Possible improvements of vanillin demethylation.

[Antoncho]

SWIM is recently broke so having nothing to do in the lab for the absence of essential chem's, he constantly annoys Antoncho w/crazy ideas, however sometimes making him curious.

This one is derived from the startinout's excellent research on eugenol demethylation. A topic so exciting for us, the sassafras-deprived. So far, from all of the routes tried only one was successful, the one w/pyridineHCl in microwave.

Now SWIM's primarily interested in demethylating vanillin since it was his impression that eugenol is very hard to deal with. Basically, there currently are two proc's at the Hive for this: 1st by Rhodium requires pyridine, AlCl3 & DCM; the 2nd by Startinout/Psychokitty - pyridine hydrochloride. Pyridine evrywhere

So the question Antoncho wants to ask the maitres is: from the chemical mechanics' point of view is triethylamine or triethylamine*HCl a conceivable alternative? From what Antoncho knows they're both strong bases and very often are employed in the same rxns. Pyridine HCl's mp is 145 and bp - 242 C, and triethylamine HCl only melts at 260 C - that should make a serious difference...

Also, is it proper to assume that by heating 1 mol NH4Cl w/3 mols CH3CHO at highest possible temp and for long enough time one will get triethylamine? - that assumption comes from Rhodium's Methylamine FAQ.

And one more note concerning the 1st route startinout researched, AlI3 in benzene/PTC. Someone named Assholium, in one of his Russian post, once said about this rxn smth like this: "...it can bee done, but the real problem w/these rxns is that the end product is extremely sensitive to the traces of Lewis acid catalyst, and if not washed from it very thoroughly, invariably turns to crap overnight" Having carefully read through startinout's posts i noticed that it was never done, and the whole picture falls in w/Assholium's hypothesis pretty well.

A curious note about using hydroquinone as a polymerization inhibitor is also found down the thread in the HI route by scooby_doo.

Anyone can develop these ideas somehow?

[Rhodium]

Triethylamine is a viable alternative. In the original article using Pyridine/AlCl3 they also tried an equimolar amount of triethylamine instead, and got about 25% lower yield, but it worked.

I don't think triethylamine can be made from acetaldehyde in the same manner as trimethylamine can be made from formaldehyde, as that reaction is a very special case. It can however be made by alkylating ammonia with an ethyl halide, and then distilling the triethylamine from the mixture of primary, secondary and tertiary amines produced.

[terbium]

Now SWIM's primarily interested in demethylating vanillin since it was his impression that eugenol is very hard to deal with.

You are suggesting that your impression is that the demethylated eugenol is less stable than the demethylated vanillin? Is this correct?

[foxy2]

I have a reference on demethylation of a methylated olivetol derivative to olivetol using 45% HBr and acetic acid under reflux. 70-99% yeilds

j. Am. Chem. Soc.
1987, 109, 3098

And a similar compound was demethylated using an excess MeMgI.
Although yeilds in this case were poor.

j. am. chem. soc.
1948, 70, 4127
Do Your Part To Win The War

[Antoncho]

Hmmm.... Haloalkanes and ammonia, you say? Interesting...

Say, to make the proc. a little simpler, why not use isopropyl chloride - while being easily made and cheap, it has a charming advantage of being a liquid at room temp(bp 37 C). Whadd'yathink,  is triisopropylamine better/worse/same compared to pyridine and triethylamine? Is it too hindered, maybee?

As a side note, let me mention that, if proper proportions are used , the only byproduct of iPrCl's rxn w/NH4Cl will bee a PTC - which, BTW, can't bee had from dryer sheets (just what IS a dryer sheet?) where SWIM lives.

I couldn't find iPr3N's bp , but by extrapolation from the analogues it should bee ~120 C.

Here's another loose end to explore...

Foxy, this HBr thing surely looks interesting! Can you by any chance het this ref.? Can anyone?

Terbium: yes. At least such was startinout's opinion.

Antoncho

[Rhodium]

Triisopropylamine is a little bit too sterically hindered to be readily formed from isopropyl halides and ammonia, the most common crowded base I think is Hünigs base (Diisopropylethylamine, used from time to time in Tihkal).

