The synthesis, structural characterization and photochemistry of some 3-phenylindenones

Article abstract of DOI:10.1055/s-2005-861799

The synthesis of 3-phenylindenone (1a), 6-methoxy-3-phenylindenone (1b), 2-bromo-6-methoxy-3-phenylindenone (1c) and 2-ethoxycarbonyl-6-methoxy-3- phenylindenone (1d) is described using two methods - synthesis via indanone precursors and synthesis via pro

Full text of DOI:10.1055/s-2005-861799

470
PAPER
The Synthesis, Structural Characterization and Photochemistry of Some
3-Phenylindenones
S
ynthesis and Photoch
i
emistry
c
of 3-Pheny
h
lindenones ael K. Seery,1 Sylvia M. Draper, John M. Kelly,* Thomas McCabe, T. Brian H. McMurry*
Chemistry Department, Trinity College, Dublin 2, Ireland
Fax +353(1)6712826; E-mail: jmkelly@tcd.ie; E-mail: tmcmurry@tcd.ie
Received 13 September 2004
1a: R=H, X=H
Abstract: The synthesis of 3-phenylindenone (1a), 6-methoxy-3-
phenylindenone (1b), 2-bromo-6-methoxy-3-phenylindenone (1c)
and 2-ethoxycarbonyl-6-methoxy-3-phenylindenone (1d) is de-
scribed using two methods – synthesis via indanone precursors and
synthesis via propanedione precursors. Crystal structures of 2-bro-
mo-6-methoxy-3-phenylindanone, the synthetic precursor to 1b and
2-bromo-6-methoxy-3-phenylindenone were obtained. Preliminary
photochemical studies showed that 1b dimerizes readily, but no
transient species were detectable using ns-flash photolysis.
1b: R=OMe, X=H
1c: R=OMe, X=Br
1d: R=OMe, X=CO2Et
X
R
O
Figure 1 Indenones 1a–d
Scheme 1 shows the synthetic route taken for 6-methoxy-
3-phenylindenone (1b). Murphy et al.4 and Gaviña et al.5
have previously described the synthesis of 6-methoxy-3-
Key words: enone, [2+2] cycloaddition, Friedel–Crafts ring clo-
sure, photochemistry
4
phenylindanone (3) using BF3 or AlCl3 from the corre-
sponding chalcone 2.5 We found that the use of trifluoro-
acetic acid gave good yields (88%) of purer material with
shorter reaction times under milder conditions. As both
Murphy and Gaviña reported, the 6-methoxy isomer 3 is
the predominant product (88%), with some 4-isomer de-
tected by NMR spectroscopy (<3%). Separation of the
two components required careful column chromatography
(CH2Cl2, silica gel) although the two components were
easily separated at the next stage in the reaction sequence
(see below).
The chemistry of 3-phenylindenone derivatives is of inter-
est, not only in their own right as analogues of the much-
studied cyclopentenones, but as synthetic precursors to
more elaborate ring structures. Thus 6-methoxyindenone
systems should be useful intermediates on routes to fura-
noindenones. These are planar aromatic molecules and
like psoralen, the well-known phototherapeutic drug, they
should intercalate into DNA, undergo photo-induced
[2+2] cycloaddition to its nucleobases and hence promote
cross-linking of the two strands of DNA.2
Reaction of 6-methoxy-3-phenylindanone (3) with bro-
mine in diethyl ether gave 2-bromo-6-methoxy-3-phe-
nylindanone (4), the site of bromination at the 2-position
There also continues to be great interest in the photophys-
ics and photochemistry of 3-cycloalkenones. Our particu-
lar interest has been with 3-arylcyclopentenones and
cyclohexenones which undergo [2+2] cycloaddition with
alkenes to provide a useful route to cyclobutane adducts.3
In addition we have observed that the 3-aryl substituents
significantly prolong the excited state triplet lifetimes,
thus allowing their excited states to be characterized
readily by laser flash photolysis methods. Studies on 3-
phenylindenone derivatives will therefore allow us to
study the effect of an additional fused ring on the photo-
chemistry and photophysics of the 3-phenylcyclopenten-
one system.
