[Cesium-137]

Hi all,
Any one know of a method to produce a nucleophilic nitrogen from an amide? My initial thought was try deprotonating the nitrogen with NaH or LDA... Any thoughts?
Thanks

[herrhansen]

Hi.

I have with sucess used NaH on an amide.

[MissPhosgene]

potassium tert-butoxide is alright too.

[Cesium-137]

I'm leaning towards the t-Butoxide for solubility reasons... The N (ideally) will attack a carbon to kick off a tosylate, would it be wise to add the base first, then the tosylated carbon link to avoid elimination? Thank you both!

[Honclbrif]

I've had luck with NaHMDS activiating some amides, but its frequently without stellar yields.

Could you convert the tosylate to an amine and then do an amide coupling?

[Cesium-137]

Yield isn't the biggest issue... It's the last step of a total synth, so I just want product in any amount. Can't do an amide coupling unfortunately for a variety of reasons. Oddly enough, the amide nitrogen was added using LiHDMS as a nucleophile... I'm tempted to try it as a base in this case simply because I have some around. I like the idea of using either base, but I assume they would largely cause elimination of the tosylate before deprotonating the amide. The Tos is on a primary carbon; will this largely lead to substitution by either t-butoxide or HDMS? Should I expect both the substitution/elimination products in addition to a small amount of the coupled amide product??

[Cesium-137]

Maybe this will help...

[Honclbrif]

Without seeing the man behind the wiggly curtain I can only give so much advice, but I understand why you're not showing it  .

Doing a quick structural search of coupling amides to primary tosylates on Reaxys seems to have several hits which favor NaH in DMF. Angewandte Chemie, International Edition,   2004 ,  vol. 43,  # 4   p. 478 - 482. [http://onlinelibrary.wiley.com/doi/10.1002/anie.200352750/abstract] has several such couplings, but utilizing gamma-lactams instead of acetamides.

I'd give the amide a good stir with the base before introducing the tosylate, unless of course its an intramolecular coupling you're doing. Formation of an olefin via elimination of a tosylate from a primary site seems like a somewhat unfavorable pathway.

[Cesium-137]

Excellent! Thank you. I'll track down the article right away!

[Dan]

Where'd your NHAc come from, and what size ring are you forming?

If you can introduce N as an azide or NHCbz instead of NAc, you can triflate the alcohol and then simply reduce the resulting azide (or Bn carbamate), and the amine snaps shut on the triflate to give the corresponding cyclic secondary amine (TsO, MsO etc. are probably not reactive enough - but this will depend on ring size, and they can be encouraged thermally). Once the ring is formed you can just acetylate the N. I've used this strategy many times and have made piperidines, pyrrolidines as well as small bicyclic systems e.g. [2,2,1], [3,2,1], [3,3,0]. If your ring size is 7+ this may not work so well though.

[Cesium-137]

Looks like I have plenty of things to try. The MSDS for K t-BuO says incompatible with ketones... how incompatible are we talking? Like keep it cold incompatible, or just ruined your reaction incompatible? If I go the base approach should I be thinking "the stronger the better" for equilibrium reasons? Deprotonating a nitrogen with oxygen seems like the reverse would be more favored to me... with both LiN(TMS)2 and t-BuO on hand would it be most wise to go with the silazane?