Chiral Cyclic Ligand-Enabled Iridium-Catalyzed Asymmetric Arylation

Letter pubs.acs.org/OrgLett

Chiral Cyclic Ligand-Enabled Iridium-Catalyzed Asymmetric Arylation of Unactivated Racemic Allylic Alcohols with Anilines Hua Tian, Pengxiang Zhang, Fei Peng, Haijun Yang, and Hua Fu* Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China S Supporting Information *

ABSTRACT: A highly enantioselective arylation of unactivated racemic secondary allylic alcohols with aniline derivatives has been developed. The transformation was enabled by an iridium−chiral cyclic phosphoramidite complex in the presence of boron trifluoride diethyl etherate as the promoter, and the reactivity and enantioselectivity of the substrates were tuned by the variation of our newly developed chiral cyclic phosphoramidite ligands together with temperature and solvents. The method shows advantages including use of the readily available starting materials, an operationally convenient protocol, full regioselectivity and excellent enantioselectivity, and tolerance of many functional groups with water as the only byproduct.

D

substitution reaction enabled by an Ir/Phox complex,13 the development of chiral ligands has attracted much attention in this field. At present, the most representative of chiral ligands on Ir-catalyzed allylic substitution reactions mainly focus on chiral phosphoramidite ligands (Figure 1), such as the Carreira

iaryl tertiary chiral centers are a structural motif that widely occur in natural products and pharmaceuticals,1 so the enantioselective synthesis of compounds with this unit has attracted considerable attention.2 The common strategy to access these compounds is through catalytic asymmetric synthesis approaches. For example, based on chiral starting materials, Jarvo et al. reported a Ni-catalyzed cross-coupling of 1,1-diaryl ethers with Grignard reagents,3a and Carreira’s group described a stereoretentive Rh-catalyzed decarbonylation of enantioenriched β,β-diarylpropionaldehydes.3b Fu’s group developed an efficient enantioselective Ni-catalyzed asymmetric synthesis of 1,1-diarylalkanes via Negishi arylation of racemic secondary benzylic alcohols.3c Gaunt et al. disclosed an enantioselective Cu-catalyzed arylation of allylic amides with diaryliodonium salts.3d Zhu and Zhou represented a cooperative rhodium/phosphoric acid-catalyzed asymmetric arylation of α-aryl-α-diazoacetates.3e In addition, other approaches to compounds with this unit have also been developed.4,5 The Friedel−Crafts reaction is a powerful C−C bond forming protocol in organic synthesis,6 and the development for an asymmetric Friedel−Crafts alkylation of aromatic compounds has attracted much attention.7,8 Furthermore, the Friedel− Crafts alkyaltion reaction was also applied to the enantioselective synthesis of diarylmethane tertiary stereogenic centers. Nishibayashi’s group reported a Ru-catalyzed enantioselective propargylation of aromatic compounds with propargylic alcohols.9 Ir-catalyzed regio- and enantioselective allylic substitution reactions have witnessed significant progress during the past decade.10−12 Remarkably, the developed direct displacement of unactivated allylic alcohols is more attractive because this strategy can reduce the number of steps to the target products and decrease cost and waste. 12 Since Helmchen’s group reported the first asymmetric allylic © 2017 American Chemical Society

Figure 1. For iridium-catalyzed allylic substitution reactions, the representative chiral phosphoramidite ligands including (S)-A, (S)-B, (S)-C, and (R)-D; our newly developed chiral cyclic phosphoramidite ligands including (R)-E, (R)-F, and (R)-G.

P,olefin ligand ((S)-A),14 Feringa15/Alexakis16 P,C ligands ((Sa,S,S)-B and (Sa,S,S)-C), and You Me-THQphos ligand ((R)-D) derived from 1,1'-bi-2-naphthol (BINOL).17 Very recently, we have developed a new type of axially chiral cyclo[1,1′-biphenyl]-2,2′-diol (CYCNOL) ligands with adjustable dihedral angles by varying the bridge chain length.18 Inspired by the excellent research above, we herein report an Ir-catalyzed asymmetric arylation of unactivated racemic secondary allylic Received: May 30, 2017 Published: June 29, 2017 3775

