Synthesis of N,N-dialkyl-9-oxoacridine-10(9H)-carbothioamides via the reaction of (2-halophenyl)(2-isothiocyanatophenyl)methanones with secondary amines, followed by cyclization with NaH

Article abstract of DOI:10.1002/hlca.201300247

The first preparation of acridin-9(10H)-ones carrying a tertiary thiocarbamoyl group at C(10), i.e., N,N-dialkyl-9-oxoacridine-10(9H)- carbothioamides 9, is described. The method is based on the reaction of (2-halophenyl)(2-isothiocyanatophenyl)methanones 7, prepared from (2-aminophenyl)(2-halophenyl)methanones 5 by a convenient three-step sequence, with secondary amines in DMF at room temperature to generate the corresponding thiourea derivatives 8 in situ, which are treated with NaH at 100-120° to provide the desired products in one-pot reactions in generally good yields.

Full text of DOI:10.1002/hlca.201300247

Helvetica Chimica Acta – Vol. 96 (2013)
2033
Synthesis of N,N-Dialkyl-9-oxoacridine-10(9H)-carbothioamides via the
Reaction of (2-Halophenyl)(2-isothiocyanatophenyl)methanones with
Secondary Amines, Followed by Cyclization with NaH
by Kazuhiro Kobayashi*, Kazuhiro Nakagawa, and Shohei Yuba
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 first preparation of acridin-9(10H)-ones carrying a tertiary thiocarbamoyl group at C(10), i.e.,
N,N-dialkyl-9-oxoacridine-10(9H)-carbothioamides 9, is described. The method is based on the reaction
of (2-halophenyl)(2-isothiocyanatophenyl)methanones 7, prepared from (2-aminophenyl)(2-halophe-
nyl)methanones 5 by a convenient three-step sequence, with secondary amines in DMF at room
temperature to generate the corresponding thiourea derivatives 8 in situ, which are treated with NaH at
100 – 1208 to provide the desired products in one-pot reactions in generally good yields.
Introduction. – There has been an increasing interest in the development of novel
and efficient methods for the synthesis of acridin-9(10H)-one derivatives [1][2]
because of their biological activities [2][3] and occurrence in nature [4]. In a previous
article [2], we have described a simple method for the preparation of 10-aryl- or 10-
(arylmethyl)acridin-9(10H)-ones, based on the reaction of (2-fluorophenyl)(2-halo-
phenyl)methanones with benzenamines or arylmethanamines. Herein, we report a
convenient method, which allows the preparation of a novel type of acridin-9(10H)-
ones, N,N-dialkyl-9-oxoacridine-10(9H)-carbothioamides 9, possessing a tertiary
thiocarbamoyl substituent at N(10). The method relies on cyclization of the
corresponding thiourea intermediates 8, derived by the addition of secondary amines
to the isothiocyanate C-atom of (2-halophenyl)(2-isothiocyanatophenyl)methanones 7.
Results and Discussion. – As outlined in Scheme 1, the key precursors of our
synthesis, (2-halophenyl)(2-isothiocyanatophenyl)methanones 7, were prepared via
six-step sequence starting with 1,1-dimethylethyl N-phenylcarbamates 1 and 2-
halobenzaldehydes 2 in general. The reaction of 1,1-dimethylethyl N-lithio-N-(2-
lithiophenyl)carbamates, generated from 1 and tBuLi by the method of Muchowski and
Venuti [5], with 2 gave the corresponding alcohols 3 in moderate yields. These alcohols
were oxidized with PCC (pyridinium chlorochromate) to produce the corresponding
ketones 4 in good yields. De(tert-butoxycarbonylation) of 4 with TFA (CF3COOH)
allowed the quite easy formation of 2-aminophenyl 2-halophenyl ketones 5a – 5c.
These ketones (without any purification) and the commercially available 2-amino-5-
chlorophenyl 2-chlorophenyl ketone (5d) were treated with HCO2H to give the
corresponding formamides 6 in good yields. Dehydrations of 6 with POCl3 gave the
corresponding isocyanides, which, without any purification, on treatment with S8 in the
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

2034
Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 1
presence of a catalytic amount of Se under the conditions reported by Fujiwara et al.
[6], afforded 7 in good overall yields.
