Sciencemadness Discussion Board - Ligands derived from niacin?

Ligands derived from niacin?

clearly_not_atara - 27-8-2016 at 15:17

A recurring topic is niacin decarboxylation, which requires high temperatures and controlled conditions and often yields poorly if at all; this suggests that we would be better off if we could avoid it, and the first alternative in my mind would be to make a similar ligand that isn't *exactly* pyridine but which is mostly the same.

There are a couple of options:

3-ethylpyridine:

Niacin undergoes acetodecarboxylation with Ac2O/NaOAc to 3-acetylpyridine which is reduced by Clemmensen or Wolff-Kishner reduction to 3-ethylpyridine.

Pros: almost certainly works just like pyridine, OTC if you can make Ac2O/N2H4

Cons: long synthesis, longer OTC, hydrazine, mercury

Ethyl nicotinate:

Actually happens to be used in some syntheses.

Pros: very easy to synthesize, possibly even available.

Cons: less basic than pyridine, susceptible to hydrolysis. It's not obvious where and when this can be substituted for pyridine.

2-(3-pyridyl)-4-methyl-5-acetyloxazole:

The product of a condensation between nicotinamide and acetylacetone catalyzed by PdCl2/CuBr2 with K2S2O8. Acetylacetone may be made from NaOEt/EtOAc/Me2CO as described on orgsyn.

Synthesis attached (actually, the similar product derived from benzene is synthesized in the paper, so we are generalizing a little).

Pros: one-step synthesis, reactivity likely very similar to pyridine, may be a bidentate ligand

Cons: uses palladium, has a ketone. Making acetylacetone is tricky. Original paper has DCE as solvent.

2-(3-pyridyl)-4-methyl-5-ethoxycarbonyloxazole:

Pros: Same as above, plus ethyl acetoacetate substitutes for acetylacetone, making the synthesis easier.

Cons: Same as above, except no ketone, but may be susceptible to hydrolysis.

Something else:

Pros: Might be better.

Cons: Synthesis and properties unknown.

Attachment: zheng2014.pdf (337kB)
This file has been downloaded 380 times

[Edited on 27-8-2016 by clearly_not_atara]

CuReUS - 27-8-2016 at 20:04

IMHO, the best bet would be using alkyl pyridines such as picoline , as adding a methyl group hardly changes the molecule( this law does not apply for rocket propellants

)
picoline , I think ,could be made easily enough - http://www.sciencemadness.org/talk/viewthread.php?tid=28198
another idea would be to come up with a better method to make pyridine.I wonder what would happen if lysine was strecker degraded, cyclised to form the imine and then dehydrogenated using Se to form pyridinehttps://en.wikipedia.org/wiki/Dehydrogenation
also can TEA or hunig's base be substituted for pyridine ?

UC235 - 27-8-2016 at 20:24

I'm confused as to what the difficulty in decarboxylating niacin is? Nicotinic acid is cheap enough to buy in bulk as a supplement. I got high yields using a simple distillation setup, it's amenable to scaleup and uses a tiny amount of catalyst (that can likely be substituted by a somewhat larger amount of CuO or copper metal powder). There's no requirement for inert gas or elaborate purification or any solvents at all.

The simplest of the alternatives requires more than a full equivalent of sulfuric acid, a large volume of methanol to run the esterification in and workup involves a distillation to get a product susceptible to acidic and basic hydrolysis and attack by other nucleophiles.

[Edited on 28-8-2016 by UC235]

DraconicAcid - 27-8-2016 at 21:22

Quote: Originally posted by CuReUS

IMHO, the best bet would be using alkyl pyridines such as picoline , as adding a methyl group hardly changes the molecule( this law does not apply for rocket propellants

)
picoline , I think ,could be made easily enough -

How easy is it to convert picoline into picolinic acid? Picolinate is a good ligand.

