Tunable Skeletal Editing of Benzothiazole and Benzisothiazole Via Carbene Transfer Reactions

Abstract

Understanding how carbene reactivity is modulated by both the heteroarene scaffold and activation mode is critical for advancing selective functionalization strategies. Herein, we report a comparative study revealing the divergent reactivity of benzothiazole and benzisothiazole under both photochemical and metal-catalyzed carbene transfer conditions. Under photochemical conditions, free carbenes induce a stepwise transformation of benzothiazole involving initial carbon-atom exchange followed by carbon atom insertion, affording benzothiazoline and benzothiazine derivatives. In contrast, benzisothiazole undergoes direct monocarbon atom insertion, selectively forming ring-expanded products. Notably, metal-catalyzed carbene transfer does not proceed with aromatic benzothiazole but can efficiently engage its dearomatized intermediate through carbon atom insertion, enabling access to the same ring-expanded benzothiazine scaffolds with an expanded substrate scope. Mechanistic studies, including control experiments, isotope labeling, and DFT calculations, support the proposed pathways and clarify how scaffolds govern the distinct reactivity patterns. These findings highlight the complementary reactivity profiles of free and metal-bound carbenes and establish a structure- and activation-mode-guided platform for the selective functionalization of heteroaromatic systems.

Introduction

Achieving precise control over carbene reactivity toward electronically complex heteroarenes requires a fundamental understanding of how scaffold topology and activation mode shape divergent reaction pathways. In particular, the reactivity and selectivity of carbenes differ markedly depending on whether they are generated photochemically as free species or formed as metal-bound intermediates under transition-metal catalysis. The divergent mechanisms and coordination environments associated with these two modes lead to distinct reactivity profiles. , Transition-metal-catalyzed carbene transfer reactions, particularly those mediated by rhodium or copper complexes, have profoundly shaped modern synthetic methodology owing to their controlled reactivity and excellent selectivity (Scheme a). , These reactions typically exhibit excellent chemo-, regio-, and stereoselectivity owing to the well-defined nature of metal carbene intermediates and the tunability of catalyst-substrate interactions. However, despite these advances, metal-catalyzed carbene transfers often fail to activate certain electronically complex aromatic heterocycles, likely due to insufficient substrate coordination or an electronic mismatch with the metal-bound carbene.

1. Reactivity of Benzothiazole and Benzisothiazole in Photochemical and Metal-Catalyzed Carbene Transfer Reactions.

Visible-light-induced free carbene generation from diazo compounds offers an attractive metal-free alternative, featuring milder conditions, operational simplicity, and improved sustainability compared to conventional metal catalyzed protocols (Scheme a). , In such systems, the resulting free carbenes are highly reactive yet less controllable, operating independently of metal coordination. This enhanced reactivity is often accompanied by reduced stability and diminished control, making it particularly challenging to predict and control product selectivity. Notably, these characteristics present both opportunities and challenges in the selective functionalization of heterocycles that are structurally similar yet electronically distinct.

Despite the mechanistic and coordination differences between free and metal-bound carbenes, it remains unclear how subtle structural variations in heteroarene scaffolds affect their reactivity in different activation modes. In this context, benzothiazole and benzisothiazole offer an ideal comparative platform (Scheme b). , These regioisomeric heterocycles share the same elemental composition but differ in the spatial arrangement of the nitrogen and sulfur atoms. Such a seemingly minor structural distinction can significantly alter the electronic properties. Despite the prevalence of both scaffolds in medicinal chemistry and materials science, their reactivity under photochemical and metal-catalyzed carbene transfer conditions has not been systematically investigated. These structural nuances may enable access to distinct reactivity pathways and pose unique challenges in carbene chemistry, thereby motivating our comparative study. Related heteroaromatic frameworks such as benzothiophenes and benzoxazoles also display characteristic reactivity patterns in carbene transfer reactions. These precedents provide broader context for heteroarene skeletal editing and underscore how heteroatom identity and connectivity govern pathway selection.

Herein, we report a direct comparative study of benzothiazole and benzisothiazole under photochemical and metal-catalyzed carbene transfer conditions, revealing distinct reactivity profiles (Scheme c). Upon visible-light irradiation, benzothiazole undergoes sequential dearomatization via carbon-atom exchange with two equiv of free carbene, forming a benzothiazoline intermediate. This intermediate can engage a third carbene equivalent to furnish ring-expanded benzothiazine derivatives. Notably, no monocarbene insertion products are observed, underscoring the highly selective nature of this transformation. In contrast, benzothiazole remains inert under standard rhodium- or copper-catalyzed carbene transfer conditions. However, the photogenerated benzothiazoline intermediate can undergo efficient ring expansion under metal-catalyzed conditions, which tolerate a broader diazo substrate scope. These findings highlight the mechanistic complementarity between free and metal-bound carbenes, each offering unique advantages in different stages of the transformation.

