Azulene, Reactivity, and Scientific Interest Inversely Proportional to Ring Size; Part 1: The Five-Membered Ring

Abstract

The lack of azulene symmetry with respect to the axis perpendicular to a molecule creates an asymmetry of the electronic system, increasing the charge density of the five-atom ring and favoring its electrophilic substitutions. The increased reactivity of this ring has contributed to ongoing interest about the syntheses in which it is involved. The aim of this review is to present briefly and mainly in the form of reaction schemes the behavior of this system. After a short chapter that includes the research until 1984, subsequent research is presented as generally accepted chapters and subchapters to describe the behavior of the azulene system: metal free catalyst reactions; reactions catalyzed by metals; various azulene five-ring substitutions. The author insists on reaction yields, and in some cases considers it useful to present the proposed reaction mechanisms.

1. Introduction

Used as a dye since the 16th century and synthesized by Lavoslav Ružička in 1937, azulene is still of great interest for researchers. The structure and physicochemical properties of azulene compounds contribute to this, as well as a series of their uses in various fields of activity. Therefore, it is not surprising that many scientific papers have appeared about azulenes: communications, articles, reviews, patents and chapters of monographs. Some of them refer to the structure and chemistry of azulene and others to the uses of azulene compounds. Thus, a large number of azulene derivatives have real or potential uses as anti-inflammatory [1], antitumor [2], and bioimaging material [3] as dyes [4,5], for solar cells [6,7,8], organic semiconductors, or modified electrode agents [9].

Much richer is the literature that deals with the chemistry of the azulenes, and any attempt to exhaust this subject would far exceed the volume of a book. A substantial chapter on the research in this field conducted until 1984 was published by Zeller in the Houben–Weyl encyclopedia [10]. That chapter included the synthesis of each of the two azulene rings as well as their reactions. After this contribution and until now, several azulene-containing reviews have appeared, and most of them are mentioned below.

The present review is to some extent a continuation of a review recently published by the author [11]. The lack of azulene symmetry with respect to the axis perpendicular to a molecule creates an asymmetry of the electronic system, increasing the charge density at the five-atom ring compared to the seven-atom ring. This permanent displacement has as a consequence an increase in the nucleophilic reactivity of azulene compared to naphthalene, with symmetry towards both x and y axes (Scheme 1). The highest negative charge density is located at C1 and C3 from HOMO calculations [12,13], and the molecular symmetry of azulene framework with respect to the x-axis makes identical the behavior of these positions [11] (Scheme 1). The involvement of the seven-membered ring as a tropylium ion in the stabilization of substitution intermediates, as shown in Scheme 1, favors supplementary electrophilic azulene substitution. Nucleophilic and radical substitution at azulenes is less common and is encountered especially at the seventh ring and only seldom at the fifth ring. Because of the interest in the study of five-ring chemistry, which was much more intense compared to that for seven-ring chemistry, the behavior of the first ring is analyzed in this review, that of the seven-atom ring being in progress.

The presentation of the material is a little different from the general organization found in other reviews, being based mostly on reaction schemes in which the reaction conditions and the yields in the products are given. It is assumed that this will facilitate the quick finding out of some concise information on a synthesis. Of course, other elements related to the reaction are also detailed, and sometimes the reaction mechanisms are discussed.

It is useful to begin with the very summary presentation of the material proposed in Zeller’s review about the behavior of five-atom rings. Besides the historic interest, some of the reported procedures continue to be used today in the synthesis of azulene compounds. Therefore, in Scheme 2 and Scheme 3, some particular aspects resulting from Zeller’s review, accompanied by brief comments about them, are briefly highlighted.

Scheme 2 shows the binding of azulene to carbon, halogen, nitrogen or sulfur atoms of the substituents (routes A, B and C, respectively). Some procedures described the generation of the electrophilic agent in the presence of a catalyst (A1, A2, A5), while compounds with efficient electrophilic activity, such as picryl chloride (A3) or electron-rich alkenes (A6), operate without the intervention of a condensing agent. Vilsmeier synthesis (A4) for formylation or acylation of azulenes by the reaction of dialkylacylamides in the presence of POCl₃ is still frequently used to obtain azulene compounds. The sensitivity of azulene compounds to halogens eliminates direct halogenation processes. Instead, halogenosuccinimide (NXS) is frequently used as halogen-substituent agent for hydrogen (B1). Scheme 2 shows also the bond generation between azulene and nitrogen and sulfur atoms (C). It should be noted that diazonium coupling (C1) continues to be a widely used procedure for the generation of azo derivatives of azulene with multiple technical purposes.

The second series of substitutions on the azulene five ring, described by Zeller, refers to the reaction of preexisting substituents (Scheme 3). As previously seen, the substitution at positions 1 and 3 is carried out relatively easily in an electrophilic way, and due to the lower electron density at position 2, it is expected that the substitution at this position will occur with more difficulty and mainly by a nucleophilic mechanism [14]. Some examples of electrophile attack at this position are however known. Thus, in order to improve the electrophilicity of this position, the presence in positions 1 and 3 of electron acceptors as CO₂H, CO₂Et or CN is favorable, and thus halogens, methoxy or diazo groups at position 2 could be replaced. In Scheme 3 are also introduced examples of azulene couplings with substituent elimination in different reaction conditions, as mentioned by Zeller. As can be seen, the reported coupling yields are low, though somewhat better in the presence of the CO₂R as substituent.

Most of Zeller’s early described procedures refer to obtaining azulenes substituted mainly with atoms or relatively simple functions. Furthermore, severe reaction conditions and/or modest obtained yields limit the use of these processes in many cases.