CHO
OH-/H2O/EtOH
+
MeO
MeO
O
O
2
CF3CO2H
Br2/Et2O
MeO
We describe here the synthesis of 3-phenylindenone (1a),
6-methoxy-3-phenylindenone (1b), 2-bromo-6-methoxy-
3-phenylindenone (1c) and 2-ethoxycarbonyl-6-methoxy-
3-phenylindenone (1d) (Figure 1). In the case of 1a–c, the
enones were synthesized from the corresponding in-
danones. For 1d, the compound was synthesized via a pro-
panedione precursor.
MeO
Br
O
O
3
4
SeO2/EtOH
Na/EtOH
MeO
O
SYNTHESIS 2005, No. 3, pp 0470–0474
x
x
.
x
x
.2
0
0
5
1b
Advanced online publication: 26.01.2005
DOI: 10.1055/s-2005-861799; Art ID: P10904SS
Scheme 1 Synthesis of 6-methoxy-3-phenylindenone (1b)
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Photochemistry of 3-Phenylindenones
471
Table 1 Some Parameters Derived from X-ray crystal structure of
2-Bromo-6-methoxy-3-phenylindanone (4) and 2-Bromo-6-meth-
oxy-3-phenylindenone (1c)
being confirmed by a C–H COSY NMR experiment. De-
hydrobromination of 4 was effected with sodium ethoxide
in ethanol giving 6-methoxy-3-phenylindenone (1b)
(13.5% overall). This compound was also prepared by di-
rect oxidation of 6-methoxy-3-phenylindanone (3) with
selenium dioxide in ethanol. Although reaction times
were longer, the yield was higher (28%) and in addition,
only reactant and product were present in the crude mix-
ture. The former could therefore be separated by chroma-
tography and recycled. This method was also used to
oxidize the parent compound 3-phenylindanone to give 3-
phenylindenone (1a). However, it required longer reac-
tion times (7 days) than the bromination-dehydrobromi-
nation method described above and yields were modest
(20%).
Parameters
Formula
Phenylindanone 4 Phenylindenone 1c
C16H13BrO2
monoclinic
1.531
C16H11BrO2
triclinic
1.356
Crystal System
|Ca–Cb| (Å)
Phenyl Torsion angle (o) 60
|C–O| (Å) 1.210
59
1.205
Interestingly, bromination of 6-methoxy-3-phenylin-
danone (3) in scrupulously dried diethyl ether led to the
formation of 2,2-dibromo-6-methoxy-3-phenylindanone.
Dehydrobromination of this compound led to the forma-
tion of 2-bromo-6-methoxy-3-phenylindenone (1c).
The ethoxycarbonyl indenone 1d was synthesized by a
different route. Anstead et al.6 describe the synthesis of
2,3-substituted indenones via a propanedione precursor.
In a modified version of this, condensation of m-anisoyl
chloride and ethyl benzoylacetate gave 2-ethoxycarbonyl-
1-(3-methoxyphenyl)-3-phenylpropane-1,3-dione
(5)
which ring-closed easily with methanesulfonic acid to
give 1d (Scheme 2).
Figure 2 X-ray crystal structure of 2-bromo-6-methoxy-3-phe-
nylindanone (4)
O
O
OEt
NaH/THF
O
O
+
Cl
MeO
MeO
CO2Et
O
5
MeSO3H
1d
Scheme 2 Synthesis of 2-ethoxycarbonyl-6-methoxy-3-phenylin-
denone (1d)
Crystal structures of 2-bromo-6-methoxy-3-phenylin-
danone (4) (Figure 2) and the corresponding indenone 1c
were obtained (Figure 3). (It was found that indenones
substituted at the 2- and 3-position recrystallized more
easily than those with substituents only in the 3-position).
