Organocatalytic direct asymmetric vinylogous Mannich reaction of γ-butenolides with isatin-derived ketimines

Abstract

The first direct asymmetric vinylogous Mannich reaction of γ-butenolides with isatin-derived ketimines has been effectively realized promoted by a bifunctional quinidine-derived catalyst. A series of chiral 3-aminooxindole derivatives bearing adjacent tertiary and quaternary stereocenters with the butenolide moiety were obtained in excellent yields (up to 97%) and high enantioselectivities (up to 96% ee).

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Vinylogous addition¹ is one of the most important reactions for the direct formation of C–C bonds. Metal complexes² and organocatalysts³ promoted asymmetric vinylogous Mannich reactions of aldimines affording optically active δ-amino-α,β-unsaturated carbonyl compounds have been reported in the past decades. For the lower reactivity of ketimines compared with aldimines, the catalytic asymmetric vinylogous Mannich reaction of ketimines⁴ is still rare. A few examples of enantioselective vinylogous Mannich reaction of ketimines catalyzed by transition metal catalysts have been documented. The first example of the addition reaction between ketimines and siloxyfurans catalyzed by a chiral phosphine–AgOAc complex was revealed by Hoveyda and co-workers.^5a Recently, Nakamura and co-workers^5b reported an enantioselective vinylogous Mannich reaction of siloxyfurans with N-phosphinoyl ketimines promoted by Cu(OAc)₂ and cinchona alkaloid amide complex. Subsequently, Shibasaki^5c disclosed a direct catalytic asymmetric vinylogous Mannich reactions of γ-butenolides with N-thiophosphinoyl ketimines in the presence of a soft Lewis acid [Cu(CH₃CN₄)]PF₆–(R,R_P)-TANIAPHOS complex and a hard Brønsted base. Except for those above cases, a more straightforward and atom-economical vinylogous Mannich reaction of ketimines used as electrophilic component is still highly desirable. To the best of our knowledge, the small molecular catalytic direct asymmetric vinylogous Mannich reaction of ketimines has not been reported.

3-Aminooxindole, as a core structure, widely exists in a variety of bioactive molecules.⁶ Over the past years, a number of efforts have been made to enantioselective syntheses of those architectures.^7,8 In 2012, Wang^8b reported the Mannich reaction of N-alkoxycarbonyl ketimines derived from isatins with 1,3-dicarbonyl compounds catalyzed by tertiary amine thioureas, in which N-alkoxycarbonyl ketimines showed extremely high reactivity. Based on those backgrounds, we envisioned that the asymmetric direct vinylogous Mannich reaction of γ-butenolides and N-alkoxycarbonyl ketimines may be realized by bifunctional organocatalyst and afforded enantioenriched 3-aminooxindoles with multifunctional groups. We recognized that the tertiary amine group would activate γ-butenolide and the hydroxyl group would activate N-alkoxycarbonyl ketimine through hydrogen bondings. Thus the synergistic interactions would ensure high stereoselectivity in this transformation, affording the corresponding optically active products via a postulated transition state (TS) as shown in Fig. 1. For further enriching the methodology for the preparations of chiral 3-aminooxindole subunits and expanding our research on asymmetric syntheses of optical oxindole derivatives.⁹ Herein, we wish to present the first direct organocatalytic asymmetric vinylogous Mannich reaction of γ-butenolides¹⁰ and N-Boc ketimines derived from isatins (Fig. 2).

Fig. 1 Proposed transition state.

Fig. 2 Catalysts screened for the direct vinylogous Mannich reaction.

Initially, ketimine 1a and γ-butenolide 2a were chosen as substrates and carried out at 30 °C in DCM. A variety of organocatalysts were tested and the results were summarized in Table 1. In all cases, the addition proceeded smoothly while with poor enantioselectivities (Table 1, entries 1–5, 0–24% ee), when thiourea and squaramide catalysts derived from cinchona alkaloids were screened. Fairly good enantioselectivity (Table 1, entry 8, 64% ee) was observed in the presence of cinchonine 4h. The enantioselectivity was further improved to 74% ee (Table 1, entry 10) when quinine derived catalyst 4j was added. Finally, quinidine derived catalyst 4k gave the desired product with the best result (Table 1, entry 11, 85% ee) and was selected as the optimal catalyst.

