Next Article in Journal
Electrochemical Performance of Nitrogen-Doped TiO2 Nanotubes as Electrode Material for Supercapacitor and Li-Ion Battery
Next Article in Special Issue
One-Pot Metal-Free Synthesis of 3-CF3-1,3-Oxazinopyridines by Reaction of Pyridines with CF3CO-Acetylenes
Previous Article in Journal / Special Issue
Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 24
Issue 16
10.3390/molecules24162951
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Communication

A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives

by
Xabier del Corte
,
Edorta Martinez de Marigorta
,
Francisco Palacios
* and
Javier Vicario
*
Departamento de Química Orgánica I, Centro de Investigación y Estudios Avanzados “Lucio Lascaray”- Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(16), 2951; https://doi.org/10.3390/molecules24162951
Submission received: 24 July 2019 / Revised: 6 August 2019 / Accepted: 11 August 2019 / Published: 14 August 2019
(This article belongs to the Special Issue Modern Strategies for Heterocycle Synthesis)
Browse Figures
Versions Notes

Abstract

:
Brønsted acids catalyze a multicomponent reaction of benzaldehyde with amines and diethyl acetylenedicarboxylate to afford highly functionalized γ-lactam derivatives. The reaction consists of a Mannich reaction of an enamine to an imine, both generated in situ, promoted by a phosphoric acid catalyst and a subsequent intramolecular cyclization. The hydrolysis of the cyclic enamine substrate can provide enol derivatives and, moreover, a second attack of the amine on the carboxylate can afford amide derivatives. An optimization of the reaction conditions is presented in order to obtain selectively cyclic enamines that can afford the enol species after selective hydrolysis.

Graphical Abstract

1. Introduction

Multicomponent reactions (MCRs) [1,2] are valuable processes where three or more substrates, which are simultaneously (or almost) added, react in a single vessel to form a new structure that contains substantial portions of all the starting materials. Strecker, Hantzsch, Biginelli, Passerini, Gröbcke-Blackburn-Bienaymé, Kabachnik-Fields, or Ugi are some of the names of classical reactions that fit with this definition, and they are widely used in organic synthesis [1,2]. Due to the high degree of molecular diversity achieved in MCRs, they are now an essential tool in diversity-oriented synthesis [3,4], with huge potential in the field of medicinal chemistry [5,6]. Considering the relevance of the γ-lactam ring I (Figure 1) [7] and the increasing demand of potentially active compounds in medicinal sciences, MCR protocols were extensively used during the last decades for the synthesis of a wide number of densely functionalized γ-lactam derivatives [8,9]. In particular, 1,5-dihydro-2H-pyrrol-2-ones II (Figure 1) are conjugated unsaturated γ-lactam substrates with huge potential as intermediates in synthetic chemistry that also show assorted pharmacological activities [10,11,12,13].
Within this family of compounds, the structure of their 3-amino substituted derivatives III (Figure 1) contains the enamine moiety and, in addition to their obvious applications as synthetic intermediates in organic synthesis [14,15], their skeleton is also present in many new bioactive ingredients such as antimicrobials with anti-biofilm activity, caspase-3 inhibitors, antipyretics, or analgesics [16,17,18,19,20]. Moreover, these cyclic α-dehydro α,β-diamino acid derivatives contain the essential structure of dithiopyrrolone antibiotics IV (Figure 1) [21] and are key intermediates for the synthesis of Amaryllidaceae and Sceletium alkaloids [22,23].
Several MCR procedures for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones were reported to date [8]. In particular, some years ago, we reported a three-component reaction of ethyl pyruvate 1, aldehydes 2, and amines 3 mediated by sulfuric acid that yields very efficiently highly functionalized γ-lactam derivatives 7 [24]. In this reaction, an initial simultaneous condensation of amines 3 with both ethyl pyruvate 1 and aldehydes 2 leads to the formation of intermediate enamine 4 and aldimine 5 that undergo a subsequent Mannich reaction, followed by a cyclization reaction driven by the formation of an internal amide bond in the resulting adduct 6 (Scheme 1).
Based on this report, some authors later described several modifications of this synthetic procedure, and the uncatalyzed [25] or solvent-free [26] reaction, and the use of recyclable catalysts [27] were reported in the last few years. Interestingly, it was also established that such reaction can be performed under organocatalysis [28] and, taking the advantage of this fact, very recently, we achieved a highly enantioselective version of this reaction using 1,1′-bi-2-naphthol (BINOL)-derived chiral phosphoric acids as catalysts [29].
A similar multicomponent process, where dialkyl acetylenedicarboxylates are used instead of ethyl pyruvate, was also reported for the synthesis of 3-amino 1,5-dihydro-2H-pyrrol-2-ones. In this case, the nucleophilic addition of aromatic amines to the activated alkyne gives rise to a deactivated enamine intermediate and 0.5 equivalents of benzoic acid are required in order to promote the subsequent Mannich reaction [30]. Activation of this process was also described by the use of molecular iodine [31] or graphene-oxide nanosheets under solvent-free conditions [32]. In this context, organocatalysis is identified to be at the heart of greening of chemistry, because this branch of science is found to reduce the environmental impact of chemical processes. Therefore, in view of the demonstrated ability of phosphoric acids to catalyze the nucleophilic addition of pyruvate-derived enamines 4 to imines 5, we thought that this activation could be extended to the enamines derived from dialkyl acetylenedicarboxylates. Consequently, continuing with the interest of our research group in the synthesis of nitrogenated heterocycles [33,34,35,36] and amino-acid derivatives [37,38,39,40], we report here the use of phosphoric acids as catalysts in a three-component reaction of amines, benzaldehyde, and diethyl acetylenedicarboxylate to afford densely functionalized γ-lactam derivatives.

