A prominent C-acylation-cyclisation synthetic sequence and X-ray structure elucidation of benzothiopyranone derivatives

Article abstract of DOI:10.1016/j.tet.2008.04.009

A novel short-step methodology to benzothiopyranone derivatives has been developed starting from an activated precursor, N-hydroxysuccinimide ester of thiosalicylic acid. The procedure is based on a tandem C-acylation-cyclisation process under mild reacti

Full text of DOI:10.1016/j.tet.2008.04.009

Tetrahedron 64 (2008) 5454–5458
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A prominent C-acylation–cyclisation synthetic sequence and X-ray
structure elucidation of benzothiopyranone derivatives
,
Stefanos Kikionis a, Vickie McKee b, John Markopoulos c, Olga Igglessi-Markopoulou a
*
a National Technical University of Athens, School of Chemical Engineering, Laboratory of Organic Chemistry, Zografou Campus, Athens 15773, Greece
b University of Loughborough, Chemistry Department, Leicestershire LE113TU, UK
c University of Athens, Department of Chemistry, Laboratory of Inorganic Chemistry, Panepistimiopolis, Zografou, Athens 15771, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel short-step methodology to benzothiopyranone derivatives has been developed starting from an
activated precursor, N-hydroxysuccinimide ester of thiosalicylic acid. The procedure is based on a tandem
C-acylation–cyclisation process under mild reaction conditions in good yields. The structure elucidation
has been established using X-ray crystallography and NMR spectral data.
Received 21 December 2007
Received in revised form 17 March 2008
Accepted 3 April 2008
Available online 8 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Benzothiopyranones
Thiocoumarins
Thiochromones
C-Acylation
N-Hydroxysuccinimide ester
1. Introduction
dimethylthiocoumarins and related compounds, containing an
aminoethyl group in the thiocoumarin ring, were tested and
The development of new methodologies for the synthesis of
functionalized benzothiopyran-2-ones (thiocoumarins) and ben-
zothiopyran-4-ones (thiochromones) (Fig.1) is a topic of continuing
interest, because of their biological and pharmacological interest.
The benzothiopyran skeleton is an important structural motif in
the preparation of pharmaceuticals,1 showing a higher biological
activity compared to the corresponding benzopyran.2 Benzothio-
pyranones serve as key intermediates for the synthesis of bio-
logically active compounds.3,4
showed significant insecticidal activity.8 Substituted benzothio-
pyranones are widely used against hypertension,9 and have been
tested for antimicrobial and antitumour activity.8 Some thio-
coumarins have exhibited anti-vitamin K activity, and plant and
animal growth arrest activity.10
The synthesis of thiochromones and thiocoumarins has been
achieved by various methods.1b,8,11,12 Standard syntheses of the
benzothiopyran skeleton typically involve multi-step procedures,
unstable starting material and the harsh reaction conditions, are
not suitable for highly functionalized benzothiopyranones.
During the course of our studies towards the development of
a new methodology on the synthesis of heterocycles containing the
Benzothiopyran-2-one derivatives have been prepared and
studied as matrix metalloproteinase inhibitors,5 as 5-HT3 (seroto-
nin 3) receptor antagonist6 for the treatment of inflammation,7
as bacteriocides and anticancer agents.1c,4
A
series of 4,6-
b,b
0-dicarbonyl system, we became interested in the possibility
of developing a new approach to the synthesis and structural elu-
cidation of fused sulfur heterocycles.
Recently, we reported13 a new synthetic route to 3-substituted
thiotetronic acids via a C-acylation reaction of active methylene
compounds with activated derivatives of S-protected thioglycolic
acids followed by an in situ cyclisation reaction. In this paper we
wish to report an extension of this coupling–cyclisation strategy for
the synthesis of biologically interesting fused sulfur heterocycles.
This chemistry proceeds by a tandem intermolecular nucleophilic
coupling of the activated ester 3 with the active methylene com-
pound and a subsequent intramolecular cyclisation to a stable
six-membered ring system (Scheme 1).
