Welcome to part 13 of the lecture on designing organic synthesis. Subject of today are aromatic heterocycles or we can use the term hetarenes.

That's a bit shorter so we already know that 1,4-dicarbonyl compounds

are nice starting materials for the synthesis of five-membered hetarenes. For instance just treating those diketones under acidic catalysis

a condensation reaction might occur giving rise to the corresponding furans.

With primary amines also under slightly acidic reaction conditions so mild and maybe buffered

otherwise under strongly acidic conditions you just have formed the ammonium salts and

the reaction won't occur anymore. So under mild buffered reaction conditions then also condensation reaction occurs minus two equivalents of water and the corresponding

pyrroles are formed. Actually this kind of procedure is called the pal-knorr-pyrrole

synthesis. With hydrogen sulfide also again under acidic catalysis then we will get

thiophenes as the result and you certainly remember that we would synthesize these one four diketones making use of the corresponding enolate or enol and

well with a second starting component we need a leaving group for instance a bromide here.

Here we form the nucleophile this is then the electrophile. Other more recently invented

methods for synthesizing furans will follow. Here we have a nice one a palladium catalyzed process

2.5 percent palladium acetate while there is 10 percent triphenylphosphine ligand present

a reaction is performed under acidic reaction conditions in acidic acid and there is

1.1 equivalent benzophenone or not benzophenone of this quinone benzoquinone

resulting in this case in this mono substituted furan. So for instance with R is this substituent an 89 percent yield was reported. So what might be the mechanism?

Well as you know from the WACKER process olefins can be activated for the attack of nucleophiles for instance water in the WACKER process by the influence of a palladium

2 catalyst. So the electrophilic palladium 2 catalyst will coordinate to the double bond activating for a nucleophilic attack and here we already have an internal nucleophile

our acetic acid will be eliminated and with this intermediate we are still at the stage

of a tetrahydrofuran derivative but we have leaving groups a better hydrogen elimination

either to this position or that just let us choose this one and then

under acidic catalysis and we have acidic reaction conditions an isopropanol is also eliminated and driving force is for formation of the aromatic furan system.

Okay so what is that benzophenone good for? Well we have a formally palladium 2 intermediate

here but this is certainly less electrophilic compared to palladium acetate the hydro

palladium acetate is less electrophilic we have to reoxidize that this plus

so what will what will happen to the benzoquinone our hydroquinone will be formed then palladium acetate again

and what we of course still need is acetic acid so and then it should be also

stoichiometrically correct so and the palladium acetate again is the active catalyst going into that catalytic cycle again. Very similar is the next example now instead of

an olefin we have an alkyne well it's just one double bond equivalent more

okay therefore you don't need another leaving group there and it's again are activated with a lewis acid zinc chloride is used as the lewis acid coordinating

to that acetylene and here that oxygen is again from the ketone the

internal nucleophile and finally this product will be formed and you will notice of course that this idea is very similar to the one we have discussed before

and the next one is even more close to that one in this case two percent

of a gold salt a gold chloride is the catalyst with the same result and not surprisingly

the reaction also works with this epoxide and in the corresponding publication

a silver catalyst silver salt as a catalyst was used and i'm pretty sure that it would also work with a gold catalyst in this case and presumably also with a platinum catalyst.

These are rather recent examples for new furan synthesis however what are the industrially most important furan synthesis

I think this is highly interesting. Well you start from phantoses regardless which stereochemistry well because a complete stereo randomization

takes place well not randomization it's it's stereochemistry is destroyed of course with simply treating with sulfuric acid heating it up a bit three equivalents of

water are eliminated so that delivers

furfural produced in high quantities very cheap material similarly glucose under

same reaction conditions will give this hydroxy methyl substituted for fural with

zinc chromite at 400 degrees so a heterogeneous catalyst and a high temperature reaction

carbon monoxide is evolved and we will receive then the parent furan as the product again

an industrial scale synthesis treating this with ammonia also at elevated temperatures

and silica or aluminum oxide as catalyst will produce the parent furan.

Let's have a look at the synthesis and also retrosynthetic analysis of this

annihilated furan it's not a bands of furan since this ring is unsaturated. So retrosynthetic analysis following the initial idea we have outlined on the first

blackboard will lead to this intermediary product again simply h plus heating up

eliminating water will produce that from from this one so and here well we could

either disconnect here as r1 having the leaving group x there or well both is r1

let's call it r1a and r1b of course you could also choose the opposite

this combination however taking cyclohexanone plus this and treating that with the base

while there we should add a question mark because the base could also deprotonate here

and and so on we would get some problems concerning selectivity. Therefore it might be much better applying for instance the tms enolate or alternatively for instance

such an enamine but these are preparative tricks you already know we discussed that before.

