Carbene–Ketene Formal [3 + 2] Cycloaddition Enabled by Visible-Light-Induced Dual Photolysis of Diazo Compounds

Abstract

Diazo compounds have long been employed through two distinct reaction pathways: carbene transfer and ketene formation, which rarely intersect within a single reaction environment. Here, we report a visible-light-induced dual photolysis strategy that unifies these divergent pathways by selectively activating two distinct diazo precursors to generate a free carbene and a ketene in situ. The resulting intermediates undergo a formal [3 + 2] cycloaddition, enabling the synthesis of densely substituted furanones bearing quaternary carbon centers. This catalyst-free protocol exhibits a broad substrate scope, operational simplicity, and scalability to gram quantities. Beyond its synthetic utility, representative products display preliminary antifibrotic activity, highlighting the potential of this platform to bridge reactive intermediate chemistry with the development of bioactive scaffolds. This dual photolytic paradigm establishes a conceptual foundation for orchestrating carbene and ketene reactivity within a unified diazo framework.

Introduction

Diazo compounds have long been central to synthetic chemistry because the extrusion of molecular nitrogen provides access to highly reactive intermediates capable of precise bond construction. Over time, two principal reaction manifolds have defined their reactivity. One proceeds through carbene formation, enabling X–H insertion, cycloaddition, and ylide intermediates under transition-metal catalysis or direct photochemical activation. The other arises from the Wolff rearrangement of diazoketones, wherein nitrogen loss is followed by a 1,2-shift to generate ketenes, versatile electrophiles that engage nucleophiles or participate in cycloaddition processes. Together, these divergent pathways have positioned diazo compounds as a unique platform connecting transient reactivity and complex molecular assembly.

Despite their shared origin, carbene and ketene chemistry has historically evolved in isolation. Established transformations are intentionally designed to channel a single diazo species into one dominant pathway while suppressing competing reactivity. Consequently, limited progress has been made toward strategies that engage two distinct diazo substrates simultaneously, with each substrate following its intrinsic reaction pathway within a single reaction manifold (Scheme A). , If such divergent intermediates could be generated and directed in concert, then this would enable programmable convergence rather than parallel isolation, opening a fundamentally new dimension in diazo-based transformations.

1. (A) Known Cross-Coupling Reactions of Two Diazoalkane Components via Visible-Light Irradiation; (B) Our Design; (C) Representative Natural Products and Pharmaceuticals Containing a Furanone Motif.

The emergence of visible-light activation has created an opportunity to reconsider this challenge under mild, catalyst-free conditions. Photolysis offers temporal and energetic control over nitrogen extrusion, allowing access to free carbenes and ketenes without the constraints imposed by metal catalysts. However, translating photochemical activation from single-substrate systems to dual diazo platforms introduces substantial obstacles. Beyond triggering nitrogen loss, a successful design must orchestrate the relative rates of intermediate formation, prevent competitive processes such as carbene dimerization and ketene self-condensation, and guide each species selectively toward productive interception rather than decomposition. These intertwined demands have thus far precluded a general approach to reconciling carbene and ketene reactivity in one pot.

Herein, we conceive a visible-light-driven dual photolysis strategy that unites two diazo families within a single reaction environment (Scheme B). Under blue irradiation, aryl diazoacetates undergo photochemical nitrogen extrusion to release free carbenes, while diazoketones concurrently experience Wolff rearrangement to generate ketenes. The two transient intermediates converge through a formal carbene–ketene [3 + 2] cycloaddition, delivering 3­(2H)-furanones bearing quaternary carbon centers, which are widely present in many natural products and pharmaceuticals (Scheme C). This platform proceeds without photosensitizers or transition metals, accommodates a wide substrate scope including late-stage diversification, and provides access to structurally dense scaffolds with functional relevance. By demonstrating that divergent diazo fates can be orchestrated within a unified photochemical framework, this work establishes a conceptual foundation for cooperative activation in diazo chemistry and expands the synthetic repertoire of carbene and ketene manifolds. It is worth noting that Liu and Sasane reported a thermally promoted formal [3 + 2] annulation to 3­(2H)-furanones. While this study establishes the feasibility of ketene–diazo coupling under heating, the key bond-forming step is initiated by nucleophilic addition of weakly nucleophilic acceptor-only diazo compounds to highly electrophilic ketenes, and thus, it does not address a visible-light dual-activation scenario in which a free carbene and a ketene are generated concurrently and selectively intercepted within one pot. Moreover, the demonstrated diazo scope in that thermal manifold is largely confined to acceptor-only diazo partners and was not shown for donor–acceptor diazoacetates under comparable conditions.

