Synthesis of Acridones by Palladium-Catalyzed Buchwald-Hartwig Amination

Article abstract of DOI:10.1055/s-0037-1612256

The Buchwald-Hartwig amination allows an efficient and convenient synthesis of biologically and pharmaceutically important acridones by formation of a six-membered ring. With the described method, a number of derivatives have been synthesized in up to 95% yield by using a variety of anilines as well as benzylic and aliphatic amines.

Full text of DOI:10.1055/s-0037-1612256

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
J. Janke et al.
Letter
Synlett
Synthesis of Acridones by Palladium-Catalyzed Buchwald–
Hartwig Amination
Julia Jankea
O
Br
O
Alexander Villingera
Peter Ehlersa,b
Peter Langer*a,b
H2N–R2
R1
R1
Br
N
R2
R1 = H, MeO, F
a Institute of Chemistry, University Rostock, Albert-Einstein-Str.
3a, 18059 Rostock, Germany
R
2 = H, Alkyl, Aryl
20 examples
(49–95%)
peter.langer@uni-rostock.de
b Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
A.-Einstein-Str. 29a, 18059 Rostock, Germany
Received: 06.12.2018
Accepted after revision: 03.02.2019
Published online: 25.03.2019
for the preparation of acridine derivatives with anti-cancer
activities.6 Classical routes to the synthesis of acridones rely
on the acid-induced ring-closure of N-phenyl anthranilic
acids, which are usually obtained from Ullmann condensa-
tion of anilines with ortho-halogen-substituted benzoic ac-
ids.9 Furthermore, the oxidation of the corresponding acrid-
inium salts by molecular oxygen under basic conditions10
and the coupling of ortho-substituted anthranilic acid ester
with arynes in the presence of CsF,11 are known approaches
(Scheme 1) as well as other methods.2,5,6,8,12 However, harsh
reaction conditions and tedious workup procedures are
usually required.
DOI: 10.1055/s-0037-1612256; Art ID: st-2018-d0791-l
Abstract The Buchwald–Hartwig amination allows an efficient and
convenient synthesis of biologically and pharmaceutically important
acridones by formation of a six-membered ring. With the described
method, a number of derivatives have been synthesized in up to 95%
yield by using a variety of anilines as well as benzylic and aliphatic
amines.
Key words palladium catalysis, Suzuki–Miyaura reaction, Buchwald–
Hartwig amination, acridones, cyclization
The two-fold Buchwald–Hartwig reaction has become a
versatile tool for the construction of carbazoles and their
heterocyclic isomers.13 In contrast, the formation of six-or
seven-memberered rings by this method has rarely been
studied. The groups of Ando and Jensen studied the synthe-
sis of Imipramine, a tricyclic antidepressant, containing a
central azepine moiety.14 More recently, Zhang et al. report-
ed the synthesis of phenoxazines and phenothiazines by
ring-closing two-fold Buchwald–Hartwig reactions.15
Highly substituted acridones are versatile building
blocks for many naturally occurring products. They have at-
tracted attention of both medicinal and synthetic chemists
because of to their various biological activities.1–5 Acridone
derivatives are promising antifungal and antiviral
agents2,4,5,6 as well as chemo-sensors and fluorescent labels
in biodiagnostics.1,6 With regard to DNA-intercalating anti-
tumor agents,2,4,5,7a,b,8 acridones are important precursors
CO2H
H
N
N+
X–
R
Allen et al. 1939
Hegde et al. 2004
O
Suzuki et al. 1981 & 1983
N
O
Br
R
CO2Me
+
TMS
TfO
Br
NHR
this work
Zhao et al. 2006
Scheme 1 Synthetic routes to acridones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
J. Janke et al.
Letter
Synlett
In the present study, we report, to the best of our
knowledge, a new and convenient synthesis of substituted
acridones that is based on a double C–N amination, forming
a six-membered ring (Scheme 1). This methodology is high-
ly efficient, versatile and allows the introduction of various
functional groups in good to excellent yields.
The starting material, 2,2'-dibromobenzophenone 3a,
was prepared by using a Suzuki–Miyaura reaction (Scheme
2). The desired product 3a was isolated in a yield of 68%.
