Formation of acridones by ethylene extrusion in the reaction of arynes with β-lactams and dihydroquinolinones

Article abstract of DOI:10.1021/jo3011073

N-Unsubstituted β-lactams react with a molecule of aryne by insertion into the amide bond to form a 2,3-dihydroquinolin-4-one, which subsequently reacts with another molecule of aryne to form an acridone by extrusion of a molecule of ethylene. 2,3-Dihydroquinolin-4-ones react under the same reaction conditions to afford identical results. This is the first example of ethylene extrusion in aryne chemistry.

Full text of DOI:10.1021/jo3011073

Article
pubs.acs.org/joc
Formation of Acridones by Ethylene Extrusion in the Reaction of
Arynes with β-Lactams and Dihydroquinolinones
Yuesi Fang,† Donald C. Rogness,† Richard C. Larock,*,† and Feng Shi*,‡
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
‡Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng,
Henan 475004, PR China
S
* Supporting Information
ABSTRACT: N-Unsubstituted β-lactams react with a mole-
cule of aryne by insertion into the amide bond to form a 2,3-
dihydroquinolin-4-one, which subsequently reacts with anoth-
er molecule of aryne to form an acridone by extrusion of a
molecule of ethylene. 2,3-Dihydroquinolin-4-ones react under
the same reaction conditions to afford identical results. This is
the first example of ethylene extrusion in aryne chemistry.
Scheme 1. Originally Anticipated Reaction of a β-Lactam
with an Aryne
INTRODUCTION
■
Benzyne is a highly reactive intermediate, which was first
proposed by Wittig in 19421 and confirmed by Roberts in
1956.2 Since the discovery of the Kobayashi aryne precursor,3
various nucleophiles have been shown to react with arynes by
nucleophilic addition to open the strained, triple bond of the
aryne.4 When the nucleophile is tethered to an electrophile, the
nucleophilic addition can trigger subsequent electrophilic
trapping of the aryl anion, leading to a formal σ-bond cleavage.5
Amide functionality is one such tethered nucleophile−electro-
phile pair, where the nitrogen and the carbonyl serve as the
nucleophile and the electrophile, respectively. Although amides
typically undergo simple NH arylation,4,6 amides with more
electrophilic carbonyl groups, including trifluoroacetamides,
trifluoromethanesulfinamides,7 ureas,8 and DMF,9 have been
shown to undergo carbonyl−nitrogen cleavage. Another class of
substrates that could potentially exhibit such reactivity is a
strained or twisted amide,10 where the poor n−π conjugation
makes the amide behave more like an independent amine and
ketone. To the best of our knowledge, the reactivity of such
amides toward arynes has received little attention.11 We wish to
report our initial results in this interesting area.
The substrates we have chosen to study are β-lactams. The
angular strain of β-lactams renders poor conjugation of the
nitrogen to the carbonyl. Thus, β-lactams have a stronger C
O double bond and a more basic nitrogen than regular
amides.12 We envisioned that the nitrogen atom of the β-lactam
should exhibit greater nucleophilicity toward arynes than
normal amides, thus leading to eventual C(O)−N bond
cleavage to afford dihydroquinolinones (Scheme 1). While
this outcome proved correct, we have observed some
interesting subsequent chemistry, which we now report.
Stirring lactam 1a with 1.0 equiv of the parent aryne precursor
2a in the presence of 2.0 equiv of CsF as the fluoride source
afforded three products in addition to unreacted 1a: the simple
N-arylation product 1b, product 3a′ resulting from C(O)−N
bond insertion and subsequent N-arylation, and acridone 4a.
Much to our surprise, not only was the originally anticipated
product 3a not observed, but also dihydroquinolinone 3a′ was
identified as only a minor product by GC−MS analysis. The
major product of this reaction was acridone 4a. It thus appeared
that the initial insertion products 3a and/or 3a′ were also
reactive toward arynes, if not even more so than lactam 1a, and
thus served merely as intermediates, eventually leading to
acridone 4a. For this to happen, however, the C2−C3 unit of
the dihydroquinolinone 3a and/or 3a′ must have been lost as a
molecule of ethylene during the course of the reaction. It is very
rare that aryne reactions lead to the extrusion of a neutral
molecule.13 To the best of our knowledge, this is the first
example of ethylene extrusion in aryne chemistry.
To test our hypothesis that 2,3-dihydroquinolin-4-ones 3a/
3a′ are reactive with arynes, pure 3a from a commercial source
RESULTS AND DISCUSSION
Initial Discovery. We initiated our study using the N-
unsubstituted β-lactam 1a as the starting material (Scheme 2).
■
Received: May 29, 2012
Published: June 28, 2012
© 2012 American Chemical Society
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Scheme 2. Initial Results Leading to an Acridone from a β-Lactam
was subjected to our standard aryne reaction conditions. We
thus found that as long as sufficient aryne was present, acridone
4a was indeed formed under quite mild conditions, regardless
of the fluoride source or the solvent used (Table 1). Thus, the
intermediacy of dihydroquinolinone 3a during the generation
of acridone 4a from β-lactam 1a is confirmed.
nolinone (such as 3a and/or its N-arylated product 3a′), all
attempts to isolate such an intermediate have thus far been
unsuccessful, even when using a 1:1 stoichiometry of the β-
lactam and the aryne precursor. The best yields of acridone 4
have been achieved by employing 3.5 equiv of the aryne
precursor (Figure 1) for the N-unsubstituted β-lactam 1a or 2.4
equiv for the N-substituted β-lactams 1b and 1c. As seen in
Table 2, compounds 4b and 4c can be obtained in reasonable
yields from the symmetrical aryne precursors 2b and 2c (entries
2 and 3), respectively. The aryne derived from 2e is known to
be attacked preferentially by nucleophiles at the meta position
(with respect to the OMe group) for both electronic and steric
reasons.4,14 In our studies, compound 4d was formed in a
surprisingly high yield as a single regioisomer (entry 4). N-
Substituted β-lactams have also been examined in this reaction
(entries 5−7). However, the N-phenyl lactam 1b proved
unreactive under our standard reaction conditions, and the N-
allyl lactam 1c was only marginally reactive, affording no more
than a trace of the desired product 4e. The N-benzyl lactam 1d
was slightly more reactive, affording compound 4f in a 13%
isolated yield (entry 7). It is worth pointing out that the yields
of these three reactions did not improve very much even when
the reactions were performed at a higher temperature. We also
examined one α,α-disubstituted β-lactam 1e (entry 8). In this
case, the anticipated chemistry would require the extrusion of
an olefin much larger than ethylene. Gratifyingly, we were able
to identify the desired product 4a in a 30% yield, indicating that
extrusion of a molecule as large as 4-methylenehepta-1,6-diene
is possible.
