Microwave-assisted three-component coupling-addition-SNAr (CASNAR) sequences to annelated 4H-thiopyran-4-ones

Article abstract of DOI:10.1039/b917627f

A whole family of annelated 4H-thiopyran-4-ones as the core structural unit was readily synthesized in good yields by a microwave-assisted coupling-addition-S_NAr (CASNAR) sequence starting from readily available (het)aroyl chlorides, alkynes and sodium sulfide nonahydrate in a consecutive one-pot three-component reaction. All representatives display a pronounced halochromicity of the absorption bands upon protonation. According to DFT calculations, the electronic ground state of the annelated 4H-thiopyran-4-ones possess a considerable zwitterionic character. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b917627f

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Microwave-assisted three-component coupling-addition-SNAr (CASNAR)
sequences to annelated 4H-thiopyran-4-ones†
Benjamin Willy,a Walter Frank‡b and Thomas J. J. Mu¨ller*a
Received 26th August 2009, Accepted 28th September 2009
First published as an Advance Article on the web 23rd October 2009
DOI: 10.1039/b917627f
A whole family of annelated 4H-thiopyran-4-ones as the core structural unit was readily synthesized in
good yields by a microwave-assisted coupling-addition-SNAr (CASNAR) sequence starting from
readily available (het)aroyl chlorides, alkynes and sodium sulfide nonahydrate in a consecutive one-pot
three-component reaction. All representatives display a pronounced halochromicity of the absorption
bands upon protonation. According to DFT calculations, the electronic ground state of the annelated
4H-thiopyran-4-ones possess a considerable zwitterionic character.
ses of heterocycles,13 we recently communicated a novel three-
Introduction
component synthesis of 4H-thiochromen-4-ones with a highly
flexible substitution pattern.14 Here, we report the methodological
extension of this innovative strategy to various classes of annelated
4H-thiopyran-4-ones and their optical properties.
Thiopyranone is the thio homologue of pyranone, a core
constituent of many natural products. In their own right,
thiochromenones, benzo-annelated thiopyranones that are related
to the class of flavones, are potent drug candidates and serve as
key intermediates for the synthesis of biologically active com-
pounds. As a consequence, many thiochromenones are known to
exhibit antimicrobial and antifungal,1 antibacterial,2 antibiotic,3
and anticarcinogenic4 activity. Some derivatives are used as
antimalaria agents,5 and oxidized representatives reversibly inhibit
the human cytomegalovirus protease.6
In general, 4H-thiochromen-4-ones are synthesized either by
condensation of b-keto esters and thiophenols with polyphospho-
ric acid7 or by cyclization of b-substituted cinnamates derived from
thiophenols and appropriate propiolates.5,8 Condensation and
subsequent acid-mediated cyclization of lithiated intermediates
derived from acetoacetanilides,9 C(a),N-benzoyl hydrazones or
C(a),N-carboalkoxy hydrazones10 with methyl thiosalicylates also
lead to the formation of 4H-thiochromen-4-ones. Just recently, a
synthesis via intramolecular thiolester carbonyl olefination using
N-phenyl(triphenylphosphorany1idene)ethenimine as a starting
material was reported.11
Results and discussion
Synthesis
Alkynones are accessible by Sonogashira coupling15 of acid
chlorides with terminal alkynes.16 However, a modified protocol
with THF as the solvent using only one stoichiometrically
necessary equivalent of triethylamine as the base has proven to
be most favorable for successful coupling.17 In turn, the resulting
alkynones are reactive Michael acceptors ready to react with
various nucleophiles18 and dipolarophiles19 in a one-pot fashion
to give a plethora of heterocycles.
Retrosynthetically, the formation of annelated 4H-thiopyran-
4-ones in a one-pot fashion can be perceived via a sequence of
intramolecular nucleophilic aromatic substitutions (SNAr) and
Michael addition of hydrosulfide yielding alkynones 5 (Scheme 1).
These alkynones should be accessible by Sonogashira coupling
of 2-halobenzoyl chlorides 1 and terminal alkynes 2. Prior to
our studies, only a few examples of SNAr-Michael addition
of hydrosulfide to alkynones had been reported.20 Hence, the
remaining methodological challenge is the development of a
general rapid one-pot three-component coupling-addition-SNAr
(CASNAR) process.
