Heterocycles arylations

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... 

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-... 

Mild oxidation of o-nitrobenzaldehyde arylhydrazones with either bromine and sodium acetate or lead tetraacetate results in the overall loss of two hydrogen atoms and production of a class of iV-aryl heterocycles, tiie structure of which was the subject of uncertainty and some controversy for more than fifty years. These oxidation products were first prepared and investigated by Chattawayj " who described them as isodiazomethanes and formulated them as the triaziridine derivates 72. Structural assignment was based entirely on evidence from degradation studies in particular, Chattaway showed that reduction of... 

Dieck, H. A. Heck, F. R. Palladium Catalyzed Synthesis of Aryl, Heterocyclic and Vinylic Acetylene Derivatives, J. Organomet. Chem. 1975, 93, 259. 

Acyl peroxides of structure (16) are known as diacyl peroxides. In this structure R1 and R2 are the same or different and can be alkyl, aryl, heterocyclic, imino, amino, or fluoro. Acyl peroxides of structures (17), (18), (19), and (20) are known as dialkyl peroxydicarbonates, OO-acyl ((-alkyl monopcroxycarbonatcs. acyl organosulfonyl peroxides, and di(oiganosulfonyl) peroxides, respectively. R1 and R2 in diesc structures are the same or different and generally are alkyl and aryl. Many diacyl peroxides (16) and dialkyl peroxydicarbonates (17) are produced commercially and used in large volumes. 

R = aryl, heterocyclic, benzylic, vinylic X = halogen, inflate... 

At raised temperature and CO pressure, terminal acetylenes can replace the organotin derivatives, giving acetylenic ketones (equation 114).491 Some of these reactions occur at normal pressure. Aryl, heterocyclic and vinyl bromides and iodides could be used. These reactions again required a stoichiometric quantity of base. The complexes (102), [PdCI2L2] (L = l,l -bis(diphenylphosphino)ferrocene) and [PdI(Ph)(AsPh3)2] were used as catalysts. The mechanism was not discussed. 

The reaction can be carried out with aryl, heterocyclic and vinyl bromides and iodides and with some vinyl chlorides. It requires raised temperature but only normal CO pressure. If the primary or secondary amine is a strong enough base, it can be used in excess and the tertiary amine is not needed. The mechanism given in Scheme 42 was proposed for the reaction. It was not known whether the primary amine enters the reaction sequence at the point shown or at an earlier stage. 

Normally, the most practical vinyl substitutions are achieved by use of the oxidative additions of organic bromides, iodides, diazonium salts or triflates to palladium(0)-phosphine complexes in situ. The organic halide, diazonium salt or triflate, an alkene, a base to neutralize the acid formed and a catalytic amount of a palladium(II) salt, usually in conjunction with a triarylphosphine, are the usual reactants at about 25-100 C. This method is useful for reactions of aryl, heterocyclic and vinyl derviatives. Acid chlorides also react, usually yielding decarbonylated products, although there are a few exceptions. Likewise, arylsulfonyl chlorides lose sulfur dioxide and form arylated alkenes. Aryl chlorides have been reacted successfully in a few instances but only with the most reactive alkenes and usually under more vigorous conditions. Benzyl iodide, bromide and chloride will benzylate alkenes but other alkyl halides generally do not alkylate alkenes by this procedure. 

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. 

However, a considerable number of articles have been devoted to the experimental and theoretical determination of the interannular angles in the equilibrium conformation of aryl heterocycles, and of heteroaryl-heteroaryl systems composed of identical or different heterocycles. A full critical analysis of these studies and the techniques used is beyond the scope of this article. However, we discuss some general trends which emerge in the absence of ortho substituents and which are useful for the separation of conjugation and intrinsic steric effects in the heterocycles. 

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). 

R = aryl, heterocyclic, benzylic, vinylic X = halogen, triflate Y = H, CO2R, CO2H, CONH2, CN, Ar, alkyl, alkenyl, OR ... 

Ragnarsson U, Grehn L. Novel amine chemistry based on DMAP-catalysed acylation. Acc. Chem. Res. 1998 31 494-501. Meshram HM, Reddy GS, Reddy MM, Yadav JS. Zinc mediated facile amide formation application to alkyl, aryl, heterocycle, carbohydrate and amino acids. Tetrahedron Lett. 1998 39 4103-4106. 

