Acylation heteroarenes

Acyl-, carbamoyl- and alkoxycarbonyl radicals have been shown to add to protonated heteroarenes with high efficiency [2, 10]. The regioselectivity of these reactions is very similar to the regioselectivities obtained in the analogous alkylations discussed above. In contrast to the Friedel-Crafts acylation, where the acylated product is highly deactivated toward further acylation, the acylated heteroarenes are more reactive towards a second radical acylation. This is because of the higher electrophilicity of the protonated heteroarene after initial acylation. To suppress... 

Elektronenreiche Carboxy-N-heteroarene erleichtern ebenfalls die Hydrogenolyse (anwesende Alkoxycarbonyl- bzw. Formyl- oder Acyl-Gruppen werden mitreduziert). Pyrrol-carbonsauren werden z. B. durch Lithiumalanat in Diathylather oder THF zu den entsprechenden Methyl-pyrrolen reduziert4 s z, B.4 ... 

Cross-linked polystyrene can be acylated with aliphatic and aromatic acyl halides in the presence of A1C13 (Friedel-Crafts acylation, Table 12.1). This reaction has mainly been used for the functionalization of polystyrene-based supports, and only rarely for the modification of support-bound substrates. Electron-rich arenes (Entry 3, Table 12.1) or heteroarenes, such as indoles (Entry 5, Table 15.7), undergo smooth Friedel-Crafts acylation without severe deterioration of the support. Suitable solvents for Friedel-Crafts acylations of cross-linked polystyrene are tetrachloroethene [1], DCE [2], CS2 [3,4], nitrobenzene [5,6], and CC14 [7]. As in the bromination of polystyrene, Friedel-Crafts acylations at high temperatures (e.g. DCE, 83 °C, 15 min [2]) can lead to partial dealkylation of phenyl groups and yield a soluble polymer. 

Reissert compounds (l-acyl-l,2-dihydro-2-quinolinecarbonitriles) have been prepared on cross-linked polystyrene and C-alkylated in the presence of strong bases (Entry 8, Table 15.25). Treatment of polystyrene-bound C-alkylated Reissert compounds with KOH leads to the release of isoquinolines into solution (Entry 9, Table 15.25). The reaction of support-bound quinoline- and isoquinoline /Y-oxides with acy-lating agents followed by treatment with electron-rich heteroarenes and enamines has been used to prepare alkylated and arylated derivatives of these heterocycles (Entry 10, Table 15.25 see also Table 15.26). 

Unsymmetric diamines can sometimes be acylated selectively at one amino group only, if one of the amino groups is sterically or electronically deactivated. If the difference in reactivity is only small, acylating agents of low reactivity will usually be required. Some polyamino heteroarenes can be monoacylated or monoalkylated with astonishingly high regioselectivity (Scheme 7.13), which is, however, difficult to predict. 

In particular, the alkylation and acylation of protonated heteroarenes under oxidative conditions, commonly known as Minisci reaction, has attracted increasing interest in recent decades because of its synthetic involvement in biochemistry and pharmacology [3]. Beyond the fact that this reaction can be applied to all heteroaromatic bases and almost all carbonyl and alkyl radicals (without electron-withdrawing groups directly bonded to the radical center), the main characteristics of this process are high chemoselectivity and regioselectivity, the substitution usually occurring only in a and y positions. 

Owing to their nucleophilic character, acyl radicals are easily trapped by protonated N-heteroarenes, leading to the formation of the corresponding acyl... 

The selective functionalization of heterocycles is of particular importance, because of the ubiquity of these structures in natural products and pharmaceutical agents. Direct utilization of a C-H bond [1] of heterocycles is a promising method for the preparation of heterocycles because no pre-functionalization is required. Although Friedel-Crafts acylation is the most commonly used method for introduction of keto functionality on an aromatic ring, it is not often applicable to N-heteroarenes because of deactivation of the Lewis acids by the coordination of N-heteroarenes and the electron-deficient aromatic character of N-heteroarenes. 

Carboxylic acids are the most general, versatile and useful source of carbon-centered radicals successfully used for selective alkylation and acylation of protonated heteroarenes. Alkyl, acyl, carbamoyl, and alkoxycarbonyl radicals have been obtained by oxidative decarboxylation of the corresponding acids with peroxydisulfate as an oxidant and Ag(I) as catalyst. 

It is generally admitted that skeletal transformations of hydrocarbons are catalyzed by protonic sites only. Indeed good correlations were obtained between the concentration of Bronsted acid sites and the rate of various reactions, e g. cumene dealkylation, xylene isomerization, toluene and ethylbenzene disproportionation and n-hexane cracking10 12 On the other hand, it was never demonstrated that isolated Lewis acid sites could be active for these reactions. However, it is well known that Lewis acid sites located in the vicinity of protonic sites can increase the strength (hence the activity) of these latter sites, this effect being comparable to the one observed in the formation of superacid solutions. Protonic sites are also active for non skeletal transformations of hydrocarbons e g. cis trans and double bond shift isomerization of alkenes and for many transformations of functional compounds e.g. rearrangement of functionalized saturated systems, of arenes, electrophilic substitution of arenes and heteroarenes (alkylation, acylation, nitration, etc ), hydration and dehydration etc. However, many of these transformations are more complex with simultaneously reactions on the acid and on the base sites of the solid... 

