Synthesis of N-fused polycyclic indoles via a Pd-catalyzed multicomponent cascade reaction consisting of an amide-directed [3+1+1] annulation reaction of 3-diazo oxindole and isocyanides

Abstract

Herein, we report a Pd-catalyzed multicomponent cascade reaction of 3-diazo oxindole and isocyanides to synthesize N-fused polycyclic indoles consisting of an in situ generated amide-assisted regioselective [3+1+1] annulation reaction. Additionally, a mechanism is proposed and investigated using DFT that strongly favors the role of amide in assisting the annulation reaction, which is further confirmed using control experiments.

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Introduction

N-Fused polycyclic indoles have attracted great attention in synthetic chemistry due to their ubiquitous presence in several natural products and pharmaceutical agents (Fig. 1). They display a wide range of biological activities such as anticancer, anti-inflammatory, antimicrobial, antiatherogenic, antihypertensive, etc. Moreover, indole-fused heterocycles are imperative structural units of various agrochemicals, plastics, and dyes that are integrated into everyday life.^1a–g

Fig. 1 Biologically important indole-fused heterocycles.

In this context, various combinations of polycyclic indole-fused heterocycles have been designed and synthesized in the past.^2a–e However, the production of these moieties is very challenging due to the requirement of multistep synthesis, which is associated with their disadvantages. So, the development of novel and efficient methodologies to synthesize indole-fused heterocyclic scaffolds is highly admirable in synthetic chemistry. Throughout the significant progress made in this area, different methods have been developed to synthesize tricyclic oxazolo[3,2-a]indole moieties. In this context, Zhu et al. synthesized oxazolo[3,2-a]indolones via a visible light-induced aerobic dearomative reaction of N-substituted indoles in the presence of a Ru-catalyst (Scheme 1a).³ Next, a metal- and solvent-free approach to synthesize oxazolo[3,2-a]indolones using propargylic alcohols and indole derivatives was developed by Oparina's group (Scheme 1b).⁴ Recently, Wang and co-workers reported a cascade approach to synthesize oxazolo[3,2-a]indolones along with indolo [2,3-b] indoles in the presence of a rhodium catalyst at 130 °C (Scheme 1c).⁵ However, most of these approaches are associated with certain limitations such as complex starting materials, longer reaction time, lower efficiency, and substrate scope.

Scheme 1 (a)–(c) Recent approaches to synthesizing tricyclic oxazolo[3,2-a]indole derivatives, (d)–(f) recent isocyanide insertion approaches, (g) our previous work, and (h) recent work.

On the other hand, cascade or tandem reactions have been found to be very advantageous to improve synthetic efficiency in modern organic chemistry.^6a–e Furthermore, the cascade reaction involves multiple bond-forming reactions in one pot, representing an attractive strategy towards the facile synthesis of novel molecular frameworks with less wastage of resources. In particular, transition metal-catalyzed one-pot cascade reactions are being used to generate novel fused heterocycles.^7a–c Interestingly, isocyanides have been considered important substrates for transition metal-catalyzed one-pot cascade reactions since they can react both as a nucleophile or an electrophile in chemical reactions.^8a–e In this context, several cascade reactions using isocyanides have been developed in the past. Recently, Tang's group reported a cerium triflate catalyzed triple isocyanide insertion approach to develop a library of oxazole derivatives.⁹ Next, Guchhait et al. developed a cascade C–H activation methodology to construct bicyclic indolyl motifs via intramolecular isocyanide insertion using Pd-catalysts.¹⁰ Another efficient approach towards consecutive triple isocyanide insertion into aldehydes to synthesize a broad library of 4-cyano oxazole derivatives was reported by Xu and co-workers. (Scheme 1d–f)¹¹ Also, we have developed a Pd-catalysed one-pot cascade reaction to access benzoxazine-fused 1,2,3-triazoles using N-aryl-α-(tosylhydrazone)acetamides with isocyanide.¹² In continuation of our efforts to develop novel cascade reactions by the use of isocyanide and diazo compounds (Scheme 1g),¹³ herein, we have developed a Pd-catalysed multicomponent cascade reaction of 3-diazo oxindole, isocyanide, and H₂O to generate tricyclic oxazolo[3,2-a]indole scaffolds (Scheme 1h).

Results and discussion

Initially, we envisioned the synthesis of indole-3-acetamide via the formation of indole-based ketenimine intermediates by the reaction of isocyanide and 3-diazo oxindole as previously reported by our group and others. To actualize our hypothesis, we set up a reaction of tert-butyl isocyanide, water, and 3-diazo oxindole using 10 mol% of Pd(PPh₃)₄ and 1.2 equivalent of Na₂CO₃ in toluene as a solvent at 80 °C, and obtained the product in a 30% isolated yield. However, characterization techniques such as ¹H-NMR, ¹³C-NMR, HRMS, and X-ray confirm the unprecedented formation of a tricyclic oxazolo[3,2-a]indole derivative (Scheme 2).

