One hundred years of benzotropone chemistry

This review focuses on the chemistry of benzo-annulated tropones and tropolones reported since the beginning of the 20th century, which are currently used as tools by the synthetic and biological communities.

There are three possible benzotropone isomers: 4,5-benzotropone (11), 2,3-benzotropone (12), and 3,4-benzotropone (13, Figure 2). The present review focuses on the chemistry of parent benzotropones and their hydroxy analogues (benzotropolones) in the hundred years from the beginning to the present day, because these classes of molecules still attract noticeable attention from the synthetic and biological communities due to emerging reports of their interesting chemical struc- tures and potential biological activities. Historically, many efforts have been devoted to the chemistry of benzotropones/ benzotropolones and a plethora of benzotropone-type molecules have been produced over 100 years. Furthermore, the scope of this review includes the chemistry of halo-benzotropones, halo-benzotropolones, dibenzotropones, dibenzotropolones, tribenzotropone, and tropoquinones in addition to parent benzotropones and benzotropolones. The numerous functionalized benzotroponoids are excluded from the review.

Chemistry of 4,5-benzotropone (11)
Several research studies have been reported on the synthesis and properties of 4,5-benzotropones since they were first prepared by Thiele and Weitz nearly a century ago [46,47]. Similar approaches of this method was independently studied by Cook [48] and Föhlisch [49] groups. In 1975, the crystal and molecular structure of 4,5-benzotropone (11) was determined by Hata's group [50]. X-ray diffraction analysis showed that the molecule is approximately planar and the bond alternation in the seven-membered ring and C=O bond length support satisfactory aromaticity.
produces a small amount of ring-contracted naphthaldehydes along with benzotropones. The oxidation with Na 2 O 2 gives slightly higher amounts of benzotropones than of naphthaldehydes. As shown in Table 1, the most suitable reaction conditions to obtain 4,5-benzotropone (11) with the Pomerantz and Swei procedure include Na 2 O 2 /Me 2 SO.
Mechanistic and synthetic aspects of the reaction of 7-bromo-5H-benzo [7]annulene (22) with CrO 3 and SeO 2 as oxidation reagents were studied (Scheme 4) [52]. All reactions provided 4,5-benzotropone (11) in addition to a few benzotroponoid compounds 23-26, the structures of which were determined by means of spectral data and chemical transformations. It is deemed that the dibromides 24 and 25 are the result of the addition of HBr, which is formed under the reaction conditions.
the reaction of the 7-oxabenzonorbornadiene 31 with dichlorocarbene, generated by the phase-transfer method. The thermolysis of dichloride 32 in nitrobenzene at 165 °C resulted in the formation of ring-expanded product 33. After the reduction of the allylic position with LiAlH 4 , the treatment of monochloride 34 with concentrated sulfuric acid in ice water afforded a quantitative yield of 4,5-benzotropone (11).
The above researchers also proposed a mechanism for the formation of 11 from 31 as shown in Scheme 7. The acid-catalyzed cleavage of the oxo-bridge of 34 gives benzylic carbocation 35. Consequently, after deprotonation and dehydration, chloro benzotropilium cation 37 undergoes hydrolysis to give 4,5-benzotropone (11) in aqueous reaction media. Using o-xylylene dibromide (38) as starting material, Ewing and Paquette designed and synthesized benzotropone 11 by an especially reliable route [54]. For this purpose, bisalkylation of o-xylylene dibromide (38) with tert-butyl lithioacetate (Rathke's salt) and subsequent Dieckmann cyclization provided simple access to 40 in 51% overall yield (Scheme 8). After bromination of 40 with molecular bromine in carbon tetrachloride, direct dehydrobromination with lithium chloride in dimethylformamide gave 11 in 85% isolated yield. Müller's group reported an alternative synthesis for 11 starting from the carbene adduct 41 over two or three steps [55]. Firstly, dichloride 41 was reduced with LiAlH 4 in ether to give the monochloride 42. The reaction of 42 with DDQ produced 4,5benzotropone (11) in 24% yield together with 28% of starting material. The key step for 11 from 42 is the electrocyclic ring expansion of dehydrogenation product 44 to the benzotropylium ion 45. Secondly, 11 is obtained in 18% yield after benzylic bromination of 42 with NBS, followed by in situ elimination reaction of the labile bromide 43 mediated by t-BuOK (Scheme 9).
Palladium-catalyzed C-C bond-formation reactions such as Heck and Sonogashira couplings are employed in a wide variety of areas in organic chemistry [56,57]. Recently, Shaabani's group synthesized and characterized palladium nanoparticles supported on ethylenediamine-functionalized cellulose (PdNPs@EDACs) as a novel bio-supported catalyst for Heck and Sonogashira couplings in water [58]. Shaabani's group reported the efficient synthesis of benzotropone 11 in a good isolated yield (83%) via PdNPs@EDACs-catalyzed Heck coupling and intramolecular condensation of 2-bromobenzaldehyde (46)  researchers have studied the synthesis of benzofulvalenes via the carbonyl group of 4,5-benzotropone (11) (Scheme 11). Halton's group applied the Peterson olefination reaction to the synthesis of benzofulvalanes 49 and 50 from the reaction of 4,5benzotropone (11) with corresponding cyclopropanes [60,61].
As polycyclic conjugated π systems can endow new properties to the original π system, conjugated systems are important in terms of both theoretical and experimental aspects. Nitta's group extensively studied the synthesis and structural and chemical properties of a new kind of cycloheptatrienylium ions using aromatic π systems ( Figure 3) [66][67][68][69][70]. In this context, Nitta  ligands [72]. Perron-Sierra's group prepared substituted benzo [7]annulenes as a novel series of potent and specific α v integrin antagonists starting from 4,5-benzotropone (11) (Figure 4 and Scheme 13) [73].  A sequence of the one-carbon homologation of ketone 69 is followed by isomerization into the α,β-unsaturated aldehyde 71. A series of reductive amination and amidation reactions then led to the formation of the targeted substituted benzo [7]annulene 72 (Scheme 13). Moreover, the structure-activity study revealed that some of the compounds showed nanoto subnanomolar IC 50 values on α v β 3 and α v β 5 integrins.
In 1978, in order to examine heteroatomic influences on the possible generation of 9C-10π homoaromatic dianions, Paquette's group described the synthesis and reducibility of benzo-fused-homo-2-methoxyazocines from benzotropones (Scheme 19) [87]. Firstly, dimethylsulfoxonium methylide addition to 4,5-benzotropone (11) provided the introduction of the cyclopropane ring required for two benzohomoazocines. Beckmann rearrangement of 104 resulted in a mixture of ring expansion products 105 and 106 in nearly equal proportions. This lactam mixture was then converted into the desired imidates and the imidates 107 and 108 were separated. Reduction of benzohomoazocine 107 proceeded without cleavage of its three-membered ring, whereas the internal cyclopropane σ bond of 108 underwent cleavage to form 110 (Scheme 19). Paquette's group were unable to determine the formation of homoazocinyl dianion intermediates due to the added benzene ring in 107 and 108 and concluded that the presence of imino ether does not enhance the homoaromaticity of 9C-10π dianions.
Homoaromaticity, homotropylium cations, and homotropones have been extensively studied  benzohomotropones to hydroxytropylium ions 117 and 118 in sulfuric acid were presumed, benzohomotropylium cation 112 was not detected from the reactions of the corresponding alcohol 114 in sulfuric acid [125].

