5 Lec Heterocyclic
5 Lec Heterocyclic
5 Lec Heterocyclic
compounds
Tapio Nevalainen
Drug synthesis II
2008
N N N N
N N
N N N O S N
H H H H
pyrrole pyrazole imidazole oxazole thiazole triazole
N N N N N
N N N N
N N N N N N
16.5 14,2 14,4 9,3 10 4.9
1
Basicities of Six-Membered Heteroaromatics and Non-
Heteroaromatics
Basicities of Azines (pKa values)
values)
N N
N N N
N N
N N N N N N
NH3 N N N
H H H N
NH2 H
ammonia pyrrolidine piperidine aniline indoline tetrahydroquinoline
9.3 11.3 11.2 4.6 4.9 5.0
Pyrrole synthesis
synthesis: Condensation of α-Aminoketone and β-
Knorr pyrrole synthesis:
ketoester O
O O CH3
R O R O
AcOH R O
+ O CH3 O CH3
R' NH2 R' R''
O R'' R' N R'' N
H H
Paal- Pyrrole-Synthesis: condensation amine and 1,4-
Paal-Knorr Pyrrole- 1,4-ketone
Example: 1,2-
1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-
Cyclooxygenase-2 (J.
(J.
Med. Chem., 40 (11), 1619 -1633, 1997)
Med. Chem.,
NH2
O O OEt
TsOH N
+ OEt O
MeO2S
O
MeO2S
F
TsOH = Toluenesulphonic acid
F
2
Pyrrole synthesis
Hantzsch pyrrole synthesis: from α-holomethyl ketones, β-keto
esters and ammonia or amines
OEt O O
OEt
O O EtO OEt
+ PhNH2 + Br
O O CH3
N
H CH3
Ph
A. Hantzsch, Ber. 23, 1474 (1890)
R' R'
R' R' ∆
+ NH3
HCl R N R
R N N R
H
Thiophenes
Hinsberg Synthesis of Thiophene Derivatives
R R R
R S CO2R'
tBuOK
+
O R'O2C CO2R'
O R'O2C S
Paal Knorr
R' P2S3
O O R R' S CO2R'R
Gewald reaction
OR'' O
R'
O S8 R''O R'
O
+
R H2N R
N S
3
Furans
Paal Knorr
R' H+ OH
R R' O R - H2O R' O R
O O
Feist-
Feist-Benary
CO2Et
O EtO2C Cl EtO2C
R'
+ - HCl
OH R OH
Cl O - H2O R O R'
R R'
Pyrazoles
Pyrazoles can be synthesized from 1,3-
1,3-dicarbonyls with
hydrazine CH
CH3 3
H2NNH2, NaOH
H3C O H3C N
H2O, 15°C N
O H
4
Example of pyrazole synthesis:
Rimonabant
+
Li O
H3C H3C OEt
1. LiHMDS. ether -
Cl O Cl O
2. NH2
O EtO O
1. HN
OEt 2. AcOH
Cl
O
O
O
N H3C
H3C Cl OEt
N
H
N
N N
N Cl
Cl Cl
Cl
SR-141716A
Rimonabant (Acomplia)
Cl
Cl
Retrosynthesis
O CH3 O O
CH3 CH3
OEt HN
N N N
OEt HN H2N
N OEt N
N
N CO2H H2N
N
O
O CH3 O CH3 O CH3 O
O
N N N O RO
H2N RO RO RO
N N N O OR
H2N O2N
O
H3C
CH3 CH3 CH3 CH3
CH3
5
Pyrazoles: The synthesis of sildenafil (Viagra)
O O O CH3
O H
O N 1. (MeO)2SO2 N
H3C EtO EtO HO
(CO2Et)2 O H2N NH2 N N
base 2. NaOH/H2O
H2O
CH3
CH3 CH3 CH3
HO N H2N N H2N N
HNO3 1. SOCl2 H2
N N N
O CH3
O CH3 O CH3
N
OEt O N H2N N
H2N N OEt HN
N pyridine NaOH N
Cl + H2N
HN
N
O
CH3
CH3 CH3
OEt
O CH3
O CH3
N
N OEt HN
OEt HN N
N
ClSO2OH HN N
N
N
CH3
CH3
CH3 O S
O S O
O N
Cl
N
CH3
Bioorg.
Bioorg. Med. Chem. Lett.
