Annulation of Benzamides with Arynes Using Palladium with Photoredox Dual Catalysis

Article abstract of DOI:10.1021/acs.joc.9b00893

Efficient annulation of benzamides with arynes using palladium and photoredox dual catalysis under an oxygen atmosphere is disclosed, which circumvents the use of external toxic metal oxidant and proceeds readily via aryne insertion at room temperature to construct the phenanthridinone backbone.

Full text of DOI:10.1021/acs.joc.9b00893

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Annulation of Benzamides with Arynes Using Palladium with
Photoredox Dual Catalysis
Jie Zhao,† Hongji Li,*,† Pinhua Li,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: Efficient annulation of benzamides with arynes using palladium and photoredox dual catalysis under an oxygen
atmosphere is disclosed, which circumvents the use of external toxic metal oxidant and proceeds readily via aryne insertion at
room temperature to construct the phenanthridinone backbone.
examples, Larock and co-workers in 2012 realized Pd-catalyzed
annulation of ortho-halobenzamides with arynes, affording N-
substituted phenanthridinones in good yields (Scheme 1a).8b
INTRODUCTION
■
Over the past years, visible light-mediated photoredox catalysis
has garnered considerable attention in the construction of
complex organic molecules that are not achievable through the
conventional transition-metal catalysis.1 Particularly, a strategy
of photoredox with transition-metal dual catalysis, also termed
metallaphotoredox catalysis pioneered by MacMillan, ex-
tremely drives the rapid advancement of photochemistry in
the field of organic synthesis.2 In fact, some elegant works
using this dual catalysis strategy have demonstrated the high
efficiency and significant advantages in enabling catalytic access
to unconventional C−C and C−heteroatom bond formation.3
Hitherto, several representative combinations of transition-
metal catalyst, such as Pd,3b,c Cu,4a and some others2d,4b,c with
the photoredox catalyst have been well established in this
area.4 Despite advances, the merger of photoredox and Pd
catalysis as a highly versatile platform is still in its infancy,
which can be further employed to establish mild and
environmentally benign synthetic methodologies for more
challenging organic transformations.
Scheme 1. Strategies for the Construction of
Phenanthridinones
Very recently, Xu’s group and Jeganmohan’s group almost
simultaneously reported the direct cyclization of benzamides
with arynes using the amide-directed C−H activation
strategy.12b,c However, a stoichiometric amount of copper
salt or persulfate salt is required for regeneration of the Pd(II)
catalyst, which is extremely detrimental in practical organic
synthesis. Inspired by the recent strategy of palladium
metallaphotoredox catalysis, we envisioned that molecular O2
theoretically may take the place of the toxic metal salts under
the visible-light irradiation to enable Pd-catalyzed annulation.
Additionally, the majority of the reactions involving arynes
Recently, aryne chemistry has been gaining the renaissance
in the construction of heterocycles and complex organic
molecules, largely due to their inherent strain that made
themselves highly reactive.5 Indeed, the unique properties of
arynes have witnessed the powerful ability to manipulate a
variety of chemical bonds.6 Particularly, noteworthy is that the
mild generation of arynes using Kobayashi’s protocol7 has
made it relatively easy to discover more reaction modes.6 In
particular, Larock,8 Biju,9 Greaney,10 Li,11 and others12
subsequently reported elegant results with respect to benzyne
insertion, enabling the difunctionalization of benzene under
mild conditions.6−12 Among such transformations, annulation
of arynes seemed to be significantly valuable in organic
synthesis for their diverse reaction modes. For selected
Received: April 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00893
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often require heating or critical conditions, which are actually
not the ideal methodologies in synthetic chemistry.13 There-
fore, the development of mild and eco-friendly benzyne
chemistry proceeding at room temperature would be highly
desirable. Herein, we will report the application of dual
palladium and photoredox catalysis strategy in room-temper-
ature annulation of benzamides with arynes under an oxygen
atmosphere (Scheme 1b).
process and improve the yield of 3a (entries 6 and 7). To our
delight, acetone was found to be the best reaction medium for
annulation of 1a with 2a, leading to 80% yield of 3a (entry 8).
However, annulation did not work when using polar solvents,
such as dimethylformamide (DMF) and dimethyl sulfoxide
(DMSO) (entries 9 and 10). Furthermore, some common
photocatalysts, including Ru(bpy)3Cl2, rose bengal, methylene
blue, and acid red 94, were evaluated in this model annulation,
and no improved results were observed (entries 11−14). In the
absence of Na2-eosin Y or CsF, no desired product 3a was
isolated (entries 15 and 16). Annulation did not proceed under
a nitrogen atmosphere, showing that the molecular oxygen
plays a crucial role in the catalytic recycle. Similarly, the
reaction did not occur when carried out at 80 °C in dark for 12
h, indicating that blue LED is irreplaceable for the excitation of
ground-stated photocatalyst Na2-eosin Y (entry 17). Finally,
the screening of the light source showed that blue LED (450−
455 nm) is most effective in this annulation (Table S1 of
Supporting Information). Finally, it is found that annulation
also can proceed under air to give the 3a in slightly decreased
yield (entry 18).
RESULTS AND DISCUSSION
■
We then started the work by optimizing the annulation
reaction conditions with N-methoxybenzamide (1a) and 2-
(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) selected
as model substrates (Table 1). Based on our recent work on
a
Table 1. Optimization of the Reaction Conditions
Then, the annulation reactions of several substituted N-
methoxylbenzamides with benzyne were examined under the
optimal conditions, and the results are listed in Table 2. It is
found that parasubstituted substrates with incorporation of
electron-donating substituents, such as Me, Et, t-Bu, MeO, and
EtO, reacted efficiently with 2a to produce the desired
products (3b−f) in good yields. Inversely, annulation of
benzyne with aryl amides having electron-withdrawing
substituents including CO2Me, CF3, NO2, and CN proceeded
smoothly to give 3g−j in decreasing yields. Moreover,
introducing halogens such as F and Cl into the phenyl ring
slightly retarded the annulation process (3k and l). Installation
of Me, MeO, and Cl at the meta-position were also allowed to
react with 2a, affording the products 3m−o in 65−81% yields.
We found that weak steric hindrance existed in this Pd-
catalyzed annulation when ortho-substituted aryl amides were
investigated (3b vs 3m, 3o vs 3q). Particularly, reactions with
some other amides possessing π-conjugated groups gave the
target products in moderate to good yields (3r−t). In case of
arylamides with bis-substitution, slightly reduced product
yields were observed, affording 72% of 3u and 75% of 3v,
respectively. Replacing Me with MeO on nitrogen of amide
retarded this cyclization process, and longer reaction time (36
h) was required for 66% of product 3w. Additionally, the
reaction of benzamide with benzyne still delivers the product
3x in 29% yield. Unfortunately, N-phenyl amide did not work
under the standard reaction conditions.
Next, we focused on exploring the scope of aryne precursors
2 under the optimized reaction conditions, and the results are
listed in Table 3. As we expected, the employment of
asymmetric arynes for annulation provided the products 4a/
4a′ (3.6:1) and 4b/4b′ (1.6:1) in satisfactory yields, albeit
with low regioselectivity. Interestingly, it is found that
introducing Cl into aryne led to the selective formation of
4c as the final product, indicating the significant halogen effect.
