Antoncho
(Official Hive Translator)
04-19-03 09:49
No 428075
      Benzaldehydes: from nitro to hydroxy in one step!
(Rated as: excellent)
    

I just found this today looking for improvements in preparation of meta-methoxy-benzaldehyde.

It turns out that a nitro-BA (crude product obtained from nitration) can bee reduced to amine with NaHSO3 (!), diazotized and decomposed into m-OH-BA - all this in one pot!

This is especially cute since aminobenzaldehydes are very very picky substances and polymerize very readily - all preps i've seen thus far involve acetal protection (such as Patent GB884765 - BTW, acetal survives diazotization despite pH<7 - as well as several preps on Orgsyn).

Moreover, it wasn't entirely clear (to me, that is smile) as to how well diazo group would beehave towards the aldehyde moiety.

Well, bees, here's the xperimental from Patent GB232392:





15 parts by weight of benzaldehyde are nitrated in the usual way with a mixture of nitric and sulphuric acids at as low temperature as conveniently possible, and the nitration mixture poured on to ice, the oil well washed with water and dilute soda, and with water again until neutral. The mixture of o- and m-nitro-benzaldehydes thus obtained is then stirred thoroughly in parts water containing sufficient sodium hydrosulphite for the complete reduction of the nitro bodies; about 96 parts will be necessary. The heat generated by the reaction causes the temperature to rise even to boiling point.

This may be allowed to continue for about quarter of an hour, when the reaction will abate; then as quickly as possible, the entire reaction product is cooled down, and the amino-benzaldehydes are diazotised. For this purpose, about 200 parts concentrated hydrochloric acid, or 120 parts 50% sulphuric acid are added, that is to say, sufficient to combine with the amines, with the nitrite to be added, and with the excess of hydrosulphite and its oxidation products contained in the liquid. About 43 parts of sodium nitrite are necessary, and this is preferably added in the form of a concentrated solution. The diazo solution should be pale red in colour.

If the cooling of the amino body took too long, a deeper shade is obtained, and a smaller yield of the final product.

Towards the end, the diazotisation proceeds slowly; when it is complete, it is decomposed by dropping it into a boiling solution of about 90 parts concentrated sulphuric acid in 400 parts water, through which a lively current of steam is passing, the salicyl aldehyde and anthranil distill over, and the m-hydroxybenzaldehyde remains in the solution.

The aldehydes are collected by extraction from their solutions. In the case of salicyl aldehyde, it must be separated from the anthranil by solution in alkali separated from the insoluble anthranil and subsequent precipitation by acid.






Now, ain't that sweet? Instead of those tedious routes from bromo- aldehydes that require either 24hrs reflux or strictly unhydrous conditions, we now have a procedure that gives us a hydroxy-substituted aldehyde in under 4hrs, with all the reagents being dirt cheap and accessible.


Ir remains to bee seen how well this route works on methoxy-subst'd BA's (such as veratraldehyde, nitration of which is described on OrgSyn).


But that's not all yet, here's another improvement to the method. As it appears from Patent US2622078, if one adds some ketone (like acetone) to the pre-diazotization mixture, the rxn proceeds w/better yields of cleaner products - moreover, the temp can bee increased thus speeding up the rxn.

It is interesting to note that the trick works equally well independently on what methods are used to diazotize the amine, whatever it is, and whatever is the pH of the reaction!

And, in addition to all that, the patent clearly states that if one adds yet more acetone to the post-diazotization mixtr, the diazonium salt crashes out! Another patent says that to effect this not only acetone may bee used, IPA (as well as butanol and amyl alcohol) will do the trick.

And the isolated solid salt can bee reacted directly w/MeOH to produce methoxylated aldehyde!

It can't bee said with certainty that such a method would work on hydroxylated diazonium salts (like the one that can bee made from vanillin) - but if it would, it'd certainly make life so much easier, since those dihydroxyaldehydes are a real bitch to isolate fro aq solutions - that is, unless you evap all water in vacuo and Soxlet the remains as Uemura didcrazy


In any case, this seems to bee a superior route to m-MeO-BA, from which one would arrive at m-MeO-PEA which is a reported aphrodisiac (yeah, i know that the o-methoxy was reported to bee a fraud, but meta- hasn't been bioassayed yetwink. And the N-methylated amphetamine is certain to bee interesting).