Lett. 6, pp. 1819, 1996
Isooxazoles
Oximation of 1,3-
1,3-Dicarbonyl Compounds
HO NH2 O N
O O NaOH
OH
OMe H2O/MeOH
Cl2 Cl Et3N +O
OH N PhNCO
R N OH R NO2
R N R or Ph3P, DEAD
nitrile oxide
6
Azoles
1,3-azoles are made in general from 1,4-dicarbonyls
by Paar-Knorr cyclization.
O N
H H2SO4
R N R'
R
R' ∆ O
O
O R''
H NH4+OAc- H
R N N
R''
HOAc, 120°C R R'
O R' N
O
H N
R N 120°C
+ P2S5
R' R R'
S
O
Imidazoles
Cl CH3 CH3
N N H H CH3
NH2 N N
HN S CH3 H3C H
N N N N
H H H N N CH3
Cl CN
CH3 N
Histamine Clonidine Cimetidine Xylometazoline
Synthesis of 1,2,5-
1,2,5-Trisubstituted Imidazoles from
N-monosubstituted amidines and 2- 2-halo-
halo-3-alkoxy-
alkoxy-
2-propenals
R' Br X R'
NH K2CO3 X
N
R + X = CHO, CN
R O
NH O CHCl3/H2O N OH
O
J. Org Chem. 1997, 62, 8449 N
OH
N
Eprosartan S
7
Imidazoles
Cimetidine
O O
O O
2 H2N H O
O O N O N
Bredereck-reaktio* N O
Cl + HN O +
O H H O
H
H H H
H
NH2 S N
O HS
LiAlH4 NH2 N
HN O HN OH HN S CN
N N N
Imidazoles
2-butyl-
butyl-4(5)-
4(5)-chloro-
chloro-5(4)-
5(4)-hydroxymethyl-
hydroxymethyl-1H-
1H-
imidazole
H O H2N
N CH3
CH3 HO
HO OH NH
N Cl
Cl
O NH3, MeOH H
H2N N
+ CH3 CH3
HO N
OH NH HO N HN N
N
1. Me3SiCl,
2.Chlorosuccinimide H
N
3. Zn, AcOH CH3 N
CH3
HO N HO N
Cl
Cl
Losartan
Synthetic Communications (1993), 23(18), 2623-30.
8
Dihydroimidazoles
Clonidine (anti-
anti-hypertensive agen)
agen)
Cl Cl Cl Cl
+ CH3 H2N H
NH4 S S S N
N CH3I
NH2 N C NH2 N C N
H H NH2 H
NH .HI N
Cl Cl Cl Cl
Clonidine
CH2O/HCl Cl KCN CN
H2N H
235°C, N2 N
CH3 CH3 CH3 CH3 N
Oxymetazoline
Imidazoles
The reaction of aldehydes,
aldehydes, primary amines and
toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5-
1,4,5-
trisubstituted imidazoles (A. M. van Leusen,
Leusen, J. Wildeman,
Wildeman, O.
H. Oldenziel,
Oldenziel, J. Org.
Org. Chem. 1977, 42,
Chem. 1977, 42, 1153. A. M. van
Leusen,
Leusen, Heterocycl.
Heterocycl. Chem. 1980, 5, S-
Chem. 1980, S-111)
R3
O
S NC R3
O CN Tos
NH2 CHO - H2O R1
R1 + R2 N R2 H 3C TOSMIC
R1
B N R2
R3 R3
Tos
N N O
B S
N R2
+ OH
N R2
H3 C
R1 R1
http://www.organic-chemistry.org/Highlights/2005/05May.shtm
9
S H
H3C S N NH2 Cl CH3
N N +
NO2 N N
Thiazoles
H3C H3C N
H
H3C N S
Nizatidine (H2-antihistamine) OH
Thiamine (vitamin B1)
S Br
Me Br NaOEt Me S 1. LiAlH4 S
CO2Et CO2Et Me
N NH2 + N N 2. PBr3
O N N
Me Me Me
2-dimethylamino- 2-dimethylaminomethyl-
thioasetamide thiazol-4-carboxylic acid
ethylester HS
NH2
MeS
S HN NO2
S H S
Me N Me Me S NH2
N N N N
Me Me N NO2
H Me
Nizatidine
Oxazoles
The oxazole ring is constructed by heating an α-haloketone with amide
R' H
O R' 100 °C O O
Br O
+ R'
R NH2 O - HBr O R' - H2 O R N
R NH R N OH
Oxazole ring can be formed also from amide and vinylene carbonate or acid
chloride and 1,2,3-
1,2,3-triazole
O
O O
O NH2
vinylene O N
(Ph3P)4Pd,
carbonate O N HO OH aq Na2CO3,
B
PPA EtOH/toluene
+ R
Br
H
N R
N /K2CO3
O Cl Br
N
S
O O
Sulfolane J. Med. Chem., 43 (16), 3111 -3117, 2000
Br
10
1,4-Dihydropyridines
Hantzsch Dihydropyridine (Pyridine) Synthesis
• 4-Aryl-1,4-dihydropyridines (e.g. nifedipine) are calcium channel
modulators for the treatment of cardiovascular diseases such as
hypertension, cardiac arrhythmias, or angina.
