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Tropones and tropolones are an important class of seven-membered non-benzenoid aromatic compounds. They can be prepared directly by oxidation of seven-membered rings. They can also be derived from cyclization or cycloaddition of appropriate precursors followed by elimination or rearrangement. This review discusses the types of naturally occurring tropones and tropolones and outlines important methods developed for the synthesis of tropone and tropolone natural products.

Cyclopenta[cd]azulenes (III), (VI), (XIII), 1,2-dihydrocyclopenta[c,d]azulenes (V), (XII), and cyclopenta[ef]heptalenes (X), (XV), (XVI) are obtained by simple reactions starting from tropolone.

For the first time, a nonbenzenoid aromatic such as tropolone is obtained via ring-closing metathesis.

Nucleophilic cyclization reaction of bis(tropolone) derivative (III), which is obtained by Claisen-Schmidt condensation between terephthalaldehyde (I) and acetyltropolone (II), with bifunctional agents such as substituted phenylhydrazine hydrochlorides (IV) and hydroxylamine hydrochloride gives rise to formation of the desired 1,4-phenylene bridged bis-pyrazolo and isoxazole-fused tropones (V) and (VI).

A facile synthesis of a series of novel bromo-, arylazo-, and heterocyclic fused troponoid compounds containing 1,3-benzodioxole system is described. The 7-bromo-, 5,7-dibromo-, and 5-arylazo-substituted 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]tropolones (2, 3, and 5, 6, 7) were obtained by direct bromination or azo-coupling reactions of 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop- 2-enoyl]tropolone (1) with bromine, and diazonium salts of aniline derivatives, respectively. 3-[(2E)-3-(1,3-Benzodioxol-5-yl)prop-2-enoyl]-5-bromotropolone (4) was obtained from 3-acetyl-5-bromotropolone via one-pot aldol dehydration reaction with piperonal. Tropolones 2, 3, and 4 were subjected to nucleophilic cyclization with bifunctional hydroxylamine hydrochloride and phenylhydrazine hydrochloride to give the corresponding isoxazolo- and pyrazolo-fused tropones (8, 9, 10, 11, 12, 13), respectively. J. Heterocyclic Chem., (2012).

Dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylates are prepared in a one-pot three-component reaction of alkyl isocyanide, dialkyl acetylenedicarboxylate, and α-tropolone (=2-hydroxycyclohepta-2,4,6-trienone). The reaction proceeds smoothly at room temperature and under neutral conditions to afford tropolone derivatives in high yield.

Condensation of tropolone derivatives (I) with aromatic hydrazines (II) afford the troponopyrazoles (III) in good yields.The electronic nature of the substituents has no significant effect on the reactions.

The electronic spectra have been measured for jet‐cooled 3‐chlorotropolone in the S1–S0 region to investigate the effect of an asymmetric substitution on proton tunneling in tropolone. Both the 0++ and 0−− transitions have been identified in the fluorescence excitation spectrum, while no 0−+ or 0+− transition has been detected. This suggests that the double minimum potential energy function is almost symmetric for both S1 and S0. The tunneling doublet separations for the origin bands of 3‐chlorotropolone and its OD derivative have been measured to be 23 and 3 cm−1, respectively. These values are very similar to the corresponding values of 19 and 2 cm−1 for tropolone and its OD derivative, indicating that the substitution of a chlorine atom influences only a little on the strength of the intramolecular hydrogen bond.

The haloform reaction of 3-acetyltropolone (1) afforded 3-carboxytropolone (2) which was treated with diazomethane to give 2-methoxy-3-methoxycarbonyltropone (3a) and 2-methoxy-7-methoxycarbonyltropone (3b). The tropolone 2 reacted with hydrazine to afford 2-hydrazino-3-hydrazinocarbonyltropone (10) or 2-hydrazinotropone (11), depending on the reaction time. The reaction of 2 with phenylhydrazine produced 3-hydroxy-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one (14). The treatment of 2-methoxy-3-methoxycarbonyltropone (3a) with hydrazine or phenylhydrazine gave cyclization products 12 and 15, respectively. The reaction of 2-methoxy-7-methoxycarbonyltropone (3b) with hydrazine, phenylhydrazine, or methylhydrazine gave 2-hydrazino- (13), 2-(2-phenylhydrazino)- (16), and 2-(2-methylhydrazino)-7-methoxycarbonyltropone (17), respectively.

