Ring A tropones

An ingenious approach to the synthesis of steroids incorporating a tropone A ring has been developed by Birch and co-workers. Addition of dibromocarbene to 3-methoxyestra-2,5(10)-dien-17-one 17-ethylene ketal (42) gives a monodibromocarbene adduct formulated as (43) accompanied by a minor amount of a bisadduct. This confirms earlier observations that electrophilic halocarbenes add mainly to 2,3- or 2,5-dihydroanisoles at the double bond bearing the methoxyl group. 

Treatment of dibromocarbene adduct (43) (Rji, = O) with aqueous methanol containing silver nitrate or perchlorate gives A-homo-estra-1 (10), 2,4a-triene-4,17-dione (45) in 21 % overall yield from the enol ether (42). The exact pathway is not known, but the first step may be formation of a bromo-homo-dienone facilitated by the methoxyl group, which then undergoes further loss of hydrogen bromide involving shift of a double bond by enolization.  

Levisalles and co-workers have prepared A-homo-5a-cholestan-4-one by the dibromocarbene procedure starting with 3-methoxy-5a-cholest-2-ene. Wieland and Anner have converted 19-mesyloxy-A -3-keto steroids into 

Ai -A-homo-4-ketones by reaction with lithium and biphenyl at The resulting dienone is transformed into the corresponding tropone by treatment with bromine. The Swiss chemists also found that base treatment of 19-mesyloxy-A -3-oximes gives directly 4-oximino-A-homo-estra-l(10),2,4a-trienes in moderate yield.  

Extension of the above method to 3-methoxyestra-3,5(10)-dien-17-one 17-ethylene ketal (46) prepared by base-catalyzed isomerization of 3-methoxy-estra-2,5(10)-dien-17-one 17-ketal (42) with potassium t-butoxide in dimethyl sulfoxide gives the isomeric tropone A-homo-estra-l,4,5(10)-triene-3,17-dione 

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Addition of dienophiles preferentially occurs onto the heterocyclic rings of tropones [c]-fused onto furan and pyrrole [cf. 84CHEC(4)67], Furotro-pone 307a and dimethyl acetylene dicarboxylate (DMAD) give a dimerized adduct that undergoes cycloreversion at higher temperature to form monomeric adduct 527 (Scheme 138 91CB2465). The 5,7-bis(carbomethoxy)... 

X-Ray structures of the HgCl2 complexes with oxa-thiacrown ethers having a tropone ring, 72-76 have been reported <1998H(47)149, 2000H(53)535> in which 72, 73, and 74 formed 1 2, 1 2, and 1 2.5 (host/HgCl2) complexes, respectively. 

As shown in Equation (52), the intramolecular [6+4] cycloaddition between a furan and a tropone was successfully achieved for the first time during the construction of the highly functionalized ABC ring of ingenol <2005SL2501>. 

A number of related compounds in which the benzenoid ring is thiophene or a tropone have also been prepared. 

Although the normal mode of reaction of acids with cycloproparenes involves breaking of the cyclopropane bond, there is one example known where attack occurs at the tr-bond and results in ring expansion to a tropone. When 1, l-dichloro-2,5-diphenylbenzocyclopropene was exposed to chloroform or dichloromethane, saturated with hydrogen chloride gas, two isomeric tropones were formed in addition to two dimers. The formation of the tropones is attributed to electrophilic attack at the bridging bond, followed by reaction of the carbenium ion with either chloride or water. 

Benzotropones (XXXIV) were first prepared more than seventy years ago utilising a condensation reaction between phthalaldehyde and acetonedicarboxylic acid [122-124]. It is interesting to note that this preparative method involved the use of a condensation reaction leading directly to a tropone ring system, for simple tropones have not been made in this way. Variants of this method have been used to prepare a number of benzotronones a recent optimised method provides yields of 70% [237]. Other more recent methods use o-di(bromomethyl)benzene as starting material [238]. 

