Synthesis of spiro isoindolinone-indolines and 1,2-disubstituted indoles from 2-iodobenzamide derivatives

Abstract

Copper catalyzed C-terminal and N-terminal attack of 2-alkynylanilines to 2-iodobenzamides afforded isoindolinones and 1,2-disubstituted indoles, respectively. Further, the isoindolinone derivatives were converted to spiro fused isoindolinone-indolines utilizing a halonium ion mediated strategy using NBS/TCC in the presence of acetic anhydride. Also, the ortho effect of the amide group in 2-iodobenzamide has been successfully applied for the synthesis of 1,2-disubstituted indoles.

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Introduction

Spiroindoline derivatives have gained huge synthetic significance over the past few decades due to their biological activities and wide existence in several natural products.¹ Particularly, the fused heterocycles spiroindolines have been known to exhibit a wide variety of biological activities including antiparasitic, antiviral, antitumor, and antibiotic agents, inhibitors of the human NK-1 receptor, and the gonadotropin-releasing hormone receptor antagonist.² Further, spiroindoline derivatives also exhibit potential activity in controlling pests.³ Furthermore, fused isoindolinone spiro heterocyclic scaffolds are found as a core structure in a large family of bioactive products (Fig. 1).⁴

Fig. 1 Spiroindoline derivative and isoindolo-spiro hetero cyclic scaffolds.

Plethora methods were available for the synthesis of various heterocyclic fused spiroindolines in the literature.⁵ Moreover, to our knowledge, spiro fused isoindolinone-indoline frameworks were not reported. However, the similar structural analogs such as isoindolinone fused oxoindole frame works were reported (Scheme 1).⁶ The unique structural features and the diverse biological activity of core structures of both isoindolinone and indoline paved us the way to pay interest for synthesizing spiro fused structures of isoindolinone and indoline using readily available starting materials.

Scheme 1 Previous reports on the synthesis of spiro-fused isoindolinone-indolinone derivatives.

On the other hand, 1,2-disubstituted indoles are also an important class of heterocycles because of their biological activities and medicinal applications including COX-2 inhibitors, estrogen receptor ligands, potential in the treatment of alzheimer's disease, in treatment of diseases associated with defects in vesicular (axonal) transport, treatment of inflammation and potent inhibitors of larval settlement by the barnacle, balanusamphitrite.⁷ A wide variety of procedures reported for the synthesis of 1,2-disubstituted indole derivatives.⁸ Among them cycloisomerization of 2-alkynylanilines⁹ is one of most frequently reported method for accessing 1,2-disubstituted indole derivatives. However, most of the reported procedures employed an expensive and air sensitive catalysts such as Pd, Au for this tranformation.¹⁰ Recently, Gao and co-workers had reported the synthesis of 1,2-disubstituted indole derivatives from aryl boronic acid and 2-alkynylanilines in the presence of copper catalyst and ligands.¹¹

We¹² and also others¹³ have explored the utility of 2-iodobenzamide derivatives for the synthesis of various bioactive N-heterocyclic compounds for the past few years. From our experience, and the literature¹⁴ available on the reaction of 2-iodobenzamide substrates under copper catalysis, we anticipated to prepare spiroisoindilinone-indoline derivatives as well as 1,2-disubstituted indole derivatives from 2-iodobenzamide derivatives as shown in proposed route (Scheme 2). We proposed that the treatment of 2-trimethylsilylethynylaniline 2a with 2-iodo-N-methylbenzamide 3a in the presence of copper catalyst may lead to form isoindolinone derivative via C-terminal attack (4a). Further, we presume that the treatment of 4a with a bromonium ion source may afford the corresponding bromospiroisoindolinone-indoline derivative 6aa. Moreover, we also expected that the replacement of 2-ethynylaniline with 2-(phenylethynyl)aniline in the present reaction, may form N-arylated compound 8aa via N-terminal attack which may further undergo cycloisomerization to furnish the corresponding 1,2-disubstituted indole 8a derivatives (Scheme 3).

Scheme 2 Proposed routes for the spiroisoindolinone-indolines and 1,2-disubstituted indoles from 2-iodobenzamide derivatives.

Scheme 3 Mechanism for the synthesis of 2-aminophenylisoindolinone derivatives.

Results and discussion

To test our assumption, we treated 2-(trimethylsilylethynyl)aniline 2a (1.0 mmol) with 2-iodo-N-methylbenzamide 3a (1.3 mmol) in the presence of potassium carbonate (2.0 equiv.), DMSO and copper iodide (20 mol%) at 100 °C for 1.5 h (entry 1, Table 1). Under these conditions, the expected compound 4a was obtained as a minor product along with unknown major product. Both these compounds were characterized using ¹H NMR, ¹³C NMR and the mass spectra analysis. From the spectral data and X-ray analysis, the structure of the major product was found as 5a. On the other hand, when the internal 2-alkynyl aniline such as 2-(phenylethynyl)aniline 7a was used as coupling partner instead of trimethylsilyl 2-alkynylaniline 2a, we obtained the expected 1,2-disubstituted indole derivative 8a along with the intermediate N-arylated compound 8aa in the presence of potassium carbonate (3.0 equiv.), copper iodide (10 mol%) in DMSO solvent at 100 °C for 12 h (entry-1, Table 5).

Table 1 Optimization of the reaction for the formation of 3-(2-aminobenzylidene)-2-methylisoindolin-1-one 4a

Entry^a	Catalyst	Base	Solvent	2a (eq.)	3a (eq.)	Yield^b (%)
						4a	5a
a All the reactions were carried out in 0.5 mmol scale using 2.0 equiv. of base in the indicated solvent (3.0 mL). b NMR yields.
1	Cul (20 mol%)	K2CO3	DMSO	1.0	1.3	15	55
2	Cul (20 mol%)	K2CO3	DMSO	1.2	1.0	62	21
3	Cul (20 mol%)	K2CO3	DMSO	1.3	1.0	80	9
4	Cul (20 mol%)	Cs2CO3	DMSO	1.3	1.0	48	34
5	Cul (20 mol%)	K2CO3	DMF	1.3	1.0	73	17
6	Cul (20 mol%)	K2CO3	IPA	1.3	1.0	40	18
7	Cu(OAc)2 (20 mol%)	K2CO3	DMSO	1.3	1.0	32	20
8	Cu(OAc)2 (20 mol%)	Cs2CO3	DMF	1.3	1.0	76	12
9	CuSO4·5H2O (20 mol%)	Cs2CO3	DMF	1.3	1.0	87	10
10	CuSO4·5H2O (10 mol%)	Cs2CO3	DMF	1.3	1.0	88	10
11	CuSO4·5H2O (5 mol%)	Cs2CO3	DMF	1.3	1.0	72	8
12	CuCl2 (10 mol%)	Cs2CO3	DMF	1.3	1.0	87	12

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Encouraged by these initial results, we decided to optimize the reaction conditions for the synthesis of both isoindolinone derivatives and 1,2-disubstituted indole derivatives. Firstly, to optimize the reaction condition for the formation of isoindolinone derivatives, we examined the reaction to suppress the formation of undesired 5a (Table 1, entries 1–3). The reaction in the presence of 1.3 equiv. of 2a with respect to 1.0 equiv. of trimethylsilyl 2-alkynylaniline 3a, produced better result as compared to other conditions (entry 3). Further, increasing the basicity by replacing K₂CO₃ with Cs₂CO₃ leads to fall in yield. Polar solvents other than DMSO like DMF, IPA were also examined for this reaction (entries 5 and 6). We found that, DMF solvent is an alternate option for this reaction (entry 5). When we performed reaction in presence of copper(II) catalyst, satisfactory result was obtained. Unlike Cu(I), Cu(II) even using strong base Cs₂CO₃ afforded good yields (entries 7–12). However, with 10 mol% of CuSO₄·5H₂O, the reaction was very smooth with best yield (entry 10). From these optimization studies, it was concluded that the reaction in the presence of 10 mol% CuSO₄·5H₂O and 2.0 equiv. of base in DMF at 100 °C gave the best result.

Having these optimized conditions in hand, we turned our attention to explore the reaction scope of this method. As shown in Table 2, various 2-alkynyl-phenylamines were reacted with 2-iodobenzamides, furnished 3-(2-aminobenzylidene)-2-substituted isoindolin-1-one derivatives. The reactions of 2-(phenylethynyl)aniline or 2-((trimethylsilyl)ethynyl)aniline with 2-iodo-N-methylbenzamide not shown much difference in the yields (Table 2, entries 1 and 2). When we conducted the reaction with 2-iodo-aliphatic N-substituted benzamides, with chloro and bromo substituents at R³ and R² positions of substrate 3 produces good yields of desired product (entries 3–7). Subsequently, we tested the reactions with phenyl substituted 2-iodo-benzamide with substrate 3 produces the corresponding compounds 4g–4k in moderate to good yields (entries 8–12).

Table 2 Scope of the reactions for the synthesis of 3-(2-aminobenzylidene)-2-substituted isoindolin-1-one derivatives with respect to 2-iodobenzamides and 2-akynylanilines^a

Entry^a	R	R^1	R^2	R^3	R^4	Product	Yield^b^,^c (%)
a Reaction conditions: 2 (1 mmol), 3 (1.2 equiv.), Cs2CO3 (2.0 equiv.), CuI (10 mol%), DMF (3.0 mL) at 100 °C. b Isolated yields. c In all the entries about 5–10% of undesired 5a analogs were observed.
1	Me	H	H	H	H	4a	88
2	Me	TMS	H	H	H	4a	86
3	Me	TMS	Br	H	H	4b	83
4	Me	TMS	H	Cl	H	4c	84
5	Ethyl	TMS	H	Cl	H	4d	84
6	Allyl	TMS	H	Cl	H	4e	85
7	–CH2CH2OMe	TMS	H	Cl	H	4f	84
8	Ph	TMS	H	H	H	4g	72
9	Ph	TMS	Br	H	Br	4h	65
10	Ph	TMS	H	Cl	Br	4i	68
11	Ph	TMS	OMe	H	H	4j	82
12	Ph	TMS	H	Cl	H	4k	71
13	–CH2Ph	TMS	H	H	H	4l	72
14	–CH2Ph	TMS	Br	H	H	4m	72
15	–CH2Ph	TMS	H	Cl	Br	4n	67

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Under optimized conditions, bromo substituted N-phenyl-2-iodobenzamides provided comparatively lower yields of the desired compounds (entries 9 and 10). Whereas in the presence of electron releasing group (OMe) on the 2-((trimethylsilyl)ethynyl)aniline resulted higher yield of the product (entry 11). Furthermore, N-benzyl-2-iodo-benzamide substrates were treated with substrate 3 under present conditions (entries 12–15). The proposed mechanism for the formation of isoindolinone derivatives from 2-iodobenzamides (3) and 2-akynylanilines was shown in Scheme 3.

