Facile synthesis of 11-aryl-6H-isoindolo[2,1-a]indol-6-ones via hypervalent iodine(III)-promoted cascade cyclization

Abstract

An efficient method was developed for the synthesis of a tetracyclic fused indole and isoindoline ring system, under metal-free conditions. The hypervalent iodine PIDA-mediated regioselective as well as chemoselective intramolecular cascade oxidative cyclization of 2-(1-arylethynyl)benzamides afforded 11-aryl-6H-isoindolo[2,1-a]indol-6-ones at room temperature in good to excellent yields.

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Indole and isoindolinone motifs, which are frequently found in natural products, pharmaceutical products and materials, have attracted chemists for decades.¹ A number of successful synthetic methods have been developed for the synthesis of these motifs over several years.² However, the development and implementation of new highly modular synthetic strategies for the effective synthesis of complex molecules from simple substrates by the domino approach is of ongoing interest in organic chemistry with perfect chemo- and regio-selectivity having a transformational effect in areas extending from material and polymer science to chemical biology and drug discovery.³ Recently, hypervalent iodine reagents have received great attention due to their environmental friendliness and low cost as well as the ease of handling and synthetic efficiency in the syntheses of complex architectures via oxidative transformations,⁴ and/or including with activation of alkynes to nucleophilic attack by heteroatoms.⁵ During the last decade, transition metal-free C–N/C–C bond formation via the cyclization of alkynes having nucleophile in close proximity to the triple bond arises as a powerful tool in the syntheses of variety of heterocyles.^6,7 In the context of annulation of enyne–amide system of o-alkynylbenzamides, regarding the O-cyclization which can provide iminoisocoumarins or iminobenzoisofurans,⁸ whilerarely reported N-cyclization providesisoindolone derivatives via 5-exo-dig cyclization under basic conditions as well as metal catalyzed condition⁹ (Scheme 1). Larock and co-workers were previously reported a selective N-cyclization leading to isoindolones, which was further revised by Opatz and co-workers as O-cyclized product rather than N-cyclized product leading to iminocoumarins and iminobenzofurans instead of isoindolines, later corrected by Larock et al. also.^8c,d,10 Hence, we were interested to synthesize rarely reported selective N-cyclized isoindolines via hypervalent iodine reagents.

Scheme 1 Previous reports on 2-(1-phenylethynyl)benzamide for electrophilic cyclization of 2-alkynyl group.

To the best of our knowledge, there are no previous reports for the construction of tetracyclic fused indoleandisoindoline ring system from 2-(1-alkynyl) benzamide derivatives via domino intramolecular C–N and C–C bond formation in a single step by using hypervalent iodine(III) reagents as the sole oxidant. However, few typical examples (isoindolo[2,1-a]indol-6-ones) are known, prepared under harsh reaction conditions in several steps or via 1,4-palladium migration followed by intramolecular Heck type reaction.¹¹ Isoindolo[2,1-a]indol-6-one derivatives possess a variety of interesting biological activities.¹²

We began our investigations by using N-phenyl-2-(phenylethynyl) benzamide 1a as a model substrate which was readily prepared from commercially available 2-iodobenzoic acid (Table 1).¹³ Treating the substrate 1a with 1.5 equiv. of PIDA as an oxidant in 1.5 mL of DCE as solvent for 12 h at room temperature did not afford the target compound 2a, starting material was remained intact (Table 1, entry 1). Further, screening with solvents such as DCM, CHCl₃ and MeCN was also unsuccessful (Table 1, entry 2–4). Again, when we moved from PIDA to PIFA as an oxidant in 1.5 equiv. and TFE as a solvent,¹⁴ we were delighted to find the targeted compound 2a in 15% yield (Table 1, entry 5), which was characterized by extensive analysis of FT-IR, HRMS, 1D and 2D NMR. All analytical data were in good agreement with previously reported one.^11a PIFA was unsuccessful to improve the yield of the product in the different solvents. Hence, we again move to PIDA with 1.2 equiv. in solvent TFE provided improved yield of the desired product with 20% unreacted starting material (Table 1, entry 7). With increasing the amount of PIDA from 1.2 equiv. to 1.7 equiv., increased the yield to 89% (Table 1, entry 8 & 9), but no further improvement in yield was observed in spite of using increased amount of PIDA. Encouraged by this result, a variety of hypervalent iodine reagents and solvents were then evaluated at room temperature to optimize the reaction conditions as shown in Table 1.

