Metal-Oxidant-Free Cobalt-Catalyzed C(sp2)-H Carbonylation of ortho-Arylanilines: An Approach toward Free (NH)-Phenanthridinones

Article abstract of DOI:10.1021/acs.joc.8b00730

A traceless directing group assisted Co-catalyzed C(sp²)-H carbonylation of ortho-arylanilines for the synthesis of free (NH)-phenanthridinones in metal-based-oxidant-free fashion was accomplished. This protocol employs diisopropyl azodicarboxylate as the CO source and oxygen as the sole oxidant, and provides good yields with various functional tolerance. The methodology has been applied for the total synthesis of PARP inhibitor PJ-34. Furthermore, the kinetic isotopic effect experiments reveal the C-H bond cleavage probably occurred in the rate-determining step.

Full text of DOI:10.1021/acs.joc.8b00730

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Article
Metal Oxidant Free Cobalt Catalyzed C(sp2)-H Carbonylation of ortho-
Arylanilines: An Approach Towards Free (NH)-Phenanthridinones
Fei Ling, Chaowei Zhang, Chongren Ai, Yaping Lv, and Weihui Zhong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00730 • Publication Date (Web): 08 May 2018
Downloaded from http://pubs.acs.org on May 8, 2018
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Metal Oxidant Free Cobalt Catalyzed C(sp2)−H Carbonylation of orthoꢀArylanilines: An
Approach Towards Free (NH)ꢀPhenanthridinones
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Fei Ling, Chaowei Zhang, Chongren Ai, Yaping Lv and Weihui Zhong*
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, People’s Republic
of China
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Eꢀmail: weihuizhong@zjut.edu.cn
ABSTRACT: A traceless directing group assisted Coꢀcatalyzed C(sp2)−H carbonylation of orthoꢀarylanilines for
the synthesis of free (NH)ꢀphenanthridinones in metal based oxidant free fashion was accomplished. This
protocol employs diisopropyl azodicarboxylate as CO source and oxygen as the sole oxidant, and provides
good yields with various functional tolerance. The methodology has been applied for the total synthesis of
PARP inhibitor PJꢀ34. Furthermore, the kinetic isotopic effect experiments reveal the C−H bond cleavage
probably occurred in the rateꢀdetermining step.
INTRODUCTION:
Transition metal catalyzed carbonylation of inert C(sp2)−H and C(sp3)−H bonds represents as a powerful
tool for the access of carbonylꢀcontaining compounds, which are widely found in organic and medicinal
chemistry.1 Among these reactions, earthꢀabundant cobalt catalyzed C−H carbonylation has attracted
considerable interest in recent years, owing to its cheap cost and environmentally benign.2 In this area,
pioneered by the studies of Murahashi,2b Daugulis and coꢀwokers,2c recent advances have remarkably
uncovered the high reactivity and regioselectivity of directing group assisted Coꢀcatalyzed C−H carbonylation
reactions for the construction of versatile cyclic amides (Scheme 1a). However, the use of toxic and unsafe CO
gas and stoichiometric amount of environmental unfriendly metal oxidant limited their further expansions. A
greener process has been achieved by Zhang’s group, who firstly employed azodicarboxylate as stoichiometric
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carbonyl source instead of CO gas in the Coꢀcatalyzed C(sp2)−H carbonylation of benzamides, although two
equivalents of silver additives still has been used as oxidant (Scheme 1b).2g Similarly, Daugulis and coꢀwokers
have developed Coꢀcatalyzed C(sp2)−H carbonylation of sulfonamide in the presence of diisopropyl
azodicarboxylate (DIAD) and stoichiometric Mn(OAc)2.2h Very recently, our group disclosed a work of traceless
directing group assisted Coꢀcatalyzed C(sp2)−H carbonylation of benzylamines using diethyl azodicarboxylate
(DEAD) as a CO source.2i Despite the great success that have been achieved, these transformations still
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needed stoichiometric amount of metal oxidants to reoxidate Co(I) or Co(II) species to Co(III) species.
Thereby, the development of practical and environmentally friendly methodologies in metal based oxidant free
fashion for the cobalt catalyzed carbonylation reactions has remained elusive, but highly desirable.
Scheme 1. Selected examples of Coꢀ or Pdꢀcatalyzed C−H carbonylation.
Phenanthridinone is a significant scaffold widely found in biologically active alkaloid natural products3 and
pharmaceuticals (Figure 1) that present broad range of potent biological activities, such as antitumor,4
antiꢀHIV,5 and antileukemic6. For example, PJꢀ34 is demonstrated as a cellꢀpermeable PARP inhibitor.7 while
ARCꢀ111 exhibits TOP1ꢀtargeting activity and pronounced antitumor activity.8 Therefore, synthetic approaches
towards penanthridinone derivatives have been intensively pursued during the past decades.9 In this context,
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the Pdꢀcatalyzed carbonylation of orthoꢀarylanilines via C−H bond activation provides more atomꢀeconomic
and straightforward method to access these compounds (Scheme 1c).10 In 2013, Chuang,10a Zhang,10b and
Zhu’s group,10c independently described palladium catalyzed C−H carbonylation of orthoꢀarylaniline using CO
as carbonyl source in the presence of copper or silver salts for the preparation of phenanthridinones. Despite
its high efficiency, its further expansion is limited by the need for noble metal catalyst, metal oxidant and toxic
CO gas. Thus, devising much greener synthetic routes for phenanthridinones though C−H bond activation is
urgentlyꢀneeded. Inspired by our previous work and as our continuing interest in pursuing the green synthetic
methodologies for natural products, we report here a protocol of metal based oxidant free Coꢀcatalyzed
C(sp2)−H carbonylation using O2 as the sole oxidant and DIAD as the CO source, to produce a variety of free
(NH)ꢀphenanthridinones (Scheme 1d).
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Figure 1 PhenanthridinoneꢀContaining Natural Products and Drugs
O
N
Me2N
NH
OMe
OMe
O
N
N
O
Me2N
R
O
O
N
H
ARCꢀ111
TOP1ꢀtargeting activity
antitumor activity
O
R = ipropyl, Nꢀisopentylcrinasiadine
R = Ph, Nꢀpehenethylcrinasiadine
PJꢀ34
PARP inhibitor
RESULT AND DISCUSSION
At the outset, we used oꢀphenylaniline (1a) as a starting material to react with DIAD in the presence of
Co(OAc)2•4H2O and PivOH in TFE (trifluoroethanol) at 130 °C under 1 atm of O2 for 24 h. Fortunately, the
expected phenanthridinone (2a) was obtained in 35% isolated yield, albeit in low yield (Table 1, entry 1). Next,
a set of cobalt salts were screened, and CoCl2 turned out to be the optimal, while high valent Co(acac)3 only
afforded 2a in 32% yield (Table 1, entries 1~4). In addition, the exploration of reaction solvents indicated that
the solvents had a little influence on yield, and 1,4ꢀdioxane gave the best result (Table 1, entries 5~7). It was
noteworthy that majority of basic additives delivered relatively higher yield than acidic additives, and NaOPiv
was found to the best additive to produce 2a in 67% yield (Table 1, entries 8~11). Furthermore, changing the
temperature did not improve the yield (Table 1, entries 12 and 13). Gratifyingly, increasing the catalyst loading
to 30 mol% dramatically promoted the reaction to access 2a in upꢀto 97% yield (Table 1, entry 14). In contrast,
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no desired product was detected in the absence of Co catalyst, and a sharp decrease in yield was observed
when the reaction was carried out under air or N2 atmosphere or catalytic amount (50 mol %) of NaOPiv
(entries 15~18). These blank tests clearly indicated that Co catalyst, O2 and stoichiometric amount of NaOPiv
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are required for this reaction.
