Straightforward Access to the Dispirocyclic Framework via Regioselective Intramolecular Michael Addition

Abstract

In this article, an efficient and straightforward protocol for the construction of complex dispirocyclic skeletons via regioselective intramolecular Michael addition is presented. Diverse dispirocyclic compounds were synthesized under mild and transition-metal-free conditions with good to excellent yields. Most stereoisomers were conveniently separated by column chromatography, and their relative configurations were identified by single-crystal X-Ray diffraction of representative compounds. A scale-up experiment validated the practicality of this method. In an in vitro assay, some dispirocyclic compounds exhibited potent cytotoxicity with an IC₅₀ value of 10⁻⁶ mol/L.

1. Introduction

Spirocyclic scaffolds occupy a prominent position in medicinal chemistry and represent a major focus in contemporary drug discovery [1]. These structures are widely distributed in various natural products and pharmaceutical molecules [1,2,3,4,5,6] (Figure 1). Owing to their relatively high content of sp³-hybridized carbons and exceptional three-dimensional expandability, spiro compounds are highly attractive for drug discovery [7].

In this regard, several efficient methods have been developed, including NHC-catalyzed [3 + 4] annulation [8], Michael–Michael cascade [9,10], organocatalytic cascade [11,12], and transition metal catalytic procedures [13]. Nevertheless, reports on the synthesis of dispirocyclic skeletons remain relatively limited to date [14,15,16]. Therefore, a simple and practical strategy for the construction of dispirocycles is highly desired.

Herein, we report a facile and efficient approach to rapidly construct dispirocyclic compounds from quinones via highly regioselective intramolecular Michael addition (Figure 2). The protocol proceeds under very mild conditions with a good functional group compatibility. A total of 68 dispirocyclic compounds were synthesized in good to excellent yields, and in nearly all the cases, stereoisomers were conveniently separated by column chromatography. The preliminary cytotoxicity of the synthetic compounds was also evaluated.

2. Results and Discussion

2.1. Synthesis

2.1.1. Conditional Screening

Our study commenced with the treatment of naphthoquinone 1a [17] with LiHMDS in THF at −78 °C for 1 h. Under these conditions, Michael addition proceeded in a non-regioselective manner. When the reaction took place at site A, compound 2a was obtained, and when it occurred at site B, the resulting product was oxidized by air during workup to yield compound 3a, with yields of 18% and 25%, respectively (

Table 1. Optimization of the reaction conditions ^a.

Entry	Base	Equiv.	Solvent	Temp. (°C)	t (h)	Yield b (%)
						2a	2′a	3a c
1	LiHMDS	1.0	THF	−78	1	18	—	25
2	NaHMDS	1.0	THF	−78	1	Trace	—	21
3	KHMDS	1.0	THF	−78	1	—	—	18
4	nBuLi d	1.0	THF	−78	1	—	—	—
5	DBU e	1.0	THF	rt	3	—	—	—
6	NaH e	1.0	THF	rt	3	—	—	—
7	NaOH	1.0	CH3OH	rt	3	18	33	14
8	KOH	1.0	CH3OH	rt	3	16	34	11
9	LiOH	1.0	CH3OH	rt	3	10	25	12
10	CH3ONa	1.0	CH3OH	rt	3	15	11	26
11	tBuOK d	1.0	tBuOH	rt	3	—	—	—
12	Cs2CO3	1.0	CH3OH	rt	3	12	24	14
13	K2CO3	1.0	CH3OH	rt	3	13	22	13
14	Na2CO3	1.0	CH3OH	rt	3	8	12	Trace
15	NaOH	1.0	CH2Cl2	rt	3	12	23	10
16	NaOH	1.0	THF	rt	3	15	21	12
17	NaOH	1.0	CH3OH	50	1	Trace	—	45
18	NaOH	1.0	CH2Cl2/CH3OH (5:1, v/v)	rt	1	22	43	17
19	NaOH	1.0	CH2Cl2/CH3OH (5:1, v/v)	0	1	36	53	5
20	NaOH	1.0	CH2Cl2/CH3OH (5:1, v/v)	−20	1	35	58	—
21	NaOH	0.2	CH2Cl2/CH3OH (5:1, v/v)	−20	1	37	55	—

^a Reaction conditions: compound 1a (0.2 mmol) and base in solvent (5.0 mL) were stirred under argon. ^b Determined after column chromatography. ^c Total yield of compound 3a and inseparable impurities. ^d Compound 1a was decomposed completely. ^e Starting material 1a was recycled completely.

, entry 1). The structure of compound 2a was identified by its ¹H NMR, ¹³C NMR spectra, and HRMS. The relative (R^*, R^*) configuration was determined by single-crystal X-Ray diffraction analysis (CCDC 2452353). However, to our disappointment, compound 3a was difficult to purify since it was accompanied by a few inseparable impurities despite our tedious purification efforts. The utilization of NaHMDS decreased the yield of dispirocycle 2a (entry 2). Exposure of substrate 1a to KHMDS or n-BuLi resulted in a complete loss of dispirocyclic products (entries 3 and 4), indicating that strong bases were disadvantageous for this transformation. Moreover, compound 1a was recovered completely in the presence of DBU or NaH in THF at room temperature for 3 h (entries 5 and 6).

To our surprise, NaOH emerged as an effective base for this intramolecular Michael addition, and a total yield of 65% was achieved in the presence of NaOH in CH₃OH at room temperature for 3 h (entry 7). Moreover, in this case, we obtained another new product 2′a (33%) apart from 2a (18%) and 3a (14%), which was the major product of this reaction. Compound 2′a was identified as a stereoisomer of compound 2a by comparison of their NMR spectra and HRMS. Treatment of compound 1a with KOH gave similar results compared with those in the presence of NaOH (entry 8). A slight decrease in yield was observed upon treatment with LiOH (entry 9). Whereas the employment of CH₃ONa led to a reduced yield of compounds 2a/2′a and an improved yield of naphthoquinone 3a (entry 10). A complete decomposition of 1a was observed in the presence of tBuOK in tBuOH at room temperature (entry 11). Subsequent reaction of compound 1a with carbonates led to the formation of three products with an overall yield from 20% to 50% (entries 12–14).

Based on the above results, NaOH was identified as the optimal base. However, it is noteworthy that compound 1a exhibited poor solubility in CH₃OH, which presumably resulted in a relatively low concentration of the substrate in this reaction. Consequently, a brief solvent screening was conducted (entries 15–18). Initially, the reaction was performed in CH₂Cl₂ or THF at room temperature for 3 h, which afforded all three products with total yields of approximately 45% and 48%, respectively (entries 15 and 16). The solubility of substrate 1a in CH₂Cl₂ and THF was generally acceptable, whereas the yields of compound 2a and 2′a were still unsatisfactory, which was probably attributed to the low solubility of NaOH. An attempt to increase the temperature to improve the solubility of 1a failed; instead, this shifted the regioselectivity of Michael addition toward the formation of naphthoquinone 3a, accompanied by a few inseparable impurities (entry 17). Finally, a mixture of CH₂Cl₂ and CH₃OH (5:1, v/v) was employed, which provided satisfactory solubility for both 1a and NaOH. After 1 h, the total yield of 2a, 2′a, and 3a achieved 82% (Entry 18).

Further investigation revealed that temperature significantly influenced the regioselectivity of this Michael addition. When the reaction was conducted at −20 °C, dispirocyclic products 2a (35%) and 2′a (58%) were afforded in 93% total yield with no detectable naphthoquinone 3a (entry 20). Additionally, we also tried to reduce the amount of NaOH utilized in this reaction, and found that the Michael addition reaction could still proceed smoothly under catalytic amounts of NaOH (0.2 eq.) (entry 21).

2.1.2. Substrate Expansion

After systematic exploration, the optimal reaction conditions were identified as the treatment of quinone 1 with a catalytic amount of NaOH (0.2 eq.) in a mixture of CH₂Cl₂ and CH₃OH (5:1) at −20 °C, which exclusively afforded dispirocycles in excellent yields.

With the optimized reaction conditions in hand, we then turned our attention to explore the substrate scope of this regioselective Michael addition to assemble structurally diverse dispirocyclic compounds (Figure 3). Initially, the variation in R₁ was surveyed. As listed in

Table 2. Cytotoxicity of some dispirocyclic compounds against different cancer cell lines.

Compound	IC50 (μmol/L)
	MCF-7	HepG2	HCT-116	HGC27	U251
2a	>10	>10	>10	>10	>10
2′a	2.861	4.335	3.433	9.252	>10
2c	>10	>10	>10	>10	>10
2′c	3.174	3.486	3.460	9.561	>10
2d	>10	>10	>10	>10	>10
2′d	2.816	2.316	5.001	8.746	>10
2e	>10	>10	>10	>10	>10
2′e	3.486	3.252	3.722	6.895	9.953
2f	3.691	5.774	2.948	>10	>10
2′f	3.819	3.231	3.950	6.971	>10
2g	>10	>10	>10	>10	>10
2′g	3.081	3.465	3.781	7.861	>10
2m	>10	>10	>10	>10	>10
2′m	2.682	1.730	2.345	5.225	8.982
2n	>10	>10	>10	>10	>10
2′n	4.343	2.901	3.708	9.271	>10
2o	>10	>10	>10	>10	>10
2′o	2.250	3.296	2.377	9.779	>10
2p	2.015	2.247	2.278	>10	>10
2′p	2.460	1.632	2.398	8.036	9.627
2q	>10	>10	>10	>10	>10
2′q	1.915	2.503	3.109	8.871	9.541
2r	4.230	2.353	3.233	9.911	>10
2′r	2.148	3.733	3.400	9.238	>10
5’b	3.732	5.307	4.220	>10	>10
5’d	1.918	2.647	1.528	9.038	4.093

, a series of phenyl rings bearing electron-withdrawing or electron-donating groups were well tolerated in this reaction, generating the corresponding dispirocyclic products in good to excellent total yields (81–95%) (entries 1–5). When R₁ was benzyl, phenylethyl, or alkyl, compounds 1g-l were smoothly converted to the desired dispirocyclic products in good yields (81–95%) (entries 6–11), indicating that R₁ exerted little if any influence on the transformation.

Subsequently, the effect of R₂ substituents was studied. As illustrated in Table 2, the Michael addition worked well with various electron-donating and weak electron-withdrawing substrates, and in all cases, the desired products were obtained in good to excellent yields (80–93%) (entries 12–17). It was noteworthy that the reaction of substrates with an electron-donating group was much faster, usually being completed within 20 min with comparable yields (entries 12 and 13). However, the reaction failed when R₂ was trifluoromethyl, which was a strong electron-withdrawing group (entries 18 and 19). Additionally, we investigated the influence of R₃ substituents: compound 1s bearing a benzyl as R₂ substituent underwent efficient Michael addition to deliver dispirocyclic products 2s/2′s in 81% total yield (entry 20).

In most cases, stereoisomers 2 and 2′ could be conveniently separated by column chromatography, except for 2l and 2′l. Dispirocyclic products 2′ were always the predominant products with an approximate d.r. value of 1:2. The relative configuration of compound 2′ was determined by single-crystal X-Ray diffraction analysis of 2′b (CCDC 2372028).