After synthesizing various structurally diverse 3-(2-aminobenzylidene)-2-substituted isoindolin-1-one derivatives, we focused our attention on the synthesis of spiro fused isoindolinone-indoline derivatives via C–N coupling. To determine suitable conditions for this reaction, we initially treated compound 4a with the combination of K₂CO₃ and NBS in the presence of acetonitrile at 25 °C and found multiple compounds which are complicate to isolate (Table 3). Then we presumed that in situ N-acetylation of compound 4a may favor the reaction to construct spiro fused isoindolinone-indoline derivatives. To determine reaction conditions for this reaction, we again treated compound 4a with a combination of acetic anhydride, K₂CO₃ and NBS sequentially, in the presence of acetonitrile at 40 °C. Under these conditions, the diastereomeric 1-acetyl-3-bromo-2′-methyl-1,3-dihydrospiro[indene-2,1′-isoindolin]-3′-one 6a product was obtained in 45% yield. The yield of the compound 6a improved to 62% by increasing the amount of acetic anhydride and NBS. When we conducted the reaction in the presence of 2.0 equiv. of Ac₂O without solvent, the desired compound was obtained in 84% with 1 : 2 diastereoselectivity ratio.

Table 3 Optimization of reaction for the formation of 1-acetyl-3-bromo-2′-methyl-1,3-dihydrospiro[indene-2,1′-isoindolin]-3′-one 6a

Entry^a	Base	Solvent	Ac2O (eq.)	NBS (eq.)	Temp (°C)	Product^b (%)	dr^c
a All the reactions were performed in 0.5 mmol scale and 3.0 equiv. of base used. b NMR yields. c dr ratio is based on crude ^1H NMR.
1	K2CO3	CH3CN	1.0	1.1	40	45	1 : 1
2	K2CO3	CH3CN	1.5	1.1	40	62	1 : 1
3	K2CO3	—	2.0	1.2	40	84	1 : 2
4	K2CO3	—	2.0	1.2	0	32	1 : 3
5	K2CO3	—	2.0	1.2	25	80	1 : 4
6	K2CO3	—	3.0	1.2	25	83	1 : 4
7	Cs2CO3	—	2.0	1.2	25	60	1 : 2

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Still, to increase the diastereoselectivity, reaction was carried out at 0 °C favoring the kinetically control rather than thermodynamic control, which results drastic fall in yield which may be due to the less driving force for the reaction to proceed forward. Furthermore, at 25 °C, satisfactory results were obtained in both yields and diastereoselectivity. The excess addition of acetic anhydride in the reaction did not show any marked improvement in terms of yields and diastereoselectivity. Usage of strong base also shows the fall in yields resulting a black charred reaction mixture which is due to the decomposition of product at highly basic condition. From these optimization studies, it was concluded that the reaction in the presence of 2.0 equiv. of Ac₂O, 3.0 equiv. of K₂CO₃ and 1.2 equiv. of NBS at 25 °C gave the best result in terms of product yields and diastereoselectivity.

Having this optimized reaction condition in hand, we next employed the synthesis of various structurally diverse 3-(2-aminobenzylidene)-2-substituted isoindolin-1-one derivatives (Table 4). In this regard, first, we conducted the reaction using methyl and ethyl substituted isoindolin-1-one derivatives 4a–4d. Under this optimized condition, these substrates produced the inseparable diastereomers of spiro fused isoindolinone-indolines with good yields and diastereoselectivity (Table 4, entries 1–4). Further, we tested the reactivity of compound 4f using different halogen sources like NBS, NCS, and NIS. The reaction in presence of NBS resulted the good yields of product with single diastereomer (entry-5). Whereas, in the case of NCS reaction was not facilitated. However, trichloroisocyanuric acid (TCCA) gave expected compound in good yield and diastereoselectivity (entry 6). The reaction in the presence of NIS resulted decomposition of the reaction (entry 7). 3-(2-Aminobenzylidene)-2-benzylisoindolin-1-one derivatives 4l–4n provided the desired inseparable diastereomeric products 6h–6j in 71–78% yield (entries 8–10). Whereas, phenyl substituted-isoindolin-1-one derivatives 4g–4i and 4k furnished these inseparable diastereomers of spiro fused isoindolinoneindolines 6k–6n in moderate yields (entries 11–14). This may be due to the restricted environment of bulky benzyl or phenyl groups, respectively, for spirocyclizations. The crystal structures of both the diastereomers of 1-acetyl-3-bromo-5-chloro-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one 6n and 6n′ were shown in Fig. 2. The reaction with methoxy substituted derivative 4j resulted the unexpected product in which the halogen was replaced by OCOCH₃ group with good yield and diastereoselectivity (entry 15). Allyl substituted-isoindolin-1-one derivative 4e, undergoes cyclo propyl bromonium ion intermediate formation predominantly to internal double bond than external double bond to afford desired spiro compound (entry 16).

Table 4 Scope of the reactions for the synthesis of 1-acetyl-3-bromo-2′-methyl-1,3-dihydrospiro[indene-2,1′-isoindolin]-3′-one derivatives (6)^a

Entry	R	R^4	R^3	R^2	X	Product	Yield^b (%)	dr^c
a Reaction conditions: 4 (0.5 mmol), Ac2O (2 equiv.), K2CO3 (2 equiv.). b Isolated yields. c dr ratio is based on ^1H NMR of crude reaction mixture and diastereomers were difficult to separate in all these reactions. d The halogen–Br was further replaced by –OCOCH3 group which is from acetic anhydride.
1	Me	H	H	H	Br	6a	82	6.3 : 1.9
2	Me	H	H	Br	Br	6b	82	6.4 : 1.8
3	Me	H	Cl	H	Br	6c	85	100 : 1
4	Ethyl	H	Cl	H	Br	6d	84	7 : 1.4
5	CH2CH2OMe	H	Cl	H	Br	6e	89	100 : 1
6	CH2CH2OMe	H	Cl	H	Cl	6f	89	100 : 1
7	CH2CH2OMe	H	Cl	H	l	6g	0	—
8	CH2Ph	H	H	H	Br	6h	71	4.8 : 2.1
9	CH2Ph	H	H	Br	Br	6i	78	5.4 : 2.6
10	CH2Ph	Br	Cl	H	Br	6j	77	6.5 : 1.2
11	Ph	H	H	H	Br	6k	62	3.1
12	Ph	Br	H	Br	Br	6l	66	6.8 : 1.7
13	Ph	Br	Cl	H	Br	6m	62	5.5 : 0.6
14	Ph	H	Cl	H	Br	6n	64	3.5 : 2.9
15	Ph	Br	H	OMe	OCOCH3	6o	88	100 : 1^d
16	Allyl	H	Cl	Br	Br	6p	72	100 : 1

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Fig. 2 Crystal structures of 1-acetyl-3-bromo-5-chloro-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one 6n and 6n1 diastereomers.

In order to check the feasibility for scale up, we synthesized compound 4f from its corresponding precursors in 15.0 mmol scale with 88% isolated yield, which is further converted to spiro fused isoindolinone-indoline 6e with 82% isolated yield and single diastereomer (Scheme 4).

Scheme 4 Scale up syntheses of compounds 4f and 6e.

Mechanism for the formation of 1-acetyl-3-bromo-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one derivatives could be depicted in Scheme 5.

Scheme 5 Plausible mechanism for formation spiro[indoline-2,1′-isoindolin]-3′-one derivatives.

On the other hand, synthesis of N-benzyl-2-(2-phenyl-1H-indol-1-yl)benzamide 8a was investigated for its optimization as shown in Table 5. Initial screening of this reaction was started with 10 mol% of CuI with 1.2 equiv. of 7a, 1.0 equiv. of 3a, and 3.0 equiv. of K₂CO₃ in DMSO. The yield is very low resulting the decomposition of 3a and unreacted 7a was recovered (Table 5, entry 1). Then the catalyst loading was increased to 20 mol% and checked the reactivity with 1.3 equiv. and 1.5 equiv. of 3a and it was found that there is an improvement in yield (entries 2 and 3). Subsequently the yield was still improved by altering the base from K₂CO₃ to Cs₂CO₃ (entry 4). But, there is no further improvement in the yield, even the addition of excess of 3a (entry 5). The other sources of copper like CuBr and CuSO₄ were also examined and found not satisfactory (entries 6–8). The usage of ligands leads to the decomposition of 3a, no further reaction and 7a was recovered (entries 9 and 10). Other kinds of polar solvents also examined which were not satisfactory (entries 11–14).

Table 5 Optimization of reaction for the formation of N-benzyl-2-(2-phenyl-1H-indol-1-yl)benzamide 8a

Entry^a	Catalyst (mol%)	Ligand	t (h)	7a (eq.)	3a (eq.)	Base (3 eq.)	Solvent	Product^c (%)
a All the reactions were performed in 0.5 mmol scale with 7a (0.5 mmol), at 100 °C and 20 mol% of catalyst. b 7a was not consumed completely. Unreacted 7a was recovered. c NMR yields. 1,10-Phen = 1,10-phenanthraline. d 10 mol% of catalyst used.
1	Cul	—	12	1.2	1	K2CO3	DMSO	22^b^,^d
2	Cul	—	12	1	1.3	K2CO3	DMSO	45^b
3	Cul	—	12	1	1.5	K2CO3	DMSO	50^b
4	Cul	—	7	1	1.5	Cs2CO3	DMSO	71
5	Cul	—	7	1	1.7	Cs2CO3	DMSO	71
6	Cul(OAc)2	—	12	1	1.5	Cs2CO3	DMSO	10^b
7	CuBr	—	12	1	1.5	Cs2CO3	DMSO	30^b
8	CuSO4	—	12	1	1.5	Cs2CO3	DMSO	—^b
9	Cul	L-Proline	12	1	1.5	Cs2CO3	DMSO	46^b
10	Cul	1,10-Phen	12	1	1.5	Cs2CO3	DMSO	—
11	Cul	—	9	1	1.5	Cs2CO3	DMF	65^b
12	Cul	—	12	1	1.5	Cs2CO3	THF	48^b
13	Cul	—	12	1	1.5	Cs2CO3	IPA	—^b
14	Cul	—	12	1	1.5	Cs2CO3	1,4-Dioxane	—^b

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Having the optimized conditions in hand, the scope of the above reaction was also examined as showed in Table 6. The reactivity of different kinds of N-substituted 2-iodo benzamides were studied (Table 6, entries 1–11) and N-substituted 3-OMe propyl group at R gives the maximum yield (entry-9). The reactivity was also checked by taking different aliphatic substituents at R¹ which afforded low or moderate yields (entries 12–14). However, presence of electron releasing functional group at R¹ results good yield (entry 15). The presence of electron releasing groups at R² position gives moderate yields (entries 16 and 17). But, the presence of electron withdrawing group –NO₂ in the same position gives good yield (entry 18). With chloro substituents at R³ position gives moderate yields (entries 19 and 20). The presence of aliphatic chain at R¹, the yield is expected to be low. But, may be due to effect of N-substituted 3-methoxy amidic group, even in the presence of aliphatic group at R¹, the yield is reasonably good (entry 21).

