Synthesis of diversified thioethers, 1-aroylalkylisoquinolin-1-yl thioethers, by electrophilic S-alkylation of 3-phenyl isoquinoline-1(2H)-thione

Article abstract of DOI:10.1080/10426500903383945

A mild and efficient method for the synthesis of thioethers has been developed. The 3-phenylisoquinoline-1(2H)-thione underwent S-alkylation to afford structurally diverse sulfides in high yield. Copyright

Full text of DOI:10.1080/10426500903383945

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Diversified Thioethers, 1-
Aroylalkylisoquinolin-1-yl Thioethers,
by Electrophilic S-Alkylation of 3-Phenyl
Isoquinoline-1(2H)-thione
P. Manivel a b , F. Nawaz Khan a & Venkatesha R. Hatwar c
a Chemistry Division , School of Science and Humanities, VIT
University , Vellore, Tamil Nadu, India
b Syngene International Limited (Biocon) , Banglore, India
c Solid State and Structural Chemistry Unit , Indian Institute of
Science , Bangalore, Karnataka, India
Published online: 25 Aug 2010.
To cite this article: P. Manivel , F. Nawaz Khan & Venkatesha R. Hatwar (2010) Synthesis of
Diversified Thioethers, 1-Aroylalkylisoquinolin-1-yl Thioethers, by Electrophilic S-Alkylation of 3-
Phenyl Isoquinoline-1(2H)-thione, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:9,
1932-1942, DOI: 10.1080/10426500903383945
To link to this article: http://dx.doi.org/10.1080/10426500903383945
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Phosphorus, Sulfur, and Silicon, 185:1932–1942, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903383945
SYNTHESIS OF DIVERSIFIED THIOETHERS,
1-AROYLALKYLISOQUINOLIN-1-YL THIOETHERS,
BY ELECTROPHILIC S-ALKYLATION OF 3-PHENYL
ISOQUINOLINE-1(2H)-THIONE
P. Manivel,1,2 F. Nawaz Khan,1 and Venkatesha R. Hatwar3
1Chemistry Division, School of Science and Humanities, VIT University, Vellore,
Tamil Nadu, India
2Syngene International Limited (Biocon), Banglore, India
3Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore,
Karnataka, India
A mild and efficient method for the synthesis of thioethers has been developed. The 3-
phenylisoquinoline-1(2H)-thione underwent S-alkylation to afford structurally diverse sul-
fides in high yield.
Keywords Halides; single crystal study; thioethers; thiols
INTRODUCTION
Organosulfur compounds and sulfur containing drugs play a significant role in many
biological processes and pharmaceutical applications and are useful synthetic intermedi-
ates and key reagents in synthesis with wide application in bio-organic, medicinal, and
heterocyclic chemistry.1–3 They are also useful as heteroatomic functional groups in or-
ganic synthesis; for example, by the oxidation of thioethers, chiral sulfoxides that can be
used as auxiliaries in asymmetric syntheses can be generated.4–7 Many syntheses have
been reported for the preparation of thioethers.8–18 Commonly employed methods are the
alkylation of thiols.19–22
Thioethers have been prepared by many methods; however, the synthetic scope is
often hampered by use of expensive materials, high temperature, hazardous and corrosive
compounds such as alkylating agents and strong reducing agents, harsh reaction conditions,
and tedious workup procedures, resulting in low product yield. Moreover, the method
invariably results in the formation of several byproducts, which in turn results in lower
yield. Thus, there is still a need to develop mild and efficient methodologies to synthesize
Received 31 January 2009; accepted 2 October 2009.
We thank the DST, India, for use of the CCD facility setup under the IRHPA-DST program at Indian
Institute of Science, Bangalore, India. We also thank Syngene International Ltd., Bangalore, India, for their
generous support in spectral analysis.
Address correspondence to F. Nawaz Khan, Chemistry Division, School of Science and Humanities, VIT
University, Vellore 632 014, Tamil Nadu, India. E-mail: nawaz f@yahoo.co.in
1932

SYNTHESIS OF DIVERSIFIED THIOETHERS
1933
aliphatic, aromatic, and hetero aromatic thioethers. To the best of our knowledge, there are
only a few reports dealing with the formation of C S bond in the compounds containing
the isoquinoline heterocyclic moiety.23–27 During the course of our synthetic studies toward
organosulfur compounds containing the sulfide moiety, the need for a mild approach for
the construction of the C S bond is clearly warranted. This has prompted us to study the
synthesis of sulfides by alkylation of isoquinoline-1-thiols with the corresponding halides
(Scheme 1).
