poix (Stranger)
02-01-02 20:50
No 263890
      alkylation of quinones     

I found this ref on the net: FREE-RADICAL ALKYLATION OF QUINONES: 2-PHENOXYMETHYL-1,4-BENZOQUINONE at http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0890

It say that 1,4 benzoquinone can be alkylated with various acids, producing the corresponding 2-alkyl-quinone minus a methyl ie: benzo + propionic acid lead to 2-ethyl-quinone, acetic acid + benzo lead to toluquinone etc.

The reaction take place in water at 60, with ammonium peroxydisulfate and silver nitrate as catalyst.

If we reduce the amount of silver nitrate used and take more  reaction time, it may be a valuable process for manufacture of the 2C-E/2C-D/2C-P aldehydes and maybe 2C-TFM with TFA. The yields are not too good but it is better than a F/C acylation I think and it is in one process, not two like F/C.

So I would like to know what you think. 

(Chief Bee)
02-02-02 00:00
No 263968
      Re: alkylation of quinones     

Oooh. 2C-TFM! Somebody try this synthesis out now!
(Official Hive Translator)
02-02-02 06:48
No 264123
      Re: alkylation of quinones     

I also remember a mention made by someone that reducing quinones in MeOH leads to dimethoxybenzenes. It's somewhere on Rh's, but no details.

Would bee nice to know the exact proc. to make this yet one step shorter.

(Hive Addict)
02-02-02 12:33
No 264179
      Re: alkylation of quinones     

I remember that somebody over here performed a reaction like this a long time ago. IIRC, the last step involved `distill and isolate product'. Reaction only produced a shitload of tar and smelly glassware. The room the reaction was performed in smelled like a crackhole for over a month.
02-02-02 16:45
No 264204
      Re: alkylation of quinones     

Uhh, aparently somewhat messy rection, still quite interesting.

Well, seems that yields drop with smaller radicals (in discussion there's said that monoalkylated product should precipitate out to avoid multiple alkylation, with small radicals like Me or Et difference in solubility may be not enough for that) so it may be not too good way for producing Me or Et quinone and other imagined goodies from them.


It may be worthwile to try to whack in whole ethylamino group in one step using N protected beta alanine or maybe even 2-amino propyl from beta aminobutyric acid.

And that seems a whole lot hotter, dear bees.cool

(Chief Bee)
02-02-02 16:56
No 264207
      Re: alkylation of quinones     

THAT would be a wundersynth! And just think how cool it would be if the methoxy groups could be tacked on by performing it in MeOH.

Benzoquinone, alanine and methanol to make 2C-H in one step (plus protection/deprotection). Wow.
02-02-02 17:33
No 264215
      Re: alkylation of quinones     

Haven't thought of THAT but it would be pretty cool! When I saw this reaction I know that it had some potential in it, but it is better than I was thinking. I'm laughing out loud!laughlaughlaugh
One sad thing is that 3-amino-butyric acid is an expensive chemical, but if this reaction work with alanine we will surely find some method to synthetise it for not too much money. Another comment is that if this reaction become popular and some research is done with it maybe we could know if it is possible to put the ethylamine chain in one run, collect the product and then alkylate para to the chain in a second run (with some tweeking of reaction condition) to make 2C-E etc in two step from benzoq, propionic acid, alanine, MeOH (Antoncho find this ref!) etc. And best of all, NO reduction required, NO messy nitroethane synth to do!

I hope some bees will try this rapidly, it may become a killer reaction, psychedelic for the masses!blush

02-02-02 19:34
No 264234
      Re: alkylation of quinones     

BTW: methoxy group without dimethyl sulfate ->
(Chief Bee)
02-02-02 19:40
No 264237
      Re: alkylation of quinones     

Methoxy groups can only be introduced like that when there is powerful electron-withdrawing substituents on the ring, such as NO2 and/or CN.

However, with catalytic Cu(I) aromatic bromides and iodides can be substituted with hydroxide or alkoxides to form phenols or phenol ethers.
(Hive Prodigy)
02-02-02 19:48
No 264240
      Re: alkylation of quinones     

Has 2C-M been investigated? The phenethylamine version of DOM.

What about making toluhydroquinone a la Rhodium's site with p-MNT and Al/H+ and then oxidizing it to the benzoquinone. Then alkylating with 3-aminopropanoic acid to add the ethylamine chain, followed by reducing the benzoquinone in methanol to form the dimethoxy diether.

MePh --> p-MNT --> MePh(OH)2 --> MePh(=O)2 --> MePh(=O)2C2H4NH2 --> 2C-M

The aminopropionic acid could be made from succinimide via reaction with NaOH and NaOCl, opening the imide to the mono-amide carboxylic salt, and the NaOCl inducing the Hoffmann hypohalite degradation to form the amine acid salt.

It is simply a modified version of cheapskate's anthranillic acid synthesis.


Vivent Longtemps la Ruche!
(Chief Bee)
02-02-02 19:53
No 264241
      Re: alkylation of quinones     

Has 2C-M been investigated? The phenethylamine version of DOM.

Yes, It is called 2C-D in Pihkal. It seems like a very nice compound.
(Ubiquitous Precursor Medal Winner)
02-02-02 20:10
No 264250
      Re: alkylation of quinones     

Might acetoacetic acid bee a more emphatic condensation reagent than beta-aminobutyric acid? obviate the need for amine protection, etc. Giving hopefully the 2-propanone.

a half a pints a half a pound a half a world a half a round
demimonde, n. Half world.
(Chief Bee)
02-02-02 20:18
No 264256
      Re: alkylation of quinones     

Halfapint: Good idea.
(Hive Prodigy)
02-02-02 20:24
No 264262
      Re: alkylation of quinones     

Same number of steps either way. You exchange amine protection for reductive amination.

halfapint, you sneaky bastard....tongue

Vivent Longtemps la Ruche!
(Ubiquitous Precursor Medal Winner)
02-02-02 21:00
No 264279
      Re: alkylation of quinones     

Reductive amination, though, puts it back on one of our well-trodden paths. We're used to handling ketones; bisulfite purification, though lossy, is mucho handy.

a half a pints a half a pound a half a world a half a round
demimonde, n. Half world.
(Chief Bee)
02-03-02 02:54
No 264417
      Re: alkylation of quinones     

An even better idea is that someone would try out the reaction with BOTH substrates and see which gives the best yields. But that is of course a pipedream of mine...

Hey you out there! If all of you just set aside 10-20% of the time, money and other resources you use to produce the commercial products the old "tried and true" way, and used that for the development of new routes and methods to known compounds (like 2C-B, MDMA, 4-MAR etc) and also some to promising untested compounds (fluoroamphetamines, 2C-TFM, 2C-CN, benzodifuranyl-ethylamines and all the all so active 4-substituted-2,6-dimethoxy-amphetamines/PEA's), this place would be teeming with new and interesting stuff!.
(Ubiquitous Precursor Medal Winner)
02-03-02 03:58
No 264458
      Re: alkylation of quinones     

Antoncho says, "I also remember ... that reducing quinones in MeOH leads to dimethoxybenzenes." Using the acetoacetic acid route to quinone-propanone, reduce with methylamine (or nitromethane) in the methanol. Home free with 2,5-dimethoxyphenyl isopropylamine, a bromination away from DOB.

Suppose that oxone would work, in place of ammonium peroxydisulfate.

a half a pints a half a pound a half a world a half a round
demimonde, n. Half world.
(Hive Prodigy)
02-03-02 04:04
No 264461
      Re: alkylation of quinones     

Holy shit, thats beautiful. halfapint, great thinking. smile

Have any other dialkoxy derivatives ever been prepared? Like Diethoxy- or propoxy/isopropoxy-phenylisopropylamine and such brominated derivatives?


Vivent Longtemps la Ruche!
(Chief Bee)
02-03-02 04:56
No 264486
      Re: alkylation of quinones     

It is possible to insert one ethoxy instead of a methoxy in either the 2- or 5-position of a PEA, retaining activity, but losing potency. Two ethoxies abolishes activity (perhaps not with the oh-so-strong DOB), as does higher alkoxy groups in either position. Search Pihkal for "tweetios" (Shulgin's designation for 2-EtO :)
(Hive Prodigy)
02-03-02 05:05
No 264489
      Re: alkylation of quinones     

Haha, that's funny, Rhodium. Tweetios, I like it.

halfapint: Wouldn't a side reaction in the Al/Hg be imine formation with methylamine and the quinone carbonyls, them being reduced to an amine? If so, that would suck and would have to be prevented.


Vivent Longtemps la Ruche!
(Chief Bee)
02-03-02 05:10
No 264492
      Re: alkylation of quinones     

PP: Antoncho said that performing the reaction in MeOH would directly methoxylate the quinone to the 2-alkyl-dimethoxyhydroquinone, so when it's time for the amination, the molecule should already be aromatic. But you are right, if there would be quinone carbonyls left, they would also aminate.

It woulde be wonderful if it could be done in one pot, but I really suspect that purification is required at least somewhere along the way.
(Hive Prodigy)
02-03-02 05:15
No 264494
      Re: alkylation of quinones     

Yes, I agree completely, it would have to be done, sadly. I was referring to the insanely beautiful idea of halfapint's: To alkylate the quinone with 3-oxobutanoic acid to form the propanone/qionone, then reductively aminate and reductively alkylate the molecule in one step with Al/Hg/MeNO2/MeOH where the MeOH is the solvent alcohol, source for the Al/Hg reduction for the propanone, and also the fuel for the reductive alkylation of the qionones in one pot. Ingenious idea, but possibly problematic.


Vivent Longtemps la Ruche!
(Ubiquitous Precursor Medal Winner)
02-03-02 05:56
No 264501
      Re: alkylation of quinones     

Boy wuz i wrong!!! n-Methyl what??? Sorry, beez.

 like i didn't say, if you wanted to reduce 2,5-dioxo-phenylpropan-2-one to the amine by first producing say the oxime... hmm. Can't be done. Wait a minute.

? About bisulfites: does benzoquinone precipitate a bisulfite addition product?

? Next: Requires more vigorous conditions to methylate benzoquinone reductively with methanol than to reductively aminate *-propanone with say benzylamine you could hydrolyze off..?

? Also: I'm lost here, beez, so if you could sorta help me out I'd bee mighty appreciative...

OK, looks like the only way out is to reduce the methanol solution, before it gets any nitrogen in the pot. With any luck the quinone's redox threshold potential, whatever it's called, is lower than that of *-isopraponone. Won't fructose reduce benzoquinone? Time to use more silver?

Oh, well, you have to lose the carbonyl to reduction, too, most probably. Then you have to take the 2,5-dimethoxyphenyl propan-2-ol, and reoxidize it back to the *-propan-2-one, so then you can re-reduce it to the amine.

Was even wanting to try the Leukart-Wallach on this one, afraid I'd end up with some kind of aniline stuff...

Oh, all that splendid simplicity, down the tubes... IMPossible.

a half a pints a half a pound a half a world a half a round
demimonde, n. Half world.
02-03-02 09:31
No 264563
      Re: alkylation of quinones     

Like to see that at least one of my post is not only replied  by rhodium only! I'm totally with rhod when he says that some investissement in new roads to new or old compounds is required. It is only with research from all the hive that we are advancing in our quest, shulgin has done very good work,  I consider himself as one of the best genius in our population, but he become more or less old and some investisment from the youth must be done. We have a big advantage on him: we are several chemists and various peoples connected by internet between us, but he was more or less alone. If we join our forces in Research and Development like any competitive enterprise should do, we could change the face of the world, and the psychedelic renewal may take place. I will be very happy if all this theoretical discussion become a practical one, with some bees puting time, money and personal failure/success for the  community. So get up, stand up and fight the war!!

Love you all, PtongueiX
(Chief Bee)
02-03-02 10:57
No 264586
      Re: alkylation of quinones     

Halfapint: Benzoquinone forms bisulfite adducts yes, and catalytic hydrogenation of N-benzyl-MDA will give toluene and MDA.

we are several chemists and various peoples connected by internet between us, but he was more or less alone. If we join our forces in Research and Development like any competitive enterprise should do, we could change the face of the world, and the psychedelic renewal may take place.

Yes, think of us as a 2500 node neural network all running 486-processors - in some instances we do approach the ingenuity of Shulgin. Give the board a few more years, and this place really should have its own quarterly journal: "Journal of Clandestine Chemistry" published free on the web with the latest advances of the area featured in it, with PDF downloads and all, and in 2012 we will attain University status, and be able to issue diplomas in different clandestine chemistry interest areas. wink
(Hive Addict)
02-03-02 13:16
No 264625
      Re: alkylation of quinones     


What the hell is 4-MAR?

(Hive Prodigy)
02-03-02 13:24
No 264630
      Re: alkylation of quinones     

4-methylaminorex. See the novel discourse thread by Rhodium called "4-MAR without CNBr" and the standard syntheses on his website.

Also known as U4Euh, and ice.


Vivent Longtemps la Ruche!
(Hive Bee)
02-03-02 19:33
No 264699
      Re: alkylation of quinones     

halfpint - i wasted alot of time trying to use bisulfite to purify post benzo wackers, i finally gave up because of all the benzoquinone (or what i thought was) that carried over using that method. i never triied react the benzoquinone directly with bisulfite sol. to test but the impression i got was that it did.

Rhodium, the quarterly is an awesomely beautiful idea!!!

02-04-02 18:41
No 265089
      Re: alkylation of quinones     

some research at library:

reductive methylation of quinone are usualy done with CH3I or DMS or DMC. This ref (synth comm 16(9), 137-42 (1986)) say that with DMS and Na2S2O8 ketone are not reduced, but quinone are. No propan-2-ol in these condition.
Two other ref may be useful: Zh.Obshch. khim (1982), 52(12), 2778-80 tell us about polarographic(? what's this) reduction of quinone in basic MeOH lead to 4-methoxy phenol. A mixture of product may emerge with our compound, and an alkylation step is required, but maybe tweetio may be doable. This last ref is the better I think: Gazz. chim. ital (1943) 73 300-305 say that quinone in 80%MeOH with AL/Hg lead to 1,4 dimethoxy benzene. Some italian bee in the hive?

