Indoles, chalcone

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. 

Sashidhara KV, Dodda RP, Sonkar R, Palnati GR, Bhatia G. Design and s)mthesis of novel indole-chalcone fibrates as lipid lowering agents. Eur. /. Med. Chem. 2014 81 499-509. 

Scheme 76 Michael-type Friedel-Crafts addition of indoles to chalcones...

The benzotriazole-functionalized pyrrole derivative 1233 was deprotonated and allowed to react with chalcone to afford a mixture of compounds 1235 and 1236, which without separation was refluxed in 2-propanol/10% H2SO4 to give the corresponding indole 1237 (Scheme 238) <2003JOC5728>. The reaction proceeded through the selective 1,4-addition of lithium derivative 1234 to the enones. Attempts to generalize this methodology with use of ot,)3-unsaturated esters failed. 

Nevertheless, the substrate specificity of peroxidases is so wide that secretory plant peroxidases are capable of accepting a plethora of natural compounds as substrates, such as indoles [43], porphyrins [44,45] including chlorophylls [46,47], terpenoids such as lutein [48], unsaturated lipid acids such as linoleic acid [49], alkaloids [50-52] including betacyanins [53], phenolics such as benzoic acids [54,55], DOPA [56], coumarins [38,57], stylbenes [58], catechins [36,59], chalcones [60], flavonols [61,62], isoflavones [63,64], cinnamyl alcohols and cinnamic acids [65,66], anthocyanins [67,68] and ascorbic acid [69,70],... 

Scheme 4.57 Enantioselective conjugate Friedel-Crafts alkylation of indoles with chalcones.

To end this section, it has to be mentioned that there is a single example of a conjugate Friedel Crafts alkylation involving enones as Michael acceptors. In particular, a camphor-based sulfonic acid (94) has been used as catalyst in the reaction of indoles with chalcones (Scheme 4.57). It has also to be noted that the best conditions involved the use of catalyst 94 together with an ionic liquid (l-butyl-3-methyl-l//-imidazolium bromide BmimBr). However, although excellent yields were obtained for a set of different substrates tested, the enantioselectivities remained in rather low values. 

In the previous section, chiral secondary amines are shown to be efficient catalysts for the AFC reaction of 4,7-dihydroindoles with a,p-unsaturated aldehydes by Wang and co-workers. Subsequently, the same group extended the AFC reaction to a,p-unsaturated ketones by using a new chiral primary/ secondary diamine catalyst derived from an amino acid. They found that chalcones, particularly challenging substrates for iminium catalysis, could afford the AFC products 122 in high yields (69-97%) with moderate to excellent enantioselectivity (66-97% ee). Note that the substitution on the 4,7-dihydroindolic nitrogen had a detrimental effect on the reactivity (<10% yield for Al-methyl indole) (Scheme 6.50). 

In 2010, the Feng group developed a catalytic AFC alkylation of indoles and pyrrole with chalcones promoted by Sc(OTf)3/l complex in moderate to excellent yields and high enantioselectivity (up to 92% ee). Catalyst loading ranging from 2 to 10 mol% shows the potential practicality of the catalyst system (Scheme 6.54). 

Unconventional activation techniques could also be used for indole functionalization. Within 10 min, including reaction and purification time, 3-p3rranyl indole derivatives could be obtained with good yields, through one-pot microwave-assisted reactions, with InCls as catalyst (Figure 18) [37]. Indolyl chalcones could be prepared from indole-3-carboxaldehyde and heteroaryl active methyl compounds under conventional heating, but the yield was much improved and reaction time was drastically reduced (from more than 9 h to less than 15 min) when microwave irradiation was introduced [38]. Ultrasounds aid the selective formation of... 

The reaction of chalcone (2) with indole (3) (1 1 molar ratios in a 1 mmol scale) was performed to optimize the experimental conditions with respect to temperature, time, and ratio of MSSA to the substrate. It was found that 200 mg of MSSA was sufficient to obtain the desired Michael adduct in 98% yield in 90 min at room temperature in CH3CN. A variety of a,p-unsaturated ketones and electron-deficient olefins were tested under the optimized reaction conditions (Scheme 1.3a). All the reactions proceeded easily and the products 4 were isolated with comparable yields (85%-98%) in short reaction times. No side products such as N-alkylation products were detected. 

Kobayashi et al. also reported asymmetric Friedel-Crafts-type alkylation reactions of an indole with a chalcone (Scheme 5) [49]. A chiral calcium complex... 

Kobayashi et al. investigated asynunetric Friedel-Crafts-type reactions of indoles with chalcone derivatives catalyzed by a chiral barium complex, and high... 

Table 20 Asymmetric Friedel-Crafts-type reactions of indole with chalcone derivatives using a chiral Hg-S.S -SiPhs-BINOL-barium catalyst...

Fig. 27.10 Michael reaction of indole with chalcone in the presence of calix[6]arene sulfonic acids...

Akiyama and coworkers explained this reversal of facial selectivity as follows. The key element is the difference in the direction of the a,P-unsaturated ketone. In the case of indole 75, TS A was preferred over TS B because of the n,7i-stacking between the indole benzene ring and the benzene ring at the 3-position of the chalcone moiety. In contrast, in the case of 4,7-dihydroindole 79, the collapse of aromaticity led to severe steric repulsion (Figure 11.6), furnishing TS D as the predominant transition state. The low selectivity in the reaction of indole with l-phenylbut-2-en-l-one clearly showed the importance of the Jt,Jt-stacking in the transition state. 

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