4-alkylthio-2,5-dimethoxybenzaldehyde, Sulfuric Duff reaction

I have found a small towel in an arabian market while visiting the Mevlevi Order of Sufis, it was more or less written this on it :

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4-Methylthio-2,5-dimethoxy-benzaldehyde (according to Duff )

5-hydroxybenzo[d][1,3]oxathiol-2-one (5-hydroxybenzothioxolone):

From JOC 55 1990 2736-2742

Benzoquinone (54 g , 0.5 mol, MW 108) dissolved in 300 ml GAA is added dropwise in 30 min to a solution of
Thiourea (42 g, 0.55 mol, MW 76) dissolved in 400 ml of 2.5 N HCl
with stirring at RT (EXO, a white ppt form). After coming back to RT, there is added 25 ml conc. HCl and the mixture is heatted on steam bath for one hour.
Then it was cooled to 0 °C, let crystallise, filtered, washed with ice water, dryed.
The thioxolone was obtained as a powder. [lit: mp 174-175 °C Rf 0.5 10% EtOH in CHCl3]


Saponification of the thioxolone : 2-mercapto-1,4-hydroquinone

The crude wet thioxolone (100 g) was dissolved in 650 ml of 3N NaOH (4 eq) at RT and the mixture is degassed with argon and then refluxed for one hour (under a good stream of argon!).
The mixture is then cooled to RT with a ice bath and then 220 ml 12 N HCl is added, pH is 1 (it must be kept under inert gaz as long as it is basic!).
The mixture is extracted three times with Et2O and the combined fractions washed once with a small amount of brine and dried on MgSO4.
After filtration and evaporation, and redissolution in MeOH then reevaporation the product is obtained as a beige solid 45 g MM 142 63% [lit: mp 118°C].


Permethylation with dimethylsulfate :

To a solution of the above product
(...)

with base (...)

ammonia to neutralise the carcinogen after reaction (...)

good yield

(...)


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Here the towel was broke, presumably he obtained 2-Methylthio-1,4-dimethoxybenzene...


BUT The Wise One will use instead of DMS the newly devised MES (Methyl Ethane Sulfonate) instead of DMS. Not because it is least toxic (which is NOT) but because it is OTC (which is IT).

...I remember a friend told me once that once when he had tried to methylate this mercaptohydroquinone using MeBr at -10°C with KOH as a base the mercapto group got alkylated in less than three hours while the hydroquinone was MUCH MUCH slower and required heating (and finally he decided to switch to DMS). Probably the person who wrote on the towel i found (I think he was a very famous Dervich living in some cave) had got the same issue. But he was unaware at that time of such useful chemical as Methyl Ethane Sulfonate, MES. :-)

BTW if the chemist do not trust the nucleophilic power of the mercapto group vs the hydroxyl ones He can still use the pkA as HCO3- will only basify the mercapto while leaving the hydroxy untouched! thats for sure ;-)

Voilà! and i acquired the following towel shortly after, it was written by the same hand. Apparently the sympathetic author was very content because of a Duff reaction he finally could make to work!

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LOOK! --> Formylation with Duff! : 4-Methylthio-2,5-dimethoxybenzaldehyde <--- Nice, its OTC :-)

To 25 mmol of the dimethoxymethylthiobenzene (MW 184, 4.6 g) in 30 ml GAA there is added 50 mmol HMTA (hexamine, urotropine, hexamethylenetetramine) (MW 140, 7 g). The mixture is placed in a 100°C bath. At that temperature, with good magnetic stirring, there is added dropwise over one hour 100 mmol H2SO4 (MW 98, d 1.84, 95%, 5.5 ml) dissolved in 20 ml GAA. No reaction had yet occured at half the addition beside some precipitation of white salt (HPLC indicate starting conversion to the HMTA adduct and alot of starting product). 5 min after the end of addition the starting product had disapeared and the HMTA addition compound was majoritarly present but also there were aldehyde and some benzylamine. Addition time can be reduced to 5 min probably and then all stirred 30 min I bet, it is very quick. The mixture is stirred with a air condensor through the night at 100°C. After the night HPLC indicated 50% benzaldehyde 50% amine and no more HMTA adduct. It was intense yellow with a white ppt. Ammonium acetate (15 g, MM 77, 200 mmol) was then added to the hot mixture and it was cooked for two hours more. The mixture was less yellow than before. HPLC showed complete disapearance of the amine and only the aldehyde. The all mixture was poured in 200 ml of 1% aqueous HCl, the all was refluxed for ten minutes then cooled to RT and treated cautiously with 50% NaOH solution with stirring until pH 8 (~1 mol). The ppt solid formed became whiter. After cooling to 0°C it was filtered, washed with water (300 ml) and dried to yield the aldehyde. Yield : 4.8 g (MW 212 23 mmol) = 92% :-)

