Metal- and base-free spirocyclization of alkylidene oxindoles via photo- and mechanochemically-generated nitrile ylides and nitrile imines as 1,3-dipoles

Abstract

Herein we have reported an expedient synthesis of spiro[pyrrolidine-3,3′-oxindole] and 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one under metal- and base-free conditions through the 3 + 2 cycloaddition reactions of in situ generated nitrile ylides and nitrile imines with alkylidene oxindoles in good to excellent yields. The nitrile ylides are generated through acetonitrile insertion onto carbenes generated from blue LED irradiation of aryl diazo esters. The nitrile imines were formed under mechanochemical conditions from diazo esters and aryl diazonium tetrafluoroborates.

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Spirocyclic oxindole scaffolds represent a privileged class of heterocyclic frameworks in medicinal chemistry and materials science.¹ Among them, spiro[pyrrolidine-3,3′-oxindole] and 2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one (spiropyrazoline oxindole) are structurally diverse and biologically significant. Their rigid 3D framework, tunable electronic properties, and wide range of biological applications make them essential in medicinal chemistry, materials science, and organic synthesis. With advancements in asymmetric catalysis, green chemistry approaches, and electrochemical methodologies, their utility continues to expand, reinforcing their role as privileged structures in modern drug discovery and functional materials.^2,3

The structural and electronic features of these building blocks include a fused indoline-lactam (2-one) system that provides hydrogen-bonding sites and contributes to molecular recognition. The spiro-carbon junction connects the oxindole nucleus to the heterocyclic system, creating steric hindrance and reducing conformational flexibility, which enhances receptor selectivity in bioactive molecules. The spiro[pyrrolidine-3,3′-oxindole] contains a fused pyrrolidine ring, increasing steric hindrance and modulating biological interactions whereas the 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one incorporates a pyrazoline moiety, providing electron-rich nitrogen atoms that enhance interaction with biomolecules. These compounds exhibit numerous biological activities including anticancer properties as inhibitors of topoisomerases, kinases, and microtubule polymerization.⁴ The spiro-framework enhances bacterial and viral enzyme binding, showing promise as antibiotics and antivirals.⁵ They are also used as modulators of CNS receptors resulting in potential anticonvulsant, antidepressant, and neuroprotective effects and as inhibitors of COX-2 enzyme and inflammatory cytokines, making them potential pain-relieving drugs.^6,7 Their application beyond medicinal chemistry includes organic semiconductor photonics.⁵ Some of their derivatives enhance guest–host interactions in supramolecular assemblies.⁵

The general synthesis of these spirocyclic frameworks involves a variety of methodologies, including [3 + 2] cycloaddition reactions of azomethine ylides (generated in situ from oxindole derivatives) with dipolarophiles (alkenes, alkynes, and nitriles) to construct the spirocycle, multicomponent reactions (MCRs) involving one-pot condensation of isatins, amines, and electron-deficient alkenes, leading to rapid access to spirocyclic products, metal-catalyzed and asymmetric synthesis with chiral Lewis acids and organocatalysts to promote enantioselective transformations, yielding optically pure derivatives, and electro-oxidative and photoredox-mediated reactions, enabling eco-friendly synthesis with enhanced selectivity.^1,8–10

Nitrile ylides belong to the class of 1,3-dipoles where a carbanionic centre is conjugated with a nitrile group, resulting in structures possessing strong nucleophilic character at the carbon adjacent to the nitrile group, allowing them to participate in cycloaddition reactions and nucleophilic addition reactions.¹¹ Whereas nitrile imines are a class of 1,3-dipolar species that consist of a conjugated system involving a nitrile group and an imine moiety. Nitrile imines exhibit nucleophilic character at the terminal nitrogen and electrophilic behaviour at the central carbon. This ambident nature makes them highly reactive toward dipolarophiles.¹²

