11 Five-Membered Hetarenes with One Chalcogen and One Additional Heteroatom
Schaumann, E., Science of Synthesis, (2002) 11, 1.
General Introduction
In this volume, the syntheses of five-membered heterocyclic compounds with one oxygen, sulfur, selenium, or tellurium ring atom and a second ring atom are discussed. The second ring atom may again be a chalcogen, or nitrogen, or phosphorus. The heterocycles under consideration are fully conjugated and can be regarded as aromatic systems, i.e. hetarenes, at least, in a formal sense. The parent ring structures of the heterocycles 1–48 covered in this volume are shown in Scheme 1, together with the method of numbering and their nomenclature.
Scheme 1 Structures, Numbering Schemes, and Nomenclature for the Parent Heterocycles Covered in Volume 11
The synthesis of the O-, S-, and/or N-heterocycles has been discussed in Houben–Weyl, Vol. E 8a[1] and E 8b.[2] Information on the tellurium-containing ring systems can be found in Houben–Weyl, Vol. E 12b,[3] and the phosphorus-containing ring systems are surveyed in Houben–Weyl, Vol. E 2.[4] Comprehensive compilations of reviews on specific heterocyclic systems can be found in each chapter.
In this volume the syntheses of hetarenes is emphasized. Their transformations are covered only in so far as is relevant to their synthesis, e.g. by modification of substituents. However, a general description of the reactivity of the heterocycles is given in the introductory section of each chapter. For each class of hetarenes, the discussion of the methods of synthesis follows a general pattern, which is outlined below. However, occasionally adjustments have been made to highlight the best procedures. This formal organization allows the identification of gaps in the methods used to synthesize specific ring systems and this may encourage future work to rectify these omissions.
For the monocyclic ring systems, the following general organization is applied:
x: volume number = 11; y: product class; z: product subclass
x.y.z.1 Synthesis by Ring-Closure Reactions
x.y.z.1.1 By Formation of Three Bonds
x.y.z.1.2 By Formation of Two Heteroatom—Heteroatom Bonds
x.y.z.1.3 By Formation of One Heteroatom—Heteroatom and One Heteroatom—Carbon Bond
x.y.z.1.4 By Formation of Two Heteroatom—Carbon Bonds
x.y.z.1.5 By Formation of Two C—C Bonds
x.y.z.1.6 By Formation of One Heteroatom—Heteroatom Bond
x.y.z.1.7 By Formation of One Heteroatom—Carbon Bond
x.y.z.1.8 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
Similarly, the following general arrangement for an annulated hetarene is used:
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 Three Bonds
x.y.z.1.1.2 By Formation of Two Heteroatom—Heteroatom Bonds
x.y.z.1.1.3 By Formation of One Heteroatom—Heteroatom and One Heteroatom—Carbon Bond
x.y.z.1.1.4 By Formation of Two Heteroatom—Carbon Bonds
x.y.z.1.1.5 By Formation of Two C—C Bonds
x.y.z.1.1.6 By Formation of One Heteroatom—Heteroatom Bond
x.y.z.1.1.7 By Formation of One Heteroatom—Carbon Bond
x.y.z.1.1.8 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 (by Oxidation of Dehydro Compounds or Elimination Reactions)
x.y.z.4 Synthesis by Substituent Modification
For each section listed above, the most important synthetic methods are given and their scope and limitations are discussed, and compared with other methods. Tables and representative experimental procedures illustrate the applicability of each approach. Often the methods are further subdivided into variations, and each variation is again fully exemplified. Less important methods, or modes, of formation with the potential for future elaboration are also documented.
The formalized arrangement of the methods of synthesis concerns the ring framework only. Thus, for example, there are no special sections dealing with thiazolamines. However, the pertinent information on the syntheses of these compounds may be found in other sections. To extract this information use of the electronic product is advised (substructure and text searches).
Heterocycles 1–23 are cations that are isoelectronic with the tropylium cation. An indication of some aromatic character can be derived from their 1H NMR spectra, which indicate the presence of a ring current, at least for 1 and 2,[5] although there is some controversy about this interpretation. In spite of their formal aromaticity, neither the 1,2-dioxolium cation 49, nor its derivatives have been described (Scheme 2).
