Heterocyclic analogs of thioflavones: Synthesis and NMR spectroscopic investigations

Article abstract of DOI:10.3390/molecules14093814

The synthesis of several hitherto unknown heterocyclic ring systems derived from thioflavone is described. Coupling of various o haloheteroarenecarbonyl chlorides with phenylacetylene gives 1-(o-haloheteroaryl)-3-phenylprop-2-yn-1- ones, which were treate

Full text of DOI:10.3390/molecules14093814

Molecules 2009, 14, 3814-3832; doi:10.3390/molecules14093814
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Heterocyclic Analogs of Thioflavones: Synthesis and NMR
Spectroscopic Investigations †
Ferdinand C. Fuchs, Gernot A. Eller and Wolfgang Holzer *
Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna,
Althanstrasse 14, A-1090 Vienna, Austria
* Author to whom correspondence should be addressed; E-Mail: wolfgang.holzer@univie.ac.at.
†
Dedicated to Prof. Peter Stanetty with best personal wishes on the occasion of his 65th birthday.
Received: 3 September 2009; in revised form: 11 September 2009 / Accepted: 21 September 2009 /
Published: 25 September 2009
Abstract: The synthesis of several hitherto unknown heterocyclic ring systems derived
from thioflavone is described. Coupling of various o-haloheteroarenecarbonyl chlorides
with phenylacetylene gives 1-(o-haloheteroaryl)-3-phenylprop-2-yn-1-ones, which were
treated with NaSH in refluxing ethanol to yield the corresponding bi- and tricyclic
annelated 2-phenylthiopyran-4-ones. Detailed NMR spectroscopic investigations of the
ring systems and their precursors are presented.
Keywords: thioflavone; Sonogashira coupling; ring closure reactions; NMR spectroscopy
1. Introduction
The flavone system (2-phenyl-4H-chromen-4-one, shown in Figure 1, is the core of many
biologically active compounds which play important roles in numerous biological processes. The
relevance of flavone-based molecules has been thoroughly described in the literature [1-5].
Replacement of the ring oxygen atom in flavone by a sulfur atom results in thioflavone (4a, Figure 1),
whose derivatives also exhibit interesting biological properties [6-13]. Moreover, thioflavones are
valuable precursors for the synthesis of other condensed heterocyclic systems, such as
benzothiazepines [14]. Analogs of type 4 thioflavone-systems – in which the condensed benzene ring
of 4a is replaced by a heteroaromatic moiety (Figure 1) – seem to be of notable interest considering the

Molecules 2009, 14
3815
concept of bioisosterism [15-17]. Type 4 compounds with a pyridine, thiophene, benzo[b]thiophene or
indole system annelated to the thiopyrane ring have been previously characterized.
Figure 1. Flavone, thioflavone and its heterocyclic analogs 4.
O
S
O
O
O
S
Het
4 (Het = hetero-
aromatic system)
thioflavone (4a)
flavone
Various approaches have been used to synthesize type 4 systems. Representative examples are
given in Scheme 1.
Scheme 1. Traditional approaches to the title compounds 4.
COOEt
COOEt
tBu-S- Na+
SH
-tBu
SH
Cl
B
C
A
O
O
O
OR
O
OEt
Ph
NaNH2
OH-
PPA
Ph
CH3
O
O
O
Ph
COOR
Ph
Ph
H+
SH
-tBu
Ph
S
S
D
E
4
pyridine . HCl
O
O
Br
Br
COCl
Ph
Br2
SnCl4
SCH3 Ph
SCH3
Ph
SCH3
G
H
F
For instance, condensation of appropriate thiophenols A with ethyl benzoylacetate followed by
subsequent cyclization of the obtained condensation products permits access to type 4 systems [18].
Another approach was employed by Becher in the synthesis of 2-phenyl-4H-thiopyrano[2,3-b]pyridin-
4-one (4f) [19]. Ethyl 2-chloronicotinate (B) was transformed into the 2-tert-butyl congener C, which
was condensed with acetophenone to yield D; the latter readily cyclized into 4f in an acidic medium.
Moreover, the reaction between phenylpropiolates and thiophenols A and subsequent ring closure
reaction of the formed substituted cinnamates E has also been used [20-21], for instance, in the
synthesis of indole annelated 2-phenylthiopyran-4-ones [22]. Variants of 4 containing a thiophene or a
benzo[b]thiophene moiety have been prepared via Friedel–Crafts acylation of the corresponding

Molecules 2009, 14
3816
methylthio(benzo)thiophenes F with cinnamoyl chloride, to yield ketones G, and addition of bromine
to the alkene double bond (compounds H) and subsequent cyclization with pyridine hydrochloride [23-
25]. However, many of these methods require precursors that are neither commercially available nor
readily synthesized. Moreover, the other above-mentioned approaches lack generality. For example,
Friedel-Crafts-based methods are restricted to π-excessive heteroaromatic systems.
Here, we present a general approach for synthesizing heterocyclic analogs of type 4 based on a
Sonogashira-type coupling of o-halo(hetero)aroyl chlorides 1 with phenylacetylene to yield alkynones
2 (Scheme 2). Reactions between 2 and NaSH in refluxing ethanol then yield the desired compounds 4
via an addition/cyclization step (Scheme 2). A related approach to thioflavone generation employing a
microwave-assisted one-pot, three-component synthesis has been recently described by Müller [26]
(based on an earlier report by Shvartsberg [27-28]). In the course of these investigations, the acetylenic
component was varied to obtain different 2-substituted 4H-thiochromen-4-ones [26].
Scheme 2. Preparation of compounds 4a-h.
O
X
O
O
Cl
Ph
Het
Het
Het
Ph
Pd(OAc)2
NEt3
S
Ph
X
4a-h
1a-j
2a-h
O
NaSH
EtOH
Het
Ph
X SH
3
O
O
X in
1,2,(3)
X in
1,2,(3)
Compd.
1,2,(3),4
Compd.
1,2,(3),4
R
R
Het
Het
(X)
(X)
Cl (a1)
F (a2)
a
b
f
Cl
Cl
Cl
N
Br
Br
g
h
N
S
S
S
c
d
e
N
N
Br
Cl
i
j
F
S
N
N
Cl

Molecules 2009, 14
2. Results and Discussion
2.1. Chemistry
3817
Synthesis of the target compounds 4 was accomplished via the sequence shown in Scheme 2.
Precursors 1 are either commercially available or can be easily prepared by treatment of the
corresponding carboxylic acids with thionyl chloride. Compounds 1 were transformed into 2 via
Sonogashira-type coupling [29-30], a very important step in forming C-C bonds with terminal
acetylenes [31]. A ligand- and copper-free Pd-catalyzed (Pd acetate, Et3N) version of this method for
the coupling of carboxylic acid chlorides with different terminal acetylenes has been recently
described by Nájera [32] and Srinivasan [33]. In preliminary tests in which the solvent, amount of
triethylamine and the acid chloride/phenylacetylene ratio were varied, we adapted the reaction
conditions for synthesis of the desired o-halo(hetero)arylynones 2a–h. The best results were obtained
using two equivalents of acid chloride, a 3–14-fold molar excess of triethylamine, dichloromethane as
the solvent and ambient temperature. Reasonably good yields of ynones 2a–h were obtained applying
these reaction conditions. However, using of 1i and 1j as starting materials (both having the COCl
group attached in the o-position to a pyridine-type nitrogen atom), we did not obtain the corresponding
coupling products 2i or 2j. Instead, the respective N,N-diethylamides 5 and 6 were isolated as the main
reaction products from the complex reaction mixtures (Scheme 3). A few reports in the literature have
described N,N-diethylamide formation from acid chlorides and triethylamine [30,34-35].
Scheme 3. Unexpected formation of N,N-diethylamides 5 and 6.
O
F
O
N
N
Cl
Ph
N
(Etcis)
(Ettrans
Pd(OAc)2
NEt3
F
)
1i
5
O
O
N
N
N
Cl
Ph
N
(Etcis)
(Ettrans
Pd(OAc)2
NEt3
Cl
Cl
N
)
1j
6
NaSH in refluxing ethanol (96%) was used for the conversion of ynones 2a–h into thiopyranones
4a–h (Scheme 2). In principle, it is possible to use Na2S as the SH donor [27-28]; however, poor
results were obtained using this technique. Evidence of the proposed mechanism, a Michael addition of
the hydrosulfide to the alkynone system [26], was obtained in the following experiment. When 2a1
was reacted with NaSH/ethanol at room temperature, we isolated a sulfur-containing product that
contained a chlorine atom and an enone group. The high-resolution mass spectrum and the spectral
data demonstrated that the product was not the expected intermediate 3a1, but rather the thioether 7
(Scheme 4), formed following reaction between two units of 3a1 by elimination of hydrogen sulfide.
The cis-position of alkene-H and the phenyl ring was confirmed by an NOE-difference experiment that
employed irradiation of alkene-H resonance (Scheme 4).

