Synthesis of tetracyclic indolin-3-ones through Pd-catalyzed intramolecular deacetylative dearomatization of 3-acetoxy-indoles

Abstract

An efficient palladium-catalyzed intramolecular deacetylative dearomatization reaction of 3-acetoxyindoles has been developed. A range of tetracyclic indolin-3-ones bearing C2-quaternary stereocenters are achieved in good yields, showing a wide substrate scope for this reaction. A preliminary enantioselective reaction is established to furnish the product in 63% ee by using (R,R,R)-phosphoramide-PE as a chiral ligand.

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Introduction

The indolin-3-one containing C2-quaternary stereocenter is an intriguing structural motif that widely appears in natural products and synthetic pharmaceuticals. Representative biologically active molecules include (−)-isatisine A, (−)-isatisine A acetonide, strobilanthoside A, (+)-austamide, and halichrome A (Fig. 1).¹ Considerable attention has been directed to the construction of such a unique framework. A number of reliable synthetic methods have been established, which mainly rely on the transformations of the pre-existing 3-indolinone ring system.² The development of a new strategy for the synthesis of structurally diverse C2-disubstituted indolin-3-ones by using readily available starting materials is still highly desirable.

Fig. 1 Selected biologically active compounds containing indolin-3-one core.

Transition-metal-catalyzed dearomatization of heteroarenes has become a reliable strategy to access heteroalicyclic compounds having carbon-based stereocenters on the ring.³ In this context, a number of dearomatizing transformations of indoles, benzofurans, pyrroles, and furans have been intensely established over the past few years.^3,4 Amongst them, the palladium-catalyzed intramolecular dearomatizing arylation of indoles through a Heck reaction pathway has turned out to be very efficient in approaching fused- or spiro-indoline derivatives containing carbon stereocenters at C2 and/or C3 position of indoline ring. Documented examples included the intramolecular dearomatizing Heck reactions,⁵ reductive-Heck reactions,⁶ and domino dearomatizing Heck/anionic capture sequences involving the capture of benzyl-Pd species with a range of external nucleophiles,⁷ such as cyanide,^7a organoboron reagents,^7b–d alkynes,^7e–h and azoles. Nevertheless, the aforementioned methods have not been applied to the construction of C2-disubstituted indolin-3-one substructure, which possesses a cyclic ketone unit at C3. On the other hand, the palladium-catalyzed dearomatizing cross-coupling of phenolates has recently been established as an powerful access to cyclohexenone molecules, in which keto–enol tautomerism of phenols under the basic conditions facilitates the dearomatization, rendering the formation of cyclic ketone motif reliable (Scheme 1a).^8,9 Inspired by these transformations, as well as the Pd-catalyzed deacetylative arylation reactions of acetoxy-dihydronaphthalene derivatives developed by Zhou's group,¹⁰ we envisioned that a similar dearomatization of 3-acetoxyindole derivatives would provide a straightforward approach to C2-disubstituted indolin-3-ones. Herein, we report the palladium-catalyzed intramolecular deacetylative dearomatization of 3-acetoxyindoles, which results in tetracyclic indolin-3-one derivatives in good yields (Scheme 1b). It represents a new dearomatizing transformation of indoles.

Scheme 1 Pd-catalyzed dearomatizing arylation of phenols and 3-acetoxyindoles.

Results and discussion

We commenced the investigation by exploring the conditions for the intramolecular deacetylative dearomatization reaction with N-(2-iodobenzoyl)-3-acetoxyindole 1a as the model substrate. Initial test using 5 mol% Pd(OAc)₂ as a catalyst, PPh₃ as a ligand, and K₂CO₃ as a base in the presence of two equivalents of water led to the target tetracyclic indolin-3-one 2a in 15% yield in THF at 100 °C for 12 h (Table 1, entry 1). Solvent effect was then investigated to improve the yield. No desired product 2a was detected in protonic solvent MeOH, while comparable yields were observed for the reactions occurred in 1,4-dioxane and toluene (Table 1, entries 2–4). To our delight, the yield was improved to 45% and 40% in DMF and NMP solvent, respectively (Table 1, entries 5 and 6). The influence of the base was then examined in DMF solvent. Na₂CO₃ proved to be better than K₂CO₃, which led to 2a in 54% yield (Table 1, entry 7). In comparison, NaHCO₃ and organic bases (NEt₃ and TMEDA) resulted in lower yields (Table 1, entries 8–10). Moreover, ligand effect was investigated. Although (o-Tol)₃P and ^tBu₃P turned out to be unsuitable ligands (Table 1, entries 11 and 12), the yield of 2a was markedly improved to 72% for JohnPhos and to 84% for ^tBu-XPhos, respectively (Table 1, entries 13 and 14). This observation might imply that JohnPhos and ^tBu-XPhos matched the electronically and sterically demanding of the oxidative addition and reductive elimination processes. In addition, RuPhos and DavePhos also furnished product 2a in satisfactory yields (Table 1, entries 15 and 16). Of note, bidentate phosphine ligands, such as dppe and XantPhos, fully suppressed the reaction. Moreover, water proved to be critical to the reaction as the reaction yield was dramatically decreased to 16% when adding 4 Å molecular sieves to the mixture in the absence of water (Table 1, entry 17). Other tests showed that no reaction occurred in pure water and a diminished yield (58%) in a mixed solvent of DMF/H₂O (10 : 1). Moreover, lowering the temperature remarkably decreased the yields even prolonging the reaction time to 48 h (62% for 80 °C and 30% for 60 °C, respectively).

