Molecular structure, characterization and stereochemicalproperties of new biologically interesting

3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones

G. Giorgia,* , L. Salvinia, A. Andreanib, A. Locatellib, A. Leonib

aCentro Interdipartimentale di Analisi e Determinazioni Strutturali, Universita` di Siena, Via Aldo Moro-53100 Siena, ItalybDipartimento di Scienze Farmaceutiche, Universita` di Bologna, Via Belmeloro 6, 40126 Bologna, Italy

Received 17 August 1999; accepted 1 December 1999

Abstract

New biologically interesting 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones have been investigated by using X-raycrystallography, mass spectrometry, tandem mass spectrometry and theoretical calculations. The study has allowed to obtaininformation on the structural characterization of the stereoisomers and their conformational properties.q 2000 Elsevier ScienceB.V. All rights reserved.

Keywords: X-ray crystallography; Molecular orbital calculations; 2-Indolinone derivatives; Thiazole compounds

1. Introduction

Imidazo[2,1-b]thiazole and indole derivatives mayhave interesting pharmacological activities. Manyanalytical tools are available for their structuralcharacterization as well as for that of different con-formers. In particular, X-ray crystallography and massspectrometry can give useful and complementaryinformation in the structure elucidation of a givenspecies. The integration of experimental methodswith theoretical calculations can help in the interpret-ation of the data and in obtaining insight into thestructural and electronic properties responsible forthe intrinsic activity of prototype compoundsbelonging to a given series.

The interest in pharmacologically active

imidazo[2,1-b]thiazole [1–3] and indole [4–6] deriv-atives led to the synthesis of 3-(5-imidazo[2,1-b]thia-zolylmethylene)-2-indolinones which showedboth antitumor and cardiotonic activity [7].These compounds have been obtained either aspure stereoisomers or as a mixture ofE and Zisomers.

In the present work our attention is focused on somemembers (1–3, Scheme 1) of this new series. Crystalstructure determination of compound1 as wellcharacterization by mass spectrometry, tandem massspectrometry and theoretical calculations ofcompounds1–3 are presented.

2. Experimental

Compounds1–3 have been synthesized and puri-fied as previously reported [7]. Compound1 was crys-tallized from ethanol solution and a single crystal has

Journal of Molecular Structure 524 (2000) 189–199

0022-2860/00/$ - see front matterq 2000 Elsevier Science B.V. All rights reserved.PII: S0022-2860(99)00463-9

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* Corresponding author. Tel.:139-0577-234-135; fax:139-0577-234-137.

E-mail address:ciads@unisi.it (G. Giorgi).

been submitted to X-ray analysis. The synthesis of thetrimethylsilyl derivative of1 (4) has been carried outby dissolving some crystals inN,O-bis(trimethyl-silyl)trifluoroacetamide (30ml)(Fluka) and heatingfor 30 min at 808C. Deuterium labeling at the –NHposition was obtained by dissolving 1 mg ofcompound 1 in CD3OD and D2O (Fluka, NMRgrade) and allowing the solution to stay at roomtemperature for a few days.

2.1. Mass spectrometry

Mass spectra were measured on a double focusingVG 70-250S mass spectrometer (VG Analytical Ltd,Manchester, UK) operating in the electron ionizationmode at 70 eV, emission current 0.2 mA, with asource temperature of 1808C. The acceleratingvoltage was 8 kV and the resolution was 1000 or8000 M/DM (10% valley), the last value used in thehigh resolution regime. The samples were introducedin the ion source via the direct inlet without heatingthe probe.

MS/MS experiments for detection of daughter andparent ions, as well as elimination of neutral specieshave been carried out by appropriate linked scansbetween the electrostatic and the magneticanalyzers.

