Isomeric_Fred
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aldehyde to amide musings and needed help
Hello fellow SM members.
Im on the lookout for a procedure that will convert an aldehyde to amide. My aldehyde has acid sensitive functional groups.
Ive been trying a procedure by Chill and Mebane (Synth Commun, 2010, 40, 2014-2017). It involves reacting the aldehyde with hydroxylamine.hcl in DMSO
@ 100degC for 30 minutes, followed by removal from heat, addition of NaOH, and then H2O2.
It yields a very clean product without purification (5% deviation in m.p. from literature), but there are 2 problems -
1. diethyl ether is used as an extraction solvent for the dmso/h2o mix. it barely dissolves my product amide.
2. color of the reaction becomes quite dark, indicating cleavage of the acid sensitive group, presumably due to too high a temp which enables
oxidative cleavage)
When doing the alkali and peroxide addition in an ice bath, and extraction with DCM (which dissolves my amide) the product is a yellow liquid. Im
assuming it is the nitrile, but it is still drying under high vac, and will only test physical properties after im done with the drying.
Anyone got any ideas that can help me with this reaction? It is quite benign, but the yield is horrible, even if the product is pretty clean post
reaction.
without temp regulation and using ether for extraction it yielded on a 50mmol scale roughly 20% of purish product.
I have also tried a stepwise procedure, first producing the oxime from the aldehyde (sodium acetate as base, MeOH solvent, 1.5hours reflux, 90%
yield), then nickel acetate catalyzed beckmann (2mol% nickel acetate tetrahydrate in xylenes, reflux for 5-10 hours). the overall yield is 40-45%, but
it requires distillation of the product amide to get a sufficiently pure product, and the nickel is a bit too toxic to my liking.
Ive recently come across another route, which utlilizes I2/aq. ammonia followed by hydrogen peroxide addition. The ref is atached.
In the article the authors state that the I2/ammonia is known to produce a shock sensitive explosive powder NI3.NH3 in the form of a black
percipitate. normally I would like to avoid explosive stuff, since i like my limbs.
Can anyone give me pointers on how to avoid the formation of this NI3.NH3? or how to decompose it when wet so i can avoid an explosion?
Also, if anyone has any other ideas regarding aldehyde->amide, i will be happy to hear. Thanks!
Attachment: beckmann nickel acetate.PDF (684kB)
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Attachment: iodine ammonia h2o2 aldehyde to amide.PDF (50kB)
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[Edited on 19-6-2010 by Isomeric_Fred]
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Melgar
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Hmm... how about this? Use [url=http://en.wikipedia.org/wiki/Tollens'_reagent]Tollens' reagent[/url] to oxidize it into a carboxylic acid. Then form
the ammonium salt, and heat to form the amide via dehydration. If you have a better way to oxidize it to a carboxylic acid, you can use that, but
I've heard Tollens' reagent is quite mild and you get a silver precipitate to verify it's working.
Also, look up "boric acid catalyzed amidation" if your aldehyde is too heat-sensitive to make an amide that way.
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S.C. Wack
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Needless to say, the amide I_F wants to make from the temporarily uncontrolled aldehyde he has, gives a highly controlled amine with bleach. Do your
own search instead of asking for spoonfeeding and offering previous spoonfeeds.
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zed
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Isomeric_Fred,
The idea of converting an aldehyde directly to an amide, sounds interesting. Since the challenge USUALLY....is converting a carboxylic acid
derivative, to an aldehyde...The contra plan is intriguing. But, the "acid sensitive functional groups" stuff, is entirely too foggy. Can you
present a more reasonable description of the molecule you are actually working on?
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Isomeric_Fred
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I am unsure to which compound S.C.Wack is hinting at. Thanks for your helpful participation anyway.
My compound is 3-(4-((2-methyl-1,3-dioxolan-2-yl)methoxy)phenyl)propanal
the cyclic ketal ether was produced via rxn of the phenol with bromoacetone ketal, and was chosen due to its availability for me.
It is apparently undergoing deprotection, and possible cleavage of the ether under the rxn conditions ive given in the first post.
Ive also confirmed that the cold naoh/h2o2 addition does not work with satisfactory yield - roughly 50% nitrile and 10% amide as product.