Galli, C. 1979. Acylation of arenes and heteroarenes with in situ generated acyl trifluoroacetates. Synthesis 303-304. 

Late-transition metal salts have been utilized as catalysts to promote Friedel-Crafts acylation of arenes and heteroarenes with anhydrides. A mismatch between their soft metal center and the hard carbonyl oxygen atoms of the products avoids the formation of a kinetically inert complex and results in catalytic turnovers. Although late-transition metal salts exhibit, a priori, rather poor Lewis acidity, sufficient reactivity can be gained by rendering them cationic. The acylation of variously substituted... 

This reaction has general application in the preparation of hydroxyl acyl phenols or heteroarenes (coumarin, carbazole, etc.)... 

Along with reactive aryl and alkenyl radicals, acyl radicals-readily generated from the corresponding acylselenides-undergo efficient homolytic aromatic substitutions in the presence of tin hydride or (Me3Si)3SiH [47]. Arenes, as well as heteroarenes, can be used as acceptors. As an example, the highly efficient radical transformation of acylselenide 20 to heteroarene 21, which readily isomerizes to phenol 22 is depicted in Scheme 13.6 ]48]. 

Several approaches have been followed for the generation of optically active heteroarenes by homogeneous asymmetric hydrogenation. One approach involves direct asymmetric hydrogenation of the unactivated heteroarene. This approach has been most successful for heteroarenes that are polycyclic, like quinolines, isoquinolines, or quinoxa-lines (benzopyrazines). Less success has been achieved on the direct asymmetric hydrogenation of pyridines. To address this limitation, the hydrogenation of modified pyridines has been conducted. In one set of examples, pyridines and related benzo-fused heteroarenes were modified at tfie nitrogen by acylation or the installation of another auxiliary to make the pyridine more electron poor and to dock the catalyst. In a second set of examples, a chiral auxiliary was placed on the pyridine, and the product was formed diastereoselectively by an achiral catalyst. 

In parallel with the directed hydroarylation of olefins, a series of papers described the formation of ketones from heteroarenes, carbon monoxide, and an alkene. Moore first reported the reaction of CO and ethylene with pyridine at the position a to nitrogen to form a ketone (Equation 18.28). Related reactions at the less-hindered C-H bond in the 4-position of an A/-benzyl imidazole were also reported (Equation 18.29). - Reaction of CO and ethylene to form a ketone at the ortho C-H bond of a 2-arylpyridine or an N-Bu aromatic aldimine has also been reported (Equations 18.30 and 18.31). Reaction at an sp C-H bond of an N-2-pyridylpiperazine results in both alkylative carbonylation and dehydrogenation of the piperazine to form an a,p-unsaturated ketone (Equation 18.32). The proposed mechanism of the alkylative carbonylation reaction is shown in Scheme 18.6. This process is believed to occur by oxidative addition of the C-H bond, insertion of CO into the metal-heteroaryl linkage, insertion of olefin into the metal-acyl bond, and reductive elimination to form the new C-H bond in the product. 

Hf(OTf)4 was also reported for Friedel-Crafts acylation of ferrocenes and heteroarenes as well as in Friedel-Crafts acylations in the biphasic medium of an ionic liquid and supercritical carbon dioxide. ... 

Ru3(CO)i2 catalyzes a Murai-like reaction in which an acyl group is introduced (3 to nitrogen in a heteroarene. Cyclometalation in clusters is particularly easy, and instead of simply forming the Ru alkyl, as in the Murai case, an additional CO insertion step occurs, to produce an ct-acyl heterocycle (Eq. 14.39). ... 

Nevertheless, such reactions catalyzed by zeolites have been discussed in the review of 2001 (1) isomerization (double-bond shift, isomerization of tricyclic molecules, like synthesis of adamantane, isomerization of terpenes, diverse rearrangements, conversion of aldehydes into ketones), (2) electrophilic substitution in arenes (alkylation of aromatics, including the synthesis of linear alkylbenzenes, alkylation and acylation of phenols, heteroarenes and amines, aromatics nitration and halogenation), (3) cyclization, including the formation of heterocycles, Diels-Alder reaction, (4) nucleophilic substitution and addition,... 

The use of transition metal catalysts to effect alkylations, alkenylations, arylations, and acylations in pyridines has been reviewed, and there has been a computational study of the ortho-alkylation of pyridine by scandium-catalysed reactions with alkenes. DFT calculations indicate that the stability of the developing metal-aryl bonds may be important in determining regioselectivity in palladium-acetate-catalysed carbon-hydrogen substitution in heteroarenes. ... 

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