Synthesis of azulenic compounds with a homo-or hetero-atomic double bond at position 1

This work reviews the synthetic routes for the generation of 1-vinylazulenes, azulen-1-yl diazenes and azulen1-yl imines. The wide range of substituents at the studied double bonds involves varied synthetic routes and a great number of exemplified compounds.


Introduction
There are four possible bicyclodecapentaene isomers, as represented in Scheme 1. However, whereas the compounds with a naphthalene or azulene core, A and B, are well known and widely studied for both their scientific and technical importance, the structures C and D show only scientific interest. [1][2][3]  Several phosphonium salts 2 with heteroaromatic Ar were also condensed in moderate to good yields with guaiazulene-3-carbaldehyde (Table 1), affording alkenes only as (E)-isomers. 23 1-Vinylazulenes with an alkyl group in position 2 of the C=C bond were prepared in good yields by Wittig reaction in the presence of very strong bases. However, the products exhibited low stability. For example, guaiazulene-3-carbaldehyde reacts with ethyltriphenylphosphonium bromide in the presence of n-BuLi in THF giving 1-(prop-1-enyl)azulene in 64% yield. 25 Such compounds proved to be good radical scavengers, more effective than α-tocopherol. Later, were reported the results of condensation between azulene-1carbaldehyde or azulene-1,3-dicarbaldehyde and ethyltriphenylphosphonium bromide, as shown in Scheme 4, however, without information on the yields and with incomplete product characterization. 26 The obtained mixture of geometric isomers of 1,3-di(prop-1-enyl)azulene (5) was used subsequently in the olefin metathesis polycondensation to polymers with potential semiconducting properties.
The reaction products depend on the starting aldehyde and the selected solvent. Thus, the condensation of 9 with aliphatic aldehydes in benzene in the presence of PhLi 28 affords only the isomer (E) of alkenes 10, slightly stable in the presence of air. By working in DMF, the reactions of 9 is less straightforward because PhLi partially reacts with DMF giving benzaldehyde which, in turn, condenses with the phosphonium salt. Thus, alongside the attempted products 10, a mixture (Z/E) of 1-styrylazulenes 3 was generated. In spite of the lower selectivity, the yields in compounds 10 are higher in this solvent, which favors the dissolution of the intermediate ylide salt.  23 16 a In brackets are the yields of 10 taking in account the recovery of salt 9 While aliphatic aldehydes react stereoselectively with salt 9 providing (E) isomer, a mixture (Z/E) resulted starting from benzaldehydes or 1-azulenecarbaldehyde (Scheme 5). 28 The interesting compounds 11, possessing simultaneous azo and vinyl bonds (Scheme 5), were obtained from (E)-4-(4-methoxyphenyldiazenyl)benzaldehyde or (E)-4-[4-(dimethylamino)phenyldiazenyl]benzaldehyde and (3-guaiazulenylmethyl)triphenylphosphonium bromide in ethanol in the presence of sodium ethoxide at 25 °C for 24 h under argon. 29 The conditions for the condensation of 1,3-bis(triphenylphosphoniummethyl)azulene, 12, with aliphatic or aromatic aldehydes (Scheme 6 and Table 3) resemble those of monosubstituted azulene ylides and yielded 1,3-divinylazulenes, 13, as a mixture of geometric isomers. 30 Scheme 6. Preparation of 1,3-divinylazulenes using the Wittig route.
Reactions between the phosphonium salt 9 and acetone or benzophenone in benzene produce the expected condensation products, 1-(2-methylprop-1-enyl)azulene and 1-(2,2-diphenylvinyl)azulene, but in lower yields than those observed with aldehydes. Among the attempted products, when condensation takes place in DMF the reaction also affords styrylazulene, (Z and E)-3Ph, formed through the intermediacy of benzaldehyde generated from PhLi and DMF. 28 Particular attention has been paid in recent decades to the preparation and properties of the ethenes and polyenes substituted with two azulen-1-yl moieties. Interest is related to the possibility that these compounds may work as a metal due to their very low oxidation potentials. An attempt to produce 1,2-di(azulen-1yl)ethene by Currie, 30 stimulated Hünig and Ort to undertake a careful study of these classes of compound. 31 (Azulen-1-ylmethyl)triphenylphosphonium iodides were treated with azulenecarbaldehydes or their vinylogs, both ylides and carbonyl compounds having substituents at different positions in the azulene moiety (Scheme 7). This results in a large number of products in good yields as mixtures of geometrical isomers. Here we deal only with the preparative route starting from the phosphonium salt 9 containing the azulen-1-yl moiety. Diazulenyl substituted polyene are obtained starting from the unsaturated aldehyde as 7 where R = H and the phosphonium salt 9. Reaction between dialdehyde 16 or 17 and two equivalents of salt 9 (Scheme 7) represents another way to access such compounds. The last procedure affords only symmetric products whereas the route described above can be used also for the asymmetric compounds. The products result as a mixture of geometric isomers. The increase of number of the double bonds between the azulene moieties lowers the stability of all-Z isomers, which are isomerized to all-E isomers even in daylight.
The reaction of phosphonate carbanions with the carbonylic reagents, the Horner-Wadsworth-Emmons reaction, is widely used for the preparation of C=C double bond. The phosphonate carbanions have the advantage to be at the same time more nucleophilic and less basic than the carbanions generated from phosphonium salts used in the Wittig reaction.
Scholz et al. 32 have prepared several 1-styrylazulenes by reacting 1-azulenecarbaldehydes, 1, or their vinylogous derivatives 7, with carbanions obtained from phosphonates 19 (Scheme 8) in the presence of sodium methoxide. Except for benzyl compounds substituted with a cyano group, the condensation products result in very low yields.
More recently, Asato and Liu found the anti-neoplasmic and anti-dermatopathic activity of some azulenic retinoid derivatives with vinylogous structure to products 21 described in a US patent. 33 The access route to these compounds starts from azulene-1-carbaldehyde and guaiazulene-3-carbaldehyde, as well as their derivatives with C=C bond between azulene and carbonyl group, which were condensed in the Horner-Wadsworth-Emmons reaction with phosphonates containing unsaturated organic moieties or even benzyl groups (Scheme 9). The carbanion, generated at low temperature in the presence of butyllithium or lithium diisopropylamine in THF, reacts with aldehydes at room temperature. After work up, the products result as a mixture of (E/Z) isomers in which the isomers ratio depends on the structure of the starting compounds. By this route, the authors obtained some products described in Scheme 8. The second example in Scheme 9 starts from a ketone as carbonyl compound for the preparation of a trisubstituted ethylene, 23. Unfortunately, the yields for several reactions are not reported in the patent. 33   The discovery that numerous condensation products between azulene-1-carboxaldehydes and indolin-2ones 25 are effective in cancer therapy by inhibiting the activity of protein kinases or phosphatases stimulated research into their synthesis and the obtained results are the subject of a patent. 39 The condensation yields are good and the compounds geometry depends on both the starting reagent and the reaction conditions (the condensation agent was pyrrolidine and the solvent ethanol). Several significances of the claimed products are shown in Scheme 11.