Conversely, benzisothiazole reacts with 1 equiv of photochemically generated free carbene to afford ring-expanded products. This behavior exhibits similar reactivity to that previously reported under metal catalysis, albeit through a distinct carbene generation pathway. Attempts to promote further carbene insertion under photochemical conditions led to only trace amounts of complex product mixtures, which proved to be difficult to isolate and characterize, suggesting a high sensitivity to subtle structural and electronic variations.

Taken together, these findings demonstrate that even minor structural differences between heterocycles can profoundly alter the carbene reactivity and selectivity. By delineating the distinct and complementary roles of photochemical and metal-catalyzed carbene transfer, this work offers new mechanistic insights and synthetic strategies for the selective functionalization of complex aromatic systems. Additionally, despite the growing interest in skeletal editing as a powerful approach to molecular diversification, , strategies for the selective remodeling of benzothiazole and benzisothiazole frameworks remain scarce, underscoring the untapped potential of these privileged heterocycles for scaffold reprogramming.

Results and Discussion

Our investigation began by evaluating the reactivity of benzothiazole 1 toward photochemically generated free carbenes. Upon visible-light irradiation of aryl diazoacetates 2 in the presence of 1, we observed the formation of both carbon-atom exchange product 3 and ring-expanded product 4 in DCM (Table , entry 1). Solvent screening revealed a pronounced effect on reactivity: whereas chlorinated solvents (DCM and DCE) promoted both carbon-atom exchange product 3 and ring-expanded product 4, polar solvents such as MeCN, THF, DMF, and DMSO were ineffective, resulting in either trace or undetectable product formation (entries 2–3). Increasing the equivalents of diazo compound significantly influenced the product distribution. Using 6 equiv of aryl diazoacetates 2 led to a higher isolated yield of 3 (68%) with modest formation of 4 (entry 4). Remarkably, when 9 equiv of 2 were added in three batches over an extended reaction time (48 h), selective formation of 4 was achieved in 89% yield and 1:1 diastereomeric ratio (entry 5), with 3 detected only in trace amounts. These findings suggest that stoichiometric control of the diazo compounds directly modulates the chemoselectivity between the carbon atom exchange and insertion pathways.

1. Optimization of Reaction Conditions .

Entry	Solvent	Ratio of 1:2	Yield of 3 (%)	Yield of 4 (%) ,
1	DCM	1:4	34	35
2	MeCN/THF	1:4	Trace	Trace
3	DMF/DMSO	1:4	N.D.	N.D.
4	DCM	1:6	68	29
5	DCM	1:9	Trace	89

^aReaction performed with 1 (0.2 mmol), 2 (0.8 to 1.8 mmol) in dry solvent (1.0 mL) at room temperature with 24 W blue LEDs for 12 h.

^bIsolated yields.

^cAdd 2 (1.8 mmol; added in three portions of 0.6 mmol each, total 9 equiv relative to 1) into the reaction solution in three batches and extend the reaction time to 48 h.

^dWith 1:1 d.r.; N.D = not detected.

With the optimized photochemical reaction conditions in hand, we next explored the substrate scope of the carbon-atom exchange reaction (Table ). Aryl diazoacetates bearing various substituents at the meta or para positions, including electron-donating groups (−Me) and electron-withdrawing groups (-F, -Cl, -Br), were well-tolerated, furnishing benzothiazoline derivatives 5-10 in moderate to good yields (47–64%). The structure of compound 6 was unambiguously confirmed by single-crystal X-ray diffraction analysis (CCDC 2356779). Notably, methyl 2-diazo-2-(naphthalen-2-yl)­acetate also underwent smooth conversion to give compound 11 in 71% yield. Variation of the ester moiety further highlighted the reaction’s functional group tolerance. Ethyl, n-hexyl, isopropyl, and allyl diazoacetates all reacted successfully, affording the corresponding products 12-15 in 54–66% yields. Importantly, the protocol proved to be applicable to the late-stage functionalization of structurally complex molecules. Aryl diazoacetates derived from natural products such as citronellol and oleyl alcohol smoothly engaged in the transformation, delivering products 16 and 17 in synthetically useful yields. These results underscore the broad applicability and robustness of the atom-exchange process, enabling the construction of structurally diverse benzothiazoline frameworks under mild, metal-free conditions.