Table 1. Formation of an Acridone from a 2,3-
a
Dihydroquinolin-4(1H)-one
b
fluoride source
yield
(%)
entry equiv of 2a
(equiv)
conditions
1
2
3
4
5
2
CsF (4)
MeCN, rt, 1 d
MeCN, rt, 1 d
THF, 65 °C, 1 d
THF, rt, 1 d
65
77
72
59
50
2.4
2.4
2.4
2.4
CsF (4.8)
CsF (4.8)
TBAF (4.8)
TBAT (4.8)
toluene, rt, 1 d
a
All reactions were carried out on a 0.25 mmol scale in 4 mL of
b
solvent. Isolated yield of acridone 4a.
To gain further evidence for the mechanism, an experiment
was carried out to trap the extruded ethylene (the C2−C3 unit
of the 2,3-dihydroquinolin-4-one). Thus, the reaction was
repeated in a sealed vessel, and bromine was injected into the
vessel after 10 h. GC−MS analysis of the crude reaction
mixture revealed the presence of a large quantity of 1,2-
dibromoethane, which supports the generation of ethylene in
this reaction (Scheme 3).
Scope of the Dihydroquinolinones. Because of the
limited availability of β-lactams and the fact that incorporation
of three molecules of aryne results in limited variability in the
substitution pattern of the acridone product, we felt that the use
of 2,3-dihydroquinolin-4-ones (series 3) as the starting material
would be more synthetically useful. Thus, we next focused our
efforts on studying the reaction of dihydroquinolinones 3 with
arynes.
Scheme 3. Ethylene Trapping
We first examined N-unsubstituted substrates (Table 3). As
shown previously, we have had preliminary success in the
reaction of 3a with 2a (cf. entry 2, Table 1). Expanding the
scope of the dihydroquinolinones 3 revealed that alkyl, ether,
and chloride substituents are well tolerated, affording the
corresponding acridones in good to excellent yields (entries 1−
3). However, 6-fluorodihydroquinolinone (3e) proved un-
reactive (entry 4), presumably because of the electron-
withdrawing nature of the fluoride. Different aryne precursors
Scope of the β-Lactams. Encouraged by these findings, we
first studied the scope of the reaction between various β-
lactams and arynes. Although we have suggested that the
reaction proceeds through the intermediacy of a dihydroqui-
Figure 1. Aryne precursors.
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a
Table 2. Scope of the β-Lactams
Table 3. Scope of the N-Unsubstituted 2,3-Dihydroquinolin-
4-ones
a
a
All reactions were carried out on a 0.25 mmol scale with 2.4 equiv of
b
c
a
2 and 4.8 equiv of CsF in 4 mL of MeCN. Isolated yield. Detected
by GC−MS.
All reactions were carried out on a 0.25 mmol scale in 4 mL of
MeCN with 3.5 equiv of the aryne precursor and 7 equiv of CsF.
b
c
d
Isolated yield. All lactam starting material was recovered. 2.4 equiv
e
of 2a and 4.8 equiv of CsF were employed. Detected by GC−MS.
using N-substituted 2,3-dihydroquinolin-4-ones are noticeably
lower. Thus, the N-methyl dihydroquinolinone 3f reacted with
1.2 equiv of benzyne precursor 2a to afford acridone 4o in a
63% yield (entry 1), a 14% drop from the corresponding N-
unsubstituted precursor 3a (cf. entry 2, Table 1). Similarly,
substrates 3g−3i were all smoothly transformed into the
corresponding acridones 4p−4r in moderate yields (entries 2−
(cf. Figure 1) have also been shown to react smoothly (entries
5−8), and compound 4n has been obtained as a single
regioisomer in a 90% yield (entry 8).
N-Substituted 2,3-dihydroquinolin-4-ones were next exam-
ined (Table 4). Compared with the results in Table 3, the yields
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a
Table 4. Scope of the N-Substituted 2,3-Dihydroquinolin-4-ones
a
b
c
All reactions were carried out on a 0.25 mmol scale with 1.2 equiv of 2 and 2.4 equiv of CsF in 4 mL of MeCN.. Isolated yield. Detected by GC−
d
1
MS. Inseparable mixtures of regioisomers. The ratios were obtained by H NMR spectroscopy. No attempts were made to identify the major
isomer.
4). Other than a methyl group on the nitrogen, an allyl group
can also be tolerated as seen in the reaction of substrate 3j,
which afforded acridone 4e in a 48% yield (entry 5). However,
placing a phenyl group on the nitrogen resulted in much
lowered reactivity, as dihydroquinolinone 3a′ afforded only a
trace of acridone 4a, as detected by GC−MS (entry 6),
indicating that the nucleophilicity and/or steric hindrance of
the nitrogen is crucial to the reaction. This chemistry has also
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Scheme 4. Mechanistic Pathway
been extended to substituted aryne precursors. Thus, silyl
triflates 2f and 2g reacted with dihydroquinolinone 3f to afford
the desired products in 57 and 60% yields, respectively (entries
7 and 8). Not surprisingly, since these two precursors are
neither electronically nor sterically biased, mixtures of two
regioisomers were obtained.
similar intermediate. It has been shown that a 5-membered ring
urea can undergo C(O)−N cleavage upon reaction with arynes
to afford products similar to compound 3.8 Thus, we examined
the reaction of the cyclic carbamate 3-methyloxazolidin-2-one
(5) with benzyne generated from 2a. Gratifyingly, we were able
to isolate acridone 4o in a 33% yield (Scheme 5). This reaction
Mechanistic Discussion. On the basis of the above results,
we propose the following mechanistic picture for this overall
process (Scheme 4). First, the nitrogen atom of the β-lactam
(1a) reacts with one molecule of the aryne to form
intermediate A. Although A could undergo a simple proton
transfer to afford lactam 1b (as shown in Scheme 2), this is
apparently a minor route and a nonproductive one with respect
to the formation of acridone 4a, since lactam 1b does not
readily react with arynes (see entry 5, Table 2). Thus, the aryl
anion of intermediate A apparently nucleophilically adds to the
carbonyl, and the resulting highly strained intermediate B
collapses to furnish dihydroquinolinone 3a with release of the
ring strain. Compound 3a presumably then reacts with a
second molecule of aryne to afford intermediate C. Once again
proton transfer from C to form dihydroquinolinone 3a′ is
apparently a minor and nonproductive route (see entry 6, Table
4). In a fashion similar to the conversion of A to B,
intermediate C most likely cyclizes to D, and subsequent
extrusion of ethylene either by the arrow-pushing sequence
described in Scheme 4 or by a retro-Diels−Alder process leads
to the acridone E. Finally, acridone E undergoes NH arylation
by a third molecule of aryne to afford the final major product
acridone 4a. In other words, the formation of acridone 4a from
lactam 1a proceeds through the intermediacy of compounds 3a
and E, and compounds 1b and 3a′ are much less important
intermediates en route to acridone 4a.
