Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry

Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid 3 5 4 5 4

4 3 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 N N1 2-Pyrazoline Pyrazolidine Quinazoline N1
7 1 7 1 5
H Cinnoline
Pyrrolidine H 2 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 7 H pKa: 19.8, 35.9 N N3 3 5
N N pKa: 1.3
pKa: 19.9 8
4 3
Pyrrole 3 4 3 4 3 4 7
1 5 Indole 7 2 7 N2 2N 6 2 6
pKa: 23.0, 39.5 2 N N1 N1 N1
2
6
pKa: 21.0, 38.1 8 8 1
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
pKa: 4.9 2 6 N N 4 5 6
4 3 N
2
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 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 6 3
8 2
3
4
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 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
N1 2 5 4
3 5 1 6 5 8 1
H 6 4 6 3
Lithiation Positions: First, Second
Piperidine Quinuclidine Isoquinoline R
2 6 4H-Quinolizine pKa: 5.4
N1 pKa: 11.2 pKa: 11.0 5 4
7 2 N N N
5 4 8
N1
1 9 8
Pyridine
6 3 N R
6 3
pKa: 5.2
2 7 Quinoline N S O O S S S N S
7 2
pKa: 4.92 Me R
3 6 8
N1 7 2 thermodynamic
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 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 N 4
N
9

N1 pKa: –4.9 pKa: 9.3

2
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 N 6 H
pKa: 6.9, 14.4, 33.7 2 N
4 2. No more than ten hydrogen bond acceptors. pyrazole 61 imidazole 43 0.042
2 5
N 5
2
2 N 5 Purine
N1 3. A molecular weight under 500. quinoline 61 0.052 pyrrole 37 0.039
N1 N 5 N1 pKa: 2.5, 8.9
H H O1 H 4. A LogP (partition coefficient) value under five. isoquinoline 0.051 benzofuran 0.036
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
1,4-Dioxane Pharmacophore: The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a
2 5 1,3-Dithiane 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
2 6
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.
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'
Me S O- CO2Me O
nBu
3SnH
O R RNH2 R
S R'
NHR DMAD R' N
R iii. base N X CO2Me R' R
AIBN R N+ N O
N R N 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
Wacker Pyrrole Synthesis Boger Pyrrole Synthesis
R2 Me R2
O R2
R2 Me i. DMFDMA Me Me +
H2NNH2
+ R1 R R Et R R1
N ii. Pd/C, H2 N Me CoI2, Δ H 2N R1
NO2 BrMg R1 NO2 H O Et N Br R N
H H H
R R Piloty Pyrrole Synthesis Hantzsch Pyrrole Synthesis
Bartoli Indole Synthesis Batcho-Leimgruber Indole Synthesis

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

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

i. (CO2Et)2,
Oxazoles and Isoxazoles:
Me Base CN CHO TosMIC
+ i. LA O
R R CO2H OH R'CHO R' O Ph
ii. [H], H+ N Cl ii. NaBH4 N K2CO3 N
NO2 NH2 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 Δ CuOTf R H R' O
NH2 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
N N HN CO2H Ac2O N
CO2R O
N3 Δ
N N N
R R O R O
H R R2 R1
O O
Hemetsberger Indole Synthesis Mori-Ban Indole Synthesis
Cornforth Rearrangement Erlenmeyer-Plöchl Azlactone Synthesis
Baran, O'Malley, Shenvi Essentials of Heterocyclic Chemistry-II Heterocyclic Chemistry
Furans: R
Diazoles:
O R'' R' O
R'' O O R''OC R3(H)
Y acid R' base O O NH2 NH2
R R R + R' N O NH2 MeN N
R'' Y R4HN MeHN
O Me
R' O Y O X Y (H)R1 R3(H) R 4N R2
both (Ph2)HC Me
Paal-Knorr Furan Synthesis Feist-Bénary Furan Synthesis (Ph2)HC
R2 regioisomers
R1(H)
Pyridines: O i. R'CHO, NH3 R' Knorr Pyrazole Synthesis
R R R Cl ii. HNO3, H2SO4
base
NH3
R
Triazoles:
R N CHCl3 iii. KOH O Ph NH2 N N
OHC N H O O O
N EtO2C iv. CaO H 2N Ph
R N R MeSO3N3
Chichibabin Pyridine Synthesis Ciamician-Dennstedt Rearrangement N2 N Ar N NH2 Ar N
Hantzsch Pyridine Synthesis Me Me Me H
N
Me Me
CN Me N
R' R' CN O CO2Et CO2Et Me NHBu Me NBu Bu
O NH3 Ar NH2, N N
+ + HN NH
O OR R
RO O HO N OH OHC CHO P4O10 N
H 2N Me R N Me Ar
Guareschi-Thorpe Pyridine Synthesis Me2N NH2
Bohlmann-Rahtz Pyridine Synthesis
BnNH2 N N N MeHN N NMe
Ph Ph R N R
AcOH R N N
N+ N N N "Cu" R
N N
TsOH N + N+
+ R Δ R' Bn
NH4OAc + NMe2 N - N
N N R R' R'N N
Ph O O Ph Ph N Ph
R' N Sharpless "Click" Chemistry
Kröhnke Pyridine Synthesis Boger Pyridine Synthesis

