Synthesis of Cyclohexanones by a Tandem Photocatalyzed Annulation

Abstract

The rapid synthesis of cyclic scaffolds is of high importance to the chemistry community. Strategies for the convergent synthesis of substituted carbocycles and heterocycles remain underexplored despite the plethora of applications that these cyclic motifs have in the pharmaceutical and materials industries. Reported herein is a tandem carbene and photoredox-catalyzed process for the convergent synthesis of substituted cycloalkanones via a formal [5+1] cycloaddition. Featuring two distinct photoredox cycles and a novel α-oxidation of benzylic ketones, this reaction offers a mild approach to construct two contiguous C–C bonds and eliminates the need for strong bases or expensive metal catalysts. The utility of this method is highlighted through various product diversification reactions that allow access to a range of important cyclic scaffolds.

Graphical Abstract

The convergent synthesis of highly functionalized carbocycles and heterocycles remains a high priority among organic chemists due to their numerous applications in the pharmaceutical and materials industries. Described herein is a tandem carbene and photoredox-catalyzed process for the synthesis of substituted cycloalkanones via a formal [5+1] cycloaddition that features a novel α-oxidation of benzylic ketones.

The convergent synthesis of privileged small molecules remains a significant challenge among the organic and medicinal chemistry communities.¹ Of particular importance is the synthesis of carbocyclic and heterocyclic scaffolds, which are highly prevalent in FDA-approved drugs² as well as a multitude of bioactive compounds³ and are common intermediates in the synthesis of various materials (Figure 1A).⁴ These scaffolds can often be accessed from cycloalkanones, thus highlighting the need for methods that enable the convergent construction of cyclic ketones.⁵ Cyclohexanones are most frequently synthesized in industry by reduction of the corresponding phenol⁶ or oxidation of cyclohexane or cyclohexanol derivatives (e.g., Chapman-Stevens oxidation).⁷ These processes often require elevated temperatures and strong redox agents or are plagued by over-reduction or over-oxidation. Cycloadditions (e.g., [4+2] reactions)⁸ and various other cyclization processes (e.g., Dieckmann condensation,⁹ Robinson annulation,¹⁰ etc.) offer alternative routes for accessing cyclic scaffolds, but their applications in the synthesis of structurally complex cyclohexanones are limited due to electronic requirements or vigorous reaction conditions (Figure 1B).

Figure 1.

A) Cyclohexanone-derived scaffolds found in bioactive compounds. B) Selected synthetic routes to prepare cyclohexanones. C) Combined light-driven carbene and photoredox catalysis and its inherent advantages. D) A new strategy to build cyclohexanones featuring intermolecular radical-radical coupling followed by intramolecular cyclization via oxidation of a benzylic enol.

The recent renaissance of radical chemistry through the emergence of photocatalysis¹¹ and electrosynthesis¹² has resulted in new approaches for the formation of C–C bonds, thus enabling non-traditional disconnections. While the versatile reactivity enabled by these radical redox strategies is unquestionable, significant limitations still exist. In particular, the majority of approaches in recent years for the photocatalytic synthesis of ketones concentrate on building acyclic products.¹³ Apart from work focused on the synthesis of fused ring systems via radical cascade mechanisms, the synthesis of carbocyclic or heterocyclic rings via radical C–C bond formation remains underexplored.^{11a, 14} Moreover, structural complexity can be achieved efficiently by the formation of multiple bonds in a one-pot procedure, yet few protocols have been established for the construction of highly functionalized cyclic products. Recent advancements in metal catalysis,¹⁵ photoredox strategies,^{13d, 16} and single-electron carbene chemistry¹⁷ have enabled the facile construction of ketones via C–C bond formation, and these reactivity modes have been extended to radical relay processes for the formation of multiple bonds in a single reaction.^{14a, 15, 18} While these strategies can afford highly functionalized products, they tend to feature 1,3-bond formation patterns, thus restricting their scope and overall utility. As a result, development of a new methodology for the synthesis of multi-functionalized cyclic scaffolds would allow for the exploration of new chemical space.

Given our recent investigations on the synthesis of ketones in combination with the rise in single-electron benzylic oxidations, we envisioned that oxidation of benzylic ketones might be possible. Benzylic C–H bonds are highly prevalent in bioactive compounds (e.g., ~40% of the top 200 small molecule drugs by retail sales in 2020 contain benzylic or benzylic-like C–H bonds),¹⁹ and their functionalization using single-electron catalysis is of great interest.²⁰ The efficient synthesis of benzylic ketones has also received significant attention, as ketones are highly valuable functional groups that are often the center of reactivity and diversification. Advancements in the construction of these prevalent motifs include the α-arylation of ketones (via transition metal catalysis) and various radical coupling strategies (via acyl/ketyl radicals).^{17b, 20a, 21} However, few strategies exist for the mild α-functionalization of benzylic ketones. We hypothesized that combined carbene and photoredox catalysis²² would allow for the construction of two contiguous C–C bonds via a novel radical α-functionalization of in-situ generated benzylic ketones under mild reaction conditions. Reported herein is the tandem carbene and organophotoredox-catalyzed convergent synthesis of α,β-disubstituted cyclohexanones (Figure 1C). This process features consecutive photoredox cycles that facilitate two distinct transformations in one pot for the rapid synthesis of complex cyclic scaffolds. In contrast to established radical relay processes wherein radical addition into an alkene occurs first, the increased stability of benzylic radicals²³ allows for initial generation of a linear ketone via a light-driven, carbene-catalyzed intermolecular radical-radical coupling. Subsequently, single-electron oxidation of the corresponding enol in a second photoredox cycle enables intramolecular cyclization to the α,β-disubstituted cyclohexanone product (Figure 1D).

