A convenient one-pot preparation of 2-methyl-3-(phenylthiomethyl) quinolines from morita-baylis-hillman adducts and their oxidation to the corresponding sulfones

Article abstract of DOI:10.3390/molecules17055081

A convenient one-pot preparation of 2-methyl-3-(phenylthiomethyl)quinolines from Morita-Baylis-Hillman adducts via conjugate addition of thiols followed by reductive cyclization with Fe/AcOH was developed. The 2-methyl-3- (phenylthiomethyl)quinolines were transformed into 2-methyl-3- (phenylsulfonylmethyl)quinolines via m-CPBA-mediated oxidation

Full text of DOI:10.3390/molecules17055081

Molecules 2012, 17, 5081-5094; doi:10.3390/molecules17055081
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.org/molecules
Article
A Convenient One-Pot Preparation of 2-Methyl-3-(phenylthio-
methyl)quinolines from Morita-Baylis-Hillman Adducts and
Their Oxidation to the Corresponding Sulfones
Chintakunta Ramesh, Po-Min Lei, Veerababurao Kavala, Chun-Wei Kuo and Ching-Fa Yao *
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road,
Taipei 116, Taiwan
* Author to whom correspondence should be addressed; E-Mail: cheyaocf@ntnu.edu.tw;
Tel.: +886-2-2930-9092; Fax: +886-2-2932-4249.
Received: 7 March 2012; in revised form: 19 April 2012 / Accepted: 20 April 2012 /
Published: 3 May 2012
Abstract: A convenient one-pot preparation of 2-methyl-3-(phenylthiomethyl)quinolines
from Morita-Baylis-Hillman adducts via conjugate addition of thiols followed by reductive
cyclization with Fe/AcOH was developed. The 2-methyl-3-(phenylthiomethyl)quinolines
were transformed into 2-methyl-3-(phenylsulfonylmethyl)quinolines via m-CPBA-mediated
oxidation.
Keywords: one-pot procedure; Morita-Baylis-Hillman adducts; quinolines; reductive
cyclization; Fe/AcOH
1. Introduction
The quinoline nucleus is a ubiquitous heterocyclic structural motif that is found in many naturally
occurring quinoline alkaloids, therapeutic and synthetic compounds with a wide spectrum of biological
activities such as antimalarial, antidiabetic, anti-inflammatory, antiasthmatic, antihypertensive,
antibacterial, tyrosine kinase inhibiting agents [1–4]. Quinoline and their derivatives have been utilized
for the construction of nano- and meso structures having enhanced electronic and photonic properties [5].
In particular, the C3-alkylsulfone-containing quinolines posess important biological activities. Some of
the important C3-alkylsulfonyl and C3-alkylsulfoxide quinoline derivatives are depicted in Figure 1 [6,7].
Compound A displayed excellent functional activity, compound B exhibits excellent in vivo/in vitro
DMPK profile and acts as potent NK3 receptor antagonists [6]. Similarly, compound C acts as

Molecules 2012, 17
5082
inhibitor of soluble human CD23 [7]. In this regard, C3-alkylthioquinoline derivatives are key
precursors for the preparation of C3-alkylsulfonylquinoline derivatives. The C3-alkylthioquinolines
are easily transformed into the corresponding C3-alkylsulfonylquinolines via oxidation reactions. Many
protocols have been developed for the synthesis of quinoline derivatives [8–18]. However, the synthesis
of C3-alkylthioquinoline and their derivatives are very rare [6]. Therefore, an easy and simple
synthesis of C3-alkylthioquinolines and their derivatives is still needed.
Figure 1. Biologically important C3-alkylsulfonyl or C3-alkylsulfoxide quinoline derivatives.
Ph
Ph
CH3
CH3
O
OH
NH
O
NH
O
NH
CH3
CH3
S
Ph
S
S
O
O
O
Ph
O
O
N
N
N
Ph
A
B
C
The Morita-Baylis-Hillman (MBH) reaction is a useful carbon-carbon bond forming reaction,
which has the propensity to afford densely functionalized adducts [19–21]. Thiol addition to Morita-
Baylis-Hillman adducts is well explored in the literature [22–25]. However, to our knowledge, the
synthesis of C3-alkylthioquinolines and their derivatives from the MBH adducts is not known.
Recently, Kim et al. attempted the synthesis of C3-arylthiomethylquinoline derivatives from
(Z)-methyl 3-(2-azidophenyl)-2-(phenylthiomethyl)acrylate (MBH adduct) using the aza-Wittig
reaction, but they failed to obtain the desired product, obtaining instead methylquinoline-3-carboxylate.
However, they obtained phenylsulfinylmethyl-containing quinolines from MBH adducts by the
aza-Wittig reaction in a multi-step synthetic route [22]. As part of our ongoing project on the synthesis
of nitrogen-containing heterocyclic molecules via reductive cyclization [26–30], herein, we wish to
report a convenient one-pot procedure for the preparation of C3-arylthiomethylquinolines from the
MBH adducts and the transformation of the reaction products into the corresponding
C3-arylsulfonylmethyl-containing quinoline derivatives via an oxidation reaction.
2. Results and Discussion
Recently, we developed an easily accessible method for the synthesis of indolylquinoline
derivatives from MBH adducts [26]. Taking cues from this reaction, we envisioned synthesizing
C3-arylthiomethylquinoline derivatives from MBH adducts derived from the reaction of
2-nitrobenzaldehydes and methyl vinyl ketone. Our synthetic strategy for accessing 2-methyl-3-
(phenylsulfonylmethyl)quinoline derivatives is outlined in Scheme 1. The starting MBH adducts were
prepared according to a previously reported procedure [31]. Initially, the MBH adduct 1a was treated
with benzenethiol 2a in the presence of triethylamine in THF at room temperature to yield
intermediate compound 3a, which was treated with Fe/AcOH heated under reflux conditions to give
the corresponding 2-methyl-3-(phenylthiomethyl)quinoline compound 4a. Subsequently, sulfide 4a
was subjected to oxidation with a stoichiometric amount of 3-chloroperoxybenzoic acid (m-CPBA)
and sodium permanganate in 1,4-dioxane/water (1:1) at room temperature for 20 min, to provide the