[Antoncho]

Here's another route (US 5,728,888):

Preparation of 2,2',4,4'-tetrahydroxybenzophenone

440 g (3.30 mol) of AlCl.sub.3 were stirred into 120 g (1.64 mol) of dimethylformamide in such a way that the temperature remained below 160.degree. C. After cooling to 30.degree. C., 60.5 g (0.20 mol) of 2,2',4,4'-tetramethoxybenzophenone were introduced into the mixture, which was easily stirrable. The mixture was stirred at about 50.degree.-52.degree. C. for 4.5 hours and then added to 1.8 l of water to which 3 g of active carbon had been added. The hydrolyzate was filtered at about 95.degree. C., and then 65 g of concentrated hydrochloric acid were added to the filtrate. The precipitate was filtered off with suction at 25.degree. C., washed with water and dried at 125.degree. C. under reduced pressure.

Yield: 45.5 g

Melting point: 198.degree.-200.degree. C.

Purity (HPLC): 99.2%.


Example 4

Preparation of 2,2',4,4'-tetrahydroxybenzophenone in the presence of urea

54.8 g of 2,2'-dihydroxy-4,4'-dimethoxybenzophenone (0.20 mol) were reacted with 400 g of AlCl.sub.3 (3.0 mol) and 120 g (2.0 mol) of urea as in Example 3, and the product was worked up as described.

Yield: 40.3 g

They say when a large excess of AlCl3 is used the yields are esp-lly good  

Hey, BTW, AlCl3 is soluble in CHCl3. So i guess it can bee made by chlorination of Al powder in it. Does anybee know if it's soluble in DCM or CCl4?

Antoncho

[foxy2]

Method for dealkylation of alkyl-aryl ethers

Patent US4695659

A method is disclosed for the dealkylation of alkylaryl ethers by reaction with aluminum triodide under reflux. The reaction is carried out in the presence of a catalytic amount of a quaternary ammonium iodide in a substantially non-aqueous organic solvent. The reaction product is then hydrolyzed with water. The quaternary ammonium iodide can be of the formula R4N+I-, wherein R is alkyl, and the solvent is preferably benzene or cyclohexane.  (In their claims they say that toluene or xylene also work, but give no examples/yeilds.)

EXAMPLE 1
Aluminium powder (2.5 g, 93 mmol) and iodine (19.0 g, 150 mmol) were mixed in 130 ml benzene (or cyclohexane) and were refluxed until the red colour of iodine disappeared (about 1.5 hours). The mixture was cooled. A solution of anisol (phenyl-methyl ether, 5.4 g, 50 mmol) and n-Bu4 N+ I- (tetra-n-butyl ammoniumiodide, 0.05 g, 0.14 mmol) dissolved in 25 ml benzene (cyclohexane) was added dropwise. The mixture was heated and was refluxed for 20 min, then cooled and hydrolysed with 150 ml water. The organic phase was separated and the water phase was extracted with 2.times.25 ml diethyl ether. The organic phases were collected and were extracted with 30 ml 2 molar NaOH. The water phase was separated, acidified with concentrated HCl and was extracted with 3.times.25 ml diethyl ether. The organic phases were dried (Na2 SO4) and were evaporated to give pure crystalline phenol. Yield=99%. M.p. 41 DEG-42 DEG C.

Vanillin to 3,4-Dihydroxybenzaldehyde
Solvent-benzene
AlI3/ether molar ratio-4.8
ether/R4NI molar ratio-360
Time(hours)-1.5
Yeild(%)-88


Isovanillin to 3,4-Dihydroxybenzaldehyde
Solvent-benzene
AlI3/ether molar ratio-4.5
ether/R4NI molar ratio-120
Time(hours)-1.5
Yeild(%)-84

Interesting Selective Demethylation
2,4,5-trimethoxybenzaldehyde to 4,5-Dimethoxysalicylaldehyde
(4 different)
Solvent-cyclohexane
AlI3/ether molar ratio-1.5, 3.3, 5.5, 10
ether/R4NI molar ratio-100, 100, 100, 50
Time (hours)          -14,  1.5, 1.5, 10
Yeild(%)              -88,  90,  91,  85
Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[foxy2]

This has a very mild method for cleaving di phenolic ethers(end of article) and a prep for 2,4,6-(MeO)3C6H2Br.


