Sciencemadness Discussion Board
Not logged in [Login ]
Go To Bottom

Printable Version  
 Pages:  1  
Author: Subject: How would you go around synthesizing this molecule?
BlackDragon2712
Hazard to Others
***




Posts: 124
Registered: 22-12-2012
Location: Everywhere
Member Is Offline

Mood: Sleepy

smile.gif posted on 19-11-2018 at 08:52
How would you go around synthesizing this molecule?


I want to experiment with molecules with a similar shape of those that are selective dopamine re-uptake inhibitors like GBR-12935. Since I don't have a lab I figured that the closest molecule I could get from OCT chemicals is this one:
Tarjet molecule.png - 17kB

I'm planning on starting with Benzhydrol, alanine and phenylalanine... Most of the reactions are variations from quite common reactions and they should be possible, my only obstacle is the piperazine ring formation. I was planing to make a chloramide derivative from the amide of phenylalanine by the TCCA method and then close the ring with the amine group on alanine but I have never messed around with neither chloramines or chloramides so I don't even know if this is possible.


Any suggestion will be greatly received! thanks in advance guys

S 2.png - 10kB S 1.png - 10kB
View user's profile View All Posts By User
Melgar
Anti-Spam Agent
*******




Posts: 2004
Registered: 23-2-2010
Location: Connecticut
Member Is Offline

Mood: Estrified

[*] posted on 19-11-2018 at 09:31


I would expect those two chlorides to react with the amino group on your phenylalanine molecule. You'll definitely have to figure out what to do there.



The first step in the process of learning something is admitting that you don't know it already.

I'm givin' the spam shields max power at full warp, but they just dinna have the power! We're gonna have to evacuate to new forum software!
View user's profile View All Posts By User
VSEPR_VOID
International Hazard
*****




Posts: 717
Registered: 1-9-2017
Member Is Offline

Mood: Fullerenes

[*] posted on 19-11-2018 at 09:32


What are your starting materials, those bottom molecules?

I imagine you could react the bottom left with the bottom right and get ring formation?

Start with DL-Phenylalanine, react that with urea (maybe) to get the corresponding amide. Then react it with a massive excess of 1-2-dichloroethane.

For the right prepare benzophenone, reduce it to an alcohol, then estify it with 2-amino-proponic acid.

This looks like a cool project, if you have all the reagents handy

You will need to protect that last amine for the final reaction.
The final reaction will be between those two to form that ring composed of the two tertiary amines.

[Edited on 19-11-2018 by VSEPR_VOID]

[Edited on 19-11-2018 by VSEPR_VOID]




Within cells interlinked
Within cells interlinked
Within cells interlinked
View user's profile View All Posts By User
BlackDragon2712
Hazard to Others
***




Posts: 124
Registered: 22-12-2012
Location: Everywhere
Member Is Offline

Mood: Sleepy

[*] posted on 19-11-2018 at 10:06


My basic idea is:

For compound A (the right bottom molecule):

1.) Phenylalanine --(Phthalimide/Ferric Nitrate*)--> Phenylalanine-Phthalimide
2.) Phenylalanine-Phthalimide --(Urea/Boric acid catalyst)--> Phenylalanylamide-Phthalimide
3.) Phenylalanylamide-Phthalimide --(TCCA method/1,2-dichloroethane)--> Phenylalanylamide-Phthalimide N,N-bis(2-chloroethyl)

*DOI: 10.1021/jo500562w



For compound B (the left bottom one):

1.) Benzhydrol --chlorination/iodation--> Diphenylhalomethane
2.) Diphenylhalomethane --Sodium alanine--> Alanine Benzhydrolate



Final reaction:

Phenylalanylamide-Phthalimide N,N-bis(2-chloroethyl) + Alanine Benzhydrolate --(??????)--> Target molecule


Deprotection:

Under 20%HCl/4h reflux, KOH or hydrazine? (Probably not going to mess up with hydrazine tho)


Sorry for the made up names! :D
View user's profile View All Posts By User
clearly_not_atara
International Hazard
*****




Posts: 1713
Registered: 3-11-2013
Member Is Offline

Mood: No Mood

[*] posted on 19-11-2018 at 13:23


Quote:
3.) Phenylalanylamide-Phthalimide --(TCCA method/1,2-dichloroethane)--> Phenylalanylamide-Phthalimide N,N-bis(2-chloroethyl)


I doubt there is any situation in which TCCA facilitates the N-alkylation of amides. Consider revising.




