Ring-Opening Functionalizations of Unstrained Cyclic Amines Enabled

Ring-Opening Functionalizations of Unstrained Cyclic Amines Enabled

ARTICLE https://doi.org/10.1038/s41467-020-18557-8 OPEN Ring-opening functionalizations of unstrained cyclic amines enabled by difluorocarbene transfer ✉ ✉ Youyoung Kim1,2, Joon Heo1,2, Dongwook Kim 1,2, Sukbok Chang 1,2 & Sangwon Seo 1,2 Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties. Given the ubiquity of unstrained cyclic amines, the ability to directly alter such motifs would grant an efficient platform to fi 1234567890():,; access unique chemical space. Here, we report a highly ef cient and practical strategy that enables the selective ring-opening functionalization of unstrained cyclic amines. The use of difluorocarbene leads to a wide variety of multifaceted acyclic architectures, which can be further diversified to a range of distinctive homologative cyclic scaffolds. The virtue of this deconstructive strategy is demonstrated by successful modification of several natural products and pharmaceutical analogues. 1 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. 2 Center for Catalytic ✉ Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:4761 | https://doi.org/10.1038/s41467-020-18557-8 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18557-8 iven the ubiquity of cyclic amines in a myriad of natural hydrogen in combination with transition metal catalysts, often products and synthetic compounds, a growing emphasis has leads to non-transformable hydrocarbon frameworks by reductive G – been placed on how we harness and manipulate such C N bond cleavage, thus limiting the degree of scaffold diversity prestigious motifs for the construction of value-added molecules1–4. (Fig. 1b, top)21–24. While significant progress has been made in the development of In an ideal scenario, the ring-opening reaction would be fol- appending processes for their peripheral variation5–10, the skeletal lowed by the installation of versatile motifs that can be further diversification by means of ring-opening, -contraction, -expansion transformed for diversity-generating chemical synthesis25–27. or -fusion approaches remains limited (Fig. 1a)11.Thisisparticu- With this regard, the oxidative strategy has enjoyed methodolo- larly pertinent for the unstrained cyclic systems, which is attributed gical prosperity in recent years28–32. In a classical reaction mode, to the fact that the structural reorganization is inevitably accom- oxidation of the α-carbons of cyclic amines generates labile panied by highly demanding C–N12,13 or C–C14–16 bond cleavage. hemiaminals, thereby enabling the conversion of otherwise inert To this end, the ability to access these robust σ-bonds in an efficient C–N bonds into amino-aldehyde or -carboxylic acid moieties and selective manner would provide a powerful handle for the (Fig. 1b, middle). While the conventional oxidative strategies diversification of azacyclic skeletons. often suffer from low functional group compatibility, improved Despite recent advances in the realm of C–C bond transforma- procedures have been recently developed by harnessing transition tions17–20,theselectivecleavageofC–N bonds would be a com- metals. A conspicuous example includes the elegant work by pelling strategy for ring-opening functionalization of cyclic amines. Sarpong33, which furnishes a deconstructive halogenation of Nonetheless, the process that cleaves and turns C–N bonds into cyclic amines via cascade decarboxylative process. versatile functionalities is still relatively scarce. For instance, the An alternative way of rendering the C–N bonds more accessible conventional reductive approach, typically employing molecular is through the formation of quaternary ammonium salts (Fig. 1b, a Me R N NR n N R n NR H n N n skeletal R n Cyclic amine diversification Opening Contraction Expansion Fusion • Manipulate the biological properties with variation of the overall molecular shape b H [H] H2, Pd/C or dissolving metal reduction N R H Non-selective reduction Reductive cleavage Non-transformable hydrocarbon H X Organic/inorganic oxidants (with TM) [O] N N R R O Via hemiaminal-aldehyde equilibrium (α-carbon oxidation) Cyclic amine Oxidative cleavage (X = H or OH) Low functional group tolerance E CNBr, alkyl chloroformate, alkyl halide E−Nu N Nucleophilic attack of 4° ammonium salt R Nu Limited functions of N−CN moiety (CNBr) von Braun type cleavage Limited scopes (alkyl chloroformate/halide) c X Versatile R TMSCF X N R 2 O N n N R O n Skeletal Cyclic amine N R R modification N Me R X n N Increased skeletal diversity N-difluoro CF2H In situ hydroylsis -methylation (CF2H to CHO) Mild & selective N-difluoromethylation Broad scope over various cyclic amines Diversification based on the reactivities at both halide and N-formyl groups Fig. 1 C–N Bond cleavage of unstrained cyclic amines. a Importance of skeletal diversification of unstrained cyclic amines. b Previously reported strategies for C–N bond cleavage of cyclic amines. c This work: Ring-opening halogenation via N-difluoromethylative C–N bond cleavage. 