In addition, we also explored the feasibility of this protocol using indolequinones 4 as substrates. It is well recognized that indole is a common and privileged motif in pharmaceutical molecules; hence, application of this methodology on indolequinones would not only broaden the substrate scope but would also merge indolequinone with the spirocyclic structure. As depicted in Figure 4, indolequinones 4 underwent smooth intramolecular Michael addition, resulting in the formation of the expected dispirocyclic compounds in good to excellent yields, which were easily separated by column chromatography after protection of the indole N- with Boc-, except compounds 5e/5’e and 5f/5’f. The R₁ substituent was found to have no apparent influence on the transformation. The yields for products 5a-5n ranged from 23% to 33%, while those for 5’a-5’n ranged from 42% to 57%. We also explored the variation in R₂ substituents and found that, similar to naphthoquinone substrates, electron-donating groups such as methoxy could accelerate the reaction (entries 11 and 12).

A scale-up synthesis of 2f and 2′f was then performed. This intramolecular Michael addition readily afforded the dispirocyclic products on a gram scale in good yields, which exemplified the potential of this protocol.

2.2. Cytotoxicity Test

Finally, the cytotoxicity of these dispirocyclic compounds was tested by MTT assay against five tumor cell lines, including human breast cancer cells (MCF-5), human liver cancer cells (HepG2), human colorectal cancer cells (HCT-16), human gastric cancer cells (HGC27), and human glioblastoma cells (U251). Some of the cytotoxicity results are listed in Table 2, and the other results (IC₅₀ > 10 μmol/L) are attached in the Supplementary Materials. As can be seen in Table 2, in general, compounds 2 and 2′ exhibited potent cytotoxicity with an IC₅₀ value of 10⁻⁶ mol/L. In contrast, compounds 5 and 5’ containing the indole motif normally did not show any inhibitory activity against tumor cells at a concentration of 10 μmol/L, except compounds 5’b and 5’d. The stronger potency of compound 2′ compared with 2 suggested that the configuration was essential for the cytotoxicity. Among all the tested compounds, most compounds were effective against MCF-7, HepG2, and HCT-116, and ineffective towards HGC27 and U251. In addition, it was apparent that R₁ played a significant role in the cytotoxicity. When R₁ was an aromatic ring, the compounds exerted more potent cytotoxicity than compounds with alkyl groups. The variation in R₂ substituents did not affect the cytotoxicity dramatically.

3. Experimental Section

3.1. Materials

Reagents and solvents were purchased from commercial suppliers and used without further purification unless otherwise stated. ¹H NMR and ¹³C NMR spectra were measured on Quantum-1 400 MHz (¹H, 400 MHz; ¹³C, 100 MHz; ¹⁹F{H}, 376 MHz) or Quantum-1Plus 500 MHz (¹H, 500 MHz; ¹³C, 125 MHz) spectrometers. Chemical shifts were given in ppm. Coupling constants were given in Hertz. High-resolution mass spectra were carried out on a Thermo Exactive Plus spectrometer. The ionization method was ESI, and the mass analyzer type was Orbitrap. Melting points were carried out on a microscopic melting point apparatus.

3.2. General Procedure for the Synthesis of Dispirocyclic Compounds

The general procedure for the preparation of (±)-(1′R*,4R*)-3-methyl-1-(m-tolyl)-1″H,3′H-dispiro [imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2a and (±)-(1′S*, 4R*)-3-methyl-1-(m-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′a is as follows:

To a solution of 5-(2-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzyl)-1-methyl-3-(m-tolyl)imidazolidine-2,4-dione 1a (450 mg, 1.0 mmol) in CH₂Cl₂ (5 mL) and CH₃OH (1 mL), NaOH (8 mg, 0.2 mmol) was added at −20 °C under argon. Then, the reaction was stirred at this temperature for 1 h. The mixture was quenched with 1N HCl solution (10 mL), extracted with CH₂Cl₂ (20 mL × 3), washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, PET/EtOAc = 5:1) to give compound 2a (white solid, 158 mg, 35%) and 2′a (white solid, 261 mg, 58%).

2a:

m.p. = 182–184 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.08–8.03 (m, 1H), 7.98 (dd, J = 7.6, 1.2 Hz, 1H), 7.73 (td, J = 7.6, 1.2 Hz, 1H), 7.66 (td, J = 7.6, 1.2 Hz, 1H), 7.41 (d, J = 6.4 Hz, 3H), 7.17 (q, J = 6.8, 5.6 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.79–6.73 (m, 1H), 6.67 (s, 1H), 3.85 (d, J = 16.8 Hz, 1H), 3.76 (d, J = 15.6 Hz, 1H), 3.18 (d, J = 16.8 Hz, 1H), 3.15 (d, J = 15.6 Hz, 1H), 2.73 (s, 3H), 2.27 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.7, 193.2, 170.6, 154.6, 140.2, 139.9, 138.8, 135.7, 135.3, 134.2, 134.0, 131.1, 129.7, 129.1, 128.8, 128.5 (2C), 126.1, 126.1, 124.5, 123.2, 122.6, 76.7, 68.6, 44.3, 39.9, 28.1, 21.4; HRMS (ESI) calcd for C₂₈H₂₃N₂O₄ [M + H]+ 451.1652, found 451.1655.

2′a:

m.p. = 181–183 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.05 (dd, J = 7.5, 1.5 Hz, 1H), 8.00 (dd, J = 7.5, 1.5 Hz, 1H), 7.81 (td, J = 7.5, 1.5 Hz, 1H), 7.73 (td, J = 7.5, 1.5 Hz, 1H), 7.47–7.40 (m, 2H), 7.43–7.35 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 3.91 (d, J = 16.5 Hz, 1H), 3.71 (d, J = 18.5 Hz, 1H), 3.23 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 18.5 Hz, 1H), 2.54 (s, 3H), 2.27 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.0, 190.9, 171.3, 154.2, 140.7, 138.7, 137.8, 136.3, 135.3, 135.1, 134.7, 130.7, 129.4, 129.1, 128.6, 128.5, 127.3, 127.2, 126.2, 125.8, 124.6, 122.7, 73.4, 67.6, 46.3, 39.9, 27.2, 21.4; HRMS (ESI) calcd for C₂₈H₂₃N₂O₄ [M + H]⁺ 451.1652, found 451.1649.

(±)-(1′R*,4R*)-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2b and (±)-(1′S*,4R*)-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′b.

Compounds 2b and 2′b were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2b (white solid, 122 mg, 27%) and 2′b (white solid, 284 mg, 63%).

2b:

m.p. = 185–187 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.46–7.37 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 3.86 (d, J = 16.4 Hz, 1H), 3.75 (d, J = 15.6 Hz, 1H), 3.17 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 2.72 (s, 3H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 193.7, 193.2, 170.5, 154.7, 140.3, 139.9, 138.2, 135.6, 135.3, 134.2, 134.0, 129.6, 129.5 (2C), 128.6, 128.4, 128.4, 126.0, 125.3 (2C), 124.4, 123.2, 76.7, 68.5, 44.2, 39.8, 28.1, 21.2; HRMS (ESI) calcd for C₂₈H₂₃N₂O₄ [M + H]⁺ 451.1652, found 451.1651.

2′b:

m.p. = 186–188 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.6 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.78 (td, J = 7.6, 1.6 Hz, 1H), 7.72 (td, J = 7.6, 1.6 Hz, 1H), 7.47–7.34 (m, 4H), 7.06 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.0 Hz, 2H), 3.89 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 18.8 Hz, 1H), 3.22 (d, J = 16.8 Hz, 1H), 3.01 (d, J = 18.8 Hz, 1H), 2.53 (s, 3H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.1, 190.9, 171.4, 154.3, 140.7, 138.2, 137.9, 136.3, 135.3, 135.1, 134.7, 129.4, 129.3 (2C), 128.5, 128.3, 127.2, 127.1, 125.8, 125.3 (2C), 124.5, 73.4, 67.5, 46.3, 39.9, 27.2, 21.2; HRMS (ESI) calcd for C₂₈H₂₃N₂O₄ [M + H]⁺ 451.1652, found 451.1655.

(±)-(1′R*,4R*)-1-(4-chlorophenyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2c and (±)-(1′S*,4R*)-1-(4-chlorophenyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′c.

Compounds 2c and 2′c were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2c (white solid, 137 mg, 29%) and 2′c (white solid, 245 mg, 52%).

2c:

m.p. = 186–188 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.48–7.36 (m, 3H), 7.30–7.24 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 3.85 (d, J = 16.4 Hz, 1H), 3.77 (d, J = 15.6 Hz, 1H), 3.18 (d, J = 16.4 Hz, 1H), 3.13 (d, J = 15.6 Hz, 1H), 2.73 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.8, 193.1, 170.3, 154.1, 140.0, 139.7, 135.5, 135.4, 134.1, 134.1, 133.9, 129.8, 129.7, 129.1 (2C), 128.6, 128.4, 126.5 (2C), 125.9, 124.5, 123.2, 76.7, 68.7, 44.3, 39.6, 28.1; HRMS (ESI) calcd for C₂₇H₂₀ClN₂O₄ [M + H]⁺ 471.1106, found 471.1104.

2′c:

m.p. = 184–186 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.03 (dd, J = 7.6, 1.2 Hz, 1H), 7.98 (dd, J = 7.6, 1.2 Hz, 1H), 7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.71 (td, J = 7.6, 1.2 Hz, 1H), 7.50–7.33 (m, 4H), 7.26–7.20 (m, 2H), 6.87–6.61 (m, 2H), 3.90 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.03 (d, J = 18.8 Hz, 1H), 2.55 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 194.9, 190.9, 171.1, 153.7, 140.5, 137.7, 136.3, 135.3, 135.1, 134.8, 133.9, 129.5, 128.9 (2C), 128.6, 127.2, 127.1, 126.5 (2C), 125.8, 124.6, 73.5, 67.7, 46.3, 39.8, 27.2; HRMS (ESI) calcd for C₂₇H₂₀ClN₂O₄ [M + H]⁺ 471.1106, found 471.1106.

(±)-(1′R*,4R*)-1-(3-chlorophenyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2d and (±)-(1′S*,4R*)-1-(3-chlorophenyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′d.

Compounds 2d and 2′d were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2d (white solid, 146 mg, 31%) and 2′d (white solid, 273 mg, 58%).

2d:

m.p. = 180–182 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.06 (dd, J = 7.5, 1.5 Hz, 1H), 7.95 (dd, J = 7.5, 1.5 Hz, 1H), 7.75 (td, J = 7.5, 1.5 Hz, 1H), 7.68 (td, J = 7.5, 1.5 Hz, 1H), 7.47–7.39 (m, 3H), 7.24–7.21 (m, 2H), 7.17–7.12 (m, 1H), 6.96 (ddd, J = 6.0, 3.5, 2.0 Hz, 1H), 6.85–6.81 (m, 1H), 3.84 (d, J = 16.5 Hz, 1H), 3.77 (d, J = 15.5 Hz, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.13 (d, J = 15.5 Hz, 1H), 2.74 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.6, 193.1, 170.3, 153.9, 140.0, 139.7, 135.6, 135.5, 134.4, 134.3, 134.1, 132.3, 129.9, 129.7, 128.6, 128.5, 128.3, 126.1, 125.5, 124.5, 123.5, 123.3, 76.6, 68.9, 44.4, 39.7, 28.2; HRMS (ESI) calcd for C₂₇H₂₀ClN₂O₄ [M + H]⁺ 471.1106, found 471.1110.

