Ring‐Opening Chlorination and Bromination of Pyrazolopyridines and Isoxazoles

Abstract

We report the development of electrophilic ring‐opening chlorination and bromination reactions of pyrazoloazines and isoxazoles using chlorinating and brominating agents. These transformations proceed via selective cleavage of heteroaromatic N─N or N─O bonds, delivering structurally diverse tertiary halogenated compounds. Furthermore, treatment of formylated pyrazolopyridines with two equivalents of chlorinating or brominating agents afforded dihalogenated products in good yields. This strategy represents a valuable platform for constructing halogenated scaffolds from simple heteroaromatic precursors and broadens the synthetic utility of skeletal transformations in the functionalization of heteroaromatics.

We report electrophilic ring‐opening halogenation of pyrazolopyridines and isoxazoles. Selective cleavage of C─N or N─O bonds enables the synthesis of tertiary chlorinated and brominated compounds under mild conditions.

1. Introduction

Halogenated compounds are indispensable synthetic intermediates in organic chemistry, owing to their versatility in cross‐coupling and other downstream functionalization reactions. A wide variety of C─X (X = Cl, Br, I, F) bonds serve as reliable handles for metal‐catalyzed transformations such as Suzuki–Miyaura, Buchwald–Hartwig, and Ullmann couplings, and for radical reactions, nucleophilic substitutions, and photoredox catalysis in the case of alkyl halides, enabling the rapid construction of diverse molecular architectures.^{[ 1 ]} In addition to their synthetic utility, halogenated structures are also frequently found in natural products, agrochemicals, and pharmaceuticals, where the presence of halogen atoms can significantly influence biological activity and physicochemical properties.^{[ 2 ]} Consequently, the development of efficient, selective, and broadly applicable halogenation methods has been a long‐standing central theme in synthetic methodology.^{[ 3} , ^{4 ]}

Ring‐opening halogenation reactions offer a powerful approach to introduce halogens while simultaneously reorganizing molecular skeletons, providing access to novel scaffolds beyond conventional substitution strategies (Figure 1a).^{[ 5} , ^{6 ]} While a wide range of ring‐opening halogenations of aliphatic (hetero)cycles—including not only highly strained small rings but also five‐ and six‐membered rings— have been reported, however, analogous transformations of (hetero)aromatic systems remain much less developed, largely due to the inherent stability and aromatic character of these substrates. As pioneering and elegant examples addressing this challenge, Yorimitsu and coworkers achieved cleavage of the C─O bond in benzofurans via a Ni‐catalyzed boron insertion reaction, followed by iodine treatment to realize ring‐opening iodination, affording iodoalkenes.^{[ 7 ]} In another specialized case, bromination of aromatic cyclopropenones coupled with tetrahydrofuran derivatives using CuBr enabled successful ring‐opening bromination.^{[ 8 ]} In addition, we previously reported electrophilic fluorination followed by deprotonative cleavage of N─N or N─O bond in pyrazolopyridines and isoxazoles, achieving selective ring‐opening fluorination.^{[ 9 ]} Additionally, Paton and McNally advanced the classical Zincke reaction by developing a strategy for selective halogenation of pyridines through a sequence of ring‐opening, halogenation, and ring‐closing processes.^{[ 10 ]} More recently, Ye and coworkers reported an electrochemical method for difluorination of furans, expanding the scope of ring‐opening halogenation through a redox‐driven approach.^{[ 11 ]}

Figure 1.

a) Ring‐opening Halogenation b) Ring‐Opening Fluorination and Difluorination of Pyrazolopyridines and Isoxazoles c) Ring‐Opening Chlorination/Bromination of Heteroaromatics.

In our previous studies on the fluorination of pyrazolopyridines and isoxazoles, upon treatment with Selectfluor, these substrates underwent initial electrophilic fluorination, followed by deprotonation at the C2 or C3 positions, promoting selective cleavage of the heterocyclic rings (Figure 1b). Notably, the resulting products were not merely fluorinated aromatics but newly generated tertiary fluorides, representing a new fluorination paradigm based on skeletal transformation rather than classical substitution chemistry. Building upon this strategy, we recently expanded the scope to a ring‐opening difluorination of pyrazoloazines.^{[ 12 ]} Treatment of pyrazoloazine derivatives bearing unsubstituted or formyl groups at the C3 position with increased amounts of Selectfluor led to the corresponding difluorinated products in good yields.

