synthesis of heterocyclic compounds -...

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Synthesis of heterocyclic compounds

Tapio Nevalainen

Drug synthesis II

2010

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

Heterocyclic compounds

•Heterocycles contain one or more hereroatoms in a ring

Z

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

XX X

YY

2

Heterocycles

•Aromatic five‐membered heterocycles

Heterocycles

•Aromatic six‐membered heterocycles

34

34

34

N45

65

65

65

N1

2

3

quinoline

1

N 2

3

isoquinoline

N1

2

N 3

quinazoline

N1

2

3N

quinoxaline

6

78

6

78

6

78

6

78

3

Heterocycles

•Aliphatic heterocycles

Heterocycles•Tautomerism

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Reactions of heterocyclesFive‐membered heterocycles are good nucleophiles

•Reaction with bromine requires no Lewis acid and leads to substitution at all four free positions.

In Friedel–Crafts reactions the 2the 2‐‐position is more reactive than position is more reactive than the 3the 3‐‐positionpositionpp

Reactions of heterocycles

Vilsmeier reaction (Vilsmeier‐Haack reaction) allows the formylation of heterocyclic and electron‐rich arenes. The formylating agent,

N N

ONH

O

CH3

CH3y g g ,chloroiminium ion, is formed in situ from N,N‐dimethylamide and POCl3

NH

NH1. POCl3 H

2. H2O

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Reactions of heterocycles

•Aromatic heterocycles undergoes aminoalkylation (Mannich reaction)

•For example N‐methylpyrrole reacts at the 2‐position . Reaction is used in the manufacture of the nonsteroidal anti‐inflammatory compound, tolmetin.compound, tolmetin.

NCH2=O

HNCH3

CH3

H3CN

H3C

N

H3C

CH3

N

CH3

NH3C

CH3

O

H3C

Tolmetin

Mannichreaction

FiveFive‐‐memberedmembered heterocyclesheterocycles act as act as dienesdienes in Dielsin Diels––Alder reactionsAlder reactions

Common building‐blocks for heterocyclic compounds

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General strategies for heterocycle synthesis

•”1+4” strategy

”1+5” strategy

General General strategiesstrategies for for heterocycleheterocycle synthesissynthesis

”3+3” ”3+3” strategystrategy ”2+3” ”2+3” strategystrategy

ExamplesExamples

H2NX H2N O

HH2N O H2NX

O

O HO

X

O

X = Cl, Br, I

O

O

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Reactions used in heterocyclic ring synthesis

AldolAldol‐‐typetype reactionsreactions of of enolsenols oror enolateenolate anionsanions withwithelectrophileselectrophiles. .

IImine/enaminemine/enamine formationformation


•Enamine is tautomeric form of imine. If dialkylamine is used, enamine is formedused, enamine is formed

EnaminesEnamines cancan functionfunction as as enolatesenolates

N

enamine

R2R1

HH N

R2R1

HHO

R3

R3

OH

N

R2R1

H

R3 O

H

- H+

+ H+ H

N

R2R1

H

R3

H

- H2O

H

N

R2R1

H

R3

- H+

H

R4

R4 R4 R4R4

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•When the process leads to C‐heteroatom bond formation, then the nucleophile is an appropriate heteroatom.then the nucleophile is an appropriate heteroatom.

Furans

Paal KnorrPaal Knorr

FeistFeist--BenaryBenary

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Thiophenes PaalPaal KnorrKnorr

•Hinsberg Synthesis of Thiophene Derivatives

GewaldGewald reactionreaction

•Knorr pyrrole synthesis: Condensation of ‐aminoketone and ‐ketoester

PyrrolesPyrroles

PaalPaal--KnorrKnorr PyrrolePyrrole--SynthesisSynthesis: : condensationcondensation amineamine and 1,4and 1,4--ketone ketone

ExampleExample: : SynthesisSynthesis of of atorvastatinatorvastatin ((LipitorLipitor))

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Pyrroles•Hantzsch pyrrole synthesis: from α‐halomethyl ketones, β‐keto esters and ammonia or amines

A. Hantzsch, Ber. 23, 1474 (1890) Huisgen Pyrrole Synthesis

From Amino acids and alkynes. Example: atorvastatinatorvastatin

1,2‐Azoles

PyrazolesPyrazoles cancan bebe synthesizedsynthesized fromfrom 1,31,3‐‐dicarbonyls dicarbonyls withwith hydrazinehydrazine

Isoxazoles can be made fromfrom 1,31,3--dicarbonyl dicarbonyl compoundscompounds oror ββ--ketoestersketoesters withwith hydroxylaminehydroxylamine

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1,2‐Azoles Example of pyrazole synthesis: Rimonabant

1,2‐AzolesThe synthesis of sildenafil (Viagra)

