Synthesis and functionalization of 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole

Abstract Starting from readily available aminocarbonyl compounds Marckwald reaction was used for the preparation of 6,7-dihydro-5H-pyrrolo[1,2-c]imidazoles. The two-step procedure afforded the product in high yield and can be used for preparation of bulk quantities. Their further reactions with various electrophiles were studied giving previously unknown functionalized derivatives. The reaction with silylformamidine that exists in an equilibrium with its carbenic form afforded C-silyl derivative. Various halogen derivatives were prepared and used as starting materials.  • Commercially available starting materials  • High yield methods  • Can be used for bulk synthesis of unsubstituted imidazoles  • Polyfunctional core  • 22 examples Graphical abstract


Introduction
Small organic molecules are invaluable scaffolds in a medicinal chemistry toolkit for probing biological systems. They are quite often used for synthesis of libraries of biologically active compounds in a search for new drugs. Availability of polyfunctional original building blocks makes it possible to produce very quickly a diverse set of biologically active compounds. Imidazole derivatives belong to privileged scaffolds in drug discovery. [1] Imidazole derivatives are small heterocyclic compounds with a wide range of applications such as ionic liquids, [2] therapeutic agents, and bioactive substances. [3,4] Many imidazole containing drugs and biologically active derivatives play an important role in the treatment of various types of diseases. [5] This is especially true in respect to imidazole-containing compounds fused with a cyclic system. The pyrroloimidazole moiety I (Fig. 1) is a part of many biologically active compounds. [6][7][8][9][10] Methods for synthesis of unsubstituted pyrroloimidazole I and its derivatives are well developed. [11][12][13][14][15][16][17][18] At the same time, 6,7-dihydro-5H-pyrrolo [1,2-c]imidazole II have recently attracted attention from medicinal chemistry (Fig. 1). For example, Osilodrostat was approved by FDA in 2020 as an inhibitor of 11b-hydroxylase (CYP11B1) for treatment of hypercortisol diseases such as Cushing's disease, [19] or other bioactive compounds such as Orteronel or Massinidine. [20] Thus, development of new methods for synthesis of 6,7-dihydro-5H-pyrrolo[1,2c]imidazole derivatives would facilitate further progress in this area. There are various well documented methods for the synthesis of 1,5-annulated imidazoles. However, the literature for the parent 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole 1 is quite scarce. [21] The published synthetic routes to 6,7-dihydro-5H-pyrrolo [1,2-c]imidazole derivatives are based on intramolecular alkylation of the imidazole nucleus, [22,23] intramolecular cyclization under Wittig reaction conditions, [21] AuCl 3 -catalyzed bimolecular [2 þ 2 þ 1] cycloaddition, [24] reductive cyclization of N-substituted imidazole derivatives, [25,26] reaction of a-aminocarbonyl compounds with thiocyanates (Marckwald reaction) (Scheme 1). [27] Despite all these methods, they do not allow an access to the parent imidazole II or its derivatives in high yield.
Therefore, the objective of our work is the development of a preparatively simple method for obtaining unsubstituted pyrroloimidazole II and its further functionalization, thus making them available for further research in drug development.