NB: some trials were done which showed NO reaction without strong acid, side reactions with 2 eq or 4 eq 37% HCl or 2 eq H2SO4 (vs substituted benzene). Only 4 eq H2SO4 vs the substituted benzene along 2 eq HMTA worked for a night at reflux in GAA.


Second trial on 100 mmol :

100 mmol dimethoxymethylthiobenzene (MW 184, 18.4 g) and 200 mmol HMTA (MW 140, 28 g) are placed in a 500 ml RBF equipped with a magnetic stirrer. There is then added 120 ml GAA and the suspension is placed in a 100°C bath. Dissolution occured while heating. With a help of a dropping funnel there is then added dropwise during 20 minutes 400 mmol H2SO4 (MW 98, d 1.84, 95%, 22 ml, 2eq relative to HMTA) dissolved in 80 ml GAA. The thick canari yellow suspension is then stirred at 100°C for one hour more. After 40 min HPLC indicated no more adduct and only aldehyde and benzylamine. So after one hour at 100°C there is added anhydrous ammonium acetate in powder by portions over five minutes (800 mmol, 2 eq relative sulfuric acid, MW 77, 62 g). Five minutes after the addition was done the ppt became white and the solution changed color to a more brown hue of yellow. It was stirred two hours at 100°C the color now was again more yellow (imine formed). The all mixture was then poured in 800 ml of warm 1% HCl. The mixture was refluxed for 15 minutes (complete dissolution occured) then cooled to RT. Meanwhile, a solution of 160 g NaOH in 200 ml water is prepared. At RT, cautiously, the cooled acidic solution is neutralized with the soda solution until pH 8 is attained. The reaction mixture is left to return at RT and then filtered on buchner. The product is then washed with a copious amount of water, recristallized from MeOH/water and air dried to constant weight. 17g of beige powder are thus obtained MW 212 80%.


Yours,
Hadji-Astvatz-Troov.

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I thought it would be nice to share!

BTW Buckminster Fuller had researched abit the Duff reaction and apparently it work this way :

- At First you need to form an ADDUCT between HMTA and the (activated, it barelly work for only two methoxy) substituted benzene. This need strong ACID condition to form CATIONIC IMMINUM species. Those imminiums are stabilized by Tensegrity on the HMTA Diamond structure like my several Domes. Those imminiums are stable but if an activated benzene is around it will attack them on the carbon! An adduct then form. It is quick if an activated benzene and strong acid in good stoechiometry - it means 2 eq sulfuric by HMTA - 4 total as 2 HTMA per benzene are present.

- Then after the adduct is formed it will decompose during the reaction forming two products (fifty - fifty) : The first one is the benzaldehyde (SOMMELET product), the second one is the benzylamine (DELEPINE product).

- Then 50% yield is reached in one hour, it remains to change the produced benzylamine into benzaldehyde. The way is trough trans-imination in the HMTA-Diamond-Tensegrity-Sphere. In that Sphere some methylimine will be reduced to methylamine meanwhile oxydizing the nearby benzylamine from its Tensegrity Structure to a benzylimine. To do this there is a need for proton exchange hence the pH should be increased. By addition of ammonia in the form of ammonium acetate the sulfuric acid is neutralized and the proton exchange process liberate the electronic pair from caged nitrogen then hydride transfert occur in the Tensegrity Sphere. Then conversion after one hour is quantitative. The benzaldehyde is then liberated from the imine by aqueous hydrolysis.


Check :
Wiki Duff reaction

Wiki Sommelet reaction

Wiki Delepine reaction



Sadly it seems to not work that great for dimethoxybenzene, unsoluble adduct form. For alkyldimethoxybenzene it works relatively OK, like a TFA modified Duff. For halogenodimethoxybenzene it works bof too. But for alkylthiodimethoxybenzene it is the best! No need POCl3! Yield great and no TFA! OTC!




