One-Pot Synthesis of 1-Hydroxyacridones from para-Quinols and ortho-Methoxycarbonylaryl Isocyanates

Article abstract of DOI:10.1021/acs.joc.9b03307

A variety of substituted acridones were synthesized via a one-pot, metal-free cascade reaction. In this event, the DBU-mediated addition between quinols and ortho-methoxycarbonylaryl isocyanates formed a bicyclic oxazolidinone, followed by a sequence of intramolecular condensation, tautomerization, and decarboxylation, which led to the formation of acridones. The acridones showed mild activity against the human cytomegalovirus.

Full text of DOI:10.1021/acs.joc.9b03307

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Note
One-Pot Synthesis of 1‑Hydroxyacridones from para-Quinols and
ortho-Methoxycarbonylaryl Isocyanates
Jing Wu, Jinzhu Zhang, Ruben Soto-Acosta, Lili Mao, Jiahui Lian, Kenny Chen, Guy Pillon,
Guoqi Zhang, Robert J. Geraghty, and Shengping Zheng*
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ABSTRACT: A variety of substituted acridones were synthesized via a
one-pot, metal-free cascade reaction. In this event, the DBU-mediated
addition between quinols and ortho-methoxycarbonylaryl isocyanates
formed a bicyclic oxazolidinone, followed by a sequence of intramolecular
condensation, tautomerization, and decarboxylation, which led to the
formation of acridones. The acridones showed mild activity against the
human cytomegalovirus.
The synthesis of multiple substituted 1-hydroxyacridones is
cridones are a subclass of acridines with a carbonyl group
Aat the 9 position (10H-acridin-9-one). Acridines have
still challenging; for example, the known synthetic routes to 1-
hydroxy-4-alkylacridone are lengthy and low-yielding13
(Scheme 1a). We report herein a rapid synthesis of substituted
1-hydroxyacridones via a one-pot condensation of quinols and
become well-known anticancer agents.1−3 Acridones are key
intermediates for the synthesis of acridines.4 Moreover,
acridones are important synthetic targets because of their
selective inhibition of diverse human pathogenic viruses.5−9 In
recent years, both naturally occurring and synthetic 1-
hydroxyacridones were found to be selective inhibitors of
both DNA and RNA viruses. For example, citrusinine-I
exhibits potent activity against the herpes simplex virus
(HSV);10 compound A is an inhibitor of the human
cytomegalovirus (HCMV);6 compound B shows inhibitory
activity of the bovine viral diarrhea virus (BVDV) and hepatitis
C virus (HCV);8 and RD6-5071 is a selective anti-HIV agent11
(Figure 1). Though the mechanism of action of these antiviral
compounds is not known, it seems that the hydroxyl group and
the carbonyl group are critical for the bioactivity from the
pattern of the substitution.12
Scheme 1. Synthetic Routes to 1-Hydroxy-4-alkylacridones
Received: December 9, 2019
Published: February 19, 2020
Figure 1. Antiviral 1-hydroxyacridones.
https://dx.doi.org/10.1021/acs.joc.9b03307
© 2020 American Chemical Society
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Note
ortho-(methoxycarbonyl)aryl isocyanates via a carbamation/
Michael addition/mixed Claisen condensation/decarboxylative
aromatization cascade (Scheme 1b). It should be noted that
our method is suitable for the synthesis of substituted 4-alkyl
or 4-arylacridones, and hence, it could not be applied to the
synthesis of the structures in Figure 1.
Quinols are 2,5-cyclohexadienones, which serve as useful
synthetic building blocks.14 They can be made in one step via
the dearomatization of para-substituted phenols.15,16 Recently,
we were interested in new methodology development from the
nucleophilic addition to 2,5-cyclohexadienones.16−19 From our
preliminary results in the synthesis of oxazolidinones from
isocyanates,16 we envisioned that acridones could be
synthesized from quinols and commercial ortho-methoxycar-
bonylphenyl isocyanate via a carbamation/Michael addition/
mixed Claisen condensation/decarboxylative aromatization
sequence (Scheme 2a). In our strategy, quinols act as a
DBU and refluxed in toluene, 5a was obtained in a quantitative
yield. Structures of 4a and 5a were confirmed by X-ray
diffraction analysis (cf the Supporting Information).
With the initial results in hand, we focused our efforts on the
effective conversion of 1 to 5 via a homogeneous one-pot
procedure, and the results are summarized in Table 1. When
excess NaOMe was used after the formation of oxazolidinone
3a, 79% of 4a was obtained along with 3% of acridone 5a
(entry 1). An improvement followed by applying toluene as the
solvent (entry 2), the addition of a stoichiometric amount
DBU seemed to facilitate the formation of enol 4a and the
following decarboxylation to afford acridone 5a (entries 3 and
4); microwave (μW) radiation provided a comparable yield
with a higher efficiency (entry 5), whereas bulkier alkyl
substituents resulted in lower yields of acridones 5b and 5c
(entries 7 and 10). Heating under reflux failed to improve
yields of 5b and 5c even with the application of prolonged
reaction times (entries 8 and 11). Optimization led to the use
of sealed tube conditions at 130 °C for 6 h and proved to be
reliable to deliver acridones 5a−c (entries 6, 9, and 12).
Under the optimized reaction conditions (sealed tube, 130
°C, 6 h, toluene) using a wide range of quinols, we explored
the scope of this one-pot acridone synthesis with ortho-
substituted phenyl isocyanate 2a. Representative results are
summarized in Table 2. Generally, 1-hydroxyacridones 5a−5i
were formed with good to excellent overall yields (entries 1−
9). For sterically hindered quinols 1j and 1k (entries 10 and
11), acridones 5j and 5k were obtained in moderate yields. For
quinol 1l, the desired acridone 5l was obtained in a good yield
(entry 12). Unlike quinol 11, where Michael addition occurred
at the less substituted double bond, Michael addition took
place at the more substituted sp2 hybridized carbon of quinol
1m, presumably due to the release of the ring strain,27 to afford
a pentacyclic product 4m (entry 13). For quinols 1n−1q with
a substituent other than the alkyl group on the double bond,
acrdiones 5n−5q were obtained in moderate to good yields.
For hydroxylcyclohexenones 1r and 1s, acridones 5r and 5s
were obtained in moderate to good yields through an
elimination/aromatization mechanism (entries 18 and 19).
Annelated quinol 1t afforded acridone 5t in a good yield27b
(entry 20). However, quinols 1u and 1v led to oxazoloacri-
dones 4u and 4v in moderate yields (entries 21 and 22).
Compounds 4u and 4v were obtained because the
aromatization could not be easily achieved. For quinol 1w
with a strong electron-withdrawing methoxycarbonyl, acridone
5a was formed in 64% yield; presumably, the Michael addition
occurred on the more electrophilic double bond, followed by
demethoxycarboxylation through a methanol attack to produce
the acridone 5a instead (entry 23). Although tetracyclic
intermediates were isolated (entries 21 and 22) when the α-
carbon or β-carbon was substituted by a methyl group so that
the decarboxylation/aromatization step was blocked; decar-
boxylative demethylation could occur when the system was
overheated to give 3,4-dimethyl acridone 5i from 3,4,5
trimethyl quinol 1v. These results strongly support the
proposed mechanism.
Scheme 2. Synthetic Strategy
regiospecifically differentiated equivalent of benzynes20−25
(Scheme 2b). In contrast to substituted benzynes,26 quinols
are more readily prepared and have controlled regiospecific
chemistry.
