PhI(OAc)2-mediated intramolecular oxidative aryl-aldehyde C sp 2-C sp 2 bond formation: Metal-free synthesis of acridone derivatives

Article abstract of DOI:10.1021/jo5011697

A metal-free protocol for direct aryl-aldehyde Csp²-Csp ² bond formation via a PhI(OAc)₂-mediated intramolecular cross-dehydrogenative coupling (CDC) of various 2-(N-arylamino)aldehydes was developed. The novel methodology requires no need of preactivation of the aldehyde group, is applicable to a large variety of functionalized substrates, and most of all provides a convenient approach to the construction of biologically important acridone derivatives.

Full text of DOI:10.1021/jo5011697

Article
pubs.acs.org/joc
PhI(OAc)2‑Mediated Intramolecular Oxidative Aryl-Aldehyde Csp2−Csp2
Bond Formation: Metal-Free Synthesis of Acridone Derivatives
Zisheng Zheng,† Longyang Dian,† Yucheng Yuan,† Daisy Zhang-Negrerie,† Yunfei Du,*,†,‡
and Kang Zhao*,†
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A metal-free protocol for direct aryl-aldehyde
Csp2−Csp2 bond formation via a PhI(OAc)2-mediated intra-
molecular cross-dehydrogenative coupling (CDC) of various
2-(N-arylamino)aldehydes was developed. The novel method-
ology requires no need of preactivation of the aldehyde group,
is applicable to a large variety of functionalized substrates, and
most of all provides a convenient approach to the construction
of biologically important acridone derivatives.
Scheme 1. Reported Metal-Free Transformations of
Aldehydes to Form Arylated Ketones
INTRODUCTION
■
During the past decade, C−H activation has gained considerable
attention in constructing C−C bonds in organic chemistry.1
One of the recent advancement is the emergence of cross-
dehydrogenative coupling (CDC), which has proven to be an
even more powerful and atom-economic approach to C−C
bond formation.2 Among them, CDC between an aromatic
C−H bonds and aldehyde C−H bonds has offered an economic
approach to produce cyclic3/diaryl ketones4 and other hetero-
cycles, including indoline-2,3-diones,5 xanthones,3c,6 and
acridones.7 For examples, Cheng and co-workers pioneered in
developing a Pd-catalyzed cross-coupling of 2-arylpyridines,
using dioxygen as oxidant, with benzaldehydes to give aromatic
ketones.4a Li and co-workers reported a solvent-free oxidative
coupling of 2-arylpridines with aliphatic aldehydes by TBHP in
the presence of Pd as a catalyst.4b Later on, other transition
metal-catalyzed coupling reactions involving substrates with
different directing groups for the direct C−H bond acylation
were described.4c−f,5,6 However, one drawback persisting
throughout the reported transformations was the requirement
of a transition metal as catalyst,3c,4a−f,5−7 until less than a decade
ago when metal-free strategies started being explored.3a,b,4g
In 2006, Barluenga reported the synthesis of cyclic ketones
by the reaction of direct intramolecular arylation of aldehydes
with IPy2BF4/HBF4 (Scheme 1, eq 1).3a In 2013, Glorius
described the synthesis of fluorenones via quaternary
ammonium salt-promoted intramolecular dehydrogenative
arylation of aldehydes by dual C−H functionalization employing
potassium persulfate (K2S2O8) as oxidant (Scheme 1, eq 2).3b
In the meantime, Antonchick reported a CDC of heterocycles
with aldehydes utilizing hypervalent iodine reagent (PhI-
(OCOCF3)2) as oxidant and trimethylsilyl azide (TMSN3) as
additive (Scheme 1, eq 3).4g
In 2013, Yang reported Sc(OTf)3-catalyzed dehydrogenative
cyclization of 2-(N-methyl-N-phenylamino)benzaldehydes 1 in
forming an active intermediate, N-methyl-aridin-9-ol, which is
then quickly oxidized in situ to afford acridones 2 (Scheme 2).7
However, there are still some limitations with this transition
metal-catalyzed annulation, such as exclusion of moisture, and
heavy metal residue in drug development. It is notable that
metal-free approaches to the constructions of acridone de-
rivatives via intramolecular aryl-aldehyde Csp2−Csp2 formation
Received: May 26, 2014
© XXXX American Chemical Society
A
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(Table 1, entry 3) was shown to be the most effective in
comparison to MeCN, EtOAc, toluene, and CHCl3 etc. (results
are not shown). Protic solvents, e.g., alcohols such as MeOH,
trifluoroethanol (TFE), and 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP), or acids such as AcOH, and trifluoroacetic acid (TFA),
led to no desired product (not shown). Further study indicated
that the reaction performance was improved by increasing the
dosage of the oxidant (Table 1, entries 3−4), though the yield
was still fairly low due to incomplete conversion of the substrate.
The conversion rate was not improved either by employing
Chang’s protocol,13 which might be due to the low thermo-
stability of the hypervalent iodine reagents at the reaction
temperature.12,14 A slightly improved yield was obtained after
lowering the reaction temperature to 100 °C and extending the
reaction time to 24 h (Table 1, entries 5−6). Various additives,
including BF3·Et2O,15a TfOH,15b Ac2O, TEA,15c NaOH,15d
Na2CO3,15e Na2SO4,7 Cu(OTf)2,15f TBAI,15g and 4 Å MS were
tested out, among which Na2SO4 was proven to be the most
effective (Table 1, entry 7; others were not shown), even though
the actual cause of this difference was still unknown.7 A paper
by Caddick et al. in 2010 which discussed the involvement
of a radical initiator to facilitate an aldehyde auto-oxidation as
the method for C−H functionalization,16 inspired us to employ
their strategy to our reaction. The overall yields were indeed
dramatically improved, with either benzoyl peroxide (BPO)
(Table 1, entry 8) or azobis(isobutyronitrile) (AIBN) (Table 1,
entry 9) added as additive, mainly due to the much improved
conversion rate of the starting material to almost completion.
On the other hand, without the oxidant PhI(OAc)2, even with
excess of BPO in the reaction mixture, almost no conversion
of the starting substrate occurred, even after 24 h of heating
(Table 1, entry 10). Further minute improvement of the yield
was observed with a decreased amount of the oxidant as well as
that of the additive (Table 1, entries 8, 11−12). The yield
Scheme 2. Reported and Designed Routes for the Formation
of 2 via CDC Reactions
have never been reported. Herein, we disclose the result of such
an approach, with PhI(OAc)2 as oxidant, which has resulted
in a convenient assemblage of the biologically important
acridone7−11 2 skeletons.
