant improvements in the efficiency of our synthetic methodology.

The structural elucidation of products 1a-d was carried out using spectroscopic techniques such as FT-IR, ¹H and ¹³C NMR, HPLC-ESI-MS analysis, and HR-MS. The results for compounds 1a, 1b, and 1d, analyzed by ART-FT-IR spectroscopy (Figures S1, S5 and S9), were compared with reports of similar compounds [21,22,23]. These results showed good agreement with the data reported in the literature, although with some small variations attributable to the influence of the substituents. The C-O stretching band characteristic of phenols was observed in the three compounds in the range of 1365–1364 cm⁻¹, which were slightly shifted with respect to the literature value (1350 cm⁻¹), which could be due to the presence of substituents in the ring that affect the vibration frequency. The C-N stretching band in pyrroles, which appeared between 1413 and 1415 cm⁻¹, was also shifted towards higher values (20–24 cm⁻¹) compared to the literature value (1391 cm⁻¹), suggesting an effect of the substituents on the vibration of this bond. As for the C=C stretching in aromatic systems, a shift towards lower values (from 14 to 19 cm⁻¹) was observed with respect to the literature, which may be a consequence of the effects of the substituents on the electronic delocalization of the aromatic ring. The O-H and N-H stretching bands, which appeared in the range of 3400–2800 cm⁻¹, showed a shift towards lower values compared to the values reported in the literature (3300–3210 cm⁻¹), which may be related to the interaction of the OH groups with other nearby functional groups. The C_sp3-H and C_sp2-H stretching bands in compounds 1a, 1b, and 1d were shifted to higher and lower values, respectively, compared to the literature, indicating the influence of the substituents on the vibration of these bonds. Finally, the C=O stretching appeared in the range of 1600–1605 cm⁻¹ and was slightly shifted to lower values with respect to the literature (1644–1590 cm⁻¹), which might reflect the effects of the substituents on the conjugation and polarity of the carbonyl group. Overall, the observed shifts were small and consistent with the moderate influence of the substituents on the vibration frequencies, confirming the ability of the substituent groups to modify the electronic and bonding properties without drastically altering the assignment of the spectroscopic bands.

From the data obtained in the ¹H and ¹³C NMR spectra (Figures S2, S6 and S10), it is possible to corroborate the structures of compounds 1a-d, considering the distribution and nature of the functional groups present in the pyrrole heterocyclic ring and its substituents. The ¹H NMR spectrum of 1a (Figure S2) shows a signal corresponding to the methyl group located at position two of the pyrrole rings, appearing as a singlet between δ_H 1.90 and 2.00 and integrating three protons. This fact suggests that the group is chemically equivalent and has no neighboring protons causing coupling, which is typical of a methyl group directly attached to a carbon ring. The methyl group at position three (adjacent to the carbonyl group) appears as a signal between δ_H 2.10 and 2.20 and integrates three protons. The proximity to the carbonyl group induces a slight downfield shift due to the depolarizing effect of electronegative oxygen, confirming the presence of a methyl group attached to a carbonyl carbon. The benzyl group at position five of the pyrrole shows two characteristic signals, a singlet between δ_H 3.70 and 3.80 corresponding to the two methylene protons (-CH₂-) attached to the aromatic ring and multiple signals (overlapping doublets and triplet) between δ_H 7.00 and 7.40 corresponding to the protons of the monosubstituted aromatic system. These signals confirm the presence of a benzyl group at position five of the pyrrole ring. A broad signal (broadened singlet) between δ_H 5.80 and 6.00 is attributed to the proton of the hydroxyl group (-OH). The broadening of the signal is characteristic of rapid proton exchange due to the formation and breaking of hydrogen bonds in the solution.

