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All 10 posts Subject: sick of methylations? easy prepn. of anisoles. Please login to post Down

phenethyl_man
(Newbee)
09-01-04 05:23
No 528777
      sick of methylations? easy prepn. of anisoles.
(Rated as: good read)

I apologize if this has already come up on here, I did use the f'ing search engine..

It seems that m-haloanisoles can be prepared from m-halonitrobenzenes consistently in very good yields. The rxn is similar to the copper-catalysed nucleophilic displacement of halogens by alkali methoxide. The halonitrobenzene is denitrated and the nitro group replaced by the methoxide ion, yielding the m-haloanisoles.

The difference here is the ease of performing this synth. In the reference, the alkali methoxide is not always employed at the beginning of the synth, it can actually be generated in situ!

All that is required is the alkali hydroxide salt (KOH or NaOH, potassium gives higher yields), a PTC and methanol in just about any non-polar solvent. At first they try it under N2 but find that it leads to the formation of some byproducts and only modest yields. So they perform it with oxygen blowing thru the mixture and obtain consistent 83%+ yields in only 2.5-3 hrs at 50-60deg C, although I doubt the oxygen is really necessary.. Using KOH to prepare the methoxide in situ, they prepare 3-bromoanisole in 84% yield. bromo, chloro, and trimethylfluoronitrobenzenes all give yields this high.. m-iodonitrobenzene does not work very well thou.. only 52% conversion after 24hrs..

Even the PTC is not entirely necessary, in the abscence of a PTC they still obtain a 53.7% conversion w/in situ KOMe.

Here is the ref:

One-Step Preparation of Some 3-Substituted Anisoles, Organic Process Research & Development 2003, 7, 303-305;

.. and here's the detailed procedure, enjoy:

Representative Procedure for the Preparation of 3-Chloroanisole, 2b, Using Solid Sodium Methoxide.

The reaction is carried out with the forced passage of air through the reaction solution. To a solution of 3-chloronitrobenzene, 1b, (47.3 g, 0.3 mol) in toluene (60 mL) are added at room temperature NaOMe powder (19.4 g, 0.36 mol), solid KOH powder (33.6 g, 0.51 mol), and tetrabutylammonium bromide (12.3 g, 0.038 mol). The heterogeneous mixture is stirred vigorously at 50 °C for 2 h. The mixture is then cooled and washed with water to remove inorganic compounds, followed by phase separation. The organic phase is washed with aqueous HCl solution to remove tetrabutylammonium bromide and products of its decomposition remaining after the washing with water. The organic phase is distilled under vacuum to afford a final pure anisole, 2b, (88 °C, 18 mmHg) as a colourless, clear liquid (35.9 g, 84%). The same procedure is employed when the solid NaOMe is replaced by solid KOMe.

Representative Procedure for the Preparation of 3-Bromoanisole, 2a, Using Potassium Methoxide Prepared in Situ.

The reaction is carried out with the forced passage of air through the reaction solution. A heterogeneous mixture of cyclohexane (210 mL), methanol (38.4 g, 1.2 mol), solid KOH (158.1 g, 2.4 mol), and tetrabutylammonium chloride (50.5 g, 0.18 mol) is stirred vigorously at 55 °C for about 5 min. A solution of 3-bromonitrobenzene, 1a, (202 g, 1 mol) in cyclohexane (110 mL) is added dropwise at 55 °C over 0.5 h. The heterogeneous reaction mixture is stirred at 60 °C for 2.5 h. The mixture is treated in a manner similar to that described above for anisole, 2b. The organic phase is distilled to afford a final pure anisole, 2a, (92-93 °C, 14 mmHg) as a colorless, clear liquid (155 g, 83%). The products, 2a-c, were identified by 1H NMR and mass spectroscopy. All the spectral data obtained were compared with those of authentic samples. The anisoles, 2d,e, the byproducts, 3a,b,e, 4a,b, 5, 6, as well as the phenetols, 7a,b, were identified by mass spectroscopy.