Another yet more interesting application for this would start from p-tolualdehyde - well, you know what i mean, don't you?wink




Tell me if you like the idea, beessmile

Antoncho
 
 
 
 
    Chimimanie
(Hive Bee)
04-19-03 10:01
No 428081
      It seem good     

And VERY good if it work on para-tolualdehyde

Hehe MMAI for the masses!wink
 
 
 
 
    Rhodium
(Chief Bee)
04-19-03 11:03
No 428090
      MMAI     

Oh, please try this on tolualdehyde, someone!
 
 
 
 
    Bandil
(Hive Bee)
04-20-03 02:34
No 428170
      I'm not totally hot on the different ...     

I'm not totally hot on the different functional groups "positioning". I suppose that the nitration of p-tolualdehyde will yeild 4-methyl-2,5-dinitro-BA? I can't imagine the groups going anywhere else, that would give you such a "chemistry boner" :D

But the tolualdehyde is really cheap(55 eur/500 g) and unsuspicious, so i guess it's worth a try!

Regards

Cops are not there to help you, they're there to bust you.
 
 
 
 
    Antoncho
(Official Hive Translator)
04-20-03 05:40
No 428180
      Not exactly...     

That would surely give you 3-nitro-4-methyl-BA. In this case you won't even get any ortho-nitrated isomer since CH3- is ortho orienting which further improves selectivity.

Nitrogroup is very deactivating, and introducing two NO2's into the ring that is already quite deactivated by -CHO group would require very drastic conditions (if possible at all w/out oxidizing the stuff to -COOH).



Antoncho
 
 
 
 
    cattleprodder
(Hive Bee)
04-21-03 12:40
No 428443
      Excellent find.     

It looks like you may have very well also found the answer as to how to make 4-ethyl-3-methoxybenzaldehyde (and others, such as vanillin derivatives) as well.
 
 
 
 
    Antoncho
(Official Hive Translator)
04-21-03 19:47
No 428537
      Another nice nitro- to hydroxy- procedure!
(Rated as: excellent)
    

This excellent addition to the posted above was made by Chemister of HyperLab.




Into a 3L beaker equipped w/an efficient mech stirrer there’s placed a soln of 450g (2mole) powdered SnCl2*2H2O in 600mls conc HCl and the mixtr is cooled to 5 C. The ice bath is removed and in one portion there’s added 100g (0,66mole) m-nitro-benzaldehyde. The temp at 1st climbs up slowly (up to 25-30 Ñ øò 5 mins), then rather quickly rises to 100 Ñ – so the beaker has to bee put into icebath again. Stirring must bee  good, otherwise the rxn can shoot thru the condenser.

During the rxn benzaldehyde dissolves and the soln turns red and almost transparent. It is cooled in salt/icebath for 2.5hrs w/slight stirring. The adduct of SnCl4 and m-amino-BA precipitates as an orange paste, is filtered thru porous glass and suspended in 600mls conc HCl in a 3L beaker which is put in salt/ice bath; all is chilled to 4-5 C. With stirring there’s slowly (over 80mins) added (beelow the level of liquid) a soln of 46g NaNO2 in 150mls water, keeping the temp at the above level. After addition’s over stirring is continued for 1 more hour so as to allow the adduct of SnCl4 to diazonium salt to fully precipitate. The reddish-brown salt is filtered thru porous glass filter.

The moist salt is cautiously added in small portions over 40mins into 1700mls boiling water (adding more water as it is lost by evaporation). The soln is treated w/4g charcoal, boiled for several mins and filtered while hot. The filtrate, which is pale red, is left for 12-16hrs refrigerated, scratching the beaker’s sides occasionally (if xtallization still doesn’t occur, a xtal of pre-made m-OH-BA is added). The yield of orange crystals with m.p. of 99-101 Ñ comprises 48-52g (59-64% of theory).

The solution of this in 1l boiling benzene is treated w/charcoal, filtered and reduced in volume to 300mls. Upon cooling there’s obtained 41-45g (51-56%) of light-brown crystals.

Further purification can bee achieved thru sublimation (in a vac exicator on a steam bath overnight).



As you can see, this method of reduction allows us to get either the aminoBA or its diazonium salt in form of their SnCl4 adducts in solid form, which could in turn allow us to react it w/methanol to arrive at MeO-substituted product w/out the need for methylation.


Now - I have some questions for everyone:

What is the role of sulfuric acid in decomposing diazonium salts to hydroxy- compounds? (as you can see in the example above they use plai water).

What happens if one reduces the volume of water/acid relatively to the diazocompound?

What is the optimal proportion of H2SO4 to water and can the solution's volume bee significantly decreased by using a higher acid concentration?







