Unusual direction of three-component reactions involving 2-amino-4-arylimidazoles and carbonyl compounds leading to Knoevenagel-Michael adducts

Three-component reaction of 2-amino-4-arylimidazoles, aldehydes and dimedone or barbituric acid proceeds in an unusual direction and instead of imidazo[1,2-a ]pyrimidine derivatives gives Knoevenagel-Michael adducts having abnormally low reactivity in heterocyclizations.


Introduction
2-Amino-1H-imidazole containing molecules are of particular interest, especially within the realm of medicinal chemistry.For example, several classes of marine natural products possessing this fragment were recently discovered and identified. 1 Many of compounds based on aminoimidazole moiety display a broad range of biological properties and were recognized as H1-and H2-receptor agonists and antagonists, 2 5-HT3 receptor antagonists, 3 antibacterial remedies and other. 4Recently, it was demonstrated that compounds of this type occurring in nature inhibit and disperse bacterial biofilms through a non-bactericidal mechanism. 5 In the past few years multicomponent reactions (MCRs) of broad range of 2-aminoazoles with CH-acids and aromatic aldehydes have attracted the interest of the synthetic community since the formation of different condensation products can be expected depending on the specific conditions and structure of the starting materials. 6Multicomponent reactions often use simple and readily available starting materials that makes them an excellent synthetic tool for combinatorial chemistry, creating high scaffold diversity and a large variety in functional groups.
To the best of our knowledge the behavior of 2-amino-1H-imidazoles in multicomponent reactions has been studied insufficiently and there are relatively few publications dealing with heterocyclizations of their 4-substituted derivatives. 7,8There is only one publication by Ryabukhin et al. which described application of 4( 5)-substituted 2-aminoimidazoles 1 in multicomponent Biginelli-type reactions with aldehydes and CH-acids in the presence of TMSCl as promoter (Scheme 1). 7  Scheme 1. Synthesis of known dihydroimidazo [1,2-a]pyrimidines.
Other publication reported sequential reactions via preliminary synthesis of α,β-unsaturated compounds.For example, it was described synthesis of 5,6-dihydroimidazo [1,2-a]pyrimidines 3 by reaction of aminoimidazoles 1 with chalcones.8a Meng and co-authors published syntheses of dihydroimidazo [1,2-a]pyrimidine-6-carboxylates and -6-carboxamides 4 via condensation of amines 1 with enones.8b-d In all the cases reported only one endocyclic nucleophilic center of aminoazole was involved in the reaction and formation of compounds like 5 as well as other types was not observed.
In continuation of our recent interests in multicomponent reactions for the synthesis of small heterocyclic molecules, 6b,9 herein we report a three-component reaction of 4-aryl-2-amino-1Himidazoles with aromatic aldehydes and dimedone and 1,3-dimethylbarbituric acid.

Scheme 2. Multicomponent microwave-assisted synthesis of adducts 10a-n.
Microwave irradiation is often used for increasing efficiency of chemical processes and for tuning selectivity of organic synthesis. 10This method was also applied for the MCRs studied.However, the treatment of the starting materials 1, 6 and 7 which was carried out in EtOH or DMF in microwave reactor in a wide range of temperatures (120 -190 °C) led to increasing the yields of adducts 10 (up to 82%) while formation of heterocyclic compounds 8 or 9 was not observed as well.
Based on these empirical observations a thorough optimization of the reaction conditions ultimately led to a microwave-assisted procedure which allowed isolation of adducts 10a-n in 70-84% yields (Table 1) with purity of 97% (TLC and NMR control).The optimal synthetic conditions consist in dissolving equimolar amounts of the starting materials in ethanol containing 1.0 equivalent of Et3N and further MW heating the reaction mixture in a sealed vial at 150 °C for 15 min.
The optimized microwave procedure were applied to closely related treatment involving 1,3dimethylbarbituric acid 11 as one of the building blocks (Scheme 3).However, it was found that under these conditions the MCR followed with intense degradation of the reaction mixture.The same situation was observed in the case of using conventional heating in ethanol or DMF.
To solve this problem we used ultrasound-assisted synthesis which application was earlier described for increasing efficiency of organic reactions at room temperature. 11In our case ultrasonication of the mixture containing 2-aminoimidazole 1a,b, barbituric acid 11 and aromatic aldehydes 6a-h in ethanol at room temperature for 30-45 min gave adducts 12a-l in 68-85% yields.A presence in the reaction mixture of acidic (AcOH, HCl) or basic (Et3N) catalysts decreased yields and purity of the compounds 12. Scheme 3. MCR of 2-amino-4-arylimidazoles, aldehydes and 1,3-dimethylbarbituric acid.
Thus, variation of the reaction conditions (solvent/additive system, temperature, time, activation type) has no influence on the unusual direction of MCRs between 2-aminoimidazoles 1, aldehydes 6 and cyclic active methylene compounds 7 or 11.
Numerous attempts to carry out further heterocyclization of compounds 10 and 12 into pyrrolo [1,2-e]imidazoles by refluxing in DFM even with help of water-consuming agents or to carry out reaction with aldehydes which should give imidazo [1,5-a]pyridines were unsuccessful and led to isolation of the unchanged adducts 10 or to decomposition of adducts 12.
It was also found another unusual result: adducts 10 and 12 were not able to react with α,βunsaturated ketones 2 with formation of imidazo [1,2-a]pyrimidines 14 as it had been described 8a for starting 2-aminoimidazoles 1 (Scheme 1).Such low reactivity can be explained by the steric influence of both R-substituent and arylmethylcyclanone moiety which prevents proceeding addition of endocyclic NH-group to enone system of ketone.Existing zwitterionic tautomeric forms (see below) may also contribute to the unusual behavior.
It seems that multicomponent reactions between of 2-amino-4-arylimidazoles, aromatic aldehydes and dimedone or 1,3-dimethylbarbituric acid proceed via preliminary formation of cyclic α,β-unsaturated carbonyls I which enone system then is attacked by CH-nucleophilic center of azole ring (Scheme 5).Scheme 5. Two-step procedure for the synthesis of adducts 10 and 12 from 2-aminoimidazole and α,β-unsaturated carbonyls.Due to low synthetic availability of arylidencyclohexan-1,3-diones in addition we carried out reaction of aminoimidazole 1a with compounds 16a-d which also led to formation of adducts 10a,b,d,e.
The difference between behavior of chalcones 8a or aryliden derivatives of acetoacetic acid esters 8b-d and cyclic α,β-unsaturated ketones 15a-d in their reaction with aminoimidazoles 1 may be connected both with steric factors and with unfavorable for the cyclocondensation S-cisconfiguration of the enone fragment in the compounds like I (Scheme 5) complicated by the high rigidity of the skeleton.
The structures of adducts 10 and 12 were established with help of elemental analyses, MS and NMR spectroscopic data and X-ray study.For instance, 1 H NMR spectra of compounds 10 exhibit the following signals: multiplets for the aromatic rings (6.5-8.0 ppm) and appropriate signals for their terminal substituents, a singlet for the CH proton (5.8 ppm), four doublets for the two CH2 groups, singlet for two methyl groups (0.9 ppm), singlet for the NH2 group (6.4-6.5 ppm) and a broad singlets for the NH-and OH-groups (or NH and NH + due to existing zwitterionic tautomeric forms, see below) at 11.0 and 16.0 ppm, respectively.Spectra of compounds 12 contain similar sets of signals taking into account the replacement of dimedone fragment with barbituric one.
Finally, the structure of compounds synthesized was proved by X-ray diffraction data obtained for crystal of 10d (Figure 1).

