5-ČLÁNKOVÉ

AROMATICKÉ

HETEROCYKLY

(II.)

1

2

1,2- & 1,3-Azoles – Nomenclature

1,2-Azoles 1,3-Azoles

Bicyclic:

Monocyclic:

3

1,3-Azoles – Bioactive molecules

• Histidine (His) is an essential amino acid in humans and acts as a common coordinating ligand in metalloproteins.

• Histamine is produced by basophils and mast cells, triggers the inflammation and local immune responses.

• Thiamine is a water-soluble B1-vitamin synthesized only in bacteria, fungi, and plants, thus essential for mammals.

NATURAL

PRODUCTS

SYNTHETIC

DRUGS

• Cimetidine (Tagamet®) is a histamine H2-receptor antagonist used for the treatment of heartburn and peptic ulcers.

• Metronidazole (Flagyl®) is an antibiotic, amebicide, and antiprotozoal drug used for anaerobic bacteria and protozoa.

• Rosiglitazone (Avandia®) binds to the PPAR receptor, acts as an insulin sensitizer and is used as an antidiabetic drug.

1,3-Azoles – Comparison of aromaticity

4

• Aromaticity and bonding in oxazole, imidazole, and thiazole were investigated through the behavior

of the isotropic shielding σiso(r) within the regions of space surrounding these molecules.

• Aromaticity decreases in the order thiazole > imidazole > oxazole suggesting the detrimental effect of

second heteroatom with O exerting the strongest effect probably due to its highest electronegativity.

LEAST

AROMATIC

MOST

AROMATIC

K. E. Horner, P. B. Karadakov: Shielding in and around Oxazole, Imidazole, and Thiazole: How Does the Second Heteroatom

Affect Aromaticity and Bonding? (J. Org. Chem. 2015, 80, 7150−7157).

1,3-Azoles – Imidazole – Structure and properties

5

• N-unsubstituted imidazoles are subject to tautomerism, and the rapid equilibrium hampers the isolation of isomers.

• In some pairs, one tautomer predominates, for example 4(5)-nitroimidazole favours the 4-nitro-tautomer by 400:1.

• Imidazole is a planar, 5-membered aromatic heterocycle (6pe) with the sp2-nitrogen lone pair lying in the ring plane.

• Imidazole, like water, is both a good donor and acceptor of H-bonds. The imine nitrogen donates an electron pair

and the N-hydrogen, being appreciably acidic, is an acceptor – this is the mode of action of several human enzymes.

• Imidazole (pKHA 7.0) is more basic than pyrrole (pKHA 0.4) and/or pyridine (pKHA 5.2) due to the amidine-like resonance.

• Imidazole is also more acidic (pKA 14.5) than pyrrole (pKA 17.5) as both N-atoms share the charges between each other.

p-electron

densities

1,3-Azoles – Imidazole – Reactivity – SEAr (Nitration)

6

Mechanism:

Application:

Metronidazole

SE of imidazole:

• C2-substituted imidazoles easily undergo SEAr (e.g. nitration) producing the equilibrating mixture of tautomers.

5 4

The tautomerism can be

stopped by alkylation at

one of the nitrogen atoms.

1 3 13

1,3-Azoles – Imidazole – Reactivity –SEAr (Halogenation, Sulfonation)

7

• (1-Alkyl-)-Imidazoles are brominated („SE“) with remarkable ease at all free nuclear positions including C-2.

• Substitution generally occurs first at C-2, but SE proceeds further yielding 2,4,5-tribromoimidazole as end-product.

• The first step involves an AdE of Br2 to imine nitrogen, then addition of Br- at C-2, and finally elimination of HBr.

4

2

• Imidazole can be sulfonated (SE) with concentrated sulphuric acid at elevated temperature at C-5 position.

• Thiazole is much less reactive, generally requiring higher temperatures and HgSO4 as catalyst for any

reaction to take place. On the other hand, electrophilic oxazole sulfonations are unknown up to date.

