Rhodium-catalyzed cycloaddition of carbonyl ylides for the synthesis of spiro[furo[2,3-a]xanthene-2,3′-indolin]-2′-one scaffolds

Abstract

An intramolecular cycloaddition of oxonium ylides generated from 3-diazooxindole and a bifunctional substrate i.e. 2-methyl-2-(4-methylpent-3-en-1-yl)-2H-chromene-3-carbaldehyde has been achieved using 5 mol% of Rh₂(OAc)₄ to produce highly substituted 3,3,5a-trimethyl-3a,5,5a,11b-tetrahydro-3H,4H-spiro[furo[2,3-a]xanthene-2,3′-indolin]-2′-ones in good yields with high diastereoselectivity. This is the first example of the synthesis of biologically relavant polycyclic frameworks from readily accessible precursors.

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Introduction

Spirooxindoles are often found in several natural products and medicinally important molecules.¹ In particular, the 4,5-dihydro-3H-spiro[furan-2,3′-indolin]-2′-one core is an integral part of many natural products and biologically active molecules (Fig. 1).² Among them, N-methylwelwitindolinone D isonitrile inhibits the growth of lung adenocarcinoma (A549) cells and hepatocellular carcinoma (HepG2) cells.³ Gelsedine-type indole alkaloids are known to exhibit strong cytotoxic effects against A431 human epidermoid carcinoma cells.⁴ Therefore, the development of efficient methods for the synthesis of novel spiro-oxindoles and evaluation of their bioactivities are of great importance in drug discovery.⁵ On the other hand, α-diazo carbonyl compounds are versatile intermediates and susceptible to undergo various transformations such as cyclopropanation, C–H or heteroatom-H insertion, cycloaddition and ylide formation.^6,7

Fig. 1 Examples of spirofurooxindole frameworks.

In particular, the cycloaddition of carbonyl ylides with dipolarophiles provides a synthetically powerful way to make a variety of 5-membered oxacycles.⁸ Furthermore, an intramolecular generation of carbonyl ylides and their subsequent cycloadditions are important for the construction of bridged oxacycles.⁹

However, the development of an operationally simple and efficient strategy in generating a novel series of polycyclic spirooxindoles is highly desirable. Because it provides a rapid access to highly substituted polycyclic compounds with high structural diversity and complexity in a single step process.

Following our research interest on α-diazocarbonyl compounds,¹⁰ we herein report a novel and efficient approach for the synthesis of biologically active polycyclic spiro compounds through a Rh-catalyzed cycloaddition of carbonyl ylides generated from diazoamide and chromene-3-carboxaldehyde (Scheme 1).

Scheme 1 Cycloaddition of 3-diazooxindole with chromene-3-carbaldehyde.

In this reaction, oxonium ylides undergo an intramolecular cycloaddition with a tethered olefin to generate the spiro cyclic frameworks. The intramolecular version is completely regio- and stereoselective affording the products in good yields. The reaction is highly chemoselective as there is no cyclopropanation between α-diazoketone and olefin. The method is operationally simple, exquisitely selective, and works with diverse substrates. As a model reaction, we investigated the cycloaddition of carbonyl ylide generated from 1 equiv. of N-methyl 3-diazoxindole (1) and 1.1 equiv. of alkene tethered chromene-3-carboxaldehyde (2) using 5 mol% Rh₂(OAc)₄ in dry dichloroethane. The reaction proceeded smoothly at room temperature affording the expected spirofurooxindole 3a in 80% yield as a single diastereomer. The structure of 3a was confirmed by NMR, IR and HRMS analysis. To optimize the reaction conditions, we screened the reaction with different amounts of the catalyst. After several experiments, we found that 5 mol% of Rh₂(OAc)₄ is optimum (entry b, Table 1). No further improvement in conversion was observed either by increasing the amount of catalyst to 10 mol% or by decreasing it to 3 mol% (entries e and f, Table 1). In addition, no further increase in yields were observed even by changing the ratio of substrate 1 and 2 to 1.5 : 1.0 (entry g, Table 1). The best conversion was achieved using 5 mol% of the catalyst. Next we examined the effect of solvents such as dichloroethane, dichloromethane, benzene and toluene at various temperatures. Among them, dicholoroethane appeared to give the best results in terms of yield and reaction time at room temperature (entries b, e and f, Table 1). Furthermore, the reactions were sluggish in other solvents like THF, dimethoxyethane and acetonitrile affording the desired product in poor yields.

