Alkynylazulenes as Building Blocks for Highly Unsaturated Scaffolds Ahmed H. M. Elwahy*[a] and Klaus Hafner[b] In memory of Klaus Hafner. Reviewdoi.org/10.1002/ajoc.202100301 2010Asian J. Org. Chem. 2021, 10, 2010–2083 © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2010/2083] 1 Hafner, Klaus: Alkynylazulenes as Building Blocks for Highly Unsaturated Scaffolds aus Asian Journal of Organic Chemistry 10, Jahrgang 2021, Nr. 10 Copyright © 2021 Wiley-VCH GmbH http://orcid.org/0000-0002-3992-9488 Abstract: Recently developed routes to the synthesis of mono- and polyethynylated azulenes and their transforma- tions into linear oligoazulenes with ethynyl and butadiynyl bridges as well as azulenyl-substituted benzenes, cyclobuta- diene complexes, and azulene-substituted tetracyanobuta- dienes are reviewed. The utility of ethynylazulene derivatives for the synthesis of azulene-substituted heterocycles has also been reviewed. 1. Introduction Among the non-benzenoid aromatic compounds, azulene has attracted the interest of many research groups because of its remarkable polarizability and tendency to form stabilized cations and anions as well as radical cations and anions.[1–3] Azulene derivatives were also found in numerous natural products with a variety of biological activities.[4] Owing to its unusual properties, the functionalization of such compounds aiming at modifying their structures has extensively been studied. Moreover, acetylenes, and their highly conjugated homo- logues, have been found to promote strong electronic communication between terminal subunits and to favor rigid, rodlike structures that have found application in the design of molecular wires.[5] Today, progress in acetylene based molecular structure is greatly fueled by the advent of powerful novel metal-catalyzed acetylenic homo- and cross coupling protocols.[5–8] Interest in the synthesis of polyethynylated substituted benzenoid and heteroaromatic compounds has increased over the last decade due to the importance of these compounds in the preparation of materials with special properties for molec- ular devices.[9] Recently attention has focused on incorporating azulenes into polyethynylated π-systems. The successful attach- ment of ethynyl groups at different positions of the azulene system make them suitable candidates for this purpose. In this respect, Ito et al.[10a] recently reviewed advances made in the preparation of aryl- and heteroarylazulenes using transition- metal-catalyzed electrophilic heteroarylation reactions of azu- lene. Ito and Morita[10b] demonstrated also the broad applic- ability of organic molecules containing azulene chromophores as terminal groups for the preparation of stabilized electro- chromic as well as polyelectrochromic materials. Emphasis on both reviews was given to study the redox properties of the synthesized molecules. The aim of this review is to cover the developed approaches to the synthesis of mono- and polyethynylated azulenes and their transformations into linear oligoazulenes with ethynyl and butadiynyl bridges as well as azulenyl-substituted benzenes, heteroarenes and cyclobutadiene complexes. Yields of the target molecules reported in this review are those given in the last step in the reaction except in some few cases in which overall yield was not given. 2. General and specific synthesis of ethynylazulenes The most commonly used methods for the synthesis of terminal alkyne derivatives are Corey-Fuchs reaction,[11] Colvin rearrangement,[12] Bestmann-Ohira reagent[13] and Gilbert-Sey- ferth reagent.[14] Recent development with transition metal- catalyzed carbon-carbon coupling reactions such as Sonoga- shira coupling,[15] has evolved into a valuable synthetic method- ology for the preparation of alkynes. Efficient ethynylation of azulene at the five or seven- membered ring are mainly performed by one of three methods: i) Pd-catalyzed cross-coupling under Sonogashira-Hagihara conditions. ii) Corey-Fuchs reaction for the conversion of aldehydes into acetylenes. iii) Ethynylation of chloroazulenes with lithium acetylide in liquid ammonia. 2.1. Ethynylation of the five membered ring 2.1.1. Synthesis of 1-ethynylazulenes The first attempt to synthesize 1-ethynylazulene (4) was performed by Wentrup and Winter through condensation of 3- methyl-5(4H)-isooxazolone (1) with 1-formylazulene (2) in ethanol-morpholine at room temperature to give the corre- sponding 4-[1-azulen-1-yl-methylidene]-3-methyl-4H-isoxazol-5- one (3). Subsequent pyrolysis of 3 at 700 °C afforded 4 in 93% yield (Scheme 1).[16] Hafner et al.[17,18] described efficient routes to mono-, di- and triethynylazulenes based on Sonogashira coupling of iodoazu- lenes. Thus, the iodoazulenes 5a,b, which are readily available by electrophilic substitution of azulene with N-iodosuccinimide in positions 1,[19] undergo alkynylation with trimeth- ylsilylacetylene (TMSA) under Sonogashira conditions to furnish the protected monoethynylazulenes 6a,b, which afforded the 1-ethynylazulenes 4a,b as blue crystals in 38 and 42% yields, upon treatment with potassium hydroxide in methanol (Scheme 2). [a] Prof. Dr. A. H. M. Elwahy Chemistry Department, Faculty of Science Cairo University, Giza (Egypt) E-mail: aelwahy@hotmail.com [b] Prof. Dr. K. Hafner Clemens Schöpf-Institut für Organische Chemie und Biochemie Technische Universität, Darmstadt Petersenstraβe 22, D-64287 Darmstadt (Germany) Part of the “ Special Collection in Memory of Klaus Hafner”. Review 2011Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2011/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner This approach could be exploited to synthesize functional- ized mono- as well as poly- ethynylazulenes. Thus ethynylazu- lenes 7 and 8a were prepared in 72 and 45% yields, respectively, by Pd-catalysed cross-coupling of the correspond- ing iodoazulenes with trimethylsilylacetylene and subsequent desilylation (Figure 1). Condensation of 8a with hydroxylamine hydrochloride and subsequent dehydration with acetic anhy- dride/pyridine led to the formation of the corresponding 3- ethynyl-1-cyanoazulene 8b as brown crystals in 70% yield.[20,21] Mono- azulene 11 could be obtained in 97% yield from diiodoazulenes 9b by cross-coupling with one equivalent of TMSA under Sonogashira conditions to give the corresponding trimethylsilyl-protected ethynylazulene 10, followed by depro- tection with potassium hydroxide in methanol (Figure 2).[17] Ito et al. and others have also synthesized some substituted ethynylazulenes 12–17 from the corresponding iodo- or bromoazulenes by employing the Sonogashira coupling meth- odology and subsequent desilylation (Figure 3).[22–27] In many cases, they carried out the iodination procedure using N- chlorosuccinimide (NCS) and NaI in acetic acid at room temper- ature, rather than the expensive NIS reagent. The synthesis of methyl 3-ethynylazulene-1-carboxylate 21 was accomplished firstly by the reaction of methyl 3-formylazu- lene-1-carboxylate 18 with tetrabromomethane in the presence of triphenylphosphine followed by dehydrobromination upon treatment with DBU to give the corresponding bromoethynyla- zulene derivative 19. Compound 19 reacted then with triphe- nylphosphine in ether at reflux to give 2-(3-meth- oxycarbonylazulen-1-yl)ethynyltriphenylphosphonium bromide 20 in 85% yield. Subsequent hydrolysis of the latter compound in aqueous sodium hydroxide afforded 21 in excellent yield (Scheme 3).[28] Shoji et al. reported also the synthesis of some functional- ized ethynylazulenes namely, N-(3-(azulen-1-yl)prop-2-yn-1-yl)- 4-methylbenzenesulfonamides 22a–h, tert-butyl (3-(azulen-1-yl) prop-2-yn-1-yl)carbamate 23a–j and 3-(azulen-1-yl)prop-2-yn-1- ol 24a–j by coupling of the appropriate 1-iodoazulenes with each of N-tosyl propargylamine, N-tert-butoxycarbonylpropar- gylamine and 2-propyn-1-ol, respectively (Figures 4–6).[29,30] Very recently, Szèkely et al. reported a gold catalyzed synthesis of alkynylazulenes 27a–r using hypervalent iodonium reagent (TIPS-EBX) 26 under mild reaction conditions. This method was found suitable for the alkynylation of azulenes 25 equipped with aldehyde, chloroacetyl, or ketoester motifs, which are also excellent functional groups for further chemical transformations (Scheme 4).[31] Ahmed H. M. Elwahy was born in 1963 in Giza, Egypt. He graduated from Cairo University, Egypt in 1984 then he got his M.Sc. and Ph.D. degrees in 1988 and 1991, respectively, at Cairo University in the field of organic synthesis. He was awarded the Alexander von Humboldt research fellowship in 1998–2000 with Prof. Klaus Hafner, at TU Darmstadt, Germany and reinvited in 2003, 2005, 2009, 2010 and 2012. In 2002 he was appointed as a full Professor of Organic chemistry at Cairo University. In 2001 he received the State-Award in Chemistry and in 2016, he also received Cairo University Appreciation-Award in Basic Science. He published around 150 scientific papers in distinguished inter- national journals. Klaus Hafner was born in Potsdam, the capital city of the German Federal State of Brandenburg in the year 1927. In Marburg, from 1946 to 1950, he studied chemistry and medicine. He was ap- pointed as a research associate from 1951 to 1955, with Prof. Dr. H.c. Mult. Karl Ziegler, Max-Planck-Institut für Kohlenforschung, Mülheim/Ruhr (Ger- many). He worked at Philipps-University Marburg/Lahn as a Chemistry lecturer from 1956 to 1961. (Germany). He served at the Technical University Darmstadt (Germany) as a Full Profes- sor of Organic Chemistry and Chairman of the Institute of Organic Chemistry from 1965 to 1996 (following Prof. Dr. H.c. Clemens Schöpf). He served as Editor-in-Chief of Liebigs Annalen from 1981 to 1997, Senior Editor of European Journal of Organic Chemistry from 1998 to 2000, Co-Editor of Chemische Be- richte from 1995 to 1997, and Co-Editor of Topics in Current Chemistry from 1966 to 1995. He served as Chairman of the German Chemical Society’s Court of Honour from 1998 to 2020. He has over 200 research papers published in presti- gious international journals. In 1980, he was awarded the Carus and Adolf von- Baeyer Gold Medals. He passed away on the 25th of January, 2021. Scheme 1. Synthesis of 1-ethynylazulene via pyrolysis of the corresponding isoxazol-5-one. Review 2012Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2012/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 2.1.2. Synthesis of 2-ethynylazulenes In a similar reaction sequence, 2-ethynylazulene (29) could be prepared in 99% yield from 2-iodoazulene 28a[32] via the trimethylsilyl-protected derivative 28b. Functionalized 2-ethy- nylazulenes 30–32 were also obtained in 68–100% yields, respectively, from the corresponding iodoazulenes via trimeth- ylsilylethynylation and subsequent desilylation (Figure 7).[33–36] On the other hand, Morita et al.