April 13, 2021, 06:27:50 AM
Forum Rules: Read This Before Posting


Topic: Weinreb amide to aldehyde in the presence of an ester  (Read 7776 times)

0 Members and 1 Guest are viewing this topic.

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4603
  • Mole Snacks: +279/-20
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #45 on: November 26, 2019, 03:36:02 PM »
One of the papers I am following claimed a 60% yield in this reaction, and their substrate was FMOC-protected.  My first attempts were with BOC-protected substrate, and I obtained only a little product.

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4603
  • Mole Snacks: +279/-20
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #46 on: December 02, 2020, 10:48:53 AM »
I hope to return to this work soon.  I plan to follow the reaction using TLC, but this time I plan to use some sort of mini-extraction on any time points.  One possibility is to use ethyl acetate vs. KHSO4.  I have also heard that with aluminum-based reagents, the Rochelle salt is a possibility.  Does anyone have any advice on what mini-extraction conditions are best, or more generally on using mini-extractions in conjunction with TLC?

Online rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1306
  • Mole Snacks: +88/-5
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #47 on: December 02, 2020, 05:18:32 PM »
Its difficult to give advice with so little info about your compound.

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4603
  • Mole Snacks: +279/-20
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #48 on: December 02, 2020, 08:00:01 PM »
The desired product is an alkyl aldehyde.  The two protecting groups are BOC on a nitrogen and tert-butyl (on a carboxylic acid).

Online rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1306
  • Mole Snacks: +88/-5
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #49 on: December 03, 2020, 06:37:57 AM »
I get the impression that you have worked for some time with this, is it possible to change the strategy? Two good ways to create an aldehyde is to oxidize a alcohol, Dess Martin is good, or to cleave a double bond with osmium tetroxide/NaIO4.

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4603
  • Mole Snacks: +279/-20
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #50 on: December 03, 2020, 09:44:55 AM »
I set this work aside in favor of reactions where I could use commercial aldehydes, but I want to come back to it now.  I have two reducing agents, and I still have some of the Weinreb amide that I made.  If that runs out, I will try another strategy, such as the Dess-Martin reagent.

Offline BobfromNC

  • Regular Member
  • ***
  • Posts: 79
  • Mole Snacks: +12/-1
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #51 on: December 08, 2020, 02:28:04 PM »
If you do the DIBAL reduction, keep it cold until the quench, that will help protect the ester.  Your quench may turn into a frozen mess, due to the temperatures, but just add the quench at a moderate speed at first to control the temps, and once some is added, then the further quench will warm the reaction.  Maybe take it out of the cold bath just before quench.    I have done some reactions like that where the quenched reaction is an icy mess, but the yield was great, so just let it thaw some under nitrogen and then extract once thawed some. 

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4603
  • Mole Snacks: +279/-20
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #52 on: December 10, 2020, 04:38:20 PM »
How does one deal with the gelatinous mess after the quench?  I tried an extraction, but I could not see the line between the aqueous layer and the ether layer.  I tried to filter through papers but it took forever, and the ether evaporated.  I am wondering about filtering in vacuo through diatomaceous earth.

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4603
  • Mole Snacks: +279/-20
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #53 on: April 01, 2021, 08:34:19 AM »
Wernic D et al., J. Org. Chem. 1989, 54, 4224-4228.
Zhang G et al, Organic Biomol. Chem 2015 13(14):4149 DOI: 10.1039/c5ob00120j
These two procedures are almost identical.

We tried to reduce the Weinreb with Dibal-H again this week.  We worked at -70 °C (dry ice/acetone)  By NMR the crude material looks like 45% aldehyde and 33% Weinreb amide.  What is odd is that the reaction seemed to be more complete at 2 hours than after 4-5 hours.  The separation between spots in our TLC solvents (35-40% ethyl acetate in hexanes) was poor.  We will need to find a different system for silica chromatography.  We found that dipping the plate into DNP solution gave a yellow spot for crude product and a white spot for starting material.

Let's say that we can get 25% yield after purification.  We can live with that, but we would like to improve this significantly. 

Online rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1306
  • Mole Snacks: +88/-5
Re: Weinreb amide to aldehyde in the presence of an ester
« Reply #54 on: April 01, 2021, 10:15:36 AM »
I would not be surpriced if the reaction is very fast, Dibal is a potent reagent. If so it could be good to quench after say 5 min. I think acetic acid can be OK to use. Its possible that the aldehyde breaks down in the reaction mixture if run too long.

Sponsored Links