RESULTS AND DISCUSSION
■
We applied Antonchick’s condition4g in our initial study on the
readily available substrate, 2-(methyl(phenyl)amino)benzaldehyde7
1a (Table 1, entry 1), prepared via Ullmann condensation of
benzoic acid and aniline, followed by N-functionalization, LAH-
reduction and subsequent IBX-oxidation; however, no desired
product was detected. Subsequent studies showed that Glorius’
conditions3b only provided a very poor yield of only 5% of the
acridone product 2a. To our delight, by switching the oxidant to
PhI(OAc)2, 2a was furnished in a much improved yield of 43%
(an overall yield of 20% due to a 47% conversion of the starting
material) (Table 1, entry 2). On the other hand, other types of
hypervalent iodine oxidants, such as PhIO (iodosobenzene),
IBX (2-iodoxybenzoic acid), or DMP (Dess−Martin periodinane),
led to either sluggish reactions or no conversion even though
under the same conditions. An attempt to improve the reactive
efficiency by having the reactive iodine(III) species generated
in situ via oxidation of aryl iodide with peracetic acid was
proven to be unsuccessful.12 Among the solvents tested, DMF
a
Table 1. Optimization of Reaction Conditions
b
entry
oxidant (equiv)
solvent
additive (equiv)
temperature (°C)
time (h)
conc. (mol/L)
yield (%)
1
2
3
4
PhI(OCOCF3)2 (2)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
−
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
benzene
DCE
NaN3 (2)
−
−
−
−
rt
2
0.13
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.05
n.d.
80
12
12
12
4
20 (43)
30 (61)
40 (67)
36 (70)
51 (73)
54 (75)
77
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
c
5
140
100
100
100
100
100
100
100
100
100
100
100
6
−
24
24
24
24
24
24
24
24
24
24
24
ce
,
7
8
9
Na2SO4 (0.5)
BPO (1)
AIBN (1)
BPO (3)
BPO (1)
BPO (0.2)
BPO (0.2)
BPO (0.2)
BPO (0.2)
BPO (0.2)
73
10
11
12
5
81
81
d
13
14
15
16
70 (78)
64 (75)
72
e
76
a
b
c
Reaction conditions: 1a (0.5 mmol), oxidant and additive in solvent, under air, unless otherwise stated. Isolated yields. Reaction performed in a
d
e
sealed tube. Under O2 atmosphere. Under N2 atmosphere. rt = room temperature, n.d. = not detected, BPO = benzoyl peroxide. Values in
parentheses indicate yields based on converted starting material.
B
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slightly decreased if the reaction was conducted under oxygen or
nitrogen atmosphere (Table 1, entries 13−14). However, either
more concentrated or diluted the reaction mixture negatively
affected the yield (Table 1, entries 12, 15−16).
With the optimized reaction conditions established (Table 1,
entry 12), the scope of the newly discovered oxidative aryl-
aldehyde Csp2−Csp2 bond formation reaction was investigated
(Table 2). It was found that both electron-withdrawing
acridone product 2p was obtained in a decreased 40% yield
(Table 2, entry 16). Finally, the substitution effect of R2 group,
the benzyl protected diarylamine substrate 1q likewise afforded
the corresponding product (2q) in very good yield. However,
as for the diarylamine substrate 1r, dehydration was occurred to
furnish the acridine product 3r in 61% yield (Scheme 3).18
Scheme 3. Dehydration of 2-Phenylaminobenzaldehyde 1r
to Afford Acridine 3r under the Optimized Conditions
Table 2. Oxidative Dehydrogenative Cyclization of Aldehyde
Substrates 1 to Acridone Derivatives 2
a
Scheme 4. Investigation of the Mechanistic Pathway for the
Dehydrogenative Cyclization
product
no.
time
(h)
yield
b
entry
R
R1
R2
(%)
1
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
24
>72
48
81
2
3′-CF3
3′-Br
4′-F
4′-Cl
4′-Br
4′-OMe
4′-Me
2′-Me
naphthalenyl
H
60(66)
70
3
4
36
58
5
48
60
6
24
80
7
2g
2h
2i
48
52
8
24
75
9
>72
60
60(73)
49
10
11
12
13
14
15
16
17
2j
2k
2l
3-Cl
4-F
24
55
H
24
57
2m
2n
2o
2p
2q
4-OMe
4-Me
3-Cl
4-Me
H
H
36
49
H
24
82
To explore the reaction mechanism, control experiments
were conducted under the optimized conditions (Scheme 4).
The reaction of 2-(benzyl(methyl)amino)benzaldehyde 1t
with PhI(OAc)2/BPO gave no corresponding acid product
4t. Meanwhile, when 2-(methyl(phenyl)amino)benzoic acid 4a
was subjected to the optimized reaction conditions, it did not
generate the cyclized acridone product 2a. These two
experimental facts demonstrated that the cyclization did not
undergo the oxidation, followed by classical Friedel−Crafts
reaction, but they suggested the involvement of an acyl radical.
Additional support rose from the results of running the reaction
in the presence of a radical scavenger TEMPO,3b,c which showed
complete inhibition of the conversion.19
A mechanism entailing a radical pathway has been proposed
for this cyclization reaction (Scheme 5). Initiation occurs at
the heating of BPO with the formation of benzoyloxy radical A,
which may react with iodosobenzene diacetate B to generate
radical C4g,20 along with PhCO2OAc. H-abstraction by radical
C of the −CHO hydrogen then takes place and generates acyl
radical D21 which subsequent breaks a π-bond and gene-
rates the cyclohexadienyl radical E.3b,c,22 Finally, a second
H-abstraction takes place by radical B of the hydrogen con-
nected to the sp3-carbon, through which aromaticity is
regained, leading to the final product 2. Alternatively, single
electron oxidation of radical E by B or radical C gives cation F,
which is deprotonated by the formed acetate anion to give the
cyclized product 2.3b The proposed mechanism depicts the
important roles of the catalytic amount of BPO as a radical
initiator as well as the stoichiometric amount of PhI(OAc)2,23
both of which are in total agreement with our experimental
observations.
4′-Br
4′-Me
H
12
63
24
40
12
74
a
Reaction conditions: 1 (0.5 mmol), PhI(OAc)2 (0.6 mmol) and
BPO (0.1 mmol) in DMF (5.0 mL, c = 0.1 M) at 100 °C, under air.
b
Isolated yields. Values in parentheses indicate yields based on
recovered starting material.
(2b−f) and electron-donating (2g−i) R1 groups were tolerated.
Reactions of substrates 1b and 1i were sluggish and the starting
material was not consumed completely, probably due to the
strong electron-withdrawing effect of the trifluoromethyl
group in the former and the ortho position of the substituent
in the latter which blocked 50% of the bonding spot. The para-
methoxy substituted substrate 1g provided a relatively lower
yield under the identical condition.17 It is worth noting that
2-(methyl(naphthalen-1-yl)- amino)benzaldehyde 1j also af-
forded the cyclized product, albeit with prolonged reaction time
and a lower yield. However, meta-nitro substituted substrate 1s
did not afford any cyclized product (not shown in Table 2).
The substitution effect of R group on the aryl ring with the
formyl group attached was then examined. It was found that
both electron-withdrawing (2k and 2l) and electron-donating
substituents (2m and 2n) were well tolerated, with methyl
group giving the highest yield, methoxy the lowest,17 and the
halogens in between. With electron-withdrawing group
substituted on both aryl rings, substrate 1o successfully cyclized
into the corresponding acridone product 2o in 63% yield.