The one-pot transformation of 7 into N,N-dialkyl-9-oxoacridine-10(9H)-carbo-
thioamides 9 was conducted as outlined in Scheme 2. The reaction of 7 with secondary
amines proceeded rapidly in DMF at room temperature to form the corresponding
thiourea derivatives 8. After complete consumption of 7 (TLC (SiO2)), NaH was
added at the same temperature. Cyclization took place generally by heating at 1008 at
an appropriate rate, and the desired products 9 were obtained, after aqueous workup
and subsequent recrystallization of the residual solid, in generally good yields as
compiled in the Table. When substrate 7b was used, cyclization required somewhat
higher temperature (1208), and the yield of the corresponding product 9d was lower
than those using the other substrates 7, probably due to the electron-donating MeO
i
substituent (Entry 4). It should be noted that the use of Pr2NH leads to the
corresponding product 9g in considerably lower yield than those of the others
i
(Entry 7). This result may be attributed to the steric bulkiness due to two Pr groups.
In conclusion, we have demonstrated that the method based on the reaction of (2-
halophenyl)(2-isothiocyanatophenyl)methanones with secondary amines, followed by
treatment of the resulting thiourea derivatives with NaH, provides the first and
convenient route to N,N-dialkyl-9-oxoacridine-10(9H)-carbothioamides. Investiga-
tions toward the synthesis of related derivatives utilizing the present methodology are
now in progress in our laboratory.

Helvetica Chimica Acta – Vol. 96 (2013)
2035
Scheme 2
Table. Preparation of N,N-Disubstituted 9-Oxo-9H-acridine-10-carbothioamides 9
Entry
7
R3
Et
R4
Temp. [8]
Time [h]
9
Yielda) [%]
1
2
3
4
5
6
7
8
9
7a
7a
7a
7b
7c
7d
7d
7d
7d
7d
7d
Et
ꢀ(CH2)4ꢀ
ꢀ(CH2)5ꢀ
ꢀ(CH2)2O(CH2)2ꢀ
Et
100
100
100
120
100
100
100
100
100
100
100
1
2
2
8
1.5
2
5
3
2
9a
9b
9c
9d
9e
9f
9g
9h
9i
78
77
82
65
72
79
50
95
90
80
82
Et
Et
iPr
Et
iPr
ꢀ(CH2)4ꢀ
ꢀ(CH2)5ꢀ
ꢀ(CH2)2O(CH2)2ꢀ
Me
10
11
2
2
9j
9k
Ph
a) Yields of isolated products.
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: Silica gel 60 PF254 (Merck). 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 or JEOL LA400 FT-NMR spectrometer (at 500 or 400 MHz, resp.) 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. %). HR-MS (DART, pos.): Thermo Scientific Exactive spectrometer; in m/z.
1,1-Dimethylethyl {2-[(2-Chlorophenyl)(hydroxy)methyl]phenyl}carbamate (3a). Representative
Procedure. To a stirred soln. of 1,1-dimethylethyl (lithio)(2-lithiophenyl)carbamate in THF (6 ml) at
ꢀ 788, generated from 1,1-dimethylethyl phenylcarbamate (1; 0.39 g, 2.0 mmol) and tBuLi (4.0 mmol) as
described by Muchowski and Venuti [5], was added 2-chlorobenzaldehyde (2; 0.28 g, 2.0 mmol). After
15 min, sat. aq. NH4Cl (20 ml) was added, and the mixture was extracted with AcOEt (3 ꢁ 15 ml). The
combined extracts were washed with brine, dried (Na2SO4), and concentrated by evaporation. The
residue was purified by CC (SiO2) to give 3a (0.32 g, 48%). Yellow oil. Rf (THF/hexane 1:10) 0.18. IR
(neat): 3366, 1704. 1H-NMR (400 MHz): 1.52 (s, 9 H); 3.39 (br. s, 1 H); 6.23 (d, J ¼ 3.9, 1 H); 6.92 (d, J ¼
7.8, 1 H); 7.02 (t, J ¼ 7.8, 1 H); 7.27 – 7.38 (m, 4 H); 7.46 (br. s, 1 H); 7.62 (d, J ¼ 7.8, 1 H); 7.72 (d, J ¼ 7.8,
1 H). Anal. calc. for C18H20ClNO3 (333.81): C 64.77, H 6.04, N 4.20; found: C 64.58, H 6.17, N 4.24.
1,1-Dimethylethyl {2-[(2-Bromo-5-methoxyphenyl)(hydroxyl)methyl]phenyl}carbamate (3b). Pale-
1
yellow solid. M.p. 109 – 1128 (hexane/THF). IR (KBr): 3388, 3348, 1696. H-NMR (400 MHz): 1.52 (s,
9 H); 3.45 (br., 1 H); 3.81 (s, 3 H); 6.12 (d, J ¼ 3.9, 1 H); 6.76 (dd, J ¼ 8.8, 2.9, 1 H); 6.93 (dd, J ¼ 7.8, 2.0,
1 H); 7.03 (dd, J ¼ 7.8, 6.8, 1 H); 7.21 (d, J ¼ 2.9, 1 H); 7.26 – 7.31 (m, 1 H); 7.34 (br. s, 1 H); 7.43 (d, J ¼ 8.8,

2036
Helvetica Chimica Acta – Vol. 96 (2013)
1 H); 7.68 (d, J ¼ 7.8, 1 H). Anal. calc. for C19H22BrNO4 (408.29): C 55.89, H 5.43, N 3.43; found: C 55.80,
H 5.44, N 3.14.