The ongoing increase in interest in the chemistry and utilization of azulene compounds is reflected by the continuous accumulation of information on this subject. As a result, the literature concerning azulene compounds has been greatly enriched with articles and comprehensive reviews. Soji and Ito group contributed mainly to the dissemination of information on the synthesis of heteroaryl-substituted azulenes. The overview about the preparation of functionalized azulenes for electrochromic applications presented by the authors in 2011 [15] was followed by reviews from 2018 [16] and 2020 [17], which deal with the synthesis of heterocycle-substituted and fused azulenes, starting with the construction of the two rings of the azulene system or with azulene substitution. In a review on the activation of C-H bond of the five-membered azulene ring by metals [18], Shi and coworkers showed the functionalization of this ring by a series of substitution reactions. The paper of Zhuang et al. [12] presents the synthesis of azulene-based aromatic compounds for optoelectronic and energy applications. Razus et al. recently published a number of reviews on the obtaining of azulenes [11,19,20,21], Elhawy’s article from 2021 discussed the synthesis of azulene derivatives through Pd-catalyzed coupling techniques [22] and Gao condensed information about the applications of azulene-based π-functional materials [23]. From this, it follows that most of these papers were directed towards particular and well-defined targets, for example, certain classes of compounds, synthesis routes, technical uses, etc.

This review selected and organized as much as possible the disseminated information about the very interesting chemical behavior of the five-membered azulene ring. In the following, it was preferred to cite the original materials and not the reviews, so that the reader can quickly access the desired material. From the widely reported results were selected only those considered more interesting or recently published, taking into account some structural features of the starting azulenes and the particularities of the synthesis routes. Therefore, this work is addressed especially to those who want a brief overview of this field or to beginners in azulene chemistry.

2. Starting Azulenyl Reagents

Before going through reactions in which the five-atom azulene ring is involved, some living groups, more often encountered in syntheses, are depicted in Scheme 4. Of course, the unsubstituted five ring of azulenes is frequently chosen in substitutions of the hydrogen atom (entry 1).

The halogenated azulenes are used less often because, as already mentioned, the halogenation (mainly with NXS; entry 2 and 3) produces a mixture of mono- and bis-halogenated derivatives. Other starting azulenes, for example, the triflates (entry 4 in Scheme 3), are unstable and require specific reaction conditions. Several examples of living-groups at position 2 that will be used for other starting compounds substituted in this position are also shown in the scheme. All these compounds together with other raw materials are discussed in more detail during this review.

3. Reactions of Azulene Five Ring

Along with other possible classifications for the azulene five-ring substitutions, these reactions can be also divided into uncatalyzed and catalyzed. As it appears after Zeller’s report and to some extent in recent research, the use of the uncatalyzed route was quite rarely encountered. The results communicated lately show a focus on the reactions catalyzed by metallic compounds, which generally take place in milder conditions and with higher yields than those in which they are not present. In addition, a number of the proposed procedures lead to valuable products whose synthesis is not possible by other routes. Therefore, only several examples from the series of reactions without a catalyst will be treated first, followed by a more consistent chapter dealing with metal-catalyzed reactions.

3.1. Metal-Free Catalyst Reactions

The reactions that are the subject of this chapter are divided into electrophilic and nucleophilic substitutions—S_EAz and S_NAz. Some other reaction routes are also briefly analyzed. Within this division, attention was paid to the behavior of the positions belonging to the five-azulene ring.

3.1.1. Azulene Electrophile Substitution, SEAz

The syntheses with which the chapter begins, start from two strong electrophiles, salts of heteroaromatic compounds. The first synthesis (Scheme 5) [24], somewhat older, uses a pyridinium salt, 5.1. Uena et al. intended to fluorinate azulene with this salt, known as a fluorination agent, but instead of halogenation, an electrophilic substitution took place with the formation of compound 5.2 as the major product.

Starting from pyrylium salts, 6.2, and azulenes, 6.1, with different substituents, Razus et al. [25] obtained a rich series of pyrylium salts substituted with azulene, 6.3 (Scheme 6). The activation of the substitution due to the positive charge of the heterocyclic ring is noteworthy. It is also worth noting that the salt with azulene substituted in position 2 of the pyrylium system, 6.4, was prepared in a similar way. The pyrylium salts 6.3 were transformed in the corresponding pyridines [26,27].

The obtaining of azulenes substituted in position 1 (and 3) with pyridine was reported in articles published by Soji, Ito, Morita and all. With the help of triflic anhydride (Tf₂O), pyridine was transformed into a strong electrophile, trifluoromethanesulfonyl pyridiniumtrifluoromethane sulfonate (TPT), depicted in Scheme 7 [28]. The nucleophilic attack of azulene can take place in position 2 of the pyridinium salt with the opening of the pyridine ring or in position 4 in a large excess of TPT with the obtaining of additional compound 7.1.py. The aromatization that followed takes place in the presence of a base and gives 7.3.py. The described procedure was extended to a large number of heteroaromatics (Scheme 7) [29]. Along with the disubstituted product, 7.4, the monosubstituted one, 7.3, is also obtained. As seen in Scheme 7, the ratio between the products is largely dependent on the ratio of the participants in the reaction.

Triflic anhydride was also reported as activating reagent in the Vilsmeier–Haack-type arylation depicted in Scheme 8 for the synthesis of 1-(indol-2-yl)azulenes, 8.2 [30].

Reissert–Henze functionalization of N-containing heterocycles, depicted in Scheme 9, is based on activation with Tf₂O of the starting heteroaryl [31]. Whereas trifluoroacetic anhydride (TFAA) only gives the substitution product 9.1, the compounds of 9.2 result after substitution and reaction with NEt₃ in MeCN.