c. Decarbonylation of 4,5-benzotropone (11):
The mechanism for the neutral and radical-cationic decarbonylation of tropone and benzannulated tropones was compared by both experimental techniques and by means of MNDO calculations (Scheme 26) [131]. While the key steps for the thermal decomposition of tropones are electrocyclic ring closure and cheletropic CO extrusion to give an aromatic system, the cationic reactions occur with ring closure followed by the opening to a benzoyl-type ion, which is the actual precursor of the CO loss (Scheme 26).

Synthesis using 1-benzosuberone (162):
In 1959, Buchanan's group realized a nontedious method for the synthesis of 2,3-benzotropone (12) starting with 1-benzosuberone (162) (Scheme 29) [134]. First, the unsaturated ketone 163, which is called Julia's ketone, was prepared by NBS-bromination in the presence of a trace of benzoyl peroxide (BPO) and followed by dehydrobromination. Another synthesis of Julia's ketone was achieved by dehydration of the known keto-alcohol 164 by boric acid. Oxidation of Julia's ketone with selenium dioxide gave 2,3-benzotropone (12). An alternative synthesis for 12, which represents a feasible route to avoid the disadvantage of selenium dioxide, is also bromination of Julia's ketone 163 followed by spontaneous elimination of hydrogen bromide at the temperature of the reaction.
2,3-Benzotropone (12) was also prepared by bromination of 1-benzosuberone (162) using both NBS and molecular bromine followed by dehydrobromination (using lithium chloride in dimethylformamide) of the resulting dibromo derivatives (Scheme 30) [135,136]. Moreover, the formation mechanism of the elimination of HBr from the germinal dibromide was investigated by Jones' group [135]. Jones' group also investigated the mechanism of the elimination of HBr from geminal-dibro- inden-7-one 167 [136]. As the reaction of 167 does not work under basic conditions, it is supposed that the reaction takes place via an acid-catalyzed double bond isomerization followed by an elimination reaction. Moreover, Ghosh's group repeated the synthesis of 12 through a molecular bromination-dehydrobromination sequence starting with 162 [137].
Hypervalent iodine(V)-based reagents such as IBX (or 2-iodoxybenzoic acid) and Dess-Martin periodinane (DMP) are commonly used in organic synthesis as oxidizing agent to form both unsaturated carbonyl compounds and conjugated aromatic carbonyl systems. Nicolaou's group reported a general method for the mild, swift, and highly efficient oxidation of alcohols, ketones, and aldehydes to unsaturated compounds in one pot (Scheme 30) [138,139]. Accordingly, an IBX-controlled dehydrogenation through single-electron-transfer-based oxidation processes of 162 gave 12 in 60% yield.

Chemistry of 3,4-benzotropone
Considering the known reactivity of benzocyclobutenes, i.e., their isomerisation to o-quinodimethanes, Tsuji's group used 6,7-benzobicyclo[3.2.0]hepta-3,6-dien-2-one (230) as a precursor to produce 13. They reported the first generation and spectroscopic characterization of this elusive molecule obtained by electrocyclic ring-opening reaction of 230 through irradiation in a rigid medium at low temperature or by thermolysis at high temperature [153]. As shown in Scheme 37, compound 230 was synthesized through the addition of benzyne to 2-cyclopentenone acetal (228) followed by hydrolysis and subsequent oxidation of the resultant ketone 229 with DDQ. Irradiation (>300 nm) of 230 in EPA (a 5:5:2 mixture of ether, isopentane, and ethanol) at −196 °C led to the formation of 13, which exhibited the development of characteristic UV-vis absorption in the range 300-550 nm. In addition to product 13, two [π8 + π10] dimers 231 and 232 at -78 °C were also isolated ( Figure 9) [153]. In a subsequent study, Tsuji's group described details of the spectral and chemical properties of 13 [154]. The IR spectroscopic results showed a substantial contribution of 13B to 13A in the ground state. Moreover, it was found that the Scheme 36: Reaction of 2,3-benzotropone (12) with various reagents and compounds. photochemical behavior of 230 depended on the state of the irradiation medium. For example, the smooth [π10 + π10] dimerization of 13 to give dimeric product 233 was realized with the irradiation (>420 nm) of 13 in a fluid EPA solution below −100 °C [154]. Furthermore, the IR spectra of 3,4-benzotropone (13) generated in matrices at 13 K by the photoisomerization of 230 were directly observed [156]. In addition, the ther-mal generation of 13 from 230 was investigated [153,154]. When 230 with 10 equiv of maleic anhydride in benzene at 220 °C was reacted, [π2 + π8] cyclo-adduct 234 as a single product was isolated in 52% yield ( Figure 9) [153,154]. The thermolysis of 230 in the presence of ethyl vinyl ether gave three volatile products 235-237 in GLC yields of 10%, 7%, and 15%, respectively ( Figure 9) [154].

