Non-racemic atropisomeric (thio)ureas as neutral enantioselective anion receptors for amino-acid...

Non-Racemic Atropisomeric (Thio)ureas as NeutralEnantioselective Anion Receptors for Amino-acid Derivatives:Origin of Smaller Kass with Thiourea than Urea Derivatives

CHRISTIAN ROUSSEL,* MIHAELA ROMAN, FEDERICO ANDREOLI, ALBERTO DEL RIO,ROBERT FAURE, AND NICOLAS VANTHUYNE

Laboratoire Stereochimie dynamique et Chiralite, UMR 6180, Chirotechnologies: catalyse et biocatalyse,CNRS-Universite ‘‘Paul Cezanne’’-Aix-Marseille III, Marseille, France

ABSTRACT The synthesis of a limited series of non-racemic atropisomeric 1-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-(hetero)aryl-(thio)ureas is described. UsingNMR titration experiments monitoring the shift of the two NH of the (thio)urea and theC-5 hydrogen of the heterocycle, the binding constants for some optically pure (thio)-ureas with the enantiomers of N-protected amino acid tetrabutylammonium salts were de-termined in CD3CN. The obtained enantioselectivities were modest. Contrary to whatwas expected on the basis of the NH acidity in thiourea versus urea group, the associa-tion constants were smaller with the thiourea than with the corresponding urea. X-raydata, DFT calculations, and NMR provided the explanation of that unexpected behavior:the urea presents a pre-organized (Z,Z) conformation suitable for a double hydrogenbond with the carboxylate anion, the thiourea presents a (Z,E) conformation, which mustbe reorganized in a constrained (Z,Z) conformation in the complex. An intramolecularhydrogen bond between one NH and the thiocarbonyl group of the heterocycle, which ispresent in the thiourea and absent in the urea, might also contribute to the smaller Kass

for the thiourea. The possible implication of these observations in the field of bifunctionalorganocatalysis is briefly discussed. Chirality 18:762–771, 2006. VVC 2006 Wiley-Liss, Inc.

KEY WORDS: supramolecular chemistry; enantiorecognition; association constants;H-bonding; chiral HPLC; heterocycles; atropisomeric thiazolin-2-thione

INTRODUCTION

In the last few years, low molecular non-racemic chiral(thio)ureas have attracted a considerable interest as ‘‘chiralorganocatalysts’’ in the field of asymmetric catalysis1–24 anddynamic kinetic resolution.25,26 Non-racemic chiral (thio)-ureas are also involved as ‘‘neutral enantioselective anionreceptors’’ in molecular recognition aiming at the enantiose-lective binding of carboxylates.27,28 In these enantioselectiveprocesses, the presence of two hydrogen bond donating(HBD) sites on the chiral (thio)urea plays a decisive role. Inthioureas, the HBD abilities of the NH is higher than in thecorresponding ureas29–31 and the acidity of the NH bondcan be further tuned by the substituent attached to the nitro-gen. Achiral (thio)ureas have also found interesting applica-tions as organocatalysts32,33 or neutral anion receptors.34–46

In this report, we introduce a focused library of new atro-pisomeric chiral thioureas 1a–1h, which present two (ormore) hydrogen bond accepting sites and two (or more)hydrogen bond donating sites (see Scheme 1), and weexplore by 1H NMR the enantioselective binding ability of afew of them towards some selected amino acid tetrabu-tylammonium salts.

MATERIALS AND METHODS

NMR spectra were recorded on BRUKER Avance DPX-200 (1H at 200 MHz, 13C at 50 MHz) and on BRUKER

Avance DPX-300 (1H at 300 MHz, 13C at 75 MHz) instru-ments. Chemical shifts are expressed in ppm and referencedto DMSO (1H, d(DMSO) ¼ 2.50; 13C, d(DMSO) ¼ 39.52). Jvalues are reported in Hertz (Hz). 2D-NMR experimentswere performed in DMSO-d6 on a BRUKER Avance DRX-500equipped with a cryoprob and are available in the Supplemen-tary Material. Melting points were measured using a Koflerhot stage apparatus and are uncorrected. The optical rotatorypowers were measured on a 241 MC Perkin-Elmer polarime-ter with a sodium lamp and a double-jacketed cell at 258C.

Chiral HPLC

The analytical chiral HPLC experiments were performedon a unit composed of a Merck D-7000 system manager,Merck-Lachrom L-7100 pump, Merck-Lachrom L-7360,

*Correspondence to: Prof. Christian Roussel, UMR Chirotechnologies,Faculte Sciences St Jerome, Case A62, 13397 Marseille, CEDEX 20,France. E-mail: [email protected] for publication 9 January 2006; Accepted 2 June 2006DOI: 10.1002/chir.20320Published online 26 July 2006 in Wiley InterScience(www.interscience.wiley.com).

This article contains supplementary material available via the Internet athttp://www.interscience.wiley.com/jpages/0899-0042/suppmatContract grant sponsor: Fifth Framework Program, European Commis-sion; Contract grant number: HPRN-CT-2001-00182.

CHIRALITY 18:762–771 (2006)

VVC 2006 Wiley-Liss, Inc.

