Welcome to another part of lecture on designing organic synthesis. Subject of today are carbon heteroatom atom bonds as strategic bonds,

especially CO, CN and CS bonds are often to be regarded as strategic bonds

since they are rather easy to make nucleophilic substitution reactions in general.

So let's start with one example, this one, a dichlorophenyl amide.

In fact, this is an early herbicide and let's think about the retrosynthetic analysis.

Well, let's discuss first the disconnection of this CN bond. And systematically, we would now start with the synthons.

As a synthon, here in this position, we would need an acceptor reactivity and on the other hand, we would prefer a donator reactivity here

since this amide moiety would be easy to deprotonate there and then we have, of course, the nitrogen as an anionic nucleophilic center.

So, this is no problem since we can translate that into the propagolic amide

as the substrate to be used, the reagent to be used, just deprotonate as I said and acceptor reactivity, you can just put on an X as a leaving group.

Of course, there is a problem. As you know, SN2 and SN1 type reactions don't work at ASPI2 hybridized centers and here a substitution would be a nucleophilic aromatic substitution.

This works best if you have, for instance, some nitro groups attached in addition. Then it could work. Here you have a problem. You don't want to have the arene mechanism of the nucleophilic aromatic substitution.

So, directly just deprotonating here, putting it together with, for instance, X-sabromide wouldn't work. However, transition metal catalysis or transition metal induction

can help to solve the problem, open up another reaction pathway and copper catalyzed, or sometimes copper induced, that is an Ullmann coupling process.

In that case, it works and meanwhile there are also some palladium catalyzed reaction conditions

known, mainly developed by Buchwald and Hartwig at MIT and Yale.

These are very well known reactions meanwhile. So, these would work and you get hands on that compound. So, as I said, this is rather early herbicide

and therefore they certainly didn't make use of this type of reaction conditions for the synthesis. They certainly had another way. Let's analyze further. Maybe we get the idea.

So, let's see, what about R2? So, in that case, here, donator reactivity and on the other hand, acceptor reactivity.

Here, as Sunfens, wow, we can save some time in just translating.

For instance, that chloride or better, let's put on better an X and X could be a chloride but also could be a carboxylate.

So, that would mean we would apply an anhydride instead of a chloride and for industrial purposes, large scale reactions, well, an anhydride very often is far better

because you avoid the formation of HCl or some salts, you know. So, in here, simply applying that aniline.

So, an oscillation of an aniline with an anhydride, carboxylic acid anhydride as a reagent is no problem at all, standard reaction. So, this is classical retrosynthetic analysis you have already learned in OC2.

So, if we start with aniline and we try a chlorination,

then we would get para and ortho selectivity and we would have some problems in stopping the reaction because, well, normally you get multiple chlorinations in that case. But on the other hand, well, better introducing the amino group

and having in mind we could not, we cannot introduce that directly but in another oxidation stage. So, let's interconvert that functional group simply changing the oxidation state.

Well, at this retrosynthetic step we call functional group interconversion and now it's easy to simplify this intermediate

and it's just a nitration reaction. So, with our retrosynthetic analysis we just got back to the ortho dichlorobenzene

and this is of course a reduction step.

Now, you might say, well, isn't that a problem? How do we get selective that ortho dichlorobenzene? Well, you don't get that selective by direct chlorination.

However, as it turns out, if you do the chlorination of benzene, this is remarkable unselective. You have a lot of para dichlorobenzene

besides quite a good amount, similar amount of that ortho dichloro and somewhat less the meta dichloro compound. You get a mixture, but you can separate that mixture,

for instance, by distillation or crystallization. No problem. And if you do that as a company on a large scale and you need preferentially this one, you might also find an application for that one.

And this was mainly the solution of the problem at that time. Finding applications for all isomers, and then it's not a problem that you don't get that selectively

since this is a rather cheap process, the direct chlorination of benzene. As an exercise, please try the retrosynthetic analysis

of this target molecule. Systematically, if you want to define our symptoms, we would, for instance, disconnect here

and have acceptory activity, donatory activity. Nevertheless, no problem. In first of all, writing down this type of acid,

phenolic acid, but later on thinking about the reactivity of that. And on the other hand, the tertiary alcohol.

Well, directly treating those together under the influence maybe of some sulfuric acid will cause some problems since that tertiary alcohol in benzylic position will tend to,

will show a tendency for an elimination reaction from an olefin here. You need something more reactive here. In fact, what is I think even cheaper as that,

if you can buy that at all, is the anhydride. This is the hydrolysis product of the anhydride. And the anhydride has a sufficient reactivity

of directly reacting with the tertiary alcohol. And if you add, for instance, some base, then for sure the reaction will work. Those two together.

So, why is this so cheap? How is this anhydride produced? Maybe some of you remember that was also part of organic chemistry too.

Oxidation of naphthalene with molecular oxygen, think at the silver contact at higher temperatures, then you oxidize one of those rings.

Here you have two electron rich rings, far more easy to oxidize than this one, where those carbonyl groups, mesomerically, diminish the electron density here.