2. Results

Based on our previous experience in MCRs for the synthesis of 3-amino 1,5-dihydro-2H-pyrrol-2-ones [11,14], we firstly used BINOL-derived phosphoric acid 9 as a Brønsted acid catalyst in the three-component reaction of benzaldehyde 2, p-toluidine 3 (R = p-MeC6H4), and diethyl acetylenedicarboxylate 8 using refluxing dichloromethane as solvent (Scheme 2). However, only the enamine and/or imine intermediates that result from the reaction of amine substrate 3 with benzaldehyde 2 or alkyne 8 were observed in the crude (Table 1, Entry 1). Considering that our previously reported three-component reaction of ethyl pyruvate, benzaldehyde, and amines smoothly yields the corresponding 3-amino 1,5-dihydro-2H-pyrrol-2-ones, we thought that the increased steric hindrance, together with the additional deactivation present in the enamine intermediate when acetylenedicarboxylates 8 are used instead of pyruvate derivatives, may be the reason for the lack of reactivity in this case.
Then, we tried to perform the reaction at higher temperature and, although the same results were observed using tetrahydrofurane (THF) or dimethoxyethane (DME) as solvents (Table 1, Entries 2 and 3), the reaction in refluxing methyl tert-butylether (MTBE) proceeded in full conversion in a few hours, affording the expected 3-amino 1,5-dihydro-2H-pyrrol-2-one 10a together with enol derivative 11a [41], which may result from the hydrolysis of enamine moiety in 10a (Table 1, Entry 4). The use of an excess of ethyl pyruvate in the parent MCR with benzaldehyde and amines proved to be very effective in reducing the reaction times and temperatures [29]; however, remarkably, when three equivalents of acetylene derivative 8 were used, no formation of γ-lactam derivatives 10a or 11a was observed due to the consumption of p-toluidine 3a (R = p-MeC6H4) by reaction with the excess of diethyl acetylenedicarboxylate 8 (Table 1, Entry 5).
Better selectivity was observed when the reaction was performed using hot dioxane as solvent. In this case, amino 1,5-dihydro-2H-pyrrol-2-one 10a was obtained together with a significant amount of amide derivative 12a, which presumably results from the nucleophilic attack of amine on the ethyl carboxylate moiety in compound 10a (Table 1, Entry 6). Finally, the selectivity of the reaction was further improved using toluene as the reaction solvent, and only a small amount (5%) of amide derivative 12a was obtained together with γ-lactam 10a (Table 1, Entry 7). Under the same conditions, the use of more nucleophilic p-anisidine 3b (R = p-MeOC6H4) in the reaction yielded 1,5-dihydro-2H-pyrrol-2-one 10b as the major product of the reaction although, in this case, together with a 30% of amide derivative 12b (Table 1, Entry 8). In order to obtain exclusively amide substrate 12b, four equivalents of amine were used under the same reaction conditions, but the same proportion of the products was observed (Table 1, Entry 9). However, the use of benzylamine 3c (R = Bn) afforded exclusively 1,5-dihydro-2H-pyrrol-2-one 10c, and no formation of enol 11c or amide 12c was observed (Table 1, Entry 10). The selectivity in this case could be explained by the lower steric crowding in the enamine moiety in benzylamine derivative 10c if compared to the aromatic derivatives 10a and 10b [42].
In view of the three compounds observed, the reaction mechanism could start with an initial concomitant addition of amines 3 to acetylene carboxylate 8 and benzaldehyde 2 that affords enamine 13 and aldimine 14. Both species 13 and 14 can be observed by 1H-NMR. Then, a subsequent Mannich reaction leads to the formation of adduct 15, which undergoes an intramolecular cyclization by the formation of an internal amide bond between the amine and carboxylate moieties to afford enamine type γ-lactam 10. Due to the presence of water and some remaining amine 3, the γ-lactam 10 may afford enol type lactam 11 through hydrolysis of the enamine moiety or amide derivative 12, through the displacement of ethanol by the amine (Scheme 3). This is supported by the fact that, using high-boiling-point solvents, no enol derivative 11 is observed, which may be due to the instantaneous evaporation of water at high reaction temperatures.
In our case, the three resulting γ-lactam structures 10, 11, and 12 could be separated in all the cases by simple chromatography, and they were fully characterized on the basis of their spectroscopic data. However, due to the structural resemblance between all the lactam derivatives, in order to unambiguously determine the identity of the substrates of the reaction, a single crystal of enol 11a was prepared, and its X-ray diffraction structure was obtained (Figure 2). Key features of the crystal structure are the almost planar shape of the five-membered ring and the presence of a hydrogen bond between the enol hydrogen and the carboxylate group in a six-membered ring configuration rather than with the amide carboxylate, forming a five-membered ring.
In order to set up the optimal conditions for the preparation of enol derivatives 11, we proposed the corresponding reactions starting from their parent 1,5-dihydro-2H-pyrrol-2-ones 10 (Scheme 4). Therefore, the hydrolysis of enamine moiety in 10 was performed by treatment of 1,5-dihydro-2H-pyrrol-2-ones 10 in the presence of aqueous hydrochloric acid in refluxing THF. Despite the strong acidic conditions, no trace of the products derived from the hydrolysis of ester of amide groups are observed and enol derivatives 11 are obtained in quantitative yields.
In addition, the treatment of benzylamine derivative γ-lactam 10 (R = Bn) with a catalytic amount of palladium under hydrogen atmosphere during several days led to the exclusive deprotection of the nitrogen at the enamine moiety in quantitative yield to afford lactam 16. Remarkably, the benzyl group at the endocyclic nitrogen and the enamine double bond remained unaltered under those reaction conditions. Although the reaction times are very long, this process can be sped up by the addition of one equivalent of aqueous hydrochloric acid (Scheme 4).
Taking into account the typical activation accepted by phosphoric acid catalysts [43,44,45], we propose a tentative transition state for the key Mannich reaction, where a dual activation of imine and enamine species takes place by the simultaneous formation of two hydrogen bonds between the phosphoryl oxygen and the acidic proton of the phosphoric acid group with the enamine proton and the iminic nitrogen, respectively (Figure 3).
According to the transition state proposed, we may expect substantial enantiomeric excesses for this reaction. However, when enantiomerically pure chiral phosphoric acids were used as catalysts, very poor enantioselectivities were observed with a maximum enantiomeric excess of 5%. This may be attributable to the high temperatures required for the reaction conditions because of the steric hindrance present in the enamine substrate, together with the additional deactivation of the nucleophile due to the presence of two carboxylate groups.
In conclusion, we report a Brønsted acid-catalyzed MCR procedure for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones where diethyl acetylenedicarboxylate, amines, and benzaldehyde are used as substrates. This is the first example of such a reaction using phosphoric acids as catalyst. Moreover, we present nine highly functionalized γ-lactam derivatives, adding some molecular diversity to the already published substrates. The hydrolysis process of 1,5-dihydro-2H-pyrrol-2-ones from enamine substrates to the enol derivatives 11 was not previously reported.