[Edited on 04-20-1969 by clearly_not_atara]
View user's profile View All Posts By User
Melgar
Anti-Spam Agent
*******




Posts: 2004
Registered: 23-2-2010
Location: Connecticut
Member Is Offline

Mood: Estrified

[*] posted on 19-11-2018 at 13:36


Would the sodium salt of alanine be sodium alanate? Or is it just MSG that works like that?



The first step in the process of learning something is admitting that you don't know it already.

I'm givin' the spam shields max power at full warp, but they just dinna have the power! We're gonna have to evacuate to new forum software!
View user's profile View All Posts By User
BlackDragon2712
Hazard to Others
***




Posts: 124
Registered: 22-12-2012
Location: Everywhere
Member Is Offline

Mood: Sleepy

[*] posted on 19-11-2018 at 21:02


Quote: Originally posted by clearly_not_atara  

I doubt there is any situation in which TCCA facilitates the N-alkylation of amides. Consider revising.


True, I messed up there, got confused with amine chlorination... my bad.
Well this makes things more difficult, the obvious thing would be n-alkylation with dichloroethylamine hydrochloride but I'm not going to mess up with potential chemical agents so what about first reacting the amide with diethanolamine which is way easier to obtain (80 bucks on ebay) and then halogenating the diethanol? I think it's the safest route unless there's another one easier.

Has anyone here worked with n-chloroalkyl amides derivatives before? is it too messy to work with them?
View user's profile View All Posts By User
Sigmatropic
National Hazard
****




Posts: 251
Registered: 29-1-2017
Member Is Offline

Mood: No Mood

[*] posted on 19-11-2018 at 22:24


I made a 1-substituted 2-chloroethyl amide en-route to an oxazoline under Appel conditions (but RT, overnight). So besides reaction with the neighboring amine it, at least theoretically, can also cyclisize onto the amide. I would choose a route starting from some piperazine, say monoboc piperazine?
View user's profile View All Posts By User
Assured Fish
National Hazard
****




Posts: 317
Registered: 31-8-2015
Location: Noo Z Land
Member Is Offline

Mood: Misanthropic

[*] posted on 20-11-2018 at 00:21


Is a protecting group out of the question?

Unknown compound synthesis.png - 22kB

Sadly can think of no way to get around side alkylations of the undesired amines.
Phenylalanine could be reacted with phthalic anhydride then chlorinated to the acyl chloride with thionyl chloride or oxalyl chloride or phosphorous pentachloride or any of your favorite chlorinating agents.


Someones gonna tell me this is over complicated :P




Sufficiently advanced science is indistinguishable from madness.
View user's profile View All Posts By User
CuReUS
International Hazard
*****




Posts: 925
Registered: 9-9-2014
Member Is Offline

Mood: No Mood

[*] posted on 20-11-2018 at 07:14


here is my method :) -

1.esterification of benzhydrol with 2-bromopropanoic acid and CDI -https://onlinelibrary.wiley.com/doi/abs/10.1002/978047084289...

2.https://www.jstage.jst.go.jp/article/cpb1958/41/1/41_1_148/_... ( the ref is given for isobutyl piperazine ,pg 8 in pdf)

3.https://pubs.rsc.org/en/content/articlelanding/2012/gc/c1gc1... ( to reduce coupling with the primary amine,the phenylalanine could be slowly dripped into a pot containing the alkylated piperazine and CDI.The moment the COOH got activated,it would react preferentially with the excess piperazine rather than another phenylalanine molecule ;) )

dopa.png - 6kB

[Edited on 20-11-2018 by CuReUS]
View user's profile View All Posts By User
Sigmatropic
National Hazard
****




Posts: 251
Registered: 29-1-2017
Member Is Offline

Mood: No Mood

[*] posted on 20-11-2018 at 11:20


Cureus, that was exactly what I was thinking. The only thing is that in the final step CDI is bound to react with the amine (piperazine or phenylalanine) to form an imidazole urea. On phenyl alanine this may ringclose to form the carbamate, which just so happens to be a peptide coupling reagent in itself (https://en.m.wikipedia.org/wiki/Bailey_peptide_synthesis https://en.m.wikipedia.org/wiki/Amino_acid_N-carboxyanhydrid...). So with just that minor adjustment that should be quite a consice route.
View user's profile View All Posts By User
Assured Fish
National Hazard
****




Posts: 317
Registered: 31-8-2015
Location: Noo Z Land
Member Is Offline

Mood: Misanthropic

[*] posted on 20-11-2018 at 20:34


I missed the post where blackdragon stated using a phthalamide protecting group, i should read these threads more carefully.