Molecules 2009, 14
Scheme 4. Formation of thioether 7 from Michael addition intermediate 3a1.
3818
Cl
O
NOE
H
H
O
Cl
O
3a1
NaSH
EtOH
S
- H2S
Ph
Ph
Cl
HS
H
2a1
3a1
H
O
Cl
7
Initial attempts to synthesize 4a and 4f in a one-pot/two-step procedure (reactants: 1a or 1f,
respectively, with phenylacetylene, by Pd(OAc)2/triethylamine catalysis in solvent; then addition of
Na2S in DMF) gave low yields (<16%) of the desired thiopyranones.
The ynones 2 described here are valuable precursors in the synthesis of other condensed
heterocyclic systems, such as annelated pyridin-4-ones 8 and pyran-4-ones 9 (Scheme 5). For example,
2a1 was reacted with methylamine to generate the corresponding Michael addition product 10 at a
73% yield (stereochemistry demonstrated by a NOESY experiment). Treatment of product 10 with
K2CO3 in dry DMF gave 1-methyl-2-phenyl-4(1H)-quinolinone (11) at a good yield. This type of
compound was reported to exhibit interesting biological properties, such as anti-platelet [36], anti-
mitotic [37], and anti-HIV-replication activity [38]. Furthermore, the well-known class of
fluoroquinolinone type [39] antibacterial drugs, such as ciprofloxacin [40] or enoxacin [41], are
structurally similar to 11. Investigations into the preparation of heterocyclic annelated pyridin-4-ones
of type 8 are currently in progress and will be reported elsewhere.
Scheme 5. Further synthetic potential of ynones 2.
O
O
O
O
Het
Het
Het
Ph
Ph
X
N
R
8
Ph
9
2
O
Cl
O
O
NOE
H
NH2CH3
EtOH
H
K2CO3
DMF
Ph
HN
CH3
10
Cl
N
Ph
CH3
11
2a1

Molecules 2009, 14
3819
2.2. Spectroscopic investigations
Alkynones 2 and thiopyranones 4 are predominantly novel structures. Representative structures
(2a1, 2a2, 4a, 4d–f) have not been thoroughly investigated by spectroscopic methods, such as NMR.
In regards to 13C-NMR spectroscopy – in cases where such data are available (4a, 4f) – little [19] to no
[27-28] signal assignments have been made. Hence, we present the results from an extensive NMR
13
15
study (1H, C, N) of compounds 2 and 4. Reliable and unambiguously assigned chemical shift data
are important reference material for NMR prediction programs, such as CSEARCH [42]/NMRPRE-
DICT [43] and ACD/C + H predictor [44]. Such programs have become very popular in the last few
years, particularly for predicting 13C-NMR chemical shifts. However, the quality of such predictions is
highly dependent on the availability of authentic reference data from related structures. This criterion
is frequently unfulfilled for rare condensed heteroaromatic systems, such as those described here.
1
13
15
Full and unambiguous assignment of all H, C and N resonances was achieved by combining
1
13
standard NMR techniques [45], such as fully H-coupled C-NMR spectra, APT, HMQC, gs-HSQC,
gs-HMBC, COSY, TOCSY, NOESY and NOE-difference spectroscopy. Moreover, experiments with
1
selective excitation (DANTE) of certain H-resonances were performed, such as long-range INEPT
[46] and 2D(δ,J) long-range INEPT [47]. The latter experiments were indispensable for the
unambiguous mapping of long-range 13C,1H coupling constants. Aside from the variable
heteroaromatic system, the obtained data of the invariant parts of 2 and 4 show a high degree of
consistency. Thus, the 3-phenyl-2-propyn-1-one substructure in 2a–h exhibits a carbonyl C-1 shift of
168.3–176.7 ppm, a C-2 shift of 87.2–88.5 ppm, and a C-3 shift of 91.9–96.2 ppm. Alkyne C-atoms,
C-2 and C-3, can be easily distinguished by their coupling patterns: the C-2 signal appears as a singlet
1
3
in the H-coupled 13C-NMR spectrum, whereas the C-3 signal is a triplet due to J coupling with
phenyl protons H-2/6 (which is confirmed by a correlation signal from the involved nuclei in the
HMBC spectrum). The signals from the phenyl-C atoms are Ph C-1: 119.3–120.1 ppm, Ph C-2/6:
133.1–133.3 ppm, Ph C-3/5: 128.6–128.8 ppm and Ph C-4: 130.9–131.6 ppm. The thiopyranone
system in compounds 4a–h is characterized by a chemical shift of 176.2–182.0 ppm for the carbonyl
C-atom (split by a ~ 1 Hz J coupling to the adjacent =C-H), 122.1–125.0 ppm for =C-H (1J 163.3–
2
164.8 Hz) and 151.5–155.1 ppm for S-C-Ph (2J to =CH ~ 3 Hz). The =C-H proton gives rise to a
characteristic singlet signal between 6.99 and 7.32 ppm. As observed with compounds 2, systems 4
also exhibit small differences in Ph-C shifts within the series a–h (Ph C-1: 136.1–136.7 ppm, Ph C-
2/6: 126.9–127.2 ppm, Ph C-3/5: 129.2–129.4 ppm, Ph C-4: 130.7–131.3 ppm). The descriptions of
NMR spectra in the Experimental section were assigned based on systematic nomenclature and, hence,
the numbering of atoms within the thiopyrane moiety is inconsistent.
The excellent utility of 2D (δ,J) long-range INEPT spectra with selective excitation for the definite
mapping of 13C,1H coupling constants is demonstrated by an example presented in Figure 2. In the 1H-
coupled 13C-NMR spectrum of 4d, the signal of C-7a is split by a 7.1, 5.9 and 4.7 Hz coupling,
whereas coupling occurs with H-2, H-3 and H-6. Unequivocal assignment of these coupling constants
based on literature data for the thiophene system is unreliable. However, after selective excitation of
the H-2 resonance, the C-7a signal appears as a doublet of 5.9 Hz, thus 3J(C7a,H2) = 5.9 Hz (Figure 2).
Moreover, the couplings 2J(C3,H2) = 4.8 Hz and 3J(C3a,H2) = 11.2 Hz emerge (Figure 2) (4J(C7,H2)

Molecules 2009, 14
3820
= 1.1 Hz also appears, but it is not displayed in Figure 2). Further experiments with selective excitation
of H-3 and H-6 assigned 3J(C7a,H3) = 7.1 Hz and 2J(C7a,H6) = 4.7 Hz.
Figure 2. Part of the long-range 2D (δ,J) INEPT spectrum of 4d obtained upon selective
excitation of the H-2 resonance; 1H- (in italics) and 13C-NMR chemical shifts in 4d.
O
176.2
7.21
137.2
H
S
7
133.2
7.65
1
3
H
6
5
123.6
7a
3a
2
7.85
H
127.2
152.8
4
7.51
H
125.3
139.0 S
136.4
129.3
7.35
H
130.7
7.65 H
H
127.2
7.51
129.3
7.51
4d
H
2J(C3,H2) = 4.8 Hz
F2
(ppm)
124
126
128
130
132
134
136
138
140
142
C-3
10
10
10
8
8
8
6
4
2
-0 -2 -4 -6 -8Hz
3J(C7a,H2) = 5.9 Hz
6
4
2
-0 -2 -4 -6 -8Hz
C-7a
C-3a
3J(C3a,H2) = 11.2 Hz
144
10
8
6
4
2
-0 -2 -4 -6 -8
F1 (Hz)
6
4
2
-0 -2 -4 -6 -8Hz
Furthermore, the NMR spectra of N,N-diethylcarboxamides 5 and 6, respectively, two different
signals sets for the ethyl moieties (Etcis, Ettrans, see Scheme 3) were found for each case. As expected,
this indicates that there is restricted rotation around the amide bond under the recording conditions
(CDCl3, ambient temperature).
In the IR spectra, the carbonyl C=O absorption from the ynones 2 appears in the range between
1,601 and 1,649 cm-1, and those from the thiopyranones 4 between 1,606 and 1,635 cm-1. Absorptions
for the C≡C vibration in the IR spectra of compounds 2 appear from 2,196–2,202 cm-1.
As reported for related structures [48], the mass spectra of 4 exhibit a fragmentation behavior that is
characterized by the loss of CO, a pathway that is also observed for ynones 2.

Molecules 2009, 14
3821
3. Conclusions
We have presented a widely applicable method for the preparation of heterocyclic annelated 2-
phenylthiopyran-4-ones via a cross-coupling addition-cyclization approach starting from o-halo-
heteroaroyl chlorides and phenylacetylene. Detailed NMR spectroscopic studies of the title compounds
and their precursors were provided.
4. Experimental
4.1. General
Melting points were determined on a Reichert–Kofler hot-stage microscope and are uncorrected.
Mass spectra were obtained on a Shimadzu QP 1000 instrument (EI, 70 eV), a Finnigan MAT 8230
instrument (EI, 70 eV, HRMS), and a Finnigan MAT 900S instrument (ESI, 4 kV, MeOH-
acetonitrile). IR spectra (KBr unless otherwise stated) were recorded on a Perkin-Elmer FT-IR 1605
spectrophotometer or an ATI Mattson Genesis series FT-IR spectrophotometer. Elemental analyses (C,
H, N and S) were performed at the Microanalytical Laboratory, University of Vienna, and were in
1
good agreement (±0.4%) with the calculated values. H- and 13C-NMR spectra were recorded on a
Varian UnityPlus 300 spectrometer at 28 °C (299.95 MHz for 1H, 75.43 MHz for 13C) or on a Bruker
1
Avance 500 spectrometer at 293 K (500.13 MHz for H, 125.77 MHz for 13C). The center of the
solvent (CDCl3) signal was used as an internal standard, which was related to TMS with δ 7.26 ppm
15
19
(1H) and δ 77.0 ppm (13C). N-NMR spectra (50.68 MHz) and F-NMR spectra (470.56 MHz) were
obtained on a Bruker Avance 500 spectrometer with a ‘directly’ detecting broadband observe probe
(BBFO). The spectra were referenced against external nitromethane (15N) or against the absolute
19
1
frequency scale (Ξ ratio, F). The digital resolution was 0.25 Hz/data point in the H spectra and 0.4
Hz/data point in the 13C-NMR spectra. Systematic names were generated with ACD/Name [49]
according to the IUPAC recommendations and were checked manually [50]. For chromatographic
separations, Kieselgel 60 (70–230 mesh, Merck) was used. Light petroleum had a boiling point of 40–
65 °C.
4.2. Synthetic procedures
4.2.1. General procedure for the synthesis of o-halo(hetero)aroyl chlorides 1b–h
A suspension of the appropriate acid (2 mmol) in toluene (20 mL), DMF (5 drops) and SOCl2
(20 mmol, 2.38 g) was refluxed for 3 h or overnight. The solvent and excess SOCl2 were removed
under reduced pressure. Additional toluene (4  5 mL) was added, and the solvent was removed under
reduced pressure. The remaining acid chloride was immediately used in subsequent reaction steps
(with no further purification).
4.2.2. General procedure for the synthesis of ynones 2a-h
The appropriate acid chloride 1 (2 mmol) was dissolved in dry CH2Cl2 (3 mL). Triethylamine
(2 mL), phenylacetylene (1 mmol, 102 mg) and Pd(II) acetate (10 µmol, 2 mg) were added to the