Peace,

Dr U

[Edited on by Ullmann]

[Edited on by Ullmann]

What is "that great" ? It isn't working at all or you can expect some yield ?

Congratulations !

Wooow! This nearly threw me off the chair.
What a brilliant adaptation of the Duff formylation WITHOUT using trifluoroacetic acid. How was the conclusion reached that partial neutralisation would make the amine/iminium equilibrium go to right? Sounds like somebody had a pure stroke of genius (or an enlightenment) with that acetate trick. This is actually publishable chemistry and I thank you for sharing it here.

First of all, amazing work. You owned a chef hat

I dunno maybe it is because it is in water that it work but I have not tried this reaction. I am welcome to any data on this... Another problem is that ethanethiol stench pretty bad and it has a high vapor pressure, also it is put in the city gaz to detect leaks hence your neighbour on smelling it (and they will!) might think of a gaz leak and call the fire brigade !

This way through the thioxolone does not stink and thiourea has some use in silver polish... beware it is listed has carcinogen... hehe but it is beter to do like this than by zinc reduction of quinone thiosulfate and huffing H2S ala Klute !

The second comment above quoted refer to the 4-chloro-2,5-dimethoxybenzaldehyde. As it is well known than chlorination of 2,5-dimethoxy-PEA gives several compounds and that those compounds are not separable by crystallisation (AFAIK). Hence it is wiser to put the chloro first from the beginning, then to methylate then to do the Duff. In litterature (JOC 58 7906 1993) the modified Duff using TFA work great, myself I had 35 % recrystallized (using TFA) on the 5-ethoxy homologue. I do not think the yield would be stellar high using sulfuric on the chloro compound but it is IMHO the only way to have a pure 4-chloro-2,5-dimethoxybenzaldehyde free of over-chlorinated or no-chlorinated or regioisomer. Hence it is the best way for the 4-Chloro. BTW it is a very cheap route... I think I have some note here... ah yes

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p-Meo-phenol

5 g BQ
50 g HQ
200 ml MeOH
20 ml H2SO4
1 night a 60°C with a glass cover
Workup :
The black solution is neutralized with NaOH, salt are filtered, the product is distilled in vacuo and recristallized from toluene. Yield 70%.

Chlorination of p-Meo-phenol
PMF 12.4 g 100 mmol dissolved in 50 ml CH3CN
add at once 1.1eq NCS MM 134 -> 14.7 g (it is a white suspension, endothermic dissolution)
Cool at 0°C and add 0.5 ml H2SO4. An exotherm develop and the reaction temperature must be controlled to not overheat (ice bath).
After 30 min the exothermic reaction is done, leaving a pronounced yellow solution. Let the reaction reach the RT during 30 min.
Stop the reaction at t+1h by slow addition of 50 ml of 10% aqueous Na2SO3. Add 1 gram of NaHCO3, the pH is neutral.
Extract the yellow aqueous phase with two times 100 ml Et2O (the first becomes yellow, the second is white)
combine the organic layers and wash three times with 150 ml 10% NaCl solution
wash once with brine, dry on MgSO4, filter and evaporate the solvent leaving a yellow oil 14.7g MW 159 92% yield.

On analysis this oil contain abit of dichloro compound and regioisomer, it is maybe 90% pure.

Another (more OTC) way to make this oil :

PMF 12.4g 100 mmol is dissolved in MeOH. The solution is well cooled with a ice-salt bath. There is then added by portion TCCA (trichloroisocyanuric acid) 0.35 eq MW 232 8.1 g. An exothermic reaction occur and the temperature is controlled during the addition. When it subsided the mixture is let reach RT. Filtration and similar workup as above should give the oil. (workup was not done but on HPLC the monochlorinated product was obtained with acceptable purity).

3-Chloro-4-Ethoxy-anisole

14.7g 2-chloro-PMF (92 mmol) with 18 ml EtBr in 50 ml DMF and 1 eq K2CO3, reflux 3 hours.