Molecules 2012, 17
5083
expected the 2-methyl-3-(phenylsulfonylmethyl)quinoline compound 5a. The first two steps of Scheme 1
were conducted in a one-pot operation.
Scheme 1. Outline of our synthetic route for the synthesis of 2-methyl-3-(phenylthiomethyl)
quinoline derivatives and 2-methyl-3-(phenylsulfonylmethyl)quinoline derivatives.
OH
O
OH
O
R
R1
R
R
S
Et3N, THF
rt, 1.5 h
Fe/AcOH
reflux, 2h
R1 SH
N
NO2
NO2
S
R1
4a-4r
2a-2o
3a-3r
Intermediate
1a-1d
m-CPBA
NaMnO4
1,4-dioxane
and water
rt
O
R
S
R1
O
N
5a-5k
A literature survey revealed that the addition of thiols to MBH acetates takes place either at the
γ-position via a SN2' reaction [22–25] or mixture of the products [major product at γ-position
(E/Z = 10:1) and trace amount of product at α-position] [25]. In order to determine the structure of the
intermediates 3a–3r in our process, we conducted the reaction of MBH adduct 1a with naphthalene
thiol 2h in the presence of triethylamine. The intermediate 3h obtained from this reaction was isolated
and analysed by the 1H- and 13C-NMR, which revealed that the intermediate 3h formed is 4-hydroxy-
3-((naphthalen-1-ylthio)methyl)-4-(2-nitrophenyl)butan-2-one and it is obtained as mixture of
diastereomers. When it was subjected to crystallization, the major diastereomer (with the relative
configuration 7S* and 8S*) was crystallized out. The structure of the major diastereomer was
confirmed by single crystal X-ray diffraction analysis (Figure 2).
Figure 2. Crystal structure of the 4-hydroxy-3-((naphthalen-1-ylthio)methyl)-4-(2-
nitrophenyl)butan-2-one intermediate 3h (relative configuration is 7S* and 8S*) [32].
OH
O
S
NO2
Hence it is quite clear that the intermediate 3h obtained from the reaction of MBH alcohol and thiol
is a conjugate adduct, which is different from the product from the reaction of MBH acetate and

Molecules 2012, 17
5084
thiol [22–25]. However, our main aim was the synthesis of 2-methyl-3-(phenylthiomethyl)quinoline
derivatives 4a–r in a one-pot operation, therefore without further isolation of other intermediates
3a–r (tetrahydrofuran solvent was simply removed under reduced pressure) we carried out the next
step to obtain the 2-methyl-3-(phenylthiomethyl)quinoline derivatives 4a–r.
The results presented in Table 1 reveal that thiophenol, thionaphthol and thiophenols containing
alkyl, methoxy and halo substituents in the phenyl ring smoothly furnished the corresponding alkyl
and arylthiomethylquinolines 4a–r in 64–75% yields. There was no significant effect of the nature of
1
the substituents on the yields of the products. All the products were fully characterized by H- and
13C-NMR as well as LR and HRMS.
Table 1. One-pot synthesis of 2-methyl-3-(phenylthiomethyl)quinolines and their
derivatives from Morita-Baylis-Hillman adducts.
OH
O
1. Et3N, THF
rt, 1.5h
R1
R
R
S
R1 SH
2. Fe/AcOH
110oC, 2h
N
NO2
2a-2o
4a-4r
1a-1d
Entry MBH adduct 1
R
R 1
C6H5
Thiol 2 Product 4 Yield(%) a,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
66
69
70
68
70
67
65
72
69
65
65
75
64
65
65
72
68
66
4-OMe-C6H4
4-Br-C6H4
4-Cl-C6H4
4-F-C6H4
4-Me-C6H4
4-Et-C6H4
1-Naphthyl
Propyl
2g
2h
2i
4g
4h
4i
Hexyl
2j
4j
Isopropyl
2-Naphthyl
3,5-Me2-C6H3
2-OMe-C6H5
4-Isopropyl-C6H4
C6H5
2k
2l
4k
4l
2m
2n
2o
2a
2a
2a
4m
4n
4o
4p
4q
4r
C6H5
C6H5
Br
a All the reactions were carried out on 3 mmol scale; b Isolated yields were based on the MBH adducts.
A plausible mechanism for the formation of the 2-methyl-3-(phenylthiomethyl)quinoline
derivatives from the corresponding MBH adducts via reductive cyclization in the presence of
Fe/AcOH is presented in Scheme 2.

Molecules 2012, 17
5085
Scheme 2. A Plausible mechanism for the formation of 2-methyl-3-(phenylthiomethyl)
quinoline derivatives.
OH
O
OH
O
OH
O
R
R
R
Et3N, THF
rt, 1.5 h
Fe/AcOH
ref lux, 2h
R1 SH
NO2
NO2
S
S
R1
NH2
R1
1a-1d
2a-2o
Intermediate 3a-3r
OH
OH
R
R1
R
R1
S
R
R1
S
Aromatization
-H2O
S
H
N
O
-H2O
N
NH2
4a-4r
Table 2. Synthesis of 2-methyl-3-(phenylsulfonylmethyl)quinoline derivatives.
m-CPBA (2.0 equiv)
NaMnO4 (2.0 equiv)
O
R1
R
R
S
R1
S
O
1,4-dioxane-water (1:1)
rt
N
N
4a-4k
5a-5k
Entry
Substrate 4
R
R 1
Time (min)
Product 5
Yield(%) a,b
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
H
H
H
H
H
C6H5
20
20
40
40
35
20
20
20
20
20
30
5a
5b
5c
5d
5e
5f
5g
5h
5i
85
89
81
80
82
87
86
87
77
75
78
4-OMe-C6H4
4-Br-C6H4
4-Cl-C6H4
4-F-C6H4
4-Me-C6H4
4-Et-C6H4
1-Naphthyl
Propyl
10
11
4j
Hexyl
Isopropyl
5j
5k
4k
a All the reactions were carried out on 2 mmol scale; b Isolated yields.
Owing to the well known bioactivity of sulfones [33], the derived alkyl and arylthiomethylquinolines
4a–k were oxidized to the corresponding sulfones 5a–k in 75–89% yields (Table 2), following a
reported procedure [34]. Here too, the substituents didn’t have any significant effect on the yields of
1
13
the products. As before, all these products were also fully characterized by H- and C-NMR and by
LR and HRMS data.
3. Experimental
3.1. General
All the reactions were performed in oven (130 °C) dried glassware under an inert atmosphere of
nitrogen unless otherwise specified. Solvents for extraction and chromatography were distilled before

