Original Article:
LiCl-Accelerated Multimetallic Cross-Coupling of Aryl Chlorides with Aryl Triflates
Liangbin Huang, et al.
J. Am. Chem. Soc. 2019, 141, 28, 10978-10983
10.1021/jacs.9b05461
The synthesis of biaryls is one of the most commonly used reactions in the pharmaceutical, agrochemical, and materials science industries. Aryl chloride is an aryl electrophile that has been used in cross-couplings to prepare biaryl compounds. However, there is currently no general method for direct cross-coupling of electron-neutral or electron-rich aryl chlorides with other aryl electrophiles. In this work, the researchers report the first general cross-Ullmann coupling reaction of aryl chlorides with aryl triflates. This strategy uses the additive lithium chloride (LiCl) to allow nonselective multimetallic reactions selectively, thereby overcoming selectivity challenges associated with the coupling of inert to reactive electrophiles.
Nickel And Palladium Multimetallic Catalytic Mechanism
To facilitate a successful cross-Ullman reaction, the electrophiles used must be reactively orthogonally paired. The slow consumption of aryl chlorides and aryl triflates suggests that the formation of aryl nickel(II) is affected by Inhibition. Inhibition can arise from slow oxidative addition, slow reduction, or non-cyclic loss of nickel catalyst.
The Role of Lithium Chloride in The Cross-Coupling Reaction
- Studies have shown that the coupling of aryl chlorides to aryl triflates has low reactivity due to self-inhibitory effects. This autoinhibitory effect is due to the formation of zinc salts (ZnCl2 and Zn(OTf)2) upon the reduction of Ni(II) to Ni(0) which inhibit subsequent reactions.
- Halide anions will accelerate the reduction of NiX2 intermediates on the zinc surface. Therefore, the Ar-Cl cross-Ullmann reaction transformation can be achieved by adding LiCl.
- Overall, LiCl accelerates the reaction of aryl chlorides with aryltriflates by accelerating the reduction of Ni(II) to Ni(0) and counteracting the self-inhibition of Zn(0) reduction by Zn(II) salts Ester cross-coupling reactions.
Examples of Lithium Chloride-Facilitated Cross-Coupling Reactions
A series of coupling reactions of aryl chlorides and triflates containing different functional groups were studied under the reaction conditions of introducing lithium chloride, including:
- More reactive aryl halides, such as aryl chlorides, heteroaryl halides, or aryl bromides with strong electron-withdrawing groups.
- Electron-deficient fluorine-containing substrates as well as electron-neutral and electron-rich substrates, such as Boc-protected amines, aldehydes, alkyl Bpin esters, and phosphonates.
- Scope of aryl triflates: Aryl triflate with electron-donating and electron-withdrawing substituents showed good yields. Aryl triflates are coupled with 2-cyano-1-chlorobenzene to form biaryls, which can be used in the synthesis of angiotensin II receptor antagonists.
- Multi-step synthesis: One of the benefits of using aryl chlorides is that their lower reactivity facilitates multi-step synthesis. A concise three-step synthesis of flurbiprofen (9) proved suitable for rapid analog synthesis.
Chemicals Related in the Paper:
| Catalog Number | Product Name | Structure | CAS Number | Price |
|---|---|---|---|---|
| ACM85144112 | Lithium chloride hydrate |  |
85144-11-2 | Price |
| ACM16712202 | Lithium chloride hydrate |  |
16712-20-2 | Price |
| ACM7447418 | Lithium Chloride (2.3% in Tetrahydrofuran, ca. 0.5mol/L) |  |
7447-41-8 | Price |
