An efficient and catalyst free methylthiolation of 4-(bromomethyl)-2H-chromen-2-ones with DMSO

Article abstract of DOI:10.1080/10426507.2017.1290628

The first simple, metal free, and efficient protocol has been established for the methylthiolation of structurally diverse 4-bromomethyl-2H-chromen-2-ones using dimethyl sulfoxide (DMSO) as methylthiolation source at higher temperature. The experimental m

Full text of DOI:10.1080/10426507.2017.1290628

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
An efficient and catalyst free methylthiolation of
4-(bromomethyl)-2H-chromen-2-ones with DMSO
Bahubali M. Chougala, S Samundeeswari, Megharaja Holiyachi, Nirmala S.
Naik, Lokesh A. Shastri & Vinay A Sunagar
To cite this article: Bahubali M. Chougala, S Samundeeswari, Megharaja Holiyachi, Nirmala S.
Naik, Lokesh A. Shastri & Vinay A Sunagar (2017): An efficient and catalyst free methylthiolation of
4-(bromomethyl)-2H-chromen-2-ones with DMSO, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2017.1290628
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1290628
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An efficient and catalyst free methylthiolation of 4-(bromomethyl)-2H-chromen-2-ones with
DMSO
1
1
1
1
Bahubali M. Chougala, Samundeeswari S, Megharaja Holiyachi, Nirmala S. Naik, Lokesh A.
1
,*
2
Shastri, Vinay A Sunagar
1
Department of Chemistry, Karnatak University, Dharwad, 580 003, Karnataka, India.
2
*
Department of Chemistry, G.S.S. College, Belagavi, Karnataka, India.
Corresponding author: E-mail: drlashastri@kud.ac.in (Lokesh A. Shastri)
ABSTRACT
The first simple, metal free and efficient protocol has been established for the methylthiolation of
structurally diverse 4-bromomethyl-2H-chromen-2-ones using dimethyl sulfoxide (DMSO) as
methylthiolation source at higher temperature. The experimental method is highly economical
and provides excellent yields of highly pure products which do not require further purification.
1
13
All novel 4-[(methylthio)methyl]-2H-chromen-2-ones were characterized by H, C NMR and
single-crystal X-ray analysis.
GRAPHICAL ABSTRACT
1
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Keywords
4
-Bromomethyl-2H-chromen-2-one,
4-[(methylthio)methyl]-2H-chromen-2-one,
DMSO,
methylthiolation.
2
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Introduction
Thioethers are very useful as synthetic intermediates with numerous features in organic
and medicinal chemistry mainly involving synthesis of heterocycles which exhibit diverse
1
, 2
biological activities. Generally, the synthesis of thioethers involves the condensation of a thiol
3
(
disulfide) with a halide in the presence of a base. On the other hand thiols are malodorous, and
handling requires more safety precautions. Therefore, the synthesis of thioethers from thiols
sometimes is disadvantageous. Thiols are commonly synthesized by the reaction of halides with
4
a source of sulfur, typically sodium hydrosulfide or thiourea derivatives. Symmetrical benzyl
thioethers were achieved using sodium hydrosulfide and benzyl bromide with less satisfactory
5
results. Moreover, gaining good quality of products with excellent yield is challenging. In the
recent development, various methodologies have been used for carbon-sulfur bond formation.
For instance, the cross-coupling reaction of thiols and aryl halides with metal catalyst has been
6
achieved with significant increase in the yield and purity of the compound.
Simple methods for the synthesis of aryl methyl thioethers involve reduction of
7
8
sulfoxide, or reaction of aryl halides with dimethyl disulfide. DMSO has been used as
9
oxidizing agent to convert alkyl/aryl halides to aldehydes. Recently, DMSO has been used for
1
0
ortho-methylthiolation of 2-arylpyridine and C-H thiolation of heteroarenes. However, the
utility is confined to heteroarene substrates. An important progress in this field using CuI as a
1
1
2
catalyst and ZnF as a promoter has been reported by Cheng et al. The methylthiolation of
heteroaryl alkyl halides reported so far involve the use of various metals as catalysts. Hence, here
we report a new, simple and efficient methodology for the heteroaryl alkyl methylthiolation of 4-
3
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(
bromomethyl)-2H-chromen-2-ones (1) to 4-[(methylthio)methyl]-2H-chromen-2-ones (2) using
DMSO as the thiomethylation agent.
Results and Discussion
The early reported methods for the methylthiolation of aryl halides using the transition-
1
2
metal by selective functionalization of C-H bonds was applied to C-S bond formation.
Recently, the transition metal catalyzed thiolation reaction via cleavage of S-S bond has been
1
3
well developed. However, DMSO decomposes slightly to MeSH and MeSSMe at elevated
1
4
temperature. In light of all the above work, the present study for the methylthiolation of
substituted 4-(bromomethyl)-2H-chromen-2-ones was aimed to find the best transformation by
use of dry DMSO as the terminal methylthiolation source (Scheme 1). The transformation has
been confirmed by spectral analysis and, in some cases, by single crystal X-ray structure
analysis.
We further optimized the reaction conditions with respect to time and temperature, taking
1
a as the substrate. Table 1 clearly indicates that at a lower temperature the product is not formed
(entry 1), whereas with gradual increase of the temperature from 80 to 150°C, the reaction
proceeds faster with a significant increase in the yield (entry 2-6). The results of the optimized
reaction are tabulated in Table 1. This approach clearly demonstrates that transition metal
catalysts and fluorides are not essential for achieving methylthiolation. Moreover, these studies
prove that the thermal condition is a comparatively better promoter than he use of metal
fluorides.
From the optimized conditions, we further examined the scope of methylthiolation for
1
5
various 4-(bromomethyl)-2H-chromen-2-ones (1) to the corresponding 4-[(methylthio)methyl]-
4
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2
H-chromen-2-ones (2a-2i), which were achieved in excellent yields. Similarly, thiomethylation
of benzyl bromide was also performed at optimized reaction condition, and the results obtained
1
13
are summarized in Table 2. All isolated compounds have been characterized by H NMR, C
NMR spectra and some of them by single crystal X-ray diffraction study. The IR spectrum of