Table 1 Catalyst screenings^a

Entry	Catalysts	t (h)	Yield^b (%)	dr^c	ee^d (%)
a Reactions were carried out with 1a (0.1 mmol), 2a (0.2 mmol) and catalyst 4 (10 mol%) in DCM (0.5 mL) at 30 °C.b Isolated yield.c Determined by HPLC analysis.d The ee value was determined by chiral HPLC analysis.
1	4a	53	81	75/25	2
2	4b	47	90	76/24	6
3	4c	53	85	77/23	0
4	4d	27	96	76/24	24
5	4e	48	75	78/22	3
6	4f	27	77	78/22	27
7	4g	27	85	79/21	51
8	4h	27	83	80/20	64
9	4i	27	78	80/20	59
10	4j	27	83	80/20	74
11	4k	24	90	79/21	85
12	4l	12	85	76/24	80
13	4m	12	94	75/25	84

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In the presence of catalyst 4k, the N-substituted groups, temperature, catalyst loading and solvent were then screened and the results were summarized in Table 2. The results showed that the N-substituted groups had slight effect on enantioselectivity (Table 2, entries 1–3) and N-Bn ketimine gave better enantioselectivity (88% ee, Table 2, entry 3). Lowering the temperature resulted in an increase of enantioselectivity (Table 2, entries 4–6) and the product was obtained with 94% ee at −30 °C (Table 2, entry 6). Lowering the catalyst loading, better enantioselectivity (Table 2, entry 7, 96% ee) was obtained in the presence of 5 mol % of 4k. Solvents slightly affected the enantioselectivity (Table 2, entries 7–12) and DCM was selected as the optimal solvent.

Table 2 Optimization of the reaction conditions^a

Entry	R	Solvent	t (h)	yield^b (%)	dr^c	ee^d
a Reactions were carried out with 1 (0.1 mmol), 2a (0.2 mmol) and catalyst 4k (10 mol%) in solvent (0.5 mL).b Isolated yield.c Determined by HPLC analysis.d The ee value was determined by chiral HPLC analysis.e At −10 °C.f At −20 °C.g At −30 °C.h 5 mol% of 4k was used.
1	Allyl	DCM	12	97	65/35	87
2	Boc	DCM	18	81	76/24	82
3	Bn	DCM	13	96	67/33	88
4^e	Bn	DCM	12	95	62/38	92
5^f	Bn	DCM	12	93	62/38	92
6^g	Bn	DCM	12	96	64/36	94
7^g^,^h	Bn	DCM	14	94	67/33	96
8^g^,^h	Bn	CHCl3	36	93	61/39	94
9^g^,^h	Bn	DCE	13	95	59/41	92
10^g^,^h	Bn	Toluene	26	91	58/42	94
11^g^,^h	Bn	THF	36	47	44/56	96
12^g^,^h	Bn	CH3CN	36	72	58/42	86

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Under the optimal reaction conditions, the substrate scope of the reaction was further explored to test the generality of this protocol (Table 3). Generally, good yields, moderate diastereoselectivities and high enantioselectivities were obtained for various substituents on the aromatic ring of ketimines 1 (Table 3, entries 1–14, 56–97% yield, 50/50–79/21 dr, 83–96% ee). N-substituted groups were also examined and good results were obtained (Table 3, entries 1–4, 66–97% yields, 68/32–79/21 dr, 83–94% ee). When 4-Br ketimine 1o was used, no product was detected (Table 3, entry 15), maybe for its larger steric hindrance. The optimal protocol was also expanded to 3,4-dibromofuran-2(5H)-one 2b with 20 mol% 4k as catalyst, and moderate to good yields, moderate diastereoselectivities and high enantioselectivities (Table 3, entries 16–26, 60–95% yield, 59/41–68/32 dr, 87–93% ee) were obtained.