RESULTS AND DISCUSSION
In continuation of our studies on the synthesis of organosulphur compounds with
medicinal potential,28–34 in this article we wish to describe an efficient method of s-
alkylation of isoquinoline-1-thiols using alkyl halides.
Initially, for the synthesis of thiazole, 8 was planned via a thiourea derivative of iso-
quinoline reaction that would employ a condensation reaction with keto halide as depicted
in Scheme 1. However, in our experiment the 1-chloro, 3-phenylisoquinoline 3 required for
the synthesis of the thiourea derivative 4 was prepared as reported earlier,35–44 with slight
modification by the reaction of 3-phenylisoquin-1(2H)-one 2 and phosphoryl chloride in a
molar ratio of 1:1. Then reactions of 1-chloro, 3-phenylisoquinoline 3 with thiourea in a mo-
lar ratio of 1:1.2 in the presence of ethanol failed to furnish the expected thiourea derivative
4, even in trace amounts. Instead, this reaction led to the formation of isoquniolinon-1-
thione derivative 5. The thiol derivative (S-nucleophile) is then further transformed into
the corresponding S-alkylated product 7 thioether by the electrophilic alkylation using keto
halides 6.
The synthesized compound 7a gave the expected C O group peaks in IR and 13C
NMR respectively at 1690 cm−1 and 194 ppm. Similarly the methylene protons and the
1
methylene carbon appeared in both H NMR and 13C NMR spectra, respectively, at 5.06
(singlet) and 37.4ppm. Similarly all the compounds 7b–7l gave the expected peaks in IR,
1H, and 13C NMR spectra.
The X-ray crystallographic structure of isoquinolin-1-one 2 intermediate and two
thioethers 7b and 7i (both orthorhombic) were reported by us,45–47 and the ORTEP diagram,
packing diagram, crystal data of the unpublished derivative 7c (monoclinic) are presented
in Figure 1 and Table I.
The compound 7c exhibits dihedral angles of 28.74 and 71.56◦, respectively, between
the mean plane of the isoquinoline system and the attached phenyl ring, and between the
isoquinoline system and fluoro phenyl ring. The dihedral angle between the phenyl and
fluoro phenyl rings is 42.84◦. Moreover, the isoquinoline ring is planar, and the max-
imum deviation observed is −0.015◦ for atom C2. The S atom is also located in the
plane. In the fluoro phenyl ring, the F C bond distances is 1.355A◦. The orientation of
the isoquinoline ring system with respect to the phenyl ring given by the torsion angles
for N1 C2 C10 C15 and C3 C2 C10 C11 is 151.2◦ and 152.4◦, respectively. Simi-
larly, angles for C16 S1 C1 N1 and C16 S1 C1 C8 are, respectively, 3.26(2)◦ and
◦
. . .
−176.5(3) . The crystal packing is stabilized by C H O intermolecular hydrogen bonds.
. . .
. . .
The carbonyl oxygen atom O1 is generating bifurcated C3 H3 O1 and C23 H23 O1
intermolecular hydrogen bonds.
