Lecture Designing Organic Syntheses 12 - 12.11.14
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| Part Number | 12 | |
| Number of Parts | 29 | |
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Aspartate transaminaseHuman subject researchOrganische ChemieHeterocyclic compoundBiosynthesisActive siteEthaneAcetoneWursthülleButylTransformation <Genetik>OxygenierungSodium hydroxideEpoxidationEpoxideHydrocarboxylierungHydrogen peroxideSulfateSaltReaction mechanismChemical reactionHydrogenHydro TasmaniaCombine harvesterPeroxideAqueous solutionFunctional groupChemical compoundSolutionOxideForkhead-GenPotenz <Homöopathie>OrlistatPolychlorierte DibenzofuraneLecture/Conference
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ButcherAreaPolychlorierte DibenzofuraneThermoformingCobaltoxideBase (chemistry)AdenineKlinisches ExperimentChemical reactionSodiumChloroformOxideZygoteDyeingMixtureElimination reactionProteinSteam distillationOxycodonStickstoffatomRedoxFireBuffer solutionGlättung <Oberflächenbehandlung>AusgangsgesteinWalkingChemical structureCombine harvesterGesundheitsstörungTransformation <Genetik>KohlenhydratchemieAcetonePressureAageNitreneLeadSulfurAzideAlkeneRetrosynthetic analysisEthanolAlpha particleThioharnstoffHeterocyclic compoundEpoxideEnantiomereAmmoniumEthaneFunctional groupTriphenylphosphinEpoxidationVerdünnerKetoneLecture/Conference
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ThiolgruppeFunctional groupKetoneDiazoSpaltflächeAusgangsgesteinUreaConnective tissueChemical compoundFireChemistryAgeingSynthetic oilLeakGesundheitsstörungThermoformingLecture/Conference
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CarboniumionFluorideLactoneFunctional groupPhotochemistryMetabolic pathwayBenzaldehydeCombine harvesterIonenbindungWursthülleCarbon (fiber)CobaltoxideHeterocyclic compoundBase (chemistry)Chemical reactionMethacroleinYield (engineering)BiosynthesisButcherOxetaneChemistryLecture/Conference
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MolekulardynamikDiet foodS-Adenosyl methionineRadical (chemistry)Chemical structureCobaltoxideEnzymkinetikChemical reactionMoleculeFunctional groupDoppelbindungSulfurPhenyl groupCyclische VerbindungenElektronenpaarLecture/Conference
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EthanolSodiumProteinActivity (UML)Sense DistrictMoleculeMethanolRetrosynthetic analysisCardiac arrestCarbon (fiber)MuffinWursthülleCondensationMethylgruppeEthylgruppeReactivity (chemistry)EsterCarbonylverbindungenAlpha particleLecture/Conference
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CycloadditionHeterocyclic compoundOximeSolutionChlorideSulfurBase (chemistry)NitrileBromideAlkeneHydrolysatProcess (computing)GlyoxylsäureRacemizationSubstituentLone pairElectronProteinDipol <1,3->ChlorineWursthülleOxideAcidBromineOxideAddition reactionChemical structureHuman subject researchLecture/Conference
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Metallmatrix-VerbundwerkstoffChemical reactionCarbon (fiber)WursthülleActivity (UML)Base (chemistry)ProteinSynthetic oilKlinisches ExperimentSetzen <Verfahrenstechnik>HydrogenCondensation reactionKetoneRetrosynthetic analysisFunctional groupWine tasting descriptorsEnamineElectronAcrylonitrileReactivity (chemistry)Conjugated systemNitrileAmmoniaAlpha particleBeta sheetCarbonylverbindungenMichael-AdditionHydrocarboxylierungEssigsäureethylesterEnolOxideChemical structureOxygenierungConcentrateProcess (computing)CyanidionLecture/Conference
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WursthülleGesundheitsstörungOxideCondensationReaction mechanismChemical structureAldolAcidAcetoneChemical reactionPolymerBase (chemistry)Lecture/Conference
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KetoneSolutionLecture/Conference
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Carbon (fiber)BiosynthesisCondensationGesundheitsstörungReducing agentChemical structureMoleculeAcrylic acidHeterocyclic compoundBeta sheetAlicyclic compoundPyridineAromaticityFunctional groupBenzoylDerivative (chemistry)AmineEsterAlkylationOxocarbonsäurenLecture/Conference
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Computer animation
Transcript: English(auto-generated)
00:05
Welcome to part 12 of the lecture on designing organic syntheses. The subject of today are heterocycles, non-aromatic heterocycles.
