Indole-oxazoline ligands

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>. 

Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyse the addition of indoles to benzylidene malonates in up to 99% ee, provided that excess of the chiral ligand is avoided.166 The paradigm followed in many asymmetric catalytic reactions that an excess of the chiral ligand with respect to the metal should improve enantioselectivity because the background reaction catalysed by a free metal is suppressed, was shown not to be applicable here,166 which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalysed processes known. Enantioselective additions of pyrroles and indoles to ,/9-unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(III) triflate complex have been accomplished.167... 

Rasappan R, Hager M et al (2006) Highly enantioselective michael additions of indole to benzylidene malonate using simple bis(oxazoline) ligands importance of metal/ligand ratio. Org Lett 8 6099-6102... 

The catalytic asymmetric Fujiwara-Moritani-type allylation reaction of indoles and pyrroles was reported by Oestreich and co-workers. Moderate yields and ee were realized by using novel oxazoline ligands and a stereo-genic quaternary center was formed (Scheme 5.12b). Nevertheless, it still leaves room for improvement, probably by designing new ligands. 

Subsequently, Fu and co-workers synthesized a series of easily accessible heteroarylidene malonate-derived bis(oxazoline) ligands 71 and 72 and their Cu complexes were found highly efficient for the catalytic AFC reaction of indoles with diethyl alkylidene malonates (Scheme 6.28). The corresponding addition products were obtained in good to excellent yields (70-99%) with up to 99.5% ee. 

Oestreich and co-workers reported an enantioselective intramolecular Fujiwara-Moritani reaction of indole and pyrrole derivatives. Using a suitable oxidant e.g., PhCOg Bu, benzoquinone, O2), they evaluated a chiral bidentate pyridyl-oxazoline ligand (PyOx) developed by Stolz and a series of nicotine-oxazoline ligands (NicOx) with Pd(OAc)2 as a catalyst precursor (Scheme 7.25). Indoles and pyrroles underwent a 5-exo-trig cyclization, but the chemical yield and enantioselectivity were generally unsatisfactoiy. 

The additions of indoles to ethenetricarboxylates as Michael acceptors in the presence of copper(II) complexes (10%) of chiral bisoxazolines (97-100) under mild conditions gave the alkylated products in high yield and up to 96% ee [101]. The observed enantioselectivity could be explained by secondary orbital interaction on approach of indole to the less hindered side of the 102-Cu(II)-ligand complex. The chiral ligands 97-99 of the catalyst gave similar ee%. The phenyl derivative 100 produced inferior results compared to 97-99, while (S,S)-2,6-bis(4-isopropyl-2-oxazoline-2-yl)pyridine (101) gave no reaction (Scheme 29) [56]. The enantioselective alkylation of indoles with arylidene malonates catalyzed by z-Pr-bisoxazoline-Cu(OTf)2 was also reported [102],... 

A series of chiral C2-symmetric tridentate bis(oxazoline) 110, 112 and bis(thiazoline) 111, in which a diphenylamine unit links the two chiral ox-azolines, was used for a more practical and efficient catalytic asymmetric alkylation of indoles with nitroalkenes (Scheme 31) [104], The alkylation of indole with frarzs-P-nitrostyrene in toluene at room temperature has been accomplished with 110d-Zn(OTf)2 or 113-Zn(OTf)2 as the catalyst. The obtained results show that the NH group in ligands 110-112 is crucial. Indole... 

Franzen and coworkers described a series of indole-phos-phine-oxazoline (IndPHOX) ligands, 231-238 (Scheme 35). The power of these ligands is demonstrated by the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphe-nyl-2-propenyl acetate with dimethyl malonate with 98%... 

The use of pseudo-C3 symmetric tris(oxazoline) 176 proved to be important in the copper-catalyzed indole addition to aryl alkylidene malonates 175 (Scheme 8.48) [139]. A comparison with the traditional tert-butyl-substituted bis(oxazoline) 173 resulted in a sharp decrease in enantioselectivity (from 92% to 69% ee). Hence, Tang proposed a sidearm effect exerted by ligand 176 to be essential for this class of acceptors. 

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