An unusual cleavage of diaryl ethers.   
Mayer, Walter; Fikentscher, Rolf; Schmidt, Johannes; Schmidt, Otto Th.   
Chem. Ber. (1960), 93 2761-76.   
CAN 55:27689   AN 1961:27689
Abstract
Dehydrodigallic acid (I) and valoneaic acid dilactone were cleaved non-hydrolytically by alkali on the diphenyl ether bridge.  This cleavage of diphenyl ethers was apparently dependent on the presence of 3 vicinal, free OH groups on one of the 2 phenyl radicals.  The cleavage was an intramol. disproportionation and its mechanism regarded as a bor vinylogous b-elimination.  2,3-HO(MeO)C6H3CO2H (II) (3.5 g.) in 60 cc. Et2O treated with CH2N2-Et2O and refrigerated 2 hrs. yielded 3.4 g. Me ester (III) of II, m. 67° (2:1 MeOH-H2O) (all m.ps. are cor.).  III (3.4 g.) dissolved with 1.31 g. MeOK in abs. MeOH and evapd., a 3.7-g. portion of the residue in 60 cc. abs. MeOH stirred 20 hrs. at 65° with 7 g. [Ph2I]Br, concd., and worked up with H2O and Et2O yielded 1.8 g. 3,2-MeO(PhO)C6H3CO2Me (IV), rodlets, m. 114-16° (3:2 MeOH-H2O).  IV (1.5 g.) in 20 cc. C6H6 treated with stirring with 2 g. AlBr3 in 8 cc. C6H6, refluxed 4 hrs., and treated dropwise with cooling with 25 cc. 2N HCl, and the product isolated with Et2O gave 0.46 g. 3-OH analog (V) of IV, prisms, m. 74-6° (3:1 (MeOH-H2O).  V (0.23 g.) and 30 cc. 2N NaOH refluxed 6 hrs. under a stream of H, cooled, and acidified with 2N HCl gave 0.17 g. 3,2-HO(PhO)C6H3CO2H, m. 154° (cyclohexane).  3,4-(MeO)2C6H3Br (30 g.), 26 g. PhOK, and 4 g. Cu bronze heated slowly to 170-80°, kept 2 hrs. at this temp., cooled, and decompd. with dil. aq. KOH, and the product isolated with Et2O yielded 15.5 g. 3,4-(MeO)2C6H3OPh (VI), leaflets, m. 47° (petr. ether).  VI (10 g.) in 50 cc. C6H6 refluxed 5 hrs. with 25 g. AlBr3 in 100 cc. C6H6 yielded 7.6 g. 3,4-(HO)2C6H3OPh, prisms, m. 104-6°, green with FeCl3 in MeOH. 3,4,5,2-(MeO)3(PhO)C6HCO2Me (9.5 g.) in 100 cc. C6H6 refluxed 4-5 hrs. with 25 g. AlBr3 in C6H6 and poured into 100 cc. concd. HCl and 200 g. ice gave 3,4,5,2-(HO)3(PhO)C6HCO2Me.H2O (VII.H2O), rodlets, m. 92-6° (H2O), which dried at 65°/1 mm. over P2O5 yielded 5.6 g. VII, m. 128-9°, deep blue with FeCl3.