Table 1 Reaction condition optimization^a

Entry	L	Base	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 5 mol% Pd(OAc)2, L (10 mol%), base (2.0 equiv.), H2O (2.0 equiv.), and solvent (2.0 mL) at 100 °C for 12 h.b Isolated yield.c No additional water and 100 mg 4 Å molecular sieves was added.
1	PPh3	K2CO3	THF	15
2	PPh3	K2CO3	MeOH	ND
3	PPh3	K2CO3	1,4-Dioxane	20
4	PPh3	K2CO3	Toluene	10
5	PPh3	K2CO3	DMF	45
6	PPh3	K2CO3	NMP	40
7	PPh3	Na2CO3	DMF	54
8	PPh3	NaHCO3	DMF	24
9	PPh3	NEt3	DMF	46
10	PPh3	TMEDA	DMF	20
11	(o-Tol)3P	Na2CO3	DMF	50
12	^tBu3P·HBF4	Na2CO3	DMF	30
13	JohnPhos	Na2CO3	DMF	72
14	^tBu-XPhos	Na2CO3	DMF	84
15	RuPhos	Na2CO3	DMF	75
16	DavePhos	Na2CO3	DMF	65
17^c	^tBu-XPhos	Na2CO3	DMF	16

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With the optimal reaction conditions in hand, we then investigated the scope of the intramolecular deacetylative dearomatization reaction. As shown in Scheme 2, a range of N-(2-iodobenzoyl)-3-acetoxyindoles were tested and all the reactions proceeded smoothly to afford the desired tetracyclic indolin-3-one products 2 in moderate to excellent yields. The analogous bromo-substrate led to a relatively lower yield (74%) of product 2a. Either electron-withdrawing or electron-donating substituents on the benzene ring of 2-iodobenzoyl moiety were well tolerated, furnishing indolin-3-ones 2b–2g in the yields ranging from 72% to 92%. The electron-donating substituents resulted in relatively higher yields. Note that a longer reaction time (18 h) was needed for the ortho-methyl product 2g. The effect of substituted groups attached on the indole ring was then examined. A range of functionalities at C5 of indole, including methyl, halide, methoxyl, –CF₃, and –CO₂Me, were compatible to this deacetylative dearomatization reaction, which smoothly delivered products 2h–2n in moderate to good yields, albeit relatively lower yields were observed for those substrates bearing electron-withdrawing substituents. It's worthy to note that a bromine atom of product 2l survived under the reaction conditions, which kept the potential for further functionalization. In addition, substrates having substituents at C6 also led to the desired products 2o–2q in good yields.

Scheme 2 Substrate scope. Reaction conditions: 1 (0.2 mmol), 5 mol% Pd(OAc)₂, ^tBu-XPhos (10 mol%), Na₂CO₃ (2.0 equiv.), H₂O (2.0 equiv.), and DMF (2.0 mL) at 100 °C for indicated time (X = I). ^aX = Br.

Scheme 3 Synthetic transformations.

To demonstrate the synthetic utility of the reaction, several transformations of the indolin-3-one products were then conducted. A reduction of indolin-3-one 2a with LiAlH₄ gave 3-hydroxylindoline 3 in 87% yield as a single isomer, which provides an efficient method to access tetracyclic indolin-3-ol in high diastereoselectivity (Scheme 3, eqn (1)). The Suzuki and Sonogashira reactions of product 2l having a bromide group were established, which furnished the coupling products 4 and 5 in 86% and 92% yields, respectively (Scheme 3, eqn (2) and (3)). The extended conjugate structure might find potential application as material molecules. In addition, a preliminary enantioselective reaction was also studied. As elucidated in Scheme 4, (R,R,R)-MONOPHOS-PE proved to be a potential ligand in the reaction of 1a′, leading to optically active indolin-3-one 2a in 63% ee albeit with a lower yield.

Scheme 4 Preliminary result of the enantioselective reaction.

A tentative mechanism is depicted in Scheme 5. Considering the key role of water in this reaction (Table 1, entry 17), an initial hydrolysis of 3-acetoxy indole 1a in the presence of base is proposed to deliver 3-hydroxyindole I. An adduct II was then achieved through oxidative addition of Pd(0) to compound I. Facilitated by a base-mediated keto–enol tautomerism, nucleophilic attack of indole at C2 to Pd-center furnishes organopalladium III. Subsequent reductive elimination affords product 2a and fulfils the catalytic cycle.

Scheme 5 A plausible reaction mechanism.

Conclusions

In summary, we have developed an efficient intramolecular deacetylative dearomatization reaction of 3-acetoxyindoles by employing the complex of Pd(OAc)₂/^tBu-XPhos as a catalyst. This protocol provides a rapid access to a range of tetracyclic indolin-3-ones in moderate to good yields. Meanwhile, a preliminary enantioselective reaction is developed to afford the product in 63% ee by using (R,R,R)-phosphoramide-PE as a chiral ligand.

