Synthesis of 10-aryl- and 10-(arylmethyl)acridin-9(10H)-ones via the reaction of (2-fluorophenyl)(2-halophenyl)methanones with benzenamines and arylmethanamines

Article abstract of DOI:10.1002/hlca.201200343

The reaction of 1-fluoro-2-lithiobenzenes, generated from 1-bromo-2-fluorobenzenes 1 and BuLi, with 2-halobenzaldehydes and subsequent oxidation of the resulting alcohols 2 afforded (2-fluorophenyl)(2-halophenyl) methanones 3, which, on treatment with ben

Full text of DOI:10.1002/hlca.201200343

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389
Synthesis of 10-Aryl- and 10-(Arylmethyl)acridin-9(10H)-ones via the
Reaction of (2-Fluorophenyl)(2-halophenyl)methanones with Benzenamines
and Arylmethanamines
by Kazuhiro Kobayashi*, Kazuhiro Nakagawa, Shohei Yuba, and Toshihide Komatsu
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4 – 101 Koyama-minami, Tottori 680 – 8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
The reaction of 1-fluoro-2-lithiobenzenes, generated from 1-bromo-2-fluorobenzenes 1 and BuLi,
with 2-halobenzaldehydes and subsequent oxidation of the resulting alcohols 2 afforded (2-fluorophen-
yl)(2-halophenyl)methanones 3, which, on treatment with benzenamines or arylmethanamines, followed
by NaH, gave rise efficiently to 10-aryl- or 10-(arylmethyl)acridin-9(10H)-ones (5 or 7), respectively.
Introduction. – Acridin-9(10H)-one derivatives have attracted much attention of
not only medicinal but also synthetic chemists, because a number of molecules with this
heterocyclic skeleton have been reported to exhibit a variety of biological activities
[1][2], and some have been isolated from nature [3]. The acridin-9(10H)-one structure
has been constructed by intramolecular FriedelꢀCrafts acylation of 2-(arylamino)ben-
zoic acids with appropriate acid catalysts under harsh conditions [2][4], while several
direct methods for the synthesis of 10-substituted acridin-9(10H)-ones have recently
reported by several groups [5]. In this article, we describe a new method for the
preparation of 10-substituted acridin-9(10H)-ones starting with 1-bromo-2-fluoroben-
zenes 1 and 2-halobenzaldehydes. We found that 10-aryl- and 10-(arylmethyl)acridin-
9(10H)-ones, 5 and 7, respectively, which are rather difficult to prepare by previously
described methods [2][4][5], can be obtained by the substitution reaction of (2-
fluorophenyl)(2-halophenyl)methanones 3, derived by an easy two-step sequence from
these starting materials, with benzenamines and arylmethanamines, followed by
cyclization of the resulting intermediates 4 and 6, respectively, by treatment with NaH.
After completion of this work, a similar approach, which allows the synthesis of
fluorinated acridin-9(10H)-ones by the reaction of highly fluorinated benzophenones
with primary amines under heating, has been reported as a special case [5d].
Results and Discussion. – The key precursors, (2-fluorophenyl)(2-halophenyl)me-
thanones 3, were prepared as outlined in Scheme 1. 1-Bromo-2-fluorobenzenes 1 were
treated with BuLi in Et2O at ꢀ 788 to generate 1-fluoro-2-lithiobenzenes, which were
allowed to react with 2-halobenzaldehydes to give (2-fluorophenyl)(2-halophenyl)me-
thanols 2. These were oxidized with pyridinium chlorochomates (PCC) in CH2Cl2 at
room temperature to give 3 in satisfactory yields.
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1
With these ketones 3 in hand, we tried to prepare 10-arylacridin-9(10H)-ones 5 in a
one-pot reaction from 3 and benzenamines. As indicated in Scheme 1, compounds 3
were heated with excess benzenamines at 1208. The substitution reaction proceeded
slowly, and it took ca. 10 h, until TLC analyses (silica gel) revealed disappearance of 3.
The cooled mixtures including the resulting substitution products 4 were dissolved in
DMF, and 2 equiv. of NaH were added at 08. At this temperature, cyclization proceeded
rapidly to give, after aqueous workup and subsequent recrystallization of the resulting
precipitate, the desired products 5 in good yields, as compiled in Table 1.
Subsequently, the preparation of 10-(arylmethyl)acridin-9(10H)-ones 7 was
achieved by a similar one-pot reaction as described above for the preparation of 5
(Scheme 2). Thus, heating of mixtures of 3 and arylmethanamines proceeded more
smoothly even at lower temperature (1008) than that of the reaction of 3 with
benzenamines to form (arylmethyl)amino-substituted intermediates 6 more cleanly
than the intermediates 4 (TLC on silica gel). Cyclization of the adducts 6 with NaH
required room temperature, and it proceeded slowly to give, after aqueous workup and
subsequent recrystallization of the resulting precipitate, the desired products 7 in fair-
to-good yields, as collected in Table 2.

