10 Fused Five-Membered Hetarenes with One Heteroatom
Thomas, E. J., Science of Synthesis, (2001) 10, 1.
This volume covers the synthesis of five-membered heterocyclic compounds with either an oxygen-, sulfur-, nitrogen-, selenium-, tellurium-, or phosphorus-containing heterocycle fused to one or two benzenoid rings. The parent ring structures of the heterocycles covered in this volume are shown in Scheme 1 together with the numbering schemes used.
Scheme 1 Structures and Numbering Schemes for the Parent Heterocycles Covered in Volume 10
The synthesis of the O-, S-, and N-heterocycles was discussed in Houben-Weyl, Vol. E 6[1] and their structure, synthesis, and chemistry has also collectively been reviewed.[2,3] References to reviews on specific heterocyclic systems are given in each chapter.
This volume presents selected procedures for the synthesis of benzo-fused five-membered hetarenes. The chemistry of these heterocycles is only presented insofar as it is relevant to their synthesis, e.g. by modification of substituents. The discussions of each class of hetarene generally follow the following pattern, although some chapters follow a slightly different order to emphasize the most useful approaches to the hetarene in question and not all subsections are relevant to all hetarenes:
x: volume number = 10; y: product class; z: product subclass
x.y.z.1 Synthesis by Ring-Closure Reactions
x.y.z.1.1 By Annulation to an Arene
x.y.z.1.1.1 By Formation of Two Heteroatom—Carbon Bonds
x.y.z.1.1.2 By Formation of One Heteroatom—Carbon Bond and One C—C Bond
x.y.z.1.1.3 By Formation of Two C—C Bonds
x.y.z.1.1.4 By Formation of One Heteroatom—Carbon Bond
x.y.z.1.1.5 By Formation of One C—C Bond
x.y.z.1.2 By Annulation to the Heterocyclic Ring
x.y.z.1.2.1 By Formation of Three C—C Bonds
x.y.z.1.2.2 By Formation of Two C—C Bonds
x.y.z.1.2.3 By Formation of One C—C Bond
x.y.z.2 Synthesis by Ring Transformation
x.y.z.3 Aromatization (by Oxidation of Dehydro Compounds or Elimination Reactions)
x.y.z.4 Synthesis by Substituent Modification
The sections listed above are further subdivided into methods which have been selected as the most useful for the preparation of the hetarene in question. Each method is presented separately as follows:
1. Introduction; comparison with other methods.
2. Presentation of the scope of the method to include: background, discussion of representative examples, safety; mechanistic information where relevant to the use of the method in synthesis; a table of examples (for selected methods); reaction schemes.
3. Representative experimental procedures.
In some cases, methods are further subdivided into variations on a method, each variation being presented according to the above format.
The coverage is not meant to be exhaustive. Rather, the most useful and reliable methods for each hetarene have been selected. In some cases, methods which are recommended for limited use or which have not yet been fully developed are listed at the end of a section for reference.
Synthetic routes to heterocycles with a specific functionality, e.g. 3-alkylindoles, are not grouped together. Within each chapter, the organizational principle is based on the synthetic methods used, not on the functionality of the heterocyclic product. Related methods, e.g. those involving the simultaneous formation of two C—C bonds, are juxtaposed, not necessarily the methods of synthesis of similarly substituted hetarenes. However, the index can be used to locate all methods recommended for synthesis of a particular type of hetarene with specific substituents.