Scheme 2 Possible structures under a Pd-catalyzed reaction.

Drawing encouragement from these findings, next, we decided to optimize the reaction conditions to improve the yield of the multicomponent cascade reaction by selecting 3-diazo oxindole (1a), tert-butyl isocyanide (2a), and H₂O as model substrates. Initially, we screened different transition metal catalysts such as Cu(OAc)₂ and Rh₂(OAc)₄ in addition to Pd(PPh₃)₄, and unexpectedly the reaction worked only with the Pd-catalyst (Table 1, entries 1–3). Afterward, we examined different palladium-based catalysts like Pd(OAc)₂, Pd(TFA)₂, Pd(OPiv)₂, PdCl₂, PdCl₂(NCC₆H₅)₂, Pd(DPPF)Cl₂, Pd₂(dba)₃etc. and obtained product (3a) in a maximum yield, i.e. 56% when 10 mol% of Pd(OAc)₂ was added as a catalyst (Table 1, entry 4–6) and (Table S2, entries 1–4, ESI†). However, on decreasing the amount of Pd(OAc)₂ from 10 mol% to 5 mol%, the yield of the model reaction got decreased (Table S2, entry 5, ESI†). Also, it must be noticed that the reaction did not work in the absence of a palladium catalyst (Table 1, entry 7). Next, we screened different bases and found that the reaction provided a maximum yield in the case of K₂CO₃ as compared to other bases such as Na₂CO₃, Cs₂CO₃, KOt-Bu, NEt₃ and DBU (Table 1, entries 8–12). Also, it was observed that in the absence of a base, the yield of product (3a) decreased, up to a 27% yield (Table S2, entry 6, ESI†). Furthermore, toluene was replaced by various solvents like 1,4-dioxane, CH₃CN, DMF, DMSO, and THF; however, 1,4-dioxane was found to be the best solvent (Table 1, entry 13) and (Table S2, entries 7–10, ESI†). Besides, there was no improvement in the outcome of the model reaction observed while adding different additives like AgOAc and CsOAc (Table S2, entries 11 and 12, ESI†). Moreover, temperature variation significantly affected the outcome of the model reaction. In particular, decreasing the temperature from 80 °C to 60 °C increases the yield of 3a to 71% (Table 1, entry 14). Then, the yield of 3a was reduced by further decreasing the temperature to 50 °C (Table 1, entry 15). The reaction was almost diminished below 50 °C and the product was observed only in trace amounts at 40 °C (Table 1, entries 16 and 17). Subsequently, increasing the equivalent of water slightly decreased the yield to 60% (Table 1, entry 18). Noticeably, in the absence of water, only a 20% yield of product 3a was observed, which suggests the requirement of water in an equimolar amount in this transformation (Table 1, entry 19). Also, the molar ratio of the substrates was varied; however, 1 : 3.2 : 1 of 3-diazo oxindole, tert-butyl isocyanide, and water, respectively, remained the best ratio (Table S2, entries 13–16, ESI†).

Table 1 Optimization of the reaction conditions^a

Entry	Deviation from standard conditions	Yield^b (%)
a Reaction conditions: 3-diazo oxindole 1a (1.0 equiv., 0.31 mmol, and 50 mg), tert-butyl isocyanide 2a (3.2 equiv., 113 μL, and 0.99 mmol), H2O (1.0 equiv., 5.6 μL), Pd-catalyst (10 mol%), base (1.2 equiv.), and solvent (2 ml), for 3 h. b Isolated yield.
1	No deviation	30
2	Cu(OAc)2 instead of Pd(PPh3)4	—
3	Rh2(OAc)4 instead of Pd(PPh3)4	—
4	Pd(OAc)2 instead of Pd(PPh3)4	56
5	Pd(TFA)2 instead of Pd(PPh3)4	38
6	Pd(OPiv)2 instead of Pd(PPh3)4	31
7	No catalyst	—
8	Cs2CO3 instead of Na2CO3	51
9	K2CO3 instead of Na2CO3	59
10	KOt-Bu instead of Na2CO3	35
11	NEt3 instead of Na2CO3	43
12	DBU instead of Na2CO3	39
13	1,4-Dioxane instead of toluene	64
14	60 °C	71
15	50 °C	36
16	40 °C	Trace
17	rt	—
18	2 equiv. of H2O	60
19	No H2O	20

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After having the optimized reaction conditions in hand, we evaluated the feasibility of the reaction with different isocyanides as well as 3-diazo oxindole as revealed in Scheme 3.

