[macman104]

I am working on the attached reaction scheme.  There are two reactions in there whose yields are rarely above 50%.  I'm wondering if anyone has any thoughts on how to modify the above scheme to either cut out steps or improve the overall yield.  In addition, the first step usually proceeds with almost a 50/50 mixture of ortho/para products so thoughts on that are appreciated as well.

I'm open to other reagents/methods/conditions.  Also, the only must in the scheme is the final product.  If you have a different idea that utilizes a completely different route, I'm all ears.

[zq]

I can tell you the reaction condition for the last step in your scheme. Use N,N-diisopropylethylamine (1.5 equivalent), acetonitrile as solvent and stir the mixture at room temperature until the reaction is complete. The reference for this procedure is Moore, J. L. et al Arkivoc 2005, vi, 287-292.

[sjb]

A few early thoughts:

If you want to start with the alkylbromide, have you tried other nitrating reagents - things like NO₂⁺BF₄^-? Fuming nitric seems fairly harsh, you may get chewing up of the side chain

Can you go directly from the bromide to the alcohol without the Finkelstein reaction - something crazy like metallation and work up with water?

Alcohol to aldehyde might be better under Swern conditions or similar.

What kind of yield are you getting in the imine formation? Seems fairly competitive with acetal formation to my mind - protect the alcohol of ethanolamine with a silyl group or something, and don't take it off until after forming the tertiary amine at the end? Can you do the reductive amination in one pot?

What kinds of cinnamaldehydes can you get hold of (cinnamaldehyde is (E)-PhCH=CHCHO, and I think the p-nitro compound is commercially available - e.g. http://www.fluorochem.net/product_details.asp?id=117495&name=4-Nitrocinnamaldehyde, or http://www.sigmaaldrich.com/catalog/search/ProductDetail/ALDRICH/281670?CHEMBUYERSGUIDE) - if too pricey why not an aldol reaction between 4-nitrobenzaldehyde and acetaldehyde?

(edit adding links to commercial compound)
S

[macman104]

A few early thoughts:

If you want to start with the alkylbromide, have you tried other nitrating reagents - things like NO₂⁺BF₄^-? Fuming nitric seems fairly harsh, you may get chewing up of the side chain

We usually don't see any side products formed aside from the ortho isomer.  Although, I thoroughly dislike separation the two isomers from one another (especially when we prepare a large scale of the reaction).

Can you go directly from the bromide to the alcohol without the Finkelstein reaction - something crazy like metallation and work up with water?

When you say metallation, you don't mean grignard, otherwise you would have said that, do you?  I'm not exactly sure what you mean.

Alcohol to aldehyde might be better under Swern conditions or similar.

I'll look into this.

What kind of yield are you getting in the imine formation? Seems fairly competitive with acetal formation to my mind - protect the alcohol of ethanolamine with a silyl group or something, and don't take it off until after forming the tertiary amine at the end? Can you do the reductive amination in one pot?

We usually get fairly decent yields.  Last time I performed the amination, it was somewhere around 85%.

What kinds of cinnamaldehydes can you get hold of (cinnamaldehyde is (E)-PhCH=CHCHO, and I think the p-nitro compound is commercially available - e.g.

This plan I like the best.  I plan to check out the aldrich prices as soon as I go into lab this morning.

- if too pricey why not an aldol reaction between 4-nitrobenzaldehyde and acetaldehyde?

Again, nice suggestion, thanks!

[sjb]

A few early thoughts:

If you want to start with the alkylbromide, have you tried other nitrating reagents - things like NO₂⁺BF₄^-? Fuming nitric seems fairly harsh, you may get chewing up of the side chain

We usually don't see any side products formed aside from the ortho isomer.  Although, I thoroughly dislike separation the two isomers from one another (especially when we prepare a large scale of the reaction).

Maybe just my bad luck then. Every time I seem to touch fuming nitric acid bad things happen. What sort of scale are you talking - are you chromatograhing, or recrystallising, or how?

When you say metallation, you don't mean grignard, otherwise you would have said that, do you?  I'm not exactly sure what you mean.

Well, not just grignard, 2 equivalents of Li etc, I'm just using metallation as a generic term for that umpolung style disconnection

What kind of yield are you getting in the imine formation? Seems fairly competitive with acetal formation to my mind - protect the alcohol of ethanolamine with a silyl group or something, and don't take it off until after forming the tertiary amine at the end? Can you do the reductive amination in one pot?

We usually get fairly decent yields.  Last time I performed the amination, it was somewhere around 85%.

Fair enough, not much real further optimisation needed there then

What kinds of cinnamaldehydes can you get hold of (cinnamaldehyde is (E)-PhCH=CHCHO, and I think the p-nitro compound is commercially available.)

This plan I like the best.  I plan to check out the aldrich prices as soon as I go into lab this morning.

Don't know how up-to-date the page is, whether it's any use chemically, or a price; but I found http://www.prosynth.com/exstock.php here in the UK who claim 600g of 4-Nitrocinnamyl alcohol (CAS RN 1504-63-8). I'm not 100% sure on reducing the isolated alkene in the presence of the nitro-group - something like Wilkinson's Catalyst? If you have the alcohol maybe then tosylate it to activate it to displacement or similar. Have you even tried direct displacement of the halide with the amine. I seem to recall a prep using something like wet dioxane and inorganic base to avoid the over substitution viz. RNH₂ -> RN(R')₂. Can try and find it if you want.