The difference in activation with Tf₂O and that with TFAA is also illustrated in Scheme 10. The monosubstituted compound 10.1 was formed after attack on sulfoxide in the presence of TFAA, whereas compound 10.2 with position 1 and also 2 occupied resulted with Tf₂O [32]. The subsequent nucleophilic substitution (S_N2) at the methyl group on the sulfonium ions 10.1 and 10.2 with 1-azulenyl sulfide, acting as a leaving group, gives the sulfides 10.3 and 10.4.

Trifluoroacetic anhydride activates the tetramethylenesulfoxide in the reaction depicted in Scheme 11 [33], and the product 11.1 will be found further as starting compound in the Suzuki–Miyaura coupling reaction.

In the following, the behavior of compound 12.1, which undergoes a S_EAz reaction at position 2, is analyzed (Scheme 12) [34]. The suitable structure of this compound with two protecting groups at positions 1 and 3 and with a strong electron donor, dimethylamino, at azulene position 6 allows the electrophilic attack at position 2. The substitution is performed by the efficient electrophile (TPT) depicted in Scheme 7. The intermediate compound 12.2 was aromatized to produce 12.3.

3.1.2. Azulene Nucleophilic Substitution, S_NAz

The increased electron density at the azulene five ring requires special conditions to allow nucleophilic substitutions, and if they occur, they will attack position 2, the poorest in electrons. Thus, the substitution of chlorine from position 2 requires electron acceptor groups in positions 1 and 3 of azulene, for example, CO₂Me, 13.1(R = CO₂Me), and highly nucleophilic reagents as the amines depicted in Scheme 13, such conditions were used in 1962 by Nozoe [35]. Hydrazine and hydrazo derivatives of azulenes 13.5 and 13.6 were also taken into account as starting nucleophiles. Later, Soji and coworkers repeated this substitution, but instead of ethanol used by Nozoe as reaction medium, they used neat condition at 80 °C or 150 °C in a sealed tube [36]. The obtained yields were higher than those previously reported. Interestingly, the substitution occurs also in the absence of the activating groups, though only with strong nucleophilic amines and with a decrease in yield (Scheme 13). The S_NAz of 13.1 with phenylhydrazine followed by the oxidation of the intermediates 13.3 or 13.4 gave 2-phenylazoazulenes 13.7 or 3.8.

3.1.3. Metalation of Position 2 and other Substitutions at This Position

The ortho-coordination of halogen atoms situated at azulene positions 1 and 3 increases the nucleophilicity of position 2 along with an increase in acidity of hydrogen in this position [37]. Thus, the proton belonging to this position can be replaced by lithium using lithium tetramethylpiperidide (LTMP) (Scheme 14), and the formed lithiated compound, 14.2, was used as starting material for several other interesting derivatives (for examples: 14.3–15.5). The lithiated compound 14.2 was also prepared following the sequence 14.1–14.7–14.6–14.2. As noted above, the increases in negative charge at the five-atom ring produced by the 6-dimethylamino group in 14.7 allowed the lithium substitution with iodine, as in 14.6. The compound 14.6 was transformed in the deuterated product 14.10 through the organomagnesium intermediate, 14.9, as shown in Scheme 14. Recently, Bredihhin and Dubovik substituted the MgBr group in 14.9 with ZnCl, giving the compound 14.8, and as shown later, used this compound in the Negishi reaction [38]. As it results from Scheme 14, the SO₂Tol group has a similar influence on the azulene position 2 [39].

The 2-azulene boronate, 15.2, one of the starting materials in the Miyaura–Suzuki reaction was obtained as shown in Scheme 15, starting from 2-iodoazulene and passing through the intermediary 15.1 [37,40]. Previously, the generation of compound 15.2 was accomplished by metal catalysis.

Despite the difficulty of substitution of the azulene 2 position, a significant number of syntheses start from 2-halogenated compounds. Scheme 13 shows, along with Nozoe’s older 2-halogenoazulenes syntheses (route A) [23], the use of the boronic compounds, 16.3, for obtaining such compounds (routes B and C in Scheme 16) [41].

3.1.4. Radical Cation Route

Radical or radical cationic reactions are less common in the chemistry of azulenes. An example of such a reaction is the production of 1,1′-biazulenes. Over time, a series of syntheses of 1,1′-bisazulenes have been carried out [42,43]. Unlike the difficult reaction conditions reported for these syntheses, such as high temperature or transition-metal reagents, the route proposed by Soji et al., depicted in Scheme 17, is more advantageous [32,44]. The synthesis starts from the sulfide 10.3 (Scheme 10), and the formed sulfoxide 17.1 reacts with acid to give the compound 17.3 as a result of the formation of a radical cation that subsequently dimerizes. Unlike other syntheses proposed for the realization of 1,1′-bisazulenes, this route does not start from complicated azulenes, avoids the presence of metals as catalysts, and takes place with good yield. In addition, the products obtained can be used to build other molecules, such as dialdehyde 17.4.

A radical mechanism was postulated in 2000 by Razus for the oxidative dimerization of azulene azulene-1-azoarenes 18.1 [45] and N-(azulen-1-ylmethylene)arylamines 18.6 [46] in the presence of FeCl₃. After the loss of one electron, the dimerization of radical cation [18.1]⁺ takes place in position 1 of azulene if the phenyl is substituted, route a in Scheme 18, or in position 4 of the phenyl, route b. As shown in Scheme 18, route a produces three oligomers 18.3, whereas on route b, the compound 18.5 results. Similar behavior was noted in the case of the Schiff base 18.6. If the yield of compounds 18.3 is more modest, the oxidation of 18.6 proceeds almost quantitatively. This is important because the product 18.7 can be transformed in the dialdehyde 18.8, a valuable starting material for the syntheses with high yields of the interesting precursor of 1,1′-bisazulenes 18.9Q [47].

