Letter Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Alkenylation of Cyanamides Antoine Nitelet,† Johan Wouters,‡ Damien F. Dewez,† and Gwilherm Evano*,† †
Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium ‡ Department of Chemistry, NAmur MEdicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium S Supporting Information *
ABSTRACT: An efficient procedure for the copper-catalyzed cross-coupling between a broad range of cyanamides and iodoalkenes is reported. Upon reaction with catalytic amounts of copper(I) iodide and 2,2′-bisimidazole in the presence of cesium carbonate in DMF at 80 °C, a fast, regioselective, and stereoretentive cross-coupling occurs. This reaction, which was found to have a broad substrate scope, provides the first general entry to N-alkenylcyanamides, building blocks that hold great synthetic potential. densation of cyanamides with β-keto esters8 or tetrazoles with propiolates9 and by the von Braun reaction from piperazines,10 respectively. Based on our long-standing interest for the synthesis of heterosubstituted alkenes and alkynes11 and copper catalysis,12 we envisioned that a solution to this limitation and a general entry to N-alkenylcyanamides 1 would rely on the cross-coupling of cyanamides with alkenyl halides. While this approach would benefit from the use of readily available starting materials and from the potential to control the stereochemistry of the double bond, it might, however, seem counterintuitive for several reasons. The starting cyanamides are indeed excellent ligands for metals,1,6 but they might poison the catalyst and inhibit the crosscoupling. Provided that additional ligands might prevent this poisoning, side reactions involving thermal and/or metalfacilitated trimerization to melamine and isomelanine derivatives of the starting and final cyanamides,13 alkenylation at the sp nitrogen to N-alkenylcarbodiimide resulting from terminal rather than proximal complexation of the cyanamide to the metal1,6 as well as isomerization of the double bond or elimination from the starting iodoalkene to the corresponding alkyne would have to be limited. An isolated example from the Louie group in the presence of a palladium catalyst,7a however, supported our approach, and we report in this paper the first general procedure for the synthesis of N-alkenylcyanamides by copper-catalyzed14 alkenylation of cyanamides with iodoalkenes. To extend the copper-catalyzed alkenylation of N-nucleophiles15 to cyanamides and to test its feasibility, (E)-βiodostyrene 2a and N-butylcyanamide 3a were chosen as model substrates (Figure 2). The nature of the ligand, which we thought would be the most important parameter for this transformation, was first evaluated using a set of representative bidentate ligands commonly used in copper catalysis: results from these studies are collected in Figure 2.
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lthough its chemistry is still underexplored, cyanamide is an exceptional functional group of major importance in various scientific areas, which can be traced back to its unique N−CN connectivity.1 In addition to its key role in prebiotic chemistry,2 this moiety can also be found in a range of natural3 and/or biologically relevant4 molecules. Cyanamides have also been demonstrated to be unique building blocks that can participate in an impressive and evergrowing number of transformations involving either the “amino” or the “cyano” groups, or even both.1,5 They are, in addition, excellent candidates for coordination chemistry, notably due to their complexation and bridging properties.1,6 These reagents can be classified depending on the nature of the substituents on the cyanamide subunit. While N-alkyl-, Nacyl-, N-sulfonyl-, and N-arylcyanamides can be readily prepared by a range of methods1 including the alkylation of cyanamides, cyanation of amines, von Braun reaction, deoxygenation of isocyanates, desulfurization of thioureas, or arylation of cyanamides,7 the synthesis of N-alkenylcyanamides 1 (Figure 1) has been far less investigated despite their strong synthetic
Figure 1. N-Alkenylcyanamides and resonance structures.
potential. They indeed possess a unique combination of sp2 and sp carbon and nitrogen atoms as well as electrophilic and nucleophilic centers, resulting basically from the merger of an enamine with a cyanamide. If they clearly hold promises as functional groups for the design of new transformations, they can, however, be hardly prepared to date. Indeed, most methods available for the synthesis of other classes of cyanamides cannot be extended to the preparation of N-alkenylcyanamides, and only push−pull or N-vinyl derivatives can be prepared by con© XXXX American Chemical Society
Received: September 13, 2017
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DOI: 10.1021/acs.orglett.7b02859 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Figure 2. Optimization of the copper-catalyzed alkenylation of cyanamides.
Figure 3. Scope of the copper-catalyzed alkenylation of cyanamides: iodoalkenes. (a) Reaction run for 12 h.