Antoncho
 
 
 
 
    GC_MS
(Hive Addict)
04-22-03 00:56
No 428585
      diazo salt     

[...] Um bei der Verkochung eine Hydrolyse des Diazoniumsalzes zu vermeiden, fuehrt man die Zersetzung in stark saurer Loesung durch. Ferner wird durch das stark saure Milieu die Kupplung des Diazoniumsalzes mit schon gebildetem Phenol zu Hydroxyazofabstoffen zurueckgedraengt 5. Da sich diese Kupplung aber auch im sehr stark sauren Bereich in einigen Faellen nicht ganz verhindern laesst, destilliert man oft das gebildete Phenol, ausreichende Fluechtigkeit vorausgesetzt, gleich nach seiner Enstehung mit Wasserdampf ab oder nimmt es waehrend der Verkochung in einem nicht mit Wasser mischbaren Loesungsmittel auf.

[5] HH Hodgson et al. Soc 1943, 379; HH Hodgson et al. Soc 1947, 327; RHC Nevile et al. Ber 13 (1880) 1949 + Ber 15 (1882) 2978.

Short translation: A strong acidic reaction environment prevents hydrolysis of the diazo salt and reaction of the formed phenol with the diazo salt to hydroxyazo substances. Since the reaction between the formed phenol and the diazo salt can ruin your yields, the phenol is sometimes removed via steam distillation during the reaction.

Houben-Weyl, Phenole I (1976), p 251. The two Ber references can be obtained via gallica.bnf.fr and if necessary, I can provide some recipies from the H-W.

The faster you run, the quicker you die.
 
 
 
 
    Antoncho
(Official Hive Translator)
04-23-03 00:24
No 428891
      Further improvements...     

As it turns out, diazonium salts can form adducts not only with SnCl4, but also w/any Lewis acid - e.g., ZnCl2.

These are much less water-soluble and can bee crushed out w/NaCl.

Moreover, the adducts are much more stable - can bee brought to RT w/out decomposition and in fact dried (mixing w/some neutral diluent like Na2SO4 is employed to eliminate certain explosiveness) and even sold in bulk to dye manufacturerssmile

Here goes a quote from Patent GB238676:





17 parts of 1-amino-2-nitro-4-chlorobenzene are dissolved at the temperature of the water bath in 30 parts of sulphuric 55 acid of 66 degrees Baume whereupon the solution is poured into cold water while stirring.

The solution is diazotised with nitrite solution in the usual manner at a low temperature, and 5 parts of zinc hydroxide and sufficient common salt are then added to precipitate the diazo compound.

The latter is obtained as a nearly colourless substance. It is filtered off, mixed with say 50 parts of pulverised dehydrated Glauber's salt or pulverised aluminium sulphate and then dried in vacuo at a moderate temperature.






Other examples include electron-rich amines as well.


I have one question for you, bees: it is known that ketones also form complexes w/Lewis acid. In one of the patents above it is stated that addirtion of acetone has a very beneficial effect on diazotisation - so my question is:

Would ZnCl2 form complexes w/acetone strong enough to compete with diazonium complexes? I.e., can one use these two improvements in one flask?

Looking forward to hear from you,

Antoncho
 
 
 
 
    Chimimanie
(Hive Bee)
04-24-03 13:56
No 429199
      tolualdehyde -> 3 MeO-tolualdehyde     

This reaction scheme is cited in Liebigs Annalen der Chemie, (7), 1413-21;  1985:

tolualdehyde ---1. KNO3,HSO4       -----------> 3 MeO-tolualdehyde
                2.1 SnCl2, water
                2.2 NaNO2,HCl,water
                3. Me2SO4,KOH,water

Maybee somebee can traduct it and post it?
 
 
 
 
    Chimimanie
(Hive Bee)
04-25-03 15:56
No 429411
      tolualdehyde -> 3-MeO-tolualdehyde
(Rated as: excellent)
    

Very useful reaction for MMAI synth!smile

Experimental: [1]

4-Methyl-3-nitrobenzaldehyd:
36.0 g (0.3 mol) p-Tolualdehyd wurden nach der Vorschrift [20] mit Kaliumnitrat in konz. Schwefelsäure nitriert. Umkristallisation aus Ether lieferte hellgelbe Nadeln; Ausb. 45.0 g (91%), Schmp. 47°C (aus Ether) (Lit. [20] 43-44°C aus Ether, 48-49°C aus Ligroin).

