Complementary regioselective synthesis of iminohydantoins from isocyanoacetamides controlled by the substituent on the amide group has been described. 4-Iminohydantoins were the major products when the starting materials were N-alkyl isocyanoamides, whereas 2-iminohydantoins were the major products with N-aryl isocyanoamides.Ministerio
de Ciencia e Innovación, Spain (Project CTQ2009-12631-
BQU), Junta de Castilla y León, Consejería de Educación y
Cultura y Fondo Social Europeo (Projects BU023A09 and
GR170)

García Valverde, María

González Ortega, Alfonso .

Marcaccini, Stefano .

Rodríguez Vidal, Francisco Javier

Rojo Cámara, Mª Josefa

Torroba Pérez, Tomás

Organic & Biomolecular Chemistry

Repositorio Institucional de la Universidad de Burgos

Organic &BiomolecularChemistryCOMMUNICATION Dynamic Article LinksView Online / Journal HomepageCite this: DOI: 10.1039/c2ob27098fReceived 27th October 2012,Accepted 4th December 2012DOI: 10.1039/c2ob27098fwww.rsc.org/obcComplementary regioselectivity in the synthesis ofiminohydantoins: remarkable eﬀect of amidesubstitution on the cyclizationQ1 †‡María García-Valverde,*a Stefano Marcaccini,*b Alfonso González-Ortega,cFrancisco Javier Rodríguez,a Josefa Rojoa and Tomás TorrobaaQ2Complementary regioselective synthesis of iminohydantoins fromisocyanoacetamides controlled by the substituent on the amidegroup has been described. 4-Iminohydantoins were the major pro-ducts when the starting materials were N-alkyl isocyanoamides,whereas 2-iminohydantoins were the major products with N-arylisocyanoamides.Apart from the interest in isocyanoacetamides for their highantimicrobial activity,1 a number of works have reported theirusefulness as starting materials in the synthesis of a widevariety of nitrogen-containing heterocycles.2 Besides thecharacteristic chemistry of isocyanides with a formally divalentcarbon,3 two diﬀerent approaches have been employed for thecyclization, the use of the active methylene4 and the use of theamide group, either through the oxygen5 or nitrogen atom.6Several factors have a significant influence on the course ofthese cyclizations such as the substitution at the α-carbon ofthe isocyanoacetamides,7 the nucleophilicity of the isocyanidegroup8 or the reaction conditions.7 However, although theimportance of the degree of the amide substitution9 in thesereactions has also been studied,10 the significance of thenature of N-substituents on the amide group has not beenreported.In previous papers we have reported the outcome of the3-component reaction of isocyanides with chloramines andaromatic amines11 and exploited it in the synthesis of nitrogenheterocycles such as quinazolines12 and imidazoles13 by two-step one-pot reactions. As a part of our eﬀorts directed towardsthe synthesis of heterocyclic compounds from isocyanides,this paper deals with a novel application of α-isocyanoacet-amides in the regioselective synthesis of iminohydantoins.These heterocycles have been described as potential drugs forthe treatment of Alzheimer’s disease acting as β-secretaseinhibitors with good potential for brain penetration.14We have studied the three centers-two component reaction(3C-2CR) of chloramines with isocyanoacetamides, where theamide moiety was expected to be chlorinated and then interactas an electrophile with the isocyanide divalent carbon, leadingdirectly to interesting heterocyclic structures. In this way, weattempted the reaction between N-alkyl- and N-aryl isocyano-acetamides15 (1) and chloramines (2) to synthesize aminoimid-azolidinones from a simple reaction under phase transferconditions. Therefore, a small amount of TEBA (benzyltriethyl-ammonium chloride) was added to a stirred suspension of iso-cyanoacetamide 1a–i (1 equiv.) and dry chloramine (B, 2a, orT, 2b) (1 equiv.) in dry chloroform at room temperature for 4days. Aqueous work-up, extraction with chloroform and recrys-tallization gave iminohydantoin derivatives 3–4 in fair yields(Table 1).The cyclization was expected to be regioselective, producing2-iminohydantoins 4 as single regioisomers. However,although all the α-isocyanocarboxamides tested aﬀordediminohydantoins, two diﬀerent regioisomers were obtaineddepending on the nature of the N-substituent in the amidegroup (Table 1). 