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Table 1. Preparation of 10-Arylacridin-9(10H)-ones 5
Entry
3
Ar
5
Yielda) [%]
1
2
3
4
5
6
7
8
9
3a R1 ¼ R2 ¼ R3 ¼ R4 ¼ H, X ¼ Cl
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
85
76
77
86
79
79
84
81
86
3b R1 ¼ R2 ¼ R4 ¼ H, R3 ¼ Cl, X ¼ Br
4-MeOꢀC6H4
3-ClꢀC6H4
4-ClꢀC6H4
4-MeOꢀC6H4
4-MeꢀC6H4
Ph
3c R1 ¼ R3 ¼ R4 ¼ H, R2 ¼ X ¼ Cl
3c
3c
3d R1 ¼ R4 ¼ H, R2 ¼ Cl, R3 ¼ MeO, X ¼ Br
3e R1 ¼ H, R2 ¼ Cl, R3 ¼ R4 ¼ MeO, X ¼ Br
3f R1 ¼ R3 ¼ Cl, R2 ¼ R4 ¼ H, X ¼ Br
3f
Ph
4-MeꢀC6H4
a) Yields of the isolated products.
Scheme 2
Table 2. Preparation of 10-(Arylmethyl)acridin-9(10H)-ones 7
Entry
3
Ar
7
Yielda) [%]
1
2
3
4
5
6
7
8
9
3a R1 ¼ R2 ¼ R3 ¼ R4 ¼ H, X ¼ Cl
Ph
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
80
74
67
82
80
71
68
81
69
3b R1 ¼ R2 ¼ R4 ¼ H, R3 ¼ Cl, X ¼ Br
3b
3b
4-ClꢀC6H4
4-MeOꢀC6H4
4-MeꢀC6H4
4-MeOꢀC6H4
4-MeOꢀC6H4
Ph
3c R1 ¼ R3 ¼ R4 ¼ H, R2 ¼ X ¼ Cl
3c
3d R1 ¼ R4 ¼ H, R2 ¼ Cl, R3 ¼ MeO, X ¼ Br
3f R1 ¼ R3 ¼ Cl, R2 ¼ R4 ¼ H, X ¼ Br
3f
4-MeOꢀC6H4
a) Yields of the isolated products.
In conclusion, we have shown that 10-substituted acridin-9(10H)-ones can be
prepared via the one-pot reaction of (2-fluorophenyl)(2-halophenyl)methanones,
derived by an easy two-step sequence starting from readily available 1-bromo-2-
fluorobenzenes and 2-halobenzaldehydes, with benzenamines and arylmethanamines,
respectively. Further synthetic applications of the present methodology are currently
being explored to develop methods for preparing related heterocycles.

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Experimental Part
General. All of the org. solvents used in this study were dried over appropriate drying agents and
distilled prior to use. BuLi was supplied by Asia Lithium Corporation. All other chemicals were
commercially available. TLC: Merck silica gel 60 PF254. Column chromatography (CC): Wako Gel C-
200E.M.p.: Laboratory Devices MEL-TEMP II melting-point apparatus; uncorrected. IR Spectra:
1
PerkinꢀElmer Spectrum65 FT-IR spectrophotometer; ˜n in cmꢀ1. H-NMR Spectra: JEOL ECP500 FT
NMR spectrometer at 500 MHz or JEOL LA400 FT NMR spectrometer at 400 MHz; in CDCl3; d in ppm
rel. to Me4Si as internal standard, J in Hz. 13C-NMR Spectra: JEOL ECP500 FT NMR spectrometer at
125 MHz; in CDCl3; d in ppm rel. to Me4Si as internal standard. EI-MS (70 eV): JEOL JMS AX505 HA
spectrometer; in m/z (rel. %).
(2-Chlorophenyl)(2-fluorophenyl)methanol (2a). Representative Procedure. To a stirred soln. of 1-
bromo-2-fluorobenzene (1a; 0.90 g, 5.0 mmol) in Et2O (20 ml) at ꢀ 788 were added successively BuLi
(1.6m soln. in hexane; 5.0 mmol) and 2-chlorobenzaldehyde (0.70 g, 5.0 mmol). After 10 min, sat. aq.
NH4Cl soln. (50 ml) was added. The mixture was warmed to r.t., and the mixture was extracted with
AcOEt (3 ꢁ 25 ml). The combined extracts were washed with brine (30 ml), dried (Na2SO4), and
concentrated by evaporation. The residue was purified by CC (SiO2; AcOEt/hexane 1:8) to give 2a
1
(0.94 g, 80%). Colorless oil. Rf 0.32. IR (neat): 3334, 1615. H-NMR (500 MHz): 2.45 (s, 1 H); 6.48 (s,
1 H); 7.05 (ddd, J ¼ 9.2, 7.4, 2.3, 1 H); 7.10 (td, J ¼ 7.4, 2.3, 1 H); 7.22 – 7.34 (m, 4 H); 7.35 (dd, J ¼ 8.0, 2.3,
1 H); 7.55 (dd, J ¼ 8.0, 1.7, 1 H). Anal. calc. for C13H10ClFO (236.67): C 65.97, H 4.26; found: C 65.96, H
4.25.
