An efficient synthesis of pyrrolo[3′,2′:4,5]thiopyrano[3,2-b] pyridin-2-one: A new ring system of pharmaceutical interest

Article abstract of DOI:10.1016/j.tet.2012.04.041

A series of pyrrolo[3′,2′:4,5]thiopyrano[3,2-b]pyridin-2-ones 4 was prepared in good yields by reacting enaminoketones with cyanomethylene active compounds such as phenylsulfonylacetonitrile, benzoylacetonitrile, and malononitrile. Derivatives of the title ring system were tested by the National Cancer Institute of Bethesda against a panel of about 60 human tumor cell lines, and one of them showed inhibitory activity against all cancer cell lines reaching on 48% of them GI₅₀ values at submicromolar level and on the majority of the remaining ones in the low micromolar concentration.

Full text of DOI:10.1016/j.tet.2012.04.041

Tetrahedron 68 (2012) 5087e5094
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient synthesis of pyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridin-2-one:
a new ring system of pharmaceutical interest
*
ꢀ
Paola Barraja , Patrizia Diana, Virginia Spano, Alessandra Montalbano, Anna Carbone,
Barbara Parrino, Girolamo Cirrincione
ꢀ
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Universita degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
A series of pyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridin-2-ones 4 was prepared in good yields by reacting
enaminoketones with cyanomethylene active compounds such as phenylsulfonylacetonitrile, benzoyl-
acetonitrile, and malononitrile. Derivatives of the title ring system were tested by the National Cancer
Institute of Bethesda against a panel of about 60 human tumor cell lines, and one of them showed in-
hibitory activity against all cancer cell lines reaching on 48% of them GI50 values at submicromolar level
and on the majority of the remaining ones in the low micromolar concentration.
Article history:
Received 23 January 2012
Received in revised form 20 March 2012
Accepted 10 April 2012
Available online 17 April 2012
Keywords:
Pyrrolo[30,20:4,5]thiopyrano[3,2-b]
pyridin-2-one
Ó 2012 Elsevier Ltd. All rights reserved.
Angelicin
Antiproliferative activity
Enaminoketones
1. Introduction
ring system thiopyrano[2,3-e]indole 3, which showed potent pho-
totoxic activity.14
Quinolinones represent a class of heterocyclic compounds
endowed with potent antitumor activity. In particular, small mol-
ecules such as substituted quinolin-2-ones of type 1 (Chart 1) are
reported as inhibitors of tyrosine kinases and as activators of the
quiescent caspase cascade, being crucial to trigger cancer cells to
suicide.1,2 In fact there is mounting evidence that cancer cells lack
parts of the molecular machinery that activate the caspase cascade.
This makes the cancer cells lose their capacity to suicide.3
Annelation of heterocyclic moieties on the positions 6-7 of the
quinoline nucleus led to Angelicin heteroanalogues, which main-
tained remarkable antiproliferative activity either in the dark and
under UVA light irradiation.4e7 In this context, in our continuing
studies aimed at the discovery and development of potential anti-
cancer drug candidates, we have recently reported the synthesis of
new classes of pyrroloquinolinones 2aec, some of which showed
very promising photoantiproliferative properties, often higher than
that of 8-methoxypsoralen (8-MOP) the most widely employed
drug for photochemotherapy.8e11
This paper reports the synthesis of the new ring system pyrrolo
[30,20:4,5]thiopyrano[3,2-b]pyridin-2-one 4 in which sulfur is in-
troduced in the central ring of the tricyclic framework.
O
O
R2
Ph
R2
H
H
N
N
9
NR
8
R1
R1
7
1
2a-c
O
O
2
1
N
R2
H
S
3
9 R1
4
Since replacement of the oxygen of the pyrone ring of Angelicin
improved the interaction with DNA both in the dark and under ir-
radiation with UV light12,13 we synthesized derivatives of the new
8
R1
S
5
N
R
N7
R
6
3
4
Chart 1. Structures of quinolin-2-ones (1), pyrrolo[2,3-h] quinolinones (2a, N-7),
pyrrolo[3,4-h]quinolinones (2b, N-8), pyrrolo[3,2-h]quinolinones (2c, N-9), thiopyrano
[2,3-e] benzopyrroles (3), and pyrrolo[30,20:4,5]thiopyrano[3,2-b] pyridin-2-ones (4).
* Corresponding author. Tel.: þ39 091 6161606; fax: þ39 091 23860854; e-mail
address: paola.barraja@unipa.it (P. Barraja).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.041

5088
P. Barraja et al. / Tetrahedron 68 (2012) 5087e5094
2. Results and discussion
We optimized a synthetic route for the preparation of the above
mentioned ketones, starting from thiopyran-3,5-dione 5, in turn
conveniently prepared by condensation of methyl sulphanylacetate
with chloroacetone, followed by intramolecular cyclization of the so
obtained methyl[(2-oxopropyl)sulphanyl]acetate in basic media.16
Thiopyran-3,5-dione 5, was then subjected to Knorr-type re-
ductive condensation with freshly prepared diethyl hydroxy-
iminomalonate yielding, by way of the intermediate 6, the 2,3-
disubstituted compound 8a (73%). This latter underwent alkyl-
ation at the pyrrole nitrogen with iodomethane or benzylchlorides,
in the presence of NaH yielding the N-substituted derivatives 8bee
(75e91%). Alternatively, compound 5, formed by reaction with
chloroacetone in the presence of potassium hydroxide in methanol
at room temperature for 48 h was converted into derivative 7 (90%).
Condensation with ammonium acetate or with primary amines
in acetic acid furnished 2-methyltetrahydrothiopyrano[3,4-b]pyr-
roles in good yields 8fek (66e77%).
One possible synthetic strategy for the target pyrrolo[30,20:4,5]
thiopyrano[3,2-b]pyridin-2-ones 4 could have made use of enam-
inoketones 9 (Scheme 1, Table 1) as tool for the annelation of the
pyridine ring. Such intermediates were obtained from thiopyr-
anones of type 8, about which not much is reported in literature.
Only one patent in 1998 reported the synthesis in poor yield (15%)
of the tetrahydrothiopyrano[3,4-b]pyrrole 2-pyridyl substituted as
interleukin antagonists in treating cytokines mediated diseases.15
O
O
O
O
O
O
HON
O
CO2Et
CO2Et
S
S
N
O
i
5
6
Having in hand a good number of starting ketones of type 8, the
O
next step would be the functionalization of
a position to the car-
Cl
ii
bonyl to introduce in the molecule a second electrophilic center
that, together with the carbonyl group, should allow the cyclization
with dinucleofiles. Direct introduction of the enamine functionality
has been studied.17 Two of the most used amide acetals for this aim
are tert-butoxybis(dimethylamino)methane (TBDMAM), also called
Bredereck’s reagent, which seemed to be the most efficient reagent
and dimethylformamide dimethylacetal (DMFDMA) that is less
reactive but far less expensive.
O
O
R2
R1
S
S
7
O
N
R
iii
O
8
a R = H, R = CO Et, R = Me;
Tetrahydrothiopyrano[3,4-b]pyrrole-2-ones 8aee bearing the 2-
ethoxycarbonyl functionality were converted into the correspond-
ing enaminoketones 9aee (71e80%) in refluxing DMFDMA (Method
A), whereas in the case of the thioketones of the 2-methyl series
8fek the use of an excess of Bredereck’s reagent in refluxing toluene
was required (Method B) to obtain enaminones 9gek (73e92%).
Only in the case of 9f, the compound was not isolated as pure sample
and the crude was used directly in the next step. To achieve the
tricyclic system 4, namely the thiopyrano[3,2-b]pyridin-2-ones, we
could react enaminoketones 9 with 1,3 dinucleophiles having
a CeCeN structure, such as phenylsulfonylacetonitrile, benzoyla-
cetonitrile, and malononitrile.
The substitution at position 3 of the pyridone ring was revealed
to be of great importance in modulating the antiproliferative ac-
tivity in the pyrroloquinolinone series.8 In particular we previously
reported that derivatives bearing the phenylsulphonyl group,
showed the highest photoreactivity.
Thus, the reaction of 9aek with phenylsulfonylacetonitrile,
afforded the corresponding pyrroloquinolinones 4aek in moderate
to good yields (42e63%). Moreover the N-methyl and the N-benzyl
enaminones 9b and 9c were reacted in the same reaction condi-
tions with malononitrile to give 4l, m (45, 53%) and with benzoyl-
acetonitrile to achieve compounds 4n, o (60, 57%).