Treatments of 3-isopropenyltropolone with quarternary ammonium tribromides in tetrahydrofuran afforded 3-methyl-8H-cyclohepta[b]furan-8-one. The reactions in methanol–dichloromethane gave 7-bromo-3-methyl-8H-cyclohepta[b]furan-8-one. Bromination of 3-acetyltropolone with the tribromides in tetrahydrofuran produced 3-(bromoacetyl)tropolone, while the reaction in the methanolic solvent gave 7-bromo- and 5,7-dibromo-substituted 3-acetyltropolones. The brominations of 4′-hydroxyacetophenone were also carried out.

3-(2-Bromoacetyl)tropolone (1) reacted with several benzaldehydes 2a-e to afford 2-arylidene-3,8-dihydro-2H-cyclohepta[b]furan-3,8-diones 3a-e in very good yields.

3-(2-Bromoacetyl)tropolone (1) reacted with benzaldehydes 2a-g in the pressence of alkali at low temperature to give 2-aryl-3-hydroxy-4,9-dihydrocyclohepta[b]pyran-4,9-diones 3a-g in good yields.

C7H5C102, Mr = 156.6, monoclinic, P21/c, a = 8.476 (2), b = 12.241 (2), c = 8.170 (2) A, /3 -- 126.47 °, V= 681.7 A 3, z = 4, Dx = 1.525 g cm -3, A(Cu Ka) = 1.54184 A, /z = 44.63 cm-~, F(000) = 320, T = 293 K, R -- 0.046 for 833 reflections with I > 3tr(I). The hydroxylic proton forms a bifurcated hydrogen bond with carbonyl O atoms, one branch intramolecular and the other intermolecular. The latter intermolecular branches form a hydrogen- bonded dimer, which is roughly planar. Introduction. The structures of tropolone and some tropolone derivatives have been studied. It has been shown that 5,isopropyltropolone (Berg, Karlasson, (P~.tti & Wiehager, 1976) as well as tropolone manouchi & Sasada, 1973) forms a bifurcated hydrogen bond with the carbonyl O atoms, one branch being intramolecular and other intermolecu- lar. On the other hand, 4-isopropyltropone does not form a dimer, but O...O hydrogen bonds of 2.8 A link the molecules in a chain (Derry & Hamor, 1972). Very recently, we have measured the electronic spectra of the isolated 3-chlorotropolone (Tsuji, Sekiya, Nishimura, Mori & Takeshita, 1991) and 3-bromotropolone (Sekiya, Sasaki, Nishimura, Mori & Takeshita, 1990). The observation of tunnel splitting provides conclusive evidence for the de- localization of the proton. We have found that the hydroxylic proton is delocalized in 3-chlorotro- polone, whereas the proton is localized in 3- bromotropolone. It has been suggested that the localization of the hydroxylic proton strongly depends on the planarity of the molecule. In order to examine the effect of the substitution of a C1 atom on the molecular and crystal structure, an X-ray

The highly oxygenated α-tropolone antibiotic 3,4-dimethoxy-α-tropolone 3 has been synthesized in a fully regiocontrolled manner from commercially available cis-1,2-dihydrocatechol 5. Demethylation of 3,4-dimethoxy-α-tropolone 3 produced the potent antitumour agent 3,4-dihydroxy-α-tropolone 4.

Feeding of [U- 13 C 6 ]glucose to Pseudomonas CB-104 gave labeled thiotropocin (1a and 1b). The 13 C NMR spectrum of the derived p-bromobenzyl thioether (2a and 2b) displayed a pattern of enhancements and couplings consistent with a shikimate origin for thiotropocin by way of a symmetrical phenylpyruvate (11) intermediate. The latter metabolite is proposed to undergo oxidative ring expansion followed by further oxidation and oxygen-sulfur exchange

2-Aminotroponimine (1) is conveniently synthesized in high yield and is isolated in pure form, starting from 2-aminotropone via 2-methoxytroponiminium fluorosulfonate. N,N′-Dimethyl derivative of 1 is prepared similarly.

The 4-pyrone, [5-acetoxy-4-oxo-4 H -pyran-2-yl]carbonyl chloride was coupled with malonate anion of bis(2,2,2-trichloroethyl) 2-ethenyl-3,4,5-trimethoxybenzylpropanedioate and analogs thereof. These adducts then underwent intramolecular thermal cyclizations (61-100% yield) to form the two fused seven member rings of the carbon skeleton of colchicine. The malonate moiety was deprotected and decarboxylated quantitatively to provide the desired ring system which contained a bridging ether, from C7a to C11 in the C ring, and a ketone at the 7 position. Removal of the bridging ether as H2O would yield the desired tropolone. Our attempts to remove the ether bridge were unsuccessful.