Table 3 The substrate scope of direct asymmetric vinylogous Mannich reaction^a

Entry	1	2	3	t (h)	Yield^b (%)	dr^c	ee^d (%)
a Reactions were carried out with 1 (0.1 mmol), 2 (0.2 mmol) and catalyst 4k in DCM (0.5 mL) at −30 °C.b Isolated yield.c Determined by HPLC analysis.d The ee value was determined by chiral HPLC analysis.e At room temperature.f 20 mol% of 4k was used.
1	1a	2a	3aa	15	95	77/23	90
2	1b	2a	3ba	17	94	79/21	91
3	1c	2a	3ca	17	97	68/32	94
4	1d	2a	3da	39	66	75/25	83
5	1e	2a	3ea	14	94	67/33	96
6	1f	2a	3fa	25	69	58/42	90
7	1g	2a	3ga	16	77	50/50	91
8	1h	2a	3ha	24	87	61/39	88
9	1i	2a	3ia	24	77	60/40	90
10	1j	2a	3ja	36	95	65/35	92
11	1k	2a	3ka	44	93	64/36	91
12	1l	2a	3la	48	70	63/37	90
13	1m	2a	3ma	15	56	59/41	91
14^e	1n	2a	3na	48	92	65/35	88
15	1o	2a	3oa	216	NR	—	—
16^f	1b	2b	3bb	22	93	59/41	90
17^f	1c	2b	3cb	36	95	68/32	92
18^f	1e	2b	3eb	90	95	65/35	91
19^f	1f	2b	3fb	209	59	60/40	90
20^f	1g	2b	3gb	216	60	64/36	92
21^f	1h	2b	3hb	216	64	64/36	89
22^f	1i	2b	3ib	209	65	63/37	87
23^f	1j	2b	3jb	209	82	66/34	91
24^f	1k	2b	3kb	36	96	60/40	91
25^f	1l	2b	3lb	36	71	60/40	93
26^f	1p	2b	3pb	209	95	66/34	88

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A plausible mechanism was proposed for the direct asymmetric Mannich reaction (Fig. 3). The substrates were activated by the bifunctional catalyst. γ-Butenolide was activated by the tertiary amine group and C=N double bond of ketimine was activated by hydroxyl group of catalyst. To avoid steric repulsion between the R moiety of ketimine and the X substituent of dienolate, the Re face of dienolate attacked the Re face of C=N double bond to form the product. The absolute configuration was determined by an X-ray analysis of the single crystal of 3aa, which was assigned as (R, R).¹¹

Fig. 3 Proposed mechanism for the direct Mannich reaction.

Conclusions

In conclusion, we have first developed a highly effective organocatalytic direct vinylogous Mannich reaction of isatin-derived ketimine with γ-butenolide. A series of 3-aminooxindoles bearing adjacent quaternary and tertiary stereocenters were obtained in good yields and excellent enantioselectivities.

