C(sp²)-N and C(sp²)-O bonds are commonly seen in natural products, pharmaceuticals, agrochemicals, and functional materials, and therefore the reactions of forming these bonds are widely used in high-throughput screening and process chemistry.¹⁾ The Buchwald-Hartwig reaction is one of the most frequently used C(sp²)-N bond-forming reactions,^3,4) and is typically catalyzed by palladium and phosphine ligands. However, palladium is a precious metal, which means it is expensive and toxic, and its removal requires a special scavenger, which poses problems in terms of environmental conservation and sustainability.

Meanwhile, the Ullmann cross-coupling is also widely used in similar bond-forming reactions, which uses inexpensive and less toxic copper in the reaction.⁵⁾ However, the conventional Ullmann reaction requires heating at 100 °C or higher in a highly polar solvent, and many practical issues remain, such as the fact that only aryl iodides can be used and the substrate range is narrow. Furthermore, phenanthrolines,⁶⁾ cyclohexyldiamines,⁷⁾ and oxalamides⁸⁾ are known as copper ligands, but there is a room for improvement in terms of reaction rate and substrate range.

Recently, benzene-1,2-diamine ligands have been reported for the use in Ullmann-type cross-coupling reactions.^9-11) These ligands coordinate to copper and catalyze a variety of C(sp²)-N and C(sp²)-O cross-coupling reactions. The active species generated in the reaction system is an electron-rich anionic complexes, which allows rapid oxidative addition even at room temperature. In addition, the ortho-aryl substituents provide π-interaction stabilization, therefore highly reactive active species do not suffer decomposition. This type of interaction is similar to that of biaryldialkylphosphine-palladium complexes.¹²⁾

TCI offers three diamine ligands (Product No. B6606、D6240、B6801). Under mild conditions, these ligands and the inexpensive copper can be utilized in the reaction, which produces a variety of functional compounds with high efficiency. In addition, the range of substrates in this reaction is wide, and it can be applied to complex drug-like compounds, so that it is useful for structure-activity relationship (SAR) research and library synthesis, in which a wide variety of compounds is needed. Furthermore, there is no need to use a large excess of one of the substrates, so there is almost no raw material loss.

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Applications

C(sp²)-N Cross-Coupling Reactions

B6606 can be used in the cross-coupling reaction of aryl bromides with amines.⁹⁾ The scope of amines includes cyclic secondary amines, linear primary amines, and non-cyclic secondary amines. In addition, as shown in the reaction example below, aryl chlorides do not react, so halogen group-selective reactions are possible. It has been reported that the ortho-aryl group of the ligand also has the effect of preventing N-arylation of the ligand, one of the pathway of deactivation.

When using highly sterically hindered raw materials such as ortho-substituted aryl bromides, D6240 gives better results than B6606. This is likely because B6606 is deactivated by C-H amination of the ligand, whereas D6240 is less susceptible to such deactivation.⁹⁾

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C(sp²)-O Cross-Coupling Reactions

In C(sp²)-O cross-coupling, B6801 gives good results. This is likely because of the higher stability of the active species.¹⁰⁾

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Cross-Coupling Reactions of base-sensitive five-membered heteroarenes

Five-membered heteroarene units such as thiazoles and pyrazoles are important coupling partners commonly found in pharmaceuticals, but they are known to decompose in the presence of a strong base. In addition, the heteroatoms coordinate to the metal center and inhibit catalysis. Good results are obtained by using B6801 as the ligand with silanolate (NaOTMS) as a weak base when using such substrates.¹¹⁾

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Switching of N-/O-selectivity

When compounds having both an amine and an alcohol are used as nucleophiles, O-selective cross-coupling proceeds when a strong base, an alkoxide, is used. On the other hand, when a weak base like a silanolate is used, the selectivity is reversed and N-selective cross-coupling proceeds.¹¹⁾ This is likely due to the difference in the deprotonation mechanisms of amines and alcohols. Amines are deprotonated even with a weak base because the acidity of the proton increases when coordinated to copper, whereas alcohols require a strong base for deprotonation, followed by transmetalation of the alkoxide on the copper.

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Guide for selection of ligands

Ligands	Usage and Features
	C(sp2)-N cross-coupling reaction Effective for the reaction of less hindered aryl bromides, primary amines, secondary amines (both cyclic and acyclic)
	C(sp2)-N cross-coupling reaction tert-Butyl groups on ligands inhibits the decomposition of ligands Effective for sterically hindered substrates
	C(sp2)-O cross-coupling reaction C(sp2)-N cross-coupling reaction with NaOTMS as weak base Applicable to Base-sensitive five-membered heteroarenes Capable of switching N-/O-selectivity depending on base

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Related Products

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Related Product Category Pages

• Cross-coupling Reaction using Transition Metal Catalysts [C-C Bond Formation]

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References

1. 1) Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes
   • Q. Yang, Y. Zhao, D. Ma, Org. Proc. Res. Dev. 2022, 26, 1690.
2. 2) Biaryl monophosphine ligands in palladium-catalyzed C–N coupling: An updated User's guide
   • B. T. Ingoglia, C. C. Wagen, S. L. Buchwald, Tetrahedron 2019, 75, 4199.
3. 3) The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
   • S. D. Roughley, A, M. Jordan, J. Med. Chem. 2011, 54, 3451.
4. 4) The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery
   • A. W. Dombrowski, A. L. Aguirre, A. Shrestha, K. A. Sarris, Y. Wang, J. Org. Chem. 2017, 82, 7085.
5. 5) Selected Copper-Based Reactions for C−N, C−O, C−S, and C−C Bond Formation
   • S. Bhunia, G. G. Pawar, S. V. Kumar, Y. Jiang, D. Ma, Angew. Chem. Int. Ed. 2017, 56, 16136.
6. 6) Copper-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
   • R. A. Altman, E. D. Koval, S. L. Buchwald, J. Org. Chem. 2007, 72, 6190.
7. 7) A General and Efficient Copper Catalyst for the Amidation of Aryl Halides and the N-Arylation of Nitrogen Heterocycles
   • A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727.
8. 8) Copper-Catalyzed Diaryl Ether Formation from (Hetero)aryl Halides at Low Catalytic Loadings
   • Y. Zhai, X. Chen, W. Zhou, M. Fan, Y. Lai, D. Ma, J. Org. Chem. 2017, 82, 4964.
9. 9) Room-Temperature Cu-Catalyzed Amination of Aryl Bromides Enabled by DFT-Guided Ligand Design
   • S. T. Kim, M. J. Strauss, A. Cabré, S. L. Buchwald, J. Am. Chem. Soc. 2023, 145, 6966.
10. 10) Room-Temperature Copper-Catalyzed Etherification of Aryl Bromides
    • M. J. Strauss, M. E. Greaves, S. T. Kim, C. N. Teijaro, M. A. Schmidt, P. M. Scola, S. L. Buchwald, Angew. Chem. Int. Ed. 2024, 63, e202400333.
11. 11) Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols
    • M. J. Strauss, K. X. Liu, M. E. Greaves, J. C. Dahl, S. T. Kim, Y. J. Wu, M. A. Schmidt, P. M. Scola, S. L. Buchwald, J. Am. Chem. Soc. 2024, 27, 18616.
12. 12) Catalysts for Suzuki−Miyaura Coupling Processes: Scope and Studies of the Effect of Ligand Structure
    • T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 4685.

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