Facile Sc(OTf)3-catalyzed generation and successive aromatization of isobenzofuran from o -dicarbonylbenzenes

Article abstract of DOI:10.1021/ol201479p

Isobenzofuran can be prepared from o-phthalaldehyde using hydrosilane. The formed isobenzofuran is trapped by an alkene via a Diels-Alder reaction. Further dehydration proceeds to furnish the conjugated aromatic compound. This multistep reaction was promoted by catalytic amounts of Sc(OTf)₃.

Full text of DOI:10.1021/ol201479p

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3960–3963
Facile Sc(OTf)3-Catalyzed Generation and
Successive Aromatization of
Isobenzofuran from
o-Dicarbonylbenzenes
Yuta Nishina,* Tatsuya Kida, and Tomonari Ureshino
Research Core for Interdisciplinary Sciences, Okayama University, Tsushima, Kita-ku,
Okayama 700-8530, Japan
nisina-y@cc.okayama-u.ac.jp
Received June 1, 2011
ABSTRACT
Isobenzofuran can be prepared from o-phthalaldehyde using hydrosilane. The formed isobenzofuran is trapped by an alkene via a DielsꢀAlder
reaction. Further dehydration proceeds to furnish the conjugated aromatic compound. This multistep reaction was promoted by catalytic amounts
of Sc(OTf)3.
Isobenzofuran (1a) has been referred to as the most
reactive isolated diene toward cycloadditions.1 Although
1a has been characterized spectroscopically, it has a short
lifetime at room temperature. The reactivity of 1a can be
attributed to its o-xylylenoid nature and readily undergoes
DielsꢀAlder reactions with a wide range of dienophiles to
achieve aromaticity. 1a and its derivatives are commonly
used to construct six-membered π-conjugate systems in
natural products and functional materials (Scheme 1).2
Scheme 1. Synthesis of Naphthalene 6 from o-Xylylene or
Isobenzofuran 1a
(1) (a) Tobia, D.; Rickborn, B. J. Org. Chem. 1987, 52, 2611–2615.
(b) Whitney, S. E.; Rickborn, B. J. Org. Chem. 1988, 53, 5595–5596.
(c) Thibault, M. E.; Pacarynuk, L. A.; Closson, T. L. L.; Dibble, P. W.
Tetrahedron Lett. 2001, 42, 789–791.
(2) (a) Levy, L. A.; Pruitt, L. J. Chem. Soc., Chem. Commun. 1980,
227–228. (b) Rodrigo, R. Tetrahedron 1988, 44, 2093–2135. (c) Chew, S.;
Wang, P.; Hong, Z.; Kwong, H. L.; Tang, J.; Sun, S.; Lee, C. S.; Lee,
S.-T. J. Lumin. 2007, 124, 221–227. (d) Paraskar, A. S.; Reddy, A. R.;
Patra, A.; Wjjsboom, Y. H.; Gidron, O.; Shimon, L. J. W.; Leitus, G.;
Bendikov, M. Chem.;Eur. J. 2008, 14, 10639–10647. (e) Chun, D.;
Cheng, Y.; Wudl, F. Angew. Chem., Int. Ed. 2008, 47, 8380–8385. (f) Ma,
X. M.; Wu, W. J.; Zhang, Q.; Guo, F. L.; Meng, F. S.; Hua, J. L. Dyes
Pigm. 2009, 82, 353–359. (g) Wu, W. J.; Guo, F. L.; Li, J.; He, J. X.; Hua,
J. L. Synth. Met. 2010, 160, 1008–1014.
(3) (a) Cava, M. P.; Mitchell, M. J.; Deana, A. A. J. Org. Chem. 1960,
25, 1481–1483. (b) Naito, K.; Rickborn, B. J. Org. Chem. 1980, 45, 4062–
4063. (c) Kappe, C. O.; Cochran, J. E.; Padwa, A. Tetrahedron Lett.