Both nitrile imines and nitrile ylides are highly versatile synthetic intermediates, offering unique electronic properties that allow for regio- and stereoselective functionalization of organic molecules. Their broad applicability in heterocyclic synthesis, medicinal chemistry, and materials science makes them indispensable tools in modern organic synthesis. Nitrile ylides, due to their unique electronic structure, are highly reactive intermediates that participate in diverse reactions, such as [3 + 2] cycloadditions with electron-deficient alkenes or alkynes, leading to aziridines, pyrroles, and other nitrogen-containing fused heterocycles, electrophilic trapping with carbonyl compounds and imines to generate heterocyclic scaffolds relevant to drug discovery,^13,14 and metal-catalysed functionalization with gold(I) or silver(I)-catalysed transformations that introduce complex heterocyclic motifs.^15,16 On the other hand, nitrile imines are widely used in 1,3-dipolar cycloaddition reactions, particularly with electron-deficient alkenes and alkynes.¹⁷ The most notable transformation is their reaction with alkenes to form pyrazoles, an important heterocyclic scaffold in medicinal chemistry.¹⁸ Key reactions involving nitrile imines are cycloaddition with alkenes to pyrazolines, which can be further oxidized to pyrazoles,¹⁹ cycloaddition with alkynes leading to the direct formation of pyrazoles via a [3 + 2] mechanism,¹⁷ reaction with isocyanates and isothiocyanates to yield triazolone or thiotriazolones, which have pharmaceutical relevance, and finally, metal-catalysed cross-coupling reactions.¹⁸ Functionalized nitrile imines can participate in transition-metal-catalysed transformations, including palladium- or copper-catalysed coupling with aryl halides.¹⁷

3-Alkylidene oxindoles are versatile compounds with significant synthetic and biological importance.²⁰ Their unique structural features facilitate diverse chemical transformations, and their presence in bioactive molecules underscores their potential in drug discovery and development. Ongoing research continues to explore novel synthetic methodologies and applications for these compounds in various therapeutic areas. The exocyclic double bond in 3-alkylidene oxindoles serves as a reactive site for various chemical transformations such as Michael addition reactions with nucleophiles, facilitating the formation of diverse functionalized oxindoles.^21,22 3-Alkylidene oxindoles can participate in [3 + 3] and [4 + 2] cycloaddition reactions with electrophiles, leading to the construction of complex polycyclic structures.^23,24 Biocatalytic reduction of the alkylidene double bond using baker's yeast has been demonstrated, providing access to 3-alkyl oxindoles with high stereoselectivity.²⁵

There are significant advances in the field of photochemical carbene transfer reactions through blue LED-induced transformations of diazo esters. Aryldiazoacetates can undergo efficient photolysis under blue light irradiation (460–490 nm) to generate free carbene intermediates without the need for metal catalysts. These carbenes participate in diverse transformations, including cyclopropanation, C–H insertion, and heteroatom–H insertion reactions, often with high yields and diastereoselectivity. These findings underscore the potential of visible-light photochemistry as a sustainable and practical alternative to traditional metal-catalyzed carbene transfer methodologies.^26–30

We report the synthesis of densely functionalized spiro[pyrrolidine-3,3′-oxindoles] and 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one as diastereomeric mixtures via a mild, metal- and base-free [3 + 2] cycloaddition of 3-alkylidene oxindoles with in situ generated nitrile ylides and nitrile imines, respectively (Scheme 1). The nitrile ylides are generated under blue LED irradiation of aryl diazo esters followed by nitrile insertion of the resulting carbenes. The cycloaddition product undergoes oxidation to afford the desired compounds. In contrast, the nitrile imines are formed spontaneously through the reaction between ethyl diazoacetate and aryl diazonium tetrafluoroborates under solvent-free mechanochemical ball milling. The target spirocyclic compounds are obtained in excellent yields under operationally simple and mild conditions (Scheme 1).

Scheme 1 Summary of our work.

These sustainable methods rival traditional thermally-induced and recent metal-catalysed variants, providing operational simplicity, cleaner reaction profiles, and enhanced environmental compatibility.

To initiate our study, we examined the intermolecular [3 + 2] cycloaddition of phenyl diazoacetate 2a with tert-butyl (E)-3-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-carboxylate 1a (2 : 1 ratio) in acetonitrile under blue LED irradiation (5 W, 440 nm) at room temperature (Table 1, entry 1). The cycloadduct formed in situ was oxidized under ambient conditions to afford spiropyrrolidine-3,3′-oxindole 4a in 85% yield. Switching to other LED sources—white, red, or green—resulted in lower yields (45–61%) and increased formation (25–30%) of 1,3-oxazole by-products (Table 1, entries 2–4).

