Letter pubs.acs.org/OrgLett
Enantioselective Direct α‑Arylation of Pyrazol-5-ones with 2‑Indolylmethanols via Organo-Metal Cooperative Catalysis Zi-Qi Zhu, Yang Shen, Jin-Xi Liu, Ji-Yu Tao, and Feng Shi* School of Chemistry and Material Science, Jiangsu Normal University, Xuzhou 221116, China S Supporting Information *
ABSTRACT: The first catalytic asymmetric α-arylation of pyrazol-5-ones has been established by using 2-indolylmethanols as direct electrophilic arylation reagents under the cooperative catalysis of Pd(0) and a chiral phosphoric acid, which afforded the αarylation products of pyrazol-5-ones in generally high yields and good enantioselectivities (up to 99% yield, >99% ee). atalytic asymmetric α-arylation of carbonyl compounds is an established method for generating a new C−C bond with the simultaneous creation of a chiral benzylic center, which has wide applications in the synthesis of natural products and biologically important molecules.1 As a result, great attention has been paid to this research area and many elegant achievements have been made in developing strategies for catalytic asymmetric α-arylation of carbonyl compounds (Scheme 1).1−3 However,
C
Scheme 2. Our Strategy of Using 2-Indolylmethanols as Direct Arylation Reagents
Scheme 1. Profile of Catalytic Asymmetric α-Arylation of Carbonyl Compounds During the course of finding suitable arenes that could serve as arylation reagents, 2-indolylmethanols caught our attention because this class of reactants can transform into delocalized cation intermediates in the presence of Brønsted acids (B−H),4,5 when they are stabilized by two Ar groups (Scheme 2). More importantly, we have found that when a nucleophile (Nu) attacks the delocalized cation, it always regioselectively attacks the C3position of the indole moiety and results in an indole-Nu coupling reaction.5,6 In this transformation, a formal C−H activation of indole has taken place. So, we conceived that this class of 2indolylmethanols could be utilized as direct electrophilic arylation reagents to perform direct catalytic asymmetric α-arylations of carbonyl compounds. Among important carbonyl compounds, pyrazol-5-one constitutes the core structure of many chiral pharmaceuticals.7 Consequently, catalytic asymmetric functionalizations of pyrazol5-ones have aroused great interest in the organic community (Scheme 3), primarily due to the nucleophilicity of the C4position in pyrazol-5-ones.8−12 Nevertheless, the majority of these reactions have employed alkyl electrophiles to perform
most of the strategies have utilized aryl halides or aryl triflates as arylation reagents and performed enantioselective α-arylations of carbonyl compounds under the catalysis of metal and chiral ligands (eq 1), which inevitably generated halide or other wastes.1,2 Contrastingly, arenes have scarcely been employed as arylation reagents (eq 2), despite the fact that this strategy can bring a more direct and atom-economic method for catalytic asymmetric α-arylation of carbonyl compounds.3 There are many difficulties in this transformation such as C−H activation of an arene, generating an aryl electrophile, and controlling the enantioselectivity of the reaction. So, it is highly desired but challenging to develop a direct catalytic asymmetric α-arylation of carbonyl compounds that uses arenes as the arylation reagents. © XXXX American Chemical Society
Received: February 3, 2017
A
DOI: 10.1021/acs.orglett.7b00351 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Profile of Catalytic Asymmetric αFunctionalization of Pyrazol-5-ones
Scheme 5. Chiral Catalysts and Model Reaction Employed for Condition Optimization
enantioselective α-alkylations of pyrazol-5-ones (eq 3).8−10 In sharp contrast, nearly no aryl electrophiles have been utilized in reactions with pyrazol-5-ones except in the case of diarylidonium salts,11 and the catalytic asymmetric α-arylation of pyrazol-5-ones remains unknown (eq 4). Thus, it is of considerable interest to develop catalytic asymmetric α-arylations of pyrazol-5-ones. In order to do this, a cooperative catalytic system of Pd(0)/ chiral phosphoric acid (CPA)9d,13,14 was used to control the enantioselectivity of the direct α-arylation of pyrazol-5-ones (Scheme 4). In this design, CPA could catalyze the generation of