1,1-Dimethylethyl {2-[(2-Chlorophenyl)(hydroxyl)methyl]-4-methylphenyl}carbamate (3c). Yellow
solid. M.p. 137 – 1388 (hexane/THF). IR (KBr): 3470, 3298, 1695. 1H-NMR (500 MHz): 1.50 (s, 9 H); 2.21
(s, 3 H); 3.52 (br. s, 1 H); 6.19 (d, J ¼ 4.0, 1 H); 6.77 (s, 1 H); 7.09 (d, J ¼ 8.0, 1 H); 7.14 (br. s, 1 H); 7.27
(dd, J ¼ 8.0, 1.7, 1 H); 7.32 – 7.36 (m, 2 H); 7.48 (d, J ¼ 8.0, 1 H); 7.64 (d, J ¼ 7.4, 1 H). Anal. calc. for
C19H22ClNO3 (347.84): C 65.61, H 6.38, N 4.03; found: C 65.56, H 6.44, N 4.01.
Compounds 4 were prepared by the PCC oxidation of 3 under conditions reported in [7].
1,1-Dimethylethyl [2-(2-Chlorobenzoyl)phenyl]carbamate (4a). Yellow oil. Rf (THF/hexane 1:4)
0.52. IR (neat): 3284, 1732, 1642, 1606. 1H-NMR (400 MHz): 1.57 (s, 9 H); 6.93 (t, J ¼ 6.9, 1 H); 7.32 – 7.37
(m, 3 H); 7.44 – 7.47 (m, 2 H); 7.55 (dd, J ¼ 7.8, 6.8, 1 H); 8.55 (d, J ¼ 7.8, 1 H); 10.85 (br. s, 1 H). Anal.
calc. for C18H18ClNO3 (331.79): C 65.16, H 5.47, N 4.22; found: C 65.14, H 5.68, N 3.93.
1,1-Dimethylethyl [2-(2-Bromo-5-methoxybenzoyl)phenyl]carbamate (4b). White solid. M.p. 118 –
1
1228 (hexane/AcOEt). IR (KBr): 3279, 1727, 1639, 1606. H-NMR (500 MHz): 1.55 (s, 9 H); 3.80 (s,
3 H); 6.81 (d, J ¼ 3.4, 1 H); 6.89 – 6.94 (m, 2 H); 7.35 (dd, J ¼ 8.0, 1.1, 1 H); 7.51 (d, J ¼ 8.6, 1 H); 7.55 (ddd,
J ¼ 8.6, 6.9, 1.8, 1 H); 8.55 (d, J ¼ 8.6, 1 H); 10.82 (br. s, 1 H). Anal. calc. for C19H20BrNO4 (406.27): C
56.17, H 4.96, N 3.45; found: C 56.02, H 5.07, N 3.37.
1,1-Dimethylethyl [2-(2-Chlorobenzoyl)-4-methylphenyl]carbamate (4c). Yellow oil. Rf (AcOEt/
1
hexane 1:4) 0.53. IR (neat): 3287, 1731, 1640. H-NMR (500 MHz): 1.54 (s, 9 H); 2.20 (s, 3 H); 7.09 (s,
1 H); 7.30 (d, J ¼ 7.4, 1 H); 7.35 – 7.38 (m, 2 H); 7.43 (d, J ¼ 8.0, 1 H); 7.47 (dd, J ¼ 8.0, 7.4, 1 H); 8.43 (d,
J ¼ 8.6, 1 H); 10.71 (s, 1 H). Anal. calc. for C19H20ClNO3 (345.82): C 65.99, H 5.83, N 4.05; found: C 66.05,
H 6.06, N 4.01.
N-[2-(2-Chlorobenzoyl)phenyl]formamide (6a). Representative Procedure. Compound 4a (0.40 g,
1.2 mmol) was dissolved in TFA (1.5 ml), and the soln. was stirred at r.t. for 10 min. TFA was removed
under reduced pressure, and the residual crude (2-aminophenyl)(2-chlorophenyl)methanone (5a) [8] was
used in the next step without any purification. The N-formylation of the crude compound with HCO2H
under conditions reported in [9] gave 6a (0.27 g, 88%). Yellow solid. M.p. 93 – 948 (hexane/CH2Cl2). IR
(KBr): 3317, 1698, 1643, 1604. 1H-NMR (400 MHz): 7.06 – 7.64 (m, 7 H); 8.59 – 11.46 (m, 3 H). Anal. calc.
for C14H10ClNO2 (259.69): C 64.75, H 3.88, N 5.39; found: C 64.71, H 3.85, N 5.21.