Molecules 2009, 14
3822
solution, which was stirred at room temperature under a N2 atmosphere (N2 balloon) for the indicated
time. The solvent was removed under reduced pressure and water (20 mL) was added to the residue.
The resulting solution was acidified with 5% HCl and extracted with CH2Cl2 or EtOAc (2  15 mL).
The combined organic layers were washed with a saturated NaHCO3 solution and a saturated NaCl
solution and were then dried over anhydrous Na2SO4. After removal of the solvent, the residue was
purified by column chromatography through a silica gel column (eluent given below). An analytically
pure sample was obtained by recrystallization from the appropriate solvent, which is indicated below.
1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-one (2a1). Reaction time: 2.5 h. Eluent: toluene/light
1
petroleum, 1:1 v/v. Yield: 209 mg, 87%; orange oil; [51] H-NMR (300 MHz): δ 8.08 (m, 1H, H-6),
7.65 (m, 2H, Ph H-2,6), 7.48 (m, 2H, H-3,4), 7.46 (m, 1H, Ph H-4), 7.41 (m, 2H, Ph H-3,5), 7.40 (m,
13
3
1H, H-5); C-NMR (75 MHz): δ 176.7 (C=O, J(CO,H6) = 5.3 Hz), 135.9 (C-1), 133.5 (C-2), 133.3
(C-4), 133.1 (Ph C-2,6), 132.4 (C-6), 131.5 (C-3), 130.9 (Ph C-4), 128.7 (Ph C-3,5), 126.8 (C-5), 120.1
(Ph C-1), 93.9 (COC≡C, 3J(C,Ph H2,6) = 5.5 Hz), 88.3 (COC≡C); IR (liquid film): 2196 (C≡C), 1649
(C=O) cm−1; MS m/z (%): 242/240 (M+, 14/40), 214/212 ([M − C=O]+, 25/72) 141/139 ([COC6H4Cl]+,
12/34), 129 ([COC≡CC6H5]+, 100), 101 ([C≡CC6H5]+, 14).
1-(2-Fluorophenyl)-3-phenylprop-2-yn-1-one (2a2). Reaction time: 45 min. Eluent: CH2Cl2/light
petroleum, 1:1 v/v. Yield: 164 mg, 73%; light orange oil; [52] 1H-NMR (500 MHz): δ 8.11 (m, 1H, H-
6), 7.67 (m, 2H, Ph H-2,6), 7.59 (m, 1H, H-4), 7.49 (m, 1H, Ph H-4), 7.42 (m, 2H, Ph H-3,5), 7.28 (m,
13
1
1H, H-5), 7.19 (m, 1H, H-3); C-NMR (125 MHz): δ 174.2 (C=O), 162.1 (C-2, J(C2,F2) = 261.7
Hz), 135.6 (C-4, 3J(C4,F2) = 9.2 Hz), 133.2 (Ph C-2,6), 131.8 (C-6), 130.9 (Ph C-4), 128.6 (Ph C-3,5),
2
4
125.6 (C-1, J(C1,F2) = 7.7 Hz), 124.2 (C-5, J(C5,F2) = 3.9 Hz), 120.1 (Ph C-1), 117.1 (C-3,
2J(C3,F2) = 21.9 Hz), 93.0 (COC≡C, J(C,F2) = 3.2 Hz), 88.5 (COC≡C); 19F-NMR (470 MHz): δ
−111.3 (F-2); IR (liquid film): 2200 (C≡C), 1647 (C=O) cm−1; MS m/z (%): 224 (M+, 17), 196
([M − C=O]+, 36), 129 ([COC≡CC6H5]+, 100), 123 ([COC6H4F]+, 84), 101 ([C≡CC6H5]+, 21), 74 (83).
1-(2-Bromothiophen-3-yl)-3-phenylprop-2-yn-1-one (2b). Reaction time: 19 h. Eluent: CH2Cl2/light
1
petroleum, 3:2 v/v. Yield: 147 mg, 67%; whitish needles, mp 66–67 °C (EtOH/H2O); H- NMR (500
MHz): δ 7.65 (m, 2H, Ph H-2,6), 7.57 (d, 3J = 5.8 Hz, 1H, H-4), 7.48 (m, 1H, Ph H-4), 7.41 (m, 2H, Ph
3
13
3
H-3,5), 7.28 (d, J = 5.8 Hz, 1H, H-5); C-NMR (125 MHz): δ 170.5 (C=O, J(CO,H4) = 2.0 Hz),
2
3
138.2 (C-3, J(C3,H4) = 4.5 Hz, J(C3,H5) = 8.4 Hz), 133.0 (Ph C-2,6), 130.9 (Ph C-4), 129.9 (C-4,
1J(C4,H4) = 173.4 Hz, J(C4,H5) = 3.8 Hz), 128.7 (Ph C-3,5), 126.0 (C-5, J(C5,H5) = 190.3 Hz,
2
1
2J(C5,H4) = 6.0 Hz), 120.3 (C-2, J(C2,H4) = 12.1 Hz, J(C2,H5) = 6.8 Hz), 120.0 (Ph C-1, J(Ph
3
3
3
4
C1,Ph H3,5) = 8.5 Hz, J(Ph C1,Ph H4) = 1.3 Hz), 93.1 (COC≡C), 88.0 (COC≡C); IR: 2202 (C≡C),
1630 (C=O) cm−1; MS m/z (%): 292/290 (M+, 22/23), 264/262 ([M − C=O]+, 28/28), 139 (65), 129
([COC≡CC6H5]+, 100), 101 ([C≡CC6H5]+, 16), 74 (79). Calcd. for C13H7BrOS: C, 53.63; H, 2.42; S,
11.01. Found: C, 53.31; H, 2.39; S, 10.92.
1-(4-Bromothiophen-3-yl)-3-phenylprop-2-yn-1-one (2c). Reaction time: 3 h. Eluent: CH2Cl2/light
1
4
petroleum, 3:2 v/v. Yield: 148 mg, 25%; brownish oil; H-NMR (500 MHz): δ 8.42 (d, J = 3.5 Hz,
1H, H-2), 7.65 (m, 2H, Ph H-2,6), 7.49 (m, 1H, Ph H-4), 7.41 (m, 2H, Ph H-3,5), 7.36 (d, 4J = 3.5 Hz,

Molecules 2009, 14
1H, H-5); 13C-NMR (125 MHz): δ 170.2 (C=O, 3J(CO,H2) = 3.6 Hz, 4J(CO,H5) = 0.6 Hz), 138.6 (C-3,
3823
3
1
3
2J(C3,H2) = 3.2 Hz, J(C3,H5) = 7.9 Hz), 137.9 (C-2, J(C2,H2) = 189.5 Hz, J(C2,H5) = 5.3 Hz),
1
3
133.0 (Ph C-2,6), 130.9 (Ph C-4), 128.7 (Ph C-3,5), 126.1 (C-5, J(C5,H5) = 192.9 Hz, J(C5,H2) =
3
4
5.0 Hz), 119.9 (Ph C-1, J(Ph C1,Ph H3,5) = 8.6 Hz, J(Ph C1,Ph H4) = 1.3 Hz), 109.7 (C-4,
3
2J(C4,H5) = 0.9 Hz, J(C4,H2) = 11.2 Hz), 91.9 (COC≡C), 87.2 (COC≡C); IR (liquid film): 2189
(C≡C), 1640 (C=O) cm−1; MS m/z (%): 292/290 (M+, 2/2), 264/262 ([M − C=O]+, 2/1), 191/189
([COC4H2SBr]+, 65/61), 129 ([COC≡CC6H5]+, 7), 101 ([C≡CC6H5]+, 1), 81 (100). Calcd. for
C13H7BrOS: C, 53.63; H, 2.42; S, 11.01. Found: C, 53.38; H, 2.50; S, 10.67.
1-(3-Bromothiophen-2-yl)-3-phenylprop-2-yn-1-one (2d). Reaction time: 23 h. Eluent: CH2Cl2/light
petroleum, 3:2 v/v. Yield: 134 mg, 46%; colorless needles, mp 74–77 °C (EtOH/H2O); 1H- NMR (500
MHz): δ 7.69 (m, 2H, Ph H2,6), 7.62 (d, 3J = 5.2 Hz, 1H, H-5), 7.50 (m, 1H, Ph H-4), 7.42 (m, 2H, Ph
H-3,5), 7.18 (d, 3J = 5.2 Hz, 1H, H-4); 13C-NMR (125 MHz): δ 168.3 (C=O), 138.0 (C-2, 3J(C2,H4) =
3
1
2
7.4 Hz, J(C2,H5) = 4.8 Hz), 134.0 (C-4, J(C4,H4) = 176.5 Hz, J(C4,H5) = 4.1 Hz), 133.6 (C-5,
1J(C5,H5) = 188.1 Hz, 2J(C5,H4) = 6.1 Hz), 133.1 (Ph C-2,6), 131.0 (Ph C-4), 128.7 (Ph C-3,5), 119.9
2
3
(Ph C-1), 116.4 (C-3, J(C3,H4) = 2.4 Hz, J(C3,H5) = 12.2 Hz), 94.1 (COC≡C), 87.3 (COC≡C); IR:
2198 (C≡C), 1627 (C=O) cm−1; MS m/z (%): 292/290 (M+, 25/22), 264/262 ([M − C=O]+, 52/47), 139
(95), 129 ([COC≡CC6H5]+, 97), 101 ([C≡CC6H5]+, 22), 84 (73), 74 (77), 43 (100). Calcd. for
C13H7BrOS: C, 53.63; H, 2.42; S, 11.01. Found: C, 53.63; H, 4.00; S, 10.85. HRMS Calcd. for
C13H7BrOS: 289.9401. Found: 289.9403.
1-(3-Chloro-1-benzo[b]thiophen-2-yl)-3-phenylprop-2-yn-1-one (2e). Reaction time: 2.5 h. Eluent:
toluene. Yield: 213 mg, 72%; light tan crystals, mp 117–120 °C (MeOH); 1H-NMR (500 MHz): δ 8.03
3
3
(d, J = 8.0 Hz, 1H, H-4), 7.85 (d, J = 8.1 Hz, 1H, H-7), 7.72 (m, 2H, Ph H-2,6), 7.57 (m, 1H, H-6),
13
7.52 (m, 2H, H-5, Ph H-4), 7.45 (m, 2H, Ph H-3,5); C-NMR (125 MHz): δ 169.3 (C=O), 139.3 (C-
7a), 137.6 (C-3a), 136.4 (C-2), 133.2 (Ph C-2,6), 131.2 (Ph C-4), 129.0 (C-6), 128.7 (Ph C-3,5), 126.9
3
(C-3, J(C3,H4) = 7.7 Hz), 125.7 (C-5), 124.4 (C-4), 122.9 (C-7), 119.9 (Ph C-1), 95.1 (COC≡C,
3J(C,Ph H2,6) = 5.4 Hz), 88.0 (COC≡C); IR: 2199 (C≡C), 1601 (C=O) cm−1; MS m/z (%): 298/296
(M+, 27/68), 270/268 ([M − C=O]+, 40/100), 129 ([COC≡CC6H5]+, 100), 101 ([C≡CC6H5]+, 14).
Calcd. for C17H9ClOS•0.2 H2O: C, 67.98; H, 3.15. Found: C, 68.11; H, 2.82.
1-(2-Chloropyridin-3-yl)-3-phenylprop-2-yn-1-one (2f). Reaction time: 2.5 h. Eluent: CH2Cl2/EtOAc,
1
20:1 v/v. Yield: 123 mg, 51%; yellowish-brown crystals, mp 69–71 °C (MeOH); H- NMR (500
MHz): δ 8.56 (dd, 3J(H5,H6) = 4.7 Hz, 4J = 1.9 Hz, 1H, H-6), 8.34 (dd, 3J = 7.7 Hz, 4J = 1.9 Hz, 1H,
13
H-4), 7.65 (m, 2H, Ph H-2,6), 7.51 (m, 1H, Ph H-4), 7.42 (m, 3H, H-5, Ph H-3,5); C-NMR (125
3
1
2
MHz): δ 175.5 (C=O, J(CO,H4) = 5.3 Hz), 152.3 (C-6, J(C6,H6) = 183.7 Hz, J(C6,H5) = 3.8 Hz,
3J(C6,H4) = 8.2 Hz), 149.5 (C-2, 3J(C2,H4) = 8.8 Hz, 3J(C2,H6) = 13.8 Hz, 4J(C2,H5) = 1.5Hz), 140.7
(C-4, 1J(C4,H4) = 166.2 Hz, 2J(C4,H5) = 1.9 Hz, 3J(C4,H6) = 6.7 Hz), 132.6 (C-3), 133.2 (Ph C-2,6),
1
2
131.3 (Ph C-4), 128.8 (Ph C-3,5), 122.4 (C-5, J(C5,H5) = 168.2 Hz, J(C5,H6) = 8.2 Hz), 119.5 (Ph
C-1, 3J(Ph C1,Ph H3,5) = 8.6 Hz, 4J(Ph C1,Ph H4) = 1.4 Hz), 95.7 (COC≡C, 3J(C,Ph H2,6) = 5.3 Hz),
87.9 (COC≡C); 15N-NMR (50 MHz): δ −70.3 (N-1); IR: 2199 (C≡C), 1636 (C=O) cm−1; MS m/z (%):

