Synthesis of hetarenoindanone based on selenium dioxide-promoted direct intramolecular cyclization

Article abstract of DOI:10.3987/COM-11-12284

An alternative and simple method to prepare hetarenoindanone via intramolecular cyclization has been studied. This reaction represents the first example of an intramolecular Friedel-Crafts reaction-oxidation cascade promoted by selenium dioxide by way of

Full text of DOI:10.3987/COM-11-12284

HETEROCYCLES, Vol. 83, No. 10, 2011
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HETEROCYCLES, Vol. 83, No. 10, 2011, pp. 2337 - 2342. © 2011 The Japan Institute of Heterocyclic Chemistry
Received, 15th June, 2011, Accepted, 21st July, 2011, Published online, 28th July, 2011
DOI: 10.3987/COM-11-12284
SYNTHESIS OF HETARENOINDANONE BASED ON SELENIUM
DIOXIDE-PROMOTED DIRECT INTRAMOLECULAR CYCLIZATION
Youlai Zhang, Hiroki Tanimoto, Yasuhiro Nishiyama, Tsumoru Morimoto,
and Kiyomi Kakiuchi*
Graduate School of Materials Science, Nara Institute of Science and Technology
(NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan; E-mail:
kakiuchi@ms.naist.jp
Abstract – An alternative and simple method to prepare hetarenoindanone via
intramolecular cyclization has been studied. This reaction represents the first
example of an intramolecular Friedel-Crafts reaction-oxidation cascade promoted
by selenium dioxide by way of Riley allylic oxidation.
In recent years, indanone derivatives have been of considerable interest because of their important
photosensitizing properties,1 biomedical applications,2 and use as key synthetic intermediates.3 Several
methods are known for the synthesis of indanone derivatives. The useful syntheses include classical
Friedel-Crafts ring closures of biarylcarboxylic acids and derivatives,4 direct intramolecular arylation of
aldehydes with IPy2BF4/HBF4,5 palladium-catalyzed cyclocarbonylation containing a halogen (Br or I),6
intramolecular cyclization of 2-hetarylbenzoic acids and their derivatives under various conditions,7
intramolecular [4+2] cycloaddition reactions of conjugated enynes,8 and oxidation of fluorenes with
t-butyl hydroperoxide over Ruthenium-exchanged Montmorillonite K10.9 However, to our knowledge,
there has been no report on direct intramolecular cyclization promoted by selenium dioxide (SeO2). In
this paper, we disclose the first example of an intramolecular Friedel-Crafts reaction-oxidation cascade
promoted by SeO2 to give hetarenoindanone 1 quantitatively.
Recently, we have developed the new photolabile protecting group (PLPG) 2 based on the thiochromene
skeleton.10 The novel PLPG 2 was synthesized from thiophenol and ethyl acetoacetate as shown in
Scheme 1. In the synthetic route, SeO2 oxidation of 2-methyl-3-phenyl thiochromone 3 afforded the
corresponding aldehyde 5 in somewhat low yield followed by reduction of the crude 5 to produce alcohol
4. To clarify the reason for the low yield of the SeO2 oxidation, we examined the reaction in detail to
isolate an unexpected formation of indeno[2,1-b]thiochromene-6,11-dione 1 as a byproduct together with

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HETEROCYCLES, Vol. 83, No. 10, 2011
the desired 5 (Scheme 1). The structure of 1 was assigned by spectroscopic data and confirmed by X-ray
crystallographic analysis as shown in Figure 1.11
Scheme 1. Synthesis of the novel PLPG 210
Figure 1. ORTEP representation of 1
It is well known that allylic and benzylic oxidation of methyl groups by selenium dioxide affords
aldehydes, but to the best of our knowledge, no example has been reported about the use of selenium
dioxide as a promoter of cyclization reactions through carbon–carbon bond formation. Therefore, several
oxidation conditions were attempted (Table 1).
Table 1. Oxidation reaction with SeO2
O
O
O
SeO2
+
solvent
O
S
S
Me
S
O
3
5
1

