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Klute
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Great! Thanks alot! Definitively on my to-do's list.. Thanks again for sharing all this exceptionnal work..
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
-Alice Parr
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jon
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what a badass!!! 
mr ulmann love your intellect can we switch brains?
i'll be glad to trade you!
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Ullmann
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This is the best yield got for the substituted benzene. The methylating agent used was MMS but MES (Methyl Ethane Sulfonate) can be used instead as
explained here.
1,4-dimethoxy-2-allylthio-benzene :
In a 250 ml RBF equipped with septum, argon inlett and a stir bar. In a methanolic (100 ml) solution of 7.3 g (MW 156, 47 mmol)
4-methoxy-2-mercaptophenol degassed (15 min at least before KOH addition) under argon there is added KOH (flakes, 1.1 eq, 52 mmol, MW 56, 85%, 3.4 g)
then after dissolution, allyl bromide (1.1 eq, MW 121, 52 mmol, 6.3 g, d 1.39, 4.5 ml) and the mixture was stirred in closed vessel at RT for a night
(the argon inlett was removed after addition of allyl bromide). Immediatelly KBr precipitate and the mixture became hot. After a night TLC indicated
one major product. The solution was used as such for methylation with 2 eq of MMS generated in another flask (below).
100 mmole generation of MMS using KOH and its in situ use. BEST ALKYLATION YIELD :
In a 500 mL RBF with a silicagel tube. To a solution of 100 ml MeOH containing 100 mmole MsCl (MM 115, 11.5 g, d 1.48, 7.7 ml) cooled to 0°C there is
added with stirring powdered KOH (1 eq, 100 mmol, MM 56, 85% -> 6.6 g ) in one portion. An exothermic reaction occur and salt precipitate. It is
then stirred to RT for one hour. To this extremely toxic solution there is added the methanolic solution (~100 ml) of the phenol (above) and 70 ml of
5% aq KOH (1.1 eq). After an hour 15 ml more of 5% aq KOH is added and the next hour 15 ml more (1.6 eq total). The reaction was stirred at 55°C for
a total of 4 hours. After three hours it was already finished (HPLC conversion > 90%). There were no precipitate and it stirred fine. After 4 hours
and cooling back to RT ammonia (4 ml 25% aq) was added and the mixture was stirred for 30 minutes to destroy excess MMS. The solvent was evaporated,
the residue partitioned between H2O/CH2Cl2, the water layer extracted a second time with CH2Cl2, the combined CH2Cl2 layers washed once with 5%
aqueous NaOH, then twice with water, evaporated and azeotropically dried with toluene to give 9.5 g amber oil (MW 210, 45 mmol, 96 %) HPLC homogenous
compound RMN 1H OK.
Regards,
Ullmann
[Edited on 13-2-10 by Ullmann]
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Sandmeyer
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Lovely work you do Ullmann. Method after method... yes, yes...
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Polverone
Now celebrating 21 years of madness
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Thread Split
21-3-2010 at 10:44 |
Magic Muzzlet
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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?
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Nicodem
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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. |
Note that Ullmann reported the formylation of this substrate using the normal trifluoroacetic acid based Duff formylation and not the sulfuric
version. Your apparent lack of success is thus not necessarily because you did something technically wrong, but it could be that at those conditions
this substrate does not formylate. Just judging from the liquid form of the product is not enough, because it might refuse to crystallize even if
there was a substantial amount of the aldehyde in there unless it is the major product. You should do at least a TLC of your product mixture and
compare it to the starting compound. This would give you an indication of what is going on. If there is a new spot on TLC, then it could well be that
you should use harsher conditions: more H2SO4 and/or hexamine, and longer reaction time. If there is no new spot then the reaction is unlikely to work
even if you apply these changes. Anyway, in my experiences with the trifluoroacetic/acetic Duff reactions, it took at least 5-10 h to achieve
acceptable conversions, though I used different substrates (using a higher TFA vs. AcOH ratio did speed up the reaction rate, so I assume this should
be the case with the sulfuric version as well, but there must be a limit to this due to the high acidity of H2SO4 and thus side reactions).
| Quote: | | 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? |
No, that would give 3-chloro-2-ethoxy-5-methoxybenzaldehyde instead of the 4-chloro-2-ethoxy-5-methoxybenzaldehyde obtainable via the Duff
formylation. Check the mechanism of the Mg-mediated o-formylation of phenols to see why.
