Star-Shaped Polycyclic Aromatic Ketones via 3-Fold Cycloadditions of Isobenzofuran Trimer Equivalent

Article abstract of DOI:10.1021/acs.orglett.7b01932

Three-directional annulations of isobenzofuran trimer equivalent are developed. Importantly, the successive cycloadditions could be controlled under suitable conditions, selectively affording the dual or triple cycloadduct, which leads to the alternative

Full text of DOI:10.1021/acs.orglett.7b01932

Letter
pubs.acs.org/OrgLett
Star-Shaped Polycyclic Aromatic Ketones via 3‑Fold Cycloadditions
of Isobenzofuran Trimer Equivalent
Hitoshi Tozawa, Takamasa Kakuda, Kazuhiko Adachi, and Toshiyuki Hamura*
Department of Applied Chemistry for Environment, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen,
Sanda, Hyogo 669-1337, Japan
*
S Supporting Information
ABSTRACT: Three-directional annulations of isobenzofuran trimer equivalent
are developed. Importantly, the successive cycloadditions could be controlled
under suitable conditions, selectively affording the dual or triple cycloadduct,
which leads to the alternative preparation of the symmetrical and unsymmetrical
1
star-shaped polycyclic aromatic ketones. H NMR analysis of the star-shaped
aromatic ketone indicated the π−π interactions through the aggregation in
solution.
ultidirectional annulations of two or more rings onto a
Scheme 2. Dual Annulation of Bisisobenzofuran
M
reactive core ring is one of the most efficient ways to
1
,2
highly condensed aromatic compounds. In this context, we
became interested in the synthetic use of isobenzofuran trimer
3
,4
1
or its equivalent as a reactive platform since, through its
successive cycloadditions, it would allow for rapid access to star-
5
shaped polycyclic compounds with potentially attractive
properties derived from the unique molecular structure
(Scheme 1).
Scheme 1. Three-Fold Annulations of Isobenzofuran Trimer
the synthetic equivalent to isobenzofuran trimer 1. Along these
lines, trisepoxytrinaphthylene 8, prepared by [4 + 2] cyclo-
addition and trimerization of two aryne species 9 and 11,
turned out to serve as a synthetic equivalent to 1 by thermally
induced elimination of carbon monoxide and subsequent retro
6
Diels−Alder reaction (eq 1 in Scheme 3). It is important to
note that protection of the double bond in epoxynaphthalene is
essential for the aryne cyclotrimerization (vide infra), and the
trimer 8 undergoes retro Diels−Alder reaction to generate the
three isobenzofurans, which are successively trapped with
dienophiles, producing the 3-fold cycloadducts. Moreover, the
successive cycloadditions can be controlled under suitable
conditions, selectively affording the dual or triple cycloadduct,
which leads to the selective preparation of the symmetrical and
unsymmetrical star-shaped polycyclic aromatic ketones.
In relation to this synthetic strategy, we previously reported
an efficient protocol of the ring-selective generation of
isobenzofuran for selective construction of linearly fused
2
polycycles (Scheme 2). In this process, diepoxyanthracene 3,
the synthetic equivalent to a bisisobenzofuran 4, was treated
with 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (5) to successively
generate the two isobenzofuran species in a ring-selective
manner, allowing the alternative synthesis of polyacene
derivatives 6 and/or 7 through the iterative [4 + 2]
cycloadditions.
Herein, we disclose 3-fold annulations of isobenzofurans for
preparation of star-shaped polycyclic aromatic compounds with
six electron-withdrawing carbonyl groups onto the aromatic
core. The key of this approach is the design and the synthesis of
7
Starting from diiodide 12, corresponding to a bisbenzyne
8
equivalent, the trimer 8 was efficiently prepared (Scheme 4).
9
Upon heating of epoxynaphthalene 13 with tetraphenylcyclo-
pentadienone, Diels−Alder reaction occurred stereoselectively
to give the silyl triflate 14 as a single isomer. The
Received: June 24, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Strategy for Preparation of Isobenzofuran Trimer
Equivalent
Scheme 5. Multiple Cycloadditions of Isobenzofuran Trimer
Equivalent
Scheme 4. Preparation of Isobenzofuran Trimer Equivalent
21 in 70% yield as a mixture of stereoisomers. TLC analysis
showed that the initially formed monocycloadduct 19 and
dicycloadduct 20 were gradually converted to the tricycload-
duct 21. Indeed, the same reaction in a shorter reaction time
(
131 °C, 45 min) selectively gave the dicycloadduct 20 in 45%
yield, accompanied by the mono- and tricycloadducts 19 (24%)
and 21 (18%), respectively. As for the solubility of the
products, introduction of the long alkyl chains into
naphthoquinone is essential since the similar reaction with
parent naphthoquinone produced extremely insoluble products
in all common organic solvents, which precluded their
characterization.