Figure 1. Thiocoumarin (I) and thiochromone (II) structure.
* Corresponding author. Tel.: þ30 210 772 3 079; fax: þ30 210 772 3 072.
E-mail address: ojmark@orfeas.chemeng.ntua.gr (O. Igglessi-Markopoulou).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.009

S. Kikionis et al. / Tetrahedron 64 (2008) 5454–5458
5455
Scheme 1. Reagents and conditions: (i) (CH3CO)2O, CH3CO2H, reflux; (ii) THF, DCC; (iii) NaH, THF; (iv) NaOEt/EtOH; (v) HCl/MeOH.
This approach would provide an alternative and ultimately more
general method to the preparation of thiocoumarins and thio-
chromones, and an extended system containing the benzothio-
pyranone ring.
Herein, we provide a full account of this efficient synthesis of
thiocoumarin and thiochromone ring system.
The C-acylation protocol involved the reaction of equimolar
amounts of sodium hydride (2 equiv) in anhydrous tetrahydrofuran
with the appropriate active methylene compound (2 equiv) (4–9),
at 0 ꢀC. After 1 h, 1 equiv of the N-hydroxysuccinimide ester 3 was
added and the mixture was stirred at room temperature for 2 h. We
noted that the C-acylation intermediates 10a–f were obtained in
admixture with the corresponding cyclised compounds, as de-
termined on the basis of the NMR data. Ring closure of the in-
termediates was achieved by treating them in sodium ethoxide in
ethanol for 24 h or with aqueous HCl (10%) in MeOH for 48 h. The
cyclisation of 10a,b,c,f by intramolecular nucleophilic attack of the
sulfur lone pair on the ester carbonyl group would produce struc-
tures such as 11, 12, 14 and 17. However, we noticed an alternative
reaction path, under the C-acylation–cyclisation reaction condi-
tions. The intermediate 10e undergoes spontaneous cyclisation to
the thiochromone 16. This cyclisation clearly involves attack of the
sulfur nucleophile on the ketonic group of this intermediate,
producing the 2-methyl-4-keto-thiochromone 16.
Then, our attention was concentrated on the use of the C-acyl-
ation intermediates 10c,d possessing the CN group as synthons
for the construction of novel 2-amino-3-methoxycarbonylthio-
chromone 13 and 2-amino-3-cyanothiochromone 15. The electron-
deficient carbon atom interacts with the nucleophilic sulfur in the
cyclisation process.15 These 2-amino-thiochromones are valuable
synthetic building blocks and have attracted considerable interest
because of their biological significance.16
2. Results and discussion
In continuation of our programme on the chemistry of fused
heterocyclic systems, quinolinones, naphthyridines, coumarins, as
potential pharmacological agents14 we report herein an improved
methodology to 3-substituted 4-hydroxythiocoumarin-2-ones and
2-methyl-2-amino-thiochrom-4-ones (Scheme 1). The key control
element of these ‘benzothiopyranone’ heterocycles was the
utilisation of the N-hydroxysuccinimide ester of S-acetylthio-
salicylic acid as a promising precursor for the synthesis of
polyfunctional ‘thiocoumarin and thiochromone’ derivatives. The
requisite acylating agent 3, N-hydroxysuccinimide ester of S-
acetylthiosalicylic acid, was prepared by a standard protocol in-
volving condensation of equimolar quantities of the S-acetyl
protected thiosalicylic acid 2 and N-hydroxysuccinimide in the
presence of 1.2 equiv of N,N0-dicyclohexylcarbodiimide. This ex-
cellent activating system 3 was isolated in very good yield as
a white solid and used in the C-acylation reaction without further
purification.

5456
S. Kikionis et al. / Tetrahedron 64 (2008) 5454–5458
Scheme 2. Enol–enol equilibrium of the 4-hydroxy-3-methoxycarbonylthiocoumarin
(11).
Figure 2. Molecular structure of 11, the dashed line represents a hydrogen bond.
Thermal ellipsoids drawn at the 50% probability level.