Notes and references

1. For selected reviews: (a) G. Casiraghi, L. Battistini, C. Curti, G. Rassu and F. Zanardi, Chem. Rev., 2011, 111, 3076; (b) S. E. Denmark, J. R. Heemstra, Jr and G. L. Beutner, Angew. Chem., Int. Ed., 2005, 44, 4682; (c) S. V. Pansare and E. K. Paul, Chem.–Eur. J., 2011, 17, 8770; (d) S. F. Martin, Acc. Chem. Res., 2002, 35, 895; (e) S. Bur and S. F. Martin, Tetrahedron, 2001, 57, 3221.
2. For selected examples: (a) S. F. Martin and O. D. Lopez, Tetrahedron Lett., 1999, 40, 8949; (b) E. L. Carswell, M. L. Snapper and A. H. Hoveyda, Angew. Chem., Int. Ed., 2006, 45, 7230; (c) A. Yamaguchi, S. Matsunaga and M. Shibasaki, Org. Lett., 2008, 10, 2319; (d) H. Mandai, K. Mandai, M. L. Snapper and A. H. Hoveyda, J. Am. Chem. Soc., 2008, 130, 17961; (e) A. S. González, R. G. Arrayás, M. R. Rivero and J. C. Carretero, Org. Lett., 2008, 10, 4335; (f) Z.-L. Yuan, J.-J. Jiang and M. Shi, Tetrahedron, 2009, 65, 6001; (g) H.-P. Deng, Y. Wei and M. Shi, Adv. Synth. Catal., 2009, 351, 2897; (h) Q.-Y. Zhao, Z.-L. Yuan and M. Shi, Adv. Synth. Catal., 2011, 353, 637; (i) Q.-Y. Zhao and M. Shi, Tetrahedron, 2011, 67, 3724; (j) L. Zhou, L.-L. Lin, J. Ji, M.-S. Xie, X.-H. Liu and X.-M. Feng, Org. Lett., 2011, 10, 3056.
3. For selected examples: (a) D. Uraguchi, K. Sorimachi and M. Terada, J. Am. Chem. Soc., 2004, 126, 11804; (b) M. Sickert and C. Schneider, Angew. Chem., Int. Ed., 2008, 47, 3631; (c) D. S. Giera, M. Sickert and C. Schneider, Org. Lett., 2008, 10, 4259; (d) T. Akiyama, Y. Honma, J. Itoh and K. Fuchibe, Adv. Synth. Catal., 2008, 350, 399; (e) M. Sickert, F. Abels, M. Lang, J. Sieler, C. Birkemeyer and C. Schneider, Chem.–Eur. J., 2010, 16, 2806; (f) Y.-L. Guo, J.-F. Bai, L. Peng, L.-L. Wang, L.-N. Jia, X.-Y. Luo, F. Tian, X.-Y. Xu and L.-X. Wang, J. Org. Chem., 2012, 77, 8338.
4. For selected reviews: (a) M. Shibasaki and M. Kanai, Chem. Rev., 2008, 108, 2853; (b) O. Riant and J. Hannedouche, Org. Biomol. Chem., 2007, 5, 873; (c) B. Karimi, D. Enders and E. Jafari, Synthesis, 2013, 45, 2769; for selected examples: (d) N. Hara, R. Tamura, Y. Funahashi and S. Nakamura, Org. Lett., 2011, 13, 1662; (e) R. Shintani, M. Takeda, Y.-T. Soh, T. Ito and T. Hayashi, Org. Lett., 2011, 13, 2977; (f) T. Kano, S.-H. Song, Y. Kubota and K. Maruoka, Angew. Chem., Int. Ed., 2012, 51, 1191; (g) F.-G. Zhang, H. Ma, J. Nie, Y. Zheng, Q.-Z. Gao and J.-A. Ma, Adv. Synth. Catal., 2012, 354, 1422; (h) H.-N. Yuan, S. Wang, J. Nie, W. Meng, Q.-W. Yao and J.-A. Ma, Angew. Chem., Int. Ed., 2013, 52, 3869; (i) L. Yin, Y.-M. Bao, N. Kumagai and M. Shibasaki, J. Am. Chem. Soc., 2013, 135, 10338; (j) M. G. Núňez, A. J. M. F. Farley and D. J. Dixon, J. Am. Chem. Soc., 2013, 135, 16348.
5. (a) L. C. Wieland, E. M. Vieira, M. L. Snapper and A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131, 570; (b) M. Hayashi, M. Sano, Y. Funahashi and S. Nakamura, Angew. Chem., Int. Ed., 2013, 52, 5557; (c) L. Yin, H. Takada, N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2013, 52, 7310.
6. For selected reviews: (a) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945; (b) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (c) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (d) J. E. M. N. Klein and R. J. K. Taylor, Eur. J. Org. Chem., 2011, 6821.
