A facile synthesis and discovery of highly functionalized tetrahydropyridines and pyridines as antimycobacterial agents

Article abstract of DOI:10.1248/cpb.58.602

The four-component reaction of ethyl-3-oxo-4-(arylsulfanyl)butanoate, substituted aromatic aldehydes and ammonium acetate afforded novel ethyl 4-hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylates. These tetrahydro-pyridine ester

Full text of DOI:10.1248/cpb.58.602

602
Regular Article
Chem. Pharm. Bull. 58(5) 602—610 (2010)
Vol. 58, No. 5
A Facile Synthesis and Discovery of Highly Functionalized Tetrahydro-
pyridines and Pyridines as Antimycobacterial Agents
Suresh Kumar RAJU,a Michael Rajesh STEPHEN,a Perumal SUBBU,*,a Banerjee DEBJANI,b
b
Yogeeswari PERUMAL,b and Sriram DHARMARAJAN
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University; Madurai 625021, India: and
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology &
Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad–500 078, Andhra Pradesh, India.
Received August 17, 2009; accepted January 28, 2010; published online February 3, 2010
The four-component reaction of ethyl-3-oxo-4-(arylsulfanyl)butanoate, substituted aromatic aldehydes and
ammonium acetate afforded novel ethyl 4-hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-tetrahydro-3-pyridinecar-
boxylates. These tetrahydro-pyridine esters upon dehydrogenation with dichlorodicyanobenzoquinone (DDQ)
afforded highly functionalized pyridines in excellent yields. These novel heterocycles were screened for their in
vitro activity against Mycobacterium tuberculosis H37Rv using agar dilution method. Among the compounds
screened, ethyl 2,6-di(2-bromophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecarboxylate was found to be the
most active with a minimum inhibitory concentration of 1.33 mM against Mycobacterium tuberculosis and is 5.74
and 38.17 times more potent than the first line anti-tuberculosis (TB) drugs, ethambutol and pyrazinamide re-
spectively.
Key words pyridinecarboxylate; Mannich reaction; stereochemistry; Mycobacterium tuberculosis
Piperidones serve an important role as intermediates to drugs or substance abuse or HIV/AIDS. The emergence of
substituted piperidines1—3) and they are found to be a part of multi-drug resistant TB (MDR-TB), defined as resistance to
more complex biologically active compounds.4) Apart from at least isoniazid and rifampicin, and the extensively drug re-
possessing analgesic,5,6) anti-inflammatory,5) central nervous sistant (XDR-TB) strains also impedes the discovery and the
system (CNS) depressant,7,8) local anesthetic,7,9) anticancer,10) development of new drugs.34,35) In the last 50 years, only a
and antimicrobial activities,11) piperidones are valuable syn- few drugs have been approved by the Food and Drug Admin-
thetic intermediates for the preparation of various alkaloids istration (FDA) for combating TB, which reflects the difficul-
and pharmaceuticals.12—14) Piperidones have also been used ties rampant in the discovery and clinical testing of new
as key chiral intermediates in the preparation of a large num- agents and the lack of pharmaceutical industry research in
ber of natural and synthetic compounds with significant anti- this area.36) Hence, the discovery of fast-acting effective
cancer,15) anti human immunodeficiency virus (HIV)16) and newer drugs to cure TB is imperative. Consequently, the
glycosidase inhibition17) activities. Tetrahydropyridine deriv- novel poly functionalized piperidines (viz. enol form of
atives are useful against several metabolic disorders and piperidones) and pyridines synthesized in the present work
human ailments and are involved in monoamine oxidase
based mechanism in Parkinson’s disease18,19) and as in-
hibitors of farnesyl transferase20) and dihydroorate dehydro-
genase21) and also play key roles in many disease processes.
The pyridine motif is found in various therapeutic agents,
including numerous antihistamines,22) antiseptic,23) antiar-
rythmic,24) antirheumatic,25) and other pharmaceutical agents
and natural products. They also play a pivotal role in catalyz-
ing both biological and chemical reactions.26) Highly func-
tionalized pyridines, including aryl- and heteroaryl-substi-
tuted derivatives, are widespread in the pharmaceutical and
agrochemical sectors.27,28) Due to their p-stacking ability,
some pyridines are used in supramolecular chemistry as
well.29,30) Hence the synthesis of polysubstituted piperidones
and pyridines is a topic of current interest.31,32) This prompted
us to perform the synthesis of poly substituted piperidines and
Chart 1. Synthesis of Tetrahydropyridines
pyridines and probe their biological potential.
It is pertinent to note that tuberculosis (TB) remains one of
the major causes of disability and death worldwide. The
WHO Global TB report released in March 200933) shows that
in 2007 there were an estimated 1.4 million new cases of tu-
berculosis among HIV-infected people and 456000 deaths. In
addition, the number of people contracting TB is on the rise,
as their immune systems are impaired by immunosuppressive
Chart 2. Synthesis of Pentasubstituted Pyridines
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: subbu.perum@gmail.com

May 2010
603
have been screened as a part of our programme to unearth
novel heterocyclic leads37—43) for antimycobacterial activities
and report the results in this paper.
Results and Discussion
Chemistry The four-component reaction of ethyl 3-oxo-
4-(arylsulfanyl)butanoates (1), substituted aromatic alde-
hydes and ammonium acetate afforded the hitherto unreport-
ed ethyl 4-hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-tetra-
hydro-3-pyridine-carboxylates (2—4) in moderate yields
(Chart 1) following the methodology reported by Baliah and
Noller for the synthesis of 2,6-diarylpiperidin-4-ones.44) The
ethyl 3-oxo-4-(arylsulfanyl)butanoates were prepared by a
literature method45) from the reaction of ethyl 4-chloro-
acetoacetate with substituted thiophenol in the presence of
Et3N in CH2Cl2.
Fig. 1. Selected HMBC Correlations of 2i (trans, trans)
A mixture of ethyl 3-oxo-4-(arylsulfanyl)butanoate, aro-
matic aldehyde and ammonium acetate in a molar ratio of
1 : 2 : 1 in ethanol was gently heated to boiling on a water
bath until orange colour appeared and then the reaction mix-
ture was kept aside for 1—2 d at ambient temperature. After
completion of the reaction, the viscous liquid was dissolved
in diethyl ether and the compound was isolated as hydrochlo-
ride, which was then neutralized with aqueous ammonia. The
product, comprising three diastereomeric enols, 2—4 was
extracted with ether and the enols separated by column chro-
matography.
Fig. 2. 1H and 13C Chemical Shifts of 2i (trans, trans)
The enols possess three stereocentres and exist in three di-
astereomeric forms, 2—4 differing in their configurations at
2, 5 and 6 positions. In case of entries 1—4, 9—12 and 17—
20 where the aryl ring is p-substituted, the isomer 2 predomi-
nates over 3 and 4. In 2, H-5 and H-6 are trans to each other
as evident from their J value of ca. 10 Hz and H-2 is trans to
H-6. In the case of b and c (entries 2 and 3), the isomer 4
predominates over 2, where the isomer 3 is not formed even
in traces. In the case of entries 5—7, 13—15, 21 and 22
Fig. 3. 1H and 13C Chemical Shifts of 3i (cis, cis)
(3e—g, 3m—o, 3u and 3v) where the aryl ring is o-substi- evident from its H,H-COSY correlation with H-6 and the
tuted, the isomer 3 is obtained as the sole product and it is signal at 53.9 ppm is assigned to C-5 from C,H-COSY corre-
pertinent to note that H-5 and H-6 are in cis relationship. lation. Further, H-5 shows HMBC correlation with C-3 be-
However, in the case of Rꢀꢁm-NO2 (entries 8, 6 and 23), the sides showing correlations with C-4 and C-6. The carbethoxy
isomers 2 and 3 was obtained as an inseparable mixture, as group affords a triplet at 0.93 ppm (Jꢁ7.2 Hz) and a multi-
they differ little in their Rf values. Repetition of this reaction plet at 3.89—4.02 ppm. The NH and aromatic hydrogens ap-
also confirmed this observation. In compound 4, H-5 and H- pear as a singlet and multiplet at 1.74 and 6.79—7.23 ppm
2 are respectively trans and cis to H-6. With the range of lim- respectively.
ited substituents on the aryl rings, it is not possible to discern
The 1H and 13C chemical shifts of 2i and 3i differ little. In
any firm trend on the influence of the substituents on the the case of 3i, H-6 appearing as a doublet at 4.51 ppm (Jꢁ
product distribution. The structure of the diasteromeric enols 2.1 Hz) is deshielded relative to H-6 of 2i. This may probably
was elucidated using NMR spectroscopic data, as illustrated be taken as an evidence for the stereochemistry of 3i, for
for 2i and 3i as representative examples. The relative orienta- which suitable crystals could not be grown and hence X-ray
tions of the aryl rings at 2 and 6 positions were unambiguously crystallographic studies could not be carried out. Presum-
determined by X-ray crystallographic studies (vide infra).
ably, the two phenyl rings in the case of 2i shield H-6, while
1
The H-NMR spectrum of 2i shows a singlet at 4.97 ppm the two phenyl rings in 3i are far away from H-6 and hence
ascribable to H-2 on the basis of its singlet nature and its het- the latter is not shielded. A doublet of doublets at 3.56 ppm
eronuclear multiple bond correlations (HMBC) (Fig. 1) with (Jꢁ2.1, 1.2 Hz) is due to H-5 of 3i, the J values respectively
(i) ipso- and ortho-carbons of the phenyl ring at C-2, (ii) C-3 ascribable to vicinal coupling with H-6 and allylic coupling
at 96.7 ppm, (iii) C-4 at 155.1 ppm, (iv) the carbethoxy car- with OH. The J value of 2.1 Hz discloses their cis relation-
bonyl at 169.0 ppm, and (v) C-6 at 56.2 ppm. The C,H-corre- ship as given in Fig. 3. The NH and OH hydrogens appear as
lation of H-2 in conjunction with its chemical shift assigns broad singlets at 1.92 and 6.08 ppm respectively. The 1H and
the signal at 56.8 ppm to C-2. From C,H-COSY correlation 13C chemical shifts of 2i and 3i are depicted in Figs. 2 and 3
spectra, the doublet at 3.72 ppm (Jꢁ10.1 Hz) is assigned to respectively. In the case of 4b, H-2 appears as a singlet at
H-6. The doublet at 3.82 ppm (Jꢁ10.1 Hz) is due to H-5 as 4.82 ppm and H-5, H-6 and CH2 of carbethoxy group occur

604
Vol. 58, No. 5
Fig. 4. ORTEP Diagram of 2k
Fig. 8. ORTEP Diagram of 5a
Fig. 5. ORTEP Diagram of 2t
Fig. 9. ORTEP Diagram of 5r
sulfanyl)pyridine-carboxylates (5) in good yield (Chart 2).
The major diastereomer in each case was subjected to dehy-
drogenation with DDQ. After completion of the reaction
(TLC), the precipitated DDQ-H2 was filtered off, the solvent
removed and the residue crystallized from ethanol to afford
the product 5.
The structure of 5 is in accord with its NMR spectroscopic
data. For instance, the 1H-NMR spectrum for 5a has a triplet
and a quartet at 0.78 and 3.98 ppm (Jꢁ7.2 Hz) due to the
ester function. The aromatic protons appear as a multiplet at
7.06—7.57 ppm, while the OH proton appears as a broad sin-
glet at 6.57 ppm. X-ray crystallographic studies50) (Figs. 8
and 9) also confirm the structure deduced from NMR spec-
troscopic data.
