Palladium(II)-Catalyzed Asymmetric Tandem Cyclization of 2

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Palladium(II)-Catalyzed Asymmetric Tandem Cyclization of 2‑Aminoaryl Alkynones: An Approach to Chiral 1,2,3,4-Tetrahydro-βcarbolines Junjie Chen, Xiuling Han,* and Xiyan Lu* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

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S Supporting Information *

ABSTRACT: A Pd(OAc)2-catalyzed asymmetric cyclization of 2-aminoaryl alkynones involving an intramolecular transaminopalladation of alkyne and 1,2-addition to the carbonyl group tandem processes was developed. This strategy represents the first example using palladium as the catalyst and 2-alkynylaniline derivatives as the starting material to allow facile access to chiral 1,2,3,4-tetrahydro-β-carbolines in high yields and excellent enantioselectivities.

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to afford carbon- or heterocycle-fused indoles in a redoxneutral way. In the past decade, we have successfully developed palladium(II)-catalyzed tandem cyclization to synthesize fiveto eight-membered ring-fused indoles and tetrahydropyrano[3,4-b]indoles using the strategy.9,10a,11 On the basis of our continued interest in the exploration of palladium(II)catalyzed tandem reactions for the synthesis of indolecontaining heterocycles, we report for the first time the enantioselective cyclization of 2-aminoaryl alkynones to provide chiral 1,2,3,4-tetrahydro-β-carbolines. This reaction would involve tandem intramolecular trans-aminopalladation of alkyne and 1,2-addition of the newly formed carbon− palladium bond to the carbonyl group (Scheme 1).

ecause some are commonly found in complex natural molecules and synthetic analogues that exhibit interesting biological activities, 1,2,3,4-tetrahydro-β-carbolines (THβCs) are attractive targets for organic chemists.1 As a consequence, the development of efficient methods to construct such architectures, especially in an asymmetric version, has attracted interest in organic chemistry.2 The methods to prepare chiral 1,2,3,4-tetrahydro-β-carbolines mainly include catalytic asymmetric Pictet−Spengler condensation of tryptamines with carbonyl compounds,3 Pictet−Spengler reactions of in situ generated cyclic iminiums,4 or asymmetric reduction of dihydro-β-carbolines.5 Recently, an alternative has been successfully realized via gold-catalyzed asymmetric cyclization of allenamides.6 Whereas these reactions can give chiral 1,2,3,4-tetrahydro-β-carbolines efficiently, all of the transformations require the use of functionalized indoles that may suffer from the inherent challenges of modular synthesis. As a result, the development of an enantioselective route to functionalized THβCs from readily available starting materials by a step-economic pathway is of interest for synthetic organic and medicinal chemistry.7 Palladium(II)-catalyzed cyclization of 2-ethynylanilines has demonstrated high versatility and efficiency for the construction of the indole scaffold.8 Substrates for this transformation are easily prepared via Sonogashira coupling reactions of 2-iodoanilines and terminal alkynes. When 2ethynylanilines are tethered with some other functionalized groups such as an alkene,9 a carbonyl,10 or a cyano group,10b,11 a tandem cyclization would be realized to lead to complex indoles. In these transformations, through π-complexation of the alkyne moiety by a palladium(II) catalyst, the triple bond in 2-ethynylanilines can be easily anti-attacked by the amino group to give a vinylpalladium species. This species undergoes a subsequent process such as intramolecular 1,4-addition to alkenes or 1,2-addition to carbon-heteroatom multiple bonds © XXXX American Chemical Society

Scheme 1. Palladium(II)-Catalyzed Enantioselective Cyclization of 2-Aminoaryl Alkynones To Produce Chiral 1,2,3,4-Tetrahydro-β-carbolines

Initially, we explored the nonasymmetric cyclization of a series of NTs-tethered 2-aminoaryl-alkynones using Pd(OAc)2/bpy as the catalytic system in dioxane/HOAc/ H2O solvent, which is similar to the reaction conditions used in our previous work.10a The result shows that achiral 1,2,3,4tetrahydro-β-carbolines can be successfully obtained in good yields. The substituents on the benzene ring (R1) and carbonyl Received: October 11, 2018

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DOI: 10.1021/acs.orglett.8b03247 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters group (R2) have no obvious influence on the reactivity of the substrate (Table 1).

