Kinetic Control of Rh(III)-Catalyzed Annulation of C-H Bonds with Quinones: Chemoselective Synthesis of Hydrophenanthridinones and Phenanthridinones

Article abstract of DOI:10.1021/acs.joc.5b02903

A temperature-dependent redox-neutral Rh(III)-catalyzed C-H bond annulation of N-methoxybenzamides with quinones was developed for the chemoselective synthesis of hydrophenanthridinones and phenanthridinones. This reaction involves an Rh(III)-catalyzed C-H bond functionalization and a subsequent cyclization through the directing group nucleophilic addition to the carbonyl group at room temperature. (Figure Presented).

Full text of DOI:10.1021/acs.joc.5b02903

Article
pubs.acs.org/joc
Kinetic Control of Rh(III)-Catalyzed Annulation of C−H Bonds with
Quinones: Chemoselective Synthesis of Hydrophenanthridinones
and Phenanthridinones
Wei Yang,† Jingyi Wang,† Zhonglin Wei,‡ Qian Zhang,† and Xianxiu Xu*,†
†Department of Chemistry, Northeast Normal University, Changchun 130024, China
‡College of Chemistry, Jilin University, Changchun 130012, China
S
* Supporting Information
ABSTRACT: A temperature-dependent redox-neutral Rh-
(III)-catalyzed C−H bond annulation of N-methoxybenza-
mides with quinones was developed for the chemoselective
synthesis of hydrophenanthridinones and phenanthridinones.
This reaction involves an Rh(III)-catalyzed C−H bond
functionalization and a subsequent cyclization through the
directing group nucleophilic addition to the carbonyl group at
room temperature.
improving the overall efficiency in an atom- and step-
economical manner. To date, various heterocycles have been
successfully constructed using this methodology.7,8 Recently,
Cheng and co-workers developed efficient Rh-catalyzed
oxidative annulations of aryl C−H bonds with either aryl
boronic acids9 or aryltriethoxysilanes10 to synthesize phe-
nanthrines through a double C−H bond activation strategy;
however, a large amount of oxidants (Ag+ and/or Cu2+ salt) is
necessary (Scheme 1, eq 1).
INTRODUCTION
■
The phenanthridine and hydrophenanthridine structural motifs
are the core of many natural products with pharmacological
relevance (Figure 1),1−5 such as ethidium,1b,2 trispheridine,3
In 2015, we reported an Rh(III)-catalyzed oxidative C−H
bond arylation with hydroquinones for the sustainable synthesis
of dibenzo[b,d]pyran-6-ones and benzo[d]naphtho[1,2-b]-
pyran-6-ones at elevated temperatures (Scheme 1, eq 2).11
Mechanistic investigation indicated that the quinone could be
produced under the standard conditions and could serve as the
coupling partner in this Rh(III)-catalyzed reaction. Although
benzoquinone is a cheap and commercially available chemical,
few articles report on the C−H bond functionalization reaction
using benzoquinone as a coupling partner.12 Herein, we report
an Rh(III)-catalyzed redox-neutral C−H bond annulation of N-
methoxybenzamides with quinones at room temperature for
divergent construction of tricyclic hydrophenanthridone
scaffolds (Scheme 1, eq 3). This protocol enables the
convenient assembly of phenanthridones by a one-pot
sequential Rh(III)-catalyzed aryl C−H bond annulation and
aromatization (Scheme 1, eq 4). Furthermore, it is worth
mentioning that distinct types of complex molecules are
constructed from identical starting materials using the same
catalyst system by tuning the role of the directing group, which
acts selectively as a nucleophile in these transformations
Figure 1. Representative natural products.
fagaronine,4 and lycorane-type alkaloids (α-lycorane, lycorine,
and fortucine).5 Therefore, a number of synthetic methods for
the construction of these frameworks have been reported.1−6
Generally, these methods rely on the intramolecular C−N or
C−C bond formation to construct the central pyridine ring
under either radical cyclization conditions or transition metal
catalysis by using 2-isocyanobiphenyls,1a biaryl-2-acyl oximes,6b
or other biaryl compounds6c as the starting materials.
