Syntheses of Azachromanones Based on Palladium-Catalyzed Heck Reaction and Ruthenium-Catalyzed Oxidative Cleavage of Olefins

doi:10.6023/cjoc202511020

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (5): 2072-2081.DOI: 10.6023/cjoc202511020 Previous Articles Next Articles

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钯催化Heck反应和钌催化烯烃氧化裂解反应合成氮杂二氢色原酮

崔入文^a^,^b, 刘晓倩^b, 杨亚玺^c, 陈超^b^,^c^,^*(), 周兵^a^,^b^,^c^,^*()

^a 安徽中医药大学药学院合肥 230012
^b 中科环渤海(烟台)药物高等研究院烟台新药创制山东省实验室山东烟台 264117
^c 中国科学院上海药物研究所原创新药研究全国重点实验室上海 201203

收稿日期:2025-11-26 修回日期:2026-01-09 发布日期:2026-02-11
基金资助:
山东省重点研发计划(2025CXPT178); 山东省重点研发计划(2024CXPT028); 中国科学院战略性先导科技专项(XDB1260102); 山东省自然科学基金(ZR2024QH472); 山东省自然科学基金(ZR2023LSW003); 山东省实验室(SYS202205)

Syntheses of Azachromanones Based on Palladium-Catalyzed Heck Reaction and Ruthenium-Catalyzed Oxidative Cleavage of Olefins

Ruwen Cui^a^,^b, Xiaoqian Liu^b, Yaxi Yang^c, Chao Chen^b^,^c^,^*(), Bing Zhou^a^,^b^,^c^,^*()

^a School of Pharmacy, Anhui University of Chinese Medicine, Hefei 2300122
^b Shandong Laboratory of Yantai Durg Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117
^c State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shangshai 201203

Received:2025-11-26 Revised:2026-01-09 Published:2026-02-11
Contact: * E-mail: cchen@baridd.ac.cn; zhoubing@simm.ac.cn
Supported by:
Key R&D Program of Shandong Province(2025CXPT178); Key R&D Program of Shandong Province(2024CXPT028); Strategic Priority Research Program of the Chinese Academy of Sciences(XDB1260102); Shandong Provincial Natural Science Foundation(ZR2024QH472); Shandong Provincial Natural Science Foundation(ZR2023LSW003); Shandong Laboratory Program(SYS202205)

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Abstract

Azachromanone represents an important structural motif among bioactive compounds and serves as a privileged scaffold in medicinal chemistry. The development of efficient synthetic approaches to azachromanones is highly desirable for accelerating the discovery of active drug molecules. However, existing synthetic methods still suffer from drawbacks such as cumbersome operations and harsh reaction conditions. In this study, an efficient synthesis of azachromanone derivatives was achieved through a palladium-catalyzed highly regioselective Heck reaction (exo∶endo>20∶1) combined with a ruthenium-catalyzed mild olefin oxidative cleavage reaction. This method features mild reaction conditions, broad substrate scope, good safety, and the capability for consecutive one-pot synthesis, providing a new synthetic strategy for the construction of azachromanones.

Key words: azachromanone, Heck reaction, regioselectivity, oxidative cleavage of alkenes

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Ruwen Cui, Xiaoqian Liu, Yaxi Yang, Chao Chen, Bing Zhou. Syntheses of Azachromanones Based on Palladium-Catalyzed Heck Reaction and Ruthenium-Catalyzed Oxidative Cleavage of Olefins[J]. Chinese Journal of Organic Chemistry, 2026, 46(5): 2072-2081.

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Fig. & Tab. 7

References 24

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Entry	Catalyst	Ligand	Base	Solvent	Yield/%	23a∶25a
1	Pd(OAc)₂	PPh₃	KOAc	DMF	54%	4∶1
2	Pd(OAc)₂	P(o-tolyl)₃	KOAc	DMF	50%	2.5∶1
3	Pd(OAc)₂	DPPh₂	KOAc	DMF	35%	3∶1
4	Pd(OAc)₂	PBu₃	KOAc	DMF	55%	2.5∶1
5	Pd(OAc)₂	TTBP	KOAc	DMF	50%	2.5∶1
6	Pd(OAc)₂	dppm	KOAc	DMF	70%	4∶1
7	Pd(OAc)₂	dppp	KOAc	DMF	78%	>20∶1
8	Pd(OAc)₂	dppp	Na₂CO₃	DMF	75%	3∶1
9	Pd(OAc)₂	dppp	K₂CO₃	DMF	72%	>20∶1
10	Pd(OAc)₂	dppp	Cs₂CO₃	DMF	70%	9∶1
11	Pd(OAc)₂	dppp	Ag₂CO₃	DMF	55%	3∶1
12	Pd(OAc)₂	dppp	Et₃N	DMF	35%	3∶1
13	Pd(OAc)₂	dppp	DIPEA	DMF	35%	9∶1
14	Pd(OAc)₂	dppp	KOAc	DMSO	65%	>20:1
15	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	82%	>20∶1
16	Pd(OAc)₂	dppp	KOAc	PhMe	<10%
17^b	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	80%	9∶1
18^c	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	<10%
19^d	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	70%	9∶1