Additionally, we noticed that on treating with aqueous HCl (10%)
in methanol, the C-acylation intermediate 10c easily undergoes an
intramolecular heterocyclisation reaction to give the 3-cyanothio-
coumarin 14 (Scheme 1).
An X-ray structure determination of compound 11 was carried
out to confirm the structure in the solid state. The molecular
structure and numbering scheme are shown in Figure 2, and bond
lengths and angles are given in Table 1. The structure resembles
that of tautomer a (Scheme 2) with an endocyclic C]C double
bond. There is some double bond character evident in the C(7)–C(8)
bond (1.3930(19) Å) and the O(1)–C(7) bond is distinctly longer
than the conventional carbonyl distance for O(4)–C(11) (1.3245(15)
and 1.2132(17) Å, respectively). There is a quite short intra-
molecular hydrogen bond between the enol and ester oxygen
atoms (O(1)–O(2) 2.4496(14) Å). Figure 3 shows the intermolecular
interactions. The molecules show
p–p stacking, unusually this
principally involves the carbonyl and C]C portions of the molecule
rather than the phenyl rings. The stacks are linked by two weak
intermolecular C–H/O interactions (Table 2).17–20
3. Conclusions
In summary, the N-hydroxysuccinimide ester of thio-
acetylsalicylic acid has been introduced as a new efficient precursor
for the synthesis of the target compounds with interesting bi-
ological properties. The activation of thioacetylsalicylic acid as the
N-hydroxysuccinimide ester is an attractive alternative to other
thiosalicylic acid species11 permitting mild reaction conditions and
short reaction times. Availability, simplicity, ease of handling of
Table 1
Bond lengths [Å] and angles [ꢀ] for 11
Figure 3. Intermolecular interactions in 11, dashed lines represent hydrogen
bonds. The central molecules are parallel, which means interplanar separation
3.488 Å (symmetry codes: A, ꢁx, ꢁy, ꢁz; B, x, (1/2)ꢁy, ꢁ(1/2)þz, C, ꢁx, ꢁ(1/2)þy,
(1/2)ꢁz).
S(1)–C(1)
S(1)–C(11)
C(1)–C(2)
C(1)–C(6)
1.7394(13)
1.7807(14)
1.3988(18)
1.4031(17)
1.380(2)
C(7)–O(1)
C(7)–C(8)
C(8)–C(11)
C(8)–C(9)
C(9)–O(2)
C(9)–O(3)
O(3)–C(10)
C(11)–O(4)
1.3245(15)
1.3930(19)
1.4637(17)
1.4763(18)
1.2368(16)
1.3122(17)
1.4568(16)
1.2132(17)
C(2)–C(3)
C(3)–C(4)
1.396(2)
Table 2
Hydrogen bonds in 11 [Å and
ꢀ
C(4)–C(5)
1.376(2)
]
C(5)–C(6)
C(6)–C(7)
1.4033(19)
1.4557(18)
106.00(6)
120.23(12)
116.84(10)
122.92(10)
120.23(12)
120.00(13)
120.01(13)
121.16(13)
118.36(12)
122.03(12)
119.61(11)
120.65(12)
D–H/A
d(D–H)
d(H/A)
d(D/A)
<(DHA)
C(1)–S(1)–C(11)
C(2)–C(1)–C(6)
C(2)–C(1)–S(1)
C(6)–C(1)–S(1)
C(3)–C(2)–C(1)
C(2)–C(3)–C(4)
C(5)–C(4)–C(3)
C(4)–C(5)–C(6)
C(1)–C(6)–C(5)
C(1)–C(6)–C(7)
C(5)–C(6)–C(7)
O(1)–C(7)–C(8)
O(1)–C(7)–C(6)
C(8)–C(7)–C(6)
C(7)–C(8)–C(11)
C(7)–C(8)–C(9)
C(11)–C(8)–C(9)
O(2)–C(9)–O(3)
O(2)–C(9)–C(8)
O(3)–C(9)–C(8)
C(9)–O(3)–C(10)
O(4)–C(11)–C(8)
O(4)–C(11)–S(1)
C(8)–C(11)–S(1)
113.39(11)
125.95(11)
122.80(12)
117.21(11)
119.98(12)
121.20(12)
122.18(12)
116.62(11)
116.03(11)
126.22(13)
114.07(10)
119.70(10)
O(1)–H(1)/O(2)
C(2)–H(2)/O(2)$1
C(2)–H(2)/O(4)$2
0.91(2)
0.95
0.95
1.59(2)
2.66
2.54
2.4496(14)
3.2941(17)
3.3732(17)
156.6(18)
125.0
146.3
Symmetry codes: $1, x, (1/2)ꢁy, (1/2)þz; $2, ꢁx, (1/2)þy, (1/2)ꢁz.