[37] reported the synthesis of 2-ethynylazulene (29) starting from 2-formylazulene (33)[38] by firstly reaction with CBr4 in the presence of triphenylphosphine to give 2-(2,2-dibromovinyl)azulene (34) in 87% yield followed by treatment with DBU to afford 2-bromoethynylazulene (35) in Scheme 2. Synthesis of 1-ethynylazulene via Sonogashira-Hagihara conditions. i) 0.04 mol% PdCl2(PPh3)2, 0.08 mol% CuI, NEt3, 1 eq. TMSA, r.t.; ii) 1 M KOH in H2O, MeOH, r.t. Scheme 3. Synthesis of methyl 3-ethynylazulene-1-carboxylate 21. Figure 1. Structures of some functionalized 1-ethynylazulenes. Figure 2. Structures of some functionalized iodoazulenes. Review 2013Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2013/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 4. Synthesis of alkynylazulenes 27a–r. Scheme 5. Synthesis of 2-ethynylazulene (29). Review 2014Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2014/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 94% yield. Conversion of the latter compound to 2-(2-azulenyl) ethynyltriphenylphosphonium bromide (36) was accomplished upon treatment with triphenylphosphane in dry ether. Reaction of 36 with water afforded 29 in 85% yield (Scheme 5). 2.1.3. Synthesis of 1,3-diethynylazulenes 1,3-Diethynylazulenes 37c and 37d could be obtained in 90 and 42% yields, respectively, from diiodoazulenes 9a and 9b by cross-coupling with two equivalents of TMSA under Sonoga- shira conditions to give the corresponding trimethylsilyl- protected ethynylazulenes 37a and 37b, followed by depro- tection with potassium hydroxide in methanol (Figure 8).[17] Shoji et al. reported also the synthesis of N,N’-((6-(tert-butyl) azulene-1,3-diyl)bis(prop-2-yne-3,1-diyl))bis(4-meth- ylbenzenesulfonamide) 38 and di-tert-butyl ((6-(tert-butyl) azulene-1,3-diyl)bis(prop-2-yne-3,1-diyl))dicarbamate 39 in 40 and 80% yields by coupling of 6-(tert-butyl)-1,3-diiodoazulene with each of N-tosyl propargylamine and N-tert-buthoxycarbo- nylpropargylamine, respectively (Figure 9).[29,30] 2.1.4. Synthesis of 1,2-diethynylazulenes2.1.5. Synthesis of 1,2,3-triethynylazulenes The reaction of 28 with one or two equivalents of N- iodosuccinimide followed by coupling with TMSA under Sonogashira conditions and subsequent desilylation afforded the 1,2-di- and 1,2,3-triethynylazulenes 40 and 41 as greenish blue crystals in 98% and 96% yields, respectively (Fig- ure 10).[17,18] Scheme 6. Synthesis of 6-ethynylazulene derivatives 43a–e and 44a–c. Scheme 7. Synthesis of 6-ethynylazulene-1,3-dicarboxylates 46a,b. Scheme 8. Synthesis of 1-cyano-6-trimethylsilylethynylazulene (48). Review 2015Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2015/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 2.2. Ethynylation of the seven membered ring 2.2.1. Synthesis of 6-ethynylazulenes Ito et al. reported also that Pd-catalyzed cross-coupling reac- tions is an an efficient method for ethynylation of azulene in a seven-membered ring. Thus, reaction of 6-bromoazulenes 42a– c[39] with trimethylsilylacetylene (TMSA) at room temperature under Pd catalysis afforded the 6-(trimethylsilylethynyl)azulenes 43a–c in 86, 84 and 100% yields, respectively. Treatment of 43a–c with potassium fluoride in DMF or DMF/THF furnished 6- ethynylazulenes 44a–c in 79, 92 and 96% yields, respectively (Scheme 6).[40–42] Moreover, Pd-catalyzed cross-coupling reaction of 42d with 1-hexyne and 1-decyne under Sonogashira- Hagihara conditions afforded diethyl 6-hexynyl- and 6-decynyl- 2-methoxyazulene-1,3-dicarboxylates (43d and 43e) in 85% and 87% yields.[43] Furthermore, Takase et al.[44] reported the synthesis of diethyl 6-ethynylazulene-1,3-dicarboxylates 46a,b by the reac- tion of diethyl 5-alkyl-2-chloroazulene-1,3-dicarboxylate 45a,b[45] with lithium acetylide in liquid ammonia by an abnormal substitution reaction (Scheme 7). A mechanism for this unusual substitution reaction seems to involve initial attack of the acetylide at the 6-position of the azulene nucleus to give an anionic intermediate with a cyclopentadienide structure which could be facilitated by the electron withdrawing groups Scheme 9. Reaction of diethyl 2-chloroazulene-1,3-dicarboxylate (49a–e) with lithium acetylide in liquid ammonia. Scheme 10. Synthesis of 1,8a-dihydro-7-ethynylazulene 55. Scheme 11. Synthesis of 7-alkynylazulene 57. Review 2016Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2016/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner at the 1- and 3-positions. Subsequent protonation at the 2- position and dehydrochlorination afforded the target ethynyla- zulene derivatives. Makosza et al. reported the synthesis of 1-cyano-6-trimeth- ylsilylethynylazulene (48) in 97% yield from 1-cyanoazulene (47) by firstly vicarious nucleophilic substitution (VNS) hydroxylation at 6-position to give 6-hydroxyazulene-1-carbonitrile followed by 6-O-sulphonylation to afford the corresponding trifluorome- thanesulfonate derivative and subsequent reaction with TMSA under Sonogashira conditions (Scheme 8).[46] 2.2.2. Synthesis of 4(8)- and 6-ethynylazulenes The reaction of diethyl 2-chloroazulene-1,3-dicarboxylate (49a) with lithium acetylide in liquid ammonia gave a mixture of diethyl 4- and 6-ethynylazulene-1,3-dicarboxylates 50a and 51a Scheme 12. Synthesis of some 1,8a-dihydroethynylazulenes 60–64. Review 2017Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2017/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 13. Conversion of 60a and 61a to azulene isomers 65–67. Scheme 14. Synthesis of 4,7-diethynyl-6-dodecylazulene 69. Scheme 15. Synthesis of 5,7-diethynylazulene 72. i) PPh3, CBr4, CH2Cl2, room temp.; ii) 6 equiv. LDA, THF, � 90 °C – room temp. Scheme 16. Synthesis of ruthenium complex 79. Review 2018Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2018/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner by an unusual substitution reaction. In a similar manner, some 2-chloroazulenes 49b–e, possessing alkoxycarbonyl and/or cyano substituents at the 1- and 3-position of azulene nucleus, gave a mixture of the corresponding 4 (or 8)- and 6- ethynylazulenes 50–52 (Scheme 9).[44,47] Scheme 17. Synthesis of the azulene complex 80. Scheme 18. Synthesis of dienes 83 and 84. Scheme 19. Synthesis of mono-diene 87 and di-diene 88. Review 2019Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2019/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner It is worthy to mention that Müller et al. reported earlier the synthesis of 4-alkynylazulene by the photochemical dimeriza- tion of o-diethynylbenzenes.[48,49] 2.2.3. Synthesis of 7-ethynylazulenes Nielsen et al. reported a protocol for the synthesis of 1,8a- dihydro-7-ethynylazulene 55 based on a regioselective bromi- Scheme 20. Synthesis of azulene derivatives bearing a methyl o-ethynylbenzoate 98a–d. Scheme 21. Synthesis of aryl-substituted 2-ethynylazulenes 103a–i. Review 2020Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2020/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner nation, followed by a regioselective elimination of HBr, and finally a palladium-catalyzed cross-coupling reaction with a terminal alkyne. Thus, treatment of the dibromide 53 with 1 molar equivalent of LiN(SiMe3)2 in THF gave 7-bromo-2-phenyl- azulene-1,1(8aH)-dicarbonitrile (54) in an 90% yield. Subsequent cross-coupling reaction of 54 with triisopropylsilylacetylene afforded the acetylenic 1,8a-dihydroazulene (DHA) 55 as yellow green solid (Scheme 10). The overall yield of the conversion of 53 to 55 was 45%. The dibromo compound 53 was obtained in quantitative yield by selective bromination of the correspond- ing dihydroazulene at the 7,8-positions (Scheme 10).[50] Scheme 22. Synthesis of diethyl 2-(phenylethynyl)-6-(pyrrolidin-1-yl)azulene-1,3-dicarboxylate 106. Scheme 23. Synthesis of 6-arylethynylazulene 110 and 4-(phenylethynyl)azulene 111. Scheme 24. Synthesis of diethyl 2,2’-diamino-6,6’-dibromo-[1,1’-biazulene]-3,3’-dicarboxylate 114. Scheme 25. Synthesis of 1,3-bis(phenylethynyl)azulene 121. Review 2021Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2021/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 26. Synthesis of 1,2-bis(phenylethynyl)azulene 95. Scheme 27. Synthesis of 2,6-bis(phenylethynyl)azulene 126. Scheme 28. Synthesis of 2,6-bis(arylethynyl)azulene 129. Scheme 29. Synthesis of 4,7-bis(arylethynyl)azulene 131. Review 2022Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2022/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Mazzanti et al. reported that subjecting of 3,7-dibromo-2- phenylazulene-1-carbonitrile 56 to a Sonogashira coupling with triisopropylsilylacetylene using the Pd(PPh3)2Cl2/CuI catalyst system gave only the mono coupled product 57 in 77% yield (Scheme 11).[51] 2.2.4. Synthesis of 4-, 5-, 6-, 7- and 8-ethynylazulenes Nielsen et al. reported the synthesis of some 1,8a-dihydroethy- nylazulenes 60–64 by the reaction of the electrophilic tropylium cation 59, obtained from 1,8a-dihydroazulenes (1,8a-DHAs) 58 incorporating two cyano groups at C-1 upon treatment with Scheme 30. Synthesis of bis(1-azulenyl)naphthalene derivatives 138–141. Scheme 31. Synthesis of 1-ethynylazulenes connected to arylamine 144 or carbazole 146 cores. Review 2023Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2023/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner [Ph3C]BF4 in refluxing 1,2-dichloroethane, with lithium triisopro- pylsilylacetylide (Scheme 12).[52] Noteworthily, generation of the azulenium ion required a long reaction time in the presence of the electron-withdrawing cyano substituent (R1). The position of attack of the acetylide anion was in general found to occur preferentially at positions C-4, C-5, and C-6, and to a minor extent at positions C-7 and C-8. The outcome was a mixture of non-photochromic, regioisomeric DHAs 60–64.[52] The 4-isomer 60a was partly tautomerized upon heating to the photoactive compound 65 (in 11%) and the corresponding azulene 66 (in 16%), arising from the loss of hydrogen cyanide. On the other hand, thermolysis of the 5-substituted isomer 61a in DMF did not yield any photoswitching products, instead significant conversion to the azulene 67 was achieved. The structure of 67 was confirmed by X-ray crystallography (Scheme 13). Scheme 32. Synthesis of azobenzene having two azulen-1-yl groups derivatives 148a and 148b. Scheme 33. Synthesis of azulene-substituted ethyne derivatives 151 and 152. Review 2024Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2024/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 2.2.5. Synthesis of 4,7-diethynylazulenes Murai et al. synthesized 4,7-diethynyl-6-dodecylazulene 69 in quantitative yield from the corresponding 4,7-dibromoazulene 68 via trimethylsilylethynylation and subsequent desilylation (Scheme 14).[53] 2.2.6. Synthesis of 5,7-diethynylazulenes Hafner et al. also achieved an ethynylation of the 5- and 7- position of azulene by using the Corey-Fuchs[11] method for the conversion of aldehydes into acetylenes. Thus, treatment of the corresponding 5,7-diformylazulene (70)[54] with triphenylphos- phane and tetrabromomethane in dichloromethane furnished the tetrabromo diolefin 71 as greenish-blue crystals in 70% yield. The latter could be converted into the 5,7-diethynylazu- lene (72; 86%) upon treatment with six equivalents of LDA (Scheme 15).