Experimental section

General information

Reactions and manipulations involving organometallic or moisture sensitive compounds were carried out under dry nitrogen and glassware heated under oven for two hours prior to use. ¹H NMR spectra were recorded on 500 MHz in CDCl₃, ¹³C NMR spectra were recorded on 125 MHz in CDCl₃. Melting points were determined on a microscopic apparatus and were uncorrected. Commercial reagents were used as received without further purification unless otherwise noticed. HRMS were recorded on a TOF LC/MS mass spectrometer equipped with an ESI source. Column chromatography was carried out using silica gel (200–300 mesh). Anhydrous THF, 1,4-dioxane, and toluene were freshly distilled over Na and benzophenone. Anhydrous methanol was freshly distilled over Mg. Anhydrous DMF and NMP were freshly distilled over calcium hydride under reduced pressure. 3-Acetoxyindoles 1 was prepared (5.0 mmol scale) according to the known method.¹¹

Synthesis of 3-acetoxyindole derivatives 1

According to the known methods,¹¹ to a stirred solution of N-2-iodobenzoyl indole derivatives^6a (5.0 mmol) in HOAc (20 mL) was added PhI(OAc)₂ (3.22 g, 10.0 mmol). The mixture was then stirred in oil-bath at 70 °C for 12 h. After the reaction was completed, HOAc was removed under vacuum. H₂O (5 mL) was added and the solution was extracted with EtOAc (3 × 20 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, v/v = 1/20–1/5) to give 1.

1-(2-Iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1a)

628 mg, 30% yield, yellow solid, mp 107–109 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.44 (m, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.25–7.19 (m, 2H), 7.14 (t, J = 7.6 Hz, 1H), 2.40 (s, 3H), 2.09 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.8, 168.5, 142.0, 140.0, 134.0, 133.8, 132.1, 129.1, 128.6, 126.2, 124.7, 124.0, 123.8, 116.9, 115.3, 93.1, 20.5, 12.1. HRMS m/z (ESI+): calculated for C₁₈H₁₅INO₃ ([M + H]⁺): 441.9911, found 441.9900.

1-(2-Iodo-5-methylbenzoyl)-2-methyl-1H-indol-3-yl acetate (1b)

650 mg, 30% yield, yellow solid, mp 112–114 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.78 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.28 (m, 2H), 7.25–7.19 (m, 1H), 7.17–7.12 (m, 1H), 7.06 (dd, J = 8.0, 1.7 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.9, 168.5, 141.8, 139.7, 139.0, 134.0, 133.7, 133.1, 129.7, 126.2, 124.7, 124.0, 123.7, 116.9, 115.3, 89.0, 20.9, 20.5, 12.1. HRMS m/z (ESI+): calculated for C₁₉H₁₆INO₃Na ([M + Na]⁺): 456.0067, found 456.0058.

1-(2-Iodo-5-methoxybenzoyl)-2-methyl-1H-indol-3-yl ace-tate (1c)

562 mg, 25% yield, yellow solid, mp 104–106 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 10 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.76 (d, J = 8.8 Hz, 1H), 7.36 (m, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.23 (m, 1H), 7.19–7.12 (m, 1H), 6.99 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 8.8, 3.1 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 2.13 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 168.5, 160.1, 142.7, 140.7, 134.0, 133.9, 126.2, 124.8, 124.0, 123.8, 118.9, 116.9, 115.3, 114.3, 81.4, 55.7, 20.5, 12.1. HRMS m/z (ESI+): calculated for C₁₉H₁₆INO₄Na ([M + Na]⁺): 472.0016, found 472.0013.

1-(5-Fluoro-2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1d)

590 mg, 27% yield, yellow solid, mp 128–130 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.87 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.27–7.24 (m, 1H), 7.19 (m, 2H), 7.03–6.97 (m, 1H), 2.40 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.4, 167.4, 162.8 (d, J = 250.0 Hz), 143.5 (d, J = 6.3 Hz), 141.6 (d, J = 7.5 Hz), 134.1, 133.9, 125.9, 124.9, 124.1, 124.0, 119.7 (d, J = 21.3 Hz), 117.1, 116.6 (d, J = 23.8 Hz), 115.2, 86.2 (d, J = 3.8 Hz), 20.5, 12.1. HRMS m/z (ESI+): calculated for C₁₈H₁₃FINO₃Na ([M + Na]⁺): 459.9816, found 459.9805.

1-(4-Chloro-2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1e)

680 mg, 30% yield, yellow solid, mp 52–53 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (d, J = 1.9 Hz, 1H), 7.49 (m, 1H), 7.36 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.25–7.21 (m, 1H), 7.19–7.14 (m, 1H), 2.40 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.4, 168.0, 140.4, 139.6, 137.3, 134.0, 133.9, 129.9, 129.0, 126.0, 124.8, 124.1, 123.9, 117.1, 115.1, 93.5, 20.5, 12.2. HRMS m/z (ESI+): calculated for C₁₈H₁₃ClINO₃Na ([M + Na]⁺): 475.9521, found 475.9512.