Quinolines: Tetrazoles:
R X X
R' N N HN3, R4
acid R' R NC O HO
R R'' O N C N R4 NaN3, N N
NaN3 N O
NH2 Δ N R2 N N
NH2 O R' MeO2C H R1 R2 Me
O O N R'' N R H+ R3 Tf2O N
CO2Me or L.A. N N Me NHR R
R = H/alkyl/aryl, R'' = H/alkyl/aryl Combes Quinoline Synthesis R' = H, X = CO2H Doebner Quinoline Synthesis Passerini Synthesis
R = O-alkyl/aryl, R'' = H/alkyl/aryl Conrad-Limpach Reaction R' = X = Me Riehm Quinoline Synthesis
R = H/alkyl/aryl, R'' = O-alkyl Knorr Quinoline Synthesis
R acid, R OH Oxadiazoles:
R' RO2C CO2R
base, R' base
O Me2N OMe O
or Δ Δ N Ph
O R'' NH2 R''O R' Me O
NH2 N R' O O NMe2 NH2OH, N Ph
N R'' OMe O O N
Gould-Jacobs Reaction Me CN N
Friedländer Quinoline Synthesis O
Ar NH2 Ar N Me AcOH N O O
Ar CN
R O CO2H
DMF R R' CN
R'
HO
POCl3 O O N
N O N Δ Cl N O R
HC(OEt)3 N N Ac2O N O
H N R NH2 N N
H Ph N
Meth–Cohn Quinoline Synthesis Pfitzinger Quinoline Synthesis Δ Ph O Ph OH Δ
H Ph
H
Isoquinolines:
OH + OR Triazanes:
P2O5 acid
RO H 2N SMe NH2
N N Me
NH decalin NH2 O Ar Ar N Me
O Me O N Me
N NiO2, N NH
R R H 2N N
Pomeranz-Fritsch Reaction Bn N N N
O Pictet–Gams Reaction N N
AcOH N N Δ
NH2 N O Me
Useful 1,3-dipoles: SMe
Me2N Me Bn

R R R R R R O
R N R R N R N N N R O R
R
NR
R
O RN O O O R R R
NR 1,2,4,5-Tetrazines:
R R
azomethine ylides azomethine imines nitrones azoxy compounds nitro compounds carbonyl ylides carbonyl imines H
N 2-Py NaNO2 N 2-Py
N 2H 4 N N
R O R N R R N R N N R N N N
O NR O H 2N N NR H 2N O Δ N AcOH
R R N CN Py-2 N Py-2 N
R
H
carbonyl oxides nitrile ylides nitrile imines nitrile oxides diazoalkanes azides nitrous oxide
Baran, O'Malley, Shenvi Essentials of Heterocyclic Chemistry-II Heterocyclic Chemistry
3
NMR Spectral Parameters Structural Properties 4 3
NMR Spectral Parameters Structural Properties
4 1H 1H
(CDCl3) ppm (Determined by microwave spectra) 5 9 (CDCl3) ppm (x-ray of 1,3,5-trinitrobenzene complex of 3-methylindole)
2 5 H-3, H-4: 6.22 Bond Lengths (Å) 2 H-1: 7.74 H-4: 7.64 H-7: 7.24 Bond Lengths (Å)
6
N1 H-2, H-5: 6.68 N-C2: 1.370 NH: 0.996 8 N1 H-2: 7.00 H-5: 7.12 N1-C2: 1.4 C4-C5: 1.37 C7-C8: 1.40
H 13C (CDCl ) C2-C3: 1.382 C2-H: 1.076 7 H C2-C3: 1.34 C5-C6: 1.42 C8-N1: 1.38
3 H-3: 6.51 H-6: 7.18
Pyrrole C-3, C-4: 109.2 C3-C4: 1.417 C3-H: 1.077 Indole 13C (CDCl ) C3-C8: 1.49 C6-C7: 1.39 C8-C9: 1.39
3
C-2,C-5: 117.3 Bond Angles C-2: 124.2 C-4: 120.7 C-7: 111.1 C8-C4: 1.37
C2-N-C5: 109.8 N-C2-H2: 121.5 Bond Angles
H-H Coupling Constants (Hz) C-3: 102.4 C-5: 119.8 C-8: 135.7
N-C2-C3: 107.7 C2-C3-C4: 125.5 C8-N1-C2: 108 C8-C9-C4: 123 C6-C7-C8: 115
J2,3 2.660 J3,4 3.359 C-9: 127.8 C-6: 121.9
C2-C3-C4: 107.4 N1-C2-C3: 111 C9-C4-C5: 116 C7-C8-C9: 122
J2,4 1.491 J1,2 2.579 H-H Coupling Constants (Hz)
C2-C3-C9: 106 C4-C5-C6: 122 C9-C8-N1: 109
J2,5 1.845 J1,3 2.458 J1,2 2.5 J2,3 3.1 J4,6 1.2 J5,7 1.3
C3-C9-C8: 106 C5-C6-C7: 121
C-H Coupling Constants (Hz) J1,3 2.0 J3,7 0.7 J4,7 0.9 J6,7 8.1
JC2-H 183.28 JC3-H 168.80 J1,4 2.8 J4,5 7.8 J5,6 7.1