1995, 36, 9285–9288. (d) Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2,
1267–1269. (e) Yamana, K.; Ibata, T.; Nakano, H. Synthesis 2006, 24,
4124–4130. (f) Jacq, J.; Einhorn, C.; Einhorn, J. Org. Lett. 2008, 10,
3757–3760. (g) Wang, F.; Wang, Y.; Cai, L.; Miao, Z.; Chen, R. Adv.
Synth. Catal. 2008, 350, 2733–2739.
There have been many reports concerning the synthesis
of isobenzofurans 1,3 but catalytic methods for their
construction have been limited to only a few examples.4
Isobenzofurans are traditionally synthesized via the partial
(4) (a) Mikami, K.; Ohmura, H. Org. Lett. 2002, 4, 3355–3357.
(b) Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K. J. Am. Chem.
Soc. 2006, 128, 12376–12377.
r
10.1021/ol201479p
Published on Web 07/06/2011
2011 American Chemical Society

reduction of o-dicarbonylbenzene 2 with KBH4 and sub-
sequent acid treatment (Scheme 2).3a Unstable isobenzo-
furan (1a) is decomposed during this procedure; therefore,
a one-step synthesis of 1 under neutral conditions is highly
desirable.4a,5 To develop a more convenient approach to 1,
intramolecular cyclization and elimination of hydroxysi-
lane then gives isobenzofuran (1a). Successive Dielsꢀ
Alder reaction with maleimide 5a and dehydration fur-
nishes naphthalene 6a. Only catalytic amounts of metal
triflate can promote these multistep reactions in one-pot.8
Scheme 2. Multistep Formation of Isobenzofuran 1 from o-
Dicarbonylbenzene 2
Scheme 4. Possible Reaction Mechanism
we have focused on o-carbonylbenzylalcohol 3 as a key
intermediate. The formation of analogue 3 has been
investigated using hydrosilane as a reductant instead of
KBH4. Herein, we have developed a novel method for a
Sc(OTf)3-catalyzed generation of isobenzofuran (1a) from
o-phthalaldehyde 2a and triethylsilane (4). The generated
1a was immediately trapped using N-methylmaleimide
(5a). Owing to the Lewis acid character of Sc(OTf)3,
successivedehydrationoccurredtoyield thecorresponding
naphthalene derivative 6a in 55% yield (Scheme 3). Metal
triflates have been known to keep their Lewis acidity active
evenin the presence ofwater,6 which enabled this multistep
reaction catalytic. The same reaction can be promoted by
other metal triflates, such as Cu(OTf)2 (50%), AgOTf
(51%), In(OTf)3 (53%), and Bi(OTf)3 (38%), but we have
focused on Sc(OTf)3 in this manuscript.
The influenceofthesubstituents on dicarbonylbenzene2
is of interest because the stability of isobenzofuran 1
strongly depends on R and R0. The nature of R and R0
were varied as shown in Table 1. The naphthalene deriva-
tive 6a was obtained in 65% yield upon the addition of 1.5
equivalents of 2a and 4 (entry 1). When o-acetylbenzalde-
hyde (2b) was used, the corresponding naphthalene 6b was
obtained in low yields (entry 2). Conversely, o-carbonyl-
benzaldehyde 2c, having phenyl group instead of methyl
group, was efficiently converted into 6b in 82% yield (entry
3). It is proposed that the phenyl group stabilizes the
isobenzofuran intermediate 1.3,8 o-Diacetylbenzene (2d)
gave a complex mixture (entry 4). When o-dibenzoylben-
zene (2e) was used, the corresponding naphthalene deriva-
tive 6e was formed in 69% yield (entry 5). These results are
strongly associated with the reactivity of the carbonyl
groups toward hydrosilylation and the stability of the iso-
benzofuran intermediates 1. Formyl groups (R or R0 = H)
are more susceptible to hydrosilylation than keto groups,9
Scheme 3. Generation and Aromatization of Isobenzofuran in
situ
Table 1. Survey of Substituents on 2a
The proposed reaction mechanism for the formation of
6a is shown in Scheme 4. Initially, the hydrosilylation of a
carbonyl group occurs to give silyl ether 30.7 The
entry
2
yield of 6/%b
65
1
2
3
4
5
6
7
2a (R = H, R0 = H)
6a
6b
6c
6d
6e
6f
2b (R = H, R0 = Me)
2c (R = H, R0 = Ph)
2d (R = Me, R0 = Me)
2e (R = Ph, R0 = Ph)
2f (R = H, R0 = 2-thienyl)
2g (R = H, R0 = 2-furyl)
18
82
(5) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron 2003,
59, 6251–6259.
