Letter Cite This: Org. Lett. 2017, 19, 6044-6047
pubs.acs.org/OrgLett
Copper-Catalyzed Oxidative Cyclization of Maleimides with Amines and Alkyne Esters: Direct Access to Fully Substituted Dihydropyrroles and Pyrrole Derivatives Jia-Nan Zhu,† Lei-Lei Chen,† Run-Xiang Zhou,† Bo Li,† Zhi-Yu Shao,† and Sheng-Yin Zhao*,†,‡ †
Department of Chemistry, Donghua University, No. 2999 North Renmin Road, Shanghai 201620, P. R. China State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
‡
S Supporting Information *
ABSTRACT: An efficient and practical Cu(I)-catalyzed oxidative cyclization cascade reaction of diverse amines, alkyne esters and maleimides has been developed. The reactions can afford 4,6-dioxopyrrolo[3,4-b]pyrrole-2,3-dicarboxylates and related derivatives with satisfactory yields by altering the reaction conditions slightly. The substrate scope highlights the flexibility of the catalyst, and a reaction mechanism is also proposed. he five-membered nitrogen-containing aromatic heterocycle moieties are universal skeletons in biologically and pharmaceutically active compounds.1 Among them, dihydropyrroles or pyrroles are a vital class of aromatic heterocycle compounds as they are not only in a large number of natural products2 but also a useful building block for the synthesis of complex natural products.3 For example, 4-aryl-2,3-dihydropyrrole derivatives are the key intermediates in the synthesis of (±)-mesembrine,4 elwesine,5 and other bioactive molecules.6 Furthermore, spiropyrroline compounds7 display good antiviral and antimicrobial activities. As for the pyrroles, they are ubiquitous in functional materials,8 pharmaceutical substances,9 and organic synthesis.2d,10 For instance, A11 is the most stable isomer and possesses a high performance pigment, and B12 is the key substance for the synthesis of kinase inhibitors (Figure 1). As a result, extensive attention has been paid to developing approaches for the construction of these privileged molecules. Over the past few years, transition-metal-catalyzed oxidative functionalization of C−H bond with a N−H group has been the most convenient and efficient procedure for the construction of N-heterocycles.13 Enamines, a class of important N-heterocycle precursors, have been widely used for the synthesis of valuable
T
pyrroles via transition-metal catalysis.14 It is a pity that the major substrates are limited to alkynes. In contrast, to the best of our knowledge, related C−H oxidative cyclization of β-enamino esters with electron-deficient alkenes toward dihydropyrroles or pyrroles is still unreported so far, and to date, only two examples for the synthesis of fulleropyrroline15 and 2,3,4-trisubstituted pyrroles16 were explored using amines and alkyne esters as the βenamino esters precursor. Most of the reaction substrates are limited to electron-rich olefins. Besides, related C−H functionalization of maleimides with various directed group substrates17 have been investigated to a great extent. However, the formation of this similar skeletons containing maleimide is extremely rare18 up to now. Accordingly, it is considerable challenging but highly desirable to discover a transition-metal-catalyzed direct oxidative cyclization of electron-deficient alkenes with amines and alkyne esters. It is well-known that β-enamino esters can be generated in situ from the readily available amines and alkene esters.19 Herein, we disclose the first direct oxidative copper-catalyzed annulation of maleimides with amines and alkyne esters toward dihydropyrrole synthesis. Subsequently, with the addition of K2S2O8 to the above reaction system, our copper-catalyzed process also offers fully substituted pyrrole derivatives. The annulation reaction of aniline (1a), dimethyl acetylenedicarboxylate (2a), and N-phenylmaleimide (3a) was chosen as a model reaction for optimization of the reaction conditions
Figure 1. Selected examples of functional pyrroles.