Regarding the ¹³C NMR spectrum (Figure S3), the methyl group at position two of the heterocyclic system is evidenced as a signal with a shift between δ_C 18 and 19, which is consistent with primary aliphatic carbon. The carbon of the methyl group attached to the carbonyl carbon is shifted between δ_C 28 and 29, slightly downfield compared to the first methyl due to the inductive effect of the carbonyl group. The carbon of the methylene group (-CH₂-) appears between δ_C 30 and 31, while the carbon of the aromatic system is distributed between δ_C 95 and 165. This assignment includes the carbons of the monosubstituted benzene ring and the carbons of the pyrrole ring. It is noteworthy that the carbon at position four of the heterocyclic ring is more greatly shifted (δ_C 162), indicating the inductive effect of the hydroxyl group at this position. The carbonyl carbon (C=O) presents a characteristic shift between δ_C 193 and 196. This high value, even within the range expected for ketone carbons, can be explained by forming an intramolecular hydrogen bond between the hydroxyl group at position four and the oxygen of the carbonyl group, stabilizing the resonance.

The analysis of compounds 1a, 1b, and 1d by HPLC-DAD and HPLC-ESI-MS revealed a clear identification for each of them based on the detected ions and the retention times (Figures S4, S8 and S12). Compound 1a presented a retention time of 8.2 min, with a single peak corresponding to the [M+H]⁺ ion at m/z 230.1 and the adduct ion [M+CH₃CN]⁺ at m/z 271.1. The expected exact mass, 229.1102 uma, fit well with the obtained values, suggesting high purity and structural correspondence. Compound 1b, with a retention time of 7.6 min, showed a [M+H]⁺ ion at m/z 246.1 and a [M+CH₃CN]⁺ ion at m/z 287.1, with an expected exact mass of 245.1051 uma, which is also consistent with the structure of the compound. Similar results were obtained for compound 1d. HRMS confirmed these results (Figures S13–S15). In the case of compound 1a, the observed ion [M+H]⁺ (m/z 230.1177) closely matched the exact expected mass (229.1102 um), with an error of 1.75 ppm with respect to the calculated mass for this ion, suggesting high accuracy in the determination of its molecular formula, C₁₄H₁₆NO₂. For compound 1b, the detected ion [M+H]⁺ (m/z 246.1121) also showed a good match with the expected mass (245.1052 uma), exhibiting an error of 3.73 ppm and confirming that the proposed molecular formula (C₁₄H₁₆NO₃) is adequate. Finally, compound 1d showed a detected ion [M+H]⁺ (m/z 154.0857) with an error of 7.16 ppm for a molecular formula of C₈H₁₂NO₂.

Finally, a reaction mechanism for the formation of compounds 1a-d was proposed. To achieve intramolecular cyclization, it was necessary to deprotonate the enamine and, thus, activate its reactivity as aza-enolate. A small, strong base, such as sodium ethoxide, was employed to complete this step. However, the attack involving 5-exo-trig cyclization required a stable boat-like conformation, which is favorable when using only aliphatic-backbone enamines. However, ring strains in cyclic-backbone enamines may discourage the possible transition state (Scheme 4). In addition, the size of the cyclic moiety can hinder the deprotonation process, hindering the progress of the reaction. An increase in the basicity of the medium or the reaction temperature may promote side reactions, such as intermolecular Claisen condensations. These reactions tend to dominate due to the acidity of the hydrogen atom attached to the enamine’s chiral center, as observed in acetoacetate-derived enamines. In the context of aldol and Claisen condensation reactions, various side processes—such as retrocondensations and reketonization reactions—could also significantly affect the yield of the expected products. Retrocondensation reactions are particularly prominent in β-diketone condensations, where intermediates can decompose into acid–ketone pairs through the cleavage of one of the involved carbonyl groups. Under specific conditions, such as treatment with bases like OH^– or CH₃O^–, this process can lead to a rearrangement, resulting in the formation of asymmetric ketones—a reaction referred to as “reketonization” [24,25]. Another type of undesired reaction involves the formation of secondary products. For instance, in the reaction of 1,3-diketones with cyclic amines, instead of yielding the desired pyrroles, the process can generate enaminones and amides through pathways such as Claisen retro-condensation [26]. These competing reactions can lead to the accumulation of unwanted products, thereby reducing synthetic efficiency. The presence of strong bases, such as sodium alkoxides, facilitates the reaction with the carbonyl group of esters in condensation processes. However, it can also lead to the formation of intermediates, such as acyloins and diketones, adding further complexity to the control of the condensation process [26].