However, most of these methods could not successfully be
applied to the synthesis of methoxy-substituted thioflavones.12
Either the reported strategies require many steps or the starting
materials are difficult to synthesize. Hence, due to the interesting
pharmacological potential of 4H-thiopyran-4-one derivatives and
as a part of our program to develop multi-component synthe-
aInstitut fu¨r Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universita¨t Du¨sseldorf, Universita¨tsstr., 1, D-40225,
Du¨sseldorf, Germany. E-mail: ThomasJJ.Mueller@uni-duesseldorf.de;
Fax: +492118114324
bLehrstuhl fu¨r Anorganische Chemie und Strukturchemie der Heinrich-
Heine-Universita¨t Du¨sseldorf, Universita¨tsstraße, 1, D-40225, Du¨sseldorf,
Germany
Scheme
(CASNAR) sequence.
1
Mechanistic rationale of the coupling-addition-SNAr
† Electronic supplementary information (ESI) available: Experimental de-
tails, X-ray coordinates, molecular modeling coordinates and fluorescence
spectrum of 4e-H+. CCDC reference numbers 754614–754615. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b917627f
Therefore, ortho-haloaroyl chloride 1a or 1b was reacted with
ethynyl benzene (2a) under modified Sonogashira conditions for
1 h at room temperature to furnish the expected alkynones
5. Subsequently, sodium sulfide nonahydrate (3) and ethanol
‡ X-Ray structure analyses.
90 | Org. Biomol. Chem., 2010, 8, 90–95
This journal is
The Royal Society of Chemistry 2010
©

View Online
Table 1 Optimization of the one-pot microwave-assisted coupling-
addition-SNAr (CASNAR) synthesis of 4H-thiochromen-4-one 4a by
reaction of ortho-halobenzoyl chlorides 1a and 1b, ethynyl benzene (2a),
and Na2S·9 H2O (3)
Entry 1 (equiv.) 2c (equiv.) 3 (equiv.) Addition-SNAr 4a Yield (%)a
1
2
3
4
5
1a (1.00) 1.00
1a (1.00) 1.00
1a (1.00) 1.00
1a (1.25) 1.00
1b (1.25) 1.00
1.10
1.10
1.50
1.50
1.50
90 ◦C, 120 minb 52
90 ◦C, 90 min
90 ◦C, 90 min
90 ◦C, 90 min
90 ◦C, 90 min
58
59
73
40
Scheme 3 Coupling-addition-substitution (CASNAR) sequence to yield
substituted 4H-thiochromen-4-ones 4.
a Isolated yield after column chromatography on silica gel (ethyl ac-
etate/hexanes). b Control experiment in an oil bath.
Table 2 One-pot three-component synthesis of 4H-thiochromen-4-
ones 4
Aroyl
Entry chloride 1 Alkyne 2
Product Yield (%)
were added to the reaction mixture and heated in a microwave
cavity to give 4H-thiochromen-4-one 4a (Scheme 2, Table 1).
Mechanistically, it is likely that the rapid Michael addition of
the hydrosulfide ion to the alkynone 5 to give adduct 6 precedes
the cyclizing SNAr, assisted by Pd and/or Cu catalysis.
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a R2 = H [TMS]
4a
4b
4c
4d
4e
4f
4g
4h
4i
39
73
76
77
73
52
59
63
51
2b R2 = C6H5
2c R2 = 4-C6H4C(CH3)3
2d R2 = 4-C6H4OCH3
2e R2 = 3,4-C6H3(OCH3)2
2f R2 = 4-C6H4Cl
n
2g R2 = butyl
2h R2 = ferrocenyl
2i R2 =
6-methoxynaphthalen-2-yl
2a R2 = H [TMS]
2b R2 = C6H5
10
11
12
13
14
15
1c
1c
1c
1c
1c
1c
4j
4k
4l
4m
4n
4o
35
61
48
66
59
47
2j R2 = 4-C6H4CH3
2c R2 = 4-C6H4C(CH3)3
2e R2 = 3,4-C6H3(OCH3)2
2k R2 = 4-C6H4F
Scheme 2 Mechanistic rationale of the coupling-addition-SNAr (CAS-
NAR) sequence.
Table 3 Comparison of existing protocols for the synthesis of 4c
Route
Steps
Time
Yield (%)a
Dielectric heating proved to be more efficient than conduc-
tive heating in an oil bath (entries 1 and 4), but only in
the concluding addition-substitution step. Sonogashira coupling
proceeded smoothly at room temperature and without formation
of side products. Fluorine as a leaving group was superior to
chlorine (entries 4 and 5). Hence, the stage was set for a novel
microwave-assisted three-component coupling-addition-SNAr
(CASNAR) synthesis of 4H-thiochromen-4-ones 4 in a one-pot
fashion.
Wittig route11
PPA7
3
2
3
1
~3 d
~10 h
~4 d
~2 h
44
71
34
73
Propiolate route5
CASNAR
a Yield over all steps, starting from commercially available compounds.
