P. S. Baran, J. M.

Richter Essentials of Heterocyclic Chemistry Heterocyclic Chemistry

Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid 3 4 3 4
5 4 5 4
6 3 6 3
3 4 3
4 5
6 4 4 2 2 N 4
3 3 3
5 5
3 4 N 5 HN 5 2
2 N1 N1 7 2 7 N N 5
2 5 2 7
NH 2 2
H H 8
N1 8
N
N1 6 6 4 3 N 5 1 2 6
3 4
H 1 N9 8
1
N
1 5 N1 2-Pyrazoline Pyrazolidine Quinazoline Cinnoline N1
7 7
Pyrrolidine H 2 H 5 4
2 5
Isoindole 3H-Indole 6 Pyrazole N
5 4 4 4 Pyrimidine
N1 pKa: 11.3,44 Carbazole N1 6 3 6 N 3 5
H 4 7 H pKa: 19.8, 35.9 N N3 3 5
N N pKa: 1.3
pKa: 19.9 8 3
Pyrrole 3 4 3 4 3 4 7
1 5 Indole 2.5 7 2 7 N2 2N 6 2 6
2 N N1
pKa: 23.0, 39.5 2 pKa: 21.0, 38.1 8 8 1 N1 N1
6
2 5 2 5 2 5 6 N N1 Pteridine Phthalazine
N1 N1 N1 4 3 7 H N
4 1,2,4-Triazine 1,3,5-Triazine 4
5
H H 3 5 pKa: <0 pKa: <0 3 5
Indolizine Indoline
3-Pyrroline 2H-Pyrrole 2-Pyrroline H 4 5 4 4
pKa: 4.9 2 6 N N 4 5 6 3
2
N 6
N1 3 5 6 3
3
N 7 5 N1
2
3 4 4 3 4 3
4 4 4 3 3 4 N
5 5 5 Pyrazine 2 6 7 2 6 Pyridazine
2 3 5 3 5 N1 N1 2 8 N1
2 5 2 O 2
2 5 pKa: 0.6 H 8
1
N10 9 7 H pKa: 2.3
6
O1 6
O1
6 2
O1
6 2 6
S1 S1 Piperazine Quinoxaline 1H-Indazole
7 7 1 O1 7 Phenazine
Furan 2H-Pyran Benzo[b]thiophene Thiophene
Benzofuran Isobenzofuran 4H-Pyran Effects of Substitution on Pyridine Basicity:
pKa: 35.6 pKa: 32.4 pKa: 33.0
pKa: 33.2
4 Me tBu NH2 NHAc OMe SMe Cl Ph vinyl CN NO2 CH(OH)2
4 8 5 4
9 1
6 3
3 2-position 6.0 5.8 6.9 4.1 3.3 3.6 0.7 4.5 4.8 –0.3 –2.6 3.8
3 5 7 4 8 2
3 5 2 3-position 5.7 5.9 6.1 4.5 4.9 4.4 2.8 4.8 4.8 1.4 0.6 3.8
4 2 6
N 7 N 3
7 N2 5 4
N1 4-position 6.0 6.0 9.2 5.9 6.6 6.0 3.8 5.5 5.5 1.9 1.6 4.7
3 5
N1 2 1 6 5 8 1
H 6 4 6 3
Lithiation Positions: First, Second
Piperidine Quinuclidine Isoquinoline R
2 6 4H-Quinolizine
N1 pKa: 11.2 pKa: 11.0 5 4
pKa: 5.4 7 2 N N N
5 4 8
N1
1 9 8
Pyridine
6 3 N R
6 3
2 7 Quinoline N S O O S S S N S
pKa: 5.2 7 2 Me R
3 6 N1 7 2 pKa: 4.92 thermodynamic
8
N10 H 8
N N1 N
4 5
Tetrahydroquinoline N
Acridine 1,8-Naphthyridine
pKa: 5.6 pKa: 5.0 pKa: 3.39 N kinetic O
S S N N
Me
4 3 4 3 3 4 3 4
3
N
4 3 4
5 N 5 N N Sites of Electrophilic Substitution: Major, Minor
2 2 2
2
2 5 N 5 N 5 2 5
N
6 6
O1 O1 O1 S1 S1 S1
7 7
Isothiazole Thiazole N S N O N
Oxazole Isoxazole Benzoxazole Benzthiazole H N N H
H
pKa: 0.8 pKa: –3 pKa: 24.4 pKa: 27.0 pKa: –0.5 pKa: 2.5, 29.4
N N
3 4 3 4 3 N
3 4 N N N
4
N N
N 2
5
N S N O S
2 5
N 5
2
H H
2 5 S1 6
3 4 N1 N1 N1
N H 7 H
H
1,3,4-Thiadiazole 3
Lipinski Rule of Five: Heterocyclic Aromaticity Values:
2 5 2-Imidazoline 1,2,3-Triazole Benzimidazole N 4
N
9
2
N1 pKa: –4.9 pKa: 1.2, 9.3 Christopher Lipinski (retired from Pfizer) formulated a set of % (of PhH) β-value % (of PhH) β-value
H pKa: 16.4 8
criteria fulfilled in most orally available drugs. pyridine 82 0.058 indole 0.047
1N
Imidazole 3 3 4 3 4 5 N7 1. Not more than five hydrogen bond donors. tetrazole 80 benzothiophene 0.044
HN
4 N N 3
4
N 6 H
pKa: 6.9, 14.4, 33.7 N 2. No more than ten hydrogen bond acceptors. pyrazole 61 imidazole 43 0.042
2 5
2 N 5 2 2N 5 Purine 3. A molecular weight under 500. quinoline 61 0.052 pyrrole 37 0.039
N1 N1 N 5 N1 pKa: 2.5, 8.9
H O1 H 4. A LogP (partition coefficient) value under five. isoquinoline 0.051 benzofuran 0.036
H
Imidazolidine Tetrazole 1,2,4-Triazole pyrazine 75 0.049 thiophene 45 0.032
pKa: 4.9 1,2,3-Oxadiazole pKa: 2.5, 10.3, 26.2 Medicinal Chemistry Glossary: 1,2,4-triazole 71 isoindole 0.029
ED50: Dose required to yield maximum therapeutic effect in 50% pyrimidine 67 0.049 furan 12 0.007
4 4
of test animals. pyridazine 65 isobenzofuran 0.002
4 5 6
S 3 5
3 7 S Efficacy: Description of the relative intensity with which agonists
S S 3 5
vary in the response they produce, even with similar affinity.
2 8 2 6 2 6 H4 Homologue: A compound belonging to a series of compounds differing from each other by a repeating unit (i.e. a CH2, a peptide residue, etc.).
4 N 10 S1 S1 N
O 1
H 9 4
3 5
Intrinsic activity: The maximal stimulatory response induced by a compound relative to that of a given reference comopund.
3 5
Phenothiazine 3S 5 1,3,5-Trithiane 1,4-Dithiane LD50: Dose required to kill 50% of test animals.
2 6 Partition coefficient (LogP): Measure of the solubiliity of a compound in water, by its partitioning between 1-octanol and water. A LogP<1
2 6
O1 H4 2 6 4 5 6 O1
3 4 N S1 O means that a compound is more soluble in water than in 1-octanol.
O 3 5 3 7
Morpholine Pharmacophore: The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a
1,4-Dioxane 2 5 1,3-Dithiane
2 6 2 8 pKa: 8.4 specific biological target structure and to trigger (or block) its biological response. This is not a real molecule or moiety, but rather an
O1 S1 pKa: 31 N 10 abstract concept that is considered the largest common denominator shared by a set of active molecules.
1 9
H
1,3-Dioxolane Potency: The dose of a drug required to produce a specific effect of given intensity as compared to a standard reference.