(2-Bromo-5-chlorophenyl)(2-fluorophenyl)methanol (2b). Colorless oil. Rf (AcOEt/hexane 1:20)
0.36. IR (neat): 3311, 1615. 1H-NMR (500 MHz): 2.47 (d, J ¼ 4.6, 1 H); 6.38 (d, J ¼ 4.6, 1 H); 7.06 – 7.22
(m, 3 H); 7.29 – 7.40 (m, 2 H); 7.47 (d, J ¼ 8.6, 1 H); 7.61 (d, J ¼ 2.3, 1 H). Anal. calc. for C13H9BrClFO
(315.57): C 49.48, H 2.87; found: C 49.45, H 2.94.
(4-Chloro-2-fluorophenyl)(2-chlorophenyl)methanol (2c). Colorless oil. Rf (THF/hexane 1:5) 0.39.
1
IR (KBr): 3305, 1610. H-NMR (400 MHz): 2.47 (d, J ¼ 3.9, 1 H); 6.44 (d, J ¼ 3.9, 1 H); 7.08 – 7.13 (m,
2 H); 7.23 (d, J ¼ 7.8, 1 H); 7.27 – 7.38 (m, 3 H); 7.53 (dd, J ¼ 7.8, 2.0, 1 H). Anal. calc. for C13H9Cl2FO
(271.11): C 57.59, H 3.35; found: C 57.50, H 3.45.
(2-Bromo-5-methoxyphenyl)(4-chloro-2-fluorophenyl)methanol (2d). Pale-yellow oil. Rf (THF/
hexane 1:5) 0.25. IR (neat): 3371, 1611. 1H-NMR (400 MHz): 2.47 (d, J ¼ 3.9, 1 H); 3.82 (s, 3 H); 6.33 (d,
J ¼ 3.9, 1 H); 6.75 (dd, J ¼ 8.8, 2.9, 1 H); 7.09 – 7.11 (m, 3 H); 7.18 (t, J ¼ 7.8, 1 H); 7.43 (d, J ¼ 8.8, 1 H).
Anal. calc. for C14H11BrClFO2 (345.59): C 48.66, H 3.21; found: C 48.57, H 3.48.
(2-Bromo-4,5-dimethoxyphenyl)(4-chloro-2-fluorophenyl)methanol (2e). Colorless oil. Rf (THF/
hexane 1:5) 0.23. IR (neat): 3448, 1605. 1H-NMR (500 MHz): 2.44 (d, J ¼ 3.7, 1 H); 3.85 (s, 3 H); 3.88 (s,
3 H); 6.32 (d, J ¼ 3.7, 1 H); 7.01 (s, 1 H); 7.05 (s, 1 H); 7.09 – 7.12 (m, 2 H); 7.20 (dd, J ¼ 8.7, 7.8, 1 H). Anal.
calc. for C15H13BrClFO3 (375.62): C 47.96, H 3.49; found: C 47.90, H 3.50.
(2-Bromo-5-chlorophenyl)(5-chloro-2-fluorophenyl)methanol (2f). White solid. M.p. 82 – 848 (hex-
1
ane/THF). IR (KBr): 3234. H-NMR (400 MHz): 2.49 (d, J ¼ 3.9, 1 H); 6.33 (d, J ¼ 3.9, 1 H); 7.02 (dd,
J ¼ 9.8, 8.8, 1 H); 7.19 (dd, J ¼ 8.8, 2.9, 1 H); 7.23 (dd, J ¼ 4.9, 2.9, 1 H); 7.25 – 7.30 (m, 1 H); 7.49 (d, J ¼ 8.8,
1 H); 7.54 (d, J ¼ 2.0, 1 H). Anal. calc. for C13H8BrCl2FO (350.01): C 44.61, H 2.30; found: C 44.50, H
2.29.
Diarylmethanones 3. These compounds were prepared by the oxidation of 2 with PCC under the
conditions reported previously by us in [6].
(2-Chlorophenyl)(2-fluorophenyl)methanone (3a). Colorless oil. Rf (AcOEt/hexane 1:16) 0.39. IR
(neat): 1673, 1609. 1H-NMR (500 MHz): 7.10 (dd, J ¼ 9.7, 8.7, 1 H); 7.26 (ddd, J ¼ 7.8, 7.3, 1.0, 1 H); 7.34 –
7.48 (m, 4 H); 7.53 – 7.59 (m, 1 H); 7.76 (td, J ¼ 7.8, 2.0, 1 H). Anal. calc. for C13H8ClFO (234.65): C 66.54,
H 3.44; found: C 66.61, H 3.51.
