A stereospecific multicomponent reaction among isocyanides, nitrile N-oxides and carboxylic acids provides an efficient synthesis of biologically relevant syn \u3b1-oximinoimides

Galli, Simona

Mossetti, Riccardo

Pirali, Tracey

Tron, Gian Cesare

Tracey Pirali

Riccardo Mossetti

Simona Galli

Gian Cesare Tron

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Organic Letters

Stereospecific Synthesis of <i>syn</i>-α-Oximinoamides by a Three-Component Reaction of Isocyanides, <i>syn</i>-Chlorooximes, and Carboxylic Acids

A stereospecific multicomponent reaction among isocyanides, nitrile N-oxides and carboxylic acids provides an efficient synthesis of biologically relevant syn α-oximinoimides

GALLI, SIMONA

Archivio istituzionale della ricerca - Università dell'Insubria

10.1021/ol201397x r 2011 American Chemical SocietyPublished on Web 06/13/2011ORGANICLETTERS2011Vol. 13, No. 143734–3737Stereospecific Synthesis of syn-r-Oximinoamides by a Three-ComponentReaction of Isocyanides,syn-Chlorooximes, and Carboxylic AcidsTracey Pirali,*,† Riccardo Mossetti,† Simona Galli,‡ and Gian Cesare Tron*,†Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,Universita degli Studi del Piemonte Orientale “A. Avogadro”, Via Bovio 6,28100 Novara, Italy, and Dipartimento di Scienze Chimiche e Ambientali,Universita dell’Insubria, Via Lucini 3, 22100 Como, Italypirali@pharm.unipmn.it; tron@pharm.unipmn.itReceived May 24, 2011ABSTRACTA stereospecific multicomponent reaction among isocyanides, syn-chlorooximes, and carboxylic acids provides an efficient synthesis ofbiologically relevant syn-R-oximinoamides.When three or more starting materials react in the sameflask to produce a molecule which contains parts of all thereactants, amulticomponent reaction (MCR) takes place.1In general, MCRs stand out as a powerful tool for therapid construction of quite complex molecules, not easilyaccessible via the classical two-component chemistry.2Among them, the Passerini reaction (Scheme 1) is theoldestMCR inwhich isocyanides have been used,3 exploit-ing their propensity to react with nucleophiles andelectrophiles at the same carbon atom. Over the past fewdecades, this reaction has gained interest as a simple andpractical methodology for the synthesis of novel molec-ular scaffolds. Besides the post-transformation strategy,4another tactic to expand the scope of this venerable reac-tion is to use surrogates of the carboxylic or the carbonylpartners.Successful examples of replacing the carboxylic moietywith water,5 hydrazoic acid,6 o-nitrophenol,7 silanol,8 andScheme 1. Passerini Reaction†Universita degli Studi del Piemonte Orientale “A. Avogadro”.‡Universita dell'Insubria.(1) Multicomponent reactions; Zhu, J., Bienayme, H., Eds.:Wiley-VCH:Weinheim, 2005 and references therein. For reviews, see: (b) D€omling, A.Chem. Rev. 2006, 106, 17–89. (c) Synthesis of heterocycles via multi-component reactions I and II; Orru, R. V. A., Ruijeter, E., Eds.; SpringerGmbH: Berlin, 2010 and references therein.(2) For reviews, see: (a) Akritopoulou-Zanze, I.; Djuric, S. W. Het-erocycles 2007, 73, 125–147. (b) Zhu, J.Eur. J. Org. Chem. 2003, 7, 1133–1144. (c) Sunderhaus, J.D.;Martin, S. F.Chem.;Eur. J. 2009, 15, 1300–1308. (d) D’Souza, D. M.; M€uller Thomas, J. J. Chem. Soc. Rev. 2007,36, 1095–1108. (e) Toure, B. B.; Hall, D. G.Chem. Rev. 2009, 109, 4439–4486. (f) D€omling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.(3) (a) Passerini,M.Gazz. Chim. Ital. 1921, 51, 126–129. (b) Riva, R.;Banfi, L.Org. React. 2005, 65, 1–140. (c) For a novel proposal regardingthe mechanism of the Passerini reaction, see: Maeda, S.; Komagawa,S.; Uchiyama, M.; Morokuma, K. Angew. Chem., Int. Ed. 2011, 50644–649.(4) (a)Marcaccini, S.; Torroba, T. InMulticomponent reactions; Zhu,J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005; pp 3375. (b) Banfi,L.; Basso, A.; Riva, R. In Synthesis of heterocycles via multicomponentreactions I; Orru, R. V. A., Ruijeter, E., Eds.: Springer GmbH: Berlin, 2010;pp 140.Org. Lett., Vol. 13, No. 14, 2011 3735alchools9 have been reported, while acyl cyanides,10epoxides,11 acylisocyanates,12 and ketenes13 emerged aselectrophilic partners in the Passerini reaction.14 In thisrespect, and in connection with our ongoing projectsaiming at the development of multicomponent reactions15and their applications inmedicinal chemistry,16we