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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, 2015 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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I've read of several related sn2 reactions. Generally the procced via an alkyl bromide, I2 catalyst and CsCO3 to drive the reaction to the right.

They all seems to be sensitive to the solvent employed. Many solvents seem to work, but the difference in yield can be very large.

From CH2Cl2 to CH3OCH(CH2) to formamide. I presume that the solvent system is the key and thus within the sphere of chemical engineering.

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A better route could be to form the alkylated amine first and use an activated carbonyl group such as an anhydride or an acyl halide.

Although stericly hindered, the amine should react with good yield to form the amide.

There is a good chance a primary amine could simply be reacted with carboxylic acid under heat to form the amide, especially if reaction water can be drawn off, and even a secondary amine would be worth a try.

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