Encouraged by these results, we have further examined this transformation using 3-
phenylisoquinolin-1-thione 5 and different halides 6 and obtained the S-alkylated products

1934

SYNTHESIS OF DIVERSIFIED THIOETHERS
1935
Table I Crystallographic data for 7c
Data
7c
Data
7c
Formula
C23 H16 F N O S
373.44
293(2)
Mo Kα
0.71073
Density (gm/cm3)
1.349
0.198
776
Formula weight
Temperature/K
Radiation
Wavelength (A◦)
µ (mm−1
)
F (000)
θ (min, max)
h, k, l (min, max)
1.9, 25.5
(−14, 14)
(−12, 12) (−15, 18)
Crystal system
Crystal size (mm)
Space group
a (Å)
Monoclinic
0.31 × 0.24 × 0.14
P 21/c
12.0663(7)
10.5372(6)
15.1246(8)
90.00
107.062(1)
90.00
1838.38(18)
4
No. refln. Measured
No. Unique refln
No of parameters
Refinement method
R all
13092
3309
308
Full matrix least squares on F2
b (Å)
0.0823
0.0789
0.1604
0.1589
0.323
c (Å)
R obs
wR2 all
α (◦)
β (◦)
wR2 obs
γ (◦)
ꢀρmax (eÅ−3
)
Volume (Å3)
Z
ꢀρmin (eÅ−3
)
−0.301
GooF
1.280
7 in good yields. The results of alkylation of isoquinolin-1-thione 5 are given in Table II
(entries 1–12). From the data, it is obvious that the reaction proceeds very smoothly in a
simple, clean, and easier protocol with very good yield. The method is very general, and a
wide range of aliphatic and aromatic alkyl halides react readily with isoquinolin-1-thione
Table II S-Alkylation of 3-phenylisoquinolinthi-one using halides
R2
Halide
R1
O
R3
R4
R
N
R2
S
R5
R1
R3
R4
Br
R
O
R5
Entry
6
Product
7
Yield (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
R = R1 = R2 = R3 = R4 = R5 = H
7a
7b
7c
7d
7e
7f
7g
7h
7i
84
81
87
79
82
86
88
83
85
89
84
77
R = H; R3 = Cl; R1 = R2 = R4 = R5 = H
R = H; R3 = F; R1 = R2 = R4 = R5 = H
R = H; R3 = CN; R1 = R2 = R4 = R5 = H
R = H; R3 = CH3; R1 = R2 = R4 = R5 = H
R = H; R3 = CF3; R1 = R2 = R4 = R5 = H
R = H; R2 = R4 = CF3; R1 = R2 = R5 = H
R = H; R1 = OCH3; R3 = Cl; R2 = R4 = R5 = H
R = H; R2 = F; R3 = Cl; R1 = R4 = R5 = H
R = CH3; R3 = Cl; R1 = R2 = R4 = R5 = H
R = p-ClC6H4; R1 = R2 = R3 = R4 = R5 = H
10
11
12
6j
6k
6l
7j
7k
7l
F
O
S
O
N
Br
F

1936
P. MANIVEL ET AL.
Figure 1 ORTEP and packing diagram of compound 7c (CCDC No. 683298).
(Table II). Also, formation of disulfide, a common side reaction in thiol chemistry, is very
much suppressed.
CONCLUSION
In conclusion, we have developed a simple and clean method for the synthesis of
novel thioethers containing the isoquinoline moiety.

SYNTHESIS OF DIVERSIFIED THIOETHERS
1937
EXPERIMENTAL
The materials were purchased from Sigma–Aldrich and Merck and were used without
any additional purification. All reactions were monitored by thin layer chromatography
(TLC) on gel F254 plates. The silica gel (230–400 meshes) for column chromatography
1
was purchased from Spectrochem Pvt. Ltd., India. H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker 400 MHz spectrometer in CDCl3 or DMSO.
X-Ray Crystallographic Data
The single crystal X-ray diffraction data were collected on an Oxford Xcalibur,
Eos(Nova) CCD diffractometer. The X-ray generator was operated at 50 kV and 1 mA
using Enhanced Mo Kα radiation. Data were collected with ω scan width of 1◦. The data
reduction, an empirical absorption correction, and space group determination were done
using CrysAlisPro RED (Oxford Diffraction, 2009).48 The crystal structure was solved by
direct methods and refined by full matrix least-squares method using SHELXL97,49 which
is part of the program suite WinGx (Version 1.63.04a).50 The molecular diagrams were
generated using ORTEP-3,51 and the packing diagrams were generated using Mercury.52
Geometrical calculations were done using PARST9553 and PLATON.54 The positions of all
hydrogen atoms were fixed geometrically and refined isotropically using the riding atom
model.
Preparation of 3-Phenylisoquinolin-1(2H)-one, 2
3-Phenylisocoumarin 1 (22 g, 0.099 mol) was dissolved in THF (100 mL), and then
liq. ammonia in excess was added. The mixture was refluxed overnight in an oil-bath until
TLC showed the completion of the reaction. Then ice-cold water (500 mL) was added
to the reaction mixture, then it was extracted with ethyl acetate (3 × 50 mL), and the
extract was dried over anhydrous sodium sulfate. Removal of the solvent under vacuum
gave the crude product, which was further purified by column chromatography on silica gel
(100–200 mesh) with ethyl acetate–hexane (25%) as the eluent to afford the pure products,
1
3-phenylisoquinolin-1(2H)-one 2 in 70% yield, which are characterized by their H, 13C
NMR spectra and compared with reports in the literature.
