A one-pot synthesis of N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines and systematic evaluation of their ability to host ethanol in crystals

A convenient one-pot method for the preparation of N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines was developed using a three-component synthesis of 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-diamines followed by their Dimroth rearrangement to the desired products. The prepared compounds crystallized from ethanol as ethanol clathrates (1 : 1). X-ray crystallography on several products confirmed the adoption of 5,6-dihydro-tautomer. The thermal analysis and powder X-ray diffraction experiments on selected compounds suggested that thermal desolvation of crystals was irreversible.

Variations of substituents on aniline (1c-j) benzaldehyde (1k), and their combinations (1b) were tolerated in the reaction. The structure of the prepared compounds 1 was conrmed by NMR spectroscopic data. The signals of the sp 3 -hydridized carbon atom in 13 C NMR spectra at 67.5-68.4 ppm and the corresponding proton in 1 H NMR spectra at 5.70-5.77 ppm conrmed formation of the dihydrotriazine ring. We found that it was critical for the success of the reaction to maintain pH at 10-11. Further increase of the pH resulted in the partial dehydrogenation of the product and aromatization of the dihydrotriazine in a process similar to the one we reported earlier. 5 The products were isolated as a racemic mixture of R-and Sstereoisomers in the form of ethanol solvates aer recrystallization from this solvent. The integration of signals at 1.06, 3.44-3.45, and 4.34-4.37 ppm, attributed to ethanol, in the 1 H NMR spectra of samples dried in air at room temperature indicated that all prepared solvates of N 2 ,6-diaryl-5,6-dihydro-1,3,5triazine-2,4-diamines (1) contained one molecule of ethanol per heterocycle molecule. This was further conrmed by X-ray crystallographic studies as described below. We did not observe formation of stable clathrates with methanol and desolvated compounds 1 can be obtained by the recrystallization from this solvent. The NMR spectra of a representative desolvated sample of 1a can be found in ESI. † In principle, three tautomeric forms of the prepared compounds are possible due to annular prototropic tautomerism in the dihydrotriazine ring (Scheme 3). In the 1 H NMR spectra of compounds 1, signals of the annular NH and the NH link between the triazine and benzene rings were very broad and not always detectable. This can be attributed to the tautomerism, proton exchange with ethanol, or both processes taking place together. X-ray crystallography (vide infra) revealed that the compounds crystallized as the 5,6-dihydro-tautomer, A.
The molecular structures of 1b, 1e and 1f were established by single crystal X-ray crystallography as their ethanol solvates (1 : 1) and found to be isostructural. The discussion will focus on 1e$EtOH with details of 1b$EtOH and 1f$EtOH available in the ESI. Crystals of 1e$EtOH adopt the non-centrosymmetric space group P2 1 with two independent molecules each of 1e and ethanol comprising the asymmetric unit of 1e$EtOH, Fig. 1; the molecular structure diagrams for 1b$EtOH and 1f$EtOH are given in ESI Fig. S1 and S2, † respectively.
The independent molecules of 1e are related by a noncrystallographic centre of inversion with the congurations at the C1 and C16 atoms being R and S, respectively; this therefore, an example of kyptoracemic behaviour. 7 Key geometric parameters are collated in Table 1 for 1e$EtOH and ESI Table S1 † for 1b$EtOH and 1f$EtOH. The parameters describing chemically equivalent bonds and angles follow the same trends across the series. At least three key parameters point to the adoption of 5,6dihydro-tautomer, A, shown in Scheme 3. These are the short C2-N1 bond, consistent with signicant double bond character, the wider angle subtended at the N3 atom compared with those at the N1 and N2 atoms, consistent with protonation at N3, and the participation of the N3-bound proton in signicant hydrogen bonding interactions with the N7 atom of the second independent molecule and conversely, the N8-bound proton to the N2 atom. Based on the closeness of the C3-N2 and C3-N3 bond lengths, there is some evidence of delocalization of the pelectron density over these atoms.
The N1-triazine ring adopts an envelope conformation whereby the C1 atom lies 0.442(3)Å out of the plane dened by The molecules have been overlapped so the N1, N2 and N3 atoms are coincident. Solvent ethanol molecules are omitted.