(2-Bromo-5-chlorophenyl)(2-fluorophenyl)methanone (3b). White solid. M.p. 110 – 1128 (hexane/
Et2O). IR (KBr): 1662, 1607. 1H-NMR (400 MHz): 7.12 (dd, J ¼ 9.9, 9.2, 1 H); 7.27 – 7.35 (m, 2 H); 7.38 (d,
J ¼ 2.3, 1 H); 7.55 (d, J ¼ 9.2, 1 H); 7.58 – 7.65 (m, 1 H); 7.79 (td, J ¼ 7.6, 2.3, 1 H). Anal. calc. for
C13H7BrClFO (313.55): C 49.80, H 2.25; found: C 49.70, H 2.29.

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(4-Chloro-2-fluorophenyl)(2-chlorophenyl)methanone (3c). White solid. M.p. 62 – 648 (hexane/
Et2O). IR (KBr): 1664, 1601. 1H-NMR (400 MHz): 7.15 (dd, J ¼ 10.7, 2.0, 1 H); 7.27 (dd, J ¼ 7.8, 2.0, 1 H);
7.38 (ddd, J ¼ 8.8, 7.8, 2.0, 1 H); 7.42 – 7.48 (m, 3 H); 7.73 (t, J ¼ 7.8, 1 H). Anal. calc. for C13H7Cl2FO
(269.10): C 58.02, H 2.62; found: C 57.95, H 2.85.
(2-Bromo-5-methoxyphenyl)(4-chloro-2-fluorophenyl)methanone (3d). White solid. M.p. 123 – 1258
(hexane/AcOEt). IR (KBr): 1656. 1H-NMR (400 MHz): 3.82 (s, 3 H); 6.90 – 6.93 (m, 2 H); 7.15 (dd, J ¼
10.7, 2.9, 1 H); 7.26 (dd, J ¼ 8.8, 2.0, 1 H); 7.49 (d, J ¼ 8.8, 1 H); 7.72 (dd, J ¼ 8.8, 7.8, 1 H). Anal. calc. for
C14H9BrClFO2 (343.58): C 48.94, H 2.64; found: C 48.70, H 2.62.
(2-Bromo-4,5-dimethoxyphenyl)(4-chloro-2-fluorophenyl)methanone (3e). Colorless oil. Rf (THF/
hexane 1: 4) 0.32. IR (KBr): 1667. 1H-NMR (500 MHz): 3.88 (s, 3 H); 3.94 (s, 3 H); 7.01 (s, 1 H); 7.05 (s,
1 H); 7.15 (dd, J ¼ 8.2, 1.8, 1 H); 7.25 (dd, J ¼ 8.2, 1.4, 1 H); 7.65 (dd, J ¼ 8.2, 7.8, 1 H). Anal. calc. for
C15H11BrClFO3 (373.60): C 48.22, H 2.97; found: C 48.06, H 2.83.
(2-Bromo-5-chlorophenyl)(5-chloro-2-fluorophenyl)methanone (3f). White solid. M.p. 106 – 1088
(hexane/AcOEt). IR (KBr): 1655, 1602. 1H-NMR (500 MHz): 7.08 (dd, J ¼ 9.7, 9.2, 1 H); 7.35 (dd, J ¼ 8.6,
2.3, 1 H); 7.39 (d, J ¼ 2.3, 1 H); 7.52 – 7.57 (m, 2 H); 7.77 (dd, J ¼ 6.3, 2.3, 1 H). Anal. calc. for
C13H6BrCl2FO (347.99): C 44.87, H 1.74; found: C 44.62, H 1.85.
10-Phenylacridin-9(10H)-one (5a) [7]. Representative Procedure. A mixture of 3a (0.23 g, 1.0 mmol)
and PhNH2 (0.46 g, 5.0 mmol) was heated at 1208 until consumption of 3a had been confirmed by TLC
(SiO2; AcOEt/hexane 1:5; ca. 10 h). The cooled mixture was dissolved in DMF (6 ml), and NaH (60 %
in mineral oil; 80 mg, 2.0 mmol) was added to the stirred soln. at 08. Stirring was continued at the same
temp. for 20 min before H2O (30 ml) and sat. aq. NH4Cl soln. (5 ml) were added. The precipitate was
collected by filtration and recrystallized from hexane/CH2Cl2 to give 5a (0.23 g, 85%). White solid. M.p.
274 – 2778 ([7]: 2768). IR (KBr): 1634. 1H-NMR (500 MHz): 6.75 (d, J ¼ 9.2, 2 H); 7.28 (dd, J ¼ 7.6, 6.9,
2 H); 7.38 (d, J ¼ 7.6, 2 H); 7.50 (td, J ¼ 7.6, 1.5, 2 H); 7.65 (t, J ¼ 7.6, 1 H); 7.72 (t, J ¼ 7.6, 2 H); 8.59 (d, J ¼
6.9, 2 H).
