The most important derivatives of the fivemember heterocyclic compounds with one heteroatom

Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. The participation of the nitrogen lone electron pair in the aromatic ring means that indole is not a base, and it does not behave like a simple amine. Indole is a solid at room temperature. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar. The indole structure can be found in many organic compounds like the amino acid tryptophan and in tryptophan-containing protein, in alkaloids, and in pigments. Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitter serotonin, and melatonin. The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum. Indole chemistry began to develop with the study of the dye indigo. This was converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust. In 1869, he proposed the formula for indole (left) that is accepted today.

Leimgruber-Batcho indole synthesis

The Leimgruber-Batcho indole synthesis

The Leimgruber-Batcho indole synthesis is an efficient method of sythesizing indole and substituted indoles. Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are comprised of specifically substituted indoles.

Fischer indole synthesis

The Fischer indole synthesis

One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions.

Chemical reactions of indole

Electrophilic substitution. The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013 times more reactive than benzene. For example, Vilsmeier-Haack formylation of indole will take place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion of indole, nucleophilic substitution of the carbocyclic (benzene) ring can take place only after N-1, C-2, and C-3 are substituted.

The Vilsmeyer-Haack formylation of indole

Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde.

Synthesis of Gramine from indole

Nitrogen-H acidity and organometallic indole anion complexes

Formation and reactions of the indole anion

Carbon acidity and C-2 lithiation. After the N-H proton, the hydrogen at C-2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C-2 position. This strong nucleophile can then be used as such with other electrophiles. Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole.

2-position lithiation of indole

 Oxidation of indole. Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

Oxidation of indole by N-bromosuccinimide

Cycloadditions of indole. Only the C-2 to C-3 pi-bond of indole is capable of cycloaddition reactions. Intermolecular cycloadditions are not favorable, whereas intramolecular variants are often high-yielding. For example, Padwa et al. have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile.

Example of a cycloaddition of indole

Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.

http://intranet.tdmu.edu.ua/data/kafedra/internal/zag_him/lectures_stud/en/pharm/prov_pharm/ptn/organic%20chemistry/2%20course/11.Fivemember_heterocycles_with_2_heteroatoms..files/image018.gif Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables.

Fivemember heterocyclic compounds with two heteroatoms

1. Fivemembered heterocycles connections are with two heteroatoms.

2. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of imidazole. Histamine. Histidine.Benzimidazole.

3. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyrazole. Analhine.

4. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of oxazole. Isoxazole.

5. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of thiazole. Thiamine. Isothiazole.

1. Fivemembered heterocycles connections are with two heteroatoms.

 Azoles are five-membered ring aromatic heterocycles containing two nitrogens, one nitrogen and one oxygen, or one nitrogen and one sulfur. They may be considered as aza analogs of furan, pyrrole, and thiophene, in the same way that pyridine is an aza analog of benze.

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 From a molecular orbital standpoint, the azoles are similar to the simpler aromatic heterocycles. For example, in imidazole, each carboneand nitrogen may be considered to be spa hybridized. One nitrogen makes two sp²-sp² σ bonds to carbone and one sp²-s σ bonds to hydrogen. The other nitrogen has its lone pair in the third spa orbital. The π molecular orbital system is made up from the рz

orbitals from each ring atom. Six p electrons (one from each carbon and from one nitrogen, two from the other nitrogen) complete the aromatic shell. 

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 2. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of imidazole. Histamine. Histidine.Benzimidazole.

 Imidazole is a organic compound with the formula C3H4N2. This aromatic heterocyclic is classified as an alkaloid. Imidazole refers to the parent compound whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents.

Structure and properties. Imidazole is a 5-membered planar ring, which is soluble in water and other polar solvents. It exists in two equivalent tautomeric forms because the hydrogen atom can be located on either of the two nitrogen atoms. The compound is classified as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring. Some resonance structures of imidazole are shown below:

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Biological significance and applications. Imidazole is incorporated into many important biological molecules. The most pervasive is the amino acid histidine, which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which is also a common biological compound. It is a component of the toxin that causes urticaria, which is another name for allergic hives.

 Industrial applications. Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion. Many compounds of industrial and technological importance contain imidazole derivatives. The thermostable polybenzimidazole PBI contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds which are used for photography and electronics.

 Salts of imidazole where the imidazole ring is in the cation are known as imidazolium salts (for example, imidazolium chloride). These salts are formed from the protonation or substitution at nitrogen of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotanated imidazole is an anion are also possible; these salts are known as imidazolide salts (for example, sodium imidazolide).

Histidine is an amino acid that is used to develop and maintain healthy tissues in all parts of the body, particularly the myelin sheaths that coat nerve cells and ensure the transmission of messages from the brain to various parts of the body. It may be useful for treatment of mental disorders as well as certain types of sexual dysfunction. Histidine levels in the body must be balanced to ensure good mental and physical health. High levels of this amino acid have been linked to the presence of psychological disorders such as anxiety and schizophrenia, while low levels of histidine are thought contribute to the development of rheumatoid arthritis and the type of deafness that results from nerve damage. Taking histidine supplements may help relieve symptoms of rheumatoid arthritis. Histidine is important to normal sexual functioning, because it gets converted into histamine, a chemical needed to stimulate sexual arousal. When taken together with vitamin B3 (niacin) and vitamin B6 (pyridoxine), histidine can increase sexual pleasure by boosting histamine levels in the body. Histamine is also needed to help the immune system know when the body is experiencing an allergic reaction, and for the production of gastric juices needed for normal digestion.