3 4
NMR Spectral Parameters Structural Properties NMR Spectral Parameters Structural Properties
1H 5 4 1H (CCl4) ppm (x-ray of NiS2PEt2 complex with quinoline)
(C6D12) ppm (Determined by gas-phase
10
6 3 Bond Lengths (Å)
2 5 H-3, H-4: 6.96 microwave spectra) H-2: 8.82 H-5: 7.73 H-8: 8.05
S1 H-2, H-5: 7.20 Bond Lengths (Å) H-3: 7.31 H-6: 7.46 N1-C2: 1.33 C10-5: 1.45 C8-C9: 1.39
7 2
13C (acetone-d ) S-C2: 1.714 9 N1 H-4: 8.05 H-7: 7.65 C2-C3: 1.44 C5-C6: 1.35 C9-N1: 1.38
Thiophene 6 8
C2-C3: 1.369 13C (CDCl ) ppm C3-C4: 1.38 C6-C7: 1.41 C9-C10: 1.43
C-3, C-4: 127.3 Quinoline 3
C3-C4: 1.423 C-2: 150.32 C-10: 128.32 C-7: 129.40 C4-C10: 1.39 C7-C8: 1.36
C-2,C-5: 125.6
Bond Angles Bond Angles
H-H Coupling Constants (Hz) C-3: 121.01 C-5: 127.72 C-8: 129.40
C2-S-C5: 92 C9-N1-C2: 119.1 C10-C5-C6: 120.5 C10-C7-N1: 120.5
J2,3 4.9-5.8 J3,4 3.45-4.35 C-4: 135.93 C-6: 126.46 C-9: 148.34
S-C2-C3: 111 N1-C2-C3: 121.1 C5-C6-C7: 120.1 C10-C9-C8: 119.7
J2,4 1.25-1.7 J2,5 3.2-3.65 H-H Coupling Constants (Hz)
C2-C3-C4: 112 C2-C3-C4: 120.4 C6-C7-C8: 120.9 C4-C10-C9: 119.1
C-H Coupling Constants (Hz) J2,3 4.18 J4,8 0.75 J5,8 0.69 J7,8 8.57
C3-C4-C10: 119.6 C7-C8-C9: 121.0 C5-C10-C9: 117.7
JC2-H 185 JC3-H 168 J2,4 1.76 J5,6 8.24 J6,7 6.88
J3,4 8.19 J5,7 1.47 J6,8 1.25
C-H Coupling Constants (Hz)
C-2: 178 C-4: 162 C-6: 161 C-8: 161
C-3: 165 C-5: 160 C-7: 162
3 4
NMR Spectral Parameters Structural Properties NMR Spectral Parameters Structural Properties
1H 5 4 1H (CCl4) ppm (x-ray of C1-hydroxymethylphenyl derivative of isoquinoline)
2 5 (CDCl3) ppm (Determined by microwave spectra) 10
6 3 Bond Lengths (Å)
O1 H-3, H-4: 6.24 Bond Lengths (Å) H-1: 9.11 H-5: 7.70 H-8: 7.85
H-2, H-5: 7.29 O-C2: 1.362 H-3: 8.45 H-6: 7.56 C1-N2: 1.318 C10-5: 1.417 C8-C9: 1.414
7 N2
Furan 13C (acetone-d ) C2-C3: 1.361 9 H-4: 7.50 H-7: 7.58 N2-C3: 1.373 C5-C6: 1.360 C9-C1: 1.426
6 8 1
C3-C4: 1.430 13C (CDCl ) ppm C3-C4: 1.349 C6-C7: 1.399 C9-C10: 1.416
C-3, C-4: 110.4 3
Bond Angles Isoquinoline C-1: 152.6 C-5: 126.4 C-8: 127.5 C4-C10: 1.414 C7-C8: 1.364
C-2,C-5: 143.6
C2-O-C5: 106.50 O-C2-H2 115.93 Bond Angles
H-H Coupling Constants (Hz) C-3: 143.1 C-6: 130.2 C-9: 128.7
O-C2-C3: 110.65 C2-C3-H3 127.83 C9-C1-N2: 123.2 C4-C10-C9: 117.8
J2,3 1.75 J3,4 3.3 C-4: 120.4 C-7: 127.2 C-10: 135.7
C2-C3-C4: 106.07 C1-N2-C3: 117.8 C4-C9-C1: 117.8
J2,4 0.85 J2,5 1.4 H-H Coupling Constants (Hz)
N2-C3-C4: 123.9
C-H Coupling Constants (Hz) J1,4 1.0 J4,5 -0.36 J5,8 0.80 J7,8 8.27
C3-C4-C10: 119.5
JC2-H 201 JC3-H 175 J3,4 5.75 J5,6 8.29 J6,7 6.92
J3,7 0.3 J5,7 1.17 J6,8 1.21
C-H Coupling Constants (Hz)
C-1: 178 C-4: 161 C-6: 161 C-8: 161
C-3: 178 C-5: 161 C-7: 163