Molecules 2012, 17
5086
use. All the chemicals used in this study were of commercial grade and used after distillation.
Analytical thin layer chromatography was performed with E. Merck silica gel 60 F254 aluminum
plates. All purifications were carried out by flash chromatography using 230–400 mesh silica gel.
13
1H and C-NMR were recorded on a Bruker Avance EX 400 FT NMR (Taipei, Taiwan). Chemical
shifts were reported in parts per million (δ) using TMS as internal standard and coupling constants
were expressed in Hertz. Mass spectra were obtained on a JOEL SX-102A spectrometer (Taipei,
Taiwan) at an ionization potential of 70 eV and data are reported as mass/charge (m/z) with the percent
relative abundance. High-resolution mass spectra (HRMS) were acquired with a Finnigan MAT-95XL
spectrometer (Taipei, Taiwan).
3.2. General Procedure for the Synthesis of Compounds 4a–r
To a stirred solution of MBH adduct 1a (3.0 mmol, 1 equiv) and benzenethiol 2a (1.2 equiv) in
THF (15 mL), triethylamine (1.5 equiv) was added dropwise, and the reaction mixture was allowed to
continue at room temperature for 1.5 h. The progress of the reaction was monitored by TLC. After
completion of the reaction, the solvent was removed under reduced pressure. The residue was diluted
with AcOH (15 mL) and Fe powder (6.0 equiv) at room temperature was added. Then the reaction
mixture was heated at 110 °C for 2 h and was cooled to room temperature. AcOH was removed under
reduced pressure and the residue was diluted with EtOAc (30 mL). The resulting mixture was filtered
to remove any iron impurities. Iron residue was washed twice with EtOAc (30 mL). Filtrate and
washings were combined and dried over anhydrous Na2SO4. Solvent was evaporated and the residue,
thus obtained was purified by column chromatography to provide the desired product 4a as yellow
solid in 66% isolated yield.
1
2-Methyl-3-(phenylthiomethyl)quinoline (4a). Yellow solid, m.p. 83–85 °C. H-NMR (DMSO-d6) δ
8.03 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.68–7.64 (m, 1H), 7.50–7.47 (m, 1H),
7.38–7.37 (m, 2H), 7.31–7.28 (m, 2H), 7.22–7.19 (m, 1H), 4.42 (s, 2H), 2.75 (s, 3H). 13C-NMR
(CDCl3) δ 158.3, 147.1, 136.1, 135.4, 131.4, 129.4, 129.3, 129.2, 128.4, 127.4, 127.3, 127.0, 126.1,
37.6, 23.3. MS (m/z) (relative intensity): 265 (M+, 100), 156 (91). HRMS calcd. for C17H15NS (M+)
265.0920, found 265.0931.
1
3-((4-Methoxyphenylthio)methyl)-2-methyl quinoline (4b). Yellow solid, m.p. 65–67 °C. H-NMR
(CDCl3) δ 7.98 (d, J = 8.4 Hz, 1H), 7.61–7.57 (m, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.47 (s, 1H),
7.40–7.36 (m, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 4.02 (s, 2H), 3.69 (s, 3H), 2.76 (s,
13
3H). C-NMR (CDCl3) δ 159.7, 158.2, 146.8, 135.9, 135.2, 129.6, 129.1, 128.3, 127.1, 126.8, 125.8,
125.0, 114.5, 55.3, 39.3, 23.1. MS (m/z) (relative intensity): 295 (M+, 8), 157 (6), 156 (100), 149 (16).
HRMS calcd. for C18H17NOS (M+) 295.1025, found 295.1032.
1
3-((4-Bromophenylthio)methyl)-2-methylquinoline (4c). Yellow solid, m.p. 118–120 °C. H-NMR
(DMSO-d6) δ 8.05 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69–7.65 (m, 1H),
7.51–7.46 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 4.43 (s, 2H), 2.75 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ
158.2, 147.2, 136.1, 134.6, 132.9, 132.3, 129.6, 128.8, 128.6, 127.4, 127.0, 126.2, 121.5, 37.7, 23.3.
MS (m/z) (relative intensity): 345 (M++2, 6), 343 (M+, 6), 157 (20), 156 (100), 129 (8), 115 (11), 69