Histamine forms colorless hygroscopic crystals that melt at 84°C, and are easily dissolved in water or ethanol, but not in ether. In aqueous solution histamine exists in two tautomeric forms, Nπ-H-histamine and Nτ-H-histamine.

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 Tautomers of histamine. Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group will be protonated, whereas the second nitrogen of the imidazole ring will not be protonated. Thus, histamine is normally protonated to a singly-charged cation. Istidine was first isolated by German physician Albrecht Kossel in 1896.

 Synthesis and metabolism. Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.

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Conversion of histidine to histamine by histidine decarboxylase

Once formed, histamine is either stored or rapidly inactivated. Histamine released into the synapses is broken down by acetaldehyde dehydrogenase. It is the deficiency of this enzyme that triggers an allergic reaction as histamines pool in the synapses. Histamine is broken down by histamine-N-methyltransferase and diamine oxidase. Some forms of foodborne disease, so-called "food poisonings," are due to conversion of histidine into histamine in spoiled food, such as fish. The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to be stimulating histamine release.

Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in an extension of the well-elaborated imidazole system, has been used as carbon skeletons for N-heterocyclic carbenes. The NHCs are usually used as ligands for transition metal complexes. They are often prepared by deprotonating an N,N'-disubstituted benzimidazolium salt at the 2-position with a base.

Preparation

Benzimidazole is commercially available. The usual synthesis involves condensation of o-phenylenediamine with formic acid, or the equivalent trimethyl orthoformate:

C6H4(NH2)2 + HC(OCH3)3 → C6H4N(NH)CH + 3CH3OH

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The benzimidazoles are a large chemical family used to treat nematode and trematode infections in domestic animals. However, with the widespread development of resistance and the availability of more efficient and easier to administer compounds, their use is rapidly decreasing. They are characterized by a broad spectrum of activity against roundworms (nematodes), an ovicidal effect, and a wide safety margin. Those of interest are mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Netobimin, albendazole, and triclabendazole are also active against liver flukes; however, unlike all the other benzimidazoles, triclabendazole has no activity against roundworms.

3. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyrazole. Analhine.

File:Pyrazole.png

Pyrazole refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids, although they are rare in nature. Pyrazoles are produced synthetically through the reaction of α,β-unsaturated aldehydes with hydrazine and subsequent dehydrogenation.

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Pyrazoles react with potassium borohydride to form a class of ligands known as Scorpionates. Structurally related compounds are pyrazoline and pyrazolidine.

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Heterocycle formation from 1,3-dinitroalkanes. A novel pyrazole synthesis

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Aliphatic nitro compounds have proved to be useful starting materials in organic synthesis. When the nitro compounds are properly substituted they can cyclize, yielding heterocyclic compounds. 1,3-Dinitroalkanes can be viewed as synthetic equivalents for 1,3-dicarbonyl compounds through a Nef, or equivalent, reaction, and therefore could be ultimately converted into azole heterocycles. Application of the Nef reaction under the usual conditions (NaOH; conc. H2SO4) to 1,3-dinitroalknes gives only trace amounts of the anticipated dione, although the yields can be increased (up to 40%) using a secondary amine as the base. We now find that 1,3-dinitroalkanes react with hydrazines giving rise to pyrazoles.The title compounds are five-membered heterocycles having two adjacent nitrogen atoms within the ring. Pyrazoles have two endocyclic bonds and possess aromatic and tautomeric properties. Pyrazolones also have two double bonds, one of which is attached to an exocyclic oxygen atom. Pyrazolines have only one endocyclic double bond. The structural elucidation of pyrazoles and derivatives has been greatly aided by nuclear magnetic resonance spectroscopy, especially for distinguishing between isomeric structures. Pyrazoles are stable compounds and their boiling points increase with an increase in the number of alkyl groups on carbon; solubility in organic solvents is also increased. Substitution on nitrogen decreases the boiling point because of the elimination of hydrogen bonding. Pyrazolines are usually liquids having high boiling points and low water solubility, and are basic in nature. Pyrazolones are often crystalline solids and their characteristics are strongly influenced by the predominant tautomeric form. Pyrazoles can react with both acids and bases, and can be halogenated, nitrated, and acylated on both N and C. Pyrazolines are much less stable, resulting in facile ring opening. Pyrazolones react with diazonium salts, an important process in the dye industry. The preferred synthetic method for the title compounds utilizes the reaction of hydrazines with bifunctional compounds, such asβ-diketones and esters, and β-keto acetylenic compounds. In an alternative procedure, diazo compounds replace hydrazines and ring formation takes place via 1,3-dipolar cycloaddition. Pyrazoles and pyrazolones are widely used in the pharmaceutical industry to alleviate inflammation, fever, pain, and infections. To a lesser extent, they are also used as insecticides and herbicides. Pyrazolones linked to azo compounds are extensively used in the dye industry; some pyrazolines display insecticidal activity. In medicine, pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.

