Welcome to the lecture on catalytic organometallics, part 14. The subject of today is gold catalysis. Well, gold is of course a noble metal, a precious metal,

and is renowned to be rather inert. It is not oxidized at air, for instance. And this inertness is restricted to elemental gold in the oxidation state zero.

That is certainly not true for gold salts, gold in higher oxidation states. And we will see that these gold salts, gold in the oxidation state plus one or plus three, is exceptionally active as catalyst.

First example, here we have an acetylenic moiety, and we treat this compound with gold III chloride,

just 2% catalyst in a methanol water mixture, reflux temperature, one hour.

And we will receive or obtain a 92% yield of the addition product,

Markovnikov addition product of water to the acetylene, while the enol, intermediary enol, will then tautomerize.

We will have a look to the mechanism very soon. Let's compare this reaction to a similar one.

An olefin, palladium dichloride, about 5% catalyst, copper chloride, oxygen present, DMA as the solvent, solvent 80 degrees, 3 hours.

And in this case, also the ketone is formed. We know this reaction as the Wacker oxidation.

Similar results and, well to some extent, similar mechanisms. Let's compare the mechanisms of these two processes. So, in the Wacker oxidation, a palladium II salt coordinates to the olefin,

as we have already discussed in detail.

In case of the gold chloride, we have an acetylene, and the gold salt coordinates to the acetylene, diminishing here the electron density,

just as the palladium chloride does for the case of that olefin. And thus, the substrate is prepared for the attack of a nucleophile, in this case water.

In both cases, Makovnikov addition,

here an aureate as intermediate, there a pallidate.

Now the next step is a bit different. Here, we eliminate HCl in the case of the aureate.

A protonation at this center is assumed,

initiating essentially an ipsosubstitution of the aureate.

So, we have an aureate. Here, in this position, we have a carbocation, which is stabilized by conjugation with the OH group. Well, however, very simple, the aureate delivers the electron density.

The active gold III catalyst evolves again

with the intermediary product formation. Well, last step is, of course, the tautomerization.

So, and here in this case, well, the better hydrogen elimination is giving rise to the enol, and the hydridyl palladium chloride,

which then has to be reoxidized. Well, therefore, we need, in that case, a copper co-catalyst and the oxygen as the oxidizing agent.

Here, in this case, for the reaction to proceed, we do not need additional reagents, no additional reoxidation. This is typical for most gold-catalyzed processes.

So, what we have learned is that gold chloride very well activates electron-rich acetylenes for the attack of a nucleophile.

It can also activate olefins for the attack of a nucleophile. So, some examples. Propagolic alcohol.

Well, in this case, we have an OH functionality, which could be a nucleophile. And here, the acetylenic moiety, which will be activated by a gold catalyst.

It won't react intramolecularly, but two equivalents of the allylic alcohol could react with each other, and they do it, indeed, well, with methanol as additional reaction partner,

55 degrees, 20 hours reaction time. This reaction has been developed in industrial labs,

in this case, the BASF.

93% of this product can be isolated, and it is, in this case, a gold-1 catalyst,

and just 0.0000, well, one's zero too much, but it's a tiny little amount of a catalyst, 0.001 mole percent of that catalyst.

So, the other examples we will discuss today have some more catalysts, but at the maximum of 5 mole percent. Not only oxygen nucleophiles react,

also an amination becomes possible. Gold III chloride, 5%.

Acetonitrile is very often used as a solvent for this type of gold catalysis. Reflux, one hour reaction time.

An amination, hydroamination of that triple bond occurs, forming an enamine, which then tautomerizes, resulting in this amine,

which is already an alkaloid, known as natural product.

So, Lenupsin A obtained in a 90% yield.

These kinds of hydroamination reactions, of course, also work with far more complicated structures, and one of these structures has been set up with a very nice domino reaction, a multi-component domino reaction,

valine as an amino acid, then benzaldehyde with an alkyne moiety in the alpha position.

In addition, the third component of that process, which is not gold catalysed,

it's just a process which is running with those ingredients, this is an isonitrile, and we need methanol as solvent,

and at the same time also one participant ingredients of that reaction. About 70% yield is obtained at room temperature,

with rather high diastereoselectivity between 5 to 1 and 10 to 1. Structure of the product is this.