1
1
compound 2a showed a stretching band at 1716 cm due to the lactone carbonyl group. The H
NMR spectrum of 2a showed a doublet at 7.50 ppm (J = 1.2 Hz) due to C5-H of the coumarin,
and C7-H of coumarin resonated as a doublet of doublets at 7.44 ppm (J = 8.4 Hz and 1.6 Hz)
respectively. The additional doublet observed at 7.30 ppm (J = 8.4 Hz) is due to C8-H of
coumarin. The singlet at 6.23 ppm due to C3-H and three singlets resonating at 3.16, 2.36 and
1
3
2
.08 are due to C4-CH
2 3 3
, C6-CH and S-CH , respectively. In the case of C NMR all carbon
atomss show signals in the expected region.
A plausible mechanism for the methylthiolation reaction is illustrated in Scheme 2.
Initially, the excess amount of DMSO decomposes at higher temperatures to yield
16
(
methylsulfonyl)methane and dimethylsulfane. Dimethylsulfane further reacts with alkyl halide
via S 2 reaction to form a alkyldimethylsulfanyl cation, which by elimination of a methyl
N
carbocation leads to the desired compound.
X-Ray Diffraction Studies
Single crystals of compound 2g were grown by slow evaporation of a methanol solution.
A suitable crystal was selected by use of a polarizing microscope and was mounted on a Mitegen
Micromount on a ‘Bruker APEX-II CCD’ diffractometer. The data were collected from the
diffractometer at 296.16 K using graphite-monochromated MoKα radiation (λ = 0.71073 Å).
1
7
Bruker SAINT software package with a narrow-frame algorithm was applied by using Olex2.
5
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1
8
The structure was solved with the ShelXT structure solution program by direct methods and
1
9
refined with the ShelXL
refinement package by Least Squares minimization. The
crystallographic information file (CIF) has been deposited at Cambridge Crystallographic Data
Centre (CCDC); the CCDC number of compound 2g is 1479809.
X-ray studies and molecular structure of the compound 2g (Figure 1) revealed that it
exists in the crystal phase as a planar molecule. The crystal structure data and refinement
parameters of 2g are presented in Table 3. Tables of bond lengths and angles are presented in the
Supplemental Materials (Tables S 1 -- S 7).
Conclusions
In conclusion, we developed a novel and efficient method for the methylthiolation of 4-
(
bromomethyl)-2H-chromen-2-ones and benzyl bromide using DMSO under thermal condition.
This method provides a practical approach to access substituted 4-[(methylthio)methyl]-2H-
chromen-2-ones. The simplicity of this method exhibits advantages such as tolerance of various
functional groups in the substrates and less usage of the malodorous reagents during the
transformation.
Experimental
All chemicals were purchased from commercial sources and used without further purification
unless otherwise stated. The reactions were monitored by thin-layer chromatography (TLC)
analysis with Merck Kieselgel 60 F254 plates and visualized using UV light at 254 nm and
KMnO
4
or iodine vapor staining. Also the purity of the compound was checked by TLC. The
1
melting points were determined by the open capillary method and are uncorrected. H NMR and
1
3
C NMR spectra were measured on a Bruker 400 MHz and Jeol solution for innovation 500
6
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1
13
MHz spectrometer (400 MHz for H and 100 MHz for C, respectively, if not stated otherwise)
6
in DMSO-d as solvent. Chemical shifts δ are reported in ppm relative to TMS as internal
standard (δ = 0.00). The X-ray diffraction studies were performed on a BRUKER AXS SMART
APEX CCD diffractometer. The mass spectra were measured on a Shimadzu GCMSQP2010SD.
LCMS/MS spectra were obtained using an MPS-SCIEX-API-2000. CHN elemental analyses
were performed with a LECO TRUSPEC CHN analyzer. The Supplemental Materials contains
sample 1H and 13C NMR and IR spectra of compounds 2 (Figures S 1 -- S 25).
General procedure for the synthesis of 4-[(methylthio)methyl]-2H-chromen-2-ones (2a-2i)
A solution of a substituted 4-(bromomethyl)-2H-chromen-2-one (1) (1.0 mmol) in dry DMSO (2
mL) was prepared. The resulting suspension was stirred at room temperature for 10 min and then
heated for ca. 8 h at 150°C on an oil bath equipped with a chilled water circulating condenser.
After the disappearance of the starting material (monitored by TLC), the reaction mixture was
allowed to cool and poured into ice cold water with stirring. The separated solid was filtered and
washed with water. The pure substituted 4-[(methylthio)methyl]-2H-chromen-2-ones (2) was
isolated (80%) as a white solid.
6
-Methyl-4-[(methylthio)methyl]-2H-chromen-2-one (2a)