reagents, satisfactory yields and mildness of the reaction conditions
make the proposed methodology prominent for the preparation of
functionalized thiocoumarins and thiochromones. Our further ef-
forts are directed towards the synthesis of more complex substrates
in the ‘benzothiopyranone’ series.

S. Kikionis et al. / Tetrahedron 64 (2008) 5454–5458
5457
4. Experimental section
4.1. General
active methylene compound (dimethyl malonate, diethyl malonate,
methyl cyanoacetate, malonitrile, ethyl acetoacetate and ethyl
benzoylacetate) (20 mmol) was then added at 0 ꢀC and after a pe-
riod of 1 h stirring at room temperature, N-hydroxysuccinimide
ester was added. The reaction mixture was allowed to stir at room
temperature for 2 h and then concentrated under reduced pressure.
The obtained gummy solid was diluted with H2O (10 mL) and
washed with Et2O (5 mL). The aqueous extract was acidified with
aqueous HCl (10%) in an ice-H2O bath to afford an oily product,
which was extracted with CH2Cl2 (3ꢂ15 mL) and the combined
organic layers were dried over anhydrous Na2SO4, concentrated
under reduced pressure and dried in vacuo to give an oily residue,
which was treated either with method A, B or C.
Melting points were determined on a Gallenkanp MFB-595
melting point apparatus and are uncorrected. The FTIR spectra were
recorded on a FTIR Jasco 4200 instrument. Mass spectra were
obtained on a TSQ 7000 Finnigan MAT (ESI) instrument. The NMR
spectra were recorded at 300 (1H) and 75 (13C) MHz on a Varian
Gemini-2000 300 MHz spectrometer; chemical shifts are quoted in
parts per million (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, br¼broad); J values are given in hertz. Elemental
analyses were obtained on a Euro EA3000 Series Euro Vector CHNS
Elemental Analyzer. Petroleum ether refers to the fraction with bp
40–60 ꢀC. Commercially available THF was dried prior to use by
refluxing over Na. All other solvents (puriss quality) were used
without further purification. Origin and purity of the other reagents
are as follows: thiosalicylic acid, puriss; N-hydroxysuccinimide,
purum; DCC, puriss.
(A) Treatment with dichloromethane, diethyl ether or petroleum
ether to afford as solids the corresponding products.
(B) The C-acylation compounds (1 mmol) were treated with a so-
lution of sodium (4.6 g, 20 mmol) in absolute EtOH (20 mL) and
stirred at room temperature for 24 h. The mixture was evapo-
rated under reduced pressure and the residue was diluted with
H2O and washed with Et2O. The aqueous layer was acidified
with aqueous HCl (10%) to afford the functionalized products as
solids. All products were filtered off, washed with petroleum
ether and dried in vacuo.
(C) The C-acylation compounds (1 mmol) were dissolved in MeOH
(20 mL) and treated with aqueous HCl (10%, 20 mL) for 48 h at
room temperature to afford a gummy solid, which was
extracted with CH2Cl2 (3ꢂ15 mL) and the combined organic
layers were dried over anhydrous Na2SO4, concentrated under
reduced pressure and dried in vacuo to afford the corre-
sponding products.
