Letter pubs.acs.org/OrgLett
Quaternary Carbon Center Forming Formal [3 + 3] Cycloaddition Reaction via Bifunctional Catalysis: Asymmetric Synthesis of Spirocyclohexene Pyrazolones Jin-Yu Liu, Jing Zhao, Jia-Lu Zhang, and Peng-Fei Xu* State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China S Supporting Information *
ABSTRACT: A variety of spirocyclohexene pyrazolones were synthesized in good yields with excellent stereoselectivities through an asymmetric, intermolecular, quaternary carbon center forming [3 + 3] cycloaddition reaction catalyzed by a bifunctional catalyst. The vinylogous pyrazolones used as binucleophilic synthons in this reaction exhibited superior ability for constructing pyrazolone related spirocyclic scaffolds.
Scheme 1. Asymmetric Synthesis of Spiropyrazolones via Organocatalytic Cascade Reaction
O
ver the past decade, with pyrazole derivatives having been extensively explored due to their widespread applications as potential pharmaceutical agents, synthetic scaffolds, photographic couplers, and chelating agents,1 increasing attention has been focused toward the synthesis of pyrazolone derivatives,2 which is one of the most important classes of nitrogen-containing heterocyclic compounds. Especially, pyrazolone related spirocyclic compounds have been proven to be important synthetic targets due to their potent bioactivities in medicinal chemistry.3 For example, pyrazolone related spirocyclic derivatives A−D (Figure 1) can
Figure 1. Bioactive pyrazolone related spirocyclic derivatives.
act as either an antibacterial agent3a or a type-4-phosphodiesterase inhibitor.3b,c Therefore, the asymmetric synthesis of pyrazolone related spirocyclic derivatives is highly desirable. Because of its great potential for constructing pharmaceutically important compounds and bioactive alkaloids, organocatalysis has emerged as a powerful strategy for extending substrate scopes and achieving unprecedented transformations.4 Therefore, α,β-unsaturated pyrazolones, used as very useful electrophilic synthons, have been broadly applied in the stereoselective synthesis of spiropyrazolones via organocatalysis (Scheme 1, eq a).5 However, vinylogous pyrazolones being © XXXX American Chemical Society
Received: February 28, 2017
A
DOI: 10.1021/acs.orglett.7b00610 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 1. Optimization of the Reaction Conditionsa
used as nucleophilic synthons, especially as binucleophilic synthons, to provide pyrazolone derivatives have received only scant attention in organocatalysis probably due to their low nucleophilicity.6 Recently, the group of Rassu and Zanardi applied α-alkylidenepyrazolinones as nucleophilic species in an asymmetric vinylogous Michael addition reaction.6a Biju and co-workers also demonstrated the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones under oxidative Nheterocyclic carbene catalysis (Scheme 1, eq b).6b With our ongoing interest in the exploration of practical asymmetric organocatalysis,4a,7 we envisioned that the asymmetric activation of challenging binucleophilic vinylogous pyrazolones might be achieved by using a bifunctional catalyst. Herein we present a bifunctional catalyst catalyzed [3 + 3] cycloaddition reaction between binucleophilic α-arylidene pyrazolinones and (E)-2-Nitroallylic acetates,8 which gave rise to quaternary spirocyclohexene pyrazolone scaffolds in moderate to high yields with excellent selectivities (Scheme 1, eq c). The study was initiated by testing the model reaction of αarylidene pyrazolinone (1a) and (E)-2-nitroallylic acetates (2a) in the presence of bifunctional thiourea I in toluene (1 mL) at 15 °C (Figure 2). The expected cycloaddition product 3aa was
entry
catalyst
solvent
yield (%)h
dri
ee (%)j
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17b 18c 19c,d 20c,d,e 21c,d,f 22d,f,g
I II III IV V VI VII VIII IX X XI X X X X X X X X X X X
THF THF THF THF THF THF THF THF THF THF THF toluene CH2Cl2 DCE CH3CN EA DCE DCE DCE DCE DCE DCE
46 69 46 60 47 72 62 NR 40 60 53 50 53 54 70 50 72 70 62 72 80 86
17:1 10:1 9:1 10:1 9:1 16:1 16:1 − 15:1 16:1 15:1 15:1 >20:1 >20:1 >20:1 15:1 10:1 >20:1 >20:1 >20:1 >20:1 >20:1
67 52 31 0 37 44 50 − 79 91 68 92 94 94 84 92 12 93 94 94 94 94
a
Conditions: Reactions performed with 1a (0.1 mmol), 2a (0.1 mmol), catalyst (20 mol %) in THF (1 mL) at 15 °C for 6−48 h. For detailed experimental procedures, see the Supporting Information. b 0.1 mmol of K2CO3 was added. c0.5 equiv of K2CO3 was added after the reaction had been stirred for 18 h. dUnder 0 °C. e0.5 mL of DCE was used. f0.25 mL of DCE was used. g0.5 equiv of K2HPO4 was added after the reaction had been stirred for 18 h. hIsolated yield. i Determined by 1H NMR analysis of the crude products. jDetermined by chiral-phase HPLC analysis.