[17] Thus with the described methods, azulene can be success- fully ethynylated at nearly all positions of its 5- and 7- membered rings. The ethynylazulenes so far prepared are slightly stable and can be easily manipulated under ambient conditions, especially as long as the alkyne groups are protected by trimethylsilyl groups. Most of the deprotected ethynylazulenes are only slightly stable at room temperature Scheme 34. Synthesis of azulene-substituted ethyne derivatives 153 and 154. Scheme 35. Synthesis of bis(6-azulenylethynyl)thiophene 159, terthiophene 160, and dithienothiophene 161. Review 2025Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2025/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner and form black solids with metallic luster after a few hours which could not be characterized so far due to their insolubility. The ethynyl substituents effect in all positions of the bicyclic system a bathochromic shift of the light absorption of azulene due to both inductive and mesomeric effects, respectively. Depending on the number and position of the ethynyl groups Scheme 36. Synthesis of bis(2-octyldodecyl)benzo[lmn][3,8]phenanthrolinetetraone 162. Scheme 37. Synthesis of naphthalenediimide (NDI) end-capped with 2-ethynylazulene units 167. Scheme 38. Synthesis of 1-ethynylazulenes connected to triphenylamine core 179. Review 2026Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2026/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner in the azulene-system the bathochromic shift ranged from 3– 48 nm. 3. Reactions of ethynylazulenes 3.1. Synthesis of bis(stannaylvinyl)-, bis(silylvinyl)- and bis (borylvinyl)azulenes Jung et al. reported a facile hydrostannation of 1,3-diethynyla- zulene 37c to the corresponding bis- stannylvinyl derivative 73 upon treatment with tributyltin hydride under thermal reaction (Figure 11).[55] Moreover, Lee et al. reported the hydrosilylation of 37c to 1,3-bis(chlorosilylvinyl)azulene 74 with dimethylsilyl chlorid in the presence of platinum catalyst (Figure 11). Among the platinum catalysts tested, the Karstedt catalyst exhibited the highest activity, completing the hydrosilylation under mild condition.[56] Lee et al. synthesized also 1,3-bis(borylvinyl) azulene products 75 by the Rh(I)-catalyzed hydroboration of 37c (Figure 11).[57] The hydrostannation, the hydrosilylation and the hydroboration products could then be used as precursors for interesting fluorescent dyes via the Stille cross-coupling reaction, substitution reactions or Suzuki cross-coupling reac- tions interesting fluorescent dyes. 3.2. Synthesis of ruthenium-alkynylazulene comlplexes Vlasceanu et al. reported on functionalization of DHA system with ruthenium-based Cp*(dppe)Ru ([Ru*]) metal complexes 76 and 77 (Figure 12).[58] Scheme 39. Synthesis of tripodal polyynes 180, 181, 183 and 184. a) 0.04 mol% PdCl2(PPh3)2, 0.08 mol% CuI, NEt3, rt; b) 1.1 equiv. 1 M KOH in H2O, MeOH, rt; c) 0.04 mol% PdCl2(PPh3)2, 0.08 mol% CuI, NEt3, 3 equiv. 10, rt; d) 0.04 mol% PdCl2(PPh3)2, 0.08 mol% CuI, NEt3, 3 equiv. 182, rt. Review 2027Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2027/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner The syntheses of ruthenium complex 79 was accomplished via the metalation strategy by combining 76 with 7-ethynyl- substituted DHA 78 (Scheme 16). The reaction proceeded through an isomerization by which the ruthenium-alkynyl substituent shifted from position 7 to position 6 on the DHA core. Scheme 40. Synthesis of 1,3,5-tris(3-ethynyl-5-isopropylazulen-1-yl)benzene 192. Figure 3. Structures of some substituted ethynylazulenes 12–17. Review 2028Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2028/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner On the other hand, a Sonogashira reaction between 77 and 7-bromo-substituted DHA 54 afforded minute quantities of the azulene complex 80 in which the alkyne substituent has moved to position 4 and a cyano group has been incorporated at position 7 via a more complex reactions (Scheme 17). 3.3. Synthesis of diene-substituted azulene Mikus et al. developed a selective synthesis of azulenes with an extended π-electron system by enyne cross-metathesis. Thus, when azulenes 81 and 82 bearing an acetylenic function on the five membered rings was subjected to enyne metathesis with ethylene in the presence of ruthenium catalyst 85, the corresponding dienes 83 and 84 were afforded in 20 and 8%, respectively (Scheme 18).[59] In the case of 1,3-diacetylenic substrate 86 a mixture of mono-diene 87 and di-diene 88 was produced in 7% and 5% yields, respectively (Scheme 19).[59] On the other hand, the metathesis of the appropriate acetylene-substituted azulenes in seven-membered ring pro- ceeds satisfactorily giving azulene-diene building blocks 89 and 90, respectively (Figure 13).[59] 3.4. Synthesis of azulenylethynylarenes and azulenylethynylheteroarenes 3.4.1. Synthesis of mono- azulenylethynylarenes or heteroarenes 3.4.1.1. From 1-ethynyl(halo)azulene Ito et al. and other research groups reported the synthesis of arylethynylazulenes 91–96 in 37–99% yield by Pd-catalyzed cross coupling of the appropriate ethynylazulene with haloar- enes or the inverse cross coupling reaction of the appropriate haloazulene with the corresponding ethynylbenzenes (Fig- ure 14).[23,25,26,60–66] Shoji et al. prepared azulene derivatives bearing a methyl o- ethynylbenzoate moiety 98a–c in excellent yields (97–99%) by the Sonogashira-Hagihara reaction of 1-iodoazulenes 97a–c Scheme 41. Synthesis of tris(1-arylacetylene) 193 and tris(1-azulenylacetylene) chromophores 194 and 195. Review 2029Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2029/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner with methyl o-ethynylbenzoate. A similar reaction was used to make compound 98d from 97d, however the yield was relatively low (58%) owing to the formation of 1,1’-biazulene 99 (17%) as a by-product. The generation of 1,1’-biazulene 99 might indicate that the transmetalation process of copper acetylide is a rate-determining step in the reaction of 97d. Scheme 42. Synthesis of tris(1-azulenylethynylarylacetylene) chromophores 196 and 197. Scheme 43. Synthesis of azulene-substituted butadiene 202. Review 2030Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2030/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner However, alkyne 98d was prepared in good yield (77%) by the reaction of 16 with methyl o-iodobenzoate, without the formation of 99, as shown in Scheme 20.[24] The Sonogashira Hagihara cross-coupling reaction of 1- ethynylazulene with excess of 1,4-diiodobenzene and 2,5- diiodothiophene at room temperature afforded methyl 3-[(4- iodophenyl)ethynyl]-7-isopropylazulene-1-carboxylate (100) and methyl 3-[(5-iodo-2-thienyl)ethynyl]-7-isopropylazulene-1-car- boxylate (101) both in 74% yield (Figure 15).[61] 3.4.1.2. From 2-ethynyl(halo)azulene Various aryl-substituted 2-ethynylazulenes 103a–i have been synthesized starting from 2-bromoazulene 102 by coupling with the corresponding ethynylarenes under Sonogashira coupling conditions using a catalytic amounts of CuI and Pd(PPh3)2Cl2 in the presence of an excess amount of Et3N. 2- Ethynylazulene 29 was also utilized as the key starting material to prepare the corresponding aryl-substituted 2-ethynylazu- lenes 103 by reacting with the appropriate aryl halides under Sonogashira coupling conditions (Scheme 21).[67] Although Sonogashira-Hagihara cross-coupling of 105, obtained upon treatment of diethyl 6-(pyrrolidin-1-yl)azulene- 1,3-dicarboxylate 104, with ethynylbenzene in the presence of 3 mol% Pd-catalyst and 10 mol% CuI produced the cross- coupling product 106 in low yield (12%) along with the recovery of 105 (85%), the use of excess CuI (50 mol%) has shown a significant improvement of the yield of 106 (89%) (Scheme 22). These results suggest the coordination of CuI to the pyrrolidine moiety in 105 that leads to a decrease in the activity of the Cu-catalyst because 2-haloazulenes without the 6-amino substituent give the products in good-to-excellent yields in the presence of catalytic amount of CuI.[68] Scheme 44. Synthesis of (1,4-phenylenebis(buta-1,3-diyne-4,1-diyl))bis(azulene) 205. Scheme 45. Synthesis of bis(azulen-1-yl)ethynes 207a and 207b. Scheme 46. Synthesis of methyl 7-isopropyl-3-((5-isopropyl-2-oxo-2H-cyclohepta[b]furan-3-yl)ethynyl)azulene-1-carboxylate 212. Review 2031Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2031/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.4.1.3. From 6-ethynyl(halo)azulene Ito et al. and other research groups reported the synthesis of arylethynylazulene 107a–e in 37–95% yield by Pd-catalyzed cross coupling of the appropriate ethynylazulene with haloar- enes or the inverse cross coupling reaction of the appropriate halooazulene with the corresponding ethynylbenzenes (Fig- ure 16). Compound 107e was subsequently thermally deal- koxycarboxylated with LiCl to give 2-hydroxy-6-phenylethynyl- azulene 108 in 56% yield.[69] 6-Arylethynylazulene 110 could be alternatively obtained in 38% yield together with 4-(phenylethynyl)azulene 111 (45%) by an unusual substitution reaction of 2-chloro-1,3-azulene dicar- boxylic acid diethylester (109) with lithium phenylacetylide in liq. ammonia (Scheme 23).[44] Förster et al. synthesized diethyl 2-amino-6-[(thiophen-3-yl) ethynyl]azulene-1,3-dicarboxylate 112[37] starting from the di- ethyl 2-amino-6-bromoazulene-1,3-dicarboxylate upon treat- ment with 3-ethynylthiophene in a mixture of diisopropylamine and tetrahydrofuran (Figure 17).[70] Scheme 47. Synthesis of di-2-azulenylacetylene 218. Scheme 48. Synthesis of 6-(1-azaazulen-2-yl)ethynylazulene (224a) and 6-(2-azulenyl)ethynylazulene (224b). Review 2032Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2032/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner The Sonogashira Hagihara reaction of diethyl 2,2’-diamino- 6,6’-dibromo-[1,1’-biazulene]-3,3’-dicarboxylate 114 with ethy- nylbenzene, using [Pd(PPh3)4] as a catalyst, afforded the cross- coupled product 115 in 91% yield. Compound 114 was obtained in 76% yield by homocoupling reaction of the corresponding 2-aminoazulene 113 using 6 mol% CuBr and 18 mol% pyridine in toluene at 60 °C under aerobic conditions (Scheme 24).[71] 3.4.1.4. From 7-bromoazulene 7-Arylethynyldihydroazulenes 116a–c were prepared by a similar palladium-catalyzed Sonogashira cross-coupling reac- tions employing a suitable bromo-functionalized dihydroazu- lene 54. The dihydroazulenes 116a–c underwent a light- induced ring-opening to vinylheptafulvenes (VHFs) which were thermally converted to a mixture of two DHA regioisomers, one of which the original dihydroazulenes 116 and the other was 6- arylethynyldihydroazulenes 117a–c, in a ratio that depends on the wavelength of irradiation and solvent polarity (Figure 18). The influence of the aryl groups on the DHA and VHF interconversion was investigated and rates of the switching events were finely tuned by the donor or acceptor strength of the aryl group.[72] Scheme 49. Synthesis of poly(azulen-1-ylethynes) 182, 225 and 226. Scheme 50. Synthesis of poly(azulen-1-ylethynes) 227 and 228. Scheme 51. Synthesis of 1,3-bis(1-azulenylethynyl)azulene 230. Review 2033Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2033/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 52. Synthesis of bis(azulen-2-ylethynyl)azulenes 235a and 235b and bis(azulen-6-ylethynyl)-1,3-azulenes 236a–c. Scheme 53. Synthesis of 1,4-di(azulen-1-yl)buta-1,3-diynes 237a and 237b. Scheme 54. Synthesis of butadiynylene-bridged trimer 245a and tetramer 245b. Review 2034Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2034/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 55. Synthesis of oligoazulene with mixed ethynyl and butadienyl bridges 247. Scheme 56. Synthesis of oligoazulene with mixed ethynyl and butadienyl bridges 247–249. Scheme 57. Synthesis of oligoazulene with mixed ethynyl and butadienyl bridges 237b, 250 and 251. Review 2035Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2035/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.4.2. Synthesis of azulenylethynyl-ferrocene (Ferrocenylethynyl)azulenes 118–120 were prepared in excel- lent yields by palladium-catalyzed alkynylation of ethynylferro- cene with the corresponding haloazulenes under the Sonoga- shira-Hagihara conditions (Figure 19).