Table 6 Scope of the reactions for the synthesis of 1,2-substituted indolyl N-substituted benzamide derivatives (8) with respect to 2-iodobenzamides (3) and 2-akynylanilines (7)

Entry^a	R	R^1	R^3	R^2	R^5	t (h)	Product	Yield^b (%)
a Reaction conditions: 7 (1 mmol), 3 (1.5 mmol), Cs2CO3 (2 mmol), CuI (20 mol%), DMSO (3 mL). b Isolated yields. c Reaction is incomplete and the starting material was recovered.
1	Me	Ph	H	H	H	6	8a	47
2	Ph	Ph	H	H	H	4	8b	59
3	o-Tolyl	Ph	H	H	H	4	8c	66
4	p-OMe-phenyl	Ph	H	H	H	4	8d	68
5	Benzyl	Ph	H	H	H	7	8e	71
6	CH2CH(Ph)2	Ph	H	H	H	4	8f	73
7	Ethyl	Ph	H	H	H	4	8g	68
8	Allyl	Ph	H	H	H	4	8h	75
9	(CH2)3–OMe	Ph	H	H	H	4	8i	79
10	CH2–CH2-Ph	Ph	H	H	H	4	8j	77
11	(CH2)4Ph	Ph	H	H	H	4	8k	74
12	Benzyl	Cyclopentyl	H	Cl	H	18	8l	48
13	Me	Cyclohexyl	H	Me	H	19	8m	49
14	Benzyl	Isopropyl	Me	H	Me	18	8n	51
15	Benzyl	–CH2OMe	OMe	H	H	3	8o	70
16	Benzyl	Ph	H	OMe	H	7	8p	63
17	Benzyl	Ph	H	Me	H	8	8q	67
18	Benzyl	Ph	H	NO2	H	6	8r	76
19	Benzyl	Ph	Cl	H	H	7	8s	55
20	Ph	Ph	Cl	H	H	7	8t	61
21	(CH2)3–OMe	Heptyl	Cl	H	H	12	8u	67
22	Benzyl	4-Cl, 2-Br-phenyl	Cl	H	H	22	8v	39^c
23	(CH2)3–OMe	4-Cl, 2-Br-phenyl	Cl	H	H	9	8w	64

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The N-benzyl substituted-2-iodobenzamide is very less reactive and less stable in the presence of other partner substrate and hence decomposed and the other substrate 2-phenylalkynylaniline derivative was recovered (entry 22). Whereas, replacing with N-substituted-3-MeO propyl group at R resulted in completion of reaction with good yield (entry 23). Further, the proposed the mechanism for the formation of 2-arylamidoindole derivatives from 2-iodobenzamides (3) and 2-akynylanilines was shown in Scheme 6.

Scheme 6 Plausible mechanism for the synthesis of I, 2 disubstituted indole derivatives.

Next, to test the limitation of this methodology and to prove that ortho effect of N-substituted amidic group is playing a key role for its reactivity, we executed some experiments which are limitations for this protocol, on reacting various ortho substituted iodo benzenes I with 2-phenylalkynylaniline 7a and found no reaction even after 24 h as shown in Scheme 7.

Scheme 7 Experiments to prove the ortho effect of N-substituted amidic group for its reactivity.

Finally, the indole substrate containing bromo group such as 1-(2-(2-(2-bromo-4-chlorophenyl)-5-chloro-1H-indol-1-yl)phenyl)-4-methoxybutan-1-one 8w was subjected for cyclization in presence of palladium acetate, triphenylphosphine and cesium carbonate in dioxane at 140 °C to synthesize 3,12-dichloro-N-(3-methoxypropyl) indolo[1,2-f]phenanthridine-8-carboxamide 9 (Scheme 8).

Scheme 8 Synthesis of N-substituted indolo[1,2-f]phenanthridinecarboxamide.

Conclusions

In conclusion, copper catalyzed synthesis of isoindolinones and 1,2-disubstituted indoles from a common starting material has been reported. We have developed an easy access for the synthesis of spiro fused isoindolinone-indolines utilizing a well-known, halogen sources mediated cyclopropylhalonium ion strategy. Very few methods are known in literature^14h where TMS terminated alkynyl anilines participated in further transformation without TMS deprotected. Also, we successfully utilized the ortho-effect of amide group in N-substituted 2-iodobenzamides for the ligand free synthesis of 1,2-disubstituted indolylcarboxamides which also provide a path for the synthesis of indolophenanthradine carboxamide derivative.

General information

Reagents and solvents were purchased from various commercial sources and were used directly without any further purification, unless otherwise stated. Column chromatography was performed with 63–200 mesh silica gel. ¹H and ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively. Chemical shifts are reported in parts per million (δ) using chloroform as internal standards and coupling constants are expressed in Hertz. Melting points were recorded using an electro thermal capillary melting point apparatus and are uncorrected.

General procedure for the synthesis of 3-(2-aminobenzylidene)-2-substituted isoindolin-1-one derivatives (4a–4n)

Copper sulphate (10 mole%) and cesium carbonate (2.0 equiv.) were added to a stirred solution of 2-iodo-N-substituted benzamide (1 mmol), 2-((trimethylsilyl)alkynyl)aniline or 2-alkynylaniline 1.3 equiv. (1.3 mmol) in dimethylsulfoxide as a solvent under open air atmosphere. The reaction mixture was then heated to 100 °C. The reaction was monitored by TLC. After completion of the reaction, the resulting reaction mixture was cooled to room temperature and was then extracted with ethyl acetate, washed with brine and dried over MgSO₄. The resulting crude compound was purified by flash column chromatography (eluent : petroleum ether/ethyl acetate, 10 : 4) on silica gel to afford desired product.

General procedure for the synthesis of 1,2 substituted indolyl N-substituted benzamide derivatives (8a–8w)

Copper iodide (20%) and cesium carbonate (3.0 equiv.) were added to a stirred solution of 2-(substituted alkynyl)aniline 1.0 equiv. (1.0 mmol), 2-iodo-N-substituted benzamide (1.5 mmol), in dimethylsulfoxide as a solvent under open air atmosphere. The reaction mixture was then heated to 100 °C. The reaction was monitored by TLC. After completion of the reaction the resulting reaction mixture was cooled to room temperature and was then extracted with ethyl acetate, washed with brine and dried over MgSO₄. The resulting crude compound was purified by flash column chromatography (eluent : petroleum ether/ethyl acetate, 10 : 4) on silica gel to afford desired product.

General procedure for the synthesis of 1-acetyl-3-halo-2′-methyl-1,3-dihydrospiro[indene-2,1′-isoindolin]-3′-one derivatives (6a–6p)

To the stirred suspension of 3-(2-aminobenzylidene)-2-substituted isoindolin-1-one derivatives (4) (0.5 mmol) and acetic anhydride (2 equiv.), added potassium carbonate (3.0 equiv.) fallowed by N-bromosuccinimide (NBS)/trichloroisocyanuric acid (TCCA) (1 equiv.) at 25 °C. The reaction was monitored by TLC. After completion of the reaction the resulting reaction mixture was cooled to room temperature and was then extracted with ethyl acetate, washed with brine and dried over MgSO₄. The resulting crude compound was purified by flash column chromatography (eluent : petroleum ether/ethyl acetate, 10 : 1) on silica gel to afford desired product.

General procedure for the synthesis of 3,12-dichloro-N-(3-methoxypropyl) indolo[1,2-f]phenanthridine-8-carboxamide (9)

To 0.5 mmol of stirred suspension of compound 8w and 1,4 dioxane, added pd(OAc)₂ 10 mol%, pph₃ 20 mole%, and Cs₂CO₃ (2.0 equiv.) under nitrogen atmosphere, and heated the contents for 30 min at 140 °C. The reaction was monitored by TLC. After completion of the reaction the resulting reaction mixture was cooled to room temperature and was then extracted with ethyl acetate, washed with brine and dried over MgSO₄. The resulting crude compound was purified by flash column chromatography (eluent : petroleum ether/ethyl acetate, 10 : 3) on silica gel to afford desired product.

N-Methyl-2-(2-phenyl-1H-indol-1-yl)benzamide (8a). 170 mg, 47% yield; colorless solid, mp 153–155 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.94 (dd, J = 7.3, 1.7 Hz, 1H), 7.70–7.68 (m, 1H), 7.53–7.47 (m, 2H), 7.33 (J = 1.1 Hz, 1H), 7.24–7.18 (m, 5H), 7.09 (t, J = 4.6 Hz, 3H), 6.86 (s, 1H), 2.50 (d, J = 4.8 Hz, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 166.2, 141.5, 139.1, 135.9, 134.1, 131.8, 131.1, 130.1, 128.8, 128.6, 128.0, 123.2, 121.5, 121.0, 110.8, 104.3, 27.0. LRMS (EI⁺) (m/z) (relative intensity): 326.1 (M⁺, 100), 268.0 (92), 296.1 (30). HRMS (TOF-ES)⁺ calcd for C₂₂H₁₈N₂O (M + Na): 349.1317, found 349.1320.

N-Phenyl-2-(2-phenyl-1H-indol-1-yl)benzamide (8b). 229 mg, 59% yield; colorless solid, mp 210–212 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.05 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 7.9, 1.5 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.27–7.12 (m, 10H), 6.98 (t, J = 7.3 Hz, 1H) 6.86 (t, J = 6.9 Hz, 3H), 6.78 (s, 1H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 163.1, 141.8, 138.8, 137.7, 135.7, 134.3, 132.3, 131.8, 131.4, 130.3, 129.2, 128.8, 128.6, 128.2, 124.4, 123.6, 121.9, 121.2, 119.9, 110.7, 104.7. LRMS (EI⁺) (m/z) (relative intensity): 296.1 (100), 388.2 (M⁺, 93), 267.1 (44). HRMS (TOF-ES)⁺ calcd for C₂₇H₂₁N₂O (M + H): 389.1654, found 389.1653.

2-Phenyl-1H-indol-1-yl)-N-(o-tolyl)benzamide (8c). 265 mg, 66% yield; colorless solid, mp 183–185 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.15–8.13 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.67–7.65 (m, 1H), 7.59–7.51 (m, 2H), 7.30 (dd, J = 2.1, 8.4 Hz, 1H), 7.31–7.29 (m, 9H), 7.13–7.09 (m, 1H), 6.95–6.90 (m, 2H), 6.83 (s, 1H), 1.26 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 163.3, 141.8, 139.4, 135.9, 135.8, 133.9, 132.4, 131.9, 131.5, 130.3, 130.1, 129.1, 129.0, 128.7, 128.7, 128.1, 126.6, 124.7, 123.6, 122.0, 121.2, 111.0, 105.1, 16.3. LRMS (EI⁺) (m/z) (relative intensity): 296.1 (100), 402.2 (M⁺, 81), 267.1 (44). HRMS (TOF-ES)⁺ calcd for C₂₈H₂₃N₂O (M + H): 403.1810, found 403.180.

