Metal-free syntheses of oxindole derivatives via a benzoylation/substitution/desulfonylation/cyclization cascade

Abstract

A benzoylation/substitution/desulfonylation/cyclization cascade reaction giving oxindole derivatives was discovered. The reaction used aromatic aldehydes and N-alkyl-N-(phenylsulfonyl)methacrylamides as starting materials, and proceeded under mild conditions without using toxic metal catalysts. 3-Methyl-3-aroyloxindole derivatives were formed in good yields.

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Oxindole derivatives are important molecules found in a wide range of natural products. They are highly valuable molecules in drug discovery due to their variety of bioactivities.¹ Many oxindole derivatives have been synthesized and screened, and different biological activities have been reported.² Fig. 1 shows four representative bioactive oxindole derivatives.³ These include convolutamydine A, a natural product with potent activity against leukemia cells.^3a Also, selective 5-HT₇ receptor antagonists,^3b an antitumor agent, and selective inhibitors of the plasmodial CDKs are included.^3c,d Thus, quick syntheses of oxindole derivatives are highly valued in high-throughput screening. Such cascade reactions are greatly desired.

Fig. 1 Biologically active oxindole derivatives.

Traditional synthetic methods⁴ for generating oxindole derivatives have been supplemented recently by some powerful cascade methods using transitional metal catalysts to carry out oxidative cross couplings of activated alkenes.⁵ These methods have attracted a lot of attention. N-Alkyl-N-(aryl)methacrylamides were normally used as core reactants. By carefully designing their substrate structures, different oxindole derivatives were produced in one-pot cascade sequences under mild conditions. These reactions are atom-economic, highly efficient and environmentally friendly.⁶ More recently, another cascade reaction that produces 3-methyl-3-aroyloxindole derivatives has quickly drawn attention.⁷ Several functionalizations using N-alkyl-N-(phenylsulfonyl)-methacrylamide as the core reactants have been reported.⁷

In this paper, a novel cascade reaction involving benzoylation/substitution/desulfonylation/cyclization to produce 3-methyl-3-aroyloxindole derivatives is reported. This process never involves a metal catalyst.

In order to find suitable reaction conditions for this cascade, metal catalysts and radical initiators were initially screened based on previously reported results.⁸ N-Methyl-N-(phenylsulfonyl)methacrylamide and benzaldehyde were used as representative reactants (Table 1) for screening. In entry 1, CuCl₂ (10 mol%) was used as a catalyst in the presence of TBHP (tert-butyl hydroperoxide, 70% in water, 2.5 equiv.). Excess benzaldehyde (5 equiv.) was used to promote conversion, giving 3a in a yield of 35%. Using TBHP as the initiator gave about 40% of 3a. In entry 3, one equivalent of NaHCO₃ was also added and 3a was produced in a good yield of 70%. NaHCO₃ can increase the yield greatly; because it may consume the SO₂ released in the reaction. When TBHP was replaced by DTBP (di-tert-butyl peroxide) in the presence of NaHCO₃, 3a was produced in 56% yield. When PhI(OAc)₂ and NaHCO₃ were both used, none or only traces of desired 3a was detected. Using solvents DCE, toluene (entries 6, 7) afforded none or only traces of 3a, while acetonitrile and EtOAc (entry 8, 9) afforded 20% and 53% of expected product 3a, respectively. Using H₂O₂ (10 mol%) in the presence of NaHCO₃ gave only traces of 3a.