There is a paper somewhere that says 2,5-dimethoxybenzaldehyde brominates selectively at position 4 (in respect to CHO). So chlorination of
2,5-dialkoxybenzaldehydes, such as 2-ethoxy-5-methoxybenzaldehyde should give 4-chloro-2-ethoxy-5-methoxybenzaldehyde as the major product. The
problem is in that electrophilic chlorinations are way less selective than electrophilic brominations, but still the selectivity could possibly be
good enough for purification with one or two recrystallizations (particularly considering the most reactive site is also the less sterically
hindered). Now, 2-ethoxy-5-methoxybenzaldehyde is obtainable from the Mg-mediated o-formylation of p-methoxyphenol followed by ethylation.
If it is just for practice rather than going after the specific product, you could practice on some other substrates derivable from p-methoxyphenol,
such as some 2-bromo-1,4-alkoxybenzene, particularly 2-bromo-1-ethoxy-4-metoxybenzene which should be attainable via the same route, but exchanging
trichloroisocyanuric acid with NBS, 1,3-dibromo-5,5-dimethylhydantoin or Br2 (or other suitable reagents). Such substrates might be slightly more
reactive in the sulfuric Duff formylation. Other alkyl aryl ethers are also suitable for practice, but I do not know what you have available.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Magic Muzzlet
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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).
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Magic Muzzlet
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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).
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xwinorb
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Sucess with ( modified ) sulfuric Duff
I was planning to use the sulfuric Duff formylation on 2,5-dimethoxytoluene. I was lucky enough to know someone from this forum, that gave me some
interesting information :
Someone from the Hyperlab reported succes with the sulfuric Duff, but with some modifications ( no ammonium acetate addition, and hydrolysis done w/o
NaOH, at RT ).
Good yields ( 70-80 % ) reported for 2-alkylthio-1,4-dimethoxybenzene.
Lower yields reported for 2,5-dimethoxytoluene, 43 %.
Does not work for 2-halo-dimethoxybenzene nor for 1,4-dimethoxybenzene.
I was able to reproduce the Hyperlab person results for 2,5-dimetoxytoluene. I got similar yield, around 40 %.
I followed his procedure, easy.
Input 17.4 g of 2,5-dimethoxytoluene, a bit of dark purple color on the oil.
I did the final workup a bit differently, I used DCM after evaporating out most of the AcOEt. It forms emulsions but it clears in a few minutes.
After evaporating out most of the solvents ( DCM, AcOEt and AcOH so it seems ) still mixed in with the oil, I got 27.1 g of oil with still a bit of
stuff mixed in. Decided to try to xtalize it from MeOH, it did so fast and easy. After about 1 h in the freezer, I got some 9 g of a cream color
powder, almost dry, still a bit of solvent but fluffy and powdery. I am planning to dry it more and probably to run a MP point test later on.
So, looks like the sulfuric Duff does not work for a lot of things where the usual Duff with TFA does. Indeed, at least for this two mentioned
substrates and with the mentioned modifications it seems to work.
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DJF90
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Can you post your experimental procedure so we can follow what you did?
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xwinorb
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Here is the information on the Hyperlab version of the sulfuric Duff.
I followed exactly what is says, except for the workup. Please see my previous post. I scaled it up by 1.25, and I used a 1 liter BF insted, 500 ml is
too small.
Some more information on the reaction :
Upon dripping in the sulfuric acid, white solids start to form. It soon becomes quite thick, but can be stirred. After dripping in all the H2SO4, the
color is white.