Benzotropolones
Benzannulation to the tropolone scaffold can give numerous tautomeric hydroxybenzotropones or benzotropolenes. Figure 10 shows 238A (or 241A-240) as single tautomers, whereas 239 and 174 are depicted as a mixture of tautomers. Moreover, benzenoid structures as 238A are more stable than o-quinoidal structures as 238B due to Clar's π-sextet rule.
The benzotropolone 174 could also be prepared from diester 301 in a similar way (Scheme 50) [179]. The simultaneous hydrolysis and decarboxylation of benzotropolone-diester 304 to 174 were catalyzed by NaOH.

Reaction of 4-hydroxy-2,3-benzotropone (174):
The structure of 174 was confirmed by the reduction of both benzotropolone 174 and diketone 300 into the diol 305 with catalytic hydrogenation (Scheme 51) [178]. benzotropones is the formation of a three-membered intermediate by addition of halocarbenes to alkoxynaphthalenes. The carbene addition step is then a simultaneous ring-opening step to give the corresponding halobenzotropone (Scheme 52). In 1969, two research groups independently reported the preparation of 2-bromo-4,5-benzotropone via adduct 308 starting from 2-methoxynaphthalene (306) using different dibromocarbene reagents (Scheme 52) [180,181]. The results for the synthesis of halo-benzotropones via carbene addition are shown in Table 2.
As shown in Table 2, the reported yields were extremely low.
To further improve the yields of the products, different carbene sources and reaction conditions were tested. Parham's group reported treatment of 2-methoxynaphthalene (306) with 0.75 equivalents of the carbene source (ethyl trichloroacetate) and sodium methoxide to give the chlorobenzotropone 309 in 13% yield [184]. Uyehara's group also performed the same reaction by changing the ratios of the carbene sources and the base to the substrate [185]. When 7 equivalents of the carbene source and sodium methoxide were used, however, 309 was obtained in lower yield (33%) and unexpected byproducts 313-315 were isolated in 6%, 23%, and 0.2% yields, respectively ( Figure 13). Several methods for the synthesis of 7-bromo-2,3-benzotropone (316) via dibromocarbene addition to 1-methoxynaphthalene (310) were reported ( Figure 14) [180,181]. However, Moncur and Grutzner repeated the reaction as described and their studies led to the structural revision of the previously published structure of 7-bromo-2,3-benzotropone (316) to that of 5-bromo-2,3-benzotropone (311, Scheme 52, Figure 14) [186]. The structure of 311 has also been confirmed by independent extensive experiments and NMR data [182,187]. The chloro-derivative 312 was synthesized from the addition of dichlorocarbene to 310 in the same manner [187]. The results indicated that the dihalocarbenes prefer the addition of the 3,4double bond rather than the 1,2-double bond to 1-methoxynaphthalene (310). The position of the halogen substituent in 311 and 312 was also determined by the cycloadducts 320 and 321 between 5-halo-2,3-benzotropones and maleic anhydride ( Figure 14) [185,187].

Multistep synthesis via dihalocarbene addition:
As shown in Scheme 6, the synthesis of the bicyclic ring 33 from the dichlorocarbene adduct of oxobenzonorbornadiene 31 has also been reported by Ranken's group in two steps [53]. Hydrolysis of 33 in water under acidic conditions led to 2-chlorobenzotropone 309 in 20% yield (Scheme 53) [53].

Synthesis via oxidation:
As shown in Scheme 4, bromobenzotropones 23 and 26 were obtained and characterized during the oxidation of both benzylic and allylic positions in 7-bromo-5H-benzo [7]annulene (22) [52]. To the best of those authors' knowledge, this is the first synthesis of 23. With the reaction conditions established, Balci's group next turned their attention to evaluating the scope and limitations of the oxidation reaction with different types of benzo [7]annulene (Scheme 56) [190]. Thus 8-bromo-5H-benzo [7]annulene (329) was oxidized with different oxidants to give a mixture of bromobenzotropones such as 23, 316, and 26. Formation of naphthaldehyde derivative 330 was also reported by SeO 2 -oxidation reaction (Scheme 56).
The first synthetic methods for 6-chloro-2,3-benzotropone (335) were presented by Balci's group (Scheme 58) [52]. When dibromide 334 was dehydrobrominated by lithium chloride in N,Ndimethylformamide, the chloro derivative 335 was formed as a sole product without any other halo derivatives. Independently, the reaction of 6-bromo-2,3-benzotropone (23) with lithium chloride under the same reaction conditions gave 6-chloro-2,3benzotropone (335) in 96% yield. The proposed mechanism involves the intermediate 336 formed by Michael addition of a chloride ion to the β-position of the carbonyl group followed by the elimination of a bromide ion as a better leaving group.