Table 1. Optimization of Reaction Conditionsa
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Entry
1
Cat.
Additive
PivOH
Solvent
T (
)
Yield (%)
35
Co(OAc)2•4H2O
CoCl2
Co(acac)2
Co(acac)3
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
-
TFE
130
130
130
130
130
130
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130
130
130
130
120
140
130
130
130
130
130
2
PivOH
TFE
41
3
PivOH
TFE
30
4
PivOH
TFE
32
5
PivOH
DCE
35
6
PivOH
1,4-dioxane
HFIP
45
7
PivOH
37
8
HOAc
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
21
9
PhCO2Na
NaOPiv
KOPiv
50
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13
14b
15
16c
17d
18e
67
47
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
51
63
97
0
CoCl2
CoCl2
CoCl2
46
14
54
aReactions conditions:1a (0.4 mmol), Co catalyst (0.08 mmol), DIAD (0.8 mmol), and additive (0.8 mmol) in
b
c
d
solvent (4 mL) at 130 for 24 h under oxygen atmosphere. Co catalyst (0.12 mmol). Under air. Under N2.
eNaOPiv (0.2 mmol).
After identifying the optimum reaction conditions, we next set out to determine the versatility of this
reaction system in the carbonylation reaction of various oꢀarylanilines. Upon experimentation, it was found that
this developed synthetic methodology offered a broad scope with respect to the selected substrates and it was
quite tolerant to a variety of functional groups (Scheme 2). For example, oꢀarylanilines with both
electronꢀwithdrawing substituents (2bꢀ2e) and electronꢀwithdrawing substituents (2fꢀ2j) on the para position of
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the nonꢀaniline rings were well tolerated, leading to the corresponding products in 90−97% yield. In addition,
the reaction conditions were compatible with Br and Cl, which are convenient handles for further
functionalization (2h and 2g). Besides, methylthio group could also be used in this reaction to give 2e in
excellent yield. It was noteworthy that the current protocol was regioselective for meta substituted substrates
where two unsymmetrical C–H bonds could be carbonylated. Only one product generated from carbonylation
of the less sterically hindered C–H bond was isolated (2kꢀ2m). However, the reactions were less efficient for
orthoꢀsubstituted substrates to yield 2n and 2o in moderate yields, due to steric effects. Pleasingly, other
aromatic rings such as naphthyl ring and thienyl ring, were also tolerated, delivering the expected products 2p
and 2q in 65% and 94% yields, respectively. On the other hand, the substrate scope with respect to the
substituents on the aniline ring was studied. The electronic effect had no influence on the reaction yield, and
the desired products were achieved in 92–96% yield. An exception was found when oꢀphenylaniline 1w
bearing ester group was used as substrate, leading to the corresponding product 2w in moderate yield.
Scheme 2. Substrate Scopes of oꢀArylanilines 1.a
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aConditions: 1 (0.4 mmol), CoCl2 (0.12 mmol), DIAD (0.8 mmol), and NaOPiv (0.8 mmol) in 1,4ꢀdioxane (4 mL)
at 130 for 24 h under 1 atm of O2.
To demonstrate the scalability and utility of this method, we applied it in the formal synthesis of PARP
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inhibitor PJꢀ34 on a gram scale (Scheme 3). The reaction was conducted with 5 mmol scale of 1a to afford
phenanthridinꢀ6(5H)ꢀone (2a) in 0.93 g, 95% yield. Next, the regioselective nitration of 2a, followed by
reduction of the nitro group to amine group, resulted in the formation of 3a in 76% yield over two steps. Finally,
using EDCI and HOBt as condensing agents, the Nꢀacylation of 3a and N,Nꢀdimethylglycine underwent
smoothly, forming the desired PJꢀ34 in 87% yield.
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Scheme 3. Total Synthesis of PARP Inhibitor PJꢀ34.
To gain insights into the reaction mechanism, several control experiments were performed. Firstly, the
intermolecular competition experiment (Scheme 4, eq 1) gave a kinetic isotope effect (KIE) of kH/kD = 1.72,
while the kH/kD value of 2.24 was obtained by two parallel reactions (Scheme 4, eq 2) using substrates 1a and
1aꢀd5. These KIE experiments indicated that the C−H bond cleavage probably occurred in the rateꢀdetermining
step. Secondly, we found that radical scavengers, such as 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) and
2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT), had little influence on the reaction outcomes, indicating that the
alkoxycarbonyl radical, generated from DIAD, might not severe as the active carbonylation species in our C−H
carbonylation reaction (Scheme 4, eq 3).
Scheme 4. Control Experiments.
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Based on the control experiments and the literature reports on Co catalysis,2 a plausible reaction
mechanism for the cobaltꢀcatalyzed C−H carbonylation is depicted in Scheme 5 with 1a as the model
substrates. The reaction is believed to be initiated by the coordination of Co(II) with benzylpicolinamide (1a) to
give intermediate A, which is then oxidized by oxygen to form a substrate coordinate Co(III) complex B.
Subsequently, C(sp2)−H bond activation of orthoꢀphenyl group takes place to generated a cyclic Co(III)
complex C. In addition, thermal decomposition of DIAD releases the CO gas,11 which then inserts into the
C−Co bond of the complex C to afford a cyclic acyl Co(III) species D. The reductive elimination of species D
results in the formation of intermediate E and generates Co(I) species. Subsequently hydrolysis of intermediate
E leads to the expected product 2a along with the release of picolinic acid derivative, might due to the
activation of the amide group by the coordination of Co(I) species with intermediate E via N,Oꢀcoordination.12
Notably, the attempts of recovery of directing group are failed, because picolinic acid is decomposed under
standard conditions. The released Co(I) species are reoxidized to active Co(II) species by oxygen to complete
the catalytic cycle.
Scheme 5. Plausible Reaction Mechanism
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CONCLUSION
In summary, we have developed a metal based oxidant free and highly efficient strategy for the C(sp2)−H
bond carbonylation of orthoꢀarylanilines to synthesize free (NH)ꢀPhenanthridinones by using earthꢀabundant
and inexpensive CoCl2 as the catalyst, the commercially available azodicarboxylates as the environmentally
benign carbonyl source and oxygen as the sole oxidant. This protocol features a wide substrate scope and
various functional group tolerances, thereby providing a facile and efficient method for the formal synthesis of
PARP inhibitor PJꢀ34. To the best of our knowledge, the current approach represents the first example of metal
based oxidant free cobaltꢀcatalyzed C−H bond carbonylation. Further researches based on this novel
approach are currently going on in our laboratory.
EXPERIMENTAL SECTION
General information: All commercial materials were used as received unless otherwise noted.
Commercially available chemicals were obtained from Energy Chemical, TCI, Alfa Aesar, J&K. 1H NMR spectra
were recorded at 400 MHz, 500 MHz, and 600 MHz using TMS as internal standard, 13C NMR spectra were
recorded at 100 MHz, 125 MHz, and 150 MHz using TMS as internal standard. The multiplicities are reported
as follows: singlet (s), doublet (d), doublet of doublets (dd), multiplet (m), triplet (t) and broad resonances (br).
Mass spectroscopy data of the products were collected on an HRMSꢀTOF instrument.
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General Procedure for the Preparation of Starting Materials 1a. To a stirred solution of phenylboronic
acid (0.73 g, 6.00 mmol) in EtOH (30 mL) was added 2ꢀiodoaniline (1.10 g, 5.00 mmol), K3PO4 (2.65 g, 12.50
mmol), Pd(PPh3)4 (0.29 g, 0.25mmol). The reaction was stirred at a reflux for 24 h under argon atmosphere
before EtOH was removed by rotary evaporation. The crude product [1,1'ꢀbiphenyl]ꢀ2ꢀamine was used directly
in the next step without further purification.
