Concise and regioselective synthesis of 5H -imidazo[1,2-e ][1,3,5]triazepines

In this communication


Introduction
Aza-heterocycles are common structural motifs found in naturally occurring systems and bioactive molecules. 1,2Among them, imidazotriazepines are privileged structural scaffolds that show a broad spectrum of potent biological activity and have been widely applied in medicinal chemistry as inhibitors of adenosine deaminase (like example 1, Figure 1), 3 inhibitors of NTPases/helicases of Flaviviridae -including the West Nile virus (WNV), hepatitis C virus (HCV), and Japanese encephalitis virus (JEV) 4 -, selective inhibitors of hepatitis B virus (HBV) 5 (for example, compound 2), inhibitors of the growth of carcinoma nasopharynx, breast cancer and cervical cancer cell lines (see compound 3) 6 and potential drug candidates for treating the central nervous system diseases (see compounds 4 and 5). 7,8gure 1.Examples of biologically active imidazotriazepine frameworks.

Results and Discussion
After carefully optimizing reaction conditions, N-(1,2,2-trichlorovinyl)-benzimidoylchlorides 6a-h were obtained in 3 steps with good yields (Scheme 1).The first stage of the synthetic sequence was the interaction of amides 7a-h with chloral while heating, resulting in the corresponding chloralamides 8a-h.Further reaction of products 8a-h with PCl5 in POCl3 while heating, gave imidoyl chlorides 9a-h, which were then treated with triethylamine in THF to obtain the target N-(1,2,2-trichlorovinyl)benzimidoylchlorides 6a-h in yields of up to 92% (Scheme 1).The purity of 8a-h and 9a-h was 98% or higher (based on 1 H NMR spectra data of reaction mixtures), and the products were successfully used in subsequent stages without additional purification and characterization (spectral data are given only for product 8g, 9f, 9g, and 9h).

Scheme 2. Synthesis of target 5H-imidazo[1,2-e][1,3,5]triazepines 11a-h.
A plausible mechanism of the reaction is presented on Scheme 3. Presumably, products 6 interact first with the amino group of 2-(aminomethyl)imidazole, first resulting in the intermediary A, for which prototropic forms B and C are possible.The direction of the imidazotriazepine system-forming process (6 to product 11) is determined by the high nucleophilicity of the side chain amino group compared to the N 1 and N 3 centers of the imidazole ring (Scheme 3).Additionally, chlorine atom mobility near C 1 and C 3 of 6 and prototropy of intermediaries A-C play an important role.The combination of these factors results in the formation of product D or its prototropic isomers E and F, which contain a 7-membered triazepine ring (Scheme 3).Among the three prototropic forms D, E, or F, the form F (products 11a-h) is more probable, as evidenced by the lack of CHCl2 group characteristic signal and the presence of the characteristic NH triplet at 7.86-8.89ppm in the DMSO-d6 1 H NMR spectra.NMR spectra obtained at a higher temperature (40°C) demonstrated the presence of all three prototropic forms D, E, and F, where a proton moved from one part of the molecule to another accompanied by the migration of the double bond.
In addition, single crystal X-ray crystallography of 11a showed that the single most energetically favorable prototropic form 11 existed in the crystal state (Figure 2).
The five-membered N3N4C3C12C13 cycle in structure 11a is planar (the rms deviation of fitted atoms is 0.0021) and bond distances and angles are typical for the pyrazole cycle.The seven-membered N1N2N3C1C2C3C4 cycle has a butterfly-like conformation with a dihedral angle between C2N3C3C4 and C2N2C1N1C4 planes of 126.4°; in addition, the bond distances indicate conjugation in the N1C1N2C2C11 fragment.In the crystal form, two molecules are connected in a centrosymmetric dimer N1H1n•••N4a by a hydrogen bond with the following parameters: N1-H1n 0.88(3), N1•••N4a 2.952(4)Å, N1-H1n-N4a 154(2)° (nitrogen atom labeled 'a' is connected to original atoms by symmetry operation -x, -y,-z).The scope of application of this heterocyclization allowed the introduction of substituted aliphatic, aromatic, and heterocyclic substituents onto the C-7 position of the imidazotriazepine system.However, the introduction of a CH3 group via this approach turned out to be impossible due to the high reactivity of methyl-2-azatetrachloro-1,3-butadiene 6 (R = CH3), which appeared to spontaneously polymerize.An attempt to perform the cyclization of this compound with 9 did not result in the desired end product 11 with a methyl group as R. Additionally, this method did not allow the introduction of hydrogen into the C-7 position of the imidazotriazepine due to isocyanate formation from the corresponding chloralamide and phosphorus pentachloride.
It should be noted that the prototropy of the obtained imidazotriazepines makes them susceptible to polymerization.Thus, heating solutions of these compounds above 60°C, or melting them, results in resinification, complicating the purification of these compounds via recrystallization from solvents with a high boiling point.
We also demonstrated that imidazotriazepines decompose in an aqueous base medium.Thus, treating product 11b in methanol with an aqueous solution of NaOH resulted in a stable amidine 12b (Scheme 4).Scheme 4. Synthesis of amidine 12b.

Experimental Section
General.The solvents were purified according to the standard procedures. 15All other starting materials were purchased from commercial sources.Analytical TLC was performed using Polychrom SI F254 plates.Elemental analyses were performed at the Analytical Laboratory of the V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry NAS of Ukraine.Melting points were measured on MPA100 OptiMelt automated melting point system.InfraRed (IR) spectra were recorded on a VERTEX 70v FT-IR spectrometer in KBr plates.NMR spectra were recorded on a Varian Unityplus 400 spectrometer (400 and 100 MHz respectively) in DMSO-d6 and CDCl3 solutions; chemical shifts are reported in ppm with solvent residual signal used as an internal standard ( 1 H, 13 C).Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (APCI)).

General procedure for the preparation of N-(1,2,2-trichlorovinyl)(het)arylchlorides (6a-h).
To a solution of 0.0535 mol of one of compounds (9a-g) in THF (100 mL) was added triethylamine (7.5 mL, 0.054 mol).The reaction mixture was then stirred for 24 h.The precipitate was filtered, washed with THF (20 mL), and the filtrate was evaporated in vacuo.The resulting imodyl chloride was subsequently obtained by distillation in vacuo.