3-Hydroxy-4-methylbenzaldehyd(4a):
60.0 g (0.36 mol) 4-Methyl-3-nitrobenzaldehyd wurden nach der Vorschrift[13] mit SnCl2.2H2O reduziert, mit NaN02 in HCl diazotiert und zum Phenol verkocht. Nach Beendigung der Stickstoffentwicklung wurde mit Aktivkohle behandelt. Es wurde heiss abfiltriert, 16 h gekühlt und das ausgefallene Phenol abgesaugt. Aus dem Filtrat konnte durch Extraktion mit Dichlormethan weiteres Produkt isoliert werden. Das Rohprodukt wurde aus Benzol umkristallisiert; Ausb. 29.0 g (60%) (Lit. [13] 60%), Schmp. 71-72°C (aus Benzol) (Lit. [13]) 73°C).

3-Methoxy-4-methylbenzaldehyd (4b):
Zu 25.0 g (16.7 mmol) 4a in 45 ml 33proz. KOH wurden unter heftigem Rühren 40 ml (30 g, 0.42 mol) Dimethylsulfat getropft, so daB die Temp. 45°C nicht überstieg; falls erforderlich, wurde gekühlt. Nach 20 min tropfte man gleichzeitig 15 ml 33proz. KOH und 10.5 g (14 ml, 0.15 mol) Dimethylsulfat zu, nach 10 min wurden die gleichen Mengen nochmals zugegeben, und es wurde weitere 30 min gerührt. Es wurde mit 60 ml 33proz. KOH versetzt, und die Mischung wurde nach 2stdg. Stehenlassen bei Raumtemp. mit Chloroform (1 x 200 ml, 2 x 100 ml) extrahiert. Der Extrakt wurde mit Wasser gewaschen, mit Na2S04 getrocknet und i. Vak. eingeengt. Der Rückstand wurde aus Ether/n-Hexan umkristallisiert; Ausb. 29.0 g (91%) (Lit. [13] 87%), Schmp. 45-46°C (aus Ether/n-Hexan) (Lit. [13] 42 -43 °C).

References:

[1] W. Flitsch, P. Russkamp und W. Langer, Liebigs Annalen der Chemie, (7), 1413 (1985)
[13] H. Fukumi, H. Kurihara und H. Mishima, Chem. Pharm. Bull. 26, 2175 (1978)
[20] L. Gattermann, Liebigs Ann. Chem. 347, 354 (1906)
 
 
 
 
    Antoncho
(Official Hive Translator)
04-25-03 23:03
No 429481
      Many thanks, Chimimanie!     

...now we know it DOES work on tolualdehyde.

One thing i can't get is why you call that cmpd 'MMAI', - if i understand correctly, 'AI' stands for 'aminoindane'.

I think the correct name should bee MeMA or something...



Antoncho
 
 
 
 
    Chimimanie
(Hive Bee)
04-26-03 03:40
No 429519
      MMAI or not MMAI?     

Yes, you are right Antoncho there is a nomenclature problem here.

I said MMAI because the doc at Rhodium's site ../rhodium/chemistry /mmai.html is called MMAI, but it is the synthesis of the MMA in fact.

Could MMAI bee used for the aminoindan (5-MeO-6-Methyl-aminoindan) and MMA for the amphetamine analog (3-MeO-4-Methyl-Amphetamine), then?

it is the nomenclature used in Mol Pharmacol 1993 Feb;43(2):271-6, cfr http://www.neurotransmitter.net/mdmatoxicity.html

We should not use MMA for any other amphetamine analogue like PMA or PMMA or their para-methyl congeners, but what is the little nickname of the 4-methyl-methamphetamine then?crazy

But the 3-methoxy-4-methyl-benzaldehyde is useful for the two drugs, MMA and MMAI, according to the reaction scheme in ../rhodium/pdf /mmai.pdf, so I was not completely false!wink
 
 
 
 
    Antoncho
(Official Hive Translator)
04-26-03 05:36
No 429535
      Nomenclature     

Well, 1st of all i object to ever calling that compound 'MMA'

The reason for this is the following: the father of this classification, Dr. Shulgin, conventionally uses the letter 'M' to denote a methoxy group. Somewhat inconsistently, he also uses it to abbreviate N-methyl as well. IIRC, nowhere in PiHKAL is 'M' used as substitute for a ring-methyl group. So i suggest we also don't do it, - so as not to create further confusement.

I suggest 'Me' symbol to stand for a ring methyl group.

Confusement between N-methyl and ring methoxy is easily resolved by the fact that metoxy-M always comes first in the abbreviation, and N-methyl-'M' always precedes the last 'A' or 'PEA' (or, for that matter, 'C' for cathinone or 'AAP' for aminoacetophenone).

Anyone agrees/disagrees?

