Synthesisofheterocycliccompounds

TapioNevalainen DrugsynthesisII 2010

http://www.scripps.edu/chem/baran/heterocycles/

Heterocycliccompounds
Heterocyclescontainoneormorehereroatomsinaring

X X Y Z

X Y

X,Y,Z are usually N,O,S

Heterocycles
Aromaticfivememberedheterocycles

Heterocycles
Aromaticsixmemberedheterocycles

5 6 7 8

4 3 6 7

4 3 6 7

N3
8

5 6 7 8

N N
1

3 2

N
1

N2
8 1

N
1

quinoline

isoquinoline

quinazoline

quinoxaline

Heterocycles
Aliphaticheterocycles

Heterocycles
Tautomerism

Reactionsofheterocycles
Fivememberedheterocyclesaregoodnucleophiles
ReactionwithbrominerequiresnoLewisacidandleadsto substitutionatallfourfreepositions.

In FriedelCrafts reactions the2positionismorereactivethan the3position p

Reactionsofheterocycles
Vilsmeierreaction(VilsmeierHaack reaction) allowstheformylationof heterocyclicandelectronrich arenes.Theformylating y gagent, g , chloroiminiumion,isformedinsitu fromN,NdimethylamideandPOCl3
O H N H CH3 N CH3

O H N H

1. POCl3 2. H2O

Reactionsofheterocycles
Aromaticheterocyclesundergoesaminoalkylation(Mannichreaction) ForexampleNmethylpyrrolereactsatthe2position.Reactionis usedinthemanufactureofthenonsteroidalantiinflammatory compound,tolmetin.
CH3 HN CH3 N H3C CH2=O Mannich reaction N H3C H3C N CH 3 H3C H3C N CH 3

N CH3

Tolmetin

Fivemembered heterocycles actasdienes inDiels Diels Alderreactions

Commonbuildingblocksfor heterocycliccompounds

Generalstrategiesforheterocyclesynthesis
1+4strategy

1+5strategy

Generalstrategies forheterocycle synthesis

2+3strategy

3+3strategy

Examples
O X H2N H2N O H2N O H X H2N

HO

O X X = Cl, Br, I O

Reactionsusedinheterocyclicringsynthesis

Aldoltype reactions ofenols or enolate anions with electrophiles. electrophiles.

Imine/enamine formation

Reactionsusedinheterocyclicring synthesis
Enamineistautomericformofimine.Ifdialkylamineis used,enamineisformed

Enamines can function asenolates

H R1 O R3 R4 R4 H R2 N H R1 OH R3 -H
+

H R1 O H - H2O H

H R2

H R2

H R1 - H+ R3

H R2

H R1 R3

+ H+

R2 R3 R4

enamine

R4

R4

Reactionsusedinheterocyclicring synthesis
WhentheprocessleadstoCheteroatombondformation, thenthenucleophileisanappropriateheteroatom.

Furans

Paal Knorr

FeistFeist -Benary

Thiophenes

Paal Knorr

HinsbergSynthesisofThiopheneDerivatives

Gewald reaction

Pyrroles
Knorrpyrrolesynthesis: Condensationof aminoketone
andketoester

PaalPaal -Knorr PyrrolePyrrole-Synthesis: condensation amine and 1,4 1,4-ketone

Example: Example : Synthesis of atorvastatin (Lipitor Lipitor) )

Pyrroles
Hantzsch pyrrole synthesis: from halomethyl ketones,keto esters and
ammonia or amines

Huisgen Pyrrole Synthesis From Amino acids and alkynes. Example: atorvastatin

A. Hantzsch, Ber. 23, 1474 (1890)

1,2Azoles

Pyrazoles can be synthesized from 1,3dicarbonyls with hydrazine

Isoxazoles can be made from 1,31,3-dicarbonyl compounds or ketoesters with hydroxylamine

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1,2Azoles
Exampleofpyrazolesynthesis:Rimonabant

1,2Azoles
Thesynthesisofsildenafil(Viagra)

Retrosynthesis

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1,2Azoles
Thesynthesisofsildenafil(Viagra)

