C-N Bond forming reactions in the synthesis of substituted 2-aminoimidazole derivatives

Carbon-nitrogen bond forming reactions oriented to the synthesis of 2-amino-imidazolidines and imidazoles have been investigated. The C-2 amination of imidazolidinones, via the corresponding 2-chlorodihydroimidazoles, led to 2-benzylaminodihydroimidazole or bis(dihydroimidazole)amino derivatives by choosing the adequate experimental conditions. On the other hand, the use of N -acyl-2-methylsulfanyldihydroimidazoles allowed carrying out the reactions with aromatic amines, such as p -anisidine. Finally, palladium catalyzed Buchwald-Hartwig amination was the method of choice for C-N coupling between 2-haloimidazoles and aromatic amines in the synthesis of the corresponding imidazoles.


Introduction
The 2-aminoimidazole or imidazoline moieties are important structural patterns present in natural and/or synthetic products that display a broad range of biological activities.2][3] Different types of substituted 2-aminoimidazoles, including the pyrrole-2aminomidazoles of the oroidin family and their synthetic analogs 4,5 possess anti-biofilm activities, 6,7 while 2-arylamino or iminoimidazolidines (e.g.[11]

Figure 1
Several synthetic methods have been reported in the literature to obtain 2-aminoimidazoles that involve the construction of the heterocycle, 1 including the addition of substituted guanidines 12,13 or 2-aminopyrimidines (protected guanidines) 14 to -haloketones, the basemediated semi cleavage of hemiaminals obtained by reaction of N-Boc protected guanidines and N-carbomethoxy-1,2-dihydropyridines, 15 or the condensation of cyanamide and α-aminoketones 16 or α-aminoesters. 6In a similar way, the corresponding 2-aminoimidazolines have been synthesized by condensation of N-arylcarbonimidodithioates and ethylenediamine, 17,18 and by intramolecular cyclization of functionalized arylthioureas, obtained by reaction of isothiocyanatobenzene and ethylenediamine. 19,20 different approach relies in the late-stage introduction of the 2-amino group into imidazoles or imidazolines.2][23][24][25][26] However, this procedure requires several steps, and has failed in the synthesis of some natural products, such as kealiiquinone. 27To solve these problems, Lovely group has recently developed a convenient procedure for the direct conversion of imidazolium salts into 2-aminoimidazoles by using Nchloroamides at room temperature. 279][30][31] Other procedures involve the condensation of amines with dihydroimidazol-3-ium-2-sulfonate 32 or with protected imidazolidine-2-thione, though the last procedure requires the use of mercury (II) chloride. 9s part of our program to develop new procedures for the synthesis of heterocyclic systems, [33][34][35] we investigated several carbon-nitrogen bond forming reactions directed to the synthesis of 2-aminoimidazole derivatives.The aim was to achieve the amination at the C-2 position of both imidazole and imidazolidine moieties, avoiding metalation with strong (and potentially nucleophilic) bases.Thus, we studied the amination of imidazolidinones via the corresponding 2-chlorodihydroimidazoles (I, X = Cl), or 2-methylsulfanylhydroimidazoles (I, X = SCH3), and palladium catalyzed reactions of 2-haloimidazoles and amines (I, X = Br).Further, we were interested in the application of these procedures to the synthesis of bisimidazolic systems, such as III, in one step (Figure 2).