Fig. 6. ORTEP Diagram of 4b
Biology Keto esters (1), tetrahydropyridines (2—4) and
pyridines (5) were screened for their in vitro antimycobacter-
ial activity against Mycobacterium tuberculosis H37Rv
(MTB) by agar dilution method for the determination of min-
imum inhibitory concentration (MIC) in triplicates. The MIC
is defined as the minimum concentration of compound
required to completely inhibit the bacterial growth. The MIC
values of 1—5 along with the standard drugs for comparison
are furnished in Table 3.
Fig. 7. ORTEP diagram of 4c
The keto esters viz. ethyl 3-oxo-4-(arylsulfanyl)butanoates
as a multiplet at 3.78—3.95 ppm. The structures of 2 and 4 (1) afford MIC ꢂ91.66 mM indicating that they are not signif-
have been fully elucidated from X-ray crystallographic stud- icantly active against MTB. The tetrahydropyridine esters
ies46—49) (Figs. 4—7).
(2—4) showed good activity with MIC ranging from 6.50—
Subsequently, the ethyl 4-hydroxy-2,6-diaryl-5-(arylsul- 57.94 mM. All the tetrahydropyridine esters, except 2a,
fanyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylates (2—4) were showed good activity with higher activity than the first-line
dehydrogenated with dichlorodicyanobenzoquinone (DDQ) anti-TB drug pyrazinamide (MIC of 50.77 mM). Three com-
in refluxing benzene to yield 4-hydroxy-2,6-diaryl-5-(aryl- pounds, 2d, 2s and 2t, with MIC of 6.81, 6.50 and 6.61 mM

May 2010
605
Table 1. Synthesis of Tetrahydropyridines
Table 3. Anti-mycobacterial Activities of Ketoesters 1, Tetrahydropy-
ridines 2—4 and Pyridines 5
Yield (%)
Entry Compd.
R
Rꢀ
Compd.
(MTB)a)
Compd.
(MTB)a)
2
3
4
1a
1b
1c
2a
2d
2i
2j
2k
2l
2q
2r
2s
2t
3e
3f
3g
3n
3o
3p
3u
3v
3w
ꢂ104.91
ꢂ91.66
ꢂ99.08
57.94
6.81
4b
4c
5a
5b
5c
5d
5e
5f
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s, t
5u
5v
24.98
13.37
29.24
25.18
6.75
6.87
6.30
1.33
12.08
27.06
23.55
6.29
12.75
23.55
10.08
10.42
7.09
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
a
b
c
d
e
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
p-Cl
p-F
p-CH3
o-Cl
45
6
5
42
—
—
—
7
—
—
6
52
42
55
53a)
7
9
26
6
49
40
50
48a)
8
—
54
50
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
26.82
46.74
12.45
12.65
14.03
12.15
6.50
f
o-Br
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
o,p-Cl2
m-NO2
H
p-Cl
p-F
p-CH3
o-Cl
o-Br
o,p-Cl2
m-NO2
H
p-Cl
p-F
p-CH3
o-Cl
o,p-Cl2
m-NO2
46
49
28
46
—
—
—
6.61
12.49
21.21
21.96
40.08
41.40
46
50
28
50
—
—
6.13
b)
7
26
8
50
45
46a)
—
3.27
b)
12.15
42.84
—
5.40
23.52
b)
—
Isoniazid
0.36
0.12
Rifampicin
Ethambutol
Pyrazinamide
7.64
50.77
a) In case of Rꢀꢁm-NO2 the products were obtained as an inseperable mixture of di-
astereomers.
a) Minimum inhibitory concentrations (mM) against Mycobacterium tuberculosis.
b) Not tested.
Table 2. Synthesis of Pentasubstituted Pyridines
Entry
Compd. 5
R
Rꢀ
Yield (%)
(phenylsulfanyl)-3-pyridinecarboxylate (5f) showed the max-
imum activity with MIC of 1.33 mM. Compared to isoniazid
and rifampicin, all the compounds were less active. With re-
gard to structure–activity point of view, most of the pyridines
(5) were found to be more potent than the corresponding
tetrahydropyridines (2—4). Presumably, the pyridines with
enhanced planarity and hence less sterically demanding may
have an advantage over tetrahydropyridine enols in penetrat-
ing the mycobacterial cell wall. It is found that the presence
of (i) methyl group in the aryl ring of 5-arylsulfanyl moiety
and (ii) electron-withdrawing groups like halogens in the aryl
rings at 2,6-positions enhance the activity.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
p-Cl
p-F
p-CH3
o-Cl
o-Br
o,p-Cl2
m-NO2
H
p-Cl
p-F
p-CH3
o-Cl
o-Br
o,p-Cl2
H
p-Cl
p-F
p-CH3
o-Cl
o,p-Cl2
m-NO2
73
84
75
72
77
72
82
75
76
87
78
72
80
70
79
70
79
72
70
74
81
78
Conclusion
The present work describes a rapid access to a series of
ethyl 4-hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylates by the four-component reaction
of ethyl 3-oxo-4-(arylsulfanyl)butanoate, aromatic aldehyde
and ammonium acetate. These tetrahydropyridine esters un-
dergo facile dehydrogenation with DDQ to furnish the highly
functionalised pyridines in excellent yields. These novel het-
erocycles showed good to excellent in vitro activity against
t
u
v
respectively are more potent than the standard drug ethambu- Mycobacterium tuberculosis H37Rv. This protocol could be
tol (MIC of 7.64 mM). The pyridine esters 5 showed good ac- employed for generating a huge library of these biologically
tivity with MICs ranging from 1.33—29.24 mM. All the com- important compounds.
pounds of series 5 are more potent than pyrazinamide (MIC
of 50.77 mM). Ten compounds, 5c—g, 5k, 5p—r and 5u,
Experimental
General The melting points were taken using open capillary tubes and
with MIC ranging from 1.33—7.09 mM are active than the
are uncorrected. 1H, 13C and 2D NMR spectra were recorded on a Bruker
drug ethambutol (MIC of 7.64 mM).
In general, pyridines 5 display better activity than the
tetrahydropyridine esters (Table 3). Among all the com-
(Avance) 300 MHz instrument in CDCl3 using tetramethylsilane (TMS) as
internal standard. Chemical shifts are given in parts per million (d-scale)
and the coupling constants are given in Hertz. IR spectra were recorded on a
pounds screened, ethyl 2,6-di(2-bromophenyl)-4-hydroxy-5- JASCO FT IR instrument (KBr pellet in case of solids and CHCl3 in case of

606
Vol. 58, No. 5
50%); mp 158—160 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.81 (t, Jꢁ7.2 Hz,
3H, CH3), 3.77—3.95 (m, 3H, H-5, H-6, CH2), 4.83 (s, 1H, H-2), 6.89—
7.22 (m, 13H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.5, 56.0, 59.3,
59.4, 62.0, 98.7, 114.9, 115.1, 115.4, 115.7, 128.2, 129.4, 129.6, 129.7,
130.0, 132.9, 133.0, 137.5, 142.5, 160.6, 161.2, 163.8, 164.5, 155.5, 169.0.
viscous liquids). Elemental analyses were performed on a Perkin Elmer
2400 Series II Elemental CHNS analyser. High resolution mass spectra (HR-
MS) were recorded in Thermo-Scientific mass spectrometer using ESI
probe. Column chromatography was performed on silica gel (230—400
mesh) using petroleum ether–ethyl acetate (8 : 2 v/v) as eluent. Crystals suit-
able for X-ray crystallographic studies were obtained by recrystallisation
from petroleum ether–ethyl acetate mixture.
Synthesis of Ethyl 4-Hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-
tetrahydro-3-pyridinecarboxylates (2—4). General Procedure To a so-
lution of ammonium acetate (0.1 g, 1.3 mmol) in ethyl alcohol (30 ml), a
mixture of ethyl 3-oxo-4-(phenylsulfanyl)butanoate (0.3 g, 1.3 mmol) and
freshly distilled aromatic aldehyde (2.6 mmol) was added and warmed on a
water bath until the solution became orange and the reaction mixture set
aside at room temperature for 1—2 d. To this reaction mixture, diethyl ether
(100 ml) was added and the solid mass obtained was filtered off. To the clear
filtrate, concentrated hydrochloric acid (2 ml) was added with stirring. The
solid piperidine hydrochlorides obtained were washed with diethyl ether
(50 ml), suspended in acetone, neutralized with ammonia, diluted with ice-
water, extracted with diethyl ether, and dried over anhydrous sodium sul-
phate. After removing the solvent, the product mixture was separated in a
pure state by column chromatography over silica gel using petroleum
ether–ethyl acetate mixture as eluent. The products were further purified by
recrystalisation using petroleum ether–ethyl acetate (8 : 2 v/v).
IR (KBr)nmax: 749, 1232, 1262, 1528, 1602, 1668, 2987, 3309, 3455 cmꢃ1
;
Anal. Calcd for C26H23F2NO3S: C, 66.79; H, 4.96; N, 3.00. Found: C, 66.75;
H, 4.92; N, 3.05.
Ethyl 4-Hydroxy-2,6-di(4-methylphenyl)-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (2d): Isolated as colorless crystals; (0.242 g,
42%); mp 128—129 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.94 (t, Jꢁ7.2 Hz,
3H, CH3), 2.27 (s, 1H, CH3), 2.32 (s, 1H, CH3), 3.76 (d, Jꢁ10.2 Hz, 1H, H-
6), 3.82 (d, Jꢁ10.2 Hz, 1H, H-5), 3.87—4.03 (m, 2H, CH2), 4.93 (s, 1H, H-
2), 6.70—7.43 (m, 13H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.6,
54.0, 55.8, 56.7, 59.5, 96.6, 127.7, 128.4, 128.9, 129.2, 129.5, 129.6, 131.2,
135.4, 136.1, 138.1, 139.3, 141.7, 155.7, 169.1. IR (KBr)nmax: 738, 1229,
1260, 1520, 1601, 1667, 2988, 3306, 3449 cmꢃ1; Anal. Calcd for C28H29
NO3S: C, 73.17; H, 6.36; N, 3.05. Found: C, 73.12; H, 6.30; N, 3.00.