High resolution two‐color threshold photoelectron spectra of tropolone and 9‐hydroxyphenalenone (9‐HPO) isolated in a free jet expansion have been measured to study the proton tunneling phenomena in the cation ground state (D0). The tunneling splitting widths of the D0 zeroth vibrational level for the both molecules lie within our experimental accuracy (2 cm−1), indicating that the proton tunneling is inhibited when compared to that obtained in their respective neutral states. By means of a comparative study of these two molecules, the tunneling inhibition has been explained in terms of a large contribution from the electronic factor which represents the changes in charge distribution of the π electrons upon ionization. The geometric factor, which is associated with the ring planarity is less important in determining the rate of tunneling in the D0 state. In the case of tropolone, we have found that the measurement of an out‐of‐plane skeletal vibration in various electronic states make it possible to desc...

The effects of electron correlation on the molecular structure and stability of tropone and tropolone molecules have been studied by MP2/6-31G* calculations. Geometry optimizations have been carried out for tropone, cis -tropolone and the non-hydrogen bonded orthogonal and trans rotamers of tropolone. The tropone seven-membered ring exhibits an appreciable triene-like character which is slightly smoothed upon OH substitution. The asymmetry of the hydrogen bonding of tropolone, emerging from previous HF/6-31G* studies, is reduced by inclusion of electron correlation, and the proton tunnelling barrier height drastically lowers from 70 kJ mol −1 (HF/6-31G*) to 25 kJ mol −1 (MP2/6-31G*). The structural changes induced by OH torsion, supported by additional MP2/6-31G* geometry optimizations of the analogous systems 1,4-pentadiene-3-one and 2-hydroxy-1,4-pentadiene-3-one indicate that intramolecular CO⋯HO hydrogen bonding is favoured by π-delocalization through the cyclic carbon skeleton. SCF calculations on the centrosymmetrical tropolone dimer indicate that self-association enhances π-delocalization in the troponoid ring and causes vibrational frequency shifts which satisfactorily agree with the changes observed in the FT-IR matrix spectra of isolated tropolone molecules and of solid samples.

Hinokitiol (6-isopropyltropolone; IUPAC nomenclature: 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one; C 10 H 12 O 2 ) has strong insecticidal and phytogrowth-inhibitory activities, and has a much more stable conformation than related brominated compounds. The hinokitiol molecule adopts a planar form and the two O atoms are hydrogen bonded to symmetry-related molecules. Furthermore, the tropolone ring is stacked with another symmetry-related tropolone ring, so that the molecule may be stabilized by resonance energy

A concise tropolone annulation applicable to rubrolone C ring introduc- tion is detailed based on the room-temperature [4+2] cycloaddition rea- ction of the cyclopropenone ketal (10) with the oxygenated diene (9). Conversion of the sensitive [4+2] cycloadduct (11) to the norcaradiene (18), low temperature electrocyclic rearrangement to a cycloheptatrie- none ketal, and tautomerization to (12) provided a fully oxygenated tropolone analogous to that found in rubrolone

3-(Bromoacetyl)tropolone was reacted with five 2-mercaptobenzimidazoles to give 3-[[(2-benzimidazolyl)thio]acetyl]tropolones. These products were heated with methylhydrazine to afford 3-[[(2-benzimidazolyl)thio]methyl]-1-methyl-1,8-dihydrocycloheptapyrazol-8-ones. In these reactions, 1-methyl-3-[(1-methylhydrazino)methyl]-1,8-dihydrocycloheptapyrazol-8-one was isolated as a minor product.

3-(Dibromoacetyl)tropolone (3) was obtained in the reaction of 3-acetyltropolone with two equimolar amounts of phenyltrimethylammonium tribromide. This tropolone 3 reacted with thiourea, 1-methyl-2-thiourea, and 1-phenyl-2-thiourea to afford N-unsubstituted and N-methyl- or N-phenyl-substituted 3-(2-amino-4-thiazolyl)tropolones. The reactions of 3 with thioacetamide and thiobenzamide gave 3-(2-methyl-and 2-phenyl-4-thiazolyl)tropolones.

