《有机化学》课程教学资源（参考书籍）TUTORIAL CHEMISTRY TEXTS（8）Heterocyclic Chemistry RSC 2001，M. SAINSBURY，University of Bath

8 TUTORIAL CHEMISTRY TEXTS RS.C Heterocyclic Chemistry by MALCOLM SAINSBURY

Preface This book provides a concise,yet thorough,introduction to the vast sub- ject of heterocyclic chemistry by dealing only with those compounds con- taining a single heteroatom.By restricting g the discussion to these,the most important classes of heterocycles,a balanced treatment is possible allowing the student to rapidly understand the importance of heterocyclic compounds in general to mankind and at the same time stimulating an ents. The contents of the book are carefully designed to meet the needs of undergraduate students in the 2nd year of a degree course in Chemistry or Biochemistry and are based upon the author's own lectures given to students at Bath.Although prim arily an undergraduate text,the e main principles that govern heterocyclic chemistry as a whole are addressed in this book,providing a sure foundation for those wishing to widen their interest in heterocyclic chemistry in later years. Malcolm Sainsbury Bath

Preface This book provides a concise, yet thorough, introduction to the vast sub￾ject of heterocyclic chemistry by dealing only with those compounds con￾taining a single heteroatom. By restricting the discussion to these, the most important classes of heterocycles, a balanced treatment is possible, allowing the student to rapidly understand the importance of heterocyclic compounds in general to mankind and at the same time stimulating an interest in the challenges this chemistry presents. The contents of the book are carefully designed to meet the needs of undergraduate students in the 2nd year of a degree course in Chemistry or Biochemistry and are based upon the author’s own lectures given to students at Bath. Although primarily an undergraduate text, the main principles that govern heterocyclic chemistry as a whole are addressed in this book, providing a sure foundation for those wishing to widen their interest in heterocyclic chemistry in later years. Malcolm Sainsbury Bath

Contents Introduction to Heterocyclic Chemistry 1 1.1 Coverage 12 nclature Importance to Life and Industry 1.4 General Principles 46 Pyridine 18 2.1 Resonance Description 2.2 Electrophilic Substitution 189 Pyridine N-Oxides 22 Nucleophilic Substitution 2.5 Lithiation e 2.6 Methods of Synthesis 28 2.7 Commonly Encountered Pyridine Derivatives 2.8 Reduc ed Pyridine 36 3 Benzopyridines 42 3.1 Introduction 42 3.2 Quinoline 3.3 Isoquinoline 50 4 Pyrylium Salts,Pyrans and Pyrones 58 4.1 Introduction 4.2 Pyrylium Salts 58

Contents I Introduction to Heterocyclic Chemistry 1.1 Coverage 1.2 Nomenclature 1.3 Importance to Life and Industry 1.4 General Principles 2 Pyridine 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Resonance Description Electrophilic Substitution Pyridine N-Oxides Nucleophilic Substitution Lit hiat ion Methods of Synthesis Commonly Encountered Pyridine Derivatives Reduced Pyridines 3 Benropyridines 3.1 Introduction 3.2 Quinoline 3.3 Isoquinoline 4 Pyrylium Salts, Pyrans and Pyrones 4.1 Introduction 4.2 Pyrylium Salts i 18 18 19 22 23 28 28 29 36 42 42 43 50 58 58 59 V

vi Contents 4.3 Pyran-2-ones(a-Pyrones) 61 44 45 Pyran-4-ones(-Pyrones Reduced Pyrans 5 4.6 Saccharides and Carbohydrates 65 Benzopyrylium Salts,Coumarins, Chrom n es,Flavonoids and Related Compounds 68 51 Structural Types and Nomenclature 5.2 Coumarins 5.3 Chromones(Benzopyran-4-ones) 80D 6 Five-membered Heterocycles containing One Heteroatom:Pyrrole,Furan and Thiophene 77 6.1 Pyrrole 6.2 Furan 6.3 Thiophene 91 Benzo[b]pyrrole,Benzo[b]furan and Benzo[b]thiophene 97 7.1 Indole(Benzo[blpyrrole) 7.2 Benzo[b]furan and Benzo[b]thiophene 110 8 Four-membered Heterocycles containing a Single Nitrogen,Oxygen or Sulfur Atom 115 Azete,Azetine and Azetidine 115 Oxetene and Oxetane 121 8.3 Thietene and Thietane 122 Answers to Problems 125 Subject Index 141