Anyone else has better/easier/more correct suggestions for nomenclature?
 
 
 
 
    Kinetic
(Hive Bee)
04-26-03 06:06
No 429540
      More nomenclature issues     

... Just to add to the confusion somewhat, I'll point you towards PIHKAL#68, now to be renamed DOMetongue. I have to agree that Antoncho's idea is still the most logical one, but it does interfere with a couple of Shulgin's creations.

This nomenclature problem is going to get a lot bigger too, if we keep inventing new drugs! Looks like somebee might have to consider renaming 4-MMC, especially if current plans get into production.

Very interesting thread Antoncho, thankyou. I'm sure it'll come in useful one day in the not too distant future.
 
 
 
 
    Chimimanie
(Hive Bee)
04-26-03 07:16
No 429556
      Really, I dunno. :-P I will call MMAI MMAI and     

Really, I dunno.tongue

I will call MMAI MMAI and the amphetamine analogue 3-MeO-4-Me-A, this way there could be no further objectionstongue

cool

Antoncho, I have another ref for you, one of the two you wanted, I translated it from french:

(...)

I have tried to prepare 3-MeO-benzaldehyde from the diazotation of metaaminobenzaldehyde, and then by the decomposition of the diazoïc derivative in the presence of methyl alcohol.

40g of the aldehyde are dissolved in 100g of cold conc. H2SO4, and 100g of methyl alcohol are added slowly, to not elevate too much the temperature. The solution is then cooled to 0°C, and the aminoaldehyde is diazoted with 24g of sodium nitrite dissolved in as little water as possible. The diazoïc derivative is then decomposited by elevating slowly the temperature to the ebullition.
After dilution in 250ml H2O, the solution is distilled with steam. The methyl alcohol pass first, then an uncolored oil (bp at ordinary pressure 228°C) which is the methylated aldehyde.
After cooling, some thick oil and a cristalline white product appear in the  flask. Its mp is ~89°C and after 3 recrystallisation in boiling water in the presence of activated carbon it is 107°C. That crystalline product is some aldehyde metaoxybenzoic.
The yield in methylated product is small, ~20% of the theoretical amount.

Ref: Reaction of diazotized m-amino-BA with MeOH to yield m-MeO-BA, Noelting, Ann. chim., (8) 19, 541 (1910).
 
 
 
 
    Antoncho
(Official Hive Translator)
04-26-03 07:22
No 429558
      On nomenclatures old and recent...     

Well, Sasha's DOX series shouldn't bee named, that's clear. Those abbreviations, originally derived from 'desoxy', cover their field - 2,5-diMeO-4-X-amphetamines - quite sufficiently.

This system would only apply for the PEAs with non-classic substitution patterns. Luckily, there shouldn't bee too many of them patterns, beecause, beesides simply mentioning presence of substituents on the ring, we have the problem of denoting their positioning...

E.g., how would we call 3-MeO-5-methyl-amphetamine? (likely, also active)tongue


Ok, this is beginning to get totally offtopic.





To get this back ontopic, here's a nice, nice idea of kitchen synth of that starting aldehyde (invented by Assholium) :

1. Nitrate p-xylene,
2. Oxidize with MnO2 (or Oxone) to 4-methyl-3-nitro-BA (the methyl ortho to NO2 is deactivated and won't get oxidized);
3. Then - as above.

Much nicer than chloromethylation of toluene (followed by nitration), in my humble opinion!

Any other thoughts, anyone?




Antoncho


P.S. Chimimanie, just saw your post, which you evidently made while i was writing minesmile Thank you very much!!!

The low yield somehow contradicts what i've read about this reaction...
 
 
 
 
    Rhodium
(Chief Bee)
04-26-03 09:56
No 429595
      MMAI reference     

Sorry, the MMAI thing is my fault, I'll rename that document to ../rhodium/chemistry /mma.html and also rename mmai.pdf

Edit: The full MMAI reference and location is now:

Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA)
Michael P. Johnson, Stewart P. Frescas, Robert Oberlender, and David E. Nichols
J. Med. Chem. 34, 1662-1668 (1991) (../rhodium/pdf /nichols/nichols-mmai-mma.pdf)


The Experimental part can also be found in Post 122807 (dormouse: "Benzofuran, indan and tetralin analogues of MDA.  -Nemesis", Serious Chemistry)

MMA is the name used for the compound in Medline (PMID=8429828) and some Nichols publications. Could somebody translate the german article above so that I can add it to the mma.html document?
 
 
 
 
    moo
(Hive Bee)
04-26-03 10:22
No 429601
      J. Chem. Soc. 121, 76 (1922) mostly discusses...     

