Multicomponent reactions of urea and its derivatives with CH 2 O and H 2 S in the synthesis of 1,3,5-thiadiazinane-4-(thi)ones and macroheterocycles

A convenient, efficient, and practical method for the synthesis of 1,3,5-thiadiazinan-4-(thi)ones via a multicomponent condensation of urea (or thiourea), formaldehyde and hydrogen sulfide in the presence of a four-fold molar excess of n -BuONa is described. It provides the novel acid-(H 2 SO 4 ) and base-( n -BuONa)-promoted approach for the one-pot synthesis of the amidine containing macroheterocycles from guanidine and diphenylguanidine. X-ray powder diffraction analysis gave insight into the structure of the 4-methyl-sulfonyl-2H -1,3,5-thiadiazine hydriodide.

In the present study, we have investigated multicomponent condensation of urea 1, thiourea 2, guanidine 8 and N,N-diphenylguanidine 12 with CH2O and H2S in purpose to synthesize 1,3,5thiadiazinane-4-(thi)ones as well as sulfur-and nitrogen-containing macrocycles with carbamoyl fragments under various conditions (promoters, temperature, molar ratio and order of mixing of starting reagents).

Results and Discussion
It is known that polycondensation of urea 1 and CH2O is widely used in the synthesis of ureaformaldehyde resins. 19Condensation of urea 1 with CH2O and H2S in aqueous medium also occurs quite intensively with the formation of oxygen-, sulfur-and nitrogen-containing crystalline net polymers 3a-d.
Note that the syntheses of 1,3,5-thiadiazines via the condensation of the acid amides and urea with isocyanates or α,α'-dichloroalkylamines are described in the literature. 3,20However, in these reactions, only one NH2 group of urea moiety is involved, as far as the imino form of acid amides or urea is involved in the cyclization reaction.
The NMR data confirmed the formation of macroheterocycles 3e and 4a-d.Thus, there are two types of signals, which correspond to the methylene and carbonyl (or thiocarbonyl) carbons.In the 1 H and 13 C NMR spectra the resonances at δH 4.33 and 4.35, δC 43.81-44.30and δC 176.26 (158.12)ppm were assigned to -SCH2N-and C=O(C=S) moiety, respectively.The broadened signals of NH group were observed at δН 6.81 and 8.63 ppm in the 1 H NMR spectra and at ν 3300 cm -1 in the IR spectrum.
The 13 C NMR spectrum of compounds 5 contains two signals at δC 63.65 and 31.82ppm attributable to the C(2,8) and C(4,6) atoms respectively, which in turn, according to the HSQC experiment, correlate to the signals at δH 4.67 and 3.90 ppm (1:1 integrated intensity ratio) in the 1 H NMR spectrum.It is interesting to note that the methylene protons of the -OCH2S-moiety magnetically nonequivalent, apparently, as a result of conformational features of the eightmembered heterocycle.The HMBC spectrum reveals the expected correlations between H(4) (δH 3.90) and C(2) (δC 63.65) as well as between H(2) (δH 4.67) and C(4) (δC 31.82), which testifies in favor of the proposed structure.Mass spectrum of 5 shows the molecular ion peak at m/z 169 [M+H] + .As a result, product 5 was identified as 1,3,5,7-oxatrithiocane.

Scheme 2
The structure of 10 is proved by 1 Н, 13 С, and 2D NMR spectroscopy, X-ray powder diffraction, high resolution MALDI TOF mass spectrometry as well as IR spectroscopy and elemental analysis data.
The HMBC experiments have shown that the sp 2 -hybridized C(4) atom interacts both with the methyl protons at C(8) and the methylene protons in positions 2 and 6.In the 13 C NMR spectra of compound 10 the methylene protons and the C(2) and C(6) atoms are magnetically equivalent (δН 4.62, δС 43.66 ppm), that is why we have assumed two resonance structures 10a and 10b in solution (Scheme 3).
The crystal structure of 10 contained two N-H … I hydrogen bonds (N … I 3.478 and 3.586 Å, N-H … I 159° and 140°, respectively).The crystal of 10 is found to be formed by infinite hydrogen-bonded chains, bonded to each other with weak C-H … S, S … S and C-H … I van der Waals interactions.
In contrast to the weakly basic urea, the strongly basic guanidinе underwent thiomethylation promoted by n-BuONa to yield three-dimensional oligomer (92%), cross-linked by the methylenesulfide -CH2SCH2-and -СH2SCH2SCH2-links.