NMR Spectral Parameters Structural Properties 3 4

NMR Spectral Parameters Structural Properties
4 1H (Determined by microwave
N 1H (D2O) ppm (Determined by X-Ray)
(CDCl3) ppm
3 5 2 5 H-4, H-5: 7.14 Bond Lengths (Å)
H-3: 7.25 and electron diffraction spectra)
Bond Lengths (Å) N1 H-2: 7.73 N1-C2: 1.349
2 6 H-4: 7.64 H
N1 13C (D O) ppm C2-N3: 1.326
H-2: 8.60 N-C2: 1.338 2
13C (CDCl ) C2-C3: 1.394 Imidazole C-4, C-5: 122.3 N3-C4: 1.378
Pyridine 3
C3-C4: 1.392 C-2: 136.2 C4-C5: 1.358
C-3: 123.46
Bond Angles H-H Coupling Constants (Hz) C5-N1: 1.369
C-4: 135.58
C6-N-C5: 116.9 Bond Angles
C-2 149.59 C-H Coupling Constants (Hz) C2-N1-C5: 107.2
N-C2-C3: 123.8
H-H Coupling Constants (Hz) N1-C2-N3: 111.3
C2-C3-C4: 118.5
J2,3 4.93 J2,6 -0.03 C2-N3-C4: 105.4
C3-C4-C5: 118.4
J2,4 1.80 J3,5 1.44 N3-C4-C5: 109.8
J2,5 1.00 J3,4 7.66 C4-C5-N1: 106.3
C-H Coupling Constants (Hz)
JC2-H 179 JC3-H 163 JC4-H 152
Baran, Hafensteiner, Richter Essentials of Heterocyclic Chemistry-III Heterocyclic Chemistry
Indazoles: Purines:
R1 R1 CHO Me NH2 Me
CuO, NH2 N N NC HCONH2
NaNO2 N Ac2O N
K2CO3, Me N N
O R'' N N
R2 N H+ Δ N N Δ
NH2NHR3 N H N N NH2 H N
H 2N N N
X R3 H Traube Synthesis
X = F, Cl, Br

R R O O Indolizidines:
RONO PIFA R O R
NHR2 NR2 Me Me
N
Δ N RCOCH2Br NaHCO3
N N
NHAc Ac NHR1 R1 N N
Δ

O i. TsOH, MeO CO2H Chichibabin Synthesis

OMe
Me NaNO2, HC(OMe)3 H2SO4
N
O O N Hydantoins:
N ii. NaH, R
NH2
AcOH N N N R3NH2, R1 N3
H
H
DppONH2
H R1 H
N
O X
NH2 O KCN, O C N R4 , R2
R2 R1 R2 NH
(NH4)2CO3 NH HN C X
Pyrones: R1 R2 R 4N
O
R2 CO2R1 Bucherer-Bergs Synthesis Ugi Reaction X = O or S
O R
CO2R CO2R O
+ Base + Base
R1
CO2R R2O2C OR2 R2O2C O O
Pyrimidines and Pyrimidones: R1=Alkyl, Aryl, R2=Carbonyl, R3=Alkyl, X=O, S
R2 R1 O O R4
R R1
O O R2 X
NH O R2
N N

+
O O R4 NH2 NH
R1 R3 R4 NH2 O
O R1 R3 R1 H
Me Base R2 R3 R3 N X
R2 Biginelli Synthesis H
Me Cl Pinner Synthesis
MeO R Me O R

Cinnolines:
Chromanones and Coumarins:
R2 OH
HNO2, HX; R2 i. NH2Cl
R1 OH Ar R1 O Ar OH O R1
H2O2 (R1CO)2O R N
Δ R N ii. PhNO2, H+
R1CO2M N H N
NH2 N
NaOH OH R R
Δ von Richter Synthesis
R2 O R2 O O O
Algar-Flynn-Oyamada Reaction Kostanecki-Robinson Reaction Cyclazines:

O n-BuLi; AcOH
R2 N N N
O Br Ar O Ar CO2R DMF Δ
R2 R1 OHC
R NaOH R Me
Br OH + R1
O O O
O OH
Auwers Flavone Synthesis Pechmann Synthesis Triazolopyridines:
N N Ph N N N
O H 2N NH
CO2R R1 OH K3Fe(CN)6, N Chloramine-T
Base + Ph
+ Base N N
RO2C N NaHCO3, Δ N Δ
R1 O O O
O Pd
OH
Perkin Condensation Trost Synthesis