Reaction conditions
Ref.
One day at room temperature The possibility of the azulen-1-yl moieties to participate as electron donors in the push-pull systems, as exemplified in Scheme 12, stimulated the investigation of condensation between azulene-1-carbaldehydes and a large number of aromatic heterocyclic salts. In the cation thus formed the positively charged heterocycle acts as an electron acceptor. Scheme 12. Contribution of tropylium structure to the stabilization of pyridinium compounds.
The methyl substituent in the starting salts, [Het-CH 3 ] + X -, when in a 2-or 4-position relative to the positively charged heteroatom, is strongly activated. Some of the salts with heterocycle cations that have been used are illustrated in Scheme 13. The reactions with aldehydes take place in basic, as well as in acidic, media. The condensations in basic medium occur under mild conditions and afford the products in good yields regardless of the azulene substituents (Exp. 1-9 in Table 6). 40  41 studied the condensation in acidic medium (acetic acid) between azulene-1carbaldehydes 1 and perchlorates of 2-methyl-pyranylium (Exp. 10-12 in Table 6). Several azulenium salts 27 with Het = K-S (Scheme 13) are claimed as suitable for the generation of photoconductive film or as electrophotographic sensitive body. For such products, condensation was promoted also by acetic anhydride or hot acetic acid. 42,43 However, from the numerous compounds claimed in the patents only for the compounds with Het = K and M, the yield and elemental analysis were reported (Exp.13 and 14 in Table 6).
with azulene-1-carbaldehydes in conventional conditions (acetic anhydride at high temperature) low yields are obtained; however, the yields significantly increase in microwave-assisted reactions (Table 7). Moreover, whereas conventional heating leads to a reaction mixture of both mono-and bis-condensation products, 29 and 30, under microwave the bis-condensation product 30 was obtained exclusively and in good yields. There is little difference in yields and in product ratio starting from unsubstituted azulene-1-carbaldehyde or its 4,6,8-trimethyl derivative.
Another synthesis employs the water elimination between 2,4,6-trimethylpyrylium salt 31 and azulene-1carbaldehydes in acetic anhydride medium. 45,46 While at high temperature the reaction mixture contained all three possible condensation products 32, 33 and 34 (Scheme 14), the microwave assisted reaction generated selectively the fully condensed compound 34. Table 7. Reaction of 4-(azulen-1-yl)-2,6-dimethylpyrylium and 2,4,6-trimethylpyrylium perchlorates, 28 and 31 with azulene-1-carbaldehydes  Whereas some azulene-1-carbaldehydes are liquid and their handling is often cumbersome, the very easy accessibility of azulenic Schiff bases spurred the investigation of this condensation for the generation of 2substituted 1-(azulen-1-yl)ethenes. The research focused on the synthesis of such compounds with aryl as the second substituent at C=C bond as well as with other functions at this bond. 50,51 The first reported pathway employed, together with azulenic Schiff base 35, a large number of arylacetic acids, 36 (Scheme 15). The reaction occurs with very good results in the absence of any solvent or catalyst by melting together the two reagents. Because during the heating of the mixture, both CO 2 and amine are eliminated, the final processing was very simple and the proposed procedure occurs with reduced pollution and lower costs.
Substitution of 4-position of phenyl with an electron donating group, such as methoxy, increases the basicity of the Schiff bases 35, promoting the ionization of arylacetic acids, while a strong withdrawing group, such as nitro, reduces its basicity. Therefore in the former case yields are improved and in the latter the reaction is inhibited. The nature of Ar moiety in arylacetic acids was widely varied and the results are shown in Table 8. Following the same route, but starting from aromatic dicarboxylic acids, products 37 -39 were obtained in good yields. Sometimes, together with compounds 39 and 40, the products of monocondensation are separated from the reaction mixture. The reaction of azulenic Schiff bases 35 with compounds containing active methylene R 1 CH 2 R 2 , described in Scheme 15 and Table 9, provides products in good yields and represents an alternative synthetic route for that described in Scheme 10 and Table 5A. When one of the substituents R 1 or R 2 was the carboxyl group, the reaction occurs with decarboxylation.
It is interesting to note that the acidity of the methylene group of the hydrocarbon indene is high enough to react with the azulenic Schiff base, affording, after a long condensation time, the product 41 (Scheme 15).