2′d:

m.p. = 181–183 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.08–8.02 (m, 1H), 8.01–7.96 (m, 1H), 7.82 (td, J = 7.6, 1.2 Hz, 1H), 7.74 (td, J = 7.6, 1.2 Hz, 1H), 7.47–7.37 (m, 4H), 7.25–7.17 (m, 2H), 6.77 (dt, J = 6.8, 2.0 Hz, 1H), 6.65–6.60 (m, 1H), 3.92 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.02 (d, J = 18.8 Hz, 1H), 2.55 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 190.8, 171.0, 153.5, 140.5, 137.7, 136.3, 135.3, 135.2, 134.9, 134.3, 131.9, 129.7, 129.5, 128.6, 128.4, 127.2 (2C), 125.8, 125.6, 124.6, 123.6, 73.5, 67.7, 46.3, 39.8, 27.2; HRMS (ESI) calcd for C₂₇H₂₀ClN₂O₄ [M + H]⁺ 471.1106, found 471.1102.

(±)-(1′R*,4R*)-1-(4-fluorophenyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2e and (±)-(1′S*,4R*)-1-(4-fluorophenyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′e.

Compounds 2e and 2′e were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2e (white solid, 150 mg, 33%) and 2′e (white solid, 250 mg, 55%).

2e:

m.p. = 186–188 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.92 (dd, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H), 7.48–7.37 (m, 3H), 7.18–7.11 (m, 1H), 7.01–6.96 (m, 4H), 3.86 (d, J = 16.4 Hz, 1H), 3.77 (d, J = 15.6 Hz, 1H), 3.18 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 2.73 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.8, 193.1, 170.4, 162.9, 161.0, 154.3, 140.1, 139.8, 135.5, 135.4, 134.2, 134.1, 129.7, 128.6, 128.4, 127.3, 127.2, 127.2, 127.1, 125.9, 124.5, 123.2, 116.0, 115.8, 76.7, 68.6, 44.3, 39.7, 28.1; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −112.8; HRMS (ESI) calcd for C₂₇H₂₀FN₂O₄ [M + H]⁺ 455.1402, found 455.1401.

2′e:

m.p. = 186–188 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.99 (dd, J = 7.6, 1.2 Hz, 1H), 7.79 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.47–7.35 (m, 4H), 6.99–6.91 (m, 2H), 6.77–6.70 (m, 2H), 3.90 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 18.4 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.03 (d, J = 18.4 Hz, 1H), 2.55 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 194.9, 190.9, 171.3, 162.9, 160.9, 153.9, 140.5, 137.8, 136.3, 135.3, 135.1, 134.8, 129.5, 128.6, 127.3, 127.2, 127.2, 127.2, 126.9, 126.8, 125.8, 124.6, 115.9, 115.7, 73.5, 67.6, 46.3, 39.8, 27.2; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −112.6; HRMS (ESI) calcd for C₂₇H₂₀FN₂O₄ [M + H]⁺ 455.1402, found 455.1400.

(±)-(1′R*,4R*)-3-methyl-1-(4-(trifluoromethyl)phenyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2f and (±)-(1′S*,4R*)-3-methyl-1-(4-(trifluoromethyl)phenyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′f.

Compounds 2f and 2′f were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2f (white solid, 152 mg, 30%) and 2′f (white solid, 328 mg, 65%).

2f:

m.p. = 176–178 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.47–7.39 (m, 3H), 7.16 (t, J = 7.6 Hz, 3H), 3.87 (d, J = 16.4 Hz, 1H), 3.78 (d, J = 15.6 Hz, 1H), 3.20 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 2.75 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.7, 193.0, 170.3, 153.8, 139.9, 139.6, 135.5, 135.5, 134.4, 134.2 (2C), 129.9 (q, J = 35.0 Hz, 1C), 129.8, 128.6, 128.5, 126.0 (q, J = 4.0 Hz, 2C), 126.0, 125.3 (2C), 124.5, 123.8 (q, J = 272.5 Hz, 1C),123.2, 76.7, 68.8, 44.4, 39.6, 28.2; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −62.6; HRMS (ESI) calcd for C₂₈H₂₀F₃N₂O₄ [M + H]⁺ 505.1370, found 505.1366.

2′f:

m.p. = 179–181 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.05–7.96 (m, 2H), 7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.69 (td, J = 7.6, 1.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.48–7.35 (m, 4H), 7.00 (d, J = 8.0 Hz, 2H), 3.92 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 18.4 Hz, 1H), 3.25 (d, J = 16.8 Hz, 1H), 3.05 (d, J = 18.4 Hz, 1H), 2.56 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 194.8, 190.9, 171.1, 153.4, 140.4, 137.6, 136.2, 135.2, 135.2, 134.8, 134.1, 129.9 (q, J = 32.5 Hz, 1C), 129.5, 128.7, 127.2, 127.1, 125.9 (q, J = 4.0 Hz, 2C), 125.8, 125.2 (2C), 124.6, 123.7 (q, J = 272.5 Hz, 1C) 73.5, 67.7, 46.3, 39.8, 27.3; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −62.6; HRMS (ESI) calcd for C₂₈H₂₀F₃N₂O₄ [M + H]⁺ 505.1370, found 505.1375.

(±)-(1′R*,4R*)-1-benzyl-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2g and (±)-(1′S*,4R*)-1-benzyl-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′g.

Compound 2g and 2′g was prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2g (white solid, 117 mg, 26%) and 2′g (white solid, 248 mg, 55%).

2g:

m.p. = 185–187 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.02 (dd, J = 7.6, 1.2 Hz, 1H), 7.69 (td, J = 7.6, 1.2 Hz, 1H), 7.60 (dd, J = 7.6, 1.2 Hz, 1H), 7.54 (td, J = 7.6, 1.2 Hz, 1H), 7.44–7.32 (m, 3H), 7.29–7.21 (m, 3H), 7.16–7.08 (m, 3H), 4.26 (d, J = 14.4 Hz, 1H), 4.21 (d, J = 14.4 Hz, 1H), 3.74 (d, J = 16.4 Hz, 1H), 3.61 (d, J = 16.0 Hz, 1H), 3.03 (d, J = 16.4 Hz, 1H), 3.03 (d, J = 16.0 Hz, 1H), 2.63 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.2, 193.2, 171.3, 155.6, 140.4, 139.9, 135.3, 135.1, 134.9, 134.0, 133.9, 129.5, 129.1 (2C), 128.7 (2C), 128.4, 128.1, 127.9, 125.9, 124.4, 123.1, 77.4, 77.2, 76.9, 76.9, 67.8, 43.9, 42.8, 39.9, 28.0; HRMS (ESI) calcd for C₂₈H₂₃N₂O₄ [M + H]⁺ 451.1652, found 451.1649.

2′g:

m.p. = 186–188 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J = 7.6, 1.2 Hz, 1H), 7.84 (dd, J = 7.6, 1.2 Hz, 1H), 7.66 (td, J = 7.6, 1.2 Hz, 1H), 7.57 (td, J = 7.6, 1.2 Hz, 1H), 7.42–7.34 (m, 3H), 7.33–7.28 (m, 1H), 7.25–7.20 (m, 3H), 7.18–7.13 (m, 2H), 4.04 (d, J = 14.0 Hz, 1H), 3.93 (d, J = 14.0 Hz, 1H), 3.75 (d, J = 16.8 Hz, 1H), 3.64 (d, J = 18.4 Hz, 1H), 3.05 (d, J = 16.8 Hz, 1H), 2.95 (d, J = 18.4 Hz, 1H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 191.1, 172.2, 155.0, 140.6, 137.9, 136.0, 135.3, 135.1, 134.8, 134.6, 129.3, 129.1 (2C), 128.7 (2C), 128.4, 128.0, 126.7, 126.6, 125.8, 124.5, 77.5, 77.2, 76.8, 73.7, 67.2, 46.1, 42.6, 39.5, 26.9; HRMS (ESI) calcd for C₂₈H₂₃N₂O₄ [M + H]⁺ 451.1652, found 451.1653.

(±)-(1′R*,4R*)-3-methyl-1-phenethyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2h and (±)-(1′S*,4R*)-3-methyl-1-phenethyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′h.

Compounds 2h and 2′h were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2h (white solid, 167 mg, 36%) and 2′h (white solid, 237 mg, 51%).

2h:

m.p. = 179–181 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.21–8.03 (m, 1H), 8.00–7.93 (m, 1H), 7.79 (td, J = 7.6, 1.2 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.43–7.33 (m, 3H), 7.26–7.15 (m, 3H), 7.14–7.03 (m, 3H), 3.72 (d, J = 16.8 Hz, 1H), 3.64 (d, J = 16.0 Hz, 1H), 3.41 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H), 3.31 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H), 3.01 (d, J = 16.0 Hz, 1H), 2.98 (d, J = 16.8 Hz, 1H), 2.68 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H), 2.62 (s, 3H), 2.40 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 193.7, 193.1, 171.3, 155.4, 140.4, 140.0, 137.7, 135.6, 135.3, 134.4, 134.1, 129.6, 128.9 (2C), 128.6 (2C), 128.4 (2C), 126.7, 125.9, 124.5, 123.1, 76.8, 67.8, 44.0, 40.2, 39.7, 33.2, 27.8; HRMS (ESI) calcd for C₂₉H₂₅N₂O₄ [M + H]⁺ 465.1809, found 465.1806.

2′h:

m.p. = 181–183 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.17–8.08 (m, 1H), 7.93–7.85 (m, 1H), 7.78–7.69 (m, 2H), 7.46–7.30 (m, 4H), 7.29–7.17 (m, 3H), 7.11–7.04 (m, 2H), 3.72 (d, J = 16.8 Hz, 1H), 3.64 (d, J = 18.4 Hz, 1H), 3.24–3.05 (m, 2H), 2.99 (d, J = 16.8 Hz, 1H), 2.96 (d, J = 18.4 Hz, 1H), 2.44 (s, 3H), 2.39–2.20 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 191.0, 172.2, 154.9, 140.7, 137.9, 137.5, 136.3, 135.4, 135.0, 134.6, 129.3, 128.9 (2C), 128.6 (2C), 128.5, 127.1, 126.8 (2C), 125.7, 124.5, 73.5, 67.2, 46.2, 39.9, 39.4, 33.6, 26.8; HRMS (ESI) calcd for C₂₉H₂₅N₂O₄ [M + H]⁺ 465.1809, found 465.1807.

(±)-(1′R*,4R*)-1-cyclohexyl-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2i and (±)-(1′S*,4R*)-1-cyclohexyl-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′i.

Compounds 2i and 2′i were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2i (white solid, 142 mg, 32%) and 2i (white solid, 213 mg, 48%).

2i:

m.p. = 171–173 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.78 (td, J = 7.6, 1.6 Hz, 1H), 7.70 (td, J = 7.6, 1.6 Hz, 1H), 7.43–7.33 (m, 3H), 7.11 (dd, J = 6.4, 2.8 Hz, 1H), 3.73 (d, J = 16.4 Hz, 1H), 3.67 (d, J = 15.6 Hz, 1H), 3.56 (tt, J = 12.4, 4.0 Hz, 1H), 3.07 (d, J = 15.6 Hz, 1H), 3.04 (d, J = 16.4 Hz, 1H), 2.59 (s, 3H), 1.85 (qd, J = 12.4, 3.6 Hz, 1H), 1.74–1.66 (m, 1H), 1.65–1.58 (m, 1H), 1.56–1.48 (m, 1H), 1.44–1.29 (m, 2H), 1.30–1.23 (m, 1H), 1.22–0.94 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.8, 193.3, 171.2, 155.5, 140.6, 140.1, 135.8, 135.2, 134.4, 133.8, 129.5, 128.4, 128.3, 126.1, 124.4, 123.0, 76.4, 67.5, 52.1, 43.9, 40.1, 28.6, 28.3, 27.9, 25.7, 25.6, 24.9; HRMS (ESI) calcd for C₂₇H₂₇N₂O₄ [M + H]⁺ 443.1965, found 443.1968.

