Friedel-Crafts-type reaction

At the end of nineteenth century, several reports appeared in the most important chemical journals of that time, Justus Liebigs Annalen der Chemie and Chemische 

Berichte, showing how the chemical behaviour of thiophene is similar to that of benzene. Preparing this chapter, we ourselves were amazed by the fact that eleven out of 51 reports published in the March 1884 issue of Chemische Berichte were devoted to thiophene and its derivatives. 

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]. 

A very important question is the regioselectivity of substitution reactions of thiophenes. A comprehensive review on electrophilic substitution on thiophenes [21] described in detail the directing effects of substituents, their position and the way the electronic properties of different functional groups activate or deactivate various positions in thiophene. Many publications (e.g. [23, 24]) and reviews [3,9, 25] discuss the mechanisms of electrophilic substitution on thiophene, proceeding through the formation of thiophenium ions. 

In the next section, the progress of Friedel-Crafts acylation of thiophene, including different acylating agents, different Lewis acids as well as catalytic and enantioselective variants, is shown. 

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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. 

In superacidic media, the carbocationic iatermediates, which were long postulated to exist duting Friedel-Crafts type reactions (9—11) can be observed, and even isolated as salts. The stmctures of these carbocations have been studied ia high acidity—low nucleophilicity solvent systems usiag spectroscopic methods such as nmr, ir, Raman, esr, and x-ray crystallography. 

Mote stable catalysts ate obtained by using fluorinated graphite or fluorinated alumina as backbones, and Lewis acid halides, such as SbF, TaF, and NbF, which have a relatively low vapor pressure. These Lewis acids ate attached to the fluorinated soHd supports through fluorine bridging. They show high reactivity in Friedel-Crafts type reactions including the isomerization of straight-chain alkanes such as / -hexane. 

A Friedel-Crafts-type reaction of phenols under basic conditions is also possible. Aqueous alkaline phenol-aldehyde condensation is the reaction for generating phenol-formaldehyde resin.34 The condensation of phenol with glyoxylic acid in alkaline solution by using aqueous glyoxylic acid generates 4-hydroxyphenylacetic acid. The use of tetraalkylammonium hydroxide instead of sodium hydroxide increases the para-selectivity of the condensation.35 Base-catalyzed formation of benzo[b]furano[60]- and -[70]fullerenes occurred via the reaction of C60CI6 with phenol in the presence of aqueous KOH and under nitrogen.36... 

Protonic acid and Lewis acids can activate carbonyls to facilitate the addition of nucleophile attacks in aqueous media. The Prins reaction, reaction with alkyne, and Friedel-Crafts-type reactions have been discussed in related chapters in detail. 

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

A number of amidines have anthelmintic activity. Bunamidine (25), indicated for treatment of human pinworm infestations, is prepared from a-naphthylhexyl-ether (23) by Friedel-Crafts type reaction with cyanogen bromide and aluminum chloride to give nitrile (24). This, then, is reacted with the magnesium bromide salt of di-n-propylamine leading to the naph-thamidine structure (25). -... 

Dibenzo[/>,/]thiepin derivative (39) has been obtained by cyclization of 2-arylthio-5-nitrophenylpyruvic acid (38) in the presence of polyphosphoric acid 33>. The use of this Friedel-Crafts type reaction is restricted to the synthesis of the stable di- and tri-annelated thiepins such as 40 33), 41 7), and 42 34). 

Derivatives 30 (R OH, R2 = iV-acetyl-indol-3-yl-(CH2)2 and (R = OEt, R2 = Ph-(CH2) (n — 2, 3)) were transformed into intramolecular Friedel-Crafts type reactions involving A-acyliminium cation intermediates into the cis-and trans-isomeric mixtures of the corresponding fused derivatives on treatment with strong acid <2000TL2745, 2001JOC5731>. 

AICI3 is a moisture-sensitive and strong Lewis acid. It is a first choice for Friedel-Crafts-type reactions, which provide numerous important transformations in laboratory and industry. It can also be applied to the transformation of alkenes to ketones via alkylaluminum halides.303 Hydrozirconation of an olefin and subsequent transmetalation from zirconium to aluminum gives the corresponding alkylaluminum dichloride, and the subsequent acetylation by acetyl chloride affords the corresponding ketone in high yield (Scheme 66). 

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. 

Facile preparations of aryldichlorophosphines and their derivatives have been accomplished with aluminum chloride in a Friedel-Crafts-type reaction system. While the reaction system has been used for more than a century,55 significant modifications have been made for improvement of yield.56-59 Conditions have been investigated that allow the destruction of the aluminum chloride complex to generate the product aryldichlorophosphine without the addition of water (Equation 4.20),60-62 or with water to isolate the free phosph-onous acid.57 58... 

