16 Six-Membered Hetarenes with Two Identical Heteroatoms
Yamamoto, Y., Science of Synthesis, (2004) 16, 1.
General Introduction
This volume covers the synthesis of six-membered heterocyclic compounds with two identical heteroatoms, i.e. oxygen, sulfur, selenium, tellurium, nitrogen, or phosphorus ring atoms. Six-membered heterocycles of this category fused to a six-membered aromatic carbocyclic or heterocyclic ring, or to a five-membered heterocyclic ring with two nitrogen atoms, are also discussed. The parent ring structures of the heterocycles covered in this volume are shown in Scheme 1, together with the numbering schemes and nomenclature used.
Scheme 1 Structures, Numbering Schemes, and Nomenclature for the Parent Heterocycles Covered in Volume 16
The synthesis of 1,2- and 1,4-dioxins, 1,2- and 1,4-dithiins, and pyridazines (1,2-diazines) and their annulated derivatives was discussed in Houben–Weyl, Vol. E 9a. The synthesis of pyrimidines (1,3-diazines) and pyrazines (1,4-diazines), and of their annulated derivatives together with purines, was discussed in Houben–Weyl, Vol. E 9b/Part 1 and Vol. E 9b/2, respectively. Bicyclic six-membered ring systems each with one to two nitrogen atoms were discussed in Houben–Weyl, Vol. E 9c. The structure, synthesis, and chemistry of these heterocycles have been reviewed.[1,2] References treating specific heterocycles or specific subjects relating to these heterocycles are given in each section of this volume.
This volume presents selected procedures for the synthesis of six-membered hetarenes with two identical heteroatoms. 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 compound generally follow the pattern shown below, although not all subsections are relevant to every hetarene. Some sections follow a slightly different order to emphasize the most useful approaches to the hetarene in question. The most notable case is the chapter on purines (see Section 16.17). The chapter on diazinodiazines (Section 16.22), which are also bicyclic systems where both rings contain heteroatoms, has additional headings under the ring-closure sections to complement this class of compounds.
x: volume number = 16; 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 Four Heteroatom—Carbon Bonds and One C—C Bond
x.y.z.1.1.2 By Formation of Four Heteroatom—Carbon Bonds
x.y.z.1.1.3 By Formation of Three Heteroatom—Carbon Bonds and One C—C Bond
x.y.z.1.1.4 By Formation of Two Heteroatom—Carbon and Two C—C Bonds
x.y.z.1.1.5 By Formation of Three Heteroatom—Carbon Bonds
x.y.z.1.1.6 By Formation of Two Heteroatom—Carbon Bonds and One C—C Bond
x.y.z.1.1.7 By Formation of One Heteroatom—Carbon and Two C—C Bonds
x.y.z.1.1.8 By Formation of One Heteroatom—Heteroatom and One Heteroatom—Carbon Bond
x.y.z.1.1.9 By Formation of One Heteroatom—Heteroatom and One C—C Bond
x.y.z.1.1.10 By Formation of Two Heteroatom—Carbon Bonds
x.y.z.1.1.11 By Formation of One Heteroatom—Carbon and One C—C Bond
x.y.z.1.1.12 By Formation of Two C—C Bonds
x.y.z.1.1.13 By Formation of One Heteroatom—Heteroatom Bond
x.y.z.1.1.14 By Formation of One Heteroatom—Carbon Bond
x.y.z.1.1.15 By Formation of One C—C Bond
x.y.z.1.2 By Annulation to the Heterocyclic Ring
x.y.z.2 Synthesis by Ring Transformation
x.y.z.3 Aromatization
x.y.z.4 Synthesis by Substituent Modification
The sections listed above are further subdivided into methods that have been selected as the most useful for the preparation of the hetarene in question. Each method is presented separately as follows:
1. An introduction containing some background information, the scope and limitation of the method described, mechanistic information, and, where relevant, a comparison with other methods.
2. Reaction schemes, most of the time associated with a table of representative examples, and a short specific description of the reaction in general. Safety indications and experimental precautions necessary for a specific reaction are noted.
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, especially for ditellurins and diphosphinines (Sections 16.7 and 16.23, respectively), only a small number of methods exist, primarily because the chemistry of these ring systems is still very young.