3.2. Reactions Catalyzed by Metals

Interest in azulene reactions catalyzed by metal compounds is revealed by the particularly large number of articles and reviews published in this field. The interest raised in this matter is attributed to the fact that reactions take place in much milder conditions and usually with very favorable yields. However, the price of the catalysts used, as well as some ecological restrictions in relation to them, must be taken into account.

3.2.1. Aluminum Chloride as Catalyst

The use of AlCl₃ in reactions of azulenes can rarely be found in the literature due to the sensitivity of many azulene compounds that do not resist in the presence of this catalyst. However, at the beginning of this chapter, a recent electrophile ipso reaction catalyzed by AlCl₃ is presented (Scheme 19). The final acylation mixture contains amounts of mono- and disubstituted products, 19.1 and 19.2, depending on the ratio of azulene:catalyst, and the tendency toward double substitution is obvious [48].

The purpose of this subchapter is to present azulenes cross-coupling reactions. Unlike the published reviews that target this very field [11,15,16,17,20,21], our goal will be the reactions that take place at the five azulene ring. As already written, the presentation is mostly graphic with schemes including the reaction conditions and yields, and where considered necessary, the proposed reaction mechanisms are presented.

3.2.2. Cross-Coupling Reactions

Probably the most accessed field in metal catalysis is the cross-coupling reaction that produces azulenes substituted with aromatics. A number of metal complexes, especially those belonging to the class of transition metals, have been successfully used to activate azulene positions in order to catalyze their substitution. The importance given to this research is related to both the scientific interest and the possible technical uses of the synthesized compounds.

A. Reactions catalyzed by Pd(OAc)₂. Dyker et al. realized the palladium-catalyzed arylation of azulene with iodobenzene or 4-chloronitrobenzene [49] and Zhao et al. arylated guaiazulene C-H bonds, as shown in Scheme 20 [50]. As in the previous procedures, the cross-coupling reactions carried out by Murai et al. used Pd(OAc)2 as Pd source (Scheme 20) [51]. As ligand for Pd, Murai added 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) to the reaction mixture, which also comprised pivalic acid (PivOH) and N,N-dimethylacetamide (DMAc). The Murai procedure takes place with the obtaining of comparable amounts of mono- and bis-product 20.7:20.8, and substitution in position 2 was not observed. Murai also obtained the dimer 18.9H in a single step, though the yield was modest (for comparison, see Scheme 18).

In more recent comprehensive studies, Soji et al. dealt with the substitution of 2-haloazulenes with thiophene derivatives [52,53]. For obtaining the products shown in Scheme 21 they used the procedure described by Schipper [54]. It should be mentioned that on routes 3 and 4, along with monosubstituted compounds, small amounts of secondary products appear as a result of bis substitution. These compounds were also obtained by the substitution of monosubstituted compounds (see route 5 in Scheme 21).

B. Reactions catalyzed by CuOAc. The difficulties encountered when introducing the amino group to the five-azulene ring are known, and therefore the synthesis proposed by Li and Wang [55] is interesting and will be examined further. As shown in scheme, 22 O-benzoylhydroxylamines, 22.2, were the amination reagents of 2-azulenol 22.1. As a result of the study, a series of interesting products, described in Scheme 22, were obtained. The catalytic cycle proposed by the authors is reproduced in Scheme 23.

In the first step of synthesis, the lithium salt, 23.1, was formed, then it replaced the ligand, obtaining the Cu(I) salt, 23.2. This step is the oxidative addition of 1-benzoylhydroxylamine, which produces the Cu(I)–Cu(III) transformation, 23.3. The equilibrium between intermediates 23.3 and 23.4 is shifted rapidly towards the last intermediate. This N-centered radical attacks azulenol at the ortho-position to give 23.5. For this path, the authors assume “a pseudo five-membered ring through inner-sphere electron-transfer model, and at the same time to regenerate CuI to close the catalytic cycle. The rearomatization of D provides the final product 22.3”.

C. Stille cross-coupling reactions. Although this condensation is found in the literature mainly for obtaining bonds in the 6 azulene position, there are also examples for the substitution of positions in the five azulene ring, and some of these will be further discussed. The presence of copper as CuI brings a significant increase in the reaction yield and is therefore used in many Stille cross-couplings.

The examined Stille reaction occurs between the halogenated azulenes at five-ring and tri-n-butylstannyl compounds in the presence of the palladium source (Pd(PPh₃)₄ or Pd₂(dba)₃) (dba: dibenzylidenacetone) (Scheme 24). A large number of 1,3 disubstituted products generated by Stille cross-coupling are detailed in the literature. Some of these compounds are shown in Scheme 24: 1,3-bis(thien-2-yl)azulene, 24.1 [56], (azolyl)azulenes, 24.(2-4) [57], 1,3-di(2-pyridyl, 3-pyridyl-3-pyridyl)azulenes, 24.(5-7) [58,59], 1,3-di(2-pyrrolyl) azulene, 24.8 [60], 1,3-bis(benzothien-2-yl)azulene, 24.9 [61].

