Application of substituted isobenzofurans in Diels-Alder reaction

Regarding our failure to functionalize following bridge position, we should admit that to the best of our knowledge, today there is no method reported which would allow to achieve this. Attempted methods were reported only for secondary and tertiary alkyl chains, and method which allows bridge oxidation¹⁰⁸ is not suitable for our system. The presence of oxygen atom near the bridge position makes this task even more complicated. All attempts to perform Diels-Alder reaction with benzo[c]thiophene 270 proved absolutely unfruitful.

This means that we should move back and try again the key Diels-Alder reaction with pre-functionalyzed isobenzofurans.

We wondered if it would be possible to synthetize 2-silyl isobenzofuran 274 in the same way as we prepared unsubstituted isobenzofuran 221 using Warrener procedure.⁸¹ The presence of following silyl group would allow a late-stage oxidation of this position using Fleming-Tamao conditions.¹⁰⁹ The silylfuran 272 was synthetized by deprotonation of furan with nBuLi ant trapping with chloro(dimethyl)phenylsilane.

Aryne generation from bromoarene 224 with consequent Diels-Alder reaction with furan 272 gave precursor 273, albeit with lower yield (Scheme 56).

Scheme 56. Synthesis of 273 as a precursor for isobenzofuran 274.

With this in hand, we started to explore the reactivity of isobenzofuran 274 (Scheme 56). Although slightly higher temperature was needed for its generation, formation of this highly reactive specie was secured by TLC analysis. Unluckily, the desired Diels-Alder reaction could not be performed and we did not detect any formation of a product 275 (Scheme 57, Table 11). Even elevated temperatures were unsuccessful (entry 2, Table 11). Possible reasons for this could be a great steric hindrance of isobenzofuran 274 or unfavorable electronic effect of silicon atom, which is more likely.

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Scheme 57. Attempts to synthesize Diels-Alder adduct 275.

Table 11. Conditions screened for the synthesis of 275.

Entry Solvent Temerature Result

1 Toluene 175 °C No reaction

2 Trichlorotoluene 250 °C Decomposition

Afterwards, we explored the Hauser-Kraus annulation, which was successfully utilized by the group of Myers in the total synthesis of (+)-dynemicin A.¹¹⁰ Starting from phthalide 276 the corresponding 2-siloxy-isobenzofuran was prepared in situ by deprotonation and trapping with silyl chloride (Scheme 58, Table 12). Unfortunately, this reaction proved unsuccessful and did not provide formation of any product, as only starting material was isolated. Even heating up the reaction mixture did not help.

Obviously, the reactivity of the obtained isobenzofuran is not sufficient for a Diels-Alder reaction with dienone 171, and furthermore, these siloxyfurans are quite unstable and presumably do not survive elevated temperatures. For this reason, we decided to synthetize 2-alkoxyfurans, in terms of their higher stability.

Scheme 58. Attempts to synthetize 277 utilizing Hauser-Kraus conditions.

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Table 12. Conditions screened for the synthesis of 277.

Entry Base Reagents Temperature Result

1 LDA TBSCl -78 °C; RT No reaction

Commercially available aldehyde 278 was reduced and after directing ortho-lithiation trapped with CO2, providing phthalide 267.¹¹¹ Based on studies from Meerwein¹¹² and Deslongchamps¹¹³, we were able to synthesize cyclic orthoester 279 (Scheme 59).

This compound proved unstable upon basic aqueous work-up and silica gel purification. Therefore, the crude mixture of 279 was evaporated and directly purified by column chromatography with activated basic Al2O3, although in unreliable yields.

Scheme 59. Synthesis of ortho-ester 279.

It was further reported that upon heating of 279 or by treatment with LDA it is possible to generate the desired 2-ethoxy-isobenzofuran in situ (by elimination of one EtOH molecule), which efficiently reacts with different dienophiles.^114,115 Encouraged by these works, we conducted a series of experiments (Scheme 60, Table 13).

Although it was reported that isobenzofuran can be formed simply by heating up compound 279, which results in ethanol elimination, we could not observe any formation of isobenzofuran and some potential product (entry 1-4, Table 13), instead only phthalide 267 was formed slowly (TLC and crude NMR control). Even the use of 1,2-dichlorobenzene as solvent and reflux in seal tube at 250 °C for several days (entry 5, Table 13) proved unfruitful.

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Scheme 60. Attempts to synthesize Diels-Alder adduct 280.

Table 13. Conditions screened for the synthesis of 280.

Entry Reagents Temperature Result

1 Benzene 175 °C No reaction

2 Benzene, 1 drop AcOH 175 °C No reaction

3 CHCl3 120 °C No reaction

4 CHCl3 200 °C No reaction

5 1,2-dichlorobenzene 250 °C No reaction

6 MeLi, iPr2NH, Et2O -30 °C to RT No reaction

Afterwards we turned our focus to a base-induced formation of isobenzofuran, which worked well (TLC control, crude NMR in benzene), but unfortunately various solvents and conditions failed to deliver any product (entry 6-9, Table 13). Only after careful exchange of diethyl ether to benzene (complete evaporation and any sort of filtration should be avoided since isobenzofuran will decompose) and refluxing at 200 °C (entry 10, Table 13) we could see formation of the aromatized Diels-Alder product 281 in very low yield.

Next, we turned to the synthesis of arene 224, which was achieved in the same manner as 225 and 273, in order to generate isobenzofuran 284 (Scheme 61). After the Diels-Alder reaction and photocyclization the presence of masked aldehyde on some stage would allow the formation of corresponding lactol moiety, utilizing the Baeyer-Villiger oxidation.

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Scheme 61. Synthesis of 283 as a precursor for isobenzofuran 284.

The desired Diels-Alder reaction was in this case successful, but had another outcome as with unsubstituted isobenzofuran 221. Here the reaction yield was relatively low, generated in situ isobenzofuran 284 was less stable (as judged by TLC control) and only endo isomer has been isolated (Scheme 62). All attempts to optimize following reaction proved fruitless, since better yields could not be achieved. Irradiation of endo 285 with high-pressure mercury lamp provided expected cyclization product 286 in 25% yield. It should be noted, that the flash column chromatography of 286 was very tedious because of small Rf difference with starting material 285. The ether hydrolysis worked fine yielding triketone 287 with unaffected acetal moiety. Interestingly, when we tried to selectively reduce triketone 287 with L-selectride (compare with reduction of 232) we obtained opposite results and exclusively alcohol 288 was formed.

Scheme 62. Synthesis of triketone 287 and its reduction with L-selectride.

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Next, we explore the reduction of 287 with several reducing reagents (Scheme 63). In all cases, complex mixture of mono-reduced 288 and double reduced alcohols 289 and 290 was obtained. Remarkably, in 290 obtained alcohol underwent formation of cyclic acetal moiety.

Scheme 63. Reduction of triketone 287.

Since no significant selectivity was achieved, we decided to extensively reduce triketone 287 with lithium aluminium hydride and in next completely protect with TBS to compound 291 (Scheme 64). Dimethyl acetal was further deprotected and corresponding aldehyde 292 was isolated in moderate yield.

Scheme 64. Synthesis of aldehyde 292.

Unluckily, the Baeyer-Villiger oxidation on substrate 292 did not provide intermediate 293, which could be further opened to desired diol moiety (Scheme 65).

Scheme 65. Attempted synthesis of intermediate 293.

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