Scale-Up Batch.

Batch preparations of 3-bromoanisole, 2a, in toluene using KOMe prepared in situ and tetrabutyammonium bromide as a catalyst, were performed in a 250-L reactor under the conditions described in the Experimental Section for the laboratory synthesis of 2a. The toluene was repeatedly recycled. The average isolated yield of 2a was 85%, based on 1a. The hazardous, aqueous waste containing potassium nitrite (7-10% w/w) underwent a special treatment based on the reduction of nitrites to nitrogen by urea or sulfamic acid. This waste treatment is rapid, environmentally acceptable, and inexpensive.

Oh, and as for our use for this little gem, need I mention the two compounds in Dr. Shulgin's book that have a bromine atom meta to a methoxy?

- phenethylman -

phenethyl_man
(Newbee)
09-06-04 03:45
No 529816
      any feedback on this?

any feedback on this? let me know if anyone gives this rxn a try cause I haven't given it a run yet myself.

I'm led to believe that this method may also work on nitrobenzenes that have a nitro or carboxyl group in either the ortho or para positions due to the electron attracting properties of these functional groups. For example, p-nitrobenzoic acid or p-dinitrobenzene -> anisic acid.

However, this is entirely untested by me and I'm just going on theory.

- phenethylman -

Nicodem
(Hive Bee)
09-06-04 11:08
No 529875
User Picture       You have to propose a use for it

The problem with these kind of nucleophilic aromatic substitutions is that you need a nitroaromatic that is quite electron deficient. In the example above you have the borderline example of a halonitrobenzene which is more electrondeficient than nitrobenzene. Unfortunately m-bromoanisole is not particularly useful.
Let's for example consider the posibility of preparing 2,5-dimethoxy-bromobenzene from anisole: p-nitroanisole from anisole, then 4-nitro-2-bromo-anisole from this. But now the aromatic is not electrondeficient enough for a nucleophilic aromatic substitution of the nitro group, as the methoxy group efficiently donates electron density to the ring. In other words: you are now out of the borders charted for this reaction. Another thing to consider is that the halogen must not be para or orto to the nitro group or you will end up substituting the halogen instead of the nitro. For example, p-bromo-nitrobenzene would yield p-nitro-anisole under the same conditions. Only when the halogens are at the meta position of the nitro are they resistant to the nucleophylic substitution.
Maybe there would be a use for it, but at the moment I can't figure out anything.

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

Rhodium
(Chief Bee)
09-06-04 13:39
No 529887
User Picture       One-Step Preparation of 3-Substituted Anisoles
(Rated as: good read)

Below you can read the full text of the article summarized in Post 528777 (phenethyl_man: "sick of methylations? easy prepn. of anisoles.", Methods Discourse)

A much more useful reaction for the introduction of methoxy groups on an aromatic ring are the Copper-catalyzed ones discussed in this thread: Post 529886 (Rhodium: "Cu(I) catalysed aromatic nucleophilic substitution", Methods Discourse)

One-Step Preparation of Some 3-Substituted Anisoles
J. Zilberman, Org. Process Res. Dev. 7, 303-305 (2003)

Abstract
A one-step preparation of 3-bromoanisole, 3-chloroanisole, and 3-trifluoromethylanisole from the corresponding 3-substituted nitrobenzenes is carried out by nucleophilic aromatic substitution of the nitro group with sodium or potassium methoxide, employing an effective amount of a phase-transfer catalyst (PTC), in a medium of a nonpolar aprotic solvent, under aerobic conditions, at a temperature of 50-65°C. The alkali methoxide used can be a pre-prepared solid, or it can be prepared in situ from the alkali hydroxide and methanol. The methoxydenitration proved to be very sensitive to the type of PTC. The effect of the solvent on the reaction is discussed. The targeted anisoles are obtained in yields of more than 80% and purities of greater than 99%.