Therefore, you can stop the reaction at this oxidation state. So, molecular oxygen as the oxidizing agent,

naphthalene as the substrate, and with some technical tricks like silver catalyst, heterogeneous catalyst, then it works. Short contact, gas phase and catalyst, that's the way to do it. Because of course you can further oxidize that,

but this literally means burning it, until you have CO2. Well, we should have a look at that one, how to synthesize this.

Well, OK. Donator reactivity, acceptor reactivity here, and these symphons are then translated to acetophenone,

and for instance, an ethyl Grignard reagent. Well, if you would analyze how do we get this one, OK, acetophenone you can buy, but it is made by a Friedel-Crafts oscillation,

of course. Next example, a very simple one.

It is part of a parfum oil.

Please analyze this one. Certainly easy to figure out, retro, the retrosynthesis or synthetic plan then for that,

but maybe it's a bit more difficult to figure out which way to synthesize that is the best one, because you have the first glimpse,

the choice, disconnecting here or disconnecting there. So please try to figure out which one is the better one. In this case, the retrosynthetic analysis is straightforward.

Just let us just write down the preferred starting material. Here either the benzyl chloride or the benzyl bromide and an alkylate as the nucleophile,

that sodium alkylate for instance, or on the other hand R2, we have the sodium alkylate of the benzylic alcohol

and again the leaving group X here.

So which one is better? Well, presumably you would try to avoid the tosylate as the leaving group, because then the leaving group has already more molecular mass

than that part you want to transfer. So in the context of atom economy, this is not a good idea in that case. Well, actually there's a simple reason

why this should be preferred. In that second case, you have a potential competing reaction which you don't have there, the elimination reaction.

You often alkylate. It could induce an elimination reaction, E2 elimination reaction. Here elimination reaction is not possible.

So that means you presumably have a much cleaner reaction in this case. Well, let's have a look at some difunctional target molecules.

For instance, 1,1-difunctional. An easy example, simple example is this one, just an acetal.

You have two functionalities at one carbon, two ether functionalities and overall we call that an acetal. And of course you know how to make these. An acid-catalyzed acetalization.

Another example for 1,1-difunctionalized targets are amino acids. There are of course several ways for synthesizing amino acids.

One possible way is in the retrosynthetic analysis functional group interconversion to convert that acid into an acid derivative.

For instance, a cyano group. A hydrolysis of a cyano group under somewhat harsh reaction conditions

will deliver a carboxylic acid here. And finally then this amino acid. So, and one could imagine that this can be formed in a three component reaction

where you have an aldehyde, HCN and NH3.

Or a primary amine, then you would have an additional substituent there.

So condensating, condensation to an imine and then, well, protonation by that and the cyano group attacks as a nucleophile. Well, this kind of reaction is known since,

I think 1850 or so, it's the Strecker synthesis. The Strecker synthesis of amino acids.

A 1,2-difunctional compound or target, 1,2-difunctional.

For instance, this type of amino alcohol. Also in this case can be a good idea for applying a functional group interconversion

while in this case also changing the oxidation state.

For instance, this one.

This leads then back to the starting compound cyclohexanone and HCN or maybe using potassium cyanide and later on acidifying.

So in this case we have changed the oxidation state of that carbon from here to there

and here we have simply a reduction. But one could also, thinking about just changing the oxidation state of that nitrogen here,

also not a bad idea. Again, you would start from cyclohexanone,

applying in this time nitromethane under basic reaction conditions. This would be a nitroaldol addition reaction.

So nitroaldol addition.

Just by the way, this is an interesting substrate for a rearrangement process.

As you might already know, the tifenor rearrangement, aqueous diluted HCl and sodium nitride

are forming the nitrozeal cation and diazonium cation here at this position

and then the rearrangement reaction would take place, which leads to a ring enlargement, a seven membered ring, start from a six membered ring,

a few simple steps and get to the seven membered ring. So this is an example of a tifenor rearrangement. Some other rather short retrosynthetic analyses.

This one. Well, OK.

Maybe this could also be an example for a very simple bidirectional analysis,

because you can easily get the idea buying something that has these skeleton already. And this is antronylic acid.

So what you need, if you have already chosen antronylic acid as your starting material,

you need a symptom with two acceptor positions side by side.

Yes, it could be that 1,2-dibromoethane.

On the other hand, well, one could also think about ethylene oxide. Of course, choosing then the right reaction conditions for that. You know, that is a gas.

And you will first easily form the CN bond here, but then you have a secondary alcohol and you will have to form the seven membered ring intramolecular esterification, maybe with phosphoroxychloride induced.

OK. But that was certainly easy. Let's analyze this structure together.

It's called salbutamol,

and it's a drug against asthma.

Of course, we could start with disconnecting here, the tertiary butane group. But certainly it's better,

or on the first glimpse looks already somewhat better, since the synthesis becomes, gets more convergent character if you disconnect there. So let's write that down.

So, acceptor reactivity here, since with the amine, you already have the deunator reactivity as the natural reactivity at this position.

So tertiary butyl amine would be one reagent, of course. Now we have to look for synthetic equivalence of that one.

Well, there is already an idea implied by that epoxide. So imagine, you could translate that, of course, in this.