N-[2-(2-Bromo-5-methoxybenzoyl)phenyl]formamide (6b). Beige solid. M.p. 125 – 1278 (hexane/
AcOEt). IR (KBr): 3300, 1696, 1644. 1H-NMR (400 MHz): 3.81 (s, 3 H); 6.83 (d, J ¼ 2.9, 1 H); 6.92 (dd,
J ¼ 8.8, 2.9, 1 H); 7.08 (t, J ¼ 7.8, 1 H); 7.41 (d, J ¼ 7.8, 1 H); 7.52 (d, J ¼ 8.8, 1 H); 7.61 (t, J ¼ 7.8, 1 H); 8.59
(s, 1 H); 8.80 (d, J ¼ 7.8, 1 H); 11.41 (br. s, 1 H). Anal. calc. for C15H12BrNO3 (334.16): C 53.91, H 3.62, N
4.19; found: C 54.01, H 3.64, N 4.15.
N-[2-(2-Chlorobenzoyl)-4-methylphenyl]formamide (6c). Pale-yellow solid. M.p. 95 – 968 (hexane/
Et2O). IR (KBr): 3289, 1702, 1631. 1H-NMR (500 MHz): 2.25 (s, 3 H), 7.15 (s, 1 H); 7.33 (d, J ¼ 7.4, 1 H);
7.38 – 7.42 (m, 2 H); 7.45 – 7.50 (m, 2 H); 8.55 (s, 1 H); 8.69 (d, J ¼ 8.6, 1 H); 11.32 (br. s, 1 H). Anal. calc.
for C15H12ClNO2 (273.71): C 65.82, H 4.42, N 5.12; found: C 65.82, H 4.43, N 5.09.
N-[4-Chloro-2-(2-chlorobenzoyl)phenyl]formamide (6d). Yellow solid. M.p. 103 – 1058 (hexane/
Et2O). IR (KBr): 3300, 1697, 1646. 1H-NMR (400 MHz): 7.33 – 7.58 (m, 6 H); 8.57 (s, 1 H); 8.81 (d, J ¼
8.8, 1 H); 11.30 (br. s, 1 H). Anal. calc. for C14H9Cl2NO2 (294.13): C 57.17, H 3.08, N 4.76; found: C 57.06,
H 3.29, N 4.75.
(2-Halophenyl)(2-Isothiocyanatophenyl)methanones 7. Compounds 6 were dehydrated with POCl3
under conditions reported in [10] to give the corresponding ketones 7. The crude isocyanides were treated
with S8 in the presence of a cat. amount of Se under conditions reported by Fujiwara et al. [6] to give 7.
(2-Chlorophenyl)(2-isothiocyanatophenyl)methanone (7a). Reddish-brown oil. Rf (AcOEt/hexane
1
1:3) 0.52. IR (neat): 2091, 1672. H-NMR (400 MHz): 7.30 – 7.57 (m, 7 H); 7.61 (d, J ¼ 7.8, 1 H). Anal.
calc. for C14H8ClNOS (273.74): C 61.43, H 2.95, N 5.12; found: C 61.47, H 2.98, N 5.08.
(2-Bromo-5-methoxyphenyl)(2-isothiocyanatophenyl)methanone (7b). Reddish-brown oil. Rf
1
(AcOEt/hexane 1:10) 0.24. IR (neat): 2106, 1674. H-NMR (400 MHz): 3.83 (s, 3 H); 6.92 (dd, J ¼ 8.8,
2.9, 1 H); 6.98 (d, J ¼ 2.9, 1 H); 7.32 – 7.35 (m, 2 H); 7.50 – 7.56 (m, 2 H); 7.61 (d, J ¼ 6.9, 1 H). Anal. calc.
for C15H10BrNO2S (348.21): C 51.74, H 2.89, N 4.02; found: C 51.65, H 3.17, N 3.85.