N-(4-Methoxyphenyl)-2-(2-phenyl-1H-indol-1-yl)benzamide (8d). 284 mg, 68% yield; colorless solid, mp 170–173 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.04 (dd, J = 7.64, 1.34 Hz, 1H), 7.73 (dd, J = 6.96, 2.72 Hz, 1H), 7.62–7.58 (m, 1H), 7.55–7.51 (m, 1H), 7.46 (d, J = 7.72 Hz, 1H), 7.26–7.13 (m, 8H), 6.84 (s, 1H), 6.80 (d, J = 9.0, 2H), 6.70 (s, 1H), 6.76 (d, J = 8.9, 2H), 3.71 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 162.8, 156.4, 141.7, 138.8, 135.6, 134.3, 132.1, 131.7, 131.4, 130.9, 130.2, 129.1, 128.8, 128.7, 128.6, 128.1, 123.5, 121.9, 121.6, 121.2, 114.0, 110.7, 104.6, 55.5. LRMS (EI⁺) (m/z) (relative intensity): 296.1 (100), 418.2 (M⁺, 88), 267 (38). HRMS (TOF-ES)⁺ calcd for C₂₈H₂₃N₂O₂ (M + H): 419.1760, found 419.1760.

N-Benzyl-2-(2-phenyl-1H-indol-1-yl)benzamide (8e). 287 mg, 71% yield; colorless solid, mp 132–134 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.02 (dd, J = 7.5, 2.04 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.55–7.48 (m, 2H), 7.28 (dd, J = 7.3, 1.46 Hz, 1H), 7.21–7.10 (m, 9H), 7.03 (d, J = 7.9 Hz, 1H), 6.75 (s, 1H), 6.70 (d, J = 6.9 Hz, 2H), 5.54 (bs, 1H), 4.20–4.11 (m, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.3, 141.1, 139.2, 137.2, 135.9, 134.1, 131.9, 131.7, 131.3, 130.5, 128.9, 128.6, 128.6, 127.9, 127.8, 127.4, 123.3, 121.5, 121.1, 110.7, 104.5, 44.4. LRMS (EI⁺) (m/z) (relative intensity): 268.1 (100), 402.2 (M⁺, 71), 296.1 (38). HRMS(TOF-ES)⁺ calcd for C₂₈H₂₃N₂O (M + H): 403.1810, found 403.1809.

N-(2,2-Diphenylethyl)-2-(2-phenyl-1H-indol-1-yl)benzamide (8f). 359 mg, 73% yield; colorless solid, mp 168–170 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.87 (dd, J = 7.26, 1.70 Hz, 1H), 7.72 (d, J = 7.80 Hz, 1H), 7.58–7.52 (m, 2H), 7.47–7.40 (m, 2H), 7.26–7.23 (m, 5H), 7.20–7.05 (m, 8H), 7.00 (d, J = 8.16 Hz, 1H), 6.91 (d, J = 8.16 Hz, 2H), 6.80 (d, J = 6.96, 2H), 6.76 (s, 1H), 5.37 (bs, 1H), 3.68 (m, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.5, 141.6, 141.5, 141.4, 139.2, 136.0, 133.8, 131.8, 131.7, 131.2, 130.0, 128.7, 128.6, 128.5, 128.5, 127.8, 127.8, 126.8, 123.3, 121.6, 121.0, 110.9, 104.7, 50.2, 44.4. LRMS (EI⁺) (m/z) (relative intensity): 296.1 (100), 492.2 (M⁺, 50), 267 (28). HRMS (TOF-ES)⁺ calcd for C₃₅H₂₉N₂O (M + H): 493.2280, found 493.2278.

N-Ethyl-2-(2-phenyl-1H-indol-1-yl)benzamide (8g). 231 mg, 68% yield; colorless solid, mp 127–129 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.97 (dd, J = 3.8, 3.14 Hz, 1H), 7.68 (d, J = 4.4 Hz, 1H), 7.52–7.45 (m, 2H), 7.28 (t, J = 4.4 Hz, 1H), 7.25–7.20 (m, 5H), 7.17 (t, J = 3.5 Hz, 2H), 7.05 (t, J = 4.3 Hz, 1H), 6.86 (s, 1H), 5.14 (bs, 1H), 3.03–2.92 (m, 2H), 0.55 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 165.3, 141.1, 139.1, 135.6, 134.4, 131.7, 131.2, 130.2, 128.9, 128.6, 128.5, 128.4, 127.9, 123.2, 121.4, 120.9, 110.7, 104.2, 34.7, 13.9. LRMS (EI⁺) (m/z) (relative intensity): 268.0 (100), 340.2 (M⁺, 90). HRMS (TOF-ES)⁺ calcd for C₂₃H₂₁N₂O (M + H): 341.1654, found 341.1653.

N-Allyl-2-(2-phenyl-1H-indol-1-yl)benzamide (8h). 264 mg, 75% yield; colorless solid, mp 119–121 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.97 (dd, J = 3.8, 3.2 Hz, 1H), 7.68 (d, J = 3.8 Hz, 1H), 7.76–7.48 (m, 2H), 7.28 (d, J = 4.3 Hz, 1H), 7.25–7.21 (m, 5H), 7.19–7.16 (m, 2H), 7.06 (t, J = 4.8 Hz, 1H), 6.86 (s, 1H), 5.28 (bs, 1H), 5.34–5.24 (m, 1H), 4.82 (d, J = 10.3 Hz, 1H), 4.68 (d, J = 17.2 Hz, 1H), 3.60–3.55 (m, 2H), ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.4, 141.1, 139.2, 135.9, 133.2, 131.9, 131.7, 131.3, 128.9, 130.3, 128.9, 128.6, 128.6, 128.0, 123.3, 121.5, 121.0, 116.5, 110.7, 104.5, 42.5. LRMS (EI⁺) (m/z) (relative intensity): 268.0 (100), 296.1 (98), 352.0 (M⁺, 94). HRMS (TOF-ES)⁺ calcd for C₂₄H₂₁N₂O (M + H): 353.1654, found 353.1651.

N-(3-Methoxypropyl)-2-(2-phenyl-1H-indol-1-yl)benzamide (8i). 274 mg, 79% yield; colorless solid, mp 126–128 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.02 (dd, J = 6.1, 3.3 Hz, 1H), 7.64 (d, J = 3.0 Hz, 1H), 7.50 (t, J = 3.9 Hz, 2H), 7.25 (dd, J = 6.6, 2.1 Hz, 2H), 7.21 (s, 1H), 7.17–7.14 (m, 3H), 7.05–7.00 (m, 3H), 6.82 (s, 1H), 5.27 (bs, 1H), 3.03–2.95 (m, 2H), 2.35 (d, J = 7.6 Hz, 2H), 1.15–1.09 (m, 2H), 0.98–0.92 (m, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.6, 141.2, 139.3, 135.8, 134.3, 131.8, 131.7, 131.2, 130.2, 128.7, 128.6, 127.9, 123.2, 121.5, 121.0, 110, 8, 104.4, 58.6, 37.9, 28.9. LRMS (EI⁺) (m/z) (relative intensity): 296.1 (100), 384.2 (M⁺, 92), 268(68). HRMS (TOF-ES)⁺ calcd for C₂₅H₂₅N₂O₂ (M + H): 385.1916, found 385.1917.

N-Phenethyl-2-(2-phenyl-1H-indol-1-yl)benzamide (8j). 320 mg, 77% yield; colorless solid, mp 135–137 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.93 (dd, J = 7.3, 1.5 Hz, 1H), 7.70 (dd, J = 6.5, 2.4 Hz, 1H), 7.50–7.46 (m, 2H), 7.26 (dd, J = 6.7 Hz, 2.32 Hz, 1H), 7.23–7.16 (m, 7H), 7.10–7.06 (m, 4H), 6.85 (s, 1H), 6.79 (dd, J = 6.9, 2.4 Hz, 2H), 5.29 (bs, 1H), 3.26–3.20 (m, 2H), 2.26 (t, J = 7.4 Hz, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.4, 142.1, 141.2, 139.2, 135.7, 134.3, 131.8, 131.7, 131.4, 130.3, 129.0, 128.6, 128.5, 128.5, 128.4, 128.0, 125.9, 123.3, 121.6, 121.0, 110.7, 104.4, 39.8, 35.5, 28.5, 28.2. LRMS (EI⁺) (m/z) (relative intensity): 296.1 (100), 416.0 (M⁺, 98), 312 (70). (M + H, 100), HRMS (TOF-ES)⁺ calcd for C₂₉H₂₅N₂O (M + H): 417.1967, found 417.1965.

2-(2-Phenyl-1H-indol-1-yl)-N-(4-phenylbutyl)benzamide (8k). 329 mg, 74% yield; colorless solid, mp 113–115 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.01–8.04 (m, 1H), 7.68–7.72 (m, 1H), 7.50 (t, J = 4.2 Hz, 2H), 7.25 (dd, J = 6.6, 1.9 Hz, 2H), 7.21 (s, 5H), 7.17–7.14 (m, 3H), 7.05–7.00 (m, 3H), 6.82 (s, 1H), 3.04–2.93 (m, 2H), 2.35 (t, J = 7.5 Hz, 2H), 1.17–1.11 (m, 2H), 0.98–0.91 (m, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.4, 142.1, 141.2, 139.2, 135.7, 134.3, 131.8, 131.7, 131.4, 130.3, 129.0, 128.6, 128.5, 128.5, 128.4, 128.0, 125.9, 123.3, 121.6, 121.0, 110.7, 104, 42, 39.8, 35.5, 28.5, 28.2. LRMS (EI⁺) (m/z) (relative intensity): 444.2 (M⁺, 100), 268.1 (72), 296 (68). HRMS (TOF-ES)⁺ calcd for C₃₁H₂₉N₂O (M + H): 445.2280, found 445.2280.

N-Benzyl-2-(6-chloro-2-cyclopentyl-1H-indol-1-yl)benzamide (8l). 205 mg, 48% yield; colorless solid, mp 115–117 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.15–8.13 (m, 1H), 7.62–7.59 (m, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 5.2, 2.5 Hz, 1H), 7.19–7.11 (m, 3H), 6.97 (dd, J = 8.6, 2.1 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 6.7 Hz, 1H), 6.26 (s, 1H), 4.16–4.05 (m, 2H), 2.78–2.70 (m, 1H), 1.80–1.43 (m, 8H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.1, 148.4, 136.8, 136.5, 134.7, 134.6, 132.1, 131.6, 130.5, 129.6, 129.4, 128.6, 127.8, 127.5, 126.5, 122.3, 119.9, 110.7, 99.0, 44.5, 37.4, 34.0, 32.7, 25.4, 25.3. LRMS (EI⁺) (m/z) (relative intensity): 428.2 (M⁺, 100), 321.1 (24). HRMS (TOF-ES)⁺ calcd for C₂₇H₂₆N₂OCl (M + H): 429.1734, found 429.1732.

