Auto-tandem catalysis: Synthesis of acridines by Pd-catalyzed C=C bond formation and C(sp2)-N cross-coupling

Article abstract of DOI:10.1002/ejoc.201201070

A facile palladium-catalyzed synthesis of acridines has been realized by consecutive C=C double bond formation and C-N cross-coupling. A variety of functionalized acridines can be accessed from easily available o-dihalobenzenes and N-tosylhydrazones in a single operation. This one-pot protocol has a wide scope with respect to both coupling partners, and provides an efficient route to functionalized acridine derivatives, which are generally difficult to synthesize by previously known methods.

Full text of DOI:10.1002/ejoc.201201070

FULL PAPER
DOI: 10.1002/ejoc.201201070
Auto-Tandem Catalysis: Synthesis of Acridines by Pd-Catalyzed C=C Bond
Formation and C(sp2)–N Cross-Coupling
Zhongxing Huang,[a] Yang Yang,[a] Qing Xiao,[a] Yan Zhang,[a] and Jianbo Wang*[a]
Keywords: Nitrogen heterocycles / Homogeneous catalysis / Auto-tandem catalysis / Cyclization / Cross-coupling /
Palladium
A facile palladium-catalyzed synthesis of acridines has been
realized by consecutive C=C double bond formation and C–
N cross-coupling. A variety of functionalized acridines can
be accessed from easily available o-dihalobenzenes and N-
tosylhydrazones in a single operation. This one-pot protocol
has a wide scope with respect to both coupling partners, and
provides an efficient route to functionalized acridine deriva-
tives, which are generally difficult to synthesize by pre-
viously known methods.
ily available, this type of Pd-catalyzed cross-coupling is a
useful method for olefin synthesis. The same group has also
developed a quinoline synthesis based on Pd-catalyzed tan-
dem transformations with N-tosylhydrazones.[2a] As part of
our continued interest in this area, we are aiming to com-
bine this transformation with other palladium-catalyzed re-
actions under the same catalytic conditions to construct
complex molecules of wide interest. In this context, we have
focused on the synthesis of acridine derivatives. The unique
planar heteropolycyclic structure of acridine has made it a
frequently-used core structural motif in fluorescent dyes
and probes.[5,6a,6b] Also, acridine derivatives have been
widely used as antibacterial, antimalarial, and anticancer
agents in the medical industry.[6]
Introduction
Transition metal-catalyzed transformations are now well-
established as indispensable tools in the research laboratory,
as well as in large-scale industrial production. In spite of
the great success achieved so far in this area, the pursuit of
efficiency in transition metal catalysis to allow the rapid
construction of complex molecules remains a limitless chal-
lenge for the organic chemistry community. An obvious ap-
proach to increase catalytic efficiency would be to use a
single transition metal to catalyze more than one chemical
transformation in the same reaction system, a process called
auto-tandem catalysis.[1] This is an appealing concept, but
the challenge in developing such transformations lies in the
difficulty in optimizing the reaction conditions for each of
the catalytic steps. Recently, a series of auto-tandem cata-
lytic reactions using palladium catalysts have been reported
in the literature, which demonstrates the potential for fur-
ther developments.[2]
However, previous synthetic routes to obtain the acridine
scaffold always involve multi-step reaction sequences or
harsh conditions.[7] The Bernthsen reaction, a classic one-
The palladium-catalyzed reaction of N-tosylhydrazones
has emerged as an efficient protocol for the construction of
C=C double-bonds since the pioneering work of Barluenga
and co-workers.[3] Carbene migratory insertion and subse-
quent β-hydride elimination are proposed to constitute the
key steps in this process.[4] Since N-tosylhydrazones are eas-
[a] Beijing National Laboratory of Molecular Science (BNLMS)
and Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry,
Peking University,
Beijing 100871, P. R. China
Fax: +86-10-6275-1708
E-mail: wangjb@pku.edu.cn
Homepage: http://www.chem.pku.edu.cn/physicalorganic/
home.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201070.
Scheme 1. Acridine synthesis documented in the literature.
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Auto-Tandem Catalysis for the Synthesis of Acridines
Scheme 2. Acridine synthesis by auto-tandem Pd catalysis.
pot approach towards acridines, requires a high tempera- methylamino)biphenyl) and BrettPhos (2-(dicyclohexyl-
ture and an excess amount of Lewis acid, which drastically phosphanyl)-3,6-dimethoxy-2Ј,4Ј,6Ј-triisopropylbiphenyl)
narrows the substrate scope (Scheme 1, a).[7a,7b] In 2010, (Table 1, entries 5 and 6) were rather poor. The use of
Buchwald and co-worker reported an acridine synthesis by RuPhos (2-dicyclohexylphosphanyl-2Ј,6Ј-diisopropoxybi-
an intramolecular Heck reaction (Scheme 1, b).[7c] The phenyl) led to the best result, and the product was isolated
Larock group developed an acridine synthesis via aryne in- in 70% yield (Table 1, entry 7). With RuPhos as ligand, we
termediates (Scheme 1, c).[7d] A similar protocol was re- went on to examine other reaction parameters. We found
ported by Kim, using a different benzyne precursor.[7e]
that the combination of LiOtBu as base and dioxane as
Our efforts to synthesize acridine derivatives are summa- solvent was optimal (Table 1, entries 8–10), and better re-
rized in a brief retrosynthetic analysis shown in Scheme 2. sults were obtained by increasing the reaction temperature
Acridine A can be considered to be an aromatized tautomer
of B. The C=C double bond in B can be constructed by the
Pd-catalyzed cross-coupling reaction of an N-tosylhydraz-
Table 1. Optimization of reaction conditions.[a]
one with an aryl halide, while the C–N bond is formed by
the Pd-catalyzed C–N coupling developed by Buchwald and
Hartwig.[8]
Since both transformations use a palladium species as
catalyst, we envisaged that the acridine scaffold could be
readily accessed from easily-available o-dibromobenzenes
and N-tosylhydrazones. In this paper, we report a highly
efficient acridine synthesis based on this strategy.
