Some results

[Chromic]

No one's going to bite? Damn you! Ok, some preliminary results...

48.6g (.3mol) isosafrole peracetic (isosaffy is known to be 99%+, peracetic aged 95 hours before use at room temp), reaction seemed to go as usual (i.e. exothermic at 5 minutes, and tapered after 20 mins). 60.5g glycol isolated. Rearranged 2.5 hours with 5M hydrochloric (15%) instead of 15% H2SO4, using methanol. 49.1g crude ketone recovered. Distilled 41.8g of light orange-red ketone at 275-295C (most coming over around 285C, this is strange, usually see a light yellow ketone). (btw, does anyone note that this is a 78% yield?! normally the highest yield I've seen before this was 64% yield when using 15% h2so4--and keep in mind, I did not vacuum distill which would up the yield further--and that 64% I saw was using anethole not isosafrole) There was no forerun and little remained in the flask after.

Went to test with some old saturated bisulfite sol'n hanging around (still stunk like SO2 so I figure it's okay), but it came up negative (not even chicken fat formed...)

Uhoh. What is this oil? Doesn't smell like isosafrole. Smells like what I remember ketone to be. What could it be?

What should I recommend to this person to do? ... distill again? throw it out? aminate anyways?

[Chromic]

The oil was then fractionally distilled... kept what came across at 280-290C, most came across at 286C (80% of the oil was recovered). (about 10% was <280C, other 10% turned to crap in the flask) This is light yellow, smells like ketone, flows like ketone... I just don't get it!?! Perhaps his bisulfite has gone bad...

[Vitus_Verdegast]

Went to test with some old saturated bisulfite sol'n hanging around

Bisulfite solutions are not something you want to keep for long, as the bisulfite will oxidize to bisulfate. SWIM had this problem once too, he tried to form the addition compound with a substituted benzaldehyde using an old aqueous solution of NaHSO₃ (also smelled/stank like SO₂ does) but failed, so he figured the bisulfite must have been oxidized. Then freshly made NaHSO₃ solution was tried, which worked without problems.

[Chromic]

V_V, you're right on the money. Thank you! *hugs*

This ketone of a friend's is good, infact, great! It turned to slush in about 1-2 minutes in the freshly made bisulfite solution (normally this can take 5-60 minutes)

May I make a suggestion to any other bee to try using a 15% HCl rearrangement? Write-up is as follows (attentive bees will notice this is actually 5M HCl):

From the extracts from a peracid rxn containing .3mol isosaffy (48.6g), the glycol is added to: 75mL MeOH, 125ml H2O then 125ml 31.25% HCl. The mixture is refluxed 2.5 hours, the oil drained from the bottom of a sep funnel and further extracted 3x60ml DCM. The ketone distilled and at least an 80% yield can be had...

I'm expecting this yield to be closer to 85% if this guy had a better lab. This really is phenomenal if it's as good as it appears to me. I always heard of 60% yields with the peracetic/performic (likely because of the losses in the acid-catalyzed rearrangement), and I knew it's possible to hit 70% with a proper vacuum distillation... so I wouldn't be surprised if one can hit 85% of theory using this HCl rearrangement. It's almost as great as Ritter's work on the tosic method, and certainly a lot more OTC.

[Chromic]

This is a 14% higher yield than I've ever seen before... plus uses an easier to find, handle, and prepare acid.

[Rhodium]

Effect of various acids at different concentrations on the pinacol rearrangement
Monica De Lezaeta, Wajiha Sattara, Paris Svoronos, Sasan Karimi, Gopal Subramaniam

Tetrahedron Letters 43(51), 9307-9309 (2002)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pinacol.various.acids.pdf)
DOI:

10.1016/S0040-4039(02)02379-1

Abstract
The formation of side products in the pinacol–pinacolone rearrangement was studied as a function of concentration and strength of various aqueous acids using 1H NMR spectroscopy. In all cases, pinacolone was the principal product and in most cases, its relative yield decreased with respect to 2,3-dimethyl-1,3-butadiene, when the acid concentration was lowered or the corresponding conjugate base was added.

