The Chemistry of Heterocycles E-Book

Theophil Eicher

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 780

Veröffentlichungsjahr: 2013

Beschreibung

This classical textbook in the best sense of the word is now completely revised, updated and with more than 40% new content. The approved
ordering system according to the ring size of the heterocycles has been retained, while the important chapter on 'Problems and their Solutions' has been almost completely renewed by introduction of up-to-date scientific exercises, resulting in a great tool for self-testing and exams. There was maintained a chapter on nomenclature and a helpful index of name reactions. With approximately 1,000 new literature citations, this book remains a brilliant gateway to modern heterocyclic science for master and graduate students, as well as PhDs and researchers entering the field.

'If you want quick information about the basic (or acidic!) properties of a heterocycle, some interesting facts, or an assorted few ways of making
it, this book provides a welcoming, accurate, and concise introduction.'
Angewandte Chemie IE

'Eicher and Hauptmann provide an up to date introduction to the field for the advanced undergraduate and graduate students. ... The book is carefully produced to a very high standard.'
European Journal of Medicinal Chemistry

Leseprobe

Table of Contents

Related Titles

Title Page

Copyright

Preface to the Third Edition

Abbreviations and Symbols

General and Spectroscopic Abbreviations and Symbols

Abbreviations for Substituents …

… and Commonly Used Compounds

… and Ligands for Transition Metal-Catalyzed Reactions

… and Retrosynthesis

Chapter 1: The Structure of Heterocyclic Compounds

Reference

Chapter 2: Systematic Nomenclature of Heterocyclic Compounds

2.1 Hantzsch-Widman Nomenclature

2.2 Replacement Nomenclature

2.3 Examples of Systematic Nomenclature

2.4 Important Heterocyclic Systems

Chapter 3: Three-Membered Heterocycles

3.1 Oxirane

3.2 Thiirane

3.3 2H-Azirine

3.4 Aziridine

3.5 Dioxirane

3.6 Oxaziridine

3.7 3H-Diazirine

3.8 Diaziridine

References

Chapter 4: Four-Membered Heterocyles

4.1 Oxetane

4.2 Thietane

4.3 Azete

4.4 Azetidine

4.5 1,2-Dioxetane

4.6 1,2-Dithiete

4.7 1,2-Dihydro-1,2-Diazete

4.8 1,2-Diazetidine

References

Chapter 5: Five-Membered Heterocycles

5.1 Furan

5.2 Benzo[b]Furan

5.3 Isobenzofuran

5.4 Dibenzofuran

5.5 Tetrahydrofuran

5.6 Thiophene

5.7 Benzo[b]Thiophene

5.8 Benzo[c]Thiophene

5.9 2,5-Dihydrothiophene

5.10 Thiolane

5.11 Selenophene

5.12 Pyrrole

5.13 Indole

5.14 Carbazole

5.15 Isoindole

5.16 Indolizine

5.17 Pyrrolidine

5.18 Phosphole

5.19 1,3-Dioxolane

5.20 1,2-Dithiole

5.21 1,2-Dithiolane

5.22 1,3-Dithiole

5.23 1,3-Dithiolane

5.24 Oxazole

5.25 Benzoxazole

5.26 4,5-Dihydrooxazole

5.27 Isoxazole

5.28 4,5-Dihydroisoxazole

5.29 2,3-Dihydroisoxazole

5.30 Thiazole

5.31 Benzothiazole

5.32 Penam

5.33 Isothiazole

5.34 Imidazole

5.35 Benzimidazole

5.36 Imidazolidine

5.37 Pyrazole

5.38 Indazole

5.39 4,5-Dihydropyrazole

5.40 Pyrazolidine

5.41 1,2,3-, 1,2,4-, 1,3,4-Oxadiazole

5.42 1,2,5-Oxadiazole

5.43 1,2,3-Thiadiazole

5.44 1,2,4-Thiadiazole

5.45 1,2,3-Triazole

5.46 Benzotriazole

5.47 1,2,4-Triazole

5.48 Tetrazole

References

Chapter 6: Six-Membered Heterocycles

6.1 Pyrylium Ion

6.2 2H-Pyran

6.3 2H-Pyran-2-One

6.4 3,4-Dihydro-2H-Pyran

6.5 Tetrahydropyran

6.6 2H-Chromene

6.7 2H-Chromen-2-One

6.8 1-Benzopyrylium Ion

6.9 4H-Pyran

6.10 4H-Pyran-4-One

6.11 4H-Chromene

6.12 4H-Chromen-4-One

6.13 Chroman

6.14 Pyridine

6.15 Pyridones

6.16 Quinoline

6.17 Isoquinoline

6.18 Quinolizinium Ion

6.19 Dibenzopyridines

6.20 Piperidine

6.21 Phosphabenzene

6.22 1,4-Dioxin, 1,4-Dithiin, 1,4-Oxathiin

6.23 1,4-Dioxane

6.24 Oxazines

6.25 Morpholine

6.26 1,3-Dioxane

6.27 1,3-Dithiane

6.28 Cepham

6.29 Pyridazine

6.30 Pyrimidine

6.31 Purine

6.32 Pyrazine

6.33 Piperazine

6.34 Pteridine

6.35 Benzodiazines

6.36 1,2,3-Triazine

6.37 1,2,4-Triazine

6.38 1,3,5-Triazine

6.39 1,2,4,5-Tetrazine

References

Chapter 7: Seven-Membered Heterocycles

7.1 Oxepin

7.2 Thiepin

7.3 Azepine

7.4 Diazepines

References

Chapter 8: Larger Ring Heterocycles

8.1 Azocine

8.2 Heteronines and Larger-Membered Heterocycles

8.3 Tetrapyrroles

References

Chapter 9: Problems and Their Solutions

References

Index

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The Authors

Prof. Dr. Theophil Eicher

Saarland University

Campus B6.1

66123 Saarbrücken

Prof. Dr. Siegfried Hauptmann†

Prof. Dr. Andreas Speicher

Saarland University

FR 8.1 — Organic Chemistry

Campus C4.2

66123 Saarbrücken

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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© 2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form — by photoprinting, microfilm, or any other means — nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

ISBN Hardcover: 978-3-527-32868-0

ISBN Softcover: 978-3-527-32747-8

Preface to the Third Edition

This enlarged and completely revised third edition of “The Chemistry of Heterocycles” is dedicated to the memory of Siegfried Hauptmann, who died after long illness on 18 April 2011. We gratefully acknowledge his achievements in the development of this book as well our fruitful collaboration with him during its first editions.

In the new edition, the structure decided on for the earlier editions of the book has been maintained. Thus, after the introductory Chapters 1 and 2 on the chemical structure and nomenclature of heterocyclic compounds, Chapters 3–8 (organized according to ring-size and number of hetero atoms) describe for a representative cross section of heterocyclic systems

structural, physical, and spectroscopic features;

chemical properties and characteristic transformations;

aspects of synthesis, organized according to retroanalysis;

selected derivatives, natural products, pharmaceuticals, and other biologically active compounds of related structure type;

utility as vehicles in specific synthetic reactions.

The information given in Chapters 1–8 is supported by references from primary literature, reviews, and textbooks of Organic Chemistry, and aims to include the literature cited in ChemInform up to the year 2011.