Molecules 2009, 14
3824
243/241 (M+, 6/15), 215/213 ([M − C=O]+, 6/21), 129 ([COC≡CC6H5]+, 100), 101 ([C≡CC6H5]+, 13).
Calcd. for C14H8ClNO: C, 69.58; H, 3.34; N, 5.80. Found: C, 69.59; H, 3.16; N, 5.67.
1-(3-Chloropyridin-4-yl)-3-phenylprop-2-yn-1-one (2g). Reaction time: 23 h. Eluent: CH2Cl2/EtOAc,
1
20:1 v/v. Yield: 70 mg, 19%; brown crystals, mp 77–79 °C (MeOH/H2O, 5:1 v/v); H- NMR (500
MHz): δ 8.76 (s, 1H, H-2), 8.68 (d, 3J = 4.9 Hz, 1H, H-6), 7.81 (d, 3J = 4.9 Hz, 1H, H-5), 7.65 (m, 2H,
Ph H-2,6), 7.52 (m, 1H, Ph H-4), 7.43 (m, 2H, Ph H-3,5); 13C-NMR (125 MHz): δ 175.3 (C=O), 151.6
(C-2, 1J(C2,H2) = 188.0 Hz, 3J(C2,H6) = 11.4 Hz, 4J(C2,H5) = 1.0 Hz), 148.4 (C-6, 1J(C6,H6) = 183.6
Hz, 2J(C6,H5) = 2.3 Hz, 3J(C6,H2) = 11.6 Hz), 141.8 (C-4, 2J(C4,H5) = not resolved, 3J(C4,H2) = 4.9
Hz, 3J(C4,H6) = 6.9 Hz), 133.3 (Ph C-2,6), 131.6 (Ph C-4), 129.3 (C-3), 128.8 (Ph C-3,5), 124.0 (C-5,
1J(C5,H5) = 167.1 Hz, 2J(C5,H6) = 9.7 Hz), 119.3 (Ph C-1, 3J(Ph C1,Ph H3,5) = 8.5 Hz, 4J(Ph C1,Ph
H4) = 1.4 Hz), 96.2 (COC≡C, 3J(C,Ph H2,6) = 5.4 Hz), 87.8 (COC≡C); IR: 2197 (C≡C), 1641 (C=O)
cm−1; MS m/z (%): 243/241 (M+, 4/12), 215/213 ([M − C=O]+, 4/8), 129 ([COC≡CC6H5]+, 100), 101
([C≡CC6H5]+, 11). Calcd. for C14H8ClNO•0.2 H2O: C, 68.56; H, 3.45; N, 5.71. Found: C, 68.69; H,
3.25; N, 5.63.
1-(2-Chloroquinolin-3-yl)-3-phenylprop-2-yn-1-one (2h). Reaction time: 200 min. Eluent: light
petroleum/EtOAc, 4:1 v/v. Yield: 181 mg, 62%; brownish-yellow crystals, mp 100–101 °C (MeOH);
1H-NMR (500 MHz): δ 8.87 (s, 1H, H-4), 8.08 (dd, 3J = 8.5 Hz, 4J = 1.1 Hz, 1H, H-8), 7.97 (dd, 3J =
8.1 Hz, 4J = 1.4 Hz, 1H, H-5), 7.88 (m, 3J(H7,H6) = 7.0 Hz, 3J(H7,H8) = 8.5 Hz, 4J = 1.4 Hz, 1H, H-
13
7), 7.68 (m, 2H, Ph H-2,6), 7.66 (m, 1H, H-6), 7.51 (m, 1H, Ph H-4), 7.44 (m, 2H, Ph H-3,5); C-
NMR (125 MHz): δ 175.3 (C=O, 3J(CO,H4) = 5.7 Hz), 148.4 (C-8a), 147.0 (C-2, 3J(C2,H4) = 9.7 Hz),
142.7 (C-4, 1J(C4,H4) = 164.4 Hz, 3J(C4,H5) = 4.6 Hz), 133.2 (C-7, Ph C-2,6), 131.3 (Ph C-4), 130.2
3
(C-3), 128.9 (C-5), 128.8 (Ph C-3,5), 128.5 (C-8), 128.0 (C-6), 126.0 (C-4a), 119.7 (Ph C-1, J(Ph
4
3
4
C1,Ph H3,5) = 8.5 Hz, J(Ph C1,Ph H4) = 1.3 Hz), 95.2 (COC≡C, J(C,Ph H2,6) = 5.3 Hz, J(C,Ph
15
H3,5) = 1.0 Hz), 88.0 (COC≡C); N-NMR (50 MHz): δ −78.4 (N-1); IR: 2197 (C≡C), 1632 (C=O)
cm−1; MS m/z (%): 293/291 (M+, 6/15), 265/263 ([M − C=O]+, 8/24), 239 (41), 129 ([COC≡CC6H5]+,
90), 101 ([C≡CC6H5]+, 45), 43 (100). Calcd. for C18H10ClNO•0.4 H2O: C, 72.32; H, 3.64; N, 4.69.
Found: C, 72.27; H, 3.37; N, 5.01.
4.2.3. General procedure for the synthesis of thiopyranones 4a–h
A suspension of NaSH hydrate (~60%, 1.2 mmol, 112 mg) was refluxed in EtOH (20 mL) until a
cloudy solution was formed. Ynone 2 (0.4 mmol) in EtOH (2 mL) was then added to the solution,
which was refluxed for the indicated time. The solvent was removed under reduced pressure and water
(20 mL) was added to the residue. The resulting solution was acidified with 5% HCl and extracted
with CH2Cl2 (2  15 mL). The combined organic layers were washed with a saturated NaHCO3
solution and a saturated NaCl solution. They were then dried over anhydrous Na2SO4. After removal
of the solvent, the residue was purified by column chromatography through a silica gel (eluent as
indicated below). An analytically pure sample was obtained by recrystallization from an appropriate
solvent.

