One-pot synthesis of 3-arylquinazoline-2,4(1H,3H)-dithiones by the reaction of 2-lithiophenyl isothiocyanates with aryl isothiocyanates

Article abstract of DOI:10.1055/s-0030-1260016

3-Arylquinazoline-2,4(1H,3H)-dithiones were synthesized in satisfactory yields from 2-bromophenyl isothiocyanates in one pot via generation of the corresponding 2-lithiophenyl isothiocyanates by bromine-lithium exchange with butyllithium followed by treatment with aryl isothiocyanates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260016

1526
SHORT PAPER
One-Pot Synthesis of 3-Arylquinazoline-2,4(1H,3H)-dithiones by the Reaction
of 2-Lithiophenyl Isothiocyanates with Aryl Isothiocyanates
S
ynthesis of 3-Ary
a
lquinazolin
z
e-2, 4(1
H
,3
u
H
)-dithioneshiro Kobayashi,* Yuki Yokoi, Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 14 February 2011; revised 24 March 2011
termediates gave 3-aryl-1-lithioquinazoline-2,4(1H,3H)-
Abstract: 3-Arylquinazoline-2,4(1H,3H)-dithiones were synthe-
dithione intermediates 5, which were protonated by aque-
sized in satisfactory yields from 2-bromophenyl isothiocyanates in
ous workup to give the desired products 6. Yields of these
products after purification by recrystallization are sum-
marized in Table 1, which are generally fair-to-good. The
structure determination of 6a was performed by compari-
son of its 1H and 13C NMR spectra to those reported pre-
viously.2b Each of the products 6 was isolated by
recrystallization and each 13C NMR spectrum uniformly
shows signals at ca. d = 172 and 188 ppm assignable to 2-
and 4-thioxo carbons, respectively.
one pot via generation of the corresponding 2-lithiophenyl isothio-
cyanates by bromine–lithium exchange with butyllithium followed
by treatment with aryl isothiocyanates.
Key words: quinazoline-2,4(1H,3H)-dithiones,
2-lithiophenyl
isothiocyanates, 2-bromophenyl isothiocyanates, aryl isothiocyan-
ates, benzothioamides
Although the first synthesis of quinazoline-2,4(1H,3H)-
dithione by the reaction of 2-aminobenzonitrile with car-
bon disulfide in refluxing pyridine was described by
Taylor and co-workers in 1966,1 there has been but limit-
ed attention paid to compounds having this skeleton until
the recent reports on the biological evaluation of 3-
arylquinazoline-2,4(1H,3H)-dithiones and related com-
pounds as antimycobacterial agents,2a phosphodiesterase
7 inhibitors,2b and so on.3 The synthesis of these com-
pounds was generally based on the treatment of the corre-
R
Br
R
Li
n-BuLi, THF, –78 °C
NCS
NCS
1a R = H
1b R = Cl
2
S
R
Ar
ArNCS (3)
N
Li
sponding
2-thioxo-2,3-dihydroquinazolin-4(1H)-ones
NCS
with phosphorous pentasulfide2a or Lawesson’s reagent.2b
On the other hand, we have demonstrated, in a recent pub-
lication, that 2-lithiophenyl isothiocyanates can be gener-
ated by the treatment of 2-bromophenyl isothiocyanates
with butyllithium and can serve as intermediates for the
synthesis of 1,4-dihydro-3,1-benzoxazine-2-thiones
through reaction with aldehydes, ketones, or butanolide.4
As part of our efforts to explore the synthetic utility and
potential of these lithium products, we have investigated
the possibility of their use in the preparation of quinazo-
line-2,4(1H,3H)-dithiones by reacting them with isothio-
cyanates. In this paper, the results of our studies, which
offer a new and efficient route to 3-arylquinazoline-
2,4(1H,3H)-dithiones by the reaction of these lithium
products with aryl isothiocyanates, are reported.