Publisher Summary The chapter discusses the structure, reactivity, and application of tropones, tropolones, and tropylium. X-ray diffraction, molecular spectra, aromaticity and stability, tautomerism, and polarographic reduction of tropones, tropolones, and tropylium are described in the chapter. The recognition, isolation, and characterization of troponoid systems have been facilitated by certain chemical properties that usually occur in both monocyclic and fused derivatives. Most tropolones give sparingly soluble, yellow or orange sodium salts, green cupric chelates, and colored ferric complexes. Valence isomerization and dimerization are common reactions in the photochemistry of troponoids. The acidity of parent tropolone lies between those of acetic acid and phenol; benzotropolones are only as acidic as phenol. Parent tropone forms very stable salts with acids; its basicity has its origin in the high stability of the hydroxytropylium ion formed by protonation. Chelate-complexes of tropolones are discussed in the chapter. Parent tropone on halogenation, affords addition products and by subsequent dehydrohalogenation affords halotropones substituted at 2- or 2,7-positions. Cyclocondensations onto the seven-membered ring are illustrated in the chapter by the reactions of pyridotropolones. Monocyclic tropylium salts on oxidation usually undergo ring contraction, benzotropylium salts give benzotropones. The troponoid system is included in many natural products, including alkaloids and antibiotics. Among heterocyclic derivatives, pyrrolotropones, tricyclic thieno- or pyrrolo-benzotropones, and other compounds have been claimed in patent applications. The pharmaceutical and photographic uses of tropones, tropolones and tropylium are discussed in the chapter.

A synthetic route was developed for preparation of 2-aminotropone oximes 10–14, a new class of compounds, from tropolone 2; 2-methoxytropone imines 7–9 and tropylium salts 17 were generated as the key intermediates.

Incorporation studies with 13C-labelled acetates and methionine in Acremonium strictum indicate that the cyclopentenone moiety in Xenovulene A® is formed via a unique pathway in which a C-methylated phenolic precursor undergoes ring expansion to a tropolone followed by two successive ring contractions resulting in incorporation of the C-methyl carbon into the five-membered ring.

3-Acetyltropolone (1) was treated with diethyl oxalate in the presence of sodium ethoxide to afford 3-(2-ethoxalyl-1-oxoethyl)tropolone (2) as a minor product and its cyclized 2-ethoxycarbonyl-4,9-dihydrocyclohetpa[b]pyran-4,9-dione (3) as the major one. The former was readily converted to the latter. Then, as a stable synthon bearing a 1,3-dicarbonyl group, 2-(2-ethoxalyl-1-oxoethyl)-7-methylaminotropone (5) was prepared. The reactions of compound 5 with hydroxylamine, hydrazine, and methylhydrazine were carried out to give troponoids possessing an isoxazole or a pyrazole ring. The parent compounds, 3-(3-pyrazolyl)tropolone (13) and 3-(1-methylpyrazol-3-yl)tropolone (21), were obtained via hydrolysis and decarboxylation. Similarly, 2-ethoxycarbonyl-4,9-dihydrocyclohepta[b]pyran-4,9-dione (3) reacted with hydroxylamine, hydrazine, and methylhydrazine to yield troponoids possessing a heterocyclic ring.

Twin-type troponoid liquid crystals show a monotropic smectic C phase while the corresponding benzenoids are non-mesogenic. The corresponding troponoid monomers, show a monotropic smectic A phase, could form a head-to-tail alignment. In the twins, molecules have to shift to form a head-to-tail alignment since the dipole moment of the two tropolone parts directs oppositely.

3-Acetyltropolone (1) reacted with benzaldehydes in trimethyl orthoformate in the presence of perchloric acid to afford 2-aryl-4-methoxy-9-oxocyclohepta[b]pyrylium perchlorates 3a-c in 25–37% yields. From the filtrates, 3-(3,4-diaryl-3-butenoyl)tropolones 4a,b and 3-(2-methoxycinnamoyl)tropolone (5) were also isolated.

Several tropolone derivatives (4-7) were designed as novel retinoids on the assumption that the tropolone ring may mimic the benzoic acid moiety in retinoid structures, such as Am80 (2). Among the synthesized compounds, 5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethynyl]tropolone (7a) showed moderate potency as a differentiation-inducer of HL-60 cells. The activities of the tropolones were greatly enhanced in the presence of HX630, an RXR agonist (retinoid synergist).