To test our idea, the addition of 0.15 equiv of 1,8-
diazabicycloundecene (DBU) to a solution of premixed quinol
1a (RCH3) and commercially available ortho-
(methoxycarbonyl)phenyl isocyanate 2 in cold CH2Cl2 and a
further reaction at room temperature for 1 h resulted in
complete consumption of 1a to form the Michael addition
intermediate 3a (RCH3); no new spot appeared on the thin-
layer chromatography (TLC) after stirring 6 h at room
temperature or under reflux for another 20 h. Eventually, after
removal of the solvent, the addition of 1.1 equiv of NaOMe in
THF to the reaction mixture at room temperature and
refluxing for 6 h produced acridone 5a (RCH3) in a trace
amount and enol 4a (RCH3) in 42% yield along with
recovery of 19% of oxazolidinone 3a (RCH3) (see Table S1
in the Supporting Information). When 4a was treated with
We further investigated the substrate scope of this reaction
in terms of the substituted phenyl isocyanates. To this end,
commercial anilines were transformed into the corresponding
isocyanates, which were trapped with quinol 1b to furnish the
acridone transformation. A typical procedure involved the
reaction of a disubstituted aniline with 0.4 equiv of triphosgene
in a mixture of saturated aqueous NaHCO3 and CH2Cl2 in an
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Note
Table 1. Optimization of the Reaction Conditions
a
b
c
entry
quinol 1 (R)
base (equiv)
solvent
temp (°C)
condition/time (h)
% yield of 5 (4)
d
1
R = Me
R = Me
R = Me
R = Me
R = Me
R = Me
R = Et
R = Et
R = Et
R = c-Hex
R = c-Hex
R = c-Hex
DBU (0.15)/NaOMe (2.2)
DBU (0.15)
DBU (1.1)
DBU (2.2)
DBU (2.2)
DBU (2.2)
DBU (2.2)
DBU (2.2)
DBU (2.2)
CH2Cl2/THF
RT/66
reflux (12)
reflux (12)
reflux (12)
reflux (12)
μW (1)
sealed tube (6)
μW (1)
reflux (20)
sealed tube (6)
μW (1)
3 (79)
44 (trace)
76 (trace)
87
81
96
83 (trace)
60 (13)
95
54 (28)
67 (18)
92
e
2
3
4
5
6
7
8
9
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
tol
RT/111
RT/111
RT/111
RT/115
RT/130
RT/115
RT/111
RT/130
RT/115
RT/111
RT/130
f
10
11
12
DBU (2.2)
DBU (2.2)
DBU (2.2)
reflux (20)
sealed tube (6)
a
The reaction was performed at room temperature until the formation of 3 along with complete consumption of 1, monitored by TLC. An elevated
b
c
temperature was then applied with a different heat source. The time required for the transformation of 3 to 5. Isolated yields of 5 and 4 from
silica gel column chromatography purification. See Table S1 in Supporting Information for a detailed experimental procedure. 3a was isolated in
13% yield. 3a was isolated in 5% yield.
d
e
f
and were recrystallized if it was applicable. Reactions were monitored
by thin-layer chromatography (TLC), which was developed on
Silicycle SiliaPlate TLC glass-backed plates with precoated silica gel
60 bearing an F-254 UV indicator and visualized by exposure to
ultraviolet light or stained with ceric ammonium molybdate, followed
by heating on a heat gun. Preparative thin-layer chromatography
(prep TLC) was done on the same TLC plates with the proper
thickness. Column chromatography was performed over silica gel with
a porosity of 60 Å and a particle size of 40−63 μm. 1H and 13C NMR
spectra were recorded on Bruker 400, 500, and 600 MHz
spectrometers. Chemical shifts (δ values) were reported in ppm
with a reference to residual solvent peaks (CHCl3 in CDCl3, 7.26
ice bath for 1 h, followed by the separation and evaporation of
the methylene chloride solvent and then the addition of quinol
1b and DBU in toluene to the in situ made arylisocyanate
under the protocol reported above. The reaction proceeded
smoothly to afford the acridones 5x−5z in good overall yields
(Scheme 3).
We conducted a preliminary screening of the antiviral
activity of several compounds synthesized by this method. It is
found that some, notably 5a, exhibited anti-HCMV activity at
10 μM, albeit with a slight reduction in cell viability. Other
compounds, such as 5c and 5h, inhibited HCMV with no
effect on cell viability (Table 3). These preliminary results
suggest, that along with the bulkiness of the alkyl substituents,
the nature and position of functionalities can be optimized for
antiviral effects. We envision that such compounds could lead
to the development of a new class of anti-HCMV molecules
with potential benefits against drug-resistant cell strains.
In summary, we have developed a highly efficient synthetic
pathway to acridones from a wide range of quinols in moderate
to excellent yields. This one-pot process represents a direct and
practical method to 1-hydoxyl-4-alkyl/aryl-acridones from
commercially available phenols in two steps. During this
process, quinols act as a traceless benzyne equivalent.
Furthermore, the acridones showed mild activity against the
human cytomegalovirus. More work on the synthesis of various
heterocycles and their antiviral activity will be reported in due
course.
1
ppm; DMSO in (CD3)2SO, 2.54 for H NMR, 77.36 and 40.45 ppm
for 13C NMR, respectively). Mass spectrometric data were measured
by the late Dr. Cliff Soll and Dr. Barney Yoo at the Hunter College
mass spectrometry facility and taken on an Agilent 6520A Q-TOF
spectrometer using electrospray ionization. The X-ray crystallography
experiments were performed on a Bruker Kappa X8 Apex II
diffractometer by Dr. Michelle Neary at the Hunter College X-ray
facility and on a Bruker AXS Smart Apex II single-crystal
diffractometer by Dr. Chunhua Hu at the Department of Chemistry,
New York University. Microwave reactions were conducted on a
CEM Discover SP reactor, where pressurized vessels were used, and
the reaction temperature was monitored by an internal probe.
Experimental Procedures. Known quinols were prepared
according to the literature procedures.15a,16,28−32 For the reported
spectral data, see: 1a, 1b, 1d, 1j;28 1c;16 1e, 1f, 1g;29 1h, 1i, 1k, 1l, 1n,
1r, 1u;15a 1o;30 1q;31 and 1s.32
General Procedure for the Synthesis of p-Quinols 1k, 1m, 1p, 1t,
and 1w (Method A).16 A solution of the corresponding alkylphenol
(1 equiv) in MeCN/H2O (3:1) was cooled to 0 °C in an ice bath, and
phenyliodine(III) diacetate (PIDA) (1.5 equiv) was added in small
portions. The reaction mixture was stirred at 0 °C until full
consumption of the starting material (monitored by TLC), then
diluted with EtOAc, and quenched with saturated aq NaHCO3, and
the layers were separated. The aqueous layer was extracted three times
with EtOAc. The organic layers were combined and washed with
water and brine, dried over Na2SO4, and then concentrated in vacuo.
The residue was purified by silica gel flash column chromatography to
provide the desired product.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under dry
nitrogen in oven-dried glassware, unless the procedure states
otherwise. Anhydrous methylene chloride (CH2Cl2) was distilled
from phosphorus pentoxide, toluene (tol) was distilled from sodium,
and tetrahydrofuran (THF) was distilled from sodium under a
nitrogen atmosphere. All reactions were performed under nitrogen
protection, and the gas exchange was done with a nitrogen balloon
and house vacuum. Reagents purchased from commercial sources
were used as received or synthesized following literature procedures
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Table 2. Substrate Scope of Quinols
4-Hydroxy-4-isopropyl-3-methylcyclohexa-2,5-dien-1-one (1k):
1.9 g, 56% yield, colorless needle-like crystals; Rf = 0.2 (EtOAc/
hexane = 1:4); mp = 65−69 °C; 1H NMR (500 MHz, CDCl3) δ 6.74
(d, J = 10.2 Hz, 1H), 5.98 (dd, J = 10.2, 1.6 Hz, 1H), 5.81 (s, 1H),
4.24 (br, s, 1H), 1.97 (s, J = 6.8 Hz, 1H), 1.85 (s, 3H), 0.98 (d, J = 7.1
Hz, 3H), 0.48 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 186.4, 163.9, 150.3, 128.9, 126.9, 74.5, 35.3, 18.1, 16.9,
16.7; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C10H14O2
167.1067, found 167.1062; [M + Na]+ calcd for C10H12O2Na
189.0886, found 189.0882.
NMR (150 MHz, CDCl3) δ 187.3, 170.1, 148.0, 128.6, 122.1, 73.5,
35.7, 28.8, 21.8; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C9H10O2 151.0754, found 151.0755.
2-Chloro-4-hydroxy-4-methylcyclohexa-2,5-dien-1-one (1p): 0.3
1
g, 57% yield, pale yellow solid; H NMR (600 MHz, CDCl3) δ 7.05
(d, J = 2.9 Hz, 1H), 6.90 (dd, J = 10.0, 2.9 Hz, 1H), 6.18 (d, J = 10.0
Hz, 1H), 2.82 (br s, 1H), 1.51 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 178.9, 152.9, 148.5, 131.7, 126.2, 69.6, 26.9; HRMS (ESI/
Q-TOF) m/z [M + H]+ calcd for C7H7ClO2 159.0207, found
159.0205.
