Tertiary Amine Synthesis by Radical Carbonyl Alkylative Amination

Abstract

Highly efficient access to structurally diverse branched tertiary amines is a long-standing challenge in synthetic chemistry. In a recent paper published in Nature, Gaunt and co-workers disclose a practical strategy for the construction of synthetically intractable tertiary amines through visible-light-mediated radical carbonyl alkylative amination of aldehydes, amines, and alkyl halides. Highly efficient access to structurally diverse branched tertiary amines is a long-standing challenge in synthetic chemistry. In a recent paper published in Nature, Gaunt and co-workers disclose a practical strategy for the construction of synthetically intractable tertiary amines through visible-light-mediated radical carbonyl alkylative amination of aldehydes, amines, and alkyl halides. Tertiary amines are a privileged structural moiety in biologically important natural products, agrochemicals, and pharmaceutical compounds.1Ricci A. Amino Group Chemistry: From Synthesis to the Life Sciences. Wiley-VCH, 2008Google Scholar The development of a new rational approach to meet the great demand of expanding chemical space to access diverse tertiary amines bearing structural skeletons is very important for drug discovery and lead optimization.2Blakemore D.C. Castro L. Churcher I. Rees D.C. Thomas A.W. Wilson D.M. Wood A. Organic synthesis provides opportunities to transform drug discovery.Nat. Chem. 2018; 10: 383-394Crossref PubMed Scopus (652) Google Scholar The most robust method for constructing this functional group should be the classical carbonyl reductive amination of iminium ions prepared from aldehydes or ketones with secondary amines (Figure 1A).3Abdel-Magid A.F. Mehrman S.J. A review on the use of sodium triacetoxyborohydride in the reductive amination of ketones and aldehydes.Org. Process Res. Dev. 2006; 10: 971-1031Crossref Scopus (362) Google Scholar However, this tactic has been widely applied only for the synthesis of linear tertiary amines from aldehydes and remains highly challenging for the synthesis of branched tertiary amines from dialkyl ketones. The major reason for this is the lack of an efficient condensation method for preparing iminium intermediates for sterically hindered ketones (Figure 1A). In addition, most dialkyl ketones need to be prepared via multiple steps, and limitations in commercially available ketones further attenuate wide application in reductive aminations of carbonyls. To facilitate access to complex tertiary amines, the alkylative amination of carbonyls should be a good choice.4Heinz C. Lutz J.P. Simmons E.M. Miller M.M. Ewing W.R. Doyle A.G. Ni-catalyzed carbon–carbon bond-forming reductive amination.J. Am. Chem. Soc. 2018; 140: 2292-2300Crossref PubMed Scopus (62) Google Scholar The direct addition of organometallic reagents—such as Grignard, alkyl-lithium, alkyl-zinc, and alkyl-cerium reagents—to iminium ions could be a promising strategy for accessing branched tertiary amines; however, it also comes with several drawbacks. For example, organometallic reagents are usually air and moisture sensitive, which requires the preparation of unstable iminium ions before the carbonyl alkylative amination. Moreover, a great challenge encountered is the influence that the α-C–H acidity of iminium intermediates can have on the reactive organometallics. This would convert the electrophilic iminium ions to nucleophilic enamine intermediates, resulting in the failure of carbonyl alkylative amination. To avoid this, one compromise is to utilize the less reactive zinc- and cerium-based organometallics.5Bloch R. Additions of organometallic reagents to C=N bonds: reactivity and selectivity.Chem. Rev. 1998; 98: 1407-1438Crossref PubMed Scopus (1043) Google Scholar These challenges have slowed down the development of alkylative amination of carbonyls for the synthesis of branched tertiary amines, even after 70 years of effort (Figure 1A). Interestingly, an alternative radical-based strategy for the synthesis of branched tertiary amines has recently emerged. In the past decades, radical carbonyl alkylative amination has gained more and more momentum because it offers an indirect route to branched tertiary amines via multi-step synthesis (Figure 1B).6Miyabe H. Yoshioka E. Kohtani S. Progress in intermolecular carbon radical addition to imine derivatives.Curr. Org. Chem. 2010; 14: 1254-1264Crossref Scopus (53) Google Scholar, 7Xu P. Li W. Xie J. Zhu C. Exploration of C-H transformations of aldehyde hydrazones: radical strategies and beyond.Acc. Chem. Res. 2018; 51: 484-495Crossref PubMed Scopus (91) Google Scholar, 8Xie J. Zhang T. Chen F. Mehrkens N. Rominger F. Rudolph M. Hashmi A.S. Gold-catalyzed highly selective photoredox C(sp2)-H difluoroalkylation and perfluoroalkylation of hydrazones.Angew. Chem. Int. Ed. 2016; 55: 2934-2938Crossref PubMed Scopus (217) Google Scholar, 9Tauber J. Imbri D. Opatz T. Radical addition to iminium ions and cationic heterocycles.Molecules. 