Molecules 2012, 17
5087
(11). HRMS calcd for C17H1479BrNS (M+) 343.0025 found 343.0031; HRMS calcd. for C17H1481BrNS
(M+) 345.0004, found 345.0016.
3-((4-Chlorophenylthio)methyl)-2-methylquinoline (4d). Red solid, m.p. 98–100 °C. 1H-NMR
(DMSO-d6) δ 8.04 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69–7.65 (m, 1H),
7.51–7.47 (m, 1H) 7.39 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 4.43 (s, 2H), 2.75 (s, 3H).
13C-NMR (CDCl3) δ 158.3, 147.2, 136.1, 133.8, 133.6, 132.9, 129.6, 129.3, 128.9, 128.5, 127.4, 127.0,
126.2, 38.0, 23.3. MS (m/z) (relative intensity): 299 (M+, 9), 157 (16), 156 (100), 129 (10), 115 (11).
HRMS calcd for C17H1435ClNS (M+) 299.0530 found 299.0540; HRMS calcd. for C17H1437ClNS (M+)
301.0500, found 301.0515.
1
3-((4-Fluorophenylthio)methyl)-2-methylquinoline (4e). Yellow solid, m.p. 106–108 °C. H-NMR
(DMSO-d6) δ 7.92 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.68–7.64 (m, 1H),
7.50–7.46 (m, 1H), 7.42–7.39 (m, 2H), 7.15–7.11 (m, 2H), 4.37 (s, 2H), 2.74 (s, 3H). 13C-NMR
(CDCl3) δ 162.6 (d, J = 247.0 Hz), 158.2, 147.1, 136.0, 134.8 (d, J = 8.0 Hz), 129.9 (d, J = 3.0 Hz),
129.4, 129.1, 128.5, 127.2, 126.9, 126.1, 116.2 (d, J = 22.0 Hz), 38.9, 23.2. MS (m/z) (relative
intensity): 283 (M+, 20), 157 (22), 156 (100), 129 (15), 115(16). HRMS calcd. for C17H14FNS (M+)
283.0826, found 283.0832.
1
2-Methyl-3-(p-tolylthiomethyl)quinoline (4f). Yellow solid, m.p. 90–92 °C. H-NMR (CDCl3) δ 7.99
(d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.66–7.62 (m, 2H), 7.45–7.42 (m, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.05
13
(d, J = 7.8 Hz, 2H), 4.17 (s, 2H), 2.81 (s, 3H), 2.30 (s, 3H). C-NMR (CDCl3) δ 158.4, 147.1, 137.6,
136.0, 132.1, 131.5, 129.9, 129.5, 129.3, 128.5, 127.3, 127.0, 126.0, 38.3, 23.3, 21.2. MS (m/z)
(relative intensity): 279 (M+, 13), 157 (10), 156 (100), 129 (8), 115 (7). HRMS calcd. for C18H17NS
(M+) 279.1076, found 279.1083.
3-((4-Ethylphenylthio)methyl)-2-methylquinoline (4g). Brown liquid. 1H-NMR (CDCl3) δ 8.00
(d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.61–7.57 (m, 2H), 7.42–7.38 (m, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.05
(d, J = 8.1 Hz, 2H), 4.12 (s, 2H), 2.79 (s, 3H), 2.57 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).
13C-NMR (CDCl3) δ 158.3, 147.0, 143.8, 135.9, 132.1, 131.7, 129.4, 129.2, 128.6, 128.3, 127.2, 126.9,
125.9, 38.1, 28.5, 23.2, 15.6. MS (m/z) (relative intensity): 293 (M+, 17), 157 (12), 156 (100), 149 (24),
129 (8). HRMS calcd. for C19H19NS (M+) 293.1233, found 293.1242.
1
2-Methyl-3-((naphthalen-1-ylthio)methyl)quinoline (4h). Yellow solid, m.p. 85–87 °C. H-NMR
(CDCl3) δ 8.44 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.2 Hz,
1H), 7.64–7.60 (m, 1H), 7.55–7.48 (m, 3H), 7.44–7.37 (m, 3H), 7.29 (d, J = 7.4 Hz, 1H), 4.23 (s, 2H),
2.85 (s, 3H). 13C-NMR (CDCl3) δ 158.3, 147.1, 136.1, 134.1, 133.7, 132.2, 131.5, 129.3, 129.2, 128.8,
128.7, 128.4, 127.2, 127.0, 126.9, 126.4, 126.0, 125.6, 125.2, 37.8, 23.3. MS (m/z) (relative intensity):
315 (M+, 100), 156 (70). HRMS calcd. for C21H17NS (M+) 315.1076, found 315.1087.
2-Methyl-3-(propylthiomethyl)quinoline (4i). Yellow solid, m.p. 44–46 °C. 1H-NMR (CDCl3) δ 8.00 (d,
J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66–7.63 (m, 1H), 7.49–7.45 (m, 1H), 3.84 (s,
2H), 2.81 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 1.66–1.57(m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C-NMR

Molecules 2012, 17
5088
(CDCl3) δ 158.6, 147.0, 135.6, 130.1, 129.2, 128.5, 127.2, 127.0, 126.1, 34.2, 34.0, 23.2, 22.7, 13.6.
MS (m/z) (relative intensity): 231 (M+, 100), 156 (51). HRMS calcd. for C14H17NS (M+) 231.1076,
found 231.1086.
1
3-(Hexylthiomethyl)-2-methylquinoline (4j). Yellow liquid. H-NMR (CDCl3) δ 8.00 (d, J = 8.4 Hz,
1H), 7.89 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66–7.62 (m, 1H), 7.49–7.45 (m, 1H), 3.84 (s, 2H), 2.81 (s,
3H), 2.46 (t, J = 7.4 Hz, 2H), 1.60–1.54 (m, 2H), 1.37–1.22 (m, 6H), 0.86 (t, J = 6.7 Hz, 3H).
13C-NMR (CDCl3) δ 158.4, 146.8, 135.3, 129.9, 129.0, 128.3, 127.0, 126.8, 125.8, 34.1, 31.8, 31.3,
29.1, 28.5, 23.0, 22.4, 13.9. MS (m/z) (relative intensity): 273 (M+, 100), 189 (7), 156 (62). HRMS
calcd. for C17H23NS (M+) 273.1546, found 273.1554.
1
3-(Isopropylthiomethyl)-2-methylquinoline (4k). Yellow liquid. H-NMR (DMSO-d6) δ 8.13 (s, 1H),
7.91–7.88 (m, 2H), 7.69–7.65 (m, 1H), 7.53–7.50 (m, 1H), 3.95 (s, 2H), 2.88–2.81 (m, 1H), 2.73
(s, 3H), 1.24 (d, J = 6.8 Hz, 6H). 13C-NMR (CDCl3) δ 158.4, 146.7, 135.4, 130.1, 129.0, 128.2, 127.0,
126.9, 125.9, 34.9, 32.7, 23.1, 22.9. MS (m/z) (relative intensity): 231 (M+, 100), 156 (46). HRMS
calcd. for C14H17NS (M+) 231.1076, found 231.1086.
1
2-Methyl-3-((naphthalen-2-ylthio)methylquinoline (4l). Yellow solid, m.p. 115–117 °C. H-NMR
(CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H), 7.79–7.77 (m, 2H), 7.75–7.73 (m, 2H), 7.68–7.57 (m, 3H),
13
7.47–7.39 (m, 4H), 4.33 (s, 2H), 2.86 (s, 3H). C-NMR (CDCl3) δ 158.3, 147.1, 136.1, 133.8, 133.0,
132.3, 129.4, 129.3, 129.1, 128.7, 128.5, 128.4, 127.8, 127.4, 127.3, 127.0, 126.7, 126.2, 126.0, 37.4,
23.3. MS (m/z) (relative intensity): 315 (M+, 21), 157 (12), 156 (100), 129 (8), 115 (18). HRMS calcd.
for C21H17NS (M+) 315.1076, found 315.1083.
3-((3,5-Dimethylphenylthio)methyl)-2-methylquinoline (4m). Yellow solid, m.p. 108–110 °C. 1H-NMR
(CDCl3) δ 8.00 (d, J = 8.7 Hz, 1H), 7.75 (s, 1H), 7.66–7.62 (m, 2H), 7.46–7.42 (m, 1H), 6.92 (s, 2H),
6.85 (s, 1H), 4.20 (s, 2H), 2.83 (s, 3H), 2.22 (s, 6H). 13C-NMR (DMSO-d6) δ 158.1, 146.3, 138.1,
135.6, 134.7, 129.2, 129.1, 128.0, 127.8, 127.2, 126.9, 126.4, 125.8, 35.0, 22.7, 20.6. MS (m/z)
(relative intensity): 293 (M+, 32), 157 (11), 156 (100), 151 (15). HRMS calcd. for C19H19NS (M+)
293.1233, found 293.1241.
1
3-((2-Methoxyphenylthio)methyl)-2-methylquinoline (4n). Yellow solid, m.p. 118–120 °C. H-NMR
(CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.63–7.59 (m, 2H), 7.43–7.39 (m, 1H), 7.23–7.19 (m,
13
2H), 6.84–6.80 (m, 2H), 4.18 (s, 2H), 3.81 (s, 3H), 2.84 (s, 3H). C-NMR (CDCl3) δ 158.7, 158.6,
147.1, 136.0, 132.9, 129.5, 129.2, 129.0, 128.4, 127.3, 127.1, 125.9, 123.0, 121.2, 110.8, 55.9, 35.8,
23.2. MS (m/z) (relative intensity): 295 (M+, 12), 157 (7), 156 (100). HRMS calcd. for C18H17NOS
(M+) 295.1025, found 295.1034.
3-((4-Isopropylphenylthio)methyl)-2-methylquinoline (4o). Red solid, m.p. 44–46°C. 1H-NMR (DMSO-d6)
δ 7.96 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.68–7.64 (m, 1H), 7.50–7.46 (m,
1H), 7.28 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 4.36 (s, 2H), 2.86–2.79 (m, 1H), 2.74 (s, 3H),
1.14 (d, J = 6.8 Hz, 6H). 13C-NMR (DMSO-d6) δ 158.1, 147.1, 146.2, 135.4, 131.8, 130.2, 129.3,

