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The regioselectivity of direct C-H arylation of 4-nitroimidazoles might be explained by an assumption that the catalyst (Pd or Ni) coordinated by the nitro group initiates the C(5)-H arylation via concerted metalation-deprotonation (CMD) as illustrated in Scheme 4.5.1 (B).

This hypothesis is strongly supported by numerous theoretical calculations and practical

observations.130,131,133-136,197 In this context, it should be mentioned that the salt of copper via double chelation by nitro group and nitrogen of imidazole ring can immobilize the nitro group in the plane of imidazole, thus supporting the C-H bond cleavage by Pd or Ni (Scheme 4.5.1, A, B). This assumption supports the recent work of Huang and coworkers in which they found that the lone pair on the nitrogen atom in benzothiazole, 1-methylbenzimidazole and related systems can bind to the copper center thereby initiating Pd-catalyzed C-H bond cleavage.²⁴⁹

Scheme 4.5.1. Proposed mechanistic explanation of the regioselectivity.

Based on these considerations we assume that the catalytic cycle starts with oxidative addition of aryl bromide to the catalyst Pd(0) delivering Ar-Pd(II)-Br complex (Scheme 4.5.2, A, similar considerations are equally true for Ni). Noteworthy, the oxidative addition of aryl halide to the catalyst represents the rate determining step for many coupling reactions. In the next step the product of oxidative addition undergoes a ligand exchange reaction with potassium pivalate (B). It should be noted that the real base of the reaction is KOPiv which is formed by the reaction of K2CO3 and PivOH and is far more soluble in DMA (DMF, NMP).

Subsequently, the Ar-Pd(II)-OPiv species first coordinates to the nitro group of imidazole which is followed by a carboxylate-assisted C-H bond cleavage via concerted metalation-deprotonation (C, D). This process is accompanied by regeneration of PivOH; therefore, the PivOH can be used in catalytic amounts (E, F). In the final step of the process the reductive elimination of catalyst Pd(0) leads to the formation of desired Ar-Ar C-C bond and regeneration of components of catalytic cycle (Scheme 4.5.2, G).

Accordingly, for Pd-catalyzed C(2)-H arylation of imidazoles we assume that a cooperative action of Pd and Cu, chelated by a bidentate ligand (solvent, carboxylate), may enable the direct C-H activation (Scheme 4.5.1, C).²⁵⁰ Concerning the low reactivity of C(4)-H bond of imidazoles towards Pd-catalyzed C-H activation, several authors described this phenomenon by the electronic repulsion between the electron lone pair on the N-(3) of imidazole and the C-Pd bond (Scheme 4.5.1, D).²⁵¹ Eventually, we do not exclude the possibility of formation of appropriate cuprates of imidazole200q,202f,252 which can be followed by transmetallation to Pd or Ni (Scheme 4.5.1, E, F). In this respect, recently DFT calculations made by Fu and

coworkers indicate that the C-H activity of different Ar-H species and both the dissociation of the Ar-H bond and the formation of the Ar-Cu bond make important contributions to the concerted C-H activation.^252g

Scheme 4.5.2. Possible mechanism of Pd-catalyzed C(5)-H arylation of 4-nitroimidazoles.

In order to obtain more insights into the reaction mechanism and the directing ability of nitro group, the imidazole 4.1.3j was synthesized applying the procedure described in Table 4.1.1.

Afterwards, the latter was subjected to our standard Pd-catalyzed reaction conditions (Scheme 4.5.3). Nevertheless, all attempts to perform the C-H arylation in standard conditions, developed for 4-nitroimidazoles were unsuccessful; an inseparable mixture of products was formed along with some quantities of starting imidazole 4.1.3j. These findings clearly show the crucial effect of nitro group on the outcome of the reaction.

Subsequently, to gain more insight into the reaction pattern, a competitive experiment was conducted between imidazole 4.1.3c and two electronically different aryl bromides, namely with 1-bromo-3-methoxybenzene and 1-bromo-3-nitrobenzene (Scheme 4.5.4).

Scheme 4.5.3. Exploration of directing ability of nitro group.

The aim of the study was the identification of comparable reactivities of electronically different aryl bromides in Pd-catalyzed direct C-H arylation of 4-nitroimidazoles. The results revealed that under applied conditions the reaction is favoured by electron-deficient aryl bromides. In particular, performing the competitive arylation with two different aryl bromides (Scheme 4.5.4, A), it was possible to isolate only one product 4.2.1u corresponding to C-H arylation by 1-bromo-3-nitrobenzene in 82% yield. This experiment clearly shows that aryl bromides with electron-withdrawing groups are much more reactive in Pd-catalyzed C-H arylation reactions than the respective aryl bromides with electron-donating groups.

Scheme 4.5.4. The competitive experiments between imidazoles and aryl bromides.

On the next stage of the study the reaction between various imidazoles (4.1.3c and 4.1.3g) and electron-deficient 1-bromo-3-nitrobenzene was explored (Scheme 4.5.4, B). In this case the aim of the study was the identification of comparable reactivities of two different N-substituted imidazoles. Understanding of the impact of steric influence of substituents in the position 1 of imidazole ring represents another actual task. Interestingly, during the course of the study it was found that there is almost no distinction between two imidazoles; in particular, a mixture of both arylated imidazoles with almost similar quantities was observed (Scheme 4.5.4, B).

The possible mechanism of Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of 5-bromo-4-nitroimidazoles is depicted on the Scheme 4.5.5. The Pd-catalyzed cross-coupling reaction of arylboronic acids with aryl halides starts with oxidative addition of aryl halide to the catalytically active Pd(0) complex affording Ar-Pd(II)-Br intermediate (Scheme 4.5.5, A).

In the next step the product of oxidative addition undergoes a ligand exchange reaction with potassium carbonate (B). Noteworthy, these two steps are very much similar to the initial steps of Pd-catalyzed C-H arylation (Scheme 4.5.2).

Scheme 4.5.5. Possible mechanism of Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.

The next step of the process represents transmetallation of the Ar-group from the parent arylboronic acid to the Ar-Pd(II)-CO3K species giving rise to the Ar2Pd(II) complex (D). As it was mentioned in the Chapter 2.1, the C-B bond possesses a strong covalent character;

however, under special circumstances the arylboronic acids can act as aryl carbanion-donors similar to other typical aryl organometallics.

In particular, the coordination of potassium carbonate to the boron atom is an efficient method for increasing the carbanionic nature of aryl group which further can be readily transferred from boron to the electrophilic Pd(II) (C, D). The final step of catalytic cycle constitutes the reductive elimination of arylated nitroimidazole with regeneration of catalytically active Pd(0) complex (E) which is closely related to the final step of Pd-catalyzed C-H arylation of nitroimidazoles (Scheme 4.5.2).