Sciencemadness Discussion Board

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

Ullmann - 5-11-2008 at 12:10

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 :

--------------------------------------

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

(...)


-------------------


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!

----------------
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.

-----------------


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]

Klute - 5-11-2008 at 14:23

Beautifull work!!!!

This is really an incredible advance, the thiolation is very very neat! no need for any messy zinc reductions, or chlorosulfonic acid!

And such a great succes with the Duff is a masterpiece!

I really think this is an incredible breakthrough! Outstandingly good chemistry!

This really is the kind of work that we should see more often! I am truely amazed.... It seems you really have a touch for incredible reactions with very availble products, between this work and the OTC ethansulfonates! I cannot express my admiration enough...

As an alternative to the duff formylation, maybe the the S-alkylated hydroquinone would give good results with a Mg-mediated formylation? But at the same time you can hardly do simplier than hexamine and H2SO4... and such outstanding yields... I am truely impressed!

Keep up the good work, and I am impatient to see what other treats you may have for us in the futur!

[Edited on 6-11-2008 by Klute]

Maja - 5-11-2008 at 14:31

I second Klute about masterwork !

I'm interested in
Quote:
Sadly it seems to not work that great for dimethoxybenzene, unsoluble adduct form.


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

Congratulations ! :)

smuv - 5-11-2008 at 15:14

Good work.

I never really realized the delepine formylation is just a mannich addition coupled with a sommelet reaction.

Am I right in assuming acidic conditions could hydrolize the thiourea adduct without requiring an inert atmosphere?


Late Edit:
I just dug this up, It looks even easier! (although uses stinky thiols)

Organic synthesis in water: Green protocol for the conjugate addition of thiols to p-quinones
Journal of Molecular Catalysis A: Chemical 274 (2007) 116–119


[Edited on 11-6-2008 by smuv]

Attachment: Thiolation_benzoquinones_RSH_H2O.pdf (184kB)
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Nicodem - 6-11-2008 at 00:02

Quote:
Originally posted by Ullmann
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% :-)

Wooow! This nearly threw me off the chair. :D
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.

stoichiometric_steve - 6-11-2008 at 01:57

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

Quote:
Originally posted by Ullmann For alkyldimethoxybenzene it works relatively OK, like a TFA modified Duff. For halogenodimethoxybenzene it works bof too.


I would be very interested in more detailed information on those Duff formylations for alkylated dimethoxybenzenes and the halogen derivatives.

Klute - 6-11-2008 at 06:09

Some article son the thiolation:

Reaction of Quinones with Thiourea.
A Novel Route to 2-Amino-6-hydroxybenzothiazoles and
2-Amino-5-hydroxynaphtho[l,2-d]thiazoles

P. T. S. Lau, T. E. Gompf
J . Org. Chem., (12)35, 4103-4108 (1970)

Abstract:
The reaction of thiourea with excess 1,4-benzoquinones and l14-naphthoquinones in the presence of concentrated
hydrochloric acid offers a convenient route for the synthesis of a variety of 2-amino-6-hydroxybenzothiazoles (3)
and 2-amino-5-hydroxynaphtho[l,2-dth] iazoles (15). These compounds could also be prepared by treating the
corresponding S-(2,5-dihydroxyphenyl)thiouronium chlorides (1) and S-(1,4-dihydroxynaphthyl)thiouronium
chlorides (13) with benzoquinones and naphthoquinones, respectively. Extension of this reaction to N-substituted
thioureas gave the related N-substituted 2-aminobenzothiazoly1(16) and naphthothiazolyl(l7) compounds.

Attachment: jo00837a003.pdf (702kB)
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Klute - 6-11-2008 at 06:12

A One- Step Synthesis of 5-Hydroxy-1,3-benzoxathiol-2-ones
P. T. S. Lau, M. Kestner
J. Org. Chem.; (12)33, 4426-4431(1968)

Abstract:
A wide variety of 5-hydroxy-1,3-benzoxathiol-2-onews ere prepared in excellent yields by a one-step synthesis
from readily available quinones and thiourea. Depending on the nature of the substituents and the reaction
conditions, the intermediate 5-(2,5-dihydroxyaryl)thiouronium salts and 5-hydroxy-2-imino-l,3-benzoxathioles
could also be readily isolated. Reactions of thiourea with unsubstituted, disubstituted, or trisubstituted quinone
gave only one end product. However, monosubstituted quinones gave one or more of the three pomible isomeric
end products, the 4-, 6,an d 7-substituted 5-hydroxy-l,3-benzoxathiol-2-ones. The directive influence of the
substituent groups on the addition of thiourea and their effect on the ease of cyclization of the resulting thiouronium
salts are described.