Molecules 2009, 14
3825
2-Phenyl-4H-thiochromen-4-one (4a). Reaction time: 4 h. Eluent: CH2Cl2/EtOAc, 15:1 v/v. Yield:
1
131 mg, 54%; beige needles, mp 121–123 °C (MeOH) (lit. [18] mp 124–126 °C); H= NMR (500
MHz): δ 8.54 (dd, 1H, H-5), 7.68 (m, 2H, Ph H-2,6), 7.65 (dd, 1H, H-8), 7.62 (dt, 1H, H-7), 7.54 (dt,
13
1H, H-6), 7.51 (m, 1H, Ph H-4), 7.50 (m, 2H, Ph H-3,5), 7.24 (s, 1H, H-3); C-NMR (125 MHz): δ
180.8 (C-4), 153.0 (C-2), 137.6 (C-8a), 136.5 (Ph C-1), 131.6 (C-7), 130.8 (C-4a, Ph C-4), 129.2 (Ph
1
C-3,5), 128.5 (C-5), 127.7 (C-6), 126.9 (Ph C-2,6), 126.4 (C-8), 123.4 (C-3, J(C3,H3) = 163.6 Hz);
IR: 1620 (C=O) cm−1; MS m/z (%): 238 (M+, 92), 210 ([M − C=O]+, 100), 136 ([COC6H4S]+, 53), 108
([C6H4S]+, 28).
6-Phenyl-4H-thieno[2,3-b]thiopyran-4-one (4b). Reaction time: 100 min. Eluent: CH2Cl2/EtOAc, 5:1
v/v. Yield: 20 mg, 50%; whitish powder, mp 115–117 °C (MeOH); 1H-NMR (500 MHz): δ 7.78 (d, 3J
= 5.3 Hz, 1H, H-3), 7.62 (m, 2H, Ph H-2,6), 7.50 (m, 1H, Ph H-4), 7.49 (m, 2H, Ph H-3,5), 7.46 (d, 3J
2
= 5.3 Hz, 1H, H-2), 7.20 (s, 1H, H-5); 13C-NMR (125 MHz): δ 177.1 (C-4, J(C4,H5) = 1.2 Hz,
3J(C4,H3) = 1.3 Hz), 151.5 (C-6, 2J(C6,H5) = 3.4 Hz), 144.3 (C-7a, 3J(C7a,H2) = 6.7 Hz, 3J(C7a,H3)
= 10.0 Hz), 137.5 (C-3a, 2J(C3a,H3) = 4.7 Hz, 3J(C3a,H2) = 9.9 Hz, 3J(C3a,H5) = 3.7 Hz), 136.1 (Ph
3
C-1, J(Ph C1,H5) = 5.4 Hz), 130.7 (Ph C-4), 129.3 (Ph C-3,5), 127.0 (Ph C-2,6), 125.5 (C-3,
2
4
1
1J(C3,H3) = 174.8 Hz, J(C3,H2) = 4.4 Hz, J(C3,H5) = 1.0 Hz), 125.3 (C-2, J(C2,H2) = 189.6 Hz,
2J(C2,H3) = 7.5 Hz), 125.0 (C-5, 1J(C5,H5) = 163.3 Hz); IR: 1606 (C=O) cm−1; MS m/z (%): 244 (M+,
100), 216 ([M − C=O]+, 31), 142 ([COC4H2S2]+, 97), 120 ([COCH=CC6H5]+, 69), 114 ([C4H2S2]+, 38),
101 ([C=CC6H5]+, 27). Calcd. for C13H8OS2: C, 63.90; H, 3.30. Found: C, 63.57; H, 3.27.
2-Phenyl-4H-thieno[3,4-b]thiopyran-4-one (4c). Reaction time: 22.5 h. Eluent: CH2Cl2/EtOAc, 5:1
1
v/v. Yield: 28 mg, 34%; brownish needles, mp 160–162 °C (MeOH/H2O); H-NMR (500 MHz): δ
8.51 (d, 4J = 3.4 Hz, 1H, H-5), 7.66 (m, 2H, Ph H-2,6), 7.52 (d, 3J = 3.4 Hz, 1H, H-7), 7.49 (m, 1H, Ph
H-4), 7.48 (m, 2H, Ph H-3,5), 6.99 (s, 1H, H-3); 13C-NMR (125 MHz): δ 178.2 (C-4, 2J(C4,H3) = 1.1
4
2
3
Hz, 3J(C4,H5) = 2.2 Hz, J(C4,H7) = 1.1 Hz), 153.3 (C-2, J(C2,H3) = 3.1 Hz), 136.7 (Ph C-1, J(Ph
2
3
3
C1,H3) = 5.5 Hz), 134.7 (C-4a, J(C4a,H5) = 3.2 Hz, J(C4a,H3) = 3.8 Hz, J(C4a,H7) = 7.8 Hz),
2
3
1
131.4 (C-7a, J(C7a,H7) = 2.8 Hz, J(C7a,H5) = 9.8 Hz), 130.8 (Ph C-4), 129.7 (C-5, J(C5,H5) =
3
4
191.8 Hz, J(C5,H7) = 4.9 Hz, J(C5,H3) = 1.3 Hz), 129.2 (Ph C-3,5), 127.0 (Ph C-2,6), 122.1 (C-3,
1J(C3,H3) = 163.6 Hz), 119.2 (C-7, 1J(C7,H7) = 189.3 Hz, 3J(C7,H5) = 5.7 Hz); IR: 1612 (C=O) cm−1;
MS m/z (%): 244 (M+, 48), 216 ([M − C=O]+, 16), 142 ([COC4H2S2]+, 100), 114 ([C4H2S2]+, 36), 82
([C4H2S]+, 22). Calcd. for C13H8OS2: C, 63.90; H, 3.30. Found: C, 62.82; H 3.28. HRMS (ESI) Calcd.
for C13H9OS2 [M+H]: 245.0095. Found: 245.0100.
5-Phenyl-7H-thieno[3,2-b]thiopyran-7-one (4d). Reaction time: 1 h. Eluent: CH2Cl2/EtOAc, 5:1 v/v.
1
Yield: 80 mg, 87%; brownish powder, mp 82–84 °C (EtOH/H2O) (lit. [24] mp 80 °C); H-NMR (500
MHz): δ 7.85 (d, 3J = 5.3 Hz, 1H, H-2), 7.65 (m, 2H, Ph H-2,6), 7.51 (m, 3H, Ph H-3,4,5), 7.35 (d, 3J =
2
5.3 Hz, 1H, H-3), 7.21 (s, 1H, H-6); 13C-NMR (125 MHz): δ 176.2 (C-7, J(C7,H6) = 1.1 Hz,
4J(C7,H2) = 1.1 Hz, 4J(C7,H3) = 1.1 Hz), 152.8 (C-5, 2J(C5,H6) = 3.1 Hz), 139.0 (C-3a, 2J(C3a,H3) =
4.4 Hz, 3J(C3a,H2) = 11.2 Hz), 137.2 (C-7a, 3J(C7a,H2) = 5.9 Hz, 3J(C7a,H3) = 7.1 Hz, 3J(C7a,H6) =
3
1
2
4.7 Hz), 136.4 (Ph C-1, J(Ph C1,H6) = 5.4 Hz), 133.2 (C-2, J(C2,H2) = 186.6 Hz, J(C2,H3) = 6.0
Hz), 130.7 (Ph C-4), 129.3 (Ph C-3,5), 127.2 (Ph C-2,6), 125.3 (C-3, 1J(C3,H3) = 173.4 Hz, 2J(C3,H2)

Molecules 2009, 14
3826
1
= 4.8 Hz), 123.6 (C-6, J(C6,H6) = 163.9 Hz); MS m/z (%): 244 (M+, 46), 243 ([M − H]+, 21), 216
([M − C=O]+, 16), 142 ([COC4H2S2]+, 94), 114 ([C4H2S2]+, 33), 102 ([CH=CC6H5]+, 19), 82
([C4H2S]+, 20), 69 (100).
2-Phenyl-4H-thiopyrano[3,2-b][1]benzothiophen-4-one (4e). Reaction time: 70 min. Eluent:
CH2Cl2/EtOAc, 15:1 v/v. Yield: 96 mg, 82%; colorless crystals, mp 166–167 °C (MeOH/EtOAc, 2:1
v/v) (lit. [25] mp 177 °C); 1H-NMR (500 MHz): δ 8.00 (m, 1H, H-9), 7.99 (m, 1H, H-6), 7.71 (m, 2H,
13
Ph H-2,6), 7.59 (m, 1H, H-7), 7.54 (m, 3H, Ph H-3,4,5), 7.53 (m, 1H, H-8), 7.32 (s, 1H, H-3); C-
NMR (125 MHz): δ 177.0 (C-4, 2J(C4,H3) = 1.1 Hz), 152.1 (C-2, 2J(C2,H3) = 3.1 Hz), 140.7 (C-5a),
137.3 (C-4a, 3J(C4a,H3) = 4.6 Hz), 136.3 (Ph C-1, 3J(Ph C1,H3) = 5.3 Hz), 136.2 (C-9a), 135.4 (C-9b,
3J(C9b,H9) = 3.9 Hz), 130.8 (Ph C-4), 129.4 (Ph C-3,5), 128.6 (C-7, 1J(C7,H7) = 162.0 Hz, 3J(C7,H9)
1
3
= 7.8 Hz), 127.2 (Ph C-2,6), 125.3 (C-8, J(C8,H8) = 162.5 Hz, J(C8,H6) = 7.6 Hz), 124.7 (C-3,
1J(C3,H3) = 163.9 Hz), 123.8 (C-6, J(C6,H6) = 164.8 Hz, J(C6,H7) = 1.5 Hz, J(C6,H8) = 8.0 Hz,
1
2
3
4J(C6,H9) = 1.5 Hz), 122.5 (C-9, J(C9,H9) = 161.1 Hz, J(C9,H8) = 1.4 Hz, J(C9,H7) = 8.1 Hz,
4J(C9,H6) = 1.4 Hz); IR: 1618 (C=O) cm−1; MS m/z (%): 294 (M+, 32), 266 ([M–C=O]+, 34), 164
([C8H4S2]+, 25), 132 ([C8H4S]+, 29), 120 (43), 68 (100). Calcd. for C17H10OS2•0.1 H2O: C, 68.94; H,
3.47; S, 21.65. Found: C, 68.91; H, 3.45; S, 21.26.
1
2
3
2-Phenyl-4H-thiopyrano[2,3-b]pyridin-4-one (4f). Reaction time: 1.5 h. Eluent: CH2Cl2/EtOAc, 15:1
v/v. Yield: 36 mg, 93%; luminous yellow needles, mp 114–117 °C (MeOH) (lit. [19] mp 113–116 °C);
1H-NMR (300 MHz): δ 8.81 (dd, 3J = 4.5 Hz, 4J = 1.9 Hz, 1H, H-7), 8.77 (dd, 3J = 8.1 Hz, 4J = 1.9 Hz,
1H, H-5), 7.71 (m, 2H, Ph H-2,6), 7.53 (m, 3H, Ph H-3,4,5), 7.50 (dd, 3J(H6,H7) = 4.5 Hz, 3J(H6,H5)
= 8.1 Hz, 1H, H-6), 7.26 (s, 1H, H-3); 13C-NMR (75 MHz): δ 181.3 (C-4, 3J(C4,H5) = 3.5 Hz), 159.1
3
3
1
(C-8a, J(C8a,H5) = 6.5 Hz, J(C8a,H7) = 14.0 Hz), 154.7 (C-2), 152.8 (C-7, J(C7,H7) = 181.7 Hz,
2J(C7,H6) = 3.8 Hz, 3J(C7,H5) = 7.8 Hz), 136.7 (C-5, 1J(C5,H5) = 168.2 Hz, J(C5,H6) not resolved,
3J(C5,H7) = 6.2 Hz), 136.3 (Ph C-1), 131.1 (Ph C-4), 129.4 (Ph C-3,5), 128.1 (C-4a), 127.0 (Ph C-
2
1
1
2
2,6), 123.6 (C-3, J(C3,H3) = 164.7 Hz), 122.9 (C-6, J(C6,H6) = 167.0 Hz, J(C6,H5) not resolved,
2J(C6,H7) = 8.2 Hz); N-NMR (50 MHz): δ −76.8 (N-8); IR: 1630 (C=O) cm−1; MS m/z (%): 239
15
(M+, 100), 211 ([M − C=O]+, 99), 137 ([COC5H3NS]+, 33), 109 ([C5H3NS]+, 57), 105 ([COC5H3N]+,
32), 102 ([CH=CC6H5]+, 33). Calcd. for C14H9NOS: C, 70.27; H, 3.79; N, 5.85. Found: C, 70.26; H,
4.04; N, 5.75.
2-Phenyl-4H-thiopyran[2,3-c]pyridin-4-one (4g). Reaction time: 1.5 h. Eluent: CH2Cl2/EtOAc, 5:1
1
v/v. Yield: 21 mg, 44%; flat brownish prisms, mp 153–154 °C (EtOH/H2O); H-NMR (500 MHz): δ
3
3
9.02 (s, 1H, H-8), 8.73 (d, J = 5.3 Hz, 1H, H-6), 8.27 (d, J = 5.3 Hz, 1H, H-5), 7.69 (m, 2H, Ph H-
2,6), 7.53 (m, 1H, Ph H-4), 7.52 (m, 2H, Ph H-3,5), 7.27 (s, 1H, H-3); 13C-NMR (125 MHz): δ 179.5
(C-4, 2J(C4,H3) = 1.0 Hz, 3J(C4,H5) = 3.6 Hz, 4J(C4,H8) = 1.6 Hz), 154.0 (C-2, 2J(C2,H3) = 2.5 Hz),
148.8 (C-8, 1J(C8,H8) = 183.4 Hz, 3J(C8,H6) = 11.1 Hz, 4J(C8,H5) = 0.8 Hz), 147.8 (C-6, 1J(C6,H6) =
2
3
3
182.7 Hz, J(C6,H5) = 3.2 Hz, J(C6,H8) = 11.6 Hz), 136.1 (Ph C-1, J(Ph C1,H3) = 5.5 Hz), 135.7
2
3
3
3
(C-4a, J(C4a,H5) not resolved, J(C4a,H3) = 3.7 Hz, J(C4a,H6) = 6.7 Hz, J(C4a,H8) = 5.1 Hz),
133.2 (C-8a, 2J(C8a,H8) = 7.9 Hz, 3J(C8a,H5) = 6.5 Hz, 4J(C8a,H6) = 1.8 Hz), 131.3 (Ph C-4), 129.4
1
1
(Ph C-3,5), 127.0 (Ph C-2,6), 123.9 (C-3, J(C3,H3) = 164.5 Hz), 120.6 (C-5, J(C5,H5) = 168.9 Hz,