Helvetica Chimica Acta – Vol. 96 (2013)
2037
(2-Chlorophenyl)(2-isothiocyanato-5-methylphenyl)methanone (7c). Reddish-brown oil. Rf
1
(AcOEt/hexane 1:3) 0.55. IR (neat): 2110, 1672. H-NMR (400 MHz): 2.37 (s, 3 H); 7.22 (d, J ¼ 7.8,
1 H); 7.34 (dd, J ¼ 8.8, 2.0, 1 H); 7.39 – 7.44 (m, 2 H); 7.45 – 7.50 (m, 3 H). Anal. calc. for C15H10ClNOS
(287.76): C 62.61, H 3.50, N 4.87; found: C 62.52, H 3.64, N 4.90.
(5-Chloro-2-isothiocyanatophenyl)(2-chlorophenyl)methanone (7d). Pale-yellow solid. M.p. 54 – 568
(hexane). IR (KBr): 2098, 1679. 1H-NMR (400 MHz): 7.27 (d, J ¼ 6.8, 1 H); 7.41 – 7.54 (m, 5 H); 7.57 (d,
J ¼ 2.0, 1 H). Anal. calc. for C14H7Cl2NOS (308.18): C 54.56, H 2.29, N 4.54; found: C 54.58, H 2.30, N
4.27.
N,N-Diethyl-9-oxoacridine-10(9H)-carbothioamide (9a). Representative Procedure. To a stirred soln.
of 7a (97 mg, 0.36 mmol) in DMF (1.2 ml) at r.t. was added Et2NH (26 mg, 0.36 mmol) dropwise. After
complete consumption of 7a (TLC (SiO2; AcOEt/hexane 1:3; within 5 min), NaH (60% in mineral oil;
14 mg, 0.36 mmol) was added, and the mixture was heated at 1008 until disappearance of the thiourea
intermediate 8a (TLC (SiO2; AcOEt/hexane 1:3; ca. 1 h). Sat. aq. NH4Cl (10 ml) was added, and the
mixture was extracted with AcOEt (3 ꢁ 10 ml). The combined extracts were washed with H2O and brine,
and dried (Na2SO4). Evaporation of the solvent gave a residual solid, which was recrystallized from
hexane/CH2Cl2 to give 9a (87 mg, 78%). Pale-yellow solid. M.p. 159 – 1618. IR (KBr): 1646, 1605, 1255.
1H-NMR (500 MHz): 0.97 (t, J ¼ 7.4, 3 H); 1.62 (t, J ¼ 6.9, 3 H); 3.28 (q, J ¼ 7.4, 2 H); 4.24 (q, J ¼ 6.9,
2 H); 7.34 – 7.40 (m, 4 H); 7.70 (dd, J ¼ 8.0, 7.4, 2 H); 8.54 (d, J ¼ 8.0, 2 H). 13C-NMR: 10.36; 13.26; 47.13;
47.77; 115.67; 121.78; 122.48; 127.55; 133.93; 139.02; 177.78; 180.31. MS: 310 (100, Mþ). Anal. calc. for
C18H18N2OS (310.41): C 69.65, H 5.84, N 9.02; found: C 69.63, H 5.64, N 9.22.
10-(Pyrrolidin-1-ylcarbonothioyl)acridin-9(10H)-one (9b). Pale-yellow solid. M.p. 163 – 1648 (hex-
1
ane/CH2Cl2). IR (KBr): 1640, 1604, 1257. H-NMR (500 MHz): 1.96 (quint., J ¼ 6.9, 2 H); 2.17 (quint.,
J ¼ 6.9, 2 H); 3.20 (t, J ¼ 6.9, 2 H); 4.14 (t, J ¼ 6.9, 2 H); 7.34 – 7.38 (m, 4 H); 7.71 (ddd, J ¼ 8.0, 6.9, 1.7,
2 H); 8.55 (dd, J ¼ 8.0, 1.7, 2 H). 13C-NMR: 24.76; 25.84; 51.21; 53.83; 115.15; 121.81; 122.43; 127.73;
134.19; 138.17; 177.55; 177.74. MS: 308 (100, Mþ). Anal. calc. for C18H16N2OS (308.40): C 70.10, H 5.23, N
9.08; found: C 69.96, H 5.26, N 9.06.
10-(Piperidin-1-ylcarbonothioyl)acridin-9(10H)-one (9c). Pale-yellow solid. M.p. 186 – 1888 (hex-
1
ane/CH2Cl2). IR (KBr): 1637, 1605, 1251. H-NMR (500 MHz): 1.44 (quint., J ¼ 5.7, 2 H); 1.72 (quint.,
J ¼ 5.7, 2 H); 1.98 (quint., J ¼ 5.7, 2 H); 3.30 (t, J ¼ 5.7, 2 H); 4.51 (quint., J ¼ 5.7, 2 H); 7.35 (dd, J ¼ 8.0, 7.4,
2 H); 7.40 (d, J ¼ 8.5, 2 H); 7.70 (ddd, J ¼ 8.5, 7.4, 1.1, 2 H); 8.54 (d, J ¼ 8.0, 2 H). 13C-NMR: 23.64; 25.39;
26.50; 50.92; 51.74; 115.65; 121.73; 122.46; 127.58; 134.00; 138.66; 177.69; 179.24. MS: 322 (100, Mþ).
