Cinchona Alkaloid Derivative Organocatalyzed Enantioselective Cascade Knoevenagel/Michael/Cyclization of Three-Components

doi:10.6023/cjoc202502037

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (12): 4443-4452.DOI: 10.6023/cjoc202502037 Previous Articles Next Articles

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金鸡纳碱衍生物有机催化三组分的不对称Knoevenagel/Michael/串联环化反应

金言^a^,^b^,^†, 穆宏文^a^,^b^,^†, 孙玉虹^a^,^b, 王黎明^a^,^*(), 金瑛^a^,^b^,^*()

^a 吉林医药学院药学院吉林吉林 132013
^b 延边大学药学院吉林延吉 133000

收稿日期:2025-05-11 修回日期:2025-05-22 发布日期:2025-06-19
通讯作者: 王黎明, 金瑛
作者简介:
^† 共同第一作者
基金资助:
吉林省科技厅医药健康重点研发(20250204067YY); 吉林省教育厅(JJKH20240595KJ); 吉林医药学院研究生创新(2023zyc02)

Cinchona Alkaloid Derivative Organocatalyzed Enantioselective Cascade Knoevenagel/Michael/Cyclization of Three-Components

Yan Jin^a^,^b, Hongwen Mu^a^,^b, Yuhong Sun^a^,^b, Liming Wang^a^,^*(), Ying Jin^a^,^b^,^*()

^a Department of Pharmacy, Jilin Medical University, Jilin, Jilin 132013
^b Department of Pharmacy, Yanbian University, Yanjin, Jilin 133000

Received:2025-05-11 Revised:2025-05-22 Published:2025-06-19
Contact: Liming Wang, Ying Jin
About author:
†These authors contributed equally to this work
Supported by:
the Key Project of Medicine and Health of Jilin Province(20250204067YY); the Department of Education of Jilin Province(JJKH20240595KJ); Postgraduate Innovation Program Project of Jilin Medical University(2023zyc02)

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Abstract

(S,S)-Quinine thiourea derivatives were used for the three component asymmetric Knoevenagel/Michael/cycli- zation cascade reaction of different isatin, maleimide, and malononitrile in organic catalysis. Under the optimal catalyst conditions, chiral spiro(indoline-3,4-pyrrolo[3,4-b]pyridine) was obtained with a chemical yield of 75% to 86% and a maximum enantioselectivity of 92% ee. This study has expanded the range of catalyst types and substrates for this reaction.

Key words: organocatalysis, enantioselective synthesis, Knoevenagel/Michael/cyclization, spiro[indoline-3,4-pyrrolo[3,4- b]pyridine]

Cite this article

Yan Jin, Hongwen Mu, Yuhong Sun, Liming Wang, Ying Jin. Cinchona Alkaloid Derivative Organocatalyzed Enantioselective Cascade Knoevenagel/Michael/Cyclization of Three-Components[J]. Chinese Journal of Organic Chemistry, 2025, 45(12): 4443-4452.

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References 10

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Entry	R¹, R²	R³, R⁴	Product	Yield^b/%	ee^c/%
1	H, Bn (2a)	ⁱBu, Ph (3a)	4aa	86	42
2	5-Me, Bn (2b)	ⁱBu, Ph (3a)	4ba	79	44
3	5-F, Bn (2c)	ⁱBu, Ph (3a)	4ca	86	92
4	5-NO₂, Bn (2d)	ⁱBu, Ph (3a)	4da	80	65
5	6-Cl, Bn (2e)	ⁱBu, Ph (3a)	4ea	82	36
6	7-Cl, Bn (2f)	ⁱBu, Ph (3a)	4fa	81	32
7	H, Me (2g)	ⁱBu, Ph (3a)	4ga	83	51
8	5-Cl, Me (2h)	ⁱBu, Ph (3a)	4ha	82	82
9	5-Br, Me (2i)	ⁱBu, Ph (3a)	4ia	81	64
10	H, H (2j)	ⁱBu, Ph (3a)	4ja	79	16
11	5-F, Bn (2c)	Bn, Ph (3b)	4cb	81	51
12	H, Me (2g)	Bn, Ph (3b)	4gb	77	50
13	5-Cl, Me (2h)	Bn, Ph (3b)	4hb	80	77
14	5-F, Bn (2d)	ⁱBu, 3-ClC₆H₄ (3c)	4cc	80	80
15	5-Cl, Me (2h)	ⁱBu, 3-ClC₆H₄ (3c)	4hc	82	80
16	5-Br, Me (2i)	ⁱBu, 3-ClC₆H₄ (3c)	4ic	77	63
17	5-Cl, Me (2h)	ⁱBu, 4-ClC₆H₄ (3d)	4hd	75	53
18	5-Br, Me (2i)	ⁱBu, 4-ClC₆H₄ (3d)	4id	80	70