Results and Discussion

To address the aforementioned challenges, our preliminary efforts focused on a model reaction between 2-diazo-2-phenylacetate (1a) and 1-diazo-1-phenylpropan-2-one (2a). Under blue-light irradiation, the coupling reaction afforded 5-methoxy-2-methyl-2,4-diphenylfuran-3­(2H)-one (3) (Table ). We first examined a series of solvents, including MeCN, tetrahydrofuran (THF), dichloromethane (DCM), dichloroethane (DCE), 1,2-dimethoxyethane (DME), PhCCl₃, PhCl, and toluene. DCM emerged as the optimal solvent, affording furan-3­(2H)-one 3 in 61% yield (entry 3). Because diazoketone 2a may decompose under the reaction conditions, increasing the amount of 2a to 1.5 equiv led to a significant increase in the yield of 3, reaching 86% (entry 9). Notably, the coupling product 3 was not detected in the absence of a light source and substrates 1a and 2a remained (entry 10). Furthermore, when the system was heated to 60 °C, the coupling product 3 was not formed; instead, the major products were trisubstituted olefins or azo compounds resulting from homocoupling reactions of the diazoalkanes (entry 11).

1. Optimization of Reaction Conditions .

entry	conditions	3 yield [%]
1	blue light, MeCN	58
2	blue light, THF	54
3	blue light, DCM	61
4	blue light, DCE	43
5	blue light, DME	58
6	blue light, PhCCl3	50
7	blue light, PhCl	61
8	blue light, toluene	58
9	blue light, DCM, 2a 1.5 equiv	86
10	dark, DCM, 2a 1.5 equiv	0
11	60 °C, DCM, 2a 1.5 equiv	0

^aReaction conditions: 1a (0.1 mmol), 2a (1.0 equiv), solvent (0.5 mL), blue-light irradiation (455 nm, 15 W), room temperature, 6 h, under N₂ atmospheres.

^bIsolated yield.

With the optimized reaction conditions in hand, the scope of diazoalkanes was further investigated to examine the generality of the reported system, as shown in Table . First, a series of aryl diazo esters (1a–p) reacted smoothly with 2a to provide coupling products (3–18) in moderate to excellent yields (36–86%) (Table A). The protocol demonstrated good functional group compatibility, and substituents such as methoxy (1b, 1h), methyl (1c, 1i), ester (1g, 1o), chloro (1e, 1m), bromo (1f, 1n), fluoro (1d, 1l), trifluoromethyl (1p), tert-butyl (1j), and phenyl (1k) were well tolerated. Additionally, polysubstituted aryl diazoalkanes (1q–v) and a naphthyl diazo ester (1w) were also compatible with this protocol, affording coupling products 19–25 in moderate to good yields (58–86%). Furthermore, complex aryl diazo esters derived from natural products or pharmaceuticals, such as menthol (1A), (−)-β-citronellol (1B), pregnenolone (1C), epicoprosterol (1D), sitosterol (1E), and epiandrosterone (1F), proceeded uneventfully to afford products 26–31 in moderate yields (56–78%). In addition, the structure of compound 3 was confirmed by X-ray crystallographic analysis (CCDC 2433550). Regrettably, ortho-substituted (1H–J) or heteroaryl (e.g., furan, thiophene, and carbazole) diazo esters (1K–M) could not smoothly produce the desired products (for details, see Supporting Information 4.3). The major reason is attributed to the difficulty in generating a stable free carbene, as well as the low reactivity and selectivity of hetero diazoalkanes.

2. Substrate Scope ^,

^aReaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), DCM (1 mL), blue-light irradiation (455 nm, 15 W), stirred for 6 h at room temperature under N₂ atmospheres.

^bIsolated yield.

Next, the scope of diazoketones was further explored (Table B). Various diazoketones bearing electron-donating or -withdrawing substituents were compatible with the protocol and reacted smoothly with methyl 2-diazo-2-phenylacetate (1a) to deliver furanones (32–50) in moderate to good yields (45–88%). The tolerated substituents included methoxy (2b, 2k), methyl (2c, 2l, 2q, 2t), phenyl (2g), fluoro (2d, 2m, 2r), chloro (2e, 2n, 2s), bromo (2f, 2o), ester (2i, 2p), trifluoromethyl (2h), and nitro (2j). Moreover, when naphthyl-substituted diazoketone 2v was used as the substrate, the desired product 51 was obtained in good yield. In addition to methyl aryl diazoketones, other aryl diazoketones, such as diphenyl (2w), isobutyl (2x), and cyclopropyl (2y), also furnished the corresponding products 52–54 in moderate yields. Notably, a cyclic diazoketone (2z) reacted with 1a to successfully deliver spirofuranone 55 in 35% yield. For the 2-diazo-1-phenylpropan-1-one (2A) and heteroaryl (e.g., furan, thiophene, and carbazole) diazo ketones (2B–D), reactions were examined under standard conditions (for details, see Supporting Information 4.3). Disappointingly, the corresponding products were not isolated, nor were traces of them detected.

