Controllable synthesis of N–H or N-Me C7-substituted indazoles via a cascade reaction of α-diazo esters with aryne precursors

Abstract

A metal-free, highly regioselective [3 + 2] cycloaddition of cyclic diaryl λ³-bromanes and α-diazo esters has been developed for the controllable synthesis of valuable C7-aryl 3-substituted 1H-indazoles. This protocol involves cascade cycloaddition/decarboxylation to afford N–H indazoles or cycloaddition/decarboxylation/methylation to deliver N-Me indazoles. Mechanistic studies revealed that the [3 + 2] cycloaddition proceeded in a highly regioselective manner, followed by decarboxylation instead of acyl group migration, likely due to steric hindrance. Both α-diazo esters and the [3 + 2] adduct can serve as methylation reagents.

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Indazole motifs are commonly found in natural products,¹ bioactive molecules² and pharmaceuticals,³ driving significant efforts towards various synthetic methods. Recent strategies include transition-metal-catalyzed C–N and N–N bond coupling reactions,⁴ diazotization or nitrosation of 2-alkyl aniline derivatives,⁵ and [3 + 2] cycloaddition between benzyne precursors and diazo compounds,⁶ among others.⁷ Indazoles bearing aryl moieties at the C7 position, in particular, have shown promising bioactivities.⁸ As shown in Scheme 1, previous efforts towards these compounds include a multi-step strategy⁹ (eqn (1)) and a Pd-catalyzed C–H activation approach¹⁰ (eqn (2)). The latter is limited to the synthesis of N-methyl indazoles. The [3 + 2] cycloaddition of Kobayashi benzyne precursors and diazo compounds has emerged as a powerful route to access indazole scaffolds. However, the synthesis of C7-aryl-1H-indazoles via this approach has yet to be achieved (eqn (3)). Typically, N-acyl-protected indazoles are obtained via a [3 + 2] cycloaddition followed by acyl group migration.^6b,c,11 Thus, the development of efficient and straightforward methods for constructing C7-substituted indazoles is highly desirable. Cyclic diaryl λ³-bromanes, analogues of cyclic diaryliodiniums,¹² have recently emerged as novel aryne precursors under mild basic conditions.^13,14

Scheme 1 Construction of C7-substituted indazoles.

Their synthetic utility has been demonstrated in diverse transformations, including cycloadditions,^15a–c nucleophilic substitutions^15d,e and Pd/Cu-catalyzed alkynylations.^15f,g Building on our ongoing interest in the cycloaddition chemistry of cyclic diaryl λ³-bromanes,^15b we envisioned that their [3 + 2] cycloaddition with α-diazo esters could offer a direct and efficient route to C7-substituted indazoles.

We report herein a metal-free, highly regioselective [3 + 2] cycloaddition between cyclic diaryl λ³-bromanes and diazo esters for rapid access to C7-substituted indazoles. In contrast to previously reported cycloaddition/migration reactions of Kobayashi aryne precursors with diazo esters,^6,16 this transformation proceeds via distinct pathways: a cascade sequence of [3 + 2] cycloaddition/decarboxylation or [3 + 2] cycloaddition/decarboxylation/methylation, affording N–H or N-Me indazoles, respectively. Mechanistic studies suggest that regioselectivity is potentially governed by steric effects, highlighting λ³-bromanes as versatile platforms for heterocycle construction.

Firstly, the investigation began with cyclic diaryl λ³-bromane-OTs (1a) and methyl 2-diazo-2-phenylacetate (2a) as model substrates to optimize the reaction conditions (Table 1). Gratifyingly, the reaction did occur at 40 °C (entry 1). Besides the direct [3 + 2] adduct 5g, the decarboxylative product 3a was unexpectedly obtained in 10% yield. Increasing the temperature improved the yield of 3a to 56% while 5g was obtained in 29% yield (entry 2). To facilitate the hydrolysis step, H₂O was added and 3a was delivered in 79% yield (entry 3). Further optimization of solvents, temperature, bases, the amount of H₂O and different counterions towards the formation of 3a is included in SI Tables S1–S5, and the improved conditions are denoted as conditions A as shown in entry 3. Notably, during the optimization process, an unexpected methylation product, 4a, was observed throughout the initial experiments (entries 1–4). This prompted a separate optimization campaign, which revealed that performing the reaction in MeCN at 90 °C was optimal, affording N-Me product 4a in 63% yield (entry 7). These conditions are defined as conditions B, with detailed optimization available in SI Tables S6–S11.

