Carboxylic acids heteroarene

Kiener, A. (1992) Enzymic oxidation of methyl groups on heteroarenes. A versatile method for the preparation of heteroaromatic carboxylic acids. Angew. Chemie... 

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. 

Because C-H bonds are usually less reactive towards dioxirane oxidation than heteroatoms and C-C multiple bonds, it is instructive to give a few general guidelines on the compatibility of functional groups within the substrate to be submitted to oxidative C-H insertion Substances with low-valent heteroatoms (N, P, S, Se, I, etc.), C-C multiple bonds, and C=X groups (where X is a N or S heteroatom) are normally not suitable for C-H insertions, because these functionalities react preferably. Even heteroarenes are more susceptible to dioxirane oxidation than C-H bonds, whereas electron-rich and polycyclic arenes are only moderately tolerant, but electron-poor arenes usually resist oxidation by dioxiranes. N-oxides and N-oxyl radicals are not compatible because they catalyze the decomposition of the dioxirane. Oxygen insertion into Si-H bonds by dioxirane is more facile than into C-H bonds and, therefore, silanes are not compatible. Substance classes normally resistant towards dioxirane oxidation include the carboxylic acids and their derivatives (anhydrides, esters, amides, and nitriles), sulfonic acids and their de-... 

Compound classes, not previously described (eg. 5- and 6-membered heteroarenes) Compound classes, for which, in the meantime, significant improvements and progresses have been made, for example carbonic acid derivatives, carboxylic acids and carboxylic acid derivatives, aldehydes, carbonyl derivatives, halogen compounds, peroxides, sulfur, selenium, tellurium, nitrogen and phosphorus compounds. 

Initial investigations showed that the direct hydrogenation of pyrazine carboxylic acid derivatives 14—16 was possible [15] (Fig. 13). This is one of the few examples known today for a homogeneous heteroarene hydrogenation [16]. With [Rh(NBD)Cl]2 and a variety of standard ligands, for example Chiraphos, Norphos, Duphos, Deguphos, PPm, BDPP, BINAP, BPPFOAc no reaction was observed. Similarly no reaction could be observed with Ir catalysts. The positive results are given in Tab. 6. 

The Minisci reaction has successfully been applied for the alkylation of various heteroarenes, i. e. lepidine, pyrazine, quinoline and quinoxaline [2e, 2g, 10]. Organic compounds such as alkanes, alkenes, carboxylic acids, esters, amides, amines, alcohols, ethers, aldehydes, ketones, halides etc. have been successfully used as radical precursors in the Minisci reaction. A good overview of the different methods which have been applied to generate the alkyl radicals in these processes is summarized in [10b]. 

The a-heteroaryl carbonyl structure has stimulated interest in organic synthesis because it is a highly prevalent motif in pharmaceuticals and natural products. In the year 2014, a manganese-catalyzed intermolecular C-H/C-H coupling of carbonyls and heteroarenes was developed (14CC4105).The presence of NaI04 is necessary for the catalytic reaction. These new reaction conditions allow gram-scale synthesis of a-heteroaryl carboxylic acids. 

Cp RhCl2]2 (Cp =pentamethylcyclopentadienyl)-catalysed ort/io-olefination of benzoic acid through oxidative coupling with alkenes using the oxidant Cu(OAc)2 has been achieved a,j8-unsaturated carboxylic acids also underwent olefination at the )3-position. Cine-olefination of heteroarene carboxylic acids progresses smoothly by decarboxylation to selectively produce the corresponding vinyl heteroarene derivatives. ... 

Catellani [61] reported a palladium/norbomene-catalyzed synthesis of heteroatom-containing o-teraryls from aryl iodides and heteroarenes (including indoles and pyrroles) through double C-H arylation. Fagnou s group [62] applied their own protocol (Pd(II)/Ag(I)/carboxylic acid) to achieve the direct arylation of azaindoles. Itami [63] demonstrated the first iridium-catalyzed C-H arylation of heteroarenes (involving indoles and pyrroles) with aryl halides. 

In 2011, Miura et al. were the pioneers on attaching a directing group in heteroaromatic substrates in order to olefinate them using a Ru(n) catalyst. Heteroarenes such as thiophenes, benzofuran, pyrrole, and indolyl carboxylic acids underwent regioselective o/tAo-alkenylation using [RuCl2(p-cymene)] and Cu(OAc)2 H2O. The presence of the carboxylic acid at C-2 provided the C-3 functionalised product. In contrast, when the carboxylic acid was at C-3, olefination at C-2 was achieved. 

In 2011, Ueyama et al. [68] reported the ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes. The vinylation occurred at the C3-position of the heteroaromatic substrate (Figure 4.34). 