However, when the electron-withdrawing group was replaced
with the electron-donating group, i.e., methyl group, the desired
C
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the aqueous phase was acidified with 3 N HCl (aq.) to pH = 2. The
precipitate was collected and dried in air overnight, which was used in
the next step without further purification. (Note: N-phenylanthranilic
acid 4r (R = R1 = H) was directly reduced into its corresponding alcohol
6r using LiAlH4, followed by oxidation to afford adehyde 1r over
three steps.)
Scheme 5. Proposed Mechanism for the Dehydrogenative
Cyclization
b. Preparation of Substituted 2-Arylaminobenzoate 5.7
To a solution of substituted N-arylanthranilic acid 4 (15 mmol) in
DMF (30 mL) was added NaH (60% in mineral oil, 45 mmol)
portionwise, with cooling in an ice−water bath. The solution was
stirred for 30 min, followed by the addition of methyl iodide/benzyl
bromide (45 mmol). The resulting mixture was stirred at room
temperature until TLC indicated the total consumption of the acid
substrate 4. The reaction mixture was poured into water (300 mL) and
extracted with EtOAc (2 × 100 mL). The organic layer was separated,
washed with water (150 mL) and brine (150 mL), and then dried
over anhydrous Na2SO4. The solvent was evaporated, and the residue
was purified through column chromatography on silica gel (EtOAc/
Petroleum ether as eluent) to afford desired ester 5, which was used in
the next reduction step.
c. Reduction of Substituted 2-Arylaminobenzoate 5.7
In summary, we have developed an intramolecular cross-
dehydrogenative coupling (CDC) reaction of various 2-(N-
arylamino)aldehydes via PhI(OAc)2-promoted oxidative cou-
pling between an aldehyde sp2-carbon and an aromatic sp2-
carbon. This reaction tolerates various functional groups and
proceeds efficiently to synthesize acridone derivatives with no
additional base required. The reaction serves as a complement
to classical Friedel−Crafts approaches and therefore expands
the area in direct acylation reaction of aldehydes. Moreover,
this is the first report on an oxidative C−C bond formation
promoted by a combination of a radical initiator (BPO) and a
hypervalent iodine(III) reagent.
A solution of N-phenylanthranilic acid 4r (10 mmol) or substituted
2-arylaminobenzoate 5 (10 mmol) in anhydrous THF (40 mL) was
added dropwise at 0 °C to a stirred solution of LiAlH4 (15 mmol) in
THF (10 mL). The resulting mixture was stirred at room temperature
until TLC indicated the total consumption of the substrate 4r or 5.
EtOAc (15 mL) and then water (10 mL) were added cautiously to the
solution. After filtration and removal of the solvent, the residue was
extracted with EtOAc (20 mL), and the organic phase was dried over
anhydrous Na2SO4. The solvent was then evaporated to give the
corresponding alcohol 6 as oil, which was used in the next oxidation
step without further purification.
d. Preparation of the Aldehyde Substrate 1.7
EXPERIMENTAL SECTION
■
I. General Information. All reactions were conducted without
precaution of air, and mixtures were stirred magnetically. H and 13C
1
NMR spectra were recorded on a 600 MHz spectrometer at 25 °C.
Chemical shift values are given in parts per million and referred to
the internal standard, TMS (tetramethylsilane). The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; dd, doublet of doublets; td, triplet of doublets; br s, broad
singlet. The coupling constants (J) are reported in hertz. High-resolution
mass spectrometry (HRMS) was conducted on a Q-TOF micro-
spectrometer. Melting points were determined with a national micro-
melting point apparatus without corrections. Reagents and solvents were
purchased as reagent grade and were used without further purification.
Flash column chromatography was performed over silica gel 200−300
mesh, and the eluent was a mixture of ethyl acetate and petroleum ether.
II. General Synthesis of the Substrate 1. a. Preparation of
Substituted N-Arylanthranilic Acid 4.24
To a suspension of IBX (12.5 mmol) in EtOAc (50 mL) was added
a solution of alcohol 6 (5 mmol) in EtOAc (50 mL). The reaction
mixture was heated at 100 °C for 3 h, cooled and filtered; the filtered
solid was washed with EtOAc (2 × 5 mL). The combined filtrate and
washings were evaporated under reduced pressure and purified by
column chromatography on silica gel, eluting with petroleum ether, to
give the desired aldehyde 1. The aldehyde substrates 1 thus obtained
were characterized as follows:
2-(Methyl(phenyl)amino)benzaldehyde (1a).25 Following the
general procedure, using 2-iodobenzoic acid and aniline as starting
materials, 1a was isolated as a yellow solid. Yield: 0.95 g, 41% (over
four steps), mp 42−43 °C (lit.26 39.5−40.5 °C); 1H NMR (600 MHz,
CDCl3) δ 10.14 (s, 1H), 7.94 (dd, 1H, J = 7.8, 1.8 Hz), 7.62 (td, 1H,
J = 7.8, 1.8 Hz), 7.33 (t, 1H, J = 7.5 Hz), 7.25 (d, 1H, J = 8.4 Hz),
7.21−7.18 (m, 2H), 6.81 (t, 1H, J = 7.5 Hz), 6.72 (d, 2H, J = 7.8 Hz),
3.35 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.3, 152.0, 150.1,
135.8, 132.8, 129.3, 129.0, 127.7, 126.0, 119.1, 115.1, 41.6.
2-(Methyl(3-(trifluoromethyl)phenyl)amino)benzaldehyde (1b).
Following the general procedure, using 2-iodobenzoic acid and
3-(trifluoromethyl)aniline as starting materials, 1b was isolated as a
yellow liquid. Yield: 1.10 g, 33% (over four steps); 1H NMR (600 MHz,
Substituted 2-halobenzoic acid (30 mmol), substituted aniline (36 mmol),
N-methylmorpholine (45 mmol), and cuprous oxide (15 mmol) were
heated to reflux in dioxane (75 mL) under nitrogen for 3 h. The reaction
mixture was allowed to cool, and 200 mL of 1 N NaOH (aq.) was then
added. The resulting mixture was extracted with DCM (100 mL), and
D
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CDCl3) δ 10.12 (s, 1H), 7.99 (d, 1H, J = 7.2 Hz), 7.69 (t, 1H, J =
7.5 Hz), 7.43 (t, 1H, J = 7.5 Hz), 7.28−7.25(m, 2H), 7.04 (d, 1H, J =
7.8 Hz), 6.94 (s, 1H), 6.79 (d, 1H, J = 8.4 Hz), 3.39 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 190.8, 150.7, 149.9, 136.3, 133.0, 131.6 (q, J =
31.5 Hz), 129.7, 129.5, 128.5, 127.2, 126.9, 124.2 (q, J = 271.5 Hz),
117.6, 115.1 (q, J = 3.5 Hz), 110.3 (q, J = 3.5 Hz), 41.4; HRMS (ESI)
calcd for C15H12F3NNaO+ [M + Na+] 302.0763, found 302.0760.