When refluxing, the white solids suddenly become canary yellow. Then soon after the bottom becomes a red/brown transparent color, like red vinegar.
Soon after the yellow solids on the top all dissolve, then it is a red-brown partly transparent liquid, with a yellow oil mixed in. Yellow oil
droplets can be seen on the top of the BF.
During the hydrolisys no much change seen, maybe the color got a bit darker and the oil a bit thinner but not quite sure.
Workup :
I did not evaporated too much AcOH, I think this part can be skipped w/o problem, just mix in the H2O and the EtOAc and stir for 12 h at RT.
If you evaporate the AcOH, make sure the BF is cool enough to avoid overboiling it. Wait till it cools down.
After the hydrolysis, just evaporate as much EtOAc as possible and extract with DCM as said before.
I just run a MP point test, I got 75 C, which is a bit low, but my thermometer was barely touching the tip on the liquid. Also, it is smelling like
there is still some AcOH mixed in. It might be lowering the MP.
It is looking good, clear yellow color, waxy powder.
| Quote: |
Sulfuric Duff formylation of 2,5-dimethoxytoluene
In a 500 mL RBF there is placed 14 g of 2,5-dimethoxytoluene (92 mmol) and hexamethylenetetramine (HMTA, urotropine) 28 g then this was dissolved in
200 ml GAA with gentle heating. After cooling back to RT there is added under stirring dropwise 22 mL of conc. sulfuric acid. The mixture warmed and a
white precipitate formed. The dark mixture is stirred under reflux in a 150°C oil bath for 1h30. It was then cooled and 100 mL GAA were evaporated
then 200 mL water were added and 100 mL EtOAc and the mixture was stirred one night. The EtOAc was decanted, the aqueous layer extracted twice more
and the combined organics washed with water and evaporated. There remained 11 g of an oil wich was crystallized from MeOH to give 7.2 g (43%) of
2,5-dimethoxy-4-methyl-benzaldehyde as a beige powder.
Оценено как: Интересно!
To be honest the above procedure was done after reading (the most impressive work) that Ullmann posted in SM, but having trouble with his ammonium
acetate addition and because I thought it was to long cooking time using his procedure and as TLC indicated complete disapearance of starting material
in one hour i thought 'Why basify, let's hydrolyse directly for one night this sticky oil obtained after evaporation'. It did the trick. The problem
with Ullmann procedure is that there is no need to basify and cook again one night, once the adduct is formed you just have to hydrolize it at acidic
pH it is OK. The benzaldehyde precipitate in a few minutes when most GAA is evaporated and water is added but the problem is the adduct is not very
water soluble hence the best to make it hydrolyse is to do a two phase solvent mixture like EtOAc/water and hydrolyse one night. This work. The
procedure as outlined here had been done on 2-alkylthio-1,4-dimethoxybenzene too and systematically a 70-80% yield is obtained with those good
substrates. I could not achieve the 90% yield of Ullmann (and I tried it like he said) but after examination the problem was always an hydrolysis
problem (insoluble oil that do not migrate on TLC) not a pH problem and this procedure here is easier and quicker than his. The procedure does not
work on 2-chloro-1,4-dimethoxybenzene tough probably because it is too much deactivated, the adduct form but no aldehyde can be obtained because it is
not hydrolisable. Strangely in JOC article the same substrate worked with the TFA/Duff and I tried it that way too and it is true. So apparently the
TFA/Duff is more compatible with less activated substrate and the Sulfuric Duff is OK for 2-alkyl-1,4-dimethoxybenzene and works well with highly
activated substrates like the 2-alkylthio-1,4-dimethoxybenzene. Forget the 2-halo or straight 1,4-dimethoxybenzene with this Sulfuric Duff it will not
work (but probably TFA Duff will work).
So I'm not sure if you were already aware of this info, but i hope it was of some help to you.
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[Edited on 3-3-2011 by xwinorb]
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postart
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Can dimethyl carbonate be used in place of dimethylsulfate in this procedure?
