Domino Synthesis of Thiochromenes through Cu-Catalyzed Incorporation of Sulfur Using Xanthate Surrogate

Article abstract of DOI:10.1021/acs.joc.6b02740

An efficient domino reaction has been developed for the synthesis of thiochromenes through Cu-catalyzed in situ incorporation of sulfur. This domino method avoids the use of less accessible and unpleasant arenethiols as starting materials, instead utilize

Full text of DOI:10.1021/acs.joc.6b02740

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Article
Domino Synthesis of Thiochromenes through Cu-
Catalyzed Incorporation of Sulfur using Xanthate Surrogate
Pandi Muthupandi, Nallappan Sundaravelu, and Govindasamy Sekar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02740 • Publication Date (Web): 26 Jan 2017
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Domino Synthesis of Thiochromenes through Cu-Catalyzed Incorporation of
Sulfur using Xanthate Surrogate
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Pandi Muthupandi, Nallappan Sundaravelu and Govindasamy Sekar*
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Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, Tamil Nadu,
India
gsekar@iitm.ac.in
An efficient domino reaction has been developed for the synthesis of thiochromenes through Cu-
catalyzed in situ incorporation of sulfur. This domino method avoids the use of less accessible
and unpleasant arenethiols as starting materials, instead utilizes very stable aryl halides along
with potassium ethyl xanthate as an odorless sulfur surrogate. The domino methodology
proceeds through C(aryl)-S coupling, thioester cleavage, sulfa-Michael addition, aldol reaction and
elimination reaction sequences to provide thiochromenes in good yields
INTRODUCTION
Synthesis of sulfur-containing compounds continues to be an important task in organic chemistry
because of their applications in biology, material science and food chemistry.1-3 Thiochromenes,
the sulfur analogues of chromenes, have been testified to exhibit many pharmaceutical properties
such as anti-cancer, anti-bacterial, anti-inflammatory and anti-psychiatric activities.4
Conventionally, thiochromenes could be prepared by four step process such as Michael addition
of thiophenol to 2-alkenoic acids followed by acid-catalyzed cyclization, reduction and
dehydration.5 Only a handful of attempts have been made to achieve efficient method for the
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synthesis of thiochromenes.6 However, most of these methods suffer from a number of
drawbacks like requirement of multistep synthesis, limited substrate scope and lower yield.
In the past years, domino sulfa-Michael-aldol reaction of 2-mercaptobenzaldehydes with α,β-
unsaturated compounds has been used as an efficient tool for the synthesis of chiral
thiochromanes.7 However, very few methods utilized cascade sulfa-Michael-aldol reaction to
synthesize chiral thiochromenes,8 cascade sulfa-Michael-aldol reaction of 2-
mercaptobenzaldehydes with simple chalcones has remained unexplored. Despite the progress
towards synthesis of thiochromenes, all the reported methods utilize arenethiols as starting
materials which are less accessible, produce unpleasant smell and concern environmental safety.
Therefore, development of a catalytic method which overcomes all above mentioned difficulties
would be highly desirable.
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In recent years, considerable effort has been devoted towards transition metal catalyzed C(aryl)-S
bond formation by means of in situ generation of sulfur.9 As a result, construction of sulfur-
containing heterocyclic compounds involving concomitant formation of C-S bonds has been
developed to some extent.10 We have previously used xanthates as coupling partner with aryl
halides under copper catalysis as a means of incorporating sulfur.11 We envisioned a domino
process for the synthesis of thiochromenes through Cu-catalyzed in situ incorporation of sulfur
using easily available and odourless potassium ethyl xanthate as source of sulfur (Scheme 1). In
this strategy, coupling of 2-halobenzaldehyde and xanthate can be achieved by copper catalyst.
Thioester cleavage could occur in the presence of base to generate 2-formylbenzenethiolate
which can undergo sulfa-Michael addition with chalcone followed by aldol reaction and then
base can facilitate the dehydration.
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Scheme 1. Our strategy for Cu-catalyzed domino synthesis of thiochromenes
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RESULTS AND DISCUSSION
Initially, 2-iodobenzaldehyde was reacted with simple chalcone in the presence of 2 equivalents
of potassium ethyl xanthate, 10 mol% of Cu(OAc)2 and 2 equivalents of NaOH in DMSO
o
solvent at 100 C. The reaction proceeded to completion after 14 h, and the desired
thiochromene was isolated in 23% yield (Table 1, entry 1). The structure of 3a was
unambiguously confirmed by single-crystal XRD analysis (see the Supporting Information,
Figure 1). Encouraged by this result, optimization of the reaction was performed with respect to
Cu source, solvents and bases. When Cu(OAc)2 was replaced with other copper salts such as
CuI, CuCl, CuBr2 and CuCl2, the yield was not improved (entries 2-5).
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Table 1. Optimization of reaction conditionsa
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Entry
1
Cu salt
Additive
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
PhMe
Dioxane
CH3CN
DMF
Time (h)
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Yield (%)b
23c
Cu(OAc)2
CuI
2
8c
3
CuCl
7c
4
CuBr2
11c
5
CuCl2
16c
6
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
ndd
ndd
ndd
38c
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DMF
34c
LiOH
DMF
25c
Na2CO3
K3PO4
NaOAc
NaOtBu
Et2NH
DABCO
AgOAc
AgOAc
DMF
21c
DMF
28c
DMF
62c
e
DMF
-
e
DMF
5
-
e
DMF
5
-
DMF
9
79
92f
DMF
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aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), xanthate (1 mmol),
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Cu(OAc)2 (10 mol%), additive (1 mmol), solvent (2 mL), 100 C. Isolated
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yield. The reaction generated a complex mixture from which pure product
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e
could nevertheless be isolated. Starting materials remained. The reaction
generated an complex, inseparable mixture from which pure product could not
be isolated. f1.5 mmol of xanthate and 0.75 mmol of AgOAc were used.
