HMSI-PHOX

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Synthesis and Application of Hexamethyl-1,1’-spirobiindanebased Phosphine-Oxazoline (HMSI-PHOX) Ligands in NiCatalyzed Asymmetric Arylation of Cyclic Aldimines Weiye Sun, Haorui Gu, and Xufeng Lin J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00422 • Publication Date (Web): 19 Mar 2018 Downloaded from http://pubs.acs.org on March 19, 2018

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The Journal of Organic Chemistry

Synthesis and Application of Hexamethyl-1,1’-spirobiindane-based Phosphine-Oxazoline (HMSI-PHOX) Ligands in Ni-Catalyzed Asymmetric Arylation of Cyclic Aldimines Weiye Sun, Haorui Gu, and Xufeng Lin* Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China E-mail: [email protected]

Abstract: With the vastly increasing applications of chiral phosphine-oxazoline (PHOX) hybrid ligands in various transition-metal-catalyzed reactions, novel PHOX ligands bearing innovative backbones are highly valuable and in great demand. This study describes the development of a new type of chiral PHOX ligands based on a hexamethyl-1,1’-spirobiindane scaffold and incorporating both a phosphine and an oxazoline moiety. The optimal ligand provided high yields and excellent enantioselectivities for the Ni-catalyzed asymmetric arylation of cyclic N-sulfonyl imines with arylboronic acids leading to chiral amines.

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INTRODUCTION The design and synthesis of novel chiral ligands are always a very important and challenging task in the development of efficient transition-metal-catalyzed asymmetric reactions.1 Chiral P, N ligands play a significant role in transition-metal-catalyzed asymmetric synthesis due to its characteristics of both phosphine ligands and nitrogen ligands.2 The chiral phosphine-oxazoline (PHOX) ligand, which coordinates to a metal center with a N- and a P-atom, is one of the more classic category among P, N ligands, and has been recognized as one of the most versatile types of chiral inducers in various transition-metal-catalyzed reactions.3 The steric and electronic properties can be tailored for a specific application by variation of the phosphine, the oxazoline ring, and the backbone moiety due to their modular structure. As pioneering works in this area, Pfaltz, Helmchen, and Williams independently reported the first synthesis and application of PHOX in 1993.4 After that, various kinds of skeletons such as biphenyl, hetero aryl, cyclophane, ferrocenyl, Ruthenocenyl, and binaphthyl backbones, also found successful applications in asymmetric catalysis during the past dacades, and the backbone of the chiral ligands had remarkable influence on its catalytic performance in many cases.5 Despite these elegant contributions, the continued innovation of novel and practical backbone of PHOX is still a highly valuable but very challenging task. On the other hand, the spiro backbone has been recognized as a privileged structure to provide an excellent platform for chiral ligand and catalyst diversification6 since the pioneering work of Chan et al. with SpirOP.7 In this context, Zhou group8 and Ding group9 have developed spirobiindane-based PHOX and spirononadiene-based PHOX respectively, which

have

shown

impressive

activity

in

versatile

transition-metal-catalyzed

asymmetric

transformations. Inspired by these elegant pioneering studies, we became interested in developing the hexamethyl-1,1’-spirobiindane-PHOX ligands (HMSI-PHOX, Scheme 1) with its readily accessible stable and rigid spiro backbone. The hexamethyl-1,1’-spirobiindane motif in HMSI-PHOX has one axially chiral center and can be easily derived from hexamethyl-1,1'-spirobiindane-6,6'-diol which is easily prepared from industrially available Bisphenol C. Herein, we report the preliminary results on the ACS Paragon Plus Environment

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development of one new type of chiral phosphine-oxazoline ligands based on a hexamethyl-1,1’spirobiindane backbone (HMSI-PHOX, 1) and their application in the Ni-catalyzed enantioselective arylation of cyclic N-sulfonyl imines with arylboronic acids. The reactions proceed smoothly under mild conditions with excellent enantioselectivities (93-99% ee), as shown in Scheme 1. Scheme 1. Ni/HMSI-PHOX-catalyzed asymmetric arylation of cyclic aldimines

RESULTS AND DISCUSSION As illustrated in Scheme 2, the synthesis of enantiopure HMSI-PHOX (1) ligands started from industrially available Bisphenol C. Bisphenol C was firstly converted into hexamethyl-1,1'spirobiindane-6,6'-diol 5 in 92% yield by acid-catalyzed rearrangement in one step at room temperature on a large scale by a modified procedure.10 Then the bromination of 5 with N-bromosuccinimide (NBS) gave the brominated product 6 in 98% yield. The subsequent esterification of 6 with trifluoromethane sulfonic anhydride afforded the ditriflate 7 in nearly quantitative yield. The Pd-catalyzed selective reduction with formic acid in DMF furnished spiro-dibromide 8 as the key intermediate in 96% yield. Then, the Pd-catalyzed cross-coupling of 8 with diphenylphosphine oxide afforded compound 9 with high selectivity despite the moderate conversion.11 The monophosphine 10 was obtained in 92% yield by reduction of 9 with LiAlH4.12 The Pd-catalyzed reaction of 10 with zinc cyanide to afford cyanide 11 in 65% yield,13 followed by hydrolyzing with dilute H2SO4 to give the acid 12 in 75% yield. The acid 12 was further transformed to the corresponding hydroxyl amides 13a-d as a diastereomer mixture in quantitative yield by reacting with a variety of enantiopure amino alcohols in the presence of EDCI and HOBt.14 Finally, the target ligands 1a-d were obtained by cyclization of 13a-d with MsCl in the 3 ACS Paragon Plus Environment