Rh(III)-catalyzed C−H functionalization has rapidly
emerged as a versatile and straightforward synthetic protocol
for the construction of heterocycles.7 This strategy obviates
prefunctionalization of the starting materials, thus dramatically
Received: December 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02903
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a
Scheme 1. Divergent Annulation of Aryl C−H Bonds with
Quinones
Table 1. Synthesis of Hydrophenanthridones 3
(Scheme 1, eqs 3 and 4). In our previous work, the directing
group acted as an electrophile (Scheme 1, eq 2).11
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), (Cp*RhCl2)2 (2.5
RESULTS AND DISCUSSION
■
mol %), CsOAc (30 mol %), HOAc (50 mol %), DCE/acetone (1
mL/1 mL). 5 mol % (Cp*RhCl2)2 was used.
b
In this study, the reaction of amide 1a with quinone 2a was
employed as model to optimize the reaction conditions
(Scheme 2). It was found that hydrophenanthridone 3a
At room temperature, the reactions of various N-methox-
ybenzamides 1 with quinones 2 proceeded smoothly to afford a
wide range of hydrophenanthridones 3 in a highly diaster-
eoselective manner in good to high yields (Table 1). Amides 1
with both electron-donating (Table 1, 3b−d) and electron-
withdrawing (Table 1, 3e) groups at the para position of aryl
groups participated well in this reaction, and the corresponding
products were obtained in good to high yields.13 Benzamides 1
with ortho-, meta-, and disubstitution reacted smoothly to give
the corresponding hydrophenanthridones (Table 1, 3f−h) in
high yields. In the case of β-naphthamide 1n, tetrahydrobenzo-
[j]phenanthridine-2,6-dione 3i was obtained in good yield. For
the quinone derivatives, methyl quinone 2b exclusively afforded
the 3-methyl tetrahydrophenanthridine-2,6-dione 3j in good
yield (the configuration of 3j was confirmed by HMBC; see
Supporting Information), whereas the bulky tert-butyl quinone
2c and naphthoquinone 2d gave dibenzo[b,d]pyran-6-one 4b
and benzo[d]naphtho[1,2-b]pyran-6-one 4c, respectively. It is
important to note that the annulation is highly regioselective
with respect to the unsymmetrical quinones 2b and 2c at room
temperature.
Structurally, the hydrophenanthridones 3 containing a 4-
hydroxycyclohex-2-enone moiety could aromatize after elimi-
nation of water and tautomerization. Thus, a one-pot synthesis
of phenanthridonones 5 from the annulation of amides 1 and
quinones 2 was accomplished by adding Tf2O and triethyl
amine to improve the elimination of the hydroxy group. As
shown in Table 2, this one-pot protocol tolerates various
aromatic amides 1 and provides the corresponding phenan-
thridines 5 in good to high yields. Although Rh(III)-catalyzed
Scheme 2. Temperature-Dependent Annulation of Amide 1a
with Quinone 2a
became the major product when amide 1a and quinone 2a
were treated with the reported reaction conditions11
((Cp*RhCl2)2 (2.5 mol %), CsOAc (30 mol %), and acetic
acid (0.5 equiv)) upon decreasing the reaction temperature
(Scheme 2). To our delight, hydrophenanthridone 3a was
chemo- and diastereoselectively obtained in 85% yield when the
annulation of amide 1a and quinone 2a was performed at room
temperature. It is very interesting that the chemoselectivity of
this annulation was tuned by only a slight change of the
reaction temperature. In this case, tricyclic hydrophenanthri-
done 3a was the major product, whereas in our previous
work,11 dibenzo[b,d]pyran-6-one 4a was the sole product. The
scope of this divergent annulation of amides 1 with quinone 2
was explored, and the results are summarized in Table 1.
B
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a
Table 2. Synthesis of Phenanthridones 5
Scheme 3. Control Experiments
of 1a occurs to produce a five-membered rhodacycle
intermediate A. Next, coordination of the benzoquinone affords
intermediate B, which undergoes migratory insertion into the
incipient Rh−C bond to form a seven-membered rhodacycle
C.14,15 Protonolysis delivers intermediate D while concom-
itantly releasing the catalyst Cp*RhX2. Then, the cyclo-
hexendione intermediate D proceeds via the two competing
pathways depicted as follows. In path a, for the formation of
dibenzo[b,d]pyran-6-one 4a, tautomerization of D generates
diphenol intermediate E, which is followed by nucleophilic
substitution to furnish the product 4a with the release of an O-
methylhydroxamine under metal- or acid-catalyzed condi-
tions.16 In path b, for the formation of hydrophenanthridinone
3a and phenanthridinone 5a, a reversible intramolecular
nucleophilic addition of intermediate D forms hydrophenan-
thridinone 3a, which produces compound 5a by a one-pot
tandem triflation, elimination, and aromatization sequence. The
proposed mechanism in Scheme 4 suggests that the amide
group of substrate 1 is a multitasking functional directing group
which acts as both a directing group and an electrophile in path
a and both a directing group and a nucleophile in path b.