1 1
Colorless solid; yield 87%; mp 162-165°C; IR (KBr): 1716 cm ; H NMR: δ 7.50 (d, J = 1.2
Hz, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.23 (s, 1H), 3.16 (s, 2H), 2.36
13
(
s, 3H), 2.08 (s, 3H). C NMR: δ 160.15, 156.26, 150.96, 133.47, 132.58, 123.84, 116.91,
+
1
16.19, 110.49, 45.95, 20.31, 18.29. GC-MS (m/z): 220 (M ). Elemental analysis for C12
H
12
O
2
S
(%), calcd: C, 65.43; H, 5.49; found: C, 65.07; H, 5.11.
6
-Bromo-4-[(methylthio)methyl]-2H-chromen-2-one (2b)
7
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
1 1
Colorless solid; yield, 85%; mp 187-190°C; IR (KBr): 1717 cm ; H NMR: δ 7.87 (d, J = 2.4
Hz, 1H), 7.77 (dd, J = 8.8, 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 3.14 (s, 2H), 2.10
1
3
(
s, 3H). C NMR: δ 159.48, 155.45, 151.98, 134.31, 126.78, 119.18, 118.75, 116.19, 111.75,
+
4
5.06, 20.27. GC-MS (m/z): 285 (M ). Elemental analysis for C11
H
9
BrO
2
S (%), calcd: C, 46.33;
H, 3.18; found: C, 45.02; H, 2.81.
-Chloro-4-[(methylthio)methyl]-2H-chromen-2-one (2c)
6

1
1
Colorless solid; yield, 83%; mp 192-195°C; IR (KBr): 1718 cm ; H NMR: δ 7.82 (d, J = 2.4
Hz, 1H), 7.71 (dd, J = 8.4, 2.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.21 (s, 1H), 3.13 (s, 2H), 2.10
1
3
(
s, 3H). C NMR: δ 159.32, 155.38, 151.92, 134.26, 126.72, 119.13, 118.70, 116.17, 111.71,
+
4
4.92, 19.93. GC-MS (m/z): 240 (M ). Elemental analysis for C11
H
9
ClO
2
S (%), calcd: C, 54.89;
H, 3.77; found: C, 54.42; H, 3.41.
-Methoxy-4-[(methylthio)methyl]-2H-chromen-2-one (2d)
Colorless solid; yield, 84%; mp 154-156°C; IR (KBr): 1723 cm ; H NMR (500 MHz): δ 7.35
6