Having the optimized reaction conditions in hand, we
carried out Buchwald–Hartwig reactions of compounds 4a–
r containing various functional groups (Scheme 3). The
yields for the double C–N coupling reaction vary from mod-
erate to excellent. With regard to the substitution pattern of
the anilines employed, electron-withdrawing and electron-
donating groups both proved to be compatible with the re-
action conditions and gave equally good results. The high-
est yield was observed for 4a (95%), whereas the lowest oc-
curred with 4l with a CF3 group attached at the ortho posi-
tion of the aniline (61%). In particular, the impact of steric
hindrance on the aromatic moiety was investigated. The
yields decrease gradually from para-substituted compound
4i (92%) to ortho-substituted compounds 4k (75%) and 4l
(61%). Furthermore, we found that the reaction conditions
could be successfully applied to various benzylic and ali-
phatic amines, giving acridinones 4m–r in slightly lower
yields of up to 67%.
O
B(OH)2
Br
O
Br
[Pd]
Cl
+
100 °C, 8 h
Br
Br
3a (68%)
1
2a
Scheme 2 Synthesis of precursor 3a. Reaction conditions: Pd(PPh3)Cl2
(0.05 equiv, 0.03 mmol), K3PO4 (3 equiv, 2.05 mmol), 2-bromophenyl-
boronic acid 1 (1.0 equiv, 0.68 mmol) and 2-bromobenzoyl chloride 2a
(1 equiv, 0.68 mmol), toluene
O
Br
O
Then, the palladium-catalyzed Buchwald–Hartwig ami-
nation of 3a with different anilines was studied (Table 1)
and the influence of different ligands and solvents was ex-
amined. To our satisfaction, an initial test reaction with use
of PtBu3·HBF4 and toluene gave the desired product 4a in
17% yield (Table 1, entry 1). Next, we screened several phos-
phorus ligands under otherwise identical conditions (Table
1, entry 2–4). It turned out that the employment of the
bidentate phosphorus ligand dppf and toluene at 100 °C for
24 hours proved to be the most efficient combination, with
the desired product 4a being isolated in up to 95% yield.16
Surprisingly, the use of xylene at 140 °C led to significantly
lower yields (Table 1, entry 6).
Pd2dba3/dppf
H2N–R
Br
N
R
3a
4a–r
MeO
OMe
Me
OMe
4a (95%)
4b (87%)
4c (78%)
4d (77%)
Table 1 Optimization of the Preparation of 4aa,b
tBu
Et
OEt
Cl
4e (92%)
4f (91%)
4g (75%)
O
4h (77%)
Me
NH2
O
Br
(3 equiv)
F
CF3
N
Br
100 °C, 24 h
F
F
4i (92%)
4j (82%)
4k (75%)
4l (61%)
3a
4a
Me
Entry
Ligand
Solvent
Temp (°C)
Yield (%)b
Me
Me
1
2
3
4
5
6
PtBu3·HBF4
BINAP
X-Phos
dppf
toluene
toluene
toluene
toluene
100
100
100
100
90
17
12
17
95
37
39
Me
4n (62%)
4m (60%)
4o (58%)
4p (57%)
nBu
nHex
dppf
1,4-dioxane
xylene
dppf
140
4q (65%)
4r (67%)
a Reaction conditions: 3a (1.0 equiv, 0.3 mmol), Pd2dba3 (0.05 equiv, 0.015
mmol), p-toluidine (3.0 equiv, 0.9 mmol) and ligand (monodentate
PtBu3·HBF4 or X-Phos 0.2 equiv; bidentate BINAP or dppf 0.1 equiv), KOtBu
(6.0 equiv, 1.8 mmol), solvent (3.0 ml).
Scheme 3 Synthesis of acridones 4a–r. Reaction conditions: 3a (1.0
equiv, 0.3 mmol), Pd2dba3 (0.05 equiv, 0.015 mmol), amine (3.0 equiv);
dppf (0.1 equiv), KOtBu (6.0 equiv), toluene, 100 °C, 24 h. Isolated
yields are given in parenthesis.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
