Design And Synthesis Of Chiral 3,4-diaminopyridine N-oxides Based On L-proline And Application In Steglich Rearrangement

The design and synthesis of chiral catalysts is one of the core issues in asymmetric catalysis,and the chiral acyl transfer catalyst is always a hot research area in organocatalyst.Over the past two decades,the acyl transfer catalysts of chiral DMAP analogues,imidazoles,isothioureas,betaine and N-heterocyclic carbene have been designed and synthesized.Among them,since the Vedejs’s central-chiral DMAP and the Fu’s planar-chiral DMAP derivatives were reported,which triggered the development of various chiral DMAP analogues for asymmetric acyl transfer reactions,and the research on chiral DMAP analogues has become a hot research area.Various chiral DMAP analogues with central-chirality,planar-chirality,helical-chirality and axial-chirality have been reported.These catalysts all use pyridine nitrogen atom as the nucleophilic site in asymmetric acyl transfer reactions,and the studies on the formation of O-acylated pyridinium cation intermediates by O-C bonding has not been reported.Therefore,we designed and synthesized chiral 3,4-diaminopyridine N-oxide catalysts with the cheap and commercially available L-proline as a chiral source,since the introduction of two strong electron donating amino groups on the pyridine ring enhances the activity of the catalyst,and the catalytic effect of this catalyst was verified in asymmetric Steglich rearrangement.This catalyst is facile preparation,and the structure is easile tunable from a cheap and commercially available chiral source.First,3-bromo-4-nitropyridine-N-oxide,possessing high reactivity at the C-3 position,was reacted with L-proliamindes to afford the chiral 3-amino-4-nitropyridine-N-oxides in excellent yields.After chlorination and amination steps,the chiral DMAP-N-oxides were obtained.The catalyst can be applied in asymmetric Steglich rearrangement.We used the oxazolyl carbonate as a template substrate to screen the catalysts,solvents,temperatures and additives.The optimized reaction conditions were as follows:the chiral pyridine N-oxide as a catalyst,toluene as a solvent,and 4?MS as an additive at-40°C.Under the optimal conditions,we synthesized a series of C-acylated azlactones with high yields（up to 97%）and excellent enantioselectivities（up to 97%）.When the reaction was performed at 3 mmol scale,C-acylated azlactone was obtained with 89%yield and 93%ee.When bulky tBu-substituted oxazolyl carbonate was examined,the desired rearrangement product was obtained in 66%yield and 90%ee.It should be noted that it was the first asymmetric rearrangement of tBu-substituted oxazolyl carbonate.With the cross experiments and the HRMS experiment,we explored a possible reaction mechanism of the Steglich rearrangement.All newly synthesized compounds in this paper have been characterized by ¹H NMR,¹³C NMR and HRMS.In summary,we have reported the design and synthesis of chiral 3,4-diaminopyridine N-oxides and application in Steglich rearrangement,which might open up a new door for the development of chiral DMAP-N-oxides for asymmetric acyl transfer reactions.