Palladium-catalyzed annulation of arynes by o-halobenzamides: Synthesis of phenanthridinones

Article abstract of DOI:10.1021/jo3016192

The palladium-catalyzed annulation of arynes by substituted o-halobenzamides produces N-substituted phenanthridinones in good yields. This methodology provides this important heterocyclic ring system in a single step by simultaneous C-C and C-N bond formation, under relatively mild reaction conditions, and tolerates a variety of functional groups.

Full text of DOI:10.1021/jo3016192

Article
pubs.acs.org/joc
Palladium-Catalyzed Annulation of Arynes by o‑Halobenzamides:
Synthesis of Phenanthridinones
Chun Lu, Anton V. Dubrovskiy, and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: The palladium-catalyzed annulation of arynes
by substituted o-halobenzamides produces N-substituted
phenanthridinones in good yields. This methodology provides
this important heterocyclic ring system in a single step by
simultaneous C−C and C−N bond formation, under relatively
mild reaction conditions, and tolerates a variety of functional
groups.
group, we have been especially interested in the palladium-
INTRODUCTION
■
catalyzed annulation of arynes.18
Phenanthridinones are important subunits found in many
compounds possessing interesting biological and pharmaceut-
ical activities. They have been used as PARP inhibitor
anticancer drugs1 and as neurotrophin activity enhancers for
the treatment of nerve diseases.2 One of the traditional
approaches for the synthesis of phenanthridinones is through
reductive cyclization of the corresponding nitrocarbonylbi-
phenyls.3 However, traditional preparations of the starting
nitrocarbonylbiaryls by Ullmann coupling or the nitration of
biaryls4 require either harsh reaction conditions or exotic
functionalized arenes, significantly limiting the broad applica-
tion of this approach. Other common approaches to
phenanthridinones include the Schmidt/Beckmann rearrange-
ment of fluorenone derivatives that are not all that readily
Herein, we report the palladium-catalyzed annulation of
arynes by substituted o-halobenzamides to produce N-
substituted phenanthridinones in good yields. In this reaction,
C−C and C−N bonds are formed simultaneously to generate
this important heterocyclic ring system.
RESULTS AND DISCUSSION
■
Optimization Studies. We attempted to optimize the
reaction of N-ethyl-2-bromobenzamide (1a) and the benzyne
precursor o-(trimethylsilyl)phenyl trifluoromethanesulfonate
(2a) in 4/1 toluene/acetonitrile with CsF as the fluoride
source (Table 1). In all cases, the cyclotrimerization side
product 4a19 and the desired benzyne annulation product 3a
were observed.
available4 5 and the photochemical rearrangement of 2-
g,
Optimization work was conducted with respect to different
palladium catalysts, ligands, solvent ratios, and temperatures
(Table 1). Without any ligand, palladium black precipitated out
very quickly with only a trace amount of the desired product
being formed and the aryl halide 1a was left in large amounts
(entry 1). The simple triphenylphosphine ligand did not
improve the yield (entry 2). Both tri-o-tolylphosphine and o-
(dicyclohexylphosphino)biphenyl ligands increased the yield to
∼50% (entries 3 and 7). Several bidentate ligands have also
been examined (entries 4−6). Among them, dppm proved the
most efficient, producing lactam 3a in 66% yield, although 10
mol % of ligand seemed necessary to obtain a decent yield
(entry 8). In addition to examining the effect of the ligand on
the yield, several bases have also been tested in this reaction
(entries 9−12). The results indicate that, with 1.0 equiv of
Na2CO3, a 73% yield of the desired product can be achieved
(entry 9). Other bases gave lower yields (entries 10 and 11).
On the basis of our previous experience, the solvent can often
prove critical for palladium-catalyzed aryne reactions, mostly
halobenzamides.6 There are also reports of phenanthridinone
synthesis involving aryne generation under harsh basic
conditions and subsequent intramolecular cyclization.7
Transition-metal-catalyzed annulation reactions are tremen-
dously valuable in organic synthesis.8 Among such processes,
palladium-mediated reactions are by far the most powerful in
constructing carbocycles and heterocycles,9 due to the high
efficiency with which they construct C−C and C−X (X = O,
N) bonds10 and their high compatibility with functional groups.
For example, some phenanthridinone derivatives have been
synthesized by palladium-catalyzed intramolecular or intermo-
lecular cyclization processes of aryl halides and amides11 or by
oxidative ortho arylation of benzanilides.12
Since a convenient approach to aryne generation by the
fluoride-induced 1,2-elimination of o-(trimethylsilyl)aryl tri-
flates was first reported,13 arynes have attracted considerable
attention.14 The high electrophilicity of arynes has been used
extensively in the construction of many heteroaromatic
structures via annulation reactions.15 To take further advantage
of aryne chemistry, many metal-catalyzed coupling16 and
annulation reactions17 of arynes have been explored. In our
Received: July 31, 2012
© XXXX American Chemical Society
A
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trimer 4a is formed; with a 6/1 ratio, the benzyne is generated
too slowly, giving a lower yield of the desired product.
An effort was made to lower the temperature and the
benzyne precursor loading (entries 15 and 16), but it appears
that 110 °C and 2 equiv of the benzyne precursor, plus 5 equiv
of CsF, are necessary in order to obtain a high yield. Several
other palladium catalysts, including PdCl2(MeCN)2 (63%),
Pd(dba)2 (65%), and Pd(PPh3)4 (61%), have also been
examined in this process, but none proved better than
Pd(OAc)2. We have chosen the reaction conditions reported
in entry 9 of Table 1 as our optimal conditions.
