Baran, O'Malley, Shenvi Essentials of Heterocyclic Chemistry-II Heterocyclic Chemistry

Furans: R
Diazoles:
O R'' R' O
R'' O O R''OC
Y acid R' base NH2
R R R R'
O O NH2 R4 N N O NH2 MeN N
R'' Y R4HN R3 MeHN
Me
R' O O X O
Y Y (H)R1 3
R (H) both
Paal-Knorr Furan Synthesis Feist-Bénary Furan Synthesis R1 (Ph2)HC Me (Ph2)HC
R2 regioisomers R2
Pyridines: O i. R'CHO, NH3 R' Knorr Pyrazole Synthesis
R R R Cl ii. HNO3, H2SO4
base
NH3
R
Triazoles:
R N iii. KOH O Ph NH2 N N
OHC N H CHCl3 O O O
N EtO2C iv. CaO H2N 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
HO OR R
RO O HO N OH OHC CHO P4O10 N
H2N 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
TsOH N + N+
+ R N 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
O O NH2 O R' MeO2C H R1 R2 Me
N R'' N R H+ or L.A. R3 Me NHR Tf2O N
CO2Me N N R
R = H/alkyl/aryl, R'' = H/alkyl/aryl Combes Quinoline Synthesis R' = H, X = CO2H Doebner Quinoline Synthesis Passerini Synthesis
R = O-alky/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 O
N O HC(OEt)3 N N Ac2O N
H Δ N Cl N O R N
H N R NH2 N
Meth–Cohn Quinoline Synthesis Ph N Δ Ph O Ph OH Δ
Pfitzinger Quinoline Synthesis H Ph
H
Isoquinolines:
OH + OR Triazanes:
P2O5 acid
RO H2N SMe NH2
N N Me
NH NH2 O Ar Ar N Me
decaline O Me O N Me
N NiO2, N NH
R R H2N 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
N2H4 N N
R O R N R R N R N N R N N N
O NR O H2N N NR H2N 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
3
NMR Spectral Parameters
4 1H
(CDCl3) ppm
2 5 H-3, H-4: 6.22
N1 H-2, H-5: 6.68
H 13C (CDCl )
3
Pyrrole C-3, C-4: 109.2
C-2,C-5: 117.3
H-H Coupling Constants (Hz)
J2,3 2.660 J3,4 3.359
J2,4 1.491 J1,2 2.579
J2,5 1.845 J1,3 2.458
C-H Coupling Constants (Hz)
JC2-H 183.28 JC3-H 168.80
Essentials of Heterocyclic Chemistry-II
Structural Properties
(Determined by microwave spectra)
Bond Lengths (Å)
N-C2: 1.370 NH: 0.996
C2-C3: 1.382 C2-H: 1.076
C3-C4: 1.417 C3-H: 1.077
Bond Angles
C2-N-C5: 109.8 N-C2-H2: 121.5
N-C2-C3: 107.7 C2-C3-C4: 125.5
C2-C3-C4: 107.4
4 3
NMR Spectral Parameters
1H
5 9 (CDCl3) ppm
2 H-1: 7.74 H-4: 7.64 H-7: 7.24
6
8 N1 H-2: 7.00 H-5: 7.12
7 H H-3: 6.51 H-6: 7.18
Indole 13C (CDCl )
3 C3-C8: 1.49 C6-C7: 1.39 C8-C9: 1.39
C-2: 124.2 C-4: 120.7 C-7: 111.1
C-3: 102.4 C-5: 119.8 C-8: 135.7
C-9: 127.8 C-6: 121.9
H-H Coupling Constants (Hz)
J1,2 2.5 J2,3 3.1 J4,6 1.2 J5,7 1.3
J1,3 2.0 J3,7 0.7 J4,7 0.9 J6,7 8.1
J1,4 2.8 J4,5 7.8 J5,6 7.1
Heterocyclic Chemistry
Structural Properties
(x-ray of 1,3,5-trinitrobenzene complex of 3-methylindole)
Bond Lengths (Å)
N1-C2: 1.4 C4-C5: 1.37 C7-C8: 1.40
C2-C3: 1.34 C5-C6: 1.42 C8-N1: 1.38
C8-C4: 1.37
Bond Angles
C8-N1-C2: 108 C8-C9-C4: 123 C6-C7-C8: 115
N1-C2-C3: 111 C9-C4-C5: 116 C7-C8-C9: 122
C2-C3-C9: 106 C4-C5-C6: 122 C9-C8-N1: 109
C3-C9-C8: 106 C5-C6-C7: 121

3 4
