Synthesis of benzofuranyl indolinones and benzonaphthoxazepinones via reaction of sulfonyl phthalide with nitroisatylidenes

Abstract

The attempted [4 + 2] Hauser–Kraus annulation of sulfonyl phthalide with nitroisatylidenes led to the formation of benzofuranyl indolinones, instead of the expected spironaphthoquinone oxindoles, via nucleophilic vinylic substitution of the nitro group. In contrast, the reaction of sulfonyl phthalide with nitroisoxazolyl isatylidenes followed the [4 + 2] Hauser–Kraus pathway, yielding benzonaphthoxazepinones via spontaneous rearrangement of the initially formed Hauser–Kraus adducts, namely, spironaphthoquinone oxindoles.

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Introduction

Nitrogen and oxygen-containing heterocycles often exhibit potent therapeutic properties and are valuable compounds in medicinal chemistry.¹ Among these, oxindole-based alkylidenes and spiro compounds, as well as oxindole-derived heterocycles, have attracted significant attention due to their versatility and significant bioactivity. These classes of compounds not only display a broad spectrum of biological activities but also serve as valuable scaffolds for the design of novel therapeutics.² Alkylidene oxindoles of types I–III exhibit a wide range of bioactivities such as anticancer, anti-inflammatory, and antimicrobial activities, making them promising candidates for drug development (Fig. 1).³ The alkylidene moiety plays a crucial role in enhancing the electronic properties of the molecule, thereby binding to key biological targets and improving its overall biological efficacy.

Fig. 1 Representative examples of biologically active compounds containing alkylidene/spirooxindoles and oxazepines.

Spirooxindoles also belong to a unique class of heterocycles that exhibit a wide range of biological activities, especially pharmacological properties such as antimalarial, antitumor, antidiabetic, and antiviral properties.^4,5 Therefore, there is considerable interest in the scientific community to synthesize various spirooxindole derivatives (e.g.IV).⁴

From another perspective, benzoxazepines, which are seven-membered heterocyclic compounds containing both nitrogen and oxygen in their ring structure, represent an important class of molecules with significant potential in medicinal chemistry.⁶ Their unique structural features are commonly found in a variety of bioactive heterocyclic compounds, making them attractive targets for synthetic chemists. These compounds exhibit a wide range of promising biological and pharmaceutical activities,⁶ including anti-inflammatory, antipyretic, antiphlogistic, AMPA receptor stimulation and antidepressant activities (e.g. compound VI). Notably, benzoxazepines (e.g., compound V) have shown strong inhibitory effects on HIV-1 reverse transcriptase, making them valuable candidates for the treatment of HIV-1 infection.⁷

The [4 + 2] annulation of stabilized phthalide anions with electron-deficient olefins, popularly known as the Hauser–Kraus (H–K) reaction, is a powerful strategy for synthesizing benzannulated quinones and naphthoquinones.^8,9 The reaction takes advantage of the 1,4-dipolar reactivity of phthalide with various Michael acceptors. It proceeds through a sequence of Michael addition, Dieckmann cyclization and elimination, resulting in the formation of naphthalene derivatives, which are essential scaffolds in medicinal chemistry and natural product synthesis.

In recent years, we and others have extensively investigated the [4 + 2] Hauser–Kraus annulation and other annulation pathways as well as alternative reactivities of sulfonyl phthalide with various Michael acceptors.^10,11 In particular, we have explored the reactivity of sulfonyl phthalide with o-hydroxynitroalkenes,^12ao-hydroxychalcones/o-hydroxynitrostyrenyl isoxazoles,^12b and nitroalkene-derived Rauhut–Currier adducts¹³ as Michael acceptors, which led to complex-fused and spiro-heterocycles (Scheme 1a). However, to the best of our knowledge, the application of isatin-derived nitroalkenes in Hauser–Kraus annulation with sulfonyl phthalide has remained unexplored. Herein, we report a base-mediated reaction of sulfonyl phthalide with various isatin-derived nitroalkenes, including nitroisoxazoles, resulting in the formation of unusual substitution and annulation products (Scheme 1b).

Scheme 1 The Hauser–Kraus annulation of nitroalkenes and nitrodienes, previous work vs. present work.

Results and discussion

We commenced our investigations by preparing nitroisatylidenes 2 using our recently reported procedure.¹⁴ In anticipation of obtaining the spirocyclic compound via Hauser–Kraus (HK) annulation (Scheme 1b), sulfonyl phthalide 1a ¹⁵ was treated with nitroisatylidene 2a in the presence of 1 equiv. of Cs₂CO₃ in THF (Table 1). This resulted in the formation of benzofuranyl indolinone 3a in 70% yield via stereoselective substitution of the sp²-nitro group instead of the anticipated spirocyclic product (entry 1). Encouraged by this unexpected result, various organic and inorganic bases were screened to improve the yield of 3a. While product 3a was obtained in a slightly lower yield (65%) in the presence of K₂CO₃ (entry 2), the yield dropped substantially to 48% in the triethylamine mediated reaction (entry 3). Furthermore, there was no reaction when DBU was used as the base even after a prolonged reaction time (entry 4). Increasing the stoichiometry of Cs₂CO₃ to 2 equiv. furnished product 3a in an excellent yield (98%) in a shorter reaction time (1 h, entry 5). However, the reaction in the presence of 2 equiv. of other bases such as K₂CO₃ and Na₂CO₃ gave inferior results (entries 6 and 7). Based on the above results, Cs₂CO₃ was chosen for further optimization studies. Thus, the effect of solvents on the reaction was systematically investigated by screening various polar protic and aprotic, halogenated, and hydrocarbon solvents (entries 8–14). Although none of them were comparable to THF, ethanol and 1,4-dioxane delivered the products in good yields (72–78%, entries 8 and 9). While the starting materials decomposed in the case of DMF and NMP (entries 10 and 11), the yields were quite low with other solvents such as acetonitrile, DCM, and toluene (entries 12–14).

Table 1 Optimization of the reaction conditions^a

Entry	Base (equiv.)	Solvent	Time (h)	Yield^b (%)
a Reaction scale: 0.1 mmol each of 1a and 2a in 1.0 ml of solvent at rt. b After silica gel column chromatography. c Starting material decomposed.
1	Cs2CO3 (1.0)	THF	5	70
2	K2CO3 (1.0)	THF	5	65
3	TEA (1.0)	THF	12	48
4	DBU (1.0)	THF	72	NR
5	Cs 2 CO 3 (2.0)	THF	1	98
6	K2CO3 (2.0)	THF	2	76
7	Na2CO3 (2.0)	THF	4	65
8	Cs2CO3 (2.0)	EtOH	6	72
9	Cs2CO3 (2.0)	1,4-Dioxane	5	78
10	Cs2CO3 (2.0)	DMF	0.5	—^c
11	Cs2CO3 (2.0)	NMP	0.5	—^c
12	Cs2CO3 (2.0)	MeCN	72	11
13	Cs2CO3 (2.0)	DCM	24	42
14	Cs2CO3 (2.0)	Toluene	6	31

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After establishing the optimal conditions (Table 1, entry 5), the reactivity of various nitroisatylidenes 2 with sulfonyl phthalides 1 was investigated for the preparation of benzofuranyl indolinones 3 (Table 2). Thus, in addition to 3a, which was formed from 1a and 2a in a nearly quantitative yield (98%) under the optimized conditions, various nitroisatylidenes 2b–g bearing substituents such as Me, Et, Pr, allyl, propargyl and benzyl on ring-N were treated with phthalide 1a to afford products 3b–g in good to excellent yields (82–95%) within short reaction times (3–4 h).