Entry Base/Solvent/Temp. [°C] Ligand
Additive Yield [%][b]
1
2
3
4
5
6
7
8
LiOtBu/dioxane/90
LiOtBu/dioxane/90
LiOtBu/dioxane/90
LiOtBu/dioxane/90
LiOtBu/dioxane/90
LiOtBu/dioxane/90
LiOtBu/dioxane/90
NaOtBu/dioxane/90
LiOtBu/toluene/90
NaOtBu/toluene/90
LiOtBu/dioxane/110
LiOtBu/dioxane/110
Xphos
P(2-furyl)3 none
MePhos
Sphos
DavePhos
BrettPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
none
Ͻ 10
–
[c]
none
none
none
none
none
none
none
none
none
H2O[d]
50
57
–
Ͻ 10
70
59
55
62
85
98
[c]
Results and Discussion
We started the investigation of the cross-coupling reac-
tion of 1a and 2a using Pd2(dba)3 (dba = dibenzylideneacet-
one) as Pd0 source, and XPhos (2-dicyclohexylphosphanyl-
2Ј,4Ј,6Ј-triisopropylbiphenyl) as ligand (Table 1). To our de-
light, the coupling partners reacted, and 9-methylacridine
was isolated, albeit in a low yield (Table 1, entry 1). When
we replaced XPhos with P(2-furyl)3, an effective ligand for
Pd carbene migratory insertion,[4d] none of the desired
product was detected (Table 1, entry 2). Careful analysis of-
the product mixtures from the two reactions indicated that
the C=C double-bond formation had proceeded smoothly.
However, by-products formed by dehalogenation of inter-
mediates were detected in significant amounts,[9] implying
that there was a difficulty in the transmetallation step of
the C–N cross-coupling. To solve this problem, we screened
a variety of ligands that have been reported to facilitate C–
N cross-coupling.[10] The reactions with MePhos (2-dicyclo-
hexylphosphanyl-2Ј-methylbiphenyl) and SPhos (2-dicyclo-
hexylphosphanyl-2Ј,6Ј-dimethoxybiphenyl) gave the prod-
uct in moderate yields (Table 1, entries 3 and 4), while the
9
10
11
12
[a] All reactions were carried out with 1a (0.2 mmol), 2a
(0.3 mmol), Pd2(dba)3 (2.5 mol-%), ligand (10 mol-%) and base
(4.0 equiv.) in 1 mL of solvent for 12 h. [b] Yields of isolated prod-
uct. [c] None of the desired product was detected. [d] H2O
results with DavePhos (2-dicyclohexylphosphanyl-2Ј-(di- (5.0 equiv.) was added.
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Z. Huang, Y. Yang, Q. Xiao, Y. Zhang, J. Wang
FULL PAPER
to 110 °C (Table 1, entry 11). Notably, the addition of H2O Table 2. Reaction scope with respect to dihalo compounds.[a]
(5 equiv.) to the reaction mixture significantly increased the
yield (Table 1, entry 12).
The optimized conditions were then applied to the reac-
tion with various dihalo compounds. As well as o-dibromo-
benzenes, aryl chlorides and iodides reacted with 2a to give
9-methylacridine (Table 2, entries 2 and 3). In addition, 2-
iodophenyl triflate 1d was found to undergo the tandem
catalytic reaction, although the addition of an equimolar
amount of LiCl was essential (Table 2, entry 4). The elec-
tronic nature of the substituents on the o-dihalobenzenes
did not have a significant effect on the reaction. Electron-
rich, electron-neutral and electron-deficient substrates all
reacted smoothly with N-tosylhydrazones to give the corre-
sponding acridines (Table 2, entries 5–8). The reaction be-
tween 1,2-dibromocyclohexene and 2a gave 9-methyl-
1,2,3,4-tetrahydroacridine (3i), in a reaction involving the
migratory insertion of a vinyl group (Table 2, entry 9).
Using this strategy, we were also able to incorporate trip-
tycene and 18-crown-6 moieties, two prevalent structural
motifs in supramolecular chemistry, into the acridine scaf-
fold (Table 2, entries 10 and 11).
We continued our study by examining the substrate scope
with respect to the N-tosylhydrazone components
(Scheme 3). Acridines with different substituents at the 9-
position (i.e., 4a,b,h) were synthesized using the catalytic
protocol. It is noteworthy that an acridine bearing a ter-
minal olefin (i.e., 4j), in which the C=C bond could be used
for further elaboration, could also be obtained. A wide
range of functional groups, including acetal, cyano, and
alkynyl groups (in 4c, 4i, and 4k) were tolerated under the
reaction conditions, although the yields of these products
were slightly diminished. In addition, the reactions with
various aryl-substituted substrates proceeded smoothly to
give the corresponding acridines (i.e., 4d–g) in excellent
yields.
[a] Unless otherwise stated, the reaction conditions were as follows:
dihalo compound (0.3 mmol), 2a (0.45 mmol), Pd2(dba)3 (2.5 mol-
%), RuPhos (10 mol-%), LiOtBu (4.0 equiv.), H2O (5.0 equiv.), di-
oxane (1 mL), 110 °C, 12 h. [b] Yields of isolated products. [c] LiCl
(1.0 equiv.) was added.
Next, the regioselectivity of the reaction was investigated
by using unsymmetrical o-dihalobenzenes (Table 3). The re-
action of 3,4-dibromotoluene (1l) with 2a gave a 1:1 mix-
ture of regioisomers, implying that the methyl group does
not have an obvious effect on the reactivity of the two
bromides. However, when substrate 1m was subjected to the tivity of the halogens in the oxidative addition process, and
catalytic reaction, only a single isomer 3m was detected. We not the electronic effect of the substituents, that is the key
speculated the high regioselectivity might originate from the factor affecting the regioselectivity. Complete regioselectiv-
higher reactivity of the C–Br group than the C–Cl group in ity was also achieved for the reaction of substrate 1o, with
the oxidative addition process, along with the faster rate of a benzyl-protected hydroxy group, from which the corre-
C=C bond formation than C–N cross-coupling.[11] How- sponding acridine was formed in moderate yield.
ever, the possibility exists that the difference in reactivity of
Given the fact that N-tosylhydrazones can be readily ob-
the halogens in 1m is significantly enhanced by the electron- tained from ketones or aldehydes, we next sought to de-
donating nature of the –OMe group, which retards the reac- velop a one-pot synthesis of acridines directly from ketones.
tion of the para C–Cl group and accelerates the reaction of Using dioxane as solvent, and a catalytic amount of TsOH,
the meta C–Br group in the oxidative addition process. To 2-aminoacetophenone and TsNHNH2 were completely con-
test this hypothesis, substrate 1n, in which the –OMe group verted into 2a after heating at 60 °C for 6 h.
is para to the C–Br group, was tested in a reaction with 2a.