For the bromoindanone, the a–b carbon bond length was
1.531 Å, and the torsion angle between the phenyl group
and the indanone was 60° to the plane of the indenone. For
the indenone, the a–b carbon bond length was 1.356 Å,
and the torsion angle of the phenyl substituent to the inde-
none ring was 59°. These and other relevant parameters
are summarized in Table 1.7
Figure 3 X-ray crystal structure of 2-bromo-6-methoxy-3-phe-
nylindenone (1c)
coefficient at this wavelength is low (ca. 300 dm3 mol–1),
it was surprising that no transient species were observed
within the time range of our instrumentation (>50 ns), nei-
ther was steady state emission observed at room tempera-
ture or at 77 K (ethanol, glass).
Preliminary flash photolysis experiments were carried out
with acetonitrile solutions of indenone 1b (10–2 < [1b] <
10–4 M) (lexcitation = 355 nm). Even though the extinction
Synthesis 2005, No. 3, 470–474 © Thieme Stuttgart · New York

472
M. K. Seery et al.
PAPER
Irradiation of indenone 1b in deuteroacetonitrile led to ef- in acetonitrile, the monomer enone methoxy peak in the
ficient dimerization (Scheme 3), as observed by NMR NMR spectrum is almost completely depleted, whereas in
spectroscopy, showing that the compound could indeed the case of benzene, the ratio of monomer to dimer at this
undergo self-cycloaddition. Dimerization proceeded effi- time was 1:3, and after 90 minutes the ratio was only 1:1
ciently up to 8 minutes after which time the ratio of dimer (Scheme 3). The extent of alkene cis-trans isomerization
to monomer peaks remained approximately constant. This is also much lower in the case of benzene.
indicates the presence of a photostationary state. More-
In benzene there is some evidence for enone-alkene ad-
over when the enone (10 mmol) was irradiated in the pres-
duct formation. In addition to peaks assigned to the enone
ence of (E)-methylstyrene (50 mmol), dimerization was
dimer, a series of peaks with very low intensity occur in
the NMR spectrum on increasing irradiation time. These
the only observed reaction and no enone-alkene adducts
were detected by NMR spectroscopy. In addition to
dimerization of the enone, cis-trans isomerization of the
are the peaks at d = 1.17 (d), 2.76 (dq), 3.00 (s) and 3.39
(d), which based on previous studies8 could be assigned to
alkene is observed. Given that a glass filter is used in the
the methyl group, the 7-H, the methoxy methyl and the 6-
experiment, this isomerization must be sensitized by the
H respectively. The amount of this product is very small
enone-excited state. A similar result was found on in-
and this must be a tentative assignment.
creasing the concentration of alkene (100 mmol). The rate
In conclusion, in this paper we have described the facile
of dimer formation was slower than in solutions of enone
synthesis of some 3-phenylindenone systems using two
only, with dimerization proceeding for 12 minutes and 22
routes. These methods can be used to synthesize a range
minutes for the enone/alkene ratio of 1:5 and 1:10, respec-
of 3-phenyl- and 2-substituted-3-phenylindenones. Crys-
tively (Figure 4).
tal structures of 2-bromo-6-methoxy-3-phenylindanone
(4) and 2-bromo-6-methoxy-3-phenylindenone (1c) are
PhPh
shown. Initial photochemical studies of 6-methoxy-3-
phenylindenone (1b) show that this compound dimerizes
MeO
OMe
H H
O
O
readily, even in the presence of excess alkene. In addition,
in the presence of alkenes, cis-trans isomerization of the
alkene occurs and given that no transient is observed us-
ing ns-flash photolysis, we surmise that the excited state
of this enone is very short lived.