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When the reaction was conducted in different solvents such as toluene, dioxane and acetonitrile,
the thiochromene formation was not observed in these solvents (entries 6-8). Interestingly, the
thiochromene was isolated in 38% yield, when the reaction was carried out in DMF solvent
(entry 9). Further optimization was performed in DMF solvent, as it provided better yield than
DMSO solvent. Replacement of NaOH with other bases such as KOH and LiOH resulted in
lower yield (entries 10 and 11). The starting materials were not consumed completely when
Na2CO3 and K3PO4 were used as base (entries 12 and 13). To our delight, thiochromene was
obtained in 62% yield, when NaOAc was used (entry 14). Other bases such as NaOtBu, Et2NH
and DABCO gave inseparable complex reaction mixtures (entries 15-17). Remarkable
improvement in yield (81%) was observed when AgOAc was employed as base (entry 18). After
studying the reaction condition with respect to temperature, equivalents of Cu(OAc)2, xanthate
and base, the domino reaction provided 92% yield for thiochromene in the presence of 10 mol%
Cu(OAc)2, 3 equivalents of xanthate and 1.5 equivalents AgOAc in DMF at 100 oC (entry 19).
Next, substrate scope of this domino reaction was explored under the optimized reaction
conditions. The domino reaction proceeded smoothly with a variety of other substrates, and the
corresponding thiochromenes were isolated in good yields (Scheme 2). Electron-releasing
substituents on the aryl ring that is attached to alkene part of chalcone facilitated the domino
reaction, and thiochromenes 3b-3e were obtained in good to excellent yields. Chalcones bearing
chloro, bromo and fluoro substituents, importantly at ortho position of aryl ring reacted
effortlessly and provided the corresponding thiochromenes (3f-3h) in good yields.
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Scheme 2. Scope of the domino reaction with respect to 2-iodobenzaldehyde
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Electron-withdrawing group containing chalcone was also tolerated in the domino reaction and
afforded thiochromene 3i in 82% yield. Replacement of the phenyl group that is attached to the
alkene part of the chalcone with naphthyl, thiophenyl and pyridyl groups gave the corresponding
thiochromenes 3j-3l in good to excellent yields. Similarly, electron-releasing and electron-
withdrawing substituents on the aryl ring that is attached to carbonyl part of chalcone were well
tolerated in this domino reaction, and the corresponding thiochromenes 3m-3r were isolated in
decent yields. Chalcones having naphthyl, thiophenyl and methyl groups attached to carbonyl
part reacted easily to give thiochromene 3s, 3t and 3u. Notably, cinnamaldehydes and
crotonaldehyde were found to be effective substrates for this domino reaction (3v-3x). Also, 2-
iodobenzaldehyde having bromo, chloro or methyl substituents offered thiochromenes 3y, 3z and
3aa in excellent yields.
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Subsequently, the domino synthesis of thiochromenes was performed using comparatively less
reactive 2-bromobenzaldehyde 4 as starting material. The domino reaction gave thiochromene in
67% yield under the standard optimized conditions. However, the yield was increased to 81%
when the reaction was conducted at 120 oC (Scheme 3).
Scheme 3. Scope of the domino reaction with respect to 2-bromobenzaldehyde
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The generality of domino synthesis of thiochromenes using less reactive 2-bromobenzaldehyde 4
as starting material was explored with various substituted chalcones. All the substituents were
well tolerated and the corresponding thiochromenes (3a, 3ab, 3i, 3d, 3ac and 3ad) were obtained
in good yields.
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In order to showcase the efficacy of domino synthesis of thiochromenes on gram scale, the
reaction was performed in 5 mmol (1.16 g) scale under standard optimized condition without
altering any reaction parameters (Scheme 4). The reaction proceeded smoothly and provided the
thiochromene in 86% yield.
Scheme 4. Gram-scale synthesis
To gain insight into the possible reaction pathway, control experiments were performed. When
the domino reaction was performed without AgOAc, formation of thiochromene 3a was not
observed, instead thiochromane 5a was isolated in 19% yield as mixture of two diastereomers
along with diarylsulfide 6a (32% yield) (Scheme 5a). Also, thiochromene 3a formation was not
observed in the absence of both Cu(OAc)2 and AgOAc (Scheme 5b).
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Scheme 5. Control experiments
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These experiments reveal that Cu(OAc)2 promotes C(aryl)-S coupling but the Lewis acidity is not
adequate to activate chalcone to undergo sulfa-Michael-aldol reaction. Thus, coupling of in situ
formed 2-formylbenzenethiolate with 2-iodobenzaldehyde might be responsible for the
formation of diarylsulfide 6a. In order to understand the importance of AgOAc, the domino
reaction was performed with other silver salts. The domino reaction with AgBr and Ag2CO3 did
not provide thiochromene 3a instead thiochromane 5a and diarylsulfide 6a (Scheme 5c) were
isolated. The dehydration of thiochromane 5a in the presence of AgOAc gave 11% yield for
product 3a and thiochromane 5a remained without reacting even after 12 hours (Scheme 5d).