Two other things:
1) I don't know if this reaction will work with acetoacetic acid because I haven't see any oxo acid used in the refs. I fear that the reaction will cleave the ketone, but I don't think so.
2) I hope that the reaction will not cleave the amides because I'm thinking of this method of protection for the amine of the 3-amino-butyric acid (with acetyl chloride for instance). Then maybe reduct the amide to the amine with Al/Hg or Zn. Or what other protection could we use?

PrimoPyro: I like your idea with succinimide, hope it work
(Chief Bee)
02-05-02 11:54
No 265412
      Re: alkylation of quinones     

Polarography is some kind of electroreduction. We have italians among us (Peyote for example), so if you post the article, he could translate it. The acetoacetate used in the reaction could easily be protected as the ethylene glycol acetal (to form the 1,3-dioxolane) with antifreeze and H2SO4, and then reacted with the quinone.
(Distinctive Doe)
02-05-02 19:48
No 265551
      Re: alkylation of quinones
(Rated as: excellent)

Reductive-alkylation and aromatic coupling reactions of 1,4-benzoquinone derivatives promoted by ethylaluminum dichloride.
Ferreira, Vitor F.; Schmitz, Francis J.   
J. Organomet. Chem.  (1998),  571(1),  1-6.

Obtained in 77% yield from 1,4-benzoquinone (120 mg, 1.10 mmol); m.p. 65-66 (lit. 65-67C);
General procedure
To a solution of the appropriate benzoquinone derivative (1 mmol) in 5 ml of dry dichloromethane, 2 ml (two equivalents) of a solution of 1 M EtAlCl2 in hexane was added dropwise under a nitrogen atmosphere over a period of 30 min at -78C. The solution turned deep blue and was stirred at this temperature for 1 h and then for 2 h at room temperature. To this mixture, 2 ml of methanol, 10 ml of water and then 5 ml of 15% HCl (to pH ~6) were slowly added sequentially. The resulting gelatinous mixture was extracted with dichloromethane (315 ml). The resulting cloudy, organic phase was filtered through a celite column, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residues were chromatographed on silica gel columns or preparative TLC plates and eluted with a mixture of hexane:ethyl acetate (9:1).

On the 1,6-addition of alkylamuninium compounds to para-quinones
Z. Florjanczyk and E. Szymanska-Zachara.
J. Organomet. Chem. 259 (1983), p. 127

The reactions were carried out under nitrogen in a vessel equipped with a stirrer and connected through a liquid seal to a burette. A toluene solution of quinone was prepared in the vessel, and a toluene solution of an organoaluminium compound or a nitromethane solution of AlCl, was then introduced with vigorous stirring. When reaction was complete, the mixture was treated with water or 1 M HCl and the organic and aqueous layers were separated. Both layers were concentrated and the products isolated from them as indicated below.  4-Ethoxyphenol was extracted with petroleum ether.
Mol ratio: quinone/organoaluminium compound = 1, solvent: toluene, 500 cm3, quinone concentration 0.07 mol 1-l; temp. -78C; time 2 h.

1,4-Benzoquinone with MeAlCl2,
Yeild 54% hydroquinone, 0% 4-Methoxyphenol

1,4-Benzoquinone with EtAlCl2,
Yeild 29% hydroquinone, 20% 4-Ethoxyphenol

1,4-Benzoquinone with Et3Al
Yeild 59% hydroquinone, 8% 4-Ethoxyphenol

Reactions of organoaluminium compounds with benzoquinone
J. Organomet. Chem. 112 (1976), p. 21
Note: Similar to above done in toluene, the yeilds suck.

Preparative electrochemical reductive methylation of ortho-hydroxy-para-benzoquinones
Tetrahedron  (1997),  53(2),  469-478.
An electrochem. methodol. for the protection of the ortho-hydroxy-para-benzoquinone functionality has been developed, by a one step formation of the arom. ethers of the reduced quinone function, improving the yields obtained for this reaction by the classical chem. methods.

Reductive methylation of quinones.    
Gripenberg, Jarl; Hase, Tapio.       
Acta Chem. Scand.  (1963),  17(8),  2250-2. 
Journal  written in English.  
Quinones with high oxidn.-redn. potentials were reductively methylated with Me2SO4 in the presence of C5H5N.  Thus, 0.8 ml. Me2SO4, 5 ml. MeOH, and 0.23 ml. C5H5N refluxed 1 hr., the soln. chilled and treated with 0.3 g. p-benzoquinone (I) in 5 ml. MeOH, and the cooled (ice-salt bath) mixt. basified with 5 g. NaOH in 10 ml. MeOH and steam distd. 5 min. later gave 285 mg. 1,4-(MeO)2C6H4.  Similarly, toluquinone gave 60% 2,5-(MeO)2C6H3Me, and p-mentha-3,6-diene-2,5-dione (redn. time 2 hrs.) afforded 30% 2,5-dimethoxy-p-cymene.  The procedure was modified for less reactive quinones as follows: 0.3 g. 2,5-diphenylbenzoquinone, 5 g. K2CO3, 0.1 ml. C5H5N, 0.33 ml. Me2SO4, and 10 ml. MeOH refluxed 8 hrs. gave 265 mg. 2',5'-dimethoxy-p-terphenyl, m. 154.  Likewise, 1,2- and 1,4-naphthoquinone gave 10% 1,2 and 14% 1,4-dimethoxynaphthalene, resp.  From reductive methylations with tetramethylbenzoquinone, 2,5-dimethoxybenzoquinone (IV), 7-isopropyl-1-methylphenanthrenequinone, and anthraquinone only unchanged quinones were recovered, while 2,5-dihydroxybenzoquinone gave IV.  I added to an ice-cold soln. of 1-methylpyridinium hydroxide in H2O produced 1-methyl-2(1H)-pyridone, which indicated that quinones of high oxidn. potential could be used to oxidize alkylpyridinium hydroxides.

This might have something interesting in it

A study of an oxidative-amination method for the synthesis of aminoquinones.    
Crosby, Alan H.; Lutz, Robert E.    
J. Am. Chem. Soc.  (1956),  78  1233-5.
Finely powd.  Cu(OAc)2.H2O (20 g.), 0.6 mole of the appropriate secondary amine, and 300 cc.  MeOH stirred, the soln. flushed with O and treated cautiously with cooling at 20-30 with 10.8 g. 1,4-benzoquinone in 200 cc. MeOH, the mixt. cooled after the O absorption ceased (30-60 min.) to 10 and filtered (if the product was sparingly sol.) or evapd. at room temp. in vacuo, the residue treated with 300 cc. Et2O and 22 cc. 96% H2SO4 and 500 cc. H2O, the aq. layer extd. with Et2O, the combined Et2O layer and ext. evapd., the residue extd. with hot iso.ovrddot.octane, and the ext. evapd. in an air stream gave the corresponding 2,5-di(substituted-amino)-1,4-quinone (substituted-amino group, phys. appearance, cor. m.p., and % yield given): Et2N (I), red needles, 112-14 (iso.ovrddot.octane-EtOH), 44; morpholino (II), red needles, 232-8 (decompn.) (from dioxane), 96 [II was also obtained by heating 2,5-dimethoxy-1.4-benzoquinone (III) in excess morpholine]; piperidino (IIIa), purple-red cubes, 179-80 (from EtOH) (decompn.), 89; Me(Me2CH)N (IV), red needles, 111-13 (from iso.ovrddot.octane-EtOH), 48; Pr2N, red clusters, 55-7 (from iso.ovrddot.octane), 45; Bu2N, red waxy solid, 45-7 (from iso.ovrddot.octane), 55; Me(PhCH2)N, red blades, 176-8 (from EtOH-dioxane) (decompn.), 86.  The appropriate quinone in a min. of Ac2O treated with several cc. dry Et3N and excess Zn dust, the mixt. warmed with stirring and filtered hot, and the filtrate cooled and poured into H2O or extd. with Et2O gave the corresponding N-substituted 2,5-diaminohydroquinone diacetates (substituted amino group, crystal form, m.p., and % yield given): Et2N, blades, 48-50 (from iso.ovrddot.octane), 40; morpholino, -, 242-3 (from EtAc-Me3COH), 58; piperidino, tabular, 166-7 (from EtOAc), 90; Me(Me2CH)N, plates, 117-19 (from iso.ovrddot.octane-EtOAc), 77; Pr2N, plates, 71-2 (from iso.ovrddot.octane), 35; Bu2N, clusters, 50-1 (from iso.ovrddot.octane), 32; Me(Ph CH2)N, prisms, 153-5 (from dioxane-EtOAc), 80. 2,5-Diethoxy-1,4-benzoquinone (V) (1.0 g.) and 4.0 g. iso-Pr2NH(VI) in 100 cc. Me3COH refluxed 3 days and evapd., and the brown residue (0.8 g.) recrystd. from 20 cc. EtOH gave 0.4 g. unchanged V, m. 186-8.  V (2.0 g.) and 4.0 g. VI in 100 cc. MeOH refluxed 1 hr. gave 1.5 g. 2,5-dimethoxyquinone, converted to 2,5-dimethoxyhydroquinone diacetate (VII).  Finely powd., crude III acetylated reductively at 90 gave VII, m. 186-8 (from Ac2O, MeOH, and iso-PrOH).  Finely powd. IIIa (5.5 g.) heated 0.5 hr. with 30 cc. 96% H2SO4 in 120 cc. H2O at 50-5 and extd. continuously with Et2O, and the ext. worked up gave 1.4 g. 2,5-dihydroxy-1,4-benzoquinone(VIII), light yellow crystals which slowly became yellow-orange on standing, also obtained from IV in the same manner.  I (1.0 g.) in 80 cc. boiling 2N NaOH dild. with dioxane to soln., refluxed 1 hr., cooled, acidified, and extd. with Et2O, the ext. evapd., the residue extd. with hot C6H6, and the C6H6 evapd. gave VIII.  VIII (0.7 g.) in 50 cc. abs. EtOH treated with 1 cc. Et2O-BF3, allowed to stand 5 hrs., distd. to beginning crystn., and cooled to room temp. gave 0.3 g. V, m. 188-9.  VIII (1.4 g.) treated 5 min. with 20 cc. Ac2O and 3 cc. Et2O-BF3 and poured into H2O gave 1.0 g. 2,5-diacetoxy-1,4-benzoquinone, canary-yellow plates, m. 150-5 (decompn.), which was converted by reductive acetylation to 1,2,4,5-tetraacetoxybenzene (IX).  VIII (1.4 g.), 30 cc. Ac2O, and 15 cc. Et3N subjected to a reductive acetylation and cooled to -20 gave 1.0 g. IX, m. 228-30, which deacetylated with HCl in MeOH and methylated with Me2SO4 yielded 1,2,4,5-tetramethoxybenzene, m. 101-2.  Cu(OAc)2 (10 g.), 21.3 g. piperidine, and 150 cc. MeOH treated with 7.9 g. 1,4-naphthoquinone in 400 cc. MeOH, the MeOH evapd., the residue treated with 8 cc. 96% H2SO4 in 250 cc. H2O, and the product recrystd. from iso.ovrddot.octane and then from 25 cc. MeOH gave 10.5 g. 2-(1-piperidyl)-1,4-naphthoquinone, m. 94-6 (from iso.ovrddot.octane), which subjected to a reductive acetylation yielded 78% 2-(1-piperidyl)-1,4-naphthoquinone diacetate, m. 130-1 (from EtOAc).