Quote:

1.esterification of benzhydrol with 2-bromopropanoic acid and CDI

I dont understand why a normal fischer esterification cannot work here, the alanine will be protonated and would not likely be soluble in a non polar solvent sure but using an excess of the benzhydrol to act as a solvent and sulfuric acid as catalyst should work fine, i see no reason to use exotic reagents like CDI.




Sufficiently advanced science is indistinguishable from madness.
View user's profile View All Posts By User
CuReUS
International Hazard
*****




Posts: 925
Registered: 9-9-2014
Member Is Offline

Mood: No Mood

[*] posted on 20-11-2018 at 22:11


Quote: Originally posted by Sigmatropic  
The only thing is that in the final step CDI is bound to react with the amine (piperazine or phenylalanine) to form an imidazole urea. On phenyl alanine this may ringclose to form the carbamate, which just so happens to be a peptide coupling reagent in itself
Yes,you are correct.In that case, we should first slowly add phenylalanine to CDI.After everything has reacted,we add the piperazine.

Alternatively,the NCA (4-Benzyloxazolidine-2,5-dione,CAS no-583-47-1) is directly available commercially.Reacting that with the piperazine would give the target compound in 1 step without the need to use CDI.
Quote: Originally posted by Assured Fish  
I dont understand why a normal fischer esterification cannot work here... i see no reason to use exotic reagents like CDI
the reason I suggested using CDI was because we would be using it anyway in the last step.This way we could carry out 2 reactions with 1 reagent,making the route more efficient.Also benzhydrol is a sterically hindered alcohol,and I wanted to get a high yield of the ester as quickly and cleanly as possible.But a fisher esterification could also be done.
Quote:
the alanine will be protonated...
we are using 2-bromopropanoic acid ,not alanine :P

[Edited on 21-11-2018 by CuReUS]
View user's profile View All Posts By User
clearly_not_atara
International Hazard
*****




Posts: 1713
Registered: 3-11-2013
Member Is Offline

Mood: No Mood

[*] posted on 20-11-2018 at 22:37


Let's pretend you have SOCl2/triethylamine available.

phthalimido-phenylalanine [1. SOCl2; 2. phenol, triethylamine] >> phthalimido-phenylalanine phenyl ester

PPPE + piperazine >> mono-[phthalimido-phenylalanoyl]-piperazine

pyruvic acid + benzhydryl chloride + triethylamine >> benzhydryl pyruvate

benzhydryl pyruvate + mono-[phthalimido-phenylalanoyl]-piperazine + [reducing agent] >> phthalimido-GBR-12935

phthalimido-GBR-12935 + hydrazine >> GBR-12935




[Edited on 04-20-1969 by clearly_not_atara]
View user's profile View All Posts By User
BlackDragon2712
Hazard to Others
***




Posts: 124
Registered: 22-12-2012
Location: Everywhere
Member Is Offline

Mood: Sleepy

[*] posted on 21-11-2018 at 17:09


CuReUS Yeah I thought of that aswell, the problem is that I don't really have access to CDI... I'm only on a house-made lab, I don't have fancy equipment or chemicals to be honest.

clearly_not_atara I've been trying to avoid working with potential chemical agents, SOCL2 is not really an option for me.


So I came up with another way I can realistically perform in my lab but I found another final obstacle:


For compound B:

1.) Benzhydrol --halogenation--> Diphenylhalomethane
2.) Diphenylhalomethane --Sodium alanine--> Alanine Benzhydrolate
3.) Alanine Benzhydrolate --NaNO2/HBr; CuBr (Sandmeyer)--> Bromo-Alanine Benzhydrolate
4.) Bromo-Alanine Benzhydrolate --Piperazine in acetonitrile/triethylammonium hydrochloride in acetonitrile*--> Alanine Benzhydrolate-Piperazine

*NOTE: Ref: http://www.arkat-usa.org/get-file/19416


For compound A:
1.) Phenylalanine --(Phthalimide/Ferric Nitrate)--> Phenylalanine-Phthalimide
2.) Phenylalanine-Phthalimide --???????????????--> N-Phthalimide-Phenylalanyl chloride

Final reaction would be similar for step 4 of compound B, Alanine Benzhydrolate-Piperazine with N-Phthalimide-Phenylalanyl chloride on triethylammonium hydrochloride with acetonitrile as solvent.
Considering that for the acyl chloride I need to use thionyl chloride I don't really think I’ll be able to complete the final reaction... I thought of maybe using PCl3 or maybe using a Boronic acid approach like so: Doi: 10.1016/S0040-4039(98)00503-6
This really escapes from my abilities and materials at my disposal.