Attachment: jo01276a025.pdf (721kB)
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Klute - 6-11-2008 at 06:43

Duff formylation of indoles using AcOH:

Acylation of Indoles by 5uff Reaction and Vilsmeier-Haack
Formylation and Conformation of N- Formylindoles

J. Org. Chem.; (23)38, 4002-4004 (1973)

Abstract:Indoles react with hexamethylenetetramine to give 3-formylindoles. Skatole on formylation with Ar,Ar-dimethylformamide
and phosphorus oxychloride gives l-formyl-3-methylindole, 2-formyl-%me thylindole, and oformamidoacetophenone.
The same reaction -with 2,3-dimethylindole gives 2,3-diniethvl-l-formylindole. 1-
Formyliridole exists in two conforniations in CCL at 30" while, under the same conditions, 2,3-dimethyl-l-formylindole
exists solely in one conformation.



Maybe the use of H2SO4 could be helpfull here too?

[Edited on 6-11-2008 by Klute]

[Edited on 6-11-2008 by Klute]

Attachment: jo00987a009_duff_indole.pdf (432kB)
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Ullmann - 6-11-2008 at 07:11

Thank you all for your nice and happy comments, they make me feel some persons appreciate the work behind the reactions...

Quote:
Originally posted by Klute
It seems you really have a touch for incredible reactions with very availble products, between this work and the OTC ethansulfonates! I cannot express my admiration enough...


Who told you you have to order chemical from a supply house to be able to do true chemistry? Everything is in the grocery store! ;-)

Quote:
Originally posted by Klute
As an alternative to the duff formylation, maybe the the S-alkylated hydroquinone would give good results with a Mg-mediated formylation? But at the same time you can hardly do simplier than hexamine and H2SO4... and such outstanding yields... I am truely impressed!


Mhh I dunno, i would methylate first and do the Duff as it works great ... its easy


Quote:
Originally posted by smuv
Am I right in assuming acidic conditions could hydrolize the thiourea adduct without requiring an inert atmosphere?


Mhh yes there is no need for inert atmosphere while hydrolyzing the thiourea adduct to the benzothioxolone, but to open the benzothioxolone to get the mercapto hydroquinone you need to use basic condition and inert gaz.


Quote:
Originally posted by smuv
I just dug this up, It looks even easier! (although uses stinky thiols)

Organic synthesis in water: Green protocol for the conjugate addition of thiols to p-quinones
Journal of Molecular Catalysis A: Chemical 274 (2007) 116–119


Yup it would be interesting to try it but the thing is that in the litterature it is the only positive result obtained with this reaction. In older paper (JACS 61 450 1939) they say it does not work :
Quote:
With ethyl mercaptan, the only products isolated were small amounts (6%) of hydroquinone and bisthioethyl-p-benzoquinone. The latter compound separated readily from the reaction mixture because of its slight solubility in alcohol. A somewhat better yield (20%) was obtained with quinone and excess ethyl mercaptan at 100°C.


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 ;) !

Quote:
Originally posted by Maja
What is "that great" ? It isn't working at all or you can expect some yield ?


Here is the attempt with 1,4-dimethoxybenzene :