Molecules 2012, 17
5089
129.1, 127.8, 127.2, 127.0, 126.4, 125.8, 35.8, 32.9, 23.6, 22.7. MS (m/z) (relative intensity): 307 (M+,
65), 156 (100). HRMS calcd. for C20H21NS (M+) 307.1389, found 307.1403.
1
6-Chloro-2-methyl-3-(phenylthiomethyl)quinoline (4p). Green solid, m.p. 74–76 °C. H-NMR (DMSO-
d6) δ 8.00 (s, 1H), 7.91–7.88 (m, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.37–7.35 (m, 2H), 7.31–7.27 (m, 2H),
13
7.22–7.19 (m, 1H), 4.40 (s, 2H), 2.74 (s, 3H). C-NMR (CDCl3) δ 158.7, 145.5, 135.1, 135.0, 131.8,
131.7, 130.4, 130.3, 130.2, 129.2, 127.7, 127.5, 125.9, 37.7, 23.3. MS (m/z) (relative intensity): 299
(M+, 10), 192 (23), 190 (100), 155 (10). HRMS calcd. for C17H1435ClNS (M+) 299.0530, found
299.0540; HRMS calcd. for C17H1437ClNS (M+) 301.0500, found 301.0515.
1
6-Fluoro-2-methyl-3-(phenylthiomethyl)quinoline (4q). Yellow solid, m.p. 44–46 °C. H-NMR (DMSO-
d6) δ 8.02 (s, 1H), 7.95 (dd, J = 9.0, 5.4 Hz, 1H), 7.62–7.53 (m, 2H), 7.37–7.35 (m, 2H), 7.31–7.27 (m,
13
2H), 7.23–7.19 (m, 1H), 4.40 (s, 2H), 2.73 (s, 3H). C-NMR (DMSO-d6) δ 159.3 (d, J = 242.0 Hz),
157.6, 143.4, 135.0, 134.9 (d, J = 5.0 Hz), 130.6 (d, J = 9.0 Hz), 130.2, 129.5, 129.0, 127.0 (d,
J = 10.0 Hz), 126.5, 118.9 (d, J = 25.0 Hz), 110.3 (d, J = 21.0 Hz), 35.0, 22.6. MS (m/z) (relative
intensity): 283 (M+, 15), 175 (7), 174 (100), 147 (6). HRMS calcd. for C17H14FNS (M+) 283.0826,
found 283.0830.
1
6-Bromo-2-methyl-3-henylthiomethyl)quinoline (4r). Yellow solid, m.p. 78–80 °C. H-NMR (DMSO-d6)
δ 8.08 (d, J = 1.9 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.77 (dd, J = 8.9, 1.8 Hz, 1H),
7.37–7.35 (m, 2H), 7.31–7.28 (m, 2H), 7.23–7.19 (m, 1H), 4.41 (s, 2H), 2.74 (s, 3H). 13C-NMR
(DMSO-d6) δ 158.9, 144.8, 134.8, 134.5, 132.1, 130.4, 130.0, 129.6, 129.1, 129.0, 127.7, 126.5, 118.6,
35.0, 22.7. MS (m/z) (relative intensity): 345 (M++2, 9), 343 (M+, 8), 236 (97), 234 (100), 156 (24),
155 (36), 149 (18), 114 (19). HRMS calcd. for C17H1479BrNS (M+) 343.0025, found 343.0024. HRMS
calcd. for C17H1481BrNS (M+) 345.004, found 345.0015.
3.3. General Procedure for the Synthesis of Compounds 5a–k
To a stirred solution of sulfide 4a (2.0 mmol, 1 equiv) in 1:1 1,4-dioxane/H2O (12 mL) was added
m-CPBA (2.0 equiv.) followed by sodium permanganate (2.0 equiv.) at room temperature (25 °C), and
the reaction mixture was stirred at same temperature for 20 min. After completion of the reaction as
monitored by TLC, the reaction mixture was extracted with EtOAc (30 mL), then organic layer was
washed with saturated NaHCO3, water, followed by brine solution and dried over Na2SO4. Solvent was
evaporated and obtained crude product was purified by column chromatography to provide the desired
sulfone 5a as yellow solid in 85 % isolated yield.
2-Methyl-3-(phenylsulfonylmethyl)quinoline (5a). Yellow solid, m.p. 148–150 °C. 1H-NMR (CDCl3) δ
7.99 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.73–7.63 (m, 5H), 7.52–7.46 (m, 3H), 4.53 (s, 2H), 2.48
(s, 3H). 13C-NMR (CDCl3) δ 158.3, 147.3, 139.6, 138.2, 134.3, 130.4, 129.4, 128.7, 128.6, 127.6,
126.6, 126.5, 120.8, 59.7, 23.2. MS (m/z) (relative intensity): 297 (M+, 3), 157 (31), 156 (100), 129
(16), 115 (19). HRMS calcd. for C17H15NO2S (M+) 297.0818, found 297.0830.
3-((4-Methoxyphenylsulfonyl)methyl)-2-methylquinoline (5b). White solid, m.p. 178–180 °C. 1H-NMR
(DMSO-d6) δ 7.99 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.74–7.71 (m, 1H), 7.65