3. Materials and Methods

General. Solvents for extraction and chromatography were technical grade. All solvents used in reactions were freshly distilled from appropriate drying agents before use. All other reagents were recrystallized or distilled as necessary. All reactions were performed under an atmosphere of dry nitrogen. Analytical thin layer chromatography (TLC) was performed with silica gel 60 F254 plates. Visualization was accomplished by ultraviolet (UV) light. 1H-, 13C-, and 31P-NMR spectra were recorded on a Varian Unity Plus (at 300 MHz, 75 MHz, and 120 MHz, respectively, Advanced Research Facilities (SGIker), by the University of the Basque Country, Vitoria-Gasteiz, Spain) and on a Bruker Avance 400 (at 400 MHz, 100 MHz, and 160 MHz, respectively, Advanced Research Facilities (SGIker), by the University of the Basque Country, Vitoria-Gasteiz, Spain). Chemical shifts (δ) are reported in ppm relative to residual CHCl3 (δ = 7.26 ppm for 1H, and δ = 77.16 ppm for 13C-NMR). Coupling constants (J) are reported in Hertz. Data for 1H-NMR spectra are reported as follows: chemical shift, multiplicity, coupling constant, integration. Multiplicity abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad. 13C-NMR peak assignments were supported by distortionless enhanced polarization transfer (DEPT). High-resolution mass spectra (HRMS) were obtained by positive-ion electrospray ionization (ESI). Data are reported in the form m/z (intensity relative to base = 100). Infrared spectra (IR) were taken in a Nicolet iS10 Termo Scientific spectrometer as neat solids. Peaks are reported in cm−1. Copies of 1H- and 13C {1H} NMR spectra for γ-lactams 10, 11, 12, and 16 are in Supplementary Materials.
Crystal structure determination for compound 11a. Intensity data were collected on an Agilent Technologies Super-Nova diffractometer (Advanced Research Facilities (SGIker), by the University of the Basque Country, Leioa, Spain), which was equipped with monochromated Cu ka radiation (λ = 1.54184 Å) and Atlas CCD detector. Measurement was carried out at 150.00 (10) K with the help of an Oxford Cryostream 700 PLUS temperature device (Advanced Research Facilities (SGIker), by the University of the Basque Country, Leioa, Spain). Data frames were processed (united cell determination, analytical absorption correction with face indexing, intensity data integration, and correction for Lorentz and polarization effects) using the Crysalis software package (Version 1.171.37.31, release 14-01-2014 CryAlis171.NET, compiled Jan 14 2014, 18:38:05, Advanced Research Facilities (SGIker), by the University of the Basque Country, Leioa, Spain). The structure was solved using ShelXS (Sheldrick, 2008, Advanced Research Facilities (SGIker), by the University of the Basque Country, Leioa, Spain) [46] and refined by full-matrix least-squares with SHELXL-97 (Sheldrick, 2008, Advanced Research Facilities (SGIker), by the University of the Basque Country, Leioa, Spain) [47]. Final geometrical calculations were carried out with Mercury [48] and PLATON [49,50] as integrated in WinGX [51].
General procedure for the synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones 10. A solution of benzaldehyde 2 (0.1 mL, 1 mmol), diethyl acetylenedicarboxylate 8 (0.16 mL, 1 mmol), amine 3 (2 mmol), phosphoric acid catalyst 9 (34.8 mg, 0.1 mmol), and anhydrous MgSO4 was stirred in toluene (5 mL) at 110 °C for 48 h. The volatiles were dried off at reduced pressure, and the crude residue was purified by column chromatography (AcOEt/hexanes) to afford pure lactams 10.
Ethyl 5-oxo-2-phenyl-1-(p-tolyl)-4-(p-tolylamino)-2,5-dihydro-1H-pyrrole-3-carboxylate (10a). The general procedure was followed, using p-toluidine (0.21 g, 2 mmol), affording 0.311 g (73%) of 10a as a white solid. Melting point (m.p.) (Et2O) 154–155 °C. 1H-NMR (400 MHz, CDCl3): δ 8.17 (bs, 1H, NH), 7.34 (d, 3JHH = 8.5 Hz, 2H, 2× CHar), 7.26–7.21 (m, 5H, 5× CHar), 7.12 (d, 3JHH = 8.3 Hz, 2H, 2× CHar), 7.08 (d, J = 8.5 Hz, 2H, 2× CHar), 7.03 (d, 3JHH = 8.3 Hz, 2H, 2× CHar), 5.77 (s, 1H, CHN), 4.01 (q, 3JHH = 7.1 Hz, 2H, CH2 OEt), 2.33 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.01 (t, 3JHH = 7.1 Hz, 3H, CH3 OEt). 13C {1H} NMR (101 MHz, CDCl3) δ 164.7 (C=O ester), 164.1 (C=O amide), 142.7 (=Cquat), 137.2 (Cquat), 136.1 (Cquat), 135.5 (Cquat), 134.6 (Cquat), 134.2 (Cquat), 129.5 (2× CHar), 129.1 (2× CHar), 128.4 (2× CHar), 128.1 (CHar), 127.83 (2× CHar), 123.2 (2× CHar), 122.8 (2× CHar), 108.9 (=Cquat), 63.3 (CHN), 60.2 (CH2 OEt), 21.1 (CH3), 21.0 (CH3), 14.0 (CH3 OEt). Fourier-transform IR (FTIR) (neat) νmax: 3289 (N–H), 1701 (C=O), 1679 (C=O), 1632 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 426.1943, found 426.1950.
