Substituent effects on reactive oxygen species (ROS) generation by hydroquinones

Article abstract of DOI:10.1021/jo501796z

In order to understand the structural aspects of stabilization of hydroquinones and their ability to generate reactive oxygen species (ROS), we designed and synthesized a series of 6-aryl-2,3-dihydro-1,4-benzoquinones. These compounds equilibrate with the corresponding 6-aryl-1,4-dihydroxybenzenes in an organic medium; a linear free energy relationship analysis gave ρ = +2.37, suggesting that this equilibrium was sensitive to electronic effects. The propensity of the compound to enolize appears to determine ROS-generating capability, thus offering scope for tunable ROS generation.

Full text of DOI:10.1021/jo501796z

Note
pubs.acs.org/joc
Substituent Effects on Reactive Oxygen Species (ROS) Generation by
Hydroquinones
Allimuthu T. Dharmaraja, Charu Jain, and Harinath Chakrapani*
Department of Chemistry, Indian Institute of Science Education and Research Pune, Dr. Homi Bhabha Road, Pashan, Pune 411021,
Maharashtra, India
S
* Supporting Information
ABSTRACT: In order to understand the structural aspects of stabilization
of hydroquinones and their ability to generate reactive oxygen species
(ROS), we designed and synthesized a series of 6-aryl-2,3-dihydro-1,4-
benzoquinones. These compounds equilibrate with the corresponding 6-
aryl-1,4-dihydroxybenzenes in an organic medium; a linear free energy
relationship analysis gave ρ = +2.37, suggesting that this equilibrium was
sensitive to electronic effects. The propensity of the compound to enolize appears to determine ROS-generating capability, thus
offering scope for tunable ROS generation.
uring aerobic respiration, inadvertent 1e transfer to
molecular O2 produces the superoxide radical anion
.
1,2 O2−• is converted to hydrogen peroxide (H2O2), which
Scheme 1. Equilibration of 6-Aryl-2,3-dihydro-1,4-
benzoquinones with Their Corresponding Diols, Which
under Physiological Conditions React with Oxygen To
Produce ROS
D
−•
O2
in the presence of trace metal ions through Fenton chemistry
can generate the highly reactive hydroxyl radical •OH.1−3
•
Together, O2−•, H2O2 and OH are considered as reactive
oxygen species (ROS) and are central to redox biology,
immune response, an understanding of the pathology of
numerous diseases, including cancer, and aging.4−6 Recently, a
number of studies provide evidence for the use of ROS as a
therapeutic.4 For example, cancers have been reported to have
impaired capability to maintain redox homeostasis4 and are
sensitive to small molecules capable of generating ROS.7,8 Drug
resistance in bacteria can be overcome by enhancement of
ROS,9 suggesting possible applications for ROS generators as
an adjuvant that can enhance the efficacy of existing drugs.10−16
However, the precise roles of ROS are yet to be completely
understood17 and the rate of ROS generation plays an
important role in the observed biological effects.11 Although
multiple strategies can be used for ROS generation with
variable rates, a single scaffold with control over ROS
generation rates is not available.18−20 Such a tool would allow
us to study the differences in biological effects of varying ROS
generation. Furthermore, due to comparable physicochemical
properties offered by a single scaffold, development of one with
diverse ROS generation profiles would be useful. We
considered 6-aryl-2,3-dihydro-1,4-benzoquinones as a possible
candidate scaffold for tunable ROS generation (Scheme 1). A
mechanism for ROS generation from these compounds
involves enolization as the first step that produces an aromatic
and are components of numerous bioactive natural prod-
ucts.24−26 Understanding substituent effects on stabilizing the
enol would hence enable us to better characterize the reactivity
of this important functional group.
In order to synthesize the 6-aryl-2,3-dihydrobenzoquinone
scaffold, substituted p-benzoquinones 15−26 were first
synthesized using a silver nitrate catalyzed arylation of 1,4-
benzoquinone (14) with functionalized arylboronic acids
(Table S1 (Supporting Information), entries 1−12).27 Next,
14−26, containing electron-withdrawing and electron-donating
groups, were independently reacted with 1,3-cyclohexadiene to
produce the corresponding Diels−Alder adducts in yields
ranging from 67 to 95% (Table 1, entries 1−13). A 1H nuclear
magnetic resonance (1H NMR) spectroscopy study conducted
on 2 showed that this compound exclusively existed in the keto
form (2a), as evidenced by signals for the hydrogens of α and β
(bridgehead) to the CO, which appeared in the range 3.0−
3.4 ppm (Figure S1 (Supporting Information)). A similar result
was recorded for the 4-methyl as well as 4-methoxyphenyl
derivatives 3 and 4 (Figure S1), suggesting no major effect of
introduction of an electron-donating group on the position of
the equilibrium (Table 1). Next, the 1H NMR spectrum for the
12
−•
1,4-diol, which reacts with oxygen to produce O2
.