Scheme 5. Extrusion of Ethylene Oxide in the Reaction of
Benzyne with 3-Methyl-2-oxazolidinone
is quite interesting on its own, because mechanistically, the first
C(O)−N cleavage presumably results in a seven-membered
ring intermediate 6, whose subsequent reaction with benzyne
must apparently extrude a molecule of ethylene oxide. Again, to
the best of our knowledge, such a process is unprecedented in
aryne chemistry.
Possibilities for the Extrusion of Small Molecules
Other than Ethylene. Inspired by the finding that
dihydroquinolinone 3a apparently reacts with an aryne to
afford structures like intermediate D (Scheme 4), we were
prompted to investigate other substrates that might afford a
CONCLUSIONS
■
In summary, we have demonstrated that the reaction of β-
lactams or 2,3-dihydroquinolin-4-ones with arynes could afford
respectable yields of acridones through the extrusion of
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organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography
(5:1 petroleum ether/EtOAc) to afford 0.52 g (2.3 mmol) of 3-allyl-1-
(tert-butyldimethylsilyl)azetidin-2-one. This intermediate was treated
with the above allylation procedure again to afford 0.3 g (1.1 mmol) of
3,3-diallyl-1-(tert-butyldimethylsilyl)azetidin-2-one. This product was
dissolved in 10 mL of methanol, and 0.334 g (2.2 mmol) of CsF was
added. After being stirred for 2 h, the mixture was quenched with
water and extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated to
afford 0.15 g (1.0 mmol, 10% overall yield from 1a) of 3,3-
ethylene. This chemistry speaks for the tendency of
intermediates like A and C to readily undergo intramolecular
nucleophilic cyclization rather than the seemingly easier proton
transfer process. Further study has suggested that the extrusion
of molecules larger than ethylene, such as 4-methylenehepta-
1,6-diene and an epoxide, are also possible in aryne processes.
EXPERIMENTAL SECTION
■
General Information. The solvent THF was distilled over Na/
benzophenone, and dichloromethane was distilled over CaH2.
Anhydrous MeCN, DMF, and DCE were used as received. The
aryne precursors were used as received. Silica gel for column
chromatography was supplied as 230−400 mesh from a commercial
source. Powdered CsF and TBAF (1 M in THF solution) were used as
received and stored in a desiccator.
1
diallylazetidin-2-one as a red oil: H NMR (400 MHz, CDCl3) δ 6.32
(s, 1 H), 5.85−5.74 (m, 2 H), 5.12 (d, J = 6.4 Hz, 2 H), 5.08 (s, 2 H),
3.07 (s, 2 H), 2.39 (d of ABq, JAB = 14.1 Hz, JAX = 6.7 Hz, JBX = 7.9 Hz,
2 H), 2.31 (d of ABq, JAB = 14.1 Hz, JAX = 6.7 Hz, JBX = 7.9 Hz, 2 H).
N-Unsubstituted 2,3-Dihydroquinolin-4-ones. Compounds 3a
and 3e were commercially available and used as received. The
remaining dihydroquinolinones were prepared as follows.
All melting points are uncorrected. The H and 13C NMR spectra
1
were recorded and are referenced to the residual solvent signals (7.26
6-Methyl-2,3-dihydroquinolin-4(1H)-one (3b).15,18 Following
the procedure described above for the synthesis of compound 1b, 2.14
g (20 mmol) of p-toluidine, 2.5 mL (24 mmol) of 3-bromopropanoyl
chloride, and 1.57 g (16.5 mmol) of sodium tert-butoxide were
employed to obtain 1.92 g of N-(p-tolyl)azetidin-2-one. To a solution
of 1.61 g (10 mmol) of 1-(p-tolyl)azetidin-2-one in 20 mL of DCE at 0
°C was added 2 mL (22 mmol) of TfOH. The mixture was allowed to
warm up to room temperature and stirred for 2 h. The reaction was
quenched with aq NaHCO3 and extracted by EtOAc three times. The
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated. The residue was purified by column
chromatography (2:1 petroleum ether/EtOAc) to afford 1.19 g (40%
overall yield from p-toluidine) of dihydroquinolinone 3b as a yellow
solid: mp 80−82 °C (lit16 82−84 °C); 1H NMR (400 MHz, CDCl3) δ
7.65 (s, 1 H), 7.13 (dd, J = 8.4, 1.6 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H),
4.26 (s, 1 H), 3.55 (td, J = 8.0, 1.6 Hz, 2 H), 2.68 (t, J = 6.8 Hz, 2 H),
2.24 (s, 3 H).
1
1
ppm for H and 77.2 ppm for 13C in CDCl3, 2.05 ppm for H and
30.19 ppm for 13C in acetone-d6). A QTOF analyzer was used for all of
the HRMS measurements.
β-Lactams. Compound 1a was commercially available and was
used as received. The rest were prepared as follows.
1-Phenylazetidin-2-one (1b).15 To a suspension of 1.8 mL (20
mmol) of aniline and 3.3 g (24 mmol) of K2CO3 in 20 mL of DCM at
0 °C was added dropwise 2.5 mL (24 mmol) of 3-bromopropanoyl
chloride. The mixture was stirred at 0 °C for minutes and allowed to
warm up to room temperature for another 3 h. The reaction was
quenched with water and extracted with EtOAc three times. The
combined organic layers were evaporated, and the residue was
recrystallized in a hot solution of 1:1 petroleum ether/EtOAc to afford
3.42 g (ca. 15 mmol, ∼75% as is) of 3-bromo-N-phenylpropanamide
as white crystals. This solid was then dissolved in DMF and cooled to
0 °C. To this solution was added 1.57 g (16.5 mmol) of sodium tert-
butoxide in one portion, and the mixture was allowed to warm up to
room temperature gradually. The reaction was quenched with water
after 3 h and extracted with EtOAc. The combined organic layers were
evaporated, and the residue was recrystallized from a hot solution of
1:1 petroleum ether/EtOAc to afford 1.76 g (60% overall yield) of 1-
phenylazetidin-2-one as a red solid: mp 78−80 °C (lit16 78−79 °C);
1H NMR (400 MHz, CDCl3) δ 7.53−7.32 (m, 5 H), 3.72 (t, J = 6.4
Hz, 1 H), 3.63 (t, J = 4.8 Hz, 1 H), 3.12 (t, J = 4.8 Hz, 1 H), 2.95 (t, J
= 6.4 Hz, 1 H).
