Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Phosphine-Catalyzed Domino [3 + 3] Cyclization of paraQuinamines with Morita−Baylis−Hillman Carbonates: Access to Hydroquinoline Derivatives Hongxing Jin,† Jingxiong Lai,† and You Huang*,†,‡ †
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State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China S Supporting Information *
ABSTRACT: A phosphine-catalyzed [3 + 3] cyclization strategy between para-quinamines and HCHO Morita− Baylis−Hillman (MBH) carbonates was discovered, delivering a series of highly functionalized hydroquinoline derivatives in moderate to good yields and excellent diastereoselectivity. Moreover, mechanistic insights, gram-scale experiments, and synthetic manipulations of the products were also discussed.
F
Scheme 1. Phosphine-Catalyzed or -Mediated Cyclizations with HCHO MBH Carbonates and Diagram of This Work
unctionalized hydroquinoline derivatives are important structure cores in bioactive or pharmaceutical molecules (Figure 1).1 Specifically speaking, Gephyrotoxin, which was
Figure 1. Examples of hydroquinoline derivatives possessing pharmaceutical and biological activities.
isolated from the tropical poison dart frog, showed obvious neurological activities.1a Aspidospermidine, a kind of indole alkaloid compound, could be obtained from the skin and leaves of Apocynaceae plants and gave excellent antibiotic activities.1b Other studies revealed that lycopodium alkaloids (such as Lycopodine) hold valuable biological activity in anticholinesterase and antipyretic aspects.1e Because of the prevalence of hydroquinoline skeletons in medicinal and biologically active compounds, it is necessary to develop original synthetic strategies to construct these architectures that contain the desired core scaffolds. Over the past decade, nucleophilic organophosphinecatalyzed or -mediated domino reactions have been developed as powerful tools for the construction of diverse heterocycles.2 Among the reported contributions, MBH carbonates possess multiple reaction sites that can participate in various Lewisbase -catalyzed reactions.3 In particular, MBH carbonates, which derived from HCHO, could be used as C3 synthons in multifarious [3 + n] (n = 2, 4, 6) cyclization reactions (Scheme 1, eqs 1, 2, and 3).4 Moreover, the MBH carbonates also acted as a 1,2,3-C3 synthesis unit in the synthesis of complex © XXXX American Chemical Society
polycyclic compounds via sequential cyclization strategies (Scheme 1, eq 4).5 As far as we know, there was just one example by Huang et al. which demonstrated that the HCHO MBH carbonates could participate in the [3 + 3] cyclization process to form six-membered cycles, and this reaction was a stoichiometric process with 1.1 equiv of phosphine catalyst (Scheme 1, eq 5).6 Despite those obvious progresses, the Received: March 7, 2019
A
DOI: 10.1021/acs.orglett.9b00834 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
different solvents had also been screened, such as DMF, DMSO, dioxane, ethanol, THF, and CHCl3. Disappointingly, no enhancement was achieved except that a mixture of 3da and 4da was obtained with high yields in CHCl3 under 60 °C (Table 1, entries 6−11). Interestingly, when we raised the reaction temperature to 85 °C (Table 1, entries 12), there was more desired product 3da than that in 60 °C. Encouraged by the exciting results, we made further efforts in raising the temperature to 100 °C in an absolute sealed tube (Table 1, entry 13), and only desired product 3da was obtained in 87% yield. Similarly, we had conducted the blank control experiment, and the result showed that the PCy3 catalyst was essential for the cyclization process (Table 1, entry 14). When we got the optimized reaction conditions, we turned to investigate the substrate scope of this reaction (Scheme 2).
exploration of the catalytic [3 + 3] reaction referring to this kind of MBH carbonate remains challenging. Catalytic desymmetrization of para-quinamines, which can efficiently change simple molecules into complex functionalized skeletons, has been an eye-catching event recently.7 In these publications, para-quinamines were used as a novel three-atom synthon for constructing the hydroindole motifs. Nevertheless, as far as we know, a solo [3 + 3] cyclization of para-quinamines has never been developed. As part of our ongoing investigation into the desymmetrization reaction of para-quinamines8 and organocatalytic domino cyclization reaction,9 herein, we documented the first phosphine-catalyzed [3 + 3] cyclization approach between para-quinamines and HCHO MBH carbonates (Scheme 1, eq 6). This tactic helped us to develop a diastereoselective method in construction of diverse hydroquinoline-containing compounds with high yields. Initially, we began our explorations with 4-methyl-N-(4′methyl-4-oxo-[1,1′-biphenyl]-1(4H)-yl)benzenesulfonamide 1d and MBH carbonates 2a in toluene at 110 °C under the catalysis of Ph3P (Table 1, entry 1), and we found that the
Scheme 2. Substrate Scope for the [3 + 3] Cyclizationa,b
Table 1. Screening of the Reaction Conditionsa
yield (%)b entry
cat.
