Preparation and isolation of isobenzofuran

Article abstract of DOI:10.3762/bjoc.13.263

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.

Full text of DOI:10.3762/bjoc.13.263

Preparation and isolation of isobenzofuran
Morten K. Peters and Rainer Herges*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2659–2662.
Otto-Diels-Institut für Organische Chemie,
Christian-Albrechts-Universität, Otto-Hahn-Platz 4, 24118 Kiel,
Germany
doi:10.3762/bjoc.13.263
Received: 16 October 2017
Accepted: 01 December 2017
Published: 12 December 2017
Email:
Rainer Herges* - rherges@oc.uni-kiel.de
Associate Editor: B. Stoltz
* Corresponding author
© 2017 Peters and Herges; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
[4 + 2] cycloaddition; Diels–Alder; isobenzofuran; trapping reagent
Abstract
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 path-
way 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 cycloaddition reactions such as [4 + 3], [4 + 4], [8 + 8] and
for Diels–Alder reactions [1-5]. Their high reactivity is mainly [4 + 6] additions [7-10]. Highly strained alkenes and alkynes
due to the resonance energy gained by formation of a benzene have been trapped with isobenzofurans. 1,3-Diphenylisobenzo-
ring in the cycloaddition product (Scheme 1) [6].
furan is the preferred trapping reagent for singlet oxygen and is
used to quantify the generation of 1O2 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
Scheme 1: Diels–Alder reaction of isobenzofuran and formation of a
benzene ring in the cycloadduct.
Isobenzofurans have been extensively used as 4 electron (diene) is difficult to prepare and to purify [1]. Therefore, it should be
components in Diels–Alder reactions, and moreover in other generated in situ, and used without isolation.
2659

Beilstein J. Org. Chem. 2017, 13, 2659–2662.
Results and Discussion
of phthalic acid (2) or phthalic acid ester 3 to 1,2-bis(hydroxy-
We now present a reliable and convenient synthesis providing methyl)benzene (4) [19], acid promoted ring closure, and subse-
high yields of isobenzofuran. In contrast to previous reports, the quent oxidation with hypochlorite in the presence of methanol
compound is stable for more than 8 months in pure form as a gives 7 in a moderate yield of 65% [18].
solid at −15 °C. The half-life of IBF (1) in solution (150 mM,
27 °C, toluene-d8) is about 12 h. A half-life of 2 h in CDCl3 has Alternatively, phthalide 5 has been reduced to 1,3-dihy-
been previously reported [14]. Isobenzofurans are light sensi- droisobenzofuran-1-ol (6) and methylated to DMIBF (7) [8].
tive. Warrener et al. reported on [8 + 8] cycloaddition products However, yields in our hands are quite low.
upon irradiation. Depending on the solvent further dimers are
formed [14].
It is known that benzyl ethers are prone to oxidative functionali-
zation [20]. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
Several procedures have been published for the synthesis of IBF has been used to selectively oxidize benzyl ethers to acetals in
(1). The key step in the majority of the reported methods is a the presence of alcohols [21]. Following a procedure of Doyle
retro Diels–Alder reaction [6,13,15-17]. Fieser and Haddadin et al. we reacted commercially available phthalan (8) with DDQ
[17] describe IBF as a transient intermediate and Warrener and and methanol in dry dichloromethane under a nitrogen atmo-
Wege [13,15] isolated IBF at −80 °C on a cold finger. The sphere at room temperature, and obtained DMIBF (7) with a
disadvantages of these methods are high reaction temperatures yield of 85% (Scheme 2) [22]. DMIBF (7) was treated with
during vacuum pyrolysis and multistep syntheses of the precur- freshly prepared lithium diisopropylamide (LDA) in benzene
sors.
and IBF (1) was obtained as a solution in benzene which was
washed with aqueous NH4Cl to remove lithium salts and
The alternative way to synthesize IBF (1) is 1,4-elimination of amines (Scheme 2) [8,18].
1,3-dihydro-1-methoxyisobenzofuran (7, DMIBF), which
provides access to IBF (1) at ambient temperature [18]. Three To determine the yield of IBF (1), this solution was reacted with
methods have been published to prepare 7 (DMIBF). Reduction acetylenedicarboxylic acid dimethyl ester (DMAD, 9) and prod-
Scheme 2: Different approaches for the synthesis of IBF (1).
2660