Chapter 9 consists of a series of problems—presented in broad variety and selected almost exclusively from the most recent literature—and is intended to deepen the knowledge and understanding of the reader and to extend the topics of heterocyclic chemistry treated in this book. The concluding chapters contain the General Subject Index (10.1) and an Index of Named Reactions (10.2).

As in the earlier editions, this book is specifically addressed to (a) advanced students and research fellows as well as chemists in industry who are looking for a survey of well-tried fundamental concepts and for information on modern developments in heterocyclic chemistry and (b) lecturers in the field of Organic Chemistry, for whom the contents of this book may serve as building blocks for advanced courses on topics of heterocyclic chemistry.

Special thanks are due to Prof. Dr. Uli Kazmaier for his maintaining and encouraging collegial interest and support. We are indebted to Dres. Matthias Groh and Judith Holz for their valuable and reliable technical assistance; in addition, we especially and cordially thank Marcus Malter for his involvement in the production of the new formula diagrams (using the program ChemDraw Ultra 12.0 throughout) introduced in this new edition.

Finally, we are grateful to Bernadette Gmeiner and the staff of the editorial office of Wiley-VCH for their efficient collaboration.

Saarbrücken

Theophil Eicher and

Spring 2012

Andreas Speicher

Abbreviations and Symbols

General and Spectroscopic Abbreviations and Symbols

Abbreviations for Substituents …

Ac

acetyl

Ar

aryl

Bn

benzyl

Boc

tert

-butoxycarbonyl

n

Bu

n

-butyl

secBu

sec

-butyl

t

Bu

tert

-butyl

Bz

benzoyl

Cy

cyclohexyl

Et

ethyl

EWG

electron-withdrawing group

Me

methyl

Mes

mesyl (methanesulfonyl)

Ms

mesityl

Ph

phenyl

i

Pr

isopropyl

n

Pr

n

-propyl

Tf

trifluoromethanesulfonyl

Tos

tosyl (

p

-toluenesulfonyl)

… and Commonly Used Compounds

ADE

diethyl acetylene dicarboxylate

AIBN

azoisobutyronitrile

BINAP

2,2’-bis(diphenylphosphino)-1,1’-binaphthyl

BINOL

1,1’-bis-2-naphthol

BMIM

1-(

n

-butyl)-3-methylimidazolium

COD

cyclooctadiene

DABCO

1,4-diazabicyclo[2.2.2]octane

DCE

1,2-dichloroethane

DCM

dichloromethane

DBU

1,8-diazabicyclo[5.4.0]undec-7-ene

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DEAD

diethyl azodicarboxylate

DET

diethyl tartrate

DIPEA

diisopropyl ethylamine (Hünig base)

DIPT

diisopropyl tartrate

DMAD

dimethyl acetylene dicarboxylate

DMAP

4-(dimethylamino)pyridine

DME

1,2-dimethoxyethane

DMF

dimethylformamide

DMPU

N

,

N

′-dimethylpropylene urea

DMSO

dimethyl sulfoxide

EDCI

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EDTA

ethylenediamine tetraacetic acid

EMIM

1-ethyl-3-methylimidazolium

HMDS

hexamethyldisilazane

HMPT

hexamethylphosphoric acid triamide

HOBt

1-hydroxybenzotriazole

LDA

lithiumdiisopropylamide

LiTMP

lithium-2,2,6,6-tetramethylpiperidide

MCPBA

m

-chloroperbenzoic acid

NBS

N

-bromosuccinimide

NCS

N

-chlorosuccinimide

NIS

N

-iodosuccinimide

NMP

N

-methylpyrrolidone

PCC

pyridinium chlorochromate

PPA

polyphosphoric acid

Py

pyridine

TBA

Ftetra-

n

-butylammonium fluoride

TBDMS

(

tert

-butyl)dimethylsilyl

TFA

trifluoroacetic acid

THF

tetrahydrofuran

TMEDA

N

,

N

,

N

′,

N

′-tetramethylethylenediamine

TMS

trimethylsilyl

TosMIC

(

p

-toluenesulfonyl)methylisocyanide

… and Ligands for Transition Metal-Catalyzed Reactions

acac

acetylaceton(ate)

dba

dibenzylidene acetone

dppf

diphenylphosphanylferrocene

dppp

1,3-bis(diphenylphosphino)propane

S-Phos

2,6-dimethoxy-(2’-dicyclohexylphosphanyl)biphenyl

Xantphos

4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

… and Retrosynthesis

FGA

functional group addition

FGI

functional group interconversion

⇒

retrosynthetic operation, in general: bond disconnection, FGA, FGI

Chapter 1

The Structure of Heterocyclic Compounds

Most chemical compounds consist of molecules. The classification of such chemical compounds is based on the structure of these molecules, which is defined by the type and number of atoms as well as by the covalent bonding within them. There are two main types of structure:

The atoms form a chain–aliphatic (

acyclic

) compounds

The atoms form a ring–

cyclic

compounds.

Cyclic compounds in which the ring is made up of atoms of one element only are called isocyclic compounds, for example, 1. If the ring consists of C-atoms only, then we speak of a carbocyclic compound, for example, 2. Cyclic compounds with at least two different atoms in the ring (as ring atoms or members of the ring) are known as heterocyclic compounds. The ring itself is called a heterocycle. If the ring contains no C-atom, then we speak of an inorganic heterocycle, for example, 3. If at least one ring atom is a C-atom, then the molecule is an organic heterocyclic compound for example, 4. In this case, all the ring atoms which are not carbon are called heteroatoms.

Along with the type of ring atoms, their total number is important, since this determines the ring size. The smallest possible ring is three-membered. The most important rings are the five- and six-membered heterocycles. There is no upper limit; there exist seven-, eight-, nine-, and larger-membered heterocycles.

In principle, all elements except the alkali metals can act as ring atoms. Although inorganic heterocycles have been synthesized, this book limits itself to organic ones. In these, the N-atom is the most common heteroatom. Next in importance are O- and S-atoms. Heterocycles with Se-, Te-, P-, As-, Sb-, Bi-, Si-, Ge-, Sn-, Pb-, or B-atoms are less common.

To determine the stability and reactivity of heterocyclic compounds, it is useful to compare them with their carbocyclic analogs. In principle, it is possible to derive every heterocycle from a carbocyclic compound by replacing appropriate CH2 or CH groups by heteroatoms. If one limits oneself to monocyclic systems, one can distinguish four types of heterocycles as follows:

1 Saturated Heterocycles (Heterocycloalkanes), e.g.

In this category, there are no multiple bonds between the ring atoms. The compounds react largely like their aliphatic analogs, for example, oxane (tetrahydropyran) and dioxane behave like dialkyl ethers, thiane and 1,4-dithiane like dialkyl sulfides, and piperidine and piperazine like secondary aliphatic amines.

2 Partially Unsaturated Systems (Heterocycloalkenes), e.g.

3 Systems with the Greatest Possible Number of Noncumulated Double Bonds (Heteroannulenes), e.g.

From the annulenes, one can formally derive two types of heterocycles:

systems of the same ring size, if CH is replaced by X

systems of the next lower ring size, if HC=CH is replaced by X.