Tetrahydrothiopyrano[3,4-b]pyrroles 4aeo and dihydrothiopyran
[3,4-b]pyrroles 8aek were submitted to the NCI of Bethesda for
antiproliferative tests. Derivatives 8aec, fej, and 4aeo were selected
for the one dose (10ꢀ5 M) screening on the full panel of about 60
human cancer cell lines derived from nine human cancer cell types,
that have been grouped in disease sub-panels including leukemia,
non-small cell lung, colon, central nervous system, melanoma, ovar-
ian, renal, prostate, and breast tumor cell lines. Only 8c and 4a, b, f
among the tricyclic compounds were selected for further screenings
at five concentrations at 10-fold dilution (10ꢀ4e10ꢀ8 M) on the full
panel. In particular 8c, 4a, and 4b showed modest activity with
growth inhibition reaching micromolar and submicromolar concen-
trations only against the HOP-92 cell line of the non-small cell lung
b R = R = Me, R = CO Et; c R = Bn, R =
CO Et, R = Me; d R = 4-OMe-Bn, R = CO Et,
R = Me; e R = 4-Me-Bn, R = CO Et, R = Me;
f R = R = H, R = Me; g R = R = Me, R = H; h
R = Bn, R = Me, R = H; i R = Ph, R = Me, R
= H; j R = 4-OMe-Bn, R = Me, R = H; k R = 4-
Me-Bn, R = Me, R = H
iv
v
O
S
R3
H
O
N
R2
R2
R1
Me2N
R1
S
N
vi
N
R
R
4a-o
9a-k
(see Table 1)
Scheme 1. Synthesis of pyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridin-2-one 4. Reagents
and conditions: (i) AcONa, Zn, 90% AcOH, 100 ꢁC, 1 h, 73%; (ii) KOH, MeOH, rt, 48 h,
90%; (iii) AcONH4, AcOH, rt, 1 h or RNH2, AcOH, reflux, 2 h, 66e77%; (iv) NaH, iodo-
methane or benzylchlorides, DMF, reflux, 2 h, 75e91%; (v) DMFDMA or TBDMAM,
toluene, reflux, 2e24 h, 71e92%; (vi) R3CH2CN, EtOH, reflux, 24 h, 42e63%.
Table 1
Pyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridin-2-ones 4
R
R1
R2
R3
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Me
Bn
4-OMeeBn
4-MeeBn
H
Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
CN
55
48
46
42
62
43
55
48
63
57
60
45
53
60
57
Bn
Ph
4j
4k
4l
4-OMeeBn
4-MeeBn
Me
Bn
Me
Me
H
CO2Et
CO2Et
CO2Et
CO2Et
Me
Me
Me
Me
4m
4n
4o
CN
COPh
COPh
cancer panel 1.21, 0.50, 1.11 mM, respectively (see Supplementary
Data). Whereas derivative 4f showed activity against all the tested
cell lines (Table 2) at micromolar and submicromolar concentrations
Bn

P. Barraja et al. / Tetrahedron 68 (2012) 5087e5094
5089
(GI50 0.14e40.3
at submicromolar level on 48% of the tested cell lines. The best se-
lectivity was achieved for the breast cancer (0.36e2.38 M), prostate
cancer (0.38e0.83 M), leukemia (0.37e4.88 M), and melanoma
(0.20e4.67 M) sub-panels. Except for the SK-OV-3 and OVCAR-5 cell
m
M) with a MID value of 1.86
m
M reaching GI50 values
CHBr3, with a Jasco FT/IR 5300 spectrophotometer; 1H and 13C NMR
spectra were measured in DMSO-d6 or CDCl3 solutions (TMS as in-
ternal reference) at 200 and 50.3 MHz, respectively, using a Bruker
Avance II series 200 MHz spectrometer. Column chromatography
was performed with Merck silica gel 230e400 mesh ASTM or with
m
m
m
m
€
lines, of the ovarian cancer sub-panel and for SF-268 cell line of the
a SEPACORE chromatography apparatus BUCHI. Elemental analyses
CNS cancer sub-panel compound 4f was active in the low micromolar
range (0.25e3.12 mM and 0.39e2.44 mM, respectively) also against
(C, H, and N) were within ꢂ0.4% of the theoretical values.
the ovarian and CNS cancer sub-panels.
4.2. Synthesis of 4-(2-oxopropyl)-2H-thiopyran-(4H,6H)-3,5-
dione (7)
Table 2
Inhibition of in vitro tumor cell growth by 4f
To a solution of 2H-thiopyran-3,5-dione 5 (1.40 g, 10.8 mmol) in
methanol (10 mL), KOH (1.40 g, 25.0 mmol) dissolved in water
(5 mL) was added. Chloroacetone (0.90 mL, 11.3 mmol) was added
dropwise at 0 ꢁC. The mixture was stirred at rt for 48 h, then
acidified with 6 M HCl, and extracted with dichloromethane. The
organic phase was dried and evaporated under reduced pressure to
afford a crude, which was purified by chromatography column
using DCM/EtOAc 8:2 as eluent. Brown oil; Rf¼0.30 (CH2Cl2/CH3OH
95:5); yield: 90%; IR (cmꢀ1) 1729 (CO), 1703 (CO), 1624 (CO). 1H
Cell lines
(GI50 mM)a,b
Cell lines
(GI50 m
M)a,b
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
CNS cancer
SF-268
M14
0.34
0.20
2.84
4.67
0.66
0.30
0.41
0.37
3.04
4.88
0.66
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-62
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Renal cancer
786-0
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
Prostate cancer
PC-3
40.3
21.2
0.91
0.25
0.51
26.2
3.12
0.45
30.1
NMR (CDCl3):
d
2.26 (3H, s, CH3), 3.09 (2H, d, J¼5.6 Hz, CH2),
3.28
0.14
17.2
2.10
27.8
24.7
5.23
3.38e3.59 (4H, m, CH2ꢃ2), 4.13 (1H, t, J¼5.6 Hz, CH). 13C NMR
(CDCl3):
d
29.9 (q), 37.0 (t), 39.2 (tꢃ2), 62.2 (d), 195.2 (CO), 195.8
(CO), 206.2 (CO). Anal. Calcd for C8H10O3S (186.23): C, 51.60; H, 5.41.
Found: C, 51.33; H, 5.32.
20.4
22.1
12.8
3.03
3.58
0.72
22.6
16.2
4.3. Synthesis of ethyl 3-methyl-4-oxo-1,4,5,7-
tetrahydrothiopyrano[3,4-b]pyrrole-2-carboxylate (8a)
16.8
2.76
0.40
0.43
0.31
0.62
0.39
A solution of 2H-thiopyran-3,5-dione 5 (8.00 g, 61.4 mmol) and
sodium acetate (15.8 g, 193 mmol) in acetic acid (90%, 80 mL) was
heated at 70 ꢁC. Zinc powder (13.5 g, 207 mmol) was added fol-
lowed by dropwise addition of a freshly prepared solution of the
hydroxyiminomalonate at a rate so as to maintain temperature at
90e100 ꢁC. This latter was prepared by stirring at rt for 3 h a solu-
tion of ethylacetoacetate (8.50 g, 65.3 mmol) in acetic acid (50 mL)
with a solution of sodium nitrite (4.60 g, 66.7 mmol) dissolved in
water (20 mL). At the end of the addition of the hydrox-
yiminomalonate the reaction mixture was heated at 100 ꢁC for 1 h.
After 24 h stirring at rt the mixture was poured into crushed ice and
the solid collected by filtration. Recrystallization with diethyl ether
furnished derivative 8a. White solid; Rf¼0.11 (CH2Cl2); mp
218e219 ꢁC; yield: 73%; IR (cmꢀ1): 3255 (NH), 1664 (CO), 1651 (CO).
0.38
0.83
10.1
DU-145
SF-295
SF-539
SNB-19
SNB-75
2.44
0.39
0.90
1.07
0.39
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
0.37
1.20
2.08
0.55
0.36
2.38
U251
BT-549
Melanoma
LOX IMVI
MALME-3M
T-47D
MDA-MB-468
0.83
0.42
a
Data obtained from NCI’s in vitro disease-oriented tumor cells screen.
GI50 is the molar concentration causing 50% growth inhibition of tumor cells.
b
1H NMR (DMSO-d6):
3.38 (2H, s, CH2), 3.85 (2H, s, CH2), 4.26 (2H, q, J¼7.1 Hz, CH2), 12.09
(1H, s, NH). 13C NMR (DMSO-d6):
11.4 (q), 14.3 (q), 22.6 (t), 35.4 (t),
d
1.30 (3H, t, J¼7.1 Hz, CH3), 2.48 (3H, s, CH3),
3. Conclusions
d
In conclusion, we have reported an efficient method for the
synthesis of derivatives of the new ring system tetrahy-
drothiopyrano[3,4-b]pyrroles in good yields. Versatile precursors
were the thiopyranes 8, which were converted into the key in-
termediate 9 by direct introduction of the enamino functionality.