Derivatives of pentahydroxybenzene and a synthesis of pedicellin.    
Baker, Wilson.   
J. Chem. Soc.  (1941)
The derivs. of C6H(OH)5 which have been isolated from plant sources are listed and 4 methods of synthesis are reviewed.  1,2,3-C6H3(OH)3 (126 g.), methylated at 18-22, gives 155 g. of the tri-Me ether; oxidation with HNO3 in EtOH at 50 gives 124 g. of 2,6-(MeO)2C6H2O2; reduction with Na2S2O4 gives 110 g. of the quinol which with Me2SO4 and NaOH in EtOH yields 54 g. of crude 1,2,3,5-C6H2(OMe)4 (I).  Addn. of 50 g. of I to 50 g. AlCl3 in 250 cc. ether with cooling, followed by 25 g. AcCl during 1 hr. with cooling and stirring for a further 6 hrs., gives 70% of 2,3,4,6-HO(MeO)3C6HAc (II), m. 103-5; oxidation of 22.6 g. of II with 142 cc. 3% H2O2 in dil. NaOH at 20 gives 12.3 g. of 1,2-dihydroxy-3,4,6-trimethoxybenzene (III), m. 82 (di-Ac deriv., m. 147).  Methylation of 10 g. of III gives about 10 g. of C6H(OMe)5 (IV), b14 150, b21 167, m. 58-9.  Gallacetophenone (67.2 g.) with Me2SO4 and K2CO3 in C6H6, refluxed 6 hrs., gives 51 g. of 2,3,4-HO(MeO)2C6H2Ac (V), m. 77, and about 10 g. of the tri-Me ether, b20 178; oxidation of 20.2 g. of V with K2S2O8 in aq. NaOH gives 6.6 g. of 2,5,3,4-(HO)2(MeO)2C6HAc (VI), m. 119.  VI (21.2 g.) yields with Me2SO4 and K2CO3 in C6H6 (refluxing 14 hrs.) 16.5 g. of 2-hydroxy-3,4,5-trimethoxyacetophenone (VII), pale yellow, m. 86; Cu(OAc)2 in dil. EtOH gives a green co.ovrddot.ordinated Cu deriv.; NaOH gives a bright yellow soln. and alc. FeCl3 gives a deep slate-blue color.  Oxidation of 11.3 g. of VII with alk. H2O2 yields 7.8 g. of 1,2-dihydroxy-3,4,5-trimethylbenzene (VIII), m. 90-1; dil. NaOH gives a light green soln. turning to yellow; aq. FeCl3 yields an orange color turning to cherry-red; excess FeCl3 gives a deep brown soln.; di-Ac deriv., m. 77.  VIII with Me2SO4 yields V.  2,5,4,6-(HO)2(MeO)2C6HAc (8 g.), Me2SO4 and K2CO3 in C6H6, refluxed 14 hrs., give 1.3 g. of 2-hydroxy-4,5,6-trimethoxyacetophenone, bright yellow oil, b27 184-6; the Cu deriv. is green; FeCl3 yields a deep violet-gray color; oxidation with alk. H2O2 gives VIII.  III (1 g.) in 20 cc. H2O, treated dropwise at 10 with 2 g. FeCl3 in 10 cc. H2O, gives after 4 hrs. 0.65 g. of 2-hydroxy-3,6-dimethoxy-1,4-benzoquinone (IX), dark red, m. about 208; from AcOH it seps. as scarlet plates which appear to contain solvent of crystn.; in dil. NaOH IX gives an intensely purple-red soln. from which it is pptd. unchanged by acid.  IX and Ac2O with a little H2SO4 give the 2-Ac deriv. (X), bright yellow, m. 147; this also results on boiling with Ac2O or with Ac2O and C5H5N at 40 or at room temp.  Reduction of X with Na2S2O4 in dil. EtOH at 60 gives 2-acetoxy-3,6-dimethoxyquinol, m. 151; methylation gives IV; boiling Ac2O gives the diacetate, m. 114-15.  Reduction of IX yields 2-hydroxy-3,6-dimethoxyquinol, m. 144; FeCl3 gives a red soln. which, if in sufficient concn., deposits IX.  II. (11.2 g.) and K2S2O8 in dil. alkali, followed by hydrolysis, give 3.5 g. of 2,5-dihydroxy-3,4,6-trimethoxyacetophenone, yellow, m. 116-17; FeCl3 in EtOH gives an apple-green color; methylation of 5.5 g. gives 4.8 g. of 2,3,4,5,6-pentamethoxyacetophenone (XI), b13 163, m. 43.  XI (0.7 g.), 0.14 g. Na and 2.1 g. BzOEt, heated 1.5 hrs. at 125, give 0.08 g. of 2,3,4,5,6-pentamethoxydibenzoylmethane, pale yellow, m. 91; FeCl3 gives a cherry-red color.  XI and BzH with EtONa give 2,3,4,5,6-pentamethoxyphenyl styryl ketone (pedicellin), m. 93.  IV (5 g.) and then 5 g. AcCl, added to 5 g. AlCl3 in 25 cc. ether, give after boiling with dil. HCl 1.7 g. of 2-hydroxy-3,4,5,6-tetramethoxyacetophenone (XII), bright yellow oil, b14 183; it is very slightly volatile with steam; aq. and alc. FeCl3 give intense brown and deep brownish-green colors, resp.; Cu gives a green co.ovrddot.ordinate Cu deriv.  Oxidation of XII with alk. H2O2 at 46 gives a crude 1,2-(HO)2C6(OMe)4 which with Me2SO4 and KOH gives C6(OMe)6, m. 81.  In the demethylation of o-MeO ketones by AlCl3 in ether, the MeO groups must be activated by CO groups in either the o- or p-positions.  Demethylation in the p-position takes place much less readily than in the o-position but has been observed in the case of 2,3,4-(MeO)3C6H2Ac which by the prolonged action of boiling ethereal AlCl3 yields 3,2,4-MeO(HO)2C6H2Ac.  The remarkably inert nucleus of 1,2,4,5-C6H2(OMe)4 is not attacked by AlCl3 and AcCl in ether.

Fully Informed Jury! (http://www.fija.org/)
02-05-02 23:13
No 265618
      Re: alkylation of quinones     

Foxy: I have seen reaction with better rdt than those you have posted. Anyway I haven't see any reaction without DMS/CH3I/DMC.
Peyote/other italian bee: Can you traduct this, this is the ialian ref I was speaking:
"Parte sperimentale: Preparazione del para-dimetossi-benzolo dall' 1-4 benzochinone.
a) riduzione con amalgama di alluminio cd idrato di potassio. -Ad una soluzione di 5gr. di chinone in 80 cc. di alcool metilico all'80% si aggiungono a freddo 5 gr. di amalgama di alluminio preparata secondo Wislicenus (11), poi lentamente 200.gr di, una soluzione al 50% di idrato di potassio.
Si fa bollire a ricadere per un'ora, poi si aggiungono a poco a poco 30 gr. di soolfato dimetilico ed altri 35 gr. di soluzione di KOH e si continua ancora a riscaldare per un'altra ora.
La soluzione giallastra, che ha netta reazione alcanica, viene distillata in corrente di vapore; in tal modo viene trascinata la maggior parte del para-dimetossi-benzolo che si puo separare quantitativamente per estrazione con etere del distillato. Per evaporazione dell'etere si ottengono gr. 4,0 (pari all'80%) del composto fondente a 51.
Acidificando il residuo ed estraendo con etere si ricavano 0.3 gr. dihidrochinone monometil-etere.
Per fissare queste condizioni sopno state fatte diverse prove variando le quantita di alcali di soolfato dimetilico e la concentrazio,ne della soluzione alcoolica."
After that they tried some variation on the concentration/ration of the reactant, with loss of dimethyl ether for monomethyl ether.
Now I thought that reduction of benzo in MeOH doesn't lead to dimethoxybenzene, it's only some misrepresentation in the summary of the reactions I think. Antocho prove me wrong if you want.
So we must have three steps:
1) radical alkylation of quinone
2) reductive methylation of quinone with alkylating agent and Na2S2O8 or Na2S2O4 (or alhg but it suck) (or maybe NaHSO3) This second step can be selective to the quinone
3) transformation of the propanone to the amine (or deprotection of the amine if we use the alanine)
Foxy: the method with the organoaluminium is not the same as  the radical decarboxylation. It is more tedious I think and less easy. I have seen other method like one reacting with pyridine and 2,4 dioxo pentane to form the phenylacetone, but poly alkylation occur.

(Hive Prodigy)
02-06-02 02:03
No 265671
      Re: alkylation of quinones     

To me, it seems quite obvious what the really ironically elegant and oh so nifty reaction scheme here is:

Bromination of benzoquinone with N-bromosuccinimide followed by recovery and purification of the formed succinimide and 2-bromo-1,4-benzoquinone.

Reaction of succinimide with NaOH/NaOCl to yield the gamma-aminopropanoic acid.

Reaction of the formed amino acid with the formed bromo-benzoquinone in water with AgNO3 and ammonium peroxydisulfate to form the 2-ethylamino-5-bromo-1,4-benzoquinone.

Reduction of this compound in methanolic Al/Hg to convert the quinone into the dimethoxy derivative, lovingly known as 2C-B


Vivent Longtemps la Ruche!
02-06-02 03:28
No 265695
      Re: alkylation of quinones     

Yeah it's fun but the problem if that the reaction is not very regioselective. One of their paper say that 2-methoxy-1,4 quinone is alkylated para to the methoxy (don't remember the %, I'll tell you latter) and that the methoxy is more directive than the methyl (toluquinone, more or less 35% para and 30% ortho). I don't know if the bromo counterpart will orient para, it is not in their article, I'll read it more carefully. Instead of the reduction with Al/Hg I prefer  the use of the same peroxydisulfate for this purpose and CH3I. I think after my research that it does not work without an alkylating agent, they use Al/Hg with DMS. It's simpler to stay with the peroxydisulfate reduction. And I think there can be side reaction with the not protected amine and the not methylated quinone.
I think that I'll stock up the succinimide from my previous bromination, convert it with NaOH/NaOCl, protect it with acetyl chloride, alkylate quinone with peroxydisulfate/AgNO3, reduce quinone with peroxydisulfate/CH3I, convert the amide to the amine with Zn, react the 2CH with NBS to give 2CB and purify the succinimide for the next run.
(Distinctive Doe)
02-06-02 05:55
No 265753
      Re: alkylation of quinones     

Is there a reference for the Al/Hg in methanol to get the dimethoxy?

Synthesis of 2-bromo-1,4-benzoquinone

From the KBrO3 oxidation of commercially available bromo hydroquinone according to McElvain, S. M.; Engelhardt, E. L. J. Am. Chem. Soc. 1944, 66, 1077-1080.

Fully Informed Jury! (http://www.fija.org/)
(Chief Bee)
02-06-02 07:01
No 265785
      Re: alkylation of quinones     

Poix - A writeup of such a novel working synthesis would get the Rhodium award 2002 for the most ingenious phenethylamine synth.
02-07-02 19:06
No 266508
      Re: alkylation of quinones     

Hello all
Can some bee get me this ref: Synth commun 2001 31(10) 1467-1475 : It describe the synthesis of some substitued gbl with oxidative decarboxilation of acids, they speak of 1,4 dmb too. They use Ag and peroxydisulfate but also Mn and Ce or Pb. I would like to know what they say about ox. decarb. with silver and the others element. If I can get the experimental section with Ag it would be cool too.

In fact I'm trying to reduce the use of AgNO3 because it's somewhat expensive. This ref: J am chem soc 1970 1651-59 it's a review of the role of silver in this reaction. They say 'the presence of 0.01M silver nitrate markedly catalyzed the decarboxylation (t1/2=11min). The half-life of the peroxydisulfate in the presence of 0.01M AgNO3 was 11min, whereas it was 600min in the absence of silver(I).' With AgNO3 0.005M the decarboxylation is more than two fold slowed. In the reaction from orgsyn, they use ~.036 M Ag.
Some equation:
 .006 in 166ml-> 0.036 M Ag
0.01M Ag is OK -> we can dilute it 3 times
 quinone MM 108, 5.4g -> 0,15 mol 16,2g
RDT 50% -> 2C-H MM 181 -> 0.15 * 90 = 13.5g
for 13.5g we use 1g of AgNO3, 25g is 45$ -> ~2$
for 50g ~8$
If the reaction work with .01M AgNO3, and if the Rdt is ~50% (it may be a little less) it will cost ~8$ of Ag for 50g 2C-H. It is reasonable I think. But if we can use Ce or recyclate Ag or maybe if we can reuse the aqueous medium more than once it will cost less.

Primo: from Acta chem Scand 27(1973) No. 9 p 3212:
Isopropylation of toluquinone: isomer ratio:
m: 25% p: 40% o: 35%
Pentylation of 2-methoxy-1,4-benzoquinone:
m: 5% p: 68% o: 27%
'In view of the nucleophilic character of the alkyl radical this distribution pattern is expected.'
pentylation of 2-meo-1,4-benzoquinone:
3-pentyl yield 2%
5-pentyl 34%
6-pentyl 13%
3,5 dipentyl 1%
3,6 dipentyl 1%
5,5 dipentyl 2%

I think that this reaction is good with simetrical quinone like benzoquinone, but not so good with unsimetrical quinone like bromoquinone.

Question: what pattern of substitution could be expected with bromoquinone and CF3-quinone? Anyone? Para? Meta?

If someone can verify the reaction from pyro with succinimide to alanine it would be cool too. Anyone wish to try it?

Aloha PcooliX
(Chief Bee)
02-07-02 20:06
No 266538
      Re: alkylation of quinones     

But that quinones can be trifluoromethylated and methanolyzed to 2,5-dimethoxy-trifluoromethylbenzene in one pot this cheap is very cool. From there it is the three usual common steps to create 2C-TFM, either via the aldehyde or via the acetonitrile.
02-08-02 21:06
No 267038
      Re: alkylation of quinones     

I've got a verification of the succinimide to B-alanine route from Merck index. It's in org synthesis: succinimide + KOBr + 2 KOH -> B-alanine +KBr +K2CO3. Bleach and NaOH could be substitued. From the same number of org. synth. there is a preparation of succinimide from distillation of succinic acid/ammonia.

So there is no problem to obtain the B-alanine. We can also obtain it from methyl acrylate with aqueous ammonia or ethyl acrylate with alcoholic ammonia. Any OTC use for methyl acrylate?

The cool thing with this synthesis is the OTCness of all it's reagents (except MeI). Do you know that MeI/MeBr are used as soil fumigant? Maybe OTCness here? Otherwise MeI can be made from aq KI with H2SO4/MeOH in 90% yield (Czech patent) or from iodine in AcOMe with Al and AcOH (65% calculated on Iodine).
(Chief Bee)
02-08-02 22:22
No 267070
      Re: alkylation of quinones     

On my page there are OTC MeI, Me2SO4 and NaMeSO4 references to be found. All works as alkylating agents. But you would have to use special reaction conditions if you want to use the CH3X for N-methylating an amino acid (also featured on my page, but illustrated for amphetamines).
(Stranger / Eraser)
02-08-02 23:18
No 267100
      alkylation of quinones     

  Greetings everybody. Italian isnt my native tongue but I think I can make a good enough translation. Here it goes:

Experimental part: Preparation of p-dimethoxybenzene from 1-4 benzoquinone

 a)reduction with Al/Hg and KOH

  To a solution of 5 grams of quinone in 80 cm3 of 80% MeOH were added, in the cold, 5 grams of Al amalgam, prepared according to Wislicenus(11), followed with slow addition of 200 grams of a 50% solution of KOH.
  The mixture is refluxed for an hour, and 30 grams of dimethyl sulfate are added in small parts, followed by the addition of 35 grams more of the KOH solution and a further 1 hour reflux.
  The solution obtained is basified (not too sure about this part) and steam-distilled; most of the p-dimehtoxy benzene distiles over and can be separated quantitatively with ether extraction of the distillate. The ether is evaporated to obtain 4 grams (~80% yield) of product mp 51 degrees. By acidifing the residue and extracting with ether 0.3 grams of hydroquinone can be obtained.

Then they say that to achieve these reaction conditions various concentrations and amounts of the reagents and the solvent were tried.
(Distinctive Doe)
02-09-02 00:19
No 267145
      Re: alkylation of quinones     

Do you have thename of that journal reference and its details?
Just to know.

Stay Informed (http://www.mapinc.org/)
(Chief Bee)
02-09-02 02:35
No 267218
      Re: alkylation of quinones     

It is a translation of Post 265618 (poix: "Re: alkylation of quinones", Novel Discourse) which comes from Gazz. chim. ital (1943) 73 300-305, mentioned a few posts higher up.
02-09-02 10:40
No 267363
      Re: alkylation of quinones     

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0562 SUCCINIMIDE
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0034 B-ALANINE
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0019 B-ALANINE

I think their workup with B-ALANINE is not so good. Another purification procedure is welcome.