HETEROCYCLES, Vol. 83, No. 10, 2011
2339
Entry
SeO2
(eq)
1.2
Solvent
Concentration Time
Temp
(°C)
100
130
130
150
150
150
150
Yield of 5 Yield of 1
(mol/L)
0.016
0.016
0.033
0.1
(h)
60
60
115
7
(%)a
(%)a
1
2
3
4
5
6
7
PhCl
no reaction
1.2
PhCl
25
39
61
46
0
0
1.2
PhCl
46
30
47
94
96
2.4
ODCB
ODCB
ODCB
ODCB
2.4
0.1
9
2.4
0.1
11
3
2.4
1.0
0
a Isolated yield
In the initial attempt, this oxidation reaction was carried out in chlorobenzene with 1.2 eq. SeO2 at 100 °C,
but no reaction was observed (entry 1). When the temperature was raised to 130 °C, aldehyde 5 was
isolated after 60 h as a sole product (25% yield, entry 2). Then increasing the concentration to 0.033
mol/L and prolonging reaction time to 115 h caused the increase of the yield of 5 to 39%. At the same
time, hetarenoindanone 1 was obtained in 46% yield (entry 3). When the reaction was carried out in
o-dichlorobenzene (ODCB) with 2.4 eq. SeO2 at 150 °C, after 7h, the best yield of 5 was obtained (61%,
entry 4). It should be noted that, for the longer reaction time, the yield of aldehyde 5 decreased and that of
hetarenoindanone 1 increased (entries 4, 5 and 6). Finally, we optimized the reaction in 1.0 mol/L
concentration for 3 h to give 1 quantitatively (entry 7).
From these data, it can be hypothesized that hetarenoindanone 1 is produced through aldehyde 5. It is well
known that the oxidation reaction of 3 to aldehyde 5 follows Riley selenium dioxide oxidation,12 but the
cyclization process was still unclear. Thus, our interest was focused on the detail from aldehyde 5 to
hetarenoindanone 1 and the following experiments were designed (Table 2).
Table 2. Cyclization of aldehyde 5
O
O
ODCB
150 oC, 3 h
S
S
CHO
O
1
5
Entry
SeO2
(eq.)

Additive
Yield
(%)a
1
2
3

no reaction
no reaction
92
2.4

2.4
H2O (10 eq.)
a Isolated yield

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HETEROCYCLES, Vol. 83, No. 10, 2011
First, the reaction was carried out in the absence of SeO2 to give no product (entry 1). This result
suggested that thermal energy did not induce cyclization. To our surprise, neither reaction with SeO2
afforded 1 (entry 2). However, when H2O was added (entry 3), the cyclization occurred smoothly. This
indicated that the selenous acid generated from SeO2 and H2O works as an acid to promote cyclization. In
the case of transformation from 3, H2O is provided during Riley allylic oxidation according to the known
mechanism through the intermediates a, b, and c as shown in Scheme 2.13 A mechanistic proposal to
account for the formation of hetarenoindanone 1 is also summarized in Scheme 2. The selenous acid
promptes intramolecular Friedel-Crafts reaction via the intermediate d to generate the tetracyclic core e.
Then aromatization and the subsequent oxidation of the resulting benzyl alcohol f gives the dione 1.
O
S
O
S
O
S
O
S
O
Ph
Se
O
OH
O
Ph
Ph
Ph
H
[Ox]
Se
O
H
Se
O
Me
H2O
c
3
a
b
H
O
S
SeO2
H2O
H2SeO3
+
H
O
5
O
S
O
S
O
O
S
[Ox]
H
H
OH
S
OH
O
O
HO
O
Se
H
O
1
f
e
d
Scheme 2. Proposed oxidation process
In summary, we developed the quantitative and cascade formation of hetarenoindanone 1 from 2-methyl
thiochromone derivative 3 by way of selenium dioxide oxidation. Intramolecular Friedel-Crafts reaction
followed by oxidation could be accomplished by selenious acid which is generated from SeO2 and H2O
by Riley allylic oxidation.
EXPERIMENTAL
All reactions were conducted in oven-dried (135 °C) glassware under an inert atmosphere of dry nitrogen.
The progress of reactions was monitored by silica gel thin layer chromatography (TLC) plates (mesh size
60Å, MERCK). Products were purified by flash column chromatography (FCC) on 40-63 m silica gel