Placing
substituents on the position adjacent to the carbonyl functional
group might affect the propensity of the keto form to enolize.
Being able to systematically alter the position of this
equilibrium might offer opportunities to tune ROS generation.
In addition to ROS generation, hydroquinones find frequent
use as a functional group capable of transferring electrons21−23
Received: August 4, 2014
Published: September 10, 2014
© 2014 American Chemical Society
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Note
1
Table 1. Synthesis of 1−13, Results of Keto−Enol Ratios Studied by H NMR, Percent Compound Remaining in Buffer
Calculated from HPLC Studies, and H2O2 Generated from 1−13 in Buffer
a
a
b
c
d
entry
R
quinone
product
1a
yield (%)
keto (%)
enol (%)
Keq
remaining (%)
H2O2 (μM)
e
e
e
e
1
H
14
15
16
17
18
19
20
21
22
23
24
25
26
70
73
83
74
81
95
66
84
84
81
67
87
70
100
100
100
100
93
n.d.
n.d.
n.d.
n.d.
0.0204
0.0204
0.0204
0.0204
0.0753
0.6129
0.1235
32
74
60
86
25
52
57
17
9.6
11.4
18
40
70
1.16
1.66
0.75
1.07
0.85
3.67
2.65
2.44
2
Ph
2a
3
4-MePh
4-MeOPh
4-BrPh
3a
4
4a
f
5
5a + 5b
6a + 6b
7a + 7b
8a + 8b
9b
7
f
6
4-ClPh
62
38
11
7
4-FPh
89
f
8
4-AcPh
74
26
0.3513
f
e
g
9
4-NO2Ph
4-CHOPh
3-NO2Ph
3-CHOPh
2-MeOPh
n.d.
n.d.
27
100
49
1.59
f
e
10
11
12
13
10b
100
49
2.703
5.42
3.55
3.55
0.45
11a + 11b
12b
73
f
e
n.d.
100
49
0.0204
e
13a
100
n.d.
a
The percent keto and enol forms were estimated by 1H NMR spectroscopy in CDCl3 unless otherwise indicated (spectra were recorded on a 400
b
MHz NMR spectrometer). n.d. = not detected. Keq was estimated by the ratio of peaks correspnding to α- and β-hydrogens to the CO (for the
c
keto form) and the bridgehead hydrogens (for the enol form). n.d. = not detected. The compound (1 mM) was incubated in pH 7.4 phosphate
d
buffer for 60 min at 37 °C under ambient aerobic conditions, and HPLC was used to determine percnet compound remaining. The compound (10
μM) was incubated in pH 7.4 phosphate buffer under ambient aerobic conditions for 60 min, and H2O2 was assayed by an Amplex Red fluorescence
e
f
g
assay. Estimated by considering 98% of the major tautomer. Experiment was conducted in DMSO-d6. HPLC analysis of this reaction mixture
showed multiple unidentified products, suggesting possible side reactions or collateral consumption of H2O2 likely contributing to the diminished
yield of H2O2.
28
Figure 1. (a) Plot of log(KX/KH) for keto−enol equilibria of 2,3-dihydrobenzoquinones versus the Hammett substitution constant σ+ (reaction
constant ρ = 2.37; R2 = 0.7420). (b) Time course of decomposition of 2 (1 mM, k2 = 0.28 h−1, R2 = 0.9875) and 10 (1 mM, k10 = 1.48 h−1, R2 =
0.9546) in acetonitrile (pH 7.4 phosphate buffer (1/1, v/v)) based on HPLC analysis. (c) Time course of H2O2 generated from 2 (10 μM) and 10
(10 μM) over 6 h in pH 7.4 phosphate buffer measured using Amplex Red based fluorescence assay.
4-bromo derivative 5 was recorded and this compound was
found to exist predominantly in its keto form 5a; however, a set
of peaks at 4.2−4.5 ppm for the bridgehead hydrogens of the
enol form 5b was also observed (Figure S1). The major
tautomer was the keto form 5a, estimated as 93% (Table 1,
entry 5). A similar result was recorded for 6−8 (Figure S1),
whose equilibria were found to be 62−89% in favor of the keto
tautomer (Table 1, entries 6−8).