2′i:

m.p. = 174–176 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.13 (dd, J = 7.0, 2.0 Hz, 1H), 7.92 (dd, J = 7.0, 2.0 Hz, 1H), 7.82–7.65 (m, 2H), 7.48–7.31 (m, 4H), 3.77 (d, J = 16.5 Hz, 1H), 3.68 (d, J = 18.5 Hz, 1H), 3.53–3.45 (m, 1H), 3.06 (d, J = 16.5 Hz, 1H), 2.96 (d, J = 18.5 Hz, 1H), 2.44 (s, 3H), 1.86–1.41 (m, 5H), 1.15–1.01 (m, 3H), 0.86 (t, J = 13.3 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 195.1, 191.2, 172.2, 155.3, 141.2, 138.0, 136.3, 135.4, 135.0, 134.5, 129.2, 128.4, 127.3, 127.1, 125.6, 124.5, 72.9, 67.0, 51.8, 46.4, 40.0, 28.9, 28.5, 27.0, 25.7, 25.6, 24.8; HRMS (ESI) calcd for C₂₇H₂₇N₂O₄ [M + H]⁺ 443.1965, found 443.1961.

(±)-(1′R*,4R*)-1-isopropyl-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2j and (±)-(1′S*,4R*)-1-isopropyl-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′j.

Compounds 2j and 2′j were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2j (white solid, 149 mg, 37%) and 2′j (white solid, 230 mg, 57%).

2j:

m.p. = 178–180 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (dd, J = 7.6, 1.2 Hz, 1H), 7.96 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 (td, J = 7.6, 1.6 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.43–7.33 (m, 3H), 7.15–7.08 (m, 1H), 3.96 (p, J = 6.8 Hz, 1H), 3.73 (d, J = 16.4 Hz, 1H), 3.68 (d, J = 16.0 Hz, 1H), 3.05 (d, J = 16.0 Hz, 1H), 3.01 (d, J = 16.4 Hz, 1H), 2.59 (s, 3H), 1.16 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.8, 193.3, 171.1, 155.4, 140.5, 140.1, 135.8, 135.2, 134.4, 133.9, 129.5, 128.4, 128.3, 126.0, 124.4, 123.0, 76.4, 67.6, 44.4, 43.9, 40.0, 27.8, 19.0, 18.8; HRMS (ESI) calcd for C₂₄H₂₃N₂O₄ [M + H]⁺ 403.1652, found 403.1648.

2′j:

m.p. = 178–180 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.17–8.08 (m, 1H), 7.97–7.89 (m, 1H), 7.82–7.68 (m, 2H), 7.45–7.30 (m, 4H), 3.98–3.84 (m, 1H), 3.77 (d, J = 16.4 Hz, 1H), 3.68 (d, J = 18.4 Hz, 1H), 3.07 (d, J = 16.4 Hz, 1H), 2.97 (d, J = 18.4 Hz, 1H), 2.44 (s, 3H), 0.90 (d, J = 5.2 Hz, 3H), 0.88 (d, J = 5.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.1, 191.1, 172.1, 155.1, 141.2, 137.9, 136.2, 135.4, 135.0, 134.7, 129.2, 128.4, 127.3, 127.1, 125.6, 124.5, 72.9, 67.0, 46.4, 44.0, 40.0, 26.9, 19.3, 19.0; HRMS (ESI) calcd for C₂₄H₂₃N₂O₄ [M + H]⁺ 403.1652, found 403.1653.

(±)-(1′R*,4R*)-1-(tert-butyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2k and (±)-(1′S*,4R*)-1-(tert-butyl)-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′k.

Compounds 2k and 2′k were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2k (white solid, 142 mg, 34%) and 2′k (white solid, 254 mg, 61%).

2k:

m.p. = 177–179 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.09 (dd, J = 7.5, 1.5 Hz, 1H), 8.02 (dd, J = 7.5, 1.5 Hz, 1H), 7.78 (td, J = 7.5, 1.5 Hz, 1H), 7.73 (td, J = 7.5, 1.5 Hz, 1H), 7.40–7.35 (m, 3H), 7.11 (dd, J = 7.0, 2.0 Hz, 1H), 3.72 (d, J = 16.5 Hz, 1H), 3.67 (d, J = 16.0 Hz, 1H), 3.03 (d, J = 16.0 Hz, 1H), 2.99 (d, J = 16.5 Hz, 1H), 2.58 (s, 3H), 1.19 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 193.7, 193.5, 171.8, 156.2, 140.5, 140.3, 135.9, 135.1, 134.5, 133.9, 129.5, 128.5, 128.3, 126.1, 124.3, 123.1, 77.5, 77.2, 76.8, 76.4, 67.9, 58.4, 44.0, 40.1, 27.9 (3C), 27.6; HRMS (ESI) calcd for C₂₅H₂₅N₂O₄ [M + H]⁺ 417.1809, found 417.1807.

2′k:

m.p. = 176–177 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.20 (dd, J = 7.5, 1.5 Hz, 1H), 8.00 (dd, J = 7.5, 1.5 Hz, 1H), 7.85 (td, J = 7.5, 1.5 Hz, 1H), 7.80 (td, J = 7.5, 1.5 Hz, 1H), 7.47–7.34 (m, 4H), 3.79 (d, J = 16.5 Hz, 1H), 3.69 (d, J = 18.5 Hz, 1H), 3.09 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 18.5 Hz, 1H), 2.45 (s, 3H), 1.18 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 195.2, 191.3, 172.8, 155.9, 141.2, 138.2, 136.4, 135.5, 135.0, 134.6, 129.2, 128.3, 127.4, 127.1, 125.6, 124.4, 77.5, 77.2, 76.8, 72.8, 67.2, 58.2, 46.5, 40.1, 28.3 (3C), 26.8; HRMS (ESI) calcd for C₂₅H₂₅N₂O₄ [M + H]⁺ 417.1809, found 417.1807.

1-ethyl-3-methyl-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2l and 2′l.

Compounds 2l and 2′l were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2l and 2′l (white solid, 342 mg, 88%). m.p. = 181–183 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.15–8.10 (m, 1H), 8.09–8.06 (m, 0.4H), 7.96–7.93 (m, 0.4H), 7.91–7.87 (m, 1H), 7.80–7.67 (m, 3H), 7.45–7.30 (m, 5H), 7.16–7.05 (m, 0.4H), 3.83–3.64 (m, 1.8H), 3.66 (d, J = 18.8 Hz, 1H), 3.26–3.11 (m, 0.8H), 3.08–2.91 (m, 4.8H), 2.61 (s, 1.2H), 2.44 (s, 3H), 0.81 (t, J = 7.2 Hz, 1.2H), 0.60 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 193.6, 193.2, 191.0, 172.2, 171.3, 155.5, 155.1, 140.8, 140.4, 140.0, 137.9, 136.3, 135.7, 135.3, 135.2, 134.9, 134.6, 134.3, 134.0, 129.5, 129.2, 128.4, 128.4, 128.3, 127.1, 126.9, 125.9, 125.7, 124.5, 124.4, 123.1, 76.8, 73.5, 67.8, 67.2, 46.2, 44.0, 39.7, 39.5, 34.2, 33.9, 27.8, 26.8, 12.8, 12.4; HRMS (ESI) calcd for C₂₃H₂₁N₂O₄ [M + H]⁺ 389.1496, found 389.1496.

(±)-(1′R*,4R*)-6’-methoxy-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2m and (±)-(1′S*,4R*)-6’-methoxy-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′m.

Compounds 2m and 2′m were prepared according to the general procedure; the reaction was completed within 20 min. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2m (white solid, 149 mg, 31%) and 2′m (white solid, 279 mg, 58%).

2m:

m.p. = 185–187 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.70 (td, J = 7.6, 1.6 Hz, 1H), 7.67–7.59 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.77 (d, J = 16.4 Hz, 1H), 3.70 (d, J = 15.6 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 3.10 (d, J = 16.4 Hz, 1H), 2.74 (s, 3H), 2.29 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.7, 193.1, 170.4, 160.1, 154.7, 141.6, 138.2, 135.6, 135.3, 134.2, 134.0, 131.7, 129.6 (2C), 128.6, 128.4, 126.0, 125.3 (2C), 125.1, 115.2, 108.9, 77.1, 68.5, 55.6, 44.2, 39.1, 28.1, 21.2; HRMS (ESI) calcd for C₂₉H₂₅N₂O₅ [M + H]⁺ 481.1758, found 481.1754.

2′m:

m.p. = 184–186 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.99 (dd, J = 7.6, 1.2 Hz, 1H), 7.79 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.09–7.02 (m, 2H), 6.99–6.90 (m, 2H), 6.60–6.53 (m, 2H), 3.86 (s, 3H), 3.82 (d, J = 16.4 Hz, 1H), 3.71 (d, J = 18.8 Hz, 1H), 3.15 (d, J = 16.4 Hz, 1H), 3.02 (d, J = 18.8 Hz, 1H), 2.57 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.1, 190.9, 171.3, 160.0, 154.3, 142.1, 138.2, 136.3, 135.3, 135.1, 134.7, 129.5, 129.4 (2C), 128.2, 127.2, 127.1, 125.4 (2C), 125.2, 115.9, 110.6, 73.8, 67.6, 55.7, 46.2, 39.2, 27.2, 21.2; HRMS (ESI) calcd for C₂₉H₂₅N₂O₅ [M + H]⁺ 481.1758, found 481.1755.

(±)-(1′R*,4R*)-5’-methoxy-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2n and (±)-(1′S*,4R*)-5’-methoxy-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′n.

Compounds 2n and 2′n were prepared according to the general procedure; the reaction was completed within 20 min. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2n (white solid, 154 mg, 32%) and 2′n (white solid, 293 mg, 61%).

2n:

m.p. = 188–190 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 7.95 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 7.70 (td, J = 7.6, 1.6 Hz, 1H), 7.63 (td, J = 7.6, 1.6 Hz, 1H), 7.12–7.06 (m, 2H), 7.04 (d, J = 9.2 Hz, 1H), 6.95–6.89 (m, 2H), 6.85–6.79 (m, 2H), 3.86 (s, 3H), 3.82 (d, J = 16.6 Hz, 1H), 3.69 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 15.6 Hz, 1H), 3.11 (d, J = 16.6 Hz, 1H), 2.75 (s, 3H), 2.29 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.8, 193.6, 170.4, 160.9, 154.6, 141.3, 138.1, 135.6, 135.2, 134.2, 133.9, 132.2, 129.5 (2C), 128.5, 128.3, 125.9, 125.3 (2C), 124.0, 114.3, 109.7, 76.8, 67.9, 55.6, 44.4, 39.7, 28.0, 21.2; HRMS (ESI) calcd for C₂₉H₂₅N₂O₅ [M + H]⁺ 481.1758, found 481.1761.

2′n:

m.p. = 186–188 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.98 (dd, J = 7.6, 1.2 Hz, 1H), 7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.09–7.03 (m, 2H), 6.98 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.62–6.46 (m, 2H), 3.87 (s, 3H), 3.86 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.16 (d, J = 16.8 Hz, 1H), 2.98 (d, J = 18.8 Hz, 1H), 2.57 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.4, 191.1, 171.3, 160.7, 154.3, 139.4, 138.2, 136.4, 135.3, 135.0, 134.6, 132.7, 129.4 (2C), 128.2, 127.1, 127.1, 126.5, 125.3 (2C), 114.6, 109.6, 73.6, 66.9, 55.7, 46.5, 39.9, 27.2, 21.2; HRMS (ESI) calcd for C₂₉H₂₅N₂O₅ [M + H]⁺ 481.1758, found 481.1757.