Alice - 28-8-2016 at 05:34

Oxidation of picoline by KMnO4:

http://orgsyn.org/demo.aspx?prep=CV3P0740

Oxidation of picoline by MnO2/H2SO4:

https://www.google.com/patents/US2109954

halogen - 28-8-2016 at 09:39

Cyclopropane is combined by radical reaction with nitrogen dioxide to form 1,3-dinitro n-propane. 1,3-DNP is reacted with a base to form the bis nitrostyrene, which is then allowed to condense with ammonia, to form the cyclic 3,5-dinitro piperidine, which undergoes pyrolysis to form pyridine. (NO2 is a good leaving group)

[Edited on 28-8-2016 by halogen]

[Edited on 28-8-2016 by halogen]

PHILOU Zrealone - 28-8-2016 at 11:22

Quote: Originally posted by halogen

Cyclopropane is combined by radical reaction with nitrogen dioxide to form 1,3-dinitro n-propane. 1,3-DNP is reacted with a base to form the bis nitrostyrene, which is then allowed to condense with ammonia, to form the cyclic 3,5-dinitro piperidine, which undergoes pyrolysis to form pyridine. (NO2 is a good leaving group)

[Edited on 28-8-2016 by halogen]

[Edited on 28-8-2016 by halogen]

Do you have one (or more) reference(s) for that beautiful sequence of reactions?
I'm interested in all intermediary molecules aswel as the final one

clearly_not_atara - 28-8-2016 at 12:48

Quote: Originally posted by UC235

I'm confused as to what the difficulty in decarboxylating niacin is? Nicotinic acid is cheap enough to buy in bulk as a supplement. I got high yields using a simple distillation setup, it's amenable to scaleup and uses a tiny amount of catalyst (that can likely be substituted by a somewhat larger amount of CuO or copper metal powder). There's no requirement for inert gas or elaborate purification or any solvents at all.

If you are referring to copper chromite then I would like to hear more details as I have heard conflicting reports on this method. Maybe I overestimated the difficulty involved?

Quote:

another idea would be to come up with a better method to make pyridine.I wonder what would happen if lysine was strecker degraded, cyclised to form the imine and then dehydrogenated using Se to form pyridinehttps://en.wikipedia.org/wiki/Dehydrogenation

If you are willing to do multiple steps I think it is possible to make phenanthroline (starting from benzene/toluene, nitrate, sulfuric acid, glycerol):

nitrobenzene (or p-nitrotoluene) + [H] >> aniline
(famous, many routes)

aniline + potassium persulfate >> 2-hydroxyaniline
https://en.wikipedia.org/wiki/Boyland%E2%80%93Sims_oxidation

2-hydroxyaniline + glycerol + nitrobenzene + H2SO4 >> 8-quinol
http://en.wikipedia.org/wiki/Schlenk_reaction
http://en.wikipedia.org/wiki/8-hydroxyquinoline

8-quinol + NH3 + NaHSO3 >> 8-aminoquinoline
http://en.wikipedia.org/wiki/Bucherer_reaction
(A little research will confirm this in fact proceeds rapidly and cleanly on quinol)

8-aminoquinoline + glycerol + nitrobenzene + H2SO4 >> 1,10-phenanthroline

It's actually shocking how parsimonious the sequence is. I considered it for that five-materials challenge, but I think it requires six or seven. Mononitrotoluenes can be substituted for all of the nitrobenzenes, making this extremely OTC.

[Edited on 28-8-2016 by clearly_not_atara]

halogen - 28-8-2016 at 14:04

no

UC235 - 28-8-2016 at 16:27

Quote: Originally posted by clearly_not_atara

If you are referring to copper chromite then I would like to hear more details as I have heard conflicting reports on this method. Maybe I overestimated the difficulty involved?

I provided a full illustrated writeup in prepublication as an add-on to magpie's thread. The original method presented is hugely wasteful of catalyst in a manner that is wholly unnecessary.

I would rate it as one of the easier preps I have done.