We must speak about the amine protection too. I don't know if anhydride acetic/acetyl chloride will work because acidic medium or aqueous NaOH are used to deprotect, but I don't know the concentration. Rhodium, do you know the conditions for deprotection of these amides? I know amide are pretty stable so I hope it will not deprotect too easily and can resist two step with silver and CH3I. Also I saw in my cursus that valine could be protected with formic acid forming N-formyl valine. My question is: is HCOOH more reactive than the ac. carb. of the valine itself? otherwise in these same condition polymerisation of the valine would do polypeptide, but it doesn't. Maybe formic acid could be used for the protection, they say NaOH,H2O,0C are the condition of deprotection, but they doesn't say the time nor the concentration, I hope it will be stable enough for the 2 steps, it would be cool to just use formic as protecting agent.

Any help with the protection/deprotection step is welcome, it is a vast subject with plenty of ref to find, especially in the resolution of amino acid. 

Fuck I'm newbee!
(Official Hive Translator)
02-09-02 12:25
No 267381
      Re: alkylation of quinones     

do you know the conditions for deprotection of these amides?

AFAIK, the general proc for deacetylation is smth like 20% HCl ~1 h at reflux.


(Hive Prodigy)
02-09-02 23:21
No 267501
      Re: alkylation of quinones     

Why must it be protected again? What is the problem with alkylating the quinone unprotected beta-alanine?


Vivent Longtemps la Ruche!
02-10-02 10:50
No 267680
      Re: alkylation of quinones     

No 208020:
You can't dimethylate tryptamines by simply reacting them with methyl iodide (MeI) or dimethylsulfate (DMS) due to overalkylation to quaternary salts.

It will form a quaternary salts of 2CH with MeI
(Official Hive Translator)
02-10-02 13:33
No 267695
      Re: alkylation of quinones     

ahem.... but in this case, acetylation also should bee of no help, no?

i mean, monomethylated 2CH ain't what we want either...

02-10-02 14:57
No 267706
      Re: alkylation of quinones     

monomethylated where? On N? That should not be of any concern, common amides could be alkylated only under somewhat harsh conditions, so unless you use excess sodium hydride as base or do something other equally perverted, amide should remain untouched while phenols are alkylated.
02-26-02 01:13
No 273478
      Re: alkylation of quinones     

Bringing back the protection subject:
At this day I think the best protecting group we can use is acetic anhydride (or acetyl chloride). We can acetylate the alanine, do the reactions, methylate with CH3I/K2CO3/sodium hydrosulfite and then deprotect with refluxing KOH. AFAIK all these reactions will work. But I don't wanna buy acetic anhydride nor acetyl chloride.
I've a DOEF synth that use magnus reagent ([CLSi(CH3)2CH2]2) for protecting the amine. Can TMSCl be used like this, as with alcools? Another protecting group I've seen is imine formation with benzaldehyde. We can make imine with acetone, can acetone be used as a protecting group? Does sodium thiosulfite reduce the imine like the carbonyl of the quinone? I don't think CH3I will add to an imine, is this true? Does the alkylating step with quinone in water interfere with these protecting group? ie does water at pH other than 4.5 deprotect the imine? is water without reflux sufficient to hydrolise the N-sylil bond? (Magnus reagent deprotection: 10% KOH, MeOH, reflux 4h)

Hope I'll have some answers from some knowledgeable bee.

(Chief Bee)
02-26-02 06:50
No 273622
      Re: alkylation of quinones     

Stuff worth looking into could be to protect the amine function as the phtalimide (Just react the amine with phtalic anhydride, deprotection is hydrazine or KOH soln). Another is the trifluoroacetamide (from amine + trifluoroacetic anhydride) which can be removed by mild acid hydrolysis.
(Hive Bee)
02-14-03 21:08
No 407846
      Proposed method (1) for 2C-H
(Rated as: excellent)

Yet another theoretical 2C-H synthesis, Chimimanie

Well after some research in this area this is what I found.

This road look feasible, but it is not tested yet. The scheme I use is the same as poix proposed but it reduce to the hydroquinone and methylate in two steps, its easier like that and better I think, in fact reduction of the quinone to the hydroquinone may be view as a workup of the first reaction since its only a wash with aqueous hydrosulfite.

This synthesis may not work (but I think it will, prove me wrong), use no watched chemicals beside benzoquinone (which must be made from hydroquinone) and acetic anhydride and probably does not give stellar yield, i think it is for small scale manufacture of 2cb only, not for 1000+ doses reaction. Theoretically I think it is the shortest synthesis of 2C-H starting from hydroquinone (with the aryne road of course).

Well some theoretical background:

The ideal reaction would be reaction of quinone with beta-alanine to yield beta-ethylamine benzoquinone, but this will not work. Why? because the silver/persulfate oxydation transform amine into aldehyde[1]. So we must protect the amine. We can't protect it with formic, because formyl is easily removed by oxydation. We can also protect it with phtalimide, but I have not searched in this direction. Trifluoroacetic anhydride could be used, the last step (hydrolysis)  would be high yielding with it[6], but it is expensive. I choose acetic anhydride. I hope than the amide will be stable in this oxydative medium, I don't know because in ref [1] they didn't speak of amide but I think so.

The alkylation proceed from a decarboxylation and generate radicals which then are scavenged by benzoquinone and alkylate it. Loss of radicals or polyalkylation are possible, read the orgsyn ref [9]. I used the orgsyn ref method in hope there is no need to use one of the variant that are in the litterature (the references of these variants are in the org syn article [9]) which use sometimes high quantity of silver and excess of acid. If this one does not work one can play with the ratios of acid/AgNO3/BQ but I think it is useless to stay with that road if it doesn't work, I will post a second road which is more reliable (ie: with no doubt that its decarboxylative alkylation work) than this. Anyway we will see, maybe this one work. (it should!wink)

The second reaction is easy, it can be considered like the work up of the first, it is a simple quinone to hydroquinone reduction by a Na2S2O4 wash, with much ref covering it in the litterature, no problem.

Third reaction is an alkylation. Medium is acetone, alcohol nor water can't be used here because of the risk of hydrolysis of the amide. I hope this will not occur too much in acetone. Hydrolysis of the amide at this step would lead to alkylation of the free amine which is a lost of reactant.

Fourth reaction is an hydrolysis of the amide, the yield are not great for this step, they would be better if we used trifluoro-acetic anhydride[6]. An high yield hydrolysis of amide is welcome.
Note: after the second reaction, if the amide of the free hydroquinone compound (B) is hydrolized, we have got 2-(2,5-dihydroxy-phenyl)-ethylamine. This compound is not stable and accordingly to ref [8] it will freely oxydise itself to 5-hydroxy-indole in about 90% yield if stirred at RT in an open vessel for 10hrs. It can then be recrystallized from ether. This indole can be used for the synthesis of bufotenine or 5-MeO-tryptamine compounds.



Beta-alanine: see post Post 267363 (poix: "Re:  alkylation of quinones", Novel Discourse)

Acetic anhydride can be synthetised from acetyl chloride and sodium acetate or with a ketene lamp, UTFSE.

Benzoquinone: see ../rhodium/chemistry /benzoquinone.html, I recommend to use the chlorate/V2O5 method or the sodium nitrite/O2 one, it is very important to get quinone(bright yellow) and not quinhydrone(metallic green).

Iodomethane: see Post 301629 (Antoncho: "Two tried-and-true ways to make MeI !", Chemistry Discourse)

N-acetyl-beta alanine: from [2]

This is the synthesis of N-acetyl-alpha alanine, it works good (tried) on beta-alanine too, same synthesis, substitute beta-alanine and Dl-alanine.

DL-Alanine (89.1 g., 1 mole) is placed in a 2L Erlenmeyer flask provided with a calcium chloride drying tube attached to the flask through a ground-glass joint. The amino acid is mixed with 900 ml. of c.p. glacial acetic acid,and brought to the boil, with gentle agitation, on an electric hot plate. The mixture is removed from the hot plate to cool for a minute or two, and 150 mL. (1.5 mole) of c.P. acetic anhydride is carefully added in portions so as to avoid superheating and explosive boiling. The resulting solution is returned to the hot plate, brought to the boil, held at this point for 2 min. longer, and then allowed to cool to 25 at room temperature. The slightly yellowish solution is then evaporated in vacuo at 40 to a syrup and the residue treated several times with water followed each time by evaporation in vacuo at 40. After the final evaporation with the aid of benzene (Chimimanie's voice: toluene can be substituted) to remove the last traces of water, the syrupy residue is taken up in the minimum quantity of dry ethyl acetate and the solution chilled. On scratching or seeding, the acetyl-dL-alanine rapidly crystallizes. After standing for 18 hr. at 5, the crystals are filtered rapidly with suction, and washed with dry ether which removes the last trace of yellow color. On drying in vacuo at 25 the yield of pure, white crystals of acetyl-dL-alanine is 10.5 g., or 80% of the theoretical; m.p. 136.

Recovery of silver: [7]

Considerable quantities of silver iodide-silver oxide residues sometimes accumulate in the laboratory, for example, in methylation studies involving the use of methyl iodide and silver oxide. While silver alone is usually recovered from silver residues, iodine is valuable enough to warrant its recovery when the residue contains a large proportion of silver iodide. In the method described, the presence of silver iodide and of silver salts soluble in concentrated aqueous ammonia is assumed. If significant quantities of contaminating salts, such as silver sulfide, are present, suitable modification is required.


A) Preliminary treatment of residue:

Ag2O + 4 NH3 + H2O -> 2 Ag(NH3)2OH

The residue containing silver iodide is freed from organic matter by extraction with a suitable solvent, dried, and ground to pass a 40-mesh sieve. The powdered residue is shaken with sufficient concentrated ammonia (sp. gr. 0.90) to dissolve all soluble silver salts. The suspension is filtered on a Buchner funnel and the filtrate (1) is reserved for subsequent recovery of silver by reduction with sodium dithionite solution.
The insoluble silver iodide is washed with water on the filter, dried, and weighed. (It is desirable to know the weight of silver iodide because a subsequent reaction involving the reduction of iodic acid with sodium dithionite requires exact quantities.)

B) Recovery of silver:

AgI + Cl2 ---aqua regia---> AgCl + ICl
AgCl + 2 NH3 -> Ag(NH3)2Cl
2 Ag(NH3)2Cl + Na2S2O4 + 2 H2O -> 2NaCl + 2Ag + 2(NH4)2SO3

The powdered silver iodide (40-mesh) is treated with excess aqua regia (under hood). A solution consisting of 81 mL of concentrated nitric acid (sp. gr. 1.42) and 216 mL of concentrated hydrochloric acid (sp. gr. 1.19) is suitable for each 100 g. of silver iodide*. The reaction proceeds vigorously but not violently. The mixture should be shaken frequently for 5 minutes until the initial vigorous reaction has subsided. The suspension is then heated gently on the steam bath for 25 minutes, with occasional shaking**. The contents of the reaction vessel are then diluted with 330 ml. of distilled water and cooled in ice. The silver chloride is filtered on a Buchner funnel and washed with distilled water on the filter. The filtrate (II) is reserved for recovery of iodine. Silver chloride obtained in the reaction is dissolved in concentrated aqueous ammonia and combined with the previous ammoniacal filtrate (I)***. This solution is treated with an excess of a 6 per cent solution of sodium dithionite, (ammonium formate works too) which quantitatively precipitates pure silver as a grey powder. The silver is washed with distilled water and dried. This method of recovering silver from silver chloride appears preferable to reduction with zinc or by other agents involving heterogeneous reactions.

* The quantities given in the subsequent description apply to 100g-lots of silver iodide.
** If the silver iodide contain no lumps, this treatment suffices for practically complete conversion to silver chloride. However, a test for completion of the reaction may be made by removing a small quantity of the precipitate, which after washings with water should all dissolve in concentrated ammonia solution.
*** Any residue remaining undissolved in ammonia should be treated again with aqua regia. Ammoniacal silver chloride solutions should not be allowed to stand too long before precipitating the silver since some insoluble material separates, which, on occasion, has produced violent explosions. shocked
(Hive Bee)
02-14-03 21:08
No 407847
(Rated as: excellent)

C) Recovery of iodine:

5 ICl + 6 NaOH -> 2 I2 + NaIO3 + 5 NaCl + 3 H2O
6 NaIO3 + 5 Na2S2O4 + 2 H2O -> 3 I2 + 6 Na2SO4 + 4 NaHSO4

To the filtrate (II) from the aqua regia treatment, cooled in ice, 20% sodium hydroxyde solution is slowly added, with stirring, until the solution is slightly basic. Then hydrochloric acid is added dropwise until the solution is just acid to litmus. This causes 80 per cent of the iodine to precipitate. To the suspension is added a solution containing exactly 12.3 g. of sodium dithionite (calculated as Na2S204), which precipitates the remaining 20 per cent of the iodine. The acidity is adjusted as before. Excess sodium hydroxide must be avoided to prevent solution of some iodine. The precipitated iodine is filtered from the ice-cold solution by means of a hardened paper on a Buchner funnel. The filtrate is tested for complete precipitation of iodine by dropwise addition of sodium dithionite. The calculated amount may not have been quite sufficient, probably because of the oxidizing action of some chlorine or hypochlorous acid. Excess sodium dithionite is to be avoided, however, to prevent loss of iodine by reduction to soluble iodide. The iodine is washed with cold water, filtered, and dried in a desiccator over concentrated sulfuric acid. If further purification is desired, sublimation may be employed. The recovery of silver and iodine from silver iodide by this method is quantitative except for slight manipulative losses.

Proposed synthesis:

N-acetyl-beta-aminoethyl benzoquinone, (A): adapted from [9]

All glassware should be washed three times with distilled H2O before use.