2.2. X-ray crystallography

Crystal data. 1. C15H11N3OS, M � 281:3;Monoclinic, a� 8:317�1�; b� 9:880�2�; c�15:961�12� �A; b � 91:17�1�8; V � 1311:3�3� �A3 (byleast-squares refinement of 50 randomly selectedand automatically centered reflections), space groupP21=c (n. 14), Z � 4; F�000� � 584; Dc �1:425 g cm23

; m�MoKa� � 0:245 mm21:

The data were collected on a Siemens P4 four-circle

diffractometer with graphite monochromated MoKaradiation�l � 0:71069 �A� in the range29 # h # 9;211 # k # 1; 218 # l # 1; v scan mode for 2:4 #Q # 25:08 scan range, scan width 0.968, constant scanspeed 3.08 min21. Three standard reflectionsmeasured every 97 reflections showed no variations.2887 total reflections�Rint � 0:05� were collected at228C. Absorption correction obtained by psi scanswas applied.

The structure was solved by direct methods imple-mented inshelx-97 [8]. The refinement was carriedout by full-matrix anisotropic least-squares onF2

for all reflections for all non-H atoms by usingshelx-97 [8]. The hydrogen atoms were localized inthe Fourier map and included in the structure-factorcalculations.

The final refinement of 225 parameters gaveR1 �0:048 andwR2 � 0:095 forF 2 . 2s �F2�: Weightingscheme wasw� 1=�s2�Fo�2 1 0:0469P2 1 0:0317P�;whereP� �Fo

2 1 2Fc2�=3: Minimum and maximum

height in the lastDr map were20.21 and 0.26e A23,respectively. Atomic scattering factors includingf 0 and f 00 were taken from Ref. [8]. Geometricalcalculations and molecular graphics were performedby using parst [9] and shelxtl [10] packages,respectively.

2.3. Theoretical calculations

Semiempirical calculations have been performedusing the modified neglect of differential overlap(MNDO) method [11] included inGaussian 94package [12] implemented on a supercomputer Origin2000 at Cineca in Bologna.

For 1 X-ray data were taken as the startinggeometry to study theE configuration. For theZconfiguration, as well as for compounds2 and3, thestarting geometries were built by modifying thedata of 1. A potential energy study has beencarried out by varying the torsion angle H(11)–C(10)–C(5)–N(4) by increment sizes of 108 in therange 0–3608. At each step, a full optimizationwithout any restraint was performed. The lowestenergy geometries were confirmed as a minimum onthe molecular potential energy surface by normal-mode vibrational frequency calculations that pro-duced all real frequencies.

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199190

Scheme 1.

3. Results and discussion

3.1. Mass spectrometry and MS/MS experiments

The electron ionization mass spectra of1–3 arereported in Fig. 1. For all the compounds, themolecular ions correspond to the base peak. Thissuggests that after the one-electron removal, highlystable radical cations are produced in the gas phase,which are able to well delocalize the positive chargeand the unpaired electron over the heterocyclicsystems. Fragmentations for1 and2 are quite scarceproducing ions with relative intensities generally lessthan 15%. Compound3 shows more extendedunimolecular fragmentation reactions occurring inthe ion source (Fig. 1).

For 1 the most abundant fragment ions are atm/z280 and 264 with relative intensities equal to 25 and38%, respectively. While the former ions areproduced by the loss of a hydrogen atom, the latterions are due to the loss ofzOH, as shown by accuratemass measurements (measured 264.0593 calcd.264.0595). This fragmentation, also occurring for2,is an unusual pathway for this class of compounds. Infact ions [M–OH]1 are produced neither by oxindolenor by a series of its derivatives characterized recently[13]. On the contrary, the losses of CO and HCOz/(H z,CO), both observed for1 and2, are typical frag-mentation processes for oxindoles [14].

