Sequential, One-Pot Access to Arylated Benzoquinones/Naphthoquinones from Phenols/Naphthols

Article abstract of DOI:10.1002/ejoc.201600119

A sequential one-pot approach towards arylated benzoquinones and naphthoquinones is reported. The reaction proceeds through oxidation of phenols/naphthols followed by CH-arylation with a catalytic amount of triflic acid. Preliminary cytotoxic studies were carried out with five different cell lines and some of the compounds show promising activity. This one-pot approach towards arylated benzoquinones and naphthoquinones proceeds through oxidation of phenols/naphthols followed by CH-arylation. Preliminary cytotoxic studies for some of the compounds showed promising activity.

Full text of DOI:10.1002/ejoc.201600119

DOI: 10.1002/ejoc.201600119
Full Paper
One-Pot Synthesis
Sequential, One-Pot Access to Arylated Benzoquinones/
Naphthoquinones from Phenols/Naphthols
Jia-Heng Jiang,[a] Siva Senthil Kumar Boominathan,[a] Wan-Ping Hu,[b] Chung-Yu Chen,[a]
Jaya Kishore Vandavasi,[a] Ying-Ting Lin,[b] and Jeh-Jeng Wang*[a]
Abstract: A sequential one-pot approach towards arylated CH-arylation with a catalytic amount of triflic acid. Preliminary
benzoquinones and naphthoquinones is reported. The reaction cytotoxic studies were carried out with five different cell lines
proceeds through oxidation of phenols/naphthols followed by and some of the compounds show promising activity.
Introduction
dium-catalyzed reactions owing to their coordinating nature.[8]
Hence, a 1,4-conjugative addition reaction followed by oxid-
ation is a preferred route for the arylation reactions of quinones
and, based on this concept, a few metal-catalyzed reactions
were reported. Despite these advances, efforts still need to be
made in terms of mild reaction conditions, metal-free ap-
proaches, inexpensive reagents, and wide substrate scope. Fur-
thermore, the direct one-pot approach to naphthoquinone/
quinones from naphthols/phenols has not been reported.
In consideration of these important points and our ongoing
efforts to develop metal-free approaches,[9] we wish to report
a sequential one-pot approach to arylated quinones through
oxidation of phenols/naphthols, followed by triflic acid (TfOH)-
catalyzed arylation with electron-rich arenes.
Benzoquinones and naphthoquinones are privileged classes of
structural motifs present in several natural products that exhibit
a wide range of applications in medicinal chemistry, biochemis-
try, pigment and dyes, and as ligands.[1] These scaffolds also
have the capability to transfer electrons and act as redox cen-
ters in biological process.[2] Of particular importance, arylated
benzoquinones/naphthoquinones possess unique electronic
properties, which have several applications in chemistry and
biology.
Over recent decades, several groups have made remarkable
advances in the direct C–H functionalization of benzoquinones
and naphthoquinones. Earlier reports of arylation of quinones
are palladium-mediated arylation reactions of arenes,[3a] aryl-
ation through the use of diazonium salts,[3b] titanium-catalyzed
arylation reactions of silyl cyclopropyl benzenes,[3c] ruthenium-
catalyzed oxidation reactions of aromatic compounds,[3d] and
Lewis-acid-catalyzed conjugative addition reactions of indoles
to quinones.[3e] In 2006, Li and co-workers developed an ele-
gant approach to the arylation of quinones by means of a cata-
lytic amount of In(OTf)3 in aqueous media.[4] In addition, bor-
onic acids were also employed as powerful coupling partners in
the arylation reactions of quinone compounds.[5a–5f] Recently,
hydroquinones were converted into aryl quinones through Pd-
catalyzed tandem oxidation/oxidative coupling reactions.[5g]
In general, the arylation of α,ꢀ-unsaturated carbonyl com-
pounds with carbon nucleophiles is achieved through Michael-
type 1,4-conjugative addition reaction of electron-rich arenes[6]
or through palladium-assisted Heck-type coupling reactions.[7]
However, benzoquinone substrates do not easily undergo palla-
Results and Discussion
The reaction between 1-naphthol (1a) and N,N-dimethylaniline
(2a) was chosen as the model for optimization studies (Table 1).
Recently, our group were interested in developing sequential
one-pot reactions and we conceived that a similar strategy
could be employed to construct arylated quinones.[9a,9d–9f]
Through reference to literature reports, the oxidation of
1-naphthol (1a) to naphthoquinone (1a′) was optimized by us-
ing meta-chloroperoxybenzoic acid (m-CPBA; 2 equiv.) in aceto-
nitrile at room temp. for 2 h (see Supporting Information for
more information). Under these initial conditions, we planned
to conduct the C–H arylation reaction in same reaction vessel
by adding Cu(OTf)2 (10 mol-%) and 2a (1.3 equiv.). To our de-
light, desired arylated product 3a was obtained in 68 % of yield.