Ethyl 1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (10b). The general procedure was followed, using p-anisidine (0.25 g, 2 mmol), affording 0.284 g (63%) of 10b as a yellow solid. m.p. (Et2O) 116–117 °C. 1H-NMR (300 MHz, CDCl3) δ 8.20 (bs, 1H, NH), 7.29 (d, 3JHH = 9.1, 2H, 2× CHar), 7.24–7.18 (m, 5H, 5× CHar), 7.15 (d, 3JHH = 8.9 Hz, 2H, 2× CHar), 6.85 (d, 3JHH = 8.9 Hz, 2H, 2× CHar), 6.74 (d, 3JHH = 9.1, 2H, 2× CHar), 5.69 (bs, 1H, CHN), 4.01 (q, 3JHH = 7.1, 2H, CH2 OEt), 3.80 (s, 3H, CH3O), 3.71 (s, 3H, CH3O), 1.02 (t, 3JHH = 7.1, 3H, CH3 OEt). 13C {1H} NMR (75 MHz, CDCl3) δ 164.9 (C=O ester), 163.9 (C=O amide, 157.5 (Cquat), 157.3 (Cquat), 143.4 (=Cquat), 137.3 (Cquat), 131.6 (Cquat), 129.7 (Cquat), 128.4 (2× CHar), 128.1 (CHar), 127.9 (2× CHar), 125.1 (2× CHar), 124.8 (2× CHar), 114.1 (2× CHar), 113.8 (2× CHar), 107.9 (=Cquat), 63.6 (CHN), 60.1 (CH2 OEt), 55.6 (CH3), 55.5(CH3), 14.1 (CH3 OEt). FTIR (neat) νmax: 3436 (N–H), 1704 (C=O), 1672 (C=O), 1629 (C=C). HRMS (Q-TOF) m/z calculated for C22H15Br2N3O3 [M]+ 458.1842, found 458.1844.
Ethyl 1-benzyl-4-(benzylamino)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (10c). The general procedure was followed, using benzylamine (0.21 g, 2 mmol), affording 0.234 g (58%) of 10c as a white solid. m.p. (Et2O) 106–108 °C. 1H-NMR (400 MHz, DMSO-d6) δ 7.36 (m, 4H, 4× CHar), 7.34–7.21 (m, 8H, 7× Char + NH), 7.08 (m, 4H, 4× CHar), 5.09 (d, 3JHH = 6.8 Hz, 2H, CH2 Bn), 4.95 (s, 1H, CHN), 4.86 (d, 3JHH = 15.1 Hz, 1H, CH2 Bn), 3.96–3.81 (m, 2H, CH2 OEt), 3.65 (d, 3JHH = 15.1 Hz, 1H, CH2 Bn), 0.91 (t, 3JHH = 7.1 Hz, 3H, CH3 OEt). 13C {1H} NMR (101 MHz, DMSO-d6) δ 164.6 (C=O ester), 163.5 (C=O amide, 145.3 (=Cquat), 139.8 (Cquat), 137.0 (Cquat), 136.2 (Cquat), 128.0 (2× CHar), 127.9 (2× CHar), 127.8 (2× CHar), 127.5 (CHar), 127.3 (2× CHar), 127.1 (2× CHar), 126.8 (CHar), 126.7 (2× CHar), 126.4 (CHar), 103.4 (=Cquat), 60.8 (CHN) , 58.4 (CH2 OEt), 45.3 (CH2 Bn), 43.4 (CH2 Bn), 13.3 (CH3 OEt). FTIR (neat) νmax: 3430 (N–H), 1691 (C=O), 1665 (C=O) 1624 (C=C). HRMS (Q-TOF) m/z calculated for C22H15F2N3O3 [M]+ 426.1943, found 426.1942.
General procedure for the hydrolysis of compounds 10. To 10 mL of a 3 M HCl/THF (1:1) solution, compound 10 (0.5 mmol) was added; the mixture was heated to 75 °C and stirred overnight. The reaction was monitored by TLC and, once it was finished, the mixture was concentrated under reduced pressure to eliminate the THF, washed with 3 M NaOH (2× 5 mL) and H2O (2× 5mL), and extracted with ethyl acetate. The combined organic phases were dried with anhydrous Mg2SO4, and the crude residue was crystalized in Et2O: pentane.
Ethyl 4-hydroxy-5-oxo-2-phenyl-1-(p-tolyl)-2,5-dihydro-1H-pyrrole-3-carboxylate (11a). The general procedure was followed, affording 0.161 g (95%) of 11a as a white solid. m.p. (Et2O) 170–172 °C. 1H-NMR (300 MHz, CDCl3) δ 9.19 (bs, 1H, OH), 7.38 (d, 3JHH = 8.2 Hz, 2H, 2× CHar), 7.32–7.25 (m, 5H, 5× CHar), 7.09 (d, 3JHH = 8.2 Hz, 2H, 2× CHar), 5.74 (s, 1H, CHN), 4.20 (q, 3JHH =, 7.1 Hz, 2H, CH2 OEt) 2.26 (s, 3H), 1.20 (t, 3JHH = 7.1Hz, 3H, CH3 OEt). 13C {1H} NMR (75 MHz, CDCl3) δ 165.0 (C=O ester), 162.9 (C=O amide), 156.4 (=Cquat), 135.7 (Cquat), 135.3 (Cquat), 133.7 (Cquat), 129.6 (2× CHar), 128.6 (2× CHar), 128.5 (CHar), 127.6 (2× CHar), 122.4 (2× CHar), 113.1 (=Cquat), 61.8 (CHN), 61.2 (CH2 OEt), 20.9 (CH3), 14.0 (CH3 OEt). FTIR (neat) νmax: 3425 (O–H), 1704 (C=O), 1675 (C=O), 1643 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 337.1314, found 337.1319.
Ethyl 4-hydroxy-1-(4-methoxyphenyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (11b). The general procedure was followed, affording 0.162 g (92%) of 11b as a white solid. m.p. (Et2O) 182 °C (dec.). 1H-NMR (300 MHz, CDCl3) δ 9.05 (bs, 1H, OH), 7.30 (d, 3JHH = 8.9 Hz, 2H, 2× CHar), 7.24–7.16 (m, 5H, 5× CHar), 6.79 (d, 3JHH = 8.8 Hz, 2H, 2× CHar), 5.63 (s, 1H, CHN), 4.17 (q, 3JHH = 7.1 Hz, 2H, CH2 OEt), 3.72 (s, 3H, CH3), 1.16 (t, 3JHH = 7.1 Hz, 3H, CH2 OEt). 13C {1H} NMR δ 165.4 (C=O ester), 162.8 (C=O amide), 157.7 (Cquat), 157.1 (=Cquat), 135.3 (Cquat), 129.3 (Cquat), 128.7 (2× CHar), 128.6 (2× CHar), 127.7 (2× CHar), 124.5 (2× CHar), 120.5 (CHar), 114.4 (2× CHar), 113.0 (=Cquat), 62.2 (CHN), 61.3 (CH2 OEt), 55.5 (CH3), 14.1 (CH3 OEt). FTIR (neat) νmax: 3431 (O–H), 1711 (C=O), 1677 (C=O), 1653 (C=CH). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 353.1263, found 353.1268.