To get an insight into the fragmentation processes,the trimethylsilyl derivative of1, that is4, and its N-d2

derivative have been synthesized. The electron ioni-zation mass spectrum of4 shows that the molecularion (m/z353) corresponds to the base peak. As typicalfor trimethylsilyl derivatives, the loss of a methylradical yields intense fragment ions (m/z338, 30%),and the species [Si(CH3)3]

1 is present with high abun-dance (50%). Unlike the mass spectrum of1, thelosses of CO and of 29 u are undetected. On thecontrary, fragment ions at [M2 17]1 are still present,and ions atm/z264 are quite abundant. Accurate massmeasurements confirm that they are due to [M–OH]1

and [M–OSi(CH3)3]1, respectively. These data can be

reasonably explained by considering that thezOH lossinvolves the hydrogen bound to the exocyclic methinegroup yielding a ring expanded structure. This is alsoconfirmed by the N-d2 derivative of 1 whose massspectrum shows prevailing losses ofzH and zOH, in

respect to those ofzD and zOD, suggesting that theH(–N) atom is not involved in these fragmentations.

In contrast to 1 and 2, the mass spectrum ofcompound 3 does not show abundant loss of ahydrogen atom, neither the loss of 17 u from themolecular ion (Fig. 1, bottom). For this compound,the fragmentation pathways yield abundant ions atm/z 372, 344, 343, attributable to the losses ofzOCH3, (zOCH3 1 CO), (zOCH3 1 HCOz), respec-tively. Unlike 1 and2, ions differing 100 u from themolecular ion are also produced by fragmentationpathways of3. In their formation, the dimethoxy-phenyl substituent plays a key role (see below).

In order to get more structural information, tandemmass spectrometry experiments have also been carriedout on molecular and main fragment ions formed inthe source by1–3. The metastable spectrum producedby the molecular ion of1 shows that the prevailingdecompositions involve the loss of a hydrogen radicaland the loss ofzOH (Fig. 2, top). A metastable decom-position involving the loss of CO also occurs, but it ismuch less favored than the previous two ones.

The metastable daughter ion spectrum obtained byselecting the fragment ions atm/z 264 as the mainbeam shows neutral losses of CH3CN, CS, C2H2 andHCN, producing ions atm/z223, 220, 238 and 237,respectively, and that of the radicalzSH. Ions atm/z179 may be reasonably attributed to two successiverapid reactions involving losses of CS, CH3CN whoseoverall kinetics is faster than the flight time of the ionsin the first field-free region. The metastable spectra ofthe ions atm/z264 produced in the ion source by1 and4 are superimposable, suggesting the same reactingion structure.

Differently from 1, the most abundant metastabledecomposition produced by molecular ion of2involves the loss of CO, yielding ions atm/z 315,that carry most of the total ion current. (Fig. 2,middle). While in the mass spectrum produced byhigh internal energy ions the species atm/z315 and314 show almost the same abundance (35 and 34%,respectively), decompositions by low internal energyions yield quite exclusively ions due to the loss of CO(Fig. 2, middle). As it occurs for1, the species[M–H] 1 and [M–OH]1 are also observed. The othermetastable ions have very low relative intensities(,3%). Reasonable rationalizations of the metastabledecompositions of1 and2 are depicted in Scheme 2.

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199 191

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199192

Fig. 1. Comparison between the electron ionization (70 eV) mass spectra of1 (top), 2 (middle) and3 (bottom).

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199 193

Fig. 2. Metastable daughter ion mass spectra produced by molecular ions of1 (top), 2 (middle) and3 (bottom).

The substitution at the imidazole ring by the2,5-dimethoxyphenyl group, as it occurs in3, givesrise to considerable changes in the metastable decom-positions. In fact, in addition to the losses ofzH andCO, observed for1 and2, other fragmentation path-ways result to be favored (Fig. 2, bottom). Theseconsist in the loss of methyl and methoxy radicalsand the formation of ions atm/z 344 attributable totwo successive decompositions involvingzOCH3 andCO. The most abundant ions are atm/z303, differing100 u from the molecular ion, probably due to two fastsuccessive processes. As ions atm/z 303 are alsoproduced by metastable fragmentations of the species[M 2 15]1 (m/z388), the remaining loss of 85 u canbe reasonably attributed to the neutral thiazole. Andindeed it is confirmed by neutral loss scans of 85 u andby the elemental composition of ions atm/z303 deter-mined by accurate mass measurements. The MS/MSspectrum obtained by selecting the species atm/z303shows ions atm/z 288, 275, 260, 244 and 158,suggesting the presence of a methyl group, CO andthe intact indolinone. A reasonable structure of theseions, together with main fragmentation pathways for3are depicted in Scheme 3.