The simplified mechanism of the Stille reaction based on data from the literature [62,63,64] is adapted in Scheme 25 to the reaction of 1,3-diiodoazulene with 2-(tri-n-butylstannyl)thiophene. The oxidative insertion of Pd between the halogen and the azulene ring activates the reactive positions 1 and 3 of azulene. Then, the electrophile reaction was favored by the transmetalation of organometallic nucleophiles. The reaction is promoted by the activation of organic electrophile—in our case, the azulene compound—by oxidative introduction of Pd. Then, the electrophile reaction is favored by the transmetalation of organometallic nucleophiles. The copper participation changes the stannyl group and the newly formed metallic compound seems to be more reactive or is at high concentration in the reaction medium [65].

A somewhat more special example is illustrated in Scheme 26. The synthesis of 2,5-(diazulen-1-yl)phosphole P-oxide, 26.2, was performed by the reaction of 2-iodoazulene and 2,5-bis(tributylstannyl)phosphole, 26.1 [66].

With the aim of activating azulene position 2,2-bromoazulene reacted with bis(tri-n-butyltin) under Pd(0) catalyzed conditions. Instead of producing the attempted organometallic compound, 2-stannylazulene, 27.1, this product results in only a 10% yield together with 2,2-biazulene, 26.2, in 48% yield (Scheme 27) [67]. For this behavior, the authors supposed either high reactivity of metalated azulene towards 2-bromoazulene or the homocoupling of the metallized compound under the reaction conditions.

It is noteworthy that Stille coupling has also been used to obtain conjugated copolymers with optoelectronic properties [68]. One of the attempts is represented in Scheme 28 [69], where m and n in the polymer 28.1 depend on the ratio of incorporation of dihalogenated azulene regioisomers.

D. Negishi and Kumada–Tamao–Corriu cross-coupling. The family of palladium-catalyzed cross-coupling reactions includes Negishi cross-coupling as an alternative to the Stille reaction. Here, Sn was replaced by Zn in the organometallic reagent, which is coupled with halogenoazulenes in the presence of the Pd catalyst. Thus, Oda et al. reported the preparation of 1,3-di(2-pyridyl)azulene, 29, (Scheme 29) [58] starting from 1,3-dihalogenoazulene and 2-pyridylzinc bromide in the catalytic presence of Pd(PPh₃)₄, with higher yield than that reported by Wakabayashi et al. for the Stille procedure used for the same coupling [59].

Later, Dubovik and Bredihhin developed this cross-coupling reaction using a wide variety of organozinc compounds, even azulenylzinc derivatives, which were first synthesized by the authors (Scheme 30). At the same time, the nature of the palladium catalyst was diversified [38,59,70,71]. The organozinc compounds were obtained by treating the halogenated derivative, preferably iodide, with turbo Grignard reagent (iPrMgCl.LiCl), followed by transmetalation with ZnCl₂. The reactions were performed with (Pd(dba)₂) as palladium source with a ligand in THF. As ligand, SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) was preferred instead of PPh₃.

As noted above [74], the azulene moiety can also act as the organometallic component Scheme 31. This coupling variant can be used if the organometallic compounds with other organic systems (as metalated pyridines and pyrimidines) are difficult to obtain.

The Kumada–Tamao–Corriu synthesis that is exemplified next is similar to the Stille reaction, the metal substituent Sn(nBu)₃ being replaced by MgCl. Thr reaction was performed with (5-alkylthiophen-2-yl)magnesium bromides, 32.1, and 1,3-dibromoazulene and was catalyzed by Ni(dppp)Cl₂ (Scheme 32). The main catalytic cycle is similar to that proposed for the Stille reaction [72]. The product mixture contains—besides the disubstituted product, 32.2—the monosubstituted one, 32.3 [73,74]. Further, the monosubstituted azulene may react with another organomagnesium reagent, affording compound 32.3, used for preparation of stimuli-responsive conjugated copolymers with azulene and bithiophene units in the polymer backbone.

E. Suzuki–Miaura coupling. Perhaps one of the most common cross-coupling reactions is the Miyaura–Suzuki reaction [75], so it is not surprising that a great number of reviews from the azulene field paid attention to this topic. For this reason, only a few references will be pointed out, mainly for information, especially the more recent ones. As the starting materials in these reactions, boronic compounds may contain the boronic substituent either to azulene or to the compound chosen to react with it. The boronic derivatives replace other substituents, mainly halogen, in the presence of a catalyst and ligand.

Both borylation reagents, boronic acids, 33.1, and pinacolboranes, 33.2 (Scheme 33), were used with the specification that compound 33.2 sometimes produces secondary reactions [33]. The known instability of 1-halogenoazulene suggested the idea of coupling boronic compounds with 1-azulenesulfonium salt 11.1 with acceptable yields, as shown in Scheme 33.

The stability of 3-bromoazulenes 34.1 allowed the generation of photoswitch compounds 34.3 (Scheme 34) [76]. Compound 34.2 is involved in the synthesis. This reagent was used without separation after the treatment of the corresponding dihalogenated derivative with B(OBu)₃.

The stability of halogenated azulenes in position 2 favors them for cross-coupling reactions with boronic compounds. In Scheme 35, the starting 2-iodoazulene reacts with 5-chlorothiophene-2-boronic acid pinacol ester or thienothiophene diboronic acid ester 35.1 or 35.2, affording 2-(2-azulenyl)-5-chlorothiophene 35.3 and 2,5-di(2-azulenyl)-thieno [3,2-b]thiophene, 35.4 [77]. The dimerization of compound 35.3 gives 35.5. Both 35.4 and 35.5 are tested as OFETs (organic field-effect transistors).

After several reactions presented above in which azulene derivatives react with boronic derivatives, reactions in which the boronic group is linked to the five azulene ring follow. Again, it must be remembered that a large part of the research undertaken in this field refers to substituted products at the seven ring of azulene.