I'll keep looking for a way to make the N-Phthalimide-Phenylalanyl chloride but if I can't find any I think I'll switch the reaction a little bit, using the amine group on the phenylalanine is my first thought, halogenating it via Sandmeyer or hell-volhard-zelinsky (EDIT: don't mind this I got confused) and then reacting it similarly as step 4 of compound B with triethylammonium hydrochloride on acetonitrile. Which is a pity because it would had been interesting to study if the shape of phenylalanine on the molecule has neuronal activity and potentiates further dopaminergic release or added noradrenergic release.

It would be something like this:
New possible tarjet 1.png - 16kB

Another idea is to look for another starting material besides phenylalanine... my first idea is 3-amino-4-phenylbutanoic acid, protecting with phthalimide/ferric nitrate, amidation with urea/boric acid and hofmann rearrangement to the amine, then it is pretty much straight forward to target molecule (No idea how to get 3-amino-4-phenylbutanoic acid tho)
If anyone knows of a potential molecule that could be converted into 3-amino-4-phenylbutanoic acid or allows me to bypass acyl chloride I would be eternally grateful to you my friend.

Thanks to everyone for your dedication and responses, they have been extremely helpful as they tend to be here on SM!




[Edited on 05/12/2013 by BlackDragon2712]
View user's profile View All Posts By User
clearly_not_atara
International Hazard
*****




Posts: 1713
Registered: 3-11-2013
Member Is Offline

Mood: No Mood

[*] posted on 21-11-2018 at 17:56


Quote:
2.) Phenylalanine-Phthalimide --???????????????--> N-Phthalimide-Phenylalanyl chloride


This step is the only reason that my suggested route used SOCl2. If you can form the acyl halide or similar of phtalimido-phenylalanine, it makes more sense to convert this to a phenyl ester and react with piperazine, vs. trying to make a bis-chloroethyl amide. The reason is that bis(chloroethyl)amine is far too dangerous to actually use, and N-alkylation of amides is nearly impossible. See:

https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/fi...

Alternatives include PBr3, POCl3, oxalyl chloride, cyanuric chloride, etc. Possibly the acyl tosylate formed with tosyl chloride could be used.

[Edited on 22-11-2018 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
View user's profile View All Posts By User
BlackDragon2712
Hazard to Others
***




Posts: 124
Registered: 22-12-2012
Location: Everywhere
Member Is Offline

Mood: Sleepy

[*] posted on 21-11-2018 at 19:20


Quote: Originally posted by clearly_not_atara  
Quote:
2.) Phenylalanine-Phthalimide --???????????????--> N-Phthalimide-Phenylalanyl chloride


Alternatives include PBr3, POCl3, oxalyl chloride, cyanuric chloride, etc. Possibly the acyl tosylate formed with tosyl chloride could be used.

[Edited on 22-11-2018 by clearly_not_atara]


Cyanuric chloride could work? 50 bucks for 250g huh? cool, now I guess it's about trying it out then.
I wonder if TCCA would also work... I only know of its use as a chlorinating agent of amines, doubt it tho.


View user's profile View All Posts By User
Texium (zts16)
Administrator
********




Posts: 3083
Registered: 11-1-2014
Location: San Marcos, TX
Member Is Offline

Mood: Graduated

[*] posted on 21-11-2018 at 19:44


TCCA will not likely work as a substitute for cyanuric chloride for anything, because the environments that the chlorine atoms inhabit in these compounds are entirely different. In TCCA, chlorine is in an oxidizing environment, in the +1 oxidation state, while in cyanuric chloride, it is in the -1 oxidation state.

Substituting one for another is like a less extreme version of substituting an acid for a hydride. Sure they can both donate hydrogen, in a sense, but their properties are very different, and switching one out for the other doesn't make sense.