the ve remaining atoms, r.m.s. deviation ¼ 0.033Å; the equivalent parameters for the N6-ring/C16 atom are 0.471(3) and 0.034Å, respectively. There are some conformational differences evident between the two independent molecules as highlighted in the overlay diagram of Fig. 1(c). These relate primarily to the relative orientation of the phenyl rings. The dihedral angles between the best plane through the triazine ring and the phenyl and chlorophenyl rings are 89.59(8) and 17.74 (12) , respectively for the N1-molecule; the equivalent angles for the N6-molecule are 72.76(9) and 19.24(14) , respectively. For the N1-and N6-molecules, the dihedral angle between the peripheral rings are 77.95(8) and 57.86(9) , respectively. Very similar trends are evident in the molecules comprising the methoxy (1b) and bromo (1f) analogues; see ESI Table S2 † for data.
An interesting feature of the crystal structure determinations of 1b$EtOH, 1e$EtOH and 1f$EtOH is that each has occluded solvent in their structures so the ratio of organic molecule to ethanol was 1 : 1. A description of the molecular packing of 1e$EtOH ensues; details of the intermolecular interactions are gathered in Table 2. Fig. 2(a) shows a view of the molecular packing for 1e$EtOH showing only contacts occurring between the organic molecules, i.e. 1e only. The two 1e molecules in the asymmetric unit are connected into helical supramolecular chains via ring amine-N-H/N(imine) hydrogen-bonding. The chains are aligned along the b-axis direction, being propagated by screw (2 1 ) symmetry. The connections between chains along the c-axis are of the type primary amine-N-H/p(chlorophenyl), again occurring between the different 1e molecules of the asymmetric unit. Links between layers along the a-axis are of the type phenyl-C-H/p(phenyl). Here, the donor and acceptor molecules are the N1-and N6-containing molecules, respectively. As there is no reciprocal contact, i.e. having the N6-and N-molecules as the donor and acceptor, this interaction distinguishes the two independent molecules. Each of the independent ethanol molecules participates in analogous hydrogen-bonding with the 1e molecules dening the host structure. The donor interactions are of the type ethanol-O-H/ N6(triazine), where the nitrogen acceptor is adjacent to the methine-carbon atom. The ethanol molecules each accept two hydrogen bonds, one from each of the exocyclic amines.
Subtle differences in the molecular packing are apparent in the crystal of 1b$EtOH; see ESI Table S3  1f$EtOH, mimics that described above with the addition of inter-layer phenyl-C-H/Br contacts; see ESI Table S4 and Fig. S4. † Additional investigations were conducted on the three crystallographically characterised compounds, i.e. simultaneous thermal analysis (STA) and powder X-ray diffraction (PXRD) studies. The original STA traces and data are given in ESI Fig. S5. † For 1b$EtOH, the results of the thermogravimetric analyses showed a single-step between 90 and 162 C corresponding to the loss of one ethanol molecule per molecule of 1b. Similar features were noted for each of 1e$EtOH and 1f$EtOH although the onset temperatures were higher and the process was completed at lower temperatures. For 1e$EtOH and 1f$EtOH, a second exothermic event corresponding to melting was also observed. This was not seen in the STA of 1b$EtOH and visual inspection showed the sample to be a paste aer desolvation in contrast to the powders generated aer the desolvation of the other samples. In order to ascertain whether desolvation altered the crystal structures of 1e$EtOH and 1f$EtOH, PXRD measurements were conducted. As   (3) x, y, z seen from ESI Fig. S6, † the desolvated forms did not retain the original crystal structures. Attempts at re-solvation of 1e and 1f were performed. Thus, powders were placed in a sample vial which was in turn placed in a larger container containing ethanol, capped and allow to stand overnight. Subsequent PXRD measurements showed no evidence of re-solvation.
The STA and PXRD data for selected compounds suggested that desolvation irreversibly change crystal structure.

General information
All the chemicals and reagents were purchased from commercial suppliers (Sigma-Aldrich, Merck, and Alfa-Aesar) and were used without additional purication. Melting points (uncorrected) were determined on a Stuart™ SMP40 automatic melting point apparatus. 1 H and 13 C NMR spectra were recorded on a Bruker Fourier NMR spectrometer (300 MHz) using DMSO-d 6 as a solvent and TMS as an internal reference. The chemical shis are reported in parts per million (ppm, d) and coupling constants are reported in Hertz with the splitting pattern described as singlet (s), broad signal (brs), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), double of doublet of doublets (ddd), or multiplet (m). Thermogravimetric analyses were performed on a PerkinElmer STA 6000 Thermogravimetric Analyzer in the range 25-600 C at the rate of 10 C min À1 under a nitrogen purge. The data was manipulated by PerkinElmer thermal analysis proprietary soware Pyris®. Powder X-ray diffraction (PXRD) patterns were measured on a Rigaku SmartLab X-ray diffractometer using Cu-Ka (l ¼ 1.5406 A) radiation in the 2q range 10 to 60 with step size 0.01 .

Conflicts of interest
There are no conicts to declare.