One-pot regioselective synthesis of new 5-(arylsulfonylamino)imidazo[2,1-b]thiazoles

N-(2,2-Dichloro-2-phenylethylidene)-4-chlorobenzenesulfonamide reacts with 2-aminothiazoles to give products of nucleophilic addition in good yields. The adducts are cyclized into the unexpected 5-(arylsulfonyl)amino-6-phenylimidazo[2,1-b]thiazoles in 70-75% yield; whereas the anticipated isomeric 6-(arylsulfonyl)amino-5-phenylimidazo[2,1-b]thiazoles were not observed.


Introduction
][3][4][5][6][7][8][9][10][11][12] Moreover, besides the carbon atom of azomethine group,-haloimines contain another electrophilic reactive site, namely the carbon atom of the polyhalomethyl group.][12] N-Sulfonyl-substituted phenyldichloroacetaldimines of the type 1 are key representatives of activated electrophilic imines, that are available through previously developed methods based on free-radical reaction of N,N-dichlorosulfonamides with phenylacetylene (Scheme 1). 13,14Until now, no alternative syntheses to N-(2,2-dichloro-2-phenylethylidene)arenesulfonamides of type 1 have been developed.The formation of imine 1 is a one-pot free-radical process proceeding via unstable intermediate N-chloro-N-vinyl adducts (see Scheme 1).The reaction is performed under argon in CCl 4 .Reagent addition order is important: when N,N-dichloroamide is added to a solution of phenylacetylene, the yields of imines are substantially higher than when the reagents are mixed in the reverse order (90-95 vs. 40-64%).The reaction has an induction period after which it proceeds with notable self-heating.It is important that the reaction mixture is cooled during the exotherm and is heated for 3 h after the exothermic process has been complete. 14Imine 1 is precipitated upon cooling of the reaction mixture and can be readily separated and used for further synthetic transformations without additional purification.