Therefore, the coupling of 2-halobenzoyl chlorides 1 with
terminal alkynes 2 under modified Sonogashira conditions for 1 h
at room temperature, and addition of sodium sulfide nonahydrate
(3) and ethanol, with reaction for 90 min at 90 ◦C in a microwave
cavity resulted in the formation of substituted 4H-thiochromen-4-
ones 4 in moderate to good yields as bright yellow solids (Scheme 3,
Table 2).
Interestingly, 2,4-dichlorobenzoyl chloride 1c selectively fur-
nished 7-chloro-substituted products (Table 2, entries 10–15) with-
out competing SNAr at the para-position. In comparison, existing
protocols for the synthesis of 4H-thiochromen-4-one 4c generally
require several steps, sometimes harsh reaction conditions, longer
reaction times and give significantly lower overall yields (Table 3).
With the method described herein, the synthesis and isolation of
4c is possible within 2 h, starting from commercially available
starting materials.
The scope was then expanded to 2-chloronicotinoyl chlo-
ride (1d), 2,5-dichlorothiophene-3-carbonyl chloride (1e) and 3-
chlorobenzo[b]thiophene-2-carbonyl chloride (1f) as heteroaroyl
chlorides, giving rise to the formation of the class of 4H-
thiopyrano[2,3-b]pyridin-4-ones 7 (Scheme 4, Table 4), 2-chloro-
4H-thieno[2,3-b]thiopyran-4-ones 8 and 7H-benzo-[b]thieno[3,2-
b]thiopyran-7-ones 9 (Scheme 4, Table 5) in modest to moderate
yields.
Since standard syntheses fail, to the best of our knowledge, only
two examples of 4H-thiopyrano[2,3-b]pyridin-4-ones 7 have been
reported in the literature prior to our studies.21 4H-thieno[2,3-
b]thiopyran-4-ones 8 and 7H-benzo-[b]thieno[3,2-b]thiopyran-7-
ones 9 are hitherto unknown heterocycles.
The structures of all annelated 4H-thiopyran-4-one derivatives
4, 7, 8 and 9 were unambiguously supported by spectroscopic
(1H, 13C and DEPT NMR experiments, IR, UV/Vis, mass
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 90–95 | 91
©

View Online
Table 5 One-pot three-component syntheses of 2-chloro-4H-thieno[2,3-
b]thiopyran-4-ones 8 and 7H-benzo-[b]thieno[3,2-b]thiopyran-7-ones 9
Heteoaroyl
Entry chloride 1
Alkyne 2
Product Yield (%)
1
2
3
4
5
6
7
8
1e
1e
1e
1e
1f
1f
1f
1f
2b R2 = C6H5
8a
8b
8c
8d
9a
9b
9c
9d
40
63
51
36
46
41
27
32
2c R2 = 4-C6H4C(CH3)3
2e R2 = 3,4-C6H3(OCH3)2
n
2g R2 = butyl
2b R2 = C6H5
2c R2 = 4-C6H4C(CH3)3
2k R2 = 4-C6H4F
2l R2 = cyclopropyl
Scheme 4 Coupling-addition-substitution (CASNAR) sequences to het-
eroaryl annelated 4H-thiopyran-4-ones 7, 8 and 9.
Table 4 One-pot three-component syntheses of 4H-thiopyrano[2,3-
b]pyridin-4-ones 7 starting from 2-chloronicotinoyl chloride (1d)
Entry
Alkyne 2
Product
Yield (%)
1
2
3
4
5
6
7
8
2a R2 = H [TMS]
2b R2 = C6H5
7a
7b
7c
7d
7e
7f
62
55
23
15
31
19
17
53
2j R2 = 4-C6H4CH3
2c R2 = 4-C6H4C(CH3)3
2f R2 = 4-C6H4Cl
2h R2 = ferrocenyl
Fig. 1 X-Ray structure of 4i.
n
2g R2 = butyl
7g
7h
2l R2 = cyclopropyl
spectrometry) and combustion analyses, and later by X-ray
structure analyses for the compounds 4i and 7h (Fig. 1 and 2§).
Methodologically, this novel one-pot three-component CAS-
NAR synthesis of annelated 4H-thiopyran-4-ones 4, 7, 8 and 9
proceeds efficiently under mild reaction conditions and with a
broad variety of structurally and electronically diverse alkynes.
Aliphatic, aromatic, heteroaromatic, and even ferrocenyl- or
Fig. 2 X-Ray structure of 7h.
