Crossed Ullmann reaction

When 2 -methoxy-2-biphenylamine is diazotized in fluoroboric acid, an 85% yield of solid 2 -methoxy-2-biphenylyldiazonium tetrafluoroborate is produced. On heating in dry benzene, this salt loses nitrogen and provides 0-methyldibenzofuranium tetrafluoroborate as an unstable solid. The latter salt, on account of the low basicity of dibenzofuran, reacts with a range of nucleophiles that undergo methylation with the release of dibenzofuran. Pyridine and pentachloropyridine are N-methylated, benzo[fc]thiophene is S-methylated, and tetrahydrofuran and phenetole are 0-methylated. ° Thus it is no surprise that diazotization of 2 -methoxy-2-biphenylamine, followed by boiling of the diazonium salt in acidic solution, provides dibenzofuran in 90% yield.The scope of this method of dibenzofuran synthesis (Scheme 18) has been little explored probably because of the difficulty of preparing the requisite biphenyls, which is usually accomplished by a crossed Ullmann reaction. A similar synthesis of xanthones from 2-amino-2 -methoxybenzophenones is known. ° ... 

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. 

Active copper powder. A highly reactive copper powder can be prepared by reduction of Cut with potassium naphthalenide in DME (8 hours). The slurry should be used immediately. It is particularly effective for Ullmann reactions high yields of biaryls are obtained even at 85°. It also promotes cross-coupling with allyl halides. ... 

The classical Ullmann reaction has also attracted renewed interest in recent years. Miyano has prepared optically enriched binaphthyl derivatives by intramolecular biaryl coupling, as shown in equation (9). " Diastereoselectivities of up to 70% have been obtained with a binaphthol chiral auxiliary in the linking chain. Intermolecular cross-coupling is best accomplished with preformed arylcopper compounds. "... 

The 1,4-conjugate addition of triorganoindium to enones is promoted by a catalytic amount of Ni(COD)2 (Scheme 8.71) [100], Allylindium reagents can be used in Pd-catalyzed cross-coupling reaction with aryl halides (Scheme 8.72). The Pd-catalyzed allylic substitution of allyl carbonate produces 1,5-dienes (Scheme 8.73) [101]. The indium-mediated palladium-catalyzed Ullmann-type reductive coupling of aryl halides proceeds in aqueous media under air (Scheme 8.74) [102]. 

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. 

Silyl enol ethers (CHj = CROSiMe3) react with cyanuryl chloride and replace only one chlorine with a carbon substituent (CH2COR R = cyclopropyl, 70 /o, R = Ph, 90 /o). Friedel-Crafts arylation <83KGS1125,92EUP497734>, the Ullmann reaction of 2-iodo-1,3,5-triazine to form 2,2 -bis-1,3,5-triazine <82NKK1425>, and a palladium-catalyzed cross-coupling reaction of 2-substituted 4,6-dichloro-... 

Several new alternatives to the classical methods of synthesis of biheterocycles have been developed. Most notable among these are low-valent transition metal-catalyzed homo-coupling reactions, which are particularly applicable to the synthesis of biheterocycles, and which give much better yields than the earlier Ullmann and Busch procedures. Furthermore, un-symmetrical biheterocycles are now more readily available by way of palladium-catalyzed cross-coupling reactions, such as the Stille and the Suzuki procedures. Thus, many new members of the biheterocyclic series are now available for study. As a consequence of the increased sophistication of molecular structure determination techniques, aromatic biheterocycles have been the subject of many recent spectroscopic and X-ray crystallographic studies, as well as numerous molecular orbital and molecular mechanics calculations. 

The Aspidosperma alkaloids are a group of more than 100 monomeric and dimeric monoterpene indole alkaloids with aspidospermidine (228) representing a key member of the class and sometimes considered to be the parent [68]. Numerous total syntheses of this pentacyclic compound have been reported. Our own contributions in the area were prompted by the discovery of a new method for preparing indoles via a palladium-catalysed Ullmann cross-coupling reaction that proceeds especially efficiently at close to room temperature [69] and which we felt could serve as the centrepiece in developing a new synthesis of compound 228 and, in the longer term, syntheses of dimeric members of the indole alkaloid class such as the clinically significant alkaloids vinblastine and vincristine. 

Yamamoto-type Ullmann Cross-coupling Reaction... 

DoM-Ullmann Cross-Coupling. Synthesis ofAr-X-Ar (X = 0, N, S) under Modified Ullmann Reaction Conditions (General Procedure, Table 14.19)... 

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