Ullmann-reaction

The Ullmann reaction can be taken to refer to two different transformations. The first is the copper mediated coupling of two aryl groups to give a biaryl compound this is the classic Ullmann reaction. The second, the Ullmann-type reaction, is the nucleophilic aromatic substitution between aryl nucleophiles and aryl halides, the most common of which is the Ullmann ether synthesis. The classic Ullmann reaction will be reviewed in this chapter the reader is refered to several excellent reviews for details on the Ullmann-type reaction.  

The reaction employing copper was utilized almost exclusively in the following decades for biaryl formation until the rising popularity of nickel, in an Ullmann-type coupling. This was followed by the use of zinc, tin, boron, and eventually, palladium, arguably the most commonly used transition metal in organic synthesis today for such transformations. 

The mechanism proceeds by oxidative addition of the copper into the aryl halide 3. The copper(I)-aryl species 4 then undergoes another oxidative 

Variations in the Ullmann reaction centre mainly on the catalysts used to carry out the transformation and modifications to the conditions in order to improve yields. Additionally, although the Ullmann reaction is traditionally the reaction of aryl halides with copper, other metals have also been utilized, often to inhibit the formation of by-products.  

The replacement of copper by other metals in the Ullmann reaction usually results in milder and more efficient pathways. The common use of Pd in conjunction with copper in the Ullmann coupling can be seen in many examples. Nicolaou et al. utilized such modifications in their total synthesis of kinamycins C, F, and J. Bromide 9 underwent coupling with iodide 10 to give aldehyde 11 in a satisfactory 83% yield. 

The overall transformation of Phi to PhCuI is an oxidative addition process. References 

Homocoupling of aryl halides in the presence of Cu or Ni or Pd to afford biaryls. 

Ulknann, F. Bielecki, J. Chem. Ber. 1901, 34, 2174. Fritz UUmann (1875-1939), bom in Ftirth, Bavaria, studied under Graebe at Geneva. He taught at the Technische Hochschule in Berlin and the University of Geneva. 

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Activated copper bronze. Commercial copper bronze does not always give satisfactory yields in the Ullmann reaction, but uniform results can... 

An interesting reaetion, which is particularly valuable for the preparation of diphenyl derivatives, consists in heating copper powder or, better, copper bronze with an aryl halide (Ullmann reaction), for example ... 

Carbon-oxygen bonds are formed by the Ullmann reaction (- coupling of aryl halides with copper) which has been varied in alkaloid chemistry to produce diaryl ethers instead of biaryls. This is achieved by the use of CuO in basic media (T. Kametani, 1969 R.W. Dos-kotch, 1971). 

An example of the use of copper as a catalyst is Acid Blue 25 [6408-78-2] (Cl 62055) in which l-amino-2-sulfonic-4-bromoanthraquinone is condensed with aniline using copper salts (Ullmann reaction) (314). Another example is oxidation to the tria2ole of Direct YeUow 106 [12222-60-5] (Cl 40300) (315,316). 

Aromatic haUdes do not react easily with phenoxide ions to produce diaryl ethers unless the aromatic haUde is substituted with one or more electron-withdrawing groups, eg, nitro or carboxyl groups. The Ullmann reaction uses finely divided copper or copper salts to cataly2e the reaction of phenoxides with aromatic haUdes to give diaryl ethers. 

An excess of guaiacol is essential. Weston and Adkins have found that the phenol, copper, and air form the active catalyst in the Ullmann reaction. 

An aryl methane- or toluenesulfonate ester is stable to reduction with lithium aluminum hydride, to the acidic conditions used for nitration of an aromatic ring (HN03/H0Ac), and to the high temperatures (200-250°) of an Ullmann reaction. Aryl sulfonate esters, formed by reaction of a phenol with a sulfonyl chloride in pyridine or aqueous sodium hydroxide, are cleaved by warming in aqueous sodium hydroxide. ... 

Limited reports on the mechanism of the Greabe-Ullmann reaction have appeared. A diradical intermediate is presumably involved in the thermolysis of the triazole 4. ... 

The extension of the method to the synthesis of y-carboline from 1-y-pyridylbenztriazole (199) and of a 3,4-benz-y-carboline from a l-(4-quinolyl)benztriazole proceeded smoothly. In an alternative approach excellent yields of y-carboline were obtained by heating l-phenylpyrido[3,4-d] -triazole (200) at 320-350°. The synthesis of halogeno-substituted j8- and y-carbolines via the Graebe-Ullmann reaction has been reported. ... 

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... 

Reduction with zinc dust in aqueous sulfuric acid gives 2-methyl-4-aminothiophenol (28) Condensation with 2-chlorobenzoic acid (Ullmann reaction) leads to 29, which can close to but one thiox-anthone (25) on treatment with sulfuric acid. Although this procedure is longer than the original, the yields are good and the sequence is regioselective. ... 

With alcohols or more often with alcoholates (refs. 51 - 56) or phenolates (refs. 57 - 64) the arylethers are formed. Typically, one of the Ullmann reactions is corresponding to the diarylethers synthesis. 

This scheme is selfexplanatory. Important in the formation of PBDD by Ullmann reaction of brominated phenoxy radicals. Influences of added water, air content and other factors on PBDD/F yield and pattern have also been studied in detail (ref. 11). 

Vinylic halides can be coupled to give 1,3-butadienes by treatment with activated copper powder in a reaction analogous to the Ullmann reaction (13-14). " This reaction is stereospecific, with retention of configuration at both carbons. 

The coupling of aryl halides with copper is called the Ullmann reaction. The reaction is of broad scope and has been used to prepare many symmetrical and... 

An asymmetric Ullmann reaction has also been reported." ... 

Stephen reaction Stobbe condensation Ullmann reaction Willgerodt reaction. ... 

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. 

The coupling of the aryl aldehyde 84 and the a-iodoenone 85 was effected by a modified Ullmann reaction (83 %, Scheme 3.16) [42], The resulting arylation... 

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