Entry	Catalyst	Ligand	Base	Solvent	Yield/%	23a∶25a
1	Pd(OAc)₂	PPh₃	KOAc	DMF	54%	4∶1
2	Pd(OAc)₂	P(o-tolyl)₃	KOAc	DMF	50%	2.5∶1
3	Pd(OAc)₂	DPPh₂	KOAc	DMF	35%	3∶1
4	Pd(OAc)₂	PBu₃	KOAc	DMF	55%	2.5∶1
5	Pd(OAc)₂	TTBP	KOAc	DMF	50%	2.5∶1
6	Pd(OAc)₂	dppm	KOAc	DMF	70%	4∶1
7	Pd(OAc)₂	dppp	KOAc	DMF	78%	>20∶1
8	Pd(OAc)₂	dppp	Na₂CO₃	DMF	75%	3∶1
9	Pd(OAc)₂	dppp	K₂CO₃	DMF	72%	>20∶1
10	Pd(OAc)₂	dppp	Cs₂CO₃	DMF	70%	9∶1
11	Pd(OAc)₂	dppp	Ag₂CO₃	DMF	55%	3∶1
12	Pd(OAc)₂	dppp	Et₃N	DMF	35%	3∶1
13	Pd(OAc)₂	dppp	DIPEA	DMF	35%	9∶1
14	Pd(OAc)₂	dppp	KOAc	DMSO	65%	>20:1
15	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	82%	>20∶1
16	Pd(OAc)₂	dppp	KOAc	PhMe	<10%
17^b	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	80%	9∶1
18^c	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	<10%
19^d	Pd(OAc)₂	dppp	KOAc	1,4-Dioxane	70%	9∶1

Entry	Catalyst/Oxidant	Additive	Solvent	Yield/%
Entry	Catalyst/Oxidant	Additive	Solvent	24a		26a
1	RuCl₃/Oxone	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	<10%	<5%
2	RuCl₃/NaOCl	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	<5%	<5%
3	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	55%	<5%
4	RuCl₃/NaIO₄	NaHCO₃	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	48%	<5%
5	RuCl₃/NaIO₄	H₂SO₄	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	44%	<5%
6	/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	<5%	0%
7	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/THF (1 mL)/H₂O (1 mL)	<10%	<5%
8	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/EtOAc (1 mL)/H₂O (1 mL)	<10%	<5%
9	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/H₂O (1 mL)	24%	<5%
10	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)	<5%	<5%
11^c	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	28%	<5%

Entry	Catalyst/Oxidant	Additive	Solvent	Yield/%
Entry	Catalyst/Oxidant	Additive	Solvent	24a		26a
1	RuCl₃/Oxone	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	<10%	<5%
2	RuCl₃/NaOCl	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	<5%	<5%
3	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	55%	<5%
4	RuCl₃/NaIO₄	NaHCO₃	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	48%	<5%
5	RuCl₃/NaIO₄	H₂SO₄	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	44%	<5%
6	/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	<5%	0%
7	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/THF (1 mL)/H₂O (1 mL)	<10%	<5%
8	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/EtOAc (1 mL)/H₂O (1 mL)	<10%	<5%
9	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/H₂O (1 mL)	24%	<5%
10	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)	<5%	<5%
11^c	RuCl₃/NaIO₄	—	CH₃CN (1 mL)/CCl₄ (1 mL)/H₂O (1 mL)	28%	<5%

钯催化Heck反应和钌催化烯烃氧化裂解反应合成氮杂二氢色原酮

Syntheses of Azachromanones Based on Palladium-Catalyzed Heck Reaction and Ruthenium-Catalyzed Oxidative Cleavage of Olefins

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Heck reaction^a

Oxidation reaction^b

Heck reaction^a

Oxidation reaction^b