[73] 3.4.3. Synthesis of bis(arylethynyl)azulene 3.4.3.1. 1,3-Bis(arylethynyl)azulene Application of Sonogashira coupling conditions on the reaction of 1,3-diiodoazulene 10a with an excess amount of phenyl acetylene at elevated temperature gave 1,3-bis(phenylethynyl) azulene 121 in very good yield (Scheme 25).[69] Using a similar approach, Förster et al. and Thanh et al. reported the synthesis of some 1,3-bis(arylethynyl)azulenes 122a–f in moderate to good yields by the reaction of 1,3- diiodoazulene with the corresponding arylacetylenes. However, the synthesis of 1,3-bis[(4-acetylthiophenyl)ethynyl]azulene 122g was adopted in 15% yield by the reaction of 1,3- diethynylazulene with 4-(acetylthio)iodobenzene (Fig- ure 20).[74–76] Schwarz et al. reported the synthesis of 122 in 93% yield by the reaction of 1,3-diiodoazulene with S-(4-ethynyl- phenyl) ethanethioate.[77] Nöll et al. also reported the synthesis of 1,3-bis[4-{N,N-di(4-methoxyphenyl)amino}phenyl-ethynyl] azulene 122h by the reaction of N,N-di(4-methoxyphenyl)-N-(4- ethynylphenyl)amine with 1,3-dibromoazulene.[78] Chen et al. employed a sealed oxygen-free two-chamber reaction system Scheme 58. Synthesis of mono- and bis(enediyne)s attached to anthracene and fluorene 255a,b and 259a,b. Figure 4. Structures of some N-(3-(azulen-1-yl)prop-2-yn-1-yl)-4-meth- ylbenzenesulfonamides 22a–h. Review 2036Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2036/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner for the synthesis of 122 i via Sonogashira coupling reaction of dihaloazulene with 2-ethynyl-6-methoxynaphthalene to over- come the presence of homocoupling side reactions.[79] Filichev et al. also reported the synthesis of 2-(4-{3-[4-(2-hydroxyeth- oxymethyl)phenylethynyl]azulen-1-ylethynyl}benzyloxy)ethanol 122 by Sonogashira coupling reaction of 1,3-diiodoazulene with 2-(4-ethynylbenzyloxy)ethanol (Figure 20). Compound 122 j was prepared to act as a precursor for intercalating linker to connect two 8-mer sequences with inverted polarity to generate a Hoogsteen-type triplex, with a considerable increase in the thermal stability.[80] 3.4.3.2. 1,2-Bis(arylethynyl)azulene 1,2-Bis(phenylethynyl)azulene 124 was prepared in 91% yield from 2-(phenylethynyl)azulene 103a by firstly iodination with 1 eq. of NIS to give 1-iodo-2-(phenylethynyl)azulene 123 followed by Sonogashira coupling with phenylacetylene (Scheme 26).[69] 3.4.3.3. 2,6-Bis(arylethynyl)azulene 2,6-Bis(phenylethynyl)azulene 126 was obtained in 96% yield starting from 6-(phenylethynyl)azulen-2-ol 108 by firstly con- version to the corresponding bromo derivative 125 (68%) upon treatment with PBr3 followed by Sonogashira coupling with phenylacetylene (Scheme 27).[69] 2,6-Bis(arylethynyl)azulene 129 was obtained in 92% yield starting from 2,6-bis(bromo)azulene 127 by Sonogashira cou- pling with S-(4-ethynylphenyl) ethanethioate 128 (Scheme 28).[77] Azulene derivative 129 could be highly interesting building blocks for memory applications or neuromorphicdevices in next-generation nanoelectronic applications. Scheme 59. Synthesis of azulene-substituted bis(enediyne) systems 263a and 263b. Review 2037Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2037/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 60. Synthesis of mono(enediyne) derivatives 267a and 267b. Scheme 61. Synthesis of 1,2,4-tris(azulen-1-yl)benzene derivatives 272a and 272b. Review 2038Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2038/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 62. A plausible mechanism for the formation of 1,2,4-tris(azulen-1-yl)benzenes 272 and 275–277. Scheme 63. Synthesis of tris(azulen-6-yl)benzenes 280 and 281. Scheme 64. Synthesis of (cyclobutadiene)cobalt complexes 283 and 284. Review 2039Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2039/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.4.3.4. 4,7-Bis(arylethynyl)azulene 4,7-Bis(phenylethynyl)azulene 131 was synthesized in 93% yield starting from 4,7-dibromoazulene 130[81,82] upon treatment with phenylacetylene under Sonogashira conditions (Scheme 29).[69] Using a similar approach, Schwarz et al. synthesized 4,7-bis (arylethynyl)azulene 132 in 84% yield starting from the corresponding 4,7-dibromoazulene (Figure 21).[77] 3.4.4. Synthesis of bis(azulenylethynyl)arenes or heteroarenes 3.4.4.1. From 1-ethynyl(halo)azulene Hafner et al.[83] reported the synthesis of 1,4-bis(azulen-1- ylethynyl)benzene 133 as well as 2,5-bis(azulen-1-ylethynyl) thiophene 134 from 1,4-diiodobenzene and 2,5- diiodothiophene,[84] respectively, via a Sonogashira coupling with the appropriate ethynylazulene in good yield (Figure 22). Likewise, the reaction of methyl 3-iodo-7-isopropylazulene- 1-carboxylate with 1,4-diethynylbenzene afforded 1,4-bis[(5- isopropyl-3-methoxycarbonyl-1-azulenyl)ethynyl]benzene (135) in 91% yield. 2,5-Bis[(5-isopropyl-3-methoxycarbonyl-1-azulenyl) ethynyl]thiophene 136 was also obtained by the reaction of 1- ethynylazulene derivative 13 with 2,5-diiodothiophene in the presence of [Pd (PPh3)4] in 72% yield (Figure 23).[23] Bis(1-azulenyl)naphthalene derivatives 138–141[65] were also synthesized by Pd-catalyzed alkynylation of iodoazulene 98b with the corresponding diethynylnaphthalenes 137 (Scheme 30).[85] Scheme 65. Synthesis of bis(trimethylsilyl)-cyclobutadiene]cobalt complexes 286 and 287. Scheme 66. Synthesis of tetrakis(azulen-1-yl)cyclobutadiene cobalt complexes 289a,b. Review 2040Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2040/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 67. Synthesis of 1-(3’,6’-diphenyl-[terphenyl]-4’-yl)azulene 294 and 1,3-bis(3’,6’-diphenyl-[terphenyl]-4’-yl)azulene 295a,b. Scheme 68. Synthesis of 1,2-bis(2-azulenyl)tetraphenylbenzene 298 and diazuleno[2,1-a:1,2-c]naphthalene (299). Review 2041Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2041/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Shoji et al. synthesized dihexyl 3,3’-(pyrene-1,6-diylbis (ethyne-2,1-diyl))bis(7-isopropylazulene-1-carboxylate) 142 us- ing a similar approach (Figure 24).[66] 1-Ethynylazulenes connected to arylamine 144 or carbazole 146 cores have been prepared in 94% and 85% yields, respectively, via cross-coupling of 3,6-diiodo-9H-carbazole 143 and bis(4-iodophenyl)amine 145, respectively, with methyl 3- ethynyl-7-isopropylazulene-1-carboxylate 13 using Pd(PPh3)4 as a catalyst (Scheme 31).[62] The azobenzene derivatives 148a and 148b having two azulen-1-yl groups were prepared in 65% and 86% yields, respectively, by a similar cross-coupling reaction of 4,4-dieth- ynylazobenzene 147 (DEABz) 147 with iodoazulenes 98d and 98b.[64] Compounds 148a and 148b could also be synthesized by copper-mediated oxidative homocoupling reaction of 91d and 91h in 86% and 77% yields, respectively (Scheme 32).[86] Kim et al. reported the synthesis of 5,15-bis(azulenylethynyl) substituted zinc(II) porphyrin 150 in 43% yield by Sonogashira coupling reactions of 5,15-diethynyl zinc(II) porphyrin 149 with 1-iodo-3-hexyloxycarbonylazulene (Figure 25).[87] Insertion of additional phenylalkyne groups to the skeleton of 91 and 92 was employed by Sonogashira coupling of phenylacetylene with the appropriate iodo derivatives 100 and 101 to give azulene-substituted ethyne derivatives 151 and 152, respectively (Scheme 33).[61] Using the same methodology, azulene-substituted ethyne derivatives 153 and 154 could be obtained by Sonogashira coupling of iodo derivatives 100 and 101 with diethynylben- zene (Scheme 34).[61] Scheme 69. Synthesis of 1-azulenylketones 300a–g. Scheme 70. Synthesis of diketone 302. Review 2042Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2042/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 71. A plausible mechanism for the formation of ketone 300. Scheme 72. Synthesis of azulene-substituted benzofurans 305a–d. Scheme 73. Synthesis of 2-(1-azulenyl)benzofurans 307a–d and 308a–d. Review 2043Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2043/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.4.4.2. From 6-ethynylazulene Likewise, diazulen-6-ylethynylbenzenes 155a,b can also be prepared in 25 and 43% yields, respectively, by the Pd catalyzed cross coupling reaction of of the appropriate 6-ethynylazulene with 1,4-diiodobenzene (Figure 26).[40] Similarly, preparation of bis(6-azulenylethynyl)thiophene 159, terthiophene 160, and dithienothiophene 161 was accom- plished by the palladium-catalyzed cross-coupling reaction of 6- ethynylazulene 44 with the corresponding diiodides 156–158, respectively, under Sonogashira-Hagihara conditions (Scheme 35).[38] The absorption band of these compounds in their UV/Vis spectra spreads into the near-infrared region due to the decrement of HOMO-LUMO energy gap basis on the expansion of the π-conjugated system.[88] Furthermore, Xin et al. reported the synthesis of 1,4,5,8- naphthalenediimide (NDI) end capped with 6-ethynylazulene units 163 by the palladium-catalyzed cross-coupling reaction of 6-ethynylazulene 44b with 4,9-dibromo-2,7-bis(2-octyldodecyl) benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone 162, under Sonogashira-Hagihara conditions (Scheme 36).[89] 5,15-Bis(azulenylethynyl) substituted zinc(II) porphyrin 164 was obtained in 87% yield by Sonogashira coupling reactions of 5,15-diethynyl zinc(II) porphyrin 149 with 6-bromo-1,3-dihex- yloxycarbonylazulene (Figure 27).[87] Porphyrin 166 was prepared in overall 87% yield from the partially silylated intermediate 165, which was prepared from 149 upon treatment with triisopropylsilyl chloride (TIPSCl) in the presence of lithium bis(trimethylsilyl)amide and pyridine. Thus, Sonogashira coupling reaction of 165 with 1-iodo-3- hexyloxycarbonylazulene followed by desilylation and subse- Scheme 74. A plausible mechanism for the formation of 2,3-bis(1-azulenyl)benzofuran derivatives 307. Scheme 75. Synthesis of 1-azulenylisocoumarin derivatives 311a–d and 312a–d. Review 2044Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2044/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner quent coupling with 6-bromo-1,3-dihexyloxycarbonylazulene afforded 166 in overa 87% yield (Figure 28).[87] Intramolecular charge transfer in 5,15-bis(azulenylethynyl) substituted zinc(II) porphyrin leads to a significant enhancement of two-photon absorption at near-IR region, which has been investigated by femtosecond Z-scan method. 3.4.4.3. From 2-ethynylazulene Using a similar approach, the same group reported the synthesis of 1,4,5,8-naphthalenediimide (NDI) end-capped with 2-ethynylazulene units 167 in 65% yield by the palladium- catalyzed cross-coupling reaction of 2-ethynylazulene 29 with 162 (Scheme 37). It is interesting that these two compounds show remarkably different physicochemical properties, thermal stabilities and organic field-effect transistors (OFET) perform- ance resulting from the different connections of an electron- rich five-membered ring and an electron-poor seven-membered ring.