[wildfyr]

I am trying to react diphenylamine (a rather poor nucleophile and base pKb=0.8 ) with a conjugated alkenyl chloride. Currently I'm using 2 equivalents of diphenylamine in damp bench acetone. Previously I tried K₂CO₃ in dry DMF, but this caused degradation of the alkene and no noticeable conversion at the alkenyl chloride.

My current reaction isn't showing much conversion (its a dye that smears on TLC,  I am trying to use UV-Vis for my quick and dirty checks since I have no NMR and haven't figured out an HPLC method yet) at room temp so I upped it to 50°C this morning. Still no noticeable conversion in a few hours.

This reaction got me thinking though, does it matter if my proton scavenger is a good base or a bad base in aprotic conditions? The reaction is driven by the amine attacking the alkenyl chloride, then being deprotonated. The presence of a stronger base (such as imidazole, triethylamine, or DBU) won't make my diphenylamine a better nucleophile...right? The rate limiting step is the attack, in comparison deprotonation is very fast, meaning the reverse reaction with chloride attacking the ammonium should be minimal.

Water shouldn't affect this reaction, but should I make a more concerted effort to run in dry solvent? Perhaps toluene, or another solvent where the diphenylammonium chloride will precipitate out (I thought it might in acetone anyways).

I'm a little frustrated with what should be a simple transformation.

[wildfyr]

A little lit research cudgeled a fact in my brain: anilines are actually better nucleophiles in water in many cases. So I set up an "on-water" reaction in DCM/water

[TheUnassuming]

This reaction got me thinking though, does it matter if my proton scavenger is a good base or a bad base in aprotic conditions? The reaction is driven by the amine attacking the alkenyl chloride, then being deprotonated. The presence of a stronger base (such as imidazole, triethylamine, or DBU) won't make my diphenylamine a better nucleophile...right? The rate limiting step is the attack, in comparison deprotonation is very fast, meaning the reverse reaction with chloride attacking the ammonium should be minimal.

I believe you are correct.  The base in this reaction is to mop up the acid you will form as the reaction progresses, so only needs to be strong enough to keep your starting material from being protonated and stalling your reaction. 

Just to be sure I'm understanding you.  You are trying to add a diphenylamine to a vinyl chloride?

[wildfyr]

Its a chloro substituent sitting along the alkene chain in a cyanine-type dye.

[wildfyr]

A deep literature dive has resulted in some important insights. Powerful nucleophiles like MeO^- apparently react with this substituent via a straightforward SnAr mechanism, however according to considerable work by the Strekowski group, it appears that chloro-substitutions occur through a radical cation mechanism for most nucleophiles ?!?!!

https://pubs.acs.org/doi/pdf/10.1021/jo00043a009

I must try this reaction under oxygen free conditions.

[kriggy]

Could you use some lithium salt of your amine to kick the nucleophility through the roof?

[wildfyr]

I am hesitant to use such a powerful base, and I would have to make it myself from the amine. Not sure the molecule can handle it. I also don't have a ton of confidence in how dry my house nitrogen is.

Lastly, this is part of an assay of derivatives I'm trying to make. So I'm using a bunch of amines, and the amount of work to lithiate them all would be staggering. If one of them works then the reaction could be scaled up hugely (tens if kg) and Im already flirting with the price on these amines.

[pgk]