Reactions with nucleophiles:
Crabbé's group reported the reactions of 7-bromo-2,3-benzotropone (316) with several primary and secondary amines (Scheme 59) [192]. Amines such as ammonia, dimethylamine, and morpholine analogous amines afforded the corresponding cine-substitution products such as 337, whereas the reactions of compound 316 with various amines such as methylamine, ethylamine isopropylamine, and ethanolamine gave aromatic lactams such as 338 and tricyclic amino derivatives as 339, in addition to the desired cine-substitution products, under similar reaction conditions. It was proposed that the aromatic lactam was formed via cleavage of the troponoid ring. The tricyclic ring was derived by a sequence of 1,6-addition reaction of the amine to the tropone and intramolecular displacement of the bromine by an attack from the nitrogen.
Namboothiri and Balasubrahmanyam also investigated transformations in bromo-and alkoxybenzotropones (Scheme 61) [182]. The treatment of bromobenzotropones 26 and 311 with sodium methoxide in methanol under reflux led to a mixture of ipso and cine products. While the ipso product 344 in the case of 311 is dramatically favored over the cine product 345 (96:4), the ipso/cine ratio 346/347 in the case of 26 is 22:76. However, a small (2%) amount of 4,5-benzotropone (11) was formed under these conditions via presumably reductive removal of the bromine. In addition, a trapping experiment with 1,3diphenylisobenzofuran (DPIBF) furnished evidence for the formation of benzodehydrotropones 348 and 350, generated by the reaction of 26 and 311 with t-BuOK (Scheme 62).

Reactions of dibromobenzotropones:
The transformations of isomeric dibromo-benzotropones 261A and 261B are summarized in Scheme 67 [163,189]. Dibromo-benzotropone 261A was treated with KOH in methanol at room temperature for 24 h followed by acidification using HCl to yield 6-methoxy-and 6-hydroxybenzotropones 360 and 361 and an uncharacterized product. Tribromide 362 was prepared by treating 162 with refluxing bromine. Treatment of dibromobenzotropones with hydroxylamine caused a cine-reaction to give oximes 363 and 364. The Diels-Alder adducts 365 and 366 of 261A and 261B with maleic anhydride were used to elucidate the position of the bromo substituents. The reduction of 261B in acetic acid with 4 mol equivalent of hydrogen in the presence of 5% palladium-on-charcoal and anhydrous sodium acetate, and by subsequent treatment with 2,4-dinitrophenylhydrazine, resulted in the formation of hydrazone 367. Moreover, the hydrazone 368 was prepared in an analogous manner using 2 equivalents of hydrogen. bromine in acetic acid under various conditions (Scheme 68) [194]. Bromobenzotropolones 372-376 and 290 were also synthesized by bromination/dehydrobromination of the corresponding benzotropolenes ( Figure 16) [165,179,[194][195][196][197].

Azo-coupling reaction of halo-benzotropolones:
The azocoupling reaction of 7-bromobenzotropolones 294 with diazonium cations, which are generated by treatment of aromatic amines with nitrous acid and a stronger mineral acid in acetic acid, resulted in 5-phenylazo-7-bromo-3,4-benzotropolone (390) in 28% yield (Scheme 73) [175]. However, when the same reaction was carried out in a pyridine solution, the formation of rearrangement products 391 and 392 in 29% and low yields (Scheme 73). The possible courses for the formation of coupling products were discussed [175].

Tribenzotropone (400)
Tribenzotropone, or 9H-tribenzo[a,c,e] [7]annulen-9-one (400A), has a tetracyclic structure, consisting of a seven-membered ring fused to benzene rings ( Figure 20). Based on experimental observations, it is suggested that tribenzotropone (400) shows structural resistance against planarity arising from an angular strain of a planar 7-membered ring as well as the unfavorable steric interactions between the ortho-hydrogen atoms ( Figure 20) [200]. As a measure of the characteristics of tropone, the calculated circuit resonance energies show that tribenzotropone (400) among the other benzotropones has a small circuit resonance energy associated with the number of benzene rings [155]. The charge density for the corresponding uniform reference frame of 400 shows that the oxygen atom occupies the site of the largest charge density.

Synthesis of tribenzotropone
The first synthesis of tribenzotropone (400) was simultaneously reported by two groups in 1957. Stiles' group reported the synthesis of 400 in 24% yield via the rearrangement of the diazonium salt of 9-(2-aminophenyl)-9H-fluoren-9-ol (402) in two steps (Scheme 74) [200]. A multistep preparation with difficulties or poor yields of 400 was reported by Bergmann's group starting from cycloaddition of butadiene and cinnamaldehyde (403) in 12 steps (Scheme 74) [201]. Moreover, Diels-Alder trapping with furan of an alkyne derivative from benzotropone 399 followed by catalytic hydrogenation and polyphosphoric acid (PPA)-assisted dehydration steps provided an excellent approach to the synthesis of tribenzotropone (400) in a 31% overall yield over five steps (Scheme 75) [202]. Wan's group also reported the deoxygenation with Fe 2 (CO) 9 of the cycloadduct 404 to 400 [203].
Koo's group reported a challenging method for the synthesis of 400 in 38% overall yield by ring-expansion method as a key step starting from readily available 9,10-phenanthraquinone (406, Scheme 76) [204]. A mild and selective indium-mediated nucleophilic addition of allyl bromide followed by the addition of vinylmagnesium bromide led to the formation of diol 407 with allyl and vinyl substituents, which underwent an oxidative ring-opening reaction to form diketone 408. Then the reaction of 408 with triisopropyl triflate (TIPSOTf) in the presence of triethylamine afforded the desired silyl enol ether 409, which contains the required electron-rich diene and electron-deficient dienophile units for intramolecular cycloaddition. Unexpectedly, the intramolecular Diels-Alder reaction of 409 at room temperature followed by filtration from silica gel gave an inseparable mixture of tribenzotropone (400) and dihydro analogue of 400. The crude mixture was reacted with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in order to complete the oxidation (DDQ).
Papaianina and Amsharaov demonstrated that thermally activated γ-aluminum oxide can be very effective for C-F bond activation in trifluoromethyl-substituted arenes to yield either cyclic ketones or the respective carboxylic acids in good to excellent yields (Scheme 77) [205]. The condensation of trifluoromethyl-substituted arene 411 on activated alumina at 150 °C resulted in the formation of the intramolecular Friedel-Crafts products 400 (52% yield) and 412 (8% yield), whereas formation of the possible acid 413 was not observed. The prevention of side reactions and the regiochemistry of the process were attributed to the confined space of alumina pores. Furthermore, the non-activated alumina-mediated hydrolysis of 412 at 200 °C afforded o-terphenyl-2-carboxylic acid (413) in close to quantitative yield. A presumable mechanism was also proposed for the formation of acylation and hydrolysis products with C-F activation in trifluoromethylated arenes in alumina nanopores.