(6) (a) Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H. Tetrahe-
dron Lett. 1993, 34, 3755–3758. (b) Kobayashi, S.; Nagayama, S.;
Busujima, T. J. Am. Chem. Soc. 1998, 120, 8287–8288.
(7) The hydrosilylation is promoted in the presence of metal triflates.
See: (a) Bach, P.; Albright, A.; Laali, K. K. Eur. J. Org. Chem. 2009,
1961–1966. (b) Wile, B. M.; Stradiotto, M. Chem. Commun. 2006,
4104–4106. (c) Roy, A. K. Adv. Organomet. Chem. 2008, 55, 1–59.
(8) (a) Genovese, S.; Epifano, F.; Pelucchini, C.; Curini, M. Eur. J.
Org. Chem. 2009, 1132–1135. (b) Sakai, H.; Tsutsumi, K.; Morimoto, T.;
Kakiuchi, K. Adv. Synth. Catal. 2008, 350, 2498–2502.
trace
69
60
6g
66
a Reaction conditions: Sc(OTf)3 (2.0 mol %), 2 (0.375 mmol), 4
(0.375 mmol), 5a (0.250 mmol), toluene (0.25 mL), under argon atmo-
sphere. b Isolated yield after recrystallization.
Org. Lett., Vol. 13, No. 15, 2011
3961

and isobenzofurans bearing an aryl group are stable enough
to undergo the subsequent DielsꢀAlder reaction with 5a.10
Heteroaryl-substituted o-dicarbonylbenzenes were also
applicable to give the naphthalenes having a thienyl (6f,
entry 6) or furyl (6g, entry 7) group.
The scope with respect to dienophile (5) was also
examined (Table 2). Simple alkenes such as cyclooctene
did not give the corresponding naphthalene derivative due
to its lack of reactivity toward 1a. Diethyl maleate (5b)
gave the corresponding product 6h, but only in low yield
(entry 1). Cyclic alkenes bearing carbonyl groups success-
fully promoted the reaction. Acid anhydride 5c and quinone
5d usually act as poisons toward Lewis acid catalysis, but
both maleic anhydride (5c) and benzoquinone (5d) were
applicable in the Sc(OTf)3-catalyzed system (entries 2 and 3).
amount of Sc(OTf)3 was reduced, longer reaction times were
required. Consequently, 1b was consumed by decomposition
and/or polymerization. In the case of o-phthalaldehyde (2a),
isobenzofuran (1a) was not observed due to its instability.11
After separation, 1b was allowed to react with 5a, then gave
adduct 7a in 86% yield via a DielsꢀAlder reaction immedi-
ately, even without any catalyst (eq 2). The dehydration of 7a
proceeded with catalytic Sc(OTf)3, to give the naphthalene
derivative 6e in 95% yield (eq 3). Sc(OTf)3 can act as a
catalyst for both the synthesis of isobenzofuran 1 and the
dehydration of 7. Previously, the synthesis of naphthalene 6e
from 7a has required a stoichiometric or excess amount of
Brønsted acid.12
Table 2. Effect of Dienophiles in Sc-Catalyzed Synthesis of 6a
To reuse the catalyst, we wanted to immobilize the
scandium onto a solid support.13 Sc(OTf)3 (10 wt%) was
dissolved in THF, immobilized on several kinds of solid
supports by the evaporation to dryness method, and
washed with diethyl ether to remove any formed trifluor-
omethanesulfonic acid. The screening revealed Amberlyst-
1514 to be the optimum support for the catalysis: silica-
supported scandium catalyst gave 6a in 5% yield, and
DOWEX- or zeolite-supported scandium did not work as
a catalyst. EDX analysis of the prepared catalyst con-
firmedthatscandium was supported on Amberlyst-15, and
the fluorine atom from the trifluoromethanesulfonyl
group was not detected. This suggests that a ligand ex-
change reaction on scandium occurred between the tri-
fluoromethanesulfonyl group and the sulfo group of
Amberlyst-15.15
a Reaction conditions: Sc(OTf)3 (2.0 mol %), 2a (0.375 mmol), 4
(0.375 mmol), 5 (0.250 mmol), toluene (0.25 mL), under argon atmo-
sphere. b Isolated yield after recrystallization. c Dichloroethane was used
as solvent.