[Chromic]

Forms the ketoxime just fine. In fact the ketoxime is white, I thought he had fucked up and it was the inorganic salt that always forms... before it's always been off-white. This is some nice ketone. I highly recommend this method to any other bee who may be reading this.

P.S. please, someone, confirm this! if this is as easy as it seems, it should go into the peracid faq ASAP.

[Antibody2]

thats really cool chromic!

[Chromic]

There was 17.9g of amine hydrochloride from 15.1g of ketone (this yield is before recrystallizing--btw this is 92% of theory from a Al/Hg). The yields on the ketoxime were likewise really good as well.

Somebody--anybody test this... I haven't heard of a smoother rearrangement in my life. (with exception of the tosic acid method that Ritter, Scoobie Doo and others mentioned) People using H2SO4 may just be throwing away 15% of their potential ketone (plus getting more crap from undesired side-reactions).

P.S. the yield on 50mmol of ketone was 92%. (8.8g ketoxime from 8.9g ketone)

[Chromic]

I wonder if this may be a decent way to TMA-2. An H2SO4 rearrangement will really chew up the asarone oxidation product (glycol, monoacetyl glycol, epoxide, whatever it is)--although it most definitely works. I wonder if this rearrangement would be more gentle and give a better yield of asarone's ketone.

[Antibody2]

that would depend chromic, if the asarone survived the peracetic rxn. My impression was that asarone decomposed/polymerized in the oxidation step not the hydrolysis step.

This assumption is based on some old pseudonitration experiments i did with asarone using HOAc as the solvent. The asarone became a purple ball of tar when left nitrating in HOAc overnight. I don't know for certain that it was the GAA alone that caused this or whether the NO2 played a role as well.

As well, goiterjoe did some peracetic trials on asarone with no sucess as far as i know, but again i am not sure if it was the oxidation or the hydrolysis that failed. Ask him.

[Chromic]

I made tma-2 with the peracetic in DCM--the problem was not the oxidation.

The problem was the H2SO4 hydrolysis. The asarone epoxide that came out of the peracetic was beautiful. The ketone was however crap, no better than 25-50% pure if I had to guess. It still made good tma-2 through your oxime reduction... I tripped my balls off and thought I was going to die.

That's why I'm wondering about the HCl hydrolysis. Does no one make ketones anymore? Come on guys! This could be a revolution for anyone using peracid techniques. (oxone, peracetic, performic)

edit: the hurry is that a lot of bees might be wasting a good part of their yields (and precious isosafrole). If this works, I'd like to see the word get out asap on rhodium's site. okay, sure, I'm impatient...    btw it's good to hear that someone else will test this out as well.

[hypo]

what's the hurry? i'll try this on iso-myristicin, but please
give me a few weeks.  

[otto]

hi Chromic,

otto has had the same experiences. the asarone epoxide has been made nicely using bleach but then h2so4 hydrolysis gave only 30% yield of the ketone after purification (chromatography).

otto

[hellman]

This is an incredible achievement,

Is this an otc dream, this with the peracetic, performic(oxalic+glcerin), many bees fear is further reduced,

Excellent chromic, this should be written up everywhere,
This is especially handy to oz bees, that have no access to h2so4, this is a great way!!!

Well done

hm

[amine]

Wow, as we speak, swim has the most beautiful ketone distilling a light green color comming over at around 147C.  Swim used chromics technique and wow, it is sooooo much easier than the H2SO4 hydrolysis, the reaction looks clean throughout and you can see product formation, the syruppy glycol slowly turns into globules of a dark golden color. The rest of the solution remains orange.
Post reaction a beautiful dark golden oil falls to the bottom.

Wow....this by far is the cleanest method swim has used.
Props to chromic.

had swims vacuum adapter break but swim ghetto rigged something that works (using a 2 neck 500ml flask...) and a stopper with a hole in it.

[ApprenticeCook]

Hellman - This is especially handy to oz bees, that have no access to h2so4, this is a great way!!!

Jesus could you be any more WRONG! oz bee, speaking from ACTUALLY BEING ONE access to sulphuric acid is a peice of piss.... waltz your ass to ANY (no sources from me) and say "hey can i have some car battery acid 98%?" and all they say is "OK that will be $4 a litre" fuck sake....    the bottle has written on it in big fat ass letters H2SO4 98% along with all the normal crap danger blah blah blah....