Received: August 28, 2017 Published: October 31, 2017
© 2017 American Chemical Society
6044
DOI: 10.1021/acs.orglett.7b02670 Org. Lett. 2017, 19, 6044−6047
Letter
Organic Letters
20). Solvent screening indicates that DMSO was the most efficient. Compared to the reaction in DMSO, the reactions in DMF and DCM gave relatively low yields in 35% and 20%, respectively (entries 22 and 23). Other solvents such as CH3CN, DMA, dioxane, HOAc, toluene, DCE, and PhCl are undesirable (entries 24−29). With the optimized reaction conditions available (Table 1, entry 8), the scope of this oxidative cyclization reaction was then investigated. The reaction showed good functional group tolerance and proved to be a practical procedure for the synthesis of target products (Scheme 1). To start with, various Nsubstituted maleimides can react successfully under the reaction conditions to give an effective access to products in 75−88% yield (4a−d). It is noteworthy that this reaction was not limited to N-protected maleimide, but it could also be extended to a free
(Table 1). First, several copper salt catalysts were investigated by using DMSO as the solvent at 90 °C (entries 1−11). Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
solvent
4a yieldb (%)
1 2 3 4 5c 6 7 8 9 10 11 12d 13e 14f 15g 16 17 18 19 20 21 22 23 24 25 26 27 28 29
CuCl2 CuBr2 CuF2 Cu(OTf)2 Cu(OAc)2 CuI CuBr CuCl Cu2O CuSCN CuCN CuCl CuCl CuCl CuCl Fe(NO3)3.9H2O CoCl3.6H2O Ag2CO3 AgOAc Pd(OAc)2 CuCl CuCl CuCl CuCl CuCl CuCl CuCl CuCl CuCl
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO CH3CN DMF DCM DMA dioxane HOAc toluene DCE PhCl
trace trace 0 0 0 63 69 75 15 63 60 trace 77 66 63 0 0 0 0 0 0 35 20 0 0 0 0 0 0
Scheme 1. Results of Cu-Catalyzed Fully Substituted Dihydropyrrole (4) Synthesisa,e
a
Reactions were carried out with 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.7 mmol), and CuCl (10 mol %) in solvent (2.0 mL) under air atmosphere at 90 °C for 5 h. bIsolated yield. cCu(OAc)2 (1 equiv) was added. dThe reaction was run under N2 atmosphere. eCuCl (20 mol %) was added. fThe reaction was run at 70 °C. gThe reaction time was 24 h.
Unfortunately, when Cu(II) was used as the catalyst, we could not afford the expected products (entries 1−5). On the contrary, Cu(I) has the better results (entries 6−11). Obviously, the reaction with CuCl as the catalyst in DMSO gave the desired product 4a in 75% yield. The structure of 4a was confirmed unambiguously by X-ray single-crystal diffraction.20 When CuI, CuBr, Cu2O, CuSCN, and CuCN were selected as the catalysts, the yields decreased, especially, Cu2O as the catalyst. However, when the quantity of the catalyst was added to 20 mol %, the yield was increased to 77% (entry 13). The control experiment revealed that oxygen was necessary in this transformation (entry 12). Additionally, the yield was decreased to 66%, while the temperature was lowered to 70 °C (entry 14). Furthermore, when the reaction time was extended to 24 h, the yield was decreased to 63% (entry 15). In addition, in the presence of other catalysts such as Fe(NO3)3·9H2O, CoCl3·6H2O, Ag2CO3, AgOAc, or Pd(OAc)2, the reaction was inefficient (entries 16−
a
Reactions were carried out with 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.7 mmol), and CuCl (10 mol %) in DMSO (2.0 mL) under air atmosphere at 90 °C for 5 h. bThe reactions were carried out for 12 h. c Compound 3 was added to 2 equiv. d1.0 mmol 1 and 2 were used. e Isolated yield. 6045
