Letter Cite This: Org. Lett. 2018, 20, 3875−3878
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Selective Synthesis of 3‑Substituted Pyrrolidinones by EnolPasserini and Anomalous Enol-Passerini Condensations Ana G. Neo* and Carlos F. Marcos* Laboratory of Bioorganic Chemistry and Membrane Biophysics (L.O.B.O.), Department of Organic and Inorganic Chemistry, Universidad de Extremadura, 10071 Cáceres, Spain
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S Supporting Information *
ABSTRACT: Enols are used for the first time in a condensation with aldehydes and isocyanides to selectively give three- or pseudo-fourcomponent adducts, depending on the reaction conditions. These new transformations have proven to be a convenient alternative for the synthesis of biologically relevant pyrrolidinones containing peptidic or pseudo-peptidic groups on carbon 3. More importantly, this work attests to the utility of heterocyclic enols containing conjugated electronwithdrawing groups as useful reagents in isocyanide-based multicomponent reactions. We have recently discovered that enols containing α,βunsaturated electron-withdrawing groups readily react with aldehydes, isocyanides, and amines affording amino acid derived heterocyclic enamines.4 This original multicomponent reaction (MCR) could be considered a variant of the classic Ugi four-component condensation, in which an enol is substituted for the traditional carboxylic acid component. The reaction of enols, isocyanides, and aldehydes in an analogous enol-Passerini condensation would constitute a useful tool to achieve a higher molecular diversity. To the best of our knowledge, enols have never been used in Passerini-type reactions. Here, we postulate that pyrrolidine2,3-diones (3a−f) could participate in enol-Passerini condensations leading to α-hydroxyamide enol-ethers. Furthermore, the high acidity of these electron-poor enols5 could induce the participation of isocyanides as amine surrogates in pseudo-enol-Ugi condensations.6 In this paper, we explore the use of enolic pyrrolidine-2,3-diones (3a−f) in Passerini-type reactions and their utility for the synthesis of pyrrolidinone enol-ethers and enamines. Accordingly, we investigated the reaction of 4-substituted pyrrolidine-2,3-diones (3a−f) with aldehydes (1) and isocyanides (2; Scheme 2). Thus, equimolar quantities of benzaldehyde (1a), cyclohexyl isocyanide (2a), and ethyl 4hydroxy-2-(4-methoxyphenyl)-5-oxo-1-phenyl-2,5-dihydro1H-pyrrole-3-carboxylate (3c) were mixed in diethyl ether. However, when the mixture was stirred at room temperature for several days, no reaction was apparent (Table 1, entry 1). After testing different solvents, the reaction effectively proceeded in 48 h in dichloromethane, giving the desired adduct 6e with a 25% yield after purification (Table 1, entry 7). Increasing the reaction temperature and using microwave
P
yrrolidinone is a nonaromatic heterocycle found in the core of many natural products and biologically active molecules.1 For example, 1,5-dihydropyrrol-2-ones containing oxygen and nitrogen substituents in position 3 have been identified as potent inhibitors of p53-MDM2 protein−protein interactions and they are promising candidates for the development of novel antitumor oral drugs.2 The possibility of introducing different substituents on the pyrrolidinone nucleus is crucial to achieve new molecules with improved biological activities. Moreover, introduction of peptidic or pseudo-peptidic groups on carbon 3 is especially important to modulate their protein binding properties. 3-Substitued pyrrolidinones can be obtained by nucleophilic substitution on readily accessible 2,3-diones.3 However, this requires rather harsh conditions and it is limited to simple oxygen and nitrogen reagents (Scheme 1).1c,d,2 Thus, finding selective procedures to introduce complex substituents on position 3 of pyrrolidinones has become of great interest. Scheme 1. Enol-Ugi Condensation Leading to Amino Acid Derived Enamines4b
Received: May 9, 2018 Published: June 26, 2018 © 2018 American Chemical Society
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DOI: 10.1021/acs.orglett.8b01462 Org. Lett. 2018, 20, 3875−3878
Letter
Organic Letters
participate in subsequent MCRs. We anticipated that the high acidity of pyrrolidine-2,3-dione could promote such a transformation if the reaction is performed in a protic solvent. Thus, we investigated the reaction of 1a, 2a, and 3c in methanol. Interestingly, in these conditions, the reaction did not yield the canonical Passerini product 6e. Instead, we found that the pseudo-enol-Ugi adduct 9e was the only identifiable product (Scheme 3). Satisfactorily, an optimal yield of 70% of 9e was obtained when 1a, 2a, and 3c are in a 1.5:2.5:1 molar ratio.