In both cases, the resulting heterocycles are iso-π-electronic with the corresponding annulenes, that is, the number of π-electrons in the ring is the same. This is because in the pyrylium and thiinium salts, as well as in pyridine, pyrimidine, azocine, and 1,3-diazocine, each heteroatom donates one electron to the conjugated system and its nonbonding electron pair does not contribute. However, with furan, thiophene, pyrrole, oxepin, thiepin, and azepine, one electron pair of the heteroatom is incorporated into the conjugated system (delocalization of the electrons). Where nitrogen is the heteroatom, this difference can be expressed by the designation pyridine-like N-atom or pyrrole-like N-atom. In imidazole both types can be found.

4 Heteroaromatic Systems

This includes heteroannulenes, which comply with the HÜCKEL rule, that is, which possess (4n + 2) π-electrons delocalized over the ring. The most important group of these compounds derives from [6]annulene (benzene). They are known as heteroarenes, for example, furan, thiophene, pyrrole, pyridine, and the pyrylium and thiinium ions. As regards stability and reactivity, they can be compared to the corresponding benzenoid compounds [1a–d].

The antiaromatic systems, that is, systems possessing 4n delocalized electrons, for example, oxepine, azepine, thiepine, azocine, and 1,3-diazocine, as well as the corresponding annulenes, are, by contrast, much less stable and very reactive.

The classification of heterocycles as heterocycloalkanes, heterocycloalkenes, heteroannulenes, and heteroaromatics allows an estimation of their stability and reactivity. In some cases, this can also be applied to inorganic heterocycles. For instance, borazine (3), a colorless liquid, bp 55 °C, is classified as a heteroaromatic system.

Reference

1 (a) von Rague Schleyer, P. and Jiao, H. (1996) Pure Appl. Chem., 68, 209; (b) von Rague Schleyer, P. and Jiao, H. (2001) Chem. Rev., 101, 1115; (c) Bird, C.W. (1998) Tetrahedron, 54, 10179; (d) Krygowski, T.M., Cyranski, M.K., Czarnocki, Z., Häfelinger, G., and Katritzky, A.R. (2000) Tetrahedron, 56, 1783.

Chapter 2

Systematic Nomenclature of Heterocyclic Compounds

Many organic compounds, including heterocyclic compounds, have a trivial name. This usually originates from the compounds occurrence, its first preparation, or its special properties.

Structure

Trivial name

Systematic name (IUPAC)

ethylene oxide

oxirane

pyromucic acid

furan-2-carboxylic acid

pyridine

pyridine (instead of azine)

nicotinic acid

pyridine-3-carboxylic acid

coumarin

2

H

-chromen-2-one

The derivation of the systematic name of a heterocyclic compound is based on its structure. Nomenclature rules have been drawn up by the IUPAC Commission and these should be applied when writing theses, dissertations, publications, and patents. These rules are listed in Section R-2 of the IUPAC “Blue Book” together with worked examples (H. R. Panico, W. H. Powell, J.-C. Richer, A Guide to IUPAC Nomenclature of Organic Compounds, Recommendations 1993; Blackwell Scientific: Oxford, 1993; the previous IUPAC Blue Book: J. Rigandy, S. P. Klesney Nomenclature of Organic Chemistry; Pergamon: Oxford, 1979).

The IUPAC rules are not given in detail here, rather instructions are given for formulating systematic names with appropriate reference to the Blue Book.

Every heterocyclic compound can be referred back to a parent ring system. These systems have only H-atoms attached to the ring atoms. The IUPAC rules allow two nomenclatures. The Hantzsch-Widman nomenclature is recommended for 3- to 10-membered heterocycles. For larger ring heterocycles, replacement nomenclature should be used.

It should be noted that in some cases, for example, for pyridine, the trivial name has become a “permitted trivial name” and should be used as the systematic name instead of the Hantzsch-Widman indication (see below).

2.1 Hantzsch-Widman Nomenclature

1 Type of Heteroatom

The type of heteroatom is indicated by a prefix according to Table 2.1. The sequence in this table also indicates the preferred order of prefixes (principle of decreasing priority).

Table 2.1 Prefixes to Indicate Heteroatoms

2 Ring Size

The ring size is indicated by a suffix according to Table 2.2. Some of the syllables are derived from Latin numerals, namely ir from tri, et from tetra, ep from hepta, oc from octa, on from nona, and ec from deca.

Table 2.2 Stems to Indicate the Ring Size of Heterocycles

Ring size

Unsaturated

Saturated

3

irene

a

irane

b

4

ete

etane

b

5

ole

olane

b

6A

c

ine

ane

6B

c

ine

inane

6C

c

inine

inane

7

epine

epane

8

ocine

ocane

9

onine

onane

10

ecine

ecane

a The stem “irine” may be used for rings containing only N.

b The traditional stems “iridine”, “etidine”, and “olidine” are preferred for N-containing rings and are used for saturated heteromonocycles having three, four, or five ring members, respectively.

c The stem for six-membered rings depends on the least preferred heteroatom in the ring: that immediately preceding the stem. To determine the correct stem for a structure, the set below containing this least-preferred heteroatom is selected.

d 6A: O, S, Se, Te, Bi, Hg, 6B: N, Si, Ge, N, Pb, and 6C: B, P, As, Sb.

3 Monocyclic Systems

The compound with the maximum number of noncumulative double bonds is regarded as the parent compound of the monocyclic systems of a given ring size. The naming is carried out by combining one or more prefixes from Table 2.1 with a suffix from Table 2.2. If two vowels succeed one another, the letter a is omitted from the prefix, for example, azirine (not azairine).

Note that trivial names are permitted for some systems, for example, pyrrole and pyridine. Permitted trivial names can be found in the latest IUPAC Blue Book pp. 166–172; if a trivial name is permitted then it should be used.

Partly or completely saturated rings are denoted by the suffixes according to Table 2.2. If no ending is specified the prefixes dihydro-, tetrahydro-, and so on should be used.

Monocyclic systems, one heteroatom

The numbering of such systems starts at the heteroatom.

Monocyclic systems, two or more identical heteroatoms

The prefixes di-, tri-, tetra-, and so on, are used for two or more heteroatoms of the same kind. When indicating the relative positions of the heteroatoms, the principle of the lowest possible numbering is used, that is, the numbering of the system has to be carried out in such a way that the heteroatoms are given the lowest possible set of locants:

In such a numerical sequence, the earlier numbers take precedence, for example, 1,2,5 is lower than 1,3,4.

Monocyclic systems, two or more different heteroatoms

For heteroatoms of different kinds, prefixes are used in the order in which they appear in Table 2.1, for example, thiazole, not azathiole; dithiazine, not azadithiine. The heteroatom highest in Table 2.1 is allocated the 1-position in the ring. The remaining heteroatoms are assigned the smallest possible set of number locants:

Although in the first example the systematic name is 1,3-thiazole, the locants are generally omitted because, except for isothiazole (1,2-thiazole), no other structural isomers exist. Similar rules apply to oxazole (1,3-oxazole) and isoxazole (1,2-oxazole).

