Modulating the reactivity of functionalized N,S-ketene acetal in MCR: Selective synthesis of tetrahydropyridines and thiochromeno[2,3-b]pyridines via DABCO-catalyzed tandem annulation

Article abstract of DOI:10.1021/jo202665q

An efficient and straightforward three-component synthetic protocol was developed to synthesize 1,2,3,4-tetrahydropyridine derivatives or thiochromeno[2,3-b]pyridine derivatives from β-aroylthioacetanilides or β-(2-haloaroyl)thioacetanilides, aldehydes, a

Full text of DOI:10.1021/jo202665q

Article
pubs.acs.org/joc
Modulating the Reactivity of Functionalized N,S-Ketene Acetal in
MCR: Selective Synthesis of Tetrahydropyridines and
Thiochromeno[2,3-b]pyridines via DABCO-Catalyzed Tandem
Annulation
Li-Rong Wen,* Yong-Jie Shi, Guang-Yuan Liu, and Ming Li*
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, 53 Zhengzhou Road, Qingdao 266042, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and straightforward three-component synthetic protocol was developed to synthesize 1,2,3,4-
tetrahydropyridine derivatives or thiochromeno[2,3-b]pyridine derivatives from β-aroylthioacetanilides or β-(2-haloaroyl)-
thioacetanilides, aldehydes, and aroyl acetonitriles via DABCO-catalyzed tandem [3 + 2 + 1] annulation and SNAr reaction. This
synthetic approach has the prominent features of high chemo-, stereo- (or enantio-), and unusual regioselectivity. In the domino
processes, at least seven reactive sites were involved, and up to three covalent bonds and one functionalized pyridine ring were
generated. This facile and efficient reaction is a quite general for the preparation of tetrahydropyridine derivatives or
thiochromeno[2,3-b]pyridine derivatives.
photosensitizing activities.6 They are also important reducing
INTRODUCTION
A major challenge of modern drug discovery is the design of
highly efficient chemical reaction sequences that provide
maximum structural complexity and diversity with a minimum
■
agents toward the application of the nicotinamide adenine
dinucleotide coenzyme [NAD(P)H] models.7 Many examples
of “privileged medicinal scaffolds” have the 1,4-dihydropyridine
scaffolds, such as nifedipine,8 which has been in clinical
number of synthetic steps to assemble compounds with
interesting properties.1 Multicomponent reactions (MCRs)
medicine since 1975. Quite recently, many novel second-
generation calcium antagonists have emerged with improved
have manifested themselves as a powerful tool for the rapid
introduction and expansion of molecular diversity.2 An
bioavailability and tissue selectivity/stability (such as Benidi-
pine and Lacidipine),9 and calcium agonists (such as BAY K
important asset of the approach is the significant increase of
the combinatorial possibilities, since a modification of the final
product is easily accomplished by implementing minor changes
in the reaction setup; this obviously allows considerable savings
in time and resources. These advantages are of particular
interest in pharmaceutical research for the construction of
8644) have been also discovered.10
A rapidly increasing recognition of the rich and fascinating
chemistry of the N,S- ketene acetals in organic synthesis has
been brought out in the past decades. Functionalized α-
oxoketene N,S-acetals with general structure 1 (Figure 1) have
libraries of biologically active compounds.3 Consequently, the
been proven to be important building blocks in the
construction of heterocyclic systems.11 Three or four active
design and development of new MCR routes for the generation
of heterocycles receive growing interest.4
centers determine the chemical properties of α-oxoketene N,S-
acetals. One of them is attributed to the nitrogen atom with an
The exploration of privileged structures in drug discovery is a
rapidly emerging theme in medicinal chemistry.5 1,4-
unshared electron pair, the second one, to the sulfur atom, the
third potential center, to the α-carbon due to the highly
Dihydropyridines, as the important “privileged scaffold”, are
polarized push (HS and RNH)−pull (CO) interaction on
very attractive targets for combinatorial library synthesis due to
their wide range of pharmaceutical activities, which have been
reported to be vasodilators, antihypertensives, and bronchodi-
the CC bond, and the last one, particularly significant, to a
lators, and to possess antiatherosclerotic, hepatoprotective,
antitumor, antimutagenic, antidiabetic, geroprotective, and
Received: December 25, 2011
Published: April 18, 2012
© 2012 American Chemical Society
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Figure 1. Functionalized α-oxoketene N,S-acetals.
Scheme 1. Two Directions of the Reaction
potential leaving halogen group on aromatic ring. Therefore,
precursors 1 could be used to develop a new strategy for the
synthesis of 1,2,3,4-tetrahydropyridine and thiochromeno[2,3-
b]pyridine derivatives.
RESULTS AND DISCUSSION
■
Our approach toward the design and development of new
domino and multicomponent procedures involves the use of
building block 1 that contains a number of chemically distinct
functionalities, which could be selectively reacted to generate
diversity with aldehydes 2 and 3-oxo-3-arylpropanenitriles 3.
So, the reaction may proceed in two directions (Scheme 1).
In direction 1, the intermediate [B] undergoes the
intramolecular N-cyclization by amino group attacking the
cyano group to produce 4 (X = H) and SNAr of the mercapto
group to give 5 (X = F, Cl, Br). In direction 2, the intermediate
[B] undergoes the intramolecular N-cyclization by amino group
attacking the carbonyl group to produce 4′ (X = H) and SNAr
of the amino group to give 5′ (X = F, Cl, Br). Surprisingly,
during our investigation, we did not detect 4′ or 5′, and only 4
and 5 were obtained exclusively. This observation is rare and
very interesting in organic chemistry. Our experimental results
demonstrated that the three-component reactions described
show high regioselectivity.
As part of our ongoing studies on the chemistry of
functionalized α-oxoketene N,S-acetals,12 we wish to report
herein a highly efficient three-component reaction based on β-
aroylthioacetanilides 1, aromatic aldehydes 2, and 3-oxo-3-aryl
propanenitriles 3, which provides high regio- and stereo-
selectively a straightforward entry to fully substituted
thiochromenopyridine derivatives and fully substituted 2-
thioxo-1,2,3,4-tetrahydropyridine derivatives, which are poten-
tial 1,4-dihydropyridine compounds due to tautomeric isomers
referring to thioenol or thione. To the best of our knowledge,
this synthetic strategy for 2-thioxo-1,2,3,4-tetrahydropyridine
and thiochromenopyridine derivatives has not been reported
before using functionalized N,S-ketene acetals as building
blocks and DABCO as a catalyst via MCR.