§ CCDC 745614 (4i) and CCDC 745615 (7h) contain supplementary
crystallographic data for these structures. For crystallographic date in
CIF or other electronic format see DOI: 10.1039/b917627f. Data were
collected on a Bruker APEX diffractometer. Mo Ka radiation (l =
heteroatom-substituted alkynes can be successfully transformed
in this reaction. If trimethylsilyl acetylene is applied, the TMS
group is presumably lost during the Michael addition and the
resulting 4H-thiopyran-4-one then bears a hydrogen atom at the
R2 position. Expectedly, free amino or hydroxy groups on the
alkynes interfering with the electrophilic aroyl chloride reactivity
should be protected. According to the substitution pattern of the
compounds 4, 7, 8 and 9, it becomes apparent that the electronic
structure of substituent R2 exerts the methodological limitation
of the terminal Michael addition-SNAr steps. Unfortunately,
alkynones resulting from the coupling with alkoxy, acetal and
electron poor aromatic substituents on the alkyne 2 were not
successfully transformed into annelated 4H-thiopyran-4-ones.
˚
0.71073 A) was used in all cases, and the intensities were corrected for
absorption effects using SADABS based on the laue symmetry of the
reciprocal space. The structures were solved by direct methods and refined
against F2 with a full matrix least square algorithm using the SHELXTL
software package. Hydrogen atoms were considered at calculated positions
and refined using appropriate riding models. Relevant crystal and data
collection parameters for the individual structures are given below. Crystal
data: 4i: C20H14O2S, M = 318.38, monoclinic, space group P21/n, a =
◦
˚
13.6458(10), b = 5.7353(3), c = 19.9386(14) A, b = 106.548(8) , V =
3
-3
˚
1495.82(18) A , T = 291(2) K, Z = 4, r = 1.414 g cm , dimensions 0.60 ¥
0.35 ¥ 0.12 mm3, m = 0.223 mm-1, 0.3◦ omega-scans, 18 476 reflections
measured, 2629 unique [Rint = 0.0826], 2629 observed [I > 2s(I)], 209
parameters refined, goodness of fit 0.994, wR2 = 0.0903, R1 = 0.0444
-3
˚
(observed reflections), residual electron density -0.317–0.337 eA , CCDC
Optical spectroscopy and electronic structure
745614. 7h: C11H9NOS, M = 203.25, monoclinic, space group◦P21/n,
˚
a = 8.2503(9), b = 22.330(3), c = 10.694(2) A, b = 103.40(3) , V =
3
-3
˚
Expectedly, UV/Vis absorption spectra of the annelated 4H-
thiopyran-4-one derivatives 4, 7, 8 and 9 are quite similar (Table 6).
1916.5(5) A , T = 291(2) K, Z = 8, r = 1.409 g cm , crystal dimensions
0.30 ¥ 0.30 ¥ 0.30 mm3, m = 0.299 mm-1, 0.3◦ omega-scans, 11 642
reflections measured, 3360 unique [Rint = 0.0983], 3360 observed [I >
2s(I)], 1000 parameters refined, goodness of fit 0.848, wR2 = 0.0469, R1 =
For 4H-thiochromen-4-ones 4, three distinct maxima lmax,abs
,
-3
appear in the spectra, whereas the longest wavelength band occurs
at ~345 nm causing the bright yellow color of the compounds
˚
0.0423 (observed reflections), residual electron density -0.157–0.252 eA ,
CCDC 745615.
92 | Org. Biomol. Chem., 2010, 8, 90–95
This journal is
The Royal Society of Chemistry 2010
©

View Online
Fig. 3 Normalized UV/Vis spectra of selected 4H-thiochromen-4-ones 4 (recorded in CH2Cl2, c0 = 10-3 M; T = 293 K).
Table 6 UV/Vis data of annelated thiopyranones 4, 7, 8 and 9 (recorded
in CH2Cl2, c0 = 10-4 M, T = 293 K)
Interestingly, all annelated 4H-thiopyran-4-one derivatives can
be easily protonated upon addition of acids. Upon adding
aliquots of trifluoroacetic acid to a solution of 4, 7, 8 or 9 in
dichloromethane, a significant change in the absorption behavior
of the compound occurred (Fig. 4).
Compound
l
max/nm (e/mol-1 L cm-1)
4a
4b
4c
4d
4e
4f
249 (7300), 287 (2300), 337 (4400)
272 (30900), 301 (6900), 344 (11700)
280 (17300), 306 (8200), 345 (7500)
265 (33700), 319 (31900), 342 (27700)
255 (23000), 284 (11400), 339 (17700)
277 (42700), 302 (14400), 345 (15300)
249 (9600), 286 (1400), 337 (5500)
260 (20600), 285 (18400), 307 (11900), 347 (9800),
389 (2200), 486 (1800)
Upon protonation, the lmax,abs value shifted from 345 to
370–440 nm. Interestingly, this was not a static phenomenon.