In a 500 ml 2-necked RBF, fitted with a thermometer and a pressure equalized graduated dropping funnel, is placed 13.1 g (0.1 mole) of (recrystallised) N-Acetyl-beta-alanine, 10.8 g (0.1 mole) of pure *1 yellow 1,4-benzoquinone, 2g of AgNO3 and 250 ml of dH2O. The mixture is then stirred and heated to 60-65C until dissolution is complete. A little CH3CN can be added if dissolution can't be achieved. The resulting solution is stirred vigorously while a freshly prepared *2 solution of 27.4g (0.12 mole) of ammonium peroxydisulfate in 50 ml of dH2O is added at a rate *3  of 1 mL per minute for the first 40 minutes and then at a rate of 0.5 mL per minute for the last 20 minutes. Throughout the addition, the reaction mixture is maintained at 60-65C.
After the addition is complete the mixture is stirred for 5 minutes at 65C and then cooled to 5-10C in an ice bath. The precipitated solid is collected by suction filtration *4, washed with 50 mL of cold dH2O and pressed to remove most of the liquid. Inorganic contaminants (if any) are removed by dissolving the solid in boiling acetone and filtering the hot solution from the insoluble. Acetone is evaporated under vacuum to give a product which is crystallized from a suitable solvent (EtOH?). After cooling to 5C the crystals are collected by filtration and air dried on buchner. Recrystallisation from a suitable solvent (EtOH?) should give (A).

*1 Freshly recrystallised or sublimed, it has to be yellow, not the green stuff as the green stuff is quinhydrone. While quinhydrone as some use in a wacker reaction it hasn't here, only yellow benzoquinone work.
*2 (NH4)2S2O8 solution are not stable, they should be prepared a short time before use.
*3 A 3 mL/min rate
might be used
*4 If the product separe as a gum, as an oil or is partly soluble in water an extraction procedure is used.

N-acetyl-beta-aminoethyl hydroquinone, (B): adapted from [3]
19.3 g of (A) (0.1 mole) in enough Et2O to dissolve it (200-300 mL) was shaken with a solution of sodium hydrosulfite (made from 35 g (200 mmole) of Na2S2O4 in 500mL water). If the color doesn't disappear fully, add some more Na2S2O4 in water. After discolouration the organic layer is separated and the water solution is extracted once with 50 mL Et2O. The combined Et2O fractions are washed once with brine and dried over anhydrous MgSO4. The ether is distilled under vacuum to yield (B).

N-Acetyl-2C-H, (C): adapted from [4]
To a stirred mixture of 19.5g of (B) (0.1 mole) dissolved in acetone (~150 mL) and anhydrous potassium carbonate (28g, 0.203 mole) is added rapidly with stirring 30g of CH3I *5 (~0.21 mole, ~13.2 mL). The whole mixture is then refluxed for ~6 hrs *6.
The mixture is then cooled and filtered, the remaining inorganic salts are washed once with acetone. The acetone is evaporated under reduced pressure *7. Some Et2O is added to dissolve the resulting product, the ether layer is washed twice with aqueous 0.1 mol NaOH solution *8, then twice with aqueous 0.1 mol HCl *9, once with water and once with brine. The ether is decanted, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to yield N-Acetyl-2C-H (C). The N-Acetyl-2C-H can be recrystallised from EtOH, nitrated like in ref [5], reduced and subjected to the sandmeyer reaction to give 2C-C (or the other halides too). It can be nitrated then hydrolized to give 2C-N. Or it can be simply hydrolized to give 2C-H.

*5 Caution! iodomethane is toxic!
*6 Maybe more, maybe less, I dont know, it should be monitored by TLC.
*7 Caution! it remains some unreacted iodomethane
*8 These washes remove the phenolates, they could be remethylated once more with CH3I.
*9 These washes remove the deprotected amines which may be present.

2C-H: from [5]
5.6 g of N-Acetyl-2C-H (C) (~0.025 mole) in aq. NaOH (from 25g NaOH and 125 mL water) and ethylene glycol (250 mL) is heated under reflux for 15 hrs and then cooled. The solution is extracted in ether, washed twice with water, extracted with aq. HCl (pH 1), washed twice with ether, basified to pH 12, extracted in ether, dried over MgSO4 and gassed with anhydrous HCl to give 2C-H.HCl. Alternatively the crude solution can be simply extracted in ether, washed twice with water, dried and then the freebase purified by distillation under reduced pressure.

Bromination give 2C-B and iodination with silver/iodine give 2C-I.

And dont forget to recover your silver from the alkylation (you can add some KI to the filtrate of the first reaction to precipitate AgI) and/or from the iodination (if you wanted some 2C-I).

[1] Unknown book with title "organic peroxyde", p324
[2] Unknown book with title "chemistry of the amino acids"
[3] J chem soc perkin trans I, 1982 + a lot of others ref with same reaction
[4] J chem soc 1958, 1602; J Chem soc 1959, 3376 and 3380
[5] Can j chem 51 1973 1402 Post 405601 (Chimimanie: "DOM analogs (Can J chem 51 1402 1973)", Novel Discourse)
[6] unknown ref, synthesis of DOEF by shulgin
[7] Recovery of silver and iodine from silver iodide residues, J R Spies, Inorganic synthesis, vol unknown, p 6
[8] Darstellung und oxidation von 2-(2,5-dihydroxy-phenyl)-ethylamin-Derivaten II, Z. Naturforsch 42 b, 1567-1577 (1987)
[9] Organic synthesis collective vol 6 p890 http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0890

I am open to discussion: what you guys do you think of that road, what critics have you got, what comments and the like...?

Who want to try it first? wink
(Hive Bee)
10-12-03 18:48
No 464190
      Reductive allylation of quinones
(Rated as: excellent)

The authors present a promising new, academical route for precursors of 2,5-dialkoxy-3-substituted-PEAs or amphetamines.

Sorry, for molecular formulas but better than the IUPAC-nomenclature wink. The left column has the substituted quinones, the second column the product (usually the substituted hydroquinone).

Tetrahedron Letters, 2003, 44, 4861-4864

Bi(OTf)3-catalyzed allylation of quinones with allyltrimethylsilane

J. S. Yadav,* B. V. S. Reddy and T. Swamy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 January 2003; revised 8 April 2003; accepted 2 May 2003

p-Quinones react smoothly with allyltrimethylsilane in the presence of 2 mol% of Bi(OTf)3 under mild reaction conditions to afford the corresponding allyl substituted benzene derivatives, p-allylquinols and allyl substituted 1,4-naphthoquinones in excellent yields with high regioselectivity. This method is very useful for the direct introduction of an allyl functionality onto a quinone moiety.

The allylation of quinones is an important reaction for the preparation of biologically active isoprenoid quinones such as vitamin E, vitamin K, coenzyme Q, and plastquinones, which play a vital role in biological processes including electron transport, blood clotting and oxidative phosphorylation.1 Functionalized quinols are not only important in the biosynthesis and metabolism of natural phenols but are also useful as synthetic precursors to naturally occurring quinones and alkaloids.2 The allylation of quinones is generally carried out with allylsilanes using acid catalysts such as titanium tetrachloride and lithium perchlorate in diethyl ether (LPDE).3 These methods involve the use of a stoichiometric amount of catalysts and prolonged reaction times especially with LPDE to produce allylated quinones. Other methods involve the addition of allyl indium, allyl magnesium, allyl nickel complexes or allylstannane to the quinones.4,5 A major side product in these procedures is the hydroquinone arising from simple reduction of p-benzoquinones. Furthermore, many of these procedures produce a mixture of products and also require a large excess of quinones to eliminate or at least minimize the formation of by-products.

Therefore, the development of simple and novel reagents, which are more efficient and provide convenient procedures with improved yields, is needed.
Recently, bismuth(III) triflate has attracted the interest of synthetic organic chemists because it is inexpensive and can be easily prepared even in multi-gram scale, in the laboratory from commercially available bismuth(III) oxide and triflic acid.6 Owing to its unique catalytic properties, bismuth(III) triflate has been extensively used for a plethora of organic transformations.7
However, there have been no reports on the allylation of quinones with allylsilane employing metal triflates as catalysts.

In this report, we wish to highlight our results on the allylation of quinones with allyltrimethylsilane using a catalytic amount of Bi(OTf)3. The treatment of p-benzoquinone with allylsilane in the presence of 2 mol% Bi(OTf)3 afforded the corresponding 2,5-diallylhydroquinone 2a in 75% yield along with 2-allylhydroquinone 2a' in 15% yield. However, substituted p-benzoquinones gave the corresponding mono-allylhydroquinones in high yields (Scheme 1).

Similarly, various substituted p-quinones reacted smoothly with allylsilane at ambient temperature to produce the mono-allylhydroquinones in high yields. Quinones having methyl groups adjacent to unsaturated positions, i.e. 2-methylbenzoquinone and 2,3-dimethyl-, 2,5-dimethyl-, 2,6-dimethylbenzoquinones or 2,6-dimethoxybenzoquinone produced the corresponding allylhydroquinones resulting from allylation at the unsubstituted ring site (entries bf). No attack at the methylated position was observed when both adjacent positions bear methyl groups (e.g. 2,3-dimethylbenzoquinone). However, 2,3,5,6-tetrasubstituted p-benzoquinone (duroquinone) and anthroquinone afforded products of addition to one of the carbonyl groups in fairly good yields (entries g, l). Furthermore, the allylation of naphthoquinones with allyltrimethylsilane in the presence of Bi(OTf)3 gave the corresponding allyl substituted naphthoquinones in high yields (entries ik, Scheme 2).

In all cases, the reactions proceeded rapidly at room temperature with high regioselectivity. Unlike other reported methods, this method does not require the use of additives or ligands to suppress reduction of quinones thereby increasing overall yields. This procedure avoids the disadvantages of polyalkylation, chromanol formation or side-chain cyclization. This method is also effective for the allylation of hindered 1,4-benzoquinones such as duroquinone while most existing methods fail to produce p-allylquinols from duroquinone. Among various metal triflates such as Bi(OTf)3, Yb(OTf)3, In(OTf)3 and Ce(OTf)3 studied for this transformation, bismuth(III) triflate was found to be the most effective in terms of conversion and reaction rates. However, similar yields and selectivity were also obtained when using (5 mol%) scandium(III) triflate under these reaction conditions. As solvent, dichloromethane appears to give the best results. The products were characterized by 1H NMR, IR and mass spectroscopic data and also by comparison with authentic samples. Other allylating agents such as allyltributylstannane and tetraallyltin also reacted smoothly with p-quinones in the presence of 2 mol% Bi(OTf)3 in dichloromethane to produce allyl benzoquinones in excellent yields. The probable pathway seems to be addition of the allyl group at the less hindered carbonyl group followed by a [3,3]sigmatropic rearrangement resulting in the formation of allyl-substituted hydroquinones (Scheme 3) or their oxidation products (entries ik).

The scope and generality of this process is illustrated with respect to various quinones and allylsilane and the results are presented in Table 1.8 In summary, this paper describes an efficient protocol for the allylation of quinones with allyltrimethylsilane using bismuth(III) triflate as the catalyst. This method offers several advantages including mild reaction conditions, enhanced rates, cleaner reactions with improved yields, no production of by-products such as polyalkylated or cyclized products, ready availability of starting materials, small quantity of catalyst, high regioselectivity, operational and experimental simplicity which makes this method a useful and attractive strategy for the synthesis of allyl substituted quinones and hydroquinones.

B.V.S. and T.S. thank CSIR, New Delhi for the award of fellowships.

Table 1. Bismuth(III) triflate catalyzed allylation of p-quinones, naphthoquinones and anthroquinone with allyltrimethylsilane

Entry Quinone 1 Producta 2 Reaction time (h) Yield (%)b

Molecule: a ("C/1=C/C(\C=C/C\1=O)=O")

Molecule: a1 ("c1(cc(c(cc1O)CC=C)O)CC=C")

10 75c

Molecule: b ("C/1=C/C(\C(=C/C\1=O)C)=O")

Molecule: b1 ("c1(cc(c(cc1O)C)O)CC=C")

15 91

Molecule: c ("C/1=C(/C(\C(=C/C\1=O)C)=O)C")

Molecule: c1 ("c1(c(c(c(cc1O)C)O)C)CC=C")

12 89

Molecule: d ("C/1(=C/C(\C(=C/C\1=O)C)=O)C")

Molecule: d1 ("c1(c(c(cc(c1O)C)O)C)CC=C")

10 87

Molecule: e ("C/1=C/C(\C(=C(/C\1=O)C)C)=O")

Molecule: e1 ("c1(cc(c(c(c1O)C)C)O)CC=C")

15 90

Molecule: f ("C/1(=C/C(\C(=C/C\1=O)OC)=O)OC")

Molecule: f1 ("c1(c(c(c(cc1O)OC)O)OC)CC=C")

10 85

Molecule: g ("C/1(=C(/C(\C(=C(/C\1=O)C)C)=O)C)C")

Molecule: g1 ("C\1(=C(\C(\C(=C(/C/1=O)C)C)(O)CC=C)C)C")

20 82

Molecule: h ("C/1=C/C(\C=C(/C\1=O)OC)=O")

Molecule: h1 ("c1(cc(cc(c1O)OC)O)CC=C")

10 87

Molecule: i ("C/1=C/C(c2c(C\1=O)cccc2)=O")

Molecule: i1 ("C/1(=C/C(c2c(C\1=O)cccc2)=O)CC=C")

15 90

Molecule: j ("C/1(=C/C(c2c(C\1=O)cccc2)=O)C")

Molecule: j1 ("C/1(=C(/C(c2c(C\1=O)cccc2)=O)C)CC=C")

18 88

Molecule: k ("C/1(=C/C(c2c(C\1=O)cccc2)=O)OC")

Molecule: k1 ("C/1(=C(/C(c2c(C\1=O)cccc2)=O)OC)CC=C ")

15 85

Molecule: l ("c13ccccc3C(C\2C(C1=O)\C=C/C=C/2)=O")

Molecule: l1 ("c12C(c3ccccc3C(c2cccc1)=O)(O)CC=C")

25 75

a All products were charaterized by 1H NMR, IR and mass spectroscopy
b Isolated and unoptimized yields
c 2-allylbenzene-1,4-diol 2a' was also obtained in 15% yield

1. (a) Thomson, R. H. Naturally Occurring Quinones, 3rd ed.; Academic Press: New York, 1987; (b) Inoue, S.; Saito, K.; Kato, K.; Nozaki, S.; Sato, K. J. Chem. Soc., Perkin Trans. 11974, 20972101; (c) Sato, K.; Inoue, S.; Saito, K. J. Chem. Soc., Perkin Trans. 11973, 22892293; (d) Inoue, S.; Yamaguchi, R.; Saito, K.; Sato, K. Bull. Chem. Soc. Jpn. 1975, 47, 30983108.
2. (a) Evans, D. A.; Hart, D. J.; Koelsch, P. M.; Cain, P. A. Pure Appl. Chem. 1979, 51, 12851300; (b) Bentley, B. M.; Campbell, I. M. In The Chemistry of Quinoid Compounds; Patai, S., Ed.; Wiley: New York, NY, 1974; Part 2, p. 683.
3. (a) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1977, 40414044; (b) Ipaktschi, J.; Heydari, A. Angew. Chem., Int. Ed. Engl. 1992, 31, 313314.
4. (a) Araki, S.; Katsumura, N.; Butsugan, Y. J. Organomet. Chem. 1991, 415, 724; (b) Hegedus, L. S.; Evans, B. R.; Korte, D. E.; Waterman, E. L.; Sjoberg, K. J. Am. Chem. Soc. 1976, 39013909; (c) Fisher, A.; Henderson, G. N. Tetrahedron Lett. 1980, 701704.
5. (a) Evans, D. A.; Hoffmann, J. M. J. Am. Chem. Soc. 1976, 98, 19831986; (b) Naruta, Y. J. Am. Chem. Soc. 1980, 102, 37743783; (c) Takuwa, A.; Soga, O.; Mishima, T.; Maruyama, K. J. Org. Chem. 1987, 52, 12611265.
6. Repichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J. Tetrahedron Lett. 2002, 43, 993995.
7. Leonard, M. N.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58, 83738397.
8. General procedure: A mixture of p-quinone (2 mmol) and Bi(OTf)3 (0.05 mmol) and allyltrimethylsilane (4 mmol) in dichloromethane (10 mL) was stirred at room temperature for the specified time (see Table 1). After completion of the reaction as indicated by TLC, the reaction mixture was quenched with water (15 mL) and extracted with dichloromethane (210 mL). Evaporation of the solvent followed by purification on silica gel (Merck, 100200 mesh, ethyl acetate-hexane, 0.59.5) afforded the pure allyl derivative.

