A tandem multi-component synthesis of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones

Article abstract of DOI:10.1016/j.tet.2006.03.009

The five-component reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, aromatic aldehydes, and ammonium acetate affords two diastereomers of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones via a novel tandem Mannich-enamine-substitut

Full text of DOI:10.1016/j.tet.2006.03.009

Tetrahedron 62 (2006) 4892–4899
A tandem multi-component synthesis of 5,7-diaryl-5,6,7,8-
tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones
*
Velanganni Paul Alex Raja and Subbu Perumal
School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
Received 7 December 2005; revised 13 February 2006; accepted 2 March 2006
Available online 30 March 2006
Abstract—The five-component reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, aromatic aldehydes, and ammonium acetate affords two
diastereomers of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones via a novel tandem Mannich-enamine-substitution
sequence. Presumably, they are generated from ethyl 2-[(4-oxo-2,6-diaryl-3-piperidinyl)sulfanyl]acetates. During the formation of the
trans-5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]-thiazin-2(3H)-ones from ethyl 2-[(4-oxo-2,6-diaryl-3-piperidinyl)sulfanyl]ace-
tates, the configuration at the carbon bearing an aryl group adjacent to the enamide C]C double bond is inverted via ring opening and closure.
When o-substituted benzaldehydes were employed in this reaction, 5,7-diaryl-5,6-dihydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones were ob-
tained via air oxidation, along with trans-5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]-thiazin-2(3H)-ones.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Accordingly, a series of 5,7-diaryl-5,6,7,8-tetrahydro-1H-
pyrido[3,4-b][1,4]thiazin-2(3H)-ones 5 (42–74%) were pre-
pared in a one-pot reaction by gently warming the reactants,
ethyl 2-[(2-oxopropyl)sulfanyl]acetate 1, aromatic aldehyde
and ammonium acetate in a 1:2:2 molar ratio in ethanol and
stirring at ambient temperature for about 5–7 days. When
1 mol of ammonium acetate was used, the reaction was
found to afford ethyl 2-[(4-oxo-2,6-diaryl-3-piperidinyl)sul-
fanyl]acetate 2, showing that the product-selectivity of the
reaction can be tuned statistically. Since, thiazinones were
targeted as the final products, only one of the intermediate
piperidones was synthesised and the cis relationship be-
tween the aryl rings in 2 was established.
Heterocycles containing nitrogen and sulfur possess im-
portant biological activities. For instance, the piperidine
sub-structure is ubiquitous in nature as it is found in many bi-
ologically active compounds such as alkaloids.1 Compounds
incorporating a piperidine ring exhibit biological activities
like anti-parkinson,2 antidepressant3 and analgesic.4 Thia-
zines display many important biological activities such as
sedative,5 neuroleptic,6 antitussive,7 anti-fungal, anti-inflam-
matory and anthelmintic,8 antipsoriatic9 and anti-HIV.10 The
derivatives of thiazine act as myocardial calcium channel
modulators11 and also as matrix metalloproteinase inhibi-
tors.12 Hence, it was considered of interest to synthesis het-
erocycles comprising these two rings in a one-pot synthesis
employing a tandem sequence. Tandem reactions are very
useful in constructing molecules of complex structures rap-
idly with elegance and economy in an eco-friendly manner
as wastage is minimised in this protocol.
Ethyl 2-[(2-oxopropyl)sulfanyl]acetate 1 required for the
synthesis of the thiazinones was prepared by the reaction
of chloroacetone and ethyl 2-sulfanylacetate in presence of
potassium carbonate in chloroform medium in 95% yield.
In contrast, the preparation of 1 was reported earlier in
62.5% yield from the reaction of chloroacetone and ethyl
2-sulfanylacetate in presence of sodium ethoxide in ethanol
under reflux.13 The ketoester 1 has one active methyl and
two active methylene groups. From the structures of 2 and
5, it follows that the reaction occurs regioselectively,
wherein the methylene and methyl adjacent to the keto car-
bonyl are involved in the reaction, although the methylene
adjacent to the sulfur and ester functions should be more
acidic relative to the acetyl methyl (Scheme 1). This may
probably be ascribed to the greater nucleophilicity of the
carbanion formed at the terminal methyl carbon relative to
the carbanion generated at the methylene carbon attached
to the ester and sulfur functionalities.
2. Results and discussion
The synthesis of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido
[3,4-b][1,4]thiazin-2(3H)-ones 5 was planned via a multi-
component reaction employing a Mannich-enamine-substi-
tution tandem sequence as depicted in Scheme 1.
Keywords: Piperidine; Thiazine; Ethyl 2-[(2-oxopropyl)sulfanyl]acetate;
Tandem; Mannich; Enamine.
* Corresponding author. Tel./fax: +91 452 2459845; e-mail: subbu.perum@
gmail.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.009

V. P. A. Raja, S. Perumal / Tetrahedron 62 (2006) 4892–4899
4893
O
EtOOC
O
NH2
HN
O
S
COOEt
S
H
S
S
1
COOEt
H
H3C
Ar
Ar
N
H
Ar
Ar
N
H
Ar
N
H
Ar
2 ArCHO
NH4OAc (excess)
5
3
2
Scheme 1. Retrosynthesis of thiazinones 5.
Table 1. Yields of thiazinones, 5a–6g
This five-component tandem reaction involving para-
substituted benzaldehydes affords two diastereomers of
thiazinones, 5-cis and 5-trans, which differ in the relative
orientations of the aryl rings at C-5 and C-7. The cis- and
trans-isomers of 5a–5d were separated using flash column
Comp
X
H
Yield (%)
Total yield (%)
5a-cis
5a-trans
38
29
67
63
54
48
1
5b-cis
5b-trans
37
26
chromatography. From the H NMR spectroscopic data of
p-Cl
p-Me
p-F
the reaction mixture, it is found that the ratio of the trans
and cis isomers, 5a–5d isw0.70:1.00. In the case of ortho-
substituted benzaldehydes, only the 5-trans and the air-
oxidised product, 5,7-diaryl-5,6-dihydro-1H-pyrido[3,4-b]
[1,4]thiazin-2(3H)-ones, 6 were obtained (Scheme 2). The
yields of 5 and 6 are given in Table 1.
