2,4,6-Cycloheptatrien-1-one1

[539-80-0]  · C7H6O  · 2,4,6-Cycloheptatrien-1-one  · (MW 106.13)

(synthon for preparation of cycloheptadien-1-ones; building block in the synthesis of troponoids, azulenes,1a,b polycyclic compounds,1c,d natural products1d,e)

Alternate Name: tropone.

Physical Data: mp -8 °C to -5 °C; bp 113 °C/15 mmHg; d422 1.10 g cm-3; n22D 1.6172.

Solubility: sol ether, dioxane, acetone, benzene, toluene, xylene, MeCN, CCl4; miscible with water.

Preparative Methods: 2,4,6-cycloheptatrien-1-one (1) is a functionalized conjugated carbocyclic compound with diversified reactivity. The most popular and simple method of preparation involves oxidation of 1,3,5-Cycloheptatriene with Selenium(IV) Oxide-KH2PO4.2a Several other procedures have also been developed,2b-f among which electrooxidation of cycloheptatrienes2e and a-pyrone ring expansion via high-pressure cycloaddition of cyclopropenone acetals2f can be considered general methods of synthesis of tropones.

Purification: by distillation.

Analysis of Reagent Purity: 1H NMR, GLC.

Handling, Storage, and Precautions: light- and oxidant-sensitive.

1,8-Additions to Tropone: Synthesis of Cycloheptadien-1-ones.

Reactions of (1) with various nucleophiles proceed through 1,8-addition to the troponoid system and offer an approach to conjugated cycloheptadienes.3 Tropone (1) is readily reduced to 3,5-cycloheptadien-1-one through 1,8-addition of hydride ion from Lithium Aluminum Hydride4 or adds alkylmagnesium compounds to form 2-alkyl-3,5-cycloheptadien-1-ones.3,5 Reaction with lithium enolates provides a very efficient route for appending functionalized substituents onto the troponoid nucleus (eq 1).6

Annulation of Tropone: Preparation of Azulenes and Other Polyunsaturated Bicyclo[5.3.0]decane Systems.

Condensation of (1) with malonodinitrile in the presence of piperidine gives 2-amino-3-cyano-8H-cyclohepta[b]furan.7 This type of reaction is widely used in a general azulene synthesis from tropone that initially involves condensation of 2-substituted tropones (2; X = OMe, Cl, OTs) with active methylene compounds (AMC) to give cyclohepta[b]furan-2-ones or -2-imines (3). Subsequent cycloadditions of (3), for example with vinyl ethers, leads to di- and trisubstituted azulenes (4) (eq 2).8

An approach to 4-ketohydroazulenes is based on [3 + 2] cyclopentane annulation reactions of tricarbonyl(tropone)iron with h5-C5H5Fe(CO)2R synthons (where R = alkenyl, alkynyl, allenyl).9

On refluxing in C6H6 with benzamidine, (1) undergoes amination via hydride replacement producing 1,3-diazaazulene.10 Aza-Wittig reactions between N-(1-phenylvinyl)iminophosphoranes and (1) or 2-alkyltropones deliver 2-phenyl-8H-cycloheptapyrroles which can be oxidized further (Nickel(II) Peroxide) to afford 1-azaazulenes.11

Photochemical [8 + 2] cycloaddition of alkenes to (1) affords 8-oxabicyclo[5.3.0]deca-2,4,6-trienes.12 Analogously, stereospecific thermally allowed [8 + 2] cycloadditions with sulfenes give bicyclic sultones, which on heating lose SO2 with stereospecific formation of 2-(cis-1-alkenyl)phenols in almost quantitative yields.13a An efficient procedure for the synthesis of indoles is based on transformation of bicyclic sultams produced via the same cycloaddition of tropone N-methylimine with sulfenes.13b

Reactions of (1) with enamines derived from cycloalkanones also proceed via [8 + 2] cycloaddition. The primary adduct (5) is readily hydrolyzed to give a substituted 3,5-cycloheptadien-1-one (eq 3).14 This example demonstrates the close relation between 1,8-addition and [8 + 2] cycloaddition in the tropone series.

In a similar way, the 2-oxyallyl cation generated from 2,4-dibromo-2,4-dimethylpentan-3-one and Nonacarbonyldiiron exhibits high periselectivity toward (1) to give the formal [2p(3C) + 8p] adduct 9,9,11,11-tetramethyl-8-oxabicyclo[5.4.0]undeca-2,4,6-trien-10-one.15

In the reaction of (1) with HS(CH2)nSH (n = 2,3), 1,2-annulation of the dithiols takes place instead of the expected dithioacetalization.16

[4 + 2] and [6 + 4] Cycloadditions: An Approach to Bicyclo[3.2.2]nona-3,6-dien-2-one and Bicyclo[4.4.1]undeca-2,4,8-trien-11-one Systems.