a higher enantioselectivity of 48% ee (see the Supporting Information (SI) for details). At this point, we tried adding palladium and other metal complexes as a cocatalyst to the reaction system, based on the idea that the delocalized cation intermediate generated from 1a would be stabilized by palladium or another metal complex. Indeed, this tactic greatly improved the enantioselectivity and yield in most cases. Among them, a palladium complex of Pd[P(o-tol)3]2 was the most suitable cocatalyst, as it improved the yield from 45% to 66% and the enantioselectivity from 48% ee to 68% ee. So, under the cooperative catalysis of CPA and a palladium complex, other reaction parameters such as solvents, concentration, additives, reaction temperature, reagent ratio, and catalyst loading were carefully evaluated (see the SI for details), leading to the optimal reaction conditions. Under these circumstances, the arylation product 3aa was obtained in a quantitative yield of 99% and 82% ee. It should be noted that the addition of 5 Å molecular sieves and the reduction of the concentration also played an important role in elevating the enantioselectivity. With the optimal reaction conditions known, we then investigated the substrate scope of 2-indolylmethanols 1 by direct arylations with pyrazol-5-one 2a. As shown in Table 1, this reaction was applicable to a wide range of 2-indolylmethanols 1 bearing different Ar/R substituents, which delivered the arylation products 3 in generally high yields (52% to 99%) and good enantioselectivities (80% to >99% ee). Several meta- or parasubstituted phenyl groups served as competent Ar groups regardless of their electronic nature. It seemed that the position of the substituents had some effect on the reactivity and enantioselectivity. For instance, a meta-fluoro-substituted phenyl group delivered the reaction in a much higher yield than a parafluoro-substituted phenyl group, while the latter afforded the product in a better enantioselectivity than the former (entry 2 vs 4). As for the R group linked to the indole moiety, the position of functionalization also influenced the yield and enantioselectivity. For example, 5-chloro-substituted 2-indolylmethanol 1e afforded the arylation product in a better yield than the 6-chlorosubstituted counterpart 1g, while the enantioselectivity of product 3ag was much higher than product 3ae (entry 5 vs 7). Apart from halogen substituents, a methoxy group also proved to be a suitable substituent in the 2-indolylmethanol, which smoothly participated in the arylation reaction in moderate yield with good enantioselectivity (entry 13). Next, the substrate scope of pyrazol-5-ones 2 was studied by the reactions with 2-indolylmethanols 1. As listed in Table 2, this protocol was amenable to a series of pyrazol-5-ones 2 with various
Scheme 4. Design of the Catalytic Asymmetric α-Arylation of Pyrazol-5-ones
the delocalized cation via dehydration of 2-indolylmethanols, and this delocalized cation could be further stabilized by the Pd(0)/ ligand. Then, the CPA anion would simultaneously activate both the enolized pyrazol-5-one and the delocalized cation−Pd complex via H-bonding and ion pair interaction, which would facilitate an enantioselective nucleophilic addition of pyrazol-5one to the delocalized cation to achieve the final α-arylation of the pyrazol-5-ones after rearomatization of the indole skeleton. Herein, we report the first catalytic asymmetric α-arylation of pyrazol-5-ones using 2-indolylmethanols as arylation electrophiles under the cooperative catalysis of Pd(0) and a chiral phosphoric acid, which afforded the α-arylation products of pyrazol-5-ones in generally high yields and with good enantioselectivities (up to 99% yield, >99% ee). In addition, this reaction serves as a good example of cooperative catalysis that will open a new window for developing 2-indolylmethanolinvolved enantioselective transformations. At the outset, the reaction of 2-indolylmethanol 1a with pyrazol-5-one 2a was employed as a model reaction to verify our hypothesis. Initially, we examined whether the reaction could be catalyzed by the CPAs 4−11 in the absence of palladium or other metal complexes. As illustrated in Scheme 5, the reaction in the presence of CPA 4 afforded the arylation product 3aa, but in a low yield of 22% and with a poor enantioselectivity of 12% ee. Then, a series of CPAs 5−11 were screened and it was found that CPA 11 was the best chiral catalyst, as it provided a better yield of 45% and B