Among the compounds with electron-withdrawing groups,
the enol form was dominant and 9, 10, and 12 were found to
exist nearly exclusively in the enol forms 9b, 10b, and 12b while
the 3-nitroaryl derivative 11 was 73% enol in DMSO-d6 (Table
1, entries 9−12). The aryl derivative 13 with a 2-methoxy
substituent was found to behave similarly to the 4-methoxy
derivative 4, and only the keto form 13a could be detected
(Table 1, entry 13).
1). In order to understand substituent effects on the position of
this equilibrium, using these Keq values, a Hammett plot was
constructed. A moderately linear correlation (R2 = 0.6751) was
observed with σ, and an overall reaction constant ρ of +3.6 was
obtained (see the Supporting Information, Figure S2). The
resonance contribution to the position of the equilibrium was
estimated using a similar plot that was constructed with σ+, and
a ρ value of +2.37 was obtained, but with better linearity (R2 =
0.7420, Figure 1a).28 Previous reports of such equilibria in
related β-diketones such as benzoylacetones and benzoylcyclo-
hexanones indicate that the keto form is stabilized by electron-
releasing groups.29−31 Although the magnitude of the reaction
constant ρ derived from σ+ and equilibrium constants in the
aforementioned studies was significantly lower (i.e. 0.6−
0.929−31) than the ρ value that we find in this study, the sign
was positive, supporting similar trends in substituent effects on
the stability of keto and enol forms.
On the basis of the ratios of the keto and enol forms, the
equilibrium constant for enolization Keq was calculated (Table
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Note
Next, the electronic effect on the keto form’s propensity to
enolize was studied by exposing the compound to base, which
would promote enolization. Compound 2, which predom-
inantly exists in the keto form 2a, was exposed to NaOD (0.2
equiv) in DMSO-d6, and the NMR spectrum was recorded after
15 min (see the Supporting Information, Figure S3). The
formation of signals that were characteristic of the bridgehead
hydrogens of the enolate was observed (indicated by arrows in
Figure S3) with concomitant disappearance of the α-keto
hydrogens. A similar experiment conducted with 4a showed
that, in the same time period, 62% of 4a remained and
complete enolization was observed in 1 h, suggesting that an
electron-donating group on the aryl ring significantly lowered
the rate of enolization (see the Supporting Information, Figure
S4). A similar experiment conducted with 5 (93/7; 5a/5b) and
8 (77/23; 8a/8b) showed nearly complete enolization in 15
min (see the Supporting Information, Figures S5 and S6).
These observations are consistent with electron-donating
groups significantly decreasing the propensity of the hydro-
quinone to enolize.
Our data suggest that the enolization of 6-aryl-2,3-
dihydrobenzoquinones is dependent on electronic effects and
the ratio of keto and enol tautomers can be modulated by
simple structural modifications on the aryl ring. Accordingly,
compounds with dominant enol forms are expected to be more
reactive in ambient aerobic buffer and vice versa. When 1a was
dissolved in pH 7.4 phosphate buffer/acetonitrile (1/1, v/v),
we found nearly 32% of the compound remaining after 60 min
(Table 1, entry 1). When a similar experiment was conducted
with 2a, 74% of the compound remained after 1 h (Table 1,
entry 2). Curve fitting of percent 2a remaining to a first-order
reaction gave a rate constant of 0.28 h−1 (R2 = 0.9875) and a
half-life (t1/2) of 2.49 h (Figure 1b). Compounds 3a and 4a
with electron-donating groups were found to have comparable
decomposition profiles after 1 h (Table 1, entries 3 and 4). In
the cases of compounds 5−8 and 11, which existed as mixtures
of keto and enol forms in organic media, the percent remaining
in these cases was calculated on the basis of the keto form and
ranged from 18 to 57%, all lower in comparison with 2a (Table
1, entries 5−8 and 11). Compounds 9b and 10b were 90%
decomposed in 1 h, while 40% of the formyl derivative 12b
remained in the same time period (Table 1, entries 9, 10, and
12). Under these conditions, the first-order rate constant k =
1.48 h−1 (R2 = 0.9546) was recorded for decomposition of 10b
(Figure 1b). The half-life of this compound was estimated as
0.47 h, which is lower in comparison with 2a (Figure 1b).