A new efficient procedure has been proposed for the synthesis of 3-aryl-5-amino-l//-pyrazoles by reaction of a-chloro-/ -arylacrylonitriles with hydrazine hydrate <2004RJ01518>. Reaction of 2-(3,3-dicyano-2-propenylidene)-4,4,5,5-tetra-methyl-l,3-dioxolane 641 with hydrazine afforded 3-(2-hydroxy-l,l,2-trimethylpropoxy)pyrazole 642 (Equation 134) <2003RJ01016>. Treatment of ethyl 3,3-dicyano-2-methoxyacrylate with alkyl, aryl, heterocyclic, and sulfonyl hydrazines led to the synthesis of N-l-substituted 3-acyM-cyano-5-aminopyrazoles, which are versatile intermediates for the synthesis of many biologically active scaffolds <2006TL5797>. 2-Hydrazinothiazol-4(5//)-one reacted with a variety of cinnamonitrile derivatives and activated acrylonitriles to yield annelated pyrazolopyrano[2,3-rf thiazole <1998JCM730>. 

A mixture of NO2 and ozone has also been used. " Clays, such as clay-supported cupric nitrate (Claycop), " " or MontmorUlonite KSF—Bi(N03) can be used to nitrate aromatic rings. Nitration of styrene poses a problem since addition occurs to the C=C unit to give a 1-nitroethyl aryl. " Heterocycles, such as pyridine, are nitrated with N2O5 and S02. " Deactivated aromatic rings, as in acetophenone, were nitrated with N2O5 and Fe(acac)2. " ... 

In the Heck reaction, aryl, heterocyclic and vinyl halides - " or aryl triflates react with excess carbon monoxide and primary or secondary amines to give substituted amides, in the presence of a palla-dium(II) catalyst (equation 41). Cis- and trans-vinyl halides react stereoselectively. 

The direct catalytic carbonylation of halides to aldehydes is not readily achieved. Aryl, heterocyclic and vinyl halides, for example, in the presence of [Pd(PPh3)2Ch], a stoichiometric quantity of tertiary amine and synthesis gas (CO/H2), are converted to aldehydes, but the conditions are somewhat drastic (80-100 bar, 80-150 Alkyl halides are even less suitable for this reaction as they tend to undergo dehydrohalogenation to form alkenes, rather than carbonylation. However, using the platinum catalyst [PtCh(PPh3)2], primary alkyl iodides can be successfully carbonylated to aldehydes in good yield under moderate conditions (equation 5). °... 

Arylations. Heterocycles typified by a-pyridone are N-arylated using Cul, KjCOj, in refluxing DMF. a-Amino acids are similarly derived jt-coordination of the copper-amino acid complexes is thought to facilitate the substitution. ... 

The R groups in this reaction can be almost anything, H, alkyl, aralkyl, aryl, heterocyclic and many others. Modifications of this procedure have employed /3-thionoesters,1006,1008 /3-oximinoesters1555 and / -ketoamides.99,197,1276... 

No rationale is provided for the particular catalytic efficiency of the [Rh(CO)2Cl]2 for this transformation, or for the suppression of catalytic activity in the presence of ligands that improve the reactivity in closely related reactions [176], Nevertheless, this reaction is likely to share a common mechanism with other heterocyle arylation processes that include heterocycle coordination, C-H insertion and tautomerization to the rhodium(I) NHC complex, oxidative addition to the bromoarene, and reductive elimination of the arylated heterocycle (Scheme 20). 

Comparable acid- (or Lewis acid) -catalysed ring closures of 2-arylthio- and 2-aryloxy- -ketones, and -2-arylthio- and 2-aryloxyacetyl- chlorides lead to 3-substituted heterocycles and 3-oxygenated heterocycles, respectively. It is possible to combine the preparation of the arylthio-ketone and the ring closure steps utilising two solid-supported reagents in a one-pot procedure, as illustrated. Formation of 3-aryl-benzothiophenes by this route can be complicated by partial or complete isomerisation to the 2-aryl-heterocycle,however using boron trifluoride as the Lewis acid produces only the 3-aryl-isomer. 3-Tosylamino-benzofurans can be prepared from aryl glyoxal hydrates. ... 

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