N-arylated heterocycles

N-Arylated heterocycles are an important class of compounds often associated with biological activity. It has been shown that yields and reaction rates in copper(II)-mediated C-N cross coupling reactions on a solid support could be dramatically im-... 

Recently, Taillefer et al. reported an Fe/Cu cooperative catalysis in the assembly of N-aryl heterocycles by C—N bond formation [90]. Similarly, Wakharkar and coworkers described the N-arylation of various amines with aryl halides in the presence of Cu—Fe hydrotalcite [91]. Interestingly, Correa and Bolm developed a novel and promising ligand-assisted iron-catalyzed N-arylation of nitrogen nucleophiles without any Cu co-catalysts (Scheme 6.19) [92]. Differently substituted aryl iodides and bromides react with various amides and N-heterocycles. The new catalyst system consists of a mixture of inexpensive FeCl3 and N,N -dimethylethylenediamine (dmeda). Clearly, this research established a useful starting point for numerous future applications of iron-catalyzed arylation reactions. 

Using the bulky AT-heterocyclic carbene 130 as a ligand for Pd(0) complexes Schneider and coworkers [104] have recently reported a novel synthetic strategy to five-, six- and seven-membered N-arylated heterocycles 131-135 via sequential Pd-catalyzed intra- and intermolecular arylamination reactions (Scheme 49). 

The aryl amination protocol described previously was found to be incompatible with the formation of N-aryl heterocycles such as N-arylindoles. The electron richness of heteroaromatic substrates limits the applicability of N-arylation of indoles to more reactive aryl iodides and bromides. However, good results were obtained in coupling a number of aryl bromides and indole derivatives employing a Pd(OAc)2/SIPr HCl/NaOH catalytic system. This protocol additionally overcomes a common problem in indole synthesis, namely the formation of C-arylation side products (Scheme 23). 

The quinazolinone structure is found in many biologically active compounds methaqualone, mecloqualone, piriqualone, afloqualone, and so on. Methaqualone (MQ, 470), 2-methyl-3-(2-methylphenyl)quinazolin (3H)-one, an hypnotic and anticonvulsive drug, is one of the leading examples of atropisomeric six-membered N-aryl heterocycles. Methaqualone gives stable atropisomers at room temperature due to the three substituents in ortho positions of the N-aryl rotating bond. 

Combs et al. [73] reported the first examples of polymer-supported aryl-heteroaryl C-N cross-coupling reactions and dramatically decreased reaction times upon microwave irradiation. The methodology provides easy access to N-arylated heterocycles from heterocycles bearing an N-H bond and readily available arylboronic acids in the presence of copper(II) acetate and pyridine. 

Boron-nitrogen heterocycles [4,5-diethyl-2,2,3-trimethyl-l-(<9-tnfluoro-methyl)phenyl-2,5-dihydro-l(-)-],2,5-azasilaboroles and -azastannaboroles] are formed in good yields The products demonstrate atropoisomensm due to the hmdered rotation about the N-aryl bond [113] (equation 88)... 

Heterocyclization by catalytic formation of N—Car bond to give indoles, amino-pyridines, and N-aryl-substituted saturated heterocycles 98ACR805. 

The N,0- and N,S-heterocyclic fused ring products 47 were also synthesized under radical chain conditions (Reaction 53). Ketene acetals 46 readily underwent stereocontrolled aryl radical cyclizations on treatment with (TMSlsSiH under standard conditions to afford the central six-membered rings.The tertiary N,0- and N,S-radicals formed on aryl radical reaction at the ketene-N,X(X = O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from (TMSlsSiH was investigated and found to provide higher selectivities than BusSnH. 

Treatment of [IrCl(CO)2(/ -toluidene)] with azine phosphines of type Z, -PPh2CH2C( Bu) =N-N=C(Q)R, Q = H, Me, R = an organic group, activates aryl, heterocyclic, alkenyl, or aliphatic C—H bonds to give cyclometalated Ir111 hydrides.339... 

In a separate study, Ohberg and Westman applied the same PS-DMAP in a one-pot microwave-induced base-catalyzed reaction of N-aryl and N-alkyl amino acids (or esters) and thioisocyanates for the library synthesis of thiohydantoins (Scheme 7.115) [136]. Thiohydantoins are of interest due to their ease of preparation and the range of biological properties associated with this heterocyclic ring system. The use of PS-DMAP as the base in this reaction gave slightly lower yields compared to when triethylamine (TEA) was used, but it resulted in a cleaner reaction mixture and an easier purification procedure. Cyclizations of a number of N-substituted... 