3. Materials and Methods

3.1. General Information

The reagents and chemicals were commercially acquired (Merck KGaA and/or Sigma-Aldrich, San Luis, MO, USA) and were employed without additional refinement. The progression of reactions and purifications of products were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 plates (Merck KGaA, Darmstadt, Germany) under detection at 254 nm or using iodine as a revelator reagent. Microwave-assisted reactions were performed in a Microwave Synthesizer Discover at constant temperature and varying power and pressure. Silica gel 60 (0.040–0.063 mm mesh) (Merck KGaA) was used for column chromatography. A Bruker Avance AV-400 MHz spectrometer was employed for nuclear magnetic resonance (NMR) experiments. TMS was utilized as a reference to give chemical shifts in δ (ppm). Liquid chromatography–mass spectrometry (LC/MS) experiments were performed on an LCMS 2020 spectrometer (Shimadzu, Columbia, MD, USA), comprising a Prominence high-performance liquid chromatography (HPLC) system coupled with a single quadrupole analyzer with electrospray ionization (ESI). A Synergi column (150 × 4.6 mm, 4.0 µm) was used for analysis at 0.6 mL/min using mixtures of acetonitrile (A) and 1% formic acid (B) in gradient elution. The ESI was operated simultaneously in positive and negative ion modes (100–2000 m/z sweep), with a desolvation line temperature of 250 °C, nitrogen as a nebulizer gas at 1.5 L/min, drying at 8 L/min, and a detector voltage at 1.4 kV. High-resolution MS (HRMS) recorded accurate mass data on an Agilent Technologies 1260 Liquid Chromatography system coupled to a Q-TOF 6545 quadrupole time-of-flight mass analyzer with electrospray ionization (Agilent Technologies, Santa Clara, CA, USA). The detection by mass spectrometry was performed in positive and negative ESI ion modes (100–2000 m/z sweep), with a desolvation line temperature of 250 °C, nitrogen as a nebulizer gas at 1.5 L/min, drying at 8 L/min, quadrupole energy at 7.0 eV, and collision energy at 14 eV.

3.2. General Methodology for the Synthesis of 1H-Pyrrol-3-ols (1a-d) from Enamines (2a-p)

Alkyl 2-aminoester precursors were prepared following the previously reported methodology [11]. Then, enamine compounds 2a-p were obtained via a reaction against acetylacetone following the Borrego-Muñoz protocol [10]. Characterization data are consistent according to the study reported previously. A mixture of the corresponding enamine 2a-2p (1 mmol), and sodium ethoxide (2 mmol) in ethanol (5 mL) was placed in a 10 mL vessel. The reaction mixture was irradiated by microwave, varying the outpower until a reaction temperature of 70 °C was reached using a Microwave Synthesizer Discover (CEM) for 30 min. TLC monitoring was implemented using ethyl acetate/petroleum ether mixtures as mobile phases. Reduced pressure was used to concentrate the reaction mixtures. Conventional CC was employed to purify the afforded products 1a-d.

1-(5-benzyl-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-one (1a). Yellow resin, obtained with a yield of 57–86%, soluble in methanol, dichloromethane, ethanol, chloroform, and ethyl acetate. Insoluble in water and petroleum ether. ATR-FT-IR υ in cm⁻¹: 3400–2800, 3050, 2980, 1605, 1580, 1413, 1365. ¹H NMR (400 MHz, CDCl₃): δ in ppm: 7.33–7.00 (m, 5H), 3.73 (s, 2H), 2.17 (s, 3H), 1.99 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.9, 136.2, 129.4, 129.2, 128.8, 128.7, 127.2, 126.7, 96.7, 30.5, 29.1, 18.8 ppm. ESI-HRMS m/z: [M+H]⁺, 230.1177 (calcd. 230.1181)

