Synthesis of unsymmetrical diaryls

Unsymmetrical diaryls may be prepared by treating an aryl diazonium salt solution with sodium hydroxide or sodium acetate in the presence of a liquid aromatic compound. Thus 2-chlorodiphenyl is readily formed from o-chloro phenyl diazonium chloride and sodium hydroxide solution (or sodium acetate solution) in the presence of benzene  

This is sometimes called the Gomberg or the Gomberg - Hey reaction. 

The mechanism of the reaction probably involves the intermediate formation ofthe covalent dlazo-hydroxide from the diazonium salt the former decomposes 

The usual directive influences are not operative in this and similar reactions for ortho - para substitution occurs (this may be modified by steric hindrance) irrespective of the nature of R in the aromatic liquid CsHjR, e.g. phenyldlazo hydroxide and nitrobenzene yield 4-nitrodiphenyl this supports the assumption that neutral free radicals are formed. 

2-Chlorodiphenyl. Diazotise 32 g. of o-chloroaniline (Section IV,34) in the presence of 40 ml. of concentrated hydrochloric acid and 22 -5 ml. of water in the usual manner (compare Section IV,61) with concentrated sodium nitrite solution. Transfer the cold, filtered diazonium solution to a 1 5 htre bolt-head flask surrounded by ice water, introduce 500 ml. of cold benzene, stir vigorously, and add a solution of 80 g. of sodium acetate trihydrate in 200 ml. of water dropwise, maintaining the temperature at 5-10°. Continue the stirring for 48 hours after the first 3 hours, allow the reaction to proceed at room temperature. Separate the benzene layer, wash it with water, and remove the benzene by distillation at atmospheric pressure distil the residue under reduced pressure and collect the 2-chlorodiphenyl at 150-155°/10 mm. The yield is 18 g. Recrystalliae from aqueous ethanol m.p. 34°. 

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Methyl aryl ketones can be synthesized via carbonylation of aryl iodides and tetramethyltin in the presence of a nickel catalyst (equation 14). Unfortunately the reaction cannot be extended to the synthesis of unsymmetrical diaryl ketones since tetraphenyltin does not react under these conditions. 

Reproduced with permission from Mukherjee N, Chatterjee T, Ranu BC. Reaction under ballmilling solvent-, ligand-, and metal-free synthesis of unsymmetrical diaryl chalcogenides. J Org Chem 2013 78 11110-4, Copyright 2013, American Chemical Society. 

A recent application of enzyme catalysis (oxalyl chloride, 50 U aminoacylase E.C. 3.5.1.14, hexane, 4 days, 20 °C) for the synthesis of unsymmetrical diaryl ketones has been reported [949]. 

Sequential synthesis of the and anions by electrochemical reduction of the elements Se or Te provides a route to both dialky 1-di- and monoselenides and tellurides [35]. Ultrasound has also been used to promote the electrochemical synthesis of unsymmetrical diaryl chalcogenides typified by 4-phenylseleno- and -tellurobenzonitrile [228]. However, the rate enhancements observed when electrochemical reactions are exposed to ultrasound would appear to stem from the increase in mass transport rather than cavitational effects [229]. 

This aryl amination protocol was next extended to aromatic diamines. In this case, IPr was found as the best ligand and iV,iV -diarylation of aromatic diamines was obtained in high yields in 1,4-dioxane at 100 C." Diamines with spacers such as biphenyl, phenoxyphenyl or benzylbenzene were also efficiently arylated. Interestingly, the selective mono-amination of unsymmetrical diamines was obtained and therefore a two-step procedure for the synthesis of unsymmetrical -diaryl aromatic diamines could be developed. 

SCHEME 5.31 Nickel-catalyzed synthesis of unsymmetrical diaryl sulfides [47]. 

The oxidative cyclization of thioacylamidines 83 is one of the best methods for the synthesis of unsymmetrical 3,5-diaryl- or dialkyl-1,2,4-thiadiazoles 84 (Equation 23) <2004HOU277>. Typical oxidants used in the cyclization step include bromine, iodine, or nitric acid, and, more recently, hydrogen peroxide in the presence of perchloric acid has been used. N-Substituted thioacylamidines give rise to 1,2,4-thiadiazolium salts <1997JOC3480>. 