Entry	R¹, R²	R³, R⁴	Product	Yield^b/%	ee^c/%
1	H, Bn (2a)	ⁱBu, Ph (3a)	4aa	86	42
2	5-Me, Bn (2b)	ⁱBu, Ph (3a)	4ba	79	44
3	5-F, Bn (2c)	ⁱBu, Ph (3a)	4ca	86	92
4	5-NO₂, Bn (2d)	ⁱBu, Ph (3a)	4da	80	65
5	6-Cl, Bn (2e)	ⁱBu, Ph (3a)	4ea	82	36
6	7-Cl, Bn (2f)	ⁱBu, Ph (3a)	4fa	81	32
7	H, Me (2g)	ⁱBu, Ph (3a)	4ga	83	51
8	5-Cl, Me (2h)	ⁱBu, Ph (3a)	4ha	82	82
9	5-Br, Me (2i)	ⁱBu, Ph (3a)	4ia	81	64
10	H, H (2j)	ⁱBu, Ph (3a)	4ja	79	16
11	5-F, Bn (2c)	Bn, Ph (3b)	4cb	81	51
12	H, Me (2g)	Bn, Ph (3b)	4gb	77	50
13	5-Cl, Me (2h)	Bn, Ph (3b)	4hb	80	77
14	5-F, Bn (2d)	ⁱBu, 3-ClC₆H₄ (3c)	4cc	80	80
15	5-Cl, Me (2h)	ⁱBu, 3-ClC₆H₄ (3c)	4hc	82	80
16	5-Br, Me (2i)	ⁱBu, 3-ClC₆H₄ (3c)	4ic	77	63
17	5-Cl, Me (2h)	ⁱBu, 4-ClC₆H₄ (3d)	4hd	75	53
18	5-Br, Me (2i)	ⁱBu, 4-ClC₆H₄ (3d)	4id	80	70

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金鸡纳碱衍生物有机催化三组分的不对称Knoevenagel/Michael/串联环化反应

Cinchona Alkaloid Derivative Organocatalyzed Enantioselective Cascade Knoevenagel/Michael/Cyclization of Three-Components

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Entry	Catalyst	Yield^b/%	ee^c/%
1	1a	73	4
2	1b	75	7
3	1c	73	8
4	1d	81	30
5	1e	80	29
6	1f	76	12
7	1g	70	3
8	1h	71	4
9	1i	72	10
10	1j	73	4
11	1k	80	22
12	1l	79	17
13	1m	77	10

Entry	Catalyst	Yield^b/%	ee^c/%
1	1a	73	4
2	1b	75	7
3	1c	73	8
4	1d	81	30
5	1e	80	29
6	1f	76	12
7	1g	70	3
8	1h	71	4
9	1i	72	10
10	1j	73	4
11	1k	80	22
12	1l	79	17
13	1m	77	10

Entry	Solvent	Cat. loading/mol%	Yield^b/%	ee^c/%
1	CH₂Cl₂	10	81	30
2	CHCl₃	10	82	24
3	C₂H₄Cl₂	10	78	21
4	CCl₄	10	79	25
5	PhMe	10	82	25
6	Et₂O	10	76	15
7	THF	10	78	3
8	MTBE	10	75	13
9	CH₃CN	10	72	8
10	CH₂Cl₂	5	73	26
11	CH₂Cl₂	20	83	27
12^d	CH₂Cl₂	10	70	30
13^e	CH₂Cl₂	10	85	40
14^f	CH₂Cl₂	10	83	36
15^g	CH₂Cl₂	10	82	35
16^h	CH₂Cl₂	10	80	26
17ⁱ	CH₂Cl₂	10	77	39
18^e^,^j	CH₂Cl₂	10	81	40
19^e^,^k	CH₂Cl₂	10	86	42
20^e^,^l	CH₂Cl₂	10	83	39
21^e^,^k^,^m	CH₂Cl₂	10	82	40

Entry	Catalyst	Yield^b/%	ee^c/%
1	1a	73	4
2	1b	75	7
3	1c	73	8
4	1d	81	30
5	1e	80	29
6	1f	76	12
7	1g	70	3
8	1h	71	4
9	1i	72	10
10	1j	73	4
11	1k	80	22
12	1l	79	17
13	1m	77	10

Entry	Catalyst	Yield^b/%	ee^c/%
1	1a	73	4
2	1b	75	7
3	1c	73	8
4	1d	81	30
5	1e	80	29
6	1f	76	12
7	1g	70	3
8	1h	71	4
9	1i	72	10
10	1j	73	4
11	1k	80	22
12	1l	79	17
13	1m	77	10

Entry	Catalyst	Yield^b/%	ee^c/%
1	1a	73	4
2	1b	75	7
3	1c	73	8
4	1d	81	30
5	1e	80	29
6	1f	76	12
7	1g	70	3
8	1h	71	4
9	1i	72	10
10	1j	73	4
11	1k	80	22
12	1l	79	17
13	1m	77	10

Entry	Catalyst	Yield^b/%	ee^c/%
1	1a	73	4
2	1b	75	7
3	1c	73	8
4	1d	81	30
5	1e	80	29
6	1f	76	12
7	1g	70	3
8	1h	71	4
9	1i	72	10
10	1j	73	4
11	1k	80	22
12	1l	79	17
13	1m	77	10