------------

50 mmol DMB (MW 138, 6.9 g) and 100 mmol HMTA (MW 140, 14 g) are placed in a 250 ml RBF equipped with a magnetic stirrer and a dropping funnel. There is then added 60 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 with stirring during 30 minutes 200 mmol H2SO4 (MW 98, d 1.84, 95%, 11 ml, 2eq relative to HMTA) dissolved in 40 ml GAA. At half the addition there was beginning of deposition of a white ppt in a yellow solution, it progressivelly became yellow and during the last 5 ml of addition the ppt became more thick. The thick canari yellow suspension is then stirred at 100°C for two hours more. The solid was completely dissolved at that time, no more reactant was observed in HPLC. So after two hours at 100°C there is added anhydrous ammonium acetate in powder by portions over five minutes (400 mmol, 2 eq relative to sulfuric acid, MW 77, 31 g). A white ppt formed directly during the addition. The white suspension in a yellow solution was stirred for two hours more. 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 the night as two hours was not enough on HPLC at 100°C the color now was again more yellow (imine formed). The all mixture was then poured in 400 ml of warm 1% HCl. The mixture was refluxed for 15 minutes (complete dissolution occured) then cooled to RT. Meanwhile, a solution of 80 g NaOH in 100 ml water is prepared. At RT, cautiously, the cooled acidic solution is neutralized with the soda solution until pH 8 is attained. Some red oil separated. After tolu extraction 4 g (< 50% yield) of a thick yellow oil containing the aldehyde as the only migrating spot + a Rf 0 on TLC (Et2O/hex:1/1) was obtained. Chromatography or distillation is needed to purify it.... It was dropped as it is a wasteful way to do this aldehyde, better via the salycilaldehyde with Mg! Only utility (beside with the 4-thio of course!) of this reaction is maybe for 4-chloro as chlorination is unselective...

H-A-T.
------------


Here I second our Sufi friend, it is best to do the 2,5-DMB trough methylgentisaldehyde (5-Meo-salicylaldehyde) via Mg-mediated ortho formylation then to methylate it using MES.

Quote:
Originally posted by stoichiometric_steve
I would be very interested in more detailed information on those Duff formylations for alkylated dimethoxybenzenes and the halogen derivatives.


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 :)

-----------------------

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.
----------------------------------


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 :

-----------------------
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.

---------------


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.

Quote:
Originally posted by Nicodem
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.


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]

stoichiometric_steve - 6-11-2008 at 10:37

Quote:
Originally posted by Ullmann
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).


I beg to differ! The chlorination of 2,5-Dimethoxyphenethylamine Hydrochloride as a 0.5M solution in GAA with 1.5eq Sulfuryl Chloride gives pretty pure 2C-C Hydrochloride in decent (>60%) yield.

Ullmann - 6-11-2008 at 11:01

Did you do NMR spectrum on the final product? and MS?

Mine (some higher homologue) was a mixture of three products and it worsened by recrystallisation. I too used SO2Cl2.

For DOC it is well known in the litterature several compounds are present.

Did you recrystallize it, with which solvent?


Quote:
Originally posted by stoichiometric_steve
Quote:
Originally posted by Ullmann
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).


I beg to differ! The chlorination of 2,5-Dimethoxyphenethylamine Hydrochloride as a 0.5M solution in GAA with 1.5eq Sulfuryl Chloride gives pretty pure 2C-C Hydrochloride in decent (>60%) yield.

stoichiometric_steve - 6-11-2008 at 11:06

Quote:
Originally posted by Ullmann
Did you do NMR spectrum on the final product? and MS?

Mine (some higher homologue) was a mixture of three products and it worsened by recrystallisation. I too used SO2Cl2.

Did you recrystallize it, with which solvent?


I don't have access to either of these instruments. The mp. was good.

IPA/Ether was the recrystallization solvent. You probably let the temperature go too high...

Ullmann - 6-11-2008 at 11:49

Quote:
Originally posted by stoichiometric_steve

I don't have access to either of these instruments. The mp. was good.

IPA/Ether was the recrystallization solvent. You probably let the temperature go too high...


The reaction was done at the freezing point of the GAA solution.

Here is from Pihkal, DOC entry :

Quote:
After filtering, Et2O washing, and air drying to constant weight, there was obtained 1.4 g of 2,5-dimethoxy-4-chloroamphetamine hydrochloride (DOC) From the mother liquors (from the original HCl saturation) an equal amount of product could be obtained by exploiting the acetone insolubility of the hydrochloride salt of the product. The ublished mp of this salt, from acetone/EtOH, is 187-188 °C. A sample of this hydrochloride salt, prepared from the amino analogue via diazotization and eventual hydrolysis of an acetylated precursor, was recrystallized from EtOH/ether and had a mp of 193-194.5


The paper he is refering to is Canadian Journal of Chemistry (1973), 51(9), 1402-9. They made DOC by diazotation. Look the mp is not that different but the DOC of Shulgin in reality is 3 products. I bet it is less than 70% pure. Some clues are in the Can J Chem article IIRC. The worse in this is that it is not purifiable by recrystallisation AFAIK. It behave like an homogeneous compound on recrystallisation. The only way to tell about purity of the final product in that case is NMR and MS.

