Modern heterocyclic chemistry

Edited by
Julio Alvarez-Builla,
Juan Jose Vaquero,
and Jose´ Barluenga
Modern Heterocyclic
Chemistry


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Edited by
Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga

Modern Heterocyclic Chemistry
Volume 4

The Editors
Prof. Dr. Julio Alvarez-Builla
Universidad de Alcalá
Facultad de Farmacia
Dpto. de Química Organíca
Campus Universitario s.n.
Alcalá de Henares
28871 Madrid
Spain
Dr. Juan Jose Vaquero
Universidad de Alcalá
Dpto. de Química Organíca
Ctra. Madrid-Barcelona km 33
Alcalá de Henares
28871 Madrid
Spain
Prof. Dr. José Barluenga
Universidad de Oviedo
Instituto Universitario de
Química Organometálica ‘‘Enrique Moles’’
33071 Oviedo
Spain

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statements, data, illustrations, procedural details or

other items may inadvertently be inaccurate.
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Printed on acid-free paper
Print ISBN: 978-3-527-33201-4
oBook ISBN: 978-3-527-63406-4

V

Contents
List of Contributors

XV

Volume 1
1

1

Heterocyclic Compounds: An Introduction
Julio Alvárez-Builla and José Barluenga

2

Three-Membered Heterocycles. Structure and Reactivity
S. Shaun Murphree

3

Four-Membered Heterocycles: Structure and Reactivity 163
Gérard Rousseau and Sylvie Robin

4

Five-Membered Heterocycles: Pyrrole and Related Systems
Jan Bergman and Tomasz Janosik

269

5

Five-Membered Heterocycles: Indole and Related Systems
José Barluenga and Carlos Valdés

377

6

Five-Membered Heterocycles: Furan 533
Henry N.C. Wong, Xue-Long Hou, Kap-Sun Yeung, and Hui Huang

7

Five-Membered Heterocycles: Benzofuran and Related Systems
Jie Wu

11

Volume 2
635

8

Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles
José Elguero, Artur M.S. Silva, and Augusto C. Tomé

9

Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles
and Isothiazoles 727
Artur M.S. Silva, Augusto C. Tomé, Teresa M.V.D. Pinho e Melo,
and José Elguero

593


VI

Contents

10

Five-Membered Heterocycles: 1,3-Azoles 809
Julia Revuelta, Fabrizio Machetti, and Stefano Cicchi

11

Five-Membered Heterocycles with Two Heteroatoms:
O and S Derivatives 925
David J. Wilkins

12

Five-Membered Heterocycles with Three Heteroatoms: Triazoles
Larry Yet

13

Oxadiazoles 1047
Giovanni Romeo and Ugo Chiacchio

989

Volume 3
14

Thiadiazoles 1253
Ugo Chiacchio and Giovanni Romeo

15

Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles
Ulhas Bhatt

16

Six-Membered Heterocycles: Pyridines 1431
Concepción González-Bello and Luis Castedo

17

Six-Membered Heterocycles: Quinoline and Isoquinoline
Ramón Alajarín and Carolina Burgos

18

Six-Membered Rings with One Oxygen: Pyrylium Ion,
Related Systems and Benzo-Derivatives 1631
Javier Santamaría and Carlos Valdés

19

Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines
and Related Systems 1683
María-Paz Cabal

20

Six-Membered Heterocycles: Triazines, Tetrazines and Other
Polyaza Systems 1777
Cristina Gómez de la Oliva, Pilar Goya Laza, and Carmen Ochoa de Ocariz

1527

Volume 4
21

21.1

1401

Seven-Membered Heterocycles: Azepines, Benzo Derivatives
and Related Systems 1865
Juan J. Vaquero, Ana M. Cuadro, and Bernardo Herradón
Introduction 1865

Contents

21.2
21.3
21.4
21.5
21.5.1
21.5.1.1
21.5.1.2
21.5.2
21.5.2.1
21.5.2.2
21.5.3
21.5.3.1
21.5.3.2
21.5.4
21.5.5
21.5.5.1
21.5.5.2
21.5.5.3
21.6
21.6.1
21.6.1.1
21.6.1.2
21.6.1.3
21.6.1.4
21.6.1.5
21.6.1.6
21.6.1.7

21.6.1.8
21.6.2
21.6.2.1
21.6.2.2
21.6.2.3
21.7
21.7.1
21.7.1.1
21.7.1.2
21.7.1.3
21.7.1.4
21.7.1.5
21.7.2
21.7.2.1
21.7.2.2
21.8
21.8.1

Relevant Natural and Useful Compounds 1867
Relevant Computational Chemistry, Physicochemical,
and Spectroscopic Data 1869
Valence Tautomerism in Seven-Membered Heterocycles 1874
Synthesis 1878
Synthesis of Azepines 1878
From Acyclic Compounds 1878
From Cyclic Compounds 1883
Synthesis of Oxepines 1885
From Acyclic Compounds 1885
From Cyclic Compounds 1890
Synthesis of Thiepines 1896