Results and Discussion
It is observed that a large number of bioactive alkaloids contain a central 2-aminoimidazole ring, substituted by one or two benzyl groups at various locations around the heterocyclic ring. 2 Although there are no examples of N-benzyl azoles, it should be interesting to prepare this type of derivative in order to test structure-activity relationships.On the other hand, it is very wellknown that the presence of a 2-arylamino or imino group is an important structural key feature of pharmacophores, such as clonidine. 8For this reason, we started our study with the synthesis of 2aminoimidazolines II starting from 2-chlorodihydroimidazoles I (X = Cl) or their methylthio analogue (X = SCH3) and using both benzylamine and p-anisidine.In this context, Cussac group has reported that 2-methylthioimidazolines can be converted into 2-iminoimidazolines by heating with primary amines.While this chemistry appears to work quite well, the alternative route of condensation of primary amines with N-acetylimidazolidin-2-one via its 2-chloro derivative formed in situ with POCl3 only led to low to moderate yields (22-74%) of the N-acetylated imino derivatives. 28e began by using the commercially available imidazolidin-2-one (1a) as substrate.We first tried the one-pot procedure developed by Cussac and col., in which the chloride 2a is generated in situ with POCl3 in the presence of the amine.Although various reaction conditions were tested, this procedure always gave a sluggish reaction, providing a complex mixture of products.After some experimentation, we found that best results were obtained by stepwise conversion of the imidazolidin-2-one into the corresponding 2-chlorodihydroimidazole 2a.This compound has been widely used in the synthesis of diverse heterocyclic structures, [36][37][38] and has been prepared mainly by chlorination of imidazolidine-2-thione. 39 The conditions outlined in Scheme 1 were the most effective overall for the subsequent reaction of 2a with the primary amine to give 2aminoimidazoline 3. Thus, the 2-chloro derivative 2a was efficiently obtained by treatment of imidazolidin-2-one 1a with phosphorus pentachloride in acetonitrile at room temperature.The reaction with phosphorus oxychloride under various conditions was always sluggish.This chloride 2a was immediately reacted with benzylamine in dichloromethane as solvent and at room temperature to give 3 in 62% yield.However, an interesting point arose when we came to perform the amination using the chloride 2a in excess.Thus, treatment of the initially formed 2chloro derivative 2a (2 mmol) with benzylamine (1 mmol) in dichloromethane under reflux for 21 h led to benzyl bis(dihydroimidazole)amine 4 (60 %).It should be pointed out that bis(2aminoimizadolines) with different linkers between the two heterocyclic rings show interesting pharmacological profiles when compare with the mono-imidazoline compounds. 11Furthermore, these compounds could be considered as bidentate nitrogen ligands in transition-metal mediated C-C bond formation reactions. 40hese conditions were tested on the N-acetylimidazolidinone 1b, prepared by acetylation of the imidazolidinone 1a. 41However, all attempts using either benzylamine or p-anisidine always failed.Similar results were obtained when the one-step Cussac protocol was used.

Scheme 1
When we tried to extend the procedure to the use of aromatic amines, the procedure failed.Several exploratory sets of conditions were employed to carry out this transformation either using imidazolidinone (1a) or its N-acetyl derivative (1b), but the results were very poor.Therefore, an alternative route involving amination of alkylthioimidazolidines was investigated.Thus, we decided to apply the procedure developed by Mundla et al. 29 to the N-acyl-2methylthioimidazolines 7a-c using p-anisidine.

Scheme 2
Synthesis of the target compounds 7a-c began with imidazolidine-2-thione 5, which was transformed into the corresponding 2-methylsulfanyldihydroimidazole 6 by treatment with methyl iodide in methanol under reflux (Scheme 2). 42Compound 6 was easily acylated with Ac2O, ClCO2CH3, or ClCO2Bn under standard conditions to the corresponding N-acyl derivatives 7a-c in good yields.
We then undertook the C-2 amination.After some preliminary experiments on the N-acyl derivatives 7a-c with p-anisidine, we settled on using N-acetyl derivative 7a in AcOH (10%) / EtOH under reflux (Scheme 2), which provided the 2-arylimidazoline 8 in moderate yield.With the methoxycarbonyl (7b) and benzyloxycarbonyl (7c) derivatives we observed the formation of complex mixtures of products, probably due to hydrolysis of the carbamate moiety in the acidic reaction media and other unidentified side reactions.Other solvents were used (EtOH, dioxane), but no reaction was observed under these conditions.Although the reaction of the unprotected 2methylsulfanyldihydroimidazole 6 with various primary alkyl amines has been reported, 28 no reaction was obtained when 6 was treated with benzylamine or p-anisidine.Thus, the use of methylsulfanyl derivatives such as 7a allowed the amination reactions with aromatic amines under mild reaction conditions, but it required protection of the nitrogen atom of the imidazoline.However, this procedure did not allow the preparation of bis-(2-aminoimidazolines) when 7a was used in excess.
1D and 2D NMR experiments allowed us to determine the predominant tautomeric form of these compounds.As expected, 3 and 8 exist as the imino tautomers, whereas the bis(guanidine) derivative 4 has perforce the 2-amino structure.In fact, the most characteristic signal for these compounds is the resonance of the quaternary carbon C-2 in the 13 C NMR, which appears at  = 162.0 and 160.0 ppm for the imino tautomers 3 and 8, respectively, and at  = 127.7 ppm for the 2-amino derivative 4. Besides, in the case of the 2-arylamino derivative 8, the ortho aromatic protons are substantially more shielded ( 6.84, d, J 8.9 Hz) than the meta protons ( 7.10, d, J 8.9 Hz).In an amino tautomer all aromatic protons should absorb in a narrow range (6.33-6.74ppm).These data are in full agreement with the predicted chemical shifts and the bibliographical data. 30,43ur next step was to replace the imidazolidine-amine unit by a 2-aminoimidazole.2][23][24][25][26] Therefore, we sought for a more direct approach for the direct introduction of an arylamino group at C-2, which may also eliminate the use of strong bases.In this context, palladium-catalyzed amination methodologies for the formation of C-N bonds 44 were the method of choice.This procedure has been successfully applied mainly to benzo or hetero fused imidazole derivatives.Thus, the reaction of 2chlorobenzimidazoles with 4-aminopiperidine led to the preparation of the antihistaminic norastemizole, 45 while a series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions. 46Thus, we set out to search for an adequate catalytic system to achieve the C-N coupling between p-anisidine and 2-bromo-1-methylimidazole (9) (Scheme 3).