Metalation and Reactivity with Electrophiles. The reaction of 2-(trimethylsilyl)thiazole (1) with carbon electrophiles such as aldehydes, ketones, ketenes, carboxylic acid chlorides, and azaaryl cations has attracted considerable attention. In this series, Nagasaki and coworkers reported the use of trimethylsilyl heteroarenes as the heteroarenyl carbanion donors in the electrophilic cyanation and described, for example, the electrophilic cyanation of 2-TST (1) with p-toluenesulfonyl cyanide in the absence of solvent (eq 25). ... 

On such reactive heteroarene rings, direct C-H arylation also occurs upon treatment with an excess amount of aryl bromides under palladium catalysis to produce multiply arylated heteroarenes (Scheme 4.42) [47]. The reaction of indole-3-carboxylic acids is of particular interest because it can provide a simple synthetic route to 2,3-diarylindole derivatives, which exhibit strong solid-state fluorescence properties (Scheme 4.43) [48]. On the other hand, the... 

Direct Amination of Azoles, Decarbonylative amidation and amination of benzoxazole andbenzothiazole couldbe achieved using a Pd VAg system, promoted by carboxylic acid additives. Silver(I) fluoride performed inferiorly to Ag2C03 (30 vs. 78%). Stoichiometric amounts of silver salt were required to maximize reactivity no reaction occurred using only catalytic silver. Silver is postulated to help rearomatize the heteroarene following amination. Diversely substituted benzoxazoles and benzothiazoles afforded the C2-aminated product in moderate to excellent yield (eq 18). 

Silver(I) carbonate functioned as an cooxidant with TEMPO. Tricyclohexylphosphine was employed to suppress homocoupling between heteroarenes. Substituted thiophenes, furans, and indoles could be selectively olefinated (C5-alkenylation for thiophenes and furans, C3-alkenylation for indoles, E/Z > 99 1). Unsubstituted thiophenes produced poor yields (24%) however, formyl, acetyl, and ketyl substituents were well tolerated. For electron-deficient substrates, tricyclohexylphosphine was reduced to 10 mol % to achieve good conversions. A variety of ketones could be employed using 2-methyl thiophene as a coupling partner. A related methodology employing saturated ketones and heterocyclic carboxylic acids via a Pd-catalyzed decarboxylative process was also reported (eq 44). ... 

Heteroarene carboxylic acids such as l-methylindole-3-carboxylic acid (10) also undergo similar decarboxylative coupling with alkynes (Scheme 25.9) [12], In these reactions, palladium catalyst systems are more effective than iridium. 

In addition to benzoic acids, heteroarene carboxylic acids 55 [24], acrylic acids 57 [25], and aromatic diacids 59 and 60 [24] also undergo annulation to form the corresponding lactones (Schemes 25.30 to 25.32). 

After the seminal work reported by Satoh and Miura in early 2011 on ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes [17], Ackermann demonstrated a ruthenium(ll)-catalyzed cross-dehydrogenative C-H bond alkenylations of benzoic acid derivatives with acrylonitrile or alkyl acrylates. Following the oxidative C—H bond alkenylation reaction, subsequent intramolecular oxa-Michael reaction occurred leading to phthalides in good yields (Eq. (7.12)) [18]. The reactions took place with water as an environmentally benign medium under mild conditions. 

Benzylic C-H bonds undergo oxidative esterification with TBHP in the presence of tetrabutylammonium iodide as catalyst and carboxylic acids in good to excellent yields. A free radical process has been proposed. Asymmetric epoxidation of electron-poor terminal alkenes bearing different carbonyl groups has been achieved with a cinchona thiourea/TBHP system. The corresponding epoxides, containing a quaternary stereocentre, were isolated in yields up to 98% and enantioselectivity up to 99%. A direct oxidative CDC of indole with A-aryltetrahydroisoquinolines in the 0 presence of a gold catalyst and TBHP resulted in the formation of a variety of alkylated heteroarenes (Scheme 24). ... 

A practical, mild and highly selective protocol for the monodeuteration of a variety of arenes and heteroarenes has been reported. Catalytic amounts of Ag(I) salts in DMSO/DjO are shown to facilitate the deutero-decarboxylation of ortho-substituted benzoic and heteroaromatic a-carboxylic acids in high yields with excellent levels of deuterium incorporation. 

The ability of palladium to mediate decarboxylations of certain heteroaromatic carboxylates was demonstrated by Steglich et al. for intramolecular couplings, as well as by Forgione and Bilodeau for intermolecular couplings (Scheme 16) [56-58]. However, the scope of this reaction indeed seems to be more limited than its bimetallic counterpart. It so far includes mainly five-ring heteroarenes with carboxylate groups in the 2-position. AUcynylcarboxylic acids have also been decarboxylatively coupled with palladium alone [59]. 

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