(±)-(1′R*,4R*)-3,5’-dimethyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2o and (±)-(1′S*,4R*)-3,5’-dimethyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′o.

Compounds 2o and 2′o were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2o (white solid, 121 mg, 26%) and 2′o (white solid, 261 mg, 56%).

2o:

m.p. = 183–185 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H), 7.24–7.17 (m, 2H), 7.10–7.06 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.86–6.79 (m, 2H), 3.81 (d, J = 16.8 Hz, 1H), 3.72 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 16.8 Hz, 1H), 2.73 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.9, 193.4, 170.5, 154.7, 139.9, 139.7, 138.2, 137.4, 135.7, 135.3, 134.2, 133.9, 129.6 (2C), 129.3, 128.6, 128.4, 126.0, 125.3 (2C), 125.1, 122.9, 76.8, 68.3, 44.3, 39.7, 28.1, 21.6, 21.2; HRMS (ESI) calcd for C₂₉H₂₅N₂O₄ [M + H]⁺ 465.1809, found 465.1811.

2′o:

m.p. = 184–186 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.33–7.22 (m, 2H), 7.18 (s, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.0 Hz, 2H), 3.85 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.17 (d, J = 16.8 Hz, 1H), 2.99 (d, J = 18.8 Hz, 1H), 2.55 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.3, 191.1, 171.4, 154.3, 139.4, 138.2, 138.0, 137.8, 136.4, 135.3, 135.0, 134.6, 129.4, 129.4 (2C), 128.2, 127.1, 127.1, 125.4, 125.3 (2C), 125.1, 73.5, 67.3, 46.4, 39.8, 27.2, 21.6, 21.2; HRMS (ESI) calcd for C₂₉H₂₅N₂O₄ [M + H]⁺ 465.1809, found 465.1805.

(±)-(1′R*,4R*)-6’-fluoro-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2p and (±)-(1′S*,4R*)-6’-fluoro-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′p.

Compounds 2p and 2′p were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2p (white solid, 155 mg, 33%) and 2′p (white solid, 267 mg, 57%).

2p:

m.p. = 181–183 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.06–8.01 (m, 1H), 8.00–7.88 (m, 1H), 7.72 (td, J = 7.6, 1.6 Hz, 1H), 7.65 (td, J = 7.6, 1.6 Hz, 1H), 7.37 (dd, J = 8.4, 5.2 Hz, 1H), 7.17–7.06 (m, 3H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H), 6.84–6.79 (m, 2H), 3.79 (d, J = 16.4 Hz, 1H), 3.67 (d, J = 15.6 Hz, 1H), 3.15 (d, J = 15.6 Hz, 1H), 3.14 (d, J = 16.4 Hz, 1H), 2.75 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.2, 192.8, 170.1, 163.11 (d, J = 246.8 Hz), 154.6, 142.31 (d, J = 7.7 Hz), 138.3, 135.4 (2C), 135.3 (d, J = 2.5 Hz), 134.2, 134.1, 129.6 (2C), 128.5, 128.4, 126.1, 125.70 (d, J = 8.7 Hz), 125.3 (2C), 116.81 (d, J = 22.6 Hz), 110.78 (d, J = 23.4 Hz), 77.0, 68.4, 44.1, 39.1, 28.1, 21.3; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −113.2; HRMS (ESI) calcd for C₂₈H₂₂FN₂O₄ [M + H]⁺ 469.1558, found 469.1561.

2′p:

m.p. = 180–182 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.6 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.80 (td, J = 7.6, 1.6 Hz, 1H), 7.74 (td, J = 7.6, 1.6 Hz, 1H), 7.37–7.29 (m, 1H), 7.16–7.08 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.0 Hz, 2H), 3.84 (d, J = 16.4 Hz, 1H), 3.71 (d, J = 18.4 Hz, 1H), 3.19 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 18.4 Hz, 1H), 2.56 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 194.6, 190.5, 170.9, 162.9 (d, J = 246.7 Hz), 154.2, 142.7 (d, J = 8.2 Hz), 138.3, 136.0, 135.3, 135.2, 134.9, 133.3 (d, J = 2.5 Hz), 129.4 (2C), 128.1, 127.2, 127.2, 125.8 (d, J = 8.8 Hz), 125.3 (2C), 116.7 (d, J = 22.7 Hz), 113.1 (d, J = 23.5 Hz), 73.8, 67.4, 45.9, 39.1, 27.2, 21.2; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −112.8; HRMS (ESI) calcd for C₂₈H₂₂FN₂O₄ [M + H]⁺ 469.1558, found 469.1558.

(±)-(1′R*,4R*)-5’-chloro-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2q and (±)-(1′S*,4R*)-5’-chloro-3-methyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′q.

Compounds 2q and 2′q were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2q (white solid, 121 mg, 25%) and 2′q (white solid, 267 mg, 55%).

2q:

m.p. = 185–187 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.71 (td, J = 7.6, 1.2 Hz, 1H), 7.65 (td, J = 7.6, 1.2 Hz, 1H), 7.45–7.35 (m, 2H), 7.12–7.05 (m, 3H), 6.85–6.75 (m, 2H), 3.82 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 15.6 Hz, 1H), 3.15 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 15.6 Hz, 1H), 2.75 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.3, 192.9, 170.1, 154.6, 141.7, 138.8, 138.4, 135.5, 135.4 (2C), 134.2, 134.1, 129.6 (2C), 128.8, 128.4 (2C), 126.1, 125.3 (2C), 124.8, 124.4, 76.7, 68.0, 44.1, 39.4, 28.2, 21.3; HRMS (ESI) (ESI) calcd for C₂₈H₂₂ClN₂O₄ [M + H]⁺ 485.1263, found 485.1261.

2′q:

m.p. = 184–186 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.47–7.31 (m, 3H), 7.06 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 3.86 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.4 Hz, 1H), 3.20 (d, J = 16.8 Hz, 1H), 2.98 (d, J = 18.4 Hz, 1H), 2.55 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 194.7, 190.6, 170.9, 154.2, 139.8, 139.2, 138.4, 136.1, 135.3 (2C), 135.2, 134.9, 129.4 (2C), 128.9, 128.1, 127.3, 127.2, 127.0, 125.3 (2C), 124.8, 73.4, 67.0, 46.1, 39.5, 27.2, 21.2; HRMS (ESI) calcd for C₂₈H₂₂ClN₂O₄ [M + H]⁺ 485.1263, found 485.1265.

(±)-(1′R*,4R*)-4’-fluoro-3,6’-dimethyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2r and (±)-(1′S*,4R*)-4’-fluoro-3,6’-dimethyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′r.

Compounds 2r and 2′r were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2r (white solid, 159 mg, 33%) and 2′r (white solid, 246 mg, 51%).

2r:

m.p. = 180–182 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.71 (td, J = 7.6, 1.2 Hz, 1H), 7.64 (td, J = 7.6, 1.2 Hz, 1H), 7.13–7.05 (m, 2H), 6.95 (d, J = 9.6 Hz, 1H), 6.85–6.78 (m, 2H), 6.75 (s, 1H), 3.72 (d, J = 16.8 Hz, 1H), 3.71 (d, J = 15.6 Hz, 1H), 3.25 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 15.6 Hz, 1H), 2.76 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.3, 192.8, 170.1, 158.4 (d, J = 248.8 Hz), 154.6, 143.3 (d, J = 5.8 Hz), 141.3 (d, J = 6.8 Hz), 138.3, 135.4, 135.4, 134.2 (2C), 129.6 (2C), 128.5, 128.4, 126.0, 125.3 (2C), 123.3 (d, J = 18.8 Hz), 119.6 (d, J = 2.6 Hz), 116.9 (d, J = 19.7 Hz), 76.8, 68.6, 44.2, 35.6, 28.0, 21.7, 21.2; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −118.0; HRMS (ESI) calcd for C₂₉H₂₄FN₂O₄ [M + H]⁺ 483.1715, found 483.1714.

2′r:

m.p. = 184–186 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (dd, J = 8.0, 1.2 Hz, 1H), 8.02–7.96 (m, 1H), 7.84–7.77 (m, 1H), 7.77–7.70 (m, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.00 (s, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.62–6.55 (m, 2H), 3.76 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 18.4 Hz, 1H), 3.30 (d, J = 16.8 Hz, 1H), 3.02 (d, J = 18.4 Hz, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.7, 190.7, 171.0, 158.5 (d, J = 248.0 Hz), 154.2, 143.7 (d, J = 5.6 Hz), 141.5 (d, J = 6.4 Hz), 138.4, 136.1, 135.3, 135.1, 134.9, 129.4 (2C), 128.2, 127.2 (2C), 125.4 (2C), 121.9, 121.9 (d, J = 2.8 Hz), 121.4 (d, J = 18.8 Hz), 116.5 (d, J = 19.5 Hz), 73.6, 67.7, 46.1, 35.7, 27.1, 21.7, 21.2; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −117.6; HRMS (ESI) (ESI) calcd for C₂₉H₂₄FN₂O₄ [M + H]⁺ 483.1715, found 483.1717.

(±)-(1′R*,4R*)-3-benzyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2s and (±)-(1′S*,4R*)-3-benzyl-1-(p-tolyl)-1″H,3′H-dispiro[imidazolidine-4,2′-indene-1′,2″-naphthalene]-1″,2,4″,5(3″H)-tetraone 2′s.

Compounds 2s and 2′s were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 2s (white solid, 137 mg, 26%) and 2′s (white solid, 290 mg, 55%).

2s:

m.p. = 182–184 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.51–7.42 (m, 2H), 7.27–7.18 (m, 4H), 7.15–7.08 (m, 3H), 6.94–6.85 (m, 4H), 4.92 (d, J = 15.2 Hz, 1H), 3.70 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 15.2 Hz, 1H), 3.68 (d, J = 16.0 Hz, 1H), 3.08 (d, J = 16.0 Hz, 1H), 2.86 (d, J = 16.8 Hz, 1H), 2.31 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 193.9, 193.2, 170.3, 155.3, 140.4, 140.3, 138.2, 137.1, 135.5, 135.3, 134.1, 134.0, 129.5 (2C), 129.5, 128.6 (2C), 128.5 (2C), 128.5 (2C), 128.4, 128.2, 126.0, 125.2, 125.2 (2C), 123.0, 78.0, 68.8, 45.7, 43.6, 39.9, 21.3; HRMS (ESI) calcd for C₃₄H₂₇N₂O₄ [M + H]⁺ 527.1965, found 527.1967.

2′s:

m.p. = 180–182 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.06–7.99 (m, 2H), 7.81 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.47 (dd, J = 4.4, 1.2 Hz, 2H), 7.38 (dt, J = 8.4, 4.0 Hz, 1H), 7.22–7.13 (m, 3H), 7.07 (d, J = 7.6 Hz, 2H), 6.97 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.2 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 4.88 (d, J = 16.0 Hz, 1H), 3.66 (d, J = 18.8 Hz, 2H), 3.52 (d, J = 16.0 Hz, 1H), 2.98 (d, J = 18.8 Hz, 1H), 2.76 (d, J = 16.8 Hz, 1H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.4, 190.8, 171.2, 154.7, 141.0, 138.2, 137.9, 137.5, 136.4, 135.3, 135.2, 134.9, 129.3 (2C), 129.0, 128.5, 128.5 (2C), 128.3, 128.1 (2C), 127.9, 127.3 (2C), 125.7, 125.4, 125.2 (2C), 74.4, 68.0, 46.6, 44.7, 40.4, 21.3; HRMS (ESI) calcd for C₃₄H₂₇N₂O₄ [M + H]⁺ 527.1965, found 527.1961.