 VII (2 g.) in Et2O treated dropwise with CH2N2Et2O, refrigerated 2 hrs., concd., and chromatographed on Al2O3 and then on silicone-impregnated cellulose powder yielded 0.180 g. 3,5,4,2-(HO)2(MeO)(PhO)C6HCO2Me (VIII), m. 117° (H2O).  VIII (0.107 g.) and 30 cc. 2N NaOH refluxed 6 hrs. under a stream of H, acidified, and extd. 24 hrs. with Et2O, and the ext. worked up gave 3,5,4,2(HO)2(MeO)(PhO)C6HCO2H (IX), prisms, m. 155-7° (H2O).  The Rf values (given) in 10:2:4 BuOH-AcOH-2H2O and in 2% aq. AcOH, and the color (given) with diazotized sulfanilic acid were detd. for the following compds.: VIII, 0.90, 0.74, orange; IX, 0.86, 0.74, orange-yellow; 3,5,4(HO)2(MeO)C6H2CO2H, 0.76, 0.60, red-brown.  3,4,5,2-(MeO)3(PhO)C6HCO2H (7 g.) in 100 cc. C6H6 refluxed 4 hrs. with stirring with 25 g. AlBr3 in 100 cc. C6H6, cooled, treated dropwise with 10 cc. H2O and 4 cc. concd. HCl, and filtered, the residue dissolved in 250 cc. H2O and extd. continuously with Et2O, and the ext. worked up gave 4.25 g. 3,4,5,2(HO)3(PhO)C6HCO2H (X), prisms, m. 172-95° (decompn.), deep blue with FeCl3.  X (2.85 g.) in 50 cc. Me2NH heated 1 hr. at 190-200° in a stream of H, cooled, treated with 500 cc. 2N H2SO4, and extd. 12 hrs. with Et2O gave 2.0 g. 2,3,4-(HO)3C6H2OPh (XI), yellowish prisms, m. 125-7° (H2O), which with CH2N2 gave 2,3,4-(MeO)3C6H2OPh, leaflets, m. 56-8°.  Syringic acid Me ester (4.3 g.) and an equiv. amt. 4N KOMe evapd., the residue in MeOH treated with 7.2 g. [Ph2I]Br, refluxed 20 hrs. with stirring, concd., dild. with H2O, and extd. with Et2O, and the residue from the ext. refluxed 4 hrs. with 4N NaOH and acidified gave 2 g. 4,2,6-HO2C(MeO)2C6H2OPh (XII), rodlets, m. 207-9° (H2O).  XII (1.3 g.) in 80 cc. C6H6 treated in the usual manner with 5 g. AlBr3 gave 0.7 g. 4,2,6-HO2C(HO)2C6H2OPh, m. 196-8°, orange-red with diazotized sulfanilic acid.  3,4,5-(MeO)3C6H2I (8 g.), an equiv. amt. PhOK, and 2 g. Cu bronze heated slowly to 150-60°, kept 2 hrs. at 150-60 and 2 hrs. at 180-90° and cooled yielded 1.9 g.
3,4,5(MeO)3C6H2OPh (XIII), prisms, m. 84-6°.  XIII (2.6 g.) in 65 cc. C6H6 cleaved with 9 g. AlBr3 yielded 1.2 g. 3,4,5(HO)3C6H2OPh, leaflets, m. 135-7° (C6H6), gray-blue with FeCl3.  1,3,5-C6H3(OMe)3 (10 g.) in 120 cc. CHCl8 (8, thats what is says, but I assume its chloroform) treated dropwise with stirring with 3 cc. Br gave 10 g. 2,4,6-(MeO)3C6H2Br (XIV), m. 97-9° (1:1 EtOH-H2O).  XIV (8 g.) and 4.4 g. PhOK heated with 2 g. Cu bronze 2 hrs. at 150-70°, 2 hrs. at 180-90°, and 2 hrs. at 200-10°, and worked up in the usual manner gave 0.6 g. 2,4,6-(MeO)3C6H2OPh (XV), m. 94-5° (aq. MeOH).  