Increasing aliquots of acid increased the bathochromic shifts,
even visible with the naked eye—the color changed from yellow
to orange. In addition, protonation caused orange luminescence
(lmax,em = 460 nm, see the ESI†) of the protonated heterocycle 4e-
H+, with a fluorescence quantum yield lower than 1%, whereas
the free base system 4e was essentially nonluminescent. This
pronounced bathochromic halochromicity of the absorption band
can be rationalized by the generation of a cyanine-type push-pull
system upon protonation. According to the HSAB principle,22
protonation occurs preferentially at the harder carbonyl oxygen
atom and not at the soft sulfur atom (Scheme 5).
4g
4h
4i
4j
249 (22000), 329 (14600), 337 (16000)
255 (24100), 337 (10700)
4k
4l
272 (31600), 304 (8200), 343 (11000)
279 (20100), 309 (9700), 343 (8700)
278 (23400), 307 (11800), 343 (9800)
259 (23300), 282 (11300), 341 (17100)
273 (41900), 305 (12000), 343 (15100)
249 (22000), 329 (14600), 337 (16000)
269 (18700), 297 (10000), 345 (8800)
274 (12300), 306 (10400), 345 (7300)
274 (23800), 306 (21900), 345 (15400)
271 (21200), 299 (14800), 343 (10100)
263 (17400), 310 (14600), 345 (10400), 395 (2300),
493 (2200)
4m
4n
4o
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
9a
252 (7800), 285 (2000), 335 (5700)
259 (18700), 329 (9600), 338 (10500)
277 (24500), 317 (8500)
284 (23700), 316 (10200)
254 (20900), 299 (19300), 325 (19700)
248 (21600), 309 (12800)
Scheme 5 Protonation of compound 4e with trifluoroacetic acid.
260 (21300), 286 (27500), 298 (26700), 307 (26600),
351 (13300)
This qualitative rationalization is also supported by DFT
calculations (B3LYP/6-311G++)23 on the thiopyranones and the
corresponding related pyranones indicating a strongly zwitterionic
character in the electronic ground state of the former (Fig. 5).
The computations clearly show that the sulfur atom in the
4H-thiochromen-4-one structure possesses a significant positive
partial charge of around +0.45 C, whereas the oxygen atom in the
chromen-4-ones clearly has a negative partial charge of around
-0.57 C. Compared to the natural product class of the flavones
this connotes a complete inversion of the polarity of the ring
system. The oxygen atoms of the carbonyl group in both systems
expectedly display a negative partial charge of around -0.39 C.
9b
9c
9d
261 (9000), 287 (12400), 299 (13400), 308 (13900),
350 (6400)
259 (25100), 286 (31500), 298 (30600), 308 (30900),
351 (15400)
250 (17000), 259 (18600), 266 (15300), 276 (17600),
295 (15400), 305 (18400), 334 (10500), 347 (12000)
(Fig. 3). Depending on the substitution pattern, the second
absorption band is not pronounced (~305 nm). The absorption
band with the highest extinction coefficient is located at ~275 nm.
This feature is characteristic for aromatic cores and can be assigned
to substituents R2.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 90–95 | 93
©

View Online
Fig. 4 Titration of 4e with trifluoroacetic acid (recorded in CH2Cl2, T = 298 K).
spectrometer. The melting points are uncorrected. IR spectra
were taken on a FT-IR-spectrometer in KBr pellets and are
reported in cm-1. Elemental analyses were carried out in the
microanalytical laboratory of the Pharmazeutisches Institut of
the Heinrich-Heine-Universita¨t Du¨sseldorf. Dielectric heating was
performed in a single-mode microwave cavity (Discover Labmate,
CEM GmbH, Kamp-Lintfort) producing continuous irradiation
at 2450 MHz. The applied temperatures for microwave heating
were held constant over the indicated reaction time by the
implemented regulation system. Temperature and pressure as well
as the cooling curve were monitored by the integrated controlling
device.
Fig. 5 DFT-computed charge distribution in selected thiochromenones
(top row) and their flavone analogues (bottom row) (atomic partial charges
are given).
General procedure for the synthesis of annelated
4H-thiochromen-4-ones 4, 7, 8 and 9
Conclusions
In a 10 ml microwave tube, PdCl2(PPh3)2 (15 mg, 0.02 mmol) and
CuI (8 mg, 0.04 mmol) were dissolved in degassed THF (4 mL).