Molecules 2009, 14
3827
4
4
15
2J(C5,H6) = 9.0 Hz, J(C5,H3) = 0.8 Hz, J(C5,H8) = 1.7 Hz); N-NMR (50 MHz): δ −60.0 (N-7);
IR: 1635 (C=O) cm−1; MS m/z (%): 239 (M+, 100), 211 ([M − C=O]+, 77), 149 (49), 139 (28), 137
([COC5H3NS]+, 66), 109 ([C5H3NS]+, 53), 105 ([COC5H3N]+, 20), 102 ([CH=CC6H5]+, 41), 81 (98).
Calcd. for C14H9NOS: C, 70.27; H, 3.79; N, 5.85; S, 13.40. Found: C, 70.28; H, 4.02; N, 5.69; S,
13.21. HRMS Calcd. for C14H9NOS: 239.0405. Found: 239.0402.
2-Phenyl-4H-thiopyrano[2,3-b]quinolin-4-one (4h). Reaction time: 100 min. Eluent: CH2Cl2/EtOAc,
1
20:1 v/v. Yield: 77 mg, 67%; off-white needles, mp 208–210 °C (CH2Cl2/EtOAc, 5:1 v/v); H-NMR
(500 MHz): δ 9.30 (s, 1H, H-5), 8.09 (d, 3J = 8.6 Hz, 1H, H-9), 8.04 (d, 3J = 8.1 Hz, 1H, H-6), 7.88 (m,
1H, H-8), 7.74 (m, 2H, Ph H-2,6), 7.62 (m, 1H, H-7), 7.54 (m, 3H, Ph H-3,4,5), 7.23 (s, 1H, H-3); 13C-
NMR (125 MHz): δ 182.0 (C-4, 2J(C4,H3) = 0.7 Hz, 3J(C4,H5) = 4.1 Hz), 157.1 (C-10a, 3J(C10a,H5)
1
3
= 8.1 Hz), 155.1 (C-2), 149.2 (C-9a), 138.6 (C-5, J(C5,H5) = 166.4 Hz, J(C5,H6) = 4.7 Hz), 136.4
(Ph C-1), 133.1 (C-8), 131.2 (Ph C-4), 129.7 (C-6), 129.4 (Ph C-3,5), 128.1 (C-9), 127.2 (C-7), 127.0
1
15
(Ph C-2,6), 126.9 (C-5a), 125.1 (C-4a), 122.1 (C-3, J(C3,H3) = 164.8 Hz); N-NMR (50 MHz): δ
−83.8 (N-10); IR: 1631 (C=O) cm−1; MS m/z (%): 289 (M+, 91), 261 ([M − C=O]+, 88), 181 (46), 159
([C9H5NS]+, 39), 130 ([COCH=CC6H5]+, 77), 101 ([C=CC6H5]+, 44), 75 (82), 68 (100). Calcd. for
C18H11NOS•0.2 H2O: C, 73.80; H, 3.92; N, 4.78. Found: C, 73.85; H, 3.71; N, 4.77.
4.2.4. Preparation of N,N-diethyl-3-fluoropyridine-2-carboxamide (5)
Under the conditions given for the synthesis of compounds 2, reaction of 1i (2 mmol, 319 mg) with
phenylacetylene (1 mmol, 102 mg), Et3N (2 mL) and Pd(II) acetate (10 µmol, 2 mg) for 26 h resulted
in formation of compound 5 after purification by column chromatography (eluent: EtOAc). Yield:
1
3
5
131 mg, 33%; brown oil; H-NMR (500 MHz): δ 8.42 (dd, J = 4.6 Hz, 4J = 1.1 Hz, J(H6,F3) = 1.4
3
3
4
Hz, 1H, H-6), 7.47 (dd, J(H4,H5) = 8.5 Hz, J(H4,F3) = 8.9 Hz, J = 1.1 Hz, 1H, H-4), 7.35 (m,
3J(H5,H6) = 4.6 Hz, J(H5,H4) = 8.5 Hz, J(H5,F3) = 4.2 Hz, 1H, H-5), 3.58 (q, J = 7.1 Hz, 2H, N-
3
4
3
CH2 cis), 3.20 (q, 3J = 7.1 Hz, 2H, N-CH2 trans), 1.27 (t, 3J = 7.1 Hz, 3H, CH3 cis), 1.10 (t, 3J = 7.1 Hz,
13
3
1
3H, CH3 trans); C-NMR (125 MHz): δ 164.7 (C=O, J(CO,F3) = 3.1 Hz), 155.8 (C-3, J(C3,F3) =
2
3
4
1
259.1 Hz, J(C3,H4) = 4.8 Hz, J(C3,H5) = 9.6 Hz, J(C3,H6) = 1.9 Hz), 145.2 (C-6, J(C6,H6) =
182.3 Hz, 2J(C6,H5) = 2.7 Hz, 3J(C6,H4) = 7.3 Hz, 4J(C6,F3) = 5.0 Hz), 144.0 (C-2, 2J(C2,F3) = 18.0
Hz, 3J(C2,H4) = 3.8 Hz, 3J(C2,H6) = 12.2 Hz, 4J(C2,H5) = 1.5 Hz), 125.1 (C-5, 1J(C5,H5) = 167.2 Hz,
2J(C5,H4) = 2.0 Hz, J(C5,H6) = 9.4 Hz, J(C5,F3) = 3.8 Hz), 123.9 (C-4, J(C4,H4) = 167.4 Hz,
2
3
1
2J(C4,F3) = 18.4 Hz, 3J(C4,H6) = 7.2 Hz), 42.8 (N-CH2 trans, J = 135.2 Hz, J(CH2,CH3) = 4.2 Hz),
1
2
39.4 (N-CH2 cis, 1J = 136.5 Hz, 2J(CH2,CH3) = 4.2 Hz), 14.0 (CH3 trans, 1J = 127.1 Hz, 2J(CH3,CH2) =
1
2
15
3.1 Hz), 12.8 (CH3 cis, J = 127.2 Hz, J(CH3,CH2) = 3.4 Hz); N-NMR (50 MHz): δ −65.8 (N-1),
−248.9 (CONR2); 19F-NMR (470 MHz): δ −124.3 (F-3, J(F3,H4) = 8.9 Hz, J(F3,H5) = 4.2 Hz,
5J(F3,H6) = 1.4 Hz); IR: 1643 (C=O) cm−1; MS m/z (%): 196 (M+, 7), 124 ([M − N(Et)2]+, 65), 97
([C5H3NF]+, 55), 72 ([N(Et)2]+, 100), 44 (63). Calcd. for C10H13FN2O•0.2 H2O: C, 60.11; H, 6.76; N,
14.02. Found: C, 60.28; H, 6.59; N, 13.90.
3
4