1,3-Azoles – Imidazole – Reactivity – N-Alkylation/Acylation

8

• Imidazole is easily quaternised (N-alkylated) at the imine nitrogen with alkyl halides (RX). The intermediate

is a protonated N-alkyl-imidazole, which looses its N-hydrogen to unreacted imidazole (acting as a base).

• The subsequent reaction produces the mixture of imidazolium, 1-alkyl- and 1,3-dialkyl-imidazolium salts.

• Due to interaction between the basic nitrogen and Lewis acid, Friedel-Crafts acylations of azoles are unknown.

• However, the aroylation of imidazole with benzoyl chloride in the presence of base (Et3N, NaOH) is feasible.

• N-acylation of imidazole yields N-acyl-imidazoles via deprotonation of initially formed N-3-acyl-imidazolium salts.

• The N-acyl-imidazoles are hydrolytically unstable and are rapidly deacylated even by standing on moist air.

• This property of N-acyl-imidazoles has found a useful synthetic application:

• Commercially available 1,1´-carbonyldiimidazole (CDI), made from imidazole

and phosgene (COCl2), can be used as a safe, phosgene synthon, and also

in the activation of carboxylic acids for the formation of amides and/or esters.

1,3-Azoles – Imidazole – Reactivity –Deprotonation / Metalation

9

• Imidazole (pKA 14.5) is appreciably stronger acid than pyrrole (pKA 17.5), thus the former is easily deprotonated.

• One convenient method is to use the dry Na/K- salt obtained by evaporation of an aq. alkaline solution or NaH/DMF.

• The stable, delocalised imidazolyl anion can be subsequently alkylated, acylated or sulfonylated on nitrogen atom.

• Metal-halogen exchange of 4(5)-bromo/iodoimidazoles can be done by BuLi or MeMgCl/LiCl without N-protection.

• Such formed dilithium salt can be trapped with an electrophile to furnish the corresponding addition product.

5-Membered azoles with multiple N-atoms –Triazoles – Structure and Properties

10

• There are two groups of triazoles – 1,2,3- and 1,2,4- – according to the relative positions of N-atoms within the ring.

• Both 1,2,3- and 1,2,4-triazole contain one „pyrrole-like“ N-atom and two „pyridine-like“ N-atoms in their structure.

• Both tautomerise (with 1,2,3-triazole the tautomers are identical) and both are deprotonated to the delocalised anion.

• Fluconazole (Diflucan®) is a 1,2,4-triazole antifungal drug used in the treatment and prevention of fungal infections.

1

3

1 2

2

4

5-Membered azoles with multiple N-atoms –Synthesis of 1,2,3-triazoles via cycloaddition

11

• The copper-catalysed azide-alkyne cycloaddition (Cu-AAC) features an enormous rate acceleration of 107 to 108 compared

to the uncatalysed 1,3-DCA. It succeeds over a broad temperature range, is insensitive to aqueous conditions and a pH

range over 4 to 12, and tolerates a broad range of functional groups. Pure 1,4-disubstituted triazoles can be isolated by

simple filtration or extraction without the need for tedious chromatography or time-consuming recrystallisation.

((

• The 1,3-dipolar cycloaddition (1,3-DCA) is highly exothermic, but the high activation barrier is responsible for a very low

reaction rate, even at elevated temperature. Another drawback is the formation of two regioisomers, as the two possible

HOMO-LUMO interactions of the substrates are closely related in terms of energy. The thermal reaction therefore often

gives approximately 1:1 mixtures of both the 1,4- and the 1,5-disubstituted regioisomers of desired 1,2,3-triazoles.

The disconnection of 1,2,3-triazoles via cycloaddition requires an alkyne and an azide which can be combined in 2 ways:

N

N

NR´

R

N

N

NR´

vs.

1,4-disubstituted1,2,3-triazole

1,5-disubstituted1,2,3-triazole

R

R

N N NR´

+

R

N N NR´

+

Rolf Huisgen

(1920)

Inventor of 1,3-DCA

Münich University

„Click Chemistry“

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The term „Click Chemistry“ was coined by K. Barry Sharpless and describes chemistry tailored to generate molecules

quickly and reliably by joining small units together in a biomimetic manner (Ref.: Angew. Chem. Int. Ed. 2001, 40, 2004).