Table 1. Optimization of the Pd-Catalyzed Annulation of
Benzyne
a
ligand
additive
(amt (equiv))
solvent ratio
(toluene/MeCN)
% yield
b
entry (amt (mol %))
of 3a
1
4/1
4/1
4/1
4/1
4/1
4/1
4/1
4/1
4/1
4/1
4/1
4/1
3/1
6/1
4/1
4/1
10
13
50
66
30
25
56
53
73
70
67
57
52
49
2
PPh3 (10)
On the basis of our experimental results and previous
experience with related processes,18 we propose that this
phenanthridinone synthesis proceeds through either of the
possible pathways shown in Scheme 1.
3
P(o-tolyl)3 (10)
dppm (10)
dppe (10)
4
5
6
dppf (10)
c
7
L (10)
One possible pathway proceeds by the oxidative cyclization
of Pd(0) with the aryne generated from the silyl triflate to form
the palladacycle I (path a).20 Oxidative addition of 1a to this
palladacycle forms the Pd(IV) intermediate II. Reductive
elimination gives rise to the arylpalladium(II) intermediate
III. However, we cannot rule out the possibility that Pd(0)
inserts directly into the C−Br bond of 1a to form the
intermediate IV, which then undergoes carbopalladation of the
aryne to give rise to intermediate III21 (path b). Regardless of
how the intermediate III is formed, under the basic conditions,
it is expected to cyclize to the intermediate V. Finally, through
reductive elimination the desired product 3a can be generated,
alongside Pd(0), which can reenter the catalytic cycle. There
does not appear to be any particular evidence favoring either of
these pathways.
8
dppm (5)
9
dppm (10)
dppm (10)
dppm (10)
dppm (10)
dppm (10)
dppm (10)
dppm (10)
dppm (10)
Na2CO3 (1)
K2CO3 (1)
Cs2CO3 (1)
Na2CO3 (2)
Na2CO3 (1)
Na2CO3 (1)
Na2CO3 (1)
Na2CO3 (1)
10
11
12
13
14
15
16
d
50
e
60
a
All reactions were run using substrate 1a (0.25 mmol), 5 mol % of
Pd(OAc)2, 2.0 equiv of 2a, 5.0 equiv of CsF, 5 mL of solvent at 110 °C
b
for 16−24 h, unless otherwise specified. Isolated yield.
c
d
o‑(Dicyclohexylphosphino)biphenyl. The reaction was conducted
e
at 90 °C for 12 h, at which time the Pd had precipitated out. 1.6 equiv
of 2a and 4.0 equiv of CsF were employed.
Reaction Scope and Limitations. To test the scope and
limitations of this reaction, we have examined a variety of
substituted 2-halobenzamides, and the results are summarized
in Table 2. Different amide nitrogen substituents, including
alkyl (entries 1−4), allyl (entry 5), phenyl (entry 6), and benzyl
groups (entries 7−10), have been examined. Among them,
excellent yields were achieved for N-primary and N-secondary
alkyl (entries 1−3) substituted amides, as well as N-benzyl
substituted amides (entries 7−10). The analogous amide with
because the aryne is generated at substantially different rates in
different solvents.17 With a toluene/acetonitrile mixed solvent
and CsF as the fluoride source, benzyne is generated more
slowly in mixtures with less acetonitrile, because CsF has a
lower solubility in toluene. Thus, the solvent ratio was
examined and 4/1 toluene/acetonitrile afforded the best result
(compare entries 9, 13, and 14). With a 3/1 ratio, more of the
Scheme 1. Tentative Mechanisms
B
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a
Table 2. Pd-Catalyzed Annulation of Benzyne 2a
a
Representative procedure: 1 (0.25 mmol), 2.0 equiv of 2, 5.0 equiv of CsF, 5 mol % of Pd(OAc)2, 10 mol % of dppm, 1.0 equiv of Na2CO3 in 5 mL
b
c
of 4/1 toluene/MeCN at 110 °C for 16−24 h. Isolated yield. An unknown mixture was generated with products overlapping with the starting
material 1d on the TLC plate.
C
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a
Table 3. Investigation of Different Arynes in the Pd-Catalyzed Annulation of o-Halobenzamide 1g
a
Representative procedure: 1g (0.25 mmol), 2.0 equiv of 2, 5.0 equiv of CsF, 5 mol % of Pd(OAc)2, 10 mol % of dppm, 1.0 equiv of Na2CO3 in 5
b
mL of 4/1 toluene/MeCN at 110 °C for 16−24 h. Isolated yield.
N-tBu (entry 4) afforded a lower yield, presumably due to the
steric hindrance of the Bu group. The presence of an N-allyl
group (entry 22), were also tested, and lower yields were
obtained in comparison to 1g. The reason for this decrease can
be explained as follows. Although the electron-withdrawing
nature of these functional groups facilitates oxidative addition
of the carbon−bromine bond in the amide to Pd(0), it at the
same time decreases the nucleophilic nature of the nitrogen in
the amide, which is critical for the cyclization step (see the later
mechanistic discussion).
In addition to these N-benzyl-2-bromobenzamide derivatives,
the pyridine-derived amide 1w has also been examined, but
only a 36% yield of the desired product was isolated, which may
be caused by deactivation of the Pd catalyst through strong
coordination of the nitrogen in the pyridine to Pd.
This reaction was also applied to 2-bromobenzamide (1x,
entry 24) and N,N-dimethyl-2-bromobenzamide (1y, entry 25).