Ethyl 4-Hydroxy-2,6-di(4-methylphenyl)-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (3d): Isolated as colorless crystals; (0.035 g, 6%);
mp 111—112 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.85 (t, Jꢁ6.9 Hz, 3H,
CH3), 1.89 (br s, 1H, NH), 2.29 (s, 1H, CH3), 2.34 (s, 1H, CH3), 3.60 (d, Jꢁ
1.8 Hz, 1H, H-5), 3.84—4.10 (m, 2H, CH2), 4.44 (d, Jꢁ1.8 Hz, 1H, H-6),
4.93 (s, 1H, H-2), 6.00 (br s, 1H, OH), 6.89—7.47 (m, 13H, aromatic). 13C-
NMR (75 MHz, CDCl3) dC: 13.8, 21.1, 21.2, 58.2, 58.9, 58.9, 59.1, 96.4,
127.0, 127.2, 127.4, 127.9, 128.5, 128.7, 128.8, 132.8, 136.3, 136.7, 136.9,
143.0, 156.7, 169.0. IR (KBr)nmax: 740, 1225, 1262, 1526, 1607, 1662,
2984, 3312, 3445 cmꢃ1; Anal. Calcd for C28H29NO3S: C, 73.17; H, 6.36; N,
3.05. Found: C, 73.24; H, 6.31; N, 3.11.
Ethyl 4-Hydroxy-2,6-diphenyl-5-(phenylsulfanyl)-1,2,5,6-tetrahydro-3-
pyridine-carboxylate (2a): Isolated as white solid; (0.245 g, 45%); mp 116—
1
117 °C; H-NMR (300 MHz, CDCl3) dH: 0.92 (t, Jꢁ7.2 Hz, 3H, CH3), 3.79
(d, Jꢁ10.0 Hz, 1H, H-6), 3.84 (d, Jꢁ10.0 Hz, 1H, H-5), 3.88—4.12 (m, 2H,
CH2), 4.97 (s, 1H, H-2), 6.83—7.28 (m, 15H, aromatic). 13C-NMR (75
MHz, CDCl3) dC: 14.5, 53.9, 56.2, 57.0, 59.5, 96.3, 126.7, 127.8, 128.2,
128.4, 128.5, 128.9, 129.3, 129.6, 131.1, 135.4, 142.1, 144.6, 155.7, 169.0.
Ethyl 2,6-Di(2-chlorophenyl)-4-hydroxy-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (3e): Isolated as colorless crystals; (0.325 g,
52%); mp 141—142 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.84 (t, Jꢁ7.2 Hz,
3H, CH3), 1.94 (br s, 1H, NH), 3.77—3.97 (m, 2H, CH2), 3.98—4.05 (m,
1H, H-5), 4.81 (s, 1H, H-6), 5.55 (s, 1H, H-2), 6.18 (br s, 1H, OH), 6.93—
7.55 (m, 13H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 13.6, 54.1, 55.0,
56.3, 59.0, 95.3, 126.7, 127.1, 127.3, 127.9, 128.6, 128.7, 128.8, 128.9,
IR (KBr) nmax: 746, 1228, 1261, 1525, 1604, 1664, 2981, 3309, 3446 cmꢃ1
;
Anal. Calcd for C26H25NO3S: C, 72.36. H, 5.84; N, 3.25; Found: C, 72.30;
H, 5.88; N, 3.29.
Ethyl 4-Hydroxy-2,6-diphenyl-5-(phenylsulfanyl)-1,2,5,6-tetrahydro-3-
pyridine-carboxylate (3a): Isolated as colorless solid; (0.036 g, 7%); mp
112—114 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.83 (t, Jꢁ6.9 Hz, 3H, CH3),
1.72 (br s, 1H, NH), 3.62 (s, 1H, H-5), 3.85—4.12 (m, 2H, CH2), 4.51 (s,
1H, H-6), 4.97 (s, 1H, H-2), 6.07 (br s, 1H, OH), 6.90—7.38 (m, 15H, aro-
matic). 13C-NMR (75 MHz, CDCl3) dC: 14.2, 58.5, 59.4, 59.6, 60.0, 97.2,
127.3, 127.8, 128.0, 128.2, 128.4, 128.5, 129.3, 133.2, 136.2, 140.1, 146.3,
157.3, 169.3. IR (KBr) nmax: 745, 1226, 1260, 1526, 1602, 1667, 2984,
3313, 3442 cmꢃ1; Anal. Calcd for C26H25NO3S: C, 72.36; H, 5.84; N, 3.25.
Found: C, 72.32; H, 5.80; N, 3.31.
Ethyl 2,6-Di(4-chlorophenyl)-4-hydroxy-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (2b): Isolated as colorless crystals; (0.038 g, 6%);
mp 110—112 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.94 (t, Jꢁ7.2 Hz, 3H,
CH3), 3.70 (d, Jꢁ10.0 Hz, 1H, H-6), 3.76 (d, Jꢁ10.0 Hz, 1H, H-5), 3.89—
4.02 (m, 2H, CH2), 4.91 (s, 1H, H-2), 6.74—7.45 (m, 13H, aromatic). 13C-
NMR (75 MHz, CDCl3) dC: 14.5, 53.5, 55.6, 56.3, 59.6, 96.0, 128.4, 129.1,
129.2, 129.6, 129.7, 129.8, 130.6, 132.5, 134.2, 135.6, 140.3, 143.1, 155.5,
168.8. IR (KBr) nmax: 738, 1230, 1261, 1529, 1604, 1664, 2987, 3313,
3453 cmꢃ1; Anal. Calcd for C26H23Cl2NO3S: C, 62.40; H, 4.63; N, 2.80.
Found: C, 62.46; H, 4.57; N, 2.84.
Ethyl 2,6-Di(4-chlorophenyl)-4-hydroxy-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (4b): Isolated as colorless crystals; (0.340 g,
54%); mp 158—159 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.82 (t, Jꢁ7.2 Hz,
3H, CH3), 3.78—3.95 (m, 4H, H-5, H-6, CH2), 4.82 (s, 1H, H-2), 7.11—
7.23 (m, 13H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.2, 55.8, 59.4,
59.5, 62.1, 98.3, 128.3, 128.4, 128.9, 129.5, 129.6, 129.8, 132.7, 132.8,
132.9, 134.2, 140.1, 145.3, 155.5, 168.9. IR (KBr) nmax: 740, 1232, 1260,
1527, 1601, 1665, 2985, 3310, 3451 cmꢃ1; Anal. Calcd for C26H23Cl2NO3S:
C, 62.40; H, 4.63; N, 2.80. Found: C, 62.36; H, 4.69; N, 2.86.
Ethyl 2,6-Di(4-fluorophenyl)-4-hydroxy-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (2c): Isolated as colorless crystals; (0.030 g, 5%);
mp 109—110 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.91 (t, Jꢁ7.2 Hz, 3H,
CH3), 3.73 (d, Jꢁ9.5 Hz, 1H, H-6), 3.82 (d, Jꢁ9.5 Hz, 1H, H-5), 3.87—4.09
(m, 2H, CH2), 4.95 (s, 1H, H-2), 6.77—7.56 (m, 13H, aromatic). 13C-NMR
(75 MHz, CDCl3) dC: 14.6, 53.6, 55.4, 56.7, 59.7, 96.0, 115.0, 115.2, 115.5,
115.8, 128.3, 129.5, 129.7, 129.9, 130.2, 132.1, 133.1, 136.1, 143.7, 160.3,
161.2, 163.5, 165.2, 155.5, 168.3. IR (KBr) nmax: 737, 1231, 1263, 1530,
1604, 1665, 2989, 3314, 3451 cmꢃ1; Anal. Calcd for C26H23F2NO3S: C,
66.79; H, 4.96; N, 3.00. Found: C, 66.85; H, 4.91; N, 3.07.
129.9, 132.0, 132.4, 133.7, 135.6, 136.9, 143.4, 157.1, 168.5. IR (KBr) nmax
:
740, 1221, 1265, 1523, 1612, 1669, 2989, 3319, 3447 cmꢃ1; Anal. Calcd for
C26H23Cl2NO3S: C, 62.40; H, 4.63; N, 2.80. Found: C, 62.47; H, 4.58; N,
2.86.
Ethyl 2,6-Di(2-bromophenyl)-4-hydroxy-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (3f): Isolated as colorless crystals; (0.310 g,
42%); mp 135—136 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.90 (t, Jꢁ7.2 Hz,
3H, CH3), 1.97 (br s, 1H, NH), 3.88—4.07 (m, 2H, CH2), 4.20 (s, 1H, H-5),
4.77 (s, 1H, H-6), 5.48 (s, 1H, H-2), 6.98—7.58 (m, 13H, aromatic), 12.3 (s,
1H, OH). 13C-NMR (75 MHz, CDCl3) dC: 13.2, 52.8, 56.4, 58.6, 60.2,
100.6, 109.0, 122.7, 126.8, 126.9, 127.7, 128.3, 128.8, 130.1, 131.8, 133.3,
133.9, 134.3, 134.8, 134.9, 135.2, 142.3, 157.1, 170.5. IR (KBr) nmax: 741,
1224, 1262, 1520, 1614, 1667, 2990, 3317, 3445 cmꢃ1; Anal. Calcd for
C26H23Br2NO3S: C, 52.99; H, 3.93; N, 2.38. Found C, 53.05; H, 4.01; N,
2.30.
Ethyl 2,6-Di(2,4-dichlorophenyl)-4-hydroxy-5-(phenylsulfanyl)-1,2,5,6-
tetrahydro-3-pyridinecarboxylate (3g): Isolated as pale yellow solid; (0.395
g, 55%); mp 150—151 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.96 (t, Jꢁ
7.2 Hz, 3H, CH3), 1.88 (br s, 1H, NH), 3.92—4.09 (m, 2H, CH2), 4.15 (s,
1H, H-5), 4.74 (s, 1H, H-6), 5.44 (s, 1H, H-2), 7.02—7.31 (m, 9H, aro-
matic), 7.38 (d, Jꢁ1.8 Hz,1H, aromatic), 7.47 (d, Jꢁ8.4 Hz,1H, aromatic),
12.3 (s, 1H, OH). 13C-NMR (75 MHz, CDCl3) dC: 13.5, 52.8, 52.9, 56.1,
60.7, 100.6, 126.7, 127.3, 127.6, 128.4, 128.6, 129.9, 130.6, 132.1, 132.9,
133.3, 133.9, 134.3, 134.8, 134.9, 140.3, 170.4, 170.6. IR (KBr) nmax: 739,
1225, 1266, 1522, 1618, 1668, 2988, 3317, 3441 cmꢃ1; Anal. Calcd for
C26H21Cl4NO3S: C, 54.85; H, 3.72; N, 2.46. Found: C, 54.78; H, 3.80; N,
2.39.
Ethyl 4-Hydroxy-2,6-di(3-nitrophenyl)-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (2h and 3h) (Appears as Mixture in a Ratio 1 :
0.62): Isolated as viscous liquid; (0.350 g, 53%); 1H-NMR (300 MHz,
CDCl3) dH: 0.95—1.05 (m, CH3), 3.94—4.16 (m, CH2), 4.26—4.37 (m, H-
5), 4.52—5.13 (m, H-6, H-2), 7.06—8.20 (m, aromatic), 12.6 (s, OH), 12.9
(s, OH). HR-MS (ESI) m/z Calcd for C26H23N3O7S: 521.1257; Found,
520.2402 (Mꢃ1).
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (2i): Isolated as colorless crystals; (0.236 g, 46%);
mp 121—122 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.93 (t, Jꢁ7.2 Hz, 3H,
CH3), 1.74 (s, 1H, NH), 3.72 (d, Jꢁ10.1 Hz, 1H, H-6), 3.82 (d, Jꢁ10.1 Hz,
Ethyl 2,6-Di(4-fluorophenyl)-4-hydroxy-5-(phenylsulfanyl)-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (4c): Isolated as colorless crystals; (0.295 g,

May 2010
607
1H, H-5), 3.89—4.02 (m, 2H, CH2), 4.97 (s, 1H, H-2), 6.79—7.23 (m, 14H, 6.67—7.41 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.6, 21.5,
aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.5, 53.9, 56.2, 56.8, 59.6, 96.7, 21.6, 58.4, 59.4, 59.6, 60.2, 96.5, 127.5, 128.4, 129.0, 129.3, 129.4, 129.7,
127.0, 127.7, 128.2, 128.4, 128.6, 129.0, 129.2, 129.6, 135.8, 137.1, 141.8, 135.9, 136.5, 137.3, 138.6, 141.0, 142.5, 156.5, 169.1. IR (KBr) nmax: 742,
144.4, 155.1, 169.0. IR (KBr) nmax: 740, 1230, 1261, 1529, 1604, 1664, 1234, 1269, 1521, 1603, 1664, 2990, 3305, 3442 cmꢃ1; Anal. Calcd for
2987, 3313, 3453 cmꢃ1; Anal. Calcd for C26H24ClNO3S: C, 67.01; H, 5.19; C28H28ClNO3S: C, 68.07; H, 5.71; N, 2.84. Found: C, 68.12; H, 5.66; N,
N, 3.01. Found: C, 67.08; H, 5.25; N, 3.06.
