Baran, Richter Essentials of Heterocyclic Chemistry-I 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
N 6
N3 N 3 5
H 4 7 H pKa: 19.8, 35.9 3 5
N N pKa: 1.3
pKa: 19.9 8 3
Pyrrole 3 4 3 4 3 4 7
1 5 Indole 7 2 7 N2 2N 6 2 6
2 N N1
pKa: 23.0, 39.5 2
6 pKa: 21.0, 38.1 8 8 1 N1 N1
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 4H-Pyran Benzo[b]thiophene Thiophene
Benzofuran Isobenzofuran 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 S N kinetic O
S Me N N
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 H N 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 2
N 4
N
9

N1 pKa: –4.9 pKa: 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.
1N pyridine 82 0.058 indole 0.047
Imidazole 3 3
N N
4 3 4 5 N7 1. No more than five hydrogen bond donors. tetrazole 80 benzothiophene 0.044
HN
4 3
4
N 6 H
pKa: 6.9, 14.4, 33.7 2 N N 2. No more than ten hydrogen bond acceptors. pyrazole 61 imidazole 43 0.042
2 5
5
2
2 N 5 Purine 3. A molecular weight under 500. quinoline 61 0.052 pyrrole 37 0.039
N1 N1 N 5 N1
H H pKa: 2.5, 8.9 4. A LogP (partition coefficient) value under five. isoquinoline 0.051 benzofuran 0.036
H O1
Imidazolidine Tetrazole 1,2,4-Triazole pyrazine 75 0.049 thiophene 45 0.032
pKa: 4.9 1,2,3-Oxadiazole pKa: 2.2, 10.3, 26.2 Medicinal Chemistry Glossary: 1,2,5-triazole 71 isoindole 0.029
ED50: Dose required to yield maximum therapeutic effect in 50% 0.049 pyrimidine 12 67 furan 0.007
of test animals. pyridazine 65 isobenzofuran 0.002
4 5 6 4 4
S 3 5 S
3 7 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): Log10 of the ratio of a compound's concentration in 1-octanol vs. water at equilibrium. A LogP<0 means that
2 6
O1 H4 2 6 4 5 6 O1
3 4 N S1 O 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
Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry
Indoles: R' R' R'
R' X X
Pyrroles: R O COY
O R' O R'
Pd0 PdII NO2 R'
R
R'
R
CN CO2X + Y
NH2 R CO2X X
N N N N base
acid, Δ N R R R R' N R NH2 N
H O X R H
H H
Fischer Indole Synthesis Knorr Pyrrole Synthesis
i. tBuOCl Barton-Zard Pyrrole Synthesis
ii.Me R' O
Me S O- CO2Me
nBu SnH O R RNH2 R
S 3 R'
NHR DMAD R' N
R iii. base N X CO2Me R' R
AIBN N R N+ N O
N R iv. Raney-Ni, H2
H H
Ph Ph
Fukuyama Indole Synthesis Gassman Indole Synthesis Paal-Knorr Pyrrole Synthesis
Huisgen Pyrrole Synthesis
R''
I R' R'' OMe
PdII; MeO CO2Me
Me Zn
Pd(OAc)2, R' RNH2
N CO2Me
NH2 [H] H NHR base N N HOAc
N MeO2C N N
R PdII R MeO2C
Hegedus Indole Synthesis Larock Indole Synthesis H
Boger Pyrrole Synthesis
R2 Me R2
O R2
NO2 R2 Me Me Me +
i. DMFDMA H2NNH2
+ R1 R R Et R R1
N ii. Pd/C, H2 N Me CoI2, Δ H2N R1
R BrMg R1 H NO2 H O Et N Br R N
H H
R
Piloty Pyrrole Synthesis Hantzsch Pyrrole Synthesis
Bartoli Indole Synthesis Batcho-Leimgruber Indole Synthesis

X N Thiophenes:
i. PhNHNH2 R N
HN Δ OH
NaHSO3, Δ N i. DMAD,
O
R R HS CO2Me piperidine
Me P4S10 Me CO2Me
ii. H+ R N Me
H Me S ii. NaOMe S
X = OH, NH2 MeO2C
O
Fiesselmann Thiophene Synthesis
Bucherer Carbazole Synthesis Graebe-Ullmann Carbazole Synthesis Paal Thiophene Synthesis

R3 R3 O i. NaOEt, Ph X
R2
R2 S(CH2CO2Et)2 Ph R1 O CN i. S8 R1
Base O HO Ph
O +
R R R2 R1
Ph CO2H + NH2
ii. acid X ii. Amine
Δ N R3HN R1 O S R2 S
N R2 O N HO2C R2
R1 R1 R R R3
Hinsberg Thiophene Synthesis Gewald Aminothiophene Synthesis
Madelung Indole Synthesis Nenitzescu Indole Synthesis

i. (CO2Et)2,
Oxazoles and Isoxazoles:
Base CN i. LA CHO TosMIC
+ O
R R CO2H OH R'CHO R' O Ph
Cl K2CO3 N
NO2 ii. [H], H+ N NH2 ii. NaBH4 N R
H H R CN HCl N
Fisher Oxazole Synthesis van Leusen Oxazole Synthesis
Reissert Indole Synthesis Sugasawa Indole Synthesis

O Ar R O OH
O R' O R'
+ H+ I R
R'' R'' CO2X NH2OH
Ar R N
R N N
X CuOTf R H R' O
NH2 Δ N O R
H NH2 N R'
X = halide H Claisen Isoxazole Synthesis
Robinson-Gabriel Oxazole Synthesis
Bischler Indole Synthesis Castro Indole Synthesis

Me R R
O O
CO2R Cl
H+ Ni0 R1 Δ R2 HN CO2H N
N N Ac2O
CO2R O
N3 Δ N N N O
R R2 R1 R O R
H R
O O
Hemetsberger Indole Synthesis Mori-Ban Indole Synthesis
Cornforth Rearrangement Erlenmeyer-Plöchl Azlactone Synthesis