Table 1 Selected optimization results for the synthesis of indazoles^a

Entry	Details of conditions	Yield 3a (%)	Yield 4a (%)	Yield 5g (%)
a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), Cs2CO3 (0.4 mmol, 2.0 equiv.), and solvent (2.0 mL) under argon. Yields reported are isolated yields. b  1a (0.15 mmol, 1.0 equiv.), 2a (0.3 mmol, 2.0 equiv.), Cs2CO3 (0.3 mmol, 2.0 equiv.), and MeCN (1.5 mL). Yields were determined by ^1H NMR using 1,3,5-trimethoxybenzene as an internal standard.
1	THF, 40 °C, 16 h	10	Trace	68
2	THF, 70 °C, 16 h	56	Trace	29
3	THF, H2O (1.0 eq.) 70 °C, 24 h (conditions A)	79	Trace	Trace
4	THF, 80 °C, 16 h	52	6	8
5	MeCN, 80 °C, 16 h	41	10	Trace
6^b	MeCN, 80 °C, 24 h		24
7^b	MeCN, 90 °C, 24 h (conditions B)		63
8^b	MeCN, 100 °C, 24 h		50

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To gain mechanistic insights, a number of experiments were performed. As shown in Scheme 2, a control experiment to capture the aryne intermediate was conducted under conditions B, successfully yielding a [4 + 2] Diels–Alder reaction adduct 5f in 15% yield (Scheme 2a). The isolated [3 + 2] cycloaddition adduct 5g was subsequently subjected to conditions B, delivering both decarboxylation product 3a and methylation product 4a (Scheme 2b). The use of deuterated α-diazo esters 2a′ resulted in the formation of a fully deuterated product 4o in 52% yield and the methyl group could be traced to α-diazo esters (Scheme 2c). Further experiments under conditions B using an equimolar mixture of 1a, α-diazo ester 2a and deuterated α-diazo ester 2a′ afforded a mixture of the methylation product in both –CD₃ (63% yield) and –CH₃ (37% yield) groups (Scheme 2d). Similarly, both adduct 5g and the deuterated α-diazo ester 2a′ were subjected to conditions B and the methylation product was detected in both –CD₃ (53%) and –CH₃ (47%) groups. Product 3a and α-diazo ester 2a were reacted under conditions B and 4a could be obtained in 49% yield (Scheme 2e). Based on these mechanistic studies, it is reasonable to speculate that cyclic diaryl λ³-bromanes could react with α-diazo esters via the aryne intermediate to undergo the [3 + 2] cycloaddition. Furthermore, α-diazo esters could serve as bifunctional reagents for both the cycloaddition reaction and the methylation reaction.

Scheme 2 Mechanistic studies.

Furthermore, DFT studies were carried out to investigate the origin of regioselectivity.¹⁷ As shown in Fig. 1, the cycloaddition between the aryne intermediate Int1 and diazo compound 2a proceeded via a concerted transition state TS1 (ΔG^‡ = 10.7 kcal mol⁻¹), leading to the formation of the [3 + 2] cycloaddition adduct 5g with a highly exergonic free energy change (ΔG = −71.6 kcal mol⁻¹). An alternative pathway proceeding through TS2 has a higher free energy barrier (ΔG^‡ = 13.8 kcal mol⁻¹), and the resulting regio-isomeric adduct Int2 is also slightly less stable (ΔG = −69.9 kcal mol⁻¹). These computational results indicated that the formation of 5g was both kinetically and thermodynamically favored, in excellent agreement with the experimentally observed regio-isomer. Additionally, a potential acyl group migration pathway^6b,e from adduct 5g was also studied (SI, Fig. S4); however, the significantly higher activation barrier suggests that this pathway is unlikely to occur under experimental conditions, which explains why 3-aryl-1H-indazoles are predominant products. To further elucidate the methylation progress, two possible reaction pathways were explored computationally (Fig. 1b). In the presence of Cs₂CO₃, methylation of 3a with the [3 + 2] adduct 5g proceeded viaTS3 with an activation free energy of 28.5 kcal mol⁻¹. Alternatively, the α-diazo ester 2a may act as the methylation reagent viaTS4, overcoming a slightly higher free energy barrier of 29.4 kcal mol⁻¹. In both cases, product 4a was formed along with CsHCO₃ as a byproduct. These DFT results suggested that both methylation pathways were energetically accessible under reaction conditions. The small energy difference between the two transition states was consistent with the experimentally observed chemoselectivity (Scheme 2d and e), indicating that both 5g and 2a served as mechanistically relevant methylation reagents.

Fig. 1 Free energy profiles for ^a regioselective [3 + 2] cycloaddition between the aryne intermediate and diazo compound. ^b Possible pathways of the unexpected methylation process.

Thus, with the optimal conditions in hand, the applicability of α-diazo esters was first examined as illustrated in Scheme 3. As anticipated, diverse α-diazo esters reacted efficiently with the cyclic diaryl λ³-bromane-OTs (1a), delivering the corresponding 1H-indazole derivatives in good yields upon isolation. For instance, the model product 3a was obtained in 79% yield, and its structure was confirmed by single-crystal X-ray diffraction (XRD) analysis.