[89] 3.4.5. Synthesis of star-shaped azulenylethynylbenzene and azulenylethynylthiophene 3.4.5.1. From 1-ethynyl(halo)azulene Elwahy and Hafner used Sonogashira coupling method in the synthesis of benzene- and thiophene-bridged polyalkynylazu- lenes. The synthesis of poly(azulen-1-ylethynyl) benzene deriva- Scheme 76. Synthesis of azuleno[2,1-b]thiophenes 313a–m. Review 2045Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2045/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner tives 168–170 was performed in 22–44% yields by coupling of the appropriate polyhalobenzene with the corresponding equivalents of 1-ethynylazulene 4b in the presence of bis (triphenylphosphine)palladium chloride and CuI in triethylamine (TEA).[90] The isolation of the pentakis(azulen-1-ylethynyl)- benzene 170 from the coupling reaction of 4b with hexaiodobenzene[91] instead of the expected hexakis analogue may be as a result of a competitive reductive deiodonation of one iodosubstituent of hexaiodobenzene.[92] Similarly, tetrakis(1- azulenylethynyl)thiophene 171 can be prepared in 75% yield by Pd-catalyzed alkynylation of tetraiodothiophene[93] with ethyny- lazulene 4b (Figure 29).[83] 6-tert-Butyl-1-ethynylazulene (4b) was chosen as a starting material to secure the solubility of the products. This procedure has been utilized by Ito et al to synthesize poly(azulenylethynyl)arene derivatives 173 and 174. Tris (azulenylethynyl)benzene was obtained by the reaction of 1- iodoazulene with the corresponding tris(ethynyl)benzene 172. On the other hand, tetrakis(azulenylethynyl)benzene 174 was obtained by the inverse cross-coupling Pd-catalyzed alkynyla- tion of tetraiodobenzene with ethynylazulene (Figure 30).[23] Scheme 77. A plausible mechanism for the formation of azuleno [2,1-b]thiophene derivatives 313. Scheme 78. Synthesis of pyrrole-fused azulene derivative 318. Scheme 79. Synthesis of ethyl 3-(5-isopropyl-3-(methoxycarbonyl)azulen-1-yl)-1-oxo-1H-azuleno[1,2-c]pyran-5-carboxylate 319. Review 2046Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2046/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Following a similar methodology, Shoji et al. reported also the synthesis of 1-ethynylazulenes connected to pyrene 175, hexaphenylbenzene 176, hexabenzocoronene 177 cores (Fig- ure 31).[72,94] Scheme 80. Synthesis of 2-[1,3-bis(ethoxycarbonyl)azulen-6-yl]benzoazoles 321a and 321b. Scheme 81. Synthesis of 5H-azuleno[5’,6’:3,4]cyclobuta[1,2-d]dibenzo[b,f]silepine 324. Scheme 82. Reaction of ethynylazulene 13 with (TCNE) and (TCNQ). Scheme 83. Synthesis of compounds 330e and 333 from the reaction of 91f with TCNQ. Review 2047Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2047/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 84. Synthesis of compound 385 by the subsequent reaction of 202 with TCNE and TTF. Scheme 85. Reaction of butadiyne 242b with TCNE. Scheme 86. Reaction of 1,4-bis(azulen-1-ylbuta-1,3-diyn-1-yl)benzene 205 with TCNE. Review 2048Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2048/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 1-Ethynylazulenes connected to triphenylamine core have also been reported. Thus, Shoji et al. reported the synthesis of trimethyl 3,3’,3’’-((nitrilotris(benzene-4,1-diyl))tris(ethyne-2,1- diyl))tris(7-isopropylazulene-1-carboxylate) 179 in 90% yield[62] by the cross-coupling reaction of tris(4-iodophenyl)amine 178[95] with methyl 3-ethynyl-7-isopropylazulene-1-carboxylate 13 in the presence of catalytic palladium (Scheme 38). Moreover, Hafner and Elwahy[90] reported on the peripheral extention of the skeleton of 168 by insertion of additional azulenylalkyne groups. Thus, the new tripodal polyynes 180, 181, 183 and 184 were synthesized as shown in scheme 28. 1,3,5-Triethynylbenzene (172)[96] underwent Pd/Cu-catalyzed cross coupling reaction with 6-tert-butyl-1-iodo-3-trimeth- ylsilylethynylazulene (10) in TEA at room temperature to afford a 53% yield of 180 as green crystals. Desilylation of the latter compound with KOH in methanol furnished the core molecule 181 in almost quantitative yield. Subsequent catalytic cross coupling reaction of 181 with 10 as well as with 1-(6-tert-butyl- 3-iodoazulene-1-yl)-2-(6-tert-butyl-3-trimethylsilylethynylazulen- 1-yl)ethyne (182) led to the formation of the corresponding tripodal polyynes 183 (36%) and 184 (29%), respectively (Scheme 39). The electronic absorption spectra of the polyynes 180, 184, and 184 exhibit an increase in the absorption maxima from 602 nm for 180 to 625 nm for 183 and 631 nm for 184. Scheme 87. Synthesis of 2-((1H-pyrrol-3-yl)(azulen-1-yl)methylene)malononitrile 391. Scheme 88. Synthesis of ((5-(azulen-1-yl)-2,4-dicyanocyclopenta-2,4-dien-1-ylidene)methyl)carbamates 392a–i. Review 2049Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2049/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Ito et al. has also synthesized tris- and tetrakis[(1-azulenyle- thynyl)phenylethynyl- and (1-azulenylethynyl)-2-thienylethynyl] benzenes 185–188 in 74–85% yield from the appropriate iodo derivatives via Sonogashira coupling with the corresonding polyalkynylbenzenes (Figure 32).[61] 1,3,5-Tris(3-ethynyl-5-isopropylazulen-1-yl)benzene 192 was prepared as outlined in scheme 2. Thus, 1,3,5-tris(5-isopropyl-3- methoxycarbonyl-1-azulenyl)benzene (189), obtained in 56% yield by trimerization of methyl 3-acetyl-7-isopropylazulene-1- carboxylate with excess thionyl chloride (SOCl2) in ethanol at Scheme 89. Synthesis of 7-(1-(azulen-1-yl)-2,2-dicyanovinyl)-1H-pyrrolo[3,2-b]pyridines 396a–e. Scheme 90. Synthesis of 2-((furan-3-yl)(azulen-1-yl)methylene)malononitrile 398a–h. Review 2050Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2050/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Scheme 91. Presumed reaction mechanism for the reaction of 3-(1-azulenyl)-2-propyn-1-ols 24 with TCNE. Figure 5. Structures of some tert-butyl (3-(azulen-1-yl)prop-2-yn-1-yl) carbamate derivatives 23a–j. Figure 6. Structures of some 3-(azulen-1-yl)prop-2-yn-1-ol derivatives 24a–j. Review 2051Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2051/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner room temperature, underwent removal of the three ester functions by heating in 100% H3PO4 to give 190. Subsequent iodination of 190 with N-iodosuccinimide (NIS) at 0 °C in excellent yield afforded 191 in 90% yield. The reaction of 191 with trimethylsilylacetylene in the presence of [Pd(PPh3)4] as a catalyst at 50 °C gave the protected alkyne derivative in 94% yield followed by desilylation upon treatment with KOH in iPrOH at reflux to afford 192 in 92% yield (Scheme 40).[97] The tris(3-iodo-1-azulenyl)benzene 191 was succefully uti- lized as a precursor for tris(1-arylacetylene) 193 and tris(1- azulenylacetylene) chromophores 194 and 195 each connected to a 1,3,5-tri(1-azulenyl)benzene core. Thus, compounds 193– 195 were prepared by the Sonogashira-Hagihara reaction of tris (3-iodo-1-azulenyl)benzene derivative 191 with the correspond- ing alkyne precursors in the presence of [Pd(PPh3)4] as a catalyst in THF/triethylamine at 50 °C (Scheme 41).[25,97] Tris(1-azulenylethynylarylacetylene) chromophores 196 and 197 connected to a 1,3,5-tri(1-azulenyl)benzene core were also prepared by simple Pd-catalyzed alkynylation of alkyne 192 with the appropriate iodo derivatives 100 and 101 under Sonogashira-Hagihara cross-coupling conditions. (Scheme 42).[97] 3.4.5.2. From 6-ethynyl(halo)azulene Ito et al. synthesized poly(azulen-6-ylethynyl)arene derivatives 198–200[40] via cross-coupling reactions of 6-bromoaloazulene Figure 7. Structures of some 2-ethynylazulene derivatives 28–32. Figure 8. Structures of some 1,3-diethynylazulenes 37a–d. Figure 9. Structures of some 1,3-diethynylazulene derivatives 38 and 39. Review 2052Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2052/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner with the corresponding polyethynylbenzene (Figure 33). These compounds exemplify a principle for multielectron redox behavior and at the same time display liquid crystalline properties.[98] 3.4.5.3. From 2-ethynyl(halo)azulene Ito et al reported also the synthesis of hexakis(azulen-2- ylethynyl)benzene 201[10b] via Pd-catalyzed alkynylation of hexa (iodo)benzene with the 2-ethynylazulene (Figure 34). 3.4.6. Synthesis of azulenyl-butadiinylbenzene Azulene-substituted butadiene 202 was obtained by Cu-medi- ated Hay cross- and Glaser homo-coupling conditions.[99] Thus, cross-coupling reaction of methyl 7-isopropyl-3-ethynylazulene- 1-carboxylate 13 with excess of ethynylbenzene, using CuI/ tetramethylethylenediamine (TMEDA) as a catalyst, afforded 202 in 74% yield (Scheme 43).[100] Butadiyne 203 was obtained in 76% yield by the reaction of 13 with 5 equiv. trimethylsilylacetylene. Deprotection of 203 with potassium carbonate solution generate the corresponding butadiyne 204. The cross-coupling reaction of 204 with 1,4- diiodobenzene using Pd(PPh3)4 as a catalyst, afforded (1,4- phenylenebis(buta-1,3-diyne-4,1-diyl))bis(azulene) 205 in 87% yield (Scheme 44).[54] Furthermore, the Eglinton[101] coupling of 1,3-diethynylazu- lene 37b in the presence of phenylacetylene as end-capping reagent afforded butadiynylene-bridged compound 206a in 58% yield. In addition to 206a, higher oligomers 206b and 206c could also be isolated in 7 and 2% yields, respectively (Figure 35).[102] Figure 10. Structures of 1,2-di- and 1,2,3-triethynylazulenes 40 and 41. Figure 11. Structures of bis(stannaylvinyl)-, bis(silylvinyl)- and bis(borylvinyl)azulenes. Figure 12. Structures of ruthenium-based Cp*(dppe)Ru ([Ru*]) metal com- plexes 76 and 77. Figure 13. Structures of azulene-dienes 89 and 90. Review 2053Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2053/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.5. Synthesis of oligoazulenes 3.5.1. Bis-azulenes with ethynyl bridges 3.5.1.1. Bis(azulen-1-yl)ethynes After the successful synthesis of arylethynylazulenes by Sonoga- shira coupling reaction, the same methodology has been applied to the synthesis of oligoazulenes with ethynyl bridges. Thus, Hafner et al. reported the synthesis of the bis(azulen-1-yl) ethynes 207a and 207b in 40% and 32% yields, respectively, by Sonogashira coupling of the deprotected 1-ethynylazulenes 4a and 4b with 1-iodoazulenes 5a and 5b (Scheme 45).[17] Similarly, bis(azulenyl)acetylenes 208–210 could be ob- tained by Pd-catalyzed coupling of the appropriate ethynylazu- lene with the corresponding iodoazulenes (Figure 36).[17,20,23–25,64] 3.5.1.2. (Cyclohepta[b]furan-3-yl)ethynylazulene The Sonogashira-Hagihara reaction of methyl 3-ethynyl-7- isopropylazulene-1-carboxylate 13 with 3-iodo-5-isopropyl-2H- Figure 14. Structures of some arylethynylazulenes 91–96. Figure 15. Structures of iodophenylethynylazulene 100 and (5-iodo-2- thienyl)ethynyl]azulene 101. Figure 16. Structures of some arylethynylazulene 107a–e and 108. Figure 17. Structure of diethyl 2-amino-6-[(thiophen-3-yl)ethynyl]azulene- 1,3-dicarboxylate 112. Review 2054Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2054/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner cyclohepta[b]furan-2-one 211 gave methyl 7-isopropyl-3-((5- isopropyl-2-oxo-2H-cyclohepta[b]furan-3-yl)ethynyl)azulene-1- carboxylate 212 in 91% yield (Scheme 46).