The Ullmann and Related reactions

The yields of symmetrical biaryls in the Ullmann reaction may vary from approximately a few to more than 90%, depending on the reactant structure and reaction conditions [1-6]. However, in many examples the yields of biaryls were moderate to high. Theoretically, the Ullmann reaction requires two equivalents of the copper metal per one equivalent of the biaryl formed, thus two equivalents of copper(I) halide are generated. Practically, several equivalents, three to tenfold excess, of the copper metal are used in order to reach high conversion of the aryl halides [3,4,5]. The reactivity of the aryl halide with the copper metal in homo-coupling reactions is 

The substituents in the phenyl (aryl) ring have a remarkable influence on the reactivity of the aryl halide in the Ullmann coupling reaction [4,5,9,10]. They can be divided into three groups  

The activating effect in the Ullmann coupling reaction of aryl halides provides the electronegative groups such as nitro, alkoxycarbonyl or cyano in the orrAo-position to the halogen atom. These activating substituents present in the meta- or pura-positions do not significantly activate the aryl halide. For example, 2-nitro-bromobenzene reacts with the copper bronze more rapidly and at a lower temperature, while the 

Ullmann coupling reaction of 4-iodotoluene with the Na2EDTA-pretreated copper powder afforded the expected 4,4 -dimetylbiphenyl with a three times faster reaction. 

Moreover, the copper metal obtained by reduction of CuCl, CuI(PEt3) or Cu(SMe2)Cl with the lithium naphthalide, known as Rieke copper, is able to couple a range of aryl halides to biaryls at room temperature in very high yields [27]. For example, simple halobenzenes react with Rieke copper at room temperature to form phenylcopper(I) reagents which, upon refluxing in DME at 80 °C for 24 h, gave 66% of biphenyl. The 

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The reaction of 1,3-dinitrobenzenes with aryl iodides can be accomplished by using copper(I) tert-butoxide in situ prepared from CuCl and potassium rert-butoxide in dry DME. In this case, the reaction can be realized under essentially milder reaction conditions, at 70-110 C in the presence of pyridine as the base with respective yields. For instance, the biaryl 40 was produced from compounds 38 and 39 after 20 h at 67 C in DME / pyridine as the reaction solvent in 95% yield, respectively [38]. Dehalogenation products were isolated from many Ullmann reactions performed with the (relatively acidic) nitro-aryl halides, even when exclusion of water or acidic (protic) substances was provided. Furthermore, nitro-aryl halides are partially converted to triarylamines by reduction and subsequent exhaustive A -arylation [44,45]. Finnaly, it can be concluded that the Ullmann and related reactions are still valuable tools in the preparative organic chemistry providing a simple and usually efficient approach to simple symmetrical and certain classes of unsymmetrical biaryls. 

Biaryls. The cross-coupling of ArMnCl with aryl halides and triflates using (PhjPljPdClj as catalyst is an alternative method to Ullmann and related reactions. 

R = CHj, R = and adenocarpine(16 R = CH=CHPh, R = H) ° are likewise dehydrogenated to 2,3 -bipyridine, and related dehydrogenation reactions afford substituted 2,3 -bipyridines. Ullmann and Grignard reactions have been used to synthesise 2,3 -bipyridine, whereas the Gomberg reaction of 3-pyridinediazonium chloride with pyridine and alkyl pyridines affords 2,3 -bipyridine, along with other isomeric bipyridines, and alkyl substituted 2,3 -bipyridines, respectively. " Photolysis of 3-... 

