Metal-free catalyst to convert aldehyde into ketone, a basic structure of pharmaceuticals

April 03, 2019

[Background]

Ketones are important organic compounds found in a variety of pharmaceuticals, agrochemicals, and natural products. The synthesis of a ketone directly from a corresponding readily-available aldehyde would be ideal and has been successfully performed using a metal catalyst. However, metal catalysts are expensive and the metal remaining in the final products may cause problems. On the other hand, N-heterocyclic carbene*1), an organic compound, is known to act as an organic catalyst*2) for such synthesis. N-heterocyclic carbene reacts with an aldehyde to form a Breslow intermediate*3). This Breslow intermediate, acting as a nucleophile followed by two-electron transfer, reacts with various electrophiles to form a ketone. However, this carbon-carbon bond formation following two-electron transfer is known to be sterically hindered and N-heterocyclic carbene is known to react only with electrophiles with activated electrons.

[Outline of research results]

The group at Kanazawa University, including two students, has succeeded in synthesizing a ketone from an aldehyde and a carboxylic acid by using N-heterocyclic carbene catalyst (Figure 1).

The key to the success of the reaction developed in this study was the discovery of a new reaction process in which radical-radical coupling followed by carbon-carbon bond formation took place after one electron transfer occurred from a Breslow intermediate of an enolate*4) formed from an aldehyde and an N-heterocyclic carbene to an electrophile (Figure 2). Since a highly reactive radical is used in the process of the carbon-carbon bond formation, it is possible to introduce a sterically bulky alkyl substituent, which used to be difficult in such a reaction.

It addition, the group succeeded in converting a carboxylic acid, part of many pharmaceutical drugs and natural products, into a ketone by the method described here (Figure 3).

[Future prospects]

The group at Kanazawa University succeeded in synthesizing a ketone, an important skeleton of many pharmaceuticals, from a readily available aldehyde and a carboxylic acid. The method makes possible the rapid synthesis of ketones even with bulky substituents, as well as those derived from pharmaceuticals or natural products.

Accordingly, our method is expected to accelerate drug discovery.

From a purely scientific viewpoint, it should be noted that the new reaction process, i.e. a radical-radical coupling after one electron transfer occurring from a Breslow intermediate, will be a new design guideline for N-heterocyclic carbene catalytic reactions.
-end-
[Glossary]

*1) Carbene
A carbene is a twofold coordination chemical species containing a neutral carbon atom with only six valence electrons.

*2) Organic catalyst
A catalyst accelerates a specific chemical reaction with itself being unchanged. An organic catalyst is a low molecular weight chemical catalyst that consists of atoms of carbon, hydrogen, oxygen, nitrogen, sulfur, etc. but without metal elements.

*3) Breslow intermediate
A Breslow intermediate is a chemical species having an enol skeleton, being formed by a reaction of aldehyde and N-heterocyclic carbene. It is regarded as an acyl anion equivalent.

*4) Enolate
An enolate is an anionic chemical species with a deprotonated hydroxyl group attached to one carbon atom of carbon-carbon double bond.

Kanazawa University

Related Pharmaceuticals Articles from Brightsurf:

A plot twist in pharmaceuticals: Single nanoparticles could pave the way for medicines on demand
For the first time, a single, twisted nanoparticle has been accurately measured and characterised in a lab, taking scientists one vital step closer to a time when medicines will be produced and blended on a microscopic scale.

New pharmaceuticals: public research combines efficiency with contained costs
Is the basic research that goes into the development of new drugs more efficiently conducted by public-sector scientists, pharmaceutical firms, or independent private laboratories?

New STM technique points way to new and purer pharmaceuticals
A research project led by chemists at the University of Warwick first used ultrahigh resolution scanning tunnelling microscopy to see the exact location of atoms and bonds within a molecule, and then employed these incredibly precise images to determine the interactions that bond molecules to one another.

Study describes cocktail of pharmaceuticals in waters in Bangladesh
An analysis revealed that water samples held a cocktail of pharmaceuticals and other compounds, including antibiotics, antifungals, anticonvulsants, anesthetics, antihypertensive drugs, pesticides, flame retardants and more.

Treating wastewater with ozone could convert pharmaceuticals into toxic compounds
With water scarcity intensifying, wastewater treatment and reuse are gaining popularity.

Study calls for improved sanitation and the environmental management of pharmaceuticals
Failure to ensure the environmental sustainability of growing patient access to medicines in developing economies could increase the risk of adverse environmental impacts, according to new research led by the University of Plymouth.

Chemicals for pharmaceuticals could be made cheaper and greener by new catalysts
High value chemicals used to make pharmaceuticals could be made much cheaper and quicker thanks to a series of new catalysts made by scientists at the University of Warwick in collaboration with GoldenKeys High-Tech Co., Ltd. in China.

Soaking up pharmaceuticals and personal care products from water
Medications excreted in the urine or dumped into the toilet can end up in the water supply, just like lotions or cosmetics that wash off the body and go down the sink or shower drain.

New study finds river wildlife contain cocaine, pharmaceuticals and pesticides
For the first time, researchers at King's College London, in collaboration with the University of Suffolk, have found a diverse array of chemicals, including illicit drugs and pesticides in UK river wildlife.

Metal-free catalyst to convert aldehyde into ketone, a basic structure of pharmaceuticals
We succeeded in synthesizing a ketone, a basic structure of many pharmaceuticals, from an aldehyde and a carboxylic acid using N-heterocyclic carbene catalyst under mild conditions.

Read More: Pharmaceuticals News and Pharmaceuticals Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.