The 2-pyridone structure was obtained by reaction of these latter
with cyanomethylene active compounds. Thiopyranes 8 and the
tricyclic derivatives 4 were evaluated for the antiproliferative ac-
tivity at the NCI of Bethesda, and 4f showed an interesting broad
spectrum of antiproliferative activity reaching the submicromolar
level on 48% of the tested cell lines. The results obtained make this
class of compounds interesting for further studies directed toward
the synthesis of more potent antiproliferative agents.
59.8 (t), 117.8 (s), 118.0 (s), 127.9 (s), 142.7 (s), 160.7 (CO), 190.1 (CO).
Anal. Calcd for C11H13NO3S (239.29): C, 55.21; H, 5.48; N, 5.85.
Found: C, 55.41; H, 5.34; N, 5.55.
4.4. General procedure for the preparation of ethyl 3-methyl-
4-oxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-2-
carboxylate (8bee)
To a solution of 8a (2.50 mmol) dissolved in anhydrous DMF
(10 mL), NaH (0.06 g, 2.50 mmol) was added at 0 ꢁC and the re-
action mixture was stirred at rt. After 1 h iodomethane or the
proper benzylchloride (2.50 mmol) was added at 0 ꢁC and the re-
action mixture was heated under reflux for 2 h. Then, the reaction
mixture was poured onto crushed ice and the precipitate was fil-
tered off. The crude material was purified by column chromatog-
raphy, using DCM/EtOAc 95:5 as eluent.
4. Experimental section
4.1. General
4.4.1. Ethyl 1,3-dimethyl-4-oxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]-
pyrrole-2-carboxylate (8b). This product was obtained byreaction of
8a with iodomethane. Yellow solid; Rf¼0.30 (CH2Cl2); mp
All melting points were taken on a BuchieTottoli capillary ap-
paratus and were uncorrected; IR spectra were determined, in

5090
P. Barraja et al. / Tetrahedron 68 (2012) 5087e5094
126e128 ꢁC; yield: 80%; IR (cmꢀ1): 1687 (CO), 1657 (CO). 1H NMR
(CDCl3):
1.38 (3H, t, J¼7.1 Hz, CH3), 2.60 (3H, s, CH3), 3.34 (2H, s,
CH2), 3.75 (2H, s, CH2), 3.80 (3H, s, CH3), 4.33 (2H, q, J¼7.1 Hz, CH2).
13C NMR (CDCl3):
12.3 (q),14.4 (q), 22.7 (t), 33.5 (q), 35.9 (t), 60.3 (t),
5.98 (1H, s, H-3), 11.28 (1H, s, NH). 13C NMR (DMSO-d6):
d 12.8 (q),
22.5 (t), 34.7 (t), 103.5 (d), 119.0 (s), 128.1 (s), 139.5 (s), 188.8 (CO).
Anal. Calcd for C8H9NOS (167.23): C, 57.46; H, 5.42; N, 8.38. Found:
C, 57.22; H, 5.29; N, 8.53.
d
d
117.8 (s), 121.1 (s), 131.0 (s), 142.8 (s), 162.1 (CO), 189.5 (CO). Anal.
Calcd for C12H15NO3S (253.32): C, 56.90; H, 5.97; N, 5.53. Found: C,
56.77; H, 6.15; N, 5.35.
4.5.2. 1,2-Dimethyl-1,7-dihydrothiopyrano[3,4-b]pyrrol-4-(5H)one
(8g). This product was obtained by reaction of 7 with methylamine
after 2 h at reflux. Pale brown solid; Rf¼0.11 (CH2Cl2); mp
147e148 ꢁC; yield: 77%; IR (cmꢀ1): 1639 (CO). 1H NMR (DMSO-d6):
4.4.2. Ethyl 1-benzyl-3-methy-4-oxo-1,4,5,7-tetrahydrothiopyrano-
[3,4-b]pyrrole-2-carboxylate (8c). This product was obtained by
reaction of 8a with benzyl chloride. White solid; Rf¼0.43 (CH2Cl2);
mp 102e103 ꢁC; yield: 91%; IR (cmꢀ1): 1691 (CO), 1657 (CO). 1H
d
2.15 (3H, s, CH3), 3.29 (2H, s, CH2), 3.42 (3H, s, CH3), 3.86 (2H, s,
CH2), 6.09 (1H, s, H-3). 13C NMR (DMSO-d6):
d
11.6 (q), 21.1 (t), 30.4
(q), 33.9 (t), 103.5 (d), 117.7 (s), 129.8 (s), 139.7 (s), 188.0 (CO). Anal.
Calcd for C9H11NOS (181.25): C, 59.64; H, 6.12; N, 7.73. Found: C,
59.44; H, 6.35; N, 7.99.
NMR (DMSO-d6):
d
1.20 (3H, t, J¼7.1 Hz, CH3), 2.54 (3H, s, CH3), 3.43
(2H, s, CH2), 3.90 (2H, s, CH2), 4.17 (2H, q, J¼7.1 Hz, CH2), 5.60 (2H, s,
CH2), 6.99 (2H, d, J¼6.5 Hz, H-20 and H-60), 7.21e7.38 (3H, m, H-30,
H-40, and H-50). 13C NMR (DMSO-d6):
d
12.1 (q),14.0 (q), 21.9 (t), 35.2
4.5.3. 1-Benzyl-2-methyl-1,7-dihydrothiopyrano[3,4-b]pyrrol-4-(5H)-
one (8h). This product was obtained by reaction of 7 with benzyl-
amine after 2 h at reflux. Brown solid; Rf¼0.14 (CH2Cl2); mp
89e90 ꢁC; yield: 72%; IR (cmꢀ1): 1645 (CO). 1H NMR (DMSO-d6):
(t), 48.3 (t), 60.0 (t), 117.3 (s), 119.7 (s), 126.0 (dꢃ2), 127.2 (d), 128.6
(dꢃ2), 129.6 (s), 137.3 (s), 144.8 (s), 160.9 (CO), 190.0 (CO). Anal.
Calcd for C18H19NO3S (329.41): C, 65.63; H, 5.81; N, 4.25. Found: C,
65.75; H, 5.99; N, 4.03.
d
2.10 (3H, s, CH3), 3.34 (2H, s, CH2), 3.81 (2H, s, CH2), 5.17 (2H, s, CH2),
6.20 (1H, s, H-3), 7.00 (2H, d, J¼6.5 Hz, H-20 and H-60), 7.24e7.40 (3H,
4.4.3. Ethyl 1-(4-methoxybenzyl)-3-methyl-4-oxo-1,4,5,7-
tetrahydrothiopyrano[3,4-b]pyrrole-2-carboxylate (8d). This prod-
uct was obtained by reaction of 8a with 4-methoxybenzyl chloride.
White solid; Rf¼0.23 (CH2Cl2); mp 104e105 ꢁC; yield: 85%; IR (cmꢀ1):
m, H-30, H-40, and H-50). 13C NMR (DMSO-d6):
d 11.7 (q), 21.4 (t), 34.1
(t), 46.6 (t), 104.3 (d), 118.2 (s), 126.1 (dꢃ2), 127.4 (d), 128.8 (dꢃ2),
129.8 (s), 137.1 (s), 140.9 (s), 188.3 (CO). Anal. Calcd for C15H15NOS
(257.35): C, 70.01; H, 5.87; N, 5.44. Found: C, 69.90; H, 5.99; N, 5.13.
