1] 1,3-dimethoxybenzene + 1) n-BuLi, 2) I2 -> 1-iodo-3,5-dimethoxybenzene (base-promoted nucleophilic aromatic addition)

2] 1-iodo-3,5-dimethoxybenzene + DMF + POCl3 -> 4-iodo-2,6-dimethoxybenzenaldehyde (Vilsmeyer RxN)

3] 4-iodo-2,6-dimethoxybenzenaldehyde + nitromethane + NH4OAc -> 4-iodo-2,6-dimethoxy-beta-nitrostyrene (Knoevenhagel RxN)

4]4-iodo-2,6-dimethoxy-beta-nitrostyrene + LiAlH4/THF, 0.0 deg.C -> pseudo-2C-I

Its always good to get technical input from competant peers, so it seems this is the ideal place to discuss this. Well what do you think? Bromination would work the same way, and formylation should be quite regioselective with with either of the heavier halides, due to the steric hindrance they offer. Admittedly, handling such water-sensitive reagents as n-BuLi prohibits this from being a kitchen-friendly synthetic route, but for bench-scale/pilot plant protocol, it looks quite sound, not to mention inexpensive. Did I do good, or am I smoking crack?

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-the good reverend drone

 
hypo
Member   posted 12-25-1999 10:31 AM          
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Terribly sorry, but it would not work. BuLi gives o-lithiation with anisol because of the coordination to O. You would end up with mostly 2,6- and some 2,4- dimethoxyiodobenzene.
 
rev drone
Member   posted 12-27-1999 05:09 AM          
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hypo,
Wouldn't the most acidic carbon on the ring be the one meta to both the methoxy groups -- the one proton that recieves the least electron donation from them?

What got me thinking along these lines was Tet 37; 23; 1981; 3957-3965, where a lithiated alkyl is reacted with 3,5-dimethoxybenzene, and adds selectively to the spot in question. Admittedly, its not the same, but that's where the idea came from.

Actually, even if this produces 1-halo-2,4-dimethoxybenzenes, such a material is a fine intermediate. What we need here is a nulceophilic substitution, and 1-halo-2,4-dimethoxybenzene is perfect for subsequent nucleophilic substitution via a benzyne intermediate. Cheap, easy, and its been done before:

Reactant BRN 1867593 1-bromo-2,4-dimethoxy-benzene
Product BRN 638013 3,5-dimethoxy-aniline
No. of Reaction Details 1
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Reaction Details

Reaction Classification Preparation
Reagent NH3
NaNH2
Other Conditions in fluessiges NH3
Ref. 1 2265405; Journal; Benkeser et al.; JACSAT; J.Amer.Chem.Soc.; 80; 1958; 5289,5292;

From 3,5-dimethoxyaniline, a quick Sandmeyer reaction leads to the desired 1-halo-3,5-dimethoxybenzene. From there, formylation as previously described.

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-the good reverend drone

Ipsa scientia potestas est

 
hypo
Member   posted 12-27-1999 03:12 PM          
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I agree. But all BuLi or BuLi/TMEDA lithiations of methoxyaromatics that I have seen so far provided o-lithiated products. Perhaps not only coordination, but induction effect is involved as well. But I am not sure.
By the way, 3,5-dimethoxy aniline is available from Fluka as "5-aminoresorscinol dimethyl ether"

chemstu
unregistered   posted 12-27-1999 10:06 PM           
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rev drone
Member   posted 12-28-1999 07:19 AM          
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The answer came to me last night. 3,5-dimethoxyaniline is commercially available, and relatively inexpensive. A Sandmeyer reaction can be performed, and you have your 1-halo-3,5-dimethoxybenzene ready for formylation, which should be rather selective.
Rh,

Could you please escort mr. chemtsu to the exit? He apparently has mistaken the Serious Chemistry Forum for one of the Information Superhighway's roadside portable toilets.

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-the good reverend drone

Ipsa scientia potestas est

 
Rhodium
Pimp Master   posted 12-28-1999 05:29 PM          
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1. Mr Chemstu is no longer with us ("oops").
2. What does this methoxyaniline cost, I haven't got a fluka catalog handy...

3. How would we place any of the following substituents in the 4-position on a compound:

-CN -N3 -CH=CH2 -CCH -C3H5

4. How to make 2C-CF3 without starting with 2C-I (as in Nichols paper).

 
hypo
Member   posted 12-29-1999 12:40 PM          
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I do not have Fluka with me too, since I got fired from grad school recently.
You can search prices and product availability at http://www.chemfinder.com  ; the best prices I have seen for 3,5-di(OMe)-aniline was $2.1-$2.5 per gram (in 10-50 gram quantity).

For introduction of -CN and -N3 on aromate, one can try Sandmayer. (No Cu salt in case of azide )

To get acetylene on, the easiest way would be to start with iodide or bromide or triflate and do TMS-acetylene coupling cat. with Pd(PPh3)4 / CuCl /diethylamine.
TMS removal (NaOH in MeOH) gives free acetylene. Lindlar hydrogenation or LAH redn. or DIBAL redn. gives vinyl group.
For an propyl group, one would do the same with propyne and then do complete hydrogenation.