Spectral data for selected products:
2,5-Diallyl benzene-1,4-diol, 2a (see Table 1): solid, mp 195197C, 1H NMR (CDCl3) : 3.32 (d, 4H, J=6.5 Hz), 4.35 (brs, 1H), 4.40 (brs, 1H), 5.15 (dd, 4H, J=1.7, 17.3 Hz), 5.90-6.0 (ddt, 2H, J=6.5, 10.2, 17.3 Hz), 6.55 (s, 2H). IR (KBr): 3461, 2935, 2861, 1610, 1219, 772 cm-1. EIMS: m/z (%): 190 M+ (100), 149 (15), 71 (8), 57 (10).
2-Allyl benzene-1,4-diol, 2a (see Table 1): solid, mp 9091C, 1H NMR (CDCl3) : 3.30 (d, 2H, J=6.5 Hz), 4.35 (brs, 1H), 4.40 (brs, 1H), 5.09 (dd, 2H, J=1.7, 17.3 Hz), 5.956.0 (ddt, 1H, J=6.5, 10.2, 17.3 Hz), 6.576.75 (m, 3H). IR (KBr):  3461, 2935, 2861, 1610, 1219, 772 cm-1. EIMS: m/z (%): 150 M+ (20), 121 (100), 71 (35), 57 (75).
2-Allylnaphthalene-1,4-dione, 2i: solid, 138140C: 1H NMR (CDCl3) : 3.38 (d, 2H, J=6.5 Hz), 5.20 (dd, 2H, J=1.8, 17.3 Hz), 5.95-6.0 (ddt, 1H, J=6.5, 10.3, 17.3 Hz), 6.80 (s, 1H), 7.607.80 (m, 2H), 8.058.15 (m, 2H). EIMS: m/z (%): 198 M+ (100), 181 (20), 169 (15), 141 (60), 115 (18), 104 (16), 176 (50), 65 (5), 50 (12). IR (KBr) : 2930, 1720, 1664, 1595, 1497, 1301, 1221, 1071, 757 cm-1.
2-Allyl-3-methyl-naphthalene-1,4-dione, 2j: 1H NMR (CDCl3) : 2.50 (s, 3H), 3.50 (d, 2H, J=6.5 Hz), 5.055.10 (dd, 2H, J=1.7, 17.3 Hz), 5.755.85 (ddt, 1H, J=6.5, 10.3, 17.3 Hz), 7.30 (d, 1H, J=8.0 Hz), 7.657.70 (m, 1H), 8.058.15 (m, 2H). EIMS: m/z (%): 212 M+ (100), 198 (25), 170 (20), 142 (55), 105 (15), 104 (40), 76 (10), 50 (25). IR (KBr) : 2925, 1720, 1659, 1521, 1460, 1294, 1219, 1078, 772 cm-1.

The candle that burns twice as bright burns half as long
10-13-03 07:09
No 464338
      Reductive Methylation of Quinones     

Post 264123 (Antoncho: "Re: alkylation of quinones", Novel Discourse)

Here's an "exact proc." :

A solution of 17.5 g 1,4-naphthaquinone in 200 mL MeOH was heated to the boiling point, and treated with 28.5 g stannous chloride at a rate that maintained a continuous rolling boil.  At the completion of the addition, the reaction mixture was saturated with anhydrous hydrogen chloride, and held at reflux on the steam bath for 2 h.  The reaction mixture was poured into 700 mL H2O and treated with aqueous NaOH.  During the addition there was transient development of a curdy white solid which redissolved when the system became strongly basic.  This was extracted with 3x200 mL CH2Cl2 and the pooled extracts were washed first with H2O, then with dilute HCl, and finally again with H2O.  Removal of the solvent under vacuum yielded 15.75 g of a low melting black flaky crystalline material which was distilled at 160-180 C at 0.05 mm/Hg to give 14.5 g of an amber, solid mass with a mp of 78-86 C.  Recrystallization from 75 mL boiling MeOH provided 1,4-dimethoxynaphthalene as white crystals melting at 87-88 C.

Does anyone want to guess where SWIM got that from??

Perhaps this will work equally well for benzoquinone to 1,4-dimethoxybenzene? Maybe we can even replace the SnCl2 with sodium dithionite.

Doesn't anybody have some trifluoroacetic acid and benzoquinone??
(Chief Bee)
10-13-03 15:09
No 464393

at a rate that maintained a continuous rolling boil

The only chemist expressing himself as graphic as that must be Sasha, right?
10-13-03 17:45
No 464425
      ;-) Of course. See 2C-G-N.     

wink Of course. See 2C-G-N.
10-14-03 09:46
No 464544

Surely one of the easiest ways would have to be the alkylation of the hydroquinone, which at least where i am is easier to get than the benzoquinone. I realise this may not be universally applicable to everyones use, but hey. :-)
Couldn't the hydroquinone be reacted with 2 equivalents of base giving the phen-1,4-dioxide (? @ naming) and reacting it in dmf with an alkyl halide, namely halomethane or haloethane. To give 1,4 dimethoxy benzene. Comments and rebuttals welcome, as its all a learning process.
(Chief Bee)
10-14-03 13:58
No 464571
      Yes, but that's different.     

If you already have the hydroquinone, yes, then it is simply a double phenol alkylation.

The above was a nifty way of going from the para-quinone to the para-dimethoxyarene in one step, without first having to reduce the quinone to the hydroquinone.
10-29-03 12:53
No 467493

Rhodium: do you know the exact mechanism of the rxn? If it involves alpha-carbonyl hydrogens, then CF3COOH won't react (and I think it does and in fact the mechanism is similar to free radical induced coupling of acetone and benzene at the alpha-carbonyl site with subsequent decarboxylation). Would manganese (III) acetate work as a catalyst then?

Another idea: reacting the quinone with cyanoacetic acid, simultaneous methylation-reduction and finally energetic reduction of the nitrile would be a quick route to 2C-H.

And then... maybe acetone methylimine would react as well... Then reduction with sodium dithionite (or what have u, maybe thiourea dioxide) and final methylation.
12-10-03 05:27
No 475847

Rhodium, or anyone, SWIM is curious about the mechanism of this reaction....

A solution of 17.5 g 1,4-naphthaquinone in 200 mL MeOH was heated to the boiling point, and treated with 28.5 g stannous chloride at a rate that maintained a continuous rolling boil.  At the completion of the addition, the reaction mixture was saturated with anhydrous hydrogen chloride, and held at reflux on the steam bath for 2 h.  The reaction mixture was poured into 700 mL H2O and treated with aqueous NaOH.  During the addition there was transient development of a curdy white solid which redissolved when the system became strongly basic.  This was extracted with 3x200 mL CH2Cl2 and the pooled extracts were washed first with H2O, then with dilute HCl, and finally again with H2O.  Removal of the solvent under vacuum yielded 15.75 g of a low melting black flaky crystalline material which was distilled at 160-180 C at 0.05 mm/Hg to give 14.5 g of an amber, solid mass with a mp of 78-86 C.  Recrystallization from 75 mL boiling MeOH provided 1,4-dimethoxynaphthalene as white crystals melting at 87-88 C.

SWIM could only think of something like this...

The SnCl2 reduces the double bond of the quinone forming 1,4-naphthahydroquinone and SnCl4. Anhydrous HCl is then gassed in and the formed SnCl4, being a lewis acid, reacts with the MeOH and HCl to form in situ methyl chloride. The methyl chloride then methylates the hydroquinone.

It seems to be the only thing that makes sense to SWIM. Can anyone think of another mechanism?

If this is the case, then might it be possible to just dissolve hydroquinone in MeOH, add some lewis acid (perhaps ZnCl2??), then gas with anhydrous HCl? Seems like that could work on any phenol.

That means the SnCl2 needs to be anhydrous, and not the dihydrate. Or could the dihydrate work? SnCl4 forms a pentahydrate, so there would be room for anhydrous material. Maybe adding some silica gel wouldn't hurt.

BTW. SWIM has an article where they alkylate benzoquinone using free radicals generated from dialkyl sulphoxides. DMSO yielded mono, and poly methylated benzoquinone.
(Official Hive Translator)
12-10-03 07:18
No 475876
      The mechanism     

I bet the mechanism is pretty similar to the one described in Post 267698 (Antoncho: "P-MeO-phenol from hydroquinone: part II", Novel Discourse) for p-benzoquinone - thru hemiacetal which is instantly reduced with SnCl2

Note that in our case the major product is the dimethylated compound - which in the HQ case is present only in trace qtties. Obviously it is the dimethylhemyacetal that is reduced, but i have no clue why. Maybee di/mono methylhemiacetal equilibrium is connected to concentration of the quinone (in the HQ patent they got diMeObenzene only when employing larger qtty of benzoquinone catalyst).

In any case, it seems to me that SnCl2 needs not bee unhydrous at all (naturally, with dihydrate one wouldn't see any exoterm as in Shulgin's report) since its only purpose is to reduce.

(One Remarkable HyperLab Bee)
12-10-03 12:51
No 475911
      Re: Mechanism???
(Rated as: good read)

If this is the case, then might it be possible to just dissolve hydroquinone in MeOH, add some lewis acid (perhaps ZnCl2??), then gas with anhydrous HCl? Seems like that could work on any phenol.
   There is something special about naphthols: they tautomerize easily into the corresponding ketones without complete loss of aromaticity. That's why both 1- and 2-naphthols form ethers (reversibly) when heated in alcohols in the presence of an acidic catalyst. The reaction was applied mainly for the manufacture of 2-ethoxynaphthalene (neroline) and 2-methoxynaphthalene (yara yara) which were used in perfumery.
(Official Hive Translator)
12-10-03 15:37
No 475930

...so, THAT's why in case of napthamethoxyphenol the reaction proceeds all the way to the diMeO compound...

Which would probably mean that it won't work for benzene nucleus-based things.
(One Remarkable HyperLab Bee)
12-10-03 18:11
No 475950
(Rated as: good read)

...so, THAT's why in case of napthamethoxyphenol the reaction proceeds all the way to the diMeO compound...


Which would probably mean that it won't work for benzene nucleus-based things.

   Phloroglucinol is an exception. It reacts (via keto tautomer) with methanolic acids (HCl [1,2] or H2SO4 [3]) to form mainly phloroglucinol dimethyl ether, which can be further methylated with MeI/KOH [1] or with Me2SO4/KOH [2,3] to 1,3,5-trimethoxybenzene.
   Direct methylation of phloroglucinol with MeX is impossible because C-methylation prevails.

1. W. Will, Ber., 21, 602-616 (1888).
2. K. Freudenberg, Ber., 53, 1416-1427 (1920).
3. http://www.erowid.org/library/books_online/pihkal/pihkal162.shtml

More references can be found in Weygand - Hilgetag, p.331 (Russian translation).
(Hive Bee)
12-10-03 19:53
No 475976
      Interesting... phloroglucinol dimethyl ether...     

Interesting... phloroglucinol dimethyl ether could be ortho-formylated and the product methylated to 2,4,6-trimethoxybenzaldehyde.

fear fear hate hate
(Hive Bee)
12-18-03 03:38
No 477519
      convenient procedure for allylation of quinone
(Rated as: excellent)

This procedure is very suited to our needs, it was more tuned up than the former http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0890 poix posted all above this thread. Both procedure use the same silver/persulfate to generate Ag2+ in situ which oxyde a suitable alkyl chain to form a radical that will get quenched by the quinone. There are two notable differences here against the former:

-first: the alkyl chain is not an acid which loss CO2 to generate the alkyl radical minus one C based on the acid (ex: butyric -> CH3CH2CH2. ) , but an ester of oxalic acid, which come from an alcohol with the same number of carbon than the alkyl chain to bee put in place. The oxalate is oxydatively hydrolised and generate a R. radical, where the former OH was, which will react with the quinone.

-second: here they solve the problem of poly alkylation of the quinone by various radicals by using a two phases mixture. This can bee used in the old orgsyn.org ref too, if you want to start with the acid in place of the oxalate. Higher yield and purity are achieved through such reaction medium change.