Identical systems connected by a single bond

Such compounds are defined by the prefixes bi-, ter-, quater-, and so on, according to the number of systems, and the bonding is indicated as follows:

4 Bicyclic Systems with One Benzene Ring

Systems in which at least two neighboring atoms are common to two or more rings are known as fused systems. For several bicyclic benzo-fused heterocycles, trivial names are permitted, for example:

If this is not the case, and only the heterocycle has a trivial name, then the systematic name is formulated from the prefix benzo- and the trivial name of the heterocyclic component as follows:

The system is dissected into its components. The heterocyclic component is regarded as the base component. The bonds between the ring atoms are denoted according to the successive numbers of the ring atoms by the letters a, b, c, and so on. The letter b in brackets between benzo and the name of the base component denotes the atoms of the base component which are common to both rings. The letter must be as early as possible alphabetically, and hence benzo[d]furan is incorrect.

It is generally accepted that the numbering of the whole system in the case of bi- and polycyclic systems should be done independently of the numbering of the components, and as follows:

The ring system is projected onto rectangular coordinates in such a way that

as many rings as possible lie in a horizontal row

a maximum number of rings are in the upper right quadrant.

The system thus oriented is then numbered in a clockwise direction commencing with that atom which is not engaged in the ring fusion and is furthest to the left

in the uppermost ring or

in the ring furthest to the right in the upper row.

C-Atoms which belong to more than one ring are omitted. Heteroatoms in such positions are, however, included. If there are several possible orientations in the coordinate system, the one in which the heteroatoms bear the lowest locants is valid:

If the base component does not have a trivial name, the entire system is numbered as explained above and the resulting positions of the heteroatoms are placed before the prefix benzo:

5 Bi- and Polycyclic Systems with Two or More Heterocycles

First the base component is established. To this end the criteria in the order set out below are applied, one by one, to arrive at a decision. The base component is

a nitrogen-containing component

a component with a heteroatom, other than nitrogen, which is as high as possible in

Table 2.1

a component with as many rings as possible (e.g., bicyclic condensed systems or polycyclic systems which have trivial names)

the component with the largest ring

the component with most heteroatoms

the component with the largest number of heteroatoms of different kinds

the component with the greatest number of heteroatoms which are highest in

Table 2.1

the component with heteroatoms which have the lowest locant numbers.

Two isomers are given as an example:

First, the system is dissected into its components. The base component cannot be established until the fifth criterion has been reached: pyrimidine. The bonds between the ring atoms are marked by consecutive lettering according to the serial numbering of the base component. In contrast to the example on p. 8, the fused component must also be numbered, always observing the principle of assignment to the lowest possible locants. The name of the fused component, by the replacement of the terminal “e” with “o,” is put before the name of the base component. The atoms common to both rings are described by numbers and letters in square brackets, where the sequence of the numbers must correspond to the direction of the lettering of the base component. Finally the whole system is numbered.

6 Indicated Hydrogen

In some cases, heterocyclic systems occur as one or more structural isomers which differ only in the position of an H-atom. These isomers are designated by indicating the number corresponding to the position of the hydrogen atom in front of the name, followed by an italic capital H. Such a prominent H-atom is called an indicated hydrogen and must be assigned the lowest possible locant.

The name pyrrole implies the 1-position for the H-atom.

Heterocyclic compounds in which a C-atom of the ring is part of a carbonyl group are named with the aid of indicated hydrogen as follows:

2.2 Replacement Nomenclature

1 Monocyclic Systems

The type of heteroatom is indicated by a prefix according to Table 2.1. As all prefixes end with the letter a, replacement nomenclature is also known as “a” nomenclature. Position and prefix for each heteroatom are written in front of the name of the corresponding hydrocarbon. This is derived from the heterocyclic system by replacing every heteroatom by CH2, CH, or C:

Sequence and numbering of the heteroatoms follow the rules given in Section 2.1. The two compounds chosen as examples could also be named according to the Hantzsch-Widman system.

2 Bi- and Polycyclic Systems

Again, position and prefix are put in front of the name of the corresponding hydrocarbon, but the numbering of the hydrocarbon is retained:

The Hantzsch-Widman nomenclature can only be applied to the first example, and this then results in different numbering.

2.3 Examples of Systematic Nomenclature

Finally, the systematic nomenclature of heterocyclic compounds will be illustrated by a few complex examples:

An analysis of the system reveals two benzene rings, one pyrazole ring and one 1,3-diazocine ring, the latter ring being the base component according to the fourth criterion. The square brackets [1,3] indicate that the position of the two heteroatoms is not the basis for numbering the whole system.

According to the third criterion, quinoxaline is the base component. The heterocycle imidazole, which is fused to the base component, is numbered in the usual way; the pyridine ring, however, is denoted by 1′, 2′, and so on, and it is not necessary to mark the double bonds. Pyrido[1′,2′ : 1,2]imidazo denotes one ring fusion, imidazo[4,5-b]quinoxaline the other. For numbering polycyclic systems, five-membered rings must be drawn as shown above and not as regular pentagons. For the orientation in a system of coordinates, an additional rule has to be observed, namely that C-atoms common to two or more rings must be given the lowest possible locant. The numbering in (b) is therefore correct, while that in (a) is wrong, because 10a < 11a.

With ring atoms such as phosphorus, which can be tri- or pentavalent, a non-standard bonding number is indicated as an exponent of the Greek letter λ after the locant. In the example, this is shown by λ5 (the 1993 Blue Book, p. 21).

The name is constructed according to replacement nomenclature. The basic hydrocarbon with the greatest number of noncumulative double bonds is cyclopenta[c,d]indene. Note the retention of the numbering.

In this case, [b,e] is omitted after dibenzo since there is no other possibility for ring fusion. This compound is also known as TCDD or Seveso dioxin.

So far, in all the examples, the base compound has been the heterocyclic system. If this is not the case, the univalent radical of the heterocyclic system is regarded as a substituent, for example:

The names of some univalent heterocyclic substituent groups are to be found in the list of trivial names in the 1993 Blue Book, p. 172.

The most important source of information on heterocyclic and isocyclic systems is the Ring Systems Handbook of the Chemical Abstracts Service (CAS) published by the American Chemical Society. The 1988 edition is arranged as follows:

Band 1:

Ring Systems File I:

RF 1–RF 27595,

Band 2:

Ring Systems File II:

RF 27596–RF 52845,

Band 3:

Ring Systems File III:

RF 52846–RF 72861,

Band 4:

Ring Formula Index, Ring Name Index.

Since 1991, cumulative supplements have been published annually.

The Ring Systems File is a catalog of structural formulas and data. It lists the systems consecutively with numbering RF 1 to RF 72861 on the basis of a ring analysis. The Ring Systems File starts with the following system:

1 RING represents a monocycle, 3 denotes the ring size. The ring atoms are listed underneath in alphabetical order followed by

RF 1

88212-44-6

[Ring File (RF) Number]

(CAS Registry Number)

Thiaphospharsirane, AsH

2

PS

the systematic name and molecular formula, and furthermore WISWESSER Notation, Chem. Abstr. reference (Chem. Abstr. volume number, abstract number), structural diagram.

An example from the Ring Systems File 1, p. 758, is given below:

The Ring Formula Index is a list of molecular formulas of all ring systems with ring atoms quoted in alphabetical order, H-atoms being omitted, for example, C6N4: 2 RINGS, CN4-C6N, 1H-Tetrazolo[1,5-a]azepine [RF 9225].