Figure 2. Bifunctional catalysts investigated in the [3 + 3] cycloaddition reaction.
successfully produced in moderate yield with an encouraging level of stereoselectivity (Table 1, entry 1). Various tertiary amine−hydrogen bond donor bifunctional organocatalysts9 were then examined, and bifunctional squaramide X turned out to be the best catalyst (Table 1, entries 1−11). Remarkably, catalyst VI with strong Brønsted basicity10 could observably improve the reaction yield albeit with poor enantioselectivity (Table 1, entry 6). In addition, catalyst VIII with large steric hindrance could not promote the reaction (Table 1, entry 8). Next, different solvents were screened, and DCE was found to be optimal (Table 1, entries 12−16). Considering the possible effect of the produced acetic acid on the reaction yield, extra K2CO3 was added after the reaction had been stirred for 18 h to neutralize the acid generated in the reaction, and the results were improved (Table 1, entry 18). Notably, the addition of base at the early stage of the reaction did not offer satisfactory results because the single inorganic base could also promote the reaction11 (Table 1, entry 17). Other reaction condition optimizations demonstrated that 0 °C and 0.25 mL of DCE were optimal (Table 1, entries 19−21). Adjusting the base in hopes of improving the yield revealed that K2HPO4 gave better results (Table 1, entry 22).12 With the optimal reaction conditions established, the cascade reactions of diverse α-arylidene pyrazolinones and (E)-2-nitroallylic acetates with different electronic and steric properties were investigated. As shown in Scheme 2, in all the
cases, the reaction proceeded smoothly to afford the corresponding spirocyclohexene pyrazolones in moderate to high yields with excellent diastereo- and enantioselectivities. The electronic properties of substrates had no pronounced effects on the stereoselectivities but noticeable influences on the yields. In general, α-arylidene pyrazolinones 1 with electron-donating substituents gave more satisfactory yields than those with electron-withdrawing substituents (Scheme 2, 3ba−3ca versus 3da−3fa, 3ja−3ka versus 3la−3na, 3pa versus 3qa−3sa), probably due to the lower nucleophilicities of the αarylidene pyrazolinones with electron-withdrawing substituents. Notably, slightly lower yields and enantioselectivities were observed with sterically demanding substrates (Scheme 2, 3ia and 3oa). Furthermore, (E)-2-nitroallylic acetates 2 with electron-donating groups exhibited higher reactivities compared with those with electron-withdrawing substituents (Scheme 2, 3ab−3ac versus 3ad−3af). Additionally, the steric influence of the substituents of the substrates 2 was not obvious (Scheme 2, 3ag) and (E)-2-nitro-3-(thiophen-2yl)allyl acetate was also well tolerated (Scheme 2, 3ah). A variety of substrates 1 and 2 with alkyl substituents were tested, but the results were unsatisfactory. The absolute B
DOI: 10.1021/acs.orglett.7b00610 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
formal [3 + 3]-annulation product with excellent results, further demonstrating the synthetic value of this reaction (Scheme 3, eq 1). In addition, the nitro group of chiral spirocyclohexene pyrazolone 3aa could be easily transformed into the amide group in good yield with high diastereo- and enantioselectivity (Scheme 3, eq 2). On the basis of our experimental results and previous reports, a plausible catalytic cycle is outlined in Figure 4. First,
Scheme 2. Scope of the Asymmetric Synthesis of Spirocyclohexene Pyrazolones
configuration of the product 3sa was determined to be (5R,8R,9S) by X-ray crystallography (Figure 3).13
Figure 4. Proposed reaction mechanism.
the α-arylidene pyrazolinones 1a and (E)-2-nitroallylic acetates 2a are synergistically activated by the bifunctional squaramide X to form the reactive intermediate A with the concurrent release of acetic acid via asymmetric vinylogous Michael addition. After a tautomerization, the intermediate B undergoes an intramolecular cyclization process to afford desired product 3a with the regeneration of the catalyst. In summary, we have developed a practical and efficient approach for an intermolecular, quaternary center-forming, asymmetric, [3 + 3] cycloaddition reaction catalyzed by a bifunctional squaramide, and a series of spirocyclohexene pyrazolones with pharmaceutical potential were obtained in moderate to high yields with excellent stereoselectivities. Notably, vinylogous pyrazolones, used as binucleophilic synthons instead of traditional electrophilic synthons, were applied to provide pyrazolone derivatives, complementing and extending our current knowledge of pyrazolones. Further studies on the pyrazolone derivatives are currently underway in our laboratory.