The organizational principles are based on the synthetic methods applied, not on the functionality of the heterocyclic product. Methods with related retrosyntheses are juxtaposed, e.g. those involving the formation of two heteroatom—carbon bonds. Therefore, heterocycles possessing a specific functional group are not grouped together. If all the syntheses of a heterocycle containing a specific functionality need to be found, these can be located using the index, as well as structure and text searches in the electronic product.
This volume covers the synthesis of heterocyclic compounds with widely different stabilities and chemical and physical properties. For example, 1,4-diphenyl-2,3-benzodioxin (1) is unstable and not isolated, but trapped in situ (see Scheme 2);[3] the parent compound 2,3-benzodioxin is not yet known (see Section 16.1).
Scheme 2 Synthesis of an Unstable 2,3-Benzodioxin[3]
Other dioxins, such as 1,2-dioxin, 1,2-benzodioxin, and dibenzo[c,e][1,2]dioxin, are not known. Similarly, 1,2-dithiins and 1,2-diselenins are relatively unstable in comparison with their corresponding 1,4-analogues, and 1,2-ditellurins are not known (Sections 16.3–16.7). Compared to the oxygen, sulfur, selenium, tellurium, and phosphorus heterocycles, so many different types of nitrogen heterocycles (1,2-, 1,3-, and 1,4-diazines and their annulated derivatives) are known and most of them are stable and exhibit certain biological activities.
The resonance structures of pyridazine (Section 16.8) indicate that there is no “unactivated” ring carbon with respect to nucleophilic attack (Scheme 3). However, Chichibabin-type aminations of unsubstituted pyridazine[4] and substitution of nucleophilic carbon-centered radicals, e.g. alkoxycarbonylation,[5,6] occurs at C4/C5 (Scheme 4, Sections 16.8.4.1.1.2.6 and 16.8.4.1.1.2.2.1, respectively).
Scheme 3 Resonance Structures of Pyridazine
Scheme 4 Chichibabin-Type Amination and Radical Alkoxycarbonylation of Unsubstituted Pyridazine[4–6]
The addition of Grignard reagents to pyridazine also takes place at C4/C5, while that of organolithium reagents is at C3/C6.[7] The electron-deficient character of the pyridazine ring makes it susceptible toward (partial) reduction, e.g. with lithium aluminum hydride. It should be noted that the reaction behavior of substituted pyridazines strongly depends on the nature of the substituents. For example, electrophilic substitution reactions can take place with pyridazines bearing (preferably at least two) electron-donating groups or with various pyridazine N-oxides. Pyridazin-3(2H)-one (2) and pyridazine-4(1H)-one (3) exist in the oxo form in the solid state and in solution (Scheme 5). An equilibrium between the oxo (lactam) form and its tautomer (lactim form) has been revealed for dilute solutions in dioxane, and the equilibrium shifts more to the lactim form on further dilution. For “maleic hydrazide”, the preferred tautomeric form is the monolactam–monolactim structure 4. The tautomeric behavior of pyridazinethiones (sulfanylpyridazines) is essentially the same as for the oxygen analogues, but pyridazinamines generally exist in the amino form.
Scheme 5 Tautomerism of Pyridazinones
Pyrimidine (Section 16.12) is an electron-deficient hetarene and significant electron depletion is observed at C2, C4, and C6, but only relatively minor depletion at C5. Therefore, nucleophiles generally attack at the 2-, 4-, or 6-positions, whereas electrophiles attack either C5 or the ring nitrogen atoms. For example, amination of 4-methylpyrimidine with sodium amide gives 4-methylpyrimidin-2-amine, 6-methylpyrimidine-2,4-diamine, and other products.[8,9] Pyrimidines bearing a strongly electron-withdrawing group undergo hydration, e.g. formation of adduct 5 from 5-nitropyrimidine (Scheme 6),[10] and in acidic media, 5-mesyl- and 5-(methylsulfinyl)pyrimidine behave similarly.[11] Simple pyrimidines undergo addition of Grignard or alkyllithium reagents usually across the N3—C4 bond; thus, pyrimidine gives the adduct 6 upon treatment with phenylmagnesium bromide or phenyllithium, and subsequent oxidation gives 4-phenylpyrimidine (Scheme 6).[12] Electrophilic attack on pyrimidines can only occur under normal conditions if at least one electron-donating group is present. In this case, halogenation, nitration, nitrosation, diazocoupling, sulfonation, formylation, and related reactions are possible at the 5-position.