Merck-Lachrom L-7400 UV-detector, and Jasco OR-1590polarimeter. Retention times Rt in minutes, retention fac-tor ki ¼ (Rti � Rt0)/Rt0 and enantioselectivity factor a ¼k2/k1 are given. Hexane, 2-PrOH, and methanol were ofHPLC grade, degassed and filtered with a 0.45 lm mem-brane before use. Whelk-O1 (S,S) (250 3 4.6 mm), avail-able from Regis (Morton Grove, USA), was used for theanalytical separations.

Semi-preparative separations were performed by succes-sive injections on a Knauer unit composed of a Smartline1000 pump, a Smartline 3900 autosampler, a Smartline 2500UV-detector, and a valve to collect separately the enantiom-ers. Chiralcel OJ (250 3 10 mm), available from ChiralTechnologies (Illkirch, France), was used for the semi-preparative separation of rac-2, in methanol at 5 ml/min,at 508C with UV detection 254 nm, 8 ml of a 8 mg/ml race-mic solution were injected every 32 min. Rt(aS) ¼ 5.01,Rt(aR) ¼ 10.05, k(aS) ¼ 0.78, k(aR) ¼ 2.56, and a ¼ 3.29.

Binding Studies

The experiments were performed as already described.28,47,48

The binding constants were evaluated by fitting the datato a 1:1 binding isotherm, and 1:1 binding was verified inall cases by Job plot. The errors for the reported associa-tion constants were estimated <15%. The absence of sig-nificant self association in the thiourea 1a and urea 1i waschecked by dilution experiments in the working concen-tration range.49,50

Synthesis

The synthesis of rac-2 and resolution to yield (aR)-2and (aS)-2 have been already described.51 The semi-preparative separation of rac-2 into (aR)-2 and (aS)-2 wasperformed for the present study using a chiral stationaryphase composed of tris(4-methylbenzoyl) cellulose (Chir-alcel OJ). rac-3 and its enantiomers (aR)-3 and (aS)-3have been described in previous work.51

rac-1a–h were obtained according to the following gen-eral procedure: 0.90 mmol of isothiocyanate rac-3 weresolubilized in dry acetonitrile (5 ml). Then, 1.05 equiv ofamine was added and the solution stirred for 24 h at roomtemperature. The solvent was partially evaporated and theproduct filtrated. Some modifications of the general proce-dure are reported later for rac-1d, rac-1g, and rac-1h.

rac-1a: 1-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-phenylthiourea. Yield 285 mg (89%); mp 1978C;For NMRs, see Table 4 for complete assignment. C17H15N3S3

requires: C, 57.11; H, 4.23; N, 11.75; S, 26.91. Found: C,57.30; H, 4.25; N 11.80; S, 26.65.

Starting from pure isothiocyanate (aR)-3, (aR)-1a wassynthesized according to the same procedure; mp 1038C,[a]D

25 �615 (c 0.1, CHCl3).

rac-1b: (2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-(pyridin-2-yl)thiourea. Yield 222 mg (69%); mp 2518C;1H NMR (300 MHz, DMSO-d6) d ¼ 1.90 (d, 3H, J ¼ 1.2,CH3); 6.77 (quad, 1H, J ¼ 1.2, H5); 7.00–8.20 (m, 8H, Ar);11.00 (s, 1H, NH); 13.66 (s, 1H, NH); 13C NMR (75 MHz,DMSO-d6) d ¼ 15.2; 107.5; 112.6; 118.47; 127.1; 128.7;128.7; 129.4; 131.8; 136.3; 139.4; 140.0; 145.1; 153.0; 179.2;189.2. C16H14N4S3 requires: C, 53.60; H, 3.94; N, 15.63; S,26.83. Found: C, 53.78; H, 3.99; N 15.63; S, 27.23.

Starting from pure isothiocyanate (aR)-3, (aR)-1b wassynthesized according to the same procedure; mp 2588C,[a]D

25 �307 (c 0.1, CHCl3).

rac-1c: 1-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-(pyridin-3-yl)thiourea. Yield 244 mg (75%); mp 1478C;1H NMR (200 MHz, DMSO-d6) d ¼ 2.00 (d, 3H, J ¼ 1.2,CH3); 6.87 (quad, 1H, J ¼ 1.2, H5); 7.10–8.60 (m, 8H, Ar);8.77 (s, 1H, NH); 10.33 (s, 1H, NH); 13C NMR (50 MHz,DMSO-d6) d ¼ 15.1; 107.3; 122.9; 127.4; 128.6; 129.4;130.3; 130.3; 132.8; 135.6; 135.6; 140.3; 144.3; 145.2; 180.7;188.3; AE C16H14N4S3 þ H2O requires: C, 51.04; H, 4.28;N, 14.88; S, 25.55. Found: C, 50.82; H, 4.22; N 15.22; S,25.53.

