17 Six-Membered Hetarenes with Two Unlike or More Than Two Heteroatoms and Larger Hetero-Rings
Weinreb, S. M.; Mahajan, Y. R., Science of Synthesis, (2004) 17, 1.
General Introduction
In this volume the synthesis of six-membered hetarenes with two unlike or more than two heteroatoms and of fully unsaturated larger-ring heterocycles is discussed. 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 of the Parent Heterocycles Covered in Volume 17
The synthesis of these oxygen-, sulfur-, and/or nitrogen-containing heterocycles was discussed in Houben–Weyl, Vol. E 9a, Vol. E 9c, and Vol. E 9d, and their structure, reactivity, and chemistry has also been extensively reviewed.[1,2] References to previous reviews on specific heterocycles can be found in each section.
This volume presents selected procedures for the synthesis of the diverse group of heterocycles shown in Scheme 1. The chemistry of these heterocycles is, in most cases, presented only when relevant to their synthesis, e.g. by modification of substituents. There are a few exceptions such as Section 17.8.4 which discusses reactions around the porphyrin periphery. The discussions of each subclass generally adhere to the following pattern, although some chapters follow a slightly different order to emphasize the most useful approaches to the heterocycle in question. Note that not all subsections are relevant to all heterocycles:
x: volume number = 17; y: product class; z: product subclass
x.y.z Product Subclass z
Introductory Text
x.y.z.1 Synthesis by Ring-Closure Reactions
x.y.z.1.1 By Formation of Three Heteroatom—Carbon Bonds
x.y.z.1.2 By Formation of Two Heteroatom—Carbon Bonds
x.y.z.1.3 By Formation of One Heteroatom—Carbon and One C—C Bond
x.y.z.1.4 By Formation of Two C—C Bonds
x.y.z.1.5 By Formation of One Heteroatom—Carbon Bond
x.y.z.1.6 By Formation of One C—C Bond
x.y.z.2 Synthesis by Ring Transformation
x.y.z.2.1 By Ring Enlargement
x.y.z.2.2 Formal Exchange of Ring Members with Retention of the Ring Size
x.y.z.2.3 By Ring Contraction
x.y.z.3 Aromatization (or Synthesis by Introduction of a Double Bond)
In this volume the term “aromatization” should be interpreted as “introduction of maximum unsaturation”, since the target ring systems can in some cases be aromatic, antiaromatic, or nonaromatic.
x.y.z.4 Synthesis by Substituent Modification
x.y.z.4.1 Substitution of Existing Substituents
x.y.z.4.2 Addition Reactions
x.y.z.4.3 Rearrangement of Substituents
x.y.z.4.4 Modification of Substituents
The sections listed above are further subdivided into methods which have been selected as the most useful for the preparation of the particular heterocycle. Each method is presented separately as follows:
1. An introduction with some background information is given, the scope of the method/variation is described, and a comparison with other variations is eventually made; safety information is given when significant, and mechanistic information is provided when relevant to the use of the method in synthesis.
2. Reaction schemes associated with a short list of representative examples.
3. Representative experimental procedures.
Within each chapter, the organizational principle is based on the synthetic methods used, and not on the functional groups or substitution patterns of the heterocyclic product. Related methods, e.g. all those involving the simultaneous formation of two heteroatom—carbon bonds, are grouped together, rather than the methods of synthesis of similarly substituted heterocycles. However, the index can be used to locate methods recommended for the synthesis of a particular type of heterocycle with specific substituents.
