Initially, we focused on developing a mild oxidation procedure starting from iodoarene precursors. Previous studies on five-membered heteroaromatic iodonium salts revealed m-chloroperoxybenzoic acid (mCPBA) as the oxidant of choice in the presence of triflic acid (TfOH) [27,29]. Based on these promising results, the conditions were optimized using o-benzimidazole-substituted iodoarenes 4aa and 4ah (Table 1).

Table 1: Optimization of reaction conditions for the synthesis of azoiodazinium salts 5aa and 5ah.a

Entry R mCPBA
(equiv) TfOH
(equiv) T
(°C) t
(d) Solvent Yield
(%) 1 H 1.1 3.0 50 3 MeCN 0 2 H 1.1 3.0 50 3 DCE 23 3 H 1.1 2.5 50 3 DCE 69 4 H 1.1 2.0 50 3 DCE 19 5 H 1.1 2.5 40 3 DCM 69 6 H 1.5 2.5 40 3 DCM 53 7 Cl 1.1 2.5 40 3 DCM 9b 8 Cl 1.3 5.0 65 14 DCM 52

aIodoarene 4aa or 4ah (200 µmol) and mCPBA were dissolved in the given solvent (1 mL) in a screw cap vial, TfOH was added, and the reaction mixture was stirred under the corresponding conditions. For full table, see Supporting Information File 1. bIncomplete conversion, product not clean.

While running the reaction in MeCN as solvent resulted in no product formation, the reaction of 4aa in DCE at 50 °C gave the product 5aa in 23% yield (Table 1, entries 1 and 2). A larger amount of TfOH turned out to increase the solubility of the product and therefore impeded the purification process. However, an excess of acid is required for the electrophilic aromatic substitution to take place. With 2.5 equivalents of TfOH as the optimum amount of acid the product 5aa was obtained in a yield of 69% (Table 1, entry 3). Similar results were observed with DCM at 40 °C (Table 1, entry 5). A higher amount of mCPBA did not lead to a better yield due to more washing required to remove the m-chlorobenzoic acid (Table 1, entry 6). When we employed the chlorinated, electron-deficient iodoarene 4ah, the yield of the product 5ah dropped significantly (Table 1, entry 7). Combining an electron-deficient heterocycle and an iodoarene with electron-withdrawing substituents results in a significantly decreased reactivity. Thus, for those substrates, harsher reaction conditions were required. A slight adaption of the original conditions to elevated temperatures (65 °C) and prolonged reaction times of 14 d finally resulted in the formation of product 5ah in 52% yield using DCM as the solvent (Table 1, entry 8).

Next, various substituted iodoarenes 4 were oxidized and cyclized using the optimized conditions to generate a diverse set of azoiodazinium salts 5 (Figure 2). The ortho-methylated salt 5ab was obtained in a low yield of 19%, and the fluorinated derivative 5ac could be obtained in 55%. Unfortunately, the MeO-substituted derivative 5ad did not form. Except for the acetamide 5ae, which could not be obtained due to decomposition, other meta- and para-substituted derivatives 5af–ak, among them derivatives with strong electron-withdrawing functionalities, could be synthesized in 39–69% yield. The electron-rich salt 5al was obtained in 75% yield using modified reaction conditions B. The harsher conditions were probably required due to a sterically hindered rotation of the benzimidazole moiety in the plane of the iodophenyl, which could also be observed in two rotamers of the starting iodoarene 4al (see Supporting Information File 1).

Figure 2: Synthesis of a set of azoiodazinium salts 5. Method A: Iodoarene 4 (200 µmol) and mCPBA (1.1 equiv) were dissolved/suspended in DCM (1 mL), TfOH (2.5 equiv) was added, and the reaction mixture was stirred for 72 h at 40 °C. Method B: Iodoarene 4 (200 µmol) and mCPBA (1.3 equiv) were dissolved/suspended in DCM (1 mL), TfOH (5.0 equiv) was added, and the reaction mixture was stirred for 14 d at 65 °C. a6.00 mmol scale, T = 50 °C, bT = 40 °C, cT = 80 °C, t = 6 d, dt = 7 d, e0.3 equiv of DCM were included in the product.