4.2. Synthesis
4.2.1. Synthesis of S-acetylthiosalicylic acid (2)21
A mixture of thiosalicylic acid (50 mmol, 7.7 g), acetic anhydride
(60 mmol, 6.1 g) and acetic acid (21.5 mL) was heated to reflux for
approximately 6 h. The reaction progress was monitored by TLC.
After cooling to room temperature the solution was poured
into aqueous hydrochloric acid (10%). The product was filtered
off, washed with water and petroleum ether, and dried in vacuo
to afford the corresponding S-acetylthiosalicylic acid as awhite solid.
4.2.1.1. S-Acetylthiosalicylic acid (2). Yield: 75%; mp 124–126 ꢀC
(lit.21 127–129 ꢀC). 1H NMR (300 MHz, DMSO-d6):
d
¼2.40 (s, 3H,
COCH3), 7.53–7.86 (m, 4H, aromatic H), 13.16 (br s, 1H, CO2H). Anal.
Calcd for C9H8O3S: C, 55.09; H, 4.11; O, 24.46; S, 16.34. Found: C,
55.22; H, 4.03; O, 24.57; S, 16.23.
4.2.3.1. 4-Hydroxy-3-methoxycarbonylthiocoumarin (11). Using di-
methyl malonate as the active methylene compound, according to
method (B), compound 11 was obtained as white crystals. Yield: 67%
(recrystallisation from methanol); mp 110–111 ꢀC. MS (ESI)
m/z¼237.2 ([MþH]þ). IR (ATR): 1698,1650,1630,1538 cmꢁ1.1H NMR
4.2.2. General procedure for the synthesis of N-hydroxysuccinimide
ester of S-acetylthiosalicylic acid (3)
(300 MHz, DMSO-d6):
d
¼3.84 (s, 3H, CO2CH3), 7.49–8.27 (m, 4H,
S-Acetylthiosalicylic acid (10 mmol, 1.96 g) was treated under
argon with N-hydroxysuccinimide (10 mmol, 1.16 g) in THF
(11.5 mL). A solution of DCC (12 mmol, 2.47 g) in THF (8.5 mL) was
then added dropwise at 0 ꢀC and the reaction mixture was allowed
to stir at 0 ꢀC for 2 h. The resulting suspension was refrigerated
overnight at 3–5 ꢀC. The precipitated solid (DCCU) was filtered off
and discarded, the THF filtrate was evaporated under reduced
pressure and dried in vacuo to afford a solid product. The product
was washed with diethyl ether and dried in vacuo to afford
N-hydroxysuccinimide ester of the corresponding S-acetylthio-
salicylic acid as a white solid.
aromatic H). 13C NMR (75 MHz, DMSO-d6):
d
¼52.8 (CO2CH3), 108.2
(C-3), 123.0, 125.6, 126.9, 127.6, 132.7, 136.2 (C6H4), 168.0 (CO2CH3),
169.1 (C-2),179.1 (C-4). Anal. Calcd for C11H8O4S: C, 55.92; H, 3.41; O,
27.09; S, 13.57. Found: C, 55.79; H, 3.29; O, 26.92; S, 13.65.
4.2.3.2. 3-Ethoxycarbonyl-4-hydroxythiocoumarin(12). Using diethyl
malonate as the active methylene compound, according to method
(B), compound 12 was obtained as a yellow solid. Yield: 62%; mp
103–104 ꢀC (lit.11 115–116 ꢀC). IR (ATR): 1734, 1680, 1650, 1633, 1590,
1540 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼1.28 (t, J¼6.9 Hz, 3H,
CO2CH2CH3), 4.31 (q, J¼6.9 Hz, 2H, CO2CH2CH3), 7.53–8.28 (m, 4H,
aromatic H). 13C NMR (75 MHz, DMSO-d6):
d
¼13.8 (CO2CH2CH3),
4.2.2.1. N-Hydroxysuccinimide ester of S-acetylthiosalicylic acid
61.9 (CO2CH2CH3), 108.0 (C-3), 122.9, 125.5, 126.8, 127.5, 132.7, 136.3
(C6H5), 167.8 (CO2CH2CH3), 169.4 (C-2), 179.0 (C-4). Anal. Calcd for
(3). Yield: 92%; mp 112–114 ꢀC. IR (ATR): 2117, 1776, 1740, 1700,
1650, 1627, 1575, 1637 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼2.44
(s, 3H, COCH3), 2.88 (s, 4H, CO2N(CO)2(CH2)2), 7.69–8.09 (m, 4H,
aromatic H). 13C NMR (75 MHz, DMSO-d6):
C12H10O4S: C, 57.59; H, 4.03; O, 25.57; S, 12.81. Found: C, 57.74; H,
4.18; O, 25.49; S, 12.68.