Table 1 Optimization of reaction conditions^a

Entry	Oxidant	Equiv.	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), solvent (1.5 mL). b Isolated yields. c BF3·Et2O (20 mol%) was added, starting material were decomposed.
1	PIDA	1.5	DCE	12	0
2	PIDA	1.5	DCM	12	0
3	PIDA	1.5	CHCl3	12	0
4	PIDA	1.5	MeCN	12	0
5	PIFA	1.5	TFE	45 min	15
6	PIFA	1.5	HFIP	40 min	10
7	PIDA	1.2	TFE	1	55
8	PIDA	1.5	TFE	35 min	70
9	PIDA	1.7	TFE	35 min	89
10^c	PIDA	1.7	TFE	35 min	0
11	PIDA	1.7	HFIP	15 min	40
12	PhI(OPiv)2	1.7	TFE	5	60
13	PhIO	1.7	TFE	12	Trace

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With the optimized conditions in hand, we then investigated the scope of substrate and the generality of the procedure. We first examined the substituent effect on the benzene ring attached to the nitrogen atom of amide group.

As shown in Scheme 2, a variety of functional groups such as hydrogen, electron-donating and -withdrawing groups as well as halogen were investigated for this intramolecular cross-coupling reaction. The substrate N-phenyl-2-(phenylethynyl)benzamide 1a reacted to produce 11-phenyl-6H-isoindolo[2,1-a]indol-6-one 2a in 89% yield. Similarly, the substituted N-aryl-2-(phenylethynyl)benzamides 1b–1i with R² having 4-ethyl, 3,4-dimethyl, 2,4-dimethyl, 2,5-dimethyl, 4-methyl, 3-methyl, 4-methoxy and 3-methoxy substituents reacted to give the corresponding substituted fused indole and indolone derivatives 2b–2i in 45–91% yields. In case of the substrates 1c, 1g and 1i bearing substituents 3,4-dimethyl, 3-methyl and 3-methoxy groups produce desired compounds 2c, 2g and 2i in 2.8 : 1, 2.7 : 1 and 6.3 : 1 mixture of regioisomers, respectively. Hydrogen or electron-donating groups such as methyl, ethyl, methoxy or fused benzene ring could afford the desired product in good to excellent yields. The reaction with the substrate, possessing weak electron-withdrawing substituent like 4-chloro as in substrate 1k provided better yield of product 2k while the substrates having strong electron-withdrawing groups like p-COMe and p-COOMe showed no reaction, might be due to destabilization of nitrenium ion formed. The manipulation of benzamide with different substituents like NO₂ and additional alkyne group at meta position to carbonyl group 1l, 1m yielded sole desired product in good yield.

Scheme 2 Substrate scope for domino C–N & C–C bond formation. Reaction conditions: PIDA (1.7 equiv.), TFE (1.5 mL), isolated yields, oxidant (2.1 equiv.).

For more generalization of the protocol, we again investigated the reactions by taking substituted alkynes (Scheme 3), which produce 2p–2s in good yield while desired compound 2t was not found due to decomposition of starting material 1t.

Scheme 3 Substrate scope for C–N & C–C bond formation. Reaction conditions: PIDA (1.7 equiv.), TFE (1.5 mL), isolated yields.

To confirm the reaction mechanism, a series of control experiments (Scheme 4) were performed at optimized reaction conditions along with different radical scavengers, TEMPO (2.0 equiv.) 2,6-di-tert-butyl-4-methylphenol (BHT) (2.0 equiv.) and 1,1-diphenylethylene (DPE) (2.0 equiv.), showed no effect on the yield of reaction product 2a, an indication of the ionic mechanism which is already accepted for such type of reactions.⁷

Scheme 4 Control experiments.

Hence, the mechanism has been proposed for PIDA-mediated tandem oxidative process (Scheme 5).

Scheme 5 Proposed mechanism.

Initially, PIDA reacts with substrate 1a to give an N-iodoamido species A with the release of an acetic acid. The intermediate species A decomposes to generate nitrenium ion B which reacts intramolecularly with the alkyne residue to form a carbonium ion intermediate C. Thus, the electrophilic aromatic substitution reaction¹⁵ takes place and gives intermediate species D, which upon H-abstraction by the in situ-generated acetate anion yields the desired product 2a. This proposed mechanism and role of solvent were confirmed by time dependent mass spectra of reaction mixture (ESI†).

In conclusion, we have developed a novel, simple, rapid and metal-free protocol to construct fused indolones under the PIDA-mediated cascade oxidative cyclization via C–N and C–C bond formation at room temperature. This elegant work should open new prospective to the research of hypervalent iodine chemistry along with the development of fused heterocyclic compounds. Currently, research is ongoing in our laboratory for construction of other heterocyclic compounds and natural product synthesis via this procedure.

Acknowledgements

Kapil Dev is thankful to Council of Scientific and Industrial Research New Delhi for providing Junior Research Fellowship. Authors are also thankful to SAIF division of CSIR-CDRI, Lucknow, India for providing spectral data. CDRI communication no. 8894.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and spectroscopic data ¹H NMR, ¹³C NMR and HRMS (ESI) for all compounds and 2D NMR for some selective compounds. See DOI: 10.1039/c4ra10452h

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