Without further work-up, o-dibromobenzene, catalysts,
This reaction also led exclusively to the single regioisomer base, and additional H2O were added directly into the reac-
3n. The consistent regioselectivities in these two cases in tion vial. The subsequent palladium-catalyzed reaction pro-
which the –OMe group either accelerates or retards the oxi- ceeded smoothly, and gave 9-methylacridine (3a) in 92%
dative addition of C–Br indicates that it is the relative reac- yield. This protocol was used with various N-tosylhydraz-
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Auto-Tandem Catalysis for the Synthesis of Acridines
Scheme 4. One-pot synthesis of acridines directly from ketones.
[a] Reaction conditions: ketone (0.45 mmol), tosylhydrazide
(0.45 mmol), dioxane (1 mL), 60 °C, 6 h; followed by Pd2(dba)3
(2.5 mol-%), RuPhos (10 mol-%), LiOtBu (4.0 equiv.), H2O
(3.5 equiv.), 110 °C, 12 h. [b] Yields of isolated products.
Next, we investigated the reaction mechanism of this
auto-tandem catalysis. Although we have speculated that
the C=C double bond is formed through Pd-carbene mi-
gratory insertion and β-hydride elimination, an alternative
route consisting of a 1,2-hydride shift of a palladium carb-
ene and a subsequent Heck–Mizoroki-type reaction cannot
be ruled out. To probe the possibility of such pathway, we
synthesized 2-aminostyrenes, the products of the proposed
1,2-hydride shift, and substituted them for N-tosylhydraz-
ones under identical reaction conditions [Equation (1)]. It
turned out that only trace amounts of the 9-methylacridines
were formed, and 5H-dibenzazepines 5 were detected as the
major products. This result indicated that the alternative
route involving a 1,2-hydride shift was not involved in the
transformation.
Scheme 3. Reaction scope with respect to N-tosylhydrazones.
[a] Reaction conditions: 1a (0.3 mmol), N-tosylhydrazone
(0.45 mmol), Pd2(dba)3 (2.5 mol-%), RuPhos (10 mol-%), LiOtBu
(4.0 equiv.), H2O (5.0 equiv.), dioxane (1 mL), 110 °C, 12 h.
[b] Yields of isolated products.
Table 3. Reaction of unsymmetrical o-dihalobenzenes.[a]
(1)
Considering the relative rates of C=C bond formation
and C–N cross-coupling, we proposed two possible path-
ways for the reaction (Scheme 5). In pathway a, the C–N
cross-coupling proceeds first, followed by the intramolecu-
lar C=C bond formation. In pathway b, a faster C=C bond
formation and subsequent C–N cross-coupling are in-
volved.
To gain further insight into the mechanism, we synthe-
sized 8, the precursor of intermediate 6 in pathway a, by an
Ullmann reaction. Under the optimized conditions of the
one-pot process, the reactions of 8a and 8b generated 9-
methylacridine in 44 and 14% yields, respectively [Equa-
tion (2)]. Although this observation confirms the viability
of pathway a for the transformation, these reactions were
[a] Unless stated otherwise, reaction conditions were as follows: di-
halo compound (0.3 mmol), 2a (0.45 mmol), Pd2(dba)3 (2.5 mol-
%), RuPhos (10 mol-%), LiOtBu (4.0 equiv.), H2O (5.0 equiv.), di-
oxane (1 mL), 110 °C, 12 h. [b] Yields of isolated products. [c] Ratio
1
determined by H NMR spectroscopy of crude product.
one precursors and o-dihalobenzene coupling partners to not efficient enough to account for the high yield achieved
give the desired products in yields similar to those obtained previously (Table 2, entry 1). On the other hand, by quench-
in the reactions using isolated N-tosylhydrazones ing the reaction of N-tosylhydrazone 2a and o-dibromo-
(Scheme 4).
benzene after 1 h, we could identify the structure of in-
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Z. Huang, Y. Yang, Q. Xiao, Y. Zhang, J. Wang
FULL PAPER
been achieved for unsymmetrical o-dihalobenzenes. A pre-
liminary mechanistic investigation has revealed a favourable
pathway consisting of a faster carbene migratory insertion
and β-hydride elimination sequence followed by intramolec-
ular C–N cross-coupling.
Experimental Section
General Methods: Unless otherwise stated, all reactions were per-
formed under a nitrogen atmosphere in an oven-dried microwave
tube, equipped with a magnetic stirrer bar and sealed with a cap
with septum. 1,4-Dioxane, toluene, diethyl ether and tetra-
hydrofuran (THF) were dried with Na and freshly distilled under
a nitrogen atmosphere prior to use. Reaction temperatures were
controlled using an IKAmag temperature modulator. Silica gel
(200–300 mesh; Qingdao, China) was used for flash column
chromatography. Pd2(dba)3, RuPhos, and LiOtBu were purchased
Scheme 5. Possible reaction pathways.
termediate 7 of pathway b by NMR spectroscopy. Com-
pound 7 could be isolated in 35% yield from the reaction
[Equation (3)]. When 7 was subjected to identical catalytic
conditions, it was converted into 9-methylacridine quantita-
tively [Equation (4)]. Notably, intermediate 6 of pathway a
could not be detected in the reaction mixture. Based on from Aldrich and used without further purification. NMR spectra
were recorded in CDCl3 with Bruker AVANCE III spectrometers
these experiments, we favour pathway b for the auto-tan-
dem catalysis, which involves a faster C=C bond formation
and a highly efficient intramolecular C–N cross-coupling.
This pathway is also consistent with the results obtained in
the studies of the regioselectivity of the reaction.
1
at 500 or 400 MHz for H NMR spectra, and 125 or 100 MHz for
13C NMR spectra. Tetramethylsilane (TMS) was used as internal
standard for 1H spectra (δ = 0.00 ppm), and residual solvent signals
were used as internal standard for 13C NMR spectra (CHCl3; δ =
1
77.00 ppm). Data for H NMR spectra are presented as following:
chemical shift (δ, ppm), multiplicity (br = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constant
(Hz) and integration. IR spectra were obtained with a Nicolet
5MX-S infra-red spectrometer. Mass spectra were recorded with an
Agilent 5975C inert 350 EI mass spectrometer. High-resolution
mass spectra (HRMS) were obtained with a Bruker Apex IV
FTMS.