2.88.
Ethyl 2,6-Di(2-chlorophenyl)-5-[(4-chlorophenyl)sulfanyl]-4-hydroxy-
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (3i): Isolated as colorless crystals; (0.036 g, 7%);
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3m): Isolated as colorless crystals;
mp 115—117 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.83 (t, Jꢁ7.2 Hz, 3H, (0.290 g, 49%); mp 138—139 °C; H-NMR (300 MHz, CDCl3) dH: 0.84 (t,
CH3), 1.92 (br s, 1H, NH), 3.56 (dd, Jꢁ2.1, 1.2 Hz, 1H, H-5), 3.76—3.98 Jꢁ7.2 Hz, 3H, CH3), 1.94 (br s, 1H, NH), 3.78—3.96 (m, 2H, CH2), 3.97—
1
(m, 2H, CH2), 4.51 (d, Jꢁ2.1 Hz, 1H, H-6), 4.96 (s, 1H, H-2), 6.08 (br s, 1H,
4.03 (m, 1H, H-5), 4.81 (d, Jꢁ1.5 Hz, 1H, H-6), 5.55 (s, 1H, H-2), 6.22
OH), 6.79—7.26 (m, 14H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.5, (br s, 1H, OH), 6.87 (d, Jꢁ8.4 Hz, 2H, aromatic), 7.07 (d, Jꢁ8.4 Hz, 2H,
58.8, 59.5, 59.6, 59.9, 97.1, 127.3, 127.8, 128.0, 128.4, 128.5, 128.6, 129.4, aromatic), 7.15—7.54 (m, 8H, aromatic). 13C-NMR (75 MHz, CDCl3) dC:
134.2, 134.6, 140.0, 146.2, 156.5, 169.3. IR (KBr) nmax: 743, 1235, 1262, 13.6, 54.3, 55.0, 56.3, 59.1, 95.7, 126.7, 127.1, 127.9, 128.7, 128.8, 128.9,
1526, 1601, 1668, 2992, 3318, 3446 cmꢃ1; Anal. Calcd for C26H24ClNO3S:
C, 67.01; H, 5.19; N, 3.01. Found: C, 66.97; H, 5.13; N, 3.08.
Ethyl 2,6-Di(4-chlorophenyl)-5-[(4-chlorophenyl)sulfanyl]-4-hydroxy- Anal. Calcd for C26H22Cl3NO3S: C, 58.38; H, 4.15; N, 2.62. Found: C,
129.8, 132.4, 133.4, 133.5, 133.7, 133.9, 136.8, 143.2, 156.4, 168.5. IR
(KBr) nmax: 740, 1225, 1261, 1523, 1614, 1661, 2986, 3319, 3445 cmꢃ1
;
1,2,5,6-tetrahydro-3-pyridinecarboxylate (2j): Isolated as colorless crystals;
(0.290 g, 49%); mp 119—120 °C; H-NMR (300 MHz, CDCl3) dH: 0.96 (t,
Jꢁ7.2 Hz, 3H, CH3), 3.63 (d, Jꢁ9.9 Hz, 1H, H-6), 3.74 (d, Jꢁ9.9 Hz, 1H, 1,2,5,6-tetrahydro-3-pyridinecarboxylate (3n): Isolated as colorless solid;
58.32; H, 4.22; N, 2.57.
Ethyl 2,6-Di(2-bromophenyl)-5-[(4-chlorophenyl)sulfanyl]-4-hydroxy-
1
1
H-5), 3.91—4.03 (m, 2H, CH2), 4.91 (s, 1H, H-2), 6.73—7.37 (m, 12H, aro- (0.274 g, 40%); mp 121—122 °C; H-NMR (300 MHz, CDCl3) dH: 0.90 (t,
matic). 13C-NMR (75 MHz, CDCl3) dC: 14.2, 53.5, 55.7, 56.1, 59.6, 96.5, Jꢁ7.2 Hz, 3H, CH3), 1.97 (br s, 1H, NH), 3.91—4.05 (m, 2H, CH2), 4.14 (s,
128.4, 128.9, 129.0, 129.2, 129.7, 129.9, 132.7, 134.4, 136.1, 137.0, 140.1, 1H, H-5), 4.77 (s, 1H, H-6), 5.47 (s, 1H, H-2), 6.91—7.57 (m, 12H, aro-
143.0, 155.0, 168.7. IR (KBr) nmax: 736, 1236, 1260, 1525, 1602, 1665, matic), 12.3 (s, 1H, OH). 13C-NMR (75 MHz, CDCl3) dC: 13.5, 53.4, 56.6,
2984, 3310, 3450 cmꢃ1; Anal. Calcd for C26H22Cl3NO3S: C, 58.38; H, 4.15; 58.8, 60.6, 101.1, 123.0, 127.1, 127.9, 128.7, 129.2, 129.3, 130.2, 130.4,
N, 2.62. Found: C, 58.31; H, 4.20; N, 2.56.
132.3, 133.4, 133.6, 134.0, 134.8, 134.9, 137.8, 140.3, 157.1, 170.7. IR
Ethyl 2,6-Di(4-chlorophenyl)-5-[(4-chlorophenyl)sulfanyl]-4-hydroxy- (KBr) nmax: 741, 1229, 1260, 1526, 1619, 1665, 2985, 3316, 3442 cmꢃ1
;
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3j): Isolated as colorless crystals;
(0.053 g, 9%); mp 109—110 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.89 (t,
Jꢁ7.2 Hz, 3H, CH3), 1.92 (br s, 1H, NH), 3.54 (s, 1H, H-5), 3.80—3.99 (m,
2H, CH2), 4.46 (d, Jꢁ1.8 Hz, 1H, H-6), 4.93 (s, 1H, H-2), 6.11 (br s, 1H,
Anal. Calcd for C26H22Br2ClNO3S: C, 50.06; H, 3.55; N, 2.25. Found C,
50.15; H, 3.49; N, 2.20.
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-2,6-di(2,4-dichlorophenyl)-4-hydroxy-
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3o): Isolated as pale yellow solid;
OH), 6.87—7.28 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.3, (0.332 g, 50%); mp 156—157 °C; H-NMR (300 MHz, CDCl3) dC: 0.96 (t,
58.4, 59.1, 59.2, 59.6, 96.6, 128.6, 128.7, 129.1, 129.5, 129.8, 133.0, 133.9, Jꢁ7.2 Hz, 3H, CH3), 1.87 (br s, 1H, NH), 3.92—4.03 (m, 2H, CH2), 4.06 (s,
134.1, 134.6, 138.4, 144.7, 156.5, 169.0. IR (KBr) nmax: 739, 1231, 1262, 1H, H-5), 4.75 (s, 1H, H-6), 5.44 (s, 1H, H-2), 6.96—7.38 (m, 9H, aro-
1
1527, 1602, 1660, 2989, 3315, 3451 cmꢃ1; Anal. Calcd for C26H22Cl3NO3S:
C, 58.38; H, 4.15; N, 2.62. Found: C, 58.45; H, 4.21; N, 2.66.
matic), 7.47 (d, Jꢁ8.4 Hz,1H), 12.3 (s, 1H, OH). 13C-NMR (75 MHz,
CDCl3) dC: 13.5, 53.2, 56.2, 59.0, 60.8, 100.7, 126.8, 127.7, 128.6, 128.7,
128.8, 130.0, 130.6, 133.0, 133.4, 133.5, 133.6, 133.7, 134.1, 134.3, 134.9,
140.2, 170.3, 170.5. IR (KBr) nmax: 739, 1228, 1260, 1527, 1615, 1660,
2984, 3318, 3447 cmꢃ1; Anal. Calcd for C26H20Cl5NO3S: C, 51.72; H, 3.34;
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-2,6-di(4-fluorophenyl)-4-hydroxy-
1,2,5,6-tetrahydro-3-pyridinecarboxylate (2k): Isolated as colorless crystals;
1
(0.155 g, 28%); mp 129—130 °C; H-NMR (300 MHz, CDCl3) dH: 0.95 (t,
Jꢁ7.2 Hz, 3H, CH3), 3.66 (d, Jꢁ10.1 Hz, 1H, H-6), 3.74 (d, Jꢁ10.1 Hz, 1H, N, 2.32. Found: C, 51.80; H, 3.25; N, 2.26.
H-5), 3.91—4.02 (m, 2H, CH2), 4.93 (s, 1H, H-2), 6.73—7.30 (m, 12H, aro-
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-4-hydroxy-2,6-di(3-nitrophenyl)-
matic). 13C-NMR (75 MHz, CDCl3) dC: 14.5, 53.9, 55.5, 56.1, 59.6, 96.8, 1,2,5,6-tetrahydro-3-pyridinecarboxylate (2p and 3p) (Appears as Mixture in
1
114.9, 115.1, 115.8, 116.0, 129.0, 129.1, 129.5, 129.8, 129.9, 130.0, 136.0, a Ratio 1 : 0.88): Isolated as viscous liquid; (0.293 g, 48%); H-NMR (300
137.1, 137.5, 137.6, 140.3, 140.4, 160.3, 161.2, 163.5, 164.5, 155.0, 168.8. MHz, CDCl3) dH: 0.84—1.05 (m, CH3), 3.82—4.16 (m, CH2), 4.56—4.65
IR (KBr) nmax: 735, 1230, 1262, 1521, 1606, 1664, 2988, 3314, 3445 cmꢃ1
;
(m, H-5), 4.80—5.15 (m, H-6, H-2), 7.08—8.27 (m, aromatic), 12.6 (s, OH),
Anal. Calcd for C26H22ClF2NO3S: C, 62.21; H, 4.42; N, 2.79. Found: C, 12.9 (s, OH). HR-MS (ESI) m/z: Calcd for C26H2235ClN3O7S: 555.0867;
62.17; H, 4.37; N, 2.85.
Found, 554.3712 (Mꢃ1).