 4. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of oxazole. Isoxazole.

Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles.

Preparation.

The Fischer oxazole synthesis is a chemical synthesis of the aromatic heterocycle oxazole from cyanohydrins and aldehydes in the presence of anhydrous hydrochloric acid. This method was discovered by Hermann Emil Fischer in 1896.

Fischer Oxazole Synthesis

Biosynthesis. In biomolecules, oxazoles result from the cyclization and oxidation of serine or threonine nonribosomal peptides:

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Where X = H, CH3 for serine and threonine respectively, B = base.
(1) Enzymatic cyclization. (2) Elimination. (3) [O] = enzymatic oxidation.

Reactions

Oxazoline CAN oxidation

 

Isoxazole is an azole with an oxygen atom next to the nitrogen. Isoxazoles are found in some natural products, such as ibotenic acid. Isoxazoles also form the basis for a number of drugs, including the COX-2 inhibitor valdecoxib (Bextra). Furoxan is a nitric oxide donor.

5. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of thiazole. Thiamine. Isothiazole.

Thiazole, or 1,3-thiazole, is a clear to pale yellow flammable liquid with a pyridine-like odor and the molecular formula C3H3NS. It is a 5-membered ring, in which two of the vertices of the ring are nitrogen and sulfur, and the other three are carbons . Thiazole is used for manufacturing biocides, fungicides, pharmaceuticals, and dyes.Thiazoles are a class of organic compounds related to azoles with a common thiazole functional group. Thiazoles are aromatic. The thiazole moiety is a crucial part of vitamin B1 (thiamine) and epothilone. Other important thiazoles are benzothiazoles, for example, the firefly chemical luciferin. Thiazoles are structurally similar to imidazoles. Like imidazoles, thiazoles have been used to give N-S free carbenes nd transition metal carbene complexes.

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 Structure of thiazoles (left) and thiazolium salts (right)

Organic synthesis

Various laboratory methods exist for the organic synthesis of thiazoles.

· The Hantzsch thiazole synthesis (1889) is a reaction between haloketones and thioamides. For example, 2,4-dimethylthiazole is synthesized from acetamide, phosphorus pentasulfide, and chloroacetone. Another example is given below:

Hantsch Thiazole Synthesis

Reactions

Thiazoles are characterized by larger pi-electron delocalization than the corresponding oxazoles and have therefore greater aromaticity. This is evidenced by the position of the ring protons in proton NMR (between 7.27 and 8.77 ppm), clearly indicating a strong diamagnetic ring current.

The calculated pi-electron density marks C5 as the primary electrophilic site, and C2 as the nucleophilic site.

Thiazole electron densities and numbering scheme

The reactivity of a thiazole can be summarized as follows:

Thiazole deprotonation

2-(trimethylsiliyl)thiazole (with a trimethylsilyl group in the 2-position) is a stable substitute and reacts with a range of electrophiles such as aldehydes, acyl halides, and ketenes

Thiazole bromination

Thiazole Nucleophilic Aromatic Substitution

Thiazole oxidation

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 Thiamin or thiamine, also known as vitamin B1 and aneurine hydrochloride, is the term for a family of molecules sharing a common structural feature responsible for its activity as a vitamin. It is one of the B vitamins. Its most common form is a colorless chemical compound with a chemical formula C12H17N4OS. This form of thiamin is soluble in water, methanol, and glycerol and practically insoluble in acetone, ether, chloroform, and benzene. Another form of thiamin known as TTFD has different solubility properties and belongs to a family of molecules often referred to as fat-soluble thiamins. Thiamin decomposes if heated. Its chemical structure contains a pyrimidine ring and a thiazole ring. Thiamin is one of only four nutrients associated with a pandemic human deficiency disease. It is essential for neural function and carbohydrate metabolism. Thiamin deficiency results in beriberi, a disease characterized by a bewildering variety of symptoms. Common symptoms often involve the nervous system and the heart. In less severe deficiency, nonspecific signs include malaise, weight loss, irritability and confusion.

Isothiazole http://intranet.tdmu.edu.ua/data/kafedra/internal/zag_him/lectures_stud/en/pharm/prov_pharm/ptn/organic%20chemistry/2%20course/11.Fivemember_heterocycles_with_2_heteroatoms..files/image118.gif

An isothiazole is a type of organic compound containing a five-membered aromatic ring that consists of three carbon atoms, one nitrogen atom, and one sulfur atom. Isothiazole is a member of a class of compounds known as azoles. In contrast to the isomeric thiazole, the two heteroatoms are in adjacent positions. The ring structure of isothiazole is incorporated into larger compounds with biological activity such as the pharmaceutical drugs ziprasidone and perosiprone.