Bicyclization of Azomethine Ylide: Access to Highly Functionalized 3H

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Letter Cite This: Org. Lett. 2017, 19, 6712−6715

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Bicyclization of Azomethine Ylide: Access to Highly Functionalized 3H‑Pyrrolo[2,3‑c]quinolines Yang Men,† Jinhuan Dong,*,‡ Shan Wang,† and Xianxiu Xu*,†,‡ †

Department of Chemistry, Jilin Province Key Laboratory of Organic Functional Molecular Design and Synthesis, Northeast Normal University, Changchun 130024, China ‡ College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China S Supporting Information *

ABSTRACT: A tandem bicyclization of azomethine ylides with methyleneaminochalcones was developed for the straightforward and facile synthesis of 2-substituted polyfunctionalized pyrrolo[2,3-c]quinolines. Both an unusual reactivity profile of azomethine ylide and a novel strategy for the construction of the tricyclic framework by the successive construction of the pyridine and pyrrole rings were exhibited in this domino reaction. Two intermediates are isolated in the control experiments, and thus a tandem bicyclization/elimination/oxidative aromatization process is proposed for the reaction mechanism.

A

Scheme 1. Intramolecular Cycloadditions and Domino Cycloadditions of Azomethine Ylides

zomethine ylides are versatile nitrogen-based 1,3-dipoles for the synthesis of five-membered heterocycles1,2 or pyrrolidine-containing complex molecular architectures.3,4 While the well-developed 1,3-dipolar cycloaddition of azomethine ylides with alkenes has become a powerful tool for both racemic and asymmetric syntheses of pyrrolidines,1,2 the intramolecular version of this reaction has proven to be a reliable way to construct fused or bridged polycyclic rings systems (Scheme 1, eq 1).3,4 However, the intramolecular reactions require dipolarophile tethered azomethine ylides or their precursors as substrates, which usually need a multistep synthesis and/or bear limited functional groups. Therefore, the domino cycloaddition of simple azomethine ylides for the preparation of polycyclic scaffolds is particularly promising because of its readily accessible starting materials, broad functional group tolerance, and high efficiency. In 1989, Grigg and co-workers reported a tandem Michael addition/ 1,3-dipolar cycloaddition process of azomethine ylides with divinyl sulfone for the synthesis of fused pyrrolidines (Scheme 1, eq 2).5 During our recent study of the bicyclization of active methylene isocyanides with 1,n-dieletrophiles as a new strategy for the construction of heterocycles,6 we envisioned that azomethine ylide and isocyanoacetate had a certain similar reactivity profile. Therefore, we recently developed a bicyclization of azomethine ylides with dialkenoyl ketene dithioacetals for the regiospecific synthesis of cyclohepta[b]pyrroles (Scheme 1, eq 3).7 This year, an aerobic oxidative [3 + 2] cycloaddition of azomethine ylides with isocyanides was also developed by our research group.8 As the result of our continuous research in this area, we herein report the bicyclization of azomethine ylide with 2-methyleneaminochal© 2017 American Chemical Society

cones9 for the efficient synthesis of highly functionalized pyrrolo[2,3-c]quinolines (Scheme 1, eq 4). The pyrrolo[2,3-c]quinoline core is found in natural products such as marinoquinoline B−F,10 aplidiopsamine A,11 and trigonoine B12 and some manmade antitubercular comReceived: November 4, 2017 Published: December 5, 2017 6712