CO2Et Ph NHt-Bu
O O O H 2N N t-BuNC,
H 2N
I CO N HC CCO2Et N PhCHO,
N N
+ Me ROCl N
N N HClO4
R Pd0
OH N N
O R OH O R
Baran, Hafensteiner, Richter Essentials of Heterocyclic Chemistry-III Heterocyclic Chemistry
Useful Methods of Forming Aryl C–N and C–O Bonds: Useful Methods of Forming Aryl C–N and C–O Bonds:
FeCl2 "Pd Source" Tetrahedron Lett. 1995, 36, 3609
ArMgCl + Ar'NO2 ArNHAr' ArX + Angew. Chem. Int. Ed. 1995, 34, 1348
J. Am. Chem. Soc. 2002, 124, 9390 RYHZ ArYRZ
NaBH4 Base J. Org. Chem. 1996, 61, 1133
X = I, Br, Cl Y = N, O, S J. Am. Chem. Soc. 1996, 118, 7215, 7217
Electron-donating and electron-withdrawing functional groups are tolerated on both coupling partners. Z = C, H J. Org. Chem. 1996, 61, 7240
Tetrahedron 1996, 52, 7525
Applicable to a wide variety of nucleophilic partners, including amines, amides, silyloxides, J. Org. Chem. 1997, 62, 1264, 1268
"Cu Source" sulfonamides, anilines, carbamates, ureas, alkoxides, vinylogous amides, phenoxides,
cyclopropylamines, tert-butylcarbamates, sulfoximes, hydrazines, hydrazones, and imines. J. Am. Chem. Soc. 1997, 119, 3395
ArB(OH)2 + RYH ArYR Tetrahedron Lett. 1998, 39, 2933 J. Org. Chem. 1997, 62, 5413
Base Tetrahedron Lett. 1998, 39, 2937 Various heterocycles can be N-arylated including indole, pyrrole, imidazole, carbazole,
Y = NH, O, S benzotriazole, and phenoxazole. A variety of aryl donors are tolerated, including electron- Tetrahedron Lett. 1997, 38, 6367
Tetrahedron Lett. 1998, 39, 2941 J. Am. Chem. Soc. 1998, 120, 827
Applicable to a wide variety of nucleophilic partners, including phenols, amines, anilines, amides, rich, electron-poor, hindered, unhindered, and heterocyclic. A tropone has even been
Org. Lett. 2000, 2, 2019 aminated using this procedure. Five and six (not seven) membered heterocycles can Tetrahedron Lett. 1998, 39, 5731
imides, ureas, carbamates, sulfonamides, thiols, and thiophenols. Can use a variety of Tetrahedron Lett. 2001, 42, 3415
heterocycles, including imidazoles, pyrazoles, triazoles, tetrazoles, benzimidazoles, and indazoles. routinely be formed via intramolecular cyclizations. J. Am. Chem. Soc. 1998, 120, 9722
Tetrahedron Lett. 2003, 44, 1691 J. Am. Chem. Soc. 1999, 121, 3224
Even styryl boronic acids are tolerated in the reaction. α-Amino esters can be arylated in good
yields and purines have been shown to react selectively at N-9. Catalytic reactions can be
Tetrahedron Lett. 2003, 44, 3359 Tetrahedron Lett. 1999, 40, 3543
performed and a wide variety of copper sources, ligands, and bases can be used. J. Org. Chem. 1999, 64, 5575
Org. Lett. 2000, 2, 219
"Cu source" Tetrahedron. 2001, 57, 2953
ArB(OH)2 + PhthNOH ArONPhth Org. Lett. 2001, 3, 139 Tetrahedron Lett. 2001, 42, 4381
Pyr, DCE Org. Lett. 2000, 2, 1109