2. Scope of Carbon Atom Exchange Reaction ^,

^aReaction conditions: in an oven-dried Schlenk flask, benzothiazoles (1.0 equiv., 0.2 mmol) and diazo compound (6.0 equiv., 1.2 mmol) were dissolved in the DCM and irradiated with 24 W blue light at room temperature for 12 h.

^bIsolated yield.

We then examined the influence of electronic and steric effects on the benzothiazole scaffold. Substituents at the C5 and C6 positions, including both electron-donating (-Me, -OMe) and electron-withdrawing (-F, -Cl, −CO₂Me) groups, were well-accommodated, affording products 18-24 in moderate yields (34–51%). Moreover, structurally extended and drug-relevant heterocycles, such as naphtho­[1,2-d]­thiazole 25 and an ibuprofen-conjugated benzothiazole derivative 26, were also competent substrates under the standard conditions, further highlighting the synthetic versatility of the method and its potential utility in medicinal chemistry and materials science. In contrast, heteroarenes lacking a benzothiazole core exhibited significantly reduced reactivity. Thiazole 27, benzofuran, and other related scaffolds failed to undergo any detectable transformation under otherwise identical conditions. The inability of benzofuran to participate suggests that the unique sulfur–nitrogen motif in benzothiazole plays a critical role in stabilizing the zwitterionic ylide intermediates proposed in the mechanistic pathway. Finally, attempts to employ structurally distinct classes of diazo compounds, including acceptor-only, aryl/aryl, and acceptor/acceptor diazoalkanes, did not yield any desired products.

Encouraged by the efficiency of the carbon-atom exchange process, we next turned our attention to the synthesis of benzothiazine derivatives via a carbon atom insertion reaction. Using 9 equiv of aryl diazoacetates and extending the reaction time to 48 h enabled direct ring expansion of benzothiazole 1 under visible light irradiation, providing benzothiazine products 28-40 in moderate to excellent yields (53–94%) with an average diastereomeric ratio of 1:1 (Table ). A variety of aryl diazoacetates bearing electron-donating (-Me) or electron-withdrawing (-F, -Br) groups on the aromatic ring participated readily in the transformation, affording products 28-30 in 61–78% yield. The reaction also tolerated a broad range of ester groups. Primary, secondary, and cyclic esters (including isopropyl and cyclopentyl) were efficiently incorporated, yielding products 31-33 in 62–68% yield. The transformation also proved to be effective for more structurally complex benzothiazole derivatives. Substituents at the C6 position such as -Me, -F, -Cl, -Br, and −CF₃ were all compatible, delivering products 34-38 in 53–94% yield. The structure of product 35 was unambiguously confirmed by single-crystal X-ray diffraction (CCDC codes 2355364 and 2355053). The method enabled the efficient functionalization of fused heterocycles like naphtho­[1,2-d]­thiazole 39, which underwent ring expansion under the standard conditions to give the desired product in a high yield. Additionally, the nerol-derived benzothiazole 40, featuring a branched aliphatic side chain, was efficiently transformed into the corresponding benzothiazine, underscoring the compatibility of the protocol with structurally complex and functionally rich substrates. Consistent with the findings from the carbon-atom exchange series, aryl diazoacetates were the only effective class of carbene precursors under these photochemical conditions. Attempts to use acceptor-only, aryl/aryl, or acceptor/acceptor diazoalkanes failed to deliver any isolable products. These results reinforce the privileged role of aryl diazoacetates in generating reactive free carbenes suitable for insertion into benzothiazoline intermediates.

3. Scope of Carbon Atom Insertion Reaction ^,

^aReaction conditions: benzothiazoles (1.0 equiv., 0.2 mmol) and diazo compound (9.0 equiv., 1.8 mmol) were dissolved in the DCM and irradiated with 24 W blue light at room temperature for 48 h.

^bIsolated yield.