In summary, a novel, temperature-dependent Rh(III)-
catalyzed C−H bond annulation with readily available,
inexpensive quinones was developed for the divergent and
convenient synthesis of hydrophenanthridinones and phenan-
thridinones. In these transformations, the bifunctional directing
groups were incorporated into the products while serving
selectively as nucleophiles in the final cyclization step. The
reaction features high efficiency, atom- and step-economy,
broad substrate scope, good functional group tolerance, and
good chemo- and diastereoselectivity. Kinetic control of the
annulation of aryl C−H bonds with quinones, complementing
that of our previous thermodynamic control,11 represents an
efficient protocol for the divergent synthesis of complex natural
product scaffolds from identical, readily available starting
materials.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), (Cp*RhCl2)2 (2.5
mol %), CsOAc (30 mol %), and HOAc (50 mol %) in DCE/acetone
(1 mL/1 mL) for time 1; then Et3N (150 mol %) and Tf2O (120 mol
b
%) for time 2. 5 mol % (Cp*RhCl2)2 was used.
annulation of aryl C−H with preactivated coupling partners
such as aryl boronic acids9 and arylsilanes10 has been reported,
this one-pot protocol is still appealing due to its mild, redox-
neutral reaction conditions and readily available starting
materials.
To shed light on the reaction mechanism of this divergent
annulation, hydrophenanthridone 3a was treated with the
standard conditions ((Cp*RhCl2)2 (2.5 mol %), CsOAc (30
mol %), and acetic acid (0.5 equiv)) at 90 °C for 2.5 h, and
dibenzo[b,d]pyran-6-one 4a was obtained in quantitative yield
(Scheme 3, eq 1). This result confirms that the hydro-
phenanthridone 3a is the product of kinetic control which is
easily converted to the stable 4a of thermodynamic control at a
higher temperature. Next, a deuterium-labeling experiment was
carried out, which showed competition between protio and
deutero 1a with a 2:1 product ratio at early conversion
(Scheme 3, eq 2). In addition, the kinetic isotope effect (KIE)
was further measured from two side-by-side reactions using
protio and deutero 1a (Scheme 3, eq 3), and a KIE value of 1.4
was observed. These results demonstrate that the C−H bond
cleavage process may not be involved in the rate-determining
step.
On the basis of our previous observations,11 present
observations, and literature precedent,12,14−17 a mechanistic
pathway is proposed (Scheme 4, taking the reaction of amide
1a with quinone 2a as an example). First, C−H bond cleavage
C
DOI: 10.1021/acs.joc.5b02903
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Scheme 4. Proposed Mechanism
9-tert-Butyl-4a-hydroxy-5-methoxy-1,4a,5,10b-tetrahydrophe-
nanthridine-2,6-dione (3c). Yellowish solid (44.1 mg, 70%). Mp
206−207 °C. 1H NMR (500 MHz, DMSO): δ 1.30 (s, 9H), 2.56−2.65
(m, 2H), 3.71−3.75 (m, 4H), 6.15 (d, J = 10.0 Hz, 1H), 7.03 (d, J =
10.0 Hz, 1H), 7.26 (s, 1H), 7.47 (s, 2H), 7.88 (d, J = 8.0 Hz, 1H). 13C
NMR (125 MHz, DMSO): δ 31.3, 35.4, 43.6, 46.6, 63.9, 85.8, 124.2,
124.9, 125.4, 127.8, 128.7, 139.1, 148.1, 156.8, 163.5, 197.2. HRMS
EXPERIMENTAL SECTION
■
General Procedures for Compounds 3a−j (with the Reaction
of 1a as an Example). Without any particular precautions to extrude
oxygen or moisture, to a stirred mixture of 1a (30.2 mg, 0.2 mmol)
and 2a (43.2 mg, 0.4 mmol) in DCE/acetone (1.0 mL/1.0 mL) were
added (Cp*RhCl2)2 (3.1 mg, 0.005 mmol), CsOAc (11.5 mg, 0.06
mmol), and HOAc (6.0 μL, 0.1 mmol), successively. The reaction
mixture was stirred at room temperature for 5 h, and then 1a was
consumed as indicated by TLC. The reaction mixture was diluted with
brine (10 mL) and extracted with EtOAc (2 × 10 mL). The combined
organics were dried (Na2SO4) and concentrated in vacuo at 35 °C. The
residue was purified by column chromatography (petroleum ether/
EtOAc = 7/1, v/v) to afford the desired product 3a (85% yield).
