Friedel-Crafts alkylation reaction scheme

Primary-secondary diamine catalyst 14 was found to be useful in the Friedel-Crafts alkylation reaction (Scheme 3.20). In the presence of 14/trifluoroacetic acid (TFA), alkylation of 4,7-dihydroindoles 85 with a,(3-unsaturated enones 86 proceeded well, and the desired alkylation products were obtained in high yields and with excellent enantioselectivities [56]. 

It should be noted that Scheme 5.1-44 shows idealized Friedel-Crafts allcylation reactions. In practice, there are a number of problems associated with the reaction. These include polyalkylation reactions, since the products of a Friedel-Crafts alkylation reaction are often more reactive than the starting material. Also, isomerization and rearrangement reactions can occur, and can result in a large number of products [74, 75]. The mechanism of Friedel-Crafts reactions is not straightforward, and it is possible to propose two or more different mechanisms for a given reaction. Examples of the typical processes occurring in a Friedel-Crafts alkylation reaction are given in Scheme 5.1-45 for the reaction between 1-chloropropane and benzene. 

Scheme 5.1-44 The Friedel-Crafts alkylation reaction (R = alkyl, X = leaving group).

The methodology of a Lewis acid dissolved in an ionic liquid has been used for Friedel-Crafts alkylation reactions. Song [85] has reported that scandium(III) tri-flate in [BMIM][PFg] acts as an alkylation catalyst in the reaction between benzene and hex-l-ene (Scheme 5.1-55). 

The mechanism for the production of 9-((chlorosilyl)alkyl)(luorenes from the Friedel-Crafts alkylation reaction of biphenyl with (l,2-dichloroethyl)silane in the presence of aluminum chloride as catalyst is outlined in Scheme 4. At the beginning stage of the reaction, one of two C—Cl bondsof (1,2-dichloroethyl)silane (CICH2—CICH—SiXi) interacts with aluminum chloride catalyst to give intermediate 1 (a polar +C-CI - ( +C-C1—Al CI3) or a carbocation C AICU ... 

The Friedel-Crafts alkylation reaction usually involves the interaction of an alkylation agent such as an alkyl halide, alcohol, or alkene with an aromatic compound, to form an alkylated aromatic compound (Scheme 5.1-44). 

In 1877, Charles Friedel and James M. Crafts discovered new methods for the preparation of alkylbenzenes, known as Friedel-Crafts alkylation reactions. The mechanism includes an electrophilic aromatic substitution whereby a carbocation is generated as the electrophile in the presence of a Lewis acid catalyst. The general scheme of F-C alkylation reaction is (16) as follows ... 

SCHEME 5.8 Michael-type Friedel-Crafts alkylation reaction mediated by chiial TlPS-pybox-[Sc(III)]... 

A related approach involves the direct decarbonylation of stable ketones. DauguUs and Brookhart demonstrated that the rhodium-catalyzed decarbonylation of diaryl ketones was feasible [11]. Efficient extrusion of CO from alkyl aryl ketones to form alkylarenes was easily achieved by rhodium(I) catalysis directed by apyridyl ortho to the RCO group (Scheme 22.6) [12]. (CO)2Rh(acac) was found to be the optimal catalyst and the methodology had a broad substrate scope. This method offers an alternative way to synthesize alkyl benzenes through an ARCIS reaction, complementary to the known Friedel-Crafts alkylation reaction of arenes. 

Cyclopenta[h]indoles can be synthesized in a multistep, one-pot procedure (Scheme 6.32). The reaction proceeds via an a-alkylation, which is catalyzed by a primary amine-substituted thiourea and two consecutive Brpnsted acid-catalyzed Friedel-Crafts alkylation reactions. Stmcturally diverse cyclopenta[ ]indoles can be obtained in high yields with excellent diastereo and enantioselectivities in this operation. Also, the cyclopenta[h]indoles can be converted into cyclopenta-[f>]indolines without loss of stereoselectivity. The potentially useful bisindole units are present in many natural and pharmaceutical products including yuehchukene. It is noteworthy... 

The same authors used the chiral phosphoric acid (300) in enantioselective asymmetric Friedel-Crafts alkylation reaction of indoles (324) with 3-sub-stituted 3-hydroxyisoindolin-l-ones (325) in synthesising 3,3-disubstituted isoindolin-l-ones (326), in excellent chemical yields (up to 99%) and with good to excellent enantioselectivities (up to 95% ee) (Scheme 85). ... 

Mohanty et al. were the first to introduce pendent r-butyl groups in die polymer backbones. The resulting material was quite soluble in aprotic dipolar solvents.83 The PEEK precursors were prepared under a mild reaction condition at 170°C. The polymer precursor can be converted to PEEK in die presence of Lewis acid catalyst A1C13 via a retro Friedel-Crafts alkylation. Approximately 50% of die rerr-butyl substitutes were removed due to die insolubility of the product in die solvent used. Later, Risse et al. showed diat complete cleavage of f< rf-butyl substitutes could be achieved using a strong Lewis acid CF3SO3H as both die catalyst and the reaction medium (Scheme 6.15).84... 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

The same group [38] also developed a double Heck reaction which was then terminated by a Friedel-Crafts alkylation to give 6/1-54 from 6/1-53 (Scheme 6/1.12) this involved an attack of an alkylpalladium(II) intermediate on an aryl or heteroaryl moiety. Noteworthy is the finding that the formal Friedel-Crafts alkylation occurs on both electron-rich and electron-poor heteroaromatic rings, as well as on substituted phenyl rings. Single Heck/Friedel-Crafts alkylation combinations have also been performed. 

The quinolizine derivative 276 was obtained through a Friedel-Crafts acylation reaction onto the C-3 indole position of 275. This precursor was obtained by a sequence comprising a Fischer cyclization leading to 5-methyl-2-(2-pyridyl)indole 274, catalytic hydrogenation, N-alkylation with ethyl bromoacetate, and hydrolysis of the ester group (Scheme 59) <1999FA479>. 

BF3 is an effective reagent for various kinds of reaction such as Friedel-Crafts alkylation and acylation reactions (Scheme 63),291 cyclization reactions, rearrangement,292 Diels-Alder reactions,293 and aldol reactions. 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

As a true testament to the potential long-term impact of H-bonding activation, a number of ureas, thioureas, and acid catalysts are now finding broad application in a large number of classical and modem carbon-carbon bond-forming processes. On one hand, Johnston s chiral amidinium ion 28 was elegantly applied to the asymmetric aza-Henry reactions (Scheme 11.12d). On the other hand, chiral phosphoric acids (e.g., 29 and 30), initially developed by Akiyama and Terada, have been successfully employed in Mannich reactions, hydrophosphonylation reac-tions, aza-Friedel-Crafts alkylations (Scheme 11.12e), and in the first example... 

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],... 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

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