One-pot sequential reaction to 2-substituted-phenanthridinones from: N -methoxybenzamides

Article abstract of DOI:10.1039/c7ob00649g

The sequential use of a hypervalent iodine reagent leads to the one-pot synthesis of 2-bromo/chloro-phenanthridinones via an amidation of arenes followed by a regioselective halogenation reaction. These consecutive C-H functionalization reactions can be used efficiently to construct 2-substituted-phenanthridinones at room temperature with good to high yields. Application of the current method is highlighted by the concise synthesis of the natural product PJ34.

Full text of DOI:10.1039/c7ob00649g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00649G
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ARTICLE
One-Pot Sequential Reaction to 2-Substituted-Phenanthridinones
from NtMethoxybenzamides
a
a
c
b
b
Dongdong Liang, Deanna Sersen, Chao Yang, Jeffrey R. Deschamps, Gregory H. Imler, Chao
Received 00th January 20xx,
Accepted 00th January 20xx
c,
a,
Jiang, * and Fengtian Xue *
DOI: 10.1039/x0xx00000x
Sequential use of hypervalence iodine reagent leads to the one-pot synthesis of 2-bromo/chloro-phenanthridinones via an
amidations of arene followed by a regioselective halogenation reaction. These consecutive C-H functionalization reactions
can be used efficiently to construct 2-substituted-phenanthridinones at room temperature with good to high yields.
Application of the current method is highlighted by the concise synthesis of natural product PJ34.
www.rsc.org/
practical method to 2-functionalized phenanthridinones.12
Although target compounds can be obtained by following
reported methods starting from functionalized N-
Introduction
Atom-economy sequential reactions using readily available
catalyst/reagent are desirable in organic chemistry. Metals such
methoxybenzamides (Scheme 1a), these strategies inevitably
led to a mixture of regioisomers that are challenging to separate.
An appealing alternative is via sequential and selective C-H
functionalization. Antonchick pioneered direct arylic C-H
amidation using hypervalent iodine (Scheme 1b).13
Experimental evidence also showed that in the presence of a
hypervalent iodine, electron rich arenes can undergo
halogenation with proper halogen sources, to yield 1,4-
disubstituted arenes (Scheme 1c).14 Exploiting these parallel
1
2
3
as Pd(II), Cu(I), and Fe(II), have been successfully used in
catalyzing sequential reactions. Organocatalysts, on the other
hand, have not found similar applications. Herein we report a
hypervalent iodine mediated one-pot process involving a C-H
amidation and selective halogenation in a sequential matter,
leading to the synthesis of 2-substituted-phenanthridinones.
Phenanthridinones is a privileged scaffold for biologically
active compounds. Phenanthridinone-based natural product
PJ34, an inhibitor of the human poly(ADP-ribose) polymerase 1,
conditions, we speculated that
a one-pot sequential
hypervalent iodine-mediated reaction would be possible with
unfunctionalized substrate (Scheme 1d), to facilitate an efficient
route to functionalized phenanthridinones.
4
5
is used as a cytoprotective and neuroprotective agent. The
[11
C]PJ34 is a novel radiotracer, to elucidate the role of PARP1
in necrosis.6 Crinasiadine, another phenanthridinone-based
natural product, shows promising antimicrobial and antifungal
7
activities. In addition, phenanthridinone derivatives have been
developed as the HIV integrase inhibitors for the treatment of
HIV infections.8 Functionalized phenanthridinones have be
reported to limit the cytotoxicity of doxorubicin.9
Syntheses to phenanthridinones are known.10 For example,
Wang,10a Cheng,10b-d and others10e-f used Pd(II)- or Rh(III)-
catalyzed C-H amidation to yield phenanthridinones. In the
presence of metal catalyst oxidative CO insertion has been used
to prepare phenanthridinones.10g-j However few organocatalyst
mediated synthesis of phenanthridinones have been
reported.11 In the development of novel inhibitors of the
transcriptional repressor protein BCL6, we are interested in a
a.Department of Pharmaceutical Sciences, University of Maryland School of
Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, United States Phone: 410-
Scheme 1. Routes to Functionalized Phenanthridinones
7
06-8521. Email: fxue@rx.umaryland.edu
b.Naval Research Laboratory, Code 6930, 4555 Overlook Ave., Washington, DC
0375, United States
2
c.
Department of Pharmaceutical Engineering, School of Chemical Engineering,
Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China,
Phone: 86-18601406179. Email: chaojiang@njust.edu.cn
Results and discussion
We initiated our studies using N-methoxy-[1,1'-biphenyl]-2-
carboxamide 1a as the starting material to build 2-bromo-
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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phenanthridinone 2a using PhI as a catalyst, AcOOH as an increased steric hindrance of the N-methoxybenzamide starting
oxidant, and TBAB as a bromide source. Different solvents material. For the reactions that gave relatively low yields (<
including HFIP, TFE, CH CN, DCM, DMSO, DMF, and H O were 60%), we repeated them and used PIDA directly instead of the
3 2
screened (entries 1-7), and the results indicated that HFIP was catalytic system. For most cases a small improvement in yields
the best. When mCPBA was used to replace AcOOH, slightly were obtained (Scheme S1).
decreased yields were obtained (entry 8). Other bromide
sources including NH
Table 2. Scope of N-Methoxybenzamidesa,b
4
Br (entry 9), LiBr (entry 10), NaBr (entry
1
1), and KBr (entry 12) all resulted in decreased yields. Direct
employment of hypervalent iodine reagents PIDA and PhIO
gave slightly higher yields (entries 13-14). To the best of our
knowledge, our results represent the first PhI-catalyzed
synthesis of 2-bromo-phenanthridinone starting from substrate
1a.
Table 1. Optimization of Conditions for Compound 2aa
b
Entry
Cat.
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
-
Oxidant
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
mCPBA
AcOOH
AcOOH
AcOOH
AcOOH
PIDA
Br source
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
Solvent
HFIP
Yield (%)
1
2
3
4
5
6
7
8
9
73
17
42
42
33
20
21
62
42
67
63
70
81
79
TFE
3
CH CN
DCM
DMSO
DMF
2
H O
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
4
NH Br
1
1
1
1
1
0
1
2
3
4
LiBr
NaBr
KBr
aReaction conditions: substrate 1 (0.25 mmol), TBAB (1.2 equiv.) PhI
20 mol %), AcOOH (2.5 equiv.) in 1.0 mL solvent was stirred at room
(
b
temperature for 3 h. Isolated yields.
TBAB
TBAB
-
PhIO
aA mixture of substrate 1a (0.25 mmol), bromide source (1.2
equiv.), PhI (20 mol %), oxidant (2.5 equiv.) in 1.0 mL solvent was
stirred at room temperature for 3 h. TBAB = tetrabutylammonium
bromide, HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol, TFE = 2,2,2-
To further extend the scope of the method, we studied the
corresponding chlorination reactions using TBAC as a chloride
source (Table 3). When compound 1a was used as a substrate
under the optimized conditions, the corresponding 2-chloro-
phenanthridinone 3a was achieved in high yields. Similar high
yields were obtained in reactions using PIDA. Other functional
groups such as Me, Cl, Br also were well-tolerated in
stoichiometric PIDA. High yields corresponding products were
produced successfully (3b-3f). While with the catalytic
trifluoroethanol, CH
DMSO = dimethyl sulfoxide, DMF = dimethylformamide,
mCPBA meta-chloroperoxybenzoic acid, PIDA
diacetoxyiodo)benzene, PhIO = iodosobenzene. Isolated yields.
