Regioselective reaction of imidazole-2-thiols with N -sulfonylphenyldichloroacetaldimines: en route to novel sulfonylamino-substituted imidazo[2,1-b ]thiazoles and thiazolo[3,2-a ]benzimidazoles

The reaction of N -(2,2-dichloro-2-phenylethylidene)arenesulfonamides with 2-mercaptoimidazoles affords N - (2-phenylimidazo[2,1-b ][1,3]thiazol-3-yl)arenesulfonamides or N -(2-phenyl[1,3]thiazolo[3,2-a ]benzimidazol-3-yl)arenesulfonamides. Formation of the annulated heterocyclic derivatives is tentatively triggered by a nucleophilic addition of mercaptoimidazole to the activated azomethine group of halogen-containing imines followed by intramolecular heterocyclization and aromatization.

In continuation of our research, [25][26][27][28] here we have studied for the first time the reaction of imidazole-2thiols with N-(2,2-dichloro-2-phenylethylidene)arenesulfonamides 1 to elaborate the approach for the synthesis of novel sulfonylamino-substituted derivatives of imidazo[2,1-b]thiazole.N-Sulfonylimines 1 represent activated electron-deficient halogen-containing imines, which are effective reagents for a wide range of sulfonamide derivatives. 58,59heme 1. Synthesis of phenyldichloroacetaldimine 1a-c. 58mines 1a-c became available owing to a convenient method for their preparation 60 via the radical reaction of phenylacetylene with N,N-dichloroarenesulfonamides (obtained in turn by chlorination of the corresponding sulfonamides 61 ) (Scheme 1).
To reach the goal of this work, the synthesized imines 1а-с were subjected to the reaction with 2imidazolethiols 2a-e.

Results and Discussion
First, screening of conditions for the reaction of imine 1c with benzimidazolethiol 2a has been performed.It has been found that the reaction proceeds via formation of the unstable intermediate adduct 3ca.Further transformations of the latter lead either to resinification of the reaction mixture or formation of the target imidazothiazole 4ca (Table 1).The reaction without a solvent in melt of reagents 1c and 2a leads to the formation of imidazothiazole 4ca also (Table 1, Entries 17).But in this case strong resinification took place, a procedure for isolation of the target product in a pure form was more labour-consuming, and yield of 4ca was less.
Next, we have tried to extend conditions, optimum for the synthesis of compound 4ac, to the reactions of imines 1a-c with benzimidazolethiol 2a and other representatives of 2-imidazolethiols 2b-e (Table 2).Besides, despite varying the process conditions, the attempts to obtain imidazothiazoles from the nitrosubstituted mercaptoimidazole 2e (Table 2, Entries 13) failed, presumably, due to a low nucleophilicity of this reagent.
The tentative mechanism of imidazothiazoles assembly (Scheme 2) is, apparently, triggered by the formation of N-adduct 3 via addition of the NH group of mercaptoimidazole 2, existing as 1,3-dihydro-2Himidazole-2-thione tautomer, to the activated azomethine fragment imine 1.Further transformations probably include tautomerization of adduct 3 with the formation of the thiol group, intramolecular heterocyclization involving this thiol group and dichloromethylene moiety followed by aromatization owing to elimination of hydrogen chloride.Scheme 2. The tentative reaction mechanism for the formation of imidazothiazole derivatives 4.
The structures of compounds 3ca and 4 were proved by NMR technique.The 1 H and 13 C NMR spectra of compounds 3ca show signals of protons and carbon atoms, which relative integrated intensities, multiplicity and chemical shifts correspond to the proposed structure.In the 13 C NMR spectrum, the signal at 171 ppm is assigned to the C=S group that, first, confirms formation of adduct 3ca due to addition of benzimidazolethiol via the NH function, and, second, demonstrates that 3ca mainly exists as a thiocarbonyl tautomer.In the IR spectra of compound 3ca, the absorption band at 1218 cm -1 also corresponds to the thiocarbonyl structure.heteroatoms from the plane is 0.026Å, 0.011Å, 0.070Å for 4ab and 0.001Å, 0.033Å, 0.025Å for 4cd correspondingly.The plane of the phenyl substituent in the position 2 is with an angle to the plane of imidazo[2,1-b]thiazole fragment: 46.78° for 4ab and 34.17° for 4cd.The plane of the aromatic ring of arenesulfonylamino group is almost parallel to the plane of the phenyl substituent in the position 2, an angle between the planes being 6.84° for 4ab and 6.15° for 4cd.Besides, atoms S2 of arylsulfonyl groups deviate from the plane of the aryl fragment: 0.014Å for 4ab and 0.229Å for 4cd.For the compound 4cd chlorine atom Cl1 deviates from the plane on 0.150Å.Distances between centroids of the aromatic rings in the position 2 and in arylsulfonyl groups are 3.681Å for 4ab and 3.653Å for 4cd that evidences the presence of intramolecular πstacking.For 4ab, the almost orthogonal planes (88.12°) of the phenyl groups in the positions 5 and 6 of imidazo[2,1-b]thiazole core and distance between their centroids (3.644Å) testify in favor of intramolecular tstacking.
A peculiarity of 4ab and 4cd structures is the conformational difference in the arrangement of the phenyl fragments (Figures 1, 2).Compound 4ab is characterized by the staggered conformation, while compound 4cd is of the eclipsed conformation.Alteration of the conformation is associated with the change of the torsion angles С3N3S2CAr [(65.9(2)° for 4ab, -90.7(2)° for 4cd] and arrangement of phenyl group in the position 2 relative to imidazothiazole core -the torsion angles N3C3C2CPh are -10.7(4)°for 4ab and 3.8(4)° for 4cd.
To establish the structure of imidazothiazole 4bc HMBC1 H- 13 C technique was used (Figure 3), which was optimized for 13 C-1 H spin-spin coupling constants of 10 Hz, which are typical for carbon and proton atoms separated by three bonds.The 13 C-1 H correlation through three bonds with participation of C-3 carbon atom permits to draw a conclusion about absence of a substituent in the position 5 of the imidazothiazol cycle, and, therefore, on presence of the phenyl group in the position 6.[1,3]thiazolo [3,2-a]benzimidazol-3-yl)arenesulfonamides.The advantages of the method for the preparation of the imidazothiazole and thiazolobenzimidazole derivatives are available starting reagents, catalyst-free one-step procedure, and high selectivity.The known methods 19,[21][22][23][24] have never been used for the preparation of sulfonylaminosubstituted derivatives containing synthetically useful and pharmacophoric sulfonamide groups.It can be argued that the method proposed herein complements the known literature protocols and expands the scope of functionalized imidazothiazoles derivatives which are now available for further investigation of biological activity and other properties.