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DrNoiZeZ
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I tried the Duff sulfuric aproach with 9,5g of 1,4-dimethoxy-2-ethoxybenzene just by the Ullman's book and I've got 9,5g of a tan product that after
recristalization with MeOH (50 ml) filtered and washed with 20 ml of cold MeOH gave 8,8g HPLC single peek. Good yield. Congrats to you all.
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Nicodem
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Thread Split
29-1-2012 at 03:35 |
ScienceSquirrel
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Thread Pruned
13-3-2012 at 05:16 |
Methyl.Magic
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I cannot understand how did you get this yield with the ullman procedure.
I tried the sulfuric duff two times following word by word the Ullmann procedure on 2,5-dimethoxy-thioanisole (1,4-dimethoxy-2-methylthio-benzene).
Everything was exactly like the procedure except the yield : both time around 45%.
I really regretted because I chose this methode to avoid the wielsmeyer-hacke and this latter gave 95% on this substrate.
I think Ullman exagerrated the yield or miscalculated it. Maybe the product was not dry ?? I am pretty sur the yield for sulfuric duff is around 50%
and the exepriment on Hyperlab told the same yield for my substrate.
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Scr0t
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I can verify this method works well for the following:
2,5-dimethoxytoluene via the hyperlab modification which gave a 56% yield of the benzaldehyde as yellow needles.
Purification was done using boiling hexane to extract the product leaving a gunk resembling toffee.
The following thio compounds gave yields of 70-80% using the method described by Ullmann but workup at the end with NaOH was found to be unnecessary.
2,5-dimethoxy-ethylthiobenzene
2,5-dimethoxy-n-propylthiobenzene
2,5-dimethoxy-i-propylthiobenzene
1,2,4-trimethoxybenzene also gave a yield of about 72% via Ullmann's method but no precipitate formed until basic workup at the end.
I haven't managed to obtain 90% yields claimed by Ullmann.
[Edited on 21-9-2013 by Scr0t]
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organichem
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What do you think on another substrate... at the moment I'm searching for an more-or-less OTC procedure for formylating tetrahydrobenzodifuran/pyran -
all procedures I found use the Rieche with SnCl4/Dichloromethyl methyl ether which is hard to obtain and needless-to-say-dangerous to
synthesize in a homelab.
So I was thinking about the sulfuric duff, but concerning the steric hindrance - I'm not sure about any success!
I would like to try the method - but atm I don't have any bis-heterocycle and synthesis takes a while, so I got time to think about alternative
formylations.
Yields in the 50-60 % would be enough I think, because taking other routes would produce also yields in this range (most are 2-step reactions e.g.
bromination with NBS and then formylating by Mg/TMOF or chloromethylation/oxidation).
By the way: I'm not interested in any 3-carbon chain derivate (then I could go for Friedel-Crafts + deoxygenation)
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thebean
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I feel like an idiot for asking this but when you say GAA is that glacial acetic acid?
"You need a little bit of insanity to do great things."
-Henry Rollins
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Texium
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Thread Untopped
17-12-2015 at 20:12 |
laserlisa
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Would sulfuric duff work for formylation of deactivated benzenes aswell?
For example 2,5-dimethoxy-4-nitrobenzene?
If not, are there any other formylation reactions that does work with deactivated benzenes?
Thanks
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byko3y
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laserlisa, Formylation of Aromatic Compounds with Hexamethylenetetramine and Trifluoroacetic Acid
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laserlisa
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Thanks for your reply, however as far as I know none of the substrates in that article are particulary electron-deficient. Maybe Im wrong?
I searched alot for articles where TFA Duff are used to formylate strongly deactivated aromatics, for example aromatics containing nitrile,nitro or
trifluoromethyl groups but with no success.
Anyone know if it is possible?
Thanks
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clearly_not_atara
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If I had to guess, it won't work under normal conditions. The Duff reaction on p-dimethoxybenzene is already so bad that people prefer to methylate
5-methoxysalicylaldehyde (a difficult methylation) in order to obtain 2,5-dimethoxybenzaldehyde.