Well nonetheless to do it from scratch it is best to make it like posted above. It is OTC and the aldehyde can be obtained in good purity. Also the 5-tweetio can be obtained by that route selectively.

[Edited on 6-11-08 by Ullmann]

Klute - 6-11-2008 at 14:09

Btw, have you tried forming the thiol via hydrolysis of the thiosulfate adduct? That would indeed be a OTC variation, I'm not sure where thiourea can be found in the commerce.

the acidic hydrolyis would only form HSO4- and the thiol, no H2S (bloody thing!), but formation of the disulfide as a byproduct is possible. Of course, the disulfide can be reduced to the thiol easily, or even directly alkylated under certain conditions (presence of Rongalite or dithionite)..

IIRC, basic hydrolysis cannot be used for the adduct of a benzoquinone and thiosulfate, as it simply regenerates the unsaturated substrate unfortunaly.

This route might be a a better option for those that can't get thiourea, hopefully the yields would be as high as the thioloxxone route!

The formation of the Bunte salt and it's hydrolysis could even be done one-pot, saving quite some time.


EDIT: A informative article on the addition of nucleophile son benzoquinone:

Regioselectivity of conjugate additions to monoalkyl-1,4-benzoquinones
T. BOZIC et al.
J.Serb.Chem.Soc.; 67(8–9), 547–551 (2002)


Abstract:
The regioselectivity of the reaction of conjugate addition of thiols, amines, methanol
and hydrogen chloride with the monoalkyl-1,4-benzoquinones avarone and 2-tert-butyl-
1,4-benzoquinone was investigated. It was shown that the regioselectivity of the reaction
is influenced by the electrophilicity of position 5 in unprotonated 2-alkylquinones, the increased
electrophilicity of position 6 in acidic medium, and by the acidity of the intermediate
hydroquinones.
Keywords: quinone, avarone, conjugate addition, regioselectivity.

[Edited on 7-11-2008 by Klute]

Attachment: thiol_addition_sub_benzo.pdf (68kB)
This file has been downloaded 1466 times


Barium - 8-11-2008 at 09:46

Very, very nice work Ullmann!

Maja - 12-11-2008 at 07:33

There is any way to exchange that Methyl to Ethyl ? :]

Klute - 13-11-2008 at 05:54

Of course, alkylate with ethyl halide or ethyl ethane sulfonate, etc.

As Ullman said, you can either bet on the difference in nucleophility of the thiolate and phenolate by using 1eq of base and 1 eq of ethylating agent, leaving the phenols alone (Alcalay does that with mercaptohydroquinone with good results using NaOh in ethanol, see my translation of his paper in the ref forum), or, as Ullman mentionned above, play on the difference of basicity, using a slight excess of ethylating agent and NaHCO3 as a base, which will deprotonate the thiol but not the phenols. Very clever BTW.

stoichiometric_steve - 23-11-2008 at 04:57

Quote:
Originally posted by stoichiometric_steve
Quote:
Originally posted by Ullmann
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).


I beg to differ! The chlorination of 2,5-Dimethoxyphenethylamine Hydrochloride as a 0.5M solution in GAA with 1.5eq Sulfuryl Chloride gives pretty pure 2C-C Hydrochloride in decent (>60%) yield.


Check: J Label Compd Radiopharm 2006; 49: 1187–1200. DOI: 10.1002/jlcr.1139

Those guys applied the same methodology and yet got a clean NMR (but shitty yield - 29%). I don't know if they lied, this is common practice amongst the asian scientific community*. Prediction of the 1H and 13C NMR spectra with ChemDraw yielded good matches.

*Another paper, describing the oxidative hydrolysis of nitroalkanes and alkenes to ketones and reduction of nitroalkenes amines using Fe/HCl by some indian guys, goes like this: They apparently succeeded in getting a decent yield of amine from nitroalkene by only employing 2eq of Fe per eq. substrate. Maybe indian Fe goes to Fe(IV) in acidic conditions, while eurasian Fe does not?