4-Iminohydantoins 3 were predominantlyobtained when N-alkyl α-isocyanocarboxamide derivatives wereused as starting materials (Table 1, entries 1–8), while 2-imino-hydantoins 4 were the major products with N-aryl derivatives(Table 1, entries 9–12). As far as we know this is the firstreported example of a complementary regioselective cyclizationcontrolled by the substituents on an amide group.These experimental data suggest that the observed regio-selectivity might be correlated to the electron density on thenitrogen of the amide group. Thus, while the N-phenyliso-cyanocarboxamides 1h and 1i aﬀord 2-iminohydantoin deriva-tives 4j–l as the overwhelming product (Table 1, entries 10–12),†This paper is dedicated to the memory of Stefano Marcaccini.‡Electronic supplementary informationQ3 (ESI) available: Experimental details,synthesis and characterization of products. CCDC 907949 and 907950.For ESI and crystallographic data in CIF or other electronic format see DOI:10.1039/c2ob27098faDepartamento de Química, Facultad de Ciencias, Universidad de Burgos, 09001Burgos, Spain. E-mail: magaval@ubu.es; Fax: +34-947-258831bDipartimento di Chimica Organica, Università di Firenze, Sesto Fiorentino, ItalycDepartamento de Química Orgánica, Facultad de Ciencias, Universidad deValladolid, SpainThis journal is © The Royal Society of Chemistry 2012 Org. Biomol. Chem., 2012, 00, 1–5 | 115101520253035404550551510152025303540455055Table 1 Synthesis of iminohydantoinsEntry 1 2 3a (%) 4a (%) 3 : 4b1 1a 2a — >95 : <52 1a 2b — >95 : <53 1b 2a — >95 : <54 1c 2a — >95 : <55 1d 2a — >95 : <56 1e 2a 85 : 157 1e 2b — >95 : <58 1f 2a — >95 : <59 1g 2a 36 : 6410 1h 2a — 6 : 94Communication Organic & Biomolecular Chemistry2 | Org. Biomol. Chem., 2012, 00, 1–5 This journal is © The Royal Society of Chemistry 201215101520253035404550551510152025303540455055when the N-phenyl group on the amide is bearing an electron-donating substituent the 4-iminohydantoin 3i was obtained infair yield (Table 1, entry 9).The structures of compounds 3 and 4 were assigned on thebasis of diﬀerent NMR studies. The most deshielded signal inthe 13C NMR spectra for compounds 3 is around 166 ppm corres-ponding to the CvN carbon while the 13C NMR spectra of com-pounds 4 displayed the most deshielded signal around 177 ppmcorresponding to the CvO group. These structures were con-firmed by single-crystal X-ray diﬀraction analysis performed oniminohydantoin derivatives 3c and 4f as shown in Fig. 1. Thetautomeric structures of the compounds synthesized were estab-lished by 13C–1H HMBC spectra analysis. The NH proton in 3and 4 regioisomers only shows cross peaks with the carbons onthe heterocycles (C2, C4 and C5) showing that the iminohydan-toin, and not the 1H-imidazole, is the tautomer form preferred.To explain the above results, some considerations on thereaction mechanism should be made. Although the formationof the carbodiimide intermediate has been discussed as thekey to the reaction of isocyanides with chloramine T,11,16 thediﬀerent results obtained from N-alkyl and N-aryl isocyano-acetamides in these reactions are not in agreement with theformation of such an intermediate, because this would lead inboth cases to 2-iminohydantoins as the only product.17 Webelieve that the answer to the complementary regioselectivityobserved