In Scheme 13, two reactions of 2-azulenylboronate were anticipated, and in Scheme 36 and Scheme 37 are exemplified the reactions starting from both isomers of azulenylboronate. Scheme 36 briefly represents the coupling performed by Wakabayashi et al. [59] between these isomers and 2-, 3-, and 4- bromopyridines with moderate to very good yields.

Another heterocyclic compound, furan, found in the structure of 3,6-bis(5-bromo-2-furyl)pyrrolo[3,4-c]pyrrole-1,4-dione, 37.1, was coupled with the two isomers of azulenylboronate, and the resulting products, 37.2, have chromophore properties [78].

Although using only azulen-2-ylboronate, Ito et al. obtained a large number of compounds in the cross-coupling with polybrominated aromatic compounds 1,2-di-, 1,4-di-, 1,3,5-tri-, 1,2,4-tri-, and 1,2,4,5-tetrabromobenzene (Scheme 37) [40].

In an article that refers to the synthesis of 2-halogenozulene, the authors also describe the synthesis of 2,2′-bisazulene, 43, with the highest yield starting from azulen-2-ylboronate and 2-iodoazulene, as shown in Scheme 38 [41]. Scheme 17 and Scheme 18 show the obtaining of isomer 1,1′, 18.9 [32,44,47] and the isomer 2,2′ appears in Scheme 27 [67].

Among the procedures proposed by Kurotobi et al. for azulene substitution in position 2, that of 2-aminoazulene (Scheme 39), a building block for the synthesis of other molecules, is also present [79]. The synthesis starts from azulen-2-ylboronic acid, which is coupled with phtalimide and the intermediate product, 39.1, is transformed in the amine 39.2.

Recently, Gao et al. realized the synthesis of the wonder azulene-embedded [n]helicenes 40.6 and 40.7, in which one terminal azulene subunit was fused with n-2 benzene rings, compounds with valuable physicochemical and optical properties [80]. Scheme 40 depicts the sequential Suzuki–Miyaura condensation of starting 40.1 to intermediates 40.4 or 40.5 followed by cycloisomerization, which leads to the products. The same scheme shows the preparation of two starting reagents, 40.1 and 40.3.

Murai et al. described compounds with the structure shown in Scheme 41 somewhat related to the [n]helicenes presented above. After Suzuki–Miyaura coupling of azulen-2-ylboronate with aromatic aldehydes followed by Wittig condensation, the obtained intermediate 41.1 was cyclized and aromatized, affording 41.2 [81]. Similar azulene-fused linear polycyclic aromatic hydrocarbons azuleno[2,1-a]-phenanthrene, 41.3, and azuleno[2,1-a]-anthracene, 41.4, were generated in the same way. The azulene derivatives 4.1–4.3 have narrow bandgaps, excellent photooxidative resistance, and good solubility.

The spectacular meso-azulenylporphyrins 42.2 and 42.3 obtained by involvement of Suzuki–Miyaura coupling as shown in Scheme 42 [82], act as electron-donating and electron-accepting substituents toward Zn(II) porphyrin 42.4.

At the end of this subchapter, a short discussion on the steps of Suzuki–Miyaura cross-coupling is useful. Scheme 43 adapts to boronic compounds the general mechanism proposed by Miyaura [75]. A similarity should be noted between this mechanism and that described in Scheme 25 for Stille reaction. The difference consists in transmetalation, which here changes the boronic substituent of boronic reagent, instead of Sn(nBu)₃.

3.3. Various Azulene Five-Ring Substitutions

3.3.1. Azulene Alkynylation and Sonogashira–Hagihara Reaction of the 1,3-Diethynylazulene

The Sonogashira–Hagihara reaction occurs between ethynyl derivatives and halogenated compounds (X = I or Br). The ethynyl group can be substituted at the five azulenic ring, compound 44.1, or can be inserted into various suitable reagents, 44.3, as shown in Scheme 44. The yields of products 44.2 and 44.4 are very good [83].

The Sonogashira–Hagihara reaction afforded also the valuable compounds 45.1 [84] and 45.2 (Scheme 45) [85]. These linear π-conjugated molecules have optical properties and stimulus-responsive behavior.

In a large study undertaken by Shoji on the reaction of tetracyanoethylene with 1,3-bis(azulenylethynyl)azulenes, the intermediate 46.1 and the reagent 46.2, together with other similar compounds, were prepared with higher yields, as per Scheme 46 [86].

The ethynylation procedure proposed by Székely is particularly advantageous, starting directly from an unsubstituted azulene position (Scheme 47) and proceeding under mild conditions [87]. The proposed procedure is general, using triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX, 2), 47.1 as an efficient alkynylating agent. The use of Au as an activating metal instead of Pd should be emphasized.

The alkylation reagent in Scheme 48, 48.1, also introduces the triple bond, as in molecule 48.2. As in the previous reaction, an Au compound activates the substitution [88].

3.3.2. Various Reactions in the Presence of Rhodium or Nickel Compounds

The metal found in most of the catalysts and discussed so far was palladium, and only in a few examples are copper or gold present. Since these are not the only metals used for this purpose, in the following, the presence of other metals is also briefly exemplified. Thus, the alkylation with propargylic alcohols (see Scheme 48) occurs similarly when a thiolate-bridged diruthenium complex works as a catalyst, instead of the compound containing Au [89].