NMR Spectral Parameters Structural Properties NMR Spectral Parameters Structural Properties
1H 1H (CCl4) ppm
(C6D12) ppm (Determined by gas-phase 5 4 (x-ray of NiS2PEt2 complex with quinoline)
10
6 3 H-2: 8.82 H-5: 7.73 H-8: 8.05 Bond Lengths (Å)
2 5 H-3, H-4: 6.96 microwave spectra)
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 13C (CDCl ) ppm
C-3, C-4: 127.3 C2-C3: 1.369 3 C3-C4: 1.38 C6-C7: 1.41 C9-C10: 1.43
C-2,C-5: 125.6 C3-C4: 1.423 Quinoline C-2: 150.32 C-10: 128.32 C-7: 129.40 C4-C10: 1.39 C7-C8: 1.36
H-H Coupling Constants (Hz) Bond Angles C-3: 121.01 C-5: 127.72 C-8: 129.40 Bond Angles
J2,3 4.9-5.8 J3,4 3.45-4.35 C2-S-C5: 92 C-4: 135.93 C-6: 126.46 C-9: 148.34 C9-N1-C2: 119.1 C10-C5-C6: 120.5 C10-C7-N1: 120.5
J2,4 1.25-1.7 J2,5 3.2-3.65 S-C2-C3: 111 H-H Coupling Constants (Hz) N1-C2-C3: 121.1 C5-C6-C7: 120.1 C10-C9-C8: 119.7
C-H Coupling Constants (Hz) C2-C3-C4: 112 J2,3 4.18 J4,8 0.75 J5,8 0.69 J7,8 8.57 C2-C3-C4: 120.4 C6-C7-C8: 120.9 C4-C10-C9: 119.1
JC2-H 185 JC3-H 168 J2,4 1.76 J5,6 8.24 J6,7 6.88 C3-C4-C10: 119.6 C7-C8-C9: 121.0 C5-C10-C9: 117.7
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 (CCl4) ppm
1H (CDCl3) ppm (Determined by microwave spectra) 5 4 (x-ray of C1-hydroxymethylphenyl derivative of isoquinoline)
2 5 10
6 3 H-1: 9.11 H-5: 7.70 H-8: 7.85 Bond Lengths (Å)
O1 H-3, H-4: 6.24 Bond Lengths Å)
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 )
6 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
8 1 13C (CDCl ) ppm
C-3, C-4: 110.4 C3-C4: 1.430 3 C3-C4: 1.349 C6-C7: 1.399 C9-C10: 1.416
C-2,C-5: 143.6 Bond Angles Isoquinoline C-1: 152.6 C-5: 126.4 C-8: 127.5 C4-C10: 1.414 C7-C8: 1.364
H-H Coupling Constants (Hz) C2-O-C5: 106.50 O-C2-H2 115.93 C-3: 143.1 C-6: 130.2 C-9: 128.7 Bond Angles
J2,3 1.75 J3,4 3.3 O-C2-C3: 110.65 C2-C3-H3 127.83 C-4: 120.4 C-7: 127.2 C-10: 135.7 C9-C1-N2: 123.2 C4-C10-C9: 117.8
J2,4 0.85 J2,5 1.4 C2-C3-C4: 106.07 H-H Coupling Constants (Hz) C1-N2-C3: 117.8 C4-C9-C1: 117.8
C-H Coupling Constants (Hz) J1,4 1.0 J4,5 -0.36 J5,8 0.80 J7,8 8.27 N2-C3-C4: 123.9
JC2-H 201 JC3-H 175 J3,4 5.75 J5,6 8.29 J6,7 6.92 C3-C4-C10: 119.5
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 (CDCl3) ppm (Determined by microwave
N 1H (D2O) ppm (Determined by X-Ray)
3 5 2 5 H-4, H-5: 7.14 Bond Lengths (Å)
H-3: 7.25 and electron diffraction spectra)
H-4: 7.64 Bond Lengths (Å) N1 H-2: 7.73 N1-C2: 1.349
2 6 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
C-3: 123.46 C3-C4: 1.392 C-2: 136.2 C4-C5: 1.358
C-4: 135.58 Bond Angles C5-N1: 1.369
C-2 149.59 C6-N-C5: 116.9 Bond Angles
H-H Coupling Constants (Hz) N-C2-C3: 123.8 C2-N1-C5: 107.2
J2,3 4.93 J2,6 -0.03 C2-C3-C4: 118.5 N1-C2-N3: 111.3
J2,4 1.80 J3,5 1.44 C3-C4-C5: 118.4 C2-N3-C4: 105.4
J2,5 1.00 J3,4 7.66 N3-C4-C5: 109.8
C-H Coupling Constants (Hz) C4-C5-N1: 106.3
JC2-H 179 JC3-H 163 JC4-H 152