➢ A desirable Click chemistry reaction would:

• be modular,

• be wide in scope,

• give very high chemical yields,

• generate only inoffensive by-products,

• be stereospecific,

• be physiologically stable,

• exhibit a large thermodynamic driving force (> 84 kJ/mol)

to favor a reaction with a single reaction product. A distinct

exothermic reaction makes a reactant "spring-loaded".

• have high atom economy.

➢ The process would preferably:

• have simple reaction conditions,

• use readily available starting materials and reagents,

• use no solvent or use a solvent that is benign or easily removed (preferably water),

• provide simple product isolation by non-chromatographic methods

(preferably crystallisation or distillation).

Karl Barry Sharpless

(1941)

The Scripps Research Institute

Nobel Prize in Chemistry 2001

(with W.S. Knowles and R. Noyori)

5-Membered azoles with multiple N-atoms –„Click Chemistry“

5-Membered azoles with multiple N-atoms –Tetrazoles – Structure and Properties

13

• There exists only single isomer of tetrazole and it has two tautomers.

• Tetrazole (pKA ~ 5) is as acidic as carboxylic acids making it an ideal

structural replacement (an isostere) for -CO2H group in medicinal drugs.

• Tetrazoles are generally surprisingly stable, although tetrazole itself

(m.p. 158°C, decomposes > 180°C) is strictly classified as an explosive.

• The isosteric replacement of -CO2H group for a tetrazole reduced the gastric irritation while retaining the NSAID activity.

12

34

5-Membered azoles with multiple N-atoms –Synthesis of tetrazoles via 1,3-dipolar cycloaddition

Synthesis of tetrazoles via 1,3-DCA 14

Retrosynthesis of tetrazoles via 1,3-DCA

• The disconnection of tetrazoles with 1,3-DCA requires nitrile (RCN) as a common component. The other one would

be either hydrazoic acid (HN3) for the neutral compound or the azide (N3-), thus leading to an anion of the tetrazole.

Toxic & explosive!

• The reaction works well if an ammonium chloride buffered mixture of sodium azide and the nitrile is heated in DMF.

• The reagent is ammonium azide (NH4+N3

-) and the reaction occurs faster with electron-withdrawing substituents.

• First, the anion of the tetrazole is formed but subsequent neutralisation with acid finally gives the free tetrazole.

5-Membered azoles with multiple N-atoms –Green synthesis of tetrazoles via 1,3-DCA

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• Convenient, rapid and metal free synthesis of 5-substituted-1H-tetrazoles is described by [3+2] cycloaddition reaction

of nitriles with sodium azide. The reaction was catalyzed by mesoporous cuttlebone in DMSO at 110 °C.

• Mechanism involves the “electrophilic activation” of RCN through H-bond formation between the cuttlebone and nitrile.

• Cuttlebone as a natural low cost heterogeneous catalyst with high porosity, high flexural stiffness, high compressive

strength and high thermal stability affords 5-substituted-1H-tetrazoles rapidly with high efficiency.

(S. S. E. Ghodsiniaa, B. Akhlaghinia: RSC Adv., 2015,5, 49849-49860)

(85-98%)

5-Membered azoles with multiple N-atoms –Tetrazole-based explosives

(Org. Lett. 2008, 10(20), 4665–4667.)

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• 5-Aminotetrazole is used as a high-speed inflator in car airbags via a controlled explosive liberation of nitrogen.

5-Membered azoles with multiple N-atoms –Tetrazole-based explosives – 1,1´-Azobis(tetrazole)

(T. M. Klapotke , D. G. Piercey: Inorg. Chem. 2011, 50 (7), 2732–2734)17

Synthesis of 1,1´-azobis(tetrazole) from 1-aminotetrazole

The result of an attempt to isolate pure and dry 1,1´-azobis(tetrazole)...