5c-cis
5c-trans
33
21
5d-cis
5d-trans
32
16
5e-trans
5f-trans
5g-trans
o-Cl
o-Me
o-MeO
39
33
60
49
42
74
The structure and stereochemistry of 2 was established from
1H, 13C and 2D NMR spectroscopic data. That the ring
system in 2f adopts a chair conformation is evident from
the splitting pattern and J values of the signals of the ring
protons. The proton H-6 gives a doublet of doublets at
4.65 ppm with J values of 12 and 3 Hz corresponding to the
vicinal diaxial and axial–equatorial couplings, respectively.
This points to the equatorial orientation of the o-chloro-
phenyl group at C-6. The axial orientation of the sulfanyl
ester side chain at C-3 is inferred from the J value of 2 Hz
for the protons, H-2 and H-3 giving signals at 4.93 and
3.79 ppm, respectively. The diastereotopic methylene pro-
tons, H-5 each appear as a doublet of doublets at 2.60 and
3.62 ppm, respectively, while the diastereotopic methylene
protons adjacent to sulfur appear as doublets at 3.01 and
3.12 ppm with a J value of 15 Hz. The methyl and the
methylenic protons of the ester functionality appear at 1.20
6e
6f
6g
o-Cl
o-Me
o-MeO
10
9
14
and 4.00 ppm, respectively. The results of X-ray studies
are also in accord with the above structure 2f14 (Fig. 1).
The cis- and trans-isomers of 5a–5g were characterised
using H, 13C and 2D NMR spectroscopic data. The H
NMR spectrum of 5a-cis gives a doublet of doublets with J
values of 11 and 4 Hz at 4.20 ppm ascribable to the axial–
pseudoaxial and axial–pseudoequatorial couplings of H-7
with the diastereotopic protons at C-8. This points to the
equatorial orientation of the phenyl ring at C-7. The diaster-
eotopic methylene protons, H-3 give two doublets at 3.12
1
1
O
O
X
4
3
S
O
O
5
O
NH4OAc
2
6
S
CHO
O
N
H
1
1
X
X
2
2 NH4OAc
NH4OAc
O
O
2
O
2
2
1
1
HN
8a
1
HN
3
4
3
3
HN
8a
8a
S
S
4
4a
S
4
8
8
7
8
7
4a
4a
7
5
N
H
N
6
5
5
N
H
6
6
H
X
X
X
X
X
X
(p-X)
5-cis
(o-X or p-X)
5-trans
(o-X)
6
Scheme 2. Formation of thiazinones 5 and 6 via tandem reactions.

4894
V. P. A. Raja, S. Perumal / Tetrahedron 62 (2006) 4892–4899
is slightly less stable than the 5-cis isomer in the case of
aryl rings with p-substituent. The C-3 of 5a-cis gives a signal
at 30.6 ppm, while the quaternary carbon, C-4a appears at
111.0 ppm. The assignment of the chemical shift of C-4a
is also further supported by the HMBC spectroscopic data,
which shows correlation between C-4a and H-3 proton.
The allylic carbons, C-5 and C-8 appear at 62.7 and
36.4 ppm, respectively, the assignments being aided by the
C,H-COSY correlations. Similarly, the homoallylic carbon
C-7 was assigned to the signal at 57.9 ppm. The signal of
another quaternary carbon C-8a appears at 142.6 ppm. The
homoallylic proton, H-7 appearing at 4.20 ppm shows a
weak correlation with quaternary carbon, C-8a at 142.6 ppm
in the HMBC spectrum. The aromatic carbons appear in
the region of 126.6–139.7 ppm.
Figure 1. X-ray structure of ethyl 2-[2,6-bis(2-chlorophenyl)-4-oxo-3-
piperidinyl]sulfanylacetate 2f.
The stereochemistry of the cis- and trans-isomers of 5
arrived at from NMR studies is also in complete agreement
with that determined by the X-ray crystallographic studies of
crystals of 5b-cis (Fig. 2), 5e-trans (Fig. 3) and 5g-trans
(Fig. 4).
and 3.39 ppm with the J value of 15 Hz, this assignment be-
ing confirmed by a HMBC correlation of these protons with
the carbonyl carbon at 164.2 ppm and the C-4a at 111.0 ppm.
One of the two protons of 8-CH2 appears as a doublet of dou-
blets of doublets at 2.37 ppm with J values of 16, 4 and 2 Hz
corresponding to the geminal coupling, pseudoequatorial–
axial coupling with H-7, and a long range coupling with
H-5. Another proton of 8-CH2 group also appears as a dou-
blet of doublets of doublets at 2.58 ppm with J values of
16, 11 and 4 Hz corresponding to the geminal coupling,
pseudoaxial–axial coupling with H-7 and a long range cou-
pling with H-5. The benzylic proton H-5 appears at
4.75 ppm as a doublet of doublets with J values of 4 and
2 Hz resulting from the long range coupling with the allylic
protons at C-8, which is evident from H,H-COSY spectro-
scopic data. The aromatic protons appear in the region of
7.27–7.46 ppm, while the amine and amide protons appear
at 1.65 and 7.65 ppm, respectively.
In the thiazinone ring of 5-cis isomers, both six membered
rings adopt a half chair conformation and the aryl rings at
5- and 7-positions are oriented equatorially and pseudoequa-
torially. For the 5-trans isomers, the aryl rings at 5- and 7-
positions are oriented equatorially and pseudoaxially in
contrast to their cis relationship for the aryl rings found in
In the 1H NMR spectrum of 5a-trans, a doublet of doublets
due to H-7 is obtained at 4.08 ppm with J values of 10 and
4 Hz, ascribable to pseudoaxial–axial and axial–pseudo-
equatorial coupling, respectively, with 8-CH2 protons. This
shows that the phenyl ring at C-7 is oriented equatorially.