6
hν
+
Ph
Ph
MeO
Ph
O
MeO
1b
Me
H H
O
7
All reagents used in synthesis of compounds as described were pur-
chased from Aldrich Chemical Company, and used without further
purification. 3¢-Methoxychalcone was synthesized according to the
method of Murphy et al.4 Solvents for synthesis and chromatogra-
phy were distilled prior to use. Et2O was dried over CaCl2 and dis-
tilled from sodium/benzophenone. EtOH was distilled over Mg
turnings and I2. Solvents for spectroscopy were obtained as spectro-
scopic grade and used as received. Deuterated solvents were used as
received (99 + % atom). NMR spectra were recorded on a Bruker
DPX 400 (400.13 MHz) instrument. NMR data are recorded in d
values relative to tetramethylsilane. J values are given in Hz. Ab-
sorption spectra were recorded on a Shimadzu UV-2401 PC spec-
trometer or a Cary 300 Scan spectrometer. IR spectra were recorded
on a Mattson Genesis II FTIR spectrometer. Samples were prepared
either as Nujol mulls or applied neat to NaCl windows. ESMS spec-
tra were recorded on a Micromass LCG TOF mass spectrometer.
Sample concentrations were made up to be less than 10–6 M. TLC
analyses were run on Merck silica gel 60 F254 pre-coated plates.
Flash chromatography was preformed using Merck grade flash sili-
ca gel. For photochemical experiments, samples were degassed in
an NMR tube by bubbling with continuous stream argon for 30 min.
Samples were then irradiated directly by a mercury lamp, using
glass and water filter (l > 330 nm) (500 W) Experiments where
samples were degassed by the freeze-pump thaw (3 cycles) gave
identical results.
Scheme 3 Irradiation of 1b in the presence of (E)-1-phenylpropene
leading to dimerization and adduct formation.
Figure 4 Relative intensities (as measured by integration of
methoxy singlets in NMR spectra) of enone monomer (filled shapes)
and dimer (hollow shapes) on increasing irradiation time for enone/
alkene ratio of 1:5 (squares) and 1:10 (triangles).
3-Phenylindenone (1a)
The above experiments were repeated in deuterobenzene.
Similar results were found, in that the enone dimerization
reaction is dominant, although the reaction is not as effi-
cient as in acetonitrile. After 40 minutes irradiation time
3-Phenylindanone (0.5 g, 2.4 mmol) and SeO2 (0.3 g, 2.7 mmol) in
anhyd EtOH (20 mL) were refluxed for 48 h under N2. The cooled
mixture was poured into H2O and extracted with CH2Cl2. The
CH2Cl2 layer was washed with aq NaHCO3 and H2O. The organic
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PAPER
Synthesis and Photochemistry of 3-Phenylindenones
473
phase was dried (MgSO4) and the solvent removed. Purification by
column chromatography (CH2Cl2, Rf 0.8) gave 100 mg (20%) of
product as a red oil.
1H NMR (CDCl3): d = 3.9 (3 H, s, OCH3), 5.9 (1 H, s, 2-H), 6.8 (1
H, dd, J = 8, 2.5 Hz, 5-H), 7.2 (1 H, d, J = 2.5 Hz, 7-H), 7.3 (1 H, d,
J = 8 Hz, 4-H), 7.7 (s, 5 H, C6H5).
IR (neat): 1704 cm–1 (C=O).
ESMS: m/z calcd for C16H13O2: 237.0916 (M+); found: 237.0922.
1H NMR (CDCl3): d = 6.0 (1 H, s, 2-H), 7.3, 7.4 (2 H, dt, J = 6.5, 1
Hz, 5-H, 6-H), 7.4, 7.5 (2 H, d, J = 6.5 Hz, 4-H, 7-H), 7.6 (5H, s,
C6H5).
Anal. Calcd for C16H13O2: C, 81.34; H, 5.12. Found: C, 81.09; H,
5.22.
2-Ethoxycarbonyl-6-methoxy-3-phenylindenone (1d)
ESMS: m/z calcd for C15H11O: 207.0810; found: 207.0793 (M+).
