The synthesis of valuable bioactive alicyclic amines containing variable substituents in multiple ring positions typically relies on multistep synthetic sequences that frequently require the introduction and subsequent removal of undesirable protecting groups. Although a vast number of studies have aimed to simplify access to such materials through the C–H bond functionalization of feedstock alicyclic amines, the simultaneous introduction of more than one substituent to unprotected amines has never been accomplished. Here we report an advance in C–H bond functionalization methodology that enables the introduction of up to three substituents in a single operation. Lithiated amines are first exposed to a ketone oxidant, generating transient imines that are subsequently converted to endocyclic 1-azaallyl anions, which can be processed further to furnish β-substituted, α,β-disubstituted, or α,β,α′-trisubstituted amines. This study highlights the unique utility of in situ-generated endocyclic 1-azaallyl anions, elusive intermediates in synthetic chemistry.
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for structures (±)-13a and (±)-13q have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. 1935815 ((±)-13a) and 1935816 ((±)-13q). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/
Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).
Taylor, R. D., MacCoss, M. & Lawson, A. D. G. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014).
Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).
Campos, K. R. Direct sp 3 C–H bond activation adjacent to nitrogen in heterocycles. Chem. Soc. Rev. 36, 1069–1084 (2007).
Mitchell, E. A., Peschiulli, A., Lefevre, N., Meerpoel, L. & Maes, B. U. W. Direct α-functionalization of saturated cyclic amines. Chem. Eur. J. 18, 10092–10142 (2012).
Vo, C.-V. T. & Bode, J. W. Synthesis of saturated N-heterocycles. J. Org. Chem. 79, 2809–2815 (2014).
Girard, S. A., Knauber, T. & Li, C.-J. The cross-dehydrogenative coupling of Csp 3-H bonds: a versatile strategy for C–C bond formations. Angew. Chem. Int. Ed. 53, 74–100 (2014).
Seidel, D. The azomethine ylide route to amine C–H functionalization: redox-versions of classic reactions and a pathway to new transformations. Acc. Chem. Res. 48, 317–328 (2015).
Beatty, J. W. & Stephenson, C. R. J. Amine functionalization via oxidative photoredox catalysis: methodology development and complex molecule synthesis. Acc. Chem. Res. 48, 1474–1484 (2015).
Cheng, M.-X. & Yang, S.-D. Recent advances in the enantioselective oxidative α-C–H functionalization of amines. Synlett 28, 159–174 (2017).
Payne, P. R., Garcia, P., Eisenberger, P., Yim, J. C. H. & Schafer, L. L. Tantalum catalyzed hydroaminoalkylation for the synthesis of α- and β-substituted N-heterocycles. Org. Lett. 15, 2182–2185 (2013).
Chen, W., Ma, L., Paul, A. & Seidel, D. Direct α-C–H bond functionalization of unprotected cyclic amines. Nat. Chem. 10, 165–169 (2018).
Lennox, A. J. J. et al. Electrochemical aminoxyl-mediated α-cyanation of secondary piperidines for pharmaceutical building block diversification. J. Am. Chem. Soc. 140, 11227–11231 (2018).
Paul, A. & Seidel, D. α-Functionalization of cyclic secondary amines: Lewis acid promoted addition of organometallics to transient imines. J. Am. Chem. Soc. 141, 8778–8782 (2019).
Takasu, N., Oisaki, K. & Kanai, M. Iron-catalyzed oxidative C(3)–H functionalization of amines. Org. Lett. 15, 1918–1921 (2013).
Griffiths, R. J. et al. Oxidative β-C–H sulfonylation of cyclic amines. Chem. Sci. 9, 2295–2300 (2018).
Xu, G.-Q. et al. Dual C(sp 3)−H bond functionalization of N-heterocycles through sequential visible-light photocatalyzed dehydrogenation/[2+2] cycloaddition reactions. Angew. Chem. Int. Ed. 57, 5110–5114 (2018).
Zhang, J., Park, S. & Chang, S. Catalytic access to bridged sila-N-heterocycles from piperidines via cascade sp 3 and sp 2 C–Si bond formation. J. Am. Chem. Soc. 140, 13209–13213 (2018).
Sundararaju, B. et al. Ruthenium-catalyzed cascade N- and C(3)-dialkylation of cyclic amines with alcohols involving hydrogen autotransfer processes. Adv. Synth. Catal. 352, 3141–3146 (2010).
Sundararaju, B., Achard, M., Sharma, G. V. M. & Bruneau, C. sp 3 C–H bond activation with ruthenium(ii) catalysts and C(3)-alkylation of cyclic amines. J. Am. Chem. Soc. 133, 10340–10343 (2011).
Millet, A., Larini, P., Clot, E. & Baudoin, O. Ligand-controlled beta-selective C(sp 3)–H arylation of N-Boc-piperidines. Chem. Sci. 4, 2241–2247 (2013).
Affron, D. P., Davis, O. A. & Bull, J. A. Regio- and stereospecific synthesis of C-3 functionalized proline derivatives by palladium catalyzed directed C(sp 3)–H Arylation. Org. Lett. 16, 4956–4959 (2014).
Ye, S. et al. N-Heterocyclic carbene ligand-enabled C(sp 3)−H arylation of piperidine and tetrahydropyran derivatives. Chem. Eur. J. 22, 4748–4752 (2016).