A series of compounds bearing an endocyclic -N-O- moiety with potential antimalarial activity based on simple derivatives of the tropolone purpurogallin was prepared by means of a hetero Diels-Alder reaction using nitrosobenzene as a dienophile. The rationale behind the design of these compounds is presented, together with the synthetic route to derivatives bearing aromatic and aliphatic esters of the C4'-position hydroxyl group of the purpurogallin framework, as well as biological data obtained from in vitro assays against Plasmodium falciparum and Trypanosoma cruzi. Several of the new compounds have activities in the 3-9 microM range, and provide leads for the development of a novel class of antiparasitic drugs with improved biological and pharmacological properties.

The synthesis and in vitro antiparasitic activity of twenty-seven novel diazabicycles based on tropolone ethers is presented. The compounds can be readily prepared by means of a high-yielding hetero Diels-Alder reaction using simple and readily available starting materials. Several of the new diazabicycles have in vitro activities against Trypanosoma cruzi, Leishmania donovani, Trypanosoma brucei rhodesiense, and chloroquine-resistant Plasmodium falciparum that are comparable or superior to those of currently employed protozoocidal agents.

An expedient ten-step synthesis of a substituted tropolone is described. The synthesis involves a 3-oxidopyrylium [5+2] cycloaddition reaction with acrylonitrile as the key step, affording a highly functionalized [3.2.1]-bicycle 10 as a single regioisomer. The nitrile substituent of the reduced cycloadduct 12 permits efficient ether-bridge cleavage and tropolone 15 is obtained after a final bis-oxidation procedure. The pyranulose acetate cycloaddition precursor was derived from 3-methyl-2-furoate.

Mitsunobu coupling between tropolones and saccharide or cyclitol derivatives featuring primary or secondary alcohol functions provides for the first time an easy, general and efficient access to the corresponding tropolonyl ethers. Selective deprotection of the carbohydrate or cyclitol units demonstrates that naked saccharides and cyclitols bearing a tropolonyl ether moiety may be prepared by this route.

The relationship between free radicals and acute or chronic inflammation has been well established. We have previously reported the significant antioxidant activity of the natural azulene derivatives chamazulene and guaiazulene. Furthermore, some synthetic azulene analogues have been found to possess anti-inflammatory activity. In this investigation we report the synthesis of five 3-alkyl or 3-(hydroxy)alkylazulene-1-carboxylic acids and esters, from tropolone, via the corresponding furanone. The synthesised compounds were tested for their effect on the peroxidation of rat hepatic microsomal membrane lipids, applying the 2-thiobarbituric acid test. Their anti-inflammatory activity was evaluated in vitro by the offered inhibition of soybean lipoxygenase. All the tested molecules were found to inhibit lipid peroxidation by 100% at 1 mM. They were also found to considerably inhibit lipoxygenase activity. The above results are discussed in relation to the structure and physicochemical properties of the examined azulene derivatives.

β-Thujaplicin (hinokitiol) 1 and γ-thujaplicin 2 , as the first naturally occurring monocyclic tropolone, were regioselectively synthesized from ( R )-(+)-limonene, by using different dienyl silyl ether intermediates, 7 and 10 , in 18% overall yield via 11 steps and 22% overall yield via 10 steps, respectively.

The reactions of 3-(bromoacetyl)tropolone with benzenethiol and heteroarenethiols gave 3-[(phenylthio)acetyl]tropolone and 3-[(heteroarylthio)acetyl]tropolones respectively. These compounds reacted with hydrazine hydrate and methylhydrazine to afford 3-phenylthiomethyl- and 3-heteroarylthiomethyl-1H,8H-cyclohepta[d]pyrazol-8-ones and their corresponding 1-methyl substituted compounds,respectively.

The laser fluorescence excitation spectra and single vibronic level fluorescence spectra have been measured for jet‐cooled tropolone (–OH) and tropolone (–OD). The ν’11(a1), ν12(a1), and ν’19(a2), modes have been newly identified in the excitation spectrum of tropolone (–OH), in addition to the previously observed ν13(a1), ν’14(a1), ν25(b1), and ν’26(b1) modes. The tunneling doublet splittings of these modes in the A 1B2 state have been determined to investigate the effect of the vibrational excitation on the proton tunneling dynamics. The tunneling splitting is highly mode specific. The ν13(a1) and ν’14(a1) skeletal deformation modes are strongly coupled to the proton transfer coordinate and enhance tunneling, whereas the ν19(a2) skeletal twisting mode as well as ν’25(b1) and ν26(b1) out‐of‐plane bending modes diminish tunneling. The ν’11(a1) C–C stretching and ν12(a1) C–C–C bending modes are considered to be weakly coupled to the proton transfer coordinate, because the tunneling splittings of these mod...