With the aid of the Ring File Number RF 9225, the structural formula can be found in the Ring Systems File.

The Ring Name Index is an alphabetical list of the systematic names of all ring systems, for example: Benzo[4,5]indeno[1,2-c]pyrrole [RF 40064]. The Ring File Number allows access to the Ring Systems File.

Organization and use of the Ring Systems File, Ring Formula Index, and Ring Name Index are, in each case, explained in detail at the beginning of the book.

2.4 Important Heterocyclic Systems

Several possibilities existed for the arrangement of Chapters 3–8. For instance, the properties of the compounds could have been emphasized and the heteroarenes dealt with first, followed by the heterocycloalkenes and finally the heterocycloalkanes. However, in this book, the reactions, syntheses, and synthetic applications of heterocyclic compounds are considered of greatest importance. In many cases, they are characteristic only of a single ring system. For this reason, we have adopted an arrangement for the systems which is similar to that shown on the cover of issues of the Journal of Heterocyclic Chemistry. The guiding principle is ring size (see Table 2.2). Heterocycles of certain ring sizes are further subdivided according to the type of heteroatoms, following the sequence shown in Table 2.1, starting with one heteroatom, two heteroatoms, and so on. The parent compound is covered first, provided it is known or of importance. It is followed by the benzo-fused systems and finally by the partially or fully hydrogenated systems. Moreover, as in GMELIN's Handbuch der Anorganischen Chemie and BEILSTEIN's Handbuch der Organischen Chemie, the principle of the latest possible classification is applied, that is, condensed systems of two or more heterocycles are discussed under the parent compound to be found last in the classification. Finally, in view of the fact that there are more than 70 000 known heterocyclic systems, a selection had to be made. We have restricted ourselves to those systems

which, because of their electronic or spatial structure, provided good examples for a theoretical illustration of molecular structure

whose reactions afford examples of important reaction mechanisms and whose syntheses illustrate general synthetic principles

which occur in natural products, drugs, or biologically active or industrially important substances

which are important as building blocks or auxiliaries for carrying out synthetic transformations.

The description of each heterocyclic system is then arranged under the following headings:

structure, physical properties, and spectroscopic properties

chemical properties and reactions

Synthesis

important derivatives, natural products, drugs, biologically active compounds, and industrial intermediates

use as reagents, building-blocks, or auxiliaries in organic synthesis.

Chapter 3

Three-Membered Heterocycles

The properties of three-membered heterocycles are mostly a result of the great bond angle strain (Baeyer strain). The resultant ring strain imparts to the compounds high chemical reactivity. Ring opening leading to acyclic products is typical. As set out above, the heterocycles will be treated in decreasing priority, starting with those with one heteroatom.

The parent system of the three-membered heterocycles with one oxygen atom is oxirene [1]; the corresponding saturated heterocycle is oxirane.

3.1 Oxirane

Oxiranes are also known as epoxides. Microwave spectra as well as electron diffraction studies show that the oxirane ring is close to being an equilateral triangle (see Figure 3.1a).

Figure 3.1 Structure of oxirane (a) bond lengths in pm, bond angles in degrees and (b) model for the bonding MO.

Apart from ring strain, a significant property of oxiranes is their BRöNSTED and LEWIS basicity, for which the nonbonding electron pairs on the O-atom are responsible. When handling oxiranes, it should also be borne in mind that many of them are carcinogenic. The most important reactions of oxiranes are described below.

1 Isomerization to Carbonyl Compounds

In the presence of catalytic amounts of LEWIS acids, for example, boron trifluoride, magnesium iodide, or nickel complexes, oxiranes isomerize to give carbonyl compounds. Oxirane itself gives acetaldehyde; mono-substituted oxiranes yield mixtures of aldehydes and ketones:

The nickel(II) complex NiBr2 (PPh3)2 yields aldehydes regioselectively [2].

2 Ring-Opening Reactions

3 Deoxygenation to Olefins

A number of reagents transform oxiranes to olefins with deoxygenation [10]. For instance, a trans-oxirane yields a (Z)-olefin on treatment with triphenylphosphane at 200 °C:

Since trans-oxiranes are stereoselectively formed from trans-olefins (cf. p. 23), the deoxygenation process allows the conversion of an (E)-olefin to a (Z)-olefin.

In general, oxiranes can be synthesized according to three (broadly defined) principles, namely (a) by cyclization of C2-moieties bearing an anionic oxygen and a leaving group in β-position, (b) by transfer of an oxygen to an olefin (“epoxidation”), and (c) by addition of a C1-fragment to a carbonyl substrate.

1 Cyclodehydrohalogenation of β-Halogeno Alcohols

β-Halo alcohols are deprotonated by bases (e.g., hydroxides or alcoholates) followed by intramolecular displacement of the halogen as rate-determining step according to the mechanism of a 1,3-elimination of HCl:

In spite of the ring strain in the product and the considerable activation enthalpy, the reaction occurs rapidly at room temperature owing to favorable entropy. The activation entropy is affected only by the loss of the degree of freedom of the internal rotation in the 2-chloroalkoxide ion because of the monomolecular rate-determining step.

Oxirane was first prepared by WURTZ (1859) by the action of sodium hydroxide on 2-chloroethanol.

2 Darzens Reaction (Glycidic Ester Synthesis)

The reaction of α-halo esters with carbonyl compounds in the presence of sodium alkoxides leads to (2-alkoxycarbonyl) oxiranes (DARZENS, 1904), known as glycidic esters. Primarily, the α-halo ester is deprotonated by the base to the corresponding ester enolate, which adds to the carbonyl compounds in the rate-determining step. Finally, the halogen atom is substituted intramolecularly, for example:

The reaction of diazoacetamides with aldehydes in the presence of chiral Ti(OiPr)4/(R)-BINOL (1,1′-bis-2-naphthol) catalyst leads to trans-(2-amidocarbonyl)oxiranes with high stereoselectivities (>95% ee) and thus can be regarded as an asymmetric catalytic Darzens reaction [11].

3 Corey Synthesis

S-Ylides derived from trialkylsulfonium or trialkylsulfoxonium halides react as nucleophiles with aldehydes or ketones to give oxiranes [12]:

This process follows the mechanistic pattern of a 1,3-elimination and formally corresponds to a (1 + 2)-cycloaddition of the ylidic (carbene-like) CH2 group to the carbonyl group. It should be mentioned that α, β-unsaturated ketones like benzalacetophenone react with sulfonium ylides to give oxiranes, but with sulfoxonium ylides to give cyclopropanes [13].