DOI: 10.1021/acs.orglett.7b01631 Org. Lett. 2017, 19, 3775−3778

Letter

Organic Letters alcohols with aniline drivatives in the presence of our newly developed chiral cyclic phosphoramidite ligands, (R)-E, (R)-F, and (R)-G (Figure 1). First, coupling of 1-(4-methylphenyl)prop-2-en-1-ol (1b) with N,N-dimethylaniline (2a) under catalysis of [Ir(cod)Cl]2 was selected as the model to optimize conditions including ligands, solvents and amount of boron trifluoride diethyl etherate (BF3·OEt2) as a promoter (see Table S1 in SI for the details). According to the results from optimization of the reaction conditions, we think that (R)-E, (R)-F and (R)-G as the ligands, MeCN and DMF as the solvents, 30 mol % BF3· OEt2 as the promoter are suitable in the present iridiumcatalyzed asymmetric arylation. After obtaining the optimized conditions, the substrate scope for iridium-catalyzed asymmetric arylation of allylic alcohols (1) with aniline derivatives (2) was surveyed. As shown in Table 1, 11 allylic alcohols (1a−1k) with neutral, electron-donating, and slightly electron-withdrawing groups on the aromatic rings performed well at rt using 2a as the partner in acetonitrile (see products 3a−3k). However, the substrates (1i−1o and 1u−1z) containing strong electron-withdrawing groups including ester, nitro, and trifluoromethyl groups on the aromatic rings provided lower yields at this temperature using 2a as the counterpart. When the reaction temperature was increased to 50 °C, the corresponding products were obtained in high yields with excellent ee values (see 3i−3o and 3u−3w). We found that the effect of solvents was obvious. For most of substrate 1, MeCN was a suitable solvent. For the allylic alcohols containing O-, S-, and N-heterocycles (see 3p−3r), MeCN afforded lower ee values. However, the excellent enantioselectivities were observed when DMF replaced MeCN as the solvent (see 3p− 3r). Coupling of 1-(4-nitrophenyl)prop-2-en-1-ol with N,Nbis(2-chloroethyl)aniline displayed a similar result (see 3x). We investigated the influence of our newly developed chiral cyclic phosphoramidite ligands, (R)-E, (R)-F, and (R)-G, and found that the different ligands showed varying reactivity and enantioselectivity for the different substrates. For most of the substrates, (R)-F containing a nine-membered ring was a suitable ligand. For synthesis of 3y in MeCN, (R)-E containing an eight-membered ring afforded a 90% yield with 96% ee, but (R)-F with a nine-membered ring and (R)-G with a tenmembered ring exhibited lower enantioselectivity in the reaction. When the solvent was changed to DMF from MeCN, both (R)-F and (R)-G provided excellent ee values (see 3y). Synthesis of 3z also showed similar results to synthesis of 3y. Therefore, the iridium-catalyzed asymmetric arylation of allylic alcohols with aniline derivatives can be tuned in reactivity and enantioselectivity by the variation of our newly developed chiral cyclic phosphoramidite ligands together with temperature and solvents. The present reaction showed tolerance of various functional groups including C−Cl bonds, C−Br bonds, C−I bond, ether, ester, nitro, CF3, and sulfamide groups. Unfortunately, the unactivated racemic secondary aliphatic allylic alcohols or N,N-dialkyl anilines containing the electron-withdrawing aryl rings did not undergo the described arylation above. To ascertain absolute configurations of the newly synthesized products (3), the single crystal of (S)-3s from a mixed solvent of hexane and dichloromethane was prepared, and its absolute configuration was unambiguously confirmed by X-ray diffraction analysis (Figure 2) (see Supporting Information). A scale experiment was attempted using coupling of 1m (3 mmol, 537 mg) with 2a (2 mmol, 242 mg) as the model in the