7-Hydroxy-7-methyl-1,2,3,7-tetrahydro-4H-inden-4-one (1t): 1.5
g, 66% yield, white solid; Rf = 0.2 (EtOAc/hexane = 1:2); mp = 48−
51 °C; 1H NMR (500 MHz, CDCl3) δ 6.80 (d, J = 9.9 Hz, 1H), 5.95
(d, J = 9.9 Hz, 1H), 3.19 (br s, 1H), 2.83−2.77 (m, 1H), 2.66−2.59
(m, 1H), 2.53 (t, J = 7.5 Hz, 2H), 1.99−1.83 (m, 2H), 1.38 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 185.4, 165.7, 153.5, 136.6,
7a-Hydroxy-1,2,3,7a-tetrahydro-5H-inden-5-one (1m): 1.0 g,
44% yield, white solid; Rf = 0.2 (EtOAc/hexane = 1:2); mp = 74−
1
77 °C; H NMR (600 MHz, CDCl3) δ 6.98 (d, J = 10.0 Hz, 1H),
6.01 (d, J = 10.0 Hz, 1H), 5.90 (s, 1H), 3.07 (br s, 1H), 2.87 (t, J =
14.3 Hz, 1H), 2.46−2.41 (m, 1H), 2.26−2.18 (m, 1H), 2.04 (dd, J =
8.0, 13.4 Hz, 1H), 1.94−1.88 (m, 1H), 1.59−1.54 (m, 1H); 13C{1H}
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Note
2H), 1.75−1.72 (m, 2H), 1.64−1.57 (m, 2H), 1.21−1.13 (m, 2H),
1.09−1.00 (m, 1H), 0.93−0.85 (m, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 186.6, 151.6, 128.7, 72.2, 46.9, 27.3, 26.6, 26.5.
Scheme 3. Substrate Scope of Isocyanates
4-Hydroxy-4-propylcyclohexa-2,5-dien-1-one (1d): 0.7 g, 64%
1
yield, white solid; H NMR (400 MHz, CDCl3) δ 6.82 (d, J = 10.2
Hz, 2H), 6.19 (d, J = 10.2 Hz, 2H), 1.76−1.72 (m, 2H), 1.34−1.25
(m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3)
δ 186.4, 152.9, 127.5, 69.8, 42.0, 16.9, 14.2.
1-Hydroxy-[1,1′-biphenyl]-4(1H)-one (1e): 1.8 g, 83% yield, white
solid; 1H NMR (500 MHz, CDCl3) δ 7.49−7.47 (m, 2H), 7.39−7.36
(m, 2H), 7.34−7.31 (m, 1H), 6.90 (d, J = 10.0 Hz, 2H), 6.19 (d, J =
10.0 Hz, 2H), 3.37 (br s, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
186.4, 151.6, 138.98, 129.2, 128.7, 126.98, 125.6, 71.3.
1′-Hydroxy-4′-oxo-1′,4′-dihydro-[1,1′-biphenyl]-4-carbonitrile
1
(1f): 0.4 g, 81% yield, white solid; H NMR (400 MHz, CDCl3) δ
7.67 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 10.0
Hz, 2H), 6.26 (d, J = 10.0 Hz, 2H), 3.53 (br s, 1H); 13C{1H} NMR
(125 MHz, CDCl3) δ 185.3, 149.6, 144.2, 133.1, 128.1, 126.6, 118.7,
112.7, 71.2.
4-Hydroxy-3,4-dimethylcyclohexa-2,5-dien-1-one (1i): 2.2 g, 65%
1
yield, white solid; H NMR (500 MHz, CDCl3) δ 6.87 (d, J = 10.0
Hz, 1H), 6.09−6.06 (m, 1H), 5.97 (d, J = 1.4 Hz, 1H), 0.85 (br s,
1H), 2.08 (s, 3H), 1.44 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
186.3, 162.5, 153.2, 127.1, 126.1, 69.4, 26.3, 18.4.
Table 3. Anti-HCMV Screening and Cytotoxicity of 1-
Hydroxyacridones
4-Hydroxy-4-isopropylcyclohexa-2,5-dien-1-one (1j). Method A
was followed, and CaCO3 (3 equiv) was added to obtain 1j: 72 mg,
1
63% yield, white solid; H NMR (600 MHz, CDCl3) δ 6.81 (d, J =
a
a
compound
ganciclovir
letermovir
5a
5c
5e
5f
5h
5i
% inhibition (10 μM)
% viable cells (10 μM)
10.3 Hz, 2H), 6.17 (d, J = 10.3 Hz, 2H), 2.85 (br s, 1H), 1.98 (sept, J
= 6.9 Hz, 1H), 0.93 (t, J = 7.1 Hz, 6H).
89 1.6
86 1.5
83 2.7
50 0.1
61 2.0
17 13
46 3.7
58 5.9
13 3.0
74 4.1
78 0.8
101 3.0
104 4.6
68 2.9
104 3.0
77 6.1
100 2.5
96 2.8
79 1.4
101 2.5
86 1.9
b
4a-Hydroxy-5,6,7,8-tetrahydronaphthalen-2(4aH)-one (1l): 0.8
g, 58% yield, white solid; 1H NMR (400 MHz, CDCl3) δ 6.74 (d, J =
10.0 Hz, 1H), 5.97 (dd, J = 10.0, 2.0 Hz, 1H), 5.84 (t, J = 1.7 Hz,
1H), 3.52 (br s, 1H), 2.64 (tdd, J = 13.1, 4.9, 1.6 Hz, 1H), 2.22
(apparently d, J = 12.3 Hz, 1H), 2.05−2.00 (m, 1H), 1.97−1.82 (m,
2H), 1.58−1.54 (m, 1H), 1.32−1.18 (m, 2H).
2-Fluoro-4-hydroxy-4-methylcyclohexa-2,5-dien-1-one (1o):
0.36 g, 69% yield, orange greenish solid; 1H NMR (400 MHz,
CDCl3) δ 6.89 (dd, J = 10.0, 2.6 Hz, 1H), 6.41 (dd, J = 12.3, 2.7 Hz,
1H), 6.10 (dd, J = 10.0, 7.1 Hz, 1H), 2.90 (br s, 1H), 1.53 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 178.9 (d, J = 22.3 Hz), 153.6 (d,
J = 2.7 Hz), 152.5 (d, J = 267.5 Hz), 128.0 (d, J = 9.6 Hz), 125.9 (d, J
= 3.7 Hz), 69.7 (d, J = 8.4 Hz), 27.3 (d, J = 2.1 Hz).
4u
5x
5a′
c
76 2.0
c
a
b
Compared to DMSO-treated cells. At 1 μM. 5a′ is the N-
methylation product of 5a.
2-Bromo-4-hydroxy-4-methylcyclohexa-2,5-dien-1-one (1q): 0.7
g, 67% yield, white solid; 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J =
2.8 Hz, 1H), 6.91 (dd, J = 10.0, 2.8 Hz, 1H), 6.26 (d, J = 10.0 Hz,
1H), 2.10 (br s, 1H), 1.53 (s, 3H).
127.4, 68.1, 32.7, 29.8, 25.8, 21.8; HRMS (ESI/Q-TOF) m/z [M +
H]+ calcd for C10H12O2 165.0910, found 165.0909.
Methyl 3-Hydroxy-3-methyl-6-oxocyclohexa-1,4-diene-1-car-
boxylate (1w). Instead of PIDA, 1.5 equiv of [bis(trifluoroacetoxy)-
iodo]benzene (PIFA) was used as an oxidant. Compound 1w: 0.1 g,
4-Hydroxy-3,4,5-trimethylcyclohexa-2,5-dien-1-one (1v): 0.6 g,
1
54% yield, white solid; H NMR (500 MHz, CDCl3) δ 5.72 (s, 2H),
4.42 (br s, 1H), 1.94 (s, 6H), 1.27 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 186.2, 165.2, 125.1, 71.5, 26.3, 18.3.
1
54% yield, white solid; Rf = 0.4 (EtOAc/hexane = 1:1); H NMR
(500 MHz, CDCl3) δ 7.44 (d, J = 3.06 Hz, 1H), 6.84 (dd, J = 10.1,
3.1 Hz, 1H), 6.03 (d, J = 10.1 Hz, 2H), 3.76 (s, 3H), 3.71 (br s, 1H),
1.46 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 181.6, 164.9,
157.5, 151.7, 129.2, 127.4, 67.2, 52.7, 26.8; HRMS (ESI/Q-TOF) m/
z [M + H]+ calcd for C9H10O4 183.0652, found 183.0649; [M + Na]+
calcd for C9H10O4Na 205.0471, found 205.0471.
For known quinols, spectroscopic data were in agreement with
those previously reported in the literature. Some representative data
are reported below.