From Acyclic Compounds 1896
From Cyclic Compounds 1897
Synthesis of Azepanes, Oxepanes, and Thiepanes 1898
Synthesis of Benzo Derivatives 1902
Synthesis of Benzazepines 1902
Synthesis of Benzoxepines 1906
Synthesis of Benzothiepines 1907
Reactivity of Azepines 1911
Reactivity of Azepines and Benzofused Derivatives 1911
Cycloaddition Reactions 1911
Reaction with Metal Carbonyl Complexes 1914
Reactions through Metal Carbonyl Complexes 1916
Pericyclic Reactions 1917
Reactions with Electrophiles 1923
Reactions with Nucleophiles 1927
Reactions with Oxidants 1929
Hydrogenation and Hydrogen Transfer 1932
Reactivity of Partially Reduced Azepine Derivatives 1934
Dihydroazepines 1934
Tetrahydroazepines 1937
Dihydroazepinones 1938
Reactivity of Oxepines 1943
Reactivity of Oxepines and Benzofused Derivatives 1944
Thermal and Photochemical Reactions 1944
Cycloaddition Reactions 1945
Reactions with Electrophiles 1948
Reactions with Nucleophiles 1949
Reactions with Oxidants 1951
Reactivity of Partially Reduced Oxepines 1953
Dihydrooxepines 1953

Tetrahydrooxepines 1955
Reactivity of Thiepines 1958
Reactivity of Thiepines and Benzofused Derivatives 1958

VII


VIII

Contents

21.8.1.1
21.8.1.2
21.8.1.3
21.8.1.4
21.8.1.5
21.8.2
21.8.2.1
21.8.2.2
21.8.2.3

Reactions with Metal Carbonyl Complexes 1958
Cycloaddition Reactions 1959
Thermal and Photochemical Reactions 1962
Reactions with Electrophiles 1965
Reactions with Oxidants 1967
Reactivity of Partially Reduced Thiepine Derivatives
Dihydrothiepines 1968
Tetrahydrothiepines 1972
Thiepinones 1975

References 1975

22

Heterocycles Containing a Ring-Junction Nitrogen 1989
Juan J. Vaquero and Julio Alvarez-Builla
Introduction 1989
Pyrrolizines 1991
General Structure and Reactivity 1991
Relevant Natural and/or Useful Compounds 1991
Relevant Computational Chemistry and Physicochemical
and Spectroscopic Data 1993
Synthesis of Pyrrolizines 1994
By Cyclization Reactions 1995
By [3 þ 2] Approaches 1997
Reactivity of Pyrrolizines 1997
Electrophilic Attack 1997
Cycloaddition Reactions 2000
Reduction Reactions 2000
Ring-Opening Reactions 2001
Derivatives 2001
Indolizines 2003
General Structure and Reactivity 2003
Relevant Natural and/or Useful Compounds 2003
Relevant Physicochemical Data, Computational Chemistry,
and NMR Data 2005
Synthesis of Indolizidines 2006
Intramolecular Condensation: Approaches Related
to the Chichibabin Synthesis 2006
By a [3 þ 2] Approach: 1,3-Dipolar Cycloaddition 2007

Organometallic Processes 2009
Rearrangement of Acetylenic Derivatives 2009
Reactivity of Indolizidines 2011
Reactions with Electrophilic Reagents 2011
Reactions with Oxidizing Agents 2016
Reactions with Nucleophilic Reagents 2016
Reactions with Bases 2017
Reactions with Reducing Agents 2017

22.1
22.2
22.2.1
22.2.2
22.2.3
22.2.4
22.2.4.1
22.2.4.2
22.2.5
22.2.5.1
22.2.5.2
22.2.5.3
22.2.5.4
22.2.6
22.3
22.3.1
22.3.2
22.3.3
22.3.4
22.3.4.1
22.3.4.2

22.3.4.3
22.3.4.4
22.3.5
22.3.5.1
22.3.5.2
22.3.5.3
22.3.5.4
22.3.5.5

1968


Contents

22.3.5.6
22.3.5.7
22.3.6
22.4
22.4.1
22.4.2
22.4.3
22.4.4
22.4.4.1
22.4.4.2
22.4.4.3
22.4.5
22.4.5.1
22.4.5.2
22.4.5.3
22.4.5.4

22.4.6
22.4.6.1
22.4.6.2
22.4.6.3
22.4.7

23
23.1
23.2
23.2.1
23.2.2
23.2.3
23.2.3.1
23.2.3.2
23.2.4
23.2.4.1
23.2.4.2
23.2.4.3
23.2.4.4
23.2.4.5
23.2.4.6
23.3
23.3.1
23.3.2

Electrocyclic Reactions 2018
Reactions of C-Metallated Indolizines 2019
Derivatives 2020
Quinolizinium Salts 2020
General Structure and Reactivity 2020