[103] 6-(tert-Butyl)-1-((6-(tert-butyl)azulen-1-yl)ethynyl)-3-ethynyla- zulene 213 was prepared by a Pd/Cu-catalyzed cross-coupling reaction of 6-tert-butyl-1-trimethylsilylethynyl-3-iodoazulene 10 with 6-tert-butyl-1-ethynylazulene 4b and subsequent desilyla- tion with methanolic potassium hydroxide (Figure 37).[17] 3.5.1.3. Bis(azulen-2-yl)ethynes Di-2-azulenylacetylenes 214a–d were obtained by the Pd- catalyzed cross-coupling reaction of the appropriate 2-iodoazu- lenes with the corresponding 2-ethynylazulenes (Fig- ure 38).[33–35] Di-2-azulenylacetylene 218 was alternatively prepared start- ing from azulene-2-carbaldehyde (33).[29] Thus, benzoin con- densation reaction of 33 in the presence of potassium cyanide afforded 215 which underwent subsequent oxidation with activated manganese-(IV) oxide to give the di-2-azulenylethane- dione (216) in 77% overall yield. The reaction of 216 with hydrazine monohydrate in ethanol at reflux afforded the dihydrazone 217 in 92% yield. Treatment of 217 with copper(II) acetate in a mixture of methanol and dichloromethane afforded the desired 218 in 76% yield (Scheme 47).[35,38] 3.5.1.4. Bis(azulen-6-yl)ethynes The cross coupling reaction of the 6-bromoazulenes with the corresponding 6-ethynylazulenes utilizing Pd(PPh3)4 as a cata- lyst exclusively gave the desired bis(azulen-6-yl)ethynes 219a and 219b in 98 and 96% yields, respectively (Scheme 39).[42] 3.5.1.5. (1-Azulenyl)(2-azulenyl)acetylene (1-Azulenyl)(2-azulenyl)acetylene 220a was obtained in 99% yield by the cross coupling reaction[104] of 13 with 2-iodoazulene 97b[35] in the presence of Pd(PPh3)4 as a catalyst in THF/Et3N at 50 °C. The reaction of diethyl 2-chloroazulene-1,3-dicarboxylate (109)[32] with 1-ethynylazulene 13 under similar reaction con- ditions afforded 220b[104] in 92% yield (Figure 39). Although azulenyl chlorides are usually less reactive toward the palladium catalyzed cross-coupling reaction than azulenyl iodides and bromides,[105] high yield of the product 220b was attributable to both the high reactivity of 1-ethynylazulene and the electro- Figure 18. Structures of 7-arylethynyldihydroazulenes 116a–c and 6-arylethynyldihydroazulenes 117a–c. Figure 19. Structures of some (ferrocenylethynyl)azulenes 118–120. Review 2055Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2055/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner nwithdrawing nature of the 1,3-bis-ethoxycarbonyl groups on the azulene ring, which should increase the reactivity toward the oxidative addition of the palladium catalyst. 3.5.1.6. (1-Azulenyl)(6-azulenyl)acetylene The cross-coupling reaction of the appropriate 6- bromoazulenes[39,106] with the corresponding 1-ethynylazulene in the presence of the palladium catalyst afforded (1-azulen- yl)(6-azulenyl)acetylenes 221a–c in 92–99% yields (Fig- ure 40).[105] Figure 20. Structures of some 1,3-bis(arylethynyl)azulenes 122a–i. Figure 21. Structures of 4,7-bis(arylethynyl)azulene 132. Figure 22. Structures of 1,4-bis(azulen-1-ylethynyl)benzene 133 and 2,5-bis(azulen-1-ylethynyl)thiophene 134. Review 2056Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2056/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.5.1.7. 6-(2-Azulenyl)ethynylazulene 6-(1-Azaazulen-2-yl)ethynylazulene (224a) and 6-(2-azulenyl) ethynylazulene (224b), were synthesized using the Sonoga- shira-Hagihara cross-coupling reaction of 6-ethynylazulene 44b with 2-iodoazaazulenes 222 and 28a, respectively, to give the corresponding diazulenylethyne 223 followed by decarboxyla- tion with concentrated phosphoric acid (Scheme 48).[107] 3.5.2. Poly(azulenylethynes) 3.5.2.1. Poly(azulen-1-ylethynes) Moreover, Hafner et al. reported on the extension of the skeleton of 207 by substitution with additional azulenylethyne groups utilizing 6-tert-butylazulene derivatives to ensure suffi- cient solubility of the higher oligomers in organic solvents and thus to enable easier isolation and purification. The trimeth- Figure 23. Structures of 1,4-bis[(3-methoxycarbonyl-1-azulenyl)ethynyl]benzene (135) and 2,5-bis[(3-methoxycarbonyl-1-azulenyl)ethynyl]thiophene 136. Figure 24. Structure of 3,3’-(pyrene-1,6-diylbis(ethyne-2,1-diyl))bis(7-isopropylazulene-1-carboxylate) 142. Figure 25. Structure of 5,15-diethynyl zinc(II) porphyrin 149 and 5,15-bis(azulenylethynyl) substituted zinc(II) porphyrin 150. Figure 26. Structures of diazulen-6-ylethynylbenzenes 155a,b. Review 2057Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2057/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner ylsilyl-protected iodoethynylazulene 182 was synthesized in 68% yield together with 13% of the trimer 225 and 6% of the tetramer 226 by cross-coupling of 6-tert-butyl-1-ethynyl-3- iodoazulene (11) with 10 (Scheme 49).[17] The trimer 227 and the pentamer 228 could be obtained in 66 and 26%, respectively, by coupling two equivalents of the ethynylazulenes 4b as well as 213 with 6-tert-butyl-1,3- diiodoazulene (9b) at room temperature under Sonogashira conditions (Scheme 50).[17] Under similar conditions, Elwahy reported the synthesis of 3,3’-((6-(tert-butyl)azulene-1,3-diyl)bis(ethyne-2,1-diyl))bis(1- (3’,6’-diphenyl-[1,1’:2’,1’’-terphenyl]-4’-yl)azulene) 229 in 41% yield by coupling two equivalents of the ethynylazulene 7 with 6-tert-butyl-1,3-diiodoazulene (9b) (Figure 41).[20] Shoji et al. used a similar approach for the synthesis of 1,3- bis(1-azulenylethynyl)azulene 230 in 95% yield by the reaction of 6-tert-butyl-1,3-diiodoazulene 9b with the 1-ethynylazulene 13 in the presence of [Pd(PPh3)4] (Scheme 51).[108] Furthermore, a cross-coupling reaction of 6-tert-butyl-1,3- diethynylazulene (37b) with 6-tert-butyl-3-iodo-1-(trimeth- ylsilylethynyl)azulene (10) under similar conditions furnished the corresponding trimethylsilyl-protected trimer 231, which was easily deprotected upon treatment with methanolic potassium hydroxide to give the 3,3’-(6-tert-butylazulene-1,3- diyl)bis(ethyne-2,1-diyl)bis(6-tert-butyl-1-ethynylazulene) 232. Sonogashira coupling of the latter with 10 or its dimer 182 led to the formation of 31% of the pentamer 233 and 19% of the heptamer 234 as green and brownish-black high melting crystals, respectively (Figure 42).[17] The UV/Vis spectra of the ethynyl-bridged oligomers 231, 233 and 234 as well as the monomer 6-tert-butyl-1,3-bis (trimethylsilylethynyl)azulene 37b showed that the longest wavelength absorption maximum (λmax) shifts bathochromi- cally with increasing chain length. However, the shift differences diminish with enhancing length of the oligomers and tend towards a limiting value. This value can be determined by plotting the longest wavelength absorption (λmax) vs. recip- rocal chain length 1/n, which gives a linear relationship.[109,110] This allows an estimation of the band gap (Eg) of poly(1,3- azulenylethynylene)s lower than 2 eV. For comparison, the Figure 27. Structure of 1,5-bis(azulenylethynyl) substituted zinc(II) porphyrin 164. Figure 28. Structure of 5,15-bis(azulenylethynyl) substituted zinc(II) porphyrin 166. Review 2058Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2058/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner corresponding value for polyacetylene was determined to be 1.4 eV, while the corresponding value for poly(p-phenyleneethy- nylene)s was determined to be about 3.25 eV.[17] 3.5.2.2. Bis(azulen-2-ylethynyl)-1,3-azulene Bis(azulen-2-ylethynyl)azulenes 235a and 235b have been prepared by palladium-catalyzed alkynylation of 1,3-diethynyla- zulene 37b with 2-iodoazulene 28a or 2-chloroazulene 45b under Sonogashira-Hagihara conditions (Scheme 52).[108] Figure 29. Structures of poly(azulen-1-ylethynyl)benzene derivatives 168–170 and tetrakis(1-azulenylethynyl)thiophene 171. Figure 30. Structures of poly(azulenylethynyl)arene derivatives 173 and 174. Review 2059Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2059/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.5.2.3. Bis(azulen-6-ylethynyl)-1,3-azulene The synthesis of bis(azulen-2-ylethynyl)azulenes 236a and 236b have been accomplished by palladium-catalyzed alkynyla- tion of 1,3-diethynylazulene 37b with 6-bromoazulenes 42a–c, under Sonogashira-Hagihara conditions (Scheme 52).[108] 3.5.3. Oligoazulenes with butadienyl bridges 3.5.3.1. Bis(azulen-1-yl)buta-1,3-diyne Hafner et al. reported also the synthesis of 1,4-di(azulen-1-yl) buta-1,3-diynes 237a and 237b in 70 and 75% yields, respectively, by oxidative Eglinton coupling[101] of 1-ethynylazu- lenes 4a,b (Scheme 53).[17] Under similar conditions, Elwahy reported the synthesis of the butadiynyl-bridged azulene system 238 in 35% yield by the copper mediated Eglinton coupling of ethynylazulene 7.[17] The conventional Eglinton coupling has also proved to be an effective methodology for the synthesis of mono- and diiodo derivative of butadiynyl-bridged oligoazulenes. Thus, oxidative Eglinton coupling of 6-tert-butyl-1-ethynyl-3-iodoazulene (11) with Cu(OAc)2 in a boiling pyridine/ methanol/diethyl ether mixture furnished 1,4-bis(6-tert-butyl-3-iodoazulen-1-yl)-1,3-bu- tadiyne (239) as brown crystals in good yield (84%).[111] Similar to 239, also 1-(6-tert-butyl-3-iodoazulen-1-yl)-4-(6- tert-butylazu- len-1-yl)-1,3-butadiyne (240) could be prepared in 40% yield by oxidative coupling of a mixture of ethynylazulenes 4b and 11 (Figure 43). Furthermore, Nielsen et al.[22] and Ito et al.[64,100] reported the synthesis of the azulene dimers 241 and 242a and 242b in 27, 91, and 97% yields, respectively, by the Glaser homo-coupling[99] reaction of the corresponding alkynylazulene using CuI/ tetramethylethylenediamine (TMEDA) as the catalysts (Fig- ure 44). 3.5.3.2. Bis(azulen-2-yl)buta-1,3-diyne Ito et al. reported also the synthesis of di(azulen-2-yl)buta-1,3- diynes 243a,b by the Pd-catalyzed (PdCl2(PPh3)2) oxidative coupling of the appropriate 2-ethynylazulenes in the presence of CuI and triethylamine as a base (Figure 45).[35,42] Figure 31. Structures of 1-ethynylazulenes connected to pyrene 175, hexaphenylbenzene 176, hexabenzocoronene 177 cores. Review 2060Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2060/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner Figure 32. Structures of tris- and tetrakis[(1-azulenylethynyl)phenylethynyl- and (1-azulenylethynyl)-2-thienylethynyl]benzenes 185–188. Figure 33. Structures of poly(azulen-6-ylethynyl)arene derivatives 198–200. Review 2061Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2061/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.5.3.3. Bis(azulen-6-yl)buta-1,3-diyne Similarly, di(azulen-6-yl)buta-1,3-diynes 244a,b were obtained in good yields by the Pd-catalyzed (PdCl2(PPh3)2) oxidative coupling of the appropriate 6-ethynylazulenes (Figure 45).[35,42] 3.5.3.4. Poly(azulen-1-ylbuta-1,3-diyne) Higher oligomers with extended π-electron systems are acces- sible by the Eglinton coupling of 1,3-diethynylazulene 37d in the presence of 1-ethynylazulene 4b as end-capping reagent. As expected, butadiynylene-bridged trimer 245a and tetramer 245b were obtained as black crystals in 25% and 21% yields, respectively. As a result of homo-coupling (oxidative acetylene dimerization) of 4b, the dimer 237b could also be isolated from the reaction mixture in 26% yield (Scheme 54).