Starting from pure isothiocyanate (aS)-3, (aS)-1c wassynthesized according to the same procedure; mp 1288C,[a]D

25 þ607 (c 0.1, CHCl3).

rac-1d: 1-(2-hydroxyphenyl)-3-(2-(4-methyl-2-thi-oxothiazol-3(2H)-yl)phenyl)thiourea. The solvent wasevaporated and replaced with CH2Cl2, and the productcrystallized: yield 306 mg (91%); mp 1808C; 1H NMR (300MHz, DMSO-d6) d ¼ 1.98 (d, 3H, J ¼ 1.2, CH3); 6.83(quad, 1H, J ¼ 1.2, H5); 6.70–7.85 (m, 8H, Ar); 8.69 (s, br,1H); 9.71 (s, 1H); 9.78 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d ¼ 15.4; 107.3; 115.6; 118.6; 125.8; 126.2; 126.2; 127.0;128.8; 129.3; 130.5; 132.7; 136.3; 140.5; 150.1; 180.2; 188.6.C17H15N3OS3 requires: C, 54.66; H, 4.05; N, 11.25; S,25.75. Found: C, 54.30; H, 4.17; N 11.12; S, 25.88.

Starting from pure isothiocyanate (aR)-3, (aR)-1d wassynthesized according to the same procedure; mp 1298C,[a]D

25 �558 (c 0.1, CHCl3).

rac-1e: 1-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-(3,5-dimethylphenyl)-thiourea. Yield 297 mg (85%); mp2308C; 1H NMR (300 MHz, DMSO-d6) d ¼ 2.01 (d, 3H,J ¼ 0.9, CH3); 2.26 (s, 6H, 2 CH3); 6.88 (quad, 1H, J ¼ 0.9,H5); 6.80–7.75 (m, 7H, Ar); 8.23 (s, 1H, NH); 10.17 (s, 1H,NH); 13C NMR (75 MHz, DMSO-d6) d ¼ 15.5; 20.9; 107.6;121.3; 127.0; 127.6; 128.5; 129.6; 130.9; 133.2; 136.2; 137.9;138.2; 140.7; 179.9; 188.3. C19H19N3S3 requires: C, 59.19;H, 4.97; N, 10.90; S, 24.95. Found: C, 59.31; H, 5.06; N10.86; S, 25.30.

Starting from pure isothiocyanate (aS)-3, (aS)-1e wassynthesized according to the same procedure; mp 2108C,[a]D

25 þ784 (c 0.1, CHCl3).

Scheme 1. Atropisomeric chiral thioureas.

763CHIRAL (THIO)UREAS AS ENANTIOSELECTIVE CARBOXYLATE RECEPTORS

Chirality DOI 10.1002/chir

rac-1f: 1-(2-methoxyphenyl)-3-(2-(4-methyl-2-thi-oxothiazol-3(2H)-yl)phenyl)thiourea. Yield 306 mg(88%); mp 1808C; 1H NMR (200 MHz, DMSO-d6) d ¼ 1.99(d, 3H, J ¼ 0.9, CH3); 3.80 (s, 3H, CH3); 6.85 (quad, 1H,J ¼ 0.9, H5); 6.85–7.81 (m, 8H, Ar); 8.63 (s, br, 1H, NH);9.73 (s, 1H, NH); 13C NMR (50 MHz, DMSO-d6) d ¼ 15.4;55.7; 107.3; 111.8; 119.9; 126.4; 126.6; 126.8; 127.2; 128.8;129.4; 130.6; 132.8; 136.3; 140.5; 152.3; 180.7; 188.6.C18H17N3OS3 requires: C, 55.79; H, 4.42; N, 10.84; S,24.82. Found: C, 55.82; H, 4.48; N 10.85; S, 24.72.

Starting from pure isothiocyanate (aS)-3, (aS)-1f wassynthesized according to the same procedure; mp 1538C,[a]D

25 þ547 (c 0.1, CHCl3).

rac-1g: 1-(3-(trifluoromethyl)phenyl)-3-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)thiourea. The solventwas evaporated and replaced with CH2Cl2 (10 ml), then sol-ution was washed with HCl 5% (2 3 10 ml), and the organicphase evaporated to dryness: yield 320 mg (83%); mp1798C; 1H NMR (300 MHz, DMSO-d6) d ¼ 2.00 (d, 3H, J ¼1.2, CH3); 6.87 (quad, 1H, J ¼ 1.2, H5); 7.35–8.15 (m, 8H,Ar); 8.76 (s, 1H, NH); 10.51 (s, 1H, NH); 13C NMR (75MHz, DMSO-d6) d ¼ 15.4; 107.6; 119.0 (quad, J ¼ 4); 120.9(quad, J ¼ 4); 124.0 (quad, J ¼ 272); 126.4; 127.7; 129.0;129.1 (quad, J ¼ 32); 129.7 (2 C); 130.7; 133.2; 135.8; 140.0;140.6; 180.5; 188.6; MS (ESI) m/z 426 (Mþ1)þ.

Starting from pure isothiocyanate (aS)-3, (aS)-1g wassynthesized according to the same procedure; mp 948C,[a]D

25 þ692 (c 0.1, CHCl3).

rac-1h: 1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)thiourea. Thesolvent was evaporated and replaced with CH2Cl2 (10 ml),the solution was washed with HCl 5% (2 3 10 ml), and theorganic phase evaporated to dryness: yield 242 mg (54%);mp 1638C; 1H NMR (300 MHz, DMSO-d6) d ¼ 1.99 (d,3H, J ¼ 1.2, CH3); 6.87 (quad, 1H, J ¼ 1.2, H5); 7.35–8.35(m, 7H, Ar); 9.01 (s, 1H, NH); 10.73 (s, 1H NH); 13C NMR(75 MHz, DMSO-d6) d ¼ 15.4; 107.7; 117.1 (sept, J ¼ 4);122.4 (2 C, quad, J ¼ 3); 123.2 (2 C, quad, J ¼ 273); 128.0;129.2; 129.9; 130.2 (2 C, quad, J ¼ 33); 130.5; 133.1; 135.5;140.5; 141.4; 180.4; 188.6; MS (ESI) m/z 494 (Mþ1)þ.

