Heterocycles, acylation coupling

An a-allenic sulfonamide undergoes Pd-catalyzed carbonylative cyclization with iodobenzene, affording a mixture of isomeric heterocycles (Scheme 16.12) [17]. The coupling reaction of an allene with a PhCOPdl species takes place at the allenyl central catrbon to form a 2-acyl-Jt-allylpalladium complex, which is attacked by an internal sulfonamide group in an endo mode, affording a mixture of isomeric heterocycles (Scheme 16.13). 

Chemical shifts and coupling constants of substituted 1,2,3,4-tetra-hydroquinoxalines indicate that the heterocyclic ring in these derivatives is in the half-chair form.263 The variation of the cis vicinal and geminal couplings resulting from acylation on nitrogen indicates that the acylated derivatives have a slightly flattened half-chair conformation.263... 

Other 7- substituents that have been introduced include the dialkylamino, acetamido, hydroxy, alkoxy and alkylthio groups (B-71MI11209). Acylation of the 7-amino group by heterocycles such as cyanuric chloride and its derivatives was inevitable, as was incorporation of a 7-triazole substitution pattern by diazotization of the 7-amino group and o-coupling with 2-naphthylamine followed by triazolization (94). 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

Following Ellman s pioneering work on benzodiazepines,2 another study from the same laboratory illustrated the vast potential of combining a variety of chemical reactions on drug-like heterocycles. In this case a preformed heterocycle was grafted as a whole onto the solid phase to be subsequently derivatized via a three-component palladium-mediated coupling reaction followed by a reductive alkylation or an acylation (Fig. 12).34... 

While there are several reports concerning electrophilic substitution on to (5,5)-fused heterocycles, very few of these involve a study with the parent system. The ir-excessive systems (50), (51), (52) and (53) were found to be susceptible to attack by electrophilic reagents at the positions indicated, leading to alkylation, formylation (Vilsmeier-Haack reaction), acylation, tritylation, metalation, tricyanoethylation, halogenation, thiocyanation, nitrosation, nitration and diazo coupling (77HC(30)l). 

Heterocyclic derivatives of a range of metals other than lithium have received considerable attention, especially as precursors for coupling reactions. These derivatives can be prepared either directly from halo compounds or from the lithio compounds. Thus, direct formation of the pyrrolylzinc compounds can be effected under very mild conditions by treatment of an iodide with a zincsilver couple deposited on graphite. The zinc reagents are formed in excellent yields and can be converted into acylated or allylated products (Scheme 140). For further discussion on this theme, see Section 3.3.3.8.8. 

This chapter is concerned with the cathodic reduction of carboxylic acids and their derivatives, that is, esters, amides, anhydrides, acyl halides, hydrazides, nitriles, and corresponding thio derivatives. Cyclic derivatives of substituted carboxylic and polycarboxylic acids, such as lactones, lactams, imides, and anhydrides, are also included. Only those transformations in which the functional group itself is involved are discussed. Reductive coupling of carboxylic acids and derivatives is covered in Chapter 22, and there is some overlap with reduction of heterocycles in Chapter 18. 

Ammonium salts with two different alkyl chains were prepared directly via subsequent alkylations of dimethylamine with primary bromides and crystallization. Commercial hexadecyl-methylamine can be conveniently applied in the same way in order to convey functionality to cationic synkinons. A recent example describes subsequent alkylations with a small functional and a long-chain primary bromide (Scheme 2.4). A-acylated / -phenylenediamine was also alkylated at the second nitrogen atom which had two different alkyl chains, with or without extra functionality . After deacylation, this head group can be diazotized or coupled oxidatively with various heterocycles in water (Scheme 2.4). Photoactive and coloured membrane surfaces are thus obtained. Phenylene-diamine, pyridine and in particular A-methyl-4,4-bipyridinium chloride are relatively weak nucleophiles. Substitution of bromides is slow and the more reactive iodides can rarely be obtained commercially, but the selection of nitromethanes as solvent for bromide substitution is of great help as well as the addition of sodium iodide to enforce a Finkelstein reaction or a combination of both. 

Instead, these heterocycles and their derivatives most commonly undergo electrophilic substitution nitration, sulfonation, halogenation. Friedel-Crafts acylation, even the Reimer-Tiemann reaction and coupling with diazonium salts. Heats of combustion indicate resonance stabilization to the extent of 22-28 kcal/ mole somewhat less than the resonance energy of benzene (36 kcal/mde), but much greater than that of most conjugateci dienes (about Tlccal/mole). On the basis of these properties, pyrrole, furan, and thiophene must be considered aromatic. Clearly, formulas I, II, and III do not adequately represent the structures of these compounds. 

Like other aromatic compounds, these five-membered heterocycles undergJ nitration, halogenation, sulfonation, and Friedel-Crafts acylation. They are mucji more reactive than benzene, and resemble the most reactive benzene derivatives (amines and phenols) in undergoing such reactions as the Reimer-Tiemann reaction, nitrosation, and coupling with diazonium salts. 

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