Transition metal-free oxidative and deoxygenative C–H/C–Li cross-couplings of 2H-imidazole 1-oxides with carboranyl lithium as an efficient synthetic approach to azaheterocyclic carboranes

The direct C–H functionalization methodology has first been applied to perform transition metal-free C–H/C–Li cross-couplings of 2H-imidazole 1-oxides with carboranyllithium. This atom- and step-economical approach, based on one-pot reactions of nucleophilic substitution of hydrogen (SNH) in non-aromatic azaheterocycles, affords novel imidazolyl-modified carboranes of two types (N-oxides and their deoxygenative analogues), which are particularly of interest in the design of advanced materials.

Thus, the development of pot-, atom-and stage-economical (PASE) [36][37][38] methods leading to novel C-modified orthocarboranes, as well as elucidation of scope and mechanistic features of these transformations, is one of the crucial steps to obtain promising boron-enriched heterocyclic ensembles and functional materials based on them. An alternative approach to exploit the C-X/C-M cross-coupling reactions, leading to heterocyclic boron clusters, is based on the C-H/C-M coupling strategy. One of the ways to realize these cross couplings is the transition metal-free methodology for direct C-H functionalization of azaheterocyclic substrates [39][40][41][42], which can be carried out by using S N H reactions (nucleophilic substitution of hydrogen) [43][44][45][46][47][48]. The S N H methodology corresponds to the basic principles of green chemistry [49][50][51][52][53], and it is now considered to be one of the most valuable approaches to functionally substituted azaheterocycles, since these transformations can be performed without any catalysis by transition metals, neither they need preliminary introduction of good leaving groups into heterocyclic substrates.
In this paper, we wish to report the first examples of the S N H methodology for the synthesis of new heterocyclic carboranes by means of direct C-H/C-Li coupling of non-aromatic 2H-imidazole 1-oxides with carboranyllithium. A growing interest in bifunctional compounds, bearing both the pharmacoactive imidazole motif and a polyhedral boron-enriched scaffold, is likely to be due to unique properties of these organoboron compounds and materials based on them.