The ring systems covered in this volume embrace a wide range of stabilities, as well as physical and chemical properties. This is in part related to whether or not cyclic π-conjugation exists in the heterocycles and, if so, whether it leads to antiaromatic destabilization or aromatic stabilization of the molecule. 1,4-Oxathiins, 1,4-thiazines, and 1,4-oxazines are nonaromatic, electron-rich heterocycles that undergo oxidation and hydrolysis reactions with considerable ease, demonstrating their relative instability. The parent 1,4-oxathiin and 1λ4,4-thiazine can be isolated but are stable only under inert atmosphere at −60°C and at room temperature, respectively.[3,4] On exposure to air at room temperature, 1,4-oxathiin rapidly decomposes to form a white insoluble polymer. Furthermore, it has not been possible to isolate 1,4-oxazine in pure form.[5] The annulated 1,4-thiazine and 1,4-oxazine analogues are aromatic when they exist as the N-substituted isomers and thus are more stable to oxidizing and hydrolytic conditions. In the benzo-fused ring systems, the heterocyclic ring is still more reactive than the carbocyclic ring toward electrophilic substitution. However, dibenzo-fused compounds undergo clean electrophilic substitution and metalation reactions at different positions on the carbocyclic rings depending on the nature of the heteroatoms. In the case of phenoxathiin (1) (Scheme 2), electrophilic attack introduces the first substituent at the C2-position and the second substituent at the C8-position, as observed in bromination and sulfonation reactions.[6] However, in acylation reactions, the C2,C7-disubstituted product is predominantly formed over the C2,C8-disubstituted product.[7] In the case of 10H-phenoxazine (2), the nitrogen atom directs the first electrophilic attack to the C3-position and the second to the C7-position in the case of bromination;[8,9] however, under standard acylation conditions, an acetyl group was introduced at the C2-position, para to the oxygen atom, a seemingly unusual site at first glance. This change in the substitution pattern is due to acetylation of the nitrogen atom prior to that of the carbocyclic ring. The N-acyl group is then removed under hydrolytic workup conditions to give the observed products.[10] The acyl-group-directing tendency of 10H-phenothiazines 3 (Scheme 2) depends on the nature of the substituent on the nitrogen atom, where alkyl substituents lead to the formation of 3,7-disubstituted compounds while acyl substituents lead to 2,8-disubstituted products.
Scheme 2 Regioselectivity of Electrophilic Substitution Reactions of Phenoxathiin, 10H-Phenoxazine, and 10H-Phenothiazine
In metalation reactions of phenoxathiin, 10H-phenoxazine, and 10H-phenothiazine, chelation plays an important role in determining the substitution pattern. The oxygen atom of phenoxathiin (1) acts as a directing group resulting in metalation ortho to the oxygen atom, as is seen in the formation of acid 4 (Scheme 3).[11] However, this directing effect of the oxygen atom can be overcome by oxidation of phenoxathiin to phenoxathiin 10,10-dioxide, which is metalated ortho to the sulfone moiety.[12] 10H-Phenoxazine (2) and 10H-phenothiazine (6) bear an acidic proton on the nitrogen atom that is removed in the first step by the organometallic reagent. Subsequent treatment of the anion with carbon dioxide leads to a lithio carbamate salt that can be metalated ortho to the nitrogen atom with another equivalent of organolithium reagent. Addition of the electrophile and subsequent workup leads to the introduction of a substituent only at the position ortho to the nitrogen atom. This effect has been used with various electrophiles to prepare derivatives 5 and 7 (Scheme 3).[13,14]
Scheme 3 Metalation Reactions of Phenoxathiin, 10H-Phenoxazine, and 10H-Phenothiazine[11–14]