2-Chloro-10-(4-methoxyphenyl)acridin-9(10H)-one (5b). Pale-yellow solid. M.p. 228 – 2308 (hexane/
CH2Cl2). IR (KBr): 1635. 1H-NMR (500 MHz): 3.96 (s, 3 H); 6.78 (d, J ¼ 9.2, 1 H); 6.82 (d, J ¼ 8.6, 1 H);
7.20 (d, J ¼ 9.2, 2 H); 7.26 (d, J ¼ 9.2, 2 H); 7.29 (d, J ¼ 7.4, 1 H); 7.42 (dd, J ¼ 9.2, 2.3, 1 H); 7.52 (ddd, J ¼
8.6, 6.9, 1.7, 1 H); 8.53 (d, J ¼ 2.3, 1 H); 8.55 (dd, J ¼ 8.0, 1.7, 1 H). 13C-NMR: 55.64; 116.25; 116.96;
118.70; 121.69; 121.79; 122.56; 126.30; 127.24; 127.42; 130.81; 130.97; 133.32; 133.51; 141.87; 143.35;
160.28; 177.06. MS: 335 (100, Mþ). Anal. calc. for C20H14ClNO2 (335.78): C 71.54, H 4.20, N 4.17; found: C
71.49, H 4.38, N 4.06.
3-Chloro-10-(3-chlorophenyl)acridin-9(10H)-one (5c). White solid. M.p. 250 – 2538 (hexane/
1
CH2Cl2). IR (KBr): 1638, 1609. H-NMR (500 MHz): 6.71 – 6.73 (m, 2 H); 7.25 (dd, J ¼ 8.6, 1.7, 1 H);
7.30 – 7.34 (m, 2 H); 7.41 (s, 1 H); 7.55 (ddd, J ¼ 8.0, 6.9, 1.1, 1 H); 7.69 – 7.71 (m, 2 H); 8.51 (d, J ¼ 8.6,
1 H); 8.56 (dd, J ¼ 8.0, 1.1, 1 H). 13C-NMR: 116.00; 116.63; 120.19; 121.92; 122.34; 122.56; 127.41; 128.31;
129.19; 130.30; 130.46; 132.32; 133.75; 136.88; 139.48; 139.94; 142.81; 143.38; 177.31. MS: 339 (100, Mþ).
Anal. calc. for C19H11Cl2NO (340.20): C 67.08, H 3.26, N 4.12; found: C 66.86, H 3.32, N 3.85.
3-Chloro-10-(4-chlorophenyl)acridin-9(10H)-one (5d). White solid. M.p. 266 – 2688 (hexane/
1
CH2Cl2). IR (KBr): 1639, 1610. H-NMR (500 MHz): 6.71 – 6.73 (m, 2 H); 7.25 (dd, J ¼ 8.6, 1.7, 1 H);
7.30 – 7.34 (m, 3 H); 7.53 (ddd, J ¼ 8.0, 6.9, 1.1, 1 H); 7.72 (d, J ¼ 8.6, 2 H); 8.51 (d, J ¼ 8.6, 1 H); 8.56 (dd,
J ¼ 8.0, 1.1, 1 H). 13C-NMR: 116.00; 116.63; 120.23; 121.95; 122.27; 122.49; 127.41; 129.29; 131.36; 131.72;
133.71; 136.08; 136.80; 139.91; 142.94; 143.51; 177.33. MS: 339 (100, Mþ). Anal. calc. for C19H11Cl2NO
(340.21): C 67.08, H 3.26, N 4.12; found: C 66.85, H 3.50, N 3.96.
3-Chloro-10-(4-methoxyphenyl)acridin-9(10H)-one (5e). White solid. M.p. 210 – 2128 (hexane/
1
CH2Cl2). IR (KBr): 1637, 1607. H-NMR (500 MHz): 3.96 (s, 3 H); 6.78 – 6.79 (m, 2 H); 7.20 – 7.30 (m,
6 H); 7.52 (dd, J ¼ 7.5, 6.9, 1 H); 8.48 – 8.56 (m, 2 H). 13C-NMR: 55.67; 116.36 (two overlapped C-atoms);
117.00; 120.23; 121.96; 122.17; 127.21; 129.02; 130.71; 130.81 (two overlapped C-atoms); 133.50; 139.67;
143.52; 144.10; 160.32; 177.47. MS: 335 (100, Mþ). Anal. calc. for C20H14ClNO2 (335.78): C 71.54, H 4.20,
N 4.17; found: C 71.38, H 4.29, N 4.16.