Molecules 2012, 17
5090
(d, J = 8.7 Hz, 2H), 7.56–7.52 (m, 1H), 7.12 (d, J = 8.7 Hz, 2H), 4.85 (s, 2H), 3.84 (s, 3H), 2.54
(s, 3H). 13C-NMR (CDCl3) δ 164.2, 158.4, 147.6, 139.6, 130.9, 130.4, 129.6, 128.6, 127.7, 126.7,
126.4, 121.3, 114.6, 59.8, 55.8, 23.3. MS (m/z) (relative intensity): 327 (M+, 27), 157 (89), 156 (100),
129 (30), 128 (12), 116 (20), 115 (63), 89 (13). HRMS calcd. for C18H17NO3S (M+) 327.0924, found
327.0936.
1
3-((4-Bromophenylsulfonyl)methyl)-2-methylquinoline (5c). White solid, m.p. 213–215 °C. H-NMR
(CDCl3) δ 8.00 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 7.74–7.71 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.53–7.51
(m, 3H), 4.52 (s, 2H), 2.51 (s, 3H). 13C-NMR (CDCl3) δ 158.2, 147.8, 139.7, 137.2, 132.8, 130.6,
130.3, 129.8, 128.7, 127.6, 126.7, 126.6, 120.5, 59.7, 23.4. MS (m/z) (relative intensity): 376
(M++2, 3), 374 (M+, 3), 157 (89), 156 (100), 154 (11), 129 (30), 115 (62), 89 (13). HRMS calcd. for
C17H1479Br NO2S (M+) 374.9923, found 374.9937; HRMS calcd. for C17H1481BrNO2S (M+) 376.9903,
found 376.9922.
1
3-((4-Chlorophenylsulfonyl)methyl)-2-methyl quinoline (5d). White solid, m.p. 190–192 °C. H-NMR
(CDCl3) δ 7.99 (d, J = 8.7 Hz, 1H), 7.91 (s, 1H), 7.74–7.71 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H),
13
7.53–7.50 (m, 1H), 7.44 (d, J = 8.5 Hz, 2H), 4.53 (s, 2H), 2.50 (s, 3H). C-NMR (CDCl3) δ 158.2,
147.8, 141.2, 139.7, 136.6, 130.6, 130.2, 129.8, 128.7, 127.6, 126.7, 126.6, 120.5, 59.7, 23.4. HRMS
calcd. for C17H14ClNO2S (M+) 331.0434, found 331.0437.
1
3-((4-Fluorophenylsulfonyl)methyl)-2-methyl quinoline (5e). White solid, m.p. 183–185 °C. H-NMR
(CDCl3) δ 7.99 (d, J = 8.5 Hz, 1H), 7.89 (s, 1H), 7.74–7.65 (m, 4H), 7.53–7.49 (m, 1H), 7.16–7.12
(m, 2H), 4.53 (s, 2H), 2.51 (s, 3H). 13C-NMR (DMSO-d6) δ 165.2 (d, J = 252.0 Hz), 158.7, 146.7, 139.4,
134.7 (d, J = 2.0 Hz), 131.4 (d, J = 10.0 Hz), 130.0, 127.9, 127.5, 126.1, 126.0, 121.2, 116.5 (d,
J = 23.0 Hz), 58.0, 22.9. HRMS calcd. for C17H14FNO2S (M+) 315.0729, found 315.0732.
1
2-Methyl-3-(tosylmethyl)quinoline (5f). Yellow solid, m.p. 180–182 °C. H-NMR (DMSO-d6) δ 8.01 (s,
1H), 7.91 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.75–7.71 (m, 1H), 7.63 (d, J = 8.0 Hz, 2H),
7.56–7.52 (m, 1H), 7.42 (d, J = 8.0 Hz, 2H), 4.88 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H). 13C-NMR (CDCl3)
δ 158.3, 147.7, 145.4, 139.6, 135.2, 130.4, 130.0, 128.7, 128.6, 127.6, 126.7, 126.4, 121.0, 59.7, 23.3,
21.7. HRMS calcd. for C18H17 NO2S (M+) 311.0980, found 311.0985.
1
3-((4-Ethylphenylsulfonyl)methyl)-2-methyl quinoline (5g). White solid, m.p. 160–162 °C. H-NMR
(DMSO-d6) δ 7.97 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75–7.71 (m, 1H), 7.66
(d, J = 7.8 Hz, 2H), 7.55–7.52 (m, 1H), 7.45 (d, J = 7.8 Hz, 2H), 4.88 (s, 2H), 2.70 (q, J = 7.5 Hz, 2H),
13
2.54 (s, 3H), 1.19 (t, J = 7.5 Hz, 3H). C-NMR (CDCl3) δ 158.4, 151.5, 147.6, 139.6, 135.3, 130.4,
128.9, 128.8, 128.5, 127.6, 126.6, 126.4, 121.0, 59.7, 29.0, 23.2, 15.2. HRMS calcd. for C19H19 NO2S
(M+) 325.1136, found 325.1125.
2-Methyl-3-((naphthalen-1-ylsulfonyl)methyl) quinoline (5h). White solid, m.p. 158–160 °C. 1H-NMR
(CDCl3) δ 8.80–8.77 (m, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.02–7.93 (m, 3H), 7.69–7.61 (m, 4H),
13
7.55–7.53 (m, 1H), 7.46–7.42 (m, 2H), 4.70 (s, 2H), 2.51 (s, 3H). C-NMR (CDCl3) δ 158.4, 147.6,

