Organic Chemistry Portal
Organic Chemistry Highlights

Friday, December 30, 2005
M. Manuel B. Marques
REQUIMTE - FCT - New University of Lisbon

Enantioselective Alkylation of the Indole Nucleus - Part Two of Two:
Enantioselective Friedel-Crafts reaction

Recently, the catalytic, enantioselective Friedel-Crafts (FC) alkylation of indoles has been the method of choice in the synthesis of important optically active targets. The Jørgensen group was the first to report (Angew. Chem. Int. Ed. 2001, 40, 160, DOI: 10.1002/1521-3773(20010105)40:1%3C160::AID-ANIE160%3E3.0.CO;2-S and Chem. Commun. 2001, 347, DOI: 10.1039/b009008p.) on the asymmetric FC alkylation of indoles (with α,β-unsaturated ketoesters and malonates), and many groups have developed different catalytic approaches since then. This highlight focuses on the most recent advances in this area.

Part II. Enantioselective Friedel-Crafts Alkylation of the Indole Nucleus

Tang et al. reported (J. Org. Chem. 2004, 69, 1309. DOI: 10.1021/jo035552p) on the enantioselective alkylation of the indole framework with alkylidene malonates using a complex of the pseudo-C3-symmetric tris(oxazoline) (1) and copper(II) salts as a catalyst (Figure 1). This group has extensively studied the solvent influence, in particular the effect of alcohols, tolerance to water, the influence of the ester group and substituents on the indole, additives, mechanism and the scope of the reaction.

Figure 1 - Pseudo-C3-symmetric tris(oxazoline) (1) used for the enantioselective FC alkylation of indole.

In preliminary tests (Scheme 1), the Tang group observed reversal of enantioselectivity wherein the stereochemistry of the products was dependent on the solvent. This gives access to both enantiomers. Another interesting point was the effect of the alcohol - with 2 equiv. of 1,1,1,3,3,3-hexafluoro-2-propanol, 91% ee and 99% yield were achieved. The presence of the alcohol not only accelerated the reaction but also improved enantioselectivity.

Scheme 1 - Preliminary tests where a reverse of enantioselectivity was observed by Tang et al.

The same group investigated the influence of the reaction conditions (solvent/ligand/copper salt/temperature) for different arylidene malonates (Scheme 2). The best enantiomeric excess was obtained in TTCE (1,1,2,2-tetrachloroethane) with the malonate containing an electron-withdrawing group on the aromatic ring. A reversal of enantioselectivity was also observed here: one enantiomer was obtained in TTCE, while in i-BuOH or mixed solvent (acetone/ether) the opposite enantiomer was formed. The presence of an aromatic substituent on the double bond is necessary for achieving a significant enantiomeric excess.

Scheme 2 - Various reaction conditions tested by Tang et al.

Umani-Rochi et al. reported on the catalytic approaches in the stereoselective FC alkylation of aromatic compounds (Angew. Chem. Int. Ed. 2004, 43, 550. DOI: 10.1002/anie.200301679). This group developed (Tetrahedron Lett. 2003, 44, 5843, DOI: 10.1016/S0040-4039(03)01400-X); J. Org. Chem. 2004, 69, 7511. DOI: 10.1021/jo0487202) a new enantioselective FC-type conjugate addition of indoles to enones catalysed by a chiral complex derived from [Al(salen)Cl] 7 and lutidine at room temperature (Scheme 3).

Scheme 3 - Enantioselective FC-type conjugate addition of indole 8 to (E)-arylcrotyl ketones 9 catalysed by [Al(salen)Cl] 7 / 2,6-lutidine complex.

Based on the results obtained in their preliminary tests with different enones and indoles, the Umani-Rochi research group realised that in order to achieve higher ees, it was essential to have a phenyl group bonded to the carbonyl moiety and a small methyl group bonded to the double bond, as in enone 9. Enone 9 with R = C6F5 gave the best result (90% yield, 88% ee) while 9 with R = 2,4,6-Mes (mesityl) or o-Br-C6H5 gave the worst results, probably due to failure to coordinate with the chiral catalyst.

When the authors screened a variety of solvents (Et2O, THF, MeCN, CH2Cl2), the best results were obtained with toluene. The use of 2,6-lutidine (10 mol%) as an additive proved to increase the stereoselectivity when compared to the reactions carried in the absence of this base. This group carried out several studies that strongly suggest an interaction between the added base and the aluminium. Moreover, a cationic hexacoordinate complex has been proposed as responsible for the observed enantioselectivity.

García et al reported (J. Am. Chem. Soc. 2005, 127, 4154. DOI: 10.1021/ja0423217) very recent advances in the catalytic enantioselective FC alkylations using a bis(oxazoline)-Cu(II) as catalyst. This group has performed several reactions between indoles 14 and α’-hydroxy enones 15, and obtained the corresponding adducts in high yield and high ee (up to 98%, Scheme 4). These reactions were carried at temperatures between 0-25ºC as well as at reflux (40ºC).

Scheme 4 - Enantioselective FC-type conjugate addition of several indoles 14 to α’-hydroxy enones 15 catalysed by bis(oxazoline)/Cu(OTf)2 13.

However, the adducts resulting from enones 15 (R3 = Me2CH and c-C6H11) were obtained in lower yield, although higher ees and higher yields were achieved when catalyst 17 (Figure 2) was used (for example: for R3 = c-C6H11, 32% yield with catalyst 13 to 80% yield with catalyst 17).

Figure 2 - Bis(oxazoline)-Cu (II) catalyst 17.

M. M. B. Marques, Org. Chem. Highlights 2005, December 30.