A wide variety of boronic acids are tolerated and hydrazinolysis reveals the O-arylhydroxylamine. Requires two equivalents of the boronic acid.
Cu(II) Tetrahedron Lett. 1986, 27, 3615
Ar3BiX2 + RYHZ ArYRZ Synthesis. 1994, 775
"Cu Source" J. Am. Chem. Soc. 1997, 119, 10539 Tetrahedron. 1997, 53, 4137
ArX + RYHZ ArYRZ J. Am. Chem. Soc. 1998, 120, 12459 X = Cl, O2CR' Y = N, O
Z = C, H Tetrahedron. 1999, 55, 1341
Base Tetrahedron Lett. 1999, 40, 2657
X = I, Br, Cl Y = N, O, S J. Org. Chem. 1999, 64, 670 Can use with various substituted aryl groups, however phenyl is the most common. The nucleophilic partner can be an amide, aniline,
Z = C, H Tetrahedron Lett. 2000, 41, 1283 alcohol, phenol, amine, or hydrazone.
Applicable to a wide variety of nucleophilic partners, including anilines, phenols, thiophenols, Tetrahedron Lett. 2001, 42, 4791
aliphatic alcohols, thiols, amines, amino alcohols, amino acids, amino esters, guanidines, J. Am. Chem. Soc. 2001, 123, 7727
amides, diamines, hydrazones, carbazoles, imidazoles, indoles, acylhydrazides, pyrroles, EWG EWG
Synlett. 2002, 231 Tetrahedron Lett. 1996, 37, 7343
pyrazoles, benzimidazoles, indazoles, azaindoles, and carbamates. The aryl ring can be a wide + R2NH Base J. Chem. Soc. Perkin Trans. 1. 1997, 2229
variety of heterocycles and the reaction tolerates a wide range of substituents, including Synlett. 2002, 427
electron-donating and electron-withdrawing groups. Inter- and intramolecular reactions are both Org. Lett. 2002, 4, 581 J. Org. Chem. 1997, 62, 3874
F NR2
possible. Unprotected functionality of all sorts is tolerated. Various ring sizes can be formed/are Org. Lett. 2002, 4, 973
tolerated in the reaction. A wide variety of copper sources and oxidation states work in the Org. Lett. 2002, 4, 3517 Various amines and electron-withdrawing groups can be used.
reaction. A variety of bases and ligands can be used and the reaction can even be run with Org. Lett. 2002, 4, 3703
catalytic copper loadings. J. Am. Chem. Soc. 2002, 124, 7421 R' R'
J. Org. Chem. 2005, 70, 5164.Tetrahedron, 2005, 61, 6553. Synlett, 2006,18, 3105. J. Am. Chem. Soc. 2002, 124, 11684
Tetrahedron, 2006, 62, 4435. Tetrahedron, 2006, 62, 4756. J. Org. Chem. 2007, 72, 2737. + R2NH Base
Org. Lett. 2003, 5, 793 J. Org. Chem. 1993, 58, 5101
Tetrahedron Letters, 2007, 48, 6573. Angew. Chem. Int. Ed. 2007, 46, 934. Org. Lett. 2003, 5, 133
J. Org. Chem. 2007, 72, 3863. Org. Lett. 2007, 9, 643. Tetrahedron Letters, 2007, 48, 7199. OMe NR2
A variety of amines can undergo the displacement. Electron-withdrawing groups are not required on the aromatic ring.
"Cu Source"
ArSnR3 + YNHZ ArNYZ Tetrahedron Lett. 2002, 43, 3091 Tetrahedron Lett. 1991, 32, 4321
Base R' R'
Z = C, H X J. Am. Chem. Soc. 1994, 116, 3684
+ TMSX PIFA Synlett. 1995, 211
Applicable to a wide variety of aryl stannanes. Nucleophilic partners include amines, anilines, indazoles, benzimiazolones, pyridones,
and aryl amides. J. Org. Chem. 1995, 60, 7144
OMe X = N3, OAc, SCN, SPh OMe Pure Appl. Chem. 1996, 68, 627
A variety of substitution can be tolerated on the aromatic ring. R can be either alkyl or methoxy. The reaction has even been performed in
Ni(0) the absence of methoxy group.
ArX + NaOR ArOR J. Org. Chem. 1997, 62, 5413
J. Am. Chem. Soc. 1997, 199, 6054
For Reviews on the Subject See:
X = Cl, Br R = alkyl
1. Ley, S. V.; Thomas, A. W. "Modern Synthetic Methods for Copper-Mediated C(aryl)–O, C(aryl)–N, and C(aryl)–S Bond Formation"
Various nucleophilic parters can be used, specifically alkoxides, silyloxides, anilines, and amines. A variety of electron-withdrawing and
electron-donating groups are tolerated on the aromatic ring. Angew. Chem. Int. Ed. 2003, 42, 5400 – 5449.
2. Koser, G. F. "C-Heteroatom-Bond Forming Reactions" Top. Curr. Chem. 2003, 224, 137 – 172.
3. Muci, A. R.; Buchwald, S. L. "Practical Palladium Catalysts for C-N and C-O Bond Formation" Top. Curr. Chem. 2002, 219, 131 – 209.
R
4. Hartwig, J. F. "Palladium-Catalyzed Amination of Aryl Halides: Mechanism and Rational Catalyst Design" Synlett. 1997, 329 – 340.
HN i. Base R Tetrahedron Lett. 1993, 34, 1395
+ N X 5. Hartwig, J. F. "Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and
X J. Org. Chem. 1996, 61, 6581
ii. Demetalate Mechanism" Angew. Chem. Int. Ed. 1998, 37, 2046 – 2067.
F Tetrahedron Lett. 1996, 37, 8487
M Tetrahedron Lett. 1997, 38, 5123 6. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. "Rational Development of Practical Catalysts for Aromatic Carbon–Nitrogen
M = Cr(CO)3 X = NH, CH2 J. Am. Chem. Soc. 1997, 119, 6488 Bond Formation" Acc. Chem. Res. 1998, 31, 805 – 818.
FeCpPF6 7. Hartwig, J. F. "Carbon–Heteroatom Bond-Forming Reductive Eliminations of Amines, Ethers, and Sulfides" Acc. Chem. Res. 1998, 31,
RuCpPF6 852 – 860.
For chromium: will tolerate electron-donating groups on the aromatic ring and a variety (lack of) protecting groups on the piperazine. For 8. Frost, C. G.; Mendonça, P. "Recent developments in aromatic heteroatom coupling reactions" J. Chem. Soc. Perkin Trans. 1. 1998,
iron: a range of amine nucleophiles can be used and some susbstitution on the aromatic ring is tolerable. 2615 – 2623.
9. Yang, B. H.; Buchwald, S. L. "Palladium-catalyzed amination of aryl halides and sulfonates" J. Organometallic Chem. 1999, 576, 125 –
146.
R R
10. Belfield, A. J.; Brown, G. R.; Foubister, A. J. "Recent Synthetic Advances in the Nucleophilic Amination of Benzenes" Tetrahedron.
+ R'NH2 Base 1999, 55, 11399 – 11428.
J. Org. Chem. 1987, 52, 2619
11. Hartwig, J. F. "Approaches to catalyst discovery. New carbon-heteroatom and carbon-carbon bond formation" Pure Appl. Chem. 1999,
Br NHR'
71, 1417 – 1423.
Ammonia, primary, and secondary amines can be used. Gives regioisomeric product mixtures if unsymmetrical. 12. Prim, D.; Campagnew, J.-M.; Joseph, D.; Andrioletti, B. "Palladium-catalysed reactions of aryl halides with soft, non-organomettalic
nucleophiles" Tetrahedron. 2002, 58, 2041 – 2075.
Baran, Newhouse, Seiple Essentials of Heterocyclic Chemistry-IV Heterocyclic Chemistry
Benzofurans: Cl
Thiazoles and Isothiazoles:
O H 2N Me S R S CO2H
S TosMIC i. Δ
X + Me NaOH
Me S Me N R H N O ii. O3 O Δ
X = N2 or Cl,H HO O O HO O
R R
Hantzsch Thiazole Synthesis von Leusen Thiazole Synthesis