Amides 1x and 1y both remained in the reaction system in very
large amounts after the reaction, and neither of the desired
products was observed. The reasons for the failure of these two
reactions may not, however, be the same. In the reaction of
amide 1x, strong coordination of the NH2 group with the Pd in
either complex III or IV (see Scheme 1) may inhibit the
cyclization, while in amide 1y two methyl groups on the
nitrogen prohibit nucleophilic attack of the nitrogen on the Pd
in complex III (see the step from III to V in Scheme 1).
In addition to the silylphenyl triflate 2a, other aryne
precursors have also been examined as an annulation partner
in our methodology (Table 3). The 4,5-dimethylbenzyne
precursor 2b, the 4,5-dimethoxybenzyne precursor 2c, and the
4,5-difluorobenzyne precursor 2d have all been examined under
our annulation conditions. They formed the expected
annulation products 3gb, 3gc, and 3gd, respectively, not
surprisingly with lower yields in comparison to that for benzyne
precursor 2a (Table 2, entries 1−3). This may be due to either
the slower rate of generation of the arynes or the lack of
stability of these arynes, as has been suggested by earlier work
in our group.18d,e
t
group (entry 5) also caused complicationsthe reaction
looked messier on the TLC plate than did the parent system
(1a) with a resulting lower yield. Aryl-substituted amide 1f
produced some uncharacterized products, which overlapped
with the starting amide left on the TLC plate (entry 6). The
reaction was also performed using 2-iodobenzamide (1k; entry
11), where a much lower yield was obtained than was the case
for the corresponding bromobenzamide 1g. Although for most
palladium-catalyzed reactions of aryl halides aryl iodides
provide better results than the corresponding aryl bromides,
because the oxidative addition of Pd(0) to the aryl halide is
easier and faster (see the later mechanistic discussion), there
are several publications where the same halide effect that is seen
here has been reported and mechanistic studies on such
reactions have been conducted.22 The reason for this halogen
effect is not clear. However, we have observed that palladium
precipitates out more quickly with a lower conversion and more
side products in the reaction of 1k than in the reaction of 1g.
To further test the scope and limitations of the reaction, we
examined a variety of 2-bromobenzamides with various
functional groups (entries 12−22). Amides with slightly
electron donating methyl groups at the 3- (entry 14), 4-
(entry 12), and 5-positions (entry 13) generally afforded
excellent yields of above 70%, although 1n provided a slightly
lower yield than the others, presumably due mainly to the steric
hindrance of the methyl group during oxidative addition of the
carbon−halogen bond to the palladium catalyst. Strongly
electron donating methoxy groups also did not lower the
yield significantly, and yields above 70% were generated from
1o,p, which suggested that the oxidative addition of the aryl
bromide to Pd(0) is not very difficult under these reaction
conditions. Halogens, such as F (entries 19 and 20) and Cl
(entry 17), were well tolerated in these reactions, providing
good yields of the corresponding amides.
o-Bromobenzamides with electron-withdrawing groups,
including CF3 (entry 18), NO2 (entry 21), and an amide
D
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CONCLUSIONS
■
In summary, we have developed a novel synthesis of
phenanthridinones, which involves the palladium-catalyzed
annulation of arynes by 2-halobenzamides. This method
provides an efficient synthesis of substituted phenanthridinones
from readily available starting materials. Our process has been
shown to be tolerant of a wide variety of functional groups,
which makes further elaboration possible.
126.6, 119.0, 42.8, 42.5; HRMS (EI) calcd for C22H19N2O2Br
422.0630, found 422.0625.
General Procedure for the Palladium-Catalyzed Synthesis of
Phenanthridinones. The 2-bromobenzamide (1a; 0.25 mmol), the
2-(trimethylsilyl)aryl triflate (2.0 equiv), CsF (5.0 equiv), Na2CO3 (1.0
equiv), Pd(OAc)2 (5 mol %), dppm (10 mol %), 4 mL of toluene, and
1 mL of MeCN were placed in a 4 dram vial, and the vial was sealed.
The reaction mixture was stirred first at room temperature for 1 min
and then heated to 110 °C for 16−24 h. The mixture was cooled to
room temperature, diluted with ethyl acetate, washed with brine, dried
over anhydrous MgSO4, and concentrated under reduced pressure.
The product was isolated by flash chromatography on silica gel using
hexanes/EtOAc as the eluent.