General Procedure for the Synthesis of p-Quinols 1n and 1r
(Method B).15a A solution of the corresponding phenol (1 equiv) in
MeCN/H2O (3:1) was vigorously stirred at room temperature, and a
mixture of Oxone (8 equiv) and NaHCO3 (15 equiv) was added in
small portions. A septum with an empty balloon was immediately
placed into the flask to trap the generated singlet oxygen. The mixture
was kept stirring until full consumption of the starting material
(monitored by TLC), then quenched with water, and extracted three
times with EtOAc. Combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was diluted with water, and
solid Na2S2O3 (15 equiv) was added in portions, and the mixture was
stirred for 30 min. The reaction mixture was quenched with water and
extracted with EtOAc. The combined organic layers were dried,
filtered, and concentrated in vacuo. The residue was purified by silica
gel flash column chromatography to provide the desired product.
4-Hydroxy-2-methoxy-4-methylcyclohexa-2,5-dien-1-one (1n):
4-Hydroxy-4-methylcyclohexa-2,5-dien-1-one (1a): 1.5 g, 67%
1
yield, white solid; H NMR (500 MHz, CDCl3) δ 6.88 (d, J = 10.1
Hz, 2H), 6.14 (d, J = 10.1 Hz, 2H), 2.02 (br s, 1H), 1.49 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 185.6, 152.2, 127.7, 67.6, 27.1.
4-Ethyl-4-hydroxycyclohexa-2,5-dien-1-one (1b): 0.7 g, 63%
1
yield, white solid; H NMR (400 MHz, CDCl3) δ 6.82 (d, J = 10.1
Hz, 2H), 6.20 (d, J = 10.1 Hz, 2H), 2.43 (br s, 1H), 1.82 (q, J = 7.5
Hz, 2H), 0.88 (t, J = 7.5 Hz, 3H).
1
0.2 g, 40% yield, white solid; H NMR (600 MHz, CDCl3) δ 6.87
1-Hydroxy-[1,1′-bi(cyclohexane)]-2,5-dien-4-one (1c): 1.2 g, 54%
1
(dd, J = 10.0, 2.5 Hz, 1H), 6.11 (d, J = 10.0 Hz, 1H), 5.78 (d, J = 2.1
yield, white solid; H NMR (500 MHz, CDCl3) δ 6.79 (d, J = 10.2
Hz, 2H), 6.11 (d, J = 10.2 Hz, 2H), 3.15 (br s, 1H), 1.85−1.82 (m,
Hz, 1H), 3.65 (s, 3H), 2.41 (br s, 1H), 1.51 (s, 3H); 13C{1H} NMR
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Note
(150 MHz, CDCl3) δ 181.1, 153.2, 149.9, 126.3, 119.4, 69.3, 55.2,
28.2.
109.4, 106.3, 18.0; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C14H11NO2 226.0863, found 226.0861.
3a-Hydroxy-3,3a,7,7a-tetrahydrobenzofuran-6(2H)-one (1r):28
1-Hydroxy-4,10-dimethylacridin-9(10H)-one (5a′). To a solution
of 5a (30 mg, 0.13 mmol) and methyl iodide (38 mg, 0.27 mmol) in
acetone (15 mL) at 0 °C was added potassium carbonate (44 mg,
0.32 mmol) in small portions; the reaction mixture was heated at
reflux for 10 h. After cooling, the mixture was concentrated in vacuo,
then diluted with EtOAc (10 mL), quenched by saturated aq NH4Cl
(10 mL), and then extracted with EtOAc (2 × 10 mL). The organic
layer was combined and washed with water (20 mL) and brine (20
mL), dried over Na2SO4, and then concentrated in vacuo to provide
N-methyl acridone 5a′ (30 mg, 0.12 mmol, 92%) as a yellow solid
without further purification: Rf = 0.5 (THF/hexane = 1:2); mp =
1
0.1 g, 38% yield, white solid; H NMR (400 MHz, CDCl3) δ 6.74
(dd, J = 10.2, 1.5 Hz, 1H), 5.96 (dd, J = 10.2 Hz, 1H), 4.22−4.19 (m,
1H), 4.06−4.00 (m, 1H), 3.93−3.87 (m, 1H), 3.39 (br s, 1H), 2.75
(dd, J = 16.9, 4.7 Hz, 1H), 2.57 (dd, J = 16.9, 5.5 Hz, 1H), 2.30 (ddd,
J = 15.0, 8.4, 6.6 Hz, 1H), 2.21−2.15 (m, 1H).
Methyl 2-(7a-Methyl-2,5-dioxo-3a,4,5,7a-tetrahydrobenzo[d]-
oxazol-3(2H)-yl)benzoate (3a). To a solution of quinol 1a (60 mg,
0.48 mmol) and 2a (94 mg, 0.53 mmol) in CH2Cl2 (5 mL) was added
DBU (11 mg, 0.07 mmol) dropwise, the reaction mixture was stirred
at an ambient temperature for 30 min until the complete consumption
of p-methyl quinol, monitored by TLC analysis. The reaction mixture
was diluted with EtOAc (5 mL), quenched by saturated aq NH4Cl
(10 mL), and then extracted with EtOAc (2 × 10 mL). The organic
layer was combined and washed with water (20 mL) and brine (20
mL), dried over Na2SO4, and then concentrated in vacuo. The residue
was purified by silica gel flash column chromatography to provide
oxazolidinone 3a (122 mg, 0.41 mmol, 84%) as colorless needle-like
1
114.5−117 °C; H NMR (600 MHz, CDCl3) δ 14.19 (s, 1H), 8.36
(dd, J = 8.0, 1.5 Hz, 1H), 7.74−7.72 (m, 1H), 7.45 (d, J = 8.6 Hz,
1H), 7.39 (d, J = 8.3 Hz, 1H), 7.29−7.26 (m, 1H), 6.67 (d, J = 8.3
Hz, 1H), 3.89 (s, 3H), 2.56 (s, 3H); 13C{1H} NMR (125 MHz,
(CD3)2SO) δ 183.5, 161.6, 146.4, 146.0, 140.5, 134.7, 126.7, 122.0,
121.96, 116.6, 114.6, 112.3, 109.1, 43.3, 22.9; HRMS (ESI/Q-TOF)
m/z [M + H]+ calcd for C15H13NO2 240.1019, found 240.1022.
General Procedure for the Preparation of 1-Hydroxyacridones
5a−5t, 4m, 4u, and 4v (Method C). A Fisherbrand 6 dr. screw
thread vial with a pulp/polyvinyl lined cap was used as the sealed
tube. The use of safety shields and/or other safety equipment is
recommended. To a mixture of p-quinol 1 (1 equiv) and methyl 2-
isocyanatobenzoate 2a (1.1 equiv) in 3 mL of toluene was added 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (2.2 equiv) dropwise at an
ambient temperature; the reaction mixture was allowed to stir until
the complete consumption of the p-quinol 1, monitored by TLC,
usually within 1 h, after which the reaction vial was heated in an oil
bath to 130 °C for 6 h, or specified otherwise. The product 1-
hydroxyacridone 5 can be monitored by TLC under UV light and as a
yellow spot under visible light. After the time required, the reaction
mixture was diluted with EtOAc (5 mL) and quenched with 1 M HCl
(10 mL), and layers were separated. The aqueous layer was extracted
with EtOAc (2 × 10 mL). The organic layers were combined and
washed with brine (15 mL) and water (15 mL), dried over Na2SO4,
and then concentrated in vacuo. The residue was added to 1 mL of
CH2Cl2; sonication was applied, and then the residue was filtered out
1
crystals: Rf = 0.2 (EtOAc/hexane = 1:1); mp = 121−126 °C; H
NMR (500 MHz, CDCl3) δ 8.03 (dd, J = 7.8, 1.0 Hz, 1H), 7.56 (td, J
= 7.7, 1.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H),
6.66 (dd, J = 10.4 1.5 Hz, 1H), 6.19 (d, J = 10.4 Hz, 1H), 4.63 (br s,
1H), 3.86 (s, 3H), 2.62 (dd, J = 17.5, 4.1 Hz, 1H), 2.56 (dd, J = 17.5,
2.1 Hz, 1H), 1.78 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
194.6, 166.0, 156.0, 145.7, 135.7, 133.8, 132.6, 130.9, 129.3, 129.1,
128.9, 63.7, 52.8, 36.8, 29.9, 23.4; HRMS (ESI/Q-TOF) m/z [M +
H]+ calcd for C16H15NO5 302.1023, found 302.1011; [M + Na]+
calcd for C16H15NO5Na 324.0842, found 324.0839.