Given this background, we hypothesized that extending the concept of our electrophilic ring‐opening fluorination to other halogens beyond fluorine could provide a general and modular strategy for skeletal transformations involving heteroaromatic ring cleavage. Specifically, we envisioned that treatment of heteroaromatic systems with electrophilic chlorinating and brominating agents would enable the direct construction of valuable ring‐opened halogenated products under mild conditions, thereby greatly expanding the synthetic utility of this emerging class of transformations. Notably, because chlorinating and brominating agents are generally less electrophilic and less oxidizing than fluorinating reagents, their application to ring‐opening transformations presents unique challenges in terms of reactivity and selectivity. Therefore, this study represents not a mere extension of our previous work but an independently significant development in the broader context of halogen‐mediated skeletal transformation. Herein, we report a general strategy for ring‐opening halogenation of heteroaromatic compounds through electrophilic halogenation followed by skeletal rearrangement. By employing pyrazolopyridines and isoxazoles as representative substrates, we demonstrate that simple treatment with electrophilic chlorinating or brominating reagents under mild conditions leads to efficient ring cleavage and the formation of valuable halogenated products (Figure 1c).

2. Results and Discussion

2.1. Optimization of Ring‐Opening Bromination and Chlorination for Pyrazolopyridines

We first investigated the electrophilic chlorination of pyrazolopyridine derivatives under conditions similar to those previously established for ring‐opening fluorination (Table 1).^{[ 9 ]} When pyrazolopyridine 1A was treated with N‐chlorosuccinimide (NCS, 1.0 equiv) in acetonitrile at 60 °C, the desired ring‐opened chlorinated product 2A was obtained in 21% yield, along with the recovery of unreacted 1A (5%) and formation of an imide byproduct (33%) via C2‐functionalization (Entry 1). Since the ring‐opening reaction proceeded with only the chlorinating agent without the addition of any external base, this suggests that the imide may have acted as a base. Lowering the reaction temperature to ambient conditions resulted in a more complex reaction profile, without any improvement in either the suppression of byproduct formation or the yield of 2A (Entry 2). Alternative chlorinating agents, including 1,3‐dichloro‐5,5‐dimethylhydantoin (DCDMH, Entry 3),^{[ 13 ]} trichloroisocyanuric acid (TCCA, Entry 4),^{[ 14 ]} and N‐chlorosaccharin,^{[ 15 ]} were also examined but proved ineffective for the formation of 2A (Entry 5). The formation of the imide byproduct was presumed to proceed via a radical pathway. In support of this hypothesis, the addition of the radical scavenger BHT (5.0 mol%) slightly improved the yield of 2A (Entry 6). Notably, switching the solvent to hexafluoroisopropanol (HFIP) dramatically improved the yield of 2A to 59% and simultaneously suppressed imide formation. (Entry 7).^{[ 15 ]} In this case, an addition of BHT had no additional benefit (Entry 8). Moreover, the reaction proceeded efficiently at room temperature in HFIP, affording 2A in 65% yield under otherwise identical conditions (Entry 9).

Table 1.

Screening of the reaction conditions.

Entry	Reagent /equiv	Solvent	BHT /mol%	Temp /°C	Recovery of 1A /% [a]	Yield of 2A or 3A /% [a]	Yield of imide /% [a]
1	NCS/1.0	MeCN	0	60	5	21	33
2	NCS/1.0	MeCN	0	RT	13	4	42
3	DCDMH/1.0	MeCN	0	RT	4	0	–
4	TCCA/1.0	MeCN	0	RT	0	0	–
5	N‐Chlorosaccharin/1.0	MeCN	0	RT	18	2	–
6	NCS/1.0	MeCN	5.0	60	0	32	30
7	NCS/1.0	HFIP	5.0	60	0	59	0
8	NCS/1.0	HFIP	0	60	0	66	0
9	NCS/1.0	HFIP	0	RT	0	65	0
10	NBS /1.0	MeCN	0	RT	24	0	49
11	NBS/1.0	HFIP	0	RT	23	15	26
12	NBS/1.4	HFIP	5.0	RT	22	19	35
13	N‐Bromosaccharin/1.4	HFIP	5.0	RT	49	3	0
14	DBDMH/0.7	HFIP	5.0	RT	22	36	0
15	NBPI/1.4	HFIP	5.0	RT	0	15	28 [b]
16	DBI/0.7	HFIP	5.0	RT	0	57	0

^[a] Yields were determined by 1H NMR using CH₂Br₂ as an internal standard.