Preparation of 1-Chloro, 3-Phenylisoquinoline, 3
To 2 (15 g, 0.068 mol), phosphoryl chloride (90 mL) was added. The mixture was
refluxed overnight under nitrogen atmosphere in an oil-bath until TLC showed completion
of the reaction. Then reaction mixture was added to ice-cold water, and it was extracted
with ethyl acetate. The extract was dried over anhydrous sodium sulfate. Removal of
the solvent under vacuum gave the crude product, which was further purified by column
chromatography on silica gel (230–400 mesh) with ethyl acetate–hexane (2%) as eluent
to afford the pure products 1-chloro, 3-phenylisoquinoline 3 in 92% yield, which are
characterized by their 1H, 13C NMR spectra and compared with reports in the literature.

1938
P. MANIVEL ET AL.
Preparation of 3-Phenyl Isoquinoline-1(2H)-thione, 5
Compound 3 (10 g, 0.042 mole) was dissolved in ethanol (100 mL), and then thiourea
(1.2 eq., 3.83 g, 0.0504 mol) was added. The mixture was refluxed in an oil-bath until TLC
showed completion of the reaction. Then ice-cold water (250 mL) was added to the reaction
mixture, then it was extracted with ethyl acetate (3 × 30 mL), and the extract was dried over
anhydrous sodium sulfate. Removal of the solvent under vacuum gave the crude product,
which was further purified by column chromatography on silica gel (230–400 mesh) with
ethyl acetate–hexane (4%) as eluent to afford pure products 3-phenyl isoquinoline-1(2H)-
thione 5 in 70% yield, which are characterized by their 1H, 13C NMR spectra.
General Procedure for S-Alkylation of 5 to the Ethanones
or Propanones, 7a–l (Table II, entries 1–12)
In a typical experiment for the synthesis of sulfide, thiol 5, and bromide 6 in the ratio
1:1.05, equivalents were mixed with ethanol in a round bottom flask. Then the mixture
was heated under nitrogen atmosphere on an oil bath at 50◦C. After 2 h, the products were
filtered, dissolved in chloroform, washed with water, dried, and concentrated, and analyzed
in on a liquid chromatography-mass spectrometer (LC-MS). Sulfides 7 are also actually
isolated and are characterized by their 1H, 13C NMR spectra.
3-Phenylisoquinolin-1-one, 2. Mp 141–142◦C, IR (ν cm−1) 3163 (NH), 3060,
2912, 1666 (CONH), 1634, 1556, 1347, 1285, 1148, 937, 768, 690, 541. 1H NMR (CDCl3):
δ 6.79 (s, 1H), 7.45 (m, 4H), 7.60 (d, J = 7.4 Hz,1H), 7.67 (m, 3H), 8.41 (m, 1H), 9.68 (s,
1H, NH). 13C NMR (CDCl3) δ 163.6 (CO), 139.3, 138.2, 134.4, 132.9, 129.6, 129.3 × 2,
127.5 × 2, 126.7, 126.5, 126.0, 125.1, 104.3. LCMS-221.9.
1-Chloro, 3-phenylisoquinoline, 3. Mp 151–153◦C, IR (ν cm−1) 3024, 2919,
1
1561, 1312, 1256, 977, 848 (C Cl), 762, 686, 516. H NMR (CDCl3): δ 7.41 (m, 3H),
7.49 (m, 1H), 7.64 (m, 1H), 7.73 (m, 1H), 7.88 (m, 1H), 8.02 (s, 1H), 8.11 (m, 1H), 8.32
(d, J = 7.6 Hz, 1H). 13C NMR (CDCl3) δ 163. 6 (C Cl), 139.3, 138.3, 134.3, 132.9, 129.6,
129.3 × 2, 127.7 × 2, 126.7, 126.6, 126.0, 125.1, 104.3. LCMS-240.1.
3-Phenyl isoquinoline-1(2H)-thione, 5. Mp 137–139◦C, 1H NMR (DMSO): δ
7.35 (s, 1H), 7.49 (m, 5H), 7.57 (m, 1H), 7.77 (m, 3H), 8.77 (d, J = 7.6 Hz, 1H). 13C NMR
(DMSO) δ 184.1 (CS), 142, 134.6, 133.6, 133.5, 132.5, 131.9 × 2, 131. 4 × 2, 129.1,
128.4, 128.1, 128, 111.0. LCMS-238.0, C15H11NS, Mol. Wt.: 237.32, Calculated C, 75.91;
H, 4.67; N, 5.90; S, 13.51, Found C, 75.84; H, 4.59; N, 5.80; S, 13.42.