[17] The UV/ Vis spectra of these butadiynyl-bridged oligomers 237b, 245a and 245b show no significant bathochromic shift of the longest wavelength absorption in their electronic spectra with increas- ing length of the oligomers, presumably due to a reduced conjugation. Similarly, oxidative coupling of 6-tert-butyl-1,3-diethynylazu- lene (37d) in the presence of 11 as end-capping reagent led to the formation of 6-tert-butyl-1,3-bis[(6-tert-butyl-3-iodoazulen-1- yl)butadiynyl] azulene (246) in 22% yield. In addition to the trimer 246, also the dimer 239 could be isolated in 24% yield (Figure 46).[111] 3.5.4. Oligoazulenes with mixed ethynyl and butadienyl bridges Oligoazulenes with mixed ethynyl and butadiynyl bridges could also be prepared by oxidative Eglinton coupling from the readily accessible ethynylazulenes as well as by Pd/Cu-catalyzed cross coupling reactions with the appropriate iodoazulenes. Thus, coupling of 239 with 2 equiv. of 6-tert-butyl-1-ethynylazu- lene (4b) resulted in the formation of the tetramer 247 with 47% yield as green crystals. The same compound can be obtained in 62% yield by Eglinton coupling of 1-(6-tert-butyl-3- ethynylazulen-1-yl)-2-(6-tert-butylazulene-1-yl)ethyne (213)[17] using Cu(OAc)2 in a boiling pyridine/methanol/diethyl ether mixture (Scheme 55).[111] Likewise, also the pentamer 248 with outer ethynyl and inner butadiynyl bridges can be synthesized in 37% yield by the Pd/Cu-catalyzed cross-coupling reaction of the trimer 246 with 2 equiv. of 4b. The latter was alternatively obtained in 17% yield by oxidative coupling of a mixture of 213 and 37b using the common copper(II)-mediated coupling conditions [Cu- (OAc)2, pyridine/methanol/diethyl ether]. In addition to 248, also the hexamer 249 as well as the tetramer 247 could be isolated as black and green crystals in 4% and 20% yields, respectively (Scheme 56).[111] Moreover, the pentamer 250 with outer butadiynyl and inner ethynyl bridges could be obtained by Pd/Cu-catalyzed cross-coupling reaction of 240 with 2 equiv. of 37b in 33% yield as black crystals. Compound 250 resulted also in 20% yield from the oxidative coupling of 6-tert-butyl 1,3-bis-{[(6-tert-butyl- 3-ethynyl)azulen-1-yl]ethynyl}azulene (232)[17] in the presence of 4b as end-capping reagent. In addition, 3% of the octamer 251 and 24% of the dimer 237b could be isolated (Scheme 57).[111] The UV/Vis spectra of the oligoazulenes 247–251 surpris- ingly show only a small hypsochromic shift of the longest wavelength absorption maximum from 615 nm for the tetramer 247 to 610 nm for the octamer 251, presumably due to a reduced conjugation which may be as a result of a less planar conjugated backbone. 3.6. Synthesis of enediyne scaffolds The enediyne unit is a unique class of π-conjugated building blocks designed for construction of molecular architectures that contain one- and two-dimensional carbon networks.[57] Interest Figure 34. Structure of hexakis(azulen-2-ylethynyl)benzene 201. Figure 35. Structures of 1,3-bis(phenylbuta-1,3-diyn-1-yl)azulene and higher oligomers 206a–c. Review 2062Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2062/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner in conjugated enediynes has grown because of their wide range of applications, for example in molecular wires, non-linear optics (NLO), and molecular switches.[112] 3.6.1. Ene-diyne systems possessing 6-azulenyl groups In this respect, Ito et al. reported the synthesis of mono- and bis (enediyne) scaffolds connected by a 9H-fluorene or 9,10- anthracenediyl spacer as a redox-active substructures with 6- azulenyl moieties as π-electron-accepting groups in their periphery by a one-pot reaction involving repeated Pd- catalyzed alkynylation of the appropriate 6-bromoazulenes with the correponding bis(enediyne) derivative.[113,114] Compounds 255a and 255b were prepared by a simple one pot reaction involving repeated Pd-catalyzed alkynylation of 6-bromoazulenes 42a and 42b with the enediyne scaffold 254, prepared by desilylation of 9,10-bis[3-trimethylsilyl-1- (trimethylsilylethynyl)-2-propynylidene]-9,10-dihydroanthracene (253),[115] under Sonogashira-Hagihara conditions (Scheme 46). Compound 253 was obtained by a Pd-catalyzed alkynylation of 9,10-bis(dibromomethylene)-9,10-dihydroanthracene 252 upon treatment with TMSA (Scheme 46).[113] Similarly, the reaction of 9-bis(ethynyl)methylene-9H-fluo- rene (258), prepared by the desilylation of 9-[bis (trimethylsilylethynyl)methylene]-9Hfluorene (257), with 6-bro- moazulenes 42a and 42c afforded the desired mono(enediyne) s attached to fluorene 259a (61%) and 259b (86%). Compound 257 was obtained by Pd-catalyzed alkynylation of 9- (dibromomethylene)-9H-fluorene[116] 256 with TMSA (Scheme 58).[113] Azulene-substituted bis(enediyne) systems 263a and 263b were prepared in 54 and 42% yields, respectively, by a simple Figure 36. Structures of some bis(azulenyl)acetylenes 208–210. Figure 37. Structure of functionalized bis(azuleny)ethynes 213. Figure 38. Structures of di-2-azulenylacetylenes 214a–d. Figure 39. Structures of bis(azulen-6-yl)ethynes 219a and 219b. Review 2063Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2063/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner one-pot reaction involving repeated Pd-catalyzed alkynylation of the bis(enediyne) scaffold 262 with 6-bromoazulenes 42b or 42c under Sonogashira-Hagihara conditions (Scheme 1). The anthracene derivative 262 was prepared by the Pd-catalyzed alkynylation of 9,10-bis(2,2-dibromovinyl) anthracene (260)[117] with (trimethylsilyl)acetylene to give 261 followed by desilyla- tion (Scheme 59).[114] The mono(enediyne) derivatives 267a and 267b were also prepared in 72 and 59% yields, respectively, by a Pd-catalyzed cross-coupling reaction of 1-(9-anthryl)-2-ethynylbut-1-en-3-yne (266), obtained by the desilylation of 1-(9-anthryl)-4-(trimeth- ylsilyl)-2-[2-(trimethylsilyl)ethynyl]-but-1-en-3-yne (265) upon treatment with potassium carbonate in methanolic THF, with 6- haloazulenes 42b and 42c. Compound 265 was obtained by the Pd-catalyzed alkynylation of 9-(2,2-dibromovinyl)anthracene 264[118] with (trimethylsilyl)acetylene under Sonogashira-Hagi- hara conditions (Scheme 60).[114] Figure 40. Structures of (1-azulenyl)(2-azulenyl)acetylene 220 and (1-azulenyl)(6-azulenyl)acetylenes 221. Figure 41. Structure of 3,3’-((6-(tert-butyl)azulene-1,3-diyl)bis(ethyne-2,1-diyl))bis(1-(3’,6’-diphenyl-[1,1’:2’,1’’-terphenyl]-4’-yl)azulene) 229. Figure 42. Structures of trimethylsilyl-protected trimer 231, pentamer 232 and heptamer 234. Review 2064Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2064/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.6.2. Ene-diyne systems possessing 1-azulenyl groups Ene-diyne systems possessing 1-azulenyl groups at the periph- ery 268 and 269 were prepared in 89 and 74% yields by palladium-catalyzed crosscoupling reaction of 1-ethynylazu- lenes with 9-dibromomethylene-9H-fluorene and 9,10-bis (dibromomethylene)-9,10-dihydroanthracene, respectively, under Sonogashira-Hagihara conditions (Figure 46).[119] 3.6.3. Ene-diyne systems possessing 2-azulenyl groups Similarly, ene-diyne systems possessing 2-azulenyl groups 270 and 2271 at the periphery were prepared in 80% yield and very small amount, by palladium-catalyzed crosscoupling reaction of 2-ethynylazulenes with 9-dibromomethylene-9H-fluorene and 9,10-bis(dibromomethylene)-9,10-dihydroanthracene. On the other hand, reaction of 2-iodoazulene with 9,10-bis (diethynylmethylene)-9,10-dihydroanthracene under Sonoga- shira-Hagihara conditions afforded 271 in 57% yield (Fig- ure 47).[119] Figure 43. Structures of butadiynyl-bridged azulene systems 238–240. Figure 44. Structures of butadiynyl-bridged azulene systems 241 and 242. Figure 45. Structures of di(azulen-2-yl)buta-1,3-diynes 243a,b and di(azulen-6-yl)buta-1,3-diynes 244a,b. Review 2065Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2065/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.7. Co- catalyzed cyclooligomerization of ethynylazulenes 3.7.1. Synthesis of azulenyl-substituted benzenes as well as cyclobutadiene complexes Since Reppe et al.[120] discovered the transition metal-catalyzed [2+2+2] cyclotrimerization of alkynes, this synthetic method was applied for the construction of highly functionalized carbo- and heterocycles.[121] Although an extensive number of different metal complexes derived from the whole range of transition metals[122] can be used for this catalytic reactions, cobalt is still the most effective.[123] In general, cobalt complexes react with alkynes to undergo cyclotrimerization reactions via a formal [2+2+2] cycloaddi- tion yielding either free arene or arene complexes. Alternatively, also cyclodimerization sometimes results in Co-cyclobutadiene complexes.[124] This is possible due to the slow insertion of the third π system into the organocobalt intermediate formed in the course of the reaction. It was shown that, as the substituents on the alkyne get larger, the cyclodimerization reaction becomes easier.[125] Hafner et al. and Ito et al. reported that the cyclooligomeri- zation of ethynylazulenes in the presence of Co-catalyst proved to be a useful protocol for the synthesis of azulenyl-substituted benzenes as well as cyclobutadiene complexes. The mode of the reaction and the product spectrum obtained was found to depend largely on the position of alkyne substituent on the azulene ring as well as on the ligand structure of the used catalyst. 3.7.1.1. Synthesis of tris(azulen-1-yl)benzene Treatment of 1-ethynylazulenes 4a,b with catalytic amounts of CpCo(CO)2 in refluxing cyclooctane for 24 h furnished 1,2,4-tris (azulen-1-yl)benzenes 272a and 272b in 11% and 16% yields, respectively (Scheme 17). In both cases, the 1,3,5-tris(azulen-1- yl)benzene derivatives 274a and 274b could not be obtained even in traces.[21] In addition to the major products 272a and 272b, the [η4-bis(azulen-1-yl)cyclobutadiene](η5-cyclopenta- dienyl)cobalt complexes 273a and 273b could also be isolated Figure 46. Structure of 6-tert-butyl-1,3-bis[(6-tert-butyl-3-iodoazulen-1-yl) butadiynyl] azulene (246). Figure 47. Structures of ene-diyne systems possessing 1-azulenyl and 2-azulenyl groups at the periphery 268–271. Review 2066Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2066/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner in 2% and 4%, yields, respectively (Scheme 61). The NMR spectroscopic data of 273a and 273b did not allow a decision between the two expected regioisomeric 1,2- and 1,3-bis (azulen-1-yl)cyclobutadiene complexes and crystals suitable for an X-ray structure analysis could not be obtained.[21] Similarly, functionalized 1,2,4-tris(azulen-1-yl)benzenes 275– 277 could be obtained in 10–14% yield upon treatment of the appropriate ethynylazulenes with catalytic amounts of CpCo (CO)2 in refluxing cyclooctane. In all cases, the corresponding 1,3,5-triazulenylbenzenes as well as cyclobutadiene cobalt complexes were not detected in the reaction products. Compound 276 could also be alternatively obtained in 45% yield by condensation of 276 with hydroxylamine hydrochloride and subsequent dehydration with acetic anhydride/pyridine (Figure 48).