vi Contents 4.3 Pyran-2-ones (a-Pyrones) 4.4 Pyran-4-ones (y-Pyrones) 4.5 Reduced Pyrans 4.6 Saccharides and Carbohydrates 61 63 65 65 5 Benropyrylium Salts, Coumarins, Chromones, Flavonoids and Related Compounds 68 5.1 Structural Types and Nomenclature 5.2 Coumarins 5.3 Chromones (Benzopyran-4-ones) 68 70 72 6 Five-membered Heterocycles containing One Heteroatom: Pyrrole, Furan and Thiophene 77 6.1 Pyrrole 6.2 Furan 6.3 Thiophene 77 85 91 7 Benzo[b]pyrrole, Benzo[b]furan and Benzo[&]thiophene 97 7.1 Indole (Benzo[b]pyrrole) 7.2 Benzo[b]furan and Benzo[b]thiophene 97 110 8 Four-membered Heterocycles containing a Single Nitrogen, Oxygen or Sulfur Atom 115 8.1 Azete, Azetine and Azetidine 8.2 Oxetene and Oxetane 8.3 Thietene and Thietane 115 121 122 Answers to Problems 125 Subject Index 141

1 Introduction to Heterocyclic Chemistry Aims By the end of this chapter you should understand: Why heterocyclic chemistry is so important to mankind The names of a few commonly encountered heterocyclic com- pounds Some of the major factors that govern the shape and stability of heterocyclic compounds 1.1 Coverage The subject of heterocyclic chemistry is vast,so in this book the focus is on the more common four-,five-and six-membered systems contain- ing one heteroatom.Little attempt is made to extend the coverage to knowledge will need to consult more advanced works.Fortunately,there is a very wide choice;excellent texts include Heterocyclic Chemistry by Gilchrist'and Heterocyclic Chemistry by Joule and Mills.2 In addition, there are many authoritative mplaions that dealhery 1.2 Nomenclature Students will be familiar with carbocyclic compounds,such as cyclo hexane and benzene,that are built from rings of carbon atoms.If one or more of the carbon atoms is replaced by another element,the prod- uct is a heterocycle.Multiple replacements are commonplace,and the elements involved need not be the same.The most common are oxygen

I Introduction to Heterocyclic Chemistry 1.1 Coverage The subject of heterocyclic chemistry is vast, so in this book the focus is on the more common four-, five- and six-membered systems contain￾ing one heteroatom. Little attempt is made to extend the coverage to more complex heterocycles, so that students interested in extending their knowledge will need to consult more advanced works. Fortunately, there is a very wide choice; excellent texts include Heterocyclic Chemistry by Gilchrist' and Heterocyclic Chemistry by Joule and Mills.2 In addition, there are many authoritative compilations that deal with heterocyclic chemistry in much more depth? I .2 Nomenclature ~~ ~~ Students will be familiar with carbocyclic compounds, such as cyclo￾hexane and benzene, that are built from rings of carbon atoms. If one or more of the carbon atoms is replaced by another element, the prod￾uct is a heterocycle. Multiple replacements are commonplace, and the elements involved need not be the same. The most common are oxygen, I

