- Research article
- Open Access
Inorganic base-catalyzed formation of antivirally active N-substituted benzamides from α-amido sulfones and N-nucleophile
© Jin et al 2011
Received: 30 January 2011
Accepted: 5 May 2011
Published: 5 May 2011
Heteronucleophiles as well as carbanionic reagents can be used to react with α-amido sulfones, thus giving the opportunity to prepare a large array of amino derivatives. Since, novel 1,3,4-oxadiazole-2-thiol derivatives can serve as potent nucleophiles, we employed 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the nucleophilic source of nitrogen in the reaction with α-amido sulfones.
A series of N-substituted benzamides bearing 1,3,4-oxadiazol unit were prepared for the first time by the reaction of in situ generated protected imine from α-amido sulfones with 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophile. Some of the synthesized products displayed favourable antiviral activity against cucumber mosaic virus (CMV) in preliminary antiviral activity tests. The title compounds 5c, 5o and 5r revealed curative activity of 42.2%, 48.7% and 40.5%, respectively against CMV (inhibitory rate) compared to the commercial standard Ningnanmycin (53.4%) at 500 μg/mL.
A practical synthetic route to N-benzoyl-α-amido sulfones by the reaction of 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophiles with in situ generated protected imine from N-benzoyl-α-amido sulfones is presented. The reaction catalyzed by an inorganic base has considerable significance to exploit the potential of α-amido sulfones in organic synthesis.
α-Amido sulfones are known for their wide range of application in asymmetric synthesis . Different carbanionic nucleophiles can be reacted with α-amido sulfones, affording a wide variety of amino derivatives [2–7]. In addition, considerable research has been conducted on the reaction of nitrogen nucleophiles and α,β-unsaturated carbonyls [8–11]. Heteronucleophiles as well as carbanionic reagents can react with α-amido sulfones, thus giving the opportunity to prepare a large array of amino derivatives. Furthermore, a series of amino derivatives containing 1, 3, 4-oxadiazole ring were synthesized by the reaction of 1, 3, 4-oxadiazole-2-thiol with suitably substituted amines and formaldehyde in ethanol . Based on these reports, we executed an inorganic base-mediated reaction of 5-subsititued phenyl-1, 3, 4-oxadiazole-2-thiols as the source of nitrogen nucleophiles with N-benzoyl-α-amido sulfones to produce N, N-aminals. Interestingly, the resulting compounds bearing a 1, 3, 4-oxadiazole ring are often associated with significant fungicidal and insecticidal activities [13–15]. Nevertheless, as of today, there has been no report on antiviral activities of N-substituted benzamides bearing 1,3,4-oxadiazol unit. We report synthetic and antiviral studies of the title compounds in the ensuing sections.
Results and Discussion
Effect of different solvents and bases for the synthesis of 5aa
Yield (%) c
Antiviral activity and structure-activity relationship
Curative effect of the title compounds 5 against CMV in vivo a
Curative effect (%)
The melting points of the products were determined on an XT-4 binocular microscope (Beijing Tech Instrument Co., China) and were not corrected. The IR spectra were recorded on a Bruker VECTOR 22 spectrometer in a KBr disk. 1H NMR (500 MHz), 13C NMR (125 MHz) and 19F NMR (470 MHz) spectral analyses were performed on a JEOL-ECX 500 NMR spectrometer at room temperature using TMS as an internal standard and CDCl3 as the solvent. Elemental analysis was performed on an Elementar Vario-III CHN analyzer. Analytical TLC was performed on silica gel GF254. Column chromatographic purification was carried out using silica gel. All the solvents and materials were of analytical-grade. Intermediate 1, intermediate 2 and 5-subsititued phenyl-1,3,4-oxadiazole-2-thiol 3 were prepared according to the reported methods [17, 18] and used without further purifications [Additional file 2].
Antiviral biological assay
Preparation of medicaments
Tested compounds and 2% Ningnanmycin aqua used as a reference antiviral agent were first dissolved in minimum volume of N, N-dimethylformamide (DMF) and then diluted with distilled water containing 1% Tween 20 at 500 μg/mL concentration.
Curative effect of compounds against CMV in vivo
We have demonstrated a general and practical route for the synthesis of the N-substituted benzamides bearing 1,3,4-oxadiazol moiety in the presence of an inorganic base as the catalyst. The reaction of 5-subsititued phenyl-1,3,4-oxadiazole-2-thiol which serves as the source of N-nucleophile with in situ generated protected imine from N-benzoyl-α-amido sulfones provides a ready access to a series of structurally diverse N, N-aminals. The antiviral tests indicated that some of the synthesized compounds possessed of moderately high curative activity against CMV. The structure of the target products needs to be optimized to enhance their antiviral activity. Further studies on mechanistic aspects, enantioselectivities and asymmetric variants of catalysts for this reaction are currently being investigated in our group.
We gratefully acknowledge the generous financial support received from the National Key Project for Basic Research (2010CB126105, 2010CB134504) and the National Natural Science Foundation of China (20872021).
