Unit 4 imidazole

Pharmaceutical organic chemistry 3 B.Pharm IV SEM

1. Lecture by
Sowmiya Perinbaraj,
M.Pharm
Assistant Professor
Dept of Pharmaceutical
Chemistry
SVCP

2. ➢Imidazoleisanimportantnucleusinheterocyclicchemistry.
➢Imidazoleisanunsaturatedfivememberedheterocyclicring
consistsoftwonitrogensasheteroatomsat1
st
and3
rd
positions.
➢ItfollowsHuckelruleandhenceitisAromaticheterocyclic
compound.
➢Molecularformula:C
3N
2H
4

3. SYNTHESIS
1.Debus Radiszewskisynthesis:
❖Thisisprobablythemostimportantsynthesisofimidazoles.
❖Itconsistsofcondensingadicarbonylcompoundssuchas
glyoxal,α-ketoaldehydesordiketoneswithanaldehydein
thepresenceofammonia.
❖Benzilwithbenzaldehydeandtwomoleculesofammonia
reactstoyield2,4,5-triphenylimidazole.

4. SYNTHESIS
2. Dehydrogenation of Imidazolines:
❖Imidazolespreparedbydehydrogenationofimidazolinesin
presenceofmilderreagent,bariummanaganate.
❖Imidazolinesobtainedfromalkylnitrilesand1,2-
ethanediamineonreactionwithBaMnO4yields2-
substitutedimidazoles.

5. SYNTHESIS
3. From α-Halo ketones:
❖Thisreactioninvolvesaninteractionbetweenanamidineand
anα-haloketone.
❖Phenacylbromideandbenzamidineaffords2,4-
diphenylimidazole.

6. SYNTHESIS
4. From oxazole:
➢Oxazoleundergoringtransformationwhen
treatedwithammonia,formamide,
hydrazineoraminesinthepresenceof
acids.

7. ❖Imidazole is an amphotericsubstance.
❖With acidact as proton acceptor
❖With baseact as proton donor

8. 1.Electrophilic substitution reactions:
✓Imidazoleismoresusceptibletoelectrophilicattackthan
pyrazole,thiazole,furanorthiophene.
✓Electrophilicattacktakesplaceat4
th
or5
th
positionin
imidazole.
✓ElectrophilicattackatC-2involvesacanonicalformwitha
highlyunfavouredpositivenitrogenatposition3.

9. i) Nitration
Imidazoleonnitrationwithnitratingmixture-fumingHNO
3&
H
2SO
4afford4(5)-nitroimidazole.
ii) Sulphonation
Imidazole on sulphonation with sulphuric acid afford
imidazole-4(5)-sulphonic acid.

10. iii) Bromination
Imidazoleisbrominatedveryreadilyinaqueoussolutionor
organicsolventwithbrominationattheavailablevacant
positionsproviding2,4,5-tribromoimidazole.
iv)Iodination
Imidazoleisiodinatedonlyunderalkalineconditionsand
produces2,4,5-triiodoimidazole.

11. iv) Diazo coupling reaction
▪N-unsubstitutedimidazolesubstitutedwithactivating
substituents(electronreleasing)undergodiazocoupling
readilyinalkalinemediumpreferentiallyattheposition2.
▪Thepresenceofelectronreleasingsubstituentsonthe
imidazolefacilitatesdiazocoupling,whiletheelectron
withdrawingsubstituentsdeactivatetheimidazoletowards
diazoniumion.

12. 2.Oxidation
Imidazoleringisresistanttooxidationbutitis
degradedbyhydrogenperoxideandperbenzoicacid.

13. 3. Cycloaddition reaction
ImidazolesundergoadditionacrosstheC=Cunder
photochemicalconditions.
Eg:Thereactionsofimidazoleswithbenzophenoneand
acrylonitrile.

14. 1.Metronidazole
Anti-amoebic agent for the treatment of
amoebic dysentery.

15. 2. Methimazole and carbimazole
Antithyroid drugs, used to control hyperthyroidism.

16. 3. Cimetidine
H2Antagonist-antiulcerdrugusedforthe
treatmentofgastricandduodenalulcers.