Further, the reaction was scrutinized with various Lewis acids
for which triflate salts showed better yields (Table 1, Entries 2–
9). Here, we suspect that the residual triflic acid from metal
triflate salts may influence the reaction, therefore a control reac-
tion was carried out with TfOH (10 mol-%). As expected, the
reaction proceeded well and the arylated product was obtained
in 87 % (Table 1, Entry 13). In addition, the catalytic amounts
of various Brønsted acids were screened, but none provided
better yields than TfOH (Table 1, Entries 14–18).The reaction
[a] Department of Medicinal and Applied Chemistry,
Kaohsiung Medical University
100, Shiquan Ist Road, Kaohsiung City, Taiwan
E-mail: jjwang@kmu.edu.tw
http://wp.kmu.edu.tw/jjwang/
[b] Department of Biotechnology, Kaohsiung Medical University
100, Shiquan Ist Road, Kaohsiung City, Taiwan
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600119.
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yields were lowered by increasing or decreasing the quantity of
catalyst (Table 1, Entries 19–20). A reduction in reaction temper-
ature (Table 1, Entry 21) and the use of nitrogen atmosphere
(Table 1, Entry 22) were also detrimental to the reaction yield.
The reaction conditions as shown in Table 1, Entry 13 were
considered optimal for this one-pot transformation.
Table 2. Scope of arylation on naphthoquinones.
Table 1. Optimization studies.
Entry[a]
Catalyst
Time
Yield 3a[c]
1
2
3
4
5
6
7
8
Cu(OTf)2
Zn(OTf)2
Cu(OAc)2
Pd(OAc)2
FeCl3
CuCl2
ZnCl2
AlCl3
AgOTf
Cu(OTf)2
Cu(OTf)2
–
TfOH
TFA
12
12
12
12
12
12
12
12
12
24
24
24
24
24
24
24
24
24
24
24
24
12
68
72
45
40
45
52
48
26
51
76
72
20
87
42
36
32
51
72
75
56
60
53
9
10
11[b]
12
13
14
15
16
17
18
19[c]
20[d]
21[e]
22[f]
HCl
H2SO4
PivOH
AcOH
TfOH
TfOH
TfOH
TfOH
[a] Reaction conditions: Unless otherwise mentioned, all reactions were car-
ried out with 1a (100 mg, 0.69 mmol), m-CPBA (2 equiv.) in CH3CN and stirred
at room temp. for 2 h. Then 2a (1.3 equiv.) and catalyst (10 mol-%) were
added to the same pot and the reaction mixture was heated to reflux for the
length of time indicated. [b] Catalyst (5 mol-%) was used. [c] TfOH (20 mol-
%) was used. [d] TfOH (5 mol-%) was used. [e] Reaction was carried out at
60 °C. [f] The reactions was carried out under a nitrogen atmosphere. TFA =
trifluoroacetic acid.
[a] Reaction conditions: Unless otherwise mentioned, all reaction were per-
formed in accordance with the following conditions: Step 1: 1a (100 mg), m-
CPBA (2 equiv.) in CH3CN (3 mL); Step 2: TfOH (10 mol-%) and 2 (1.3 equiv.)
was added and heated to reflux for 24 h. [b] Traces of the other regioisomer
were observed. [c] An inseparable mixture of regio isomers was obtained.
isolated in moderate to high yields. Even though addition may
occur on both carbon atoms (C-2 and C-3), surprisingly, we ob-
served high regioselectivity in these instances, probably attribu-
table to the electronic effects of the substituents within the
ring system (Figure 1, I–III).[10] The C-5 position was substituted
with a hydroxy group (Figure 1, I), which can form a hydrogen
bond with the adjacent keto group and only the C-1 carbonyl
will be available for coordination with TfOH, which enhances
the electrophilicity at position C-3. Thus, the preferred addition
takes place at position C-3 and the structure was unambigu-
ously confirmed by X-ray analysis.[12] Next, position C-5 was
substituted with an electron-donating group, such as methoxy
(Figure 1, II), the electron delocalization makes the C-4 carbonyl
group electron rich and it becomes reluctant to undergo conju-
gative addition. Although the C-1 carbonyl becomes electron
With optimized results in hand (Table 1, Entry 13), the scope
and limitations of the reaction were investigated with different
electron-rich arenes with naphthols (Table 2). A series of disub-
stituted anilines, such as dimethyl, dibenzyl, dipropargyl, dialkyl,
and cycloalkylamine compounds, were examined and the de-
sired arylated products obtained in high yields (3a–3f). Mono-
substituted aniline derivatives (3g, 3h,[12] and 3i) were con-
verted into the respective products in moderate to good yields.