Reactions of tribenzotropone (400)
Herold's group reported ESR and ENDOR/TRIPLE resonance studies of ion pairs derived from the reduction of tribenzotropone (400), dibenzotropone 399, and dibenzosuberone 414 ( Figure 21) with different alkali metals, which may be evidence of the existence of three different stereoisomers [206]. The INDO calculations of the spin densities at the lithium cation also supported the geometries proposed for the three stereoisomers. An experimental study on the excited-state carbon acidity of several dibenzosuberene derivatives was reported by Wan's group ( Figure 22) [203]. To this end, tribenzotropone (400) from the selected substrate was reduced with both LiAlH 4 (with   Bergmann and Klein reported the synthesis of the condensation product 419a by the reaction of 400 with benzylmagnesium chloride (Figure 24) [201]. The UV absorption spectrum for 419a was measured and it was evaluated that 419a has no fulvenic properties. Later, Tochtermann's group reported the synthesis of the racemic 9-methylene-9Htribenzo[a,c,e] [7]annulenes such as 420 via Wittig reaction followed by carboxylation of vinylic bromide using lithium/carbon dioxide ( Figure 24) [209]. The classical resolution of the vinyl carboxylic acids as its brucine salt was also studied and the thermal racemization barrier was 31 kcal/mol at 139 °C. Udayakumar and Schuster were the first to show the direct asymmetric synthesis of a series of 9-benzylidene-9Htribenzo[a,c,e] [7]annulenes 419a-e and they examined the photochemistry of optically active potential triggers for physical amplification of a photoresponse in liquid crystalline media ( Figure 24) [210]. The optically active compounds were prepared from the reaction of 400 with chiral phosphonamides 421a-d as an application of the Hanessian chiral olefination reaction. The acetyl derivative 419e was prepared by reaction of 419c with methyllithium. The optical purities of the compounds were determined to be 92% and 5% by NMR spectroscopy in the presence of chiral shift reagents. While UV irradiation of the benzylidene-9H-tribenzo[a,c,e] [7]annulenes resulted in high-efficiency photoracemization, thermal racemization was not observed at temperatures below 100 °C. Although the Grignard reaction between tribenzotropone (400) and 4-methoxyphenylmagnesium bromide provided the alcohol 422 in good yield (72%), O-dealkylation of the tetracyclic alcohol 422 gave the corresponding p-quinone methide 423 in low yield (23%, Figure 25) [211]. This result was attributed to the relatively low stability of the formed cation 424 due to the aromatic system twisted out of plane. Tribenzotropone (400) was also used as starting material for host molecules 425-427 ( Figure 26) [212,213].
As outlined in Scheme 78 with regard to the synthesis of a series of non-helical overcrowded derivatives, syn-431 was also prepared using 400 in four steps, which covered pinacol coupling and then pinacol rearrangement, carbonyl reduction, and Wagner-Meerwein rearrangement occured [214]. Isomers syn-431 and anti-431 were converted as quantitative to each other at thermal and photochemical conditions as shown in Scheme 78. At the same time, the unambiguous characterization of syn-431 and anti-431 revealed that the previously claimed synthesis of hexabenzooctalene 432 by Tochtermann [215] was incorrect ( Figure 27).

Naphthotropones
Although eight isomers 433-440 for naphthotropone, which possess an XH-cyclohepta[y]naphthalen-Z-one (X = Y = 7, 8, 9 or 10; y = a, b) skeleton system, are possible, only five isomers 433-437 were found experimentally ( Figure 28). Sudoh's group reported the annulation effects of benzene rings to tropone (1) on the ground-state dipole moment, which can be useful for the study of molecular interactions in solution and excited states, as both the experimental and computational for the first time [216]. The ground-state dipole moments of a series of annulated tropones were computationally calculated using the Hartree-Fock (HF), density functional theory (DFT), and Møller-Plesset second-order perturbation (MP2) methods. While the ground-state dipole moment for 4,5-naphthotropone (433) was experimentally determined as 5.19 D, the MP2 method gave the result corresponding best to the experimental one for 433 among the three methods. The electronic transitions observed in tropone and tropolone derivatives condensed with benzene and naphthalene were studied experimentally and   theoretically [217][218][219]. Ohkita's group characterized the aromaticity of π-extended o-quinoidal tropone derivatives 433-435 along with five other tropone derivatives via the nucleus-independent chemical shifts (NICS), which is a computational method proven to be the most reliable probe of aromaticity due to its simplicity and efficiency [220,221]. Interestingly, the NICS(1) value calculated for the tropone ring in 433 is negative (−7.4), and indicates significantly increased aromatic character relative to the parent system. Moreover, NICS calculations demonstrated that the annulation of a benzene or naphthalene ring to the 2,3-or 4,5-position of tropone resulted in diminution of aromaticity. Furthermore, the elongations of the calculated C=O bond in the studied molecules as 433 were attributed to substantial contributions of polar resonance structures to these molecules.