5-Hydroxy-2a-methyl-2a,2a1-dihydro-1H,6H-oxazolo[5,4,3-de]-
acridine-1,6-dione (4a). To a solution of quinol 1a (50 mg, 0.4
mmol) and methyl 2-isocyanatobenzoate 2a (78 mg, 0.44 mmol) in
CH2Cl2 (10 mL) was added DBU (9 mg, 0.06 mmol) dropwise at an
ambient temperature. The reaction was monitored by TLC to
complete the consumption of 1a, after which the solvent was
evaporated under reduced pressure; NaOMe (48 mg, 0.89 mmol) was
added in small portions to the residue in THF at 0 °C, and the
reaction mixture was heated under reflux for 12 h. After cooling, the
mixture was diluted with EtOAc (10 mL), quenched by saturated aq
NH4Cl (10 mL), and then extracted with EtOAc (2 × 10 mL). The
organic layer was combined and washed with water (20 mL) and
brine (20 mL), dried over Na2SO4, and then concentrated in vacuo.
The residue was purified by silica gel flash column chromatography to
provide enol 4a (86 mg, 0.32 mmol, 79%) as a white solid: Rf = 0.5
through a Buchner funnel. After washing with CH2Cl2 (3 × 1 mL),
̈
the yellow solid residue was collected from the filter paper to afford
the desired product without further purification. The filtrate was
transferred into a round-bottom flask and concentrated under reduced
pressure. The residue was purified by prep TLC to afford additional
acridones. A combined total yield was reported, unless otherwise
stated.
1
(EtOAc/hexane = 1:1); mp = 187−190 °C; H NMR (500 MHz,
CDCl3) δ 13.65 (br s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 8.2
Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.53 (d, J =
10.2 Hz, 1H), 6.31 (d, J = 10.2 Hz, 1H), 4.75 (s, 1H), 1.77 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 176.6, 173.5, 153.0, 139.1,
138.0, 134.4, 129.1, 126.9, 126.3, 123.8, 123.2, 98.9, 74.2, 58.6, 28.5;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C15H11NO4 270.0761,
found 270.0737; [M + Na]+ calcd for C15H11NO4Na 292.0580, found
292.0580.
Hydroxy-4-methylacridin-9(10H)-one (5a). To a solution of enol
4a (11 mg, 0.04 mmol) in toluene (10 mL) was added DBU (12 mg,
0.08 mmol) dropwise at an ambient temperature. The reaction
mixture was heated under reflux for 5 h. After cooling, the mixture was
diluted with EtOAc (10 mL), quenched by 1 N HCl (10 mL), and
then extracted with EtOAc (2 × 10 mL). The organic layer was
combined and washed with water (20 mL) and brine (20 mL), dried
over Na2SO4, and then concentrated in vacuo. The residue was
purified by prep TLC to provide 5a (9 mg, 0.04 mmol, quant. yield)
as a yellow solid: mp = 290−295 °C; 1H NMR (500 MHz,
(CD3)2SO) δ 14.02 (s, 1H), 10.88 (br s, 1H), 8.25 (d, J = 8.0 Hz,
1H), 7.99 (d, J = 8.5 Hz, 1H), 7.82 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H),
7.47 (d, J = 8.1 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 8.1 Hz,
1H), 2.49 (s, 3H); 13C{1H} NMR (125 MHz, (CD3)2SO) δ 182.9,
160.9, 142.0, 140.6, 137.4, 135.0, 125.8, 122.7, 119.9, 119.0, 114.1,
1-Hydroxy-4-methylacridin-9(10H)-one (5a): 96 mg, 96% yield,
yellow solid. Spectroscopic data were in agreement with those made
through the stepwise synthesis (reported in the previous section).
4-Ethyl-1-hydroxyacridin-9(10H)-one (5b): 82 mg, 95% yield,
yellow solid; mp = 267−270 °C; 1H NMR (500 MHz, (CD3)2SO) δ
14.10 (s, 1H), 10.85 (br s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.00 (d, J =
8.5 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.33
(t, J = 7.5 Hz, 1H), 6.54 (d, J = 8.1 Hz, 1H), 2.89 (q, J = 7.4 Hz, 2H),
1.27 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, (CD3)2SO) δ
183.0, 161.0, 142.0, 140.0, 135.7, 135.0, 125.8, 122.7, 120.0, 119.8,
119.0, 109.5, 106.6, 23.5, 15.1; HRMS (ESI/Q-TOF) m/z [M + H]+
calcd for C15H13NO2 [M + H]+ 240.1019, found 240.1019.
4-Cyclohexyl-1-hydroxyacridin-9(10H)-one (5c): 71 mg, 92%
1
yield, yellow solid; mp > 300 °C; H NMR (500 MHz, (CD3)2SO)
δ 14.23 (s, 1H), 10.83 (br s, 1H), 8.25 (dd, J = 8.1, 1.2 Hz, 1H), 8.06
(d, J = 8.5 Hz, 1H), 7.83 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.56 (d, J =
8.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 3.31
(looks like a triplet, J = 11.7 Hz, 1H), 1.85−1.79 (m, 5H), 1.67−1.60
(m, 2H), 1.49−1.42 (m, 2H), 1.35−1.28 (m, 1H); 13C{1H} NMR
(125 MHz, (CD3)2SO) δ 183.1, 160.9, 142.0, 139.3, 135.1, 133.8,
125.8, 124.1, 122.7, 119.6, 119.1, 109.5, 106.9, 35.7, 34.3, 27.2, 26.6;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C19H19NO2 294.1489,
found 294.1487.
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Note
1-Hydroxy-4-propylacridin-9(10H)-one (5d): 58 mg, 72% yield,
yellow solid; mp = 237−243 °C; 1H NMR (500 MHz, (CD3)2SO) δ
14.13 (s, 1H), 10.83 (br s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.01 (d, J =
8.4 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.35
(t, J = 7.4 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H),
1.67 (sext, J = 7.3 Hz, 2H), 1.00 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(125 MHz, (CD3)2SO) δ 183.0, 161.0, 142.0, 140.1, 136.8, 135.1,
125.8, 122.7, 119.7, 119.0, 118.5, 109.6, 106.6, 32.1, 23.4, 14.6;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C16H15NO2 254.1176,
found 254.1175.
1-Hydroxy-4-phenylacridin-9(10H)-one (5e): 69 mg, 88% yield,
yellow solid; mp = 215−217 °C; 1H NMR (500 MHz, (CD3)2SO) δ
14.45 (s, 1H), 10.78 (br s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.90 (d, J =
8.5 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.60−7.55 (m, 4H), 7.52−7.50
(m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H); 13C{1H}
NMR (125 MHz, (CD3)2SO) δ 183.0, 162.5, 142.0, 139.5, 138.34,
138.25, 135.1, 130.6, 130.1, 128.6, 125.8, 122.9, 120.3, 119.8, 119.5,
109.6, 107.2; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C19H13NO2 288.1019, found 288.1019.
Hz, 1H), 6.46 (s, 1H), 3.64 (septet (looks like a triplet), J = 6.7 Hz,
1H), 2.52 (s, 3H); 1.32 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (125
MHz, (CD3)2SO) δ 183.1, 160.9, 142.1, 139.3, 135.1, 133.0, 125.8,
124.6, 122.7, 119.6, 119.1, 109.5, 106.9, 26.3, 24.1; HRMS (ESI/Q-
TOF) m/z [M + H]+ calcd for C17H17NO2 268.1332, found
268.1333.
6-Hydroxy-1,3,4,12-tetrahydrobenzo[c]acridin-7(2H)-one (5l): 83
mg, 83% yield, yellow solid; mp = 298−300 °C; 1H NMR (500 MHz,
(CD3)2SO) δ 13.90 (s, 1H), 10.67 (br s, 1H), 8.21 (dd, J = 8.1, 1.1
Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.77 (ddd, J = 8.5, 6.9, 1.5 Hz,
1H), 7.32 (t, J = 7.5 Hz, 1H), 6.29 (s, 1H), 2.79−2.76 (m, 4H),
1.91−1.87 (m, 2H), 1.79−1.76 (m, 2H); 13C{1H} NMR (125 MHz,
(CD3)2SO) δ 182.3, 159.7, 146.2, 141.8, 140.5, 134.7, 125.7, 122.6,
119.95, 119.1, 113.1, 108.1, 107.4, 31.3, 24.4, 23.0, 22.8; HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C17H15NO2 [M + H]+
266.1176, found 266.1176.
