10-29-02 21:18
No 374179
      Important advance in the propagation of 2C-H
(Rated as: excellent)

Reaction of 2-Bromo-1,4-dimethoxybenzene with various Nucleophiles via Aryne Reaction


We report herein that 2-bromo-1,4-dimethoxybenzene does react with nitriles in the presence of potassium amide in liquid ammonia to yield predominantly 2-(alpha-cyanoalkyl)-1,4-dimethoxybenzenes in 56-83%. A small quantity of 2,5-dimethoxyaniline was isolated in each of these reactions. (...) The nitrile products should serve as valuable precursors to biogenic amines possessing both a phenetylamino side chain and 2,5-dimethoxy-substituted benzene ring. (...) The reaction of 2-bromo-1,4-dimethoxybenzene with several primary and secondary amines was found also to give the corresponding 2,5-dimethoxyanilines in excellent yields (85-94%).

Experimental Section

General reaction of 2-bromo-1,4-dimethoxybenzene with nitriles

Potassium amide (0.2 mol) was prepared by adding potassium (0.2 mol) to 150 ml of liquid ammonia containing 0.01g of ferric nitrate. The discharge of the initial blue color of the solution to gray indicated the conversion of potassium to potassium amide. The appropriate nitrile (0.5 mol) was added over a period of 5 min and the solution was stirred for 10 min at which time 2-bromo-1,4-dimethoxybenzene (0.05 mol) was added dropwise and the resulting solution was stirred for 1h. Then the ammonia was evaporated by heating on a steam bath, and the residue was dissolved in ether and extracted with two 200-ml portions of 6N HCl. The ether was dried (Na2SO4) and the residue distilled to yield the nitrile product.

Yield with acetonitrile: 83% of 2,5-dimethoxyphenylacetonitrile

ref: j org chem 1983,48,4397-4399
EDIT: true ref: J org chem vol 50, 8, 1985, 1334-1337

Reduction of this nitrile with any of the know method give the 2C-H

OTC 2CB is no more a dream... cool
    ... Sorry Antoncho! wink
(Hive Bee)
10-29-02 21:37
No 374188
      WoW fucking beat!  Bookmark   

Yes you definitelly beat us on that one!

Time to buy lithium battery and ammonia fertilizer!

This is a great advance in 2CB clan chem I think...

As a sidenote i will PM you for advance in the quinone road to 2CH, I have idea to share..

(Chief Bee)
10-29-02 22:55
No 374241
      Reaction improvement  Bookmark   

The article above does not specifically mention 2,5-dimethoxybromobenzene, and no substrate gave 83% yield, so I wonder - is that result above from your own experimentation, or just extrapolation?

The mechanism is that the sodium amide creates the anion of acetonitrile - -CH2CN  - which reacts with benzyne, formed by elimination of HBr from the bromobenzene.

Now my question is - can we substitute the liquid ammonia for something else? DMSO? The ammonia is responsible for the main side-reaction, where the benzyne reacts with the solvent forming 2,5-dimethoxyaniline. Ammonia is also very noxious - if we could use KOtBu in DMSO I'd be very glad.
(I'm Yust a Typo)
10-29-02 23:18
No 374254
      BuLi/CH3CN? I thought the yields for nitrile ...  Bookmark   


I thought the yields for nitrile reduction given in pihkal weren't spectactular. Anyone got better yields/methods with nitrile reductions?

When all you've got is a nailgun, every problem looks like a messiah...
10-30-02 02:02
No 374306
      Rhodium: clarification
(Rated as: excellent)

Houps sorry blush
I have posted the wrong referenceblush

The true ref was J org chem vol 50, 8, 1985, 1334-1337!!

In it you will find that the authors has got a 83% yield with acetonitrile and 2-bromo-1,4-dmb

And not I haven't synth it at all, I was searching for a new way to 2,5-diMeo-thiophenol through 2-amino-1,4-dmb and potassium xanthate (I have a ref that say 2,5-diMeo-thiophenol was prepared in 48% yield from 2-amino-1,4-dmb, I will post it soon)

The ref I gave was from the same authors but not the same compound...

