A formal intermolecular [4 + 1] cycloaddition reaction of 3-chlorooxindole and o-quinone methides: a facile synthesis of spirocyclic oxindole scaffolds

Abstract

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions. The products could be obtained in excellent yields with numerous types of 3-chlorooxindole. This methodology features mild reaction conditions, high atom-economy and broad substrate scope.

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions.

The structural diversity of spirocyclic oxindole scaffolds is a reason for their frequent occurrence in many relevant natural products and medicinal agents (Fig. 1).¹ In particular, natural spirocyclic-2-oxindole scaffolds have been proven to exhibit a broad range of biological activities and have attracted increasing attention in the synthetic field. For instance, XEN 907 is a novel pentacyclic spirooxindole with excellent activities as sodium channel blockers.² Due to their unique structure and intriguing biological activity, numerous methodologies have been developed for the construction of these privileged frameworks.³ For example, in the past few years, transition-metal catalyzed or organocatalytic [3 + 2] cycloaddition reactions have been developed for the synthesis of spirocyclic oxindole scaffolds.⁴ Despite the emergence of these elegant approaches, exploiting new strategies for the construction of spirocyclic oxindole derivatives is still highly desirable.

Fig. 1. Examples of biologically active spirocyclic oxindole scaffolds.

Ortho-quinone methides (o-QMs) as highly reactive versatile intermediates have been of great interest to the chemical and biological community.⁵o-QMs react with various classes of reagents by three typical reaction pathways: 1,4-addition of nucleophiles, [4 + 2] cycloaddition with dienophiles and oxa-6π-electrocyclization.⁶ Because most o-QMs are unstable, these reactions generally depend on the reaction conditions used for the generation of o-QMs in situ. Rokita et al. reported that o-silylated phenols when exposed to fluoride could also produce o-QMs under mild reaction conditions.⁷

Because of the dual nature (nucleophilic/electrophilic) of the C-3 position, 3-chlorooxindole serves as a highly reactive starting material in the synthesis of spirocyclic oxindole scaffolds. The introduction of a chloro group at the C-3 position of indoles serves as an excellent leaving group in favour of the subsequent cyclization. In addition, this also increases the acidity of the C–H bond for directly entering the C-3 quaternary centers.⁸ Inspired by this reactivity profile, 3-chlorooxindoles have been successfully utilized for [2 + 1]⁹ and [4 + 1]¹⁰ cyclization to synthesize spirocyclic oxindole scaffolds (Fig. 2).

Fig. 2. Representation of the synthesis and applications of 3-chlorooxindoles.

We designed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindoles via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-QMs, which were generated under mild conditions. In this study, using TBAF as the fluoride source and base ensures that the one-pot domino reaction will occur in mild reaction conditions, with high atom-economy and broad substrate scope.

Initially, we carried out optimization studies by examining the reaction between O-silylated phenol 2a and 3-chlorooxindole 1a. Indeed, when TBAF was employed as the fluoride source, a smooth [4 + 1] cyclization reaction occurred, affording the spirocyclic oxindole product 3a with 75% yield (entry 1, Table 1). This indicated that our design for the [4 + 1] cyclization reaction required is feasible. When the molar concentration of substrate 2a was raised to 1.5 equiv., the product yield increased to 87% (entry 2, Table 1). Other fluoride sources were then evaluated and TBAF was found to be the optimal one; however, when CsF was employed in this reaction, the product yield decreased to 11% (entry 4, Table 1). When the loading quantity of TBAF was decreased to 3.0 equiv., the desired product 3a yield decreased to 80% (entry 5, Table 1). Finally, numerous solvents including CHCl₃, THF, toluene, DMF, MeCN, and MeOH were tested at room temperature, revealing THF as the optimal solvent for this reaction, affording the spirocyclic oxindole product 3a with 94% yield (entries 6–11, Table 1).

Optimization of the reaction conditions^a.

Entry	F− source	X	Y	Solvent	Temp (°C)	Yieldb
1	TBAFc	1.2	4.0	DCM	rt	75%
2	TBAF	1.5	4.0	DCM	rt	87%
3	TBAF	2.0	4.0	DCM	rt	85%
4	CsF	1.5	4.0	DCM	rt	11%
5	TBAF	1.5	3.0	DCM	rt	80%
6	TBAF	1.5	4.0	CHCl3	rt	83%
7	TBAF	1.5	4.0	THF	rt	94%
8	TBAF	1.5	4.0	Toluene	rt	90%
9	TBAF	1.5	4.0	DMF	rt	72%
10	TBAF	1.5	4.0	MeCN	rt	84%
11	TBAF	1.5	4.0	MeOH	rt	ND

^aReaction conditions: 1a (0.3 mmol), solvent (3.0 mL), 6 h.

^bIsolated yield.

^cTBAF (1 M in THF solution).

With the optimal conditions known, we next investigated the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenol 2a as a representative (Table 2). First, we examined the substituents on the benzene ring of the indole core regardless of the electronic properties, such as 4-Me, 5-Me, 6-Me, 7-Me, 5-OMe, 7-OMe, 4-Cl, 5-Cl, 6-Cl, 7-Cl, 4-Br, 5-Br, 6-Br, 7-Br, 4-F, 5-F and 6-F. We found that all the reactions could proceed smoothly, affording the corresponding products generally with good yields (62–87%). Second, the substrates 1s with hydrogen atoms linked to the nitrogen were all tolerated to furnish the corresponding products in moderate yields (65%). Finally, different alkyl substituents at the nitrogen position of 3-chlorooxindole 1 did not affect the outcome significantly and gave the products 3t–3v in well-tolerated yields. For example, the reaction of the ethyl-substituted derivative 1t with 2a afforded the desired product 3t in 75% yield.

Substrate scope^a,b.

^aReaction conditions: 1 (0.3 mmol), 2a (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.

^bIsolated yields.

Next, we also explored the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenols 2a′ (Table 3). When the substrate 2a′ was substituted with a chlorine atom, the yield of the desired product 3 yield decreased to 50–62%. For all the obtained products, the substrates 2a had an influence on reaction yield.

Substrate scope^a,b.

^aReaction conditions: 1 (0.3 mmol), 2a′ (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.

^bIsolated yields.

On the basis of above-mentioned results, a plausible mechanism for this formal [4 + 1] cycloaddition reaction is depicted in Scheme 1. Initially, the highly reactive o-QMs are generated via the desilylation/elimination reaction. Then, 3-chlorooxindole 1a as a nucleophile attacks the external carbon of o-QMs, affording zwitterion Int-1. Finally, the zwitterion Int-1 loses one molecular HCl through a nucleophilic attack, yielding the spirocyclic oxindole product 3a.

Scheme 1. Possible mechanism.

Conclusions

In summary, we have established a formal [4 + 1] cycloaddition reaction of 3-chlorooxindole with O-silylated phenols. This transformation provides an efficient method for the synthesis of the spirocyclic oxindoles in good yields (up to 94%). This methodology features mild reaction conditions and a broad substrate scope.

Conflicts of interest

There are no conflicts to declare.