Van Steijvoort, B. F., Kaval, N., Kulago, A. A. & Maes, B. U. W. Remote functionalization: palladium-catalyzed C5(sp 3)–H arylation of 1-Boc-3-aminopiperidine through the use of a bidentate directing group. ACS Catal. 6, 4486–4490 (2016).
Maetani, M. et al. Synthesis of a bicyclic azetidine with in vivo antimalarial activity enabled by stereospecific, directed C(sp 3)–H arylation. J. Am. Chem. Soc. 139, 11300–11306 (2017).
Antermite, D., Affron, D. P. & Bull, J. A. Regio- and stereoselective palladium-catalyzed C(sp 3)–H arylation of pyrrolidines and piperidines with C(3) directing groups. Org. Lett. 20, 3948–3952 (2018).
Chen, W., Kang, Y., Wilde, R. G. & Seidel, D. Redox-neutral α,β-difunctionalization of cyclic amines. Angew. Chem. Int. Ed. 53, 5179–5182 (2014).
Ma, L., Paul, A., Breugst, M. & Seidel, D. Redox-neutral aromatization of cyclic amines: mechanistic insights and harnessing of reactive intermediates for amine α- and β-C−H functionalization. Chem. Eur. J. 22, 18179–18189 (2016).
Topczewski, J. J., Cabrera, P. J., Saper, N. I. & Sanford, M. S. Palladium-catalysed transannular C–H functionalization of alicyclic amines. Nature 531, 220–224 (2016).
Cabrera, P. J., Lee, M. & Sanford, M. S. Second-generation palladium catalyst system for transannular C–H functionalization of azabicycloalkanes. J. Am. Chem. Soc. 140, 5599–5606 (2018).
Willems, L. I. & IJzerman, A. P. Small molecule antagonists for chemokine CCR3 receptors. Med. Res. Rev. 30, 778–817 (2010).
Jia, L. et al. Discovery of VTP-27999, an alkyl amine renin inhibitor with potential for clinical utility. ACS Med. Chem. Lett. 2, 747–751 (2011).
Schönherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Ed. 52, 12256–12267 (2013).
Ye, Z., Gettys, K. E. & Dai, M. Opportunities and challenges for direct C–H functionalization of piperazines. Beilstein J. Org. Chem. 12, 702–715 (2016).
Källström, S. & Leino, R. Synthesis of pharmaceutically active compounds containing a disubstituted piperidine framework. Bioorg. Med. Chem. 16, 601–635 (2008).
Rao, G. A. & Periasamy, M. Cycloaddition of enamine and iminium ion intermediates formed in the reaction of N-arylpyrrolidines with T-HYDRO. Synlett 26, 2231–2236 (2015).
Shu, X.-Z. et al. Selective functionalization of sp 3 C−H bonds adjacent to nitrogen using (diacetoxyiodo)benzene (DIB). J. Org. Chem. 74, 7464–7469 (2009).
Wittig, G. & Hesse, A. Hydrid-übertragung von lithium-pyrrolidid auf azomethine. Liebigs Ann. Chem. 746, 174–184 (1971).
Wittig, G. & Hesse, A. Zur reaktionsweise N‐metallierter acyclischer und cyclischer sekundärer amine. Liebigs Ann. Chem. 746, 149–173 (1971).
Pal, K., Behnke, M. L. & Tong, L. A general stereocontrolled synthesis of cis-2,3-disubstituted pyrrolidines and piperidines. Tetrahedron Lett. 34, 6205–6208 (1993).
Nenajdenko, V. G., Pronin, S. V. & Balenkova, E. S. Synthesis of aminoalkylpyrazoles and-isoxazoles from cyclic β-(trifluoroacetyl) enamines. Russ. Chem. Bull. 56, 336–344 (2007).
Whitesell, J. K. & Whitesell, M. A. Alkylation of ketones and aldehydes via their nitrogen derivatives. Synthesis 1983, 517–536 (1983).
Mangelinckx, S., Giubellina, N. & De Kimpe, N. 1-Azaallylic anions in heterocyclic chemistry. Chem. Rev. 104, 2353–2400 (2004).
Fandrick, D. R. et al. Copper-catalyzed asymmetric propargylation of cyclic aldimines. Org. Lett. 18, 6192–6195 (2016).
De Lucca, G. V. et al. Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency. J. Med. Chem. 48, 2194–2211 (2005).
Financial support from the NIH–NIGMS (grant no. R01GM101389) is gratefully acknowledged. We thank I. Ghiviriga (University of Florida) for assistance with NMR experiments. Mass spectrometry instrumentation was supported by a grant from the NIH (S10 OD021758-01A1). We further acknowledge the National Science Foundation (grant no. 1828064) and the University of Florida for funding the purchase of the X-ray equipment.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Materials and methods, evaluation of reaction conditions, characterization data, GCOSY and NOESY analyses, crystallographic summaries and NMR spectra.
Crystallographic data of compound (±)-13a. CCDC reference 1935815.
Crystallographic data of compound (±)-13q. CCDC reference 1935816.
About this article
Cite this article
Chen, W., Paul, A., Abboud, K.A. et al. Rapid functionalization of multiple C–H bonds in unprotected alicyclic amines. Nat. Chem. 12, 545–550 (2020). https://doi.org/10.1038/s41557-020-0438-z
Advances in Fe(II)/2-ketoglutarate-dependent dioxygenase-mediated C–H bond oxidation for regioselective and stereoselective hydroxyl amino acid synthesis: from structural insights into practical applications
Systems Microbiology and Biomanufacturing (2021)
Nature Communications (2020)