Workup :
The suspension is diluted with 250 ml acetone, the salts are let to precipitate for a night in freezer then are filtered, wash with water and the red filtrate is recuperated. All solvent are rotavaped. A red oil is obtained. It is dissolved in DCM and washed with dilute NaOH and then water and brine. After drying on MgSO4 and filtration and evaporation of the solvent a red oil is again obtained. On HPLC there is 3 products:
the major one is the monochlorinated
two dichlorinated impurities in minor amount (~10%).
Yield is 14.7g MW 187 79 mmol (86%).


Modified Duff using TFA : 4-Chloro-5-Ethoxy-2-Methoxy-benzaldehyde

The crude red oil with the dichloro impurities is used as such 79 mmol 14.7g. There is added 80 mmol HMTA and 80 ml TFA. Reflux 24 h @ 95°C.
The next day a dark yellow solution is obtained. After cooling to RT it is poured in a 1L erlenmeyer with 250 ml H2O and stirred 30 min at RT. The pH is increased to 9-10 with Na2CO3 ! there is a lot of CO2 evolving!. After it is back to RT the beige solid is filtered on buchner and washed with plenty of water.
Recrystallization from ~150 ml boiling MeOH, hot filtration is required to get rid of a black oil : 8.5 g powder is obtained. The purity is not high enough hence a second recristallisation from boiling MeOH is done which yields 6.1 g beige crystalline powder not very soluble in MeOH (MW 215, 28 mmol, 35%). GC-MS purity indicate 97% and RMN 1H is OK mp 91-92°C.

Hadji-Asvatz-Troov.
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Well apparently the Duff in that case was only done with one equivalent of HMTA, maybe it would yields better with two equivalent. It should not yield less than 40% if done on this substrate using the sulfuric acid Duff reaction instead of TFA. But this was not tested.

Well I have also some clues about the 4-ethyl-2,5-dimethoxybenzaldehyde case. Once again the same hand had writen this on an (incomplete) towel just found in Tajikistan. Luckily for us the important information was saved :

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Attempt in Formylation of 2-ethyl-1,4-dimethoxybenzene using the vilsmeier procedure :
The oil (16.6 g, 100 mmol) was dissolved in a mixture of DMF (180 mmol, MM 73, d0.94, 14 ml) and POCl3 (150 mmol, MM 153, d1.64, 14 ml) that was first allowed to stand for fifteen minutes at RT. The dark red mixture was stirred at 60°C trough the night with a guard tube. Analysis by HPLC revealed the reaction was not finished, hence it was refluxed for 5h at 100°C. A precipitate deposited in the viscous reaction mixture. 400 ml water was added and the dark mixture was stirred for one hour at 100°C. Toluene (100 ml) was then added and the mixture was decanted then extracted with two fresh portion of toluene. The combined organic layers were washed once with deionised water then the solvent was evaporated to leave 16g of dark brown oil that cristallized. It was recrystallized from 250 ml boiling MeOH. A beige cristalline product was thus obtained (6.6 g). This product had a mass of 527(25), 526(75), 344(28), 343(100), 179(10) MSMS: 343-> 179. Its 1H NMR and 13C NMR described the lack of an aldehyde and also some shift in the Ar-H proton and carbon were the aldehyde should have been. One carbon more in C13, no supplementary proton in 1H. Its melting point was superior to the boiling point of MeOH.

As Sacha wrote the vilsmeier procedure does not work in this case. He used Tin chloride and dichloromethylmethylether but beeing quite toxic I prefered to try the Duff on this particulare case. At that time I did not know about the Sulfuric Duff hence I use a Modified Duff using TFA instead.


Formylation using Duff procedure (modified) :
To 16.6g of the benzene (100 mmol) there was added HMTA (110 mmol, MM 140, 15.4 g) followed by 100 ml TFA. The solution was placed in a preheated (90°C) bath and hold at reflux for a day. The red reaction mixture was then pourred in cold water, after 30 minutes it was basified using excess Na2CO3 and let stir one night at RT. The following day the somewhat solid residue was decanted off and rinced with water by trituration. It was then tried to crystallise it from MeOH but it was too soluble and/or oiled out. It was then distilled at 160°C at water pump instead. The water pump did not have a high enough vacuum. This produced 9g of solid residue but extensive decomposition took place while trying to distill more product and a thick yellow oil passed at 200+ °C. The solid residue was rinced with some MeOH to get rid of the contaminating oil and the 7g residue remaining were recrystallized from MeOH to give 3.5 g of aldehyde.