Molecules 2009, 14
3828
4.2.5. Preparation of 3-chloro-N,N-diethylquinoxaline-2-carboxamide (6)
Under the conditions given for synthesis of compounds 2, reaction of 1j (2 mmol, 455 mg) with
phenylacetylene (1 mmol, 102 mg), Et3N (2 mL) and Pd(II) acetate (10 µmol, 2 mg) for 20 h resulted
in formation of compound 6 after purification by column chromatography (eluent: CH2Cl2/EtOAc, 5:1
v/v.). Yield: 256 mg, 49%; brownish needles, mp 91–93 °C (MeOH); 1H-NMR (500 MHz): δ 8.10 (m,
3
1H, H-8), 8.03 (m, 1H, H-5), 7.83 (m, 1H, H-6), 7.80 (m, 1H, H-7), 3.65 (q, J = 7.2 Hz, 2H, N-CH2
cis), 3.20 (q, 3J = 7.1 Hz, 2H, N-CH2 trans), 1.34 (t, 3J = 7.2 Hz, 3H, CH3 cis), 1.16 (t, 3J = 7.1 Hz, 3H,
13
CH3 trans); C-NMR (125 MHz): δ 164.8 (C=O), 149.1 (C-3), 143.8 (C-2), 141.6 (C-4a), 140.0 (C-
8a), 131.6 (C-6), 130.8 (C-7), 129.2 (C-8), 128.3 (C-5), 42.9 (N-CH2 trans), 39.5 (N-CH2 cis), 13.8
15
(CH3 trans), 12.5 (CH3 cis); N-NMR (50 MHz): δ –52.1 (N-1), −63.0 (N-4), −249.2 (CONR2); IR:
1635 (C=O) cm−1; MS m/z (%): 265/263 (M+, 0.5/1.5), 191 ([M − N(Et)2]+, 3), 165/163 ([C8H4N2Cl]+,
7/18), 128 ([C8H4N2]+, 5), 72 ([N(Et)2]+, 100). Calcd. for C13H14ClN3O: C, 59.21; H, 5.35; N, 15.93.
Found: C, 59.43; H, 5.42; N, 15.99.
4.2.6. Preparation of (2Z,2'Z)-3,3'-sulfanediylbis[1-(2-chlorophenyl)-3-phenylprop-2-en-1-one] (7)
Ynone 2a1 (0.5 mmol, 120 mg) in EtOH (2 mL) was added to a suspension of NaSH hydrate
(~60%, 1.3 mmol, 121 mg) in EtOH (20 mL). The resulting solution was stirred at room temperature
for 30 min, and then processed as described in the preparation of compounds 4. The residue was
purified by column chromatography through silica gel (eluent: CH2Cl2). Yield: 48 mg, 19%; yellow
1
powder, mp 161–164 °C (EtOH); H-NMR (300 MHz): δ 7.65 (m, 2H, H-6), 7.43 (m, 2H, H-3), 7.42
(m, 2H, H-4), 7.38 (m, 2H, H-5), 7.18 (m, 2H, Ph H-4), 7.05 (m, 4H, Ph H-3,5), 6.97 (m, 4H, Ph H-
2,6), 6.92 (s, 2H, COCH=C); 13C-NMR (75 MHz): δ 189.7 (C=O), 155.4 (COCH=C), 140.6 (Ph C-1),
139.7 (C-1), 131.9 (C-4), 131.4 (C-2), 130.5 (C-6), 130.2 (C-3), 128.9 (Ph C-4), 128.3 (Ph C-2,6),
1
128.0 (Ph C-3,5), 127.7 (COCH=C, J = 161.5 Hz), 127.1 (C-5); IR: 1638 (C=O) cm−1; MS m/z (%):
516/514 (M+, 0.3/0.4), 275/273 ([M − C15H10ClO]+, 13/33), 238 (19), 149 ([COC(S)C6H5]+, 80),
141/139 ([COC6H4Cl]+, 37/100), 113/111 ([C6H4Cl]+, 29/49), 105 (38), 85 ([COCH=CS]+, 32), 77
([C6H5]+, 33), 57 (83). HRMS (ESI) Calcd. for C30H21Cl2O2S [M + H]: 515.0639. Found: 515.0642.
4.2.7. Preparation of (2Z)-1-(2-chlorophenyl)-3-(methylamino)-3-phenylprop-2-en-1-one (10)
Ethanolic methylamine-solution (33 wt%, 6 mL, 48 mmol) was added to a solution of ynone 2a1
(0.5 mmol, 120 mg) in pyridine (0.4 mL) and H2O (3 drops). The solution was refluxed for 1 h. The
solvent was then removed under reduced pressure and water (20 mL) was added to the residue. The
resulting solution was adjusted to pH 5 with 5% HCl and extracted with CH2Cl2 (2  15 mL). The
combined organic layers were washed with a saturated NaHCO3 solution and a saturated NaCl solution
and then dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by
column chromatography through silica gel (eluent: CH2Cl2/EtOAc, 20:1 v/v.), which produced 10 as a
1
slowly crystallizing oil. Yield: 99 mg, 73%; pale orange solid, mp 77–80 °C; H-NMR (500 MHz): δ
11.18 (broad, 1H, N-H), 7.49 (m, 1H, H-6), 7.44 (m, 3H, Ph H-3,4,5), 7.42 (m, 2H, Ph H-2,6), 7.37 (m,
1H, H-3), 7.27 (m, 1H, H-4), 7.26 (m, 1H, H-5), 5.44 (s, 1H, COCH=C), 2.96 (d, 3J = 5.4 Hz, 3H, N-
CH3);13C-NMR (125 MHz): δ 189.2 (C=O), 167.6 (COCH=C), 141.3 (C-1), 134.8 (Ph C-1), 130.8 (C-

Molecules 2009, 14
3829
2), 130.1 (C-3), 129.9 (C-4), 129.7 (Ph C-4), 129.2 (C-6), 128.5 (Ph C-3,5), 127.7 (Ph C-2,6), 126.5
(C-5), 97.3 (COCH=C, 1J = 164.5 Hz, 3J(C,NH) = 3.6 Hz), 31.6 (N-CH3, 1J = 138.5 Hz, 2J(NCH3,NH)
4
15
= 3.4 Hz, J(NCH3,COCH=C) = 1.1 Hz); N-NMR (50 MHz): δ −281.5 (N-CH3); IR: 1595 (C=O)
cm−1; MS m/z (%): 273/271 (M+, 12/43), 256/254 (22/45), 236 ([M − Cl]+, 100), 160 ([M–C6H4Cl]+,
57), 141/139 ([COC6H4Cl]+, 14/33), 117 ([CH=C(NH)C6H5]+, 66), 113/111 ([C6H4Cl]+, 13/38), 104
([HNCC6H5]+, 25), 102 ([CH=CC6H5]+, 97), 77 ([C6H5]+, 74). Calcd. for C16H14ClNO: C, 70.72; H,
5.19; N, 5.15. Found: C, 70.32; H, 5.22; N, 5.32.
4.2.8. Preparation of 1-methyl-2-phenylquinolin-4(1H)-one (11)
Potassium carbonate (2 mmol, 277 mg) was added to a solution of 10 (220 µmol, 60 mg) in DMF
(5 mL). The resulting mixture was refluxed for 52 h under a N2 atmosphere (N2 balloon). The solvent
was then removed under reduced pressure and water (20 mL) was added to the residue. The resulting
solution was adjusted to a slightly basic pH with 5% HCl and extracted with CH2Cl2 (2  15 mL). The
combined organic layers were washed with a saturated NaHCO3 solution and a saturated NaCl solution
and then dried over anhydrous Na2SO4. After removal of the solvent, the oily residue was purified by
column chromatography through silica gel (eluent: EtOAc/NEt3, 20:1 v/v.) to generate 11. Yield:
1
37 mg, 72%; yellowish crystals, mp 137–140 °C (EtOH/H2O) (lit. [53] mp 142–145 °C); H-NMR
(500 MHz): δ 8.50 (dd, 3J = 8.1 Hz, 4J = 1.7 Hz, 1H, H-5), 7.71 (ddd, 3J(H7,H6) = 7.0 Hz, 3J(H7,H8) =
4
3
8.6 Hz, J = 1.7 Hz, 1H, H-7), 7.55 (d, J = 8.6 Hz, 1H, H-8), 7.50 (m, 3H, Ph H-3,4,5), 7.42 (m,
3J(H6,H7) = 7.0 Hz, J(H6,H5) = 8.1 Hz, J = 1.0 Hz, 1H, H-6), 7.41 (m, 2H, Ph H-2,6), 6.29 (s, 1H,
3
4
13
2
3
H-3), 3.60 (s, 3H, N-CH3); C-NMR (125 MHz): δ 177.6 (C-4, J(C4,H3) = 1.4 Hz, J(C4,H5) = 3.9
2
3
3
Hz), 154.7 (C-2, J(C2,H3) = 3.7 Hz, J(C2,NCH3) = 3.1 Hz), 141.9 (C-8a, J(C8a,H5) = 7.6 Hz,
3J(C8a,H7) = 9.5 Hz, J(C8a,NCH3) = 2.9 Hz), 135.9 (Ph C-1, J(Ph C1,H3) = 3.9 Hz), 132.3 (C-7),
3
3
3
129.6 (Ph C-4), 128.8 (Ph C-3,5), 128.5 (Ph C-2,6), 126.8 (C-4a, J(C4a,H3) = 4.8 Hz), 126.7 (C-5,
3J(C5,H7) = 7.8 Hz), 123.6 (C-6), 115.9 (C-8), 112.7 (C-3, 1J(C3,H3) = 165.8 Hz), 37.2 (N-CH3, 1J =
140.1 Hz); N-NMR (50 MHz): δ −262.1 (N-1); MS m/z (%): 235 (M+, 100), 207 ([M–C=O]+, 100),
15
206 ([M–H,–C=O]+, 55), 102 (40), 77 ([C6H5]+, 47).
Acknowledgements
We are grateful to L. Jirovetz and Ing. P. Unteregger for recording the mass spectra.
References and Notes
1. Harborne, J.B., Ed. The Flavonoids – Advances in Research Since 1986; Chapman & Hall:
London, UK, 1994.
2. Anderson, O.M., Markham, K.R., Eds. Flavonoids: Chemistry, Biochemistry and Applications;
CRC Press: New York, NY, USA, 2006.
3. Birt, D.F.; Hendrich, S.; Wang, W. Dietary agents in cancer prevention: Flavonoids and
isoflavonoids. Pharmacol. Ther. 2001, 90, 157–177.
4. Kim, H.P.; Son, K.H.; Chang, H.W.; Kang, S.S. Anti-inflammatory Plant Flavonoids and Cellular
Action Mechanisms. J. Pharmacol. Sci. 2004, 96, 229–245.