2 Heterocyclic Chemistry sulfurornitrogen,but many other elements can function in this way including boron,silicon and phosphorus.Chemists have been working with heterocycles for more than two centuries,and trivial names were often applied long before the structures of the compounds were known. As a result,many heterocycles retain these names;a selection of com- mon five-and six-membered heterocycles that contain one oxygen,nitro gen or sulfur atom are included in Box 1.1.The ring atoms are normally numbered such that the heteroatom carries the lowest number. of substitution in much the same Box 1.1 Some Common Heterocycles Pyrrole Pyrrolidine Furan Thiophene Pyridine Pyrylium salts A problem arises with trivial names when a sphybridized atom is present in an otherwise unsaturated ring.A good example is pyran,a hetero- cycle that is formally the product of the addition of a single hydride ion to the pyrylium cation.However,as this addition could occur either at C-2 or C-4,two isomers of pyrar are possible. so the question is,how can you distinguish between them?The solution is to call one compound 2H-pyran and the other 4//-pyran,using the number of the ring atom and the letter H,in italics,to show the position of the hydrogen (see Box 1.2).This tem of nom enclature works tolerably y well in many related cases and is widely used;other examples will be found in this book. It is also customary to use the prefixes di-,tetra-,hexahydro-...(rather than tri-,penta-or he eptahydro. …)when referring to omp nds that are partly or fully reduced.This terminology reflects the fact that hydro gen atoms are added two at a time during the hydrogenation of multi- ple bonds,and it is used even when the compound contains an odd number of hydrogen atoms relative to its fully unsaturated parent.As before,the position of the 'extra hydrogen'atom is located by means of the ring atom number,followed by the letter H.It is important to note

2 Heterocyclic Chemistry sulfur or nitrogen, but many other elements can function in this way, including boron, silicon and phosphorus. Chemists have been working with heterocycles for more than two centuries, and trivial names were often applied long before the structures of the compounds were known. As a result, many heterocycles retain these names; a selection of com￾mon five- and six-membered heterocycles that contain one oxygen, nitro￾gen or sulfur atom are included in Box 1.1. The ring atoms are normally numbered such that the heteroatom carries the lowest number. Some authors use Greek letters, a, p and y, etc., in place of numbers, to indicate the position of substitution in much the same way that the terms ortho, meta and para are used for benzenes. A problem arises with trivial names when a sp3 hybridized atom is present in an otherwise unsaturated ring. A good example is pyran, a hetero￾cycle that is formally the product of the addition of a single hydride ion to the pyrylium cation. However, as this addition could occur either at C-2 or C-4, two isomers of pyran are possible; so the question is, how can you distinguish between them? The solution is to call one compound 2H-pyran and the other 4H-pyran, using the number of the ring atom and the letter H, in italics, to show the position of the hydrogen (see Box 1.2). This system of nomenclature works tolerably well in many related cases and is widely used; other examples will be found in this book. It is also customary to use the prefixes di-, tetra-, hexahydro- . . . (rather than tri-, penta- or heptahydro- ...) when referring to compounds that are partly or fully reduced. This terminology reflects the fact that hydro￾gen atoms are added two at a time during the hydrogenation of multi￾ple bonds, and it is used even when the compound contains an odd number of hydrogen atoms relative to its fully unsaturated parent. As before, the position of the ‘extra hydrogen’ atom is located by means of the ring atom number, followed by the letter H. It is important to note