Beilstein J. Org. Chem. 2017, 13, 2659–2662.
uct 10 was obtained with a yield of 78% relative to the precur- gen carbonate solution and filtered over Celite. The aqueous
sor DMIBF (7, Scheme 3).
phase was extracted three times with dichloromethane. The
combined organic layers were dried over magnesium sulfate
and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography on silica gel
(cyclohexane/ethyl acetate 8:2, Rf 0.58) A colorless oil was ob-
tained. Yield: 2.13 g (14.2 mmol, 85%); 1H NMR (500 MHz,
300 K, CDCl3) δ 7.41 (d, 3J = 7.3 Hz, 1H), 7.39–7.33 (m, 2H),
7.27 (d, 3J = 7.4 Hz, 1H), 6.19 (d, 4J = 2.2 Hz, 1H), 5.22 (dd,
2J = 12.7 Hz, 4J = 2.2 Hz, 1H), 5.05 (d, 2J = 12.7 Hz, 1H), 3.44
(s, 3H) ppm; 13C NMR (150 MHz, 300 K, CDCl3) δ 140.0,
137.3, 129.3, 127.9, 123.0, 121.0, 107.3, 72.2, 54.2 ppm.
Scheme 3: Reaction of in situ prepared IBF (1) with DMAD (9).
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).
Isobenzofuran (1, IBF) [18]: Diisopropylamine (1.43 g,
14.2 mmol) was dissolved in benzene (5.00 mL), and cooled to
0 °C. 2.5 M n-butyllithium solution in hexane (6.70 mL) was
added dropwise and the mixture was stirred for 15 min. The
freshly prepared LDA solution was warmed up to room temper-
ature. Then 1-methoxy-1,3-dihydroisobenzofuran (7, 800 mg,
Conclusion
Isobenzofuran (1) is one of the most reactive dienes in 5.33 mmol), dissolved in benzene (8 mL), was added dropwise
Diels–Alder reactions and other cycloadditions. For practical and stirred for 5 min. The mixture was washed with ammonium
applications it has been generated and reacted in situ, because it chloride solution and then twice with water. The combined
rapidly dimerizes or polymerizes in solvents of medium polarity organic layers were dried over magnesium sulfate and the sol-
such as chloroform (t1/2 = 2 h). We observed longer half-lives vent was removed under reduced pressure. The crude product
in low polarity solvents (t1/2 = 12 h in toluene-d8, 150 mM, was purified by column chromatography on silica gel (cyclo-
27 °C). We have been able to purify the compound by chroma- hexane/ethyl acetate 8:2, Rf 0.92). The solvent was carefully
tography and to isolate it as a colorless solid (mp 20 °C). In evaporated at 20 °C. A colorless solid was obtained. Yield:
crystalline form, it is stable for 8 months at −15 °C without de- 415 mg (3.52 mmol, 66%); mp 20 °C; IR (ATR): 3138 (w),
composition. Upon oxidative methoxylation of commercially 3044 (w), 2923 (w), 1774 (w), 1695 (m), 1462 (m), 1428 (m),
available phthalane (85% yield) [22], and subsequent 1,4-elimi- 1368 (m), 1195 (w), 1043 (s), 976 (s), 950 (s), 888 (s), 871 (m),
nation with LDA [18] we obtained isobenzofuran (1) in 78% 758 (s), 672 (m), 635 (s), 601 (s), 539 (s), 496 (s) cm−1;
yield (trapping reaction) or in 66% isolated yield after chroma- 1H NMR (600 MHz, 300 K, DMSO-d6) δ 8.32 (s, 2H), 7.45
tography.
(dd, 3J = 6.8 Hz, 4J = 2.8 Hz, 2H), 6.86 (dd, 3J = 6.8 Hz, 4J =
2.8 Hz, 2H) ppm; 13C NMR (150 MHz, 300 K, DMSO-d6) δ
136.1, 124.2, 123.5, 119.0 ppm; HRMS (EI) m/z: [M]+ calcd.
Experimental
NMR spectra were measured in deuterated solvents (Deutero). for C8H6O, 118.04173; found, 118.04186.
Analytic measurements were performed by the following instru-
ments: Bruker CABAV 500neo (1H NMR: 500 MHz, Dimethyl 1,4-epoxy-1,4-dihydronaphthalene-2,3-dicarboxy-
13C NMR: 125 MHz) and Bruker AV 600 (1H NMR: 600 MHz, late (10): Dimethyl acetylenedicarboxylate (9, 1.00 g,
13C NMR: 150 MHz). Infrared spectra were recorded on a 7.04 mmol) was dissolved in benzene (25 mL) under a nitrogen
Perkin-Elmer 1600 Series FTIR spectrometer with an A531-G atmosphere. A freshly prepared solution of isobenzofuran (1),
Golden-Gate-Diamond-ATR-unit. The high-resolution (HR) which was prepared from DMIBF (7, 1.10 mmol, 165 mg),
mass spectra were measured with an APEX 3 FT-ICR with a prior to purification by chromatography (see procedure above)
7.05 T magnet by co. Bruker Daltonics. Electron impact (EI). was added dropwise and stirred for 16 h at 50 °C. The crude
product was purified by column chromatography on silica gel
1,3-Dihydro-1-methoxyisobenzofuran (7) [22]: 2,3-Dichloro- (cyclohexane/ethyl acetate 8:2, Rf 0.27). A colorless oil was ob-
5,6-dicyano-1,4-benzoquinone (DDQ, 5.00 g, 22.0 mmol), dry tained. Yield: 223 mg (858 µmol, 78%); IR (ATR): 2953 (w),
dichloromethane (100 mL), methanol (900 μL, 22.2 mmol) and 1710 (s), 1637 (m), 1435 (m), 1291 (m), 1250 (s), 1211 (s),
phthalan (8, 2.00 g, 16.7 mmol) were dissolved under a nitrogen 1109 (s), 1064 (m), 976 (m), 910 (m), 854 (s), 755 (s), 734 (m),
atmosphere. The reaction mixture was stirred for 13 h at room 655 (s) cm−1; 1H NMR (600 MHz, 300 K, CDCl3) δ 7.43 (dd,
temperature. The reaction was quenched with aq sodium hydro- 3J = 5.2 Hz, 4J = 3.0 Hz, 2H), 7.07 (dd, 3J = 5.2 Hz, 4J =
2661