2-((3-Bromophenyl)(methyl)amino)benzaldehyde (1c). Following
the general procedure, using 2-iodobenzoic acid and 3-bromoaniline as
starting materials, 1c was isolated as a yellow liquid. Yield: 1.23 g, 39%
(over four steps); 1H NMR (600 MHz, CDCl3) δ 10.11 (s, 1H), 7.97
(d, 1H, J = 7.8 Hz), 7.67 (t, 1H, J = 7.5 Hz), 7.41 (t, 1H, J = 7.5 Hz),
7.26 (d, 1H, J = 7.8 Hz), 7.03 (t, 1H, J = 8.1 Hz), 6.92 (d, 1H, J = 7.8
Hz), 6.84 (s, 1H), 6.56 (dd, 1H, J = 8.4, 2.1 Hz), 3.34 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 190.9, 151.0, 150.9, 136.2, 133.0, 130.5,
129.3, 128.4, 127.0, 123.4, 121.6, 117.1, 113.2, 41.4; HRMS (ESI)
calcd for C14H12BrNNaO+ [M + Na+] 311.9994, found 311.9998.
2-((4-Fluorophenyl)(methyl)amino)benzaldehyde (1d). Following
the general procedure, using 2-iodobenzoic acid and 4-fluoroaniline as
starting materials, 1d was isolated as a yellow liquid. Yield: 1.01 g, 40%
(over four steps); 1H NMR (600 MHz, CDCl3) δ 10.16 (s, 1H), 7.92
(d, 1H, J = 7.8 Hz), 7.62 (t, 1H, J = 7.8 Hz), 7.31 (t, 1H, J = 7.5 Hz),
7.23 (d, 1H, J = 7.8 Hz), 6.92 (t, 2H, J = 9.3 Hz), 6.72−6.70 (m, 2H),
3.34 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.2, 156.9 (d, J =
238.5 Hz), 152.3 146.8, 135.8, 132.1, 129.2, 126.8, 125.7, 117.2 (d, J =
7.5 Hz), 115.8 (d, J = 22.5 Hz), 42.2; HRMS (ESI) calcd for
C14H12FNNaO+ [M + Na+] 252.0795, found 252.0796.
2.21 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 190.7, 153.5, 150.8,
134.7, 133.2, 132.0, 129.9, 127.5, 127.4, 125.1, 124.6, 121.6, 119.9, 43.1,
18.5; HRMS (ESI) calcd for C15H15NNaO+ [M + Na+] 248.1046,
found 248.1050.
2-(Methyl(naphthalen-1-yl)amino)benzaldehyde (1j). Following
the general procedure, using 2-iodobenzoic acid and naphthalen-1-
amine as starting materials, 1j was isolated as a yellow solid. Yield:
1
1.05 g, 36% (over four steps), mp 84−85 °C; H NMR (600 MHz,
CDCl3) δ 10.00 (s, 1H), 8.19 (d, 1H, J = 7.8 Hz), 7.85 (d, 1H, J = 7.2
Hz), 7.76 (d, 1H, J = 6.6 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.52−7.48 (m,
3H), 7.31 (t, 1H, J = 7.8 Hz), 7.15 (d, 1H, J = 8.4 Hz), 7.06 (t, 1H, J =
7.5 Hz), 6.99 (d, 1H, J = 7.2 Hz), 3.37 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 190.9, 154.0, 150.0, 135.3, 134.8, 129.6, 129.0, 128.9, 127.6,
126.8, 126.5, 126.1, 125.7, 123.1, 122.2, 121.9, 119.7, 43.4; HRMS
(ESI) calcd for C18H15NNaO+ [M + Na+] 284.1046, found 284.1047.
4-Chloro-2-(methyl(phenyl)amino)benzaldehyde (1k).7 Following
the general procedure, using 2-bromo-4-chlorobenzoic acid and aniline
as starting materials, 1k was isolated as a yellow liquid. Yield: 1.03 g,
38% (over four steps); 1H NMR (600 MHz, CDCl3) δ 10.05 (s, 1H),
7.84 (d, 1H, J = 8.4 Hz), 7.24−7.21 (m, 4H), 6.88 (t, 1H, J = 7.2 Hz),
6.80 (d, 2H, J = 7.8 Hz), 3.36 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
190.0, 152.9, 149.9, 141.6, 130.4, 129.5, 126.9, 125.9, 120.4, 116.5, 41.8
(one carbon peak was missing due to overlapping).
2-(Methyl(naphthalen-1-yl)amino)benzaldehyde (1l).7 Following
the general procedure, using 2-bromo-5-fluorobenzoic acid and aniline
as starting materials, 1l was isolated as a orange solid. Yield: 0.99 g,
39% (over four steps), mp 55−56 °C; 1H NMR (600 MHz, CDCl3) δ
10.08 (d, 1H, J = 3.0 Hz), 7.61 (dd, 1H, J = 7.8, 3.3 Hz), 7.34 (td, 1H,
J = 8.1, 3.0 Hz), 7.25 (dd, 1H, J = 8.7, 4.5 Hz), 7.21 (t, 2H, J = 8.1
Hz), 6.82 (t, 1H, J = 7.2 Hz), 6.68 (d, 2H, J = 8.4 Hz), 3.34 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 190.3, 160.6 (d, J = 247.5 Hz), 149.9,
148.1 (d, J = 3.0 Hz), 134.7 (d, J = 7.5 Hz), 130.3 (d, J = 7.5 Hz),
129.4, 123.2 (d, J = 22.5 Hz), 119.1, 114.7, 114.7 (d, J = 22.5 Hz),
41.6.
2-((4-Chlorophenyl)(methyl)amino)benzaldehyde (1e). Following
the general procedure, using 2-iodobenzoic acid and 4-chloroaniline as
starting materials, 1e was isolated as a yellow solid. Yield: 1.04 g, 44%
1
(over four steps), mp 58−59 °C; H NMR (600 MHz, CDCl3) δ
10.12 (s, 1H), 7.95 (dd, 1H, J = 7.8, 1.8 Hz), 7.62 (td, 1H, J = 7.5, 2.1
Hz), 7.37 (t, 1H, J = 7.5 Hz), 7.25 (d, 1H, J = 7.8 Hz), 7.14 (d, 2H, J =
9.0 Hz), 6.63 (d, 2H, J = 9.0 Hz), 3.34 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 191.0, 151.4, 148.6, 136.0, 132.7, 129.3, 129.1, 127.9,
126.5, 124.0, 116.1, 41.7; HRMS (ESI) calcd for C14H1235ClNNaO+
[M + Na+] 268.0500, found 268.0499.
