Friedel-Crafts Type Alkylation

Very recently, the enantioselective Friedel-Crafts alkylation of the simple phenols 157 with trifluoropyruvate was also accomplished by using the bifunctional quinidine 

Deng and coworkers also found that the bifunctional quinidine- or quinine-based thioureas 36 and 40 effectively catalyze the asymmetric Friedel-Crafts reaction of indoles with a variety of aromatic and alkyl-substituted aldimine derivatives 159. Both enantiomeric forms of the products 160 were obtained with uniformly high 

Other types of cinchona-catalyzed enantioselective Friedel-Crafts type reactions such as the conjugate addition of naphthols to nitroalkenes [77] and Friedel-Crafts amination [78] are discussed in the respective sections of Chapters 6 and 9. 

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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. 

Many of the reactions of BF3 are of the Friedel-Crafts type though they are perhaps not strictly catalytic since BF3 is required in essentially equimolar quantities with the reactant. The mechanism is not always fully understood but it is generally agreed that in most cases ionic intermediates are produced by or promoted by the formation of a BX3 complex electrophilic attack of the substrate by the cation so produced completes the process. For example, in the Friedel-Crafts-type alkylation of aromatic hydrocarbons ... 

Jung etal. reported the Friedel-Crafts type alkylation of ferrocene with allylchlo-rosilancs. The reaction of ferrocene with allylchlorosilanes in the presence of Lewis acid afforded regiospecific alkylated ferrocenes bearing chlorosilyl groups at the /J-carbon to the ferrocene ring (Eq. (4)). 

The cyclization to structurally defined, soluble LPPP takes place in a two-step sequence, consisting of a reduction of the keto group followed by ring closure of the secondary alcohol groups of 28 in a Friedel-Crafts-type alkylation. 

A fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

Gold-catalyzed direct C-H functionalizations enable the formation of polyalkylated arenes under mild conditions. In many cases, branched products are obtained. Two mechanisms are thought to operate with electron-rich arenes, an S si2-type mechanism via Au(lll) leads to the linear product. The branched product is obtained via a Friedel-Craft-type alkylation. A silver salt is often added and is believed to generate a more electrophilic Au(m) species. Often regioselectivities are poor and symmetric arenes are employed. Intramolecular variants as well as Michael additions are also known (Equations (72)-(74)).71,71a,71b... 

Extensions of the electrophilic activation of the alkyne moiety as well as an alkene moiety have been developed and applied. The applications include various reactions, for instance, Friedel-Crafts type alkylations,323 anchimeric assistance of heteroatomic moiety generally followed by rearrangements (see below), implementation of more sophisticated functional groups such as ynamides and allenynes, which are discussed below. 

Scheme 9 Mechanism of a Friedel-Crafts-type alkylation of a-diazoesters...

While its precise role remains unclear, the catalyst 3m is supposed not only to activate the electrophile (26), but also to lower the nucleophilicity of the amide nitrogen atom (Fig. 5). The latter interaction may account for a chemoselective Friedel-Crafts-type alkylation versus an aza-Darzens reaction. 

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. 

Scheme 9 (a) Friedel-Crafts-type alkylation of P-hydroxyesters. (b) Bi(OTf)3-catalyzed synthesis of fluorenes... 

Beside the Friedel-Crafts-type alkylation of arenes, the direct functionalization of 2,4-pentanediones is of great interest in Lewis acid catalysis. Although Pd-catalyzed Tsuji-Trost type allylations of 1,3-diketones are known, direct benzylation procedures catalyzed by Lewis acids are less explored [40-43]. Based on the previously described Friedel-Crafts alkylation of arenes and heteroarenes, the Rueping group developed a Bi(OTf)3-catalyzed benzylation of 2,4-pentanediones. Alcohols such as benzyl, allyl or cinnamyl alcohols were used as the electrophilic component to yield important 2-alkylated 1,3-dicarbonyl compounds. Initially, different Bi(III) salts were screened. In contrast... 

Besides the high efficiency of this route, many styrenes are readily available. This widens the product scope for 1,1-diarylalkanes and would additionally complement the previously described benzyl-alcohol-based Friedel-Crafts-type alkylations. 

Ethynylcarbazole was apparently formed by sodamide treatment of 9-dichlorovinylcarbazole (97) and zinc reduction of 97 gave 98. Where no reaction occurred with the Z isomer, 99 gave the dimer 100 with boron trifluoride the process presumably involves Lewis acid-catalyzed alkylation of one double bond by another double bond, complexed to boron trifluoride, followed by intramolecular Friedel-Crafts type alkylation at the carbazole 1-position. ... 