Table 2 Scope of nitroisatylidenes and sulfonyl phthalides in the synthesis of benzofuranyl indolinones^a

a Reaction scale: 0.2 mmol each of 1 and 2, and 0.4 mmol of Cs₂CO₃ in 2 ml THF. b Yield after silica gel column chromatography. c Scale-up synthesis with 1 mmol each of 1 and 2 and 2 mmol of Cs₂CO₃ in 6 ml THF. d Nitroisatylidene 2 decomposed after 2 h.

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Subsequently, several nitroisatylidenes with substituents such as OMe, Cl and Br at position 5 of the benzo ring (2h–j) were screened. As in the case of various ring N-substituents, the strongly electron donating OMe group and weakly electron withdrawing halogens (Cl and Br) delivered products 3h–j in comparable yields (83–86%) and reaction times (3–4 h).

The substrate scope was further investigated by varying the aryl group in the arylsulfonyl phthalide 1. Notably, phthalides bearing both weakly and strongly electron-donating (Me and OMe) and weakly electron-withdrawing (Cl and Br) groups on the arene of the aryl sulfonyl moiety delivered the corresponding products 3k–n in excellent yields (91–95%) in 2–5 h, indicating minimal electronic influence of the aryl sulfonyl group on the transformation. Later, the reactivity of bulky 2-naphthyl sulfonyl phthalide 1f was investigated, which afforded product 3o in 91% yield. We attempted to further expand the scope of the reaction by using electron donating as well as electron withdrawing groups present on the benzo ring of sulfonyl phthalide 1. In these cases, the desired products 3p and 3q were formed only in traces and nitroisatylidene 2 decomposed upon prolonging the reaction time beyond 2 h. A representative reaction was also carried out on a millimolar scale, which afforded product 3a, although in a lower yield (78%) and a longer reaction time (3 h).

Inspired by the above results, we investigated the reactivity of another 1,2-dipolarophile, i.e. isatin derived nitroisoxazole¹⁶4, with sulfonyl phthalide 1 (Table 3). Initially, the reaction of unprotected isatin derived nitroisoxazole 4a and sulfonyl phthalide 1a was performed using 1 equiv. of Cs₂CO₃ in THF at room temperature. Surprisingly, instead of the expected spirooxindole (see Scheme 1b), highly rearranged seven membered cyclic carbamate 5a was isolated in 65% yield after 24 h.

Table 3 Optimization of the reaction conditions^a

Entry	Base (equiv.)	Solvent	Time (h)	Yield^b (%)
a Reaction scale: 0.2 mmol of 4a and 0.22 mmol of 1a in 2 ml solvent. b After silica gel column chromatography. c NR = no reaction. d Incomplete reaction. e Starting material decomposed.
1	Cs2CO3 (1.0)	THF	24	65
2	K2CO3 (1.0)	THF	24	58
3	LiO^tBu (1.0)	THF	24	62
4	DBU (1.0)	THF	48	NR^c
5	Cs2CO3 (0.5)	THF	72	45^d
6	Cs2CO3 (0.2)	THF	72	30^d
7	Cs2CO3 (2.0)	THF	24	80
8	Cs 2 CO 3 (2.5)	THF	2	86
9	Cs2CO3 (3)	THF	2	73
10	Na2CO3 (2.5)	THF	9	64
11	K2CO3 (2.5)	THF	3	71
12	LiO^tBu (2.5)	THF	3	68
13	Cs2CO3 (2.5)	EtOH	2	52
14	CS2CO3 (2.5)	1,4-Dioxane	3	61
15	CS2CO3 (2.5)	NMP	3	—^e
16	CS2CO3 (2.5)	DMF	3	—^e
17	Cs2CO3 (2.5)	DCM	24	68
18	Cs2CO3 (2.5)	MeCN	24	75

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To further improve the yield in the above reaction, various bases and solvents were screened. Inorganic bases, such as K₂CO₃ and LiO^tBu, resulted in the isolation of product 5a in 58% and 62% yields, respectively (entries 2 and 3). In contrast, when DBU was used, no reaction occurred even after 48 h (entry 4). We further intended to modify the stoichiometry of the base to improve the reaction efficiency. Lowering the base loading from 1 equiv. to 0.5 equiv. and 0.2 equiv. led to incomplete reactions even after 3 days and product 5a was isolated in 45% and 30% yields, respectively (entries 5 and 6). Conversely, a significant improvement in product yield to 80% was achieved by increasing the base loading to 2 equiv. (entry 7). Further increasing the base loading to 2.5 equiv. led to the formation of 5a in 86% yield (entry 8), but increasing the base loading to 3 equiv. decreased the yield to 73% (entry 9). As in the previous case, other bases such as K₂CO₃, Na₂CO₃, and LiO^tBu were screened at a higher loading (2.5 equiv.), but the results (entries 10–12) were not superior to that obtained with Cs₂CO₃ (entry 8). Later, the effect of solvent on the reaction was also investigated as before, which revealed that while NMP and DMF were not suitable for our reaction (entries 15 and 16), ethanol, 1,4-dioxane, DCM and acetonitrile delivered the product in much lower yields when compared to THF (52–75%, entries 13, 14, 17, and 18).

After confirming 2.5 equiv. Cs₂CO₃ in THF at room temperature as the optimal conditions for the reaction (Table 3, entry 8), the reactivity of various isatin derived nitro-isoxazoles 4 with sulfonyl phthalide 1 was investigated for the preparation of the oxazepine 5 skeleton (Table 4). Besides 4a, which afforded oxazepine 5a in 86% yield, several benzo-substituted nitroisoxazolyl isatylidenes 4b–e were screened. Gratifyingly, the strongly electron donating 4-methoxy and weakly electron donating 4-methyl analogs 4b and 4c underwent the reaction smoothly to give oxazepines 5b and 5c in excellent yields (95% and 90%, respectively).

Table 4 Scope of protected and unprotected nitroisoxazolyl isatylidenes^a,b

a Reaction scale: 0.2 mmol each of 1 and 4 and 0.5 mmol of Cs₂CO₃ in 2 ml THF. b Yield after silica gel column chromatography. c Scale up: 1 mmol each of 1 and 4 and 2.5 mmol of Cs₂CO₃ in 6 ml THF. d Isatylidene 4 decomposed after 3 h.