DOI: 10.1021/acs.orglett.7b03434 Org. Lett. 2017, 19, 6712−6715

Letter

Organic Letters

temperature to 40 °C or increasing it to 80 °C led to lower yield of 3aa compared with 60 °C (Table 1, entries 5 and 6 vs 1). When NaH or Cs2CO3 was used as base, the desired product 3aa was not detected (Table 1, entries 7 and 8). Organobase TMG gave a comparable yield of 3aa (Table 1, entry 9). The yield of 3aa was not increased when the reaction was performed in the atmosphere of O2 (Table 1, entry 10). Gratifyingly, it was found that the yield of 3aa was improved when DDQ was added (Table 1, entries 11−14). Thus, the product 3aa could be obtained in 75% isolated yield by adding DDQ (2.5 equiv) into the reaction mixture of 1a and 2a after being stirred for 5 h (Table 1, entry 14). With the optimal conditions in hand (Table 1, entry 14), the scope of viable 2-methyleneaminochalcone substrates 1 was examined (Scheme 2). In general, a series of polyfunctionalized pyrrolo[2,3-c]quinolines (3aa−xa) (Scheme 2) were obtained in good to high yields by the reaction of imine 2a with substrates 1 bearing various R1 groups, such as para- (1a−c, 1e, 1f), meta- (1g and 1h), or ortho-substituted aryl formyl (1i), benzoyl (1d), heteroaryl formyl (1j and 1k), acetyl (1l), cyano

pounds.13 So far, great efforts have been devoted to the preparation of this tricyclic scaffold,14−16 which mainly relies on the construction of the central pyridine ring from the cyclization of aryl-substituted pyrroles14 or the formation of the pyrrole ring from the quinoline substrates.15 Recently, an elegant protocol for the synthesis of pyrrolo[2,3-c]quinolin4(5H)-ones by the sequential formation of two rings through a domino reaction of 3-(2-oxo-2-ethylidene)indolin-2-ones with alk-1-enyl-substituted TosMICs was reported by Wang, Ji, and co-workers.16 In contrast, our bicyclization of azomethine ylides with 2-methyleneaminochalcones (Scheme 1, eq 4) not only provides an efficient protocol for the synthesis of a wide range of 2-substituted polyfunctionalized pyrrolo[2,3-c]quinolines in a single operation from readily available substrates but also considerably expands the scope of the azomethine ylide-based domino cycloaddition reaction for the construction of complex molecular architectures in a highly efficient manner. Initially, the reaction using 2-methyleneaminochalcone 1a and imine 2a as a simple model substrate was investigated to optimize the reaction conditions (Table 1). When the reaction Table 1. Optimization of Reaction Conditionsa

Scheme 2. Scope of 2-Methyleneaminochalcones 1a,b

yieldb (%) entry

base

oxidant

solvent

time (h)

3aa

4a

1 2 3 4 5c 6d 7 8 9 10 11e 12f 13g 14h

DBU DBU DBU DBU DBU DBU NaH Cs2CO3 TMG DBU DBU DBU DBU DBU

air air air air air air air air air O2 DDQ DDQ DDQ DDQ

THF CH2Cl2 DMF EtOH THF THF THF THF THF THF THF THF THF THF

40 40 40 40 40 40 40 40 40 40 26 26 26 26

53

33

20 46 40 33

52 18 40 34

46 50 60 62 67 75

32 30

a Reaction conditions: 1a (0.2 mmol), 2a (0.21 mmol), base (0.4 mmol), solvent (2 mL), at 60 °C, air atmosphere. bIsolated yields. cAt 40 °C. dAt 80 °C. eDDQ (2.0 equiv) was added after the reaction mixture of 1a, 2a, and base was stirred for 1 h. fDDQ (2.0 equiv) was added after 3 h. gDDQ (2.0 equiv) was added after 5 h. hDDQ (2.5 equiv) was added after 5 h.

mixture of 1a (0.2 mmol), imine 2a (1.05 equiv), and DBU17 (2.0 equiv) in THF (2 mL) was stirred at 60 °C in the open air for 40 h, pyrrolo[2,3-c]quinoline 3aa was obtained in 53% yield, along with hexahydro-1H-pyrrolo[2,3-c]quinoline 4a in 33% yield (Table 1, entry 1). Different solvents such as CH2Cl2, EtOH, and DMF were then explored (Table 1, entries 2−4). The reaction failed to generate the desired product 3aa in the weakly polar solvent (Table 1, entry 2), whereas more polar solvent (Table 1, entry 3) or protonic solvent (Table 1, entry 4) gave lower yield of 3aa than in THF (Table 1, entry 1). Subsequently, the reaction temperatures were elevated to observe the variation of yields of 3aa. Decreasing the reaction

a

Reaction conditions: 1 (0.2 mmol), 2a (0.21 mmol), and DBU (2.0 equiv) in THF (2 mL) at 60 °C, DDQ (2.5 equiv) was added after the reaction mixture of 1a, 2a, and base was stirred for 5 h. bIsolated yields. 6713