This volume covers the synthesis of heterocyclic compounds with widely different stabilities and chemical and physical properties ranging from unstable hetarenes such as benzo[c]furans, e.g. the parent system 1 which is normally generated and trapped in situ (see Scheme 2),[4] to very stable dibenzohetarenes such as dibenzothiophene (2), which undergoes decomposition at only 1% per hour when heated at 545°C.[5]
Scheme 2 Stabilities of Benzo[c]furans and Dibenzothiophenes
Benzo[b]furans, benzo[b]thiophenes, and indoles can generally be isolated and show chemistry typical of electron-rich heterocyclic compounds. However, indoles tend to be unstable in the presence of acid. They are weak bases with pKa values of ca. −3. Protonation occurs at C3 to generate 3H-indolium cations, e.g. 3 (Scheme 3). These are reactive species and are susceptible toward nucleophilic attack, leading to oligomerization under acidic conditions.[6,7]
Scheme 3 Protonation of Indoles
Electrophilic substitution of benzo[b]furans, -thiophenes, and indoles occurs preferentially at C3, the 3-position in indole being 5.5 × 1013 more reactive toward tritium exchange than a position in benzene.[8] However, electrophilic substitution of benzo[b]furans and indoles is hampered by their acid sensitivity and susceptibility to oxidation. Nevertheless, procedures have been developed for the electrophilic substitution of indoles at C3, as exemplified in Scheme 4.[9–12] If a substituent is already present at the 3-position in an indole, initial attack still takes place at this site to give 3,3-disubstituted intermediates which often rearrange to give 2,3-disubstituted indoles.[13–16]
Scheme 4 Examples of Electrophilic Substitution of Indole[9–12]
Indoles with functionalized alkyl groups at the 3-position are reactive towards nucleophilic substitution. For example, the quaternary ammonium salt of gramine (4) reacts with cyanide to give 3-cyanomethylindole (5; Scheme 5).[17] 1-Substituted indoles are regioselectively deprotonated at C2 by alkyllithium or lithium amide bases to give 2-lithio derivatives which can be trapped by electrophiles to yield 2-substituted indoles, as illustrated by the generation of the 2-lithioindole 7 from 1-methoxyindole (6) and its reactions with a range of electrophiles, e.g. N,N-dimethylformamide.[18]
Scheme 5 Representative Reactions of Functionalized Indoles[17,18]
Benzo[b]thiophene (8) also undergoes electrophilic substitution, e.g. bromination, at C3 (Scheme 6).[19] As with N-substituted indoles, deprotonation at C2 can be carried out using strong bases and subsequent reaction of the metalated intermediate with an electrophile gives 2-substituted benzo[b]thiophenes, e.g. the preparation of the 2-carboxylic acid 10 by carboxylation of the lithiated intermediate 9.[20]
Scheme 6 Some Reactions of Benzo[b]thiophene[19,20]
Benzo[c]furans and benzo[c]thiophenes are less stable than their benzo[b] isomers. Benzo[c]furans can only be isolated if they are substituted at the 1- and 3-positions with aryl or electron-withdrawing substituents, e.g. 1,3-diphenylbenzo[c]furan (12) can be obtained as a crystalline solid, mp 129–130°C, by reduction of 1,2-dibenzoylbenzene (11) followed by elimination (Scheme 7).[21] Otherwise, benzo[c]furans are generated as reactive intermediates which are intercepted by other reagents (see Scheme 2).
Scheme 7 Synthesis of 1,3-Diphenylbenzo[c]furan[21]
Benzo[c]thiophenes tend to be more stable than their benzo[c]furan counterparts. The parent benzo[c]thiophene (13; Scheme 8) has been isolated as a crystalline solid by vacuum sublimation and can be stored under nitrogen at −30°C, although it quickly decomposes in air.[22] The 1,3-diaryl derivatives, e.g. 14, once again are much more stable, as are the 1-methoxycarbonyl and 1,3-bis(methoxycarbonyl) derivatives 15 and 16.
Scheme 8 Representative Benzo[c]thiophenes
The position of equilibrium between 1H- and 2H-isoindoles (Scheme 9) is quite finely balanced and the ratio is influenced by substituents and by solvent, hydroxylic solvents favoring the 1H-tautomer whereas dipolar aprotic solvents seem to favor the 2H-isomer.[23] The kinetic instability of isoindoles in solution may reflect the presence of both isomers, allowing condensation between the 1H- and 2H-isomers to take place since N-alkylisoindoles, e.g. 2-phenylisoindole (17), which must exist as 2H-isomers, are kinetically much more stable than their N-unsubstituted counterparts. Electron-deficient isoindoles are more stable than electron-rich ones. Electrophilic substitution tends to occur at C1 and 2H-isoindoles are reactive dienes in Diels–Alder reactions.