1-(4-hydroxy-5-(4-hydroxybenzyl)-2-methyl-1H-pyrrol-3-yl)ethan-1-one (1b). Yellow resin, obtained with a yield of 55–82%, soluble in methanol, dichloromethane, ethanol, chloroform, and ethyl acetate. Insoluble in water and petroleum ether. ATR-FT-IR υ in cm⁻¹: 3400–2800, 3050, 2950, 1600, 1575, 1411, 1362. ¹H NMR (400 MHz, CDCl₃): δ in ppm: 7.00 (d, J = 7.1 Hz, 2H), 6.67 (d, J = 7.1 Hz, 2H), 3.10 (s, 2H), 2.46 (s, 3H), 2.36 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.6, 162.1, 136.3, 126.9, 124.2, 119.0, 111.6, 108.6, 96.5, 30.3, 28.7, 18.8 ppm. ESI-HRMS m/z: [M+H]⁺, 246.1121 (calcd. 246.1130)

1-(5-((1H-indol-3-yl)methyl)-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-one (1c). Yellow resin, obtained with a yield of 56–77%, soluble in methanol, dichloromethane, ethanol, chloroform, and ethyl acetate. Insoluble in water and petroleum ether. ¹H NMR (400 MHz, CDCl₃): δ in ppm: 9.33 (s, 1H), 7.58 (m, 1H), 7.32 (m, 1H), 7.11 (m, 1H), 7.10 (m, 2H), 3.32 (s, 2H), 2.03 (s, 3H), 1.68 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.6, 162.2, 136.3, 127.0, 124.2, 121.7, 121.4, 119.1, 118.1, 118.0, 111.6, 111.1, 108.9, 96.5, 69.4, 29.4, 26.6 ppm. Data are consistent according to the report by Quiroga et al. [12]

1-(4-hydroxy-2,5-dimethyl-1H-pyrrol-3-yl)ethan-1-one (1d). Yellow resin, obtained with a yield of 57–85%, soluble in methanol, dichloromethane, ethanol, chloroform, and ethyl acetate. Insoluble in water and petroleum ether. ATR-FT-IR υ in cm⁻¹: 3400–2800, 3050, 2960, 1605, 1560, 1415, 1364. ¹H NMR (400 MHz, CDCl₃): δ in ppm: 3.76 (s, 2H), 2.17 (s, 3H), 2.00 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 196.0, 130.5, 126.0, 115.9, 96.8, 28.4, 19.1, 13.7 ppm. ESI-HRMS m/z: [M+H]⁺, 154.0857 (calcd. 154.0868).

4. Conclusions

The study expanded the scope of an intramolecular cyclocondensation strategy to synthesize novel 2,3,4,5-tetrasubstituted pyrroles from 2-aminoacid-derived enamine-type Schiff bases. This optimized methodology, employing microwave irradiation and sodium ethoxide, demonstrated the successful formation of pyrrole derivatives with moderate-to-high yields, showcasing steric and electronic influences of substituents on reaction efficiency. Notably, the highest yield (86%) was achieved with benzyl-substituted derivatives from methyl ʟ-phenylalaninate, which can be attributed to the favorable balance of steric effects and resonance stabilization. Conversely, steric hindrance from bulkier groups, such as n-Bu, significantly reduced yields, emphasizing the role of substituent size in reaction outcomes. Spectroscopic analyses confirmed the structural integrity of the synthesized pyrroles, corroborating the functional group distribution within the heterocyclic framework. The use of enamines derived from acetylacetone was critical to achieving the desired cyclization, whereas derivatives of ethyl acetoacetate and cyclohexane-1,3-dione failed to yield pyrroles due to steric and conformational challenges in the transition states. This work underscores the importance of steric and electronic effects in designing efficient synthetic strategies for complex heterocyclic compounds. The findings provide valuable insights for developing biologically relevant pyrrole derivatives with potential applications in medicinal chemistry and materials science. Future studies should explore alternating precursors and conditions to expand the scope of this synthetic approach.