In ambient aerobic buffer, the hydroquinone is expected to
rapidly react with oxygen to produce the corresponding 1,4-
benzoquinone (see the Supporting Information, Table S3,
compounds 27−29). Its keto tautomer, on the other hand,
would have to first tautomerize to generate hydroquinone
enolate in buffer, and a sequential one-electron transfer from
generation (Table 1, entries 1−13). This result is consistent
with enolization being the critical step in ROS production; once
formed, the enolate reacts rapidly with O2 to generate ROS
(Scheme 1). Hence, the keto−enol ratio in organic media was a
good indicator of the ability to generate ROS in buffer,
suggesting that enolization is the key step to control ROS
generation by these compounds.37 Finally, the tunability offered
by this scaffold is illustrated by time courses of H2O2 generated
by 2a, which is gradual, and 10b, which rapidly dissociates to
generate ROS (Figure 1c). Taken together, we provide
evidence for predictably tuning keto−enol tautomerism in
dihydrobenzoquinones by varying substituent electronics and
the position of this equilibrium significantly affects ROS
generation.
EXPERIMENTAL SECTION
■
Compounds 1,34 2,35 and 15−2627,36 have been previously reported,
and analytical data that we recorded were consistent with the reported
values.
General Procedure for Synthesis of Compounds 1a−13a. To
a solution of 2-aryl-1,4-benzoquinone (1 mmol) in toluene (10 mL)
was added freshly distilled 1,3-cyclohexadiene (2 mmol), and the
mixture was refluxed. Upon complete consumption of the starting
material (TLC analysis), the reaction mixture was evaporated to
dryness under reduced pressure to obtain the crude product. The
crude material was purified by silica gel column chromatography using
an ethyl acetate (5 → 15%) and petroleum ether solvent system. This
material was recrystallized in chloroform to obtain pure material.
General Procedure for Synthesis of 27−29. To a solution of
2,3-dihydro-1,4-benzoquinone (0.2 mmol) in tetrahydrofuran (THF, 5
mL) was added potassium carbonate (0.5 mmol, 2.5 equiv), and the
reaction mixture was stirred at room temperature overnight. The
reaction mixture was washed with 5 mL of deionized water and
extracted with ethyl acetate (4 × 5 mL). The combined organic layer
was dried (anhydrous Na2SO4, 5 g) and filtered, and the filtrate was
evaporated under reduced pressure to obtain the crude product. The
crude mixture was purified by a silica gel column by washing with ethyl
acetate/petroleum ether (1/3 ratio, v/v). The organic solvent was
evaporated under reduced pressure to obtain pure material.
6-(4-Methylphenyl)-1,4,4a,8a-tetrahydro-1,4-ethanonaph-
thalene-5,8-dione (3a). Starting from 16 (150 mg, 0.76 mmol), 3a
(174 mg, 66%) was isolated as a pale yellow solid: mp 116−118 °C;
FT-IR (νmax, cm−1) 2927, 2861, 1743, 1681, 1653, 1516, 1462, 1208,
1
1029; H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.2 Hz, 2H), 7.20
(d, J = 8.0 Hz, 2H), 6.74 (s, 1H), 6.15−6.31 (m, 2H), 3.21−3.27 (m,
2H), 3.15 (dd, J = 2.5, 9.3 Hz, 1H), 3.06 (dd, J = 2.5, 9.3 Hz, 1H), 2.37
(s, 3H), 1.69−1.76 (m, 2H), 1.34−1. 69 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 199.6, 198.9, 151.7, 140.6, 137.7, 133.8, 133.4, 130.5,
129.3, 128.8, 50.7, 50.2, 35.6, 35.5, 24.8, 21.5; HRMS (ESI-TOF) for
[C19H18O2 + Na]+ calcd 301.1204, found 301.1194. Anal. Calcd for
C19H18O2: C, 81.99; H, 6.52. Found: C, 81.71; H, 6.42.