The diastereotopic protons at C-3 give two doublets at
3.31 and 3.44 ppm (J¼15 Hz). The two allylic protons at
C-8 appear as a multiplet at 2.53 ppm. Unlike in the case
of 5a-cis, the proton, H-5 of 5a-trans appears as a singlet
at 4.74 ppm, while the amine and amide protons give signals
at 1.70 and 7.45 ppm, respectively.
Figure 2. X-ray structure of cis-5,7-bis(4-chlorophenyl)-5,6,7,8-tetrahydro-
1H-pyrido[3,4-b][1,4]thiazin-2(3H )-one 5b-cis.
An unambiguous assignment of the heterocyclic ring carbon
chemical shifts for 5a-cis and 5a-trans was arrived at from
the proton chemical shift values and C,H-COSY correla-
tions. The 13C chemical shifts of 5,7-diaryl-5,6,7,8-tetrahy-
dro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones show that the
carbon signals of 5a-trans isomers appear slightly more
shielded than the corresponding carbons of the cis isomer
(5a-cis). For instance, the quaternary carbon, C-4a and the
homoallylic carbon, C-7 of 5a-trans appear shielded by
3.7 and 6.7 ppm, respectively, compared to the correspond-
ing carbons of the cis isomer. Presumably, this is ascribable
to the syn axial interaction between the C-5 aryl ring and the
axial proton H-7 of the 5a-trans isomer. The ratio of the 5-
1
trans to 5-cis isomersw0.70:1.00 found from the H NMR
spectrum of the reaction mixture suggests that the 5-trans
Figure 3. X-ray structure of trans-5,7-bis(2-chlorophenyl)-5,6,7,8-tetra-
hydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H )-one 5e-trans.

V. P. A. Raja, S. Perumal / Tetrahedron 62 (2006) 4892–4899
4895
(J¼14 Hz). The H-5 appears as a singlet at 4.77 ppm, while
the alkenic proton, H-8 appears as a singlet at 5.49 ppm. The
amino and the amide protons give broad singlets at 1.70 and
7.76 ppm, respectively. That the reaction proceeding
through an alternative mechanistic pathway via an initially
formed 7 depicted in Scheme 4 is not involved under the
present reaction conditions is evident from the following.
The reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate 1
with ammonium acetate both under room temperature and
at reflux for 8 days in the absence of benzaldehyde and the
subsequent examination of the reaction mixture employing
1H NMR, 13C NMR and GC–MS techniques failed to
show the formation of even a small amount of the thiazine 7.
+
NH4OAc
NH3 HOAc
O
Figure 4. X-ray structure of trans-5,7-bis(2-methoxyphenyl)-5,6,7,8-tetra-
hydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H )-one 5g-trans.
O
O
2 PhCHO
NH3
HN
S
S
+
5 and 6
NH3
X
O
7
piperidone 2f, although 2f is the precursor for 5e-trans as
found from the conversion of 2f into 5e-trans upon treatment
of the former with ammonium acetate under the reaction
conditions in a separate reaction. This suggests that during
the formation of 5e-trans from 2f, the configuration at C-5
is inverted, presumably via the opening and reformation of
the ring with inversion at one of the benzylic positions of
the piperidine ring as shown in Scheme 3. The probable
mechanism of formation of the thiazinones is given in
Scheme 3, wherein two Mannich reactions, enamine forma-
tion, ring opening and closure and condensation occur in
a tandem sequence. In the case of o-substituted benzalde-
hydes, the trans-tetrahydrothiazinones undergo air oxidation
to furnish the dihydrothiazinones 6 as minor product, whose
structure was elucidated from NMR spectroscopic data. For
instance, in the 1H NMR spectrum of 6e, the two diastereo-
topic protons at C-3 give two doublets at 3.33 and 3.44 ppm
Scheme 4. Mechanism for the formation of thiazinones 5 and 6 through 7.
3. Conclusion
The present study reports a concise, one-pot, multi-compo-
nent tandem synthesis of thiazinones, which could possess
important biological activities. The complete structure and
stereochemistry of the products have been elucidated using
NMR spectroscopic and X-ray crystallographic studies. In
view of the pharmacophoric nature of the piperidine and thia-
zine ring systems, investigations are now currently in prog-
ress in our group with a view to using the thiazinones as
synthons for the construction of more complex molecules
and to prepare enantiomerically pure compounds belonging
to this class.
H
+
H2N
ArCHO + NH4OAc
Ar
O
:
OH
Mannich
reaction
O
S
COOEt
S
COOEt
H3C
ArCHO
S
COOEt
H3C
H3C
+
1
Ar
H2N
Ar
H2N
Mannich
reaction
EtOOC
NH2
EtOOC
NH2
O
S
S
COOEt
S
H
NH4OAc
H
H
Ar
Ar
NH
2 H
N
H
Ar
Ar
N
H
Ar
Ar
2
3
O
O
EtOOC
NH2
O
HN
HN
HN
S
S
S
S
H
Ar
H
Ar
H
H
N
H
N
H
Ar
Ar
Ar
N
H
N
H
H
Ar
H
Ar
Ar
4
6
5-trans
5-cis
Scheme 3. Mechanism of formation of thiazinones.