Reactions other than those of the nucleophilic reactivity of alkyl sulfates involve reactions with hydrocarbons, thermal degradation, sulfonation, halogenation of the alkyl groups, and reduction of the sulfate groups. Aromatic hydrocarbons, eg, benzene and naphthalene, react with alkyl sulfates when catalyzed by aluminum chloride to give Friedel-Crafts-type alkylation product mixtures (59). Isobutane is readily alkylated by a dipropyl sulfate mixture from the reaction of propylene in propane with sulfuric acid (60). 

Detailed coverage of Friedel-Crafts-type alkylations is to be found in relevant reviews and monographs,77-86 and the reader is advised to consult these for detailed information. 

Enantioselective Friedel-Crafts Type Alkylation Reactions... 

Enantioselective Friedel-Crafts Type Alkylation Reactions 150 Marco Bandirti, Alfonso Melloni, and Fabio Piccinelli... 

A Friedel-Crafts type alkylation of 1,1,2,3,3-pentamethylindane with (R)- or (.S )-ructhylcpoxide followed by acid-catalyzed condensation of the resulting alcohols with paraformaldehyde affords two diastereomeric pairs of isochro-mans 586, 587 (Scheme 127) <1999HCA1656>. Separation of the enantiomers of (4.S, 7/ /.S )-isochromans 586 is achieved by flash chromatography of their corresponding tricarbonylchromium complexes and subsequent oxidative demetallation the result of this synthetic work establishes that (4,y,71J)-isochroman is found to be responsible for the intense musk odour of the perfume galaxolide (Scheme 127) <1999HCA1656>. 

Indoles can be used as radical acceptors instead of 63 [120, 121]. Simple and twofold reactions giving either 3-alkylindoles [120] or l,l-bis(3-indolyl)alkanes [121] were observed in 16-72% and 54-90% yield, respectively. In both methods the indole is subject to radical addition in 3-position. The resulting a-amino radical undergoes a further oxidation and deprotonation to the 3-substituted indole. In the case of twofold additions, the second indole unit is introduced by a subsequent polar Friedel-Crafts-type alkylation. 

Section 5.2 aromatic Friedel-Crafts-type alkylations C. Perego and P. Ingallina, Catal. Today 2002, 73, 3 A. Corma, Chem. Rev. 1995, 95, 559 alkane cracking and isomerization Y. Ono, Catal. Today 2003,81, 3 A. Feller and J. A. Lercher, Adv. Catal. 2004, 48, 229 isoparaffin-olefin alkylation A. Corma and A. Martinez, Catal. Rev. Sci. Eng. 1993, 35, 483 acid-base catalysis with metal oxides K. Tanabe and W. F. Floelderich, Appl. Catal. A Gen. 1999, 181, 399. 

Titanium tetrachloride promoted a three-component cyclization involving a carbonyl compound, an allylsilane, and an acetal, as shown in Eq. (69) [188]. The reaction was initiated by allyl addition to the aldehyde this was followed by acetal exchange and intramolecular Friedel-Crafts-type alkylation of the olefinic moiety. 

Table 19. The Friedel-Crafts type alkylation of olefins and acetylenes. Substrate Titanium sail Product...

Friedel Crafts type alkylations of benzene by alkenes involve the initial formation of a lattice associated carbenium ion, formed by protonation of the sorbed olefin. The chemisorbed alkene is covalently bound to the zeolite in the form of an alkoxy group and the carbenium ion formed exists only in the transition state. As would be expected fixjm conventional Friedel Crafts alkylation, the reaction rate over acidic molecular sieves also increases with the degree of substitution of the aromatic ring (tetramethyl > trimethyl > dimethyl > methyl > unsubstituted benzene). The spatial restrictions induced by the pore size and geometry frequently inhibit the formation of large multisubstituted products (see also the section on shape selectivity). 

Ipatieff and coworkers carried out the first alkylation with alkenes and branched and normal chain alkanes (except methane and ethane) in the presence of AlCb as the catalyst. The sulfuric acid catalyzed alkylation reaction of arenes and isoalkanes, developed in 1938, is a still widely used industrial process to produce alkylates with high octane numbers. For synthetic applications, however, Friedel-Crafts-type alkylations of alkenes and alkanes have limited value since they tend to give mixtures of products, including oligomers of alkenes. ... 

N-Acyliminium ion pools react with various carbon nucleophiles as summarized in Scheme 5.16. For example, allylsilanes, silyl enol ethers, Grignard reagents, and 1,3-dicarbonyl compounds serve as good nucleophiles. Aromatic and heteroaromatic compounds also react as nucleophiles with N-acyliminium ion pools to give Friedel-Crafts-type alkylation products.N-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4 -F 2] cycloaddition with alkenes and alkynes. Usually these reactions take place very quickly, and therefore N-acyliminium ion pools serve as effective reagents for flash chemistry. 

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