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The crude product [1,1'ꢀbiphenyl]ꢀ2ꢀamine was dissolved in 8 mL of anhydrous DMF, 2ꢀpicolinic acid (740
mg, 6 mmol) was added, followed by addition of EDCI (1.16 g, 6 mmol), HOBt (920 mg, 6 mmol) and DIPEA
(2.2 mL, 12.5 mmol). The mixture was stirred at rt for 3 h. The mixture was quenched with water, and extracted
with EtOAc. The combined organic layers were washed with H2O and brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography
(nꢀhexane/EtOAc:30:1) to give the desired product 1a.
N-([1,1'-Biphenyl]-2-yl)picolinamide (1a): Rf 0.28 (hexane/EtOAc = 30/1). White solid, 82% yield, m.p.
96ꢀ97 °C. 1H NMR (600 MHz, CDCl3, ppm) δ 10.31 (s, 1H), 8.65 – 8.63 (m, 1H), 8.36 (d, J = 4.2 Hz, 1H), 8.25
(d, J = 7.8 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.51 – 7.46 (m, 4H), 7.44 – 7.42 (m, 2H), 7.37 – 7.35 (m, 1H), 7.33 (dd,
J = 7.8, 1.8 Hz, 1H), 7.22 – 7.20 (m, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 162.0, 150.0, 147.9, 138.2,
137.5, 134.9, 132.6, 130.2, 129.5, 128.9, 128.4, 127.8, 126.1, 124.3, 122.3, 120.7. HRMSꢀESI: calcd for
C18H15N2O [M + H]+: 275.1179; Found: 275.1177.
N-(4'-Methyl-[1,1'-biphenyl]-2-yl)picolinamide (1b): Rf 0.30 (hexane/EtOAc = 30/1). White solid, 68% yield,
m.p. 107ꢀ108 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.34 (s, 1H), 8.64 (dd, J = 8.4, 4.8 Hz, 1H), 8.40 (d, J =
4.8 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.85 – 7.83 (m, 1H), 7.43 – 7.40 (m, 1H), 7.38 – 7.36 (m, 3H), 7.32 – 7.30
(m, 3H), 7.21 – 7.19 (m, 1H), 2.44 (s, 3H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 162.0, 150.1, 148.0, 137.5,
137.5, 135.2, 134.9, 132.6, 130.4, 129.6, 129.4, 128.2, 126.1, 124.3, 122.3, 120.7, 21.33. HRMSꢀESI: calcd for
C19H17N2O [M + H]+: 289.1335; Found: 289.1330.
N-(4'-Ethyl-[1,1'-biphenyl]-2-yl)picolinamide (1c): Rf 0.27 (hexane/EtOAc = 30/1). White solid, 65% yield,
m.p. 77ꢀ78 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.33 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 4.2 Hz,
1H), 8.25 (d, J = 7.8 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.42 – 7.35 (m, 4H), 7.33 – 7.31 (m, 3H), 7.21 – 7.19 (m, 1H),
2.76 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.8 Hz, 3H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 161.9, 150.1, 147.9,
143.9, 137.5, 135.4, 134.9, 132.6, 130.2, 129.5, 128.4, 128.2, 126.1, 124.2, 122.3, 120.6, 28.70, 15.71.
HRMSꢀESI: calcd for C20H19N2O [M + H]+: 303.1492; Found: 303.1496.
N-(4'-Methoxy-[1,1'-biphenyl]-2-yl)picolinamide (1d): Rf 0.28 (hexane/EtOAc = 30/1). White solid, 69%
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yield, m.p. 103ꢀ104 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 10.31 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.40 (d, J =
4.5 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.86 – 7.82 (m, 1H), 7.42 – 7.36 (m, 4H), 7.31 (dd, J = 8.5, 1.5 Hz, 1H),
7.21 – 7.18 (m, 1H), 7.04 – 7.01 (m, 2H), 3.88 (s, 3H). 13C {1H} NMR (125 MHz, CDCl3, ppm) δ 161.9, 159.2,
149.9, 147.9, 137.4, 134.8, 132.2, 130.6, 130.3, 130.3, 128.0, 126.1, 124.1, 122.1, 120.6, 114.3, 55.28.
HRMSꢀESI: calcd for C19H17N2O2 [M + H]+: 305.1285; Found: 305.1286.
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N-(4'-(Methylthio)-[1,1'-biphenyl]-2-yl)picolinamide (1e): Rf 0.24 (hexane/EtOAc = 30/1). White solid, 69%
yield, m.p. 108ꢀ109 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 10.28 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H), 8.41 (d, J =
4.5 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.44 – 7.36 (m, 6H), 7.30 (dd, J = 8.0, 1.5 Hz, 1H),
7.22 – 7.19 (m, 1H), 2.55 (s, 3H). 13C {1H} NMR (125 MHz, CDCl3, ppm) δ 162.0, 149.9, 148.0, 138.3, 137.5,
134.8, 132.0, 130.2, 129.9, 128.4, 126.8, 126.2, 124.3, 122.2, 120.9, 15.7. HRMSꢀESI: calcd for C19H17N2OS
[M + H]+: 321.1056; Found: 321.1061.
N-(4'-Fluoro-[1,1'-biphenyl]-2-yl)picolinamide (1f): Rf 0.29 (hexane/EtOAc = 30/1). White solid, 65% yield,
m.p. 110ꢀ111 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 10.22 (s, 1H), 8.62 (dd, J = 9.0, 0.5 Hz, 1H), 8.39 (d, J =
4.0 Hz, 1H), 8.26 (d, J = 7.5 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.45 – 7.40 (m, 3H), 7.40 – 7.37 (m, 1H), 7.29 (dd, J
= 7.5, 1.5 Hz, 1H), 7.22 – 7.16 (m, 3H). 13C {1H} NMR (125 MHz, CDCl3, ppm) δ 163.4 (JC-F = 245.6 Hz), 161.9,
149.8, 147.9, 137.5, 134.8, 134.1 (JC-F = 3.3 Hz), 131.5, 131.3 (JC-F = 8.1 Hz), 131.2, 130.2, 128.6, 126.2, 124.3,
122.2, 120.8, 115.9 (JC-F = 21.4 Hz). HRMSꢀESI: calcd for C18H14FN2O [M + H]+: 293.1085; Found: 293.1085.
N-(4'-Chloro-[1,1'-biphenyl]-2-yl)picolinamide (1g): Rf 0.21 (hexane/EtOAc = 30/1). White solid, 67% yield,
m.p. 145ꢀ146 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.22 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 4.8 Hz,
1H), 8.26 (d, J = 7.8 Hz, 1H), 7.87 – 7.85 (m, 1H), 7.47 – 7.43 (m, 3H), 7.41 – 7.39 (m, 3H), 7.30 (dd, J = 7.8,
1.2 Hz, 1H), 7.23 – 7.20 (m, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 162.0, 149.8, 148.0, 137.6, 136.7,
134.7, 133.9, 131.5, 130.9, 130.2, 129.1, 128.8, 126.3, 124.5, 122.3, 121.1. HRMSꢀESI: calcd for C18H14ClN2O
[M + H]+: 309.0789; Found: 309.0779.