A new ring system, which is a combination of a tropone and quinolines, was synthesized as a potential pharmaceutical target (Scheme 67). The approach involves preparation of 2-styrylquinoline-3-carboxylic acids from the Arbuzov reaction of ethyl 2-(bromoethyl)quinoline-3-carboxylate followed a Horner—Wadsworth—Emmons reaction to form the alkene.The ester can then be hydrolyzed to provide the free acid. AU three of these reactions can be carried out in one pot and in good yields, 18 examples, 68-83%. Heteroaryl aldehydes can also be employed in the Horner-Wadsworth-Emmons step, although the yields were lower, 54—61%. While the final Friedel-Crafts step should be catalyzed by a number of acids, only PPA (polyphosphoric... 

Tropone ring. A soln. of 5,5-dibromo-5,6,7,8-tetraliydro-2-methyl-4H-cyclohepta-[b]thiophen-4-one and Li-carbonate refluxed 2.5 hrs. in anhydrous dimethyl-formamide 2-methyl-4H-cycIohepta[b]thiophen-4-one. Y 77%. F. e. s. G. and R. K. Jones, and M. J. Robinson, Soc. Perkin I 1973, 968. 

Nine-membered ring systems are potentially accessible via a TMM cycloaddition with conjugated trienes in a [6-1-3] fashion. However, tropone is the only reported system that undergoes such a reaction. Interestingly, these cydoadditions are remarkably selective in that only nine-memhered ring products are formed. 

Trichlorinated tropones [10] have been prepared by a one-pot procedure based on thermal cycloaddition of tetrachlorocyclopropene 9 with electron-rich butadienes (Scheme 2.6) followed by spontaneous ring-expansion/dehydro-chlorination of the resulting cycloadducts. 

SCHEME 2.18 Generation of tropone from o-QM via a ring-opening process. Enthalpies of formation for the intermediates and activation enthalpies (data above the arrows) are reported in kcal/mol. Enthalpies of formation and activation enthalpy for the rate-determining step are in bold (data have been taken from Ref. [23]). 

The UV spectrum closely resembles that of tropone and exhibits a batho-chromic shift over those of cycloheptatriene (unconjugated). Although the "B signal at 53.6 ppm is not much shifted over that in 1-phenyl-4,5-dihydroborepin (54.6 ppm), the borepin ring protons occur at markedly... 

Machiguchi, Nozoe and coworkers have very recently observed that in contrast to chemical reactivity of tropones, the tosylate of tropone oxime undergoes a facile ring-opening to 6-substituted (Z,Z,Z)-1,3,5-hexatriene nitriles on reaction with various nucleophiles305. For example, reaction of phenyl lithium results in the corresponding hexatriene carbonitrile (equation 183). 

The anodic oxidation of 7-MeO-CHT in MeOH results in the formation of benzalde-hyde dimethyl acetal through a ring contracting rearrangement, whereas 3-MeO-CHT and 1-MeO-CHT are prepared by thermal rearrangement of 7-MeO-CHT and afford 7,7-diMeO-CHT in 83% and 85% yields, respectively, upon the anodic oxidation. The hydrolysis of 7,7-diMeO-CHT in 5% aqueous H2SO4 gives tropone in 85% yield (equation 17). 

Tropone (255) cycloadds to allene 71c to construct a 5,7-fused ring system, probably via a concerted mechanism [109]. The reaction of 71c with azaheptafulvenes 256 took place much more readily at room temperature to produce the relatively unstable adducts 257, which isomerized gradually to the stable pyrroles. 

Similarly, a number of 2-(2-arylhydrazino) tropones undergo the benzidine rearrangement when treated with HC1 in EtOH to give 2-amino-5-(4-aminoaryl)tropones, which can be hydrolysed to the corresponding 5-aryl-tropolones. This is a useful route to a synthesis for open B ring colchine analogues25. 

In general, this approach can be represented by equations 207 and 208 wherein the formation of cis- and fraws-substituted seven-membered rings (e.g. tropones or oxepines) is controlled by selection of appropriate isomeric divinylcyclopropanes or divinylepoxides as precursors. We will discuss here a series of examples which are not covered by a recent review260. 

Examples of different types of tropones and tropolones fused to a five-membered heterocyclic ring are given in Scheme 1. Different fusion with respect to the heteroatom or group (Z) leads to... 

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