Accordingly, the addition of simple carbenes or carbenoids to carbonyl compounds is realizable in the presence of rhodium salts (via intermediary formation of a Rh-carbenoid) [14], for example:

In an asymmetric version of the Corey oxirane synthesis, aryl aldehydes are reacted with benzyl bromide in the presence of the cyclic sulfide (cat*) derived from D-camphor as a chiral catalyst to give 1,2-diaryloxiranes with high stereoselectivities [15], for example:

4 Epoxidation of Alkenes

For the addition of oxygen to a C—C double bond, reactive (electrophilic) oxygen has to be produced in situ by means of an activator from a stable oxygen donor. Activation of oxygen can be accomplished (1) by O–O bond transformation like in the classical percarboxylic acid–carboxylic acid system (see (a)) or (2) by interaction of O2, peroxides, or H2O2 with transition metals (see (b)/(c)) [16].

a. In the PRILESCHAJEW reaction, peroxy acids like peroxybenzoic acid, m-chloroperoxybenzoic acid, or monoperoxyphthalic acid react with alkenes to give oxiranes. In weakly polar solvents, this epoxidation is likely to occur as a concerted process due to its stereospecific outcome [17]:

The above mechanism is in accord with the findings that (1) peroxy acids possess strong intramolecular hydrogen bonds, and (2) (Z)-alkenes yield cis-oxiranes while (E)-alkenes yield trans-oxiranes.

b. For the epoxidation of non-activated alkenes (i.e., only H, alkyl, or phenyl substituents at C—C) methods of “Green Chemistry” (i.e., methods claimed to be environmentally benign) with H2O2 as oxygen donor are available, such as (1) epoxidation with H2O2 and Mn(II) sulfate as catalyst in NaHCO3-buffered aqueous medium [18] or (2) epoxidation with urea/H2O2-complex (an anhydrous form of hydrogen peroxide) and catalytic amounts of Novozym 435 in ethyl acetate (leading to generation of peracetic acid) [19], for example:

c. For the formation of stereoselective oxirane from non-functionalized alkenes, the JACOBSEN epoxidation [20] is of great importance. In this method, an oxidizing agent, preferentially NaOCl, is reacted with the alkene in the presence of a chiral catalyst such as the Mn(III)-salen-complex (X*) (JACOBSEN catalyst):

The highest stereoselectivities are reached with disubstituted (Z)-alkenes (with ee-values up to 99%) as well as trisubstituted alkenes, whereas mono-substituted olefins are poorer substrates. Concerning the mechanism of the JACOBSEN epoxidation (see Ref. [21]), asymmetric epoxidation of non-activated olefins can be performed with numerous other transition-metal catalysts [22].

d. For olefinic systems containing an allyl alcohol moiety, the SHARPLESS-KATSUKI epoxidation [23] is the method of choice. According to this protocol, a hydroperoxide (commonly tert-butyl or cumene hydroperoxide) is reacted with an allyl alcohol in the presence of catalytic amounts of Ti(OiPr)4 with a tartrate (usually DET or DIPT) as a chiral auxiliary:

The SHARPLESS-KATSUKI epoxidation occurs chemo- and stereoselectively, that is, (1) allylic alcohol moieties are epoxidized selectively in the presence of other olefinic double bonds and (2) both enantiomers (P1/P2) of the oxirane can be obtained with ee-values >90% by using either (R,R)- or (S,S)-dialkyl tartrate. Concerning the mechanism of the SHARPLESS-KATSUKI epoxidation, see Ref. [24].

Oxirane (ethylene oxide), a colorless, water-soluble, very poisonous gas of bp 10.5 °C, is produced on an industrial scale by direct air oxidation of ethene in the presence of a silver catalyst. Oxirane is important as an intermediate in the petrochemical industry. The annual production worldwide is estimated to be more than 7 million tonnes.

Methyloxirane (propylene oxide) is a colorless, water-miscible liquid, bp 35 °C. It is obtained commercially from propene and tert-butyl hydroperoxide in the presence of molybdenum acetylacetonate [25].

(Chloromethyl)oxirane (epichlorohydrin) is prepared from allyl chloride as follows:

Epichlorohydrin is the starting material for epoxy resins. When used in excess, for example, with bis-2,2-(4-hydroxyphenyl)propane, the so-called bisphenol A, in the presence of sodium hydroxide, it reacts to give linear polymers with oxirane end-groups.

Propagation proceeds in two steps which are continuously repeated: opening of the oxirane ring by phenol interaction and closing of the oxirane ring by dehydrogenation. When mixed with diacid anhydrides, diamines, or diols, an interaction with the oxirane end-groups of the macromolecules ensues, resulting in cross-linking (hardening). Epoxy resins find use as surface coatings, laminated materials, and adhesives.

(Hydroxymethyl)oxirane (glycidol) is produced industrially by the oxidation of allyl alcohol with hydrogen peroxide in the presence of sodium hydrogen tungstate. It serves as a useful starting material in various syntheses [26].

Benzene oxide (7-oxabicyclo[4.1.0]hepta-2,4-diene) was obtained in an equilibrium mixture with the valence isomer oxepine (see p. 529):

Benzene dioxide and benzene trioxide are also known [27]. Arene oxides are crucial intermediates in the carcinogenic action of benzo[a]pyrene and other polycondensed arenes [28]. Oxiranes are found relatively rarely in nature. An example of an oxirane in a natural product is, however, juvenile hormone (1) of the sphinx moth.

Furthermore, attention must be drawn to the part played by squalene epoxide (2) as an initiator of steroid biosynthesis in eukaryotes. Antibiotics with oxirane rings, for example, oleandomycine, have also been isolated.

Oxiranes are of considerable importance as intermediates for multistep stereospecific syntheses of complex target molecules, because closing and opening reactions of the oxirane ring often occur without side reactions. Moreover, they proceed stereospecifically. The first steps in the total syntheses of all 16 stereoisomeric hexoses may serve as an example. These syntheses start from (E)-but-2-ene-1,4-diol (3), which is obtained from acetylene and formaldehyde via butyne-1,4-diol [29].

First, a hydroxy group is protected by reaction with benzhydryl chloride (4). This is followed by a SHARPLESS epoxidation in the presence of (R,R)-(+)-DET to give 5. This reacts with thiophenol and sodium hydroxide to give 6, in which the C-atoms 4, 5, and 6 of the L-hexoses are already in place. The SHARPLESS epoxidation leads into the D-series with (S,S)-(−)-DET. In the course of steps 5 → 6, two openings and one closure of oxirane rings are observed. The presence of the thioether group CH2SPh in 6 is essential for linking the remaining two C-atoms by a PUMMERER rearrangement and a WITTIG reaction.

Another broad class of oxirane reactions are viewed as “heterocyclic interconversions,” as they transform the epoxide system into another heterocyclic entity. This is illustrated by the following examples, in which epoxides are transformed

a. to 1,3-dioxolanes by reaction with acetone in the presence of Bi(OTf)3 [30] and

b. to 1,3-oxazolidines by reaction with N-alkylimines in the presence of SmI2 [31]:

These transformations might be envisaged as formal (3 + 2)-cycloadditions of the oxirane as C–C–O-synthon to C—O or C—N bonds, respectively.

3.2 Thiirane

Thiiranes are also known as episulfides. As a result of the greater atomic radius of the S-atom, the three atoms form an acute-angled triangle (see Figure 3.2).

Figure 3.2 Structure of thiirane (bond lengths in pm, bond angles in degrees).

The properties of the thiiranes are primarily due to ring strain. In spite of the smaller strain enthalpy, thiirane is thermally less stable than oxirane. Even at room temperature, linear macromolecules are formed because of polymerization of ring-opened products. Substituted thiiranes are thermally more stable. The following reactions are typical for thiiranes [32].