The reaction of asymmetric arynes possessing electron-
donating alkyl or 1,3-dioxole at both 3- and 4-positions with
1a proceeded efficiently to form the corresponding annulation
products in acceptable yields (4d−f). Particularly, we found
that one asymmetric aryne generated from 1a with 2-
(trimethylsilyl)naphthalen-1-yl trifluoromethansulfeo-nate re-
acted to generate 4g as a sole product in 62% yield.
b
Entry
photocatalyst
F-source
solvent
yield (%)
1
2
3
4
5
6
7
8
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
Ru(bpy)3Cl2
rose bengal
methylene blue
acid red 94
CsF
TBAF
KF
CH3CN
CH3CN
CH3CN
PhMe
THF
DCM
DCE
acetone
DMF
DMSO
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
12
trace
11
8
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
0
26
40
80
trace
0
9
10
11
12
13
14
15
16
17
18
0
21
15
9
0
Na2-eosin Y
Na2-eosin Y
Na2-eosin Y
0
0, 0
73
c
d
CsF
CsF
e
a
Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol), Pd(OAc)2 (5
mol %), photocatalyst (1 mol %), F-source (2.2 equiv), and solvent
(1.0 mL), irradiated with blue light-emitting diode (LED) (450−455
nm) at room temperature under an O2 atmosphere for 12 h. Isolated
b
c
d
e
yield. N2. 80 °C in dark for 12 h. Air.
aryne insertion,14 the model reaction was preferentially
performed using acetonitrile as the solvent and CsF as a
base, mainly because of which facilitates the formation of the
benzyne intermediate at room temperature. This annulation
could proceed by using 5 mol % Pd(OAc)2 and 1 mol % Na2-
eosin Y as a photocatalyst with blue LED (1.5 W) irradiation
under an oxygen atmosphere for 12 h, affording the desired
product 3a in 12% yield (entry 1). Instead of CsF, both tetra-
n-butylammonium fluoride (TBAF) and potassium fluoride
(KF) did not effectively promote this annulation under the
similar reaction conditions (entries 2 and 3). Then, the solvent
effect was explored under the above conditions. It was found
that PhMe resulted in the formation of 3a in 8% yield (entry
4). Annulation did not proceed in tetrahydrofuran (THF), and
no 3a was detected (entry 5). The use of dichloromethane
(DCM) and 1,2-dichloroethane (DCE) can accelerate the
B
DOI: 10.1021/acs.joc.9b00893
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The Journal of Organic Chemistry
Article
a
Table 2. Scope of Substituted Benzamides
Table 3. Scope of Aryne Precursors
a
Reaction conditions: 1a (0.20 mmol), 2 (0.22 mmol), Pd(OAc)2 (5
mol %), Na2-eosin Y (1 mol %), and CsF (2.2 equiv) in acetone (1
mL) irradiated with blue LED (450−455 nm) at room temperature
b
under an O2 atmosphere for 12 h. Isolated yield.
Scheme 2. Mechanistic Studies
a
Reaction conditions: 1 (0.20 mmol), 2a (0.22 mmol), Pd(OAc)2 (5
mol %), Na2-eosin Y (1 mol %), CsF (2.2 equiv) in acetone (1.0 mL)
irradiated with blue LED (450−455 nm) at room temperature under
b
c
d
an O2 atmosphere for 12 h. Isolated yield. 1 mmol scale. 36 h.
Although Pd-catalyzed cyclization of benzoamides with
arynes has been established under traditional conditions, a
reasonable reaction pathway in which employing stoichio-
metric copper salt to regenerate the palladium catalyst was also
provided. When it comes to palladium metallaphotoredox
catalysis in this annulation, the reaction seemed to proceed via
a distinct pathway. To figure out the issue, a series of control
experiments were carried out to investigate this catalytic
system (Scheme 2). A mixture of [D5]-1a/1a (1:1) was used to
react with 2a under optimized conditions, resulting into the
eosin Y (Scheme 2b), but no product 3a was observed,
excluding the possibility that O2 acts as an oxidant.
Additionally, employing stoichiometric 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO, a common radical scavenger) as an
additive in the reaction system did not produce 3a,
demonstrating that a highly reactive radical species may be
involved in the photoredox catalysis (Scheme 2c). Following
that, the electron spin resonance (ESR) experiment with 5,5-
dimethyl-1-pyrroline N-oxide (DMPO) as the radical trapping
1
formation of 3a in 22% yield. Then, the H NMR analysis
determined the kinetic isotope effect (KIE) value (kH/kD = 5.9,
Scheme 2a), indicating that the insertion of Pd(II) into the C−
H bond may be the rate-determining step in the catalytic cycle
(Scheme 3). The annulation reaction was specially performed
under an oxygen atmosphere (balloon) in the absence of the
C
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eosin Y•− = +0.83 V),16 which was theoretically quenched by
Pd(0) to give eosin Y•− as well as the regeneration of Pd(II)
for the catalytic cycle. Furthermore, the interaction of
molecular oxygen with Na2-eosin Y•− yielded superoxygen
anion radical species, which is detected by ESR experiment
(Figure 1).15a In addition, the formation of H2O2 was also
examined by a starch potassium iodide test paper, and the
paper changed to blue. However, the possibility of the
superoxygen anion radical acts as an oxidant to enable the
same oxidation of Pd(0) into Pd(II) should not be ruled out.3b
Scheme 3. Proposed Reaction Mechanism
CONCLUSIONS
■
In conclusion, we have established mild annulation of
benzamides with arynes under air using dual palladium and
organophotoredox catalysis, providing a useful tool to
construct the phenanthridinone derivatives in an efficient
manner. Mechanistic studies indicate the crucial role of O2 in
this dual catalytic system. The further applications of palladium
and organophotoredox catalysis are currently underway in our
laboratory.
EXPERIMENTAL SECTION
■
reagent successfully detected the trapping adducts (Scheme
2d), confirming the presence of the superoxygen radical anion
(Figure 1) and which is crucial for the regeneration of the
Pd(II) catalyst (Scheme 3).
1
General Information. All H NMR and 13C NMR spectra were
recorded on a 400 MHz Bruker FT-NMR spectrometer (400 and 100
MHz, respectively) and 600 MHz Bruker FT-NMR spectrometer
(600 and 150 MHz, respectively). All chemical shifts are given as the
δ value (ppm) with reference to tetramethylsilane as an internal
standard. The peak patterns are indicated as follows: s, singlet; d,
doublet; t, triplet; m, multiplet; and q, quartet. The coupling
constants, J, are reported in hertz. High-resolution mass spectroscopy
data of the products were collected on Agilent Technologies 6540
UHD Accurate-Mass Q-TOF LC/MS (ESI) and a Thermo Fisher
Scientific LTQ FTICR-MS instrument. Infrared (IR) spectra were
recorded on a Nicolet 6700 spectrophotometer and are reported as
wavenumber (cm−1). Melting points were determined in an open
capillary tube using a WRS-1B digital melting point apparatus.
The starting materials, benzamide derivatives and 2-
(trimethylsilyl)phenyl trifluoromethanesulfonates, were prepared
according to the reported methods.7,17 All the solvents were dried
and freshly distilled prior to use. Products were purified by flash
chromatography on silica gels, eluting with petroleum ether/ethyl
acetate (3:1 to 5:1).
Typical Procedure for Annulation of Benzamides with
Arynes. Under an air atmosphere, a 10 mL oven-dried quartz
photoreactor equipped with a magnetic stirrer bar was charged with
N-methoxybenzamide (1a, 30.2 mg, 0.20 mmol), Pd(OAc)2 (2.2 mg,
5 mol %), Na2-esoin Y (1.4 mg, 1 mol %), CsF (66.9 mg, 0.44 mmol),
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a, 65.7 mg, 0.22
mmol), and freshly distilled acetone (1.0 mL). Then, the resulted
solution was placed in a distance of ∼1.5 cm from 1.5 W blue LED
(450−455 nm) at room temperature for 12 h. The reaction process
was detected by thin-layer chromatography (TLC). After the reaction,
the crude product was purified by flash chromatography (silica gel,
petroleum ether/ethyl acetate = 3:1 to 5:1), affording the desired
product 3a as a white solid (36.0 mg, 80% yield).