Ethyl 1-benzyl-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (11c). The general procedure was followed, affording 0.157 g (94%) of 11c as a white solid. m.p. (Et2O) 178–179 °C. 1H-NMR (300 MHz, CDCl3) δ 9.11 (bs, 1H, OH), 7.39–7.33 (m, 3H, 3× CHar), 7.32–7.27 (m, 3H, 3× CHar), 7.15–7.08 (m, 4H, 4× CHar), 5.20 (d, 3JHH = 14.8 Hz, 1H, CH2 Bn), 4.88 (s, 1H, CHN), 4.08 (q, 3JHH = 7.2, 2H, , CH2 OEt), 3.55 (d, 3JHH = 14.8 Hz, 1H, CH2 Bn), 1.06 (t, 3JHH = 7.1 Hz, 3H, CH3 OEt). 13C {1H} NMR (75 MHz, CDCl3) δ 165.59 (Cquat), 163.59 (Cquat), 157.91 (Cquat), 136.43 (Cquat), 134.68 (Cquat), 128.97 (CH), 128.68 (CH), 128.02 (CH), 127.98 (CH), 113.37 (Cquat), 61.14 (CH2), 59.75 (CH), 44.11 (CH2), 13.97 (CH3). FTIR (neat) νmax: 3450 (N–H), 1735 (C=O), 1675 (C=O), 1632 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 337.1314, found 337.1333.
General procedure for the isolation of amides 12. A solution of benzaldehyde 2 (0.1 mL, 1 mmol), diethyl acetylenedicarboxylate 8 (0.16 mL, 1 mmol), amine 3 (2 mmol), phosphoric acid catalyst 9 (34.8 mg, 0.1 mmol), and anhydrous MgSO4 was stirred in toluene (5 mL) at 110 °C for 48 h. The volatiles were dried off at reduced pressure, and the crude residue was purified by column chromatography (AcOEt/hexanes) to afford pure lactams 12.
5-oxo-2-phenyl-N,1-di-p-tolyl-4-(p-tolylamino)-2,5-dihydro-1H-pyrrole-3-carboxamide (12a). The general procedure was followed, affording 0.02 g (4%) of 12a as a white solid. m.p. (Et2O) 226 °C (dec.). (300 MHz, CDCl3) δ 8.31 (bs, 1H, NH), 7.38–7.28 (m, 6H, 6× CHar), 7.11–7.04 (m, 7H, 7× CHar), 6.96 (d, 3JHH = 8.5 Hz, 2H, 2× CHar), 6.84 (d, 3JHH = 8.5 Hz, 2H, 2× CHar), 6.63 (bs, 1H, NH), 5.85 (s, 1H, CHN), 2.28 (s, 3H,CH3), 2.25 (s, 3H, CH3), 2.24 (s, 3H, CH3). 13C {1H} NMR (75 MHz, CDCl3) (75 MHz, CDCl3) δ 164.75 (C=O), 162.12 (C=O), 139.1 (=Cquat), 136.6 (Cquat), 136.1 (Cquat), 135.8 (Cquat), 134.8 (Cquat), 134.6 (Cquat), 133.9 (Cquat), 133.8 (Cquat), 129.7 (4× CHar), 129.5 (2× CHar), 129.4 (2× CHar), 129.3 (CHar), 128.0 (2× CHar), 123.3 (2× CHar), 122.5 (2× CHar), 119.8 (2× CHar), 112.4 (=Cquat), 63.8 (CHN), 21.1 (CH3), 21.0 (CH3), 21.0 (CH3). FTIR (neat) νmax: 3309 (N–H), 3251 (N–H), 1685 (C=O), 1632 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 487.22598, found 487.2255.
N,1-bis(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxamide (12b). The general procedure was followed, affording 0.07 g (13%) of 12b as a white solid. m.p. (Et2O) 228–229 °C. 1H-NMR (400 MHz, CDCl3) δ 8.46 (bs, 1H, NH), 7.37–7.28 (m, 5H, 5× CHar), 7.26–7.22 (m, 2H, 2× CHar), 7.17 (d, 3JHH = 8.8 Hz, 2H, 2× CHar), 6.90 (d, 3JHH = 9.1 Hz, 2H, 2× CHar), 6.82 (d, 3JHH = 8.9 Hz, 2H, 2× CHar), 6.78 (d, 3JHH = 9.1 Hz, 2H, 2× CHar), 6.71 (d, 3JHH = 9.1 Hz, 2H, 2× CHar), 6.56 (bs, 1H, NH), 5.76 (s, 1H, CHN), 3.74 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.72 (s, 3H, CH3). 13C {1H} NMR (101 MHz, CDCl3) δ 164.6 (C=O), 162.4 (C=O), 157.8 (Cquat), 157.2 (Cquat), 156.5 (Cquat), 140.2 (=Cquat), 136.7 (Cquat), 131.6 (Cquat), 130.5 (Cquat), 129.5 (2× CHar), 129.3 (CHar), 128.0 (2× CHar), 125.4 (2× CHar), 124.5 (2× CHar), 121.5 (2× CHar), 114.3 (2× CHar), 114.3 (2× CHar), 114.1 (2× CHar), 110.9 (=Cquat), 64.1 (CHN), 55.6 (CH3), 55.6 (CH3), 55.5 (CH3). FTIR (neat) νmax: 3344 (N–H), 3286 (N–H), 1662 (C=O), 1682 (C=O), 1632 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 535.2107, found 535.2105.
Ethyl 4-amino-1-benzyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (16). A mixture of 10c (21.3 mg, 0.5 mmol), 10% palladium on carbon (276 mg, 0.025 mmol), and 37% HCl (0.05 mL, 0.5 mmol) in methanol (30 mL) was stirred for 10 h under hydrogen pressure at 70 psi. The reaction mixture was filtered through Celite, and the filtered solution was treated with NaHCO3 until neutral and extracted with dichloromethane (3 × 15 mL). The combined organic fractions were dried with anhydrous MgSO4, and distilled off at reduced pressure; the residue was crystallized in Et2O/pentane (1:2) to afford 0.163 g (97%) of 11c as a white solid. m.p. (Et2O) 139–142 °C. 1H-NMR (400 MHz, CDCl3) δ 7.37–7.27 (m, 6H, 6× CHar), 7.18–7.05 (m, 4H, 4× CHar), 5.74 (bs, 2H, NH), 5.13 (d, 3JHH = 14.8 Hz, 1H, CH2 Bn), 4.89 (s, 1H, CHN), 4.10–3.87 (m, 2H, CH2 OEt), 3.57 (d, 3JHH = 14.8 Hz, 1H, CH2 Bn), 1.05 (t, 3JHH = 7.1 Hz, 3H, CH3 OEt). 13C {1H} NMR (75 MHz, CDCl3) δ 165.5 (C=O ester), 165.0 (C=O amide), 145.9 (=Cquat), 136.6 (Cquat), 136.6 (Cquat), 128.9 (2× CHar), 128.7 (2× CHar), 128.5 (2× CHar), 128.4 (CHar), 128.0 (2× CHar), 127.9 (CHar), 104.8 (=Cquat), 61.5 (CHN) , 59.8 (CH2 OEt), 44.2 (CH2 Bn), 14.2 (CH3 OEt). FTIR (neat) νmax: 3450 and 3319 (N–H2), 1685 (C=O), 1654 (C=O), 1643 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 336.1474, found 336.1476.