The initial attempt to perform a reaction of 3-oxo-N,3-
diphenylpropanethioamide 1a and 4-chlorobenzaldehyde 2a
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with 3-oxo-3-phenylpropanenitrile 3a was focused on the
optimization of the reaction conditions (Table 1). Initially,
preparation of 4a. Compared to other bases, DABCO has been
regarded as an unhindered and nucleophilic base, and
considered one of the best versatile amine catalysts because
of its unique properties.13
Table 1. Optimization of Reaction Conditions for the
a
To further demonstrate the scope and versatility of this
procedure for regiospecific synthesis of 1,2,3,4-tetrahydropyr-
idines 4, 11 β-aroylthioacetanilides 1 and 14 variously
substituted aldehydes 2 were examined for their reactions
with three aroyl acetonitriles 3 under the optimized conditions
(Table 2). As can be seen from Table 2, for precursors 1 and 2
bearing either electron-donating or electron-withdrawing
substituents on the aroyl group (for 1) or on the aromatic
ring (for 2), the reactions all proceeded very smoothly to
provide the corresponding pyridine derivatives. With regard to
the reactivities of precursors 1 and 2, it is very clear that the
reactions of various aromatic aldehydes 2 containing electron-
withdrawing substituents provided generally higher yields than
those containing an electron-donating substituent. For example,
the yields of 4a−f were obviously higher than the
corresponding ones of 4h−k, respectively (Table 2, entries
1−6 and 8−11). Aromatic aldehydes bearing an ortho
substituent showed certain steric hindrance (Table 2, entries
2 and 3), which led to a lower yield of the product. However,
when 3- or 4-nitrobenzaldehydes were employed, the reaction
system became disordered and did not give desired products.
The property of substituents on the aroyl group of β-
aroylthioacetanilides 1 did not assert an obvious effect on the
reaction yield (Table 2, entries 12−16). Our attempt to use
aliphatic aldehydes such as n-butanalaldehydes in this MCR was
unsuccessful, with no separable product being formed; instead,
significant tarring was observed, which was caused most likely
by self-condensation of the aliphatic aldehydes under this
reaction condition.
Synthesis of 4a
b
entry
catalyst/mmol %
solvent
time/h
20
yield /%
c
d
1
−
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
−
−
e
d
2
Et3N (1.0)
20
3
Et3N (0.5)
15
14
14
54
62
64
4
Et3N (1.0)
5
Et3N (1.5)
e
d
6
DABCO (0.2)
DABCO (0.2)
DABCO (0.5)
DABCO (1.0)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
pyridine (0.5)
DBU (0.5)
20
−
7
13
5.5
10
14
14
10
21
20
9
68
85
71
55
56
53
30
35
60
8
9
10
11
12
13
14
15
16
17
CH3CN
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
DMAP (0.5)
K2CO3 (0.5)
KOH (0.5)
d
20
20
−
−
d
a
Unless otherwise noted, reactions were carried out using 1a (1
mmol), 2a (1.2 mmol), and 3a (1 mmol) under refluxing. Isolated
b
c
d
e
In this domino process, two C−C bonds, one C−N bond,
and one six-membered ring were formed with the concomitant
creation. Importantly, this three-component reaction for
tetrahydropyridines 4 generates two chirality centers, but only
yield. No base. No reaction. At room temperature.
triethylamine was selected as a base in this reaction. The
reaction was carried out in the presence of 50 mmol %
triethylamine, affording the product 4a successfully in 54% yield
within 15 h (Table 1, entry 3). However, an additional increase
of the amount of Et3N to 100 or 150 mmol % did not improve
the yield of the product (Table 1, entries 4 and 5), and no
product was observed in the absence of a catalyst (Table 1,
entry 1). These results revealed that a base is favored to this
MCR. Then, other bases also were employed for this MCR.
First, DABCO (1,4-diazabicyclic[2,2,2]octane) was examined at
room temperature or under reflux condition (Table 1, entries 6
and 7), and the results suggested that DABCO in refluxing
EtOH as a catalyst was superior to Et3N. Furthermore, when
raising the amount of DABCO up to 50 mmol %, the yield of
4a reached 85%, and reaction time was shortened to 5.5 h
(Table 1, entry 8). However, further raising the amount of
DABCO did not obviously increase the yield (Table 1, entry 9).
Next, pyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), or
DMAP as a catalyst for this reaction also were investigated, but
the results were unsatisfactory (Table 1, entries 13−15). In
addition, the inorganic bases such as K2CO3 and KOH were
both ineffective for this reaction (Table 1, entries 16 and 17).
Screening of the solvents revealed that ethanol turned out to be
an appropriate solvent, which provided not only a shorter
reaction time, but also a higher yield than other examined
solvents such as DMF, CH3CN, THF (Table 1, entries 8 and
10−12). Therefore, the reaction conditions of 50 mmol %
DABCO as a catalyst in refluxing EtOH were best for the
1
one stereoisomer was observed through H NMR and 13C
NMR spectra, and X-ray diffraction analysis of 4i reveals that
the products 4 adopt trans configuration.
Functionalized thiochromones and their fused analogues are
of interest because they represent an important class of
heterocycles, many of them exhibit useful biological activities,
and many have been tested and applied as drugs.14 Although a
few known methods have been developed for thiochromone
structural motifs, partly because it is difficult to access,15 it is
still challenging to explore efficient synthetic routes for this
class of compounds.
Conducting a postcondensation reaction can generate more
complicated molecules.2e On the basis of the results as
described above and in continuation of our ongoing research
toward the discovery of new reactions for the synthesis of
heterocycles containing pyridine-based frameworks, we de-
signed a novel protocol by simply introducing an o-halo group
into the aryl ring of β-aroylthioacetanilides for the preparation
of thiochromeno[2,3-b]pyridine derivatives 5.