6-Hydroxy-2,3-dihydro-1H,7H-3a,12-(epoxymethano)-
cyclopenta[d]acridine-7,13-dione (4m). Method C was applied
where the reaction ran at room temperature in toluene for 6 h after
complete consumption of p-quinol. Also, silica gel flash column
chromatography was applied to provide the titled product: 99 mg,
4-(1-Hydroxy-9-oxo-9,10-dihydroacridin-4-yl)benzonitrile (5f):
1
50 mg, 68% yield, yellow solid; mp = 296−298 °C; H NMR (500
1
84% yield, white solid; mp = 165−172 °C; H NMR (400 MHz,
MHz, (CD3)2SO) δ 14.54 (s, 1H), 10.89 (br s, 1H), 8.28 (d, J = 8.0
Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.85−7.77 (m, 4H), 7.55 (d, J =
8.2 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H);
13C{1H} NMR (125 MHz, (CD3)2SO) δ 183.0, 163.3, 143.5, 142.0,
139.5, 138.4, 135.3, 133.9, 131.7, 125.8, 123.1, 119.9, 119.4, 118.6,
111.1, 109.5, 107.4; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C20H12N2O2 313.0972, found 313.0971.
CDCl3) δ 13.49 (br s, 1H), 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.82 (d, J =
8.1 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 6.72
(d, J = 10.2 Hz, 1H), 6.24 (d, J = 10.2 Hz, 1H), 2.63−2.58 (m, 1H),
2.34−2.30 (m, 1H), 1.93−1.84 (m, 1H), 1.77- 1.63 (m, 2H), 1.58−
1.50 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.1, 173.1,
152.9, 138.9, 136.5, 134.3, 127.0, 126.3, 125.6, 122.99, 122.58, 104.3,
84.0, 67.5, 41.8, 40.8, 19.0; HRMS (ESI/Q-TOF) m/z [M + H]+
calcd for C17H13NO4 296.0923, found 296.0919.
4-(4-Bromophenyl)-1-hydroxyacridin-9(10H)-one (5g): 50 mg,
1
89% yield, yellow solid; mp = 285−288 °C; H NMR (500 MHz,
1-Hydroxy-2-methoxy-4-methylacridin-9(10H)-one (5n): 40 mg,
(CD3)2SO) δ 14.49 (s, 1H), 10.81 (br s, 1H), 8.28 (d, J = 8.1 Hz,
1H), 7.88 (d, J = 8.5 Hz, 1H), 7.79−7.75 (m, 3H), 7.52−7.50 (m,
3H), 7.36 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H); 13C{1H}
NMR (125 MHz, (CD3)2SO) δ 182.9, 162.8, 142.2, 139.7, 138.2,
137.6, 135.1, 132.94, 132.93, 125.8, 122.9, 122.0, 119.9, 119.5, 119.1,
109.6, 107.1; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C19H12BrNO2 366.0124, found 366.0125.
1
87% yield, yellow solid; mp decomposed at 143 °C; H NMR (600
MHz, (CD3)2SO) δ 14.13 (s, 1H), 10.82 (br s, 1H), 8.22 (d, J = 8.1
Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.45 (s,
1H), 7.30 (t, J = 7.5 Hz, 1H), 3.85 (s, 3H), 2.52 (s, 3H); 13C{1H}
NMR (150 MHz, (CD3)2SO) δ 183.2, 149.4, 142.1, 139.6, 134.9,
134.8, 125.8, 125.5, 122.2, 118.89, 118.87, 113.4, 110.1, 58.1, 18.1;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C15H13NO3 256.0968,
found 256.0969.
1-Hydroxy-2,4-dimethylacridin-9(10H)-one (5h): 151 mg, 87%
yield, yellow solid; mp = 283.7−286.2 °C; 1H NMR (400 MHz,
(CD3)2SO) δ 14.23 (s, 1H), 10.79 (br s, 1H), 8.24 (d, J = 8.0 Hz,
1H), 7.95 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.36 (s, 1H),
7.31 (t, J = 7.5 Hz, 1H), 2.45 (s, 3H), 2.17 (s, 3H); 13C{1H} NMR
(100 MHz, (CD3)2SO) δ 182.7, 158.0, 142.0, 139.3, 138.7, 134.8,
125.8, 122.3, 119.7, 118.9, 114.2, 113.2, 109.2, 17.9, 15.2; HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C15H13NO2 240.1019, found
240.1018.
1-Hydroxy-3,4-dimethylacridin-9(10H)-one (5i): 111 mg, 94%
yield, yellow solid; mp = 279−281 °C; 1H NMR (500 MHz,
(CD3)2SO) δ 14.00 (s, 1H), 10.75 (br s, 1H), 8.23 (d, J = 8.0 Hz,
1H), 7.99 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.4
Hz, 1H), 6.51 (s, 1H), 2.39 (s, 6H); 13C{1H} NMR (125 MHz,
(CD3)2SO) δ 182.6, 160.2, 145.8, 142.2, 140.6, 134.96, 125.8, 122.6,
119.6, 119.1, 112.1, 109.2, 108.2, 22.2, 13.5; HRMS (ESI/Q-TOF)
m/z [M + H]+ calcd for C15H13NO2 240.1019, found 240.1020.
1-Hydroxy-4-isopropylacridin-9(10H)-one (5j). Method C was
applied where the reaction was refluxed in toluene for 6 h after
complete consumption of p-quinol: 47 mg, 55% yield, yellow solid;
mp = 233−234 °C; 1H NMR (500 MHz, (CD3)2SO) δ 14.21 (s, 1H),
10.90 (br s, 1H), 8.26 (dd, J = 8.2, 1.4 Hz, 1H), 8.04 (d, J = 8.2 Hz,
1H), 7.83 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H),
7.36 (t, J = 7.4, 0.8 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 3.64 (septet, J =
6.7 Hz, 1H), 1.32 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (125 MHz,
(CD3)2SO) δ 183.1, 160.9, 142.1, 139.3, 135.1, 133.0, 125.8, 124.6,
122.7, 119.6, 119.1, 109.5, 106.9, 26.3, 24.1; HRMS (ESI/Q-TOF)
m/z [M + H]+ calcd for C16H15NO2 [M + H]+ 254.1176, found
254.1177.
2-Fluoro-1-hydroxy-4-methylacridin-9(10H)-one (5o): 95 mg,
1
79% yield, orange solid; mp decomposed at 298 °C; H NMR (400
MHz, (CD3)2SO) δ 14.20 (s, 1H), 11.01 (br s, 1H), 8.23 (d, J = 8.1
Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.61 (d, J
= 12.0 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 2.51 (s, 3H); 13C{1H} NMR
(100 MHz, (CD3)2SO) δ 182.7 (d, J = 3.4 Hz), 149.1 (d, J = 12.9
Hz), 142.3 (d, J = 234.4 Hz), 141.6, 136.4, 134.8, 125.2, 124.9 (d, J =
20.2 Hz), 122.5, 118.7, 118.6, 114.1 (d, J = 6.3 Hz), 109.9 (d, J = 4.2
Hz), 17.3; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C14H10FNO2 244.0768, found 244.0770.
2-Chloro-1-hydroxy-4-methylacridin-9(10H)-one (5p): 79 mg,
1
75% yield, yellow solid; mp decomposed at 226 °C; H NMR (400
MHz, (CD3)2SO) δ 14.82 (s, 1H), 11.09 (br s, 1H), 8.26 (d, J = 8.0
Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 6.9 Hz, 1H), 7.65 (s,
1H), 7.39 (t, J = 7.3 Hz, 1H), 2.50 (s, 3H); 13C{1H} NMR (100
MHz, (CD3)2SO) δ 182.4, 155.9, 142.0, 139.6, 136.9, 135.4, 125.8,
123.2, 119.7, 119.2, 115.9, 109.8, 108.8, 17.8; HRMS (ESI/Q-TOF)
m/z [M + H]+ calcd for C14H10ClNO2 260.0473, found 260.0474.
2-Bromo-1-hydroxy-4-methylacridin-9(10H)-one (5q): 43 mg,
41% yield, yellow solid, 11% of 5a was also isolated; mp decomposed
1
at 224 °C; H NMR (500 MHz, (CD3)2SO) δ 14.95 (s, 1H), 11.12
(br s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.87 (t,
J = 7.5 Hz, 1H), 7.79 (s, 1H), 7.41 (t, J = 7.5 Hz, 1H), 2.52 (s, 3H);
13C{1H} NMR (125 MHz, (CD3)2SO) δ 182.2, 157.1, 141.95, 140.1,
139.4, 135.5, 125.9, 123.3, 119.7, 119.3, 116.5, 109.9, 97.7, 17.7;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C14H10BrNO2
303.9968, found 303.9966.