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Quite remarkably, isatylidenes bearing a mild electron-withdrawing group, namely, the 5-bromo and 5-chloro analogs 4d and 4e, also afforded the corresponding products 5d and 5e in excellent yields (92% and 89%, respectively). The reaction of a phthalide bearing multiple electron-donating groups, as in the 3,5-dimethoxy analog 1g, with isatylidene 4a also proceeded well, providing product 5f in 85% yield. However, an electron withdrawing group such as CN on the benzo ring of phthalide 1 was not tolerated, thus preventing access to product 5g. To our surprise, the N-substituted isatylidene 4g, although it reacted with phthalide 1a, delivered the H–K annulated spirocyclic product 6, instead of the oxazepine. Although lower yields and longer reaction times were encountered upon scale-up, the representative product 5a was synthesized on a millimolar scale in 73% yield in 4 h.

Based on the above results, the proposed mechanism for the reaction of nitroisatylidene 2 with phthalide 1 begins with base-mediated deprotonation of phthalide 1 to generate intermediate II (Scheme 2a). Intermediate II then attacks the α-position of nitroalkene 2 to give intermediate III, which undergoes elimination of HNO₂ to provide benzofuranyl indolin-2-one 3 as a single geometrical isomer. However, in the case of nitroisoxazolyl isatylidene 4, intermediate III, in which the sulfonyl group and the isoxazole moiety, which is not a leaving group, are cis to each other, undergoes intramolecular Dieckmann cyclization with the lactone carbonyl carbon from the opposite side of the isoxazole moiety, followed by elimination of the sulfonyl group, resulting in the formation of the Hauser–Kraus annulated product 6 (Scheme 2b). However, in the absence of any protecting group on N, product 6 becomes quite unstable and undergoes further rearrangement, which involves the deprotonation of NH followed by ring opening to yield the isocyanate intermediate V. Later, the isocyanate moiety of intermediate V is trapped intramolecularly by the in situ generated phenoxide ion to afford the ring expansion product 5.

Scheme 2 Plausible reaction mechanism.

To explore the synthetic applications of our methodology, we treated two benzofuranyl indolin-2-one analogs 3 with α-methyl nitroisatylidene 7a in the presence of DABCO in MeCN (Table 5a).¹⁷ To our delight, dispirobisoxindoles 8a and 8b were isolated in 75% and 71% yields in short reaction times (10–30 min) with complete diastereoselectivity, presumably via the less hindered enolate VI. In another product diversification strategy, the product obtained from the reaction of 3b with nitroisatylidene 7b was subjected to in situ reduction using NaBH₄. To our surprise, instead of simple reduction of lactone to lactol, product 9, formed via the attack of methoxide on the lactone carbonyl, followed by ring opening and elimination of the sulfone moiety, was isolated in 68% yield (Table 5b).

Table 5 Synthetic applications of benzofuranyl indolin-2-one^a,b

a Reaction scale: 0.2 mmol of phthalide 3, 0.2 mmol of nitroalkene 7, 0.2 mmol of DABCO, 2 ml of acetonitrile. b Yield after silica gel column chromatography.

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Conclusions

In conclusion, we have investigated the reactivity of the Hauser–Kraus (H–K) donor 3-sulfonyl phthalide with two distinct H–K acceptors, viz. nitroisatylidene and nitroisoxazolyl isatylidene. The reaction with nitroisatylidene efficiently produces benzofuranyl indolin-2-one through stereoselective nucleophilic vinylic substitution of the nitro group, with a broad substrate scope. These products were further transformed into bis-spiro compounds via base-mediated [3 + 2] cycloaddition with α-methyl nitroisatylidene in good yields. On the other hand, the reaction of sulfonyl phthalide with nitroisoxazolyl isatylidene offers a rapid synthetic pathway to obtain biologically relevant fused oxazepine scaffolds in excellent yields through H–K annulation and a cascade of rearrangements involving an isocyanate intermediate. Overall, these studies established an efficient and versatile synthetic strategy for constructing diverse heterocyclic frameworks in excellent yields and with broad functional group tolerance utilizing 3-sulfonyl phthalides.

Experimental

The reagents and solvents were purchased from commercial sources and were used as received, unless mentioned otherwise. The reactions were monitored by thin layer chromatography (TLC). The melting points recorded are uncorrected. NMR spectra (¹H, ¹H decoupled ¹³C, and ¹H–¹H COSY) were recorded with TMS as the internal standard. The coupling constants (J values) are given in Hz. High resolution mass spectra (HRMS) were recorded under ESI Q-TOF conditions. X-ray data were collected on a diffractometer equipped with graphite monochromated Mo Kα radiation. The structure was solved by direct methods using SHELXS97 and refined by full-matrix least squares against F² using SHELXL97 software. Sulfonyl phthalides 1,¹⁵ nitroisatylidenes 2 ¹⁴ and nitroisoxazolyl isatylidenes 4 ¹⁶ were prepared according to literature methods.

General procedure for the synthesis of benzofuranyl indolin-2-one 3

To a stirred solution of sulfonyl phthalide 1 (0.2 mmol, 1.0 equiv.) in THF (2 ml), Cs₂CO₃ (130 mg, 0.4 mmol, 2.0 equiv.) was added. After 5 min, nitroisatylidene 2 (0.2 mmol, 1.0 equiv.) was added and the stirring was continued at room temperature. After the completion of the reaction (monitored by TLC), the solvent was removed in vacuo and the crude reaction mixture was purified by silica gel column chromatography via gradient elution with 20% ethyl acetate–petroleum ether.

(E)-3-((3-Oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3a). Yellow solid; yield 82 mg, 98%; mp 164–165 °C; IR (neat, cm⁻¹) 2927 (vw), 2853 (vw), 1797 (s), 1719 (s), 1616 (m), 1467 (m), 1448 (m), 1327 (m), 1311 (m), 1152 (m), 1065 (m), 963 (m), 738 (vs); ¹H NMR (400 MHz, DMSO-d₆) δ 6.78 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.64 (overlapped t, J = 7.4 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 7.4 Hz, 1H), 7.83 (t, J = 7.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 8.05 (t, J = 7.5 Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 10.74 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 98.9, 110.1, 118.4, 121.5, 121.9, 124.5, 124.7, 126.1, 127.1, 129.4, 130.2, 131.8, 132.3, 132.4, 134.6, 135.6, 136.3, 141.7, 144.3, 166.5, 167.1; HRMS (ES+) calcd for C₂₃H₁₅NNaO₅S (MNa⁺) 440.0563, found 440.0562.

(E)-1-Methyl-3-((3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3b). Yellow solid; yield 71 mg, 82%; mp 154–156 °C; IR (neat, cm⁻¹) 3058 (w), 2924 (w), 1793 (vs), 1711 (vs), 1607 (s), 1468 (m), 1327 (m), 1150 (s), 956 (m), 736 (s), 593 (m); ¹H NMR (400 MHz, CDCl₃) δ 3.16 (s, 3H), 6.68 (d, J = 7.8 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.34 (overlapped t, J = 7.6 Hz, 2H), 7.35 (overlapped s, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.86 (d, J = 7.8 Hz, 1H), 7.88 (overlapped t, J = 7.6 Hz, 1H), 7.89 (overlapped d, J = 7.4 Hz, 1H), 8.14 (d, J = 7.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 26.4, 99.5, 108.1, 118.7, 122.9, 123.8, 125.0, 125.7, 126.3, 127.9, 129.0, 131.0, 131.5, 131.9, 133.5, 134.0, 135.1, 135.6, 142.5, 145.4, 167.0, 167.1; HRMS (ES+) calcd for C₂₄H₁₇NNaO₅S (MNa⁺) 454.0720, found 454.0719.