Starting from pure isothiocyanate (aS)-3, (aS)-1h wassynthesized according to the same procedure; mp 1108C,[a]D

25 þ465 (c 0.1, CHCl3).

rac-1i: 1-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-phenylurea. Thiazoline-thione (0.9 mmol) rac-2 was solu-bilized in acetonitrile (5 ml). Then, 1.05 equiv of phenylisocya-nate was added and the solution stirred for 24 h. The solventwas evaporated and replaced with CH2Cl2 (10 ml), thenthe solution was washed with HCl 5% (2 3 10 ml), andthe organic phase evaporated to dryness: yield 0.84 mmol(93%); mp 2108C; For NMRs, see Table 4 for completeassignment. C17H15N3OS2 requires: C, 59.80; H, 4.43; N,12.31; S, 18.78. Found: C, 59.54; H, 4.43; N 12.23; S, 18.97.

Urea (195 mg) was then crystallized in ethanol for X-ray. Starting from pure thiazoline-thione (aS)-2, (aS)-1iwas synthesized according to the same procedure; mp1848C, [a]D

25 þ371 (c 0.1, CHCl3).

X-ray Analysis

CCDC 254794, 294510, and 294511 contain the supple-mentary crystallographic data for this paper. These datacan be obtained free of charge from The Cambridge Crys-tallographic Data Centre via www.ccdc.cam.ac.uk/data_request.cif

RESULTS AND DISCUSSIONChiral Selectors: Synthesis and Characterization

Thioureas 1a–h were prepared according to scheme 2.The parent amino-thiazoline-2-thione 252,53 was transformedinto the corresponding isothiocyanate 3,51 which was thenreacted with the desired aniline derivatives. This process isvery efficient if one wants to prepare a small library of thio-ureas, since one has to prepare a single isothiocyanate. Itwas preferred to the alternative process where amino-thiazo-line-thione 2 is reacted with the isothiocyanate of the corre-sponding aniline. This later method should be reserved forthe preparation of the urea analogues of 1, since a largevariety of arylisocyanates are commercially available. It wasused to prepare the urea derivative 1i.

The reactions proceeded smoothly at room temperaturein dry acetonitrile and the expected mixed thioureas wereobtained without noticeable formation of the symmetricalones. The formation of symmetrical thioureas is oftenobserved in the reaction of isothiocyanates with aminesdue to the reversibility of the reaction, which cross-splitsthe dissymmetrical thiourea into the isothiocyanate of theengaged amine and amine of the engaged isothiocya-nate.42 The very high selectivity of the reaction might arisefrom the presence of the sulfur atom of the thiazoline-thione, which might strongly direct the possible decompo-sition of the thiourea towards the initial isothiocyanate andamine through intramolecular hydrogen bond. A noticeableexception, which supports the above argument, wasobserved in the case of the reaction between 3 and the thi-azoline-2-one analogue of 2. In that case, a complex mixture

Scheme 2. Synthesis of thioureas 1a–h from amino-2-thiazoline 2.

764 ROUSSEL ET AL.


of dissymmetrical and symmetrical thioureas (includingdiastereomeric forms) was obtained (data not shown).

Racemic amino-thiazoline-thione 2 can be resolved intoenantiomers by semi-preparative chiral chromatographyon various chiral stationary phases and operating condi-tions (see experimental). The barrier to rotation in 2 wasestimated to be larger than 145 kJ/mol and thus it is highenough to give stable atropisomers during further chemi-cal transformations. In our initial report about the enan-tiomers of 2, they were nicely obtained by semi-prepara-tive chiral HPLC on Chiralcel OD column (250 3 10 mm),eluted with a mixture hexane–ethanol (1/1).51 The pro-ductivity of the separation was found to be largely im-proved using Chiralcel OJ eluted with pure methanol at508C. The use of a single solvent is a decisive advantagefor semi-preparative separation.

From the isolated pure enantiomers of 2, optically pureisothiocyanates 3 were prepared without racemization. Thebarrier to rotation in 3 (>145 kJ/mol) is high enough topreserve the configurational integrity of the starting aminothiazoline-thione during the synthesis process. The configu-rational stability was checked on immobilized amylosetris(3,5-dimethylphenylcarbamate) (Chiralpak IA from Dai-cel), which tolerates a large variety of eluents and cleanlyseparated racemic 3 using a mixture of hexane/CHCl3(1/1).51 An alcoholic modifier in the mobile phase shouldnot be used, since we observed, under these conditions, aslow transformation of the isothiocyanate group into the

corresponding thiocarbamate at room temperature. The thio-carbonyl group of the heterocycle is probably situated in asuitable position to catalyze the reaction. Separation on ana-lytical Chiralpak IA column was found suitable for obtainingsome milligram of pure enantiomers in order to determinethe specific rotation of the enantiomers of 3.51

The absolute configuration of enantiomers of 2 hadbeen determined after X-ray analysis of the urea 1j result-ing from the reaction of (�)-2 with (S)-1-(1-naphthyl)ethylisocyanate.54 It was shown that the (�)-2 (sign in CHCl3)enantiomer is (�)-(aR)-2. We learned from the X-ray thatthe conformation of the urea group in the crystal is suit-able to provide a double hydrogen bond donating site (seeFig. 1). The urea framework is coplanar with the N-arylgroup and perpendicular to the heterocyclic plane.