EXPERIMENTAL SECTION
■
1
General Considerations. The H and 13C NMR spectra were
recorded at 300 and 75.5 MHz or 400 and 100 MHz, respectively. All
melting points are uncorrected. High-resolution mass spectra (HRMS)
were obtained using EI at 70 eV (TOF) or using an Agilent QTOF
6540 mass spectrometer (APCI at 70 eV). All reagents were used
directly as obtained commercially unless otherwise noted. All reactions
were carried out in oven-dried glassware and monitored by thin-layer
chromatography (SiO2, hexanes or hexanes/EtOAc). THF was
distilled over Na. The silylaryl triflate 2a, CsF, TBAF solution (1 M
in THF), and acetonitrile were purchased from Sigma-Aldrich Co. The
4,5-dimethyl-substituted silylaryl triflate 2b, the 4,5-dimethoxy-
substituted silylaryl triflate 2c, and the 4,5-difluoro-substituted silylaryl
triflate 2d were prepared according to a previous literature
procedure.18e,23
5-Ethylphenanthridin-6(5H)-one (3a). White solid (41.0 mg,
73%): mp 98−99 °C (lit.25 mp 87−90 °C); H NMR (300 MHz,
1
Noncommercially Available Compounds. Noncommercially
available starting materials were prepared according to literature
procedures.24
d6-acetone) δ 8.48−8.44 (m, 3H), 7.82 (td, J = 9.0, 3.0 Hz, 1H), 7.65−
7.59 (m, 3H), 7.35−7.30 (m, 1H), 4.46 (q, J = 6.0 Hz, 2H), 1.35 (t, J =
6.0 Hz, 3H); 13C NMR (300 MHz, d6-acetone) δ 160.4, 137.3, 133.8,
132.6, 130.0, 128.5, 128.0, 125.9, 123.9, 122.4, 122.2, 119.3, 115.7,
37.3, 12.4; HRMS (EI) calcd for C15H13NO 223.0997, found
N-Benzyl-2-bromo-5-methylbenzamide (1m). White solid: mp
1
133−135 °C; H NMR (300 MHz, CDCl3) δ 7.41−7.21 (m, 7H),
1
223.0995. The H and 13C NMR spectral data are in good agreement
with the literature data.26
5-Isopropylphenanthridin-6(5H)-one (3b). White solid (41.4 mg,
70%): mp 99−101 °C; 1H NMR (300 MHz, d6-acetone) δ 8.44 (dd, J
7.04 (dd, J = 9.0, 3.0 Hz, 1H), 6.47 (s, 1H), 4.59 (d, J = 3.0 Hz, 2H),
2.28 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 167.8, 137.8, 137.7,
137.4, 133.2, 132.2, 130.3, 128.8, 128.1, 127.7, 115.9, 44.2, 20.9;
HRMS (EI) calcd for C15H14NOBr 303.0259, found 303.0265.
N-Benzyl-2-bromo-5-(trifluoromethyl)benzamide (1r). White
1
solid: mp 148−150 °C; H NMR (300 MHz, d6-DMSO) δ 9.17 (t,
= 9.0, 3.0 Hz, 3H), 7.84−7.76 (m, 2H), 7.64−7.54 (m, 2H), 7.32 (t, J
= 9.0 Hz, 1H), 5.42 (m, 1H), 1.68 (d, J = 9.0 Hz, 6H); 13C NMR (300
MHz, d6-acetone) δ 162.5, 135.1, 133.8, 130.8, 129.6, 129.2, 128.0,
125.3, 123.5, 123.3, 121.1, 117.2, 49.1, 20.5; HRMS (EI) calcd for
C16H15NO 237.1154, found 237.1152.
J = 6.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.80 (s, 1H), 7.74 (dd, J =
9.0, 3.0 Hz, 1H), 7.42−7.25 (m, 5H), 4.50 (d, J = 6.0 Hz, 2H); 13C
NMR (300 MHz, d6-DMSO) δ 166.0, 139.9, 138.7, 134.1, 128.4,
127.4, 127.4, 127.0, 125.5, 125.4, 123.9, 121.9, 42.7; HRMS (EI) calcd
for C15H11NOBrF3 356.9976, found 356.9973.
5-Cyclohexylphenanthridin-6(5H)-one (3c). White solid (60.1 mg,
1
87%): mp 117−120 °C; H NMR (300 MHz, CDCl3) δ 8.50 (d, J =
N-Benzyl-2-bromo-4-nitrobenzamide (1u). White solid: mp 148−
150 °C; 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 8.17 (dd, J = 9.0,
7.8 Hz, 1H), 8.23 (dd, J = 10.0, 7.5 Hz, 2H), 7.74−7.45 (m, 4H), 7.26
(t, J = 7.2 Hz, 1H), 2.72 (m, 2H), 2.00−1.76 (m, 6H), 1.56−1.36 (m,
3H); 13C NMR (300 MHz, CDCl3) δ 162.2, 138.1, 133.7, 132.3,
129.1, 128.7, 128.0, 126.8, 123.7, 122.2, 121.5, 120.3, 115.9, 57.9, 29.3,
26.9, 25.7; HRMS (EI) calcd for C19H19NO 277.1467, found
277.1465.
3.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.37−7.26 (m, 5H), 6.39 (br s,
1H), 4.63 (d, J = 6.0 Hz, 2H); 13C NMR (300 MHz, CDCl3) δ 165.9,
148.7, 143.5, 137.1, 130.3, 129.1, 128.6, 128.2, 128.2, 122.7, 120.2,
44.6; HRMS (EI) calcd for C14H11N2O3Br 333.9953, found 334.9960.
N,N′-Dibenzyl-2-bromo-1,4-benzenedicarboxamide (1v). White
solid: mp 219−221 °C; 1H NMR (300 MHz, d6-DMSO) δ 9.28 (t, J =
6.0 Hz, 1H), 9.09 (t, J = 6.0 Hz, 1H), 8.18 (s, 1H), 7.95 (d, J = 9.0 Hz,
1H), 7.55 (d, J = 9.0 Hz, 1H), 7.41−7.25 (m, 10H), 4.49 (d, J = 6.0
Hz, 2H); 13C NMR (300 MHz, d6-DMSO) δ 168.9, 164.2, 141.4,
139.3, 139.0, 136.3, 131.4, 128.8, 128.4, 128.4, 127.3, 126.9, 126.9,
5-tert-Butylphenanthridin-6(5H)-one (3d). White solid (40.3 mg,
64%): mp 128−130 °C; 1H NMR (300 MHz, d6-acetone) δ 8.30−8.21
E
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(m, 3H), 7.76−7.72 (m, 2H), 7.56 (t, J = 9.0 Hz, 1H), 7.42 (t, J = 9.0
Hz, 1H), 7.25 (td, J = 9.0, 3.0 Hz, 1H), 1.79 (s, 9H); 13C NMR (300
MHz, CDCl3) δ 165.6, 138.1, 133.9, 132.1, 129.6, 127.9, 127.7, 126.8,
123.8, 122.7, 122.2, 121.5, 120.8, 60.7, 30.7; HRMS (EI) calcd for
C17H17NO 251.1310, found 251.1311.