1-(5-Chloro-2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1f)

680 mg, 30% yield, yellow solid, mp 112–113 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 6.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.26–7.21 (m, 2H), 7.19 (m, 1H), 2.40 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.4, 167.4, 143.4, 141.1, 135.3, 134.1, 133.9, 132.2, 129.0, 125.9, 124.9, 124.1, 124.0, 117.1, 115.2, 90.2, 20.5, 12.2. HRMS m/z (ESI+): calculated for C₁₈H₁₃ClINO₃Na ([M + Na]⁺): 475.9521, found 475.9513.

1-(2-Iodo-3-methylbenzoyl)-2-methyl-1H-indol-3-yl acetate (1g)

650 mg, 30% yield, yellow solid, mp 119–120 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.39 (s, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.22–7.19 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 2.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.4, 168.5, 143.4, 143.3, 134.1, 133.8, 131.4, 128.7, 126.3, 126.1, 124.7, 124.0, 123.8, 116.9, 115.5, 99.6, 28.8, 20.5, 12.2. HRMS m/z (ESI+): calculated for C₁₉H₁₆INO₃Na ([M + Na]⁺): 456.0067, found 456.0069.

1-(2-Iodobenzoyl)-2,5-dimethyl-1H-indol-3-yl acetate (1h)

606 mg, 28% yield, yellow solid, mp 116–118 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 7.7 Hz, 1H), 7.49 (m, 1H), 7.44–7.41 (m, 1H), 7.25–7.15 (m, 2H), 7.09–6.90 (m, 2H), 2.40 (s, 3H), 2.39 (s, 3H), 2.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.7, 168.6, 142.1, 141.9, 139.9, 133.5, 132.3, 131.9, 129.0, 128.6, 128.0, 126.0, 124.2, 116.8, 115.0, 93.1, 21.3, 20.5, 12.1. HRMS m/z (ESI+): calculated for C₁₉H₁₆INO₃Na ([M + Na]⁺): 456.0067, found 456.0060.

1-(2-Iodobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl ace-tate (1i)

404 mg, 18% yield, yellow solid, mp 132–134 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 10 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 7.9 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.43 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.23 (m, 1H), 6.77–6.70 (m, 2H), 3.82 (s, 3H), 2.40 (s, 3H), 2.05 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.5, 168.4, 156.6, 142.1, 139.9, 133.8, 131.9, 128.9, 128.59, 128.55, 126.8, 125.0, 116.4, 113.0, 99.9, 93.1, 55.6, 20.5, 12.2. HRMS m/z (ESI+): calculated for C₁₉H₁₆INO₄Na ([M + Na]⁺): 472.0016, found 472.0006.

5-Chloro-1-(2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1j)

454 mg, 20% yield, yellow solid, mp 117–119 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J = 7.6 Hz, 1H), 7.51 (td, J = 7.6, 0.8 Hz, 1H), 7.44 (dd, J = 7.6, 1.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.26–7.24 (m, 1H), 7.11 (dd, J = 8.9, 2.1 Hz, 1H), 2.40 (s, 3H), 2.05 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 168.4, 141.6, 140.0, 132.9, 132.4, 132.3, 129.6, 129.1, 128.7, 127.7, 125.3, 124.8, 116.8, 116.4, 93.0, 20.5, 12.2. HRMS m/z (ESI+): calculated for C₁₈H₁₃ClINO₃Na ([M + Na]⁺): 475.9521, found 475.9515.

5-Fluoro-1-(2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1k)

437 mg, 20% yield, yellow solid, mp 114–116 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.95–7.91 (m, 1H), 7.52–7.49 (m, 1H), 7.44 (m, J = 7.6, 1.6 Hz, 2H), 7.25 (m, J = 7.6, 6.0 Hz, 1H), 6.96 (dd, J = 8.2, 2.6 Hz, 1H), 6.89 (td, J = 9.1, 2.6 Hz, 1H), 2.39 (s, 3H), 2.03 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 168.3, 159.7 (d, J = 241.3 Hz), 141.8, 140.0, 133.4 (d, J = 3.8 Hz), 132.2, 130.3, 129.0, 128.6, 127.8, 125.2 (d, J = 8.8 Hz), 116.7 (d, J = 8.8 Hz), 112.4 (d, J = 23.8 Hz), 103.0 (d, J = 25.0 Hz), 93.0, 20.5, 12.2. HRMS m/z (ESI+): calculated for C₁₈H₁₃FINO₃Na ([M + Na]⁺): 459.9816, found 459.9813.

5-Bromo-1-(2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1l)

697 mg, 28% yield, yellow solid, mp 143–145 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J = 7.7 Hz, 1H), 7.51 (td, J = 7.5, 0.7 Hz, 1H), 7.46–7.41 (m, 2H), 7.28–7.23 (m, 3H), 2.40 (s, 3H), 2.05 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 168.3, 141.6, 140.0, 132.7, 132.7, 132.3, 129.1, 128.7, 127.6, 127.5, 125.7, 119.8, 117.2, 116.7, 93.0, 20.5, 12.1. HRMS m/z (ESI+): calculated for C₁₈H₁₃BrINO₃Na ([M + Na]⁺): 519.9016, found 519.9003.

