Synthesis and characterization of a Zn(II) complex of a pyrazole-based ligand bearing a chiral l -alaninemethylester

Polyhedron 20 (2001) 1961– 1965 www.elsevier.com/locate/poly

Synthesis and characterization of a Zn(II) complex of a pyrazole-based ligand bearing a chiral L-alaninemethylester Soo-Gyun Roh a, Yu-Chul Park a, Dong-Kyu Park b, Tae-Jeong Kim b,*, Jong Hwa Jeong a,* b

a Department of Chemistry, Kyungpook National Uni6ersity, Taegu 702 -701, South Korea Department of Industrial Chemistry, Kyungpook National Uni6ersity, Taegu 702 -701, South Korea

Received 13 December 2000; accepted 22 March 2001

Abstract Reaction of ZnCl2 with a new ligand N,N-bis(3,5-dimethylpyrazolylmethyl)-L-alaninemethylester (bdmpame) in methanol gives [ZnCl2(bdmpame)]. The structure of [ZnCl2(bdmpame)]·CH2Cl2 has been resolved by X-ray crystallographic analysis. The Zn atom has a distorted tetrahedral geometry involving a nitrogen atom from each pyrazole in bdmpame and two chloro ligands with bond lengths in the range 2.037(4)–2.237(2) A, . The nitrogen atom of the L-alaninemethylester group in the compound was not coordinated to the metal center, giving an eight-membered ring in which the nitrogen atoms of each pyrazole in bdmpame are coordinated to the metal center. The results of the catalytic enantioselective reduction of acetophenone promoted by ligand/ Zn(OTf)2 =1:1 mole ratio in the presence of catecholborane for 48 h at 0°C gives (S)-(− )-1-phenylethanol in 21% ee with 68% yield. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Crystal structures; Zinc complexes; Chiral N-substituted pyrazole

1. Introduction The coordination chemistry of zinc is of considerable interest [1]. The active binding sites of zinc could be applied to highly efficient and catalytic reactions by using a variety of coordination possibilities such as the variability and flexibility of ligands in biologically relevant coordination spheres [2]. Since changes in coordination geometry due to the flexibility of the binding ability of ligands can lead to an open position at the metal ion site, these may be beneficial for catalytic reactions to occur [3]. The ligands containing imidazole or substituted imidazole groups, similar to pyrazole or substituted pyrazole groups, are known to occur in metalloproteins [4]. We have embarked upon the study of a new chiral ligand, an L-alanine methylester derivative containing 3,5-dimethylpyrazole. In order to investigate the exact

* Corresponding authors. Tel.: + 82-53-950-6343; fax: +82-53950-6330. E-mail address: [email protected] (J.H. Jeong).

nature of the coordination environments at the zinc center, several spectroscopic and crystallographic studies were required. The metal centers at the active site of many enzymes, such as carbonic anhydrase (NNN) [5], thermolysin (NNO) [6], liver alcohol dehydrogenase (NNS) [7], bacteriophage T7 lysozyme (NNS) [8] and peptide deformylase (NNS) [8], have the donor atoms of nitrogen, oxygen and sulfur. The structural studies of amino acid compounds provide information for modeling the properties of metalloproteins and the pursuit of various different proteins play a considerable role in new models for metalloproteins. Although a large variety of N-substituted pyrazole derivatives are now known [9], the design and synthesis of chiral N-substituted pyrazole derivatives, not to mention their complex formation, have not yet been reported. In recent years, the synthesis of optically active secondary alcohols and their application as catalysts for enantioselective addition reactions promoted by zinc compounds to aldehydes have been considered [10].

0277-5387/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 2 7 7 - 5 3 8 7 ( 0 1 ) 0 0 7 8 8 - 4

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S.-G. Roh et al. / Polyhedron 20 (2001) 1961–1965

Herein, we describe our results on the reaction of ZnCl2 with N,N-bis(3,5-dimethylpyrazolylmethyl)-Lalaninemethylester as a potential tridentate ligand as well as the catalytic reduction of acetophenone.

the solvent was removed in vacuo to afford the colorless oil. Yield: 8.12 g (67%). 1H NMR (CDCl3): l 5.95 (s, HPz), 5.21 (d, CH2, J=15.0 Hz), 5.05 (d, CH2, J = 14.7 Hz), 3.49 (s, OCH3), 3.41 (q, CH), 2.57 (s, CH3Pz), 2.25 (s, CH3Pz), 1.33 (d, CH3, J =7.2 Hz).

