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Preparation of aromatic nitroso compounds


Scheme 10: Preparation of aromatic nitroso compounds

Chapter 2

2.8 Scope of successive C(sp2)-H / C(sp3)-H amination with various nitroso compounds and cyclic secondary amines:

The optimized conditions were then used to check the scope of the reaction. Various nitrosoarenes 2.40a - m containing different substituents were reacted with pyrrolidine to obtain the corresponding benzimidazoles 2.9a - q with good yields (Scheme 11). Both electron-donating and -withdrawing substituents in the nitrosoarenes were tolerated in the reactions. The yield of imidazole derivative 2.9g significantly reduced due to the presence of strongly electron-donating dimethyl-amino substituents. Regioisomeric products 2.9h and 2.9h’ were obtained from the reaction of m-chloronitrosobenzene. C(sp2)−H aminations para to the chloro substituent were preferred over the ortho-position to provide p-substituted products 2.9h as the major isomers. In a reaction of o-fluoronitrosobenzene with pyrrolidine, classical nucleophilic aromatic substitution (SNAr) followed by amine C−H functionalization occurred to provide 2.9a in 79% yield. To my surprise, in cases of other o-halo- nitrosobenzenes, halogenated imidazoles 2.9l - n were obtained as the major products via domino C(sp2)−H and C(sp3)−H amination reactions. Interestingly, the yields of halogenated imidazoles 2.9l - n, which were formed through C(sp2)−H functionalization, decrease with the increase in the electronegativity of halogens. Consequently, it was also found that the yield of imidazole 2.9a that is formed via SNAr reaction increases with the electronegativity.

The reactions of nitrosobenzene with other N-heterocycles such as piperidine and homopiperidine provided lower yields of the corresponding benzimidazoles 2.9p - 2.9q.

Nevertheless, satisfactory yields of those were obtained when the reactions were carried out with 2-fluoronitrosobenzene.

Metal-Free Sequential C(sp2)−H and C(sp3)−H Aminations of Nitrosoarenes and N Heterocycles to Ring-Fused Imidazoles

Scheme 11: Scope of successive C(sp2)-H and C(sp3)-H amination. a Yields of the imidazoles starting from corresponding o-fluoro-nitrosobenzene.

2.9 Crystal structures of ring fused imidazoles:

The structure of the imidazole derivative 2.9l was confirmed by X-ray crystallographic analysis. The structure of the compound have given below (Table 2).

Chapter 2

Compound Crystal structure


Table 2: X-ray crystal structure of ring fused imidazole.

2.10 Plausible mechanism:

A plausible mechanism for unprecedented domino C(sp2)−H and C(sp3)−H amination reaction is presented in Scheme 12. Nucleophilic addition of pyrrolidine to nitrosobenzene occurred in the first step. The oxidation of resulting intermediate 2.41 and/or 2.42 could lead to corresponding 2-amino nitrosoarene 2.43.25 Amino nitroso derivative 2.43 then readily undertook a 1,5-hydride shift to provide the iminium ion 2.44.26 A similar 1,5-H shift was reported for a related reaction involving an amino aldehyde corresponding to 2.43.26o Alternatively, the iminium ion 2.44 could also be produced through deprotonation and consequent mesomerization of the corresponding isomeric iminium ion 2.46, which resulted from 2.43. Annulation of 2.44 followed by acid mediated dehydration of resulting N-hydroxy derivative 2.45 provided the desired imidazole 2.9a. Amino phenylhydroxylamine 2.42 was detected through mass spectrometry. Further, the thermal/aerial oxidation of arylhydroxylamine to the corresponding nitroso compound is known to be facile.25 These support the intermediacy of 2.42 and 2.43 in the reaction.

Metal-Free Sequential C(sp2)−H and C(sp3)−H Aminations of Nitrosoarenes and N Heterocycles to Ring-Fused Imidazoles Scheme 12: Proposed mechanism for the annulation of nitrosoarene and secondary cyclic amines.

The preference of the SNArH reaction at the para-carbon of nitrosobenzene would be expected because it has the highest Fukui electrophilicity coefficient value at that carbon (Figure 2). However, the substitution reaction occurred selectively at the ortho-position probably due to the hydrogen bond assisted directing effect of the nitroso group as shown in 2.43a (Scheme 12). This hypothesis was supported by DFT studies.27 The transition state for ortho-substitution (TS in Figures 3) in the SNArH reaction between nitrosobenzene and pyrrolidine is obtained with an activation barrier of 18.23 kcal/mol. However, all attempts to obtain transition states for substitution at the para-position of nitrosobenzene remained unsuccessful. The presence of an intramolecular hydrogen bond (O···H = 1.925 Å) between the nitroso-oxygen and amine-hydrogen having a stable six-membered cyclic structure is evident from the optimized transition state geometry (Figure 3, TS).

Figure 3. Optimized geometries of transition states and corresponding calculated activation barriers (in kcal/mol).

Except for 2-fluoronitrosobenzene, SNArH was preferred over conventional SNAr in the reaction of o-halo-nitrosobenzene. This is probably due to the H-bond aided nucleophilic attack as shown in the preferred conformation 2.43b28 (Scheme 12) where bulky halogens remain away from the nitroso to avoid unfavourable steric interaction. This is presumably the cause of the increase in the experimental yields of imidazoles (2.9l2.9m2.9n) with increasing sizes of the halogens (Cl → Br → I) in o-halonitrosobenzene. In contrast, fluorine that has comparable size with hydrogen and strong electron-withdrawing ability facilitates the nucleophilic addition at the carbon bearing a fluorine atom to exclusively provide imidazole 2.9a. The calculated lower activation barrier for F-substitution (TS-F: 12.92 kcal/mol) as compared to H-substitution (TS-H: 16.37 kcal/mol) supported the experimental results on the exclusive formation of F-substituted products 2.9a (Figures 3).

An alternative mechanistic possibility where pyrrolidine could be oxidized to pyrroline 2.47 which then can react with nitroso compound 2.35 to directly provide intermediate 2.44

Chapter 2

(Scheme 13) was considered. To examine this feasibility, pyrroline 2.47 was reacted separately with nitrosobenzene 2.35 under the standard reaction conditions. However, desired imidazole 2.9a was not formed in the reaction, which eliminated the possibility of formation of imidazole involving pyrroline.

Scheme 13: Elimination of alternate mechanism.

2.11 Gram scale synthesis:

The desired benzimidazole 2.9a can also be synthesized in gram scale following the standard procedure using nitrosobenzene 2.35, pyrrolidine 2.38 and 2,4-DCBA in toluene refluxing conditions. The fused imidazole was obtained with 51% yield (Scheme 14).