Scheme 2 1,2-Dioxolium Cation
Potential precursors of type 50 have been made, but they are highly unstable and undergo ready isomerization to diastereomeric oxiranes 51 (Scheme 3).[6]
Scheme 3 3H-1,2-Dioxole Decomposition[6]
In contrast to 49 which contains a peroxide unit, the corresponding system 1, which contains an 1,3-arrangement of oxygen atoms is known. Even so, compounds of type 1 are extremely unstable and can only be synthesized if additional stabilization by donor substituents, or by benzoannulation is present.[7] Apparently, the cationic ring is perturbed by the two highly electronegative oxygen atoms, but this perturbation is reduced, if one ring oxygen is replaced by a sulfur and 1,2-derivatives 3 can be isolated. Similarly, donor-substituted 1,3-oxathiolium salts 4 are moderately stable.
The inclusion of two ring sulfur atoms, as in the heterocycles 10–13, leads to stable and generally crystalline salts. In line with the aromatic character of these ring systems, X-ray data confirm the presence of a planar five-membered ring and of bond delocalization. The formation of triheterapentalenes 52 represents a special case, in which the bicyclic system contains a three-coordinated λ4-sulfur (or selenium, or tellurium) atom Y and vicinally disposed heteroatoms X and Z (Scheme 4). These compounds are heterocyclic analogues of the bicyclic pentalene dianion.
Scheme 4 Heteropentalenes
The introduction of selenium or tellurium atoms into five-membered hetarenium systems results in reduced stability. Thus, simple 1,2-ditellurolium salts are known only in solution. Structurally, hypervalent selenium (or tellurium) with three-center, four-electron bonding appears to be involved in systems with a vicinal oxygen ring atom (Scheme 5, 53B). Nevertheless, the nomenclature used to describe them is based upon the resonance structure 53A.
Scheme 5 Structural Representation of Oxaselenolium and Oxatellurolium Systems
1,2-Thiaselenolium, 1,2-thiatellurolium, and 1,2-selenatellurolium salts appear to be unknown. However, the selenatellurolium fragment can be found in the nonaromatic heterocycle 54 (Scheme 6).[8]
Scheme 6 The Selenatellurolium Fragment in a Nonaromatic Heterocycle[8]
In contrast to the charged systems 1–23, the heterocycles 24–48 show features of more typically aromatic compounds, i.e. the ease by which electrophilic substitution occurs, and little tendency to undergo addition reactions. The monocycles are formally derived from benzene and all, including isoselenazoles, are stable under normal conditions. The corresponding bicyclic systems may be considered as derivatives of naphthalene, but two sets of heteronaphthalenes are possible, depending on whether a chalcogen atom (55A) replaces a formal lateral ethene unit, or whether this formal exchange affects the C1—C2 unit (55B) (Scheme 7). The former type displays an efficient aromatic 10-π electron delocalization with a quinoid double bond arrangement in the carbocyclic ring.
Scheme 7 Heteronaphthalenes
There has been some controversy about applying the principles of aromaticity to heterocycles, but even from a qualitative standpoint the systems in question differ widely in double-bond delocalization and reactivity. Scheme 8 shows a rough order of resonance stabilization and stability.
Scheme 8 Order of Increasing Resonance Stabilization and Stability
The presence of a ring nitrogen makes the hetarenes basic but, with the exception of benzothiazole (35, pKa 7.84),[9] the parent ring systems are all less basic than pyridine (pKa 5.22) as shown in Scheme 9. As none of the systems have a pronounced sensitivity to acid, their basic character allows their extraction and isolation from mixtures by treatment with acid.
Scheme 9 Parent Ring Systems in Order of Increasing Basicity
Hetarenes 24–48 are also weak acids. For the 1,2-diheteroatom systems, metalation and H/D exchange occur in different positions (Scheme 10). In the 1,3-systems, the proton at C2, located between the heteroatoms, is the most acidic (pKa of oxazole 20 ± 2).
Scheme 10 Most Acidic Sites
In spite of their aromatic character, the heteroatom—heteroatom bond reduces the stability of hetarenes 24–26, 31–33, 36, 37, 40, 41, 45, and 46. This bond is usually the point of fission, both on thermolysis and photolysis, but in most cases it is also readily cleaved under reductive, and even oxidative, conditions. This bond cleavage is exploited in synthesis, particularly for derivatives of isoxazole (24), where it allows ready access to 4-amino-3-en-2-ones and further to 1,3-diketones.[10,11] In derivatives of 2,1-benzisoxazole (26) a similar bond cleavage is used to form 2-acylarylnitrenes,[12] or 2-(aminoaryl)ketones, both of which are important intermediates for the syntheses of 1,4-benzodiazepines (cf. Scheme 11).[13]
Scheme 11 Isoxazoles – Bond Cleavage[10–12]
The presence of an acidic hydroxy, sulfanyl, or amino substituent next to a ring nitrogen allows two tautomeric forms 56A and 56B.[46] By analogy, a vinylogous arrangement leads to the alternatives 57A and 57B and, in addition, 57C (Scheme 12). In most cases, when X = O or S, the (thio)lactam form 56B predominates, i.e. the possibility of amide or thioamide resonance overrules aromatic resonance stabilization. However, in the crystalline state or in nonpolar solvents either form may be preferred, or an equilibrium is established (as in the case of isoxazoles).[14] Compounds with an exocyclic primary or a secondary amino group (X = NR1) usually exist in form 56A, rather than as imino derivatives 56B, although exceptions such as 58 are known.[15] In this volume, tautomeric preferences are ignored when the syntheses of compounds 56 and 57 are considered.