Scheme 2. Proposed Mechanism of the Enol-Passerini Condensation
Scheme 3. Anomalous Enol-Passerini Pseudo-4CC Leading to Enamine 9e
Table 1. Optimization of Reaction Conditionsa
entry
solvent
equiv of 1a
equiv of 2a
6e (%)
1 2 3 4 5 6 7 8 9
Et2O CH3CN dioxane THF EtOAc cyclohexane CH2Cl2 CH2Cl2 dichloroethaneb
1 1 1 1 1 1 1 2 1
1 1 1 1 1 1 1 2 1
NR NR NR NR NR NR 25 62 NR
In order to confirm the structure of compound 9e, we have alternatively synthesized it by the enol-Ugi four-component condensation4b of benzaldehyde (1a), cyclohexyl amine (4a), cyclohexyl isocyanide (2a), and methyl 4-hydroxy-2-(4methoxyphenyl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (3c; Scheme 4). This product was identical to that obtained in the anomalous enol-Passerini reaction in methanol, although it was obtained in a significantly lower yield. Scheme 4. Enol-Ugi 4CC Leading to Compound 9e
a Reaction procedure: A mixture of enol 3c (0.25 mmol) and the corresponding amounts of aldehyde 1a and isocyanide 2a in 0.5 mL of the appropriate solvent was stirred at rt 48 h. bMW irradiation, 70 °C for 15 min, and then rt for 24 h.
Obtaining a pseudo-four-component product from the anomalous Passerini reaction in methanol implies that the role corresponding to the amine (4a) in the analogous Ugi four-component condensation is played here by a molecule of isocyanide (2a). Consequently, the isocyanide (2a) must be transformed in the reaction conditions, either into amine 4a or, more likely, into an imine intermediate. Sello and co-workers suggested an acid-catalyzed [2 + 2] cycloaddition of an isocyanide and an aldehyde to explain a similar transformation.6a Therefore, the proposed mechanism of the anomalous enol-Passerini condensation, outlined in Scheme 5, involves an initial [2 + 2] cycloaddition of the protonated isocyanide (2) with the aldehyde (1), followed by the cycloreversion and transfer of a formyl group to the solvent to give an intermediate iminium ion (12) and methyl formate.6a This reaction would then undergo an enol-Ugi reaction, as previously described.4b According to this mechanism, the solvent plays a crucial role, enabling the
irradiation did not improve the yields or the reaction times (Table 1, entry 9). Successfully, the yield was considerably increased to 62% when 2 equiv of aldehyde (1a) and isocyanide (2a) were used with respect to the enol (3c; Table 1, entry 8). The mechanism of this new enol-Paserini reaction can be rationalized considering an α-addition of the enol (3) and the aldehyde (1) to the isocyanide (2) to give a primary adduct (7) such as that obtained by the classic Passerini condensation.7 The unstable primary adduct (7) then takes a different course, rearranging to a stable amide (6) through an intramolecular conjugate addition of the hydroxyl group to the heterocyclic ring, followed by β-elimination of the imidate oxygen (Scheme 2). It is known that isocyanides and aldehydes can react in the presence of Brönsted6a or Lewis acids,6b to give imines that can 3876
DOI: 10.1021/acs.orglett.8b01462 Org. Lett. 2018, 20, 3875−3878
Letter
Organic Letters
the anomalous Passerini condensation of 1a, 2a, and 3c in heptanol. Although the reaction takes place more slowly than in methanol, we observed the formation of the expected pseudo-Ugi adduct 9e, and we were able to detect by GC-MS both the intermediate imine (12a) and heptyl formate side product (see the Supporting Information). The presence of these compounds in the reaction medium is in agreement with the proposed mechanism. The pseudo-Ugi four-component reaction also takes place, although in lower yields, in other nucleophilic solvents, such as isopropanol, and also in toluene with the presence of NH4Cl.8 Surprisingly, when water was used as the reaction medium, the regular three-component enol-Passerini adduct (6e) was obtained. Remarkably, the reaction takes place almost immediately, and the formation of a sticky agglomerate was apparent after a few minutes. Under these conditions, we reason that all the isocyanide is consumed before it can be converted into the imine (12) required for the formation of