Another ref say a similar reaction may bee done from KOt-Bu in toluene (J org chem vol 66,4,2001,1403-1412), this paper describe the synthesis of various amine from benzyne intermediate generated from substituted chloro-benzene, I think that if we use the acetonitrile instead ot the amine the benzyne will react the same and give the phenylacetonitrile:

Synthesis of N-Aryl-2,3-dihydroindoles ans N arylindoles:
Starting from commercially available halostyrene (2-chlorostyrene, 3-chlorostyrene, 2,6-dichlorostyrene) various 2,3-dihydroindoles were obtained in the presence of KOt-Bu in toluene at 135C. Since KOt-Bu is a precatalyst for the hydroamination reaction and a mediator for the aryne-amination reaction, stoichiometric amounts of base have to be used in order to obtain full conversion. In general 3 equiv of KOt-Bu were applied in these reactions; however, the amount of base could be reduced to 1,5 equ. (relative to the aryl chloride) without significantly decreasing the yield. Electron withdrawing (F,CF3,Ph) as well as electron-donating (OCH3) substituents on the aniline. Despite possible side reactions to give alternative aryne intermediates, 3-chlorostyrene reacts with 4-fluoroaniline to yield the substituted 2,3-dihydroindole in a similar yield (50 vs 54%) to 2-chlorostyrene.
Attempts to react alpha or beta-methyl-2-chlorostyren with aniline in the presence of stoichiometric amounts of bKOt-Bu do not result in the corresponding 2- and 3-substituted 2,3-dihydroindoles. In this case aryne generation as a first reaction step is favored compared to olefin hydroamination. The resulting3-substituted anilines are unable to undergo intramolecular cyclisation via hydroamination.

Well the KOt-Bu in toluene form an aryne derivative with halo-compound, this aryne can be reacted with acetonitrile in the same fashion and you got the phenylacetonitrile.

But wath's wrong with amonia/K-Na or Li, the texas farmers use it to get meth so I think it's not that bad if you are cautious and don't spill it on yourself, just do it like a ghetto birch and all will be fine, thats a nice and rapid proc for 2CH, and you have got greater yield than all the others method afaik. Just reduce the nitrile with Cobalt/NaBH4 or Ni-Raney/hydrazine(which can be synthetised OTC).

It's hardcore chemistry but it's doable and a great proc from easy to get chemicals...  tongue

Speak about 2C-B for the Masseswink
(Hive Bee)
10-30-02 08:04
No 374410
      My understanding  Bookmark   

The way I see it,

OTC 2-CB based on 'Antoncho' route:

1. HQ + H2SO4/MeOH __> p-MeO phenol
2. p-MeO phenol + CHCl3/NaOH __> 2-OH-5-MeO benzaldehyde
3. 2-OH-5-MeO benzaldehyde + MeI __> 2,5-di MeO benzaldehyde
4. 2,5-di MeO benzaldehyde + CH3NO2 __> 2,5-DMNS
5. 2,5-DMNS + Zn/HCl __> 2-CH
6. 2-CH + Br2 __> 2-CB

OTC 2-CB based on 'Chimimanie' route:

1. HQ + NaOCH3 __> 1,4-di MeO benzene
2. 1,4-di MeO benzene + Br2 __> 1-Br-2,5-di MeO benzene
3. 1-Br-2,5-di Meo benzene + Li/NH3(l),Fe(NO3)3 __> 2,5-di MeO benzyl cyanide
4. 2,5-di MeO benzyl cyanide + Co/NaBH4 or Raney Ni/Hydrazine __> 2-CH
5. 2-CH + Br2 __> 2-CB

So I would say that the former is more OTC but requires an extra step.

Question: Can the benzyl cyanide reduction be done with Li/EtOH instead ?

[Btw: Great work Chimimanie smile!]

Mountain Boy
(Official Hive Translator)
10-30-02 10:00
No 374449
      Heh....  Bookmark   

Well, since you mentioned my name... smile

Very nice indeed, Chimimanie! Seeing your recent postings, i can't resist saying that it is always a great pleasure for us at The Hive to meet such a promising bee like you.

Specifically of this route - well, metallic potassium in liquind ammonia doesn't sound too much OTC.

But all in all this is a great route!

Seems very much similar to the semilegendary "enolate route" - actually, almost the same, only the nucleophyllic part is different.

And just like in case of enolate route, it needs some experimentation to beecome OTCly functional. Something is needed to strip that haloid off the ring - other than the usually employed alkali metal/ammonia, BuLi or palladium complexes.

If you read Drone's doc on Rh's, you'll see that ultraviolet irradiation (which CAN bee arranged otc) seems to work.

Too bad that noone seems to bee interested in researching this (Barium, are you reading this?laughsmileblush)

Your Antoncho

P.S. Just so that you know, the first (and the second too) home-made 2C-B has been biotested by both SWIAntoncho and SWIVitsh a few days ago, so it already is no longer a dreamcool The yields were shitty though so for a formal write-up to appear on the Hive we'll have to waitwink.
(Hive Bee)
10-30-02 13:37
No 374486
      Antoncho/Vitsh: my inspiration  Bookmark   

Just so that you know, the first (and the second too) home-made 2C-B has been biotested by both SWIAntoncho and SWIVitsh a few days ago, so it already is no longer a dream The yields were shitty though so for a formal write-up to appear on the Hive we'll have to wait.

u both beat me to it
you see
MG is hoping to be
with home-made 2C-B

I can't wait to read your bio assay results!