Synthesis and characterization studies of naphthotropones
Elad and Ginsburg reported the synthesis of a naphthotropone isomer for the first time (Scheme 79) [222]. Catalytic reduction of the key diketone 442, which was prepared by multi-stage synthesis of 1-phenylcycloheptene (441), removed the carbonyl group conjugated to the benzene ring and stepwise bromination and dehydrobromination of ketone 443 afforded the desired 11H-cyclohepta[a]naphthalen-11-one (437) [222,223]. Treibs and Herdmann [224] reported the synthesis of 10-hydroxy-11Hcyclohepta[a]naphthalen-11-one (448) in very low yield starting from 2-naphthaldehyde and diethyl 2-ethylidenemalonate as outlined in Scheme 80 [224]. The condensation product 445 was converted to the ketone 444 in four steps: hydrolysis, catalytic hydrogenation, decarboxylation, and Friedel-Crafts acylation. After hydrolysis of oxime 446 derived from ketone 444, diketone 447 was subjected to an oxidation reaction with elemental sulfur, Pd/C, or SeO 2 to give naphthotropolene 448 in very low yield.
Jones' group prepared naphthotropone 436 using published procedures and known intermediates (Scheme 84) [228][229][230][231]. The ketone 461 prepared in 11 steps starting from naphthalene (17) was converted to 462 through ring-opening of cyclopropane with a base followed by oxidation. After previous successful  7H-cyclohepta[b]naphthalen-7-one (435), which displayed characteristic UV-vis absorption extending to 700 nm and underwent rapid dimerization to give the dimers 467 and 468 (Scheme 86). However, Okhita's group applied this strategy to generate the corresponding anthracene-tropone from 466 under the same reaction conditions (Scheme 85). However, anthrocyclobutene derivative 466 failed to result in ring-opening for the expected tropone and the starting material 466 was recovered quantitatively. The products were unambiguously characterized as syn-[π12 + π14] dimers 467 and 468 by X-ray crystallography, and the preferential syn-dimerization was attributed to the extended secondary orbital interactions. Sato's group also reported the IR spectra of 435 generated in nitrogen matrices at 13 K by monochromic irradiation with a XeCl excimer laser to investigate medium effects on the molecular structures of tropones [156].

Applications of naphthotropones
In connection with the completion of the benzologue tropylium series, Naville's group also prepared the tropylium cations 469 and 470 from the corresponding naphthotropones 433 and 436 and described the absorption spectra and the relative acidities of all cations ( Figure 30) [225]. After hydride reduction of tropones, the alcohols in sulfuric acid provided the corresponding cations.  Due to encouraging initial results obtained regarding the synthesis, properties, and reactivity of catacondensed aromatic π-systems as well as their photoinduced autorecycling oxidizing reactions toward some alcohol and amines [66][67][68][69][70][71] of spectroscopic methods as well as elemental analysis and X-ray analysis, their chemical shifts provided quite noteworthy information for determining structural properties such as diatropicity and bond alternation. The carbocation stability is expressed in terms of its pK R+ value, which is the affinity of the carbocation toward hydroxide ions, and this value is the most common criterion for carbocation stability. Although the pK R+ values for cations 471 + , 472 + , and 473 + were determined spectrophotometrically as the values of ca. 0.5-9.0, the pK R+ value of napthotropylium ion 479 + was clarified as much lower, at <0. Autorecycling oxidation properties of some amines as well as Jang and Kelley studied the exited-state intramolecular proton transfer (ESIPT) and relaxation of 7-hydroxy-8H-cyclohepta[b]naphthalen-8-one (505) in room temperature solutions studied using static and time-resolved absorption as well as emission spectra for the equations indicated in Scheme 91 [235,236]. Dual fluorescence (normal and tautomer fluorescence) is observed in the protic solvent (ethanol), while only tautomer fluorescence is observed in the nonpolar solvent (cyclohexane). The dual green and red fluorescence arise from the intermolecular hydrogen-bonded normal molecules and the tautomer molecules with proton transfer in the excited state (ESIPT), respectively. The observed fluorescence lifetimes and quantum yields in ethanol and cyclohexane solutions could be attributed to competition between intersystem crossing and proton transfer in the first excited singlet state.

Benzoditropones
Although benzoditropone has many isomeric possibilities, only two isomers 506 and 507 of the benzoditropone system have been reported (Figure 33). The X-ray diffraction studies for benzo [1,2:4,5]di [7]annulene-3,9-dione (506e) as the main skeleton revealed a nearly planar geometry [237]. The intermolecular distances confirmed good agreement with normal van der Waals interactions, while the intramolecular distances led to a significant bond alternation within the seven-membered rings.
Agranat and Avnir reported the synthesis of the benzoditropone systems 525 and 526, which may be considered double dibenzotropones (Scheme 95) [241]. Double Perkin condensation between pyromellitic dianhydride (527) and phenylacetic acid gave a mixture of the two isomeric lactones, 528 and 529, in the ratio of 5:3, which were separable by repeated fractional crystallization. The reduction of 528 and 529 with red phosphorus in boiling hydroiodic acid led to the formation of isophthalic acid derivatives (such as 530), which underwent intramolecular Friedel-Crafts acylation by polyphosphoric acid (PPA) to construct a seven-membered ring. The synthesis of benzoditropones 525 and 526 involved the dehydrogenation of the corresponding Friedel-Crafts products with N-bromosuccinimide (NBS) in the presence of benzoyl peroxide followed by treatment with trimethylamine.