Surprisingly, the reactionwhich did not proceed in the absence of the copper catalyst and only with limited efficiency without a ligandwas found to be quite rapid compared to related cross-couplings since completion was reached within 6 h. Equally surprising was the fact that all ligands evaluated actually facilitated the alkenylation of 3a with 2a, the resulting Nalkenylcyanamide 1a being, however, formed with modest efficiency (24−40%) using classical ligands such as diketones L1 and L2, proline L3, N,N’-dimethylethylenediamine L4, 2,2′bipyridine L5, or 1,10-phenanthroline L6. Moving to a less classical 2,2′-bisimidazole L7 ligand16 was met with more success, with 1a being formed with 69% NMR yield (60% isolated yield), a result that compares favorably with the only example reported to date of a palladium-catalyzed alkenylation of a cyanamide with a bromoalkene by the Louie group (41%).7a Using other bisimidazoles such as L8 and L9 did not improve the yield, although a full conversion of the starting iodoalkene was noted in all cases, and the use of other bases (K2CO3, K3PO4 or CsF) and solvents (EtOH, DMSO, CH3CN, dioxane or toluene) was found to be highly detrimental. As a note, the amount of starting cyanamide 3a could be successfully reduced from 3 to 1.5 equiv, although with an erosion of the yield (57%). Importantly, the stoichiometry could be reversed, and using 2 equiv of 2a with respect to 3a resulted in 59% isolated yield. With the optimized conditions, relying on the use of 3 equiv of cyanamide, 10 mol % of copper(I) iodide, 20 mol % of 2,2′bisimidazole, and 2 equiv of cesium carbonate in DMF at 80 °C for 6 h, in hand, we next moved to the study of the scope and limitations of this alkenylation. The influence of the nature of the starting alkenyl iodide was first evaluated by reacting a series of iodinated alkenes 2 possessing representative substitution patterns and electronic properties with N-butyl- and N-benzylcyanamides 3a and 3b. As evidenced by results collected in Figure 3, the reaction proceeded well in most cases starting from monosubstituted (E)-βiodostyrenes, the corresponding N-alkenylcyanamides 1a−h being isolated in good yields regardless of the electronic properties of the aromatic ring. Importantly, no isomerization
was found to occur before or after the cross-coupling, with all alkenylated cyanamides being formed as single stereoisomers. The alkenylation was, moreover, found to be highly regioselective since we could not detect traces of Nalkenylcarbodiimides resulting from alkenylation at the sp nitrogen atom in crude reaction mixtures. Finally, the coupling products were gratifyingly found to be stable under the reaction conditions, and no competitive elimination of cyanamide was found to occur. Replacing the aromatic substituent on the starting iodoalkene by an alkyl chain had virtually no effect on the reaction, β-alkyl-Nvinyl-cyanamides 1i-l being isolated, with yields in the 55−62% range. Switching to more substituted coupling partners such as 1iodocyclohex-1-ene or (iodomethylene)cyclohexane also provided the corresponding products 1m−p, although with reduced efficiency due to a more sluggish reaction, and sterically hindered (iodomethylene)cyclohexane required increased reaction time to reach decent yields. Quite expectedly, much more hindered 2iodo-3-methylbut-2-ene led to poor efficiency, even when the reaction conditions were forced, with the corresponding Nalkenylcyanamides 1q and 1r being formed in low yields (4% and 20%, respectively). Except for this last case, our procedure globally provides an easy and stereospecific access to otherwise inaccessible N-alkenylcyanamides that can be obtained in fair to good yields. We next briefly moved to the study of the scope of the reaction with respect to the other coupling partners. A set of cyanamides 3 were therefore reacted with both (E)-β-iodostyrene 2a and (E)2-(2-iodovinyl)naphthalene 2b under our standard conditions. Results collected in Figure 4 reveal that aliphatic cyanamides such as N-butyl, N-benzyl, N-allyl, or N-cyclopropyl are good substrates for the copper-catalyzed alkenylation as evidenced with the isolation of 1a−d,s−v in 46−63% yields. Increasing the steric hindrance when starting from the more challenging Nisopropylcyanamide still pleasantly led to the corresponding products 1w and 1x, although with diminished efficiency. In contrast, the alkenylation of N-tert-butyl- and N-p-tolylcyanaB
DOI: 10.1021/acs.orglett.7b02859 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Figure 5. XRD structure of N-benzyl-N-(cyclohex-1-en-1-yl)cyanamide 1n, NBO charges computed on N-methyl-N-(prop-1-en-1-yl)cyanamide 1ad and selected bond lengths within the CC−N−C N systems.