DOI: 10.1021/acs.orglett.7b00351 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 1. Substrate Scope of 2-Indolylmethanols 1a
utilized substrate 2i bearing a simple 4-methyl group, which smoothly took part in the reaction in an excellent yield of 99% with an acceptable enantioselectivity of 72% ee (entry 14). The absolute configuration of product 3aa (98% ee after recrystallization) was unambiguously determined to be (S) by single crystal X-ray diffraction analysis (in Scheme 6).15 The
entry
3
Ar/R (1)
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13
3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma
Ph/H (1a) m-FC6H4/H (1b) m-MeOC6H4/H (1c) p-FC6H4/H (1d) Ph/5-Cl (1e) p-FC6H4/5-Br (1f) Ph/6-Cl (1g) m-FC6H4/6-Cl (1h) m-MeC6H4/6-Cl (1i) m-MeOC6H4/6-Cl (1j) p-FC6H4/6-Cl (1k) Ph/6-Br (1l) Ph/6-MeO (1m)
99 98 99 52 93 52 71 80 99 73 60 96 65
82 84 82 >99 80 80 >99 86 80 88 84 81 80
Scheme 6. Suggested Reaction Pathway and Catalytic Cycle
absolute configurations of other products 3 were assigned by analogy. Based on the experimental results and previous reports on Pd/CPA catalysis,9d,13,14 we suggest a possible reaction pathway and catalytic cycle for the catalytic asymmetric arylation of pyrazol-5-ones 2 with 2-indolylmethanols 1. As exemplified by the formation of product 3aa (Scheme 6), 2-indolylmethanol 1a was initially activated by CPA 11 to generate a delocalized cation via dehydration. In the presence of the PdL2 complex and CPA anion, the delocalized cation is stabilized by the formation of the Pd(II) complex A, which is supported by MS study because the complex could be detected ([M − H]− m/z 1584). Subsequently, enolizable pyrazol-5-one 2a attacks the intermediate A from the inside position of the plane of the delocalized cation. In this transition state B, the CPA anion forms a hydrogen bond and an ion pair interaction with both of the enolized pyrazol-5-one 2a and the Pd(II) complex, which renders the enantioselective generation of intermediate C. Simultaneously, the two catalysts of the PdL2 complex and CPA 11 are regenerated to continue the catalytic cycle. Finally, intermediate C rapidly isomerizes into product 3aa due to the driving force of rearomatization of the indole moiety. In the reaction process, there is a synergistic effect of the dual catalytic system of the Pd complex and chiral phosphoric acid. In order to demonstrate the synergistic effect of the dual catalyst system and the action of the Pd complex, we performed some control experiments (Scheme 7). During our optimization
a
Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale for 12 h, and the molar ratio of 1:2a was 1:1.2. bIsolated yields. cThe ee value was determined by HPLC.
Table 2. Substrate Scope of Pyrazol-5-ones 2a
entry
3
1
R1/R2 (2)
yield (%)b
ee (%)c
1 2 3 4 5 6 7d 8 9 10 11 12 13d 14
3aa 3db 3dc 3dd 3de 3df 3dg 3gb 3gc 3gd 3ge 3af 3gh 3ai
1a 1d 1d 1d 1d 1d 1d 1g 1g 1g 1g 1a 1g 1a
Ph/Me (2a) 2-FC6H4/Me (2b) 3-FC6H4/Me (2c) 4-FC6H4/Me (2d) 2-naphthyl/Me (2e) 4-MeC6H4/Me (2f) 4-MeOC6H4/Me (2g) 2-FC6H4 /Me (2b) 3-FC6H4/Me (2c) 4-FC6H4/Me (2d) 2-naphthyl/Me (2e) 4-MeC6H4/Me (2f) Ph/Ph (2h) H/Me (2i)
99 71 81 90 77 76 71 81 83 68 73 99 77 99
82 80 80 80 80 81 80 80 80 80 80 81 80 72
a
Scheme 7. Control Experiments
Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale for 12 h, and the molar ratio of 1:2 was 1:1.2. bIsolated yields. cThe ee value was determined by HPLC. dIn the presence of 10 mol % Pd[P(o-tol)3]2 and 20 mol % catalyst 11.