Benzocyclobutatropones
Cyclobutadiene (532), the smallest annulene, is an unstable hydrocarbon with an extremely short lifetime in the free state and has attracted much attention from both experimental and theoretical viewpoints ( Figure 34). Although 532 rapidly dimerizes via a Diels-Alder reaction, its dibenzo-derivative 533 (biphenylene) is thermally stable and shows many of the properties associated with aromatic compounds (Figure 33) [242][243][244][245][246]. Three possible isomeric benzocyclobutatropones, 534-536, which are analogues of biphenylene in which one benzenoid ring has been replaced by the tropone ring, are of significant interest due to the question of the extent of π-electron delocalization in the seven-membered ring ( Figure 34). Benzo-  Wege's group attempted to prepare the main analogues 534-536 of a benzocyclobutatropone system [247][248][249]. Allylic oxidation of diene 537 with chromium trioxide-pyridine complex in dichloromethane occurred to afford dienone 538 in 21% yield, which was exposed to DDQ in refluxing benzene to give 534 in low yield (9-10%) as a stable and crystalline solid at room temperature along with some of the starting material 537 (Scheme 96) [247,248]. Deuterated derivative 539 was prepared to confirm structural assignments. NMR results showed that the seven-membered ring of 534 has a more localized π-bond system than tropone itself [248]. The CrO 3 -oxidation product 542 of the benzyne-cycloheptatriene adduct 540 was also converted to 534 after a sequence of NBS-bromination and dehydrobromination with DBU. However, the major oxidation product 542 did not react with DDQ in refluxing benzene. All attempts to prepare the other benzocyclobutatropone, 545, have failed so far (Scheme 97). The potential precursor 543 of 545 was verified to be extremely acid-sensitive, and ketone 543 was rearranged to afford the bridged ketone 545 in high yield via cationic intermediates [247,248]. Another attempt then aimed to introduce a second double bond into the seven-membered ring of ketone 546, which reacted with N-bromosuccinimide followed by treatment with tetrabutylammonium bromide to yield fluoren-9-ol (547) as the only isolable product [248]. After unsuccessful attempts resulting from the propensity of reaction intermediates to undergo skeletal rearrangements, Wege's group attempted the preparation of ketone 548, in which π-electrons binding to the iron carbonyl moiety as the driving force for isomerization should be suppressed [248]. However, attempts towards the preparation of the complex 548 were not successful.
To access the symmetrical tropone derivative 536, the cycloadduct 537 was again used as a starting material since this compound contains the necessary ring skeleton of 536 and possesses the diene function permitting the introduction of the essential carbonyl group (Scheme 98) [248,249]. Compound 537 was transformed to monobromo 549 in 8 steps, which reacted with trimethylamine in the presence of cyclopentadiene (202) in dichloromethane at 0 °C to give the trapping product 550 in 20% yield as [6 + 4] cycloadduct. This result was attributed to the formation of benzocyclobutatropone 536. The reaction performed without 202 gave no recognizable product.
Ebine's group were the first to report the addition reaction between 1-methoxybiphenylene (551) and dichlorocarbene generated from chloroform to give chloro-benzocyclobutatropone 552 (1.7%) together with two fluorenone derivatives, 553a (0.8%) and 553b (1.3%), in very low yields (Scheme 99) [250]. The formation mechanism for the products is also provided as depicted in Scheme 99. Moreover, Ebine's group investigated the reaction of 1,2-dimethoxybiphenylene with dichlorocarbene to detect the bond fixation in biphenylene derivatives [251]. While the reaction gave two chloro-methoxy-benzocyclobutatropones and four fluorenones with chloro and methoxy substituents, similar products were obtained with dibromocarbene. The formation of these products was attributed to unequivocal chemical evidence for bond fixation of 1,2-dimethoxybiphenylene. Furthermore, cleavage of the ether functionality with boron tribromide in dichloromethane at −65 °C provided the first example of tropolone analogue 559a (93%) of biphenylene (Scheme 100). Electronic spectra and NMR coupling constants of the compound showed that 559a exists as only one tautomer due to instability of the antiaromatic cyclobutadiene structure in the central four-membered ring of 559b.
At the same time, Ebine's group reported the reaction of biphenylene-2,3-quinone (560) with diazomethane in the presence of boron trifluoride etherate to give another tropolone analogue 561 and its boron difluoride chelate 562, which was hydrolyzed in acidic aqueous ethanol to 561 quantitatively (Scheme 101) [252,253]. On the other hand, some electrophilic reactions, including nitration, bromination, and azo coupling for 561 yielded only 7-substituted tropolones.
Due to the highly hygroscopic nature of 566, chemical reactions of hydrated 569 were studied [254]. The reaction of 569 with o-phenylenediamine at room temperature afforded the quinoxaline derivative 575 (15%) along with Scheme 103: Synthesis of benzotropoquinone 567 via a Diels-Alder reaction. benzo[a]phenazine (13%, Figure 36). While the reaction between NaN 3 and 569 gave 576 through conjugate addition followed by dehydration (Figure 36), treatment of 569 with concentrated HCl at room temperature provided 568 in 80% yield. Furthermore, the corresponding diacetate 577 was obtained in 87% yield from the acetylation of 569 in the presence of H 2 SO 4 ( Figure 36). Acetylation of 569 with BF 3 catalyst resulted in the formation of 1,2-diacetoxy-naphthalene (25%) and 3,3',4,4'-tetraacetoxy-1,1'-binaphthyl (15%) together with 577 (15%). Although 1,2,5-benzotropoquinone 567 is highly sensitive to moisture, it is stable under anhydrous conditions in the dark and, its hygroscopic form returns to 567 when dried under a vacuum. While the reaction of tropoquinone 567 with o-phenylenediamine gives a quinoxaline derivative 578, the reduction of 567 to 579 was realized via catalytic hydrogenation with Pd/C (Scheme 104) [252]. A naphthaldehyde derivative 580 was derived from Thiele acetylation (Ac 2 O, H 2 SO 4 , room temperature) of 567 in 11% yield. Treatment of tropoquinone 567 with hydrogen chloride in ethanol gave the adduct 581 (74% yield), which was oxidized with silver carbonatecelite to yield the indigoid 582 (30%). Upon the addition of methanol, 567 reversibly forms a mixture of the corresponding methyl acetals through adjacent diketone.
Conjugated carbon nanomaterials such as fullerenes, carbon nanotubes, and graphene have received tremendous attention and have great potential application in nanoscience due to their exceptional electrical, thermal, chemical, and mechanical properties. Starting from dibenzotropoquinone 584, Miao's group reported the synthesis of saddle-shaped ketone 592 containing two tropone subunits embedded in the well-known framework of peri-hexabenzocoronene as depicted in Scheme 105 [261]. However, bistropone 592 was used as a precursor for the successful synthesis of two novel large aromatic saddles (C 70 H 26 and C 70 H 30 ) by reactions on the carbonyl groups. Local aromaticity and nonplanarity of individual rings in these saddleshaped π-backbones were confirmed by crystal structure analysis. Moreover, preliminary studies on semiconductor properties were performed.