View user's profile Visit user's homepage View All Posts By User
CuReUS
International Hazard
*****




Posts: 925
Registered: 9-9-2014
Member Is Offline

Mood: No Mood

[*] posted on 22-11-2018 at 06:28


Quote: Originally posted by BlackDragon2712  

1.) Benzhydrol --halogenation--> Diphenylhalomethane
2.) Diphenylhalomethane --Sodium alanine--> Alanine Benzhydrolate
3.) Alanine Benzhydrolate --NaNO2/HBr; CuBr (Sandmeyer)--> Bromo-Alanine Benzhydrolate
I suggest you do the sandmeyer on alanine first and then react it with benzhydrol,rather than after,since the sandmeyer is very messy and leads to a lot of crap formation,which translates to a lower yield.Also there is no need to convert benzhydrol to halide,just do a direct fisher esterification with 2-bromopropionic acid.
Quote: Originally posted by BlackDragon2712  

1.) Phenylalanine --(Phthalimide/Ferric Nitrate)--> Phenylalanine-Phthalimide
could you give a ref for this step ?
generally the amine is reacted with phthalic anhydride to convert it to phthalimide.
Quote: Originally posted by BlackDragon2712  

Deprotection:

Under 20%HCl/4h reflux, KOH or hydrazine? (Probably not going to mess up with hydrazine tho)
Quote: Originally posted by clearly_not_atara  
phthalimido-GBR-12935 + hydrazine >> GBR-12935
wouldn't this step destroy the ester too ? ;)
Quote:
my first idea is 3-amino-4-phenylbutanoic acid, protecting with phthalimide/ferric nitrate, amidation with urea/boric acid and hofmann rearrangement to the amine, then it is pretty much straight forward to target molecule
I fail to see how this is straight forward to the TM.After you carry out these steps ,there would be no COOH left to do the amidation reaction with piperazine.
Quote:
allows me to bypass acyl chloride
One thing you could do would be to oxidise the NH2 of phenylalanine to nitro using oxone,doing the amidation with piperazine ,and then reducing it back to amine using dithionite to get the TM.The nitro might also activate the COOH enough to directly react with the piperazine :cool:

[Edited on 22-11-2018 by CuReUS]
View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 32
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 23-11-2018 at 14:34


Quote: Originally posted by clearly_not_atara  
phthalimido-GBR-12935 + hydrazine >> GBR-12935


Say goodbye to the other amides and especially that ester.
View user's profile View All Posts By User
BlackDragon2712
Hazard to Others
***




Posts: 124
Registered: 22-12-2012
Location: Everywhere
Member Is Offline

Mood: Sleepy

[*] posted on 26-11-2018 at 14:14


Quote: Originally posted by CuReUS  
I suggest you do the sandmeyer on alanine first and then react it with benzhydrol,rather than after,since the sandmeyer is very messy and leads to a lot of crap formation,which translates to a lower yield.Also there is no need to convert benzhydrol to halide,just do a direct fisher esterification with 2-bromopropionic acid.
Quote: Originally posted by BlackDragon2712  

1.) Phenylalanine --(Phthalimide/Ferric Nitrate)--> Phenylalanine-Phthalimide
could you give a ref for this step ?
generally the amine is reacted with phthalic anhydride to convert it to phthalimide.
[Edited on 22-11-2018 by CuReUS]


Sure here: pubs.acs.org/doi/10.1021/jo500562w
I wont be doing the phthalimide protection tho, you guys are right, deprotecting it would be rather problematic

Quote: Originally posted by CuReUS  

Quote: Originally posted by BlackDragon2712  

Deprotection:

Under 20%HCl/4h reflux, KOH or hydrazine? (Probably not going to mess up with hydrazine tho)
Quote: Originally posted by clearly_not_atara  
phthalimido-GBR-12935 + hydrazine >> GBR-12935
wouldn't this step destroy the ester too ? ;)
[Edited on 22-11-2018 by CuReUS]


Yes it will, didn't think of that.


Quote: Originally posted by CuReUS  

Quote:
my first idea is 3-amino-4-phenylbutanoic acid, protecting with phthalimide/ferric nitrate, amidation with urea/boric acid and hofmann rearrangement to the amine, then it is pretty much straight forward to target molecule
I fail to see how this is straight forward to the TM.After you carry out these steps ,there would be no COOH left to do the amidation reaction with piperazine.
[Edited on 22-11-2018 by CuReUS]

Yeah in there I was thinking on doing a sandmeyer and then reacting it with piperazine on a similar fashion as before with triethylamine on acetonitrile, the other amine would had been protected

Quote: Originally posted by CuReUS  

Quote:
allows me to bypass acyl chloride
One thing you could do would be to oxidise the NH2 of phenylalanine to nitro using oxone,doing the amidation with piperazine ,and then reducing it back to amine using dithionite to get the TM.The nitro might also activate the COOH enough to directly react with the piperazine :cool:

[Edited on 22-11-2018 by CuReUS]


I like this idea... This is what I'm going to try so far:

New pathway (Extended).png - 46kB

This really looks extremely doable and fun, I'm getting exiting over this! thanks CuReUS for your corrections and suggestions, extremely helpful!