*D. Channe Gowda, one of the worst authors ever, also indian. Claims that Zinc can "catalyse" a reduction of nitro compounds and oximes with ammonium salts. He probably never heard of dissolving metal reductions. Nonetheless, none of the reductive procedures described in his papers works, i tried them all.

[Edited on 23-11-2008 by stoichiometric_steve]

Klute - 23-11-2008 at 05:01

Hehe well we should try going there to perform reductions..

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

Ullmann - 21-8-2009 at 10:40

@Maja
Quote:
There is any way to exchange that Methyl to Ethyl ? :]


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

Quote:
Pihkal #167 (4T-MMDA-2) :
To a suspension of 100 g finely powdered anhydrous K2CO3 in 400 mL acetone containing 50 g methyl iodide there was added 41 g 5-hydroxy-1,3-benzoxathiol-2-one, and the mixture stirred overnight at room temperature. The solids were removed by
filtration, and the solvent removed under vacuum. The residue was distilled to give a fraction subliming over as a solid at an oven temperature of 110 °C at 0.1 mm/Hg. This was a yellowish solid, weighing 27.4 g and having a mp of 66-72 °C. Recrystallization from MeOH gave 5-methoxy-1,3-benzoxathiol-2-one as a white solid with a mp of 75.5-76.5 °C.



Hydrolysis : 4-ethoxy-2-mercaptophenol

Following the procedure for the lower homologue with a methyl group :
Quote:
Pihkal #167 (4T-MMDA-2) :
To a solution of 30 g 85% KOH (455 mmol) in 75 mL warm H2O, there was added an equal volume of warm MeOH followed by 16 g 5-methoxy-1,3-benzoxathiol-2-one (88 mmol) , and the mixture was held under reflux conditions for 2 h. After cooling to room temperature, the mix was acidified with HCl and extracted with 2×100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a yellow oil that crystallized on standing. The product, 2-mercapto-4-methoxyphenol, weighed 14 g and had a mp of 56-57 °C.


A solution of 40 g NaOH (1 mol) in 100 ml of H2O and 100 ml MeOH was degassed for 15 minutes with argon. There was then added 36 g of 5-ethoxy-1,3-benzoxathiol-2-one (MW 196, 183 mmol) and the mixture was held on reflux for 2 hour under argon. After a short period a whole mass of ppt deposed and at 30 min of reflux 100 ml of degassed water was added, this dissolved the ppt but a second one came. The mixture was green with a pale ppt. Reflux was maintained until the end of the two hours period. It was then allowed to get back at RT and then poured in 200 ml 6 N HCl. The brown oil that separated was extracted with 2 x 100 ml CH2Cl2, the combined organic phase dried on MgSO4 then filtrated and rotavaped : 31 g of a fluid stinky pale brown oil was obtained in a quantitative yield (182 mmol).


One pot dialkylation of the thiocatechol : 2-ethoxy-5-methoxy-4-alkylthio-benzene

A) 2-ethoxy-5-methoxy-4-ethylthio-benzene :

In a methanolic (100 ml) solution of 6.8 g (MW 170, 40 mmol) 4-ethoxy-2-mercaptophenol degassed under Argon there is added KOH (flakes, 1.1 eq, 44 mmol, MW 56, 85%, 2.9 g) then after dissolution, bromoethane (1.1 eq, MW 109, 44 mmol, 4.8 g, d 1.46, 3.3 ml) and the mixture was stirred at RT for a night. After 5 min KBr precipitate. After a night TLC indicated one major product. KOH (44 mmol, MW 56, 85%, 2.9 g) and DMS (60 mmol, MW 126, 7.6 g, d1.33, 5.7 ml) (EXO) were then added and the reaction refluxed for three hours. After this time ammonia (100 mmol) was added and the mixture was left to come back at RT for 30 min before workup. The ppt was filtered and washed with MeOH, the solvent evaporated, the residue partitioned between CH2Cl2 and NaOH aq, the org layer washed twice with water then dried on MgSO4, filtration, evaporation. Yield : 6.3 g (MW 212, 30 mmol, 75 %) amber oil that crystallize in needles.