3
CN = acetonitrile, DCM = dichloromethane,
=
=
b
(
With the optimized conditions in hand, we next explored the conditions, a mixture of the inseparable chlorinated and
substrate tolerance of the reaction using other N- unchlorinated phenanthridinones was obtained (supporting
methoxybenzamide (Table 2). Moderate yields were observed information). The chemical structure of compound 3f was
for substrates that contain halogen substituents on the A-ring confirmed by X-ray crystallography.
(2b-f). When a phenyl group was present on the A-ring, the
corresponding product 2g was formed in high yields. We were
pleased to find that the bromination only took place at the para-
position of newly formed C-N bond. When methylated
substrates were used, slightly increased yields of compounds
2
h-i were obtained. The substrate containing the electron-
donating 1,3-dioxole group reacted smoothly to generate
compound 2j in excellent yields. Compound 2j represents the
core structure of natural product crinasiadine. Substrates
bearing various substitutions on the B-ring were also studied. In
general products with two functional groups on the B-ring could
be constructed with moderate yields (2k-n), likely due to the
2
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3 2 2 2 3 2
) Cl , K CO , dioxane, H
O, 100 oC,
Table 3. Scope of Chlorinationa,b
phenylboronic acid, Pd(PPh
6%; d) CuCN, L-proline, DMF, 120 C, 32%; e) 2-
dimethylamino)acetamide, Pd (dba) , Xantphos, Cs CO , dioxane,
00 C, 85%; f) NaOH, DMF, 120 C, 55%.
o
8
(
1
2
3
2
3
o
o
Next, we expanded the method to construct other heterocycles
Scheme 3). Under our optimized conditions using PIDA,
protected [1,1'-biphenyl]-2-amine was cyclized to give
(
9
compound 10 in modest yields.16 When N-phenylpyridin-2-
amine 11 was used, the cross-dehydrogenative coupling
product 8-bromobenzo[4,5]imidazo[1,2-a]pyridine 12 was
generated in modest yields.17
aReaction conditions: 1 (0.25 mmol), TBAC (1.2 equiv.), PIDA (2.5
equiv.) in 1.0 mL HFIP was stirred at room temperature for 12 h.
b
Isolated yields TBAC = tetrabutylammonium chloride.
Scheme 3. Construction of Other Heterocycle
To gain insight into the mechanism of the sequential reaction,
2-Bromo-phenanthridinones represent key intermediates to
other 2-functionalized phenanthridinones (Scheme 2). Heck
substrate 1a was treated with AcOOH in the presence of TBAB.
reaction between compound 2a and ethyl acrylate gave No obvious reaction was detected in 12 h. This result supported
compound in modest yields. Sonogashira coupling of 2a with the important role of the in situ generated hypervalence iodine
trimethylsilylacetylene using Pd(PPh Cl in the present of CuI reagent in the reactions. Results from NMR studies indicated
afforded the arylethynylene in high yields. When treated with
phenylboronic acid, compound 2a reacted smoothly to give 5-
methoxy-2-phenylphenanthridin-6(5H)-one in good yields.
Treatment of 2a with CuCN upon heating yielded 2-cyano-
phenanthridinones in modest yields. Finally, Pd-catalyzed
amidation of compound 2a with 2-(dimethylamino)acetamide
generated compound in high yields, which was further
4
3
)
2
2
5
the formation of PIDA when mixing PhI with AcOOH in the
presence of TBAB (Figure S1),14g which again, supported the key
6
role of hypervalence iodine in the sequential reaction. Reaction
of substrate 1a with PhI (10 mol%) and AcOOH (1.2 equiv.)
yielded phenanthridinone íꢀ[ in good yields (Scheme 4). When
compound íꢀ[ was submitted to our optimal conditions, as
expected, phenanthridinone 2a was isolated as the only product
in good yields. This result is in consistent with our hypothesis
that the sequential reaction is through the intermediate íꢀ[. We
also performed a reaction of 1a with decreased amount of
AcOOH (1.2 equiv.), and the result showed the formation of 2a
as the only new product in 36% yield, along with the recovery
of starting material 1a in 56%. This result indicated that the first
C-H amidation reaction was the slow step comparing to the
bromination step.
7
8
deprotected to yield PJ34 in good yields.10(h),15
Scheme 4. Sequential Generation of Compound 2a
Based on the results above, a possible mechanism is
proposed for the formation of product 2a under the PhI-
catalyzed conditions (Scheme 5). Methoxybenzamide 1a reacts
with the hypervalence iodine reagent that is generated from
AcOOH oxidation of PhI, to give intermediate A. Electrophilic
Scheme 2. Derivatization of Compound 2a. Reaction conditions: a)
attack of this intermediate by B-ring provides B. Fast
deprotonation of intermediate leads to compound íꢀ[. The
o
ethyl acrylate, Pd(OAc)
2
, PPh
3
, K
2
CO
3
, TBAC, DMF, 120 C, 40%;
B
second equivalence of AcOOH generated hypervalence iodine
o
b) trimethylsilylacetylene, Pd(PPh
3
)
2
Cl
2 3
, CuI, Et N, 80 C, 92%; c)
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reagent reacts with the bromide source in-situ to generate Br
Electrophilic aromatic substitution of compound íꢀ[ with Br
generates the final product 2a via intermediate
2
.
doublet, t = triplet, q = quartet, m = multiplet. Coupling
constants, J values were reported in Hertz unit (Hz). High-
resolution mass spectra (HRMS) were obtained on a JEOL
AccuTOF with ESI/APCI ion sources coupled to an Agilent 1100
HPLC system.
2
C.
General Procedure for the Synthesis of Compounds íꢀ>n.
A mixture of substituted 2-halogenated methyl benzoate (2
mmol), arylboronic acid (3 mmol, 1.5 equiv), Pd(PPh
mmol, 0.04 equiv, 56 mg) and potassium carbonate (6 mmol, 3
equiv, 828 mg) in dioxone/H O (6 mL / 2 mL) was stirred at 100
3 2 2
) Cl (0.08
2
oC under argon atmosphere until the starting material was
completely consumed (typically 20 h). The reaction mixture was
diluted with brine (25 mL). The mixture was then extracted with
EtOAc (25 mL × 2), and the combined organic layers were dried
Scheme 5. Proposed Mechanism for the Formation of 2a
2 4
over Na SO . The concentrated crude product was purified by
column chromatography to afford substituted methyl [1,1'-
biphenyl]-2-carboxylate, which was used directly in the next
Conclusions
In summary, we disclose a one-pot sequential hypervalence step.
iodine-mediated amindation/bromination reaction to furnish 2- To
substituted-phenanthridinones. Using our optimized conditions
a
solution of substituted methyl [1,1'-biphenyl]-2-
carboxylate in EtOH/H O (9 mL, 1:2 (v/v)) was added potassium
2
employing PhI as a catalyst, AcOOH as an oxidant, and TBAB as
a bromide source, the reaction goes smoothly at room
hydroxide (336 mg, 6 mmol). The resulting mixture was heated
under reflux until TLC indicated total consumption of the
substrate. The solvent was removed under vacuum, and the
resulting residue was dissolved into water (20 mL). To the
aqueous solution was added HCl (2 M) until no more precipitate
was formed. The mixture was extracted with EtOAc (25 mL × 3),
temperature to yield
a
wide range of 2-bromo-
phenanthridinones in good yields. By switching to a chloride
source TBAC in the presence of PIDA and AcOOH, analogs of 2-
chloro-phenanthridinones were also obtained in good efficiency.
The resulting 2-bromo-phenanthridinones provide a key
2 4
intermediate for the synthesis of 2-functionalized and the combined organic layer was dried with Na SO . The
phenanthridinones, which is highlighted by the concise solvent was removed by rotary evaporation, and the resulting
synthesis of natural product PJ34. Similar reaction conditions solid was dissolved in DCM (10 mL). To the solution was added
can be used to the construction of other heterocyclic systems.