10
stereochemistry of 14 was determined by X-ray analysis,
where the two protons (H ) on the bridge-head carbon and the
b
carbonyl group were antioriented with respect to the epoxy
bridge. This is due to the concave topology of the
epoxynaphthalene 13, which forces the tetraphenylcyclopenta-
The stereochemistry of the dicycloadduct 20 was determined
by NMR analysis, where two sets of the coupled aliphatic
methine protons (H and H , H and H ), characteristic as an
11
1
dienone to approach along the convex side of 13. H NMR
analysis of 14 showed the absence of vicinal coupling between
H and H , indicating the dihedral angle approached 90°, which
c
d
e
f
2
,4f
endo isomer, were observed.
Moreover, the two peaks of
a
b
aliphatic methine protons H and H ′, which were noncoupled
b
b
was also confirmed by the X-ray structure.
with H and H ′ on the right fused ring (vide supra), were
a
a
The silyl triflate 14, thus obtained, was subjected to Pd-
12
independently located at 3.17 and 3.21 ppm as the doublet
indicated the structure as the endo-endo/anti isomer with C1
symmetry rather than the symmetrical endo-endo/syn isomer
catalyzed aryne cyclotrimerization by treatment with CsF,
cleanly affording the trimer 8, which consisted of a mixture of
two diastereomers (ds 6:1) with respect to the three epoxy
rings. The important point in this reaction is that
tetraphenylcyclopentadienone played a key role not only as a
protecting group of the double bond in 13 but also as an
initiator for the generation of isobenzofuran (vide infra).
Indeed, the corresponding reaction of nonprotected substrate
(
Figure 1). This result showed that the two successive
cycloadditions occurred in an endo manner, where the two
dienophiles approached across opposite faces of the tripheny-
lene core.
1
3 gave no trimer 15, which would be also a suitable precursor
3a
of 1 by tetrazine methodology (Scheme 2). This is due to the
existence of the double bond within the rigid oxabicyclic
structure in 13, which may react with Pd catalyst under the
13
reaction conditions to give a complex mixture of products. In
this case, however, the cyclotrimerization proceeded cleanly
with the saturated aryne precursor 16 under the same reaction
conditions, affording triepoxytrinaphthylene 17 in 64% yield.
Scheme 5 shows the successive generation of isobenzofuran
and its trapping with dienophile. Upon heating of 8 in the
presence of naphthoquinone 18 (131 °C, 4 h), iterative [4 + 2]
cycloadditions occurred cleanly to give the 3-fold cycloadduct
Figure 1. Stereochemistry of the dual cycloadduct 20.
B
DOI: 10.1021/acs.orglett.7b01932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The 3-fold cycloadduct 21, initially produced by heating at
31 °C for 45 min (Scheme 5), was composed of two
Scheme 6. Acid-Promoted Aromatization of the Cycloadduct
21 to Star-Shaped Polyketone 23
1
diastereomers (ds 4:1). The major product 21a has two endo
and one exo stereochemistries on the oxabicyclomoieties, which
were determined by the presence of both coupled and
noncoupled aliphatic methine signals. Moreover, the six singlets
corresponding to the aromatic protons on the triphenylene
moiety indicated the product as a nonsymmetric exo-endo-endo/
syn-anti isomer (Figure 2). On the other hand, the lack of
Figure 3. Temperature-dependent 1H NMR spectra of 23 in o-
−2
C D Cl (2.97 × 10 M).
6
4
2
Figure 2. Stereochemistry of the 3-fold cycloadduct 21.
noncoupling protons on the oxabicyclo moieties and the three
singlets on the aromatic protons on the triphenylene moiety
established the minor product 21b as an endo-endo-endo/anti-
syn isomer. The formation of the major cycloadduct 21a was
explained by the exo attack of the dienophile to the
isobenzofuran 22 to avoid the steric repulsion by both sides
of the polycyclic framework in 22.
Further study on the stereochemistry of the 3-fold
cycloadduct 21 revealed that stereoisomerization was observed
by heating the same reaction for a longer reaction time to
produce several kinds of diastereomers (exo-exo-endo and exo-
exo-exo isomers) in addition to the above-mentioned major
1
1
4
Figure 4. Concentration-dependent H NMR spectra of 23 at 50 °C
stereoisomer 21a, which were cleanly converted to the
corresponding star-shaped polyketone 23 by acid-promoted
aromatization (TsOH in toluene at 50 °C). Purification of the
crude product by silica-gel column chromatography gave the
poly ketone 23 in high yield (Scheme 6). Owing to the six long
alkyl chains introduced to three directions at the end of the
aromatic rings, the product 23 was highly soluble in hexane,
in CDCl3.
When dual-cycloadduct 20 was treated with TsOH in toluene
at 50 °C, dehydrative aromatization occurred cleanly to give
tetraketone 24 in 71% yield.