2-(2-Cyclohexyl-6-methyl-1H-indol-1-yl)-N-methylbenzamide (8m). 169 mg, 49% yield; colorless solid, mp 139–141 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.18 (dd, 7.3, 2.0 Hz, 1H), 7.63–7.59 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 4.4 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.68 (s, 1H), 6.41 (s, 1H), 4.96 (bs, 1H), 2.45 (d, J = 4.5 Hz, 3H), 2.36 (s, 3H), 1.81–1.49 (m, 7H), 1.26–1.11 (m, 4H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 166.2, 147.4, 138.2, 135.2, 134.1, 132.1, 132.0, 131.8, 130.3, 129.2, 126.4, 122.7, 120.1, 110.0, 99.4, 35.7, 34.7, 32.5, 27.0, 26.5, 26.4, 26.1, 21.9. LRMS (EI⁺) (m/z) (relative intensity): 346.2 (M⁺, 100), 303.1 (22). HRMS (TOF-ES)⁺ calcd for C₂₃H₂₇N₂O (M + H): 347.2123, found 347.2121.

N-Benzyl-2-(2-isopropyl-5,7-dimethyl-1H-indol-1-yl)benzamide (8n). 202 mg, 51% yield; colorless solid, mp 116–118 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.23 (dd, 7.6, 1.8 Hz, 1H), 7.61–7.52 (m, 2H), 7.34 (dd, J = 7.6, 1.6 Hz, 1H), 7.17–708 (m, 4H), 6.65 (t, J = 4.4 Hz, 3H), 6.25 (s, 1H), 5.56 (bs, 1H), 4.17–4.07 (m, 2H), 2.25–2.46 (m, 1H), 2.38 (s, 3H), 1.74 (s, 3H), 1.04 (dd, J = 15.4, 6.6 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 164.9, 148.7, 137.3, 137.2, 134.7, 133.9, 131.6, 131.4, 131.3, 130.2, 129.6, 129.5, 128.5, 127.8, 127.2, 126.7, 120.8, 118.5, 99.4, 44.4, 25.9, 24.1, 22.6, 21.3, 18.7. LRMS (EI⁺) (m/z) (relative intensity): 396.2 (M⁺, 100), 397.2 (66), 381.2 (65). HRMS (TOF-ES)⁺ calcd for C₂₇H₂₉N₂O (M + H): 397.2280, found 397.2280.

N-Benzyl-2-(5-methoxy-2-(methoxymethyl)-1H-indol-1-yl)benzamide (8o). 280 mg, 70% yield; brown oil, ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.94–7.98 (m, 1H), 7.60–7.55 (m, 2H), 7.46 (dd, J = 7.6, 1.6 Hz, 1H), 7.20–7.17 (m, 1H), 7.12–7.03 (m, 4H), 6.80 (dd, J = 8.6, 2.2 Hz, 1H), 6.62 (d, J = 6.9 Hz, 2H), 6.49 (s, 1H), 6.38 (d, J = 1.7, 1H), 4.40 (d, J = 11.6, 1H), 4.20 (dd, J = 14.9, 6.1 Hz, 1H), 2.25–4.04 (dd, J = 14.8, 5.2 Hz, 1H), 3.68 (s, 3H), 2.91 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 166.7, 157.6, 140.2, 137.76, 136.7, 134.3, 134.2, 131.3, 130.9, 129.5, 129.3, 128.3, 127.5, 127.0, 121.7, 121.2, 111.6, 105.3, 93.5, 66.5, 57.9, 55.8, 43.9. LRMS (EI⁺) (m/z) (relative intensity): 400.2 (M⁺, 100), 191.1 (80), 250 (60). HRMS (TOF-ES)⁺ calcd for C₂₅H₂₄N₂O₃Na (M + Na): 423.1685, found 423.1689.

N-Benzyl-2-(6-methoxy-2-phenyl-1H-indol-1-yl)benzamide (8p). 272 mg, 63% yield; colorless solid, mp 130–132 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.06–8.03 (m, 1H), 7.53–7.48 (m, 3H), 7.26–7.24 (m, 1H), 7.18–7.14 (m, 4H), 7.12–7.09 (m, 3H), 6.84 (dd, J = 8.2,2.2 Hz, 1H), 6.74 (d, J = 6.8 Hz, 1H), 6.68 (s, 1H), 6.45 (d, J = 2.00, 1H), 4.42–4.41 (m, 2H), 3.68 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 166.3, 157.4, 140.1, 139.9, 137.3, 136.0, 133.9, 132.0, 131.9, 131.5, 130.4, 128.9, 128.63, 128.56, 128.34, 127.86, 127.6, 127.4, 122.7, 121.8, 111.6, 105.1, 104.5, 94.1, 55.8, 44.4. LRMS (EI⁺) (m/z) (relative intensity): 432.2 (M⁺, 100), 298.1 (32), 212.1 (22). HRMS (TOF-ES)⁺ calcd for C₂₉H₂₅N₂O₂ (M + H): 433.1913, found 433.1912.

N-Benzyl-2-(6-methyl-2-phenyl-1H-indol-1-yl)benzamide (8q). 278 mg, 67% yield; colorless solid, mp 175–177 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.05 (dd, J = 5.66, 2.0 Hz, 1H), 7.53–7.50 (m, 3H), 7.27 (dd, J = 5.76, 1.76 Hz, 1H), 7.19–7.09 (m, 7H), 7.01 (dd, J = 7.96, 0.84 Hz, 1H), 6.72–6.70 (m, 3H), 5.65 (bs, 1H), 4.24–4.10 (m, 2H), 2.35 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.3, 140.5, 139.7, 137.3, 136.1, 134.0, 133.4, 132.0, 131.9, 131.47, 130.57, 128.9, 128.6, 128.5, 128.5, 127.8, 127.7, 126.4, 123.4, 120.8, 110.6, 104.4, 44.4, 22.0. LRMS (EI⁺) (m/z) (relative intensity): 211.1 (100), 416.0 (M⁺, 85), 282.1 (65). HRMS (TOF-ES)⁺ calcd for C₂₉H₂₅N₂O (M + H): 417.1967, found 417.1966.

N-Benzyl-2-(6-nitro-2-phenyl-1H-indol-1-yl)benzamide (8r). 339 mg, 76% yield; yellow solid, mp 182–184 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.55 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 9.6, 2.2 Hz, 1H), 7.81 (dd, J = 7.6, 1.8 Hz, 1H), 7.59–7.54 (m, 2H), 7.35 (dd, J = 7.5, 1.5 Hz, 1H), 7.27–7.14 (m, 9H), 7.02 (d, J = 9.2 Hz, 1H), 5.38 (bs, 1H), 6.88 (s, 1H), 6.85 (d, J = 6.8 Hz, 2H), 4.24–4.08 (m, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.4, 144.4, 142.9, 141.8, 137.1, 135.01, 134.98, 132.0, 130.9, 130.3, 129.6, 128.9, 128.7, 128.7, 128.1, 127.8, 127.6, 118.4, 118.0, 110.5, 105.4, 44.4. LRMS (EI⁺) (m/z) (relative intensity): 326.1 (100), 268.1 (98), 447.2 (M⁺, 62). HRMS (TOF-ES)⁺ calcd for C₂₈H₂₂N₃O₃ (M + H): 448.1661, found 448.1661.

N-Benzyl-2-(5-chloro-2-phenyl-1H-indol-1-yl)benzamide (8s). 186 mg, 55% yield; colorless solid, mp 161–163 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.93 (dd, J = 7.4, 2.5 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.52–7.49 (m, 1H), 7.27–7.25 (m, 1H), 7.22–7.13 (m, 8H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 0.5 Hz, 1H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.3, 142.4, 137.6, 137.1, 135.49, 134.4, 131.9, 131.3, 131.04, 130.36, 129.45, 129.20, 128.70, 128.64, 128.26, 127.89, 127.60, 127.04, 123.40, 120.45, 111.70, 103.71, 44.41. LRMS (EI⁺) (m/z) (relative intensity): 436.1 (M⁺, 100), 302.1 (68), 438.1 (38). HRMS (EI⁺) calcd for C₂₈H₂₁ClN₂O (M⁺): 436.1342, found 436.1342.

2-(5-Chloro-2-phenyl-1H-indol-1-yl)-N-phenylbenzamide (8t). 257 mg, 61% yield; colorless solid, mp 197–199 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.96 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.65–7.61 (m, 1H), 7.55–7.52 (m, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.24–7.15 (m, 5H), 7.12–7.09 (m, 3H), 7.01 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.76 (s, 1H), 6.69 (bs, 1H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 163.0, 143.0, 137.5, 137.2, 135.3, 134.4, 132.3, 131.5, 131.0, 130.1, 129.7, 129.3, 128.9, 128.8, 128.6, 128.4, 127.4, 124.5, 123.7, 120.5, 119.9, 111.7, 103.9. LRMS (EI⁺) (m/z) (relative intensity): 422.1 (M⁺, 100), 295.1 (46), 424.1 (38). HRMS (EI⁺) calcd for C₂₇H₁₉ClN₂O (M⁺): 422.1186, found 422.1186.

2-(5-Chloro-2-heptyl-1H-indol-1-yl)-N-(3methoxypropyl)benzamide (8u). 295 mg, 67% yield; colorless solid, mp 66–68 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.14 (dd, J = 5.40, 2.6 Hz, 1H), 7.65–7.61 (m, 1H), 7.61–7.58 (m, 3H), 7.55 (d, J = 1.8 Hz, 1H), 7.29–7.26 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 5.27 (bs, 1H), 3.1–3.02 (m, 5H), 2.97–2.85 (m, 2H), 2.55–2.38 (m, 2H), 1.62–1.51 (m, 2H), 1.31–1.13 (m, 10H), 0.84 (t, J = 6.9 Hz, 1H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.7, 144.1, 136.6, 135.0, 134.3131.8, 131.4, 130.0, 129.6, 129.5, 126.5, 122.1, 119.7, 110.8, 100.8, 58.7, 37.6, 31.8, 29.3, 29.1, 29.0, 28.3, 26.9, 22.7, 14.2. LRMS (EI⁺) (m/z) (relative intensity): 440.2 (M⁺, 100), 356.1 (64), 442.2 (34). HRMS (EI⁺) calcd for C₂₆H₃₃ClN₂O₂ (M⁺): 440.2231, found 440.2231.

N-Benzyl-2-(2-(2-bromo-4-chlorophenyl)-5-chloro-1H-indol-1-yl)benzamide (8v). 214 mg, 39% yield; colorless solid, mp 120–123 °C; ¹H NMR (400 MHz, CDCl₃) δ_H (ppm) 7.81 (d, J = 9.08 Hz, 1H), 7.62 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.46–7.43 (m, 2H), 7.30–7.06 (m, 6H), 6.90 (d, J = 6.7 Hz, 1H), 6.80 (d, J = 6.6 Hz, 2H), 6.79 (s, 2H), 5.61 (bs, 1H), 4.31–4.15 (m, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 165.6, 139.5, 137.0, 136.5, 135.5, 134.6, 134.5, 133.6, 132.7, 132.7, 131.7, 131.2, 130.5, 130.4, 129.3, 128.9, 128.8, 128.0, 127.8, 127.0, 125.0, 123.7, 120.9, 111.5, 105.9, 44.6. LRMS (EI⁺) (m/z) (relative intensity): 532.0 (100), 548.0 (M⁺, 60), 534.0 (55). HRMS (EI⁺) calcd for C₂₈H₁₉BrCl₂N₂O (M⁺): 548.0058, found 548.0057.