(2)
(3)
Preparation and Characterization of Dihalo Compounds: Substrates
1a–c, 1e–f, 1h, 1l–n were commercially available, and were used
without further purification. Substrates 1d, 1g, 1i–k and 1o were
synthesized from commercially available materials according to lit-
erature procedures. For details, see Supporting Information.
For the preparation and characterization of N-tosylhydrazone pre-
cursors, see the Supporting Information.
Typical Procedure for the Pd0-Catalyzed Reaction of N-Tosylhydraz-
ones and Dihalo Compounds: Pd2(dba)3 (7 mg, 0.025 equiv.),
RuPhos (14 mg, 0.1 equiv.), and 1,4-dioxane (1 mL) were added to
an oven-dried microwave tube equipped with a Teflon®-coated
magnetic stirrer bar. The tube was evacuated and back-filled with
N2 three times. The mixture was heated and stirred at 90 °C for
5 min, and then allowed to cool to room temperature. LiOtBu
(96 mg, 4.0 equiv.) and N-tosylhydrazone 2a (136 mg, 1.5 equiv.)
were added to the tube. The tube was evacuated and back-filled
with N2 three times. o-Dibromobenzene 1a (71 mg, 0.3 mmol) and
water (27 mg, 5.0 equiv.) were added to the tube by syringe. The
reaction mixture was heated and stirred at 110 °C for 12 h, and
then it was allowed to cool to room temperature. The mixture was
filtered through a silica plug (washing with petroleum ether/ethyl
acetate = 1:1). The filtrate was concentrated in vacuo, and the resi-
due was purified by flash column chromatography (petroleum
ether/ethyl acetate = 15:1) to yield 9-methylacridine 3a (56 mg,
98%) as a yellowish solid.
(4)
Conclusions
In conclusion, we have developed a facile and convergent
palladium-catalyzed synthesis of acridines using easily ac-
cessible o-dihalobenzenes and N-tosylhydrazones. A single
palladium species was used to catalyze two independent re-
action steps in a one-pot fashion. This protocol is broad in
scope with respect to both coupling partners, providing an
efficient method to access heavily-functionalized acridine
moieties, which have been difficult and complicated to syn-
General Procedure for the One-Pot Synthesis of Acridine Derivatives
from Ketones: An oven-dried microwave tube was charged with a
2-aminophenyl ketone (the N-tosylhydrazone precursor;
0.45 mmol), 4-methylbenzenesulfonohydrazide (TsNHNH2, 84 mg,
thesize previously. In addition, regioselective reactions have 0.45 mmol), a catalytic amount of 4-methylbenzenesulfonic acid
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Auto-Tandem Catalysis for the Synthesis of Acridines
(TsOH) and dioxane (1 mL). The tube was sealed using a cap with
a septum, and heated to 60 °C. The mixture was stirred at this
temperature for 6–12 h, and the reaction was monitored by TLC.
After completion of the reaction, the mixture was allowed to cool
down to room temperature. Pd2(dba)3 (7 mg, 0.0075 mmol),
RuPhos (14 mg, 0.03 mmol), LiOtBu (96 mg, 1.2 mmol), o-di-
bromobenzene (0.3 mmol), and water (19 mg, 1.1 mmol) were
added to the mixture. The tube was evacuated and back-filled with
N2 three times, and then it was heated to 110 °C. The mixture was
stirred at this temperature for 12 h, and then it was allowed to cool
to room temperature. The mixture was filtered through a short sil-
ica plug. The filtrate was concentrated in vacuo, and the residue
was purified by flash column chromatography to give the acridine
derivatives.
H), 7.28 (s, 1 H), 4.39–4.34 (m, 4 H), 4.08–4.03 (m, 4 H), 3.85–3.81
(m, 4 H), 3.77–3.72 (m, 8 H), 3.01 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.45, 129.50, 124.93, 124.56, 124.13,
121.85, 102.05, 70.85, 70.67, 70.61, 70.52, 70.40, 69.11, 68.95,
68.82, 68.76, 14.09 ppm. HRMS (ESI): calcd. for C24H30NO6 [M
+ H]+ 428.2068; found 428.2076.
(7r,12r)-14-Methyl-7,12-dihydro-7,12-[1,2]benzenonaphtho[2,3-b]-
acridine (3k): Following the general procedure, a solution of
Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos (14 mg, 0.03 mmol), 1k
(124 mg, 0.3 mmol), N-tosylhydrazone 2a (136 mg, 0.45 mmol), Li-
OtBu (96 mg, 1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane
(1 mL) was stirred under N2 at 110 °C for 12 h. Flash column
chromatography (petroleum ether/ethyl acetate = 5:1) of the crude
product gave 3k (78 mg, 70%) as a reddish-yellow solid. IR (film):
The following acridine products are known and they were charac-
terized by comparing their 1H NMR and 13C NMR with the re-
ported data: 3a,[12] 3e,[12] 3f,[12] 3i,[13] 3m,[14] 4a,[15] 4c,[12] 4h.[16]
ν = 1244, 1373, 1433, 1458, 1607, 1736, 2925 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.14–8.06 (m, 4 H), 7.66 (t, J = 6.8 Hz, 1
H), 7.47–7.43 (m, 5 H), 7.07 (br., 4 H), 5.61 (d, J = 6.8 Hz, 2 H),
3.01 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 147.98,
147.79, 145.64, 143.87, 143.72, 141.14, 129.91, 129.12, 125.93,
125.88, 125.46, 124.99, 124.28, 124.09, 123.93, 123.75, 123.31,
117.59, 53.74, 53.52, 13.60 ppm. MS (EI): m/z (%) = 369 (100)
[M]+, 354 (33), 184 (20), 120 (15), 44 (5). HRMS (ESI): calcd. for
C28H20N [M + H]+ 370.1590; found 370.1586.