HETEROCYCLES, Vol. 83, No. 10, 2011
2341
60 (MERCK). Proton nuclear magnetic resonance spectra (1H NMR) were recorded on JEOL JNM-ECP
500 (500 MHz). Chemical shifts are reported in ppm relative to tetramethylsilane (TMS) as the internal
standard. Data is reported as follows: chemical shift, integration, coupling constants (Hz), multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, sept = septet, br = broad, m = multiplet). Carbon nuclear
magnetic resonance spectra (13C NMR) were recorded on a JEOL JNM-ECP 500 instrument (125 MHz).
Chemical shifts are reported in ppm relative to tetramethylsilane (TMS) as the internal standard (0 ppm in
1H NMR) or the middle peak of chloroform-d (77.0 ppm in 13C NMR).
Starting Materials. 2-Methyl-3-phenyl-4H-thiochromen-4-one (3) was prepared using previously
reported procedures.10 All other chemicals in this study were commercially available.
4-Oxo-3-phenyl-4H-thiochromene-2-carbaldehyde (5).
A
mixture of 2-methyl-3-phenyl-4H-
thiochromen-4-one (3) (1.0 mmol, 252 mg) and SeO2 (2.4 mmol, 266 mg) was added to dichlorobenzene
(10.0 mL). Then the mixture was heated at 150 °C. The progress of the reaction was monitored by
1H-NMR. After completion of the reaction, sat. NaHCO3 aq. was added, and the aqueous layer was
extracted with CH2Cl2. The combined organic extract was washed with water and brine, and then dried
over anhydrous MgSO4. The solvent was evaporated and the obtained residue was purified by flash
chromatography on silica gel (HexaneEtOAc, 10:1) to obtain pure product (163 mg, 61%). Yellow solid;
mp 138.0-148.2 °C. IR (KBr): 1686, 1669 cm-1. 1H-NMR (500 MHz, CDCl3/TMS): δ = 9.73 (1H, s), 8.53
13
(1H, d, J = 7.9 Hz), 7.74 (2H, m), 7.60 (1H, dd, J = 6.7, 6.7 Hz), 7.51 (3H, m), 7.39 (2H, m). C-NMR
(125 MHz, CDCl3/TMS): δ = 190.35, 180.93, 143.80, 143.74, 136.41, 132.51, 132.29, 131.54, 131.21,
129.57, 129.43, 128.38, 128.19, 127.54. HRMS (EI) Calcd for C16H10O2S: 266.0402; Found: 266.0401.
Indeno[2,1-b]thiochromene-6,11-dione (1). A mixture of 2-methyl-3-phenyl-4H-thiochromen-4-one (3)
(1.0 mmol, 252 mg) and SeO2 (2.4 mmol, 266 mg) was added to dichlorobenzene (1.0 mL). Then the
similar manner was followed as described for 5. After purified by flash chromatography to give 1 (254
mg, 96%). Red solid; mp 241.0-242.5 °C. UV-vis (in methanol): λmax = 313 (ε = 1.37 x 104 M-1 cm-1), 262
(ε = 1.90 x 104 M-1 cm-1) nm. IR (KBr): 1712, 1620 cm-1. 1H-NMR (500 MHz, CDCl3/TMS): δ = 8.65 (1H,
d, J = 7.9 Hz), 8.27 (1H, d, J = 7.9 Hz), 7.77 (1H, d, J = 7.9 Hz), 7.69 (3H, m), 7.53 (1H, dd, J = 7.3, 7.3
13
Hz), 7.28 (1H, d, J = 7.9 Hz). C-NMR (125 MHz, CDCl3/TMS): δ = 192.21, 177.86, 144.31, 143.24,
137.80, 135.70, 135.59, 134.18, 132.03, 130.06, 129.08, 128.71, 128.52, 128.38, 124.68, 124.11. HRMS
(EI) Calcd for C16H8O2S: 264.0245; Found: 264.0247.
ACKNOWLEDGEMENTS
This research was supported by grant-in-aid for scientific research from Nara Institute of Science and
Technology (NAIST) and NAIST Advanced Research Partnership Project, which is gratefully appreciated.

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We also thank Ms. Huan Zhang, Mr. Yannick Escudie, and Dr. Hiroshi Nomura for their kind help with
syntheses of 3, Ms. Yoshiko Nishikawa for HRMS measurement, and Mr. Shouhei Katao for X-ray
Crystallographic analysis.
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