To further demonstrate the synthetic applications of this protocol, a scale-up experiment was performed. Specifically, the reaction of 1a (8 mmol) with 2a under the standard conditions afforded compound 3 on a 1.6 g scale in 72% yield (Scheme A). To assess the practicality and scalability of this dual photolysis strategy, we also conducted the reaction under continuous-flow conditions with visible-light irradiation, which gave the desired product in a slightly lower but still comparable yield relative to the batch reaction (Scheme A). Further transformations of 3 were also investigated. For example, hydrolysis of 3 with HCl and isomerization produced the lactone compound 57 in excellent yield (91%). Reaction with butylamine, a nucleophilic reagent, afforded the amino-substituted furanone 58 in 92% yield (Scheme B), providing a rapid route to flurtamone derivatives, a class of furanone herbicides. Debenzylation of 64 under Pd/C hydrogenation smoothly converted 59 to the furanone 60 in 75% yield. This strategy can efficiently synthesize the core framework of natural products (−)-vertinolide and plakinidone B with antimicrobial activity (Scheme C). When alkenyl aryl diazo ester (1G) was used as the substrate, furanone 61 was also isolated in 40% yield. Interestingly, Claisen rearrangement of 61 led to product 62, which was isolated in 13% yield. Inspired by this result, we employed BINOL as a catalyst, and furanone 61 was smoothly converted to the furan-2,4­(3H,5H)-dione 62 in CHCl₃ under an air atmosphere with a good yield (Scheme D). The furanone unit is considered one of the pharmacophores of biologically active substances and plays a significant role in the discovery, design, and development of various pharmacologically active compounds. Among its notable bioactivities, anti-inflammatory activity is particularly important. Therefore, we focused on evaluating the bioactivity of these compounds against liver fibrosis (Scheme E). After assessing the inhibition of hepatic stellate cells (HSCs) by the furanone compounds, compounds 4, 11, 16, 17, 19, 31, 43, 44, 46, 51, and 53 exhibited potential bioactivity comparable to that of the positive control, pirfenidone (PFD), a broad-spectrum antifibrotic agent. These compounds may serve as promising lead candidates for the future development of antiliver fibrosis therapies.

2. Synthetic Applications .

^a (A) Gram-scale experiment. (B) Transformations of product 3. (C) Transformations of product 64. (D) Further Claisen rearrangement. (E) Inhibition of HSC-T6 cell by selected compounds.

To gain insight into the reaction mechanism of the transformation, several control experiments were conducted (for details, see the Supporting Information). In addition to phenyl diazoesters, the alkyl diazoester 1P was also explored. The corresponding desired product 64 was obtained, albeit in only 36% yield. The acceptor-only type diazoalkane 1N also delivered the desired product 63 in low yield (33%) after a prolonged reaction time of 24 h. Notably, the bis-acceptor diazo compounds 1T and 1U failed to afford the products 66 and 67 even after a prolonged reaction time of 24 h. A possible reason is that this bis-acceptor diazo compound has difficulty forming a carbene intermediate under blue-light irradiation. For styryl diazoalkane 1S, the reaction resulted in a complex mixture, and no desired product 68 could be isolated (Scheme A). The ultraviolet absorption spectra of 1N, 1P, and 1x showed that phenyl diazoesters and diazoketones exhibit strong absorption at around 440 nm, which is close to the wavelength of the blue light used in the reaction (455 nm). In contrast, alkyl diazoesters and acceptor-only-type diazoalkanes show strong absorption in a higher-energy range (380–400 nm). As a result, 1N and 1P do not efficiently undergo nitrogen extrusion to generate the carbene intermediate required for forming furanones 63 and 64. However, because 1N is a weak nucleophile, it could react to some extent with the strongly electrophilic ketene. Additionally, radical trapping agents, including 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 1,1-diphenylethylene, butylated hydroxytoluene (BHT), and styrene, were introduced into the reaction system. Nevertheless, the reaction still furnished product 3 in moderate yields (43–68%) (Scheme B). This suggests that a radical pathway is unlikely to be involved in this transformation. Moreover, a ketene is likely involved as a key intermediate, which is generated from 2a upon visible-light irradiation. When ketene was allowed to react with 1a under blue light, compound 3 was obtained in 83% yield. In contrast, product 3 was not detected in the absence of light (Scheme C). These results confirm that light activation is essential for this transformation, which is consistent with the outcome of the turn-off experiment (Scheme D­(b)). Moreover, this protocol exhibits good reactivity because of the rapid decomposition of diazoketone 2a, which is complete within approximately 2 h and contrasts with the slower decomposition of aryl diazo esters. This rapid decomposition helps to avoid both homo- and cross-coupling side reactions involving diazoketones and diazoesters (Scheme D­(a)).