Relevant Natural and/or Useful Compounds 2021
Relevant Computational Chemistry, and Physicochemical
and Spectroscopic Data 2023
Synthesis of Quinolizinium Salts 2026
By [3 þ 3] Approaches 2026
By [4 þ 2] Approaches 2029
By Cyclization Reactions 2035
Reactivity of Quinolizinium Salts 2038
Reactions with Electrophilic Reagents 2039
Reactions with Nucleophilic Reagents: Ring-Opening
Reactions 2040
Reactions with Reducing Reagents 2042
Cycloaddition Reactions 2042
Quinolizinium Derivatives 2043
Alkyl Derivatives 2043
Hydroxy and Amino Derivatives 2045
Halo Derivatives 2048
Benzoquinolizinium Salts and Related Systems 2052
References 2062
Phosphorus Heterocycles 2071
Franç ois Mathey
Introduction 2071
Phospholes 2071
History and Nomenclature 2071
Spectral, Structural and Theoretical Studies 2072
Synthesis 2073
Synthesis of Phospholes 2073
Synthesis of Phospholide Ions 2075
Reactivity 2076
Reactions at Phosphorus 2076

Reactions at the Diene 2077
[1,5]-Sigmatropic Shifts 2079
Functionalization Reactions 2082
Ring Openings and Expansions 2082
Phospholes and Phospholides in Coordination
Chemistry 2083
Phosphinines 2084
History and Nomenclature 2084
Spectral, Structural and Theoretical Studies 2085

IX


X

Contents

23.3.3
23.3.4
23.3.4.1
23.3.4.2
23.3.4.3
23.3.4.4
23.4
23.4.1
23.4.2
23.4.3
23.5
23.6
23.6.1

23.6.2

Synthesis 2086
Reactivity 2089
Reactions at Phosphorus 2089
Substitution and Functionalization Reactions 2092
Cycloaddition Reactions 2095
Phosphinines in Coordination Chemistry 2096
Other P Heterocycles 2097
Three-Membered Rings: Phosphiranes and
Phosphirenes 2097
Four-Membered Rings: Phosphetanes, Dihydrophosphetes
and Phosphetes 2100
Five-Membered Rings: Phospholenes 2102
Applications of Phosphorus Heterocycles 2103
Addendum 2105
Phospholes 2105
Phosphinines 2107
References 2109

The Chemistry of 2-Azetidinones (b-Lactams) 2117
Benito Alcaide, Pedro Almendros, and Amparo Luna
24.1
Monocyclic Derivatives 2117
24.1.1
Introduction 2117
24.1.2
Physicochemical Data 2117
24.1.2.1 Computational Chemistry 2117
24.1.2.2 Experimental Structural Methods 2119

24.1.3
Biologically Relevant Monocyclic b-Lactams 2120
24.1.4
2-Azetidinone Nucleus Synthesis 2121
24.1.4.1 Ketene-Imine Cycloaddition (Staudinger Reaction) 2121
24.1.4.2 Metalloester Enolate-Imine Condensation 2124
24.1.4.3 Isocyanate-Alkene Cyclocondensation 2125
24.1.4.4 Chromium Carbene-Imine Cyclization 2126
24.1.4.5 Cyclization of b-Amino Acids and Derivatives 2126
24.1.4.6 Hydroxamate Cyclization 2127
24.1.4.7 Metal-Catalyzed Insertions of Diazo
Compounds 2127
24.1.4.8 Multicomponent Reactions 2129
24.1.4.9 Coupling of Terminal Alkynes and Nitrones
(Kinugasa Reaction) 2130
24.1.4.10 Photochemical and Radical Methods 2130
24.1.4.11 Synthesis from Carbo- or Heterocycles 2131
24.1.4.12 Miscellaneous 2133
24.1.5
Reactivity of the 2-Azetidinone Ring 2134
24.1.5.1 Nucleophilic Attack at Carbon 2134
24.1.5.2 Electrophilic Attack at Carbon 2136
24.1.5.3 Electrophilic Attack at Nitrogen 2136
24


Contents

24.1.5.4
24.1.5.5

24.1.5.6
24.1.5.7
24.1.5.8
24.1.5.9
24.2
24.2.1
24.2.2
24.2.2.1
24.2.2.2
24.2.3
24.2.3.1
24.2.3.2
24.2.4
24.2.4.1
24.2.4.2
24.2.4.3
24.2.4.4
24.2.4.5
24.2.4.6

25
25.1
25.1.1
25.1.2
25.2
25.2.1
25.2.2
25.2.3
25.2.4
25.3

25.3.1
25.3.2
25.3.2.1
25.3.2.2

Radical Transformations 2137
Reduction Reactions 2138
Cis/Trans Isomerization 2139
Ring-Opening and Rearrangement Reactions 2140
Reactions of Substituents Attached to Carbon
Atoms 2142
Reactions of Substituents Attached to Nitrogen Atom
Penicillins and Cephalosporins 2144
Introduction 2144
Physicochemical Data 2146
Computational Chemistry 2146
Experimental Structural Methods 2147
Synthesis of Penicillins and Cephalosporins 2148
Classical Syntheses 2148
Industrial Production of b-Lactam Antibiotics 2150
Reactivity of Penicillins and Cephalosporins 2153
Basicity of b-Lactam Nitrogen 2153
Hydrolysis 2153
Alcoholysis, Thiolysis, and Aminolysis 2155
Destruction of b-Lactam Antibiotics by
b-Lactamases 2156
Conversion of Penicillins into Cephalosporins 2158
Reactions for the Transformation of Functional
Groups in Side Chains 2159
References 2163