Thiomorpholine Phenoxazine
Therapeutic index: LD50/ED50
P. S. Baran, J. M. Richter Essentials of Heterocyclic Chemistry Heterocyclic Chemistry
Indoles: R' R' R' Furans:
R' R
O R'' O R''OC
O R' X X acid R'' O O
R' Pd0 PdII Y R' base
R R R R R'
NH2 R O R'' Y O
N Acid, Δ N N N R' O Y X Y
H N R R R Paal-Knorr Furan Synthesis Feist-Bénary Furan Synthesis
H
Fischer Indole Synthesis
i. tBuOCl R' Pyridines:
O i. R'CHO, NH3 R'
Me ii. S R'
Cl
R NH3 R R base ii. HNO3, H2SO4
nBu SnH O
S 3 R
R N OHC R N CHCl3 iii. KOH
NHR iii. base N H N EtO2C
N R iv. CaO R N R
N R AIBN iv. Raney-Ni
H H Chichibabin Pyridine Synthesis Ciamician-Dennstedt Rearrangement
Hantzsch Pyridine Synthesis
Fukuyama Indole Synthesis Gassman Indole Synthesis Me Me
R'' R' CN R' CN O
O NH3 CO2Et CO2Et
PdII; I R' R''
Me R
Pd(OAc)2, R' RO O O OR HO N OH
NH2 [H] N H2N Me R N Me
H NHR base N
R Guareschi-Thorpe Pyridine Synthesis Bohlmann-Rahtz Pyridine Synthesis
Hegedus Indole Synthesis Larock Indole Synthesis
Ph Ph
AcOH R
Pyrroles: O N+
R COY N R N R'
R' O R' Δ
NO2 R' NH4OAc
R CN CO2X Y N N
X Ph O O Ph Ph N Ph
R' CO2X R' N
base R NH2 N
N O X R H Kröhnke Pyridine Synthesis Boger Pyridine Synthesis
R
Knorr Pyrrole Synthesis Quinolines:
Barton-Zard Pyrrole Synthesis
R X
O- CO2Me O R'
RNH2 acid R' R
R'' R'' R R'' O
DMAD R'
X CO2Me R' N Δ
N+ N R NH2 NH2 O R' N R
O O O N R''
Ph Ph R = H/alkyl/aryl, R'' = H/alkyl/aryl Combes Quinoline Synthesis R' = H, X = CO2H Doebner Quinoline Synthesis
Paal-Knorr Pyrrole Synthesis
Huisgen Pyrrole Synthesis R = O-alky/aryl, R'' = H/alkyl/aryl Conrad–Limpach Reaction R' = X = Me Riehm Quinoline Synthesis
OMe R = H/alkyl/aryl, R'' = O-alkyl Knorr Quinoline Synthesis
MeO CO2Me Zn OH
RNH2 R R
R' acid, RO2C CO2R
N HOAc CO2Me base, R' base
PdII N MeO2C N N O
R MeO2C H Δ
or NH2 R''O R'
NH2 O R'' Δ N R'' N R'
Thiophenes: Gould–Jacobs Reaction
OH Friedländer Quinoline Synthesis
O i. DMAD,
Me P4S10 piperidine O CO2H
Me Me CO2Me R DMF R
HS CO2Me R' R'
Me S ii. NaOMe S
O MeO2C
POCl3 O
Paal Thiophene Synthesis Fiesselmann Thiophene Synthesis N O N Cl
H Δ N O R N R
H
O Ph Meth–Cohn Quinoline Synthesis Pfitzinger Quinoline Synthesis
i. NaOEt Ph
Ph Isoquinolines: OR
Ph EtO2C S CO2Et CO2H
ii. acid OH
O HO2C S RO acid
Hinsberg Thiophene Synthesis P2O5
NH2 N
N O
NH decaline
Oxazoles, Isoxazoles and Pyrazoles: O
O OH R
R Pomeranz-Fritsch Reaction
OH R'CHO R' R' O Pictet–Gams Reaction
O TosMIC O CO2X NH2OH
R Ph R N Useful 1,3-dipoles:
R CN HCl N
K2CO3 N R' O
Fisher Oxazole Synthesis R
R R R R R
van Leusen Oxazole Synthesis Claisen Isoxazole Synthesis R N R R N R N N N R O R R O
NR O RN O O O NR
R R R R R R R
R'' R azomethine ylides azomethine imines nitrones azoxy compounds nitro compounds carbonyl ylides carbonyl imines
O R' R O R' R N
XNHNH2 R "Cu" R
R'' R'' R R'' N+
R N N R' N
H N N N- R O R N R R N R N N R N N
R R'N N O NR O N N NR N O
O O O X R' R R R
R'
Robinson-Gabriel Oxazole Synthesis Knorr Pyrazole Synthesis Sharpless-Huisgen Cycloaddition carbonyl oxides nitrile ylides nitrile imines nitrile oxides diazoalkanes azides nitrous oxide