The broad tolerance for various R1 and R2 substituents to the
formation of 5 was investigated (Table 2, entries 18−31). The
results showed that whether it is electron-donating or electron-
withdrawing substituents on the aromatic ring of precursors 2,
the reaction could afford the corresponding thiochromeno[2,3-
b] pyridines 5 in good to excellent yields. Different to the
formation of 4, 4-nitrobenzaldehyde could react well with
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a
Table 2. Synthesis of Products 4 and 5 from Thioacetanilides
b
entry
1, R1
X
2, R2
2a, 4-Cl
3, R3
3a, H
4/5
time/h
yield /%
1
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
4a
4b
4c
4d
4e
4f
5.5
7.5
7
85
78
81
82
78
84
80
77
77
76
75
83
80
83
82
82
75
82
76
85
88
79
73
75
76
75
83
82
88
76
76
2
2b, 2-Cl
2c, 2, 4-Cl2
2d, 3-Br
2e, 3-F
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3b, 4-CH3
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3a, H
3c, 4-Cl
3c, 4-Cl
3
4
6.5
6
5
6
2f, 4-F
5.5
8
7
2g, H
4g
4h
4i
8
2h, 3,4-OCH2O
2i, 4-CH3
2j, 4-OCH3
2k, 3-OCH3
2a, 4-Cl
7.5
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4j
8.5
8
4k
4l
1b, 4-F
7
1c, 4-Cl
1d, 4-Br
1e, 4-CH3
1f, 4-OCH3
1a, H
2a, 4-Cl
4m
4n
4o
4p
4q
5a
5b
5c
5d
5e
5f
7.5
7.5
7
2a, 4-Cl
2a, 4-Cl
2a, 4-Cl
8
2c, 2, 4-Cl2
2a, 4-Cl
8.5
5.5
7
1g, 4-Cl
1g, 4-Cl
1g, 4-Cl
1g, 4-Cl
1g, 4-Cl
1g, 4-Cl
1g, 4-Cl
1g, 4-Cl
1g, 4-Cl
1h, 4-F
2b, 2-Cl
2l, 4-Br
6
2e, 3-F
6
2m, 2-F
7.5
8
2n, 4-NO2
2g, H
5g
5h
5i
6.5
8
2i, 4-CH3
2j, 4-OCH3
2a, 4-Cl
8
5j
6
1i, H
Br
Cl
Cl
Cl
2a, 4-Cl
5k
5l
7
1j, 4-(4-ClC6H4O)
1k, 6-Cl-3-F
1g, 4-Cl
2a, 4-Cl
6
2l, 4-Br
5m
5n
7
2h, 3,4-OCH2O
8
a
Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), and 3 (1 mmol), refluxing EtOH, DABCO (0.5 equiv) for products 4 or DABCO (1.0 equiv) for
b
products 5. Isolated yield.
precursors 1 to yield the desired product (Table 2, entry 23).
Moreover, β-aroylthioacetanilides 1 bearing an electron-
donating substituent provided higher yields than ones with an
electron-withdrawing substituent. For example, the yield of 5l
was higher than 5a (Table 2, entries 18 and 29), presumably
because of the higher electron density of the methylene, making
it easy to attack the carbonyl group of the aldehydes.
It is worthy to note that all isolated products only need
recrystallization rather than column chromatography. This ease
of purification makes this methodology facile, practical, and
rapid to execute.
Unfortunately, however, the results were unsatisfactory when
the N,S-ketene acetal 1 bearing either electron-donating or
electron-withdrawing substituents on the N-aryl group at p-
position, such as CH3, OEt, and CF3, were employed to react
with 2a and 3a to prepare compounds 4. The three N-(4-
substituted-phenyl)-3-oxo-3-phenylpropanethioamides only
gave an unexpected mixture, which could not be separated by
the conventional methods such as column chromatography and
recrystallization. On the basis of the fact that the N,S-ketene
acetal 1 bearing the CH3 and OEt on the N-aryl ring at p-
position, which should be helpful to arylamino group attacking
the cyano group, could not provide the expected products, we
inferred that the steric hindrance of the N-aryl ring might have
a great effect on the intramolecular N-cyclization by arylamino
group attacking the cyano group.
The structures of all new compounds were characterized by
1
IR, H NMR, 13C NMR, and HRMS spectroscopy. The regio-
and stereoselectivity outcome of the cycloaddition was
unambiguously ascertained by X-ray diffraction analysis of
single crystals of 4i and 5a (see Figure S1 in the Supporting
Information).
The possible mechanism for the formation of products 4/5 is
shown in Scheme 2. The Knoevenagel-type reaction of
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Scheme 2. Plausible Mechanism for the Formation of Products 4 and 5
aldehydes 2 with 3-oxo-3-arylpropanenitriles 3 results in the
formation of intermediates [A]. Then, the β-aroylthioacetani-
lides 1 undergo Michael addition to intermediates [A] to
generate in situ the intermediates [B], which successively form
[C] via the novel intramolecular N-cyclization by arylamino
group attacking the cyano group with less steric hindrance
between the arylamino and cyano groups, rather than [C]′,
which could be given by amino group attacking the carbonyl
carbon of aroyl group as in previous reports.16 Next, the
intermediates [C] would undergo a rapid imine−amine
tautomerization to give [D], and 1,2,3,4-tetrahydropyridines 4
are obtained. Finally, an intramolecular SNAr reaction of the
ortho-halogen by attack of mercapto group leads to a new and
highly functionalized thiochromenopyridines 5 with elimination
of a molecular HX. X-ray analysis of 4i and 5a reveals that there
exist intramolecular hydrogen bonds between amino on the
pyridine ring and carbonyl from 3, helping to further stabilize
the structures of the products, which further corroborate our
proposed mechanism.
pyridine derivatives from readily accessible starting materials.
The three-component reaction of β-aroylthioacetanilides or β-
(2-haloaroyl)thioacetanilides, aldehydes, and aroylacetonitriles
proceeds smoothly under DABCO-catalyzed conditions. This
synthetic approach has the prominent features of high chemo-,
regio-, and stereoselectivity, high efficiency, good yields, as well
as broad scope of substrate tolerance. This study not only adds
a useful entry to increasingly demanding multicomponent
reactions, but also provides plenty of novel tetrahydropyridine
or thiochromeno[2,3-b]pyridine compounds with structural
diversity for further bioassay.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Products 4 and 5
(4a). A mixture of 3-oxo-N,3-diphenylpropanethioamide 1a (1 mmol,
0.255 g), 4-chlorobenzaldehyde 2a (1.2 mmol, 0.169 g), and 3-oxo-3-
phenylpropanenitrile 3a (1 mmol, 0.145 g) was refluxed for 5.5 h in
EtOH (15 mL) containing DABCO (0.5 mmol, 0.110 g). After
completion of the reaction as indicated by TLC (petroleum ether−
EtOAc, 2:1, v/v), the mixture was cooled to room temperature, and
the solid product was filtered, washed with EtOH, and subsequently
dried and recrystallized from EtOH to give the pure product 4a.
((3R,4R)-6-Amino-4-(4-chlorophenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydropyridine-3,5-diyl)bis(phenylmethanone)
CONCLUSION
■
In summary, we have developed an efficient method for the
synthesis of tetrahydropyridine or thiochromeno[2,3-b]-
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(4a). Yellow powder: mp 243−245 °C; 1H NMR (500 MHz, DMSO-
d6) δ 4.16 (s, 1H), 5.58 (d, J = 2 Hz, 1H), 6.35−8.08 (m, 19H); 13C
NMR (125 MHz, DMSO-d6) δ 40.9, 67.9, 88.1, 125.0, 128.0, 128.7,
128.9, 129.2, 129.4, 129.7, 130.1, 130.3, 130.8, 132.1, 134.3, 134.9,
138.7, 140.4, 141.4, 156.5, 192.3, 196.3, 201.8; IR (KBr) υ 3440, 3059,
2924, 1673, 1615, 1597, 1489, 1459, 1305, 1195, 1124, 774, 701, 604
cm−1; HRMS (ESI-TOF, [M + H]+) calcd for C31H24ClN2O2S,
523.1247, found 523.1262.