DDTea - 28-11-2016 at 16:27

Quote: Originally posted by clearly_not_atara

8-aminoquinoline (8-AQ) is a remarkably useful ligand. It can temporarily mask a carboxylic acid as the corresponding 8-AQ amide. The 8-AQ moiety then serves as a directing group for a metal center, allowing reaction selectivity (often transformations of C-H bonds) at the beta position of the carboxylic acid. Picolinic acid acid enables similar directed catalysis for amides. In essence, directing groups are tethers that allow an otherwise unselective catalyst to react at only specific positions on a molecule.

The examples I'm most familiar with involve Pd(OAc)2 as catalyst. But the strategy has been applied to rhodium and copper as well for alkylation, carbonylation, and sulfenylation.

For more on this, these are good references to start.

http://onlinelibrary.wiley.com/doi/10.1002/047084289X.rn0183...
http://onlinelibrary.wiley.com/doi/10.1002/anie.201301451/ab...
http://dx.doi.org/10.1016/j.tet.2015.03.085

NitratedKittens - 20-12-2016 at 00:55

Quote: Originally posted by halogen

What, no to the multi step complex synth for a substitute for something that can be made in one go as outlined in this video: https://youtu.be/FNsqYwzm40M

Or just no in general

Boffis - 8-1-2017 at 06:24

I have recently come across an interesting ligand related to pyridine, 1,5-diazanapthalene. This is prepared by subjecting niacin to hoffmann's degradation to produce 3-aminopyridine and then Skraup's quinoline synthesis on this. I'll try and dig out the papers again.

PHILOU Zrealone - 8-1-2017 at 10:37

Quote: Originally posted by Boffis

I have recently come across an interesting ligand related to pyridine, 1,5-diazanapthalene. This is prepared by subjecting niacin to hoffmann's degradation to produce 3-aminopyridine and then Skraup's quinoline synthesis on this. I'll try and dig out the papers again.

Interesting molecule!
Doesn't the Skraup's step also makes 1,7-diazanaphtalene (1,7-naphtyridine)?

Boffis - 9-1-2017 at 04:21

Hi Philou, I don't have the original paper to hand but I would expect so. I mean to check this procedure out sometime as I am interested in this compound but as usual its the time problem

Eddygp - 9-1-2017 at 07:18

(possibly N-substituted) nicotinamide? More stable and much less reactive than acids or esters under most conditions, you don't need too much hassle to prepare it and allows inner sphere electron transfer, potentially.

Boffis - 12-1-2017 at 10:00

Hi Philou, I have dug out some of my references on naphthyridines and it appears that 3-aminopyridine give almost exclusively the 1,5-naphthyridine in a standard Skraup reaction but yields can vary from 25 to 90% depending on conditions, see the attached papers. There do appear to be modifications that yield the 1,7 isomer.

Attachment: Preparation of 1,X-naphthyridines JCS A Albert 1960.pdf (90kB)
This file has been downloaded 273 times
Attachment: Synthesis of Naphthyridines by a one step process ChemPharmBull Hamada et al 1971.pdf (613kB)
This file has been downloaded 238 times

The Hoffmann degradation of nicotinamide to 3-aminopyridine is discribed in a European or worldwide patent referred to, but not posted, by Nicodem in an old thread. I managed to track down the US patent equivalent.

Attachment: Manufacture of 2,3-dichloropyridine, 3-chloro and 3-aminopyridine from nicotinamide US 20070161797.pdf (850kB)
This file has been downloaded 262 times

This last ref. also contains some interesting pyridine chemistry including the preparation of 3-chloro and 2,3-dichloro pyridine from nicotinamide.

PHILOU Zrealone - 13-1-2017 at 12:57

@Boffis,

Thank you.

Very much appreciated.

UC235 - 13-1-2017 at 16:29

Quote: Originally posted by NitratedKittens

Quote: Originally posted by halogen

What, no to the multi step complex synth for a substitute for something that can be made in one go as outlined in this video: https://youtu.be/FNsqYwzm40M

The video that runs my procedure posted on this forum in prepub?

Starts halfway down the page: https://www.sciencemadness.org/whisper/viewthread.php?tid=13...