Beilstein J. Org. Chem. 2017, 13, 2659–2662.
19.Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1947, 69, 1197.
doi:10.1021/ja01197a060
3.0 Hz, 2H), 5.96 (s, 2H), 3.80 (s, 6H) ppm; 13C NMR
(150 MHz, 300 K, CDCl3) δ 162.8, 151.2, 146.2, 126.1, 121.4,
84.8, 52.4 ppm; HRMS (EI) m/z: [M]+ calcd. for C12H12O5,
260.06847; found, 260.06800.
20.Goh, S. H. J. Org. Chem. 1972, 37, 3098. doi:10.1021/jo00985a013
21.Shen, Z.; Dai, J.; Xiong, J.; He, X.; Mo, W.; Hu, B.; Sun, N.; Hu, X.
Adv. Synth. Catal. 2011, 353, 3031. doi:10.1002/adsc.201100429
22.Arendt, K. M.; Doyle, A. G. Angew. Chem., Int. Ed. 2015, 54, 9876.
doi:10.1002/anie.201503936
Supporting Information
Supporting Information File 1
Analytical equipment and methods, experimental
procedures and NMR spectra.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-263-S1.pdf]
(http://creativecommons.org/licenses/by/4.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Acknowledgements
The authors gratefully acknowledge funding from the collabora-
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
tive research center SFB 677 Function by Switching.
(http://www.beilstein-journals.org/bjoc)
References
1. Tobia, D.; Rickborn, B. J. Org. Chem. 1987, 52, 2611.
The definitive version of this article is the electronic one
which can be found at:
doi:10.1021/jo00388a055
2. Rickborn, B. In Advances in Theoretically Interesting Molecules;
Thummel, R. P., Ed.; JAI Press: Greenwich, 1989; Vol. 1.
3. Rodrigo, R. Tetrahedron 1988, 44, 2093.
doi:10.1016/S0040-4020(01)81720-8
doi:10.3762/bjoc.13.263
4. Friedrichsen, W. Adv. Heterocycl. Chem. 1980, 26, 135.
doi:10.1016/S0065-2725(08)60141-5
5. Haddadin, M. J. Heterocycles 1978, 9, 865.
doi:10.3987/R-1978-07-0865
6. Packe-Wirth, R.; Enkelmann, V. J. Mol. Struct. 1998, 448, 1.
doi:10.1016/S0022-2860(98)00324-X
7. Takeshita, H.; Wada, Y.; Mori, A.; Hatsui, T. Chem. Lett. 1973, 2, 335.
doi:10.1246/cl.1973.335
8. Man, Y. M.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 1990, 55,
3214. doi:10.1021/jo00297a043
9. Itô, S.; Ohtani, H.; Narita, S.; Honma, H. Tetrahedron Lett. 1972, 13,
2223. doi:10.1016/S0040-4039(01)84811-5
10.Sasaki, T.; Kanematsu, K.; Hayakawa, K.
J. Chem. Soc., Perkin Trans. 1 1972, 1951.
doi:10.1039/P19720001951
11.Rio, G.; Scholl, M.-J. J. Chem. Soc., Chem. Commun. 1975, 474.
doi:10.1039/c39750000474
12.Wong, H. N. C.; Man, Y.-M.; Mak, T. C. W. Tetrahedron Lett. 1987, 28,
6359. doi:10.1016/S0040-4039(01)91373-5
13.Warrener, R. N. J. Am. Chem. Soc. 1971, 93, 2346.
doi:10.1021/ja00738a057
14.Warrener, R. N.; Pitt, I. G.; Russell, R. A. Aust. J. Chem. 1993, 46,
1515. doi:10.1071/CH9931515
15.Wege, D. Tetrahedron Lett. 1971, 12, 2337.
doi:10.1016/S0040-4039(01)96856-X
16.Wiersum, U. E.; Mijs, W. J. J. Chem. Soc., Chem. Commun. 1972, 347.
doi:10.1039/C39720000347
17.Fieser, L. F.; Haddadin, M. J. J. Am. Chem. Soc. 1964, 86, 2081.
doi:10.1021/ja01064a044
18.Naito, K.; Rickborn, B. J. Org. Chem. 1980, 45, 4061.
doi:10.1021/jo01308a028
2662