So, a marvellous reaction, and this is the stereogenic centre,

which is formed with rather high diastereoselectivity, initiated by this initial stereogenic centre, and since this is a four-component reaction,

and has been invented by Iwa Ugi, it's the Ugi four-component reaction. Well, the Ugi group invented, I think,

also multi-component reactions up to seven components, which react with each other to form rather a nice product with high complexity. So, here we now have a set-up of an alkyne moiety,

intramolecularly offered that amine functionality for the hydroamination, and with 3% gold chloride,

again aceto-nitrile, six hours, the hydroamination occurs, in this case in two directions,

the six-andodeg cyclisation and the five-axodeg process. The six-andodeg process, of course, gives a six-membered hydrocycle here.

So, selectivity two to one,

the five-axodeg product initially is this one.

However, it's not isolated. You can imagine you have the gold chloride acidic conditions.

If you protonate here and deprotonate there, then a fully conjugated system is formed.

So, ratio two to one, overall yield is depending on R, 70 to 80%,

and this structure here is then a so-called isoindole, the first isoindole with, well, a chiral centre attached close to this reactive diene system.

So, an isoindole, in this case an autoquinonoid heterine, that's the way you should classify that, and you can imagine that this system likes to react in a Diels-Alder reaction

at these two positions because it gains the aromaticity of that benzene ring. Well, and then you can study the influence of that chiral centre

of the diastereoselectivity of a Diels-Alder process. So, a very interesting molecule. Let's have a look at other examples. Now, examples with oxygen.

Again, oxygen nucleophiles, not water or methanol, but now carbonyl groups and nucleophiles which are offered intramolecularly. So, we need the carbonyl group and the acetylenic moiety.

Intramolecularly connected and, well, mainly gold chloride as the catalyst. So, this acetylene, as well as the corresponding allene,

both react to the presence of gold chloride, 1%, aceto-nitrile at room temperature to give a quantitative yield

of this substituted furan. So, you can imagine the gold chloride coordinating at the acetylene,

then three electron pairs of the oxygen, one three electron pair will attack here. So, one, two, three, four, five, a five-membered ring is formed.

Another interesting example with an allene. Moiety, you know, allenes can be chiral with a chiral axis.

In the preceding semester with stoichiometric organometallics, we have talked about systems like that,

thoroughly investigated by Norbert Krause's group at our neighboring university Dortmund, and indeed, this is an example from Norbert Krause's group. Again, gold chloride as a catalyst,

catalytically, while room temperature three hours, or dichloromethane in this case as the catalyst. All the gold chloride coordinates to that double bond,

activates for the nucleophilic attack here, and afterwards an ipsosubstitution will take place and restores the gold catalyst and puts in a proton at that position.

So, tertiary butyl group here, and there is a methyl group.

Well, 95% yield, so this is a reaction which works very well.

Now to a substrate. The process is a bit more complicated. The Es symbolize ester functionalities, ethyl esters in this case,

but it could also be methyl esters. We have 5% gold chloride, acetonitrile, 80 degrees, three hours.

Actually this type of reaction sometimes works even better with platinum chloride as a catalyst.

The resulting product looks like this.

Obtained again 95% yield. Well, spectroscopically interesting.

This proton experiences a significant downfield shift in the proton NMR to delta 9.43 ppm.

Well, because of the anisotropic influence of the free electron pairs of oxygen here. So I think a remarkable reaction. You have to think about that mechanism.

As a net result it is clear that initially we had an oxygen bound with a double bond to that carbon and later on the oxygen is again double bound to a carbon but this one.

So it migrates from this position to that one. Strange reaction. So how is this possible?

As we have already discussed, gold chloride, the Lewis acid, coordinates to the triple bond, might coordinate here and there, but in this case if it coordinates here, then that oxygen is already in close proximity forming this intermediate.

All this intermediate certainly profits from the fact that the benzoperillium cation is formed with that internal rate

as we encounter an ion and as you know, perillium moiety is an aromatic system. So it then undergoes an intramolecular Diels-Alder reaction.

At least this was the first interpretation of the result we later on see.

So here we have the acetylene as the dienophile. Here we have the diene system.