could be found in the diﬀerent ability of N-alkyl andN-aryl amides to undergo N-chlorination.The ionic character of chloramine18 favors the hydrogenbond between the amido hydrogen and the sulfonamideanion. The rate of reaction of chlorination depends upon theease of formation of such a bond, that is, the reaction is fasterwhen there is lower electron density on the amide N atom.19 Inthis way, the reaction with N-aryl isocyanoacetamides presum-ably starts with the N-chlorination of the amide to yield theN-chlorinated amide 5. Q4The α-addition on the isocyanide fromthe sulfonylamide anion and the N-chloroamide explains thering closure to give 2-arylsulfonylamino-3-arylimidazolonederivatives, tautomers of the corresponding 2-iminohydantoinderivatives 4 (Scheme 1).The higher electron density on the nitrogen and oxygen inN-alkyl amides could explain the diﬀerent regiochemistryobtained when N-alkyl isocyanoacetamides are used as startingcompounds. The slower rate of chlorination on the amidegroup19 would allow the competitive reaction of α-addition onthe isocyanide group from the chloronium cation20 and theamide oxygen atom to give 2-chlorooxazoline 6 as the inter-mediate. The addition of the sulfonamide anion to the imidicgroup in 6 would induce the ring opening of oxazoline withthe formation of isocyanate 7 and the subsequent intramole-cular attack by the most nucleophilic nitrogen atom in theamidine group yielding 4-arylsulfonyliminoimidazolidin-2-one3 as the major product as shown in Scheme 2.The synthesis of 4-sulfonyliminoimidazolidin-2-one hasbeen previously described by the sequential treatment ofTable 1 (Contd.)Entry 1 2 3a (%) 4a (%) 3 : 4b11 1i 2a — 7 : 9312 1i 2b — 9 : 91a Isolated yield. bDetermined by 1H NMR analysis of the crude reaction mixture.Organic & Biomolecular Chemistry CommunicationThis journal is © The Royal Society of Chemistry 2012 Org. Biomol. Chem., 2012, 00, 1–5 | 315101520253035404550551510152025303540455055α-azido esters with triphenylphosphine, tosyl isocyanate andprimary amines at room temperature,21 the drawbacks of thissequence as the use of azides and the generation of triphenyl-phosphine oxide are overcome in this new synthesis. On theother hand, examples in the synthesis of 3-alkyl-2-sulfonylimi-noimidazolidin-4-one are scarce and with low yields.22In conclusion, a highly eﬃcient synthesis of iminohydan-toin derivatives by means of a very simple and general reactionbetween α-isocyanoacetamides and chloramines T and B hasbeen described. This reaction, which can be regarded as a newisocyanide-based reaction, is the first example of acomplementary regioselective cyclization controlled by thesubstitution on an amide group. The ability of the amidegroup to undergo N-chlorination has been proposed as beingkey to the regioselectivity observed.AcknowledgementsWe gratefully acknowledge financial support from the Minis-terio de Ciencia e Innovación, Spain (Project CTQ2009-12631-BQU), Junta de Castilla y León, Consejería de Educación yCultura y Fondo Social Europeo (Projects BU023A09 andGR170). We thank Marta Mansilla and Dr Jacinto Delgado(SCAI-Universidad de Burgos) for the X-ray determination ofcompounds 3c and 4f.Notes and references1 (a) R. Bossio, S. Marcaccini, R. Pepino, G. Pellegrini andM. Polsinelli, Farmaco, 1992, 47, 1173; (b) R. Bossio,S. Marcaccini, G. Pellegrini and R. Pepino, Arzneim.-Forsch./Drug Res., 1992, 42, 1494.2 A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru andV. G. Nenajdenko, Chem. Rev., 2010, 110, 5235.3 J. Campo, M. García-Valverde, S. Marcaccini, M. J. Rojo andT. Torroba, Org. Biomol. Chem., 2006, 4, 757.4 (a) K.