Table 1. Substrate Scope for Iridium-Catalyzed Asymmetric Arylation of Allylic Alcohols with Aniline Derivativesa

a Reaction conditions: under nitrogen, 1 (0.3 mmol, 1.5 equiv), 2 (0.2 mmol, 1.0 equiv), [Ir(cod)Cl]2 (5.0 μmol, 2.5 mol %), ligand (0.02 mmol, 10 mol %), BF3·OEt2 (0.06 mmol, 0.3 equiv), anhydrous MeCN or DMF (2.0 mL), temperature (rt (∼25 °C) or 50 °C), time (24 h) in a sealed Schlenk tube. Isolated yield, and the ee values were determined by HPLC analysis. Absolute configurations were determined by comparing structure of (S)-3s (its absolute configuration was assigned by X-ray diffraction analysis).

presence of a lower loading of [Ir(cod)Cl]2 (1.25 mol %) and (R)-F (5 mol %); the reaction provided 3m in 88% yield with more than 99% ee without reduction of the yield and enantioselectivity (Scheme 1a). Therefore, the present 3776

DOI: 10.1021/acs.orglett.7b01631 Org. Lett. 2017, 19, 3775−3778

Letter

Organic Letters

affords product complex V leaving BF3·OEt2 and water. Finally, displacement of the product (3) by 1 regenerates complex I. We investigated applications of the synthesized chiral prop-2ene-1,1-diyldibenzenes (3) (Scheme 3). Reduction of 3m Scheme 3. Applications of the Synthesized Chiral Prop-2ene-1,1-diyldibenzenes 3m and 3u

Figure 2. Crystal structure of (S)-3s.

Scheme 1. (a) Scale Synthesis of 3m; (b) Coupling of Vinyl Benzoxazinanone 4 with N,N-Dimethylaniline (2a)

provided 5 in 92% yield with 96% ee (Scheme 3a). Addition of 3u with 9-borabicyclo[3.3.l]nonane (9-BBN) followed by oxidation with H2O25i delivered 6 in 90% yield with >99% ee (Scheme 3b). The results show that the synthesized products (3) are very useful through the iridium-catalyzed arylation of unactivated racemic secondary allylic alcohols with anilines. In summary, we have developed an efficient, highly enantioselective Ir-catalyzed arylation of unactivated racemic secondary allylic alcohols with aniline derivatives enabled by our newly developed chiral cyclic phosphoramidite ligands with boron trifluoride diethyl etherate as the promoter, and the method provided prop-2-ene-1,1-diyldibenzene derivatives with diaryl tertiary chiral centers in good yields showing advantages including use of the readily available starting materials, an operationally convenient protocol, full regioselectivity, excellent enantioselectivity, and numerous functional group tolerance. It is noteworthy that the reactivity and enantioselectivity were tuned by variation of our newly developed chiral cyclic phosphoramidite ligands together with temperature and solvents. We believe that our newly developed chiral cyclic ligands will find wide application in asymmetric synthesis.

iridium-catalyzed asymmetric arylation is a very effective strategy for the construction of diaryl tertiary chiral centers. Coupling of an activated allylic alcohol derivative, vinyl benzoxazinanone 4, with N,N-dimethylaniline (2a) was investigated under the standard conditions (Scheme 1b), and product 3s was obatined in a high yield with an excellent ee value. However, no target product was obtained in the absence of the Lewis acid (BF3·OEt2). According to our experiments and previous references,3e,9,19 a reaction pathway of this Ir-catalyzed asymmetric arylation is proposed in Scheme 2. Coordination of allylic alcohol (1) with in situ formed IrXL* from [Ir(cod)Cl]2 and chiral cyclic phosphoramide ligand provides complex I,19 and dehydroxylation of I with BF3·OEt2 yields II and allyl−iridium intermediate III.9,19 Friedel−Crafts reaction of III with aniline (2) affords IV,3e and deprotonation of IV in the presence of II

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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.7b01631. Experimental details, NMR data (PDF) Crystallographic data for 3s (CIF)

Scheme 2. A Possible Reaction Mechanism for the IridiumCatalyzed Asymmetric Arylation

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hua Fu: 0000-0001-7250-0053 Notes

The authors declare no competing financial interest. 3777

DOI: 10.1021/acs.orglett.7b01631 Org. Lett. 2017, 19, 3775−3778

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ACKNOWLEDGMENTS The authors would like to thank Dr. Haifang Li in this department for her great help in analysis of high resolution mass spectrometry and the National Natural Science Foundation of China (Grant No. 21372139) for financial support.

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