Molecules 2012, 17
5091
139.6, 135.8, 134.2, 133.2, 131.7, 130.4, 129.5, 129.3, 129.0, 128.5, 127.5, 127.3, 126.5, 126.4, 124.5,
124.0, 120.9, 59.3, 23.4. HRMS calcd. for C21H17NO2S (M+) 347.0980, found 347.0976.
1
2-Methyl-3-(propylsulfonylmethyl)quinoline (5i). White solid, m.p. 148–150 °C. H-NMR (CDCl3) δ
8.15 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.73–7.69 (m, 1H), 7.53–7.49 (m, 1H),
13
4.42 (s, 2H), 3.00–2.96 (m, 2H), 2.86 (s, 3H), 1.96–1.88 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). C-NMR
(CDCl3) δ 158.4, 147.9, 139.4, 130.5, 128.7, 127.7, 126.8, 126.6, 120.3, 56.2, 54.3, 23.9, 15.8, 13.3.
HRMS calcd. for C14H17NO2S (M+) 263.0980, found 263.0986.
1
3-(Hexylsulfonylmethyl)-2-methylquinoline (5j). White solid, m.p. 127–129 °C. H-NMR (CDCl3) δ
8.15 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.73–7.69 (m, 1H), 7.53–7.49 (m, 1H),
4.42 (s, 2H), 3.01–2.97 (m, 2H), 2.86 (s, 3H), 1.91–1.84 (m, 2H), 1.46–1.39 (m, 2H), 1.33–1.25 (m,
13
4H), 0.86 (t, J = 6.8 Hz, 3H). C-NMR (CDCl3) δ 158.4, 147.9, 139.4, 130.5, 128.7, 127.7, 126.8,
126.6, 120.3, 56.1, 52.7, 31.3, 28.3, 24.0, 22.4, 22.0, 14.0. HRMS calcd. for C17H23NO2S (M+)
305.1449, found 305.1460.
3-(Isopropylsulfonylmethyl)-2-methylquinoline (5k). White solid, m.p. 145–147 °C. 1H-NMR (CDCl3) δ
8.15 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.72–7.68 (m, 1H), 7.50 (s, 1H), 4.39 (s,
13
2H), 3.25–3.18 (m, 1H), 2.85 (s, 3H), 1.14 (d, J = 6.8 Hz, 6H). C-NMR (CDCl3) δ 158.7, 147.7,
139.6, 130.3, 128.6, 127.6, 126.7, 126.4, 119.8, 53.5, 52.1, 23.8, 15.7. HRMS calcd. for C14H17NO2S
(M+) 263.0980, found 263.0988.
Crystallographic description of 3h: crystal size = 0.44 × 0.32 × 0.08 mm3; C21H19NO4S; Mr = 381.43;
Monoclinic; Space group P 21/c; a = 32.290(4) Å, α = 90°, b = 7.4466(9) Å, β = 103.742(6)°,
c = 15.7324(16) Å, γ = 90°, V = 3674.6(7) Å3; Z = 8; ρcal = 1.379 mg/m3;  = 0.204 mm−1;
F(000) = 1600; Theta range for data collection = 1.30 to 25.02°; Index ranges = −29 ≤ h ≤ 38, −7 ≤ k ≤ 8,
−16 ≤ l ≤ 18; Reflections collected / Independent reflection = 13232/6139 [R(int) = 0.0734];
Completeness to theta = 25.02° 94.4%; Absorption correction = multi-scan; Max. and min.
transmission = 0.9839 and 0.9158; Refinement method = Full-matrix least-squares on F2; Data /
restraints / parameters = 6139/0/277; Goodness-of-fit on F2 = 1.183; Final R indices = [I>2sigma(I)]
R1 = 0.2457, wR2 = 0.4913; R indices (all data) = R1 = 0.2811, wR2 = 0.5062; Largest diff. peak and
hole = 1.222 and −0.713 e.Å−3.
4. Conclusions
In conclusion, we have successfully synthesized 2-methyl-3-(phenylthiomethyl)quinoline
derivatives in good yields from MBH adducts via a convenient one-pot procedure. The 2-methyl-3-
(phenylthiomethyl)quinoline reaction products of were transformed into the corresponding 2-methyl-3-
(phenylsulfonylmethyl)quinoline derivatives in good yields. The C3-alkylthiomethylquinolines are
very useful precursors for the synthesis of C3-alkylsulfonyl or C3-alkylsulfinyl containing quinoline
derivatives.

Molecules 2012, 17
5092
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/5/5081/s1.
Acknowledgements
Financial support for this work by the National Science Council of the Republic of China and the
National Taiwan Normal University (99T3030-2, 99-D, 100-D-06) is gratefully acknowledged.
References and Notes
1. Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 1997, 14, 605–608.
2. Bilker, O.; Lindo, V.; Panico, M.; Etiene, A.E.; Paxton, T.; Dell, A.; Rogers, M.; Sinden, R.E.;
Morris, H.R. Identification of xanthurenic acid as the putative inducer of malaria development in
the mosquito. Nature 1998, 392, 289–292.
3. Edmont, D.; Rocher, R.; Plisson, C.; Chenault, J. Synthesis and evaluation of quinoline
carboxyguanidines as antidiabetic agents. Bioorg. Med. Chem. Lett. 2000, 10, 1831–1834.
4. Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. Synthesis and antibacterial
evaluation of certain quinolone derivatives. J. Med. Chem. 2001, 44, 2374–2377.
5. Zhang, X.; Shetty, A.S.; Jenekhe, S.A. Electroluminescence and photophysical properties of
polyquinolines. Macromolecules 1999, 32, 7422–7429.
6. Xiong, H.; Kang, J.; Woods, J.M.; McCauley, J.P., Jr.; Koether, G.M.; Albert, J.S.; Hinkley, L.;
Li, Y.; Gadient, R.A.; Simpson, T.R. Synthesis and SAR of sulfoxide substituted carboxyquinolines
as NK3 receptor antagonists. Bioorg. Med. Chem. Lett. 2011, 21, 1896–1899.
7. Bruton, G. Sulphonyl Hydroxymic Acid Derivatives as Inhibitors of S-CD23. U.S. Patent WO
2004/067502, PCT/EP2004/000954, 2004.
8. Familoni, O.B.; Kaye, P.T.; Klaas, P.J. Application of Baylis-Hillman methodology in a novel
synthesis of quinoline derivatives. Chem. Commun. 1998, 2563–2564.
9. Familoni, O.B.; Klaas, P.J.; Lobb, K.A.; Pakade, V.E.; Kay, P.T. The Baylis-Hillman approach to
quinoline derivatives. Org. Biomol. Chem. 2006, 4, 3960–3965.
10. Basavaiah, D.; Reddy, R.M.; Kumaragurubaran, N.; Sharada, D.S. Applications of Baylis-Hillman
chemistry: One-pot convenient synthesis of functionalized (1H)-quinol-2-ones and quinolines.
Tetrahedron 2002, 58, 3693–3697.
11. Basavaiah, D.; Rao, J.S.; Reddy, R.J. Simple, facile, and one-pot conversion of the Baylis-
Hillman adducts into functionalized 1,2,3,4-tetrahydroacridines and cyclopenta[b]quinolines.
J. Org. Chem. 2004, 69, 7379–7382.
12. Basavaiah, D.; Veeraraghavaiah, G. The Baylis-Hillman reaction: A novel concept for creativity
in chemistry. Chem. Soc. Rev. 2012, 41, 68–78.
13. Zhong, W.; Liu, Y.; Wang, G.; Hong, L.; Chen, Y.; Chen, X.; Zheng, Y.; Zhang, W.; Ma, W.;
Shen, Y.; et al. Recent advances in construction of nitrogen-containing heterocycles from
Baylis-Hillman adducts. Org. Prep. Proc. Int. 2011, 43, 1–66.
14. Basavaiah, D.; Reddy, B.S.; Singh, B.S. Recent contributions from the Baylis-Hillman reaction to
organic chemistry. Chem. Rev. 2010, 110, 5447–5674.