6-(4-Methoxyphenyl)-1,4,4a,8a-tetrahydro-1,4-ethanonaph-
thalene-5,8-dione (4a). Starting from 17 (100 mg, 0.47 mmol), 4a
(101 mg, 74%) was isolated as an orange-yellow solid: mp 121−123
°C; FT-IR (νmax, cm−1) 2928, 2859, 1743, 1678, 1652, 1515, 1462,
1258, 1023; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.7 Hz, 2H),
6.90 (d, J = 8.7 Hz, 2H), 6.72 (s, 1H), 6.18−6.33 (m, 2H), 3.82 (s,
3H), 3.23 (s, 2H), 3.13 (dd, J = 2.1, 9.3 Hz, 1H), 3.05 (dd, J = 2.1, 9.3
Hz, 1H), 1.72 (d, J = 6.9 Hz, 2H), 1.38 (d, J = 7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 199.5, 199.2, 161.4, 151.0, 136.7, 133.8, 133.4,
130.5, 125.6, 114.1, 55.5, 50.8, 50.1, 35.5, 35.4, 24.9; HRMS (ESI-
TOF) for [C19H18O3 + Na]+ calcd 317.1153, found 317.1149. Anal.
Calcd for C19H18O3: C, 77.53; H, 6.16. Found: C, 77.64; H, 5.82.
6-(4-Bromophenyl)-1,4,4a,8a-tetrahydro-1,4-ethanonaph-
thalene-5,8-dione (5a). Starting from 18 (500 mg, 1.9 mmol), 5
(531 mg, 81%) was isolated as a pale yellow solid: mp 132−134 °C;
FT-IR (νmax, cm−1) 3531, 2920, 2873, 1741, 1651, 1460, 1339, 1201,
−•
the enolate to molecular oxygen produces ROS such as O2
and H2O2 (Scheme S2, Supporting Information).12,13 We
studied superoxide (O2−•) generated from 1−13 using a
reported chemiluminescence assay,32 and results of this assay
confirmed that 1−13 were capable of generating O2−• in buffer
(see the Supporting Information, Figure S12). Addition of an
−•
electron to O2 would lead to the formation of H2O2, which
was assayed using a commercially available Amplex Red
reagent.33,14 All compounds tested were found to generate
H2O2, and in a majority of the cases, we found that the
presence of an electron-withdrawing substituent enhanced ROS
1
1073; H NMR (400 MHz, CDCl3) δ 7.50−7.54 (m, 2H), 7.24−7.27
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Note
(m, 2H), 6.69−6.77 (m, 1H), 6.19−6.28 (m, 2H), 3.23 (dd, J = 2.5,
5.0 Hz, 2H), 3.15 (d, J = 2.5 Hz, 1H), 3.13 (d, J = 2.5 Hz, 1H), 1.66−
1.79 (m, 2H), 1.33−1.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
199.3, 198.4, 150.5, 138.4, 133.9, 133.4, 132.3, 132.1, 131.8, 130.9,
130.5, 124.8, 50.6, 50.2, 35.6, 35.5, 24.8; HRMS (ESI-TOF) for
[C18H15BrO2 + Na]+ calcd 365.0152, found 365.0152. Anal. Calcd for
C18H15BrO2 calcd. C, 62.99; H, 4.41. Found, C, 63.21; H, 4.09. Note:
NMR data presented here are for the major isomer.
6-(4-Chlorophenyl)-1,4,4a,8a-tetrahydro-1,4-ethanonaph-
thalene-5,8-dione (6a). Starting from 19 (300 mg, 1.4 mmol), 6
(391 mg, 95%) was isolated as a yellow solid: mp 149−151 °C; FT-IR
(νmax, cm−1) 3581, 3422, 3055, 2952, 2869, 1742, 1653, 1467, 1259,
1040; 1H NMR (400 MHz, DMSO-d6) δ 7.41−7.45 (m, 4H), 6.82 (s,
1H), 6.12−6.23 (m, 2H), 3.23 (dd, J = 2.4, 9.5 Hz, 1H), 3.01−3.13
(m, 3H), 1.67 (d, J = 8.2 Hz, 2H), 1.20−1.40 (m, 2H); 13C NMR (100
MHz, DMSO-d6) δ 199.2, 198.4, 150.4, 138.4, 133.9, 133.4, 130.6,
130.2, 129.4, 128.7, 113.3, 63.8, 50.6, 50.2, 35.6, 35.5, 25.0, 24.8 (a
mixture of keto (62%) and enol (38%) tautomers); HRMS (ESI-
TOF) for [C18H15ClO2 + Na]+ calcd 321.0658, found 321.0656. Note:
NMR data presented here are for the major isomer.
