Biaryl sulfone

The positive results observed in biaryl amide (Scheme 22) and O-carbamate (Scheme 23) DreM reactions, chemists Gilman, Truce, and Narasimhan, and the prince of serendipity all played roles in triggmng studies of caibanionic reactions of 2-amido 124 (DMG = CONEt2, X = SO2) and 2-O-carbamoyl 124 (DMG = OCONEt2, X = SO2) biaryl sulfones (Scheme 30). In fact, the mental insertion of any heteroatom X into biaryl 124 provokes questions regarding its anionic chanistry for DMG = CONEt2, by... 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

Scheme 17 illustrates another fluorous sulfonate-based synthesis of library scaffolds. The tagged substrates were taken through aldol condensation and cycloaddition reactions to form the pyrimidine ring 18. The intermediates were then reacted with boronic acids for Suzuki reactions to form biaryl compounds 19 [31], reacted with HCO2H to give traceless detagged products 20 [34], or reacted with amine to form products 21 [33]. 

X = CH2, 31h-k) and sulfones (Y = S02. X = CH2, 311,m) participated effectively in the oxidative coupling reaction. Dibenzyl ethers (Y = O, X = CH2, 31n-r) were also coupled in fair to good yields. Cleavage of the temporary tether subsequently delivers the acyclic biaryls 33a-r. 

Similarly superior results in comparison to the application of sulfonated phosphine ligands were achieved in the Pd-catalyzed biaryl coupling of arylboronic acids in aqueous media by use of the ligand glcaPHOS 11 [16]. The phosphine was prepared in a single step by the condensation of D-glucono-1,5-lactone with p-diphenylphosphinobenzylamine. 

Cobalt chloride (ous) Diethyl pyrocarbonate Lithium citrate BHT substitute, polyolefins Octadecyl 3,5-di-t-butyM-hydroxyhydrocinnamate Bi detection Dimethyl glyoxime biaryl formation Trifluoromethane sulfonic acid bilirubin testing, urine 5-Sulfosalicylic acid 5-Sulfosalicylic acid dihydrate binder... 

The use of dry aryldiazonium salts of naphthalene-1-sulfonic [70], naphthalene-1,5-disulfonic [70], ZnCl2 complex [70], hexafluorophosphoric or tetrafluoroboric acid [61] in non-aqueous medium under as mild as possible reaction conditions is substantial to reach higher yields of biaryls. An alternative method for non-aqueous GBH reaction is the aprotic diazotation of aromatic amines with alkyl nitrites such as butyl or pentyl nitrite with subsequent arylation of aromatic compound, as demonstrated by Cadogan [71,72]. This method is realized by simple heating the mixture of aromatic amine, alkyl nitrite and liquid arene at an elevated temperature. When a mixture of 3-aminopyridine (46), benzene and pentyl nitrite is heated at reflux, 3-phenylpyridine (47) is obtained with a 55% yield [71], Scheme 16. 

Exactly the same method was successfully employed in the synthesis of 2,2 -bipyridines bearing a free amino group. Thus 4,4 -diamino-2,2 -bipyridine was prepared from 5-amino-2-chloropyridine in 60% yield, respectively [38]. Nickel-catalysed synthesis of biaryls and related vinyl halides were successfully used in a great number of examples [39,40], including the strained aromatic ether-sulfone oligomers [41]. For instance, compound 84 was cyclized to a very strained cyclic... 

Apart from aryl halides, other very easily available substrates for nickel-catalysed biaryl (II) synthesis are aryl sulfonates (XII). Method D is very efficient in the homocoupling reactions of substituted aryl sulfonates in good to excellent yields [15], Table 6. Substituted aryl sulfonates are readily obtained from phenols and trifluoromethanesulfonic anhydride, benzenesulfonyl-, tosyl- or methanesulfonyl chloride in pyridine, or in a suitable inert solvent such as dichloromethane in the presence of triethylamine or Hiinig s base. Among other nickel complexes, Ni(dppe)Cl2 and Ni(dppf)Cl2 have been used (10 mo1%) as slightly less versatile catalysts for the homo-couplings of naphthyl sulfonates in refluxing THF, DMF or their mixtures [42]. 

Table 6. Homo-coupling of aryl sulfonates (XII) to biaryls (II) using method D [15]...

The reactivity of aryl triflates [24,32,36,49] and other sulfonates [45,48] can be slightly different than is presented here, what depends on the catalyst and the reaction conditions used. For example, the SM reactions of aryl chlorides in the presence of aryl triflates catalysed by Pd2(dba)3 / 2Pt-Bu3 have given exclusively the biaryl derived from the chloride, whereas the use of Pd(OAc)2 / 2PCy3 catalytic system leads to predominant SM reaction of aryl triflate. The latter results indicate the fact, that the (phosphine) ligand(s), not the palladium (nickel) source, controls chloride / triflate selectivity, as well as other closely reactive substrates. 

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