11-Methyl-2,3-dihydro-[1,4]dioxino[2,3-b]acridine (3g): Following
the general procedure,
a
solution of Pd2(dba)3 (7 mg,
0.0075 mmol), RuPhos (14 mg, 0.03 mmol), 1g (88 mg, 0.3 mmol),
N-tosylhydrazone 2a (136 mg, 0.45 mmol), LiOtBu (96 mg,
1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
stirred under N2 at 110 °C for 12 h. Flash column chromatography
(petroleum ether/ethyl acetate = 10:1) of the crude product gave 3g
9-Hexyl Acridine (4b): Following the general procedure, a solution
(69 mg, 92%) as a yellow solid. IR (film): ν = 1204, 1297, 1487, of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos (14 mg, 0.03 mmol), o-
˜
1
1607, 1736, 2928 cm–1. H NMR (400 MHz, CDCl3): δ = 8.00 (d, dibromobenzene (71 mg, 0.3 mmol), N-tosylhydrazone (168 mg,
J = 9.2 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.49 (s, 1 H), 7.42 (s, 1
H), 7.33 (t, J = 8.0 Hz, 1 H), 4.30–4.26 (m, 4 H), 2.82 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 147.94, 147.61, 145.92, 144.11,
139.65, 129.56, 128.72, 124.53, 124.41, 124.11, 122.40, 112.84,
107.70, 64.44, 64.34, 13.65 ppm. MS (EI): m/z (%) = 251 (100)
[M]+, 196 (21), 167 (42), 139 (15), 77 (10). HRMS (ESI): calcd. for
C16H14NO2 [M + H]+ 252.1019; found 252.1020.
0.45 mmol), LiOtBu (96 mg, 1.2 mmol), and water (27 mg,
1.5 mmol) in dioxane (1 mL) was stirred at under N2 110 °C for
12 h. Flash column chromatography (petroleum ether/ethyl acetate
= 15:1) of the crude product gave 4b (74 mg, 94%) as a pale yellow
solid. IR (film): ν = 751, 1460, 1518, 1560, 2926 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.22 (dd, J = 3.3, 8.7 Hz, 4 H), 7.74 (t, J
= 7.6 Hz, 2 H), 7.52 (t, J = 8.0 Hz, 2 H), 3.56 (t, J = 8.0 Hz, 2 H),
1.83–1.75 (m, 2 H), 1.57–1.51 (m, 2 H), 1.40–1.28 (m, 4 H), 0.90
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.65,
147.07, 130.35, 129.58, 125.38, 124.80, 124.28, 31.61, 31.33, 29.90,
27.64, 22.57, 14.02 ppm. MS (EI): m/z (%) = 263 (100) [M]+, 206
(33), 192 (96), 179 (31), 165 (28). HRMS (ESI): calcd. for C19H22N
[M + H]+ 264.1747; found 264.1747.
2,3-Difluoro-9-methylacridine (3h): Following the general pro-
cedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
(14 mg, 0.03 mmol), 1h (82 mg, 0.3 mmol), N-tosylhydrazone 2a
(136 mg, 0.45 mmol), LiOtBu (96 mg, 1.2 mmol), and water
(27 mg, 1.5 mmol) in dioxane (1 mL) was stirred under N2 at
110 °C for 12 h. Flash column chromatography (petroleum ether/
ethyl acetate = 20:1) of the crude product gave 3h (49 mg, 72%) as
9-Methyl-2-phenylacridine (4d): Following the general procedure, a
a yellow solid. IR (film): ν = 1161, 1244, 1454, 1497, 1616, solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos (14 mg,
˜
2925 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 8.8,
15.9 Hz, 2 H), 7.89–7.94 (m, 2 H), 7.78 (t, J = 7.4 Hz, 1 H), 7.58
0.03 mmol), o-dibromobenzene (71 mg, 0.3 mmol), corresponding
N-tosylhydrazone (171 mg, 0.45 mmol), LiOtBu (96 mg,
(t, J = 7.4 Hz, 1 H), 3.05 (s, 3 H) ppm. 13C NMR (100 MHz, 1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
CDCl3) (due to the complexity of the spectra, all peaks are listed
without considerating C,F couplings): δ = 154.51, 154.33, 151.95,
151.77, 151.33, 151.15, 148.63, 148.59, 154.98, 145.89, 141.96,
141.89, 130.11, 129.98, 125.96, 125.25, 124.24, 122.71, 122.64,
115.08, 114.93, 109.40, 109.23, 104.18 ppm. MS (EI): m/z (%) =
229 (100) [M]+, 201 (20), 115 (15), 102 (13). HRMS (ESI): calcd.
for C14H10F2N [M + H]+ 230.0776; found 230.0779.
stirred under N2 at 110 °C for 12 h. Flash column chromatography
(petroleum ether/ethyl acetate = 15:1) of the crude product gave 4d
(72 mg, 89%) as a yellowish solid. IR (film): ν = 1417, 1480, 1513,
˜
1
1549, 1630 cm–1. H NMR (400 MHz, CDCl3): δ = 8.36 (s, 1 H),
8.27 (d, J = 9.2 Hz, 1 H), 8.21 (d, J = 8.8 Hz, 2 H), 8.03 (d, J =
8.8 Hz, 1 H), 7.77–7.72 (m, 3 H), 7.53–7.50 (m, 3 H), 7.41 (t, J =
7.2 Hz, 1 H), 3.11 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 148.29, 147.70, 142.15, 140.67, 137.75, 130.60, 130.15, 129.80,
129.59, 128.90, 127.63, 127.39, 125.66, 125.43, 125.39, 124.39,
121.94, 13.53 ppm. MS (EI): m/z (%) = 269 (100) [M]+, 254 (20),
239 (16), 135 (12), 77 (5). HRMS (ESI): calcd. for C20H16N [M +
H]+ 270.1277; found 270.1274.