RetrosynthesisRetrosynthesis

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


O CH3

O CH3 O CH3

H2NN

NC 3

CH3

H2NCl

O

+pyridine

H2NN

N

CH3

HN

OEt

O

HNN

N3

CH3

N

HNN

N

O CH3

N HN

N

HNN

N

O CH3

N

NaOH

ClSO2OH

OEtEtO

EtO EtO

EtO

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

CH3SO O

Cl

NCH3

N

NCH3

CH3SO

O

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1,2‐Azolessynthesis of isoxazoles

By 1,3By 1,3--cycloaddition cycloaddition fromfrom nitrilenitrile oxidesoxides and and unsaturatedunsaturated compoundscompoundsunsaturatedunsaturated compoundscompounds

NitrileNitrile oxidesoxides cancan bebe preparedprepared byby thethe --eliminationelimination ofof chlorooximeschlorooximes NitrileNitrile oxidesoxides cancan bebe preparedprepared byby the the --eliminationelimination of of chlorooximeschlorooximesoror the the dehydrationdehydration of of nitroalkanesnitroalkanes

1,3‐Azoles

•Oxazoles and thiazoles can be obtained by the Robinson‐Gabriel synthesis from 2‐acylamino‐ketones.

22‐‐acylaminoacylamino‐‐ketones reacts with phosphorus ketones reacts with phosphorus pentasulfide to form pentasulfide to form thiazolesthiazoles

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1,3‐Azoles

•Oxazoles can be made by Blümlein‐Lewy Synthesis: heating an haloketone with amide

MostMost importantimportant methodmethod for for thiazolesthiazoles is is HantzschHantzsch thiazolethiazole synthesissynthesisfromfrom thioamidesthioamides and and aa‐‐halocarbonylhalocarbonyl compoundscompounds

1,3‐Azoles

ExampleExample: : synthesissynthesis of of nizatidinenizatidine

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1,3‐Azoles: Synthesis of imidazoles

•From amidines and hydroxy or halocarbonyl compounds

DebusDebus‐‐RadziszewskiRadziszewski imidazoleimidazole synthesissynthesis:: diketonediketoneand ammonia form an diimine, which condenses with and ammonia form an diimine, which condenses with the the aldehydealdehyde

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

1,3‐Azoles: Imidazoles from isocyanides

•The reaction of aldehydes, primary amines and

toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5‐

trisubstituted imidazoles (van Leusen et al. J. Org. Chem. 1977, 42, 1153).

R1NH2 +

R1 N R2

CH3

S

O

ON

R3

N R2

R3

TOSMIC

NTsR3

NR3

S

O

- H2O

Base

CH

O

R2

N TsC

R1

Base

H

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

R1

NR1

N R2+

H3C

SOH

Base

R2

H

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1,3‐Azoles: Imidazoles from isocyanides

•Substituted tosylmethyl isocyanides (TosMICs) are synthesized from tosylmethyl formamides and p‐methylphenylsulphinic acid.

•Synthesis of the GSK p38 kinase inhibitor

1,3‐Azoles

Synthesis of 2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazole

HN

N

CH3HO

H2N

HN

CH3HO

O

OHNHO

Cl

HNN

NN

N CH3

H2N

HN

CH3

HN

N

CH3HO

HN CH3

HO

HNOH

HO

O

OH+

1. Me3SiCl,2.Chlorosuccinimide3. Zn, AcOH

NH3, MeOH

Cl

N

CH3HO

Cl

Losartan

NHO

Cl

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

2-Butyl-4-chloro-5-hydroxy-methyl-1H-imidazole

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Dihydroimidazoles

Clonidine (anti-hypertensive agent)

Oxymetazoline (topical decongestant)

CH3HOCH3HOCH3HOCH3HOH2N

Oxymetazoline

HN

NCH3

3

CH3

CN3

CH3

Cl3

CH3

CH2O/HCl H2N

235°C, N2

KCN

1,4‐Dihydropyridines

• Hantzsch Dihydropyridine (Pyridine) Synthesis

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

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Pyridines

•Pyridoxine, vitamin B6, has been synthesised by Guareschi ring synthesis

Glutarimides

TThalidomide

NHN

O

O

O

O

O

O

O

NH2

N

OO

OH

NH2

H2N

O

O

OHAc2O

A i l t thi idA i l t thi id

ThalidomideOOO OO

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

N

O

O

CO2H

CO2H

2-phthalimido-D-glutaric acid

NHN

O

O

O

O

(R)-Thalidomide

O

NH2HOBt = N-hydroxybenzotriazole

EDCCl = N-(3-dimethylamino)propyl-N'-ethylcarbodiimide hydrochloride

EDCCI NN

N

OH

C NNH3C NH+

CH3

CH3Cl-

HOBt

F3C

AminoglutethimideAminoglutethimide

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Pyrimidines

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

NHH2N

R4NN

R4

R1 R3

NHN

O

R1 R3NH2H2N

O

Instead of amidines, pyrimidines are obtained also by using guanidine, urea and thiourea