2-(3-Phenylisoquinolin-1-ylthio)-1-phenylethanone, 7a. Colorless solid,
mp 145–147◦C, IR (ν cm−1) 3056, 2904, 1690 (CO), 1554, 1308, 1200, 958, 768, 688,
517. 1H NMR (DMSO): δ 5. 06 (s, 2H), 7.13 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H),
7.57 (t, J = 7.7 Hz, 2H), 7.67–7.72 (m, 2H), 7.79–7.82 (m, 2H), 7.85 (d, J = 7.3 Hz, 1H),
7.99 (d, J = 8.1 Hz, 1H), 8.14–8.17 (n, 2H), 8.19 (d, J = 8.3 Hz, 2H). 13C NMR (DMSO)
δ 194.00 (CO), 152.6, 148.8, 138.4, 136.7, 136.4, 133.9, 131.6, 129.3, 128.9 × 2, 128.9 ×
2, 128.8, 128.4, 128.2 × 2, 126.7 × 2, 125.4, 124.3, 113.5, 37.4 (CH2). LCMS-356.0.
C23H17NOS, Mol. Wt.: 355.45 Calculated C, 77.72; H, 4.82; N, 3.94; O, 4.50; S, 9.02,
Found C, 77.62; H, 4.78; N, 3.74; O, 4.45; S, 8.92.
2-(3-Phenylisoquinolin-1-ylthio)-1-(4-chlorophenyl)ethanone, 7b. Color-
less solid, mp 154–156◦C, IR (ν cm−1) 3052, 2915, 1692, 1588, 1359, 1201, 987, 788,
691, 520. 1H NMR (DMSO): δ 5. 03 (s, 2H), 7.15 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.3 Hz,
1H), 7.64–7.70 (m, 3H), 7.78–7.83 (m, 3H), 7.98 (d, J = 8.2 Hz, 1H), 8.10–8.19 (m, 4H),

SYNTHESIS OF DIVERSIFIED THIOETHERS
1939
13C NMR (DMSO) δ 193.2, 157.5, 148.9, 138.8, 138.5, 135.5, 131.6, 130.8, 129.4 × 2,
129.0 × 2, 128.7 × 2, 128.4 × 2, 128.2 × 2, 126.1, 125.4, 124.3, 113.6, 37.3. LCMS-390.1,
C23H16ClNOS, Mol. Wt.: 389.9, Calculated C, 70.85; H, 4.14; Cl, 9.09; N, 3.59; O, 4.10;
S, 8.22, Found C, 70.81; H, 4.04; Cl, 8.99; N, 3.52; O, 4.01; S, 8.17.
2-(3-Phenylisoquinolin-1-ylthio)-1-(4-fluorophenyl)ethanone, 7c. Color-
less solid, mp 147–149◦C, IR (ν cm−1) 3055, 2921, 1689, 1596, 1309, 1200, 988, 785,
689, 519. 1H NMR (DMSO): δ 5. 034 (s, 2H), 7.15 (t, J = 7.64 Hz,2H), 7.28 (t, J = 7.30
Hz, 1H), 7.39 (t, J = 8.88 Hz, 2H), 7.67–7.71 (m, 1H), 7.79–7.85 (m, 3H), 7.99 (d, J =
8.12 Hz,1H), 8. 11 (s, 1H), 8.18–8.25 (m, 3H). 13C NMR (DMSO) δ 192.7, 166.9, 164.4,
157.5, 148.9, 138.5, 136.4, 133.6, 133.5, 131.9, 131.8, 131.6, 129.0, 128.8, 128.4, 128.2,
126.7, 125.5, 124.3, 116.4, 116.2, 113.6, 37.4. LCMS-374.2, C23H16FNOS, Mol. Wt.:
373.44, Calculated C, 73.97; H, 4.32; F, 5.09; N, 3.75; O, 4.28; S, 8.59, Found C, 73.91;
H, 4.22; F, 5.01; N, 3.65; O, 4.22; S, 8.51.