2. Experimental

2.2.2. ZnCl2(bdmpame) ·dichloromethane (2) To a solution of ZnCl2 (1.96 g, 6.14 mmol) in methanol (25 ml) was added dropwise a solution of 1 (0.83 g, 6.14 mmol) in methanol (25 ml). The mixture was stirred for 5 h at ambient temperature, the solution was filtered off, the solvent was removed in vacuo and the residue was washed with ether to give a white solid. Diffusion of n-hexane into a solution of 2 in dichloromethane gave colorless crystals within a week. Yield: 2.45 g (87%). Anal. Found: C, 37.55; H, 5.09; N, 12.90. Calc. for C16H25Cl2N5O2Zn·CH2Cl2: C, 37.77; H, 5.03; N, 12.95%. 1H NMR (CDCl3): l 5.95 (s, HPz), 5.21 (d, CH2, J=16.2 Hz), 5.05 (d, CH2, J=14.7 Hz), 3.67 (m, CH), 3.47 (s, OCH3), 2.55 (s, CH3Pz), 2.25 (s, CH3Pz), 1.32 (d, CH3, J= 7.2 Hz).

2.1. General procedures All reagents and solvents used were of reagent grade. 3,5-Dimethylpyrazole-1-methanol was prepared as described in the literature [11]. 1H NMR spectra were recorded on a Varian 300-NMR spectrometer at ambient temperature and chemical shifts were referenced to the internal tetramethylsilane. Elemental analyses were performed at the Chemical Analysis Laboratory, Korea Basic Science Institute, Kyungpook National University.

2.2. Synthesis of the compounds 2.2.1. N,N-Bis(3,5 -dimethylpyrazolylmethyl) L -alaninemethylester (bdmpame) (1) To a suspension of L-alanine methyl ester hydrochloride (5.33 g, 38 mmol) in dichloroethane (70 ml) 3,5dimethylpyrazole-1-methanol (9.67 g, 76 mmol) was added slowly followed by 2,6-lutidine (4.45 ml, 38 mmol) with stirring at room temperature. The solution was stirred for 3 days at ambient temperature and then Table 1 Crystallographic data and structure refinement of 2 Empirical formula Formula weight Temperature (K) Wavelength, u (Mo Ka) (A, ) Crystal system Space group Unit cell dimensions a (A, ) b (A, ) c (A, ) V (A, 3) Formula units per cell (Z) Calculated density (Mg m−3) Absorption coefficient (mm−1) F(000) 2q range for data collection (°) Index ranges Reflections collected/unique Refinement method Data/restraints/parameters Goodness-of-fit on F 2 Final R indices [I\2|(I)] Largest difference peak and hole (e A, −3)

C16H25Cl2N5O2Zn·CH2Cl2 540.61 293(2) 0.71073 orthorhombic P212121 11.822(1) 13.103(1) 15.7962(7) 2446.9(4) 4 1.467 1.463 1112 2.02–25.47 05h514, 05k515, 05l519 2630/2576 [Rint = 0.0000] full-matrix least-squares on F 2 2576/0/262 1.001 R1 = 0.035, wR2 = 0.087 0.404 and −0.338

2.3. Crystal structure determination of 2 A colorless single crystal of 2 suitable for X-ray crystallography was mounted on an Enraf–Nonius CAD4 diffractometer with Mo Ka radiation (u= 0.71073 A, ). Unit cell dimensions with estimated standard deviations were determined by least-square methods using 25-well centered reflections. A total of 2576 unique reflections were collected in the q range 2.02–25.47° (05 h514, 05 k5 15, 05 l5 19) in the …–2q scan mode. The intensities of the reflections were corrected for Lorentz and polarization effects. Crystal data, data collection and refinement parameters for the complex are listed in Table 1. Data reductions were carried out using a MOLEN program package; a decay correction based on the intensities of two standard reflections and monitoring every hour was performed; empirical absorption corrections were applied based on C scans [12]. The structure with space group P212121 was determined by direct methods and refined by fullmatrix least-squares using SHELXS-97 and SHELXL-97 program packages [13] using reflections with I\2|(I). All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were constrained by using riding modes. The final cycle of the refinement yielded R= 0.035 and wR2 = 0.087. Selected bond distances and bond angles are given in Table 2.

