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Author: Subject: 4-alkylthio-2,5-dimethoxybenzaldehyde, Sulfuric Duff reaction
Ullmann
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biggrin.gif posted on 5-11-2008 at 12:10
4-alkylthio-2,5-dimethoxybenzaldehyde, Sulfuric Duff reaction


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

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

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]
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Klute
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[*] posted on 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]




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[*] posted on 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 ! :)
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[*] posted on 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]

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[*] posted on 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.




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[*] posted on 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.




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[*] posted on 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.

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[*] posted on 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.

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[*] posted on 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]

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[*] posted on 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]




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[*] posted on 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.




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[*] posted on 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.




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[*] posted on 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...




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[*] posted on 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]




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[*] posted on 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]

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[*] posted on 8-11-2008 at 09:46


Very, very nice work Ullmann!
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[*] posted on 12-11-2008 at 07:33


There is any way to exchange that Methyl to Ethyl ? :]
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[*] posted on 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.




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[*] posted on 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]




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[*] posted on 23-11-2008 at 05:01


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



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[*] posted on 21-8-2009 at 10:40
2-ethoxy-5-methoxy-4-alkylthio-benzene


@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]




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[*] posted on 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!



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[*] posted on 23-8-2009 at 07:07


This is so fullfilling ! Thank you very much. I can't add anything useful.
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[*] posted on 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]




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[*] posted on 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]




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