dioulasso (Stranger)
02-21-03 17:23
No 410450
      p-dimethoxybenzene to 2C-X  Bookmark   


Though there have been discussed procedures to p-dimethoxybenzaldehyde from hydroquinone, like the elegant one by Antoncho, through pMeO-phenol, these methods require the use of strong methylating agents (like DMS or MeI) to methylate the deactyvated OH p to the formyl groop.
Some person named BOBO was wondering wether he could get some usefull 2C-X precursor without using such strong methylateing agents.
The ideal intermediate for him seems to be pDMeO-Benzene, prepared according to:

Post 256342 (Antoncho: "Methylation of hydroquinone w/NaMeSO4: good news!", Novel Discourse)
How to proceed from here?
Well neither Gatterman nore Willsmeier seemed to apetizing to BOBO.
Now there have been mentioned several interesting methods from here. Most of them were only slightly discussed.


1.Post 382264 (Antoncho: "Zealot: azomethinic (Haack) formylation", Novel Discourse)
It requires either p-nitroso-dimethylaniline or p-nitrosophenol. Since the latter can easily be made from widely available phenol, this seems to be nice method for the prepn. of the aldehyde w/ 56% yeald.

2. Post 299551 (karel: "Chloromethylation", Chemistry Discourse)
pDMeO-Benzene -->2-Br-pDMeO-benzene y: 82%
2-Br-pDMeO-benzene + HCl + HCHO --> 4-Br-2,5-DMeO-BzCl y: ~50%

3. An alternative to the above seems to be this one found by Rhodium:

Post 384897 (Rhodium: "Chloromethylation of p-dimethoxybenzene - 61%!", Methods Discourse)
This looks wery interesting!
Though BOBO finds a few things a bit strange: How does this mix throughly? Shouldn't one need a PTC catlyst here?, Why just benze? Wouldn't dioxane be better? Or could toluine be substituted?
BOBO would appreciate the comments of some more experienced bee.

The latter two would bee better in that sense that one wouldnt need nitromethane.
From the BzCl BzCN could be formed. The best way to do this would be w/ NaCN in DMSO.
But BOBO would rather prefer to do it in EtOH like in:
How would downscaling so much affect the reaction.
An alternative could be the finkelstein swap to convert the BzCl into BzI and then to BzCN. BOBO is wondering wether to do the finkelstein in acetone than the nitrile formation in another solvent. Or add the NaI/KI and the NaCN/KCN in the same solvent (preferably EtOH).

To the reduction of the nitrile to the amine there are several alternatives.
The most novel would be in situ[i] generated AlH3 from LAH. But this is no option for those (like BOBO) who lack LAH.
A wery good method is:

Post 373778 (Chimimanie: "Nitrile reduction using Cobalt Chloride and NaBH4", Methods Discourse)
Though NaBH4 and CoCl2 are both wery expensive.

Finally there was word about the Urushibara reduction of nitriles:

Post 270027 (Rhodium: "Zn/NiCl2 reduction of oxime/nitro/nitriles/ketone", Chemistry Discourse)
also in the Urushibara paper on Rhodiums page:

../rhodium/chemistry /urushibara.html

it is mentioned that:

U-Ni-B is effectively employed in catalytic reductions for which the presence of alkali is favorable; whereas U-Ni-A is appropriate for those
 reductions where the presence of alkali interferes. For example, a trace amount of alkali favors the reduction of ketones, aldehydes,
 nitriles, and oximes, for which the use of U-Ni-B is desirable.[quote]

Though it is not stated directly that Urushibara was succesfully used for the reduction of nitriles.

It would bee really great if for exmple an U-Ni-B or the Al warint of it could reduce BzCNs w/ ~50% yeald.
If anyone has any experiences with a procedure like this please comment.

As BOBO has made it quite clear already he would strongly favour chloromethylation followed by nitrile formation w/ CN salts than a reduction attampt w/ U-Ni catalyst. BOBO is also ready to act on this, though first some chlarification at uncertain points would be highly wellcomed.
(Hive Bee)
02-24-03 07:49
No 411377
      Re: How does this mix throughly?  Bookmark   

How does this mix throughly? Shouldn't one need a PTC catlyst here?, Why just benze? Wouldn't dioxane be better? Or could toluine be substituted?

I think (& I may or may not bee a more experienced bee who could bee wrong):
A PTC would probably help. Just guessing though.
Toluene could be substituted but there would probably be more chloromethylated toluene as byproduct, since ring substitutions make a dramatic difference to the ease of chloromethylation. I'm thinking that the reaction with benzene should not be allowed to run too long in order to reduce BzCl formation and other associated funky byproducts. 

To the reduction of the nitrile to the amine there are several alternatives.
Have you considered Na/EtOH ?

Forgot to add that if you can get dimethyl carbonate it might be an alternative to DMS or MeI as in:

Preparation of phenolic ethers.
Iori, Giuseppe; Romano, Ugo (Anic S.p.A., Italy).  Brit. UK Pat. Appl. GB 2026484 6 Feb 1980, 3 pp.  (English). (United Kingdom).  CODEN: BAXXDU.  CLASS: IC: C07C043-20; C07C065-21.  PRIORITY: IT 78-25974 21 Jul 1978.  DOCUMENT TYPE: Patent CA Section: 25 (Noncondensed Aromatic Compounds) Section cross-reference(s): 36, 62
Phenolic ethers were prepd. by reaction of phenols with alkyl carbonates at <160 in the presence of a catalyst consisting of a base and an org. or inorg. iodide.  E.g., PhOH with (MeO)2CO in the presence of NaOH/KI (150, 2 h) gave 78% PhOMe (100% selectivity).  The ethers are known antioxidants for edible oils and greases and stabilizers for plastics, and are important in the prodn. of perfumes.  The etherifications avoid the use of highly toxic dialkyl sulfates

Mountain Boy