General Procedures for the Synthesis of 5a−k (with the
Reaction of 1a as an Example). According to the general procedure
to afford 3a, when the substrate 1a was consumed (detected by TLC),
Et3N (0.3 mmol, 42.0 μL) and Tf2O (0.24 mmol, 40.0 μL) were added
to the reaction mixture directly. The resulting mixture was stirred at
room temperature until 3a was consumed as indicated by TLC. The
reaction mixture was diluted with brine (10 mL) and extracted with
EtOAc (2 × 10 mL). The combined organics were dried (Na2SO4)
and concentrated in vacuo. The residue was purified by column
chromatography (petroleum ether/EtOAc = 5/1, v/v) to afford the
desired product 5a (77% yield).
+
(ESI-TOF) m/z: calcd for C18H22NO4 [M + H]+ 316.1543; found
316.1548.
4a-Hydroxy-5,9-dimethoxy-1,4a,5,10b-tetrahydrophenanthri-
dine-2,6-dione (3d). Yellowish solid (30.0 mg, 52%). Mp 173−174
°C. 1H NMR (500 MHz, DMSO): δ 2.60 (d, J = 9.0 Hz, 2H), 3.65 (t,
J = 9.0 Hz, 1H), 3.70 (s, 3H), 3.82 (s, 3H), 6.14 (d, J = 10.5 Hz, 1H),
6.97 (d, J = 8.5 Hz, 1H), 7.01−7.04 (m, 2H), 7.22 (s, 1H), 7.88 (d, J =
9.0 Hz, 1H). 13C NMR (125 MHz, DMSO): δ 43.3, 46.6, 56.1, 63.9,
85.8, 113.1, 114.0, 119.4, 128.6, 130.1, 141.6, 148.2, 163.5, 163.5,
+
197.2. HRMS (ESI-TOF) m/z: calcd for C15H15NNaO5 [M + Na]+
312.0842; found 312.0850.
9-Bromo-4a-hydroxy-5-methoxy-1,4a,5,10b-tetrahydrophenan-
thridine-2,6-dione (3e). Yellowish solid (27.0 mg, 40%). Mp 223−224
1
°C. H NMR (400 MHz, DMSO): δ 2.58−2.68 (m, 2H), 3.71−3.75
(m, 4H), 6.17 (d, J = 10.0 Hz, 1H), 7.03 (d, J = 10.0 Hz, 1H), 7.38 (s,
1H), 7.65 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H).
13C NMR (125 MHz, DMSO): δ 44.0, 46.7, 64.0, 85.9, 125.1, 127.8,
129.4, 129.8, 131.9, 135.1, 135.5, 148.1, 163.2, 197.1. HRMS (ESI-
+
TOF) m/z: calcd for C14H13BrNO4 [M + H]+ 338.0022; found
4a-Hydroxy-5-methoxy-1,4a,5,10b-tetrahydrophenanthridine-
2,6-dione (3a). Yellowish solid (44.0 mg, 85%). Mp 205−206 °C. H
1
338.0027.
NMR (500 MHz, DMSO): δ 2.54−2.67 (m, 2H), 3.72−3.74 (m, 4H),
6.16 (d, J = 10.5 Hz, 1H), 7.04 (d, J = 10.0 Hz, 1H), 7.29 (s, 1H), 7.44
(t, J = 7.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H).