4-(2-(3-Phenylisoquinolin-1-ylthio) acetyl)benzonitrile, 7d. Colorless solid,
mp 165–167◦C, IR (ν cm−1) 3058, 2921, 2231 (CN), 1693, 1554, 1311, 1203, 988, 828,
785, 699, 583, 519. 1H NMR (DMSO): δ 5. 08 (s, 2H), 7.14 (t, J = 7.68 Hz, 2H), 7.27 (q,
J = 4.88 Hz, 1H), 7.67 (t, J = 7.64 Hz, 1H), 7.79 (m, 3H), 7.98–8.09 (m, 3H), 8.17 (d,
J = 8.32 Hz, 4H), 8.25 (d, J = 8.08 Hz, 1H). 13C NMR (DMSO) δ 193.4, 156.8, 148.5,
139.6, 138.0, 136.0, 132.9, 131.3, 129.0 × 2, 128.6 × 2, 128.4 × 2, 128.0 × 2, 127.9,
126.3, 125.0, 123.8, 115.4, 113.3, 37.20. LCMS-381.0, C24H16N2OS, Mol. Wt.: 380.46,
Calculated C, 75.77; H, 4.24; N, 7.36; O, 4.21; S, 8.43, Found C, 75.67; H, 4.14; N, 7.39;
O, 4.26; S, 8.47.
2-(3-Phenylisoquinolin-1-ylthio)-1-p-tolylethanone, 7e. Pale yellow solid,
mp 156–158◦C, IR (ν cm−1) 3055, 2999, 2908, 1690, 1554, 1309, 1201, 983, 785, 694,
518. 1H NMR (DMSO): δ 2.3 (s, 3H), 5.02 (s, 2H), 7.14 (t, J = 7.66 Hz, 2H), 7.26–7.30
(m, 1H), 7.38 (d, J = 8.08 Hz, 2H), 7.66–7.70 (m, 1H), 7.78 (q, J = 5.02 Hz, 1H), 7.86
(d, J = 8.08 Hz, 2H), 7. 98 (d, J = 8.08 Hz, 1H), 8.04 (d, J = 8.16 Hz, 2H), 8. 11 (s, 1H),
8.18 (d, J = 8.36 Hz, 1H). 13C NMR (DMSO) δ 193.5, 157.6, 148.8, 144.4, 138.5, 136.4,
134.2, 131.6, 129.8, 128.9, 128.8, 128.4, 128.2, 126.6, 125.5, 124.3, 113.5, 37.3, 21.70.
LCMS-370.1, C24H19NOS, Mol. Wt.: 369.48, Calculated C, 78.02; H, 5.18; N, 3.79; O,
4.33; S, 8.68, Found C, 77.92; H, 5.12; N, 3.74; O, 4.29; S, 8.62.
2-(3-Phenylisoquinolin-1-ylthio)-1-(4-(trifluoromethyl)phenyl) ethanone,
7f. Colorless solid, mp 179–181◦C, IR (ν cm−1) 3054, 2917, 1702, 1555, 1310, 1165,
1
1066, 990, 825, 768, 690, 518. H NMR (DMSO): δ 5. 09 (s, 2H), 7.10 (t, J = 6.90 Hz,
2H), 7.24 (d, J = 8.28 Hz, 1H), 7.67 (t, J = 7.30 Hz, 1H), 7.78 (d, J = 6.76 Hz, 3H),
7.93–7.95 (d, J = 7.44 Hz, 3H), 7.99 (d, J = 7.64 Hz, 1H), 8.18 (d, J = 8.00 Hz, 1H), 8.30
(d, J = 7.32 Hz, 2H). 13C NMR (DMSO) δ 193.8, 157.3, 148.9, 140.0, 138.4, 136.4, 133.3,
133.01, 131.6, 129.6, 128.9, 128.6, 128.4, 128.2, 126.6, 126.2, 126.2, 125.6, 125.4, 124.3,
122.9, 113.7, 37.5. LCMS-424, C24H16F3NOS, Mol. Wt.: 423.45, Calculated C, 68.07; H,
3.81; F, 13.46; N, 3.31; O, 3.78; S, 7.57, Found C, 68.00; H, 3.76; F, 13.41; N, 3.21; O,
3.68; S, 7.49.