Scheme 3 The substrate scope of the Pd-catalyzed multicomponent cascade reaction. Reaction conditions: 3-diazo oxindoles (1) (1.0 equiv.), isocyanides (2) (3.2 equiv.), H₂O (3) (1.0 equiv.), Pd(OAc)₂ (10 mol%), K₂CO₃ (1.2 equiv.), and 1,4-dioxane (2 mL), for 3 h, at 60 °C.

Firstly, we have replaced tert-butyl isocyanide with 1,1,3,3-tetramethyl butyl isocyanide or cyclohexyl isocyanide, and as a result, the corresponding products (3b and 3c) were obtained in slightly lower yields in comparison of the product 3a (Scheme 3). These results represent the structural role of isocyanides; as the steric hindrance increases, the yield of the reaction decreases. Besides, we have tried reactions with other isocyanides like p-methoxy phenyl isocyanide and p-toluene sulphonyl methyl-isocyanide; however, no product formation was observed with these isocyanides. Next, we have examined the effect of various electron-donating, electron-withdrawing, and halide substituents at different positions of 3-diazo oxindole. Initially, a range of electron-donating groups at different positions of the phenyl ring of 3-diazo oxindole were tested. Noticeably, in the case of 5-OMe-substituted 3-diazo oxindole, the reaction provided products (3d) and (3e) in 76% and 68% yields, respectively, whereas the reaction provided moderate to good yields of the desired products when 5-CH₃-substituted 3-diazo oxindole was employed with tert-butyl isocyanide, 1,1,3,3-tetramethyl butyl isocyanide, and cyclohexyl isocyanide, respectively (3f–h, Scheme 3). Also, 6-OMe-substituted 3-diazo oxindole provided products 3i and 3j in slightly lower yields, i.e., 59 and 53% (Scheme 3). It should be noted that the yield diminished when the electron-donating group, i.e. –CH₃, was incorporated at the 7-position of 3-diazo oxindole and it might be due to hindrance enhancement near the fringe where the reaction occurred (3k, Scheme 3). This abatement of yield indicated the significance of the electronic and steric effects of the substituents at different positions of 3-diazo oxindole. Next, electron-withdrawing groups i.e., 5-nitro and 5-OCF₃ substituted 3-diazo oxindole were used in the reaction and the products (3l and 3m) were attained in 56% and 37% isolated yield (Scheme 3), which slightly lower in comparison to 3-diazo oxindole having an electron-donating group at the same position. However, there was no product formation observed when 7-CF₃-containing 3-diazo oxindole was employed in the reaction (3n, Scheme 3). Afterward, we examined the effect of halides at different positions of 3-diazo oxindoles and found that in the case of 4-Cl and 4-Br substitutions, the yields almost diminished (3o and 3p, Scheme 3). Next, 5-F-substituted 3-diazo oxindole provides product 3q in a lower yield as compared to 3-diazo oxindole having electron-withdrawing and -donating groups. Next, 5-Cl- and 5-Br-substituted 3-diazo oxindoles were employed in the reaction, and the corresponding products (3r to 3u) were obtained in lower yields, i.e., 46 to 54% as compared to electron-donating and electron-withdrawing substitutions at 3-diazo oxindole. However, the reaction provided the product in a moderate yield when 6-Cl-substituted 3-diazo oxindole was used in the reaction (3v, Scheme 3). Again, halide substitution at the 7-position of 3-diazo oxindole did not work (3w, Scheme 3).

Besides, a Hammet study was performed to get further information about the effect of substituents on the rate of the reaction.¹⁴ In this view, 3-diazo oxindole having substituents like 5-OMe, 5-Me, 5-Cl and 5-NO₂ along with unsubstituted 3-diazo oxindole was employed in the multicomponent reaction (Scheme 4). The best linear fit (R² = 0.91) was achieved using the standard σ_p parameters vs. log k_X/k_H, providing a ρ value (slope value) of –0.28. The value of ρ is less than 1, which indicates that a positive charge is built up during the rate-determining step. Also, the positive slope value suggests that the rate of reaction increases in the presence of the electron-donating groups.

Scheme 4 Hammett plot for the reaction of isocyanide with electronically varied 3-diazo oxindoles.^{a a}Reaction conditions: 3-diazo oxindole 1a (1.0 equiv., 0.31 mmol), substituted 3-diazo oxindole 1a′ (1.0 equiv., 0.31 mmol), tert-butyl isocyanide 2a (3.2 equiv., 0.99 mmol), H₂O (1.0 equiv.), Pd(OAc)₂ (10 mol%), K₂CO₃ (1.2 equiv.), and 1,4-dioxane (2 mL), for 3 h, at 60 °C.