Scheme 3
Initial efforts to effect this palladium-catalyzed reaction employed the protocol developed by the Rizzo group 47 for the coupling of related substrates, 8-bromodeoxyguanosine derivatives: Pd2(dba)3 (10 mol%) as a catalyst in the presence of BINAP (30 mol%) with lithium hexamethyldisilazide as the base in toluene at 100 °C.However, in our case, a complex mixture of products was formed, and the 2-aminoimidazole could not even be detected.A series of bases was screened in an effort to develop a cleaner reaction.Gratifyingly, on changing the base to Cs2CO3, the C-N coupling product, N-aryl-1-methyl-1H-imidazole-2-amine (10), was obtained in very good crude yield (90%), based on 1 H NMR. However, this product was unstable and could not be purified by column chromatography.Because of the aromatic nature of the imidazole ring, this compound presents the 2-arylamino structure.In particular C-2 resonates at  = 139.9ppm in 13 C NMR, while the aromatic protons meta and ortho appear at  6.67, (d, J 9.0 Hz) and  6.72, (d, J 9.0 Hz), respectively. 43Decreasing the catalyst loading led to a lower yield and conversion.It should also be mentioned that attempts to apply the procedure to the 2bromoimidazole with a free NH group or to the corresponding 2-haloimidazolines always failed.

Conclusions
In summary, 2-benzylamino and 2-arylaminoimidazolines were prepared by C-2 amination via the corresponding 2-chlorodihydroimidazoles or 2-methylsulfanyldihydroimidazoles, respectively.The first procedure is the method of choice when primary amines, such as benzylamines, are employed and also allows the preparation of bis(dihydroimidazole)amino derivatives by choosing the adequate experimental conditions.On the other hand, the use of N-acyl-2-methylsulfanyldihydroimidazoles allows the reactions with aromatic amines, such as p-anisidine, to be carried out, though it requires protection of imidazole nitrogen atom as its acetyl derivative.Finally, palladium catalyzed Buchwald-Hartwig amination allows the C-N coupling between 2haloimidazoles and aromatic amines.

Experimental Section
General experimental methods.Melting points were determined in unsealed capillary tubes.IR spectra were obtained on KBr pellets (solids) or in film over NaCl pellets (oils).NMR spectra were recorded at 20-25 ºC, running at 300 or 500 MHz for 1 H and 75.5 or 125.7 MHz for 13 C in CDCl3 solutions, unless stated otherwise.Assignment of individual 13 C and 1 H resonances is supported by DEPT experiments and 2D experiments (COSY, HMBC, HSQC, NOESY) when necessary.Mass spectra were recorded under electron impact at 70 eV.Exact mass was obtained using a TOF detector.GC-MS analyses were performed using a TRB-1 column (methyl polysiloxane, 30 m  0.25 mm  0.25 m).TLC was carried out with 0.2 mm thick silica gel plates.Visualization was accomplished by UV light.Flash column chromatography on silica gel was performed with Kieselgel 60 (230-400 mesh).All solvents used in reactions were anhydrous and purified according to standard procedures.All air-or moisture-sensitive reactions were performed under argon; the glassware was dried (130 ºC) and purged with argon.