Table 1 Optimization of reaction condition^a

Entry	Cat. (mol%)	Reagent	Solvent	Yield^b (%)
a Reaction conditions: benzaldehyde (5 equiv.), N-methyl-N-(phenylsulfonyl)methacrylamide (1 equiv.), aqueous TBHP (tert-butyl hydroperoxide, 70 wt% in water, 2.5 equiv.), H2O2 (30 wt% in water, 2.5 equiv.), DTBP (tert-butyl peroxide, 2.5 equiv.), CuCl2 (10 mol%, for entry 1); NaHCO3 (1 equiv.), reaction time 18 h.b Yield is based on reactant 2a.
1	CuCl2	TBHP, NaHCO3	—	35
2		TBHP	—	40
3		TBHP, NaHCO3	—	70
4		DTBP, NaHCO3	—	56
5		PhI(OAc)2, NaHCO3	—	Trace
6		TBHP, NaHCO3	DCE	Trace
7		TBHP, NaHCO3	Toluene	Trace
8		TBHP, NaHCO3	CH3CN	20
9		TBHP, NaHCO3	EtOAc	53
10		H2O2, NaHCO3	—	Trace

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Based on these screening results, the optimized reaction conditions employed were: aldehyde (5 equiv.), TBHP (2.5 equiv.), 90 °C, NaHCO₃ (2 equiv.), 18 h. Under these conditions, fourteen reactions with different substituents were thoroughly studied (Table 2). All these cascade reactions gave 3-methyl-3-aroyloxindole derivatives 3a–m in good yields except entry 14 using the electron-withdrawing 3-nitrobenzaldehyde as a starting material. This fact indicates that the nitro function may influence radical reaction process, since it didn't give the expected product.

Table 2 Cascade reactions to generate 3-methyl-3-aroyl oxindole derivatives^a

Entry	R	R^1	Product	Yield^b (%)
a Reaction conditions: aldehydes (5 equiv.), N-alkyl-N-(phenylsulfonyl)methacrylamides (1 equiv.), aqueous TBHP (tert-butyl hydroperoxide, 70 wt% in water, 2.5 equiv.), NaHCO3 (1 equiv.), reaction time 18 h.b Yield calculation is based on reactant 2.
1	H	Me		70
2	4-MeO	Me		77
3	4-Me	Me		75
4	4-t-Bu	Me		81
5	4-MeO	Et		68
6	4-Me	Et		70
7	H	Et		72
8	4-t-Bu	Et		85
9	4-MeO	i-Pr		76
10	H	i-Pr		74
11	4-CH3	i-Pr		73
12	4-Br	i-Pr		70
13	2-F	i-Pr		60
14	3-NO2	i-Pr		Trace

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Based on previous reports⁷ and our mass spectrometry analysis results, it is obvious that the SO₂ functions were lost during the reaction. No sultams was in the products. To further confirm the product structures; a comparison experiment was conducted (Scheme 1). N-Methyl-N-phenylmethacrylamide was used as a representative starting material to compare with the reaction of 2a. The ¹H and ¹³C-NMR of the products from each reaction confirmed that 3a was produced in both reactions. Obviously, SO₂ is lost in this cascade sequence from 2a. This conclusion is further supported by the reactions in ref. 7. Based on the above, a reaction mechanism is proposed in Scheme 2. When heated, TBHP gives a tBuO˙ and an ˙OH radical, which abstract a hydrogen atom from the aryl aldehyde 1 to generate the aroyl radical. This aroyl radical adds to the double bond of N-alkyl-N-(phenylsulfonyl)acrylamide to give delocalized radical intermediate 5, which undergoes intramolecular radical substitution at the aromatic ring with loss of SO₂. This forms radical 6. The addition of resultant radical 6 to the aromatic ring generates radical intermediate 7, which loses a hydrogen atom to give ketone oxindole derivatives 3 in good yields.

Scheme 1 Comparison reactions.

Scheme 2 Proposed cascade reaction mechanism.

In summary, we have developed a novel, metal-free cascade reaction involving sequential benzoylation/substitution/desulfonylation/cyclization steps to give 3-methyl-3-aroyloxindole derivatives. The reaction used aromatic aldehydes and N-alkyl-N-(phenylsulfonyl)methacrylamides as starting materials and proceeded under mild and environmentally friendly conditions to give good yields. This result enriches current methods of generating oxindole derivatives. All of these 3-methyl-3-aroyloxindole derivatives will be screened soon for biological activities.

Acknowledgements

We gratefully acknowledge Jiangsu University for financial support (1281290006).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra06810f

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