NMR (500 MHz, DMSO-d6) δ 4.11 (d, J = 2 Hz, 1H), 5.59 (d, J = 2
Hz, 1H), 6.04 (s, 2H), 6.41−8.09 (m, 18H); 13C NMR (125 MHz
DMSO-d6) δ 41.1, 68.2, 88.7, 101.6, 107.8, 108.7, 120.4, 125.2, 127.9,
128.6, 128.8, 129.6, 130.0, 130.8, 134.2, 135.0, 135.2, 138.8, 141.5,
146.7, 148.2, 156.4, 192.3, 196.3, 202.0; IR (KBr) υ 3437, 3057, 2891,
1683, 1620, 1483, 1462, 1356, 1298, 1196, 1121, 1040, 775, 700, 601
cm−1; HRMS (ESI-TOF, [M + H]+) calcd for C32H25N2O4S,
533.1535, found 533.1538.
((3R,4S)-6-Amino-4-(2-chlorophenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydropyridine-3,5-diyl)bis(phenylmethanone)
(4b). Yellow powder: mp 258−259 °C; 1H NMR (500 MHz, DMSO-
d6) δ 4.33 (d, J = 1.5 Hz, 1H), 5.28 (d, J = 1.5 Hz, 1H), 6.37−7.96 (m,
19H); 13C NMR (125 MHz, DMSO-d6) δ 39.0, 65.8, 88.6, 124.9,
128.0, 128.4, 128.5, 128.8, 129.3, 129.6, 129.8, 130.2, 130.4, 130.9,
132.3, 134.1, 135.7, 138.2, 138.7, 141.4, 157.2, 192.2, 196.9, 201.4; IR
(KBr) υ 3408, 3060, 2926, 1674, 1615, 1580, 1489, 1461, 1359, 1312,
1262, 1194, 1122, 978, 756, 693, 601 cm−1; HRMS (ESI-TOF, [M +
H]+) calcd for C31H24ClN2O2S, 523.1247, found 523.1251.
((3R,4R)-6-Amino-1-phenyl-2-thioxo-4-p-tolyl-1,2,3,4-tetra-
hydropyridine-3,5-diyl)bis(phenylmethanone) (4i). Yellow pow-
der: mp 251−252 °C; 1H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H),
4.16 (s, 1H), 5.56 (s, 1H), 6.39−8.07 (m, 19H); 13C NMR (125 MHz,
DMSO-d6) δ 21.0, 41.0, 68.3, 88.4, 125.2, 127.3, 127.9, 128.6, 128.8,
129.7, 129.9, 130.1, 130.3, 130.7, 134.3, 134.9, 136.5, 138.4, 138.8,
141.5, 156.5, 192.3, 196.4, 202.0; IR (KBr) υ 3439, 3066, 2856, 1673,
1617, 1596, 1459, 1351, 1312, 1296, 1193, 1124, 697, 604 cm−1;
HRMS (ESI-TOF, [M + H]+) calcd for C32H27N2O2S, 503.1788,
found 503.1780.
((3R,4S)-6-Amino-4-(2,4-dichlorophenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydropyridine-3,5-diyl)bis(phenylmethanone)
(4c). Yellow powder: mp 247−249 °C; 1H NMR (500 MHz, DMSO-
d6) δ 4.26 (d, J = 2 Hz, 1H), 5.24 (d, J = 2 Hz, 1H), 6.34−7.93 (m,
18H); 13C NMR (125 MHz, DMSO-d6) δ 38.7, 65.6, 88.3, 124.8,
128.1, 128.5, 128.8, 129.4, 129.8, 130.3, 130.9, 131.3, 133.2, 133.3,
134.1, 135.6, 137.5, 138.7, 141.3, 157.1, 192.2, 196.7, 201.2; IR (KBr)
υ 3435, 3061, 2927, 1671, 1616, 1490, 1456, 1301, 1193, 1123, 697,
604 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for C31H23Cl2N2O2S,
557.0857, found 557.0853.
((3R,4R)-6-Amino-4-(4-methoxyphenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydro-pyridine-3,5-diyl)bis(phenylmethanone)
1
(4j). Yellow powder: mp 223−225 °C; H NMR (500 MHz, DMSO-
d6) δ 3.73 (s, 3H), 4.11 (d, J = 2 Hz, 1H), 5.53 (d, J = 2 Hz, 1H),
6.37−8.04 (m, 19H); 13C NMR (125 MHz, DMSO-d6) δ 55.5, 68.4,
88.8, 114.6, 125.3, 127.9, 128.5, 128.7, 128.8, 129.7, 130.1, 130.8,
133.3, 134.3, 135.1, 138.9, 141.6, 156.4, 158.6, 192.4, 196.3, 202.1; IR
(KBr) υ 3412, 3066, 2920, 1683, 1611, 1508, 1457, 1305, 1199, 1123,
696, 669, 604 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for
C32H27N2O3S, 519.1733, found 519.1742.
((3R,4R)-6-Amino-4-(3-bromophenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydropyridine-3,5-diyl)bis(phenylmethanone)
(4d). Yellow powder: mp 244−245 °C; 1H NMR (500 MHz, CDCl3)
δ 4.26 (d, J = 2 Hz, 1H), 5.41 (d, J = 2 Hz, 1H), 6.59−7.96 (m, 19H);
13C NMR (125 MHz, CDCl3) δ 41.3, 67.4, 88.8, 123.1, 125.3, 125.5,
127.7, 128.1, 128.4, 128.6, 129.1, 129.8, 130.1, 130.2, 130.6, 130.8,
133.7, 134.8, 138.2, 140.9, 144.0, 155.8, 193.8, 194.8, 200.4; IR (KBr)
υ 3395, 3052, 2988, 1685, 1612, 1458, 1294, 1201, 1123, 694, 601
cm−1; HRMS (ESI-TOF, [M + H]+) calcd for C31H24BrN2O2S,
567.0742, found 567.0742.