1 Ring-Opening by Nucleophiles

Ammonia, or primary or secondary amines, react with thiiranes to give β-amino thiols:

The mechanism is the same as that described on p. 18 for oxiranes. However, the yields are lower, due to competing polymerization. Concentrated hydrochloric acid reacts with thiiranes to give β-chlorothiols (protonation on the S-atom and nucleophilic ring-opening by the chloride ion).

2 Oxidation

Thiiranes are oxidized by sodium periodate or peroxy acids to give thiirane oxides. These undergo fragmentation at higher temperature to give alkenes and sulfur monoxide:

3 Desulfurization to Alkenes

Triphenylphosphane, as well as trialkyl phosphites, have proved to be reliable reagents for this purpose. The reaction is stereospecific. cis-Thiiranes yield (Z)-olefins and trans-thiiranes yield (E)-olefins. The electrophilic attack of the trivalent phosphorus on the heteroatom is different from that described on p. 20.

Organometallics, for example, n-butyllithium, also bring about a stereospecific desulfurization of thiiranes.

The synthesis of thiiranes starts either from β-substituted thiols or from oxiranes and can be achieved as follows.

1 Cyclization of β-Substituted Thioles

By analogy with the oxirane synthesis described on p. 21, halo thiols react with bases to give thiiranes. β-Acetoxythiols also yield thiiranes under similar conditions. 2-Sulfanylethanol reacts with phosgene in the presence of pyridine to give 1,3-oxathiolan-2-one, which on heating to 200 °C decarboxylates to give CO2 and thiirane.

2 Ring Transformation of Oxiranes

Oxiranes react with thiocyanates to give thiiranes, preferentially with [NH4]SCN in acetonitrile in the presence of iodine as catalyst [33]:

The reaction is thought to proceed via activation of the oxirane by I2 (situation 1), followed by nucleophilic ring-opening with thiocyanate (to give 2) and subsequent formation of an oxathiolane intermediate (3); 3 undergoes rearrangement to the thiolate 4, which closes the thiirane ring by SNi displacement of cyanate ion.

Thiirane (ethylene sulfide) is a colorless liquid, sparingly soluble in water, and of bp 55 °C.

A method for C–C coupling which is based on closing a thiirane ring and opening it by desulfurization is known as sulfide contraction according to ESCHENMOSER, for example:

Pyrrolidine-2-thione is S-alkylated with bromodiethylmalonate. On treatment with a solution of KHCO3, the resulting iminium salt 5 yields a thiirane 6 which desulfurizes at 60 °C to give the enamino ester 7 [34].

3.3 2H-Azirine

Like oxirenes, 1H-azirines are thermally very labile and thus represent intermediates of short life-time [35]. 2H-Azirines, however, are even of preparative utility regardless of their high ring strain enthalpy ( ∼ 170 kJ mol−1), which is substantially higher than that of aziridines ( ∼ 110 kJ mol−1), their saturated analogs.

The parent compound 2H-azirine is thermally unstable and has to be stored at very low temperatures. Substituted 2H-azirines are more stable. They are liquids or low melting solids. Their basicity is substantially lower than that of comparable aliphatic compounds. For instance, 2-methyl-3-phenyl-2H-azirine is not soluble in hydrochloric acid.

The ring strain endows the C—N double bond with an exceptionally high reactivity. Electrophilic reagents attack the N-atom, nucleophilic reagents the C-atom. For example, methanol added in the presence of a catalytic amount of sodium methoxide produces 2-methoxyaziridines:

Carboxylic acids also add to the C=N double bond, and the products rearrange to more stable compounds with opening of the aziridine ring. A method for peptide synthesis is based on these reactions [36]:

Accordingly, the carboxyl group of the Z-protected amino acid 1 adds to the C=N bond of 3-(dimethylamino)-2H-azirine 2; already at room temperature, the adduct 3 rearranges to the N,N-dimethylamide of a Z-protected dipeptide 4, which is obtained quantitatively and yields the dipeptide 5 after acid hydrolysis.

3-Substituted 2H-azirines 8 are prepared by thermolysis or photolysis of vinyl azides 6 [37]. Vinyl azides can be obtained from alkenes on several pathways, for example, α-phenyl vinyl azide from styrene [38]. The dediazoniation of the vinyl azides 6 proceeds via intermediary formation of a vinyl nitrene (7) and its cyclization to the 2H-azirine (8):

A modification of this methodology allows the preparation of 3-(dialkylamino)-2H-azirines 10 from N,N-disubstituted carboxamides 9 [39]:

2,3-Trisubstituted 2H-azirines are formed from the methoiodides 11 of ketone dimethylhydrazones on interaction with alcoholates:

1. 2H-Azirines like 12 carrying an aldehyde function in 3-position are transformed to oxazoles 14 on treatment with BF3-etherate or to isoxazoles 16 on treatment with Rh2(OAc)4 [40]:

For these heterocyclic interconversions, ring-opening at the 2H-azirine single bonds is obvious. In the Rh-mediated reaction, intermediate 15 might be stabilized as Rh-nitrene complex; the LEWIS acid-mediated case (probably via intermediate 13) is mechanistically uncertain. For the overall conversion of the azirine 12 to oxazole or isoxazole, 1,5-electrocyclizations via 13 or 15 give a plausible description (cf. p. 192).

2. It should be remembered that the historically first pathway to 2H-azirines is the NEBER rearrangement, in which oxime sulfonates of type 17 are transformed to α-aminoketones 18 by interaction with base, for example:

α-Deprotonation of 17 and intramolecular elimination of tosylate in the anion 19 gives rise to intermediary formation a 2H-azirine 20, which undergoes hydrolysis of the imine function to the aminoketone 18 [41].

3.4 Aziridine

Aziridine was once known as ethylene imine. Bond lengths and bond angles are essentially the same as those in oxirane. The plane in which the N-atom, its nonbonding electron pair and the N–H bond are situated is perpendicular to the plane of the aziridine ring (see Figure 3.3).

Figure 3.3 Structure of aziridine (bond lengths in pm, bond angles in degrees).

2-Methylaziridine would be expected, therefore, to display diastereoisomerism. Trivalent N-atoms are, however, liable to pyramidal inversion.

Care is advisable when handling aziridines, because many of them show considerable toxicity. The following reactions of aziridines are due to their nitrogen basicity and to their ability to undergo ring-opening reactions.

1 Acid-Base Reactions

Aziridines unsubstituted on the N-atom behave like secondary amines; N-substituted aziridines behave like tertiary amines. They react with acids to give aziridinium salts:

2 Reactions with Electrophilic Reagents

Aziridines, like amines, are nucleophiles and react with electrophiles. Nucleophilic substitution on a saturated C-atom and MICHAEL addition to an acceptor-substituted olefin serve as examples:

3 Ring-Opening by Nucleophiles

Ammonia and primary amines react with aziridines to give 1,2-diamines. The mechanism and the stereochemistry of this reaction are similar to the corresponding reactions of the oxiranes [42].

