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Topic: Weinreb amide to aldehyde in the presence of an ester  (Read 3173 times)

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Offline Babcock_Hall

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Weinreb amide to aldehyde in the presence of an ester
« on: February 09, 2019, 02:29:30 PM »
I was looking over a synthesis recently in which a Weinreb amide was made and then reduced with DIBAL.  It was done in the presence of a tertiary-butylester.  Would there be some chance that the ester would also reduce?  Are there any special tricks when making aldehydes with DIBAL?  There was a thread here a few years ago, which mentioned this reduction, but there was not much discussion about it.

Offline zarhym

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #1 on: February 10, 2019, 09:50:25 PM »
tert-Butyl esters are less reactive in reduction compare to weinreb amide.
In my experience, reduction of weinreb amide to aldehyde requires low temperature (-78 to 0°C) to provent over reduction.

You can read this paper for more infomation.
https://onlinelibrary.wiley.com/doi/pdf/10.1002/bkcs.10571

You can check the table 3 in this paper to compare the reduction on ester and weinreb amide.

Offline Babcock_Hall

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #2 on: February 11, 2019, 12:51:37 PM »
Thank you; this paper looks quite helpful.

Offline pgk

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #3 on: February 11, 2019, 01:58:16 PM »
Theoretically, DIBAL reduction occurs via formation of a >=O-Al Lewis complex that forces the hydride to attack from the less bulky side, which is impossible in case of a bulky tertiary ester, especially in low temperatures.
(But I have never worked with DIBAL and thus, I cannot know what happens in real life.)
 
« Last Edit: February 11, 2019, 02:14:17 PM by pgk »

Offline Babcock_Hall

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #4 on: June 17, 2019, 06:58:22 PM »
C. L. Bailey et al. / Tetrahedron Letters 56 (2015) 706–709.  http://dx.doi.org/10.1016/j.tetlet.2014.12.066

This paper uses MgAB an alternative to DIBAL in reducing a Weinreb amide.  The reaction takes place at room temperature.  An ordinary ester is not reduced.  So many reducing agents, so little time...

Offline pgk

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #5 on: June 18, 2019, 12:14:23 PM »
Yes, indeed!
But is this reducing agent, conveniently being prepared?

Offline Babcock_Hall

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #6 on: June 18, 2019, 02:19:22 PM »
MgAB is prepared from dimethyamine-borane adduct and methyl magnesium chloride, and it can be stored for 3 months at room temperature.  I suppose that there are particular circumstances where it would be handy, but I have no specific knowledge of it.

Offline pgk

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #7 on: June 18, 2019, 02:46:02 PM »
Although not being a specialist of the issue, the overall preparation procedure of MgAB doesn’t seem very simple. Besides, MgAB doesn’t seem to be largely offered by suppliers.
Nevertheless, the article is very interesting because a chemoselective reducing agent that leads to aldehydes and works at room temperature within half an hour, is always a very useful and convenient tool.

Offline Babcock_Hall

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #8 on: June 19, 2019, 03:33:04 PM »
I am following a literature protocol, and the yield is 60% after column chromatography.  I am inclined to try DIBAL and if I also obtain 60%, to stay with DIBAL.

Offline Babcock_Hall

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #9 on: June 27, 2019, 03:21:30 PM »
I am waiting on some reagents, but I will do this reaction as soon as I can.  My question concerns the quench.  DIBAL is in 1.5-fold excess.  The protocol calls for potassium bisulfate to be added, then ethyl acetate.  The temperature at this point is not specified, but it was -10 °C for the addition of DIBAL, and I assume that the temperature should remain there.  KHSO4 is also used a washing solution.  My question concerns whether or not I will see gas evolution (I assume that I will) and any other problems or issues that might happen in this quench and work-up.  I looked up the pKa of HSO41-, and it is about 2.

Offline Babcock_Hall

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #10 on: June 28, 2019, 09:56:54 AM »
Obtaining the potassium bisulfate is proving more difficult than I expected.  Are there other washing protocols that would perform equivalently?  I have a feeling that if I tried phosphoric acid, I would form a precipitate with aluminum that could be problematic.

Offline pgk

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #11 on: June 28, 2019, 12:02:43 PM »
KHSO4 is usually supplied as a mixture of KHSO4.xK2SO4 (x<1) crystals that are hydrites and have absorbed a little SO3 in their mass.
But I am afraid that with KHSO4, you will form the non-soluble potassium alum.
K2SO4.Al2(SO4)3.24H2O↓
Phosphoric acid will also form the insoluble AlPO4.
Alternatively, you could try saturated ammonium chloride solution that might form among others, a mixture of hexaminealuminium chloride and basic aluminium chlorides that all are water soluble.
[Al(NH3)6]Cl3  and AlCl3 + Al(OH)Cl2 + Al(OH)2Cl + Al(OH)3
But firstly, try this with a small amount, in order to see if it works.
Good luck.
1). Reaction study of aluminium chloride with ammonia and mechanisms leading to aluminium nitride, Journal of the European Ceramic Society, 16(5), 521-527, (1996)
https://www.sciencedirect.com/science/article/abs/pii/0955221995001689
2). Water-soluble basic aluminum compounds, United States Patent 2196016, (1940)
« Last Edit: June 28, 2019, 12:25:15 PM by pgk »

Offline rolnor

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #12 on: June 30, 2019, 06:25:44 AM »
Alternate ways to reduce a carboxyl is to make a acid chloride, this can be made near neutral with a complex DMAP/SOCl2, then reduce the acid chloride with Bu3SnH or by catalytic hydrogenation.

Offline wildfyr

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #13 on: June 30, 2019, 12:18:32 PM »
I've always felt going the acid chloride route was a recipe for pain due to its hydorlytic stability making it much more of a pain to isolate and handle than any other carbonyl species.

Offline rolnor

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Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #14 on: June 30, 2019, 12:22:06 PM »
You make the acid chloride and reduce it one-pot, no isolation.

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