In retrospect it is wiser to distill at high vacuum (<1mmHg, bp 120°C@0.2mmHg) and to not recrystallise the product next time as it is wastefull. NMR 1H and 13C both showed the correct spectra including aldehyde group. The problem was not with the Duff but because I first burned the product and secondly because methanol is not a good recrystallisation solvent for that particular aldehyde.

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So it seems that the alkylated dimethoxybenzene are activated enough for the Modified Duff reaction hence they should work too for the Sulfuric Duff reaction. The biggest problem there was with the normal Duff reaction was because the conditions descibed were not acidic enough and no attack on the iminium occured (ie not ADDUCT formed). Once this particular barrier is passed by using a strong acid in the reaction there is no need for strong acid condition and the pH can be placed anywhere between pH 1 and pH 5.

Yup someone told that chemist long ago about the possibility of using sulfuric acid as a strong acid along with GAA as a solvent Then by loooking at wiki and in the Ogata, Y.; Sugiura, F. Tetrahedron 1968, 24, 5001 reference then trial and error and chromatography equipment.

Dr U

[Edited on 6-11-08 by Ullmann]

2-ethoxy-5-methoxy-4-alkylthio-benzene

This could interest you, Maja


2-ethoxy-5-methoxy-4-alkylthio-benzene

5-hydroxy-1,3-benzoxathiol-2-one :

Quinone MM 108 1 mol 108 g dissolved in 500 ml GAA added dropwise in 30 min to
Thiourea MM 76 1.1 mol 84 g dissolved in 1000 ml of 2 N HCl with stirring at RT (EXO, a white ppt form). After coming back to RT (one hour), added 50 ml conc. HCl and heat on steam bath for one hour.
Cool to 0 °C and let crystallise for a night, filter, wash with ice water, dry. Get the thioxolone [lit: mp 174-175 °C Rf 0.5 10% EtOH in CHCl3] and dry in vacuo and by heating to 110°C.

Yield: 156 g MW 168 --> 93% beige needles :-)


5-ethoxy-1,3-benzoxathiol-2-one :

To a stirred solution of 5-hydroxy-1,3-benzoxathiol-2-one (0.1 mol, MW 168, 16.8 g) in DMF (50 ml) there was added finely powdered anhydrous K2CO3 (MW 138, 0.12 mmol, 16.8 g) and EtBr (MW 109, 14 g, 0.13 mmol) and KI (1 g) the brown mixture was stirred at RT for 20 h with a guard tube (without KI it is 2 times slower). Acetone (150 ml) was then added and the salt filtered. The solvents are rotavaped with a bath at 80°C and to the dark amber residue (22 g) there is added 20 ml of warm MeOH to crystallize the product. After filtration and air-drying 12 g of beige needles are obtained (61 %).

Several trials were done : with Na2CO3 as a base in DMF the reaction is very slow (30% after 5 days). In acetone instead of DMF with Na2CO3 no reaction occur at RT for 5 days. With K2CO3 in acetone neither in contrast to Sasha's report (using CH3I see quotation below)! NaOH or KOH in MeOH do not work as saponification occur. With too much EtBr in DMF overalkylation occur.

This is a failed reaction using acetone that worked after switching the solvent to DMF:

To a stirred solution of 5-hydroxy-1,3-benzoxathiol-2-one (0.1 mol, MW 168, 16.8 g) in acetone (100 ml) there was added finely powdered anhydrous K2CO3 (MW 138, 0.15 mmol, 21 g) and EtBr (MW 109, 17 g, 0.15 mmol) and KI (1 g) the brown mixture was stirred at RT for 20 h with a guard tube. No reaction had occured at that time hence it was refluxed two hours. No reaction had occured after that hence the solvents were rotavaped and DMF (50 ml), EtBr (17 g) and KI (1 g) were added and the stirring restarted for a night at RT. 12.5 g after reX...

It was done following this

what a badass!!!
mr ulmann love your intellect can we switch brains?
i'll be glad to trade you!

Lovely work you do Ullmann. Method after method... yes, yes...

Hello, I am looking for a little help/opinions/whatever else regarding the Sulfuric Duff.