J. Janke et al.
Letter
Synlett
O
O
Br
5a R =
5b R =
Me
OMe
69%
49%
Pd2dba3/dppf
H2N–R
N
R
Br
3b (54%)
O
OMe
Br
Me
O
5c R =
5d R =
Me
70%
62%
Pd2dba3/dppf
H2N–R
N
R
F
Br
F
nHexyl
3c (51%)
Scheme 4 Synthesis of 5a–d
Next, we turned our attention to the employment of
substituted 2,2'-dibromobenzophenones. As examples, we
chose benzophenones that contained an electron-donating
methoxy group (3b) and an electron-withdrawing fluorine
functionality (3c). The starting materials 3b,c were pre-
pared according to the conditions of the Suzuki–Miyaura
reaction mentioned above. However, isolated compounds
3b (54%) and 3c (51%) were accompanied by low amounts
of diarylated side products 6b,c, derived from arylation of
the bromine of the aryl chloride.17 Fortunately, such side
products did not affect the following cyclizations and,
hence, slightly contaminated products 3b and 3c were used
as isolated. The reaction with p-toluidine gave equally good
yields of about 70% for 5a and 5c from starting materials 3b
and 3c, respectively. However, yields decreased slightly
with an aromatic N-substituted compound 5a (69%) and 5c
(70%) to an aliphatic 5d (62%) and a benzylic N-substituted
compound 3b (49%) (Scheme 4).
In conclusion, we have developed a simple and conve-
nient synthetic pathway for the preparation of acridones by
formation of a six-membered ring by a palladium-catalyzed
Buchwald–Hartwig amination. The optimized reaction con-
ditions allow the modular synthesis of various functional-
ized acridones and tolerate a range of functional groups on
the aryl rings as well as the employment of anilines, benzyl-
ic and aliphatic amines, leading to the corresponding prod-
ucts in good to very good yields.
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Langer, P. Org. Biomol. Chem. 2018, 16, 6543. (b) Pham, N. N.;
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Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612256.
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(16) Typical Procedure
– Synthesis of 10-(4-Methylphenyl)-
acridin-9(10H)-one (4a)
References and Notes
A dried glass pressure tube under argon was charged with 2,2'-
dibromobenzophenone 3a (100 mg, 0.3 mmol), Pd2dba3 (14 mg,
0.015 mmol), dppf (16 mg, 0.03 mmol), KOtBu (200 mg,
1.8 mmol), and amine (0.1 ml, 0.9 mmol). The solids were dis-
solved in dry toluene (3 mL), sealed with a Teflon® cap before
being heated to 100 °C. After 24 h, the mixture was allowed to
cool to room temperature. The residue was dissolved in CH2Cl2
(20 mL), washed with hydrochloric acid (1 M, 20 mL) and dried
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M.; Rizzato, S.; Miozzo, L. Eur. J. Org. Chem. 2011, 2265.
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19, 460.
(3) Kobayashi, K.; Nakagawa, K.; Yuba, S.; Komatsu, T. Helv. Chim.
Acta 2013, 96, 389.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
J. Janke et al.
Letter
Synlett
with Na2SO4. After filtration and removal of the solvents under
reduced pressure, the crude solid was purified by column chro-
matography (heptane/ethyl acetate 10:1) to give 10-(4-methyl-
phenyl)acridin-9(10H)-one (4a) as a yellow solid (80 mg, 95%),
mp 290–292 °C. 1H NMR (300 MHz, CDCl3): δ = 8.58 (dd, 3J =
8.0 Hz, 4J = 2.1 Hz, 2 H, CHAr), 7.53–7.45 (m, 4 H, CHAr), 7.30–
7.21 (m, 4 H, CHAr), 6.80 (d, 3J = 9.0 Hz, 2 H, CHAr), 2.54 (s, 3 H,
CH3). 13C NMR (75 MHz, CDCl3): δ = 178.2 (CO), 143.3 (2 CAr),
139.8 (CAr), 136.3 (CAr), 133.3 (2 CHAr), 131.8 (2 CHAr), 129.7 (2
CHAr), 127.3 (2 CHAr), 121.9 (2 CAr), 121.5 (2 CHAr), 117.0 (2
CHAr), 21.4 (CH3). IR (ATR, cm–1): 3033 (w), 2921 (w), 2853 (w),
1630 (m), 1596 (m), 1485 (m), 1456 (m), 1299 (m), 1271 (m),
1156 (m), 1038 (m), 1025 (m), 935 (m), 824 (m), 753 (s), 673
(m), 520 (m). MS (EI, 70 eV): m/z (%) = 286 (20), 285 ([M]+, 100),
284 (12), 241 (15), 166 (11), 140 (17), 139 (10), 91 (12), 89 (13),
77 (12), 76 (13), 65 (22), 63 (15), 50 (11), 39 (15). HRMS (EI):
m/z [M]+ calcd for C20H15O1N1: 285.11482; found: 285.11482.
(17) Gao, Q.; Xu, S. Org. Biomol. Chem. 2018, 16, 208.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D