To assess the practicality and scalability of this photochemical carbene transfer strategy, we conducted continuous-flow reactions under visible-light irradiation (Scheme a). Both the carbon-atom exchange and insertion pathways proceeded efficiently on the gram scale, providing yields comparable to those obtained under batch conditions. These results validate the operational robustness of the method and its potential for a preparative-scale synthesis. We then turned our attention to the mechanistic distinction between photochemically generated free carbenes and transition-metal-bound carbenes. As shown in Scheme b, treatment of benzothiazole 1 under standard rhodium- or copper-catalyzed carbene transfer conditions did not afford either the carbon-atom exchange product 3 or the carbon-atom insertion product 4. This lack of reactivity is likely due to the inherent electronic mismatch and limited coordination ability of the aromatic NC–S framework, which lacks a strongly nucleophilic donor site to effectively engage the electrophilic metal-carbene species. In striking contrast, when dearomatized intermediate 3 was employed as the substrate under identical metal-catalyzed conditions, ring-expanded product 4 was readily obtained. These observations indicate that while metal-catalyzed carbene transfer reactions are unreactive toward benzothiazole 1, they proceed efficiently with the preactivated, nonaromatic intermediate 3, affording the ring-expanded product 4.

2. Gram-Scale Reaction in Continuous Flow and Differentiation between Free and Metal Carbenes.

Building on the reactivity of intermediate 3, we further evaluated the substrate scope for both photochemical and metal-catalyzed carbene insertion into this dearomatized scaffold (Table ). Under photochemical conditions, a broad range of aryl diazoacetates participated smoothly in the transformation, delivering unsymmetrically substituted benzothiazines 41-53 in 78–94% yield with an average diastereomeric ratio of 1:1. Substrates bearing electron-donating (-Me, -Ph) and electron-withdrawing (-F, -Cl, and -Br) groups on the aryl ring were well-tolerated. Variations in the ester moiety were also compatible with the transformation. Linear, branched, cyclic, alkenyl, and alkynyl esters each afforded the corresponding products in high yield, and the resulting diastereomers were readily separable. The absolute configuration of compound 43 isomer II, obtained from a C6-substituted benzothiazole, was confirmed by single-crystal X-ray diffraction (CCDC 2355051). In contrast to the limited diazo scope observed under photochemical conditions, rhodium-catalyzed insertion of carbene into intermediate 3 significantly expanded the substrate scope. Under Rh₂(OAc)₄ catalysis, not only aryl diazoacetates but also acceptor/acceptor diazo compounds and vinyldiazo reagents underwent efficient insertion, furnishing products 54-59 in excellent yields. These results clearly demonstrate that the metal-bound carbene platform is better suited to structurally diverse diazo reagents. Taken together, these findings emphasize the orthogonal reactivity profiles of photochemically generated free carbenes and metal-bound carbenes. While photochemical conditions uniquely enable activation of benzothiazole by overcoming electronic and coordination barriers that render it inert to metal carbenes, they exhibit a more limited substrate scope in the subsequent carbon-atom insertion stage. Conversely, metal catalysis cannot initiate reactivity from the benzothiazole starting material, but once the dearomatized intermediate 3 is generated, it enables broad functionalization with structurally diverse diazo reagents. This divergence highlights a modular strategy in which free and metal-bound carbenes act in sequence to accomplish transformations that are inaccessible to either mode alone.

4. Carbon Atom Insertion of Dihydrobenzothiazole 3 ^,

^aPhotochemical reaction conditions: benzothiazoles (1.0 equiv., 0.2 mmol) and diazo compound (3.0 equiv., 0.6 mmol) were dissolved in the DCM and irradiated with 24 W blue light at room temperature for 24 h. Rhodium-catalyzed reaction conditions: benzothiazoles (1.0 equiv., 0.2 mmol), diazo compound (3.0 equiv., 0.6 mmol), and Rh₂(OAc)₄ (10 mol %, 0.02 mmol) were dissolved in the DCM and stirred at room temperature for 12 h.

^bIsolated yield.

To gain deeper insight into the mechanism underlying the benzothiazole to benzothiazine transformation, we performed a series of control experiments, isotopic labeling studies, and DFT calculations (Scheme ). The results from the control experiment and radical capture experiment suggest that both the carbon atom exchange process and the carbon atom insertion process are dependent on visible light irradiation and likely do not involve radical intermediates (Scheme a). We then performed labeling experiments to deeply understand the carbon atom exchange process. Reaction of D-benzothiazole 1 with aryl diazoacetate 2 under the standard conditions led to the formation of D-3 in 51% yield, where the hydrogen atom attached to the alkene moiety in product 3 was derived from benzothiazole (Scheme b). The ¹³C-labeling experiment result further confirmed that the C2-atom of benzothiazole had indeed exchanged with aryl diazoacetates in this carbon atom insertion step (Scheme c).

