Efficient enantioselective synthesis of CF₂H-containing dispiro[benzo[b]thiophene-oxindole-pyrrolidine]s via organocatalytic cycloaddition

Abstract

An efficient and practical organocatalytic asymmetric [3 + 2] cycloaddition of difluoromethylated ketoimines and methyleneindolinones catalyzed by a quinine-derived squaramide has been disclosed. Under mild conditions, a broad range of CF₂H-containing dispiro[benzo[b]thiophene-oxindole-pyrrolidine]s bearing four adjacent chiral centers including two vicinal spiro quaternary stereocenters were obtained in high yields (up to 99% yield) with excellent diastereoselectivities (>20 : 1 dr, in all cases) and enantioselectivities (up to 99% ee).

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The incorporation of F into compounds is considered a useful approach to improve the physical, chemical and biological properties of bioactive molecules.¹ Besides the general advantages brought about by the replacement of a hydrogen atom by fluorine, the double displacement of the H atom by the F atom in the –methyl group makes the resulting –CF₂H exhibit slight acidity and can act as a H-bond donor group.² So, it is becoming increasingly attractive to use –CF₂H as a bioisostere of hydroxyl (OH) or thiol (SH) to optimize drug performance.³ At the point of the molecular mechanism of drug action, a suitable installation of –CF₂H imparted into the molecule on the rule of steric complementarity is associated with enhanced binding affinity. Therefore, the asymmetric synthesis of the CF₂H-containing molecule is highly desired in medicinal research, especially application in the improvement of the moderator of protein–protein interactions because an additional H-bond is of benefit to drug binding with the flat feature protein target.⁴

Natural products with the 3,3′-spirooxindole skeleton have shown various bioactivities, including insecticidal, cytotoxic, anthelmintic, calmodulin inhibition, osteoclast inhibition, antibacterial, and analgesic properties.⁵ Considerable efforts have been devoted to the construction of oxindole derivatives and multifunctional compounds with fascinating biological activities were obtained.⁶ For example, both compounds MI77301 and A (Fig. 1) can be used as non-peptide inhibitors of P53-MDM2 protein–protein interactions, and compound A has advanced to phase I clinical trials.⁷ Spurred by the demands of drug research, plenty of groups have been incorporated into the 3,3′-pyrrolidinyl-spirooxindole skeleton in an asymmetric manner.⁸ Attracted by the properties of molecules with fluorine groups, lots of asymmetric syntheses of CF₃-containing molecules with 3,3′-pyrrolidinyl-spirooxindole motifs have been reported.⁹ Recently, a dual inhibitor of molecule B (Fig. 1) has been discovered.¹⁰ However, for –CF₂H, there remains a blank area. Herein, we wish to describe a new approach in the synthesis of CF₂H-containing 3,3′-pyrrolidinyl-spirooxindoles.

Fig. 1 Selected examples of biologically relevant compounds.

Synthetically, to construct a five-member nitrogen heterocycle especially for a spirocyclic pyrrolidine, 1,3-dipolar cycloaddition is one of the most direct methods.¹¹ In this context, a polyfunctional pyrrolidine can be furnished by a N-central 1,3-dipole under appropriate conditions. Even thus, considering the great differences in the electronic property, group radius and acidity between –CF₃ and –CF₂H, there is no CF₂H-containing 1,3-dipole that has been reported to date.¹² Most recently, we have developed a CF₂H-containing ketoimine by the condensation of thioisatin with difluoroethylamine.¹³ Promoted by a Brønsted base, the deprotonation group in methylene of thioisatin-derived α-(difluoromethyl)imine can be achieved. We supposed that the resulting methylene ylide intermediate could be used as a 1,3-dipole and may be applied to construct CF₂H-containing 3,3′-pyrrolidinyl-dispirooxindoles.

