Author Topic: Grignard reagents and methylenedioxy rings  (Read 1230 times)

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dormouse

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Grignard reagents and methylenedioxy rings
« on: April 19, 2000, 03:53:00 AM »
Author  Topic:   Grignard reagents and methylenedioxy rings 
drone 342
Member   posted 09-21-98 05:48 PM          
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This topic came up earlier, and I wanted to discuss this further, especially in light of recent pet projects of mine regarding my favorite alkali Earth metal.
Now for some reason we disccussed earlier, bromosafrole was not a good candidate for a grignard reaction due to side reactions involving the methylendioxy ring. Now if memory serves, wasn't this due to the methylene's high electrophilicity, or am I just smoking crack? I remember the yields invonving bromosafrole were abysmal, but I can't remember with 100% certainty why. Was this it? When I do a search, I can't find this discussion. Any ideas?

-drone #342


Strike
Administrator   posted 09-21-98 10:07 PM          
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Drone - Do you have anything to offer this board except question after question after question. It is not exclusively your board to ask everything you want answered simply because you know that only chemists haunt the board.
You keep reasking in the threads why no one is answering your questions. The reason may be that you are asking things that have little relevance to direct amphetamine chemistry except to assuade your own interests. Can you please think of more relevant topics.


drone 342
Member   posted 09-22-98 10:47 AM          
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All the questions I've raised in the last week or so are DIRECTLY relevant to amphetamine chemistry!
I brought up enolate chemistry of P2P -- hard to get more relevant to amphetamines than that. In that thread, I don't believe I even asked any questions -- I just pointed out for everybody the simplicity and elegance of a reaction that a lot of people want to know about. Its well-documented, quick, and has excellent yields using chemicals anybody can get. Its a straight-forawrd method thoroughly relevant to this board, and all P2P chemists would fare quite well to investigate it.

I brought up potentially newer, faster reactions for going from halosafrole to MDMA -- under extremely fast, extremely agreeable reaction conditions. I trust that such a reaction might have some value to SOMEBODY around here besides myself. Think about it: Safrole to halosafrole (using the article I provided from JOC, involving a two-phase system of concentrated aq. HCl or HBr, safrole, and a phase-transfer catalyst), then follwed by a quick reaction invonving lithium, sodium or (perhaps) magnesium methylamide. In a couple minutes, its done. How can you not find that relevant or interesting?

I brought up the possibility of a better alternative to sodium or lithium in the Birch reduction. For those who are interested in the Birch reduction, but who are not too keen on playing with such pyrophoric metals, this is a great step forward.

Virtually everybody diverges from amphetamine chemistry around here from time to time. Ironically, I've kept to a relatively straight and narrow path in the last week, but am chastized regardless.

This is "serious chemists only"; what would a person discuss in this forum other than this type of stuff? Discussing what is meant by "molarity"? Rehashing for the millionth time the performic acid method for making MDP2P? Discussing the best methods of extracting p-fed? I think not. There are already forums for that. From my understanding, This forum is for the type of chemistry a little bit above common practice, but still of practical use. I think I've stayed well within the bounds of what would be protocol.

Real-live, professional chemists are a small but crucial minority on The Hive. While much of what's discussed may be esoteric and fly above most people's heads, its still important. It may not be for everybody YET, but with enough work in these preminimary stages, some of it will be.

-drone #342


drone 342
Member   posted 09-22-98 11:18 AM          
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Strike, as grand poobah of the site, you're perfectly able to ask and answer whatever questions you want. So if there's something missing in the discussion, feel free to add it. What topic isn't getting its fair share of analysis that you feel should?
-ddrone #342


Strike
Administrator   posted 09-22-98 10:15 PM          
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Look, Strike knows that you are offended by the comment, and Strike knows it would take nothing less than a complete delineation of each example of your posts to adequately explain what Strike means. But that would be a waste of time.
If you see what Strike means fine. If you don't, fine. You can continue to post as is. Strike won't comment further.


drone 342
Member   posted 09-23-98 01:22 PM          
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Getting back to the original subject, why won't this work, or will it? Strangely, All records of grignard reactions involving halosafroles are nowhere to be found on Beilstein -- though a few months ago, it was there. Thankfully, I dug up most of the relevant articles already, though I know there are people out there with a more extensive collection on this subject.
Is there anybody willing to come forward with the needed information?