-I. Nunami, M. Suzuki and N. Yoneda, J. Org. Chem.,1979, 44, 1887; (b) S. Kamijo, C. Kanazawa andY. Yamamoto, J. Am. Chem. Soc., 2005, 127, 9260;(c) C. Kanazawa, S. Kamijo and Y. Yamamoto, J. Am. Chem.Soc., 2006, 128, 10662; (d) D. Monge, K. L. Jensen, I. Marínand K. A. Jørgensen, Org. Lett., 2011, 13, 328.5 (a) J. P. Chupp and K. L. Leschinsky, J. Heterocycl. Chem.,1980, 17, 705; (b) R. Bossio, S. Marcaccini, R. Pepino,C. Polo and T. Torroba, Heterocycles, 1989, 29, 1829;(c) X. Sun, P. Janvier, G. Zhao, H. Bienaymé and J. Zhu, Org.Fig. 1 X-ray diﬀraction structures of 4-iminohydantoin 3c (above) and 2-imino-hydantoin 4f (below).Scheme 1 Proposed mechanism to explain the formation of 2-imino-hydantoins.Scheme 2 Proposed mechanism to explain the formation of 4-imino-hydantoins.Communication Organic & Biomolecular Chemistry4 | Org. Biomol. Chem., 2012, 00, 1–5 This journal is © The Royal Society of Chemistry 201215101520253035404550551510152025303540455055Lett., 2001, 3, 877; (d) Q. Wang, Q. Xia and B. Ganem, Tetra-hedron Lett., 2003, 44, 6825.6 (a) U. Schöllkopf, H.-H. Hausberg, M. Segal, U. Reiter,I. Hoppe, W. Saenger and K. Lindner, Liebigs Ann. Chem.,1981, 439; (b) R. Bossio, S. Marcaccini, S. Papaleo andR. Pepino, J. Heterocycl. Chem., 1994, 31, 397.7 N. Elders, E. Ruijter, F. J. J. de Kanter, M. B. Groen andR. V. A. Orru, Chem.–Eur. J., 2008, 14, 4961.8 X.-T. Zhou, Y.-R. Lin, L.-X. Dai and J. Sun, Tetrahedron,1998, 54, 12445.9 For a survey on the preparation of N-substituted- and N,N-disubstituted α-isocyanoamides and their synthetic appli-cations see: A. Dömling, B. Beck, T. Fuchs and A. Yazbak,J. Comb. Chem., 2006, 8, 872.10 N. Elders, E. Ruijter, F. J. J. de Kanter, E. Janssen, M. Lutz,A. L. Spek and R. V. A. Orru, Chem.–Eur. J., 2009, 15, 6096.11 R. Bossio, S. Marcaccini and R. Pepino, Tetrahedron Lett.,1995, 36, 2325.12 R. Bossio, S. Marcaccini and R. Pepino, J. Heterocycl. Chem.,1995, 32, 1115.13 R. Bossio, S. Marcaccini, R. Pepino and T. Torroba, J. Org.Chem., 1996, 61, 2202.14 (a) J. C. Barrow, J. C. S. R. Stauﬀer, K. E. Rittle, P. L. Ngo,Z.-Q. Yang, H. G. Selnick, S. L. Graham, S. Munshi,G. B. McGaughey, M. K. Holloway, A. J. Simon, E. A. Price,S. Sankaranarayanan, D. Colussi, K. Tugusheva, M.-T. Lai,A. S. Espeseth, M. Xu, Q. Huang, A. Wolfe, B. Pietrak,P. Zuck, D. A. Levorse, D. Hazuda and J. P. Vacca, J. Med.Chem., 2008, 51, 6259; (b) J. N. Cumming, E. M. Smith,L. Wang, J. Misiaszek, J. Durkin, J. Pan, U. Iserloh, Y. Wu,Z. Zhu, C. Strickland, J. Voigt, X. Chen, M. E. Kennedy,R. Kuvelkar, L. A. Hyde, K. Cox, L. Favreau, M. F. Czarniecki,W. J. Greenlee, B. A. McKittrick, E. M. Parker andA. W. Stamford, Bioorg. Med. Chem. Lett., 2012, 22, 2444.15 Isocyanocarboxamides were prepared according to theliterature. (a) K. Matsumoto, M. Suzuki, N. Yoneda andM. Miyoshi, Synthesis, 1977, 249; (b) R. Bossio,S. Marcaccini and R. Pepino, Liebigs Ann. Chem., 1990, 935.16 W. Aumüller, Angew. Chem., Int. Ed. Engl., 1963, 2, 616.17 S. Bepary, I. K. Youn, H.-J. Lim and G. H. Lee, Eur. J. Org.Chem., 2012, 2542.18 S. Minakata, Acc. Chem. Res., 2009, 42, 1172.19 E. W. C. W. Thomm and M. Wayman, Can. J. Chem., 1969,47, 3289.20 (a) R. Bossio, S. Marcaccini and R. Pepino, Heterocycles,1986, 24, 2003; (b) T. Mitamura, A. Nomoto, M. Sonoda andA. Ogawa, Bull. Chem. Soc. Jpn., 2010, 83, 822.21 P. Molina, P. M. Fresneda and M. A. Sanz, J. Org. Chem.,1999, 64, 2540.22 (a) E. Schaumann and S. Grabley, Chem. Ber., 1980, 113,934; (b) G. A. Orekhova, O. V. Lebedev, Y. A. Strelenko andA. N. Kravchenko, Mendeleev Commun., 1996, 68.Organic & Biomolecular Chemistry CommunicationThis journal is © The Royal Society of Chemistry 2012 Org. Biomol. Chem., 2012, 00, 1–5 | 515101520253035404550551510152025303540455055

Complementary regioselectivity in the synthesis of iminohydantoins: remarkable effect of amide substitution on the cyclization

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