N-(4'-Bromo-[1,1'-biphenyl]-2-yl)picolinamide (1h): Rf 0.30 (hexane/EtOAc = 30/1). White solid, 69% yield,
m.p. 144ꢀ145 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.20 (s, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.42 (d, J = 4.8 Hz,
1H), 8.25 (d, J = 7.8 Hz, 1H), 7.86 – 7.84 (m, 1H), 7.62 – 7.60 (m, 2H), 7.45 – 7.42 (m, 1H), 7.41 – 7.39 (m, 1H),
7.35 – 7.33 (m, 2H), 7.29 (dd, J = 7.8, 1.8 Hz, 1H), 7.22 – 7.19 (m, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm)
δ 162.0, 149.8, 148.1, 137.6, 137.2, 134.7, 132.1, 131.5, 131.2, 130.1, 128.8, 126.3, 124.5, 122.3, 122.1,
121.2. HRMSꢀESI: calcd for C18H14BrN2O [M + H]+: 353.0284; Found: 353.0268.
N-(4'-(Trifluoromethyl)-[1,1'-biphenyl]-2-yl)picolinamide (1i): Rf 0.28 (hexane/EtOAc = 30/1). White solid,
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66% yield, m.p. 128ꢀ129 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 10.19 (s, 1H), 8.61 – 8.59 (m, 1H), 8.36 – 8.35
(m, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.87 – 7.84 (m, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.49 –
7.46 (m, 1H), 7.41 – 7.38 (m, 1H), 7.33 (dd, J = 8.0, 1.5 Hz, 1H), 7.26 – 7.23 (m, 1H). 13C {1H} NMR (125 MHz,
CDCl3, ppm) δ 162.0, 149.7, 148.0, 142.0, 137.6, 134.7, 131.3, 130.3 (JC-F = 32.5 Hz), 130.0, 129.9, 129.2,
127.4 (JC-F = 270.4 Hz), 126.3, 125.8 (JC-F = 3.6 Hz), 124.5, 122.3, 121.2. HRMSꢀESI: calcd for C19H14F3N2O [M
+ H]+: 343.1053; Found: 343.1048.
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N-(4'-Cyano-[1,1'-biphenyl]-2-yl)picolinamide (1j): Rf 0.26 (hexane/EtOAc = 30/1). White solid, 65% yield,
m.p. 157ꢀ158 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.13 (s, 1H), 8.56 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 4.2 Hz,
1H), 8.25 (d, J = 7.8 Hz, 1H), 7.89 – 7.86 (m, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.50 – 7.47
(m, 1H), 7.44 – 7.42 (m, 1H), 7.31 – 7.30 (m, 1H), 7.27 – 7.24(m, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ
162.0, 149.6, 148.1, 143.2, 137.7, 134.6, 132.7, 131.0, 130.3, 130.0, 129.6, 126.5, 124.8, 122.4, 121.6, 118.8,
111.6. HRMSꢀESI: calcd for C19H14N3O [M + H]+: 300.1131; Found: 300.1129.
N-(3'-Methyl-[1,1'-biphenyl]-2-yl)picolinamide (1k): Rf 0.29 (hexane/EtOAc = 30/1). White solid, 62% yield,
m.p. 95ꢀ96 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.43 (s, 1H), 8.70 – 8.66 (m, 1H), 8.39 (d, J = 4.2 Hz, 1H),
8.27 (dd, J = 7.8, 1.2 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.45 – 7.41 (m, 1H), 7.40 – 7.36 (m, 2H), 7.35 – 7.32 (m,
2H), 7.28 – 7.27 (m, 2H), 7.23 – 7.20 (m, 1H), 2.43 (s, 3H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 162.o,
150.1, 147.9, 138.6, 138.0, 137.5, 134.9, 132.5, 130.2, 130.2, 128.9, 128.5, 128.4, 126.6, 126.2, 124.2, 122.3,
120.5, 21.52. HRMSꢀESI: calcd for C19H17N2O [M + H]+: 289.1335; Found: 289.1328.
N-(3'-Methoxy-[1,1'-biphenyl]-2-yl)picolinamide (1l): Rf 0.28 (hexane/EtOAc = 30/1). Yellow solid, 64%
yield, m.p. 90ꢀ91 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.41 (s, 1H), 8.68 (d, J = 7.8 Hz, 1H), 8.39 (d, J = 4.8
Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.45 – 7.37 (m, 3H), 7.35 (dd, J = 7.8, 1.8 Hz, 1H), 7.22 ꢀ
7.19 (m, 1H), 7.06 (d, J = 7.2 Hz, 1H), 7.02 – 7.01 (m, 1H), 7.00 (dd, J = 7.8, 1.8 Hz, 1H), 3.82 (s, 3H),. 13C {1H}
NMR (150 MHz, CDCl3, ppm) δ 162.0, 159.9, 150.1, 147.9, 139.5, 137.5, 134.9, 132.3, 130.1, 130.0, 128.5,
126.2, 124.2, 122.3, 121.9, 120.6, 114.4, 114.1, 55.30. HRMSꢀESI: calcd for C19H17N2O2 [M + H]+: 305.1285;
Found: 305.1286.
N-(3'-Chloro-[1,1'-biphenyl]-2-yl)picolinamide (1m): Rf 0.26 (hexane/EtOAc = 30/1). White solid, 61% yield,
m.p.129ꢀ130 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.33 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 4.2 Hz,
1H), 8.25 (d, J = 7.8 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.49 (s, 1H), 7.46 – 7.43 (m, 1H), 7.42 – 7.40 (m, 2H), 7.39 –
7.37 (m, 1H), 7.36 – 7.34 (m, 1H), 7.30 (dd, J = 7.8, 1.2 Hz, 1H), 7.22 – 7.19 (m, 1H). 13C {1H} NMR (150 MHz,
CDCl3, ppm) δ 161.9, 149.8, 148.0, 140.0, 137.6, 134.8, 134.8, 131.0, 130.2, 130.1, 129.7, 129.0, 127.9, 127.8,
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126.3, 124.4, 122.3, 120.9. HRMSꢀESI: calcd for C18H14ClN2O [M + H]+: 309.0789; Found: 309.0785.
N-(2'-Methyl-[1,1'-biphenyl]-2-yl)picolinamide (1n): Rf 0.30 (hexane/EtOAc = 30/1). White solid, 66% yield,
m.p. 160ꢀ161 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 9.93 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 4.2 Hz,
1H), 8.21 (d, J = 7.8 Hz, 1H), 7.80 – 7.78 (m, 1H), 7.45 – 7.42 (m, 1H), 7.38 – 7.34 (m, 2H), 7.32 – 7.30 (m, 2H),
7.26 – 7.24 (m, 1H), 7.23 – 7.18 (m, 2H), 2.12 (s, 3H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 161.9, 150.0,
148.0, 137.4, 137.2, 136.9, 135.5, 132.0, 130.5, 130.3, 129.9, 128.4, 128.3, 126.3, 126.1, 123.9, 122.1, 119.9,
19.79. HRMSꢀESI: calcd for C19H17N2O [M + H]+: 289.1335; Found: 289.1333.
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N-(2'-Fluoro-[1,1'-biphenyl]-2-yl)picolinamide (1o): Rf 0.26 (hexane/EtOAc = 30/1). White solid, 61% yield,
m.p. 45ꢀ46 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 10.12 (s, 1H), 8.57 (dd, J = 8.5, 1.0 Hz, 1H), 8.35 (d, J = 4.0
Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.83 – 7.80 (m, 1H), 7.49 – 7.38 (m, 3H), 7.37 – 7.32 (m, 2H), 7.29 (dd, J =
7.5, 1.0 Hz, 1H), 7.26 – 7.20 (m, 2H). 13C {1H} NMR (125 MHz, CDCl3, ppm) δ 162.0, 160.7 (JC-F = 245.8 Hz),
149.8, 147.9, 137.4, 135.5, 132.1, 132.0, 130.7, 130.1 (JC-F = 8.0 Hz), 129.1, 126.8, 126.2, 125.5 (JC-F = 15.9
Hz), 124.6 (JC-F = 3.6 Hz), 124.2, 122.2, 121.2, 116.2 (JC-F = 22.1 Hz). HRMSꢀESI: calcd for C18H14FN2O [M +
H]+: 293.1085; Found: 293.1083.