Typical Procedure for the Synthesis of 3a in the 1 mmol
Scale. Under an air atmosphere, a 10 mL oven-dried quartz
photoreactor equipped with a magnetic stirrer bar was charged with
N-methoxybenzamide (1a, 151.1 mg, 1.0 mmol), Pd(OAc)2 (11.2 mg,
5 mol %), Na2-esoin Y (6.9 mg, 1 mol %), CsF (334.2 mg, 2.2 mmol),
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a, 327.8 mg, 1.1
mmol), and freshly distilled acetone (1.0 mL). Then, the resulted
solution was placed in a distance of ∼1.5 cm from 1.5 W blue LED
(450−455 nm) at room temperature for 12 h. The reaction process
was detected by TLC. After the reaction, the crude product was
purified by flash chromatography (silica gel, petroleum ether/ethyl
Figure 1. All the ESR spectra were measured in a solution of DMPO
(2.0 × 10−2 M), Na2-eosin Y (1 mol %) in oxygen-saturated acetone.
(A) Without blue LED irradiation; (B) with blue LED irradiation for
5 s; (C) with blue LED irradiation for 10 s; (D) with blue LED
irradiation for 15 s.
Based on the above experimental results and relating
reports,3b,c,12b,c,15a a possible reaction mechanism is proposed
in Scheme 3. Initially, Pd(II) coordinated with nitrogen of 1a
to form I, followed by the ortho C−H insertion (activation),
afforded the five-membered palladacycle species II.15a Then,
benzyne was in situ generated from 2a using CsF as a base and
which underwent coordinative insertion into II, delivering the
intermediate III or III′. The key reductive elimination of III or
III′ released the product 3a and Pd(0). In addition, upon
irradiation under blue LED, ground-stated eosin Y was easily
excited to its excited-state Na2-eosin Y* (Na2-eosin Y*/Na2-
D
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acetate = 3:1 to 5:1), affording the desired product 3a as a white solid
(177.8 mg, 79% yield).
δ 156.2, 136.2, 134.2 (q, J = 32.0 Hz), 133.3, 130.9, 129.6, 128.7,
124.1 (q, J = 3.4 Hz), 123.7 (q, J = 270.0 Hz), 123.6, 123.3, 119.3 (q,
J = 4.0 Hz), 117.6, 112.8, 62.8.
5-Methoxyphenanthridin-6(5H)-one (3a).18 It is obtained as a
white solid; 36.0 mg, 80% yield; mp 107−109 °C. H NMR (400
5-Methoxy-9-nitrophenanthridin-6(5H)-one (3i).18 It is obtained
as a white solid; 42.7 mg, 79% yield; mp 210−212 °C. 1H NMR (400
MHz, CDCl3): δ 9.13 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 8.39−8.33
(m, 2H), 7.76−7.68 (m, 2H), 7.46 (td, J1 = 8.2 Hz, J2 = 1.6 Hz, 1H),
4.18 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.9, 150.5,
136.4, 134.2, 131.6, 130.6, 130.3, 124.0, 123.7, 121.7, 117.8, 117.4,
113.1, 62.9.
1
MHz, CDCl3): δ 8.56 (d, J = 8.0 Hz, 1H), 8.27 (dd, J1 = 8.0 Hz, J2 =
3.2 Hz, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.59
(m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 4.14 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 157.2, 135.8, 132.9, 132.6, 129.9, 128.5, 128.0,
126.3, 123.2, 121.9, 118.5, 112.6, 62.7.
5-Methoxy-9-methylphenanthridin-6(5H)-one (3b).18 It is ob-
1
tained as a white solid; 39.7 mg, 83% yield; mp 152−154 °C. H
5-Methoxy-6-oxo-5,6-dihydrophenanthridine-9-carbonitrile (3j).
It is obtained as a white solid; 33.5 mg, 67% yield; mp 150−152 °C.
IR (KBr): 3440, 2920, 1652, 1608, 1559, 1327, 1112, 946, 886, 748.
1H NMR (600 MHz, CDCl3): δ 8.67 (d, J = 8.4 Hz, 1H), 8.59 (s,
1H), 8.24 (d, J = 7.9 Hz, 1H), 7.82 (dd, J1 = 8.2 Hz, J2 = 1.6 Hz, 1H),
7.73 (dd, J1 = 8.4 Hz, J2 = 1.0 Hz, 1H), 7.71−7.66 (m, 1H), 7.43 (t, J
= 8.4 Hz, 1H), 4.16 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ
156.0, 136.3, 133.6, 131.4, 129.9, 129.7, 129.0, 126.8, 123.9, 123.4,
118.0, 116.9, 116.4, 113.0, 62.9. HRMS (ESI): ([M + H]+) calcd for
[C15H11N2O2]+, 251.0815; found, 251.0813.
NMR (400 MHz, CDCl3): δ 8.44 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0
Hz, 1H), 8.05 (s, 1H), 7.66 (dd, J1 = 8.4 Hz, J2 = 0.9 Hz, 1H), 7.57
(td, J1 = 8.4 Hz, J2 = 0.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.34 (t, J =
7.6 Hz, 1H), 4.13 (s, 3H), 2.57 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 157.3, 143.2, 135.9, 132.9, 129.8, 129.5, 128.5, 124.0,
123.1, 123.0, 121.9, 118.5, 112.6, 62.7, 22.1.
9-Ethyl-5-methoxyphenanthridin-6(5H)-one (3c). It is obtained
as a white solid; 41.0 mg, 81% yield; mp 158−160 °C. IR (KBr):
3071, 2968, 2934, 1672, 1617, 1509, 1308, 1127, 1023, 955, 827, 739.
1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 8.0 Hz, 1H), 8.27 (d, J =
8.0 Hz, 1H), 8.07 (s, 1H), 7.66 (dd, J1 = 8.4 Hz, J2 = 0.8 Hz, 1H),
7.57 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.34
(t, J = 8.4 Hz, 1H), 4.13 (s, 3H), 2.86 (q, J = 7.6 Hz, 2H), 1.35 (t, J =
7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 157.3, 149.3,
135.9, 133.0, 129.7, 128.6, 128.3, 124.2, 123.1, 122.9, 120.8, 118.6,
112.55, 62.6, 29.4, 15.4. HRMS (ESI): ([M + H]+) calcd for
[C16H15NO2]+, 254.1176; found, 254.1174.
9-Fluoro-5-methoxyphenanthridin-6(5H)-one (3k).19 It is ob-
tained as a pale yellow solid; 37.4 mg, 77% yield; mp 157−159 °C. 1H
NMR (400 MHz, CDCl3): δ 8.59−8.55 (m, 1H), 8.15 (d, J = 8.0 Hz,
1H), 7.88 (dd, J1 = 10.0 Hz, J2 = 1.2 Hz, 1H), 7.68 (dd, J1 = 8.4 Hz, J2
= 1.2 Hz, 1H), 7.62 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.36 (td, J1 =
7.6 Hz, J2 = 1.2 Hz, 1H), 7.33−7.27 (m, 1H), 4.14 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 165.7 (d, J = 251.3 Hz), 156.6, 136.3,
135.6 (d, J = 9.0 Hz), 131.7 (d, J = 9.7 Hz), 130.7, 123.4, 123.2,
122.8, 117.7 (d, J = 3.1 Hz), 116.3 (d, J = 22.0 Hz), 112.8, 107.9 (d, J
= 24.0 Hz), 62.8.