Triazines and tetrazines are highly electron-deficient heterocycles, and, therefore, are resistant to electrophilic substitution reactions, even though 1,3,5-triazine is aromatic in nature. The 1,2,3-triazines cannot be subjected to the usual methods of nucleophilic substitution because, after attack of a nucleophile at the 4-position, the 1,2,3-triazine ring opens and nitrogen is evolved (see Houben–Weyl, Vol. E 9c, p 561). The parent 1,3,5-triazine is also a very labile compound and undergoes cleavage to afford hydrogen cyanide easily in the presence of nucleophiles.[15] However, this instability of 1,3,5-triazine, in fact, makes it a convenient source of hydrogen cyanide, as exemplified by its use in the Gattermann aldehyde synthesis.[16] On the other hand, 1,2,4-triazines are stable to nucleophilic attack and the low electron density in the ring helps in site-specific substitution. The vast majority of carbon, nitrogen, and sulfur nucleophiles preferentially add to C5, eventually leading to 5-substituted 1,2,4-triazines. The preferred attack at the C5-position is probably due to a 1,4-quinonoid contribution to the intermediate anion when a formal negative charge is placed at N2. On the other hand, attack at the C3- or C6-position leads to a comparatively more energetic intermediate that requires less stable 1,2-quinonoid contributions in order to place the negative charge upon a nitrogen atom.[17] However, once attack at C5 has occurred, subsequent substitution does take place at C3, while reaction at C6 is only rarely observed. Only Grignard reagents possess a differing reactivity pattern, wherein substitution at C6 is known to occur prior to substitution at C3 (Scheme 4).[18]
Scheme 4 Sequential Reactions of 1,2,4-Triazine with Grignard Reagents[18–21]
The highly electron-deficient nature of triazines and tetrazines makes them good dienes in inverse-electron-demand Diels–Alder cycloadditions with electron-rich dienophiles, such as alkenes, alkynes, or enamines, to form a wide range of condensed heterocyclic ring systems such as pyrimidines 8, pyridines 9, and pyridazines 10 (Scheme 5).[22] The pyridazine products can act as dienophiles for a second hetero-Diels–Alder reaction to form carbocyclic compounds. 1,2,4-Triazines rapidly undergo inverse-electron-demand Diels–Alder cycloadditions across C3/C6 with many electron-rich dienophiles and systems containing strained double bonds. Similarly, 1,3,5-triazines participate in Diels–Alder addition reactions where the positions of attack on the ring depend on the nature of the substituents present. Both inter- and intramolecular cycloadditions of these systems have been reported, providing, after expulsion of nitrogen or nitriles, pyridines and pyrimidines (or sometimes pyrazines). This methodology, combined with the ability to functionalize the triazine core easily and selectively through nucleophilic substitution, provides an attractive route to condensed heterocycles, whose synthesis would otherwise be quite laborious. Of additional importance is the construction of dihydropyridines through cycloaddition reactions of 1,2,4-triazines with ketenes, enol ethers, enamines, imidates, and similar compounds.[22,23] Here the products may react further and eliminate a substituent to form the corresponding pyridines. 1,2,4,5-Tetrazines undergo Diels–Alder addition reactions with electron-rich alkenes and, after nitrogen extrusion, form dihydropyridazine derivatives which either tautomerize to the stable 1,4-dihydro derivative or eliminate HX to form pyridazines 10.
Scheme 5 Hetero-Diels–Alder Reactions of Triazines and Tetrazines with Electron-Rich Dienophiles[22,23]
Azepines, thiepins, and oxepins have attracted attention due to their close relation to cycloheptatriene and their potentially antiaromatic 8π-electron nature. The most important feature of the oxepin structure is its ability to undergo valence isomerization to benzene oxide (11, X = O) (Scheme 6). The equilibrium between the two valence isomers can also be shifted in either direction by different methods such as by increasing solvent polarity that moves the equilibrium toward benzene oxide,[24] or by introducing substituents at the C2- and C7-positions that, according to ab initio calculations, can destabilize the benzene oxide form.[25] Isolation of the parent thiepin has not been possible, perhaps due to the decomposition of thianorcaradiene (11, X = S) to benzene and elemental sulfur; however, it is possible to suppress this decomposition pathway by introducing bulky substituents such as tert-butyl groups at the C2- and C7-positions, which inhibit the electrocyclic reaction leading to the formation of the corresponding thianorcaradiene.
