Letter Cite This: Org. Lett. 2018, 20, 1158−1161
pubs.acs.org/OrgLett
Synthesis of Chiral Pyrazolone and Spiropyrazolone Derivatives through Squaramide-Catalyzed Reaction of Pyrazolin-5-ones with o‑Quinone Methides Ji Zhou, Wen-Jun Huang, and Guo-Fang Jiang* State Key Lab of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China S Supporting Information *
ABSTRACT: A bifunctional squaramide-catalyzed reaction of pyrazolin-5-ones with o-quinone methides in situ generated from 2-(1-tosylalkyl)phenols has been successfully developed, providing a facile access to chiral pyrazolones with high enantioselectivities. In addition, the chiral spiropyrazolones with adjacent tertiary and quaternary stereogenic centers can also be obtained through cascade chlorination/cyclization of the chiral pyrazolones.
A
spiropyrazolone heterocyclic molecules is still considered an arduous challenge owing to the difficulties in controlling the diastereo- and enantioselectivities, and only sporadic examples have been reported regarding the direct use of simple 4unsubstituted pyrazolones.9 Moreover, the methodology to acquire different types of enantiopure pyrazolones including the spirocyclic ones with a multistereogenic center through a cascade reaction is still rare. Hence, development of more efficient catalytic asymmetric strategies for the synthesis of chiral prazolones and their derivatives remains highly desirable. It is fairly well-known that the o-quinone methides (o-QMs) are a pivotal class of key intermediates in various biological processes10 and have been regarded as highly reactive chemical motifs.11 As part of our ongoing interest toward the utilization of o-QMs,12 we focused on asymmetric cascade reactions of in situ generated o-QMs. Accordingly, we envisioned the combination of 2-(1-tosylalkyl)phenols and pyrazolin-5-ones would enable synthesis of chiral pyrazolone derivatives, even spiropyrazolones, in the presence of inorganic bases and bifunctional organocatalysts (Scheme 1). The bifunctional organocatalyst could be used for deprotonation of pyrazolones to form the nucleophilic species in the chiral environment, and those intermediates then react with the in situ generated o-QMs via Michael addition to get adducts, which could further convert to spiropyrazolones catalyzed by a bifunctional organocatalyst in the presence of N-chlorosuccinimide (NCS) and base through cascade chlorination/cyclization. Herein, we present a facile bifunctional squaramide-catalyzed synthesis of chiral pyrazolone and spiropyrazolone derivatives via the in situ
mong the various nitrogen-containing heterocyclic compounds, prazolones and their derivatives are important molecular skeletons that widely occur in natural products and pharmaceutical agents.1 Although the pyrazolone moiety is not a common feature of biologically active natural products, a broad range of synthetic pyrazolone derivatives exhibit significant pharmacological activities (Figure 1). For example,
Figure 1. Pyrazolone drugs and bioactive compounds.
the C. I. Acid Yellow 11 is used as a reactive dye in the chemical industry;2 metamizole is considered as the strongest antipyretic;3 and the prazolone derivatives A and B act as an antibacterial agent and P38 inhibitor, respectively.4,5 Pyrazolin-5-ones are unique scaffolds with availability of many reactive centers, which enable further modifications and transformations to access new valuable compounds. Undoubtedly, the enantioselective synthesis of the structurally diverse pyrazolone derivatives employing the pyrazolin-5-ones stands at the forefront, and many methods have been reported over the past few years.6 Although various simple C−C and C−X7 bond formations as well as cascade sequences8 involving the pyrazolin-5-one derivatives provide diversely functionalized pyrazolones, the highly enantiocontrolled construction of © 2018 American Chemical Society
Received: January 9, 2018 Published: February 8, 2018 1158
DOI: 10.1021/acs.orglett.8b00025 Org. Lett. 2018, 20, 1158−1161
Letter
Organic Letters Scheme 1. Strategy for the Synthesis of Chiral Pyrazolones Based on o-Quinone Methides (o-QMs) with Pyrazolin-5ones
Table 1. Optimization of Reaction Parameters for Michael Additiona