These control experiments show that Cu(OAc)2 and AgOAc are essential for the domino reaction
to complete. From these observations, a possible reaction pathway has been proposed as shown
in Scheme 6. Oxidative addition of copper acetate with 2-iodobenzaldehyde may lead to
intermediate A which undergoes ligand exchange with potassium ethyl xanthate to generate
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intermediate B. Subsequently, reductive elimination of intermediate B affords intermediate C
which may undergo thioester cleavage and the reaction of resulting thiolate with chalcone 2a by
Michael-aldol-elimination reaction sequence in the presence of AgOAc to give the product 3a.
Scheme 6. Possible reaction pathway
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CONCLUSION
In summary, we have accomplished the domino synthesis of thiochromenes using Cu-catalyzed
in situ incorporation of sulfur as a key step. Stable and odourless potassium ethyl xanthate has
been utilized as an efficient sulfur source. The domino methodology proceeds through C(aryl)-S
coupling, thioester cleavage, sulfa-Michael addition, aldol reaction and elimination reaction
sequences to provide thiochromenes in good yields. A variety of thiochromenes have been
synthesized in good to excellent yields from commercially available and easily accessible
starting materials and catalyst. The gram scale synthesis and avoidance of foul-smelling
arenethiols make this domino process practical and environmentally friendly.
EXPERIMENTAL SECTION
General information. All reactions were carried out in oven-dried reaction tubes. Reactions
were monitored by thin-layer chromatography (TLC) using silica gel 60 F254 precoated plates
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(0.25 mm) and visualized by UV fluorescence. Column chromatography was performed using
Silica gel (particle size: 100-200 mesh) and eluted with hexanes/ethyl acetate mixture. All the
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reactions were carried out in temperature controlled magnetic stirrers. H and C NMR spectra
were recorded on 400 MHz and 500 MHz (100 MHz and 125 MHz for 13C) instrument. 1H NMR
spectra were reported relative to residual CDCl3 (δ 7.26 ppm). When the residual peak is
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overlapping with compound, spectra reported to residual TMS. C NMR were reported relative
to CDCl3 (δ 77.16 ppm). Chemical shifts were reported in parts per million and coupling
constants (J) are reported in Hertz. Melting points were recorded on melting point apparatus and
are corrected with benzoic acid as reference. Infrared spectra were recorded on a FTIR 4000
Series spectrometer using dry KBr pellet. The wave numbers of recorded IR signals are quoted in
cm-1. High resolution mass spectra (HRMS) were recorded on Q-TOF Micro mass spectrometer.
Cu(OAc)2 and potassium ethyl xanthogenate were obtained from commercial source and used
directly as received.
General procedure for the synthesis of thiochromenes. A oven dried reaction tube was loaded
with 2-iodobenzaldehyde (0.5 mmol), chalcone (0.5 mmol), potassium ethyl xanthate (1.5
mmol), AgOAc (1.5 mmol) and Cu(OAc)2 (0.05 mmol) and then DMF (2mL) was added. The
reaction tube was closed with glass-stopper and stirred at 100 ºC (120 ºC in case of 2-
bromobenzaldehyde) for recommended time. The reaction mixture was brought to room
temperature and diluted with ethyl acetate and then washed with brine. The aqueous layer was
extracted twice with ethyl acetate and the combined organic extractions were dried over
anhydrous Na2SO4. Solvent was removed under reduced pressure and the residue was purified by
silica gel column using hexanes/ethyl acetate (90:10, v/v) mixture to afford the thiochromene.
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[2-(Phenyl)-2H-thiochromen-3-yl](phenyl)methanone (3a). 152mg, 92% yield; pale yellow solid;
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mp 156-158 C; Rf 0.52 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.48 (s,
1H), 7.10-7.15 (m, 1H), 7.17-7.30 (m, 8H), 7.39 (s, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.56 (tt, J = 7.6
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Hz, 2.4 Hz, 1H), 7.69 (d, J = , 7.8 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 40.3, 125.8, 126.7,
127.8, 127.9, 128.5, 128.8, 129.3, 130.5, 130.9, 131.2, 132.0, 132.8, 133.3, 138.2, 140.1, 142.0,
195.8; FTIR (KBr) 3056, 1644, 1586, 1559, 1490, 758 cm-1; HRMS (m/z) calculated for
C22H17OS [M+H]+ : 329.1000; found: 329.1018.
[2-(p-Tolyl)-2H-thiochromen-3-yl](phenyl)methanone (3b). 139 mg, 81% yield; pale yellow
solid; mp 117-119 oC; Rf 0.41 (5% ethyl acetate in hexanes); 1H NMR (CDCl3, 400 MHz) δ 2.17
(s, 3H), 5.36 (s, 1H), 6.93 (d, J = 6.4 Hz, 2H), 7.04 (td, J = 6.2 Hz, 1.2Hz, 1H), 7.08 (d, J = 6.4
Hz, 2H), 7.13-7.18 (m, 3H), 7.30 (s, 1H), 7.38 (t, J = 6.4 Hz, 2H), 7.48 (tt, J = 6.0 Hz, 1.6 Hz,
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1H), 7.62 (d, J = 6.4 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 21.2, 40.1, 125.7, 126.6, 127.8,
128.5, 129.3, 129.5, 130.5, 130.9, 131.1, 132.0, 132.8, 133.5, 137.5, 138.2, 139.1, 140.0, 195.9;
FTIR (KBr) 3054, 1641, 1507, 1441, 754 cm-1; HRMS (m/z) calculated for C23H19OS [M+H]+ :
343.1157; found: 343.1135.