Scheme 5. Proposed Mechanism of the Anomalous EnolPasserini Reaction
formation of an imine equivalent (12) from the isocyanide (2) and the aldehyde (1). To probe the mechanism, we performed
Table 2. Enol-Passerini Condensation of Pyrrolidine-2,3-diones with Aldehydes and Isocyanides in Dichloromethane and MeOH
entry
aldehyde
1 2
1a 1b
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
1c 1a 1a 1a 1d 1a 1c 1a 1a 1d 1a 1d 1e 1f 1f 1a 1d 1a 1f 1f 1f 1c 1a 1a
R1 C6H5 3,4-(OCH2O) C6H3 o-Br-C6H4 C6H5 C6H5 C6H5 p-NO2-C6H4 C6H5 o-Br-C6H4 C6H5 C6H5 p-NO2-C6H4 C6H5 p-NO2-C6H4 p-CH3O-C6H4 p-CH3-C6H4 p-CH3-C6H4 C6H5 p-NO2-C6H4 C6H5 p-CH3-C6H4 p-CH3-C6H4 p-CH3-C6H4 o-Br-C6H4 C6H5 C6H5
isocyanide
R2
enol
R3
R4
method A product (yield, %; dr)a
2a 2a
cC6H11 cC6H11
3a 3a
C6H5 C6H5
C6H5 C6H5
6a (75; 70:30) 6b (40; 60:40)
2a 2a 2a 2a 2a 2b 2b 2c 2c 2d 2e 2e 2a 2a 2a 2a 2a 2b 2f 2f 2d 2d 2e 2g
cC6H11 cC6H11 cC6H11 cC6H11 cC6H11 tBu tBu C5H11 C5H11 CH2CO2tBu 2,6-Me2-C6H3 2,6-Me2-C6H3 cC6H11 cC6H11 cC6H11 cC6H11 cC6H11 tBu CH2C6H5 CH2C6H5 CH2CO2tBu CH2CO2tBu 2,6-Me2-C6H3 p-OMe-C6H4
3a 3b 3c 3d 3e 3c 3a 3b 3d 3b 3d 3e 3a 3a 3d 3f 3b 3c 3b 3a 3b 3b 3d 3c
C6H5 CH2C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 CH2C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 CH2C6H5 C6H5 CH2C6H5 C6H5 CH2C6H5 CH2C6H5 C6H5 C6H5
C6H5 H p-CH3O-C6H4 p-Cl-C6H4 3,4-(OCH2O)C6H3 p-CH3O-C6H4 C6H5 H p-Cl-C6H4 H p-Cl-C6H4 3,4-(OCH2O)C6H3 C6H5 C6H5 p-Cl-C6H4 p-F-C6H4 H p-CH3O-C6H4 H C6H5 H H p-Cl-C6H4 p-CH3O-C6H4
6c (93;55:45) 6d (71) 6e (62; 65:35) 6f (60; 70:30) 6g (92;60:40) 6h (48; 80:20) 6i (35; 75:25) 6j (49) 6k (57; 60:40) 6l (60) 6m (41; 70:30) 6n (70; 60:40)
method B product (yield, %; dr)b 9a (45; 50:50)
6d (21) + 9d (26)d 9e (70; 55:45) 9f (67; 55:45) 6g (16) + 9g (38)d
9j (43) 9k (45; 50:50)
9o (59; 55:45) 9p (57; 55:45) 9q (54; 55:45) 9r (67; 60:40) 6s (20) + 9s (20)d NRc 9t (57) 9u (41; 52:48) 9v (48) 9w (48) NRc 9x (42; 50:50)
a
Method A: A mixture of aldehyde 1 (0.5 mmol), isocyanide 2 (0.5 mmol), and enol 3 (0.25 mmol) in CH2Cl2 (0.5 mL) is stirred 48 h at rt. Method B: A mixture of aldehyde 1 (0.38 mmol), isocyanide 2 (0.63 mmol), and enol 3 (0.25 mmol) in MeOH (0.5 mL) is stirred 48 h at rt. c NR: No reaction. dIsolated as a mixture of the Passerini and pseudo-Ugi products; individual yields calculated from the integration of NMR signals. b
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DOI: 10.1021/acs.orglett.8b01462 Org. Lett. 2018, 20, 3875−3878
Letter
Organic Letters ORCID
the pseudo-enol-Ugi product. This is in agreement with previous work reporting that the Passerini condensation is favored by the use of on-water conditions.9 Unfortunately, we were not able to find suitable aqueous conditions leading to consistent results, and variable yields of 6e are obtained after decanting the water and a laborious purification. To explore the scope of the new enol-Passerini and anomalous enol-Passerini condensations, we applied the optimized reaction conditions to different combinations of aldehydes (1), isocyanides (2), and pyrrolidinodiones (3), respectively in dicloromethane (Table 2, Method A) and methanol (Table 2, Method B). In the first case, the reaction proceeds as expected in all cases, giving the corresponding adducts (6) in moderate to excellent yields. Analogously, the pseudo-Ugi adducts (9) are selectively obtained from the reaction in methanol with aromatic, primary, and secondary isocyanides (Table 2, entries 15−18, 21−24, 26). The reaction, however, does not proceed with bulky isocyanides, such as tert-butyl