Next, we have presented a plausible mechanism for the synthesis of tricyclic oxazolo[3,2-a]indole scaffolds as shown in Fig. 2.¹⁵ Initially, tert-butyl isocyanide reacts with Pd(OAc)₂ to generate complex (I).^12,16a–d Then, tert-butyl isocyanide acts as a neutral ligand in complex (I), and palladium remains in its divalent oxidation state. Complex (I) then linked with the 3-diazo oxindole (1a) substrate to generate square planar complex (II) that served as our starting complex. In this context, Fig. 2 shows the overall mechanism's steps, and Fig. 3(a) displays the associated DFT-computed potential free energy profiles in relation to the energies of the initial complex (I + 1a). Furthermore, Fig. 3(b) depicts the optimized transition states computed at the B3LYP/6-31+G(d,p) level of theory.

Fig. 2 The plausible mechanism for Pd-catalyzed multicomponent cascade reaction.

Fig. 3 (a) The potential energy profiles computed at the M06/6-31++G(2d,2p)/B3LYP/6-31+G(d,p) level of theory related to the plausible mechanism represented in Fig. 2. (b) Optimized transition states computed at the B3LYP/6-31+G(d,p) level of theory.

Furthermore, the elimination of N₂ from complex (II) took place and generated Pd–carbene complex (III) viaTS1 (Fig. 3(b)) with the free energy of activation ΔG^‡ = 29.2 kcal mol⁻¹. The next step is the migration of isocyanide into the Pd–carbene complex through the three-membered ring transition state, TS2 (Fig. 3(b)), which has a 21.5 kcal mol⁻¹ free energy of activation and produces Pd-ketenimine complex (IV), which readily releases Pd(OAc)₂ to form highly unstable ketenimine intermediate (V). Furthermore, H₂O is connected to the central electrophilic carbon of the ketenimine intermediate (V) with simultaneous proton transfer to the nitrogen of the isocyanide unit viaTS3 (Fig. 3(b)) with ΔG^‡ = 13.3 kcal mol⁻¹ to form intermediate VI, which is stabilized by –37.2 kcal mol⁻¹ from TS3 (Fig. 3(b)).

After that, the tautomerization step takes place via proton transfer to the C-3 carbon of VI from the OH group to form amide intermediate (N-(tert-butyl)-2-oxoindoline-3-carboxamide) 4, through TS4 (Fig. 3(b)) with a barrier of 40.3 kcal mol⁻¹.^17a,b Afterward, N-(tert-butyl)-2-oxoindoline-3-carboxamide (4) interacts with palladium acetate to form six-membered complex VII, which releases the proton from the C-3 position and acetate group from the palladium catalyst as acetic acid to form complex VIIIvia transition state TS5 (Fig. 3(b)) with ΔG^‡ = 14.6 kcal mol⁻¹. During this step, the oxidation state of Pd remains unchanged, which is further coordinated with a second tert-butyl isocyanide to form a highly stabilized (–80.0 kcal mol⁻¹) tetravalent Pd-containing intermediate IX. Then, the amidic C=O group at the C2-position gets activated and an isocyanide unit is inserted into the Pd–O bond to form seven-membered complex X, which readily converts to five-membered palladacyclic intermediate complex XI having an energy of 22.3 kcal mol⁻¹, higher than complex X. Next, the third tert-butyl isocyanide proceeds to link to the Pd atom of complex (XI) to form stable tetravalent complex XII. Again, this isocyanide is inserted into the Pd–C bond and regains its six-membered intermediate to form intermediate XIII, having a higher energy of 8.6 kcal mol⁻¹ from complex XII. The acetate group present at the palladacyclic intermediate (XIII) abstracts the N–H proton via transition state TS6 (Fig. 3(b)), which is located at the point of –35.8 kcal mol⁻¹ in the PES and form another complex XIV, which possesses 44.6 kcal mol⁻¹ less energy from the starting complex. Afterward, complex XIV releases AcOH and forms another complex XV having slightly higher energy (3.8 kcal mol⁻¹) than complex XIII. Finally, C–N bond formation takes place via transition state, TS7 (Fig. 3(b)), having ΔG^‡ = 19.4 kcal mol⁻¹ from complex XV and forms complex XVI. Afterward, reductive elimination of palladium occurs in the form of palladium acetate to give the final product (3a) through intermediate XVII.

Finally, several control studies were carried out to confirm the role of amide in this synthesis. We set up a reaction using tert-butyl 3-diazo-2-oxoindoline-1-carboxylate (1p) with tert-butyl isocyanide under standard reaction conditions (Scheme 5i) and got product N-(tert-butyl)-2-oxoindoline-3-carboxamide (4) in a 78% yield. In continuation, we performed a reaction of N-(tert-butyl)-2-oxoindoline-3-carboxamide (4) with tert-butyl isocyanide under the same reaction conditions. Delightfully, we got the desired product (3a) in a good yield (Scheme 5ii), which confirmed the formation of N-(tert-butyl)-2-oxoindoline-3-carboxamide (4) as an intermediate in this transformation. To further confirm the role of in situ generated amide, we have tried the reaction with three different oxindole derivatives such as ethyl 2-oxoindoline-3-carboxylate (5), indolin-2-one (6), and 3-hydroxy-3-(2-oxopropyl)indolin-2-one (7). Surprisingly there was no reaction with these substrates {Scheme 5(iii–v)}. So, these control experiments suggest that the amide group at the C-3 position of oxindole is required to assist the reaction for further steps.^8,18 Next, we tried a reaction with D₂O in place of H₂O, and product formation was confirmed with HRMS analysis. HRMS data of the crude reaction mixture showed a peak at 398.2648, equivalent to a deuterated amide-based product. Hence, this experiment suggests the participation of H₂O molecules in the formation of amide {Scheme 5(vi)}.