-drone #342


drone 342
Member   posted 09-27-98 04:53 PM          
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For those interested, I've found over a hundred examples of grignard reagetns successfully being employed in reactions involving reagents with 3,4-methylenedioxybenzyl compounds- though apparently the reaction is very sensetive to the choice of solvent. In addition, I've also found plenty of examples where the ring is cleaved -- just for comparison. This is exceedingly good news. From this, we can decipher that really strong nucleophiles can leave the ring alone under the right conditions. This opens a huge new group of synthetic reagents and methods for the clandestine chemist-- a whole slew of quick, clean, and fascile reactions that could make MDMA chemistry A LOT more fun.
What's interesting is here's another example of how the many reactions of Grignards can be manipulated simply by a choice os solvent and temerature. Where Benzene or toluene were used, the methylenedioxy ring get's popped. However, when Et2O is used, the gringard complex formed leaves the ring alone!

In fact, I've found an exaple of a sort of 3,4-methylenedioxyephedrine being made via this way:

Tetrahedron: Asymmetry; 8; 3; 1997; 459-468;

Please comment. Soon, I will post a proposed synthetic method for making MDMA from bromobenzene.

drone #342


drone 342
Member   posted 09-27-98 05:01 PM          
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Whoops, sorry about that. That should read "...MDMA from bromosafrole".
 
Labrat
Member   posted 09-28-98 08:46 AM          
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A Grignard reagent is made by adding an alkyl/aryl halide to Mg in ethereal solution. The synth you're proposing is more like adding magnesium amide to bromosafrole, right? It has to be, cuz it's pretty impossible to react safrole Grignard with methylamine, at least to made MDMA that is.
So the synth you're proposing is not a Grignard reaction. But I understand your concern for the methylenedioxyring.

Thus, if I'm correct, you're first going to react magnesium with liquid/ethereal methylamine to make the magnesium amide + H2. Then bromosafrole in ether is dripped in to make MDMA. Looks good to me. I'm curious what the results will be. Lr/


 
drone 342
Member   posted 09-29-98 01:58 PM          
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LR,
Why would the addition of grignard safrle not work with dry methylamine in Et2O? Actually, I'm proposing *both* reactions; first the formation of magnesium methylamide b reacting the amalamated metal with liq/ethereal methylamine in the presence of Fe(NO3)3. Poof, off goes the hydrogen, and the halosafrole is added. In about two seconds (give or take a minute  ), the reaction is complete.

The actual Grignard reaction I forsee two possible methods: first the formation of safrole grignard, reacting it with nitromethane, then maybe a quick reduction. The second would be with safrole grignard and methylamine. Those protons are loose, and methylamine would quickly react, forming H2 and MDMA magnesium halide. When quenched, this would produce straight MDMA, or so I believe. Please, honestly, enlighten me why it won't work. I'm curious.

-drone #342


Labrat
Member   posted 09-30-98 09:27 AM          
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>Why would the addition of grignard safrole not work with dry methylamine in Et2O?
=>First of all, a Grignard reagent is an nucleophile, but so is methylamine! So these two substances won't react like you want to.
Maybe the Grignard will be strong enough to abstract a proton from the methylamine, with formation of methylamide, but I'm not sure of this.
>first the formation of safrole grignard,
reacting it with nitromethane...
=>This could very well work. The nitrogen in nitromethane is very electrophilic. But the alpha-hydrogen is also acidic and can split off. Or maybe it can be abstracted by the Grignard reagent. I'm curious what the main reaction will be.

I've already commented on the second route you're proposing, reacting magnesium methylamide with bromosafrole. In my opinion, the methylamide is a strong enough base to abstract the benzylic proton of bromosafrole. Elimination of the bromide will give as product isosafrole. Lr/


drone 342
Member   posted 09-30-98 05:12 PM          
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Protons are readily abstracted from amines by Grignard reagents.
I have some articles in German on the addition of nitroalkanes to Grignards, but I have them packed away. If I remember, it worked really well, in spite of the acidity. Otherwise, perhaps if you could generate anhydrous oxidized version of methylamine, you might be in business.