substrates that could therefore capitalize on their combined enamine and cyanamide character. This conjugation is also apparent from ab initio (B3LYP/631G*+) calculated NBO (natural bond orbital) charges of model N-methyl-N-(prop-1-en-1-yl)cyanamide 1ad (Figure 5, right) in which the enamine character is apparent from the partial negative charge (−0.249) on the β-carbon atom of the alkene and the important electron density on the terminal sp nitrogen atom (−0.369). As a note, the bond lengths obtained from the computed structure are, taking into account experimental errors, in agreement with those of the XRD structure. The XRD structure in addition shows an s-trans conformation of the enamine moiety, which might be more properly described in this case as an E configuration as with N-alkylamides, which can also be observed in solution as demonstrated by the NOE observed between the benzylic and C(sp2)H vinylic protons. While this seems to be in contradiction with the previously computed structure of vinyl cyanamide CH2CH−NH−C N, which was predicted to predominantly exists as its Z isomer,17 the presence of an additional substituent on the central sp nitrogen atom in our case would induce an allylic interaction and therefore favor the E isomer. Ab initio calculations at the B3LYP (6-31G*+) level performed on N-methyl-N-(prop-1-en-1-yl)cyanamide indeed indicate a rather important difference of energy (12 kJ mol−1) between the two isomers in favor of the E configuration. In conclusion, we have developed an efficient procedure for the copper-catalyzed cross-coupling between a broad range of cyanamides and iodoalkenes. This reaction is efficiently catalyzed by a combination of copper(I) iodide and 2,2′-bisimidazole in the presence of cesium carbonate in DMF at 80 °C. Its scope was found to be rather broad, and it provides the first general entry to N-alkenylcyanamides, useful building blocks that possess a unique combination of sp2 and sp carbon and nitrogen atoms as well as electrophilic and nucleophilic centers resulting from the merger of an enamine with a cyanamide. The use of these building blocks, which clearly hold an important synthetic potential, for the design of innovative transformations is underway and will be reported in due course.
Figure 4. Scope of the copper-catalyzed alkenylation of cyanamides. (a) With 2 equiv of 2a for 12 h.
mides led to poor results due to steric hindrance and lower nucleophilicity, respectively. Gratifyingly, the alkenylation of a more complex cyanamide derived from 3-aminomethylpiperidine using a reversed stoichiometry (2 equiv 2a) provided the corresponding N-alkenylcyanamide 1ac in 49% yield. In an attempt to assess the efficiency of our procedure further, two double cross-coupling were finally attempted, the first one from bis(iodoalkene) 4 and N-butylcyanamide 3a and the second one from bis(cyanamide) 6 and (E)-β-iodostyrene 2a (Scheme 1). By doubling the amounts of the copper salt, the ligand, as well Scheme 1. Copper-Catalyzed Double Alkenylations
as the base and increasing the reaction time to 12 h, we could obtain the corresponding bis(N-alkenylcyanamide) 5 and 7 in 42% and 37% yield, respectively, a reversed stoichiometry being used in these two reactions. Having in hand a set of novel cyanamide derivatives, we finally focused our efforts on gaining insights into their structures, conformations, and electronic properties, which might come in handy for future developments from these building blocks. X-ray diffraction analysis of N-benzyl-N-(cyclohex-1-en-1-yl)cyanamide 1n (Figure 5, left), which was selected on the basis of the highly symmetrical nature of the cyclohexene ring, reveals an almost planar arrangement of the CC−N−CN system with CC, CC−N, and N−CN bond lengths of 1.349, 1.402, and 1.325 Å, respectively. This involves conjugation of the central sp2 nitrogen atom with both the alkene and cyano groups, a crucial point for the development of new processes from such
