Substituted-phenylsulfonylpiperazines such as sildenafil and vardenafil (Figure 1), are being marketed for the treatment of erectile dysfunction because of their phosphodiesterase inhibitor-5 inhibitory activity [1,2,3,4,5]. Ordonafil, a cyclic ether analog of sildenafil, has also been shown to prevent myocardial hypertrophy [6]. Other substituted-phenylsulfonylpiperazines have adenosine A_2B receptor antagonistic activity [7], anti-inflammatory activity [8] and IKK2 inhibitory activity [9].

In general, the synthesis of sildenafil and its closely related analogs requires a long multistep synthetic pathway, which is due, in part, to the presence of the aromatic heterocyclic ring [10] and only became less tedious after 4-amino-4,5-dihydro-1-methyl-3-propyl-1H-pyrazole-5-carboxamide became commercially available [1]. Other analogs containing similar and sometimes more complicated heterocyclic aromatic systems have been reported, namely, imidazolotriazinones [11], xanthines [12], pyrrolopyrimidinediones [13], imidazoquinazoline [14], pyridopurinone [15] and triazolopurinones [13]. The xanthine and pyrrolopyrimidinedione derivatives (Figure 1), in which the phenyl-sulfonylpiperazine is connected to the five membered ring of the aromatic system rather than the six member ring as in sildenafil, have shown nanomolar inhibitory activity against PDE-5 [12,13]. Herein, simpler benzimidazole analogs of sildenafil that are related to xanthines and pyrrolopyrimidinediones are reported. The target compounds have the general formulas 3-benzimidazolyl-3-methoxyphenyl-sulfoylpiperazines and 3-benzimidazolyl-4-methoxy-N,N-dimethylbenzenesulfonamide. The synthesis proceeded using readily available inexpensive starting materials and reagents and the synthesized compounds were characterized by ¹H-NMR, ¹³C-NMR and Mass Spectrometry.

We were interested in an efficient, fast and inexpensive synthesis of the target compounds. The primary concern was to find and then execute a simple one-pot procedure for the preparation of the tricyclic benzimidazole backbone starting from o-anisaldehyde. Many procedures which can attain this goal have been reported in recent literature. For example, the treatment of the appropriate aldehyde with an ortho-diaminobenzene in the presence of an oxidizing agent can afford the corresponding benzimidazole [16,17,18,19,20]. Also, the treatment of o-nitroanilines with aldehydes in the presence of Na₂S₂O₄ can also afford benzimidazoles [21]. Another procedure called for the treatment of 2-halo-anilines with aldehydes in the presence of copper (I) chloride and sodium azide [22]. For this work, an addition-oxidation of phenylenediamine to o-anisaldehyde in the presence of 1,4-benzoquinone, as an oxidizing agent, was employed to afforded the desired benzimidazole (1) in good yields [23]. It was critical to add all the starting materials together and wait for 30 min before adding the solvent, ethanol. The benzimidazole 1 was then chlorosulfonated selectively at the para-position of the anisyl moiety and the resultant sulfonyl chloride was extensively washed with water and used in the next step without further purification. To obtain the final compounds, the sulfonyl chloride, dissolved in dichloromethane, was coupled to 1-methylpiperazine, N-ethylpiperazine and piperazine dihydrochloride in the presence of excess amounts of triethylamine [24,25]. The resultant amines were then converted to the hydrochloride salts and purified by crystallization from methanol/ethyl acetate to afford compounds 2, 3 and 4 in good yields. To obtain compound 5, the sulfonyl chloride was treated with an aqueous solution of dimethylamine and the product was crystallized form ethyl acetate in good yields. The synthetic pathway for the preparation of target compounds 2–5 is illustrated in Scheme 1.

Compounds 1–5 were characterized by ¹H-NMR, ¹³C-NMR and Mass Spectrometry. While the NMR and mass spectra have confirmed the identity of these compounds, there was a peak in the mass spectra of compounds 2–4 that caught our attention. The m/z = 316 was present with medium to high intensities, 52-97%, in the mass spectra of the piperazine ring-containing compounds only, although, it was expected that compound 5 would be the one to form this m/z by simple cleavage of one of the methyl groups on the dimethylsulfonamide moiety, but such m/z was not present in its spectrum. This peak could not be explained by simple fragmentation and hence a possible scheme for the formation of this fragment is proposed, as seen in Scheme 2, in accordance with the work of Shetty et al. on the fragmentation of piperazine-containing phenothiazine antispcyhotic agents [26]. The unique mass spectra of the herein reported compounds 2–4 can be considered diagnostic for their identity. In addition, it is worth mentioning that there are reports of detailed MS analyses of sildenafil and other chemically similar compounds [27,28,29] but none of these reports suggested this pattern of fragmentation, which led to the belief that it is novel for these phenylsulfonylpiperazines. Other fragments that were present and their molecular formulae are also shown in Scheme 2.

Four benzimidazole analogs of sildenafil have been successfully synthesized using a straightforward, short and cost effective pathway. The reaction times were 3 h or less and yields were 67.40-84.20%. The identity of the synthesized compounds was verified using NMR and MS analyses. The MS analysis of the piperazine containing compounds showed a novel fragmentation pattern for phenyl sulfonylpiperzines leading to the formation of a diagnostic peak with m/z = 316. A mechanism for the formation of the characteristic m/z (316) was proposed and the molecular formulas of the most prominent peaks in the mass spectra of the synthesized compounds, 99, 113, 222, 223 and 224, have been proposed.