Scheme 5 Control experiments. Reaction conditions for (i)–(v): substrates 1p/4/5/6 or 7 (1 equiv.), isocyanides (2) (3.2 equiv.), H₂O (1.0 equiv.), Pd(OAc)₂ (10 mol%), K₂CO₃ (1.2 equiv.), and 1,4-dioxane (2 mL), for 3 h, at 60 °C. (vi) 1a (1 equiv.), isocyanides (2) (3.2 equiv.), D₂O (4.0 equiv.), Pd(OAc)₂ (10 mol%), K₂CO₃ (1.2 equiv.), and 1,4-dioxane (2 mL), for 3 h, at 60 °C.

Conclusions

In summary, we have developed a Pd-catalysed and amide-assisted multicomponent reaction of 3-diazo oxindole, isocyanide, and water to generate oxazole-fused indole scaffolds. The functional group tolerance at different positions of 3-diazo oxindole along with different isocyanides was tested and the corresponding products were obtained in 37–76% isolated yields. Besides, a DFT study was performed to get an overview of the proposed mechanism, which recommended that the reaction involved amide formation at the C-3 position via isocyanide insertion, which subsequently assisted a [3+1+1] annulation reaction to furnish oxazole-fused indoles. Also, the role of in situ-generated amide to assist the annulation reaction was confirmed by setting up different control experiments.

Procedure and characterization

General procedure to synthesize (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3a–3q)

In a glass tube equipped with a stirrer bar, 3-diazo oxindole (1.0 equiv., 50 mg, 0.31 mmol), H₂O (1.0 equiv., 5.6 μL, 0.31 mmol), Pd(OAc)₂ (10 mol%, 7 mg), K₂CO₃ (1.5 equiv., 65 mg, 0.47 mmol) and 2 mL of 1,4-dioxane as a solvent were added. Then, the resulting reaction mixture was stirred at 60 °C in a preheated oil bath and tert-butyl isocyanide (3.2 equiv., 116 μL, 0.99 mmol) was added slowly with the help of a syringe. After completion of the reaction as indicated by TLC, work-up of the reaction mixture was done using ethyl acetate and distilled water in a 2 : 1 ratio followed by evaporation of volatiles under a reduced pressure. Next, the crude mixture was purified by column chromatography using ethyl acetate in hexane as an eluent affording the corresponding (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-2,3-dihydrooxazolo[3,2-a]indole-9 carboxamide (3a–3w) in 37–76% yields.

