Friedel-Crafts Synthesis Of Glyoxylates

We were further interested to elaborate our catalytic conditions to the Friedel-Crafts reaction of indoles with α-amido sulfone 8 as a precursor of N-Boc α-imino ethyl glyoxylate. The use of imino derivatives of glyoxylates as electrophiles in aza-Friedel–Crafts reaction afforded the corresponding 3-indolyl glycine derivatives, an important class of nonproteinogenic amino acids useful for synthetic intermediates and building blocks for natural products such as dragmacidins.[14] Although some catalytic methods are available, enantioselectivities obtained to date are still unsatisfactory (up to 88% ee even at low temperatures).[12,13] Furthermore, catalysts were found to be less effective for 2-substituted indole derivatives.[15,16] Because of …show more content…
At the first step, complex I is formed by the complexation of KF with catalyst which then forms complex II by reaction with amido sulphone. Subsequently, elimation of the sulfinate group from the amido sulfone affords an imine being activated complex through hydrogen bonding. Subsequent addition of the activated indole to the imine (complex III) then delivers the alkylation products. The enforced proximity of the catalyst and substrates by chiral cage in situ formed by the incorporation of potassium salt can enhance the reactivity and efficiently transfer the stereochemical information, mimicking the action of enzymes. To our delight and suprise, all the proposed intermediates I, II, and III were identified by electrospray ionization high-resolution mass spectroscopy (ESI-HRMS) (the positive ion mode), strongly supporting our proposed mechanism. The peaks at m/z 1228.8160, 1571.9253, and 1546.9745 are consistent with [I – F-], [II - F-], and [III - PhSO2-], respectively. Moreover, the H-bonding interactions of indole N-H play an important role for this catalytic cycle and drive the forward reaction. As expected, no product was isolated using N-Me indole, further confirming our