Enolates Friedel-Crafts alkylation

Other methods for the regioselective SN2-opening of vinyloxiranes include intramolecular enolate addition for formation of cyclohexane systems [135, 136] and Friedel-Crafts alkylations [49, 137, 138]. 

The concept of a diastereoselective Friedel-Crafts alkylation of a-chiral benzyl alcohols was first examined by Bach and coworkers [62, 63]. The initial protocol required stoichiometric amounts of strong Brpnsted acids like HBF4 and was followed by a more valuable methodology in which catalytic amounts of AuC L were employed for the diastereoselective functionalization of chiral benzyl alcohols [64], Beside arenes, allyl silanes, 2,4-pentanediones and silyl enol ethers have been used as nucleophiles. Depending on the diastereodiscriminating group and on the catalyst (Brpnsted or Lewis acid), the authors observed either the syn or the anti diastereoisomer as the major product. 

Friedel-Crafts alkylation has been used in an important synthesis of aryl C-glycosides, which are potent anti-tumor agents, from glycosyl fluorides (equation 99)65 661. The reaction takes place rapidly in dichloromethane, at room temperature using a novel zirconium complex and silver perchlorate combination catalyst. A similar alkylation has been performed by replacing the aromatic compound with either a silyl enol ether or an allylic compound using silver triflate as the catalyst662,663. 

Michael reaction of an oc,p-unsaturated ketone with a silyl enol ether (Scheme 26) and a Diels-Alder reaction of an oxazolidinone derivative with cy-clopentadiene (Scheme 27) also worked well using MC Sc(OTf)3. Moreover, a Friedel-Crafts acylation proceeded smoothly to produce an aromatic ketone in a good yield (Scheme 28). Friedel-Crafts alkylation and acylation reactions are fundamental and important processes in organic synthesis as well as in indus-... 

The introduction of a t-butyl group a - to a carbonyl group has been achieved by Friedel-Crafts alkylation of the appropriate trimethylsilyl enol ether. In the presence of a nickel(ii) catalyst, u/c-bromotrimethylsilyloxyalkenes couple with Grignard reagents to produce alkylated and arylated silyl enol ethers, which, after hydrolysis, furnish the corresponding a-alkylated or a-arylated ketones (Scheme 36). ... 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

There are several reactions that have more direct analogs to organic reactions. Aromatic rings coordinated to metals can undergo Friedel-Crafts alkylations and acylations (see Eq. 12.56 for an example). Alkylation of enolate analogs is also a common reaction (Eq. 12.57). In this case, the alkylation leads to a complex with a heteroatom directly attached to an alkyli-dene carbon, creating what is known as a Fischer carbene. 

A similar strategy was used by Fehr and co-workers to achieve the enantioselective (5,5)-vulcanolide (5, 5)-26 synthesis (Scheme 31.12). Li-enolate of ketone 33 was protonated by ( )-//-E affording the enantioenrichied ketone 34. Then, Friedel-Craft alkylation of o-xylene followed by reduction provides the secondary alcohol 35. The trans cyclohexyl derivative 36 was easily obtained under acidic conditions in 44% over three steps. Then, a monooxidation affords the (5,5)-vulcanolide (S,5)-26) in ca. 29% yield over five steps with 83% ee. 

Use in C-C Bond-Forming Reactions. Since MOMCl is an excellent electrophile it readily reacts with enolates and other carbanions and thus serves as an easily handled one-carbon synthon. Friedel-Crafts alkylation with MOMCl and a Lewis acid such as Tin(IV) Chloride, Titanium(IV) Chloride, Zinc Chloride,and Aluminum Chloride or Acetic AcU is a common method for introduction of a chloromethyl group onto an aromatic nucleus (eqs 9 and 10). The reaction is quite general and tolerates a broad range of functionality. 

EtAlCb catalyzes the Friedel-Crafts acylation of alkenes with acid chlorides, the formal [3 + 2] cycloaddition of alkenes with cyclopropane-1,1-dicarboxylates (eq 21), the Friedel-Crafts alkylation of anilines and indoles with ct-aminoacrylate esters, and the formation of allyl sulfoxides from sulfinyl chlorides and alkenes. EtAlCU induces the Beckmann rearrangement of oxime sulfonates. The cationic intermediates can be trapped with enol silyl ethers (eq 22). EtAlC is the preferred catalyst for addition of the cation derived from an a-chloro sulfide to an alkene to give a cation which undergoes a Friedel-Crafts alkylation (eq 23). ... 

The first step in the sequence may involve Friedel-Crafts-type condensation of resorcinol with the enolate of 10 to afford the unsaturated ester, 11. Alkylation of the free phenol on 12 by means of ethyl bromoacetate affords chromonar (13). ... 

Titanium-mediated intramolecular Friedel-Crafts acylation and alkylation are important methods for construction of fused-ring systems (Scheme 29).107 As well as aromatics, olefin units also react in the same way.108 Alkylation of electron-rich olefins such as enol ethers or silyl enol ethers proceeds effectively in the presence of TiCl4.109... 

IrCl2H(cod)]2 catalyzed the synthesis of substituted quinolines, where the reachon of aniline derivahves, aromatic and alkyl aldehydes efficiently proceeds under an oxygen atmosphere (Scheme 11.34) [46]. The plausible mechanism consists of a Mannich reaction, a Friedel-Craft-type aromahc substituhon, dehydration, and dehydrogenation. This can be recognized as a formal [4+2] cycloaddition of N-aryl imine and enol (Scheme 11.35). 

So far, most of the reactions presented in the book that are useful in synthesis have made C-O, C-N, or C-halogen bonds and only a few (Wittig, Friedel-Crafts, and reactions of cyanides and alkynes) make C-C bonds. This limitation has severely restricted the syntheses that we can discuss in this chapter. This is by design as we wanted to establish the idea of synthesis before coming to more complicated chemistry. The next four chapters introduce the main C-C bond-forming reactions in the chemistry of enols and enolates. You met these valuable intermediates in Chapter 21 but now you are about to see how they can be alkylated and acylated and how they add directly to aldehydes and ketones and how they do conjugate addition to unsaturated carbonyl compounds. Then in Chapter 30 we return to a more general discussion of synthesis and develop a new approach in the style of the last synthesis in this chapter. 

Three reactions, which were known from the literature to be catalyzed by Lewis acids were selected as test reactions. A, was the Reetz alkylation of silyl enol ethers with -butyl chloride for which titanium tetrachloride is known to be useful [52]. B, was the Diels-Alder reaction between furan and acetylenedicarboxylic ester for which aluminium trichloride is a good catalyst [53]. C, was a Friedel-Crafts acylation for which aluminium trichloride is the preferred catalyst [54]. The reactions are summarized in Scheme 6. 

A Alkylation of silyl enol ether B, Diels-Alder reaction, C, Friedel-Crafts reaction. b As a rough estimate of the kinetics, f50, which is defined as the time necessary to obtain 50% of the final yield was used. 

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