Aromatization-driven deconstruction/refunctionalization of unstrained rings

Abstract

Aromatization-driven ring-opening/functionalization of common unstrained rings has been developed with the in situ generation of pre-aromatic fused spiro heterocycles as the key step, featuring (1) simple operation via a convenient one-pot reaction and (2) broad scope of various ring systems which do not require pre-activation.

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As is well known, aromatization is an important thermodynamic driving force for the formation of stable aromatic rings in organic synthesis.¹ And the C–C bond activation as a significant route for molecular modification is a hot research field.² Remarkably, the exploitation of aromatization-driven C–C bond cleavage can be traced back to 1972 with the assistance of transition metals.³ However, since then, the utilization of aromatization as a driving force for C–C bond cleavage has been unappreciated for a long time, and only a few relevant studies have been reported.^3,4 Recently, this strategy has been revived gradually for elaborate transformations and has drawn increasing attention from chemists.^5–8 For example, Melchiorre,^6a Molander,^6b and Chen^6c developed C–H alkylation reactions independently by employing the aromatization-driven C–C bond homolysis strategy of 4-alkyl-1,4-dihydropyridines 1 (Scheme 1a). The Ma group performed the pioneering work on the aromatization-driven 1,2-migration of Pt- or Au-carbene intermediates for the synthesis of carbazoles (Scheme 1b).⁷ Besides, You^8a–e and other groups^8f–g reported the aromatization-driven ring-expanding rearomatization of spiroindolenines 7 for the construction of polycyclic indoles 8via acid-mediated migration, respectively. In addition, the spirocyclization-dienone-phenol rearrangement cascade reactions have been reported as well with the promotion of aromatization (Scheme 1c).⁹ Yet the major reason that restricts the wide application of aromatization as a driving force for synthetic transformations is the difficulty in the in situ generation of pre-aromatic substrates, which usually need to be prefabricated through tedious steps.

Scheme 1 Representative types of aromatization-driven C–C bond cleavage.

Aliphatic rings are ubiquitous in various kinds of organic compounds including pharmaceutical drugs, natural products, and functional materials.¹⁰ Thus, employing the widely-sourced aliphatic rings as starting materials for deconstruction and re-functionalization would be significantly important for the development of organic synthesis and industrial production. However, for a long time, chemists have been limited in the cleavage of strained rings, which were equipped with an inherent thermodynamic driving force for releasing the ring strain (Fig. 1).¹¹ The C–C bond cleavage/editing of unstrained aliphatic rings is a compelling challenge owing to the high C–C bond dissociation energy.

Fig. 1 Strain energies of different sizes of aliphatic rings.

This highlight article aims to provide a concise overview of the aromatization-driven ring deconstruction strategy of readily available unstrained cycloalkanones and cycloalkanamines via radical-mediated C–C bond fragmentation. The protocol features the in situ generation of pre-aromatic fused spiro cycles 13, as shown in Scheme 1d, which might bring a distinct research direction for the development of organic chemistry.

Aromatization-driven C–C bond cleavage of unstrained cycloalkanones

C–C bond activation/functionalization of cycloalkanones emerged as a useful method for synthesizing complex scaffolds. Seminal work by Jun developed the rhodium(I)-catalyzed ring-opening of medium to large cycloalkanone imines to provide various aliphatic chain decorated ketones in 2001.¹² Afterwards, the pursuit for the C–C bond activation/functionalization of cycloalkanones went on uninterrupted, but only sporadic works were reported for unstrained ring activation.¹³ Among them, the Dong group has made outstanding contributions to the transition-metal catalyzed unstrained C–C bond activation with the assistance of in situ formed directing groups.^13b–e

Very recently, Dong and co-workers reported the efficient ring-opening reactions of unstrained cycloalkanones based on radical fragmentation involved aromatization-driven C–C bond activation (Scheme 2).¹⁴ These deacylative transformations provided various skeleton-functionalized aliphatic chains linking pyrazole via a three-component coupling in the presence of an iridium/phosphine combination. Considering the less-accessible carbocyclic pre-aromatics, the authors designed the three component involved 1,3-dipolar addition to prepare the precursor of the pre-aromatized heterocycle which serves as the key intermediate for the subsequent conversion. Various cycloalkanones 15 with different substitutions and ring sizes are available for the aromatization-driven deconstructive transformations. In addition, good regioselectivity has been observed when unsymmetrical ketones and heterocyclic ketones were used, and the bond scission preferentially occurred at more substituted carbons or the α-position of heteroatoms. Besides, various natural products were well tolerated for the C–C bond transformation.

Scheme 2 Deconstructive pyrazole synthesis from unstrained cycloalkanones.

Based on mechanistic studies and DFT calculations, an aromatization-promoted homolytic C–C cleavage/radical recombination mechanism was proposed (Scheme 3). The initial [3 + 2] cycloaddition occurs between 1,3-butadiene and the hydrazone intermediate A, generating cyclic adduct B which could be isolated. Then olefin migration takes place to afford the dihydropyrazole intermediate C which serves as the pre-aromatic substrate to drive the following homolytic C–C bond cleavage with the promotion of an iridium catalyst. The control experiments indicate that no C–C cleavage occurs without the endocyclic double bond or the five-membered ring structure, which demonstrates the significant role of the intermediate C. Subsequently, the aromatization-driven deconstruction of the unstrained ring occurs, providing the iridium complex D bearing aromatized pyrazole. Then the C–H reductive elimination or coupling with 1,3-butadiene of iridium complex D takes place to afford the corresponding products 16 and 17, respectively. In addition to cycloalkanones, the deacylative transformations are suitable for a variety of linear ketones as well, which offer strategic bond disconnections for editing of the molecular skeleton.