N-(2-(Naphthalen-1-yl)phenyl)picolinamide (1p): Rf 0.27 (hexane/EtOAc = 30/1). White oily liquid, 64%
yield. 1H NMR (500 MHz, CDCl3, ppm) δ 9.93 (s, 1H), 8.75 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.96 –
7.91 (m, 3H), 7.69 – 7.65 (m, 1H), 7.60 – 7.57 (m, 2H), 7.54 – 7.49 (m, 2H), 7.46 – 7.43 (m, 1H), 7.37 – 7.32 (m,
2H), 7.27 – 7.24 (m, 1H), 7.17 – 7.14 (m, 1H). 13C {1H} NMR (125 MHz, CDCl3, ppm) 162.0, 149.7, 147.7, 137.2,
136.1, 135.4, 134.0, 132.0, 131.0, 130.6, 128.8, 128.6, 128.3, 128.0, 126.6, 126.1, 125.9, 125.8, 125.6, 123.9,
121.9, 120.3. HRMSꢀESI: calcd for C22H17N2O [M + H]+: 325.1335; Found: 325.1332.
N-(2-(Thiophen-2-yl)phenyl)picolinamide (1q): Rf 0.26 (hexane/EtOAc = 30/1). White solid, 67% yield, m.p.
112ꢀ113 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.57 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 4.2 Hz, 1H),
8.29 (d, J = 7.8 Hz, 1H), 7.88 – 7.86 (m, 1H), 7.47 – 7.40 (m, 4H), 7.27 (dd, J = 3.0, 0.6 Hz, 1H), 7.20 – 7.17 (m,
2H). 13C {1H} NMR (125 MHz, CDCl3, ppm) δ 162.0, 149.6, 147.9, 137.5, 136.7, 134.3, 134.0, 132.8, 131.2,
129.3, 129.0, 128.3, 126.3, 122.2, 122.0, 116.8. HRMSꢀESI: calcd for C16H13N2OS [M + H]+: 281.0743; Found:
281.0750.
N-(5-Methyl-[1,1'-biphenyl]-2-yl)picolinamide (1r): Rf 0.23 (hexane/EtOAc = 30/1). White solid, 68% yield,
m.p. 106ꢀ107 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.23 (s, 1H), 8.52 – 8.49 (m, 1H), 8.37 (d, J = 4.8 Hz, 1H),
8.25 (d, J = 7.8 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.50 – 7.46 (m, 4H), 7.44 – 7.41 (m, 1H), 7.38 – 7.35 (m, 1H),
7.26 – 7.24 (m, 1H), 7.15 (s, 1H), 2.39 (s, 3H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 161.9, 150.1, 147.9,
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138.3, 137.5, 133.9, 132.6, 132.3, 130.9, 129.5, 129.0, 128.9, 127.7, 126.1, 122.2, 120.8, 20.96. HRMSꢀESI:
calcd for C19H17N2O [M + H]+: 289.1335; Found: 289.1334.
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N-(5-Fluoro-[1,1'-biphenyl]-2-yl)picolinamide (1s): Rf 0.27 (hexane/EtOAc = 30/1). White solid, 64% yield,
m.p. 143ꢀ144 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.21 (s, 1H), 8.58 (dd, J = 9.6, 5.4 Hz, 1H), 8.36 (d, J =
4.2 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.85 – 7.83 (m, 1H), 7.51 – 7.49 (m, 2H), 7.46 – 7.44 (m, 3H), 7.38 – 7.36
(m, 1H), 7.14 – 7.11 (m, 1H), 7.06 (dd, J = 9.0, 3.0 Hz, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 161.9,
159.9 (JC-F = 242.7 Hz), 149.8, 148.0, 137.5, 137.1, 134.6 (JC-F = 7.6 Hz), 131.0 (JC-F = 2.5 Hz), 129.3, 129.0,
128.3, 126.2, 122.6 (JC-F = 7.9 Hz), 122.3, 116.9 (JC-F = 22.8 Hz), 114.9 (JC-F = 21.7 Hz). HRMSꢀESI: calcd for
C18H14FN2O [M + H]+: 293.1085; Found: 293.1095.
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N-(5-Chloro-[1,1'-biphenyl]-2-yl)picolinamide (1t): Rf 0.30 (hexane/EtOAc = 30/1). White solid, 67% yield,
m.p. 154ꢀ155 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.29 (s, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 4.2 Hz,
1H), 8.23 (d, J = 7.8 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.52 – 7.50 (m, 2H), 7.47 – 7.43 (m, 3H), 7.40 – 7.36 (m, 2H),
7.31 (d, J = 2.4 Hz, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 162.0, 149.7, 148.0, 137.5, 136.8, 134.0,
133.6, 130.0, 129.3, 129.1, 129.1, 128.3, 128.3, 126.3, 122.3, 121.8. HRMSꢀESI: calcd for C18H14ClN2O [M +
H]+: 309.0789; Found: 309.0793.
N-(5-Bromo-[1,1'-biphenyl]-2-yl)picolinamide (1u): Rf 0.32 (hexane/EtOAc = 30/1). White solid, 70% yield,
m.p. 165ꢀ166 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.30 (s, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.36 – 8.31 (m, 1H),
8.24 (d, J = 7.8 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.55 – 7.50 (m, 3H), 7.48 – 7.44 (m, 4H), 7.39 – 7.37 (m, 1H). 13C
{1H} NMR (150 MHz, CDCl3) δ 162.01, 149.69, 147.99, 137.55, 136.72, 134.34, 134.07, 132.83, 131.24,
129.37, 129.08, 128.35, 126.31, 122.28, 122.06, 116.81, 77.26, 77.05, 76.84. HRMSꢀESI: calcd for
C18H14BrN2O [M + H]+: 353.0284; Found: 353.0291.
N-(5-(Trifluoromethyl)-[1,1'-biphenyl]-2-yl)picolinamide (1v): Rf 0.28 (hexane/EtOAc = 30/1). White solid,
73% yield, m.p. 100ꢀ101 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.50 (s, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.36 (d,
J = 4.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.87 – 7.84 (m, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.58 – 7.53 (m, 3H), 7.50
(d, J = 6.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.40 – 7.38 (m, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 162.3,
149.5, 148.0, 138.0, 137.6, 136.7, 132.4, 129.4, 129.2, 128.5, 127.2 (JC-F = 3.7 Hz), 126.5, 125.9 (JC-F = 32.4
Hz), 125.5 (JC-F = 3.7 Hz), 125.1 (JC-F = 270.0 Hz), 122.4, 120.1. HRMSꢀESI: calcd for C19H14F3N2O [M + H]+:
343.1053; Found: 343.1069.
N-(4-Chloro-[1,1'-biphenyl]-2-yl)picolinamide (1x): Rf 0.30 (hexane/EtOAc = 30/1). White solid, 74% yield,
m.p. 133ꢀ135 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 10.34 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 4.2 Hz,
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1H), 8.24 (d, J = 7.8 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.52 – 7.50 (m, 2H), 7.47 – 7.42 (m, 3H), 7.39 – 7.37 (m, 1H),
7.24 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H). 13C {1H} NMR (150 MHz, CDCl3, ppm) δ 162.0, 149.6,
148.0, 137.6, 137.1, 135.9, 134.1, 131.1, 130.7, 129.4, 129.1, 128.1, 126.4, 124.1, 122.3, 120.4. HRMSꢀESI:
calcd for C18H14ClN2O [M + H]+: 309.0789; Found: 309.0792.