The anti-lymphoma activities of the synthesized 2-substituted-
phenanthridinones are currently undergoing.
4
-dimethylaminopyridine (DMAP) (366 mg, 3 mmol) and
methoxylamine hydrochloride (166 mg, 2 mmol) in one portion,
followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(
EDCI) (573 mg, 3 mmol). The reaction mixture was allowed to
stir at room temperature until TLC indicated completion of the
reaction. Saturated aqueous NaHCO (10 mL) was added to the
Acknowledgements
3
We thank the American Association for Cancer Research grant reaction mixture. The mixture was extracted with EtOAc (25 mL
00167155 to F.X., the Samuel Waxman Cancer Research × 3), and the combined organic layers were dried using Na SO .
#
2
4
Foundation, and the X-ray crystallographic support by NIDA The solvent was removed under vacuum, and the crude product
Interagency Agreement #Y1-DA1101 with NRL).
was purified by silica gel column chromatography using
EtOAc/hexanes to give substrates íꢀ>n
N-Methoxy-[1,1'-biphenyl]-2-carboxamide (1a).18 1H NMR (400
MHz, CDCl ): w 7.79 (br s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.52 (t, J
8.0 Hz, 1H), 7.43-7.38 (m, 7H), 3.54 (s, 3H); 13C NMR (100 MHz,
(
.
Experimental section
3
=
General Considerations
3
CDCl ): w 167.4, 139.9, 139.6, 132.2, 130.8, 130.1, 129.2, 128.8,
All reagents were purchased without further purification unless
otherwise noted. Reactions were monitored using thin-layer
chromatography (TLC) on commercial silica gel plates (GF254).
Visualization of the developed plates was performed under UV
light (254 nm). Flash column chromatography was performed
on silica gel (200-300 mesh). H and 13C NMR spectra were
recorded on a Varian INOVA 400 MHz NMR spectrometer at
1
28.7, 128.1, 127.7, 127.2, 64.0.
-Fluoro-N-methoxy-[1,1'-biphenyl]-2-carboxamide (1b).18 1H
3
NMR (400 MHz, CDCl
3
): w 8.10 (br s, 1H), 7.43-7.37 (m, 6H), 7.20
d, J = 7.6 Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 3.57 (s, 3H); 13C NMR
100 MHz, CDCl ) w 162.7, 160.0 (J = 250 Hz), 142.5, 138.3, 131.6,
J = 8.9 Hz), 130.8, 128.7, 128.5, 128.3, 125.5, 114.7 (J = 20.9 Hz),
(
(
(
3
1
6
4.2.
-Fluoro-N-methoxy-[1,1'-biphenyl]-2-carboxamide (1c).18 1H
2
5 °C. Chemical shifts (w) are reported in ppm referenced to an
internal tetramethylsilane standard, or the DMSO-d residual
peak (w 2.50) for H NMR. Chemical shifts of 13C NMR are
reported relative to CDCl (w 77.0) or DMSO-d (w 39.5). The
4
6
NMR (400 MHz, CDCl
3
): w 7.69 (br s, 1H), 7.42-7.35 (m, 7H), 7.25-
1
7
1
1
.20 (m, 1H), 3.54 (s, 3H); 13C NMR (100 MHz, CDCl
3
): w 165.9,
3
6
63.1, 138.6, 136.0, 133.8, 132.0, 131.9, 128.9, 128.7, 128.2,
18.0, 117.8, 116.2, 116.0, 64.0.
following abbreviations were used to describe peak splitting
patterns when appropriate: br s = broad singlet, s = singlet, d =
4
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4
-Chloro-N-methoxy-[1,1'-biphenyl]-2-carboxamide (1d).18 1
NMR (400 MHz, CDCl ): w 7.79 (br, 1H), 7.67 (s, 1H), 7.50-7.39 carboxamide (0.25 mmol, 1 equiv) and tetrabutyl ammonium
m, 6H), 7.33 (d, J = 7.6 Hz, 1H), 3.54 (s, 3H); 13C NMR (100 MHz, bromide (TBAB) (97 mg, 0.3 mmol, 1.2 equiv) in 1,1,1,3,3,3-
H
Method A: To a solution of N-methoxy-[1,1'-biphenyl]- 2-
3
(
3
CDCl ): w 165.9, 138.3, 133.9, 133.6, 131.5, 130.9, 129.2, 128.9, hexafluoro-2-propanol (HFIP) (1.0 mL) was added PhI (5.6 …[U
1
28.6, 128.4, 64.0.
0.05 mmol, 20 mol%) and peroxyacetic acid (2.5 equiv) (32 wt.%
4
-Bromo-N-methoxy-[1,1'-biphenyl]-2-carboxamide (1e).18 1
H
in dilute acetic acid, 131 …[U ìX625 mmol, 2.5 equiv) or
NMR (400 MHz, CDCl
3
): w 7.91 (br s, 1H), 7.79 (s, 1H), 7.63 (d, J iodosobenzene diacetate (PIDA) (201 mg, 0.625 mmol, 2.5 equiv)
=
7.2 Hz, 1H), 7.42-7.39 (m, 5H), 7.26 (m, 1H), 3.53 (s, 3H); 13C at 25 ºC under air. The resulting mixture was allowed to stir at
o
NMR (100 MHz, CDCl
3
): w 165.8, 138.8, 138.4, 133.8, 132.0, 25 C for an additional 3 h. The reaction was monitored using
31.7, 128.9, 128.5, 121.8, 64.0. TLC until the starting material was completely consumed. The
-Chloro-N-methoxy-[1,1'-biphenyl]-2-carboxamide (1f).18 1H reaction mixture was diluted with EtOAc (20 mL) and washed
): w 7.69-7.63 (m, 2H), 7.46-7.40 (m, 7H), with brine (20 mL). The organic layer was dried over Na SO , and
.54 (s, 3H); 13C NMR (100 MHz, CDCl
): w 166.4, 141.6, 138.3, concentrated under vacuum. The resulting crude product was
36.7, 130.7, 130.0, 128.9, 128.6, 128.5, 127.8, 64.0. purified by column chromatography (hexane/EtOAc) to give the
1
5
NMR (400 MHz, CDCl
3
2
4
3
1
3
N-Methoxy-[1,1':4',1''-terphenyl]-2'-carboxamide (1g).18 1H desired products 2a-n.
NMR (400 MHz, CDCl ): w 7.92 (br s, 1H), 7.75 (d, J = 7.6 Hz, 2H), To improve yields of the reactions that gave relatively low yields
.65 (d, J = 8.0 Hz, 2H), 7.48-7.39 (m, 9H), 3.58 (s, 3H); 13C NMR (< 60%), we repeated them and used PIDA directly instead of
100 MHz, CDCl ): w 167.4, 140.7, 139.5, 139.2, 138.6, 132.6, the catalytic system. For most of cases a slightly higher yields
3
7
(
3
1
30.6, 129.3, 128.94, 128.86, 128.7, 128.2, 127.9, 127.1, 64.0.
were obtained as follows.
N-Methoxy-4-methyl-[1,1'-biphenyl]-2-carboxamide (1h).18 1
H
Method B: To a solution of N-methoxy-[1,1'-biphenyl]- 2-
NMR (400 MHz, CDCl
3
): w 7.76 (br s, 1H), 7.50 (s, 1H), 7.45-7.38 carboxamide (0.25 mmol, 1 equiv) and tetrabutyl ammonium
m, 5H), 7.34-7.29(m, 2H), 3.53 (s, 3H), 2.41 (s, 3H); 13C NMR bromide (TBAB) (97 mg, 0.3 mmol, 1.2 equiv) in 1,1,1,3,3,3-
100 MHz, CDCl ): w 167.7, 139.5, 137.8, 137.0, 131.9, 131.6, hexafluoro-2-propanol (HFIP) (1.0 mL) iodosobenzene diacetate
30.0, 129.7, 128.8, 128.7, 127.9, 63.9, 20.9.