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-2,6-di(4-fluorophenyl)-4-hydroxy-
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3k): Isolated as colorless crystals;
Ethyl 4-Hydroxy-5-[(4-methylphenyl)sulfanyl]-2,6-diphenyl-1,2,5,6-
tetrahydro-3-pyridinecarboxylate (2q): Isolated as colorless crystals; (0.244
g, 46%); mp 110—111 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.92 (t,
Jꢁ7.2 Hz, 3H, CH3), 2.41 (s, 1H, CH3), 3.78 (s, 2H, H-5, H-6), 3.87—4.01
(m, 2H, CH2), 4.95 (s, 1H, H-2), 6.78—7.29 (m, 14H, aromatic). 13C-NMR
1
(0.144 g, 26%); mp 112—113 °C; H-NMR (300 MHz, CDCl3) dH: 0.88 (t,
Jꢁ7.2 Hz, 3H, CH3), 1.79 (br s, 1H, NH), 3.52 (d, 1H, Jꢁ1.8 Hz, H-5),
3.81—4.00 (m, 1H, CH2), 4.47 (d, 1H, Jꢁ1.8 Hz, H-6), 4.94 (s, 1H, H-2),
6.85—7.30 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.3, 58.7, (75 MHz, CDCl3) dC: 14.5, 21.7, 53.8, 56.0, 57.0, 59.4, 96.4, 126.7, 127.1,
59.0, 59.2, 59.5, 96.6, 115.1, 115.3, 115.4, 115.6, 129.3, 129.4, 129.5,
129.8, 130.0, 134.3, 134.4, 134.5, 135.7, 135.8, 141.9, 142.0, 160.7, 161.0,
163.9, 164.2, 156.5, 169.1. IR (KBr) nmax: 738, 1236, 1260, 1524, 1601,
127.8, 128.1, 128.4, 128.5, 128.9, 130.4, 136.0, 139.6, 142.2, 144.6, 155.8,
169.0. IR (KBr) nmax: 735, 1234, 1261, 1525, 1605, 1662, 2990, 3311, 3442
cmꢃ1; Anal. Calcd for C27H27NO3S: C, 72.78; H, 6.11; N, 3.14. Found: C,
1662, 2985, 3310, 3447 cmꢃ1; Anal. Calcd for C26H22ClF2NO3S: C, 62.21; 72.84; H, 6.17; N, 3.21.
H, 4.42; N, 2.79. Found: C, 62.27; H, 4.48; N, 2.72.
Ethyl 4-Hydroxy-5-[(4-methylphenyl)sulfanyl]-2,6-diphenyl-1,2,5,6-tetrahy-
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-4-hydroxy-2,6-di(4-methylphenyl)- dro-3-pyridinecarboxylate (3q): Isolated as colorless crystals; (0.042 g, 8%);
1,2,5,6-tetrahydro-3-pyridinecarboxylate (2l): Isolated as colorless crystals;
(0.250 g, 46%); mp 131—132 °C; H-NMR (300 MHz, CDCl3) dH: 0.96 (t,
Jꢁ6.9 Hz, 3H, CH3), 2.29 (s, 1H, CH3), 2.32 (s, 1H, CH3), 3.67 (d, Jꢁ9.9
mp 107—108 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.74 (t, Jꢁ7.2 Hz, 3H,
CH3), 1.79 (br s, 1H, NH), 3.45 (s, 1H, H-5), 3.69—4.02 (m, 2H, CH2), 4.40
(d, Jꢁ1.5 Hz, 1H, H-6), 4.87 (s, 1H, H-2), 6.00 (br s, 1H, OH), 6.72—7.41
1
Hz, 1H, H-6), 3.79 (d, Jꢁ9.9 Hz, 1H, H-5), 3.85—4.03 (m, 2H, CH2), 4.93 (m, 14H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 13.7, 58.3, 58.9, 59.1,
(s, 1H, H-2), 6.66—7.43 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) 59.5, 96.0, 126.8, 127.3, 127.9, 128.0, 128.1, 128.3, 129.6, 131.9, 135.5,
dC: 14.3, 21.5, 21.6, 53.9, 55.8, 56.4, 59.5, 97.1, 127.6, 128.3, 128.9, 129.5, 137.9, 139.8, 145.9, 157.1, 168.9. IR (KBr) nmax: 738, 1231, 1265, 1529,
29.7, 135.7, 136.3, 137.0, 138.3, 139.0, 141.5, 155.1, 169.1. IR (KBr) nmax
:
1601, 1659, 2993, 3315, 3440 cmꢃ1; Anal. Calcd for C27H27NO3S: C, 72.78;
739, 1237, 1265, 1528, 1602, 1668, 2993, 3308, 3450 cmꢃ1; Anal. Calcd for H, 6.11; N, 3.14. Found: C, 72.82; H, 6.07; N, 3.20.
C28H28ClNO3S: C, 68.07; H, 5.71; N, 2.84. Found: C, 68.13; H, 5.76; N,
2.79.
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-4-hydroxy-2,6-di(4-methylphenyl)- (0.306 g, 50%); mp 148—149 °C; H-NMR (300 MHz, CDCl3) dH: 0.95 (t,
Ethyl 2,6-Di(4-chlorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]-
1,2,5,6-tetrahydro-3-pyridinecarboxylate (2r): Isolated as colorless crystals;
1
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3l): Isolated as colorless crystals;
(0.033 g, 6%); mp 120—122 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.94 (t,
Jꢁ7.2 Hz, 3H, CH3), 2.29 (s, 1H, CH3), 2.30 (s, 1H, CH3), 3.67 (s, 1H, H-5),
3.82—4.03 (m,1H, CH2), 4.57 (d, 1H, Jꢁ1.8 Hz, H-6), 4.97 (s, 1H, H-2),
Jꢁ7.2 Hz, 3H, CH3), 2.43 (s, 1H, CH3), 3.68 (s, 2H, H-5, H-6), 3.89—4.02
(m, 2H, CH2), 4.90 (s, 1H, H-2), 6.71—7.33 (m, 12H, aromatic). 13C-NMR
(75 MHz, CDCl3) dC: 14.5, 21.7, 53.4, 55.4, 56.2, 59.6, 96.2, 126.7, 128.3,
129.1, 129.2, 129.8, 130.5, 132.4, 134.2, 136.0, 139.9, 140.5, 143.2, 155.7,

608
Vol. 58, No. 5
(0.312 g, 45%); mp 141—142 °C; H-NMR (300 MHz, CDCl3) dH: 0.95 (t,
1
168.8. IR (KBr) nmax: 739, 1230, 1267, 1525, 1601, 1660, 2987, 3308, 3445
cmꢃ1; Anal. Calcd for C27H25Cl2NO3S: C, 63.03; H, 4.90; N, 2.72. Found: C, Jꢁ7.2 Hz, 3H, CH3), 1.87 (br s, 1H, NH), 2.27 (s, 3H, CH3), 3.94—4.03 (m,
63.09; H, 4.84; N, 2.67.
2H, CH2), 4.06 (s, 1H, H-5), 4.72 (s, 1H, H-6), 5.43 (s, 1H, H-2), 6.89—
Ethyl 2,6-Di(4-chlorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]- 6.95 (m, 4H, aromatic), 7.15 (d, Jꢁ2.1 Hz, 1H), 7.22—7.29 (m, 3H, aro-
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3r): Isolated as colorless crystals;
matic), 7.38 (d, Jꢁ1.8 Hz, 1H), 7.47 (d, Jꢁ8.4 Hz, 1H), 12.3 (s, 1H, OH).
(0.043 g, 7%); mp 144—146 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.89 (t,
13C-NMR (75 MHz, CDCl3) dC: 13.5, 21.1, 53.1, 56.2, 59.0, 60.7, 100.5,
Jꢁ7.2 Hz, 3H, CH3), 1.79 (br s, 1H, NH), 2.29 (s, 1H, CH3), 3.53 (dd, 1H, 126.7, 127.7, 128.5, 128.7, 129.0, 129.5, 130.7, 131.2, 132.5, 133.0, 133.3,
Jꢁ2.1, 1.2 Hz, H-5), 3.84—3.95 (m, 2H, CH2), 4.45 (d, Jꢁ2.1 Hz, 1H, H-6),
4.92 (s, 1H, H-2), 6.12 (br s, 1H, OH), 6.85—7.33 (m, 12H, aromatic). 13C- 1265, 1520, 1614, 1667, 2988, 3318, 3446 cmꢃ1
C27H23Cl4NO3S: C, 55.59; H, 3.97; N, 2.40. Found: C, 55.55; H, 3.91; N,
134.0, 134.4, 135.0, 137.7, 140.3, 170.5, 170.9. IR (KBr)nmax: 743, 1228,
;
Anal. Calcd for
NMR (75 MHz, CDCl3) dC: 14.3, 21.5, 58.2, 59.0, 59.2, 59.5, 95.9, 128.6,
129.1, 129.8, 130.3, 131.9, 132.9, 133.6, 133.7, 138.6, 138.7, 140.4, 144.9, 2.48.
157.3, 169.1. IR (KBr) nmax: 738, 1235, 1262, 1524, 1606, 1665, 2991,
Ethyl 4-Hydroxy-5-[(4-methylphenyl)sulfanyl]-2,6-di(3-nitrophenyl)-
3312, 3441 cmꢃ1; Anal. Calcd for C27H25Cl2NO3S: C, 63.03; H, 4.90; N, 1,2,5,6-tetrahydro-3-pyridinecarboxylate (2w and 3w) (Appears as Mixture
2.72. Found: C, 63.10; H, 4.95; N, 2.76.
in a Ratio 1 : 0.30): Isolated as viscous liquid; (0.293 g, 46%); 1H-NMR
(300 MHz, CDCl3) dH: 0.83—1.01 (m, CH3), 2.23 (s, CH3), 2.27 (s, CH3),
3.86—4.21 (m, CH2), 4.58—5.10 (m, H-5, H-6, H-2), 6.91—8.48 (m, aro-
matic), 12.3 (s, OH), 12.8 (s, OH). HR-MS (ESI) m/z: Calcd for
Ethyl 2,6-Di(4-fluorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]-
1,2,5,6-tetrahydro-3-pyridinecarboxylate (2s): Isolated as colorless crystals;
1
(0.160 g, 28%); mp 112—113 °C; H-NMR (300 MHz, CDCl3) dH: 0.94 (t,
Jꢁ7.2 Hz, 3H, CH3), 2.43 (s, 1H, CH3), 3.70 (s, 2H, H-5, H-6), 3.86—4.03 C27H25N3O7S: 535.1413; Found, 534.2901 (Mꢃ1).
(m, 2H, CH2), 4.92 (s, 1H, H-2), 6.68—7.19 (m, 12H, aromatic). 13C-NMR
Synthesis of Ethyl 4-Hydroxy-2,6-diaryl-5-(arylsulfanyl)-3-pyridinecar
-
(75 MHz, CDCl3) dC: 14.5, 21.7, 53.7, 55.3, 56.2, 59.5, 96.4, 114.7, 115.0,
boxylates (5). General Procedure To a solution of ethyl 4-hydroxy-2,6-
115.7, 116.0, 126.8, 129.2, 129.3, 130.0, 130.1, 130.4, 136.0, 137.8, 137.9, diaryl-5-(arylsulfanyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylate (1 mmol) in
139.8, 140.4, 140.5, 160.2, 161.1, 163.4, 164.4, 155.6, 168.8. IR (KBr) nmax
:
benzene (20 ml), dichloro-dicyanobenzoquinone (2 mmol) was added and re-
738, 1230, 1264, 1530, 1609, 1662, 2997, 3306, 3440 cmꢃ1; Anal. Calcd for fluxed over a water bath for 30 min. The precipitated DDQ-H2 was filtered
C27H25F2NO3S: C, 67.34; H, 5.23; N, 2.91. Found: C, 67.30; H, 5.29; N, off and the filterate evaporated under vaccum. The residue was crystallized
2.85.
Ethyl 2,6-Di(4-fluorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]-
from ethanol to give the product.
