Welcome back, I'm That Chemist,
and we have five more important papers in organic synthesis, this time for the month of July.
So in the first paper, we have the halogenation of electron-deficient arenes.
And so some highlights from this paper include
the use of meta-nitrobenzene sulfonic acid and hexafluoroisopropanol to do bromination and iodination.
Additionally, they were able to do chlorination in hexafluoroisopropanol;
however, in this case they had to use triflic acid as their activator.
Instead of using dibromodimethylhydantoin, they use trichlorocyanuric acid with trifluoroacetic acid.
So this worked on both electron-rich as well as electron-poor arenes,
this builds on prior work where only electron-rich arenes had been examined,
and their method works on electron-rich as well as electron-poor methods.
In the case of the prior work, only hexafluoroisopropanol was used,
but in this work both hexafluoroispropanol as well as an acid catalyst were used.
So the scope of this chemistry is pretty good,
you can see some examples such as this sulfonamide, this aldehyde, and this nitrile;
it follows the typical substitution directing effect pattern that
you might anticipate based on what's known for the substitution patterns of arenes,
although normally these types of transformations are quite challenging to do with existing methodology.
You can also see that a few different heteroarenes were tolerated,
although an electron donating group was needed to mediate this transformation.
The authors were also able to demonstrate that iodination could be accomplished, as well as as chlorination;
in the case of iodination,
this worked with carboxylic acids, for instance, esters, as well as some other electron deficient derivatives,
if you'd like to see a list of all of them,
you should look at the paper to see everything that they show,
I just include some interesting ones here.
Additionally, they show this one at a gram scale, which is noteworthy;
and in the case of chlorination they have several examples that are kind of interesting here.
So, a couple extra cool examples that they had include the bromination of this pyrrole (correction: imidazole),
the bromination of this arene here,
you can see that this oxadiazole here was chlorinated selectively on this ring,
while tolerating the more electron deficient ring;
here you can see some other interesting heterocycles with various different motifs,
which is kind of unique,
so the site of reactivity usually follows what you might anticipate
where the most electron rich center will be the one that typically reacts,
although they had a couple exceptions.
And so some limitations were that if they had a monochlorobenzene,
they didn't get good regioselectivity for the bromination;
the same applied for if they had bromobenzene.
In the case of pyridine, 1,4-dinitrobenzene, and 1,4-dicyanobenzene,
they didn't obtain any brominated products,
this is just likely due to it being too electron deficient,
and it's also worth noting that if they try to do chlorination on any of the monohalobenzenes,
such as chlorobenzene, bromobenzene or iodobenzene,
low regioselectivity was observed.
In the second paper for today, we're going to be talking about the synthesis of Collybolide.
And so what I want to highlight is that they synthesize Collybolide.
Additionally, they do this using an organocatalyzed cycloaddition reaction
using the Hayashi–Jørgensen diarylprolinol triethylsilyl ether ammonium catalyst;
they also use the work of the Tomkinson group;
finally, they demonstrate that the Kappa-Opioid receptor agonism
that was previously thought to occur from Collybolide is actually not the case —
it's disproven now that they've made this compound.
And so, the first reaction I want to highlight is their use of this organocatalyzed cycloaddition reaction.
You can see here that they have an aldehyde, and they're able to form an iminium,
which can then undergo a cycloaddition.
They optimize this chemistry quite well.
Additionally, there's this cool reaction,
they take the Tomkinson group's work, and what they actually do is
they take this O-benzoyl and tert-butyl ammonium salt,
this is able to form an iminium,
and this iminium is able to do a [3,3] sigmatropic rearrangement
because they were actually struggling to install a benzoyl group in that alpha center.
Now here you can see that after the sigmatropic rearrangement has occurred,
they have their alpha O-benzoyl species,
which they needed as an intermediate in their synthesis towards Collybolide.
Now, another reaction that they did that I thought was cool was
the diastereoselective reduction of this ketone with L-selectride.
Once that alcohol is formed on the top face of the cyclohexane ring,
the methyl ester is the only ester group on the same side,
so it isn't able to form a lactone on the ethyl derivative because it's on the wrong side of the ring,
and so in situ they lactonize just the ester group, which is kind of interesting.
Okay, so the third paper for today is some work from the MacMillan group doing deoxytrifluoromethylation,
and this chemistry features their NHC reagent,
which is able to form radicals under photoredox conditions to generate carbon-centered radicals,
which is kind of interesting from alcohols, they've got a couple papers in this vein.
Additionally, they demonstrate that this works for primary, secondary, and a few tertiary alcohols,
and they also include a scope of pharmaceutically relevant molecules.
Now the neat thing here is they couple this radical using copper,
and they're able to form a C-C bond to a trifluoromethyl group.
And so the mechanism of this reaction is as follows:
First, their alcohol is able to react with this benzoxazolium salt
in the presence of pyridine to form this orthoester-like species,
this orthoester-like species is then able to get oxidized to a carbon-centered radical,
this carbon-centered radical then undergoes radical cleavage to form this carbamate derivative shown here,
as well as a carbon-centered radical.
