Baran, Richter

3 2 3 2 4 5 4 5 2 1 3 4 5 6 5 7 4 3

Essentials of Heterocyclic Chemistry-I

3 2 3 2 6 7 2 4 5 2 6 7 2 6 7 3 4 5 4 2 5 3 4 5 5 6 7 8 4 2 5 3

Heterocyclic Chemistry
4 5 4 3 2 3 4 5

Deprotonation of NH, Deprotonation of CH, Deprotonation of Conjugate Acid

N N1
4 5 6

6 7 8

N1 H

NH
6 7 1

N1 H

Pyrrolidine pKa: 11.3,44

3 2 4 5 2 3

N9 H

N
1

N1 H
4

HN

N1 H
6 7

2-Pyrazoline
5

N1 H
5 4

N
1

N
2

Pyrazolidine
6 7 8 1

Quinazoline
N3 N2
3 2N

Cinnoline
3 4 5

N1

Pyrrole pKa: 23.0, 39.5

Carbazole pKa: 19.9

4 5 2 3 4 5 7 6

Isoindole
8 1 2 5

3H-Indole
4 3

N1 H

Pyrazole pKa: 19.8, 35.9

N N

N N1

N
2

N N1
6

Pyrimidine pKa: 1.3

N1 H

N1

3-Pyrroline 2H-Pyrrole
3 2 4 5 5 2 6 7 4 3 5 4 3

N1 H

N
5 4 3

N1 H

Indole pKa: 21.0, 38.1

3 2

N1

4 5 6

Pteridine
H N
4 5 6 6 7

Phthalazine
5

2-Pyrroline
4

Indolizine
4 5 3 2 5

Indoline pKa: 4.9

4 5 2 6 7 2 3 3 4 5

1,2,4-Triazine pKa: <0

4 3 2 1

N1

3 2

4 3 2

1,3,5-Triazine pKa: <0

4 7 8 5 3

4 3 5

N 2 N
2

N1

O
6 7 1

3 2

O1

O1

O1

Furan pKa: 35.6

O1

S1

S1

Pyrazine pKa: 0.6

Piperazine

N1 H

N1

6 7

N10

N1 H

Pyridazine pKa: 2.3

Quinoxaline

Phenazine OMe 3.3 4.9 6.6 SMe 3.6 4.4 6.0 Cl 0.7 2.8 3.8 Ph 4.5 4.8 5.5 vinyl 4.8 4.8 5.5

1H-Indazole

Benzofuran pKa: 33.2

4 3 5

Isobenzofuran
8 7 3 4 5

2H-Pyran
9 8 7

4H-Pyran
1 2

Benzo[b]thiophene pKa: 32.4

5 6 7 8 1 4 3

Thiophene pKa: 33.0

4 3 2 5

N1

Piperidine pKa: 11.2

1 2 3 4

N1 H

6 2

N
1

N
6 5 4

N2

5 6 7 8

4 3 2

Effects of Substitution on Pyridine Basicity: Me tBu NH2 NHAc 4 3 2-position 6.0 5.8 6.9 4.1 3-position 5.7 5.9 6.1 4.5 2 N1 4-position 6.0 6.0 9.2 5.9 Lithiation Positions: First, Second
N N Me N S S S N O O

CN 0.3 1.4 1.9

R

NO2 2.6 0.6 1.6

N

CH(OH)2 3.8 3.8 4.7

N S N

Quinuclidine pKa: 11.0

9 8 7 7 6 5 6

4H-Quinolizine
5 4 3 6 2 7 8 5

Isoquinoline pKa: 5.4

4 3 2

Pyridine pKa: 5.2

N1

N10

Acridine pKa: 5.6

3 2

Tetrahydroquinoline pKa: 5.0

4 5

N1 H

N1

Quinoline pKa: 4.92

thermodynamic
N Me

N R

1,8-Naphthyridine pKa: 3.39

N
3 2 2 3 4 5 2 3

kinetic

N O1

4 5 2

4 5

3 5 2 6

N S1

4 5

Sites of Electrophilic Substitution: Major, Minor

N N H S N N N H O N N N H O S N N N H

O1

6 7

O1

S1

S1

Oxazole pKa: 0.8

Isoxazole pKa: 3
3 2 4

Benzoxazole pKa: 24.4

3

Benzthiazole pKa: 27.0

3 2

Isothiazole pKa: 0.5

4 5

Thiazole pKa: 2.5, 29.4

3 2

N N1 H

N N S1

4 5

N N N1 H

4 5

2 5

3 2

N N1 H

4 5

6 7

N H
3 2 1N 6

1,3,4-Thiadiazole 2-Imidazoline pKa: 4.9

3

1,2,3-Triazole pKa: 9.3

3 2

N1 H

Benzimidazole pKa: 16.4

3

9 8

Lipinski Rule of Five:

Christopher Lipinski (retired from Pfizer) formulated a set of criteria fulfilled in most orally available drugs. 1. No more than five hydrogen bond donors. 2. No more than ten hydrogen bond acceptors. 3. A molecular weight under 500. 4. A LogP (partition coefficient) value under five.