DOI: 10.1021/acs.orglett.7b03434 Org. Lett. 2017, 19, 6712−6715

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Organic Letters (1m), and ester groups (1n). Substrates 1 with both electronwithdrawing (1o) and electron-donating (1p) R2 groups were also well tolerated in this domino reaction. Furthermore, this reaction was compatible with substrates 1 bearing various R3 groups such as electron-poor (1q, 1t, 1u), -neutral (1r) and -rich (1s) aryl, heteroaryl (1v and 1w) and vinyl (1x) groups. Unfortunately, alkyl R3 groups such as benzyl and tert-butyl were not compatible under the optimal conditions. The bicyclization of azomethine ylides with 1,5-bielectrophilic 2-methyleneaminochalcones described above represents a simple and efficient protocol for the direct synthesis of pyrrolo[2,3-c]quinolines from acyclic starting materials. Next, the bicyclization of selected examples of imines 2 with substrate 1d was examined (Scheme 3). The azomethine ylide precursor

Scheme 4. Control Experiments

Scheme 3. Selected Examples of Imines 2a,b

Scheme 5. Proposed Mechanism

a

Reaction conditions: 1d (0.2 mmol), 2 (0.21 mmol) and DBU (2.0 equiv) in THF (2 mL) at 60 °C, and DDQ (2.5 equiv) was added after the reaction mixture of 1a, 2a and DBU was stirred for 5 h. bIsolated yields.

imines bearing electron-rich (2b), -neutral (2c) and -poor (2d) aryl groups and heteroaryl group (2e) reacted smoothly with 1d to give pyrrolo[2,3-c]quinolines (3db−de) in high yields. To shed light on the reaction mechanism of this bicyclization process, control experiments were performed. First, when the reaction of 2-methyleneaminochalcone 1a and imine 2a was worked up at 3 h, hexahydro-1H-pyrrolo[2,3-c]quinoline 4a and tetrahydroquinoline 5a were obtained in 32% and 52% yields, respectively (Scheme 4, eq 1). Then, when tetrahydroquinoline 5a was treated with DBU (2.0 equiv) in THF at 60 °C for 10 h in the open air, pyrrolo[2,3-c]quinoline 3a and hexahydro-1H-pyrrolo[2,3-c]quinoline 4a were obtained in 42% and 21% yields, respectively (Scheme 4, eq 2). Finally, treatment of 4a with the standard conditions for 11 h led to formation of 3a in 70% yield (Scheme 4, eq 3). These results uncover the identity of 4a and 5a being the intermediates in the formation of pyrrolo[2,3-c]quinoline 3a. On the basis of the above results and the related work,5,7 a mechanistic pathway for the bicylization of azomethine ylide with 2-methyleneaminochalcone is proposed in Scheme 5. There are two possible pathways for the formation of tetrahydroquinoline 5 from substrates 1 and 2. In path a, Michael addition of 2 to 1 occurred to give intermediate I, which was followed by intramolecular Mannich reaction to deliver tetrahydroquinoline 5;9 or Mannich reaction of 1 and 2 gave intermediate II, then followed by intramolecular Michael addition to produce 5 (path b).18 Intramolecular Mannich

reaction of tetrahydroquinoline 5 gave hexahydro-1H-pyrrolo[2,3-c]quinoline 4, which followed by the elimination of HCN and oxidative aromatization to furnish the final product 3. To test the synthetic utility of this tandem bicyclization, a gram-scale synthesis of pyrrolo[2,3-c]quinolone 3aa was carried out under the optimal reaction conditions (Scheme 6). In the presence of 2.0 equiv of DBU and 2.5 equiv of DDQ, the reaction of aminochalcone 1a and imine 2a delivered 3aa with a slightly decreased 57% isolated yield. In summary, a new domino bicyclization of azomethine ylides with 2-methyleneaminochalcones was developed. This Scheme 6. Gram-Scale Synthesis

