Diaryl amine

ULLMANN GOLDBERG Aromatic substitution Cu catalyzed substitution of aromatic halides in the synthesis of disryls, diaiyl ethers, diaryl amines, phenols... 

Secondary amines have been converted to tertiary amines by treatment with lithium dialkylcuprate reagents R2CuLi -t- NHR RNR2 The reaction was also used to convert primary amines to secondary, but yields were lower. However, primary aromatic amines (ArNH2) were converted to diaryl amines (ArNHPh) by treatment with Ph3Bi(OAc)2 and a copper powder catalyst. 

Proximity effects and ortho interactions in 2,2/-disubstituted diaryl amines have been reported104. Thus, phenazine, phenazine-N-oxide and carbazole were formed by loss of small neutral fragments, such as NO, NO2 and NO3, from the molecular ions, as illustrated by the formation of carbazole from 2,2/-dinitrodiphenylamine see Scheme 34. Of particular interest is the loss of NO3, as demonstrated by high-resolution MS data and metastable ion spectra104. 

Diaryl amines, ethers or sulphides, or their aryl vinyl analogues, provide another 6-electron system related to stilbene, but for these a pair of electrons is provided by the single heteroatom (ArXAr or ArXC=C). With dtaryl compounds the initial photocydized product is a zwitterion that undergoes a proton shift to give, for example, N-methyl-4a,4b-dihydrocarbazole from methyldiphenylamine, with subsequent oxidation to N-methylcarbazole (3.74). With the aryl vinyl analogues the product after the proton shift can normally be isolated (3.751. An especially useful variation of this reaction employs... 

AMINES - AMINES,AROMATIC - DIARYL AMINES] (Vol2)... 

Fig. 16.6. Copper-mediated nucleophilic substititon reactions with aryl iodides or bromides for the preparation of diaryl ethers, diaryl sulfides, diaryl amines and arylmalonic esters (A). Often, these reactions are also referred to as Ullmann reactions.

Two recent reports have detailed the palladium-catalyzed formation of diaryl-amines to prepare nucleosides of damaged DNA. Sigurdsson et al. reported the formation of a precursor to an interstrand cross-link by the reaction in Eq. (35) [158]. Lakshman reported the reaction of bromonucleosides with amines shown in Eq. (36) as a route to the DNA adducts of carcinogenic aminobiphenyls [159]. In this case, a number of reaction conditions were attempted and those using potassium phosphate and the P,N ligand 13 were effective for the transformation, albeit with high catalyst loads. 

Nolan reported the use of the 2,6-diisopropylphenyl imidazolium carbene precursor, which contains an unsaturated backbone, for the reaction of aryl chlorides with a variety of amines at 100 °C [165, 166]. This temperature is lower than those conventionally used for reactions of aryl chlorides, but is higher than those used with P(tBu)3 or the 2-biphenylyl di-tert-butylphosphines. Reaction yields were high when 2 mol % palladium was used. Reactions of primary amines occurred in good yield, even when unhindered aryl halides were used. The monoarylamine was obtained in 86 % yield, and only a 5 % yield of the diaryl-amine by-product was isolated. Notably, reactions of both aryl bromides and iodides proceeded at room temperature. 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules of biological relevance. The ability to prepare haloarenes selectively by an ortfio-metalation-halogenation sequence allows the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metalation to form aryl halides that were subsequently allowed to react with anilines to form diarylamines (Eq. (34)) [209]. Frost and Mendonqa have reported an iterative strategy to prepare, by the palladium-catalyzed chemistry, amides and sulfonamides that may act as peptidomimetics. Diaryl-amine units were constructed using the DPPF-ligated palladium catalysts, and the products were then acylated or sulfonated with 4-bromobenzoyl or arylsulfonyl chlorides [210]. Le-miere has coupled primary arylamines with 4-chloro-3(2H)-pyridazinones to form compounds with possible analgesic and antiinflammatory properties. 

In the diaryl amine series 191 (Scheme 47), additional, synthetically valuable, anionic pathways provide routes to anthranilates 190, oxindoles 192, and dibenzazepinones 194. Although not explored in terms of its scope [75c], the lateral metalation-cydization, 191 -> 192, is extensively precedented [69] but harbors intriguing potential for subsequent DreM chemistry. The rearrangement 191 —> 190 is an N —> ortho C anionic Fries equivalent of the aryl O-carbamate migration (Scheme 3E) [75c] and after N-methylation, 190 may be transformed into 1,2,3-trisubstituted systems 193 [76]. In another appealing manifestation of CIPE, the efficient conversion of 191 into dibenzazepinone 194 has been applied in an effective synthesis of the antiepileptic drug oxcarbazepine (Trileptal ) 195 [77] and may also be... 

In the second classical method (Bischler synthesis), an aromatic primary or secondary (arylalkyl, but not diaryl) amine is condensed with an obromo (or better, hydroxy) ketone to give a 2,3-dialkylindole. This in turn is alkylated directly to the 1,2,3,3-tetraalkylindoleninium salt. Use of acetoin gives 2,3-dimethylindole, which is easily isolated and purified. The Bischler synthesis from a substitued aniline, and especially from anilines bearing one or more alkoxy groups, is much preferred in practice for indoles substitued in the 4-7-positions, since the substituted aiylhy-drazines needed for the Fischer synthesis are costly, unstable, or unavailable. 

Sawyer, J. S., Schmittling, E. A., Palkowitz, J. A., Smith, W. J., III. Synthesis of diaryl ethers, diaryl thioethers, and diaryl amines mediated by potassium fluoride-alumina and 18-crown-6 Expansion of scope and utility. J. Org. Chem. 1998, 63, 6338-6343. 

Molybdate esters These compounds are prepared by reaction of alkanols and molybdenum sources such as ammonium molybdate and molybdenum oxides, and are believed to form mononuclear mono- and dioxo- structures, as in Reaction (4.44) [54,55], These preparations are condensation reactions and require removal of water to drive the reaction to completion. Molybdate esters, like molybdenum carboxylates, show synergistic effects with diaryl amines [52] and with combinations of diaryl amines and sulphurised hindered phenols and/or sulphurised olefins [53],... 

Substitution of aromatic halides or recrystes in the synthesis of diaryls, diaryl ethers, diaryl amines, phenols etc catalyzed by Cu and other catalysts... 

Ammonia, mono and dialkyl or mono and diaryl amines form 1 1 adducts with organoaluminum compounds A1R3 (R = hydride, alkyl, aryl) at below 0°C and these split off hydrogen (from R2A1H) or alkane (from RjAl) on warming (12, 56, 73, 151, 152, 153,164, 330, 351) e.g., the products are dialkyl(aryl)-dialkyl(aryl)amino alanes ... 

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). 

Acridines are an important structural feature of many natural products and medicinally important compounds. They can be produced in a straightforward manner by a Friedel-Crafts reaction, the Bernthsen acridine synthesis, 1 9 which couples diaryl amines (such as diphenylamine) with a carboxylic acid (such as benzoic acid) in the presence of a Lewis acid (zinc chloride, ZnCl2, is a typical reagent). Heating to 260°C (10 h) gave a 48% yield of acridine 317.1 9 ... 

---