Scheme 6 Hydration of Pyrimidine Bearing an Electron-Withdrawing Group and Arylation of Pyrimidine Using a Metal Reagent[10,11]
Resonance structures of pyrimidine can be written with charge-separated structures in a similar manner to that shown with pyridazine (see Scheme 3). Tautomerism occurs in pyrimidines that are substituted by hydroxy, sulfanyl, or amino groups. In most cases, 2-, 4-, and 6-hydroxy-substituted pyrimidines exist not as pyrimidinols, but as pyrimidin-2(1H)-one (8), pyrimidin-4(3H)-one (7), and pyrimidin-6(1H)-one, respectively. Similarly, the sulfur analogue of pyrimidin-4(3H)-one, pyrimidine-4(3H)-thione (9) forms a thiolactam structure (Scheme 7). On the other hand, the amino-substituted pyrimidines exist as aromatic pyrimidinamines rather than favoring the imino form.
Scheme 7 Tautomerism of Pyrimidinones and Pyrimidinethiones
The resonance structures of pyrazine (Section 16.14) are represented in Scheme 8, and pyrazine is also an electron-deficient heteroaromatic compound, similar to pyridazine and pyrimidine. Electrophilic substitution reactions of unsubstituted quinoxaline or phenazine (Sections 16.15 and 16.16, respectively) are unusual under ordinary reaction conditions. When activating substituents are present on the benzenoid ring, substitution usually becomes more facile. Nucleophilic substitution takes place through the direct displacement of hydrogen, as observed in the reaction of pyridazine (Scheme 4), but this type of reaction is rare with pyrazine. The ease of displacement of the substituents varies depending on the substitution pattern. There is a tendency to formulate nucleophilic substitution as simple addition/elimination reactions (Scheme 8).
Scheme 8 Resonance Structures and Reactivity of Pyrazine
Tautomerism exists in pyrazines when they are substituted by a hydroxy group. There is overwhelming evidence to suggest that in these cases the molecules exist largely in the amide form 10 (Scheme 9). However, in the case of pyrazinamine and quinoxalin-2-amine, the amino tautomer is favored rather than the imino form.
Scheme 9 Tautomerism of Pyrazinone
Purines (Section 16.17) are one of the most ubiquitous heterocycles; the quantity of naturally occurring purines is enormous as 50% of ribonucleic acid and deoxyribonucleic acid bases are purines. There are various forms of tautomerism that operate in the different purine species. Four NH-tautomeric forms exist depending on the site of attachment of the proton at the ring nitrogens (Scheme 10); the CH-tautomers, e.g. 11, are of minor importance. Amine–imine tautomerism can be considered for amino-substituted purines such as adenine (12A and 12B, Scheme 10), guanine, isoguanine, or purinediamine. Lactam–lactim tautomers exist in hypoxanthine (13A and 13B), guanine, isoguanine, or xanthine. Similar structures can be discussed for sulfanylpurines. The purine ring system can undergo both electrophilic and nucleophilic reactions. The anionic form of purine is readily attacked by electrophiles, such as alkylating or glycosylating agents, to produce, in general, the N9-substituted derivatives (Scheme 11). In the neutral form, the products may vary. The large movement of negative charge in purines from the π-electron-excessive five-membered ring to the π-electron-deficient six-membered ring results in the C8 atom becoming the most electron-deficient site in the nonionized molecule. Therefore, nucleophilic substitution at this position occurs easily, and the order for displacement is C8 > C6 > C2. On the other hand, purine anion formation causes nucleophilic attack predominantly at C6 in the pyrimidine ring and the order for replacement of appropriate substituents is C6 > C2 > C8. Electrophilic attack is rare, but if one or more strongly electron-donating groups exist in the ring system, electrophiles may attack the C8 atom. In the presence of substrates capable of producing acyl radicals, purines give the 8-acyl derivatives.
Scheme 10 Purine Tautomers
Scheme 11 Anionic Form of Purine
Pyridopyridazines are compounds in which a pyridine ring is attached directly to a pyridazine (Section 16.18). The benzo-fused derivatives of pyridazines are cinnolines and phthalazines (see Sections 16.9 and 16.10, respectively). Similarly, pyridopyrimidines and pyridopyrazines (Sections 16.19 and 16.20, respectively) are compounds with a pyridine ring fused to a pyrimidine or pyrazine, respectively. Among these three classes of pyrido-fused 1,2-diazines, pyridopyrimidines are the most investigated. Reduction of their ring system takes place readily. Upon catalytic reduction, the tetrahydro derivatives in the pyridine ring are obtained,[13] but borohydride reduction gives pyrimidine ring reduced derivatives.[13] Lithium aluminum hydride reduction often proceeds further with reductive ring opening to the aminomethyl-substituted pyridine derivatives.[13] In general, nucleophilic attack of pyridopyrimidines occurs at the pyrimidine ring and the pyridine ring is stable under ordinary nucleophilic conditions. For example, Grignard reagents add to pyrido[2,3-d]pyrimidine to give 4-substituted derivatives[14] (Scheme 12). Electrophilic attack at ring nitrogen, e.g. protonation, occurs at the pyrimidine nitrogen because of favorable resonance considerations and is accompanied by covalent hydration and/or ring opening (Scheme 12).