Scheme 3 Scope of various diazo compounds for N–H indazoles. Conditions A: 1a (0.2 mmol, 1.0 equiv.), 2 (0.4 mmol, 2.0 equiv.), Cs₂CO₃ (0.4 mmol, 2.0 equiv.), THF (2.0 mL), and H₂O (1.0 equiv.) at 70 °C under argon for 24 h. Yields reported are isolated yields. ^aat room temperature.

Then, the effect of different substituents on the R¹ group was studied. The reactions proceeded smoothly to afford products (3a–3g) in moderate to good yields. The direct [3 + 2] cyclization product 3h was isolated instead of the typical 3-aryl-1H-indazole derivative. Substrates with other functional groups at the ortho- (2i) or meta-position (2j–2l) of the R¹ group were also tolerated. A sterically hindered α-diazo ester (2m) afforded the product in a slightly diminished yield (42%). To our delight, diazo molecules incorporating heterocycles also furnished the products in moderate yields (3n 62% and 3o 54%). Moreover, the scope of the substituents R² (R¹ = Ph) was explored.

Not surprisingly, varying R² to other groups (2p–2t), 3-aryl-1H-indazole derivatives can be successfully obtained in moderate to high yields (66%–75%). When R² is p-trifluorobenzyl, the product can be obtained in 91% yield. Furthermore, when R² featured a heterocyclic group (2v), 3a can also be produced in 77% yield. Finally, modification of both R¹ and R² groups was investigated. The corresponding products 3d, 3g and 3n were afforded in acceptable yields (44%–73%). The R¹ group could be altered to an alkyl group (2z). Due to the low boiling point of 2z, the reaction was first carried out at room temperature and the [3 + 2] cycloaddition adduct 3z was obtained in 72% yield. The regular product 3z′ was also obtained under conditions A. Collectively, this comprehensive scope investigation demonstrates good functional group tolerance for synthesizing 3,7-diaryl-1H-indazole derivatives.

We subsequently explored the substrate scope for methylated products as shown in Scheme 4. 3-Phenyl-1-methyl-1H-indazole 4a was obtained in 60% yield, with its structure confirmed by single-crystal X-ray diffraction (XRD) analysis. Diazo compounds bearing different substituents afforded the corresponding N-Me products 4b–4i in good yields. Given the demonstrated advantages of deuterated drugs, including reduced toxicity, altered metabolic profiles, and prolonged half-lives,¹⁸ we incorporated –CD₃ groups to access deuterated analogues. Diverse R¹ substituents were surveyed, delivering numerous 3-aryl-1-CD₃-1H-indazoles (4j–4n) with slightly improved yields.

Scheme 4 Scope of various diazo compounds for N-Me indazoles. Conditions B: 1a (0.2 mmol, 1.0 equiv.), 2 (0.4 mmol, 2.0 equiv.), Cs₂CO₃ (0.4 mmol, 2.0 equiv.), and MeCN (2.0 mL) at 90 °C under argon for 24 h. Yields reported are isolated yields.

To emphasize and illustrate the practical utility of this controllably selective methodology, we performed further synthetic transformation of indazole derivatives. Fundamentally, both reactions towards the formation of model products 3a and 4a could be scaled up to the gram scale and subsequently were applied as powerful building blocks to readily construct highly functionalized molecules via rhodium-catalyzed oxidative annulation^19a (5a), Pd-catalyzed Suzuki cross-coupling reaction^19b (5b), Pd-catalyzed Miyaura borylation reaction^19c (5c) and Pd-catalyzed Buchwald–Hartwig C–N coupling reaction^19d (5d) (Scheme 5).

Scheme 5 Synthetic utility.

Conclusions

In conclusion, a metal-free, controllable synthesis of N–H or N-Me C7-substituted 1H-indazoles was described via cycloaddition/decarboxylation or cycloaddition/decarboxylation/methylation cascade reactions of α-diazo esters with cyclic diaryl λ³-bromanes as aryne precursors. DFT studies revealed that regioselectivity is potentially governed by the inherent steric hindrance of these aryne precursors. α-Diazo esters were identified as bifunctional reagents for both cycloaddition and serving as in situ methylating sources. This study might accelerate the development of bioactive molecules containing C7-aryl-substituted indazole motifs.

Conflicts of interest

There are no conflicts to declare

Data availability

Supplementary information (SI): experimental procedures, characterization of products, DFT calculation data and spectroscopic data for compounds 1 to 5 (ZIP). See DOI: https://doi.org/10.1039/d5qo01181g.

CCDC 2383447, 2385968 and 2415285 contain the supplementary crystallographic data for this paper.^20a–c

Acknowledgements

We are grateful to the Ministry of Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules (no. KLSAOFM2512) for the financial support of this work. Prof. Qiang Wang acknowledges financial support from the Fundamental Research Funds for the Central Universities (no. CCNU25JC040; Q. W.). Prof. Linxing Zhang is grateful for financial support from the National Natural Science Foundation of China (no. 22403028).

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