[2-(4-(Methylthio)phenyl)-2H-thiochromen-3-yl](phenyl)methanone (3c). 162 mg, 86% yield;
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yellowish viscous liquid; Rf 0.39 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ
2.39 (s, 3H), 5.42 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 6.6 Hz, 2.4 Hz, 1H), 7.19 (d, J =
8.4 Hz, 2H), 7.22-7.28 (m, 3H), 7.38 (s, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H),
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7.69 (d, J = 7.2 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 15.8, 39.9, 125.8, 126.8, 127.2, 127.8,
128.5, 129.3, 130.5, 130.9, 131.2, 132.0, 132.6, 133.2, 138.0, 138.1, 138.8, 140.1, 195.8; FTIR
(KBr) 3059, 1642, 1583, 1486, 1556, 754 cm-1; HRMS (m/z) calculated for C23H18ONaS2
[M+Na]+ : 397.0698; found: 397.0691.
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[2-(3-Methoxyphenyl)-2H-thiochromen-3-yl](phenyl)methanone (3d). 164 mg, 91% yield;
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yellow solid; mp 147-149 C; Rf 0.36 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400
MHz) δ 3.68 (s, 3H), 5.45 (s, 1H), 6.71 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.82 (s, 1H), 6.87 (d, J =
8.0 Hz, 1H), 7.08-7.15 (m, 2H), 7.19-7.27 (m, 3H), 7.38 (s, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.55 (t,
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J = 7.6 Hz, 1H), 7.69 (d, J = 7.2 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 40.2, 55.2, 112.6,
113.1, 119.1, 125.8, 127.7, 128.5, 129.3, 129.8, 130.5, 130.9, 131.2, 132.0, 132.8, 133.3, 138.2,
140.2, 143.5, 159.8, 195.8; FTIR (KBr) 3056, 2834, 1641, 1600, 1556, 1487, 755 cm-1; HRMS
(m/z) calculated for C23H19O2S [M+H]+ : 359.1106; found: 359.1125
[2-(3,4,5-Trimethoxyphenyl)-2H-thiochromen-3-yl](phenyl)methanone (3e). 157 mg, 75% yield;
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brownish viscous liquid; Rf 0.54 (30% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ
3.67 (s, 6H), 3.76 (s, 3H), 5.40 (s, 1H), 6.51 (s, 2H), 7.12-7.17 (m, 1H), 7.26-7.29 (m, 2H), 7.32
(d, J = 7.2 Hz, 1H), 7.39 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.58 (tt, J = 7.6 Hz, 1.6 Hz, 1H), 7.71
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(dd, J = 8.4 Hz, 1.6 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 40.6, 56.0, 60.9, 103.7, 125.9,
127.9, 128.6, 129.3, 130.6, 131.2, 132.1, 132.9, 133.8, 137.5, 137.6, 138.1, 139.9, 153.2, 195.9;
FTIR (KBr) 3051, 2862, 1647, 1592, 1541, 1436, 751 cm-1; HRMS (m/z) calculated for
C25H22O4NaS [M+Na]+ : 441.1137; found: 441. 1153.
[2-(4-Chlorophenyl)-2H-thiochromen-3-yl](phenyl)methanone (3f): 151 mg, 83% yield; yellow
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viscous liquid; Rf 0.65 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.41 (s,
1H), 7.13-7.23 (m, 5H), 7.24-7.27 (m, 3H), 7.41 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.57 (tt, J = 7.6
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Hz, 2.0 Hz, 1H), 7.69 (d, J = 7.2 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 39.8, 126.0, 127.8,
128.1, 128.6, 128.9, 129.3, 130.4, 131.0, 131.4, 132.1, 132.4, 133.0, 133.6, 138.0, 140.4, 140.5,
195.7; FTIR (KBr) 3038, 1651, 1613, 1578, 1476, 818, 757 cm-1; HRMS (m/z) calculated for
C22H15OClNaS [M+Na]+ : 385.0424; found: 385.0432.
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[2-(2-Bromophenyl)-2H-thiochromen-3-yl](phenyl)methanone (3g). 155 mg, 76% yield; pale
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yellow solid; mp 148-150 C; Rf 0.38 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400
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7.2 Hz, 2H), 7.54-7.62 (m, 3H), 7.72 (d, J = 7.2 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 40.0,
122.9, 126.0, 127.6, 127.7, 128.2, 128.6, 129.1, 129.3, 130.5, 131.0, 131.4, 132.1, 132.2, 132.5,
133.8, 137.9, 139.6, 141.8, 195.2; FTIR (KBr) 3059, 1641, 1585, 1556, 1461, 1109, 754 cm-1;
HRMS (m/z) calculated for C22H15OBrNaS [M+Na]+ : 428.9919; found: 428.9929.
