Friedel-Crafts alkylation cyclization

Scheme 64 Asymmetric Friedel-Crafts alkylation-cyclization cascade in the synthesis of flustramine B (283)...

Figure 6.18 Schematical Synthesis of (AII-rac)-a-Tocopherol (Vitamin E) via Two-Step Friedel-Crafts Alkylation-Cyclization of 2,3,6-Trimethylhydroquinone (TMHQ) with Isophytol (IP).

The industrial synthesis of this valuable compound is based on the condensation of 2,3,6-trimethylhydroquinone (TMHQ) with isophytol (IP), which proceeds through consecutive Friedel-Crafts alkylation-cyclization (Figure 6.18) steps [91] in the presence of ZnClj/HCl as catalyst [92],... 

Dichloroalkyl)chlorosilanes undergo the Friedel-Crafts alkylation type reaction with biphenyl in the presence of aluniinurn chloride catalyst to afford 9-((chlorosilyl)alkyl)fluorenes through two step reactions (Eq. (16)). The results obtained from the alkylation of biphenyl and the cyclization reaction to 5-membered-ring product are summarized in Table XIIE... 

Friedel-Crafts alkylation can occur intramolecularly to form a fused ring. Intramolecular Friedel-Crafts reactions provide an important method for constructing polycyclic hydrocarbon frameworks. It is somewhat easier to form six-membered than five-membered rings in such reactions. Thus, whereas 4-phenyl-1-butanol gives a 50% yield of a cyclized product in phosphoric acid, 3-phenyl-1-propanol is mainly dehydrated to alkenes.43... 

The possible importance of side reactions such as Friedel Craft alkylation, inter or intramolecular Diels Alder cyclization or re-addition of HC1 in this context have also been emphasised (43). 

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. 

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. 

More recently, a catalyst-free aqueous version of this strategy was proposed with simple acyclic 1,3-dicarbonyls, formaldehyde, and styrene or anilines derivatives (Scheme 40) [131], In the first case (Scheme 40), the very reactive 2-methylene-1,3-dicarbonyl intermediate reacts smoothly at 80°C with a variety of substituted styrenes to give the corresponding dihydropyrans in moderate to good yields. Remarkably, when styrenes were replaced by A-ethylaniline, a novel five-component reaction involving twofold excess of both formaldehyde and 1,3-dicarbonyl selectively occurred (Scheme 41). The result is the formation of complex fused pyranoquinolines following a Friedel-Craft alkylation - dehydration sequence to furnish the quinoline nucleus, which suffers the Hetero-Diels-Alder cyclization in synthetically useful yields. 

The first, and one of the most straightforward, syntheses of racemic 69 was that of Schach von Wittenau and Els ° after they had determined the stmcmre. Friedel-Crafts alkylation of indole with ethyl 2,3-epoxybutyrate gave the a-indolmycenic acid ester 119a. Cyclization of 119a with Af,//-dimethylguanidine yielded both 69 and isoindolmycin 120 (Scheme 6.32). In this case, facile epimerization of H-5 had occurred under the basic cyclization conditions. 

Recent efforts in the area of Friedel-Crafts alkylations have focused on the direct introduction of alkyl groups bearing functionalities, and on intramolecular alkylative cycliz-ations. The cyclization of the 2-substituted thiophene (55) to (56) has been achieved in 65% yield (80JOC3159). Similarly, the 3-substituted thiophene (57) has been cyclized to the isomeric (58). In both cases, detosylation of the product was achieved by treatment with diisobutylaluminum hydride (DIBAL). An elegant bis-cyclization of the diene (59) to the octahydrodibenzothiophene (60) has been reported (70CJC2587). 

Bicyclic 3a//-cyclopentene[8 annulcnc-l,4-(5//,9a//)-dioncs undergo three types of acid-induced transannular reactions (1) Michael addition (5-exo-trig or 6-exo-trig) leading to the tetracyclic diones, (2) 3 + 2-cycloaddition followed by a novel sequential skeletal rearrangement to 2-naphthalenone derivatives, (3) ipso-Friedel-Crafts alkylation accompanied by the rearomatization and the loss of water (Scheme 25). The factors that control the reaction mode of these transannular cyclizations are discussed... 

Pertinent examples of zeolite-catalyzed reactions in organic synthesis include Friedel-Crafts alkylations and acylations and other electrophilic aromatic substitutions, additions and eliminations, cyclizations, rearrangements and isomeriza-tions, and condensations. 

The use of alkenes as sources of electrophiles in Friedel-Crafts alkylations has also been studied. The intramolecular alkylation of l-(2-tolyl)-( )-pent-3-ene gives 1,5-dimethyl-l,2,3,4-tetrahydronaphthalene in 95 % yield [55]. BF3 has been shown to form a complex with nitromethane which is particularly effective in catalyzing proton-initiated cascade cyclization like that shown in Eq. (29) [56]. 

SnCU-promoted intramolecular additions of allylsilanes to /3-lactones proceed smoothly to give differently substituted cyclopentanes (Eq. 61) [94], When the a-ben-zyloxy-/3-lactone is subjected to standard cyclization conditions, the expected cyclopentane product is only obtained as a minor product the major product, isochroman, is derived from a Friedel-Crafts alkylation (Eq. 62). 

Although considered mild in comparison with other metals, copper(I) and (II) Inflates are suitable Lewis acids for affecting Friedel-Crafts alkylation and acylation reactions (Sch. 22). The intramolecular acylaminoalkylation of the indole derivative 88 afforded the cyclized product 89 in high yield [49]. The nitrogen functionality was not a requirement for formation of the benzylic cation, because the benzylic alcohol 90 reacted similarly with 91, even with an electron-withdrawing ester group adjacent to the cationic center. 

Table 18. Intramolecular cyclization via Friedel-Crafts alkylation. Ar-H Titanium salt Product...

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