4896
V. P. A. Raja, S. Perumal / Tetrahedron 62 (2006) 4892–4899
4. Experimental
(1H, s), 2.34 (1H, ddd, J¼16, 4, 2 Hz), 2.52 (1H, ddd,
J¼16, 11, 4 Hz), 3.12 (1H, d, J¼15 Hz), 3.37 (1H, d,
J¼15 Hz), 4.15 (1H, dd, J¼11, 4 Hz), 4.72 (1H, dd, J¼4,
2 Hz), 7.28–7.49 (10H, m), 8.18 (1H, s). 13C NMR
(75 MHz, CDCl3) dC 30.5, 36.5, 57.2, 61.9, 110.4, 128.0,
128.6, 128.7, 128.8, 130.2, 133.6, 134.3, 138.2, 141.0,
164.0. Anal. Calcd for C19H16Cl2N2OS: C, 58.32; H, 4.12;
N, 7.16. Found C, 58.29; H, 4.18; N, 7.14.
4.1. General methods
All melting points reported in this work were measured in
open capillaries. Flash chromatography was performed on
1
silica gel (230–400 mesh). The H and 13C NMR spectra
have been measured at 300 and 75 MHz, respectively, using
Bruker 300 MHz (Avance) instrument in CDCl3 solvent
using tetramethylsilane as internal standard. Chemical shifts
were reported as d values (ppm). All one- and two-dimen-
sional NMR spectra were obtained using standard Bruker
software throughout. IR spectra were recorded on a JASCO
FTIR instrument (KBr pellet in case of solids and CH2Cl2 in
case of liquids). Elemental analysis were done using Vario
EL III instrument. Crystals suitable for X-ray analysis
were obtained by crystallisation from ethanol and ethyl ace-
tate mixture.
4.2.4. trans-5,7-Bis(4-chlorophenyl)-5,6,7,8-tetrahydro-
1H-pyrido[3,4-b][1,4]thiazin-2(3H)-one 5b-trans. Isolated
ꢀ
as colourless solid. (288 mg, 26%) mp¼180 C; ymax (KBr)
3350, 1681 cmꢁ1; 1H NMR (300 MHz, CDCl3) dH 2.33 (1H,
m), 3.21 (1H, d, J¼15 Hz), 3.35 (1H, d, J¼15 Hz), 4.34
(1H, s), 4.63 (1H, s), 3.97 (1H, m), 7.15–7.27 (10H, m),
8.83 (1H, s). 13C NMR (75 MHz, CDCl3) dC 30.2, 35.2,
50.6, 59.1, 107.1, 128.1, 128.8, 128.9, 129.5, 130.0, 133.6,
134.1, 140.1. Anal. Calcd for C19H16Cl2N2OS: C, 58.32;
H, 4.12; N, 7.16. Found C, 58.39; H, 4.08; N, 7.21.
4.2. Synthesis of thiazin-2(3H)-ones from benzaldehyde
and p-substituted benzaldehydes—general procedure
4.2.5. cis-5,7-Bis(4-methylphenyl)-5,6,7,8-tetrahydro-
1H-pyrido[3,4-b][1,4]thiazin-2(3H)-one 5c-cis. ꢀ Isolated
as colourless solid. (328 mg, 33%) mp¼180 C; ymax
Ammonium acetate (0.663 g, 8.4 mmol) was dissolved
in ethanol (3 mL) by heating. Benzaldehyde (0.582 mL,
5.7 mmol) and ethyl 2-[(2-oxopropyl)sulfanyl]acetate
(0.338 mL, 2.8 mmol) were added to this solution, the mix-
ture heated until the colour of the solution turned yellow and
left at room temperature for 5–7 days. After the completion
of the reaction, the two diastereomers were separated using
flash column chromatography performed on silica gel (230–
400 mesh) and petroleum ether and ethyl acetate mixture.
The products were further recrystallised from ethanol and
ethyl acetate.
1
(KBr) 3402, 1675 cmꢁ1; H NMR (300 MHz, CDCl3) dH
2.1 (1H, s), 2.31 (3H, s), 2.32 (2H, m), 2.34 (3H, s), 2.54
(1H, ddd, J¼14, 11, 4 Hz), 3.10 (1H, d, J¼15 Hz), 3.37
(1H, d, J¼15 Hz), 4.14 (1H, dd, J¼11, 4 Hz), 4.70 (1H,
dd, J¼4, 2 Hz), 7.11–7.33 (8H, m), 8.9 (1H, s). 13C NMR
(75 MHz, CDCl3) dC 21.1, 21.2, 30.6, 36.5, 57.6, 62.4,
111.1, 126.4, 128.6, 129.1, 129.2, 136.7, 137.4, 138.3,
139.7, 164.1. Anal. Calcd for C21H22N2OS: C, 71.97; H,
6.33; N, 7.99. Found C, 71.90; H, 6.35; N, 8.07.
4.2.6. trans-5,7-Bis(4-methylphenyl)-5,6,7,8-tetrahydro-
1H-pyrido[3,4-b][1,4]thiazin-2(3H)-one 5c-trans. Isolated
4.2.1. cis-5,7-Diphenyl-5,6,7,8-tetrahydro-1H-pyrido
[3,4-b][1,4]thiazin-2(3H)-one 5a-cis. Isolated as colourless
as paste. (208 mg, 21%); ymax (CH2Cl2) 3328, 1675 cmꢁ1
;