isocyanide (Table 2, entry 20) and 2,6-dimethylphenyl isocyanide (entry 25), because they are likely too sterically hindered to allow the [2 + 2] cycloaddition leading to the imine (12). In the cases where pnitrobenzaldehyde is used (entries 7 and 19), the regular enolPasserini condensation is relatively rapid, competing with imine formation, and thus, a mixture of adducts 6 and 9 is obtained. A mixture of 6 and 9 is also obtained from the reaction of pyrrolidine-2,3-dione unsubstituted in position 5 (3b), benzaldehyde (1a), and cyclohexyl isocyanide (2a; entry 4). This can be explained by the relatively high reactivity of enol 3b and isocyanide 2a toward the regular enol-Passerini condensation and the poor reactivity of cyclohexyl isocyanide (2a) toward the [2 + 2] cycloaddition. Additionally, minor traces of enol-Passerini adducts (6) are always detected, along with pseudo-enol-Ugi products (9), in the reactions with cyclohexyl isocyanide in methanol. In conclusion, 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3carboxylates have shown to be suitable acidic counterparts in Passerini and pseudo-Ugi-type reactions leading to pyrrolidinone-derived enol-ethers and enamines, respectively. The course of the reaction is readily controlled by the election of the solvent. These unprecedented enol-Passerini and pseudoenol-Ugi condensations open up new possibilities for the synthesis of biologically relevant amino acid derived pyrrolidinones, complementing our previous work on the enol-Ugi reaction. Also, our results confirm enols as valuable reagents in the multicomponent reactions of isocyanides.
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Carlos F. Marcos: 0000-0003-2278-7118 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank financial support from Junta de Extremadura and FEDER (IB16095). REFERENCES
(1) (a) Thiel, P.; Kaiser, M.; Ottmann, C. Angew. Chem., Int. Ed. 2012, 51, 2012. (b) Rose, R.; Erdmann, S.; Bovens, S.; Wolf, A.; Rose, M.; Hennig, S.; Waldmann, H.; Ottmann, C. Angew. Chem., Int. Ed. 2010, 49, 4129. (c) Armisheva, M.; Kornienko, N.; Gein, V.; Vakhrin, M. Russ. J. Gen. Chem. 2011, 81, 1893. (d) Jourdan, F.; Kaiser, J. T.; Lowe, D. J. Synth. Commun. 2005, 35, 2453. (2) Zhuang, C.; Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.; Wang, S.; Zhang, Y.; Wu, Y.; Yao, J.; Sheng, C.; Zhang, W. J. Med. Chem. 2012, 55, 9630. (3) (a) Wasserman, H. H.; Koch, R. C. J. Org. Chem. 1962, 27, 35. (b) Metten, B.; Kostermans, M.; Van Baelen, G.; Smet, M.; Dehaen, W. Tetrahedron 2006, 62, 6018. (c) Taylor, W.; Vadasz, A. Aust. J. Chem. 1982, 35, 1227. (d) Sun, J.; Wu, Q.; Xia, E.-Y.; Yan, C.-G. Eur. J. Org. Chem. 2011, 2011, 2981. (4) (a) Neo, A. G.; Castellano, T. G.; Marcos, C. F. Synthesis 2015, 47, 2431. (b) Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Org. Lett. 2012, 14, 6218. (c) Neo, A. G.; Castellano, T. G.; Marcos, C. F. ARKIVOC 2017, 2017 (3), 21. (5) (a) Yao, X.; Pollack, R. M. Can. J. Chem. 1999, 77, 634. (b) Mishima, M.; Eventova, I.; Rappoport, Z. Journal of the Chemical Society, Perkin Transactions 2 2000, 1505. (6) (a) Okandeji, B. O.; Sello, J. K. J. Org. Chem. 2009, 74, 5067. (b) Dai, W.-M.; Li, H. Tetrahedron 2007, 63, 12866. (7) Maeda, S.; Komagawa, S.; Uchiyama, M.; Morokuma, K. Angew. Chem., Int. Ed. 2011, 50, 644. (8) Neo, A. G.; Carrillo, R. M.; Barriga, S.; Moman, E.; Marcaccini, S.; Marcos, C. F. Synlett 2007, 2007, 327. (9) Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004, 126, 444.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01462. Experimental procedures, product characterization data,
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and 1H and (PDF)
13
C NMR spectra for new compounds
AUTHOR INFORMATION
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DOI: 10.1021/acs.orglett.8b01462 Org. Lett. 2018, 20, 3875−3878