H i. Na2S2O3 CHO Ac2O, NaOAc, Me Me

O H 2N SMe i. aq. ROH S BF3, AcOH
Me
+ S Δ
X ii. NH3 AcOH, Δ O N O
S ii. Li/NH3 N O N O CO2H O

O Me RO2C NHTs CO2Me R

S RO2C i. TsNCS
NH4OAc I MeO OMe I
R2 Me O R TIPS
R1 S ii. I2, py S TIPS
N NH2 Me N Pd(OAc)2, base
O Me O OH Pd(OAc)2, base O
OH then BF3
Robinson–Gabriel Thiazole Synthesis

Imidazoles: iPrO Br NH2 K2CO3 ArHN

Benzothiophenes:
H N
O O NH3, Δ N +
ArN R
+ CHO OHC EtO OEt CHO
PPA HS CO2Me
O H 2N H N Ar CO2Me
Br i. ArNH2 NaH
EtO TsN(Na)Cl N S S F S
R1 H CN
O H 2N NH2 N NHTs
OEt ii. H+, Δ
Br + NHR2 N
R1 NR2 N NR2 R2 Benzo[c]thiophenes: Me
H OH R1 Me Me Me
NH TosMIC R N N N
Cl Ph
R1 R1 Ph O HF
R1 base S S
R H N N S O S O Δ
Lantos–Eggleston Imidazole Synthesis
X Me
O R1 H NH2 i. Me Me Me
H 2N N R1 H
NHR + N
N NHR2 NHR Cl Cl
R1 R1 X O O
N OH Ph
ii. [O] N Ph
R Me Ph S Ph Me Me
Ph P4S10
S S
Thiadiazoles: Me Me
Ph
HO2C OHC CHO Me
CO2H SOCl2 N Ph O P4S10 Ph S Ph
H OH O O Ph
N N Δ
Me N CO2Et S N N N N
RHN
Isoindoles:
S8, Na2S N S (OEt)3CH S
Cl3C NNHTs N NH2 O Ph
H 2O Δ N N O
S RHN N Ph
NaS H N 2H 4 MeNH2
EtOH Ph
Ph NMe
S2Cl2 NH
H 2N Ph I2 N S NH2 N S Δ
Ph NaBH4
Ph H 2N N NPhthal
S O Ph
Ph N
O
HN Me CCl3SCl N S Ph O
Cl O H 2N NH2 H+ N S Beta-lactams: R R R R
NaOH N S N
NH2 Me +
O O O
Ph Ph O NHR
HO2C NHR
Cl Ph
DIC tBuMgCl StBu
PhthN
N
S
N N S H2S, MeOH
N S
Me2N N R R
S S N NMe2 R R Ar RO2C R
Cl N Cl N N LHMDS Zn N
NPhth
EtO2C NHR NR Br
Oxetanes: O R