1H NMR (300 MHz, CDCl3) dH 2.53 (2H, m), 3.27
(3H, s), 3.25 (1H, d, J¼15 Hz), 3.41 (1H, d, J¼15 Hz),
3.39 (3H, s), 4.07 (1H, m), 4.75 (1H, s), 5.03 (1H, s),
7.08–7.26 (8H, m), 8.50 (1H, s). 13C NMR (75 MHz,
CDCl3) dC 21.0, 21.1, 30.2, 35.4, 50.9, 59.4, 107.2, 126.7,
128.1, 129.3, 129.4, 130.0, 137.1, 137.6, 138.1, 138.6,
164.8. Anal. Calcd for C21H22N2OS: C, 71.97; H, 6.33; N,
7.99. Found C, 71.94; H, 6.25; N, 7.91.
ꢀ
solid. (347 mg, 38%) mp¼202 C; ymax (KBr) 3199,
1
1672 cmꢁ1; H NMR (300 MHz, CDCl3) dH 1.65 (1H, s),
2.37 (1H, ddd, J¼16, 4, 2 Hz), 2.58 (1H, ddd, J¼16, 11,
4 Hz), 3.12 (1H, d, J¼15 Hz), 3.39 (1H, d, J¼15 Hz), 4.20
(1H, dd, J¼11, 4 Hz), 4.75 (1H, dd, J¼4, 2 Hz), 7.27–7.46
(10H, m), 7.65 (1H, s). 13C NMR (75 MHz, CDCl3) dC
30.6, 36.4, 57.9, 62.7, 111.0, 126.6, 127.8, 128.4, 128.5,
128.6, 128.7, 128.8, 139.7, 142.6, 164.2. Anal. Calcd for
C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found C, 70.73;
H, 5.67; N, 8.70.
4.2.7. cis-5,7-Bis(4-fluorophenyl)-5,6,7,8-tetrahydro-1H-
pyrido[3,4-b][1,4]thiazin-2(3H)-one 5d-cis. Isolated as
ꢀ
4.2.2. trans-5,7-Diphenyl-5,6,7,8-tetrahydro-1H-pyr-
ido[3,4-b][1,4]thiazin-2(3H)-one 5a-transꢀ. Isolated as col-
ourless solid. (265 mg, 29%) mp¼199 C; ymax (KBr)
colourless solid. (325 mg, 32%) mp¼205 C; ymax (KBr)
1
3212, 1671 cmꢁ1; H NMR (300 MHz, CDCl3) dH 1.83
(1H, s), 2.35 (1H, ddd, J¼16, 4, 2 Hz), 2.54 (1H, ddd,
J¼16, 11, 4 Hz), 3.10 (1H, d, J¼15 Hz), 3.37 (1H, d,
J¼15 Hz), 4.16 (1H, dd, J¼11, 4 Hz), 4.73 (1H, dd, J¼4,
2 Hz), 6.98–7.43 (8H, m), 8.50 (1H, s). 13C NMR
(75 MHz, CDCl3) dC 30.9, 57.7, 62.3, 36.9, 111.1, 115.6,
115.7, 115.9, 116.0, 128.6, 128.7, 130.8, 130.9, 135.9,
138.8, 164.6. Anal. Calcd for C19H16F2N2OS: C, 63.67; H,
4.50; N, 7.82. Found C, 63.66; H, 4.57; N, 7.72.
1
3430, 1648 cmꢁ1; H NMR (300 MHz, CDCl3) dH 1.70
(1H, s), 2.53 (2H, m), 3.31 (1H, d, J¼15 Hz), 3.44 (1H, d,
J¼15 Hz), 4.08 (1H, dd, J¼10, 4 Hz), 4.74 (1H, s), 7.22–
7.39 (10H, m), 7.45 (1H, s). 13C NMR (75 MHz, CDCl3)
dC 30.4, 36.0, 51.2, 60.1, 107.3, 126.6, 127.7, 128.0,
128.1, 128.6, 128.7, 130.0, 140.8, 142.3, 164.1. Anal. Calcd
for C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found C, 70.76;
H, 5.69; N, 8.60.
4.2.8. trans-5,7-Bis(4-fluorophenyl)-5,6,7,8-tetrahydro-
1H-pyrido[3,4-b][1,4]thiazin-2(3H)-one 5d-trans. Isolated
4.2.3. cis-5,7-Bis(4-chlorophenyl)-5,6,7,8-tetrahydro-1H-
pyrido[3,4-b][1,4]thiazin-2(3H)-one 5b-ciꢀs. Isolated as
pale yellow solid. (410 mg, 37%) mp¼195 C; ymax (KBr)
ꢀ
as colourless solid. (163 mg, 16%) mp¼198 C; ymax (KBr)
3091, 1650 cmꢁ1; 1H NMR (300 MHz, CDCl3) dH 2.51 (m),
3.29 (1H, d, J¼15 Hz), 3.44 (1H, d, J¼15 Hz), 4.06 (1H, m),
1
3285, 1671 cmꢁ1; H NMR (300 MHz, CDCl3) dH 1.78

V. P. A. Raja, S. Perumal / Tetrahedron 62 (2006) 4892–4899
4897
4.70 (1H, s), 6.15 (1H, s), 6.99–7.50 (8H, m), 7.71 (1H, s).
13C NMR (75 MHz, CDCl3) dC 30.3, 35.7, 50.5, 59.2,
107.6, 115.3, 115.4, 115.6, 115.7, 115.8, 116.1, 128.4,
128.8, 129.7, 129.8, 130.0, 164.6. Anal. Calcd for
C19H16F2N2OS: C, 63.67; H, 4.50; N, 7.82. Found C,
63.64; H, 4.49; N, 7.89.
130.2, 130.6, 133.4, 134.5, 136.5, 163.5. Anal. Calcd for
C19H14Cl2N2OS: C, 58.62; H, 3.62; N, 7.20. Found C,
58.58; H, 3.60; N, 7.23.
4.3.5. 5,7-Bis(2-methylphenyl)-5,6-dihydro-1H-
pyrido[3,4-b][1,4]thiazin-2(3H)-onꢀe 6f. Isolated as colour-
less solid. (90 mg, 9%) mp¼155 C; ymax (KBr) 3400,
1
4.3. Synthesis of thiazin-2(3H)-ones from o-substituted
benzaldehydes—general procedure
1670 cmꢁ1; H NMR (300 MHz, CDCl3) dH 1.7 (1H, s),
2.26 (3H, s), 2.29 (3H, s), 3.25 (1H, d, J¼14 Hz), 3.45
(1H, d, J¼14 Hz), 4.44 (1H, s), 5.20 (1H, s), 6.64–7.25
(9H, m), 8.60 (1H, s). 13C NMR (75 MHz, CDCl3) dC
18.7, 19.1, 30.7, 54.5, 119.8, 120.0, 125.5, 126.2, 127.1,
128.1, 128.3, 130.0, 130.4, 131.3, 134.8, 136.9, 137.2,
137.3, 137.7, 138.3, 164.6. Anal. Calcd for C21H20N2OS:
C, 72.38; H, 5.79; N, 8.04. Found C, 72.39; H, 5.75; N, 8.00.