1693 (CO),1660 (CO).1H NMR (DMSO-d6):
d
1.23 (3H, t, J¼7.1 Hz, CH3),
2.52 (3H, s, CH3), 3.41 (2H, s, CH2), 3.71 (3H, s, CH3), 3.91 (2H, s, CH2),
4.20 (2H, q, J¼7.1 Hz, CH2), 5.52 (2H, s, CH2), 6.88 (2H, d, J¼8.8 Hz, H-30
and H-50), 6.97 (2H, d, J¼8.8 Hz, H-20 and H-60). 13C NMR (DMSO-d6):
4.5.4. 2-Methyl-1-phenyl-1,7-dihydrothiopyrano[3,4-b]pyrrol-4-
(5H)one (8i). This product was obtained by reaction of 7 with an-
iline after 2 h at reflux. Pale brown solid; Rf¼0.52 (CH2Cl2); mp
162e163 ꢁC; yield: 68%; IR (cmꢀ1): 1648 (CO). 1H NMR (DMSO-d6):
d
12.1 (q), 14.0 (q), 21.9 (t), 35.2 (t), 47.7 (t), 55.0 (q), 60.0 (t), 114.0
(dꢃ2), 117.2 (s), 119.7 (s), 127.6 (dꢃ2), 129.1 (s), 129.6 (s), 144.6 (s),
158.4 (s), 161.0 (CO), 190.0 (CO). Anal. Calcd for C19H21NO4S (359.44):
C, 63.49; H, 5.89; N, 3.90. Found: C, 63.15; H, 6.01; N, 4.15.
d 2.00 (3H, s, CH3), 3.37 (2H, s, CH2), 3.59 (2H, s, CH2), 6.30 (1H, s, H-
3), 7.39 (2H, d, J¼6.6 Hz, H-20 and H-60), 7.52e7.59 (3H, m, H-30, H-
40, and H-50). 13C NMR (DMSO-d6):
d 12.2 (q), 22.0 (t), 34.3 (t), 104.4
(d), 118.6 (s), 127.5 (dꢃ2), 128.9 (d), 129.7 (dꢃ2), 130.2 (s), 135.9 (s),
140.0 (s), 188.6 (CO). Anal. Calcd for C14H13NOS (243.32): C, 69.11; H,
5.39; N, 5.76. Found: C, 69.38; H, 5.08; N, 6.02.
4.4.4. Ethyl 3-methyl-1-(4-methylbenzyl)-4-oxo-1,4,5,7-
tetrahydrothiopyrano[3,4-b]pyrrole-2-carboxylate (8e). This prod-
uct was obtained by reaction of 8a with 4-methylbenzyl chloride.
White solid; Rf¼0.20 (CH2Cl2); mp 127e129 ꢁC; yield: 75%; IR (cmꢀ1):
4.5.5. 1-(4-Methoxybenzyl)-2-methyl-1,7-dihydrothiopyrano[3,4-b]-
pyrrol-4-(5H)one (8j). This product was obtained by reaction of 7
with 4-methoxybenzylamine after 2 h at reflux. Brown solid;
Rf¼0.14 (CH2Cl2); mp 125e126 ꢁC; yield: 70%; IR (cmꢀ1): 1647 (CO).
1695 (CO),1658 (CO).1H NMR (DMSO-d6):
d
1.22 (3H, t, J¼7.1 Hz, CH3),
2.26 (3H, s, CH3), 2.53 (3H, s, CH3), 3.42 (2H, s, CH2), 3.89 (2H, s, CH2),
4.18 (2H, q, J¼7.1 Hz, CH2), 5.55 (2H, s, CH2), 6.89 (2H, d, J¼8.0 Hz, H-30
and H-50), 7.13 (2H, d, J¼8.0 Hz, H-20 and H-60). 13C NMR (DMSO-d6):
1H NMR (DMSO-d6):
d 2.11 (3H, s, CH3), 3.34 (2H, s, CH2), 3.72 (3H, s,
d
12.1 (q), 14.0 (q), 20.6 (q), 21.9 (t), 35.2 (t), 48.0 (t), 60.0 (t), 117.2 (s),
CH3), 3.82 (2H, s, CH2), 5.08 (2H, s, CH2), 6.17 (1H, s, H-3), 6.90 (2H,
119.7 (s), 126.0 (dꢃ2), 129.2 (dꢃ2), 129.6 (s), 134.2 (s), 136.4 (s), 144.7
(s), 161.0 (CO), 190.0 (CO). Anal. Calcd for C19H21NO3S (343.44): C,
66.45; H, 6.16; N, 4.08. Found: C, 66.22; H, 6.41; N, 3.85.
d, J¼9.1 Hz, H-30 and H-50), 6.97 (2H, d, J¼9.1 Hz, H-20 and H-60). 13C
NMR (DMSO-d6):
d 11.7 (q), 21.4 (t), 34.0 (t), 46.1 (t), 55.0 (q), 104.2
(d), 114.2 (dꢃ2), 118.1 (s), 127.5 (dꢃ2), 128.9 (s), 129.7 (s), 139.9 (s),
158.5 (s), 188.2 (CO). Anal. Calcd for C16H17NO2S (287.38): C, 66.87;
H, 5.96; N, 4.87. Found: C, 67.02; H, 5.80; N, 4.65.
4.5. General procedure for the preparation of 2-methyl
tetrahydrothiopyrano[3,4-b]pyrrol-4-ones (8fek)
4.5.6. 2-Methyl-1-(4-methylbenzyl)-1,7-dihydrothiopyrano[3,4-b]-
pyrrol-4-(5H)one (8k). This product was obtained by reaction of 7
with 4-methylbenzylamine after 2 h at reflux. Pale brown solid;
Rf¼0.17 (CH2Cl2); mp 110e111 ꢁC; yield: 75%; IR (cmꢀ1): 1647 (CO).
To a solution of 4-(2-oxopropyl)-2H-thiopyran-(4H,6H)-3,5-
dione 7 (0.60 g, 3.20 mmol) in acetic acid (40 mL) ammonium ac-
etate (1.00 g, 13.0 mmol) or the proper amine (3.2 mmol) was
added. The mixture was stirred at rt or heated at the proper tem-
perature for the suitable time then poured onto crushed ice. The
desired compounds were separated as solids upon filtration or al-
ternatively were extracted with dichloromethane, dried with so-
dium sulfate, and evaporated under reduced pressure. The crude
material was purified by column chromatography, using DCM/
EtOAc 98:2 as eluent.
1H NMR (DMSO-d6):
d 2.09 (3H, s, CH3), 2.27 (3H, s, CH3), 3.36 (2H, s,
CH2), 3.80 (2H, s, CH2), 5.11 (2H, s, CH2), 6.18 (1H, s, H-3), 6.90 (2H, d,
J¼8.0 Hz, H-30 and H-50), 7.16 (2H, d, J¼8.0 Hz, H-20 and H-60). 13C
NMR (DMSO-d6): d 11.7 (q), 20.6 (q), 21.4 (t), 34.0 (t), 46.4 (t), 104.2
(d), 118.1 (s), 126.1 (dꢃ2), 129.3 (s), 129.8 (dꢃ2), 134.0 (s), 136.6 (s),
139.9 (s),188.3 (CO). Anal. Calcd for C16H17NOS (271.38): C, 70.82; H,
6.31; N, 5.16. Found: C, 70.62; H, 6.19; N, 5.33.
4.5.1. 2-Methyl-1,7-dihydrothiopyrano[3,4-b]pyrrol-4-(5H)one
(8f). This product was obtained by reaction of 7 with ammonium
acetate after 1 h at rt. Pale brown solid; Rf¼0.10 (CH2Cl2); mp
225e227 ꢁC; yield: 66%; IR (cmꢀ1): 3221 (NH), 1620 (CO). 1H NMR
4.6. General procedure for the preparation of
enaminoketones 9aek
Method A. A solution of the suitable 8aee (5.00 mmol) in
DMFDMA (7 mL, 50.0 mmol) was heated under reflux for the
(DMSO-d6):
d 2.13 (3H, s, CH3), 3.29 (2H, s, CH2), 3.79 (2H, s, CH2),

P. Barraja et al. / Tetrahedron 68 (2012) 5087e5094
5091
proper time 3e24 h. The reaction mixture was poured onto crushed
ice, filtered, and dried. Recrystallization with diethyl ether afforded
the desired enaminoketones.
Method B. To a solution of the proper 8fek (45.0 mmol) in an-
hydrous toluene (10 mL), TBDMAM (2.79 mL, 13.5 mmol) was
added. The reaction was heated under reflux for 2 h. Upon cooling
at rt, a solid separated from the reaction mixture, which was col-
lected and dried.
method A after 24 h reflux. Orange solid; Rf¼0.54 (CH2Cl2/EtOAc
9:1); mp 150e151 ꢁC; yield: 77%; IR (cmꢀ1): 1685 (CO), 1628 (CO).
1H NMR (DMSO-d6):
d
1.21 (3H, t, J¼7.1 Hz, CH3), 2.24 (3H, s, CH3),
2.53 (3H, s, CH3), 3.16 (6H, s, CH3ꢃ2), 3.78 (2H, s, CH2), 4.16 (2H, q,
J¼7.1 Hz, CH2), 5.52 (2H, s, CH2), 6.84 (2H, d, J¼8.0 Hz, H-30 and H-
50), 7.11 (2H, d, J¼8.0 Hz, H-20 and H-60), 7.62 (1H, s, CH). 13C NMR
(DMSO-d6):
d
12.2 (q), 14.1 (q), 20.6 (q), 23.4 (t), 43.1 (qꢃ2), 47.6 (t),
59.7 (t), 90.4 (s), 118.5 (s), 119.1 (s), 125.9 (dꢃ2), 129.1 (dꢃ2), 130.1
(s), 134.8 (s), 136.3 (s), 142.0 (s), 147.9 (d), 161.1 (CO), 181.5 (CO).