23-Methyl-2,3,5,6,8,9,11,12,14,15-decahydro-[1,4,7,10,13,16]hexa-
oxacyclooctadecino[2,3-b]acridine (3j): Following the general pro-
cedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
(14 mg, 0.03 mmol), 1j (141 mg, 0.3 mmol), N-tosylhydrazone 2a
(136 mg, 0.45 mmol), LiOtBu (96 mg, 1.2 mmol), and water
(27 mg, 1.5 mmol) in dioxane (1 mL) was stirred under N2 at
110 °C for 12 h. Flash column chromatography (dichloromethane/
9-Methyl-2-(naphthalen-2-yl)acridine (4e): Following the general
procedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
methanol = 40:1) of the crude product gave 3j (109 mg, 85%) as a (14 mg, 0.03 mmol), o-dibromobenzene (71 mg, 0.3 mmol), corre-
reddish-yellow solid. IR (film): ν = 755, 1127, 1226, 1287, 1451,
sponding N-tosylhydrazone (194 mg, 0.45 mmol), LiOtBu (96 mg,
˜
1
1491, 2924 cm–1. H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
8.6, 17.2 Hz, 2 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.53 (t, J = 6.8 Hz, 2 stirred under N2 at 110 °C for 12 h. Flash column chromatography
Eur. J. Org. Chem. 2012, 6586–6593
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6591

Z. Huang, Y. Yang, Q. Xiao, Y. Zhang, J. Wang
FULL PAPER
(petroleum ether/ethyl acetate = 15:1) of the crude product gave 4e
9-(But-3-en-1-yl)acridine (4j): Following the general procedure, a
solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos (14 mg,
0.03 mmol), o-dibromobenzene (71 mg, 0.3 mmol), corresponding
N-tosylhydrazone (154 mg, 0.45 mmol), LiOtBu (96 mg,
1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
(87 mg, 91%) as a reddish-yellow solid. IR (film): ν = 752, 815,
˜
1
1463, 1514, 2924 cm–1. H NMR (400 MHz, CDCl3): δ = 8.41 (s,
1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.22–8.10 (m, 4 H), 7.92 (t, J =
8.8 Hz, 2 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.72 (t, J = 7.2 Hz, 1 H),
7.51–7.49 (m, 3 H), 3.07 (s, 3 H) ppm. 13C NMR (125 MHz, stirred under N2 at 110 °C for 12 h. Flash column chromatography
CDCl3): δ = 148.32, 147.74, 142.25, 137.89, 137.59, 133.63, 132.72, (petroleum ether/ethyl acetate = 20:1) of the crude product gave 4j
130.68, 130.16, 129.93, 129.65, 128.62, 128.22, 127.63, 126.44,
126.23, 126.18, 125.73, 125.52, 125.44, 124.44, 122.23, 13.61 ppm.
MS (EI): m/z (%) = 319 (100) [M]+, 245 (8), 159 (20), 71 (5), 43
(28 mg, 40%) as a pale yellow solid. IR (film): ν = 751, 1456, 1493,
˜
1
1518, 1609, 2926 cm–1. H NMR (400 MHz, CDCl3): δ = 8.24 (d,
J = 8.8 Hz, 4 H), 7.77 (t, J = 7.6 Hz, 2 H), 7.56 (t, J = 8.0 Hz, 2
(5). HRMS (ESI): calcd. for C24H18N [M + H]+ 320.1434; found H), 6.05–5.95 (m, 1 H), 5.20–5.00 (m, 2 H), 3.72 (t, J = 8.0 Hz, 2
320.1433.
H), 2.60–2.54 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
148.68, 145.85, 137.27, 130.42, 129.71, 125.63, 124.84, 124.22,
115.60, 34.99, 27.01 ppm. MS (EI): m/z (%) = 233 (42) [M]+, 192
(100), 177 (15), 165 (21), 139 (10). HRMS (ESI): calcd. for
C17H16N [M + H]+ 234.1277; found 234.1274.
9-Methyl-2-(thiophen-3-yl)acridine (4f): Following the general pro-
cedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
(14 mg, 0.03 mmol), o-dibromobenzene (71 mg, 0.3 mmol), corre-
sponding N-tosylhydrazone (174 mg, 0.45 mmol), LiOtBu (96 mg,
1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
stirred under N2 at 110 °C for 12 h. Flash column chromatography
(petroleum ether/ethyl acetate = 15:1) of the crude product gave 4f
9-Methyl-2-(phenylethynyl)acridine (4k): Following the general pro-
cedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
(14 mg, 0.03 mmol), o-dibromobenzene (71 mg, 0.3 mmol), corre-
sponding N-tosylhydrazone (181 mg, 0.45 mmol), LiOtBu (96 mg,
1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
stirred under N2 at 110 °C for 12 h. Flash column chromatography
(77 mg, 93%) as a reddish yellow solid. IR (film): ν = 1245, 1372,
˜
1495, 1556, 1628, 2924 cm–1. 1H NMR (400 MHz, CDCl3): δ =
8.32 (s, 1 H), 8.19 (dd, J = 8.4, 16.4 Hz, 3 H), 8.00 (d, J = 5.0 Hz,
1 H), 7.72 (t, J = 7.4 Hz, 1 H), 7.61 (s, 1 H), 7.56 (d, J = 5.0 Hz, (petroleum ether/ethyl acetate = 15:1) of the crude product gave 4k
1 H), 7.50 (t, J = 7.4 Hz, 1 H), 7.46–7.45 (m, 1 H), 3.06 (s, 3 H) (33 mg, 38%) as a reddish-yellow solid. IR (film): ν = 1442, 1491,
˜
1
ppm. 13C NMR (100 MHz, CDCl3): δ = 148.20, 147.70, 141.91, 1552, 1726, 2925 cm–1. H NMR (400 MHz, CDCl3): δ = 8.48 (s,
141.84, 132.40, 130.65, 130.17, 129.58, 129.37, 126.66, 126.27,
1 H), 8.26 (d, J = 8.6 Hz, 1 H), 8.20 (dd, J = 9.1, 12.8 Hz, 2 H),
125.76, 125.53, 125.49, 124.40, 121.27, 120.69, 13.56 ppm. MS (EI): 7.84 (d, J = 8.6 Hz, 1 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.62–7.56 (m,
m/z (%) = 275 (100) [M]+, 259 (21), 241 (21), 138 (15), 89 (4). 3 H), 7.40–7.39 (m, 3 H), 3.14 (s, 3 H) ppm. 13C NMR (100 MHz,
HRMS (ESI): calcd. for C18H14NS [M + H]+ 276.0842; found
276.0840.
CDCl3): δ = 148.72, 147.68, 142.20, 132.10, 131.71, 130.39, 130.32,
130.13, 128.56, 128.45, 128.27, 125.90, 125.82, 125.21, 124.62,
123.02, 120.24, 90.91, 89.77, 13.70 ppm. MS (EI): m/z (%) = 293
(100) [M]+, 147 (25), 71 (10), 43 (19). HRMS (ESI): calcd. for
C22H16N [M + H]+ 294.1277; found 294.1276.