The ring-opening of the aziridines is catalyzed effectively by acids (A2 mechanism, see p. 20). The acid-catalyzed hydrolysis to give amino alcohols serves as an example:

This process can be envisaged as alkylation of a nucleophilic system (here: H2O) by the protonated aziridine. Reactions of this type can be used to explain the cytostatic and antitumor activity of aziridines and (β-chloroethyl)-substituted amines. An example is bis(2-chloroethyl)amine (1), which in solution forms an equilibrium with 1-(2-chloroethyl)aziridinium chloride (2):

Tris(2-chloroethyl)amine (3) was used under the name N-Lost as a chemical weapon in World War I.

Nucleophilic cell components, for example, the amino groups of the guanine bases in DNA, are alkylated by the aziridinium ion as a result of a nucleophilic ring-opening. In the case of bis(2-chloroethyl)amine, the reaction can be repeated on a guanine base of the other DNA strand of the double helix. This results in cross-linking of the two DNA strands and consequently blocks replication.

4 Deamination to Alkenes

Aziridines unsubstituted at the N-atom are stereospecifically deaminated by nitrosyl chloride; via the corresponding N-nitroso compound, alkenes are formed stereoselectively:

The syntheses of aziridines fall into four major categories:

1. cyclization of N–C–C systems with a leaving group in β-position to nitrogen,

2. (N + C—C)-cycloaddition (aziridination of alkenes),

3. (C + C=N)-cycloaddition (aziridines from imines),

4. cyclization of β-(N-chloroethylamino)carbanions.

1 Cyclization of β-Substituted Amines

β-Amino alcohols, which are conveniently prepared from oxiranes and ammonia or amines, react with thionyl chloride to give chloramines, which can be cyclized to aziridines by alkali hydroxide (GABRIEL, 1888).

Sulfate esters, obtained from amino alcohols and sulfuric acid, when treated with alkali also form aziridines. In both cases, the amine is liberated from the ammonium salts by base. The leaving group Cl− or OSO3− is substituted intramolecularly by the amino group on the β-C-atom.

The direct cyclodehydration of β-amino alcohols can be effected with the MITSUNOBU reagent (triphenylphosphane/diethyl azodicarboxylate) [43].

2 Aziridination of Alkenes

Aziridination of C—C double bonds is readily accomplished by azides as nitrogen donors. The mechanism of nitrogen transfer is markedly influenced by the azide substituent (R1).

3 Aziridines from Imines

Imines can be transformed to aziridines by addition of suitable C1-building-blocks, as shown

a. by the imino-COREY reaction (cf. p. 22) of phenyl N-tosyl imine (9) with benzylbromide in the presence of a sulfide mediator (instead of dimethylsulfide or -sulfoxide) and a base,

b. by the reactions of phenyl-N-SES imine (10) with phenyldiazomethane in the presence of Rh2(OAc)4 (thought to proceed via an in situ generated Rh-carbenoid):

Both reactions can be conducted stereoselectively in the presence of appropriate chiral auxiliaries [45].

4 Cyclization of β-(N-Chloroethylamino)Carbanions

N-Chloroethylamines 12 bearing an acceptor-functionality (ester, benzoyl, cyano, phenylsulfonyl) in β-position to nitrogen are readily cyclized in a 1,3-elimination of HCl by strong base (e.g., tBuOK) to give N-alkyl-2-acceptor-substituted aziridines 13 [46]:

The N-chloramines 12 are conveniently obtained by addition of aliphatic primary amines to acceptor-substituted olefins and N-chlorination of the resulting secondary amines 11 with trichloroisocyanuric acid.

Aziridine, a colorless, water-soluble, poisonous liquid (bp 57 °C) of ammoniacal odor is relatively stable, thermally, but is best stored in a refrigerator over sodium hydroxide.

Some natural products contain an aziridine ring, for example, mitomycins (14: mitomycin C). This is responsible for the cytostatic and antitumor activity of these antibiotics. Many synthetic aziridines have been screened for their antitumor activity. Some are used in medical treatment, especially as antileukemic agents, for example, 15 and 16.

Aziridines with C2 symmetry have been used successfully as chiral auxiliaries for alkylations and aldol reactions [47].

Aziridines (e.g., 17) have the potential to undergo heterolytic ring-opening at the C-2/C-3 bond (facilitated by C-2/C-3 acceptor substituents) leading to 1,3 dipoles (e.g., 18) which can be trapped by 1,3-dipolar cycloaddition to electron-deficient olefins (e.g., maleic anhydride) to give pyrrolidine derivatives (e.g., 19) [48]:

The ring expansion 17 → 19 represents another example of heterocyclic interconversion.

3.5 Dioxirane

Dioxiranes have been available only since the mid-1980s [49]. They are synthesized by oxidation of ketones with potassium hydrogenperoxysulfate, for example:

Dimethyldioxirane, together with acetone, is removed from the reaction vessel by distillation. The yellow 0.1–0.2 M solution can be used as an oxidizing agent, for example, for the epoxidation of olefins [50], for the oxidation of enolates to α-hydroxycarbonyl compounds, and for the oxidation of primary amines to nitro compounds [51]:

Boron trifluoride catalyzes the isomerization of dimethyldioxiranes to methyl acetate [52].

Difluorooxirane is formed as a pale-yellow, normally stable gas when an equimolar mixture of FCO2F and ClF is passed over a CsF catalyst [53].

3.6 Oxaziridine

Oxaziridines are structural isomers of oximes and nitrones. Trialkyl oxaziridines are colorless liquids, sparingly soluble in water. The following reactions are typical for oxaziridine.

1 Isomerization to Nitrones

As a reversal to the photoisomerization of nitrones (see p. 39), oxaziridines can be converted into nitrones by thermolysis. The required temperature depends on the type of oxaziridine substituents.

2 Ring-Opening by Nucleophiles

On acid-catalyzed hydrolysis, 2-alkyl-3-phenyloxaziridines yield benzaldehyde and N-alkylhydroxyl-amines, for example:

3 Reduction to Imines

Oxaziridines, particularly 2-(phenylsulfonyl)oxaziridines, are used as reagents in a number of oxidation procedures. The oxidation of sulfides to sulfoxides may serve as an example:

The synthesis of oxaziridines can be accomplished from imines, nitrones, or carbonyl compounds:

1 Oxidation of Imines with Peroxy Compounds

For the transformation of imines to oxaziridines, in general peroxy acids (e.g., Ph–CO3H) can be used. For the selective oxygenation of aryl aldimines tert-BuOOH and alumina-supported MoO3 (as a recyclable heterogeneous catalyst) are recommended [54].

2 Photoisomerization of Nitrones

Nitrones are isomerized to oxaziridines photochemically. This reaction is reversed thermally:

3 Amination of Carbonyl Compounds

In the presence of a base, hydroxylamine-O-sulfonic acid or chloramine aminate carbonyl compounds nucleophilically, for example:

In this reaction, the intramolecular nucleophilic substitution occurs on an N-atom.

Oxaziridines are oxidizing agents as well as important synthetic intermediates [55]. For instance, N-hydroxyaminocarboxylic esters 2 can be prepared from α-aminocarboxylic acid esters with oxaziridines 1 as intermediates as follows:

3.7 3H-Diazirine

3H-Diazirines are structural isomers of diazoalkanes. They are gases or colorless liquids, for example, 3,3-dimethyldiazirine, bp 21 °C. Liquid 3H