Enantioselective Synthesis of Planar Chiral Pyridoferrocenes via

Letter Cite This: Org. Lett. 2018, 20, 1837−1840

pubs.acs.org/OrgLett

Enantioselective Synthesis of Planar Chiral Pyridoferrocenes via Palladium-Catalyzed Imidoylative Cyclization Reactions Shuang Luo,*,†,‡ Zhuang Xiong,†,‡ Yongzhi Lu,†,‡ and Qiang Zhu*,†,‡ †

State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China ‡ University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China S Supporting Information *

ABSTRACT: A highly efficient synthesis of planar chiral pyrido[3,4-b] ferrocenes by a palladium-catalyzed enantioselective isocyanide insertion/desymmetric C(sp2)−H bond activation reaction was developed. Various planar chiral pyridoferrocenes were obtained in high yields with good to excellent enantioselectivity under mild conditions (up to 99% yield, 99% ee), enabled by a unique SPINOL-derived phosphoramidite ligand.

P

He, as well as other research groups.8 Although these present methods exhibited their individual advantages, the synthesis of chiral backbone of pyrido[3,4-b] ferrocene has not been reported. We hypothesized that the ferrocene-derived vinyl isocyanide could be an ideal class of functionalized isocyanide, which could participate in Pd-catalyzed enantioselective imidoylation through desymmetrizing activation of planar C(sp2)−H bond (see Scheme 1d). In this communication, we report herein the synthesis of a new class of pyrido[3,4-b] ferrocenes formed via Pd-catalyzed imidoylative C−H bond activation in high yields with good to excellent enantioselectivity (up to 99% ee). The investigation commenced with the reaction of PhI and isocyanide 1a (R = Me), which was readily prepared via the condensation of acyl ferrocene and ethyl isocyanoacetate. By using bidentate phosphine ligands L1−L3, product 3a could be isolated in good yields. However, all of the reactions showed no selectivity, and the product was essentially racemic (see entries 1−3 in Table 1). Fortunately, when monodentate phosphine ligand L4 was used as a ligand, the reaction afforded 3a in 68% yield with 22% ee (entry 4 in Table 1). Encouraged by this result, other monodentate phosphine ligands were further screened. However, the reactions with L5 and L6 gave no product at all (see entries 5 and 6 in Table 1). To our delight, when methyl-substituted phosphoramidites L7 was subjected to the reaction, 3a was isolated in 73% yield with 60% ee (entry 7 in Table 1). The best selectivity was obtained when L8 was used, and the reaction delivered 3a in 86% yield and 87% ee (entry 8 in Table 1). Lowering the reaction temperature resulted in an increased isolated yield (91%) without a loss in enantioselectivity (entry 9 in Table 1). Control experiments indicated that both the base Cs2CO3 and the additive PivOH

alladium-catalyzed isocyanide (RNC) insertion, which is also known as imidoylation, is a powerful approach in the synthesis of various imine derivatives, compared with the analogous carbonylation through carbon monoxide (CO) insertion.1 However, the Pd-catalyzed asymmetric imidoylation process is a challenging issue2 and has rarely been explored,3 because of the strong coordinating ability of isocyanide to palladium catalysts when competing with chiral ligands. In 2016, Zhu and the co-workers reported an enantioselective imidoylation reaction via isocyanide insertion to a C(sp3)− Pd(II) complex, affording oxindole derivatives bearing a chiral quaternary carbon center (see Scheme 1a).4 In this reaction, the enantio-determining carbopalladition process occurred prior to isocyanide insertion. It was believed that the moderate enantiomeric excess (ee) value (up to 75%) was ascribed to the competing coordination of isocyanide with chiral ligand. We envision that if isocyanide insertion precedes the chirality generating step by using a functionalized isocyanide, the effect of competing coordination could be minimized (see Scheme 1b). By using this strategy, we recently applied symmetric dibenzyl isocyanoacetates as functionalized isocyanide in Pdcatalyzed imidoylation, followed by enantioselective desymmetric C(sp2)−H bond activation (see Scheme 1c). 3,4Dihydroisoquinolines containing C3 quaternary stereogenic centers were obtained in high yields with improved, but still not satisfactory, enantioselectivity (up to 92% ee).5 Planar chiral ferrocenes have attracted widespread attention because this class of compounds has been widely employed as ligands and catalysts for asymmetric catalysis.6 Therefore, considerable efforts have been devoted to the synthesis of these planar chiral ferrocenes.7 In this context, a series of remarkable reports for the synthesis of planar chiral ferrocenes via direct C−H bond functionalization, including asymmetric arylation, oxidative Heck reaction, acylation, and annulation reactions, have been realized by the groups of You, Gu, Wu, Zhao, and © 2018 American Chemical Society

Received: January 30, 2018 Published: March 14, 2018 1837

DOI: 10.1021/acs.orglett.8b00348 Org. Lett. 2018, 20, 1837−1840

Letter

Organic Letters Scheme 1. Enantioselective Pd-Catalyzed Imidoylationa

Table 1. Optimization of the Reaction Conditionsa

entry

R

ligand

temp (°C)