N-alkyl- and N-aryl-substituted acyclic or cyclic imines and the subsequent cycliza-tions providing the heterocyclic target compounds [74, 79]. ... 

Elguero, J., Jacquier, R. and Mondon, S. (1970) NMR studies in the heterocyclic series, IV conformation of N-aryl azoles influence of sp hybridized nitrogen atoms on the deshielding of o-protons of the neighboring aromatic nucleus. Bull. Soc. Chim. Fr. 1346-1351. 

Heterocycles containing an NH group, such as pyrroles, indoles, imidazoles, triazoles, etc., can be linked to insoluble supports as N-alkyl, N-aryl, or N-acyl derivatives (Table 3.29). The optimal choice depends mainly on the NH acidity of the heterocycle in question. Increasing acidity will facilitate the acidolytic cleavage of N-benzyl groups and the nucleophilic cleavage of /V-acyl groups from these heterocycles. 

The cycloaddition of diazomethane to SchifT bases from heterocyclic aldehydes and anilines provides a useful route to heterocyclic substituted triazolines. Unlike olefins bearing heterocyclic substituents, the heterocyclic imines can be obtained readily by reaction of the appropriate aldehyde and amine thus the diazomethane-imine addition has greater scope than the olefin-azide reaction. NMR spectroscopic studies of the orientation of addition are in accord with previously reported mechanistic considerations (see, e.g., Scheme 93).329 In addition to the influence of the N-aryl group, the electron-withdrawing power of the heterocyclic substituent on the Schiff-base carbon also has a substantial effect on imine reactivity, in the order 2-quinolyl 2-, 3-, or 4-pyridyl > phenyl > 2-thienyl as 2-furyl.329... 

Furthermore, direct halogenation sometimes leads to substitution in the C-residue of the aldehyde hydrazone. For example, hydrazonoyl bromide 28c was obtained by direct bromination of hydrazone 58a or 58b (75CJC1484). Electron-withdrawing substituents in the N-aryl moiety of the arylhydrazone derivatives of heterocyclic aldehydes inhibit ring bromi-... 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

Ambident reactivity was shown by oximate anions normally, Oarylation predominated over N-arylation, with ratios of oxime ethers to nitrones ranging from 9 1 (for the benzophenone oxime anion) to 1.7 1 (for the fluorenone oxime anion) [77]. The arylation of two heterocyclic oximes was performed under mild conditions and led mainly to the corresponding oxime ethers which served as good precursors for the generation of unstable aryl fulminates, ArONC [79,80],... 

Azoles can be produced from the products of palladium-catalyzed hydrazone arylation and can themselves serve as substrates for arylation reactions to produce N-aryl azoles by the Fischer indole synthesis. N-Aryl pyrazoles and related heterocycles can also be prepared after obtaining N-aryl hydrazines by palladium-catalyzed procedures. Benzophenone hydrazone was first found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (25) [183, 184]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields in the presence of either DPPF- or BINAP-ligated palladium. These reactions are general and proceed with electron-rich, electron-poor, hindered, or unhindered aryl halides. The products of these re-... 

For a recent study concerning intermolecular aza-Diels-Alder reactions of N-aryl imines see Narasaka K, Shibata T (1993) Heterocycles 35 1039... 

Furthermore, 6-phenanthridinones 41 and their heterocyclic analogs 42-46 could be obtained in modest to excellent yields via a sequence of Pd-catalyzed aryl-aryl and N-aryl coupling from iodoarenes, ortho-substituted by electron-releasing substituents and amides of o-bromoarene-and heteroarenecarboxylic acids (Scheme 16) [73]. 

N-Aryl and N-heteroaryl derivatives of aminomethylene malonates are also very useful and fruitful synthons for formation of 4-aminoquinolines used as antimalarials (equation 215), of the anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates and of antibacterial nalidixic acid derivatives (equation 216). Each of these is an important group of pharmaceuticals, developed in the last twenty years. Because of its medicinal interest this route is widely used for synthesis of quinolines and pyridinofused heterocycles. The chemistry has been comprehensively reviewed in a recent monograph292. Hence, no further details are given here. 

Stannyl ketyl radicals were generated from an amide carbonyl group and when incorporated in cinnamic enamides, indolizidinone rings can be assembled [37]. Du and Curran have shown that a-thioaminoalkyl radicals such as 24 resulting from the addition of a tris(trimethylsilyl)radical onto N-aryl thiocarbamates, thioamides or thioureas 22, can be exploited in the context of the synthesis of carbocyclic and heterocyclic fused quinolines 23 (Scheme 8) [38]. 

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