Scheme 3 Plausible mechanism for deconstructive pyrazole synthesis from unstrained cycloalkanones.

In addition, Fan and co-workers described the ring-opening reactions through [3 + 2] cycloaddition of enone with unstrained cyclic ketone hydrazone followed by an aromatization-driven homolytic C–C bond cleavage/radical reorganization (Scheme 4).¹⁵ In this reaction, the in situ generated pre-aromatic I is considered as the key intermediate likewise to drive the subsequent C–C bond disconnection for aromatization.

Scheme 4 Ring-opening reactions for the synthesis of 4-acylpyrazole from unstrained cyclic ketone hydrazine.

Aromatization-driven C–C bond cleavage of unstrained cycloalkanamines

Cycloalkanamines as essential structural units are widely found in natural products, pharmaceuticals, and agrochemicals. The development of convenient methods to make use of the widespread cycloalkanamines is extremely meaningful for modern chemical production. At present, the utilization of cycloalkanamines via ring-opening reconstruction is underdeveloped, and the scarce cases that are reported are almost limited to strained rings.¹⁶

For example, Zheng and co-workers conducted the pioneering work on the photogenerated amine radical cation-involved ring-extension reactions of cyclopropyl- and cyclobutyl-anilines with alkenes and alkynes.^16a–d Recently, Waser and co-workers described an oxidative ring-opening strategy to transform aminocyclopropanes into 1,3-dielectrophilic carbon intermediates bearing a halide atom (Br, I) and a N,O-acetal which could be converted into a wide range of α,γ-difunctionalized amines in a one-pot or two-step operation.^16e

Despite the developments mentioned above on the application of cycloalkanamines as building blocks through ring-reconstruction and functionalization, ring-opening of unstrained cycloalkanamines still remains a compelling challenge. This situation can be attributed to ring-strain release as a thermodynamic driving force for strained cycloalkanamines, and the high reverse exo-cyclization rate constant of nitrile and imine for unstrained cycloalkanamines, especially for 5- or 6-membered cycloalkanamines.^11,17 In this context, Han and co-workers achieved the introduction of aromatization as both dynamic and thermodynamic driving forces for driving ring-opening of unstrained primary cycloalkanamines.¹⁸ In this metal-free reaction, the deconstruction/functionalization of unstrained primary cycloalkanamines has been developed unprecedentedly, producing carbonyl compound tethered aliphatic chains and 1,2,4-triazole directly through the autooxidative aromatization-driven C(sp³)–C(sp³) bond cleavage (Scheme 5). Similarly, the C–C bond cleavage of cycloalkanamines preferentially at more substituted carbons or the α-position of heteroatoms was achieved. The wide substrate scope tolerance of this protocol has been revealed by meticulous evaluations, including monocyclic, bicyclic, bridged, and complex natural product derivatives containing primary cycloalkanamine moieties, which indicated its potential application in the pharmaceutical and chemical industries. In addition, the in situ generation of the pre-aromatic heterocycle remains the core of this transformation, which is consistent with Dong and Fan's work.

Scheme 5 Deconstruction/functionalization of unstrained primary cycloalkanamines.

In the proposed catalytic cycle (Scheme 6), the initial nucleophilic substitution occurs between cycloalkanamine 21 and hydrazonyl chloride 22 to produce hydrazonamide L which is auto-oxidized by air to generate aminyl radical M. Then radical M undergoes the tandem 1,5-hydrogen atom shift/further oxidation/annulation process to form the key pre-aromatic heterocycle N, which could be isolated. The spiro heterocycle N tends to be oxidized by air to afford the cyclic amino radical intermediate O which appears in many N-containing heteroaryl migration reactions.¹⁹ Then aromatization serves as a driving force to promote the radical C–C bond cleavage to furnish the aromatic 1,2,4-triazole. The generated distal alkyl radical P linking aromatic 1,2,4-triazole is immediately intercepted by TEMPO to give the ring-opening product Q. The final acyclic carbonyl compounds 23 and 24 carrying 1,2,4-triazole could be obtained by the treatment of mCPBA via the oxidation/Cope-elimination sequence.

Scheme 6 Proposed mechanism for the deconstruction/functionalization of unstrained primary cycloalkanamines.

Conclusions

The C–C bond disconnection is of significant importance for editing the molecular skeleton in organic synthesis, especially for the cleavage of ubiquitous unstrained aliphatic rings. Aromatization as both dynamic and thermodynamic driving forces for promoting C–C bond cleavage could compensate for the chemical inertness of unstrained aliphatic rings. We have highlighted the aromatization-driven homolytic C–C bond cleavage of common unstrained rings promoted by the in situ generated pre-aromatic fused spiro cycles, which featured (1) simple operation via a convenient one-pot reaction and (2) broad scope of various ring systems which do not require pre-activation. From our viewpoint, the aromatization-driven deconstruction/refunctionalization of organic molecules would be a powerful toolbox for modifying molecular skeletons and enriching the diversity of molecules.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the NSFC (21978144, 21702117, and 21776148), the Key Research & Development Program of Shandong Province (2018GSF118224, 2019GSF108020, 2019GGXI02036, and 2019RKB01027), the Support Plan on Science and Technology for Youth Innovation of Universities in Shandong Province (2019KJM002) and the Opening Funding of Qingdao University of Science & Technology (QUSTHX201916 and QUSTHX202004). The Central Laboratory of Qingdao Agricultural University is also gratefully acknowledged for NMR determination.

Notes and references

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