4
S
S
R
R
H3O+
NAr
NAr
N
S
N
S
Li
H
5
6
Scheme 1 Preparation of 3-arylquinazoline-2,4(1H,3H)-dithiones 6
Our attempt to obtain 3-butylquinazoline-2,4(1H,3H)-
dithione by the reaction of 2-lithiophenyl isothiocyanate
(2a) with n-butyl isothiocyanate was unsuccessful. In-
stead of the expected product, 3-phenylquinazoline-
2,4(1H,3H)-dithione (6a) was obtained in 56% yield
based on 1a. The formation of 6a may be interpreted as
follows. Part of lithiated compound 2a is protonated prob-
ably by proton abstraction from the a-position of n-butyl
isothiocyanate to give phenyl isothiocyanate (3a), which
reacts with remaining 2a to provide 6a, as shown in
Scheme 2.
The synthesis of 3-arylquinazoline-2,4(1H,3H)-dithiones
6 from 2-bromophenyl isothiocyanates 1 was conducted
as illustrated in Scheme 1. Treatment of 1 with an
equimolar amount of butyllithium at –78 °C in THF gen-
erated 2-lithiophenyl isothiocyanates 2, which were al-
lowed to react with aryl isothiocyanates 3 to give the
lithium thioamide intermediates 4. Cyclization of these in-
3-Aryl-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones could
be expected to be formed by the application of the present
reaction using aryl isocyanates in place of aryl isothiocy-
anates. But, the reaction of 2-lithiophenyl isothiocyanate
(2a) with phenyl isocyanate only resulted in the formation
SYNTHESIS 2011, No. 10, pp 1526–1528
x
x.
x
x
.
2
0
1
1
Advanced online publication: 19.04.2011
DOI: 10.1055/s-0030-1260016; Art ID: F19411SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of 3-Arylquinazoline-2,4(1H,3H)-dithiones
1527
Compound 3c5 was prepared from 3,5-dimethylphenyl isocyanide6
according to the procedure employed for the preparation of 1b.4
Table 1 Preparation of 3-Arylquinazoline-2,4(1H,3H)-dithiones 6
Entry
1
Ar in 3
6
Yield (%)a
3-Phenylquinazoline-2,4(1H,3H)-dithione (6a);2 Typical Proce-
dure
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
Ph (3a)
6a
6b
6c
6d
6e
6f
6g
6h
6i
74
71
72
62
80
58
70
64
63
61
To a stirred solution of 1a (0.21 g, 1.0 mmol) in THF (4 mL) at –78
°C was added n-BuLi (1.6 M in hexane, 0.03 mL, 1.0 mmol) drop-
wise. After 1 min, 3a (0.14 g, 1.0 mmol) was added and the stirring
was continued for an additional 10 min at the same temperature be-
fore sat. aq NH4Cl (10 mL) was added. The mixture was warmed to
r.t. and extracted with EtOAc (3 × 10 mL). The combined extracts
were washed with brine (10 mL) and dried (Na2SO4). Evaporation
of the solvent gave a residual solid, which was recrystallized from
hexane–CHCl3 to give 6a as an orange solid; yield: 0.20 g (74%);
mp 253–255 °C (Lit.2b mp 253–256 °C).
3-MeC6H4 (3b)
3,5-Me2C6H3 (3c)
2-ClC6H4 (3d)
3-ClC6H4 (3e)
2-BrC6H4 (3f)
3-MeOC6H4 (3g)
naphthalen-2-yl (3h)
Ph (3a)
3
4
5
6
7
1H and 13C NMR spectral data for this product were identical with
those reported previously.2b
8
9
3-(3-Methylphenyl)quinazoline-2,4(1H,3H)-dithione (6b)
Yellow solid; mp 176–178 °C (hexane–THF).
IR (KBr): 3158, 1616, 1604, 1371 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.31 (s, 3 H), 6.98–7.01 (m, 2
H), 7.17 (d, J = 7.3 Hz, 1 H), 7.32–7.37 (m, 2 H), 7.42 (d, J = 7.8
Hz, 1 H), 7.78 (ddd, J = 8.3, 7.8, 1.5 Hz, 1 H), 8.32 (d, J = 8.3 Hz,
1 H), 13.44 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 20.9, 116.0, 123.7, 125.3,
125.6, 128.67, 128.69, 129.1, 131.8, 135.3, 135.8, 138.6, 144.1,
172.8, 189.7.
10
2-Br,4-ClC6H3 (3j = 1b)
6j
a Isolated yields.
S
H
2a
n-BuNCS
NPh
2a
NCS
N
H
S
3a
6a 56%
MS: m/z (%) = 284 ([M+], 100).