Scheme 9 Isoindoles
The dibenzo-fused five-membered hetarenes are typically stable, aromatic compounds which undergo electrophilic substitution in a benzene ring para to the heteroatom. Representative examples are given in Scheme 10.[24–26]
Scheme 10 Representative Electrophilic Substitution of Dibenzo-Fused Five-Membered Hetarenes[24–26]
Deprotonation of dibenzohetarenes also provides useful regioselective access to substituted derivatives. Examples include the sequential metalation of dibenzofuran (18), trapping the 4-lithiated derivative with N,N-dimethylformamide, repeated metalation, and finally quenching with methyl iodide to give 4-formyl-6-methyldibenzofuran (19; Scheme 11).[27] This chemistry is particularly applicable to the preparation of functionalized dibenzothiophenes, e.g. the conversion of dibenzothiophene (2) into its 4-trimethylsilyl derivative 20.[28]
Scheme 11 Regioselective Metalation of Dibenzo-Fused Hetarenes[27,28]
Many compounds covered in this volume have considerable importance, both commercially and from an environmental point of view. Understandably, the longest chapter is devoted to the synthesis of indoles. These are of fundamental importance biologically since the proteinogenic amino acid tryptophan (21; Scheme 12) is a 3-substituted indole. The biosynthetic incorporation of tryptophan into secondary metabolites means that thousands of natural products are known which have incorporated an indole fragment into their structure.[29] Many of these play crucial metabolic roles and others exhibit a wide range of biological activities. Examples include 5-hydroxytryptamine (serotonin, a neurotransmitter; 22), lysergic acid diethylamide (23), the tranquilizer reserpine (24), and, vincristine (25), which is used in cancer chemotherapy. Many important pharmaceuticals have been developed which are substituted indoles. These include indomethacin (26; anti-inflammatory), ondansetron (27; antiemetic), pindolol (28; antihypertensive), and, sumatriptan (29; antimigraine).
Scheme 12 Biologically Active Indoles
Benzo[b]thiophenes are used for the synthesis of thioindigo dyes and, in the pharmaceutical and agrochemical industries, as isosteres for indoles with increased lipid solubility. They have been used in a wide variety of pharmaceuticals including contraceptives, laxatives, and anti-influenza, antihypertensive, anti-inflammatory, antiviral, and anticancer drugs.
Benzo[c]thiophenes are important for the preparation of conducting polymers. Electrochemical oxidation of benzo[c]thiophene (13) in polar aprotic solvents leads to the formation of an oxidized polymer 30 (Scheme 13) which is both electrically conducting and optically transparent.[30] The reduced form 31 is a blue insulator. Aspects of the preparation of polybenzo[c]thiophene are discussed in the chapter on benzo[c]thiophenes.
Scheme 13 Benzo[c]thiophene Polymers
The isoindole moiety is found in the phthalocyanines, e.g. 32 (Scheme 14), metal complexes of which are of importance as dyes. Unsymmetric derivatives have nonlinear optical properties and they have found applications as liquid crystals and chemical sensors.
Scheme 14 Isoindole-Containing Phthalocyanine
Because of their wide range of structures and biological activities, the precautions which have to be taken in handling benzo-fused five-membered hetarenes vary widely. However, because so many indoles show pronounced biological activities which can be mimicked and modulated by close isosteres, caution is recommended in handling these compounds until their toxicity has been established. Most are relatively nonvolatile, however, so good laboratory practice normally suffices for handling these compounds on a small scale in a well-ventilated chemical laboratory.
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