(
(
3
o
1
(PIDA) (201 mg, 0.625 mmol, 2.5 equiv) at 25 C under air. The
N-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxamide (1i).18 1H resulting mixture was allowed to stir at 25 C for an additional 3
o
NMR (400 MHz, CDCl3) w 7.61 (d, J = 7.6 Hz, 1H), 7.46-7.40 (m, h. The reaction was monitored using TLC until the starting
5
H), 7.25 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 3.54 (s, 3H), 2.42 (s, 3H); material was completely consumed. The reaction mixture was
13C NMR (100 MHz, CDCl
) w 167.5, 141.0, 139.9, 139.8, 130.7, diluted with EtOAc (20 mL) and washed with brine (20 mL). The
29.3, 128.71, 128.66,128.4, 128.0, 63.9, 21.4. organic layer was dried over Na SO , and concentrated under
N-Methoxy-6-phenylbenzo[d][1,3]dioxole-5-carboxamide vacuum. The resulting crude product was purified by column
1j).18 1H NMR (400 MHz, CDCl
): w 7.70 (br s, 1H), 7.42-7.35 (m, chromatography (hexane/EtOAc) to give the desired products
H), 7.14 (s, 1H), 6.80 (s, 1H), 6.04 (s, 2H), 3.48 (s, 3H); 13C NMR 2a-d
2f 2h 2k-m (see supporting information Scheme S1).
100 MHz, CDCl ): w 166.9, 149.6, 147.3, 139.5, 135.0, 128.9, 2-Bromo-5-methoxyphenanthridin-6(5H)-one (2a). White solid,
3
1
2
4
(
3
5
,
,
,
(
3
1
4
28.7, 128.1, 125.8, 109.9, 109.2, 101.9, 63.8.
'-Chloro-N-methoxy-[1,1'-biphenyl]-2-carboxamide (1k).18 1
method A: 55 mg, 73% yield; method B: 61 mg, 81% yield, mp
o
1
H
3
156-158 C; H NMR (400 MHz, CDCl ) w 8.56 (d, J = 8.8 Hz, 1H),
NMR (400 MHz, CDCl
.49 (d, J = 8.0 Hz, 1H), 7.44-7.34 (m, 6H), 3.59 (s, 3H); 13C NMR 7.63 (m, 2H), 7.56 (d, J = 9.2 Hz, 1H), 4.13 (s, 3H); 13C NMR (100
100 MHz, CDCl ): w 167.3, 138.8, 138.0, 134.2, 132.2, 130.9, MHz, CDCl ) w 156.9, 134.8, 132.9, 132.7, 131.7, 128.8, 128.6,
126.5, 126.0, 122.0, 120.2, 116.3, 114.4, 62.8; HRMS (ESI): Exact
3
): w 8.04 (br s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.69-
7
(
3
3
1
4
30.03, 129.95, 129.0, 128.9, 127.9, 64.1.
'-Bromo-N-methoxy-[1,1'-biphenyl]-2-carboxamide (1l).18 1
+
H
2
mass calcd for C14H11BrNO [M+H] 303.9968, found 303.9983.
NMR (400 MHz, CDCl
3
): w 8.14 (br s, 1H), 7.58-7.50 (m, 4H), 7.42 2-Bromo-7-fluoro-5-methoxyphenanthridin-6(5H)-one (2b).
(t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), White solid, method A: 35 mg, 43% yield; method B: 49 mg, 61%
o
1
3
1
.59 (s, 3H); 13C NMR (100 MHz, CDCl
3
): w 167.2, 138.8, 138.4, yield, mp 188-190 C; H NMR (400 MHz, CDCl
8.01 (d, J = 8.8 Hz, 1H), 7.77-7.67 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H),
) w
): w 7.81 (br s, 1H), 7.67 (d, J = 6.8 Hz, 162.9 (J = 264.9 Hz), 154.2, 135.2, 134.4, 133.8 (J = 10.4 Hz),
H), 7.50 (t, J = 8.0 Hz, 1H), 7.43-7.31 (m, 4H), 7.24 (d, J = 7.6 Hz, 133.5, 126.5, 119.1, 117.9 (J = 4.5 Hz), 116.32 (J = 20.8 Hz),
H), 3.58 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl
): w 167.6, 116.31, 115.5, 114.3, 62.8; HRMS (ESI): Exact mass calcd for
3
) w 8.32 (s, 1H),
32.2, 131.8, 130.9, 130.3, 130.0, 129.0, 127.0, 122.4, 64.0.
N-Methoxy-4'-methyl-[1,1'-biphenyl]-2-carboxamide (1m).18 7.30 (t, J = 8.8 Hz, 1H), 4.12 (s, 3H); 13C NMR (100 MHz, CDCl
1H NMR (400 MHz, CDCl
3
3
1
2
1
1
2
3
+
40.0, 137.8, 136.6, 132.1, 130.7, 130.1, 129.4, 129.1, 128.5,
27.4, 63.8, 21.2.
'-(Methoxycarbamoyl)-[1,1'-biphenyl]-4-yl acetate (1n). 1
14 2
C H10BrFNO [M+H] 321.9873, found 321.9887.
2-Bromo-8-fluoro-5-methoxyphenanthridin-6(5H)-one (2c).
H
White solid, method A: 47 mg, 59% yield; method B: 49 mg, 61%
o
1
NMR (400 MHz, CDCl
3
) w 7.98 (s, 1H), 7.61 (d, J = 6.8 Hz, 1H), yield, mp 176-178 C; H NMR (400 MHz, CDCl
.50 (d, J = 7.2 Hz, 1H), 7.43-7.37 (m, 4H), 7.14 (d, J = 7.2 Hz, 2H), 8.21-8.17 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.55-7.49 (m, 2H), 4.12
.54 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl ) w 169.4, (s, 3H); 13C NMR (100 MHz, CDCl
) w 162.5 (J = 250 Hz), 156.0,
67.2, 150.5, 139.0, 137.2, 132.4, 130.8, 130.0, 129.7, 129.1, 134.2, 132.6, 128.6, 128.2, 125.9, 124.7 (J = 7.5 Hz), 121.3 (J =
3
) w 8.27 (s, 1H),
7
3
1
1
3
3
27.8, 121.9, 64.0, 21.1.
22.3 Hz), 119.6, 116.6, 114.5, 114.2 (J = 23.1 Hz), 62.9; HRMS
General Procedure for Bromination.
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DOI: 10.1039/C7OB00649G
ARTICLE
Journal Name
+
(
ESI): Exact mass calcd for C14
found 321.9881.
-Bromo-8-chloro-5-methoxyphenanthridin-6(5H)-one (2d).
H
10BrFNO
2
[M+H] 321.9873, 154.0, 138.9, 137.2, 133.6, 131.3, 126.6, 125.0, 120.8, 119.6,
110.3, 107.9, 107.3, 67.9; HRMS (ESI): Exact mass calcd for
+
2
15
C H
11BrNO
4
[M+H] 347.9866, found 347.9887.
