Acylation 6- membered rings

Alkyl- and arylmercury(II) halides are used for the ketone formation[402]. When active methylene compounds. such as /f-keto esters or malonates are used instead of alcohols, acylated / -keto esters and malonates 546 are produced, For this reaction, dppf is a good ligand[403]. The intramolecular version of the reaction proceeds by trapping the acylpalladium intermediate with eno-late to give five- and six-membered rings smoothly. Formation of 547 by intramolecular trapping with malonate is an example[404]. 

Other forms of tautomerism are much less commonly encountered in heterocyclic six-membered rings. Like protons, acyl groups can occupy alternative positions, on a ring atom or a substituent (e.g. 92 93), and their migration from one position to another is frequently... 

Aminofurans substituted with electron-withdrawing groups e.g. NO2) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Amino-3-acetylfurans are converted into 3-cyano-2-methylpyrroles on treatment with aqueous ammonia. This transformation is a further illustration of the relative instability of the amino derivatives of five-membered ring heterocycles compared with anilines (Scheme 67) (781003821). 

An investigation of acylaziridines was carried out by comparison of IR, NMR and MS data and included some 1,2-dibenzoylaziridines as well as 2-p-nitrobenzoyl-3-phenyl-oxaziridine (68IZV1530). Amide conjugation in acylated nitrogen-containing three-membered rings is weaker than in open chain acid amides. 

A number of examples of acid catalyzed ring expansion of acyl and thioacyl azetidines to sbc-membered rings have been reported (B-73MI50903). This type of rearrangement (Scheme 2) is similar to the more general vinylaziridine to pyrroline ring expansion. 

During electrochemical fluorination retention of important functional groups or atoms in molecules is essential. Acyl fluorides and chlorides, but not carboxylic acids and anhydrides (which decarboxylate), survive perfluorination to the perfluorinated acid fluorides, albeit with some cyclization in longer chain (>C4) species [73]. Electrochemical fluorination of acetyl fluoride produces perfluoro-acetyl fluoride in 36-45% yields [85]. Electrochemical fluorination of octanoyl chloride results in perfluorinated cyclic ethers as well as perfluorinated octanoyl fluonde. Cyclization decreases as initial substrate concentration increases and has been linked to hydrogen-bonded onium polycations [73]. Cyclization is a common phenomenon involving longer (>C4) and branched chains. a-Alkyl-substituted carboxylic acid chlorides, fluorides, and methyl esters produce both the perfluorinated cyclic five- and six-membered ring ethers as well as the perfluorinated acid... 

Acylation yields products retaining the three-membered ring only if the diaziridine is derived from an aldel yde. 3,3-DiaIkyl-diaziridines... 

An important application of the Friedel-Crafts acylation is the intramolecular reaction, leading to ring closure. This variant is especially useful for the closure of six-membered rings, but five-membered ring products and larger rings, as well as heterocycles, are also accessible ... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

Gas phase reactivity toward allyltrimethylsilane was used to compare the reactivity of several cyclic A-acyliminium ions and related iminium ions.203 Compounds with endocyclic acyl groups were found to be more reactive than compounds with exocyclic acyl substituents. Five-membered ring compounds are somewhat more reactive than six-membered ones. The higher reactivity of the endocyclic acyl derivatives is believed to be due to geometric constraints that maximize the polar effect of the carbonyl group. 

A classical procedure for fusing a six-membered ring to an aromatic ring uses succinic anhydride or a derivative. An intermolecular acylation is followed by reduction and an intramolecular acylation. The reduction step is necessary to provide a more reactive ring for the second acylation. 

Preparation of nefopam starts with the acylation of aminobenzhydrol 1 (obtainable by reduction of the corresponding benzoylbenzamide) with chloroacetyl chloride treatment of the chloroamide (2) with potassium tertiary butoxide results in internal alkylation to give the eight-membered ring (3). Reduction of the lactam function with lithium aluminum hydride gives the amine and, thus, nefopam (4). ... 

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