Functionalized 4-methyl-5-phenylthiazole and 1,3-bis(4 ′ -methyl-5 ′ - phenylthiazol-2 ′ -yl)benzene. Approaching thiazole macrocycles

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Introduction
Design and development of methods for synthesis of macrocyclic ligands, containing nitrogen heterocycles, aimed at building the systems of molecular recognition and efficient catalytic systems, attract great attention. 1Another cause of interest to these structures is the possibility of design on their basis such macrocycles and related 1,3-dihetarylbenzenes 1 of mono-and binuclear metal complexes, related to non-heme metalloproteines. 2 There are several examples of macrocycles, synthesized just for binuclear comlexation. 3Some of them include biologically active imidazole rings.

2
Functionalized thiazoles are a good basis for planning the synthesis of thiazole-containing chelating agents, macrocycle precursors like compound 1 and macrocycles from them.Such structures are of interest for organic chemists and biochemists. 17The use of side-chain functionalized thiazoles, which can be obtained on the basis of the mentioned functionalized thiazoles opens up additional possibilities.
The task of this work is to clear up the possibility of transformation of 2,5-diphenyl-4methoxycarbonylthiazole into 2,5-diphenylthiazoles, bearing different functional groups in 4methyl substitute.The expansion of this strategy over bisthiazole -1,3-bis(4′-methoxycarbonyl-5′-phenylthiazol-2′-yl)benzene 10 gave hope to get bifunctionalized in 4-methyl groups bisthiazoles, presenting potential precursors of thiazole-containing macrocycle precursors and macrocycles.Bis(4-mercaptomethyl)thiazole, the macrocycle precursor with not less than two types of binding sites, being the reduced form of thiol-sulfide redox system with thiazole-containing disulfide macrocycle (or macrocycles) or disulfide oligomers as the oxidized form, would be of special interest in this group.

Results and Discussion
The successive transformation of ester 3 into functionalized at methyl group 4-methyl-2,5diphenylthiazoles -4 (alcohol), 5 (chloro), 6 (amidiniummercapto), 7 (thiol) and 8 (disulfide) was realized with almost quantitative yields (Scheme 1), what gives a good opportunity of using thus formed functional groups in the synthesis of various new mono-and polycyclic derivatives of thiazole.The transformations presented in scheme 1 are the model ones for the development of the synthesis of bis-thiazoles chelating agents and macrocycle precursors, bearing functional groups 4-CH 2 OH, 4-CH 2 Cl, 4-CH 2 S(NH 2 ) 2 + , 4-CH 2 SH in any thiazole cycle, and, since, fit for the construction of several types of macrocycles.
We realized this possibility (scheme 2) starting from thioisophthalamide 9, which Hantzsch condensation with chloropyruvate 2 results in the formation of 1,3-bis[2-(4-carbmethoxy-5phenyl)thiazolyl]benzene 10.If to perform the condensation in MeOH, then under the action of HCl and H 2 O, isolated in the Hantzsch reaction, partial methanolysis and dethionation of one thioamide group proceeds, and compound 11 is secondary formed.The reaction similar direction was not observed at the condensation of chloropiruvate 2 with thiobenzamide in EtOH.16c Further transformations of diester 10 into diol 12, dichloride 13, bisdiamidiniummercapto compound