DOI: 10.1021/acs.orglett.7b02670 Org. Lett. 2017, 19, 6044−6047
Letter
Organic Letters NH maleimide although the yield is 40% (4e). A variety of amines containing an electron-donating substituent such as a methoxyl, cyclopentyl, n-butyl, or allyl group furnished the corresponding products in 66−78% yield (4f, 4k−m). It should be noted that the lower yield of product 4f might be due to the steric effect of the σ-methoxyl group. Diverse amines including electron-withdrawing substituents were smoothly tolerated in the reaction, and the desired products were obtained in moderate to good yields (51−70%). Fortunately, we unexpectedly delivered the dihydropyrrole compounds containing nitro functional group, which definitely extended their further derivatization in a certain extent (4g−4j). When diverse alkyne esters were used as the substrates, the reaction was well compatible with alkyl- as well as aryl-substituted alkyne esters, thus providing the corresponding products in moderate to excellent yield (4n−q). Intriguingly, the combination of dihydropyrrole formation and subsequent dehydrogenation aromatization in one process was realized in our copper-catalyzed process. When the abovementioned reaction conditions were altered slightly, with 2.5 equiv of oxidant in DMSO at 90 °C for another 12 h, the synthetically more attractive fully substituted pyrroles 5 were isolated as single products in high yield (Table 2). Different
Scheme 2. Results of Cu-Catalyzed Fully Substituted Pyrrole (5) Synthesisa,c
a
Reactions were carried out with 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.7 mmol), CuCl (10 mol %), and K2S2O8 (1.25 mmol) in a solvent DMSO (4.0 mL) under air atmosphere at 90 °C for 12 h. bCompound 3 was added to 2 equiv. cIsolated yield.
Scheme 3. Control Experiments
Table 2. Optimization of the Reaction Conditionsa
entry
oxidants
solvent
5a yieldb (%)
1 2c 3 4 5 6 7 8 9 10 11 12
DDQ DDQ K2S2O8 TBHP H2O2 MnO2 DTBP CH3CO3H K2S2O8 K2S2O8 K2S2O8 K2S2O8
none none none none none none none none toluene DMF DCM CH3CO2H
0 12 72 55 trace 0 0 0 55 45 68 57
a Reactions were carried out with 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.7 mmol), CuCl (10 mol %), and oxidant (1.25 mmol) in a mixed solvent (DMSO/solvent = 1:1, totally, 4 mL) under air atmosphere at 90 °C for 12 h. bIsolated yield. cDDQ (1.5 mmol) was added, and the reaction time was extended to 40 h.
4ao1 and 4ao2 was 2:1, confirmed by NMR (Scheme 3A). Notably, when TEMPO was added to the reaction of p-anisidine, dimethyl acetylenedicarboxylate and N-phenylmaleimide under the standard conditions, the desired product 4o was not detected. Instead, the tautomers 4ao1 as well as 4ao2 was observed in the ratio of 2:1 (Scheme 3B). The control experiments showed that the reaction proceeded through a radical process. On the basis of our experimental results and previous reports,14g a possible radical mechanism for oxidative coupling of maleimides with amines and alkyne esters is proposed in Scheme 4. Initially, β-enamino esters were generated in situ from amines and alkene esters. Subsequently, single-electron oxidation of the β-imine ester derived from the tautomer of β-enamino esters generates a radical intermediate. The succedent singleelectron inserts into CC of maleimide to form C−C propagation, which is further oxidized by copper(I) to obtain a carbocation. Subsequent intramolecular cyclization leads to the