The procedure described above for benzaldehyde and
p-substituted benzaldehydes was used as such here. In these
reactions, a mixture of 5-trans and 6 were obtained, which
were separated by flash column chromatography using silica
gel (230–400 mesh) and petroleum ether and ethyl acetate
mixture.
4.3.6. 5,7-Bis(2-methoxyphenyl)-5,6-dihydro-1H-
pyrido[3,4-b][1,4]thiazin-2(3H)-one 6g. Isolated as paste.
(151 mg, 10%); ymax (CH2Cl2) 3425, 1665 cmꢁ1; 1H NMR
(300 MHz, CDCl3) dH 1.7 (1H, s), 3.10 (1H, d, J¼15 Hz),
3.27 (1H, d, J¼15 Hz), 3.80 (3H, s), 3.85 (3H, s), 4.81(1H,
s), 5.60 (1H, s), 6.64–7.53 (9H, m), 8.00 (1H, s). 13C NMR
(75 MHz, CDCl3) dC 33.0, 49.7, 55.1, 55.4, 109.8, 111.4,
111.1, 119.8, 120.1, 120.4, 124.0, 127.6, 127.9, 128.2,
128.8, 129.6, 129.8, 133.2, 133.6, 170.0. Anal. Calcd for
C21H20N2O3S: C, 66.29; H, 5.30; N, 7.36. Found C, 66.27;
H, 5.26; N, 7.38.
4.3.1. trans-5,7-Bis(2-chlorophenyl)-5,6,7,8-tetrahydro-
1H-pyrido[3,4-b][1,4]thiazin-2(3H)-one 5e-trans. Isolated
ꢀ
as colourless solid. (432 mg, 39%) mp¼181 C; ymax (KBr)
1
3295, 1658 cmꢁ1; H NMR (300 MHz, CDCl3) dH 2.02
(1H, s), 2.53 (2H, m), 3.33 (1H, d, J¼15 Hz), 3.44 (1H, d,
J¼15 Hz), 4.38 (1H, dd, J¼11, 4 Hz), 5.21 (1H, s), 7.16–
7.57 (8H, m), 8.49 (1H, s). 13C NMR (75 MHz, CDCl3) dC
30.3, 34.3, 47.5, 56.9, 106.0, 126.5, 127.3, 127.5, 128.8,
129.3, 129.4, 129.6, 131.0, 130.2, 133.1, 134.2, 137.3,
139.3, 164.3. Anal. Calcd for C19H16N2Cl2OS: C, 58.32;
H, 4.12; N, 7.16. Found C, 58.33; H, 4.10; N, 7.11.
4.4. Synthesis of ethyl 2-[2,6-bis(2-chlorophenyl)-4-oxo-
3-piperidinyl]sulfanylacetate 2f
4.3.2. trans-5,7-Bis(2-methylphenyl)-5,6,7,8-tetrahydro-
1H-pyrido[3,4-b][1,4]thiazin-2(3H)-one 5f-transꢀ. Isolated
as colourless solid. (328 mg, 33%) mp¼141 C; ymax
Ammonium acetate (0.215 g, 2.8 mol) was dissolved in
ethanol (3 mL) by heating. ortho-Chlorobenzaldehyde
(0.630 mL, 5.7 mol) and ethyl 2-[(2-oxopropyl)sulfanyl]
acetate (0.338 mL, 2.8 mmol) were added to this solution
and the mixture was heated until the colour of the solution
turned yellow. The solution was kept at room temperature
for 4 days. The solid precipitated was filtered off, washed
with ethanol, and recrystallised from ethanol and ethyl ace-
1
(KBr) 3420, 1678 cmꢁ1; H NMR (300 MHz, CDCl3) dH
1.96 (1H, s), 2.39 (3H, s), 2.42 (3H, s), 2.57 (2H, m), 3.27
(1H, d, J¼15 Hz), 3.40 (1H, d, J¼15 Hz), 4.24 (1H, dd,
J¼11, 4 Hz), 4.96 (1H, s), 7.03–7.42 (8H, m), 8.99 (1H,
s). 13C NMR (75 MHz, CDCl3) dC 19.0, 19.4, 30.3, 33.9,
46.7, 56.7, 107.3, 125.4, 125.6, 126.3, 127.4, 127.5, 127.9,
130.5, 130.8, 131.2, 136.0, 136.6, 137.8, 139.7, 164.6.
Anal. Calcd for C21H22N2OS: C, 71.97; H, 6.33; N, 7.99.
Found C, 71.90; H, 6.31; N, 8.06.
ꢀ
tate as colourless solid. (597 mg, 49%) mp¼178 C; ymax
(CH2Cl2) 3307, 1731, 1706 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) dH 1.20 (3H, t, J¼7 Hz), 1.65 (1H, s), 2.60 (1H,
dd, J¼15, 3 Hz), 3.01 (1H, d, J¼15 Hz), 3.12 (1H, d,
J¼15 Hz), 3.62 (1H, dd, J¼15, 12 Hz), 3.79 (1H, d,
J¼2 Hz), 4.00 (2H, m), 4.65 (1H, dd, J¼12, 3 Hz), 4.93
(1H, d, J¼2 Hz), 7.23–7.90 (8H, m). 13C NMR (75 MHz,
CDCl3) dC 13.9, 33.5, 42.3, 55.2, 56.4, 59.3, 61.5, 126.5,
127.6, 127.8, 129.0, 129.1, 129.5, 129.6, 129.7, 132.2,
132.4, 136.0, 139.5, 169.4, 203.6. Anal. Calcd for
C21H21Cl2NO3S: C, 57.54; H, 4.83; N, 3.20. Found C,
57.49; H, 4.88; N, 3.13.
