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Can amides be N-alkylated with alkyl halides? Say I was trying to make N-propyl acetamide. Would iodopropane and acetamide react to form it? Would they react to form N,N-dipropyl acetamide? If so, what catalysts would I need, and if not, why not and how would it be possible?

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  • $\begingroup$ Anecdotic evidence is no evidence, but trying to methylate two free hydroxides on a $\ce{C5}$-amide I got full methylation, i.e. on the nitrogen, too. Conditions used were $\ce{Ag2O}$, $\ce{MeI}$ and stirring over the weekend at room temperature. $\endgroup$ – Jan Oct 2 '15 at 11:59
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Sure, there are a number of ways to do this with copper, iridium, or palladium catalysts. This link should hopefully be helpful.

http://www.organic-chemistry.org/synthesis/C1N/amides2.shtm

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The amide nitrogen is not a good nucleophile to react. But it can become nucleophilic in the form of $\mathrm N^-$ as a conjugate base of a weaker acid. This means that you need a strong enough base to deprotonate the amide. Some standard conditions are NaH in THF or DMF, or n-BuLi, LDA and the like in THF/ether etc.

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