XV (2.4 g.), 20 cc. AcOH, 10 cc. Ac2O, and 25 cc. 57% HI refluxed 3 hrs. in the presence of a small amt. of red P, cooled, and dild. with 40 cc. H2O, and the product isolated with Et2O, sublimed at 150-70°, and recrystd. from C6H6 yielded 1.13 g. 2,4,6-(HO)3C6H2OPh, rodlets, m. 175-7°, red-brown with diazotized sulfanilic acid. 1,2,3-C6H3(OH)3 (XVI) (5 g.), 12 g. Na2SO3, and 1.6 g. NaOH in 100 cc. H2O treated 5-6 hrs. with a stream of air, acidified with 6N HCl, extd. 48 hrs. with Et2O, treated with Ba(OAc)2, filtered, passed through Amberlite IR-120, treated with C, and evapd., and the residue dried 48 hrs. at 70°/0.2 mm. over P2O5 yielded 4 g. 4(5)-SO3H deriv. (XVII) of XVI, m. 158-60° (decompn. from 115°), Rf 0.86 (10% aq. AcOH), blue with FeCl3, and ruby-red with aq. KCN.  XVII and 4N HCl heated 3 hrs. at 140° gave a resin and XVI, Rf 0.71 (10% AcOH).  XVII (1 g.) with CH2N2-Et2O kept 2 hrs. in the refrigerator yielded 1 g. tetra-Me ester (XVIII) of XVII, prisms, m. 123-4° (MeOH).  X (1.1-1.4 g.) added under H to 50 cc. 2N KOH, heated 6 hrs. at 100° under a stream of H, and acidified with 2N HCl gave 31% PhOH; 24-hr. heating gave 49.5% PhOH.  X and 2% aq. Na2CO3 heated 6 hrs. at 100° gave 62% PhOH, 49% 3,4,5-(HO)3C6H2CO2H (XIX), and 22% unchanged X; 24-hr. heating yielded 77% PhOH and 47% XIX.  X and NaOAc-AcOH buffer of pH 5.7 heated 6 hrs. at 100° resulted in the decarboxylation of X to XI; after 12 hrs., small amts. (5%) of PhOH and XIX were formed.
 X (1.7 g.) in NaOAc-AcOH buffer heated 72 hrs. yielded in addn. to PhOH, XIX, and XI 0.022 g. unidentified solid which sublimed from 265° with darkening, but without melting.  The Rf values were detd. for the following compds. in 2% AcOH and in 10:2:4 BuOH-AcOH-H2O: XIX, 0.40, 0.63; X, 0.65, 0.82.  XI and 2% aq. Na2CO3 heated 6 hrs. at 100° gave 8.2% PhOH; XIII gave similarly 14% PhOH.  XIII and 2N NaOH heated 6 and 20 hrs. at 100° gave 20% PhOH in both cases.  I and 3.8% aq. Na2CO3 refluxed 4 hrs. gave 0.59 g. XIX; the mother liquor methylated with CH2N2 and sapond. with alkali gave 0.015 g. (MeO)3C6H2CO2H and 0.070 g. 1,2,3-C6H3(OMe)3.  I (1.48 g.), 1.2 g. Na2CO3, and 2.0 g. Na2SO3 in 60 cc. H2O refluxed 4 hrs. under a stream of H, treated with 10 cc. 6N HCl, and extd. continuously with Et2O, and the ext. evapd. gave 0.69 g. XIX[/b]; the aq. phase treated with BaCl2, filtered, passed through Amberlite IR-120, and evapd. gave 0.4 g. XVII.  X (0.080 g.), 0.6 g. Na2CO3, 1 g. Na2SO3, and 30 cc. H2O refluxed 6 hrs. gave XIX, m. 236-7°, and XVIII.
Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[Dr_Sister]

