High Bees
,
I 've been wondering a bit about the general applicability of the Mannich reaction procedure in
Patent US6538136
. Me thinks this happens in example 2:
Flask 1:
1 mol Bzl-NH
2 + 2,25 eq. CH
2O --> Bzl-NH-CH
2-OH + 1,25 eq. excess CH
2O (don't know if imine will be formed without acid, since the optimal pH for this is 4 - 5)
Flash 2:
1,06 eq. CH
3-CO-CH-CH(CH
3)
2 + 1,11 eq. HCl --> CH
3-COH-C=C(CH
3)
2 + 1,11 eq. HCl (acid catalysed keto-enol equilibrium, notice the thermodynamic enol will be generated predominantly)
Drip flask 1 in flask 2:
Bzl-NH-CH
2-OH + 1,25 eq. excess CH
2O + CH
3-COH-C=C(CH
3)
2 + 1,11 eq. HCl --> iminium ion formed in situ Bzl-NH(+).Cl=CH
2 + H20 & reacts with enol --> Bzl-NH-CH
2-C(CH
3)
2-CO-CH
3 + HCl regenerated & reacts with just formed secundary amine or protonates another aminoalcohol
Add 1,1 eq. iPr
2EtN to freebase the secundary amine --> Bzl-NH-CH
2-C(CH
3)
2-CO-CH
3 + iPr
2EtN.HCl + 1,25 eq. + 0.3 eq.(yeah, why not add some more) CH
2O --> Bzl-N(CH
2-OH)-CH
2-C(CH
3)
2-CO-CH
3Now comes the tricky part:
We have Bzl-N(CH
2-OH)-CH
2-C(CH
3)
2-CO-CH
3, 1,1 eq. iPr
2EtN.HCl (and 0,01 eq. HCl, but in example 1 there is more base used to neutralize the HCl, so no HCl is present, just Et
3N.HCl and 0.05 eq Et
3N) with an excess CH
20 in a H
2O / EtOH solution
Me thinks the aminoalcohol gets protonated first with the HCl liberated from iPr
2EtN.HCl <__--> iPr
2EtN + HCl. At the same time iPr
2EtN is generated which supposedly abstracts a proton from the CH
3-CO-C(CH
3)
2-R ketone.
Now, the problem with the general applicability of this patent is that a weak base in a protic solvent gives the thermodynamic enolate (the one with the least H 's attatched to it). To generate the 3,3-dimethyl piperidone this is no problem, since only the kinetic enolate can be formed. But with 3-methyl piperidone (and even worse with ordinary piperidone), the wrong enolate will be formed. A sterically hindered base is used, but do you think that will solve the problem of the inherently favored thermodynamic enolate formation? It makes me rather suspicous, since they don't demonstrate the general applicability of the patent with some other examples ... (mabey the yields sucks)
This is how me thinks the reaction proceeds further:
Bzl-N(CH
2-OH)-CH
2-C(CH
3)
2-CO-CH
3 + iPr
2EtN.HCl --> Bzl-N(+).Cl(=CH
2)-CH
2-C(CH
3)
2-CO-CH
2(-) + iPr
2EtNH(+) --> N-benzyl-3,3-dimethyl-4-piperidone + iPr
2EtN.HCl regenerated
I think an excess of formaldehyde is used to shift the equilibrium in the favorable way, but mabey this isn't a good idea for other piperidones than the 3,3-dimethyl ones.
What do you bees think about the proposed reaction mechanism? It is rather amazing that this all takes place in one pot
. Do you also forsee problems for other (less 3 substituted) piperidones.