^[b] Phthalimide adduct was obtained instead of imide.

Subsequently, we turned our attention to the bromination of 1A. Treatment of 1A with N‐bromosuccinimide (NBS) in acetonitrile at room temperature predominantly afforded the imide byproduct (49%), with 24% recovery of the starting material; the desired ring‐opened brominated product 3A was not detected (Entry 10). Upon switching the solvent to HFIP, 3A was successfully obtained, albeit in low yield (15%, Entry 11).^{[ 16 ]} Increasing the amount of NBS to 1.4 equivalents and adding BHT resulted in a slight improvement in yield (Entry 12). Although the BHT effect is less evident in HFIP, it was still included for consistency. Screening of alternative brominating agents revealed that N‐bromosaccharin gave inferior yields,^{[ 17 ]} whereas 1,3‐dibromo‐5,5‐dimethylhydantoin (DBDMH) significantly enhanced the yield of 3A (Entries 13 and 14).^{[ 18 ]} N‐bromophthalimide (NBPI) afforded comparable results to NBS, accompanied by the formation of a phthalimide byproduct (Entry 15). Ultimately, the use of dibromoisocyanuric acid (DBI) provided the best result, delivering 3A in 57% yield (Entry 16),^{[ 19 ]} which represents the most effective bromination conditions identified.

2.2. Substrate Scope for Ring‐Opening Chlorination and Bromination of Pyrazolopyridines

Having established optimal conditions for both chlorination and bromination reactions, we next explored the substrate scope for pyrazolopyridine derivatives (Figure 2). For chlorination, pyrazolopyridines 1 were treated with NCS (1.0 equiv) in HFIP at room temperature for 24 hours. Substrates bearing an aryl group in place of the ester group, such as 1B and 1C, underwent smooth ring‐opening chlorination to afford the corresponding products 2B and 2C. Pivalate (1D), alkyl (1E), and ethoxy (1F) derivatives also reacted to give 2D–2F in moderate yields. Notably, 2D partially decomposed during purification, resulting in a lower isolated yield. In the case of 1G, bearing a tosyl group directly attached to the pyrazolopyridine core, the corresponding product 2G was obtained. When NCS was used, more than 40% of 1G remained unreacted; however, switching to TCCA led to complete consumption of 1G, and the reaction proceeded smoothly to give 2G in excellent yield. To assess the site‐selectivity between the pyrazolopyridine core and an electron‐rich aromatic ring, substrate 1H, bearing an electron‐rich arene, was subjected to the standard conditions. The chlorination selectively occurred at the pyrazolopyridine moiety, affording 2H, and no chlorination product at the aromatic ring was detected. In contrast, substrate 1I bearing an acetal group led to a complex reaction mixture, and the chlorinated product 3I was isolated in low yield.

Figure 2.

Substrate Scope. Reaction conditions for chlorination: 1 (0.1 mmol), NCS (0.1 mmol), HFIP (0.5 mL), RT, 24 hours. Reaction conditions for bromination: 1 (0.1 mmol), DBI (0.07 mmol), BHT (5.0 mol%), HFIP (0.5 mL), RT, 24 hours. ^aReaction performed at 60 °C. ^bTCCA (0.60 equiv) was used instead of NCS (1.0 equiv).

We then applied the optimized bromination conditions to these substrates. Bromination was performed with DBI (0.7 equiv) in HFIP in the presence of BHT (5 mol%) at room temperature for 24 hours. Similar to the chlorination reactions, substrates bearing aryl groups afforded the corresponding ring‐opened brominated products 3B and 3C in moderate yields, and no brominated aromatic products were observed. Substrates with pivalate (1D), alkyl (1E), and ethoxy (1F) groups also underwent the bromination reaction, furnishing 3D–3F in moderate yields. As with the chlorination reactions, the tosyl‐substituted substrate gave the desired product in high yield. These results suggest that substrates bearing electron‐withdrawing groups favor the desired transformations, likely because the ring‐opening of the intermediate proceeds more efficiently than the electrophilic halogenation step. Interestingly, treatment of bis‐pyrazolopyridine substrate 1J, which was prepared by dimerization of the corresponding monomer according to Itami's method,^{[ 20 ]} under the bromination conditions furnished a unique bipyridine derivative 3J. This result demonstrates the synthetic potential of this method for accessing various bipyridine scaffolds via further functionalization.