9-(tert-Butyl)-5-methoxyphenanthridin-6(5H)-one (3d).18 It is
1
obtained as a white solid; 43.3 mg, 77% yield; mp 135−137 °C. H
9-Chloro-5-methoxyphenanthridin-6(5H)-one (3l).18 It is ob-
NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 7.8
Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 7.69−7.66 (m, 2H), 7.58 (td, J1 =
8.0 Hz, J2 = 1.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 4.13 (s, 3H), 1.45
(s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 156.1, 135.9, 132.6,
129.7, 128.3, 126.1, 124.0, 123.0, 122.9, 118.9, 118.0, 112.6, 62.6,
35.5, 31.2.
1
tained as a white solid; 36.3 mg, 70% yield; mp 170−172 °C. H
NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H),
8.18 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.62 (td, J1 = 7.8
Hz, J2 = 0.8 Hz, 1H), 7.54 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 7.35 (t, J
= 7.6 Hz, 1H), 4.14 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
156.6, 139.4, 136.2, 134.4, 130.7, 130.3, 128.4, 124.7, 123.4, 123.3,
121.9, 117.4, 112.8, 62.8.
5,9-Dimethoxyphenanthridin-6(5H)-one (3e).18 It is obtained as a
1
white solid; 43.9 mg, 86% yield; mp 133−135 °C. H NMR (400
5-Methoxy-8-methylphenanthridin-6(5H)-one (3m).18 It is ob-
MHz, CDCl3): δ 8.47 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H),
7.65 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.57
(td, J1 = 7.8 Hz, J2 = 1.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.15 (dd, J1
= 8.8 Hz, J2 = 2.4 Hz, 1H), 4.13 (s, 3H), 3.98 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 163.1, 157.1, 136.2, 134.9, 130.6, 130.0, 123.2,
122.9, 119.8, 118.2, 115.8, 112.6, 104.9, 62.7, 55.6.
1
tained as a white solid; 38.7 mg, 81% yield; mp 107−109 °C. H
NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H),
8.16 (d, J = 8.0 Hz, 1H), 7.66 (dd, J1 = 8.4 Hz, J2 = 0.8 Hz, 1H),
7.61−7.53 (m, 2H), 7.33 (t, J = 8.4 Hz, 1H), 4.13 (s, 3H), 2.52 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 157.3, 138.3, 135.4, 133.9,
130.5, 129.4, 128.2, 126.2, 123.1, 122.9, 121.9, 118.7, 112.5, 62.6,
21.3.
9-Ethoxy-5-methoxyphenanthridin-6(5H)-one (3f). It is obtained
as a white solid; 44.1 mg, 82% yield; mp 142−144 °C. IR (KBr):
3037, 2934, 2890, 1657, 1608, 1446, 1249, 1205, 1175, 1018, 955,
5,8-Dimethoxyphenanthridin-6(5H)-one (3n).12c It is obtained as
1
1
a white solid; 35.7 mg, 70% yield; mp 141−143 °C. H NMR (400
758. H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 8.8 Hz, 1H), 8.15
MHz, CDCl3): δ 8.20−8.17 (m, 2H), 7.97 (s, 1H), 7.67 (d, J = 8.0
Hz, 1H), 7.54 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.38−7.32 (m, 2H),
4.15 (s, 3H), 3.97 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
159.6, 157.1, 134.7, 128.8, 127.7, 126.5, 123.7, 123.2, 122.6, 122.5,
118.6, 112.5, 108.9, 62.7, 55.7.
(d, J = 8.0 Hz, 1H), 7.63 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.60 (d, J
= 2.4 Hz, 1H), 7.56 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.30 (t, J = 6.8
Hz, 1H), 7.12 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 4.20 (q, J = 6.8 Hz,
1H), 4.12 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 162.5, 157.1, 136.1, 134.8, 130.5, 129.9, 123.1,
122.8, 119.6, 118.2, 116.1, 112.5, 105.4, 63.8, 62.6, 14.7. HRMS
(ESI): ([M + H]+) calcd for [C16H16NO3]+, 270.1125; found,
270.1123.
8-Chloro-5-methoxyphenanthridin-6(5H)-one (3o).12b It is ob-
1
tained as a white solid; 33.7 mg, 65% yield; mp 152−154 °C. H
NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.20 (d, J = 8.0 Hz, 2H),
7.71 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.61
(t, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 4.14 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 156.2, 135.7, 134.3, 132.9, 131.4, 130.3,
128.0, 127.6, 123.6, 123.4, 123.2, 117.8, 112.8, 62.8.
Methyl 5-Methoxy-6-oxo-5,6-dihydrophenanthridine-9-carboxy-
late (3g).18 It is obtained as a white solid; 39.6 mg, 70% yield; mp
163−165 °C. 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 8.61 (d, J
= 8.0 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.19 (dd, J1 = 8.4 Hz, J2 = 1.2
Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.39 (t, J =
8.0 Hz, 1H), 4.16 (s, 3H), 4.02 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 166.3, 156.6, 136.0, 133.6, 133.0, 130.5, 129.2, 128.9,
128.1, 123.9, 123.5, 118.1, 112.7, 62.8, 52.6.
5-Methoxy-7-methylphenanthridin-6(5H)-one (3p).18 It is ob-
1
tained as a white solid; 33.0 mg, 69% yield; mp 197−199 °C. H
NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0
Hz, 1H), 7.60−7.48 (m, 3H), 7.31 (d, J = 7.2 Hz, 1H), 7.26 (td, J1 =
7.6 Hz, J2 = 1.6 Hz, 1H), 4.09 (s, 3H), 2.97 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 158.0, 142.7, 135.8, 134.3, 131.6, 131.5, 129.7,
124.4, 123.4, 122.7, 120.0, 118.3, 112.0, 62.3, 24.0.
5-Methoxy-9-(trifluoromethyl)phenanthridin-6(5H)-one (3h).18
It is obtained as a white solid; 42.2 mg, 72% yield; mp 153−155
°C. 1H NMR (400 MHz, CDCl3): δ 8.67 (d, J = 8.4 Hz, 1H), 8.51 (s,
1H), 8.27 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 (dd, J1 =
8.4 Hz, J2 = 0.8 Hz, 1H), 7.64 (td, J1 = 6.8 Hz, J2 = 1.2 Hz, 1H), 7.39
(t, J = 8.4 Hz, 1H), 4.16 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
7-Chloro-5-methoxyphenanthridin-6(5H)-one (3q).12c It is ob-
1
tained as a white solid; 31.1 mg, 60% yield; mp 135−137 °C. H
NMR (600 MHz, CDCl3): δ 8.17 (t, J = 8.4 Hz, 2H), 7.61−7.56 (m,
E
DOI: 10.1021/acs.joc.9b00893
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4H), 7.30 (t, J = 8.4 Hz, 1H), 4.12 (s, 3H). 13C{1H} NMR (150
MHz, CDCl3): δ 155.6, 136.3, 135.9, 132.0, 131.6, 130.6, 123.6,
123.1, 122.6, 120.9, 117.3, 112.3, 62.5.
MHz, CDCl3): δ 8.63 (d, J = 8.0 Hz, 0.27H), 8.50 (d, J = 8.0 Hz,
1H), 8.43 (d, J = 8.4 Hz, 0.28H), 8.20 (d, J = 8.0 Hz, 1H), 8.09 (d, J =
7.8 Hz, 1H), 7.77−7.67 (m, 1.3H), 7.63−7.58 (m, 0.35H), 7.54 (t, J =
8.0 Hz, 1.3H), 7.42 (t, J = 8.0 Hz, 0.29H), 7.31 (d, J = 7.2 Hz, 1H),
7.22−7.12 (m, 1.3H), 4.10 (s, 0.8H), 3.96 (s, 3H), 2.90 (s, 0.8H),
2.76 (s, 3.0H). 13C{1H} NMR (100 MHz, CDCl3): δ 158.3, 156.9,
136.3, 134.9, 134.4, 134.1, 133.3, 132.5, 131.6, 128.7, 128.5, 128.2,
127.9, 127.8, 127.1, 126.5, 125.9, 124.2, 124.1, 123.1, 122.1, 121.4,
119.7, 110.8, 62.8, 62.4, 26.2, 23.2.
