P2P's from aryl halides and acetylacetonate

[Bandil]

High Bees!

The following post by Lego has sparked my interest:

Post 464635 (missing)

(Lego: "P2P from bromobenzene/CuI/Acetylacetone", Methods Discourse). Obvisouly this means that the ideas has to be tested on various interesting substrates. The first compound i have chosen to test is 5-bromo-1,3-benzodioxole to MDP2P.

As the substrate is a bromo substituted halide and not a iodo substitudedhalide, the reactiontime is about 30 hrs. This means that the results from the reaction wont be presented untill monday (i dont have internet at home yet - so I can post before that). This is what happened anyway:

The following reagents/solvents where used:

500 mL DMSO (99%+ purity)
3,8 g / 20 mmole CuI (99,999%+ purity   )
8,5 g Na₂CO₃/ 80 mmole (99%+ purity)
40 g / 0,4 mole AcetylAcetone (99%+ purity)
40 g 5-bromo-1,3-benzodioxole / 200 mmole (97%+ purity)

The DMSO was placed in a 2 L RBF and put in an oil bath. CuI was added in one portion. This caused the solvent to take on a beautiful green color. Immediately after Na₂CO₃ was added. The color switced to a pale opaque green. Acetylacetone was then poured into the mixture. This caused quite a spectacular reaction. Immediately the mixture turned very deeply green and after 10 seconds it turned bloody-red. After one minute the 5-bromo-1,3-benzodioxole was added. This caused the solution to turn even more deeply red. The whole shebang was submerged in an oilbath and stirring was commensed at 120 ^oC.

The workup will be commensed tomorrow morning. Hopefully it'll give some nice results   .

Finally i have a few questions regarding the workup. The article says that the deacetylation can be done in the same pot as the reaction. Exactly what does this mean? Should i simply add the NaOH mixture once the reaction is done? Or do they extract the mixture first and then treat the crude reaction with NaOH? Finally, how dilute should the NaOH mixture be, and how much is to be used?

I'll follow the thread up with results. Just got access to GC-MS and HPLC-MS, so i'll analyse whatever comes out of the porrage  

The following substrates will also be tested once the schedule time is right:

Iodobenzene
2,5-dimethoxybromobenzene
p-isopropoxy-bromobenzene

Regards
Bandil

[GC_MS]

I'll follow the thread up with results. Just got access to GC-MS and HPLC-MS, so i'll analyse whatever comes out of the porrage

From my experiences in brominating 1,3-benzodiole, I remember that one of the contaminants was the dibrominated product (although present in only very small amounts). It would be interesting to know if you have the same impurity present, and if yes, how it reacts in further syntheses.

The dibromo was, off course, easily removed via distillation. When working with MS, I assume you know bromo compounds should be easily distinguished from not-bromo containing substances.

Maybe you have access to GC-ECD?  

[Bandil]

The substrate was not something i whipped up myself. The source of the compound is as reliable as they get, so i'm quite sure that the dibromo-compound is very non-present  

[Bandil]

After 48 hrs. at 120 degrees the reaction vessel was removed from the oil bath and 500 mL 10% hydrochloric acid was added in one portion. After stirring for 30 mins, the mixture was extracted with 2 X 100 mL's DCM. Both phases were very dark and a separation line was very hard to spot; but with the aid of a flashlight it was found. After separating the phases the DCM was evaporated at atmospheric pressure.

Warning: Apparently the reaction generated monohaloacetone of something like it, because i was weaping like a little girl for 10 mins after approaching the reaction vessel.

The remains where removed by proper distillation. The sludgy remains where mixed with 200 mL 15% NaOH and stirred for 45 mins. The reaction was quite exothermic, so something did happen   . I tried to extract the mixture with DCM, but separation was completely impossible. It turned out as a dark-black ugly porrage; damn...

This is where i left it. The mix is sitting in the frigde untill tomorrow. I'll attempt to remove the DCM under reduced pressure, and then perform steam distillation on the water phase to recover the product. Hopefully it'll turn out nice.

All in all the reaction is quite difficult to work with and produces very nasty gasses; so it's not on my favorite reaction list yet   .

I'll post the final verdict monday morning!

Have a good one!

Regards
Bandil

[Bandil]

Yeah, now things are starting to look really good!

