Heteroaromatic compounds coupling reactions

The CDC reaction of arenes and alkenes can be applied to heteroaromatic compounds. Coupling with furan, thiophene, pyrrole, benzofuran. 

Aromatic diazonium compounds became industrially very important after Griess (1866a) discovered in 1861/62 the azo coupling reaction, by which the first azo dye was made by C. A. Martius in 1865 (see review by Smith, 1907). This is still the most important industrial reaction of diazo compounds. Hantzsch and Traumann (1888) discovered that a heteroaromatic amine, namely 2-aminothiazole, can also be diazotized. Heteroaromatic diazonium compounds were, however, only used for azo dyes much later, to a small extent in the 1930 s, but intensively since the 1950 s (see Zollinger, 1991, Ch. 7). 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

C-coupling is of outstanding importance in the azo coupling reaction for the synthesis of azo dyes and pigments. An aromatic or heteroaromatic diazonium ion reacts with the so-called coupling component, which can be an aromatic primary, secondary, or tertiary amine, a phenol, an enol of an open-chain, aromatic, or heteroaromatic carbonyl compound, or an activated methylene compound. These reactions at an sp2-hybridized carbon atom will be discussed in Chapter 12. In the... 

There are also some couplings in which hydrazones are formed but for which the azo tautomer is not detectable and probably does not exist. This is the case in some coupling reactions involving methyl groups of aromatic heterocycles (see, for example, 12.48 and 12.49 in Sec. 12.5). Replacement of a methyl proton by an arylazo group (Scheme 12-3) would result in an azo compound containing an sp3-hybridized — CH2 — group (12.1). The latter is less stable than the tautomeric hydrazone (12.2), in which there is a n-n orbital overlap from the heteroaromatic to the aromatic system. 

In spite of the large amount of scientific and industrial activity on diazo compounds and azo coupling reactions since the 19th century, heteroaromatic diazo components have been studied intensively only since the 1950s. 

Most diazotized heteroaromatic amines undergo normal coupling reactions with common aromatic coupling components, as well as with CH acidic compounds (review Butler, 1975). 

The arylation of heteroaromatic compounds is also achieved by aryl-aryl coupling reaction. The arylation of A-methylimidazole with bromobenzene occurs under palladium catalysis (Equation (62)).72 The arylation of thiazole with aryl iodide occurs at the 2-position under PdCl2(PPh3)2/CuI catalysis.73 In this case, tetrabutylammonium fluoride improves the activity of the catalyst. Alternatively, thiazoles and benzothiazole are efficiently arylated... 

The diazonium ions 13 with electron-withdrawing substituents are not h texoaromatic compounds and therefore do not strictly come within the scope of this chapter. They are formally related to the alkenediazonium ions. Nevertheless, they are discussed here because in their properties they bear a close resemblance to heteroaromatic and arenedi-azonium ions rather than to alkenediazonium ions. In particular they can be obtained by direct diazotization of the amines, they are stable in an aqueous medium and they are capable of undergoing an azo coupling reaction. 

The coupling of aryl- and alkenylzinc reagents with various halides has widespread use in the cross-coupling of aromatic rings [101]. The reactions of zinc derivatives of aromatic and heteroaromatic compounds with aryl and heterocyclic halides have wide synthetic applications [103,104],... 

As described in Section III.1.4.1.1, the catalytic direct arylation reactions of aromatic compounds occurs effectively via C-H bond cleavage when the substrates are appropriately functionalized. On the other hand, various five-membered heteroaromatic compounds involving one or two heteroatoms, even without a functional group, are known to undergo arylation, usually at their 2- and/or 5-posi-tion(s), on treatment with aryl halides under the action of palladium catalysis. The coupling has recently been developed significantly [1, 2]. Representative examples with some mechanistic discussion are summarized in this section. 

Palladium catalysed coupling reaction of a heteroaromatic zinc compound with a functionalized aryl iodide preparation of N-benzyl-6-(4-ethylcarboxyphenyi)-purine33... 

Finet JP (1998) Ligand Coupling reactions with Heteroaromatic Compounds. Perga-mon, Oxford (Tetrahedron Organic Chemistry Series, vol 18)... 

Bromoisoquinoline did not react with MeS ions in liquid ammonia, but 80% yield of the substitution product 4-isoquinolyl methyl sulphide was formed in the presence of amide ions. Isoquinoline and many other nitrogen-containing heteroaromatic compounds are known to react with amide ions to give anionic adducts 242289, which have been proposed to initiate the S l reaction by an ET to the substrate, which leads to the hetaryl radical. The radical couples only with MeS" ions 29°. 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

The Suzuki coupling reaction is a powerful tool for the construction of biaryl compounds and their homologues, which are key structural elements of various natural products, polymers, and compounds of medicinal interest. Aryl boronic acids and their esters are the usual substrates in reactions with aryl or heteroaromatic halides and... 

Takagi, J., Sato, K., Hartwig, J. F., Ishiyama, T., Miyaura, N. Iridium-catalyzed C-H coupling reaction of heteroaromatic compounds with bis(pinacolato)diboron regioselective synthesis of heteroarylboronates. Tetrahedron Lett. 2002,43, 5649-5651. 

Nickel- or palladium-catalyzed coupling reactions of alkyl Grignard or zinc reagents can be applied to heteroaromatic halides and sulfides. The characteristic features are, therefore, based on those described in the preceding sections and hence details are not repeated in this section. Aspects are summarized by the types of heteroaromatic compounds NiCh(DPPP) is used as catalyst, unless stated otherwise hereafter. 

The pioneering work of a coupling of aromatic and heteroaromatic compounds with acetylenes was reported by Yamazaki et al. in 1979 [35]. Reaction of benzene with diphenylacetylene gives triphenylethene in 45% yield. In the case of the monosubstituted benzene, the reaction of toluene proceeds at the meta position selectively but the reaction of anisol takes place at the ortho position (Eq. 21). They proposed that the site-selectivity stems from an inductive effect of an elec-... 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

Coupling reactions. Alkylation of heteroaromatic compounds at a site adjacent to the heteroatom (e.g., N) by alkenes in the presence of [(coe)2RhCl]2 is vahdated forpyridines and quinohnes. ... 

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