Characterization data

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3a). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3a; yellow solid, yield = 71% (88 mg, 0.223 mmol), ¹H NMR (400 MHz, CDCl₃): 8.20 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.27–7.18 (m, 2H), 5.70 (s, 1H), 1.52 (s, 9H), 1.50 (s, 9H), 1.47 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.3, 148.8, 136.5, 133.0, 128.9, 127.4, 124.2, 123.1, 121.9, 112.6, 87.8, 57.6, 55.9, 51.4, 30.0, 29.5, 29.4 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₃N₄O₂ 397.2604; found 397.2601.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-(2,4,4-trimethylpentan-2-yl)-2,3-bis((2,4,4-trimethylpentan-2-yl)imino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3b). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3b: yellow solid, yield = 57% (101 mg, 0.179 mmol), ¹H NMR (400 MHz, CDCl₃): 8.24 (d, J = 8 Hz, 1H), 7.94 (d, J = 8 Hz, 1H), 7.28–7.19 (m, 2H), 5.62 (s, 1H), 2.01 (s, 2H), 1.92 (s, 4H), 1.58 (s, 6H), 1.55 (s, 6H), 1.51 (s, 6H), 1.03 (s, 9H), 1.00 (s, 9H), 1.00 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.3, 148.4, 136.2, 131.8, 129.0, 127.5, 124.2, 123.1, 122.1, 112.5, 87.7, 61.4, 60.0, 55.3, 54.3, 54.1, 51.1, 32.2, 32.1, 32.0, 31.9, 31.7, 31.6, 31.0, 30.3, 30.2 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₅H₅₇N₄O₂ 565.4487; found 565.4487.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-cyclohexyl-2,3-bis(cyclohexylimino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3c). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3c: yellow solid, yield = 60% (89 mg, 0.188 mmol), ¹H NMR (400 MHz, CDCl₃): 8.11 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.27–7.19 (m, 2H), 5.78 (d, J = 8.0 Hz, 1H), 4.78–4.71 (m, 1H), 4.09–3.97 (m, 2H), 2.00–1.26 (m, 30H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 160.7, 148.1, 138.2, 133.3, 127.6, 126.1, 123.1, 122.1, 120.5, 111.6, 86.7, 56.3, 55.3, 46.2, 32.9, 32.1, 32.0, 24.8, 24.7, 24.6, 23.4, 23.3, 22.7 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₉N₄O₂ 475.3069; found 475.3073.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-7-methoxy-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3d). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3d: yellow solid, yield = 76% (86 mg, 0.201 mmol), ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 6.80 (dd, J = 8.8, 2.8 Hz, 1H), 5.70 (s, 1H), 3.86 (s, 3H), 1.50 (s, 9H), 1.49 (s, 9H), 1.46 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.6, 157.1, 149.2, 136.4, 132.8, 130.0, 121.8, 113.3, 112.2, 104.5, 87.8, 57.6, 55.8, 51.4, 30.0, 29.5, 29.4 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₅N₄O₃ 427.2709; found 427.2712.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-cyclohexyl-2,3-bis(cyclohexylimino)-7-methoxy-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3e). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3e: yellow solid, yield = 68% (137 mg, 0.272 mmol), ¹H NMR (400 MHz, CDCl₃): 7.75–7.73 (m, 2H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 5.74 (d, J = 8.0 Hz, 1H), 4.76–4.69 (m, 1H), 3.86 (s, 3H), 2.00–1.27 (m, 30H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.0, 157.1, 149.4, 139.2, 134.3, 130.0, 121.7, 113.5, 112.1, 104.7, 87.7, 57.4, 56.4, 55.7, 47.3, 34.0, 33.2, 33.1, 29.8, 25.85, 25.77, 25.72, 24.5, 24.4, 23.8 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₀H₄₁N₄O₃ 505.3179; found 505.3179.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-7-methyl-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3f). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3f: yellow solid, yield = 73% (86.5 mg, 0.211 mmol), ¹H NMR (400 MHz, CDCl₃): 8.04 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.01 (dd, J = 1.2, 8.4 Hz, 1H), 5.69 (s, 1H), 2.41 (s, 3H), 1.51 (s, 9H), 1.49 (s, 9H), 1.46 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.6, 148.9, 136.6, 133.9, 132.9, 129.0, 125.6, 124.2, 122.1, 112.2, 87.6, 57.6, 55.8, 51.4, 30.0, 29.5, 29.3, 21.8 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₅N₄O₂ 411.2760; found 411.2755.