J. Chem. Soc. 121, 76 (1922) mostly discusses acetalisation of  aldehydes, but here is what is told about the aromatic nitro reduction.


Reduction of m-Nitrobenzaldehydediethylacetal

The reduction of nitro-acetals in the aromatic series dose not seem to have been previously accomplished. The authors effected the reduction of m-nitrobenzaldehydediethylacetal as follows: Sodium sulphide crystals (50 grams) were dissolved in water (50 c.c.) and partly converted into the hydrosulphide by addition of concentrated hydrochloric acid (25 grams); the resulting solution, which had an alkaline reaction, was added to alcohol (90 c.c.) containing 15 grams of the acetal, when heat was evolved and the mixture became red. Reduction was completed by boiling for six hours, the alcohol was then removed by distillation through a column, and the residue, which still showed a distinct alkaline reaction, was cooled and extracted with ether. Evaporation of the washed and dried ethereal extract yielded a yellow oil, which was freed from volatile impurities by heating for some time in a vacuum at 100°. There is little doubt that the above oil was impure m-aminobenzaldehydediethylacetal. It contained no free aldehyde, as it was unaffected by cold "neutralised bisulphite" solution, free hydroxylamine, or phenylhydrazine. It was nearly insoluble in water, but dissolved in dilute mineral acid, being at once converted into a salt of m-aminobenzaldehyde, which was precipitated in a powder on subsequent addition of alkali.
 
 
 
 
    GC_MS
(Hive Addict)
04-26-03 10:36
No 429604
      translation     

Could somebody translate the german article above so that I can add it to the mma.html document?

4-methyl-3-nitrobenzaldehyde: 36.0 g (0.3 mol) 4-methylbenzaldehyde is nitrated with KNO3 in concentrated H2SO4 [20]. Recrystallization from ether gave brightly yellow coloured needles; yield 45.0 g (91%), mp: 47°C (from ether) (literature [20] 43-44°C from ether, 48-49°C from petroleum ether).

3-hydroxy-4-methylbenzaldehyde: 60.0 g (0.36 mol) 4-methyl-3-nitrobenzaldehyde was reduced applying SnCl2.2H2O (according [13]), subjected to a diazotation reaction involving NaNO2 and HCl, and boiled down to the phenol. When there was no more nitrogen gas evolution, the mixture was treated with activated coal. It was filtered while hot and allowed to cool down for 16 h, after which the precipitated phenol was sucked away. Some more phenol can be obtained by extracting the filtrate with DCM. Crystallization of the raw product from benzene yields 29.0 g (60%) of the phenol (literature [13] 60%), mp: 71-72°C (from benzene) (literature [13] 73°C)

3-methoxy-4-methylbenzaldehyde: 40 mL (30.0 g, 0.42 mol) dimethyl sulfate (DMS) is added to 25.0 g (16.7 mmol) 3-hydroxy-4-methylbenzaldehyde dissolved in 45 mL 33% KOH. Fierce stirring is necessary, and the temperature is not allowed to exceed 45°C. Otherwise, cooling is necessary. After 20 minutes, 15 mL 33% KOH and 10.5 g (14 mL, 0.15 mol) DMS are simultaneously drop-wise added. This is repeated after 10 min, and the reaction mixture is stirred for 30 more min. The mixture is diluted with 60 mL 33% KOH and allowed to rest at room temperature for two hours. The mixture is extracted with 1 x 200 mL and 2 x 100 mL chloroform, the combined extracts washed zith water, dried over Na2SO4 and freed from solvent in vacuo. The residue is crystallized from ether/n-hexane, yielding 29.0 g (91%) (literature [13] 87%), mp: 45-46°C (from ether/n-hexane) (literature [13] 42-43°C).

[13] H. Fukumi, H. Kurihara und H. Mishima, Chem. Pharm. Bull. 26, 2175 (1978)
[20] L. Gattermann, Liebigs Ann. Chem. 347, 354 (1906)

I'm not sure about the translation for "falls erforderlich".

The faster you run, the quicker you die.
 
 
 
 
    Rhodium
(Chief Bee)
04-26-03 11:30
No 429612
      Thanks!     

Thank you, "falls erforderlich" means "if needed", so the translation is correct. It has now been added to mma.html
 
 
 
 
    catastrophe
(Hive Bee)
04-26-03 15:37
No 429642
      Nice Idea     


1. Nitrate p-xylene,
2. Oxidize with MnO2 (or Oxone) to 4-methyl-3-nitro-BA (the methyl ortho to NO2 is deactivated and won't get oxidized);
3. Then - as above.