5-Allylphenanthridin-6(5H)-one (3e). White solid (38.4 mg, 65%):
mp 97−98 °C (lit.27 mp 99 °C); 1H NMR (600 MHz, CDCl3) δ 8.60
5-(4-Nitrobenzyl)phenanthridin-6(5H)-one (3j). White solid (68.5
mg, 83%): mp 235−237 °C; 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J
= 9.0 Hz, 1H), 8.36 (d, J = 9.0 Hz, 2H), 8.25 (dd, J = 6.0, 3.0 Hz, 1H),
7.85 (t, J = 9.0 Hz, 1H), 7.65 (t, J = 9.0 Hz, 1H), 7.42−7.27 (m, 4H),
7.09 (d, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.0, 3.0 Hz, 1H), 6.05 (s, 2H);
13C NMR (300 MHz, CDCl3) δ 166.6, 137.3, 134.4, 133.3, 132.6,
130.1, 129.4, 128.5, 128.4, 127.7, 125.9, 125.4, 123.8, 123.3, 122.1,
119.9, 115.7, 45.1; HRMS (EI) calcd for C20H14N2O3 330.1004, found
330.1011.
(d, J = 8.0 Hz, 1H), 8.33 (dd, J = 8.3, 3.7 Hz, 2H), 7.81 (t, J = 7.6 Hz,
1H), 7.63 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.4
Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.12−5.98 (m, 1H), 5.27 (d, J = 10.5
Hz, 1H), 5.20 (d, J = 17.3 Hz, 1H), 5.10 (d, J = 4.7 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 161.4, 137.3, 133.7, 132.6, 132.0, 129.5,
129.0, 128.0, 125.5, 123.3, 122.5, 121.7, 119.5, 117.0, 115.8, 45.1;
HRMS (APCI) calcd for C16H14NO [M + H]+ 236.1070, found
236.1073.
5-Benzyl-9-methylphenanthridin-6(5H)-one (3l). White solid
1
(62.6 mg, 84%): mp 173−175 °C; H NMR (300 MHz, d6-acetone)
5-Benzylphenanthridin-6(5H)-one (3g). Pale yellow solid (from
1g, 58.5 mg, 82%; from 1k, 27.4 mg, 38%): mp 126−129 °C (lit.28 mp
δ 8.47 (d, J = 6.0 Hz, 1H), 8.42 (d, J = 6.0 Hz, 1H), 8.35 (s, 1H), 7.51
(d, J = 9.0 Hz, 1H), 7.43 (dd, J = 6.0, 3.0 Hz, 2H), 7.31−7.23 (m, 6H),
5.70 (s, 2H), 2.59 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 162.1,
143.4, 137.7, 136.9, 134.0, 129.7, 129.6, 129.4, 129.0, 127.3, 126.7,
123.4, 122.6, 121.9, 119.7, 116.2, 46.6, 22.4; HRMS (EI) calcd for
C21H17NO 299.1310, found 299.1304.
5-Benzyl-8-methylphenanthridin-6(5H)-one (3m). White solid
(59.0 mg, 79%): mp 173−175 °C; H NMR (300 MHz, CDCl3) δ
1
1
112−113 °C); H NMR (600 MHz, CDCl3) δ 8.66 (d, J = 8.7 Hz,
1H), 8.35−8.27 (m, 2H), 7.82 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.5 Hz,
1H), 7.41 (t, J = 8.4 Hz, 1H), 7.36−7.23 (m, 7H), 5.70 (s, 2H); 13C
NMR (150 MHz, CDCl3) δ 162.0, 137.3, 136.6, 133.9, 132.8, 129.6,
129.2, 128.8, 128.1, 127.2, 126.6, 125.4, 123.3, 122.6, 121.7, 119.6,
116.1, 46.5; HRMS (APCI) calcd for C20H16NO [M + H]+ 286.1226,
found 286.1232. The H and 13C NMR spectral data are in good
1
agreement with the literature data.29
8.43 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.61
(dd, J = 8.1, 1.8 Hz, 1H), 7.38−7.21 (m, 8H), 5.67 (s, 2H), 2.54 (s,
3H); 13C NMR (300 MHz, CDCl3) δ 162.2, 138.4, 137.2, 136.9,
134.2, 131.6, 129.2, 129.1, 129.0, 127.3, 126.7, 125.5, 123.2, 122.7,
121.9, 119.8, 116.1, 46.6, 21.6; HRMS (EI) calcd for C21H17NO
299.1310, found 299.1306.
5-(4-Methylbenzyl)phenanthridin-6(5H)-one (3h). White solid
(57.7 mg, 77%): mp 106−108 °C; H NMR (300 MHz, CDCl3) δ
1
5-Benzyl-10-methylphenanthridin-6(5H)-one (3n). White solid
1
(55.1 mg, 74%): mp 122−123 °C; H NMR (300 MHz, CDCl3) δ
8.62 (d, J = 8.1 Hz, 1H), 8.27 (t, J = 6.3 Hz, 1H), 7.77 (t, J = 7.2 Hz,
1H), 7.60 (t, J = 7.2 Hz, 1H), 7.36−7.07 (m, 8H), 5.61 (s, 2H), 2.28
(s, 3H); 13C NMR (300 MHz, CDCl3) δ 162.1, 137.6, 137.0, 134.0,
133.7, 132.8, 129.7, 129.6, 129.3, 128.2, 126.7, 125.6, 123.4, 122.7,
121.9, 119.7, 116.2, 46.4, 21.3; HRMS (EI) calcd for C21H17NO
299.1310, found 299.1307.
