Abstract
Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3-carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C–C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kharasch, M. S. & Fields, E. K. Factors determining the course and mechanisms of Grignard reactions. IV. The effect of metallic halides on the reaction of aryl Grignard reagents and organic halides. J. Am. Chem. Soc. 63, 2316–2320 (1941).
Tamura, M. & Kochi, J. Vinylation of Grignard reagents. Catalysis by iron. J. Am. Chem. Soc. 93, 1487–1489 (1971).
Molander, G. A., Rahn, B. J., Shubert, D. C. & Bonde, S. E. Iron-catalyzed cross-coupling reactions. Synthesis of arylethenes. Tetrahedron Lett. 24, 5449–5452 (1983).
Bolm, C., Legros, J., Le Paih, J. & Zani, L. Iron-catalyzed reactions in organic synthesis. Chem. Rev. 104, 6217–6254 (2004).
Sherry, B. D. & Fürstner, A. The promise and challenge of iron-catalyzed cross-coupling. Acc. Chem. Res. 41, 1500–1511 (2008).
Fürstner, A. From oblivion into the limelight: iron (domino) catalysis. Angew. Chem. Int. Ed. 48, 1364–1367 (2009).
Bauer, I. & Knölker, H.-J. Iron catalysis in organic synthesis. Chem. Rev. 115, 3170–3387 (2015).
Welsch, M. E., Snyder, S. A. & Stockwell, B. R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol. 14, 347–361 (2010).
Dal Piaz, F. et al. Identification and mechanism of action analysis of the new PARP-1 inhibitor 2″-hydroxygenkwanol A. Biochim. Biophys. Acta 1850, 1806–1814 (2015).
Zhou, M. et al. Aspergillines A−E, highly oxygenated hexacyclic indole−tetrahydrofuran−tetramic acid derivatives from Aspergillus versicolor. Org. Lett. 16, 5016–5019 (2014).
Franz, A. K., Dreyfuss, P. D. & Schreiber, S. L. Synthesis and cellular profiling of diverse organosilicon small molecules. J. Am. Chem. Soc. 129, 1020–1021 (2007).
Hartwell, K. A. et al. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat. Chem. Biol. 9, 840–848 (2013).
Wu, J.-S., Zhang, X., Zhang, Y.-L. & Xie, J.-W. Synthesis and antifungal activities of novel polyheterocyclic spirooxindole derivatives. Org. Biomol. Chem. 13, 4967–4975 (2015).
Badillo, J. J., Hanhan, N. V. & Franz, A. K. Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery. Curr. Opin. Drug Discov. Devel. 13, 758–776 (2010).
Zhuo, C.-X., Zheng, C. & You, S.-L. Transition-metal-catalyzed asymmetric allylic dearomatization reactions. Acc. Chem. Res. 47, 2558–2573 (2014).
Adams, R. & Voorhees, V. Furfural. Org. Synth. 1, 49–51 (1921).
Fürstner, A. et al. Preparation, structure, and reactivity of non-stabilized organoiron compounds. Implications for iron-catalyzed cross coupling reactions. J. Am. Chem. Soc. 130, 8773–8787 (2008).
Cahiez, G. & Avedissian, H. Highly stereo- and chemoselective iron-catalyzed alkenylation of organomagnesium compounds. Synthesis 1199–1205 (1998).
Martín-Matute, B., Nevado, C., Cárdenas, D. J. & Echavarren, A. M. Intramolecular reactions of alkynes with furans and electron rich arenes catalyzed by PtCl2: the role of platinum carbenes as intermediates. J. Am. Chem. Soc. 125, 5757–5766 (2003).
Bedford, R. B. How low does iron go? Chasing the active species in Fe-catalyzed cross-coupling reactions. Acc. Chem. Res. 48, 1485–1493 (2015).
Cassani, C., Bergonzini, G. & Wallentin, C.-J. Active species and mechanistic pathways in iron-catalyzed C–C bond-forming cross-coupling reactions. ACS Catal. 6, 1640–1648 (2016).
Daifuku, S. L., Al-Afyouni, M. H., Snyder, B. E. R., Kneebone, J. L. & Neidig, M. L. A combined mössbauer, magnetic circular dichroism, and density functional theory approach for iron cross-coupling catalysis: electronic structure, in situ formation, and reactivity of iron-mesityl-bisphosphines. J. Am. Chem. Soc. 136, 9132–9143 (2014).
Noda, D., Sunada, Y., Hatakeyama, T., Nakamura, M. & Nagashima, H. Effect of TMEDA on iron-catalyzed coupling reactions of ArMgX with alkyl halides. J. Am. Chem. Soc. 131, 6078–6079 (2009).
Hatakeyama, T. et al. Iron-catalyzed suzuki−miyaura coupling of alkyl halides. J. Am. Chem. Soc 132, 10674–10676 (2010).
Przyojski, J. A., Veggeberg, K. P., Arman, H. D. & Tonzetich, Z. J. Mechanistic studies of catalytic carbon–carbon cross-coupling by well-defined iron NHC complexes. ACS Catal. 5, 5938–5946 (2015).
Krivykh, V. V., Gusev, O. V., Petrovskii, P. V. & Rybinskaya, M. I. Investigation of the stereochemistry of transition metal allyl cationic complexes. J. Organomet. Chem. 366, 129–145 (1989).
Sekine, M., Ilies, L. & Nakamura, E. Iron-catalyzed allylic arylation of olefins via C(sp3)-H activation under mild conditions. Org. Lett. 15, 714–717 (2013).
Ekomi, A. et al. Iron-catalyzed reductive radical cyclization of organic halides in the presence of NaBH4: evidence of an active hydrido iron(I) catalyst. Angew. Chem., Int. Ed. 51, 6942–6946 (2012).
Acknowledgements
The authors acknowledge financial support from the Engineering and Physical Sciences Research Council (Organic Synthesis Studentship grant EP/G040247/1), AstraZeneca Pharmaceuticals and the University of Huddersfield. J.B.S. is grateful to the Royal Society, for the award of an Industry Fellowship. Dedicated to the memory of Sarah Hicks, a young chemist who died at Hillsborough.
Author information
Authors and Affiliations
Contributions
K.A., A.K.B., J.B., B.C., P.K.T.L. and J.R. carried out all cyclization experiments, under the supervision of J.B.S., aided by D.M.G. and P.R. Isolation of complex 15 was carried out by L.B. and J.B. under the supervision of N.J.P. and J.B.S. X-ray crystallography was carried out by C.R.R. The ideas were conceived by B.C. and J.B.S. Reactions were conceived and designed by J.B.S. The manuscript was written by J.B.S.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary information
Supplementary information (PDF 8482 kb)
Supplementary information
Crystallographic data for compound 6c (CIF 673 kb)
Supplementary information
Crystallographic data for compound 15 (CIF 1145 kb)
Rights and permissions
About this article
Cite this article
Adams, K., Ball, A., Birkett, J. et al. An iron-catalysed C–C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks. Nature Chem 9, 396–401 (2017). https://doi.org/10.1038/nchem.2670
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchem.2670
This article is cited by
-
Rapid syntheses of N-fused heterocycles via acyl-transfer in heteroaryl ketones
Nature Communications (2022)
-
Deacylation-aided C–H alkylative annulation through C–C cleavage of unstrained ketones
Nature Catalysis (2021)