((3R,4R)-6-Amino-4-(3-methoxyphenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydro-pyridine-3,5-diyl)bis(phenylmethanone)
(4k). Yellow powder: mp 225−226 °C; 1H NMR (500 MHz, CDCl3)
δ 3.81 (s, 3H), 4.27 (d, J = 2 Hz, 1H), 5.48 (d, J = 2 Hz, 1H), 6.64−
7.97 (m, 19H); 13C NMR (125 MHz, CDCl3) δ 41.5, 55.3, 67.6, 89.4,
111.9, 113.6, 119.2, 125.5, 127.7, 128.2, 128.5, 129.1, 129.9, 130.1,
130.5, 130.7, 133.6, 134.9, 138.4, 141.1, 143.4, 155.7, 160.1, 194.0,
195.1, 201.0; IR (KBr) υ 3401, 2921, 2851, 1682, 1614, 1456, 1304,
1198, 1123, 695, 669, 602 cm−1; HRMS (ESI-TOF, [M + H]+) calcd
for C32H27N2O3S, 519.1743, found 519.1742.
((3R,4R)-6-Amino-4-(3-fluorophenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydropyridine-3,5-diyl)bis(phenylmethanone)
(4e). Yellow powder: mp 233−235 °C; 1H NMR (500 MHz, DMSO-
d6) δ 4.17 (d, J = 2 Hz, 1H), 5.61 (d, J = 2 Hz, 1H), 6.34−8.07 (m,
19H); 13C NMR (125 MHz, DMSO-d6) δ 41.1, 67.7, 88.1, 114.2,
114.4, 114.6, 123.5, 125.1, 127.9, 128.7, 128.9, 129.7, 130.1, 130.8,
131.3, 134.3, 134.9, 138.7, 141.4, 144.5, 156.5, 161.8, 163.8, 192.3,
196.2, 201.8; IR (KBr) υ 3447, 3396, 3060, 2985, 1683, 1612, 1489,
1458, 1357, 1303, 1198, 1123, 693, 601 cm−1; HRMS (ESI-TOF, [M
+ H]+) calcd for C31H24FN2O2S, 507.1543, found 507.1533.
((3R,4R)-6-Amino-4-(4-fluorophenyl)-1-phenyl-2-thioxo-
1,2,3,4-tetrahydropyridine-3,5-diyl)bis(phenylmethanone)
((4R,5R)-2-Amino-4-(4-chlorophenyl)-5-(4-fluorobenzoyl)-1-
phenyl-6-thioxo-1,4,5,6-tetrahydropyridin-3-yl)(phenyl)-
1
methanone (4l). Yellow powder: mp 233−234 °C; H NMR (500
MHz, CDCl3) δ 4.23 (d, J = 2 Hz, 1H), 5.38 (d, J = 2 Hz, 1H), 6.63−
7.99 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 41.1, 67.4, 88.9,
116.2, 116.4, 125.2, 127.7, 128.2, 128.7, 129.2, 129.7, 130.2, 130.6,
131.1, 133.3, 138.1, 140.0, 140.9, 155.7, 165.1, 167.0, 193.2, 193.8,
200.1; IR (KBr) υ 3447, 2852, 1682, 1615, 1457, 1294, 1198, 1124,
701, 669, 602 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for
C31H23ClFN2O2S, 541.1153, found 541.1162.
((4R,5R)-2-Amino-5-(4-chlorobenzoyl)-4-(4-chlorophenyl)-1-
phenyl-6-thioxo-1,4,5,6-tetrahydropyridin-3-yl)(phenyl)-
1
1
(4f). Yellow powder: mp 248−249 °C; H NMR (500 MHz, DMSO-
methanone (4m). Yellow powder: mp 223−224 °C; H NMR (500
d6) δ 4.14 (s, 1H), 5.56 (d, J = 1.5 Hz, 1H), 6.34−8.06 (m, 19H); 13
C
MHz, CDCl3) δ 4.21 (d, J = 2 Hz, 1H), 5.36 (d, J = 2 Hz, 1H), 6.61−
7.87 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 41.1, 67.5, 88.8,
125.2, 127.8, 128.2, 128.7, 129.3, 129.4, 129.7, 130.2, 130.6, 133.1,
133.3, 138.1, 139.9, 140.3, 140.8, 155.7, 193,7, 200.0; IR (KBr) υ 3423,
3061, 2927, 1684, 1613, 1457, 1356, 1304, 1199, 1124, 700, 604 cm−1;
HRMS (ESI-TOF, [M + H]+) calcd for C31H23Cl2N2O2S, 557.0868,
found 557.0857.
NMR (125 MHz, DMSO-d6) δ 40.7, 68.1, 88.4, 115.9, 116.1, 125.1,
127.9, 128.7, 128.9, 129.4, 129.5, 129.7, 130.1, 130.8, 134.3, 134.9,
137.5, 138.7, 141.4, 156.3, 156.4, 160.6, 162.5, 192.4, 196.3, 201.9; IR
(KBr) υ 3424, 3062, 2914, 1677, 1621, 1581, 1504, 1460, 1354, 1308,
1198, 1122, 696, 603 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for
C31H24FN2O2S, 507.1543, found 507.1521.
((3R,4R)-6-Amino-1,4-diphenyl-2-thioxo-1,2,3,4-tetrahydro-
pyridine-3,5-diyl)bis(phenylmethanone) (4g). Yellow powder:
mp 244−245 °C; 1H NMR (500 MHz, DMSO-d6) δ 4.21 (d, J = 1 Hz,
1H), 5.60 (d, J = 1 Hz, 1H), 6.89−8.09 (m, 20H); 13C NMR (125
MHz, DMSO-d6) δ 41.4, 68.1, 88.4, 125.2, 127.4, 127.5, 127.9, 128.6,
128.8, 129.3, 129.7, 130.1, 130.8, 134.3, 135.0, 138.8, 141.5, 156.2,
156.3, 156.4, 192.4, 196.3, 201.9; IR (KBr) υ 3439, 3066, 2856, 1673,
1617, 1596, 1459, 1351, 1312, 1296, 1193, 1124, 697, 604 cm−1;
HRMS (ESI-TOF, [M + H]+) calcd for C31H25N2O2S, 489.1637,
found 489.1619.
((4R,5R)-2-Amino-5-(4-bromobenzoyl)-4-(4-chlorophenyl)-1-
phenyl-6-thioxo-1,4,5,6-tetrahydropyridin-3-yl)(phenyl)-
1
methanone (4n). Yellow powder: mp 240−242 °C; H NMR (500
MHz, CDCl3) δ 4.21 (d, J = 2 Hz, 1H), 5.34 (d, J = 2 Hz, 1H), 6.60−
7.77 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 41.0, 67.5, 88.8,
125.2, 127.8, 128.2, 128.7, 129.0, 129.3, 129.7, 129.8, 130.2, 130.6,
132.4, 133.3, 133.5, 138.0, 139.9, 155.7, 193.7, 193.9, 200.0; IR (KBr)
υ 3428, 2923, 2852, 1684, 1615, 1457, 1357, 1305, 1199, 1124, 700,
604 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for C31H23BrClN2O2S,
601.0352, found 601.0359.