Thus starting from optically pure 2 of known absoluteconfiguration, optically pure thioureas 1 with the same ab-solute configuration were obtained. The absolute configu-rations and the associated specific rotations of thioureas1a–h are given in Table 1.

It was of interest to propose an alternative process in whichthe optically pure thioureas 1a–h and urea 1i were obtainedby chiral HPLC of the racemic precursors. However, in thisprocess the absolute configuration of the separated enantiom-ers is not directly available and should be determined after-wards through hydrolysis of the thiourea to yield 2.

The enantioseparations are reported in Table 1. All thethioureas and urea were nicely separated on the (S,S)Whelk O1 (Table 1) using hexane/2-PrOH 8/2 (v/v) forcharacterization purposes. Interestingly, for all the deriva-tives, the same elution order was observed as is the casefor series of homologous compounds on Whelk O1 col-umn.54 However, the solubility and the stability of thecompounds in hexane/alcohol mixtures were not suitablefor semi-preparative separation.

Binding Studies via 1H NMR

The atropisomeric thioureas are poorly soluble in CDCl3and thus the binding studies with the tetrabutylammoniumsalts of diverse N-acetyl amino-acids were performed inCD3CN. In this solvent, the two NH protons of the thio-urea appeared well separated in a clean region of the spec-tra, one of them between 7.7 ppm and 7.95 ppm and theother between 8.5 ppm and 8.83 ppm depending on thearyl group. Upon addition of the tetrabutylammonium salt

Fig. 1. Structure of the urea 1j obtained by X-ray diffraction analysis.

TABLE 1. Specific rotation and chiral HPLC data on Whelk-O1 (S,S)a

Rt1 (aS) k1 Rt2 (aR) K2 a Rs [a]D25

2 15.94 (þ) 4.24 20.35 (�) 5.69 1.34 3.70 (aS): þ414 (c 0.5, CHCl3)1a 11.31 (þ) 2.65 16.91 (�) 4.45 1.68 6.27 (aR): �615 (c 0.1, CHCl3)1b 13.15 (þ) 3.36 17.81 (�) 4.90 1.46 4.02 (aR): �307 (c 0.1, CHCl3)1c 33.42 (þ) 10.07 49.75 (�) 15.47 1.54 4.61 (aS): þ607 (c 0.1, CHCl3)1d 10.72 (þ) 2.55 15.34 (�) 4.08 1.60 5.17 (aR): �558 (c 0.1, CHCl3)1e 9.24 (þ) 2.06 13.92 (�) 3.61 1.75 5.91 (aS): þ784 (c 0.1, CHCl3)1f 18.31 (þ) 5.06 29.65 (�) 8.82 1.74 8.04 (aS): þ547 (c 0.1, CHCl3)1g 7.25 (þ) 1.34 9.74 (�) 2.14 1.60 4.27 (aS): þ692 (c 0.1, CHCl3)1h 5.21 (þ) 0.68 6.52 (�) 1.10 1.62 2.67 (aS): þ465 (c 0.1, CHCl3)1i 6.47 (þ) 1.09 8.28 (�) 1.67 1.54 3.75 (aS): þ371 (c 0.1, CHCl3)

aHexane/2-PrOH 8:2, 1 ml/min, 258C, detection UV 254 nm, and polarimeter.



of amino-acid, the two NH protons were shifted downfieldup to �5 ppm depending on the amount of added salt,whereas the hydrogen in position 5 of the thiazoline-2-thionewas shifted upfield up to 0.4 ppm under the same conditions.Using NMR titration experiments, monitoring the shift of thetwo NH of the thiourea and the C-5 hydrogen of the hetero-cycle, we obtained the 1-1 binding constants for opticallypure thioureas 1a, 1c, and 1g with the enantiomers of N-pro-tected amino-acid tetrabutylammonium salts (Table 2).

The association constants are modest in acetonitrile, theyincrease when the phenyl group of the parent thiourea 1ais replaced by a more electron-attracting group such as 3-pyridyl 1c or substituted by a 3-CF3 1g, reflecting theincrease of the acidity of the NH group. The very acidic thi-ourea 1h with the 3,5-CF3-phenyl group showed a singularbehavior since upon addition of the salt; one of the NH pro-

tons presented a downfield field, as usually, up to a maxi-mum and then started shifting upfield. This particularbehavior might indicate a full proton transfer as it has beenshown recently in the association of neutral acidic (thio)-ureas with carboxylate anion or fluorine anion.55–58

(aR)-1a poorly discriminated the enantiomers of N-Ac-Phe-CO2

� (NBu4)þ, with a larger binding constant for the

L-enantiomer than for the D-antipode. Valine enantiomerswere not discriminated in spite of higher binding constants.Discrimination of N-Ac-Phe-CO2

� (NBu4)þ enantiomers was

also observed for (aS)-1c but it was lost for (aS)-1g.Urea 1i poorly discriminated the tetrabutylammonium

salts of N-Ac-Phe and N-Ac-Val. However, N-Ac-Leu andN-Ac-Trp salts were discriminated. Tetrabutylammoniumsalt of (þ)-(S)-Naproxen discriminated the enantiomers ofrac-1i.