And so the carbon-centered radical that's formed is able to engage with the copper(II) species,
copper(II) is generated in situ through oxidative addition of the electrophilic trifluoromethylating agent to copper(I),
once this copper(II) species engages this radical, it forms a copper(III) species,
which is able to undergo reductive elimination, forming this C-CF₃ bond,
as well as regenerating the copper catalyst.
And so some highlights of this scope are shown here,
there's many other cool examples in the paper and I'd encourage you to go check it out.
You can see that amino acid derivatives were tolerated,
as well as this pyrazole derivative, this protected amino group,
as well as some other amino acid derivatives,
this lactone, as well as these fused four-membered rings like this shown here,
which is definitely an interesting motif,
as well as some interesting sulfonamide derivatives,
as well as some other med chem looking motifs, which are shown here.
You can see a couple examples of their tertiary alcohols are shown here,
but they're just tertiary cyclopropanols.
So the fourth paper for today is the synthesis of bipolamine I,
and so this is from JACS.
The highlights of this paper include a 15-step synthesis of bipolamine I, which is a racemic synthesis;
they utilize Krische's ruthenium-catalyzed hydrogen autotransfer reaction,
which is kind of a cool reaction, if you want to see it you should go check out this paper here;
and they also do a really nice alkyne isomerization which was quite interesting to me,
which just goes through the allene and we'll talk about that in a minute.
So in this first step, we have this propargyl pyrrole derivative,
and using tert-butoxide and tert-butanol via the allene —
just deprotonation here and protonation of the terminus —
we get an allene, and then through subsequent deprotonation and reprotonaiton,
we get the N-alkyne species, which is definitely interesting to me.
After this, they do this hydrogen autotransfer reaction to
convert this alcohol into this terminal alkene shown here,
and this is a really cool methodology, I'd encourage you to go check out this paper.
Now, a couple other cool things that they do here are at one stage they have this allylic alcohol,
and so what they plan to do is oxidize this using manganese dioxide to the α,β-unsaturated ketone,
but when they did this reaction, they got a different product that they characterized by x-ray crystallography,
and it actually turned out that they formed this bond,
which was actually something that they were wanting to form later,
and so they unintentionally were able to do this,
and simultaneously this alcohol was able to engage and form a C-O bond here, so that's kind of interesting.
We have a couple new ring systems formed unintentionally when just trying to oxidize an alcohol to a ketone,
so this is kind of cool.
Another cool reaction is their use of samarium iodide here,
and so they go from this ketone to this hemiketal shown here,
and the way that this works is the samarium iodide is able to reduce this ketone to an alkoxide as well as a carbanion,
that carbanion is then able to eliminate off this alkoxide, and then upon workup,
the enolate and the alkoxide are both protonated, and the alcohol can engage the ketone to form this hemiketal.
Another reaction that's not as noteworthy, but I thought I'd point out here in case anybody's not familiar with it,
is they utilize Barton–McCombie deoxygenation, and they use triethylborane as their radical initiator.
And so, if you ever have an undesired oxygen,
one clever trick that you can use is Barton–McCombie,
this is relatively old chemistry,
although it was used in this case and I just thought I'd briefly highlight it.
And so, the fifth paper for today is the tricarbonyl-ene reaction.
And so this is kind of a cool paper, they do an in situ process to generate their tricarbonyl species,
and then they spontaneously undergo a carbonyl-ene reaction to form this 1,3-diketo-2-alcohol species,
and they also demonstrate this scope on a range of different tricarbonyls that they generate in situ,
and they also convert those products into a few different derivatives.
So essentially, the way that this works is it utilizes a reaction known as Golec oxidation,
which I wasn't familiar with before recording this episode,
where an aldol adduct is able to get oxidized first to the 1,3-dicarbonyl,
and then subsequently further oxidized using DMP to a 1,2,3-tricarbonyl species,
and once this is generated it just spontaenously undergoes an intramolecular ene reaction,
which is kind of cool.
If you'd like to check out the Golec oxidation, you can check out this paper shown here.
So here you can see a number of different aldol adducts were used, although they could also use β-ketoesters,
and these could be converted in situ to the 1,3-dicarbonyl in the case of the aldol adducts.
You can see that these were cyclized from 39 to 40, for example, to form the 1,3-dicarbonyl with the alcohol as shown.
Now, in addition to the main papers that I discussed today, I want to give soem honorable mentions.
The first one is the conversion of phenols to benzoxazoles,
this is kind of interesting chemistry, even thought it's somewhat limited;
additionally, there is the synthesis of cyclopropylamines from cyclopropanols from the Rousseaux group;
the use of BCPs from trifluoroborates with propylene from the Molander group was also demonstrated;
it's also worth noting that inpyrfluxam was developed and there's a good OPRD article about the process,
I'd encourage you to check that out;
additionally, the asymmetric cycloaddition of 2-indolylalcohols was demonstrated by List and co-workers;
we also saw the asymmetric sulfinimine Mannich reaction,
which I'd encourage you to check out, from Maryasin and Maulide and co-workers;
additionally, the final paper I wanted to mention today was
the conversion of trifluorotoluene derivatives to functionalized analogs,
where just one of the fluorines is removed and then you can diversify what's connected to it,
I really like this one from Bandar and co-workers,
although I'm a little bit biased as a fluorine chemist.
So thanks for watching and have a great day.