6-Chloro-2-methoxy-10-(4-methylphenyl)acridin-9(10H)-one (5f). Pale-yellow solid. M.p. 240 – 2428
(hexane/CH2Cl2). IR (KBr): 1638, 1616, 1597. 1H-NMR (500 MHz): 2.55 (s, 3 H); 3.94 (s, 3 H); 6.74 (d,
J ¼ 9.2, 1 H); 6.78 (s, 1 H); 7.15 (dd, J ¼ 9.2, 2.3, 1 H); 7.20 – 7.23 (m, 3 H); 7.50 (d, J ¼ 8.0, 2 H); 7.94 (d,

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Helvetica Chimica Acta – Vol. 96 (2013)
J ¼ 2.3, 1 H); 8.52 (d, J ¼ 8.6, 1 H). 13C-NMR: 21.42; 61.99; 105.91; 116.14; 118.85; 121.94; 124.21; 124.28;
126.99; 128.97; 129.47; 131.86; 135.76; 139.40; 139.98; 143.32; 146.57; 154.96; 177.18. MS: 349 (100, Mþ).
Anal. calc. for C21H16ClNO2 (349.81): C 72.10, H 4.61, N 4.00; found: C 72.12, H 4.64, N 4.03.
6-Chloro-2,3-dimethoxy-10-phenylacridin-9(10H)-one (5g). White solid. M.p. 251 – 2538 (hexane/
CHCl3). IR (KBr): 1617, 1595. 1H-NMR (500 MHz): 3.64 (s, 3 H); 4.02 (s, 3 H); 6.07 (s, 1 H); 6.72 (d, J ¼
1.7, 1 H); 7.22 (dd, J ¼ 8.6, 1.7, 1 H); 7.38 (dd, J ¼ 8.6, 1.1, 2 H); 7.69 (t, J ¼ 7.4, 1 H); 7.74 (dd, J ¼ 8.6, 7.4,
2 H); 7.93 (s, 1 H); 8.52 (d, J ¼ 8.6, 1 H). 13C-NMR: 55.75; 56.25; 98.42; 106.36; 115.75; 116.05; 119.78;
122.08; 128.83; 129.81; 130.04; 131.27; 138.54; 138.81; 139.42; 143.18; 145.92; 154.56; 175.88. MS: 365
(100, Mþ). Anal. calc. for C21H16ClNO3 (365.81): C 68.95, H 4.41, N 3.83; found: C 68.90, H 4.48, N 3.70.
2,7-Dichloro-10-phenylacridin-9(10H)-one (5h). White solid. M.p. 271 – 2738 (hexane/CH2Cl2). IR
(KBr): 1639. 1H-NMR (500 MHz): 6.71 (d, J ¼ 8.0, 2 H); 7.36 (d, J ¼ 8.0, 2 H); 7.43 (dd, J ¼ 8.0, 2.9, 2 H);
7.68 (t, J ¼ 7.4, 1 H); 7.73 (dd, J ¼ 8.0, 7.4, 2 H); 8.50 (d, J ¼ 2.9, 2 H). 13C-NMR: 118.69; 122.34; 126.35;
127.93; 129.72; 130.08; 131.36; 133.71; 138.31; 141.35; 175.91. MS: 339 (100, Mþ). Anal. calc. for
C19H11Cl2NO (340.20): C 67.08, H 3.26, N 4.12; found: C 67.06, H 3.29, N 4.08.
2,7-Dichloro-10-(4-methylphenyl)acridin-9(10H)-one (5i). White solid. M.p. 329 – 3318 (hexane/
1
CH2Cl2). IR (KBr): 1637, 1621, 1609. H-NMR (500 MHz): 2.55 (s, 3 H); 6.75 (d, J ¼ 9.2, 2 H); 7.22 (d,
J ¼ 8.0, 2 H); 7.42 (dd, J ¼ 8.0, 2.9, 2 H); 7.51 (d, J ¼ 8.0, 2 H); 8.49 (d, J ¼ 2.9, 2 H). 13C-NMR: 21.36;
118.82; 122.42; 126.35; 126.37; 127.89; 131.94; 133.69; 135.58; 140.31; 141.51; 176.03. MS: 353 (100, Mþ).
Anal. calc. for C20H13Cl2NO (354.23): C 67.81, H 3.70, N 3.95; found: C 67.72, H 3.82, N 4.05.
10-(Phenylmethyl)acridin-9(10H)-one (7a) [8]. Representative Procedure. A mixture of 3a (0.23 g,
1.0 mmol) and BnNH2 (0.53 g, 5.0 mmol) was heated at 1008 until consumption of 3a had been confirmed
by TLC (SiO2; AcOEt/hexane 1:3; ca. 5 h). The mixture was cooled to r.t. and dissolved in DMF (6 ml).
Then, NaH (60% in mineral oil; 80 mg, 2.0 mmol) was added, and the mixture was stirred overnight at
the same temp. To the cooled (08) mixture were added H2O (30 ml) and sat. aq. NH4Cl soln. (5 ml). The
precipitate was collected by filtration and recrystallized from hexane/CH2Cl2 to give 7a (0.23 g, 80%).
