A highly efficient DBU-catalyzed green synthesis of spiro-oxindoles

Abstract

A DBU-catalyzed green synthesis of spiro-oxindoles with 100% atom economy has been developed under environmentally benign conditions. This highly efficient transformation could be explained by its superior carbon basicity combined with nucleophilicity of DBU compared to other bases.

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The spiro-oxindole nucleus is an important motif found in many natural products, synthetic pharmaceuticals and leading compounds, with significant biological and pharmaceutical activity (Fig. 1).¹ Thus, the construction of spiro-oxindole frameworks has always attracted much attention and many approaches have been developed for synthesis of spiro-oxindole skeletons with different functionality.^1,2 Among various naturally occurring as well as synthetic scaffolds, the 3,3′-pyrrolidonyl spiro-oxindole is an important family with wide biological activity.³ Recently, several elegant methodologies have been reported to achieve this nucleus either in an enantioselective or stereoselective way.⁴ In 2011, Wang and co-workers described a chiral bifunctional thiourea catalyzed highly efficient enantioselective synthesis of 3,3′-pyrrolidonyl spiro-oxindoles.⁵ In this case, the spiro-oxindoles were obtained with three contiguous stereocenters in excellent yields and trans-selectivity was observed for the two carboxylate groups (Scheme 1).

Fig. 1 Leading compounds containing spiro-oxindole cores.

Scheme 1 The previous report and our approach toward synthesis of 3,3′-pyrrolidonyl spiro-oxindoles.

Despite these advances, generally the presence of transition metal complexes or thiourea catalysts (>5 mol%) has been essential to realize this transformation, which has inevitably limited their applications because of practicability and the large amount of synthesis required. Moreover, relatively expensive and toxic solvents such as dichloromethane and toluene have often been used. Clearly, the development of novel protocols with environmentally benign and transition-metal free catalysts, shorter reaction times and less toxic solvents for the construction of spiro-oxindole skeletons is highly desirable, especially if the synthesis could be considered “green” and would be suitable for carrying out on a large scale.⁶ Herein, we report the highly efficient and green synthesis of 3,3′-pyrrolidonyl spiro-oxindoles in the presence of a catalytic amount of DBU (low to 0.5 mol%) in ethanol under mild conditions. Furthermore, in contrast with the former trans-selective transformation reported by Wang and co-workers, this DBU-catalyzed protocol is cis-selective for the two carboxylate groups.

Initially, several bases (20 mol%) were screened to evaluate their catalytic activity to promote the cyclization of methyleneindolinone (1a) and isothiocyanato ester (2a) at room temperature in dichloromethane. Among the bases examined, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provided 3a in the highest yield although with poor selectivity within 8 h. However, the attempts to use other organic bases such as triethylamine, diisopropyl ethylamine (DIPEA) and 1,4-diazabicyclo[2.2.2]octane (DABCO) afforded 3a in very low yields (Table 1, entries 1, 3 and 4.). The use of KO^tBu gave low yield too (Table 1, entry 5). Next, solvent screening showed that the relatively low polar solvents such as dichloroethane (DCE), tetrahydrofuran (THF), chloroform and methyl tert-butyl ether (MTBE) gave 3a in moderate to high yields but with very low stereoselectivity in the presence of DBU (Table 1, entries 6 to 9). In contrast, the use of more polar solvents such as N,N-dimethylformamide (DMF) and ethanol gave 3a almost in quantitative yields and better stereoselectivity (Table 1, entries 10 and 11). Notably, the reaction was completed immediately when 5 mol% of DBU was added to the DMF solution (Table 1, entry 12). Furthermore, even in the presence of 1 mol% of DBU, the reaction could be finished in 10 seconds in DMF (Table 1, entry 13). In contrast, the use of DABCO (1 mol%) in DMF still gave a very low yield (Table 1, entry 14). More gratifyingly, the use of cheaper and greener ethanol as solvent also gave the product in quantitative yield and 84 : 16 d.r. value in the presence of 1 mol% of DBU although with a longer reaction time (Table 1, entry 15). Moreover, when 0.5 mol% of DBU was used, the reaction could be finished in 3 minutes for DMF (Table 1, entry 16) and 8 h for ethanol (Table 1, entry 17). Based on these results, we used ethanol as the ideal solvent and DBU as the catalyst (1 mol%) for further studies.

Table 1 Optimization of the reaction conditions^a

Entry	Base (mol%)	Solvent	Time	Yield^b (%)	d.r.^c
a All reactions were carried out with 1a (1 mmol), 2a (1.1 mmol), solvent (3 mL) at rt under air unless otherwise noted.b Isolated yields of 3a for two diastereomers.c d.r. values were determined by ^1H-NMR analysis of crude products.
1	Et3N (20)	DCM	8 h	10%	60 : 40
2	DIPEA (20)	DCM	8 h	7%	—
3	DABCO (20)	DCM	8 h	8%	—
4	DBU (20)	DCM	8 h	86%	60 : 40
5	KO^tBu (20)	DCM	8 h	7%	—
6	DBU (20)	DCE	1.5 h	77%	60 : 40
7	DBU (20)	THF	1.5 h	84%	65 : 35
8	DBU (20)	CHCl3	1.5 h	70%	60 : 40
9	DBU (20)	MTBE	1.5 h	66%	56 : 44
10	DBU (20)	DMF	<5 s	97%	80 : 20
11	DBU (20)	EtOH	3 min	97%	84 : 16
12	DBU (5)	DMF	<5 s	97%	80 : 20
13	DBU (1)	DMF	10 s	97%	80 : 20
14	DABCO (1)	DMF	5 h	10%	—
15	DBU (1)	EtOH	1.5 h	96%	84 : 16
16	DBU (0.5)	DMF	3 min	96%	80 : 20
17	DBU (0.5)	EtOH	8 h	96%	84 : 16

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Under the above optimized conditions, various N-protecting groups of the methyleneindolinone bearing different electronic and steric parameters were examined (Table 2). As observed, the protecting groups did not affect the yield significantly and all of the corresponding products were obtained almost in quantitative yield, though with lower stereoselectivity than 1a (Table 2, entries 2 to 6).