6-Methoxybenzo[i]phenanthridin-5(6H)-one (3r). It is obtained
as a white solid; 34.7 mg, 63% yield; mp 167−169 °C. IR (KBr):
3055, 2919, 1650, 1605, 1475, 1443, 1298, 1237, 1186, 1152, 952,
824, 739. 1H NMR (400 MHz, CDCl3): δ 10.27 (d, J = 8.8 Hz, 1H),
8.40 (d, J = 8.0 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 9.2 Hz,
1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81−7.72 (m, 2H), 7.68−7.62 (m,
2H), 7.39 (t, J = 7.6 Hz, 1H), 4.2 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 158.1, 136.1, 134.1, 134.0, 132.9, 132.3, 130.3, 128.7,
128.2, 127.8, 126.9, 123.9, 122.9, 120.3, 119.3, 118.0, 112.2, 62.7.
HRMS (ESI): ([M + H]+) calcd for [C18H14NO2]+, 276.1019; found,
276.1022.
5-Methoxybenzo[j]phenanthridin-6(5H)-one (3s). It is obtained
as a white solid; 37.4 mg, 68% yield; mp 148−150 °C. IR (KBr):
3045, 2943, 1672, 1626, 1602, 1469, 1347, 1322, 1225, 1151, 1033,
956, 881, 755. 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 8.70 (s,
1H), 8.40 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.02 (d, J =
8.4 Hz, 1H), 7.68−7.62 (m, 2H), 7.58 (t, J = 7.8 Hz, 2H), 7.37 (t, J =
7.6 Hz, 1H), 4.17 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
157.7, 135.7, 135.1, 132.1, 129.8, 129.7, 129.2, 129.0, 128.5, 128.1,
126.8, 124.2, 123.3, 123.3, 121.1, 118.9, 112.8, 62.7. HRMS (ESI):
([M + H]+) calcd for [C18H14NO2]+, 276.1019; found, 276.1012.
5-Methoxy-9-phenylphenanthridin-6(5H)-one (3t).19 It is ob-
tained as a pale yellow solid; 49.4 mg, 82% yield; mp 149−151 °C. 1H
NMR (400 MHz, CDCl3): δ 8.62 (d, J = 8.0 Hz, 1H), 8.44 (s, 1H),
8.35 (d, J = 8.0 Hz, 1H), 7.82 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H),
7.73−7.67 (m, 3H), 7.60 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H),
7.45 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 4.16 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 157.2, 145.5, 140.2, 136.1,
133.3, 130.1, 129.1, 129.0, 128.3, 127.5, 127.2, 125.1, 123.2, 123.2,
120.4, 118.6, 112.7, 62.7.
5-Methoxy-2-methylphenanthridin-6(5H)-one (4b) and 5-Me-
thoxy-3-methylphenanthridin-6(5H)-one (4b′).12b It is obtained as a
1
white solid; 36.4 mg, 76% yield; mp 136−138 °C. H NMR (400
MHz, CDCl3): δ 8.57−8.52 (m, 1.6H), 8.27 (d, J = 8.0 Hz, 0.68H),
8.23 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.06 (s, 0.6H),
7.79−7.73 (m, 1.7H), 7.60−7.55 (m, 2H), 7.48 (s, 1H), 7.40 (d, J =
8.4 Hz, 0.6H), 7.17 (d, J = 8.0 Hz, 1H), 4.14 (s, 3H), 4.13 (s, 1.8H),
2.53 (s, 3H), 2.50 (s, 1.8H). 13C{1H} NMR (100 MHz, CDCl3): δ
157.4, 157.0, 140.5, 137.6, 135.8, 133.7, 133.0, 132.6, 132.5, 132.4,
132.2, 130.9, 128.5, 128.4, 128.3, 127.8, 127.5, 124.3, 123.2, 123.0,
121.8, 121.6, 118.4, 116.1, 112.6, 112.5, 62.6, 62.5, 21.8, 21.0.
2-Chloro-5-methoxyphenanthridin-6(5H)-one (4c).19 It is ob-
1
tained as a white solid; 36.8 mg, 71% yield; mp 142−144 °C. H
NMR (600 MHz, CDCl3): δ 8.55 (dd, J1 = 6.6 Hz, J2 = 0.8 Hz, 1H),
8.21−8.19 (m, 2H), 7.81−7.78 (m, 1H), 7.64 (t, J = 8.1 Hz, 1H),
7.61 (d, J = 8.8 Hz, 1H), 7.53 (dd, J1 = 8.8 Hz, J2 = 2.2 Hz, 1H), 4.13
(s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 156.9, 134.4, 132.8,
131.8, 129.9, 128.9, 128.7, 128.6, 126.6, 123.0, 122.0, 119.8, 114.1,
62.8.
5-Methoxy-2,3-dimethylphenanthridin-6(5H)-one (4d).19 It is
1
obtained as a white solid; 33.4 mg, 66% yield; mp 152−154 °C. H
NMR (400 MHz, CDCl3): δ 8.52 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H),
8.20 (d, J = 8.2 Hz, 1H), 7.95 (s, 1H), 7.72 (t, J = 8.4 Hz, 1H), 7.53
(t, J = 8.0 Hz, 1H), 7.41 (s, 1H), 4.13 (s, 3H), 2.41 (s, 3H), 2.38 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 157.2, 139.4, 133.9, 133.0,
132.3, 131.7, 128.4, 127.3, 126.0, 123.7, 121.6, 116.3, 113.2, 62.6,
20.3, 19.5.
5,8,9-Trimethoxyphenanthridin-6(5H)-one (3u).19 It is obtained
as a white solid; 41.1 mg, 72% yield; mp 195−197 °C. 1H NMR (400
MHz, CDCl3): δ 8.12 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.65 (dd, J1 =
8.0 Hz, J2 = 0.8 Hz, 1H), 7.57 (s, 1H), 7.54 (td, J1 = 7.8 Hz, J2 = 1.2
Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 4.13 (s, 3H), 4.09 (s, 3H), 4.04 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 156.8, 153.3, 149.8, 135.2,
128.9, 127.6, 122.9, 122.5, 120.2, 118.3, 112.6, 108.6, 102.8, 62.7,
56.2, 56.1.
6-Methoxy-6,8,9,10-tetrahydro-5H-cyclopenta[b]phenanthridin-
5-one (4e). It is obtained as a white solid; 33.9 mg, 64% yield; mp
161−163 °C. IR (KBr): 2954, 2896, 2831, 2361, 1642, 1422, 1316,
1173, 1033, 979, 777. 1H NMR (600 MHz, CDCl3): δ 8.53 (dd, J1 =
8.0 Hz, J2 = 1.3 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 7.75−
7.72 (m, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 4.13 (s, 3H),
3.08−3.03 (m, 4H), 2.20−2.16 (m, 2H). 13C{1H} NMR (150 MHz,
CDCl3): δ 157.2, 147.3, 139.6, 134.7, 133.3, 132.4, 128.4, 127.3,
125.8, 121.7, 118.4, 117.0, 108.3, 62.5, 33.3, 32.4, 25.7. HRMS (ESI):
([M + H]+) calcd for [C17H16NO2]+, 266.1176; found, 266.1174.