Scheme 6 Instability of Oxepins and Thiepins
Arene oxides are postulated to be biosynthetic intermediates in the monooxygenase-catalyzed formation of phenolic metabolites from aromatic substrates, based upon an observation of substituent migration. Other evidence includes the isolation of some arene oxides from natural sources such as methyl oxepin-2-carboxylate (cf. 15, Scheme 7) obtained from the fungus Phellinus tremulae.[26,27] Labeling experiments in Phellinus ribis using methyl benzoate-2,6-d2 (12) led to the isolation of methyl oxepin-2-carboxylate (15) with 70% deuterium incorporation, along with two differently labeled salicylates 16 and 17 which were proposed to be formed via intermediates 13 and 14, respectively (Scheme 7).[28] In addition, studies on the mechanism of catechol dioxygenase induced C—C cleavage reactions that lead to ring-opened products indicate that these reactions may also proceed via oxepins/arene oxides.[29] Hence, the formation of oxepin may be a critical step in the conversion of benzene into carcinogenic products by photooxidation in the environment,[30] or through metabolism inside the body.
Scheme 7 Oxepins as Products of Enzymatic Arene Oxidations[28]
While monocyclic oxepins, as well as their sulfur and nitrogen analogues, are of considerable theoretical interest, their annulated derivatives have practical importance due to their pharmacological activity. Different methods have been developed to introduce various functional groups at the C10-position owing to the pharmaceutical interest in dibenz[b,f]oxepins with diverse side chains at this position. In one such approach, treatment of dibenz[b,f]oxepin-10(11H)-one derivatives 18 with a nucleophile, in the presence of a Lewis acid, leads to formation of C10-substituted dibenz[b,f]oxepins 19 (Scheme 8).[31]
Scheme 8 Introduction of Nucleophiles into Dibenz[b,f]oxepins[31]
Along with studies to understand their aromatic properties, diazepines (seven-membered heterocycles containing two nitrogen atoms) are interesting because of their pharmacological properties. The diazepines can exist in different tautomeric forms, and the equilibrium ratios are highly dependent on the ability of the ring substituents to stabilize a particular isomer. Although most systems favor one tautomer, in some cases it is possible to interconvert the tautomers by chemical transformations. An example of the chemical interconversion of annulated 1H- and 3H-1,2-diazepines 20 and 21, respectively, is shown in Scheme 9.[32–34]
Scheme 9 Interconversion of Annulated 1H- and 3H-1,2-Diazepines[32–34]
Cyclazines are planar conjugated cyclic molecules with either (4n+2) or 4n π-electrons and a central nitrogen atom which is covalently bonded to three of the peripheral carbon atoms. Cyclazines are very interesting from both a theoretical and chemical point of view and have been widely studied, particularly to evaluate their degree of aromaticity. Of the different types of cyclazines, the [2.2.3]cyclazines having a planar 10π-electron system are most widely studied with respect to their stability and chemical behavior.[35] The parent [2.2.3]cyclazine is the best known and most important compound in the cyclazine series because of its novel structural properties, as well as for the fact that its partially saturated framework occurs in some natural products.[35,36] Along with [2.2.3]cyclazines, the [2.2.4]cyclazinium ion is an example of an “odd-membered” annulene, consisting of a (4n+2) π-electron system and exhibiting aromatic properties.
On the other hand, cyclazines bearing a peripheral π-electron system related to the [12]annulenes have been shown to be paratropic. [3.3.3]Cyclazine (22) was found to be highly reactive, having a propensity toward both oxidation and reduction. [3.3.3]Cyclazine (22) is readily oxidized by halogens initially to produce a stable radical cation and eventually to the dication 23 (Scheme 10), indicating a small energy gap between the frontier orbitals of [3.3.3]cyclazine.[37,38]
Scheme 10 Oxidation of [3.3.3]Cyclazine by Bromine[37,38]
Like the cyclazines, heterocyclic compounds containing eight-membered and larger-membered fully unsaturated rings have been studied to probe their aromatic or nonaromatic nature. The interest in azocines (i.e., azacyclooctatetraenes) is primarily due to their structural similarity to cyclooctatetraene and hence their stability and valence isomerization have been studied. Similar to cyclooctatetraene, azocines adopt a tub-shape conformation lacking conjugative stability and are nonaromatic systems. However, planar dianions (e.g., 24) (Scheme 11) can be generated by two-electron reduction of 2-alkoxyazocines, and are aromatic 10π-electron systems.[39] The 1H NMR spectra of the stable dipotassium salts of 2-methoxyazocines reveal substantial deshielding of their methyl and vinyl protons, indicating extensive charge delocalization and the presence of an appreciable ring current. In diheterocines, 1,4-dioxocin with 10π-electrons is polyalkenic in nature, whereas 1,4-dihydro-1,4-diazocines are planar and probably aromatic. N-Substituted 4H-1,4-oxazocines behave similarly to the 1,4-dihydro-1,4-diazocines in that the nitrogen substituent dictates the degree of π-delocalization. More specifically, the incorporation of electron-withdrawing substituents (e.g., N-tosyl) into 4H-1,4-oxazocine systems leads to derivatives with twisted, nonplanar conformations, while hydrogen substitution or electron-donating groups (e.g., N-alkyl) lead to highly delocalized, planar molecules.