Although there is a possibility of NH-attack on quinones, we
exclusively observed the C–C products. The R2 was replaced
with methoxy groups at various positions to afford correspond-
ing naphthoquinones 3j–3l. Heterocyclic compounds, such as
indoles (C-3) and pyrrole (C-2), were successfully arylated under
the optimized conditions (3m–3o).
To extend the scope of naphthols, R1 was replaced with deficient, the preferred addition occurs at C-3. Similarly, hydroxy
hydroxy, methoxy, and nitro groups at different positions and and methoxy groups at C-6 (Figure 1, III) undergo electron delo-
the corresponding compounds (Table 2, Entries 3p–3u) were calization that facilitates preferred addition at C-2. If the nitro
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group was substituted in naphthols, regioselectivity was not zation by means of H abstraction. Finally, intermediate C under-
observed. Conjugated addition occurred in both carbons and goes air oxidation to give quinones.
resulted in an inseparable mixture of regioisomers (3t–3u).
Next, the cytotoxic activities of the synthesized compounds
were evaluated with different cell lines, such as A2058, A375,
H1335, A549, and BCC (See the Supporting Information for
complete data). The respective cells were cultured with respec-
tive compounds at a concentration of 5 μM for 24 and 48 h.
Notably, compounds 3i, 3j, 3l, 3n, and 3u were found to be
most active among the synthesized compounds after 48 hour
incubation (Figure 2).
Figure 1. Regioselective outcome of substituted naphthols.
Next, the scope of phenols was studied and the results are
shown in Table 3. The phenols were oxidized and treated with
different electron-rich arenes, such as disubstituted anilines
(3v–3w) and trimethoxy benzene (3x),[12] were successfully con-
verted into respective arylated benzoquinones.
Table 3. Scope of arylated benzoquinones.
Figure 2. Evaluation of cytotoxicity of selected compounds. Cells were cul-
tured with respective compounds at a concentration of 5 μM for 48 h before
growth and viability were assessed by using the MTT assay.
Conclusions
In conclusion, we have developed a straight-forward method
for the C–H arylation of benzoquinone and naphthoquinone
scaffolds. This sequential, one-pot strategy allows oxidation of
phenols and arylation under mild reaction conditions. A range
of substrates are compatible with the protocol. Other notable
features include inexpensive reagents, metal-free, moderate-to-
high yields, and operational simplicity.
[a] Reaction Conditions: Unless otherwise mentioned, all reactions were car-
ried out in accordance with the following conditions: Step 1: 1 (100 mg), m-
CPBA (2 equiv.) in CH3CN (3 mL); Step 2: TfOH (10 mol-%) and 2 (1.3 equiv.)
were added and heated to reflux for 24 h.
Based on the literature[4,5c,11] and the observed experimental
results, a plausible reaction mechanism was proposed in
Scheme 1. First the naphthols/phenols were oxidized with m-
CPBA into naphthoquinones/quinones (1′). Then, triflic acid co-
ordinates to the carbonyl oxygen of the quinones, which in-
creases the electrophilicity and assists 1,4-conjugative addition.
The electrophilic aromatic substitution of electron-rich arenes
on quinones by 1,4-addition gives intermediate B and aromati-
Experimental Section
General Information: The starting materials and HPLC grade sol-
vents were purchased from commercial suppliers and used without
purification. Commercial-grade hexanes and ethyl acetate were
used for column chromatography. Analytical thin-layer chromatog-
raphy (TLC) was performed with aluminum-backed UV F254 pre-
coated silica gel flexible plates. Melting points were measured in
open capillary tubes with a “MelTemp” melting point apparatus.
NMR spectra were recorded with 400 MHz nuclear magnetic reso-
nance spectrometers. The proton resonances are annotated as
chemical shifts (δ) relative to tetramethylsilane (δ = 0.0 ppm) with
[D]chloroform (δ = 7.26, singlet) or the residual solvent signal as an
internal standard with multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br., broad); coupling constant; and the num-
ber of protons for a given resonance, indicated by nH. The chemical
shifts reported for 13C NMR spectroscopic data are relative to the
central line of the triplet at δ = 77.0 ppm for CDCl3. High-resolution
mass spectra (HRMS) were measured by means of electrospray ioni-
zation (ESI, 70 eV, ion trap) technique.