White solid, method A: 44 mg, 52% yield, method B: 66 mg, 78% 2-Bromo-3-chloro-5-methoxyphenanthridin-6(5H)-one (2k).
o
1
yield, mp 224-226 C; H NMR (400 MHz, CDCl
Hz, 1H), 8.32 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.76-7.68 (m, 2H), yield, mp 228-230 C; H NMR (400 MHz, CDCl
.56 (d, J = 8.8 Hz, 1H), 4.13 (s, 3H); 13C NMR (100 MHz, CDCl
Hz, 1H), 8.45 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 7.2 Hz,
w 155.9, 135.2, 134.7, 133.2, 133.0, 130.2, 128.2, 127.8, 126.0, 1H), 7.76 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 4.14 (s, 3H); 13C NMR
23.8, 119.5, 116.6, 114.6, 62.9; HRMS (ESI): Exact mass calcd (100 MHz, CDCl ) w 156.9, 136.0, 135.6, 133.1, 131.1, 129.0,
128.8, 128.1, 126.4, 122.0, 118.6, 116.4, 114.2, 63.0; HRMS (ESI):
3
) w 8.53 (d, J = 1.6 White solid, method A: 45 mg, 53% yield; method B: 48 mg, 57%
o
1
3
) w 8.53 (d, J = 8.0
7
3
)
1
3
+
for C14
2
H10ClBrNO [M+H] 337.9578, found 337.9573.
+
2
,8-Dibromo-5-methoxyphenanthridin-6(5H)-one (2e). White Exact mass calcd for C14H10BrClNO [M+H] 337.9578, found
2
o
1
solid, method A: 61 mg, 65% yield, mp 258-260 C; H NMR (400 337.9599.
MHz, DMSO-d ) w 8.73 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.42 (s, 2,3-Dibromo-5-methoxyphenanthridin-6(5H)-one (2l). White
H), 8.05 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.61 (d, J = solid, method A: 49 mg, 51%, method B: 60 mg, 63% yield, mp
6
1
8
1
1
C
2
.4 Hz, 1H), 4.03 (s, 3H); 13C NMR (100 MHz, DMSO-d
o
1
6 3
) w 160.0, 224-226 C; H NMR (400 MHz, CDCl ) w 8.53 (d, J = 7.6 Hz, 1H),
41.0, 139.8, 138.5, 135.9, 134.9, 132.8, 131.6, 131.1, 127.4, 8.45 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.81 (t, J = 8.0
24.5, 121.2, 120.0, 68.0; HRMS (ESI): Exact mass calcd for Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 4.14 (s, 3H); 13C NMR (100 MHz,
+
14
H
10Br
2
NO
2
[M+H] 381.9073, found 381.9021.
3
CDCl ) w 156.9, 135.5, 133.1, 131.2, 129.0, 128.8, 127.8, 126.4,
-Bromo-9-chloro-5-methoxyphenanthridin-6(5H)-one (2f). 126.1, 122.0, 119.2, 118.7, 117.4, 63.0; HRMS (ESI): Exact mass
+
White solid, method A: 48 mg, 57% yield; method B: 51 mg, 61% calcd for C14
H
10Br
2
NO
) w 8.47 (d, J = 8.8 2-Bromo-5-methoxy-3-methylphenanthridin-6(5H)-one (2m).
Hz, 1H,), 8.27 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.70 (d, Yellow solid, method A: 42 mg, 53%, method B: 52 mg, 65% yield,
2
[M+H] 381.9073, found 381.9089.
o
1
yield, mp 220-222 C; H NMR (400 MHz, CDCl
3
J = 9.2 Hz, 1H), 7.59-7.54 (m, 2H), 4.12 (s, 3H); 13C NMR (100 mp 228-230 C; H NMR (400 MHz, CDCl
MHz, CDCl ) w 156.3, 139.8, 135.2, 133.5, 133.1, 130.4, 129.2, 1H), 8.37 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 8.8 Hz, 1H),
26.1, 124.9, 122.0, 119.0, 116.5, 114.6, 62.9; HRMS (ESI): Exact 7.60 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 4.13 (s, 3H), 2.56 (s, 3H); 13
o
1
) w 8.53 (d, J = 8.0 Hz,
3
3
1
C
+
mass calcd for C14
1 2 3
H BrClNO [M+H] 337.9578, found 337.9598. NMR (100 MHz, CDCl ) w 157.1, 140.0, 134.9, 132.8, 131.8,
2
-Bromo-5-methoxy-8-phenylphenanthridin-6(5H)-one (2g). 128.6, 128.3, 126.8, 126.2, 121.8, 119.2, 118.1, 114.3, 62.8, 23.5;
o
1
+
White solid, method A: 81 mg, 85% yield, mp 178-180 C; H HRMS (ESI): Exact mass calcd for C15
NMR (400 MHz, CDCl ) w 8.77 (s, 1H), 8.36 (s, 1H), 8.25 (d, J = 8.8 found 318.0130.
Hz, 1H), 8.03 (dd, J = 1.6, 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 2-Bromo-5-methoxy-6-oxo-5,6-dihydrophenanthridin-3-yl
2
H13BrNO [M+H] 318.0124,
3
7
4
1
1
.66 (d, J = 7.6 Hz, 1H), 7.56-7.48 (m, 3H), 7.42 (t, J = 7.6 Hz, 1H), acetate (2n). Pink solid, method A: 38 mg, 42% yield, mp 156-
1
.15 (s, 3H); 13C NMR (100 MHz, CDCl
o
3 3
) w 157.0, 141.5, 139.1, 158 C; H NMR (400 MHz, CDCl ) w 8.51 (d, J = 8.0 Hz, 1H), 8.44
34.7, 132.6, 131.5, 130.5, 129.0, 128.2, 127.2, 126.9, 126.5, (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.62 (t, J
26.0, 122.7, 120.1, 116.4, 114.4, 62.9; HRMS (ESI): Exact mass = 8.0 Hz, 1H), 7.45 (s, 1H), 4.12 (s, 3H), 2.43 (s, 3H); 13C NMR
+
calcd for C20
H
15BrNO
2
[M+H] 380.0281, found 380.0282.
3
(100 MHz, CDCl ) w 168.3, 157.0, 149.2, 136.0, 133.0, 131.3,
2
-Bromo-5-methoxy-8-methylphenanthridin-6(5H)-one (2h). 128.71, 128.68, 127.9, 126.2, 122.0, 117.9, 110.5, 108.1, 63.0,
[M+H]+
White solid, method A: 61 mg, 77% yield; method B: 55 mg, 69% 20.8; HRMS (ESI): Exact mass calcd for C16
H13BrNO
4
o
1
yield, mp 176-178 C; H NMR (400 MHz, CDCl
3
) w 8.31 (s, 1H), 362.0022, found 362.0029.
.28 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.62-7.57 (m, 2H), 7.51 (d, J General Procedure for Chlorination.
8.8 Hz, 1H), 4.11 (s, 3H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl
To a solution of N-methoxy-[1,1'-biphenyl]- 2-carboxamide
8
=
3
)
w 157.0, 139.2, 134.3, 134.2, 132.1, 129.2, 128.3, 126.4, 125.7, (0.25 mmol, 1 equiv) and tetrabutyl ammonium chloride (TBAC)
1
22.0, 120.3, 116.3, 114.3, 62.8, 21.4; HRMS (ESI): Exact mass (104 mg, 0.375 mmol, 1.5 equiv) in HFIP (1.0 mL) was added PhI
+
calcd for C15
H
13BrNO
2
[M+H] 318.0124, found 318.0132.