CO2Me
CO2Me
NH3 H2N Me NO2
+
NO2 NO2 MeO2C CO2Me
O Me
CHO CO2Me
Me N Me
O Me H
Nifedipine
CO2Me NH3
NO2
O Me MeO2C CO2Me
Me Me
O O
Glutarimides
Thalidomide O
NH2
O
O O
H2N O NH2
Ac2O
OH
O N O
O N
N
OH H
O O O
O O
Thalidomide
O
O CO H O
2 CF3
CO2H NH2 HOBt = N-hydroxybenzotriazole
N N O N
HOBt N N
N
O EDCCI O O H OH
2-phthalimido-D-glutaric acid (R)-Thalidomide
EDCCl = N-(3-dimethylamino)propyl-
N'-ethylcarbodiimide hydrochloride
Tetrahedron Letters (1999), 40(19), 3697-3698.
CH3
N +
Cl
H3C N
N H CH3
Aminoglutethimide
O2N O E tO O2N H2N
O2N O H2SO4
OE t Ac OH H2
CN O O
Bu 4N+OH- N Ni N
C H H
N O O
Aminoglutethimide
(Aromatase Inhibitor,
breast cancer)
11
Pyrimidines
From 1,3-dicarbonyl compounds and amidines
Example: trimethoprim (bacteriostatic antibiotic)
NH2 NH2
guanidine O O O O
N N H2N NH
EtO OEt EtO OEt
NH2 O O FGI MeO Br
MeO
MeO
H NH2
MeO
MeO
MeO OMe MeO
OMe
OMe
MeO
OMe
O O
O
MeO
OMe MeO MeO
OMe OMe
Pyrimidines
Biginelli Reaction:
Reaction: acid-
acid-catalyzed,
catalyzed, reaction between an aldehyde,
a,ß-
a,ß-ketoester and urea constitutes a rapid and facile synthesis of
tetrahydropyrimidones.
tetrahydropyrimidones.
Ph
Ph
H O
H+ EtO2C
EtO2C NH Biginelli, P. Gazz.
+ NH2 Chim. Ital. 1893, 23, 360.
EtOH, ∆ R N O
R O H 2N O H
Yb(OTf)3
H O
EtO2C Dondoni, A., et. al.
EtO2C THF, reflux NH Tet. Lett. 2001, 43, 5913
+ NH2 12h
H3C N S
H3C O H2N S H
(+/-) Monastrol
12
Tetrazoles
N N N N
Carboxylic acid isostere N NH N N +
+ H
Synthesis R R
pKa = 5
NaN3, NH4Cl R N R R
+
N H N
R N
LiCl, DMF + N N N NH
100 °C N N N N N
H
N N
CH3 CH3
HO N (HO)2B HO N
Br Cl
N Cl
CH3
(HO)2B DMA HO Losartan
N
Cl
Indoles
Fischer Indole Synthesis:
The conversion of aryl hydrazones to R
R
indoles;
indoles; requires elevated R' ZnCl2, ∆
R'
temperatures and the addition of N NH
H
N
H
Brønsted or Lewis acids
Synthesis of Sumatriptan
CN
O O CN
O O
S S
HN HNO2 HN S S
O O Sn Cl 2 HN O HN
CH3 NH2 O H O
CH3 N NO
H CH3 N NH2 CH3 N N
H H
I
CN
CN
O O H CN
O
S S H+
HN HN S +
O O NH HN NH3
CH3 N NH CH3 NH O
H CH3 N
H
Me
N Me
CN NH2
O H2 CH2O/ Na BH4 O
S O S
HN Pd - C S HN
O O
CH3 N HN N
O CH3 H
CH3 N
H Sumatriptan
13
Quinolines
Quinoline nucleus is usually formed in one of
two ways
H3C
C
+ CH3
Skraup. Döbner von Miller and
N NH2 Conrad-Limpach syntheses
CH3
CH3
+ CH3 Friedländer and Pfitzinger synthesis
N NH2
Skraup-
Skraup-reaction
OH
H2SO4
+ HO OH
NH2 As2O5, ∆
N
CHO
Mechanism: OH H+ H2C
O NH2
HO OH
H N
H
[O]
N N
H
Quinolines
α,β-unsaturated ketone or aldehyde can be used instead of glycerol