Anal. Calcd for C22H26N2O3S (398.52): C, 66.31; H, 6.58; N, 7.03.
Found: C, 66.46; H, 6.77; N, 6.85.
4.6.1. Ethyl 5-[(dimethylamino)methylidene]-3-methyl-4-oxo-1,4,5,
7-tetrahydrothiopyrano[3,4-b]pyrrole-2-carboxylate
(9a). This
product was obtained by reaction of 8a with method A after 3 h
reflux. Yellow solid; Rf¼0.31 (CH2Cl2/EtOAc 9:1); mp 196e197 ꢁC;
yield: 80%; IR (cmꢀ1): 3420 (NH), 1653 (CO), 1628 (CO). 1H NMR
4.6.6. 5-[(Dimethylamino)methylidene]-2-methyl-1,7-
dihydrothiopyrano[3,4-b]pyrrol-4-(5H)-one (9f). This product was
obtained by reaction of 8f with method B. Purification by re-
crystallization or chromatography column was not possible as
compound 9f was unstable with respect to hydrolysis of the en-
amine so it was used for the next step without purification.
(DMSO-d6):
s, CH3ꢃ2), 3.74 (2H, s, CH2), 4.24 (2H, q, J¼7.1 Hz, CH2), 7.59 (1H, s,
CH), 11.79 (1H, s, NH). 13C NMR (DMSO-d6):
11.4 (q), 14.4 (q), 24.1
d
1.29 (3H, t, J¼7.1 Hz, CH3), 2.49 (3H, s, CH3), 3.16 (6H,
d
(t), 43.1 (qꢃ2), 59.5 (t), 90.9 (s),117.4 (s),118.9 (s),128.3 (s),139.4 (s),
147.7 (d), 160.9 (CO), 181.8 (CO). Anal. Calcd for C14H18N2O3S
(294.37): C, 57.12; H, 6.16; N, 9.52. Found: C, 57.25; H, 6.03; N, 9.33.
4.6.7. 5-[(Dimethylamino)methylidene]-1,2-dimethyl-1,7-
dihydrothiopyrano[3,4-b]pyrrol-4-(5H)-one (9g). This product was
obtained by reaction of 8g with method B. Yellow solid; Rf¼0.28
(CH2Cl2/EtOAc 9:1); mp 150e151 ꢁC; yield: 92%; IR (cmꢀ1): 1658
4.6.2. Ethyl
5-[(dimethylamino)methylidene]-1,3-dimethyl-4-oxo-
1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-2-carboxylate (9b). This
product was obtained by reaction of 8b with method A after 4 h
reflux. Brown solid; Rf¼0.35 (CH2Cl2/EtOAc 9:1); mp 150e151 ꢁC;
yield: 74%; IR (cmꢀ1): 1684 (CO), 1628 (CO). 1H NMR (DMSO-d6):
(CO). 1H NMR (DMSO-d6):
d
2.14 (3H, s, CH3), 3.14 (6H, s, CH3ꢃ2),
3.38 (3H, s, CH3), 3.81 (2H, s, CH2), 6.05 (1H, s, H-3), 7.48 (1H, s, CH).
13C NMR (DMSO-d6):
d
11.7 (q), 23.1 (t), 30.0 (q), 43.0 (qꢃ2), 90.1 (s),
d
1.29 (3H, t, J¼7.1 Hz, CH3), 2.51 (3H, s, CH3), 3.17 (6H, s, CH3ꢃ2),
3.71 (3H, s, CH3), 3.85 (2H, s, CH2), 4.24 (2H, q, J¼7.1 Hz, CH2), 7.59
(1H, s, CH). 13C NMR (DMSO-d6):
12.1 (q), 14.2 (q), 23.1 (t), 33.0
104.5 (d), 119.0 (s), 128.8 (s), 135.8 (s), 146.3 (d), 180.4 (CO). Anal.
Calcd for C12H16N2OS (236.33): C, 60.99; H, 6.82; N, 11.85. Found: C,
61.18; H, 6.69; N, 11.54.
d
(q), 43.1 (qꢃ2), 59.6 (t), 90.4 (s), 118.0 (s), 119.6 (s), 129.4 (s), 141.8
(s), 147.6 (d), 161.3 (CO), 181.5 (CO). Anal. Calcd for C15H20N2O3S
(308.40): C, 58.42; H, 6.54; N, 9.08. Found: C, 58.09; H, 6.67; N,
8.88.
4.6.8. 1-Benzyl-5-[(dimethylamino)methylidene]-2-methyl-1,7-
dihydrothiopyrano[3,4-b]pyrrol-4-(5H)-one (9h). This product was
obtained by reaction of 8h with method B. Brown solid; Rf¼0.30
(CH2Cl2/EtOAc 9:1); mp 146e147 ꢁC; yield: 80%; IR (cmꢀ1): 1624
4.6.3. Ethyl 1-benzyl-5-[(dimethylamino)methylidene]-3-methyl-4-
oxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-2-carboxylate
(9c). This product was obtained by reaction of 8c with method A
after 5 h reflux. White solid; Rf¼0.38 (CH2Cl2/EtOAc 9:1); mp
134e135 ꢁC; yield: 71%; IR (cmꢀ1): 1685 (CO), 1628 (CO). 1H NMR
(CO). 1H NMR (DMSO-d6):
d
2.08 (3H, s, CH3), 3.13 (6H, s, CH3ꢃ2),
3.75 (2H, s, CH2), 5.13 (2H, s, CH2), 6.15 (1H, s, H-3), 6.96 (2H, d,
J¼6.6 Hz, H-20 and H-60), 7.26e7.38 (3H, m, H-30, H-40 and H-50),
7.52 (1H, s, CH). 13C NMR (DMSO-d6):
d
11.7 (q), 23.3 (t), 43.0 (qꢃ2),
46.2 (t), 90.0 (s), 105.4 (d), 119.6 (s), 126.0 (dꢃ2), 127.2 (d), 128.7
(dꢃ2), 136.0 (s), 137.6 (s), 146.6 (d), 150.1 (s), 180.5 (CO). Anal. Calcd
for C18H20N2OS (312.43): C, 69.20; H, 6.45; N, 8.97. Found: C, 69.55;
H, 6.10; N, 9.12.
(DMSO-d6):
d
1.19 (3H, t, J¼7.1 Hz, CH3), 2.54 (3H, s, CH3), 3.16 (6H, s,
CH3ꢃ2), 3.79 (2H, s, CH2), 4.16 (2H, q, J¼7.1 Hz, CH2), 5.58 (2H, s,
CH2), 6.94 (2H, d, J¼6.6 Hz, H-20 and H-60), 7.19e7.36 (3H, m, H-30,
H-40, and H-50), 7.62 (1H, s, CH). 13C NMR (DMSO-d6):
d 12.3 (q), 14.0
(q), 23.0 (t), 43.1 (qꢃ2), 47.8 (t), 59.7 (t), 90.4 (s), 118.5 (s), 119.1 (s),
125.9 (dꢃ2), 127.1 (d), 128.6 (dꢃ2), 130.2 (s), 137.8 (s), 142.0 (s),
147.9 (d), 161.1 (CO), 181.5 (CO). Anal. Calcd for C21H24N2O3S
(384.49): C, 65.60; H, 6.29; N, 7.29. Found: C, 65.79; H, 6.14; N, 7.44.
4.6.9. 5-[(Dimethylamino)methylidene]-2-methyl-1-phenyl-1,7-
dihydrothiopyrano[3,4-b]pyrrol-4-(5H)-one (9i). This product was
obtained by reaction of 8i with method B. Brown solid; Rf¼0.31
(CH2Cl2/EtOAc 9:1); mp 144e145 ꢁC; yield: 74%; IR (cmꢀ1): 1642
(CO). 1H NMR (DMSO-d6):
d
2.01 (3H, s, CH3), 3.14 (6H, s, CH3ꢃ2),
4.6.4. Ethyl 5-[(dimethylamino)methylidene]-1-(4-methoxybenzyl)-
3-methyl-4-oxo-1,4,5,7-tetrahydrothiopyrano [3,4-b]pyrrole-2-
carboxylate (9d). This product was obtained by reaction of 8d
with method A after 24 h reflux. Yellow solid; Rf¼0.56 (CH2Cl2/
EtOAc 9:1); mp 130e131 ꢁC; yield: 72%; IR (cmꢀ1): 1684 (CO), 1630
3.54 (2H, s, CH2), 6.25 (1H, s, H-3), 7.36 (2H, d, J¼6.6 Hz, H-20 and
H-60), 7.49e7.59 (4H, m, H-30, H-40, H-50, and CH). 13C NMR
(DMSO-d6):
d
12.3 (q), 23.8 (t), 43.0 (qꢃ2), 90.1 (s), 105.6 (d),
120.0 (s), 127.5 (dꢃ2), 128.5 (d), 129.1 (s), 129.5 (dꢃ2), 135.8 (s),
136.1 (s), 146.7 (d), 180.6 (CO). Anal. Calcd for C17H18N2OS
(298.40): C, 68.43; H, 6.08; N, 9.39. Found: C, 68.59; H, 6.31; N,
9.01.