Table 1 Optimization for the generation of spiropyrrolidine-3,3′-oxindole 4a

Entry	LED source	Temperature (°C)	Solvent	Yield of 5a ^a (%)
a Isolated yield. b Under nitrogen (N2). c Under an oxygen balloon (O2); BL: blue LED.
1	BL (5 W) (440 nm)	rt	ACN	85
2	White	rt	ACN	70
3	Green	rt	ACN	62
4	Red	rt	ACN	40
5	Blue	rt	CH3CN (15 eq.) + MeOH	0
6	Blue	rt	CH3CN (15 eq.) + DCE	0
7	Blue	rt	CH3CN + DCM (15 eq.)	Trace
8	Blue	rt	CH3CN + TFE (15 eq.)	0
9	Blue	rt	CH3CN + DMF (15 eq.)	0
10	Blue	rt	CH3CN + acetone (15 eq.)	0
11	BL (34 W) (440 nm)	rt	CH3CN	92
12	370 nm UVA	rt	CH3CN	73
13^b	BL (34 W) (440 nm)	rt	CH3CN	56 (40% oxazole)
14^c	BL (34 W) (440 nm)	rt	CH3CN	2 (majority keto ester)

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Using 15 equivalents of acetonitrile as the nitrile source in alternative solvents such as MeOH, DCE, DCM, TFE, DMF, and acetone either suppressed product formation or yielded only trace amounts of products (2–5%) (Table 1, entries 5–10). Increasing the blue LED intensity from 5 W to 34 W enhanced the yield to 92% (Table 1, entry 11). UVA irradiation afforded 4a in 73% yield (Table 1, entry 12).

Reactions under nitrogen slowed significantly, giving 4a in 56% yield with ∼40% 1,3-oxazole formation (Table 1, entry 13). Under an oxygen atmosphere, only 2% of 4a was obtained, with the keto ester as the major product, suggesting that oxygen insertion inhibited ylide formation (Table 1, entry 14).

All reactions were conducted at room temperature. The desired product 4a was consistently obtained as a diastereomeric mixture (dr 70 : 30 to 80 : 20). Thus, the optimized conditions involve irradiating a 1 : 1 mixture of 1a and 2a in acetonitrile with a blue LED (34 W, 440 nM) under open air at room temperature for 8–12 h.

With the optimized conditions in hand (blue LED, 34 W, 450 nm), we next evaluated the scope and robustness of our photolytic protocol using a variety of alkylidene oxindoles 1a–1l and aryl diazo esters 2a–2j in acetonitrile at room temperature under open-air conditions (Schemes S1 and S2, ESI†). The desired spiropyrrolidine-3,3′-oxindoles 4a–4r were obtained in moderate to excellent yields as mixtures of diastereomers (dr = 78 : 28 → 10 : 1) (Scheme 2a).

Scheme 2 The generic library of spiropyrrolidine-3,3′-oxindole 4a → 4r.

The alkylidene oxindoles tested included N-protected derivatives bearing tert-butoxycarbonyl 1a–1f, acetyl 1g–1h, methyl 1i, tosyl 1j, and benzyl 1k–1l groups. All were well tolerated under the optimized conditions, affording products in yields ranging from 69 to 92% (Scheme 2a). Among them, Boc-protected substrates performed the best, followed by acetylated analogues, with other protecting groups showing slightly diminished efficiency.

Along with products 4a, 4f–4h, 4j, 4l and 4o–4q from phenyl diazo esters, the aryl diazo esters bearing both electron-donating and electron-withdrawing groups at the para- and meta-positions were also compatible. However, diazo esters with electron-donating substituents at the phenyl ring provided the desired products such as 4b, 4c, 4d, 4e, 4i, 4k, 4n and 4r in better yields compared to the electron-withdrawing substituent 4m (p-fluorophenyl). In contrast, o-nitrophenyl methyl diazoacetate 2k failed to deliver the desired product, likely due to the electronic or steric inhibition of ylide formation. All the products were obtained as a mixture of diastereomers (Scheme 2a).