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Typical procedure for the Preparation of 9-bromo-6H-chromeno[4,3-b]quinolin-6-one (2a): A mixture
of 1a (84.9 mg, 0.4 mmol), DIAD (0.8 mmol, 161.6 mg, 2.0 eq.), CoCl2 (0.12 mmol, 15.6 mg, 30 mol %),
NaOPiv (113.7 mg, 0.8 mmol, 2.0 eq.) and 1,4ꢀdioxane (4.0 mL) in a 10 mL tube was heated at 130 oC under
O2 (1 atm) for 24 hours. The reaction mixture was cooled to room temperature, and then the solvent was
removed under vacuum. The crude product was purified by column chromatography on silica gel (DCM/EtOAc:
10:1 to 6:1) to yield 2a (75.7 mg, 97%) as a white solid.
Phenanthridin-6(5H)-one (2a): Rf 0.30 (DCM/EtOAc = 10/1). White solid, 75.7 mg, 97% yield, m.p.
297ꢀ298 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.70 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 7.8 Hz,
1H), 8.34 (d, J = 7.8 Hz 1H), 7.86 – 7.83 (m, 1H), 7.66 – 7.63 (m, 1H), 7.50 – 7.47 (m, 1H), 7.39 (d, J = 7.8 Hz,
1H), 7.27 – 7.24 (m, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.3, 137.0, 134.7, 133.2, 130.0, 128.4,
127.9, 126.2, 123.7, 123.1, 122.7, 118.0, 116.6. HRMSꢀESI: calcd for C13H8NO [M – H]ꢀ: 194.0611; Found:
194.0610.
8-Methylphenanthridin-6(5H)-one (2b): Rf 0.28 (DCM/EtOAc = 10/1). White solid, 77.8 mg, 93% yield, m.p.
266ꢀ267 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.62 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 7.8 Hz,
1H), 8.13 (s, 1H), 7.67 (dd, J = 7.8, 1.2 Hz, 1H), 7.47 – 7.44 (m, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.25 – 7.22 (m,
1H), 2.48 (s, 3H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.3, 138.0, 136.7, 134.4, 132.3, 129.5, 127.7,
126.1, 123.4, 123.1, 122.6, 118.1, 116.5, 21.40. HRMSꢀESI: calcd for C14H10NO [M – H]ꢀ: 208.0768; Found:
208.0765.
8-Ethylphenanthridin-6(5H)-one (2c): Rf 0.27 (DCM/EtOAc = 10/1). White solid, 84.8 mg, 95% yield, m.p.
254ꢀ255 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.64 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 7.8 Hz,
1H), 8.15 (s, 1H) 7.72 (dd, J=6.0, 1.8 Hz, 1H), 7.47 – 7.45 (m, 1H), 7.36 (dd, J = 7.8, 0.6 Hz, 1H) , 7.26 – 7.23
(m, 1H) , 2.80 (q, J = 7.8 Hz, 2H) , 1.27 (t, J = 7.8 Hz, 3H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.3,
144.2, 136.7, 133.4, 132.5, 129.6, 126.4, 126.1, 123.5, 123.2, 122.7, 118.1, 116.5, 28.4, 15.8. HRMSꢀESI:
calcd for C15H12NO [M – H]ꢀ: 222.0924; Found: 222.0925.
8-Methoxyphenanthridin-6(5H)-one (2d): Rf 0.28 (DCM/EtOAc = 10/1). White solid, 84.7 mg, 94% yield,
m.p. 267ꢀ268 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.72 (s, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.30 (d, J = 7.8
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Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.45 – 7.41 (m, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.25 – 7.23 (m, 1H) , 3.91 (s,
3H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.0, 159.5, 136.0, 128.9, 128.1, 127.6, 125.0, 123.1, 122.7,
122.1, 118.2, 116.4, 109.2, 55.9. HRMSꢀESI: calcd for C14H10NO2 [M ꢀ H]ꢀ: 224.0717; Found: 224.0716.
8-(Methylthio)phenanthridin-6(5H)-one (2e): Rf 0.30 (DCM/EtOAc = 10/1). White solid, 90.7 mg, 94% yield,
m.p. 269ꢀ270 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.76 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 7.6
Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 9.0, 2.4 Hz, 1H), 7.47 – 7.45 (m, 1H), 7.35 (dd, J = 8.4, 1.8 Hz,
1H), 7.26 – 7.23 (m, 1H), 2.60 (s, 3H). 13C {1H} NMR (125 MHz, DMSOꢀd6, ppm) δ 160.3, 138.8, 136.1, 131.0,
130.4, 129.2, 126.2, 123.3, 122.9, 122.7, 122.3, 117.4, 116.1, 14.4. HRMSꢀESI: calcd for C14H10NOS [M ꢀ H]ꢀ:
240.0489, found: 240.0487.
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8-Fluorophenanthridin-6(5H)-one (2f): Rf 0.23 (DCM/EtOAc = 10/1). White solid, 79.3 mg, 93% yield, m.p.
279ꢀ280 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.84 (s, 1H), 8.58 – 8.56 (m, 1H), 8.35 (d, J = 7.8 Hz, 1H),
7.96 (dd, J = 9.0, 3.0 Hz, 1H), 7.73 – 7.70 (m, 1H), 7.50 ꢀ 7.47 (m, 1H), 7.38 – 7.36 (m, 1H), 7.27 – 7.25 (m, 1H).
13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 162.8 (JCꢀF = 368.8 Hz), 161.2, 136.5, 131.5 (JCꢀF = 2.2 Hz), 129.9,
128.1 (JCꢀF = 7.3 Hz), 126.3 (JCꢀF = 7.9 Hz), 123.7, 122.9, 121.5 (JCꢀF = 22.8 Hz), 117.5, 116.6, 113.0 (JCꢀF = 22.3
Hz). HRMSꢀESI: calcd for C13H7FNO [M ꢀ H]ꢀ: 212.0517; Found: 212.0518.
8-Chlorophenanthridin-6(5H)-one (2g): Rf 0.24 (DCM/EtOAc = 10/1). White solid, 82.7 mg, 90% yield, m.p.
289ꢀ290 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.86 (s, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 7.8 Hz,
1H), 8.23 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 8.4, 2.4 Hz, 1H), 7.53 – 7.50 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.29 –
7.26 (m, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 160.1, 136.9, 133.5, 133.2, 133.2, 130.4, 127.6,
127.0, 125.6, 123.9, 123.0, 117.3, 116.7. HRMSꢀESI: calcd for C13H7ClNO [M ꢀ H]ꢀ: 228.0222; Found:
228.0199.
8-Bromophenanthridin-6(5H)-one (2h): Rf 0.28 (DCM/EtOAc = 10/1). White solid, 99.8 mg, 91% yield, m.p.
287ꢀ288 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.85 (s, 1H), 8.48 (d, J = 9.0 Hz, 1H), 8.39 – 8.37 (m, 2H),
8.01 (dd, J = 9.0, 2.4 Hz, 1H), 7.54 – 7.51 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.29 – 7.27 (m, 1H). 13C {1H} NMR
(150 MHz, DMSOꢀd6, ppm) δ 160.1, 137.0, 136.0, 133.9, 130.5, 130.1, 127.8, 125.8, 123.9, 123.0, 121.6, 117.4,
116.7. HRMSꢀESI: calcd for C13H7BrNO [M ꢀ H]ꢀ: 271.9717; Found: 271.9707.
8-(Trifluoromethyl)phenanthridin-6(5H)-one (2i): Rf 0.26 (DCM/EtOAc = 10/1). White solid, 102.1 mg, 97%
yield, m.p. 292ꢀ293 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.96 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.54 (s,
1H), 8.45 (d, J = 7.8 Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.58 – 7.56 (m, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.32 –
7.29 (m, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 160.4, 138.0, 137.7, 131.4, 129.1 (JC-F = 6.6 Hz),
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128.7 (JC-F = 32.3 Hz), 127.1 (JC-F = 270.5 Hz), 126.3, 124.9 (JC-F = 3.6 Hz), 124.8 ,124.5, 123.1, 117.0, 116.9.