Scheme 11 Large-Ring Heterocycles with Aromatic Character
In heteronines, the nine-membered ring heterocycles that are isoelectronic with the cyclononatetraenyl anion, oxonin (25) and 1H-azonines 26 where the R1 substituents are electron-withdrawing groups (e.g., acyl, sulfinyl), have puckered, polyalkenic constitutions (Scheme 11). Conversely, the parent 1H-azonine (26, R1 = H) and 1-alkyl-1H-azonines 26 (R1 = alkyl) are planar, aromatic compounds that satisfy Hückel's (4n + 2) π-electron rule. Therefore, they exhibit more thermodynamic stability and are diatropic.[40–42] Similarly, alkali metal azonides (azonine salts) 27 are also planar, π-delocalized, aromatic compounds.
Unlike heterocycles with smaller rings, eight- and larger-ring compounds are mainly synthesized through valence isomerizations of suitable precursors. The valence isomerizations can often be induced under thermal or photolytic conditions, as can be seen from the two examples in Scheme 12.[43,44]
Scheme 12 Preparation of Larger-Ring Heterocycles via Valence Isomerization[43,44]
Porphyrins are macrocyclic compounds made up of four pyrrole-type subunits joined by methylene bridges. The macrocycle contains 22π-electrons of which 18π-electrons form a delocalized aromatic system according to Hückel's rule for aromaticity. The aromaticity of porphyrins has been confirmed on the basis of their heat of combustion and the X-ray structures of numerous porphyrin derivatives. The high aromatic stabilization of porphyrins and metalloporphyrins is relevant in the various roles they play in biological systems as the core of various macromolecules (e.g., heme, chlorophylls, bacteriochlorophylls). The method of synthesis of particular porphyrins depends on the substitution patterns desired. The oligomerization of the 2-(aminomethyl)pyrrole 28 leads to a simple, symmetrical porphyrin 29 (Scheme 13).[45]
Scheme 13 Synthesis of 2,3,7,8,12,13,17,18-Octaethylporphyrin[45]
The chemical reactivity of porphyrins is closely related to that of large aromatic hydrocarbons. The reactivity of porphyrins can be altered by the introduction of metals into the inner core, influencing the conjugated π-system by inductive effects. Vilsmeier formylation of the porphyrin core has long been one of the most effective methods for introducing carbon substituents onto the periphery (Scheme 14).[46] The formyl group can then be converted into various other functional groups, such as alcohols using Grignard or organolithium reagents, nitriles via oxime formation, and E- and Z-(2-substituted vinyl)porphyrins using Wittig reagents, making formylporphyrins very versatile synthetic intermediates.
