I'm new here, so hi everyone. I intended for this to be short, but it snowballed totally out of control, so my advance apologies for the insane length that this has become! Sedit suggested I post here - so blame him [EDIT: or her as the case may be - I ought not make assumptions] 
Obligatory disclaimer: I am neither a chemist by trade nor education so take that for what it is. These are not procedures, just a dash of thoughts and a twist of substrates.The purpose of these potential routes are to functionalize (specifically, C-methylate) the carbon alpha to nitrogen on the subtrates given below. I look forward to any feedback - postive or negative!
Route 1 uses phenylalanine
Route 2 uses phenethylamine
Route 3 uses phenethylamine <- coolest yet imho
ROUTE 1. PhI(OAc)2/I2 system:
"A one-pot oxidative decarboxylation–Friedel-Crafts reaction of acyclic ?-amino acid derivatives activated by the combination of iodobenzene diacetate/iodine and iron dust"
h**p://pubs.rsc.org/en/content/articlelanding/2008/ob/b815227f
This is not really new as it goes through an acyliminium ion for which there is a lot of really great literature. But what is interesting I feel is their use of hypervalent iodine which is fascinating (to me)!
The pro here is of course a theoretically quick one-pot decarboxylation / alkylation. That's pretty rare where I'm from! The cons with this route: it suffers from 2 equivs of PhI(OAc)2 and 3 equivs of I2. I2 could be recycled though. Far worse however, we need a carbanion to methylate alpha to the nitrogen... generated in the same pot preferentially as the authors did. Finding a home-brew carbanion is a little tougher than it looks. Options (so far as i am aware are) grignards (joy), organometallic chemistry (even better), or a dimsyl ion which actually sounds great on paper but where in the world do you find such a non-nucleophilic base strong enough to deprotonate DMSO? Not in my back pocket, that's for sure. So the dimsyl is still in distress. Additionally, I do not have evidence yet to suggest that this one-pot procedure on this substrate could be perfomed in DMSO, though I truly hope that to be the case!
@Sedit has the best option with lithium amide in my opinion
One can make iodobenzene diacetate without too much trouble if you have GAA, benzene, and I2. Oh also, I almost forgot, you have to bis-N-protect (is that the right terminology?) with phthalic anhydride (the acid straight up might work fine though). I recently read that phthalic acid is the only carboxylic acid that can dehydrate by simple heating back to its anhydride form. Don't you wish AcOH could pull that off.
Anyway, N-phthaloylation / dephthaloylation is not hard. Speaking of protecting groups and totally off-topic, anyone out there who uses BOC protection may like to know that they can protect their amines by merely stirring the amine in water with (BOC)2O at rt. Then similarly, you can unprotect by heating a bath up (to ~80C I think?) and put your flask containing your boc-protected amine solvated or suspended in water into the warm water bath (can't remember length of times, fairly short though).
In summary, the route may look roughly like:
1. Iodine, benzene, GAA -> PhI(OAc)2
2. Phthaloyl the phenylalanine (say that 3 times)
3. Decarboxylate / alkylate with PhI(OAc)2/I2 with a carbanion in appropriate solvent or methylsulfinyl anion in DMSO
4. deprotect the amine
Questions:
A. will the substrate and reagents work DMSO?
B. Anyone have an idea on OTC non-nucleophilic super base? There is the lithium amide Sedit brought up somewhere else.
ROUTE 2. Asymmetric Mannich reaction catalyzed by proline:
Proline-catalysed Mannich reactions of acetaldehyde
h**p://course.zjnu.cn/orgchem/kcwz/lunwen/4.pdf
and
Asymmetric Mannich Reaction of Acetaldehyde
h**ps://www.thieme-connect.com/ejournals/abstract/synfacts/doi/10.1055/s-2008- 1072685
Why acetaldehyde? Well, if anyone can think of something we can eliminate down into a single methyl group through some kind of cleavage (which I'm never opposed to), then I'd love to hear! This one I was initially very excited about but acetaldehyde is not as easy to synthesize as I thought. Unless one enjoys tube furnaces - there is a guy on SM who was semi-successful using strictly copper oxide as oxidant. Be sure it is polymerized for storage after distillation. Also, if acetaldehyde is produced home-brew style I have a significant concern about certain impurities from the gas phase oxidation process getting into the reaction and going right through the Mannich with everything else. I don't think it wise to stray far from well travelled paths, when it comes to brain chemistry. some are more brave than I.
In any case, I feel this whole acetaldehyde problem needs to be solved first before this route is really of any utility.
Anyway, after the Mannich, then one would have to eliminate the aldehyde along with its carbon. I was thinking of oxidizing the aldehyde with something like TEMPO and a co-oxidant of some kind (lots to choose from it appears), and then decarboxylating (thermally or otherwise?)
Question: in the articles with which this route is concerned, how do they produce an imine with BOC attached - I can't recall seeing that before, was it a =NH prior to boc protection? Or did they somehow remove a bond from a nitrile (?!) by adding BOC, somehow? Help me out, I'm not seeing it. My lack of any formal chemistry education is really shining here I know.