1-Hydroxy-4-isopropyl-3-methylacridin-9(10H)-one (5k): 60 mg,
1-Hydroxy-4-(2-hydroxyethyl)acridin-9(10H)-one (5r): 64 mg,
1
1
42% yield, yellow solid; mp = 135−140 °C; H NMR (500 MHz,
(CD3)2SO) δ 14.24 (s, 1H), 10.52 (br s, 1H), 8.22 (d, J = 8.1 Hz,
1H), 8.08 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 7.0 Hz, 1H), 7.34 (t, J = 7.3
70% yield, yellow solid; mp = 205−209 °C; H NMR (500 MHz,
(CD3)2SO) δ 14.16 (s, 1H), 11.04 (br s, 1H), 8.25 (d, J = 7.9 Hz,
1H), 7.95 (d, J = 8.4 Hz, 1H), 7.84−7.81 (m, 1H), 7.51 (d, J = 8.0
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Note
Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 4.94 (br s,
1H), 3.75 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 6.3 Hz, 2H); 13C{1H} NMR
(125 MHz, (CD3)2SO) δ 183.0, 161.3, 142.0, 140.7, 137.8, 135.1,
125.9, 122.7, 119.7, 119.0, 116.4, 109.6, 106.6, 61.9, 34.1; HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C15H13NO3 256.0968, found
256.0969.
General Procedure for the Preparation of Aryl Isocyanates 2b−
2d33 and 1-Hydroxyacridones 5x−5z (Method D). To a solution of
commercial aniline (1 equiv) in a 1:1 mixture of methylene chloride
(10 mL) and saturated aqueous NaHCO3 (10 mL) at 0 °C was added
triphosgene (0.4 equiv). The reaction mixture was stirred at 0 °C for
1 h. After the layers were separated, the aqueous layer was extracted
with CH2Cl2 (2 × 10 mL). The organic layers were combined and
washed with water (20 mL) and brine (20 mL), dried over Na2SO4,
and then concentrated in vacuo. The residue was used directly in the
next step without further purification. Method C was then applied to
deliver the desired acridones.
Methyl 5-Bromo-2-isocyanatobenzoate (2b): 0.3 g, quant. yield,
white solid; mp decomposed at 121.1 °C; 1H NMR (600 MHz,
CDCl3) δ 8.14 (d, J = 2.4 Hz, 1H), 7.58 (dd, J = 8.5, 2.4 Hz, 1H),
7.00 (d, J = 8.6 Hz, 1H), 3.97 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 165.4, 137.0, 134.6, 133.9, 128.3, 125.7, 125.3, 118.7, 53.1;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C9H6BrNO3
255.9604, found 255.9604.
Dimethyl 2-Isocyanatoterephthalate (2c): 0.4 g, quant. yield,
white solid; mp decomposed at 126 °C; 1H NMR (500 MHz, CDCl3)
δ 8.06 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 8.2, 1.7 Hz, 1H), 7.76 (d, J =
1.7 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 166.0, 165.6, 135.2, 134.8, 132.0, 127.8, 127.4, 126.4, 125.5,
53.1, 53.0; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C11H9NO5
236.0553, found 236.0553.
Methyl 2-Isocyanato-3-methylbenzoate (2d): 1.7 g, quant. yield,
white solid; mp = 124−126 °C; 1H NMR (500 MHz, CDCl3) δ 7.84
(d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.15−7.12 (m, 1H),
3.95 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
167.0, 136.2, 135.2, 134.9, 133.2, 129.4, 125.1, 124.1, 52.7, 19.2;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C10H9NO3 192.0655,
found 192.0653.
5-Hydroxy-3-tosyl-1,2,3,3a,4,5a1-hexahydro-6H,12H-oxazolo-
[5,4,3-de]pyrrolo[2,3-c]acridine-6,12-dione (4s). Method C was
applied where the reaction ran at room temperature in toluene for
1 h; also, recrystallization with EtOAc/hexane (10:1) was applied to
afford the titled compound: 40 mg, 94% yield, white solid; mp =
1
261−268 °C; H NMR (500 MHz, CDCl3) δ 14.31 (br s, 1H), 7.99
(dd, J = 7.9, 1.4 Hz, 1H), 7.75−7.73 (m, 3H), 7.59 (t, J = 7.7 Hz,
1H), 7.35 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 4.86 (s, 1H),
3.92−3.88 (m, 1H), 3.81−3.78 (m, 1H), 3.33−3.25 (m, 2H), 2.48−
2.40 (m, 5H), 2.28−2.21 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 181.0, 178.1, 152.3, 144.8, 137.5, 135.1, 133.2, 130.3, 128.0,
127.5, 126.0, 123.4, 121.6, 101.6, 86.2, 62.4, 56.4, 46.7, 39.3, 36.2,
22.0; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C23H20N2O6S
453.1115, found 453.111; [M + Na]+ calcd for C23H20N2O6SNa
475.0934, found 475.0930.
N-(2-(1-Hydroxy-9-oxo-9,10-dihydroacridin-4-yl)ethyl)-4-methyl-
benzenesulfonamide (5s): 48 mg, 57% yield, yellow solid; mp =
234−242 °C; 1H NMR (500 MHz, (CD3)2SO) δ 14.17 (s, 1H),
10.75 (br s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H),
7.85−7.82 (m, 1H), 7.61−7.59 (m, 1H), 7.54 (d, J = 8.1 Hz, 2H),
7.43 (d, J = 8.2 Hz, 1H), 7.38−7.35 (m, 1H), 7.23 (d, J = 8.0 Hz,
2H), 6.53 (d, J = 8.2 Hz, 1H), 3.13−3.09 (m, 2H), 3.06−3.03 (m,
2H), 2.32 (s, 3H); 13C{1H} NMR (125 MHz, (CD3)2SO) δ 182.9,
161.6, 143.3, 141.9, 140.2, 138.1, 137.9, 135.2, 130.3, 127.3, 125.8,
122.8, 119.8, 118.9, 114.9, 109.6, 106.6, 43.0, 30.5, 21.8; HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C22H20N2O4S 409.1217,
found 409.1214.
7-Bromo-4-ethyl-1-hydroxyacridin-9(10H)-one (5x): 93 mg, 82%
yield, yellow solid; mp = 257−260 °C; 1H NMR (500 MHz,
(CD3)2SO) δ 13.80 (s, 1H), 11.02 (br s, 1H), 8.31 (d, J = 2.3 Hz,
1H), 7.99 (d, J = 9.0 Hz, 1H), 7.95 (dd, J = 9.0, 2.3 Hz, 1H), 7.53 (d,
J = 8.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 2.90 (q, J = 7.4 Hz, 2H),
1.29 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, (CD3)2SO) δ
181.8, 160.8, 140.9, 139.8, 137.6, 136.2, 127.7, 121.7, 121.1, 120.4,
114.9, 109.6, 107.1, 23.5, 15.1; HRMS (ESI/Q-TOF) m/z [M + H]+
calcd for C15H12BrNO2 318.0124, found 318.0121.
11-Hydroxy-4-methyl-1,2,3,5-tetrahydro-10H-cyclopenta[b]-
acridin-10-one (5t): 90 mg, 80% yield, yellow solid; mp > 300 °C; 1H
NMR (500 MHz, (CD3)2SO) δ 14.13 (s, 1H), 10.71 (br s, 1H), 8.22
(dd, J = 8.1 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.77 (t, J = 7.7 Hz,
1H), 7.31 (t, J = 7.4 Hz, 1H), 2.96 (t, J = 7.2 Hz, 2H), 2.86 (t, J = 7.2
Hz, 2H), 2.39 (s, 3H), 2.06 (quint, J = 7.2 Hz, 2H); 13C{1H} NMR
(125 MHz, (CD3)2SO) δ 182.6, 155.6, 153.6, 141.9, 139.8, 134.6,
125.8, 122.2, 120.4, 119.5, 118.9, 109.1, 108.7, 33.7, 29.3, 25.0, 14.4;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C17H15NO2 266.1176,
found 266.1177.
Methyl 5-Ethyl-8-hydroxy-9-oxo-9,10-dihydroacridine-3-carbox-
1
ylate (5y): 90 mg, 73% yield, yellow solid; mp = 254−257 °C; H
2a,4,5a-Trimethyl-2a1,5a-dihydro-1H,5H-oxazolo[5,4,3-de]-
acridine-1,5,6(2aH)-trione (4u). Method C was applied where the
reaction was refluxed in toluene for 6 h. Also, the residue was purified
by silica gel flash column chromatography to provide the titled
NMR (500 MHz, (CD3)2SO) δ 13.81 (s, 1H), 11.00 (br s, 1H), 8.63
(d, J = 1.3 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.4, 1.5 Hz,
1H), 7.47 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 3.96 (s, 3H),
2.85 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H); 13C{1H} NMR
(125 MHz, (CD3)2SO) δ 182.6, 166.4, 160.8, 141.5, 140.1, 136.2,
134.7, 126.5, 122.0, 121.6, 121.0, 120.3, 109.9, 107.0, 53.5, 23.5, 15.2;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C17H15NO4 298.1074,
found 298.1076.