Scheme 2
To control the structure of the formed products diole 12 was investigated with X-ray diffraction analysis.The compound crystallizes in the space group P-1 with two independent molecules of 12 and solvate THF and H 2 O molecules.Figure 1 shows that the molecules are non-planar, the selected bond lengths and angles are presented in Table 1.It should be noted that the molecules of 12 have non-crystallographic two-fold symmetry but loses it in crystal not only owing to deviations of six-and five-membered rings planes from the plane of central rings of molecule, but due to different positions (orientation) of hydroxyl groups from plane of the molecule, as can be seen from the picture of docking two independent molecules in Figure 2.   Equivalent positions: In contrast the independent molecules, B participates in O-H…O contacts with solvate THF molecules.The solvate H 2 O molecules form hydrogen bonds with nitrogen atoms of thiazole rings of molecules A. Packing of the molecules in crystal results in formation of colon-like areas, which are filled by the solvate molecules (Figures 4).Such localization of solvate molecules in crystal can be considered as the pseudochannels, and indicates the existence of selected direction and probably the anisotropy of the crystalline properties.Dithiol 15, similarly to aliphatic mercaptans, is susceptible to easy oxidation even under the action of the air oxygen, what results in the occurrence of insolvable in chloroform and infusible fraction, evidently presenting the oligomeric disulfide, the product of oxidative polycondensation of thiazolecontaining dithiol 15.At this dithiol oxidation under the conditions of high dilution one may expect the formation of macrocyclic thiazole-containing disulfides similarly to described for other dithiols HS-A-SH of general formula 16. 18 However, in contrast to dithiols 16, used in the above-mentioned works, which interthiol fragment contained rather extensive flexible chains, there are no such chains in our dithiol 15.Thus, as distinct from the works, 18 the intramolecular oxidative cyclization according to the scheme 3 is problematic for dithiol 15.Rigidity and rather small value of thizole-containing macrocycle of 17-type should prevent from free (without geometry distortion) geometrical arrangement of the composing fragments, and, as a consequence, it should be too strained.Actually, the quantum-chemical calculations demonstrated that although the geometry of the fragment -CH 2 -S-S-CH 2 -in macrocycle 18 virtually does not differ from the geometry of dimethyldisulfide, the geometry of dithiazolylphenylene fragment in this macrocycle is distorted substantially compared to the geometry of the same fragment in dithiol 15.In contrast to absolutely plane aromatic phenylene and two thiazol cycles, in dithiol 15 the mean-root-square deviation from the plane of the same atomic cycles in the macrocyclic thiazole-containing disulfide 18 consists 0.088 and 0.011Å, correspondingly, i.e. the system aromaticity partially decreases.The hydrogen atoms of the macromonodisulfide phenyl fragment deviate noticeably from the planes, formed by the triple of the nearest to them carbon atoms.It is particularly evident for the hydrogen atom at C 2 (the atoms numeration is given here only for the phenylene fragment), displaced inside the macrocycle (11.6° with respect to the plane C 1 -C 2 -C 3 ).The phenylene fragment bonds with two thiazole cycles deviate notably from the corresponding triples of the carbon atoms (9.2°).All this should result in substantial destabilization of the considered macrocycle.
However, there exists the possibility to realize another direction of dithiols oxidative macrocyclization -with participation of two dithiol molecules according to general scheme 4 with the formation of macrocycles 19 (AS 2 ) 2 .