((3R,4R)-6-Amino-4-(benzo[d][1,3]dioxol-5-yl)-1-phenyl-2-
thioxo-1, 2,3, 4-tetra-hydropyridine-3, 5-diyl)bis-
(phenylmethanone) (4h). Yellow powder: mp 240−242 °C; 1H
((4R,5R)-2-Amino-4-(4-chlorophenyl)-5-(4-methylbenzoyl)-
1-phenyl-6-thioxo-1,4,5,6-tetrahydropyridin-3-yl)(phenyl)-
1
methanone (4o). Yellow powder: mp 224−225 °C; H NMR (500
4257
dx.doi.org/10.1021/jo202665q | J. Org. Chem. 2012, 77, 4252−4260

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 2.48 (s, 3H), 4.28 (d, J = 2 Hz, 1H), 5.41 (d, J = 2 Hz,
1H), 6.60−7.85 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 21.8, 41.1,
67.3, 89.0, 125.3, 127.7, 128.1, 128.2, 128.6, 129.2, 129.8, 130.2, 130.7,
132.1, 133.1, 138.2, 140.2, 140.9, 144.8, 155.7, 193.8, 194.5, 200.9; IR
(KBr) υ 3423, 2925, 2854, 1675, 1618, 1457, 1356, 1305, 1195, 1126,
701, 603 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for
C32H26ClN2O2S, 537.1404, found 537.1400.
128.4, 128.5, 129.2, 130.1, 131.0, 131.1, 131.4, 131.9, 132.5, 132.6,
134.6, 134.8, 137.1, 142.3, 148.7, 154.6, 154.7, 160.4, 162.4, 176.5,
193.1; IR (KBr) υ 3458, 3055, 1620, 1580, 1542, 1487, 1444, 1388,
1352, 1269, 1228, 1139, 752, 696 cm−1; HRMS (ESI-TOF, [M + H]+)
calcd for C31H21ClFN2O2S, 539.0996, found 539.0983.
(R)-2-Amino-3-benzoyl-8-chloro-4-(4-nitrophenyl)-1-phe-
nyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one (5f). Yellow pow-
der: mp 203−206 °C; 1H NMR (500 MHz, DMSO-d6) δ 5.65 (s, 1H),
7.14−7.17 (m, 4H), 7.39−8.16 (m, 13H); 13C NMR (125 MHz,
DMSO-d6) δ 37.8, 88.2, 116.5, 124.1, 126.6, 126.8, 127.3, 128.3, 128.7,
129.4, 130.2, 131.1, 131.4, 132.0, 134.1, 134.9, 137.3, 142.0, 146.3,
148.9, 154.2, 155.0, 176.6, 192.8; IR (KBr) υ 3455, 3061, 1615, 1583,
1518, 1446, 1389, 1346, 1267, 1223, 700 cm−1; HRMS (ESI-TOF, [M
+ H]+) calcd for C31H21ClN3O4S, 566.0941, found 566.0961.
(R)-2-Amino-3-benzoyl-8-chloro-1,4-diphenyl-1H-
thiochromeno[2,3-b]pyridin-5(4H)-one (5g). Yellow powder: mp
((4R,5R)-2-Amino-4-(4-chlorophenyl)-5-(4-methoxybenzo-
yl)-1-phenyl-6-thioxo-1,4,5,6-tetrahydropyridin-3-yl)(phenyl)-
1
methanone (4p). Yellow powder: mp 245−246 °C; H NMR (500
MHz, CDCl3) δ 3.93 (s, 3H), 4.28 (d, J = 1.5 Hz, 1H), 5.41 (d, J = 1.5
Hz, 1H), 6.63−7.95 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 41.2,
55.6, 67.1, 89.1, 114.3, 125.4, 127.5, 127.7, 128.1, 128.2, 128.5, 129.1,
129.8, 130.1, 130.6, 130.8, 133.1, 138.3, 140.3, 141.0, 155.7, 164.1,
193.1, 193.8, 201.0; IR (KBr) υ 3424, 2922, 2851, 1670, 1613, 1600,
1458, 1306, 1199, 1171, 1125, 702, 603 cm−1; HRMS (ESI-TOF, [M
+ H]+) calcd for C32H26ClN2O3S, 553.1353, found 553.1372.
1
217−220 °C; H NMR (500 MHz, DMSO-d6) δ 5.59 (s, 1H), 6.96−
8.19 (m, 18H); 13C NMR (125 MHz, DMSO-d6) δ 37.3, 89.4, 118.0,
126.6, 126.7, 127.0, 127.1, 127.6, 128.6, 128.8, 129.4, 130.3, 131.0,
131.5, 131.9, 134.5, 134.9, 137.2, 142.2, 146.9, 148.0, 155.3, 176.8,
192.8; IR (KBr) υ 3435, 3051, 2923, 1612, 1585, 1489, 1442, 1391,
1355, 1218, 1135, 832, 747, 700 cm−1; HRMS (ESI-TOF, [M + H]+)
calcd for C31H22ClN2O2S, 521.1091, found 521.1098.
((3R,4S)-6-Amino-4-(2,4-dichlorophenyl)-5-(4-methylbenzo-
yl)-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyridin-3-yl)(phenyl)-
1
methanone (4q). Yellow powder: mp 243−244 °C; H NMR (500
MHz, CDCl3) δ 2.22 (s, 3H), 4.52 (d, J = 2 Hz, 1H,), 5.35 (d, J = 2
Hz, 1H), 6.47−8.01 (m, 17H); 13C NMR (125 MHz, CDCl3) δ 21.2,
38.7, 65.1, 89.1, 125.0, 127.5, 128.0, 128.4, 128.5, 128.7, 129.7, 130.0,
130.1, 130.2, 130.6, 130.7, 133.4, 133.5, 133.9, 135.5, 137.1, 137.8,
138.1, 138.6, 156.5, 193.8, 195.9, 200.6; IR (KBr) υ 3448, 3063, 2923,
1677, 1612, 1453, 1303, 1195, 1122, 1048, 750, 696, 599 cm−1; HRMS
(ESI-TOF, [M + H]+) calcd for C32H25Cl2N2O2S, 571.1008, found
571.1013.