Conclusions
In summary, the multicomponent reactions of 2-amino-4-arylimidazoles, aromatic aldehydes and dimedone or 1,3-dimethylbarbituric acid under conventional heating, microwave or ultrasonic irradiation were studied and unusual directions resulting in formation of Knoevenagel-Michael adducts instead of imidazoquinazolinone fragment was established and discussed.Abnormally low reactivity of these adducts was found therefore attempts to carry out their further modifications were unsuccessful.

Experimental Section
General.Melting points were obtained on a standard melting point apparatus in open capillary tubes. 1 H and 13 C NMR were recorded on a Varian-Mercury VX-200 spectrometer (200 MHz, 50 MHz for 13 C) in DMSO-d6.Mass spectra were recorded on GS/MS spectrometer Varian 1200L (70 eV) using direct input of sample.Elemental analysis was made on a EuroVector EA-3000.TLC analyses were performed on pre-coated (silica gel 60 HF254) plates.Ultrasonication was carried out with help of standard ultrasonic bath producing irradiation at 44.2 kHz in round-bottom flasks equipped with a condenser.Microwave experiments were performed using the Emrys TM Creator EXP reactor from Biotage AB possessing a single-mode microwave cavity producing controlled irradiation at 2.45 GHz.Experiments were carried out in sealed microwave process vials using high absorbance level settings and IR temperature monitoring.Reaction time reflect irradiation times at the set reaction temperature (fixed hold times).All solvents and chemicals were obtained from standard commercial vendors and were used without any further purification.Intensities of 27690 reflections (16080 independent, Rint=0.154)were measured on the «Xcalibur-3» diffractometer (graphite monochromated MoKα radiation, CCD detector, ωscaning, 2Θmax = 60).The structure was solved by direct method using SHELXTL package. 13 The absorption correction was performed by multi-scan method (Tmin =0.751, Tmax =0.928).Positions of the hydrogen atoms were located from electron density difference maps and refined by "riding" model with Uiso = nUeq (n= 1.5 for methyl groups and n=1.2 for other hydrogen atoms) of the carrier atom.Full-matrix least-squares refinement against F 2 in anisotropic approximation for non-hydrogen atoms using 15870 reflections was converged to wR2 = 0.181 (R1 = 0.079 for 3731 reflections with F>4σ(F), S = 0.768).The final atomic coordinates, and crystallographic data for molecule 10d have been deposited to with the Cambridge Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk) and are available on request quoting the deposition numbers CCDC 881950).38, 21.96, 31.52, 34.04, 55.62, 113.13, 114.52, 121.13, 122.94, 127.38, 128.15, 128.76, 129.52, 133.41, 143.05, 147.11, 158.15

Figure 2 .
Figure 2. Zwitterionic tautomeric forms of the compound 10d in the crystal phase according Xray diffraction data.

15a-d and aminoimidazole 1a leading to adducts 12a,b,d,e both
under conventional and microwave (150 °C) heating confirmed this hypothesis.