Facile Synthesis of Novel Chiral Bicyclic Thioureas and Their Crystal Structures

The novel well-defined chiral bicyclic thioureas based on enantiopure unsymmetric cis-2,5-disustituted pyrrolidine skeleton were firstly synthesized and fully characterized by their H NMR, C NMR and HRMS. Their absolute configurations were also determined by single-crystal X-ray analysis.

In our previous research work [27,28], we established a facile synthetic route to enantiopure unsymmetric cis-2, 5-disubstituted pyrrolidines containing hydroxyl-diamino skeleton (Figure 1), and herein we wish to report an efficient synthesis of novel chiral bicyclic thioureas based on the skeleton of these enantiopure pyrrolidines.
With the chiral cis-2,5-disustituted pyrrolidines 1a and 1b in hand, the synthesis of novel bicyclic thioureas 2 was investigated.Initially, the compound 1a was directly used to react with thiophosgene in CH 2 Cl 2 by using triethylamine (TEA) as base (Scheme 1), and the reaction result is complex.The chiral bicyclic thiourea 2a was obtained only in 26% yield after purification by flash column chromatography.Because pyrrolidine 1a possesses hydroxyl-diamino group and thiophosgene is a very active reagent, maybe thiophosgene attacks these three active reaction sites in pyrrolidine 1a at the same time to result in some competing side reactions.In order to obtain the chiral bicyclic thiourea 2a in high yield, the hydroxyl group in pyrrolidine 1a should be protected.
Usually, the hydroxyl group was converted into its silyl ether in the organic protection strategy and trimethylsilyl (TMS) ether is readily stable in the presence of Et 3 N, 2,6-lutidine and N,N-diisopropylethylamine (DIPEA, Hünig's base).The chiral pyrrolidine 1a firstly reacted with trimethylsilyl trifluoromethanesulfonate (TMSOTf) to give TMS-protected pyrrolidine 3a in quantitative yield, and which was immediately used to react with thiophosgene to furnish TMS-protected thiourea 4a (Scheme 2).In this key step, the reaction conditions were optimized and the results were shown in Table 1.It was found that in the presence of Hünig's base, TMS-protected thiourea 4a was obtained in 89% crude yield by using CH 2 Cl 2 as solvent.Then 4a was deprotected by tetrabutylammonium fluoride (TBAF) in anhydrous THF to release the novel chiral bicyclic thiourea 2a in excellent yield (94%), and 2a was fully characterized by its 1 H NMR, 13 C NMR and HRMS.
To our satisfaction, the suitable crystals of 2a were grown from hexane-EtOAc for X-ray diffraction analysis (Figure 2).The chiral bicyclic thiourea 2a adopted monoclinic system and its space group is P 21.From the X-ray structure of 2a, the pyrrolidine ring is obviously in cis-configuration, which indicates that the configurations of 1a were retained in the synthetic process.The two five-membered rings (N1-C14-C15-C16-C17 and N1-C17-C18-N2-C19) in 2a all adopt envelope conforma- tion, and the absolute configurations of two chiral carbon atoms C14 and C17 in pyrrolidine ring are R and S respectively.
More interestingly, one cell of X-ray structure of 2a contains two complete molecules, but the bond lengths, angles and torsion angles of these two molecules are not same.For example, two intramolecular hydrogen bonds between hydroxyl and thionyl groups were found in the X-ray structure of 2a, but the lengths and angles of these two intramolecular hydrogen bonds are different, the length of H1---S1 (2.290 Å) is 0.039 Å shorter than H2---S2 (2.329 Å), and the angle of O2-H2---S2 (161.28˚) is 9.41˚ bigger than O1-H1---S1 (151.87˚).Some selected bond lengths, angles and X-ray crystallographic parameters of 2a are listed in Table 2.The enantiomer 2b was synthesized following the same procedure as 2a.
The chiral thioureas 2 have several attractive features.First, the two incorporated binding sites in 2 should afford a rigid backbone for coordination with metals.Second, the steric and electronic properties of chiralthioureas 2 can be easily modified by fine-tuning the substituents.Third, the chiral thioureas 2 enjoy a good stability to air and moisture.In addition, the hydroxyl group in 2a and 2b can provide a hydrogen-bond donor, and the thionyl group can serve as a hydrogen-bond acceptor, so, these chiral bicyclic thioureas 2 should have potential utilities to be used as ligands or organocatalysts in asymmetric catalysis.