[20,21] The formation of 272a and 272b and 275–277 is in accordance with results obtained by Vollhardt and others[126] for the cyclotrimerization of alkynes, and let assume the formation of the cobaltacycle 278 as an intermediate which reacts with a further molecule of 4a and 4b, or 7 and 8 via a metal-mediated [4+2]-cycloaddition to generate the η4-benzene complex 279. A subsequent displacement of the ligand in 279 by the appropriate ethynylazulenes should result in the formation of 272a and 272b and 275–277. Therefore, it can be expected that 273a and 273b are formed via a reductive cycloelimina- tion of the cobaltacycle 278 and hence should be the 1,2-bis Figure 48. Structures of functionalized 1,2,4-tris(azulen-1-yl)benzenes 275–277. Figure 49. Structures of tetrakis(azulen-1-yl)cyclobutadiene cobalt com- plexes 290a,b. Figure 50. Structures of tetrakis(azulenyl)cyclobutadiene cobalt complexes 291a,b and 292a,b. Review 2067Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2067/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner (azulenyl)cyclobutadiene complexes (Scheme 62). The absence of cyclobutadiene cobalt complexes in the cyclooligomerization of 7 or 8 let assume a relatively high reactivity of the cobaltacycle 278 towards 7–9 to give 275–277, respectively, compared with that of the reductive cycloelimination.[21] 3.7.1.2. Synthesis of tris(azulen-6-yl)benzene On the other hand, Ito et al. reported that the cyclooligomeriza- tion of 6-ethynylazulenes 44a and 44b in the presence of CpCo (CO)2 in refluxing 1,4-dioxane afforded as major products the [η4-bis(azulen-6-yl)cyclobutadiene](η5-cyclopentadienyl)cobalt complexes 282a and 282b in 19% and 47% yields, respectively, besides the 1,2,4- and 1,3,5-tris(azulen-6-yl)benzene derivatives 280a and 280b and 281a and 281b in minor yields (Scheme 63).[42,127] The regiochemistry of the cobalt complex 281 could be confirmed by the 13C satellite signals in the 1H NMR spectrum,[128] which were definitely identified by the 2D HMQC spectrum measured under non-decoupling conditions. The negligibly small coupling constant (<1 Hz) between the cyclobutadiene protons clearly shows the presence of the 1,2- disubstitution pattern in the cyclobutadiene ring.[129] 3.7.1.3. Synthesis of bis(azulen-6-yl)cyclobutadiene cobalt complexes Reaction of 6-trimethylsilylethynylazulene 43b with CpCo(CO)2 afforded a mixture (1 : 4.1) of the cis- and trans-(η5-cyclo- pentadienyl)[bis(1,3-diethoxycarbonyl-6-azulenyl)bis (trimethylsilyl)cyclo-butadiene]cobalt complexes (283a and 284a) in 82% yields, which were separable by gel permeation chromatography (GPC) with chloroform (Scheme 64). The regiochemistry of 283a and 284a could not be determined by NMR spectroscopy. Thus, the relative stereochemistry of the major isomer 284a was established by X-ray crystallography as a trans-cobalt complex. The reaction of 6-phenylethynylazulene 107b with CpCo(CO)2 also afforded a mixture (1 : 1.1) of the cis- and trans-(η5-cyclopentadienyl)-[bis(1,3-diethoxycarbonyl-6-azu- lenyl)di(phenyl)cyclobutadiene] cobalt complexes (283b and 284b) in 94% yields (Scheme 64).[42] The regiochemistries of 283b and 284b were tentatively assigned by the comparison of the chemical shifts of their azulene and benzene ring protons in 1H NMR spectra.[130] The exclusive formation of the (cyclo- butadiene)cobalt complexes 283a,b and 284a,b may be attributable to the steric effect among the aromatic rings and/ or the trimethylsilyl groups.[42] The deprotection of the trimeth- Figure 51. Structures of hexakis(azulen-2-yl)benzenes 293a,b. Figure 52. Structures of (6-azulenyl)tetraphenylbenzenes 296a,b and 1,2-bis(6-azulenyl)tetraphenylbenzenes 297a,b. Figure 53. Structures of 2-aryl-1-(3-phenylazulen-1-yl)ethan-1-ones 301a–c. Review 2068Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2068/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner ylsilyl groups of 284a upon treatment with tetrabutylammo- nium fluoride in tetrahydrofuran furnished 285 in 53% yield.[42] 3.7.1.4. Synthesis of bis(2-azulen-2-yl)cyclobutadiene cobalt complex Reaction of 2-(trimethylsilylethynyl)azulene (28b) with CpCo (CO)2 produced a mixture (16 :84) of the cis- and trans-(η5- cyclopentadienyl)[bis(1,3-diethoxycarbonyl-6-azulenyl)bis (trimethylsilyl)-cyclobutadiene]cobalt complexes (286 and 287) in 50% yields. The major isomer 287 could be separated by recrystallization and its regiochemistry was determined to be a trans-cobalt complex by X-ray structure determination (Scheme 65).[33] Figure 54. Structures of tetracyanobutadienes (TCBDs) and dicyanoquinodimethanes (DCNQs), 327–332 from aryl/heteroaryl-substituted -ethynylazules. Figure 55. Structure of TCBD derivative 334. Review 2069Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2069/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.7.1.5. Synthesis of tetrakis(azulen-1-yl)cyclobutadiene cobalt complex The reaction of the bis(azulen-1-yl)ethynes 207a,b with CpCo (CO)2 (20 mole %) in refluxing cyclooctane did not yield the expected hexakis(azulen-1-yl)benzenes 288a,b obviously due to steric hindrance. Instead, the interesting black crystalline tetrakis(azulen-1-yl)cyclobutadiene cobalt complexes 289a,b were obtained with 20–25% yield which could be raised to 60– 70% by increasing the amount of CpCo(CO)2 to 60 mole % (Scheme 66). Repeated attempts to cyclotrimerize 207a,b in the presence of bis(benzonitrile)palladium chloride or cobaltoctacarbonyl[131] were also unsuccessful and the starting materials were recovered almost completely.[21] Similarly, the tetrakis(azulen-1-yl)cyclobutadiene cobalt complex 290a could be obtained in 60% yield upon treatment of the bis(azulen-1-yl)ethyne 208a with CpCo(CO)2 (60 mole%) in refluxing cyclooctane. Condensation of 290a with hydroxyl- amine hydrochloride and subsequent dehydration with acetic anhydride/pyridine led to the formation of the tetrakis(azulen- 1-yl)cyclobutadiene cobalt complexe 290b in 30% yield (Fig- ure 49).[21] 3.7.1.6. Synthesis of tetrakis(azulen-2-yl)cyclobutadiene cobalt complex Ito et al. reported also the exclusive formation of the tetrakis (azulen-2-yl)cyclobutadiene cobalt complexes 291a,b by the cyclodimerization of the corresponding bis(azulenyl)ethynes 214a,c in the presence of CpCo(CO)2 in refluxing 1,4-dioxane (Figure 49).[33,34,42,127] Figure 56. Structures of AzTCBDs 335–337 from Ferrocenyl-substituted -ethynylazules. Figure 57. Structures of AzTCBDs and AzDCNQs 338–342 from naphthalene/pyrene-substituted -ethynylazules. Review 2070Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2070/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner 3.7.1.7. Synthesis of tetrakis(azulen-6-yl)cyclobutadiene cobalt complex Likewise, cyclodimerization of the appropriate bis(azulenyl) ethynes 219a,b, in the presence of CpCo(CO)2 in refluxing 1,4- dioxane afforded exclusively the corresponding tetrakis (azulenyl)cyclobutadiene cobalt complexes 292a,b by the (Fig- ure 50).[33,34,42,127] 3.7.1.8. Synthesis of hexakis(azulen-2-yl)benzene Contrary to this, the cyclooligomerization of bis(6-octylazulen-2- yl)ethynes 214a,c with Co2(CO)8 as a catalyst in refluxing dioxane led to the formation of the hexakis(azulen-2-yl)benzene 293a,b in 91 and 78% yields, respectively. The latter com- pounds seem to be less sterically hindered in comparison to the corresponding hexakis(azulen-1-yl)benzenes 288a,b or hexakis (azulen-6-yl)benzenes (Figure 51).[33,34] 3.8. Synthesis of azulenyl-substituted benzenes by Diels-Alder cycloaddition reactions [4+2] Cycloaddition reactions of tetraphenylcyclopentadienone with suitable aryl acetylene derivatives are an effective route to branched oligophenylenes.[132] In analogy, Diels-Alder reaction[133] of azulenyl-substituted acetylene with tetraphenyl- cyclopentadienone offer another interesting route to azulenyl- and polyazulenylbenzene derivatives. 3.8.1. Synthesis of (1-azulenyl)tetraphenylbenzene Diels-Alder cycloaddition of tetraphenylcyclopentadienone to 1- ethynylazulenes 4a,b and 1,3-diethynylazulenes 37a,b fur- nished the the corresponding 1-(3’,6’-diphenyl-[1,1’ : 2’,1’’-ter- phenyl]-4’-yl)azulene 294 and 1,3-bis(3’,6’-diphenyl-[1,1’:2’,1’’- terphenyl]-4’-yl)azulene 295a,b, respectively (Scheme 67).[20] 3.8.2. Synthesis of (6-azulenyl)tetraphenylbenzene Likewise, cycloaddition of tetraphenylcyclopentadienone with 6-ethynylazulenes 107a,b furnished the the corresponding (6- azulenyl)tetraphenylbenzenes 296a,b.[41,42] Under similar condi- tions, Diels-Alder reaction of 1,2-di(6-azulenyl)benzene deriva- tive 219a,b with tetraphenylcyclopentadienone afforded 1,2-bis (6-azulenyl)tetraphenylbenzenes 297a,b in 13 and 90% yields, respectively (Figure 52).[41,42] 3.8.3. Synthesis of (2-azulenyl)tetraphenylbenzene Azulene-fused naphthalene derivative (299a), were obtained in 47% yield by the Diels-Alder reaction of di(2-azulenyl)acetylene (214a) with tetraphenylcyclopentadienone in one pot.[35] Direct formation of 299a is ascribed to the autoxidation of the presumed cycloaddition product, 1,2-bis(2-azulenyl) tetraphenylbenzene derivative (298a), under the reaction conditions. A similar reaction of bis(1-methoxycarbonyl-2- azulenyl)acetylene (214b) gives the presumed 1,2-bis(2-azulen- Figure 58. Structures of AzTCBDs and AzDCNQs 343–347 from bis(azulenylethynyl)arenes or heteroarenes. Review 2071Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2071/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner yl)benzene derivative (298b), which is transformed into diazuleno[2,1-a : 1,2-c]naphthalene (299b, 78%) by the cyclo- dehydrogenation with iron(III) chloride (Scheme 68).[35] 3.9. Synthesis of azulen-1-ylyl ketones from 1-azulenylketones 1-Azulenylketones 300a–g were successfully synthesized in good to excellent yields by metal-free hydration of methyl 7- isopropyl-3-(arylethynyl)azulene-1-carboxylate 91 using tri- fluoroacetic acid as a Brønsted acid. The reaction was accom- Figure 59. Structures of AzTCBDs and AzDCNQs 348–354 from bis-azulenylethynylnaphthalenes or pyrenes. Review 2072Asian J. Org. Chem. 2021, 10, 2010–2083 www.AsianJOC.org © 2021 Wiley-VCH GmbH Wiley VCH Donnerstag, 29.07.2021 2108 / 211361 [S. 2072/2083] 1 https://chemistry-europe.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1099-0690.KlausHafner plished at a relatively low temperature with complete regiose- lectivity and compatibility of several functional groups (Scheme 69).[134] Under similar conditions, 2-aryl-1-(3-phenylazulen-1-yl) ethan-1-ones 301a–c were also obtained in 71%, 82% and 97% yields, respectively, from the corresponding 1-phenylazulenylal- kynes (Figure 53).[134] Likewise, hydration of bis-alkyne 144 afforded the desired diketone product 302 in 72% yield (Scheme 70).[134] The presumed reaction mechanism is illustrated in scheme 59. At the first, alkyne 91 is protonated with Brønsted acid to give the azulenium allene intermediate 303 due to the electrondonating nature of the azulene ring at the 1-position. Addition of water to the azulenium allene intermediate 303 should afford the enol 304, which then tautomerized to form ketone 300 (Scheme 71).[134] 3.10. Synthesis of heterocycles-substituted azulenes 3.10.1. Synthesis of 2-(azulen-1-yl)benzofuran Shoji et al. established an efficient method for the preparation of azulene-substituted benzofurans 305a–d via the intramolec- ular cyclization of the appropriate 1-ethynylazulenes with 2- iodophenol under Sonogashira-Hagihara conditions (Scheme 72). On the other hand, the reaction of 1-iodoazulenes with 2- ethynylphenol 306 gave 2,3-bis(1-azulenyl)benzofurans 307a– d, unexpectedly, along with the 2-(1-azulenyl)benzofurans 308a–d under the Sonogashira-Hagihara conditions (Scheme 73).[24] The formation of 2,3-bis(1-azulenyl)benzofurans 307a–d by the reaction of 1-iodoazulenes with 2-ethynylphenol