Enantioselectivity F-C reaction

The Friedel Crafts (F C) reaction via activation of electrophiles functionalized by a nitrogen atom, such as imines, is undoubtedly the most practical and atom eco nomical approach to introduce a nitrogen substituted side chain to aromatic com pounds. The enantioselective version of the F C reaction of nitrogen substituted substrates, including imines, with electron rich aromatic compounds enables effi cient access to enantioenriched aryl methanamine derivatives [37[. Several excellent approaches to highly enantioselective F C reactions have been established using chiral phosphoric acid catalysts. 

The enantioselective F C reactions catalyzed by chiral phosphoric acids were further applied to such electron rich aromatic compounds as pyrroles (Scheme 3.19a and b) [45, 46] and 4,7 dihydroindoles (Scheme 3.19c) [47]. The reaction of 4,7 dihydroindoles yielded 2 substituted indole derivatives following oxidation of the F C products. The present approach well complements current studies of enantio selective F C reactions of parent indoles (see Scheme 3.18), where 3 substituted indole derivatives were obtained in most cases. 

Whereas a,P-unsaturated aldehydes and enones, nitroolefins, and imines have been used extensively in organocatalyzed enantioselective F-C reactions with various aromatic nucleophiles since 2001, the introduction of new classes of electrophiles in such transformations only started in the last four or five years. In 2007, two independent groups described how N-protected enamines could act as good substrates for preparing, in the presence of chiral phosphoric acids 26e and... 

Asymmetric ring-opening of saturated epoxides by organoctiprates has been studied, hut only low enantioselectivities f -c 1596 ee) have so far been obtained [49, 50]. Muller et al., for example, have reported that tlie reaction between cyclohexene oxide and MeMgBr, catalyzed by 1096 of a chiral Schiffhase copper complex, gave froiis-2-metliylcyclohexanol in 5096 yield and with 1096 ee [50]. 

Additionally, You reported a F-C reaction of indole with electronically diverse aryl aldimines (Scheme 5.8) [16]. In general, products could be obtained in excellent yields and enantioselectivities in short reaction times. 

Scheme 3.16 Enantioselective 1,2 aza F C reaction of N Boc imines with 2 methoxyfuran.

The present F C reaction proceeded through the in situ generation of aliphatic imines that were delivered via the protonation of the enecarbamates by the phos phoric acid catalyst (Figure 3.4). Phosphoric acid functioned as an efficient catalyst for the dual transformation that involved the in situ generation of imine and the enantioselective carbon carbon bond formation with indole. This protocol offers the distinct advantage of generating in situ unstable aliphatic imines from storable and thus easily handled enecarbamates, and hence is applicable to other organic transformations. In fact, Terada et al. applied the present method to an enantiose lective direct Mannich reaction [51]. The method provides an efficient pathway to p alkyl P aminocarbonyl derivatives in optically active forms. 

Shortly thereafter, Zhou and coworkers independently reported the enantioselec tive F C reaction of indoles with a aryl substituted enamides catalyzed by chiral phosphoric acid catalyst lq (Scheme 3.22) [52], in which the quaternary stereogenic center bearing the nitrogen atom vas constructed in a highly enantioselective manner. 

Scheme 3.22 Enantioselective formation of quaternary stereogenic center bearing a nitrogen atom in the F C reaction.

The use of chiral Bronsted acids (organocatalyst class) in asymmetric F-C reactions has been extensively reviewed. They can be used instead of oxophilic chiral Lewis acids for the asymmetric coupling of indoles to less reactive ketone substrates such as trihalopyruvates. The use by Mikami (2000) of a chiral phenol cocatalyst in boosting enantioselectivity ( 10%) perhaps provided the first clue to such a possibility. 

Asymmetric synthesis of organofluorine compounds is an important issue in pharmaceutical chemistry 1,2) and optoelectronic material science 3,4). In particular, asymmetric catalysis of carbon-carbon bond-forming reactions is the most attractive method, because the carbon skeleton of chiral organofluorine molecules can be constructed at the time of asymmetric induction 5-10). The Friedel-Crafts (F-C) reaction is one of the most fundamental carbon-carbon bondforming reactions in organic synthesis 11-14). However, its application to catalytic asymmetric synthesis has been quite limited (diastereoselective 25-22, enantioselective 23-25, stereospecific 2d,2. Herein, we report the catalytic... 

The F-C reactions of aromatic compounds can provide a practical synthetic route for chiral a-trifluorobenzylalcohols of synthetic importance (Scheme 1). In previous asymmetric syntheses of a-trifluorobenzylalcohols, the asymmetric reductions of trifluoromethyl ketone were used as a key step 30-34). In this F-C reaction, the catalytic activity and enantioselectivity of BINOL-Ti catalysts (55-57) were found to be critically influenced by the substituents of BINOL derivatives (Table I). 1) (i )-6,6 -Br2-BINOL-Ti catalyst was the most effective catalyst. This F-C reaction did not proceed easily as compared with the carbonyl-ene reaction (7,8) or the Mukaiyama-aldol reaction (7) with fluoral. Therefore, the role of the electron-witiidrawing group at the 6,6 -position of BINOL is very important for increasing the Lewis acidity (runs 1 3). Relatively high enantio-... 

BINOL-Ti catalyst in sharp contrast to the F-C reaction of aromatic compounds. The higher enantioselectivity was obtoined in the reaction of methyl vinyl ether (3b) possessing -methyl substituent irrespective of the geometry (run 4). This F-C reaction with alkyl vinyl ethers was found to more easily proceed compared with that of aromatic compounds. Therefore, an excess amount of fluoral was not necessary because of the high nucleophilicity of alkyl vinyl ethers. 

The above transformation has two different goals 21,22) 1) To increase chemo-, regio-, diastereo- and enantioselectivity in the reaction with carbonyl compounds (Sections C-E), and 2) to make certain reaction types amenable which do proceed readily with classical reagents, e.g., methylation of tertiary alkyl halides, alcohols and ethers, and direct geminal dialkylation of ketones (Section F). It turns out that organotitanium compounds are usually complementary to Li, Mg, Zn, Fe, Ni, Cu and Pd reagents. So far, experience in the above two areas points to the following positive aspects ... 

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