Chemoselectivity in direct N-alkylation of amines

Amine moieties play a central role in chemotherapeutics of numerous diseases, many of them act effectively on the nervous central system, and so are popular targets in combinatorial approaches in drug development. From a synthetic point of view, secondary amines are challenging and although a pocketful of methods have been developed so far, including direct N-alkylation, amide reduction or reductive amination, all of them share the often unsolved problem of overalkylation.The classical solution to this problem is, focusing on the N-alkylation approach, use excess of amine and further purification, which is an expensive and environmentally unfriendly way. Therefore, considerable interest exists in developing efficient protocols for the construction of carbon-nitrogen bonds.

One of the strategies that have been taken into the attention of synthetic chemists in very recent years is the use of cesium bases as H-scavenger (I refer hereafter to carbonate or other mild or weakly nucleophilic counteranions mainly since strong bases as hydroxide may behave very differently as u may notice between the lines below).

OK, in particular cases, the use of Cesium instead of potassium or sodium counterparts may lead to a dramatic decrease on overalkylation. But why? What about the mechanism? Which conditions favour the monoalkylation /overalkylation ratio?

Here is how I see it: As N-alkylation undergoes a classical SN2 mechanism, the problem of overalkylation is a kinetic problem. That is, alkylations (including overalkylation) are favoured in those conditions in which the SN2 kinetics is generally favoured (1-4):

1. Solvents with ability to solvate the transition state favour the kinetics of the substitution, i.e. acetonitrile.

2. Use of a suitable catalyst favours the kinetics of the substitution, i.e. iodide anion salts or PTC.

3. Presence of water may favour the kinetics of the substitution in some cases.

4. The higher the temperature faster the reaction.Unfortunately, overalkylation is also favoured by 1-4.

So, the counterintuitive strategy of using conditions 5-8 below is worthy to check.

5. Solvents unable to solvate the transition state,

6. Do not use a catalyst such as iodide anion,

7. Work in dried conditions,

8. The lower temperature the better.

Moreover, in these conditions (5-8), the use of cesium instead of potassium may be dramatically good – and perhaps the reaction may be now faster than one could think based on "potassium timeframes". Why? As d orbitals of cesium are quite accessible for the hard, starting primary amine, and its ratio charge/nuclear radium is quite low, amine may be able to solvate –preferently, in apolar conditions and in absence of oxoanions- the cesium cation and, further on, undergo a catalytic cycle which leads to alkylation products. As monoalkylated products are not so effective in solvating the cesium cation, because of both, electronic and steric effects, overalkylation is not enhanced but reduced if not practically avoided.