00:25
So let us begin with three-membered heterocycles, which one comes to your mind? Of course, epoxides.
00:49
And you can easily synthesize epoxides regularly from olefins,
01:03
or the so-called epoxidation reaction, of course. So you can achieve an epoxidation with peroxides.
01:24
For instance, meta-chloro-per-beno-benzoic acid, MCP-BA.
01:45
Also with, for instance, tertiary butyl hydro peroxide. And in the case of alpha-beta unsaturated carbonyl compounds,
02:08
then H2O2, hydrogen peroxide, in combination with sodium hydroxide in aqueous solution,
02:28
will also give a transformation to the epoxide, than a special functionalized epoxide.
02:40
The mechanism, I think you should know. So the peroxide, the hydrogen peroxide, is deprotonated in equilibrium. This is the nucleophile attacking the alpha-beta unsaturated carbonyl.
03:13
And then it's just the enolate reacting intramolecularly with the
03:26
hydro peroxo group, and that's the mechanism of this reaction.
03:42
So for the direct epoxidation of an olefin, also this interesting oxidizing reagent is highly interesting.
04:02
Dimethyl dioxirane. You can produce that in situ from acetone and peroxo sulfate triple salt.
04:33
It's called caroate, or as a trade mark oxone.
04:47
You can generate that in situ, but you can also not isolate it, but isolate acetone dimethyl dioxirane mixture just by distillation under reduced pressure.
05:03
No problem. And what is interesting, there is also the possibility to form chiral dioxiranes. For instance, this one, this chiral ketone is easily synthesized in two or three
05:48
steps from sugars, and then you can form in situ the dioxirane, and it will transfer the oxygen enantioselectively.
06:02
And this reaction is called the Xi epoxidation developed by my dear colleague Yian Xi.
06:21
So let's go on with aziridines. These are three membered nitrogen heterocycles.
06:53
Well, retrosynthetic analysis.
07:01
Then can lead us, for instance, to that combination olefin plus a nitrene.
07:22
Or you can also think about something like that and a leaving group X here. So, but this method is all quite popular.
07:46
So one example, how to get to a nitrene.
08:15
Just treating with a base, you can achieve an alpha elimination.
08:24
This should remind you of the alpha elimination in chloroform generating dichlorocarbene. So deprotonating here, and then you have nice stabilized anionic leaving group here,
08:45
and it will then smoothly produce that nitrene. And if you do so in the presence of an appropriate olefin, should already be present,
09:07
then this nitrene is trapped by the olefin giving rise to this final product.
09:44
Another interesting method is transforming an epoxide to the corresponding aziridine.
10:09
And there is a rather nice two-step method. You treat this epoxide with sodium azide
10:21
in ethanol under buffered reaction conditions, ammonium chloride. This will lead to this azide.
11:00
And now treating this with triphenylphosphine in acetonitrile,
11:14
then triphenylphosphine is a reducing agent. It will be oxidized to triphenylphosphine oxide.
11:34
Molecular nitrogen will be formed. And this aziridine and this two-step procedure was proven to deliver
11:58
this highly strained product in 61% yield.
12:13
The corresponding three-membered sulfur heterocycles are also known.
12:23
The thiranes with this parent structure.
12:46
Well, one can think about synthesizing that from this setup a thiol and in better position a leaving group just treating with a base.
13:02
Yes, it will work under high dilution. You of course can get oligomeric or polymeric product. The competing reaction.
13:21
It is also possible to target these sulfur heterocycles by treating epoxides, for instance, the thiourea.
13:55
Actually, this is similar to that one here.