2.3. Optimization of Ring‐Opening Chlorination and Bromination for Isoxazoles

Next, we investigated the ring‐opening halogenation of isoxazole derivatives (Table 2). We first examined the ring‐opening chlorination of isoxazole 4B. Treatment of 4B with NCS (1.0 equiv) in acetonitrile at 60 °C for 24 hours afforded the desired chloroketone 5B in 90% yield (Entry 1). Screening of alternative chlorinating agents revealed that DCDMH, N‐chlorosaccharin, and TCCA also afforded 5B in quantitative to high yields (Entries 2–4). Among these, TCCA proved to be the most efficient, completing the reaction within 5 minutes to quantitatively afford 5B (Entry 4). Thus, TCCA was identified as the optimal chlorinating agent for the ring‐opening transformation. Furthermore, although the reaction at room temperature required extended reaction times, increasing the amount of TCCA slightly enabled efficient conversion, delivering 5B in 96% yield (Entry 5). These results demonstrate that, in addition to pyrazolopyridines, isoxazoles exhibit high reactivity under the developed ring‐opening halogenation conditions.

Table 2.

Screening of the reaction conditions.

Entry	Isoxazole	Reagent /equiv	Solvent	BHT /mol%	Temp /°C	Time /h	Yield of 5 or 6 /% [a]	Yield of byproducts /% [a]
1	4B	NCS/1.0	MeCN	0	60	24	90	–
2	4B	DCDMH/0.6	MeCN	0	60	4	quant.	–
3	4B	N‐Chlorosaccharin/1.0	MeCN	0	60	5 minutes	93	–
4	4B	TCCA/0.4	MeCN	0	60	5 minutes	quant.	–
5	4B	TCCA/0.6	MeCN	0	RT	24	96	–
6	4B	NBS/1.0	MeCN	0	60	24	0	13 (compound 7)
7	4B	NBS/1.0	HFIP	0	RT	24	57	3 (compound 7)
8	4B	NBS/1.0	HFIP	5.0	RT	24	69	0
9	4B	NBS/1.4	HFIP	5.0	RT	24	99	0
10	4G	NBS/1.4	HFIP	5.0	RT	24	28	23 (compound 8)
11	4G	NBPI/1.4	HFIP	5.0	RT	24	39	44 (compound 8)
12	4G	N‐Bromosaccharin/1.4	HFIP	5.0	RT	24	91	0
13	4G	DBDMH/0.7	HFIP	5.0	RT	24	56	22 (compound 8)
14	4G	DBI/0.7	HFIP	5.0	RT	0	quant.	0

^[a] Yields were determined by ¹H NMR using CH₂Br₂ as an internal standard.

Subsequently, we explored the bromination of isoxazoles. Treatment of 4B with NBS in acetonitrile at 60 °C resulted in a complex mixture, and the desired ring‐opened brominated product 6B was not obtained. Instead, a side product, 7, resulting from bromination of the methyl group, was isolated in 13% yield (Entry 6). When the solvent was switched to HFIP, the desired product 6B was obtained in 57% yield, although a small amount of side product 7 was still detected (Entry 7). This observation suggests the involvement of bromine radicals in the side reactions. Accordingly, the addition of BHT as a radical scavenger improved the yield and completely suppressed the formation of the side product (Entry 8). Furthermore, increasing the amount of NBS to 1.4 equivalents led to a dramatic improvement, affording 6B in 99% yield (Entry 9).

However, when the substrate was changed from 4B to 4G, the reaction proceeded with lower efficiency, furnishing 6G in only 28% yield (Entry 10). Careful analysis of the reaction mixture revealed that a substantial amount of intermediate 8 (23% yield) was formed. To address this issue, we investigated alternative brominating agents. It was found that both the product distribution (between the ring‐opened product and intermediate) and the overall conversion varied depending on the brominating agent employed. For instance, use of NBPI improved the yield of 6G to 39%, but also resulted in significant formation of the intermediate 8 (44% yield, Entry 11). In contrast, N‐bromosaccharin provided 6G in a dramatically improved yield of 91% without the formation of the intermediate (Entry 12). Use of DBDMH afforded both the ring‐opened product 6G and the intermediate 8 (Entry 13). Ultimately, DBI was identified as the optimal brominating agent, delivering 6G quantitatively and selectively, indicating efficient bromination and ring‐opening (Entry 14).