(E)-1-Ethyl-3-((3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3c). Yellow solid; yield 79 mg, 89%; mp 142–144 °C; IR (neat, cm⁻¹) 3062 (w), 2981 (w), 1796 (vs), 1712 (vs), 1608 (s), 1468 (m), 1363 (m), 1329 (m), 1152 (s), 960 (m), 749 (vs); ¹H NMR (400 MHz, CDCl₃) δ 1.22 (t, J = 7.2 Hz, 3H), 3.71, 3.75 (ABqq, J = 14.3, 7.2 Hz, 2H), 6.70 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.32 (overlapped t, J = 7.7 Hz, 2H), 7.33 (overlapped s, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.4 Hz, 1H), 7.78 (d, J = 7.7 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.87 (t, J = 7.4 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 8.16 (d, J = 7.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.7, 34.9, 99.5, 108.2, 118.8, 122.6, 123.5, 124.9, 125.6, 126.2, 128.1, 129.0, 130.9, 131.5, 131.9, 133.4, 134.2, 135.1, 135.6, 142.5, 144.5, 166.6, 167.0; HRMS (ES+) calcd for C₂₅H₁₉NNaO₅S (MNa⁺) 468.0876, found 468.0875.

(E)-3-((3-Oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)-1-propylindolin-2-one (3d). Yellow solid; yield 85 mg, 93%; mp 152–154 °C; IR (neat, cm⁻¹) 3061 (w), 2966 (m), 2934 (w), 2875 (w), 1795 (vs), 1712 (vs), 1606 (s), 1467 (s), 1448 (m), 1361 (s), 1329 (s), 1151 (s), 960 (s), 737 (vs); ¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J = 7.4 Hz, 3H), 1.64 (sextet, J = 7.4 Hz, 2H), 3.61, 3.68 (ABqt, J = 14.1, 7.4 Hz, 2H), 6.68 (d, J = 7.7 Hz, 1H), 6.88 (t, J = 7.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.32 (overlapped t, J = 7.4 Hz, 2H), 7.33 (overlapped s, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.79 (d, J = 7.4 Hz, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 11.4, 20.8, 41.7, 99.5, 108.4, 118.7, 122.6, 123.5, 124.9, 125.7, 126.2, 128.0, 128.9, 130.9, 131.4, 131.9, 133.4, 134.1, 135.1, 135.6, 142.4, 144.9, 166.9, 167.0; HRMS (ES+) calcd for C₂₆H₂₁NNaO₅S (MNa⁺) 482.1033, found 482.1032.

(E)-1-Allyl-3-((3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3e). Yellow solid; yield 82 mg, 90%; mp 153–154 °C; IR (neat, cm⁻¹) 3065 (vw), 2926 (vw), 1796 (vs), 1714 (s), 1607 (s), 1467 (m), 1448 (w), 1356 (m), 1329 (m), 1151 (m), 962 (m), 748 (s); ¹H NMR (400 MHz, CDCl₃) δ 4.29, 4.35 (ABqdt, J = 18.0, 5.1, 1.5 Hz, 2H), 5.16 (dd, J = 17.1, 1.5 Hz, 1H), 5.19 (dd, J = 11.5, 1.5 Hz, 1H), 5.79 (ddt, J = 17.1, 11.5, 5.1 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.33 (overlapped t, J = 7.5 Hz, 2H), 7.36 (overlapped s, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 7.5 Hz, 2H), 7.85 (overlapped d, J = 7.8 Hz, 1H), 7.88 (overlapped t, J = 7.7 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 42.5, 99.5, 109.0, 117.7, 118.6, 122.8, 123.9, 124.9, 125.7, 126.3, 127.9, 129.0, 130.9, 131.1, 131.4, 131.9, 133.4, 133.9, 135.1, 135.6, 142.4, 144.6, 166.7, 167.0; HRMS (ES+) calcd for C₂₆H₁₉NNaO₅S (MNa⁺) 480.0876, found 480.0876.

(E)-3-((3-Oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)-1-(prop-2-ynyl)indolin-2-one (3f). Yellow solid; yield 77 mg, 85%; mp 161–162 °C; IR (neat, cm⁻¹) 3277 (m), 3061 (w), 2955 (w), 2927 (w), 2126 (w), 1792 (vs), 1722 (vs), 1609 (s), 1468 (s), 1357 (s), 1152 (s), 975 (m), 753 (vs), 737 (vs), 688 (m); ¹H NMR (500 MHz, CDCl₃) δ 2.23 (s, 1H), 4.48, 4.52 (ABq, J = 18.1 Hz, 2H), 6.91 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 7.27 (overlapped t, J = 7.5 Hz, 1H), 7.34 (overlapped t, J = 7.4 Hz, 2H), 7.37 (merged s, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.69 (t, J = 7.3 Hz, 1H), 7.80 (d, J = 7.4 Hz, 2H), 7.85 (overlapped d, J = 7.5 Hz, 1H), 7.90 (t, J = 7.3 Hz, 1H), 7.95 (d, J = 7.3 Hz, 1H), 8.17 (d, J = 7.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 29.6, 72.6, 76.7, 99.5, 109.1, 118.7, 123.3, 124.5, 124.9, 125.7, 126.4, 128.1, 129.1, 131.0, 131.6, 132.0, 133.4, 133.7, 135.2, 135.7, 142.4, 143.5, 166.2, 167.0; HRMS (ES+) calcd for C₂₆H₁₇NNaO₅S (MNa⁺) 478.0720, found 478.0718.

(E)-1-Benzyl-3-((3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3g). Yellow solid; yield 96 mg, 95%; mp 167–169 °C; IR (neat, cm⁻¹) 3060 (vw), 2922 (vw), 1796 (vs), 1713 (s), 1607 (s), 1467 (m), 1329 (m), 1151 (m), 962 (m), 747 (s); ¹H NMR (400 MHz, CDCl₃) δ 4.87, 4.94 (ABq, J = 15.8 Hz, 2H), 6.58 (d, J = 7.8 Hz, 1H), 6.88 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.24–7.32 (poorly resolved m, 7H), 7.41–7.43 (overlapped m, 1H), 7.42 (s, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 7.4 Hz, 2H), 7.87 (d, J = 7.6 Hz, 1H), 7.91 (overlapped d, J = 7.8 Hz, 1H), 7.92 (overlapped t, J = 7.6 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 44.0, 99.6, 109.1, 118.7, 123.0, 124.2, 125.0, 125.8, 126.4, 127.3, 127.9, 128.0, 129.0 (× 2), 131.0, 131.5, 131.9, 133.4, 133.9, 135.1, 135.6, 135.7, 142.4, 144.5, 167.0, 167.2; HRMS (ES+) calcd for C₃₀H₂₁NNaO₅S (MNa⁺) 530.1033, found 530.1033.