Anal. calc. for C19H18N2OS (322.42): C 70.78, H 5.63, N 8.69; found: C 70.81, H 5.80, N 8.72.
2-Methoxy-10-(morpholin-4-ylcarbonothioyl)acridin-9(10H)-one (9d). Yellow solid. M.p. 196 – 1988
(hexane/CH2Cl2). IR (KBr): 1643, 1605, 1274. 1H-NMR (400 MHz): 3.29 (t, J ¼ 4.9, 2 H); 3.50 (t, J ¼ 4.9,
2 H); 3.94 (s, 3 H); 4.00 (t, J ¼ 4.9, 2 H); 4.52 – 4.56 (m, 2 H); 7.35 – 7.38 (m, 4 H); 7.68 – 7.72 (m, 1 H); 7.94
(br. s, 1 H); 8.55 (dd, J ¼ 7.8, 2.0, 1 H). 13C-NMR: 49.94; 50.38; 55.83; 66.02; 66.29; 106.82; 115.18; 117.12;
120.97; 122.40; 122.57; 124.83; 127.73; 133.40; 133.96; 138.18; 155.45; 177.15; 180.36. MS: 354 (100, Mþ).
Anal. calc. for C19H18N2O3S (354.42): C 64.39, H 5.12, N 7.90; found: C 64.35, H 5.13, N 7.70.
N,N-Diethyl-2-methyl-9-oxoacridine-10(9H)-carbothioamide (9e). Pale-yellow solid. M.p. 157 – 1588
(hexane/CH2Cl2). IR (KBr): 1648, 1604, 1258. 1H-NMR (500 MHz): 0.96 (t, J ¼ 7.4, 3 H); 1.60 (t, J ¼ 7.4,
3 H); 2.48 (s, 3 H); 3.26 (q, J ¼ 7.4, 2 H); 4.23 (q, J ¼ 7.4, 2 H); 7.30 (d, J ¼ 8.6, 1 H); 7.33 – 7.38 (m, 2 H);
7.52 (dd, J ¼ 8.6, 2.3, 1 H), 7.67 (ddd, J ¼ 8.6, 6.9, 1.7, 1 H); 8.32 (s, 1 H); 8.53 (dd, J ¼ 8.0, 1.7, 1 H).
13C-NMR: 10.38; 13.28; 20.72; 47.09; 37.74; 115.54; 115.66; 121.68; 121.70; 122.22; 126.87; 127.58; 132.27;
133.74; 135.34; 137.20; 138.91; 177.75; 180.57. MS: 324 (100, Mþ). Anal. calc. for C19H20N2OS (324.44): C
70.34, H 6.21, N 8.63; found: C 70.17, H 6.21, N 8.60.
2-Chloro-N,N-diethyl-9-oxoacridine-10(9H)-carbothioamide (9f). Pale-yellow solid. M.p. 184 – 1858
(hexane/CH2Cl2). IR (KBr): 1648, 1605, 1257. 1H-NMR (400 MHz): 0.98 (t, J ¼ 6.8, 3 H); 1.60 (t, J ¼ 6.8,
3 H); 3.22 – 3.31 (m, 2 H); 4.15 – 4.31 (m, 2 H); 7.35 – 7.38 (m, 3 H); 7.63 (dd, J ¼ 8.8, 2.9, 1 H); 7.71 (dd,
J ¼ 8.8, 6.9, 1 H); 8.49 (d, J ¼ 2.9, 1 H); 8.51 (d, J ¼ 7.8, 1 H). 13C-NMR: 10.36; 13.36; 47.17; 47.84; 115.68;
117.57; 121.60; 122.67; 122.86; 126.77; 127.65; 128.44; 134.00; 134.29; 137.45; 138.88; 176.70; 179.71. MS:
344 (100, Mþ). Anal. calc. for C18H17ClN2OS (344.86): C 62.69, H 4.97, N 8.12; found: C 62.64, H 5.14, N
8.14.

2038
Helvetica Chimica Acta – Vol. 96 (2013)
2-Chloro-N,N-bis(1-methylethyl)-9-oxoacridine-10(9H)-carbothioamide (9g). Beige solid. M.p.