The syntheses of flavanoid alkaloids also rest on A-l-pyrroline chemistry and on Friedel-Crafts-type reactions. In Govindachari s pioneering synthesis of ficine (167), pyrrolidine 126 is formed by condensation of trimethoxybenzene and y-aminobutyric acid in the presence of PPA (Scheme 19). Although the mechanism of this reaction has not been precisely determined, it may involve a A-l-pyrrolinium cation. These conditions were later used by Koch et al. in their synthesis of vochysine (Scheme 20) (108). 

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. 

Ohwada, T. Yamagata, N. Shudo, K. Friedel-Crafts-Type Reactions Involving Di- and Tricationic Species. Onium-Allyl Dications and 0,0-Diprotonated aci-Nito Species Bearing a Protonated Carbonyl Group. J. Am. Chem. Soc. 1991,113,1364-1373. 

While the //-dichloroboryl-pentaborane(9) obtained from KB5H8 and BC13 is stable only up to 0 °C [54], the 1-dichloroboryl isomer is a comparatively stable liquid. It is obtained from B5 H9 and BC13 in the presence of A1C13 as a catalyst in a Friedel-Crafts type reaction [55] ... 

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],... 

Typically, stoichiometric amounts of a Lewis acid such as AICI3 are required and produce stoichiometric amounts of salts and mineral acids (HX) as side products. Furthermore, undesired side reactions such as multiple alkylations and a low functional group tolerance are observed. With the need for more environmentally and economically benign processes, the development of Friedel-Crafts-type reactions using catalytic amounts of a Lewis acid catalyst is desirable. In addition, the substitution of benzyl halides for other environmentally friendly alkylating reagents constitutes an attractive goal. In particular, benzyl alcohols are suitable... 

The first systematic investigations of the catalytic Friedel-Crafts-type reaction with alcohols and olefines were performed by Yamamoto and colleagues. After reporting the development of a Pd-catalyzed method for the allylation of different naphthol derivatives [24], the authors used Mo(CO)g for the Friedel-Crafts-type alkylation of electron-rich arenes with allyl acetates [25], The same molybdenum catalyst was additionally used for a Friedel-Crafts-type alkylation of arenes using 1-phenylethanol and styrene as alkylating reagents [26], However, Mo(CO)g is toxic and must be handled under strictly inert conditions. Thus, more stable Lewis acids were necessary. 

This first example of a Bi(OTf)3-catalyzed Friedel-Crafts alkylation originated in the following procedures, including benzylations of 2,4-pentanediones or hydroarylation and hydroalkylation reactions. A related procedure was simultaneously developed by Bonrath et al. [39]. The authors utilized Bi(OTf)3 in the synthesis of (all-rac)-a-tocopherol (Vitamin E) [39], Besides rare earth metal triflates, such as Ga(OTf)3, Hf(OTf)3, Sc(OTf)3 and Gd(OTf)3, Bi(OTf)3 was shown to be the most efficient catalyst for the Friedel-Crafts-type reaction between trimethylhydroquinone acetate 10b and isophytols 11a, b. With only 0.02 mol% Bi(OTf)3 (substrate to catalyst ratio 5,000 1) the desired a-tocopherols 12a and 12b were isolated in excellent yields (Scheme 10). 

A Friedel-Crafts-type reaction can be carried out with hexachlorofullerene and, e.g., benzene, fluorobenzene, anisol or toluene, but due to steric hindrance not with mesitylene [85, 86]. Upon stirring benzene solutions of CgoClg with ferric chloride for 20 min, CgoPh5Cl can be obtained (Scheme 9.12). Replacement of the sixth chlorine is prevented by steric hindrance. This hindrance can be overcome by addition of the more reactive toluene to CgoPhsCl to give C6oPh5(C6H4CH3) [86]. 

A series of calpain I inhibitors such as 184 were prepared in a similar fashion from a-chloronitrile 185 in four steps (Scheme 24) <2001JME3488>. The key steps of this synthesis are the aforementioned Friedel-Crafts-type reaction of chloronittile 185 with CISO3H and a one-pot amidation/N-alkylation of dichloride 186 which furnishes the benzosulfonamide core 188 of these inhibitors via intermediate 187. 

The synthesis of C-glycosylflavones has been achieved mainly by Friedel-Crafts-type reactions or Koenigs-Knorr glycosylations. However, yields were poor due to steric hindrance of the substrates. Several other procedures have been proposed in the last decade. 

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