2-(2-(2-Bromo-4-chlorophenyl)-5-chloro-1H-indol-1-yl)-N-(3-methoxypropyl)benzamide (8w). 340 mg, 64% yield; colorless solid, mp 163–165 °C; ¹H NMR (400 MHz, CDCl₃) δ_H (ppm) 7.40 (dd, J = 6.2, 2.9 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.45–7.40 (m, 2H), 7.28–7.22 (m, 2H), 7.14 (dd, J = 5.5, 1.9 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 5.90 (bs, 1H), 3.23–3.12 (m, 6H), 1.41 (t, J = 6.06 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 165.9, 139.5, 136.6, 135.4, 134.9, 134.6, 133.7, 132.7, 131.4, 130.2, 130.5, 130.1, 129.0, 127.5, 126.8, 125.0, 123.4, 120.7, 111.7, 105.9, 71.4, 58.9, 38.5, 28.8. LRMS (EI⁺) (m/z) (relative intensity): 532.0 (100), 530 (M⁺, 62), 534.0 (50). HRMS (EI⁺) calcd for C₂₅H₂₁BrCl₂N₂O₂ (M⁺): 530.0163, found 530.0162.

3,12-Dichloro-N-(3-methoxypropyl)indolo[1,2-f]phenanthridine-8-carboxamide (10). 226 mg, 85% yield; colorless solid, mp 271–273 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.31 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.0–8.04 (m, 2H), 7.89 (d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.48 (d, J = 7.7, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.08 (bs, 1H), 3.14 (d, J = 4.9 Hz, 2H), 2.97 (s, 5H), 1.21 (s, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 167.5, 136.1, 134.8, 134.6, 131.8, 131.2, 130.6, 129.3, 128.4, 128.2, 127.4, 125.6, 125.3, 124.5, 124.4, 123.8, 123.0, 122.4, 120.0, 114.6, 97.8, 72.1, 58.8, 39.4, 27.9. LRMS (EI⁺) (m/z) (relative intensity): 450.1 (M⁺, 100), 327.0 (78), 452.1 (66), 362.0 (60). HRMS (EI⁺) calcd for C₂₅H₂₀BrCl₂N₂O₂ (M⁺): 450.0902, found 450.0900.

3-(2-Aminobenzylidene)-2-methylisoindolin-1-one (4a). 180 mg, 72% yield; yellow solid, mp 174–176 °C; ¹H NMR (400 MHz, CDCl₃) δ_H (ppm) 7.83 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.44, 1H), 7.16–7.09 (m, 2H), 6.79–6.72 (m, 2H), 6.51 (s, 1H), 3.87 (bs, 2H), 3.04 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.7, 145.0, 137.7, 137.6, 132.0, 130.9, 129.2, 128.7, 123.7, 119.9, 119.5, 118.1, 115.1, 102.5, 29.3. LRMS (+ESI) (m/z) (relative intensity): 251.46 (M + H, 100), 220.58. HRMS (EI⁺) calcd for C₁₆H₁₄N₂O (M⁺): 250.1106, found 250.1107.

3-(2-Amino-4-bromobenzylidene)-2-methylisoindolin-1-one (4b). 243 mg, 74% yield; yellow solid, mp 193–195 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.85 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 6.2 Hz, 1H), 6.39 (s, 1H), 3.89 (bs, 2H), 3.05 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.7, 146.2, 137.5, 137.6, 132.2, 132.1, 129.5, 128.8, 123.4, 122.8, 121.1, 119.6, 119.5, 118.9, 117.7, 100.8, 29.3. LRMS (EI⁺) (m/z) (relative intensity): 297.0 (100), 328.0 (M⁺, 92), 330.0 (88). HRMS (EI⁺) calcd for C₁₆H₁₃BrN₂O (M⁺): 328.0211, found 328.0211.

3-(2-Amino-5-chlorobenzylidene)-2-methylisoindolin-1-one (4c). 210 mg, 74% yield; yellow solid, mp 163–165 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.85 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 2.4 Hz, 1H), 7.11 (t, J = 2.6 Hz, 2H), 6.67 (d, J = 9.2 Hz, 1H), 6.42 (s, 1H), 3.86 (s, 2H), 3.07 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.7, 143.6, 137.4, 138.5, 137.4, 132.2, 130.3, 129.6, 129.0, 128.8, 123.4, 122.8, 121.4, 119.6, 116.24, 100.7, 29.3. LRMS (+ESI) (m/z) (relative intensity): 285.52 (M + H, 100), 287.36 (38), 254.47 (28). HRMS (EI⁺) calcd for C₁₆H₁₃ClN₂O (M⁺): 284.0716, found 284.0716.

3-(2-Amino-5-chlorobenzylidene)-2-ethylisoindolin-1-one (4d). 232 mg, 78% yield; yellow solid, mp 172–174 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.85 (d, J = 7.52 Hz, 1H), 7.75 (d, J = 7.72, 1H), 7.60 (t, J = 7.54, 1H), 7.51 (t, J = 7.48, 1H), 7.06 (t, J = 7.76 Hz, 1H), 6.76 (t, J = 4.62 Hz, 2H), 6.39 (s, 1H), 3.92 (s, 2H), 0.86 (t, J = 7.48, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.5, 145.9, 137.9, 136.8, 134.8, 132.1, 131.8, 129.4, 128.9, 123.4, 119.6, 118.2, 118.1, 114.7, 100.8, 36.0, 13.7. LRMS (EI⁺) (m/z) (relative intensity): 253.0 (100), 298.1 (M⁺, 75), 300.1(28). HRMS (EI⁺) calcd for C₁₇H₁₅ClN₂O (M⁺): 298.0873, found 298.0873.

(2-Allyl-3-(2-amino-5-chlorobenzylidene)isoindolin-1-one (4e). 232 mg, 75% yield; yellow solid, mp 132–134 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.87 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.11 (t, J = 5.3 Hz, 2H), 6.65 (d, J = 8.2 Hz, 1H), 6.39 (s, 1H), 5.49–5.43 (m, 1H), 4.93 (d, J = 10.4, 1H), 4.6 (d, J = 17.1 Hz, 1H), 4.30 (d, J = 4.9 Hz, 1H), 3.79 (bs, 1H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.9, 143.6, 137.8, 137.1, 132.3, 130.3, 129.5, 129.0, 129.2, 128.5, 123.5, 122.7, 121.2, 119.6, 116.3, 100.7, 69.5, 58.6, 40.2. LRMS (+ESI) (m/z) (relative intensity): 311.52 (M + H, 100), 313.31 (37). HRMS (EI⁺) calcd for C₁₈H₁₅ClN₂O (M⁺): 310.0873, found 310.0875.

3-(2-Amino-5-chlorobenzylidene)-2-(2-methoxyethyl)isoindolin-1-one (4f). 229 mg, 71% yield; yellow solid, mp 132–134 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.86 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.72 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.34 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.13–7.09 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 6.40 (s, 1H), 3.90 (t, J = 6.1 Hz, 2H), 3.84 (s, 2H), 3.24 (t, J = 6.0 Hz, 2H), 3.1 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.9, 143.6, 137.8, 137.1, 132.3, 130.3, 129.5, 129.2, 128.5, 123.5, 122.7, 121.2, 119.6, 116.3, 100.7, 69.5, 58.6, 40.2. LRMS (+ESI) (m/z) (relative intensity): 351.64 (M + Na, 100), 353.51 (33). HRMS (EI⁺) calcd for C₁₈H₁₇ClN₂O₂ (M⁺): 328.0979, found 328.0981.

3-(2-Aminobenzylidene)-2-phenylisoindolin-1-one (4g). 193 mg, 62% yield; yellow solid, mp 175–177 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.95 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.11 (t, J = 6.8 Hz, 5H), 6.8 (t, J = 7.5 Hz, 1H), 6.62 (s, 1H), 6.49 (d, J = 6.5 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 6.22 (t, J = 6.6 Hz, 1H), 3.68 (bs, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.0, 143.7, 138.2, 135.8, 135.4, 132.6, 130.6, 129.4, 129.0, 129.0, 128.4, 128.1, 128.04, 127.42, 127.0, 124.0, 119.7, 119.3, 117.8, 114.7, 103.5. LRMS (+ESI) (m/z) (relative intensity): 313.42 (M + H, 100), 181.06 (13). HRMS (EI⁺) calcd for C₂₁H₁₆N₂O (M⁺): 312.1263, found 312.1262.

3-(2-Amino-4-bromobenzylidene)-6-bromo-2-phenylisoindolin-1-one (4h). 300 mg, 64% yield; yellow solid, mp 212–214 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.05 (d, J = 1.2 Hz, 1H), 7.77 (dd, J = 8.2, 1.52 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.11–7.09 (m, 3H), 7.02–7.00 (m, 2H), 6.56 (d, J = 1.4 Hz, 1H), 6.45 (s, 1H), 6.33–6.27 (m, 2H), 3.75 (bs, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 166.5, 144.9, 136.6, 135.7, 135.6, 134.9, 131.7, 129.8, 129.0, 128.8, 128.3, 127.5, 127.3, 127.1, 123.6, 122.2, 121.3, 120.6, 117.8, 117.3, 102.9. LRMS (EI⁺) (m/z) (relative intensity): 376.9 (100), 470.0 (85), 299.0 (72), 468.0 (M⁺, 44). HRMS (EI⁺) calcd for C₂₁H₁₄Br₂N₂O (M⁺): 467.9473, found 467.9475.

3-(2-Amino-5-chlorobenzylidene)-6-bromo-2-phenylisoindolin-1-one (4i). 289 mg, 68% yield; yellow solid, mp 212–214 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.08 (d, J = 1.4 Hz, 1H), 7.79 (dd, J = 8.2, 1.6 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.16–7.03 (m, 5H), 6.74 (dd, J = 8.5, 2.3 Hz, 1H), 6.46 (s, 1H), 6.41 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 8.6 Hz, 1H), 3.69 (s, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 166.4, 142.4, 136.7, 136.2, 135.7, 130.4, 129.9.3, 128.4, 127.8, 127.3, 127.2, 123.8, 122.5, 121.3, 120.23, 115.84, 102.54. LRMS (EI⁺) (m/z) (relative intensity): 93.0 (100), 426.0 (82), 332.9 (80), 424.0(M⁺, 64). HRMS (EI⁺) calcd for C₂₁H₁₄BrClN₂O (M⁺): 423.9978, found 423.9980.

3-(2-Amino-4-methoxybenzylidene)-2-phenylisoindolin-1-one (4j). 280 mg, 82% yield; yellow solid, mp 196–198 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.49 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.68–7.64 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.12–7.05 (m, 5H), 6.57 (s, 1H), 6.37 (s, 2H), 5.99 (s, 3H), 5.85 (q, J = 7.5 Hz, 1H), 3.72 (s, 2H), 3.63 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.0, 160.2, 145.0, 138.4, 135.6, 135.0, 132.5, 131.7, 129.2, 128.1, 128.0, 127.4, 126.9, 124.0, 119.6, 112.4, 104.0, 103.3, 100.2, 55.3. LRMS (+ESI) (m/z) (relative intensity): 343.52 (M + H, 100), 181.20 (12). HRMS (EI⁺) calcd for C₂₂H₁₈N₂O₂ (M⁺): 342.1368, found 342.1369.