Results and discussion
The reaction of commercially available N-Boc protected a-amino carbonyl compounds 2 with potassium thiocyanate has been studied (Scheme 2). It was found that under Marckwald reaction conditions thioderivatives 3 formed and the subsequent desulfurization with Raney nickel led to the target imidazole derivatives 1. [28] Thus, starting from commercially available compounds and using the well-developed literature procedure we elaborated a simple method for synthesis of imidazoles 1 in high yield. The method opened a synthetically simple approach to 6,7-dihydro-5H-pyrrolo[1,2-c]imidazoles 1a,b. The closest structural analogue of these imidazole derivatives is 1,5-dimethyl imidazole. [29] For the introduction of the imidazole motif or its functionalization, cross-coupling reactions have recently become widely used (Stille, Suzuki, Sonogashira reactions, etc.), [30][31][32][33] for which the presence of a halogen in a substrate or a reactant is required. A simple method for obtaining halo derivatives at the 1 and 3 positions of 6,7-dihydro-5H-pyrrolo[1,2-c]imidazoles 1 has been proposed, that allowed us to expand a number of substrates and increase the synthetic potential of this heterocyclic system. Thus, bromo derivatives 4 and 5 were obtained by direct bromination of compounds 1a,b. It should be noted that the bromination of imidazole 1a with one equivalent of bromine led to the formation of a mixture of 1-bromo derivative 6 and 1,3-dibromo derivative 5. At the same time, the bromination with two equivalents of bromine led to complete bromination of the imidazole nucleus so that dibromoimidazole 5 was prepared in high yield. By analogy to the methodology described in the literature, [34,35]  dibromo derivative 5 was selectively reduced by boiling in aqueous-alcoholic solution of Na 2 SO 3 to afford bromo derivative 6 (Scheme 3). The reaction of 1a derivative with paraform was also investigated. It was found that it led to the formation of hydroxymethyl derivative 8a in a low yield.
Metallation of dibromo compound 5 with BuLi at À78 followed by treatment with C 2 Cl 6 or I 2 led to dihalo derivatives 7a,b featuring different halogens in the structure, which allows using selective cross-coupling reactions by successively replacing each halogen in the C1 and C3 positions. [36,37] Compound 7a was studied by X-ray method (Fig. 2). In the crystal phase, molecule 7a is planar, where all the non-hydrogen atoms are situated in a special position in relation to the mirror plane. The neighboring molecules of 7a are bound by stacking interaction of "head-to-tail" type (distance between p-systems is 3.45 Å, plane to plane shift is 1.419 Å) forming columns in the [010] crystallographic direction. Its deposition number is (CCDC 2205162).  . Molecular structure of compound 7a according to X-ray diffraction data. Thermal displacement ellipsoids are shown at 50% probability level.
The following scheme was used to synthesize compound 11 that is isomeric to 7b derivative (Scheme 4).
In the first step, diiodide derivative 9 was obtained by reacting imidazole 1a with Niodosuccinimide (NIS). Unlike the bromination, this reaction proceeded only at increased temperature and resulted in lower yield. The attempts to reduce the iodine in the C3 position by boiling in an aqueous-alcoholic Na 2 SO 3 solution resulted in a mixture of unidentified compounds. Iodo derivative 10 was prepared by reacting compound 9 with methyl magnesium bromide. [38][39][40] Subsequent bromination led to the formation of compound 11 in a low yield. Nevertheless, the method makes it possible to obtain compound 11 that is an isomer of compound 7b.
In order to further functionalize 1,5-annelated imidazoles 1, the corresponding carboxylic acids 12a,b were obtained by lithiation of compounds 1a,b with n-butyl lithium at À78 C followed by treatment with CO 2 (Scheme 5). At the same time, isomeric C1 carboxylic acid 12c was synthesized by the palladium-catalyzed carbonylation reaction followed by hydrolysis. Carboxylic ester 13 was prepared in quantitative yield and the corresponding free carboxylic acid was isolated as a white powder (Scheme 6). Also, the reduction of the ester group of compound 13 with LiAlH 4 led to the formation of hydroxymethyl derivative 8b in a moderate yield.
It was found that despite the presence of an acceptor substituent, ester 13 was easily brominated with bromine to form a bifunctional derivative 14 in high yield, which with subsequent hydrolysis allowed us to obtain carboxylic acid 15.
In order to obtain C3 amino derivative 16, the reaction of lithiated compound 1a with tosyl azide was investigated. [40][41][42] The resulting heteroaryl azide without any purification was hydrogenated over palladium on carbon to give amine 16 in a moderate yield (Scheme 7). The reaction of compound 1a with latent carbene [43] led to an unexpected and interesting result. The main product of the reaction with silylformamidine is not a product of insertion into a C-H bond, but silylated derivative 17, which indicates high C-H acidity of imidazole 1a. It would be reasonable to expect that silylated derivative 17 can be prepared by lithiation of compound 1a followed by treatment with trimethylsilyl chloride. Unfortunately, our numerous attempts failed to prepare the silyl derivative 17 by this method.

Conclusion
It has been shown that Marckwald reaction can be used for preparation of 6,7-dihydro-5H-pyrrolo [1,2-c]imidazoles. The procedure is simple and starting materials are readily available. 6,7-Dihydro-5H-pyrrolo [1,2-c]imidazoles were used in various reactions to prepare their functionalized derivatives.