Molecules 2009, 14
3830
5. Seelinger, G.; Merfort, I.; Schempp, C.M. Anti-oxidant, anti-inflammatory and anti-allergic
activities of luteolin. Planta Med. 2008, 74, 1667–1677.
6. Nakazumi, H.; Ueyama, T.; Kitao, T.; Synthesis and antibacterial activity of 2-phenyl-4H-
benzo[b]thiopyran-4-ones (Thioflavones) and related Compounds. J. Heterocycl. Chem. 1984, 21,
193–196.
7. Nakazumi, H.; Ueyama, T.; Kitao, T. Antimicrobial activity of 3-(substituted methyl)-2-phenyl-
4H-1-benzothiopyran-4-ones. J. Heterocycl. Chem. 1985, 22, 1593–1596.
8. Nakazumi, H.; Kobara, Y.; Kitao, T. Synthesis and insecticidal activity of 4-(aminomethyl)-2H-1-
benzothiopyran-2-ones (thiocoumarins) and related compounds. J. Heterocycl. Chem. 1992, 29,
135–139.
9. Razdan, R.K.; Bruni, R.J.; Mehta, A.C.; Weinhardt, K.K.; Papanastassiou, Z.B. A new class of
antimalarial drugs: derivatives of benzothiopyrans. J. Med. Chem. 1978, 21, 643–649.
10. Ares, J.J.; Outt, P.E.; Randall, J.L.; Johnston, J.N.; Murray, P.D.; O’Brien, L.M.; Weisshaar, P.S.;
Ems, B.L. Synthesis and biological evaluation of flavonoids and related compounds as
gastroprotective agents. Bioorg. Med. Chem. Lett. 1996, 6, 995–998.
11. Dhanak, D.; Keenan R.M.; Burton, G.; Kaura, A.; Darcy, M.G.; Shah, D.H.; Ridgers, L.H.; Breen,
A.; Lavery P.; Tew, D.G.; West, A. Benzothiopyran-4-one based reversible inhibitors of the
human cytomegalovirus (HCMV) protease. Bioorg. Med. Chem. Lett. 1998, 8, 3677–3682.
12. Wang, H.-K.; Bastow, K.F.; Cosentino, L.M.; Lee, K.-H. Antitumor Agents. 166. Synthesis and
biological evaluation of 5,6,7,8-substituted-2-phenylthiochromen-4-ones. J. Med. Chem. 1996,
39, 1975–1980.
13. Dekermendjian, K.; Kahnberg, P.; Witt, M.-R.; Sterner O.; Nielsen, M.; Liljefors, T. Structure-
activity relationships and molecular modeling analysis of flavonoids binding to the
benzodiazepine site of the rat brain gabaa receptor complex. J. Med. Chem. 1999, 42,
4343–4350.
14. Dike, S.Y.; Ner, D.H.; Kumar, A. A New chemoenzymatic enantioselective synthesis of optically
active benzothiopyran and benzothiazepin ring system. Synlett 1991, 443–444.
15. Burger, A. Isosterism and bioisosterism in drug design. Progr. Drug Res. 1991, 37, 287–371.
16. Patani, G.A.; LaVoie, E.J. Bioisosterism: A rational approach in drug design. Chem. Rev. 1996,
96, 3147–3176.
17. Lima, L.M.; Barreiro, E.J. Bioisosterism: A Useful strategy for molecular modification and drug
design. Curr. Med. Chem. 2005, 12, 23–49.
18. Bossert, F. Über eine neue thiochromon-synthese. Justus Liebigs Ann. Chem. 1964, 680, 40–51.
19. Becher, J.; Christensen, M.C.; Møller, J.; Winckelmann, I. The Synthesis of 4H-thiopyrano[2,3-
b]pyridin-4-ones. Sulfur Lett. 1982, 1, 43–52.
20. Wadsworth, D.H.; Detty, M.R. Regiochemical control of the addition of aryl selenols and aryl
thiols to the triple bond of arylpropiolates. Synthesis of seleno- and thioflavones and seleno- and
thioaurones. J. Org. Chem. 1980, 45, 4611–4615.
21. Taylor, A.W.; Dean, D.K. A new synthesis of thioflavones. Tetrahedron Lett. 1988, 29, 1845–1848.
22. Brown, R.E. Indolothiopyrones. U.S. Patent 3 971 806, 1976; [Chem. Abstr. 1977, 86, 5436].
23. Henrio, G.; Morel, J. First synthesis of flavone type compounds containing a thiophen ring.
Tetrahedron Lett. 1974, 25, 2167–2168.

Molecules 2009, 14
3831
24. Henrio, G.; Morel, J.; Pastour, P. Sur la synthèse d’isostères thiophèniques des flavones,
thioflavones et xanthones. Tetrahedron 1977, 33, 191–198.
25. Netchitailo, P.; Decroix, B.; Morel, J., Pastour, P. Synthèse de flavones et de xanthones dans la
série du benzo[4,5]thiophène. J. Heterocycl. Chem. 1978, 15, 337–342.
26. Willy, B.; Müller, T.J.J. A novel consecutive three-component Coupling-Addition-SNAr
(CASNAR) synthesis of 4H-thiochromen-4-ones. Synlett 2009, 1255–1260.
27. Shvartsberg, M.S.; Ivanchikova, I.D. Synthesis of sulfur-containing heterocyclic compounds by
cyclo-condensation of acetylenic derivatives of anthraquinone with sodium sulfide. ARKIVOC
2003, xiii, 87–100.
28. Ivanchikova, I.D.; Shvartsberg, M.S. Synthesis of anthrathiopyrantriones by heterocyclization of
alkynoyl derivatives of chloroanthraquinones. Russ. Chem. Bull. 2004, 53, 2303–2307.
29. Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis of acetylenes: Catalytic
substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes, and bromopyridines.
Tetrahedron Lett. 1975, 50, 4467–4470.
30. Tohda, Y.; Sonogashira, K.; Hagihara, N. A Convenient synthesis of 1-alkynyl ketones and 2-
alkynamides. Synthesis 1977, 777–778.
31. Chinchilla, R.; Nájera, C. The Sonogashira reaction: A booming methodology in sythetic organic
chemistry. Chem. Rev. 2007, 107, 874–922.
32. Alonso, D.A.; Nájera, C.; Pacheco, M.C. Synthesis of ynones by palladium-catalyzed acylation of
terminal alkynes with acid chlorides. J. Org. Chem. 2004, 69, 1615–1619.
33. Palimkar, S.S.; Kumar, P.H.; Jogdand, N.R.; Daniel, T.; Lahoti, R.J.; Srinivasan, K.V. Copper-,
ligand- and solvent-free synthesis of ynones by coupling acid chlorides with terminal alkynes.
Tetrahedron Lett. 2006, 47, 5527–5530.
34. Chowdhury C.; Kundu, N.G. Studies on copper(I) catalysed cross-coupling reactions: A
convenient and facile method for the synthesis of diversely substituted α,β-acetylenic ketones.
Tetrahedron 1999, 55, 7011–7016.
35. Cox, R.J.; Ritson, D.J.; Dane, T.A.; Berge, J.; Charmant, J.P.H.; Kantacha, A. Room temperature
palladium catalysed coupling of acyl chlorides with terminal alkynes. Chem. Commun. 2005,
1037–1039.
36. Huang, L.-J.; Hsieh, M.-C.; Teng, C.-M.; Lee, K.-H.; Kuo, S.-C. Synthesis and Antiplatelet
Activity of Phenyl Quinolones. Bioorg. Med. Chem. 1998, 6, 1657–1662.
37. Kuo, S.-C.; Lee, H.-Z.; Juang, J.-P.; Lin, Y.-T.; Wu, T.-S.; Chang, J.-J.; Lednicer, D.; Paull, K.D.;
Lin, C.M.; Hamel, E.; Lee, K.-H. Synthesis and Cytotoxicity of 1,6,7,8-substituted 2-(4’-
Substituted phenyl)-4-quinolones and related compounds: Identification as antimitotic agents
interacting with tubulin. J. Med. Chem. 1993, 36, 1146–1156.
38. Gatto, B.; Tabarrini, O.; Massari, S.; Giaretta, G.; Sabatini, S.; Del Vecchio, C.; Parolin C.;
Fravolini, A.; Palumbo, M.; Cecchetti, V. 2-phenylquinolones as inhibitors of the HIV-1 Tat-TAR
interaction. ChemMedChem. 2009, 4, 935–938.
39. Hooper, D.C., Rubinstein, E., Eds. Quinolone Antimicrobial Agents, 3rd Ed.; American Society
for Microbiology Press: Washington, DC, USA, 2003.
40. Kleemann, A.; Engel, J. Pharmaceutical Substances, 3rd ed.; Thieme: New York, NY, USA,
1999; pp. 450–452.

Molecules 2009, 14
3832
41. Kleemann, A.; Engel, J. Pharmaceutical Substances, 3rd ed.; Thieme: New York, NY, USA,
1999; pp. 699–700.
42. Kalchhauser, H.; Robien, W. CSEARCH: A computer program for identification of organic
compounds and fully automated assignment of carbon-13 nuclear magnetic resonance spectra. J.
Chem. Inf. Comput. Sci. 1985, 25, 103–108.
43. NMR Predict, version 3.2.8. Modgraph Consultants, Ltd.: Herts, UK, 2004;
www.modgraph.co.uk/product_nmr.htm, accessed on 24 September 2009.
44. ACD/C+H Predictors and DB, version 10.04. Advanced Chemistry Development, Inc.: Toronto,
ON, Canada, 2006; www.acdlabs.com, accessed on 24 September 2009.
45. Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More Basic NMR Experiments, 2nd ed.; Wiley–
VCH: New York, NY, USA, 1998.
46. Bax, A. Structure determination and spectral assignment by pulsed polarization transfer via long-
range proton-carbon-13 couplings. J. Magn. Reson. 1984, 57, 314–318.
47. Jippo, T.; Kamo, O.; Nagayama, N. Determination of long-range proton-carbon 13 coupling
constants with selective two-dimensional INEPT. J. Magn. Reson. 1986, 66, 344–348.
48. Kuhn, F.; Oehme, M.; Romero, F.; Abou-Mansour, E.; Tabacchi, R. Differentiation of isomeric
flavon/isoflavone aglycones by MS2 ion trap mass spectrometry and a double neutral loss of CO.
Rapid Commun. Mass Spectrom. 2003, 17, 1941–1949.
49. ACD Name, version 10.01. Advanced Chemistry Development, Inc.: Toronto, ON, Canada; 2006;
www.acdlabs.com, accessed on 24 September 2009.
50. Eller, G.A. Improving the quality of published chemical names with nomenclature software.
Molecules 2006, 11, 915–928.
51. Laliberte, R.; Campbell, D.J.; Bruderlein, F. Antihelmintic activities of chalcones and related
compounds. Can. J. Pharm. Sci. 1967, 2, 37–43.
52. Utekhina, N.V.; Surov, Yu.N.; Korzhova, N.V.; Kazantseva, V.M.; Orlov, V.D.; Korshunov, S.P.
Basicity and polarity of aromatic α,β-acetylenic ketones. Zhur. Obsh. Khim. 1987, 57, 1362–1366.
53. Coppola, G.M. The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (Isatoic Anhydride). 9.
synthesis of 2-arylquinoline alkaloids. J. Heterocycl. Chem. 1982, 19, 727–731.
Sample Availability: Samples of the compounds are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).