Experimental
1 H and 13 C NMR spectra were measured in CDCl 3 solutions on a Bruker AV-300 or AV-500 spectrometer using TMS as an internal reference.Coupling constant (J) values are given in Hz.Mass spectra and High-resolution mass spectra were performed on a VG Micromass 7070F Mass Spectrometer with ES ionization (ESI).Crystal structure determination of compounds 2a was carried out on a Bruker SMART CCD Single Crystal X-ray Diffractometer equipped with graphite-monochromatized Mo Kα (λ = 0.71073 Å) radiation.The structure was solved by direct methods and refined on F 2 by full-matrix leastsquares methods using SHELX-97.Melting points are uncorrected and expressed in degree Celsius.Optical rotations analyses were performed on a Perkin-Elmer Model 343 Polarimeter.TMSOTf was prepared from trimethylsilyl chloride and trifluoromethanesulfonic acid by Corey's procedure [29].Solvents and reagents were purified and dried by standard methods prior to use.All reactions involving air or moisture sensitive species were performed in oven-dried glassware under inert atmosphere.Products were purified by flash column chromatography on silica gel purchased from Qingdao Haiyang Chemical Co. Ltd.

Direct Synthesis of 2a from Unprotected Pyrrolidine 1a and Thiophosgene
The chiral pyrrolidine 1a (1.08 g, 3.0 mmol) was dissolved in 40.0 mL anhydrous CH 2 Cl 2 and Et 3 N (3.6 mL, 25.6 mmol) and the solution was cooled to -15˚C by ice-salt bath.Thiophosgene (0.3 mL, 3.9 mmol, CAU-TION!Thiophosgene is a highly corrosive and toxic reagent) was added dropwise to the mixture and the reaction mixture was stirred at -15˚C for 45 min, then, it was continued to stir at room temperature (r.t.) overnight.The reaction was examined by thin layer chromatography (TLC).After the reaction was finished, the mixture was cooled to 0˚C and quenched by addition of 5.0 mL H 2 O.The solvents were removed under reduced pressure and the residue was dissolved in 100.0 mL ethyl acetate.The organic layer was washed by water (2 × 20 mL) and brine (2 × 20 mL), and dried over anhydrous Na 2 SO 4 .The solvent was evaporated under reduced pressure to give the crude product as yellow foam which was purified by flash column chromatography to yield 0.31 g chiral bicyclic thiourea 2a as pale yellow powder.

Preparation of TMS-Protected Pyrrolidine 3a
To a solution of 1a (1.44 g, 4.0 mmol) in anhydrous CH 2 Cl 2 (20.0 mL) and 2,6-lutidine (5.0 mL) added dropwise TMSOTf (2.5 mL, 12.5 mmol, CAUTION!TMSOTf is a highly corrosive and moisture sensitive reagent) at 0˚C and the mixture was stirred for 1.0 h at r.t.The reaction mixture was recooled to 0˚C and quenched by addition of saturated NH 4 Cl solution (2.0 mL).The mixture was diluted by 60.0 mL CH 2 Cl 2 and washed by saturated NH 4 Cl solution (2 × 20 mL), water (2 × 20 mL) and brine (2 × 20 mL).The organic layer was dried over anhydrous Na 2 SO 4 and the solvent was evaporated to give TMS protected pyrrolidine 3a as brown oil in quantitative yield (1.28 g).The product was directly used in the next step without further purification.

Preparation of Chiral Bicyclic Thiourea 2a (5S,7aR)-Hexahydro-5-(hydroxydiphenylmethyl)-2-ph enylpyrrolo(1,2-e)imidazole-3-thione (2a)
To a solution of 4a (1.1 g, 2.3 mmol) in anhydrous THF (30 mL) added tetrabutylammonium fluoride (TBAF, 1.4 g) and the mixture was stirred for 2.0 h at 0˚C.The reaction was examined by TLC.After the reaction was finished, the solvents were removed under reduced pressure and the residue was dissolved in 150.0 mL ethyl acetate.The organic layer was washed by water (2 × 30 mL) and brine (2 × 30 mL), and dried over anhydrous Na 2 SO 4 .The solvent was evaporated under reduced pressure to give the crude product as yellow foam which was purified by flash column chromatography (n-hex/ EtOAc = 5:1, V/V) to yield chiral bicyclic thiourea 2a as pale yellow powder in 94% yield (0.87 g The X-ray crystallographic data for chiral bicyclicthiourea 2a are summarized in Table 2.
The chiral bicyclic thiourea 2b was prepared by the same procedure as the preparation of 2a in 82% yield.

Conclusion
In summary, we provide an efficient and practical synthetic route to the novel chiral bicyclic thioureas 2a and 2b based on backbone of enantiopure unsymmetric cis-2, 5-disubstituted pyrrolidines 1a and 1b by three steps in good yields, and the absolute configurations of 2a was determined by X-ray single-crystal diffraction analysis.The applications of these novel chiral thioureas in organic synthesis were currently studied in our laboratory.

Figure 2 .
Figure 2. The X-ray structure of chiral bicyclic thiourea 2a, H atoms were omitted for clarity.

Scheme 2. The synthesis of 2a by three steps. Table 1. The optimization of the reaction conditions of 3a with thiophosgene.
a 4 eq.base was used in all entries; b Crude yield of product based on 3a.