TABLE 2. Binding constants (Kass) for the 1:1 complexes formed between thioureas 1a, 1c, 1g, and urea 1i andtetrabutylammonium salts of some N-Acetyl amino-acid or Naproxen in CD3CN at 208C (1H NMR titration)

Chiral selectorsN-Ac-amino-acid

tetrabutylammonium saltAssociation constants

(M�1) Discrimination

(L)-N-Ac-Phe-COO� 540 L/D 1.60(D)-N-Ac-Phe-COO� 330(L)-N-Ac-Val-COO� 600 D/L 1.15a

(D)-N-Ac-Val-COO� 700

(L)-N-Ac-Phe-COO� 1150 D/L 2.00(D)-N-Ac-Phe-COO� 2300

(L)-N-Ac-Phe-COO� 800 D/L 1.20a

(D)-N-Ac-Phe-COO� 960

(L)-N-Ac-Phe-COO� 1250 L/D 1.25a

(D)-N-Ac-Phe-COO� 1550(L)-N-Ac-Val-COO� 2150 D/L 1.10a

(D-N-Ac-Val-COO� 2350

(aR)-1i (L)-N-Ac-Leu-COO� 2750 1.42(aS)-1i 3900(aR)-1i (S)-Naproxenate 1330 1.43(aS)-1i 1900(aR)-1i (L)-N-Ac-Trp-COO� 825 1.47(aS)-1i 1150

aRatio less than 1.3 are under the limit of confidence.

766 ROUSSEL ET AL.


The most intriguing result is that contrary to expecta-tion based on the well documented relative acidity of theNH proton in urea and thiourea, the urea 1i gave higherbinding constants than the corresponding thiourea 1a. Toprovide a plausible explanation for that unexpected behav-ior, we focused our attention on the possible difference inconformation in thiourea 1a and urea 1i using X-ray analy-sis (solid state), DFT calculations (gas phase), and com-plete NOESY assignment (solution).

X-ray analysis (solid state). In urea 1i, the ureidogroup adopts a (Z,Z) conformation as we have already ob-served in urea 1j, whereas in 1a a (Z,E) conformation ispreferred as in a large majority of the reported structuresfor 1,3-dissymmetric acyclic thioureas (Fig. 2).59 In somecases, (Z,Z) conformation was observed in thioureas bear-ing on the nitrogen one or two secondary alkyl groups,60

these ‘‘Janus’’ groups61 adopt a conformation in which themethine proton is directed toward the sulfur thus offeringthe minimal interaction. The occurrence of a (Z,Z) confor-mation in 1i and a (Z,E) conformation in 1a is not the solestriking difference in the two structures, the urea groupstands into a plane, which is nearly coplanar with the twoN-aryl groups in 1i, whereas in 1a the thiourea plane isnearly perpendicular to both the N-aryl groups. It resultsfrom these two very different conformations that an intra-molecular H-bond between the thiocarbonyl group of theheterocycle and the nearby NH is detected in the thiourea,and such an intramolecular H-bond is not observed in theurea. Inspection of the Cambridge Crystallographic data-base reveals that a full planar (Z,Z) conformation is found

for N,N0-diphenyl urea, whereas a twisted (Z,E) conforma-tion is observed for N,N0-diphenylthiourea in close agree-ment with our observation in 1i and 1a, respectively(Peseke K, Goetze L, Reinke H, private communicationCCDC 127327, 1999; Hursthouse MB, Hibbs DE, TebbyJC, private communication CCDC 216331, 2003; LynchVM, private communication CCDC 212684, 2003).

DFT calculations (gas phase). Some interesting infor-mation have been obtained from the X-ray data but as usu-ally one may argue that packing interactions are responsi-ble for the observed conformations. Density functionaltheory (DFT) calculations were performed using B3LYPhybrid functional and 6-31G** basis set throughout. Allcalculations were performed with Gaussian 98 softwarepackage running on a biprocessor 2.4 GHz workstation.62

Single point energy calculations were done on crystallo-graphic structures of the urea 1i and of the thiourea 1a.Further optimizations of these structures were carried out,respectively, on (Z,Z) and (Z,E) conformations. Since theflexibility of the structures is limited to the atropisomericdihedral angle and, for a little extent, to the thiourea- andurea-CN bonds, no constrains have been imposed duringoptimizations. The energies obtained via quantum wave-functions were consistently compared for the urea deriva-tive 1i and the thiourea derivative 1a (Table 3). In the caseof urea 1i, the (Z,Z) conformer is the most stable one com-pared to the (Z,E), with an energy difference of 1.10 kcal/mol (Table 3). The more stable (Z,Z) conformer located byquantum chemical calculations is the one observed for 1iin the X-ray analysis as shown in Figure 2.