Just two questions:
Did u use Zn/HCl for final redn ?
How did u crystallize 2C-H (gassing or IPA/HCl) ?
[I know u will be posting a write-up later but this very morning tears of pity welled up in my eyes as I gazed upon lovely sunny powder* that begged me to relieve it of it's oxygen...& I hate to see anything suffer..wink]

*I'm just assuming it's 2,5-DMNS cos if it ain't...well..fuck I hope it is..

Mountain Boy
10-30-02 22:00
No 374651
      Well Antoncho/VItsh & Moutain Girl, Congratulation  Bookmark   

'OTC 2CB is no more a dream...
    ... Sorry Antoncho! '

... Silly I was, what I mean was

'OTC 2CB is no more a dream...
    ... Thanks to Antoncho! '

No man I have to thank you for all the good work you did on that quest, from the new CH3I synths to the p-Meo-phenol/O-methyl-gentil-z-aldehyde synth.

You made that dream come true, YOU are propagating 2-CH...

Look at Mountain-girl, she wanna bee the next... and believe what: its a girl(I think)! If all the girls were home synthetizing 2-CB and testing its hmmm special blush properties on us, the men, that would bee a wonderful world!

GOGOGO let's continue, some day the world will be covered with 2-CB and with its pihkal's brothers/sisters...
...And nobody will be able to stop itcool, and several years afters, with the succeding of generations, nobody will want to stop itlaugh, because it is good... And you, the bees in the hive (except those hided DEA fiends, if ever they are bees) are working to it, to reunify the civilization with psychedelia...  tongue

Yeah thats beautiful,

Psychedelia for the Masses,
Good ol'2CB for the Masses!

Thank you, Rhodium, Sunlight, Barium, Vitsh, you Antoncho and the many other that I forgot...

We are propagating the light, and the light is good!
11-06-02 20:52
No 377116
      PTC nitrile alkylation  Bookmark   

hmmmmmmm would a catalytic alkylation similar to the one detailed in but using 2,-5-dimethoxybenzyl bromide + MeCN work here? Or does this only work with phenylacetonitriles?
11-08-02 01:30
No 377454
      Do you want alpha alkyl phenylacetonitrile?  Bookmark   

I dont understand what you want, is it alpha alkylphenylacetonitrile?

If so, I have some refs to share (another new road I'm studiing) but why do you want them?

If not I just don't understand but I've just drunk a bottle of St Emilion and that may be that....mhhh great winewink

Clarify this please.... we are talking about benzyne derivative here, your link was about an alkylation of nitrile, and your post about a Sn2 on a benzyl bromide, I don't understand....crazy
11-17-02 20:01
No 380532
      A ref in 1,2 dimethoxyethane
(Rated as: excellent)

Arynic condensation of nitrile anions in the presence of the complex base NaNH2-CH3CH2(OCH2CH2)2ONa

: Nitrile anions are easily condensed with aryl halides in the presence of the Complex Base NaNH2-CH3CH2(OCH2CH2)2ONa via the intermediate arynes.


General procedure for arynic condensation of nitrile anions.

CH3CH2(OCH2CH2)2OH (25mmol,3.35g) in DME (10 ml) was added dropwise to a mechanically-stirred suspension of NaNH2 (125 mmol, 5 g) in DME (10 ml), under a nitrogen atmosphere and the mixture was heated at 45C for 2 h. A solution of CH3CN (50 mmol, 5.85 g) in DME (10 ml) was then added dropwise at -10C and the mixture stirred for 2 h. After cooling to -45C, 4-bromoveratrole (25 mmol, 5.42 g) in DME (20 ml), was slowly added. On completion (4.5 h, disappearance of 4-bromoveratrole monitored by GLC analysis), the mass was poured on ice, extracted with diethyl ether and dried over MgSO4. After evaporation of the solvents under reduced pressure, the residual oil was chromatographed on HPLC preparative apparatus (eluent: 15 % EtOAc / P. E.) to successively yield (3,4-dimethoxyphenyl)acetonitrile (78%) and bis(3,4-dimethoxyphenyl)acetonitrile (8%, mp 115C)

yield from bromobenzene is 79% ArCHRCN and 17% Ar2CRCN
4-bromo-1,3-diMeObenzene 85%
4-Bromo-1,2,3-triMeObenzene 83% and 11% of the bis compound
2-Bromo-1,4-dimethoxybenzene 81% and 12% of the bis compound

ref: Synth. Commun., 19(19) 3323-3330 (1989)
(Chief Bee)
11-17-02 22:29
No 380549
      2C-H - here we come!  Bookmark   

Chimimanie: That is absolutely excellent! One thing I don't get though; what is that CH3CH2(OCH2CH2)2ONa? Could you give it any IUPAC name?
(I'm Yust a Typo)
11-18-02 17:42
No 380739
      Possibly glyme or diglyme? see http://www.ferro.  Bookmark   

Possibly glyme or diglyme?