6-(4-Fluorophenyl)-1,4,4a,8a-tetrahydro-1,4-ethanonaph-
thalene-5,8-dione (7a). Starting from 20 (300 mg, 1.48 mmol), 7
(277 mg, 66%) was isolated as a yellow semisolid: FT-IR (νmax, cm−1)
3567, 2961, 1742, 1695, 1652, 1513, 1462, 1220, 1157; 1H NMR (400
MHz, CDCl3) δ 7.36−7.41 (m, 2H), 7.03−7.12 (m, 2H), 6.72 (s, 1H),
6.24 (dd, J = 3.4, 4.3 Hz, 2H), 3.22−3.27 (m, 2H), 3.14 (dd, J = 2.5,
9.3 Hz, 1H), 3.06 (dd, J = 2.5, 9.3 Hz, 1H), 1.67−1.78 (m, 2H), 1.32−
1.43 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 199.3, 198.6, 165.2,
162.7, 150.4, 138.2, 133.9, 133.3, 131.0, 130.9, 115.8, 115.6, 113.5,
50.6, 50.2, 35.6, 35.5, 24.8; HRMS (ESI-TOF) for [C18H15FO2 + Na]+
calcd 305.0953, found 305.0957. Note: NMR data presented here are
for the major isomer.
Hz, 2H), 6.37−6.58 (m, 3H), 4.40 (s, 1H), 4.26 (s, 1H), 1.40 (d, J =
7.9 Hz, 2H), 1.28 (d, J = 8.9 Hz, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 193.2, 146.6, 145.1, 140.9, 135.7, 135.6, 134.5, 134.3, 132.3,
130.3, 129.7, 126.0, 113.7, 33.7, 33.3, 25.4, 25.3; HRMS (ESI-TOF)
for [C19H16O3 + H]+ calcd 293.1177, found 293.1173.
6-(3-Nitrophenyl)-1,4-dihydro-1,4-ethanonaphthalene-5,8-
diol (11b). Starting from 24 (100 mg, 0.46 mmol), 11 (96 mg, 67%)
was isolated as a yellow solid: mp 163−165 °C; FT-IR (νmax, cm−1)
3615, 2928, 1741, 1688, 1517, 1462, 1339, 1272, 1154; 1H NMR (400
MHz, DMSO-d6) δ 8.78 (s, 1H), 8.27−8.32 (m, 1H), 8.17 (s, 1H),
8.07 (dd, J = 1.8, 8.1 Hz, 1H), 7.82−7.88 (m, 1H), 7.62 (t, J = 8.0 Hz,
1H), 6.46 (dd, J = 9.1, 12.9 Hz, 3H), 4.39 (s, 1H), 4.26 (s, 1H), 1.40
(d, J = 8.0 Hz, 2H), 1.22−1.31 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 199.2, 198.4, 148.8, 148.0, 145.2, 141.6, 140.8, 139.2,
136.1, 135.9, 135.7, 135.6, 135.4, 134.3, 134.1, 132.4, 130.4, 130.0,
124.9, 124.7, 124.3, 124.2, 121.4, 113.5, 50.4, 50.1, 34.8, 33.7, 33.3,
25.4, 25.3, 24.7, 24.6 (a mixture of keto/enol (27/73) tautomers);
HRMS (ESI-TOF) for [C18H15NO4 + Na]+ calcd 332.0899, found
332.0898. Note: NMR data presented here are for the major isomer.
6-(3-Formylphenyl)-1,4-dihydro-1,4-ethanonaphthalene-
5,8-diol (12b). Starting from 25 (400 mg, 1.88 mmol), 12b (477 mg,
87%) was isolated as a yellow solid: mp 158−160 °C; FT-IR (νmax
,
cm−1) 3455, 3323, 2913, 2865, 1833, 1742, 1675, 1514, 1459, 1288,
1146, 1071; 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.72 (s,
1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.76 (dd, J = 1.4, 7.6 Hz, 2H), 7.56 (t,
J = 7.6 Hz, 1H), 6.45−6.48 (m, 3H), 4.40 (s, 1H), 4.27 (s, 1H), 1.40
(d, J = 7.8 Hz, 2H), 1.29 (d, J = 9.4 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 193.9, 145.1, 141.0, 140.7, 136.5, 135.8, 135.7, 135.7,
134.2, 131.7, 130.8, 129.3, 127.8, 125.9, 113.7, 33.7, 33.3, 25.4, 25.3;
HRMS (ESI-TOF) for [C19H16O3 + H]+ calcd 293.1177, found
293.1170. Anal. Calcd for C19H16O3: C, 78.06; H, 5.52. Found: C,
77.66; H, 5.31.