(E)-5-Methoxy-1-methyl-3-((3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3h). Yellow solid; yield 78 mg, 85%; mp 163–165 °C; IR (neat, cm⁻¹) 3059 (vw), 2936 (vw), 2834 (vw), 1795 (vs), 1709 (s), 1595 (m), 1474 (s), 1327 (m), 1233 (m), 1151 (s), 1048 (m), 964 (s), 734 (s); ¹H NMR (500 MHz, CDCl₃) δ 3.13 (s, 3H), 3.80 (s, 3H), 6.56 (d, J = 8.5 Hz, 1H), 6.77 (dd, J = 8.5, 2.5 Hz, 1H), 7.35 (overlapped t, J = 7.6 Hz, 2H), 7.35 (overlapped s, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.86 (overlapped d, J = 7.7 Hz, 1H), 7.87 (overlapped t, J = 7.7 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 26.5, 55.9, 99.5, 108.5, 113.4, 117.6, 119.1, 123.9, 124.9, 125.6, 126.3, 129.0, 130.9, 131.9, 133.5, 134.2, 135.1, 135.6, 139.2, 142.3, 155.6, 166.8 (× 2); HRMS (ES+) calcd for C₂₅H₁₉NNaO₆S (MNa⁺) 484.0825, found 484.0825.

(E)-5-Chloro-1-methyl-3-((3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3i). Yellow solid; yield 80 mg, 86%; mp 140–141 °C; IR (neat, cm⁻¹) 1795 (vs), 1719 (s), 1608 (m), 1466 (m), 1328 (m), 1152 (m), 962 (m), 738 (s); ¹H NMR (500 MHz, CDCl₃) δ 3.18 (s, 3H), 6.61 (d, J = 8.3 Hz, 1H), 7.20 (dd, J = 8.3, 2.0 Hz, 1H), 7.38 (overlapped s, 1H), 7.39 (overlapped t, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.90 (overlapped d, J = 7.6 Hz, 1H), 7.91 (overlapped t, J = 7.6 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 26.6, 99.2, 108.9, 119.8, 124.8, 125.7, 125.9, 126.5, 127.8, 128.2, 129.2, 131.0, 131.1, 132.0, 133.1, 133.3, 135.3, 135.7, 142.2, 143.8, 166.5 (× 2); HRMS (ES+) calcd for C₂₄H₁₆Cl³⁵NNaO₅S (MNa⁺) 488.0330, found 488.0329.

(E)-5-Bromo-1-methyl-3-((3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3j). Yellow solid; yield 84 mg, 83%; mp 152–154 °C; IR (neat, cm⁻¹) 3067 (w), 1796 (s), 1713 (vs), 1644 (s), 1608 (s), 1466 (m), 1328 (m), 1152 (m), 963 (m), 736 (s); ¹H NMR (500 MHz, CDCl₃) δ 3.18 (s, 3H), 6.56 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.3, 2.0 Hz, 1H), 7.39 (overlapped s, 1H), 7.41 (overlapped t, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.90 (overlapped t, J = 7.7 Hz, 1H), 7.91 (overlapped d, J = 7.7 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 26.6, 99.2, 109.4, 115.5, 120.2, 124.9, 125.8, 126.0, 126.6, 129.2, 130.5, 131.1, 132.1, 132.9, 133.4, 134.0, 135.3, 135.7, 142.1, 144.2, 166.5 (× 2); HRMS (ES+) calcd for C₂₄H₁₆Br⁷⁹NNaO₅S (MNa⁺) 531.9825, found 531.9824.

(E)-1-Methyl-3-((3-oxo-1-tosyl-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3k). Yellow solid; yield 82 mg, 92%; mp 150–15 °C; IR (neat, cm⁻¹) 3056 (vw), 2981 (w), 2937 (vw), 1793 (s), 1717 (s), 1608 (m), 1468 (m), 1375 (w), 1150 (s), 737 (vs); ¹H NMR (500 MHz, CDCl₃) δ 2.23 (s, 3H), 3.18 (s, 3H), 6.68 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.1 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.33 (s, 1H), 7.63 (overlapped d, J = 7.1 Hz, 2H), 7.67 (overlapped t, J = 7.0 Hz, 1H), 7.85–7.88 (poorly resolved m, 3H), 8.15 (d, J = 7.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 21.7, 26.5, 99.4, 108.0, 118.7, 122.7, 124.0, 124.9, 125.7, 126.2, 127.9, 129.7, 130.0, 130.9, 131.3, 131.8, 134.0, 135.5, 142.6, 145.3, 146.6, 167.1 (× 2); HRMS (ES+) calcd for C₂₅H₁₉NNaO₅S (MNa⁺) 468.0876, found 468.0876.

(E)-3-((1-(4-Methoxyphenylsulfonyl)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methylene)-1-methylindolin-2-one (3l). Yellow solid; yield 84 mg, 91%; mp 144–146 °C; IR (neat, cm⁻¹) 3054 (vw), 2939 (vw), 1794 (vs), 1713 (s), 1608 (m), 1468 (m), 1266 (s), 1146 (s), 958 (m), 737 (vs); ¹H NMR (400 MHz, CDCl₃) δ 3.16 (s, 3H), 3.68 (s, 3H), 6.67 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 8.7 Hz, 2H), 6.88 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.32 (s, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.67 (overlapped t, J = 7.5 Hz, 1H), 7.83 (overlapped d, J = 7.7 Hz, 1H), 7.84 (overlapped d, J = 7.5 Hz, 1H), 7.87 (overlapped t, J = 7.5 Hz, 1H), 8.13 (d, J = 7.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 26.4, 55.8, 99.4, 108.0, 114.3, 118.7, 122.7, 124.0, 124.1, 124.7, 125.6, 126.2, 127.8, 131.3, 131.7, 133.1, 133.8, 135.5, 142.7, 145.3, 165.0, 167.0, 167.1; HRMS (ES+) calcd for C₂₅H₁₉NNaO₆S (MNa⁺) 484.0825, found 484.0823.

(E)-3-((1-(4-Chlorophenylsulfonyl)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methylene)-1-methylindolin-2-one (3m). Yellow solid; yield 86 mg, 93%; mp 138–140 °C; IR (neat, cm⁻¹) 3090 (vw), 3059 (w), 2933 (vw), 1797 (vs), 1714 (s), 1608 (s), 1469 (s), 1335 (m), 1153 (s), 957 (m), 752 (s), 737 (s); ¹H NMR (500 MHz, CDCl₃) δ 3.17 (s, 3H), 6.69 (d, J = 7.5 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 7.25 (overlapped t, J = 7.5 Hz, 1H), 7.28 (overlapped d, J = 8.2 Hz, 2H), 7.30 (overlapped s, 1H), 7.70 (overlapped t, J = 7.6 Hz, 1H), 7.71 (overlapped d, J = 8.2 Hz, 2H), 7.82 (d, J = 7.5 Hz, 1H), 7.88 (overlapped t, J = 7.6 Hz, 1H), 7.88 (overlapped d, J = 7.6 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 26.4, 99.4, 108.2, 118.3, 122.7, 123.4, 124.8, 125.6, 126.4, 127.6, 129.4, 131.7 (× 2), 132.0, 132.2, 134.1, 135.7, 142.0, 142.2, 145.3, 166.8 (× 2); HRMS (ES+) calcd for C₂₄H₁₆Cl³⁵NNaO₅S (MNa⁺) 488.0330, found 488.0323.