NO ACCESS my ass.... cant name a source but if you think hard enough you'll figure it out... hellman may not though..

[Vitus_Verdegast]

He doesn't seem to know that the degree of industrialization of a country is measured in the tonnes of sulfuric acid it consumes every year.  

[Vitus_Verdegast]

Preparation of 2,3-dimethoxy-4,5-methylenedioxyphenylacetone by buffered performic acid oxidation of isodillapiole, followed by Pinacol rearrangement of the intermediate glycol (formyl ester) using aqueous hydrochloric acid.
by Vitus Verdegast

In a 1L three-neck flask, set up with an addition funnel, was added 29.5 g (0.142 mol) isodillapiole dissolved in 55 ml dichloromethane, followed by 7.1 g (0.08 mol) sodium bicarbonate. To the addition funnel was added a solution of performic acid, which was prepared an hour before by mixing 30.6 g (0.225 mol) 25% hydrogen peroxide and 29 ml (35 g, 0.645 mol) 85% formic acid. This was added dropwise to the stirring suspension in the flask, which caused a lot of foaming due to the liberation of CO₂. The addition took around 90 minutes, and the two-phase mixture was allowed to stir for an additional 16 hours. At the 3 hour point, a TLC was done on a sample (solvent: methanol, detection: iodine vapours) which showed a large spot -presumably of both the glycol and glycol formyl ester- and only a very minor spot of isodillapiole, so it is safe to say that most of the olefin was consumed at this point.

The organic layer was separated and washed twice with water. The dichloromethane was distilled off and the resulting dark-red oil was taken up in 40 ml methanol. To this was added 60 ml water, followed by 60 ml 29.5% hydrochloric acid. This mixture was refluxed for 3 hours and after letting it cool to room temperature, the dark oily precipitate was separated, and the mother liquor extracted once with 60 ml dichloromethane. The extract and the oil were pooled, washed twice with water and once with an aqueous NaHCO₃ solution. The washings and the mother liquor were pooled and a small amount of oil was separated off and added to the organic solution¹. The dichloromethane was distilled off, then vacuum was applied and 17 g of greenish-yellow 2,3-dimethoxy-4,5-methylenedioxyphenylacetone came over at 195°C at the fridge pump (50% overall yield)².


1. TLC (solvent: petroleum ether, detection: iodine vapours) showed that all glycol (formyl ester) was consumed and the post-reaction extract gave a single spot of the ketone, at a somewhat lower Rf value than the former. It must be noted that both the glycol (formyl ester) and the ketone contained an impurity which did not elute with this solvent system.

2. The somewhat low yield was due to the use of an insufficient vacuum, as during the whole distillation smoke was seen entering the receiver. The column was warmed with an electric insulating mantle to prevent massive polymerisation caused by heating the oil too long. To obtain better results, the boiling point of the ketone must be kept under at least 185°C, as was observed before by Antibody2 ³. A dark, viscous, sharp-smelling residue was left in the distilling flask, which solidified on cooling. The colour of the ketone went from greenish-yellow to a more golden tint after standing an hour at room temperature.

3.

Post 250280

(Antibody2: "Complete synthesis of DMMDA-2 and DMMDMA-2", Methods Discourse)

[Vitus_Verdegast]

Here is what you asked for, although the final part is probably not what you wanted   .
I should have known that my good friend the fridge pump would not be able to do the job properly, but at least it is proven that it is possible to obtain a workable amount of 2,3-dimethoxy-4,5-methylenedioxyphenylacetone using a fridge pump (or an aspirator for that matter).

I'm thinking of trying your procedure again with a lower boiling ketone, like 4-methoxyphenylacetone, to get a more accurate view on the differences between using HCl and H₂SO₄.

While we are at it, by the way, does anyone know of some good parfumery formulas? I was thinking of utilizing these good scenting compounds (especially the latter 4-methoxy compound) in deodorant or candles maybe.