6-(4-Acetylphenyl)-1,4,4a,8a-tetrahydro-1,4-ethanonaph-
thalene-5,8-dione (8a). Starting from 21 (500 mg, 2.2 mmol), 8
(566 mg, 84%) was isolated as a yellow solid: mp 127−128 °C; FT-IR
(νmax, cm−1) 3563, 2980, 2862, 1742, 1659, 1519, 1461, 1354, 1170,
6-(2-Methoxyphenyl)-1,4,4a,8a-tetrahydro-1,4-ethanonaph-
thalene-5,8-dione (13a). Starting from 26 (200 mg, 0.93 mmol),
13a (193 mg, 70%) was isolated as an orange-yellow solid: mp 143−
145 °C; FT-IR (νmax, cm−1) 2927, 2856, 1743, 1655, 1518, 1462, 1256,
1167, 1019; 1H NMR (400 MHz, CDCl3) δ 7.37 (ddd, J = 1.8, 7.3, 8.3
Hz, 1H), 7.08 (dd, J = 1.8, 7.4 Hz, 1H), 6.94−6.99 (m, 1H), 6.90 (d, J
= 8.3 Hz, 1H), 6.65 (s, 1H), 6.16−6.39 (m, 2H), 3.76 (s, 3H), 3.13−
3.26 (m, 3H), 3.07 (dd, J = 2.7, 9.2 Hz, 1H), 1.66−1.78 (m, 2H),
1.34−1. 46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 198.3, 196.8,
155.8, 151.5, 138.0, 133.1, 131.8, 130.2, 128.8, 122.9, 119.9, 110.2,
54.5, 49.4, 49.1, 34.1, 33.8, 24.1, 23.4; HRMS (ESI-TOF) for
[C19H18O3 + Na]+ calcd 317.1153, found 317.1149. Anal. Calcd for
C19H18O3: C, 77.53; H, 6.16. Found: C, 77.19; H, 6.04.
1
1044; H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 2.1, 8.4 Hz, 2H),
7.46 (dd, J = 1.8, 8.3 Hz, 2H), 6.76 (d, J = 2.2 Hz, 1H), 6.25 (dd, J =
2.5, 4.8 Hz, 2H), 3.04−3.30 (m, 4H), 2.59 (d, J = 2.2 Hz, 3H), 1.73 (d,
J = 7.4 Hz, 2H), 1.38 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 199.3, 198.3, 197.6, 150.6, 144.4, 139.1, 134.0, 133.4, 129.2,
129.1, 128.4, 127.5, 50.6, 50.2, 35.7, 35.5, 26.8, 24.8; HRMS (ESI-
TOF) for [C20H18O3 + Na]+ calcd 329.1153, found 329.1154. Anal.
Calcd for C20H18O3: C, 78.41; H, 5.92. Found: C, 78.09; H, 5.57.
Note: NMR data presented here are for the major isomer.
NMR Data of Enol Tautomer, 6-(4-Acetylphenyl)-1,4-dihy-
6-Phenyl-1,4-dihydro-1,4-ethanonaphthalene-5,8-dione
(27). Starting from 2a (50 mg, 0.19 mmol), 27 was isolated as a yellow
semisolid (41 mg, 83%): FT-IR (νmax, cm−1) 2928, 2817, 1648, 1585,
1488, 1337, 1011; 1H NMR (400 MHz, CDCl3) δ 7.33−7.48 (m, 5H),
6.68 (s, 1H), 6.33−6.50 (m, 2H), 4.39 (dd, J = 1.7, 18.5 Hz, 2H), 1.50
(dd, J = 4.8, 6.0 Hz, 2H), 1.35−1.44 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 183.7, 182.8, 148.6, 148.5, 144.4, 134.0, 133.2, 132.8, 132.1,
131.7, 130.9, 124.5, 34.2, 33.8, 24.8, 24.7; HRMS (ESI-TOF) for
[C18H14O2 + H]+ calcd 263.1072, found 263.1063.
1
dro-1,4-ethanonaphthalene-5,8-diol (8b). H NMR (400 MHz,
DMSO-d6) δ 8.73 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.57
(d, J = 7.8 Hz, 2H), 6.42−6.49 (m, 3H), 4.39 (s, 1H), 4.26 (s, 1H),
2.54 (s, 3H), 1.40 (d, J = 8.1 Hz, 2H), 1.28 (d, J = 9.6 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 198.05, 145.1, 145.0, 140.9, 135.8,
135.6, 135.0, 134.2, 132.0, 129.9, 128.4, 126.1, 113.7, 33.7, 33.3, 27.2,
25.4, 25.3; HRMS (ESI-TOF) for [C20H18O3 + H]+ calcd 307.1334,
found 307.1330.