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-7-methyl-N-(2,4,4-trimethylpentan-2-yl)-2,3-bis((2,4,4-trimethylpentan-2-yl)imino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3g). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3g: yellow solid, yield = 65% (108 mg, 0.188 mmol), ¹H NMR (400 MHz, CDCl₃): 8.08 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 5.61 (s, 1H), 2.42 (s, 3H), 2.00 (s, 2H), 1.92 (s, 2H), 1.91 (s, 2H), 1.57 (s, 6H), 1.54 (s, 6H), 1.51 (s, 6H), 1.02 (s, 9H), 1.00 (s, 9H), 0.99 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.5, 148.6, 136.3, 133.9, 131.7, 129.2, 125.6, 124.2, 122.2, 112.1, 87.4, 61.4, 59.9, 55.3, 54.4, 54.1, 51.0, 32.2, 32.1, 32.0, 31.9, 31.7, 31.6, 31.0, 30.3, 30.1, 29.8, 21.8 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₆H₅₉N₄O₂ 579.4638; found 579.4632.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-cyclohexyl-2,3-bis(cyclohexylimino)-7-methyl-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3h). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3h: yellow solid, yield = 63% (88.8 mg, 0.182 mmol), ¹H NMR (400 MHz, CDCl₃): 7.95 (s, 1H), 7.73 (d, 1H), 7.03 (dd, J = 8.4, 1.2 Hz, 1H), 5.75 (d, J = 7.6 Hz, 1H), 4.77–4.71 (m, 1H), 4.08–3.96 (m, 2H), 2.43 (s, 3H), 1.82–1.24 (m, 30H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 160.8, 148.1, 138.3, 133.3, 132.8, 127.8, 124.3, 123.2, 120.8, 111.3, 86.4, 56.3, 55.3, 46.2, 32.9, 32.1, 32.0, 28.6, 24.74, 24.67, 24.6, 23.4, 23.3, 22.7, 20.8 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₀H₄₁N₄O₂ 489.3230; found 489.3224.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-6-methoxy-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3i). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3i: yellow solid, yield = 59% (66.5 mg, 0.156 mmol), ¹H NMR (400 MHz, CDCl₃): δ 8.06 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 5.67 (s, 1H), 3.83 (s, 3H), 1.51 (s, 9H), 1.49 (s, 9H), 1.46 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.4, 156.7, 147.9, 136.8, 133.1, 128.1, 122.5, 122.4, 111.6, 98.2, 87.7, 57.5, 55.9, 55.7, 51.3, 30.0, 29.5, 29.4 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₅N₄O₃ 427.2709; found 427.2714.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-cyclohexyl-2,3-bis(cyclohexylimino)-6-methoxy-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3j). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3j: yellow solid, yield = 53% (70 mg, 0.140 mmol), ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.8 Hz, 2.4 Hz), 4.77–4.71 (m, 1H), 4.08–3.95 (m, 1H), 3.85 (s, 3H), 2.00–1.24 (m, 30H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 170.8, 161.9, 156.9, 148.2, 139.5, 134.5, 128.0, 122.3, 122.2, 111.7, 98.3, 87.6, 57.3, 56.4, 55.8, 47.3, 34.0, 33.2, 29.8, 25.9, 25.8, 25.7, 24.5, 24.4, 23.8, 23.1 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₀H₄₀N₄O₃ 505.3179; found 505.3177.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-7-nitro-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3l). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3l: yellow solid, yield = 56% (60.5 mg, 0.137 mmol), ¹H NMR (400 MHz, CDCl₃): δ 9.15 (d, J = 2.0 Hz, 1H), 8.13 (td, J = 8.8, 2.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 5.68 (s, 1H), 1.53 (s, 9H), 1.51 (s, 9H), 1.47 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.2, 149.7, 144.8, 135.0, 132.3, 130.3, 129.2, 119.0, 118.5, 112.4, 88.7, 58.2, 56.6, 51.7, 30.0, 29.34, 29.27, 28.8 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₂N₅O₄ 442.2454; found 442.2463.