(R)-2-Amino-3-benzoyl-8-chloro-1-phenyl-4-p-tolyl-1H-
thiochromeno[2,3-b]pyridin-5(4H)-one (5h). Yellow powder: mp
247−248 °C; 1H NMR (500 MHz, DMSO-d6) δ 2.17 (s, 3H), 5.57 (s,
1H), 6.88−6.99 (m, 4H), 7.21−8.19 (m, 13H); 13C NMR (125 MHz,
DMSO-d6) δ 21.0, 36.7, 89.3, 118.2, 126.5, 126.8, 127.0, 127.6, 128.4,
129.3, 130.2, 130.9, 131.4, 131.8, 134.5, 134.9, 135.6, 137.1, 142.2,
143.9, 147.7, 155.3, 176.8, 192.7; IR (KBr) υ 3409, 3048, 1616, 1580,
1536, 1489, 1445, 1395, 1353, 1274, 1226, 1136, 700 cm−1; HRMS
(ESI-TOF, [M + H]+) calcd for C32H24ClN2O2S, 535.1247, found
535.1255.
(R)-2-Amino-3-benzoyl-8-chloro-4-(4-chlorophenyl)-1-phe-
nyl-1H-thio-chromeno[2,3-b]pyridin-5(4H)-one (5a). Pale yellow
powder: mp 265−267 °C; 1H NMR (500 MHz, DMSO-d6) δ 5.55 (s,
1H), 6.95−7.24 (m, 6H), 7.39−8.19 (m, 11H); 13C NMR (125 MHz,
DMSO-d6) δ 36.9, 88.9, 117.6, 126.6, 126.9, 127.6, 128.6, 128.7, 128.9,
129.4, 130.3, 131.1, 131.2, 131.5, 132.0, 134.4, 134.9, 137.2, 142.2,
145.8, 148.3, 155.2, 176.8, 192.9; IR (KBr) υ 3462, 3062, 1612, 1581,
1487, 1446, 1389, 1271, 1223, 1137, 699 cm−1; HRMS (ESI-TOF, [M
+ H]+) calcd for C31H21Cl2N2O2S, 555.0701, found 555.0720.
(R)-2-Amino-3-benzoyl-8-chloro-4-(2-chlorophenyl)-1-phe-
nyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one (5b). Yellow
(R)-2-Amino-3-benzoyl-8-chloro-4-(4-methoxyphenyl)-1-
phenyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one (5i). Yellow
1
powder: mp 234−235 °C; H NMR (500 MHz, CDCl3) δ 3.72 (s,
3H), 5.69 (s, 1H), 6.70−8.34 (m, 17H); 13C NMR (125 MHz,
CDCl3) δ 36.5, 55.1, 90.5, 113.6, 119.1, 125.2, 126.7, 127.9, 128.0,
128.1, 128.2, 129.1, 130.5, 130.6, 131.0, 131.6, 134.3, 134.4, 137.6,
138.6, 141.4, 146.3, 154.2, 158.1, 177.5, 195.0; IR (KBr) υ 3448, 2929,
1614, 1582, 1507, 1490, 1447, 1265, 1224, 1137, 831, 701 cm−1;
HRMS (ESI-TOF, [M + H]+) calcd for C32H24ClN2O3S, 551.1213,
found 551.1196.
1
powder: mp 170−172 °C; H NMR (500 MHz, CDCl3) δ 5.92 (s,
1H), 6.65−6.98 (m, 3H), 7.15−8.23 (m, 14H); 13C NMR (125 MHz,
CDCl3) δ 39.4, 88.5, 115.1, 125.1, 125.7, 126.7, 127.4, 127.6, 128.0,
128.5, 129.1, 130.2, 130.4, 131.1, 131.8, 132.9, 133.7, 134.2, 137.6,
141.7, 141.8, 148.1, 153.7, 177.6, 195.3; IR (KBr) υ 3455, 3060, 1617,
1583, 1489, 1446, 1390, 1266, 1226, 1138, 757, 699 cm−1; HRMS
(ESI-TOF, [M + H]+) calcd for C31H21Cl2N2O2S, 555.0701, found
555.0728.
(R)-2-Amino-3-benzoyl-4-(4-chlorophenyl)-8-fluoro-1-phe-
nyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one (5j). Yellow pow-
1
der: mp 238−240 °C; H NMR (500 MHz, CDCl3) δ 5.75 (s, 1H),
6.97−8.45 (m, 17H); 13C NMR (125 MHz, CDCl3) δ 37.0, 89.9,
111.9, 112.1, 115.8, 116.0, 118.1, 126.1, 126.7, 128.3, 128.4, 128.7,
129.3, 130.6, 131.1, 131.8, 132.0, 132.0, 134.2, 135.0, 135.1, 141.3,
144.8, 146.7, 154.3, 162.8, 164.9, 177.4, 195.0; IR (KBr) υ 3467, 2925,
1618, 1592, 1480, 1447, 1271, 1224, 1136, 700, 608 cm−1; HRMS
(ESI-TOF, [M + H]+) calcd for C31H21ClFN2O2S, 539.0996, found
539.0986.
(R)-2-Amino-3-benzoyl-4-(4-bromophenyl)-8-chloro-1-phe-
nyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one (5c). Yellow pow-
der: mp 275−277 °C; 1H NMR (500 MHz, DMSO-d6) δ 5.53 (s, 1H),
6.89−7.17 (m, 4H), 7.35−8.18 (m, 13H); 13C NMR (125 MHz,
DMSO-d6) δ 36.9, 88.8, 126.6, 126.9, 127.5, 128.5, 129.2, 129.4, 130.3,
131.0, 131.4, 131.6, 131.9, 134.3, 134.9, 137.2, 142.1, 146.1, 148.3,
155.2, 170.7, 176.7, 192.8; IR (KBr) υ 3463, 3062, 1621, 1579, 1484,
1445, 1388, 1266, 1273, 1223, 1137, 698 cm−1; HRMS (ESI-TOF, [M
+ H]+) calcd for C31H21BrClN2O2S, 599.0196, found 599.0188.
(R)-2-Amino-3-benzoyl-8-chloro-4-(3-fluorophenyl)-1-phe-
nyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one (5d). Yellow
(R)-2-Amino-3-benzoyl-4-(4-chlorophenyl)-1-phenyl-1H-
thiochromeno[2,3-b]pyridin-5(4H)-one (5k). Yellow powder: mp
1
247−248 °C; H NMR (500 MHz, DMSO-d6) δ 5.59 (s, 1H), 6.97−
8.23 (m, 18H); 13C NMR (125 MHz, DMSO-d6) δ 36.9, 70.5, 89.0,
117.6, 127.0, 127.3, 128.3, 128.4, 128.6, 128.7, 128.9, 129.4, 131.1,
131.4, 131.9, 132.3, 133.2, 134.6, 136.7, 142.2, 146.0, 148.3, 155.4,
177.5, 192.8; IR (KBr) υ 3443, 3065, 2922, 1615, 1590, 1488, 1439,
1364, 1268, 1223, 1137, 701 cm−1; HRMS (ESI-TOF, [M + H]+)
calcd for C31H22ClN2O2S, 521.1075, found 521.1091.
