Abstract
A successful one-pot methodology for the synthesis of chiral 2-tetrazolyl-2H-azirines has been established, resorting to organocatalysis. The protocol involves the in situ tosylation of β-ketoxime-1H-tetrazoles followed by the Neber reaction, in the presence of chiral organocatalysts. Among the organocatalysts studied a novel thiourea catalyst derived from 6β-aminopenicillanic acid afforded excellent enantioselectivities.
Highlights
Due to their unique structural features, 2H-azirines have been widely used as valuable synthetic intermediates in the synthesis of a plethora of nitrogen-containing compounds.[1,2,3,4,5,6,7] the high ring-strain along with the activated iminic bond and the Nlone pair on the azirine, make these heterocycles highly reactive and enable them to participate in organic reactions as nucleophiles and electrophiles, and as dienophiles and dipolarophiles
We reported the synthesis of (1H-tetrazol-5yl)-allenes,[15] tetrazolyl-tryptamines and 2-halo-2-(tetrazol-5yl)-2H-azirines and the use of these compounds for the construction of tetrazolyl-heterocycles, namely 3-tetrazolyl-βcarbolines with anti-cancer activity.[15,16,17,18]
The established synthetic methodology involves the preparation of β-ketoximes-1H-tetrazoles which undergo in situ tosylation and the subsequent Neber reaction to Template for SYNLETT © Thieme Stuttgart · New York
Summary
It is noteworthy that this synthetic methodology involves two consecutive reactions, the in situ tosylation followed by the Neber reaction, and the efficiency and selectivity obtained with this catalyst is quite remarkable This selectivity can be rationalized as resulting from the double hydrogenbonding interaction between the thiourea NH groups and the S=O moieties of the in situ generated ketoxime tosylate, as previously observed in asymmetric Neber reactions promoted by other chiral thioureas. In the synthesis of 2-(tetrazol-5-yl)-3(thiophen-2yl)-2H-azirine 14a, higher selectivity for the R isomer was achieved under thiourea 12 catalysis with an enantiomeric excess of up to 74% (entry 1) whereas the quinidine-mediated reaction afforded 14a in the highest yield (86%) albeit with slightly lower enantioselectivity (55% ee, entry 3). These rather disappointing results could be derived from the lower stability of these furanyl-substituted 2H-azirine derivatives
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