McMurry reductive condensation
In the 1970s several research teams simultaneously found that two carbonyl derivatives may react in a reductive coupling under action of low-valent titanium (e.g. obtained from TiCl 3 /Mg, TiCl 4 /Zn, TiCl 3 /LiAlH 4 ) to generate a C=C double bond. 52,53 Unlike pinacol condensation, which usually occurs at room temperature, the reductive coupling, generally called the McMurry reaction, requires higher temperatures. Nevertheless, most of the reductive condensations are accompanied by pinacolization. Moreover, the proposed reaction mechanism for McMurry condensation involves as intermediate titanapinacolate. 53 Numerous synthetic applications have attracted a great interest in this reaction and, therefore, an extensively investigation in this research field. Thus, to obtain low-valent titanium from Ti(IV) or Ti(III) species, various reducing reagents were used and different reaction conditions were tested. The addition of pyridine or another auxiliary was tried in order to change the nature and the ratio of the reaction products. 54 The activation of reductive coupling was sometimes successful in the microwave (MW) field. 55 Unfortunately, McMurry coupling can be used only for the preparation of symmetrical products because mixtures of ketones give all possible condensation products. Exceptionally, and under special conditions, this route was used to get unsymmetrically substituted alkenes.
Recently, attention has been paid to the reductive McMurry coupling of 1-acetylazulene, 41 (Scheme 16). 56 The reduction system was TiCl 4 /Zn in THF and the reaction conditions were widely varied (Table 10). where the attempted unsaturated compound was accompanied by pinacol and its pinacol→pinacolone transposition product. This behavior was adopted by [3]ferrocenophan-1-one 57 , (η 5 -acetylcyclopentadienyl)cobalt-(η 4 -tetraphenylcyclobutadiene) 58 and 1,n-bis-(5-acetyl-2-methoxyphenyl) alkanes. 59 It has been assumed that the presence of a moiety that strongly stabilizes the carbonium ions represents the common structural feature for these three ketones and 1-acetylazulene. The reaction mechanism, which explains the products generation, (Scheme 17) involves as key intermediate the cyclic Data given in Table 10 show that, at low temperature, the major product is a pinacol and, by increasing the temperature, the yields in all products collapse. The yields both in pinacol and in alkene can be improved by adding pyridine. The MW heating levels the products ratio. However, the addition of pyridine in these conditions increases the yields in pinacolone and alkene until the disappearance of pinacol. It should be noted that, regardless of the reaction conditions, the pinacol resulted only as a racemic mixture 60 and the (Z)-isomer of alkene 42 always exceeds the isomer (E). Both of these results are consistent with the mechanism depicted in Scheme 17.
In connection with the results of McMurry reaction of (1-azulenyl)ketones, an investigation on the intramolecular condensation of 1,ω-di(azulen-1-yl)-1,ω-diketones was also undertaken. 61,62 The possibility to obtain by this route unsaturated carbocyclic and heterocyclic derivatives containing azulen-1-yl moieties at the C=C bond (compounds 46 in Scheme 18) is attractive due to the potential technical properties of these compounds with applications in the field of π-conjugated materials (modified electrodes, photochromic materials, etc.).