But, with the base, the presence of a base,

which could, this could eliminate HX, having this epoxide as an intermediate.

Or, on the other hand, this should be rather sensitive. An epoxide at a benzylic position, it opens up rather easily,

and this benzylic iron is then, even better, stabilized by the mesomeric stabilization with that phenol group.

Okay? But it might not be that bad. On the other hand, we could change the oxidation state here,

and we'll get to that structure within our retrosynthetic analysis.

So, for the synthesis, we can say, okay, we synthesize this first, then let that react with the aniline,

not the aniline, with the tertiary butyl amine, then reduce the carbonyl group to the alcohol. It's not necessary directly reducing that to this structure,

and then letting that react with a nucleophile. Actually, if we need to introduce a reduction step, this might help to solve other problems, for instance, where does this hydroxymethyl group derive from?

You can introduce a hydroxymethyl group by a reaction called hydroxymethylation. So, a hydroxymethylation in the presence of this aceto group

maybe won't work, since the hydroxymethylation could also proceed here. It's a simple aldol addition process, followed by an aldol condensation.

And all those problems you can solve if you just get the idea that you can get an hydroxymethyl group by a reduction of a carboxylic acid. So, you need to reduce this carbonyl group.

Why not reducing another group, a carboxylic acid at the same time in one step, leading to that hydroxymethyl group? And then, having these ideas in mind, you will get to this structure.

This can be synthesized. So, the transformation from... Well, you would first brominate here. Yeah, okay. Bromination here, then reaction with the tertiary-butyl amine,

having the amino group there, and then reducing with lithium aluminum hydride. And you will then already get to that structure. So, very simple. And how to synthesize that?

Well, okay. Here you have the moiety of salicylic acid, and you need an acetylation. You can indeed start from acetyl-salicylic acid.

You know, this famous drug against headache. And think with aluminum chloride, you get that rearrangement done.

Essentially, it's a Friedel-Crafts acetylation power position of that phenol. The last retrosynthetic analysis for today,

this time as an exercise. And as you will see, this is already strongly related to the salbutamol synthesis.

This is an intermediate also in the synthesis of a drug for treating, I think, also asthma or similar diseases.

Please try retrosynthetic analysis. So, following the idea that we have outlined already here with that, amino alcohol. It's certainly a good idea to get the first disconnection here,

right in the center, forming two parts of a very similar size.

So, and to get a shortcut here,

we just say, well, let's take the epoxide in this case. Also in this case, that epoxide is somewhat sensitive, but it's less sensitive as in the case of salbutamol synthesis,

since we have the phenol protected here. So, with our age group here, it would be especially acidic, and we could get, well, an acid-driven ring opening there,

forming a power quinonoid intermediate, which then will tend to polymerize, for instance. So, these would be reactions that could occur, exemplifying the sensitivity of that system with an OH group here.

Here, with a benzoyl protected one, it's, of course, somewhat better, less sensitive. So, and on the other hand, this one.

Well, unfortunately, synthesizing a drug for treating diseases, which is, has chiral centers, we need it enunciate selectively.

So, how do we get that one enunciate selectively?

The company that synthesized it had the idea, well,

we need that, getting it by reduction of the ketone, and they choose a nice way to separate the enunciomers,

just synthesizing the resomate, getting the acetylated derivative, and treating that resomate with an enzyme, an esterase,

and that enzyme will preferentially hydrolyze one of the enunciomeric esters. So, then, we got this one, and so on.

Here, you see the similarity to the salbutamol stuff. Also, in the salbutamol stuff, we had that alpha-bromoketone. Here also in that synthesis plan.

So, now to this problem. In that case, they also synthesized the resomate, and then separating the enunciomers via diastereoisomeric salts with a chiral carboxylic acid.

You know that from our undergraduate lab, where you had that diamino cyclohexane, and forming the salt with tartaric acid, and separating those diastereoisomeric salts.

So, how to synthesize a primary amine like that? One idea could be, we discussed that,

a reductive amination of that ketone.

But certainly not a good idea for an industrial scale synthesis of that.

For instance, these two starting materials don't look favorable. At least not this one, the bromoacetone.

In a case like that, where you run into some problems, with ideas as outlined as there, just think about that what you need is that type of skeleton.

You don't care about the oxidation state. Just change the oxidation state, and everything might become very easy. For instance, let's change the oxidation state here at the amino group,

and also at those carbons.

So, catalytic, a transition metal catalyst, and catalytic hydrogenation. And maybe you find even a chiral, homogeneous catalyst,

which directly, which also does the hydrogenation, enhances selectively. And at the same time, reducing also the nitro group. Maybe this type of catalyst already exists,

otherwise you try to develop it. And if you don't get that, and then selectively, well, you can then nevertheless separate a racemic mixture. So, and how do we get this one? Well, that should be easy again.

This is a nitroaldol condensation in this direction, anise, or anisic alite,

and nitroethane, and sodium ethanolate in ethanol, heating it up a bit, this will work.

Okay, finished for today. Thanks for listening. Have a nice weekend. Next lesson will take place on next Tuesday.