oxidants were examined, and the result indicated that none of the other oxidants was superior to K2S2O8 (entries 1−8). Moreover, additional solvent could not facilitate better reaction progress (entries 9−12). As shown in (Scheme 2), the results showed that both electron-donating (5a,c,e,f) and electron-withdrawing (5b,d,g,h) substituents were tolerated well and provided the corresponding products in moderate to excellent yield (42− 72%). We then conducted a series of experiments to unveil the nature of the reaction mechanism (Scheme 3). The reaction using panisidine, dimethyl acetylenedicarboxylate, and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was tested under the standard conditions. Interestingly, the proportion of tautomers 6046
DOI: 10.1021/acs.orglett.7b02670 Org. Lett. 2017, 19, 6044−6047
Letter
Organic Letters
(4) Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2011, 133, 10376. (5) Matsumura, Y.; Terauchi, J.; Yamamoto, T.; Konno, T.; Shono, T. Tetrahedron 1993, 49, 8503. (6) Hayashi, Y.; Inagaki, F.; Mukai, C. Org. Lett. 2011, 13, 1778. (7) Zhao, B.; Liang, H.-W.; Yang, J.; Yang, Z.; Wei, Y. ACS Catal. 2017, 7, 5612. (8) Selected recent reviews: (a) Labuta, J.; Hill, J. P.; Ishihara, S.; Hanyková, L.; Ariga, K. Acc. Chem. Res. 2015, 48, 521. (b) Kim, S. K.; Sessler, J. L. Acc. Chem. Res. 2014, 47, 2525. (c) Lakshmi, V.; Rao, M. R.; Ravikanth, M. Org. Biomol. Chem. 2015, 13, 2501. (d) Ding, Y.; Tang, Y.; Zhu, W.; Xie, Y. Chem. Soc. Rev. 2015, 44, 1101. (9) (a) Huffman, J. W.; Padgett, L. W. Curr. Med. Chem. 2005, 12, 1395. (b) Rochais, C.; Lisowski, V.; Dallemagne, P.; Rault, S. Bioorg. Med. Chem. 2006, 14, 8162. (c) Zeng, L.; Miller, E. W.; Pralle, A.; Isacoff, E. Y.; Chang, C. J. J. Am. Chem. Soc. 2006, 128, 10. (10) (a) Pyrroles, The Synthesis Reactivity and Physical Properties of Substituted Pyrroles, Part II; Jones, R. A., Ed.; Wiley: New York, 1992. (b) Black, D. St. C. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996; Vol. 2, p 39. (c) Sundberg, R. J. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996; Vol. 2, p 119. (11) Nourmohammadian, F.; Yavari, I.; Mirhabibi, A. R.; Moradi, S. Dyes Pigm. 2005, 67, 15. (12) Lin, J.; Wrobleski, S. T.; Liu, C.-J.; Leftheris, K. US 20060019928, 2006; Chem. Abstr. 2006, 144, 171024. (13) For selected recent reviews, see: (a) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (b) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem. Rev. 2015, 115, 1622. (c) Yang, L.; Huang, H. Chem. Rev. 2015, 115, 3468. (d) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Chem. Rev. 2015, 115, 12138. (e) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007. (f) Huang, F.; Liu, Z.; Yu, Z. Angew. Chem., Int. Ed. 2016, 55, 862. (g) Gensch, T.; Hopkinson, M.; Glorius, F. Chem. Soc. Rev. 2016, 45, 2900. (14) (a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (b) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326. (c) Yan, R.-L.; Luo, J.; Wang, C.-X.; Ma, C.-W.; Huang, G.-S.; Liang, Y.-M. J. Org. Chem. 2010, 75, 5395. (d) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew. Chem. 2011, 123, 1374. (e) Li, B.; Wang, N.; Liang, Y.; Xu, S.; Wang, B. Org. Lett. 2013, 15, 136. (f) Wang, L.; Ackermann, L. Org. Lett. 2013, 15, 176. (g) Zhao, M.; Wang, F.; Li, X. Org. Lett. 2012, 14, 1412. (h) Zhang, M.; Fang, X.; Neumann, H.; Beller, M. J. Am. Chem. Soc. 2013, 135, 11384. (15) Yang, H.