- Petrini M: α-Amido sulfones as stable precursors of reactive N-acylimino derivatives. Chem Rev. 2005, 105: 3949-3977. 10.1021/cr050528s.View ArticleGoogle Scholar
- Murry JA, Frantz DE, Soheili A, Tillyer R, Grabowski EJJ, Reider PJ: Synthesis of α-amido ketones via organic catalysis: thiazolium-catalyzed cross-coupling of aldehydes with acylimines. J Am Chem Soc. 2001, 123: 9696-9697. 10.1021/ja0165943.View ArticleGoogle Scholar
- Palomo C, Oiarbide M, Laso A, López R: Catalytic enantioselective aza-Henry reaction with broad substrate scope. J Am Chem Soc. 2005, 127: 17622-17623. 10.1021/ja056594t.View ArticleGoogle Scholar
- Song J, Shih HW, Deng L: Asymmetric Mannich reactions with in situ generation of carbamate-protected imines by an organic catalyst. Org Lett. 2007, 9: 603-606. 10.1021/ol062837q.View ArticleGoogle Scholar
- Gomez-Bengoa E, Linden A, Lόpez R, Múgica-Mendiola I, Oiarbide M, Palomo C: Asymmetric aza-Henry reaction under phase transfer catalysis: an experimental and theoretical study. J Am Chem Soc. 2008, 130: 7955-7966. 10.1021/ja800253z.View ArticleGoogle Scholar
- Zhang H, Syed S, Barbas CF: Highly enantio- and diastereoselective Mannich reactions of glycine Schiff bases with in situ generated N-Boc-imines catalyzed by a cinchona alkaloid thiourea. Org Lett. 2010, 12: 708-711. 10.1021/ol902722y.View ArticleGoogle Scholar
- Mazzotta S, Gramigna L, Bernardi L, Ricci A: One-pot synthesis of optically active β-amino-α-methylene carbonyl derivatives from α-amidosulfones using quinine-based phase-transfer catalysts. Org Process Res Dev. 2010, 14: 687-691. 10.1021/op1000308.View ArticleGoogle Scholar
- Kobayashi S, Kakumoto K, Sugiura M: Transition metal salts-catalyzed aza-Michael reactions of enones with carbamates. Org Lett. 2002, 4: 1319-1322. 10.1021/ol0256163.View ArticleGoogle Scholar
- Wabnitz TC, Spencer JB: A general, Brønsted acid-catalyzed hetero-Michael addition of nitrogen, oxygen, and sulfur nucleophiles. Org Lett. 2003, 5: 2141-2144. 10.1021/ol034596h.View ArticleGoogle Scholar
- Palomo C, Oiarbide M, Halder R, Kelso M, Gómez-Bengoa E, García JM: Catalytic enantioselective conjugate addition of carbamates. J Am Chem Soc. 2004, 126: 9188-9189. 10.1021/ja047004e.View ArticleGoogle Scholar
- Rowland GB, Zhan H, Rowland EB, Chennamadhavuni S, Wang Y, Antilla JC: Brønsted acid-catalyzed imine amidation. J Am Chem Soc. 2005, 127: 15696-15697. 10.1021/ja0533085.View ArticleGoogle Scholar
- Koparır M, Çetin A, Cansız A: 5-Furan-2yl134oxadiazole-2-thiol, 5-furan-2yl-4H124 triazole-3-thiol and their thiol-thione tautomerism. Molecules. 2005, 10: 475-480. 10.3390/10020475.View ArticleGoogle Scholar
- Wu J, Song BA, Chen HJ, Bhadury PS, Hu DY: Synthesis and antifungal activity of 5-chloro-6-phenylpyridazin-3(2H)-one derivatives. Molecules. 2009, 14: 3676-3687. 10.3390/molecules14093676.View ArticleGoogle Scholar
- Zheng XM, Li Z, Wang YL, Chen WD, Huang QH, Liu CX, Song GH: Syntheses and insecticidal activities of novel 2,5-disubstituted 1,3,4-oxadiazoles. J Fluorine Chem. 2003, 123: 163-169. 10.1016/S0022-1139(03)00168-4.View ArticleGoogle Scholar
- Ram VJ, Vlietinck AJ: Chemotherapeutical agents. VII. synthesis and pesticidal activities of sulphides and sulphones derived from bis[4-aryl-1,2,4-triazoline-5-thione-3-yl]alkane and 5-phenyl-1,3,4-oxadiazole-2-thione. J Heterocycl Chem. 1988, 25: 253-256. 10.1002/jhet.5570250141.View ArticleGoogle Scholar
- Chemla F, Hebbe V, Normant JF: An easy synthesis of aliphatic and aromatic N-sulfonyl aldimines. Synthesis. 2000, 32: 75-77.View ArticleGoogle Scholar
- Chen Z, Xu WM, Liu KM, Yang S, Fan HT, Bhadury PS, Hu DY, Zhang YP: Synthesis and antiviral activity of 5-(4-chlorophenyl)-1,3,4-thiadiazole sulfonamides. Molecules. 2010, 15: 9046-9056. 10.3390/molecules15129046.View ArticleGoogle Scholar
- Liu F, Luo XQ, Song BA, Bhadury PS, Yang S, Jin LH, Xue W, Hu DY: Synthesis and antifungal activity of novel sulfoxide derivatives containing trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-oxadiazole moiety. Bioorg Med Chem. 2008, 16: 3632-3640. 10.1016/j.bmc.2008.02.006.View ArticleGoogle Scholar