If you have the enal, I'm fairly sure you can 1,4 reduce that and then tautomerism to the aldehyde ought to be facile.

S

[macman104]

Maybe just my bad luck then. Every time I seem to touch fuming nitric acid bad things happen. What sort of scale are you talking - are you chromatograhing, or recrystallising, or how?

We've done anywhere on the scale of a few grams up to 50g starting bromocompound.  Then we chromatograph it, since effectively recrystallizing the ortho or para and not the other isomer was pretty unlikely.  The chromatography is equally frustrating on a large scale if you don't use a large enough column.  Additionally, since the spots are so close it uses an incredible amount of solvent.  Last time, I chromatographed a large column and went through about 5L of Hexane and probably 100+ fractions.

Well, not just grignard, 2 equivalents of Li etc, I'm just using metallation as a generic term for that umpolung style disconnection

Ah ok.

Don't know how up-to-date the page is, whether it's any use chemically, or a price; but I found http://www.prosynth.com/exstock.php here in the UK who claim 600g of 4-Nitrocinnamyl alcohol (CAS RN 1504-63-8).

Yea, I found out the prices.  Pretty decent, and the 4-nitrocinnamylaldehyde is comercially available

I'm not 100% sure on reducing the isolated alkene in the presence of the nitro-group - something like Wilkinson's Catalyst?

This was the hardest part to figure out, but I did find a very nice synthesis that I'm going to look into.

If you have the alcohol maybe then tosylate it to activate it to displacement or similar. Have you even tried direct displacement of the halide with the amine. I seem to recall a prep using something like wet dioxane and inorganic base to avoid the over substitution viz. RNH₂ -> RN(R')₂. Can try and find it if you want.

If you could find a reference for that, that would be great, I'd appreciate it.  More options are better.

I don't have the reference in front of me, but I'll post when I do.  It selectively reduces the double bond in the cinnamylaldehyde with 94% yield and very mild conditions.

Thanks again for the thoughts, greatly appreciated!

Additionally, are you aware of any protecting groups for a nitro group?  If we could protect the nitro, we could use a more standard reduction of the double bond.  My cursory search didn't turn up anything though.

[agrobert]

Additionally, are you aware of any protecting groups for a nitro group?  If we could protect the nitro, we could use a more standard reduction of the double bond.  My cursory search didn't turn up anything though.

No but oxidation of the aniline derivative using MCPBA or others may be more selective.  Of course this is backtracking, but it may increase your yields.

[macman104]

Here is the link to the reference I referred to.

Agrobert, I don't ever remember reading about oxidation of amines to nitro groups.  I'll have to go look that up.

[sjb]

I'll try and find that reference for you, but it was about a year ago, and being out of (chemical) work at the minute means I have very limited access to primary literature

Like agrobert, I can't say I've heard of "protection" of the nitro group. However, oxidation of amine -> nitro is something I've seen en papier, but never in the lab - perhaps http://www.organic-chemistry.org/abstracts/literature/263.shtm ?

More crazy thoughts came to me last night (beats the crap on the television )

I know we're moving slowly away from the alkyl bromide as a starting material,  but what kind of recovery are you getting from your column for the nitration? If you take crude all the way through to a tosylation step (or similar, perhaps even the bromide - how do Baldwin's rules hold up? http://en.wikipedia.org/w/index.php?title=Baldwin%27s_rules&oldid=187219262) would the o-aniline cyclise and give you 1,2,3,4-tetrahydroquinoline (I know that's a commercial compond, so you can have authentic to compare for TLC or similar), and how does that run compared to the p-isomer.

Of course you might be able to reduce, diazotise, and rehydrogenate with H₃PO₂ to recycle the o-isomer back to the alkyl bromide if you have some clean?

S

[macman104]

I'll try and find that reference for you, but it was about a year ago, and being out of (chemical) work at the minute means I have very limited access to primary literature

Ah, I see.  I'll go hope on SciFinder and see if I can't track it down.

Like agrobert, I can't say I've heard of "protection" of the nitro group. However, oxidation of amine -> nitro is something I've seen en papier, but never in the lab - perhaps http://www.organic-chemistry.org/abstracts/literature/263.shtm ?

Thanks for the link, I'll go look at that more carefully tonight.

I know we're moving slowly away from the alkyl bromide as a starting material,  but what kind of recovery are you getting from your column for the nitration? If you take crude all the way through to a tosylation step (or similar, perhaps even the bromide - how do Baldwin's rules hold up? http://en.wikipedia.org/w/index.php?title=Baldwin%27s_rules&oldid=187219262) would the o-aniline cyclise and give you 1,2,3,4-tetrahydroquinoline (I know that's a commercial compond, so you can have authentic to compare for TLC or similar), and how does that run compared to the p-isomer.

Hmmm....It's not that we don't get a good recovery from the column, it's just that it's very tedious and long, so I'm not sure the extra step of cyclisizing would be worth it.

Of course you might be able to reduce, diazotise, and rehydrogenate with H₃PO₂ to recycle the o-isomer back to the alkyl bromide if you have some clean?

That is an interesting thought, since we do lose alot of possible ortho product to the o-isomer.