14:03
Because if these react together, what will happen? This is the nucleophile and it will open up the epoxide.
14:50
So what will happen next? Well, I'm just guessing, but it's I think an educated guess.
15:00
Nucleophilic center, electrophilic center, five-membered ring.
15:33
So then a hetero cleavage will take place here.
16:02
So now have a look. Here we have the thiolate. There the leaving group and the thirane is formed plus just urea as
16:32
well the co-product.
16:51
This retrosynthetic disconnection is also, I think, a nice idea.
17:07
Let us assume we have a thio ketone and let this react, for instance, with just the parent carbine naphthalene.
17:29
This idea has been proven to work out well.
17:50
Here we have the thio ketone which has been tested with this diazo compound.
18:23
If I remember it correctly. Well, I'm not sure was it under thermal or photochemical conditions, but at least it is important that you don't have that CH3 group here. If a free carbine is formed and you would have a CH3 group,
18:42
then CH insertion would occur and olefin would be formed. But the CF3 group doesn't allow the insertion into a carbon fluoride bond. So a carbine or a carbine equivalent is reacting with this final product with a 68% yield.
19:30
Let's change to four-membered rings, four-membered heterocycles.
19:50
One could think about disconnection like this or just leaving group X, X here plus
20:48
primary amine and treating with a base. In principle this works and this could derive from, wow, this alcohol.
21:18
However, this of course has some tendency to form a lactone.
21:29
Essentially we could start from such a lactone.
21:47
The oxytanes are the corresponding oxygen heterocycles and I think it should be known
22:08
what is the preferred way to synthesize oxytanes. It's a photochemical pathway called the Paterno Buchi reaction.
22:46
Photochemically as I said and in this case we would combine isobutene with benzaldehyde.
23:08
Or you might notice that this is kinetically favored and certainly not the thermodynamically favored product.
23:26
Thermodynamically favored would be this one with that dimethylmethylene group.
23:40
Far away from the other sterically demanding group, the phenyl group. However, you can assume diradicalic intermediate like that and this is
24:08
therefore with this diradical preferred to other possible diradicals. This is the preferred reactive intermediate, the kinetically favored one.
24:30
Five membered rings, five membered heterocycles.
24:51
So let's try this as an exercise.
25:05
Please try to make a suggestion how to synthesize this molecule. So one suggestion I have seen was to disconnect here.
25:39
Yes, it would work.
25:46
This is quite okay but please don't forget that this reaction does not work.
26:12
Why? Because of Baldwin rules. This is a five endotric cyclization which does not work according to Baldwin
26:37
because all the three electron pairs of the oxygen have to reach above that double bond.
26:51
And this doesn't fit. On the other hand, with the bigger sulfur it again works.
27:02
This kind of reactions have been tested in similar structures. However, let's call that R1. Should be a good idea to choose this position as for the disconnection.
27:26
We have a 1-3 relationship between two carbonyl groups.
27:41
And please remember, donate a reactivity here, accept a reactivity there, and we can translate that easily to this synthetic equivalent.
28:22
Deprotonating at this position alpha to that ester. Oh, this is then an ester condensation and intramolecularly we call that then a Dichmann condensation.
28:53
Just treating with sodium ethanolate and ethanol. Ah, well, OK.
29:03
Better in this case with sodium methanolate and methanol since we want to have a methyl ester. Otherwise we would get the ethyl ester.
29:23
So we should hope for this position to be deprotonated easier, to be more acidic. Although, well, here the sulfur is sitting. Making it more acidic due to the electrophilicity of a sulfur.
29:45
On the other hand, we have, well, we have those free electron pairs. And free electron pairs here deprotonating there would mean repulsion.
30:03
So I'm not sure what will happen in that case, but one just has to try. So if we don't get this product in that case, then this one is the competing one.
30:41
So we would get either this product or that. However, if we would target for this molecule, then this is not necessary, but we care.
31:04
Do we get this one or that? Because after hydrolysis and decarboxylation, we get always this product. OK, I think this is clear.
31:23
So another five membered heterocycle. We are targeting for a racemate of this heterocycle.
