Heterocycles, acylation reaction

A surpnsing feature of the reactions of hexafluoroacetone, trifluoropyruvates, and their acyl imines is the C-hydroxyalkylation or C-amidoalkylaOon of activated aromatic hydrocarbons or heterocycles even in the presence of unprotected ammo or hydroxyl functions directly attached to the aromatic core Normally, aromatic amines first react reversibly to give N-alkylated products that rearrange thermally to yield C-alkylated products. With aromatic heterocycles, the reaction usually takes place at the site of the maximum n electron density [55] (equaUon 5). 

These alkylation and acylation reactions are important because Friedel-Crafts alkylation and acylation (11-12, 11-14) cannot be applied to most nitrogen heterocycles. See also 13-15. 

Other thietane derivatives have been obtained by isomerization of nitrogen-containing heterocycles. The reaction of an acyl isothiocyanate (RCONCS) with diphenyldiazomethane gave 20 and this isomerized in solution to the tetraphenyl-3-thietanone 21 <96BSB253>. Additionally, the isoxazolidine 22 was converted into 23 by the action of trimethylsilyl iodide and zinc iodide <96H1211>. 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

From the synthetic viewpoint, a particularly interesting trifluoroacetylation reaction of simple vinyl ethers was reported first by Hojo et al in 1976 [73] The scope and limitation of this particular reaction were elaborated intensively, the reaction proved to be of general applicability with practically no restrictions on substituents of the vinyl ether moiety 9] (equation 34) This general validity is particularly beneficial because a trifluoroacetylated vinyl ether is the synthetic equivalent of a specifically protected tnfluoromethyl-substituted 1,3-dicarbonyl compound 19], thus the reaction provides access to a broad spectrum of variously substituted synthetic building blocks with selective reactivities on each carbon acceptor (a) and donor (d) center (equation 35) Obviously, such building blocks can react as heterodiene systems m cycloaddition reactions [< 74] or can be treated with a wide variety ot 1,2 or 1 3-dinucleophihc species to give any desired tnfluoromethyl-substituted carbocychc or heterocyclic system [8 75] Treatment of simple vinyl ethers with an excess of trifluoroacetic anhydride at elevated temperature leads to doubly acylated products [76] Comparable acylation reactions occur with vinyl thioethers [73], and the mesoiomc l,3-oxathiol-4-ones show, at least in a formal sense, similar behavior [77] (equation 36)... 

Several aromatic and heterocyclic acyl trimethylsilanes have been used as acyl anion equivalents by treatment with fluoride ion (Scheme 81, path a)23 133 154b160191192. Provided that the acyl substituent is electron-withdrawing, and that there are no aryl substituents on the silicon atom, acyl anions can be trapped by various electrophiles in moderate to good yields indeed, acyl anions and pentacoordinate silicon anionic species have both been detected in gas-phase reactions of acyl silanes with fluoride ion193. 

However, acylation reactions of N-unsubstituted pyrazolines with halogen anhydrides of acids are very often followed by the destruction of the heterocyclic ring owing to the ease of breaking the C(5)—Nq) bond located at the (3-position of the azomethine group [140, 141, 142, 166]. For example, pyrazoline 108 treated with halogen anhydrides of acids yields a,(3-unsaturated ketone 109 and diacyl-hydrazine 110 [166] (Scheme 2.29). 

Alkylation or acylation reactions of dihydroazines can proceed as intramolecular processes and follow with heterocyclizations [308, 310] (Scheme 3.98). 

Grasa GA, Gueveli T, Singh R, Nolan SP (2003) Efficient transesterification/ acylation reactions mediated by A-heterocyclic carbene catalysts. J Qrg Chem 68 2812-2819... 

Grasa GA, Kissling RM, Nolan SP (2002) A-Heterocyclic carbenes as versatile nucleophilic catalysts for transesterification/acylation reactions. Qrg Lett... 

Five- to seven-membered O-, N-, and S-heterocycles Acyl ylides with a tethered terminal ester function requisite for the construction of five- to seven-membered heterocycles are very conveniently accessible by reaction of the cumulated ylide ketenylidenetriphenylphosphorane 11 with various carboxylic esters bearing OH-, NHR-, and SH-groups in a-, -, or y-position. 

Kinetic studies of acylation reactions are somewhat limited by the insolubility of the acyl halide-Lewis acid complexes in many of the solvent systems that are used. However, useful results have been obtained and, as far as we are concerned, relative rates of reactions are of greater importance than absolute values. In any case it is not possible to distinguish between the two mechanistic extremes on the basis of the observed kinetics." Friedel-Crafts acylations are generally characterized by high substrate selectivity and frequently by high positional selectivity. Relative rate data show, as expected, that toluene is more reactive than benzene and that /n-xylene is the most reactive of the dimethylbenzenes. Values, relative to benzene, for benzoylation catalyzed by aluminum chloride were r-butylbenzene (72), toluene (1.1 X 10 ), p-xylene (1.4 x 10 ), o-xylene (1.12 x 10 ), and m-xylene (3.94 x 10- ). Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 "C gave the relative rates thiophene (1.0), furan (1.4 x lO ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). ... 

Heterocycles such as furan and pyrrole can be efficiently acetylated with AAN in the presence of zeolite ZSM-5. The higher yields are % of 2-acetylfuran at 93% conversion of furan and 76% of 2-acetylp5u-role af 78% conversion of pyrrole over ZSM-5(30). On the contrary, the catalytic activity of Y is low due to its higher acidity compared to ZSM-5-type catalysts this confirms that the pyrrole acylation reaction prefers moderate acidic centers. 

The relative reactivities of the five-membered-ring heterocycles are reflected in the Lewis acid required to catalyze a Friedel-Crafts acylation reaction (Section 15.13). Benzene requires AICI3, a relatively strong Lewis acid. Thiophene is more reactive than benzene, so it can undergo a Friedel-Crafts reaction using SnCl4, a weaker Lewis acid. An even weaker Lewis acid, BF3, can be used when the substrate is furan. Pyrrole is so reactive that an anhydride is used instead of a more reactive acyl chloride, and no catalyst is necessary. 

Friedel-Crafts alkylation and acylation reactions are quite versatile. They form the basis of several named reactions that have been used to synthesize heteroatom-containing compounds such as quinolines, isoquinolines, indoles, and many others. This section will examine several more common transformations that will show the scope and utility of these processes. It will also introduce a modest amount of heterocyclic chemistry into our synthetic discussion. 

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