Taking into account the difficulties reported in the literature for the acylation of azulenes, Lee et al. achieved a synthesis that can produce azulene ketones with good yields [90]. In the first step, rhodium-catalyzed reaction between azulene and N-sulfonyl-1,2,3-triazoles, 49.1, affords the N-sulfonylaminoalkenylated intermediate, 49.2 (Scheme 49). The attempted ketones 49.3 result after the oxidative cleavage of the C=C bond of N-sulfonyl enamides 49.2 in the presence of Cs₂CO₃ in air and sunlight. A plausible mechanism for the last somewhat strange reaction step based on the involvement of air oxygen was proposed by the authors.

The conditions exemplified in Scheme 50 for the hydroarylation of azulene involve, besides the Rh catalyst, α-dicationic chelating phosphines, 50.1. The allyl-substituted azulenes 50.3 result in moderate yields after the reaction between azulene and diene 50.2 [91].

Nakatani et al. realized the alkylation of guaiazulene with the halogenated compound 51.1, as shown in Scheme 51, using a nickel compound, Ni(cod)₂, with dppp as ligand in the presence of a base. The reaction occurred with acceptable yield; however, unfortunately, both 1- and 2-alkylated isomers, 51.2 and 51.3, resulted [92].

3.3.3. Some More Special Reactions at the 5th Ring

Recently, Png et al. applied the peculiar ortho-arylation of benzoic acid procedure [93] to the similar azulenic acid 52.1 [94]. In this way a large variety of 2-arylazulenes 52.2 are synthesized (Scheme 52). To explain the course of the reaction, the authors assume that “the reaction likely proceeds through a carboxylate group directed C−H activation to form a putative palladacycle dimer intermediate which then undergoes oxidative addition by the aryl iodide to form a Pd(IV) intermediate (Scheme 52). Subsequent reductive elimination followed by decarboxylation yields the 2-aryl azulene products.”

Anderson et al. realized the reaction of azulene with aliphatic diazo derivatives already in 1965. The acidic medium or the light presence ensured a moderate yield for several products, one of which, 53.1, is shown in Scheme 53 [95]. The compounds substituted at 1 or 1 and 2 positions of azulene were realized by Carreras et al. by incorporation of carbene/nitrene in C-H bond [96]. The nitrene transfer from N-tosyliminoiodanes derivatives 53.2 to azulene or its functionalization with diazoacetates 53.3 in the presence of Rh or Cu catalysts (Scheme 53) generates the compounds 53.4 and 53.5, respectively. Under certain conditions, the disubstituted compound 53.6 is also formed.

Recently, Murfin et al. functionalized azulenes with cationic η⁵-iron carbonyl diene complexes [97]. To the three used electrophilic iron complexes, 54.1, azulenes were added, as depicted in Scheme 54, affording the products 54,2 with 43–98% yield. In the scheme, the pathway is exemplified for generation of the products with phenyl as substituent after photolytic decomplexation of addition products and aromatization of free diene: 54.2–54.3–54.4.

3.3.4. Heterocycle-Substituted and Fused Azulenes That Involve the Five-Membered Ring

Although Soji and Ito et al. have published comprehensive reviews on heterocycle-substituted and fused azulenes [15,16,17], to complete the topic proposed in the current review, some examples for the obtaining of these products will be given based on the most recent information. Syntheses in which the heteroaromatic system is substituted as such at azulenes were previously discussed. Apart from this pathway, the azulenes can be substituted with precursors of the heteroaromatic rings, and in a subsequent step they are transformed into the desired heteroaromatics. Another target of this subchapter is focused on the reactions affording derivatives where azulene is condensed with aromatic or heteroaromatic rings. Among the investigated reactions for the building of heterocycles substituted at the five-atom azulene ring, only recent examples are given below, namely, the generation of derivative containing the furan and pyrrole moiety. In addition to obtaining these compounds, the recent syntheses of several systems in which azulene is substituted with other heterocycles is also analyzed.

The 2-(Azulen-1-yl)benzo[b]furans, 55.1, were obtained via cross-coupling Sonogashira–Hagihara reaction of 1-ethynylazulenes with 2-iodophenol, followed by intramolecular cyclization of the produced intermediate, 55.2, as shown in Scheme 55 [98]. For the similar 2-(azulen-2-yl)benzo[b]furan, 55.3, the reaction starts from 2-ethynylphenol and 2-iodoazulene [99]. Scheme 55 shows the mechanism proposed by the authors for the discussed syntheses.

In the following, some multicomponent reactions are presented that allow the obtaining of azulenes functionalized with heterocycles. The reactions reported by Sato et al. afforded guaiazulene–heterocycle hybrids, 56.1 and 56.2, via a zwitterionic intermediate 56.3 [100]. Scheme 56 contains only two examples from a large number of compounds prepared in this way. Cyclic CH- acids, phenols, aldehydes or amines were used instead of benzaldehyde and 4-methoxianiline with acceptable yields.

To achieve the 3-(guaiazulen-3-yl)dihydro-1H-indol-4(5H)-ones, 57.1, with the pyrrolic system included in the molecule, Wang et al. proposed a three-component domino reaction [101]. The reaction starts from guaiazulene, methylglyoxal and enaminones, and takes place with good yield in the presence of acetic acid, as shown in Scheme 57.

The next synthesis starts from the Knoevenagel condensation between aryl glyoxal and a 1,3-dicarbonyl compound, affording intermediate 58.1. The azulenes present in the reaction medium add to this intermediate, and in the last step a proton transfer in the intermediate 58.2 would produce the desired azulene derivative (Scheme 58) [102]. Depending on the reaction conditions and the structure of the starting materials, diketone 58.3 or ketoenol 58.4 results with the structure and yields described in Scheme 58.