A classical pyrrole synthesis we will analyze targeting for this structure e should be

an astral functionality we don't care is it a methyl or an ethyl astral. The analogous

retrosynthesis will of course lead us again to a 1-4 di ketone or we could

think about it stepwise no the other way around having that as an intermediate or as

an isolated reagent and this would then derived from this one so now i found it interesting

that if we have this within our retrosynthetic analysis we could also think about that this has

that there is an alternative with a double bond at another position here at this position so

and then you have an alpha beta unsaturated ketone that this could help to simplify the structures we are dealing with we would get to this one hoping that we could

get an aldol condensation here and then another condensation there. However if we would try that

we have several problems again what about the selectivity of deprotonating here compared to that one okay the amino group is sitting here on the other hand this is rather sensitive starting material since we have an amino and a carbonyl functionality in the same molecule and

in term molecular this could of course as a starting material already form condensation products but nevertheless this analysis could have to help to develop ideas how to synthesize

that and therefore now let's have a look what the real synthesis looks like

acetoacetic acid ester was reacted with acrylic acid ester under

basic reaction conditions and this then gave the corresponding

Michael adduct this one let's call that structure a then again

same starting material treated with sodium nitrite and diluted hydrochloric acid

all same reaction conditions you would use for forming a diazonium salt and then

azo coupling nitrozeal cation is formed as the electrophile which will react with the corresponding enol reacting as the electrophile at this then nucleophilic carbon the nitrization

occurs oh sorry first of all that nitrozo compound is formed which then

titomerizes to give the oxime let's call that structure b if you take a plus b

and put it into acetic acid and add stoichiometric amounts of elemental zinc a zinc powder to it

then hydrogen in statunacendi will be formed reducing the oxime until the stage of the amino functionality and that condensation process will take place

we don't need the nh3 and ammonia anymore because we form the amino functionality by

reduction this is oh well okay i'll call it t is the target molecule this is one example of the knor pyrolysis well mr paul was not involved in this pyrolysis um well if you notice

acetoacetic acid aster as a starting material in hydrocyclic synthesis you can be sure

it is a classical heterocycle synthesis synthesis from the 19th century or acetoacetic acid aster was used rather frequently since this is a nice starting material

and it is easily synthesized just from the corresponding

acetic aster as the condensation treating it with the sodium alkylate

and easily produced then of course after um hydrolysis under mild reaction conditions

another classical pyrolysis synthesis is the hunch pyrolysis synthesis and also starting from

acetoacetic acid aster plus ammonia forming this enamine and then you have this

alpha functionalized carbonyl ketone nucleophilic substitution tautomerization

than condensation and finish of the synthesis synthesis well actually that hunch pyrolysis

is essentially the same as the park nor pyrolysis just the um which step comes first has changed so enamine formation is here the last step

and there it is the first step here it is an enolate that reacts with this and in the hunch pyrolysis synthesis they already have an enamine here okay but the reaction principle

the idea is always same i think so let's have an exercise please try to develop an idea

how to synthesize this target molecule so you already have developed a lot of ideas and as i

again should point out well there are a lot of possibilities to synthesize such a molecule now we will think about what would be most straightforward

well most straightforward should be somewhere disconnecting centrally however the most sensitive part of that molecules might be this here this yodo substituent maybe this compound becomes light sensitive or so one can think about first

for instance disconnecting here because it will um oh well let's let's write it out it will lead to a nice simplification or first get rid of the yodo substituents

so the most nucleophilic part of these molecules are indeed

these awful positions to the hydroxy group at least if you work in basic medium where you deprotonate the phenol the phenolate will be yordinated here this will work out highly selective and then you would disconnect here so both sequences

will lead to essentially the same starting materials it's just the decision when will you

do the iodination already with that one or after the Friedel-Crafts oscillation there are arguments for both what important is that one should think about the

Friedel-Crafts oscillation because well you have of course the alternative

making that type of disconnection but then you have a highly functionalized molecule a lot of functional groups okay means that there are

potentially a lot of competing reactions that could occur and this step from here to there or from here to there and there it's especially this Friedel-Crafts reaction

real simplification then of the starting compounds and this will be a highly selective

reaction because what else should happen while one might think about does that work with the OH group but i looked it up in in literature yes you can do the Friedel-Crafts oscillation with this phenolic hydroxy group

present well then we should think about how to synthesize this sorry okay it's

two awful bands of Iran well if you don't need to synthesize ring system you just can

buy that it's not a bad idea so why not here donator reactivity

there the acceptor reactivity unfortunately you can't translate that simply to benzofuran

and bromoethane and thinking about a Friedel-Crafts alkylation because the benzofuran will be selectively calculated in the three position therefore you should increase the nucleophilicity of this position yes you can do that

by the lithiation of simply benzofuran with n-butyllithium it will be deprotonated or

metalated here in alpha position to the oxygen this works plus bromoethane and this reaction

has been performed and the result was an 84 yield of this there is an alternative

that has also been chosen for the synthesis let's add a carbonyl group we can reduce that

carbonyl group simply under basic conditions with high design this is

the so-called valv-kishner reduction you might remember and it has been done for that in this case with 90 yield this molecule you don't get by Friedel-Crafts assimilation again with

benzofuran electrophilic aromatic substitution takes place in three position but now you have

the opportunity to disconnect this double bond of the alpha beta unsaturated ketone

well okay and from here you could disconnect there and our retrosynthetic analysis

leads us to zolic-zolic aldehyde which is cheap plus that functionalized acetone with the leaving group there and indeed this condensation reaction has been applied 85

percent yield so very good yield simply treating this molecule with potassium carbonate

25 minutes at 100 degrees in polyethylene glycol as solvent

okay i think that's enough for today thank you for listening see you next week tuesday