(5.6 …[U ìXì5 mmol, 20 mol%) and peroxyacetic acid (2.5 equiv)
2
-Bromo-5-methoxy-9-methylphenanthridin-6(5H)-one (2i). (32 wt.% in dilute acetic acid, 131 …[U ìX625 mmol, 2.5.0 equiv)
o
1
o
White solid, method A: 58 mg, 73% yield, mp 212-214 C; H or PIDA (201 mg, 0.625 mmol, 2.5 equiv) at 25 C under air. The
o
3
NMR (400 MHz, CDCl ) w 8.41 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 1.6 resulting mixture was stirred at 25 C for 12 h. The reaction was
Hz, 1H), 7.96 (s, 1H), 7.64 (dd, J = 1.6, 8.8 Hz, 1H), 7.52 (d, J = 8.4 monitored using TLC until the starting material was completely
Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.11 (s, 3H), 2.57 (s, 3H); 13C consumed. The reaction mixture was diluted with EtOAc (20 mL)
NMR (100 MHz, CDCl
3
) w 157.0, 143,6, 134.9, 132.5, 131.7, and washed with brine (20 mL). The organic layer was dried over
30.2, 128.6, 125.9, 124.2, 122.0, 120.2, 116.2, 114.4, 62.8, 22.1; Na SO , and concentrated under vacuum. The resulting crude
[M+H] 318.0124, product was purified by column chromatography
(hexane/EtOAc) to give the desired products 3a-f
2-Chloro-5-methoxyphenanthridin-6(5H)-one (3a).19 White
1
2
4
+
HRMS (ESI): Exact mass calcd for C15
H13BrNO
2
found 318.0127.
.
2
-Bromo-5-methoxy-[1,3]dioxolo[4,5-j]phenanthridin-6(5H)-
o
1
one (2j). White solid, method A: 77 mg, 89% yield, mp 258-260 solid, 57 mg, 88% yield, mp 158-160 C; H NMR (400 MHz, CDCl
1
3
)
o
C; H NMR (400 MHz, DMSO-d
6
) w 8.64 (s, 1H), 8.17 (s, 1H), 7.76 w 8.53 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 7.6 Hz, 2H), 7.78 (t, J = 8.0
(
d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 6.27 (s, Hz, 1H), 7.64-7.58 (m, 2H), 7.51 (dd, J = 1.6, 8.8 Hz, 1H), 4.12 (s,
H), 4.01 (s, 3H); 13C NMR (100 MHz, DMSO-d ) w 160.4, 157.7, 3H); 13C NMR (100 MHz, CDCl
2
6
3
) w 156.9, 134.3, 132.8, 131.8,
6
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB00649G
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ARTICLE
1
6
2
2
29.9, 128.9, 128.7, 128.6, 126.5, 123.0, 122.0, 119.8, 114.1, 1H), 7.82-7.74 (m, 3H), 7.68-7.61 (m, 2H), 6.52 (d, J = 16.4 Hz,
[M+H]+ 1H), 4.30 (q, J = 6.8 Hz, 2H), 4.14 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl
) w 166.9, 157.1, 143.5, 137.0, 132.9,
2.8; HRMS (ESI): Exact mass calcd for C14
60.0473, found 260.0477.
H
11ClNO
2
3
,8-Dichloro-5-methoxyphenanthridin-6(5H)-one (3b). White 132.4, 129.5, 128.9, 128.6, 128.5, 126.4, 123.6, 121.9, 118.7,
o
1
solid, 54 mg, 74% yield, mp 238-240 C; H NMR (400 MHz, CDCl
w 8.50 (d, J = 2.4 Hz, 1H), 8.14-8.11 (m, 2H), 7.73 (dd, J = 2.4, 8.8
Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.54 (dd, J = 1.6, 8.8 Hz, 1H), General Procedure for the Synthesis of Compound 5.
3
) 118.0, 113.3, 62.9, 60.6, 14.3; HRMS (ESI): Exact mass calcd for
+
19 4
C H18NO [M+H] 324.1230, found 324.1240.
4
1
1
.12 (s, 3H); 13C NMR (100 MHz, CDCl
33.2, 132.9, 130.2, 129.2, 128.2, 127.8, 123.7, 123.0, 119.1, (2a) (75.5 mg, 0.25 mmol) in triethylamine (2 mL) were added
14.3, 62.9; HRMS (ESI): Exact mass calcd for C14 NO Pd(PPh )Cl (105 mg, 0.15 mmol), CuI (47.6 mg, 0.25 mmol) and
ethynyltrimethylsilane (123 mg, 1.25 mmol). The reaction
3
) w 155.9, 135.2, 134.2, To a solution of 2-bromo-5-methoxyphenanthridin-6(5H)-one
H10Cl
2
2
3
2
+
[
M+H] 294.0083, found 294.0098.
o
8
-Bromo-2-chloro-5-methoxyphenanthridin-6(5H)-one (3c). mixture was stirred at 80 C under nitrogen atmosphere for 8 h,
o
1
White solid, 65 mg, 77% yield, mp 254-256 C; H NMR (400 MHz, then, saturated aqueous NH
DMSO-d ) w 8.65-8.60 (m, 2H), 8.44 (d, J = 1.6 Hz, 1H), 8.07 (dd, reaction mixture. The organic layer was dried using MgSO
J = 2.0 Hz, 8.4 Hz, 1H), 7.76-7.67 (m, 2H), 4.04 (s, 3H); 13C NMR the solvent was removed under vacuum. The crude product was
100 MHz, DMSO-d ) w 160.0, 141.0, 139.5, 136.0, 135.7, 134.9, purified by column chromatography to afford 5-methoxy-2-
33.3, 132.9, 131.2, 128.8, 127.4, 124.1, 119.7, 68.0; HRMS (ESI): ((trimethylsilyl)ethynyl)phenanthridin-6(5H)-one (74 mg, 92%)
[M+H] 337.9578, found as a white solid: mp 156-158 C; H NMR (400 MHz, CDCl ) w 8.53
(d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.77 (t, J
-Chloro-5-methoxy-8-methylphenanthridin-6(5H)-one (3d). = 8.0 Hz, 1H), 7.66-7.58 (m, 3H), 4.12 (s, 3H), 0.30 (s, 9H); 13C
4
Cl and EtOAc were added to the
6
4
, and
(
6
1
5
+
o
1
Exact mass calcd for C14
H
10BrClNO
2
3
3
37.9496.
2
o
1
White solid, 54 mg, 79% yield, mp 152-154 C; H NMR (400 MHz, NMR (100 MHz, CDCl
CDCl ) w 8.33 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 128.5, 128.4, 127.1, 126.4, 122.1, 118.4, 118.0, 112.6, 104.3,
H), 7.60-7.57 (m, 2H), 7.48 (dd, J = 2.4, 8.4 Hz, 1H), 4.12 (s, 3H), 94.4, 62.9, 0.0; HRMS (ESI): Exact mass calcd for C19 Si
3
) w 157.1, 135.6, 133.3, 132.8, 132.2,
3
1
2
1
6
2
2
H20NO
2
.53 (s, 3H); 13C NMR (100 MHz, CDCl
) w 157.0, 139.2, 134.1, [M+H] 322.1258, found 322.1269.
+
3
34.0, 129.3, 128.8, 128.4, 126.4, 122.7, 122.0, 120.0, 114.0, General Procedure for the Synthesis of Compound 6.
2.8, 21.4; HRMS (ESI): Exact mass calcd for C15
H
13ClNO
2
[M+H]+
A
mixture of 2-bromo-5-methoxyphenanthridin-6(5H)-one
(75.5 mg, 0.25 mmol), phenylboronic acid (45.8 mg, 0.375
)Cl (9 mg, 0.0125 mmol), K CO (104 mg, 0.75
O (1.5 mL/0.5 mL) was stirred at 100 oC
) w 8.54 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 8.16 (d, J = 8.8 Hz, under nitrogen atmosphere for 8 h, then cooled to room
H), 7.77 (t, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.53 (s, 1H), temperature. To the reaction was added H O (20 mL), and the
.13 (s, 3H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl
) w 157.1, resulting mixture was extracted using EtOAc (15 mL × 2), and
38.3, 134.3, 132.8, 131.9, 129.4, 128.6, 128.2, 126.2, 123.4, the combined organic layers were washed using brine, and
21.8, 117.8, 114.5, 62.8, 20.7; HRMS (ESI): Exact mass calcd for dried over Na SO . The concentrated crude product was
purified by column chromatography to afford 5-methoxy-2-
74.0629, found 274.0634.