3. Mechanistic Investigations and DFT Calculation.

To gain a deeper understanding of the mechanism at the molecular level, density functional theory (DFT) calculations were conducted for the model reaction of benzothiazole 1 and methyl 2-diazo-2-phenylacetate 2 at the M06–2X/6–311+G­(d,p)­(SMD, DCM)//M06–2X/6–31G­(d) level (Scheme d). Starting with 1, the free carbene species A, generated in situ through photolysis of 2 under visible light irradiation, , is readily trapped by the nitrogen atom of 1 through transition state TS1 (ΔG ^‡ = 8.9 kcal mol^–1), resulting in the formation of the nitrogen ylide intermediate B. This process is significantly exothermic by −34.2 kcal mol^–1. Subsequently, due to the nucleophilic nature of the sulfur atom in intermediate B, another free carbene molecule A is rapidly trapped via TS2, forming bis-ylide intermediate C. Rearrangement of C through TS3 (ΔG ^‡ = 16.5 kcal mol^–1) then yields the more stable six-membered intermediate D. DFT calculations suggest that the C–S bond in intermediate D can cleave through TS4 with a moderate energy barrier (ΔG ^‡ = 21.7 kcal mol^–1), resulting in ring opening and formation of zwitterionic intermediate E. Subsequently, driven by thermodynamic forces, the experimentally observed product 3 can be obtained through intramolecular cyclization (C–S bond formation). Moreover, in the presence of excess free carbene, product 3 can further serve as a carbene capture reagent through its nucleophilic sulfur atom, forming sulfur ylide F with an energy barrier of 10.1 kcal mol^–1. Subsequent C–S bond cleavage and intramolecular cyclization (C–C bond formation) of sulfur ylide F ultimately yield the desired ring expansion product 4. The energy barriers for transition states TS1 (ΔG ^‡ = 8.9 kcal mol^–1) and TS6 (ΔG ^‡ = 10.1 kcal mol^–1) are quite similar, indicating that once the initial carbon atom exchange product is formed, it can readily react with additional carbene to form the subsequent carbon atom insertion product. This facile reaction pathway likely contributes to the lower yields observed in some cases in Table , as the system may preferentially proceed through carbon atom insertion rather than stopping at the carbon atom exchange stage. For clarity, a simplified schematic outlining the overall multicarbene pathway is provided in the Supporting Information.

To further elucidate the scaffold-dependent reactivity of free carbenes, we investigated the transformation of benzisothiazole, a regioisomer of benzothiazole differing only in the connectivity of the nitrogen and sulfur atoms. Under otherwise identical photochemical conditions, benzisothiazole exhibited a fundamentally distinct reactivity profile. Instead of undergoing sequential multicarbene insertions, as observed for benzothiazole, it selectively afforded the monocarbene insertion product 61 in 66% isolated yield (Scheme a). Interestingly, this selective behavior mirrors the reactivity previously reported under rhodium-catalyzed conditions, highlighting that while the overall reactivity resembles that of benzothiazole, the distinct sulfur–nitrogen arrangement in benzisothiazole may subtly influence its interaction with carbene species. Optimization studies identified DCM as the optimal solvent, with 2.5 equiv of benzisothiazole and 3 h of visible-light irradiation providing the highest yield. Shorter reaction times resulted in incomplete conversion, whereas extended irradiation or excess diazo reagent led to diminished yields due to nonselective background overinsertion and formation of complex mixtures. These observations suggest that monocarbene insertion is kinetically favored, while further insertions occur only under forcing or uncontrolled conditions. In contrast, benzothiazole did not yield any monocarbene insertion product under comparable conditions, instead producing only di- and tri-insertion adducts. This stark divergence underscores how subtle differences in heteroatoms can dramatically alter reactivity and selectivity in carbene transfer reactions, even between closely related heterocyclic scaffolds.

4. Carbon Atom Insertion of Benzisothiazole with Free Carbene.

Encouraged by the observed monocarbene insertion selectivity, we next explored the scope of diazo compounds compatible with this transformation (Scheme b). A variety of aryl diazoacetates bearing electron-donating or electron-withdrawing substituents on the aromatic ring were well-tolerated, affording products 62-67 in moderate to good yields (45–68%). The reaction also accommodated extended 1,3-benzodioxole (68, 77%) and naphthalene (69, 65%), which underwent smooth conversion to the corresponding spirocyclic product, albeit in a slightly reduced yield. Furthermore, diazo compounds derived from complex molecules such as L-menthol (70, 61%), cholesterol (71, 57%), and gemfibrozil (72, 60%) also participated efficiently, affording ring-expanded products under standard conditions. Interestingly, this strategy was also applicable to 9-diazo-9H-fluorene, delivering the monocarbene spirocyclic product 73 in 23% yield, albeit with lower efficiency compared to aryl diazoacetates. In contrast, acceptor-only and acceptor-acceptor type diazoalkanes failed to provide isolable products. This limited reactivity is likely attributable to their lower efficiency in generating reactive free carbenes under photochemical conditions as well as their reduced compatibility with the electronic environment of benzisothiazole.