4.3.3. trans-5,7-Bis(2-methoxyphenyl)-5,6,7,8-tetrahy-
dro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-one 5g-traꢀns.
Isolated as colourless solid. (651 mg, 60%) mp¼161 C;
ymax (KBr) 3442, 1679 cmꢁ1; 1H NMR (300 MHz, CDCl3)
dH 1.92 (1H, s), 2.46 (2H, m), 3.32 (1H, d, J¼15 Hz), 3.43
(1H, d, J¼15 Hz), 3.62 (3H, s), 3.83 (3H, s), 4.24 (1H, dd,
J¼11, 4 Hz), 5.16 (1H, s), 6.76–7.42 (8H, m), 7.93 (1H,
s). 13C NMR (75 MHz, CDCl3) dC 30.4, 34.4, 45.2, 54.4,
55.1, 55.2, 106.5, 110.3, 110.4, 120.0, 120.8, 126.2, 128.3,
128.4, 128.9, 129.0, 130.8, 131.0, 156.7, 157.4, 164.2.
Anal. Calcd for C21H22N2O3S: C, 65.95; H, 5.80; N, 7.32.
Found C, 65.86; H, 5.75; N, 7.34.
4.5. Synthesis of ethyl 2-[(2-oxopropyl)sulfanyl]acetate 1
Ethyl 2-sulfanylacetate (0.912 mL, 5.6 mmol) was dissolved
in chloroform (10 mL). To this solution, chloroacetone
(0.451 mL, 5.6 mmol) and potassium carbonate (0.392 g,
2.8 mmol) were added. The mixture was stirred under cold
condition for 4–5 h. After the completion of the reaction,
the product was extracted with chloroform, washed with
water, dried over anhydrous calcium chloride and the solvent
evaporated in vacuo. The pure product was obtained as a
4.3.4. 5,7-Bis(2-chlorophenyl)-5,6-dihydro-1H-pyr-
ido[3,4-b][1,4]thiazin-2(3H)-one 6e. Isolated as colourless
ꢀ
solid. (111 mg, 10%) mp¼136 C; ymax (KBr) 3307,
1
1680 cmꢁ1; H NMR (300 MHz, CDCl3) dH 1.70 (1H, s),
3.33 (1H, d, J¼14 Hz), 3.44 (1H, d, J¼14 Hz), 4.77 (1H,
s), 5.49 (1H, s), 6.75–7.53 (9H, m), 7.76 (1H, s). 13C NMR
(75 MHz, CDCl3) dC 30.9, 48.5, 110.2, 118.9, 120.3,
126.5, 126.8, 127.3, 128.7, 129.0, 129.3, 129.6, 129.8,
ꢀ
pale yellow liquid (0.936 g, 95%) bp 97 C, density

4898
V. P. A. Raja, S. Perumal / Tetrahedron 62 (2006) 4892–4899
1.4760 mg mꢁ3. ymax (CH2Cl2) 1725, 1649, 1203; 1H NMR
(300 MHz, CDCl3) dH 1.29 (3H, t, J¼7 Hz), 2.30 (2H, s),
3.25 (2H, s), 3.46 (1H, s), 4.17 (2H, q, J¼7 Hz). 13C NMR
(75 MHz, CDCl3) dC 13.7, 27.8, 32.9, 41.7, 61.0, 169.3,
202.5. Anal. Calcd for C7H12O3S: C, 47.71; H, 6.86. Found
C, 47.68; H, 6.81.
Dc¼1.316 mg mꢁ3. The reflections collected were 4046 of
which 3392 unique [R(int)¼0.0110]; 2694 reflections
I>2s(I ), R1¼0.0347 and wR2¼0.0970 for 2694 [I>2s(I )]
and R1¼0.0492 and wR2¼0.1062 for all (3392) intensity
data. Goodness of fit¼1.037, residual electron density in
the final Fourier map was 0.261 and ꢁ0.215 eAꢁ3. CCDC
˚
number is 290759.
4.6. X-ray crystallographic determination of
compounds of 2f, 5b-cis, 5e-trans and 5g-trans
5. Supplementary material
Data were collected at room temperature on an Enraf-Nonius
MACH 3 four-circle diffractometer (Mo Ka radiation,
l¼0.71073 A) for compounds 2f, 5b-cis, 5e-trans and 5g-
Crystal data and structure refinement for 2f, 5b-cis, 5e-trans
and 5g-trans. Atomic coordinates (ꢂ104) and equivalent
˚
2
3
˚
trans. The data collection, integration, and data reduction
for 2f, 5b-cis, 5e-trans, and 5g-trans were performed using
CAD-4 EXPRESS15 and XCAD416 programmes and an
empirical absorption correction was applied using c scan
method.17 The unit cell parameters were determined by
a least square fitting of 25 randomly selected strong reflec-
tions and an empirical absorption correction was applied us-
ing the azimuthal scan method. The structures were solved
by direct methods (SHELXS 97)18 and subsequent Fourier
synthesis and refined by full matrix least squares on
SHELXL 9719 for all non-hydrogen atoms for 2f, 5b-cis,
5e-trans and 5g-trans. All hydrogen atoms were placed in
calculated positions.
isotopic displacement parameters (A ꢂ10 ) for 2f, 5b-cis,
5e-trans and 5g-trans.
Acknowledgements
S.P. thanks the Council of Scientific and Industrial Research,
New Delhi for a major research project ([No. 01(1926/04/
EMR II)]) and the Department of Science and Technology,
New Delhi for funds under (i) IRHPA programme for the
purchase of high resolution NMR spectrometer and (ii)
FIST programme and the University Grants Commission,
New Delhi for funds under the DRS and ASIST pro-
grammes.