The true problem now is synthetising the allyl oxalate, as I said in another thread, it can bee done by transesterification of oxalate diethyl ester, then basic hydrolyse of one of the allyl ester to the free acid. Sadly the patents are in Japanese. Refs to make this allyl oxalate are highly wanted. Well, at worst using some proper acid (like N-acetyl beta-alanine or the acetal of acetoacetic acid) and this biphasic medium in place of the one phase of orgsyn ref will give rise to better yields and next to zero polyalkylation of the quinones. The convenience of this route gained a few points here, bees. wink

Check the table: 96% for the allylation of quinone! Yeesh! cool

Here is the gem:

A New Selective Method for the Homolytic Alkylation and Carboxylation of Quinones by Monoesters of Oxalic Acid Fausta COPPA, Francesca FONTANA, Edoardo LAZZARINI, and Francesco MINISCI Chem. lett. 1992 7 1299


Alkyl and alkoxycarbonyl radicals were generated by oxidative decarboxylation of oxalic acid monoesters by persulfate; they were then utilized for the selective substitution of quinones.

The oxidative decarboxylation of oxalic acid monoesters proved to be a very effective source of alkoxycarbonyl and alkyl radicals, useful for selective syntheses. The alkylation of heteroaromatic bases was described in the preceding Letter [1] and in a recent report [2] of a more expensive and less effective procedure.

Now we report how this radical source can be successfully utilized for the selective alkylation (Eq.1) or carboxylation (Eq.2) of quinones in a two-phase system. The results are shown in Table 1. With esters of tertiary or secondary alcohols, alkylation (Eq.1) mainly occurs, whereas with primary alcohols carboxylation (Eq.2) becomes the main process. With esters of allylic alcohols only allylation occurs and we expect a similar behaviour with esters of benzylic alcohols.

Operating in a two-phase system, constituted by water and an organic solvent, such as CH2Cl2 or benzene, is particularly important for minimizing polysubstitution, because the reaction products are generally more lipophilic than the starting quinones and are therefore preferentially extracted by the organic solvent, whereas the substitution reaction takes place in the aqueous phase. With quinones of very low solubility in water, such as the naphthoquinone derivatives, using two-phase system constituted by three solvents (CH2Cl2, CH3CN, and H20) improves the effectiveness of the reaction.

The mechanism of the reaction involves the following steps:

i) generation of the carbon-centered radicals (Eqs.3-5)

ii) addition to the quinone ring (Eq.6)

iii) oxidation of the radical adduct in a redox chain (Eq.7)

It is noteworthy that when alkoxycarbonylation (Eq.2) is the prevailing reaction, as in the case of the reaction between benzoquinone and ethyl monoester, a minor amount of 2,6-diethoxycarbonylhydroquinone is formed. We explain this result by the fact that the introduction of an alkoxycarbonyl radical, instead of an alkyl radical, on the quinone ring increases the redox potential of the resulting phenoxy radical and makes its oxidation by persulfate slower (Eq.7). This allows to reach stationary concentration of the phenoxy radical, suitable for acting as scavenger towards another alkoxycarbonyl radical (Eq.7b).

Considering that the reaction takes place in the aqueous phase, in which the solubility of the quinone is generally very low, that the ethyl radical is not formed in siqnificant amount and that the rate is given by the expression r = k [-COOR] [quinone], it follows that the rate constant for the addition of the ethoxycarbonyl radical to the quinone ring must be high (>10^6 M-1 s-1). The lower solubility of naphthoquinone explains its lower degree of alkoxycarbonylation compared to benzoquinone under identical reaction conditions.

A general experimental procedure is given:

A solution of 10 mmol of monoester of oxalic acid and 5 mmol of quinone in 20 ml of the solvents reported in the Table was added to 20 ml of an aqueous solution containing 10 mmol of Na2S208 and 0.5 mmol of AgN03. The mixture was refluxed for 2 h, then the organic layer was separated, dried and analyzed by GC and GC/MS. The reaction products were isolated by flash-chromatography on silica gel and identified by comparison with authentic samples.[3] This is the first example, to the best of our knowledge, where the homolytic carboxylation, of quinones is achieved. On the other hand, the above described alkylation represents the only procedure so far known for the radical alkylation of quinones by alcohols, whereas alkylation by carboxylic acids has been reported by several groups.[4]


[1] F. Coppa, F. Fontana, E. Lazzarini, F. Minisci, and L. Zhao, Chem.Lett., preceding paper.
[2] H. Togo, M. Aoki, and M. Yokoyama, Chem.Lett., 1991, 1691.
[3] F. Coppa, F. Fontana, F. Minisci, M. C. Nogueira Barbosa, and E. Vismara, Tetrahedron, 47, 7343 (1991) and references therein.
[4] Ref.3; D. H. R. Barton, D. Bridan, and S. Z. Zard, Tetrahedron, 43, 5307 (1987); B. Lin, L. Gu, and J. Zhang, Rec.Trav.Chim.Pays-Bas, 110, 104 (1991) and references therein.
12-19-03 11:25
No 477804
      Just wanted to remember all that the ...     

Just wanted to remember all that the phtalimido protection would be the most obvious choice for two reasons:

1. The phtalimido-2C-H can be either chlorinated, brominated and especially iodinated with elemental halogens without any troubles. It is very stabile in basic as well as acidic conditions. Besides it gives no wary of sidereactions during the dimethylation with DMS or MeI. The other amides might interact with radicals (if it is a radical mechanism) because of the amide hydrogen.

2. Most importantly the phtalimido-beta-alanine is accesible trough the Michael addition of the potassium phtalimide to the acrylic acid (or crotonic acid if you are up to the 2,5-diMeO-amphetamines):


Where R is H or Me.
To my opinion there is no other simplier route to a perfectly protected beta-alanine and it can be done in a water solution. Besides acrylic and crotonic acids are so cheap.

Edit: Maybe I was to fast with that reaction above. There is a similar synth of beta-amino-alanine in the Organikum in the chapter 7.4.4. (6th edition). It uses acrylonitrile as a starting material and the nitrile is then hydrolised together with the phtalimido protection. There is no statement why acrylonitrile is used and nothing is said that it would not work on acrylic acid (or its ester). I have set a test reaction with acrylic acid and will report on the results.

The real drug-problem is that we need more and better drugs. J. Ott
12-20-03 21:21
No 478030
      Preparation of phtalimido-beta-alanine
(Rated as: excellent)

Since this is an ancient tread I have to remember those that don't have the time to go trough all of it that the most ingenious idea that it contains somewhere is to alkylate benzoquinone with the http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0890 procedure forming directly a protected ethylamine or isopropylamine side chain, and then addition of HX followed with the methylation of the hydroquinone product, deprotection and voila, you have your 2C-X or DOX. For this we need phtalimido-beta-alanine.

Here are the results of the test reaction mentioned in the previous post for the...

Preparation of phtalimido-beta-alanine

Molecule: the reaction scheme ("c21ccccc1C(NC2=O)=O.C=CC(=O)O>>C(CC(=O)O)N2C(c1ccccc1C2=O)=O")

In a 50ml flask there was added 0.8g of sodium hydroxide (20mmol) in 10ml of water (note 1), 1g of phtalimide (6.8mmol) and 1ml of acrylic acid (13.6mmol). This was set to reflux for 9h and then left at room temperature over night (note 2). The next day (today) the clear and only slightly yellow solution was slowly acidified with 12ml of 10% hydrochloric acid and after a minute of stirring beautiful, microscopic needle-like crystals started to grow. The product was collected by suction filtration after being cooled on an ice bath and was washed three times with ~10ml of cold water. It was then left to dry on air. 0.98g of colorless crystalline product was obtained (66%).

To test the identity of the product a heating experiment was performed (sorry, but I dont have a microscope to determine the melting point). I put a few mg of the product as well as phtalimide ~2cm from each other on a flat glass on a hot plate. I covered it with a round glass and begun heating. The phtalimide slowly sublimated on the upper glass while the product remained unchanged all the time. Only after all of the phtalimide already condensed on the upper glass the product started decomposing slowly without any visible melt or sublimation. The only other compound that I think could be a product is phtalic acid, but it decomposes to phtalanhidride at about 205C and this also readily sublimates. Phtalic acid is also relatively more soluble in water than the product. If some was formed it would probably not crystallize out after the acidification and water washings. If there are no reasonable objections Ill conclude that the product is quite probably the desired phtalimido-beta-alanine.

Note 1: This might have been too much of sodium hydroxyde. After the ftalimide gets consumed in the reaction the mixture gets more basic and this might cause some hydrolysis of the phtalimides, therefore lowering the yield and producing phtalic acid as a byproduct. I would use less hydroxide the next time or maybe change it with the less nucleophilic and less basic carbonate.
Note 2: Some bigger chunks of phtalimide took an hour or more of reflux to dissolve completely. For some unrelated reasons I had to stop the heating for half an hour during the beginning of the reflux and I observed that the phtalimide salt had precipitated on cooling. So it seems the sodium hydroxide would be better substituted with potassium hydroxide or carbonate since the potassium phtalimide should be more soluble in water. Anyway it is interesting to note that after 9 hours of reflux no precipitate formed on cooling indicating that most of the phtalimide got consumed.

To bad I dont have any ammonium peroxydisulfate to check this alkylation of benzoquinone. Somebody else will have to continue from here on tongue.

The real drug-problem is that we need more and better drugs. J. Ott
(Chief Bee)
12-21-03 00:45
No 478070
      Synthesis of N,N-phthaloyl-beta-alanine
(Rated as: good read)

Synthesis of N,N-phthaloyl-beta-alanine
Arch. Pharm. 334, 323331 (2001)

74 g (0.5 mol) of phthalic acid anhydride and 0.5 mol of beta-alanine (3-aminopropionic acid) were refluxed in 300 ml toluene in the presence of 6.5 ml triethylamine for 2 h in a Dean-Stark apparatus. The organic solvents were removed in vacuo, 700 ml of water and 10 ml of concentrated HCl were added and the mixture stirred for 30 minutes, filtered, and dried. Recrystallization from ethanol yielded 3-phthalimidopropionic acid, 99.9 g, 91%, mp 151152C.

Alternative prep from beta-alanine and phthalic acid (96% yield): Nucleosides & Nucleotides 17(9-11), 2021-2026 (1998)

The Hive - Clandestine Chemists Without Borders
(Hive Bee)
12-21-03 05:11
No 478123
      Obviously its easier     

Good suggestions Nicodem! smile

True obviously the phtalimide is a far nicer protecting group than the acetyl here:
-the preparation is easier, quick and doesn't require listed precursors (like acetic anhydride).
-the removal is better yielding than the hydrolyse of the acetamide.
-maybe you are right and the fact there are no free H on the azote is good, but I dont think that is important, a H on an amide is not labile (i know this is radical chemistry but heh).

I searched some data on the phthalimido-b-alanine and its methylated congener:

The solubility of phthalimido-b-alanine in water (calculated) range from sparingly soluble at pH 1, to very soluble above pH 7, and slightly soluble at pH4. So it look ok for this reaction. Its melting point is 150-151C.

The solubility is more or less the same for the methylated one (from 3-amino butyric acid), the melting point of this chemical is more disparate tough: ~105C or ~120C, recrystallized from H2O or benzene.

Finally I have a synth again for the protected beta-alanine, from Patent US4849436, example 12:

Preparation of N-phthalyl-b-alanine:

A mixture of 89.09 g (1.0 mol) of beta-alanine and 148.12 g (1.0 mol) of phtallic anhydride was stirred at 180-190C for 30 minutes. Upon adding water, a solid formed which was filtered, washed with water, and recrystallized in ethanol/water to give 178.0g of a white powder, mp 152-153C.

I hope the phtalimide moiety will resist the harch oxydative condition it will bee subjected here, but I think it should work well.

HQ -> BQ -> BQ-ethyl-2-phtalimide -> *insert halogenation here maybe* -> HQ-ethyl-2-phtalimide -> 2C-H (X) phtalimide --*or halogenation here maybe*--> 2C-H (X) -> 2C-X

6 steps from hydroquinone, its ok, especially since the deprotection is better, the phtalimide is easier to synth, and the two phase medium is higher yielding.  I think this route is officially convenient now, lets practice it! wink
12-21-03 12:19
No 478156
      You got me confused     

Rhodium: Is that beta-alanine they used? It is written alanine, but the product is 3-phthalimidopropionic acid (a typo ?). But if its m.p. is 151C I don't know what the hell I got out of the reaction (phtalimide has a m.p. of 238C and phtalanhidride 131C). I can only see the 1,4-addition on the acrylic acid possible here even though it immensely bothers me why I can't find a reasonable explanation on why acrylonitrile is used for the synth of beta-alanine. I would prefer getting the 3-phthalimidopropionic acid directly as the nitrile hydrolysis can't effectively be done without phtalimide deprotection, right? I'll try to make an IR of the product in the next few days if I'll have the opportunity and solve this mystery.

Chimimanie: You may be right. The amide hydrogen probably does not interfere, but I'm not 100% sure. The radicals abstract hydrogen atoms if there is a possibility of forming a more stable radical. I don't have any tables of radical's stability/energies at hand but I can tell you that the primary C-radical that forms in the proposed reaction is the least stable possible and therefore the more prone to side reactions. Actually I would not be surprised if it would rearrange to form the secondary radical that would be highly stabile (also because of the phtalimide nitrogen). This would be a big disappointment, as it would yield the alpha-phenylethylamines.
I count on the hope that the primary radicals would react faster than they would rearrange (I just hope they are not completely unselective as the phtaloyl ring is also a possible substrate even though many magnitudes less reactive than BQ). For example, in the table I of Org. Synth. procedure, all the acids have a substituent at the alpha-position that stabilizes the formed radical (PhO, t-Bu, Cl...) with the exception of adipic acid. Without this exception I would consider our reaction impossible.
I also think that it would be worth trying the nucleophilic addition on the BQ-CH2-CH2-Phtaloyl. If doing an addition of, for example, HBr in as anhydrous condition as possible the phtaloyl protection would probably resist and the major product would (again) probably be the 4 and 5-Br substituted HQ-CH2-CH2-Phtaloyl. Therefore avoiding both the reduction of BQ and the halogenation in the last step.

The real drug-problem is that we need more and better drugs. J. Ott
(Chief Bee)
12-21-03 16:32
No 478184
      beta-alanine (3-aminopropionic acid)     

Is that beta-alanine they used? It is written alanine, but the product is 3-phthalimidopropionic acid (a typo?).