6-Methoxy-[1,3]dioxolo[4,5-b]phenanthridin-5(6H)-one (4f).12b
It is obtained as a white solid; 25.4 mg, 49% yield; mp 202−204
°C. 1H NMR (600 MHz, CDCl3): δ 8.53 (dd, J1 = 8.0 Hz, J2 = 1.1 Hz,
1H), 8.05 (d, J = 8.2 Hz, 1H), 7.75−7.73 (m, 1H), 7.64 (s, 1H), 7.54
(t, J = 8.0 Hz, 1H), 7.19 (s, 1H), 6.10 (s, 2H), 4.13 (s, 3H). 13C{1H}
NMR (150 MHz, CDCl3): δ 157.1, 150.0, 144.7, 133.0, 132.5, 132.2,
128.6, 127.0, 125.3, 121.5, 112.4, 102.0, 101.9, 94.0, 62.7.
5-Methoxy-8,10-dimethylphenanthridin-6(5H)-one (3v). It is
obtained as a white solid; 38.0 mg, 75% yield; mp 197−199 °C. IR
(KBr): 3074, 2929, 1662, 1607, 1334, 1250, 1162, 1054, 965, 762. 1H
NMR (400 MHz, CDCl3): δ 8.44 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H),
7.73 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.44
(s, 1H), 7.32 (t, J = 7.8 Hz, 1H), 4.12 (s, 3H), 2.93 (s, 3H), 2.48 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 157.5, 138.4, 137.3, 135.6,
134.8, 129.8, 128.6, 127.5, 126.9, 122.4, 120.2, 112.3, 62.5, 25.9, 20.9.
HRMS (ESI): ([M + H]+) calcd for [C16H16NO2]+, 254.1176; found,
254.1179.
5-Methylphenanthridin-6(5H)-one (3w).12c It is obtained as a
1
white solid; 28.8 mg, 66% yield; mp 104−106 °C. H NMR (400
6-Methoxybenzo[a]phenanthridin-5(6H)-one (4g).19 It is ob-
MHz, CDCl3): δ 8.55 (d, J = 8.0 Hz, 1H), 8.28 (dd, J1 = 8.0 Hz, J2 =
4.0 Hz, 2H), 7.8 (t, J = 8.0 Hz, 1H), 7.61−7.54 (m, 2H), 7.43 (d, J =
8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 3.83 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 161.5, 137.8, 133.4, 132.3, 129.4, 128.7, 127.8,
125.4, 123.1, 122.3, 121.5, 119.1, 114.9, 29.8.
1
tained as a white solid; 34.1 mg, 62% yield; mp 137−139 °C. H
NMR (600 MHz, CDCl3): δ 8.84 (d, J = 8.6 Hz, 1H), 8.76 (d, J = 8.4
Hz, 1H), 8.69 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 8.03 (d, J = 9.0 Hz,
1H), 7.98 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.84 (t, J = 8.4
Hz, 1H), 7.69−7.63 (m, 2H), 7.56 (t, J = 7.0 Hz, 1H), 4.20 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3): δ 157.3, 134.8, 133.4, 131.9,
Phenanthridin-6(5H)-one (3x).15a It is obtained as a white solid;
11.6 g, 29% yield; mp 101−103 °C. 1H NMR (600 MHz, DMSO-d6):
δ 10.85 (br, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H),
7.49 (dd, J1 = 7.9 Hz, J2 = 0.8 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 6.81
(t, J = 8.0 Hz, 1H), 6.65 (t, J = 8.3 Hz, 1H), 6.54 (dd, J1 = 8.1 Hz, J2 =
1.0 Hz, 1H), 6.43 (t, J = 8.2 Hz, 1H). 13C{1H} NMR (150 MHz,
DMSO-d6): δ 161.3, 137.0, 134.7, 133.3, 130.0, 128.4, 127.9, 126.1,
123.7, 123.1, 122.8, 118.0, 116.6. HRMS (ESI): ([M + H]+) calcd for
[C13H10NO]+, 196.0757; found, 196.0756.
131.1, 130.9, 129.9, 129.0, 128.5, 127.6, 127.3, 127.1, 127.0, 125.8,
125.0, 112.8, 112.5, 63.2.
General Procedure for the Kinetic Isotope Effect Experi-
ment. Under an air atmosphere, a 10 mL oven-dried quartz
photoreactor equipped with a magnetic stirrer bar was charged with
1a (0.20 mmol), [D5]-1a (0.20 mmol), (2a, 0.44 mmol), Pd(OAc)2
(5 mol %), Na2-esoin Y (1 mol %), and CsF (0.88 mmol), and freshly
distilled acetone (2.0 mL) was added to the resulted mixture. Then,
the solution was placed in a distance of ∼1.5 cm from 1.5 W blue
LED (450−455 nm) at room temperature for 4 h. After this, the
5-Methoxy-1-methylphenanthridin-6(5H)-one (4a) and 5-Me-
thoxy-4-methylphenanthridin-6(5H)-one (4a′).20 It is obtained as a
1
white solid; 38.3 mg, 80% yield; mp 159−161 °C. H NMR (400
F
DOI: 10.1021/acs.joc.9b00893
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The Journal of Organic Chemistry
Article
mixture in the reaction tube was detected by TLC. The crude product
was purified by flash chromatography (silica gel, petroleum ether/
ethyl acetate = 3:1 to 5:1) to give the desired product 3a in 22% yield,
9.9 mg (the yield of 3a was calculated based on 1a). The KIE value of
114.1, 64.1, 63.5, 14.5. HRMS (ESI): ([M + H]+) calcd for
[C10H14NO3]+, 196.0968; found, 196.0969.
Methyl 4-(Methoxycarbamoyl)benzoate (1g).12b It is obtained as
1
a white solid; 0.39 g, 93% yield; mp 115−117 °C. H NMR (400
1
MHz, CDCl3): δ 10.47 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.84 (d, J =
8.4 Hz, 2H), 3.93 (s, 3H), 3.84 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 166.2, 165.3, 135.7, 132.9, 129.6, 127.2, 64.2, 52.4.
N-Methoxy-4-(trifluoromethyl)benzamide (1h).12b It is obtained
5.9 was determined by H NMR of 3a and [D4]-3a.
General Procedure for the Control Experiment. Under an air
atmosphere, a 10 mL oven-dried quartz photoreactor equipped with a
magnetic stirrer bar was charged with N-methoxybenzamide (1a, 30.2
mg, 0.20 mmol), Pd(OAc)2 (2.2 mg, 5 mol %), CsF (66.9 mg, 0.44
mmol), and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a,
65.7 mg, 0.22 mmol), and freshly distilled acetone (1.0 mL) was
added to the resultant mixture. Then, the solution was placed in a
distance of ∼1.5 cm from 1.5 W blue LED (450−455 nm) at room
temperature for 12 h. After this, no 3a was detected by TLC.
General Procedure for the TEMPO Experiment. Under an air
atmosphere, a 10 mL oven-dried quartz photoreactor equipped with a
magnetic stirrer bar was charged with N-methoxybenzamide (1a, 30.2
mg, 0.20 mmol), Pd(OAc)2 (2.2 mg, 5 mol %), Na2-esoin Y (1.4 mg,
1 mol %), CsF (66.9 mg, 0.44 mmol), 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate (2a, 65.7 mg, 0.22 mmol), and TEMPO
(34.7 mg, 0.22 mmol), and freshly distilled acetone (1.0 mL) was
added to the resultant mixture. Then, the solution was placed in a
distance of ∼1.5 cm from 1.5 W blue LED (450−455 nm) at room
temperature for 12 h. After this, the mixture was detected by TLC,
and no 3a was formed.