Scheme 4
Quantum-chemical calculations demonstrated, that thiazole-containing macrocycle 20 (AS 2 ) 2 , which can be formed according to the general scheme 4 from dithiole 15 (scheme 5), has almost standard geometrical parameters of all its fragments, and so, it is free of strain.
If both macrocycles 18 (AS 2 ) and 20 (AS 2 ) 2 were not tensioned, the macrocycle 18 formation enthalpy would be half less than that of macrocycle 20.However, as the calculation demonstrated, the macrocycle 18 formation enthalpy is greater by 12.9 kcal/mol than half of the macrocycle 20 formation enthalpy.This value may serve the measure of compound 18 destabilization.So, at bismercaptane oxidation the macrocycle (AS 2 ) 2 20 (and, probably, the highest cyclohomologues (AS 2 ) n , where n > 2) formation should be expected, but not macrocycle AS Actually, at oxidation of thiazole-containing dithiol 15 by iodine under the conditions of high dilution in the presence of the base 18 the dissoluble in organic solvents substance, not containing the group SH in contrast to the initial dithiol 15, is formed with practically quantitative yield, according to the data of IR and 1 H-NMR spectroscopy.Other spectrum parameters of initial and final compounds are practically identical.In MALDI-TOF spectrum of the obtained substance there is a peak corresponding to macrocycle 20 in the value m/z, but the peak, corresponding to macrocycle 18, is absent.
Interesting results were obtained in the course of mass-spectrometric investigations of the above-described compounds, containing the fragment CH 2 -S.In particular, their spectra contain rather intensive peaks with m/z value, substantially exceeding that of molecular peaks of mother compounds.
At temperature about 250°C in monothiazoles 6-8 mass-spectra the peaks were fixed, being the evidence of the products of loss by the mother compounds 6-8 the sulfur-containing functional groups in the vapor over these substances; these peaks correspond to the products 25 and 26.The compound 25 was also detected in the course of chromato-mass-spectrometric experiment.
This phenomenon can be explained by low energy of the bond C sp 3 -S(II) cleavage -about 235 kJ/mol. 19At the temperature 200 -250°C this bond homolysis occurs.As a consequence of it, the carbon-centralized radical 21 and sulfur-centralized radicals 22-24 are formed from the compounds 6-8 (scheme 6).Radical 21 can be stabilized in two ways -it tears away the hydrogen atom from some molecule of the matrix (S H 2 reaction at hydrogen atom), forming 2,5-diphenyl-4-methylthiazole 25, or it recombines, forming 1,2-bis(2′,5′-diphenylthiazol-4′-yl)ethane 26 (scheme 7).Chromatographic detection of the product 25 in the vapor of monothiazols 6-8 and fixation of molecular ion of the recombination product 26 in their mass-spectra gives a strong evidence of proceeding the mentioned processes independently on the fortune of molecular ions of the initial monothiazols 6-8.In particular, the peak, corresponding to the compound 26 by the m/z value, exceeds this value for molecular ions of mother compounds, and thus in the conditions of mass-spectral experiment, where the ion-molecular reactions are practically excluded, the compound 26 can't be formed in the course of fragmentation of the latter in the gas phase.In addition to the molecular peaks, corresponding to the products 25 and 26, in MALDI-TOF spectrum of disulfide 8 the peaks of sulfide 28 (the product of the radicals 21 and 27 recombination) and trisulfide 29 (the product of the radicals 24 and 27 recombination) were observed (see scheme 8).Sulfur centralized radical 27 is formed as a consequence of thermal homolysis of S-S bond in disulfide 8, proceeding in parallel with the CH 2 -S bond homolysis: the S-S bond rapture energy is rather low -about 280 kJ/mol.   .

Scheme 9
The loss of four sulfur-containing functional groups by the molecules of bis-isothiouronium salt 14 with the formation of cyclophan 32 can be explained by the gas phase monomolecular cyclization by means of S H 2 reaction at carbon atom of the radical 35, formed in the course of homolysis of compound 36, formed, in its turn, by means of the radicals 37 recombination (Scheme 10).As well as considered here the homolysis reactions, the S H 2 reaction with CH 2 -S bond cleavage is possible due to low energy of this bond.Finally, the detection in the vapor over the compound 14 of a large molecule 32, built of the fragments of two molecules of the mother compound, clearly demonstrates that the macrocycle 32 is actually formed not in the course of the fragmentation of the molecular ion of the mother compound in gas phase.

Scheme 10
The dithiol 15 mass-spectrum also bears witness to the homolysis of the CH 2 -S -bond -it contains a peak, which could be ascribed by the value m/z to the molecular ion of compound 31, formed from the radical 38.In addition to it, in MALDI-TOF spectrum the molecular peak, corresponding to the product of the same radical recombination -the compound 39, was detected (Scheme 11).

Scheme 11
The characteristic feature of the mass-and MALDI-TOF spectra of cyclophan 20 is the presence of the peak, corresponding by the value m/z to the molecular ion of cyclophan 32, different from the initial cyclophan by the absence of all the four nonthiazole atoms of sulfur.Its formation is illustrated by the scheme 12.This scheme includes the stages of thermal homolysis of the bonds