solvent
temp (°C)
time (h)
3da
4da
1 2 3 4 5 6 7 8c 9 10c 11d 12 13 14c
PPh3 PBu3 PCy3 DABCO DMAP PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 none
toluene toluene toluene toluene toluene DMF DMSO dioxane EtOH THF CHCl3 CHCl3 CHCl3 CHCl3
110 110 110 110 110 110 110 100 78 66 60 85 100 100
3 0.5 0.5 0.5 0.5 0.5 0.5 20 2 24 24 6 1 24
trace 54 66 0 0 trace trace 0 trace 0 86 84 87 0
56 0 trace 85 52 34 40 6
a
Unspecified remarks. 1 (0.10 mmol) and 2 (0.25 mmol) were carried out in 1.0 mL of CHCl3 with 20 mol % catalyst loading. b Isolated yields. c50 mol % catalyst was used. dReaction for 3 h. e Reaction for 4 h.
trace 0
Generally speaking, this process is suitable for substrates with various different substituents. Specifically, electron-rich aryl substituents on the benzene ring were more favorable for the reaction than that with electron-deficient substituents when it refers to yield (Scheme 2, 3aa−3la), and substrates with alkyl substituents also delivered corresponding products 3ma, 3na, 3oa, and 3pa with excellent yield. Then the substrates 1q (with vinyl chain) and 1r (with ethynyl chain) were also tested in the cyclization reaction, and the desired products 3qa and 3ra were obtained smoothly. Investigation on the substrate bearing α-naphthyl or β-naphthyl groups gave 3sa and 3ta in 95% and 63%, respectively. The protecting group on the nitrogen atom could be varied, and there was no effect on yield (3ua). Then, the different changes on the ester group of the MBH carbonate
a
Unspecified remarks. 1d (0.10 mmol) and 2a (0.25 mmol) were carried out in 1.0 mL of solvent in an absolute sealed tube with 20 mol % catalyst loading. bIsolated yields. cRecovery of 1d. dMixture of 3da and 4da.
noncyclized intermediate 4da was formed in 56% yield unfortunately. To our gratification, stronger nucleophilic catalyst Bu3P yielded the desired cyclized product 3da in 54% yield (Table 1, entry 2). After that, several other catalysts were also tested in the optimization, such as PCy3, DABCO, DMAP, and PCy3 showed a higher yield with product 3da, albeit with trace byproduct intermediate 4da (Table 1, entries 3−5). To increase the yield and purity of desired 3da, a routine solvent screening process was necessary. As usual, B
DOI: 10.1021/acs.orglett.9b00834 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
C. Then, the intermediate ylide D is formed via an umpolung proton transfer process from intermediate B. The ylide D undergoes an intramolecular Michael addition and a second proton transfer to furnish intermediate F. Finally, elimination of the phosphine catalyst affords the target product 3. In order to verify the practicability of this cyclization reaction, we conducted the multigram-scale process. To our delight, we could obtain the desired product 3aa in 1.76 g with 78% yield smoothly (Scheme 5, eq 1). Then several
substrate did not affect the smooth progress of the reaction and also delivered the bicyclic product with high yield (2b−2e). Notably, the MBH adduct with an acetyl-protecting group (2f) offered an opportunity to expand the range of substrate scope, albeit with moderate yield, and the product 3df shared the same structure with product 3da (see Supporting Information). Moreover, we also tested other substrates (with red marks); however, no corresponding products were obtained in these cases under the optimized conditions. The structure of 3ia was clearly characterized by NMR spectra, HRMS spectra, and single-crystal X-ray analysis. To be clear, we could only get one single diastereomer in these cases. With the goal of understanding the domino reaction, the two control experiments were conducted under standard conditions (see Scheme 3). First, when the N-Me-protected
Scheme 5. Gram Synthesis and Synthetic Manipulations
Scheme 3. Mechanism-Driven Experiments
transformations were carried out to show the potential in the synthesis of functionalized hydroquinoline compounds. First, the bromination of 3ma generated corresponding product 5 in 65% yield (Scheme 5, eq 2). Then, the carbonyl group of paraquinamines could be reduced with NaBH4 and gave the product 6 in 70% yield (Scheme 5, eq 3). A Michael addition process with thiophenol was also explored, delivering product 7 in 70% yield (58% conversion), albeit with a longer reaction time (Scheme 5, eq 4). Moreover, the hydrolysis of the ester group in 3da gave the desired acid product 8 in 89% yield (Scheme 5, eq 5). In general, we have reported the first phosphine-catalyzed [3 + 3] cyclization strategy between para-quinamines and HCHO MBH carbonates, and a series of functionalized hydroquinoline derivatives could been obtained efficiently with good yields and excellent diastereoselectivity. Then, this cyclization process possessed a wide range of substrate scopes. Controlled experiments gave compelling evidence for the proposed mechanism and the reaction process involving a sequential catalytic and recatalytic process. Further investigations on the potential value of this reaction in the construction of drug molecules are underway in our laboratory.