Well it is then a Diels-Alder reaction with inverse electron demand because an electron-poor heterodyne and an electron-rich dienophile.

The opposite as what we are used to, but nevertheless this is known, this is possible. Connecting the Diels-Alder reaction will connect this position with that and this carbon with that one.

So let us try to draw the result.

So and clearly this is a strained system and now the O-rate can deliver this electron pair

with the result that at this six-membered ring, well aromaticity is introduced

and of course the positively polarized oxygen. Well it is not really positively polarized, we know that. This bond will break. We have the benzolicate ion here and the electron density is filled up here with forming the aromatic naphthalene system.

Yeah well that's it. All what I have to draw is this, that result you see.

Here we have that six-membered ring with the carbonyl group and there is that annihilated benzene system, so resulting in the naphthalene.

Okay, nice mechanism until, and I think it was again Antonio Eshavaran's group who made some calculations in this type of reactions

found out that presumably it's more complicated, not just a simple Diels-Alder reaction but you can understand the structure, of the reactivity of that structure

by drawing a mesomeric structure of it, a 1,3-dipolar mesomeric structure with a gold-cabin complex as part of this structure.

So plus here, minus there, just as a mesomeric structure

and this should then undergo a 1,3-dipolar cycloaddition process

which is according to the calculations of the Eshavaran group,

the one that should be faster compared to the Diels-Alder process. So the next intermediate does not make things easier

but it explains that in certain cases, in certain reaction conditions

such a structure has been isolated and identified by X-ray crystal structure analysis not with a gold chloride sitting here but with a keto functionality. These by-products, minor by-products are then explained by this mechanistic model.

Well, do we get from here to there? Well, this is a carbine complex and carbine-matter complexes to some extent react similar to carbenes.

They can undergo insertion reaction and well, in this case simply assume that this bond migrates to that. This is some kind of insertion to this carbon.

This is some kind of insertion reaction. The oxygen delivers electron density.

Then this C-C bond breaks and a new C-C bond is formed

with the electron pair of sitting at that carbon and connecting then this carbon with that one

and an R-rate is formed. Well, it sounds complicated but please think about it at home. The result of this process simply is this structure.

Therefore, one should better draw this arrow with dotted lines since the calculations and some by-products

tell us that this should be the reaction mechanism which is more close to the truth.

Here we see we can easily form in just one reaction step from the functionalized benzene such an annihilated ring system and of course this type of process has been used to synthesize some natural products.

So five percent gold chloride dichloromethane 50 degrees one hour.

So, again it's all the time the same mechanism. A benzoperillium system is formed.

The oxygen forms a single bond to that and then, well, a complete double bond will break here and the oxygen migrates to this position and intercepted by a somewhat strange Diels-Alder reaction

which presumably runs via a 1,3-dipolar cycle addition reaction and additional rearrangement involving a gold-cabin complex.

So, 84% yield of this. It's on the way to a natural product. You only have to get rid of that methyl group having an OH group here and oxidizing this to the paraquinone system.

Then you have a natural product.

Similar case, the TBDMS group at that oxygen. Now five percent platinum chloride.

As I said, it reacts similarly. Dioxane, a solvent 120 degrees three hours.

And secondly, with HF, aceto nitrile, the siloed protecting group is removed.

So this is heliothanantrone. And one last example, an approach to steroids through this type of process.

Well, of course, it takes some time to synthesize the appropriate model compounds.

Three percent gold chloride and aceto nitrile 80 degrees.

Then the ABCD ring system of a steroid moiety is formed already with a methyl group sitting at the right position.

This was a racemic synthesis.

Nevertheless, this as a racemate was the main product. 62% yield while the byproducts were, for instance, elimination products with a double bond here. Nevertheless, you want to eliminate and then do a hydrogenation to form the right stereochemistry of the enolate ring system.

But again, a nice reaction and I would say some kind of homework. Just write down in one or two cases the mechanism of that reaction that you really understand how you get from here to there.

So all those examples we have discussed are those where the acetylenic moiety is activated for the attack of an oxygen or a nitrogen nucleophile.

Of course, highly interesting are carbon nucleophiles for using them to form C-C bonds with gold-catalyzed processes.

This will be the subject of tomorrow's lecture. Thank you for listening. See you tomorrow.