Preparation and isolation of isobenzofuran

The synthesis, isolation and characterization of isobenzofuran are described in this publication. Isobenzofuran is of general interest in synthetic and physical organic chemistry because it is one of the most reactive dienes known. A number of synthetic pathways have been published which all suffer from disadvantages such as low yields and difficult purification. We present a synthetic pathway to prepare isobenzofuran in laboratory scale with high yields, from affordable, commercially available starting materials.


Introduction
Isobenzofurans have been described as the most reactive dienes for Diels-Alder reactions [1][2][3][4][5]. Their high reactivity is mainly due to the resonance energy gained by formation of a benzene ring in the cycloaddition product (Scheme 1) [6]. Isobenzofurans have been extensively used as 4 electron (diene) components in Diels-Alder reactions, and moreover in other cycloaddition reactions such as [4 + 3], [4 + 4], [8 + 8] and [4 + 6] additions [7][8][9][10]. Highly strained alkenes and alkynes have been trapped with isobenzofurans. 1,3-Diphenylisobenzofuran is the preferred trapping reagent for singlet oxygen and is used to quantify the generation of 1 O 2 in photodynamic therapy [4,11]. The most important synthetic application is probably the preparation of annulated polycyclic aromatic hydrocarbons by cycloaddition to arynes [8,12]. However, the high reactivity of isobenzofurans comes at the cost of low stability [13]. 1,3-Diphenylisobenzofuran is reasonably stable and commercially available and therefore the most frequently used isobenzofuran derivative. The parent system isobenzofuran (IBF, 1) is about 10 times more reactive but generally described as a reagent that is difficult to prepare and to purify [1]. Therefore, it should be generated in situ, and used without isolation.

Results and Discussion
We now present a reliable and convenient synthesis providing high yields of isobenzofuran. In contrast to previous reports, the compound is stable for more than 8 months in pure form as a solid at −15 °C. The half-life of IBF (1) in solution (150 mM, 27 °C, toluene-d 8 ) is about 12 h. A half-life of 2 h in CDCl 3 has been previously reported [14]. Isobenzofurans are light sensitive. Warrener et al. reported on [8 + 8] cycloaddition products upon irradiation. Depending on the solvent further dimers are formed [14].
Several procedures have been published for the synthesis of IBF (1). The key step in the majority of the reported methods is a retro Diels-Alder reaction [6,13,[15][16][17]. Fieser and Haddadin [17] describe IBF as a transient intermediate and Warrener and Wege [13,15] isolated IBF at −80 °C on a cold finger. The disadvantages of these methods are high reaction temperatures during vacuum pyrolysis and multistep syntheses of the precursors.
It is known that benzyl ethers are prone to oxidative functionalization [20]. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) has been used to selectively oxidize benzyl ethers to acetals in the presence of alcohols [21]. Following a procedure of Doyle et al. we reacted commercially available phthalan (8) with DDQ and methanol in dry dichloromethane under a nitrogen atmosphere at room temperature, and obtained DMIBF (7) with a yield of 85% (Scheme 2) [22]. DMIBF (7) was treated with freshly prepared lithium diisopropylamide (LDA) in benzene and IBF (1) was obtained as a solution in benzene which was washed with aqueous NH 4 Cl to remove lithium salts and amines (Scheme 2) [8,18].
To determine the yield of IBF (1), this solution was reacted with acetylenedicarboxylic acid dimethyl ester (DMAD, 9) and prod-uct 10 was obtained with a yield of 78% relative to the precursor DMIBF (7, Scheme 3). To further purify isobenzofuran (1), the benzene solution was carefully evaporated and the residue was subjected to column chromatography over silica gel (cyclohexane/ethyl acetate). We were able to isolate IBF (1) as a colorless solid (mp 20 °C) with a yield of 66%. The solid compound can be stored for up to 8 months at −15 °C without decomposition (polymerization).

Conclusion
Isobenzofuran (1) is one of the most reactive dienes in Diels-Alder reactions and other cycloadditions. For practical applications it has been generated and reacted in situ, because it rapidly dimerizes or polymerizes in solvents of medium polarity such as chloroform (t 1/2 = 2 h). We observed longer half-lives in low polarity solvents (t 1/2 = 12 h in toluene-d 8 , 150 mM, 27 °C). We have been able to purify the compound by chromatography and to isolate it as a colorless solid (mp 20 °C). In crystalline form, it is stable for 8 months at −15 °C without decomposition. Upon oxidative methoxylation of commercially available phthalane (85% yield) [22], and subsequent 1,4-elimination with LDA [18] we obtained isobenzofuran (1) in 78% yield (trapping reaction) or in 66% isolated yield after chromatography.

Supporting Information
Supporting Information File 1 Analytical equipment and methods, experimental procedures and NMR spectra.