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DOI: 10.1021/acs.orglett.7b03434 Org. Lett. 2017, 19, 6712−6715

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Q.; Lin, N.; Long, X.-W.; Pan, W.-G.; Xiong, Y.-S.; Weng, J. Org. Chem. Front. 2017, 4, 472. (m) Liu, H.; Zheng, C.; You, S.-L. Chin. J. Chem. 2014, 32, 709. (n) Xu, B.; Zhang, Z.-M.; Liu, B.; Xu, S.; Zhou, L.-J.; Zhang, J. Chem. Commun. 2017, 53, 8152. (o) Zhang, Z.-M.; Xu, B.; Liu, B.; Xu, S.; Wu, H.-L.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 6324. (3) For reviews, see: (a) Pandey, G.; Dey, D.; Tiwari, S. K. Tetrahedron Lett. 2017, 58, 699. (b) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. (4) For selected recent examples, see: (a) Sugita, S.; Takeda, N.; Tohnai, N.; Miyata, M.; Miyata, O.; Ueda, M. Angew. Chem., Int. Ed. 2017, 56, 2469. (b) Chen, S.; Bacauanu, V.; Knecht, T.; Mercado, B. Q.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2016, 138, 12664. (5) Barr, D. A.; Donegan, G.; Grigg, R. J. Chem. Soc., Perkin Trans. 1 1989, 1, 1550. (6) (a) Tan, J.; Xu, X.; Zhang, L.; Li, Y.; Liu, Q. Angew. Chem., Int. Ed. 2009, 48, 2868. (b) Li, Y.; Xu, X.; Tan, J.; Xia, C.; Zhang, D.; Liu, Q. J. Am. Chem. Soc. 2011, 133, 1775. (c) Xu, X.; Zhang, L.; Liu, X.; Pan, L.; Liu, Q. Angew. Chem., Int. Ed. 2013, 52, 9271. (d) Xu, X.; Li, Y.; Zhang, Y.; Zhang, L.; Pan, L.; Liu, Q. Adv. Synth. Catal. 2011, 353, 1218. (e) Zhang, L.; Xu, X.; Tan, J.; Pan, L.; Xia, W.; Liu, Q. Chem. Commun. 2010, 46, 3357. (f) Li, Y.; Xu, X.; Shi, H.; Pan, L.; Liu, Q. J. Org. Chem. 2014, 79, 5929. (g) Zhang, L.; Xu, X.; Xia, W.; Liu, Q. Adv. Synth. Catal. 2011, 353, 2619. (h) Zhang, X.; Feng, C.; Jiang, T.; Li, Y.; Pan, L.; Xu, X. Org. Lett. 2015, 17, 3576. (i) Gao, Y.; Hu, Z.; Dong, J.; Liu, J.; Xu, X. Org. Lett. 2017, 19, 5292. (j) Lin, Z.; Hu, Z.; Zhang, X.; Dong, J.; Liu, J.-B.; Chen, D.-Z.; Xu, X. Org. Lett. 2017, 19, 5284. (7) Zhang, Y.; Pan, L.; Xu, X.; Luo, H.; Liu, Q. Chem. Commun. 2014, 50, 11039. (8) Hu, Z.; Dong, J.; Xu, X. Adv. Synth. Catal. 2017, 359, 3585. (9) Jia, Z.-X.; Luo, Y.-C.; Xu, P.-F. Xu and co-workers prepared 2methyleneaminochalcones by the condensation of aminochalcones with aldehydes. Org. Lett. 2011, 13, 832. (10) Okanya, P. W.; Mohr, K. I.; Gerth, K.; Jansen, R.; Müller, R. J. Nat. Prod. 2011, 74, 603. (11) Carroll, A. R.; Duffy, S.; Avery, V. M. J. Org. Chem. 2010, 75, 8291. (12) Li, S.-F.; Di, Y.-T.; He, H.-P.; Zhang, Y.; Wang, Y.-H.; Yin, J.-L.; Tan, C.-J.; Li, S.-L.; Hao, X.-J. Tetrahedron Lett. 2011, 52, 3186. (13) Akula, M.