I am following the example given by Ullmann, where 4-methoxyphenol is chlorinated with TCCA, and the resulting phenol is ethylated with EtBr. Both of these reactions were carried out without any problems.
So i have my oil ready for the Sulfuric Duff, but this is where I began to get some problems. This is what I did:

To a 500ml 3-neck rbf fitted with a reflux condenser and thermometer, 4.6g 3-chloro-4-Eto-anisole and 30ml GAA was added, followed by 3.5g HMTA.
Heating with an oil bath to 100ºC was begun. A solution of 2.7ml H2SO4 in 20ml GAA was added to an addition funnel, which was then fitted to the flasks neck.
At 100º the H2SO4/GAA solution was slowly dripped in. Addition lasted about 15 mins, with a white precipitate forming near the end of addition. The solution was stirred, and the formed precipitate slowly dissolved. Stirring was continued at ~100º for 24hrs. The solution was a dark red color at the end. 15g of ammonium acetate was added in 4 portions over 5 mins, and the solution took on a more yellow color and got thicker. Strirring was continued for another 2hrs, then 200ml of 1% HCl was poured in, and brought to reflux for 10 minutes. The flask was then cooled, and there was visible oil droplets in the solution and on the flasks walls. In an ice bath 50% NaOH was dripped in. Even more of the oil seperated, but it was thicker. The oil never solidified and it smelled just like the starting compound. So im guessing it failed, or does it have to be purified with a column?
I should mention I have also tried only heating for 2 hours, then adding the ammonium acetate and heating another 2hrs.


Any thoughts/comments appreciated. Also, would it be possible to get around the Duff, even though it would be a longer route, through a mg-formylation of 2-chloro-4-methoxyphenol, followed by the alkylation?

Quote: Originally posted by Magic Muzzlet

Hello, I am looking for a little help/opinions/whatever else regarding the Sulfuric Duff. I am following the example given by Ullmann, where 4-methoxyphenol is chlorinated with TCCA, and the resulting phenol is ethylated with EtBr. Both of these reactions were carried out without any problems. So i have my oil ready for the Sulfuric Duff, but this is where I began to get some problems.

Thanks for your reply Nicodem.

I have been trying the Sulfuric Duff on a few more substrates and I am getting really annoyed, because all I ever receive is a tar at the end! I have tried to do TLC on it but since no proper plates are available I use filter paper. This hasnt given results worth mentioning. The substrates I have tried so far are 2-chloro-1,4-dimethoxybenzene and the ethoxy variant I posted above, 2-ethylthio-1,4-dimethoxybenzene and 2-bromo-1,4-dimethoxybenzene. Multiple trials have been done with longer/shorter heating times, 100-105ºC vs refluxing the mixture but nothing else as I am unsure what will really help. But each time I am getting a horrible tar. Im currently in the process of making 2-methylthio-1,4-dimethoxybenzene to hopefully see a success with this method.


Now I have POCl3 and sure the vilsmeier-haack works, but I really want to see the Sulfuric Duff give positive results for obvious economic/safety reasons, and it is OTC. Nicodem, you said you had experiences with the TFA/acetic duff, have you ever had experience with the sulfuric duff in particular? I'm also curious to know which substrates were tested with this method other than the methylthiodimethoxybenzene. I cannot find any reports other than on SM of any write ups or experiences. Maybe I didn't look hard enough.

Any more insight on this subject is greatly appreciated, I am willing to try any suggestions you have (if I am able to).

Well I am back reporting in this thread again, in short still no success at all with the sulfuric duff. I have even followed Ullmanns procedure stated at the beginning of the thread, and I received tar. No solids. Each substrate I try gives me a very dark brown oil/tar that is a bitch to get off the flask, and not to mention the stench that comes from the synthesis of many of the precursors. Enough of my complaining, I just want to know HAS ANYONE ACTUALLY HAD SUCCESS with this? I tried doubling the equivalents of acid/hexamine/ammonium acetate, 2hrs vs. 24hrs, same tars, I've tried the substrate that Ullmann reported success with in the first place but I am unable to replicate the results for reasons unknown to me!
I will not be attempting the duff again as I already used enough of my time on it, unless of course someone has a great suggestion that I can try. Unfortunate as it is, the benzenes are best saved for the POCl3.(unless you love tar and a strong smell of fish).

Sucess with ( modified ) sulfuric Duff

Quote: Originally posted by byko3y

laserlisa, Formylation of Aromatic Compounds with Hexamethylenetetramine and Trifluoroacetic Acid