Scheme 18. Intramolecular Vilsmeier-Haack reaction.
For the synthesis of starting diketones 45, Vilsmeier-Haack or Friedel-Crafts reactions are employed (Scheme 18). The subsequent McMurry reaction of diketones generates, along desired cyclic alkene 46, as side products, the pinacol 47 and its rearranged product, ketone 48 (Scheme 19) in a ratio depending on the starting diketone and the reaction conditions. Therefore, several conditions for the increase of the reaction selectivity in each product were tested and the results are shown in Table 11. Scheme 19. Products in intramolecular Vilsmeier-Haack reaction. The electronic, as well as the steric effects, of the azulen-1-yl substituents substantially modifies the reaction pathway. When the azulenyl moiety is not substituted, alkene 46 was accompanied by ketone 48 in 22% yield. However, bulky methyl groups situated in position 8, as in 45 where X = CH 2 , R = 4,6,8-Me 3 or 3,8-Me 2 -5-iPr do not allow the azulenyl migration and, therefore, no ketones are formed. The presence of heteroatom in cycle forces the hydroxyl and azulenyl groups to stay in the eclipsed configuration increasing the energy of pinacolic structure. Therefore, elimination of the hydroxyl groups becomes easier than in the case of 1-acetylazulene which, under the same reaction conditions, forms a stable pinacolic derivative with a staggered structure in 89% yield. Starting from 45, the hydroxyl elimination occurs even at the working temperature of 0 o C that is unusual for common McMurry reactions, which require higher temperatures and longer reaction times. 63 Therefore, to avoid the OH removal in order to obtain a larger amount of pinacol, the reaction temperature is decreased to -45 o C. However, even under these conditions, the pinacol 47 (where R = H) was generated in a small amount together with the alkene 46, which is formed even at this low temperature as the main product.
The low-valent titanium reagent is obtained by the action of zinc dust on TiCl 4 without or in the presence of pyridine and eventually also by catechol as an auxiliary system (Table 11). Addition of pyridine increases the alkene/ketone ratio and improves, to some extent, the yield in pinacol. Literature data show that the presence of chelating agents, such as catechol, stops the McMurry reaction to the pinacol stage 54 what can be also observed to some extent in the results in Table 11.
Replacement of CH 2 group in the diketone 45 by a hetereoatom influences in a decisive way the McMurry cyclization. While alkene 46, and sometimes the ketone 48, represents the sole products when X = CH 2 , working with diketones 45 where X = O or S, the alkene always results together with pinacol and sometimes with pinacolone (Table 10).

Scheme 24. Reactions of azulenes with dimethyl acetylenedicarboxylate.
The destructive effect of aluminum chloride on azulene moiety limits the valuable Friedel-Crafts reaction for azulene chemistry. However, it was used in the peculiar reaction between the 2-(2-bromovinyl)-5nitrofuran, 77, and guaiazulene in 1,2-dichloroethane at 0 o C (48% yield). 74 In this case, the effect of the nitro group is transmitted through the π-electronic system of the furan ring, as indicated in Scheme 25.

Scheme 25. Example of Friedel-Crafts substitution of guaiazulene.
More recently was reported the electrophilic reaction of 1,2-diphenylethane-1,2-diols in which the phenyl groups are substituted in position 4 with OH, OMe or NMe 2 groups, with azulenes in the presence of concentrated hydrochloric acid in methanol. 24,75 As it is illustrated for guaiazulene in Scheme 26, the reaction leads to the product of pinacol rearrangement, 82. While good yields are obtained for guaiazulene and 1chloroazulene, azulene reacts in lower yield and methyl azulene-1-carboxylate gives no product.
Changing the solvent and working in a mixture of methanol and acetonitrile instead of methanol, the reaction becomes not regioselective and several products were formed. 76  It is likely that the bulky methyl group situated in position 8 of the guaiazulenyl moiety prevents the presence of a guaiazulenyl and an aryl or two guaiazulenyl groups at the same alkene carbon and explains why the reaction stops at the product 82. This supposition is confirmed by the unusual reaction which takes place between 82 where X = NMe 2 and azulene, when the guaiazulenyl moiety is partially replaced by azulenyl.

