 [2+2] cycloaddition:
benzoxazole
reactivity:
 salt formation, quaternization: analogous to oxazoles.
 nitration: substitution of the benzene ring at the 5- or 6-position.
 nucleophiles attack: at position 2.
• relatively acidic alkyl group at position 2:
synthesis:
 cyclocondensation: of o-aminophenol with carboxylic acids or their derivatives.
Paruch Medicinal Chemistry C9115Fused Five-Membered Heterocycles with 2 Heteroatoms
1
synthesis:
 cyclocondensation of o-aminothiophenols or their salts with carboxylic acids,
their derivatives or with aldehydes.
benzothiazole
reactivity: benzothiazole is a weaker base than thiazole.
 metallation: n-BuLi, at position 2.
 electrophilic substitutions: only on the benzene ring.
nitration → mixture of 4-, 5-, 6-, and 7-nitrobenzothiazole.
 reactions with nucleophilic reagents: analogous to thiazoles.
 cyclization:
Paruch Medicinal Chemistry C9115Fused Five-Membered Heterocycles with 2 Heteroatoms
2
 reaction with n-BuLi: Benzimidazoles substituted at position 1 → litiation at position 2.
 Mannich reaction:
benzimidazole
reactivity: benzimidazole is less basic than imidazole, but more NH-acidic.
• tautomerism:
Paruch Medicinal Chemistry C9115Fused Five-Membered Heterocycles with 2 Heteroatoms
 deprotonation of alkyl at position 2: relatively facile for N-protected benzimidazoles.
3
synthesis:
 cyclocondensation of o-phenylenediamine or substituted o-phenylenediamines
with carboxylic acids or their derivatives.
Paruch Medicinal Chemistry C9115Fused Five-Membered Heterocycles with 2 Heteroatoms
 electrophilic substitutions: first at position 5, then at position 6 or 7.
 reactions with nucleophiles: attack of position 2 (e.g. the Chichibabin reaction).
4
indazole
reactivity: indazole is less basic than pyrazole but a stronger N-H acid (pKa = 13.9).
 reaction with n-BuLi: 1-methylindazole → 1-lithiomethylindazole
2-methylindazole → 3-lithio-2-methylindazole
 alkylation: in the presence of bases proceeds via the ambident indazolyl anion
→ mixture of 1- and 2-alkylindazoles
 halogenation: preferentially at position 5
 nitration: with fuming nitric acid → 5-nitroindazole
 sulfonation (with oleum) → indazole-7-sulfonic acid
 coupling with diazonium salts: at position 3
Paruch Medicinal Chemistry C9115Fused Five-Membered Heterocycles with 2 Heteroatoms
5
synthesis:
 from o-substituted anilines:
1,2,5-oxadiazole (furazan)
Heterocycles 1984, 22, 1571.
reactivity: ca. 100 times less basic than isoxazole; only slow (if any) reactions with electrophiles.
 quaternization: slow, even with dimethyl sulfate.
 reactions with nucleophiles: do not react at all or only slowly.
synthesis:
 cyclodehydration of dioximes of 1,2-dicarbonyl compounds
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
find at least one drug
with the 1,2,5-oxadiazole motif
& its mode of action
6
reactivity:
 weak base.
 electrophiles preferentially attack the heteroatoms.
 nucleophiles attack position 5.
 quaternization with dimethyl sulfate → mixture of 2- and 3-methylated isomers
 reaction with nucleophiles → ring-opening.
 thermolysis and photolysis → elimination of N2.
synthesis:
 Hurd-Mori reaction: cyclocondensation of tosylhydrazones.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
1,2,3-thiadiazole
find the mechanism
of the Hurd-Mori reaction
7
1,2,4-thiadiazole
reactivity:
• weak base.
• electrophilic substitution at the C-atoms practically impossible.
 methylation: with CH3I occurs at N-4, with trimethyloxonium tetrafluoroborate at both Ns.
 reaction with hydroxides → ring-opening.
 reaction with HCl → ring-opening occurs via the 1,2,4-thiadiazolium ion.
 nucleophiles attack the position 5 and/or 3.
synthesis:
 oxidation of thioamides: with H2O2 or by the action of SOCl2, SO2Cl2 or PCl5.
 cyclocondensation of amidines: with trichloromethylsulfenyl chloride.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
8
1,2,3-triazole
reactivity:
 acid-base reactions:
• 1,2,3-triazole is a weak base, less basic than pyrazole.
• triazoles unsubstituted on the N-atom are NH-acidic.