2143

The Chemistry of Benzodiazepines 2175
Carlos Valdés and Miguel Bayod
Introduction 2175
General Introduction 2175
Structural Classification of Benzodiazepines 2177
Relevant Benzodiazepines 2177
Most Common 1,4-Benzodiazepines 2177
1,4-Benzodiazepines with a Heterocycle Condensed
at sides a or d 2179
Other Benzodiazepines with Clinical
Application 2181
Naturally Occurring Benzodiazepines 2181
1,4-Benzodiazepines: General Synthetic
Methods 2182
1,4-Benzodiazepines Ring Synthesis: Introduction 2182
Ring Synthesis of 1,4-Benzodiazepin-2-ones 2182
Quinazoline N-Oxide Route: Sternbach’s
Classical Synthesis 2182
2-Aminobenzophenone Route 2184

XI


XII

Contents

25.3.3
25.3.3.1
25.3.3.2
25.3.4
25.4
25.4.1
25.4.2
25.4.3
25.4.4
25.5
25.5.1
25.5.2
25.5.3
25.5.3.1
25.5.3.2
25.6
25.7
25.7.1
25.7.2
25.8
25.8.1
25.8.2

26

26.1
26.1.1
26.1.2
26.1.2.1
26.1.2.2

26.1.2.3
26.1.2.4
26.2
26.3
26.3.1
26.3.1.1
26.3.1.2

Synthesis of 1,4-Benzodiazepine-2,5-diones 2186
Standard Synthesis: from Anthranilic Acid and a-Amino
Acid Derivatives 2186
Ugi 4CC Reaction in the Synthesis of
1,4-Benzodiazepines-2,5-diones 2188
Other 1,4-Benzodiazepines 2192
Modifications of the 1,4-Benzodiazepine Ring 2193
Introduction 2193
Reactions of the C2 Carbonyl Group 2194
Functionalization at C3 2196
Substitutions at C5 2197
1,4-Benzodiazepines with a Fused Heterocycle 2198
Benzodiazepines with a Heterocycle Fused at
the a Side (N1-C2 Position) 2198
Benzodiazepines with a Heterocycle Fused
at the d Side (N4-C5 Position) 2204
Cycloaddition Reactions in the Synthesis
of 1,4-Benzodiazepines with Fused Heterocycles 2206
[3 þ 2] Cycloadditions 2206
[2 þ 2] Cycloadditions 2208
Pyrrolo[2,1-c][1,4]Benzodiazepines (PBDs) 2210
1,5-Benzodiazepines 2213

General Methods of Synthesis of 1,5-Benzodiazepines 2214
1,5-Benzodiazepines with a Fused Heterocycle 2217
2,3-Benzodiazepines 2217
2,3-Benzodiazepine Ring Synthesis 2218
2,3-Benzodiazepines with a Fused Heterocycle 2221
References 2222
Porphyrins: Syntheses and Reactions 2231
Venkataramanarao G. Anand, Alagar Srinivasan,
and Tavarekere K. Chandrashekar
Introduction 2231
General Introduction 2231
System Isomers 2232
Tetrapyrrolic Systems 2232
Pyrrole Inverted Systems 2233
Core-Modified Porphyrins 2233
Expanded Porphyrins 2235
Synthetic Chemistry of Porphyrins and Expanded
Porphyrins 2236
Reactivity of Porphyrins 2254
Electrophilic Reactions 2255
Formylation 2255
Reactions of Formyl Porphyrins 2256


Contents

26.3.1.3
26.3.1.4
26.3.1.5
26.3.1.6

26.3.2
26.3.2.1
26.3.2.2
26.3.2.3
26.3.2.4
26.3.2.5

Halogenation 2257
Nitration 2260
Acylation 2262
Cyanation 2262
Nucleophilic Reactions 2262
Reactions of p-Cation Radicals 2262
Substitution Reactions. Reactions with H2(OEP) 2263
Reactions with 5,15-Disubstituted Porphyrins 2265
Reactions with H2TPP 2266
Reactions with Porphine 2268
References 2268

27

New Materials Derived From Heterocyclic Systems 2275
Javier Santamaría and José L. García-Álvarez
Introduction 2275
Color and Fluorescent Agents 2275
Heterocyclic Pigments and Industrial Applications 2275
Fluorescence and Fluorescent Heterocycles 2282
Self-Assembling Materials and Molecular Containers 2286
Introduction 2286
Assembly Mediated by Electrostatic and p-Stacking

Interactions 2286
Self-Assembly Through Coordination Chemistry 2288
Self-Assembly Through Hydrogen-Bond Chemistry 2293
Capsules and Encapsulation Behavior 2297
Unnatural Enzyme Models 2300
Organic Conductors 2304
Introduction 2304
Conducting Heterocyclic Polymers 2305
Conducting Heterocyclic Molecules in the Bulk 2308
Single Molecule Conductivity 2313
References 2314