To verify our hypothesis, methyleneindolinone 2a was selected as a dipolarophile. Interestingly, the cycloaddition of imine 1a with 2a proceeded smoothly in the presence of cinchonidine-derived thiourea C1 (Fig. 2) and the product was obtained in 73% ee and 75% yield (Table 1, entry 1). When thiourea C2 (Fig. 2) derived from quinine was the catalyst, an improved yield and ee were observed. When squaramide C7 was employed, the yield and ee of the product increased to 90% and 94%, respectively. Further screening provided the cycloadduct in 96% ee and 89% yield (Table 1, entry 8) when squaramide C8 (Fig. 2) was selected as the catalyst. The effects of the solvent and temperature were then evaluated with C8 as the catalyst. A 95% yield in 98% ee at 0 °C with DCE (1,2-dichloroethane) was obtained as a result.

Fig. 2 Typical catalysts.

Table 1 Screening of reaction conditions^a

Entry	Solvent	Catalyst	T (°C)	Time (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: catalyst (0.01 mmol, 10 mol%), 1a (0.10 mmol), 2a (0.12 mmol), solvent (1 ml), and the product dr values were determined by chiral phase HPLC or ^1H NMR and ^19F NMR (>20 : 1 dr, in all cases). b Isolated yield. c Determined by chiral phase HPLC.
1	Tol	C1	25	3	75	73
2	Tol	C2	25	2.5	85	89
3	Tol	C3	25	4	80	81
4	Tol	C4	25	2	89	85
5	Tol	C5	25	3	76	−69
6	Tol	C6	25	3	86	−83
7	Tol	C7	25	3	90	94
8	Tol	C8	25	3	89	96
9	Tol	C8	0	4	92	97
10	Tol	C8	−10	4	89	94
11	DCM	C8	0	8	90	98
12	DCE	C8	0	4	95	98
13	PhCl	C8	0	4.5	91	97
14	THF	C8	0	5.5	87	94
15	MTBE	C8	0	5	94	94

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Under the optimized conditions, the scope of the substrates was subsequently investigated. As shown in Scheme 1, methyleneindolinones substituted at the 1-position showed good reactivity. Partially because of the poor solubility, the addition was completed in a prolonged time even at room temperature for methylpolylinone without substitution at position 1. Strikingly, R² groups had no significant effect on the reaction, and the single crystals of 3aa and 3ag showed that the same reaction pattern had occurred.

Scheme 1 The variation of PGs on methyleneindolinones. Reaction conditions: 1a (0.10 mmol), 2 (0.12 mmol), and catalyst C8 (10 mol%) in DCE (1 ml) at 0 °C; the reaction time required for each substrate is given. The yields of the isolated products are reported. The ee and dr values were determined by HPLC or ¹H NMR and ¹⁹F NMR. ^a Furnished at room temperature.

The following analyses were focused on substituents on the benzene ring of methyleneindolinones and the results are shown in Scheme 2. Both electron-donating and electron-withdrawing substituents of 5-alkenyl methyleneindolinones worked well with excellent stereoselectivities. Compared with the 5, 6 and 7 positions, a substituent at the 4-position showed significantly lowered reactivity. For example, when 4-chloro-methyleneindolinone (Scheme 2, 3ah) was subjected to the standard conditions, the reaction completed within 24 hours, while for substrates substituted at the 5-position (Scheme 2, 3aj) and the 7-position (Scheme 2, 3ar), only 2.5 (Scheme 2, 3ah) and 1.5 h were needed. For 6-methoxy 3ap (Scheme 2), a very slow reaction was observed (28 h). Disubstituted substrates were generally well tolerated under standard conditions.

Scheme 2 Substrate scope of methyleneindolinones. Reaction conditions: 1a (0.10 mmol), 2 (0.12 mmol), and catalyst C8 (10 mol%) in DCE (1 ml) at 0 °C; the reaction time required for each substrate is given. The yields of the isolated products are reported. The ee and dr values were determined by HPLC or ¹H NMR and ¹⁹F NMR.