Ethyl benzoylacetate (3.5 mL, 3.89 g, 20.2 mmol) was added to a
suspension of NaH (1.1 g, 45.8 mmol) in anhyd THF (20 mL) and
the mixture was stirred for 1 h. m-Anisoyl chloride (2.8 mL, 3.4 g,
19.9 mmol) was added dropwise over 45 min and the solution
turned an intense red color. The solution was carefully poured into
cold 5% HCl solution and extracted with CH2Cl2. After drying
(MgSO4), the solvent was evaporated to give a red oil. This was dis-
solved in CH2Cl2 (30 mL) and the solution cooled in an ice-bath. A
solution of MeSO3H (1 mL, 15.4 mmol) in CH2Cl2 (10 mL) was
added over 45 min. The ice-bath was removed and the solution
stirred for 3 days. The red solution was worked up [washing with aq
NaHCO3 and brine, and drying (MgSO4)] and the solvent was evap-
orated. On addition of a hexane–EtOAc (10:1) mixture, the product
precipitated as red crystals; yield: 2.3 g (47%).
6-Methoxy-3-phenylindanone (3)
3¢-Methoxychalcone (2; 9.2 g, 38.7 mmol) in trifluoroacetic acid
(20 mL) was refluxed for 2 days under N2. Work-up [addition of
H2O, extraction with CH2Cl2, and drying (MgSO4)] and evaporation
of solvent gave a red-brown oil; yield: 8.1 g (88%). A sample was
purified by column chromatography (CH2Cl2, Rf 0.4) to give yellow
needles; mp 69–71 °C. Partially purified product could also be used
in the oxidation step.
IR (Nujol): 1705 cm–1 (C=O).
1H NMR (CDCl3): d = 2.7 (1 H, dd, J = 19, 3.5 Hz, 2-H), 3.3 (1 H,
dd, J = 19, 7 Hz, 2-H), 3.9 (3 H, s, OCH3), 4.5 (1 H, dd, J = 7, 3.5
Hz, 3-H), 7.14 (2 H, dd, J = 7, 1.5 Hz, o-Harom), 7.18 (2 H, d, J = 1.5,
4-H and 7-H overlapping), 7.26 (2 H, m, 5-H, p-Harom), 7.3 (2 H, m,
m-Harom).
1H NMR (CDCl3): d = 1.2 (3 H, t, J = 7 Hz, CH3), 4.2 (2 H, q, J = 7
Hz, OCH2), 6.8 (1 H, dd, J = 8.5, 2.5 Hz, 5-H), 7.1 (1 H, d, J = 8 Hz,
4-H), 7.2 (1 H, d, J = 2.5 Hz, 7-H), 7.5 (s, 5 H, C6H5).
ESMS: m/z calcd for C16H15O2: 239.1072; found: 239.1058
ESMS: m/z calcd for C16H15O2: 309.1227 (M+); found; 309.1218.
Anal. Calcd for C16H15O2: C, 87.36; H, 4.89. Found: C, 87.16; H,
5.02.
Anal. Calcd for C16H15O2: C, 74.01; H, 5.23. Found: C, 73.89; H,
5.40.
2-Bromo-6-methoxy-3-phenylindanone (4)
Br2 (1.0 mL) was added dropwise to an ice-cooled solution of 6-
methoxy-3-phenylindanone (3; 8.1 g, 33.9 mmol) in Et2O (20 mL)
and the mixture was stirred for 20 min. At this time, a precipitate
started to fall out of solution. The solution was stirred for a further
10 min and H2O was added. The solution was allowed to stand over-
night and the precipitate that formed was collected by suction filtra-
tion. Recrystallization (Et2O) gave 4; yield: 6.1 g (55%); mp 83–
85 °C.
2-Bromo-6-methoxy-3-phenylindenone (1c)
Br2 (1.0 mL) was added dropwise to an ice-cooled solution of 6-
methoxy-3-phenylindanone (5 g, 21 mmol) in anhyd Et2O (20 mL).
Almost immediately, a precipitate started to fall out of solution. The
solution was stirred for 10 min and H2O added. The precipitate that
formed was collected by suction filtration. This was reacted with
NaOEt [prepared from Na (0.2 g, 8.8 mmol) in EtOH (5 mL)] in
EtOH (15 mL) for 1 h at r.t. Work-up [washing with brine, and dry-
ing (MgSO4)] gave a red oil. Addition of hexane–EtOAc (1:10)
prompted precipitation of red crystals of product; yield: 3.4 g
(52%); mp 96–98 °C.