R1/R2 groups, leading to the production of arylation products 3 in overall high yields (71% to 99%) with 72% to 82% ee. It seemed that the electronic nature and the position of the substituents linked to the R 1 group had no evident effect on the enantioselectivity of the reaction because all of the substrates 2 bearing different aromatic R1 groups gave similar enantioselectivities around 80% ee (entries 1−12). In addition, the R2 group could be altered from a methyl group to a phenyl group with a retained enantioselectivity of 80% ee (entry 13). Moreover, apart from 4-benzylic substituted pyrazol-5-ones 2a−2h, we also C
DOI: 10.1021/acs.orglett.7b00351 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050. (c) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195. (d) Dai, X.; Strotman, N. A.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302. (e) Huang, Z.; Liu, Z.; Zhou, J. R. J. Am. Chem. Soc. 2011, 133, 15882. (3) Bogle, K. M.; Hirst, D. J.; Dixon, D. J. Org. Lett. 2007, 9, 4901. (4) For C3-substituted 2-indolylmethanol-involved enantioselective transformations: (a) Qi, S.; Liu, C.-Y.; Ding, J.-Y.; Han, F.-S. Chem. Commun. 2014, 50, 8605. (b) Liu, C.-Y.; Han, F.-S. Chem. Commun. 2015, 51, 11844. (c) Gong, Y.-X.; Wu, Q.; Zhang, H.-H.; Zhu, Q.-N.; Shi, F. Org. Biomol. Chem. 2015, 13, 7993. (d) Bera, K.; Schneider, C. Chem. Eur. J. 2016, 22, 7074. (e) Bera, K.; Schneider, C. Org. Lett. 2016, 18, 5660. (5) For C3-unsubstituted 2-indolylmethanol-involved enantioselective transformations: (a) Sun, X.-X.; Zhang, H.-H.; Li, G.-H.; He, Y.-Y.; Shi, F. Chem. - Eur. J. 2016, 22, 17526. (b) Zhu, Z.-Q.; Shen, Y.; Sun, X.-X.; Tao, J.-Y.; Liu, J.-X.; Shi, F. Adv. Synth. Catal. 2016, 358, 3797. (c) Zhang, H.H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F. Angew. Chem., Int. Ed. 2017, 56, 116. (6) Li, C.; Zhang, H.-H.; Fan, T.; Shen, Y.; Wu, Q.; Shi, F. Org. Biomol. Chem. 2016, 14, 6932. (7) For some examples: (a) Kimata, A.; Nakagawa, H.; Ohyama, R.; Fukuuchi, T.; Ohta, S.; Suzuki, T.; Miyata, N. J. Med. Chem. 2007, 50, 5053. (b) Chande, M. S.; Barve, P. A.; Suryanarayan, V. J. Heterocycl. Chem. 2007, 44, 49. (c) Ebner, S.; Wallfisch, B.; Andraos, J.; Aitbaev, I.; Kiselewsky, M.; Bernhardt, P. V.; Kollenz, G.; Wentrup, C. Org. Biomol. Chem. 2003, 1, 2550. (8) For a recent review: Chauhan, P.; Mahajan, S.; Enders, D. Chem. Commun. 2015, 51, 12890. (9) For some examples on alkylation: (a) Lin, H.-C.; Wang, P.-S.; Tao, Z.-L.; Chen, Y.-G.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2016, 138, 14354. (b) Amr, F. I.; Vila, C.; Blay, G.; Munoz, M. C.; Pedro, J. R. Adv. Synth. Catal. 2016, 358, 1583. (c) Bao, X.; Wang, B.; Cui, L.; Zhu, G.; He, Y.; Qu, J.; Song, Y. Org. Lett. 2015, 17, 5168. (d) Tao, Z.-L.; Zhang, W.Q.; Chen, D.-F.; Adele, A.; Gong, L.-Z. J. Am. Chem. Soc. 2013, 135, 9255. (e) Wang, Z.; Chen, Z.; Bai, S.; Li, W.; Liu, X.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2012, 51, 2776. (f) Wang, Z.; Yang, Z.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2011, 50, 4928. (g) Liao, Y.-H.; Chen, W.-B.; Wu, Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2010, 352, 827. (10) For cyclizations based on alkylation: (a) Ni, C.; Tong, X. J. Am. Chem. Soc. 2016, 138, 7872. (b) Kumarswamyreddy, N.; Kesavan, V. Org. Lett. 2016, 18, 1354. (c) Hack, D.; Dürr, A. B.; Deckers, K.; Chauhan, P.; Seling, N.; Rübenach, L.; Mertens, L.; Raabe, G.; Schoenebeck, F.; Enders, D. Angew. Chem., Int. Ed. 2016, 55, 1797. (d) Hack, D.; Chauhan, P.; Deckers, K.; Mizutani, Y.; Raabe, G.; Enders, D. Chem. Commun. 