The base promoted N-alkylation [SN2] using NaOH, KOH, NaH, K2CO3 etc of simple aromatic amines is well reported. Can the alkylation of amides be performed easily, then which method should be preferred in order to avoid amide-hydrolysis?
In our hands, good conditions, with a primary mesylate as the electrophile, are powdered KOH (2.0 equiv.), nBu4HSO4 (5% equiv.) in toluene at reflux overnight.
Chem. Eur. J. 2013, 19, 11759–11767.
These conditions are inspired from earlier work (T. Gajda, A. Zwierzak, Synthesis 1981, 1005–1008). We simplified the procedure a little bit (KOH instead of a mixture of NaOH and K2CO3, if I remember correctly).
In our hands, good conditions, with a primary mesylate as the electrophile, are powdered KOH (2.0 equiv.), nBu4HSO4 (5% equiv.) in toluene at reflux overnight.
Chem. Eur. J. 2013, 19, 11759–11767.
These conditions are inspired from earlier work (T. Gajda, A. Zwierzak, Synthesis 1981, 1005–1008). We simplified the procedure a little bit (KOH instead of a mixture of NaOH and K2CO3, if I remember correctly).
I also don't understand, what is going on. Why first two answers were removed? The voters who give negative vote should provide justification if they are not agree with that answer.
yes simple methods also available.first form the sodium salt by using sodium methoxide solution and then convert into N-alkyl by methyl iodide.
Aromatic amides are quite easy to alkylate as the pKa is lower, and if the amides aren't hydrolysed by powdered KOH in refluxing toluene then you can most likely use a wide range of different conditions.
NaH i DMF will be the best choice. You can use K2CO3 in DMF at 140 degree. But in that case you may get some O-alkylated products also.
@Soumyaditya Mula - not all have possibilities to work in ATOM ☢ RESEARCH CENTRE like you - with NaH in DMF at 140oC :-). Below of this temperature, runaway (thermal explosion) is possible ♨⇒ ☄ ⇒ ☠ https://books.google.ru/books?id=AfSFwiNNekQC&lpg=PA31&ots=I0hCtLb-dY&dq=nah%20dmf%20runaway&hl=ru&pg=PA31#v=onepage&q=nah%20dmf%20runaway&f=false
Urben PG. Bretherick’s Handbook of Reactive Chemical Hazards (7). Elsevier San Francisco, CA2007; 1:1672.
But your note about O-alkylation is really true, especially for highly electrophilic alkylating agents - sulfonates (triflates) and oxonium salts. In presence of poor bases (K2CO3 for instance), part of amide is neutral and alkylation goes at most nucleophilic atom (amide oxygen). In addition, good cation solvation properties play negative role in this synthesis, because ambident nature of amide-anion will increase ( in low-polar solvents Na+ coordinates preferably with amide oxygen). By this reasons dimethylformamide is worse choice, IMHO. See also http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286627/ .
Most of aprotic dipolar solvents ( like DMSO, DMAA, CH3CN etc) are prone to alkylation with strong alkylating agents. Sulfolane is one of rare exclusions. From my hands-on practice, O-alkylation is best method of imine esters (lactim esters) synthesis by reaction of (CH3)2SO4 and Et3O+BF4- with lactams.
In comparison with the O-alkylation, hydrolysis of amides is less relevant. All mentioned bases are also desiccants so water activity in organic solvent is low. It is low even in conditions of phase transfer catalysis as it can be seen from the data of Yvan Six (commercial KOH contain 15% H2O)
Iodides and bromides as alkylating agents are less agressive and are useful for N-alkylation. However, full transformation of amide in salt is desirable. From this point of view, NaH is best from the list. Xylene, toluene, diglym, THF and 1,2-dimethoxyethane are suitable as solvents . With toluene as solvent and sodium acetanilide + 1,6-dibromohexane yield was close to 100% DOI: 10.1021/jo50001a004
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