Several of the methods of synthesis of 2,2 -bipyridines have their counterpart in the preparation of 4,4 -bipyridine. The Ullmann reaction has been used to prepare 4,4 -bipyridine. Thus 4-halogenated pyridines afford 4,4 -bipyridine. Dehalogenation and dimerization of 4-bromopyridine may be accomplished too with hydrazine and alkali at 65°C in the presence of a palladium catalyst, whereas 4-chloropyridine is converted to 4,4 -bipyridine in 46% yield by reaction with alkaline sodium formate in the presence of palladium on charcoal and a surfactant. Several extensions of the Ullmann reaction have recently been reported, especially for the synthesis of substituted 4,4 -bipyridines. Thus 4-iodo-2-methylpyridine gives 2,2 -dimethyl-4,4 -bipyridine, 3-nitro-4-chloropyridine affords 3,3 -dinitro-4,4 -bipyridine, 4-bromo- or 4-iodotetrafluoropyridine gives octafluoro-4,4 -bipyridine, and 4-iodo- or 4-bromotetrachloropyridine gives octachloro-4,4 -bipyridine. Related syntheses have been de-... 

A bromine atom on the benzene ring of chromones takes part in the Rosenmund-von Braun reaction to give moderately good yields of the nitrile, for example ethyl 8-cyano-6-methylchromone-2-carboxylate (545) (72JCS(Pl)779). Iodochromones and iodoflavones undergo the Ullmann reaction to form bis-compounds, some of which occur naturally or are related to such biflavonoids (B-75MI22302, 72JMC583). 

The reactions between i-dinitrobenzene or 1,3,5-trinitrobenzene, aryl halides, and copper(I) oxide in quinoline 17-19, 21) provide a simple synthesis of nitrobiphenyls uncontaminated by symmetrical biphenyls. These couplings may be related to the Ullmann reaction, the decarboxylative coupling of benzoic acids with aryl halides, and the preparation of ethers from phenols 165). Although no intermediates... 

A related reaction is the coupling of two molecules of aryl halide by metallic copper at temperatures above 100° (Ullmann). Activated copper bronze or freshly precipitated copper is used. The order of activity of the aryl halides is I > Br > Cl. Both symmetrically and unsymmetrically substituted biaryls may be prepared in fair yields. An excellent review of the literature to 1945 has been made. Most functional groups do not interfere hydroxyl, carboxyl, amino, and acetamino groups are exceptions. ... 

The coupling of aryl halides with copper is called the Ullmann reaction The reaction is clearly related to 13-9, but involves aryl copper intermediates. The reaction is of broad scope and has been used to prepare many symmetrical and unsym-metrical biaryls." When a mixture of two different aryl hahdes is used, there are three possible products, but often only one is obtained. For example, picryl chloride and iodobenzene gave only 2,4,6-trinitrobiphenyl." The best leaving group is iodo, and the reaction is most often done on aryl iodides, but bromides, chlorides, and even thiocyanates have been used. 

Since articles in the encyclopedias of general knowledge as well as in the technical encylopedias are written by specialists, one may find authoritative information in those works, though an oblique approach may be needed in order to find some subjects. Thus, Ullmann s Encykhpddie der technischen Chemie relates detailed information on the metallurgical and other commercial uses of the thermite reaction under Aluminothermie (Vol. 1) and treats the subject of fireworks rather extensively under Pyrotechnik (Vol. 14). This edition has not as yet (1966) reached its final volume, which will contain the subject of matches under Ziindwaren. 

As we saw briefly in Chapter 53, the photochemical version of the Graebe-Ullmann carbazole-carboUne synthesis can be an excellent route to these heterocycles. Similar to this benzotriazole reaction is the photolysis of aryl azides to give carbazoles and related fused indoles. 

Kametani T, Fukumoto K, Shibuya S, Nakano T (1963) (Tularine and related compounds. V. Investigation of the Ullmann reaction products of methyl (2-bromo-4,5-dimethoxyphenyl) acetate with phenolic compounds, and an approach to the total synthesis of cularine. Chem Pharm Bull 11 1299-1305... 

The butadienylphosphine L8 and related molecules, obtained from a synthetic method based on the phosphorus ylides, are efficient ligands in Ullmann-type copper-catalyzed arylation reactions, particularly for nitrogen heterocycles (Table 1, entry 4). The reactions often proceed to completion in a very short time. 

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