Fig. 2. Structures of the urea 1i and of the thiourea 1a obtained by X-ray diffraction analysis.

TABLE 3. DFT calculations for urea 1i and thiourea 1a

Atomic units Relative energies (au) Relative energies (kcal/mol)

Urea (1i) X-ray structure (Z,Z) �1692.55843434 0 0Z-Z conformation �1692.75705029 �0.19861595 �124.63Z-E conformation �1692.75528805 �0.19685371 �123.53

Thiourea (1a) X-ray structure (Z,E) �2015.29258593 0 0Z-Z conformation �2015.70334872 �0.41076279 �257.76Z-E conformation �2015.70665905 �0.41407312 �259.83

(Z,Z) and (Z,E) conformers were fully optimized and their energies compared. The energy of the single point calculation obtained on experimental crys-tallographic structure has been taken as zero reference.



The same analysis for the thiourea 1a (Table 3) revealsthat the stable conformer in this case is the (Z,E) form andthat the (Z,Z) conformation is 2.07 kcal/mol less stable.Here again the more stable conformer located by quantumchemical calculations is the same as the one observed inthe crystal structure shown for 1a in Figure 2.

In summary, the same preferred conformations wereobtained by X-ray analysis and DFT calculations. The car-toons of the DFT calculations are given in the supplemen-tary material.

NOESY assignment (solution). The full assignment ofall the hydrogen and carbon in urea 1i and thiourea 1a isreported in Table 4. Valuable conformational information

was obtained by considering the chemical shift of the protonattached to carbon 10. In urea 1i, it appears at 8.10 ppm inagreement with a cis coplanar arrangement with the carbo-nyl group of the urea; in thiourea 1a, it appears at 7.73 ppmin agreement with a through space shielding arising from aperpendicular arrangement of the thiourea and the aryl group.More interesting was the comparison of chemical shifts forcarbon 6 and carbon 10, which are flanking the (thio)ureagroup and for which one expected an identical change ongoing from urea to thiourea for symmetry reasons: carbon 6in urea 127.7 ppm, carbon 6 in thiourea 133.1 ppm (Dd ¼ 5.4ppm), carbon 10 in urea 122.9 ppm, carbon 10 in thiourea130.8 ppm (Dd ¼ 7.9 ppm). If one takes as a reference theobserved Dd ¼ 5.1 ppm for carbon 20, carbon 10 is signifi-cantly more shielded than expected in the urea. In 1i, theobservation of an anomalous shielding for the carbon 10 asso-ciated with an anomalous deshielding for C10-H is consistentwith the occurrence of an H-bond between the oxygen of theurea and the proton C10-H (X-ray distance 2.46 A), which isabsent in the thiourea. Etter and coworkers have already sug-gested that an intramolecular H-bond between a relativelyacidic ortho C��H bond of an aromatic system and a urea car-bonyl group may play a role in cocrystallization studies.63

Such an intramolecular H-bond would serve to enhance inter-molecular H-bonding ability by acidifying the N��H bonds.

NOESY correlations were particularly relevant to assignon a qualitative basis the conformations in solution. Figure 3shows that a strong correlation existed between the twoN��H in 1i, whereas a weak one was obtained in 1a. Fur-thermore the NaH in 1i did not show a correlation with theprotons in positions 20 and 10, whereas significant oneswere observed in the case of 1a. All these arguments mili-tated in favor of a (Z,Z) conformation in the case of 1i and ofa largely populated (Z,E) conformation in 1a.

In summary, from the analysis of the data provided byX-ray, DFT calculations, and NMR solution, we drewtogether a large number of evidences that in the urea 1i a(Z,Z) conformation is largely preferred whereas in the thio-urea 1a a (Z,E) conformation is largely preferred. Thesetwo different conformations are at the origin of (or issuefrom) one intramolecular H-bond between the Na��H andthe thiocarbonyl group of the heterocycle in 1a and oneintramolecular H-bond between the ortho C10��H of thearomatic system and the urea carbonyl group in 1i.

TABLE 4. Full NMR assignment in urea 1i and thiourea 1a

Atom

Proton Carbon

(1a) (1i) (1a) (1i)

1 – – 188.5 189.23 6.86, q 6.90, q 107.5 107.84 – – 140.6 140.06 – – 133.1 127.77 7.35, d 7.17, d 128.7 129.18 7.43, t 7.19, t 127.5 123.79 7.53, t 7.46, t 129.5 129.910 7.73, d 8.10, d 130.8 122.911 – – 136.1 135.812 – – 180.2 152.310 – – 138.6 139.320 7.45, d 7.40, d 123.3 118.130 7.31, t 7.25, t 128.7 128.840 7.13, t 6.95, t 124.9 122.0CH3 1.98, d 1.83, d 15.4 14.9NHa 8.43 7.69 – –NHb 10.24 9.15 – –

Fig. 3. NOESY correlations in thiourea (1a) and in urea (1i).