2.4. Substrate Scope for Ring‐Opening Chlorination and Bromination of Isoxazoles

Using the optimized conditions, we next explored the substrate scope of the ring‐opening chlorination of isoxazole derivatives (Figure 3). Aryl isoxazoles bearing electron‐donating groups at the para‐position of the C5‐aryl group (4A–4I) underwent smooth transformations to afford the corresponding chlorinated products 5A–5I in good yields. In contrast, isoxazoles bearing electron‐withdrawing groups such as esters or ketones afforded the chlorinated products in only moderate yields and were found to be highly unstable, making isolation difficult (see Supporting Information for details). Next, substrates bearing substituents at different positions on the aryl ring were examined. Isoxazoles bearing a methyl group (4J), a methoxy group (4K), or a fluoro group (4L) at the ortho‐position, as well as those bearing a fluoro group at the meta‐position (4M) or a naphthyl group (4N and 4O), smoothly underwent the reaction to afford the corresponding chlorinated products 5J–5O in good yields. However, in the case of 4K, additional chlorination occurred at the para‐position of the methoxy group, giving rise to the formation of 5K. Isoxazoles with alicyclic frameworks, such as 4P and 4Q, also afforded the desired chlorinated products 5P and 5Q in good yields. On the other hand, when isoxazole 4R bearing a highly nucleophilic site outside the C4‐position was subjected to the reaction, chlorination selectively occurred at the isoxazole moiety to give 5R (37%); however, a significant amount of dichlorinated product 5S (44%) resulting from additional chlorination on the aryl ring was also observed. These results indicate that although ring‐opening chlorination preferentially occurs at the isoxazole moiety, electron‐rich aromatic rings can still undergo competitive chlorination under the reaction conditions.

Figure 3.

Substrate scope for chlorination of isoxazoles. Reaction conditions: 4 (0.20 mmol), TCCA (0.12 mmol), MeCN (1.0 mL), RT, 24 hours. Isolated yields were shown. The yields shown in parentheses were determined by ¹H NMR using CH₂Br₂ as an internal standard.

Subsequently, we investigated the ring‐opening chlorination of isoxazole derivatives bearing various R² substituents. Substrates possessing a linear alkyl group (4T), a branched alkyl group (4U), or a phenyl‐substituted alkyl group (4V) underwent smooth transformations to afford the corresponding chlorinated products 5T–5V in good yields, and the products were readily isolated. In contrast, the compound bearing an acetyl‐protected hydroxymethyl group (4W) afforded product 5W in moderate yield; however, 5W was found to be unstable and underwent decomposition upon purification. Similar instability was observed for substrates bearing pivaloyl (4X) and benzoyl (4Y) groups, leading to decomposition of the corresponding products 5X and 5Y upon isolation. Although the exact decomposition pathway remains unclear, it is presumed that a retro‐aldol‐type mechanism may be operative. Therefore, the products 5W–5Y were derivatized immediately after the reaction to enable successful isolation (see Figure 5).

Figure 5.

One‐pot derivatization of halocyanoketones.

We next examined the substrate scope for the ring‐opening bromination of isoxazoles (Figure 4). We first investigated the influence of various R¹ substituents. Aryl isoxazoles bearing alkyl groups, electron‐donating groups, or halogens at the para‐position of the aryl ring underwent smooth bromination to afford the corresponding products 6A–6G in high yields. In the case of biphenyl 5I, the bromination proceeded efficiently; however, a small amount of brominated phenyl byproduct 6I was also formed, and separation of the desired product from the byproduct was unsuccessful. For substrates bearing a cyano group at the para‐position, no brominated product was obtained at room temperature; however, upon heating to 60 °C, the reaction proceeded to afford the desired brominated compound 6Z in moderate yield. Nonetheless, the product proved unstable during purification, and isolation was not achieved. Substrates bearing fluoro groups at the ortho‐ or meta‐position of the aryl ring provided the desired products 6J–6M in good yields. In contrast, for the substrate bearing a methoxy group at the ortho‐position, bromination of both the isoxazole ring and the aryl ring occurred, affording a dibrominated product, 6K. Similarly, in the case of the isoxazole bearing a thienyl group, competitive bromination of the aromatic ring led to the formation of the dibrominated product 6AA in high yield. An isoxazole bearing an alkyl group at the C4 position (6AB) underwent bromination in moderate yield, although isolation of the product was challenging. Upon purification, only partial amounts of a deacetylated byproduct were obtained, and compound 6AB itself could not be isolated. In addition, isoxazoles derived from arylcycloalkanones also underwent bromination smoothly to furnish products 6P and 6Q in good yields.