Supplementary Materials

Copies of 1H- and 13C {1H} NMR spectra for γ-lactams 10, 11, 12, and 16 are available online. CCDC 1938640 contains the supplementary crystallographic data for this paper (compound 11a). The data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures

Author Contributions

Conceptualization, X.C., E.M.M, F.P. and J.V.; methodology, X.C.; software, X.C.; validation, E.M.M and J.V.; formal analysis, X.C; investigation, X.C; resources, E.M.M., F.P. J.V.; data curation, X.C.; writing—original draft preparation, J.V.; writing—review and editing, X.C, E.M.M., F.P., J.V.; visualization, E.M.M., F.P., J.V..; supervision, E.M.M. and J.V.; project administration, E.M.M. and J.V.; funding acquisition, F.P.

Funding

Financial support was provided by the Ministerio de Ciencia, Innovación, y Universidades (RTI2018-101818-B-I00, MCIU/AEI/FEDER, UE), and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X. del Corte thanks Gobierno Vasco for a predoctoral grant.

Acknowledgments

The authors thank the technical and human support provided by SGIker (UPV/EHU/ ERDF, EU).

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Zhu, J.; Wang, Q.; Wang, M.-X. (Eds.) Multicomponent Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germnay, 2015. [Google Scholar]
  2. Müller, T.J. J in Science of Synthesis, Multicomponent Reactions, Vol 1 and 2; Thieme: Stutgart, Germnay, 2014. [Google Scholar]
  3. Knapp, J.M.; Kurth, M.J.; Shaw, J.T.; Younai, A. Diversity-Oriented Synthesis; Trabocchi, A., Ed.; Willey: New York, NY, USA, 2013; Volume 41, pp. 29–57. [Google Scholar]
  4. Schreiber, S.L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 2000, 287, 1964–1969. [Google Scholar] [CrossRef] [PubMed]
  5. de Moliner, F.; Kielland, N.; Lavilla, R.; Vendrell, M. Modern Synthetic Avenues for the Preparation of Functional Fluorophores. Angew. Chem. Int. Ed. 2017, 56, 3758–3769. [Google Scholar] [CrossRef] [PubMed]
  6. Hall, D.G.; Rybak, T.; Verdelet, T. Multicomponent Hetero-[4 + 2] Cycloaddition/Allylboration Reaction: From Natural Product Synthesis to Drug Discovery. Acc. Chem. Res. 2016, 49, 2489–2500. [Google Scholar] [CrossRef] [PubMed]
  7. Caruano, J.; Muccioli, G.G.; Robiette, R. Biologically active γ-lactams: Synthesis and natural sources. Org. Biomol. Chem. 2016, 14, 10134–10156. [Google Scholar] [CrossRef] [PubMed]
  8. Martinez de Marigorta, E.; de los Santos, J.; Ochoa de Retana, A.M.; Vicario, J.; Palacios, F. Multicomponent Reactions in the Synthesis of γ –Lactams. Synthesis 2018, 50, 4539–4554. [Google Scholar]
  9. Martinez de Marigorta, E.; de los Santos, J.; Ochoa de Retana, A.M.; Vicario, J.; Palacios, F. Multicomponent reactions (MCRs): A useful access to the synthesis of benzo-fused γ-lactams. Beilstein J. Org. Chem. 2019, 150, 1065–1085. [Google Scholar] [CrossRef] [PubMed]
  10. Kirpotina, L.N.; Schepetkin, I.A.; Khlebnikov, A.I.; Ruban, O.I.; Ge, Y.; Ye, R.D.; Kominsky, D.J.; Quinn, M.T. 4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists. Biochem. Pharmacol. 2017, 142, 120–132. [Google Scholar] [CrossRef]
  11. Ma, K.; Wang, P.; Fu, W.; Wan, X.; Zhou, L.; Chu, Y.; Ye, D. Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase. Bioorg. Med. Chem. Lett. 2011, 21, 6724–6727. [Google Scholar] [CrossRef]
  12. Zhuang, C.; Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.; Wang, S.; Zhang, Y.; Wu, Y.; Yao, J.; Sheng, C.; et al. Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction. J. Med. Chem. 2012, 55, 9630–9642. [Google Scholar] [CrossRef]
  13. Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.; Schaechtele, C.; Heidenreich, R.; Roecken, M.; Schollmeyer, D.; Laufer, S. Design, Synthesis, and Biological Evaluation of Novel 3-Aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as Vascular Endothelial Growth Factor Receptor (VEGF-R) Inhibitors. J. Med. Chem. 2008, 51, 3814–3824. [Google Scholar] [CrossRef]
  14. Liu, Q.-J.; Wang, L.; Kang, Q.-K.; Zhang, X.P.; Tang, Y. Cy-SaBOX/Copper(II)-Catalyzed Highly Diastereo- and Enantioselective Synthesis of Bicyclic N,O Acetals. Angew. Chem. Int. Ed. 2016, 55, 9220–9223. [Google Scholar] [CrossRef] [PubMed]
  15. Bures, J.; Armstrong, A.; Blackmond, D. Explaining Anomalies in Enamine Catalysis: “Downstream Species as a New Paradigm for Stereocontrol G. Acc. Chem. Res. 2016, 49, 214–222. [Google Scholar] [CrossRef] [PubMed]
  16. Khalaf, A.I.; Waigh, R.D.; Drummond, A.J.; Pringle, B.; McGroarty, I.; Skellern, G.G.; Suckling, C.J. Distamycin Analogues with Enhanced Lipophilicity:  Synthesis and Antimicrobial Activity. J. Med. Chem. 2004, 47, 2133–2156. [Google Scholar] [CrossRef] [PubMed]
  17. Ye, Y.; Fang, F.; Li, Y. Synthesis and anti-biofilm activities of dihydro-pyrrol-2-one derivatives on Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett. 2015, 25, 597–601. [Google Scholar] [CrossRef] [PubMed]
  18. Zhu, Q.; Gao, L.; Chen, Z.; Zheng, S.; Shu, H.; Li, J.; Jiang, H.; Liu, S. A novel class of small-molecule caspase-3 inhibitors prepared by multicomponent reactions. Eur. J. Med. Chem. 2012, 54, 232–238. [Google Scholar] [CrossRef] [PubMed]