6-Methoxy-2,3-dihydroquinolin-4(1H)-one (3c). Following the
procedure described above for the synthesis of compound 1b, 2.46 g
(20 mmol) of p-anisidine, 2.5 mL (24 mmol) of 3-bromopropanoyl
chloride, and 1.62 g (17 mmol) of sodium tert-butoxide were
employed to obtain 2.3 g of N-(4-methoxyphenyl)azetidin-2-one.
Next, 1.77 g (10 mmol) of N-(4-methoxyphenyl)azetidin-2-one was
treated with 2 mL (22 mmol) of TfOH as described above to yield
1.28 g (47% overall yield from 4-methoxyaniline) of dihydroquino-
linone 3c as a yellow solid: mp 110−112 °C (lit16 113−114 °C); H
1
1-Allylazetidin-2-one (1c). The above procedure was applied to
1.14 g (20 mmol) of allylamine and 2.5 mL (24 mmol) of 3-
bromopropanoyl chloride, followed by 1.52 g (16 mmol) of sodium
tert-butoxide to afford 1.22 g (55% overall yield) of lactam 1c as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.80−5.70 (m, 1 H), 5.22
(d, J = 5.2 Hz, 1 H), 5.19 (s, 1 H), 3.82 (d, J = 6.0 Hz, 2 H), 3.22 (t, J
= 4.0 Hz, 2 H), 2.94 (t, J = 4.0 Hz, 2 H).
NMR (400 MHz, CDCl3) δ 7.32 (d, J = 2.8 Hz, 1 H), 6.98 (dd, J =
8.8, 2.8 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 1 H), 4.17 (s, 1 H), 3.77 (s, 3
H), 3.54 (t, J = 6.0 Hz, 2 H), 2.69 (t, J = 6.0 Hz, 2 H).
6-Chloro-2,3-dihydroquinolin-4(1H)-one (3d). Following the
procedure described above for the synthesis of compound 1b, 2.55 g
(20 mmol) of 4-chloroaniline, 2.5 mL (24 mmol) of 3-
bromopropanoyl chloride, and 1.57 g (16.5 mmol) of sodium tert-
butoxide were employed to obtain 2.18 g of N-(4-chlorophenyl)-
azetidin-2-one. Next, 1.82 g (10 mmol) of N-(4-chlorophenyl)-
azetidin-2-one was treated with 2 mL (22 mmol) of TfOH as
described above to yield 1.12 g (37% overall yield from 4-
chloroaniline) of dihydroquinolinone 3d as a yellow solid: mp 123−
125 °C (lit16 125−126 °C); 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J
= 2.7 Hz, 1 H), 7.23 (dd, J = 8.4, 2.7 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1
H), 4.40 (s, 1 H), 3.58 (td, J = 7.8, 1.5 Hz, 2 H), 2.69 (t, J = 7.5 Hz, 2
H).
N-Substituted 2,3-Dihydroquinolin-4-ones. Compound 3a′
was commercially available and used as received. The other N-
substituted dihydroquinolinones were prepared as follows.
1-Methyl-2,3-dihydroquinolin-4(1H)-one (3f). To an oven-
dried vial was added 0.367 g (2.5 mmol) of 2,3-dihydroquinolin-
4(1H)-one (3a) and 5 mL of DMF, followed by 0.15 g (3.75 mmol,
60% dispersed in mineral oil) of NaH. The mixture was stirred under a
N2 atmosphere at room temperature for 2 h and charged with 0.31 mL
(5 mmol) of MeI. The vial was then capped and heated in an 80 °C oil
bath for 12 h. After being quenched with water, the mixture was
1-Benzylazetidin-2-one (1d). The above procedure was applied
to 2.14 g (20 mmol) of benzylamine and 2.5 mL (24 mmol) of 3-
bromopropanoyl chloride, followed by 1.57 g (16.5 mmol) of sodium
tert-butoxide to afford 1.87 g (58% overall yield) of lactam 1d as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.39−7.23 (m, 5 H), 4.38
(s, 2 H), 3.14 (t, J = 3.9 Hz, 2 H), 2.95 (t, J = 3.9 Hz, 2 H).
3,3-Diallylazetidin-2-one (1e).17 A mixture of 0.71 g (10 mmol)
of azetidin-2-one (1a), 2.25 g (15 mmol) of tert-butyldimethylsilyl
chloride, and 2.08 mL (15 mmol) of triethylamine in 20 mL of DCM
was stirred for 12 h at room temperature. The mixture was then
washed with water, and the aqueous phase was extracted with EtOAc
three times. The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated to afford a colorless oil
consisting of N-tert-butyldimethylsilylazetidin-2-one and residual
TBSCl. This mixture was dissolved in THF, cooled to −78 °C
under an N2 atmosphere, and charged with 6.67 mL (1.8 M THF
solution) of LDA. After being stirred for 2 h at −78 °C, 1.04 mL (12
mmol) of allyl bromide was added, and the mixture was gradually
warmed up to room temperature for another 12 h. The reaction was
quenched with water and extracted with EtOAc. The combined
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extracted with EtOAc three times. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated. The
residue was purified by column chromatography (2:1 petroleum ether/
EtOAc) to afford 0.173 g (1.07 mmol, 43% yield) of dihydroquino-
linone 3f as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J =
8.0, 1.2 Hz, 1 H), 7.40 (td, J = 4.4, 1.6 Hz, 1 H), 6.77−6.70 (m, 2 H),
3.47 (t, J = 7.2 Hz, 2 H), 2.99 (s, 3 H), 2.74 (t, J = 7.2 Hz, 2 H).