R2

O

R3

OR2

R1

R2

NN

NH2

R1 R3

R2

R2

NHN

S

R1 R3

NHH2N

NH2

NH2H2N

S

Pyrimidines

•Example: trimethoprim (bacteriostatic antibiotic)

NN

NH

NH2

NHH2N

NH2guanidine

FGI

OO

OEt

OO

OEtEtO EtO

OMe

NH2

OMe

NH2

OO

H

FGI

OMe

OMe

BrMeO

MeO MeO

MeO

MeO

MeO

MeO

MeO

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Pyrimidines

•Biginelli Reaction: acid‐catalyzed, reaction between an aldehyde, a,ß‐ketoester and urea constitutes a rapid and facile

synthesis of tetrahydropyrimidones.

•Synthesis of rac‐Monastrol (Mitosis blocker by kinase Eg5 inhibition)

Tetrazoles Carboxylic acid isostereCarboxylic acid isostere

SynthesisSynthesis

SynthesisSynthesis of of LosartanLosartan ((antihypertensiveantihypertensive))

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Indoles Fischer Indole Synthesis:

The The conversionconversion of of arylaryl hydrazoneshydrazones to to indolesindoles; ; requiresrequires elevatedelevated temperaturestemperaturesand the and the additionaddition of of BrønstedBrønsted oror Lewis Lewis acidsacids

Synthesis of Sumatriptany p

((Daniel Daniel LednicerLednicer:: StrategiesStrategies for for OrganicOrganic DrugDrug SynthesisSynthesis and Design)and Design)

Quinolines

QuinolineQuinoline nucleusnucleus is is usuallyusually formedformed in in oneone of of twotwowaysways

•Skraup‐reaction

MechanismMechanism::OH O

H2CNH2H+

O

OHHOH2C

H N

NH N

[O]

- 2 H2O

HH

NH

O

NH

OH

- H2O

H

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Quinolines•Doebner‐Miller –reaction: ‐unsaturated ketone or aldehyde can beused instead of glycerol to form a quinoline

ConradConrad‐‐Limpach reactionLimpach reaction: Synthesis of 4: Synthesis of 4‐‐oxyquinolines by oxyquinolines by condensation of esters of betacondensation of esters of beta‐‐keto acids with aromatic amines keto acids with aromatic amines

Quinolines

•Friedländer‐quinoline synthesis

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Isoquinolines

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

Isoquinolines

•Bischler‐Napieralski Reaction:

--PhenylethylaminePhenylethylamine is is acylatedacylatedthen then cyclodehydratedcyclodehydrated using using phosphorylphosphoryl chloride, phosphorous chloride, phosphorous pentoxidepentoxide or other or other lewislewis acids. This acids. This gives the gives the dihydroisoquinolinedihydroisoquinoline, , which can be aromatised by which can be aromatised by dehydrogenation with palladium. dehydrogenation with palladium. E.g. in the synthesis of E.g. in the synthesis of papaverinepapaverine

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Isoquinolines

•Pictet‐Spengler synthesis: β‐Arylethylamine is heated in the presence of an aldehyde and acid.

•A special case of the Mannich reaction.

SynthesisSynthesis of of TadalafilTadalafil

Isoquinolines

•Pomeranz‐FritschReaction NH2

EtO OEt

R

ON

OEt

OEt

R

N

O

R

C Pomeranz Monatsh 14 116 (1893)

+- H2O H3O

+

R

N

R

N

OH

- H2O

C. Pomeranz, Monatsh. 14, 116 (1893)P. Fritsch, Ber. 26, 419 (1893)

SchlittlerSchlittler--MüllerMüllerü eü e

ReactionReaction

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Quinolones•Retrosynthesis

Synthesis

Thiadiazoles•Synthesis of Timolol (‐blocker)

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Benzodiazepines The The retrosynthesisretrosynthesis of of diazepamdiazepam

The The synthesissynthesis of of diazepamdiazepam (Sternbach et al, 1961).

Cl

NH

CH3

Cl

N

O

CH3

C

O

ClPh

AlCl3Cl

N

O

CH3

ONaOH, H2O

Cl

NH

O

CH3

OCHCH

Ac2O

ClCl

Cl

N

O

CH3O

ClNH3

Cl N

NO

CH3

Diazepam

Benzodiazepines

Ugi Reaction (Ugi, I., et. al. Angew. Chem. 1959, 71, 386)

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

synthesis of heterocyclic compounds -...

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