-drone #342


Labrat
Member   posted 10-01-98 09:05 AM          
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It looks like there's only one way left: reacting safrole Grignard with nitromethane. Can you give me the German refs on that subject? Danke!
>Otherwise, perhaps if you could generate anhydrous oxidized version of methylamine, you might be in business.
=>What are you suggesting? The imine formed between ammonia and formaldehyde? Even if this could be made to work, no MDMA would be formed. The Grignard adds to the carbon portion of the imine, which puts the nitrogen on the wrong position. So, what do you mean with "anhydrous oxidized version of methylamine"? Lr/


drone 342
Member   posted 10-01-98 01:00 PM          
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Dammit! I'm currently in the process of moving, and all my files are tucked away. The frustrating part happens when I look using Beilstein crossfire, and the journal articles that I found before are nowhere to be seen! I'll dig through my boxes, and find 'em for you. In the meantime, I found several other articles relevant to this kind of Grignard reaction.
J.Chem.Soc.; 1947; 1493;
J.Org.Chem.; EN; 57; 22; 1992; 5834-5840;
Justus Liebigs Ann. Chem.; 585; 1954; 220, 225;
J.Org.Chem.; EN; 55; 14; 1990; 4456-4459;
Chem.Ber.; 40; 1907; 3080;
C.R.Hebd.Seances Acad.Sci.; 132; 1901; 838;
CHBEAM; Chem.Ber.; GE; 96; 1963; 2387-2393;

All of these describe N-alkylation of nitroalkanes via organomagnesium compounds. When I find the more thorough ones at home, you'll be the first people to know.

-drone #342


drone 342
Member   posted 10-01-98 01:21 PM          
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For oxidized forms of methylamine, I was thinking of:
nitromethante
N-methylhydroxylamine
methylaminooxyl <-> nitrosomethane
hydroxy-methyl-aminooxyl

Essentially, anything that might leave the nitrogen open for a good clean attack by the grignard, without involving too many side-reactions, and still able to be reduced or perhaps hydrolyzed off. Nitromethane is my favorite candidate, since its so widely available.

-drone #342


 
Labrat
Member   posted 10-02-98 09:09 AM          
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Those N-alkylation refs you gave are nice, but they're a bit off subject here. I'll check them out...
Nitromethane is probably the best oxidised form of methylamine to do the reaction with. N-methylhydroxylamine is expensive and rather hard to get; nitrosomethane will have to be synthesized; and I'm not sure what hydroxy- methyl-aminooxyl is normally called, but I don't think it's hydroxy-nitrosomethane.

So I think you're right. You can probably use nitromethane and add the safrole Grignard to that. After quenching, you'll still have to reduce the product to the amine. I think that aluminum amalgam can be used to accomplish that. Now all we need is a protocol with decent literature and we're there! Lr/


 
drone 342
Member   posted 10-02-98 12:14 PM          
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Yo, homeslice, I'll hook you up phat! I found my pile-o-ref's, and hopefully I'll scan them in this afternoon!
I gotcha back,

-drone 3:42


drone 342
Member   posted 10-02-98 04:43 PM          
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Scanning them is going to have to wait; considering the number of projects laying before me, this is reasonable. Still, I have my ref's in front of me now.
The most relevant one is, as I said, a German article, by Alfred Dornow, Hans Gehrt, and Friedrich Ische, titled "Umsetzung einiger aliphatischer Nitroverbindungen mit Gringard-Verbindungen", submitted 23.Nov.1953. Unfortunately, I can't find the journal name, but judging by the page layout, it looks like Justus Liebigs Ann. Chem., or maybe Chem. Ber. The pages are 220-228.


Actually, looking at the dates and page numbers, I think I already listed this one. Additionally, the one by the Italians, J.Org.Chem.; EN; 57; 22; 1992; 5834-5840, was particularily excellent.

As you can see, fortunately for our purposes, it looks like methylenedioxybenzyl compounds are perfectly stable under relatively similar conditions. Yields look a bit low, but the price is right, and it looks reasonably simple.

The one difference, and admitedly this is a considerable difference, is that the best reactions involving the Grignard were in THF, while the safrole would most likely be most stable in a solution of Et2O. Admittedly, I haven't seen any literature stating that THF would be innapropriate, but I haven't seen any that says it would be either. More research has to be done in trhis arena. Comment please.