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02859. Detailed experimental procedures and characterization data for all new compounds and crystallographic data (PDF) C
DOI: 10.1021/acs.orglett.7b02859 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Accession Codes
Tetrahedron Lett. 2017, 58, 2318. (h) Zhu, X.; Shen, X.-J.; Tian, Z.-Y.; Lu, S.; Tian, L.-L.; Liu, W.-B.; Song, B.; Hao, X.-Q. J. Org. Chem. 2017, 82, 6022. (i) Rydfjord, J.; Skillinghaug, B.; Brandt, P.; Odell, L. R.; Larhed, M. Org. Lett. 2017, 19, 4066. (6) For a review, see: Crutchley, R. J. Coord. Chem. Rev. 2001, 219, 125. (7) (a) Stolley, R. M.; Guo, W.; Louie, J. Org. Lett. 2012, 14, 322. (b) Li, P.; Cheng, G.; Zhang, H.; Xu, X.; Gao, J.; Cui, X. J. Org. Chem. 2014, 79, 8156. (c) Li, J.; Zheng, X.; Li, W.; Zhou, W.; Zhu, W.; Zhang, Y. New J. Chem. 2016, 40, 77. (8) Brigl, P. Ber. Dtsch. Chem. Ges. 1912, 45, 1557. (9) Luo, K.; Meng, L.; Zhang, Y.; Zhang, X.; Wang, L. Adv. Synth. Catal. 2013, 355, 765. (10) von Braun, J.; Goll, O.; Zobel, F. Ber. Dtsch. Chem. Ges. B 1926, 59, 936. (11) For representative contributions from our group, see: (a) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2009, 48, 4381. (b) Coste, A.; Couty, F.; Evano, G. Org. Lett. 2009, 11, 4454. (c) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272. (d) Evano, G.; Tadiparthi, K.; Couty, F. Chem. Commun. 2011, 47, 179. (e) Laouiti, A.; Rammah, M. M.; Rammah, M. B.; Marrot, J.; Couty, F.; Evano, G. Org. Lett. 2012, 14, 6. (f) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756. (g) Jouvin, K.; Bayle, A.; Legrand, F.; Evano, G. Org. Lett. 2012, 14, 1652. (h) Laouiti, A.; Jouvin, K.; Rammah, M. M.; Rammah, M. B.; Evano, G. Synthesis 2012, 44, 1491. (i) Jouvin, K.; Veillard, R.; Theunissen, C.; Alayrac, C.; Gaumont, A.-C.; Evano, G. Org. Lett. 2013, 15, 4592. (j) Gérard, P.; Veillard, R.; Alayrac, C.; Gaumont, A.-C.; Evano, G. Eur. J. Org. Chem. 2016, 2016, 633. (12) For representative contributions from our group, see: (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007, 46, 572. (b) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2007, 72, 9003. (c) Coste, A.; Toumi, M.; Wright, K.; Razafimahaléo, V.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841. (d) Toumi, M.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027. (e) Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 4166. (f) Pradal, A.; Evano, G. Chem. Commun. 2014, 50, 11907. (g) Nitelet, A.; Evano, G. Org. Lett. 2016, 18, 1904. (h) Theunissen, C.; Wang, J.; Evano, G. Chem. Sci. 2017, 8, 3465. (13) (a) Pankratov, V. A.; Chesnokova, A. E. Ups. Khim. 1989, 58, 1528. (b) Korshak, V. V.; Kutepov, D. F.; Pankratov, V. A.; Antsiferova, N. P.; Vinogradova, S. V. Zh. Vsesoy. Khim. Obs. 1974, 19, 472. (c) Wu, Y.-Q. In Science of Synthesis; Ley, S. V., Knight, J. G., Eds.; Thieme: New York, Stuttgart, 2005, Vol. 18, pp 17−63. (d) Brand, H.; Mayer, P.; Schulz, A.; Soller, T.; Villinger, A. Chem. - Asian J. 2008, 3, 1050. (14) For general references on copper catalysis, see: (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (c) Copper-Mediated Cross-Coupling Reactions; Evano, G., Blanchard, N., Eds.; Wiley: Hoboken, 2013. (15) Jouvin, K.; Evano, G. In Copper-Mediated Cross-Coupling Reactions; Evano, G., Blanchard, N., Eds.; Wiley: Hoboken, 2013; pp 187−238. (16) (a) Hu, Z.; Ye, W.; Zou, H.; Yu, Y. Synth. Commun. 2009, 40, 222. (b) Hu, Z.; Li, S.-d.; Hong, P.-z.; Wu, Z. ARKIVOC 2011, xi, 147. (17) Badawi, H. M. J. Mol. Struct.: THEOCHEM 2002, 584, 201.
CCDC 1572446 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Gwilherm Evano: 0000-0002-2939-4766 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Our work was supported by the Université libre de Bruxelles (ULB). A.N. and D.F.D. acknowledge the Fonds pour la formation à la Recherche dans l’Industrie et dans l’Agriculture (FRIA) for graduate fellowships. Access to equipment available at the PC2 technological platform (UNamur) is acknowledged.