General Experimental Procedure for Sequential One-pot Aryl-
ation of Quinones (3a–3x): m-Chloroperbenzoic acid (2 equiv.) was
added to a solution of 1a (100 mg, 1 equiv.) in acetonitrile (5 mL)
and stirred at room temp. and open to the atmosphere for 2 h.
Scheme 1. Proposed reaction mechanism.
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After the reaction was complete (reaction monitored by TLC), 2a
185.1, 149.2, 147.3, 133.4, 133.2, 132.9, 132.3, 131.0 (2 C), 130.4,
(1.3 equiv.) and TfOH (10 mol-%) were added and the reaction mix- 126.8, 125.5, 119.7, 111.5 (2 C), 47.4 (2 C), 25.4 (2 C) ppm. HRMS
ture was heated to reflux for 24 h. After the reaction was complete
the reaction mixture was poured into ice-cold water (25 mL) and
extracted with ethyl acetate (2 × 25 mL). The combined organic
layer was washed with brine (1 × 20 mL), dried with sodium sulfate,
and evaporated under vacuum to give the crude product. The crude
residue was purified by flash column chromatography (hexanes/
ethyl acetate, 20:1) to afford compound 3a (165 mg, 87 %).
(ESI): calcd. for [M + 1]+ C20H18NO2 304.1332; found 304.1332.
2-[4-(Methylamino)phenyl]naphthalene-1,4-dione (3g): Purple
1
solid, 89 % yield. M.p. 135–137 °C. H NMR (CDCl3, 400 MHz): δH
=
8.15–8.12 (m, 1 H), 8.08–8.06 (m, 1 H), 7.74–7.71 (m, 2 H), 7.54–7.51
(m, 2 H), 6.99 (d, J = 1.6 Hz, 1 H), 6.64 (dd, J = 8.8, 1.2 Hz, 2 H), 2.88
(d, J = 1.6 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.1 (2
C), 150.9, 147.3, 133.4, 133.3, 132.7, 132.1, 131.3, 131.0 (2 C), 126.8,
125.5, 111.9 (2 C), 30.2 (2 C) ppm. HRMS (ESI): calcd. for [M + 1]+
C17H13NO2 264.1019; found 264.1019.
2-[4-(Dimethylamino)phenyl]naphthalene-1,4-dione (3a): Purple
solid, 87 % yield. M.p. 96–98 °C. 1H NMR (CDCl3, 400 MHz): δH
=
8.17–8.13 (m, 1 H), 8.10–8.06 (m, 1 H), 7.75–7.70 (m, 2 H), 7.59 (d,
J = 7.2 Hz, 2 H), 7.01 (s, 1 H), 6.75 (d, J = 8.8, 2.0 Hz, 2 H) 3.03 (s, 6
H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.4, 185.1, 151.6, 147.3,
133.4, 133.3, 132.8, 132.2, 131.0, 130.9 (2 C), 126.8, 125.6, 120.4,
111.6 (2 C), 40.0 (2 C) ppm. HRMS (ESI): calcd. for [M + 1]+
C18H16NO2 278.1173; found 278.1175.
2-[4-(Benzylamino)phenyl]naphthalene-1,4-dione (3h): Purple
solid, 85 % yield. M.p. 114 °C. 1H NMR (CDCl3, 400 MHz): δH = 8.13–
8.08 (m, 1 H), 8.07–8.03 (m, 1 H), 7.73–7.67 (m, 2 H), 7.50–7.47 (m,
2 H), 7.34–7.23 (m, 5 H), 6.95 (s, 1 H), 6.64 (d, J = 8.8 Hz, 2 H), 4.60
(br. s, 1 H), 4.35 (s, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.2,
185.1, 149.8, 147.2, 138.52, 133.4, 133.3, 132.7, 132.1, 131.4, 131.0
(2 C), 128.6 (2 C), 127.3, 127.2 (2 C), 126.7, 125.5, 121.8, 112.3 (2 C),
47.6 (2 C) ppm. HRMS (ESI): calcd. for [M + 1]+ C23H18NO2 340.1333;
found 340.1332.