27.1
27.2
27.2.1
27.2.2
27.3
27.3.1
27.3.2
27.3.3
27.3.4
27.3.5
27.4
27.5
27.5.1
27.5.2
27.5.3
27.5.4

28

28.1
28.1.1
28.1.2
28.1.3
28.2
28.2.1
28.2.2
28.2.3
28.2.4

Solid Phase and Combinatorial Chemistry in the
Heterocyclic Field 2321
José M. Villalgordo
Introduction 2321
Natural Products 2322
Peptides, Peptoids and Peptidomimetics 2324
Small Synthetic Organic Molecules 2324
Solid Supports 2327
Crosslinked Polystyrene-Derived Matrices 2329
Functionalized Polystyrene Resins 2329
Chloromethylated Polystyrenes 2330
Aminomethylated Polystyrene Resins 2333

XIII


XIV

Contents

28.2.5
28.2.6
28.2.7
28.2.8
28.2.9
28.3
28.3.1
28.3.1.1
28.3.1.2
28.3.1.3
28.3.1.4
28.3.1.5
28.3.2
28.3.3
28.3.3.1
28.3.3.2
28.3.3.3
28.4
28.4.1
28.4.2
28.4.3
28.4.4
28.4.5
28.4.6
28.4.7

Other Functionalized Polystyrene Resins 2334
Polyacrylamide Resins 2339
TentaGel Resins 2340

Novel Polymeric Supports 2341
CLEAR Resins 2343
Linkers for Solid-Phase Organic Synthesis 2343
Linker Molecules Releasing One Specific Functional
Group. Monofunctional Cleavage 2344
Linkers Releasing Carboxylic Acids 2345
Linkers Releasing Amides 2345
Linkers Releasing Amines 2345
Linkers Releasing Alcohols, Diols and Phenols 2345
Linkers Releasing Hydroxamic Acids 2345
Cyclization-Assisted Cleavage 2348
Multidirectional Cleavage Strategies 2352
Direct Cleavage by Nucleophilic Substitution 2352
Direct Cleavage by Electrophiles 2353
‘‘Safety-Catch’’ Linkers 2354
Heterocyclic Synthesis on Solid-Phase 2357
Synthesis of b-Lactams 2358
Synthesis of Pyrrolidines 2359
Synthesis of Pyrroles 2362
Synthesis of Furans 2363
Synthesis of Thiophenes 2366
Synthesis of Imidazoles 2369
Synthesis of Thiazoles 2372
References 2375
Index

2381


XV

List of Contributors
Ramón Alajarín
Universidad de Alcalá
Departamento de Química Orgánica
Alcalá de Henares
28871 Madrid
Spain
Benito Alcaide
Universidad Complutense de Madrid
Facultad de Química
Departamento de Química Orgánica I
28040 Madrid
Spain
Pedro Almendros
Instituto de Química Orgánica General
(CSIC)
Juan de la Cierva, 3
28006 Madrid
Spain
Julio Alvárez-Builla
Universidad de Alcalá
Facultad de Farmacia
Departamento de Química Orgánica
Alcalá de Henares
28871 Madrid
Spain

Venkataramanarao G. Anand
Regional Research Laboratory (CSIR)

Chemical Sciences and Technology
Division
Photosciences and Photonics Section
Trivandrum 695 019
India
José Barluenga
Universidad de Oviedo
Instituto Universitario de Química
Organometálica ‘‘Enrique Moles’’
Julián Clavería 8
33006 Oviedo
Spain
Miguel Bayod
Asturpharma S.A.
Peña Brava 23
Polígono Industrial Silvota
33192 Llanera, Asturias
Spain
Jan Bergman
Karolinska Institute
Department of Biosciences and
Nutrition
Unit of Organic Chemistry
Novum Research Park
141 57 Huddinge
Sweden


XVI

List of Contributors

Ulhas Bhatt
Albany Molecular Research, Inc.
Albany, NY 12212
USA
Carolina Burgos
Universidad de Alcalá
Departamento de Química Orgánica
Alcalá de Henares
28871 Madrid
Spain
María-Paz Cabal
Universidad de Oviedo
Instituto Universitario de Química
Organometálica ‘‘Enrique Moles’’
Julián Clavería 8
33006 Oviedo
Spain
Luis Castedo
Universidad de Santiago de Compostela
Facultad de Química
Departamento de Química Orgánica
15782 Santiago de Compostela
Spain
Tavarekere K. Chandrashekar
Regional Research Laboratory (CSIR)
Chemical Sciences and Technology
Division
Photosciences and Photonics Section

Trivandrum 695 019
India
and

Stefano Cicchi
Università degli Studi di Firenze
Dipartimento di Chimica ‘‘Ugo Schiff’’
via della Lastruccia 13
50019 Sesto Fiorentino-Firenze
Italy
Ana M. Cuadro
Universidad de Alcala
Departamento de Química Orgánica
Alcalá de Henares
28871 Madrid
Spain
José Elguero
University of Aveiro
Instituto de Química Médica (CSIC)
Department of Chemistry
Juan de la Cierva, 3
28006 Madrid
Spain
José L. García-lvarez
Universidad de Oviedo
Instituto Universitario de Química
Organometálica ‘‘Enrique Moles’’
Departamento de Química Orgánica e
Inorgánica
Unidad asociada al CSIC