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10d 11e 12 13

Me (1a) Me (1a) Me (1a) Me (1a) Me (1a) Me (1a) Me (1a) Me (1a) Me (1a) Me (1a) Me (1a) Ph (1b) H (1c)

L1 L2 L3 L4 L5 L6 L7 L8 L8 L8 L8 L8 L8

80 80 80 80 80 80 80 80 75 75 75 75 75

73 87 76 68 0 0 73 86 91 trace 0 95 0

0 0 0 22

60 87 87

92

a Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)2 (5 mol %), ligand (L1, L2, L3: 5 mol %; L4−L8: 10 mol %), Cs2CO3 (0.12 mmol), PivOH (0.06 mmol) under argon. A solution of 1a in solvent (1 mL) was added to the reaction mixture (in 0.5 mL of solvent) via a syringe pump within 1 h. bIsolated yield. cEnantiomeric excess. Determined by HPLC analysis. dWithout Cs2CO3. eWithout PivOH.

a

FG denotes functional group. Asterisk symbol (*) denotes chirality. Ar represents arene.

were essential for this reaction (entries 10 and 11 in Table 1). The R group in compound 1 was also found to be important to this reaction. When a phenyl group was used instead of a methyl group, the corresponding product 3b was isolated in 95% yield with 92% ee (entry 12 in Table 1). However, when 1c (R = H) was subjected to the standard conditions, no product was generated (entry 13 in Table 1). Under the above optimized reaction conditions, the substrate scope of aryl iodide 2 was investigated first (Scheme 2). Substituents regardless of varied electronic natures, such as Me, OMe, Cl, Ph, F, CO2Et, CHO, CF3, CN, and Ac on the paraor meta-positions of aryl iodide were well-tolerated in reactions with ferrocenyl isocynaide (1b), generating the corresponding products in moderate to high yields and excellent enantioselectivity (3ba−3bn). These survived functionalities (CO2Et, CHO, CN, Ac) provide the potential for further diversification of the products. PhBr was also found efficient for the reaction, generating the product in a decreased isolated yield (81%) without a loss in enantioselectivity (92%). It is notable that 1mmol-scale synthesis of 3ba was equally as efficient as the small-scale reaction. However, with 2-iodotoluene or 1iodonaphthalene, the corresponding products were obtained in moderate ee value (3bo, 72%; 3bp, 82%) albeit in excellent yields, which indicated that the steric hindrance of aryl iodide influenced the enantioselectivity, to some extent. Heteroaromatic iodides, such as 3-iodopyridine, 4-iodopyridine, and 6iodoquinoline, reacted efficiently with ferrocenyl isocyanide to give 3bs, 3bt, and 3bu in moderate to excellent yields and good enantioselectivity. The stereochemistry of the products was

confirmed unambiguously via X-ray crystallographic analysis of a crystal of enantiopure 3bp. The absolute configuration was assigned as Sp (see the Supporting Information (SI) for details). The ferrocenyl isocyanides 1 were readily prepared by condensation of acyl ferrocene with ethyl isocyanoacetate, and their viability in the reaction was then investigated, as summarized in Scheme 3. With 4-iodobenzonitrile as the coupling partner, the reaction showed high efficiency both in yield and enantioselectivity. Alkyl-substituted ferrocenyl isocyanides, such as methyl (1a), ethyl (1d), and benzyl (1e), could react smoothly and generate the corresponding products in good yields with excellent enantioselectivity (3aj−3ej). When phenyl-substituted substrates were investigated, the products were obtained in excellent yields and enantioselectivities, regardless of varied electronic natures and location of substituents on the phenyl ring. Different substituents, such as Cl, F, Ph, Me, and OMe on the para- or meta-positions of phenyl ring of ferrocenyl isocynaide were well-tolerated (3fj− 3lj). Their corresponding planar chiral ferrocenyl products were obtained in excellent yields and enantioselectivity (yields of 79%−99%, 95%−98% ee). Substrates bearing a naphthyl (1m) or thiophenyl (1n) substituent proceeded smoothly to afford the desired product 3mj or 3nj in excellent yield and enantioselectivity (96% ee, 98% ee). When the ester moiety in 1 was changed to methyl ester, the asymmetric C−H 1838

DOI: 10.1021/acs.orglett.8b00348 Org. Lett. 2018, 20, 1837−1840

Letter

Organic Letters Scheme 2. Scope of Aryl Iodidesa

to install an oxindole moiety on the planar chiral ferrocene with a methylene tether (see Scheme 4). Compound 5 features a Scheme 4. Enantioselective Domino Process between 1b and 4a

a

Reaction conditions: 1b (0.1 mmol), 4 (0.15 mmol), Pd(OAc)2 (5 mol %), ligand (10 mol %), Cs2CO3 (1.2 equiv), PivOH (0.6 equiv) under Ar. A solution of 1b in toluene (1 mL) was added to the reaction mixture (in 0.5 mL of toluene) via a syringe pump within 1 h.