Bioorg.Med.Chem.Lett.6,pp.1819,1996

1,2Azoles
Thesynthesisofsildenafil(Viagra)
O OEt O Cl + H2N H2N CH3 O EtO ClSO2OH HN N CH3 CH3 N N HN N O S O Cl CH3 O S O N N CH3 O C 3 CH N N pyridine H2N EtO HN O OEt EtO HN N CH3 CH3 N N O NaOH EtO HN N CH3 O CH3 N N CH3 CH3 N N

Bioorg. Med. Chem. Lett. 6, pp. 1819, 1996

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1,2Azoles
synthesisofisoxazoles

By 1,3 1,3-cycloaddition from nitrile oxides and unsaturated compounds

Nitrile oxides can be prepared by the -elimination of chlorooximes or the dehydration of nitroalkanes

1,3Azoles
Oxazolesandthiazolescanbeobtainedbythe RobinsonGabrielsynthesisfrom2acylaminoketones.

2acylaminoketonesreactswithphosphorus pentasulfidetoformthiazoles

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1,3Azoles
OxazolescanbemadebyBlmleinLewySynthesis:heatingan haloketonewithamide

Most important method forthiazoles isHantzsch thiazole synthesis from thioamides andahalocarbonyl compounds

1,3Azoles

Example: Example : synthesis of nizatidine

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1,3Azoles:Synthesisofimidazoles Fromamidinesandhydroxyorhalocarbonylcompounds

DebusRadziszewski imidazole synthesis synthesis: : diketone andammoniaformandiimine,whichcondenseswith thealdehyde

For more imidazole syntheses, look: http://www.scripps.edu/chem/baran/images/grpmtgpdf/Zografos_Feb_04.pdf

1,3Azoles:Imidazolesfromisocyanides
Thereactionofaldehydes,primaryaminesand toluenesulphonylmethylisocyanide (TOSMIC)yield1,4,5 trisubstitutedimidazoles(vanLeusenetal.J.Org.Chem. 1977,42,1153).
R3 O R1 NH2 + H R2 R3 N N R1 Ts Base H R2 - H2O R1 N N C R2 R3 R2 + H3C O S O TOSMIC Base N N R1 O S

CH3

C N

R3 Ts

N R H 2 R1 OH

http://www.organic-chemistry.org/Highlights/2005/05May.shtm

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1,3Azoles:Imidazolesfromisocyanides
Substitutedtosylmethylisocyanides(TosMICs)aresynthesizedfrom tosylmethylformamides andpmethylphenylsulphinicacid.

SynthesisoftheGSKp38kinaseinhibitor

1,3Azoles

Synthesis of 2-Butyl-4-chloro-5-hydroxymethyl-1Himidazole
H N O CH3 N HO Cl H N HO N H2N OH HN CH3

HO Cl O HO

H2N + OH HN

CH3

NH3, MeOH

CH3 HN

N N N

1. Me3SiCl, 2.Chlorosuccinimide 3. Zn, AcOH HO

H N N

CH3 HO Cl

N N

CH3

Cl 2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazole

Losartan

Synthetic Communications (1993), 23(18), 2623-30.

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Dihydroimidazoles
Clonidine (anti-hypertensive agent)

Oxymetazoline (topical decongestant)

HO CH3 CH2O/HCl CH3 CH3 HO CH3 Cl KCN CH3 HO CH3 CN H2N H2N 235C, N2 CH3 N Oxymetazoline HO CH3 H N

1,4Dihydropyridines
Hantzsch Dihydropyridine (Pyridine) Synthesis

4-Aryl-1,4-dihydropyridines (e.g. nifedipine) p ) are calcium channel modulators for the treatment of cardiovascular diseases such as hypertension, cardiac arrhythmias, or angina.