Then, to this orange solution, acid chloride 1 (1.25 mmol), alkyne
2 (1.00 mmol) and triethylamine (1.05 mmol) were added. The
reaction mixture was stirred at room temperature for 1 h. Finally,
sodium sulfide nonahydrate (3) followed by ethanol (1 mL) were
added to this suspension and the reaction mixture was heated at
90 ◦C in the microwave cavity for 90 min. After cooling to room
temperature, the solvent was removed under reduced pressure
and the crude products were purified by silica gel flash column
chromatography (hexane/ethyl acetate) to afford the analytically
pure 4H-thiochromen-4-ones 4, 7, 8 and 9 (for experimental details
see the ESI, Tables 1–3†).
The CASNAR sequence represents a straightforward and rapid
method access to 4H-thiopyran-4-ones in the sense of a con-
secutive one-pot process and with a broad scope in the starting
materials. Methoxy groups, which proved to be unfavorable in
standard syntheses, are perfectly tolerated in this sequence. Fur-
thermore, as a consequence of pronounced zwitterionic character
of the computed electronic ground state, intense bathochromic
halochromicity of the longest wavelength absorption bands with
concomitant weak orange fluorescence can be observed upon
protonation. This novel one-pot protocol now opens new avenues
to related classes of annelated heterocycles. Studies addressing the
detailed photophysics and the biological activity of 4H-thiopyran-
4-ones are currently under investigation.
2-(4-Methoxyphenyl)-4H-thiochromen-4-one (4d)
Experimental
Yellow solid, mp 97 ◦C. 1H NMR (500 MHz, CDCl3): d 3.88 (s, 3
H), 7.01 (d, 3J = 8.8 Hz, 2 H), 7.20 (s, 1 H), 7.54 (ddd, 3J = 8.2 Hz,
3J = 6.9 Hz, 4J = 1.3 Hz, 1 H), 7.61 (ddd, 3J = 8.2 Hz, 3J = 6.9 Hz,
4J = 1.3 Hz, 1 H), 7.64-7.67 (m, 3 H), 8.54 (dd, 3J = 8.1 Hz, 4J =
1.3 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d 55.5 (CH3), 114.7
(2 CH), 122.2 (CH), 126.4 (CH), 127.6 (CH), 128.3 (2 CH), 128.5
(CH), 128.8 (Cquat), 130.9 (Cquat), 131.5 (CH), 137.6 (Cquat), 152.7
(Cquat), 161.9 (Cquat), 180.9 (Cquat). EI MS (Rf = 20.3 min, 70 eV,
m/z (%)): 269 (19), 268 (M+, 100), 267 (17), 240 (39), 225 (25), 197
(11), 136 (34), 132 (56), 120 (10), 117 (14), 108 (29), 89 (22), 69
(10), 63 (13). IR (KBr): v˜ = 1628 cm-1 (s), 1605 (s), 1551 (w), 1509
All reactions involving water-sensitive compounds were carried
out in flame-dried glassware under an argon atmosphere. Reagents
and catalysts were purchased reagent grade and used without
further purification. Solvents were dried by a solvent purification
system. Flash column chromatography: silica gel 60, mesh 230–
400. TLC: silica gel plates (60 F254). 1H, 13C, DEPT, NOESY,
COSY, HMQC and HMBC spectra were recorded with a 500 MHz
NMR spectrometer using CDCl3 as the solvent. The assign-
ments of Cquat, CH, CH2 and CH3 were made on the basis of
DEPT spectra. Mass spectra were recorded with a quadruple
94 | Org. Biomol. Chem., 2010, 8, 90–95
This journal is
The Royal Society of Chemistry 2010
©

View Online
(s), 1438 (w), 1336 (m), 1311 (w), 1269 (s), 1246 (w), 1184 (m),
1130 (w), 1117 (w), 1103 (w), 1020 (m), 862 (w), 831 (s), 798 (m),
774 (m), 732 (m), 666 (w), 623 (w), 568 (w), 517 (m). Anal. calcd
for C16H12O2S (268.3): C 71.62, H 4.51; found: C 71.66, H 4.21%.
2 H. Nakazumi, T. Ueyama and T. Kitao, J. Het. Chem., 1984, 21,
193.
3 J. Couquelet, P. Tronche, P. Niviere and G. Andraud, Trav. Soc. Pharm.
Montpellier, 1963, 23, 214.
4 M. H. Holshouser, L. J. Loeffler and I. H. Hall, J. Med. Chem., 1981,
24, 853.
5 R. K. Razdan, R. J. Bruni, A. C. Mehta, K. K. Weinhardt and Z. B.
Papanastassiou, J. Med. Chem., 1978, 21, 643.