1-(2-Iodobenzoyl)-2-methyl-5-(trifluoromethyl)-1H-indol-3-yl acetate (1m)

487 mg, 20% yield, white solid, mp 139–141 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.97–7.92 (m, 1H), 7.57 (s, 1H), 7.55–7.50 (m, 1H), 7.46 (dd, J = 7.8, 1.5 Hz, 2H), 7.42–7.38 (m, 1H), 7.30–7.26 (m, 1H), 2.43 (s, 3H), 2.10 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.8, 168.4, 141.4, 140.2, 135.5, 133.4, 132.5, 129.3, 128.8, 128.3, 126.1 (q, J = 32.5 Hz), 124.4 (q, J = 270.0 Hz), 123.9, 121.5 (q, J = 3.8 Hz), 115.5, 114.6 (q, J = 5.0 Hz), 93.0, 20.5, 12.2. HRMS m/z (ESI+): calculated for C₁₉H₁₃F₃INO₃Na ([M + Na]⁺): 509.9784, found 509.9776.

Methyl 3-acetoxy-1-(2-iodobenzoyl)-2-methyl-1H-indole-5-carboxylate (1n)

597 mg, 25% yield, white solid, mp 148–150 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 5 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J = 1.2 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.85 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.47 (m, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.27 (m, 1H), 3.92 (s, 3H), 2.43 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.7, 168.4, 166.9, 141.4, 140.1, 136.5, 133.6, 132.4, 129.2, 128.7, 127.8, 125.9, 125.6, 123.9, 119.1, 114.8, 93.0, 52.1, 20.5, 12.1. HRMS m/z (ESI+): calculated for C₂₀H₁₆INO₅Na ([M + Na]⁺): 499.9965, found 499.9953.

1-(2-Iodobenzoyl)-2,6-dimethyl-1H-indol-3-yl acetate (1o)

433 mg, 20% yield, yellow solid, mp 57–58 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.94–7.91 (m, 1H), 7.50–7.41 (m, 3H), 7.23 (m, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 1.96 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.9, 168.4, 142.1, 139.8, 134.9, 134.5, 134.0, 131.9, 129.0, 128.5, 125.2, 124.9, 121.7, 116.5, 116.0, 93.2, 22.0, 20.5, 12.1. HRMS m/z (ESI+): calculated for C₁₉H₁₆INO₃Na ([M + Na]⁺): 456.0067, found 456.0059.

6-Chloro-1-(2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1p)

408 mg, 18% yield, yellow solid, mp 110–112 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 7.7 Hz, 1H), 7.65 (s, 1H), 7.50 (m, 1H), 7.43 (m, 1H), 7.27–7.19 (m, 3H), 2.37 (s, 3H), 1.95 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 168.3, 141.5, 139.9, 134.3, 133.4, 132.2, 130.8, 129.0, 128.6, 126.5, 124.4, 122.5, 117.7, 115.9, 93.0, 20.4, 12.1. HRMS m/z (ESI+): calculated for C₁₈H₁₃ClINO₃Na ([M + Na]⁺): 475.9521, found 475.9512.

6-Fluoro-1-(2-iodobenzoyl)-2-methyl-1H-indol-3-yl acetate (1q)

437 mg, 20% yield, yellow solid, mp 96–98 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, J = 7.9 Hz, 1H), 7.52 (m, 1H), 7.44 (m, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.26–7.19 (m, 2H), 7.00 (td, J = 8.8, 2.2 Hz, 1H), 2.39 (s, 3H), 2.00 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 168.3, 160.9 (d, J = 240.0 Hz), 141.5, 139.9, 134.1 (d, J = 11.3 Hz), 133.3, 132.2, 128.7 (d, J = 40.0 Hz), 126.1, 126.0, 120.3, 117.6 (d, J = 10.0 Hz), 111.9 (d, J = 23.8 Hz), 103.2 (d, J = 28.8 Hz), 92.9, 20.4, 12.0. HRMS m/z (ESI+): calculated for C₁₈H₁₃FINO₃Na ([M + Na]⁺): 459.9816, found 459.9809.

General procedure for the deacetylative dearomatization of 3-acetoxyindoles

To a Schlenk tube were added Pd(OAc)₂ (5 mol%), ^tBu-XPhos (10 mol%), Na₂CO₃ (2.0 equiv., 0.4 mmol), indole 1 (0.2 mmol), and 2.0 mL anhydrous DMF under N₂, after which H₂O (2.0 equiv., 0.4 mmol) was added to the reaction mixture by a syringe. The mixture was then stirred in oil-bath at 100 °C for 12–18 h. When the reaction was completed, the mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layer was concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (ethyl acetate/petroleum ether, v/v = 1/20–1/10) to give products 2.