1 1
(d, J = 9.0 Hz, 1H), 7.21 (dd, J = 9.0, 3.0 Hz 1H), 7.11 (d, J = 3.0 Hz, 1H), 6.26 (s, 1H), 3.80 (s,
1
3
3
1
H), 3.16 (s, 2H), 2.08 (s, 3H). C NMR (125 MHz): δ 160.23, 156.28, 155.48, 147.21, 119.02,
+
17.56, 117.50, 110.88, 107.08, 55.76, 44.51, 20.37. GC-MS (m/z): 236 (M ). Elemental analysis
for C12
H
12
O
3
S (%), calcd: C, 61.00; H, 5.12; found: C, 60.72; H, 4.89.
-Methyl-4-[(methylthio)methyl]-2H-chromen-2-one (2e)
Colorless solid; yield, 86%; mp 177-180°C; IR (KBr): 1696 cm ; H NMR: δ 7.35 (s, 1H), 7.14
7

1 1
(dd, J = 8.0, 1.2 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 3.15 (s, 2H), 2.38 (s, 3H), 2.08
1
3
(
s, 3H). C NMR: δ 159.87, 158.88, 154.47, 141.61, 136.49, 129.28, 115.43, 115.09, 110.17,
8
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+
4
6
7
3.98, 23.14, 18.97. GC-MS (m/z): 220 (M ). Elemental analysis for C12
12 2
H O S (%), calcd: C,
5.43; H, 5.49; found: C, 65.08; H, 5.13.
-Hydroxy-4-[(methylthio)methyl]-2H-chromen-2-one (2f)

1 1
Colorless solid; yield, 82%; mp 184-186°C; IR (KBr): 1703 cm ; H NMR (500 MHz): δ 10.51
(br, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.76 (dd, J = 8.5, 2.5 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.22
1
3
(
s, 1H), 3.15 (s, 2H), 2.10 (s, 3H). C NMR (125 MHz): δ 160.63, 158.07, 156.95, 154.85,
+
1
25.49, 112.82, 112.44, 109.54, 106.87, 45.09, 19.89. GC-MS (m/z): 222 (M ). Elemental
analysis for C11
,7-Dimethyl-4-[(methylthio)methyl]-2H-chromen-2-one (2g)
Colorless solid; yield, 85%; mp 198-200°C; IR (KBr): 1716 cm ; H NMR (500 MHz): δ 7.06
10 3
H O S (%), calcd: C, 59.44; H, 4.53; found: C, 59.03; H, 4.10.
5

1 1
1
3
(
s, 1H), 6.98 (s, 1H), 6.21 (s, 1H), 3.11 (s, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 2.03 (s, 3H). C
NMR: δ 159.27, 155.34, 152.32, 141.73, 136.42, 129.64, 115.66, 114.76, 110.88, 44.87, 23.13,
+
2
0.57, 19.68. GC-MS (m/z): 234 (M ). Elemental analysis for C13
H O
14 2
S (%), calcd: C, 66.64;
H, 6.02; found: C, 66.19; H, 5.71.
-[(Methylthio)methyl]-3H-benzo[f]chromen-3-one (2h)
1