@Sedit, I was totally wrong, can't do this via schiff base, because the carbon from carbon-carbon bond from the Mannich would wind up on the wrong aldehyde side.
Speaking of oxidations, if you haven't seen it there's a great 4-oxo-TEMPO synth by Klute on SM. Who thought something like THAT would be OTC?
Also speaking of oxidants, something I thought was hilarious: a JOC article with a picture of a bottle of bleach in the abstract. If there had been a roll of duck tape and red green in the background, I would have laughed myself to tears. They use bleach and nickel acetate (surely the tetrahydrate some of you are likely have lying around... funny that).
h**p://pubs.acs.org/doi/abs/10.1021/jo0612574
Speaking of nickel acetate, if you want some but not in a big hurry to get it, just open a bottle of GAA, toss in a bunch of black nickel oxide, close the cap and shake every so often for a several weeks. When happily green, decant and evaporate (add more GAA to bottle if you still have NiO black sludge at the bottom). I noticed a decrease in pressure within the bottles, but nothing serious, a very small amount of leakage.
Moving right along...
ROUTE 3. Asymmetric PTC a-carbon anionic alkylation
So I saved the best one for last! This is my favorite so far.
Pros: lots of PTC's possible, novel route for the given substrates (as far as I am aware), common electrophilic methylation reagents may be used (no dimsyl), cheap materials, only a few steps, can be enantioselective or provide a racemic mixture based on PTC used (wow)!
Cons? You guys tell me!
There's quite a bit of literature on this mechanism, but this article is a good overview, though it is from '94.
Tetrahedron Volume 50, Issue 15, 11 April 1994, Pages 4507-4518
h**p://www.sciencedirect.com/science/article/pii/S0040402001893820
Here's a more recent document on the subject:
Recent Advances in Asymmetric Phase-Transfer Catalysis
h**p://isites.harvard.edu/fs/docs/icb.topic208898.files/Wed_Oct_3/Phase_Transfer_Catalysis.pdf
From what I can tell, the carboxyl group of the amino acid (or carboxy ester) in many examples in those documents are irrelevant to the mechanism. So that means we can use phenethylamine again - or substituted variety. [Edit: On closer inspection, I am likely wrong here - if it is required then just switch substrate to phenylalanine and decarboxylate after the c-c bond has been formed]
As for PTC's BINOL looks good, but there's a lot of room for creativity here.
Ok that's it, so just when you thought the trail of broken glass and polymerized tar had come to a its bitter end, faced at last with the grim choice between 10% yields or a life behind hydrazine and grignards, suddenly there is hope!
... or a guy in orange pointing to garden and pool supply “TC-huh?”.
Obligatory disclaimer: I am neither a chemist by trade nor education so take that for what it is. These are not procedures, just a dash of thoughts and a twist of substrates.The purpose of these potential routes are to functionalize (specifically, C-methylate) the carbon alpha to nitrogen on the subtrates given below. I look forward to any feedback - postive or negative!
Route 1 uses phenylalanine
Route 2 uses phenethylamine
Route 3 uses phenethylamine <- coolest yet imho
ROUTE 1. PhI(OAc)2/I2 system:
"A one-pot oxidative decarboxylation–Friedel-Crafts reaction of acyclic ?-amino acid derivatives activated by the combination of iodobenzene diacetate/iodine and iron dust"
h**p://pubs.rsc.org/en/content/articlelanding/2008/ob/b815227f
This is not really new as it goes through an acyliminium ion for which there is a lot of really great literature. But what is interesting I feel is their use of hypervalent iodine which is fascinating (to me)!
The pro here is of course a theoretically quick one-pot decarboxylation / alkylation. That's pretty rare where I'm from! The cons with this route: it suffers from 2 equivs of PhI(OAc)2 and 3 equivs of I2. I2 could be recycled though. Far worse however, we need a carbanion to methylate alpha to the nitrogen... generated in the same pot preferentially as the authors did. Finding a home-brew carbanion is a little tougher than it looks. Options (so far as i am aware are) grignards (joy), organometallic chemistry (even better), or a dimsyl ion which actually sounds great on paper but where in the world do you find such a non-nucleophilic base strong enough to deprotonate DMSO? Not in my back pocket, that's for sure. So the dimsyl is still in distress. Additionally, I do not have evidence yet to suggest that this one-pot procedure on this substrate could be perfomed in DMSO, though I truly hope that to be the case!
@Sedit has the best option with lithium amide in my opinion
One can make iodobenzene diacetate without too much trouble if you have GAA, benzene, and I2. Oh also, I almost forgot, you have to bis-N-protect (is that the right terminology?) with phthalic anhydride (the acid straight up might work fine though). I recently read that phthalic acid is the only carboxylic acid that can dehydrate by simple heating back to its anhydride form. Don't you wish AcOH could pull that off.
Anyway, N-phthaloylation / dephthaloylation is not hard. Speaking of protecting groups and totally off-topic, anyone out there who uses BOC protection may like to know that they can protect their amines by merely stirring the amine in water with (BOC)2O at rt. Then similarly, you can unprotect by heating a bath up (to ~80C I think?) and put your flask containing your boc-protected amine solvated or suspended in water into the warm water bath (can't remember length of times, fairly short though).
