Synthesis of a Class of Chiral-Bridged Phosphoramidite Ligands and Their Applications in the First Iridium-Catalyzed Asymmetric Addition of Arylboronic Acids to Isatins.

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Synthesis of a class of chiral-bridged phosphoramidite ligands and their applications in the first iridium-catalyzed asymmetric addition of arylboronic acids to isatins Yue Zhuang, Yuwei He, Zihong Zhou, Wang Xia, Chuyu Cheng, Meng Wang, Bin Chen, Zhongyuan Zhou, Jiyan Pang, and Liqin Qiu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00595 • Publication Date (Web): 23 Jun 2015 Downloaded from http://pubs.acs.org on July 2, 2015

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The Journal of Organic Chemistry

Synthesis

of

a

class

of

chiral-bridged

phosphoramidite ligands and their applications in the first

iridium-catalyzed

asymmetric

addition

of

arylboronic acids to isatins Yue Zhuang,† Yuwei He,† Zihong Zhou,† Wang Xia,† Chuyu Cheng,† Meng Wang,† Bin Chen,† Zhongyuan Zhou, § Jiyan Pang† and Liqin Qiu*,†,‡ †

School of Chemistry and Chemical Engineering, South China Sea Bio-Resource

Exploitation and Utilization Collaborative Innovation Center, The Key Laboratory of Low-carbon Chemistry & Energy Conservation of Guangdong Province, Sun Yat-sen University, No. 135 Xingangxi Road, Guangzhou 510275, People’s Republic of China ‡

Huizhou Research Institute of Sun Yat-sen University, Dayawan, Huizhou, People’s

Republic of China §

Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University,

HK (China)

Fax: (+86)-20-8411-0996; e-mail: [email protected]

Abstract. A series of novel chiral phosphoramidite ligands based on chiral-bridged biphenyl backbones have been prepared conveniently and characterized. The ligands complexed with [IrCodCl]2 provided the first iridium catalyst system for the asymmetric addition of arylboronic acids to N-protected isatins with high efficiency. 1

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When performed in THF/H2O at 80℃ with 2 equiv. of the arylboronic acids, the transformations acquired good to excellent results (up to 98% yield and 95% ee). INTRODUCTION Transition metal-catalyzed asymmetric reactions lie at the core of organic synthesis, in which design and synthesis of efficient chiral ligands plays a key role. Since Monophos was synthesized in 19941 and employed in asymmetric addition reaction later,2 a plenty of phosphoramidite ligands were developed for their easy synthesis, convenient modification and potential applications in many kinds of enantioselective catalytic reactions.3 Nowadays chiral phosphoramidite compounds have become one of the most widely used ligands. Chiral 3-substituted oxindoles are common structural motifs which constitute a useful class of compounds that can be found in various biologically active molecules and natural products.4 A number of successful methods for 3-hydroxyoxindoles have been developed in recent years,5 and the formation of quaternary carbon centers via addition of arylboronic acids to isatins seems to be one of the most useful methods for efﬁcient construction of this structural scaffold. In 2006，Hayashi and coworkers first reported the asymmetric addition of arylboronic acids to N-protected isatins catalyzed with Rh/(R)-MeO-mop complex, achieving high enantioselectivities and excellent yields. In their paper, a chiral phosphoramidite ligand was also tested, however, the obtained enantioselectivity was only 39% ee.6 Meanwhile, use of a rhodium/chiral H8-BINOL-derived phosphoramidite as the catalyst afforded 55% ee in the similar reaction.7 Recently, several ligands including Me-BIPAM,8 H8-BINOL-derived 2