(E)-3-((1-(4-Bromophenylsulfonyl)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methylene)-1-methylindolin-2-one (3n). Yellow solid; yield 96 mg, 95%; mp 141–143 °C; IR (neat, cm⁻¹) 3058 (vw), 2933 (vw), 1797 (s), 1715 (m), 1609 (m), 1469 (m), 1335 (m), 1265 (m), 1153 (m), 957 (w), 739 (vs); ¹H NMR (500 MHz, CDCl₃) δ 3.20 (s, 3H), 6.71 (d, J = 7.7 Hz, 1H), 6.92 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.31 (s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.90 (overlapped t, J = 7.6 Hz, 1H), 7.91 (overlapped d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 26.5, 99.4, 108.2, 118.4, 122.8, 123.5, 124.9, 125.7, 126.5, 127.6, 131.1, 131.8, 132.1, 132.2, 132.3, 132.4, 134.2, 135.7, 142.0, 145.4, 166.9 (× 2); HRMS (ES+) calcd for C₂₄H₁₆Br⁷⁹NNaO₅S (MNa⁺) 531.9825, found 531.9826.

(E)-1-Methyl-3-((1-(naphthalen-2-ylsulfonyl)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methylene)indolin-2-one (3o). Yellow solid; yield 87 mg, 91%; mp 163–165 °C; IR (neat, cm⁻¹) 3057 (w), 2981 (w), 2935 (vw), 1795 (vs), 1712 (vs), 1608 (s), 1468 (s), 1325 (s), 1151 (s), 961 (m), 749 (s); ¹H NMR (500 MHz, CDCl₃) δ 3.12 (s, 3H), 6.48 (d, J = 7.6 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.51–7.58 (m, 2H), 7.65–7.72 (m, 4H), 7.77 (d, J = 7.7 Hz, 1H), 7.83 (overlapped d, J = 7.6 Hz, 1H), 7.83 (overlapped d, J = 7.5 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.34 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 26.4, 99.7, 107.7, 118.3, 122.4, 123.8, 124.6, 125.0, 125.8, 126.3, 127.5, 127.7, 127.9, 129.0, 129.4, 129.9 (× 2), 131.2, 131.9, 132.0, 133.7, 134.2, 135.6, 135.8, 142.4, 145.1, 167.0, 167.1; HRMS (ES+) calcd for C₂₈H₁₉NNaO₅S (MNa⁺) 504.0876, found 504.0876.

General procedure for the synthesis of benzo[d]naphtho[2,1-f][1,3]oxazepin-2(3H)-one (5)

To a stirred solution of 3-sulfonyl phthalide 1 (0.2 mmol, 1.0 equiv.) in THF (2 ml), Cs₂CO₃ (163 mg, 0.5 mmol, 2.5 equiv.) was added. After 5 min, nitroisoxazolyl isatylidene 4 (0.2 mmol, 1.0 equiv.) was added and the stirring was continued at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed in vacuo and the crude residue was purified by silica gel column chromatography via gradient elution with 20% ethyl acetate–petroleum ether.

9-Hydroxy-8-(3-methyl-4-nitroisoxazol-5-yl)benzo[d]naphtho[2,1-f][1,3]oxazepin-2(3H)-one (5a). Yellow solid; yield 69 mg, 86%; mp 185–186 °C; IR (neat, cm⁻¹) 3357 (br, vs), 2940 (vw), 1731 (vs), 1608 (m), 1509 (m), 1377 (m), 1285 (w), 1055 (m), 1035 (m), 907 (m), 825 (m), 756 (s); ¹H NMR (500 MHz, CD₃OD) δ 2.51 (s, 3H), 6.88 (d, J = 7.8 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), ¹³C NMR (125 MHz, CD₃OD) δ 11.7, 107.2, 122.9 (× 2), 124.0 (× 2), 125.5, 127.2, 128.3, 128.6, 130.3, 130.4, 130.6, 130.7, 138.4, 138.5, 144.0, 153.1, 157.1, 159.7, 169.3; HRMS (ES+) calcd for C₂₁H₁₃N₃O₆ (MH⁺) 404.0886, found 404.0885.

9-Hydroxy-6-methoxy-8-(3-methyl-4-nitroisoxazol-5-yl)benzo[d]naphtho[2,1-f][1,3]oxazepin-2(3H)-one (5b). Yellow solid; yield 82 mg, 95%; mp 165–166 °C; IR (neat, cm⁻¹) 3434 (br, vs), 2961 (s), 2925 (s), 2853 (m), 1726 (s), 1674 (s), 1613 (s), 1514 (m), 1379 (w), 1262 (vs), 1094 (vs), 1036 (vs), 803 (s), 740 (s); ¹H NMR (500 MHz, CD₃OD) δ 2.54 (s, 3H), 3.58 (s, 3H), 6.40 (unresolved d, 1H), 6.91 (dd, J = 8.8, 2.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H); ¹³C NMR (125 MHz, CD₃OD) δ 11.6, 56.1, 107.0, 114.1, 117.3, 124.1 (× 2), 124.2, 124.3, 125.7, 127.3, 128.7, 129.3, 130.7, 130.8, 131.7, 144.1, 153.2, 157.3, 157.7, 159.8, 169.7; HRMS (ES+) calcd for C₂₂H₁₅N₃O₇ (MH⁺) 434.0973, found 434.0973.

9-Hydroxy-6-methyl-8-(3-methyl-4-nitroisoxazol-5-yl)benzo[d]naphtho[2,1-f][1,3]oxazepin-2(3H)-one (5c). Yellow solid; yield 75 mg, 90%; mp 221–222 °C; IR (neat, cm⁻¹) 3423 (br, vvs), 2925 (s), 2855 (m), 1733 (m), 1634 (m), 1520 (w), 1378 (m), 1264 (m), 1156 (m), 1019 (m), 824 (s), 739 (vs); ¹H NMR (500 MHz, DMSO-d₆) 2.11 (s, 3H), 2.53 (s, 3H), 6.61 (s, 1H), 7.11 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.88 (t, J = 7.2 Hz, 1H), 8.40 (2 × d, J = 7.2 Hz, 2H), 10.44 (br s, 1H), 10.82 (br s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 11.0, 20.1, 105.3, 121.6, 122.4, 123.4, 124.1, 125.3, 125.9, 127.4, 128.8, 129.0, 129.8 (× 2), 133.4 (× 2), 134.5, 141.3, 151.5, 155.5, 156.3, 167.3; HRMS (ES+) calcd for C₂₂H₁₅N₃NaO₆ (MNa⁺) 440.0853, found 440.0857.

