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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 October 15.
Published in final edited form as:
Tetrahedron Lett. 2007 August 20; 48(34): 5938–5941.
doi:  10.1016/j.tetlet.2007.06.118
PMCID: PMC2955265

An Approach Toward Oxidopyrylium Ylides Using Rh(II)-Catalyzed Cyclization Chemistry


The Rh(II)-catalyzed reaction of the E-isomer of 2-diazo-3,6-dioxo-6-phenyl-hex-enoic acid methyl ester was carried out in the presence of various carbonyl compounds and was found to give 1,3-dioxoles in moderate to good yield. In an attempt to prepare the starting -diazo substrate, an unexpected pseudo-dimerization reaction was encountered when 5-phenyl-furan-2,3-dione was heated in the presence of sodium methoxide.

In recent years, a widespread upsurge of activity in the application of carbonyl ylide dipoles to new synthetic transformations has occurred.1,2 This research has also stimulated interest in the use of carbenes and carbenoids as reactive intermediates for the generation of other types of ylides.3 A diverse range of chemistry has already surfaced.14 In 1986, work started in the Padwa laboratory to synthesize bridged oxa-substituted bicycloalkanes from the Rh(II)-catalyzed cyclization cascade of -diazo carbonyl compounds.5a The domino reaction was shown to proceed by the formation of a rhodium carbenoid intermediate and a subsequent transannular cyclization of the electrophilic carbon onto an adjacent carbonyl group to generate a cyclic carbonyl ylide dipole.57 This was followed by a 1,3-dipolar cycloaddition reaction with an added dipolarophile A=B (Scheme 1).

Our ongoing interest in this procedurally simple methodology led us to focus on the cycloaddition behavior of the related oxidopyrylium dipole 5, where the extra double bond contained within the ring would not only allow for the formation of the [5+2]-dipolar cycloadduct 6, but also could produce the isomeric cycloadduct 7. The [5+2]-cycloaddition of 3-oxidopyrylium ylides is a well precedented reaction and has been used for the rapid access of functionalized seven-membered ring structures.8 Henderson and Farina originally discovered that [5+2]-cycloadditions can be carried out by heating acetoxy-pyranones such as 8 and a dipolarophile at 130 °C to afford up to 69% of cycloadduct 10.9 This reaction was further developed by Sammes, who found that electron rich dipolarophiles were more reactive toward dipole 9 and that the reaction can also be carried out using Et3N to generate the oxypyrylium zwitterion at room temperature.10 Substituted allenes11 and dienes12 have also been successfully engaged as dipolarophiles in intra and intermolecular reactions. The rapid generation of molecular complexity in a relatively easy manner has made this cycloaddition reaction extremely useful for the synthesis of seven-membered ring containing natural products. Notably, Wender and coworkers have successfully applied this strategy, in an intramolecular fashion, to the total synthesis of the natural products phorbol and resiniferatoxin.13 Further examples of intramolecular [5+2]-cycloadditions of pyranones of type 11 for natural product synthesis have also been reported by Heathcock,14 Ohmori,15 Magnus16 and Williams.17

Since we were interested in using the Rh(II)-catalyzed reaction of -diazo ketoesters such as 4 as a way to generate various oxidopyrylium ylides, we undertook a study of several methods to synthesize the required precursor -diazo ketoesters. To this end, 5-phenylfuran-2,3-dione (13) was prepared in 80% yield by reacting trimethyl (1-phenylvinyloxy)silane with oxalyl chloride.18 Our intention was to heat 13 with methyl acetate in the presence of sodium methoxide with the hope that we'd be able to prepare methyl 3,4,6-trioxo-6-phenylhexanoate acid (14), which would then be transformed into the corresponding -diazoketo ester 4.