13C NMR (125 MHz, DMSO): δ 43.4, 46.4, 63.9, 85.7, 126.7, 127.8,
127.9, 128.5, 128.7, 133.7, 139.3, 147.9, 163.4, 197.0. HRMS (ESI-
4a-Hydroxy-5-methoxy-7-methyl-1,4a,5,10b-tetrahydrophenan-
thridine-2,6-dione (3f). Yellowish solid (39.9 mg, 73%). Mp 140−141
°C. 1H NMR (500 MHz, DMSO): δ 2.53−2.61 (m, 2H), 2.65 (s, 3H),
3.66 (dd, J = 4.5, 13.0 Hz, 1H), 3.70 (s, 3H), 6.14 (d, J = 10.0 Hz, 1H),
7.02 (d, J = 10.0 Hz, 1H), 7.16 (s, 1H), 7.24 (q, J = 7.5 Hz, 2H), 7.44
(t, J = 7.5 Hz, 1H). 13C NMR (125 MHz, DMSO): δ 23.3, 43.8, 46.8,
63.7, 85.0, 124.3, 127.0, 128.6, 131.7, 132.8, 140.6, 141.3, 148.3, 164.2,
+
TOF) m/z: calcd for C14H13NNaO4 [Na + H]+ 282.0737; found
282.0745.
+
197.2. HRMS (ESI-TOF) m/z: calcd for C15H15NNaO4 [M + Na]+
4a-Hydroxy-5-methoxy-9-methyl-1,4a,5,10b-tetrahydrophenan-
thridine-2,6-dione (3b). Yellowish solid (45.9 mg, 84%). Mp 201−202
°C. 1H NMR (400 MHz, DMSO): δ 2.65 (s, 3H), 2.70−2.75 (m, 2H),
3.79 (dd, J = 5.2, 12.4 Hz, 1H), 3.85 (s, 3H), 6.29 (d, J = 10.0 Hz, 1H),
7.17 (d, J = 10.0 Hz, 1H), 7.38−7.40 (m, 3H), 7.99 (d, J = 7.6 Hz,
1H). 13C NMR (125 MHz, DMSO): δ 21.7, 43.4, 46.4, 63.9, 85.8,
124.2, 128.0, 128.6, 128.7, 128.9, 139.3, 144.0, 148.0, 163.5, 197.1.
296.0893; found 296.0897.
4a-Hydroxy-5-methoxy-8-methyl-1,4a,5,10b-tetrahydrophenan-
thridine-2,6-dione (3g). Yellowish solid (36.0 mg, 66%). Mp 183−184
°C. 1H NMR (500 MHz, DMSO): δ 2.35 (s, 3H), 2.54−2.63 (m, 2H),
3.67 (d, J = 12.0 Hz, 1H), 3.71 (s, 3H), 6.14 (d, J = 10.0 Hz, 1H), 7.02
(d, J = 10.0 Hz, 1H), 7.25 (s, 1H), 7.31 (d, J = 7.0 Hz, 1H), 7.40 (d, J
= 7.0 Hz, 1H), 7.77 (s, 1H). 13C NMR (125 MHz, DMSO): δ 21.1,
43.4, 46.0, 63.9, 85.8, 126.5, 128.1, 128.5, 128.7, 134.4, 136.4, 137.3,
+
HRMS (ESI-TOF) m/z: calcd for C15H16NO4 [M + H]+ 274.1074;
found 274.1079.
D
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+
148.0, 163.5, 197.2. HRMS (ESI-TOF) m/z: calcd for C15H15NNaO4
134.6, 138.7, 154.2, 155.3. HRMS (ESI-TOF) m/z: calcd for
+
[M + Na]+ 296.0893; found 296.0879.
C14H11ClNO3 [M + H]+ 276.0422; found 276.0420.
