Multi-component C—H Annulation of α-Oxocarboxylic Acids, Allynes and Primary Amines to Yield Isoquinolinium Skeletons

doi:10.6023/cjoc202507007

Abstract

The Rh(III)-catalyzed three-component C—H activation/annulation reaction of α-oxocarboxylic acids, alkynes, and primary amines to construct bicyclic and tetracyclic isoquinolinium derivatives is reported. The in-situ generated α-imino acid intermediates from keto-amine condensation between α-oxocarboxylic acid and primary amine enable a directing group switch from weak oxygen to strong nitrogen. By using alkylamines as N-source, N-directed C—H activation of α-imino acids and alkynes afforded bicyclic N-alkyl isoquinolinium salts (ionic liquids) in high yields. When using arylamines instead, the sequential N- and carboxyl-directed C—H activation/annulation process furnished tetracyclic dibenzo[a,f]quinolizinium salts with moderate to good yields. Seven key intermediates, including three carboxylate-retained species, have been characterized by time-dependent ESI-MS analysis, supporting a plausible mechanism involving keto-amine condensation, decarboxylation, C—H activation, alkyne insertion, and reductive elimination.

Key words: α-oxocarboxylic acids, C—H activation/annulation, multi-component, rhodium-catalysis, isoquinolinium

Cite this article

Yiling Zeng, Fangpeng Liang, Hui Li, Rongrong Liu, Shiqing Li. Multi-component C—H Annulation of α-Oxocarboxylic Acids, Allynes and Primary Amines to Yield Isoquinolinium Skeletons[J]. Chinese Journal of Organic Chemistry, 2026, 46(2): 554-563.

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Entry	Variation from above conditions^a	3a/4a^b/%
1	None	74/trace
2	[(p-cymene)RuCl₂] as catalyst	0/0
3	[Cp*Co(CO)I₂] as catalyst	0/0
4	[Cp*RhCl₂]₂ (2.5 mol%)	10/47
5	Cu(OTf)₂ instead of Cu(OAc)₂	21/0
6	AgOAc instead of Cu(OAc)₂	12/31
7	Cu(OAc)₂ (2 equiv.)	26/55
8	Without Cu(OAc)₂	9/56
9	Without NaOAc	<5/48
10	HOAc instead of NaOAc	25/51
11	PivOH instead of NaOAc	26/50
12	CsOAc instead of NaOAc	29/36
13	NaBF₄ instead of Zn(OTf)₂	66/<5
14	NaSbF₆ instead of Zn(OTf)₂	67/<5

Entry	Variation from above conditions^a	3a/4a^b/%
1	None	74/trace
2	[(p-cymene)RuCl₂] as catalyst	0/0
3	[Cp*Co(CO)I₂] as catalyst	0/0
4	[Cp*RhCl₂]₂ (2.5 mol%)	10/47
5	Cu(OTf)₂ instead of Cu(OAc)₂	21/0
6	AgOAc instead of Cu(OAc)₂	12/31
7	Cu(OAc)₂ (2 equiv.)	26/55
8	Without Cu(OAc)₂	9/56
9	Without NaOAc	<5/48
10	HOAc instead of NaOAc	25/51
11	PivOH instead of NaOAc	26/50
12	CsOAc instead of NaOAc	29/36
13	NaBF₄ instead of Zn(OTf)₂	66/<5
14	NaSbF₆ instead of Zn(OTf)₂	67/<5

α-氧代羧酸、炔和伯胺的多组分碳氢环化构筑异喹啉鎓骨架