Scheme 12 Substituent Tautomerism in Azahetarenes[14,15]
Among the reactions of the uncharged hetarenes, electrophilic substitution reactions deserve special interest as being typical of aromatic compounds. In fact, the majority of these hetarenes undergo smooth displacement of hydrogen when reacted with electrophiles, usually halogen or nitrating agents. An exception is oxazole (27), which has a particularly low tendency to participate in SE reactions. The preferred site of electrophilic attack depends on the hetarene and also on the presence of other substituents. Benzo derivatives are normally attacked at the carbocyclic ring, but an exception is observed in the chlorination of benzothiazole (35), which is attacked at C2 as well as C6 (Scheme 13).
Scheme 13 Regioselectivity of Electrophilic Substitution Reactions
All the cationic hetarenes 1–23 react readily with nucleophiles, implying that the counterion should be a non-nucleophilic species, such as tetrafluoroborate or trifluoromethanesulfonate. The primary addition product may be unstable. For example, in most cases when 1,2-dithiolium systems 59 are the starting materials, sulfur-containing 61 or sulfur-free ring-opened products 62 are formed via 60.[16] The addition of nucleophiles to 1,3-dithiolium salts 63 gives useful derivatives 64, making the salts 63 valuable synthetic intermediates (Scheme 14).[17]
Scheme 14 Reactions of Hetarenium Systems with Nucleophiles[16,17]
Halogen-substituted uncharged hetarenes normally undergo smooth displacement reactions with nucleophiles. Alternatively, the nucleophile may form an adduct that may subsequently undergo ring opening. Addition is favored when the substrates are N-alkylated heterocycles, e.g. 2-alkylisoxazolium salts (Scheme 15).[18] The same activation to addition applies to oxazoles,[19] although oxazoles already show a pronounced tendency to take part in addition reactions, including cycloadditions. Thus, a Diels–Alder reaction with singlet oxygen allows the use of oxazoles as masked triacylamines (Scheme 16).[20,47]
Scheme 15 Addition Reactions of Organometallics to Isoxazoles[18]
Scheme 16 Oxazoles as Masked Triacylamines[20]
Derivatives of 2,1-benzisoxazole (26) and -benzisothiazole (33), containing quinoid carbocyles, seem ideally suited as dienes in Diels–Alder cycloadditions. However, 10-π aromatic resonance makes 26 and, in particular, 33 poor dienes. By contrast, derivatives of 1,2-thiaphosphole (36) do behave as dienes, although dienophilic reactivity is observed for derivatives of 1,3-benzoxaphosphole (30).
The family of ortho- and peri-fused naphthalene derivatives 65 includes representatives where X and Y are both chalcogen atoms, or a chalcogen atom and a nitrogen. However, a description of their chemistry is beyond the scope of this volume. Scheme 17 serves as a guide to the literature.[21–45]
Scheme 17 ortho and peri-Fused Naphthalenes with a Chalcogen-Containing Heterocyclic Component[21–45]
| Ring Atom X | Ring Atom Y | Synthesis Ref | Chemical or Physical Properties Ref |
|---|---|---|---|
| O | S(O) | [21] | [22] |
| O | SO2 | [23] | [24] |
| S | S | [25–32] | [22,33] |
| S | S(O) | [22,33] | [22,32] |
| S | SO2 | [26] | [27] |
| SO2 | SO2 | [34] | [32] |
| S | Se | [31,35] | – |
| S | Te | [36] | – |
| Se | Se | [29–31,37–39] | – |
| Se | Te | [36] | – |
| Te | Te | [31,35,40–42] | – |
| SO2 | NH | [43] | [44] |
| Si | Si | [45] | – |
References
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