1-(3, 5-Bis(trifluoromethyl)phenyl)-2-(3-phenylisoquinolin-1-ylthio)etha-
none, 7g. Colorless solid, mp 157–159◦C, IR (ν cm−1) 3060, 2908, 1698, 1552, 1282,
1
1127, 913, 748, 681, 515. H NMR (DMSO): δ 5.18 (s, 2H), 7.08 (t, J = 7.70 Hz, 2H),
7.24 (t, J = 7.34 Hz, 1H), 7.68 (t, J = 7.62 Hz, 1H), 7.75 (d, J = 7.56 Hz, 2H), 7.80 (t, J
= 7.52 Hz, 2H), 7.99 (d, J = 8.16 Hz, 2H), 8.08 (s, 1H), 8.17 (d, J = 8.28 Hz, 1H), 8.46
(s, 1H), 8.64 (s, 2H). 13C NMR (DMSO) δ 192.9, 157.1, 149.1, 139.0, 138.5, 136.4, 131.7,
131.5, 131.2 129.2, 128.9, 128.5, 128.4, 128.3, 126.9, 126.7, 125.4, 124.7, 124.3, 122.1,

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P. MANIVEL ET AL.
114.0, 37.4. LCMS-492.1, C25H15F6NOS, Mol. Wt.: 491.45, Calculated C, 61.10; H, 3.08;
F, 23.19; N, 2.85; O, 3.26; S, 6.52, Found C, 61.02; H, 3.00; F, 23.11; N, 2.76; O, 3.14; S,
6.42.
2-(3-Phenylisoquinolin-1-ylthio)-1-(4-chloro-2-methoxyphenyl)ethanone,
7h. Colorless solid, mp 140–142◦C, IR (ν cm−1) 3025, 2924, 1666, 1588, 1310, 1251,
1098, 987, 830, 748, 686, 517. 1H NMR (DMSO): δ 3.98 (s, 3H), 4.88 (s, 2H), 7.02 (q, J =
3.40 Hz, 1H), 7.30–7.37 (m, 4H), 7.52 (d, J = 8.32 Hz, 1H), 7.64–7.68 (m, 1H), 7.77–7.81
(m, 1H), 7.97–8.00 (m, 3H), 8.14 (d, J = 7.76 Hz, 2H). 13C NMR (DMSO) δ 194.2, 159.2,
157.4 148.3, 138.7, 138.1, 135.9, 131.5, 131.1, 128.6, 128.5, 127.9, 127.7, 126.2, 125.4,
125.0, 123.8, 120.7, 113.0, 56.5, 41.2. LCMS-420.1, C24H18ClNO2S, Mol. Wt.: 419.92,
Calculated C, 68.65; H, 4.32; Cl, 8.44; N, 3.34; O, 7.62; S, 7.64, Found C, 68.52; H, 4.26;
Cl, 8.37; N, 3.25; O, 7.49; S, 7.55.
2-(3-Phenylisoquinolin-1-ylthio)-1-(4-chloro-3-fluorophenyl)ethanone, 7i.
Pale yellow solid, mp 159–161◦C, IR (ν cm−1) 3069, 2917, 1692, 1553, 1417, 1306, 1237,
989, 889, 741, 693, 517. 1H NMR (DMSO): δ 5.04 (s, 2H), 7.15 (t, J = 7.68 Hz, 2H), 7.28
(t, J = 7.32 Hz, 1H), 7.67–7.71 (m, 2H), 7.80–7.84 (m, 2H), 7.98–8.00 (m, 2H), 8.12–8.15
(m, 2H), 8.19 (d, J = 8.28 Hz, 2H). 13C NMR (DMSO) δ 192.7, 157.3, 156.5, 149.0, 138.5,
137.6, 137.6, 136.4, 131.7, 129.3, 129.0, 128.7, 128.4, 128.3, 126.7, 126.1, 125.4, 125.3,
124.3, 117.1, 116.9, 113.8, 97.5, 37.3. LCMS-408.0, C23H15ClFNOS, Mol. Wt.: 407.89,
Calculated C, 67.73; H, 3.71; Cl, 8.69; F, 4.66; N, 3.43; O, 3.92; S, 7.86, Found C, 67.66;
H, 3.64; Cl, 8.61; F, 4.49; N, 3.32; O, 3.86; S, 7.73.
2-(3-Phenylisoquinolin-1-ylthio)-1-(4-chlorophenyl)propan-1-one,
7j.