2-[4-(Dibenzylamino)phenyl]naphthalene-1,4-dione (3b): Purple
1
solid, 81 % yield. M.p. 144–146 °C. H NMR (CDCl3, 400 MHz): δH
=
8.14–8.11 (m, 1 H), 8.08–8.05 (m, 1 H), 7.72–7.68 (m, 2 H), 7.51 (d,
J = 9.2 Hz, 2 H), 7.35–7.22 (m, 10 H), 6.97 (s, 1 H), 6.79 (d, J = 8.4 Hz,
2 H), 4.71 (s, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.3, 185.1,
150.7, 147.1, 137.5 (2 C), 133.5, 133.3, 132.7, 132.2, 131.3, 131.1 (2
C), 128.7 (4 C), 127.1 (2 C), 126.8, 126.4 (4 C), 125.6, 121.1, 112.0 (2
2-[4-(Decylamino)phenyl]naphthalene-1,4-dione (3i): Purple
solid, 71 % yield. M.p. 81–83 °C. 1H NMR (CDCl3, 400 MHz): δH
=
8.12–8.01 (m, 1 H), 8.06–8.02 (m, 1 H), 7.72–7.67 (m, 2 H), 7.50 (d,
J = 8.4 Hz, 2 H), 6.95 (d, J = 0.8 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 2 H),
C), 53.9 (2 C) ppm. HRMS (ESI): calcd. for [M + 1]+ C30H24NO2 4.20 (br. s, 1 H), 3.11 (t, J = 6.8 Hz, 2 H), 1.60 (qui, J = 14.8, 7.6 Hz,
430.1802; found 430.1802.
2 H), 1.43–1.25 (m, 14 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δC = 185.2, 184.9, 150.2, 147.1, 133.3, 133.1, 133.0,
132.7, 132.9, 132.0, 131.0 (2 C), 130.8, 126.7, 125.4, 121.2, 112 (2 C),
43.3, 32.7, 29.4 (2 C), 29.3, 29.2, 29.1, 26.9, 22.5, 13.9 ppm. HRMS
(ESI): calcd. for [M + 1]+ C26H32NO2 390.2429; found 390.2427.
2-{4-[Benzyl(methyl)amino]phenyl}naphthalene-1,4-dione (3c):
Brown solid, 79 % yield. M.p. 172–174 °C. 1H NMR (CDCl3, 400 MHz):
δH = 8.11–8.09 (m, 1 H), 8.04–8.02 (m, 1 H), 7.69–7.67 (m, 2 H), 7.54
(d, J = 8.8 Hz, 2 H), 6.97 (s, 1 H), 6.93 (d, J = 8.8 Hz, 2 H) 4.13 (d, J =
2.4 Hz, 4 H), 2.21 (t, J = 2.4 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz):
δC = 185.2, 185.0, 148.9, 147.2, 133.6, 133.5, 132.7, 132.6, 132.2,
130.8 (2 C), 126.9, 125.8, 123.6, 114.2 (2 C), 78.6, 72.9, 40.13 ppm.
HRMS (ESI): calcd. for [M + 1]+ C22H16NO2 326.1177; found 326.1175.
2-(3,4,5-Trimethoxyphenyl)naphthalene-1,4-dione (3j): Yellow
1
solid, 79 % yield. M.p. 106–108 °C. H NMR (CDCl3, 400 MHz): δH
=
8.167–8.11 (m, 2 H), 7.76 (q, J = 5.6, 3.6 Hz, 2 H), 6.97 (d, J = 8.0 Hz,
2 H), 6.74 (d, J = 8.8 Hz, 1 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.85 (s, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.1, 185.4, 155.3, 151.9,
147.9, 142.0, 136.1, 133.7, 133.5, 132.6, 132.6, 126.9, 126.0, 124.8,
120.8, 107.0, 60.7, 56.0, 61.1 ppm. HRMS (ESI): calcd. for [M + Na]+
2-{4-[Methyl(pentyl)amino]phenyl}naphthalene-1,4-dione (3d):
Purple sticky solid, 75 % yield. 1H NMR (CDCl3, 400 MHz): δH = 8.15–
8.12 (m, 1 H), 8.08–8.06 (m, 1 H), 7.73–7.70 (m, 2 H), 7.58 (d, J = C19H16O5Na 347.0892; found 347.0889.