Molecules 2012, 17
5093
15. Declerck, V.; Martinez, J.; Lamaty, F. aza-Baylis-Hillman reaction. Chem. Rev. 2009, 109, 1–48.
16. Singh, V.; Batra, S. Advances in the Baylis-Hillman reaction-assisted synthesis of cyclic
frameworks. Tetrahedron 2008, 64, 4511–4574.
17. Madapa, S.; Tusi, Z.; Batra, S. Advances in the syntheses of quinoline and quinoline-annulated
ring systems. Curr. Org. Chem. 2008, 12, 1116–1183.
18. Singh, V.; Hutait, S.; Batra, S. Reductive-cyclization-mediated synthesis of fused polycyclic
quinolines from Baylis-Hillman adducts of acrylonitrile: Scope and limitations. Eur. J. Org.
Chem. 2009, 3454–3466.
19. Ciganek, E. The catalyzed α-hydroxyalkylation and α-aminoalkylation of activated olefins (the
Morita-Baylis-Hillman reaction). Org. React. 1997, 51, 201–350.
20. Basavaiah, D.; Rao, P.D.; Hyma, R.S. The Baylis-Hillman reaction: A novel carbon-carbon bond
forming reaction. Tetrahedron 1996, 52, 8001–8062.
21. Basavaiah, D.; Rao, A.J.; Satyanarayana, T. Recent advances in the Baylis-Hillman reaction and
applications. Chem. Rev. 2003, 103, 811–892.
22. Han, E.-G.; Kim, H.J.; Lee, K.-J. Quinolines from Morita-Baylis-Hillman acetates of
2-azidobenzaldehydes. Tetrahedron 2009, 65, 9616–9625.
23. Cha, M.J.; Song, Y.S.; Lee, K.-J. Synthesis of symmetric diallyl disulfides from Baylis-Hillman
acetates. Bull. Korean Chem. Soc. 2006, 27, 1900–1902.
24. Das, B.; Chowdhury, N.; Damodar, K.; Banerjee, J. A mild and efficient stereoselective
synthesis of (Z)- and (E)-allyl sulfides and potent antifungal agent, (Z)-3-(4-
methoxybenzylidene)thiochroman- 4-one from Morita-Baylis-Hillman acetates. Chem. Pharm.
Bull. 2007, 55, 1274–1276.
25. Lee, H.-S.; Kim, S.H.; Kim, J.N. Regioselective synthesis of poly-substituted thiophenes from
Baylis-Hillman adducts.Tetrahedron Lett. 2009, 50, 6480–6483.
26. Ramesh, C.; Kavala, V.; Raju, B.R.; Kuo, C.W.; Yao, C.-F. Novel synthesis of indolylquinoline
derivatives via the C-alkylation of Baylis-Hillman adducts. Tetrahedron Lett. 2009, 50,
4037–4041.
27. Ramesh, C.; Kavala, V.; Kuo, C.W.; Raju, B.R.; Yao, C.-F. An unprecedented route for the
synthesis of 3,3'-biindoles by reductive cyclization of 3-[2-nitro-1-(2-nitrophenyl)ethyl]-1H-
indoles mediated by iron/acetic acid. Eur. J. Org. Chem. 2010, 3796–3801.
28. Ramesh, C.; Kavala, V.; Kuo, C.W.; Yao, C.-F. Iron/acetic acid-mediated carbon degradation:
A facile route for the synthesis of quinoline derivatives. Tetrahedron Lett. 2010, 51, 5234–5237.
29. Ramesh, C.; Raju, B.R.; Kavala, V.; Kuo, C.W.; Yao, C.-F. A simple and facile route for the
synthesis
of
2H-1,4-benzoxazin-3-(4H)-ones
via
reductive
cyclization
of
2-(2-
nitrophenoxy)acetonitrile adducts in the presence of Fe/acetic acid. Tetrahedron 2011, 67, 1187–
1192.
30. Reddy, D.J.; Kavala, V.; Bosco, J.J.W.; Kuo, C.W.; Yao, C.-F. An easy access to carbazolones
and 2,3-disubstituted indoles. Eur. J. Org. Chem. 2011, 2360–2365.
31. Shi, M.; Jiang, J.-K.; Li, C.-Q. Lewis base and L-proline co-catalyzed Baylis-Hillman reaction of
arylaldehydes with methyl vinyl ketone. Tetrahedron Lett. 2002, 43, 127–130.
32. CCDC number of the intermediate 3h is 836385. These data can be obtained free of charge from
Cambridge Crystallographic Data Center via http://www.ccdc.cam.ac.uk/datarequest/cif.

Molecules 2012, 17
5094
33. Petrov, K.G.; Zhang, Y.; Carter, M.; Cockerill, G.S.; Dickerson, S.; Gauthier, C.A.; Guo, Y.;
Mook, R.A.; Rusnak, D.W.; Walker, A.L.; et al. Optimization and SAR for dual ErbB-1/ErbB-2
tyrosine kinase inhibition in the 6-furanylquinazoline series. Bioorg. Med. Chem. Lett. 2006, 16,
4686–4691.
34. Dishington, A.; Fillery, S.; Finalay, M.R.V. A one-pot sulfide to sulfone oxidation with
m-chloroperoxybenzoic acid and sodium permanganate. Tetrahedron Lett. 2010, 51, 4211–4213.
Sample Availability: Samples of all compounds are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).