The reaction pathway was further explored using the
following investigations. o-Dibenzoylbenzene (2e) was sub-
jected to the reaction conditions shown in eq 1 without
dienophile 5. The isobenzofuran derivative 1b was obtained
in 37% yield (eq 1). To obtain the isobenzofuran 1b, the
reaction conditions were modified as necessary. When the
(11) (a) Wiersum, U. E.; Mijs, W. J. J. Chem. Soc., Chem. Commun.
1972, 347–348. (b) Wege, D. Tetrahedron Lett. 1971, 2337–2338.
(c) Warrener, R. N. J. Am. Chem. Soc. 1971, 93, 2346–2348.
(12) (a) Allen, C. F. H.; Bell, A.; Gates, J. W., Jr. J. Org. Chem. 1943,
8, 373–379. (b) Tobia, D.; Rickborn, B. J. Org. Chem. 1986, 51, 3849–
3858. (c) Cafeo, G.; Giannetto, M.; Kohnke, F. H.; La Torre, G. L.;
Parisi, M. F.; Menzer, S.; White, A. J. P.; Williams, D. J. Chem.;Eur. J.
1999, 5, 356–368.
(13) Polymer supported scandium catalyst has been developed, see:
(a) Kobayashi, S.; Nagayama, S. J. Org. Chem. 1996, 61, 2256–2257. (b)
Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977–8978.
(c) Takeuchi, M.; Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2005,
127, 13096–13097.
(14) Only Amberlyst-15 promoted the reaction, but 6a was obtained
in a low yield (17%).
(15) (a) Yu, L.; Chen, D.; Li, J.; Wang, P. G. J. Org. Chem. 1997, 62,
3575–3581. (b) Nagayama, S.; Kobayashi, S. Angew. Chem., Int. Ed.
2000, 39, 567–569.
(9) (a) Benderradji, F.; Nechab, M.; Einhorn, C.; Einhorn, J. Synlett
2006, 13, 2035–2038. (b) Chan, S.-H.; Yick, C.-Y.; Wong, H. N. C.
Tetrahedron 2002, 58, 9413–9422. (c) Shang, M.; Butler, D. N.;
Warrener, R. N. Chem. Commun. 2001, 1550–1551.
(10) Diarylisobenzofurans are frequently used as the diene moiety in
Diels-Alder reaction. See recent reports: (a) Uchiyama, M.; Kobayashi,
Y.; Furuyama, T.; Nakamura, S.; Kajihara, Y.; Miyoshi, T.; Sakamoto,
T.; Kondo, Y.; Morokuma, K. J. Am. Chem. Soc. 2008, 130, 472–480. (b)
Tran, B. L.; Pink, M.; Mindiola, D. J. Organometallics 2009, 28,
2234–2243. (c) Ehm, C.; Lentz, D. Chem. Commun. 2010, 46, 2399–2401.