drone 342
Member   posted 10-02-98 05:05 PM          
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...And here are a few examples of xstableMD-benzene-species complexes in THF:
J.Amer.Chem.Soc.; EN; 112; 9; 1990; 3464-3466;
Gazz.Chim.Ital.; EN; 120; 1990; 793-803;
Synthesis; EN; 4; 1989; 291-292;
Gazz.Chim.Ital.; EN; 120; 1990; 783-791;
Heterocycles; EN; 25; 1987; 409-418;
Synth.Commun.; EN; 21; 5; 1991; 713-719;
Synth.Commun.; EN; 18; 9; 1988; 893-898;
J.Amer.Chem.Soc.; EN; 109; 18; 1987; 5446-5452;
J.Org.Chem.; EN; 62; 20; 1997; 6716-6721;

This is of course only a partial list of the vast number of relevant Grignard reactions. The ring in question seems quite stable in these conditions, which range from -78 deg C to 75 deg C, which means a lovely degree of freedom. In fact, it looks as though its as stable in THF, if not more so than in Et2O. This is good.

-drone #342


Labrat
Member   posted 10-03-98 08:05 AM          
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Allright, now we're back in business!
The first article you mean is probably Justus Liebigs Ann.Chem. 585: 220-8 ('54). I'll make sure to get that. And that JOC article too.

It's great that the methylenedioxyring is stable to the conditions we want to use, but what did I hear about low yields?

Why do you think that the methylenedioxyring is more stable in Et2O then in THF? If I were you I'd simply use THF. The reason why THF is not so often used, is that THF only recently substituted for diethyl ether. So in the old procedures they always used diethyl ether to do Grignard reactions in. But that doesn't mean that the reaction works best in diethyl ether. Lr/


drone 342
Member   posted 10-06-98 01:28 PM          
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Lr,
Well, I don't have a reason to believe that the Grignard reagent would be more stable in Et2O than THF; I simply found out first that it would be stable in Et2O, then later found out about its stability in THF. Sorry about the linguistic confusion, there.

As you know, its important not to make assumptions about Grignard reactions in various solvents, and I was being cautious about what could or could not be done.


drone 342
Member   posted 10-06-98 01:28 PM          
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Lr,
Well, I don't have a reason to believe that the Grignard reagent would be more stable in Et2O than THF; I simply found out first that it would be stable in Et2O, then later found out about its stability in THF. Sorry about the linguistic confusion, there.

As you know, its important not to make assumptions about Grignard reactions in various solvents, and I was being cautious about what could or could not be done.


Labrat
Member   posted 10-08-98 09:42 AM          
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Drone, I've checked the refs you gave. The JOC article and the Justus Liebigs Ann. Chem. were the most interesting ones.
The biggest concern I can think of is proton abstraction: safrole Grignard would abstract a proton from nitromethane, forming dihydrosafrole and wasting thus one mole of valuable safrole Grignard. But there are more sidereactions possible. This reaction won't give great yields, I reckon.

Furthermore, which product will arise from the reaction between nitromethane and safrole Grignard? A nitrone? A hydroxylamine? I'm not sure here. Lr/


drone 342
Member   posted 10-08-98 09:31 PM          
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The yields won't be in the best, but for conditions, I still like this idea.
True, there are a myriad of potential side reactions, but that's not necessarily a problem Grignard reaction is all about. There are plenty of ways to avoid these. The product of the reactions is a hydroxy amine odixe, meaning that the nitrogen is +5, and that means you still have to reduce the two oxygens off (Al will do the trick.)

The ref's I provided are examples of the ways one can avoid these side reactions; Once the nitro reacts with the Grignard reagent, it no longer is a nitroalkane, which means its acidity drops, and the problems associated with dialkylation are less of an issue as well. This really should work.

-drone #342


Osmium
Member   posted 10-09-98 07:00 AM          
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Nitroalkanes are more acidic than alcohols! They will kill your Grignard instantly. All right, they aren't nitroalkanes anymore, but the Grignard still will be gone. I don't understand this.
 
Labrat
Member   posted 10-09-98 10:18 AM          
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The idea is good, but I don't like the yields!
You admit there are a lot of sidereactions possible here. And you mention that they can be avoided under the right circumstances. But is the protocol still suited for underground organic chemistry or is it more tailored for the laboratory?

And how were you going to solve the problem of nitroalkane acidity? In the articles I read one mole of Grignard is sacrificed for this purpose, but that's unforgiveable in the case of safrole Grignard! It is possible to abstract the proton of the nitroalkane with a metal hydride before adding the Grignard, but you'll need a hard-to-handle metal hydride to do the trick. Sometimes the solution is worse then the problem...