Scheme 4
So, in the temperature range from 20 to 60 ºC the guanidine sulfate salt 11 is not practically involved in the reaction with CH2O and H2S.Apparently, the guanidine sulfate salt 11 appears as a promoter in cyclocondensation of CH2O and H2S to produce O,S-containing heterocycles 5 and 12.

Conclusions
Thus, for the first time, we have synthesized 1,3,5-thiadiazinane-4-(thi)ones by multicomponent condensation of (thio)urea with CH2O and H2S in the presence of four moles of n-BuONa promoter.Equimolar amount of n-BuONa promotes the formation of macrocycles containing urea fragments and the methylenesulfide -CH2SCH2-chains (n = 4-15).A new possibility to design the amidine macroheterocycles containing the methylenesulfide links through the multicomponent condensation of guanidine or N,N'-diphenylguanidine with CH2O and H2S in one preparative stage has been shown.

Experimental Section
General.The original reagents (materials) are commercially available (ZAO "Khimreactivsnab") and, in all experiments, have been used with a purity of not less than 95%.The solvents were purified, dried, and exploited freshly distilled according to. 28he 1 H and 13 C NMR spectra were recorded in DMSO-d6 (δС = 39.50) on a spectrometer Bruker Avance 400 [400.13MHz ( 1 H) and 100.62 MHz ( 13 C)] in accordance with a standard Bruker protocol.The chemical shifts (δ) are given in ppm relative to TMS (tetramethylsilane).Homoand heteronuclear HSQC, HMBC and COSY methods were carry out by standard Bruker program.Infrared spectra (IR) were recorded using FT-IR spectrometer Bruker Vertex 70 v (vaseline oil).Chromatography-mass-spectrometric analysis of compounds 5, 12, 13 was performed on SHIMADZU LCMS-2010 EV instrument by atmospheric pressure chemical ionization (APCI) mass spectrometry; the maximum temperature of the APCI probe was 500 C; the temperature of the heating source was 200 C, the temperature of the vaporizer was 250 C; nitrogen that was produced by an NM18L ultra-high purity nitrogen generator was used as the nebulizing gas; the liquid flow rate was 0.05 mL min -1 , the nebulizing gas flow rate was 2.5 mL min -1 ; the ion source voltage was as follows: (+), 4.5 kV; (-), 3 kV.Mass spectra of high-resolution of compounds 6, 8, and 10 (regime of negative ions) was recorded in DMSO on a spectrometer "MALDI-TOF Autoflex III" (Bruker, Germany), α-cyano-4-hydroxycinnamic acid as a matrix.Sample of 6 or 8 or 10 was prepared by the "dried droplet method" (1:10).The powder pattern of 10 was measured on Bruker D8 Advance Vario diffractometer with LynxEye detector and Ge (111) monochromator, (CuKα1) = 1.54060Å, θ/2θ scan from 10° to 80°, step size 0.009188°.The measurement was performed in transmission mode, with 10 deposited on sticky tape.Elemental analysis of the samples was carried out using Carlo-Erba Elemental Analyzer model 1106.The melting points were measured using an RNMK 80/2617 melting point apparatus.The pH values of the solutions were measured adjusted using a pH-340 pH-meter.

X-Ray crystal data for (10)
The crystal structure of 10 was solved with direct-space methods using the simulated annealing global optimization algorithm.The starting model starting geometry of the cation for the structure solution was taken from M05-2X/6-311G* isolated state calculation performed in Gaussian software package. 25During the solution and subsequent refinement, the organic cation was treated as a rigid body (translations and Eulerian angles refined) with geometry taken from quantum-chemical calculation (except for hydrogen atoms moved to idealized x-ray positions) and one torsion angle (C4 S2 C3 N2) refined.The iodine atom was refined isotropically without any constraints and/or restraints (Figure 3).After structure solution, the thermal parameters for lighter atoms were refined isotropically, with one common thermal parameter Ueq(S) chosen for sulphur atoms, and one more (Ueq(N,C)) for nitrogen and carbon atoms combined.The refinement converged to Rp/RP'/ RWP/ RWP'/RBragg values of 2.399/2.231/4.266/3.833/4.787 %.The reasonable geometry of intermolecular contacts and values of isotropic thermal parameters after Rietveld refinement confirmed the correctness of chosen molecular model.The difference curve showed the presence of small amount of unidentifiable impurity in 10, however, its presence did not affect the Rietveld refinement significantly.All calculations were performed in TOPAS 4.2 software suite. 23,24Additional details of the Rietveld refinement, refined lattice parameters and atomic coordinates of 10 are included in the crystallographic information file (CCDC 783903) deposited in the Cambridge Structural Database.

Figure 2 .Figure 3 .
Figure 2. The general view of 10 in crystal.