9.2 Hz, 2 H), 6.99 (s, 1 H), 6.70 (d, J = 9.2 Hz, 2 H), 3.35 (t, J = 7.6 Hz,
2-(2,4-Dimethoxyphenyl)naphthalene-1,4-dione (3k): Yellow
2 H), 3.00 (s, 3 H), 1.60 (qui, J = 11.6, 7.2 Hz, 2 H), 1.42–1.25 (m, 4
1
solid, 72 % yield. M.p. 145–147 °C. H NMR (CDCl3, 400 MHz): δH
=
H), 0.91 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δC
=
8.16–8.08 (m, 2 H), 7.76–7.72 (m, 2 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.03
(s, 1 H), 6.58–6.54 (m, 2 H), 3.85 (s, 3 H), 3.77 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δC = 185.7, 183.9, 162.2, 158.5, 147.3, 136.1, 133.5,
133.4, 132.6, 132.1, 131.6, 126.8, 125.8, 115.8, 104.6, 98.9, 55.6,
55.4 ppm. HRMS (ESI): calcd. for [M + Na]+ C18H14O4 Na 317.0785;
found 317.0784.
185.4, 185.0, 150.5, 147.1, 133.4, 133.2, 132.8, 132.2, 131.0 (2 C),
130.5, 126.7, 125.6, 119.8, 111.2 (2 C), 52.3, 38.2, 29.1, 26.4, 22.5,
14.0 ppm. HRMS (ESI): calcd. for [M + 1]+ C22H24NO2 334.1802; found
334.1801.
2-{4-[Decyl(methyl)amino]phenyl}naphthalene-1,4-dione (3e):
Purple solid, 70 % yield. M.p. 50–52 °C. 1H NMR (CDCl3, 400 MHz):
δH = 8.15–8.13 (m, 1 H), 8.10–8.06 (m, 1 H), 7.73–7.69 (m, 2 H), 7.58
(d, J = 8.8 Hz, 2 H), 7.00 (s, 1 H), 6.70 (d, J = 9.2 Hz, 2 H), 3.36 (t, J =
7.6 Hz, 2 H), 3.00 (s, 3 H), 1.59 (m, 2 H), 1.31–1.25 (m, 14 H), 0.88 (t,
J = 6.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.4, 185.1,
150.5, 147.2, 133.4, 133.2, 132.8, 132.2, 131.0 (2 C), 130.6, 126.8,
125.5, 119.8, 111.3 (2 C), 52.3, 38.2, 31.8, 29.6, 29.5, 29.4, 29.2, 27.0,
26.7, 22.6, 14.0 ppm. HRMS (ESI): calcd. for [M + 1]+ C27H34NO2
404.2585; found 404.2584.
2-(4-Methoxyphenyl)naphthalene-1,4-dione (3l): Yellow solid,
1
70 % yield. M.p. 117–119 °C. H NMR (CDCl3, 400 MHz): δH = 8.18–
8.16 (m, 1 H), 8.12–8.09 (m, 1 H), 7.78–7.74 (m, 2 H), 7.58 (d, J =
8.4 Hz, 2 H), 7.04 (s, 1 H), 6.99 (d, J = 8.4 Hz, 2 H), 3.87 (s, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δC = 185.1, 184.8, 161.3, 147.3, 133.7 (2
C), 133.6, 132.5, 132.1, 131.0 (2 C), 126.9, 125.8, 125.6, 114.0 (2 C),
55.3 ppm. HRMS (ESI): calcd. for [M + Na]+ C17H12O3Na 287.0681;
found 287.0678.
2-(1H-Indol-3-yl)naphthalene-1,4-dione (3m): Red solid, 92 %
1
2-[4-(Pyrrolidin-1-yl)phenyl]naphthalene-1,4-dione (3f): Purple
yield. M.p. 198–200 °C. H NMR (CDCl3, 400 MHz): δH = 8.78 (br. s,
1
solid, 88 % yield. M.p. 193–195 °C. H NMR (CDCl3, 400 MHz): δH
=
1 H), 8.25 (d, J = 2.8 Hz, 1 H), 8.18–8.15 (m, 1 H), 8.14–8.11 (m, 1 H),
8.16–8.13 (m, 1 H), 8.12–8.06 (m, 1 H), 7.74–7.69 (m, 2 H), 7.59 (d,
8.01–7.97 (m, 1 H), 7.78–7.72 (m, 2 H), 7.49–7.45 (m, 2 H), 7.32–7.26
J = 8.8 Hz, 2 H), 6.99 (s, 1 H), 6.59 (d, J = 8.8 Hz, 2 H) 3.33–3.36 (m (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.5, 185.3, 142.0,
4 H), 2.01–2.04 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 185.5,
136.3, 133.7, 133.2, 132.8, 132.2, 130.9, 129.7, 126.8, 125.7, 123.3,
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121.8, 120.4, 111.9, 108.9 ppm. HRMS (ESI): calcd. for [M + 1]+ C), 126.3 (4 C), 119.8, 112.2 (2 C), 54.0 (2 C) ppm. HRMS (ESI): calcd.