Dehydration of 2-(azulen-1-yl)ethanols.
Water removal is one of the most well-known ways to form a C=C bond. Difficulties for the preparation of azulenic alcohols and the modest yields in dehydrated products limit this route. However, -hydroxyethyl substituted azulenes (or their derivatives) have been dehydrated to the corresponding vinylazulenes either in the presence of strong acids, such as tetrafluoroboric acid, at 60-70 o C, in fair yields 77 or under basic condition with poorer results. 18 Passage through an alumina column was also used for water elimination from the alcohols 90 and 91, obtained from 3-acetylguaiazulene (Scheme 28), but the reported yields for alkenes 92a and 92b are low. 79 Scheme 28. Dehydration of 2-(azulen-1-yl)ethanols.

Radical and concerted reactions.
Coupling of azulene derivatives with readily accessible reagents in the presence of transition metal catalysts, such as in the Heck reaction, represents an attractive route towards a number of 1-vinylazulenes that can then be used as building blocks of different interesting molecules. Thus, the reaction of many halogen-azulenes with monosubtituted ethenes in the presence of Pd(PPh 3 ) 4 /(NEt 3 ) was reported. 79 However, a drawback of this synthesis is the difficulty encountered in the monohalogenation of the parent azulene as compared with its 1,3-dihalogenation. Therefore, the use of this pathway has been limited to 1,3-disubstituted azulenes. Halogenation of position 3 becomes almost quantitative when the azulenes are already substituted with electron withdrawing groups at the 1-position. Therefore, good yields are reported in the Heck reaction of ethyl 3-bromo-1-azulenecarboxylate, 93 with styrene or methyl acrylate (yields 66% and 88%, respectively). The vinylation occurs regioselectively only at the carbon substituted with halogen (Scheme 29).
Ethenes are not always reactive enough to participate in the Heck reaction. Therefore, they can be activated as an organostannic derivative, 96, which reacts with the bromo compound 95, as represented in Scheme 30, leading to compound 97 in 81% yield. 80 Unfortunately, the nitrogen elimination is not stereoselective; moreover, in the case of the photochemical reaction, an important isomerization of double bond position takes place and therefore side products are formed. The reaction mechanism proves to be radicalic. Thus, after nitrogen elimination, the intermediate diradical suffers a 1.5-hydrogen shift from one of the alkyl groups toward the 8-position of azulene via a sixmembered ring transition state affording the normal or rearranged alkene structures.
An unusual synthesis was recently been accomplished for the generation of compounds 103 by the diastereoselective N-sulfonylaminoalkenylation of azulene or its derivatives using alkynes and N-sulfonylazides via a three-component semi-one-pot process with copper and rhodium as catalysts (Scheme 33). 83 Scheme 33. Three-component semi-one-pot process catalyzed by copper and rhodium for vinylation of azulenes.

Introduction
The synthesis of azulen-1-yl diazenes can be accomplished by two main routes: the electrophilic azo coupling or the substitution of already obtained azulen-1-yl diazenes. The azo coupling of azulene under radical conditions has also been tried, but it proceeds with low efficiency.
The azo coupling starting from (azulen-1-yl)diazonium salts is prohibited due to the high instability of 1aminoazulene, 104, and to the very low reactivity of its diazonium salt with the positive charge at tropylium moiety. This diazonium salt, which is obtained and right away reacted in situ, was involved only in a few coupling reactions and even those with low yields such as, for example, reaction with the highly reactive coupling component 2-hydroxynaphthalene (Scheme 34). 84 Scheme 34. Diazotization + coupling starting from 1-aminoazulene.
The prominent nucleophilic character of the azulene system, mainly at the 1-position, allows attack at this position by the relatively weak electrophilic aryldiazonium cation. This represents an impressive exception to common experience because only a small number of aromatic hydrocarbons (e.g. 1,3,5-trimethylbenzene) react in this way with diazonium salts and then only when these salts are derived from amines with strongly electron-withdrawing groups in their structure (e.g. 2,4,6-trinitroaniline). This valuable property allows a very wide variety of diazenes with an N=N bond in the azulene 1-position to be obtained, starting from azulene and other substituted azulenes with a free 1-position.
The alternative used route that affords the azulen-1-yl diazenes, namely the electrophilic substitution in position 3 of the already obtained diazene, occurs to be difficult due to the deactivating influence of preexisting azo group. Nevertheless, for azulene derivatives where the azo coupling is difficult or impossible for some reason this route remains the only accessible pathway.

