Friedel-Crafts reaction With heterocycles

Friedel-Crafts reaction with heterocyclic chlorides -... 

Thio- and selenoacetals and esters are excellent substrates for mild Friedel-Crafts reactions, because of the affinity of sulfur and selenium for copper (Sch. 23). Anisole was readily acylated with methylselenoesters 94 at room temperature with activation by CuOTf to affordpnra-substituted (> 95 %) derivatives 95 [50,51]. Mercury(II) and copper(II) salts, which were effective for the activation of selenyl esters for reaction with alcohols, amines, and water, were not effective for the Friedel-Crafts reaction. Aromatic heterocycles 96 could be acylated in high yields, and the alkylation product 100 was obtained from dibutylthioacetal 99 and anisole. Vedejs has utilized this methodology in the cyclization of 101 to afford 102 in 77 % yield [52]. This intramolecular variant did not require the use of the more reactive bis copper triflate-benzene complex. 

The importance of the solvent, in many cases an excess of the quatemizing reagent, in the formation of heterocyclic salts was recognized early. The function of dielectric constants and other more detailed influences on quatemization are dealt with in Section VI, but a consideration of the subject from a preparative standpoint is presented here. Methanol and ethanol are used frequently as solvents, and acetone,chloroform, acetonitrile, nitrobenzene, and dimethyl-formamide have been used successfully. The last two solvents were among those considered by Coleman and Fuoss in their search for a suitable solvent for kinetic experiments both solvents gave rise to side reactions when used for the reaction of pyridine with i-butyl bromide. Their observation with nitrobenzene is unexpected, and no other workers have reported difficulties. However, tetramethylene sulfone, 2,4-dimethylsulfolane, ethylene and propylene carbonates, and salicylaldehyde were satisfactory, giving relatively rapid reactions and clean products. Ethylene dichloride, used quite frequently for Friedel-Crafts reactions, would be expected to be a useful solvent but has only recently been used for quatemization reactions. ... 

Friedel-Crafts acylation with nitriles and HC1 is called the Hoesch or the Houben-Hoesch reaction,354 In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds, e.g., pyrrole, but it can be extended to aromatic amines by the use of BCly.355 Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones354 but are attacked at the oxygen to produce imino esters. 

Despite its V-excessive character , thiazole, just as with pyridine, is resistant to electrophilic substitution, the ring nitrogen atom deactivating the heterocyclic nucleus towards electrophilic attack. Moreover, most electrophilic substitutions which proceed in strongly acid media (nitration, sulfonation, Friedel-Crafts reactions) involve the protonated form... 

Padwa and Kuethe have also used vinylogous Pummerer reactions of amido sulfoxides in the preparation of nitrogen-containing heterocycles. Vinyl amido sulfoxide (224) underwent an additive Pummerer reaction, on treatment with trifluoroacetic anhydride, to yield product 226 (Scheme 57).123 The a-thiocarbo-cation 225 generated from the Pummerer reaction of N-methyl-N-phenyl-2-[2-(toluene-4-sulfinyl)phenyl]acetamide (224) underwent a Friedel-Crafts reaction at the y-carbon with the tethered aromatic ring. Reductive removal of the... 

Friedel-Crafts reaction of phosgene with heterocyclic aromatic compounds is also difficult to stop at the acid chloride stage. However, under selected conditions, heteroaromatics such as thiophene can be directly acylated to give thiophenecarbonyl chloride [Scheme T9] (Ref. 15) ... 

The Heck reaction makes a C-C bond and adds a highly functionalised fragment that can be elaborated into many other functional groups. The same is true of the Friedel-Crafts reaction that generally works well with azoles or other heterocycles able to do electrophilic substitution. As usual, it is best to have only one free position so that no regioselectivity problems arise. In the Heck reaction, the site of attack is marked by the iodine atom, but the Friedel-Crafts can occur at any free position. Our example is a pyrazole that acylates cleanly with Lewis acid catalysts to give eventually the herbicide pyrazolate 196. 

Arylthiophens and Di- and Poly-heterocycles. - The reaction of (201) with sulphur gave (202) in 45% yield. Treatment of the hydrazone (203) with PPA at 110°C gave (204), the structure of which was proven by desulphurization of a degradation product with Raney nickel. From the simple phenyl-hydrazone of ethyl 2-thienyl glyoxylate, (205) and (206) were obtained in a 7 3 ratio. Authentic (206) was prepared via the Friedel-Crafts reaction of... 

In Scheme 10, examples of eaiantioseleetive cycloadditions with formation of three-, four-, five-, and six-membered carbocyclic or heterocyclic rings are presented, to demonstrate the use of Ti-TADDOLates as Lewis acids. The Diels-Alder reaction has, so far, been studied most extensively, and many protocols have been proposed for the preparation of the Ti catalyst, of which as little as 5 mol-% and as much as several equivalents were employed (more often than not, Lewis acids bind strongly to the products of reactions they have mediated cf. the classical Friedel-Crafts acylation with AICI3 ). 

The enantioselective Friedel-Crafts reaction of a. unsaturated 2-acyl iV-methylimidazoles with electron-rich heterocycles, such as indole derivatives, 2-methoxyfuran, and pyrrole, was catalyzed by Sc(OTf)3 conjointly used with a chiral bis(oxazolinyl)pytidine ligand (eq 31). The reaction afforded good enantioselectivities (>90% ee) for a broad range of substrates. 

In contrast to the alkynylation of acidic C-H bonds which can also be achieved using alkynyliodonium salts, the direct C-H functionalization of aromatic compounds or olefins has never been realized with this class of reagents so far. However, after several unsuccessful attempts using palladium or copper catalysts and alkynyliodonium salts for the alkynylation of heterocycles, Waser and Brand reported in 2009 the first efficient alkynylation of indoles using TIPS-EBX 52 and AuCl as catalyst (Scheme 18) [117]. With indole, selective C3-aIkynylation was obtained. The reaction was tolerant to many functional groups such as bromides, acids, or alcohols. The method was already used in the synthesis of starting materials for Friedel-Crafts reactions of aminocyclopropanes [118] and for hydroamidation to access indole c -enamides [119]. In 2010, Nevado and de Haro demonstrated that alkynylation was also possible using directly terminal propiolic ester derivatives and (diacetoxyiodo)benzene as co-oxidant [120]. 

The A-heterocyclic carbene precursor 49 is a photo-switchable catalyst for amidation reactions. The synthesis of this catalyst begins with two Friedel-Crafts reactions firstly, 2-melhyl-5-phenylthiophene was 3-acetylated with acetic anhydride using SnCLj, then product ketone oxidised to a glyoxal by SeOa- The glyoxal itself was used as acylating agent to react with 2-methyl-5-phenylthiophene with the assistance of SnCLj. After several further steps, the salt 49 was obtained (Scheme 51) [69]. 

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