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5-Membered azoles with multiple N-atoms –Synthetic approaches to aminotetrazoles

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Zhrnutie: Syntéza aromatických heterocyklov

• Vytvorenie heterocyklu iónovými reakciami

▪ Paal-Knorr (pyrol, furán, tiofén...)▪ Hantzsch (pyridín...)

• Vytvorenie heterocyklu pericyklickými reakciami

▪ Cykloadície (tetrazol...)▪ Fischer (indol...)

• Modifikácia už existujúceho heterocyklu

▪ SE (pyrol, furán, tiofén, indol...)▪ SN (pyridín, chinolín...)▪ Lítiácie (pyrol, furán, tiofén...)

19

Zhrnutie: Syntéza aromatických heterocyklovVytvorenie heterocyklu iónovými reakciami

20

Zhrnutie: Syntéza aromatických heterocyklovVytvorenie heterocyklu pericyklickými reakciami

21

Zhrnutie: Syntéza aromatických heterocyklovModifikácia už existujúceho heterocyklu - SE

22

Zhrnutie: Syntéza aromatických heterocyklovModifikácia už existujúceho heterocyklu – SN a lítiácia

23

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SYNTÉZA HERBICÍDU

PACLOBUTRAZOLU

Efektívny a účinný herbicíd

Paclobutrazol (Pestanal, Cultar, Bonzi)

• Triazolový fungicíd, herbicíd a regulátor rastu neželanej vegetácie.

• Funguje ako účinný inhibítor biosyntézy fytohormónov giberelínov.

• Extrémne nízke efektívne dávky, selektívna likvidácia „širokolistých“

rastlín - efekt lokálnej koncentrácie v závislosti od plochy olistenia.

N

N

N

OH

Cl

25

Rastové fytohormóny – Giberelíny

Fusarium moniliforme

OH

CO2H

HO2C

HO

H3C

H

H

giberelín 452D

Ryža siata (Oryza sativa)

1926 - Eiichi Kurosawa

バカナエ (bakanae)

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Príprava Paclobutrazolu – (Retro)Syntéza

N

N

N

OH

Cl N

N

N

O

X

O

N

N

HN

+

O Br2, AlCl3

dietyléter

O 1,2,4-triazol

K2CO3, acetón

Br

O

NN

N

NaH, THF

Cl

Br

N

N

N

O

Cl

NaBH4

MeOH N

N

N

OH

Cl

27

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SYNTÉZA VÝBUŠNINY

ANTA

Vysokoúčinné explozívum

ANTA (5-amino-3-nitro-1,2,4-triazol)

• Energetická výbušnina, vypočítaná VoD ~ 8460 m/s.

• Vykazuje značnú termálnu stabilitu (b.t. = 238°C).

• Má extrémne nízku senzitivitu na mechanický náraz.

N

N

NH

NH2

O2N

29

Príprava ANTA – Syntézy

30

N

N

NH

O2N

NH2

10% HCl

reflux5 h

N

N

NH

O2N

NHAc

HNO3/AcOH

0-25°C5 h

N

N

NH

NHAc

Ac2O, H+

reflux

1 h

N

N

NH

NH2

5-amino-1,2,4-triazole

ANTA

N

N

NH

O2N

NH2

NH2NH2.H2O

80°C, 1.5 hN

N

N

O2N

NO2N

N

NH

NO2

H2SO4, NaNO2

60°C, 1 hN

N

NH

NH2

3,5-diamino-1,2,4-triazole

ANTA

H2N O2N

NH4+

NH3

(overall 50%)

(~ 20%)

-

(70%)(90%)

(80%)

•Starting from commercially available 5-amino-1,2,4-triazole, the originally developed three-step synthesis is the most

direct route to ANTA. However, this sequence suffers from variable and very poor yields (~ 20%) in the nitration step.

•The alternative two-step synthesis of ANTA, starting from commercially available 3,5-diaminotriazole, employs

the problematic nitration first. However, its scale-up poses a challenge due to the presence of diazonium salts.