(1,2,3-triazole pKa value is 9.3; comparable to HCN)
 tautomerism:
 metalation: N-substituted 1,2,3-triazoles are metalated by n-BuLi at low temperature.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
9
 reactions with electrophiles:
• acetylation, tosylation → usually mixtures of 1- and 2-isomers
• bromination (Br2) → 4,5-dibromo-1,2,3-triazole
• nitration: note: 2-phenyl-1,2,3-triazole undergoes nitration first on the benzene ring and
then on the 1,2,3-triazole ring.
 Dimroth rearrangement: with nucleophiles, 1,2,3-triazoles do not react at all or react
only slowly with ring opening.
 ring cleavage by pyrolysis or photolysis with loss of nitrogen.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
10
 dipolar cycloaddition: azides react with alkynes.
synthesis:
 oxidation: of bishydrazones of 1,2-dicarbonyl compounds.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
11
find at least 3 applications
of the „click reaction“ in cells
1,2,4-triazole
 tautomerism: two 1H-tautomers and one 4H-.
reactivity:
 acid-base reactions: 1,2,4-triazole is a weak base; protonation on N4 (pKa = 2.19);
1,2,4-triazoles unsubstituted on nitrogen are NH-acidic.
 reactions with electrophiles:
• the N-atoms are preferentially attacked.
• benzylation, methoxycarbonylation, trimethylsilylation, acylation → mainly 1-substituted
compounds.
• nitration, sulfonation: very slow
• bromination, chlorination (Br2 or Cl2) → (3)5-chloro- or 3(5)-bromo-1,2,4-triazole.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
12
 quaternization of 1-methyl-1,2,4-triazole with trimethyloxonium tetrafluoroborate:
synthesis:
 Einhorn-Brunner synthesis: hydrazines condense with diacylamines.
 Pellizzari synthesis: acid hydrazides cyclize with acid amides or thioamides.
 cyclocondensation:
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 3 Heteroatoms
13
benzotriazole
reactivity:
• benzotriazole is a very weak base;
but a stronger NH-acid than benzimidazole or 1,2,3-triazole (pKa = 8.2).
• forms complexes with metals → frequently used as a ligand.
• alkylation: → mixtures of 1- and 2-alkylbenzotriazoles.
• acylation, sulfonation: occur at N-1.
 reactions with electrophiles: only the benzene ring carbon atoms are available.
chlorination (mixture of concentrated HCl and HNO3) → 4,5,6,7 tetrachlorobenzotriazole,
nitration → 4-nitrobenzotriazole)
 Graebe-Ullmann reaction (dediazoniation of 1-phenylbenzotriazole).
synthesis:
 cyclocondensation of o-phenylenediamines with sodium nitrite under H+ conditions.
Paruch Medicinal Chemistry C9115Fused Five-Membered Heterocycles with 3 Heteroatoms
14
tetrazole
J. Am. Chem. Soc. 1998, 120, 4723.
reactivity:
 acid-base reactions:
• tetrazole is a very weak base; protonation occurs at position 4 (pKa = -3.0).
• of all azoles, tetrazole has the strongest NH-acidity (pKa = 4.9); comparable to acetic acid.
 tautomerism: 1H-form predominates over the 2H-form in solution.
 ring-chain tautomerism: 1,5-disubstituted tetrazoles can isomerize to give azidoimines.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 4 Heteroatoms
15
reactivity:
 metalation: 1-methyltetrazole is lithiated by n-BuLi in THF at -60 °C at position 5.
 reactions with electrophiles:
• quaternization → mixture of 1- and 2-methyltetrazole
• acylation (acyl halides) → at position 2 (but the products are not stable)
• nitration → substitution e.g. of the benzene ring, when available
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 4 Heteroatoms
(5-alkyltetrazoles substituted at position 1 undergo metalation of the alkyl
substituent as a result of the acceptor action of the tetrazolyl moiety.)
16
 thermal of photochemical extrusion of N2:
synthesis:
 [3+2] cycloaddition: azide + nitriles:
 reactions with nucleophiles: 5-halotetrazoles react with nucleophiles → substitution.
Paruch Medicinal Chemistry C9115Five-Membered Heterocycles with 4 Heteroatoms
17
imidoyl halides react with sodium azide:
• planar, slightly distorted hexagon with C-C and C-O bonds of approximately equal length
reactivity:
• pyrylium ion is an aromatic system.
• the distribution of the π-electron density can be represented by mesomeric structures.