The general procedure for the preparation of (±)-tert-butyl (1′R*,4R*)-3-methyl-2,4″,5,7″-tetraoxo-1-(4-(trifluoromethyl)phenyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylaten 5a and (±)-tert-butyl (1′S*,4R*)-3-methyl-2,4″,5,7″0-tetraoxo-1-(4-(trifluoromethyl)phenyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’a is as follows:

To a solution of 6-(2-((3-methyl-2,5-dioxo-1-(4-(trifluoromethyl)phenyl)imidazolidin-4-yl)methyl)phenyl)-1H-indole-4,7-dione 4a (493 mg, 1.0 mmol) in CH₂Cl₂ (5 mL) and CH₃OH (1 mL), NaOH (8 mg, 0.2 mmol) was added at −20 °C under argon. Then, the reaction was stirred at this temperature for 1 h. The mixture was quenched with 1N HCl solution and extracted with CH₂Cl₂ (3 × 20 mL), washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.

The residue was dissolved in THF (10 mL), and DMAP (49 mg, 0.4 mmol) was added. The mixture was stirred, followed by the dropwise addition of (Boc)₂O (0.46 mL, 2 mmol). The reaction was allowed to proceed at room temperature for 3 h. The mixture was quenched with hydrochloric acid, extracted with CH₂Cl₂ (3 × 20 mL), washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc = 5:1) to afford compound 5a (white solid, 184 mg, 31%) and compound 5’a (white solid, 303 mg, 51%).

5a:

m.p. = 163–165 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 3.2 Hz, 1H), 7.42–7.35 (m, 3H), 7.24–7.14 (m, 5H), 6.52 (d, J = 3.2 Hz, 1H), 3.79 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H), 3.21 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.71 (s, 3H), 1.50 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.1, 183.0, 170.6, 154.3, 148.4, 147.1, 139.7, 139.4, 134.3, 132.5, 130.0, 129.9, 129.5, 128.3, 127.2 (2C), 124.5, 123.7, 121.4 (2C), 120.4 (q, J = 248.8 Hz, 1C), 106.7, 86.7, 76.5, 70.4, 46.0, 39.0, 28.2, 27.5 (3C); ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −57.8; HRMS (ESI) calcd for C₃₁H₂₇F₃N₃O₆ [M + H]⁺ 594.1846, found 594.1848.

5’a:

m.p. = 161–163 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 3.2 Hz, 1H), 7.44–7.35 (m, 4H), 7.22–7.17 (m, 2H), 7.11–7.06 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.90 (d, J = 16.8 Hz, 1H), 3.56 (d, J = 18.4 Hz, 1H), 3.21 (d, J = 16.8 Hz, 1H), 2.90 (d, J = 18.4 Hz, 1H), 2.60 (s, 3H), 1.61 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.2, 183.6, 171.3, 153.4, 148.3, 146.7, 140.1, 137.5, 135.1, 133.7, 130.3, 129.7, 129.3, 128.4, 126.9 (2C), 126.1, 124.5, 121.4 (2C), 120.4 (q, J = 256.8 Hz, 1C), 107.8, 87.4, 73.6, 68.6, 48.5, 39.8, 27.8 (3C), 27.6; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −57.8; HRMS (ESI) calcd for C₃₁H₂₇F₃N₃O₆ [M + H]⁺ 594.1846, found 594.1847.

(±)-tert-butyl (1′R*,4R*)-1-(4-chlorophenyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5b and (±)-tert-butyl (1′S*,4R*)-1-(4-chlorophenyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’b.

Compounds 5b and 5’b were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5b (white solid, 157 mg, 28%) and 5’b (white solid, 252 mg, 45%).

5b:

m.p. = 163–165 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 3.2 Hz, 1H), 7.40–7.36 (m, 3H), 7.37–7.29 (m, 2H), 7.17–7.14 (m, 1H), 7.13–7.06 (m, 2H), 6.51 (d, J = 3.2 Hz, 1H), 3.79 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H), 3.19 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 16.4 Hz, 1H), 2.69 (s, 3H), 1.51 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 188.5, 181.5, 169.2, 153.3, 146.1, 138.9, 138.5, 133.6, 133.2, 131.7, 129.3, 129.2, 128.8, 128.4 (2C), 127.6, 126.3 (2C), 123.8, 123.1, 106.3, 86.6, 76.7, 70.6, 46.5, 39.7, 29.0, 28.3 (3C); HRMS (ESI) calcd for C₃₀H₂₇ClN₃O₆ [M + H]⁺ 560.1583, found 560.1581.

5’b:

m.p. = 165–167 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 3.2 Hz, 1H), 7.44–7.34 (m, 4H), 7.34–7.29 (m, 2H), 7.02–6.96 (m, 2H), 6.61 (d, J = 3.2 Hz, 1H), 3.89 (d, J = 16.4 Hz, 1H), 3.55 (d, J = 18.4 Hz, 1H), 3.20 (d, J = 16.4 Hz, 1H), 2.89 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 1.61 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.2, 183.8, 171.3, 153.5, 146.7, 140.2, 137.7, 135.2, 133.8, 130.4, 129.9, 129.6, 129.3 (2C), 129.1, 128.4, 126.6 (2C), 126.1, 124.6, 107.9, 87.5, 73.6, 68.7, 48.5, 39.9, 27.9 (3C), 27.6; HRMS (ESI) calcd for C₃₀H₂₇ClN₃O₆ [M + H]⁺ 560.1583, found 560.1582.

(±)-tert-butyl (1′R*,4R*)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5c and (±)-tert-butyl (1′S*,4R*)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’c.

Compounds 5c and 5’c were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5c (white solid, 157 mg, 25%) and 5’c (white solid, 327 mg, 52%).

5c:

m.p. = 168–180 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.40–7.35 (m, 4H), 7.17–7.11 (m, 1H), 6.50 (d, J = 3.2 Hz, 1H), 3.78 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H), 3.20 (d, J = 16.4 Hz, 1H), 2.98 (d, J = 16.4 Hz, 1H), 2.71 (s, 3H), 1.50 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.1, 183.0, 170.6, 153.9, 147.0, 139.6, 139.3, 134.4, 132.5, 132.1, 131.8, 130.3, 130.3, 129.8, 129.7, 129.1 (q, J = 32.0 Hz), 128.4, 124.9 (q, J = 5.3 Hz), 124.6, 123.8, 122.4 (q, J = 273.4 Hz), 106.8, 86.9, 76.6, 70.8, 46.3, 39.0, 28.3, 27.5 (3C); ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −62.7; HRMS (ESI) calcd for C₃₁H₂₆ClF₃N₃O₆ [M + H]⁺ 628.1457, found 628.1459.

5’c:

m.p. = 166–168 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.43–7.34 (m, 4H), 7.32–7.26 (m, 2H), 6.54 (d, J = 3.2 Hz, 1H), 3.90 (d, J = 16.8 Hz, 1H), 3.51 (d, J = 18.4 Hz, 1H), 3.21 (d, J = 16.8 Hz, 1H), 2.89 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 1.61 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.0, 183.6, 171.1, 152.9, 146.5, 139.9, 137.5, 135.1, 133.8, 132.1, 131.7, 130.3, 130.1, 129.6, 129.4, 129.0 (q, J = 31.1 Hz), 128.5, 126.2, 124.6, 124.6 (q, J = 5.3 Hz), 122.35 (q, J = 273.8 Hz), 107.9, 87.6, 73.8, 68.8, 48.5, 39.7, 27.8 (3C), 27.6; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −62.7; HRMS (ESI) calcd for C₃₁H₂₆ClF₃N₃O₆ [M + H]⁺ 628.1457, found 628.1452.

(±)-tert-butyl (1′R*,4R*)-1-(4-fluorophenyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5d and (±)-tert-butyl (1′S*,4R*)-1-(4-fluorophenyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’d.

Compounds 5d and 5’d were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5d (white solid, 141 mg, 26%) and 5’d (white solid, 261 mg, 48%).

5d:

m.p. = 166–168 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 3.2 Hz, 1H), 7.41–7.35 (m, 3H), 7.19–6.99 (m, 5H), 6.52 (d, J = 3.2 Hz, 1H), 3.79 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H), 3.19 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.69 (s, 3H), 1.50 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.3, 183.1, 170.8, 162.1 (d, J = 248.1 Hz), 154.7, 147.2, 139.8, 139.5, 134.5, 132.5, 130.1, 129.5, 128.3, 127.8 (d, J = 8.8 Hz, 2C), 127.4 (d, J = 3.1 Hz), 124.5, 123.8, 116.0 (d, J = 22.8 Hz, 2C), 106.7, 86.7, 76.7, 70.4, 46.0, 39.1, 28.2, 27.5 (3C); ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −112.7; HRMS (ESI) calcd for C₃₀H₂₇FN₃O₆ [M + H]⁺ 544.1878, found 544.1872.

5’d:

m.p. = 165–167 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 3.2 Hz, 1H), 7.46–7.33 (m, 4H), 7.08–6.94 (m, 4H), 6.62 (d, J = 3.2 Hz, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.56 (d, J = 18.4 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 2.89 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 1.61 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 188.2, 183.8, 171.5, 161.8 (d, J = 248.2 Hz), 153.7, 146.8, 140.2, 137.7, 135.3, 133.8, 130.3, 129.3, 128.4, 127.4 (d, J = 8.6 Hz, 2C), 127.3 (d, J = 3.1 Hz), 126.1, 124.6, 115.95 (d, J = 22.7 Hz, 2C), 107.9, 87.5, 73.6, 68.7, 48.5, 39.8, 27.8 (3C), 27.6; ¹⁹F{H} NMR (376 MHz, CDCl₃) δ −112.8; HRMS (ESI) calcd for C₃₀H₂₇FN₃O₆ [M + H]⁺ 544.1878, found 544.1877.

(±)-tert-butyl 1-ethyl-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5e and 5’e.

Compounds 5e and 5’e were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5e and 5’e (white solid, 325 mg, 68%). m.p. = 161–163 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.53 (d, J = 3.5 Hz, 1H), 7.49 (d, J = 3.5 Hz, 0.7H), 7.41–7.32 (m, 6.1H), 7.12 (d, J = 6.5 Hz, 0.7H), 6.65 (d, J = 3.5 Hz, 1H), 6.54 (d, J = 3.5 Hz, 0.7H), 3.79 (d, J = 17.0 Hz, 1H), 3.71 (d, J = 16.5 Hz, 0.7H), 3.52 (d, J = 18.5 Hz, 1H), 3.51 (d, J = 16.5 Hz, 0.7H), 3.43–3.21 (m, 3.4H), 3.05 (d, J = 17.0 Hz, 1H), 3.00 (d, J = 16.5 Hz, 0.7H), 2.91 (d, J = 16.5 Hz, 0.7H), 2.83 (d, J = 18.5 Hz, 1H), 2.55 (s, 2.1H), 2.47 (s, 3H), 1.61 (s, 9H), 1.58 (s, 6.3H), 0.97 (t, J = 7.0 Hz, 2.1H), 0.71 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 190.1, 188.4, 183.8, 183.4, 172.2, 171.5, 155.6, 154.9, 147.3, 146.9, 140.6, 139.9, 137.8, 136.7, 135.5, 134.7, 133.7, 132.3, 130.3, 129.4, 129.1, 128.3, 128.2, 127.7, 125.9, 124.5, 124.3, 123.5, 107.8, 106.7, 87.2, 86.4, 76.9, 73.7, 69.5, 68.2, 48.5, 45.3, 39.4, 39.3, 34.1, 33.8, 27.8 (3C), 27.7, 27.6 (3C), 27.3, 13.2, 12.8; HRMS (ESI) calcd for C₂₆H₂₈N₃O₆ [M + H]⁺ 478.1973, found 478.1976.

