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Regioselectivity in the formation of an imidazo[1,2-a]pyrimidine
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Khalida Dilshad
Regioselectivity in the formation of an imidazo[1,2-a]pyrimidine
I propose the route in the following scheme. I don’t see any unfavourable intermediates. In short, the first step would be formation of a Schiff base with the extracyclic amino group and the aldehyde. This — in one of many orientations as shown below — places the bromide nicely so that one of the pyrimidine nitrogens can attack it nucleophilicly. Upon displacement, an intermediate nitrogen-centred cation is generated; loss of a proton and switching of electrons regenerates aromaticity and gives the desired product.
Scheme 1: Proposed reaction scheme. The attacking nitrogen $\mathrm{sp^2}$ orbital in step 2 is drawn explicitly.
We can draw structures of the Schiff base intermediate that would allow either of the pyrimidine nitrogens to attack. However, the top one experiences a stronger $-I$ effect by the neighbouring $\ce{CF3}$ group hence its electron density and nucleophilicity should be reduced. The para-nitrogen does not experience this inductive effect since it greatly weakens with greater distance.
The ortho-nitrogen’s lone pair is indeed affected since inductive effects affect both σ and π bonds while mesomeric effects mainly affect π electrons only.
I propose the route in the following scheme. I don’t see any unfavourable intermediates. In short, the first step would be formation of a Schiff base with the extracyclic amino group and the aldehyde. This — in one of many orientations as shown below — places the bromide nicely so that one of the pyrimidine nitrogens can attack it nucleophilicly. Upon displacement, an intermediate nitrogen-centred cation is generated; loss of a proton and switching of electrons regenerates aromaticity and gives the desired product.
Scheme 1: Proposed reaction scheme. The attacking nitrogen $\mathrm{sp^2}$ orbital in step 2 is drawn explicitly.
We can draw structures of the Schiff base intermediate that would allow either of the pyrimidine nitrogens to attack. However, the top one experiences a stronger $-I$ effect by the neighbouring $\ce{CF3}$ group hence its electron density and nucleophilicity should be reduced. The para-nitrogen does not experience this inductive effect since it greatly weakens with greater distance.
The ortho-nitrogen’s lone pair is indeed affected since inductive effects affect both σ and π bonds while mesomeric effects mainly affect π electrons only.
@Martin-マーチン Concerted mechanism for what? The entire addition? Don’t know, can’t think of one. The nucleophilic substitution/elimination? Why not, never sold on the details.More
@Jan. Thanks for the answer. I had considered that mechanism, but I feel a little uncomfortable using the nitrogen LP like that without making use of the ring in some way (plus admittedly I had a feeling the DMAP pathway was more likely due to reactions of similar systems- this of course doesnt help get to the product).More
I propose the route in the following scheme. I don’t see any unfavourable intermediates. In short, the first step would be formation of a Schiff base with the extracyclic amino group and the aldehyde. This — in one of many orientations as shown below — places the bromide nicely so that one of the pyrimidine nitrogens can attack it nucleophilicly. Upon displacement, an intermediate nitrogen-centred cation is generated; loss of a proton and switching of electrons regenerates aromaticity and gives the desired product.
Scheme 1: Proposed reaction scheme. The attacking nitrogen $\mathrm{sp^2}$ orbital in step 2 is drawn explicitly.
We can draw structures of the Schiff base intermediate that would allow either of the pyrimidine nitrogens to attack. However, the top one experiences a stronger $-I$ effect by the neighbouring $\ce{CF3}$ group hence its electron density and nucleophilicity should be reduced. The para-nitrogen does not experience this inductive effect since it greatly weakens with greater distance.
The ortho-nitrogen’s lone pair is indeed affected since inductive effects affect both σ and π bonds while mesomeric effects mainly affect π electrons only.
I propose the route in the following scheme. I don’t see any unfavourable intermediates. In short, the first step would be formation of a Schiff base with the extracyclic amino group and the aldehyde. This — in one of many orientations as shown below — places the bromide nicely so that one of the pyrimidine nitrogens can attack it nucleophilicly. Upon displacement, an intermediate nitrogen-centred cation is generated; loss of a proton and switching of electrons regenerates aromaticity and gives the desired product.
Scheme 1: Proposed reaction scheme. The attacking nitrogen $\mathrm{sp^2}$ orbital in step 2 is drawn explicitly.
We can draw structures of the Schiff base intermediate that would allow either of the pyrimidine nitrogens to attack. However, the top one experiences a stronger $-I$ effect by the neighbouring $\ce{CF3}$ group hence its electron density and nucleophilicity should be reduced. The para-nitrogen does not experience this inductive effect since it greatly weakens with greater distance.
The ortho-nitrogen’s lone pair is indeed affected since inductive effects affect both σ and π bonds while mesomeric effects mainly affect π electrons only.
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