¹H NMR (700 MHz, CDCl₃), ¹³C{¹H} NMR (175 MHz, CDCl₃) and ¹⁹F{¹H} NMR (376 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-7-(trifluoromethoxy)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3m). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3m: yellow solid, yield = 37% (36.5 mg, 0.076 mmol), ¹H NMR (700 MHz, CDCl₃): 8.17 (d, J = 1.4 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.11 (dd, J = 8.4, 1.4 Hz, 1H), 5.70 (s, 1H), 1.55 (s, 9H), 1.54 (s, 9H), 1.50 (s, 9H) ppm. ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 161.8, 149.4, 145.97, 145.96, 135.7, 132.5, 129.9, 125.6, 121.37, 119.91, 116.7, 115.1, 113.1, 88.0, 57.8, 56.0, 51.4, 29.9, 29.3, 29.2 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): −57.86 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₂F₃N₄O₃ 481.2427; found 481.2430.

¹H NMR (700 MHz, CDCl₃), ¹³C{¹H} NMR (175 MHz, CDCl₃) and ¹⁹F{¹H} NMR (376 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-7-fluoro-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3q). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3q: yellow solid, yield = 41% (48 mg, 0.116 mmol), ¹H NMR (700 MHz, CDCl₃): δ 7.96 (dd, J = 9.8 Hz, 2.8 Hz, 1H), 7.84 (q, J = 4.2 Hz, 1H), 6.95 (td, J = 8.4 Hz, 2.1 Hz, 1H), 5.69 (s, 1H), 1.55 (s, 9H), 1.53 (s, 9H), 1.50 (s, 9H) ppm. ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 162.0, 160.9, 159.5, 149.4, 135.9, 132.6, 130.2, 130.1, 123.7, 113.3, 113.2, 110.6, 110.5, 108.6, 108.4, 87.9, 57.7, 56.0, 51.4, 29.9, 29.4, 29.3 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): −117.66 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₂FN₄O₂ 415.2509; found 415.2513.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-7-chloro-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3r). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3r; yellow solid, yield = 54% (60 mg, 0.140 mmol), ¹H NMR (400 MHz, CDCl₃): 8.25 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 2.0, 8.0 Hz, 1H), 5.66 (s, 1H), 1.51 (s, 9H), 1.50 (s, 9H), 1.46 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.9, 149.2, 135.9, 132.6, 130.2, 130.0, 125.7, 123.3, 121.9, 113.4, 87.6, 57.8, 56.1, 51.5, 30.0, 29.4, 29.3 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₂ClN₄O₂ 431.2214; found 431.2212.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-7-chloro-N-(2,4,4-trimethylpentan-2-yl)-2,3-bis((2,4,4-trimethylpentan-2-yl)imino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3s). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3s; yellow solid, yield = 46% (71 mg, 0.119 mmol), ¹H NMR (400 MHz, CDCl₃): δ 8.28 (d, J = 4.0 Hz, 1H), δ 7.83 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 5.58 (s, 1H), 1.99 (s, 2H), 1.91 (s, 4H), 1.57 (s, 6H), 1.54 (s, 6H), 1.50 (s, 6H), 1.02 (s, 9H), 1.00 (s, 9H), 0.99 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.8, 148.9, 135.5, 131.4, 130.3, 129.9, 125.7, 123.4, 122.0, 113.3, 87.5, 61.6, 60.2, 55.4, 54.3, 54.1, 51.0, 32.14, 32.09, 32.05, 31.9, 31.7, 31.6, 31.0, 30.2, 30.1 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₅H₅₆ClN₄O₂ 599.4092; found 599.4091.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-7-bromo-N-(tert-butyl)-2,3-bis(tert-butylimino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3t). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3t: yellow solid, yield = 51% (51 mg, 0.107 mmol), ¹H NMR (400 MHz, CDCl₃): 8.41 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 2.0, 8.0 Hz, 2H), 5.66 (s, 1H), 1.51 (s, 9H), 1.50 (s, 9H), 1.46 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.9, 149.1, 135.8, 132.6, 130.6, 126.1, 126.0, 124.8, 117.7, 113.8, 87.4, 57.8, 56.1, 51.5, 30.0, 29.4, 29.3 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₂BrN₄O₂ 475.1709; found 475.1709.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of (2Z,3E)-7-bromo-N-cyclohexyl-2,3-bis(cyclohexylimino)-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3u). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3u: yellow solid, yield = 48% (56 mg, 0.101 mmol), ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 5.71 (d, J = 7.6 Hz, 1H), 4.76–4.70 (m, 1H), 4.08–3.96 (m, 1H), 2.00–1.24 (m, 30H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.3, 149.3, 138.7, 134.1, 130.5, 126.1, 125.8, 124.7, 117.7, 114.0, 87.4, 57.6, 56.6, 47.5, 33.9, 33.2, 33.1, 29.8, 25.81, 25.76, 25.7, 24.5, 24.4, 23.8 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₈BrN₄O₂ 553.2178; found 553.2180.

¹H NMR (700 MHz, CDCl₃) and ¹³C{¹H} NMR (175 MHz, CDCl₃) spectra of (2Z,3E)-N-(tert-butyl)-2,3-bis(tert-butylimino)-6-chloro-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (3v). Purification by column chromatography (EtOAc : hexane v/v 1 : 19) afforded 3v:; yellow solid, yield = 50% (56 mg, 0.129 mmol), ¹H NMR (700 MHz, CDCl₃): δ 8.17 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.26 (dd, J = 8.4, 1.4 Hz, 1H), 5.71 (s, 1H), 1.55 (s, 9H), 1.53 (s, 9H), 1.50 (s, 9H) ppm. ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 161.9, 148.6, 135.9, 132.5, 128.7, 124.50, 122.8, 112.1, 87.8, 57.8, 56.1, 51.4, 29.9, 29.3, 29.2 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₃N₄O₂ 431.2213; found 431.2214.

¹H NMR (400 MHz, CDCl₃) and ¹³C{¹H} NMR (100 MHz, CDCl₃) spectra of N-(tert-butyl)-2-oxoindoline-3-carboxamide (4). Purification by column chromatography (EtOAc : hexane v/v 1 : 9) afforded 4; off-white solid, yield = 78% (70 mg, 0.301 mmol), ¹H NMR (400 MHz, CDCl₃): δ 8.25 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.33 (s, 1H), 7.24 (t, J = 6.8 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.2, 1H), 4.18 (s, 1H), 1.37 (s, 9H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 175.7, 162.5, 140.5, 128.6, 127.4, 124.4, 123.2, 109.8, 51.7, 51.4, 28.8 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₆N₂O₂Na 255.1109; found 255.1110.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

We are thankful to the Science and Engineering Research Board (SERB), India (CRG/2021/002077) and Centre of Excellence for Emerging Materials, Thapar Institute of Engineering and Technology, Patiala (TIET/CEEMS/Regular/2022/042) for financial support. Also, we acknowledge the DST-FIST grant (SR/FST/CS-II/2018/69) at the School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Patiala and Single Crystal X-ray Diffraction (SCXRD) facility at the Department of Chemistry, Panjab University, Chandigarh for providing the X-ray crystallography data.

References

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Footnote

† Electronic supplementary information (ESI) available: X-ray crystal data of compound 3a, copies of ¹H NMR and ¹³C NMR data of the compounds (3a–3q, 4), computational details, optimized transition states and optimized Cartesian coordinates and electronic energies. CCDC 2291510. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3nj04886a

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