HRMSꢀESI: calcd for C14H7F3NO [M ꢀ H]ꢀ: 262.0485; Found: 262.0483.
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6-Oxo-5,6-dihydrophenanthridine-8-carbonitrile (2j): Rf 0.28 (DCM/EtOAc = 10/1). White solid, 80.2 mg, 91%
yield, m.p. 284ꢀ285 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.96 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.63 (d, J
= 1.8 Hz, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.23 (dd, J = 8.4, 1.8 Hz, 1H), 7.60 – 7.57 (m, 1H), 7.40 (dd, J = 8.4, 1.2
Hz, 1H), 7.33 – 7.30 (m, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 160.0, 138.4, 138.0, 135.4, 132.6,
131.8, 126.5, 124.8, 124.7, 123.2, 118.8, 116.9, 110.7. HRMSꢀESI: calcd for C14H7N2O [M ꢀ H]ꢀ: 219.0564;
Found: 219.0562.
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9-Methylphenanthridin-6(5H)-one (2k): Rf 0.27 (DCM/EtOAc = 10/1). White solid, 77.8 mg, 93% yield, m.p.
257ꢀ258 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.60 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.30 (s, 1H), 8.21 (d,
J = 7.8 Hz, 1H), 7.48 – 7.43 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.25 – 7.23 (m, 1H), 2.52 (s, 3H). 13C {1H} NMR
(150 MHz, DMSOꢀd6, ppm) δ 161.3, 143.4, 137.2, 134.7, 129.9, 129.6, 127.9, 123.9, 123.6, 122.9, 122.5, 118.0,
116.5, 22.0. HRMSꢀESI: calcd for C14H10NO [M ꢀ H]ꢀ: 208.0768; Found: 208.0762.
9-Methoxyphenanthridin-6(5H)-one (2l): Rf 0.24 (DCM/EtOAc = 10/1). White solid, 82.9 mg, 92% yield,
m.p. 248ꢀ249 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.53 (s, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 8.4
Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.49 – 7.46 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.25 – 7.20 (m, 2H), 3.98 (s, 3H).
13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 163.3, 161.1, 137.5, 136.8, 130.1, 130.0, 124.1, 122.4, 119.7,
117.9, 116.7, 116.5, 105.5, 56.2. HRMSꢀESI: calcd for C14H10NO2 [M ꢀ H]ꢀ: 224.0717; Found: 224.0716.
9-Chlorophenanthridin-6(5H)-one (2m): Rf 0.26 (DCM/EtOAc = 10/1). White solid, 79.9 mg, 87% yield, m.p.
330ꢀ331 oC. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 11.79 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 9.0 Hz,
1H), 8.31 (d, J = 10.2 Hz, 1H), 7.68 (dd, J = 10.2, 1.8 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.38 – 7.36 (m, 1H), 7.29 –
7.25 (m, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 160.6, 138.7, 137.5, 136.5, 130.8, 130.2, 128.5,
124.8, 124.3, 122.9, 117.1, 116.6. HRMSꢀESI: calcd for C13H7ClNO [M ꢀ H]ꢀ: 228.0222; Found: 228.0223.
10-Methylphenanthridin-6(5H)-one (2n): Rf 0.27 (DCM/EtOAc = 10/1). White solid, 69.5 mg, 83% yield,
m.p. 294ꢀ296 oC. 1H NMR (600 MHz, CDCl3, ppm) δ 11.71 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 7.8 Hz,
1H), 7.71 (d, J = 6.6 Hz, 1H), 7.55 – 7.52 (m, 1H), 7.50 – 7.47 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.27 – 7.24 (m,
1H), 2.92 (s, 3H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.4, 137.4, 135.6, 133.7, 129.2, 127.9, 127.8,
127.7, 126.5, 122.1, 119.2, 116.7, 26.1. HRMSꢀESI: calcd for C14H10NO [M ꢀ H]ꢀ: 208.0768; Found: 208.0767.
10-Fluorophenanthridin-6(5H)-one (2o): Rf 0.27 (DCM/EtOAc = 10/1). White solid, 72.5 mg, 85% yield,
m.p. 304ꢀ305 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.84 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.69 – 7.63 (m,
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2H), 7.50 (s, 1H), 7.39 (s, 1H), 7.24 (s, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 160.9 (JC-F = 250.0 Hz),
160.1, 137.1, 130.2, 129.2, 128.7, 127.4, 127.3, 124.4, 123.1, 120.6 (JC-F = 24.2 Hz), 116.7, 115.3. HRMSꢀESI:
calcd for C13H7FNO [M ꢀ H]ꢀ: 212.0517; Found: 212.0516.
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Benzo[k]phenanthridin-6(5H)-one (2p): Rf 0.28 (DCM/EtOAc = 10/1). White solid, 63.8 mg, 65% yield, m.p.
285ꢀ286 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.98 (s, 1H), 8.95 ꢀ 8.94 (m, 1H), 8.62 (d, J = 7.8 Hz, 1H),
8.33 (d, J = 9.0 Hz, 1H), 8.16 – 8.15 (m, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.78 – 7.77 (m, 2H), 7.57 – 7.55 (m, 1H),
7.52 – 7.51 (m, 1H), 7.36 – 7.33 (m, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.3, 137.8, 136.2,
133.3, 129.7, 129.4, 129.0, 128.8, 128.6, 128.3, 127.8, 127.7, 125.0, 123.2, 122.5, 117.9, 116.8. HRMSꢀESI:
calcd for C17H10NO [M ꢀ H]ꢀ: 244.0768; Found: 244.0769.
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Thieno[3,2-c]quinolin-4(5H)-one (2q): Rf 0.23 (DCM/EtOAc = 10/1). White solid, 75.7 mg, 94% yield, m.p.
285ꢀ286 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.77 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 4.8 Hz,
1H), 7.60 (d, J = 4.8 Hz, 1H), 7.50 – 7.47 (m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.24 – 7.22 (m, 1H). 13C {1H} NMR
(150 MHz, DMSOꢀd6, ppm) δ 158.6, 146.0, 136.6, 131.6, 129.8, 127.1, 125.7, 123.8, 122.9, 116.7, 116.6.
HRMSꢀESI: calcd for C11H6NOS [M ꢀ H]ꢀ: 200.0176; Found: 200.0169.
2-Methylphenanthridin-6(5H)-one (2r): Rf 0.26 (DCM/EtOAc = 10/1). White solid, 77.8 mg, 93% yield, m.p.
258ꢀ259 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.61 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.33 – 8.31 (m, 1H),
8.19 (s, 1H), 7.85 – 7.82 (m, 1H) , 7.64 – 7.62 (m, 1H) , 7.32 – 7.30 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H) , 2.41 (s,
3H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.1, 134.9, 134.7, 133.1, 131.7, 131.0, 128.2, 127.9, 126.2,
123.5, 123.0, 117.9, 116.5, 21.2. HRMSꢀESI: calcd for C14H10NO [M ꢀ H]ꢀ: 208.0768; Found: 208.0773.
2-Fluorophenanthridin-6(5H)-one (2s): Rf 0.30 (DCM/EtOAc = 10/1). White solid, 81.0 mg, 95% yield, m.p.
302ꢀ303 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.73 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 7.8 Hz,
1H), 8.26 (d, J = 9.6 Hz, 1H), 7.87 – 7.84 (m, 1H), 7.69 – 7.66 (m, 1H), 7.38 – 7.37 (m, 2H). 13C {1H} NMR (150
MHz, DMSOꢀd6, ppm) δ 161.0, 159.1 (JC-F = 236.0 Hz), 134.0, 133.6, 133.3, 129.0, 127.9, 126.3, 123.6, 119.3
(JC-F = 8.3 Hz), 118.2 (JC-F = 8.4 Hz), 117.7 (JC-F = 23.9 Hz), 109.7 (JC-F = 23.9 Hz). HRMSꢀESI: calcd for
C13H7FNO [M ꢀ H]ꢀ: 212.0517; Found: 212.0525.
