Ullmann Ligands

Brief history

In 1901 Ullmann discovered that aryl iodides in the presence of stoichometric amount of Cu salts at high temperature undergo a coupling reaction to furnish biaryls (Figure 1). The seminal discovery was shortly extended to oxygen and nitrogen containing compounds and also to the use of Cu in catalytic amounts.1-3

Brief History
Figure 1: Early developments in Ullmann couplings

Today, Ullmann couplings have become an essential tool in organic synthesis, and they find numerous applications in medicinal chemistry, natural products total synthesis, and process development. The scope of the Ullmann reaction has evolved enormously over the past few decades, thanks to the development of efficient Cu ligands which allow C-C, C-N, C-O, C-S and C-P bond formations to take place under mild conditions. In addition, Cu catalysis is particularly attractive in the pharmaceutical, agrochemical and chemical industry as a valid and cheap alternative to more expensive metal catalysts (Pd, Rh, Ir).

Reaction mechanism

Copper exists in various oxidation states of which the most common ones are: Cu(0), Cu(I), Cu(II), Cu(III) and Cu(IV). Oxidation states 0, +1, +2 and +3 are quite commonly found in many Cu salts and complexes, while only certain oxides and fluorides can exist in the +4 state. Additionally Cu(I) can reversibly disproportionate into Cu (0) and Cu (II) in water1 and this characteristic may explain the fact that catalysis can occur using different oxidation states. Cu(I) species however are considered by most authors as the “real” catalytic species.

Figure 2: Generally accepted mechanism for Ullmann coupling

According to the previous considerations, one of the most generally accepted mechanisms involves oxidative addition of Cu (I) to ArX forming an intermediate biaryl Copper(III) species, which in turn undergoes reductive elimination to furnish the desired product with concomitant regeneration of the Cu I catalyst. In alternative to the mechanism in Figure 2 several different reaction pathways have been proposed, and the debate still remains open. However there are three widely described alternative possibilities:

   1) Involving radical species via a sngle electron transfer mechanism or halide atom transfer
   2) Involving a four centered intermediate and σ-bond metathesis
   3) Π-complexeation of Cu (I) with ArX

In both transmetallation and radical process Cu oxidation change varies during the cycle, while mechanisms 2 and 3 involve no oxidation state change at the metal center.

Ullmann transformations are quite unique and despite their general synthetic usefulness, their successful outcome largely relies on experimentation on a case to case basis. It is quite difficult to generalize ideal reaction conditions with a broad substrate scope. The question that remains is if there is actually only one mechanism involved in Ullmann’s reactions, or more.

Development of novel Cu-Ligands for Ullmann couplings

Ullmann couplings with amides, poorly nucleophilic amines and low reactive halogens typically require strong bases, stoichiometric Cu and higher reaction temperatures. Accordingly, the discovery of more powerful and convenient Cu-based catalytic systems is highly desirable and it is indeed an important research area. Conversion rates can be increased enormously using different Cu sources, appropriate bases and solvents, and by choosing suitable Cu Ligands. In recent years a number of bidentate ligands like diketones, diamines, aminoacids, proline derivatives, phenantrolines have appeared in the literature allowing effective C-C, C-N, and C-O couplings using typically a small excess of the amine. 4, 5 The choice of the halide is also an important stand-point as the general reactivity increases in the following order: Cl >Br>I.

Recently, oxalate diamine ligands of the type depicted in Figure 4 have proven to be synthetically useful for a number of difficult C-N Ullmann reactions.6 Ligand D-5480, for example provided a viable solution for the difficult coupling of acyclic secondary amines with aryl halides. Additionally, it is worth mentioning, that the electronic nature of the ligands seem to play a crucial role in the catalytic system.6

A catalytic system constituted by ligand P-9010 and CuI used in 5 mol% enables several reactions of aryl iodides with amines under mild condotions. Remarkably, reaction of 4-iodoanisole with aniline occurred at room temperature, being a rare example of Ulmann that does not require heating.5

Amination of aryl halides with amines
Figure 3: Amination of aryl halides with amines (Example for Ligand P-9010).5

bis(N-aryl) substituted oxalamides like B-3985 (Figure 4) proved to be efficient ligands in combination with K3PO4 as the base and DMSO as the solvent hit the best result showing good yields and a relatively large substrate scope. Some remarkable examples are shown in Figure 4.6

Examples for the BTMPO Catalyzed Reaction
Figure 4: Examples of the BTMPO (B-3985) Catalyzed Coupling Reaction.6

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1) Sperotto E.; Van Klink G. P. M.; Van Koten G.; De Vries J. G.; Dalton Trans., 2010, 39, 10338-10351.
2) Cambiago C.; Mardsen S. P.; Blacker J.A.; McGowan P.C.; Chem. Soc. Rev., 2014, 43, 3525.
3) Sun D.; Lin H.; Org. Prep. Proced. Intl. 2013 45, doi:10.1080/00304948.2013.816208.
4) De S.; Yin J.; Ma D. ; Org. Lett., 2017, doi:10.1021/acs.orglett.7b02326.
5) Ding X.; Huang M.; Yi Z.; Du D.; Zhu X.; Wan Y.; J. Org. Chem., 2017, 82 (10), 5416-5423.
6) Zhou W.; Fan M.; Yin J.; Jiang Y.; Ma D.; J. Am. Chem. Soc., 2015, 137, 11942-11945.

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