(±)-tert-butyl 1-benzyl-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5f and 5’f.

Compounds 5f and 5’f were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5f and 5’f (white solid, 410 mg, 76%). m.p. = 166–178 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.30 (m, 6.4H), 7.30–7.25 (m, 2.2H), 7.25–7.17 (m, 5.8H), 7.12–7.07 (m, 0.6H), 7.03 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 0.6H), 6.20 (d, J = 3.2 Hz, 1H), 4.42–4.39 (m, 3.2H), 3.80 (d, J = 16.8 Hz, 1H), 3.71 (d, J = 16.4 Hz, 0.6H), 3.48 (d, J = 18.4 Hz, 1H), 3.42 (d, J = 16.8 Hz, 0.6H), 3.04 (d, J = 16.8 Hz, 1H), 3.03 (d, J = 16.4 Hz, 0.6H), 2.91 (d, J = 16.8 Hz, 0.6H), 2.77 (d, J = 18.4 Hz, 1H), 2.58 (s, 1.8H), 2.47 (s, 3H), 1.61 (s, 9H), 1.58 (s, 5.2H); ¹³C NMR (125 MHz, CDCl₃) ¹³C NMR (100 MHz, CDCl₃) δ 189.7, 188.3, 183.5, 183.2, 172.0, 171.6, 155.8, 155.2, 147.3, 147.0, 140.8, 140.4, 139.7, 137.7, 135.7, 135.5, 135.4, 135.1, 130.5, 129.7, 129.3, 129.1 (2C), 129.0, 128.9 (2C), 128.7 (2C), 128.6 (2C), 128.4, 128.3, 128.3, 128.1, 127.9 (2C), 125.8, 124.5, 124.4, 123.6, 107.1, 106.7, 86.9, 86.4, 76.8, 73.9, 69.5, 68.0, 48.6, 45.3, 42.8, 42.6, 39.8, 39.6, 27.8, 27.8 (3C), 27.6 (3C), 27.5; HRMS (ESI) calcd for C₃₁H₃₀N₃O₆ [M + H]⁺ 540.2129, found 540.2129.

(±)-tert-butyl (1′R*,4R*)-3-methyl-2,4″,5,7″-tetraoxo-1-phenethyl-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5g and (±)-tert-butyl (1′S*,4R*)-3-methyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’g.

Compounds 5g and 5’g were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5g (white solid, 183 mg, 33%) and 5’g (white solid, 316 mg, 57%).

5g:

m.p. = 163–165 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.50 (d, J = 3.0 Hz, 1H), 7.40–7.30 (m, 3H), 7.27–7.23 (m, 2H), 7.21–7.14 (m, 3H), 7.09 (d, J = 7.0 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 3.72 (d, J = 16.5 Hz, 1H), 3.57 (ddd, J = 13.5, 10.5, 6.0 Hz, 1H), 3.49 (ddd, J = 13.5, 10.5, 6.0 Hz, 1H), 3.41 (d, J = 16.5 Hz, 1H), 2.98 (d, J = 16.5 Hz, 1H), 2.85 (d, J = 16.5 Hz, 1H), 2.76 (td, J = 13.0, 11.0, 6.0 Hz, 1H), 2.62 (td, J = 13.0, 11.0, 6.0 Hz, 1H), 2.55 (s, 3H), 1.59 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.3, 183.1, 171.5, 155.6, 147.4, 140.5, 139.9, 137.9 (2C), 132.5, 130.1, 129.4, 129.0 (2C), 128.6 (2C), 128.2, 126.7, 124.5, 123.4, 106.8, 86.6, 77.6, 69.2, 45.2, 40.2, 39.4, 33.5, 27.8, 27.7 (3C); HRMS (ESI) calcd for C₃₂H₃₂N₃O₆ [M + H]⁺ 554.2286, found 554.2288.

5’g:

m.p. = 164–166 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.50 (d, J = 3.2 Hz, 1H), 7.42–7.27 (m, 6H), 7.22 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.4 Hz, 2H), 6.65 (d, J = 3.2 Hz, 1H), 3.75 (d, J = 16.8 Hz, 1H), 3.51 (d, J = 18.4 Hz, 1H), 3.47–3.38 (m, 2H), 2.99 (d, J = 16.8 Hz, 1H), 2.83 (d, J = 18.4 Hz, 1H), 2.50–2.42 (m, 4H), 2.30 (ddd, J = 12.4, 11.6, 5.6 Hz, 1H), 1.61 (s, 9H);¹³C NMR (125 MHz, CDCl₃) δ 188.4, 183.9, 172.3, 154.8, 146.9, 140.5, 137.8, 137.6, 135.5, 133.8, 130.3, 129.2, 128.9 (2C), 128.7 (2C), 128.3, 126.9, 126.0, 124.6, 107.8, 87.3, 73.8, 68.3, 48.5, 40.1, 39.5, 34.1, 27.9 (3C), 27.4; HRMS (ESI) calcd for C₃₂H₃₂N₃O₆ [M + H]⁺ 554.2286, found 554.2282.

(±)-tert-butyl (1′R*,4R*)-1-cyclohexyl-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5h and (±)-tert-butyl (1′S*,4R*)-1-cyclohexyl-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’h.

Compounds 5h and 5’h were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5h (white solid, 133 mg, 25%) and 5’h (white solid, 250 mg, 47%).

5h:

m.p. = 167–169 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 3.2 Hz, 1H), 7.41–7.30 (m, 3H), 7.14–7.07 (m, 1H), 6.54 (d, J = 3.2 Hz, 1H), 3.68 (d, J = 16.4 Hz, 1H), 3.66 (tt, J = 12.4, 4.0 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.89 (d, J = 16.4 Hz, 1H), 2.54 (s, 3H), 1.96 (qd, J = 12.4, 3.6 Hz, 1H), 1.73 (dd, J = 20.4, 12.0 Hz, 3H), 1.59 (s, 9H), 1.64–1.53 (m, 2H), 1.51–1.35 (m, 2H), 1.27–1.06 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 190.2, 183.5, 171.5, 155.7, 147.4, 140.3, 140.0, 134.8, 132.4, 129.8, 129.3, 128.1, 124.4, 123.5, 106.8, 86.4, 76.4, 69.5, 51.9, 45.4, 39.6, 28.9, 28.8, 27.8, 27.7 (3C), 25.8, 25.8, 25.0; HRMS (ESI) calcd for C₃₀H₃₄N₃O₆ [M + H]⁺ 532.2442, found 532.2441.

5’h:

m.p. = 167–169 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 3.2 Hz, 1H), 7.41–7.29 (m, 4H), 6.65 (d, J = 3.2 Hz, 1H), 3.77 (d, J = 16.8 Hz, 1H), 3.67 (tt, J = 13.2, 4.0 Hz, 1H), 3.51 (d, J = 18.4 Hz, 1H), 3.03 (d, J = 16.8 Hz, 1H), 2.80 (d, J = 18.4 Hz, 1H), 2.45 (s, 3H), 1.95–1.82 (m, 1H), 1.81–1.62 (m, 3H), 1.60 (s, 9H), 1.24–1.01 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 188.5, 184.0, 172.3, 154.9, 147.0, 140.8, 137.9, 135.6, 133.7, 130.2, 129.0, 128.2, 125.8, 124.5, 107.9, 87.2, 73.0, 68.1, 51.5, 48.6, 39.8, 29.2, 28.7, 27.8 (3C), 27.3, 25.8, 25.7, 24.9; HRMS (ESI) calcd for C₃₀H₃₄N₃O₆ [M + H]⁺ 532.2442, found 532.2445.

(±)-tert-butyl (1′R*,4R*)-1-(tert-butyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5i and (±)-tert-butyl (1′S*,4R*)-1-(tert-butyl)-3-methyl-2,4″,5,7″-tetraoxo-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’i.

Compounds 5i and 5’i were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5i (white solid, 132 mg, 26%) and 5’i (white solid, 217 mg, 43%).

5i:

m.p. = 166–168 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 3.2 Hz, 1H), 7.41–7.29 (m, 3H), 7.14–7.06 (m, 1H), 6.59 (d, J = 3.2 Hz, 1H), 3.69 (d, J = 16.4 Hz, 1H), 3.50 (d, J = 16.4 Hz, 1H), 2.97 (d, J = 16.4 Hz, 1H), 2.88 (d, J = 16.4 Hz, 1H), 2.52 (s, 3H), 1.58 (s, 9H), 1.32 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.3, 184.0, 172.2, 156.3, 147.4, 140.1, 140.1, 135.0, 132.5, 129.7, 129.4, 128.1, 124.3, 123.7, 107.0, 86.4, 76.5, 69.9, 58.2, 45.6, 39.7, 28.1 (3C), 27.6 (3C), 27.5; HRMS (ESI) calcd for C₂₈H₃₂N₃O₆ [M + H]⁺ 506.2286, found 506.2288.

5’i:

m.p. = 164–166 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 3.2 Hz, 1H), 7.39–7.29 (m, 4H), 6.69 (d, J = 3.2 Hz, 1H), 3.77 (d, J = 16.8 Hz, 1H), 3.47 (d, J = 18.4 Hz, 1H), 3.01 (d, J = 16.8 Hz, 1H), 2.80 (d, J = 18.4 Hz, 1H), 2.42 (s, 3H), 1.60 (s, 9H), 1.29 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.6, 184.1, 172.6, 155.5, 147.1, 140.8, 138.1, 135.7, 134.0, 130.4, 129.0, 128.2, 125.8, 124.5, 107.9, 87.2, 73.0, 68.4, 58.1, 48.7, 39.7, 28.4 (3C), 27.8 (3C), 27.1; HRMS (ESI) calcd for C₂₈H₃₂N₃O₆ [M + H]⁺ 506.2286, found 506.2287.

(±)-tert-butyl (1′R*,4R*)-5’-chloro-3-methyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5j and (±)-tert-butyl (1′S*,4R*)-5’-chloro-3-methyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’j.

Compounds 5j and 5’j were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5j (white solid, 166 mg, 29%) and 5’j (white solid, 276 mg, 48%).

5j:

m.p. = 163–165 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 3.2 Hz, 1H), 7.36 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 3.2 Hz, 1H), 3.73 (d, J = 16.8 Hz, 1H), 3.47 (d, J = 16.4 Hz, 1H), 3.17 (d, J = 16.8 Hz, 1H), 2.98 (d, J = 16.4 Hz, 1H), 2.71 (s, 3H), 2.32 (s, 3H), 1.47 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 189.6, 182.9, 170.5, 154.9, 147.3, 141.5, 138.6, 138.4, 135.3, 134.2, 132.8, 130.2, 129.7 (2C), 128.8, 128.6, 125.8 (2C), 125.2, 124.8, 107.0, 86.7, 76.5, 70.0, 46.1, 38.8, 28.4, 27.5 (3C), 21.3; HRMS (ESI) calcd for C₃₁H₂₉ClN₃O₆ [M + H]⁺ 574.1740, found 574.1744.