3-(2-Amino-5-chlorobenzylidene)-2-phenylisoindolin-1-one (4k). 245 mg, 71% yield; yellow solid, mp 163–165 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.85 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 2.4 Hz, 1H), 7.11 (t, J = 2.6 Hz, 2H), 6.67 (d, J = 9.2 Hz, 1H), 6.42 (s, 1H), 3.86 (s, 2H), 3.07 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 167.9, 142.4, 137.9, 136.9, 135.3, 132.7, 130.4, 129.8, 128.3, 128.2, 128.2, 127.6, 127.4, 124.1, 122.4, 120.6, 119.7, 115.7, 101.6. LRMS (EI⁺) (m/z) (relative intensity): 253 (100), 219.1 (72), 93.1 (64), 346.1 (M⁺, 65). HRMS (EI⁺) calcd for C₂₁H₁₅ClN₂O (M⁺): 346.0873, found 346.0871.

3-(2-Aminobenzylidene)-2-benzylisoindolin-1-one (4l). 234 mg, 72% yield; yellow solid, mp 169–171 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.94 (d, J = 7.5, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.14–7.02 (m, 4H), 6.97 (d, J = 7.4 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.57–6.51 (m, 3H), 6.41 (s, 1H), 4.96 (s, 2H), 3.19 (s, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 169.0, 145.5, 138.2, 137.3, 135.8, 132.3, 131.2, 129.3, 129.0, 128.4, 128.1, 126.9, 126.6, 123.8, 120.4, 119.8, 118.2, 115.4, 103.8, 44.72. LRMS (+ESI) (m/z) (relative intensity): 327.54 (M + H, 100), 220.52 (24). HRMS (EI⁺) calcd for C₂₂H₁₈N₂O (M⁺): 326.1419, found 326.1419.

3-(2-Amino-4-bromobenzylidene)-2-benzylisoindolin-1-one (4m). 291 mg, 72% yield; yellow solid, mp 169–171 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.94 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.11–7.06 (m, 3H), 6.83–6.70 (m, 2H), 6.69 (s, 1H), 6.56 (d, J = 6.7 Hz, 2H), 6.27 (s, 1H), 4.93 (s, 2H), 3.27 (s, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 168.9, 146.8, 138.0, 137.0, 136.4, 132.5, 132.3, 129.5, 128.3, 128.2, 127.1, 126.3, 123.9, 122.7, 120.9, 119.8, 119.2, 117.8, 102.3, 44.7. LRMS (EI⁺) (m/z) (relative intensity): 254.1 (100), 406.1 (64), 404.1 (M⁺, 63). HRMS (EI⁺) calcd for C₂₂H₁₇BrN₂O (M⁺): 404.0524, found 404.0526.

3-(2-Amino-5-chlorobenzylidene)-6-bromo-2-phenylisoindolin-1-one (4n). 294 mg, 67% yield; yellow solid, mp 209–211 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.06 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 9.3 Hz, 4H), 6.83 (s, 1H), 6.49 (t, J = 9.1 Hz, 3H), 6.28 (s, 1H), 4.93 (s, 2H), 3.24 (s, 2H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 167.4, 144.0, 138.6, 136.5, 135.8, 135.5, 130.4, 130.0, 129.2, 128.3, 129.2, 128.3, 127.2, 127.0, 126.3, 123.7, 122.9, 121.4, 121.4, 116.4, 103.0, 44.9. LRMS (+ESI) (m/z) (relative intensity): 439.41 (M + H, 76), 441.34 (100). HRMS (EI⁺) calcd for C₂₂H₁₆BrClN₂O (M⁺): 438.0135, found 438.0135.

N-Methyl-2-((2-((2-methyl-3-oxoisoindolin-1-ylidene)methyl)phenyl)amino)benzamide (5a). Yield 74%, 210 mg; yellow solid, mp 189–191 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 9.33 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.46–7.42 (m, Hz, 2H), 7.37–7.26 (m, 6H), 7.04 (t, J = 7.4 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.66 (s, H), 6.10 (bs, 1H), 3.06 (s, 3H), 2.88 (d, J = 4.7 Hz, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.0, 169.1, 144.9, 141.5, 138.2, 137.9, 132.0, 131.6, 129.3, 129.0, 128.7, 128.6, 127.6, 127.5, 127.0, 123.2, 123.1, 121.8, 119.8, 119.68, 119.53, 118.83, 116.50, 107.00, 102.9, 30.2, 26.8. LRMS (+ESI) (m/z) (relative intensity): 406.63 (M + Na, 100), 381.70 (14). HRMS (EI⁺) calcd for C₂₄H₂₁N₃O₂ (M⁺): 383.1634, found 383.1634.

1-Acetyl-3-bromo-2′-methylspiro[indoline-2,1′-isoindolin]-3′-one (6a). 152 mg, 82% yield; colorless solid, mp 173–175 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 9.33 (s, 1H), 8.25 (d, J = 6.6 Hz, 1H), 7.95 (d, J = 6.9 Hz, 1H), 7.71–7.62 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 8.3 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 5.86 (s, 1H), 2.80 (s, 3H), 1.57 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.0, 166.8, 144.1, 142.2, 133.4, 132.6, 133.9, 130.8, 127.1, 125.2, 124.5, 121.3, 117.0, 86.2, 57.3, 25.9, 24.0. LRMS (+ESI) (m/z) (relative intensity): 393.40 (M + Na, 95), 395.30 (100). HRMS (EI⁺) calcd for C₁₈H₁₅BrN₂O₂ (M⁺): 370.0317, found 370.0316.

1-Acetyl-3,6-dibromo-2′-methylspiro[indoline-2,1′-isoindolin]-3′-one (6b). 184 mg, 82% yield; colorless solid, mp 195–197 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.51 (s, 1H), 7.95 (dd, J = 6.68, 1.06 Hz, 1H), 7.72–7.63 (m, 2H), 7.53 (d, J = 8.00 Hz, 1H), 7.37 (dd, J = 8.04, 1.72 Hz, 1H), 7.27 (dd, J = 8.04, 1.72 Hz, 1H), 5.76 (s, 1H), 2.81 (s, 3H), 1.53 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.2, 166.6, 143.7, 143.1, 133.5, 132.5, 131.0, 128.2, 126.2, 126.1, 124.6, 124.5, 121.3, 120.3, 86.5, 56.4, 25.9, 23.8. LRMS (EI⁺) (m/z) (relative intensity): 447.94 (M⁺, 15), 371 (100), 227 (97). HRMS (TOF-ES)⁺ calcd for C₁₈H₁₅N₂O₂Br₂ (M + H): 448.9500, found 448.9504.

1-Acetyl-3-bromo-5-chloro-2′-methylspiro[indoline-2,1′-isoindolin]-3′-one (6c). 172 mg, 85% yield; colorless solid, mp 178–182 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.23 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 7.1 Hz, 1H), 7.71–7.64 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.38–7.33 (m, 2H), 5.8 (s, 1H), 2.79 (s, 3H), 1.52 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.1, 166.7, 143.7, 140.85, 133.5, 132.5, 131.0, 130.8, 130.2, 128.9, 125.2, 124.6, 121.3, 118.3, 86.4, 56.0, 25.9, 23.8. LRMS (EI⁺) (m/z) (relative intensity): 429.14 (100), 427 (M + Na, 86), 296.1 (38). HRMS (TOF-ES)⁺ calcd for C₁₈H₁₅N₂O₂ClBr (M + H): 405.0005, found 405.0007.

1-Acetyl-3-bromo-5-chloro-2′-ethylspiro[indoline-2,1′-isoindolin]-3′-one (6d). 175 mg, 84% yield; colorless solid, mp 193–195 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.38 (s, 1H), 7.94 (d, J = 1.1 Hz, 1H), 7.72–7.62 (m, 2H), 7.54 (d, J = 7.36 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 7.36, 1.2 Hz, 1H), 5.83 (s, 1H), 3.95–3.86 (m, 1H), 2.75–2.66 (m, 1H), 1.56 (s, 3H), 1.07 (t, J = 7.20 Hz, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.2, 166.7, 144.0, 143.0, 136.6, 133.5, 132.5, 131.0, 125.9, 125.7, 125.3, 124.6, 121.2, 117.8, 87.2, 56.9, 36.5, 24.1, 13.9. LRMS (EI⁺) (m/z) (relative intensity): 418.01 (M⁺, 46), 420.0 (68), 339.1 (100). HRMS (TOF-ES)⁺ calcd for C₁₉H₁₇N₂O₂ClBr (M + H): 419.0162, found 419.0160.

1-Acetyl-3-bromo-5-chloro-2′-(methoxyethyl)spiro[indoline-2,1′-isoindolin]-3′-one (6e). 199 mg, 89% yield; colorless solid, mp 180–183 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.30 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.72–7.62 (m, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.35–7.33 (m, 2H), 5.85 (s, 1H), 4.04–3.98 (m, 1H), 3.62–3.57 (m, 1H), 3.30–3.26 (m, 1H), 3.15 (s, 1H), 2.81–2.74 (m, 1H), 1.51 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.5, 167.0, 144.1, 141.5, 136.6, 133.4, 132.0, 130.7, 130.6, 129.5, 128.5, 124.6, 124.3, 121.2, 118.5, 86.6, 69.6, 58.4, 57.1, 42.2. LRMS (+ESI) (m/z) (relative intensity): 471.50 (M + Na, 74), 473.34 (100). HRMS (EI⁺) calcd for C₂₀H₁₈BrClN₂O₃ (M⁺): 448.0189, found 448.0188.

1-Acetyl-3,5-dichloro-2′-(methoxyethyl)spiro[indoline-2,1′-isoindolin]-3′-one (6f). 180 mg, 89% yield; colorless solid, mp 192–194 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 7.93 (d, J = 6.1 Hz, 1H), 7.69 (d, J = 5.8 Hz, 2H), 7.64 (d, J = 6.2 Hz, 1H), 7.36 (s, 2H), 5.73 (s, 1H), 3.99 (d, J = 14.2 Hz, 1H), 3.59 (s, 1H), 3.28 (s, 1H), 3.15 (s, 3H), 2.8 (d, J = 9.3 Hz, 1H), 1.50 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.8, 167.4, 144.5, 141.5, 133.6, 132.0, 130.9, 129.7, 128.5, 124.5, 124.0, 121.4, 118.8, 87.2, 69.9, 66.3, 58.6, 42.5, 24.1. LRMS (+ESI) (m/z) (relative intensity): 427.58 (M + Na, 100), 429.32 (63). HRMS (EI⁺) calcd for C₂₀H₁₈Cl₂N₂O₃ (M⁺): 404.0694, found 404.0695.