generated o-QMs with pyrazolin-5-ones in excellent diastereoand enantioselectivities under the basic conditions. At the outset, 2-(1-tosylalkyl)phenol 1a and pyrazolin-5-one 2a were chosen as model substrates for Michael addition. The experiment was conducted in THF (tetrahydrofuran) by using quinine 4a as catalyst and sodium carbonate as base. The reaction proceeded smoothly to give the desired product 3aa in 72% yield with 4% ee (Table 1, entry 1). Encouraged by this result, we continued to test the solvent effect (Table 1, entries 2−5), and 1,2-dichloroethane (DCE) was proven to be the most favorable solvent in terms of enantioselectivity and yield. Subsequently, a series of common bifunctional organocatalysts were investigated (Table 1, entries 6−10). In contrast to quinine 4a, bifunctional thiourea and squaramide catalysts gave higher enantioselectivities. Obviously, quinine-based squaramide catalyst 4f was the best catalyst to deliver the target product 3aa in 88% yield with 99% ee. Increasing the reaction temperature gave no improvement of activity (Table 1, entry 11). Gratifyingly, the adduct 3aa was obtained in 96% yield with 99% ee when 1.2 equiv of 1a was used (Table 1, entry 12). Thus, the optimized conditions were established as quininebased squaramide catalyst 4f (10 mol %), sodium carbonate (1.5 equiv), DCE, 30 °C, and 48 h. With the optimal conditions identified, the substrate generality with respect to both the 2-(1-tosylalkyl)phenol and pyrazolin-5-one components was evaluated, and the results are shown in Scheme 2. It indicates that a broad spectrum of 2-(1tosylalkyl)phenols and pyrazolin-5-ones were amenable to this Michael addition, providing a diverse array of pyrazolones in high yields with good enantioselectivities (up to 97% yield, 99% ee). First, the substrate scope with respect to the pyrazolin-5-one partner was surveyed. When the methyl was changed to phenyl, the transformation could furnish the corresponding adduct 3ac in excellent enantioselectivity. However, for the ethyl group, the corresponding adduct 3ab was obtained in lower enantioselectivity for 83% ee. The influence of the steric and electronic properties of substituents on the phenyl rings at the C3 position of pyrazolin-5-ones was exploited. Not surprisingly, slightly lower enantioselectivity was observed upon increasing the steric hindrance of phenyl ring (3af vs 3ae). Electrondonating groups are favored to the control of enantioselectivity apparently (3ad−af), fluorine on the phenyl ring decreased the ee to moderate level 77% (3ag). Meanwhile, 2-naphthylsubstituted pyrazolin-5-one 2h could be converted to 3ah in
entry
solvent
cat.
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11d 12e
THF toluene CHCl3 CH2Cl2 DCE DCE DCE DCE DCE DCE DCE DCE
4a 4a 4a 4a 4a 4b 4c 4d 4e 4f 4f 4f
72 52 83 85 84 90 54 77 59 88 88 96
4 53 38 43 45 93 76 93 89 99 99 99
a Conditions: 1a (0.10 mmol), 2a (0.10 mmol), cat. 4 (0.01 mmol), Na2CO3 (0.12 mmol), solvent (1.5 mL), 30 °C, 48 h. bIsolated yields. c Determined by chiral HPLC. d50 °C. e1a (0.12 mmol), 2a (0.10 mmol), cat. 4f (0.01 mmol), Na2CO3 (0.15 mmol), DCE (1.5 mL).
92% yield with 97% ee. In addition, when methoxy group was placed in the para-position of phenyl ring on nitrogen, the reaction also performed smoothly in 97% yield with 83% ee (3ai). Following the establishment of the broad generality of the pyrazolin-5-one components, we continued to investigate into the variation of the 2-(1-tosylalkyl)phenols. For 2-(1-tosylalkyl) phenols 1b,c, the electronic property had a slight influence on the enantioselectivities and yields. Furthermore, the reaction proceeded smoothly with simple 2-(1-tosylalkyl) phenol 1d, 2(1-tosylalkyl)naphthols 1e, and the methoxy substituent substrate 1f, though only moderate yield for 3da was obtained. In addition, the alkyl-substituted substrate 1g could also participate in this transformation as well and delivered the desired product 3ga in 93% yield with moderate ee (43% ee). Morever, the substrate with an electron-withdrawing group bromo on the phenyl ring of the 2-(1-tosylalkyl)phenols (1h, 1i) could convert to the corresponding adducts in satisfying results. Lastly, reaction of 2-(1-tosylalkyl)naphthols 1e with pyrazolin-5-one 2c successfully gave the 3ec in 91% yield and 95% ee (Scheme 2). To extend the utilization of this method, we have made further efforts to synthesize the spiropyrazolones from adducts 3 through organocatalyzed chlorination and following intramolecular cyclization in the presence of base and organo1159
DOI: 10.1021/acs.orglett.8b00025 Org. Lett. 2018, 20, 1158−1161
Letter
Organic Letters Scheme 2. Substrate Scope for Synthesis of Chiral Pyrazolones*
Scheme 3. Substrate Scope for Synthesis of Spiropyrazolonesa
a
Unless otherwise noted, all reactions were carried out under these conditions: 3 (0.20 mmol), NCS (0.26 mmol), K2CO3 (0.24 mmol), cat. 4h (0.02 mmol), DCE (3.0 mL), 50 °C, 5 h.