4a-Hydroxy-5-methoxy-8,9-dimethyl-1,4a,5,10b-tetrahydrophe-
nanthridine-2,6-dione (3h). Yellowish solid (47.1 mg, 82%). Mp
197−198 °C. 1H NMR (500 MHz, DMSO): δ 2.26 (s, 6H), 2.55−2.58
(m, 2H), 3.60 (dd, J = 4.5, 12.0 Hz, 1H), 3.70 (s, 3H), 6.13 (d, J =
10.0 Hz, 1H), 7.01 (d, J = 10.5 Hz, 1H), 7.18 (d, J = 7.0 Hz, 2H), 7.71
(s, 1H). 13C NMR (125 MHz, DMSO): δ 19.5, 20.1, 43.4, 46.0, 63.9,
85.9, 124.3, 128.6, 128.7, 129.4, 136.1, 136.8, 142.8, 148.0, 163.7,
9-(Trifluoromethyl)-2-hydroxy-5-methoxyphenanthridin-6(5H)-
one (5f). Yellowish solid (34.0 mg, 55%). Mp 234−235 °C. 1H NMR
(500 MHz, DMSO): δ 4.02 (s, 3H), 7.21 (d, J = 8.0 Hz, 1H), 7.55 (d,
J = 9.0 Hz, 1H), 7.97 (s, 2H), 8.53 (d, J = 8.5 Hz, 1H), 8.72 (s, 1H),
9.76 (s, 1H). 13C NMR (125 MHz, DMSO): δ 63.1, 109.8, 114.4,
118.8, 120.1, 120.7, 124.3 (q, J = 271.6 Hz), 124.6, 129.3, 129.7, 133.1
(q, J = 31.9 Hz), 133.4, 154.4, 155.0. HRMS (ESI-TOF) m/z: calcd for
+
C15H11F3NO3 [M + H]+ 310.0686; found 310.0689.
+
197.2. HRMS (ESI-TOF) m/z: calcd for C16H17NNaO4 [M + Na]+
2-Hydroxy-5-methoxy-7-methylphenanthridin-6(5H)-one (5g).
310.1050; found 310.1047.
1
Yellowish solid (35.7 mg, 70%). Mp 199−200 °C. H NMR (500
4a-Hydroxy-5-methoxy-1,4a,5,12b-tetrahydrobenzo[j]-
phenanthridine-2,6-dione (3i). Yellowish solid (34.0 mg, 55%). Mp
MHz, DMSO): δ 2.86 (s, 3H), 3.96 (s, 3H), 7.11 (d, J = 7.5 Hz, 1H),
7.42 (s, 2H), 7.68 (s, 1H), 7.75 (s, 1H), 8.22 (d, J = 7.5 Hz, 1H), 9.63
(s, 1H). 13C NMR (125 MHz, DMSO): δ 24.3, 62.6, 109.4, 113.8,
119.1, 119.4, 121.4, 124.6, 129.2, 132.2, 132.5, 134.2, 142.0, 153.8,
1
216−217 °C. H NMR (500 MHz, DMSO): δ 2.62 (d, J = 14.0 Hz,
1H), 2.77 (t, J = 14.0 Hz, 1H), 3.77 (s, 3H), 3.90 (d, J = 10.5 Hz, 1H),
6.19 (d, J = 10.0 Hz, 1H), 7.08 (d, J = 9.5 Hz, 1H), 7.37 (s, 1H), 7.58
(s, 1H), 7.65 (s, 1H), 7.93 (s, 2H), 8.14 (d, J = 7.5 Hz, 1H), 8.64 (s,
1H). 13C NMR (125 MHz, DMSO): δ 44.0, 46.7, 64.0, 85.9, 125.1,
127.1, 127.2, 127.8, 129.0, 129.1, 129.4, 129.8, 131.9, 135.1, 135.5,
+
156.9. HRMS (ESI-TOF) m/z: calcd for C15H13NNaO3 [M + Na]+
278.0788; found 278.0791.
2-Hydroxy-5-methoxy-8-methylphenanthridin-6(5H)-one (5h).
1
+
Yellowish solid (28.1 mg, 55%). Mp 214−215 °C. H NMR (500
148.1, 163.2, 197.2. HRMS (ESI-TOF) m/z: calcd for C18H15NNaO4
[M + Na]+ 332.0893; found 332.0897.