Next, we investigated substrates 4 having various substituents in the benzimidazole motif. Starting from 2-bromo-derivative 4am, the moisture-sensitive, brominated salt 5am was obtained in an excellent yield of 85%. Also, the C2-alkyl- and phenyl-substituted benzimidazoles gave the expected products 5an–ap in 50–60% yield. The pyrazole-substituted salt 5aq was obtained with 65% yield. Using an electron-rich 5,6-dimethylbenzimidazole substrate yielded dimethylated product 5ar in 85% yield. Unfortunately, even under harsher reaction conditions, the corresponding electron-deficient dibrominated salt 5as could not be obtained. This further demonstrated the crucial influence of the electronic properties on the reactivity of those substrates. Especially, electron deficiency is particularly counterproductive for the final cyclization step. To prove the influence of the electron-rich dimethylated benzimidazole, this moiety combined with the chlorinated and brominated iodoarene gave the corresponding salts 5at and 5au in good yields under milder reaction conditions, in particular in direct comparison to the unsubstituted analogs 5ah–aj. N-Substituted iodoarenes were then used to create dicationic iodonium salts. The N-Me and N-Ph-iodonium-benzimidazolium salts 5av and 5aw were obtained in 47% and 36% yield, respectively. The introduction of additional ortho-methyl groups resulted in the formation of the σ-hole-protected N-substituted salts 5ax–az in up to 97% yield. Next, the iodonium center was stabilized through an additional N-coordination via ortho-pyrazole substitution, giving the iodonium salts 5ba and 5bb in 88% and 50% yield. When replacing imidazoles by indazoles the oxidation was not as efficient giving the products 5bc and 5bd with only 24% and 44% yields. In the latter case, the initially generated hydroxy-iodonium salt is stabilized via the indazole nitrogen [26] and the steric hindrance by the methyl group is likely destabilizing this intermediate by an out-of-plane distortion [28,34] and hence accelerating the cyclization. The dicationic indazole salt 5be was isolated in 30% yield and the benzyl-bridged, seven-membered salt 5bf could not be obtained under our optimized reaction conditions.

Single crystal structures of selected salts were obtained to gain a better understanding of the bonding situation and the coordination states in these novel azoiodazinium salts (Figure 3). An N4–I1 distance of 2.540 Å with a typical T-shape structure (N4–I1–C1 angle 185.74°) implies a significant interaction between the N-heterocycle and the iodine atom for the ortho-pyrazole-substituted derivative 5bb [35]. However, the presence of an ortho-methyl group significantly disturbs the triflate coordination to the other iodine σ-hole, which results in a C15–I1–O5 angle of 145.50°. In contrast to other six-membered iodonium salts, this molecule is nearly in plane with an I1–C1–C15–N4 dihedral angle of 2.03° [30,32]. For the dicationic salt 5av, we observed a coordination of the triflates along the C–I axis with distances of 2.705 Å (I1–O1) and 2.898 Å (I1–O5). For the ortho-methyl-substituted analogue 5ax, no halogen bonding to the triflates was observed, indicating an effective steric protection of the σ-holes [36]. Instead, there were only two weak interactions with one of the triflates (I1–O3: 3.354 Å, I1–O5, 3.078 Å).

Figure 3: Single crystal structures (ORTEP drawing with 50% probability) of the pyrazole-coordinated salt 5bb (dimer, a second structure was omitted for clarity. For full structure, see Supporting Information File 1; CCDC 2216124) and the two N-methylated, dicationic salts 5av (CCDC 2216134) and 5ax (CCDC 2216127). Selected bond lengths and angles: For 5bb: N4–I1: 2.540 Å, I1–O5: 2.905 Å, N4–I1–C1: 185.74°, C15–I1–O5: 145.50°; for 5av: I1–O1: 2.705 Å, I1–O5: 2.898 Å, C8–I1–O1: 173.80°, C6–I1–O5: 167.75°, C6–I1–C8: 94.05°; for 5ax: I1–O3: 3.354 Å, I1–O5, 3.078 Å, C1–I1–O3: 154.71°, C8–I1–O5: 148.91°, C1–I1–C8: 94.53°.

