Heterocycles reaction with carboxylic acids

Neidlein. R.. Jochheim, M., Krieger, C., and Kramer, W., Synthesis of l,3-dithietane-2,4-diylideneWr)cyanomethylphosphonates) and -phenylphosphinates and their reaction with carboxylic acid hydrazides, Heterocycles, 39, 185, 1994. 

This experiment illustrates the classic method of forming the benzimidazole ring system. This heterocycle is generally prepared from 1,2-diaminobenzene (o-phenylenediamine) derivatives by reaction with carboxylic acids, or their derivatives, under acidic conditions. The ring system is aromatic thus it is difficult to oxidize or reduce, and it is stable to both acids and bases. It is an important heterocyclic ring system that occurs in vitamin B12 and in many other biologically important compounds. Benzimidazole itself inhibits the growth of certain yeasts and bacteria. 

Nonclassical Wittig reaction, olefination by phosphoranes interaction with carboxylic acid derivatives, in transformation of heterocycles 99JCS(P1)3049. 

The furoxan ring is notably resistant to electrophilic attack and reaction normally takes place at the substituents. Thus aryl groups attached to monocyclic furoxans and the homocyclic ring of benzofuroxans are nitrated and halogenated without disruption of the heterocycle. Reaction with acid is also slow protonation is predicted to occur at N-5 <89KGS1261> and benzofuroxans have pKj, values of ca. 8, similar to those of benzofurazans. Monosubstituted furoxans are, as expected, less stable and can be hydrolyzed to the corresponding carboxylic acid. Treatment of the parent furoxan (3) with concentrated sulfuric acid results in rearrangement to (hydroxyimino)acetonitrile oxide (HON=CHC=N —O ) and subsequent dimerization to bis(hydroxyiminomethyl)furoxan... 

The reaction of sulfur tetrafluoride with carboxylic acids (aliphatic, aromatic, and heterocyclic) is of particular importance as the most general and simplest route to trifluorotnethyl derivatives. The reaction proceeds in two steps, the first step gives acyl or aroyl fluorides 1, and then catalysis in the second step by hydrogen fluoride released in the first step results in the tri-fluoromethyl derivatives 2.41... 

Dienes (allenes) are also used for heteroannulation with 68 and 69. The eight-membered nitrogen heterocycle 78 is constructed by the reaction of 1,2-undecadiene (77) with o-(3-aminopropyl)iodobenzene (76) [34]. The lactones are prepared by trapping the 7i-allyl intermediates with carboxylic acids as an oxygen nucleophile. The unsaturted lactone 81 is prepared by the reaction of /1-bromo-v,/ -unsaturated carboxylic acid 79 with the allene 80 [35]. In the carboannulation of 82 with 1,4-cyclohexadiene (83), the 1,3-diene 85 is generated by / -elimination of 84, and the addition of H-PdX forms the 7i-allylpalladium 86, which attacks the malonate to give 87 [36],... 

The reaction of amines with carboxylic acids can also be used to build heterocyclic ring systems. Aliphatic 1,2-diamines and carboxylic acids or their derivatives give imidazolines 716 boiling o-phenylenediamine with a carboxylic acid for 0.5 hour gives the 2-alkylbenzimidazole 717... 

A procedure for the preparation of nitriles from carboxylic acids or heterocycles via N-chlorosulfonylcarboxamides (173) is illustrated in equation 87. The reaction of carboxylic acids with CSI gives adduct 172, which loses C02 to give iV-chlorosulfonylcarboxamide... 

Due to the unique bivalent carbene and diversity of the N-heterocyclic motif, NHCs have been demonstrated to be efficient organocatalysts for various enantioselective reactions. In addition to the traditional thioazolium and imidazolium NHCs, triazolium NHCs have become the most successful organocatalysts. Recently, NHC/Lewis acid cocatalysis and bifunctional NHCs have shown a very promising future. Beyond the classic NHC-catalysed umpolung of aldehydes, the extended umpolung of functionalised aldehydes are extremely successful. A series of NHC-catalysed reactions of ketenes have been developed for the synthesis of various enantioriched heterocycles. Esters, anhydrides, carboxylic acids and even Michael acceptors are useful alternative substrates for NHC-catalysed reactions. With increasing interest and rapid development of NHC catalysis, new structures of the catalysts, new reaction modes, and synthetic applications can be expected in the near future. 

Poly phosphoric acid (PPA), a highly viscous liquid, is a useful reagent and catalyst in various rearrangements and isomerizations, especially in intramolecular reactions (24,25). Cyclization of various compovmds into aromatic rings and formation of heterocycles are the most important transformations where PPA usually ensures high yields. It is especially useful when Friedel-Crafts acylations are carried out with carboxylic acids. 

One of the most commonly used methods to obtain 2-amino-l, 3,4-thiadiazolines is the heterocyclization of thiosemicarbazides. An efficient one-pot synthesis of 2-amino-l,3,4-thiadiazoles 125 features the in situ formation of thiosemicarbazides 123 by the reaction of carboxylic acid hydrazides 121 with trimethylsilyl isothiocyanate (TMSNCS) 122, followed by cyclodehydration of thiosemicarbazides 123 under acidic conditions (13RSC6813). 

A modification of the Hunsdiecker reaction uses NCS catalyzed with tetrabutylammonium trifluoroacetate (TBATFA) and gives 8-chlorostyrenes in excellent yields. The use of the NCS/ TBATFA-catalyzed Hunsdiecker reaction has been extended to various heterocyclic a. -unsaturated carboxylic acids. ... 

Carboie lic acids have also been utilised as electrophiles for N-alkylation. Beller reported the reaction of primary or secondary amines with carboxylic acids in the presence of a platinum catalyst and phenylsilane to directly provide the products of reductive amination. The proposed mechanism involves initial amide formation followed by reduction to the amine. A diverse range of functional groups are tolerated, including olefins, alcohols, heterocycles, and esters (Scheme 12.15). 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

---