Introduction to Heterocyclic Chemistry 3 Box 1.2 Pyrans 2H-Pyran 4H-Pyran 3.4.5.6-Tetrahydro-2H/-pyran not pentahydropyran that the lowest possible mmber is always selected for the locant: example, fully reduced pyrylium cation is referred to as3.4.5.6- tetrahydro-2H-pyran (see Box 1.2). Since trivial names are so well established,it is now very difficult to abandon them in favour of a logical nomencature system that provides structural information.Nevertheless,a predictive method of this type is very desirable,especially for molecules where there may be two or more heteroatoms present in the ring.One approach is to use a prefix,which is indicative of the heteroatom [aza(N).oxa(O),thia(S),bora(B),phos- pha (P),sil (Si),ete.],to the name of the corresponding carbocycle Thus,pyridine becomes azabenzene and piperidine is azacyclohexane. This method is useful when dealing with simple heterocycles,but it can become clumsy with more complex ones.An alternative is the Hantzsch-Widman system,which uses the same prefixes,but adds a stem name designed to indicate not only the ring size but also the state of unsaturation or saturation (note:when the stem name begins with a vowel the last letter,a,of the prefix is dropped).The stem names for rings containing are shown in Table 1.1. Using this terminology,furan becomes oxole and tetrahydrofuran is named oxolane;pyridine is azine and piperidine is azinane.As with trivial names,the potential difficulty over partly reduced heterocycles is resolved Table1.1 Hantzsch-Widman stem names for heterocycles with 3-10 ring atoms Ring size Unsaturated Saturated 3 irene irane ete etane olane 6 ine epine 。 ecane

Introduction to Heterocyclic Chemistry 3 that the lowest possible number is always selected for the locant; so, for example, the fully reduced pyrylium cation is referred to as 3,4,5,6- tetrahydro-2H-pyran (see Box 1.2). Since trivial names are so well established, it is now very difficult to abandon them in favour of a logical nomenclature system that provides structural information. Nevertheless, a predictive method of this type is very desirable, especially for molecules where there may be two or more heteroatoms present in the ring. One approach is to use a prefix, which is indicative of the heteroatom [aza (N), oxa (0), thia (S), bora (B), phos￾pha (P), sila (Si), etc.], to the name of the corresponding carbocycle. Thus, pyridine becomes azabenzene and piperidine is azacyclohexane. This method is useful when dealing with simple heterocycles, but it can become clumsy with more complex ones. An alternative is the Hantzsch-Widman system, which uses the same prefixes, but adds a stem name designed to indicate not only the ring size but also the state of unsaturation or saturation (note: when the stem name begins with a vowel the last letter, a, of the prefix is dropped). The stem names for rings containing up to 10 atoms are shown in Table 1.1. Using this terminology, furan becomes oxole and tetrahydrofuran is named oxolane; pyridine is azine and piperidine is azinane. As with trivial names, the potential difficulty over partly reduced heterocycles is resolved - Table 1.1 Hantzsch-Widman stem names for heterocycles with 3-10 ring atoms Ring size Unsaturated Saturated 3 irene irane 4 ete etane 5 ole olane 6 ine inane 7 epine epane 8 ocine ocane 9 onine onane 10 ecine ecane

4 Heterocyclic Chemistry by using the usual numbered H prefix;thus,the four possible isomers of For a full discussion of how to azepine are termed as in Box 1.3. Box 1.3 Azepines 1H-Azepine 2H-Azepine 3H-Azepine 4H-Azepine Many heterocycles are fused to other ring systems,notably benzene,giv ing in this case benzo derivatives;some of these compounds are also extremely well known and have trivial names of their own,such asindole and Here,however,it is possible to relate these compounds back to the parent monoeycles by indicating to which face the ringfusion applies.To do this,each face of the ring is given a letter (lower case ital- ic),beginning with the face that bears the heteroatom (see Box 1.4). Box 1.4 Naming Benzo Derivatives 河 Azacyclobutadiene Benzo[b]azacyclobutadiene Indole (benzo[b]pyrrole) ge 1.3 Importance to Life and Industry Many heterocyclic compounds are biosynthesized by plants and animals and are biologically active.Over millions of years these organisms have been under intense evolutionary pressure,and their metabolites may be used to advantage;for example as toxins to ward off predators,or as colouring agents to attract mates or pollinating insects.Some heterocy- cles are fundamental to life,such as haem derivatives in blood and the