Using our optimized reaction conditions for the synthesis of aliphatic ketones as a starting point,^21m it was determined that further optimization of the solvent, N-heterocyclic carbene (NHC) precursor, and base was unnecessary. Given that this process features two distinct photoredox cycles by the same photocatalyst, choice of photocatalyst unsurprisingly was found to be critical in optimizing for the desired reactivity. Use of [Ir(dF[CF₃]ppy)₂(dtbpy)]PF₆ led primarily to linear ketone 3a’ (Table 1, entry 2), confirming the feasibility of the first reaction step. Highly oxidizing or highly reducing photocatalysts were not suitable for this process (Table 1, entries 3–4), as their range of redox potentials were not broad enough to enable the various oxidations and reductions. When organophotocatalyst 3DPAFIPN was employed, significant cyclized product was observed (Table 1, entry 1), suggesting that the necessary redox potentials fall near its redox range (E_1/2 PC*/PC^•− to E_1/2 PC/PC^•− = +1.09 to −1.59 V vs. SCE).^11g Although this process was optimized with Hantzsch esters,²⁴ use of organophotocatalyst 4CzIPN afforded product using benzyl potassium trifluoroborate salts (Bn–BF₃Ks)²⁵ as an alternative oxidatively-generated radical precursor (ORP; Table 1, entry 5). Final optimization of the reaction concentration proved to be essential, as this one-pot transformation features both intermolecular and intramolecular bond-forming steps. The screening of various reaction concentrations revealed that the cyclization occurred most readily under dilute reaction conditions (Table 1, entries 1,6–8).

Table 1.

Optimization of reaction conditions and reaction sensitivity.^a

^aSee SI for details.

^b1H NMR yield using 1,3,5-trimethoxybenzene as an internal standard.

^cIsolated yield.

The optimized reaction was evaluated for its sensitivity to demonstrate the practical nature of this protocol and ensure a high degree of reproducibility with differing reaction setups (Table 1, right, see SI for details).²⁶ Only minor deviations in yield were observed for small changes in concentration, light intensity, and temperature. As expected, it was found that high oxygen levels are detrimental to the reaction efficiency, with a dramatic change in yield (i.e., 0% yield) when air was bubbled through the reaction solution prior to irradiation. Similarly, addition of water decreased the reaction efficiency, but normal reactivity was restored using non-degassed acetonitrile without additional drying under inert atmosphere (i.e., low oxygen and low water). The demonstrated overall robustness of this reaction suggests that little-to-no difficulty should be encountered when these reactions are run in other laboratories.

These reaction conditions were used to synthesize cycloalkanones with a variety of substituted α-aryl substituents and a diverse array of β-substituents (Table 2). Substituted benzyl radical precursors featuring electron-withdrawing or electron-donating groups were found to be suitable coupling partners and allowed for significant conversion to the corresponding cyclohexanone products (3b-3f).²⁷ Many benzylic oxidation strategies are inefficient or completely ineffective with electron-poor arenes, as electron-withdrawing groups increase the oxidation potential of the arene ring significantly. The strategy reported herein, however, tolerates electron-withdrawing groups, with yields up to 66% (3d) over two C–C bond-forming steps in our one-pot procedure. This difference in reactivity likely stems from the mechanism of oxidation, wherein deprotonation of the α-position gives the enol, which can be oxidized at lower potentials.

Table 2.

Substrate scope of reaction and application of the products to synthesize heterocyclic scaffolds in high yields.^a,b

^aSee SI for details.

^bDiastereomers were assigned by analogy to X-ray crystal structures of 3a and 3k. A single diastereomer was observed by ¹H NMR spectroscopic analysis for all reactions.

^cIsolated from the corresponding pentenoyl imidazole 1.