  19. Gein, V.L.; Popov, A.V.; Kolla, V.E.; Popova, N.A.; Potemkin, K.D. Synthesis and biological activity of 1,5-diaryl-3-arylamino-4-carboxymethyl-2,5-dihydro-2-pyrrolones and 1,5-diaryl-4-carboxymethyltetrahydropyrrole-2, 3-diones. Pharm. Chem. J. 1993, 27, 343–346. [Google Scholar] [CrossRef]
  20. Gein, V.L.; Popov, A.V.; Kolla, V.E.; Popova, N.A. Synthesis and biological activity of 1,5-diaryl-3-alkylamino-4-carboxymethyl-2,5-dihydropyrrol-2-ones and 1,5-diaryl-4-carboxymethyl-tetrahydropyrrol-2,3-diones. Pharmazie 1993, 8, 107–109. [Google Scholar]
  21. Li, B.; Wever, W.J.; Walsh, C.T.; Bowers, A.A. Dithiolopyrrolones: Biosynthesis, synthesis, and activity of a unique class of disulfide-containing antibiotics. Nat. Prod. Rep. 2014, 31, 905–923. [Google Scholar] [CrossRef] [PubMed]
  22. Rigby, J.H.; Hughes, R.C.; Heeg, M.J.J. Endo-Selective Cyclization Pathways in the Intramolecular Heck Reaction. Am. Chem. Soc. 1995, 117, 7834–7835. [Google Scholar] [CrossRef]
  23. Lewis, J.R. Amaryllidaceae and Sceletium alkaloids. Nat. Prod. Rep. 1994, 11, 329–332. [Google Scholar] [CrossRef]
  24. Palacios, F.; Vicario, J.; Aparicio, D. An efficient synthesis of achiral and chiral cyclic dehydro-α-amino acid derivatives through nucleophilic addition of Amines to β,γ-unsaturated α-keto esters. Eur. J. Org. Chem. 2006, 2843–2850. [Google Scholar] [CrossRef]
  25. Shaterian, H.R.; Ranjbar, M. Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones. Res. Chem. Intermed. 2014, 40, 2059–2074. [Google Scholar] [CrossRef]
  26. Niknam, K.; Mojikhalifeh, S. Synthesis of new 1,5-diaryl-3-(arylamino)-1H-pyrrol-2(5H)-ones under catalyst-free and solvent-free conditions. Mol. Diver. 2014, 18, 111–117. [Google Scholar] [CrossRef] [PubMed]
  27. Quian, J.; Yi, W.; Cai, C. Recyclable fluorous organocatalysts promoted three-component reactions of pyruvate, aldehyde and amine at room temperature. Tetrahedron Lett. 2013, 54, 7100–7102. [Google Scholar] [CrossRef]
  28. Li, X.; Deng, H.; Luo, S.; Cheng, J.-P. Organocatalytic Three-Component Reactions of Pyruvate, Aldehyde and Aniline by Hydrogen-Bonding Catalysts. Eur. J. Org. Chem. 2008, 4350–4356. [Google Scholar] [CrossRef]
  29. del Corte, X.; Maestro, A.; Vicario, J.; Martinez de Marigorta, E.; Palacios, F. Brönsted-Acid-Catalyzed Asymmetric Three-Component Reaction of Amines, Aldehydes, and Pyruvate Derivatives. Enantioselective Synthesis of Highly Functionalized γ-Lactam Derivatives. Org. Lett. 2018, 20, 317–320. [Google Scholar] [CrossRef] [PubMed]
  30. Gao, H.; Sun, J.; Yan, C.-G. Synthesis of functionalized 2-pyrrolidinones via domino reactions of arylamines, ethyl glyoxylate and acetylenedicarboxylates. Tetrahedron 2013, 69, 589–594. [Google Scholar] [CrossRef]
  31. Khan, A.T.; Gosh, A.; Khan, M.M. One-pot four-component domino reaction for the synthesis of substituted dihydro-2-oxypyrrole catalyzed by molecular iodine. Tetrahedron Lett. 2012, 53, 2622–2626. [Google Scholar] [CrossRef]
  32. Saha, M.; Das, A.R. Access of Diverse 2-Pyrrolidinone, 3,4,5-Substituted Furanone and 2-Oxo-dihydropyrroles Applying Graphene Oxide Nanosheet: Unraveling of Solvent Selectivity. ChemistrySelect 2017, 2, 10249–10260. [Google Scholar] [CrossRef]
  33. Palacios, F.; Aparicio, D.; García, J.; Vicario, J.; Ezpeleta, J.M. Regioselective alkylation reactions of enamines derived from phosphane oxides - Synthesis of phosphorus substituted enamino esters, δ-amino-phosphonates, pyridone derivatives and pyrroles. Eur. J. Org. Chem. 2001, 3357–3365. [Google Scholar] [CrossRef]
  34. Palacios, F.; Aparicio, D.; Vicario, J. Synthesis of quinolinylphosphane oxides and -phosphonates from N-arylimines derived from phosphane oxides and phosphonates. Eur. J. Org. Chem. 2002, 4131–4136. [Google Scholar]
  35. Palacios, F.; Vicario, J.; Aparicio, D. Aza-Diels-Alder reaction of α,β-unsaturated sulfinylimines derived from α-amino acids with enolethers and enamines. Tetrahedron Lett. 2007, 48, 6747–6750. [Google Scholar] [CrossRef]
  36. Palacios, F.; Vicario, J.; Aparicio, D. A diastereoselective aza-Diels-Alder reaction of N-aryl-1-azadienes derived from α-amino acids with enamines. Tetrahedron Lett. 2011, 52, 4109–4111. [Google Scholar]
  37. Palacios, F.; Vicario, J.; Aparicio, D. Efficient synthesis of 1-azadienes derived from α-aminoesters. Regioselective preparation of α-dehydroamino acids, vinylglycines, and α-amino acids. J. Org. Chem. 2006, 71, 7690–7696. [Google Scholar] [CrossRef] [PubMed]
  38. Vicario, J.; Ortiz, P.; Ezpeleta, J.M.; Palacios, F. Asymmetric Synthesis of Functionalized Tetrasubstituted α-Aminophosphonates through Enantioselective Aza-Henry Reaction of Phosphorylated Ketimines. J. Org. Chem. 2015, 80, 156–164. [Google Scholar] [CrossRef] [PubMed]
  39. Vicario, J.; Ezpeleta, J.M.; Palacios, F. Asymmetric Cyanation of α-Ketiminophosphonates Catalyzed by Cinchona Alkaloids: Enantioselective Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives from Trisubstituted α-Aminophosphonates. Adv. Synth. & Catal. 2012, 354, 2641–2647. [Google Scholar]
  40. Maestro, A.; Martinez de Marigorta, E.; Palacios, F.; Vicario, J. Enantioselective alpha-Aminophosphonate Functionalization of Indole Ring through an Organocatalyzed Friedel-Crafts Reaction. J. Org. Chem. 2019, 84, 1094–1102. [Google Scholar] [CrossRef] [PubMed]