768 ROUSSEL ET AL.


As it was shown by the NH NMR shifts upon addition ofthe carboxylate anion, the two NH of the thioureas andurea were participating in the binding of the bidendateanion. It indicated that a (Z,Z) conformation was attainedin both complexes. The internal steric strain in theinduced (Z,Z) form of the diaryl-thioureas might accountfor the smaller binding constants we observed in thioureascompared to the urea. In the case of urea 1i, the structureis already pre-organized in a (Z,Z) form to afford the dou-ble hydrogen bonding.

Furthermore, in 1a the intramolecular H-bond betweenthe N��H and the heterocyclic thiocarbonyl group mightdecrease the availability of the NH for binding, on the con-trary in 1i the intramolecular H-bond between the C��Hof the aromatic and the urea carbonyl group mightenhance the binding capability of the N��H through a‘‘cooperative polarization effect.’’34 These different behav-iors are originating from the higher basicity of the car-bonyl group compared to the thiocarbonyl group andreciprocally from the higher acidity of the NH in thioureathan in urea. Figure 4 summarizes the two hydrogen bond-ing situations that might affect the binding.

Search in the literature for structures having a thioureaor a urea in the vicinity of a Lewis base reveals some inter-esting cases in which the presence or the absence of intra-molecular H-bond might account for unexpected experi-mental results.

Kilburn, De Mendoza and coworkers in their very inter-esting study of enantioselective amino acid recognitionusing acyclic thiourea receptors have compared the bind-

ing of two thiourea receptors (2a) and (2b) (see Scheme 3)towards tetrabutylammonium phenylacetate.28 The bindingconstant was slightly weaker with pyridyl receptor. Theauthors concluded ‘‘the pyridyl receptor may be more pre-organized for binding as desired, but the absolute binding ofthe carboxylate anion may be disfavored by electrostaticrepulsion between the anion and the pyridine nitrogen lonepair . . . ’’ The concept of an electrostatic repulsion is particu-larly appealing and could also be invoked in our observa-tions; however, an explanation based on the attested exis-tence of a strong intramolecular H-bond between the pyridylnitrogen and the thiourea NH’s might also account for theweaker binding in the pyridyl receptor.

Takemoto’s bifunctional organocatalyst (3a) and (3b)(see Scheme 3) proved to be very efficient in many con-densation reactions or in the DKR. In 2005, Takemoto andcoworkers22 and Berkessel et al.25 published independ-ently the X-ray structure of the thiourea (3b) and of theurea (3a), respectively. Inspection of the CIF files revealsthat both urea and thiourea are in the crystal in a (Z,Z)conformation already suitable for a double binding; aninteresting point is that in the thiourea the distancebetween the hydrogen of the N��H and the nitrogen ofthe tertiary amine is shorter than in the urea analogue(2.69 A versus 2.89 A). This could be taken as an indica-tion of an H-bond in the case of the thiourea. Takemotoand coworkers22 mentioned the intramolecular H-bond inthiourea to explain a better solubility of the catalyst andBerkessel et al.25 stated that there is no intramolecular H-bond in the urea. The fact that a stronger intramolecularH-bond is developed in the thiourea (3b) might accountfor the cases in which the thiourea catalyst, contrary toexpectation, is less efficient than the urea analogue. Fur-ther inspection of the data involving catalysts (3a) and(3b) is underway.

CONCLUSIONS

We have prepared a series of non racemic atropisomeric(thio)ureas starting from the atropisomers of N-(2-amino-phenyl)thiazoline-2-thione, which are easily obtained in anoptically pure form by semi-preparative chiral chromatog-raphy from the racemate. These thioureas were tested as

Fig. 4. Possible influence of intramolecular hydrogen bond on bindingcapacity.

Scheme 3. Acyclic thiourea receptors: (2a) and (2b) described by Kilburn and coworkers,28 (3a) and (3b) described by Takemoto andcoworkers.22



neutral anion receptors and they showed moderate bind-ing affinities and discrimination towards some amino-acidsderivatives. The thiourea derivatives were not in a suitable(Z,Z) conformation to allow a direct double H-bonding withthe carboxylate anions. The energy cost adjusting the struc-ture to obtain the observed double H-bonding is unfavora-ble for a high binding. In contrast, the urea analogue was ina suitable conformation for binding and higher associationconstants were obtained. We have shown that intramolecu-lar H-bonding might also play a role in the fine tuning ofthe binding. Intramolecular H-bonding might lead to activa-tion or deactivation according to the site of bonding. Keep-ing in mind that N-(2-aminophenyl)-thiazoline-thiones areeasily prepared from CS2, 1,2-diaminobenzene and 1-chloro-propan-2-one, a large diversity of urea analogues, can beprepared to optimize the enantioselective recognition.

ACKNOWLEDGMENTS

We thank the ‘‘Conseil General des BdR,’’ ‘‘Conseil Re-gional PACA,’’ and ‘‘Fonds Europeens de DeveloppementRegional’’ for the chiral chromatography unit. We thank Dr.M. Giorgi (Universite Paul Cezanne, Marseille) for data col-lection and structure resolution (1i and 1j). For compound1a, we thank Dr. J.-C. Daran (Universite Paul Sabatier, Tou-louse) for data collection and Dr. Gerard Pepe (Universitede la Mediterranee, Marseille) for structure resolution.

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