3.2. X-ray results

Atomic coordinates and equivalent isotropicthermal parameters for1 are reported in Table 1while its molecular structure is depicted in Fig. 3.Selected geometrical parameters are reported inTable 2.

The indolinone moiety shows metrical and topo-logical parameters close to those found in analogousstructures [15,16]. The bond length C(12)–O(11) isequal to 1.223(4) A˚ and within the e.s.d. to values of1.211 [15] and 1.213(8) A˚ [16] found in analogousstructures. The exocyclic bond Csp2yCsp2 is equal to1.334(4) A, shorter than both the values found in(E)-3-(30-methyl-20-butenylidene)-2-indolinone(1.357 A) [15], and in (E,E)-1-acetyl-3-(10-(p-bromophenyl)-30-ethoxycarbonyl-allylidene)-2-oxoindoline (1.373(9) A˚ ) [16]. The torsion angleC(5)–C(10)–C(11)–C(12), relevant to the mutualorientation of the two fused heterocyclic systems, isequal to2173.2(3)8.

The two distances S–C are quite close each other,being 1.731(3) and 1.736(4) A˚ for S(1)–C(8) andS(1)–C(2), respectively. The bond length S(1)–C(8)

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199194

Scheme 2.

G.

Gio

rgie

ta

l./

Jou

rna

lof

Mo

lecu

lar

Stru

cture

52

4(2

00

0)

18

9–

19

9195

Scheme 3.

is longer than the corresponding values found inchloro(ethylendiamine)(6-phenylimidazo[2,1-b]thiazole-N7)Pt(II) nitrate (1.716(5) A˚ ) [17]and in 7-methyl-6-phenylimidazo[2,1-b]thiazoliumiodide (1.716(3) A˚ ) [18], while in ethyl-6-(p-chloro-phenyl)-3-phenylimidazo[2,1-b]thiazol-2-ylacetatethe corresponding value is 1.747(3) A˚ [19]. Asobserved in analogous compounds [17–19], theN(4)–C(8) bond length (1.361(4) A˚ ), constitutingthe fusion between the imidazole and the thiazole, isshorter than the other two distances involving thebonds N�4�–Csp2: A conjugation between the imidazo-thiazole and the indolinone systems is present asshown by the partial character of the double bond ofC(5)–C(10) (1.460(4) A˚ ). This also occurs in analo-gous compounds [17–20].

The imidazothiazole system is quite planar with thelargest deviations from its least-squares plane shownby C(3) (20.020(3) A) and C(2) (20.018(4) A) fromone side, and by N(4) (0.021(2) A˚ ) from the other. Inthe 2-indolinone, each ring is planar. The dihedralangle formed by their least-squares planes is equalto 5.1(1)8.

The crystal structure confirms that compound1 hasa E configuration. The two fused heterocyclicsystems, i.e. the 2-indolinone and the imidazothiazole,show a twisted conformation, their least-squaresplanes forming a dihedral angle equal to 59.03(5)8.This reflects the conformation found in solution by1H-NOE experiments [7]. The crystal structure isstabilized by van der Waals interactions and hydrogenbonds. For instance, the distance O(1)···H(13)�2x;2y 2 1;2z1 1� is equal to 3.98(3) A˚ .

3.3. Theoretical calculations and stereochemicalproperties

In order to evaluate the stability of different config-urations and conformations of the imidazo[2,1-b]thia-zolylmethylene-2-indolinone moiety, theoreticalcalculations have been performed on compounds1–3. In each case, an energy potential curve has beenproduced by varying the H(10)–C(10)–C(5)–N(4)torsion angle (f ) by 108 step in the range0 4 3608.

