Synthesis of heterocyclic compounds

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1. Synthesis of heterocyclic compounds. Tapio Nevalainen. Drug synthesis II. 2010 http://www.scripps.edu/chem/baran/heterocycles/. Heterocyclic compounds.

Synthesis of heterocyclic compounds

Tapio Nevalainen Drug synthesis II 2010

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

Heterocyclic compounds • Heterocycles contain one or more hereroatoms in a ring

X X Y

X Z

Y

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

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Heterocycles • Aromatic five‐membered heterocycles

Heterocycles • Aromatic six‐membered heterocycles

5

7 8

5

4

6

N 1

quinoline

3

6

2

7 8

5

4 3

6

N2

7

1

isoquinoline

8

4

N

5

N3

6

2

7

1

quinazoline

8

4

N N

3 2

1

quinoxaline

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Heterocycles • Aliphatic heterocycles

Heterocycles • Tautomerism

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Reactions of heterocycles Five‐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 2 the 2‐‐position is more reactive than  the 3‐position the 3‐ p

Reactions of heterocycles Vilsmeier reaction (Vilsmeier‐Haack  reaction) allows the formylation of  heterocyclic and electron‐rich  arenes. The formylating agent,  y g g , chloroiminium ion, is formed in situ  from N,N‐dimethylamide and POCl3

O H N H

CH3 N CH3

1. POCl3

O H

N 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. CH3 HN CH3 N H3C

CH2=O Mannich reaction

N H3C

H3C N CH 3

H3C

O

N CH3

H3C N CH 3

Tolmetin

 Five Five‐‐membered heterocycles act as dienes act as dienes in Diels– in Diels–Alder reactions

Common building‐blocks for  heterocyclic compounds

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General strategies for heterocycle synthesis • ”1+4” strategy

”1+5” strategy



General strategies General  strategies for  for heterocycle heterocycle synthesis ”2+3” strategy ”2+3”  strategy







”3+3” strategy ”3+3”  strategy

Examples O X

H2N

H2N

O

HO

O

H2N

O H

X

H2N

O X X = Cl, Br, I

O O

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Reactions used in heterocyclic ring synthesis Aldol‐‐type reactions of  Aldol of enols enols or enolate anions with electrophiles.  electrophiles. 





Imine/enamine formation

Reactions used in heterocyclic ring  synthesis •Enamine is tautomeric form of imine. If dialkylamine is  used, enamine is formed used, enamine is formed



H R2

N

Enamines can function as  as enolates enolates H

O

H

R3

R1 enamine

N

H

H R1 OH R3

R2

R4 R4

N

H

+

-H

+ H+

H R1

R2 R3

O

H - H2O

N

R1

R2

- H+

N

R4

H R1

R2

R3

R3

H R4

H

H

R4

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Reactions used in heterocyclic ring  synthesis •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 Knorr

Feist--Benary Feist

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Thiophenes  Paal Knorr



•Hinsberg Synthesis of Thiophene Derivatives 



Gewald reaction

Pyrroles •Knorr pyrrole synthesis: Condensation of ‐aminoketone  and ‐ketoester 



Paal--Knorr PyrrolePaal Pyrrole-Synthesis: condensation amine and 1,4 1,4--ketone 

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

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



Huisgen Pyrrole Synthesis

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

From Amino acids and alkynes. Example: atorvastatin

1,2‐Azoles Pyrazoles can be synthesized from 1,3 1,3‐‐dicarbonyls  with hydrazine





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

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1,2‐Azoles  Example of pyrazole synthesis: Rimonabant

1,2‐Azoles The synthesis of sildenafil (Viagra)

Retrosynthesis

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1,2‐Azoles The synthesis of sildenafil (Viagra)

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

1,2‐Azoles The synthesis of sildenafil (Viagra) O OEt O

H2N Cl +

O C 3 CH N N pyridine

H2N

CH3 N N

H2N EtO

CH3

EtO

HN

ClSO2OH

CH3 N N

N CH3 O EtO

HN

HN

CH3 N N

N N

CH3

HN

CH3

OEt

CH3 N N

N

O S O Cl

NaOH

HN O

O

O EtO

CH3

CH3

O S O N N

CH3

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

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1,2‐Azoles synthesis of isoxazoles 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

1,3‐Azoles •Oxazoles  and thiazoles can be obtained by the  Robinson‐Gabriel synthesis from 2‐acylamino‐ketones.