(CO). 1H NMR (DMSO-d6):
d
1.23 (3H, t, J¼7.1 Hz, CH3), 2.53 (3H, s,
CH3), 3.16 (6H, s, CH3ꢃ2), 3.70 (3H, s, CH3), 3.80 (2H, s, CH2), 4.18
(2H, q, J¼7.1 Hz, CH2), 5.50 (2H, s, CH2), 6.86 (2H, d, J¼9.0 Hz, H-30
and H-50), 6.93 (2H, d, J¼9.0 Hz, H-20 and H-60), 7.61 (1H, s, CH). 13C
4.6.10. 5-[(Dimethylamino)methylidene]-1-(4-methoxybenzyl)-2-
NMR (DMSO-d6):
d
12.2 (q), 14.1 (q), 23.4 (t), 43.1 (qꢃ2), 47.2 (t),
methyl-1,7-dihydrothiopyrano[3,4-b]pyrrol-4-(5H)-one
(9j). This
55.0 (q), 59.7 (t), 90.4 (s), 114.0 (dꢃ2), 118.5 (s), 119.0 (s), 127.4
(dꢃ2), 129.7 (s), 130.1 (s), 141.9 (s), 147.9 (d), 158.3 (s), 161.2 (CO),
181.5 (CO). Anal. Calcd for C22H26N2O4S (414.52): C, 63.75; H, 6.32;
N, 6.76. Found: C, 64.02; H, 6.55; N, 6.44.
product was obtained by reaction of 8j with method B. Brown solid;
Rf¼0.35 (CH2Cl2/EtOAc 9:1); mp 130e131 ꢁC; yield: 78%; IR (cmꢀ1):
1624 (CO). 1H NMR (DMSO-d6):
d 2.09 (3H, s, CH3), 3.13 (6H, s,
CH3ꢃ2), 3.71 (3H, s, CH3), 3.75 (2H, s, CH2), 5.04 (2H, s, CH2), 6.13
(1H, s, H-3), 6.88 (2H, d, J¼9.6 Hz, H-30 and H-50), 6.93 (2H, d,
4.6.5. Ethyl 5-[(dimethylamino)methylidene]-3-methyl-1-(4-
methylbenzyl)-4-oxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-2-
carboxylate (9e). This product was obtained by reaction of 8e with
J¼9.6 Hz, H-20 and H-60), 7.51 (1H, s, CH). 13C NMR (DMSO-d6):
d 11.7
(q), 23.4 (t), 43.0 (qꢃ2), 45.7 (t), 55.0 (q), 90.1 (s), 105.3 (d), 114.1
(dꢃ2), 119.5 (s), 127.4 (dꢃ2), 128.7 (s), 129.4 (s), 135.9 (s), 146.5 (d),

5092
P. Barraja et al. / Tetrahedron 68 (2012) 5087e5094
158.4 (s), 180.5 (CO). Anal. Calcd for C19H22N2O2S (342.46): C, 66.64;
H, 6.48; N, 8.18. Found: C, 66.33; H, 6.69; N, 7.95.
132.6 (s), 133.3 (d), 136.9 (s), 137.7 (s), 138.0 (s), 140.4 (s), 141.3 (s),
142.4 (s), 157.4 (CO), 160.8 (CO). Anal. Calcd for C27H24N2O5S2
(520.62): C, 62.29; H, 4.65; N, 5.38. Found: C, 62.41; H, 4.47; N, 5.52.
4.6.11. 5-[(Dimethylamino)methylidene]-2-methyl-1-(4-
methylbenzyl)-1,7-dihydrothiopyrano[3,4-b]pyrrol-4-(5H)-one
(9k). This product was obtained by reaction of 8k with method B.
Red solid; Rf¼0.26 (CH2Cl2/EtOAc 9:1); mp 148e149 ꢁC; yield: 73%;
4.7.4. Ethyl 7-(4-methoxybenzyl)-9-methyl-2-oxo-3-(phenylsulfonyl)-
1,2,6,7-tetrahydropyrrolo[30,20:4,5]thiopyrano [3,2-b]pyridine-8-
carboxylate (4d). This product was obtained by reaction of 9d with
phenylsulfonylacetonitrile. Yellow solid; Rf¼0.47 (CH2Cl2/EtOAc 8:2);
mp 252edec ꢁC; yield: 42%; IR (cmꢀ1): 3392 (NH), 1689 (CO), 1641
IR (cmꢀ1): 1624 (CO). 1H NMR (DMSO-d6):
d 2.08 (3H, s, CH3), 2.26
(3H, s, CH3), 3.13 (6H, s, CH3ꢃ2), 3.73 (2H, s, CH2), 5.07 (2H, s, CH2),
6.14 (1H, s, H-3), 6.86 (2H, d, J¼8.0 Hz, H-30 and H-50), 7.14 (2H, d,
(CO). 1H NMR (DMSO-d6):
d
1.23 (3H, t, J¼7.1 Hz, CH3), 2.54 (3H, s,
J¼8.0 Hz, H-20 and H-60), 7.51 (1H, s, CH). 13C NMR (DMSO-d6):
d
11.7
CH3), 3.70 (3H, s, CH3), 4.11 (2H, s, CH2), 4.21 (2H, q, J¼7.1 Hz, CH2),
5.56 (2H, s, CH2), 6.86 (2H, d, J¼8.7 Hz, H-30 and H-50), 6.96 (2H, d,
J¼8.7 Hz, H-20 and H-60), 7.55e7.73 (3H, m, H-300, H-400, and H-500),
7.98 (2H, d, J¼6.8 Hz, H-200 and H-600), 8.19 (1H, s, H-4), 11.87 (1H, s,
(q), 20.6 (q), 23.4 (t), 43.0 (qꢃ2), 46.0 (t), 90.1 (s), 105.3 (d), 119.5 (s),
126.0 (dꢃ2), 128.7 (s), 129.3 (dꢃ2), 134.5 (s), 135.9 (s), 136.4 (s),
146.5 (d), 180.5 (CO). Anal. Calcd for C19H22N2OS (326.46): C, 69.90;
H, 6.79; N, 8.58. Found: C, 69.71; H, 6.55; N, 8.85.
NH). 13C NMR (DMSO-d6):
d 12.3 (q),14.1 (q), 21.9 (t), 47.7 (t), 55.0 (q),
60.0 (t), 114.0 (dꢃ2), 116.8 (s), 120.5 (s), 124.6 (s), 127.5 (d), 127.6
(dꢃ2), 128.0 (dꢃ2), 128.9 (dꢃ2), 129.5 (s), 133.4 (d), 134.0 (s), 137.5
(s), 137.9 (s), 140.4 (s), 151.9 (s), 157.2 (s), 158.4 (CO), 160.9 (CO). Anal.
Calcd for C28H26N2O6S2 (550.64): C, 61.08; H, 4.76; N, 5.09. Found: C,
60.95; H, 4.61; N, 5.39.
4.7. General procedure for the preparation of pyrrolo
[30,20:4,5]thiopyrano[3,2-b]pyridin-2-ones (4aeo)
To a solution of the enaminones 9 (20.0 mmol) in anhydrous
ethanol (10 mL), the suitable cyanomethylene compound
(22.0 mmol) was added and heated under reflux for 24 h. The solid
material, which separated from the solution was filtered off,
washed with fresh ethanol, and dried. Recrystallization from
methanol gave the desired compounds as yellow solids.