That is an excellent idea Antoncho!

ArCH3 + 2MnO2 + 2H2SO4 --> ArCHO + 3H20 + 2MnSO4

This will probably have to be done with some acetic anhydride to prevent oxidation of the aldehyde through the diacetate. And, as you stated, the -CH3 ortho to the nitro group will most probably indeed be unaffected. Very nice idea!

As for as the nitration of aldehydes, SWIM is aware that the aldehyde moiety is strongly meta directing to nitration. Phenols are strongly ortho directing, so this would be great for vanillin. Isolation of the diazonium salt and reaction with MeOH should yield syringaldehyde. About nitration, under what conditions should it be performed to prevent oxidation of the aldehyde??? If one wanted to attempt this on say Piperonal to obtain 2-nitro-4,5-methylenedioxybenzaldehyde would the strongly acidic conditions in the diazotization cleave the methylenedioxy bridge? Strongly acidic conditions are absolutely required to prevent coupling reactions of the diazo salt with the unreacted amine.

ANY thoughts would be appreciated. Thanks Antoncho!

 
 
 
 
    catastrophe
(Hive Bee)
04-26-03 15:40
No 429643
      WOW, this thread has really been dominated for     

WOW, this thread has really been dominated for an MMAI synthesis. Is that all everyone's interested in? Didn't know neurotoxicity was becoming that popular.
 
 
 
 
    Chimimanie
(Hive Bee)
04-26-03 16:09
No 429649
      Hehe     

Yes it is directed to MMA(I)

neurotoxicity is not fun, and making legal analogs of popular drugs is fun....

MMA seem very interesting, it merit some more researchtongue
 
 
 
 
    catastrophe
(Hive Bee)
04-26-03 16:28
No 429651
      Other interesting ideas other than 3-MeO-4-Me-A     

SWIM was pondering while running through Rhodium's page, and what about these ideas...

2C-CN?
------
From Rhodium's we have 4-nitro-2,5-Dimethoxybenzaldehyde ../rhodium/chemistry /4-alkylthio-25-dmb.html ...

2,5-Dimethoxy-4-nitrobenzaldehyde (1)

2,5-dimethoxybenzaldehyde (3.00 g, 18 mmol) diluted in AcOH (5mL) was treated with 12 mL 65% HNO3 in small portions, with good stirring and cooling in a water bath. The reaction mixture, partially crystallized, was left at room temp around 10 min and then it was diluted in 50 mL water. Filtering, washing with water and drying gave 3.27g (86%) of product, the majority being 3,6-dimethoxy-2-nitrobenzaldehyde (2), 4-nitro- 2,5-dimethoxybenzaldehyde (1) in ~20% yield, and a small quantity of a third unidentified isomer. The crude product was fractionated by chromatography in a silica gel column with ethyl acetate as eluent, from which firstly the minor product (1) appeared, which after recrystallization from IPA had a mp of 163-164°C (lit. 163-165°C [7]).




Now we reduce to the 4-amino compound, diazotizate, and react our diazo salt (the sulphate) with a solution of the cuprous cyanide-sodium cyanide complex, NaCu(CN)2, to get our nitrile. Pretty simple compared to the current method.

How about p-fluoroamphetamine?
-------------------------------
p-nitrobenzaldehyde is reduced to the p-amino compound. Now we diazotize the aromatic amine in the presence of fluoboric acid, when the fluoborate precipitates. Heating the DRY fluoborate will give the fluoro derivative and some BF3 too, no? Something like this...

ArNH2 + 2HBF4 + NaNO2 --> [ArN2+]-BF4 + NaBF4 + 2H2O

Now, obviously if we heat the fluoborate we'll get the fluoride compound and some boron flouride as well.

Also, if you wanted a -Cl or a -Br instead, you could just do a Sandmeyer on the diazonium salt.
And boy!, this would be a GREAT way to put -I on the ring. Just add potassium iodide to an aq. sol. of the sulphate and heat.

Anyways diazo compounds are really useful. Thanks for bringing this thread up Antoncho; a lot of the times here at The Hive, a really reputable bee needs to bring something up in order for the less reputable bees to get their ideas heard. So thanks again!smile

 
 
 
 
    Rhodium
(Chief Bee)
05-04-03 08:45
No 431302
      Sandmeyer not working on unprotected aldehyde     

Catastrophe: You cannot prepare p-Fluorobenzaldehyde that way. First, the aminoaldehyde is very polymerization-prone as is, and that gets  worse when diazotizing, and then infinitely horrible in the presence of HBF4 - black, toxic tar galore! And please, stay on topic - if you want to discuss the above ideas of yours, please re-post your post above in another thread, this one is dedicated to MMA and its precursors.

