Ullmann reaction biaryl synthesis

Traditionally, the synthesis of symmetrical biaryls was routinely accomplished using the Ullmann reaction. Recently, palladium-catalyzed homocoupling of aryl halides has also been demonstrated to rival the utility of the Ullmann coupling. As illustrated in Scheme 21, using Pd(OAc)2 as the... 

Although the copper mediated Ullmann reaction is a well known method for biaryl synthesis, drastic conditions in the range of 150-280 °C are required. Zerovalent nickel complexes such as bis(l,5-cyclooctadiene)nickel or tetrakis(triphenylphosphine)nickel have been shown to be acceptable coupling reagents under mild conditions however, the complexes are unstable and not easy to prepare. The method using activated metallic nickel eliminates most of these problems and provides an attractive alternative for carrying out aryl coupling reactions(36,38). 

The Ullmann biaryl synthesis(lQl,102) invokes the reaction of copper powder with aryl halides at relatively high temperatures, typically 100-300 °C, to give biaryl products. The intermediacy of arylcopper species is presumed but not specifically proven due to the instability of the arylcopper at the temperatures required for reaction. The Ullmann reaction has seen appreciable usage as it allows considerable functionality to be incorporated in the products. 

Cycloamidation has been used extensively to prepare 17-membered cycloisodityrosines. The acyclic biaryl ether precursors were prepared by methods including the Ullmann reaction 2-5 and nucleophilic aromatic substitution (SNAr)J6 7 Since these methods have all been used intramolecularly in cyclization reactions, they will be discussed in Sections 9.5.3 and 9.5.4. Evans and co-workers employed the pentafluorophenyl ester method of macrolactamization 8] to prepare 11, an intermediate in their total synthesis of OF4949-III (7) (Scheme 2)J3 In this case, the acidic removal of a Boc group was employed to release the cyclization substrate, although hydrogenolysis of a Z group is also effective 3 ... 

There are two different transformations referred as the Ullmann Reaction. The classic Ullmann Reaction is the synthesis of symmetric biaryls via copper-catalyzed coupling, the Ullmann-type Reactions include copper-catalyzed Nucleophilic Aromatic... 

The Ullmann reaction (Figure 16.5) represents another synthesis of biaryls that reliably leads to the formation of symmetric biaryls (upper and middle reaction examples), but, in particular cases, is also suitable for the synthesis of unsymmetrical biaryls (lower reaction example). To prepare a symmetric biaryl in the traditional way, an aryl iodide is heated with Cu powder in order to prepare the parent compound of biaryls, i.e., biphenyl, one starts with iodobenzene. The metal reduces 50% of the substrate to phenylcopper in situ. The latter... 

The name Ullmann is not only associated with the biaryl synthesis (Figure 16.4, 16.5), but is also known from the synthesis of diaryl ethers (Ullmann synthesis of diaryl ethers). An example is given in the topmost reaction of Figure 16.6. Remember Side Note 5.6, where we asked the following question How can diphenyl ethers be prepared Now you are ready to give a correct answer, which is By way of Ullmann synthesis. ... 

Fig. 16.5. Biaryl synthesis via arylcopper compounds II— in-situ preparation of the nucleophile with the classical Ullmann procedure ("variant 1"), with a procedure that may also be applied to aryl bromides ("variant 2") and with a crossed classical Ullmann coupling (bottom-most reaction example).

The Ullmann reaction (Figure 13.4) represents another synthesis of substituted biphenyls. In this process an aryl iodide or—as in the present case—an aryl iodide/aryl chloride mixture is heated with Cu powder. It is presumed that under standard conditions the aryl iodide reacts in situ with Cu to form the aryl copper compound. Usually, the latter couples with the remaining aryl iodide and a symmetric biphenyl is formed. In a few instances it is also possible to generate asymmetric biaryls via a crossed Ullmann reaction. In these cases one employs a mixture of an aryl iodide and another aryl halide (not an iodide ) the other aryl halide must exhibit a higher propensity than the aryl iodide to couple to the arylcopper intermediate. It is presumed that the mechanism of the Ullmann reaction parallels the mechanism of the Cadiot-Chodkiewicz coupling, which we will discuss in Section 13.4. 

The biaryl synthesis by Ullmann coupling, as well as a large number of related coupling reactions, constitutes another type of copper-mediated or -catalyzed reaction used extensively for the formation of carbon-carbon and carbon-heteroatom bonds. These transformations have been reviewed recently17,177,177a,177b and will not be discussed in detail here. 

Two reviews have detailed the reactions of aryl halides with copper and copper compounds these are (1) the Ullmann biaryl synthesis, by Fanta 113) and (2) copper-promoted reactions, by Bacon and Hill (9). The mechanism of the Ullmann biaryl synthesis was discussed the possible routes are shown in Eq. (110). No evidence had been obtained... 

The Ziegler-modified Ullmann reaction was used for the total synthesis of pyrrolophenanthridinium alkaloid tortuosine by L.A. Flippin and co-workers. First, A/-Boc-5-methoxyindoline was lithiated at C7 with s-BuLi in the presence of TMEDA, and then it was transmetallated to the corresponding organocopper species that smoothly underwent the Ullmann reaction with a 3-iodoaryl imine. The resulting biaryl product was treated with anhydrous HCI in chloroform, which promoted the cyclization followed by dehydration to give the natural product. 

Ullmann reaction. During a study of the synthesis of biaryls with nickel catalysts (4, 33 6, 654), Tsou and Kochi2 found that nickcl(II) complexes such as 1 readily yield biaryls on treatment with an aryl halide and that they are important intermediates in the radical-chain process of nickel-catalyzed Ullmann reactions. 

The nickel-catalyzed reductive homocoupling of haloarenes is an excellent method for the synthesis of symmetrical biaryls (Eq. 22). The remarkable ability of [Ni(cod)2] to promote the stoichiometric formation of biaryls from aryl iodides and bromides was originally reported by Semmelhack, Helquist, and Jones [25a]. Unlike the Ullmann reaction [3], the Ni-promoted homocoupling of... 

Lithium-cuprate complexes obtained by the reaction of Cu(I) iodide and the corresponding aryllithium were also successfully applied in the synthesis of unsymmetrical biaryls [23]. An alternative strategy involves the low temperature oxidative coupling of higher order mixed diarylcuprates [24]. The classical Ullmann reaction can be accelerated by using, instead of copper... 

Organocopper reagents, such as methylcopper prepared from MeLi were also used as catalyst recently [148]. Yields could be further improved by ultrasonic irradiation [149],.as well as under phase transfer conditions [150]. It is surprising that, in contrast to the Ullmann biaryl synthesis, activated aromatic fluoro compounds (e.g. fluoro-esters, -nitrils, -aldehydes and -acetophenones) can couple with phenols in good yield. The reaction does not require any catalysts, but only K2CO3 as a base, [146] (Scheme 56). ... 

The formation of a biaryl by the condensation of two molecules of an aryl halide in the presence of finely divided copper is known as the Ullmaim reaction [1-4]. Although several newer methods for synthesis of biaryls were developed, the Ullmann reaction still remained its importance in some specific cases. Due to its efficiency and simplicity, the reaction is very useful in the synthesis of simple symmetrical and some classes of unsymmetrical biaryls. More than a century old, the classical Ullmaim reaction involves heating the mixture of the aryl halide(s) (I) with the copper powder or bronze at 100-360 °C in or without any solvent. Products of this reaction are the biaryl(s) (II) and the corresponding copper(I) halide. Scheme 1. 

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