6 D. Dhanak, R. M. Keenan, G. Burton, A. Kaura, M. G. Darcy, D. H.
Shah, L. H. Ridgers, A. Breen, P. Lavery, D. G. Tew and A. West,
Bioorg. Med. Chem. Lett., 1998, 8, 3677.
7 F. Bossert, Liebigs Ann. Chem., 1964, 40, 680; S. W. Schneller, Adv.
Heterocycl. Chem., 1975, 18, 59; H. Nakazumi, S. Wanatabe, T.
Kitaguchi and T. Kitao, Bull. Chem. Soc. Jpn., 1990, 63, 847.
8 W. E. Truce and D. L. Goldhamer, J. Am. Chem. Soc., 1959, 81, 5795;
K. Buggle, J. J. Delahunty, E. M. Philbin and N. D. Ryan, J. Chem. Soc.
C, 1971, 3168.
9 A. J. Angel, A. E. Finefrock, K. L. French, D. R. Hurst, A. R. Williams,
M. E. Rampey, S. L. Studer-Martinez and C. F. Beam, Can. J. Chem.,
1999, 77, 94.
4H-Thiopyrano[2,3-b]pyridin-4-one (7a)
◦
1
Yellow solid, mp 135 C. H NMR (500 MHz, CDCl3): d 7.04
(d, 3J = 10.6 Hz, 1 H), 7.50 (dd, 3J = 8.1 Hz, 3J = 4.5 Hz, 1 H),
7.93 (d, 3J = 10.6 Hz, 1 H), 8.77 (dd, 3J = 8.1 Hz, 4J = 1.8 Hz, 1
H), 8.80 (dd, 3J = 4.5 Hz, 4J = 1.8 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): d 123.0 (CH), 126.1 (CH), 129.7 (Cquat), 136.9 (CH), 139.5
(CH), 152.7 (CH), 158.8 (Cquat), 180.6 (Cquat). EI MS (70 eV, m/z
(%)): 164 (11), 163 (M+, 100), 137 (18), 135 (28), 109 (11). IR
(KBr): v˜ = 1625 cm-1 (s), 1579 (m), 1509 (w), 1450 (w), 1398 (s),
1366 (m), 1305 (w), 1265 (w), 1157 (w), 1072 (w), 842 (w), 791 (m),
717 (w), 670 (w). Anal. calcd for C8H5NOS (163.2): C 58.88, H
3.09, N 8.58; found: C 58.81, H 3.18, N 8.45%.
10 K. L. French, A. J. Angel, A. R. Williams, D. R. Hurst and C. F. Beam,
J. Heterocycl. Chem., 1998, 35, 45.
11 P. Kumar, A. T. Rao and B. Pandey, J. Chem. Soc., Chem. Commun.,
1992, 1580; P. Kumar and M. S. Bodas, Tetrahedron, 2001, 57,
9755.
6-(4-tButylphenyl)-2-chloro-4H-thieno[2,3-b]thiopyran-4-one (8b)
12 D. H. Wadsworth and M. R. Detty, J. Org. Chem., 1980, 45,
◦
1
Brown solid, mp. 157 C. H NMR (500 MHz, CDCl3): d 1.35
4611.
3
3
(s, 9 H), 7.16 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.55 (d, J =
8.8 Hz, 2 H), 7.57 (s, 1 H). 13C NMR (125 MHz, CDCl3): d 31.1
(3 CH3), 34.9 (Cquat), 124.1 (CH), 124.4 (CH), 126.4 (2 CH), 126.6
(2 CH), 131.0 (Cquat), 133.0 (Cquat), 137.2 (Cquat), 142.6 (Cquat), 151.5
(Cquat), 154.6 (Cquat), 175.7 (Cquat). EI MS (Rf = 32.0 min, 70 eV,
m/z (%)): 336 (37Cl-M+, 32), 335 (12), 334 (35Cl-M+, 62), 321 (40),
320 (19), 319 (100), 290 (11), 263 (16), 207 (11), 179 (13), 178 (13),
177 (25), 176 (20), 148 (18), 147 (15), 146 (27), 128 (15), 127 (11),
115 (27), 69 (19). IR (KBr): v˜ = 2961 cm-1 (w), 1607 (s), 1508 (w),
1436 (w), 1414 (w), 1361 (w), 1271 (w), 1240 (w), 1114 (w), 1001
(w), 902 (w), 879 (w), 849 (w), 822 (w), 714 (w), 663 (w), 587 (w),
522 (w). Anal. calcd for C17H15ClOS2 (334.9): C 60.97, H 4.51;
found: C 60.80, H 4.60%.