8.62 (d, J = 9.0 Hz, 1H), 8.46 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 9.0 Hz,
1H), 7.52 (t, J = 9.0 Hz, 1H), 7.38−7.23 (m, 8H), 5.67 (s, 2H), 2.97
(s, 3H); 13C NMR (300 MHz, CDCl3) δ 162.4, 137.7, 137.4, 136.8,
134.7, 133.5, 129.0, 128.8, 128.1, 127.8, 127.5, 127.3, 126.7, 121.9,
121.3, 116.0, 47.0, 26.3; HRMS (EI) calcd for C21H17NO 299.1310,
found 299.1303.
5-(4-Methoxybenzyl)phenanthridin-6(5H)-one (3i). Pale brown
1
glassy solid (59.4 mg, 75%): mp 136−137 °C; H NMR (600 MHz,
5-Benzyl-8-methoxyphenanthridin-6(5H)-one (3o). White solid
(58.3 mg, 74%): mp 133−135 °C; 1H NMR (300 MHz, d6-acetone) δ
CDCl3) δ 8.66 (d, J = 8.0 Hz, 1H), 8.31 (t, J = 9.1 Hz, 2H), 7.81 (t, J =
8.3 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.38 (d,
J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.7 Hz, 2H), 6.86
(d, J = 8.7 Hz, 2H), 5.63 (s, 2H), 3.78 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 161.9, 158.8, 137.4, 133.8, 132.7, 129.6, 129.2, 128.7, 128.1,
127.9, 125.5, 123.3, 122.6, 121.7, 119.5, 116.1, 114.2, 55.3, 46.0;
HRMS (APCI) calcd for C21H18NO2 [M + H]+ 316.1332, found
8.42 (d, J = 9.0 Hz, 1H), 8.36 (d, J = 6.0 Hz, 1H), 7.96 (d, J = 3.0 Hz,
1H), 7.46−7.24 (m, 9H), 5.71 (s, 2H), 3.98 (s, 3H); 13C NMR (300
MHz, d6-acetone) δ 162.3, 161.2, 138.8, 137.8, 130.1, 129.9, 128.7,
1
316.1322. The H and 13C NMR spectral data are in good agreement
with the literature data.29
F
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128.4, 128.3, 128.0, 125.5, 124.3, 123.9, 123.3, 120.8, 117.4, 110.9,
56.5, 47.1; HRMS (EI) calcd for C21H17NO2 315.1259, found
315.1259.
(600 MHz, CDCl3) δ 8.67 (dd, J = 8.9, 5.9 Hz, 1H), 8.19 (d, J = 7.3
Hz, 1H), 7.94 (dd, J = 10.3, 2.4 Hz, 1H), 7.46 (t, J = 8.5 Hz, 1H),
7.37−7.25 (m, 8H), 5.68 (s, 2H); 13C NMR (150 MHz, CDCl3) δ
166.7, 165.0, 161.3, 137.8, 136.5, 136.5, 136.4, 132.5, 132.4, 130.3,
129.6, 128.9, 127.3, 126.5, 123.6, 122.7, 122.0, 122.0, 118.8, 118.8,
116.4, 116.3, 116.2, 115.4, 107.8, 107.6, 46.5 (extra peaks due to C−F
coupling); 19F NMR (600 MHz, CDCl3) δ −105.4; HRMS (APCI)
5-Benzyl-8,9-dimethoxyphenanthridin-6(5H)-one (3p). White
solid (60.2 mg, 70%): mp 210−212 °C; 1H NMR (300 MHz,
1
calcd for C20H15FNO [M + H]+ 304.1132, found 304.1136. The H
and 13C NMR spectral data are in good agreement with the literature
data.28
5-Benzyl-9-nitrophenanthridin-6(5H)-one (3u). Yellow solid (58.0
mg, 70%): decomposes above 300 °C; 1H NMR (300 MHz, CDCl3) δ
CDCl3) δ 8.13 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.38−
7.21 (m, 8H), 5.65 (s, 2H), 4.09 (s, 3H), 4.04 (s, 3H); 13C NMR (300
MHz, CDCl3) δ 161.5, 153.6, 150.0, 137.0, 137.0, 128.9, 128.8, 128.8,
127.3, 126.7, 122.8, 122.5, 119.5, 119.5, 116.2, 109.4, 102.7, 56.4, 56.3,
46.6; HRMS (EI) calcd for C22H19NO3 345.1365, found 345.1370.
5-Benzyl-8-chlorophenanthridin-6(5H)-one (3q). White solid
1
(53.5 mg, 67%): mp 155−157 °C; H NMR (300 MHz, CDCl3) δ
9.18 (d, J = 2.1 Hz, 1H), 8.80 (d, J = 8.7 Hz, 1H), 8.41−8.36 (m, 2H),
7.56−7.50 (m, 2H), 7.40−7.27 (m, 6H), 5.69 (s, 2H); 13C NMR (300
MHz, CDCl3) δ 160.4, 147.2, 139.1, 138.4, 136.8, 132.3, 129.0, 127.5,
127.0, 126.9, 125.8, 125.5, 125.1, 124.2, 123.7, 118.0, 116.9, 46.2;
HRMS (EI) calcd for C20H14N2O3 330.1004, found 330.1001.