The potential energy profiles of different confor-mations of compounds1–3 in the configurationEare quite similar and they are characterized by twoenergy maxima (Fig. 4). The energy differencebetween the first maximum and the energy minimumis in the range 14–16 kcal mol21, while the second isat a higher energy level. The valley separating the two

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199196

Fig. 3. X-ray molecular structure of compound1 showing 50%probability displacement ellipsoids.

Table 1Fractional atomic coordinates and equivalent isotropic thermalparameters (Ueq, A2) for non-hydrogen atoms for 3-(4-methyl-5-imidazo[2,1-b]thiazolyl-methylene)-2-indolinone (1). Ueq is definedas one third of the trace of the orthogonalizedUij tensor

Atom x y z Ueq

S(1) 0.1252(1) 0.08373(9) 0.31060(6) 0.0536(3)O(1) 0.0925(3) 20.5375(2) 0.6057(1) 0.0445(6)N(4) 0.1460(3) 20.1021(2) 0.4211(1) 0.0365(6)N(7) 0.2423(3) 0.0886(2) 0.4786(2) 0.0466(7)N(13) 0.2422(3) 20.6158(2) 0.4956(2) 0.0402(6)C(2) 0.0569(5) 20.0788(4) 0.2890(2) 0.0516(9)C(3) 0.0732(4) 20.1643(3) 0.3518(2) 0.0443(8)C(5) 0.1911(4) 20.1339(3) 0.5037(2) 0.0356(7)C(6) 0.2488(4) 20.0147(3) 0.5370(2) 0.0398(8)C(8) 0.1788(4) 0.0318(3) 0.4109(2) 0.0402(8)C(9) 0.3244(6) 0.0051(4) 0.6213(3) 0.0561(10)C(10) 0.1721(4) 20.2687(3) 0.5396(2) 0.0364(7)C(11) 0.2170(3) 20.3852(3) 0.5049(2) 0.0309(7)C(12) 0.1742(4) 20.5189(3) 0.5439(2) 0.0364(7)C(14) 0.3293(4) 20.5589(3) 0.4303(2) 0.0352(7)C(15) 0.4242(4) 20.6236(3) 0.3733(2) 0.0477(9)C(16) 0.5085(4) 20.5431(4) 0.3177(2) 0.0527(9)C(17) 0.4989(4) 20.4036(4) 0.3199(2) 0.0516(9)C(18) 0.4023(4) 20.3402(3) 0.3772(2) 0.0429(8)C(19) 0.3152(3) 20.4173(3) 0.4327(2) 0.0335(7)

maxima is quite wide and it encompassesf values inthe range 80–1108, suggesting that the imidazothia-zole moiety has a large range of rotational freedom inthe isolated molecule.

For compound1 the energy minimum is calculatedwhen the torsion anglef is equal to2938 (Fig. 4). Inthe crystal structure this value is equal to2132(2)8.The stabilities of these two conformations are calcu-lated to be very close to each other, the energy differ-ence being less than 2 kcal mol21. Of course,intermolecular interactions and packing forces in thecrystal might play a driving role in favoring oneconformation with respect to another, while calcu-lations are performed on isolated molecules. Thetwo energy maxima are calculated whenf is equalto 17 and 2078, respectively. In both cases, sterichindrance between the hydrogen atoms of the twoheterocyclic system is present with interatomicdistances in the range 2.3–2.8 A˚ .

A study of 1 in the Z configuration has also beencarried out. Its energy profile is very close to thatcalculated for theE isomer. In the energy minimumstructure, the torsion anglef has a value equal to 1048(Fig. 4), while the dihedral angle defined by the least-squares planes of the two heterocyclic systems isequal to 808 (Fig. 5). By considering the isolatedmolecule, like it occurs in calculations, the energyminima of the two configurations are predicted tohave similar stability. In fact for the configurationsE and Z the calculated energy values are 55.6 and55.3 kcal mol21, respectively.

The potential energy profiles obtained forcompounds2 and3 with theE configuration resemblethat of 1. In the lowest minimum energy conformers(Fig. 5) the least-squares planes of the two hetero-cyclic systems form a dihedral angle equal to 83 (2)and 808 (3). In both the compounds, the pendantphenyl ring, replacing the methyl group present in1, is almost perpendicular to the other two hetero-cyclic rings.