It is noteworthy that to establish the involvement of the nitrile ylide 3 as a dipolarophile, the reaction between 1a and 2a in acetonitrile was monitored by LCMS-QTof and the mass spectrum clearly indicated the formation of the nitrile ylide 3a (Scheme 2b). At the same time, isolating intermediate A from the reaction mixture of 1g with 2a and 3a (Scheme 2c) and confirming its structure by single crystal X-ray indicate putatively the formation of the final product 4j as well as the relative stereochemistry between the quaternary carbon centre adjacent to the pyrrolidine nitrogen and the quaternary carbon at the spiro junction. Additionally, the 2D-NOESY spectrum of the final representative compound 4i recorded in CDCl₃ indicated a through-space ¹H–¹H coupling between the methyl (CH₃) group and the hydroxyl (OH) proton (refer to Scheme S7†). This Nuclear Overhauser Effect (NOE) suggests that the CH₃ and OH protons are spatially close, supporting their proximity within the molecule's 3D conformation. This observation helps to establish the relative stereochemistry of the building block 4.

Next, we developed a novel one-pot mechanochemical protocol for the synthesis of densely functionalized 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one 8via in situ generation of nitrile imines 7 from ethyl diazoacetate 5 and aryl diazonium tetrafluoroborates 6, followed by their 1,3-dipolar cycloaddition with alkylidene oxindoles 1. As a model system, we selected N-methyl alkylidene oxindole 1m, ethyl diazoacetate 5a, and 4-bromophenyl diazonium tetrafluoroborate 6a in a 1 : 1 : 1 stoichiometric ratio to investigate the formation of the desired 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one derivative 8a (see ESI Table S1† and Table 2).

Table 2 Optimization of the mechanochemical reaction conditions

Entry	Material of the jar and ball	Ball size and number	Frequency and time	Yield^a
a Isolated yield after column chromatography.
1	ZrO2-Y	∅ 10 mm, 1	30 Hz, 90 min	60%
2	ZrO2-Y	∅ 7 mm, 2	30 Hz, 75 min	65%
3	ZrO2-Y	∅ 7 mm, 3	30 Hz, 60 min	65%
4	ZrO2-Y	∅ 7 mm, 3	50 Hz, 45 min	68%
5	ZrO2-Y	∅ 7 mm, 3	70 Hz, 30 min	75%
6	ss	∅ 7 mm, 3	70 Hz, 30 min	81%

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Initial solvent screening at room temperature identified dichloromethane (DCM) as the optimal medium, affording 8a in 61% yield (Table S1,† entry 6). Elevating the temperature to 50 and 70 °C expedites the completion of the limiting reagent 1m; however the overall yield decreased to ∼35% and 40% respectively (Table S1,† entries 7 and 8). Increasing the equivalents of 5a (2 and 4 eq.) and 6a (2 eq.) led to an enhanced yield of 72% (Table S1,† entries 9 and 10). Notably, under solvent-free (“neat”) conditions, 8a was obtained in 68% yield with increased amounts of 5a and 6a, as depicted in entry 10 (Table S1,† entry 11). These preliminary reactions required an average reaction time of 8–10 hours.

Motivated by the promising outcome under neat conditions and with the goal of enhancing sustainability, we systematically optimized the reaction parameters under solvent-free mechanochemical ball-milling conditions using a Retsch MM400™ high-frequency mixer mill (see ESI Fig. S5†). A series of variables including jar material, ball type/size/number, milling frequency, and duration were thoroughly examined (Table 2).

Initial milling of the reactants in a 10 mL yttria-stabilized zirconia (ZrO₂-Y) jar with a single 10 mm ball at 30 Hz afforded 8a in 60% yield within 90 minutes (Table 2, entry 1). Reducing the ball diameter to 7 mm and increasing the number of balls to 2 and 3, respectively, improved both the reaction kinetics and yield (65% in 75 min and 60 min, respectively; Table 2, entries 2 and 3). Further enhancement was achieved by increasing the milling frequency. At 70 Hz, the reaction completed in just 30 minutes with no compromise in yield (75%, Table 2, entry 5). Finally, employing a stainless steel (ss) jar equipped with three 7 mm stainless steel balls at 70 Hz furnished 8a in 81% yield within 30 minutes (Table 2, entry 6). These were deemed the optimal conditions for the mechanochemical synthesis of 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one 8.

With the optimized reaction conditions established, the substrate scope was subsequently investigated using a diverse set of electronically varied alkylidene oxindoles 1m–1s for their spirocyclization with ethyl and methyl diazoacetate 5a/5b and aryl diazonium tetrafluoroborates 6a–6i (Scheme 3). The N-methyl-substituted alkylidene oxindoles 1m–1p (ESI Fig. S1†) underwent smooth spirocyclization with 5a and various aryl diazonium salts 6a–6h, affording the desired 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-ones 8a–8j in commendable yields ranging from 76% to 87%, with moderate diastereoselectivities (dr = 7 : 3 to 8.5 : 1.5), irrespective of the electronic nature of the substituents on 6 (Scheme 3).