10b-Methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2a)

42.0 mg, 84% yield, white solid, mp 135–136 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, J = 8.0 Hz, 1H), 7.83 (m, 2H), 7.78–7.73 (m, 2H), 7.73–7.68 (m, 1H), 7.53 (m, 1H), 7.29 (t, J = 7.5 Hz, 1H), 1.81 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.4, 169.6, 151.7, 145.6, 137.4, 134.4, 131.1, 129.5, 127.5, 125.3, 125.24, 125.16, 122.8, 118.6, 73.6, 25.9. HRMS m/z (ESI+): calculated for C₁₆H₁₁NO₂Na ([M + Na]⁺): 272.0682, found 272.0672. For the reaction with (R,R,R)-phosphoramide-PE as a chiral ligand: 30% yield, 63% ee [Daicel Chiralpak AD-H column (25 cm × 0.46 cm ID), ⁿhexane/ⁱPrOH = 95/5, 0.7 mL min⁻¹, 254 nm; t_major = 18.6 min, t_minor = 21.4 min].

8,10b-Dimethyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2b)

44.7 mg, 85% yield, yellow solid, mp 105–107 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J = 8.1 Hz, 1H), 7.78–7.72 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.53–7.50 (m, 1H), 7.29 (d, J = 7.4 Hz, 1H), 2.44 (s, 3H), 1.78 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.8, 169.9, 151.8, 143.1, 139.9, 137.4, 135.6, 131.3, 127.6, 125.4, 125.3, 125.2, 122.5, 118.7, 73.5, 26.0, 21.4. HRMS m/z (ESI+): calculated for C₁₇H₁₄NO₂ ([M + H]⁺): 264.1019, found 264.1016.

8-Methoxy-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2c)

51.4 mg, 92% yield, white solid, mp 110–112 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 10 (v/v); R_f = 0.4. ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J = 8.0 Hz, 1H), 7.79–7.73 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.31–7.27 (m, 2H), 7.27–7.25 (m, 1H), 3.86 (s, 3H), 1.77 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.7, 169.8, 161.1, 151.6, 138.2, 137.4, 132.5, 127.8, 125.4, 125.2, 123.7, 122.9, 118.7, 107.6, 73.3, 55.8, 25.9. HRMS m/z (ESI+): calculated for C₁₇H₁₃NO₃Na ([M + Na]⁺): 302.0788, found 302.0788.

8-Fluoro-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2d)

39.0 mg, 73% yield, yellow solid, mp 108–110 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 7.9 Hz, 1H), 7.78 (m, 3H), 7.50 (dd, J = 7.4, 2.4 Hz, 1H), 7.41 (td, J = 8.6, 2.4 Hz, 1H), 7.34–7.28 (m, 1H), 1.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.0, 168.43, 168.41, 163.6 (d, J = 248.8 Hz), 151.3, 141.2 (d, J = 1.3 Hz), 137.5, 133.3 (d, J = 7.5 Hz), 127.5, 125.4 (d, J = 6.3 Hz), 124.4 (d, J = 8.8 Hz), 122.1, 121.9, 118.6, 111.7 (d, J = 22.5 Hz), 73.2, 25.9. HRMS m/z (ESI+): calculated for C₁₆H₁₁FNO₂ ([M + H]⁺): 268.0768, found 268.0768.

9-Chloro-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2e)

40.8 mg, 72% yield, yellow solid, mp 159–161 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.4. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.76 (m, 3H), 7.50 (dd, J = 8.2, 1.8 Hz, 1H), 7.30 (m, 1H), 1.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.7, 168.5, 151.5, 147.0, 141.1, 137.6, 130.3, 129.6, 127.3, 126.4, 125.4, 123.3, 118.6, 73.1, 25.9. HRMS m/z (ESI+): calculated for C₁₆H₁₁ClNO₂ ([M + H]⁺): 284.0473, found 284.0466.

8-Chloro-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2f)

46.5 mg, 82% yield, yellow solid, mp 125–127 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.79–7.74 (m, 3H), 7.67 (m, 1H), 7.31 (t, J = 7.5 Hz, 1H), 1.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.8, 168.2, 151.3, 143.7, 137.6, 136.0, 134.5, 132.9, 127.5, 125.5, 125.4, 125.2, 124.0, 118.6, 73.3, 25.9. HRMS m/z (ESI+): calculated for C₁₆H₁₀ClNO₂Na ([M + Na]⁺): 306.0292, found 306.0286.

10,10b-Dimethyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2g)

40.0 mg, 76% yield, yellow solid, mp 40–41 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, J = 8.0 Hz, 1H), 7.78–7.71 (m, 2H), 7.68 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 5.0 Hz, 1H), 2.84 (s, 3H), 1.88 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.5, 169.0, 150.7, 143.5, 137.3, 136.5, 135.0, 132.0, 129.4, 127.8, 125.2, 125.0, 122.6, 118.3, 74.9, 24.4, 19.3. HRMS m/z (ESI+): calculated for C₁₇H₁₄NO₂ ([M + H]⁺): 264.1019, found 264.1011.

2,10b-Dimethyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2h)

47.4 mg, 90% yield, yellow solid, mp 97–98 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.89–7.78 (m, 3H), 7.69 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 2.40 (s, 3H), 1.79 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.4, 169.6, 149.7, 145.6, 138.4, 135.2, 134.2, 131.2, 129.4, 127.6, 125.1, 125.0, 122.7, 118.2, 73.8, 25.9, 20.9. HRMS m/z (ESI+): calculated for C₁₇H₁₃NO₂Na ([M + Na]⁺): 286.0838, found 286.0829.