Figure 4.

Substrate scope for bromination of isoxazoles Reaction conditions: 4 (0.20 mmol), DBI (0.14 mmol), 5.0 mol% BHT, HFIP (1.0 mL), RT, 24 hours. Isolated yields were shown. The yields shown in parentheses were determined by ¹H NMR using CH₂Br₂ as an internal standard. ^aReaction performed at 60 °C. ^bDBI (1.40 equiv) was used.

We next explored the effect of R² substituents. Similar to the chlorination reactions, substrates bearing various alkyl groups reacted well to afford the corresponding brominated products (6T and 6U) without issues in isolation and purification. However, substrates bearing a hydroxymethyl group at the R² position, although showing complete conversion by NMR analysis, yielded unstable products that could not be isolated as 6Q–6AC. We speculate that these products underwent benzoyl group cleavage or OR group elimination to form volatile decomposition products (see Supporting Information for details).

To overcome the difficulty in isolating certain unstable ring‐opening halogenated products and to demonstrate the synthetic utility of their derivatives, we further developed one‐pot sequential transformations (Figure 5). Specifically, after performing the ring‐opening halogenation of isoxazoles 4, the reaction solvent was removed, and the resulting crude products 5 or 6 were subjected to a Ritter reaction with tert‐butyl acetate and a catalytic amount of concentrated sulfuric acid, affording the corresponding amides 9 or 10.

For example, although the cyanated product 5G derived from 4G was isolable, treatment under the above conditions afforded amide 9G in 81% yield. Likewise, substrates 4W, 4Y, and 4Z, which previously gave unstable and nonisolable products, were successfully converted into the corresponding amides 9W–9Y in moderate yields. In the case of 4AD, the amide product 9AD was obtained in lower yield but could be successfully isolated. Notably, for substrate 4Z bearing a cyano group on the aromatic ring, double Ritter reactions occurred, affording the bis‐amidated product 10Z.

2.5. Ring‐Opening Dichlorination and Dibromination of Pyrazolopyridines

Finally, we investigated the development of ring‐opening dihalogenation reactions of pyrazolopyridine derivatives (Figure 6). Treatment of pyrazolopyridine 1K or 3‐formyl‐ pyrazolopyridine 1L with 2 equivalents of NCS or 1.4 equivalents of DBI afforded the corresponding ring‐opened dichlorinated and dibrominated products 11 and 12 in moderate to high yields. In our previous studies on fluorination reactions,^{[ 12 ]} the formyl‐substituted substrate 1L exhibited higher reactivity and provided better yields compared to the unsubstituted analogue 1K. In contrast, in the present chlorination and bromination reactions, no significant difference in reactivity was observed between 1K and 1L.

Figure 6.

Ring‐opening dihalogenation of pyrazolopyridines. The yields were determined by ¹H NMR using CH₂Br₂ as an internal standard.

3. Conclusion

In summary, we have developed general and efficient methods for the electrophilic ring‐opening chlorination and bromination of pyrazolopyridines and isoxazoles. These transformations proceed through selective cleavage of heteroaromatic C─N or N─O bonds, enabling the direct construction of structurally diverse tertiary halogenated compounds under mild conditions. Furthermore, we demonstrated that formylpyrazolopyridines could be successfully converted into dihalogenated products, further expanding the synthetic potential of this methodology. The reactions exhibited broad substrate scope, tolerating a variety of substituents on both the heterocyclic core and the appended aromatic rings. Although some ring‐opening halogenated intermediates displayed instability upon isolation, we established a one‐pot sequential derivatization strategy using the Ritter reaction, allowing access to stable amide derivatives and thereby highlighting the synthetic utility of the unstable intermediates. Compared to fluorinating agents, the chlorinating and brominating reagents employed here exhibit lower electrophilicity, necessitating distinct considerations in reaction design and highlighting the uniqueness of this transformation.

Overall, this study provides a new platform for skeletal transformation of heteroaromatics via electrophilic activation, offering a modular approach to constructing highly functionalized halogenated scaffolds. We anticipate that the strategies developed herein will contribute to the application of ring‐opening functionalization in synthetic organic chemistry.

Supporting Information

Full experimental procedures, characterization of products, and, spectral data (PDF) The authors have cited additional references within the Supporting Information.

Conflict of Interest

The authors declare no conflict of interest.

Supporting information

Supporting Information

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.