We finally investigated the further reactivity of the synthesized azoiodazinium salts to elaborate their potential as synthetic building blocks (Scheme 1). Treatment of 5aa with Ac2O led to a non-selective ring opening at both C–I bonds giving the iodinated N-arylbenzimidazoles 6a and 6b as a mixture with 54% and 25% yield [37]. A ring opening/closing cascade reaction with elemental sulfur resulted in the formation of the imidazo[4,5,1-kl]phenothiazine (7a) in 47% yield.

Scheme 1: Derivatizations of the iodonium salt 5aa. a) Ac2O, CuSO4·5H2O, NaOAc, AcOH, 120 °C, 5 h; b) S8/Se/Te, Cs2CO3, DMSO, rt–100 °C, 2.5–24 h; c) I: PhNH2, Cu(OAc)2·H2O, Na2CO3, iPrOH, 40 °C, 17 h, II: CuI, Cs2CO3, DMF, 120 °C, 40 h; d) TsNH2, (CH2OH)2, iPrOH, Na2CO3, 100 °C, 24 h, e) KX, H2O, EtOH, reflux; f) CuI, DMEDA, 1,4-dioxane, TBAI, rt, 24 h; g) MeOTf, DMF, 40 °C, 24 h.

The corresponding phenoselenazine 7b and the phenotellurazine 7c were isolated in lower yields of 16% and 6%, likely due to undesired oxidations of selenium and tellurium [38]. Substitutions with nitrogen nucleophiles were performed, giving the N-phenylphenazine 8 in 26% yield [39,40] and the N-tosyl derivative 9 in 18% yield [41]. Anion exchange reactions to iodide and bromide were performed giving the salts 10a and 10b in excellent yields [27]. A copper-catalyzed iodination gave the diiodinated product 11 in quantitative yield [42]. Finally, N-methylation of 5aa was performed, to yield the dicationic salt 5av in 56% yield without decomposition of the iodonium center [43]. In this reaction, however, no complete conversion could be achieved, even by adding excess MeOTf.

Inspired by the latter results, we were interested to investigate other post-oxidation functionalizations on the benzimidazole ring while keeping the highly reactive hypervalent iodine center intact. Treatment of the ortho-pyrazole-substituted salt 5bb with MeOTf resulted in a selective benzimidazole N-methylation. A reaction on the pyrazole nitrogen is impeded due to its coordination with the iodane’s σ-hole (Scheme 2a). Besides nitrogen-substitution, the benzimidazole C-2 position of the dicationic salts is a reactive site for oxidative transformations [44,45]. The reaction of the iodine-protected benzimidazolium salts 5ax–az and 12 with different oxygen sources revealed K2CO3 and NCS as the optimal system to form the benzimidazole-2-ones 13a–d in 18–48% yield, with the best result obtained when using the stabilized salt 12 (Scheme 2b) [44]. Here, no counter-ion exchange to chloride was observed. The favored counter ion is determined by the pKa value of the corresponding acids but not by halogen bonding due to the steric hindrance at the iodines’ σ-holes. The reaction of TsNH2 in combination with NaOCl as an oxidant was investigated next. Under these conditions, the N-Me salts 5ax and 12 gave the desired products 14a and 14b in 55% and 26% yield, respectively. The corresponding N-Ph- and N-Mes-derivatives 5ay and 5az failed to give products 14c and 14d and only underwent undesired ring openings.

Scheme 2: Post-functionalization of mono- and dicationic iodonium salts under preservation of the hypervalent iodine center.

Treating 12 with BocNH2 resulted in the formation of protected guanidine 15 in 80% yield (Scheme 2c), which would not be possible to obtain via an oxidative cyclization of the corresponding iodine(I) species due to a carbamate cleavage with acid. The other dicationic salts underwent ring openings in this reaction. This reactivity demonstrates the highly stabilizing effect of N-heterocycles on hypervalent iodine species. Furthermore, the formed 2-aminobenzimidazoles reveal new access to potential bioactive compounds [46,47]. Even the formation of the free guanidine 16 via cleavage of the Boc-group was possible in quantitative yield.