Ethyl 4-Hydroxy-2,6-diphenyl-5-(phenylsulfanyl)-3-pyridinecarboxylate
(5a): Isolated as colorless crystals (0.072 g, 73%); mp 148—149 °C; 1H-
NMR (300 MHz, CDCl3) dH: 0.78 (t, Jꢁ7.2 Hz, 3H, CH3), 3.98 (q, Jꢁ
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3s): Isolated as colorless crystals;
1
(0.150 g, 26%); mp 110—111 °C; H-NMR (300 MHz, CDCl3) dH: 0.87 (t,
Jꢁ7.2 Hz, 3H, CH3), 1.75 (br s, 1H, NH), 2.27 (s, 1H, CH3), 3.56 (dd, 1H, 7.2 Hz, 2H, CH2), 6.57 (br s, 1H, OH), 7.06—7.57 (m, 15H, aromatic). 13C-
Jꢁ2.1, 1.2 Hz, H-5), 3.78—3.99 (m, 2H, CH2), 4.45 (d, Jꢁ2.1 Hz, 1H, H-6),
NMR (75 MHz, CDCl3) dC: 13.6, 61.5, 108.2, 108.7, 126.2, 126.5, 128.0,
4.94 (s, 1H, H-2), 6.09 (br s, 1H, OH), 6.84—7.34 (m, 12H, aromatic). 13C- 128.4, 128.8, 128.9, 129.0, 129.6, 129.7, 135.8, 140.8, 142.3, 156.5, 161.5,
NMR (75 MHz, CDCl3) dC: 14.3, 21.5, 58.6, 59.0, 59.2, 59.4, 96.2, 115.1,
115.2, 115.3, 115.4, 129.3, 129.4, 129.9, 130.0, 130.2, 132.1, 133.6, 135.9,
165.2, 169.6. IR (KBr) nmax: 732, 1020, 1099, 1245, 1480, 1536, 1585,
1679, 2971, 3355 cmꢃ1; Anal. Calcd for C26H21NO3S: C, 73.04; H, 4.95; N,
136.0, 138.6, 142.1, 142.2, 160.6, 160.9, 163.9, 164.2, 157.4, 169.2. IR 3.28. Found: C, 73.10; H, 4.99; N, 3.22.
(KBr) nmax: 735, 1236, 1268, 1532, 1603, 1669, 2991, 3310, 3447 cmꢃ1
;
Ethyl 2,6-Di(4-chlorophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecar-
Anal. Calcd for C27H25F2NO3S: C, 67.34; H, 5.23; N, 2.91. Found: C, 67.39;
boxylate (5b): Isolated as colorless crystals (0.083 g, 84%); mp 115—
1
H, 5.18; N, 2.97.
116 °C; H-NMR (300 MHz, CDCl3) dH: 0.87 (t, Jꢁ7.2 Hz, 3H, CH3), 4.02
Ethyl 4-Hydroxy-2,6-di(4-methylphenyl)-5-[(4-methylphenyl)sulfanyl]- (q, Jꢁ7.2 Hz, 2H, CH2), 6.65 (br s, 1H, OH), 6.65—7.50 (m, 13H, aro-
1,2,5,6-tetrahydro-3-pyridinecarboxylate (2t): Isolated as colorless crystals;
matic). 13C-NMR (75 MHz, CDCl3) dC: 13.8, 61.6, 108.0, 109.0, 126.5,
128.2, 128.6, 129.8, 130.2, 131.0, 135.1, 135.2, 135.3, 139.0, 140.6, 142.3,
1
(0.282 g, 50%); mp 137—138 °C; H-NMR (300 MHz, CDCl3) dH: 0.95 (t,
Jꢁ7.2 Hz, 3H, CH3), 2.27 (s, 1H, CH3), 2.33 (s, 1H, CH3), 2.42 (s, 1H, 156.7, 160.4, 164.0, 169.2. IR (KBr) nmax: 738, 1012, 1083, 1238, 1486,
CH3), 3.72 (d, Jꢁ10.0 Hz, 1H, H-5), 3.76 (d, Jꢁ10.0 Hz, 1H, H-6), 3.74— 1525, 1587, 1683, 2985, 3336 cmꢃ1; Anal. Calcd for C26H19Cl2NO3S: C,
4.03 (m, 2H, CH2), 4.91 (s, 1H, H-2), 6.64—7.37 (m, 12H, aromatic). 13C- 62.91; H, 3.86; N, 2.82. Found: C, 62.85; H, 3.80; N, 2.87.
NMR (75 MHz, CDCl3) dC: 14.6, 21.5, 21.6, 21.7, 53.8, 55.6, 56.6, 59.4,
Ethyl 2,6-Di(4-fluorophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecar-
96.6, 127.1, 127.8, 128.4, 128.8, 129.6, 130.4, 135.9, 136.0, 138.1, 139.3, boxylate (5c): Isolated as colorless crystals; (0.074 g, 75%); mp 117—
1
139.5, 141.7, 155.6, 168.8. IR (KBr) nmax: 741, 1235, 1261, 1534, 1607,
1665, 2993, 3312, 3441 cmꢃ1; Anal. Calcd for C29H31NO3S: C, 73.54; H, (q, Jꢁ7.2 Hz, 2H, CH2), 6.62 (br s, 1H, OH), 6.62—7.56 (m, 13H, aro-
6.60; N, 2.96. Found: C, 73.50; H, 6.67; N, 2.91.
matic). 13C-NMR (75 MHz, CDCl3) dC: 13.7, 61.6, 108.1, 108.8, 114.9,
Ethyl 4-Hydroxy-2,6-di(4-methylphenyl)-5-[(4-methylphenyl)sulfanyl]- 115.1, 115.2, 115.5, 126.4, 126.5, 129.8, 130.7, 130.8, 131.5, 131.6, 135.5,
118 °C; H-NMR (300 MHz, CDCl3) dH: 0.87 (t, Jꢁ7.2 Hz, 3H, CH3), 4.02
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3t): Isolated as colorless crystals;
136.6, 138.3, 156.7, 160.3, 161.8, 161.9, 164.1, 165.1, 165.2, 169.4. IR
(KBr) nmax: 735, 1015, 1080, 1239, 1480, 1533, 1592, 1681, 2989, 3339
(0.045 g, 8%); mp 120—120 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.84 (t,
Jꢁ7.2 Hz, 3H, CH3), 1.79 (br s, 1H, NH), 2.25 (s, 1H, CH3), 2.32 (s, 1H, cmꢃ1; Anal. Calcd for C26H19F2NO3S: C, 67.37; H, 4.13; N, 3.02. Found: C,
CH3), 2.45 (s, 1H, CH3), 3.54 (dd, 1H, Jꢁ2.0, 1.2 Hz, H-5), 3.77—4.00 (m,
2H, CH2), 4.43 (d, Jꢁ2.0 Hz, 1H, H-6), 4.90 (s, 1H, H-2), 6.04 (br s, 1H,
OH), 6.75—7.43 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 14.2,
21.3, 21.6, 21.9, 58.5, 58.9, 59.0, 59.1, 96.3, 127.5, 127.9, 128.3, 128.5,
67.41; H, 4.08; N, 3.09.
Ethyl 4-Hydroxy-2,6-di(4-methylphenyl)-5-(phenylsulfanyl)-3-pyridinecar-
boxylate (5d): Isolated as colorless crystals; (0.071 g, 72%); mp 107—
1
109 °C; H-NMR (300 MHz, CDCl3) dH: 0.80 (t, Jꢁ6.6 Hz, 3H, CH3), 2.31
129.7, 130.2, 135.7, 136.5, 138.6, 139.1, 139.2, 141.8, 157.2, 169.5. IR (s, 1H, CH3), 2.35 (s, 1H, CH3), 3.85 (q, Jꢁ6.6 Hz, 2H, CH2), 6.60 (br s, 1H,
(KBr) nmax: 737, 1230, 1259, 1538, 1602, 1662, 2984, 3305, 3452 cmꢃ1
Anal. Calcd for C29H31NO3S: C, 73.54; H, 6.60; N, 2.96. Found: C, 73.59; 21.7, 21.8, 61.5, 108.2, 108.6, 126.3, 126.5, 128.7, 128.9, 129.0, 129.5,
H, 6.56; N, 2.92.
129.7, 135.7, 139.0, 156.6, 161.1, 164.8, 169.5. IR (KBr) nmax: 739, 1017,
Ethyl 2,6-Di(2-chlorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]- 1086, 1237, 1482, 1538, 1590, 1686, 2992, 3341 cmꢃ1; Anal. Calcd for
;
OH), 6.62—7.56 (m, 13H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 13.6,
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3u): Isolated as colorless crystals;
(0.305 g, 50%); mp 133—134 °C; H-NMR (300 MHz, CDCl3) dH: 0.83 (t,
C28H25NO3S: C, 73.82; H, 5.53; N, 3.07. Found: C, 73.87; H, 5.59; N, 3.00.
Ethyl 2,6-Di(2-chlorophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecar-
boxylate (5e): Isolated as colorless crystals; (0.076 g, 77%); mp 135—
136 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.79 (t, Jꢁ7.2 Hz, 3H, CH3),
3.92—4.31 (m, 2H, CH2), 6.62—7.56 (m, 13H, aromatic). 13C-NMR (75
1
Jꢁ7.2 Hz, 3H, CH3), 1.88 (br s, 1H, NH), 2.25 (s, 1H, CH3), 3.70—4.20 (m,
3H, CH2 and H-5), 4.70—4.89 (m, 1H, H-6), 5.54 (s, 1H, H-2), 6.19 (br s,
1H, OH), 6.83 (d, Jꢁ7.8 Hz, 2H, aromatic), 6.92 (d, Jꢁ7.8 Hz, 2H, aro-
matic), 7.10—7.55 (m, 8H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 13.6, MHz, CDCl3) dC: 13.5, 61.5, 108.9, 112.2, 126.6, 127.2, 127.3, 129.0,
21.0, 54.6, 55.0, 56.4, 59.0, 95.0, 126.5, 127.1, 127.8, 128.6, 128.8, 128.9,
129.4, 129.7, 130.0, 131.9, 132.4, 132.7, 133.7, 137.1, 137.7, 143.5, 157.5, 141.9, 156.7, 159.6, 163.9, 168.3. IR (KBr) nmax: 734, 1013, 1083, 1240,
168.6. IR (KBr) nmax: 746, 1227, 1261, 1521, 1610, 1664, 2985, 3315,
1479, 1531, 1593, 1682, 2990, 3347 cmꢃ1; Anal. Calcd for C26H19Cl2NO3S:
3442 cmꢃ1; Anal. Calcd for C27H25Cl2NO3S: C, 63.03; H, 4.90; N, 2.72. C, 62.91; H, 3.86; N, 2.82. Found: C, 62.95; H, 3.80; N, 2.75.
129.3, 129.4, 129.6, 129.7, 129.9, 130.7, 132.2, 132.8, 133.1, 134.7, 139.6,
Found: C, 63.08; H, 4.97; N, 2.65.