2-Chlorophenanthridin-6(5H)-one (2t): Rf 0.21 (DCM/EtOAc = 10/1). White solid, 85.4 mg, 93% yield, m.p.
329ꢀ330 oC. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ11.82 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.48 (d, J = 5.6 Hz,
1H), 8.33 (d, J = 6.0 Hz, 1H), 7.88 – 7.85 (m, 1H), 7.70 – 7.67 (m, 1H), 7.54 (dd, J = 7.2, 2.0 Hz, 1H), 7.38 (d, J
= 6.8 Hz, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.1, 135.8, 133.6, 133.4, 129.9, 129.1, 127.9,
127.0, 126.3, 123.6, 123.3, 119.6, 118.3. HRMSꢀESI: calcd for C13H7ClNO [M ꢀ H]ꢀ: 228.0222; Found:
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2-Bromophenanthridin-6(5H)-one (2u): Rf 0.28 (DCM/EtOAc = 10/1). White solid, 103.1 mg, 94% yield,
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m.p. 328ꢀ329 C. H NMR (400 MHz, DMSOꢀd6, ppm) δ 11.81 (s, 1H), 8.59 (d, J = 5.2 Hz, 2H), 8.32 (s, 1H),
7.86 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 6.4 Hz, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ
161.1, 136.2, 133.6, 133.4, 132.6, 129.1, 127.9, 126.3, 126.2, 123.6, 120.1, 118.6, 114.9. HRMSꢀESI: calcd for
C13H7BrNO [M ꢀ H]ꢀ: 271.9717; Found: 271.9713.
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2-(Trifluoromethyl)phenanthridin-6(5H)-one (2v): Rf 0.24 (DCM/EtOAc = 10/1). White solid, 101.1 mg, 96%
yield, m.p. 294ꢀ295 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 12.00 (s, 1H), 8.70 (s, 1H), 8.66 (d, J = 7.8 Hz,
1H), 8.34 (dd, J = 7.8, 1.2 Hz, 1H), 7.89 – 7.88 (m, 1H), 7.81 (dd, J = 8.4, 1.2 Hz, 1H), 7.71 – 7.69 (m, 1H), 7.53
(d, J = 8.4 Hz, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 161.4, 139.7, 133.7, 133.6, 129.3, 127.9, 127.7
(JC-F = 270.2 Hz), 126.4 (JC-F = 3.9 Hz), 126.3, 123.6, 123.3 (JC-F = 32.0 Hz), 121.3 (JC-F = 3.5 Hz), 118.1, 117.4.
HRMSꢀESI: calcd for C14H7F3NO [M ꢀ H]ꢀ: 262.0485; Found: 262.0486.
Methyl 6-oxo-5,6-dihydrophenanthridine-2-carboxylate (2w): Rf 0.26 (DCM/EtOAc = 10/1). White solid,
54.7 mg, 54% yield, m.p. 272ꢀ273 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 12.00 (s, 1H), 8.83 (s, 1H), 8.50 (d,
J = 8.4 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.01 (dd, J = 8.4, 1.8 Hz, 1H), 7.89 – 7.86 (m, 1H), 7.70 – 7.67 (m, 1H),
7.42 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ 166.3, 161.4, 140.5, 133.9,
133.6, 130.4, 129.0, 127.9, 126.1, 125.1, 123.7, 123.1, 117.7, 116.8, 52.5. HRMSꢀESI: calcd for C15H10NO3 [M
ꢀ H]ꢀ: 252.0666; Found: 252.0665.
3-Chlorophenanthridin-6(5H)-one (2x): Rf 0.24 (DCM/EtOAc = 10/1). White solid, 84.5 mg, 92% yield, m.p.
312ꢀ313 oC. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.77 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.4 Hz,
1H), 8.31 (d, J = 7.8 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.66 – 7.64 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.27 (dd, J=8.4,
1.8 Hz, 1H). 13C {1H} NMR (150 MHz, DMSOꢀd6, ppm) δ161.3, 138.1, 134.2, 134.0, 133.5, 128.7, 128.0, 126.0,
125.7, 123.2, 122.6, 117.0, 115.8. HRMSꢀESI: calcd for C13H7ClNO [M ꢀ H]ꢀ: 228.0222; Found: 228.0228.
Typical procedure for the Preparation of PJ-34: 5ꢀHꢀPhenanthridinꢀ6ꢀone 2a (0.97g, 5.0 mmol) was
dissolved in 15 mL nitric acid with stirring for 24 h at room temperature. A thick yellow precipitate formed. The
mixture was filtered through a plug of Celite and the residue was washed with cold water (25 mL), ethyl ether
(25 mL), dried under vacuum at 55 °C. The crude product was used directly in the next step without further
purification. The crude product was dissolved in EtOH (25 mL), water (10 mL) was added, followed by addition
of Iron powder (20 mol, 1.12 g) and a drop of concentrated hydrochloric acid. The mixture was stirred at 90 °C
for 6 hours under nitrogen, and then cooled to room temperature and filtered through a pad of Celite. The
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solvents were evaporated under reduced pressure. The resulting residue was dissolved in diethyl ether and
extracted with 2 M hydrochloric acid. The aqueous fraction was basified using concentrated aqueous sodium
hydroxide solution and the product amine was extracted with EtOAc (10 mL × 3). The combined organic
fractions were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column
chromatography with ethyl acetate (EA) as eluent to afford 2ꢀaminophenanthridinꢀ6(5H)ꢀone 3a (0.70 g, 76%).
A solution of 2ꢀaminophenanthridinꢀ6(5H)ꢀone 3a (0.80 g, 3.8 mmol), dimethylglycine (0.47 g, 4.6 mmol),
EDCI (0.80 g, 4.2 mmol), HOBt (0.57 g, 4.2 mmol) and DIPEA (1.78 mL, 8.4 mmol) were dissolved in 8 mL of
anhydrous DMF. The mixture was stirred at rt for 5 h. The mixture was quenched with water, and extracted with
EtOAc. The combined organic layers were washed with H2O and brine, dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel flash chromatography (ethyl
acetate/methanol: 10:1) to give the desired product PJꢀ34 (0.97 g, 87%).
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2-(Dimethylamino)-N-(6-oxo-5,6-dihydrophenanthridin-2-yl)acetamide
(PJ-34):
Rf
0.28
(ethyl
acetate/methanol = 10/1). White solid, 0.92 g, 89%. 1H NMR (600 MHz, DMSOꢀd6, ppm) δ 11.67 (s, 1H), 9.83 (s,
1H), 8.68 (d, J = 1.8 Hz, 1H), 8.34 – 8.30 (m, 2H), 7.89 – 7.86 (m, 1H), 7.82 (dd, J = 8.4, 1.8 Hz, 1H), 7.66 –
7.64 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 3.11 (s, 2H), 2.32 (s, 6H). 13C {1H} NMR (100 MHz, DMSOꢀd6, ppm) δ
168.6, 160.5, 134.0, 133.6, 132.8, 132.7, 128.0, 127.6, 125.8, 122.3, 122.0, 117.4, 116.2, 113.5, 63.3, 45.5.
HRMSꢀESI: calcd for C17H18N3O2 [M + H]+: 296.1394; Found: 296.1403.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: weihuizhong@zjut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (No. 21676253 and 21706234) for financial
support.
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Supporting Information
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Copies of H and 13C NMR spectra of all starting materials and products. This material is available free of
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charge via the Internet at http:// pubs.acs.org.
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