substrate 1v was used, as expected, no reaction occurred, and 70% starting material 1v was recovered (Scheme 3, eq 1). Then, a transformation process with the isolated intermediate 4da had been done, and the product 3da was formed in 70% yield, albeit with 18% byproduct 1d (Scheme 3, eq 2). These suggested that the [3 + 3] cyclization could be a stepwise process, in which the N−H on the para-quinamine substrate was crucial for the one-pot domino process. Based on our experimental results and literature reports,5b,10 we proposed a possible mechanism for this process (Scheme 4). Initially, the nucleophilic addition of phosphine (PCy3) on the substrate 2a and with the elimination of carbon dioxide and tert-butoxide anion creates intermediate A. The tertbutoxide then deprotonates substrate 1 and generates intermediate A′. Subsequently, a SN2′ process between intermediate A and A′ delivers the key isolated intermediate Scheme 4. Proposed Mechanism
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00834. Experimental details, characterization data for new compounds, NMR spectra, and X-ray crystal structure of 3ia (PDF) Accession Codes
CCDC 1887577 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The CamC
DOI: 10.1021/acs.orglett.9b00834 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Chem., Int. Ed. 2016, 55, 13316. (r) Yang, W.; Sun, W.; Zhang, C.; Wang, Q.; Guo, Z.; Mao, B.; Liao, J.; Guo, H. ACS Catal. 2017, 7, 3142. (s) Zhang, J.; Wu, H.-H.; Zhang, J. Org. Lett. 2017, 19, 6080. (t) Zhou, T.; Xia, T.; Liu, Z.; Liu, L.; Zhang, J. Adv. Synth. Catal. 2018, 360, 4475. (u) Wang, C.; Gao, Z.; Zhou, L.; Wang, Q.; Wu, Y.; Yuan, C.; Liao, J.; Xiao, Y.; Guo, H. Chem. Commun. 2018, 54, 279. (4) For [3 + 2] cyclizations, see: (a) Du, Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42, 1035. (b) Feng, J.; Lu, X.; Kong, A.; Han, X. Tetrahedron 2007, 63, 6035. (c) Zhou, R.; Wang, J.; Song, H.; He, Z. Org. Lett. 2011, 13, 580. (d) Xiao, H.; Duan, H.; Ye, J.; Yao, R.; Ma, J.; Yuan, Z.; Zhao, G. Org. Lett. 2014, 16, 5462. (e) Zhang, Q.; Meng, L.-G.; Wang, K.; Wang, L. Org. Lett. 2015, 17, 872. For [3 + 4] cyclizations, see: (f) Zhou, R.; Wang, J.; Duan, C.; He, Z. Org. Lett. 2012, 14, 6134. (g) Chen, J.; Huang, Y. Org. Lett. 2017, 19, 5609. (h) Jia, J.; Yu, A.; Ma, S.; Zhang, Y.; Li, K.; Meng, X. Org. Lett. 2017, 19, 6084. For [3 + 6] cyclizations, see: (i) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987. (5) (a) Zheng, J.; Huang, Y.; Li, Z. Chem. Commun. 2014, 50, 5710. (b) Zhang, Q.; Zhu, Y.; Jin, H.; Huang, Y. Chem. Commun. 2017, 53, 3974. (6) Xie, P.; Huang, Y.; Chen, R. Chem. - Eur. J. 2012, 18, 7362. (7) (a) Pantaine, L.; Coeffard, V.; Moreau, X.; Greck, C. Org. Lett. 2015, 17, 3674. (b) Xu, D.; Zhao, Y.; Song, D.; Zhong, Z.; Feng, S.; Xie, X.; Wang, X.; She, X. Org. Lett. 2017, 19, 3600. (c) Kishi, K.; Arteaga, F. A.; Takizawa, S.; Sasai, H. Chem. Commun. 2017, 53, 7724. (d) Nguyen, T. L. N.; Incerti-Pradillos, C. A.; Lewis, W.; Lam, H. W. Chem. Commun. 2018, 54, 5622. (e) Kishi, K.; Takizawa, S.; Sasai, H. ACS Catal. 2018, 8, 5228. (f) Li, K.; Jin, Z.; Chan, W.; Lu, Y. ACS Catal. 2018, 8, 8810. (g) Wu, W.; Chen, T.; Chen, J.; Han, X. J. Org. Chem. 2018, 83, 1033. (8) (a) Jia, P.; Zhang, Q.; Jin, H.; Huang, Y. Org. Lett. 2017, 19, 412. (b) Jin, H.; Zhang, Q.; Li, E.; Jia, P.; Li, N.; Huang, Y. Org. Biomol. Chem. 2017, 15, 7097. (c) Jin, H.; Dai, C.; Huang, Y. Org. Lett. 2018, 20, 5006. (9) (a) Li, E.; Huang, Y.; Liang, L.; Xie, P. Org. Lett. 2013, 15, 3138. (b) Li, E.; Jia, P.; Liang, L.; Huang, Y. ACS Catal. 2014, 4, 600. (c) Liang, L.; Li, E.; Dong, X.; Huang, Y. Org. Lett. 2015, 17, 4914. (d) Li, E.; Jin, H.; Jia, P.; Dong, X.; Huang, Y. Angew. Chem., Int. Ed. 2016, 55, 11591. (e) Liang, L.; Dong, X.; Huang, Y. Chem. - Eur. J. 2017, 23, 7882. (10) Scott, L.; Nakano, Y.; Zhang, C.; Lupton, D. W. Angew. Chem., Int. Ed. 2018, 57, 10299.
bridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hongxing Jin: 0000-0001-6024-3600 You Huang: 0000-0002-9430-4034 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the financial support by the National Natural Science Foundation of China (NO. 21672109, 21871148, and 21472097) and the Natural Science Foundation of Tianjin (15JCYBJC20000).
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DEDICATION Dedicated to 100th anniversary of Nankai University and 100th anniversary of the birth of Academician Ruyu Chen. REFERENCES
(1) (a) Daly, J. W.; Witkop, B.; Tokuyama, T.; Nishikawa, T.; Karle, I. L. Helv. Chim. Acta 1977, 60, 1128. (b) Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872. (c) Vrijsen, R.; Berghe, D. A. V.; Vlietinck, A. J.; Boeyé, A. J. Biol. Chem. 1986, 261, 505. (d) Jahn, S.; Seiwert, B.; Kretzing, S.; Abraham, G.; Regenthal, R.; Karst, U. Anal. Chim. Acta 2012, 756, 60. (e) Ortega, M. G.; Agnese, A. M.; Cabrera, J. L. Phytomedicine 2004, 11, 539. (2) For reviews on phosphine catalysis, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (d) Cowen, B. J.; Miller, S. Chem. Soc. Rev. 2009, 38, 3102. (e) Marinetti, A.; Voituriez, A. Synlett 2010, 2010, 174. (f) Wang, S.-X.; Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Synlett 2011, 2011, 2766. (g) Zhao, Q.-Y.; Lian, Z.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48, 1724. (h) Gomez, C.; Betzer, J.-F.; Voituriez, A.; Marinetti, A. ChemCatChem 2013, 5, 1055. (i) Xie, P.; Huang, Y. Eur. J. Org. Chem. 2013, 2013, 6213. (j) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (k) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O. Beilstein J. Org. Chem. 2014, 10, 2089. (l) Voituriez, A.; Marinetti, A.; Gicquel, M. Synlett 2015, 26, 142. (m) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Acc. Chem. Res. 2016, 49, 1369. (n) Ni, H.; Chan, W.-L.; Lu, Y. Chem. Rev. 2018, 118, 9344. (o) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Chem. Rev. 2018, 118, 10049. (3) For reviews on MBH carbonates, see: (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (b) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659. (c) Fan, Y. C.; Kwon, O. Chem. Commun. 2013, 49, 11588. (d) Xie, P.; Huang, Y. Org. Biomol. Chem. 2015, 13, 8578. For reactions on MBH carbonates, see: (e) Ye, L.-W.; Sun, X.L.; Wang, Q.-G.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 5951. (f) Zheng, S.; Lu, X. Org. Lett. 2009, 11, 3978. (g) Han, X.; Ye, L.-W.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2009, 74, 3394. (h) Xie, P.; Huang, Y.; Chen, R. Org. Lett. 2010, 12, 3768. (i) Chen, Z.; Zhang, J. Chem. Asian J. 2010, 5, 1542. (j) Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am. Chem. Soc. 2011, 133, 4672. (k) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837. (l) Tian, J.; Zhou, R.; Sun, H.; Song, H.; He, Z. J. Org. Chem. 2011, 76, 2374. (m) Zhang, X.-N.; Deng, H.-P.; Huang, L.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48, 8664. (n) Zhong, F.; Chen, G.-Y.; Han, X.; Yao, W.; Lu, Y. Org. Lett. 2012, 14, 3764. (o) Xie, P.; Yang, J.; Zheng, J.; Huang, Y. Eur. J. Org. Chem. 2014, 2014, 1189. (p) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2015, 137, 4316. (q) Chen, P.; Yue, Z.; Zhang, J.; Lv, X.; Wang, L.; Zhang, J. Angew. D
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