Draft:Oxalamide ligands
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oxalamide ligands, were first discovered by Dawei Ma research group, which acted as the second-generation bidentate ligand for copper-catalyzed cross coupling reactions of aryl halides and nucleophiles.[1][2] This type of reaction is recognized as Ullmann-Ma reactions and has found extensive applications in organic synthesis.[1]
Background
[edit]Copper-mediated cross-coupling reactions (historically Ullmann reactions) traditionally required harsh conditions and were mostly limited to activated aryl halides (iodides, bromides). In the late 1990s, researchers began discovering that certain ligands could dramatically accelerate these reactions. A seminal report in 1998 by Ma and co-workers demonstrated that simple amino acids (e.g. L-proline) acted as effective ligands in Cu-catalyzed N- arylation, greatly lowering the temperature and improving yields.[3]
This finding helped launch the "ligand-accelerated" era of Ullmann couplings. Over the next decade, Ma's group and others developed a first generation of ligands (often amino acids or diamines) that enabled copper to couple aryl iodides and bromides with nucleophiles under relatively mild conditions.[2] Building on this foundation, Ma led the discovery of second-generation ligands in the 2010s – particularly oxalamides and related amides – which proved even more powerful. These new bidentate ligands allowed previously unreactive aryl chlorides to be used as coupling partners and drove catalyst loadings down to very low levels. Such advances firmly established copper/oxalamide systems as practical tools in organic synthesis, with the term "Ullmann–Ma reaction" now used to recognize Ma's contributions.[2]
The discovery of oxalic diamides and related amide ligands by Ma and coworkers opened a new chapter in copper-catalyzed cross-couplings. Two important goals have been achieved with these novel catalytic systems: aryl chlorides were used as general substrates and low catalyst loading was realized for most of the reactions. These advances have made copper-catalyzed coupling reactions more attractive for practical applications, particularly for large-scale production in industry due to the high turnover and the mild, environmentally friendly reaction conditions.
Catalytic Applications
[edit]Oxalamide–Cu complexes have been widely used in cross-coupling reactions:
C–N Coupling (Ullmann–Ma Amination): Oxalamide ligands such as BFMO (N, N'-bis(furan-2-ylmethyl) oxalamide), BTMPO (N, N′-bis (2,4,6- trimethoxyphenyl) oxalamide) enabled the efficient N-arylation of (hetero)arylamines and secondary amines, often at catalyst loadings as low as 5–10 mol%.[1]
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Nowadays, the method has been extended beyond forming Aromatic amines to include diarylamines (ArNHAr'), heteroaryl amines (Het-NH₂), amides, and hydrazines (Ar-NHNH₂).[2][4][5][6][7]
C–O Coupling (Diaryl Ether Formation): With N-aryl-N'-alkyloxalamide ligands, Ma developed coupling aryl halides (including aryl chlorides) with phenols under mild conditions. This method represented a rare example of copper catalysis rivaling Pd in C–O bond formation.[8]
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Hydroxylation of Aryl Halides: A Cu(acac)2/BHMPO system was developed for converting aryl halides to phenols using water or hydroxide. This method achieved high efficiency under relatively mild conditions, with catalyst loadings as low as 0.5 mol%.[9]
These reactions offer important advantages: they use inexpensive copper, require low catalyst loadings, and proceed under mild, environmentally friendly conditions. The main limitation is that they may not match the full reactivity and scope of palladium-catalyzed systems.
Mechanism discussion
[edit]A 2023 study using Ma's oxalamide systems revealed a involving the addition of aryl halide to Cu (II).[10] Rather than following the typical Cu(I) → Cu (III) path like palladium, the Cu (II)–oxalamide complex undergoes concerted oxidative addition with the aryl halide. The ligand plays an active role, stabilizing the transition state by radical character on the oxalamide ligand. This mechanism was supported by EPR spectroscopy and DFT calculations showing spin density on the ligand. This helps explain the high efficiency and air-stability of these catalytic systems.