6-Bromo-9-hydroxy-8-(3-methyl-4-nitroisoxazol-5-yl)benzo[d]naphtho[2,1-f][1,3]oxazepin-2(3H)-one (5d). Yellow solid; yield 88 mg, 92%; mp 167–168 °C; IR (neat, cm⁻¹) 3452 (br, vvs), 2922 (vs), 2852 (m), 1710 (s), 1674 (vs), 1596 (m), 1520 (s), 1379 (w), 1288 (s), 1249 (m), 1095 (m), 827 (m); ¹H NMR (500 MHz, DMSO-d₆) δ 2.54 (s, 3H), 6.89 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.4 Hz, 1H), 7.90 (t, J = 7.4 Hz, 1H), 8.41 (overlapped d, J = 7.4 Hz, 1H), 8.43 (overlapped d, J = 7.4 Hz, 1H), 10.68 (br s, 1H), 10.95 (br s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 11.1, 104.8, 115.9, 122.3, 122.5, 122.7, 123.3, 123.7, 125.6, 127.9, 128.0, 128.7, 130.1, 131.1, 131.9, 136.2, 141.4, 151.8, 155.6, 155.8, 167.1; HRMS (ES+) calcd for C₂₁H₁₂BrN₃NaO₆ (MNa⁺) 503.9802, found 503.9797.

6-Chloro-9-hydroxy-8-(3-methyl-4-nitroisoxazol-5-yl)benzo[d]naphtho[2,1-f][1,3]oxazepin-2(3H)-one (5e). Yellow solid; yield 78 mg, 89%; mp 147–148 °C; IR (neat, cm⁻¹) 3418 (br, vvs), 2949 (vw), 1736 (s), 1615 (m), 1526 (m), 1414 (w), 1378 (w), 1283 (m), 1220 (w), 1146 (w), 1035 (m), 829 (m); ¹H NMR (500 MHz, DMSO-d₆) δ 2.54 (s, 3H), 6.78 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.3 Hz, 1H), 7.90 (t, J = 7.3 Hz, 1H), 8.40 (overlapped d, J = 7.3 Hz, 1H), 8.42 (overlapped d, J = 7.3 Hz, 1H), 10.68 (br s, 1H), 10.96 (br s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 11.1, 104.8, 122.5, 122.8, 123.5, 123.6, 125.7, 127.8, 127.9, 128.1, 128.2, 128.7, 129.1, 130.1, 131.9, 135.8, 141.5, 151.9, 155.7, 155.9, 167.0; HRMS (ES+) calcd for C₂₁H₁₂ClN₃NaO₆ (MNa⁺) 460.0307, found 460.0300.

9-Hydroxy-8-(3-methyl-4-nitroisoxazol-5-yl)-6-nitrobenzo[d]naphtho[2,1-f][1,3]oxazepin-2(3H)-one (5f). Yellow solid; yield 79 mg, 85%; mp 208–209 °C; IR (neat, cm⁻¹) 3360 (br, m), 2924 (vs), 2851 (s), 1790 (vs), 1732 (m), 1606 (s), 1464 (m), 1332 (m), 1265 (m), 1153 (s), 1028 (s), 738 (s); ¹H NMR (500 MHz, DMSO-d₆) δ 2.50 (s, 3H), 3.96 (s, 3H), 4.06 (s, 3H), 6.88 (s, 1H), 6.95 (s, 1H), 7.04 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.36–7.39 (unresolved m, 2H), 10.07 (br s, 1H), 10.55 (brs, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 11.3, 55.8, 57.0, 94.5, 99.8, 101.6, 109.6, 121.9, 124.6, 124.7, 125.7, 126.0, 129.1, 129.4, 132.0, 136.9, 140.0, 152.1, 155.6, 156.3, 158.2, 161.1, 167.3; HRMS (ES+) calcd for C₂₃H₁₈N₃O₈ (MH⁺) 464.1088, found 464.1083.

Procedure for the synthesis of spirooxindole 6

To a stirred solution of 3-sulfonyl phthalide 1a (55 mg, 0.2 mmol, 1.0 equiv.) in THF (2 ml), Cs₂CO₃ (163 mg, 0.5 mmol, 2.5 equiv.) was added. After 5 min, N-allyl protected nitroisoxazolyl isatylidene 4 (62 mg, 0.2 mmol, 1.0 equiv.) was added and the stirring was continued at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed in vacuo and the crude residue was purified by silica gel column chromatography via gradient elution with 20% ethyl acetate–petroleum ether.

1-Allyl-3′-(3-methyl-4-nitroisoxazol-5-yl)-1′H-spiro[indoline-3,2′-naphthalene]-1′,2,4′(3′H)-trione (6). Yellow solid; yield 79 mg, 89%; mp 189–190 °C; IR (neat, cm⁻¹) 3069 (vw), 2913 (vw), 1718 (vs), 1700 (vs), 1613 (s), 1525 (s), 1490 (m), 1418 (m), 1363 (s), 1258 (s), 1182 (m), 1052 (m), 998 (m), 762 (s), 738 (s); ¹H NMR (400 MHz, CDCl₃) δ 2.44 (s, 3H), 4.27, 4.38 (ABqd, J = 16.2, 5.9 Hz, 2H), 5.27 (d, J = 10.2 Hz, 1H), 5.29 (d, J = 17.3 Hz, 1H), 5.84 (ddd, J = 17.3, 10.2, 5.9 Hz, 1H), 6.18 (s, 1H), 6.87 (d, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.83 (t, J = 7.4 Hz, 1H), 7.87 (t, J = 7.4 Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 11.7, 43.4, 52.4, 66.0, 110.4, 118.9, 123.8, 124.4, 124.8, 127.0, 128.8, 130.4, 130.5, 132.7, 133.4, 135.1, 135.5, 136.0, 143.7, 155.5, 166.2, 170.5, 187.6, 188.5; HRMS (ES+) calcd for C₂₄H₁₇N₃NaO₆ (MNa⁺) 466.1010, found 466.1008.

General procedure for the synthesis of dispirocyclopentyl bisoxindoles 8

To a stirred solution of α-methyl nitroisatylidene 7a (44 mg, 0.2 mmol, 1.0 equiv.) and DABCO (22.4 mg, 0.2 mmol) in acetonitrile (2 ml), benzofuranyl indolin-2-one 3 (0.2 mmol, 1.0 equiv.) was added. This reaction mixture was stirred for 10–30 min at room temperature. The reaction mixture was then concentrated in vacuo and the crude residue was directly subjected to silica gel column chromatography to get pure dispirocyclopentyl bisoxindole 8 by eluting with 25% EtOAc–petroleum ether (gradient elution).