Figure 3. X-ray crystal structure of compound 3sa.
To explore the practicality of this chiral spirocyclohexene pyrazolone producing reaction further, a gram-scale asymmetric synthesis of 3aa was performed (Scheme 3), and the reaction proceeded smoothly to afford the corresponding Scheme 3. Synthetic Application of the Chiral Spirocyclohexene Pyrazolone
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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.7b00610. Detailed experimental procedures and full spectroscopic data for all new compounds (PDF) X-ray data for 3sa (CIF) C
DOI: 10.1021/acs.orglett.7b00610 Org. Lett. XXXX, XXX, XXX−XXX
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Chem. Commun. 2015, 51, 3596. (h) Xiao, Y.; Lin, J.-B.; Zhao, Y.-N.; Liu, J.-Y.; Xu, P.-F. Org. Lett. 2016, 18, 6276. (i) Wang, Y.; Xu, P.-F. Application of Organocatalytic Cascade Reactions in Natural Product Synthesis and Drug Discovery. In Catalytic Cascade Reactions; Xu, P.F., Wang, W., Eds.; John Wiley & Sons: Canada, 2014; pp 123−144. (8) For selected examples on (E)-2-nitroallylic acetates, see: (a) Cao, C.-L.; Zhou, Y.-Y.; Zhou, J.; Sun, X.-L.; Tang, Y.; Li, Y.X.; Li, G.-Y.; Sun, J. Chem. - Eur. J. 2009, 15, 11384. (b) Huang, W.Y.; Chen, Y.-C.; Chen, K. Chem. - Asian J. 2012, 7, 688. (c) Anwar, S.; Huang, W.-Y.; Chen, C.-H.; Cheng, Y.-S.; Chen, K. Chem. - Eur. J. 2013, 19, 4344. (d) Nair, D. K.; Menna-Barreto, R. F. S.; da Silva, E. N., Jr.; Mobin, S. M.; Namboothiri, I. N. N. Chem. Commun. 2014, 50, 6973. (e) Xiao, W.; Yin, X.; Zhou, Z.; Du, W.; Chen, Y.-C. Org. Lett. 2016, 18, 116. (f) Shu, T.; Ni, Q.; Song, X.; Zhao, K.; Wu, T.; Puttreddy, R.; Rissanen, K.; Enders, D. Chem. Commun. 2016, 52, 2609. (g) Zheng, Y.; Cui, L.; Wang, Y.; Zhou, Z. J. Org. Chem. 2016, 81, 4340. (9) For selected recent reviews on bifunctional organocatalysts, see: (a) Connon, S. J. Chem. - Eur. J. 2006, 12, 5418. (b) Yu, X.; Wang, W. Chem. - Asian J. 2008, 3, 516. (c) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. - Eur. J. 2011, 17, 6890. (d) Fang, X.; Wang, C.-J. Chem. Commun. 2015, 51, 1185. (e) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253. (f) Li, P.; Hu, X.; Dong, X.-Q.; Zhang, X. Molecules 2016, 21, 1327. (10) For selected examples on bifunctional organocatalysts with strong Brønsted basicity, see: (a) Núňez, M. G.; Farley, A. J. M.; Dixon, D. J. J. Am. Chem. Soc. 2013, 135, 16348. (b) Farley, A. J. M.; Sandford, C.; Dixon, D. J. J. Am. Chem. Soc. 2015, 137, 15992. (c) Yang, J.; Farley, A. J. M.; Dixon, D. J. Chem. Sci. 2017, 8, 606. (11) K2CO3 was used as a catalyst to obtain the racemic products 3. (12) For more details, see the Supporting Information. (13) CCDC 1522631 (3sa) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam. ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Peng-Fei Xu: 0000-0002-5746-758X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the NSFC (21632003, 21372105, and 21572087) and the “111” program from the MOE of P. R. China for financial support.
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DOI: 10.1021/acs.orglett.7b00610 Org. Lett. XXXX, XXX, XXX−XXX