planar chirality on the ferrocene moiety and a central chirality on the oxindole moiety. Fortunately, the two diastereoisomers of 5 could be isolated by column chromatography, and the absolute configuration of 5′ was confirmed by X-ray crystallographic analysis (see the SI for details). When PPh3 was used as a ligand, the diastereomeric ratio (dr) was evaluated to be 3.9:1. When L8 was used as a ligand, the two isomers were obtained in excellent enantioselectivity (90% ee, 97% ee), and the dr value was 1.7:1. The central chirality on the oxindole moiety of compound 5 was generated prior to isocyanide insertion, which was a poor enantioselective process. On the other hand, the planar chirality on the ferrocene moiety, generated posterior to isocyanide insertion, showed excellent enantioselectivity. The result agreed with our hypothesis outlined in Scheme 1. In summary, we have developed an efficient method to access a new class of planar chiral pyrido[3,4-b] ferrocenes via palladium-catalyzed enantioselective imidoylative C−H bond activation reaction. The reaction showed good functional group tolerance and excellent enantioselectivity. The “isocyanide insertion-first” strategy effectively overcame the difficulty in Pd-catalyzed asymmetric imidoylation reactions. These planar chiral pyrido[3,4-b] ferrocene derivatives may serve as important building blocks in organic synthesis for catalyst or ligand design.

a

Reaction conditions: 1b (0.1 mmol), 2 (0.15 mmol), Pd(OAc)2 (5 mol %), L8 (10 mol %), Cs2CO3 (1.2 equiv), PivOH (0.6 equiv) under Ar. A solution of 1b in toluene (1 mL) was added to the reaction mixture (in 0.5 mL of toluene) via a syringe pump within 1 h. b Numbers in parentheses are results with PhBr. cOne mmol scale with PhI.

Scheme 3. Scope of Isocyanidesa

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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.8b00348. Experimental procedures and compound characterization data (PDF)

a Reaction conditions: 1 (0.1 mmol), 2j (0.15 mmol), Pd(OAc)2 (5 mol %), L8 (10 mol %), Cs2CO3 (1.2 equiv), PivOH (0.6 equiv) under Ar. A solution of 1 in toluene (1 mL) was added to the reaction mixture (in 0.5 mL of toluene) via a syringe pump within 1 h.

Accession Codes

imidoylation reactions were conducted efficiently, giving 3oj with excellent ee value. A domino process involving oxidative addition of N-(2iodophenyl)methacrylamide 4 to Pd(0), intramolecular alkene insertion, and imidoylative cyclization of the resulting C(sp3)− Pd(II) intermediate with ferrocenyl isocyanide 1b, was realized

CCDC 1535346−1535347 contain 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 Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033. 1839

DOI: 10.1021/acs.orglett.8b00348 Org. Lett. 2018, 20, 1837−1840

Letter

Organic Letters

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Soc. 2014, 136, 4841. (e) Ma, X.; Gu, Z. RSC Adv. 2014, 4, 36241. (f) Pi, C.; Cui, X.; Liu, X.; Guo, M.; Zhang, H.; Wu, Y. Org. Lett. 2014, 16, 5164. (g) Liu, L.; Zhang, A.-A.; Zhao, R.-J.; Li, F.; Meng, T.-J.; Ishida, N.; Murakami, M.; Zhao, W.-X. Org. Lett. 2014, 16, 5336. (h) Shibata, T.; Shizuno, T. Angew. Chem., Int. Ed. 2014, 53, 5410. (i) Murai, M.; Matsumoto, K.; Takeuchi, Y.; Takai, K. Org. Lett. 2015, 17, 3102. (j) Shibata, T.; Shizuno, T.; Sasaki, T. Chem. Commun. 2015, 51, 7802. (k) Zhang, Q.-W.; An, K.; Liu, L.-C.; Yue, Y.; He, W. Angew. Chem., Int. Ed. 2015, 54, 6918. (l) Gao, D.-W.; Zheng, C.; Gu, Q.; You, S.-L. Organometallics 2015, 34, 4618. (m) Urbano, A.; HernándezTorres, G.; del Hoyo, A. M.; Martinez-Carrión, A.; Carreño, M. C. Chem. Commun. 2016, 52, 6419. (n) Gao, D.-W.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2016, 138, 2544. (o) Gao, D.-W.; Gu, Q.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2017, 50, 351. (p) Xu, J.; Liu, Y.; Zhang, J.; Xu, X.; Jin, Z. Chem. Commun. 2018, 54, 689.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (S. Luo). *E-mail: [email protected] (Q. Zhu). ORCID

Qiang Zhu: 0000-0002-1243-2391 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (Nos. 21472190, 21532009, and 21772198) and Youth Innovation Promotion Association of CAS for financial support. We thank Prof. Jinsong Liu at GIBH for assistance in X-ray crystallographic analysis.

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DOI: 10.1021/acs.orglett.8b00348 Org. Lett. 2018, 20, 1837−1840