Yellow solid. M.p. 178 – 1808 ([8a]: 180 – 1818). The 1H-NMR data for this product were identical to those
reported in [8b].
2-Chloro-10-(phenylmethyl)acridin-9(10H)-one (7b). Yellow solid. M.p. 194 – 1968 (hexane/
CH2Cl2). IR (KBr): 1630. 1H-NMR (500 MHz): 5.59 (s, 2 H); 7.19 (d, J ¼ 6.9, 2 H); 7.29 – 7.38 (m,
6 H); 7.55 (dd, J ¼ 9.2, 2.9, 1 H); 7.65 (ddd, J ¼ 9.2, 7.4, 1.7, 1 H); 8.54 (d, J ¼ 2.9, 1 H); 8.57 (dd, J ¼ 8.0, 1.7,
1 H). 13C-NMR: 50.91; 115.23; 117.03; 121.99; 122.42; 123.38; 125.54; 126.89; 127.60; 127.82; 127.98;
129.33; 134.07; 134.38; 135.01; 140.91; 142.39; 177.13. MS: 319 (100, Mþ). Anal. calc. for C20H14ClNO
(319.78): C 75.12, H 4.41, N 4.38; found: C 74.91, H 4.26, N 4.28.
2-Chloro-10-[(4-chlorophenyl)methyl]acridin-9(10H)-one (7c). Yellow solid. M.p. 221 – 2238 (hex-
1
ane/CH2Cl2). IR (KBr): 1631. H-NMR (500 MHz): 5.55 (s, 2 H); 7.13 (d, J ¼ 8.0, 2 H); 7.25 (d, J ¼ 9.2,
1 H); 7.30 – 7.35 (m, 4 H); 7.56 (dd, J ¼ 9.2, 2.9, 1 H); 7.66 (dd, J ¼ 8.0, 7.4, 1 H); 8.54 (d, J ¼ 2.9, 1 H); 8.58
(d, J ¼ 8.0, 1 H). 13C-NMR: 50.34; 114.98; 116.78; 122.14; 122.41; 123.39; 126.99 (two overlapped C-
atoms); 127.74; 127.90; 129.53; 133.52; 133.89; 134.14; 134.46; 140.70; 142.18; 177.03. MS: 353 (100, Mþ).
Anal. calc. for C20H13Cl2NO (354.23): C 67.81, H 3.70, N 3.95; found: C 68.01, H 3.62, N 4.03.
2-Chloro-10-[(4-methoxyphenyl)methyl]acridin-9(10H)-one (7d). Yellow solid. M.p. 205 – 2078
1
(hexane/CH2Cl2). IR (KBr): 1634. H-NMR (500 MHz): 3.79 (s, 3 H); 5.53 (s, 2 H); 6.89 (d, J ¼ 9.2,
2 H); 7.10 (d, J ¼ 9.2, 2 H); 7.30 – 7.33 (m, 2 H); 7.38 (d, J ¼ 8.6, 1 H); 7.56 (dd, J ¼ 9.2, 2.3, 1 H); 7.66 (dd,
J ¼ 8.6, 6.9, 1 H); 8.54 (d, J ¼ 2.3, 1 H); 8.57 (d, J ¼ 8.0, 1 H). 13C-NMR: 50.36; 55.27; 114.68; 115.28;
117.11; 121.92; 122.33; 123.28; 126.72; 126.77; 127.49; 127.72 (two overlapped C-atoms); 134.02; 134.34;
140.84; 142.33; 159.27; 177.11. MS: 349 (100, Mþ). Anal. calc. for C21H16ClNO2 (349.81): C 72.10, H 4.61,
N 4.00; found: C 72.26, H 4.65, N 3.73.
3-Chloro-10-[(4-methylphenyl)methyl]acridin-9(10H)-one (7e). Yellow solid. M.p. 197 – 1998 (hex-
ane/CH2Cl2). IR (KBr): 1637, 1607. 1H-NMR (500 MHz): 2.36 (s, 3 H); 5.52 (s, 2 H); 7.09 (d, J ¼ 8.0, 2 H);
7.18 (d, J ¼ 8.0, 2 H); 7.25 (d, J ¼ 1.7, 1 H); 7.31 – 7.36 (m, 3 H); 7.64 (ddd, J ¼ 8.6, 6.9, 1.7, 1 H); 8.52 (d, J ¼
8.6, 1 H); 8.57 (dd, J ¼ 8.0, 1.7, 1 H). 13C-NMR: 21.08; 50.73; 114.92; 115.41; 120.95; 122.09; 122.31;
122.68; 125.49; 127.71; 129.42; 130.01; 131.69; 134.27; 137.78; 140.47; 142.52; 143.24; 177.51. MS: 333 (100,
Mþ). Anal. calc. for C21H16ClNO (333.81): C 75.56, H 4.83, N 4.20; found: C 75.43, H 4.87, N 4.08.