1 1
Colorless solid; yield, 83%; mp 194-196°C; IR (KBr): 1717 cm ; H NMR: δ 8.24 (d, J = 8.4
Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.31-7.26 (m, 2H), 6.92 (d, J = 8.5
1
3
Hz, 1H), 6.26 (s, 1H) 3.10 (s, 2H), 2.08 (s, 3H). C NMR: δ 159.83, 157.27, 150.87, 134.98,
1
28.94, 127.46, 126.95, 124.16, 122.71, 121.76, 120.69, 113.04, 110.37, 44.93, 20.11. GC-MS
+
(
m/z): 256 (M ). Elemental analysis for C15
H
12
O
2
S (%), calcd: C, 70.29; H, 4.72; found: C,
6
4
9.89; H, 4.43.
-[(Methylthio)methyl]-2H-benzo[h]chromen-2-one (2i)
9
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
1 1
Colorless solid; yield, 84%; mp 206-208°C; IR (KBr): 1716 cm ; H NMR (500 MHz): δ 8.37-
8
3
1
2
4
.35 (m, 2H), 8.04 (dd, J = 9.5, 5.5 Hz, 1H), 7.87-7.78 (m, 1H), 7.72-7.69 (m, 2H), 6.27 (s, 1H),
1
3
.12 (s, 2H), 2.09 (s, 3H). C NMR (125 MHz): δ 160.01, 157.39, 149.60, 134.18, 128.61,
27.93, 127.35, 123.94, 122.22, 121.57, 121.21, 120.19, 113.87, 45.04, 18.66. GC-MS (m/z):
+
56 (M ). Elemental analysis for C15
12 2
H O S (%), calcd: C, 70.29; H, 4.72; found: C, 69.89; H,
.43.
Benzyl methyl sulfane (2h)
A solution of benzyl bromide (1h) (1.0 mmol) in dry DMSO (2 mL) was prepared. The resulting
suspension was stirred at room temperature for 10 min and the reaction mixture heated for ca.
1
6-24 h at 150°C on an oil bath equipped with chilled water circulating condenser. After the
disappearance of most of the starting material (monitored by TLC), the reaction mixture was
allowed to cool and poured into ice cold water with stirring. The product was extracted with
ethyl acetate and the ethyl acetate layer was washed repeatedly with water. The obtained crude
product was purified by column chromatography using hexane solvent. Colorless liquid; yield
5
1%; bp 205-207°C (lit. 197°C); LC-MS (m/z): 139.2 (M+1).
Acknowledgements
The authors acknowledge the Department of Science and Technology (DST) and also UGC-UPE
and UGC-DSA New Delhi, India, for the financial support. The authors also thank the University
Scientific Instrumentation Centre (USIC), Karnatak University, Dharwad for single crystal X-ray
analysis and NMR Research Centre, Indian Institute of Science, Bengaluru, India for carrying
out the spectral analysis.
1
0
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Table 1. Optimizing reaction condition of methylthiolation.
Entry
Substrate
Product
2a
Temp. (°C) Time (hrs) Yield (%)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
50
80
6-8
6-8
6-8
6-8
6-8
6-8
-
2a
20
41
62
84
87
2a
100
120
135
150
2a
2a
2a
1
3
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Table 2. Synthesis of substituted 4-[(methylthio)methyl]-2H-chromen-2-ones (2a-2h):
a
Entry
Substrate
Product
Time (hrs)
Yield (%)
1
Br
S
8
87
CH3
H C
H C
3
3
O
O
O
O
1
a
2a
2
3
4
Br
S
8
8
8
85
83
84
CH3
Br
Cl
Br
Cl
O
O
O
O
2b
O
1
b
Br
S
CH3
O
O
O
1
c
2c
Br
S
CH3
H CO
H CO
3
3
O
O
O
O
1
d
2
d
5
6
Br
S
8
8
86
82
CH3
O
H C
O
O
H C
O
3
3
1
e
2e
2f
Br
S
CH3
O
HO
O
O
HO
O
1
f
1
4
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7
Br
S
8
8
85
83
CH3
CH3
CH3
O
H C
O
O
H C
O
3
3
1
g
2g
8
Br
S
CH3
O
O
O
O
1
h
2h
Br
S
CH3
9
8
84
51
O
O
O
O
1
i
2i
Br
S
1
0
16-24
1
h
2h
a
Isolated yield
1
5
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Table 3. The crystal data and structure refinement parameters of compounds 2g.
Identification code
Chemical formula
Formula weight
Temperature
2g
13 14 2
C H O S
234.30
296.15 K
MoKα radiation, λ
Crystal system
0.71073 Å
monoclinic
Space group
P21/c
Unit cell dimensions
a = 9.016(4) Å α = 90°
b = 14.400(5) Å β = 90.151(10)°
c = 8.842(5) Å γ = 90°
3
Volume
1148.1(9) Å
Z
4
3
Density
1.356 g/cm
−1
Absorption coefficient μ
F(000)
0.263 mm
496.0
3
Crystal size
0.27 × 0.18 × 0.12 mm
4.518 to 50.936°
2
θ range for data collection/°
Index ranges
-10 ≤ h ≤ 10, -17 ≤ k ≤ 9, -10 ≤ l ≤ 10
4002
Reflections collected
Independent reflections
1948 [Rint = 0.0639, Rsigma =
0
.0919]
Data / restraints / parameters
1948/0/148
1.032
2
Goodness-of-fit on F
Final R indices [I> = 2σ(I)]
R
1
= 0.0642, wR
2
2
= 0.1368
= 0.1637
R indices (all data)
R
1
= 0.1162, wR
Largest diff. peak and hole/ e Å 0.23/-0.33 e Å3
3
1
6
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CCDC Number
1479809
1
7
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Figure 1. ORTEP and Packing diagrams of compound 2g, ORTEP diagram with labeling
showing 50% displacement ellipsoids.
1
8
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Br
S
CH3
O
O
o
1
50 C, 8 hrs
S
R
R
H C
CH3
3
O
O
O
1
2
Scheme 1. Methylthiolation of 4-(bromomethyl)-2H-chromen-2-ones with DMSO as
methylthiolation source.
1
9
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O
O
S
R
X
X
2
H C S CH3
3
H C S CH3
3
R
S
R
S
H C
CH3
-CH3X
3
-X
O
Scheme 2. Plausible mechanism for the formation of heteroaryl alkyl thiomethyl compounds.
2
0
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