Back on topic: Here are two references related to the discussion, posted by Antoncho in a no longer existing post in the "Wanted References" thread:

Nitration of benzaldehyde: Patent US1509412

Diazotization of m-amino-BA: http://orgsyn.org/orgsyn/prep.asp?prep=cv3p0564
 
 
 
 
    cattleprodder
(Hive Bee)
05-14-03 15:59
No 433211
      ? for Rhodium     

Could this method be used to convert piperonal or
3,4-methylendioxybenzoic acid (from safrole and KMnO4) to myristicinaldehyde?
 
 
 
 
    Rhodium
(Chief Bee)
05-14-03 16:43
No 433214
      Not MMDA, but MMDA.2     

No, piperonal undergoes aromatic substitution (nitration etc) in the 6-position (see ../rhodium/chemistry /tma2.vanillin.html) and thus it will not work. You could however use the procedure to synthesize 6-MeO-3,4-MDA (also called 2-MeO-4,5-MDA or MMDA-2).
 
 
 
 
    GC_MS
(Hive Addict)
05-14-03 23:22
No 433265
      sesamol     

I have had the idea once to synthesize sesamol from benzedioxol via diazotation. In my opinion, the B-V reaction of piperonal sounded to wasteful crazy
I never went any further then the nitration of benzedioxol, which really was no problem. Stupid as I am, I didn't write down the reaction details, but I remember the solvent being GAA and the yield was to be found in the 90s%. GC/MS analysis indicated the presence of ca 1% of a (tentatively identified) dinitrated product, but aside this impurity, everything looked OK. Colour test with concentrated sulfuric acid also matched the literature references in Beilstein (was it red? Not of importance now...).
The idea behind this was to find a precursor for 5-alkoxy-piperonal. Sesamol can be methylated, ethylated... and subsequently thrown in a Vilsmeier-Haack reaction mixture to magically yield 5-alkoxypiperonal.
Bromination of the benzedioxol worked out well, but substitution of the Br by OH (Cu catalyzed) seemed to be a problem... Maybe I should try to find my nitrated benzodioxol in the fridge and look for what it does with the one-pot thing... smile

The faster you run, the quicker you die.
 
 
 
 
    Rhodium
(Chief Bee)
05-23-03 16:36
No 435053
      3-NO2-4-Me-BA -> 3-MeO-4-Me-BA (53% Yield)     

Post 434913 (GC_MS: "3-methoxy-4-methylbenzaldehyde", Methods Discourse)
 
 
 
 
    imp
(Stranger)
10-15-03 23:19
No 464923
      General Info.
(Rated as: good read)
    

Earlier in this thread the question of why an acidic aqueous solution should be used to decompose the diazonium salt into a phenol was brought up. A very nice response was given... Post 428585 (GC_MS: "diazo salt", Chemistry Discourse)


A strong acidic reaction environment prevents hydrolysis of the diazo salt and reaction of the formed phenol with the diazo salt to hydroxyazo substances. Since the reaction between the formed phenol and the diazo salt can ruin your yields, the phenol is sometimes removed via steam distillation during the reaction.




SWIM just wanted to add a few useful points to this. Yes, diazonium salts react with phenols in weakly acid, neutral, or alkaline solution, to form highly coloured azo compounds. This coupling reaction generally causes substitution in the position para to the hydroxyl group. If the para position is occupied, coupling takes place in the ortho position. If the para position and both ortho positions are blocked, coupling usually does not take place, although occasionally a group such as the carboxyl group at the para position may actually be displaced. However this sort of coupling is only seen in highly activated phenolic rings. 

As far as replacing the diazo moiety with an alkoxyl group, certain complications arise. Firstly, this type of alkoxylation gives a mixture of two products - the alkoxy and the hydroxyl group. Using ethanol as the alcohol for replacement usually leads mainly to the hydroxyl...

[ArN2+]-OSO2H + CH3CH2OH ---> ArH + N2 + H2SO4 + CH3CHO

[ArN2+]-OSO2H + CH3OH ---> ArOCH3 + N2 + H2SO4

(If using MeOH, you might be able to smell for the presence of any formaldehyde generated)

Furthermore, an acidic environment must be created in order to prevent side-rxns. MeOH saturated with HCl should be acceptable, as it will remain anhydrous and help increase yields. Experimentation is heavily warranted in order to find answers.