what's up with all the FeCl3? is that some form of analytical technique to test for the presence of HO groups?
7.10.01

[Osmium]

For phenolic OH groups, yes.
I'm not fat just horizontally disproportionate.

[mellow]

What's wrong with pyridine for the demethylation of eugenol?

OK - I already know - it stinks. But for those of you who think they might be having trouble getting hold of it how about niacin as a precursor-precursor?

Niacin (nicotinamide) is pyridine with a carboxylic acid. It ought to be easy to get rid of that carboxylic acid to leave pyridine.

Niacin is available everywhere in pills or capsules (with hardly any filler) or in the pure form.

[kid_trippin]

So has there been any success in synthing pyridine from niacin?  I've heard of a few proposals using copper II hydroxide.
Resistance to government is so valuable on certain occasions that I wish it to be always kept alive.

[SPISSHAK]

It`s possible to decarboxylate niacin, just requires harsh conditions.
Picoline is another carboxylic acid of pyridine it decarboxylates more easily because the carboxyl group is closer to the nitrogen atom.
If you study Decarboxylation mechanisms, I think it`s because
the aza-nitrogen has electron withdrawling properties with respect to the carbon that the carboxyl group is bound to.
Maybe tautomerism would explain it.
Look at that thread entitled "pyridine"
In the general discourse.
SWIM is curios to know if that aluminum trihalide demethylation of eugenol would work on codiene.
Hmmmm???
The boron tribromide demethylation goes by the same mechanism as the alumium demethylation.
They are both group 3A elements.
Boron and aluminum that is.
Would somebody know about these things?
It seems it would go, or is this trihalide too strong of a
Lewis acid, which would Wreak havok on that phenanthrene skeleton?

[Rhodium]

> SWIM is curios to know if that aluminum trihalide
> demethylation of eugenol would work on codiene.

I think the codeine is a too delicate molecule for that, and you will probably end up with a lot of apomorphine. Use any of the other codeine demethylation methods that can be found on my page.

[SPISSHAK]

However, since the mechanism of apomorphine formation starts by protic attack at C-14, then a chain reaction ensues which transfers thru the C-7,8 double bond SWIM believes this can be circumvented by reducing the 7,8 double bond.
This explains why there are processes for demethylating oxycodone using hydrobromic acids.
The yields are low (35%) but it works.
On poppies.org there was a discussion called "hypothetical hydromorphone failure"
Where a guy catalytically rearranges codiene with Pd black in HCl, then goes on to demethylate it with hydroiodic acid.
At first he fucked it up, but on the second try he got 15%
Yeilds, and if you look closely at how he did it he was sloppy.
Because he refluxed it too long (1 hour), and in most journals they specify 15 minutes at 135 degress centigrate, add the dihydro (phenanthrene) whatever, when the acid (48% HBr) reflux is underway and not before, etc.
So it the personal conviction of SWIM that codeine can conveniently be converted to hydrocodone, then hydromorphone, using very accessible chems, an opiate for the masses type mission.
The link for that thread is:

http://www.poppies.org/foru/DCForumID16/143.html

I think there is another possible side reaction in this case
(H-X) demethylation, that could screw things up.
That is, H-X cleavage of the oxygen bridge on the phenanthrene skeleton to the catechol.
See:
Rice,K.C., J.MED.Chem., (1977),20,164
For details.
He also rambles on in that thread that he tries to demethylate hydrocodone with pyridine.HCl and got a discouraging 5-7 %, so that`s a no go.
If you were to use any method to prepare hydrococdone that gives anything less than quantitative yields from codiene SWIM would recommend that you seperate unreacted codiene from the hydrocodone by forming bitatrate salts of the two.
codiene bitartrate is water insoluble, hydrocodone bitartrate is water soluble, hence seperation.
If you overshoot the tartaric acid in this titration you`ll get tartrate salts which are both soluble, hence no seperation.
Failure to do so in this case will result in you blowing chunks for some time.
(Gee blowing chunks was never this fun !)

Regarding pyridine via decarboxylation of aryl type acids
See: "copper quinoline decarboxylation of aromatic acids"
Nilsson M., Acta. Chem. Scand. 1966, 20, 423-426

Any more info on this would be welcome.
Spisshak Out!

[SPISSHAK]

Got the tough shit response when I tried that link, hope this fixes things.

http://www.poppies.org/forum/DCForumID16/143.html

[SPISSHAK]

Could triethylamine hydrochloride be used to demethylate codiene, albeit in lower yeilds than with pyridine.
Also why hydrochloride why not hydrobromide or hydroiodide,
These Ions have lower enthalapy of dissociation than hydrochloride Ion which makes me think that the demethylation would proceed at a lower temperature.

No sources! /Rhodium

[Rhodium]

Could triethylamine hydrochloride be used to demethylate codiene

Yes, that is probably possible.

[SPISSHAK]

Appreciate the help, I`ll take heed, just rying to bee helpful.