Heteroaromatics acylation

A special application of heteroaromatic acylation via a modified Dakin-West reaction leads to a-fluoro ketone derivatives [50] (equation 30) Such fluoro ketones have been successfully used as enzyme inhibitors in modern bioorganic chemistry [5, 6]... 

Many aromatic and heteroaromatic acyl silanes have been prepared by transition metal catalysed coupling (e.g. Scheme 10)23,81. This is a very successful approach for most aromatic substrates, including furyl, thienyl, pyrryl and electron-deficient aryl acyl silanes, which can otherwise be difficult to prepare. 

Thallium(I) cyanide was introduced by Taylor and McKillop as a reagent. Aromatic and heteroaromatic acyl cyanides are produced in go yield, whereas aliphatic acid halides lead under these conditions mainly to dimerization products. 18-Crown-6 is a good catalyst for the preparation of cyanoformate in methylene chloride with potassium cyanide and chloroformates. Similarly, tetraethylammonium cyanide gives cyanoformates in high yield under very mild conditions. Aroyl cyanides are generated easily by phase transfer catalysis with tetra-n-butylammonium bromide. Tri- -butyltin cyanide proved successful only with aromatic acid halides, leading to dimerization products with aliphatic compounds. ... 

Aromatic and Vinyl Nitriles. Aromatic haUdes (Br, I) have been converted into nitriles in excellent yields by Pd(Ph3P)4 catalysis in the presence of Sodium Cyanide Alumina,Potassium Cyanide, or Cyanotrimethykilane (eq 24). While the latter two procedures require the use of Arl as substrates, a more extensive range of substituents are tolerated than the alternative method employing ArBr. A Pd(Ph3P)4-catalyzed extrasion of CO from aromatic and heteroaromatic acyl cyanides (readily available from cyanohydrins) at 120 °C provides aryl nitriles in excellent yields (eq 25). ... 

In this paper, we give some examples of ethylaluminum dichloride (EtAlCl2)-induced acylations with different acylating agents such as saturated acyl chlorides, dicarboxylic acid dichlorides, cyclic anhydrides, unsaturated acyl chlorides, and aromatic and heteroaromatic acyl chlorides. 

Acylations with Aromatic and Heteroaromatic Acyl Chlorides... 

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

The regioseleciivicy of Fnedel-Crafts-lypc acylations on heteroaromatic compounds has been studied intensively [57 58, 59] In the case of pyrroles, the orientation of the entering acyl group strongly depends on the bulkiness of the group at the nitrogen atom (equation 29)... 

The introduction of a formyl or acyl group can be achieved by transformation of VNS products. Hydrolysis of dichloromethylnitroarenes, VNS products between heteroaromatic nitro compounds and chloroform, is a method of choice for the preparation of heterocyclic aldehydes, as shown in Eq. 9.41, in which 4-nitroimidazole is converted into 5-formyl-4-nitroimidazole.69... 

Nickel-bpy and nickel-pyridine catalytic systems have been applied to numerous electroreductive reactions,202 such as synthesis of ketones by heterocoupling of acyl and benzyl halides,210,213 addition of aryl bromides to activated alkenes,212,214 synthesis of conjugated dienes, unsaturated esters, ketones, and nitriles by homo- and cross-coupling involving alkenyl halides,215 reductive polymerization of aromatic and heteroaromatic dibromides,216-221 or cleavage of the C-0 bond in allyl ethers.222... 

Benzophenones are usually attached as a complete photophore. Apart from the standard chemical techniques, new C-C coupling procedures extend the synthetic repertoire. However, in some cases direct benzoylation (e.g., Friedel-Crafts acylation) of aromatic or heteroaromatic rings can provide an easy access to BP or BP-like photophores (Scheme 4D) [38,39]. 

The greater acidities of the heteroaromatic azoles (pKa ca. 15), compared with simple acyclic and non-aromatic cyclic amines, is reflected in the ease with which the systems are /V-alkylated and /V-acylated. 

The two-phase alkylation reactions have been extended to the acylation of simple heteroaromatic systems. Generally, the required conditions are milder than those employed for the alkylation reactions, but an excess of the acylating agent is usually required, owing to its facile hydrolysis in the basic media. Thus, benzimidazole and its 2-alkyl and 2-aryl derivatives have been benzoylated [46], and pyrrole and indole have been converted into a range of A-acyl [47, 48] and A-sulphonyl derivatives [48-53] (Table 5.35 and Table 5.36). 