d
¼25.6 (COCH3), 30.2
(CO2N(CO)2(CH2)2), 128.8, 129.4, 130.4, 131.2, 134.3, 137.5 (C6H4),
161.3 (COCH3), 170.1 (CO2N(CO)2(CH2)2), 192.0 (CO2N(CO)2(CH2)2).
Anal. Calcd for C13H11O5NS: C, 53.24; H, 3.78; N, 4.77; O, 27.27; S,
10.93. Found: C, 53.38; H, 3.63; N, 4.52; O, 27.39; S, 10.78.
4.2.3.3. 2-Amino-3-methoxycarbonylthiochromone(13). Using methyl
cyanoacetate as the active methylene compound, according to
method (A), compound 13 was obtained as a yellow solid. Yield: 57%;
mp 205–207 ꢀC. IR (ATR): 2215, 1745, 1679, 1633, 1590, 1530 cmꢁ1. 1H
NMR (300 MHz, DMSO-d6):
aromatic H), 8.31 (br s, 2H, NH2). 13C NMR (75 MHz, DMSO-d6):
¼51.5 (CO2CH3), 102.1 (C-3), 125.0, 126.0, 128.1, 131.6, 133.3, 138.9
(C6H5), 161.6 (C-2), 167.6 (CO2CH3), 175.9 (C-4). Anal. Calcd for
11H9O3NS: C, 56.16; H, 3.86; N, 5.95; O, 20.40; S, 13.63. Found: C,
56.30; H, 3.71; N, 5.84; O, 20.55; S, 13.49.
d
¼3.74 (s, 3H, CO2CH3), 7.43–8.17 (m, 4H,
4.2.3. General procedure for the synthesis of 3-substituted
thiocoumarins and thiochromones
NaH (60% suspension in oil) (20 mmol, 0.8 g) was added in an-
hydrous THF (65 mL) at 0 ꢀC and the resulting mixture was stirred
under argon for 15 min at room temperature. The appropriate
d
C

5458
S. Kikionis et al. / Tetrahedron 64 (2008) 5454–5458
4.2.3.4. 3-Cyano-4-hydroxythiocoumarin (14). Using methyl cya-
noacetate as the active methylene compound, according to method
(C), compound 14 was obtained as yellow solid. Yield: 60%; mp
229–232 ꢀC. MS (ESI) m/z¼204.1 ([MþH]þ). IR (ATR): 2233, 1747,
structure was solved by direct methods and refined on F2 using all
the reflections.22 All the non-hydrogen atoms were refined using
anisotropic atomic displacement parameters and hydrogen atoms
were inserted at calculated positions using a riding model, except
for the hydrogen bonded to O1, which was located and refined with
a fixed, isotropic displacement parameter. Crystallographic data
(excluding structure factors) for the structure in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 682433. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
1680, 1630, 1583, 1530 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
d
¼7.30–8.16 (m, 4H, aromatic H). 13C NMR (75 MHz, DMSO-d6):
d¼88.5 (C-3), 119.0 (CN), 125.3, 125.6, 127.6, 129.1, 131.1, 135.1
(C6H4), 178.1 (C-2), 178.2 (C-4). Anal. Calcd for C10H5O2NS: C, 59.10;
H, 2.48; N, 6.89; O, 15.74; S, 15.78. Found: C, 59.22; H, 2.53; N, 6.95;
O, 15.59; S, 15.61.