1-Acetyl-2′-benzyl-3-bromospiro[indoline-2,1′-isoindolin]-3′-one (6h). 158 mg, 77% yield; colorless solid, mp 174–177 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.07 (s, 1H), 7.91 (dd, J = 6.68, 1.20 Hz, 1H), 7.56 (d, J = 7.16 Hz, 2H), 7.40 (t, J = 8.38 Hz, 3H), 7.21 (t, J = 8.2 Hz, 1H), 7.20–6.88 (m, 3H), 6.87 (s, 1H), 5.82 (s, 1H), 5.25 (d, J = 15.0 Hz, 3H), 3.49 (d, J = 15.2 Hz, 1H), 0.97 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 169.7, 167.2, 144.4, 142.6, 136.6, 133.6, 132.1, 130.8, 128.7, 128.5, 128.3, 128.1, 127.0, 125.1, 124.8, 124.7, 121.2, 118.1, 86.6, 58.4, 45.0, 23.7. LRMS (EI⁺) (m/z) (relative intensity): 446.1 (M⁺, 45), 367.0 (100), 220 (82). HRMS (TOF-ES)⁺ calcd for C₂₄H₂₀N₂O₂Br (M + H): 447.0708, found 447.0709.

1-Acetyl-2′-benzyl-3,6-dibromospiro[indoline-2,1′-isoindolin]-3′-one (6i). 205 mg, 78% yield; colorless solid, mp 163–165 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.28 (s, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.65 (s, 2H), 7.44–7.38 (m, 3H), 7.21 (s, 3H), 6.91 (s, 2H), 5.79 (s, 1H), 5.36 (d, J = 14.5 Hz, 3H), 1.07 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 167.1, 143.9, 136.2, 133.6, 132.0, 130.9, 128.8, 128.5, 128.2, 128.0, 126.1, 125.8, 124.7, 124.4, 121.1, 86.9, 57.2, 44.9, 23.8. LRMS (+ESI) (m/z) (relative intensity): 547.11 (M + Na, 44), 549.14 (100). HRMS (TOF-ES)⁺ calcd for C₂₃H₁₉N₂O₂Br₂ (M + H): 524.9813, found 524.9811.

1-Acetyl-2′-benzyl-3,5′-dibromo-5-chlorospiro[indoline-2,1′-isoindolin]-3′-one (6j). 215 mg, 77% yield; colorless solid, mp 210–212 °C; ¹H NMR (400 MHz, CDCl₃) δ_H (ppm) 8.10 (d, J = 0.6 Hz, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.46 (s, 1H), 7.3 (bs, 1H), 7.2–7.16 (m, 3H) 6.92 (s, 2H), 5.78 (s, 1H), 5.34 (d, J = 14.7 Hz, 1H), 3.53 (d, J = 15.3 Hz, 1H), 1.07 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 169.3, 165.6, 142.7, 141.0, 136.7, 136.0, 135.8, 133.9, 131.1, 130.8, 130.3, 128.9, 128.2, 128.6, 128.1, 128.0, 127.5, 126.0, 124.9, 122.7, 119.2, 86.6, 56.7, 45.1, 23.8. LRMS (+ESI) (m/z) (relative intensity): 581.06 (M + Na, 29), 583.08 (100). HRMS (TOF-ES)⁺ calcd for C₂₄H₁₈N₂O₂ClBr₂ (M + H): 558.9424, found 558.9426.

1-Acetyl-3-bromo-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one (6k). 134 mg, 62% yield; colorless solid, mp 181–185 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.23 (s, 1H), 8.00 (s, 1H), 7.99 (dd, J = 5.3, 2.2 Hz, 1H), 7.65–7.59 (m, 2H), 7.41–7.25 (m, 8H) 7.10 (t, J = 7.5 Hz, 1H), 5.78 (s, 1H), 1.89 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.3, 167.6, 144.1, 142.6, 134.6, 133.2, 131.0, 130.8, 130.0, 128.4, 127.4, 127.0, 125.8, 124.9, 124.4, 123.6, 117.2, 89.5, 52.7, 24.2. LRMS (EI⁺) (m/z) (relative intensity): 432.0 (M⁺, 34), 353.1 (100), 281.1 (52). HRMS (TOF-ES)⁺ calcd for C₂₃H₁₈N₂O₂Br (M + H): 433.0552, found 433.0556.

1-Acetyl-3,5′,6-tribromo-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one (6l). 195 mg, 66% yield; colorless solid, mp 190–193 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.40 (s, 1H), 8.13 (d, J = 1.3 Hz, 1H), 7.76–7.74 (m, 1H), 7.56 (t, J = 7.22 Hz, 2H), 7.35–7.29 (m, 1H) 7.26–7.20 (m, 2H), 7.17 (s, 2H), 7.10 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 1.93 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 169.9, 165.9, 143.2, 142.4, 136.3, 134.0, 132.6, 128.9, 128.8, 128.5, 128.1, 127.7, 127.0, 126.9, 126.2, 125.5, 125.2, 124.8, 120.4, 89.9, 51.5, 24.3. LRMS (EI⁺) (m/z) (relative intensity): 587.86 (M⁺, 22), 510.9 (100), 508 (94), 388 (84). HRMS (TOF-ES)⁺ calcd for C₂₃H₁₆N₂O₂Br₃ (M + H): 588.8762, found 588.8759.

1-Acetyl-3,5′-dibromo-5-chloro-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one (6m). 169 mg, 62% yield; colorless solid, mp 193–195 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.15 (s, 1H), 7.86 (bs, 2H), 7.49 (bs, 1H), 7.25–7.10 (m, 7H), 5.83 (s, 1H), 1.73(bs, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 169.3, 165.2, 142.2, 141.0, 136.9, 134.0, 130.1, 129.8, 128.9, 128.4, 128.1, 125.8, 125.3, 125.0, 124.4, 122.9, 118.2, 114.3, 88.3, 57.1, 24.1. LRMS (+ESI) (m/z) (relative intensity): 566.82 (M + Na, 100), 568.81 (100). HRMS (TOF-ES)⁺ calcd for C₂₃H₁₅N₂O₂ClBr₂ (M + H): 544.9267, found 544.9271.

1-Acetyl-3-bromo-5-chloro-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one (6n). 81 mg, 35% yield; colorless solid, mp 165–167 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.23 (s, 1H), 8.01–7.99 (m, 1H), 7.67–7.62 (m, 2H), 7.44–7.40 (m, 2H), 7.35–7.27 (m, 5H) 7.23 (s, 1H), 5.71 (s, 1H), 1.86 (s, 3H). ¹³C NMR (100 MHz CDCl₃) δ_C (ppm): 170.3, 167.5, 143.8, 141.2, 134.4, 133.5, 131.3, 130.8, 130.7, 130.2, 130.0, 129.2, 128.6, 127.0, 125.8, 124.5, 123.6, 118.6, 90.1, 51.4, 24.0. LRMS (+ESI) (m/z) (relative intensity): 489.08 (M + Na, 82), 491.03 (100). HRMS (TOF-ES)⁺ calcd for C₂₃H₁₇N₂O₂ClBr (M + H): 467.0162, found 467.0164.

1-Acetyl-3-bromo-5-chloro-2′-phenylspiro[indoline-2,1′-isoindolin]-3′-one (6n1). 68 mg, 29% yield; colorless solid, mp 168–190 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.03 (d, J = 7.3 Hz, 1H), 8.00–7.95 (m, 1H), 7.75–7.63 (m, 3H), 7.22–7.11 (m, 8H), 5.89 (s, 1H), 1.68 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 169.8, 166.8, 143.7, 141.2, 134.0, 132.2, 131.2, 130.2, 129.9, 128.9, 128.3, 125.2, 124.5, 121.34, 118.3, 88.6, 57.4, 24.7. LRMS (EI⁺) (m/z) (relative intensity): 466.0 (M + H, 24), 387.1 (72), 345.1 (100). HRMS (EI⁺) calcd for C₂₃H₁₇N₂O₂ClBr (M⁺): 466.0084, found 466.0083.

1-Acetyl-6-methoxy-3′-oxo-2′-phenylspiro[indoline-2,1′-isoindolin]-3yl acetate(6o). 196 mg, 88% yield; colorless solid, mp 143–145 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.02–8.00 (m, 1H), 7.67–7.65 (m, 2H), 7.53–7.51 (m, 1H), 7.32 (d, J = 4.4 Hz, 4H), 7.28–7.25 (m, 1H) 7.01 (d, J = 8.4 Hz, 1H), 6.60 (dd, J = 8.36, 2.44 Hz, 1H), 6.31 (s, 1H), 3.84 (s, 3H), 1.77 (s, 3H), 1.70 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 169.7, 167.0, 162.1, 146.3, 141.3, 134.6, 132.6, 132.4, 130.7, 129.6, 128.3, 127.4, 125.8, 124.8, 124.7, 117.0, 111.2, 103.2, 89.2, 55.8, 24.3, 20.4. LRMS (+ESI) (m/z) (relative intensity): 464.99 (M + Na, 100), 383.11 (9). HRMS (TOF-ES)⁺ calcd for C₂₆H₂₃N₂O₅ (M + H): 443.1607, found 443.1611.

1-Acetyl-2′-allyl-3-bromo-5-chlorospiro[indoline-2,1′-isoindolin]-3′-one (6p). 155 mg, 72% yield; colorless solid, mp 171–173 °C; ¹H NMR (400 MHz CDCl₃) δ_H (ppm) 8.23 (s, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.72–7.62 (m, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.40 (s, 1H), 7.37–7.34 (m, 1H), 7.26 (s, 1H), 5.83 (s, 1H), 5.75–5.65 (m, 1H), 4.97 (d, J = 10.0 Hz, 1H), 4.7 (d, J = 17.0 Hz, 1H), 3.1 (q, J = 8.8 Hz, 1H), 1.50 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_C (ppm): 169.9, 166.4, 143.9, 141.1, 133.6, 132.3, 131.6, 131.0, 130.6, 130.1, 128.9, 124.9, 124.7, 121.2, 119.1, 118.7, 86.8, 56.6, 43.8, 24.2. LRMS (+ESI) (m/z) (relative intensity): 453.33 (M + Na, 74), 455.23 (100). HRMS (EI⁺) calcd for C₂₀H₁₆BrClN₂O₂ (M⁺): 430.0084, found 430.0085.

Conclusions

In conclusion, we have developed an easy access for the synthesis of spiro fused isoindolinone-indolines utilizing a well-known, halogen sources mediated cyclopropylhalonium ion strategy. Also, we successfully utilized the ortho-effect of amide group in N-substituted 2-iodo benzamides for the ligand free synthesis of 1,2-substituted indolylcarboxamides which also provide a path for the synthesis of indolophenanthradinecarboxamide derivative.

Acknowledgements

Financial support by the Ministry of Science and Technology of the Republic of China (MOST 103-2113-M-003-008-MY3), National Taiwan Normal University (103-07-C) and Instrumentation Centre at National Taiwan Normal University is gratefully acknowledged. The authors are grateful to Ms Hsiu-Ni Huan, Ms Chiu-Hui He and Ting-Shen Kuo for providing HRMS, NMR spectral and Crystallographic data respectively.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1484056–1484061. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra15002k

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