1
compound: 71 mg, 44% yield, white solid; mp = 188−192 °C; H
NMR (500 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 8.06 (dd, J =
7.8, 1.4 Hz, 1H), 7.59−7.56 (m, 1H), 7.19 (t, J = 7.3 Hz, 1H), 6.41 (s,
1H), 1.85 (d, J = 1.1 Hz, 3H), 1.82 (s, 3H), 1.58 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 194.1, 188.7, 151.7, 139.5, 138.1, 136.2,
135.9, 129.1, 124.5, 120.2, 117.3, 76.5, 67.7, 55.3, 24.6, 18.3, 16.6;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C17H15NO4 298.1074,
found 298.1067; [M + Na]+ calcd for C17H15NO4Na 320.0893, found
320.0889.
4-Ethyl-1-hydroxy-5-methylacridin-9(10H)-one (5z). The crude
material was purified by silica gel flash column chromatography to
provide the titled compound: 124 mg, 85% yield, yellow solid; mp =
1
163−170 °C; H NMR (500 MHz, CDCl3) δ 13.73 (br s, 1H), 8.24
(d, J = 8.2 Hz, 1H), 7.93 (br s, 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.38 (d,
J = 8.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H),
2.76 (q, J = 7.5 Hz, 2H), 2.55 (s, 3H), 1.40 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 183.5, 161.2, 138.9, 138.4,
5-Hydroxy-2a,2a1,3-trimethyl-2a,2a1-dihydro-1H,6H-oxazolo-
[5,4,3-de]acridine-1,6-dione (4v). Method C was applied where the
reaction was refluxed in toluene for 6 h. The sealed tube condition led
to 1-hydroxy-3,4-dimethylacridin-9(10H)-one (5i) as the side
product. Also, the residue was purified by silica gel flash column
chromatography to provide the titled compound: 54 mg, 54% yield,
white solid; mp = 202−206 °C; 1H NMR (500 MHz, CDCl3) δ 14.06
(br s, 1H), 8.00 (dd, J = 7.8, 1.4 Hz, 1H), 7.65−7.62 (m, 1H), 7.57
(dd, J = 8.0, 0.9 Hz, 1H), 7.43−7.40 (m, 1H), 2.17 (d, J = 1.5 Hz,
3H), 1.74 (s, 3H), 1.35 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
179.2, 170.8, 154.7, 150.1, 136.9, 133.9, 127.9, 127.1, 126.4, 125.8,
124.2, 105.7, 81.0, 62.1, 22.6, 20.9, 20.6; HRMS (ESI/Q-TOF) m/z
[M + H]+ calcd for C17H15NO4 298.1074, found 298.1069; [M +
Na]+ calcd for C17H15NO4Na 320.0893, found 320.0892.
135.0, 134.7, 124.7, 123.5, 121.9, 120.2, 117.5, 109.3, 107.2, 23.1,
16.7, 13.3; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C16H15NO2 254.1176, found 254.1176.
Anti-Human Cytomegalovirus (HCMV) Activity Analysis.
Compound Preparation. Seven 1-hydroxyacridones (5a, 5c, 5e, 5f,
5h, 5i, and 5x) and one tetracyclic compound 4u were synthesized
according to Method C and used in this study. Compound 5a′ was an
N-methyl derivative of 5a. Substrates were dissolved in dimethyl
sulfoxide (DMSO), and stocks of 10 mM were stored at −80 °C.
HCMV Replication Assay. Human foreskin fibroblasts (HFF) cells
(ATCC CRL-2088) were plated at approximately 2 × 104 cells/well
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Note
in white-bottom 96-well tissue culture plates and the next day
inoculated with the ADCREGFP virus (obtained from Wade
Bresnahan, University of Minnesota) in Dulbecco’s modified Eagle’s
medium (DMEM) containing 5% fetal bovine serum for 2 h at a
multiplicity of infection of 0.05. The cells were washed with
phosphate-buffered saline and incubated with 100 μL of DMEM
containing 5% fetal bovine serum, and test compounds were
incubated at 37 °C and 5% CO2 for 7 days. Next, the extent of
virus replication was determined by lysing the infected cells and
measuring green fluorescent protein (GFP) expression. For lysis, each
well-received 200 μL of lysis buffer (25 mM Tris (pH 7.8), 2 mM
dithiothreitol (DTT), 2 mM trans-1,2-diaminocyclohexane-
N,N,N′,N′-tetraacetic acid, 1% Triton X-100, 10% glycerol) for 10
min at 37 °C, followed by 30 min of incubation at room temperature
on a shaker. GFP relative fluorescence units were determined at
excitation/emission = 495/515 nm in a Molecular Devices M5e plate
reader.
Guy Pillon − Department of Chemistry, Hunter College, New
York, New York 10065, United States
Guoqi Zhang − Ph.D. Program in Chemistry, The Graduate
Center of the City University of New York, New York, New York
10016, United States; Department of Sciences, John Jay College
of Criminal Justice, New York, New York 10019, United States;
orcid.org/0000-0001-6071-8469
Robert J. Geraghty − Center for Drug Design, University of
Minnesota, Minneapolis, Minnesota 55455, United States;
orcid.org/0000-0002-0560-6509
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03307
Notes
The authors declare no competing financial interest.
Compounds were evaluated in triplicate, and mean values of
triplicate wells were determined and compared to the mean value for
the wells that received DMSO alone.
ACKNOWLEDGMENTS
■
We are grateful to Professors Richard Franck and Klaus
Grohmann at Hunter College for helpful discussions. We also
thank Drs. Barney Yoo, Matthew Devany, Michelle Neary, and
Tony Hu for mass spectrometric, NMR spectroscopic, and X-
ray crystallographic assistance, respectively. Financial support
from the Bertha and Louis Weinstein Research Grant, NIH
(SC2GM100783), NSF (CHE-1464543), and PSC−CUNY
Research Award is gratefully acknowledged.
Cell Viability Assay. HFF cells were plated at approximately 2 ×
104 cells/well and the next day incubated in culture medium with
testing compounds at 37 °C for 7 days. Cellular viability was
determined using the MTS-based tetrazolium reduction assay,
CellTiter 96 Aqueous Non-Radioactive cell proliferation assay
(Promega), as per manufacturer’s instructions. Compounds were
evaluated in triplicate, and mean values of triplicate wells were
determined and compared to the mean value for the wells that
received DMSO alone.
DEDICATION
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03307.
■
■
This work is dedicated to the memory of Professors Gilbert
Stork, Koji Nakanishi, and Ronald Breslow.
sı
REFERENCES
■
Additional experimental details and copies of NMR
spectra (PDF)
Crystal structure data of 5a (CIF)
Crystal structure data of 4a (CIF)
Crystal structure data of 4a″ (CIF)
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AUTHOR INFORMATION
Corresponding Author
Shengping Zheng − Department of Chemistry, Hunter College,
New York, New York 10065, United States; Ph.D. Program in
Chemistry, The Graduate Center of the City University of New
York, New York, New York 10016, United States; orcid.org/
0000-0003-0668-8849; Email: szh0007@hunter.cuny.edu
■
Authors
Jing Wu − Department of Chemistry, Hunter College, New York,
New York 10065, United States; Ph.D. Program in Chemistry,
The Graduate Center of the City University of New York, New
York, New York 10016, United States
Jinzhu Zhang − Department of Chemistry, Hunter College, New
York, New York 10065, United States; Ph.D. Program in
Chemistry, The Graduate Center of the City University of New
York, New York, New York 10016, United States
Ruben Soto-Acosta − Center for Drug Design, University of
Minnesota, Minneapolis, Minnesota 55455, United States
Lili Mao − Center for Drug Design, University of Minnesota,
Minneapolis, Minnesota 55455, United States
Jiahui Lian − Department of Chemistry, Hunter College, New
York, New York 10065, United States
Kenny Chen − Department of Chemistry, Hunter College, New
York, New York 10065, United States
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https://dx.doi.org/10.1021/acs.joc.9b03307
J. Org. Chem. 2020, 85, 4515−4524

The Journal of Organic Chemistry
pubs.acs.org/joc
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J. Org. Chem. 2020, 85, 4515−4524