^{The Hive - Clandestine Chemists Without Borders}

phenethyl_man
(Newbee)
09-07-04 02:24
No 530030
      rhodium; well, not everyone has access to...

rhodium; well, not everyone has access to sodium or potassium methylate, so the main aspect I found to be particularly interesting about the article was the in situ generation of the alkoxide which I haven't seen demonstrated for any of the Cu(I) nucleophilic displacement of halogens. This is the first time I have seen this employed although I would love to be proven wrong. I have seen the patents for the synthesis of alkoxides from the hydroxide, a PTC, and CaO, however, this requires lengthy reaction times to generate any useful amounts and the above rxn gives 80%+ yields in 2-3 hrs?

nicodem; Hmm, let's take toluene for a starting point; how about this route to the corresponding allylbenzene for MMA in 4 steps:

toluene -> p-bromotoluene (bromination)
p-bromotoluene -> 2-nitro-4-bromotoluene (mono-nitration)
2-nitro-4-bromotoluene -> 2-methoxy-4-bromotoluene (above rxn)
2-methoxy-4-bromotoluene -> 3-methoxy-4-methylallylbenzene (Mg/allyl bromide)

.. or you could react the grignard w/DMF to get the benzaldehyde.

.. or from the 2-methoxy-4-bromotoluene you could chlorinate the methyl group to get 2-methoxy-4-bromobenzyl chloride and eventually 2-methoxy-4-bromophenethylamine (unknown but probably active; I'm guessing similar to 2C-B but with lowered potency perhaps)

- phenethylman -

longimanus
(Hive Bee)
09-07-04 07:30
No 530077
User Picture       Toluene to DOM questions

p-Toluenesulfonic acid -> 2-nitro-4-methylBENZENEsulfonic acid:

Since -SO₃H is meta orientant, and -CH₃ is ortho and para, how could 2-nitro-4-methylbenzenesulfonic acid possibly be the product?

2-Methoxy-4-methylBENZENEsulfonic acid -> o-methoxytoluene (hydrolysis)
If you mean NaOH or KOH hydrolysis I think the product should be 2-methoxy-4-methylphenol. If you don`t, please, excuse me.

2-Methyl-4-methoxyphenol -> 2-hydroxy-4-methyl-5-methoxybenzaldehyde:

Rather strange isomerisation, don`t you think?

An advice - sleep more wink

Nicodem
(Hive Bee)
09-07-04 07:55
No 530082
User Picture       Are alkoxydes realy difficult to get?

Longimanus, that was obviously a PEA_man's mistake since the next product listed was o-methoxy-toluene which can only derive from 4-methyl-2-nitro-benzenesulfonic acid. Anyway, what is wrong with that sequence (besides the lenght, work and too much chemicals) is that p-toluenesulphonic acid can't bee efficiently nitrated due to the deactivating role of the sulphonic group. If heat is apllied to force the nitration you get the ipso supstitution and the product would be o,p-dinitro-toluene.

well, not everyone has access to sodium or potassium methylate, so the main aspect I found to be particularly interesting about the article was the in situ generation of the alkoxide which I haven't seen demonstrated for any of the Cu(I) nucleophilic displacement of halogens

Do we have to put on a sticker thread "Alkoxydes OTC!" to finaly get all bees to read:
Post 511796 (pink_dust_angel: "sodium salt of alcohols", Newbee Forum)
Post 512239 (psyloxy: "some great alkali alkoxide patents", Chemistry Discourse)
?

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

phenethyl_man
(Newbee)
09-07-04 08:01
No 530083
      ugh, you are right.. that should have been...

ugh, you are right.. that should have been 3-nitro-4-methylbenzenesulfonic acid.. and of course I meant acid hydrolysis, which is an electrophilic rxn that displaces the group by a proton, effectively removing it from the nucleus.