[Vitus_Verdegast]

These are the Rf values for those who are interested:

silica gel plates, solvent methanol:
dillapiole: 0.58
isodillapiole: 0.57
isodillapiole glycol (formyl ester): 0.52 (taken during performic oxidation after 3 hours of stirring)

silica gel plates, solvent petroleum ether:
isodillapiole glycol (formyl ester): 0.07-0.15 (a streak rather than a spot, probably due to mixture of glycol and ester?)
2,3-dimethoxy-4,5-methylenedioxyphenylacetone: 0.05

[ephemeral]

Could advice be given on the appropriate ratio of acid to glycol for rearrangement.
 The acid molar concentration is there, but swim didnt see how to extrapolate an acid/glycol ratio.  Sorry if it was missed, TFSE is down right now and cant get to a library for a little while.

 Thanks

[hypo]

but same problem as vitus: major scorching, so no difference
between HCl/H2SO4 noted. otoh needing only catalytic amounts
of H2SO4 is a huge plus on the aquisition side.

[hypo]

the ketone crystallised overnight to give pretty yellow crystalls,
making me believe that it's of outstanding purity. but the oxime
oiled out. at least the oil is clear and not yellow like it used
to be with H2SO4-ketone. i wonder if MMDP2P needs longer for oximation?

[Rhodium]

I found these references for the myristicin ketone mp:

55°C (from H₂O) Scandola; AANLAW; Atti Accad.Naz.Lincei Cl.Sci.Fis.Mat.Nat.Rend.; <5> 21 I; 1912; 49.
(prepared from either isomyristicin dibromide or from beta-nitro-isomyristicin)

49-50°C Takeya, Tetsuya; Okubo, Toru; Nishida, Shoichi; Tobinaga, Seisho; Chem.Pharm.Bull. 33(9), 3599-3607 (1985)
(prepared by Fe/HCl reduction of beta-nitro-isomyristicin)

The oxime is described as prisms, mp 111-112°C (from petroleum ether), referencing Scandola above.

[hypo]

no mp of the ketone was taken. next time.

the oxime is starting to crystallise.  

[Aurelius]

Take a small amount of your oxime back to the ketone- then take the mp.  And be sure to take the mp of your oxime.

[hypo]

> And be sure to take the mp of your oxime.

crude oxime (took 3 days(!) to crystallise):
mp: about 98°C
color: white with a hint of yellow
smell: a hint of the ketone
no recrystallisation will be attempted.

> Take a small amount of your oxime back to the ketone- then take the mp.

what for? the identity is well known.

two notes:
a) H2SO4 rearrangement never gave crystalline oxime. fractionating was
never an option due to scorching.
b) only 50% (pretty exactly!) of the oxime crystallised in the above
way. the rest oiled ot as orange oil on addition of more water. but
this fraction is starting to crystallise too. so my suggestion is to
not add more water than given by sonson. the alcohol (ethanol in this
case) seems to hold the impurities better than the oxime.

[otto]

TMP2P from asarone¹

100 mL tap water, 5 g Na2CO3, 3.5 g KBr (30 mmol), 100 mL acetonitril, asarone (5 g of a 90% pure batch, from vacdest of etheral oil of calamus, 21.4 mmol), were put into a 500 mL beaker. Under magnetic stirring bleach solution was added in portions of 10 mL three times over 10 min. A TLC of the upper phase showed remaining starting material² and more bleach was added in 1 mL portions (to a total of 36 mL, titrated to be 1.25 mmol/mL, 45 mmols, 2.1 equivalents) until the dissapearance of asarone on TLC. Stirring was continued for 25 min. Then, the upper phase was separated and the lower aqueous extracted twice with 50 mL of ethyl acetate. The combined organic phases were rotavapped and to the residue were added 30 mL of methanole and 100 mL 15% hydrochloric acid. This mixture was kept at 75°C for 90 min with stirring. After cooling down, the mixture was extracted three times with 30 mL of CHCl3. The combined extracts were rotavapped and the residue vacuum-destilled³. 2.16 g (45% molar yield) of a dark yellow oil with the typical smell of TMP2P.

This is the highest yield otto has obtained so far for this reaction. May be 90 min rearrangement time is too short and 75°C are too low a temperature. However, we clarly see that HCl is superior to H2SO4 in rearrangement also for TMP2P.