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phosphine-oxazoline ligands,9 chiral NHC10 and chiral sulfoxide phosphine11 complexed with ruthenium, palladium, copper or rhodium were also employed for the catalysis. However, most of the obtained ee values via these cheaper central metal catalytic systems such as Ru or Pd are still lower than those with Rh complex. Relatively economical and efficient catalytic system is warmly expected. Herein, we disclose the development of a new type of chiral phosphoramidite ligands based on chiral-bridged

biphenyl

backbones12

and

their

applications

in

the

first

iridium-catalyzed asymmetric addition of arylboronic acids to N-protected isatins. The addition reactions acquired high yields and good to excellent enantioselectivities. RESULTS AND DISCUSSION Scheme 1. Synthesis of ligands 4

3



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Fig.1. X-ray crystal structure of ligand (S,S,Ra,S,S)-4a (ORTEP drawing at 30% ellipsoid probability). As shown in Scheme 1, synthesis of ligands 4 was quite simple and robust. The key desymmetrized annulation diphenol intermediates 3a-c were readily prepared from prochiral 2,2,6,6-tetrahydroxy-biphenyl with different chiral bis(mesylate) or bis(tosylate) by a Williamson synthesis.13 Following SN2 substitution reaction mechanism, the central chirality configuration of the ether-linked backbone became reversed from 2. Meanwhile, perfect chirality transfer from central to axial chirality was performed and products 3a-c were given in 76%, 53% and 68% yields respectively.14 Reaction of 3a-c with phosphorus trichloride yielded corresponding intermediates phosphoryl chlorides first. Subsequent addition of the desired amine to the reaction system in the presence of a base finally acquired the phosphoramidite ligands 4a-d and 4f-n. Dimethylamine-derived phosphoramidite ligand (S,S,Ra)-4e was prepared via another reaction of (S,S,Ra)-3b with hexamethylphosphorus triamide (HMPT).1 Through a single-crystal X-ray diffraction analysis of ligand (S,S,Ra,S,S)-4a, all its chiral configurations were confirmed (Fig. 1). It is worthy to note that these ligands are stable enough and can be puriﬁed by common silica gel column 4


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chromatography without special precaution to water or air. Table 1. Metal Sources and Ligands Screeninga

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 a

Metal Rh(Cod)2BF4 Rh(Cod)2Cl2 [RhNBDCl]2 Pd(OAc)2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2

Ligand (S,S,Ra,S,S)-4a (S,S,Ra,S,S)-4a (S,S,Ra,S,S)-4a (S,S,Ra,S,S)-4a (S,S,Ra,S,S)-4a (S,S,Ra,R,R)-4b (S,S,Ra)-4c (S,S,Ra)-4d (S,S,Ra)-4e (S,Ra)-4f (R,R,Sa,S,S)-4g (R,R,Sa,R,R)-4h (Ra)-5 (Ra,S,S)-6

Yield (%)b 86 69 86 81 88 87 53 61 75 84 48 43 32 83

Ee (%)c 8 14 2 8 84 15 17 21 10 13 55 76 6 81

Reaction conditions: 0.2 mmol of N-benzyl isatin, phenylboronic acid (2 equiv.), [IrCodCl]2 (1 mol%),

ligand (2.2 mol%), KF (2 equiv.), 50℃, 48 h, solvent: THF-H2O (2 mL-0.1 mL). b Yield of isolated product. c Determined by chiral HPLC.

Fig. 2. Ligands (R)-5 and (Ra,S,S)-6.

Table 2. Solvents, Bases, and Temperature Screeninga

5



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Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

a

Metal [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 [IrCodCl]2 -[IrCodCl]2 [IrCodCl]2

Base KF KF KF KF KF KF KF KF KF KF KF HKF K2CO3 KOH K3PO4 KOtBu CsF Cs2CO3 Et3N LiOH H2O DIPEA KF KF KF KF KF KF KF --

Solvent EtOH/H2O i PrOH/H2O t BuOH/H2O THF/H2O MTBE /H2O DCM/H2O Dioxane/H2O DME/H2O DMF/H2O xylene/H2O THF THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O THF/H2O

Yield(%)b 76 66 93 95 97 45 58 92 28 96 37 81 88 83 64 trace 31 54 39 73

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