C18H12NO2 274.0863; found 274.0862.
for [M + 1]+ C30H23N2O4 475.1654; found 475.1652.
2-(2-Phenyl-1H-indol-3-yl)naphthalene-1,4-dione (3n): Red solid,
82 % yield. M.p. 210–212 °C. 1H NMR (CDCl3, 400 MHz): δH = 9.03
(br. s, 1 H), 8.12 (dd, J = 8.0, 1.6 Hz, 1 H), 7.68 (td, J = 8.0, 1.6 Hz, 1
H), 7.74 (td, J = 7.6, 1.6 Hz, 2 H), 7.63–7.60 (m, 1 H), 7.43–7.30 (m, 3
H), 7.29–7.20 (m, 5 H), 7.19 (s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz):
δC = 185.17, 184.1, 145.0, 139.3, 136.2, 135.8, 133.6, 133.4, 132.8,
132.5, 132.2, 128.9 (2 C), 128.3, 128.1, 128.0 (2 C), 126.9, 125.8, 123.0,
121.2, 119.4, 111.4 ppm. HRMS (ESI): calcd. for [M + 1]+ C24H16NO2
350.1177; found 350.1175.
2-[4-(Methylamino)phenyl]-8-nitronaphthalene-1,4-dione (3u):
Purple solid, 71 % yield. M.p. 208–210 °C. 1H NMR (CDCl3, 400 MHz):
δ
H = 8.28 (dd, J = 7.6, 1.2 Hz, 1 H), 7.84 (t, J = 8.0 Hz, 1 H), 7.76 (dd,
J = 7.2, 2.0 Hz, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.05 (s, 1 H), 6.65 (d,
J = 8.0 Hz, 2 H), 2.90 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δC
=
182.9, 182.4, 151.4, 148.3, 133.9, 133.4, 131.3 (2 C), 131.0, 128.8,
128.4, 127.2, 125.4, 120.45, 112.3 (2 C), 30.3 ppm. HRMS (ESI): calcd.
for [M + 1]+ C17H13N2O4 309.0867; found 309.0869.
4′-(Dibenzylamino)-[1,1′-biphenyl]-2,5-dione (3v): Purple solid,
1
2-(1H-Pyrrol-2-yl)naphthalene-1,4-dione (3o): Red solid, 78 %
71 % yield. M.p. 89–91 °C. H NMR (CDCl3, 400 MHz): δH = 7.42 (d,
1
yield. M.p. 118–120 °C. H NMR (CDCl3, 400 MHz): δH = 10.95 (br. s,
J = 9.2 Hz, 2 H), 7.37–7.22 (m, 10 H), 6.80–6.78 (m, 5 H) 4.72 (s, 4
H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 187.7 (2 C), 150.8, 145.0,
137.4, 136.9, 136.2 (2 C), 130.9 (2 C), 128.8 (4 C), 128.6, 127.2 (2 C),
126.5 (4 C), 120.5, 112.1 (2 C), 53.9 (2 C) ppm. HRMS (ESI): calcd. for
[M + 1]+ C26H22NO2 380.1646; found 380.1645.
1 H), 8.12–8.06 (m, 2 H), 7.77–7.69 (m, 3 H), 7.12–7.11 (m, 2 H), 6.98–
6.96 (m, 1 H), 6.36–6.34 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz):
δC = 185.0, 184.5, 138.6, 134.2, 133.9, 133.2, 132.1, 126.6, 126.3,
125.9, 125.7, 125.6, 124.5, 113.3, 111.1 ppm. HRMS (ESI): calcd. for
[M + 1]+ C14H10NO2 224.0707; found 224.0706.
4′-(Pyrrolidin-1-yl)-[1,1′-biphenyl]-2,5-dione (3w): Purple solid,
1
2-[4-(Dibenzylamino)phenyl]-8-hydroxynaphthalene-1,4-dione
(3p): Purple solid, 71 % yield. M.p. 142–143 °C. 1H NMR (CDCl3,
400 MHz): δH = 12.23 (s, 1 H) 7.61–7.57 (m, 2 H), 7.48 (d, J = 9.2 Hz,
2 H), 7.36–7.23 (m, 10 H), 6.91 (s, 1 H), 6.80 (d, J = 9.2 Hz, 2 H), 4.72
(s, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δC = 190.8, 184.2, 161.8 (2
C), 150.8, 147.3, 137.3 (2 C), 136.3, 132.4, 132.3, 131.1 (2 C), 128.8
(4 C), 127.1 (2 C), 126.4 (4 C), 124.0, 120.5, 118.3, 112.0 (2 C), 54.0
(2 C) ppm. HRMS (ESI): calcd. for [M + 1]+ C30H24NO3 446.1752;
found 446.1750.