5-Methoxy-2-(methyl(phenyl)amino)benzaldehyde (1m).7 Fol-
lowing the general procedure, using 2-bromo-5-methoxybenzoic acid
and aniline as starting materials, 1m was isolated as a orange
2-((4-Bromophenyl)(methyl)amino)benzaldehyde (1f).7 Follow-
ing the general procedure, using 2-iodobenzoic acid and 4-bromoani-
line as starting materials, 1f was isolated as a light yellow solid. Yield:
solid. Yield: 1.06 g, 40% (over four steps), mp 58−59 °C; H NMR
1
(600 MHz, CDCl3) δ 10.10 (s, 1H), 7.43 (d, 1H, J = 3.0 Hz), 7.24−
7.16 (m, 4H), 6.78 (t, 1H, J = 7.2 Hz), 6.65 (d, 2H, J = 8.4 Hz), 3.87
(s, 3H), 3.31 (s, 3H).13C NMR (150 MHz, CDCl3) δ 191.5, 158.0,
150.2, 145.4, 134.2, 130.1, 129.2, 123.9, 118.3 114.0, 110.5, 55.8, 41.5.
5-Methyl-2-(methyl(phenyl)amino)benzaldehyde (1n).7 Follow-
ing the general procedure, using 2-bromo-5-methylbenzoic acid and
aniline as starting materials, 1n was isolated as a yellow liquid. Yield:
1
1.29 g, 42% (over four steps), mp 85−86 °C; H NMR (600 MHz,
CDCl3) δ 10.11 (s, 1H), 7.95 (dd, 1H, J = 7.5, 0.9 Hz), 7.65 (t, 1H, J =
7.5 Hz), 7.38 (t, 1H, J = 7.5 Hz), 7.28 (d, 2H, J = 9.0 Hz), 7.25 (d, 1H,
J = 8.4 Hz), 6.58 (d, 2H, J = 8.4 Hz), 3.34 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 191.0, 151.3, 149.0, 136.1, 132.8, 132.0, 129.3, 128.0,
126.6, 116.4, 111.2, 41.6.
1
1.02 g, 43% (over four steps); H NMR (600 MHz, CDCl3) δ 10.12
(s, 1H), 7.76 (s, 1H), 7.45 (d, 1H, J = 7.8 Hz), 7.19 (t, 2H, J = 7.8
Hz), 7.15 (d, 1H, J = 8.4 Hz), 6.79 (t, 1H, J = 7.5 Hz), 6.69 (d, 2H, J =
8.4 Hz), 3.33 (s, 3H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
191.7, 150.1, 149.6, 136.9, 136.3, 132.7, 129.2, 128.9, 128.1, 118.7,
114.6, 41.5, 21.0.
2-((4-Methoxyphenyl)(methyl)amino)benzaldehyde (1g). Follow-
ing the general procedure, using 2-iodobenzoic acid and 4-
methoxyaniline as starting materials, 1g was isolated as a red liquid.
1
Yield: 1.11 g, 45% (over four steps); H NMR (600 MHz, CDCl3)
δ 10.17 (s, 1H), 7.86 (dd, 1H, J = 7.8, 1.2 Hz), 7.57 (td, 1H, J = 7.8,
1.5 Hz), 7.22 (t, 1H, J = 7.2 Hz), 7.20 (d, 1H, J = 8.4 Hz), 6.79 (s,
4H), 3.76 (s, 3H), 3.33 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
191.4, 153.9, 152.9, 145.0, 135.4, 131.1, 129.0, 125.2, 124.4, 118.9,
2-((4-Bromophenyl)(methyl)amino)-4-chlorobenzaldehyde (1o).
Following the general procedure, using 2-bromo-4-chlorobenzoic
acid and 4-bromoaniline as starting materials, 1o was isolated as
a light yellow oil. Yield: 0.91 g, 28% (over four steps); 1H NMR
(600 MHz, CDCl3) δ 10.03 (s, 1H), 7.86 (d, 1H, J = 8.4 Hz), 7.31 (d,
3H, J = 8.4 Hz), 7.23 (s, 1H), 6.63 (d, 2H, J = 9.0 Hz), 3.33 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 189.4, 152.2, 148.7, 141.7, 132.3,
130.7, 130.7, 127.4, 126.6, 117.5, 112.5, 41.7; HRMS (ESI) calcd for
C14H1179Br35ClNNaO+ [M + Na+] 345.9605, found 345.9600.
5-Methyl-2-(methyl(p-tolyl)amino)benzaldehyde (1p). Following
the general procedure, using 2-bromo-5-methylbenzaldehyde and
4-methylaniline as starting materials, 1p was isolated as a light yellow
oil. Yield: 0.72 g, 30% (over four steps); 1H NMR (600 MHz, CDCl3)
δ 10.12 (s, 1H), 7.73 (s, 1H), 7.41 (d, 1H, J = 7.8 Hz), 7.13−7.11 (m,
1H), 6.99 (d, 2H, J = 6.6 Hz), 6.63−6.62 (m, 2H), 3.30 (s, 3H), 2.39
(s, 3H), 2.24 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.6, 150.1,
148.3, 136.6, 135.7, 132.4, 129.8, 128.9, 128.3, 127.4, 115.4, 41.7, 20.9,
20.4; HRMS (ESI) calcd for C16H17NNaO+ [M + Na+] 262.1202,
found 262.1205.
+
114.8, 55.6, 42.5; HRMS (ESI) calcd for C15H15NNaO2 [M + Na+]
264.0995, found 264.0999.
2-(Methyl(p-tolyl)amino)benzaldehyde (1h).7 Following the gen-
eral procedure, using 2-iodobenzoic acid and 4-methylaniline as starting
materials, 1h was isolated as a yellow solid. Yield: 1.01 g, 42% (over
1
four steps), mp 39−40 °C; H NMR (600 MHz, CDCl3) δ 10.15 (s,
1H), 7.91 (d, 1H, J = 7.8 Hz), 7.60 (t, 1H, J = 8.4 Hz), 7.28 (t, 1H, J =
7.5 Hz), 7.23 (d, 1H, J = 7.8 Hz), 7.02 (d, 2H, J = 8.4 Hz), 6.68 (d, 2H,
J = 8.4 Hz), 3.34 (s, 3H), 2.25 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 191.5, 152.5, 148.2, 135.7, 132.2, 129.9, 129.0, 128.9, 126.8, 125.4,
116.1, 41.9, 20.5.
2-(Methyl(o-tolyl)amino)benzaldehyde (1i). Following the general
procedure, using 2-iodobenzoic acid and 2-methylaniline as starting
materials, 1i was isolated as a light yellow solid. Yield: 1.00 g, 39%
(over four steps), mp 87−88 °C; 1H NMR (600 MHz,CDCl3) δ 10.02
(s, 1H), 7.75 (s, 1H), 7.46 (s, 1H), 7.20−6.97 (6H), 3.25 (s, 3H),
E
dx.doi.org/10.1021/jo5011697 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
2-(Benzyl(phenyl)amino)benzaldehyde (1q).27 Following the
general procedure, using 2-iodobenzoic acid and aniline as starting
materials, 1q was isolated as a light yellow solid. Yield: 1.23 g, 44%
IV. Preparation of the Acridone Derivatives 2 and 3.
1
(over four steps), mp 107−108 °C; H NMR (600 MHz, CDCl3) δ
10.13 (s, 1H), 7.92 (d, 1H, J = 8.4 Hz), 7.61 (t, 1H, J = 8.4 Hz), 7.36−
7.28 (m, 6H), 7.24−7.22 (m, 1H), 7.16 (t, 2H, J = 7.8 Hz), 6.80
(t, 1H, J = 7.5 Hz), 6.74 (d, 2H, J = 8.4 Hz), 5.00 (s, 2H); 13C NMR
(150 MHz, CDCl3) δ 191.1, 150.6, 150.0, 138.1, 135.9, 132.9, 129.4,
129.4, 128.7, 128.4, 127.3, 127.2, 126.2, 119.4, 115.7, 57.7.