Azo coupling reactions 3.2.1. Synthesis of azulen-1-yl diazenes starting from benzenoid amines.
It was only in the 1950s that the first coupling of azulene was achieved, by Anderson et al. in diethyl ether/acetic acid with an aqueous solution of phenyldiazonium chloride, in 70% yield. 85 However, over a relatively short period a large number of couplings between azulene derivatives and various aryldiazonium salts had been performed (several examples are reviewed in Scheme 35). [86][87][88][89][90][91][92][93] All described couplings are regioselective occurring in 1(3) position of azulenes. Substitution with a second arylazo group at 3-position is not possible, except when starting from the electron rich 2-aminoazulene. 94 Limited information is related in the older literature on the coupling conditions, as the reaction medium and temperature or on the used anion for diazonium salts. Absence of yields for most of the reported azo couplings makes it difficult to ascertain the role played by starting reagents on the reaction route and to establish a rule in this regard. Many variations in reported yields are rather a result of the low solubility of diazenes, which hinders their processing and purification. Usually, in buffered alcoholic medium (acetic acid/acetate), the reaction occurs in 0.5 -1 hour, 93 while in acetic acid-diethyl ether it needs several hours. 89 Anhydrous solvents were occasionally used for special diazonium salts. 92

Scheme 35. Azo coupling of azulene derivatives with aryldiazonium salts.
A notable decrease in product yield is observed either when Ar represents a phenyl group possessing a strongly electron-withdrawing group such as Me 3 N + in the para-position, or when Ar is an aromatic polycyclic radical, such as 2-anthracenyl or even 1-naphthyl. The resulted diazonium salts starting from aniline substituted with strong electron donating groups, as for example NMe 2 , are too stable to interact with the azulene moiety. They can, however, react with activated azulenes that contain strong electron donating group, NH 2 or OH, as in ethyl (2-amino)-or (2-hydroxy)-azulene-1-carboxylate. 97 Substitution of azulene with alkyl groups improves the product yield due to the electron-repelling effect of these groups, which enhances the azulene nucleophlicity (e.g. when Ar = 1-naphthyl in Scheme 35, the coupling yield raises from 45% for azulene to 70% for guaiazulene). The influence of other groups in position 1 of azulene on the coupling reaction with diazotized 4-toluidine was investigated using substituents with varying electron demand (Scheme 35). 95 Thus, despite the electron donor properties of groups such as MeO, PhCO 2 , AcNH or halogen, their low ionization potential can promote the product oxidation with concomitant decrease of yield. Further decrease in yield occurred with the substituent PhCO 2 due to its hydrolysis during the coupling. As attempted, the electron acceptors (Ac or NO 2 ) limit or prevent coupling. In the case of formyl or acetyl groups, small amounts of the coupling products can be obtained depending on the reactivity of the diazonium salts.
The crown ethers are colorless compounds, however, some of their technical uses require the presence of a chromophore in the molecular structure. Therefore, the (azulen-1-yl)azo moieties were attached to several crown ethers in the aim to obtain such colored materials. 97 Thus, the crown ethers with one or two (azulen-1yl)azo chromophores, 112 or 113 were generated in good or moderate yields (Scheme 37) from commercially available 3-aminobenzo-crown ethers, 110 or from diaminodibenzo-18-crown-6 ether, 111. The low reactivity of the diazonium salts favors the electron transfer between the diazonium salts and guaiazulene, therefore, the yields in products 112 where R = 3,8-Me 2 -5-iPr fall below those of the products with azulen-1-yl group. At the same time, the yields of trimethylazulene derivatives, 112 where R = 4,6,8-Me 3 , decrease due their poor solubility.
To avoid the partial diazotization when weakly basic aromatic amines (such as 4-nitroaniline) were used, they were dissolved in a little amount of concentrated H 2 SO 4 with the rising of the temperature and were transformed in the corresponding sulfamic acid 114. This intermediate is more soluble than the amine and the diazonium salt was obtained at 0 o C and was coupled in good yields with a number of 1-substituted azulene at room temperature with the generation of the compounds 115 (Scheme 38) (see also the next section). 98 Scheme 38. Azo coupling of the azulene derivatives with diazotized weak bases (in the presence of H 2 SO 4 ).
As mentioned above, the presence of electron withdrawing groups in 1-position of azulenes significantly reduces their reactivity toward electrophiles. Compounds 106 where X = Ac, CHO, CN or NO 2 (Scheme 39) are coupled under severe conditions and only with reactive diazonium salts, such as 3-nitrobenzenediazonium tetrafluoroborate with the removal of the X substituent. 99,100 This substitution probably take places because these groups are good electrophilic leaving groups and are eliminated in acidic medium (H 3 PO 4 ), with the generation of azulene, which is further azo-coupled generating diazenes 116. 1,3-Diacetylazulene reacts in good yield with 3-nitrobenzenediazonium salt with the substitution of an acetyl group. 92 Scheme 39. Behavior of azulene derivatives with different reactivity by azo coupling.
Formyl group shows a specific behavior being removed in the protic medium. At the same time, it is retained if an aprotic solvent, such as acetonitrile and an anhydrous tetrafluoroborate aryldiazonium salt are used for coupling. However, in the latter case, coupling requires a longer reaction time to substitute selectively the proton. Under these conditions, the bond of azulene to formyl becomes even stronger than that with chlorine. Therefore, in 3-chloroazulene-1-carbaldehyde, the chlorine atom was replaced by the diazonium ion whereas CHO group was preserved as in compound 118 in Scheme 39. 98,99 The deactivating influence of the azo group in 1-position of azulene on a second azo coupling can be signaled even for [1,1]biazulene, which can be substituted only at one azulenic moiety (compound 119 in Scheme 40). However, by coupling with an electron rich diazonium salt, such as 4-methoxybenzenediazonium chloride, small amounts of disubstituted product are also obtained. 101 Scheme 40. Azo coupling with 1,1'-biazulene and the coupling of guaiazulene with 2-azulene diazonium salt The resulted salts at the diazotization of 2-aminoazulenes are unstable due to the very fast reaction of the azulene moiety of these salts with nucleophiles, however, curiously, they can be coupled with guaiazulene affording 1-(azulen-2-yl)-2-(guaiazulen-3-yl)diazene, 120 (Scheme 40). 102 3.2.2. Synthesis of (azulen-1-yl)diazenes starting from heteroaromatic amines. As in the case of 1-vinylazulenes, the powerful push-pull electronic effect developed by diazenes where azulen-1-yl, as electron donor, is coupled to a withdrawing heteroaromatic group, stimulated a careful investigation of the synthesis and properties of 1-(azulen-1-yl)-2-heteroaromatic diazenes. The difficulties encountered in their synthesis were related either to the resistance of many heteroaromatic amines to the diazotization or to the low selective reactivity or stability of their diazonium salts. Moreover, it is known that the coupling of these diazonium salts was possible only with basic aromatics and the reaction occurred slowly. For example, the 4-pyridinediazonium salt, obtained mainly in strong acidic medium, reacts with difficulty with aromatic amines, 103 or with veratrole. 104 3.2.2.1. Synthesis starting from aminopyridines. The satisfactory basicity of 3-aminopyridine allows the successfully coupling of the corresponding diazonium salts with azulene in the presence of HCl, in ethanolic buffered medium (azulene conversion 64% and yield 71%, Scheme 41). 105 The yield increases by a further 10% when the reaction was performed in concentrated H 2 SO 4 or in tetrafluoroboric acid.