Table 2. Optimization of the Reaction Conditions for the Asymmetric Tandem Cyclizationa

Table 1. Pd(OAc)2/bpy-Catalyzed Tandem Cyclization of NTs-Tethered 2-Aminoaryl Alkynonesa

entry

R1, R2 (1)

2

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

H, Ph (1a) H, 4-MeC6H4 (1b) H, 4-OMeC6H4 (1c) H, 4-FC6H4 (1d) H, 4-ClC6H4 (1e) H, 4-BrC6H4 (1f) H, 4-CNC6H4 (1g) H, 4-CF3C6H4 (1h) H, 4-PhC6H4 (1i) H, 2-thiophenyl (1j) H, β-naphthyl (1k) H, t-Bu (1l) H, Me (1m) 4-Me, Ph (1n) 5-Me, Ph (1o) 4-OMe, Ph (1p) 4-F, Ph (1q) 4-Cl, Ph (1r) 4-Br, Ph (1s) 4-CF3, Ph (1t) 4-CO2Me, Ph (1u)

2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m 2n 2o 2p 2q 2r 2s 2t 2u

91 90 87 82 83 83 78 96 89 74 69 81 91 87 89 81 88 90 88 93 84

a Reaction conditions: 1 (0.1 mmol, 1.0 equiv), Pd(OAc)2 (5 mol %), and bpy (10 mol %) were dissolved in dioxane/HOAc/H2O (1 mL/ 0.1 mL/0.1 mL); the mixture was stirred at 80 °C for 4.0 h. bIsolated yield.

Subsequently, the asymmetric version of this cascade cyclization was studied under the catalysis of Pd(OAc)2/chiral N,N-bidentate ligands. For optimization of the reaction conditions, NTs-tethered 2-aminoaryl alkynone 1a was chosen as the model substrate, and the results are shown in Table 2. The chiral bipyridines L1 and L2 delivered 2a in good yields. However, the product is a racemic mixture (entries 1 and 2). Then, we chose the t-Bu-substituted PyrOx L3 as the ligand, but it did not lead to the tandem cyclization (entry 3). When the substituent on the oxazoline ring was changed to Ph (L4), product 2a could be afforded in 18% yield with 29% ee (entry 4). Introducing a CF3 group on the para position of the pyridine ring (L5) did not make any contribution to the transformation (entry 5). Interestingly, when substituents such as i-Pr, Bn, and Ph2CH (L6−L8) were located on the ortho position of pyridine, the product could be obtained in encouraging ee values, albeit in low yields (entries 6−8). This result indicates that increasing the hindrance of the ligand may favor asymmetric induction. Further investigation showed that ligand L9 with a fluorine atom on the phenyl ring can lead to an improved yield but at the cost of reduced enantioselectivity (entry 9). Then, we used L8 as the optimal ligand to improve the asymmetric reaction further. Solvent screening showed that chlorobenzene can increase the

entry

ligand

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15e 16 17 18f 19g 20h

L1 L2 L3 L4 L5 L6 L7 L8 L9 L8 L8 L8 L8 L8 L8 L8 L8 L8 L8 L8

dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane toluene PhCl DMF CH3CN PhCl PhCl PhCl PhCl PhCl PhCl PhCl

additive

yieldb (%)

AgOAc Cu(OAc)2 BQ BQ MA

85 87 trace 18 22 28 40 39 50 36 39 58 17 26 18 14 50 57 82 18

eec (%) 0 0 29 31 72 67 73 49 81 92 41 55 ndi ndi 91 88 91 93 75

a

Reaction conditions: 1a (0.1 mmol, 1.0 equiv), Pd(OAc)2 (5 mol %), and L* (10 mol %) were dissolved in solvent/HOAc/H2O (1 mL/0.1 mL/0.1 mL); the mixture was stirred at 80 °C for 6.0−8.0 h. b Isolated yields. cee value was detected by HPLC. dNo HOAc was added. eNo water was added. fIncreasing the amount of BQ to 0.4 equiv, a similar yield and ee value of 2a were obtained. gThe reaction was conducted in the presence of 10 mol % Pd(OAc)2, 20 mol % L8, and 0.3 equiv of BQ. hThe reaction was conducted in the presence of 10 mol % Pd(OAc)2, 20 mol % L8, and 0.3 equiv of MA (maleic anhydride). ind = not detected.

enantioselectivity greatly (92% ee, entry 11). The control experiment shows that the presence of HOAc and H2O is beneficial for the cyclization (entries 14 and 15). Then, we turned our attention to increasing the yield for the cyclization. The addition of AgOAc only gave a very low yield, and Cu(OAc)2 led to an improved yield with a diminished enantioselectivity (entries 16 and 17). After continued experimentation, we found that performing the reaction with a catalytic amount of benzoquinone (BQ) can give a moderate yield (57%) of 2a without reduction of the ee value (entry 18). These results suggest that BQ is beneficial for the cyclization.12 Finally, increasing the amount of the catalyst, ligand, and BQ B

