Friedel-Crafts type reactions acylations

Concerning my research during my Dow years, as I discuss iu Chapter 4, my search for cationic carbon intermediates started back in Hungary, while 1 was studying Friedel-Crafts-type reactions with acyl and subsequently alkyl fluorides catalyzed by boron trifluoride. In the course of these studies I observed (and, in some cases, isolated) intermediate complexes of either donor-acceptor or ionic nature. 

While benzene could not be acylated according to method A, such an acylation did succeed with triazolides in a Friedel-Crafts-type reaction [98]... 

An intermediate acylnickel halide is first formed by oxidative addition of acyl halides to zero-valent nickel. This intermediate can attack unsaturated ligands with subsequent proton attack from water. It can give rise to benzyl- or benzoin-type coupling products, partially decarbonylate to give ketones, or react with organic halides to give ketones as well. Protonation of certain complexes can give aldehydes. Nickel chloride also acts as catalyst for Friedel-Crafts-type reactions. 

Besides the intramolecular acyl-transfer reactions, electrophilic activation is shown to occur with intermolecular Friedel-Craft-type reactions.18 When the simple amides (45a,b) are reacted in the presence of superacid, the monoprotonated species (46a,b) is unreactive towards benzene (eq 18). Although in the case of 45b a trace amount of benzophenone is detected as a product, more than 95% of the starting amides 45a,b are isolated upon workup. In contrast, amides 47 and 48 give the acyl-transfer products in good yields (eqs 19-20). It was proposed that dications 49-50 are formed in the superacidic solution. The results indicate that protonated amino-groups can activate the adjacent (protonated) amide-groups in acyl-transfer reactions. 

In conjunction with their Friedel-Crafts alkylation, Terada et al. found phosphoric acid (R)-3m (2 mol%, R = 9-anthryl) bearing a bulky 9-anthryl group to mediate the asymmetric Friedel-Crafts-type reaction of a-diazoester 22a with iV-acylated aldimines 26 (Scheme 10). a-Diazo-P-amino esters 27 were obtained in moderate yields (62-89%) and very good enantioselectivities (91-97% ee) [20],... 

An alternative method for the substitution of a hydrogen atom in -electron deficient heterocycles is using the nucleophilic character of radicals in homolytic aromatic displacement reactions <74AHC(16)123>. Acylation with acyl radicals derived from aldehydes is an especially important approach since Friedel-Crafts-type reactions are not applicable to pteridines. 

The first example of a Friedel-Crafts type reaction in an ionic liquid medium dates back to 1976 when the electrochemical oxidation of hexamethylbenzene in [C2py]Br-AlCl3 afforded a mixture of alkylated polyphenyl compounds.[69] Other early examples include the alkylation of benzene in C2Ciim C1-A1C137 and the acylation of ferrocene in [C2Ciim]I-AlClJ71 There are now numerous examples of Lewis- or Bronsted acid-catalysed Friedel-Crafts type reactions in ionic liquids. These include alkylation,[72 76] acylation,[71,77"83] arylation,[77 841 sulfonylation,[851 sulfoamylation[86] and O-acetylation of alcohols.[87,881... 

Friedel-Crafts Type Reactions 18.3.1 Acylation and Alkylation Reactions... 

Acylations with Nitriles. With particularly reactive aromatic nuclei such as phenols, a Friedel-Crafts type reaction may be effected with nitriles in the presence of an acid catalyst such as hydrogen chloride, aluminum chloride, or zinc chloride. The reaction is usually called the IIouben-Hoesch synthesis.700 When hydrogen cyanide is employed, the process leads to aromatic aldehydes even with a number of aromatic... 

Acylation of B15C5 in a Friedel-Crafts type reaction with the classical Lewis acid AICI3 can be performed only with poor yields (about 30%) in the presence of a large excess of... 

The general Friedel-Crafts acylation principle [36] can be applied to aromatic nitrations involving nitryl halides, dinitrogen pentoxide, and dinitrogen tetroxide (the halides and anhydrides of nitric acid). These should be considered as Friedel-Crafts type reactions, as obviously a very... 

Acylketenes generated by Wolff rearrangement undergo uncatalyzed Friedel-Crafts type reactions with different nitrogen heterocycles, including N-methylpyrrole, as in the example shown (Eqn (4.126)). The acylation was also successful with dihydrofuran and dihydropyran. At higher temperatures ketene dimerization also occurred. 