17. 4. Ketoconazole, Miconazole, Clotrimazole
Antifungal drug used to treat fungal infections

18. 5. Albendazole, Mebendazole
Anthelmintic drug used for the treatment of
helminthiasis.

19. ➢Oxazoleisanunsaturatedfivemembered
heterocyclicringconsistsofoxygenandnitrogenas
heteroatomsat1
st
and3
rd
positions.
➢ItfollowsHuckelruleandhenceitisAromatic
heterocycliccompound.
➢Molecularformula:C
3H
3ON

20. ➢Partiallyreducedoxazolesarecalledoxazolinesand
threetypesarepossibledependingonthepositionof
thedoublebond.
➢Thefullysaturatedsystemofoxazoleisoxazolidine.
➢Oxazoleisliquid,b.p-69°Candhasanodour
resemblinglikepyridine.
➢Itisweaklybasic.
2-oxazoline 3-oxazoline4-oxazoline oxazolidine

21. SYNTHESIS
1.Robinson-Gabriel synthesis:
❖Thisismostcommonmethodusedforthe
preparationofoxazoles.
❖Thismethodinvolvesanα-acylaminoketone
whichundergoescyclizationanddehydrationin
thepresenceofphosphoruspentoxideorastrong
mineralacid.

22. SYNTHESIS
1.Robinson-Gabriel synthesis:
Eg:

23. SYNTHESIS
2. From α-hydroxy ketones:
➢ItisasimplemethodreportedbyBredereckand
Bangert
➢Itinvolvesareactionbetweenethylα-hydroxy
ketosuccinateandformamidetogive
diethyloxazole-4,5-dicarboxylatewhichis
subsequentlyhydrolysedanddecarboxylatedto
oxazole.

24. SYNTHESIS
2. From α-hydroxy ketones:
Eg:

25. SYNTHESIS
3. From isocyanides:
❑Reactionofisocyanideswithacid
chloridesoranhydridesyields
substitutedoxazoles.

26. SYNTHESIS
4. Fischer oxazole synthesis:
❑Reactionofcyanohydrinwitharomatic
aldehydeinpresenceofanhydrousether
anddryHClaffordoxazolederivatives.

27. 1.Electrophilic substitution reactions
✓Oxazoleismorereactivetowardselectrophilic
substitutionthanthiazolebutlessthanimidazole.
✓Thepreferredattacktakesplaceatposition-5.
✓Electrophilicattack,however,occursreadilywhen
theringisactivatedbyelectrondonating
substituents.
✓Theringpositionsreactintheorder5>4>2

28. i) Bromination
✓BrominationinpresenceofN-bromosuccinimide(NBS)
of2-phenyloxazoleresultsin5-bromo-2-phenyloxazole.

29. ii)Nitration
✓Nitrationandsulfonationofoxazoleitselfaredifficultbecauseofthe
presenceofpyridinetypenitrogen.
✓Nitrationof2-phenyloxazolefurnishesp-nitrophenyloxazole.
iii)Sulphonation

30. 2) Diels-Alder reaction
▪Diel’s-Aldercycloadditionofoxazole(conjugated
diene)anddienophileproducespyridine
derivatives.

31. 3) Oxidation
▪Oxazoleringisnotstabletooxidativeconditionsandthusisopenedbythe
actionofoxidisingagentssuchascoldpotassiumpermanganate,chromic
acidandOzone.
▪2,4,5-triphenyloxazoleaffordsaquantitativeyieldofbenzoicacidwith
chromicacid.
▪Oxazoleisnormallystabletotheactionofhydrogenperoxide.
▪4-(2-oxazolyl)pyridinewithH
2O
2givesthepyridineN-oxidederivative.

32. 4) Reduction
▪Oxazoleonreductionwithsodiuminethanolyields
oxazolidines.
▪2,5-diphenyloxazoleisreducedfinallyto2-benzylamino-1-
phenylethanolbylithiumaluminiumhydride(LiAlH
4)

33. 1. Oxaprozin
Oxaprozinis a NSAIDused symptomatically treat
inflammation, painand rheumatoid arthritis.