DOI: 10.1021/acs.orglett.8b03247 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

such as tert-butyl and methyl also showed good compatibility with the asymmetric cyclization (2l and 2m). Subsequently, the reaction was performed using various substituents (R2) on the aminoaryl ring. Introducing a methyl group maintained a high enantioselectivity, but decreased the yield (2n and 2o). A methoxyl group had a negative effect on the cyclization, which led to 2p in 32% yield with 81% ee. In contrast, halide (F, Cl, and Br) and trifluoromethyl groups had little effect on the transformation, providing the desired products in good yield with high enantioselectivity (2q, 2r, 2s, and 2t). An ester group on the aminoaryl ring resulted in product 2u in a good yield (80%), but in dramatically decreased ee (56%). The absolute configuration of 2r was assigned by X-ray crystallographic analysis, and those of other products were assigned on the basis of analogy to 2r (CCDC 1866405). In summary, we have developed a Pd(II)-catalyzed asymmetric cyclization of 2-aminoaryl alkynones involving tandem intramolecular trans-aminopalladation of the alkyne and 1,2-addition to the carbonyl group. The transformation provides facile and economical access to chiral 1,2,3,4tetrahydro-β-carbolines in high yields (up to 92%) and excellent enantioselectivities (up to 93%) by utilizing a chiral pyridinooxazoline as the ligand. In contrast to the reported methods for the synthesis of chiral 1,2,3,4-tetrahydro-βcarbolines, this represents the first example using palladium as the catalyst and 2-alkynyl aniline derivatives as the starting materials. Further studies to explore the possibility for the synthesis of natural alkaloids are ongoing in our laboratory.

further improved the cyclization with good yield and high enantioselectivity (82% yield, 93% ee, entry 19). Nevertheless, when maleic anhydride (MA)13 was used to replace BQ, 2a was formed in a low yield and ee value (entry 20). Having identified the optimal reaction conditions, we proceeded to explore the scope of this asymmetric palladium(II)-catalyzed cascade reaction (Scheme 2). Initially, Scheme 2. Asymmetric Synthesis of THβCsa−c

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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.8b03247. Experimental procedures, characterization data, NMR spectra, and HPLC data for all new compounds (PDF) Accession Codes

CCDC 1866405 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 Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

a

Reaction conditions: 1 (0.1 mmol, 1.0 equiv), Pd(OAc)2 (10 mol %), L8 (20 mol %), and BQ (30 mol %) were dissolved in PhCl/ HOAc/H2O (1 mL/0.1 mL/0.1 mL); the mixture was stirred at 80 °C for 8.0 h. bIsolated yield. cee value is detected by HPLC.

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the substituent effect on the benzene ring tethered to the carbonyl group was investigated. Electron-donating groups such as methyl gave the corresponding product 2b in high yield and ee value. However, a methoxyl group deteriorated the transformation and provided the product 2c in a dramatically lower yield (42%) and a slightly decreased enantioselectivity (85%). The reason may be due to the electron-donating effect of the methoxyl group to deactivate the polarizability of the carbonyl in substrate 1c. Halides (F, Cl, and Br) were welltolerated in the reaction to give 2d, 2e, and 2f in excellent ee, accompanied by a slightly lower chemical yield. The phenyl group and electron-withdrawing groups such as CN and CF3 also had a minor influence on the reaction outcome (2g, 2h, and 2i). The reaction of substrates bearing a thiophenyl or naphthyl group on the carbonyl group was then evaluated, and the result indicates that both of them can deliver the corresponding products (2j and 2k) in good enantioselectivity and moderate yield. In addition to aryl groups, alkyl groups

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiuling Han: 0000-0001-5946-0296 Xiyan Lu: 0000-0001-7414-3352 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21232006, 21642002) and the Chinese Academy of Sciences for financial support. C

DOI: 10.1021/acs.orglett.8b03247 Org. Lett. XXXX, XXX, XXX−XXX

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124, 764. (f) Bäckvall, J.-E.; Nordberg, R. E.; Wilhelm, D. J. Am. Chem. Soc. 1985, 107, 6892. (13) For examples using maleic anhydride (MA) as an additive to improve the reactions, see the following: (a) Goliaszewski, A.; Schwartz, J. Organometallics 1985, 4, 417. (b) Goliaszewski, A.; Schwartz, J. J. Am. Chem. Soc. 1984, 106, 5028. (c) Kohara, T.; Komiya, S.; Yamamoto, T.; Yamamoto, A. Chem. Lett. 1979, 8, 1513. (d) Doyle, M. J.; McMeeking, J.; Binger, P. J. Chem. Soc., Chem. Commun. 1976, 376.

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DOI: 10.1021/acs.orglett.8b03247 Org. Lett. XXXX, XXX, XXX−XXX