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D.; Bhattacharya, A. Monatsh. Chem. 2014, 145, 811. (14) Synthesis of pyrrolo[2,3-c]quinolones by construction of central pyridine ring: (a) Ni, L.; Li, Z.; Wu, F.; Xu, J.; Wu, X.; Kong, L.; Yao, H. Tetrahedron Lett. 2012, 53, 1271. (b) Schwalm, C. S.; Correia, C. R. D. Tetrahedron Lett. 2012, 53, 4836. (c) Ma, X.; Vo, Y.; Banwell, M. G.; Willis, A. C. Asian J. Org. Chem. 2012, 1, 160. (d) Mahajan, J. P.; Suryawanshi, Y. R.; Mhaske, S. B. Org. Lett. 2012, 14, 5804. (e) Panarese, J. D.; Lindsley, C. W. Org. Lett. 2012, 14, 5808. (f) Yamaoka, Y.; Yoshida, T.; Shinozaki, M.; Yamada, K.; Takasu, K. J. Org. Chem. 2015, 80, 957. (15) Synthesis of pyrrolo[2,3-c]quinolones by construction of pyrrole ring: (a) Lindsay, A. C.; Sperry, J. Synlett 2013, 24, 461. (b) Wang, Z.; Xing, X.; Xue, L.; Gao, F.; Fang, L. Org. Biomol. Chem. 2013, 11, 7334. (c) Wang, Z.; Xue, L.; He, Y.; Weng, L.; Fang, L. J. Org. Chem. 2014, 79, 9628. (16) Wang, R.; Wang, S.-Y.; Ji, S.-J. Tetrahedron 2013, 69, 10836. (17) For selected DBU-mediated tandem reactions, see: (a) Yu, X.; Zhou, G.; Zhang, J. Chem. Commun. 2012, 48, 4002. (b) Xiao, Y.; Zhang, J. Chem. Commun. 2009, 3594. (c) Wang, F.; Cai, S.; Wang, Z.; Xi, C. Org. Lett. 2011, 13, 3202. (d) Alford, A. J.; Lin, Q. J. Org. Chem. 2017, 82, 9873. (18) Patra, A.; Mukherjee, S.; Das, T. K.; Jain, S.; Gonnade, R. G.; Biju, A. T. Angew. Chem., Int. Ed. 2017, 56, 2730.

reaction provides an efficient one-pot protocol for the efficient and direct synthesis of 2-substituted polyfunctionalized pyrrolo[2,3-c]quinolines from readily accessible starting materials by the successive construction of the pyridine and pyrrole rings of the tricyclic framework. Two intermediates were isolated in the control experiments, and a multistep process for this bicyclization transformation was proposed. Meanwhile, the practicality of this transformation was illustrated by a gramscale synthesis. This reaction features high efficiency, broad substrate scope, and readily available substrates. Further investigations on the bicyclization strategy for the synthesis of complex architecture are currently underway in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03434. Experimental procedures and characterization data for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xianxiu Xu: 0000-0001-7435-7449 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support provided by the NSFC (21672034), the Natural Sciences Foundation of Jilin Province (20160101330JC) and Shandong Normal University (108100801) is gratefully acknowledged.

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DOI: 10.1021/acs.orglett.7b03434 Org. Lett. 2017, 19, 6712−6715