-T.; Liang, X.-C.; Wang, Y.-H.; Yang, Y.; Sun, X.-Q.; Miao, C.-B. J. Org. Chem. 2013, 78, 11992. (16) Zhang, X.; Xu, X.; Chen, G.; Yi, W. Org. Lett. 2016, 18, 4864. (17) (a) Bettadapur, K. R.; Lanke, V.; Prabhu, K. R. Org. Lett. 2015, 17, 4658. (b) Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2015, 17, 4662. (c) Sharma, S.; Han, S. H.; Oh, Y.; Mishra, N. K.; Lee, S. H.; Oh, J. S.; Kim, I. S. Org. Lett. 2016, 18, 2568. (d) Morita, T.; Akita, M.; Satoh, T.; Kakiuchi, F.; Miura, M. Org. Lett. 2016, 18, 4598. (e) Han, S.; Park, J.; Kim, S.; Lee, S. H.; Sharma, S.; Mishra, N. K.; Jung, Y. H.; Kim, I. S. Org. Lett. 2016, 18, 4666. (f) Manna, S.; Antonchick, A. P. Angew. Chem., Int. Ed. 2015, 54, 14845. (g) Chen, H.; Wang, Z.-F.; Zhang, Y.-N.; Huang, Y. J. Org. Chem. 2013, 78, 3503. (18) (a) Yu, C.-G.; Zhang, Y.-N.; Zhang, S.-L.; Li, H.; Wang, W. Chem. Commun. 2011, 47, 1036. (b) Miura, W.; Hirano, K.; Miura, M. Org. Lett. 2015, 17, 4034. (c) Yang, Y.; Ren, H.-X.; Chen, F.; Zhang, Z.-B.; Zou, Y.; Chen, C.; Song, X.-J.; Tian, F.; Peng, L.; Wang, L.-X. Org. Lett. 2017, 19, 2805. (19) (a) Sarrafi, Y.; Sadatshahabi, M.; Alimohammadi, K.; Tajbakhsh, M. Green Chem. 2011, 13, 2851. (b) Cao, H.; Wang, X.; Jiang, H.; Zhu, Q.; Zhang, M.; Liu, H. Chem. - Eur. J. 2008, 14, 11623. (20) CCDC 1561778 (4a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data-request/cif. See the Supporting Information.
Scheme 4. Proposed Reaction Mechanism for the Synthesis of Dihydropyrrole and Pyrrole Compounds
formation of dihydropyrrole compounds. Finally, the dihydropyrrole compounds were oxidized by additional oxidizing agent to afford the pyrrole derivatives. In conclusion, we have developed a copper-catalyzed oxidative annulation of maleimides with amines and alkyne esters to synthesize fully substituted dihydropyrroles via the cleavage of C(sp2)−H/N−H bonds. The reaction features mild conditions, a relatively broad scope, and high efficiency. With the addition of K2S2O8, our copper-catalyzed process can afford fully substituted pyrrole derivatives. Further biological activity evaluation of these compounds and application of this methodology for the preparation of new potent bioactive molecules are ongoing in our group and will be reported in due course.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02670. Experimental details, characterization data of all compounds, and 1H and 13C NMR spectra (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sheng-Yin Zhao: 0000-0002-5778-8068 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We acknowledge financial support from Shanghai Municipal Natural Science Foundation (No. 15ZR1401400) and the Open Funds from the State Key Laboratory of Bioorganic & Natural products Chemistry (2013).
■
REFERENCES
(1) For reviews, see: (a) Khajuria, R.; Dham, S.; Kapoor, K. K. RSC Adv. 2016, 6, 37039. (b) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. RSC Adv. 2015, 5, 15233. (c) Janin, Y. L. Chem. Rev. 2012, 112, 3924. (d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (2) (a) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006, 23, 517. (b) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (c) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264. (d) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (3) Wiest, J. M.; Pöthig, A.; Bach, T. Org. Lett. 2016, 18, 852. 6047
DOI: 10.1021/acs.orglett.7b02670 Org. Lett. 2017, 19, 6044−6047