1
as a white solid; 0.38 g, 87% yield; mp 122−124 °C. H NMR (400
MHz, CDCl3): δ 10.36 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.64 (d, J =
8.0 Hz, 2H), 3.84 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
165.1, 135.0, 133.8 (q, J = 31.7 Hz), 127.7, 125.6 (q, J = 3.0 Hz),
124.8 (q, J = 272.0 Hz), 64.3.
N-Methoxy-4-nitrobenzamide (1i).12b It is obtained as a white
solid; 0.36 g, 91% yield; mp 176−179 °C. 1H NMR (400 MHz,
(CD3)2SO): δ 6.39 (d, J = 8.6 Hz, 2H), 6.13 (d, J = 8.3 Hz, 2H), 1.85
(s, 3H). 13C{1H} NMR (100 MHz, (CD3)2SO): δ 161.4, 148.8,
138.6, 128.4, 123.4, 62.9.
4-Cyano-N-methoxybenzamide (1j). It is obtained as a white
solid; 0.32 g, 91% yield; mp 87−89 °C. 1H NMR (400 MHz, DMSO-
d6): δ 11.21 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz,
2H), 2.94 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 136.2,
132.5, 127.8, 118.2, 113.9, 63.2. HRMS (ESI): ([M + H]+) calcd for
[C9H9N2O2]+, 177.0659; found, 177.0658.
4-Fluoro-N-methoxybenzamide (1k).19 It is obtained as a white
solid; 0.32 g, 96% yield; mp 70−72 °C. 1H NMR (400 MHz, CDCl3):
δ 11.21 (s, 1H), 7.87−7.84 (m, 2H), 7.04 (t, J = 8.6 Hz, 2H), 3.79 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.0 (d, J = 251.0 Hz),
165.2, 129.6 (d, J = 8.9 Hz), 127.7, 115.5 (d, J = 21.8 Hz), 63.8.
HRMS (ESI): ([M + H]+) calcd for [C8H9FNO2]+, 170.0612; found,
170.0611.
General Procedure for the Determination of Superoxide
Radical Anions. A superoxide radical anion (O2•−) was assumed to
be generated from molecular oxygen by single electron transfer.3b,c
DMPO was used as a probe to capture active species (O2•−).21 As
shown in Figure 1, the solution of DMPO, eosin Y in acetone solution
was performed without irradiation of blue LED, leading to no signal
was detected. In contrast, upon irradiation with blue LED, each
irradiation was performed for 5 s for three consecutive irradiations, a
4-Chloro-N-methoxybenzamide (1l).12b It is obtained as a white
solid; 0.36 g, 97% yield; mp 74−76 °C. 1H NMR (400 MHz, CDCl3):
δ 7.71 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 138.2, 129.9, 128.8, 128.5, 64.2.
N-Methoxy-3-methylbenzamide (1m).12b It is obtained as a white
solid; 0.31 g, 95% yield; mp 70−72 °C. 1H NMR (400 MHz, CDCl3):
δ 10.60 (s, 1H), 7.58 (t, J = 6.5 Hz, 2H), 7.27−7.22 (m, 2H), 3.78 (s,
3H), 2.30 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.3,
138.2, 132.5, 131.5, 128.2, 127.7, 124.1, 63.9, 21.1.
•−
single radical species O2 was trapped with the characteristic signal
clearly observed by ESR experiments.
General Procedure for the Synthesis of Benzamides
Derivatives. The starting materials (benzamides, 1a−w) were
prepared according to the reported method.17
N-Methoxybenzamide (1a).12b It is obtained as a white solid; 0.28
g, 95% yield; mp 63−65 °C. 1H NMR (400 MHz, CDCl3): δ 10.98 (s,
1H), 7.78 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 7.8
Hz, 2H), 3.76 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.4,
131.9, 131.9, 128.5, 127.3, 64.0.
N-Methoxy-3-methoxybenzamide (1n).12c It is obtained as a
1
white solid; 0.34 g, 93% yield; mp 78−80 °C. H NMR (400 MHz,
CDCl3): δ 10.56 (s, 1H), 7.33 (t, J = 3.2 Hz, 2H), 7.25 (t, J = 8.0 Hz,
1H), 7.00 (dd, J1 = 8.3 Hz, J2 = 2.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.2, 159.7, 133.1, 129.6,
119.3, 118.3, 112.2, 64.1, 55.3.
N-Methoxy-4-methylbenzamide (1b).12b It is obtained as a white
solid; 0.32 g, 97% yield; mp 70−72 °C. 1H NMR (400 MHz, CDCl3):
δ 10.07 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H),
3.81 (s, 3H), 3.80 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
166.2, 162.5, 129.1, 124.0, 113.8, 64.3, 55.4.
3-Chloro-N-methoxybenzamide (1o).12b It is obtained as a white
solid; 0.36 g, 98% yield; mp 76−78 °C. 1H NMR (400 MHz, CDCl3):
δ 10.4 (s, 1H), 7.78 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 8.0
Hz, 1H), 7.30−7.28 (m, 1H), 3.83 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 165.1, 134.6, 133.3, 131.9, 129.8, 127.4, 125.3, 64.2.
N-Methoxy-2-methylbenzamide (1p).12b It is obtained as a white
solid; 0.28 g, 95% yield; mp 70−72 °C. 1H NMR (400 MHz, CDCl3):
δ 9.02 (s, 1H), 7.33−7.25 (m, 2H), 7.20−7.13 (m, 2H), 3.81 (s, 3H),
2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 167.9, 136.8,
132.6, 131.0, 130.5, 127.1, 125.6, 64.5, 19.4.
4-Ethyl-N-methoxybenzamide (1c). It is obtained as a white solid;
1
0.35 g, 96% yield; mp 76−78 °C. H NMR (400 MHz, CDCl3): δ
9.61 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.83
(s, 3H), 2.67 (q, J = 7.8 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 148.7, 129.1, 128.0, 127.2, 64.3, 28.7,
15.2. HRMS (ESI): ([M + H]+) calcd for [C10H14NO2]+, 180.1019;
found, 180.1016.
4-(tert-Butyl)-N-methoxybenzamide (1d).12b It is obtained as a
1
2-Chloro-N-methoxybenzamide (1q).12b It is obtained as a white
solid; 0.36 g, 96% yield; mp 75−77 °C. 1H NMR (400 MHz, CDCl3):
δ 9.00 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.46−7.29 (m, 3H), 3.90 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 164.5, 131.9, 131.1, 130.2,
127.1, 64.7.
white solid; 0.39 g, 95% yield; mp 63−65 °C. H NMR (400 MHz,
CDCl3): δ 9.74 (br, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz,
2H), 3.83 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ 155.4, 128.8, 126.9, 125.5, 64.3, 34.9, 31.0.
N-Methoxy-4-methoxybenzamide (1e).12b It is obtained as a
1
N-Methoxy-1-naphthamide (1r).22 It is obtained as a white solid;
0.37 g, 93% yield; mp 162−163 °C. 1H NMR (400 MHz, DMSO-d6):
δ 8.19 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0
Hz, 1H), 7.67−7.49 (m, 4H), 3.81 (s, 3H). 13C{1H} NMR (100
MHz, DMSO-d6): δ 165.3, 133.1, 131.5, 130.3, 129.9, 128.3, 126.9,
126.3, 125.7, 124.9, 124.8, 63.3.
white solid; 0.34 g, 93% yield; mp 79−81 °C. H NMR (400 MHz,
CDCl3): δ 9.90 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz,
2H), 3.82 (s, 3H), 3.81 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 166.2, 162.4, 129.0, 123.9, 113.7, 64.2, 55.3.