Scheme 41. Diazotization and coupling starting from pyridinamines.
Unfortunately, the electronic system of the diazenes, such as 122, obtained from 3-aminopyridine, does not provide the optimal push-pull activity as the corresponding 2-or, mainly, 4-isomer. Developing a protocol for the preparation of azo dyes from the last two amines represented a challenging task due to the low basicity of 2-or 4-aminopyridine. In addition, the resulting diazonium salts are unstable in acidic medium due to the ipso-nucleophilic elimination of a nitrogen molecule prompted by the positive charge on the pyridine nitrogen in position 2 or 4. 106 Relatively good yields are obtained when the diazotization of 4-aminopyridine 121b is accomplished in the mixture of HNO 3 (65%) with a polybasic acid, e.g. H 3 PO 4 (85%), followed by coupling with azulenes in buffered medium (Scheme 41). 105 These results can be assigned to the formation of a complex 123 where the positive charge on 4-C is reduced by the polybasic acid which, thus, increases the stability of the azo group. Other polybasic acids, such as H 2 SO 4 or H 3 BO 3 have been also used, however, with lower success.
An alternative and general route to obtain (azulen-1-yldiazenyl)pyridines starts from aminopyridine-1oxides, 125, and is depicted in Scheme 42. 107 This is the sole procedure for the synthesis of diazenes with an azo bond in the 2-position of pyridine, as in compound 127. The diazotization of aminopyridine-1-oxides is suitably performed in aqueous acidic media and occurs with high yields. 108 However, the problem to be solved remains the removal of the oxygen atom from the coupled product without disturbing the reducible azulene moiety and even the azo bond. The method most often used for the oxygen elimination, namely using PPh 3 , produces in this case only tar and the reaction with PCl 3 gives the product in only 10% yield. However, a mixture of PCl 3 and PPh 3 proves to be effective in the N-O bond breaking (Scheme 42). Despite the very good results from the diazotization-coupling sequence, this pathway remains useful only for generation of 2-(azulen-1-yldiazenyl)pyridine, 127, due to the low yield obtained at the oxygen elimination.