4.2.3.5. 2-Amino-3-cyanothiochromone (15). Using malonitrile as
the active methylene compound, according to method (B), com-
pound 15 was obtained as a brown solid. Yield: 62%; mp 295–
297 ꢀC (lit.16 291–293 ꢀC). IR (ATR): 2213, 1683, 1642, 1633, 1580,
Acknowledgements
1538 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6):
d
¼7.47–8.20 (m, 4H,
S.K. would like to thank the National Technical University of
Athens, Chemical Engineering Department for financial support.
J.M. would like to thank the National and Kapodistrian University of
Athens for financial support (special account for research grant
No. 70/4/3337).
aromatic H), 8.74 (br s, 2H, NH2). 13C NMR (75 MHz, DMSO-d6):
d
¼84.1 (C-3), 115.7 (CN), 126.1, 127.5, 127.6, 127.9, 130.7, 132.3
(C6H4), 166.1 (C-2), 176.5 (C-4). Anal. Calcd for C10H6ON2S: C, 59.39;
H, 2.99; N, 13.85; O, 7.91; S, 15.85. Found: C, 59.45; H, 3.13; N, 13.69;
O, 7.83; S, 15.71.
References and notes
4.2.3.6. 3-Ethoxycarbonyl-2-methylthiochromone (16). Using ethyl
acetoacetate as the active methylene compound, according to
method (A), compound 16 was obtained as a yellow solid. Yield:
56%; mp 125–127 ꢀC (lit.11 145–146 ꢀC). IR (ATR): 1705, 1678, 1602,
1. (a) Nakazumi, H.; Kitao, T. Chem. Lett. 1978, 929; (b) Nakazumi, H.; Asada, A.;
Kitao, T. Bull. Chem. Soc. Jpn. 1980, 53, 2046; (c) Nakazumi, H.; Ueyama, T.;
Sonoda, H.; Kitao, T. Bull. Chem. Soc. Jpn. 1984, 57, 2323; (d) Tamura, K.; Ishihara,
T.; Yamanaka, H. J. Fluorine Chem. 1994, 68, 25.
2. Rios, R.; Sunde`n, H.; Ibrahem, I.; Zhao, G.-L.; Co´rdova, A. Tetrahedron Lett. 2006,
47, 8679.
3. Panetta, J. A.; Rapoport, H. J. Org. Chem. 1982, 47, 2626.
4. Kumar, P.; Bodas, M. S. Tetrahedron 2001, 57, 9755.
5. Watanabe, K.; Saito, T.; Niimura, K. Eur. Pat. Appl. EP 758649, 1997; Chem. Abstr.
1997, 126, 199456.
6. Sano, T.; Saijo, K.; Tomizawa, K.; Kameo, K.; Yokomori, S.; Hatayama, K. Jpn.
Kokai Tokkyo Koho JP 04082887, 1992; Chem. Abstr. 1992, 117, 150893.
7. Carter, J. S.; Obukowicz, M. G.; Devadas, B.; Talley, J. J.; Brown, D. L.; Graneto, M.
J.; Bertenshaw, S. R.; Rogier, D. J., Jr.; Nagarajan, S. R.; Hanau, C. E.; Hartmann, S.
J.; Ludwig, C. L.; Metz, S. PCT Int. Appl. WO 9847890, 1998; Chem. Abstr. 1998,
129, 330653.
8. Nakazumi, H.; Kobara, Y.; Kitao, T. J. Heterocycl. Chem. 1992, 29, 135.
9. Prasanna, B.; Chandramouli, G. V. P. Phosphorus, Sulfur Silicon Relat. Elem. 2004,
179, 2059.
10. Meth-Cohn, O.; Tarnowski, B. Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Boulton, A. J., Eds.; Academic: New York, NY, 1980; Vol. 26, p 122.