References
[edit]- ^ a b c Zhou, Wei; Fan, Mengyang; Yin, Junli; Jiang, Yongwen; Ma, Dawei (2015-09-23). "CuI/Oxalic Diamide Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amines". Journal of the American Chemical Society. 137 (37): 11942–11945. Bibcode:2015JAChS.13711942Z. doi:10.1021/jacs.5b08411. ISSN 0002-7863. PMID 26352639.
- ^ a b c d Cai, Qian; Zhou, Wei (August 2020). "Ullmann-Ma Reaction: Development, Scope and Applications in Organic Synthesis †". Chinese Journal of Chemistry. 38 (8): 879–893. doi:10.1002/cjoc.202000075. ISSN 1001-604X.
- ^ Ma, Dawei; Zhang, Yongda; Yao, Jiangchao; Wu, Shihui; Tao, Fenggang (1998-12-01). "Accelerating Effect Induced by the Structure of α-Amino Acid in the Copper-Catalyzed Coupling Reaction of Aryl Halides with α-Amino Acids. Synthesis of Benzolactam-V8". Journal of the American Chemical Society. 120 (48): 12459–12467. Bibcode:1998JAChS.12012459M. doi:10.1021/ja981662f. ISSN 0002-7863.
- ^ Bhunia, Subhajit; Kumar, S. Vijay; Ma, Dawei (2017-12-01). "N , N ′-Bisoxalamides Enhance the Catalytic Activity in Cu-Catalyzed Coupling of (Hetero)Aryl Bromides with Anilines and Secondary Amines". The Journal of Organic Chemistry. 82 (23): 12603–12612. doi:10.1021/acs.joc.7b02363. ISSN 0022-3263. PMID 29117476.
- ^ Gao, Jie; Bhunia, Subhajit; Wang, Kailiang; Gan, Lu; Xia, Shanghua; Ma, Dawei (2017-06-02). "Discovery of N -(Naphthalen-1-yl)- N ′-alkyl Oxalamide Ligands Enables Cu-Catalyzed Aryl Amination with High Turnovers". Organic Letters. 19 (11): 2809–2812. doi:10.1021/acs.orglett.7b00901. ISSN 1523-7060. PMID 28530100.
- ^ Kumar, Siripuram Vijay; Ma, Dawei (November 2018). "Synthesis of Aryl Hydrazines via CuI/BMPO Catalyzed Cross-Coupling of Aryl Halides with Hydrazine Hydrate in Water". Chinese Journal of Chemistry. 36 (11): 1003–1006. doi:10.1002/cjoc.201800326. ISSN 1001-604X.
- ^ De, Subhadip; Yin, Junli; Ma, Dawei (2017-09-15). "Copper-Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amides". Organic Letters. 19 (18): 4864–4867. doi:10.1021/acs.orglett.7b02326. ISSN 1523-7060. PMID 28858514.
- ^ Zhai, Yuntong; Chen, Xiaofei; Zhou, Wei; Fan, Mengyang; Lai, Yisheng; Ma, Dawei (2017-05-05). "Copper-Catalyzed Diaryl Ether Formation from (Hetero)aryl Halides at Low Catalytic Loadings". The Journal of Organic Chemistry. 82 (9): 4964–4969. doi:10.1021/acs.joc.7b00493. ISSN 0022-3263. PMID 28427259.
- ^ Xia, Shanghua; Gan, Lu; Wang, Kailiang; Li, Zheng; Ma, Dawei (2016-10-19). "Copper-Catalyzed Hydroxylation of (Hetero)aryl Halides under Mild Conditions". Journal of the American Chemical Society. 138 (41): 13493–13496. Bibcode:2016JAChS.13813493X. doi:10.1021/jacs.6b08114. ISSN 0002-7863. PMID 27682010.
- ^ Delaney, Connor P.; Lin, Eva; Huang, Qinan; Yu, Isaac F.; Rao, Guodong; Tao, Lizhi; Jed, Ana; Fantasia, Serena M.; Püntener, Kurt A.; Britt, R. David; Hartwig, John F. (2023-09-08). "Cross-coupling by a noncanonical mechanism involving the addition of aryl halide to Cu(II)". Science. 381 (6662): 1079–1085. Bibcode:2023Sci...381.1079D. doi:10.1126/science.adi9226. ISSN 0036-8075. PMC 11723509. PMID 37676958.