4 Heterocyclic Chemistry by using the usual numbered H prefix; thus, the four possible isomers of azepine are termed as in Box 1 .3.7 For a full discussion of how to name heterocycles by this and other methods, see Panico et a/.7 Many heterocycles are fused to other ring systems, notably benzene, giv￾ing in this case benzo derivatives; some of these compounds are also extremely well known and have trivial names of their own, such as indole and isoquinoline. Here, however, it is possible to relate these compounds back to the parent monocycles by indicating to which face the ring fusion applies. To do this, each face of the ring is given a letter (lower case ital￾ic), beginning with the face that bears the heteroatom (see Box 1.4). 1.3 Importance to Life and Industry Many heterocyclic compounds are biosynthesized by plants and animals and are biologically active. Over millions of years these organisms have been under intense evolutionary pressure, and their metabolites may be used to advantage; for example, as toxins to ward off predators, or as colouring agents to attract mates or pollinating insects. Some heterocy￾cles are fundamental to life, such as haem derivatives in blood and the

Introduction to Heterocyclic Chemistry 5 chlorophyllsessential for photosynthesis(Box 1.5).Similarly,the paired bases found in RNA and DNAare heterocycles,as are the sugars that in combination with phosphates provide the backbones and determine the topology of these nucleic acids Box 1.5 Some Heterocycles Important for Life Chlorophyll a Dyestuffs of plant origin include indigo blue,used to dye jeans.A poi- son of detective novel fame is strychnine,obtained from the plant resin curare (Box 1.6). Box 1.6 Some Other Natural Heterocycles ndigo (indigotin) trychn The biological properties of heterocycles in general make them one of the prime interests of the pharmaceutical and biotechnology indus- tries.A selection of just six biologically active pyridine or piperidine

Introduction to Heterocyclic Chemistry 5 chlorophylls essential for photosynthesis (Box 1.5). Similarly, the paired bases found in RNA and DNA are heterocycles, as are the sugars that in combination with phosphates provide the backbones and determine the topology of these nucleic acids. Dyestuffs of plant origin include indigo blue, used to dye jeans. A poi￾son of detective novel fame is strychnine, obtained from the plant resin curare (Box 1.6). The biological properties of heterocycles in general make them one of the prime interests of the pharmaceutical and biotechnology indus￾tries. A selection of just six biologically active pyridine or piperidine

6 Heterocyclic Chemistry derivatives is shown in Box 1.7.It includes four natural products(nico- tine,pyridoxine,cocaine and morphine)and two synthetic compounds (nifedipine and paraquat). Box 1.7 Biologically Active Pyridine and Piperidine Heterocycles NO Nifedipine (addictive drug (vitamin B) (cardiovascular drug) and an insecticide HO Me CO-M OCOPh Cocaine Morphine tate of mophine) There are many thousands of other heterocyclic compounds,both nat- ural and synthetic,of major importance,not only in medicine but also in most other activities known to man.Small wonder then that their chemistry forms a major part of both undergraduate and postgraduate curricula. 1.4 General Principles 1.4.1 Aromaticity Many fully unsaturated heterocyclic compounds are described as aro matic,and s some have a close similarity to benzene and its derivatives For example,pyridine(azabenzene)is formally derived from benzene through the replacement of one CH unit by N.As a result,the consti-

6 Heterocyclic Chemistry derivatives is shown in Box 1.7. It includes four natural products (nico￾tine, pyridoxine, cocaine and morphine) and two synthetic compounds (nifedipine and paraquat). There are many thousands of other heterocyclic compounds, both nat￾ural and synthetic, of major importance, not only in medicine but also in most other activities known to man. Small wonder then that their chemistry forms a major part of both undergraduate and postgraduate curricula. 1.4 General Principles I =4=1 Aromaticity Many fully unsaturated heterocyclic compounds are described as aro￾matic, and some have a close similarity to benzene and its derivatives. For example, pyridine (azabenzene) is formally derived from benzene through the replacement of one CH unit by N. As a result, the consti-