Friedel-Crafts reactions asymmetric activation

Ricci and co-workers introduced a new class of amino- alcohol- based thiourea derivatives, which were easily accessible in a one-step coupling reaction in nearly quanitative yield from the commercially available chiral amino alcohols and 3,5-bis(trifluoromethyl)phenyl isothiocyanate or isocyanate, respectively (Figure 6.45) [307]. The screening of (thio)urea derivatives 137-140 in the enantioselective Friedel-Crafts reaction of indole with trans-P-nitrostyrene at 20 °C in toluene demonstrated (lR,2S)-cis-l-amino-2-indanol-derived thiourea 139 to be the most active catalyst regarding conversion (95% conv./60h) as well as stereoinduction (35% ee), while the canditates 137, 138, and the urea derivative 140 displayed a lower accelerating effect and poorer asymmetric induction (Figure 6.45). The uncatalyzed reference reaction performed under otherwise identical conditions showed 17% conversion in 65 h reaction time. 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

Jorgensen, K. A. Asymmetric Friedel-Crafts reactions Cataiytic enantioselective addition of aromatic and heteroaromatic C-H bonds to activated aikenes, carbonyi compounds, and imines. Synthesis 2003,1117-1125. 

In 2009, Nicolaou and co-workers reported an organocatalytic total synthesis of demethyl calamenene (168), a potent cytotoxic agent, which is a beautiful application of SOMO-activated catalysis (Scheme 17.29) [68]. The key step involved an asymmetric intramolecular Friedel-Crafts reaction of aldehyde 166 to achieve the bicyclic aldehyde 167 using imidazolidinone 122 as a SOMO-activated catalyst (56% yield, 90% ee). 

For other examples of use of chiral phosphoric acid as catalyst in the synthesis of indole derivatives, see (a) Q. Kang, Z.-A. Zhao, S.-L. You, Tetrahedron 2009, 65, 1603-1607. Enantioselective synthesis of (3-indolyl)glycine derivatives via asymmetric Friedel-Crafts reaction between indoles and glyoxylate imines. (b) M. Terada, K. Machioka, K. Sorimachi, Angew. Chem. Int. Ed. 2009, 48, 2553-2556. Activation of hemiaminal ethers by chiral Brpnsted acids for facile access to enantioselective two-carbon homologation using enecarbamates. 

Recently, the Michael-type asymmetric Friedel-Crafts reaction of electron-deficient alkenes has been established as an important route to chiral benzylic stereocentres. " However, applications of this methodology for the synthesis of all-carbon quaternary stereocentres are conspicuously limited. PFMonosubstituted nitroalkenes have turned out to be active substrates in... 

Asymmetric catalysis of Friedel-Crafts reaction with fluoral is established using chiral binaphthol-derived titanium catalysts with or without asymmetric activation to provide a practical synthetic route not only for chiral a-trifluorobenzylalcohols but so for highly enantiopure functionalized jS-trifluoroaldols through the sequential diastereoselective reactions of the resultant vinyl ethers or silyl enol ethers with electrophiles. 

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... 

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. 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

The synthesis of the optically active chroman 489 can be achieved by use of a catalytic asymmetric tandem oxa-Michael addition Friedel-Crafts alkylation sequence between 3-methoxyphenol and (/. (-methyl 2-oxo-4-phenylbut-3-enoate. The chiral C2-symmetric box managanese(n)- complex 490 exerts excellent stereocontrol upon the reaction (Equation 200) <20030BC1953>, whereas only moderate enantioselectivity is observed in the presence of a chiral C2-symmetric 2,2 -bipyridyl copper(n)- complex (42% = ee) <20050L901>. 

Uraguchi D, Sorimachi K, Terada M (2004) Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan. J Am Chem Soc 126 11804-11805 Uraguchi D, Terada M (2004) Chiral Brpnsted acid-catalyzed direct Mannich reactions via electrophilic activation. J Am Chem Soc 126 5356-5357 Vachal P, Jacobsen EN (2000) Enantioselective catalytic addition of HCN to ketoimines. Catalytic synthesis of quaternary amino acids. Org Lett 2 867-870... 

Friedel-Crafts Alkylation Reactions. The activation of glyoxylate esters,trifluoromethyl pyruvate esters, and unsaturated a-ketoesters by catalyst 2 converts these materials into effective electrophiles for asymmetric Friedel-Crafts alkylation reactions with activated arenes (eqs 16 and 17). In fact, bis(triflate) (2) is far superior to tbe bis(hexafluoroantimonate) complex at catalyzing the enantioselective alkylation of benzene derivatives. Aniline and anisole derivatives both give the reaction, as do heterocyclic aromatic compounds such as indole and furan. 

Asymmetric Friedel-Crafts alkylations, besides affording interesting mechanistic problems, also offer valuable synthetic utility. For example, reaction of benzene with optically active 2-chloro-l-phenyl-propane or 1-chloro-2-phenylpropane in the presence of AICI3 affords good yield (60%) of alkylated product with up to quantitative optical yields (see Scheme 3). ... 

We developed two highly efficient approaches toward the 5HT2b receptor antagonist LY414197. The first route utilized a Pictet-Spengler reaction to construct the racemic TH(3C derivative. Access to the most active (5)-enantiomer was then achieved in up to 70% yield through a one-pot resolu-tion-racemization process. The second approach is based on the chiral A-arenesulfonylated-1,2-diamine/ruthenium(II)-catalyzed asymmetric reduction of a 3,4-dihydro- 3-carboline precursor, obtained from a Bischler-Napieralski or related Friedel-Crafts methodology. 

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