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REFERENCES
(1) For reviews on the chemistry of cyanamides, see: (a) Nekrasov, D. D. Russ. J. Org. Chem. 2004, 40, 1387. (b) Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C.; Fensterbank, L.; Lacôte, E. Synthesis 2012, 44, 1279. (c) Prabhath, M. R. R.; Williams, L.; Bhat, S. V.; Sharma, P. Molecules 2017, 22, 615. (d) Bolotin, D. S.; Rassadin, V. A.; Bokach, N. A.; Kukushkin, V. Yu Inorg. Chim. Acta 2017, 455, 446. (2) For representative examples, see: (a) Duvernay, F.; Chiavassa, T.; Borget, F.; Aycard, J. P. J. Am. Chem. Soc. 2004, 126, 7772. (b) Duvernay, F.; Chiavassa, T.; Borget, F.; Aycard, J. P. J. Phys. Chem. A 2005, 109, 603. (c) Anastasi, C.; Crowe, M. A.; Powner, M. W.; Sutherland, J. D. Angew. Chem., Int. Ed. 2006, 45, 6176. (d) Lavado, N.; Escamilla, J. C.; Á valos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Palacios, J. C. Chem. Eur. J. 2016, 22, 13632. (3) For representative examples, see: (a) Bisset, N. G.; Choudhury, A. K.; Walker, M. D. Phytochemistry 1974, 13, 255. (b) Matsunaga, S.; Kobayashi, H.; van Soest, R. W. M.; Fusetani, N. J. Org. Chem. 2005, 70, 1893. (c) Kamo, T.; Endo, M.; Sato, M.; Kasahara, R.; Yamaya, H.; Hiradate, S.; Fujii, Y.; Hirai, N.; Hirota, M. Phytochemistry 2008, 69, 1166. (d) Fu, P.; Zhuang, Y.; Wang, Y.; Liu, P.; Qi, X.; Gu, K.; Zhang, D.; Zhu, W. Org. Lett. 2012, 14, 6194. (4) For representative examples, see: (a) Shirota, F. N.; Stevens-Johnk, J. M.; DeMaster, E. G.; Nagasawa, H. T. J. Med. Chem. 1997, 40, 1870. (b) Falgueyret, J. P.; Oballa, R. M.; Okamoto, O.; Wesolowski, G.; Aubin, Y.; Rydzewski, R. M.; Prasit, P.; Riendeau, D.; Rodan, S. B.; Percival, M. D. J. Med. Chem. 2001, 44, 94. (c) Barrett, D. G.; Deaton, D. N.; Hassell, A. M.; McFadyen, R. B.; Miller, A. B.; Miller, L. R.; Payne, J. A.; Shewchuk, L. M.; Willard, D. H.; Wright, L. L. Bioorg. Med. Chem. Lett. 2005, 15, 3039. (d) Ronn, R.; Gossas, T.; Sabnis, Y. A.; Daoud, H.; Akerblom, E.; Danielson, U. H.; Sandstrom, A. Bioorg. Med. Chem. 2007, 15, 4057. (e) Closon, C.; Didone, V.; Tirelli, E.; Quertemont, E. Alcohol.: Clin. Exp. Res. 2009, 33, 2005. (f) Guay, D.; Beaulieu, C.; Percival, M. D. Curr. Top. Med. Chem. 2010, 10, 708. (5) For representative examples from 2017 only, see: (a) Spahn, N. A.; Nguyen, M. H.; Renner, J.; Louie, J. J. Org. Chem. 2017, 82, 234. (b) Chowdhury, H.; Goswami, A. Adv. Synth. Catal. 2017, 359, 314. (c) Pandya, A. N.; Villa, E. M.; North, E. J. Tetrahedron Lett. 2017, 58, 1276. (d) Ye, F.; Haddad, M.; Ratovelomanana-Vidal, V.; Michelet, V. Org. Lett. 2017, 19, 1104. (e) Song, F.; Salter, R.; Chen, L. J. Org. Chem. 2017, 82, 3530. (f) Spahn, N. A.; Nguyen, M. H.; Renner, J.; Lane, T. K.; Louie, J. J. Org. Chem. 2017, 82, 234. (g) Machicao, P. A.; Burt, S. R.; Christensen, R. K.; Lohner, N. B.; Singleton, J. D.; Peterson, M. A. D
DOI: 10.1021/acs.orglett.7b02859 Org. Lett. XXXX, XXX, XXX−XXX