78 % yield. M.p. 76–78 °C. H NMR (CDCl3, 400 MHz): δH = 7.49 (d,
J = 9.2 Hz, 2 H), 6.80–6.73 (m, 3 H), 6.59 (d, J = 9.2 Hz, 2 H), 3.37–
3.33 (m, 4 H), 2.05–2.02 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz):
δC = 187.9, 187.7, 149.1, 145.2, 136.9, 136.2, 130.8 (2 C), 119.2, 111.7
(2 C), 47.6 (2 C), 25.4 (2 C) ppm. HRMS (ESI): calcd. for [M + 1]+
C16H16NO2 254.1175; found 254.1175.
3′,4′,5′-Trimethoxy-[1,1′-biphenyl]-2,5-dione (3x): Yellow solid,
75 % yield. M.p. 76–77 °C. 1H NMR (CDCl3, 400 MHz): δH = 6.87–6.67
(m, 4 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.81 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δC = 187.5, 186.0, 155.37, 151.7, 145.6, 141.8,
136.8, 136.1, 133.6, 124.7, 119.9, 106.9, 60.9, 60.5, 55.9 ppm. HRMS
(ESI): calcd. for [M + Na]+ C15H14O5Na 297.0732; found 297.0733.
2-[4-(Dibenzylamino)phenyl]-7-hydroxynaphthalene-1,4-dione
(3q): Purple oil, 70 % (3:1) yield. 1H NMR (CDCl3, 400 MHz): δH
=
8.07 (d, J = 8.4 Hz, 1 H), 7.53–7.50 (m, 3 H), 7.36–7.32 (m, 4 H), 7.29–
7.23 (m, 7 H), 7.15 (dd, J = 8.8, 2.8 Hz, 1 H), 7.00 (br. s, 1 H), 6.93 (s,
1 H), 6.80 (d, J = 9.2 Hz, 2 H), 4.72 (s, 4 H) ppm. 13C NMR (CDCl3,
100 MHz): δC = 185.4, 184.2, 160.9, 150.8, 147.7, 137.5 (2 C), 134.4,
131.3 (2 C), 130.9, 130.8, 130.0, 128.8 (4 C), 127.2 (2 C), 126.4 (4 C),
126.2, 121.4, 120.5, 112.0, 111.7, 54.0 (2 C) ppm. HRMS (ESI): calcd.
for [M + 1]+ C30H24NO3 446.1742; found 446.1740.
Acknowledgments
We gratefully acknowledge the financial support from Ministry
of Science and Technology (MOST) and thank the Centre for
Research Resources and Development of Kaohsiung Medical
University for 400 MHz NMR analyses.
2-[4-(Dimethylamino)phenyl]-8-methoxynaphthalene-1,4-dione
(3r): Purple solid, 81 % yield. M.p. 101–103 °C. 1H NMR (CDCl3,
400 MHz): δH = 7.82 (dd, J = 7.6, 1.2 Hz, 1 H) 7.67 (t, J = 8.0 Hz, 1
H), 7.61–7.57 (m, 2 H), 7.30 (dd, J = 8.4, 0.8 Hz, 1 H), 6.94 (s, 1 H),
6.77 (d, J = 8.4 Hz, 2 H), 4.02 (s, 3 H), 3.04 (s, 6 H) ppm. 13C NMR
(CDCl3, 100 MHz): δC = 185.5, 184.8, 159.1, 145.0, 147.5, 134.3, 131.3
(2 C), 130.7, 129.3, 128.0, 126.4, 120.1, 111.7, 110.3, 108.7 (2 C), 55.86
(2 C), 40.1 ppm. HRMS (ESI): calcd. for [M + 1]+ C19H18NO3 308.1283;
found 308.1281.
Keywords: Synthetic methods · Metal-free · Quinones ·
Cytotoxicity · Triflic acid
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(3s): Purple solid, 79 % yield. M.p. 99–100 °C. 1H NMR (CDCl3,
400 MHz): δH = 8.09 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 9.2 Hz, 2 H),
7.51 (d, J = 2.8 Hz, 1 H), 7.18 (dd, J = 8.4, 2.8 Hz, 1 H), 6.97 (s, 1 H),
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131.2 (2 C), 131.1 (2 C), 128.8 (4 C), 128.6 (2 C), 128.3 (2 C), 127.2 (2
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Received: February 2, 2016
Published Online: March 29, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim