New fluolination reaction from JACS #memo #organicchemistry

Trifuloromethylation is useful reaction in drug discovery. Because CF3 and other fluorinated substituent are often used in drug like molecules. It is also useful that the reaction can conduct in asymmetric manner.

I read interesting article in JACS today published by Trost’s group. The URL of the article is below.
https://pubs.acs.org/doi/10.1021/jacs.9b06231

You can see abstract without account.

My boss when I was student liked pi-allyl palladium reaction named Tsuji-Trost reaction. So allyl halide based palladium coupling is familiar for me. But in the reaction allyl bromide is used for substrate. The article uses allyl-fuluoride as a substrate. It is key point of the reaction, it is well designed!

In the reaction TMS-Rf(Rf means CF3, F5Ph and some fluorinated substituent). Fluorine atom from allyl fuluoride activates the TMS-Rf reagent and the reaction proceeds well.

They used chiral ligand in the reaction so these reactions proceeds enantio selective.

You can see many examples in scheme2 and all reaction shows good yield and enantio selectivity. The example in the article was limited in cyclic allyl fuluride. I thought cyclic substrate is suitable for stereo selective reaction compared to acyclic compound.

Process of something new is very exciting for me. Not only drug discovery but also compound synthesis, reaction design and etc…. ;-)

Advertisements

Efficient site-selective functionalization with TFT #organic_synthesis #organic_chemistry #memo

There are many new functionalization reactions of molecules in these days such as electrochemistry, photo-redox and cross-coupling etc. New reaction will give more choices for synthetic route.

Chemists often use cross coupling or another functinalyzation reactions, but these reactions are required foothold such asAr- halogen or ArOTf groups. And the reaction precursor is synthesized by using halogenation when the compound is not commercially available.
So, I think direct C-H activation reaction is an attractive but I had very few experiences in my project because it often has selectivity and/or functional group tolerance issue. But!!!! today I found an exciting article from Florian Berger’s group in nature.

URL is below
https://www.nature.com/articles/s41586-019-0982-0

The group developed new C-H functinalization chemistry with thianthrene derivatives(TFT). In their reaction, cation radical is generated with TFT and TFT sulfide at first and the the radical reacts the substrate and produces thianthrenated intermediate. The reaction can be conducted with high site selectivity and good yield. And also the reaction is not affected with small amount of water, and oxygen. It means the reaction handling is very easy I think.

In the Fig2 shows many example of the thianthrenation. Most of the reaction proceeded moderate ~ high yield and good selectivity with very wide functional group tolerance. The reactivity is controlled with electronic condition of the substrate if target aromatic ring has electronwithdrawing group they used non fluorinated thiantherene instead of TFT.

And following section the authors shows the wide range application of the intermediate.

The thianothreated intermediate can be used for many reactions, transition metal catalyzed cross couplings such as carbonylation, suzuki, sonogashira, negishi, heck and sulfonynlation and photo redox catalyzed reaction such as borylation, phosphonylation, cyanation, pseudohalogenation(ex. SF5), chlorination, idonation.

There are many applications!

In fig3 the author showed many example of these reactions. One is Strychinine acylation. The yield was 48% in 2 steps. Strychinine is an alkaloid with complex molecular structure, normally it is difficult to conduct direct C-H functionalyzation but can do it by using the reaction.

I would like to use the reaction if I have chance. ;)

Recent trends of Flow Chemistry #memo #chemistry #technology

I enjoyed reading the article in my lunch break. Researchers at Abbie published nice review about the flow chemistry in the pharmaceutical industry. The URL is below.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01760

The review describes wide range of the flow chemistry from large scale synthesis to lab scale synthesis.

Flow chemistry can run the reaction under high temperature and high pressure reaction conditions. Photo redox reaction is also available. I like rearrangement reactions because the reaction is atom economic and stereo selective I feel it is elegant. But theres reactions often requires high temperature condition. In scheme 10 shows example of Overman Rearrangement with flow. The example shows >95Kg scale synthesis in 84hr! Continuous synthesis is powerful tool for production.

One of the strong point of flow reaction is flush chemistry that can conduct reaction in very short time. It means the method can handle unstable(reactive) intermediates. In scheme 15 shows flow synthesis example of Eribulin intermediate. You know Eribulin is a laboratory-made form of halichondrin B, a substance. It has very complex structure. The researchers conducted DIBAL-H reduction of ester to aldehyde and then conducted julia coupling type anion addition. To use flow reaction reaction temperature was raise up from -70 deg to 10 deg.

There many examples are described in the article and scheme35 Flow diazomethane chemistry seems very useful. Diazomethane is useful reagent but sometime it is difficult to use in lab for safety reason so TMS-diazomethane was used. But TMS-diazomethane is not cost effective. The Scheme35 shows example tube-in-tube reactor. What is tube-in-tube reactor? I would like to draw the image below. The inner tube is made with teflon AF-2400 which is gas-permeable tube. The tube can through diazomethane only so outer layer trap CH2N2 and generate pure CH2N2/THF solution. I have not known the technology. It is cool. Reader who has interest, pls read the article.

___________________________________________________ outer tube
THF>>>>>>>> CH2N2/THF
___________________________________________________ AF2400
Diazald+KOH >>> CH2N2 aq + side products >> side products
___________________________________________________ AF-2400
TFH>>>>>>> CH2N2/THF
___________________________________________________ outer tube

Above examples are production. BTW, how about parallel chemistry?

According to the article, Abbie was developed SWIFT (synthesis with integrated flow technology, nice naming sense!). The system integrates flow reactor and HPLC/MS and be able to synthesize 6 pure compound per hour in 10 ~ 20mg scale! It is very productive I think. Even if I use parallel reactor such as miniblock, it is difficult to synthesis pure compounds such speed. Fig 24 shows SWIFT platform. It seems not so large. And there are some examples continuous synthesis and assay cycles. In Japan there are few examples of parallel chemistry with flow I think.

If we can run DMTA cycle within few hours, what will be task of medicinal chemists.

New scalable Flow photo Chemistry Platform New Flow Chemistry Platform #photochemistry #flowchemistry

Recently visible light used organic reaction is attractive area for me. Because it can make difficult bond in short steps under mild reaction conditions.
But scale up is difficult because key factor of photo reaction is light. It means photo absorbance is important and so it is difficult to scale up. One approach is Plug Flow Reactor. It can increase illumination of the reaction solution by increasing surface-area-to volume ratio. But kilo gram scale up is still difficult.

Today I read an exciting article to overcome the issue. The article is published from researcher of AbbVie.
https://pubs.acs.org/doi/10.1021/acscentsci.8b00728

They proposed to use high intensity lasers for light source and Continuously stirred-tank reactor(CSTR) with Beam Expander. From freely available supporting information, reactor looks like below.

They optimized reaction condition and succeeded to conduct 1.54kg synthesis of substituted benzene derivative with C-N cross coupling in 100ml CSTR. It took only 32h!

CSTR has advantage for solid handling compared to flow reactor. I think this reactor is interesting and attractive for large scale photo chemical reaction.

It is worth to know that big pharma try to develop not only drug but also science and technology I think.

(new?) medchem tool box for compound synthesis

This mini perspective shows recent progress of the direct C-H alkylation with Alkyl Sulfinates.
https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01303

There are many heterocyclic moieties such as pyridine, pyrrole etc. in drug like molecules.
The C-H alkylation reaction of heterocycles is useful but difficult to conduct it under mild reaction conditions.
So mild and universal reaction is very attractive for chemists I think.

In the article, Phil S. Baran’s group reported many examples of their developed reaction.
They used alkyl sulfinates as a radical precursors and developed many kind of commercial sulfinates, fluoroalkyl, heterocyclic, alkyl, aromatic and linker-type.

Surprisingly most of the reactions proceed room temperature. Also they shows reactivity guid lines, it is very practical!

And also this reaction can apply not only early stage of synthesis but also late stage of synthesis.
(Fig3-6)
It means that this is very specific reaction.
I had few successful cases C-H alkylation with sulfinate…. I would like to use the reaction condition when I have chance.

New finding of the Chan-Lam coupling

Copper catalyzed boronic acids and OH or NH containing reaction is called Chan-Lam reaction. The reaction often perform in mild conditions under oxygen atmosphere.
Yes I have used the reaction to synthesize my target compound. But always yield was moderate and depends on steric effect.
Today I found useful article that is reported by researchers from Pfizer and Scripps research institute.
https://pubs.acs.org/doi/abs/10.1021/acs.joc.7b03100

They focused on cyclopropylation of phenols and azaheterocycles. Because cylopropyl group is very important and unique substituent for Medicinal Chemistry but sometime has difficulty to introduce. So new methodologies are required still now.

At first they optimized the reaction condition for O-cyclopropylation of phenols.
In table1 they found good condition with bidentate ligand and it gave high yield (84%). Next they investigated scope and limitation of the reaction.
It was interesting for me that the condition give high yield against not only para substituted electron rich phenol but also ortho substituted phenols.
And also the condition gave low – moderate yield against para meta substituted electron poor phenols.
Procedure of the reaction is not so complicate. I would like to try to use the reaction if I have chance. Organic synthesis and medicinal chemistry is fun and creative task I think.

BTW, I think that introduction of cyclopropan MMP sounds like sudden.