Two cycloaddition modes common for (1) involve [4 + 2] cycloaddition across C(2)-C(5) or C(2)-C(3) and [6 + 4] cycloaddition across C(2)-C(7). Tropone undergoes thermal [4 + 2] cycloadditions with both electron-deficient17 and electron-rich18 dienophiles and endo products usually predominate. With unsymmetrical electron-rich dienophiles, cycloaddition proceeds regiospecifically and only 9-substituted bicyclo[3.2.2]nona-3,6-dien-2-ones are formed18a,b while, for example, electron-deficient acrylonitrile produces both regioisomeric cycloadducts (eq 4).17e

Tropone (1) also enters into thermally induced [6 + 4] cycloadditions with nonfunctionalized open-chain dienes (eq 5),19 cyclopentadiene,20 and functionalized dienes.21

The rearrangement of [6 + 4] cycloadducts into thermodynamically more stable [4 + 2] products via sigmatropic isomerization or by stepwise cycloreversion-readdition has also been reported.22 Lower temperatures favor the [6 + 4] mode of cycloaddition. Generally, electron-rich dienes give [6 + 4] adducts kinetically, but these cycloadducts are thermodynamically less stable than the adducts derived from electron-deficient dienes.21 [6 + 4] Adducts are always formed via an exo transition state whereas alternative [4 + 2] adducts often originate via an endo transition state.21,22c However, the photoinduced reaction of tricarbonyl(7,7-dimethoxy-1,3,5-cycloheptatriene)iron, as a masked version of (1), with (E)-1,3-pentadiene affords the exo [6 + 4] cycloadduct.23 Therefore transition metal-mediated [6 + 4] cycloaddition extends the scope of the thermal reaction. Besides these reactions, (1) is also known to react with 1,3-dipoles in [6 + 4] cycloadditions.22c

Intramolecular [6 + 4] and [4 + 2] tropone-alkene cycloaddition reactions of 2-alkenyltropones have been used to prepare polycyclic troponoids.24

[6 + 3] Cycloaddition: A Route to the Bicyclo[4.3.1]decadien-9-one System.

In the presence of Pd0 catalysts, 2-[(trimethylsilyl)methyl]allyl carboxylates undergo regioselective addition to C(2) and C(7) of (1) (eq 6).25a The stereochemistry of the reaction widely varies, depending on the nature of substituents in the trimethylenemethane (TMM) precursors. A phenylthio substituent in the TMM precursor behaves as an effective selectivity control element.26b

[6 + 2] Cycloaddition.

In contrast to the low periselectivity observed in intermolecular photoinduced [6 + 2] cycloaddition reactions of (1),26 intramolecular [6 + 2] reactions of 2-(4-alkenyl)- or 2-(4-alkynyl)tropones on irradiation in acidic MeOH proceed with high regioselectivity and stereoselectivity (eq 7). These reactions offer an elegant approach to bridged bicyclo[6.3.0]undecanes.27

Tricarbonyl[(2,3,4,5-h)-2,4,6-cycloheptatrien-1-one]iron (6).

In most instances the uncomplexed double bond of (6)28 reacts as an electron-rich partner that results in nucleophilic addition to C(3),9 periselective inverse electron demand cycloaddition across the free C(6)-C(7) double bond,29 or acylation at C(2) under standard Friedel-Crafts conditions.30 At the same time, in a number of reactions (6) exhibits reactivity which is characteristic of an electron-deficient enone. For example, (6) behaves like a cycloheptenone in Diels-Alder [4 + 2] cycloaddition with dienes. Stereoselective conjugate addition of nucleophiles proceeds at the C(6)-C(7) bond to give bicyclo[5.4.0]undeca-3,5,8-trien-2-ones32,22b or C(6)-alkylated complex (7) (eq 8).31 With simple nucleophiles (Vinylmagnesium Bromide, Sodium Borohydride/Cerium(III) Chloride), 1,2-addition is observed.32 Because (6) serves as an equivalent of (1) that exhibits electron-deficient enone reactivity, it has been used as a building block in natural product synthesis. Syntheses of cis-hydroazulenes,4a,9a guaianolides,4b grosshemin,5a barbarolones,28b ingenane and cedrane ring systems,24a,b prostaglandins,32 colchicine and its analogs,1e,33 sesquicarene,34 and heptitol derivatives35 have been based on reactions of (1) and its derivatives.

Miscellaneous Reactions.

A unique and extremely simple route to 4-alkyltropones involves homolytic alkylation of (1) in the presence of a Lewis acid with alkyl radicals generated from N-acyloxy-2-thiopyridones.36 Tropone oxime tosylate undergoes a stereospecific ring opening reaction with secondary amines and alkoxides to give 6-substituted (1Z,3Z,5Z)-hexa-1,3,5-trienecarbonitriles in almost quantitative yield.37


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Emmanuil I. Troyansky

Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia



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