5’j:

m.p. = 162–164 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 3.2 Hz, 1H), 7.43–7.29 (m, 3H), 7.17–7.11 (m, 2H), 6.86–6.80 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.86 (d, J = 16.8 Hz, 1H), 3.54 (d, J = 18.4 Hz, 1H), 3.17 (d, J = 16.8 Hz, 1H), 2.83 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 2.33 (s, 3H), 1.61 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 187.8, 183.5, 171.1, 153.9, 146.7, 139.8, 138.9, 138.3, 135.4, 135.1, 133.5, 130.5, 129.6 (2C), 128.7, 128.6, 127.3, 125.5 (2C), 124.8, 108.1, 87.5, 73.6, 68.1, 48.3, 39.5, 27.9 (3C), 27.6, 21.3; HRMS (ESI) calcd for C₃₁H₂₉ClN₃O₆ [M + H]⁺ 574.1740, found 574.1737.

(±)-tert-butyl (1′R*,4R*)-6’-methoxy-3-methyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5k and (±)-tert-butyl (1′S*,4R*)-6’-methoxy-3-methyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’k.

Compounds 5k and 5’k were prepared according to the general procedure; the reaction was completed within 20 min. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5k (white solid, 137 mg, 24%) and 5’k (white solid, 279 mg, 49%).

5k:

m.p. = 166–168 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 3.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.97–6.90 (m, 2H), 6.86–6.79 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H), 3.81 (d, J = 16.4 Hz, 1H), 3.56 (d, J = 18.4 Hz, 1H), 3.12 (d, J = 16.4 Hz, 1H), 2.88 (d, J = 18.4 Hz, 1H), 2.61 (s, 3H), 2.32 (s, 3H), 1.61 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.1, 183.1, 170.7, 159.9, 155.0, 147.3, 141.4, 138.3, 134.5, 132.6, 131.5, 130.0, 129.7 (2C), 128.9, 125.9 (2C), 125.1, 115.2, 109.5, 106.8, 86.6, 76.9, 70.4, 55.6, 46.0, 38.5, 28.2, 27.6 (3C), 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₇ [M + H]⁺ 570.2235, found 570.2240.

5’k:

m.p. = 165–167 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 3.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 3.81 (s, 3H), 3.71 (d, J = 16.4 Hz, 1H), 3.51 (d, J = 16.4 Hz, 1H), 3.11 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.70 (s, 3H), 2.33 (s, 3H), 1.50 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.3, 183.9, 171.5, 159.8, 154.1, 146.9, 141.8, 138.2, 135.4, 133.8, 130.3, 129.6 (2C), 129.5, 128.7, 125.6 (2C), 125.2, 115.8, 110.9, 108.0, 87.4, 74.0, 68.6, 55.7, 48.5, 39.2, 27.9 (3C), 27.6, 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₇ [M + H]⁺ 570.2235, found 570.2233.

(±)-tert-butyl (1′R*,4R*)-5’-methoxy-3-methyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5l and (±)-tert-butyl (1′S*,4R*)-5’-methoxy-3-methyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’l.

Compounds 5l and 5’l were prepared according to the general procedure; the reaction was completed within 20 min. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5l (white solid, 177 mg, 31%) and 5’l (white solid, 302 mg, 53%).

5l:

m.p. = 169–171 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 6.8 Hz, 1H), 6.89 (s, 1H), 6.54 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H), 3.74 (d, J = 16.4 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 16.4 Hz, 1H), 2.72 (s, 3H), 2.33 (s, 3H), 1.49 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.3, 183.7, 170.8, 160.8, 155.0, 147.3, 141.1, 138.3, 134.6, 132.7, 132.0, 129.9, 129.7 (2C), 128.8, 125.9 (2C), 124.7, 114.1, 109.8, 106.8, 86.5, 76.8, 69.8, 55.6, 46.4, 39.2, 28.2, 27.5 (3C), 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₇ [M + H]⁺ 570.2235, found 570.2232.

5’l:

m.p. = 166–168 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.49 (m, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H), 6.90–6.78 (m, 3H), 6.63–6.59 (m, 1H), 3.85 (s, 3H), 3.85 (d, J = 16.4 Hz, 1H), 3.54 (d, J = 18.4 Hz, 1H), 3.13 (d, J = 16.4 Hz, 1H), 2.84 (d, J = 18.4 Hz, 1H), 2.61 (s, 3H), 2.33 (s, 3H), 1.60 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.5, 184.3, 171.4, 160.5, 154.1, 146.9, 139.3, 138.2, 135.3, 133.9, 132.4, 130.3, 129.6 (2C), 128.7, 126.8, 125.5 (2C), 114.3, 109.6, 108.0, 87.2, 73.8, 67.9, 55.6, 48.8, 40.0, 27.9 (3C), 27.6, 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₇ [M + H]⁺ 570.2235, found 570.2237.

(±)-tert-butyl (1′R*,4R*)-3,5’-dimethyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5m and (±)-tert-butyl (1′S*,4R*)-3,5’-dimethyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’m.

Compounds 5m and 5’m were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5m (white solid, 144 mg, 26%) and 5’m (white solid, 232 mg, 42%).

5m:

m.p. = 161–163 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.43 (d, J = 3.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 3H), 7.15 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 3.0 Hz, 1H), 3.74 (d, J = 16.5 Hz, 1H), 3.51 (d, J = 16.5 Hz, 1H), 3.14 (d, J = 16.5 Hz, 1H), 2.99 (d, J = 16.5 Hz, 1H), 2.70 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 1.48 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.3, 183.6, 170.9, 155.1, 147.4, 139.7, 139.5, 138.3, 137.1, 134.6, 132.6, 129.9, 129.7 (2C), 129.1, 128.9, 125.9 (2C), 125.1, 123.5, 106.8, 86.5, 76.7, 70.2, 46.2, 39.1, 28.3, 27.5 (3C), 21.6, 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₆ [M + H]⁺ 554.2286, found 554.2281.

5’m:

m.p. = 164–166 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 3.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.84 (d, J = 16.8 Hz, 1H), 3.54 (d, J = 18.4 Hz, 1H), 3.14 (d, J = 16.8 Hz, 1H), 2.85 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 1.60 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.4, 184.1, 171.6, 154.1, 146.9, 139.2, 138.1, 137.9, 137.5, 135.3, 133.8, 130.3, 129.6 (2C), 129.2, 128.7, 125.7, 125.5 (2C), 125.1, 108.0, 87.3, 73.7, 68.4, 48.6, 39.8, 27.9 (3C), 27.6, 21.5, 21.2; HRMS (ESI) calcd for C₃₂H₃₂N₃O₆ [M + H]⁺ 554.2286, found 554.2286.

(±)-tert-butyl (1′R*,4R*)-3,6’-dimethyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5n and (±)-tert-butyl (1′S*,4R*)-3,6’-dimethyl-2,4″,5,7″-tetraoxo-1-(p-tolyl)-4″,7″-dihydro-3′H-dispiro[imidazolidine-4,2′-indene-1′,6″-indole]-1″(5″H)-carboxylate 5’n.

Compounds 5n and 5’n were prepared according to the general procedure. Purification by column chromatography (silica gel, PET/EtOAc = 5:1, v/v) generated compounds 5n (white solid, 127 mg, 23%) and 5’n (white solid, 244 mg, 44%).

5n:

m.p. = 162–164 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 3.2 Hz, 1H), 7.25–7.13 (m, 4H), 7.01–6.89 (m, 3H), 6.54 (d, J = 3.2 Hz, 1H), 3.74 (d, J = 16.4 Hz, 1H), 3.53 (d, J = 16.4 Hz, 1H), 3.13 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 16.4 Hz, 1H), 2.68 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 1.50 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 190.3, 183.4, 170.8, 155.0, 147.3, 140.1, 138.3, 138.0, 136.7, 134.6, 132.6, 130.4, 130.0, 129.7 (2C), 128.9, 125.9 (2C), 124.4, 124.1, 106.8, 86.5, 77.4, 77.2, 76.9, 70.2, 46.0, 38.9, 28.2, 27.5 (4C), 21.7, 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₆ [M + H]⁺ 554.2286, found 554.2288.

5’n:

m.p. = 165–167 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.51 (d, J = 3.2 Hz, 1H), 7.25–7.17 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.83 (d, J = 16.8 Hz, 1H), 3.54 (d, J = 18.4 Hz, 1H), 3.14 (d, J = 16.8 Hz, 1H), 2.87 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H), 1.61 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 188.3, 184.1, 171.6, 154.1, 146.9, 140.5, 138.1, 138.1, 135.4, 134.8, 133.8, 130.3, 130.1, 129.6 (2C), 128.7, 126.6, 125.5 (2C), 124.2, 107.9, 87.3, 73.8, 68.5, 48.6, 39.6, 27.9 (3C), 27.6, 21.7, 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₆ [M + H]⁺ 554.2286, found 554.2285.

48.6, 39.6, 27.9 (3C), 27.6, 21.7, 21.3; HRMS (ESI) calcd for C₃₂H₃₂N₃O₆ [M + H]⁺ 554.2286, found 554.2283.

3.3. Scale-Up Synthesis of 2f and 2′f

To a solution of 5-(2-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)imidazolidine-2,4-dione 1f (3.02 g, 6.0 mmol) in CH₂Cl₂ (50 mL) at −20 °C under argon, a solution of NaOH (48 mg, 1.2 mmol) in CH₃OH (10 mL) was added dropwise over 5 min. The reaction mixture was stirred for 1 h. Then, the reaction was quenched with 1N HCl (50 mL), extracted with CH₂Cl₂ (3 × 50 mL), washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, PET/EtOAc = 5:1), yielding compound 2f (white solid, 0.97 g, 32%) and compound 2′f (white solid, 1.87 g, 62%).

3.4. Cytotoxicity

MTT assay was used to detect the antiproliferative effects of the compounds in vitro. U251 cells were seeded in 96-well plates at 1 × 10⁴ per well. The cells were treated with different concentrations (10, 1, and 0.1 μM) of the compounds and Epacadostat (positive control) and incubated at 37 °C with 5% CO₂ for 48 h. MTT solution with a final concentration of 0.5 mg/mL was added to each well, and incubated at 37 °C for 3 h in dark conditions. DMSO was added to each well, and the OD value was measured at 570 nm. The inhibition of compounds on cell proliferation was calculated as follows: cell proliferation inhibition (%) = (OD control-OD compound)/(OD control-OD blank) × 100%. The IC₅₀ value was calculated by GraphPad Prism 8.0 software.

4. Conclusions

In conclusion, a classic intramolecular Michael addition with high regioselectivity was employed in our work, which enabled facile transformation of naphthoquinone or indolequinone to a biologically interesting dispirocyclic skeleton. This method was mild, efficient, operationally simple, scalable, and transition-metal free. A wide variety of functional groups were well tolerated in this reaction, and the corresponding dispirocyclic products were obtained in good to excellent yields. A gram-scale experiment exemplified the practicality of this protocol. In addition, some compounds exhibited potent cytotoxicity in vitro. Further exploration of the potential of dispirocyclic compounds in the development of novel anti-cancer agents is ongoing in our laboratory, and the results will be reported in due course.