becameinterested in developing multicomponent processes ex-ploiting novel electrophilic species. We reasoned that,as in principle there are no restrictions on the nature ofthe electrophile and nucleophile which can react with theisocyanide forming the so-called R-adduct,17 syn-chlor-ooximes could be excellent surrogates for the carbonylgroup. Herein, we report a multicomponent reactionamong syn-chloroximes, isocyanides, and carboxylic acidsto afford syn-R-oximinoamides with a high level of stereo-specificity (Scheme 2).To validate our hypothesis, to a solution of cyclohexylisocyanide (2a) and phenylacetic acid (3a) in dichloro-methane as solvent was added 1 equiv of triethylamine todeprotonate the carboxylic acid. After the addition of syn-phenylchlorooxime (1a),18,19 the reaction was stirred atroom temperature for 1 h. To our delight, the desired syn-oximinoamide20 (4a) was formed in 70% yield, along witha trace of its anti isomer (syn/anti ratio 94:6)21 (Scheme 3).The use of a base, to avoid the generation of HCl, wascompulsory for the success of this transformation. Indeed,the reaction carried out in the absence of triethylaminegave the desired product in only 21% of yield.Our proposedmechanism for this reaction is depicted inScheme 4. The syn-chlorooxime reacts with the isocyanide,forming the transient R-adduct, which is in equilibriumwith its nitrilium form. The nitrilium intermediate isthen intercepted by the carboxylate ion. The intermedi-ate so obtained undergoes an irreversible Mumm-typeScheme 2. Novel Multicomponent Passerini-Type ReactionScheme 3. Three-Component Reaction of Cyclohexylisocya-nide 2a, Phenylacetic Acid 3a, and Benzylchloroxime 1aScheme 4. Proposed Mechanism for the Three-ComponentReaction(5) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.; Weigand, W.Chem. Ber. 1988, 121, 507–517.(6) (a) Ugi, I.; Meyr, R. Chem. Ber. 1961, 94, 2229–2233. (b) Nixey,T.; Hulme, C. Tetrahedron Lett. 2002, 43, 6833–6835. (c) For anasymmetric version of this reaction, see: Yue, T.; Wang, M. X.; Wang,D. X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 9454–9457.(7) El-Kaim, L.; Gizolme, M.; Grimaud, L.Org. Lett. 2006, 8, 5021–5023.(8) Soeta, T.; Kojima, Y.; Ukaji, Y.; Inomata, K.Org. Lett. 2010, 12,4341–4343.(9) Yanai, H.; Oguchi, T.; Taguchi, T. J. Org. Chem. 2009, 74, 3927–3939.(10) Oaksmith, J. M.; Peters, U.; Ganem, B. J. Am. Chem. Soc. 2004,126, 13606–13607.(11) (a) Kern, O. T.; Motherwell, W. B.Chem. Commun. 2003, 2988–2989. (b) Revised structure: Kern, O. T.; Motherwell, W. B. Chem.Commun. 2005, 1787.(12) Neidlein, R. Naturforsch 1964, 19, 1159–1160.(13) Ugi, I.; Rosendahl, F. K. Chem. Ber. 1961, 94, 2233–2235.(14) Replacing of the aldehyde or ketone with an imine leads to thewell-known four-component Ugi reaction.(15) (a) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I.;Pirali, T. Angew. Chem. 2006, 118, 1117–1120. Angew. Chem., Int. Ed.2006, 45, 1099–1102. (b) Mossetti, R.; Pirali, T.; Tron, G. C. J. Org.Chem. 2009, 74, 4890–4892. (c) Pirali, T.; Tron, G. C.;Masson, G.; Zhu,J. Org. Lett. 2007, 9, 5275–5278. (d) Mossetti, R.; Caprioglio, D.;Colombano, G.; Tron, G. C.; Pirali, T. Org. Biomol. Chem. 2011, 9,1627–1631. (e) Mossetti, R.; Pirali, T.; Seggiorato, D.; Tron, G. C.Chem. Commun. 2011, 47, 6966–6968.(16) (a) Pirali, T.; Faccio, V.; Mossetti, R.; Grolla, A. A.; Di Micco,S.; Bifulco, G.; Genazzani, A. A.; Tron, G. C.Mol. Diversity 2010, 14,109–121. (b) Grolla, A. A.; Podesta, V.; Chini, M. G.; Di Micco, S.;Vallario, A.; Genazzani, A. A.; Canonico, P. L.; Bifulco, G.; Tron,G. C.; Sorba,G.; Pirali, T. J.Med. Chem. 2009, 52, 2776–2785. (c) Pirali,T.; Callipari, G.; Ercolano, E.; Genazzani, A. A.; Giovenzana, G. B.;Tron, G. C. Org. Lett. 2008, 10, 4199–4202.(17) Saegusa, T.; Ito, Y. In Isonitrile Chemistry; Ugi, I., Ed.; AcademicPress: New York, 1971; pp 6592.(18) E-Oximes were prepared from the corresponding aldehydes. Allthe chlorooximeswere prepared following the procedure reportedbyLiuand Howe: Liu, K. C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980,45, 3916–3918. A small amount of E-chlorooximes was always present.See the experimental part for the general procedures.(19) Z-Chlorooximes are stable in solution see: Smolikovta, J.;Exner, O.; Barbaro, G.; Macciantelli, D.; Dondoni, A. J. Chem. Soc.,Perkin Trans 2 1980, 1051–1056.