7. For selected reviews and examples: (a) R. Dalpozzo, G. Bartoli and G. Bencivenni, Chem. Soc. Rev., 2012, 41, 7247; (b) K. Shen, X.-H. Liu, L.-L. Lin and X.-M. Feng, Chem. Sci., 2012, 3, 327; (c) B.-D. Cui, W.-Y. Han, Z.-J. Wu, X.-M. Zhang and W.-C. Yuan, J. Org. Chem., 2013, 78, 8833; (d) Y.-Q. Zhang, Y.-A. Yuan, G.-S. Liu and H. Xu, Org. Lett., 2013, 15, 3910; (e) L. Ren, X.-L. Lian and L.-Z. Gong, Chem.–Eur. J., 2013, 19, 3315; (f) F.-L. Hu, Y. Wei, M. Shi, S. Pindic and G.-G. Li, Org. Biomol. Chem., 2013, 11, 1921.
8. (a) Q.-X. Guo, Y.-W. Liu, X.-C. Li, L.-Z. Zhong and Y.-G. Peng, J. Org. Chem., 2012, 77, 3589; (b) W.-J. Yan, D. Wang, J.-C. Feng, P. Li, D.-P. Zhao and R. Wang, Org. Lett., 2012, 14, 2512; (c) J.-C. Feng, W.-J. Yan, D. Wang, P. Li, Q.-T. Sun and R. Wang, Chem. Commun., 2012, 48, 8003; (d) N. Hara, S. Nakamura, M. Sano, R. Tamura, Y. Funahashi and N. Shibata, Chem.–Eur. J., 2012, 18, 9276; (e) H. Lv, B. Tiwari, J.-M. Mo, C. Xing and Y.-G. Chi, Org. Lett., 2012, 14, 5412; (f) D. Wang, J.-Y. Liang, J.-C. Feng, K.-R. Wang, Q.-T. Sun, L. Zhao, D. Li, W.-J. Yan and R. Wang, Adv. Synth. Catal., 2013, 355, 548; (g) Y.-L. Liu and J. Zhou, Chem. Commun., 2013, 49, 4421; (h) X.-J. Chen, H. Chen, X. Ji, H.-L. Jiang, Z.-J. Yao and H. Liu, Org. Lett., 2013, 15, 1846; (i) S. Nakamura, K. Hyodo, M. Nakamura, D. Nakane and H. Masuda, Chem.–Eur. J., 2013, 19, 7304; (j) T.-Z. Li, X.-B. Wang, F. Sha and X.-Y. Wu, Tetrahedron, 2013, 69, 7314; (k) X.-B. Wang, T.-Z. Li, F. Sha and X.-Y. Wu, Eur. J. Org. Chem., 2014, 739.
9. (a) Q.-L. Wang, L. Peng, F.-Y. Wang, M.-L. Zhang, L.-N. Jia, F. Tian, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2013, 49, 9422; (b) L.-L. Wang, J.-F. Bai, L. Peng, L.-W. Qi, L.-N. Jia, Y.-L. Guo, X.-Y. Luo, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2012, 48, 5175; (c) L.-L. Wang, L. Peng, J.-F. Bai, L.-N. Jia, X.-Y. Luo, Q.-C. Huang, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2011, 47, 5593; (d) L.-L. Wang, L. Peng, J.-F. Bai, Q.-C. Huang, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2010, 46, 8064.
10. For selected examples on vinylogous aldol reaction of furanones: (a) K. D. Sarma, J. Zhang and T. T. Curran, J. Org. Chem., 2007, 72, 3311; (b) H. Ube, N. Shimada and T. Terada, Angew. Chem., Int. Ed., 2010, 49, 1858; (c) J. Luo, H.-F. Wang, X. Han, L.-W. Xu, J. Kwiatkowski, K.-W. Hang and Y.-X. Lu, Angew. Chem., Int. Ed., 2011, 50, 1861; (d) Y. Yang, K. Zhang, J.-N. Zhao, J. Shi, L.-L. Lin, X.-H. Liu and X.-M. Feng, J. Org. Chem., 2012, 75, 5382; (e) S. V. Pansare and E. K. Paul, Chem. Commun., 2011, 47, 1027; (f) A. Claraz, S. Oudeyer and V. Levacher, Adv. Synth. Catal., 2013, 355, 841; selected vinylogous Michael addition of furanones: (g) B. M. Trost and J. Hitce, J. Am. Chem. Soc., 2009, 131, 4572; (h) H.-C. Huang, F. Yu, Z.-C. Jin, W.-J. Li, W.-B. Wu, X.-M. Liang and J.-X. Ye, Chem. Commun., 2010, 46, 5957; (i) J.-F. Wang, C. Qi, Z.-M. Ge, T.-M. Cheng and R.-T. Li, Chem. Commun., 2010, 46, 2124; (j) M. Terada and K. Ando, Org. Lett., 2011, 13, 2026; (k) L. Yin, H. Takasa, S.-Q. Lin, N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2013, 53, 5327.
11. ESI.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 985942. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra04824e

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