Ullmann-type couplings

As seen in the retro-synthetic Scheme 5.3, intermediate 15 is useful for both routes. The choice of benzyl protection group was made based on the robust stability of benzyl phenol ethers toward most reactions and several possible avenues to remove it, although it was reported from Medicinal Chemistry that benzyl group removal via hydrogenolysis posed challenges in this compound. The choice of iodide substitution was born out of the known high reactivity of iodides in the Ullmann-type coupling reaction with alcohols and the robust stability of aryl iodides in many other common reactions. 

The indium-mediated palladium-catalyzed Ullmann-type coupling of aryl halides proceeds in aqueous media under air (Equation (88)).352... 

Figure 39 Aminoarenethiolate Cu(i) oomplexes as active catalysts for Ullmann-type couplings.

Cohen, T., TIrpak, J. G. Rapid, room-temperature Ullmann-type couplings and ammonolyses of activated aryl halides In homogeneous solutions containing copper(l) Ions. Tetrahedron Lett. 1975, 143-146. 

A series of diarylamines and diaryl ethers based on combretastatin A-4 was prepared, via coupling of a benzyl protected phenol or aniline, and evaluated for anticancer activity [39]. The target ether 66 was prepared via the new copper-catalyzed Ullmann-type coupling recently described by Buchwald and co-workers (Scheme 17). 

Over the past century, several methods have been developed for the synthesis of biaryl compounds [7]. Among these are the Ullmann-type coupling [8,9], the Scholl reaction [10], the Gomberg-Bachmann reaction [11], and recently transition-metal-catalyzed cross-coupling reactions [12], In particular, palladium-catalyzed crosscoupling reactions have been successfully applied to the synthesis of biaryls due to their generally high yields and excellent selectivities. 

Copper-Catalyzed Ligand Promoted Ullmann-type Coupling Reactions... 

Figure 9.1 Some typical ligands used for Ullmann-type coupling reactions.

Quinazoline derivatives were prepared by Fu and co-workers using an Ullmann-type coupling. Treatment of (2-bromophenyl)methylamine with benzamide in the presence of potassium carbonate and a copper(I) catalyst under thermal conditions in isopropanol gave the corresponding quinazoline in 87% yield. The authors also reported modest to good yields using several substituted (2-bromophenyl)methylamine and benzamide derivatives (not shown). 

Palladium-catalyzed reductive couplings are among the most important carbon-carbon bond forming reactions in modem synthetic organic chemistry (18). These reactions are generally air sensitive. Recently we found that, in water, palladium catalysts are air-stable. Under such conditions several important palladium catalyzed reactions are more reactive and proceed smoothly at room temperature. For example, a zinc mediated Ullmann-type coupling provides high yield of the products catalyzed by palladium in water and under air-atmosphere (eq. 10) (79). 

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