Be aware that an aromatic nitro group may be reduced by any conditions you use to reduce an aliphatic nitro group. This means that some derivatives of
4-nitro-2,5-dimethoxybenzaldehyde cannot be synthesized in the way you might expect.
Consider the Vilsmeier-Haack formylation, or a similar reaction. IIRC it might be possible to activate DMF with SO3, if you're feeling brave.
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byko3y
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laserlisa, if you have some articles (at least links) that can prove your point, then I would be glad to see them. But for now I'm
sure TFA-HMTA is able to formylate deactivated aromatic, although yields may vary dramatically.
Duff formylation principle lays in inability to formylate a deactivated aromitic, thus the aromatic is usually not double-formylated, unlike a
phenol+formaldehyde reaction or even Riemer-Tiemann yielding a resin because of multi-formylation.
A normal duff works for highly activated phenols (it's basically a mannich reaction). Methoxy group is only slightly activating, HTMA+sulfuric acid is
strong enough to attack this ring. Even slight deactivation of dimethoxybenzene (e.g with chlorine) leads to very low yields of product, although the
yield is non-zero in that case, which means the reaction is something like 10-30 times slower for deactivated ring. HMTA+TFA works for particular
deactivated aromatics, but is tricky because slight change in the ring activity will lead to doule formylation or very slow reaction rate.
AFAIK, vilsmeier-Haack can't be used for deactivated rings and there's no way you can tune the conditions.
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laserlisa
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Thank you both for taking your time and giving me such detailed answers. Your reply motivated me to look harder for relevant articles. And I came
across an interesting article where they manage to formylate fluorinated aromatics with TFA Duff and Rieche formylation.
Synthesis and anticancer activity of fluorinated analogues of combretastatin A-4
DOI: 0.1016/S0022-1139(03)00117-9
Article is attached.
| Quote: |
Abstract:
... 3,5- Difluoro-4-hydroxybenzaldehyde (6) and 3-fluoro-4-methoxybenzaldehyde (11) are prepared by Duff formylation of 3,5-difluorophenol and
2-fluoroanisole, respectively. 2-Methoxy-3,4-difluorobenzaldehyde was obtained by Friedel–Crafts formylation of 2,3-difluoroanisole with
a,a-dichloromethyl methyl ether... |
(Note they call it Friedel-Crafts formylation, but this is usually called Rieche formylation is it not?)
The Rieche formylation with dichloromethyl methyl ether looks very interesting I must say, given the quick reaction and high yield. Is this perhaps
the go-to formylation for deactivated aromatics? Is it likely that the Rieche would work for nitrobenzenes or similiar strongly deactivated aromatics?
In the article the TFA Duff formylation of 2,3-difluoroanisole fails, but succeeds with Rieche. Could the failure with Duff be because the substrate
is even more electron-deficient than the monfluoro aromatics?
Thanks
Attachment: Synthesis and anticancer activity of fluorinated analogues of combretastatin A-4.pdf (183kB)
This file has been downloaded 857 times
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byko3y
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It's interesting to see that they were able to formylate 2-fluoro-methoxybenzene, while the same formylation with 2,3-difluoro-methoxybenzene failed
and produced a sticky black tar. The question is - what did cause the starting material to react, forming something other than a benzaldehyde.
I've realized that you need a strongly deactivated phenol, like nitrophenol, to successfully formylate it. 4-cyanophenol also gives raise to polymeric
products when treated with HMTA-TFA. The article you've mentioned cites the Synthesis and structure-activity studies of some disubstituted phenylisoxazoles against human picornavirus, which has an example of formylation of
2,6-difluorophenol with TFA-HMTA.
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clearly_not_atara
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I actually think that the formylation is impossible with any reagent. Specifically the nitro group causes formylation of 2,5-dimethoxynitrobenzene to
occur at the 3 position, forming 3-nitro-2,5-dimethoxybenzaldehyde.
However, it is possible to nitrate 2,5-dimethoxytoluene at the 4 position.
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