I removed that entire scheme from the post. I really should write this stuff down before I post it instead of going off the top of my head.. hopefully the MMA scheme holds up to scrutiny.

nicodem; I believe I have seen those threads I still can't recall any copper-catalyzed nucleophilic substitutions in which the alkoxide is generated in situ.

- phenethylman -

yei
(Newbee)
09-07-04 21:11
No 530173
      This is interesting for another reason

Since this means that alkoxides can be generated with weak base/PTC in alcohol, and more importantly, that the weak base will not interfere {i.e. hydrolyze water/hydroxide-sensitive compounds}, it suggests that the CLAISEN CONDENSATION can be run in alcohol with KOH/PTC.

This means that ethyl acetoacetate and the Reissert synthesis might be with reach of the alkoxide-deprived.
Since ethyl and methyl oxalate are easy to make from OTC materials, this suggests a very nice OTC method for indoles and other lovelies.

_{It's good to bee back! Don't trust your computer!!}

phenethyl_man
(Newbee)
09-16-04 03:50
No 531561
      okay.. since no one was impressed by my ...

okay.. since no one was impressed by my proposal for the utilization of this reaction in the production of MMA, let me know what you think of this theoretical synthesis of either a DOM analogue, Desoxy, pseudo-2CB, or pseudo-DOB, again starting from toluene:

1) brominate toluene to p-bromotoluene

2) dinitrate p-bromotoluene (is this possible?; may require a high H2SO4 conc. and heat)

3) now you have 2,6-dinitro-4-bromotoluene and can theoretically use the above nucleophilic reaction to displace both nitro groups, providing 2,6-dimethoxy-4-bromotoluene.

Once you have this intermediate, you have two options:

a) oxidise the methyl group to 2,6-dimethoxy-4-bromobenzaldehyde; a precursor for pseudo-2cb/dob;

b) react w/magnesium to form the grignard and react this w/DMF to get 3,5-dimethoxy-4-methylbenzaldehyde; a precursor for Desoxy or a DOM analogue;

.. on second thought, this will never work, it sounds way too easy. wink

- phenethylman -

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	All 10 posts		Subject: sick of methylations? easy prepn. of anisoles.		Please login to post		Down