They used beta-alanine (3-aminopropionic acid) in both syntheses, the greek symbol didn't carry over when I did my copy-paste thing and then I forgot to add it again. I have now edited my post.

I would prefer getting the 3-phthalimidopropionic acid directly as the nitrile hydrolysis can't effectively be done without phtalimide deprotection, right?

That is indeed possible, I have seen that transformation being done in one of the articles I went through searching for the above preps. Want me to re-retrieve it?

The Hive - Clandestine Chemists Without Borders
12-21-03 20:33
No 478223
      That is indeed possible, I have seen that...     

That is indeed possible, I have seen that transformation being done in one of the articles I went through searching for the above preps. Want me to re-retrieve it?

Im glad its possible and I hope it is an easy preparation. Unfortunately I dont have any acrylonitrile. By the time Ill get that and the peroxydisulphate Ill be able to retrieve that paper by myself. Thanx anyway, maybe if someone else is interested?

The real drug-problem is that we need more and better drugs. J. Ott
(Hive Bee)
01-10-04 10:09
No 481577
      UV promoted BQ acylation w/aldehydes
(Rated as: excellent)

Seams like quinones are among the best substrates for the free-radicals! They even bind to UV light induced radicals.
Here I found a green chem alternative to the Friedel-Crafts acylation of hydroquinones. It uses an aldehide, a benzoquinone or a naphtoquinone and optionally ~15mol% benzophenone to improve yields. I stretched my imaginaton for its use and came to propose it for the introduction of the side chain of 2C-E and other 2C- alkyl, for the synth of 2,5-diMeO-cathinone, the cathinone versions of 2C-G-N (if someone is finally going to test them). You can also nitrosate the resulting 2,5-diMeO-propiophenone (or acetophenone) and reduce the oxime to 2,5-DMA (or 2C-H) with H2/Pd-C. Or whatever. I don't see a big usefullness for it but maybe somebody else has more imagination.  The solvents used were hydrocarbons or acetonitrile or acetonirile/water mixtures. Looks like all you need are just the solvent, the reactants and a mercury lamp (no acid chloride/anhydride, no anhydrous AlCl3!).
If it only worked with formaldehide we would have another nice OTC formylation method (there acutely isn't claimed that it does not work, but even if it does the benzophenones would probably be the side products - due to double addition). Does anybody knows if UV generates also H2C*-O* diradicals?

Taken from Green Chemistry. Frontiers in benign chemical synthesis and processes. Ed. by Anastas and Williamson. (Oxford university press, 1998): A photochemical alternative to certain Fridel-Crafts reactions. Kraus et all. pp-72-86.

(...)This photochemical alternative was discovered by Klinger and Kolvenbach in 1898.1 Given the equipment avaible at the time, they undoubtedly used visible light to mediate the reaction. (...) Bruce studied this reaction and contributed significantly to the understanding of its mechanism.2 Maruyama used this reaction to prepare substituted acetophenones for natural products synthesis.3(...)
The results of our initial experiments are listed in the Table. In these experiments benzoquinone and naphthoquinone were employed as substrates. A variety of aldehydes including aliphatic, alpha,betta-unsaturated, and aromatic aldehydes were used to determine the generality of the reaction with regard to the aldehyde component.

Quinone + R-CHO  --(UV light)--> 2-(R-C=O)-Hydroquinone

Entry Substrate R Yield(%)*
1 Benzoquinone Pr 54
2 Benzoquinone Ph 60
3 Benzoquinone Me-CH=CH 57
4 Benzoquinone Ph-CH=CH 65
5 Benzoquinone o-MeO-C6H4 62(77)
6 Benzoquinone p-NO2-C6H4 0
7 Benzoquinone o-NH2-C6H4 0
8 Benzoquinone o-Cl-C6H4 61(78)
9 Benzoquinone o-F-C6H4 68
10 Benzoquinone o-Me-C6H4 57(65)
11 Benzoquinone p-Me-C6H4 70(79)
12 Benzoquinone p-Cl-C6H4 65(73)
13 Naphthoquinone Pr 77
14 Naphthoquinone Ph 88
15 Naphthoquinone Me-CH=CH 65
16 Naphthoquinone CH2=CH 12
17 Naphthoquinone Ph-CH=CH 65

* Yield in parentheses is for benzophenone catalisys

1.) Klinger et al. (1898). Chem. Ber. 31, 1214.
2.) Bruce et al. (1967). J. Chem. Soc. (C), 1486.
3.) Maruyma et al. (1974). Bull. Chem. Soc. Jpn, 47, 1303.

Multigram quantities were successfully tried to check a larger scale preparation. No experimental details are given here, but should be in:
Kraus, G. A. and Kirihara, M. (1992). J. Org. Chem., 57, 3256.
Kraus, G. A. and Liu, P. (1994). Tetrahedron Lett., 35, 7723.

The real drug-problem is that we need more and better drugs. J. Ott
(Chief Bee)
06-16-04 00:54
No 513654
      Reductive Methylation of Quinones
(Rated as: good read)

Reductive Methylation of Quinones
J. Gripenberg & T. Hase
Acta Chem. Scand. 17, 2250-2252 (1963) (../rhodium/chemistry /quinone.reductive.methylation.html)

A reductive methylation of quinones using dimethyl sulfate in the presence of pyridine is described. It is probable that methylpyridinium hydroxide, formed in the reaction, is the actual reductant.

This article has been referenced in Post 265551 (foxy2: "Re: alkylation of quinones", Novel Discourse)

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
06-17-04 12:44
No 513937
      2-Alkylhydroquinones from 1,4-cyclohexanedione
(Rated as: excellent)

A Convenient Synthesis of 2-Alkylated 1,4-Benzenediols
Y. Ozaki, A. Hosoya, K. Okamura, S.-W. Kim
Synlett 365-366 (1997) (../rhodium/chemistry /2-alkyl-hydroquinones.html)

Reaction of 1,4-cyclohexanedione with a variety of aldehydes in the presence of metal halides generated the 2-alkylated 1,4-benzenediols in good yields without any aromatic by-products.

Microwave-assisted eco-friendly synthesis of 2-alkylated hydroquinones in dry media
H. M. Sampath Kumar, B. V. Subba Reddy, E. Jagan Reddy and J. S. Yadav
Green Chemistry 141-142 (1999)

An environmentally benign process for the synthesis of 2-alkylated hydroquinones under microwave irradiation using 1,4-cyclohexadione and aldehydes catalysed by KF-Al2O3 in dry media is reported.

2-Alkylated hydroquinones are versatile chemicals with wide application in synthesis and industry1 and efforts towards the synthesis of these compounds involve C-C bond forming reactions starting from hydroquinones or quinones. However, harsh reaction conditions limit the use of these methods with regard to the nature of the side chain requirements on the hydroquinone.

An attractive approach for the synthesis of 2-alkylated hydroquinones has been reported2 recently, which involves heating of cyclohexa-1,4-dione and aldehydes with lithium or magnesium halides as catalysts in solvents such as DMI (N,N'-dimethylimidazolidinone), pyridine, HMPA, DMF, TMEDA, DMPU (N,N'-dimethylpropylurea), etc. Surface mediated solid phase reactions involving inorganic solids are becoming increasingly important and condensation of a variety of active methylene and carbonyl compounds has been reported both under conventional and microwave heating.3
In this context, we report here a convenient method for the synthesis of 2-alkylated hydroquinones catalyzed by KF-Al2O3 under microwave irradiation.

Results and discussion
Thus several aldehydes undergo condensation with 1,4-cyclohexadione when subjected to microwave irradiation in the presence of KF-Al2O34 in dry media. From the results summarized in Table 1 the generality of the reaction is evident, as a variety of aromatic, aliphatic, and heterocyclic aldehydes react to form 2-alkylated hydroquinones in good yields (75-95%) within a very short time of irradiation (2-5 min). The conversions are fairly clean, free from aromatic by-products and, unlike conventional approaches for the synthesis of these compounds which involve heating (150-160C) in expensive and often hazardous solvents, our method under microwave irradiation occurs at a much lower temperature range (100-110C, highest observed temperature after irradiation) in the absence of such solvents. Also, unlike the conventional approach for this transformation which involves aqueous work-up generating high volumes of toxic effluents, our method is almost effluent free and safe.

In conclusion we have demonstrated a quick and convenient method for the high yield preparation of 2-alkylated hydroquinones, using the inexpensive surface bound reagent KF-Al2O3 under solvent-free conditions and employing microwave irradiation techniques, which may find applications in organic synthesis.

In a typical procedure a mixture of benzaldehyde (1.6 g, 10 mmol), cyclohexa-1,4-dione (1.12 g, 10 mmol) and 37% w/w KF-Al2O3 (3 wt. equiv. of aldehyde) was placed in a Pyrex test tube and subjected to microwave irradiation at an output of 600W. After completion of the reaction (3 min) as indicated by TLC, the reaction mass was cooled to room temperature, directly charged on a silica gel column (100-200 mesh) and eluted (ethyl acetate/hexane, 3:7) to afford 2-benzylhydroquinone as a white crystalline solid (1.7 g, 85%).

Table 1
Microwave assisted preparation of 2-alkylated hydroquinones

Entry R Time Yield (3)
a Ph 3 85%
b p-MeOC6H4 3 90%
c p-MeC6H4 3 95%
d p-BrC6H4 4 85%
e p-O2NC6H4 5 75%
f p-ClC6H4 4 82%
g β-Naphtyl 4 80%
h 9-Anthracenyl 5 78%
i 3,4-(CH2O2)Ph 3 87%
j 2-Thienyl 2 90%
k 2-Furyl 2 88%
l n-Hexyl 2 75%
m n-Octyl 2 77%
n n-Decyl 2 80%

[1] a. T. Yamamura. K. Nishiwaki, Y. Tanigaki, S. Terauchi, S. Tomiyama and T. Nishiyama, Bull. Chem. Soc. Jpn., 1995, 68, 2955; b. W. Brugging, U. Kampschulte, H. Schmidt and W. Heitz, Makromol. Chem., 1988, 189, 2755; c. Y. Ozaki, K. Okamura, A. Hosoya and S. W. Kim, Chem. Lett., 1997, 679; d. L. W. Butz and A. W. Rytina, in Organic Reactions, ed. R. Adams, Wiley, New York, 1949, vol. 5, p. 136: e. G. Cimino, S. De Stefano and L. Minale, Tetrahedron, 1972, 28, 1315: f. B. M. Howard and K. Clarkson, Tetrahedron Lett., 1979, 4449; g. K. Ishihara, M. Kubota and H. Yamamoto, Synlett, 1996, 1045.
[2] Y. Ozaki, A. Hosoya. K. Okamura and S. W. Kim, Synlett 365-366 (1997) (../rhodium/chemistry /2-alkyl-hydroquinones.html)
[3] a. R. A. Abramovitch, Org. Prep. Proced. Int., 1991, 23, 685; b. S. Caddick, Tetrahedron, 1995, 51, 10403.
[4] E. A. Schmittling and J. S. Sawyer, Tetrahedron Lett., 1991. 32, 7207.

The Hive - Clandestine Chemists Without Borders
(Hive Addict)
06-22-04 09:28
No 514739

The recently posted article by Rh somewhat caught my attentions:

../rhodium/chemistry /2-alkyl-hydroquinones.html

1.4-Cyclohexanedione is commercially available, but not very cheap. But some literature browsing gives a few good alternatives to synthesize this in the lab.

However, I was thinking a bit further about the possibilities of using 1.4-cyclohexanedione as precursor for p-benzenediol derivatives. The aforementioned article only used (substituted) benzaldehydes and aliphatic aldehydes to furnish the corresponding 2-alkyl-1.4-dihydroxybenzene. However, I was wondering about the possibility to use glyoxilic acid and/or pyruvaldehyde. Theoretically, glyoxilic acid yields 2.5-dihydroxyphenylacetic acid, and pyruvaldehyde would give 2.5-dihydroxyphenylacetone.

However, I see the theoretical possibility for both compounds to form other, (possibly) not targeted compounds as well (maybe the β-keto functional group of pyruvaldehyde may condense with 1.4-cyclohexanedione as a competing reaction, or maybe there won't be any reaction at all...).

However, if the reaction between 1.4-cyclohexanedione and pyruvaldehyde would yield 2.5-dihydroxyphenylacetone, that would be very nice cool. Pyruvaldehyde is widely used as food additive.

Ideas? Input? Comments?

Aztecunnilingus Maximus
(Hive Bee)
06-22-04 15:40
No 514774
      Looks good
(Rated as: good read)

That reaction has been echoing in my mind since I first saw a reference to that Green Chem paper in a microwave chemistry paper ( ../rhodium/pdf /microwave.organic.chemistry.review.pdf ; p9240). Unfortunately I have never come across any cyclohexa-1,4-dione since and dont own a microwave either smile.
GC, I think your idea of using pyruvaldehyde might just work since aldehydes are generally more elctrophylic than ketones, but I must admit I see no OTC source of this chemical. There are a lot of useful chemicals used as food additives and yet I have no idea how to buy them pure.frown However I would be very glad to hear your results if you ever end up experimenting with this route.wink
Since I lately came across some succinic acid I was also thinking of the Org. Synth. procedure for cyclohexa-1,4-dione ( http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0288 ). The possibility of using the intermediate diethyl 2,5-dioxocyclohexane-1,4-dicarboxylate to alkylate it with something like chloroacetone diethylketal or with allylbromide caught my attention. It might just bee possible to monoalkylate it, hydrolyze/decarboxylate and only then condense it with an aldehyde. For example:

The keto group should not interfere since it is much less reactive than the aldehydes. But even if all these steps would, work which I doubt, it still bothers me which positional isomer would prevail at the last step? I suspect some unbearable number of minor side product separable only with a column.frown

There is one intriguing thing about these two papers as well as the reaction described in Post 481577 (Nicodem: "UV promoted BQ acylation w/aldehydes", Novel Discourse). Why, oh, why they never rapport any example with paraformaldehyde? Is formaldehyde not considered an aldehyde or what!?

The real drug-problem is that we need more and better drugs. J. Ott