Scheme 2 Attempted synthesis of 3-butylquinazoline-2,4(1H,3H)-
dithione
Anal. Calcd for C15H12N2S2: C, 63.35; H, 4.25; N, 9.85. Found: C,
63.18; H, 4.30; N, 9.69.
of intractable mixture of products, from which no more
than a trace amount of the desired product could be ob-
tained in a pure form. This result is most likely due to sus-
ceptibility of isocyanates to oligomerization under the
reaction conditions.
3-(3,5-Dimethylphenyl)quinazoline-2,4(1H,3H)-dithione (6c)
Pale-yellow solid; mp 188–189 °C (hexane–THF).
IR (KBr): 3160, 1605, 1368 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 2.71 (s, 6 H), 6.51 (s, 2 H),
6.83 (s, 1 H), 7.35 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.46 (d, J = 8.4
Hz, 1 H), 7.66 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 8.14 (dd, J = 8.4, 1.5
Hz, 1 H), 13.32 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 21.0, 116.7, 118.1, 119.1,
125.5, 125.8, 126.6, 134.0, 138.8, 139.0, 148.7, 172.5, 185.8.
In conclusion, we have demonstrated that the reaction of
2-lithiophenyl isothiocyanates with aryl isothiocyanates
provides rapid access to 3-arylquinazoline-2,4(1H,3H)-
dithiones. The present new method may find some value
in synthesis, because it is operationally simple and the
starting materials are readily available.
MS: m/z (%) = 298 ([M+], 100).
Anal. Calcd for C16H14N2S2: C, 64.39; H, 4.73; N, 9.39. Found: C,
64.29; H, 4.76; N, 9.22.
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were de-
termined as KBr disks with a Shimadzu FTIR-8300 spectrophotom-
eter. The 1H NMR spectra were determined using TMS as an
internal reference with a JEOL ECP500 FT NMR spectrometer op-
erating at 500 MHz or a JEOL LA400 FT NMR spectrometer oper-
ating at 400 MHz. The 13C NMR spectra were determined using
TMS as an internal reference with a JEOL ECP500 FT NMR spec-
trometer operating at 125 MHz or a JEOL LA400 FT NMR spec-
trometer operating at 100 MHz. Low-resolution mass spectra (EI,
70 eV) were measured by a JEOL JMS AX505 HA spectrometer.
TLC was carried out on a Merck Kieselgel 60 PF254. Column chro-
matography was performed using Wako Gel C-200E. All of the or-
ganic solvents used in this study were dried over appropriate drying
agents and distilled prior to use. All chemicals, excluding 2-bromo-
4-chlorophenyl isothiocyanate (1b) and 3,5-dimethylphenyl
isothiocyanate (3c), were commercially available. Compound 1b
was prepared according to the procedure reported previously.4
3-(2-Chlorophenyl)quinazoline-2,4(1H,3H)-dithione (6d)
Orange solid; mp 239–241 °C (hexane–THF).
IR (KBr): 3161, 1614, 1398 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.33–7.49 (m, 5 H), 7.57 (dd,
J = 8.8, 1.5 Hz, 1 H), 7.82 (ddd, J = 8.3, 7.3, 1.5 Hz, 1 H), 8.32 (dd,
J = 8.3, 0.9 Hz, 1 H), 13.58 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 116.2, 123.2, 125.6, 128.4,
129.9, 130.0, 130.8, 130.9, 131.6, 135.3, 136.3, 141.0, 171.9, 188.7.
MS: m/z (%) = 304 ([M+], 100).
Anal. Calcd for C14H9ClN2S2: C, 55.16; H, 2.98; N, 9.19. Found: C,
55.35; H, 2.76; N, 9.05.
3-(3-Chlorophenyl)quinazoline-2,4(1H,3H)-dithione (6e)
Orange solid; mp 256–258 °C (hexane–THF).
IR (KBr): 3165, 1618, 1603, 1400 cm–1.