  41. Metten, B.; Kostermans, M.; Van Baelen, G.; Smet, M.; Dehaen, W. Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles. Tetrahedron 2006, 62, 6018. [Google Scholar] [CrossRef]
  42. Winstein-Holnes values: ABn = 1.68 kcal.mol-1 and APh = 2.80 kcal.mol-1. In Stereochemistry of Organic Compounds; Eliel, E.L.; Wilen, S.H.; Mander, L.N. (Eds.) Wiley: New York, NY, USA, 1994. [Google Scholar]
  43. Ávila, E.P.; Justo, R.M.S.; Gonçalves, V.P.; Pereira, A.A.; Diniz, R.; Amarante, G.W. Chiral Brønsted Acid-Catalyzed Stereoselective Mannich-Type Reaction of Azlactones with Aldimines. J. Org. Chem. 2015, 80, 590–594. [Google Scholar] [CrossRef] [PubMed]
  44. Shaoa, Y.-D.; Chengb, D.-J. Catalytic Asymmetric 1,2-Difunctionalization of Indolenines with α-(Benzothiazol-2-ylsulfonyl) Carbonyl Compounds. Adv. Synth. Catal. 2017, 359, 2549–2556. [Google Scholar] [CrossRef]
  45. Huang, Q.; Cheng, Y.; Yuan, H.; Chang, X.; Li, P.; Li, W. Organocatalytic enantioselective Mannich-type addition of 5H-thiazol-4-ones to isatin-derived imines: Access to 3-substituted 3-amino-2-oxindoles featured by vicinal sulfur-containing tetrasubstituted stereocenters. Org. Chem. Front. 2018, 5, 3226–3230. [Google Scholar] [CrossRef]
  46. Sheldrick, G.M. A short history of SHELX. Acta Cryst. 2008, A64, 112–122. [Google Scholar] [CrossRef] [PubMed]
  47. Sheldrick, G.M. Crystal Structure Refinement with SHELXL. Acta Cryst. 2015, C71, 3–8. [Google Scholar]
  48. Macrae, C.F.; Bruno, I.J.; Chisholm, J.A.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P.A. Mercury CSD 2.0 – new features for the visualization and investigation of crystal structures. J. Appl. Cryst. 2008, 41, 466–470. [Google Scholar] [CrossRef]
  49. Spek, A.L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, The Netherlands, 2010. [Google Scholar]
  50. Spek, A.L. Single-crystal structure validation with the program. PLATON J. Appl. Cryst. 2003, 36, 7–13. [Google Scholar] [CrossRef]
  51. Farrugia, L.J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Cryst. 1999, 32, 837–838. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds 10, 11, 12, and 16 are available from the authors.
Molecules 24 02951 g001 550
Figure 1. General structure of γ-lactams I, 1,5-dihydro-2H-pyrrol-2-ones II, 3-amino 1,5-dihydro-2H-pyrrol-2-ones II, and dithiopyrrolone antibiotics IV.
Figure 1. General structure of γ-lactams I, 1,5-dihydro-2H-pyrrol-2-ones II, 3-amino 1,5-dihydro-2H-pyrrol-2-ones II, and dithiopyrrolone antibiotics IV.
Molecules 24 02951 g001
Molecules 24 02951 sch001 550
Scheme 1. Three-component reaction of ethyl pyruvate 1, aldehydes 2, and amines 3.
Scheme 1. Three-component reaction of ethyl pyruvate 1, aldehydes 2, and amines 3.
Molecules 24 02951 sch001
Molecules 24 02951 sch002 550
Scheme 2. Three-component reaction of diethyl acetylenedicarboxilate 8, benzaldehyde 2, and amines 3.
Scheme 2. Three-component reaction of diethyl acetylenedicarboxilate 8, benzaldehyde 2, and amines 3.
Molecules 24 02951 sch002
Molecules 24 02951 sch003 550
Scheme 3. Reaction mechanism for the three-component reaction of diethyl acetylenedicarboxylate 8, benzaldehyde 2, and amines 3.
Scheme 3. Reaction mechanism for the three-component reaction of diethyl acetylenedicarboxylate 8, benzaldehyde 2, and amines 3.
Molecules 24 02951 sch003
Molecules 24 02951 g002 550
Figure 2. X-ray structure of 11a. (blue ball, Nitrogen; gray ball, Carbon).
Figure 2. X-ray structure of 11a. (blue ball, Nitrogen; gray ball, Carbon).
Molecules 24 02951 g002
Molecules 24 02951 sch004 550
Scheme 4. Preparation of enol derivatives 11 and deprotection of benzylamine derivative 10.
Scheme 4. Preparation of enol derivatives 11 and deprotection of benzylamine derivative 10.
Molecules 24 02951 sch004
Molecules 24 02951 g003 550
Figure 3. Transition state proposed for the Mannich reaction in the three-component reaction.
Figure 3. Transition state proposed for the Mannich reaction in the three-component reaction.
Molecules 24 02951 g003
Table
Table 1. Three-component reaction of ethyl pyruvate 1, benzaldehyde 2, and amines 3.
Table 1. Three-component reaction of ethyl pyruvate 1, benzaldehyde 2, and amines 3.
EntryR2/3/8SolventT (°C)Yield (%) 110/11/12 2
1p-MeC6H41/2/1CH2Cl2400n.d.
2p-MeC6H41/2/1THF650n.d.
3p-MeC6H41/2/1DME850n.d.
4p-MeC6H41/2/1MTBE557240/60/0
5p-MeC6H41/2/3MTBE550n.d.
6p-MeC6H41/2/1Dioxane1018180/0/20
7p-MeC6H41/2/1Toluene1107795/0/5
8p-MeOC6H41/2/1Toluene1107670/0/30
9p-MeOC6H41/4/1Toluene1107670/0/30
10Bn1/2/1Toluene11058100/0/0
1 Isolated total yield. 2 Determined by 1H-NMR. n.d.—not determined.

Share and Cite

MDPI and ACS Style

del Corte, X.; Martinez de Marigorta, E.; Palacios, F.; Vicario, J. A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives. Molecules 2019, 24, 2951. https://doi.org/10.3390/molecules24162951

AMA Style

del Corte X, Martinez de Marigorta E, Palacios F, Vicario J. A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives. Molecules. 2019; 24(16):2951. https://doi.org/10.3390/molecules24162951

Chicago/Turabian Style

del Corte, Xabier, Edorta Martinez de Marigorta, Francisco Palacios, and Javier Vicario. 2019. "A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives" Molecules 24, no. 16: 2951. https://doi.org/10.3390/molecules24162951

Article Metrics

Back to TopTop