Melgar : thanks for the input. the boric acid i think will not work here. I need to carry the reaction under basic/neutral conditions. The option of
oxidizing first to carboxylic acid is a valid one, i just want something that can be done in a onepot, or a continous pot (carry reaction 1, filter or
seperate, then carry reaction 2) manner. If all else fails, i will inevitably have to choose a 2 step route.
S.C.Wack : why dont you contribute to the thread instead of imagining things? I thought this was a chemistry forum. I was not spoonfed, and found the
refs myself, by a literature search.
Didnt know the beckmann nickel acetate route, or the dmso/nh2oh.hcl/h2o2/naoh route were so known. the latter is quite new (2010), and the former is
an oldy, but not cited too often in the literature, except for oximes/beckmann reviews.
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not_important
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Yeah, the H2NOH.HCl is pretty acidic for a ketal. It is possible dithiolanes might work as protection of the ketone http://www.organic-chemistry.org/protectivegroups/carbonyl/1...
http://newjournal.kcsnet.or.kr/main/j_search/j_download.htm?...
http://nopr.niscair.res.in/bitstream/123456789/6449/1/IJCB%2045B(5)%201291-1295.pdf
http://www.arkat-usa.org/get-file/19691/
You'll need to do some research on the deprotection to see if your target can stand up to it.
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S.C. Wack
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Anyone can read your posts, see your interests, and imagine a slightly different ether function and side chain.
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zed
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This doesn't sound too bad. The trick needed, is a method to partially hydrolyse the resultant Nitrile (Which you have obtained in fairly high
yield) to produce the desired amide.
Since the nitrile, the amide and the carboxylic acid,.....Are in essence the same product...except for their degree of hydolyses. Partial hydrolysis
of the Nitrile is in order.
Naturally, I have no idea how to do that. But, someone here may.
Failing that, perhaps direct oxidation of the Aldehyde to Carboxylic acid, followed by creation of a mixed anhydride, and reaction of that anhydride
with ammonia, might be in order. Provided your protecting group can withstand the strain......THAT road is fairly well traveled, and many references
might be available.
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Arrhenius
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Lindgren oxidation followed by coupling reaction with a carbodiimide - 99% over 2 steps. That is by far the mildest way to go from an aldehyde to the
acid oxdation state, and coupling reactions will access any amide your heart desires. The other one that comes to mind is PDC in N,N-DMF, which was
specifically developed to oxidize acid sensitive substrates. Don't ask me where the oxygen comes from in that reaction though. Going directly to the
amide with transition metal chemistry would be fun, but probably not preparatively viable for your purposes.
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Sandmeyer
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I have recently posted a ref. using a rather inexpensive and scalable method (utfse!): https://www.sciencemadness.org/whisper/viewthread.php?tid=13...
http://linkinghub.elsevier.com/retrieve/pii/S004040390084893...
doi:10.1016/S0040-4039(00)84893-5
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retoga
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when i try the direct route to amide from aldehyde with dmso/h2o2/naoh, after the bubbling of h2o2 i see the amide precipitate. however, when i try to
filter it, after 5 minute, the dmso crystallize almost completely.
does anyone know how to avoid these? what i am doing wrong?
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Rich_Insane
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What about reaction of the aldehyde with hydroxylamine followed be rearrangement to amide via the Cu(II) ion?
The conditions are rather gentle, and require hydroxylamine, a weakly basic compound (sodium acetate, or if needed, sodium carbonate) and a catalytic
amount of a Cu(II) salt (copper sulfate and copper acetate are mentioned in the two references I have attached).
There was also another article which mentioned using Zn(II), but I cannot find it.
Alternatively, I suppose one could oxidize the aldehyde (using bleach and a catalyst as per J. Org. Chem., 2006, 71 (25), pp 9291–9296. The
resulting carboxylic acid could be reacted with either a) NH3 bubbled into solution or b) Aq. ammonia aka "ammonium hydroxide," which I believe does
indeed contain at least some of the simple aq. NH3 species (not sure what the outcome of the NH4+ vs dissolved NH3 argument was). The amidation could
be catalyzed with boric acid, as per Org. Synth. 2009, Coll. Vol. 11, 733 .
Attachment: copperaldehyde.pdf (417kB)
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Attachment: coppersulfateazldehyde.pdf (364kB)
This file has been downloaded 1863 times
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