Julian Claveria 8
33006 Oviedo
Spain

Indian Institute of Technology
Department of Chemistry
Kanpur 208 016
India

Cristina Gómez de la Oliva
Instituto de Química Médica (CSIC)
Juan de la Cierva, 3
28006 Madrid
Spain

Ugo Chiacchio
Università di Catania
Dipartimento di Scienze Chimiche
Viale Andrea Doria 6
95125 Catania
Italy

Concepción González-Bello
Universidad de Santiago de Compostela
Facultad de Ciencias
Departamento de Química Orgánica
27002 Lugo
Spain

List of Contributors

Pilar Goya Laza
Instituto de Química Médica (CSIC)
Juan de la Cierva, 3
28006 Madrid
Spain
Bernardo Herradón
Instituto de Química Orgánica (CSIC)
Juan de la Cierva, 3
28006 Madrid
Spain
Xue-Long Hou
The Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
Shanghai-Hong Kong Joint Laboratory
in Chemical Synthesis and State Key
Laboratory of Organometallic Chemistry
354 Feng Lin Road
Shanghai 200032
China
Hui Huang
The Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
Shanghai-Hong Kong Joint Laboratory
in Chemical Synthesis
354 Feng Lin Road
Shanghai 200032

China
Tomasz Janosik
Karolinska Institute
Department of Biosciences and
Nutrition
Unit of Organic Chemistry
Novum Research Park
141 57 Huddinge
Sweden

Amparo Luna
Universidad Complutense de Madrid
Facultad de Química
Departamento de Química Orgánica I
28040 Madrid
Spain
Fabrizio Machetti
Instituto Chimica dei Composti
Organometallica del CNR c/o
Dipartimento di Chimica Organica
‘‘Ugo Schiff’’
Via Madonna del Piano 10
50019 Sesto Fiorentino (Firenze)
Italy
François Mathey
Nanyang Technical University
School of Physical and Mathematical
Sciences
Division of Chemistry and Biological
Chemistry

21 Nanyang Link
637371 Singapore
Singapore
S. Shaun Murphree
Allegheny College
Department of Chemistry
520 N, Main Street
Meadville, PA 16335
USA
Carmen Ochoa de Ocariz
Instituto de Química Médica (CSIC)
Juan de la Cierva, 3
28006 Madrid
Spain
Teresa M.V.D. Pinho e Melo
Universidade de Coimbra
Departamento de Química
3004-535 Coimbra
Portugal

XVII


XVIII

List of Contributors

Julia Revuelta
Instituto de Quimica Organica General
(CSIC)

Grupo de Quimica Organica Biologica
C/Juan de la Cierva, 3
28006 Madrid
Spain
Sylvie Robin
Université de Paris-Sud
ICMMO
Laboratoire ed Synthèse Organique et
Méthodologie
Université de Paris-Sud
91405 Orsay
France
Giovanni Romeo
Università di Messina
Dipartimento Farmaco-Chimico
Via SS Annunziata
98168 Messina
Italy
Gérard Rousseau
Université de Paris-Sud
ICMMO
Laboratoire ed Synthèse Organique et
Méthodologie
Université de Paris-Sud
91405 Orsay
France
Javier Santamaría
Universidad de Oviedo
Instituto Universitario de Química
Organometálica ‘‘Enrique Moles’’

Departamento de Química Orgánica e
Inorgánica
Unidad asociada al CSIC
Julian Claveria 8
33006 Oviedo
Spain

Artur M.S. Silva
University of Aveiro
Department of Chemistry
3810-193 Aveiro
Portugal
Alagar Srinivasan
Regional Research Laboratory (CSIR)
Chemical Sciences and Technology
Division
Photosciences and Photonics Section
Trivandrum 695 019
India
Augusto C. Tomé
University of Aveiro
Department of Chemistry
3810-193 Aveiro
Portugal
Carlos Valdés
Universidad de Oviedo
Instituto Universitario de Química
Organometálica ‘‘Enrique Moles’’
Julián Clavería 8
33006 Oviedo

Spain
Juan J. Vaquero
Universidad de Alcala
Departamento de Química Orgánica
Alcalá de Henares
28871 Madrid
Spain
José M. Villalgordo
Villalpharma S.L.
Polígono Industrial Oeste
C/Paraguay, Parcela 7/5-A, Módulo A-1
30169 Murcia
Spain


List of Contributors

David J. Wilkins
Key Organics Ltd.
Highfield Industrial State
Camelford
Cornwall PL32 9QZ
UK

Jie Wu
Fudan University
Department of Chemistry
220 Handan Road
Shanghai 200433
China

Henry N.C. Wong
The Chinese University of Hong Kong
Institute of Chinese Medicine, and
Central Laboratory of the Institute of
Molecular Technology for Drug
Discovery and Synthesis
Department of Chemistry
Center of Novel Functional Molecules
Shatin, New Territories
Hong Kong SAR, China