3. Mechanistic Studies .

^a (A) Screening of selected acceptor-only and alkyl diazoalkane. (B) Radical trapping experiments. (C) Intermediate validation experiment. (D) (a) Dynamic experiment. (b) Light on–off experiment.

Based on our mechanistic experiments and previous reports, we propose a plausible reaction mechanism. Under visible-light irradiation, the diazoketone first undergoes photochemical denitrogenation to generate a free carbene, which subsequently undergoes Wolff rearrangement to afford the ketene intermediate. In parallel, the aryl diazoacetate undergoes photochemical N₂ extrusion to release a free carbene, which then intercepts the in situ generated ketene to initiate the bond-forming sequence and ultimately furnishes product 3. To further elucidate the detailed mechanism, particularly the light-enabled activation of the aryl diazoacetate and the subsequent reaction steps, density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were performed. Computational details are provided in the Supporting Information. As illustrated in Scheme , our initial investigations focused on the direct interaction between ground-state species ¹ 1a and Int-0. This pathway proceeds via transition state ¹ TS1b, exhibiting a prohibitively high energy barrier of 38.7 kcal/mol. This result indicates that the ground-state reaction (i.e., in the absence of visible light) is mechanistically unfavorable under the prevailing reaction conditions. Alternatively, our calculations revealed that compound ¹ 1a displays a maximum absorption wavelength at 460 nm. Upon visible-light irradiation, ¹ 1a can be readily excited to its first excited state ( ¹ 1a*), which subsequently relaxes to an equilibrium structure in the S1 state ( ¹ 1aeq*). Intersystem crossing (ISC) then occurs to form the triplet-state intermediate ³ 1a. This species undergoes C–N bond cleavage via ³ TS1a, characterized by a remarkably low energy barrier of 7.2 kcal/mol, thereby generating the carbene intermediate ³ Int-1 and releasing N₂. The intermediate ³ Int-1 can either proceed directly to the triplet-state intermediate ³ Int-2 via transition state ³ TS2 (14.0 kcal/mol) or undergo a spin crossover to its singlet-state configuration ¹ Int-1 via a minimum energy crossing point (MECP), with comparative analysis showing that the latter pathway is more favorable due to a lower activation barrier of only 6.2 kcal/mol. Following this, the direct addition of ¹ Int-1 to Int-0 proceeds through ¹ TS3 (10.1 kcal/mol), yielding the intermediate ¹ Int-3. Ultimately, ¹ Int-3 undergoes intramolecular isomerization via ¹ TS4, overcoming an energy barrier of 23.9 kcal/mol, to furnish the final product 3.

4. DFT Calculations .

^a All structures were optimized at the M062X/6-31G­(d,p) level. Harmonic vibrational frequencies were calculated at the same level to verify the nature of stationary points (no imaginary frequency for minima and only one imaginary frequency for transition states). With the M062X/6-31G­(d,p) geometries, the energies were further refined by M062X/6-311++G­(d,p) single-point calculations with solvent effects accounted for by the SMD solvent model, using dichloromethane as the experimental solvent. The vertical excitation energies of ¹ Int-1 were calculated at TD-M062X/6-311++G­(d,p). All DFT and TD-DFT calculations were carried out using the Gaussian 16 program.

Conclusions

We have developed a visible-light-induced dual photolysis strategy that enables the concurrent generation of a free carbene and a ketene from two distinct diazo precursors. These reactive intermediates converge through a formal [3 + 2] cycloaddition, providing access to densely substituted furanones bearing quaternary carbon centers under mild, catalyst-free conditions. This approach not only overcomes the long-standing separation of carbene and ketene reactivity but also establishes a unified platform for diazo chemistry under photochemical control. The broad functional group tolerance, applicability to complex substrates, and preliminary antifibrotic activity of representative products illustrate the synthetic and exploratory potential of this method. We anticipate that this dual photolytic paradigm will inspire further strategies for orchestrating multiple reactive intermediates within a single photochemical framework.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.6c00336.

• Experimental details, spectra, and X-ray crystallography (PDF)

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

We gratefully acknowledge the financial support of the Natural Science Foundation of Anhui University of Chinese Medicine (2021rczd003 and JCLCA2025015) and Key Laboratory of Xin’an Medicine (Anhui University of Chinese Medicine) (RZ2500000361) and the financial support of the Natural Science Foundation of Fuyang Normal University (FYKFKT24001) and Anhui Provincial Department of Education Outstanding Talent Cultivation Program for Universities (gxgwfx2021016).

The authors declare no competing financial interest.