B) 2-ethoxy-5-methoxy-4-propylthio-benzene :

In a 250 ml RBF equipped with septum, argon inlett and a stir bar. In a methanolic (100 ml) solution of 6.8 g (MW 170, 40 mmol) 4-ethoxy-2-mercaptophenol degassed (15 min at least before KOH addition) under Argon there is added KOH (flakes, 1.1 eq, 44 mmol, MW 56, 85%, 2.9 g) then after dissolution, 1-bromopropane (1.1 eq, MW 123, 44 mmol, 5.4 g, d 1.35, 4.0 ml) and the mixture was stirred at RT for a night (the argon inlett was removed after addition of bromopropane). After 5 min KBr precipitate. After a night TLC indicated one major product. KOH (44 mmol, MW 56, 85%, 2.9 g) and MMS (60 mmol, 60 ml of a 1 M in MeOH solution) (EXO) were then added and the reaction refluxed for a total of 5 hours. A lot of solid precipitated and it had to be dilute with 50 ml more of MeOH to make it barely stirrable. After cooling to RT ammonia (5 ml 25% aq) was added and the mixture was stirred for 30 minutes to destroy excess MMS. It was then filtered on buchner and the salt rinced with some MeOH. The solvent was evaporated, the residue partitioned between 10% NaOH/CH2Cl2, the CH2Cl2 layer washed twice with water, evaporated to give 7.2 g amber oil (MW 226, 32 mmol, 80 %) TLC homogene enough, Rf 6.5 @ 50/50:Hex/Et2O.

In that previous example MMS stand for methyl methane sulfonate see https://sciencemadness.org/talk/viewthread.php?tid=9921&... for more info. Note the good yield for both alkylation steps.


C) 2-ethoxy-5-methoxy-4-isopropylthio-benzene :

In a methanolic (125 ml) solution of 8.5 g (MW 170, 50 mmol) 4-ethoxy-2-mercaptophenol degassed under Argon there is added KOH (flakes, 1.1 eq, 55 mmol, MW 56, 85%, 3.6 g) then after dissolution, 2-bromopropane (2 eq, MW 123, 100 mmol, 12.3 g, d 1.31, 9.4 ml) and the mixture was stirred (closed vessel with septum under Ar) at 40°C for a night (T bath = 50°C). After 1 h KBr precipitate. After a night TLC indicated one major product. KOH (55 mmol, MW 56, 85%, 3.6 g) and DMS (75 mmol, MW 126, 9.5 g, d1.33, 7.2 ml)) (EXO) were then added and the reaction stirred for a night. After a night ammonia (5 ml 25% aq) was added and the mixture was stirred for 30 minutes to destroy excess DMS. It was then filtered on buchner and the salt rinced with some MeOH. The solvent was evaporated, the residue partitioned between 10% NaOH/CH2Cl2, the CH2Cl2 layer washed twice with water, evaporated to give 10.8 g amber oil (MW 226, 48 mmol, 96 %) :-) NMR correct.


The benzaldehydes can be done with POCl3/DMF (good yields) or with the sulfuric Duff reaction as posted above but with those substrates the yields are like 20-30% and flash chromatography had to be used probably because the ortho-ethoxy hinder the second step or the hydrolysis of the Duff reaction, most of the product remain as an oil that do not migrate on TLC that is I think the hexamine adduct.

[Edited on 21-8-09 by Ullmann]

Klute - 21-8-2009 at 13:21

Great work as always! I am really impressionned... I'd love to try these reactions out myself someday.. Keep up the good work!

Maja - 23-8-2009 at 07:07

This is so fullfilling ! Thank you very much. I can't add anything useful.

Klute - 24-8-2009 at 10:28

I have a proposition: this thread is so remarquable, could we make it a sticky? I would love to see more work like this, maybe having this as a permenant sticky will encourage more outstanding publications!

Oh, and Ullman, could we have an experimental for the Vilsmeir-Hack?