Colorless solid, mp 136–138 ◦C, IR (ν cm−1) 3057, 2929, 1692, 1552, 1307, 1201, 1092,
1
989, 842, 766, 689, 518. H NMR (DMSO): δ 1. 67 (d, J = 7.16 Hz, 3H), 5.99 (q, J =
7.16 Hz, 1H), 7.26 (t, J = 7.44 Hz, 1H), 7.31–7.33 (m, 2H), 7.54–7.56 (m, 2H), 7.65–7.67
(m, 1H), 7.79–7.81 (m, 2H), 7.87–7.89 (m, 2H), 7. 98 (d, J = 8.16 Hz, 2H), 8.11 (t, J =
8.00 Hz, 2H). 13C NMR (DMSO) δ 196.9, 157.2, 149.2, 138.8, 138.5, 136.5, 134.3, 131.7,
130.8, 129.4, 129.0, 128.8, 128.4, 128.3, 126.8, 125.2, 124.3, 114.1, 43.6 (CH), 17.2
(CH3). LCMS-404.1, C24H18ClNOS, Mol. Wt.: 403.92, Calculated C, 71.36; H, 4.49; Cal,
8.78; N, 3.47; O, 3.96; S, 7.94, Found C, 71.28; H, 4.37; Cal, 8.65; N, 3.39; O, 3.88; S,
7.81.
2-(3-Phenylisoquinolin-1-ylthio)-2-(4-chlorophenyl)-1-phenylethanone, 7k.
Pale yellow solid, mp 145–147◦C, IR (ν cm−1) 3055, 2924, 1681, 1552, 1305, 1209, 1091,
1
988, 742, 697, 517. H NMR (DMSO): δ 7.04 (t, J = 7.7 Hz, 2H), 7.21 (t, J = 6.9 Hz,
2H), 7.33 (t, J = 7.3 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.63–7.71
(m, 5H), 7.78 (t, J = 7.6 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 8.09 (s, 2H), 8.19 (d, J = 8.6
Hz, 2H). 13C NMR (DMSO) δ 192.9 (CO), 158.4, 149.4, 139.1, 138.4, 136.4, 134.6, 133.9,
131.4, 131.7, 131.4, 129.9 × 2, 129.8 × 2, 129.7, 129.5, 129.1, 128.8, 128.5 × 2, 128.4 ×
2, 128.3, 126.8, 124.7, 124.3, 114.2, 54.1 (CH2). LCMS-465.94, C29H20ClNOS, Mol. Wt.:
465.99, Calculated C, 74.75; H, 4.33; Cl, 7.61; N, 3.01; O, 3.43; S, 6.88, Found C, 74.68;
H, 4.26; Cl, 7.52; N, 2.91; O, 3.31; S, 6.76.
1-(3-Phenylisoquinolin-1-ylthio)-3-(2-fluorophenyl)propan-2-one,
7l.
Colorless solid, mp 146–148◦C, IR (ν cm−1) 3056, 2909, 1728, 1554, 1494, 1309, 1232,
1
1045, 989, 757, 690, 519. H NMR (DMSO): δ 4.11 (s, 2H, CH2), 4.54 (s, 2H, CH2),
7.02–7.04 (m, 3H), 7.08 (d, J = 7.7 Hz, 1H), 7.43–7.51 (m, 3H), 7.68 (t, J = 7.4 Hz, 1H),
7.81 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 8.13–8.18 (m, 4H), 13C NMR (DMSO)
δ 217.1 (CO), 162.8, 159.0, 157.5, 149.3, 138.9, 136.5, 132.5, 132.4, 131.7, 129.2, 128.4,
128.2, 127.0, 125.5, 124.6, 124.6, 124.3, 122.3, 122.1, 115.6, 115.3, 113.9, 41.60 (CH2).

SYNTHESIS OF DIVERSIFIED THIOETHERS
1941
LCMS-388, C24H18FNOS, Mol. Wt.: 387.47, Calculated C, 74.39; H, 4.68; F, 4.90; N,
3.61; O, 4.13; S, 8.28, Found C, 74.29; H, 4.59; F, 4.79; N, 354; O, 4.06; S, 8.19.
Supplementary Material
CCDC 683298 contains the supplementary crystallographic data for this article.
Copies may be obtained free of charge from the Director, CDC, 12 Union Road, Cambridge,
CB2 1EZ, UK; e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk.
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