Larry Yet
299 Georgetown Ct
Albany, NY 12203
USA

and
The Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
Shanghai-Hong Kong Joint Laboratory
in Chemical Synthesis
354 Feng Lin Road
Shanghai 200032
China

Kap-Sun Yeung
Bristol-Myers Squibb Pharmaceutical
Research Institute

5 Research Parkway
P.O. Box 5100
Wallingford, CT 06492
USA

XIX


j1

1
Heterocyclic Compounds: An Introduction
Julio Alvarez-Builla and Jose Barluenga

1.1
Heterocyclic Compounds: An Introduction

The IUPAC Gold Book describes heterocyclic compounds as:
“Cyclic compounds having as ring members atoms of at least two different elements,
e.g. quinoline, 1,2-thiazole, bicyclo[3.3.1]tetrasiloxane” [1].
Usually they are indicated as counterparts of carbocyclic compounds, which
have only ring atoms from the same element. Another classical reference book,
the Encyclopaedia Britannica, describes a heterocyclic compound, also called a
heterocycle, as:
“Any of a class of organic compounds whose molecules contain one or more rings of
atoms with at least one atom (the heteroatom) being an element other than carbon,
most frequently oxygen, nitrogen, or sulfur” [2].
Although heterocyclic compounds may be inorganic, most contain within the ring
structure at least one atom of carbon, and one or more elements such as sulfur,
oxygen, or nitrogen [3]. Since non-carbons are usually considered to have replaced

carbon atoms, they are called heteroatoms. The structures may consist of either
aromatic or non-aromatic rings.
Heterocyclic chemistry is the branch of chemistry dealing with the synthesis,
properties, and applications of heterocycles.
Heterocyclic derivatives, seen as a group, can be divided into two broad areas:
aromatic and non-aromatic. In Figure 1.1, five-membered rings are shown in the first
row, and the derivative 1 corresponds to the aromatic derivative, furan, while
tetrahydrofuran (2), dihydrofuran-2-one (3), and dihydrofuran-2,5-dione (4) are not
aromatic, and their reactivity would be not unlike that expected of an ether, an ester, or

Modern Heterocyclic Chemistry, First Edition.
Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga.
Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.


j 1 Heterocyclic Compounds: An Introduction

2

O
1

2

N

N
H
6

5

O

O

O

O

O

O
4

3

N
H
7

O

N
H
8

Figure 1.1 Examples of heterocyclic compounds.

a carboxylic anhydride, respectively. The second row shows six-membered rings,

initially in an aromatic form as pyridine (5), while piperidine (6), piperidin-2-one (7),
and 1,2,3,4-tetrahydropyridine (8) are not aromatic; their reactivity would not be very
different from that expected of an amine, amide, or enamine, respectively. In general,
the reactivity of aromatic heterocycles, which is a combination of that expected from
an aromatic system combined with the influence of the heteroatoms involved, is
usually more complex, while the reactivity of the non-aromatic systems is not too
different from the usual non-cyclic derivatives. Thus, most books on heterocyclic
chemistry are mainly devoted to the reactivity of aromatic compounds.
Tables 1.1–1.4 indicate models of the heterocyclic derivatives described in these
volumes. Table 1.1 shows simple heterocyclic systems of three or four members. In
this case, the literature examples are mainly non-aromatic, as indicated in the table,
and the expected reactivity is always related to the ring strain present in all of them,
which produces a release of energy when they are opened to give aliphatic products.

Table 1.1 Main three- and four-membered heterocycles.

Ring size

Heteroatom
N

3

4

O

N
H
Aziridine

O
Oxirane

NH
N
H
Diaziridine

O
O
Dioxirane

NH

Azetidine

O
Oxetane

S

Other

S
Thiirane

NH
O
Oxaziridine

S
Thietane

Se

P

R

Seletane Phosphetane


1.1 Heterocyclic Compounds: An Introduction
Table 1.2 Main five-membered heterocycles.

Ring size

Heteroatom
N

5

5

Benzo

N
H
Pyrrole

N
H

Benzo

O
Furan

Indole

N
N
H
Pyrazole

O

O
Benzofuran

S

S
Thiophene

N

Isoxazole

N

S

O
Oxazole

N
N
H

Triazoles

N N
N
N
H

N

N
N
N N
O
O
N
N N
N
O
O

Oxadiazoles

N

Isothiazole

N

N
H
Imidazole
N
N
N
H

O

N
S
Thiazole
S
N

N
N N

S

S

N

N N
N

S

Thiadazoles

Tetrazole

Table 1.2 indicates five-membered heterocyclic systems, such as pyrrole, furan,
their benzo derivatives, and thiophene, and a set of heterocycles with more than one
heteroatom, as 1,2-azoles, 1,3-azoles, triazoles, oxa- and thiadiazoles, and tetrazole.
Table 1.3 shows six-membered rings, namely, pyridine, its benzo derivatives
quinoline and isoquinoline, the pyrilium cation, and, as in Table 1.2, other common
heterocycles with more than one heteroatom, such as diazines, triazines, and
tetrazines.
Finally, Table 1.4 shows the simplest seven-membered ring, that is, azepine and its
benzo derivative, as well as examples of the nitrogen bridgehead bicyclic systems,
pyrrolizine, indolizines, and quinolizinium cation.
Other additional chapters have been included with special systems relevant from
different points of view: 2-azetidinones or b-lactams, benzodiazepines, and two
general chapters on new materials based on heterocyclic systems and solid phase and
combinatorial chemistry related to heterocyclic derivatives.

j3

j 1 Heterocyclic Compounds: An Introduction

4

Table 1.3 Main six-membered heterocycles.