[1] according to a previous experiment (

Post 427073 (missing)

(otto: "the next day otto tried it.", Novel Discourse))
[2] Rf values in

Post 427073 (missing)

(otto: "the next day otto tried it.", Novel Discourse)
[3] during vacdest there was a lot of bumping. This could possibly be circumvented by drying the compound prior to destillation.

[psychokitty]

"There was no forerun and little remained in the flask after . . ."

Chromic:  Do you think that then that the final undistilled ketone product from your aqueous HCl glycol dehydration is clean enough to be used directly in the next reductive amination step?

If so, this new application of HCl could allow one to go directly from the starting alkene all the way to the final amine-HCl without any need to purify the intermediates via possibly unneccessary distillation steps.  Hence, in the future, crystallization of the final amine-HCl might prove to be the only real purification step necessary to get a clean product.

This is just a suggestion for those bees who have often wondered whether tedious vac distillation -- or even just simple distillation -- of intermediates would forever remain necessary.

[Rhodium]

I believe that it would be a *very* sucky idea to skip the ketone distillation. There are surely other carbonyl-containing products formed in the peracid oxidation/acid rearrangement procedures, and the Al/Hg will aminate any aldehyde, ketone or carboxylic acid in that mixture. I doubt that a simple recrystallization will remove all those byproducts reliably.

[psychokitty]

First and foremost, we are scientists here at the Hive.  I'm only interested in determining the full dynamics and parameters of this popular synthesis.  There is valuable scientific knowledge to be had in knowing that one COULD -- theoretically speaking -- carry this synthesis straight-through without the need for vac distillation or simple distillation along the way.

But for what it's worth, I completely agree with you that crystallization at the end would likely not be good enough to remove all of the by-products.  While some may find this alarming, I would say purity of the final product for CONSUMPTION is an area of concern for the black market, fundamentally both a legal and health issue, and not one that should necessarily be limiting to the field of scientific research.

I merely intersted in proving one thing:  That this synthesis can continue to provide relatively pure intermediates by changing the reaction conditions. 

That's all.

[abolt]

In a 3L flatbottom flask, fitted with a condensor and magnetic stirring, was added 600 ml dichloromethane and 56 g sodium bicarbonate followed by 180 g (1.11 mol) isosafrole. A solution of performic acid, prepared from 120 ml 50% hydrogen peroxide and 230 ml 85% formic acid, was added dropwise over the course of 3 hours, and the mixture was allowed to stir for an additional 22 hours. The organic layer was separated and washed with 3x 200 ml distilled water. After evaporation of the solvent there was left 255 g of a dark red oil, which was stored in the refridgerator for 12 hours, after which it took on the viscosity of motor oil.

The dark red glycol was dissolved in 250 ml methanol in a 3L flatbottom flask fitted with condensor and magnetic stirring, 400 ml distilled water were added and the mixture was heated to reflux with stirring. 430 ml 30% HCl was added and refluxing was continued for 3 hours and the contents were allowed to cool to room temperature. The bottom dark oily layer was separated off (honey-mint smell) and the aqueous layer was extracted twice with 200 ml DCM. The oil and extracts were pooled and washed twice with 200 ml distilled water, once with 300 ml 10% NaHCO3, and once with 300 ml brine. The bicarbonate washing took on a brown color, the other washings were clear. The solvent was stripped off and the residue was distilled with aspirator vacuum: first came a small forerun (15 ml) of isosafrole, followed by 133 gr rose/golden 3,4-methylenedioxyphenylacetone, an overall yield of 67%.

MDP2P was tested positive with bisulfite.

The remainder left in the distilling flask was 25-28ml tar, which had some transparency to it. Aside from the extra yield, this hydrolysis also seems much cleaner, in appearance and work up.

Previous yields using H2SO4 hydrolysis were around 50%.

Well done Chromic.

[Rhodium]

The Pinacol Rearrangement
Clair J. Collins

JCS Quarterly Reviews 14, 357-377 (1960)

(https://www.thevespiary.org/rhodium/Rhodium/djvu/pinacol.rearrangement.review.djvu)