O MsO LDA Ar nBuLi

hν O OH nBuNOAc O TMS
N N Ph
R
R R1 R2 R3 R R3 R Δ R
R1 R2 R Ar O
R1 R1 tBu
CO2 N
Paterno-Büchi Reaction Ph
Baran, Newhouse, Seiple Essentials of Heterocyclic Chemistry-IV Heterocyclic Chemistry
Top 15 Brand-Name Pharmaceuticals with Heterocycles: Top 19 Generic Pharmaceuticals with Heterocycles:
F MeO HO O MeO
OMe Bn
Me Me
NH O O
Me CO2Me NMe O N
N O NH
O S O N
N N O
Ph S N O Me S Me
N H H H
N Me Me Me
HO N S Cl OMe
HN O
HO NHPh HO N
Me
N EtOC Ph
Me O Plavix (BMS) F3C Hydrocodone/ Me
OMe O Me
HO2C Me 2008 rank: 3 Acetaminophen Fentanyl
2008 sales: $3.80B Simvastatin Omeprazole
Lipitor (Pfizer) Nexium (Astra-Zeneca) Prevacid (TAP) 2008 rank: 1 2008 rank: 2 2008 rank: 4 2008 rank: 6
2008 rank: 2 Treats: stroke/heart attack 2008 sales: $1.78B 2008 sales: $1.45B 2008 sales: $1.00B
2008 rank: 1 2008 rank: 5 2008 sales: $1.15B
2008 sales: $5.88B 2008 sales: $4.79B 2008 sales: $3.30B Treats: pain Treats: cholesterol Treats: heartburn Treats: pain
Treats: high LDL cholesterol Treats: heartburn/esophigitis Treats: gastric reflux OH
Me F
F H 2N
Cl
O O O
OH MeO H
N Cl N O
O Me HN
O O
H O N
OMe N
N
N O N Me N MeO S O
Me H N N
S CO2H
Me O H Me
OH N HO
HO Me Me
S S O CO2H
NH2 Pantoprazole Amoxicillin/
Seroquel (Astra-Zeneca) HO2C Oxycontin (Purdue) Amlodipine Besylate 2008 rank: 8 Pot Clav
2008 rank: 6 2008 rank: 9 2008 rank: 7 2008 sales: $0.95B 2008 rank: 10
2008 sales: $2.91B Singulair (Merck) 2008 sales: $2.5B 2008 sales: $0.96B Treats: esophagus inflammation and 2008 sales: $0.81B
Treats: schizophrenia/bipolar mania 2008 rank: 7 Treats: moderate to severe pain Treats: hypertension erosion Treats: bacterial infections
2008 sales: $2.90B Me Me
Treats: asthma N Bn
HO2C MeO
Cl Cl Me
N
NC Me CO2H
O
N O O N N H 2N HN O NMe
S O O
NH OH OH CO2H
NMe2 N OH
HO CO2H
Me Me2N O Ph N HO2C O
O
Ph OH Oxycodone
F HN Zolpidem Tartrate Lisinopril
Actos (Eli Lilly) Fexofenadine 2008 rank: 15
2008 rank: 12 2008 rank: 14
2008 rank: 10 Lexapro (Forest) O 2008 rank: 11 2008 sales: $0.68B
2008 sales: $0.74B 2008 sales: $0.69B
2008 sales: $2.45B 2008 rank: 11 Abilify (Otsuka) 2008 sales: $0.77B Treats: pain
Treats: insomnia Treats: hypertension
Treats: type 2 diabetes 2008 sales: $2.41B 2008 rank: 12 Treats: allergies
Treats: depression and anxiety 2008 sales: $2.37B Me
OH N Me N
Treats: schizoprenia and bipolar mania NH2
N O N
Me Me N N
O NH2 H N
N N
S H S H 2N
O HN N N O
O O O N N
N N N Cl
O N S Cl Cl F
O S O Ph
Me Lamotrigine
Me NH2 CO2H 2008 rank: 20 Risperidone
O O Cefdinir
Me N 2008 sales: $0.54B 2008 rank: 24 N O Alprazolam
Me 2008 rank: 17
H S Me Treats: seizures and bipolar 2008 sales: $0.51B 2008 rank: 25
Topamax (J & J) 2008 sales: $0.59B Treats: schizoprenia and bipolar 2008 sales: $0.47B
Cymbalta (Eli Lilly) Zyprexa (Eli Lilly) Treats: infections disorder
2008 rank: 13 2008 rank: 14 mania Treats: anxiety, panic
2008 sales: $2.18B 2008 rank: 15 F
2008 sales: $2.17B 2008 sales: $1.75B O
Treats: seizures and migranes H O
Treats: depression Treats: schizophrenia/bipolar mania N
O H
O H
O OH
F
N Me Cl N
HN N HN N
O Cl
O N N HO2C
N O S O OEt
H 2N N Me O NH2
Me O O Me O
O N
N Ramipril
H 2N Crestor (AstraZeneca) H Oxcarbazepine
Me 2008 rank: 17 2008 rank: 31 Lorazepam
Valtrex (GSK) Paroxetine 2008 sales: $0.34B 2008 rank: 32 2008 rank: 35
Me Me CO2H 2008 sales: $1.68B 2008 rank: 29
2008 rank: 16 Treats: hypertension 2008 sales: $0.34B 2008 sales: $0.33B
2008 sales: $1.68B OH OH Treats: high LDL cholesterol 2008 sales: $0.36B Treats: seizures
and heart disease Treats: anxiety
Treats: shingles, cold sores and genital herpes Treats: depression, panic