Ring size
N

Benzo

O

N

6

Quinoline

N

Pyridine

O

+

Pyrilium

N

Isoquinoline
N

N
N

N

N

N

Diazines
Pyridazine Pyrimidine Pyrazine

N

N
N

N
N

N
N

N
N

Triazines
N
N

NN
N

N
N

N
N

N
N

N

Tetrazines

Table 1.4 Other simple heterocycles.

Ring size

Heteroatom

7

N

Benzo

N
H

N
H

Benzoazepine

Azepine

5-5, 5-6, 6-6

N

N

Pyrroline

Indolizine

N

+

Quinolizinium

1.2 Structure and Reactivity of Aromatic Five-Membered Systems

1.2
Structure and Reactivity of Aromatic Five-Membered Systems

As is indicated in most handbooks of heterocyclic chemistry [3, 4], a pictorial valence
bond resonance description is used in most chapters, as a simple way to rationalize
the reactivity of the most important aromatic heterocycles. Two examples are
described in detail as representative of most of the aromatic rings considered:
pyrrole as a model of the p-excessive rings, and pyridine as a model of the p-deficient
ones.
Pyrrole has a structure that is isoelectronic with the cyclopentadienyl anion, but is
electrically neutral, having a nitrogen atom with a pair of electrons, which is part of
the aromatic sextet, and its resonance hybrid can be represented as a combination
of main forms I–V (Scheme 1.1), one without charge, and the others with charge
separation. As expected, not all forms contribute equally to the structure of the
pyrrole, with the order of importance being I > III, IV > II, V, that is, the major
contribution is produced by the non-charged form, and, of the charged ones, those in
which the nitrogen is using its lone pair of electrons. As a combination of all forms,
structure 9 indicates how the heteroatom bears a partial positive charge, while the
carbon positions show an increase in electronic density, compared with the typical
aromatic system, benzene. Thus, a p-excessive system such as pyrrole would be easily
attacked by electrophiles and not by nucleophiles.

N

N

H

H

I

+

-

N

+

N
H

H

II

IV

III

-

N

+

H

V

δ−

δ−
δ−

+

N
H
9

δ−
δ+

Scheme 1.1 Resonance hybrids of pyrrole.

Scheme 1.2 indicates how the attack of an electrophile usually proceeds. The major
isomer 13 is formed through intermediates 10–11–12, of which the intermediate 10
contributes most to the stabilization of the intermediate. Alternatively, a minor
isomer 16 is produced through the less stable intermediates 14 and 15.
Alternatively, Scheme 1.3 shows the attack of a nucleophile on pyrrole. Intermediate 17 is not stabilized, and the lone pair of electrons on the heteroatom does not
contribute to the progress of the process. The only process that usually can be
detected is deprotonation of the N–H bond to generate the pyrrolate (18), which can
be used to make a bond with a suitable electrophile (i.e., an alkyl halide) to produce the
N-substituted pyrrole 19.

j5

j 1 Heterocyclic Compounds: An Introduction

6

+
N
H

+

H
10

E+

N
H 9

+

E

N
H

E
H
N
H

+

N
H

14

H
11

E

E
H
+

N
H

-H+
E

H
12

N
H

E

13

E
-H+

15

N
H 16
Minor isomer

Scheme 1.2 Electrophilic attack on pyrrole.

_
N
H
_
Nu
N
H

H

No stabilization

Nu
17

E+

9

N
18

NuH

N
E

19

Scheme 1.3 Attack on pyrrole by nucleophiles.

This behavior can be extended with small differences to other p-excessive
heterocycles, with the limit due to the existence or not of a N–H bond at position
1. In the case of rings like thiazole or isoxazole, the lack of the acidic bond makes the
process 9–18–19 impossible. Attack by radicals or complex organometallic reagents
are more complex and are discussed in every chapter.

1.3
Structure and Reactivity of Aromatic Six-Membered Systems

The structure of pyridine is analogous to that of benzene, with one of the carbons
replaced by a nitrogen atom. This produces alterations in the geometry, which is no
longer perfectly hexagonal, due to the shorter CN bonds; the existence of an unshared
pair of electrons, not related with the aromatic sextet, gives the pyridine basic
character, along with a permanent dipole in the ring, due to the electronegative
character of the heteroatom compared with carbon.

Scheme 1.4 indicates the main canonical forms (I–V) that contribute to the
resonance hybrid of the structure of pyridine. Obviously, not all of them contribute
equally – the two Kekule forms I and II, which are not charged, are the more stable