2-(Furan-3-yl)-9-methylacridine (4g): Following the general pro-
cedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
(14 mg, 0.03 mmol), o-dibromobenzene (71 mg, 0.3 mmol), corre-
sponding N-tosylhydrazone (166 mg, 0.45 mmol), LiOtBu (96 mg,
1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
stirred under N2 at 110 °C for 12 h. Flash column chromatography
(petroleum ether/ethyl acetate = 15:1) of the crude product gave 4g
2,9-Dimethylacridine (3l) and 3,9-Dimethylacridine (3lЈ): Following
the general procedure,
a
solution of Pd2(dba)3 (7 mg,
0.0075 mmol), RuPhos (14 mg, 0.03 mmol), 3,4-dibromotoluene
(1l) (75 mg, 0.3 mmol), N-tosylhydrazone 2a (136 mg, 0.45 mmol),
LiOtBu (96 mg, 1.2 mmol), and water (27 mg, 1.5 mmol) in diox-
(67 mg, 86%) as a yellow solid. IR (film): ν = 1053, 1240, 1164,
˜
1517, 1738, 2925 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.24–8.18 ane (1 mL) was stirred under N2 at 110 °C for 12 h. Flash column
(m, 4 H), 7.89 (d, J = 10.8 Hz, 2 H), 7.74 (t, J = 7.2 Hz, 1 H),
7.56–7.52 (m, 2 H), 6.90 (s, 1 H), 3.11 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 148.13, 147.75, 144.07, 141.58, 139.30,
130.72, 130.18, 129.53, 129.13, 128.81, 126.31, 125.77, 125.57,
125.51, 124.39, 119.83, 108.67, 13.54 ppm. MS (EI): m/z (%) = 259
(100) [M]+, 230 (35), 202 (10), 130 (10), 114 (5). HRMS (ESI):
calcd. for C18H14NO [M + H]+ 260.1070; found 260.1069.
chromatography (petroleum ether/ethyl acetate = 15:1) of the crude
product gave an inseparable 1:1 mixture of 3l and 3lЈ (60 mg, 97%)
as a pale yellow solid. IR (film): ν = 751, 1445, 1515, 1561,
˜
2922 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.17 (dd, J = 2.8,
8.7 Hz, 1 H), 8.12 (d, J = 8.8 Hz, 1 H), 8.08 (d, J = 8.8 Hz, 0.5 H),
8.01 (d, J = 8.8 Hz, 0.5 H), 7.93 (s, 0.5 H), 7.86 (s, 0.5 H), 7.71–
7.66 (m, 1 H), 7.54 (d, J = 8.8 Hz, 0.5 H), 7.48–7.43 (m, 1 H), 7.29
(d, J = 8.8 Hz, 0.5 H), 2.97 (s, 3 H), 2.54 (2 s, integrated as 3 H in
total) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.59, 148.30,
147.78, 147.19, 141.77, 140.78, 139.90, 134.91, 132.43, 130.07,
129.92, 129.77, 129.44, 129.09, 128.33, 128.05, 125.49, 125.37,
125.11, 124.79, 124.39, 124.32, 124.06, 123.76, 122.63, 22.08, 21.87,
13.39, 13.34 ppm. MS (EI): m/z (%) = 207 (46) [M]+, 84 (96), 61
(70), 43 (95), 29 (100). HRMS (ESI): calcd. for C15H14N [M +
H]+ 208.1121; found 208.1119.
9-Methylacridine-2-carbonitrile (4i): Following the general pro-
cedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
(14 mg, 0.03 mmol), o-dibromobenzene (71 mg, 0.3 mmol), corre-
sponding N-tosylhydrazone (148 mg, 0.45 mmol), LiOtBu (96 mg,
1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL) was
stirred under N2 at 110 °C for 12 h. Flash column chromatography
(petroleum ether/ethyl acetate = 15:1) of the crude product gave 4i
(20 mg, 30%) as a reddish-yellow solid. IR (film): ν = 1240, 1496,
˜
1
1741, 2221, 2925 cm–1. H NMR (400 MHz, CDCl3): δ = 8.69 (d, 3-Methoxy-9-methylacridine (3n): Following the general procedure,
J = 1.2 Hz, 1 H), 8.28–8.21 (m, 3 H), 7.88–7.84 (m, 1 H), 7.81 (dd, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos (14 mg,
J = 1.6, 9.0 Hz, 1 H), 7.64 (t, J = 7.2 Hz, 1 H), 3.15 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 149.93, 148.19, 144.20, 132.32,
131.83, 131.56, 130.41, 128.82, 126.67, 125.98, 124.77, 124.33,
0.03 mmol), 2-bromo-1-chloro-4-methoxybenzene (1n) (66 mg,
0.3 mmol), N-tosylhydrazone 2a (136 mg, 0.45 mmol), LiOtBu
(96 mg, 1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane (1 mL)
119.09, 108.93, 13.82 ppm. MS (EI): m/z (%) = 218 (100) [M]+, 190 was stirred under N2 at 110 °C for 12 h. Flash column chromatog-
(25), 164 (21), 109 (10), 82 (5). HRMS (ESI): calcd. for C15H11N2
raphy (petroleum ether/ethyl acetate = 15:1) of the crude product
gave a single isomer 3n (50 mg, 71%) as a yellow solid. IR (film):
[M + H]+ 219.0917; found 219.0916.
6592
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6586–6593

Auto-Tandem Catalysis for the Synthesis of Acridines
ν = 753, 1206, 1288, 1466, 1613, 1633, 2928 cm–1. 1H NMR
ens, Org. Lett. 2010, 12, 2754; j) T.-P. Liu, C.-H. Xing, Q.-S.
Hu, Angew. Chem. 2010, 122, 2971; Angew. Chem. Int. Ed.
2010, 49, 2909; k) M. C. Willis, G. N. Brace, I. P. Holmes, An-
gew. Chem. 2005, 117, 407; Angew. Chem. Int. Ed. 2005, 44,
403.
˜
(400 MHz, CDCl3): δ = 8.19–8.08 (m, 3 H), 7.73 (t, J = 7.8 Hz, 1
H), 7.48 (t, J = 7.8 Hz, 1 H), 7.43 (s, 1 H), 7.20 (d, J = 9.2 Hz, 1
H), 3.98 (s, 3 H), 3.04 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 160.95, 150.20, 148.49, 142.20, 129.78, 129.35, 125.83, 124.54,
124.43, 131.65, 120.63, 105.62, 55.53, 13.61 ppm. MS (EI): m/z (%)
= 223 (100) [M]+, 180 (91), 152 (23), 120 (26), 55 (22). HRMS
(ESI): calcd. for C15H14NO [M + H]+ 224.1070; found 224.1070.
[3] For related reviews, see: a) J. Barluenga, C. Valdés, Angew.