6-(4-Nitrophenyl)-1,4-dihydro-1,4-ethanonaphthalene-5,8-
diol (9b). Starting from 22 (100 mg, 0.41 mmol), 9b (64 mg, 47%)
was isolated as a pale yellow semisolid: FT-IR (νmax, cm−1) 3517, 3452,
2936, 2869, 1741, 1653, 1517, 1460, 1196, 1021; 1H NMR (400 MHz,
DMSO-d6) δ 8.79 (s, 1H), 8.17−8.20 (m, 3H), 7.69 (d, J = 8.7 Hz,
2H), 6.49 (s, 1H), 6.44−6.46 (m, 2H), 4.40 (s, 1H), 4.26 (s, 1H), 1.40
(d, J = 7.6 Hz, 2H), 1.27 (d, J = 9.9 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 172.8, 166.1, 147.3, 146.1, 145.2, 140.9, 135.7, 135.6,
134.4, 132.9, 130.7, 125.0, 123.6, 113.6, 33.7, 33.4, 25.3, 25.1; HRMS
(ESI-TOF) for [C18H15NO4 + H]+ calcd 310.1079, found 310.1078.
6-(4-Formylphenyl)-1,4-dihydro-1,4-ethanonaphthalene-
5,8-diol (10b). Starting from 23 (150 mg, 0.71 mmol), 10b (168 mg,
81%) was isolated as a pale yellow solid: mp 193−195 °C; FT-IR
(νmax, cm−1) 3568, 2930, 2862, 1743, 1684, 1598, 1551, 1520, 1461,
6-(4-Methoxyphenyl)-1,4-dihydro-1,4-ethanonaphthalene-
5,8-dione (28). Starting from 4a (50 mg, 0.17 mmol), 28 was isolated
as an orange semisolid (19 mg, 38%): FT-IR (νmax, cm−1) 2924, 1649,
1563, 1511, 1460, 1340, 1240, 1181, 1028; 1H NMR (400 MHz,
CDCl3) δ 7.32−7.54 (m, 2H), 6.84−7.02 (m, 2H), 6.64 (s, 1H),
6.31−6.50 (m, 2H), 4.27−4.47 (m, 2H), 3.83 (s, 3H), 1.42−1.53 (m,
2H), 1.31−1.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 184.1,
183.6, 161.1, 148.5, 148.3, 144.8, 134.0, 133.9, 131.0, 130.6, 125.7,
114.0, 55.4, 34.2, 33.7, 24.8, 24.7; HRMS (ESI-TOF) for [C19H16O3 +
H]+ calcd 293.1177, found 293.1174.
6-(4-Acetylphenyl)-1,4-dihydro-1,4-ethanonaphthalene-5,8-
dione (29). Starting from 8a (50 mg, 0.16 mmol), 29 (31 mg, 62%)
was isolated as a yellow semisolid: FT-IR (νmax, cm−1) 2929, 2872,
1682, 1650, 1602, 1460, 1359, 1268, 1142, 1041; 1H NMR (400 MHz,
CDCl3) δ 7.91−7.99 (m, 2H), 7.51−7.56 (m, 2H), 6.72 (s, 1H),
6.40−6.44 (m, 2H), 4.35−4.43 (m, 2H), 2.61 (s, 3H), 1.49−1.54 (m,
1
1266, 1067, 1020; H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H),
8.73 (s, 1H), 8.03 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.1
9416
dx.doi.org/10.1021/jo501796z | J. Org. Chem. 2014, 79, 9413−9417

The Journal of Organic Chemistry
Note
2H), 1.37−1.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 197.7,
183.6, 182.6, 148.6, 144.5, 137.8, 137.6, 134.0, 133.8, 132.9, 129.7,
128.5, 128.4, 128.3, 34.2, 33.8, 26.8, 24.8, 24.7; HRMS (ESI-TOF) for
[C20H16O3 + H]+ calcd 305.1177, found 305.1172.
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1
DMSO-d6. The H NMR spectrum was recorded for 2 (10 mg) in
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μL of a premixed solution of 10-acetyl-3,7- dihydroxyphenoxazine or
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ASSOCIATED CONTENT
* Supporting Information
Tables and figures giving NMR spectra, HPLC traces, and yield
data for 15−29. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail for H.C.: harinath@iiserpune.ac.in
■
Notes
The authors declare no competing financial interest.
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