34. 2. Benoxaprofen, Flunoxaprofen
Theseareusedasanalgesic,antipyreticandanti-
inflammatorydrugs.Itwasgiventopatientswith
rheumatoidarthritisandosteoarthritis.

35. 3. Trimethadione, Paramethadione
Theseanticonvulsantsdrugsusedtotreat
petitmalseizures.

36. 4. Ditazole
It is NSAIDwith analgesic and antipyretic. It is
also act as platelet aggregation inhibitor.

37. 5. Sulphamoxole
It is sulphonamide derivatives used to treat
bacterial infections.

38. ➢Thiazoleisanunsaturatedfivemembered
heterocyclicringconsistsofsulphurandnitrogen
asheteroatomsat1
st
and3
rd
positions.
➢ItfollowsHuckelruleandhenceitisAromatic
heterocycliccompound.
➢Molecularformula:C
3H
3SN

39. ➢ThePartiallyreducedthiazolesarecalled
thiazolinesandthreetypesarepossibledependingon
thepositionofthedoublebond.
➢Thiazoleisacolourlessliquid,b.p-177°Candhasan
odourresemblinglikepyridine.
➢Itisweaklybasic.
2-thiazoline 3-thiazoline 4-thiazoline

40. SYNTHESIS
1.Robinson-Gabriel synthesis:
❖Thissynthesisinvolvesheatingofacylaminoketone
withphosphoruspentasulphidetogivethiazole
derivatives.
❖ThecarbonylgroupisprobablyattackedfirstbyP
2S
5,
theoxygenatombeingreplacedbysulphurandthe
intermediatecyclizestothiazole.
N-(2-Oxopropyl)acetamide

41. SYNTHESIS
2. HanstchThiazole synthesis:
❖Thismethodinvolvescondensationofanα-
haloketoneswiththioamidesorthioureatoyield
thiazolederivatives.
❖Eg:Chloroacetaldehydeoncondensationwith
thioformamideaffordsthiazole.

42. SYNTHESIS
3. Cook Heilbornsynthesis:
❖Thissynthesisinvolvescondensationofα-
aminonitrilewithcarbondisulphide.

43. SYNTHESIS
4. From thioamides :
❖Thiazolederivativesmayobtainedbyreactinga
thioamidewithsubstituted2-chloro2-
chloromethyl)oxiranes.

44. 1.Electrophilic substitution reactions
✓Theelectrophilicattackpreferablytakesplaceatposition-5
inpresenceofelectronreleasinggroups.
Bromination
▪Ifelectronreleasinggroupsarepresent,thenbrominationis
easilyachieved.

45. Sulphonation
✓sulphonationofthiazolemaybeachievedunder
drasticconditionsinthepresenceofmercury
sulphateascatalysttogivethiazole-5-sulphonic
acid.
HgSO4

46. 2. Nucleophilic substitution reactions
✓TheC-2positionbeingsusceptibletonucleophilicattack.
✓Thereactionofpotassiumamideinliq.ammoniawith
thiazoleaffords2-aminothiazole.
✓Withn-butyllithium,theposition-2ismetalatedtoyield
thiazole-2-lithium.

47. 3. Reduction
✓Thiazoleringisresistanttotheactionofmany
reducingagents,althoughRaneyNickelcanbe
usedfordesulphurizationreactions.

48. 4. Formation of Quaternary ammonium
salts
✓Thequaternizationofthiazoletakesplaceat
position-3.

49. 1. Sulphathiazole
➢Itisshortactingsulphonamideantibiotics
usedtotreatbacterialinfections.

50. 2. Thiabendazole
➢Itisananthelminticdrugusedtotreatinfections
causedbywormssuchasthreadworm.Itmayalso
beusedtotreatpinworm,hookwormand
roundworminfections.

51. 3. Niridazole
➢Itisanthelminthicdrugusedasschistosomicide.
Schistomiasisishelminthicdiseasecausedbycertain
flatworms.

52. 4. Famotidine
➢ItisH2receptorantagonist,usedtotreatand
preventulcersinthestomachandintestines.