Synthesis 2011, No. 10, 1526–1528 © Thieme Stuttgart · New York

1528
K. Kobayashi et al.
SHORT PAPER
1H NMR (500 MHz, DMSO-d6): d = 7.22 (dd, J = 8.4, 1.5 Hz, 1 H),
7.35 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.40–7.45 (m, 3 H), 7.50 (t,
J = 7.6 Hz, 1 H), 7.79 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 8.32 (dd,
J = 8.4, 1.5 Hz, 1 H), 13.50 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 116.0, 123.7, 125.3, 127.7,
128.1, 128.8, 130.8, 131.6, 133.2, 135.3, 135.9, 145.3, 172.6, 189.8.
1H NMR (400 MHz, CDCl3): d = 7.10 (d, J = 8.8 Hz, 1 H), 7.21 (d,
J = 7.8 Hz, 2 H), 7.50–7.60 (m, 4 H), 8.47 (d, J = 2.4 Hz, 1 H),
10.87 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 116.5, 125.4, 128.1, 129.0, 129.9,
132.2, 132.5, 135.5, 135.5, 143.7, 173.2, 188.5.
MS: m/z (%) = 304 ([M+], 100).
MS: m/z (%) = 304 ([M+], 100).
Anal. Calcd for C14H9ClN2S2: C, 55.16; H, 2.98; N, 9.19. Found: C,
54.93; H, 3.23; N, 9.03.
Anal. Calcd for C14H9ClN2S2: C, 55.16; H, 2.98; N, 9.19. Found: C,
55.18; H, 3.02; N, 9.25.
3-(2-Bromo-4-chlorophenyl)-6-chloroquinazoline-2,4(1H,3H)-
dithione (6j)
Orange solid; mp 188–190 °C (hexane–THF).
3-(2-Bromophenyl)quinazoline-2,4(1H,3H)-dithione (6f)
Orange solid; mp 250–254 °C (hexane–THF).
IR (KBr): 3161, 1614, 1395 cm–1.
IR (KBr): 3154, 1611, 1386 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.31–7.38 (m, 2 H), 7.43–7.45
(m, 2 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.71 (dd, J = 7.8, 7.3 Hz, 1 H),
7.81 (dd, J = 7.8, 7.3 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 13.57 (br
s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 7.46 (d, J = 8.6 Hz, 1 H), 7.49
(d, J = 8.6 Hz, 1 H), 7.60 (dd, J = 8.6, 2.3 Hz, 1 H), 7.88 (dd,
J = 8.6, 2.3 Hz, 1 H), 7.89 (d, J = 2.3 Hz, 1 H), 8.24 (d, J = 2.3 Hz,
1 H), 13.51 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 116.1, 121.8, 123.3 125.5,
128.9, 130.0, 130.9, 131.6, 133.1, 135.3, 136.2, 142.5, 171.9, 188.5.
13C NMR (125 MHz, CDCl3): d = 118.6, 122.8, 124.3, 129.3, 129.7,
130.1, 132.2, 132.6, 133.7, 134.2, 136.1, 141.6, 171.7, 187.2.
MS: m/z (%) = 348 ([M+], 100).
MS: m/z (%) = 415 ([M+], 100).
Anal. Calcd for C14H9BrN2S2: C, 48.14; H, 2.60; N, 8.02. Found: C,
48.02; H, 2.71; N, 8.04.
Anal. Calcd for C14H7BrCl2N2S2: C, 40.21; H, 1.69; N, 6.70. Found:
C, 40.24; H, 1.75; N, 6.55.
3-(3-Methoxyphenyl)quinazoline-2,4(1H,3H)-dithione (6g)
Orange solid; mp 269–271 °C (hexane–THF).
Acknowledgment
IR (KBr): 3153, 1620, 1605, 1396 cm–1.
This work was partially financial supported by a Grand-in-Aid for
Scientific Research (C) 22550035 from Japan Society for the Pro-
motion of Science. The authors thank Mrs. Miyuki Tanmatsu of this
university for recording the mass spectra and performing com-
bustion analyses.