Much abundant is the literature that describes the obtaining of grafted heterocyclics on azulenes and some examples for the synthesis of such compounds follow to illuminate this subject. The atoms with which azulene is bound to the extra-system are very different, as well as the heteroatoms involved in the grafted system. Thus, at the condensation two atoms belonging to the five-atom ring can participate, one to the five- and the other to the seven-atom ring or both to the seven-atom ring, generating an extra ring with five or six atoms. Atoms such as oxygen, sulfur or nitrogen can be included in the extra-system. A six-atom ring containing an oxygen atom was attached to the five-azulene ring by Wang et al. [103] and Ito et al. [104]. Wang performed a three-component reaction: between ethyl 2-hydroxyazulene-1-carboxylate, aromatic aldehydes, and malononitriles (Scheme 59). A rich range of 2-amino-3-cyano-4-aryl-10-ethoxycarbonylazuleno[2,1-b]pyrans, 59.1, with varied R substituents was synthesized in this way.

Somewhat surprising seems to be the Ito condensation of 2-hydroxyazulenes with ethyl acetoacetate or ethyl benzoylacetate (Scheme 60) [103], considering they are rarely used as a catalyst of AlCl₃ in other reactions. The yield in the products 60.1 is quite low.

A considerable contribution to the realization of compounds with azulene systems grafted with other rings was brought by the recent works of Maeng et al. In the first paper is described the rhodium- and iridium-catalyzed oxidative cyclization of azulene carboxylic acids with alkynes (Scheme 61) [105]. After the catalytic activation of C-H bond with formation of iridacycle 61.1 follows the alkyne insertion with the generation of intermediate 61.2, which is decarboxylated and the new obtained intermediate 61.3 undergoes a new alkyne insertion. The reductive elimination from 61.4 under the influence of Ag(I) leads to the product, tetra(substituted) benzoazulene 61.5.

In addition to the series of benzoazulenes 61.5, the authors also synthesized some azulenolactone derivatives, 62.1 and 62.2. In this case, a Rh-based catalyst replaces the Ir-based catalyst in a cyclization reactions of azulenic acids with alkynes. Scheme 62 summarizes aspects related to the conditions in which both series of reactions take place and the yields in which the products are obtained.

The second target pursued by Maeng was the reaction of azulene 1-carboxylic acid with diaryliodonium salts, and Scheme 63 shows the reaction pathway [106]. The synthesis consists of iridium-catalyzed sequential C(2)-arylation reaction and intramolecular C−O bond formation. Interesting is the intramolecular attack on the seven-atom ring. The reaction can stop at the arylated product in position 2, 63.1, or it can progress until the formation of 3-arylazulenofuranones, 63.2. The last product can also be obtained starting from the acid 63.1.

As shown above, apart from the oxygen atom, the literature also includes articles dealing with azulenes grafted with the extra-system containing sulfur or nitrogen. From the large amount of information that has been published, only a few examples are selected that are presented as reactions in Scheme 64 with the specification of the reaction conditions and the yields obtained.

In 2022, Gao et al. synthesized an analogue of indigo, continuing the group’s series of investigations in the field of π-functionalized materials [110]. Scheme 65 shows the procedure for obtaining intermediate azulenoisatine, 65.1 and of the separable azulenoisoindigo, 65.2.

Gao et al. also describes the first synthesis of azulene-based BN-heteroaromatics, building block 66.2, for synthesizing polycyclic aromatic hydrocarbons [111]. The synthesis occurs through nitrogen-directed aromatic borylation (Scheme 66).

3.3.5. Calixarene, Azulenophane, and Azuliporphyrin

Many efforts have been focused on the investigation of calixarene, azulenophane and azuliporphyrin, and two reviews have recently appeared regarding this topic [17,21]. Therefore, to complete the information on the behavior of the azulene five ring, only a few examples from these classes of compounds will be given.

The formation of calixarene 67.1 by the reaction of azulenes with formaldehyde in the presence of Florisil (activated magnesium silicate) is illustrated in Scheme 67. The acid-catalyzed reaction affords as major product a polymer with only a low proportion of calixarene [112,113].

To get to azulenophanes, Fujimura used the route described in Scheme 68 [114]. As can be seen, the reaction mixture is complex and contains, along with azulenophane, 68.1, the product with the open ring, 68.2, as well as the dimer 68.1. It should be noted that very small quantities of products result from the reaction.

Much wider interest has been in obtaining azuliporphyrines, a special contribution being made by Lash et al. [115,116] and Sprutta et al. [117,118]. One of the many existing procedures for obtaining azuliporphyrines, namely, Rothemund synthesis, exemplified in Scheme 69, affords the desired macrocycles in low yields (~13%) due to the shifted equilibrium in favor of porphyrinogen systems 69.3 and 69.4. A careful investigation into the structure of azuliporphyrine with two azulene in the porphyrin rings was also carried out by Lash et al. [118,119].

4. Conclusions

This review proposed a brief presentation of the behavior of the five-membered azulenic ring based on the information from the literature and our results in order to familiarize researchers with the chemistry of this ring. Neither an exhaustive exposition of the synthesis procedures nor a detailed description of them was pursued. It was preferred to introduce reaction schemes that include the reaction conditions and the yields of the obtained products. In this way, the reader can get an idea about the usefulness of the procedures. In a series of cases, the reaction mechanism was briefly discussed in order to allow the researchers’ imagination to use the information in possible similar syntheses. The division into chapters took into account reaction conditions and was guided to some extent by the divisions in the published reviews. After the introduction and some considerations about starting azulene, the description of the chemical behavior of azulene was divided into reactions without catalyst and with catalyst. The last chapter summarizes reactions that do not belong to one of the previous series.