2015, 51, 2266. (e) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu, Y. Angew. Chem., Int. Ed. 2014, 53, 5643. (11) For a limited example on arylation: Mao, S.; Geng, X.; Yang, Y.; Qian, X.; Wu, S.; Han, J.; Wang, L. RSC Adv. 2015, 5, 36390. (12) For some examples on halogenation: (a) Bao, X.; Wei, S.; Zou, L.; He, Y.; Xue, F.; Qu, J.; Wang, B. Chem. Commun. 2016, 52, 11426. (b) Li, F.; Sun, L.; Teng, Y.; Yu, P.; Zhao, C.-G.; Ma, J.-A. Chem. - Eur. J. 2012, 18, 14255. (13) For some reviews on chiral phosphoric acid catalysis: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008, 35, 4097. (c) Terada, M. Synthesis 2010, 2010, 1929. (d) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156. (e) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. (f) Wu, H.; He, Y.-P.; Shi, F. Synthesis 2015, 47, 1990. (14) For some examples on Pd/CPA catalysis: (a) Jiang, G.-X.; List, B. Angew. Chem., Int. Ed. 2011, 50, 9471. (b) Yu, S.-Y.; Zhang, H.; Gao, Y.; Mo, L.; Wang, S.; Yao, Z.-J. J. Am. Chem. Soc. 2013, 135, 11402. (c) Wang, P.-S.; Lin, H.-C.; Zhai, Y.-J.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2014, 53, 12218. (d) Tao, Z.-L.; Li, X.-H.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2015, 137, 4054. (e) Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322. (15) CCDC 1523417 for 3aa; see the SI for details.
of the reaction conditions, we found that the addition of Pd[P(otol)3]2 could significantly improve the yield and enantioselectivity (eq 5). In addition, under the optimal conditions, we also compared the two reactions in the presence or absence of the Pd[P(o-tol)3]2 catalyst (eq 6). As expected, in the absence of the Pd complex, both the yield and enantioselectivity of the reaction were decreased to some extent (73% yield, 70% ee), which verified that the cocatalyst of the Pd complex did indeed have a synergistic effect on the arylation reaction by stabilizing the delocalize cation and forming an ion pair interaction with CPA. Finally, we carried out a preparative scale synthesis of product 3af under the standard conditions (Scheme 8). Compared with Scheme 8. Preparative Scale Synthesis
the small scale reaction (Table 2, entry 12), this reaction smoothly generated the arylation product 3af in a similar yield of 98% and maintained an enantioselectivity of 81% ee, which indicated that this arylation reaction could be scaled up. In summary, we established the first catalytic asymmetric αarylation of pyrazol-5-ones by using 2-indolylmethanols as direct electrophilic arylation reagents under the cooperative catalysis of a Pd complex and a chiral phosphoric acid, which afforded the αarylation products of pyrazol-5-ones bearing a quaternary stereogenic center in generally high yields and good enantioselectivities (up to 99% yield, >99% ee). This approach provides a direct catalytic asymmetric α-arylation of pyrazol-5-ones.
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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.7b00351. Optimization, experimental procedures, characterization data, NMR and HPLC spectra for products 3 (PDF) Crystallographic data for compound 3aa (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Feng Shi: 0000-0003-3922-0708 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21372002 and 21232007), PAPD, and Natural Science Foundation of Jiangsu Province (BK20160003).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00351 Org. Lett. XXXX, XXX, XXX−XXX
