[Polly Murs]

I'm trying to react dansyl hydrazine with a series of bromoalkanes (increasing methylene units). the alkyl chain is joined to N-3 of a protected thymidine
the hydrazine will attack the C-Br bond at the other end, so I'm guessing I will get condensation of HBr?

I've used DCM as solvent and triethylamine as base, r.t., 12h. these are standard conditions for additon of the dansyl hydrazine

looking at the TLCs, the shorter chain (2 methylenes) was completely used up in the reaction and I was able to collect the product

for the longer chains (4, 8 and 12 methylene units), I haven't been so lucky. I'm seeing a fluorescent spot which would correspond to my product, but when I column the reaction mixture I don't see any fluorescence in the relevant fractions. I even combined them to see if that would make a difference. nothing

I reasoned that perhaps rxn temperature was an issue (even though these should be fine at room temp), so used dichloroethane and refluxed at 60C. still no luck

so either the base is the problem, or the thymidine has been deprotected somehow... there was some very polar stuff on my column which I eluted with 9% MeOH/DCM, and this was fluorescent... I'm going to do NMR and MS top see if this is perhaps my compound

thoughts/suggestions welcome

[opsomath]

So if I understand correctly, the dansyl hydrazine nitrogen is substituting the alkyl bromide in an SN2 reaction? In that case, the N = 2 thymidine alkyl bromide might well be more reactive than the N = 4, 8, etc. due to neighboring group participation of the imide nitrogen or oxygen. You might have to use better SN2 reaction conditions. Use of DCM seems a little odd, I would guess DMF or THF would be better. Also, you can add catalytic KI to generate small quantities of alkyl iodide, which reacts more rapidly.

[Polly Murs]

hi opsomath,

many thanks for the suggestion, will try that out

I'm a synthetic chem novice to be honest

[opsomath]

Good luck. Let me know if you need further help or are trying to figure out how to do workup after you change the solvent

[Polly Murs]

ok, so let me go back to the beginning

I wanted to alkylate thymidine at N3... I used a dibromoalkane
solvent was DMF and base Cs2CO3

I realise I probably could've used these for the incorporation of the fluorophore aswell, as in both cases you're attacking a C-Br bond with an amine! silly me

so I'm going to try this today

@opsomath... once I've added my dansyl, I need to deprotect the silyl ethers in methanolic HCl
how would you quench this/work it up?

also, can you expand on your reasoning for using KI? sounds interesting

many thanks

PM

[Polly Murs]

my last post might be unclear, sorry

1. alkylate the protected thymidine with dibromo
2. attack remaining C-Br with nucleophilic dansyl hydrazine
3. deprotect silyl ethers in methanolic HCl

assuming repeat of step 2 works ok, how might I work up the deprotection?

ty

[discodermolide]

ok, so let me go back to the beginning

I wanted to alkylate thymidine at N3... I used a dibromoalkane
solvent was DMF and base Cs2CO3

I realise I probably could've used these for the incorporation of the fluorophore aswell, as in both cases you're attacking a C-Br bond with an amine! silly me

so I'm going to try this today

@opsomath... once I've added my dansyl, I need to deprotect the silyl ethers in methanolic HCl
how would you quench this/work it up?

also, can you expand on your reasoning for using KI? sounds interesting

many thanks

PM

Using small amounts of KI generates the C-I in situ which is more reactive towards substitution.

[Polly Murs]

hi disco

so I just add KI as reagent? how much?

edit: can you give me more details, in terms of how the KI will catalyse the reaction...
what's actually happening in terms of mechanism?

thanks

edit2: I've just read that KI can quench fluorescence, which is not desirable (the dansyl is a fluorophore)
however, it does say that uM to mM amounts will in fact increase intensity, i.e. "small amounts"?!!

edit3: the iodide will displace Br? I thought iodide was a better leaving group than Br, therefore wouldn't displace it?

[Polly Murs]

I think the Cs2CO3 is meant to the same job
I used it in place of K2CO3 as it's more soluble in DMF

see here http://www.oup.com/uk/orc/bin/9780199277896/01student/solutions/ch20student.pdf

however, if you think KI will work better, then I'll give it a go

[Honclbrif]

I^- is a better leaving group than Br^-, but its also a better nucleophile so it can be used to activate brominated substrates by replacing the bromide. When I do this I usually just add a catalytic amount (i.e a spatula tip's worth) of KI to the reaction and it works like a charm. I've even used it to shift a chloride. Be forewarned though, if you care about the configuration of your particular site KI can scramble it, but if its a primary site you've got nothing to worry about.

As for quenching, an aqueous workup should remove all the salts.

[opsomath]

The workup should be pretty straightforward, I would dilute into water and extract into DCM unless I knew better conditions somehow.

Usually you use like 5-10 mole percent KI. The role of Cs2CO3 is very different, that is a proton scavenger (if you draw the full reaction for the nitrogen substituting the alkyl bromide, you'll see that it generates HBr as a byproduct). I have no idea if this works in your case, it's just a pretty common hack for slow SN2 reactions. There's a small chance that it might be incompatible with your sulfonylhydrazine group, but I don't think so. The KI is removed in workup, so you don't have to worry about it quenching your fluorescence.

I is a better nucleophile than Br, so it substitutes it. The reaction doesn't go to completion but it generates a bit of alkyl iodide in equilibrium, which is more reactive.

[Polly Murs]

I ran the reaction today (addition of fluorophore) in DMF and Cs2CO3.
after 2 hours didn't see anything that would indicate product, still some of the starting material there
it was the same problem when I ran the reaction using DCM/TEA... still loads of starting material left over

I've left the rxn overnight, in the hope that I will see something in the morning.
if not, is it a simple case of adding a spatula tip's worth of KI to the existing rxn?

many thanks for advice, really appreciated

edit: opso... which work-up are you referring to? the deprotection?
do I need to neutralise the HCl first?

[Polly Murs]

perhaps if I provide the structures?

how do I paste them in here?

[opsomath]

Yeah, I was talking about the workup of the deprotection. I wouldn't bother neutralizing HCl, it'll stay in the water layer. First you gotta get your product though, right?

Definitely try KI and/or gentle heating if you still don't see anything. I don't think that nitrogen is such a super awesome nucleophile that it'll go quickly with an unactivated alkyl bromide. DMF should be a good solvent for you.

What is your TLC system? Silica and what? Make sure you don't have two things just sticking to the baseline.

[Polly Murs]

ethyl acetate/pet ether

from doing the rxn before, both the reactant and product had similar Rf. this seems fairly feasible to me. or do you think the hydrazine will make my molecule very polar?