Ethyl 2,6-Di(2,4-dichlorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]-
Ethyl 2,6-Di(2-bromophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecar-
boxylate (5f): Isolated as solid (0.071 g, 72%); mp 103—104 °C; H-NMR
1
1,2,5,6-tetrahydro-3-pyridinecarboxylate (3v): Isolated as pale yellow solid; (300 MHz, CDCl3) dH: 0.83 (t, Jꢁ6.9 Hz, 3H, CH3), 3.80—4.31 (m, 2H,

May 2010
609
CH2), 7.16—7.59 (m, 14H, OH and aromatic). 13C-NMR (75 MHz, CDCl3) CH2), 6.98—7.61 (m, 13H, OH and aromatic). 13C-NMR (75 MHz, CDCl3)
dC: 12.9, 62.5, 110.0, 121.9, 122.3, 126.5, 126.9, 127.2, 127.9, 128.3, 128.9, dC: 12.9, 62.5, 110.0, 121.9, 122.4, 126.5, 126.9, 127.2, 127.9, 128.3, 128.9,
129.3, 129.7, 130.2, 131.9, 132.1, 132.5, 134.8, 135.3, 141.1, 149.9, 159.3, 129.3, 129.7, 130.2, 131.9, 132.1, 132.5, 134.8, 135.3, 141.1, 143.1, 149.9,
163.6, 169.4. IR (KBr) nmax: 732, 1016, 1081, 1245, 1480, 1535, 1590, 159.4, 169.5. IR (KBr) nmax: 736, 1043, 1096, 1265, 1497, 1540, 1582,
1684, 2992, 3345 cmꢃ1; Anal. Calcd for C26H19Br2NO3S: C, 53.35; H, 3.27; 1688, 2997, 3351 cmꢃ1; Anal. Calcd for C26H18Br2ClNO3S: C, 50.39; H,
N, 2.39. Found: C, 53.30; H, 3.34; N, 2.31.
2.93; N, 2.26. Found: C, 50.45; H, 2.99; N, 2.18.
Ethyl 2,6-Di(2,4-dichlorophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-
pyridinecarboxylate (5g): Isolated as solid (0.080 g, 82%); mp 83—84 °C;
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-2,6-di(2,4-dichlorophenyl)-3-
pyridinecarboxylate (5o): Isolated as solids (0.078 g, 79%); mp 109—
1H-NMR (300 MHz, CDCl3) dH: 0.93 (t, Jꢁ7.2 Hz, 3H, CH3), 3.99—4.14 110 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.93 (t, Jꢁ7.2 Hz, 3H, CH3),
(m, 2H, CH2), 7.05—7.43 (m, 12H, OH and aromatic). 13C-NMR (75 MHz,
4.09—4.26 (m, 2H, CH2), 7.04—7.43 (m, 11H, OH and aromatic). 13C-
CDCl3) dC: 13.0, 62.7, 110.0, 119.0, 126.6, 126.8, 127.1, 127.9, 128.7, NMR (75 MHz, CDCl3) dC: 13.0, 62.8, 110.0, 118.5, 126.9, 127.1, 128.3,
128.9, 129.3, 132.0, 133.1, 133.6, 134.2, 134.7, 134.9, 135.2, 136.5, 138.5, 128.6, 129.0, 129.4, 130.2, 130.5, 132.6, 133.0, 133.2, 133.6, 134.8, 135.3,
157.5, 163.2, 169.5. IR (KBr) nmax: 736, 1015, 1084, 1243, 1478, 1534, 136.5, 138.5, 157.0, 163.3, 168.8, 169.5. IR (KBr) nmax: 737, 1044, 1098,
1594, 1680, 2988, 3343 cmꢃ1; Anal. Calcd for C26H17Cl4NO3S: C, 55.24; H, 1260, 1496, 1545, 1579, 1691, 2995, 3356 cmꢃ1
;
Anal. Calcd for
3.03; N, 2.48. Found: C, 55.32; H, 2.97; N, 2.55.
C26H16Cl5NO3S: C, 52.07; H, 2.69; N, 2.34. Found: C, 52.15; H, 2.62; N,
Ethyl 4-Hydroxy-2,6-di(3-nitrophenyl)-5-(phenylsulfanyl)-3-pyridinecar- 2.41.
boxylate (5h): Isolated as solid (0.074 g, 75%); mp 75—76 °C; 1H-NMR
Ethyl 4-Hydroxy-5-[(4-methylphenyl)sulfanyl]-2,6-diphenyl-3-pyridinecar-
(300 MHz, CDCl3) dH: 0.91 (t, Jꢁ7.2 Hz, 3H, CH3), 4.17 (q, Jꢁ7.2 Hz, 2H,
boxylate (5p): Isolated as colorless crystals; (0.069 g, 70%); mp 95—96 °C;
CH2), 7.07—7.66 (m, 5H, OH and aromatic), 7.85—8.48 (m, 9H, aromatic).
1H-NMR (300 MHz, CDCl3) dH: 0.77 (t, Jꢁ6.9 Hz, 3H, CH3), 2.30 (s, 1H,
13C-NMR (75 MHz, CDCl3) dC: 13.2, 62.7, 109.0, 118.0, 123.5, 123.8, CH3), 3.97 (q, Jꢁ6.9 Hz, 2H, CH2), 6.95—7.54 (m, 14H, aromatic). 13C-
123.9, 124.7, 126.7, 128.1, 128.3, 128.8, 129.0, 129.2, 134.6, 134.8, 135.4, NMR (75 MHz, CDCl3) dC: 13.5, 21.4, 61.9, 108.5, 111.3, 126.6, 127.4,
140.2, 142.3, 147.8, 159.0, 164.2, 169.2. IR (KBr) nmax: 735, 1016, 1085, 128.2, 128.5, 129.0, 129.7, 130.7, 130.9, 137.0, 137.7, 139.2, 157.3, 160.4,
1246, 1360, 1481, 1535, 1590, 1683, 2991, 3346 cmꢃ1; Anal. Calcd for 165.2, 168.5. IR (KBr) nmax: 748, 1056, 1091, 1260, 1499, 1553, 1587,
C26H19N3O7S: C, 60.34; H, 3.70; N, 8.12. Found: C, 60.26; H, 3.76; N, 8.05.
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-4-hydroxy-2,6-diphenyl-3-pyridinecar-
boxylate (5i): Isolated as colorless crystals; (0.075 g, 76%); mp 92—93 °C;
1681, 2987, 3357 cmꢃ1; Anal. Calcd for C27H23NO3S: C, 73.44; H, 5.25; N,
3.17. Found: C, 73.49; H, 5.31; N, 3.23.
Ethyl 2,6-Di(4-chlorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]-3-
1H-NMR (300 MHz, CDCl3) dH: 0.79 (t, Jꢁ7.2 Hz, 3H, CH3), 3.99 (q, Jꢁ pyridine-carboxylate (5q): Isolated as colorless crystals; (0.078 g, 79%); mp
7.2 Hz, 2H, CH2), 6.58 (br s, 1H, OH), 6.96—7.58 (m, 14H, aromatic). 13C- 119—120 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.87 (t, Jꢁ7.2 Hz, 3H, CH3),
NMR (75 MHz, CDCl3) dC: 13.5, 61.5, 108.4, 108.5, 127.9, 128.1, 128.4, 2.29 (s, 1H, CH3), 4.01 (q, Jꢁ7.2 Hz, 2H, CH2), 6.66 (br s, 1H, OH), 6.93—
128.9, 129.0, 129.1, 129.5, 129.8, 132.2, 134.3, 142.0, 156.4, 160.4, 165.2,
7.51 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 13.7, 21.3, 61.6,
108.1, 109.7, 126.8, 128.3, 128.5, 130.3, 130.6, 131.1, 131.6, 135.0, 135.2,
169.5. IR (KBr) nmax: 735, 1025, 1095, 1248, 1486, 1541, 1589, 1689, 2978,
3351 cmꢃ1; Anal. Calcd for C26H20ClNO3S: C, 67.60; H, 4.36; N, 3.03. 136.5, 138.9, 140.6, 156.7, 160.2, 163.8, 169.2. IR (KBr) nmax: 742, 1051,
Found: C, 67.68; H, 4.29; N, 2.97.
Ethyl 2,6-Di(4-chlorophenyl)-5-[(4-chlorophenyl)sulfanyl]-4-hydroxy-3- C27H21Cl2NO3S: C, 63.53; H, 4.15; N, 2.74. Found: C, 63.59; H, 4.11; N,
1084, 1267, 1506, 1559, 1582, 1678, 2993, 3349 cmꢃ1; Anal. Calcd for
pyridine-carboxylate (5j): Isolated as colorless crystals; (0.086 g, 87%); mp
2.68.
Ethyl 2,6-Di(4-fluorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]-3-
125—126 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.88 (t, Jꢁ7.2 Hz, 3H, CH3),
4.03 (q, Jꢁ7.2 Hz, 2H, CH2), 6.65 (br s, 1H, OH), 6.94—7.50 (m, 12H, aro- pyridine-carboxylate (5r): Isolated as colorless crystals; (0.071 g, 72%); mp
matic). 13C-NMR (75 MHz, CDCl3) dC: 13.7, 61.7, 108.2, 108.7, 127.8, 107—108 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.87 (t, Jꢁ7.2 Hz, 3H, CH3),
128.3, 128.6, 129.9, 130.3, 130.9, 132.5, 133.8, 135.2, 135.3, 138.7, 140.4, 2.29 (s, 1H, CH3), 4.01 (q, Jꢁ7.2 Hz, 2H, CH2), 6.63 (br s, 1H, OH), 6.93—
156.7, 160.5, 164.0, 169.1. IR (KBr) nmax: 730, 1029, 1092, 1243, 1484, 7.57 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 13.7, 21.3, 61.5,
1532, 1594, 1696, 2995, 3347 cmꢃ1; Anal. Calcd for C26H18Cl3NO3S: C,
58.83; H, 3.42; N, 2.64. Found: C, 58.89; H, 3.46; N, 2.69.
108.1, 109.4, 114.8, 115.1, 115.5, 115.5, 126.8, 130.5, 130.7, 130.8, 131.5,
131.6, 131.7, 136.5, 136.6, 138.2, 156.6, 160.2, 161.9, 164.9, 169.3. IR (KBr)
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-2,6-di(4-fluorophenyl)-4-hydroxy-3-
pyridine-carboxylate (5k): Isolated as colorless crystals; (0.077 g, 78%); mp
n ;
max: 740, 1056, 1079, 1260, 1502, 1568, 1589, 1681, 2988, 3341 cmꢃ1
Anal. Calcd for C27H21F2NO3S: C, 67.91; H, 4.43; N, 2.93. Found: C, 67.98;
109—110 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.88 (t, Jꢁ6.9 Hz, 3H, CH3), H, 4.49; N, 2.89.
4.03 (q, Jꢁ6.9 Hz, 2H, CH2), 6.61 (br s, 1H, OH), 6.95—7.57 (m, 12H, aro-
Ethyl 4-Hydroxy-2,6-di(4-methylphenyl)-5-[(4-methylphenyl)sulfanyl]-3-
matic). 13C-NMR (75 MHz, CDCl3) dC: 13.7, 61.6, 108.2, 108.4, 114.9, pyridine-carboxylate (5s): Isolated as viscous liquid; (0.069 g, 70%); 1H-
115.2, 115.5, 127.8, 128.7, 129.9, 130.7, 130.8, 131.4, 131.6, 132.4, 134.0,
136.5, 138.2, 156.6, 160.5, 162.0, 164.1, 165.1, 166.3, 169.3. IR (KBr) nmax
742, 1038, 1085, 1254, 1491, 1540, 1598, 1690, 2991, 3340 cmꢃ1; Anal.