A diverse array of β-substituted cycloalkanones was accessed using this protocol. Various substituted β-benzyl cyclohexanone products were isolated in moderate-to-good yields (3g-i,k). Disubstituted alkenes were also tolerated, with isolation of 3j in 81% yield. Cyclohexanones featuring heteroaromatic substitution were also constructed using this tandem cyclization process, with thiophene-substituted 3l and furan-containing 3m isolated in moderate-to-good yields. The diversity of products that may be synthesized under these reaction conditions was further showcased by isolation of δ-ester 3n in high yield, providing a functional group handle for diversification. Isolation of 4-geminal-diester 3o in excellent yield suggests that highly functionalized cyclohexanones may be synthesized using this method by pre-functionalization of the linear starting material; moreover, the excellent yield obtained for 3o demonstrates the potential utility of this method for the construction of key synthetic building blocks. Although these conditions were optimized for the synthesis of cyclohexanone derivatives, isolation of 3p and 3q suggests that this process may be employed for the synthesis of cyclopentanones and other cycloalkanones with additional optimization.

Reactions of cyclic ketones have been extensively reported in the literature (e.g., reduction to the corresponding cyclohexane, condensation with an amine, etc.), highlighting their versatility as synthetic intermediates.²⁸ As such, the utility of this process in synthesis was demonstrated through a brief series of product diversification reactions (Table 2). When 3a was subjected to modified Beckmann conditions, the corresponding caprolactam 4a was isolated in 77% yield.²⁹ Similarly, subjecting 3a to standard Baeyer-Villiger conditions enabled the corresponding lactone 4b to be furnished in quantitative yield.³⁰ A multitude of additional diversification directions can be envisioned for these products given their synthetic utility.

While the mechanism of the carbene-catalyzed radical-radical coupling has been studied,^{21m, 31} key mechanistic experiments were employed to study the reaction mechanism of the benzylic ketone/enol oxidation. Subjecting linear ketone 3a’ to the organophotocatalyst and light under basic conditions yielded cyclic 3a in 90% yield, supporting linear ketone 3a’ as an intermediate in this reaction (Scheme 1A) and offering an alternative route to access these products. Control experiments strongly indicate a photocatalytic transformation, as no reaction occurred in the absence of base, photocatalyst, or light (Scheme 1A). A TEMPO-trapping experiment further suggests production of an α-benzylic radical, as the mass of TEMPO-adduct 5a was observed by high-resolution mass spectrometry (HRMS; Scheme 1B). Stern-Volmer fluorescence quenching experiments reveal that both 3a’ and a basic mixture of 3a’ with cesium carbonate quench the photocatalyst, with the basic mixture being the more prominent quencher (Scheme 1C). Together with the requirement of basic reaction conditions as indicated by the control experiments (vide infra), these results suggest that the enol or enolate form of 3a’ likely undergoes single-electron oxidation by the photocatalyst. Lastly, the reaction was run under standard reaction conditions in deuterated acetonitrile to shed light on the final step of this reaction. Analysis of the isolated cyclized product revealed significant deuterium incorporation at the ketone α-positions, an expected result given the acidity of these protons. Moreover, approximately 50% deuterium incorporation was identified at the γ-benzylic position (blue highlight, Scheme 1D), suggesting that the mechanism terminates by hydrogen-atom abstraction³² or reduction followed by protonation.³³

Scheme 1.

A) Control reactions for the benzylic oxidation. B) TEMPO-trapping experiment. C) Stern-Volmer fluorescence quenching experiment used to identify the species that is oxidized by the photocatalyst. D) Deuterium labeling experiment that reveals deuterium incorporation from the solvent terminates the reaction approximately 50% of the time (blue highlighted deuterium atom). TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl radical.

Using our previous knowledge and the results of these mechanistic experiments, we propose a mechanism featuring two distinct photoredox cycles which operate productively in concert (Scheme 2; see SI p12 for detailed mechanism including NHC catalytic cycle). Single-electron oxidation of the oxidatively-generated radical precursor yields radical cation I, which fragments to provide benzyl radical II. Single-electron reduction of acyl azolium III, derived in situ from acyl imidazole 1, affords acyl azolium radical IV. Intermolecular radical-radical coupling and loss of the NHC gives linear ketone intermediate 3’. Single-electron oxidation of the corresponding enol or cesium enolate V affords α-benzylic radical VI, which engages in an intramolecular cyclization with the alkene. The resulting γ-benzylic radical VII may undergo hydrogen atom transfer (HAT) or be reduced by the photocatalyst to the corresponding anion, which deprotonates the solvent or bicarbonate to afford the desired cyclohexanone product 3.

Scheme 2.

Proposed mechanism for the tandem cyclization process.

In summary, we have developed a tandem carbene and photoredox-catalyzed strategy for the convergent synthesis of α,β-disubstituted cyclic ketones. This process enables the construction of two contiguous C–C bonds via a formal [5+1] cycloaddition and highlights a novel method for the α-functionalization of ketones under mild reaction conditions. Through the combination of two distinct processes in one pot, this reaction offers a route to synthesize complex cycloalkanone products that can be leveraged to access scaffolds relevant in both the pharmaceutical and materials industries.

ABBREVIATIONS

HAT

hydrogen atom transfer

NHC

N-heterocyclic carbene

ORP

oxidatively-generated radical precursor

SET

single-electron transfer