1
257 – 2598 (hexane/CH2Cl2). IR (KBr): 1646, 1604, 1258. H-NMR (500 MHz): 1.04 (d, J ¼ 6.9, 6 H);
1.97 (br. s, 6 H); 3.83 – 3.89 (m, 1 H); 4.07 (br., 1 H); 7.36 (dd, J ¼ 8.0, 7.4, 1 H); 7.41 (d, J ¼ 8.6, 1 H); 7.43
(d, J ¼ 8.0, 1 H); 7.63 (dd, J ¼ 8.6, 1.1, 1 H); 7.72 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 8.50 (d, J ¼ 1.1, 1 H); 8.52 (dd,
J ¼ 8.0, 1.1, 1 H). 13C-NMR: 18.12; 20.34; 51.12; 56.38; 115.75; 117.50; 121.61; 122.66; 122.78; 126.79;
127.66; 128.34; 133.87; 134.10; 137.26; 138.75; 176.66; 177.48. HR-MS: 373.1139 ([M þ H]þ,
C20H22ClN2OSþ; calc. 373.1141). Anal. calc. for C20H21ClN2OS (372.91): C 64.42, H 5.68, N 7.51; found:
C 64.20, H 5.75, N 7.48.
2-Chloro-10-(pyrrolidin-1-ylcarbonothioyl)acridin-9(10H)-one (9h). Pale-yellow solid. M.p. 228 –
2308 (dec.; hexane/CH2Cl2). IR (KBr): 1638, 1604, 1256. 1H-NMR (400 MHz): 1.94 – 2.05 (m, 2 H);
2.14 – 2.20 (m, 2 H); 3.18 (t, J ¼ 6.3, 2 H); 4.13 (t, J ¼ 6.9, 2 H); 7.34 – 7.38 (m, 3 H); 7.63 (dd, J ¼ 8.6, 2.3,
1 H); 7.72 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 8.50 (d, J ¼ 2.3, 1 H); 8.52 (d, J ¼ 8.0, 1 H). 13C-NMR: 24.74; 25.85;
51.26; 63.86; 115.22; 117.09; 121.63; 122.70; 122.79; 126.91; 127.78; 128.39; 134.25; 134.54; 136.62; 138.08;
176.65; 176.95. MS: 342 (100, Mþ). Anal. calc. for C18H15ClN2OS (342.84): C 63.06, H 4.41, N 8.17; found:
C 62.97, H 4.43, N 8.15.
2-Chloro-10-(piperidin-1-ylcarbonothioyl)acridin-9(10H)-one (9i). Pale-yellow solid. M.p. 177 –
1788 (dec.; hexane/CH2Cl2). IR (KBr): 1640, 1602, 1257. 1H-NMR (500 MHz): 1.42 – 1.47 (m, 2 H);
1.70 – 1.75 (m, 2 H); 1.95 – 2.00 (m, 2 H); 3.27 – 3.29 (m, 2 H), 4.44 – 4.54 (m, 2 H); 7.35 – 7.40 (m, 3 H);
7.63 (dd, J ¼ 9.2, 2.3, 1 H); 7.71 (ddd, J ¼ 8.6, 6.9, 1.7, 1 H); 8.49 (d, J ¼ 2.3, 1 H); 8.52 (dd, J ¼ 8.0, 1.7, 1 H).
13C-NMR: 23.61; 25.41; 26.59; 50.98; 51.81; 115.75; 117.56; 121.58; 122.65; 122.83; 126.81; 127.68; 128.44;
134.09; 134.34; 137.11; 138.58; 176.61; 178.69. MS: 356 (100, Mþ). Anal. calc. for C19H17ClN2OS (356.87):
C 63.95, H 4.80, N 7.85; found: C 63.76, H 4.94, N 7.70.
2-Chloro-10-(morpholin-4-ylcarbonothioyl)acridin-9(10H)-one (9j). Pale-yellow solid. M.p. 255 –
1
2578 (hexane/CHCl3). IR (KBr): 1645, 1606, 1260. H-NMR (500 MHz): 3.31 – 3.33 (m, 2 H); 3.50 –
3.53 (m, 2 H); 4.00 – 4.02 (m, 2 H); 4.53 – 4.55 (m, 2 H); 7.35 – 7.40 (m, 3 H); 7.65 (dd, J ¼ 8.6, 2.9,
1 H); 7.74 (ddd, J ¼ 8.0, 7.4, 1.7, 1 H); 8.50 (d, J ¼ 2.9, 1 H); 8.52 (dd, J ¼ 8.0, 1.7, 1 H). 13C-NMR: 50.00;
50.42; 66.03; 66.29; 115.40; 117.19; 121.59; 122.68; 123.07; 127.01; 127.88; 128.72; 134.30; 134.55; 137.04;
138.52; 176.49; 179.65. MS: 358 (100, Mþ). Anal. calc. for C18H15ClN2O2S (358.84): C 60.25, H 4.21, N
7.81; found: C 60.04, H 4.29, N 7.76.