NMR (300 MHz, CDCl3) dH: 0.80 (t, Jꢁ6.6 Hz, 3H, CH3), 2.26 (s, 1H,
CH3), 2.30 (s, 1H, CH3), 2.35 (s, 1H, CH3), 3.97 (q, Jꢁ6.6 Hz, 2H, CH2),
6.54 (br s, 1H, OH), 6.94—7.46 (m, 12H, aromatic). 13C-NMR (75 MHz,
:
Calcd for C26H18ClF2NO3S: C, 62.71; H, 3.64; N, 2.81. Found: C, 62.65; H, CDCl3) dC: 13.7, 21.4, 21.7, 21.8, 61.5, 108.2, 109.0, 126.7, 128.7, 128.9,
3.60; N, 2.87. 129.0, 129.6, 130.5, 132.2, 136.2, 137.6, 138.8, 138.9, 139.0, 156.5, 161.1,
Ethyl 5-[(4-Chlorophenyl)sulfanyl]-4-hydroxy-2,6-di(4-methylphenyl)-3- 164.9, 169.7. IR (CHCl3) nmax: 745, 1052, 1082, 1268, 1513, 1561, 1582,
pyridine-carboxylate (5l): Isolated as colorless crystals; (0.071 g, 72%); mp
1676, 2980, 3357 cmꢃ1; Anal. Calcd for C29H27NO3S: C, 74.17; H, 5.80; N,
105—106 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.78 (t, Jꢁ6.9 Hz, 3H, CH3), 2.98. Found: C, 74.23; H, 5.86; N, 2.91.
2.31 (s, 1H, CH3), 2.35 (s, 1H, CH3), 3.99 (q, Jꢁ6.9 Hz, 2H, CH2), 6.87—
Ethyl 2,6-Di(2-chlorophenyl)-4-hydroxy-5-[(4-methylphenyl)sulfanyl]-3-
7.61 (m, 12H, aromatic). 13C-NMR (75 MHz, CDCl3) dC: 13.5, 21.7, 21.8, pyridine-carboxylate (5t): Isolated as colorless crystals; (0.073 g, 74%); mp
62.0, 108.6, 112.2, 126.6, 127.2, 128.1, 128.9, 129.0, 129.1, 129.4 130.0, 98—99 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.84 (t, Jꢁ7.2 Hz, 3H, CH3),
132.7, 133.2, 140.0, 157.3, 160.4, 165.2, 168.5. IR (KBr) nmax: 731, 1046, 2.28 (s, 1H, CH3), 3.91—4.20 (m, 2H, CH2), 6.77—7.80 (m, 12H, aro-
1081, 1250, 1487, 1549, 1592, 1696, 2995, 3350 cmꢃ1; Anal. Calcd for matic). 13C-NMR (75 MHz, CDCl3) dC: 13.5, 21.3, 61.8, 108.5, 112.6,
C28H24ClNO3S: C, 68.63; H, 4.94; N, 2.86. Found: C, 68.59; H, 4.88; N, 126.7, 127.2, 127.4, 128.7, 129.0, 129.3, 129.5, 129.7, 130.0, 130.4, 132.0,
2.90.
Ethyl 2,6-Di(2-chlorophenyl)-5-[(4-chlorophenyl)sulfanyl]-4-hydroxy-3- 749, 1058, 1076, 1271, 1507, 1565, 1589, 1681, 2973, 3348 cmꢃ1; Anal.
pyridine-carboxylate (5m): Isolated as colorless crystals; (0.079 g, 80%); mp Calcd for C27H21Cl2NO3S: C, 63.53; H, 4.15; N, 2.74. Found: C, 63.48; H,
132.5, 133.0, 134.3, 139.6, 141.6, 156.3, 159.0, 163.6, 169.4. IR (KBr) nmax:
112—113 °C; 1H-NMR (300 MHz, CDCl3) dH: 0.85 (t, Jꢁ7.2 Hz, 3H, CH3), 4.21; N, 2.80.
3.94—4.25 (m, 2H, CH2), 6.95—7.49 (m, 12H, aromatic). 13C-NMR (75
Ethyl 2,6-Di(2,4-dichlorophenyl)-4-hydroxy-5-[(4-methylphenyl)-3-
MHz, CDCl3) dC: 13.6, 61.7, 108.7, 112.8, 126.9, 127.4, 127.6, 128.9, pyridinecarboxylate (5u): Isolated as solid (0.080 g, 81%); mp 76—77 °C;
129.2, 129.5, 129.7, 129.9, 130.1, 130.6, 132.2, 132.7, 133.2, 134.5, 139.7, 1H-NMR (300 MHz, CDCl3) dH: 0.92 (t, Jꢁ7.2 Hz, 3H, CH3), 2.23 (s, 3H,
141.7, 156.2, 159.2, 163.8, 168.5. IR (KBr) nmax: 738, 1041, 1097, 1263, CH3), 3.94—4.14 (m, 2H, CH2), 7.03—7.49 (m, 11H, OH, aromatic). 13C-
1495, 1542, 1581, 1690, 2998, 3353 cmꢃ1; Anal. Calcd for C26H18Cl3NO3S:
C, 58.83; H, 3.42; N, 2.64. Found: C, 58.88; H, 3.37; N, 2.59.
NMR (75 MHz, CDCl3) dC: 13.0, 21.0, 62.6, 110.0, 119.2, 126.8, 127.0,
128.3, 128.6, 129.3, 129.4, 129.7, 130.0, 130.7, 131.0, 132.5, 133.1, 134.8,
Ethyl 2,6-Di(2-bromophenyl)-5-[(4-chlorophenyl)sulfanyl]-3-pyridinecar- 135.1, 136.7, 138.7, 157.0, 163.1, 168.8, 169.5. IR (KBr) nmax: 745, 1057,
boxylate (5n): Isolated as solid (0.069 g, 70%); mp 77—78 °C; 1H-NMR 1078, 1270, 1508, 1562, 1590, 1685, 2976, 3346 cmꢃ1; Anal. Calcd for
(300 MHz, CDCl3) dH: 0.84 (t, Jꢁ7.2 Hz, 3H, CH3), 4.00—4.28 (m, 2H, C27H19Cl4NO3S: C, 55.98; H, 3.31; N, 2.42. Found: C, 55.92; H, 3.25; N,

610
Vol. 58, No. 5
2.48.
Tatsuoka T., Ohno T., Inoue T., Bioorg. Med. Chem. Lett., 15, 2990—
2993 (2005).
Ethyl 4-Hydroxy-5-[(4-methylphenyl)sulfanyl]-2,6-di(3-nitrophenyl)-3-
pyridine-carboxylate (5v): Isolated as solid (0.077 g, 78%); mp 120—121
22) Hisaki M., Kashima K., Sakamoto Y., Hojo M., Katayama O., Hata H.,
Eur. Pat. Appl. EP 220653 (1987).
1
°C; H-NMR (300 MHz, CDCl3) dH: 0.91 (t, Jꢁ7.2 Hz, 3H, CH3), 2.28 (s,
3H, CH3), 4.17 (q, Jꢁ7.2 Hz, 2H, CH2), 6.91—8.52 (m, 13H, OH, aro- 23) Attia A., Michael M., Pharmazie, 37, 551—553 (1982).
matic). 13C-NMR (75 MHz, CDCl3) dC: 13.2, 20.9, 62.6, 109.3, 117.5,
24) Quintela J. M., Peinador C., Botana L., Estevez M., Riguera R.,
Bioorg. Med. Chem., 5, 1543—1553 (1997).
123.8, 124.7, 127.3, 128.3, 128.7, 129.0, 129.9, 130.3, 130.5, 131.1, 134.6,
135.4, 136.9, 140.3, 142.2, 147.7, 158.5, 162.5, 168.9, 169.3. IR (KBr) nmax
:
;
25) Zhu G. D., Arendsen D. L., Gunawardana I. W., Boyd S. A., Stewart A.
O., Fry D. G., Cool B. L., Kifle L., Schaefer V., Meuth J., Marsh K. C.,
Kempf-Grote A. J., Kilgannon P., Gallatin W. M., Okasinski G. F., J.
Med. Chem., 44, 3469—3487 (2001).
733, 1019, 1084, 1245, 1357, 1483, 1539, 1592, 1688, 2994, 3347 cmꢃ1
Anal. Calcd for C27H21N3O7S: C, 61.01; H, 3.98; N, 7.91. Found: C, 61.07;
H, 3.95; N, 7.98.
In-Vitro Antimycobacterial Activity All compounds were screened for 26) Roth H. J., Kleeman A., “Pharmaceutical Chemistry,” John Wiley &
their in vitro anti-mycobacterial activity against MTB, in Middlebrook Sons, New York, 1988.
7H11agar medium supplemented with OADC by agar dilution method simi- 27) Bashford K. E., Burton M. B., Cameron S., Cooper A. L., Hogg R. D.,
lar to that recommended by the National Committee for Clinical Laboratory
Kane P. D., MacManus D. A., Matrunola C. A., Moody C. J., Robert-
son A. A. B., Warne M. R., Tetrahedron Lett., 44, 1627—1629 (2003).
Standards for the determination of MIC in triplicate.51) The MIC is defined
as the minimum concentration of compound required to give complete inhi- 28) Raw S. A., Taylor R. J. K., Chem. Commun., 2004, 508—509 (2004).
bition of bacterial growth.
29) Constable E. C., Housecroft C. E., Neuburger M., Phillips D., Raithby
P. R., Schofield E., Sparr E., Tocher D. A., Zehnder M., Zimmermann
Y., J. Chem. Soc. Dalton Trans., 2000, 2219—2228 (2000).
Acknowledgements S.P. thanks the Department of Science and Tech-
nology, New Delhi, for funding for a major research project (No. SR/S1/OC- 30) Cave G. W. V., Hardie M. J., Roberts B. A., Raston C. L., Eur. J. Org.
70/2006) and for funds under (i) IRHPA program for funds for the purchase
of a high resolution NMR spectrometer and (ii) FIST program and the Uni-
versity Grants Commission, New Delhi, for (i) funds under the DRS and
Chem., 2001, 3227—3231 (2001).
31) Cutshall N. S., Kucera K. A., Ursion R., Latham J., Ihle N. C., Bioorg.
Med. Chem. Lett., 12, 1517—1520 (2002).
ASIST programs and (ii) for funding for a major research project [F. No. 36- 32) Comins D. L., Smith E. D., Tetrahedron Lett., 47, 1449—1451 (2006).
155/2008(SR)]. RSK thanks CSIR, New Delhi for Senior Research Fellow- 33) http://www.who.int/mediacentre/news/releases/2009/tuberculosis_re-
ship and SMR thanks UGC, New Delhi for Junior Research Fellowship.
port_20090324/en/index.html.
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51) Ten fold serial dilutions of each test compound/drug were incorporated
into Middlebrook 7H11 agar medium with OADC Growth Supple-
ment. Inoculum of M. tuberculosis H37Rv were prepared from fresh
Middlebrook 7H11 agar slants with OADC Growth Supplement ad-
justed to 1 mg/ml (wet weight) in Tween 80 (0.05%) saline diluted to
10ꢃ2 to give a concentration of approximately 107 cfu/ml. A 5 ml
amount of bacterial suspension was spotted into 7H11 agar tubes con-
taining 10-fold serial dilutions of drugs per milliliter. The tubes were
incubated at 37 °C, and final readings were recorded after 28 d. The
minimum inhibitory concentration (MIC) is defined as the minimum
concentration of compound required to give complete inhibition of
bacterial growth.
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