4-Ethoxy-N-methoxybenzamide (1f). It is obtained as a white
solid; 0.38 g, 97% yield; mp 123−125 °C. 1H NMR (400 MHz,
CDCl3): δ 10.26 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz,
2H), 4.02 (d, J = 7.0 Hz, 2H), 3.79 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 166.1, 161.8, 129.0, 123.7,
N-Methoxy-2-naphthamide (1s).22 It is obtained as a white solid;
1
0.36 g, 90% yield; mp 160−162 °C. H NMR (400 MHz, CDCl3): δ
9.23 (br, 1H), 8.3 (s, 1H), 7.91−7.88 (m, 3H), 7.80 (d, J = 8.8 Hz,
G
DOI: 10.1021/acs.joc.9b00893
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 7.61−7.53 (m, 2H), 3.95 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 134.9, 132.5, 128.9, 128.6, 127.9, 127.8, 127.7, 126.9,
123.3, 64.5.
1-(Trimethylsilyl)naphthalen-2-yl Trifluoromethanesulfonate
(2h).23 It is obtained as colorless viscous oil; 0.30 g, 43% yield. H
1
NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 6.0
Hz, 2H), 7.60−7.52 (m, 2H), 7.40 (d, J = 9.2 Hz, 1H), 0.60 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ 152.4, 137.5, 132.4, 132.3,
129.0, 128.7, 128.3, 126.6, 126.2, 119.1, 2.2.
N-Methoxy-[1,1′-biphenyl]-4-carboxamide (1t).22 It is obtained
1
as a white solid; 0.44 g, 97% yield; mp 164−166 °C. H NMR (400
MHz, CDCl3): δ 9.06 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.69 (d, J =
8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.44
(t, J = 7.8 Hz, 1H), 3.95 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 144.9, 139.7, 128.9, 128.1, 127.6, 127.3, 127.1, 64.7.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00893.
■
S
N-Methoxy-3,4-dimethoxybenzamide (1u).12b It is obtained as a
white solid; 0.38 g, 91% yield; mp 128−130 °C. 1H NMR (400 MHz,
CDCl3): δ 9.14 (s, 1H), 7.40 (s, 1H), 7.33 (d, J = 9.2 Hz, 1H), 6.87
(dd, J1 = 8.4 Hz, J2 = 2.0 Hz 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (d, J
= 4.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 149.1, 124.1,
119.8, 112.8, 110.3, 107.4, 64.5, 56.0.
Mechanistic experiments, characterization of N-methox-
ylbenzamides 1, arynes 2, and cyclization products 3 and
4, and NMR spectra of compounds (PDF)
N-Methoxy-3,5-dimethylbenzamide (1v). It is obtained as a white
solid; 0.34 g, 94% yield; mp 120−122 °C. 1H NMR (400 MHz,
CDCl3): δ 9.40 (br, 1H), 7.39 (s, 2H), 7.16 (s, 1H), 3.88 (s, 3H),
2.35 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.8, 138.4,
133.7, 131.7, 124.8, 64.5, 21.2. HRMS (ESI): ([M + H]+) calcd for
[C10H14NO2]+, 180.1019; found, 180.1021.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: hongjili@chnu.edu.cn (H.L.).
*E-mail: leiwang88@hotmail.com (L.W.).
■
N-Methylbenzamide (1w).12c It is obtained as a white solid; 0.26
g, 98% yield; mp 57−59 °C. 1H NMR (400 MHz, CDCl3): δ 7.81 (d,
J = 7.2 Hz, 2H), 7.53−7.43 (m, 3H), 6.53 (s, 1H), 3.05 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 168.4, 134.6, 131.4, 128.5,
126.9, 26.9.
ORCID
Pinhua Li: 0000-0002-8528-8087
Lei Wang: 0000-0001-6580-7671
Notes
General Procedure for the Synthesis of Aryne Precursor 2.
The starting materials (arynes, 2a−h) were prepared according to the
reported method.7,12g
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
2-(Trimethylsilyl)phenyl Trifluoromethanesulfonate (2a).12b It is
■
1
This work is financially supported by the National Science
Foundation of China (21772061, 21772062), the Natural
Science Foundation of Anhui Province (1708085QB28), and
the Scientific Research Project of Anhui Provincial Education
Department (KJ2015TD002).
obtained as colorless viscous oil; 0.41 g, 68% yield. H NMR (400
MHz, CDCl3): δ 7.60 (d, J = 7.2 Hz, 1H), 7.51 (t, J = 6.4 Hz, 1H),
7.44−7.37 (m, 2H), 0.44 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ 155.1, 136.3, 135.3, 132.5, 131.2, 127.5, 120.1, 119.5, 116.7 (d, J =
40 Hz), 0.9.
3-Methyl-2-(trimethylsilyl)phenyl Trifluoromethanesulfonate
1
(2b). It is obtained as colorless viscous oil; 0.29 g, 46% yield. H
REFERENCES
■
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2.46 (s, 3H), 0.46 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
151.0, 136.9, 136.1, 134.5, 133.7, 131.4, 127.9, 118.6 (q, J = 317.7
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+
H]+) calcd for
[C11H16F3O3SSi]+, 313.0536; found, 313.0534.
5-Methyl-2-(trimethylsilyl)phenyl Trifluoromethanesulfonate
(2c).12b It is obtained as colorless viscous oil; 0.41 g, 66% yield. H
1
NMR (400 MHz, CDCl3): δ 7.31 (s, 1H), 7.20 (s, 2H), 2.34 (s, 3H),
0.36 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.1, 137.3,
136.7, 132.2, 131.7, 118.6 (q, J = 317.8 Hz), 20.7, −0.9.
5-Chloro-2-(trimethylsilyl)phenyl Trifluoromethanesulfonate
(2d).20 It is obtained as colorless viscous oil; 0.38 g, 57% yield. H
1
NMR (600 MHz, CDCl3): δ 7.46 (d, J = 2.6 Hz, 1H), 7.38 (dd, J1 =
8.8 Hz, J2 = 2.7 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 0.37 (s, 9H).
13C{1H} NMR (150 MHz, CDCl3): δ 153.1, 135.8, 135.3, 133.5,
131.0, 121.0, 118.5 (q, J = 212.2 Hz), −1.0.
4,5-Dimethyl-2-(trimethylsilyl)phenyl Trifluoromethanesulfo-
nate (2e).12b It is obtained as colorless viscous oil; 0.33 g, 50%
yield. 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.19 (s, 1H), 2.36
(d, J = 5.2 Hz, 1H), 0.45 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ 153.1, 140.3, 137.0, 136.0, 132.0, 129.0, 119.0 (d, J = 286.8 Hz),
19.9, 19.1, 2.0, 0.6, −0.8.
6-(Trimethylsilyl)-2,3-dihydro-1H-inden-5-yl Trifluoromethane-
sulfonate (2f).12g It is obtained as colorless viscous oil; 0.41 g, 61%
1
yield. H NMR (600 MHz, CDCl3): δ 7.34 (s, 1H), 7.18 (s, 1H),
2.94−2.09 (m, 4H), 2.14−2.09 (m, 2H), 0.35 (s, 9H). 13C{1H} NMR
(150 MHz, CDCl3): δ 153.9, 148.3, 143.6, 131.3, 129.4, 118.5 (q, J =
318.3 Hz), 115.7, 33.1, 32.1, 25.7, −0.7.
6-(Trimethylsilyl)benzo[d][1,3]dioxol-5-yl Trifluoromethanesul-
fonate (2g).12b It is obtained as colorless viscous oil; 0.36 g, 52%
yield. 1H NMR (400 MHz, CDCl3): δ 6.91 (s, 1H), 6.87 (s, 1H), 6.05
(s, 2H), 0.36 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 149.5,
148.7, 146.9, 124.9, 118.5 (q, J = 318 Hz), 113.2, 102.4, −0.7.
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The Journal of Organic Chemistry
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