To a solution of aldehyde 1 (0.5 mmol) in DMF (5 mL) was added
PIDA (0.6 mmol) and BPO (0.2 mmol). The resulting mixture
was heated to 100 °C with vigorous stirring and maintained at the
same temperature until TLC indicated the total consumption of the
aldehyde substrate 1. The reaction mixture was cooled to room
temperature, diluted with water (25 mL) and then extracted with
EtOAc (2 × 20 mL). The organic layers were combined, saturated
with brine (20 mL), and dried over anhydrous Na2SO4. The solvent
was then evaporated under reduced pressure, and the residue was
purified by column chromatography on silica gel, eluting with EtOAc
and petroleum ether, to give the product 2. The acridone derivatives 2
thus obtained were characterized as follows:
2-(Phenylamino)benzaldehyde (1r).28 Following the general pro-
cedure, using 2-iodobenzoic acid and aniline as starting materials, 1r
was isolated as a yellow solid. Yield: 0.89 g, 56% (over three steps),
1
mp 71−72 °C; H NMR (600 MHz, CDCl3) δ 10.02 (s, 1H), 9.87
(s, 1H), 7.53 (d, 1H, J = 7.8 Hz), 7.36−7.32 (m, 3H), 7.26 (d, 2H, J =
7.8 Hz), 7.22 (d, 1H, J = 8.4 Hz), 7.13 (t, 1H, J = 7.5 Hz), 6.80 (t, 1H,
J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) δ 194.3, 147.8, 139.7,
136.7, 135.6, 129.5, 124.4, 123.2, 119.4, 117.2, 112.9.
2-(Methyl(3-nitrophenyl)amino)benzaldehyde (1s). Following the
general procedure, using 2-iodobenzoic acid and 3-nitroaniline as
starting materials, 1s was isolated as a orange solid. Yield: 1.07 g, 33%
10-Methylacridin-9(10H)-one (2a).7 Following the general pro-
cedure, 2a was isolated as a light yellow solid. Yield: 85 mg, 81%, mp
203−204 °C (lit.7 202−203 °C); 1H NMR (600 MHz, CDCl3) δ 8.56
(dd, 2H, J = 7.8, 1.2 Hz), 7.73−7.71 (m, 2H), 7.52 (d, 2H, J = 9.0 Hz),
7.29 (t, 2H, J = 7.5 Hz), 3.89 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
178.0, 142.4, 133.7, 127.6, 122.4, 121.1, 114.7, 33.5.
1
(over four steps), mp 83−84 °C; H NMR (600 MHz, CDCl3) δ
10.10 (s, 1H), 8.00 (d, 1H, J = 7.8 Hz), 7.73 (t, 1H, J = 7.8 Hz), 7.59
(d, 1H, J = 7.8 Hz), 7.52 (s, 1H), 7.49 (t, 1H, J = 7.5 Hz), 7.32−7.28
(m, 2H), 6.91 (dd, 1H, J = 8.4, 2.4 Hz), 3.44 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 190.4, 150.4, 149.7, 149.3, 136.4, 133.0, 130.1,
129.8, 128.8, 127.7, 119.8, 113.0, 107.8, 41.4; HRMS (ESI) calcd for
10-Methyl-3-(trifluoromethyl)acridin-9(10H)-one (2b).10h Follow-
ing the general procedure, 2b was isolated as a light yellow solid. Yield:
83 mg, 60%, mp 195−196 °C (lit.10h 169−170 °C); 1H NMR
(600 MHz, d6-DMSO) δ 8.49 (d, 1H, J = 8.4 Hz), 8.33 (dd, 1H, J =
7.8, 1.2 Hz), 8.13 (s, 1H), 7.91−7.85 (m, 2H), 7.59 (d, 1H, J = 7.8
Hz), 7.40−7.37 (m, 1H), 3.99 (s, 3H); 13C NMR (150 MHz,
d6-DMSO) δ 176.1, 142.5, 142.0, 134.6, 133.3 (q, J = 31.5 Hz), 128.2,
126.5, 123.9 (q, J = 271.5 Hz), 123.4, 121.9, 121.9, 116.6 (q, J =
3.0 Hz), 116.5, 113.8 (q, J = 4.0 Hz), 34.1.
+
C14H12N2NaO3 [M + Na+] 279.0740, found 279.0739.
e. Preparation of the Aldehyde Substrate 1t.29
To a solution of 2-fluorobenzaldehyde (1.24 g, 10 mmol) and
potassium carbonate (1.59 g, 11.5 mmol) in DMF (10 mL) was added
N-methyl-N-benzylamine (1.39 g, 11.5 mmol). The resulting reaction
mixture was heated under reflux for 4 h. The reaction mixture was
subsequently allowed to cool to room temperature, diluted with water
(50 mL), and extracted with EtOAc (2 × 40 mL). The combined
organic layers were washed with brine (50 mL) and subsequently dried
(Na2SO4). The solvent was removed under reduced pressure, and the
residue was purified by column chromatography on silica, eluting with
petroleum ether, to afford the product 1t.
3-Bromo-10-methylacridin-9(10H)-one (2c).10h Following the
general procedure, 2c was isolated as a light brown solid. Yield:
101 mg, 70%, mp 177−178 °C (lit.10h 178−180 °C); H NMR (600
1
MHz, CDCl3) δ 8.42 (d, 1H, J = 7.8 Hz), 8.29 (d, 1H, J = 7.8 Hz),
7.65 (t, 1H, J = 7.5 Hz), 7.55 (s, 1H), 7.38 (d, 1H, J = 8.4 Hz), 7.30
(d, 1H, J = 7.8 Hz), 7.24 (t, 1H, J = 7.2 Hz), 3.73 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 177.4, 143.0, 142.2, 134.0, 129.2, 128.9, 127.5,
124.6, 122.4, 121.7, 121.0, 117.7, 114.9, 33.7.
2-Fluoro-10-methylacridin-9(10H)-one (2d/l).7 Following the
general procedure, 2d was isolated as a light yellow solid. Yield:
66 mg, 58%. 2l was isolated as a light yellow solid. Yield: 65 mg, 57%,
2-(Benzyl(methyl)amino)benzaldehyde (1t).29 Isolated as a light
yellow liquid. Yield: 1.58 g, 70%; 1H NMR (600 MHz, CDCl3) δ 10.39
(s, 1H), 7.82 (dd, 1H, J = 7.5, 1.5 Hz), 7.48 (td, 1H, J = 8.4, 1.5 Hz),
7.32 (t, 2H, J = 7.5 Hz), 7.28−7.25 (m, 3H), 7.10 (d, 1H, J = 8.4 Hz),
7.06 (t, 1H, J = 7.5 Hz), 4.33 (s, 2H), 2,81 (s, 3H).