1,6-Dimethyl-2,3-dihydroquinolin-4(1H)-one (3g). The above
procedure used for the synthesis of dihydroquinolinone 3f was applied
to 0.402 g (2.5 mmol) of dihydroquinolinone 3b, 0.15 g (3.75 mmol,)
of NaH, followed by 0.31 mL (5 mmol) of MeI to afford 0.197 g (45%
2 H), 2.45 (s, 3 H), 2.37 (s, 3 H), 2.35 (s, 6 H), 2.23 (s, 6 H); 13C
NMR (100 MHz, CDCl3) δ 177.7, 143.2, 141.9, 140.0, 138.1, 137.0,
132.0, 130.8, 130.4, 127.3, 127.0, 120.2, 117.3, 21.0, 20.2, 19.9, 19.3;
HRMS (ESI) calcd for C25H26NO (M + H) 356.2009, found
356.2012.
10-(3,4-Dimethoxyphenyl)-2,3,6,7-tetramethoxyacridin-9-
(10H)-one (4c). The representative procedure was employed to afford
45.1 mg (0.10 mmol, 40% yield) of 4c as a brown solid: mp 256−257
1
°C; Rf = 0.25 (2:1 petroleum ether/EtOAc); H NMR (400 MHz,
CDCl3) δ 7.92 (s, 2 H), 7.14 (d, J = 8.0 Hz, 1 H), 6.98 (dd, J = 8.0, 1.2
Hz, 1 H), 6.85 (d, J = 1.6 Hz, 1 H), 6.18 (s, 2 H), 4.04 (s, 3 H), 4.01
(s, 6 H), 3.87 (s, 3 H), 3.68 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ
175.2, 154.0, 151.0, 149.9, 145.7, 139.2, 132.0, 122.3, 115.4, 112.4,
112.3, 106.4, 98.4, 56.51, 56.49, 56.3, 56.1; HRMS (ESI) calcd for
C25H26NO7 (M + H) 452.1704, found 452.1708.
1
overall yield) of compound 3g as a yellow oil: H NMR (400 MHz,
CDCl3) δ 7.72 (s, 1 H), 7.23 (dd, J = 8.0, 1.2 Hz, 1 H), 6.65 (d, J = 7.6
Hz, 1 H), 3.42 (t, J = 7.2 Hz, 2 H), 2.95 (s, 3 H), 2.72 (t, J = 7.2 Hz, 2
H), 2.25 (s, 3 H).
1,8-Dimethoxy-10-(3-methoxyphenyl)acridin-9(10H)-one
(4d). The representative procedure was employed to afford 74.9 mg
(0.21 mmol, 83% yield) of 4d as a brown solid: mp 250−253 °C; Rf =
0.11 (pure EtOAc); 1H NMR (400 MHz, acetone-d6) δ 7.65 (t, J = 8.0
Hz, 1 H), 7.39 (t, J = 8.4 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 1 H), 6.96−
6.94 (m, 2 H), 6.79 (d, J = 8.4 Hz, 2 H), 6.27 (d, J = 8.4 Hz, 2 H), 3.96
(s, 6 H), 3.87 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 179.2, 163.1,
161.6, 145.7, 142.1, 134.1, 123.7, 122.8, 120.6, 116.4, 115.0, 110.0,
104.8, 57.1, 56.3; HRMS (ESI) calcd for C22H20NO4 (M + H)
362.1387, found 362.1389.
Compounds 4f−4n were prepared according to the following
procedure (representative procedure for N-substituted β-lactams/N-
unsubstituted 2,3-dihydroquinolin-4-ones where 2.4 equiv of arynes
were used): the general procedure used above for the synthesis of
compound 4a was applied to 0.6 mmol of aryne precursor, 0.25 mmol
of N-substituted β-lactam/N-unsubstituted 2,3-dihydroquinolin-4-one
starting material, 4 mL of MeCN, and 0.182 g (1.2 mmol) of CsF to
afford the desired products.
6-Methoxy-1-methyl-2,3-dihydroquinolin-4(1H)-one (3h).
The above procedure used to synthesize compound 3f was applied
to 0.442 g (2.5 mmol) of dihydroquinolinone 3c, 0.15 g (3.75 mmol)
of NaH, followed by 0.31 mL (5 mmol) of MeI to afford 0.205 g (43%
1
overall yield) of compound 3h as a yellow oil: H NMR (300 MHz,
CDCl3) δ 7.41 (d, J = 2.4 Hz, 1 H), 7.07 (dd, J = 8.1, 2.4 Hz, 1 H),
6.70 (d, J = 8.1 Hz, 1 H), 3.79 (s, 3 H), 3.39 (t, J = 7.5 Hz, 2 H), 2.94
(s, 3 H), 2.73 (t, J = 7.5 Hz, 2 H).
6-Chloro-1-methyl-2,3-dihydroquinolin-4(1H)-one (3i). The
above procedure used to synthesize compound 3f was applied to 0.454
g (2.5 mmol) of dihydroquinolinone 3d, 0.15 g (3.75 mmol) of NaH,
followed by 0.31 mL (5 mmol) of MeI to afford 0.200 g (41% overall
yield) of compound 3i as a yellow oil: 1H NMR (300 MHz, CDCl3) δ
7.83 (d, J = 2.7 Hz, 1 H), 7.31 (dd, J = 9.0, 2.7 Hz, 1 H), 6.65 (d, J =
9.0 Hz, 1 H), 3.46 (t, J = 7.2 Hz, 2 H), 2.97 (s, 3 H), 2.72 (t, J = 7.2
Hz, 2 H).
1-Allyl-2,3-dihydroquinolin-4(1H)-one (3j). The above proce-
dure used to synthesize compound 3f was applied to 0.367 g (2.5
mmol) of dihydroquinolinone 3a, 0.15 g (3.75 mmol) of NaH,
followed by 0.605 g (5 mmol) of allyl bromide to afford 0.182 g (39%
10-Benzylacridin-9(10H)-one (4f). The representative procedure
was employed to afford 9.3 mg (0.03 mmol, 13% yield) of 4f as a
brown solid: mp 178−180 °C (lit20 176−179 °C); Rf = 0.37 (2:1
1
overall yield) of compound 3i as a yellow oil: H NMR (400 MHz,
1
petroleum ether/EtOAc); H NMR (400 MHz, CDCl3) δ 8.60 (dd, J
CDCl3) δ 7.90 (dd, J = 8.0, 1.6 Hz, 1 H), 7.36 (td, J = 4.4, 1.6 Hz, 1
H), 6.73−6.70 (m, 2 H), 5.90−5.82 (m, 1 H), 5.28−5.20 (m, 2 H),
3.99 (d, J = 5.2 Hz, 2 H), 3.52 (t, J = 7.2 Hz, 2 H), 2.72 (t, J = 7.2 Hz,
2 H).
3-Methyloxazolidin-2-one (5). This compound was commer-
cially available and used as received.