When all you've got is a nailgun, every problem looks like a messiah...
11-18-02 18:47
No 380765
      2-(2-ethoxyethoxy)ethanol  Bookmark   

The solvent is 1,2-dimethoxyethane aka ethylene glycol dimethyl ether aka monoglyme
and the precursor of the activating agent is CH3CH2(OCH2CH2)2OH aka 2-(2-ethoxyethoxy)ethanol=MEDEG aka diethylene glycol monoethyl ether aka carbitol CAS=111-90-0

They say that condensation of C6H5Br on CH3CN in the presence of NaNH2 alone in DME at -30C led to 94% of a mixture of phenylacetonitrile (47%)(79% with carbitol), diphenylacetonitrile (31%) and triphenylacetonitrile (16%), under the same condition (with no carbitol) 4-bromo-1,2,3-trimethoxybenzene led to 3,4,5-trimethoxyphenyl-acetonitrile in 39% yield (with carbitol 83%)

So the selectivity is better and they say that alkoxide activation of alkaline amides resulted in an increase of the basicity of NH2- accompanied by a simultaneous decrease of its nucleophilicity.

Hey Rhod, don't forget that with the phenylacetonitriles we can get easily by the Claisen's reaction with ethyl acetate and sodium ethoxyde followed by hydrolysis to the phenylacetones in about 60% yield! It's not only '2C-H here we come!' but also 'Mescaline, TMA, 2,5-DMA, 3,4-DMA and (Meth)amphetamine here we come!'winkcool

What I really like about this reaction is that there is not too much solvent 40 ml for 5g its much scalable that the first one in liquid ammonia. By the way yellium I see a ref with the use of Buli for generate aryne so it may be used too...
(Master Whacker)
11-19-02 06:33
No 381058
      related info  Bookmark   

It's nice to know there is a base/solvent pair that successfully alkylates phenylacetonitrile with bromobenze because experience shows that NaH/DMF and NaOH/DMF yield <5% diphenylacetonitrile.  The red nitrile anion alway formed with no problem but alkylation way not successful for some reason.
12-08-02 00:37
No 387268
      Arynes from KO-T-Bu
(Rated as: excellent)

The formation of arynes from aryl halides by reaction of potassium t-butoxide with aryl halides.(4)

The formation of arynes from aryl halides by reactions with amide and substituted amide ions is well known, and it has been reported that a similar elimination of hydrogen bromide from bromobenzene can be effected in dimethyl sulphoxide by potassium t-butoxide.(1) Use of t-butyl alcohol instead of dimethyl sulphoxide led to a much slower reaction to give a much lower yield (35%). Complications arising from interaction of the aryne with the solvent also occur in the amide reactions.(2),(3) In connection, with another investigation, a route to arynes not involving reactive solvents, such as ammonia, dimethyl sulphoxide, or t-butyl alcohol, was required.

Arynes can be produced conveniently by reaction of an aryl halide, usually the bromide, although  chlorides also react, with potassium t-butoxide alone, such reactions being effected either in an excess of the halide at an elevated temperature or, more conveniently, in boiling t-butylbenzene as solvent.



Bromobenzene (46,7g) and potassium t-butoxide (4,093g) were boiled under reflux for 4 hr. The precipitated potassium bromide was filtered off and the filtrate examined by g.l.c. (10% SIL, 140) ; this showed a product peak with a retention time relative to bromobenzene of 1,63. A sample of the product was obtained by preparative g.l.c. (20% PPE, 150) ; i.r. and H n.m.r. spectra were consistent with formulation of the product as phenyl t-butyl ether. The yield was 92% based on potassium t-butoxide.

The yields are in the range of 80-70 % for the bromo benzene o,m, or p substituted with Me or OMe

I think that acetonitrile is a better nucleophile than the formed HO-tBu, and so phenylacetonitrile will form if some CH3CN is put in it but it appear that this reaction require elevated temperature, t-butyl benzene boil at 169C and CH3CN at 80C, so I don't know it this will work without an autoclave?

FUCK IT, I prefer the ref in DME, sad that sodium amide is such a pain in the ass to makemadfrown! But I think that I will still play with ammonia....crazy or maybe with di-isopropylamine like Antoncho said in post Post 381200 (Antoncho: "Alkali metal amides: strong basses for the masses!", Novel Discourse)

(1) D. J. Cram, B. Rickborn, and G. R. Knox, J. Amer. Chem.
Soc., 1960, 82, 6412.
(2) D. J. Cram and A. C. Day, J. Org. Chem., 1966, 31, 1227.
(3) M. Kise, T. Asari, N. Furukwa, and S. Oae, Chem. and Ind.,1967, 276.
(4) J Chem Soc 196?(7,8,9?) p 1860