Scheme 12
Experimental Section General Procedures.All melting points were determined with Boetius hot-stage apparatus and uncorrected. 1H-NMR spectra were recorded on Bruker MW-250 (250.13MHz), Bruker MSL-400 (400.13MHz) and Bruker ASPECT-600 (600 MHz) spectrometers using the corresponding solvent as the internal standard.Electron ionization (EI) mass spectra (60 eV) were obtained on "Finnigan" MAT-212 instrument.GC-MS analysis were performed with Trace MS "Thermo-Quest" instrument (SE-30 capillary column).Matrix-assisted laser desorption ionization (MALDI) mass spectra were obtained on "Finnigan" Dynamo instrument (MALDI-TOF) with 1,8,9-trihydroxyantracene matrix.The IR spectra of compounds were measured on a Bruker FTIR Vector-22.Microanalyses were performed with an elemental analyzer (CHN-3-analyzer, USSR).Quantum-chemical calculations were carried out using the program MOPAC 6 in the PM3 approach.Methyl 3-chloro-2-oxo-3-phenylpropanoate 2 was prepared by the condensation of benzaldehyde with methyl dichloroacetate according to Ref. 16c.X-ray crystallographic data for 12 were collected at 293(2) K on an Enraf-Nonius CAD-4 diffractometer in the ω/2θ-scan mode, θ ≤ 74.1°, using CuK α radiation with graphite monochromator.The structure was solved by direct method using the SIR 22 program and refined by fullmatrix least-squares using SHELXL97 23 program.All the non-hydrogen atoms were refined with anisotropic atomic displacement parameters, and hydrogen atoms bonded to carbon were inserted at calculated positions using a riding model.Hydrogen atoms bonded to oxygens were located from difference maps.All calculations were performed on PC using WinGX 24 suit of programs.Data collection and data reduction were performed on Alpha Station 200 computer using MoLEN 25 program.A summary of the crystal data, data collection, and refinement procedures is given in Table 3.

2,5-Diphenyl-4-hydroxymethylthiazole (4).
To suspension of LiAlH 4 (0.80 g, 21 mmol) in 35 ml THF at stirring under Ar atmosphere at -60°С the ether 3 16b (3.60 g, 12 mmol) was added in portions during 45 min.Then the reaction mixture was stirred for 2 h at the same temperature, and then the temperature was raised up to the room temperature, the reactive mixture was treated with the ice water (50 ml), the formed suspension was acidified by the 5% HCl solution, then it was extracted by AcOEt (3×50 ml) and Et 2 O (3×50 ml).The joint extract was washed with the water (2×25ml), with the saturated solution NaCl (25ml) and dried over Na 2 SO 4 .After the solvent removal in vacuo 3.10 g (95%) of product 4 was obtained, mp 104-106°С.IR (nujol, cm  9).(a) From isophthalamide.To a suspension of isophthalamide (2.00 g, 12.2 mmol) in 20 ml of THF Lowesson's reagent (4.95 g, 12.2 mmol) was added at room temperature, and the mixture was refluxed up to the formation of homogeneous solution (for 2 h).After removal of the solvent the residue was solved in 15 ml CH 2 Cl 2 and allowed to solidify.The crystals were dried and recrystallized from acetone.The thioisophthalamide 9 (1.43 g, 60 %) was obtained, yellow crystals, mp 203 -205°С (acetone) (212 С о , ref. 20 , 203 о С ref. 23 ).(b) From isophthalodinitrile.The solution (2 g, 15.6 mmol) of isophtalodinitrile in 80 ml of the mixture triethylamine -pyridine (1:1) was bubbled with dry H 2 S for 8 h at room temperature.By this time, according to the TLC data, the initial dinitrile is completely spent.The reaction mixture was poured out onto ice, the yellow-lemon precipitate was separated, washed with water (3×20 ml), and 2.82 g (92%) of compound 9 was obtained with mp 211 -212°С (EtOH).IR (nujol, cm

Figure 1 .
Figure 1.ORTEP plot of two independent molecules in crystal of 12. (THF and H 2 O solvate molecules are omitted)

Figure 2 .
Figure 2. View of docking of two independent molecules of 12; hydrogen atoms and solvent molecules are omitted; blue -molecule B (central ring numbering C11-C16), green -molecule A (central ring numbering C1-C6 on Figure.1).

Figure 3 .
Figure 3. Intermolecular interactions in the crystal of 12. Color map: green -molecule A, bluemolecule B, red -THF, yellow -H 2 O. Hydrogen atoms not participating in hydrogen bonding are omitted.

Figure 4 .
Figure 4. Crystal packing diagram in the crystal of 12. View along 0a axis.Color map as in Figure 3.
14, and dithiol 15 proceed smoothly and with almost quantitative yields.