General Procedures for Aryne Reactions Affording Acri-
dones. Compounds 4a−4d were prepared according to the following
procedure (representative procedure for β-lactams where 3.5 equiv of
arynes were used): to an oven-dried vial were added 0.875 mmol of
aryne precursor, 0.25 mmol of β-lactam, 4 mL of MeCN, and 0.266 g
(1.75 mmol) of CsF, sequentially. A nitrogen atmosphere was not
required, except that a balloon of nitrogen was attached to the reaction
vial for the ventilation of ethylene. The reaction was allowed to stir for
24 h before being quenched with aq Na2CO3 and extracted with
EtOAc. The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated. The residue was purified by
column chromatography (petroleum ether/EtOAc) to afford the
desired products.
= 8.0, 1.2 Hz, 2 H), 7.64 (td, J = 8.0, 1.6 Hz, 2 H), 7.38−7.15 (m, 9
H), 5.61 (s, 2 H); 13C NMR (100 MHz, CDCl3) δ 178.5, 142.8, 135.7,
134.3, 129.5, 128.1, 125.9, 122.8, 121.9, 115.4, 109.5, 51.1; HRMS
(ESI) calcd for C20H16NO (M + H) 286.1226, found 286.1229.
2-Methyl-10-phenylacridin-9(10H)-one (4g). The representa-
tive procedure was employed to afford 62.7 mg (0.22 mmol, 88%
yield) of 4g as a yellow solid: mp 220−221 °C; Rf = 0.38 (2:1
petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J =
7.2 Hz, 1 H), 8.36 (s, 1 H), 7.71−7.63 (m, 3 H), 7.46 (t, J = 7.6 Hz, 1
H), 7.35−7.29 (m, 3 H), 7.23 (t, J = 7.6 Hz, 1 H), 6.73 (d, J = 8.8 Hz,
1 H), 6.66 (d, J = 8.4 Hz, 1 H), 2.44 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 178.1, 143.1, 141.4, 139.2, 134.9, 133.2, 131.3, 131.2, 130.2,
129.6, 127.4, 126.6, 121.82, 121.77, 121.4, 116.9, 116.8, 20.9; HRMS
(ESI) calcd for C20H16NO (M + H) 286.1226, found 286.1233.
2-Methoxy-10-phenylacridin-9(10H)-one (4h). The represen-
tative procedure was employed to afford 56.4 mg (0.19 mmol, 75%
yield) of 4h as a yellow solid: mp 158−159 °C; Rf = 0.24 (2:1
petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J =
7.2 Hz, 1 H), 7.96 (d, J = 1.2 Hz, 1 H), 7.69−7.63 (m, 3 H), 7.47 (t, J
= 7.6 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 2 H), 7.24 (d, J = 7.6 Hz, 1 H),
7.13 (dd, J = 7.6, 1.2 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.72 (d, J =
8.4 Hz, 1 H), 3.93 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 177.7,
154.8, 142.8, 139.2, 138.2, 133.1, 131.2, 130.2, 129.7, 127.3, 124.2,
122.5, 121.4, 121.2, 118.7, 116.8, 106.2, 56.0; HRMS (ESI) calcd for
C20H16NO2 (M + H) 302.1176, found 302.1182.
10-Phenylacridin-9(10H)-one (4a). The representative proce-
dure was employed to afford 33.9 mg (0.13 mmol, 50% yield) of 4a as
a yellow solid: mp 271−273 °C (lit19 276 °C); Rf = 0.38 (2:1
1
petroleum ether/EtOAc); H NMR (400 MHz, CDCl3) δ 8.58 (dd, J
= 8.0, 1.2 Hz, 2 H), 7.71 (t, J = 8.0 Hz, 2 H), 7.65 (t, J = 8.0 Hz, 1 H),
7.49 (td, J = 8.0, 1.6 Hz, 2 H), 7.37 (d, J = 7.6 Hz, 2 H), 7.27 (t, J = 8.0
Hz, 2 H), 6.75 (d, J = 8.4 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
178.3, 143.3, 139.2, 133.4, 131.3, 130.2, 129.8, 127.5, 122.0, 121.7,
117.0; HRMS (APCI) calcd for C19H14NO (M + H) 272.1070, found
272.1076.
10-(3,4-Dimethylphenyl)-2,3,6,7-tetramethylacridin-9(10H)-
one (4b). The representative procedure was employed to afford 39.9
mg (0.11 mmol, 45% yield) of 4b as a yellow solid: mp 306−308 °C;
Rf = 0.37 (2:1 petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3)
δ 8.31 (s, 2 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.06−7.04 (m, 2 H), 6.53 (s,
2-Chloro-10-phenylacridin-9(10H)-one (4i). The representative
procedure was employed to afford 61.1 mg (0.20 mmol, 80% yield) of
4i as a yellow solid: mp 228−230 °C (lit21 229−230 °C); Rf = 0.45
1
(2:1 petroleum ether/EtOAc); H NMR (400 MHz, CDCl3) δ 8.52
(d, J = 8.4 Hz, 1 H), 8.49 (d, J = 2.8 Hz, 1 H), 7.73−7.67 (m, 3 H),
7.51 (td, J = 8.0, 1.2 Hz, 1 H), 7.42−7.37 (m, 3 H), 7.26 (t, J = 7.6 Hz,
1 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H); 13C NMR
(100 MHz, CDCl3) δ 177.1, 143.2, 141.7, 138.8, 133.7, 133.5, 131.4,
6268
dx.doi.org/10.1021/jo3011073 | J. Org. Chem. 2012, 77, 6262−6270

The Journal of Organic Chemistry
Article
130.0, 127.6, 127.4, 126.5, 122.7, 122.1, 121.8, 118.8, 117.6, 117.1;
HRMS (ESI) calcd for C19H13ClNO (M + H) 306.0680, found
306.0688.
10-Methylacridin-9(10H)-one (4o). The representative proce-
dure was employed to afford 32.9 mg (0.16 mmol, 63% yield) of 4o as
a yellow solid: mp 201−203 °C (lit23 201−203 °C); Rf = 0.22 (2:1
petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J =
7.2 Hz, 2 H), 7.68 (t, J = 6.4 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.25
(t, J = 6.4 Hz, 2 H), 3.82 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
178.2, 142.7, 133.9, 127.9, 122.6, 121.4, 114.9, 33.8; HRMS (ESI)
calcd for C14H12NO (M + H) 210.0913, found 210.0918.