So please, tell me (and Osmium and all the other that read this) how you're going to solve this problem. Lr/


 
drone 342
Member   posted 10-09-98 11:56 AM          
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Os,
...and yet, and yet, I've given references for dozens of examples of where this (the acidity of nitromethane quenching the reaction) is not the case! Like I said, the Grignard reaction is something that is manipulatable -- using the appropriate methods is key, and often times the modifications are as simple as solvent choice.

From a rudimentary overview of the literature, it seems using a mild, aprotic Lewis base like THF as the solvent at temps around 0 deg C should do the trick for conditions.

Admittedly, yields are not quatitative, but I still believe there is the possiblity for improvement. You're right in saying a molar equivalent sacrifice is too high, but I still feel that this is avoidable.

One possible solution is to scrap the idea of nitromethane, and look to something else altogether. Methyl nitrite might be a worthy candidate under the right conditions.

I still feel a Grignard reaction still looks interesting; there are no high temps, the reagents aren't too exotic, and its really not *THAT* bad of conditions to have to manage.

-drone


drone 342
Member   posted 10-09-98 12:10 PM          
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Of course, the possibility exists that this method just isn't going to be "the next big thing". More work needs to be done, but I'm not sure where to go with it beyond here right now. Perhaps this one ought to go on the back burner for a while.
-drone #342


drone 342
Member   posted 10-14-98 11:34 AM          
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Here's the little breakthrough we've been looking for!
for primary amines (like MDA):

RMgX + Reagent -> RNH2

Reagent Ref
NH2Cl JACS, 58, 27 (1936)
JACS, 63, 1692 (1941)
NH2OMe JCS 781 (1946)
HN2O2PPh2 TL 23, 5399 (1982)

for secondary amines (e.g. MDMA):

1.LiNMeOMe,2.H20 JACS 108, 6016 (1986)


My suspicion is that these methods can be adapted somewhat to fit clandestine needs more readily.

-drone #342

-drone #342


Labrat
Member   posted 10-15-98 10:13 AM          
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Great work, Drone! I'll check those refs!
The relevant amine sources are thus chloramine, methoxylamine and HN2O2PPh2. I think that chloramine is best suited for underground purposes. Methoxylamine was very expensive last time I checked. The latter reagent is definitely not suited for underground purposes!

It's interesting they're using a lithium amide, LiNMeOMe, to make the secondary amine.
Maybe lithium methylamide will work too, who knows? Lr/


 
Labrat
Member   posted 10-15-98 10:14 AM          
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Maybe lithium methylamide will work too, who knows?
=>Forget I said that! Lr/
 
Rhodium
Administrator   posted 10-15-98 01:28 PM          
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Say, have Tet. Lett. 39, 5073-5076 (1998) been mentioned yet? They add various lithium amides to styrenes to give phenethylamines.
 
drone 342
Member   posted 10-15-98 02:58 PM          
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Rh,
A bit off topic, yet oh so intersting! As I've demonstrated, the methylendioxy rings are stable in the presence of strong nucleophiles (like lithium amides), and looking at the article, I see they use THF.
With this in mind, its easy to envision isosafrole at 0 deg C, reacting with lithium methylamide. The yields look pretty shitty, but what can you do? Still, quite stylish!

-drone #342


Rhodium
Administrator   posted 10-15-98 06:53 PM          
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The yields are probably pretty low when using the olefin, but shouldn't they be much improved if using a halosafrole instead?
 
drone 342
Member   posted 10-16-98 01:08 PM          
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That's exactly what I originally thought, though LR believes that due to some acidity of the benzylic protons, a strong base like lithium amide or lithium methylamide is going to catalyze the formation of isosafrole.
Originally, what got me thinking in this direction was the Sn2 reactions (which is what you're proposing), can be greatly improved kinetically by two ways: getting a better leaving group, and by using a stronger base. Iodine is about as good as you can do clandestinely for a leaving group (if you can think of a better one, say so), but the base (ammonia or methylamine) could use a little tweeking. By using a metal amide (pKa is around 45), you're gonna have a very fast, very nice reaction. However, a side reaction that may happen is the abstraction of the benzylic proton, followed by the leaving of the halide, resulting in isosafrole.


There is a lot of reason to believe this is the case; there are examples in the literature where a strong base did this to safrole-based compound. However, I still remain somewhat skeptical that this cannot be avoided. I still believe reasonable conditions exist where this side-reaction scenario would hardly occur, and the result would be a very high-quality final product in good yields.

-drone #342