2-Methoxy-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2i)

44.7 mg, 80% yield, white solid, mp 87–88 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 10 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 14.8, 7.7 Hz, 2H), 7.70 (td, J = 7.7, 1.0 Hz, 1H), 7.53 (m, 1H), 7.35 (dd, J = 8.8, 2.7 Hz, 1H), 7.19 (d, J = 2.7 Hz, 1H), 3.83 (s, 3H), 1.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.5, 169.9, 157.5, 146.2, 145.5, 134.3, 131.2, 129.5, 128.3, 126.1, 125.2, 122.7, 119.6, 106.5, 74.3, 55.9, 25.9. HRMS m/z (ESI+): calculated for C₁₇H₁₃NO₃Na ([M + Na]⁺): 302.0788, found 302.0778.

2-Chloro-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2j)

47.6 mg, 84% yield, yellow solid, mp 118–120 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.74–7.68 (m, 3H), 7.57–7.52 (m, 1H), 1.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.4, 169.5, 150.1, 145.4, 137.3, 134.7, 131.2, 130.9, 129.8, 128.8, 125.5, 125.0, 122.8, 119.8, 74.2, 26.0. HRMS m/z (ESI+): calculated for C₁₆H₁₁ClNO₂ ([M + H]⁺): 325.2420, found 325.2411.

2-Fluoro-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2k)

43.8 mg, 82% yield, yellow solid, mp 180–182 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (dd, J = 8.8, 4.1 Hz, 1H), 7.83 (m, 2H), 7.74–7.70 (m, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.48 (td, J = 8.7, 2.7 Hz, 1H), 7.43 (dd, J = 6.9, 2.7 Hz, 1H), 1.81 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.8, 169.7, 160.1 (d, J = 246.3 Hz), 148.0, 145.4, 134.6, 131.0, 129.7, 128.7 (d, J = 8.8 Hz), 125.4, 124.8 (d, J = 25.0 Hz), 122.8, 120.0 (d, J = 7.5 Hz), 111.1 (d, J = 23.8 Hz), 74.4, 25.9. HRMS m/z (ESI+): calculated for C₁₆H₁₁FNO₂ ([M + H]⁺): 268.0768, found 268.0762.

2-Bromo-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2l)

34.1 mg, 52% yield, white solid, mp 103–105 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.4. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (m, 2H), 7.86–7.82 (m, 2H), 7.80 (d, J = 7.7 Hz, 1H), 7.72 (td, J = 7.6, 0.9 Hz, 1H), 7.55 (m, 1H), 1.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.2, 169.4, 150.5, 145.3, 140.0, 134.7, 130.9, 129.7, 129.2, 128.0, 125.4, 122.8, 120.1, 118.4, 73.9, 25.9. HRMS m/z (ESI+): calculated for C₁₆H₁₀BrNO₂Na ([M + Na]⁺): 349.9787, found 349.9796.

10b-Methyl-2-(trifluoromethyl)-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2m)

40.0 mg, 63% yield, white solid, mp 52–54 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J = 8.5 Hz, 1H), 8.05 (s, 1H), 8.00 (dd, J = 8.4, 1.5 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.75 (m, 1H), 7.59–7.54 (m, 1H), 1.83 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.4, 169.2, 153.7, 145.3, 134.9, 134.1 (q, J = 3.8 Hz), 130.7, 129.9, 127.7, 127.6 (q, J = 33.8 Hz), 125.6, 124.6, 122.88, 122.85, 119.0, 74.1, 26.0. HRMS m/z (ESI+): calculated for C₁₇H₁₀F₃NO₂Na ([M + Na]⁺): 347.2224, found 347.2226.

Methyl 10b-methyl-6,11-dioxo-10b,11-dihydro-6H-isoindolo [2,1-a]indole-2-carboxylate (2n)

30.7 mg, 50% yield, white solid, mp 125–127 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 10 (v/v); R_f = 0.2. ¹H NMR (500 MHz, CDCl₃) δ 8.47–8.41 (m, 2H), 8.03 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.76–7.71 (m, 1H), 7.56 (m, 1H), 3.95 (s, 3H), 1.82 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.6, 169.1, 165.7, 154.4, 145.5, 138.5, 134.8, 130.8, 129.8, 127.6, 127.3, 127.2, 125.5, 122.8, 118.2, 74.1, 52.5, 26.1. HRMS m/z (ESI+): calculated for C₁₈H₁₄NO₄ ([M + H]⁺): 308.0917, found 308.0903.

3,10b-Dimethyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2o)

46.3 mg, 88% yield, yellow solid, mp 149–150 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.87–7.78 (m, 3H), 7.70 (td, J = 7.7, 1.0 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.53 (m, 1H), 7.10 (d, J = 7.8 Hz, 1H), 2.52 (s, 3H), 1.79 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.8, 169.7, 152.0, 149.5, 145.8, 134.3, 131.2, 129.4, 126.5, 125.2, 125.1, 125.0, 122.7, 118.8, 73.9, 26.1, 22.6. HRMS m/z (ESI+): calculated for C₁₇H₁₄NO₂ ([M + H]⁺): 264.1019, found 264.1009.