2‐acylamino acylamino‐‐ketones reacts  with phosphorus  pentasulfide to form thiazoles pentasulfide to form  thiazoles

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1,3‐Azoles • Oxazoles  can be made by Blümlein‐Lewy Synthesis: heating an  haloketone with amide



Most important method for thiazoles for thiazoles is  is Hantzsch Hantzsch thiazole synthesis from thioamides and a and a‐halocarbonyl compounds

1,3‐Azoles  

Example:: synthesis of nizatidine Example

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1,3‐Azoles:  Synthesis of imidazoles •From amidines and hydroxy or halocarbonyl compounds 



Debus‐Radziszewski imidazole synthesis Debus‐ synthesis:: diketone and ammonia form an diimine, which condenses with  the aldehyde the  aldehyde

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).  R3 N

O R1

NH2

+ H

R2

- H2O

R1

C R2

N

O S O

CH3

TOSMIC

C N

R3 N R1

Ts Base H R2

N N R1

R3 R2

O S

+

Ts

N R H 2 R1

Base N

R3

OH

H3C

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

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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-1Himidazole



O

H N HO

CH3

HO

N

H2N OH

CH3

HN

Cl

Cl O HO

H2N + OH HN

H N

NH3, MeOH

CH3

HO

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

H N HO

CH3 N

HN

N N N

CH3 N

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

N HO

CH3 N

Cl Losartan

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

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Dihydroimidazoles Clonidine (anti-hypertensive agent)

Oxymetazoline (topical decongestant) HO

CH3

HO

CH3

HO Cl

CH2O/HCl

H2N

CH3 CN

KCN

HO

CH3

H2N

H N

235°C, N2 CH3

CH3

CH3

CH3 N Oxymetazoline

1,4‐Dihydropyridines • 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, vitamin B6, has been synthesised by  Guareschi ring synthesis

Glutarimides 

Thalidomide

O NH2

O

O O

H2N

O

Ac2O N

N

O

O O

O CO H 2

F3C CO2H

O 2-phthalimido-D-glutaric acid

NH2 HOBt EDCCI

O O Thalidomide

O O N

O NH

O O (R)-Thalidomide

HOBt = N-hydroxybenzotriazole N N N OH EDCCl = N-(3-dimethylamino)propylN'-ethylcarbodiimide hydrochloride

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



O NH

OH

O

N

O

NH2

OH

N N C

CH3 NH+ Cl CH3

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

R4

N

N

NH

H2N

R3

R1

O

R2

R3

R1 NH2

NH2

N

N

H2N

NH

R2

S

S

NH

N

NH2

H2N

R3

R1

R3 R2

O

O

NH

N NH2 R1

H2N

R3

R1

R2

R2

Pyrimidines •Example: trimethoprim (bacteriostatic antibiotic)  NH2 N

NH2

N

H2N NH2

O

O

guanidine EtO FGI

O

MeO

MeO

NH2

EtO

O OEt Br

MeO MeO OMe

OMe

OEt

MeO

MeO H

O

O

NH

MeO OMe

MeO OMe

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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 isostere Synthesis

Synthesis of Losartan (antihypertensive antihypertensive))

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Indoles 



Fischer Indole Synthesis:

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

Synthesis y of Sumatriptan p

(Daniel Lednicer Lednicer::

Strategies for Organic Drug Synthesis and Design)

Quinolines 

Quinoline nucleus is usually is usually formed in  in one one of  of two two ways

•Skraup‐reaction



O

Mechanism:

OH HO

+

H OH O

O

H2C

- 2 H2O

NH2

H

N H H

H OH [O]

N H

N H

- H2O

N H

N

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Quinolines • Doebner‐Miller –reaction: ‐unsaturated ketone or aldehyde can be used instead of glycerol to form a quinoline



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

Quinolines •Friedländer‐quinoline synthesis

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Isoquinolines 

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

Isoquinolines •Bischler‐Napieralski 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 •Pictet‐Spengler synthesis: β‐Arylethylamine  is heated in the  presence of an aldehyde and acid. • A special case of the Mannich reaction. 

Synthesis of Tadalafil

Isoquinolines • Pomeranz‐ Fritsch Reaction

EtO O R

+

OEt

OEt - H2O

O

OEt

H3O+ N

N

H2N

R

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

OH - H2O N R



N R

SchlittlerSchlittlerMüller ü e Reaction

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Quinolones •Retrosynthesis



Synthesis

Thiadiazoles •Synthesis of Timolol (‐blocker)

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Benzodiazepines

 The retrosynthesis of diazepam

 The synthesis of diazepam (Sternbach et al, 1961). O CH3 NH Ac2O Cl

O N

N

O Ph C Cl

CH3

AlCl3

CH3 O

Cl

CH3 N H NaOH, H2O

O

Cl

Cl CH3 O N

CH3 O N NH3

Cl

N

Cl

O

O Cl

Cl

Cl

Diazepam

Benzodiazepines 

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

71, 386)



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

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