The porrage which remained from the attempted separation last time, was placed in a 2 L RBF and the DCM was distilled of at atmospheric pressure. After stripping the DCM, steam distillation was commensed.

400 mL's of water was added to the mix, and the whole thing was heated using the oil bath. Within a short time a nice stream of water, with small oily droplets in it, started coming over in the reciever. After 350-400 mL's distillate was collected the oily droplets where no longer present and the steam distillation was ceased. The distillate was somewhat opaque with a nice and yellowish oil floating on top¹   . The water was saturated with NaCl and extracted three times with 75 mL's DCM. Separation was a breeze and the slightly yellow colored DCM phases where dried with MgSO₄ and placed in the freezer for final work up tonight. A small sample of the DCM phase was stored in a micronix tube and shipped of to GC-MS analysis along with a sample of the pre-NaOH mixture. So far things are looking really good and I have very high hopes for the result    Hopefully i'll have the yields for you guys/guys'ettes tomorrow. The GC-MS analysis should be here in a few days. I have taken pictures along the way, so i'll make a nicely coherent writeup of the reaction once everything is done.

Have a nice one!

Regards
Bandil


(1)
The original bromobenzodioxole compound was a brown and ugly mess, so it's definately not the bromo compound.

[Bandil]

Alas this reaction did not work for the MD halogen compound   . The DCM phase was stripped of solvent and fractionallly distilled under aspirator vacuum. At 110^oC-115^oC 21.5 grammes of a prismatic oil (actually looking like safrole, but not with the right smell), came over. Both the temperature and the appearence of the oil was far from MDP2P, so something obviously happened. The oil is curretly being analysed on a GCMS and NMR to figure out what the heck it is. A sample from the first reaction is also analysed, to figure out where the reaction went wrong.

I have made a preliminary writeup XXX about the whole reaction. The GCMS + NMR analysis will be included in the writeup tomorrow, so if you (Rhodium) want to use this experiment for anything, such as upload please wait a day or two untill the final results are presented.

I'll retry the reaction with iodobenzene to confirm it with a know-to-work substrate...

Regards
Bandil

[Bandil]

GOD DAMMIT!!!

I'm not even smoking weed at the moment, so how can i be so stupid? I used 1/10 the amount of required sodium carbonate. That's the second ten fold error i have made in two weeks. Why oh why don't i have some drug addiction to blame these kinds of errors on.

I will dig myself down under some rock and try the reaction again within the next few days.

Someone please give me a virtual kick in the butt - i surely deserve it   !

Regards
A non stoned Bandil

[Xicori]

Keep it up, bandil! - very interesting work, indeed!

I´ll enjoy the further experiments and the LC/MS-data you will post here soon  

This 10-fold errors may happen from time to time, and they are especially painful... i made this once before using way to less (1/10) AlCl₃ in a friedl crafts acylation...    always doublecheck the calculations before starting... but the enthusiasm is the driving force  

so, i wish you good luck with your experiments! - would indeed be a very nice P2P-source!

xicori

[homeslice]

Definately keep it up. When i was readin your 2nd or 3rd post talking about yellow oily droplets coming over, i was like no shit... heh then i glanced down and seen the title to the next post: Failure. I was like fuck... hehe

Interesting read to say the least. I like how ya kept us updated step by step    Definately keep it up.

[Bandil]

I did not analyse the oil from the previous reaction using the GCMS + NMR... Slight waste of resources IMO  

Allright, the new reaction is running on it's 12'th hour about now. Here's what happened:

Reagents:
500 mL DMSO (99%+ purity)
3,8 g / 20 mmole CuI (99,999%+ purity )
86 g Na₂CO₃/ 80 mmole (99%+ purity)
40 g / 0,4 mole AcetylAcetone (99%+ purity)
40 g 5-bromo-1,3-benzodioxole / 200 mmole (97%+ purity)

The Reaction:
Most of the DMSO was placed in a 2 L RBF and submerged in an oilbath at 120^oC. The acetylacetone was added in one portion, and the beaker rinsed with some DMSO to get everything over. Immediately the dry Na₂CO₃ was added with heavy stirring. After a few minutes the CuI was added aswell, causing the reaction to go very pretty light green -> dark green over two minutes. After everything seemed to have stabilized the bromocompound was added in the remaining DMSO. The resulting solution was a nicely dark green one (much prettier than the last experiment where it resembled something following heavy diarrhoea). The flask was covered with some foil and stirred while sleeping like a pretty little princess.