[2-(2-Fluorophenyl)-2H-thiochromen-3-yl](phenyl)methanone (3h). 137 mg, 79% yield;
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yellowish viscous liquid; Rf 0.41 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ
5.77 (s, 1H), 6.88 (t, J = 7.6 Hz, 1H), 7.00-7.07 (m, 2H), 7.10-7.16 (m, 2H), 7.18-7.23 (m, 2H),
7.27 (d, J = 7.0 Hz, 1H), 7.43-7.52 (m, 3H), 7.56 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 6.8 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 33.3 (d, J = 3.9 Hz), 116.0 (d, J = 21.6 Hz), 124.1(d, J = 3.7 Hz),
125.9, 127.7 (d, J = 3.0 Hz), 127.9, 128.5, 128.6 (d, J = 11.5 Hz), 129.3 (d, J = 7.8 Hz), 129.4,
130.4, 130.9, 131.3, 131.7, 132.1, 132.6, 137.9, 141.3, 159.1(d, J = 246.9 Hz), 195.2; FTIR
(KBr) 3056, 1641, 1598, 1583, 1436, 1264, 754 cm-1; HRMS (m/z) calculated for C22H15OFNaS
[M+Na]+ : 369.0725; found: 369.0722.
[2-(4-(Trifluoromethyl)phenyl)-2H-thiochromen-3-yl](phenyl)methanone (3i). 140 mg, 82%
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yield; yellowish viscous liquid; Rf 0.46 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400
MHz) δ 5.39 (s, 1H), 7.06-7.12 (m, 1H), 7.18-7.21 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 7.37-7.44
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(m, 5H), 7.51 (tt, J = 7.6 Hz, 2.4 Hz, 1H), 7.63 (dd, J = 8.2 Hz, 1.6 Hz, 2H); C NMR (CDCl3,
100 MHz) δ 40.0, 124.1 (q, J = 270.2 Hz), 125.7 (q, J = 3.7 Hz), 126.1, 127.1, 127.8, 128.6,
129.3, 129.8 (q, J = 32.2 Hz), 130.4, 131.1, 131.5, 132.16, 132.19, 132.6, 137.9, 140.8, 145.8,
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195.5; FTIR (KBr) 3064, 1641, 1617, 1597, 1446, 1325, 1120, 754 cm-1; HRMS (m/z) calculated
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for C23H15OSNaF3 [M+Na]+ : 419.0693; found: 419.0705.
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[2-(Naphthalen-1-yl)-2H-thiochromen-3-yl](phenyl)methanone (3j). 178 mg, 94% yield; yellow
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viscous liquid; Rf 0.40 (5% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 6.34 (s,
1H), 7.09-7.25 (m, 5H), 7.34 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.46-7.61 (m, 4H), 7.62-7.68 (m, 2H),
7.70 (d, J = 7.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.85 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 8.4 Hz,
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1H); C NMR (CDCl3, 100 MHz) δ 35.8, 123.4, 124.4, 125.2, 125.88, 125.93, 126.7, 128.2,
128.5, 128.6, 129.2, 129.4, 129.7, 130.4, 131.1, 131.2, 132.0, 132.8, 133.2, 134.7, 135.7, 138.2,
141.6, 195.5; FTIR (KBr) 3056, 1641, 1594, 1554, 1441, 754 cm-1; HRMS (m/z) calculated for
C26H18ONaS [M+Na]+ : 401.0971; found: 401.0973.
[2-(Thiophen-2-yl)-2H-thiochromen-3-yl](phenyl)methanone (3k). 125 mg, 74% yield;
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brownish viscous liquid; Rf 0.35 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ
5.76 (s, 1H), 6.81 (t, J = 3.6 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 7.15 (t, J
= 7.6 Hz, 1H), 7.24-7.30 (m, 2H), 7.31-7.36 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.57 (t, J = 7.2 Hz,
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1H), 7.73 (d, J = 7.2 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 35.7, 124.8, 125.0, 126.0, 126.8,
128.1, 128.5, 129.4, 130.4, 131.1, 131.2, 132.1, 132.5, 133.8, 138.1, 139.8, 145.4, 195.4; FTIR
(KBr) 3059, 1640, 1590, 1553, 1445, 754 cm-1; HRMS (m/z) calculated for C20H14ONaS2
[M+Na]+ : 357.0378; found: 357.0381.
[2-(Pyridin-2-yl)-2H-thiochromen-3-yl](phenyl)methanone (3l). 148 mg, 90% yield; brownish
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viscous liquid; Rf 0.41 (20% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.57 (s,
1H), 7.05-7.13 (m, 2H), 7.19 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.22-7.28 (m, 3H), 7.43 (s, 1H), 7.45-
7.54 (m, 3H), 7.57 (tt, J = 7.2 Hz, 2.0 Hz, 1H), 8.48 (ddd, J = 4.8 Hz, 1.6 Hz, 0.8 Hz, 1H), 7.79
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(dd, J = 8.2 Hz, 1.6 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 42.4, 121.0, 122.3, 125.8, 127.6,
128.5, 129.6, 130.7, 130.9, 131.0, 132.1, 132.5, 132.9, 136.8, 138.1, 140.6, 149.7, 160.2, 195.9;
FTIR (KBr) 3056, 1641, 1585, 1465, 751 cm-1; HRMS (m/z) calculated for C21H15ONNaS
[M+Na]+ : 352.0767; found: 352.0772.