7
1
mp 185−186 °C (lit. 179−180 °C); H NMR (600 MHz, CDCl3) δ
8.40 (d, 1H, J = 7.8 Hz), 8.04 (dd, 1H, J = 8.4, 2.4 Hz), 7.63 (t, 1H, J =
7.5 Hz), 7.38−7.31 (m, 3H), 7.20 (t, 1H, J = 7.2 Hz), 3.75 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 177.1, 157.4 (d, J = 241.5 Hz), 142.1,
138.9, 133.9, 127.4, 123.1 (d, J = 6.0 Hz), 122.0 (d, J = 24.0 Hz),
121.5, 121.3, 116.9 (d, J = 7.5 Hz), 114.7, 111.7 (d, J = 21.0 Hz), 33.8.
2-Chloro-10-methylacridin-9(10H)-one (2e).7 Following the gen-
eral procedure, 2e was isolated as a light brown solid. Yield: 73 mg,
60%, mp 176−177 °C (lit.7 175−176 °C); 1H NMR (600 MHz,
CDCl3) δ 8.46 (d, 1H, J = 7.8 Hz), 8.41 (d, 1H, J = 2.4 Hz), 7.69
(t, 1H, J = 7.8 Hz), 7.55 (dd, 1H, J = 9.0, 2.4 Hz), 7.45 (d, 1H, J =
9.0 Hz), 7.38 (d, 1H, J = 9.0 Hz), 7.26 (t, 1H, J = 7.2 Hz), 3.81 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 176.9, 142.3, 140.8, 134.1,
133.7, 127.7, 127.1, 126.7, 123.1, 122.2, 121.6, 116.6, 114.9, 33.8.
2-Bromo-10-methylacridin-9(10H)-one (2f).7 Following the gen-
eral procedure, 2f was isolated as a light brown solid. Yield: 115 mg,
80%, mp 199−200 °C (lit.7 194−195 °C); 1H NMR (600 MHz,
CDCl3) δ 8.49 (d, 1H, J = 1.8 Hz), 8.39 (d, 1H, J = 7.8 Hz), 7.65
(t, 1H, J = 7.5 Hz), 7.61 (dd, 1H, J = 9.0, 1.8 Hz), 7.39 (d, 1H, J = 8.4
Hz), 7.25−7.20 (m, 2H), 3.74 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 176.7, 142.1, 141.0, 136.3, 134.1, 129.7, 127.5, 123.4, 122.2, 121.6,
116.8, 114.9, 114.5, 33.7.
III. Preparation of the Acid Substrate 4a.30
To a solution of methyl 2-(methyl(phenyl)amino)benzoate (0.72 g,
3 mmol) in MeOH/H2O (15 mL, v:v = 2:1) was added KOH (0.34 g,
6 mmol). The resulting mixture was heated under reflux until TLC
indicated the total consumption of substrate. The reaction mixture was
subsequently allowed to cool to room temperature. The solvent was
removed under vacuum. The residue was diluted with water (10 mL),
and acidified with 3 N HCl (aq.) to pH = 2. The precipitate was
collected and dried under reduced pressure to afford the desired
acid 4a.
2-(Methyl(phenyl)amino)benzoic acid (4a).30 Isolated as a yellow
solid. Yield: 0.63 g, 93%, mp 101−102 °C (lit.30 103−104 °C);
1H NMR (600 MHz, CDCl3) δ 14.22 (s, 1H), 8.36 (dd, 1H, J = 8.4,
1.2 Hz), 7.58 (td, 1H, J = 8.1, 1.2 Hz), 7.45 (t, 1H, J = 7.5 Hz), 7.29
(t, 2H, J = 7.8 Hz), 7.12 (d, 1H, J = 7.8 Hz), 7.06 (t, 1H, J = 7.2 Hz),
6.92 (d, 2H, J = 8.4 Hz), 3.22 (s, 3H).
2-Methoxy-10-methylacridin-9(10H)-one (2g/m).7 Following the
general procedure, 2g was isolated as a light yellow solid. Yield: 62 mg,
F
dx.doi.org/10.1021/jo5011697 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
52%. 2m was isolated as a light yellow solid. Yield: 59 mg, 49%, mp
141−142 °C (lit.7 141−142 °C); 1H NMR (600 MHz, CDCl3) δ 8.54
(d, 1H, J = 7.8 Hz), 7.91 (s, 1H), 7.66 (t, 1H, J = 7.5 Hz), 7.43 (t, 2H, J =
9.0 Hz), 7.31 (d, 1H, J = 9.0 Hz), 7.24 (t, 1H, J = 7.5 Hz), 3.92 (s, 3H),
3.82 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 177.4, 154.3, 142.0, 137.3,
133.5, 127.6, 124.4, 123.0, 121.6, 120.9, 116.5, 114.6, 106.5, 55.8, 33.7.
2,10-Dimethylacridin-9(10H)-one (2h/n).7 Following the general
procedure, 2h was isolated as a light yellow solid. Yield: 79 mg, 71%.
2n was isolated as a light yellow solid. Yield: 91 mg, 82%, mp 151−
152 °C (lit. 150−151 °C); H NMR (600 MHz, CDCl3) δ 8.52 (d,
1H, J = 7.8 Hz), 8.29 (s, 1H), 7.65 (t, 1H, J = 7.5 Hz), 7.47 (d, 1H, J =
7.8 Hz), 7.42 (d, 1H, J = 9.0 Hz), 7.34 (d, 1H, J = 9.0 Hz), 7.23 (t, 1H,
J = 7.2 Hz), 3.78 (s, 3H), 2.43 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 178.0, 142.3, 140.5, 135.2, 133.6, 130.8, 127.6, 126.9, 122.2, 122.2,
120.9, 114.8, 114.7, 33.5, 20.6.
ASSOCIATED CONTENT
* Supporting Information
Spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
*E-mail: duyunfeier@tju.edu.cn.
*E-mail: kangzhao@tju.edu.cn.
Notes
■
7
1
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
4,10-Dimethylacridin-9(10H)-one (2i).7 Following the general
procedure, 2i was isolated as a light brown solid. Yield: 67 mg, 60%,
mp 85−86 °C (lit.7 86−87 °C); 1H NMR (600 MHz, CDCl3) δ 8.40
(dd, 1H, J = 7.8, 1.2 Hz), 7.32 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J =
8.4 Hz), 7.48 (d, 1H, J = 7.2 Hz), 7.42 (d, 1H, J = 8.4 Hz), 7.23 (t, 1H,
J = 7.2 Hz), 7.18 (t, 1H, J = 7.2 Hz), 3.85 (s, 3H), 2.64 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 179.1, 146.4, 145.5, 137.4, 133.7,
127.0, 126.4, 125.1, 125.1, 123.0, 122.1, 121.4, 116.5, 42.8, 23.1.