Scheme 4. Scale-up Experiment
Additionally, we have attempted the one-pot reaction of 2(1-tosylalkyl)phenol 1a with pyrazolin-5-one 2a for direct access to the spiropyrazolones 5a. The excellent yields and enantioselectivities could also be obtained, although the dr was poor with or without organocatalyst 4h (Scheme 5), which may be ascribed to the fact that the excess of 2-(1-tosylalkyl)phenol affects the coordination of organocatalyst 4 with adducts 3 and NCS.
*
Unless otherwise noted, all reactions were carried out under these conditions: 1a (0.24 mmol), 2 (0.20 mmol), Na2CO3 (0.30 mmol), cat. 4f (0.02 mmol), DCE (3.0 mL), 30 °C, 48 h. aCat. 4d was used. PMP = 4-methoxyphenyl.
catalyst. According to the optimization of reaction parameters (see the Supporting Information), it is worth noting that the use of the bifunctional organocatalyst is essential for diastereocontrol, which could remarkably increase the dr up to 13:1 together with K2CO3 and NCS.7c Encouraged by the satisfying results above, we turned our attention to the investigation of the generality regarding different substituted adducts 3, and the results are depicted in Scheme 3. Generally, various type of spiropyrazolones were synthesized in high yields, excellent enantioselectivities as well as diastereoselectivities (up to 98% yield, ee = 99%, dr >20:1) under mild condition. To further demonstrate the versatility of our method, the scale-up reaction of 2-(1-tosylalkyl)phenol 1a and pyrazolin-5one 2a was performed. Reaction of 1.2 mmol of 1a and 1.0 mmol of 2a proceeded well under the standard reaction conditions, affording the desired Michael addition product 3aa in 95% yield (0.369 g) with 98% ee (Scheme 4) without any loss of reactivity and enantioselectivty.
Scheme 5. One-Pot Reaction for the Synthesis of Spiropyrazolone
To determine the absolute configuration of products, optically pure (2R,3S)-6-methoxy-3′-methyl-1′,3-diphenyl-3Hspiro[benzofuran-2,4′-pyrazol]-5′(1′H)-one (+)-5a was obtained as a colorless crystal after recrystallization from dichloromethane/n-hexane, and the absolute configuration was determined to be (2R,3S) based on the single-crystal Xray diffraction analysis. (For details, see the Supporting Information.) In summary, we have successfully realized a bifunctional squaramide-catalyzed reaction of pyrazolin-5-ones with o1160
DOI: 10.1021/acs.orglett.8b00025 Org. Lett. 2018, 20, 1158−1161
Letter
Organic Letters
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quinone methides in situ generated from 2-(1-tosylalkyl)phenols under basic conditions, providing an efficient and mild access to synthesize chiral pyrazolones with high enantioselectivities. In addition, the chiral spiropyrazolones with adjacent tertiary and quaternary stereogenic centers can be also obtained through cascade chlorination/cyclization of the above chiral pyrazolones. Further explorations on the extension of this strategy to synthesize other compounds are ongoing 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.8b00025. Experimental procedures, characterization data, and NMR spectra (PDF) Accession Codes
CCDC 1579061 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 data_
[email protected], or by contacting The Cambridge 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
Ji Zhou: 0000-0003-1827-4686 Wen-Jun Huang: 0000-0001-8120-6286 Guo-Fang Jiang: 0000-0002-2295-7677 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of China (51578224). REFERENCES
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DOI: 10.1021/acs.orglett.8b00025 Org. Lett. 2018, 20, 1158−1161