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(2-Phenyl-2H-thiochromen-3-yl)(p-tolyl)methanone (3m). 147 mg, 86% yield; yellow viscous
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liquid; Rf 0.36 (5% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 2.43 (s, 3H), 5.46
(s, 1H), 7.12 (td, J = 6.0 Hz, 1.2 Hz, 1H), 7.16-7.22 (m, 3H), 7.23-7.29 (m, 7H), 7.38 (s, 1H),
7.62 (d, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.7, 40.5, 125.8, 126.7, 127.72,
127.74, 128.8, 129.2, 129.6, 130.6, 130.8, 131.0, 132.7, 133.5, 135.4, 139.5, 142.1, 142.8, 195.6;
FTIR (KBr) 3046, 1642, 1596, 1543, 1472, 753 cm-1; HRMS (m/z) calculated for C23H18ONaS
[M+Na]+ : 365.0976; found: 365.0965.
(2-Phenyl-2H-thiochromen-3-yl)(3-bromophenyl)methanone (3n). 159 mg, 78% yield; brownish
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viscous liquid; Rf 0.45 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.43 (s,
1H), 7.11-7.16 (m, 1H), 7.17-7.22 (m, 3H), 7.23-7.28 (m, 5H), 7.33 (t, J = 6.0 Hz, 1H), 7.38 (s,
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1H), 7.58 (d, J = 6.0 Hz, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.80 (s, 1H); C NMR (CDCl3, 100
MHz) δ 40.2, 122.8, 125.9, 126.7, 127.7, 127.8, 127.9, 128.8, 130.0, 130.3, 131.1, 131.5, 132.0,
132.9, 133.0, 134.8, 140.1, 140.8, 141.8, 194.2; FTIR (KBr) 3059, 1643, 1617, 1557, 1436,
1112, 758 cm-1; HRMS (m/z) calculated for C22H16OBrS [M+H]+ : 407.0100; found: 407.0103.
(2-Phenyl-2H-thiochromen-3-yl)(4-chlorophenyl)methanone (3o). 150 mg, 82% yield; yellow
solid; mp 144-146 oC; Rf 0.48 (5% ethyl acetate in hexanes); 1H NMR (CDCl3, 400 MHz) δ 5.43
(s, 1H), 7.13 (td, J = 8.4 Hz, 2.4 Hz, 1H), 7.16-7.23 (m, 3H), 7.23-7.28 (m, 5H), 7.35 (s, 1H),
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7.44 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 40.3, 125.9,
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126.7, 127.8, 127.9, 128.8, 130.3, 130.7, 131.0, 131.4, 132.9, 133.1, 136.5, 138.4, 140.1, 141.9,
194.6; FTIR (KBr) 3060, 1648, 1616, 1586, 1487, 828, 761 cm-1; HRMS (m/z) calculated for
C22H15OClNaS [M+Na]+ : 385.0424; found: 385.0429.
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(2-Phenyl-2H-thiochromen-3-yl)(4-fluorophenyl)methanone (3p). 129 mg, 74% yield; yellow
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viscous liquid; Rf 0.45 (5% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.35 (s,
1H), 7.01-7.07 (m, 3H), 7.07-7.13 (m, 3H), 7.14-7.20 (m, 5H), 7.26 (s, 1H), 7.61-7.67 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 40.5, 115.7 (d, J = 21.7 Hz), 125.8, 126.7, 127.7, 127.8, 128.8,
130.4, 130.9, 131.2, 131.8 (d, J = 9.0 Hz), 132.8, 133.2, 134.3 (d, J = 3.3 Hz), 139.7, 141.9,
165.1 (d, J = 251.8 Hz), 194.4; FTIR (KBr) 3054, 1643, 1560, 1421, 751 cm-1; HRMS (m/z)
calculated for C22H15OFNaS [M+Na]+ : 369.0725; found: 369.0727.
(2-Phenyl-2H-thiochromen-3-yl)[4-(trifluoromethyl)phenyl]methanone (3q). 132 mg, 66%
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yield; yellow viscous liquid; Rf 0.48 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400
MHz) δ 5.39 (s, 1H), 7.05-7.10 (m, 1H), 7.11-7.17 (m, 3H), 7.18-7.21 (m, 5H), 7.28 (s, 1H),
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7.64-7.72 (m, 4H); C NMR (CDCl3, 125 MHz) δ 40.0, 123.7 (q, J = 270.9 Hz), 125.5 (q, J =
3.6 Hz), 125.9, 126.6, 127.7, 127.9, 128.8, 129.4, 130.1, 131.1, 131.6, 132.8, 132.9,133.2 (q, J =
32.5 Hz), 141.1, 141.4, 141.8, 194.5; FTIR (KBr) 3058, 1647, 1617, 1585, 1406, 1324, 1129,
752 cm-1; MS (m/z): HRMS (m/z) calculated for C23H15OF3NaS [M+Na]+ : 419.0688; found:
419.0693.
(2-Phenyl-2H-thiochromen-3-yl)(naphthalen-2-yl)methanone (3r). 160 mg, 84% yield; yellow
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viscous liquid; Rf 0.70 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.51 (s,
1H), 7.08 (t, J = 7.2 Hz, 1H), 7.15-7.27 (m, 6H), 7.32 (d, J = 7.2 Hz, 2H), 7.45 (s, 1H), 7.49-
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7.59 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.84-7.92 (m, 3H), 8.18 (s, 1H); C NMR (CDCl3, 100
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MHz) δ 40.5, 125.6, 125.8, 126.7, 126.9, 127.7, 127.8, 127.9, 128.2, 128.5, 128.8, 129.3, 130.2,
130.5, 130.9, 131.1, 132.4, 132.8, 133.5, 135.0, 135.4, 140.1, 142.0, 195.7; FTIR (KBr) 3056,
1640, 1584, 1555, 1490, 758 cm-1; HRMS (m/z) calculated for C26H19OS [M+H]+ : 379.1157;
found: 379.1164.