2.4. Catalytic enantioselecti6e reduction of acetophenone A flame-dried flask was charged with 1 (0.078 mmol), Zn(OTf)2 (0.078 mmol), and dry CH2Cl2 (2 ml) under nitrogen. The solution was stirred for 30 min, cooled to

S.-G. Roh et al. / Polyhedron 20 (2001) 1961–1965 Table 2 Selected bond lengths (A, ) and angles (°) for 2 Bond lengths ZnN(1) ZnCl(1) N(1)N(2) N(2)C(11) N(5)C(11) N(5)C(13) C(15)O(1) O(2)C(16)

2.037(4) 2.237(2) 1.359(6) 1.447(7) 1.453(7) 1.461(7) 1.188(7) 1.440(7)

ZnN(4) ZnCl(2) N(3)N(4) N(3)C(12) N(5)C(12) C(13)C(15) C(15)O(2)

Bond angles N(1)ZnN(4) N(1)ZnCl(2) N(4)ZnCl(2) N(2)N(1)Zn N(2)C(11)N(5) N(5)C(13)C(15) O(1)C(15)C(13) C(15)O(2)C(16)

108.6(2) 106.4(1) 110.9(1) 122.8(3) 109.9(4) 114.3(4) 125.9(6) 115.7(5)

N(1)ZnCl(1) N(4)ZnCl(1) Cl(1)ZnCl(2) N(4)N(3)C(12) N(3)C(12)N(5) O(1)C(15)O(2) O(2)C(15)C(13)

2.069(4) 2.235(2) 1.375(5) 1.466(6) 1.439(6) 1.524(8) 1.342(7)

113.8(1) 102.6(1) 114.54(7) 121.4(4) 116.4(4) 124.3(5) 109.8(5)

Fig. 1. Crystal structure with the labeling scheme for compound 2.

0°C and then acetophenone (0.078 mmol) was added. The mixture was then stirred for 5 min and catecholborane (100 ml, 0.94 mmol) was added. The solution was kept without stirring for 48 h at 0°C, diluted with Et2O (5 ml) and quenched with 2 M NaOH (5 ml). The organic phase was separated and the aqueous phase was extracted with Et2O (3 × 5 ml). The combined organic phases were dried over anhydrous MgSO4 and evaporated in vacuo. The crude product was purified by column chromatography (hexane– Et2O, 9:1). The enantiomeric excess was measured by HPLC (a chiral OD column), affording (S)-( −)-1-phenylethanol in 21% ee with 68% yield.

3. Results and discussion

3.1. Synthesis and chemical properties The ligand 1 was prepared readily from the reaction of 3,5-dimethylpyrazole-1-methanol with L-alanine methyl ester hydrochloride and 2,6-lutidine in a 2:1:1

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ratio. The reaction of ZnCl2 with 1 afforded 2 as white crystals after the usual workups. This compound is quite soluble in most chlorinated solvents and THF, yet poorly so in hydrocarbon solvents and diethylether. The structural confirmation for 1 and 2 comes from their 1H NMR spectra, which are as expected.