Alkylation of potentially tautomeric heteroaromatic systems under basic phase-transfer catalytic conditions normally occurs on the softer heteroatom [cf 57]. Thus, although 2- and 4-pyridones are alkylated on the annular nitrogen atom and the exocyclic oxygen atom, -alkylation of the 2-pyridones predominates to the extent of ca. 5 1 (or greater under soliddiquid reaction conditions [58]), whereas the relative predominance of A -alkylation of the 4-isomer is only ca. 3 1 [59] (Table 5.37 and 5.38). These ratios are comparable with those obtained for the base-catalysed alkylation of the pyridones by traditional methods and, not unexpectedly, S-alkyla-tion of the corresponding pyridthiones occurs to the total exclusion of A-alkylation [60]. Catalysed soliddiquid acylation has also been reported [58]. 

The acyl radicals obtained by hydrogen abstraction from aldehydes easily attack protonated heteroaromatic bases. With secondary and tertiary acyl radicals decarbonylation competes with the aromatic acylation [Eq. (12)]. 

Two sources of acyl radicals have proved to be useful for the homolytic acylation of protonated heteroaromatic bases the oxidation of aldehydes and the oxidative decarboxylation of a-keto acids. The oxidation... 

Also in this case the acyl radical can be oxidized by the ferric salt, but in the presence of protonated heteroaromatic bases the aromatic attack successfully competes with the oxidation. The process has great versatility and can be carried out with a large variety of aldehydes (aliphatic, a,jS-unsaturated, aromatic, and heteroaromatic). 

The acyl radicals attack the protonated heteroaromatic bases with good results, although the oxidizing medium can lead to the competitive processes of Eqs. (31) and (32). 

The high reactivity of protonated heteroaromatic bases towards acyl radicals is shown by the success of the reaction with the pivaloyl radical, which usually undergoes rapid decarbonylation [Eq. (33)]. 

Protonated heteroaromatic bases are therefore more reactive than simple olefins toward acyl radicals. The radical addition of pivalaldehyde to olefins is, in fact, characterized by a radical chain, whose propagation is determined by decarbonylation of the pivaloyl radical and addition of <-butyl radical to the olefin. The synthetic interest is great in the case of substrates with only one reactive position, such as benzothiazole, ... 

It is possible to obtain selective monoacylation even if the heteroaromatic base has more free reactive positions, by taking advantage of the protonation equilibria of the starting base and the reaction products. Thus with 4-cyanopyridine, which has two free reactive positions, the introduction of an acyl group in position 2 decreases the basic character and therefore allows selective monoacylation by the precipitation of the unprotonated reaction product. 

Two steps must be considered in the mechanism of homolytic acylation, in addition to the formation of the acyl radical. The first fits in with the generally accepted mechanism of homolytic aromatic substitution, that is, the addition of the acyl radical to the aromatic nucleus to give an adduct in which the unpaired electron is delocalized over the residual heteroaromatic system (u-complex 6). 

The homolytic acylation of protonated heteroaromatic bases is, as with alkylation, characterized by high selectivity. Only the positions a and y to the heterocyclic nitrogen are attacked. Attack in the position or in the benzene ring of polynuclear heteroaromatics has never been observed, even after careful GLC analysis of the reaction products. Quinoline is attacked only in positions 2 and 4 the ratio 4-acyl- to 2-acylquinoline was 1.3 with the acetyl radical from acetaldehyde, 1.7 with the acetyl radical from pyruvic acid, and 2.8 with the benzoyl radical from benzaldehyde. 

The high selectivity of homolytic acylation of protonated heteroaromatic bases and the fact that under the same experimental conditions homocyclic substrates (benzene, anisole, nitrobenzene, protonated aniline, and A,A-dimethylaniline) are not attacked, indicate that polar effects play a dominant role. Only aromatic substrates with very strong electron-deficient character give rise to significant homolytic acylation. 

Also, the results of the substituent effects in homolytic acylation of protonated heteroaromatic bases must be connected, as for homolytic alkylation, with the polar characteristics of the acyl radicals and the aromatic substrates, but not with the stabilization of the intermediate a-complexes. 

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