2 NATURE COMMUNICATIONS | (2020) 11:4761 | https://doi.org/10.1038/s41467-020-18557-8 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18557-8 ARTICLE bottom). The increased bond polarity ameliorates the leaving post-modifications. Control experiments established the importance group ability of amino moiety, ultimately allowing the C–Nbond of base (entry 2), which is required for the generation of cleavage by means of elimination34 or nucleophilic substitution difluorocarbene intermediate. Notably, an alternative difluorocar- reactions35–37. This chemistry has been widely utilized in the ring- bene source (entry 3), a dichlorocarbene variant61 (entry 4) and the opening reaction of strained rings38–42, however, its use in conditions developed by Cho55 (entry 5) were found to be unstrained cyclic systems is somewhat thwarted by the stability of incompetent (see Supplementary Table 1 for details). Encouraged the involved salts. Of a great potential for further development is by the above promising result, we also examined the feasibility of the von Braun reaction, which employs cyanogen bromide (CNBr) N-ethylpyrrolidine 1b in the ring-opening bromoformylation in ring-opening bromination of azacyclic compounds43,44.This (Fig. 2b). We could obtain the presupposed intermediacy of reaction outperforms other strategies in terms of efficiency and quaternary ammonium salt by treating 1b under the optimized applicability, but has found relatively narrower synthetic applica- conditions at room temperature (int1, 78%). A moderate heating of tions45–48. This is mainly due to the limited function of the the isolated intermediate int1 consequently resulted in a facile ring- resulting N–CN group and the requirement of harsh conditions for cleavage to afford 2b (83%). its removal. Additionally, cyanogen bromide is highly toxic, and can undergo explosive trimerization to cyanuric bromide or Substrate scope of 5-membered rings. Having established the decompose to hazardous hydrogen cyanide (HCN)49. Chlor- – optimal conditions, we next evaluated the substrate scope over a oformates have been utilized as milder reagents50 54, however range of 5-membered azacyclic compounds (Fig. 3). All substrates generally applied for strained ring systems38,41, with an exceptional examined were smoothly reacted under mild conditions irre- report by Cho still limited to N-alkyl-substituted 5-membered spective of the nature of N-substituents, furnishing the ring- cyclic amines55. One of the main challenges associated with such opening bromoformylation products in excellent selectivity and reagents comes from a poor capability to access the key ammo- high efficiency (2a–2r). Noteworthy is that 1.1 equiv. of the nium salt intermediates, which in turn restricts the employable difluorocarbene precursor was sufficient enough for N-alkyl ring types. substrates (2b–2c). Methoxy, trifluoromethyl, ketone and amide Here we report a highly efficient and practical strategy for the functionalities on N-aryl groups were found to be well-tolerated ring-opening functionalization of a wide variety of unstrained in ring-opening of pyrrolidines (2d–2g,77–91%). Benzo-fused cyclic amines, including but not limited to 5- and 6-membered and fully saturated bicyclic amines were also effectively trans- rings (Fig. 1c). The use of difluorocarbene allows a prominently formed (2h–2l,50–83%). In case of octahydroindolizine (1k), the selective N-difluoromethylation, with subsequent ring-opening skeleton was ring-opened exclusively at the 5-membered unit. halogenation and in situ hydrolysis furnishing acyclic N-formyl A dihydropyrrole 1m was readily ring-opened without affecting haloamines. The resulting pluripotent motifs further enable the olefin moiety (2m, 86%), proving its orthogonality to the the construction of diverse arrays of homologated scaffolds by previously reported cyclopropanation reactions58. transforming both N-formyl and halide functional groups Significantly, reactivity differentiation by basicity of amines or incorporated in products, providing a unique platform for scaf- steric influences allows the reaction to occur in excellent fold diversity that cannot be accessed by the conventional von regioselectivities. For

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