Experimental Section
General.Imines 1a-c were synthesized according to the known procedure 60 from corresponding N,Ndichloroarensulfonamides. 61All other used reagents were reagent grade.The solvents were dried by standard procedures and distilled prior to use.NMR spectra were recorded on a Bruker DPX 400 spectrometer ( 1 H, 400.13 MHz; 13 C, 100.61MHz) at 25 °C with HMDS as an internal standard.Chemical shifts are reported in ppm values (δ) and coupling constants (J) in Hz.IR spectra were recorded on a Bruker IFS-25 spectrophotometer in KBr.All melting points were measured on a Kofler micro hot stage apparatus.Elemental analyses for C, H, N and S were obtained using a Thermo Finnigan Flash series1112 EA analyzer.Column chromatography was carried out in a glass column with a diameter 2 sm and length of silica gel 30 sm (230-400 mesh).Sorbent : product ratio was 100 : 1. X-Ray crystallographic data were collected on a BRUKER D8 VENTURE PHOTON 100 CMOS diffractometer with MoKα radiation ( 0.71073 Å) using the φ and  scans technique.The structures were solved and refined by direct methods using the SHELX 62 .Data were corrected for absorption effects using the multi-scan method (SADABS).All non-hydrogen atoms were refined anisotropically using SHELX. 62The coordinates of the hydrogen atoms were calculated from geometrical positions.Crystallographic data for the structures 4ab and 4cd in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1564758 for 4ab and 1564759 for 4cd.Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].

Figure 1 .
Figure 1.Molecular structures of 4ab according to X-ray diffraction analysis

Figure 2 .
Figure 2. Molecular structures of 4cd according to X-ray diffraction analysis.

Table 1 .
Conditions for reaction of imine 1c with benzimidazolethiol 2aAdduct 3ca has been isolated in highest yield, when the reaction is carried out in acetonitrile (Table1, Entry 4).Further heating of adduct a Yields were calculated on starting imine 1c.

3ca delivers imidazothiazole 4ca. Upon refluxing the starting reagents 1c and 2a in o-xylene or
toluene, a one-pot synthesis of imidazothiazole 4ca in a highest yield has been implemented (

Table 1 ,
Entries 14, 15).The reaction is carried out without isolation of the intermediate adduct 3ca.But the reaction in toluene takes much more time (Table1, Entries 14), presumably because of lower temperature of refluxing.Therefore, we used refluxe in o-xylene for futher synthesis.
a Reflux in о-xylene for 5 h.b Heating at 100ºС in DMF for 5 h.It has been established that 4,5-diphenyl and 4-phenylsubstituted 2-mercaptoimidazoles 2b,c, like benzimidazolethiol 2a, smoothly form the corresponding sulfonylaminoimidazothiazoles, when carrying out the reaction in o-xylene.At the same time, 2-mercaptoimidazole 2d, unlike its substituted derivatives 2a-c, in o-xylene as a solvent, do not afford the target imidazothiazoles 4ad, 4bd, 4cd.