In summary, the route may look roughly like:
1. Iodine, benzene, GAA -> PhI(OAc)2
2. Phthaloyl the phenylalanine (say that 3 times)
3. Decarboxylate / alkylate with PhI(OAc)2/I2 with a carbanion in appropriate solvent or methylsulfinyl anion in DMSO
4. deprotect the amine
Questions:
A. will the substrate and reagents work DMSO?
B. Anyone have an idea on OTC non-nucleophilic super base? There is the lithium amide Sedit brought up somewhere else.
ROUTE 2. Asymmetric Mannich reaction catalyzed by proline:
Proline-catalysed Mannich reactions of acetaldehyde
h**p://course.zjnu.cn/orgchem/kcwz/lunwen/4.pdf
and
Asymmetric Mannich Reaction of Acetaldehyde
h**ps://www.thieme-connect.com/ejournals/abstract/synfacts/doi/10.1055/s-2008- 1072685
Why acetaldehyde? Well, if anyone can think of something we can eliminate down into a single methyl group through some kind of cleavage (which I'm never opposed to), then I'd love to hear! This one I was initially very excited about but acetaldehyde is not as easy to synthesize as I thought. Unless one enjoys tube furnaces - there is a guy on SM who was semi-successful using strictly copper oxide as oxidant. Be sure it is polymerized for storage after distillation. Also, if acetaldehyde is produced home-brew style I have a significant concern about certain impurities from the gas phase oxidation process getting into the reaction and going right through the Mannich with everything else. I don't think it wise to stray far from well travelled paths, when it comes to brain chemistry. some are more brave than I.
In any case, I feel this whole acetaldehyde problem needs to be solved first before this route is really of any utility.
Anyway, after the Mannich, then one would have to eliminate the aldehyde along with its carbon. I was thinking of oxidizing the aldehyde with something like TEMPO and a co-oxidant of some kind (lots to choose from it appears), and then decarboxylating (thermally or otherwise?)
Question: in the articles with which this route is concerned, how do they produce an imine with BOC attached - I can't recall seeing that before, was it a =NH prior to boc protection? Or did they somehow remove a bond from a nitrile (?!) by adding BOC, somehow? Help me out, I'm not seeing it. My lack of any formal chemistry education is really shining here I know.
@Sedit, I was totally wrong, can't do this via schiff base, because the carbon from carbon-carbon bond from the Mannich would wind up on the wrong aldehyde side.
Speaking of oxidations, if you haven't seen it there's a great 4-oxo-TEMPO synth by Klute on SM. Who thought something like THAT would be OTC?
Also speaking of oxidants, something I thought was hilarious: a JOC article with a picture of a bottle of bleach in the abstract. If there had been a roll of duck tape and red green in the background, I would have laughed myself to tears. They use bleach and nickel acetate (surely the tetrahydrate some of you are likely have lying around... funny that).
h**p://pubs.acs.org/doi/abs/10.1021/jo0612574
Speaking of nickel acetate, if you want some but not in a big hurry to get it, just open a bottle of GAA, toss in a bunch of black nickel oxide, close the cap and shake every so often for a several weeks. When happily green, decant and evaporate (add more GAA to bottle if you still have NiO black sludge at the bottom). I noticed a decrease in pressure within the bottles, but nothing serious, a very small amount of leakage.
Moving right along...
ROUTE 3. Asymmetric PTC a-carbon anionic alkylation
So I saved the best one for last! This is my favorite so far.
Pros: lots of PTC's possible, novel route for the given substrates (as far as I am aware), common electrophilic methylation reagents may be used (no dimsyl), cheap materials, only a few steps, can be enantioselective or provide a racemic mixture based on PTC used (wow)!
Cons? You guys tell me!
There's quite a bit of literature on this mechanism, but this article is a good overview, though it is from '94.
Tetrahedron Volume 50, Issue 15, 11 April 1994, Pages 4507-4518
h**p://www.sciencedirect.com/science/article/pii/S0040402001893820
Here's a more recent document on the subject:
Recent Advances in Asymmetric Phase-Transfer Catalysis
h**p://isites.harvard.edu/fs/docs/icb.topic208898.files/Wed_Oct_3/Phase_Transfer_Catalysis.pdf
From what I can tell, the carboxyl group of the amino acid (or carboxy ester) in many examples in those documents are irrelevant to the mechanism. So that means we can use phenethylamine again - or substituted variety. [Edit: On closer inspection, I am likely wrong here - if it is required then just switch substrate to phenylalanine and decarboxylate after the c-c bond has been formed]
As for PTC's BINOL looks good, but there's a lot of room for creativity here.
Ok that's it, so just when you thought the trail of broken glass and polymerized tar had come to a its bitter end, faced at last with the grim choice between 10% yields or a life behind hydrazine and grignards, suddenly there is hope!
... or a guy in orange pointing to garden and pool supply “TC-huh?”.
A one-pot oxidative decarboxylation–Friedel-Crafts reaction of acyclic amino acid derivatives activated by the combination of iodobenzene diacetate-iodine and iron dust.pdf