π-Extended polyketone 24 was then heated in chlorobenzene
at 131 °C to generate the highly condensed isobenzofuran 25,
which was trapped with naphthoquinone 26 to give the
unsymmetrical star-shaped polyketone 28 after acid-induced
aromatization. As for the third [2 + 4] cycloaddition of the π-
extended isobenzofuran 25, aromatization of dual cycloadduct
20 to tetraketone 24 was indispensable since the corresponding
thermal reaction of 20 with naphthoquinone 26 gave the
desired cycloadduct in low yield due to the retro Diels−Alder
reaction of 20.
1
5
3c
CH Cl , CHCl , toluene, and Et O.
2
2
3
2
1
H NMR analysis of the product 23 showed that all peaks
were significantly broadened at room temperature. On the
other hand, these broadened signals gradually sharpened at
higher temperature (90 °C). Moreover, the aromatic signals
were shifted downfield by increasing the temperature (Figure
3
) or decreasing concentration (Figure 4), which indicated the
16
aggregation in solution.
Finally, it should be emphasized that the unsymmetrical star-
shaped polyketone 28 could be accessed by using the π-
extended isobenzofuran 25 as a key intermediate (Scheme 7).
In summary, successive cycloaddition of isobenzofuran trimer
equivalent allowed us to construct symmetrical and unsym-
C
DOI: 10.1021/acs.orglett.7b01932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
013, 42, 1013. (f) Asahina, K.; Matsuoka, S.; Nakayama, R.; Hamura,
Scheme 7. Preparation of Unsymmetrical Star-Shaped
Polyketone 28
T. Org. Biomol. Chem. 2014, 12, 9773.
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(
(
(
9
(
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(
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7) The diiodide 12 was prepared from resorcinol in four steps. For
details, see Supporting Information.
8) For pioneering studies by Hart on the generation and trapping of
2
(
(
(
1
,4-benzdiyne equivalents, see: (a) Hart, H.; Ok, D. J. Org. Chem.
1
986, 51, 979. (b) Hart, H.; Lai, C.-Y.; Nwokogu, G.; Shamouilian, S.;
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metrical star-shaped polycyclic aromatic ketones with valuable
synthetic potential. Further synthetic applications are under
active investigation in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01932.
(9) Epoxynaphthalene 13 was prepared by a five-step protocol
including the [2 + 4] cycloaddition of benzyne with furan. For details,
see Supporting Information.
Experimental procedures and compound characterization
data (PDF)
(10) For details, see Supporting Information.
(11) By now, there has been no report on the determination of the
stereochemistry of the Diels−Alder adduct like 14 by X-ray analysis.
Among various possibilities, long-range 13C−H coupling is a reliable
probe to evaluate the stereochemistry of the cycloadduct. See: (a) Tan,
R. Y. S.; Russell, R. A.; Warrener, R. N. Tetrahedron Lett. 1979, 20,
5031. (b) Coxon, J. M.; Battiste, M. A. Tetrahedron 1976, 32, 2053 For
the X-ray structure of 14, see Supporting Information..
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: thamura@kwansei.ac.jp.
ORCID
(
12) (a) Pen
̃
a, D.; Escudero, S.; Per
́
ez, D.; Guitian
́
, E.; Castedo, L.
ez, D.; Guitian
a, D.; Cobas, A.; Perez,
, E.; Castedo, L. Org. Lett. 2000, 2, 1629. (d) Pena, D.;
ez, D.; Guitian, E.; Castedo, L. J. Org. Chem. 2000, 65, 6944.
e) Romero, C.; Pena, D.; Perez, D.; Guitian, E. Chem. - Eur. J. 2006,
12, 5677.
(13) (a) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc.
Toshiyuki Hamura: 0000-0003-2857-2273
Notes
Angew. Chem., Int. Ed. 1998, 37, 2659. (b) Pena, D.; Per
́
́
,
̃
E.; Castedo, L. Org. Lett. 1999, 1, 1555. (c) Pen
D.; Guitian
Per
̃
́
́
̃
The authors declare no competing financial interest.
́
́
(
̃
́
́
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP15H05840 in Middle Molecular Strategy and JST ACT-C
Grant Number JPMJCR12YY, Japan.
2
2
2
001, 123, 6834. (b) Shih, H.-T.; Shih, H.-H.; Cheng, C.-H. Org. Lett.
001, 3, 811. (c) Li, Y.; Yang, W.; Cheng, G.; Yang, D. J. Org. Chem.
016, 81, 4744.
(
14) For the stereoisomerization of the cycloadduct 21, see
Supporting Information.
15) The star-shaped polyketone 23 was insoluble in polar solvents,
e.g., EtOAc, acetone, DMF, and DMSO.
16) Watson, M. D.; Fechtenkotter, A.; Mu
01, 1267.
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DOI: 10.1021/acs.orglett.7b01932
Org. Lett. XXXX, XXX, XXX−XXX