Scheme 14 Formylation of a Porphyrin Derivative[46]
Phthalocyanines are planar macrocycles consisting of four isoindole-type units joined together by aza bridges to form an 18π-electron system. Although they are similar to porphyrins, these heterocycles do not occur in nature. Phthalocyanines have been extensively investigated owing to their properties as dyes. More recently, these compounds have been exploited commercially for optical data storage, as catalysts, and as photoconductors in xerography. A large number of methods exist for the synthesis of phthalocyanines based on cyclooligomerization of suitably substituted precursors such as the phthalimide derivative 30 (Scheme 15).[47]
Scheme 15 Preparation of a Metal–Phthalocyanine Complex[47]
Although many compounds covered in this volume have been synthesized mainly to study their physical properties, some of the ring systems have also been found in naturally occurring compounds. A few examples of such natural products include C-1027 (an enediyne antibiotic possessing a 1,4-benzoxazine unit that is responsible for its DNA binding ability, 31), trichochrome F (a natural pigment found in red hair and feathers, 32), the 2H-azepine chalciporone (a pungent component isolated from the common mushroom Chalciporus piperatus, 33), perilloxin (a cyclooxygenase-1 inhibitor, 34), aranotin (a metabolite of Arachniotus aureus, 35), LL-Z1220 [a fungal metabolite possessing antibiotic and antimicrobial activity that occurs as a mixture of two valence tautomers: the syn-benzene dioxide 36 (R1 = 4-oxo-4H-pyran-2-yl) and 2-(1,4-dioxocin-6-yl)-4H-pyran-4-one (37, R1 = 4-oxo-4H-pyran-2-yl)],[48] and chlorophyll a (38) and chlorophyll b (39) (Scheme 16).
Scheme 16 Naturally Occurring Compounds
Derivatives of 1,4-thiazine, 1,2,3- and 1,2,4-triazine, oxepins, and azepines are also found in a number of pharmaceuticals. Scheme 17 shows the following pharmaceutically active compounds: chlorpromazine (inhibits prion cellular infections, 40), lamotrigine (a novel anticonvulsant for the treatment of epilepsy, 41), temozolomide (an antitumor agent, 42), CGP 3466 (protects neuronal cells from apoptotic cell death and shows neuroprotective effects, 43), doxepin (an antidepressant drug, 44), opipramol (an antidepressant and antipsychotic agent, 45), and chlordiazepoxide (Librium, a tranquilizer, 46).
Scheme 17 Selected Examples of Pharmacologically Active Compounds
Some agrochemicals have also been developed based on the triazine or tetrazine ring skeleton, such as azinphos-methyl (a nonsystemic insecticide and acaricide of lasting persistence, chiefly effective against biting and sucking pests, mainly used on citrus, cotton, grapes, maize, some ornamentals, fruit, and vegetables, 47), metribuzin (Sencor, a herbicide, 48), atrazine (a herbicide based on the 1,3,5-triazine skeleton, which acts as an inhibitor of photosynthesis in plants by interrupting the light-driven flow of electrons from water to NADP+, 49), and clofentezine (highly effective against mites and used as an acaricide, 50) (Scheme 18).
Scheme 18 Selected Examples of Agrochemicals
Along with compounds having significant biological activity, some of the heterocyclic compounds in this volume have also found industrial, analytical, and synthetic applications (Scheme 19). For example, 1,3,5-triazine-2,4,6-triamine (melamine, 51), 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride, 52), and 1,3,5-triazine-2,4,6(1H,3H,5H)-trione (cyanuric acid, 53) are starting materials for the preparation of polymers with a wide range of applications including the formation of high-pressure laminates, coatings, fiber-reactive dyes, and optical brightners. In chemical analysis, methylene blue (54) is widely used as an oxidation–reduction indicator. Ferene (55), an iron(II) chelator, is used both as a colorimetric indicator as well as a corrosion inhibitor. Along with their use as dienophiles in hetero-Diels–Alder reactions, triazines such as 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODhbt, 56) and 3-[(diethoxyphosphoryl)oxy]-1,2,3-benzotriazin-4(3H)-one (DEPBT, 57) are used as reagents in the formation of amide bonds with negligible racemization in the coupling of protected α-amino acids.
Scheme 19 Selected Examples of Commercially and Synthetically Useful Compounds
References
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