Scheme 3 The generic library of 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one, 8a → 8q.

Similarly, the N-tosyl-substituted alkylidene oxindole 1q reacted efficiently with meta-trifluoromethyl 6g and para-chlorophenyl diazonium tetrafluoroborates 6h to furnish the corresponding 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one derivatives 8k and 8l in 79% and 76% yields, respectively, with comparable diastereomeric ratios (dr = 6 : 4). Notably, the N-unsubstituted alkylidene oxindoles 1r and 1s also participated effectively in the spirocyclization, delivering products 8j, 8m and 8n in moderate yields and diastereoselectivity (dr ≈ 70 : 30 → 85 : 15). As a demonstration for the late-stage functionalisation of drugs, benzocaine, a topical anaesthetic, pain and itch reliever, was converted to its corresponding diazonium salt 6i and was reacted under the optimized conditions to afford the desired dimethyl 2′-(4-(ethoxycarbonyl)phenyl)-1-methyl-2-oxo-2′,4′-dihydrospiro[indoline-3,3′-pyrazole]-4′,5′-dicarboxylate 8o in 71% yield (Scheme 3). Finally, 7-chloro and 7-methoxy alkylidene oxindoles 1t and 1u afforded the desired products 8p and 8q in 75 and 77% yields, respectively, when reacted with 5b and 6h (Scheme 3).

This mechanochemical approach thus offers a green and efficient protocol for the synthesis of structurally complex and densely functionalized 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-ones under mild, catalyst-free conditions.

In a bid to evaluate the scalability of our mechanochemical protocol, we investigated the synthesis of 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one 8r using the DYNO®-MILL (DM) bead milling machine, a horizontal agitator bead mill used commonly under industrial settings. In spite of its diverse usage for pigment dispersion, pharmaceutical processing, and nanoparticle fabrication, the application of DYNO®-MILL in mechanochemical organic reactions under dry or minimal solvent conditions is limited (Table 3).³¹

Table 3 Scale-up synthesis of azaindazole 6a using the bead mill DYNO®-MILL

Entry	Rotor speed	Filling degree of beads	Time (minutes)	Yield^a (%)
a Isolated yield.
1	5000 rpm	60 v/v	120	44
2	4000 rpm	60 v/v	88	66
3	3000 rpm	60 v/v	48	65
4	3000 rpm	45 v/v	35	75
5	3000 rpm	20 v/v	120	25

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A representative scale-up experiment involved milling alkylidene oxindole 1v (10 mmol), diazonium salt 6a (20 mmol), and 5b (40 mmol) under dry conditions using 0.5 mm yttria-stabilized zirconia (ZrO₂/Y₂O₃) DYNO®-BEADS as grinding media. The milling was performed at 5000 rpm, corresponding to approximately 66% of the maximum rotor speed of the DYNO®-ACCELERATOR, with the optimized stoichiometric ratios reported in Table 2. This process provided 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one 8r in 44% isolated yield after 120 minutes (Table 3, entry 1). Considering a nominal handling loss during recovery of the product from the instrument, the actual yield may vary slightly.

Next, we systematically evaluated the milling parameters, viz rotor speed and bead filling volume. Decreasing the rotor speed to 4000 rpm resulted in an increased yield of 66% (Table 3, entry 2), while further reduction of the speed to 3000 rpm did not prove detrimental, maintaining a yield of 65% (Table 3, entry 3). These results suggest that 3000 rpm balances optimally between energy input and reaction efficiency for this system.

While optimizing the rotor speed, the filling degree of the reactor chamber with grinding media was also assessed. Decreasing the bead fill to 45% v/v could have enhanced the frequency of bead-particle collisions; subsequently, a significantly improved yield of approximately 75% of 8r in 35 minutes was observed (Table 3, entry 4). The grinding media type and size were held constant throughout all experiments to ensure reproducibility. Further reduction of the filling degree to 20% v/v led to a decrease in the yield of 8r (Table 3, entry 5).