-Chloro-5-methoxy-3-methylphenanthridin-6(5H)-one (3e). mmol), Pd(PPh
3
2
2
3
o
1
White solid, 48 mg, 70% yield, mp 232-234 C; H NMR (400 MHz, mmol) in dioxane/H
CDCl
2
3
1
4
1
1
C
2
2
3
2
4
+
15
H
13ClNO
2
[M+H] 274.0629, found 274.0634.
o
,3-Dichloro-5-methoxyphenanthridin-6(5H)-one (3f). White phenylphenanthridin-6(5H)-one
6
(62 mg, 86%): mp 146-148 C;
) w 8.57 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H),
w 8.53 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.79 (t, J = 8.0 Hz, 2H), 7.72 (d, J = 8.8 Hz,
.81 (t, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 4.14 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.50 (t, J =
s, 3H); 13C NMR (100 MHz, CDCl ) w 156.9, 135.0, 134.1, 133.1, 8.0 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 4.17 (s, 3H); 13C NMR (100
31.2, 129.0, 128.8, 127.2, 126.4, 124.8, 122.0, 118.3, 114.3, MHz, CDCl ) w 157.2, 140.3, 136.4, 135.1, 132.9, 132.7, 129.0,
[M+H]+ 128.9, 128.6, 128.2, 127.5, 127.1, 126.5, 121.9, 121.7, 118.8,
o
1
3 3
solid, 45 mg, 61% yield, mp 164-166 C; H NMR (400 MHz, CDCl )
1H NMR (400 MHz, CDCl
7
(
3
1
6
2
3
3.0; HRMS (ESI): Exact mass calcd for C14
94.0083, found 294.0090.
2 2
H10Cl NO
113.1, 62.8; HRMS (ESI): Exact mass calcd for C20
302.1176, found 302.1186.
H16NO
2
[M+H]+
General Procedure for the Synthesis of Compound 4.
To a solution of compound 2a (75.5 mg, 0.25 mmol) in DMF (2 General Procedure for the Synthesis of Compound 7.
mL) was added potassium carbonate (104 mg, 0.75 mmol), tert- To a mixture of CuCN (45 mg, 0.5 mmol), L-proline (28.8 mg,
butylammonium chloride (70 mg, 0.25 mmol), and ethyl 0.25 mmol), and DMF (2 mL) under argon was added compound
acrylate (100 mg, 1 mmol). The reaction mixture was stirred at 2a (75.5 mg, 0.25 mmol). The mixture was stirred at 120 °C for
room temperature for 20 min, then heated at 120 °C overnight. 48 h and then cooled to room temperature. The reaction was
The reaction mixture was cooled and concentrated. The diluted using EtOAc (15 mL) and washed by H
resulting residue was diluted by H O and extracted with EtOAc organic layer was dried over Na SO , and concentrated. The
3 x 20 mL). The combined organic layers were dried over crude product was purified by flash chromatography
2
O (3 × 10 mL). The
2
2
4
(
Na
2
SO
4
and concentrated. The crude product was purified by EtOAc/hexane
to
yield
5-methoxy-6-oxo-5,6-
as a white solid (20 mg,
flash chromatography (hexane/EtOAc) to give ethyl (E)-3-(5- dihydrophenanthridine-2-carbonitrile
7
o
1
methoxy-6-oxo-5,6-dihydrophenanthridin-2-yl) acrylate
4
as a 32%): mp 190-192 C; H NMR (400 MHz, CDCl
white solid (32 mg, 40%): mp 160-162 C; H NMR (400 MHz, 7.2 Hz, 2H), 8.26 (d, J = 8.4 Hz, 1H), 7.89-7.82 (m, 2H), 7.77-7.69
CDCl ) w 157.1, 138.6,
) w 8.54 (d, J = 7.6 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J = 8.8 Hz, (m, 2H), 4.16 (s, 3H); 13C NMR (100 MHz, CDCl
3
) w 8.57 (d, J =
o
1
3
3
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DOI: 10.1039/C7OB00649G
ARTICLE
Journal Name
1
1
C
33.4, 132.8, 131.3, 129.4, 128.8, 127.9, 126.5, 122.0, 119.0, 116.9, 115.9, 27.7; HRMS (ESI): Exact mass calcd for C14H11BrNO
+
18.6, 113.5, 106.8, 63.1; HRMS (ESI): Exact mass calcd for [M+H] 288.0019, found 288.0019.
+
[M+H] 251.0815, found 251.0821.
8-Bromobenzo[4,5]imidazo[1,2-a]pyridine (12)21 mp 192-194
15
H
11
N
2
O
2
o
1
General Procedure for the Synthesis of Compound 8.
3
C; H NMR (400 MHz, CDCl ) w 8.35 (d, J = 6.8 Hz, 1H), 8.03 (s,
To a solution of compound 2a (75.5 mg, 0.25 mmol) in dioxane 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.60 (d, J =
(
(
(
1 mL) was added cesium carbonate (244 mg, 0.75 mmol), 2- 8.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H); 13C
dimethylamino)acetamide (25.5 mg, 0.25 mmol), xantphos NMR (100 MHz, CDCl ) w 148.8, 143.3, 129.8, 129.0, 126.4,
20.3 mg, 0.035 mmol), and Pd (dba) (22.9 mg, 0.025 …u}o•X 125.0, 121.2, 118.2, 113.8, 113.6, 110.9; HRMS (ESI): Exact mass
3
2
3
o
+
The reaction mixture was stirred at 100 C under nitrogen calcd for C11
8 2
H BrN [M+H] 246.9865, found 246.9875.
atmosphere for 36 h, then cooled to room temperature. The
reaction was diluted using H
organic layer was dried over MgSO
crude product was purified by column chromatography to
afford 2-(dimethylamino)-N-(5-methoxy-6-oxo-5,6-
dihydrophenanthridin-2-yl)acetamide as a red liquid (69 mg,
5%, red liquid): H NMR (400 MHz, CDCl ) w 9.31 (s, 1H), 8.70
d, J = 1.6 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H),
.75 (t, J = 7.6 Hz, 1H), 7.66 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 7.61-7.56
m, 2H), 4.11 (s, 3H), 3.14 (s, 2H), 2.42 (s, 6H); 13C NMR (100 MHz,
CDCl ) w 169.0, 156.9, 133.6, 132.6, 132.5, 132.2, 128.4, 128.2,
26.5, 122.4, 121.7, 119.0, 113.8, 113.2, 63.6, 62.7, 46.1; HRMS
2
O and extracted using EtOAc. The
Notes and references
4
, and concentrated. The
1
(a) C. Jiang, D. J. Covell, A. F. Stepan, M. S. Plummer, M. C
White, Org. Lett., 2012, 14, 1386; (b) G. Zhao, C. Chen, Y. Yue,
Y. Yu, J. Peng, J. Org. Chem., 2015, 80, 2827; (c) X. Wang, L.-H.
Liu, J.-H. Shi, J. Peng, H.-Y. Tu, A.-D. Zhang, Eur. J. Org. Chem.,
8
1
8
3
2
013, 6870; (d) M. Yamaguchi, H. Katsumata, K. Manabe, J.