		phenethyl_man (Newbee) 09-01-04 05:23 No 528777				sick of methylations? easy prepn. of anisoles. (Rated as: good read)
						I apologize if this has already come up on here, I did use the f'ing search engine.. It seems that m-haloanisoles can be prepared from m-halonitrobenzenes consistently in very good yields. The rxn is similar to the copper-catalysed nucleophilic displacement of halogens by alkali methoxide. The halonitrobenzene is denitrated and the nitro group replaced by the methoxide ion, yielding the m-haloanisoles. The difference here is the ease of performing this synth. In the reference, the alkali methoxide is not always employed at the beginning of the synth, it can actually be generated in situ! All that is required is the alkali hydroxide salt (KOH or NaOH, potassium gives higher yields), a PTC and methanol in just about any non-polar solvent. At first they try it under N2 but find that it leads to the formation of some byproducts and only modest yields. So they perform it with oxygen blowing thru the mixture and obtain consistent 83%+ yields in only 2.5-3 hrs at 50-60deg C, although I doubt the oxygen is really necessary.. Using KOH to prepare the methoxide in situ, they prepare 3-bromoanisole in 84% yield. bromo, chloro, and trimethylfluoronitrobenzenes all give yields this high.. m-iodonitrobenzene does not work very well thou.. only 52% conversion after 24hrs.. Even the PTC is not entirely necessary, in the abscence of a PTC they still obtain a 53.7% conversion w/in situ KOMe. Here is the ref: *One-Step Preparation of Some 3-Substituted Anisoles, Organic Process Research & Development 2003, 7, 303-305;* .. and here's the detailed procedure, enjoy: Representative Procedure for the Preparation of 3-Chloroanisole, 2b, Using Solid Sodium Methoxide. The reaction is carried out with the forced passage of air through the reaction solution. To a solution of 3-chloronitrobenzene, 1b, (47.3 g, 0.3 mol) in toluene (60 mL) are added at room temperature NaOMe powder (19.4 g, 0.36 mol), solid KOH powder (33.6 g, 0.51 mol), and tetrabutylammonium bromide (12.3 g, 0.038 mol). The heterogeneous mixture is stirred vigorously at 50 °C for 2 h. The mixture is then cooled and washed with water to remove inorganic compounds, followed by phase separation. The organic phase is washed with aqueous HCl solution to remove tetrabutylammonium bromide and products of its decomposition remaining after the washing with water. The organic phase is distilled under vacuum to afford a final pure anisole, 2b, (88 °C, 18 mmHg) as a colourless, clear liquid (35.9 g, 84%). The same procedure is employed when the solid NaOMe is replaced by solid KOMe. Representative Procedure for the Preparation of 3-Bromoanisole, 2a, Using Potassium Methoxide Prepared in Situ. The reaction is carried out with the forced passage of air through the reaction solution. A heterogeneous mixture of cyclohexane (210 mL), methanol (38.4 g, 1.2 mol), solid KOH (158.1 g, 2.4 mol), and tetrabutylammonium chloride (50.5 g, 0.18 mol) is stirred vigorously at 55 °C for about 5 min. A solution of 3-bromonitrobenzene, 1a, (202 g, 1 mol) in cyclohexane (110 mL) is added dropwise at 55 °C over 0.5 h. The heterogeneous reaction mixture is stirred at 60 °C for 2.5 h. The mixture is treated in a manner similar to that described above for anisole, 2b. The organic phase is distilled to afford a final pure anisole, 2a, (92-93 °C, 14 mmHg) as a colorless, clear liquid (155 g, 83%). The products, 2a-c, were identified by 1H NMR and mass spectroscopy. All the spectral data obtained were compared with those of authentic samples. The anisoles, 2d,e, the byproducts, 3a,b,e, 4a,b, 5, 6, as well as the phenetols, 7a,b, were identified by mass spectroscopy. Scale-Up Batch. Batch preparations of 3-bromoanisole, 2a, in toluene using KOMe prepared in situ and tetrabutyammonium bromide as a catalyst, were performed in a 250-L reactor under the conditions described in the Experimental Section for the laboratory synthesis of 2a. The toluene was repeatedly recycled. The average isolated yield of 2a was 85%, based on 1a. The hazardous, aqueous waste containing potassium nitrite (7-10% w/w) underwent a special treatment based on the reduction of nitrites to nitrogen by urea or sulfamic acid. This waste treatment is rapid, environmentally acceptable, and inexpensive. Oh, and as for our use for this little gem, need I mention the two compounds in Dr. Shulgin's book that have a bromine atom meta to a methoxy? - phenethylman -



		phenethyl_man (Newbee) 09-06-04 03:45 No 529816				any feedback on this?
						any feedback on this? let me know if anyone gives this rxn a try cause I haven't given it a run yet myself. I'm led to believe that this method may also work on nitrobenzenes that have a nitro or carboxyl group in either the ortho or para positions due to the electron attracting properties of these functional groups. For example, p-nitrobenzoic acid or p-dinitrobenzene -> anisic acid. However, this is entirely untested by me and I'm just going on theory. - phenethylman -



		Nicodem (Hive Bee) 09-06-04 11:08 No 529875				You have to propose a use for it
						The problem with these kind of nucleophilic aromatic substitutions is that you need a nitroaromatic that is quite electron deficient. In the example above you have the borderline example of a halonitrobenzene which is more electrondeficient than nitrobenzene. Unfortunately m-bromoanisole is not particularly useful. Let's for example consider the posibility of preparing 2,5-dimethoxy-bromobenzene from anisole: p-nitroanisole from anisole, then 4-nitro-2-bromo-anisole from this. But now the aromatic is not electrondeficient enough for a nucleophilic aromatic substitution of the nitro group, as the methoxy group efficiently donates electron density to the ring. In other words: you are now out of the borders charted for this reaction. Another thing to consider is that the halogen must not be para or orto to the nitro group or you will end up substituting the halogen instead of the nitro. For example, p-bromo-nitrobenzene would yield p-nitro-anisole under the same conditions. Only when the halogens are at the meta position of the nitro are they resistant to the nucleophylic substitution. Maybe there would be a use for it, but at the moment I can't figure out anything. “The real drug-problem is that we need more and better drugs.” – J. Ott