Heterocyclic Aromaticity Values:

% (of PhH) -value pyridine tetrazole pyrazole quinoline isoquinoline pyrazine 1,2,5-triazole pyrimidine pyridazine 82 80 61 61 75 71 67 65 0.058 % (of PhH) -value indole benzothiophene imidazole pyrrole benzofuran thiophene isoindole furan isobenzofuran 0.047 0.044 0.042 0.039 0.036 0.032 0.029 0.007 0.002

Imidazole pKa: 6.9, 14.4, 33.7

HN
2

4 5 2

N N N1 H

4 5

N N O1

4 2 5

N N1 H

4 5

N7 H

N1 H

Purine pKa: 2.5, 8.9

Imidazolidine
4 3 2 3 2 5 6 7 8 9

Tetrazole pKa: 4.9

1,2,3-Oxadiazole
3 4

1,2,4-Triazole pKa: 2.2, 10.3, 26.2

5

0.052 0.051 0.049

43 37 45

Medicinal Chemistry Glossary:

S
2 4 3S 5

S S1
6

3 2

4 5 6 3 2

4 5 6 3 2

Phenothiazine
O O1
4 3 5 2

N 10 H

S1

H4 N O1

1,3,5-Trithiane
4 3 2 1

1,4-Dithiane
5 6 7 8 9

5 6

O1

H4 N S1

2 5 6

1,4-Dioxane

S1

1,3-Dithiane pKa: 31

1,3-Dioxolane

Thiomorpholine

Phenoxazine

N 10 H

Morpholine pKa: 8.4

0.049 12 ED50: Dose required to yield maximum therapeutic effect in 50% of test animals. Efficacy: Description of the relative intensity with which agonists vary in the response they produce, even with similar affinity. 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.). Intrinsic activity: The maximal stimulatory response induced by a compound relative to that of a given reference comopund. LD50: Dose required to kill 50% of test animals. Partition coefficient (LogP): Log10 of the ratio of a compound's concentration in 1-octanol vs. water at equilibrium. A LogP<0 means that a compound is more soluble in water than in 1-octanol. Pharmacophore: The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or block) its biological response. This is not a real molecule or moiety, but rather an abstract concept that is considered the largest common denominator shared by a set of active molecules. Potency: The dose of a drug required to produce a specific effect of given intensity as compared to a standard reference. Therapeutic index: LD50/ED50

Baran, Richter
Indoles:
O

Essentials of Heterocyclic Chemistry-I

R' R' X R N H N R R' Pd0 N R i. tBuOCl ii.Me S O R N H NHR iii. base iv. Raney-Ni, H2 N R PdII X N R R'

Heterocyclic Chemistry
R' O O COY R' Y R N H X

Pyrroles:
R R' NO2
CN CO2X

R R' CO2X base

N H

NH2

R'

+
R NH2

acid, Fischer Indole Synthesis

N H Barton-Zard Pyrrole Synthesis OCO2Me DMAD N Ph CO2Me

O X Knorr Pyrrole Synthesis

S N H R

nBu SnH 3

Me

R' R' N+

O R' O R RNH2 R' N R R

AIBN

X Ph

Fukuyama Indole Synthesis PdII; NH2 [H] N H

Gassman Indole Synthesis I Me NHR R' R'' R'' R' N R

Huisgen Pyrrole Synthesis MeO RNH2 PdII N R Me MeO2C N N CO2Me OMe Zn HOAc MeO2C Boger Pyrrole Synthesis Me H2NNH2 O CoI2, Me Et Et N H Piloty Pyrrole Synthesis R Br O R2 R1 CO2Me N H R2 R1 R N H

Paal-Knorr Pyrrole Synthesis

Pd(OAc)2, base

Hegedus Indole Synthesis R2 NO2 R R2

Larock Indole Synthesis

Me R1 N H R R NO2

+
BrMg R1

i. DMFDMA R ii. Pd/C, H2 N H

+
H2N

Me

Bartoli Indole Synthesis X R X = OH, NH2 Bucherer Carbazole Synthesis R3 R N R1 O R2 Base R N R1 R2 R R3 O i. PhNHNH2 NaHSO3, ii. H+ R

Batcho-Leimgruber Indole Synthesis N HN R N N R N H Graebe-Ullmann Carbazole Synthesis O R1 R3HN R1 R N R3 Ph O Me O

Hantzsch Pyrrole Synthesis

Thiophenes:
Me P4S10 Me S Me HS CO2Me i. DMAD, piperidine ii. NaOMe OH CO2Me

O Paal Thiophene Synthesis i. NaOEt, S(CH2CO2Et)2 ii. acid Ph Ph CO2H R2 R1

S MeO2C Fiesselmann Thiophene Synthesis

R2

R2 HO

X O CN i. S8 ii. Amine R1 NH2

+
O

Ph

+
X

S HO2C Hinsberg Thiophene Synthesis

S R2 Gewald Aminothiophene Synthesis

Madelung Indole Synthesis i. (CO2Et)2, Base R NO2 ii. [H], H+ R N H CO2H

Nenitzescu Indole Synthesis

Oxazoles and Isoxazoles:

+
NH2 Cl CN i. LA ii. NaBH4 N H R OH CN R'CHO HCl R' N CHO O R K2CO3 TosMIC N O Ph

Reissert Indole Synthesis O Ar Ar X X = halide Bischler Indole Synthesis H+ N H

Sugasawa Indole Synthesis O R N H Me R N H

Fisher Oxazole Synthesis R' R'' O R N O R'' R O

van Leusen Oxazole Synthesis OH CO2X R' NH2OH R' N

+
NH2

I NH2

R CuOTf Castro Indole Synthesis Cl R

R' Robinson-Gabriel Oxazole Synthesis O N R1 R2 R N O O R2 R1

O R Claisen Isoxazole Synthesis

CO2R N3

H+ CO2R N H

Ni0 N R

HN R O

CO2H

Ac2O R

N O

N R Mori-Ban Indole Synthesis

Hemetsberger Indole Synthesis

Cornforth Rearrangement

Erlenmeyer-Plchl Azlactone Synthesis