12-Methylbenzo[c]acridin-7(12H)-one (2j).7 Following the general
procedure, 2j was isolated as a light brown solid. Yield: 63 mg, 49%,
■
We acknowledge the National Natural Science Foundation of
China (#21072148), Foundation (B) for Peiyang Scholar −
Young Core Faculty of Tianjin University (2013XR-0144), the
Innovation Foundation of Tianjin University (2013XJ-0005)
and the National Basic Research Project (2014CB932200) for
financial support.
REFERENCES
■
7
1
(1) For recent reviews on C−H activation, see: (a) Bras, J. L.;
Muzart, J. Chem. Rev. 2011, 111, 1170. (b) Wencel-Delord, J.; Droge,
mp 173−174 °C (lit. 141−142 °C); H NMR (600 MHz, CDCl3) δ
8.49 (d, 1H, J = 7.8 Hz), 8.40 (d, 1H, J = 8.4 Hz), 8.21 (d, 1H, J =
8.4 Hz), 7.86 (d, 1H, J = 7.8 Hz), 7.69 (t, 1H, J = 7.5 Hz), 7.60−7.55
(m, 3H), 7.49 (t, 1H, J = 7.5 Hz), 7.30 (t, 1H, J = 7.5 Hz), 4.07
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 177.7, 145.5, 144.0, 137.3,
133.3, 128.8, 128.2, 127.3, 126.8, 124.8, 124.6, 123.9, 123.2, 122.5,
122.4, 121.4, 117.3, 44.8.
̈
T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (c) Sun, C.-L.;
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F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (f) Li, B.-J.; Shi, Z.-J. Chem.
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Chem. Res. 2013, 46, 412. (i) Lin, B.; Dixneuf, P. H. Chem. Soc. Rev.
2013, 42, 5744.
(2) For recent reviews on cross-dehydrogenative coupling (CDC)
reactions, see: (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
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Angew. Chem., Int. Ed. 2011, 50, 7479.
3-Chloro-10-methylacridin-9(10H)-one (2k).7 Following the gen-
eral procedure, 2k was isolated as a light yellow solid. Yield: 67 mg,
55%, mp 175−176 °C (lit.7 155−156 °C); 1H NMR (600 MHz,
CDCl3) δ 8.48 (d, 1H, J = 7.2 Hz), 8.43 (d, 1H, J = 8.4 Hz), 7.69 (t,
1H, J = 7.8 Hz), 7.45 (d, 1H, J = 9.6 Hz), 7.28 (t, 1H, J = 6.6 Hz), 7.20
(d, 1H, J = 9.0 Hz), 3.80 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
177.3, 143.1, 142.4, 140.2, 134.1, 129.4, 127.7, 122.5, 121.9, 121.8,
120.8, 114.9, 114.7, 33.8.
2-Bromo-6-chloro-10-methylacridin-9(10H)-one (2o). Following
the general procedure, 2o was isolated as a light yellow solid. Yield:
1
́
(3) (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew.
102 mg, 63%, mp >250 °C; H NMR (600 MHz, CDCl3) δ 8.61 (d,
Chem., Int. Ed. 2006, 45, 3140. (b) Shi, Z.; Glorius, F. Chem. Sci. 2013,
4, 829. (c) Wertz, S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928.
(4) (a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett.
1H, J = 2.4 Hz), 8.44 (d, 1H, J = 8.4 Hz), 7.69 (dd, 1H, J = 9.0,
2.4 Hz), 7.50 (s, 1H), 7.38 (d, 1H, J = 9.6 Hz), 7.26−7.24 (m, 1H),
3.84 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 176.1, 143.1, 141.3,
140.7, 136.8, 130.2, 129.5, 123.9, 122.4, 120.9, 116.9, 115.2, 114.8,
34.0; HRMS (ESI) calcd for C14H9BrClNNaO+ [M + Na+] 343.9448,
found 343.9447.
́
2009, 11, 3120. (b) Basle, O.; Bidange, J.; Shuai, Q.; Li, C.-J. Adv.
Synth. Catal. 2010, 352, 1145. (c) Chan, C.-W.; Zhou, Z.; Chan, A. S.
C.; Yu, W.-Y. Org. Lett. 2010, 12, 3926. (d) Li, C.; Wang, L.; Li, P.;
Zhou, W. Chem.Eur. J. 2011, 17, 10208. (e) Wu, Y.; Li, B.; Mao, F.;
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2082.
2,7,10-Trimethylacridin-9(10H)-one (2p). Following the general
procedure, 2p was isolated as a light yellow solid. Yield: 47 mg, 40%,
1
mp 183−185 °C; H NMR (600 MHz, CDCl3) δ 8.34 (s, 2H), 7.51
(d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4 Hz), 3.84 (s, 3H), 2.46
(s, 6H); 13C NMR (150 MHz, CDCl3) δ 177.9, 140.6, 135.0, 130.5,
127.1, 122.3, 114.6, 33.5, 20.6; HRMS (ESI) calcd for C16H15NNaO+
[M + Na+] 260.1046, found 260.1042.
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see: (a) Smee, D. F.; Bailey, K. W.; Sidwell, R. W. Antiviral Res. 2002,
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10-Benzylacridin-9(10H)-one (2q).10h Following the general pro-
cedure, 2q was isolated as a light yellow solid. Yield: 105 mg, 74%,
mp 184−185 °C (lit.10h 178−181 °C); H NMR (600 MHz, CDCl3)
1
δ 8.58 (d, 2H, J = 7.8 Hz), 7.60 (t, 2H, J = 7.5 Hz), 7.36−7.26 (m,
7H), 7.19 (d, 2H, J = 7.2 Hz), 5.57 (s, 2H); 13C NMR (150 MHz,
CDCl3) δ 178.3, 142.5, 135.5, 134.1, 129.3, 127.8, 127.7, 125.7, 122.5,
121.7, 115.3, 50.8.
Acridine (3r).9m Following the general procedure, 3r was isolated as
a light yellow solid. Yield: 59 mg, 61%, mp 105−106 °C (lit.9m 105−
1
108 °C); H NMR (600 MHz, CDCl3) δ 8.74 (d, 1H, J = 5.4 Hz),
8.24 (d, 2H, J = 8.4 Hz), 7.99−7.97 (m, 2H), 7.78 (t, 2H, J = 7.5 Hz),
7.52 (t, 2H, J = 6.9 Hz); 13C NMR (150 MHz, CDCl3) δ 149.0, 136.2,
130.4, 129.4, 128.3, 126.6, 125.7; 13C NMR (150 MHz, CDCl3) δ
149.0, 136.2, 130.4, 129.4, 128.3, 126.6, 125.7.
G
dx.doi.org/10.1021/jo5011697 | J. Org. Chem. XXXX, XXX, XXX−XXX

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dx.doi.org/10.1021/jo5011697 | J. Org. Chem. XXXX, XXX, XXX−XXX