Nevertheless, there are certainly a number of painful limitations. There is no simple and efficient method for the synthesis of unsymmetrical N,N -diaryl-substituted imidazolium salts, very desirable compounds. Furthermore, the Buchwald-Hartwig-like cross-coupling reaction of N-monosubsti-tuted imidazoles with arylhalides, which would result in the formation of imidazolium salts, has not been reported yet. However, unsymmetrical N,N -... 

A promising method for the synthesis of unsymmetrical diorgano tellurium compounds uses carboxylic acid derivatives and diaryl ditellurium as starting materials. The carboxylic acid chloride, prepared in quantitative yield from the acid and oxalyl chloride is added slowly to a mixture of a diaryl ditellurium and the sodium salt of 2-mercaptopyridine N-oxide in toluene at 35". Under normal laboratory light the aryl tellurium radicals... 

A stepwise Stille reaction enables the synthesis of unsymmetrical 3,3-diaryl-2-propen-l-ol derivatives. The first reaction occurs by replacement of the (Z)-substituted stannyl group of 3,3-bis(tributylstannyl)allyl methoxymethyl ether. ... 

This ligand class is quite useful for the synthesis of unsymmetrical alkyl diaryl amines.39 Typically, a primary aliphatic amine is first arylated using the Pd/BINAP catalyst system. The second arylation is then carried out with L6, Xantphos, or PPF-OMe (with CS2CO3 if a base sensitive aryl bromide). Ligand choice for the second arylation depends upon the electronic nature of the N-alkylaniline and Ar2Br as outlined in the table. They were unable to couple 2-bromobenzaldehyde, 4-(4 -bromophenyl)-2-butanone, or 4 -bromoacetophenone with N-alkylanilines (alkyl > Me). 

The method can be used for synthesis of unsymmetrical olefins if one component is used in excess. Highest yields are obtained for diaryl ketones in some cases mixed coupling can occur in a 1 1 ratio.- ... 

Reaction of aryl diazonium tetrafluoroborate 90 and diaryl dichalcogenides (disul-fane, diselenide, and ditelluride) 91 under ball milling at ambient temperature was applied in the synthesis of unsymmetrical aryl chalcogenides 92 by Ranu et al. 

Figure 2.11 A cross-section of results for the Pd-catalyzed synthesis of unsymmetrical and symmetrical diaryl sulfides with potassium thioacetate, as reported by Park et al. [52],...

Singh et al. (2008) studied a microwave-assisted [4+2] cycloaddition reaction for the synthesis of unsymmetrically substituted 1,4-dihydropyridines. 1,4-Dihy-dropyridine analogs such as Nifedipine and Nimodipine are well known for their potent biological activities. Microwave-assisted [4+2] cycloaddition of 1,4-diaryl-1-aza-1,3-butadienes with allenic esters at 100°C for 5-17 min gave cycloadducts in excellent yields (83-96%), which after a tandem 1,3-H-shift furnished unsymmetrically substituted 1,4-dihydropyridines. 

A closely related protocol for the synthesis of imidazoles was independently investigated by Sparks and Combs (Scheme 6.199) [362]. Here, the authors employed readily available unsymmetrical keto-oximes as building blocks, initially leading to N-hydroxyimidazoles. Diaryl keto-oximes were condensed with various aldehydes (1.1 equivalents) in the presence of 4 equivalents of ammonium acetate under microwave conditions at 160 °C. In this way, the N-hydroxyimidazoles were formed... 

The coupling of thioamides with a variety of oxidizing agents is a widely utilized method for the synthesis of 3,5-diaryl-l,2,4-thiadiazoles (see Section 5.08.9.2). This method is not suitable for alkyl derivatives. 3,5-Dialkyl derivatives can be more effectively prepared from a suitably substituted thioacylamidine (see Equation 22), and this method allows a range of unsymmetrical derivatives to be prepared. 

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