• typical reactions: attack of nucleophiles onto the positions 2/6 and 4; and subsequent reactions.
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom: Pyrylium
18
 reactions with aqueous hydroxides:
 reactions with organometallic compounds: → predominantly form 2H-pyrans.
benzylmagnesium chloride is an exception → 4H-pyrans.
• this reactivity of pyrylium ions can be reversed by donor substituents at positions 2, 4 and 6.
• for instance, 2,4,6-tris(dialkylamino)pyrylium ions are stable towards nucleophilic attack, but are
easily substituted by electrophiles (e.g. HNO3/H2SO4 or BrCN/AlCl3).
• this behavior may be due to the fact that the donor-substituted pyrylium ion does not possess the
structure of cyclic delocalized 6π-systems, but rather that of a localized trimethine cyanine.
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom: Pyrylium
→→
19
 reactions with nucleophilic reagents: alkyl groups at positions 2, 4 and 6 display marked CH-acidity.
action of bases → deprotonation on CH groups attached to the ring forming 2- or 4-methylenepyrans.
 aldol condensation: regioselective
synthesis:
 condensation: 1,3-dicarbonyl compounds and aryl methyl ketones in acetic anhydride in the
presence of strong acids.
(chlorovinyl ketones or chlorovinyl immonium salts also condense with aryl methyl ketones.)
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom: Pyrylium
20
synthesis:
 Balaban synthesis: double acylation of propene derivatives with acid chlorides
or anhydrides in the presence of Lewis acids, e.g. AlCl3.
 Dilthey synthesis: in the presence of a hydride akceptor (e.g. FeCl3) chalcones afford
trisubstituted pyrylium salts.
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom: Pyrylium
21
• the parent compound has not yet been isolated; 2,2-disubstituted derivatives have been prepared.
reactivity: 2H-pyrans behave like oxacyclohexadienes.
 thermal ring opening: process is reversible → dienones can be used to prepare 2H-pyrans.
 [4+2] cycloadditions: with activated double/triple bonds.
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom: 2H-Pyran
22
• it possesses the bond parameters of an enol-lactone system with localized C-C double and single bonds
reactivity: behaves as 1,3-diene and also as a lactone.
 Diels-Alder reaction: with activated alkenes or alkynes.
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom: 2H-Pyran-2-one
23
 reactions with nucleophiles: attack on the C-atom of the carbonyl group.
 reactions with electrophiles:
 bromination → position 3 (higher temp.),
→ trans-5,6-dibromide (lower temp.)
synthesis:
 base-catalyzed cyclocondensation of alkynones with malonic esters
 Pd-catalyzed reaction: of allenyl stannanes with ß-iodo acrylic acids.
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom: 2H-Pyran-2-one
24
• oxa-analog of cyclohexene derived from 2H-pyran.
reactivity: reactions of electron-rich double-bonded systems.
 electrophilic addition: HX, HOX (X = halogen) or hydroboration.
 [2+1], [2+2] and [4+2] cycloadditions
 nucleophilic additions: e.g. with alcohols or phenols.
 ozonolysis:
synthesis:
 [4+2] cycloaddition: a,ß-unsaturated carbonyl compounds + vinyl ethers.
 intramolecular Wittig reaction:
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom
3,4-dihydro-2H-pyran
25
• chair conformation
• electronegative substituents (alkoxy groups, halogens) at position 2(6) prefer to adopt the
axial position (anomeric effect).
synthesis:
 cyclodehydration of 1,5-diols:
 acid-catalyzed cyclization of 4-hydroxybutyloxiranes
 cyclization of hex-5-en-l-ol with electrophilic halogen reagents
→ 2-substituted tetrahydropyrans
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom
tetrahydropyran
26
• in contrast to 2H-pyran, the parent compound 4H-pyran is known and spectroscopically characterized.
synthesis:
 cyclocondensation of ß-disbustituted enone systems with ß-keto esters
(via 1,5-dicarbonyl compounds):
 Diels-Alder reaction:
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom
pyran
27
• cross-conjugated, localized cycloenone system.
reactivity:
 irradiation → 4H-pyran-4-one isomerizes to 2H-pyran-2-one.
 O-alkylation: with strong electrophiles.
 electrophilic substitution: typically not regioselective.
 nucleophiles attack C-2 or C-4.
 reaction with Grignard reagents:
synthesis:
 y-acylation of 1,3-diketones with carboxylic esters.
Paruch Medicinal Chemistry C9115Six-Membered Heterocycles with 1 Heteroatom
4H-pyran-4-one
28