Scheme 12 Reactivity of Pyridopyrimidines[14]
Pteridine (pyrazino[2,3-d]pyrimidine, Section 16.21) is the pyrimidine derivative to which a pyrazine ring is fused. Tautomerism is possible in heteroatom-substituted pteridines, as observed with pyrimidines and pyrazines. For example, tautomeric structures of pteridines substituted at the 4-position by a heteroatom are shown in Scheme 13. The character of the heteroatom X determines which tautomer is preferred. As mentioned for pyrimidine (vide supra), when X is nitrogen, the amino form is favored over the imino form, whereas the amide or thioamide form is the more stable tautomer when X is oxygen or sulfur, respectively. Accordingly, pterin (14) mainly exists in the 2-amino-4-oxo form, rather than as the 2-amino-4-hydroxy derivative (Scheme 13). Pteridine is attacked by nucleophiles such as water, alcohols, and amines to form “covalent adducts”, especially at the highly reactive 4- and 7-positions, e.g. 15.[15] Heating of the covalent hydrate 15 under acidic conditions causes ring cleavage to give 3-aminopyrazine-2-carbaldehyde (Scheme 14).[16]
Scheme 13 Tautomerism of Heteroatom-Substituted Pteridines
Scheme 14 Covalent Hydration of Pteridine and Ring Cleavage[15,16]
Many compounds covered in this volume have considerable importance from a commercial point of view and, in particular, the nitrogen heterocycles are extremely important since most of them exhibit a wide range of biological activities. Accordingly, the longer chapters are devoted to the synthesis of nitrogen heterocycles. Scheme 15 illustrates the structures of some pyridazine-derived drug molecules that have made their way onto the market: antibiotic cefozopran, antidepressant minaprine, and analgesic/anti-inflammatory agent emorfazone. Phthalazine-derived drug molecules, hydralazine and budralazine, which are currently on the market, are also shown in the Scheme 15.
Scheme 15 Pyridazine- and Phthalazine-Derived Drug Molecules
Pyrimidines play an important role in nature. Uracil, thymine, and cytosine (Scheme 16) are the main components of the nucleosides uridine, deoxythymidine, and cytidine, respectively. A nonproteinogenic α-amino acid containing a pyrimidine ring is lathyrine, which can be isolated from the seeds of Lathyrus tingotanus. Variolin B was discovered in the antarctic sponge Kirkpatrickia varialosa and is an example of a pyrimidine-based alkaloid that shows some cytostatic and antiviral activity (Scheme 16).
Scheme 16 Pyrimidine-Based Natural Products
One of the most widely used pyrimidine-based drugs is trimethoprim, which is active against many gram-positive and -negative bacteria by inhibiting their dihydrofolate reductase. Another dihydrofolate reductase inhibitor is pyrimethamine. 5-Fluorouracil is a clinically established anticancer drug and component of various multidrug regimes for the treatment of tumors (Scheme 17). The pyrimidine moiety is also present in a variety of pesticides.
Scheme 17 Pyrimidine-Based Drug Molecules
Pyrazinecarboxamide is a well-known synthetic antimycobacterial agent and is used for the treatment of tuberculosis. Glipizide is a 5-methylpyrazine-2-carboxamide derivative and is an oral antidiabetic agent (Scheme 18).
Scheme 18 Pyrazine-Based Drug Molecules
Purine itself has not been found in nature, but purine derivatives are one of the most ubiquitous natural products. The purine heterocycle is a constituent of nucleosides and nucleotides. Adenosine 5′-triphosphate (ATP) is used for the storage of energy, and nicotinamide adenine dinucleotide (NAD) is involved in cellular redox processes (Scheme 19).
Scheme 19 Important Purine Derivatives in Metabolism
References
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