Synthesis starting from 2-aminothiazole or 2-aminobenzothiazole.
The similarity between the electronic density of pyridine and thiazole, as well as the know high β-hyperpolarizability of 2thiazolyldiazenes with a NO 2 group in the 5-position, 110,111 has stimulated interest in the synthesis and behavior of 2-(azulen-1-yldiazenyl)thiazoles, 129. The procedure described above for the 4-aminopyridine has also been applied for the tandem diazotization-coupling of 2-aminothiazoles, 128 (Scheme 43). 112 Various substituents X were introduced in the 5-position of the thiazole ring with the intention to influence the dyeing properties of the resulted azulene diazenes. The procedure was then extended to the coupling of diazonium salts arising from 2-amino-4-phenylthiazole, 130 leading to several new diazenes 131. 112 It can be pointed out that the synthesis of compounds 132 by diazotization/coupling of 2-amino-4-phenylthiazole N-oxide (Scheme 43) 112 represents the first example which starts from an amine with a fivemembered nitrogenous heterocycle moiety with N-oxide group, thus opening a way for the generation of other derivatives with interesting properties. At the same time, the N + -Me derivatives were obtained by alkylation of the compounds 129 with MeI. 112 Scheme 43. Diazotization and coupling starting from 2-thiazolamines and their N-oxides.
Only benzothiazol-2-amine or its derivatives with poor electron donor or withdrawing groups in the 6position, 133, can be diazotized and coupled with azulenes. The same protocol as for the thiazole-2-amines was used providing 2-(azulen-1-yldiazenyl)benzothiazoles, 134, in good yields (Scheme 44). 113 The nitrosation step in the diazotization of 2-amino-6-nitrobenzothiazole is reversible and favors the generation of the unstable 1-nitrosoazulene, resulting in severe reduction of the diazene yield (to 4 %) with the formation of a large amount of tar. The use of nitrosyl sulfate as the diazotization reagent and an excess of both sulfate and amine produces enough diazonium ions to react with azulene and the yield in diazene increases to 84 %. When a methoxy group is present in position 6, it assists the nitration of all positions of the benzo ring by the nitric acid present in the diazotization medium. Therefore, taking into account the stronger basicity of 2amino-6-methoxy-benzothiazole, the diazotization was performed in phosphoric acid instead of nitric acid with a very good yield (over 80 %).
Because the push-pull effect in 2-(azulen-1-yldiazenyl)benzothiazoles can be improved by the substitution of the azulene moiety with alkyl groups, several alkylazulenes were used, as shown in Scheme 44.

Synthesis of bis and tris diazenes containing one or two azulen-1-yl moieties.
The direct relationship between the extension of the electron system conjugation and the dyes features, as well as of other properties of the bis and tris diazenes with phenylene moiety as a spacer between the azo linkages with the azulen-1-yl and phenyl group(s), have stimulated a broad investigation of these compound classes. 3.2.3.1. Synthesis of bis diazenes with azulene and phenyl at the ends of the system. Commercially available 3-and 4-(phenyldiazenyl)anilines, 138, were diazotized and the diazonium salts coupled with azulenes. 115 As shown in Scheme 46, diazotization occurs with difficulty in aqueous HCl due to the low solubility in water of

Conclusion
The present review is intended as an overlook of the literature data, including our own contributions, to the preparation of azulene compounds with the most common and technically useful double bond at 1-position, namely vinyl, azo and imine bonds. The most used routes for building C=C bonds are: (a) Wittig synthesis starting from azulene-1-carbaldehydes or the phosphonium salt of an azulen-1-ylmethyl moiety, (b) Horner-Wadsworth-Emmons reaction of phosphonate carbanions with azulene carbonylic reagents, (c) condensation between azulenic aldehydes and compounds containing an active methylene group and (d) McMurry synthesis between the carbonyl derivatives of azulene. The substitution of the carbonyl by imine function to the azulene for a milder condensation with compounds containing active methylene, was also described. The next section deals with the synthesis of azulen-1-yl diazenes by azo coupling starting from benzenoid aromatic and heteroaromatic amines and with the synthesis of bis and tris diazenes. A short section presents the preparation of azulen-1-imines. For all classes of the compounds several unusual synthetic procedures have been mentioned.