Furthermore, the generality of dipoles 1 was evaluated and the results are presented in Scheme 3. In general, electron-donating groups showed lower reactivity (Scheme 3, 3ca, 3ga, 3ha) while electron-withdrawing groups showed good reactivity (Scheme 3, 3ba, 3da, 3ea, 3fa). Disubstituted (Scheme 3, 3ja, 3ka) and polyaryl substrates (Scheme 3, 3ia) all performed well with excellent yields and stereoselectivities.

Scheme 3 Substrate scope of ketoimines. Reaction conditions: 1 (0.10 mmol), 2a (0.12 mmol), and catalyst C8 (10 mol%) in DCE (1 ml) at 0 °C; the reaction time required for each substrate is given. The yields of the isolated products are reported. The ee and dr values were determined by HPLC or ¹H NMR and ¹⁹F NMR.

Encouraged by the good results of ester substrates, carbonyl aryl methyleneindolinones were also examined. As shown in Scheme 4, various aryl ketones were well tolerated and gave the corresponding cycloaddition products with good yields and stereoselectivities. Heterocyclic and naphthalene substrates (Scheme 4, 5ah, 5ai and 5aj) also worked well. Methyleneindolinones were also compatible, giving the product in 80% yield with >20 : 1 dr and 91% ee.

Scheme 4 The variation of methyleneindolinones. Reaction conditions: 1a (0.10 mmol), 4 (0.12 mmol), and catalyst C8 (10 mol%) in DCE (1 ml) at 0 °C; the reaction time required for each substrate is given. The yields of the isolated products are reported. The ee and dr values were determined by HPLC or ¹H NMR and ¹⁹F NMR.

As indicated in Scheme 5, a gram-scale synthesis was carried out to demonstrate the utility of the present process. In the presence of 10 mol% C8, 1a (2.5 mmol, 0.567 g) and 2a (3.0 mmol, 0.693 g) were consumed within 4.5 h to give 3aa in 92% yield with 96% ee, and a further N-methylation product of 6a was obtained without racemization in the presence of potassium carbonate. Furthermore, 3aa was converted to optically pure sulfone 7a in 50% yield with 94% ee by treatment with HCO₂H/H₂O₂. Pleasingly, a scale-up reaction between 1a and 2g still proceeded well and furnished the desired product 3ag with almost untouched yield (84% yield) and enantioselectivity (96% ee).

Scheme 5 Gram-scale experiments and further transformations.

Control experiments were subsequently performed to shed light on the reaction mechanism. As shown in Scheme 6, when phenyl or methyl 3-alkenyloxindole was used, this reaction did not occur under standard conditions. When adjusted to room temperature, no reaction was observed either. A possible reaction mechanism was suggested on the basis of control experiments and the absolute configuration of 3aa and 3ag (Scheme 1). The potential transition mechanism as shown in Fig. 3, the acidic N-2,2-difluoroethyl thioisatin ketoimines hydrogen bonded with the basic tertiary N atom of the catalyst to form a five-membered ring, concurrently, the two squaramide N–H bonds of catalyst hydrogen bonding with the methyleneindolinones. The chiral bifunctional squaramide-tertiary amine catalyst anchored the two substrates close to each other and the two consecutive re-face additions delivered the corresponding products with X-ray configurations.

Scheme 6 Control experiments. Reaction conditions: 1a (0.10 mmol), 2aa or 2ab (0.12 mmol), and catalyst C8 (10 mol%) in DCE (1 ml) at 0 °C. ^a Stirred at room temperature.

Fig. 3 Potential transition mechanism.

Conclusions

In summary, a novel kind of CF₂H-containing 3,3′-dispiro-pyrrolidine-3,3′-oxindole has been achieved through an organocatalyzed 1,3-dipole reaction. In the presence of cinchona alkaloid-derived bifunctional squaramide, the cycloaddition of thioisatin-derived α-(difluoromethyl)imine and methyleneindolinone carbonyl gave the cycloadducts smoothly.

Various esters and ketones were well tolerated and, in general, gave the products in excellent yields, ee and dr.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

We are grateful for the grants from the National Natural Science Foundation of China (no. 81872723 and 82073679).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2087188 and 2087189. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo01392k

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