1
powder: mp 244−245 °C; H NMR (500 MHz, DMSO-d6) δ 5.57
(s, 1H), 6.52−6.93 (m, 3H), 7.17−8.19 (m, 14H); 13C NMR (125
MHz, DMSO-d6) δ 37.2, 88.7, 113.4, 113.6, 113.7, 117.2, 123.0, 126.6,
126.9, 127.4, 128.6, 129.4, 130.3, 130.9, 131.0, 131.5, 132.0, 134.3,
134.9, 137.2, 142.1, 148.4, 149.7, 155.1, 161.3, 163.2, 176.8, 192.8; IR
(KBr) υ 3454, 3053, 1610, 1581, 1541, 1484, 1445, 1388, 1351, 1271,
1220, 1136, 697 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for
C31H21ClFN2O2S, 539.0996, found 539.0981.
(R)-2-Amino-3-benzoyl-8-(4-chlorophenoxy)-4-(4-chloro-
phenyl)-1-phenyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one
(5l). Yellow powder: mp 248−250 °C; 1H NMR (500 MHz, CDCl3) δ
5.74 (s, 1H), 6.83−8.39 (m, 21H); 13C NMR (125 MHz, CDCl3) δ
36.9, 89.9, 112.7, 118.1, 121.6, 124.7, 126.7, 128.3, 128.6, 129.2, 130.2,
130.5, 131.0, 131.3, 131.7, 131.9, 134.2, 135.0, 141.3, 144.8, 146.5,
153.7, 154.3, 159.9, 177.5, 194.8; IR (KBr) υ 3450, 2927, 1615, 1582,
1487, 1447, 1248, 1220, 1090, 701 cm−1; HRMS (ESI-TOF, [M +
H]+) calcd for C37H25Cl2N2O3S, 647.0963, found 647.0975.
(S)-2-Amino-3-benzoyl-8-chloro-4-(2-fluorophenyl)-1-phe-
nyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-one (5e). Yellow pow-
der: mp 251−253 °C; 1H NMR (500 MHz, DMSO-d6) δ 5.65 (s, 1H),
6.51−6.99 (m, 3H), 7.09−8.11 (m, 14H); 13C NMR (125 MHz,
DMSO-d6) δ 35.3, 88.0, 115.0, 115.9, 116.1, 123.8, 126.5, 126.9, 127.4,
4258
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Article
(R)-2-Amino-4-(4-bromophenyl)-6-chloro-3-(4-chlorobenzo-
yl)-9-fluoro-1-phenyl-1H-thiochromeno[2,3-b]pyridin-5(4H)-
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1
one (5m). Yellow powder: mp 278−279 °C; H NMR (500 MHz,
DMSO-d6) δ 5.61 (s, 1H), 6.96−7.67 (m, 15H); 13C NMR (125 MHz,
DMSO-d6) δ 36.9, 89.5, 116.4, 116.6, 119.0, 120.4, 124.6, 126.7, 128.1,
128.6, 128.9, 130.4, 131.3, 131.5, 132.0, 133.6, 135.2, 139.5, 140.2,
143.8, 144.9, 154.4, 155.0, 156.9, 177.2, 193.4; IR (KBr) υ 3443, 2927,
1617, 1592, 1487, 1445, 1263, 1225, 1137, 824, 775, 700 cm−1; HRMS
(ESI-TOF, [M + Na]+) calcd for C31H18BrCl2FN2O2SNa, 672.9526,
found 672.9533.
(R)-2-Amino-4-(benzo[d][1,3]dioxol-5-yl)-8-chloro-3-(4-
chlorobenzoyl)-1-phenyl-1H-thiochromeno[2,3-b]pyridin-
1
5(4H)-one (5n). Yellow powder: mp 279−280 °C; H NMR (500
MHz, CDCl3) δ 5.65 (s, 1H), 5.89 (d, 2H), 6.59−8.38 (m, 15H); 13
C
NMR (125 MHz, CDCl3) δ 36.8, 90.1, 100.8, 107.7, 107.9, 118.7,
120.1, 125.3, 127.8, 128.0, 128.3, 128.4, 130.5, 131.1, 131.7, 134.0,
134.3, 135.2, 137.7, 139.6, 140.0, 146.1, 146.5, 147.6, 154.4, 177.5,
193.3; IR (KBr) υ 3448, 2924, 1615, 1582, 1487, 1444, 1268, 1223,
1134, 928, 797, 698 cm−1; HRMS (ESI-TOF, [M + H]+) calcd for
C32H21Cl2N2O4S, 599.0594, found 599.0591.
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ASSOCIATED CONTENT
* Supporting Information
■
(9) Cosconati, S.; Marinelli, L.; Lavecchia, A.; Novellino, E. J. Med.
Chem. 2007, 50, 1504−1513.
S
Experimental procedures, ORTEP drawings of compounds 4i
and 5a, 1H and 13C NMR spectra of all new compounds, and X-
ray data for compounds 4i and 5a in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
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1983, 303, 535−537.
́
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Chem. 2005, 70, 9644−9647. (c) Venkatesh, C.; Singh, B.; Mahata, P.
K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7, 2169−2172. (d) Mahata, P.
K.; Venkatesh, C.; Syam, K. U. K.; Ila, H.; Junjappa, H. J. Org. Chem.
2003, 68, 3966−3975. (e) Zhang, Q.; Sun, S.; Hu, J.; Liu, Q.; Tan, J. J.
Org. Chem. 2007, 72, 139−143. (f) Zhao, Y.; Zhang, W.; Wang, S.; Liu,
Q. J. Org. Chem. 2007, 72, 4985−4988. (g) Rao, H. S. P.; Sivakumar, S.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: liming928@qust.edu.cn; wenlirong@qust.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (No. 20872074 and 21072110)
and the Natural Science Foundation of Shandong Province
(No. ZR2010BM007 and Z2008B03).
́
2005, 18, 3085−3094. (m) Jagodzinski, T. S.; Jacek, G. S.; Aneta, W.
Tetrahedron 2003, 59, 4183−4192. (n) Mathew, P.; Asokan, C. V.
Tetrahedron 2006, 62, 1708−1716. (o) Kumar, S.; Ila, H.; Junjappa, H.
J. Org. Chem. 2009, 74, 7046−7051.
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