However, in our attempts to convert furandione 13 into 14, we encountered a rather unusual reaction. The major (80%) and unexpected product obtained from the thermal reaction of 14 under basic conditions was identified as 3-benzoyl-4-hydroxy-6-phenyl-2H-pyran-2-one (15) on the basis of its spectral data19 and by the procurement of an X-ray crystal structure. The pseudo-dimerization of 13 to 15 can be accounted for by an initial thermal extrusion of carbon monoxide from 13 to give benzoyl ketene 16 as a transient species. Attack of methoxide anion at the electrophilic ketene center in 16 generates the stable anion 17, which in turn reacts with another molecule of the ketene to furnish the 1,3-dicarbonyl anion 18. Cyclization of 18 to 19 followed by tautomerization to the more stable enol form nicely accounts for the formation of pyranone 15 (Scheme 5).

In an alternate approach that we next employed for the preparation of -diazo ketoester 4, we made use of an oxidation reaction of furan 20.20 Thus, methyl 2-(furan-2-yl)acetate (20) was treated with mCPBA at 0 °C in CH2Cl2 and this resulted in a 6:1-stereomeric mixture of the expected ring-opened butene-diones which were immediately converted to the corresponding -diazo ketoesters (i.e., 4 and 21) using p-nitrobenzenesulfonyl azide and Et3N according to the standard Regitz protocol.21 The two isomeric -diazo compounds were separated by fractional recrystallization. Treatment of the minor Z-isomer 4 with a catalytic quantity of rhodium(II) acetate in benzene at 25 °C afforded an unknown dimer (i.e. 22) in 45% yield. Unfortunately, all of our attempts to trap an oxidopyrylium ylide intermediate from the Z-isomer 4 using various trapping agents failed to afford any signs of a [5+2]-cycloadduct. The only compound detected in these reactions was dimer 22.22

We also studied the Rh(II)-catalyzed behavior of the major E-diazo isomer 21. This isomeric -diazo ketoester cannot undergo internal cyclization to give a carbonyl ylide dipole and we were curious as to what pathway would be followed with this system. Toward this end, 21 was added to a benzene solution containing DMAD and a catalytic amount of Rh2(OAc)4 under an argon atmosphere at 80 °C. The reaction was monitored by TLC and column chromatographic purification of the crude reaction mixture afforded cycloadduct 23 as the only isolable product in 42% yield. A related cycloadduct (i.e., 24) was isolated when N-methyl maleimide was used as the trapping dipolarophile (Scheme 7). When N-methyl succinimide, benzaldehyde, cyclohexanone, or acetone were used as the trapping agents, the analogous cycloadducts 2629 were obtained in 25–80% yield. Ethyl acetate turned out to be a very efficient trapping agent producing cycloadduct 30 in 80% yield. The overall cycloaddition can be rationalized by an initial reaction of -diazo ketoester 21 with the Rh(II)-catalyst to first generate an electrophilic metallo carbenoid. This species then reacts with the nucleophilic carbonyl oxygen atom of the added dipolarophile to furnish the highly reactive carbonyl ylide intermediate 25. The presence of the adjacent enone carbonyl group facilitates an intramolecular [1,5]-electrocyclization that leads to the corresponding 1,3- dioxole derivatives 2630.23 A resonance structure of the carbonyl ylide with the negative charge on the oxygen atom of the enone carbonyl group and a positive charge on the carbonyl C-atom of the added dipolarophile contributes significantly to the resonance hybrid of the transient ylide 25, thereby favoring the [1,5]-electrocyclization pathway (Scheme 8).

In summary, we have investigated the Rh(II)-catalyzed reaction of the Z-isomer of 2-diazo-3,6-dioxo-6-phenyl-hex-4-enoic acid methyl ester and found that a dimer was formed as the major product. We have also shown that the Rh(II)-catalyzed reaction of the related E-isomer in the presence of various carbonyl compounds undergoes cyclization to give substituted 1,3-dioxoles as the major products. An unexpected pseudo-dimerization process was also encountered when the thermolysis of 5-phenyl-2,3-dione was carried out in the presence of sodium methoxide.


We appreciate the financial support provided by the National Institutes of Health (GM 059384) and the National Science Foundation (Grant CHE-0450779).


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