To further elucidate the origin of scaffold-dependent reactivity, we performed DFT calculations on the reaction of benzisothiazole 60 with photochemically generated free carbene A (Scheme c). Similar to benzothiazole 1, the carbene preferentially engages the nitrogen atom, forming nitrogen ylide intermediate H via transition state TS8 (ΔG ^‡ = 9.9 kcal mol^–1), accompanied by significant exergonicity (ΔG = −32.5 kcal mol^–1). In contrast to the benzothiazole system, however, intermediate H undergoes highly facile N–S bond cleavage through TS9 (ΔG ^‡ = 3.6 kcal mol^–1), generating ring-opening species I. Intramolecular cyclization via C–S bond formation then furnishes the experimentally observed monocarbene insertion product 62. Notably, attempts to locate an alternative pathway involving the initial addition of carbene to the sulfur atom of 60 did not converge to a stable ring-opening intermediate, suggesting a strong kinetic preference for nitrogen attack.

These computational findings align well with the experimental outcomes and reveal a mechanistic divergence in carbene transfer reactions, rooted in the distinct atomic connectivities of benzothiazole and benzisothiazole. The distinct reactivity of benzisothiazole likely arises from its direct N–S connectivity, which generates a polarized electronic environment that facilitates N–S bond cleavage, following nitrogen ylide formation. The resulting ring-opened intermediate then undergoes efficient intramolecular cyclization to deliver the monocarbene insertion product. In contrast, benzothiazole does not exhibit this selectivity and instead follows a sequential multicarbene pathway. The nitrogen ylide initially formed rapidly captures a second carbene at the sulfur atom, affording a stabilized bis-ylide intermediate. This step proceeds with a low energy barrier and occurs readily under the reaction conditions. Subsequent rearrangement of the bis-ylide furnishes the carbon-atom exchange product. Notably, this intermediate can further engage a third free carbene at the sulfur center, generating a sulfur ylide that undergoes ring expansion to afford the thermodynamically favored six-membered ring-expanded product. This scaffold-dependent divergence in reactivity illustrates how subtle differences in atomic connectivity and electronic polarization can decisively alter the carbene reaction trajectories. These insights offer a guiding principle for the rational design of regioselective heteroarene functionalization via carbene transfer chemistry.

Conclusion

In conclusion, this study reveals a scaffold-specific divergence in carbene transfer reactivity governed by the distinct atomic connectivity of benzothiazole and benzisothiazole. Through a combination of photochemical and metal-catalyzed approaches, we demonstrate that subtle differences in the N/S arrangement can fundamentally alter reaction pathways, enabling orthogonal reactivity modes for closely related heterocycles. Under visible-light conditions, benzothiazole undergoes a stepwise, multicarbene transformation sequence involving carbon-atom exchange and ring expansion. In contrast, benzisothiazole engages in a highly selective monocarbene insertion. Mechanistic investigations, supported by isotope labeling and DFT analysis, indicate that this divergence stems from scaffold-specific electronic polarization. The N–S connectivity in benzisothiazole promotes rapid ylide fragmentation and single carbene insertion, while the less-polarized NC–S framework in benzothiazole facilitates sequential carbene trapping and rearrangement. Furthermore, although benzothiazole is inert to metal-catalyzed carbene transfer, its photogenerated carbon-atom exchange intermediate can participate in subsequent metal-mediated carbene insertion, thus expanding the diazo substrate scope. This modular sequence illustrates the complementary roles of free and metal-bound carbenes in enabling transformations otherwise inaccessible through either activation mode alone. Collectively, these findings establish a strategic framework for controlling carbene transfer reactions through scaffold engineering and activation-mode pairing. By decoding the structure–reactivity relationship across heteroarene classes, this work paves the way for the rational design of site- and pathway-selective carbene functionalization strategies in complex molecular settings.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01282.

• Full experimental data for the compounds described in the paper, details of the theoretical calculations (PDF)

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(B.-G.C., X.T.) These authors contributed equally. CRediT: Ningjie Xu data curation, formal analysis, writing - original draft.

The authors declare no competing financial interest.