Results and Discussion
2H-Imidazole 1-oxides are known to be non-aromatic heterocyclic compounds, bearing the electrophilic center C(5)-H, which is active for interaction with nucleophilic reagents. This feature enables one to carry out the direct nucleophilic functionalization of the C(sp 2 )-H bond, thus leading to novel C(5)modified 2H-imidazoles. We have established that carboranyllithium, generated in situ from 1,2-dicarba-closo-dodecaborane [66], can be involved in the above mentioned C-H/C-Li coupling reactions successfully as a nucleophilic partner. In order to accomplish the nucleophilic substitution of hydrogen according to the "addition-elimination" scheme S N H (AE), the key factor has been shown to be the presence of a deoxygenating reagent in the reaction mixtures, containing the σ H -adducts 3(a-d)-OLi. Indeed, it has been found that addition of acylating agents to intermediates 3(a-d)-OLi facilitates elimination of hydrogen from the σ H -adducts along with the oxygen-containing fragment from the N + -O − moiety to form imidazolyl-substituted carboranes 4a-d with the loss of the N-oxide function (Scheme 1).
In order to find out the optimal reaction conditions for the S N H (AE) pathway, affording the maximum yields of the target products 4, the effects of various factors (type of acylating The reactions were carried out in accordance with the optimized coupling conditions according to the "addition-elimination" S N H (AE) or "addition-oxidation" S N H (AO) pathways (Table 1 and  Table 2). agents, exposure time for which the reaction mass is kept after mixing 2H-imidazole N-oxide 1 with carboranyllithium 2 and quenching with an acylating agent, as well as the temperature regime, at which the deoxygenative agent is added) have been studied. The cross-coupling reaction of 2,2-dimethyl-4-phenyl-2H-imidazole 1-oxide (1a) with carboranyllithium 2 was chosen as a model reaction. It has finally been found that the best yield of 4a is achieved using AcCl as a deoxygenative agent at room temperature with stirring of the resulted reaction mixture for 15 min (Table 1, entry 11). Thus, a number of novel heterocyclic carboranes 4a-d have been synthesized in 40-55% yields following the optimized reaction conditions (Scheme 1).
In case of the "addition-oxidation" protocol realization for the S N H (AO) reactions, an oxidative agent to convert the σ H -adducts 3(a-d)-OLi into the corresponding imidazolyl carboranes 5a-d with retention of the N-oxide function in the imidazole moiety, has been found to play a key role. It should be noted that optimization of the reaction conditions for oxidative C-C couplings has been carried out by using the model reaction of 2,2-dimethyl-4-phenyl-2H-imidazole 1-oxide (1a) with carboranyllithium 2. The experiments performed have shown effects of the used oxidants, temperature regime, and exposure time after addition of an oxidant into the reaction mixture. As a result, the optimal conditions have been found to involve the use of DDQ as oxidant and refluxing of the reaction mixture in argon atmosphere for 1 h ( Table 2, entry 12). It has also been observed that further increase in the exposure time does not improve yields (39-52%) of the target carboranylsubstituted imidazole 1-oxides 5a-d (Scheme 1). Besides compounds 5a-d, the formation of their deoxygenated analogues 4a-d has been shown to take place in trace amounts under the optimized reaction conditions. The latter are supposed to be derived from elimination of hydrogen and the oxygen-containing moiety from the corresponding σ H -adducts. The reaction was carried out in dry THF using 2H-imidazole 1-oxide 1a (1.1 equiv), carboranyllithium 2 prepared from o-carborane (1.0 equiv) and n-BuLi (1.1 equiv) at −78 °C. b The temperature at which the acylating agent was added. c Between addition of 2H-imidazole 1-oxide 1a to carboranyllithium 2 and quenching with the acylating agent.  The novel imidazolyl carboranes 4a-d and 5a-d obtained are considered to be complex closo-cluster structures formed by polyboron and heterocyclic scaffolds linked to each other through the C-C bond. In order to correlate the resonance signals with the assumed structure unambiguously, two-dimensional NMR correlation 1 H-13 C spectra, showing direct (HSQC) and distant (HMBC) spin-spin constants, have been recorded for compound 5d (Figure 2). The presence of the crosspeak {6.09, 57.64} in the HSQC spectrum of 5d and absence of any signals in these regions in the HMBC spectrum enables one to state that these signals belong to proton (δ 6.09 ppm) and carbon (δ 57.64 ppm) resonances of the C Carb -H fragment. Also, the 2D spectra allow one to distinguish the carbon resonances of 2H-imidazole methyl (δ 24.06 ppm) and ethyl (δ 6.74 and 31.12 ppm) groups. In addition, the interaction observed in the HMBC spectra of quaternary carbons with protons of methyl and ethyl groups through the long-range constants allows the signal at δ 103.85 ppm in the 13 C NMR spectra of 5d to be attributed to C-2 of the imidazole ring.
The structure of imidazolyl carborane 5d has also been proved by the X-ray analysis (Figure 3). The single crystals were obtained by slow evaporation of imidazolyl carborane 5d from a mixture of CH 2 Cl 2 /heptane, 8:2. According to the XRD data, two independent molecules have been found to be crystallized in the P12 1 1 chiral space group of the monoclinic system. General views for molecules 1 and 2 are shown in Figure 3, atoms of the molecule 2 being labeled with the additional index "A". Both independent molecules proved to be characterized by the (R)-configuration of the C(2)-chiral center and the appropriate bond and angle distances. Both heterocyclic rings have been found to be planar with 4-BrC 6 H 4 substituent being turned towards the heterocyclic fragments, thus forming the angles of 74° and 80°, respectively. In the crystals of molecule 1, the 2H-imidazole 1-oxide fragment is disordered into two positions with occupancy coefficient of 0.8/0.2. The minor disordered moiety has been confirmed to be in the (S)-configuration. Also it is worth mentioning that no shortened contacts have been observed in the crystals.

Conclusion
The direct C(sp 2 )-H functionalization methodology has first been applied to design the synthesis of polyhedral boron closo- clusters. Novel heterocyclic carboranes have been obtained through a one pot-, atom-and stage-economical approach, based on nucleophilic substitution of hydrogen (S N H ) in 2H-imidazole 1-oxides by action of carboranyllithium, generated in situ from commercially available o-carborane. It has also been found that the S N H (AE, «addition-elimination») scheme leads to carboranyl-substituted 2H-imidazoles, while alternative S N H (AO, «addition-oxidation») results in the corresponding N-oxide analogues. In summary, novel organoelement bifunctional ensembles, bearing heterocyclic and carborane moieties, which are of particular interest in the design of advanced materials, have been obtained in good yields.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization data, copies of the 1 H, 13 C, 11 B NMR spectra and X-ray diffraction studies.