Conclusion
Tropones and tropolones are an important class of seven-membered aromatic compounds. In addition, hundreds of tropone or tropolone derivatives are known in the literature. These kinds of products have a wide range of biological activity and are building blocks in the synthesis of many molecules. All these factors have made these molecules a focus of intense interest among both organic chemists and medical chemists for nearly a century. This chemistry is one of the milestones leading to a deeper understanding of static, dynamic, and multidisciplinary aspects of organic chemistry such as spectroscopic studies, mechanistic and synthetic investigations, theoretical calculations, aromaticity, evolution, and design of bioactive molecules and molecular materials.
In this review, we have described the numerous efforts concerning synthesis and applications in benzotropone chemistry spanning over 100 years, from the first works up to the most recent. The review covers isomeric benzotropones and tribenzotropones as well as their benzotropolone analogues. As it is well known, halogenated compounds are very valuable as they are the key compounds for many functionalizations. Therefore, halogenated benzotropones and benzotropolones are also included in this review. Tropoquinones are a topic of interest in organic research and these compounds are used for many functionalization reactions. Works on benzo analogues of tropoquinones are also summarized in this review. Carbene-carbene and carbene-allene rearrangements on benzo [7]annulene ringderived benzotropones are investigated in detail in the literature and discussed in this review. Carbene insertion reaction, synthesis of azocine, synthesis and physical properties of homo-and bis-homobenzotropones, and their conversation to corresponding homotropolium cations are also other well-investigated issues reviewed in this work. Knowledge of the chemistry of benzocyclobutenotropones, naphthotropones, and their tropolone analogues is limited and more research on those compounds is required in the future.
Numerous synthetic efforts towards the synthesis and chemical reactivity of benzotropones and benzotropolones were reported from the 20th century to date. In addition to being natural products, many benzotropone derivatives can be prepared directly by oxidation of seven-membered rings. They can also be derived from cyclization, ring expansion, or cycloaddition of appropriate precursors followed by elimination or rearrangement. The oxidation of seven-membered rings generally gives a mixture, whereas cyclization of suitable acylic compounds or ring expansion reactions generally produces one isomer in high yield. Although 2,3-and 4,5-benzotropone have been investigated in detail, research on 3,4-benzotropone is rather limited due to instability of this kind of compound, which is attributed to the o-quinoidal structure, and because it does not have a sextet electron system in the benzene ring.
In general, two kinds of reactions on benzotropone and their analogues are common: i) reaction on the carbonyl group, which is generally a nucleophilic addition or condensation, ii) reaction on the double bond in the seven-membered ring, which is generally with a nucleophile since the tropone ring is behaving as an electrophile. The double bonds in the seven-membered ring give a cycloaddition reaction as both a diene and a dienophile. Although many reactions on this hydrocarbon have been reported, we think that there is still a need for the scientific community to develop many synthetic methods and investigate their possible interesting synthetic applications in various fields. We consider the objectives of this review as helping in the systematization of the literature data collected to date and allowing a better understanding of them, and possibly bringing new ideas to the field. We strongly believe that the synthetic potential and applications of this chemistry have not yet been fully revealed, and there are certainly further challenges and opportunities for reinvestigation, and plenty of room for further studies on the chemistry of benzotropones for medicinal, material, and synthetic organic chemists. Based on the progress in benzotropone chemistry including synthesis and applications summarized in this work, we feel certain that this review will find broad interest and will continue to attract much attention in organic synthesis applications. We hope that this review will facilitate the synthesis of tropolone-containing compounds discovered in nature or designed by medicinal chemists. They are also expected to be applied in new material fields due to their high functionalization capacity via their benzene ring, seven-membered ring, and carbonyl group.