Keep your fingers crossed!

Regards
Bandil

[homeslice]

Now i havent read much or know much from reading about reactions outside the scope of mdma so this might be a dumb easy question, but, why the foil on top of the flask?

[Xicori]

I think bandil used the foil to keep back the noxious, nasty fumes that he recognized at the first run  

good luck on your rnx!

[Bandil]

@Xicori>
Right on  

Additionally they use inert atmosphere in the article, so i thought it was a half-way-descent way of keeping atleast some of the atmospheric crap out of the brew!

The reaction was quenched with dilute HCl last night. Unfortunately i had to use ALOT of acid to kill the last carbonate, which meant that the total volume of the fluid was above 1 L. A small sample was taken out and sent to GC-MS / NMR analysis. Untill 5 minutes ago I only had a 1 L sep funnel as the largest, so i had to wait untill tonight with separating the stuff with my brand new 4 L sep funnel  

I apologize the delay...

Regards
Bandil

[Bandil]

The water/acid/DMSO/diketone phase was extracted three times with 90 mL's of toluene. The toluene phases where separated from the rest. It was totally impossible to get a clean separation so the toluene extracts had 70% more volume after separting. This obvisouly means that a shitload of water/DMSO is present. In retrospect i can see that toluene was a poor choice of solvent, as the BP is higher than that of water. This means that the solvent cant be stripped plain and simple, without risking alot of product being steam distilled out of the mixture.

I am planning on working it up in the following manner (feel free to make suggestions if you have some ideas):

1: The Toluene/water is azeotropically distilled using a Dean Stark trap to remove the water, while keeping the product in the tolly phase.

2: Most of the toluene is stripped under vacuum.

3: Basic hydrolysis of the diketone followed by direct steam distillation.

4: Keeping my fingers crossed!

Regards
Bandil

[Nicodem]

I might bee wrong but I think a steam distillation effect is possible only when you have a two phase system.
I don't think there is a lot of water there. If you do a wash or two with brine and then dessicate over MgSO4 of Na2SO4 it should bee just fine for the water, but the DMSO will just hang in there.

[Xicori]

high!

so you should strip also most of the DMSO unter vacuum, this shouldnt be much of a problem! Then i would suspend the remaining product in water and steam distill...

good luck!

[Lilienthal]

With repeated plain water washes you should be able to get rid of the DMSO. With less DMSO in the mixture you will also get a better phase separation. For the first extraction use a large excess of water (maybe divide the reaction into several portions so everything fits into your separating funnel).

[bio]

While this seems logical it is not correct. I found this out the hard way recently. The PhMe/H20 azeo at about  84deg did carry some amine with it even thru a short wire coil packed fractionating column. When I took the 96-101 degree fraction to steam out the product about 20% was missing from expected, couple days later it occured to me it might be in the 82-92deg fraction which I had saved. Sure enough it was in there! My product boiled at about 215deg 760mm so a higher boiling compound might not have co distilled.

Brine washes will get the water out even if you have to do 3 equal volume washes it is easy and fast (usually).

[Bandil]

Hi!

I am currently awaiting GC-MS results on the final product. It came over at 135 ^oC under aspirator vacuum. Safrole usually comes over at 110^oC, so it's not looking to shabby!

I have a complete HTML writeup with pictures and everything ready the second the GC-MS analysis is here! Just want to make sure that it actually did work, so i won't make an ass of myself!

Regards
Bandil

[Bandil]

 *SOB*  

The GC-MS analysis results just came in. The product was very pure indeed, but alas it was the original bromo compound (95% of the fraction). It seems that if any diketone/ketone formed, it was extremely small amounts...

It seems strange that the methylenedioxy-bridge should make it THAT unreactive? Is it certain that the carbonate is a strong enough base to deprotonate the acetylacetone? Perhaps sodium hydroxide would deprotonate it better? Any suggestions for making this stuff work?

Oh well, guess i'll try it out on iodobenzene now to confirm the synthesis first...

Regards
Bandil