Table 2 Screening of N-protecting groups for methyleneindolinone^a

Entry	R (methyleneindolinone)	Yield^b (%)	d.r.^c
a All reactions were carried out with 1a–8a (1 mmol), 2a (1.1 mmol), DBU (0.01 mmol) and ethanol (3 mL) at rt under air for 1.5 h.b Isolated yields for two diastereomers.c d.r. values were determined by ^1H-NMR analysis of crude products.
1	Me (1a)	96% (3a)	84 : 16
2	H (4a)	95% (9a)	65 : 35
3	Ac (5a)	97% (10a)	70 : 30
4	Bn (6a)	96% (11a)	65 : 35
5	Cbz (7a)	96% (12a)	60 : 40
6	Boc (8a)	96% (13a)	65 : 35

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With the optimal reaction condition in hand, we further investigated the substrate scope. A variety of methyleneindolinones (1) and isothiocyanato carbonyl compounds (2) were subjected to the reaction (Table 3). Both electron-donating and electron-withdrawing substituents at different positions on the aromatic ring of methyleneindolinones gave the corresponding products in excellent yields and good stereoselectivities. The major isomer for each reaction could be isolated in pure form with good yields (71% to 85%). The introduction of a bromo group on the phenyl ring afforded the products in higher yields and better selectivities (Table 3, 3e to 3h). An increase of the steric hindrance introduced by a bulkier ester group decreased the d.r. value of the corresponding product (Table 3, 3n). Moreover, isothiocyanato imide (2b) was also tolerated in this reaction and gave one isomer in 81% isolated yield and 5 : 1 d.r. value (Table 3, 3m).

Table 3 Substrate scope^a,b,c

a All reactions were carried out with 1 (1.0 mmol), 2 (1.1 mmol) and DBU (0.01 mmol) in ethanol (3 mL) at rt for 1.5 hours.b Isolated yields for one single isomer.c d.r. values were determined by ¹H-NMR analysis of crude products.

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The relative configurations of the 3,3′-pyrrolidonyl spiro-oxindoles were unambiguously determined by X-ray crystallography of 3b (Fig. 2).⁷ The relative configuration of 3b disclosed that the two carboxylate groups of the newly formed five-membered ring located on the same side, which is different from the former report developed by Wang and co-workers.^5a

Fig. 2 X-ray crystal structure of compound 3b.

A plausible reaction mechanism is proposed in Scheme 2. One possible explanation is that DBU acted only as a base (path A). The α-carbon atom of the α-isothiocyanatoacetate (2a) is deprotonated by DBU to afford the carbon anion intermediate. The carbon anion undergoes Michael addition to the electron-deficient methyleneindolinone (1a) to produce a cis-dicarboxylates intermediate (B). Subsequently, B undergoes rapid intramolecular cyclization leading to the nitrogen anion intermediate (C), which abstracts one hydrogen ion from the DBUH⁺ to produce the spiro-oxindole (3a) and regenerate the DBU to complete the catalytic cycle. However, the fact that a smaller amount of DBU (0.5 to 1 mol%) displayed a significantly enhanced rate compared with other bases indicated that DBU acted not only as a base but also as a nucleophilic trigger.⁸ Firstly, the addition of DBU to 1a generates the active intermediate A (Scheme 2, path B). Secondly, the protonated anion (2a′) attacks the zwitterionic intermediate A to produce intermediate B and regenerate DBU. Clearly, the cis-selective addition is preferred over the trans-addition according to the possible transition state (Scheme 2). Finally, intramolecular cyclization affords 3a and recovers DBU. The significant acceleration of the reaction by DBU compared to DABCO and other bases made us believe that path B probably was the superior reaction way.

Scheme 2 Plausible reaction mechanism.

To test the feasibility of this approach, we further conducted the large scale synthesis of 3f in 0.1 mol scale (Scheme 3). The reaction was finished in 2 h and delivered 34.6 g of 3f in single isomer without column chromatography. Moreover, most of the ethanol can be recovered by simple distillation.

Scheme 3 Large scale synthesis of spiro-oxindole 3f.

Conclusions

In conclusion, we have developed a highly efficient and green synthesis of 3,3′-pyrrolidonyl spiro-oxindoles in the presence of catalytic amounts of DBU, and ethanol was used as a “greener” solvent. Also, the reaction was very fast and clean. Moreover, the large scale synthesis could be finished in 2 hours at room temperature without column chromatography. We believe that DBU acted not only as a base but also as a nucleophilic trigger in this highly efficient transformation.

Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (no. 21172023), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110) for their financial supports.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1016506. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra08812c

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