2,10-Dimethylacridin-9(10H)-one (4p). The representative
procedure was employed to afford 34.6 mg (0.16 mmol, 62% yield)
of 4p as a yellow solid: mp 149−151 °C (lit24 153 °C); Rf = 0.25 (2:1
petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J =
8.0 Hz, 1 H), 8.31 (s, 1 H), 7.66 (t, J = 7.2 Hz, 1 H), 7.49−7.43 (m, 2
H), 7.36 (d, J = 8.8 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 3.80 (s, 3 H),
2.44 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 178.1, 142.6, 140.8,
135.3, 133.7, 131.0, 127.9, 127.2, 122.6, 122.5, 121.1, 114.9, 114.8,
33.7, 20.8; HRMS (ESI) calcd for C15H14NO (M + H) 224.1070,
found 224.1075.
10-(3,4-Dimethylphenyl)-2,3-dimethylacridin-9(10H)-one
(4k). The representative procedure was employed to afford 59.8 mg
(0.18 mmol, 73% yield) of 4k as a yellow solid: mp 245−247 °C; Rf =
1
0.37 (2:1 petroleum ether/EtOAc); H NMR (400 MHz, CDCl3) δ
8.56 (d, J = 8.0 Hz, 1 H), 8.31 (s, 1 H), 7.46−7.41 (m, 2 H), 7.21 (t, J
= 8.0 Hz, 1 H), 7.08−7.05 (m, 2 H), 6.77 (d, J = 8.4 Hz, 1 H), 6.58 (s,
1 H), 2.43 (s, 3 H), 2.36 (s, 3 H), 2.35 (s, 3 H), 2.23 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 177.9, 143.7, 143.3, 142.0, 139.8, 138.2,
136.8, 132.8, 132.0, 130.8, 127.3, 127.2, 127.0, 121.9, 121.1, 120.0,
117.4, 117.3, 117.0, 20.9, 20.1, 19.9, 19.3; HRMS (ESI) calcd for
C23H22NO (M + H) 328.1696, found 328.1704.
10-(3,4-Dimethoxyphenyl)-2,3-dimethoxyacridin-9(10H)-
one (4l). The representative procedure was employed to afford 83.2
mg (0.21 mmol, 85% yield) of 4l as a yellow solid: mp 234−235 °C; Rf
1
= 0.62 (pure EtOAc); H NMR (400 MHz, CDCl3) δ 8.51 (dd, J =
8.0, 1.2 Hz, 1 H), 7.86 (s, 1 H), 7.43 (td, J = 8.0, 1.2 Hz, 1 H), 7.21 (t,
J = 8.0 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 6.95 (dd, J = 8.4, 1.6 Hz, 1
H), 6.84 (d, J = 1.6 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 6.18 (s, 1 H),
4.00 (s, 3 H), 3.95 (s, 3 H), 3.86 (s, 3 H), 3.66 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 176.5, 154.5, 151.0, 149.8, 145.7, 143.0, 139.7,
132.5, 131.7, 127.0, 122.2, 121.4, 121.3, 116.8, 115.7, 112.5, 112.4,
106.4, 98.5, 56.4, 56.32, 56.28, 56.0; HRMS (ESI) calcd for
C23H22NO5 (M + H) 392.1492, found 392.1490.
2-Methoxy-10-methylacridin-9(10H)-one (4q). The represen-
tative procedure was employed to afford 32.9 mg (0.14 mmol, 55%
yield) of 4q as a yellow solid: mp 139−141 °C (lit25 138 °C); Rf =
1
0.12 (2:1 petroleum ether/EtOAc); H NMR (400 MHz, CDCl3) δ
8.54 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 2.8 Hz, 1 H), 7.66 (td, J = 7.6,
1.2 Hz, 1 H), 7.46−7.42 (m, 2 H), 7.31 (dd, J = 9.2, 3.2 Hz, 1 H), 7.23
(d, J = 7.6 Hz, 1 H), 3.92 (s, 3 H), 3.82 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 177.6, 154.5, 142.2, 137.5, 133.7, 127.9, 124.5, 123.3, 121.9,
121.0, 116.7, 114.8, 106.8, 55.9, 33.8; HRMS (ESI) calcd for
C15H14NO2 (M + H) 240.1019, found 240.1021.
5-(2,3-Dihydro-1H-inden-5-yl)-2,3-dihydro-1H-cyclopenta-
[b]acridin-10(5H)-one (4m). The representative procedure was
employed to afford 60.6 mg (0.17 mmol, 69% yield) of 4m as a yellow
1
solid: mp 176−178 °C; Rf = 0.48 (2:1 petroleum ether/EtOAc); H
2-Chloro-10-methylacridin-9(10H)-one (4r). The representative
procedure was employed to afford 30.5 mg (0.13 mmol, 50% yield) of
4r as a yellow solid: mp 171−173 °C; Rf = 0.21 (2:1 petroleum ether/
NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.0 Hz, 1 H), 8.41 (s, 1 H),
7.51−7.43 (m, 2 H), 7.24−7.21 (m, 1 H), 7.15 (s, 1 H), 7.07 (d, J =
8.0 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 6.66 (s, 1 H), 3.10−2.98 (m, 6
H), 2.87 (t, J = 7.6 Hz, 2 H), 2.24 (t, J = 7.6 Hz, 2 H), 2.08 (t, J = 7.6
Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 178.2, 151.5, 147.6, 145.8,
143.4, 142.9, 138.5, 137.5, 132.8, 127.7, 127.3, 126.6, 125.9, 121.9,
121.8, 121.1, 121.0, 117.1, 112.4, 33.8, 33.2, 33.0, 32.0, 26.0, 25.8;
HRMS (ESI) calcd for C25H22NO (M + H) 352.1696, found
352.1705.
1
EtOAc); H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 7.6 Hz, 1 H),
8.39 (s, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.53 (dd, J = 9.2, 2.0 Hz, 1 H),
7.43 (d, J = 8.8 Hz, 1 H), 7.36 (d, J = 9.2 Hz, 1 H), 7.23 (d, J = 7.2 Hz,
1 H), 3.79 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 177.0, 142.4,
140.9, 134.2, 133.8, 127.8, 127.3, 126.8, 123.3, 122.4, 121.7, 116.7,
115.0, 34.0; HRMS (ESI) calcd for C14H11ClNO (M + H) 244.0524,
found 244.0523.