IR (Nujol): 1713 cm–1 (C=O).
1H NMR (CDCl3): d = 3.9 (3 H, s, OCH3), 4.4 (1 H, d, J = 6 Hz, 2-
H), 4.6 (1 H, d, J = 6 Hz, 3-H), 6.8 (1 H, dd, J = 8, 2.5 Hz, 5-H), 7.3
(1 H, d, J = 2.5 Hz, 7-H), 7.4 (1 H, d, J = 8 Hz, 4-H), 7.7 (s, 5 H,
C6H5).
ESMS: m/z calcd for C16H13BrO2 (M+): 316.0102, 318.0142; found:
316.0124, 318.0165.
IR (Nujol): 1705 cm–1 (C=O).
1H NMR (CDCl3): d = 3.8 (3 H, s, OCH3), 6.7 (1 H, dd, J = 8, 2 Hz,
5-H), 7.0 (1 H, d, J = 8 Hz, 4-H), 7.1 (1 H, d, J = 2 Hz, 7-H), 7.4–
7.6 (m, 5 H, C6H5).
ESMS: m/z calcd for C16H11BrO2: 313.9904, 315.9945; found:
313.9913, 315.9921 (M+). Anal. Calcd for C16H11BrO2: C, 60.98; H,
3.52. Found: C, 60.63; H, 3.71.
Anal. Calcd for C16H13BrO2: C, 60.59; H, 4.13. Found: C, 60.23; H,
4.42.
6-Methoxy-3-phenylindenone (1b)
Method A: 2-Bromo-6-methoxy-3-phenylindanone (4; 6.1 g, 19.2
mmol) was refluxed with NaOEt [prepared from Na (0.2 g, 8.8
mmol) in EtOH (5 mL)] for 3 h under inert atmosphere. Work-up
[washing with brine, and drying (MgSO4)] and column chromatog-
raphy (CH2Cl2, then 3:2 CH2Cl2–hexane) gave 1b; yield: 1.1 g
(13.5% overall from 2).
Acknowledgment
MKS thanks Trinity College Dublin and Enterprise Ireland for fi-
nancial support.
References
Method B: 6-Methoxy-3-phenylindanone (0.5 g, 2.1 mmol) and
SeO2 (0.5 g, 2.7 mmol) in anhyd EtOH (20 mL) was refluxed for 48
h under N2. The mixture was cooled, and added to H2O. The product
was extracted with CH2Cl2 and washed with aq NaHCO3 and H2O.
The organic extract was dried (MgSO4) and the solvent removed.
Purification by column chromatography (CH2Cl2, Rf 0.6) gave 100
mg (28%) of product; mp 81–83 °C.
(1) Current Address: School of Chemistry, Dublin Institute of
Technology, Kevin St., Dublin 8, Ireland.
(2) Bensasson, R. V.; Land, E. J.; Truscott, T. G. Excited States
and Free Radicals in Biology and Medicine; Oxford
University Press: New York, 1993.
(3) Kelly, J. F. D.; Kelly, J. M.; McMurry, T. B. H. J. Chem.
Soc., Perkin Trans. 2 1999, 1933.
IR (Nujol): 1700 cm–1 (C=O).
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M. K. Seery et al.
PAPER
(7) Full crystal structure data have been deposited with the
Cambridge Crystallographic Data Centre. Deposition
numbers are 249671 and 249672 for 4 and 1c, respectively.
(8) McMurry, T. B. H.; Murphy, A. G.; Work, D. N.; Avent, A.
G.; James, J. P. J. Chem. Res., Synop. 2002, 7, 317.
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1980, 1555.
(5) Gaviña, F.; Costero, A. M.; González, A. M. J. Org. Chem.
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Synthesis 2005, No. 3, 470–474 © Thieme Stuttgart · New York