(
Org. Chem., 2013, 78, 9270; (e) S. Paul, S. Samanta, J. K. Ray,
Tetrahedron Lett., 2010, 51, 5604; (f) H. Xu, C. Golz, C.
Strohmann, A. P. Antonchick, H. Waldmann, Angew. Chem. Int.
Ed., 2016, 55, 7761.
7
(
3
2
(a) A. Martins, S. Lemouzy, M. Lautens, Org. Lett., 2009, 11,
1
3
1
81; (b) C. Peng, J. Cheng, J. Wang, Adv. Synth. Catal., 2008,
50, 2359.
+
(
20 3 3
ESI): Exact mass calcd for C18H N O [M+H] 326.1499, found
3
26.1502.
3
4
A. Wagner, N. Hampel, H. Zipse, A. R. Ofial, Org. Lett., 2015,
17, 4770.
P. Jagtap, F. G. Soriano, L. Virag, L. Liaudet, J. Mabley, E. Szabo,
G. Hasko, A. Marton, C. B. Lorigados, F. Gallyas, B. Sumegi, D.
G. Hoyt, E. Baloglu, J. VanDuzer, A. L. Salzman, G. J. Southan,
C. Szabo, Crit. Care. Med., 2002, 30, 1071.
B. A. Stoica, D. J. Loane, Z. R. Zhao, S. V. Kabadi, M. Hanscom,
K. R. Byrnes, A. I. Faden, J. Neurotraum., 2014, 31, 758.
Z. D. Tu, W. H. Chu, J. Zhang, C. S. Dence, M. J. Welch, R. H.
Mach, Nucl. Med. Biol., 2005, 32, 437.
S. Mishra, S. De, B. N. Kakde, D. Dey, A. Bisai, Indian J. Chem.
A, 2013, 52, 1093.
General Procedure for the Synthesis of PJ34.
To a solution of compound 8 (26 mg, 0.08 mmol) in DMF (1 mL)
was added NaH (60% in mineral, 10 mg, 0.24 mmol). The
reaction mixture was stirred at 120 oC under nitrogen
atmosphere for 1 h, and then cooled to room temperature. The
5
6
7
8
9
1
reaction was diluted using H
2
O and extracted using EtOAc. The
, and the solvent was
organic layer was dried over MgSO
4
removed under reduced pressure. The crude product was
purified by column chromatography to afford PJ3415 as a white
1
solid (13 mg, yield: 55%): H NMR (400 MHz, DMSO-d
6
) w 11.67
S. Patil, S. Kamath, T. Sanchez, N. Neamati, R. F. Schinazi, J. K.
Buolamwini, Bioorg. Med. Chem., 2007, 15, 1212.
V. Holl, D. Coelho, D. Weltin, J. W. Hyun, P. Dufour, P. Bischoff,
Anticancer Res., 2000, 20, 3233.
(
s, 1H), 9.86 (s, 1H), 8.68 (s, 1H), 8.32 (t, J = 8.4 Hz, 2H), 7.89 (t,
J = 7.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H),
.31 (d, J = 8.8 Hz, 1H), 3.14 (s, 2H), 2.33 (s, 6H); 13C NMR (100
MHz, DMSO-d ) w 173.7, 165.7, 139.2, 138.8, 138.0, 137.8,
33.2, 132.8, 131.0, 127.4, 127.2, 122.6, 121.4, 118.6, 68.4, 50.6.
7
0 (a) G.-W. Wang, T.-T. Yuan, D.-D. Li, Angew. Chem., Int. Ed.,
2
6
011, 50, 1380; (b) J. Karthikeyan, C.-H. Cheng, Angew. Chem.,
1
Int. Ed., 2011, 50, 9880; (c) J. Karthikeyan, R. Haridharan, C.-H.
Cheng, Angew. Chem., Int. Ed., 2012, 51, 12343; (d) N.
Senthilkumar, K. Parthasarathy, P. Gandeepan, C.-H. Cheng,
General Procedure for the Synthesis of other Heterocycles 10
and 12.
Chem. Asian J., 2013, 8, 2175; (e) S. L. Yedage, B. M. Bhanage,
To a solution of N-([1,1'-biphenyl]-2-yl)acetamide 9 or N-
phenylpyridin-2-amine 11 (0.25 mmol, 1 equiv) and TBAB (97
mg, 0.3 mmol, 1.2 equiv) in HFIP (1.0 mL) was added PIDA (201
J. Org. Chem., 2016, 81, 4103; (f) D. Li, N. Xu, Y. Zhang, L. Wang,
Chem. Commun., 2014, 50, 14862; (g) V. Rajeshkumar, T. H.
Lee, S. C. Chuang, Org. Lett., 2013, 15, 1468; (h) Z. Liang, J.
Zhang, Z. Liu, K. Wang, Y. Zhang, Tetrahedron, 2013, 69, 6519;
o
mg, 0.625 mmol, 2.5 equiv) at 25 C under air. The reaction
(
2
7
i) D. Liang, Z. Hu, J. Peng, J. Huang, Q. Zhu, Chem. Commun.,
013, 49, 173; (j) X. Li, J. Pan, S. Song, N. Jiao, Chem. Sci., 2016,
, 5384; (k) Y. Kikugawa, M. Shimada, K. Matsumoto,
mixture was stirred at room temperature for 12 h. The reaction
mixture was diluted using EtOAc (20 mL) and washed using
brine (20 mL). The organic layer was dried over Na
2 4
SO , and
Heterocycles, 1994, 37, 293; (l) Q. Gui, Z. Yang, X. Chen, J. Liu,
Z. Tan, R. Guo, W. Yu, Synlett, 2013, 24, 1016.
concentrated. The crude product was purified by column
chromatography (hexane/EtOAc) to give 1-(3-bromo-9H- 11 For direct oxidant-mediated synthesis of quinolinones
derivatives, see: (a) A. R. Forrester, E. M. Johansson, R. H.
carbazol-9-yl)ethan-1-one 10 (51 mg, 71%) or 8-
Thomson, J. Chem. Soc., Perkin Trans. 1, 1979, 1112; (b) S. A.
bromobenzo[4,5]imidazo[1,2-a]pyridine 12 (30.8 mg, 50%)
Glover, A. Goosen, C. W. McCleland J. L. Schoonraad, J. Chem.
Soc., Perkin Trans. 1, 1984, 2255; (c) M. T. Herrero, I.Tellitu, E.
respectively.
-(3-Bromo-9H-carbazol-9-yl)ethan-1-one (10.)20 mp 102-104
1
Domínguez, S. Hernández, I. Moreno, R. SanMartín,
Tetrahedron, 2002, 58, 8581; (d) X. Zhang, D. Zhang-Negrerie,
J. Deng, Y. Du, K. Zhao, J. Org. Chem., 2013, 78, 12750; (e) Y.
Kikugawa, A. Nagashima, T. Sakamoto, E. Miyazawa, M. Shiiya,
J. Org. Chem., 2003, 68, 6739; (f) X. Guo, D. Zhang-Negrerie, Y.
o
1
C; H NMR (400 MHz, CDCl
3
) w 8.15 (d, J = 8.8 Hz, 1H), 8.08-8.04
(
m, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.39 (t, J = 8.0
Hz, 1H), 2.84 (s, 3H); 13C NMR (100 MHz, CDCl
) w 169.8, 138.6,
37.4, 130.0, 128.1, 128.0, 125.2, 123.8, 122.5, 120.1, 118.0,
3
1
Du, RSC Adv., 2015, 5, 94732.
8
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DOI: 10.1039/C7OB00649G
Journal Name
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3 R. Samanta, J. O. Bauer, C. Strohmann, A. P, Antonchick, Org.
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