32:06
A 1,3-dipolar cycloaddition processes the solution to the problem, the so-called Husken cycloaddition.
32:25
We need an olefin and a 1,3-dipole. This concerted process solves the problem of diastereoselectivity. You just have to start from the trans olefin.
32:45
And you will have these two substituents trans to each other at that heterocycle. And in this case, you have a nitrile oxide as the 1,3-dipole.
33:20
Here's the 1,2-dipolar mesomeric structure drawn. So and where do you get that from? From the corresponding oxime chloride or oxime bromide.
34:10
The oxime of glyoxylic acid, Astru, you can oxidatively chlorinate or brominate.
34:20
And then you just need a base triethylamine, for instance. In equilibrium, it's deprotonated here. And this chloride then is eliminated.
34:47
There are lots of others, of other five-membered heterocycles which can be made by a 1,3-dipolar cycloaddition reaction.
35:01
You should look out for various 1,3-dipoles. Maybe we make one lesson about this type of reaction and concentrate on this type of reaction then. Let's now change to six-membered rings.
35:50
For this case, the retrosynthetic analysis is fairly easy. Such enamines we have already discussed.
36:03
But these are formed by a condensation reaction with a corresponding carbonyl compound.
36:25
So we could disconnect here, accept a reactivity here, donate a reactivity there.
36:51
So synthetic equivalent for this could be such a strained acetidine.
37:17
But maybe it's easier to think about a change in the functional group here.
37:38
Let's change the oxidation state to a nitrile.
37:54
Then this disconnection is straightforward.
38:01
Just Michael addition process in the presence of a base with acrylonitrile.
38:23
Maybe we find a catalyst which could hydrogenate the nitrile in presence of these
38:40
carbonyl groups. Actually this seems to be a problem, I think. However, maybe we could deprotonate here and have an enolate or for instance a TMS
39:11
enolate. Structure like that. Relatively electron rich here, electron poor there.
39:25
Then it should be no problem to find a catalyst which is selective for the hydrogenation of the cyano group clearly favored this hydrogenation compared to the hydrogenation of
39:43
that carbon. Last two examples for today.
40:18
First idea of course should be disconnection here and disconnection there.
40:26
Conjugate addition of ammonia to that alpha beta unsaturated ketone.
40:43
Twice the reaction should not be much of a problem. And it is possible under basic reaction conditions to get the condensation done of
41:13
three units of acetone to form this. Please remember here we have
41:31
mesotube oxide as the monocondensation product.
41:40
Actually getting the second one there is not that easy selectively because you have a nice acidity also here forming the linear really conjugated anion preferred to this one here.
42:01
Okay, but with the right reaction conditions you will get quite a lot of that target here. This is mesotube oxide while this is mesotulene.
42:25
Mesotulene is also an aldol condensation product of acetone. You can achieve that under acidic conditions and maybe at home you can figure out the
42:43
mechanism how is this structure set up from acetone. Now to the last structure for today. To be analyzed and again as an exercise please make a suggestion.
43:07
If we follow also in this case the basic idea we have discussed here then we would get to these two starting compounds.
43:29
However this one looks like it would have a distinct tendency for polymerization
43:42
and therefore question mark for this starting material. There is one very simple solution which has also been tested and works quite nicely.
44:04
Remember that you can synthesize various ketones by just
44:28
idolizing and decarboxylating the corresponding beta keto esters and we've discussed an example
44:43
for the Dichmann condensation today already and this example is especially nice because
45:02
these two moieties are identical. So benzoyl amine plus two equivalents of
45:22
acrylic acid ester will work just fine. Maybe another idea for targeting the structure one should always look for a heterocycle or a carbocycle
46:01
in favor of synthesizing that cycle. Maybe we can start from a pyridine derivative like that
46:24
for hydroxy pyridine. Maybe this works an alkylation and then reduction.
47:07
Maybe this is also an idea which could work. Just an idea I didn't check. Has this been done? However while there are more than certainly more than one way to synthesize
47:24
a molecule like that. Thanks for listening for today. Next lecture will take place next week Wednesday. We will discuss the synthesis of aromatic heterocycles.
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