Dear Wildfyr,
Don’t be frustrated because this seems a simple transformation but it is not simple at all.
1). “…The reaction is driven by the amine attacking the alkenyl chloride, then being deprotonated…”
Theoretically and if so, you don’t need an additional base at all; because the second molecule of diphenylamine will deprotonate the intermediate, diphenyliminium chloride. But this is not feasible because a borderline base (diphenylamine) cannot displace a hard base (Cl-).
2). By adding a base, you form the diphenyliminium anion, which is a strong and hard base that can diplace the chlorine atom by an ordinary SN2 substitution. But in that case, the second molecule of diphenylamine is not necessary.
3). However a hard base (K2CO3, MeO-, LiOH, etc.) will react the alkenyl chloride, in preference and not with the diphenylamine.
4). Except if using a tertiary amine as a base, which is a borderline base that cannot displace the chlorine atom but it can deprotonate diphenylamine, in equilibrium. But in this case, the second molecule of diphenylamine is necessary, in order to deprotonate the intermediately formed, diphenyliminium chloride.
Consequently, the desired product could be obtained:
1). Either by reacting 2 moles diphenylamine with 1 mole of alkenyl bromide or alkenyl iodide that are borderline and soft bases, respectively and in the absence of base.
2). Or by using a strong tertiary amine (e.g. DBU) in adequate amounts that are higher than catalytic ones, together with 2 moles diphenylamine and 1 mole of alkenyl chloride (or better, alkenyl bromide if possible).
Good luck!

[pgk]

Alternatively, another synthetic pathway could be based on forming the quaternary alkenyl ammonium chloride salt of N,N-dimethylaniline or N-methyl-diphenylamine as potential leaving groups, followed by nucleophilic attack of diphenylamine in the presence of a base.
Note that the amine must not contain higher aliphatic substituents, in order to avoid any Hoffman type degradation reactions (however and although easier, the alternative use of trimethylamine does not seem convenient due to the extremely low boiling point).

[wildfyr]

[pgk,
For the TEA suggestion (I don't have DBU on hand, though I could order), it seems simpler and cheaper to use 1 eq dye 1.1 eq diphenylamine, and 2 eq TEA.

Using dimethylaniline intermediate is interesting. Did you read my earlier comment about a possible radical cation mechanism of SnAr?

[wildfyr]

Update:
I have setup another reaction in DMF at 50°C with 1 eq chloro alkenyl-dye, 1.1 eq diphenylamine, 2 eq TEA under as strict air and water free conditions as I have at my disposal short of doing the dreaded freeze-pump thaw.

[phth]

Update:
I have setup another reaction in DMF at 50°C with 1 eq chloro alkenyl-dye, 1.1 eq diphenylamine, 2 eq TEA under as strict air and water free conditions as I have at my disposal short of doing the dreaded freeze-pump thaw.

It is known that radical cations and radical anions cause changes in the kinetics of SnAr mechanisms. People can get fluoride to substitute via SnAr at elevated temperature. If there are side reactions heat it less, and I would suggest a trying the reaction at elevated temperature dark in this case because SnAr via a two electorn mechanism proceeds in the dark.

[wildfyr]

There aren't side reactions I can see, just no reaction.

I was thinking about this last night some after looking at the literature. Two electron SnAr is pretty conventional so to speak, its this radical cation stuff that is curious to me. I'm wondering something, I work in a lab that uses yellow light only, but the literature says some of these reactions are catalyzed (initiated?) by light. I do have overhead white fluorescent bulbs I can turn on. I'm gonna check my TEA reaction this morning, but I didnt see anything after 2 hours yesterday.

[clarkstill]

Wildfyr,

Yeah I can see that being a really tricky substrate. It's an abysmal nucleophile...

We recently did a 1,4-addition/elimination of 3-aminonaphthalene into a beta-chloro enone, which I guess is mechanistically (and sterically) similar to what you're trying? We used 1.5 eq. of the amine, 2 eq. K2CO3, in THF in a sealed tube at 110 C, so you could give those conditions a try. I guess your main problem is the sensitivity of your SM, which wasn't really an issue for our stuff.

Pd catalysis also did the job (at a lower temperature) - we've been using Pd(PPh3)4, XPhos, KOtBu - so that could be worth a try too.

Good luck!

[rolnor]

I suggest adding some iodide to get alkenyliodide. TEA could get quaternized faster then the diphenylamine react I think. I would use high temperature, reflux in DMF could work.