3962
Org. Lett., Vol. 13, No. 15, 2011

The catalyst was found to be recyclable in the reaction
(Table 3). The EDX measurement revealed that the
atom ratio of sulfur (derived from sulfo group of
Amberlyst) and scandium was 8:2, before and after the
reaction. This suggests that any leaching of scandium is
minimal.
corresponding endoxide adduct, then the yield of the
product decreases.17 This technique can allow pentacenes
having substituents at different positions to be synthesized
in few steps.18,19
Table 3. Recycle of the Catalyst Supported on Amberlyst-15a
cycle
1
2
3
4
5
6
yield/%b
67
59
65
57
65
67
a Reaction conditions: catalyst (28 mg, Sc: 0.005 mmol), 2a (0.375
mmol), 4 (0.375 mmol), 5 (0.250 mmol), toluene (0.25 mL), under argon
atmosphere. b Isolated after recrystallization.
Having established a new and efficient Sc-catalyzed
system, its application toward functional materials was
investigated. Pentacene derivatives are often used as or-
ganic electronics materials such as in organic field-effect
transistors and solar cells.16 We wanted to synthesize
pentacenediones, which are used as precursors to penta-
cenes. The reaction of o-bisformylnaphathalene (2h) with
benzoquinone (5d) yielded 5,14-pentacenedione (6k) in
69% yield (eq 4). Similarly, 6,13-pentacenedione (6l) was
synthesized from o-phthalaldehyde (2a) and anthracene-
dione 5e (eq 5). The successive dehydration is convenient,
since, in some cases, the retro-DielsꢀAlder reaction occurs
in equilibrium between the isobenzofuran and the
In conclusion, we have developed a novel method for the
preparation of isobenzofuran derivatives 1. These isobenzo-
furans were trapped by a dienophile 5 via a DielsꢀAlder
reaction and finally converted to the corresponding naphtha-
lene derivative 6 via dehydration. We have also confirmed
that the Sc/Amberlyst-15 catalyst is efficient and recyclable.
The 5,14- and 6,13-pentacenediones, 6k and 6l, were also
synthesized as precursors to substituted pentacenes.
Acknowledgment. Financial support for this study was
provided by Special Coordination Funds for Promoting
Science and Technology of MEXT.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(16) (a) Watkins, N. J.; Yan, L.; Gao, Y. Appl. Phys. Lett. 2002, 80,
4384–4386. (b) Chu, C.-W.; Li, S.-H.; Chen, C.-W.; Shrotriya, V.; Yang,
Y. Appl. Phys. Lett. 2005, 87, 193508. (c) DiBenedetto, S. A.; Frattarlli,
D.; Rantner, M. A.; Facchetti, A.; Marks, T. J. J. Am. Chem. Soc. 2008,
130, 7528–7529.
(17) (a) Christopfel, W. C.; Miller, L. L. J. Org. Chem. 1986, 51,
4169–4175. (b) Yick, C.-Y.; Chan, S.-H.; Wong, H. N. C. Tetrahedron
Lett. 2000, 41, 5957–5961.
(18) Recent reports on synthesis of 5,14-substituted pentacenes. See:
(a) Lin, Y. -C.; Lin, C.-H. Org. Lett. 2007, 9, 2075–2078. (b) Palayangoda,
S. S.; Mondal, R.; Shah, B. K.; Neckers, D. C. J. Org. Chem. 2007, 72,
6584–6587. (c) Vets, N.; Dilien, H.; Toppet, S.; Dehaen, W. Synlett 2006,
1359–1362.
(19) Recent reports on synthesis of 6,13-substituted pentacenes. See:
(a) Lehnherr, D.; Murray, A. H.; McDonald, R.; Ferguson, M. J.;
Tykwinski, R. R. Chem.;Eur. J. 2009, 15, 12580–12584. (b) Huang, Z.;
Jiang, Y.; Yang, X.; Fu, Y.; Cao, W.; Zhang, J. Synth. Met. 2009, 159,
1552–1556. (c) Wang, J.; Liu, K.; Liu, Y.-Y.; Song, C.-L.; Shi, Z.-F.;
Peng, J.-B.; Zhang, H.-L.; Cao, X.-P. Org. Lett. 2009, 11, 2563–2566.
(d) Tang, M. L.; Oh, J. H.; Reichardt, A. D.; Bao, Z. J. Am. Chem. Soc.
2009, 131, 3733–3740.
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