		Rhodium (Chief Bee) 09-06-04 13:39 No 529887				One-Step Preparation of 3-Substituted Anisoles (Rated as: good read)
						Below you can read the full text of the article summarized in Post 528777 (phenethyl_man: "sick of methylations? easy prepn. of anisoles.", Methods Discourse) A much more useful reaction for the introduction of methoxy groups on an aromatic ring are the Copper-catalyzed ones discussed in this thread: Post 529886 (Rhodium: "Cu(I) catalysed aromatic nucleophilic substitution", Methods Discourse) One-Step Preparation of Some 3-Substituted Anisoles J. Zilberman, Org. Process Res. Dev. 7, 303-305 (2003) Abstract A one-step preparation of 3-bromoanisole, 3-chloroanisole, and 3-trifluoromethylanisole from the corresponding 3-substituted nitrobenzenes is carried out by nucleophilic aromatic substitution of the nitro group with sodium or potassium methoxide, employing an effective amount of a phase-transfer catalyst (PTC), in a medium of a nonpolar aprotic solvent, under aerobic conditions, at a temperature of 50-65°C. The alkali methoxide used can be a pre-prepared solid, or it can be prepared in situ from the alkali hydroxide and methanol. The methoxydenitration proved to be very sensitive to the type of PTC. The effect of the solvent on the reaction is discussed. The targeted anisoles are obtained in yields of more than 80% and purities of greater than 99%. ^{The Hive - Clandestine Chemists Without Borders}



		phenethyl_man (Newbee) 09-07-04 02:24 No 530030				rhodium; well, not everyone has access to...
						rhodium; well, not everyone has access to sodium or potassium methylate, so the main aspect I found to be particularly interesting about the article was the in situ generation of the alkoxide which I haven't seen demonstrated for any of the Cu(I) nucleophilic displacement of halogens. This is the first time I have seen this employed although I would love to be proven wrong. I have seen the patents for the synthesis of alkoxides from the hydroxide, a PTC, and CaO, however, this requires lengthy reaction times to generate any useful amounts and the above rxn gives 80%+ yields in 2-3 hrs? nicodem; Hmm, let's take toluene for a starting point; how about this route to the corresponding allylbenzene for MMA in 4 steps: toluene -> p-bromotoluene (bromination) p-bromotoluene -> 2-nitro-4-bromotoluene (mono-nitration) 2-nitro-4-bromotoluene -> 2-methoxy-4-bromotoluene (above rxn) 2-methoxy-4-bromotoluene -> 3-methoxy-4-methylallylbenzene (Mg/allyl bromide) .. or you could react the grignard w/DMF to get the benzaldehyde. .. or from the 2-methoxy-4-bromotoluene you could chlorinate the methyl group to get 2-methoxy-4-bromobenzyl chloride and eventually 2-methoxy-4-bromophenethylamine (unknown but probably active; I'm guessing similar to 2C-B but with lowered potency perhaps) - phenethylman -



		longimanus (Hive Bee) 09-07-04 07:30 No 530077				Toluene to DOM questions
						p-Toluenesulfonic acid -> 2-nitro-4-methylBENZENEsulfonic acid: Since -SO₃H is meta orientant, and -CH₃ is ortho and para, how could 2-nitro-4-methylbenzenesulfonic acid possibly be the product? 2-Methoxy-4-methylBENZENEsulfonic acid -> o-methoxytoluene (hydrolysis) If you mean NaOH or KOH hydrolysis I think the product should be 2-methoxy-4-methylphenol. If you don`t, please, excuse me. 2-Methyl-4-methoxyphenol -> 2-hydroxy-4-methyl-5-methoxybenzaldehyde: Rather strange isomerisation, don`t you think? An advice - sleep more