These findings indicate that the efficiency of reactions in bead milling is governed not only by chemical stoichiometry but also by mechanical factors such as the rotor speed, bead packing density and quantity, and milling time. The successful scale-up of the solvent-free DYNO®-MILL process highlights the practical viability of this method—comparable reaction time for scale-up (35 minutes) while maintaining comparable yields. It demonstrates the potential to transition bench-scale mechanochemical techniques into industrially relevant batch or continuous-flow systems, providing a greener, more energy-efficient pathway for synthesizing complex heterocycles.

To gain insight into the reaction mechanism, a series of control experiments were conducted (Scheme 4). First, the reaction of 1a, 5a, and 6a under the optimized conditions was carried out in the presence of 2 equivalents of either 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or butylated hydroxytoluene (BHT). Notably, the reaction proceeded efficiently in both cases, affording the desired products in 75% and 79% yields, respectively (Scheme 4A[1]). These results suggest that the transformation likely follows an ionic, rather than a radical, pathway.

Scheme 4 (A) Control experiments to ascertain the mechanism of 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one, 8. (B) Assessing correct trajectory in the [3 + 2] cycloaddition between in situ nitrile imine 7 and 1. (C) Density functional theory calculations to ascertain the mode of attack. (D) Putative mechanism for the formation of 8.

Next, to probe the formation of a nitrile imine intermediate, a trapping experiment was performed using N-ethyl maleimide in place of 1a under otherwise identical conditions. The reaction between 5a, 6a, and N-ethyl maleimide led to the formation of compound 9, a fused maleimide–pyrazoline hybrid, in 74% yield (Scheme 4A[2]). This outcome supports the in situ formation of nitrile imine species in the reaction.

Based on the control experiment in Scheme 4A[2], we propose that nitrile imine 7 forms in situ and undergoes a [3 + 2] cycloaddition with alkylidene oxindole 1. To evaluate the feasibility of the two possible regioselective pathways (Scheme 4B), we conducted density functional theory calculations (M06-2X/def2-SVP) to model the cycloaddition between 1 and 7. The results (Scheme 4C) show that both pathways have comparable activation barriers, but the formation of regioisomer 8a is thermodynamically favoured, with a more negative reaction free energy (−52.3 kcal mol⁻¹) than that of 8a′ (−49.3 kcal mol⁻¹).

Based on the results of the control experiments and supported by DFT calculations (Scheme 4A–C), a plausible reaction mechanism is proposed for the mechanochemical synthesis of 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one 8 (Scheme 4D). The key intermediate in this process is the nitrile imine 7, which is generated in situ from the reaction between alkyl diazo acetate 5 and aryl diazonium tetrafluoroborates 6via intermediate A. The conversion of A to B occurs with the extrusion of nitrogen gas (N₂↑), followed by decomposition of B through the elimination of HBF₄ to afford nitrile imine 7. This reactive intermediate then undergoes a [3 + 2] cycloaddition with the alkylidene oxindole 1, furnishing the desired product 8 (Scheme 4D).

Conclusion

In conclusion, we have developed an efficient and sustainable strategy for the synthesis of spirocyclic oxindole frameworks via photochemical and mechanochemical spirocyclization of alkylidene oxindoles 1 under completely additive-free conditions, avoiding the use of acids, bases, or metal catalysts. The photochemical protocol, employing blue LED irradiation, enables the in situ generation of nitrile ylides 3 from acetonitrile and aryl diazoacetates 2, which subsequently undergo [3 + 2] cycloaddition and oxidation with 1 to afford spiro[pyrrolidine-3,3′-oxindoles] 4. In parallel, the mechanochemical approach facilitates the solvent-free generation of nitrile imines 7 from ethyl diazoacetate 5 and aryl diazonium tetrafluoroborates 6via ball milling, enabling the diastereoselective construction of 2′-aryl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one 8.

This dual activation platform not only underscores the versatility of diazo precursors under complementary reaction conditions but also exemplifies an environmentally benign route to access two pharmaceutically relevant spirocyclic scaffolds, widely recognized for their prevalence in bioactive natural products and drug-like molecules.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the ESI.†

Acknowledgements

The authors would like to thank Shiv Nadar Institution of Eminence (Deemed to be University) for funding and support for Ms. Swetha Singh and Mr. Roopam Pandey. S.S. would like to thank Willy A. Bachofen AG (WAB, Switzerland), in the persons of Erich Ermel and Jan Parduhn, for the loan of DYNO®-MILL system adapted for mechanochemical applications.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2356680. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5qo00851d

‡ Equal contributors.

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