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Pyridines
Pyridoxine,vitaminB6,hasbeensynthesisedby Guareschiringsynthesis

Glutarimides

Thalidomide
O O O O CO H 2 N H2N O

O NH2 O O OH N OH O O F3C O O N NH O O (R)-Thalidomide O HOBt = N-hydroxybenzotriazole N N N OH EDCCl = N-(3-dimethylamino)propylN'-ethylcarbodiimide hydrochloride N N C CH3 NH+ Cl CH3 NH2 Ac2O N NH O O Thalidomide O O

CO2H

NH2 HOBt EDCCI

O 2-phthalimido-D-glutaric acid

Tetrahedron Letters (1999), 40(19), 3697-3698. H3C

A i Aminoglutethimide l t thi id

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Pyrimidines
Pinner pyrimidine sythesis: from 1,3-dicarbonyl compounds and amidines

Instead of amidines, pyrimidines are obtained also by using guanidine, urea and thiourea
R4 O N R1 R2 R1 NH2 N R1 R2 N R3 H2N NH2 NH R2 H2N N R3 H2N R4 NH O O R3 S NH2 R1 R2 N S NH R3 H2N O NH2 R1 R2 N NH R3

Pyrimidines Example:trimethoprim(bacteriostaticantibiotic)
NH2 N N NH2 MeO H MeO OMe MeO OMe MeO NH2 MeO OMe MeO OMe H2N O NH2 NH EtO O FGI MeO MeO OEt guanidine O O EtO O O OEt Br

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Pyrimidines
BiginelliReaction:acidcatalyzed,reactionbetweenan
aldehyde,a,ketoesterandureaconstitutesarapidandfacile synthesisoftetrahydropyrimidones.

SynthesisofracMonastrol(MitosisblockerbykinaseEg5
inhibition)

Tetrazoles

Carboxylic acid isostere Synthesis

Synthesis of Losartan (antihypertensive antihypertensive) )

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Indoles

The conversion of aryl hydrazones to indoles; indoles ; requires elevated temperatures and the addition of Brnsted or Lewis acids

Fischer Indole Synthesis:

Synthesis y of Sumatriptan p

(Daniel Lednicer Lednicer: :

Strategies for Organic Drug Synthesis and Design)

Quinolines

Quinoline nucleus isusually formed inone oftwo ways

Skraupreaction
O OH HO OH O H
+

Mechanism:

H2C H OH

NH2 N H H [O]

- 2 H2O H

N H

N H

- H2O

N H

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Quinolines
DoebnerMiller reaction:unsaturated ketone or aldehyde can be used instead ofglycerol toform aquinoline

ConradLimpachreaction:Synthesisof4oxyquinolinesby condensationofestersofbetaketoacidswitharomaticamines

Quinolines Friedlnderquinolinesynthesis

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Isoquinolines

The general synthetic routes to isoquinolines involve the following g skeletal types: yp

Isoquinolines
BischlerNapieralski Reaction:

-Phenylethylamine is acylated then cyclodehydrated using phosphoryl chloride, phosphorous pentoxide or other lewis acids. This gives the dihydroisoquinoline, dihydroisoquinoline, which can be aromatised by dehydrogenation with palladium. E.g. in the synthesis of papaverine

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Isoquinolines
PictetSpenglersynthesis: Arylethylamineisheatedinthe
presenceofanaldehydeandacid. AspecialcaseoftheMannichreaction.

Synthesis of Tadalafil

Isoquinolines
Pomeranz Fritsch Reaction
EtO O R OEt - H2O N R C. Pomeranz C Pomeranz, Monatsh Monatsh. 14 14, 116 (1893) P. Fritsch, Ber. 26, 419 (1893) OH - H2O N R R N R OEt OEt H3O+ N O

+
H2N

SchlittlerSchlittlerMller e Reaction

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Quinolones
Retrosynthesis

Synthesis

Thiadiazoles
Synthesis ofTimolol (blocker)

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Benzodiazepines

The retrosynthesis of diazepam

The synthesis of diazepam (Sternbach et al, 1961).

O CH3 NH Ac2O Cl Cl CH3 O N NH3 Cl N Cl CH3 O N O O Cl Cl Cl O N O Ph C Cl AlCl3 Cl N CH3 O NaOH, H2O Cl CH3 N H O

CH3

Diazepam

Benzodiazepines

71, 386)

Ugi Reaction (Ugi, I., et. al. Angew. Chem. 1959,

Concise synthesis of benzodiazepines with Ugi Reaction (Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021)

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