2-Chloro-N-methyl-9-oxo-N-phenylacridine-10(9H)-carbothioamide (9k). Pale-yellow solid. M.p.
184 – 1858 (hexane/CH2Cl2). IR (KBr): 1645, 1603, 1254. 1H-NMR (500 MHz): 3.98 (s, 3 H); 6.79 (d, J ¼
8.0, 1 H); 6.93 (dd, J ¼ 8.0, 6.9, 1 H); 7.02 (dd, J ¼ 6.9, 7.4, 1 H); 7.29 (dd, J ¼ 8.0, 7.4, 2 H); 7.64 – 7.65 (m,
4 H); 7.73 (dd, J ¼ 8.6, 6.9, 1 H); 8.30 (s, 1 H); 8.31 (d, J ¼ 8.0, 1 H). 13C-NMR: 46.03; 116.42; 118.13;
121.13; 122.19; 122.59; 123.02; 126.55; 127.37; 128.14; 129.06; 129.18; 133.52; 133.76; 137.93; 139.42;
142.47; 176.45; 180.69. MS: 378 (100, Mþ). Anal. calc. for C21H15ClN2OS (378.87): C 66.57, H 3.99, N 7.39;
found: C 66.51, H 4.14, N 7.26.
This work was supported in part by a Grant-in-Aid for Scientific Research (C) 22550035 from the
Japan Society for the Promotion of Science. We thank Mrs. Miyuki Tanmatsu at our university for
recording mass spectra and performing combustion analyses.
REFERENCES
[1] A. I. S. Almeida, V. L. M. Silva, A. M. S. Silva, D. C. G. A. Pinto, J. A. S. Cavaleiro, Synlett 2012,
889; Y. Fang, D. C. Rogness, R. C. Larock, F. Shi, J. Org. Chem. 2012, 77, 6262; A. V. Dubrovskiy,
R. C. Larock, J. Org. Chem. 2012, 77, 11232.
[2] K. Kobayashi, K. Nakagawa, S. Yuba, T. Komatsu, Helv. Chim. Acta 2013, 96, 389.
[3] A. H. Abadi, S. M. Abou-Seri, Q. Hu, M. Negri, R. W. Hartmann, Med. Chem. Commun. 2012, 3,
663; V. Verones, N. Flouquet, M. Lecoeur, A. Lemoine, A. Farce, B. Baldeyrou, C. Mahieu, N.
Wattez, A. Lansiaux, J.-F. Gossens, P. Berthelot, N. Lebegue, Eur. J. Med. Chem. 2013, 59, 39.
[4] X.-L. Yang, Z.-H. Xie, X.-J. Jiang, Y.-B. Huang, J.-K. Liu, Chem. Pharm. Bull. 2009, 57, 734; R. M.
Ngoumfo, J.-B. Jouda, F. T. Mousfo, J. Komguem, C. D. Mbazoa, T. C. Shiao, M. I. Choudhary, H.

Helvetica Chimica Acta – Vol. 96 (2013)
2039
Laatsch, J. Legault, A. Pichette, R. Roy, Bioorg. Med. Chem. 2010, 18, 3601; B. V. Tsassi, H. Hussain,
A. Geagni, E. Dongo, I. Ahmed, M. Riaz, K. Krohn, Helv. Chim. Acta 2011, 94, 1035; D. Lacroix, S.
Prado, D. Kamoga, J. Kasenene, B. Bodo, J. Nat. Prod. 2011, 74, 2286.
[5] J. M. Muchowski, M. C. Venuti, J. Org. Chem. 1980, 45, 4798.
[6] S. Fujiwara, T. Shin-Ike, N. Sonoda, M. Aoki, K. Okada, N. Miyoshi, N. Kambe, Tetrahedron Lett.
1991, 32, 3503.
[7] K. Kobayashi, T. Suzuki, Heterocycles 2012, 86, 403.
[8] G.-S. J. Chen, M. S. Gibson, J. Chem. Soc., Perkin Trans. 1 1975, 1138; E. Rizzetto, S. Castellano, C.
Florio, M. Vadori, G. Stefancich, Pharmazie 2006, 61, 505.
[9] K. Kobayashi, K. Yoneda, K. Miyamoto, O. Morikawa, H. Konishi, Tetrahedron 2004, 60, 11639.
[10] Y. Ito, K. Kobayashi, N. Seko, T. Saegusa, Bull. Chem. Soc. Jpn. 1984, 57, 73.
Received June 17, 2013