Table 1 Optimization of reaction conditions for 3a

Entry	Substrate (1) (equiv.)	Substrate (2) (equiv.)	Catalyst^a (mol%)	Solvent	Time (min)	Yield of 3a^b (%)
a Reaction was performed in 1 mmol scale. b Yield refers to pure products after chromatography.
a	1.0	1.1	5	DCM	30	73
b	1.0	1.1	5	DCE	30	80
c	1.5	1.0	5	Benzene	50	65
d	1.5	1.0	5	Toluene	60	68
e	1.0	1.1	10	DCE	20	75
f	1.0	1.1	3	DCE	50	70
g	1.5	1.0	5	DCE	30	79

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These initial findings encouraged us to study its scope with other substrates. The reaction was performed with different 3-diazooxindoles possessing substituents on aromatic ring and N-protecting groups. The halo substituents such as chloro- and bromo- at 5-position of 3-diazooxindole gave the desired products in good yields (entries d–f j–l, Table 2). The presence of protective group on nitrogen showed some effect on conversion. The 3-diazooxindole bearing electron-releasing N-protective groups such as N-methyl, N-benzyl, and N-propargyl furnished the products in high yields (entries a–m, Table 2). Conversely, N-Boc protected 3-diazooxindoles gave the products in lower yields than N-methyl-, N-benzyl- and N-propargyl derivatives (entries n–p, Table 2). However, 1-methyl-5-methoxy-3-diazooxindole gave the desired product in 75% yield under similar conditions (entry q, Table 2). The scope of this method was further extended to substituted chromene-3-carboxaldehydes such as 5-chloro-, and 5-bromo- derivatives (entries b, c, e, f, h, i, k, l, Table 2). No significant electronic effect of the substituents on substrate 2 was observed.

Table 2 [3 + 2] cycloadditon of carbonyl ylides^a

Entry	R^1/R^2	R^3	Product (3)^a	Yield^b (%)
a All the reactions were performed using Rh2(OAc)4 (5 mol%), diazoamide (1 equiv.), chromene-3-carboxaldehyde (1.1 equiv.) in dry DCE at 25 °C over 30 min. b Yield refers to pure product after column chromatography.
a	CH3/H	H	3a	81
b	CH3/H	Cl	3b	80
c	CH3/H	Br	3c	78
d	CH3/Cl	H	3d	83
e	CH3/Cl	Cl	3e	79
f	CH3/Cl	Br	3f	81
g	Bn/H	H	3g	85
h	Bn/H	Cl	3h	84
i	Bn/H	Br	3i	84
j	Bn/Br	H	3j	85
k	Bn/Br	Cl	3k	82
l	Bn/Br	Br	3l	83
m	Propargyl/H	H	3m	88
n	Boc/H	H	3n	70
o	Boc/H	Cl	3o	60
p	Boc/H	Br	3p	65
q	CH3/CH3O	H	3q	75

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Finally, the structure of 3j was confirmed unambiguously by a single crystal X-ray analysis as shown in Fig. 2 (Table 2, entry j).¹¹

Fig. 2 ORTEP diagram of 3j.

Mechanistically, the reaction was assumed to be proceeded through a [3 + 2] cycloaddition between 1 and 2. The rhodium carbenoid 4, formed in situ from 3-diazooxindole (1) and Rh₂(OAc)₄ and reacts with chromene-3-carboxaldehyde (2) to generate the carbonyl ylide 5. A subsequent cycloaddition of carbonyl ylide (5) with an internal olefin would give the desired product 3 (Scheme 2).

Scheme 2 A plausible mechanism.

Finally, we were interested to examine the reactivity of the analogue of 2 (2x) with N-methyl 3-diazoxindole (1) using 5 mol% of Rh₂(OAc)₄ in DCE at room temperature. To our surprise, no desired product was obtained under similar conditions (Scheme 3).

Scheme 3 Cycloaddition between 3-diazooxindole (1) and 2x.

Conclusion

In conclusion, we have developed an efficient strategy for the stereoselective synthesis of polycyclic frameworks through a 1,3-dipolar cycloaddition. This method is operationally simple and works under mild conditions. Due to a broad range of biological activity of spirooxindole derivatives, this method will find a significant application in medicinal chemistry.

Acknowledgements

EPR thanks UGC, New Delhi, for the award of a fellowship. BVS thanks BRNS, Mumbai, for the financial support under BSC grant number 37(2)/14/24/2015 for this research.

References and notes

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11. CCDC 893601 contains supplementary crystallographic data of 3j.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra of products. CCDC 893601. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra05661j

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