5-Chloro-1,1′′-dimethyl-3′-nitro-(3-oxo-1-(phenylsulfonyl)-1,3-dihydroisobenzofuran-1-yl)dispiro[indoline-3,1′-cyclopentane-2′,3′′-indoline]-2,2′′-dione (8a). White solid; yield 102 mg, 75%; mp 201–202 °C; IR (neat, cm⁻¹) 3057 (w), 2924 (m), 1789 (s), 1720 (vs), 1714 (vs), 1611 (s), 1489 (m), 1470 (s), 1372 (s), 1154 (w), 1090 (w), 981 (w), 754 (vs), 689 (m); ¹H NMR (500 MHz, CDCl₃) δ 2.80 (s, 3H), 2.95 (s, 3H), 3.64 (ddd collapsed to dt, J = 12.3, 6.7 Hz, 1H), 4.47 (ddd collapsed q, J = 12.3 Hz, 1H), 4.61 (dd, J = 12.3, 6.7 Hz, 1H), 5.67 (s, 1H), 5.91 (dd, J = 12.3, 6.7 Hz, 1H), 6.36 (d, J = 8.2 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 6.95 (overlapped d, J = 8.2 Hz, 1H), 6.95 (overlapped t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.23–7.29 (unresolved m, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 7.0 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.0 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 8.00 (t, J = 7.4 Hz, 1H), 8.43 (d, J = 7.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 26.0, 26.7, 31.7, 42.7, 60.4, 61.3, 85.6, 99.4, 108.3, 109.0, 122.9, 123.4, 123.6, 124.8, 124.9, 126.6, 127.9, 128.0, 128.6, 128.9, 129.7, 129.9, 130.8, 131.6, 132.0, 134.8, 135.0, 140.6, 142.9, 144.0, 165.5, 173.6, 177.3; HRMS (ES+) calcd for C₃₅H₂₆Cl³⁵KN₃O₈S (MNa⁺) 722.0761, found 722.0765.

1-Ethyl-1′′-methyl-3′-(nitro-3-oxo-1-((p-tolylperoxy)thio)-1,3-dihydroisobenzofuran-1-yl)dispiro[indoline-3,1′-cyclopentane-2′,3′′-indoline]-2,2′′-dione (8b). White solid; yield 96 mg, 71%; mp 205–206 °C; IR (neat, cm⁻¹) 2929 (m), 1792 (vs), 1707 (vs), 1610 (s), 1549 (s), 1468 (m), 1376 (s), 1150 (s), 1084 (w), 986 (w), 752 (vs), 737 (vs); ¹H NMR (500 MHz, CDCl₃) δ 0.89 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 2.75 (s, 3H), 3.42 (dq, J = 14.2, 7.2 Hz, 1H), 3.63 (ddd collapsed to dt, J = 11.8, 6.7 Hz, 1H), 3.67 (overlapped dq, J = 14.2, 7.2 Hz, 1H), 4.44 (ddd collapsed to q, J = 11.8 Hz, 1H), 4.48 (dd, J = 11.8, 6.7 Hz, 1H), 5.83 (d, J = 7.4 Hz, 1H), 5.87 (dd, J = 11.8, 6.7 Hz, 1H), 6.18 (t, J = 7.4 Hz, 1H), 6.44 (overlapped d, J = 7.4 Hz, 1H), 6.45 (overlapped d, J = 7.6 Hz, 1H), 6.93 (overlapped t, J = 7.4 Hz, 1H), 6.95 (overlapped t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.93 (t, J = 7.5 Hz, 1H), 8.37 (d, J = 7.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 12.3, 21.9, 25.9, 31.9, 35.1, 42.8, 60.5, 61.2, 85.9, 99.6, 108.1, 108.3, 120.9, 122.4, 122.8, 123.9, 124.9, 125.3, 127.6, 127.7, 128.7, 128.9, 129.4, 129.5, 129.6, 130.7, 131.2, 134.6, 141.4, 143.4, 144.2, 146.3, 165.5, 174.0, 177.1; HRMS (ES+) calcd for C₃₇H₃₂N₃O₈S (MH⁺) 678.1905, found 678.1903.

Procedure for the synthesis of dispirocyclopentyl bisoxindole ketoester 9

To a stirred solution of α-methyl nitroisatylidene 7b (59 mg, 0.2 mmol, 1.0 equiv.) and DABCO (22.4 mg, 0.2 mmol) in acetonitrile (2 ml), benzofuranyl indolin-2-one 3b (86 mg, 0.2 mmol, 1.0 equiv.) was added at room temperature. The reaction mixture was stirred for 10 min at room temperature (monitored by TLC). It was then concentrated in vacuo and the crude residue was dissolved in methanol (10 ml). To the methanol solution, cooled to 0 °C, was added NaBH₄ (7.5 mg, 0.2 mmol, 1.0 equiv.) and the resulting mixture was refluxed for 30 min (monitored by TLC). The reaction mixture was then cooled to room temperature and concentrated in vacuo and the crude residue was diluted with water (5 ml) and ethyl acetate (10 ml). The layers were separated, the aqueous layer was extracted with ethyl acetate (2 × 10 ml) and the combined organic layer was dried (anhydrous Na₂SO₄) and concentrated in vacuo. The crude residue was subjected to silica gel column chromatography by eluting with 25% EtOAc–petroleum ether (gradient elution) to afford pure 9.

Methyl 2-(5-bromo-1,1′′-dimethyl-5′-nitro-2,2′′-dioxodispiro[indoline-3,1′-cyclopentane-2′,3′′-indoline]-3′-carbonyl)benzoate (9). White solid; yield 84 mg, 68%, mp 191–192 °C; IR (neat, cm⁻¹) 2956 (vw), 1709 (vvs), 1610 (m), 1547 (s), 1490 (m), 1373 (s), 1352 (s), 1282 (s), 1264 (s), 1101 (m), 737 (s); ¹H NMR (400 MHz, CDCl₃) δ 3.05 (s, 3H), 3.10 (s, 3H), 3.29 (td, J = 12.2, 6.6 Hz, 1H), 3.41 (ddd, J = 12.2, 11.3, 8.6 Hz, 1H), 3.86 (s, 3H), 5.28 (dd, J = 12.2, 8.6 Hz, 1H), 6.10 (dd, J = 11.3, 6.6 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.29 (overlapped d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.43 (overlapped t, J = 7.5 Hz, 1H), 7.45 (overlapped s, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 26.1, 26.4, 29.6, 52.2, 52.9, 61.7, 61.8, 85.7, 108.5, 109.8, 115.4, 122.6, 123.2, 123.8, 126.1, 126.7, 127.4, 129.2, 129.7, 130.1, 130.6, 132.1, 132.6, 140.8, 143.1, 143.9, 167.0, 174.2, 176.4, 201.8; HRMS (ES+) calcd for C₃₀H₂₄BrN₃NaO₇ (MNa⁺) 640.0690, found 640.0690.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: NMR spectra of all the new compounds, CIF and X-ray data tables of 3b, 5a, 6 and 8b. See DOI: https://doi.org/10.1039/d5ob01255d.

CCDC 2484007 (3b), 2455323 (5a), 2456364 (6) and 2477485 (8a) contain the supplementary crystallographic data for this paper.^18a–d

Acknowledgements

The authors thank SERB/ANRF India for financial support and Mr Deepak Kumar, Department of Chemistry, IIT Bombay for his support. AS thanks IIT Bombay and LS thanks CSIR India for a research fellowship. RK thanks the Government of India for a Prime Minister's Research Fellowship (PMRF).

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