Two ways of cyclization of 5-imidazolylthioureas with dimethyl acetylenedicarboxylate

Two ways of cyclization of imidazolyl derivatives of thiourea with dimethylacetylene dicarboxylate (DMAD) were studied. Reaction of N,N'-disubstituted thioureas with DMAD led to formation of a thiazoline ring whereas transformation of trisubstituted thioureas under the same conditions give the novel imidazo[1,5-c][1,3,5]thiadiazine heterocyclic system.


Introduction
Organic dithiocarbamates and thioureas are valuable synthetic intermediates, 1 which are used widely in the synthesis of biologically active compounds. 2Functionalization of such moieties offers an attractive method for the generation of derivatives which may possess interesting medicinal and biological properties. 3For these reasons, the transformation of dithiocarbamate and thiourea derivatives with different substituents has become a field of increasing interest in synthetic organic chemistry during the past few years.
We have reported earlier some aspects of the chemistry of imidazolylthioureas. 4 Recently we communicated the reaction of imidazolylalkyl dithiocarbamates 1a,b and thioureas 2a,b with DMAD which are the first examples of the construction of the novel heterocyclic system of imidazo [1,5-c][1,3,5]thiadiazines 5 3a-d (Scheme 1).These compositions are close structural analogs of pyrazolo [1,3,5]thiadiazine which are a potent antifungal pro-drugs and inhibitors of photosynthetic electron transport. 6ue to our interest to the chemistry of imidazolyl derivatives of alkyldithiocarbamate and thiourea, now we present the extended studies of reaction of imidazolylthioureas with DMAD.The aim of this work was to determine the scope and limitations of annelation of 1,3,5thiadiazine ring to imidazoles.

Results and Discussion
It is well known that acetylenedicarboxylic acid esters are very reactive dienophiles and may form both cycloaddition products (way A, for example: 1,4-diazines, pyrimidines, etc.) 7 and cyclocondensation products with elimination of one alcohol molecule (way B, for example: thiazolidines, thiazines, etc.). 8Therefore it was very surprising to find another type of cyclization involving only one carbon atom of acetylene component resulting in formation of 1,3,5thiadiazines ring (way C) (Scheme 2).
For expansion of the series of new imidazo[1,5-c][1,3,5]thiadiazines we used the secondary amines 4a,b with a tryptamine core prepared by means of reductive amination of aromatic and heteroaromatic aldehydes (Scheme 3).To determine the influence of substituents on the new transformation of 5-imidazolylthioureas we synthesized disubstituted thioureas 9a-e by reacting 5-amino-imidazoles with isothiocyanates (Scheme 5).In this case, reaction of imidazolyl derivatives with DMAD led to a thiazoline ring and formation of compounds 10a-e.The 1 H NMR spectra of 10a-e show one OMe and a CH singlet on the exocyclic double bond.The 13 C NMR spectrum has characteristic doublets for the CH group (134.3-134.9ppm, J 157.9-161.2Hz).Parent ions in mass-spectra confirm the formation of cyclocondensation products resulting from the elimination of one methanol molecule.As a result of conjugation of a carbon-carbon double bond with two heterocycles, all substances 10a-e have a bright yellow color.In summary, contrary to prior art we have found that reactions of DMAD with 5imidazolylthioureas bearing tert-amino group involves the nitrogen atom of the imidazole ring and the only one carbon atom of the acetylene component leading to formation of novel system of imidazo [1,5-c][1,3,5]thiadiazine.

Experimental Section
General Procedures. 1 H NMR spectra were recorded on a Bruker WM-250 instrument (250.13MHz) and Bruker AVANCE II instrument (400 MHz) in DMSO-d 6 with Me 4 Si as the internal standard. 13C NMR spectra were recorded on a Varian Mercury-300 (75.5 MHz) in DMSO-d 6 .The course of the reaction was monitored and the purity of the products was checked by TLC on Sorbfil UV-254 plates in ethyl acetate Mass spectra (EI, 70 eV) were recorded on a Varian MATT 311A instrument.Melting points are uncorrected. 1H NMR data of all compounds are in Tables 1 and 2. Tryptamine derivatives 4a,b were prepared according to known procedures. 21Trisubstituted thioureas 6a-d and imidazothiadiazines 7a-d were synthesized by the conditions described in our earlier communication. 5

General procedure for the synthesis of compounds (10a-e)
A solution of each of the compounds 9a-e (0.69 mmol) and 0.09 ml (0.71 mmol) DMAD in 20 mL of methanol was stirred for 1-4 h.The precipitates of compounds 10a-e were filtered off and recrystallized from methanol.

Table 2 .
1H NMR data of compounds 9a-c and 10a-e (all J values in Hz).

Table 3 .
Selected chemical shifts of13C NMR of compounds 7a-d and 10a-e * Signals are overlapped with signal of solvent.