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3-Chloro-10-[(4-methoxyphenyl)methyl]acridin-9(10H)-one (7f). Yellow solid. M.p. 199 – 2018
(hexane/CH2Cl2). IR (KBr): 1637. 1H-NMR (500 MHz): 3.80 (s, 3 H); 5.50 (s, 2 H); 6.91 (d, J ¼ 8.6,
2 H); 7.12 (d, J ¼ 8.6, 2 H); 7.25 (dd, J ¼ 8.0, 1.7, 1 H); 7.32 (dd, J ¼ 8.0, 6.9, 1 H); 7.36 (d, J ¼ 1.7, 1 H); 7.37
(d, J ¼ 7.4, 1 H); 7.65 (ddd, J ¼ 8.6, 6.9, 1.7, 1 H); 8.52 (d, J ¼ 8.6, 1 H); 8.57 (dd, J ¼ 8.0, 1.7, 1 H).
13C-NMR: 50.42; 55.32; 114.75; 114.92; 115.40; 120.93; 122.10; 122.28; 122.67; 126.53; 126.77; 127.72;
129.43; 134.29; 140.48; 142.50; 143.24; 159.31; 177.50. MS: 349 (100, Mþ). Anal. calc. for C21H16ClNO2
(349.81): C 72.10, H 4.61, N 4.00; found: C 72.07, H 4.62, N 3.73.
6-Chloro-2-methoxy-10-[(4-methoxyphenyl)methyl]acridin-9(10H)-one (7g). Yellow solid. M.p.
205 – 2078 (hexane/CH2Cl2). IR (KBr): 1637, 1619. 1H-NMR (500 MHz): 3.79 (s, 3 H); 3.94 (s, 3 H);
5.50 (s, 2 H); 6.89 (d, J ¼ 8.6, 2 H); 7.10 (d, J ¼ 8.6, 2 H); 7.24 (d, J ¼ 8.6, 1 H); 7.28 (dd, J ¼ 9.2, 2.9, 1 H);
7.33 (d, J ¼ 9.2, 1 H); 7.36 (s, 1 H); 7.96 (d, J ¼ 2.9, 1 H); 8.53 (d, J ¼ 8.6, 1 H). 13C-NMR: 50.40; 55.32;
55.82; 106.69; 114.67; 114.74; 117.20; 120.16; 121.98; 124.82; 126.65; 126.74 (two overlapped C-atoms);
129.44; 137.19; 140.25; 142.73; 155.00; 159.33; 176.98. MS: 379 (100, Mþ). Anal. calc. for C22H18ClNO3
(379.84): C 69.57, H 4.78, N 3.69; found: C 69.67, H 4.70, N 3.68.
2,7-Dichloro-10-(phenylmethyl)acridin-9(10H)-one (7h). Yellow solid. M.p. 280 – 2828 (hexane/
CHCl3). IR (KBr): 1630. 1H-NMR (500 MHz): 5.58 (s, 2 H); 7.16 (d, J ¼ 7.4, 2 H); 7.30 (d, J ¼ 9.2, 2 H);
7.34 – 7.39 (m, 3 H); 7.57 (dd, J ¼ 9.2, 2.3, 2 H); 8.51 (d, J ¼ 2.3, 2 H). 13C-NMR: 51.13; 117.14; 123.24;
124.87; 125.46; 127.14; 128.18; 129.55; 134.47; 134.55; 140.92; 176.07. MS: 353 (100, Mþ). Anal. calc. for
C20H13Cl2NO (354.23): C 67.81, H 3.70, N 3.95; found: C 67.73, H 3.75, N 3.86.
2,7-Dichloro-10-[(4-methoxyphenyl)methyl]acridin-9(10H)-one (7i). Yellow solid. M.p. 283 – 2858
(hexane/CHCl3). IR (KBr): 1632. 1H-NMR (500 MHz): 3.79 (s, 3 H); 5.51 (s, 2 H); 6.89 (d, J ¼ 8.6, 2 H);
7.07 (d, J ¼ 8.6, 2 H); 7.32 (d, J ¼ 9.2, 2 H); 7.57 (dd, J ¼ 9.2, 2.9, 2 H); 8.50 (d, J ¼ 2.9, 2 H). 13C-NMR:
50.56; 55.31; 114.79; 117.18; 123.14; 126.27; 126.67; 126.85; 127.94; 134.37; 140.71; 159.41; 175.99. MS: 383
(100, Mþ). Anal. calc. for C21H15Cl2NO2 (384.26): C 65.64, H 3.93, N 3.65; found: C 65.53, H 3.88, N 3.54.
We are indebted to Mrs. Miyuki Tanmatsu of our University for recording mass spectra and
performing combustion analyses.
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Received July 3, 2012