[Edited on 24-8-2009 by Klute]

Ullmann - 1-9-2009 at 09:12

Vilsmeir-Haack : 2-ethoxy-4-ethylthio-5-methoxy-benzaldehyde

POCl3 (7 g, MW 153, 1.5 eq, 46 mmol) and DMF (4 ml, d 0.94, MW 73, 52 mmol) are stirred together (EXO) and heated briefly to 100°C. To the claret solution obtained after return to RT is added at once crude 2-ethoxy-4-ethylthio-5-methoxy-benzene (1 eq, 30 mmol, MW 212, 6.3 g). The mixture is heated to 100°C for 20 min and then pourred in a large excess of 55°C H2O and let stir for one hour. The cristallized aldehyde is filtered and washed with plenty of water and then a small amount of cold MeOH. The product is recrystallized from MeOH to give after air drying 5.8 g (24 mmol, MW 73, 80 %) of brown crystals. One spot in TLC.

A condensation test was made to prove the presence of the aldehyde :

2-ethoxy-4-ethylthio-5-methoxy-nitrostyrene

To a solution of 20 mmol 2-ethoxy-4-ethylthio-5-methoxy-benzaldehyde (MW 240, 4.8 g) in 20 ml MeOH and 4 mL of GAA there was added aqueous MeNH2 (MW 31, 0.2 eq, 7 mmol, 40% aq, d 0.9, 0.4 mL) and then 22 mmol nitromethane (MW 61, d1.12, 1.2 mL). The solution was incubated at 80°C for three hours. After one hour the NS was crystallizing already. The red cristals were left to cristallize further at -20°C for a night. The MeOH was then decanted, the crystals triturated in some cold MeOH, the solvent was decanted and the crystals were recrystallized from boiling MeOH then cooling to -10°C and filtration then washing then drying there was obtained 4.6 g MW 283 (81%) of red needles.

Thank you for your comments, it is good to know the work is appreciated.

[Edited on 1-9-09 by Ullmann]

Klute - 1-9-2009 at 09:32

Great! Thanks alot! Definitively on my to-do's list.. Thanks again for sharing all this exceptionnal work..

jon - 13-11-2009 at 05:27

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

Ullmann - 13-2-2010 at 11:43

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]

Sandmeyer - 15-2-2010 at 09:38

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

Magic Muzzlet - 5-8-2010 at 12:55

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. :cool:
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?




Nicodem - 9-8-2010 at 13:57

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. :cool:
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.

Magic Muzzlet - 30-10-2010 at 10:32

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).:)




Magic Muzzlet - 28-12-2010 at 11:26

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

xwinorb - 27-2-2011 at 12:02

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.

DJF90 - 2-3-2011 at 09:50

Can you post your experimental procedure so we can follow what you did?

xwinorb - 3-3-2011 at 09:11

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.



[Edited on 3-3-2011 by xwinorb]

postart - 31-3-2011 at 11:52

Can dimethyl carbonate be used in place of dimethylsulfate in this procedure?

DrNoiZeZ - 27-11-2011 at 07:20

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.

Methyl.Magic - 15-9-2013 at 08:45

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.


Scr0t - 21-9-2013 at 10:38

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]

organichem - 10-1-2014 at 02:18

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)

thebean - 2-5-2014 at 10:57

I feel like an idiot for asking this but when you say GAA is that glacial acetic acid?

laserlisa - 5-2-2016 at 06:58

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

byko3y - 5-2-2016 at 12:50

laserlisa, Formylation of Aromatic Compounds with Hexamethylenetetramine and Trifluoroacetic Acid

laserlisa - 6-2-2016 at 06:39

Quote: Originally posted by byko3y  
laserlisa, Formylation of Aromatic Compounds with Hexamethylenetetramine and Trifluoroacetic Acid

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

clearly_not_atara - 6-2-2016 at 20:14

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.

byko3y - 7-2-2016 at 07:25

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.

laserlisa - 7-2-2016 at 10:09

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 588 times

byko3y - 7-2-2016 at 13:16

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.

clearly_not_atara - 7-2-2016 at 15:44

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.

byko3y - 7-2-2016 at 17:53

clearly_not_atara, I can remember a paper where 3-nitrophenol was formylated to 50:50 mixture of 2- and 6-formylated products ( Studies on the Nucleophilic Aromatic 18F-Fluorination ). But I have never heard about exclusive ortho-nitro formylation. Were you going to say the same?