4.7.5. Ethyl 9-methyl-7-(4-methylbenzyl)-2-oxo-3-(phenylsulfonyl)-
1,2,6,7-tetrahydropyrrolo[30,20:4,5]thiopyrano [3,2-b]pyridine-8-
carboxylate (4e). This product was obtained by reaction of 9e
with phenylsulfonylacetonitrile. Yellow solid; Rf¼0.28 (CH2Cl2/
EtOAc 8:2); mp 225e226 ꢁC; yield: 62%; IR (cmꢀ1): 3357 (NH), 1689
4.7.1. Ethyl 9-methyl-2-oxo-3-(phenylsulfonyl)-1,2,6,7-
tetrahydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridine-8-carboxylate
(4a). This product was obtained by reaction of 9a with phenyl-
sulfonylacetonitrile. Yellow solid; Rf¼0.12 (CH2Cl2/EtOAc 8:2); mp
214edec ꢁC; yield: 55%; IR (cmꢀ1): 3251 (NH), 3226 (NH), 1666 (CO),
(CO), 1639 (CO). 1H NMR (DMSO-d6):
d
1.22 (3H, t, J¼7.1 Hz, CH3),
2.24 (3H, s, CH3), 2.55 (3H, s, CH3), 4.09 (2H, s, CH2), 4.19 (2H, q,
J¼7.1 Hz, CH2), 5.59 (2H, s, CH2), 6.88 (2H, d, J¼8.0 Hz, H-30 and H-
50), 7.11 (2H, d, J¼8.0 Hz, H-20 and H-60), 7.55e7.96 (3H, m, H-300, H-
400, and H-500), 7.98 (2H, d, J¼6.7 Hz, H-200 and H-600), 8.19 (1H, s, H-
1635 (CO).1H NMR (DMSO-d6):
d
1.30 (3H, t, J¼7.1 Hz, CH3), 2.55 (3H,
4), 11.88 (1H, s, NH). 13C NMR (DMSO-d6):
d 12.3 (q), 14.0 (q), 20.6
s, CH3), 3.99 (2H, s, CH2), 4.26 (2H, q, J¼7.1 Hz, CH2), 7.59e7.69 (3H, m,
(q), 21.8 (t), 47.9 (t), 60.0 (t), 115.0 (s), 120.5 (s), 120.7 (s), 126.0
(dꢃ2), 127.5 (s), 127.6 (s), 127.7 (s), 128.0 (dꢃ2), 128.9 (dꢃ2), 129.1
(d), 129.2 (dꢃ2), 133.4 (d), 134.6 (s), 136.4 (s), 137.3 (s), 140.0 (s),
157.2 (CO), 160.8 (CO). Anal. Calcd for C28H26N2O5S2 (534.64): C,
62.90; H, 4.90; N, 5.24. Found: C, 62.54; H, 4.76; N, 5.51.
H-300, H-400 and H-500), 7.97 (2H, d, J¼8.2 Hz, H-200 and H-600), 8.16 (1H,
s, H-4),11.78 (1H, s, NH),12.19 (1H, s, NH).13C NMR (DMSO-d6):
d 11.3
(q),14.3 (q), 22.7 (t), 59.7 (t),118.8 (s),126.1 (s),127.9 (d),128.0 (dꢃ2),
128.8 (dꢃ2),133.3 (d),135.1 (s),140.4 (s),144.2 (s),149.1 (s),151.3 (s),
153.3 (s), 157.1 (CO), 160.6 (CO). Anal. Calcd for C20H18N2O5S2
(430.49): C, 55.80; H, 4.21; N, 6.51. Found: C, 56.15; H, 4.06; N, 6.23.
4.7.6. 8-Methyl-3-(phenylsulfonyl)-6,7-dihydropyrrolo [30,20:4,5]thio-
pyrano[3,2-b]pyridin-2-(1H)-one (4f). This product was obtained by
reaction of 9f with phenylsulfonylacetonitrile. Dark brown solid;
Rf¼0.10 (CH2Cl2/EtOAc 8:2); mp >410 ꢁC; yield: 43%; IR (cmꢀ1): 3382
4.7.2. Ethyl 7,9-dimethyl-2-oxo-3-(phenylsulfonyl)-1,2,6,7-
tetrahydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridine-8-carboxylate
(4b). This product was obtained by reaction of 9b with phenyl-
sulfonylacetonitrile. Yellow solid; Rf¼0.31(CH2Cl2/EtOAc 8:2); mp
185e186 ꢁC; yield: 48%; IR (cmꢀ1): 3390 (NH),1689 (CO),1643 (CO).1H
(NH), 3259 (NH), 1645 (CO). 1H NMR (DMSO-d6):
d 2.15 (3H, s, CH3),
4.00 (2H, s, CH2), 6.44 (1H, s, H-9), 7.56e7.66 (3H, m, H-300, H-400, and
H-500), 7.96 (2H, d, J¼6.8 Hz, H-200 and H-600), 8.01 (1H, s, H-4), 11.49
NMR (DMSO-d6):
d
1.30 (3H, t, J¼7.1 Hz, CH3), 2.52 (3H, s, CH3), 3.78
(1H, s, NH), 12.24 (1H, s, NH). 13C NMR (DMSO-d6):
d 12.5 (q), 22.8 (t),
(3H, s, CH3), 4.12 (2H, s, CH2), 4.26 (2H, q, J¼7.1 Hz, CH2), 7.56e7.69 (3H,
103.3 (d), 110.2 (s), 119.9 (s), 120.3 (s), 127.8 (dꢃ2), 128.6 (d), 128.7
(dꢃ2), 131.0 (s), 133.3 (d), 140.8 (s), 148.5 (s), 154.3 (s), 162.4 (CO).
Anal. Calcd for C17H14N2O3S2 (358.43): C, 56.97; H, 3.94; N, 7.82.
Found: C, 57.14; H, 4.22; N, 7.65.
m, H-300, H-400, and H-500), 7.98 (2H, d, J¼7.1 Hz, H-200 and H-600), 8.17
(1H, s, H-4), 11.83 (1H, s, NH). 13C NMR (DMSO-d6):
d 12.2 (q), 14.2 (q),
21.7 (t), 33.4 (q), 59.9 (t),121.2 (s),126.8 (s),127.9 (d),128.0 (dꢃ2),128.9
(dꢃ2), 132.8 (s), 133.4 (d), 137.9 (s), 140.4 (s), 144.3 (s), 148.6 (s), 150.6
(s), 157.1 (CO), 161.0 (CO). Anal. Calcd for C21H20N2O5S2 (444.52): C,
56.74; H, 4.53; N, 6.30. Found: C, 56.81; H, 4.43; N, 6.01.
4.7.7. 7,8-Dimethyl-3-(phenylsulfonyl)-6,7-dihydropyrrolo[30,20:4,5]-
thiopyrano[3,2-b]pyridin-2-(1H)-one (4g). This product was
obtained by reaction of 9g with phenylsulfonylacetonitrile. Brown
solid; Rf¼0.19 (CH2Cl2/EtOAc 8:2); mp 263e264 ꢁC; yield: 55%; IR
4.7.3. Ethyl 7-benzyl-9-methyl-2-oxo-3-(phenylsulfonyl)-1,2,6,7-
tetrahydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridine-8-carboxylate
(4c). This product was obtained by reaction of 9c with phenyl-
sulfonylacetonitrile. Yellow solid; Rf¼0.46 (CH2Cl2/EtOAc 8:2); mp
270e272 ꢁC; yield: 46%; IR (cmꢀ1): 3351 (NH), 1705 (CO), 1674 (CO).
(cmꢀ1): 3417 (NH), 1626 (CO). 1H NMR (DMSO-d6):
d 2.17 (3H, s,
CH3), 3.45 (3H, s, CH3), 4.11 (2H, s, CH2), 6.54 (1H, s, H-9), 7.52e7.69
(3H, m, H-300, H-400, and H-500), 7.97 (2H, d, J¼6.7 Hz, H-200 and H-600),
8.02 (1H, s, H-4), 12.23 (1H, s, NH). 13C NMR (DMSO-d6):
d 11.8 (q),
1H NMR (DMSO-d6):
d
1.20 (3H, t, J¼7.1 Hz, CH3), 2.57 (3H, s, CH3),
22.0 (t), 30.5 (q), 103.5 (d), 111.0 (s), 120.2 (s), 127.8 (dꢃ2), 128.6 (d),
128.7 (dꢃ2), 131.1 (s), 132.4 (s), 133.0 (d), 140.8 (s), 141.2 (s), 157.0
(s), 160.3 (CO). Anal. Calcd for C18H16N2O3S2 (372.46): C, 58.05; H,
4.33; N, 7.52. Found: C, 58.18; H, 4.17; N, 7.32.