The energy difference between the lowest unoccu-pied (LUMO) and the highest occupied (HOMO)molecular orbital, being related to the polarizabilityof the molecules, expresses the potential ability toestablish attractive short-range interactions with thereceptor. For the energy minima ofE-1–3 thesevalues are 7.984, 7.968, and 7.961 eV21, respec-tively.

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199 197

Table 2Selected geometric parameters (A˚ , 8) for 1

S(1)–C(2) 1.736(4)C(2)–C(3) 1.316(5)C(3)–N(4) 1.393(4)N(4)–C(5) 1.399(4)C(5)–C(6) 1.375(4)C(6)–C(9) 1.487(5)C(6)–N(7) 1.382(4)N(7)–C(8) 1.318(4)C(8)–S(1) 1.731(3)C(8)–N(4) 1.361(4)C(5)–C(10) 1.460(4)C(10)–C(11) 1.334(4)C(11)–C(12) 1.505(4)C(12)–O(1) 1.223(4)C(12)–N(13) 1.360(4)N(13)–C(14) 1.399(4)C(14)–C(15) 1.373(4)C(15)–C(16) 1.392(5)C(16)–C(17) 1.381(5)C(17)–C(18) 1.380(5)C(18)–C(19) 1.384(4)C(19)–C(11) 1.461(4)C(19)–C(14) 1.404(4)C(8)–S(1)–C(2) 89.2(2)C(3)–C(2)–S(1) 114.5(3)C(2)–C(3)–N(4) 111.0(3)C(3)–N(4)–C(5) 138.8(3)C(3)–N(4)–C(8) 114.8(3)C(8)–N(4)–C(5) 106.3(2)N(4)–C(5)–C(6) 104.9(2)N(4)–C(5)–C(10) 123.1(3)C(6)–C(5)–C(10) 132.0(3)C(5)–C(6)–N(7) 111.3(3)C(5)–C(6)–C(9) 126.9(3)C(8)–N(7)–C(6) 104.4(2)N(7)–C(8)–N(4) 113.2(3)N(7)–C(8)–S(1) 136.3(2)N(4)–C(8)–S(1) 110.5(2)C(11)–C(10)–C(5) 126.2(3)C(10)–C(11)–C(19) 132.9(3)C(10)–C(11)–C(12) 121.0(3)C(19)–C(11)–C(12) 106.1(2)O(1)–C(12)–N(13) 126.6(3)O(1)–C(12)–C(11) 127.3(3)N(13)–C(12)–C(11) 106.1(2)C(12)–N(13)–C(14) 111.6(2)C(15)–C(14)–N(13) 128.3(3)N(13)–C(14)–C(19) 109.5(3)C(18)–C(19)–C(11) 133.9(3)C(14)–C(19)–C(11) 106.6(3)

4. Conclusions

This study has allowed us to characterize some3-(5-imidazo[2,1-b]thiazolyl-methylene)-2-indo-

linone derivatives having interesting biological prop-erties by X-ray crystallography and in the gas phaseby mass spectrometry and tandem mass spectrometry.

Theoretical calculations have allowed us to obtain

G. Giorgi et al. / Journal of Molecular Structure 524 (2000) 189–199198

Fig. 5. Energy minimum structures of compound1 (top row) with configurationE (left) andZ (right), and for compoundsE-2 andE-3 (bottomrow).

Fig. 4. Energy profiles for the configurationE-1, Z-1, E-2 andE-3 obtained by varying the torsion angle H(10)–C(10)–C(5)–N(4).

information on both theE andZ stereoisomers of1 aswell as on the phenyl derivatives2 and3. Even thoughthe E andZ stereoisomers of1 are predicted to havesimilar stability by the calculations, the X-ray datahave allowed us to establish that1 has theE config-uration in the crystal state, in agreement with previousdata obtained in solution.

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