Known for 140 years, the functionahsation of thiophene under Friedel-Crafts conditions stUl remains very popular. Friedel-Crafts-type reactions allow for convenient, direct and thus atom-economic formation of a new C-C bond to the thiophene ring. In some cases, it is stUl performed under classical conditions using AICI3 in an equimolar amount as Lewis acid together with the acyl chloride however, this produces strongly acidic waste. The Friedel-Crafts-type reactimi applied to thiophene has been reviewed several times [19—22]. 

Alkyl halides and sulfonates are the most frequently used alkylating acceptor synthons. The carbonyl group is used as the classical a -synthon. O-Silylated hemithioacetals (T.H. Chan, 1976) and fomic acid orthoesters are examples for less common a -synthons. In most synthetic reactions carbon atoms with a partial positive charge (= positively polarized carbon) are involved. More reactive, "free carbocations as occurring in Friedel-Crafts type alkylations and acylations are of comparably limited synthetic value, because they tend to react non-selectively. 

Although in general azoles do not undergo Friedel-Crafts type alkylation or acylation, several isolated reactions of this general type are known. 3-Phenylsydnone (120) undergoes Friedel-Crafts acetylation and Vilsmeier formylation at the 4-position, and the 5-alkylation of thiazoles by carbonium ions is known. 

Ferrocene behaves in many respects like an aromatic electron-rich organic compound which is activated toward electrophilic reactions.In Friedel-Crafts type acylation of aromatic compounds with acyl halides, ferrocene is lO times more reactive than benzene and gives yields over 80%. However, ferrocene is different from benzene in respect to reactivity and yields in the Friedel-Crafts alkylation with alkyl halides or olefins. The yields of ferrocene alkylation are often very low. and the separations of the polysubstituted byproducts are tedious. 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

Other Formylations. Formyl fluoride, the only known stable formic acid derivative, can be used to perform Friedel-Crafts-type acylation to form aromatic aldehydes. The method was developed by Olah and Kuhn.105 Although a number of Lewis acids may be used, BF3 is the best catalyst. It is dissolved in the aromatic compound to be formylated then formyl fluoride is introduced at low temperature and the reaction mixture is allowed to warm up to room temperature. The aldehydes of benzene, methylbenzenes, and naphthalene were isolated in 56-78% yields. Selectivities are similar to those in the Gattermann synthesis ( toiuene benzene = 34.6, 53.2% para isomer). The reacting electrophile was suggested to be the activated HCOF BF3 complex and not the free formyl cation. Clearly there is close relationship with the discussed CO—HF—BF3 system. 

Probably the two most generally useful methods for effecting intramolecular acylation are by the Friedel-Crafts type of reaction on the acid chloride and the action of anhydrous hydrogen fluoride on the free acid. In addition to these methods, cyclizations have been effected by the use of sulfuric acid and other reagents. 

In comparison with molecular catalysts, solid catalysts can be isolated from the reaction mixtures by filtration or used in continuous processes this is both environmentally friendly and useful in laboratory-scale experiments. The most important reactions catalyzed by solid superbases are isomerization reactions and the alkylation of substituted arenes in the side chain (Scheme 2). They proceed at room temperature or below with high yield (typically >99%). The surperbase-cata-lyzed alkylation of aromatic compounds complements the acid-type Friedel-Crafts alkylation and acylation, because the latter results in ring alkylation, whereas the former results in side-chain alkylation. 

Nearly all of the cyclization reactions covered in this section aim at formation of the seven-membered ring. A distinction can be made between acylations at pyrrole rings and Friedel-Crafts type cyclizations at benzene rings. 

The parent TMM complex (190 R = H) undergoes photochemical ligand substitution with trifluorophosphine or trimethylamine Al-oxide assisted substitution with tertiary phosphines or t-butyl isocyanide (Scheme 5A) Trimethylamine A-oxide assisted substitution using isoprene as the incoming ligand results in C-C bond formation to afford the bis-TT-allyl complex (197). An intramolecular version of this reaction is also known.The parent complex (190 R = H) reacts with electrophiles. Addition of HCl or Br2 gives the methallyl complexes (192) and (198), respectively. Tetrafluoroethylene adds across the Fe bond to afford (199) under photochemical conditions. Complex (190) undergoes Friedel-Crafts-type acylation with... 

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