Chem. 2011, 123, 7626; Angew. Chem. Int. Ed. 2011, 50, 7486;
b) Z. Shao, H. Zhang, Chem. Soc. Rev. 2012, 41, 560.
[4] For selected examples, see: a) J. Barluenga, P. Moriel, F. Aznar,
C. Valdés, Angew. Chem. 2007, 119, 5683; Angew. Chem. Int.
Ed. 2007, 46, 5587; b) J. Barluenga, M. Tomás-Gamasa, P. Mo-
riel, F. Aznar, C. Valdés, Chem. Eur. J. 2008, 14, 4792; c) J.
Barluenga, M. Escribano, P. Moriel, F. Aznar, C. Valdés,
Chem. Eur. J. 2009, 15, 13291; d) Q. Xiao, J. Ma, Y. Yang, Y.
Zhang, J. Wang, Org. Lett. 2009, 11, 4732; e) Z. Zhang, Y. Liu,
M. Gong, X. Zhao, Y. Zhang, J. Wang, Angew. Chem. 2010,
122, 1157; Angew. Chem. Int. Ed. 2010, 49, 1139; f) X. Zhao,
J. Jing, K. Lu, Y. Zhang, J. Wang, Chem. Commun. 2010, 46,
1724; g) L. Zhou, F. Ye, Y. Zhang, J. Wang, J. Am. Chem. Soc.
2010, 132, 13590; h) J. Barluenga, L. Florentino, F. Aznar, C.
Valdés, Org. Lett. 2011, 13, 510; i) L. Zhou, F. Ye, J. Ma, Y.
Zhang, J. Wang, Angew. Chem. 2011, 123, 3572; Angew. Chem.
Int. Ed. 2011, 50, 3510; j) Z.-S. Chen, X.-H. Duan, L.-Y. Wu,
S. Ali, K.-G. Ji, P.-X. Zhou, X.-Y. Liu, Y.-M. Liang, Chem.
Eur. J. 2011, 17, 6918; k) L. Zhou, F. Ye, Y. Zhang, J. Wang,
Org. Lett. 2012, 14, 922; l) J. Barluenga, M. Tomás-Gamasa,
F. Aznar, C. Valdés, Adv. Synth. Catal. 2010, 352, 3235.
[5] a) R. D. Dsouza, U. Pischel, W. M. Nau, Chem. Rev. 2011, 111,
7941; b) P. Yan, A. Xie, M. Wei, L. M. Loew, J. Org. Chem.
2008, 73, 657, and references cited therein.
2-(Benzyloxy)-9-methylacridine (3o): Following the general pro-
cedure, a solution of Pd2(dba)3 (7 mg, 0.0075 mmol), RuPhos
(14 mg, 0.03 mmol), 4-(benzyloxy)-1-chloro-2-iodobenzene (1o)
(115 mg, 0.3 mmol), N-tosylhydrazone 2a (136 mg, 0.45 mmol), Li-
OtBu (96 mg, 1.2 mmol), and water (27 mg, 1.5 mmol) in dioxane
(1 mL) was stirred under N2 at 110 °C for 12 h. Flash column
chromatography (petroleum ether/ethyl acetate = 15:1) of the crude
product gave a single isomer 3o (38 mg, 42%) as a yellow solid. IR
(film): ν = 1221, 1376, 1454, 1631, 2926 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 8.19 (d, J = 8.4 Hz, 2 H), 8.14 (d, J = 9.6 Hz, 1 H),
7.70 (t, J = 6.8 Hz, 1 H), 7.54–7.53 (m, 4 H), 7.43–7.35 (m, 4 H),
5.25 (s, 2 H), 3.00 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 155.96, 146.95, 145.46, 139.44, 136.45, 131.85, 130.19, 128.68,
128.64, 128.20, 127.67, 126.17, 125.69, 125.53, 124.87, 124.06,
101.66, 70.27, 13.70 ppm. MS (EI): m/z (%) = 299 (52) [M]+, 208
(15), 180 (34), 152 (27), 91 (100). HRMS (ESI): calcd. for
C21H18NO [M + H]+ 300.1383; found 300.1384.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the preparation of starting mate-
rials and the mechanistic studies, and 1H NMR and 13C NMR
spectra for all products.
[6] a) R. M. Acheson (Ed.), Acridines, 2nd ed., John Wiley & Sons,
New York, 1973; b) A. Albert, The Acridines, 2nd ed., Edward
Arnold Ltd., London, 1966; c) W. A. Denny, Med. Chem. Rev.
Online 2004, 1, 257, and references cited therein.
[7] a) A. Bernthsen, Justus Liebigs Ann. Chem. 1878, 192, 1; b)
A. Bernthsen, Justus Liebigs Ann. Chem. 1884, 224, 1; c) D.
Tsvelikhovsky, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132,
14048; d) D. C. Rogness, R. C. Larock, J. Org. Chem. 2010, 75,
2289; e) K. Yoon, S. M. Ha, K. Kim, J. Org. Chem. 2005, 70,
5741.
[8] For selected reviews of Pd-catalyzed aryl amination, see: a) J. P.
Wolfe, S. Wagaw, J. F. Marcoux, S. L. Buchwald, Acc. Chem.
Res. 1998, 31, 805; b) J. F. Hartwig, Acc. Chem. Res. 1998, 31,
852; c) A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002,
219, 133; d) J. F. Hartwig, in: Modern Amination Methods (Ed.:
A. Ricci), Wiley-VCH, Weinheim, Germany, 2000.
[9] The by-product was isolated and characterized as 2-(1-phen-
ylvinyl)aniline.
[10] For investigations on the ligands in Pd-catalyzed amination,
see: a) D. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120,
6438; Angew. Chem. Int. Ed. 2008, 47, 6338; b) D. S. Surry,
S. L. Buchwald, Chem. Sci. 2011, 2, 27.
[11] In a previous article by Barluenga and co-workers, C=C double
bond formation has been found to be favoured over amination
of secondary amines under Pd0/Xphos conditions. See ref.[2b]
[12] D. C. Rogness, R. C. Larock, J. Org. Chem. 2010, 75, 2289.
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Acknowledgments
The project is supported by National Basic Research Program of
China (973 Program, No. 2009CB825300), National Natural Sci-
ence Foundation of China (NSFC). The authors thank Mr. Bo
Wang for the preparation of the reactants for 4e.
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Received: August 8, 2012
Published Online: October 10, 2012
Eur. J. Org. Chem. 2012, 6586–6593
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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