1H NMR (400 MHz, DMSO-d6): d = 3.73 (s, 3 H), 6.78 (dd, J = 7.8,
2.0 Hz, 1 H), 6.82 (t, J = 2.0 Hz, 1 H), 6.94 (dd, J = 8.3, 2.0 Hz, 1
H), 7.33 (t, J = 7.8 Hz, 1 H), 7.37 (dd, J = 8.3, 7.8 Hz, 1 H), 7.41 (d,
J = 8.3 Hz, 1 H), 7.77 (ddd, J = 8.3, 7.8, 1.5 Hz, 1 H), 8.31 (d,
J = 7.8 Hz, 1 H), 13.40 (br s, 1 H)
13C NMR (100 MHz, DMSO-d6): d = 55.3, 113.4, 114.6, 116.1,
120.8, 123.8, 125.3, 130.0, 131.8, 135.4, 135.9, 145.2, 160.2, 172.8,
189.6.
References
(1) Taylor, E. C.; Warrener, R. N.; Mckillop, A. Angew. Chem.,
Int. Ed. Engl. 1966, 5, 309; Angew. Chem. 1966, 78, 333.
(2) (a) Walsser, K.; Gregor, J. V.; Kunes, J.; Kubicova, L.;
Klimeova, V.; Kaustova, J. Farmaco 2001, 56, 803.
(b) Castano, T.; Wang, H.; Campillo, N. E.; Ballester, S.;
Gonzalez-Garcia, C.; Hernandez, J.; Perez, C.; Cuenca, J.;
Perez-Castillo, A.; Martinez, A.; Huertas, O.; Gelpi, J. L.;
Luques, F. J.; Ke, H.; Gil, C. ChemMedChem 2009, 4, 866.
(3) (a) Dyke, H. J.; Richard, M. D.; Haughan, A. F.; Sharpe, A.
PCT Int. Pat. Appl. WO 053958, 2003; Chem. Abstr. 2003,
139, 85370. (b) Gil Ayuso-Gontan, C.; Castano Calduch,
T.; Campillo Martin, N.; Ballester Jareno, S.;
MS: m/z (%) = 300 ([M+], 100).
Anal. Calcd for C15H12N2OS2: C, 59.97; H, 4.03; N, 9.33. Found: C,
59.85; H, 4.05; N, 9.27.
3-(Naphthalen-2-yl)quinazoline-2,4(1H,3H)-dithione (6h)
Pale-yellow solid; mp 171–173 °C (hexane–THF).
IR (KBr): 3160, 1614, 1373 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.29–7.60 (m, 5 H), 7.70–7.89
(m, 2 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.97 (d, J = 8.3 Hz, 1 H), 8.00
(d, J = 8.8 Hz, 1 H), 8.33 (dd, J = 8.3, 1.0 Hz, 1 H), 13.55 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 116.1, 123.8, 125.4, 126.1,
126.6, 126.8, 126.9, 127.7, 128.1, 128.9, 131.7, 132.4, 133.5, 135.4,
135.9, 141.7, 173.0, 190.0.
Gonzalez Garcia, C.; Hernandez Torres, F. J. PCT Int. Pat.
Appl. WO 113881, 2008; Chem. Abstr. 2008, 149, 402387.
(c) Martizez Gil, C.; Gil Ayuso-Gontan, A.; Perez Martin,
C.; Perez Castillo, A.; Moralez Garcia, J.; Redondo Sancho,
M.; Sanz San Cristobal, M. PCT Int. Pat. Appl. WO 133740,
2010; Chem. Abstr. 2008, 153, 643513.
MS: m/z (%) = 320 ([M+], 100).
(4) Kobayashi, K.; Yokoi, Y.; Komatsu, T.; Konishi, H.
Anal. Calcd for C18H12N2S2: C, 67.47; H, 3.77; N, 8.74. Found: C,
67.21; H, 3.95; N, 8.65.
Tetrahedron 2010, 66, 9336.
(5) Yan, S.; Appleby, T.; Gunic, E.; Shim, J. H.; Tasu, T.; Kim,
H.; Rong, F.; Chen, H.; Hamatake, R.; Wu, J. Z.; Hong, Z.;
Yao, N. Bioorg. Med. Chem. Lett. 2007, 17, 28.
6-Chloro-3-phenylquinazoline-2,4(1H,3H)-dithione (6i)
Pale-pink solid; mp 225–230 °C (hexane–CHCl3).
(6) Tobisu, M.; Yamaguchi, S.; Chatani, N. Org. Lett. 2007, 9,
IR (KBr): 3150, 1611, 1387 cm–1.
3351.
Synthesis 2011, No. 10, 1526–1528 © Thieme Stuttgart · New York