CH3
FeCl3
+ H2C
CH3
ZnCl2
NH2 N
O
R'
conc. HCl NH2
R' CH2 CH C CHO
R' CH2 CHO
100 °C R'
N CH2R'
14
Quinolines
Conrad-Limpach reaction: Synthesis of 4-
oxyquinolines by condensation of esters of beta-keto
acids with aromatic amines Skraup-
Skraup-reaction
CH3 CH3
< 100 °C O H+
- H2O
EtO2C - H2O
N O N O
+ H H
NH2 O CH3
O
EtO2C
∆
260 °C
- EtOH
N CH3 - EtOH
N CH3
H
Quinolines
Friedländer-quinoline synthesis
CHO O
pH 12
+
NH2 H3C CH3
N CH3
Mechanism:
O O
CHO O
CH2
+
NH2 H3C CH3 +
N CH3 N CH3
H H
OH
-H2O
N CH3
N CH3
15
Isoquinolines
The general synthetic routes to
isoquinolines involve the following skeletal
types:
types:
N NH2
+ C Pictet-Spengler and
Bischler-Napieralski syntheses
C
C
N
+ NH2
Pomeranz-Fritsch synthesis
C
C
N NH2
+ C Schlittler-Müller synthesis
Isoquinolines
Bischler-
Bischler-Napieralski Reaction:
Reaction:
β-Phenylethylamine is
P2O5, ∆
acylated then HN O N
cyclodehydrated using CH3 CH3
phosphoryl chloride,
phosphorous pentoxide or
other lewis acids. This gives MeO
CN
H2, Raney-Ni MeO NH2
the dihydroisoquinoline,
dihydroisoquinoline,
which can be aromatised by
MeO MeO
H2SO4
dehydrogenation with
palladium. E.g. in the
MeO MeO Cl
CO2H SOCl 2
MeO
MeO MeO
N N NH
MeO
MeO MeO POCl
Pd , 250 3
O
- H2O
OMe OMe
Papaverine OMe
OMe OMe MeO
Bischler-Napieralski
16
Isoquinolines
Pictet-
Pictet-Spengler synthesis: β-Arylethylamine is heated in the presence
of an aldehyde and acid.
acid.
A special case of the Mannich reaction.
reaction.
O H HCl
+ N N
NH2 R
R R
A. Pictet and T. Spengler, Ber. 44, 2030 (1951)
Isoquinolines
Pomeranz-
Pomeranz- EtO OEt
- H2O
OEt
H3O+
O
Fritsch O +
H2N N
OEt
N
Reaction R
R R
C. Pomeranz, Monatsh. 14, 116 (1893)
P. Fritsch, Ber. 26, 419 (1893)
OH
- H2O
N
N
R
R
EtO OEt
Schlittler-
Schlittler- OEt
Müller O
NH2OH
NOH NH2
O
N
OEt
Reaction R R R
R
H3O+
E. Schlittler and J. Muller, Helv. Chim. Acta 31,914,1119(1948)
17
O
Quinolones F CO2H
N N
N O
Retrosynthesis H3C CH3
ofloxacin (antibiotic)
O O O
CO2H O OH
EtO OEt
EtO OEt
N NH2 O H
H
EtO OEt
OEt
Synthesis - EtOH
ethyl orthoformate O O O O
O O HC(OEt)3 Ph NH2 EtO H OEt
EtO OEt
EtO OEt Ac2O EtO OEt
EtO
- EtOH
O O O
CO2H O O
EtO OEt 1. Heat
EtO OEt
2.NaOH,
N 3. H+ N EtO
H H
Thiadiazoles
CH3
O
O
OH
N H
H N O N CH3
CH3
N N H3C
S
18
Benzodiazepines
The retrosynthesis of diazepam
O
N Cl
O O
Cl
NH
Cl N + +
Diazepam H2N
Cl
Diazepam
Benzodiazepines
Ugi Reaction (Ugi, I., et. al. Angew. Chem.
1959, 71, 386)
O R
O NH2 R CN H
N
+ + + R3 N R4
R3 OH R2 H O R4
R2 O
19