Synthesis of BINOL-thiourea Derivatives

Research Article

Austin J Anal Pharm Chem. 2017; 4(2): 1086.

Synthesis of BINOL-thiourea Derivatives

Chen S, Zhang X, Yu Q, Lu W and Dai Z*

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, China

*Corresponding author: Zhenya Dai, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, China

Received: May 19, 2017; Accepted: June 13, 2017; Published: June 20, 2017

Abstract

Herein a convenient synthesis of BINOL-thiourea derivatives I, II and III via the reaction of phosphorylisothiocycanide C with amines was described in modest yield.

Introduction

It is well documented that enantiopure R-BINOL-derivatives and thiourea-derivatives belong to privileged compounds which were widely applied in the field of asymmetric synthesis and organocatalysis [1]. Dual hydrogen bonding (DHB) catalyst have been received much attention in the field of enantioseletive synthesis [2]. Among the hydrogen-bonding complex, thiourea derivatives have been proved to be one of the most promising scaffolds, and much effort has been dedicated to find alternative motifs [3]. As a result, several scaffolds such as guandines, squaramides, were identified. On the other hand, Bronsted acid catalyst especially BINOL-derivatives has attracted much Attention [4]. Whereas thiourea and BIONLderivatives are well known as scaffolds and have been explored successfully as catalysts as well as ligand, however, combining the two units as a whole has scarecely been reported? The synthesis of phosphorylthiourea through the addition nucleophilic reaction of phosphorylisothiocycanide and substitude amines was published in 1987 [5,6]. Phorylthioureas have been used as insecticide, herbicide figicide plant growth regulator and so on [7,8]. Due to our current interests in the synthesis and applications of thiourea as well as R-BINOL-derivatives, we herein report a convenient and efficient protocol for the preparation of chiral organocatalyst I, II and III, which are promising reagents for further and diverse application.

Experimental

General

Melting points were determined in a capillary using a Melt Temp. II apparatus (Aldrich) or STUART SMP 30 and are uncorrected. 1H NMR spectra were measured on a Bruker Avance III instrument (300MHZ). Chemical shifts (d) are given in ppm and coupling constants J in Hz.

Staring material

All solvents and reagents are commercially available and used as received.

Procedure: Phosphorus oxychloride (0.1mol) was added with stirring into a solution of (R)-(+)-1,1’-Bi-2-naphthol A (0.1mol) in CH2Cl2 (5ml), the reaction mixture was stirred at room temperature for 12 hours, then the formed hydrogen chloride and solvent were evaporated and a white solid was obtained.

The compound was used for next step without further purification (Yield: 88%).

Synthesis of compound C

To a solution of 2 (0.12mol) in acetonitrile (20mL), KSCN (0.25mol) was added gradually with stirring, and the mixture was stirred at 65°C for 10 hours, which was filtrated and extracted with dichloromethane (15mL*2), the solvent was evaporated under reduced pressure to give a yellow liquid, which was used for the next step without further purification.

The synthesis of I, II and III

General procedure: To a mixture of 3 (10mmol) in chloroform (30mL), a solution of aniline (10mmol) in chloroform (10mL) was added drop wise with stirring. The mixture was refluxed until reaction completion was detected by thin-layer chromatography. The solvent was evaporated under the reduced pressure, the residue was diluted with ether (10mL) and cooled in ice-water bath, the crude product was crystallized with DMF-H2O to give the target compound.

Compound I: White solid, mp: 152-154oC, yield: 64%.

¹H-NMR (CDCl3, 300MHZ): 8.5812 (m, 1H): 8.5525-8.0446 (m, 1H), 7.9772-7.8824 (m, 4H): 7.8139-7.7832 (m, 1H), 7.7232-7.6962 (m, 1H), 7.5431-7.5145 (m, 3H), 7.3224—7.2597 (m, 4H), 6.7526- 6.7230 (m, 1H), 6.3390 (s, 1H), 2.5864-2.5562 (m, 1H), 2.3828-2.3453 (m, 1H), 1.8722-1.8195 (m, 3H), 1.4284-1.2335 (m, 4H), 0.9577- 0.8556 (m, 1H).

HRMS: [M+Na]: 656.1; found: 656.4

Compound II: Yellow solid, mp: 178-181oC, yield: 70%.

¹H-NMR (CDCl³, 300MHZ): 8.5812-8.5525 (m, 1H), 8.6446- 8.0152 (s, 1H); 7.9772-7.8824 (m, 4H), 7.8139-7.7842 (m, 1H), 7.7232-7.7135 (m, 2H), 7.5431-7.5145 (m, 3H). 7.3226- 7.3121 (m, 4H); 6.7526-6.7230 (d, 1H); 6.3390 (s, 1H); 2.5864-2.5562 (d, 1H); 2.3828-2.3453 (m, 1H); 2.0407 (s, 1H).

HRMS: [M+Na]: 519.4; found: 519.1

Compound III: Yellow solid, mp: 155-156oC, yield%: 63%.

¹H-NMR (CDCl3, 300MHZ): 10.9985 (s, 1H), 8.2316 s, 2H), 8.1535-8.1358 (m, 1H), 8.0182-7.9923 (m, 2H), 7.7506 (s, 1H), 7.6158-7.5335 (m, 4H), 7.4101-7.3632 (m, 4H), 6.8569 (s, 1H).

HRMS: [M+Na]: 641.5; found: 641.1

Citation: Chen S, Zhang X, Yu Q, Lu W and Dai Z. Synthesis of BINOL-thiourea Derivatives. Austin J Anal Pharm Chem. 2017; 4(2): 1086. ISSN:2381-8913