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presence of triethylamine.15 To our delight, the two diastereomers of 1a-d, respectively, could all be readily separated by flash chromatography with high yields (72-85% for two steps from racemic 12) to provide the enantiopure phosphine-oxazoline ligands based on a hexamethyl-1,1’-spirobiindane scaffold (HMSI-PHOX, 1). The absolute configuration of the ligand (Sa,S,S)-1d was determined by X-ray crystallographic analysis of a single crystal which was obtained from diisopropyl ether (Figure 1). Scheme 2. Synthesis of HMSI-PHOX ligands


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Figure 1. X-ray crystal structure of the complex of (Sa,S,S)-1d and diisopropyl ether

With the new chiral HMSI-PHOX ligands (1) in hand, we next evaluated the enantioselective arylation of cyclic N-sulfonyl imines with arylboronic acids. Highly efficient transition-metal-catalyzed asymmetric addition of arylboron reagents to imines to generate chiral amines is a current topic of interest,16 and many excellent examples have been reported using Rh17 or Pd18 catalysts. The development of nickel catalyst which is cheap and abundant remains at the forefront and desirable, only one nice Ni-catalyzed example for such asymmetric transformation has been realized recently by the group of Zhang.19 To our delight, with the newly synthesized (Ra,S)-1a (7.5 mol %) as the ligand and Ni(ClO4)2·6H2O (5 mol %) as the catalyst precursor, the model reaction between 2a and 3a was initially performed in trifluoroethanol (TFE) at 60 oC to give the desired chiral amine 4a with 97% ee despite in low yield (Table 1, entry 1). To our delight, when the ligand was replaced with (Ra,S)-1b, the model reaction proceeded smoothly to afford the addition product 4a with 99% ee and in 80% yield, indicating the high efficiency of this novel chiral HMSI-PHOX ligand (Table 1, entry 2). After screening of these new chiral ligands, we found that the chirality at the spiro backbone of 1 had a significant impact on the ACS Paragon Plus Environment

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reactivity and asymmetric induction of the catalysis (Table 1, entries 1-8). The combination of a Ra configuration of the spiro backbone and the S configuration of the oxazoline moiety was revealed as the well matched case, such as in (Ra,S)-1a-c and (Ra,S,S)-1d. Furthermore, investigation of the substituent effect of the oxazoline moiety of ligands with a Ra configuration of the spiro backbone on the catalysis disclosed that the ligand (Ra,S,S)-1d, bearing two Ph group in the oxazoline moiety, was the best choice in terms of both reactivity and enantioselectivity (Table 1, entries 1-4). With the best ligand (Ra,S,S)-1d, the corresponding product 4a was afforded in 88% yield and 99% ee (Table 1, entry 4). On the basis of this result, different nickel and iron salts were exampled instead of Ni(ClO4)2·6H2O to give only low yield and low enantioselectivity or trace amounts of the product (Table 1, entries 9-13). Further evalutation of solvents indicated that the solvent had a remarkable impact on the reactivity and asymmetric induction of the catalysis (Table 1, entries 14-18). The experiments showed that dichloromethane, toluene, chloroform, acetonitrile and ethanol all gave a poor result with low reactivity and only moderate enantioselectivity, and trifluoroethanol was the best solvent for the Ni/HMSI-PHOXcatalyzed enantioselective arylation reaction. As a comparison, we tested the known spiro ligand (Ra,S)Ph-Bn-SIPHOX8 in the Ni-catalyzed asymmetric reaction with the model reaction under the current standard conditions to give the desired product in 85% yield and 97%. Table 1. Optimization of reaction parametersa

Entry

Ligand

[M]

Solvent

Yield [%]b

ee [%]c

1

(Ra,S)-1a

Ni(ClO4)2·6H2O

TFE

30

97

2

(Ra,S)-1b

Ni(ClO4)2·6H2O

TFE

80

99

3

(Ra,S)-1c

Ni(ClO4)2·6H2O

TFE

55

99


6

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a

4

(Ra,S,S)-1d

Ni(ClO4)2·6H2O

TFE

88

99

5

(Sa,S)-1a

Ni(ClO4)2·6H2O

TFE

HMSI-PHOX

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