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(2-Phenyl-2H-thiochromen-3-yl)(thiophen-2-yl)methanone (3s). 115 mg, 68% yield; yellow
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viscous liquid; Rf 0.40 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.38 (s,
1H), 7.12-7.20 (m, 5H), 7.22-7.29 (m, 4H), 7.33 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 5.0 Hz, 1.2
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Hz, 1H), 7.68 (s, 1H), 7.71 (dd, J = 3.6 Hz, 1.2 Hz, 1H); C NMR (CDCl3, 100 MHz) δ 40.9,
125.9, 126.8, 127.8, 127.9, 128.8, 130.5, 130.7, 131.0, 132.6, 133.4, 133.6, 133.7, 137.8, 141.8,
143.1, 186.7; FTIR (KBr) 3058, 1617, 1584, 1553, 1411, 759 cm-1; HRMS (m/z) calculated for
C20H15OS2 [M+H]+ : 335.0564; found: 335.0557.
1-(2-Phenyl-2H-thiochromen-3-yl)ethan-1-one (3t). 112 mg, 84% yield; yellow viscous liquid;
Rf 0.42 (10% ethyl acetate in hexanes); 1H NMR (CDCl3, 400 MHz) δ 2.48 (s, 3H), 5.36 (s, 1H),
7.14-7.20 (m, 6H), 7.23-7.26 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 25.7, 38.9, 125.8, 126.7, 127.7, 127.8, 128.7, 130.6, 130.9, 131.2, 133.0, 134.1,
137.5, 142.1, 196.6; FTIR (KBr) 3058, 2924, 1659, 1622, 1584, 1438, 754 cm-1; HRMS (m/z)
calculated for C17H14ONaS [M+Na]+ : 289.0663; found: 289.0687.
2-Phenyl-2H-thiochromene-3-carbaldehyde (3u).8a 123 mg, 97% yield; pale yellow viscous
liquid; Rf 0.44 (10% ethyl acetate in hexanes); 1H NMR (CDCl3, 400 MHz) δ 5.21 (s, 1H), 7.16-
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7.22 (m, 6H), 7.27 (t, J = 7.2 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 9.67 (s, 1H); C
NMR (CDCl3, 100 MHz) δ 38.5, 126.0, 126.6, 127.8, 128.0, 128.8, 130.0, 131.1, 131.9, 134.3,
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calculated for C16H12OKS [M+K]+ : 291.0246; found: 291.0245.
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2-Phenyl-2H-thiochromene-3-carbaldehyde (3v). 131 mg, 98% yield; yellow viscous liquid; Rf
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0.47 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 2.16 (s, 3H), 5.10 (s, 1H),
6.92 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 7.08-7.13 (m, 1H), 7.16-7.21 (m, 2H), 7.33 (d,
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J = 7.2 Hz, 1H), 7.37 (s, 1H), 9.58 (s, 1H); C NMR (CDCl3, 100 MHz) δ 21.2, 38.3, 125.9,
126.5, 127.8, 129.5, 130.0, 131.1, 131.8, 134.3, 135.0, 137.8, 138.9, 145.2, 191.4; FTIR (KBr)
3056, 2934, 1665, 1593, 1564, 1427, 753 cm-1; HRMS (m/z) calculated for C17H14ONaS
[M+Na]+ : 289.0663; found: 289.0670.
2-Methyl-2H-thiochromene-3-carbaldehyde (3w). 77 mg, 81% yield; yellow viscous liquid; Rf
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0.50 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 1.29 (d, J = 7.2 Hz, 3H),
4.08 (q, J = 7.2 Hz, 1H), 7.18 (td, J = 7.4 Hz, 1.2 Hz, 1H), 7.23 (s, 1H), 7.30 (td, J = 7.2 Hz, 1.6
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Hz, 1H), 7.33-7.37 (m, 2H), 9.61 (s, 1H); C NMR (CDCl3, 100 MHz) δ 22.3, 30.4, 125.8,
128.4, 130.0, 131.0, 131.5, 134.2, 138.0, 144.3, 191.3; FTIR (KBr) 3057, 2813, 1673, 1584,
1556, 1439, 751 cm-1; HRMS (m/z) calculated for C11H10ONaS [M+Na]+ : 213.0350; found:
213.0348.
(6-Bromo-2-phenyl-2H-thiochromen-3-yl)(phenyl)methanone (3x). 176 mg, 86% yield; yellow
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viscous liquid; Rf 0.58 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.44 (s,
1H), 7.09 (d, J = 8.4 Hz, 1H), 7.15-7.23 (m, 5H), 7.26 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.37 (s,
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1H), 7.42 (t, J = 7.6 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H); C NMR
(CDCl3, 100 MHz) δ 40.4, 118.8, 126.7, 128.0, 128.6, 128.8, 128.9, 129.1, 129.3, 131.8, 132.3,
133.1, 133.7, 134.5, 137.9, 138.4, 141.5, 195.6; FTIR (KBr) 3057, 1643, 1537, 1491, 1448,
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(6-Chloro-2-phenyl-2H-thiochromen-3-yl)(phenyl)methanone (3y). 146 mg, 80% yield; yellow
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viscous liquid; Rf 0.32 (5% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.48 (s,
1H), 7.18-7.29 (m, 8H), 7.31 (s, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.56 (tt, J = 7.6 Hz, 2.4 Hz, 1H),
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7.68 (dd, J = 8.2 Hz, 1.6 Hz, 2H); C NMR (CDCl3, 100 MHz) δ 40.4, 126.7, 128.0, 128.6,
128.8, 128.9, 129.3, 130.2, 130.8, 131.1, 131.2, 131.9, 132.3, 134.5, 137.8, 138.6, 141.4, 195.6;
FTIR (KBr) 3054, 1641, 1564, 1501, 1468, 821, 736 cm-1; HRMS (m/z) calculated for
C22H15OClNaS [M+Na]+ : 385.0430; found: 385.0449.