11. Jung, J.-C.; Kim, J.-C.; Park, O.-S. Synth. Commun. 2000, 30, 1193.
12. Huang, B.-N.; Liu, J.-T.; Huang, W.-Y. J. Chem. Soc., Perkin Trans. 1 1994, 101.
13. Kikionis, S.; Prousis, K. C.; Detsi, A.; Igglessi-Markopoulou, O. ARKIVOC 2006, 28.
14. (a) Mitsos, C. A.; Zografos, A. L.; Igglessi-Markopoulou, O. J. Org. Chem. 2003, 68,
4567; (b) Zografos, A.; Mitsos, C.; Igglessi-Markopoulou, O. Heterocycles 1999,
51, 1609; (c) Athanaselis, G.; Melagraki, G.; Chatzidakis, H.; Afantitis, A.; Detsi,
A.; Igglessi-Markopoulou, O.; Markopoulos, J. Synthesis 2004, 11, 1775.
15. Stacy, G. W.; Eck, D. L.; Wollner, T. E. J. Org. Chem. 1970, 35, 3495.
16. Rudorf, W. D.; Augustin, M. J. Prakt. Chem. 1981, 323, 55.
17. Munshi, P.; Row, T. N. G. J. Phys. Chem. A 2005, 109, 659.
18. Steiner, T. Crystallogr. Rev. 2003, 9, 177.
1538 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
¼1.24 (t, J¼7.3 Hz, 3H,
CO2CH2CH3), 2.43 (s, 3H, CH3), 4.12 (q, J¼7.3 Hz, 2H, CO2CH2CH3),
7.40–8.08 (m, 4H, aromatic H). 13C NMR (75 MHz, CDCl3):
d¼14.4
(CO2CH2CH3), 20.7 (CH3), 60.1 (CO2CH2CH3), 99.3 (C-3), 116.8, 128.6,
132.1, 133.2, 133.6, 135.3 (C6H5), 156.8 (C-2), 165.4 (CO2CH2CH3),
170.4 (C-4). Anal. Calcd for C13H12O3S: C, 62.88; H, 4.87; O, 19.33; S,
12.91. Found: C, 62.75; H, 4.96; O, 19.48; S, 12.81.
4.2.3.7. 3-Benzoyl-4-hydroxythiocoumarin (17). Using ethyl ben-
zoylacetate as the active methylene compound, according to
method (B), compound 17 was obtained as yellow crystals. Yield:
65% (recrystallisation from methanol); mp 150–153 ꢀC. MS (ESI) m/
z¼283.2 ([MþH]þ). IR (ATR): 1698, 1630, 1595, 1530 cmꢁ1. 1H NMR
(300 MHz, DMSO-d6):
(75 MHz, DMSO-d6):
128.8, 131.8, 133.5, 136.0, 137.0 (C6H5), 164.8 (COC6H5), 181.1 (C-2),
193.8 (C-4). Anal. Calcd for C16H10O3S: C, 68.07; H, 3.57; O, 17.00; S,
11.36. Found: C, 68.17; H, 3.43; O, 16.86; S, 11.29.
d
¼7.49–8.29 (m, 9H, aromatic H). 13C NMR
d
¼116.4 (C-3), 123.7, 126.0, 126.8, 127.0, 128.8,
4.3. Crystal structure determination of 11
Compound 11: C11H8O4S, monoclinic, P21/c,
a
¼8.2037(5),
b¼6.9587(4), c¼17.4291(11) Å,
b
¼90.949(1)ꢀ, V¼994.84(10) Å3,
19. Taylor, R.; Kennard, O. J. Chem. Am. Soc. 1982, 104, 5063.
20. Sarma, J. A. R. P.; Desiraju, G. R. Acc. Chem. Res. 1986, 19, 222.
21. Taiyoung, S. J.; Russell, M. P.; Howard, J. Eur. Pat. Appl. EP 54936, 1982; Chem.
Abstr. 1982, 97, 198562.
T¼150(2) K,
l
¼0.71073 Å, Z¼4,9239 reflections measured, 2272
unique (Rint¼0.0233), wR2¼0.0830 (all data), R1¼0.0302 (I>2
s(I)).
Data were collected on a Bruker APEX II diffractometer. The
22. Sheldrick, G. M. SHELXTL Version 6.12; Bruker AXS: Madison WI, 2001.