5-Benzyl-9-[(benzylamino)carbonyl]phenanthridin-6(5H)-one
1
(3v). White solid (57.9 mg, 55%): mp 197−200 °C; H NMR (300
8.59 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.22 (d, J = 8.1 Hz,
1H), 7.73 (dd, J = 8.1, 2.4 Hz, 1H), 7.41 (m, 1H), 7.32−7.24 (m, 7H),
5.65 (s, 2H); 13C NMR (300 MHz, CDCl3) δ 161.1, 137.4, 136.5,
134.5, 133.2, 132.5, 130.1, 129.1, 128.9, 127.5, 126.9, 126.7, 123.7,
123.5, 123.0, 119.0, 116.4, 46.8; HRMS (EI) calcd for C20H14NOCl
319.0764, found 319.0756.
5-Benzyl-8-(trifluoromethyl)phenanthridin-6(5H)-one (3r). White
solid (45.7 mg, 52%): mp 186−188 °C; 1H NMR (300 MHz, CDCl3)
MHz, CDCl3) δ 8.80 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 7.8
Hz, 1H), 7.85 (dd, J = 8.4, 1.5 Hz, 1H), 7.33−7.22 (m, 13H), 6.88 (s,
1H), 5.61 (s, 2H), 4.72 (d, J = 5.7 Hz, 2H); 13C NMR (300 MHz,
CDCl3) δ 166.8, 161.4, 138.1, 138.0, 136.4, 134.3, 130.3, 129.8, 129.0,
129.0, 128.2, 127.9, 127.4, 126.6, 125.3, 123.8, 123.0, 121.9, 119.2,
116.2, 46.7, 44.6; HRMS (EI) calcd for C28H22N2O2 418.1681, found
418.1689.
6-Benzylbenzo-1,6-naphthyridin-5-one (3w). White solid (25.7
δ 8.92 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.30 (dd, J = 8.1, 1.5 Hz, 1H),
7.99 (dd, J = 8.7, 1.8 Hz, 1H), 7.47 (m, 1H), 7.36−7.24 (m, 7H), 5.67
(m, 2H); 13C NMR (300 MHz, CDCl3) δ 161.3, 138.1, 136.3, 131.1,
129.1, 129.0, 129.0, 127.6, 127.1, 127.0, 126.7, 125.7, 124.1, 123.2,
122.9, 118.6, 116.5, 46.9; HRMS (EI) calcd for C21H14NOF3
353.1027, found 353.1035.
mg, 36%): mp 129−131 °C; 1H NMR (300 MHz, CDCl3) δ 9.04 (dd,
5-Benzyl-8-fluorophenanthridin-6(5H)-one (3s). Pale solid (49.3
1
mg, 65%): mp 164−166 °C; H NMR (600 MHz, CDCl3) δ 8.33−
J = 6.0, 3.0 Hz, 1H), 8.90 (d, J = 9.0 Hz, 1H), 8.83 (dd, J = 9.0, 3.0 Hz,
1H), 7.57−7.47 (m, 2H), 7.37−7.24 (m, 7H), 5.66 (s, 2H); 13C NMR
(300 MHz, CDCl3) δ 162.1, 154.2, 138.8, 137.2, 136.4, 131.5, 129.1,
127.6, 126.7, 125.5, 123.3, 123.2, 121.1, 115.7, 46.7; HRMS (EI) calcd
for C19H14N2O 286.1106, found 286.1098.
5-Benzyl-2,3-dimethylphenanthridin-6(5H)-one (3gb). White
solid (39.0 mg, 50%): mp 155−157 °C; 1H NMR (300 MHz,
8.29 (m, 2H), 8.24 (d, J = 7.9 Hz, 1H), 7.54 (td, J = 8.4, 2.9 Hz, 1H),
7.43 (t, J = 8.4 Hz, 1H), 7.38−7.24 (m, 7H), 5.68 (s, 2H); 13C NMR
(150 MHz, CDCl3) δ 162.0, 137.3, 136.6, 133.9, 132.8, 129.6, 129.2,
128.8, 128.1, 127.2, 126.6, 125.4, 123.3, 122.6, 121.7, 119.6, 116.1, 46.5
(extra peaks due to C−F coupling); 19F NMR (600 MHz, CDCl3) δ
−112.0; HRMS (APCI) calcd for C20H15FNO [M + H]+ 304.1132,
found 304.1136.
5-Benzyl-9-fluorophenanthridin-6(5H)-one (3t). Pale white solid
(60.1 mg, 79%): mp 155−158 °C (lit.28 mp 157−158 °C); H NMR
1
CDCl3) δ 8.64−8.58 (m, 1H), 8.32−8.25 (m, 1H), 8.01 (s, 1H),
7.78−7.73 (m, 1H), 7.65−7.54 (m, 1H), 7.32−7.25 (m, 3H), 7.09 (s,
1H), 6.87 (d, J = 12.0 Hz, 2H), 5.64 (s, 2H), 3.90 (s, 3H), 3.88 (s,
3H); 13C NMR (300 MHz, CDCl3) δ 162.1, 138.9, 137.1, 132.9,
132.7, 129.8, 129.4, 129.0, 129.0, 128.2, 127.3, 126.7, 123.5, 121.9,
116.2, 46.6, 20.7, 19.6; HRMS (EI) calcd for C22H19NO 313.1467,
found 313.1470.