MHz, DMSO): δ 2.48 (s, 3H), 3.99 (s, 3H), 7.11 (d, J = 9.0 Hz, 1H),
7.48 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 8.15
(s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 9.68 (s, 1H). 13C NMR (125 MHz,
DMSO): δ 21.4, 62.9, 109.0, 114.2, 118.6, 119.6, 123.2, 126.4, 127.9,
128.6, 130.4, 134.5, 138.6, 154.1, 155.8. HRMS (ESI-TOF) m/z: calcd
4a-Hydroxy-5-methoxy-3-methyl-1,4a,5,10b-tetrahydrophenan-
thridine-2,6-dione (3j). Yellowish solid (34.9 mg, 64%). Mp 182−183
°C. 1H NMR (400 MHz, DMSO): δ 1.81 (s, 3H), 2.59−2.64 (m, 2H),
3.69−3.72 (m, 4H), 6.82 (d, J = 1.2 Hz, 1H), 7.14 (s, 1H), 7.41−7.45
(m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H). 13C NMR
(125 MHz, DMSO): δ 15.5, 43.4, 46.0, 63.8, 86.2, 126.8, 127.7, 127.8,
128.5, 133.6, 135.0, 139.2, 143.0, 163.2, 197.0. HRMS (ESI-TOF) m/
+
for C15H14NO3 [M + H]+ 256.0968; found 256.0963.
2-Hydroxy-5-methoxy-8,9-dimethylphenanthridin-6(5H)-one
(5i). Yellowish solid (37.7 mg, 70%). Mp 216−217 °C. 1H NMR (500
MHz, DMSO): δ 2.38 (s, 3H), 2.44 (s, 3H), 3.98 (s, 3H), 7.10 (d, J =
7.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 8.08 (s, 1H), 8.14
(s, 1H), 9.63 (s, 1H). 13C NMR (125 MHz, DMSO): δ 19.9, 20.5,
62.9, 109.0, 114.1, 118.5, 119.6, 123.6, 124.4, 128.3, 128.8, 130.7,
138.0, 142.9, 154.0, 155.9. HRMS (ESI-TOF) m/z: calcd for
+
z: calcd for C15H15NNaO4 [M + Na]+ 296.0893; found 296.0884.
The spectra of compounds 4b and 4c are consistent with our
previous work11 and H NMR (see Supporting Information).
1
2-Hydroxy-5-methoxyphenanthridin-6(5H)-one (5a). Yellowish
solid (37.1 mg, 77%). Mp 215−216 °C. 1H NMR (500 MHz,
DMSO): δ 4.00 (s, 3H), 7.14 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 9.0 Hz,
1H), 7.66 (t, J = 7.0 Hz, 1H), 7.79 (s, 1H), 7.85 (t, J = 7.0 Hz, 1H),
8.34−8.38 (m, 2H), 9.72 (s, 1H). 13C NMR (125 MHz, DMSO): δ
62.9, 109.2, 114.3, 119.1, 119.5, 123.2, 126.5, 128.2, 128.8, 129.0,
132.8, 133.3, 154.1, 155.9. HRMS (ESI-TOF) m/z: calcd for
+
C16H16NO3 [M + H]+ 270.1125; found 270.1114.
2-Hydroxy-5-methoxybenzo[j]phenanthridin-6(5H)-one (5j). Yel-
1
lowish solid (30.3 mg, 52%). Mp 208−209 °C. H NMR (500 MHz,
DMSO): δ 4.03 (s, 3H), 7.13 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 9.0 Hz,
1H), 7.66 (s, 1H), 7.73 (s, 1H), 7.97 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H),
8.25 (d, J = 8.0 Hz, 1H), 9.01 (d, J = 12.5 Hz, 2H), 9.72 (s, 1H). 13C
NMR (125 MHz, DMSO): δ 62.9, 109.8, 114.4, 118.6, 120.1, 122.4,
124.6, 127.6, 128.8, 129.0, 129.1, 129.4, 129.6, 132.2, 135.2, 154.3,
+
C14H12NO3 [M + H]+ 242.0812; found 242.0816.
2-Hydroxy-5-methoxy-9-methylphenanthridin-6(5H)-one (5b).
1
Yellowish solid (38.3 mg, 75%). Mp 208−209 °C. H NMR (500
+
156.2. HRMS (ESI-TOF) m/z: calcd for C18H14NO3 [M + H]+
MHz, DMSO): δ 2.5 (s, 3H), 3.97 (s, 3H), 7.11 (d, J = 7.5 Hz, 1H),
7.45 (s, 2H), 7.77 (s, 1H), 8.16 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 9.65
(s, 1H). 13C NMR (125 MHz, DMSO): δ 22.0, 62.9, 109.2, 114.2,
119.0, 119.5, 123.1, 124.2, 128.2, 129.1, 130.0, 132.8, 143.6, 154.0,
292.0968; found 292.0976.
