N-Vinylation of Imidazole and Benzimidazole with a Paramagnetic Vinyl Bromide

An N-vinylation of imidazole and benzimidazole with a paramagnetic vinyl bromide was investigated. Among the tested procedures, Pd-catalyzed reaction was the most powerful one. The N-vinylation of 2-aminobenzimidazole with a β-bromo-α,β-unsaturated pyrroline nitroxide aldehyde offered 1,1,3,3-tetramethyl-1H-benzimidazo[1,2-a]pyrrolo[3,4-e]pyrimidin-2(3H)-yloxyl radical and the corresponding non-cyclized Schiff base. The reaction of a β-bromo-α,β-unsaturated pyrroline nitroxide aldehyde with imidazole gave β-imidazo-α,β-unsaturated pyrroline nitroxide aldehyde, which was reduced to the alcohol and converted to an unstable allyl chloride.


Introduction
Nitroxides belong to a group of stable organic radicals, containing the nitroxyl group as a part of aliphatic, aromatic, bicyclic, or heterocyclic scaffolds.The most commonly used nitroxides are piperidine, pyrrolidine, pyrroline, isoindoline, oxazolidine, imidazoline, and imidazolidine nitroxides with a broad range of applications.They are used as co-oxidants in organic chemistry [1], spin labels on biomolecules [2], as antioxidants and antiproliferative drugs [3,4], mediators of polymerization [5], redox active materials in batteries [6], sensor molecules [7], and as magnetic imaging (MRI) [8] and electron paramagnetic imaging (EPRI) [9] contrast agents, just to name a few examples.
To fulfill these various requirements, a broad range of different nitroxides with miscellaneous substitution patterns need to be prepared, sometimes by using complex synthetic procedures.In the last two decades, transition-metal-catalyzed cross-coupling reactions have proven to be a powerful tool in modifications of vinyl or aryl halide derived stable nitroxide free radicals [10][11][12] including Heck-, Sonogashira-, and Suzuki-type cross-coupling reactions.In our laboratory, we used these reactions to introduce new substituents onto the pyrroline or tetrahydropyridine ring and to construct nitroxide-condensed heterocycles as well [13,14].Very recently, we have reported Buchwald-Hartwig amidation procedures for nitroxide-condensed lactam and pyrimidine ring constructions [15] starting from β-bromo-α,β-unsaturated pyrroline nitroxide aldehyde.In this paper, we report the extension of the Buchwald-Hartwig cross-coupling for the N-vinylation of imidazoles and benzimidazoles with paramagnetic vinyl bromides.
To achieve reactive spin label compounds [20,21] aldehyde, 3a was reduced with NaBH4 in EtOH at 0 °C to give alcohol 7, which was converted to allylic chloride 8 via mesylate by nucleophilic substitution with LiCl in acetone (Scheme 3).However, this compound proved to be unstable, as decomposition products appeared after several days despite low temperature (−18 °C) storage.The freshly prepared chloromethyl compound 8 can be applied for irreversible SH specific labeling of proteins.In order to explore the scope of the coupling reactions, N-vinylation of 2-aminobenzimidazole 4 with compound 1 was conducted under Pd-catalyzed conditions, as mentioned above, yielding the desired polycondensed heterocyle 5 in 27% yield and Schiff base 6 in 37% yield as a by-product (Scheme 2).The formation of Schiff base was revealed by mass spectrometry measurements, which showed molecular ion peaks at 361/363 with 1/1 intensity.
To achieve reactive spin label compounds [20,21] aldehyde, 3a was reduced with NaBH4 in EtOH at 0 °C to give alcohol 7, which was converted to allylic chloride 8 via mesylate by nucleophilic substitution with LiCl in acetone (Scheme 3).However, this compound proved to be unstable, as decomposition products appeared after several days despite low temperature (−18 °C) storage.The freshly prepared chloromethyl compound 8 can be applied for irreversible SH specific labeling of proteins.To achieve reactive spin label compounds [20,21] aldehyde, 3a was reduced with NaBH 4 in EtOH at 0 • C to give alcohol 7, which was converted to allylic chloride 8 via mesylate by nucleophilic substitution with LiCl in acetone (Scheme 3).However, this compound proved to be unstable, as decomposition products appeared after several days despite low temperature (−18 • C) storage.The freshly prepared chloromethyl compound 8 can be applied for irreversible SH specific labeling of proteins.
To achieve reactive spin label compounds [20,21] aldehyde, 3a was reduced with NaBH4 in EtOH at 0 °C to give alcohol 7, which was converted to allylic chloride 8 via mesylate by nucleophilic substitution with LiCl in acetone (Scheme 3).However, this compound proved to be unstable, as decomposition products appeared after several days despite low temperature (−18 °C) storage.The freshly prepared chloromethyl compound 8 can be applied for irreversible SH specific labeling of proteins.

Materials and Methods
Melting points were determined with a Boetius micro-melting point apparatus (Franz Küstner Nachf.K. G., Dresden, Germany) and were uncorrected.Elemental analyses (C, H, N, and S) were performed with a Fisons EA 1110 CHNS elemental analyzer (Fisons Instruments, Milan, Italy).Mass spectra were recorded on an Automass Multi spectrometer (ThermoQuest, CE, Instruments, Milan, Italy) in EI mode.NMR spectra were recorded on a Bruker Avance III Ascend 500 spectrometer (Bruker BioSpin Corp., Karsluhe, Germany); chemical shifts are referenced to TMS.The paramagnetic compound was reduced to N-hydroxylamine with five equivalents of hydrazobenzene (DPPH)/radical.Measurements were performed at a probe temperature of 298 K in CDCl 3 or DMSO-d 6 solution.ESR spectra were recorded on a Miniscope MS 200 (Magnettech Gmbh., Berlin, Germany) in CHCl 3 solution.All monoradicals gave a triplet line at 14.4-15.6G. IR spectra were recorded with a Bruker Alpha FT-IR instrument (Bruker Optics, Ettlingen, Germany) with ATR support (ZnSe plate).Flash column chromatography was performed on a Merck (Darmstadt, Germany) Kieselgel 60 (0.040-0.063 mm).Compound 1 [16] was prepared as described previously; compound 5 was reduced to diamagnetic NH form by Fe/AcOH [22].Other reagents were purchased from Sigma Aldrich (St. Louis, MO, USA), Alfa Aesar (Karlsruhe, Germany), Acros (Geel, Belgium), and TCI (Tokyo, Japan).

Conclusions
The N-vinylation of imidazole and benzimidazole with activated paramagnetic vinyl bromide (β-bromo-α,β-unsaturated pyrroline nitroxide aldehyde) was accomplished by Pd-catalyzed Buchwald-Hartwig cross-coupling reaction, offering the desired products with moderate yields.As far as we know, this is the first report on N-vinylation of heterocycles with nitroxide free radicals.Currently, extending the scope of the developed methodology on other heterocycles, such as nucleic bases [23], is being pursued in our laboratory.