(20) El-Kaim et al. have described the synthesis of a syn/antimixtureof R-oximinoamides by reacting primary nitro compounds, isocyanides,and anhydrides. See: (a) Dumestre, P.; El Kaim, L.; Gregoire, A. Chem.Commun. 1999, 755–756. (b) Dumestre, P.; El Kaim, L. TetrahedronLett. 1999, 40, 7985–7986.(21) The ratio was established by 1H NMR, by integrating the bestresolved peaks.3736 Org. Lett., Vol. 13, No. 14, 2011rearrangement mediated by the syn-oxime driving all theequilibria to the final syn-R-oximinoamide.Under these buffered conditions (1 equiv of carboxylicacid and 1 equiv of TEA), no generation of nitrileN-oxidesand the subsequent formation of the corresponding furox-ans from chloroximes were detected, as confirmed inseparate experiments, ruling out a direct involvement ofnitrile N-oxides in the reaction.22With the anti isomer of chloroximes, it is the lone pair ofthe nitrogen atomwhich captures the acyl group to give anacylimide23 and finally the anti-oximinoamide (Scheme 5).As shown in Figure 1, the syn stereochemistry for themajor stereoisomerof compound4awas further confirmedby X-ray diffraction analysis.The scope and limitation of this MCR were next exam-ined. Different chlorooximes (1ah), isocyanides (2ae),and carboxylic acids (3ai) were chosen (Figure 2).As it is possible to see in Figure 3, this transformationproved to be highly versatile, and the level of stereospecificityFigure 2. Building blocks.Figure 1. X-ray crystal structure of 4a.Figure 3. Synthesized R-oximinoamides.Scheme 5. Proposed Mechanism for the Formation of the synand anti Isomers of R-Oximinoamides(22) Reaction between isocyanides and nitrile N-oxides to give iso-cyanates and nitriles has been reported: (a) Vita Finzi, P.; Arbasino, M.Tetrahedron Lett. 1965, 6, 4645–4646. (b) Alpoim, C. M.; Barrett,A. G: M.; Barton, D. H. R.; Hiberty, P. C. New J. Chim. 1980, 4, 127–129. (c) El Kaim, L.; Gacon, A. Tetrahedron Lett. 1997, 38, 3391–3394.(23) Acylimides have been reported. See: Ziegler, E.; Belegratis, K.Monatsh. Chem. 1968, 99, 995–998.Org. Lett., Vol. 13, No. 14, 2011 3737dependson the syn/anti ratioof the startingR-chlorooximes.The reaction was tolerant to primary, secondary, andtertiary isocyanides but failed with aromatic isocyanides.Both aliphatic and aromatic carboxylic acids participatedwell in the reaction. The presence of electron-withdrawingor electron-releasing groups on the benzoic acid did notaffect the course of the reaction.The R-oximinoamide motif occupies a relevant role inthe core of numerous pharmaceuticals and natural pro-ducts. It can be found in its syn configuration inmost of thesecond- and third-generation cephalosporins, either assuch or as the oximino ether (e.g., cefmatilen, cefixime,cefdinir, and cefditoren) and β-lactamase inhibitors (e.g.,aztreonam),24 as well as in some natural products such asthe antibacterial nocardicin A. The anti form is displayedin marine natural products such as verongamine, basta-dines, and psammaplin A.25Very recently, R-oximinoamides have been reported asan effective zinc chelating moiety in a series of potentHDAC inhibitors.26In conclusion, we have successfully developed a MCRwhere chlorooximes are involved to produce syn-R-oximi-noamides in a stereospecific manner. The reaction iseffective across a range of structures in each component,producing diverse oximinoamides in a single step.Acknowledgment. Financial support from Universitadel Piemonte Orientale is gratefully acknowledged.Supporting Information Available. Experimental pro-cedures and characterization data for all new com-pounds synthesized. This material is available free ofcharge via the Internet at http://pubs.acs.org.(24) Foye’s principles ofmedicinal chemistry; Foye,W.O., Lemke, T. L.,Williams, D. A. Wolters Kluver: the Netherlands, 2008; p 1057.(25) Hentschel, F.; Lindel, T. Synthesis 2010, 2, 181–204.(26) Botta, C. B.; Cabri, W.; Cini, E.; De Cesare, L.; Fattorusso, C.;Giannini, G.; Persico, M.; Petrella, A.; Rondinelli, F.; Rodriquez, M.;Russo, A.; Taddei, M. J. Med. Chem. 2011, 54, 2165–2182.

Stereospecific synthesis of syn-alpha-oximinoamides by a three-component reaction of isocyanides, syn-chlorooximes, and carboxylic acids

Stereospecific synthesis of syn-alpha-oximinoamides by a three-component reaction of isocyanides, syn-chlorooximes, and carboxylic acids

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