3-Chloro-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2p)

44.3 mg, 78% yield, white solid, mp 160–162 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.73 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.56–7.53 (m, 1H), 7.26 (m, 1H), 1.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.2, 169.4, 152.3, 145.6, 144.0, 134.7, 130.8, 129.7, 126.2, 125.92, 125.90, 125.5, 122.8, 118.9, 74.0, 26.0. HRMS m/z (ESI+): calculated for C₁₆H₁₀ClNO₂Na ([M + Na]⁺): 306.0292, found 306.0280.

3-Fluoro-10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-dione (2q)

39.6 mg, 74% yield, white solid, mp 168–170 °C; purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether 1 : 20 (v/v); R_f = 0.3. ¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.77 (dd, J = 8.5, 5.5 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.66 (dd, J = 8.9, 2.1 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 6.98 (td, J = 8.6, 2.1 Hz, 1H), 1.81 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.7, 169.4, 168.7 (d, J = 256.3 Hz), 153.6 (d, J = 13.8 Hz), 145.7, 134.7, 130.7, 129.6, 127.4 (d, J = 12.5 Hz), 125.4, 123.7, 122.8, 113.4 (d, J = 23.8 Hz), 106.1 (d, J = 26.3 Hz), 74.2, 26.0. HRMS m/z (ESI+): calculated for C₁₆H₁₁FNO₂ ([M + H]⁺): 279.2795, found 279.2784.

Reduction of 2a

To a solution of 2a (1.0 equiv., 0.2 mmol) in THF (2.0 mL) was added LiAlH₄ (10.0 equiv., 2.0 mmol) in portions at 0 °C, after which the mixture was stirred at 90 °C for 12 h. The resulting mixture was then quenched with H₂O at 0 °C, and extracted with EtOAc. After the solvent EtOAc was removed under vacuum, the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether, v/v = 1/3) to give compound 3 (41.0 mg, 87%) as a white solid, R_f = 0.4. Mp 85–87 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.32–7.25 (m, 2H), 7.20 (m, 3H), 7.14 (d, J = 6.7 Hz, 1H), 6.83 (m, 2H), 5.40 (s, 1H), 4.61 (d, J = 15.2 Hz, 1H), 4.41 (d, J = 15.2 Hz, 1H), 2.31 (brs, 1H), 1.52 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 154.4, 147.1, 138.5, 132.0, 130.3, 128.0, 127.4, 125.9, 122.9, 122.3, 121.5, 113.3, 80.4, 78.6, 56.9, 21.0. HRMS m/z (ESI+): calculated for C₁₆H₁₆NO ([M + H]⁺): 238.1226, found 238.1223.

Suzuki reaction of 2l with PhB(OH)₂

The mixture of PhB(OH)₂ (1.2 equiv., 0.24 mmol), Pd(PPh₃)₄ (8 mol%), K₂CO₃ (2.5 equiv., 0.5 mmol), and 2l (1.0 equiv., 0.2 mmol) in THF (2.0 mL) and H₂O (1.0 mL) was stirred at 65 °C for 12 h under N₂ atmosphere. The resulting mixture was then extracted with EtOAc and the combined organic phases were concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether, v/v = 1/10) to give compound 4 (55.8 mg, 86%) as a white solid, R_f = 0.5. Mp 120–122 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.05 (d, J = 8.3 Hz, 1H), 7.99 (m, 2H), 7.85 (dd, J = 14.9, 7.7 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.59–7.52 (m, 3H), 7.46 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 1.84 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.5, 169.7, 150.9, 145.6, 139.4, 138.7, 136.5, 134.5, 131.1, 129.6, 129.0, 128.1, 127.8, 127.0, 125.3, 123.4, 122.8, 118.8, 74.1, 26.0. HRMS m/z (ESI+): calculated for C₂₂H₁₅NO₂Na ([M + Na]⁺): 348.0995, found 348.0997.

Sonogashira reaction of 2l with phenylacetylene

The mixture of phenylacetylene (1.5 equiv., 0.3 mmol), CuI (5 mol%), Pd(PPh₃)₂Cl₂ (2 mol%), and 2l (1.0 equiv., 0.2 mmol) in Et₃N (2.0 mL) was stirred at 100 °C for 12 h under N₂ atmosphere. After the reaction was completed, Et₃N was removed under vacuum. The crude was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether, v/v = 1/10) to give compound 5 (64.4 mg, 92%) as a yellow solid, R_f = 0.2. Mp 145–146 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 8.3 Hz, 1H), 7.93–7.83 (m, 3H), 7.81 (d, J = 7.6 Hz, 1H), 7.71 (m, 1H), 7.53 (m, 3H), 7.39–7.30 (m, 3H), 1.81 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.6, 169.3, 150.8, 145.5, 140.3, 134.5, 131.6, 131.0, 129.6, 128.6, 128.4, 128.2, 127.7, 125.3, 122.74, 122.66, 120.6, 118.5, 90.4, 87.7, 73.8, 26.0. HRMS m/z (ESI+): calculated for C₂₄H₁₆NO₂ ([M + H]⁺): 350.1176, found 350.1178.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (21702184 and 21772175).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9ra02569c

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