EDIT: on reaction (I) I wrote CuI, I meant CuBr my bad... Also, is it a good idea to do the sandmeyer with HI and CuI instead of bromine? since iodide is a better leaving group than bromide it should react easier with piperazine right? also workup would be simpler I think.

[Edited on 05/12/2013 by BlackDragon2712]
View user's profile View All Posts By User
clearly_not_atara
International Hazard
*****




Posts: 1713
Registered: 3-11-2013
Member Is Offline

Mood: No Mood

[*] posted on 26-11-2018 at 15:03


Quote: Originally posted by Cactuar  
Quote: Originally posted by clearly_not_atara  
phthalimido-GBR-12935 + hydrazine >> GBR-12935


Say goodbye to the other amides and especially that ester.


:P I didn't think about that very long, did I?

Unfortunately, BOC is out too as a protecting group. Hydrogenolysis of BOC will also cleave the benzhydryl ester. There are some photolabile protecting groups that could work (including ortho-nitrobenzyloxycarbonyl and phenacyloxycarbonyl), although you now have to work in the dark!

Quote:
One thing you could do would be to oxidise the NH2 of phenylalanine to nitro using oxone,doing the amidation with piperazine ,and then reducing it back to amine using dithionite to get the TM.The nitro might also activate the COOH enough to directly react with the piperazine


As far as I'm aware the simple version with Oxone is limited to non-enolizeable amines. There are some versions that use e.g. dimethyldioxirane or Zr(OtBu)4 etc, but most are involved.

A more practical procedure might be to perform the Sandmeyer reaction on phenylalanine to make the alpha-chlorophenylalanine, which forms the nitroacid with sodium nitrite. I'm a bit unsure about the stability of nitroacids... it seems like unexpected condensations and rearrangements are a possibility. The CH acidity of the alpha proton will be large.




[Edited on 04-20-1969 by clearly_not_atara]
View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 32
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 27-11-2018 at 04:47


Quote: Originally posted by BlackDragon2712  
I like this idea... This is what I'm going to try so far:


I think step 3 will be difficult. The Et3N could E2 the bromide to an acryl ester. Too little piperazine and you might end up with a dimer, too much and you will probably cleave the ester.

I would use MeCN like you suggested to promote Sn2 and I would slowly drop 1 eq ester into 1 eq piperazine in MeCN at 0 C and not letting it go above 0 C. Hoping that the HBr formed would quench the second amine on the piperazine which would minimize side reactions. The low temperature to minimize elimination and ester cleavage. Maybe stir for 1h at 0C and then let it slowly reach RT and check progress on TLC. Then if necessary add small amounts of Et3N with checking reaction progress repeatedly.

How will you do step 5?
View user's profile View All Posts By User
CuReUS
International Hazard
*****




Posts: 925
Registered: 9-9-2014
Member Is Offline

Mood: No Mood

[*] posted on 27-11-2018 at 06:28


Quote: Originally posted by BlackDragon2712  
is it a good idea to do the sandmeyer with HI and CuI instead of bromine? since iodide is a better leaving group than bromide it should react easier with piperazine right? also workup would be simpler I think.
You don't need Cu for iodination.NaNO2/HCl followed by KI works fine.Also the yield of sandmeyer is almost quantitative for iodination http://www.prepchem.com/synthesis-of-iodobenzene/
lastly,I2 is easier to handle than Br2 :D

As for the better leaving group idea,you are correct in assuming that it would react faster with the piperazine.Generally,the reason why Br2 is preferred over I2 is due to cost.That's why Br2 is also called "poor man's I2" ;)
Quote: Originally posted by Cactuar  
How will you do step 5?
Quote: Originally posted by CuReUS  
The nitro might also activate the COOH enough to directly react with the piperazine :cool:


[Edited on 27-11-2018 by CuReUS]
View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 32
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 28-11-2018 at 04:22


Quote: Originally posted by CuReUS  
The nitro might also activate the COOH enough to directly react with the piperazine :cool:


I don't really know anything about a-nitro carboxylic acids but doubt the amine and acid would condense. IFAIK that only happens intramolecularly. And if the nitro group destabilize the acid that much, wouldn't it also very easily decarboxylate?

It would be worth a try but I think using a metyl ester or some peptide synthesis would be more successful.
View user's profile View All Posts By User
 Pages:  1  

  Go To Top