3.2. Crystal structure of complex 2 Further structural confirmation for 2 is obtained from the X-ray crystal structure as shown in Fig. 1. The geometry around the Zn atom is a distorted tetrahedron containing two nitrogen atoms of pyrazole groups in 1 and two chloro ligands. The nitrogen atom of the L-alaninemethylester group was not bound to zinc, probably due to the large ring strain that would result from the formation of an imaginary metallaazacyclooctane. In the case of N,N-bis[(3,5-dimethyl-1-pyrazolyl)methyl]amine derivatives, however, the central sp3-N atom is coordinated frequently to the central transition metals with the range of bond distances, 2.073(2)–2.191(2) A, [14]. The ZnCl2N2 coordination mode in 2 results in an unusually large chelate ring size such as those found in bis(cysteinyl)thiolates [15] and bis(benzimidazolylmethyl)sulfides [16]. The bond distances ZnN(1) and ZnN(4) are 2.037(4) and 2.069(4) A, , respectively, which are comparable with those observed in related compounds of the type Zn(LL)2, i.e. 2.002(5)–2.007(5) A, with LL being H2B(3,5-Me2Pz)2 and 2.014(3)–2.039(3) A, with LL being H2B[3,5(CF3)2Pz]2 [17], 2.029(3) and 2.157(3) A, in ZnCl2(Clemizole) where Clemizole is 1-(p-chlorophenylmethyl) - 2 - (1 - pyrrolidinylmethyl)benzimidazole [14a], 2.006(3) and 2.008(3) A, in ZnCl2(1,2-dimethylimidazole)2 [14b], and 2.050(3) and 2.074(3) A, in ZnCl2(quinoline) [14c]. The bond distances ZnCl(1) and ZnCl(2) [2.237(2) and 2.235(2) A, ] are also in accordance with those of related complexes which have values in the range of 2.196(2)–2.2509(8) A, [14]. The bond angles of NZnCl are in the range 102.6(1)– 113.8(1)°. The distortion from ideal tetrahedral geometry is a consequence of the opening of the two chloro ligands due to the steric repulsion, but the bond angle NZnN is close to the ideal tetrahedral geometry. The bond angle N(1)ZnN(4) [108.6(2)°] is larger than those found in other related compounds ZnX2(2,2%bis(pyrazolyl-1-ylpropane) [X= Cl, 89.5(1)°; X =Br, 89.8(2); X= I, 90.2(3)°] [18] and ZnCl2(Clemizole) (NZnN: 81.7(1)°) [14a], while it is quite similar to the analogous bond angle in ZnCl2(quinoline)2 (NZnN: 109.3(1)°) [14c]. The angle of 114.54(7)° for Cl(1)ZnCl(2) is nearly the same as that in ZnCl2(MeImOH)2 (MeImOH =2-hydroxy-methyl-1methylimidazole) (114.59(8)°) [19] and that in ZnCl2(quinoline)2 (115.47(5)°) [14c] but is smaller than that found in ZnCl2(Clemizole) (120.18(6)°) [14a].

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3.3. Catalytic enantioselecti6e reduction

Acknowledgements

The enantioselective reduction of ketones catalyzed by chiral zinc complexes has been well established recently and very high enantioselectivity has been accomplished by employing various chiral diimines ligands [20]. Prompted by recent success we have investigated the catalytic enantioselective reduction of acetophenone (Eq. (1)) using in situ Zn(OTf)2/1 as a catalyst.

We gratefully acknowledge the financial support from the Korean Research Foundation Grant (KRF2000-DP-0217) and BK21 program.

(1) The reaction was carried out under the standard set of conditions described in Section 2. The enantiomeric excess is disappointingly low at 21% ee. The low enantiomeric excess may be explained in terms of the chiral center being too distant from the reaction center, with the additional fact that the free rotation of the ester group bearing the chiral center washes out any chiral discrimination formed in the catalyst.

4. Conclusions We have investigated the synthesis and characterization of a Zn complex of a new chiral N-substituted pyrazole including L-alaninemethylester. This study may contribute to the model of NNN donor atoms as the active site of carbonic anhydrase. The catalytic enantioselective reduction of acetophenone promoted by Zn(OTf)2 with 1 in the presence of catecholborane as reductant shows a new catalytic precursor of a chiral pyrazole-based ligand derivative. Through related ligand modification, zinc catalysts of new chiral N-substituted pyrazole derivative ligands could produce significant enantiometric excess. We are currently pursuing research in this area.

5. Supplementary material Crystallographic data for the structural analysis have been deposited with the Cambridge Crystallographic Data Centre, CCDC No. 153776 for compound 2. Copies of this information may be obtained free of charge from The Director, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: + 44-1223-336033; e-mail: [email protected] or www: http://www.ccdc. cam.ac.uk).

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