2-Hydroxy-5-methoxy-3-methylphenanthridin-6(5H)-one (5k).
1
Yellowish solid (29.1 mg, 57%). Mp 207−208 °C. H NMR (500
+
155.9. HRMS (ESI-TOF) m/z: calcd for C15H14NO3 [M + H]+
MHz, DMSO): δ 2.32 (s, 3H), 4.01 (s, 3H), 7.42 (s, 1H), 7.63 (t, J =
7.5 Hz, 1H), 7.73 (s, 1H), 7.86 (t, J = 7.0 Hz, 1H), 8.21 (d, J = 8.0 Hz,
1H), 8.34 (d, J = 7.5 Hz, 1H), 9.66 (s, 1H). 13C NMR (125 MHz,
DMSO): δ 17.1, 62.9, 108.2, 114.8, 116.9, 122.6, 126.1, 128.2, 128.9,
129.2, 132.8, 133.4, 152.4, 155.9. HRMS (ESI-TOF) m/z: calcd for
256.0968; found 256.0971.
9-tert-Butyl-2-hydroxy-5-methoxyphenanthridin-6(5H)-one (5c).
1
Yellowish solid (38.0 mg, 64%). Mp 199−200 °C. H NMR (500
MHz, DMSO): δ 1.41 (s, 9H), 3.99 (s, 3H), 7.13 (dd, J = 2.0, 9.0 Hz,
1H), 7.49 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 2.0
Hz, 1H), 8.27−8.28 (m, 2H), 9.65 (s, 1H). 13C NMR (125 MHz,
DMSO): δ 31.4, 35.8, 62.9, 109.2, 114.2, 118.9, 119.1, 119.7, 124.3,
126.6, 128.2, 129.1, 132.5, 154.0, 155.7, 156.3. HRMS (ESI-TOF) m/
+
C15H14NO3 [M + H]+ 256.0968; found 256.0947.
ASSOCIATED CONTENT
■
S
* Supporting Information
+
z: calcd for C18H20NO3 [M + H]+ 298.1438; found 298.1427.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02903.
2-Hydroxy-5,9-dimethoxyphenanthridin-6(5H)-one (5d). Yellow-
1
ish solid (24.4 mg, 45%). Mp 195−196 °C. H NMR (500 MHz,
DMSO): δ 3.97 (s, 3H), 3.98 (s, 3H), 7.14 (dd, J = 2.5, 9.0 Hz, 1H),
7.22 (dd, J = 2.0, 8.5 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 2.0
Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 9.66 (s,
1H). 13C NMR (125 MHz, DMSO): δ 56.3, 62.9, 105.6, 109.7, 114.1,
117.2, 119.3, 119.3, 119.9, 129.3, 130.3, 134.9, 153.9, 155.7, 163.3.
Experimental procedures and analytical data for all new
compounds (PDF)
X-ray structure and crystallographic data for compound
3h (CIF)
+
HRMS (ESI-TOF) m/z: calcd for C15H14NO4 [M + H]+ 272.0917;
found 272.0912.
AUTHOR INFORMATION
9-Chloro-2-hydroxy-5-methoxyphenanthridin-6(5H)-one (5e).
Yellowish solid (38.5 mg, 70%). Mp 236−237 °C. H NMR (500
MHz, DMSO): δ 4.00 (s, 3H), 7.18 (d, J = 9.0 Hz, 1H), 7.51 (d, J =
9.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 8.32 (d, J = 8.5 Hz,
1H), 8.48 (s, 1H), 9.74 (s, 1H). 13C NMR (125 MHz, DMSO): δ
63.0, 109.8, 114.4, 118.6, 119.9, 123.0, 125.2, 128.9, 129.4, 130.4,
■
1
Corresponding Author
*E-mail: xuxx677@nenu.edu.cn.
Notes
The authors declare no competing financial interest.
E
DOI: 10.1021/acs.joc.5b02903
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
36, 48. (f) Zhou, T.; Li, L.; Li, B.; Song, H.; Wang, B. Org. Lett. 2015,
17, 4204.
(13) CCDC 1443965 (3h) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Sciences
Foundation of China (21172030) for financial support.
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DOI: 10.1021/acs.joc.5b02903
J. Org. Chem. XXXX, XXX, XXX−XXX