4.6.1. Compound 2f. C21H21Cl2NO3S, M¼438.35, mono-
˚
clinic,
space
group
Pccn,
a¼25.5182(15) A,
3
˚
˚
˚
b¼19.3676(11) A, c¼8.3266(5) A, V¼4115(3) A , Z¼8,
F(000)¼1824, m¼0.439 mmꢁ1, Dc¼1.415 mg mꢁ3. The
reflections collected were 3845 of which 3594 unique
[R(int)¼0.0459]; 1664 reflections I>2s(I ), R1¼0.0677 and
wR2¼0.1772 for 1664 [I>2s(I )] and R1¼0.1731 and
wR2¼0.2397 for all (3594) intensity data. Goodness of
fit¼1.027, residual electron density in the final Fourier
References and notes
1. Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2, 3193.
2. Morais, L. C.; Quintans-Junior, L. J.; Franco, C. I.; Almeida,
J. R.; Almeida, R. N. Pharmacol., Biochem. Behav. 2004, 79,
745.
3. Geraud, G.; Lanteri-Minet, M.; Lucas, C.; Valade, D. Clin.
Ther. 2004, 26, 1305.
map was 0.372 and ꢁ0.637 eAꢁ3. CCDC number is 290756.
˚
4.6.2. Compound 5b-cis. C19H16Cl2N2OS, M¼391.31,
4. Durieux, P.; Bruxelle, J.; Savignoni, A.; Coste, J. Presse. Med.
2001, 30, 572.
5. Iwahara, S.; Iwasaki, T.; Hasegawa, Y. Psychopharmacologia
1968, 13, 320.
6. Oelssner, W., Jr.; Peinhardt, G.; Buge, A. Pharmazie 1985, 40,
341.
7. Parish, F. A. Med. Times 1959, 87, 1488.
8. Srivastava, S. K.; Yadav, R.; Srivastava, S. D. Indian J. Chem.,
Sect. B 2004, 43, 399.
9. Moriyama, H.; Tsukida, T.; Inoue, Y.; Yokota, K.; Yoshino, K.;
Kondo, H.; Miura, N.; Nishimura, S. J. Med. Chem. 2004, 47,
1930.
10. Arranz, M. E.; Diaz, J. A.; Ingate, S. T.; Witvrouw, M.; Panne-
couque, C.; Balzarini, J.; De Clercq, E.; Vega, S. Bioorg. Med.
Chem. 1999, 7, 2811.
11. Budriesi, R.; Cosimelli, B.; Ioan, P.; Lanza, C. Z.; Spinelli, D.;
Chiarini, A. J. Med. Chem. 2002, 45, 3475.
12. Schroder, J.; Henke, A.; Wenzel, H.; Brandstetter, H.; Stamm-
ler, H. G.; Stammler, A.; Pfeiffer, W. D.; Tschesche, H. J. Med.
Chem. 2001, 44, 3231.
13. Rabinovich, M. S.; Levitov, M. M.; Kulikova, G. N.; Ver-
khovtseva, T. P.; Meller, F. M. Zh. Obshch. Khim. 1963, 33,
3135.
˚
monoclinic, space group P21/n, a¼17.891(4) A,
3
˚
˚
˚
b¼5.052(6) A, c¼24.603(5) A, V¼4115(3) A , Z¼4,
F(000)¼808, m¼0.402 mmꢁ1
,
Dc¼1.195 mg mꢁ3
. The
reflections collected were 4179 of which 3792 unique
[R(int)¼0.0334]; 1114 reflections I>2s(I ), R1¼0.0661 and
wR2¼0.1873 for 1664 [I>2s(I )] and R1¼0.1882 and
wR2¼0.2241 for all (3792) intensity data. Goodness of
fit¼0.752, residual electron density in the final Fourier
map was 0.453 and ꢁ0.271 eAꢁ3. CCDC number is 290758.
˚
4.6.3. Compound 5e-trans. C19H16Cl2N2OS, M¼391.31,
˚
monoclinic, space group P21/c, a¼7.1010(4) A, b¼
3
˚
˚
˚
26.6410(14) A, c¼9.8301(8) A, V¼1789.7 A , Z¼4,
F(000)¼808, m¼0.489 mmꢁ1
,
Dc¼1.452 mg mꢁ3
. The
reflections collected were 3893 of which 3157 unique
[R(int)¼0.0118]; 2128 reflections I>2s(I ), R1¼0.0355 and
wR2¼0.0912 for 2128 [I>2s(I )] and R1¼0.0729 and
wR2¼0.1200 for all (3157) intensity data. Goodness of
fit¼1.053, residual electron density in the final Fourier
map was 0.463 and ꢁ0.455 eAꢁ3. CCDC number is 290757.
˚
4.6.4. Compound 5g-trans. C21H22N2O3S, M¼382.47,
˚
˚
monoclinic, space group P-1, a¼9.764 A, b¼10.972 A, c¼
14. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
3
ꢁ1
˚
˚
11.061 A, V¼965.3 A , Z¼2, F(000)¼404, m¼0.191 mm
,

V. P. A. Raja, S. Perumal / Tetrahedron 62 (2006) 4892–4899
4899
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 290756–290759. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK, +44
1223 336408 or e-mail: deposit@ccdc.cam.ac.uk).
16. Harms, K.; Wocadio, S. XCAD4; University of Marburg:
Germany, 1995.
17. North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta Crystal-
logr., Sect. A 1968, 24, 351.
18. Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467.
19. Sheldrick, G. M. SHELX97; University of Gottingen: Germany,
1997.
15. Enraf-Nonius CAD-4. Express Version 5.0; Enraf-Nonius:
Delft, The Netherlands, 1994.