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Article
F. Tetrahedron Lett. 1995, 36, 8553. (g) Li, J. H.; Serdyuk, L.; Ferraris,
D. V.; Xiao, G.; Tays, K. L.; Kletzly, P. W.; Li, W.; Lautar, S.; Zhang, J.;
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5-Benzyl-2,3-dimethoxyphenanthridin-6(5H)-one (3gc). White
solid (39.6 mg, 46%): mp 153−155 °C; 1H NMR (300 MHz,
CDCl3) δ 8.61 (dd, J = 8.1, 1.5 Hz, 1H), 8.14 (d, J = 8.1, 1H), 7.76 (td,
J = 8.1, 1.5 Hz, 1H), 7.64 (s, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.30−7.23
(m, 5H), 6.79 (s, 1H), 5.66 (s, 2H), 3.99 (s, 3H), 3.75 (s, 3H); 13C
NMR (300 MHz, CDCl3) δ 162.2, 150.8, 145.3, 137.1, 134.0, 132.8,
132.4, 129.5, 129.1, 127.5, 127.2, 126.8, 124.7, 121.3, 112.4, 105.4,
100.1, 56.5, 56.1, 47.1; HRMS (EI) calcd for C22H19NO3 345.1365,
found 345.1370.
(7) (a) Hey, D. H.; Leonard, J. A.; Rees, C. W. J. Chem. Soc. 1963,
5266. (b) Gonzal
5195. (c) For the synthesis of dihydrophenanthridines with
subsequent oxidation, see: Sanz, R.; Fernandez, Y.; Castroviejo, M.
P.; Perez, A.; Fananas, F. J. Eur. J. Org. Chem. 2007, 2007, 62.
́ ́
ez, C.; Guitian, E.; Castedo, L. Tetrahedron 1999, 55,
5-Benzyl-2,3-difluorophenanthridin-6(5H)-one (3gd). White solid
1
(34.7 mg, 43%): mp 187−189 °C; H NMR (300 MHz, CDCl3) δ
́
́
́
̃
(8) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem.
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8.61 (d, J = 9.0 Hz, 1H), 8.05 (m, 1H), 7.82 (t, J = 9.0 Hz, 1H), 7.65
(d, J = 9.0 Hz, 1H), 7.35−7.08 (m, 7H), 5.60 (s, 2H); 13C NMR (300
MHz, CDCl3) δ 161.9, 152.7, 148.1, 136.8, 135.9, 133.3, 129.6, 129.2,
129.0, 128.7, 128.3, 127.8, 127.4, 126.7, 116.3, 111.8, 105.6, 47.2;
HRMS (EI) calcd for C20H13NOF2 321.0965, found 321.0973.
(11) For some recent publications, see: (a) Donati, L.; Leproux, P.;
́
Prost, E.; Michel, S.; Tillequin, F.; Gandon, V.; Poree, F.-H. Eur. J.
ASSOCIATED CONTENT
■
Chem. 2011, 17, 12809. (b) Nakamura, M.; Aoyama, A.; Salim, M.;
Okamoto, M.; Baba, M.; Miyachi, H.; Hashimoto, Y.; Aoyama, H.
Bioorg. Med. Chem. 2010, 18, 2402. (c) Furuta, T.; Kitamura, Y.;
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(d) Bernardo, P. H.; Fitriyanto, W.; Chai, C. L. L. Synlett 2007, 1935.
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S
* Supporting Information
Figures giving 1H and 13C NMR data for the compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: larock@iastate.edu.
Notes
■
(12) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci.
2010, 1, 331.
(13) Himeshina, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
The authors declare no competing financial interest.
(14) For recent comprehensive reviews on aryne chemistry, see:
(a) Tadross, P. M; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
(b) Bhojgude, S. S.; Biju, A. T. Angew. Chem., Int. Ed. 2012, 51, 1520.
(c) Chen, Y.; Larock, R. C. Modern Arylation Methods; Wiley/VCH:
New York, 2009; pp 401−473.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health Kansas University
Center of Excellence for Chemical Methodologies and Library
Development (P50 GM069663) and the National Science
Foundation for support of this research. Thanks are also
extended to previous group member Dr. Zhijian Liu for many
valuable suggestions.
(15) For some recent publications, see: (a) Huang, X.; Zhang, T.
Tetrahedron Lett. 2009, 50, 208. (b) Zhang, T.; Huang, X.; Wu, L. Eur.
J. Org. Chem. 2012, 3507. (c) Yoshioka, E.; Kohtani, S.; Miyabe, H.
Angew. Chem., Int. Ed. 2011, 50, 6638. (d) Markina, N. A.; Dubrovskiy,
A. V.; Larock, R. C. Org. Biomol. Chem. 2012, 10, 2409. (e) Rogness,
D. C.; Markina, N. A.; Larock, R. C. J. Org. Chem. 2012, 77, 2743.
(f) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117.
(16) For some recent publications on palladium-catalyzed coupling
reactions of arynes, see: (a) Pi, S.; Tang, B.; Li, J.; Liu, Y.; Liang, Y.
Org. Lett. 2009, 11, 2309. (b) Kim, H.; Gowrisankar, S.; Kim, E.; Kim,
J. Tetrahedron Lett. 2008, 49, 6569. For some recent publications on
other metal-catalyzed (Ni and Cu) coupling reactions of arynes, see:
(c) Morishita, T.; Yoshida, H.; Ohshita, J. Chem. Commun. 2010, 46,
640. (d) Akubathini, K. S.; Biehl, E. Tetrahedron Lett. 2009, 50, 1809.
(e) Yoshida, H.; Morishita, T.; Nakata, H.; Ohshita, J. Org. Lett. 2009,
11, 373. (f) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C. Chem.
Commun. 2008, 5013.
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