Results and Discussion
4,5-Diaryl-substituted 2-aminothiazoles 3a and 3b, required for the directed synthesis of the target imidazothiazole derivatives, were prepared according to Scheme 3. The first step was the synthesis of sulfonylimine 1 followed by C-amidoalkylation of anisole or thioanisole.Next, the amidoalkylation products 2a and 2b were reacted with thiourea (Scheme 3).Anisole derivatives 2a and 3a were previously prepared according to this protocol. 30The corresponding thioanisole derivatives 2b and 3b were synthesized during the present work and have not been previously described.
C-Amidoalkylation of thioanisole was more difficult than the analogous reaction of anisole.Anisole reacts with imine 1 in the presence of boron trifluoride etherate. 1Unfortunately, under the same conditions thioanisole gave no C-amidoalkylation product 2b.Apparently, BF 3 affords a stable, poorly nucleophilic and non-reactive complex with thioanisole.
We have found that compounds 2a and 2b are produced in satisfactory yield in the presence of H 2 SO 4 /P 4 O 10 mixture.When H 2 SO 4 is employed without P 4 O 10 or oleum as a strong acid, the yield of amidoalkylated derivatives 2a and 2b was significantly lower.
The reaction proceeded at room temperature under vigorous stirring.An excess of aromatic substrate contributes to an increased yield of amidoalkylated products 2a and 2b.Substitution was directed to the para-position and the ortho-or meta-isomeric products were not observed.
It can be assumed that, in the presence of H 2 SO 4 or oleum, anisole and thioanisole are deactivated due to sulfonation.However, the H 2 SO 4 /P 4 O 10 combination was an effective protonating medium that readily promoted the formation for sulfonamidoalkyl cations, key intermediates of C-amidoalkylation; whereas the sulfonation side reaction was probably less favourable in the H 2 SO 4 /P 4 O 10 mixture.In the present investigation, we did not isolate intermediate structures A, B, and C.However, the proposed pathway for formation of aminothiazoles 3a and 3b is in agreement with previously published results regarding formation of the similar chloroaziridine from N-[1-(4-methylphenyl)-2-phenyl-2,2-dichloroethyl]-4-chlorobenzenesulfonamide 7 and synthesis of enamide C from anisole derivative 2a occurs in the absence of thiourea at room temperature. 8ynthesized compounds 3a and 3b were further investigated in the reaction with imine 1.It has been found that the process results in the formation of previously unknown adducts 4a and 4b (Scheme 5).Maximum yields of adducts 4a and 4b have been achieved in dioxane.The formation of these adducts occurs without heating in the absence of catalysts and this was tentatively attributed to the high electrophilicity of the activated azomethine group of imine 1.
The formation of adducts 4a and 4b was confirmed by spectroscopic analysis.The 1 H and 13 C NMR spectra of compounds 4a and 4b were in agreement with the proposed structures.The resonances due to the NH-CH-NH fragment, the double doublet at 6.46-6.48ppm, corresponding to the CH group, as well as two doublets at 8.17-8.24and 8.93-8.95ppm, corresponding to NH groups with a coupling constant of 9.5-9.8Hz, are symptomatic for these adducts.
NaOH in dioxane was the most efficient combination for the preparation of compounds 5a and 5b via a two-stage one-pot method without isolation of intermediate adducts 4a and 4b (Scheme 7).To rationalize the selective formation of the 5-amino-substituted derivatives 5, ab initio and DFT methods were used to model the structures 5 and 6 (Table 1 and 2), and the relative energies of the 5-and 6-amino-substituted derivatives was estimated.
With an unsubstituted amino group in the imidazothiazole structure (Table 1, entries 1 and 4), the 6-amino isomer was energetically preferred by 2.8-3.2kcal/mol.However, with a strong electron-withdrawing substituent at the exocyclic nitrogen atom, the energy difference between the isomers either disapppeared (according to MP2, Table 1, entries 2 and 3) or was inversed (according to B3LYP, Table 1, entries 5 and 6).
Bearing in mind that N-sulfonyl-substituted aminoimidazothiazoles are potent NH-acids, and the reaction was carried out in the presence of strong base (NaOH), it was logical to suggest that in the reaction mixtures the products existed as their corresponding anions.Modeling the corresponding anions (Table 2) showed that 5-sulfonylamino-substituted imidazothiazoles were significantly preferred (6-8 kcal/mol), compared to 6-substituted isomers.
It should be noted that the structure of 5a, derived by the MP2 method, corresponded best with the SAR data.The structure of imidazo[2,1-b]thiazole 5a was unequivocally supported by single crystal Xray crystallographic analysis (Fig. 1) and confirmed our conclusions from the spectroscopic data.In the crystal structure of 5a, the molecule associated with a solvent molecule.The benzene ring in the position 6 and the aromatic ring of arylsulfonyl group were substantially parallel, and the distance between them at 3.53 Å indicated intramolecular π-stacking between the aromatic fragments.
For molecules of 5 and 6 or their amide anions, the calculation of charge distribution obtained by AIM showed that C-3 carbon atom has a moderate positive charge (~+0.4 and ~+0.5 for neutral molecules and sulfonamide anions, correspondingly).This data could suggest the reaction path including possible nucleophilic attack of hydroxyl anion on C-3 atom of imidazothiazole ring followed by the Dimroth rearrangement (Scheme 8).At the same time, the reaction path, presented in the scheme 8, is not proved to the full extent.Although Dimroth type isomerization is described for a range of heterocyclic compounds, 38 similar transformations are not typical for 1,3-thiazole fragments.Therefore, further investigation of a possible reaction path is needed.

Experimental Section
General.Compound 3a was synthesized according to the previously developed method. 30 1H, 13 С NMR spectra were recorded on a Bruker DPX-400 spectrometer (400.61,100.13 MHz, respectively) with TMS as an internal standard.IR spectra were recorded on a Bruker IFS-25 instrument on KBr discs.Crystal data were collected on a Bruker D8 Venture diffractometer with MoK  radiation ( = 0.71073) using the  and  scans.The structure was solved and refined by direct methods using the SHELX program. 39Data were corrected for absorption effects using the multi-scan method (SADABS).Non-hydrogen atoms were refined anisotropically using SHELX. 39For details of the data collection and the structure solution and refinement, see Supplementary data.CCDC 996956 contains the supplementary crystallographic data for this paper.These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Table 1 .
Relative energies of neutral molecules in gas phase at completely optimized geometries, kcal/mol 33MP2 calculations were performed using the Firefly QC package31which is partially based on Gamess US source code.32 b DFT calculations were performed using the Gaussian 09 program package.33