(7-Methyl-2-phenyl-2H-thiochromen-3-yl)(phenyl)methanone (3z). 151 mg, 88% yield; yellow
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viscous liquid; Rf 0.62 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 2.19 (s,
3H), 5.37 (s, 1H), 6.94-7.00 (m, 2H), 7.03-7.13 (m, 4H), 7.20 (d, J = 7.2 Hz, 2H), 7.28 (s, 1H),
7.37 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 6.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ 20.9, 40.3, 126.7, 127.6, 127.7, 128.4, 128.7, 129.2, 129.3, 130.4, 131.5, 131.9, 132.16,
133.4, 135.5, 138.2, 140.5, 142.0, 195.9; FTIR (KBr) 3052, 2920, 1673, 1584, 1555, 1438, 751
cm-1; HRMS (m/z) calculated for C23H19OS [M+H]+ : 343.1157; found: 343.1129.
[2-(4-Fluorophenyl)-2H-thiochromen-3-yl](phenyl)methanone (3aa). 122 mg, 70% yield; yellow
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viscous liquid; Rf 0.50 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) δ 5.36 (s,
1H), 6.80 (tt, J = 10.8 Hz, 2.4 Hz, 2H), 7.03-7.08 (m, 1H), 7.13-7.19 (m, 5H), 7.32 (s, 1H), 7.39
(t, J = 7.2 Hz, 2H), 7.48 (tt, J = 7.2 Hz, 1.2 Hz, 1H), 7.61 (dd, J = 8.2 Hz, 1.6 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 39.7, 115.6 (d, J = 21.4 Hz), 125.9, 127.8, 128.4 (d, J = 8.1 Hz), 128.5,
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129.3, 130.4, 131.0, 131.3, 132.1, 132.5, 133.3, 137.9 (d, J = 3.2 Hz), 138.1, 140.2, 162.3 (d, J =
244.7 Hz), 195.8; FTIR (KBr) 3053, 1648, 1598, 1564, 1423, 1198, 751 cm-1; HRMS (m/z)
calculated for C22H15OFNaS [M+Na]+ : 369.0720; found: 369.0721.
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[2-(6-Methoxynaphthalen-1-yl)-2H-thiochromen-3-yl](phenyl)methanone (3ab). 159 mg, 78%
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yield; brownish viscous liquid; Rf 0.32 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400
MHz) δ 3.78 (s, 3H), 5.53 (s, 1H), 6.93-7.01 (m, 2H), 7.05 (td, J = 6.8 Hz, 1.6 Hz, 1H), 7.11-
7.17 (m, 2H), 7.21(d, J = 7.6 Hz, 1H), 7.31-7.41 (m, 4H), 7.44-7.55 (m, 4H), 7.63 (d, J = 7.6 Hz,
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2H); C NMR (CDCl3, 100 MHz) δ 40.5, 55.4, 105.7, 118.9, 125.2, 125.76, 125.79, 127.7,
127.8, 128.5, 128.7, 129.3, 129.7, 130.5, 131.0, 131.2, 132.0, 132.8, 133.2, 134.2, 136.9, 138.2,
140.2, 157.9, 195.9; FTIR (KBr) 3056, 2933, 1638, 1505, 1481, 1441, 754 cm-1; HRMS (m/z)
calculated for C27H20O2NaS [M+Na]+ : 431.1082; found: 431.1079.
(2-Phenyl-2H-thiochromen-3-yl)(benzo[d][1,3]dioxol-5-yl)methanone (3ac). 138 mg, 74%
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yield; brownish viscous liquid; Rf 0.35 (10% ethyl acetate in hexanes); H NMR (CDCl3, 400
MHz) δ 5.34 (s, 1H), 5.98 (q, J = 0.8 Hz, 2H), 6.80 (d, J = 6.4 Hz, 1H), 7.07 (td, J = 5.8 Hz, 1.2
Hz, 1H), 7.10-7.15 (m, 3H), 7.15-7.20 (m, 6H), 7.25 (dd, J = 6.4 Hz, 1.2 Hz, 1H), 7.29 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 40.8, 101.9, 108.0, 109.7, 125.5, 125.8, 126.7, 127.7, 127.8,
128.8, 130.5, 130.7, 131.0, 132.3, 132.6, 133.5, 138.7, 142.0, 148.0, 151.3, 194.2; FTIR (KBr)
3064, 2920, 1636, 1605, 1503, 1439, 761 cm-1; HRMS (m/z) calculated for C23H17O3S [M+H]+ :
373.0898; found: 373.0879.
ACKNOWLEDGMENT
We thank the DST New Delhi (Project No. SB/S1/OC-72/2013) for financial support. NS thanks
CSIR for fellowship.
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SUPPORTING INFORMATION
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1H and 13C NMR spectra. Crystallography data.
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REFERENCES
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