2014; 19: 16190-16222Crossref PubMed Scopus (124) Google Scholar Along with the emergence of visible-light photocatalysis, a series of alkyl radicals have become accessible from different kinds of precursors in the presence of Ru-based, Ir-based, or organic photosensitizers. However, this strategy requires the installment of auxiliary-activated functional groups on either the nitrogen atom or the carbonyl component to improve the reactivity of imine intermediates. The limited scope and poor step economy unfortunately compromise its synthetic application. Now, in a recent paper published in Nature, Gaunt and co-workers report a very practical, general, and direct radical carbonyl alkylative amination protocol for constructing unbiased tertiary amines from the three commercially available feedstocks: aldehydes, secondary amines, and alkyl halides (Figure 1C).10Kumar R. Flodén N.J. Whitehurst W.G. Gaunt M.J. A general carbonyl alkylative amination for tertiary amine synthesis.Nature. 2020; https://doi.org/10.1038/s41586-020-2213-0Crossref Scopus (57) Google Scholar As shown in Figure 1C, under irradiation with blue light-emitting diodes, the neutral carbon-centered alkyl radical (6) could be generated directly from alkyl iodides (3) without an external photocatalyst, and radical 6 subsequently underwent addition to alkyl-iminium intermediates (5) that had been generated in situ from secondary amines (1) and aldehydes (2). Although alkyl radical addition to the C=N moiety of imines had been accomplished before,6Miyabe H. Yoshioka E. Kohtani S. Progress in intermolecular carbon radical addition to imine derivatives.Curr. Org. Chem. 2010; 14: 1254-1264Crossref Scopus (53) Google Scholar the addition to positively charged iminium ions was still an issue. A key point for successful alkyl radical addition is to maintain a high concentration of iminium intermediates under mild conditions, and TBSOTf (tert-butyldimethylsilyl trifluoromethylsulfonate) proved to be the most effective additive to achieve this. The resulting amine radical cation (7) could then be rapidly intercepted through hydrogen atom transfer with (TMS)3Si-H, which is important for promoting the carbonyl alkylative amination and suppressing carbonyl reductive amination. Interestingly, the resulting silyl radical (TMS)3Si˙ was not involved in the formation of the new bond, enabling the desired C(sp3)–C(sp3) coupling. Finally, deprotonation of ammonium salts (8) gave rise to the desired tertiary amines (4). To develop a preliminary mechanistic understanding of this novel radical reaction, Gaunt and co-workers proposed a multi-component interaction model based on in-depth investigation of light-absorbing properties of each component and the likely intermediate in the reaction. The future study of this interaction model will significantly expedite the development of metal-free radical transformations without the assistance of chemical initiators. The scope of this carbonyl alkylative amination was found to be exceptionally broad, as demonstrated by the excellent compatibility of highly functionalized cyclic and heterocyclic secondary alkyl amines (9–14, Figure 1D). Generally, bridged ring secondary amines are a challenging substrate class in traditional tertiary amine synthesis. This protocol developed by Gaunt and co-workers offers a facile solution and shows great synthetic application potential. The excellent functional-group compatibility, including ketones, unprotected amides, terminal alkynes and alkenes, and a series of heterocycles, inarguably enhances the synthetic robustness and practicability given that some of these functional groups are prone to react under traditional carbonyl alkylative amination conditions with organometallics. It is noteworthy that the complex tertiary amines containing potential drug fragments—such as 12 from aliperidine fragment, 13 from donepezil fragment, and 14 from quetapine fragment—can be obtained in synthetically useful yields in only a single step. Both aliphatic and aromatic aldehydes, as well as readily available alkyl iodides, are uniformly viable, and they can provide a wealth of structurally divergent tertiary amines in moderate to good yields (15–18). Moreover, Gaunt and co-workers also demonstrated an alternative protocol for synthesizing tertiary amines in reasonable yields by using unactivated alkyl bromides (19). Because abundant feedstocks of aldehydes, amines, and alkyl iodides or bromides are commercially available, this carbonyl alkylative amination enables a great number of complex tertiary amines that have diverse constitutions and are easily accessible in one step. In summary, Gaunt and co-workers have disclosed a highly useful and concise method for the practical synthesis of structurally diverse branched tertiary amines through radical alkylative amination of carbonyls. A wide range of secondary amines, aliphatic and aromatic aldehydes, and alkyl halides are viable substrates in this reaction, significantly expanding the access to branched tertiary amines.