Copper(II) Bromide–Catalyzed C-C/C-N Bond-Forming Reactions: Synthesis of Pyrrole-Incorporated Triarylmethanes

Abstract We have achieved a facile copper(II) bromide–catalyzed synthesis of 2,3,4-trisubtitued pyrrole incorporated into unsymmetrical triarylmethanes through direct replacement of hydroxyl group in the pyrrolyl phenyl methanol with electron-rich aromatic and heteroaromatic compounds. The newly developed method has been applied to a facile synthesis of a C2 symmetric bis-triarylmethane in which the two triarylmethanes were bridged through piperzine. The copper(II) bromide catalysis led to C-C bond formation at the C(5) position when the reacting partner was imidazole. In contrast, C-N bond formation took place with benzimdazole or 2-methylbenzimidazole. GRAPHICAL ABSTRACT


INTRODUCTION
Triarylmethanes are a group of organic molecules that have three aryl groups appended to the central carbon atom. This group has diverse applications as dyes (e.g., malachite green), drugs (e.g., turbomycin), and pH indicators (e.g., cresol red). [1] Incorporating heteroaromatic rings in place of normal aromatic rings makes the triarylmethanes much different from the parent molecules. [2] For example, when heteroaromatic rings such as pyrrole, indole, and imidazole are placed in the network of triarylmethanes, the resulting molecules exhibit enhanced biological activity. [2a] Triarylmethanes are mostly synthesized by treatment of electrophilic reagents such as triethyl orthoformate or arene aldehydes with various arene nucleophiles in the presence of Lewis acids. Generally, only symmetrical triarylmethanes result by application of these methods. [3] Although synthesis of some unsymmetrical triarylmethanes has been achieved through direct replacement of benzylic hydroxyl group with arene nucleophiles, the reactions require a stiochometric amount of Lewis acid. [4] In view of the recent developments [5] and in continuation of our work on copper-mediated C-C bond-forming reactions, [6] we disclose here a new method for the synthesis of unsymmetrical triarylmethanes. We now show that facile and direct replacement of free hydroxyl group in diaryl methanols with arene nucleophles takes place under copper(II) bromide catalysis.

DISCUSSION
We have recently described a convenient method for the synthesis of pyrrolyl aryl ketones, for example, 1 from a-oxoketene dithioacetals and tosylmethyl isocyanide (TOSMIC). [7] The reaction involved 1,3-dipolar cycloaddition of TOSMIC to a-oxoketene dithioacetals in the presence of sodium hydride. The pyrrolyl aryl ketone 1 was reduced to pyrrolyl phenyl methanol 2 with sodium borohydride to furnish the secondary alcohol 2 in 86% yield (Scheme 1). We targeted replacement of the hydroxy group in 2 with aryl groups to achieve synthesis of unsymmetrical triarylmethanes of the type 3.

PYRROLE-INCORPORATED TRIARYLMETHANES
With optimized conditions in hand, we repeated the reaction of alcohol 2 with two electron-rich arene nucleophiles such as N,N-diethylaniline and b-napthol to yield corresponding triarylmethanes 3b and 3c in good yield (Scheme 2). Next, we extended the strategy with an aim to incorporate heteroaromatic moities such as pyrrole, indole, and imidazole into unsymmetrial triarylmethane framework. Each of these reactions worked well to furnish corresponding triarylmethanes 3d-f. As expected, for pyrrole the electrophilic substitution took place on C(2), i.e., a position to provide 3d [for indole it was on C(3)] and b position to provide 3e [for imidazole the substitution was on C(4) position to provide 3f]. Regiochemistry of the substitutions was ensured from NMR spectral data.
In continuation of this study we treated hydroxy compound 2 with benzimidazole [8] 4h under copper(II) bromide catalysis to incorporate the benzimdazole motif into the unsymmetrical triarylmethanes 3. Benzimidazole 4h has two possible nucleophillic sites, namely N(1) and C(2). [9] The reaction of 2 with benzimidazole was regioselective to provide 3h exclusively in 89% yield through CN bond formation. Generation of 3h was ensured from the NMR spectra; the 1 H NMR spectrum exhibited a singlet at 6.63 ppm for methine hydrogen. This signal got downfield shifted from about 5.5 ppm for 3a owing to attached electronegative nitrogen atom. Finally, we treated 2 with 2-methylbenzimidazole 4i to obtain triarylmethane 3i in 83% yield via C-N bond formation.
Mechanistically, substitution of the hydroxyl group in 2 could go through generation of copper-bound carbocation in the first step. Quenching of the soft carbocation in the second step by aryl groups at their respective electron-rich carbon=nitrogen centers leads to triarylmethanes. Copper(II) bromide appears to be most suitable catalyst for both the steps.

CONCLUSION
In conclusion, we have demonstrated a facile method for synthesis of pyrroleincorporated unsymmetrical triarylmethanes via C-C or C-N bond formation under copper(II) bromide catalysis. The method is general and applicable to a synthesis of a variety of triarylmethanes.