1-Methoxy-10-(3-methoxyphenyl)acridin-9(10H)-one (4n).
The representative procedure was employed to afford 74.6 mg (0.22
mmol, 90% yield) of 4n as a pale white solid: mp 221−222 °C; Rf =
2,10-Dimethylacridin-9(10H)-one and 3,10-dimethylacridin-
9(10H)-one (4s + 4s′). The representative procedure was employed
to afford 31.8 mg (0.14 mmol, 57% total yield) of 4s + 4s′ as a yellow
1
0.52 (2:1 petroleum ether/EtOAc); H NMR (400 MHz, CDCl3) δ
8.52 (d, J = 7.6 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.41 (t, J = 7.6 Hz,
1 H), 7.32 (t, J = 8.4 Hz, 1 H), 7.20 (t, J = 7.2 Hz, 1 H), 7.13 (d, J =
8.0 Hz, 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 6.84 (s, 1 H), 6.66 (t, J = 9.6
Hz, 2 H), 6.33 (d, J = 8.4 Hz, 1 H), 4.01 (s, 3 H), 3.82 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 177.9, 161.9, 161.6, 145.7, 142.2, 140.7,
133.4, 132.8, 131.8, 127.4, 123.6, 122.0, 121.7, 116.5, 115.5, 115.3,
112.7, 109.3, 102.9, 56.4, 55.7; HRMS (ESI) calcd for C21H18NO3 (M
+ H) 332.1281, found 332.1285.
Compounds 4e, 4o−4r, and the inseparable mixtures of 4s + 4s′
and 4t + 4t′ were prepared according to the following procedure
(representative procedure for N-substituted 2,3-dihydroquinolin-4-
ones where 1.2 equiv of arynes were used): the general procedure used
above for the synthesis of acridone 4a was applied to 0.3 mmol of
aryne precursor, 0.25 mmol of N-substituted 2,3-dihydroquinolin-4-
one, 4 mL of MeCN, and 0.091 g (0.6 mmol) of CsF to afford the
desired product.
1
solid: Rf = 0.25 (2:1 petroleum ether/EtOAc); H NMR (400 MHz,
CDCl3) δ 8.54−8.51 (m, 2 H), 8.39 (d, J = 8.0 Hz, 1 H), 8.30 (s, 1 H),
7.65 (t, J = 7.6 Hz, 2 H), 7.47 (dd, J = 8.4, 2.0 Hz, 1 H), 7.43 (d, J =
8.8 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 1 H), 7.22 (d, J = 10.0 Hz, 3 H), 7.05
(d, J = 8.0 Hz, 1 H), 3.79 (s, 3 H), 3 78 (s, 3 H), 2.48 (s, 3 H), 2.43 (s,
3 H); 13C NMR (100 MHz, CDCl3) δ 178.1, 177.9, 144.8, 142.8,
142.7, 142.6, 140.8, 135.3, 133.7, 131.0, 127.8, 127.4, 123.1, 123.0,
122.7, 122.6, 122.5, 121.2, 121.0, 120.7, 114.85, 114.82, 33.73, 33.71,
22.8, 20.8; HRMS (ESI) calcd for C15H14NO (M + H) 224.1070,
found 224.1072.
2-Methoxy-10-methylacridin-9(10H)-one and 3-methoxy-
10-methylacridin-9(10H)-one (4t + 4t′). The representative
procedure was employed to afford 35.9 mg (0.15 mmol, 60% total
yield) of 4t + 4t′ as a yellow solid: Rf = 0.18 (2:1 petroleum ether/
1
EtOAc); H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.0 Hz, 1 H),
10-Allylacridin-9(10H)-one (4e). The representative procedure
was employed to afford 28.2 mg (0.12 mmol, 48% yield) of 4e as a
yellow solid: mp 131−132 °C (lit22 132−134 °C); Rf = 0.36 (2:1
petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J =
7.6 Hz, 2 H), 7.69 (t, J = 7.6 Hz, 2 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.28
(t, J = 7.6 Hz, 2 H), 6.18−6.09 (m, 1 H), 5.31 (d, J = 10.8 Hz, 1 H),
5.10 (d, J = 17.2 Hz, 1 H), 4.96 (s, 2 H); 13C NMR (100 MHz,
CDCl3) δ 178.4, 142.4, 134.1, 130.8, 127.6, 122.7, 121.4, 117.6, 115.2,
49.5; HRMS (ESI) calcd for C16H14NO (M + H) 236.1070, found
236.1067.
8.49 (d, J = 7.6 Hz, 0.5 H), 8.43 (d, J = 8.8 Hz, 0.5 H), 7.91 (d, J = 2.8
Hz, 1 H), 7.67−7.61 (m, 1.5 H), 7.44−7.38 (m, 2.5 H), 7.30 (dd, J =
9.2, 3.2 Hz, 1 H), 7.25−7.21 (m, 1.5 H), 6.81 (dd, J = 8.8, 2.0 Hz, 0.5
H), 6.72 (s, 0.5 H), 3.91 (s, 3 H), 3.90 (s, 1.5 H), 3.81 (s, 3 H), 3.72
(s, 1.5 H); 13C NMR (100 MHz, CDCl3) δ 177.6, 177.2, 164.3, 154.5,
144.5, 142.8, 142.2, 137.5, 133.6, 133.4, 127.8, 124.5, 124.4, 123.2,
122.7, 121.8, 121.0, 117.2, 116.7, 114.7, 106.8, 98.0, 56.0, 55.7, 33.9,
33.8; HRMS (ESI) calcd for C15H14NO2 (M + H) 240.1019, found
240.1020.
6269
dx.doi.org/10.1021/jo3011073 | J. Org. Chem. 2012, 77, 6262−6270

The Journal of Organic Chemistry
Article
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full 1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: fshi@henu.edu.cn; larock@iastate.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(16) Lange, J.; Bissember, A. C.; Banwell, M. G.; Cade, I. A. Aust. J.
Chem. 2011, 64, 454.
■
We thank the National Science Foundation, the National
Institutes of Health Center of Excellence for Chemical
Methodology and Library Development at the University of
Kansas (P50 GM069663) (both to R.C.L.), the National
Natural Science Foundation of China (No. 21002021), and the
Ministry of Education of China (Scientific Research Founda-
tion for the Returned Overseas Chinese Scholars) (both to
F.S.) for financial support. Dr. Hung-An Ho and Dr. Kermal
Harrata (both at Iowa State University) are acknowledged for
their help in the spectroscopic analysis.
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