13 For reviews, see: B. Willy and T. J. J. Mu¨ller, ARKIVOC, 2008, Part
(i), 195; B. Willy and T. J. J. Mu¨ller, Curr. Org. Chem., 2009, 13, 1777,
DOI: 10.2174/138527209789630479.
14 B. Willy and T. J. J. Mu¨ller, Synlett, 2009, 1255.
15 For lead reviews on Sonogashira couplings, see e.g.: S. Takahashi,
Y. Kuroyama, K. Sonogashira and N. Hagihara, Synthesis, 1980,
627; K. Sonogashira, in Metal catalyzed cross-coupling reactions, ed.
F. Diederich and P. J. Stang, Wiley-VCH, Weinheim, 1998, p. 203; H.
Doucet and J.-C. Hierso, Angew. Chem., Int. Ed., 2007, 46, 834; L. Yin
and J. Liebscher, Chem. Rev., 2007, 107, 133.
16 Y. Toda, K. Sonogashira and N. Hagihara, Synthesis, 1977,
777.
17 A. S. Karpov and T. J. J. Mu¨ller, Org. Lett., 2003, 5, 3451; D. M.
D’Souza and T. J. J. Mu¨ller, Nat. Protoc., 2008, 3, 1660.
18 T. J. J. Mu¨ller, Chimica Oggi/Chemistry Today, 2007, 25, 70; T. J. J.
Mu¨ller, Targets in Heterocyclic Systems, 2006, 10, 54; B. Willy and
T. J. J. Mu¨ller, Eur. J. Org. Chem., 2008, 4157.
19 B. Willy, F. Rominger and T. J. J. Mu¨ller, Synthesis, 2008, 293; B. Willy,
W. Frank, F. Rominger and T. J. J. Mu¨ller, J. Organomet. Chem., 2009,
694, 942; A. V. Rotaru, I. D. Druta, T. Oeser and T. J. J. Mu¨ller, Helv.
Chim. Acta, 2005, 88, 1798.
20 M. S. Shvartsberg and I. D. Ivanchikova, ARKIVOC, 2003, (13), 87;
I. D. Ivanchikova and M. S. Shvartsberg, Russ. Chem. Bull., 2004, 53,
2303.
6-Phenyl-4H-benzothieno[2,3-b]thiopyran-4-one (9a)
◦
1
Beige solid, mp 157 C. H NMR (500 MHz, CDCl3): d 7.30
(s, 1 H), 7.49-7.53 (m, 4 H), 7.55–7.59 (m, 1 H), 7.68–7.70 (m, 2
H), 7.96–7.98 (m, 2 H). 13C NMR (125 MHz, CDCl3): d 122.4
(CH), 132.7 (CH), 124.6 (CH), 125.2 (CH), 127.2 (2 CH), 128.6
(CH), 129.4 (2 CH), 130.8 (CH), 135.3 (Cquat), 136.1 (Cquat), 136.3
(Cquat), 137.3 (Cquat), 140.7 (Cquat), 152.1 (Cquat), 176.9 (Cquat). EI MS
(70 eV, m/z (%)): 296 (12), 295 (20), 294 (M+, 100), 266 (33), 192
(13), 164 (18), 133 (20), 120 (21), 40 (56). IR (KBr): v˜ = 1620 cm-1
(s), 1593 (s), 1544 (m), 1528 (w), 1499 (m), 1443 (m), 1345 (m),
1300 (m), 1242 (w), 1085 (m), 1052 (m), 951 (m), 864 (m), 753 (s),
727 (m), 684 (s), 578 (s). Anal. calcd for C17H10OS2·1/8 CH2Cl2
(294.4 + 10.6): C 67.44, H 3.49; found: C 67.49, H 3.79%.
21 A. Couture, P. Grandclaudon and E. Huguerre, Synthesis, 1989, 456;
J. Becher, M. C. Christensen, M. C. Mo¨ller and J. Winckelmann, Sulfur
Lett., 1982, 1, 43.
22 R. G. Pearson, Inorg. Chim. Acta, 1995, 240, 93.
23 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N.
Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone,
B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H.
Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene,
X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. Ochterski, P. Y. Ayala, K. Morokuma, G. A.
Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul,
S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W.
Gill, B. G. Johnson, W. Chen, M. W. Wong, C. Gonzalez and J. A.
Pople, GAUSSIAN 03 (Revision B.3), Gaussian, Inc., Wallingford, CT,
2004.
Acknowledgements
The authors gratefully acknowledge the Fonds der Chemischen
Industrie and CEM for a research corporation.
Notes and references
1 H. Nakazumi, T. Ueyama and T. Kitao, J. Het. Chem., 1985, 22,
1593.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 90–95 | 95
©