		Nicodem (Hive Bee) 09-07-04 07:55 No 530082				Are alkoxydes realy difficult to get?
						Longimanus, that was obviously a PEA_man's mistake since the next product listed was o-methoxy-toluene which can only derive from 4-methyl-2-nitro-benzenesulfonic acid. Anyway, what is wrong with that sequence (besides the lenght, work and too much chemicals) is that p-toluenesulphonic acid can't bee efficiently nitrated due to the deactivating role of the sulphonic group. If heat is apllied to force the nitration you get the ipso supstitution and the product would be o,p-dinitro-toluene. well, not everyone has access to sodium or potassium methylate, so the main aspect I found to be particularly interesting about the article was the in situ generation of the alkoxide which I haven't seen demonstrated for any of the Cu(I) nucleophilic displacement of halogens Do we have to put on a sticker thread "Alkoxydes OTC!" to finaly get all bees to read: Post 511796 (pink_dust_angel: "sodium salt of alcohols", Newbee Forum) Post 512239 (psyloxy: "some great alkali alkoxide patents", Chemistry Discourse) ? “The real drug-problem is that we need more and better drugs.” – J. Ott



		phenethyl_man (Newbee) 09-07-04 08:01 No 530083				ugh, you are right.. that should have been...
						ugh, you are right.. that should have been 3-nitro-4-methylbenzenesulfonic acid.. and of course I meant acid hydrolysis, which is an electrophilic rxn that displaces the group by a proton, effectively removing it from the nucleus. I removed that entire scheme from the post. I really should write this stuff down before I post it instead of going off the top of my head.. hopefully the MMA scheme holds up to scrutiny. nicodem; I believe I have seen those threads I still can't recall any copper-catalyzed nucleophilic substitutions in which the alkoxide is generated in situ. - phenethylman -



		yei (Newbee) 09-07-04 21:11 No 530173				This is interesting for another reason
						Since this means that alkoxides can be generated with weak base/PTC in alcohol, and more importantly, that the weak base will not interfere {i.e. hydrolyze water/hydroxide-sensitive compounds}, it suggests that the CLAISEN CONDENSATION can be run in alcohol with KOH/PTC. This means that ethyl acetoacetate and the Reissert synthesis might be with reach of the alkoxide-deprived. Since ethyl and methyl oxalate are easy to make from OTC materials, this suggests a very nice OTC method for indoles and other lovelies. _{It's good to bee back! Don't trust your computer!!}



		phenethyl_man (Newbee) 09-16-04 03:50 No 531561				okay.. since no one was impressed by my ...
						okay.. since no one was impressed by my proposal for the utilization of this reaction in the production of MMA, let me know what you think of this theoretical synthesis of either a DOM analogue, Desoxy, pseudo-2CB, or pseudo-DOB, again starting from toluene: 1) brominate toluene to p-bromotoluene 2) dinitrate p-bromotoluene (is this possible?; may require a high H2SO4 conc. and heat) 3) now you have 2,6-dinitro-4-bromotoluene and can theoretically use the above nucleophilic reaction to displace both nitro groups, providing 2,6-dimethoxy-4-bromotoluene. Once you have this intermediate, you have two options: a) oxidise the methyl group to 2,6-dimethoxy-4-bromobenzaldehyde; a precursor for pseudo-2cb/dob; b) react w/magnesium to form the grignard and react this w/DMF to get 3,5-dimethoxy-4-methylbenzaldehyde; a precursor for Desoxy or a DOM analogue; .. on second thought, this will never work, it sounds way too easy. - phenethylman -

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