4.05 (2H, s, CH2), 4.18 (2H, q, J¼7.1 Hz, CH2), 5.65 (2H, s, CH2), 6.98
(2H, d, J¼6.4 Hz, H-20 and H-60), 7.23e7.36 (3H, m, H-30, H-40, and H-
50), 7.56e7.73 (3H, m, H-300, H-400, and H-500), 7.98 (2H, d, J¼6.8 Hz, H-
200 and H-600), 8.19 (1H, s, H-4),11.88 (1H, s, NH).13C NMR (DMSO-d6):
d
12.4 (q), 14.0 (q), 21.8 (t), 48.1 (t), 60.0 (t), 120.5 (s), 125.9 (dꢃ2),
4.7.8. 7-Benzyl-8-methyl-3-(phenylsulfonyl)-6,7-dihydropyrrolo -
[30,20:4,5]thiopyrano[3,2-b]pyridin-2-(1H)-one (4h). This product
127.2 (d), 128.0 (dꢃ2), 128.5 (d), 128.6 (dꢃ2), 128.9 (dꢃ2), 129.7 (s),

P. Barraja et al. / Tetrahedron 68 (2012) 5087e5094
5093
was obtained by reaction of 9h with phenylsulfonylacetonitrile.
Yellow solid; Rf¼0.31 (CH2Cl2/EtOAc 8:2); mp 290e292 ꢁC; yield:
(2H, s, CH2), 4.28 (2H, q, J¼7.1 Hz, CH2), 8.08 (1H, s, H-4), 12.02 (1H,
s, NH). 13C NMR (DMSO-d6):
12.3 (q),14.2 (q), 21.5 (t), 33.4 (q), 59.9
(t), 111.3 (s), 114.9 (s), 116.3 (s), 121.2 (s), 127.0 (s), 132.5 (s), 137.7 (s),
143.0 (d), 149.3 (s), 161.0 (CO), 161.3 (CO). Anal. Calcd for
C16H15N3O3S (329.37): C, 58.35; H, 4.59; N, 12.76. Found: C, 58.05;
H, 4.77; N, 12.99.
d
48%; IR (cmꢀ1): 3411 (NH), 1635 (CO). 1H NMR (DMSO-d6):
d
2.10
(3H, s, CH3), 4.07 (2H, s, CH2), 5.21 (2H, s, CH2), 6.62 (1H, s, H-9),
6.99 (2H, d, J¼6.4 Hz, H-20 and H-60), 7.26e7.39 (3H, m, H-30, H-40,
and H-50), 7.52e7.70 (3H, m, H-300, H-400, and H-500), 7.97 (2H, d,
J¼6.7 Hz, H-200 and H-600), 8.04 (1H, s, H-4), 12.33 (1H, s, NH). 13C
NMR (DMSO-d6):
d
11.9 (q), 22.2 (t), 46.6 (t), 104.4 (d), 126.0
4.7.13. Ethyl 7-benzyl-3-cyano-9-methyl-2-oxo-1,2,6,7-
tetrahydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridine-8-carboxylate
(4m). This product was obtained by reaction of 9c with malono-
nitrile. Yellow solid; Rf¼0.18 (CH2Cl2/EtOAc 8:2); mp 273e275 ꢁC;
yield: 53%; IR (cmꢀ1): 3405 (NH), 2221 (CN), 1663 (CO), 1639 (CO).
(dꢃ2), 127.4 (d), 127.8 (dꢃ2), 128.7 (dꢃ2), 128.7 (d), 128.8 (dꢃ2),
130.9 (s), 132.4 (s), 133.0 (d), 137.1 (s), 138.6 (s), 140.7 (s), 144.3 (s),
146.1 (s), 157.0 (s), 163.1 (CO). Anal. Calcd for C24H20N2O3S2
(448.55): C, 64.27; H, 4.49; N, 6.25. Found: C, 64.59; H, 4.12; N,
6.57.
1H NMR (DMSO-d6):
d
1.21 (3H, t, J¼7.1 Hz, CH3), 2.64 (3H, s, CH3),
4.08 (2H, s, CH2), 4.19 (2H, q, J¼7.1 Hz, CH2), 5.21 (2H, s, CH2), 6.99
4.7.9. 8-Methyl-7-phenyl-3-(phenylsulfonyl)-6,7-dihydropyrrolo-
[30,20:4,5]thiopyrano[3,2-b]pyridin-2-(1H)-one (4i). This product
was obtained by reaction of 9i with phenylsulfonylacetonitrile.
Dark green solid; Rf¼0.25 (CH2Cl2/EtOAc 8:2); mp 295e296 ꢁC;
yield: 63%; IR (cmꢀ1): 3386 (NH), 1633 (CO). 1H NMR (DMSO-d6):
(2H, d, J¼6.5 Hz, H-20 and H-60), 7.20e7.36 (3H, m, H-30, H-40, and
H-50), 8.11 (1H, s, H-4), 12.10 (1H, s, NH). 13C NMR (DMSO-d6):
d 12.5
(q), 13.9 (q), 21.7 (t), 48.3 (t), 60.1 (t), 116.3 (s), 120.6 (s), 120.8 (s),
125.9 (dꢃ2), 126.0 (s), 127.1 (d), 127.2 (s), 128.4 (dꢃ2), 128.6 (d),
132.6 (s), 137.7 (s), 137.8 (s), 137.9 (s), 160.8 (CO), 160.9 (CO). Anal.
Calcd for C22H19N3O3S (405.47): C, 65.17; H, 4.72; N,10.36. Found: C,
65.45; H, 4.67; N, 10.08.
d
2.03 (3H, s, CH3), 3.81 (2H, s, CH2), 6.70 (1H, s, H-9), 7.38 (2H, d,
J¼6.6 Hz, H-20 and H-60), 7.55e7.67 (6H, m, Ar), 7.98 (2H, d,
J¼6.7 Hz, H-200 and H-600), 8.05 (1H, s, H-4), 12.38 (1H, s, NH). 13C
NMR (DMSO-d6):
d
12.4 (q), 22.6 (t), 104.4 (d), 107.7 (s), 112.2 (s),
4. 7.14. Ethyl 3-(benzoyl)-7,9-dimethyl-2-oxo-1, 2, 6, 7-
tetrahydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridine-8-carboxylate
(4n). This product was obtained by reaction of 9b with benzoy-
lacetonitrile. Yellow solid; Rf¼0.58 (CH2Cl2/EtOAc 9:1); mp
232e233 ꢁC; yield: 60%; IR (cmꢀ1): 3401 (NH), 1699 (CO), 1695
121.2 (s), 127.4 (dꢃ2), 127.8 (d), 127.9 (dꢃ2), 128.7 (dꢃ2), 129.0
(d), 129.6 (dꢃ2), 131.1 (s), 131.9 (s), 133.1 (d), 135.5 (s), 140.6 (s),
157.0 (s), 162.3 (CO). Anal. Calcd for C23H18N2O3S2 (434.53): C,
63.58; H, 4.18; N, 6.45. Found: C, 63.30; H, 4.47; N, 6.71.
(CO), 1662 (CO). 1H NMR (DMSO-d6):
2.66 (3H, s, CH3), 3.80 (3H, s, CH3), 4.13 (2H, s, CH2), 4.28 (2H, q,
d
1.33 (3H, t, J¼7.1 Hz, CH3),
4.7.10. 7-(4-Methoxybenzyl)-8-methyl-3-(phenylsulfonyl)-6,7-
dihydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridin-2-(1H)-one
(4j). This product was obtained by reaction of 9j with phenyl-
sulfonylacetonitrile. Green solid; Rf¼0.19 (CH2Cl2/EtOAc 8:2); mp
272e274 ꢁC; yield: 57%; IR (cmꢀ1): 3430 (NH), 1641 (CO). 1H NMR
J¼7.1 Hz, CH2), 7.47e7.78 (6H, m, Ph and H-4), 11.33 (1H, s, NH).
13C NMR (DMSO-d6):
d 12.4 (q), 14.2 (q), 21.6 (t), 33.3 (q), 59.8 (t),
90.1 (s), 120.9 (s), 126.9 (s), 128.4 (dꢃ2), 129.0 (d), 129.1 (dꢃ2),
132.8 (d), 137.0 (s), 137.4 (s), 159.6 (s), 161.2 (s), 170.4 (s), 172.3
(CO), 179.9 (CO), 194.2 (CO). Anal. Calcd for C22H20N2O4S
(408.47): C, 64.69; H, 4.94; N, 6.86. Found: C, 64.40; H, 5.08; N,
6.98.
(DMSO-d6):
d 2.11 (3H, s, CH3), 3.71 (3H, s, CH3), 4.07 (2H, s, CH2),
5.12 (2H, s, CH2), 6.57 (1H, s, H-9), 6.88 (2H, d, J¼8.9 Hz, H-30 and H-
50), 6.95 (2H, d, J¼8.9 Hz, H-20 and H-60), 7.53e7.65 (3H, m, H-300, H-
400, and H-500), 7.96 (2H, d, J¼7.0 Hz, H-200 and H-600), 8.01 (1H, s, H-
4),12.34 (1H, s, NH). 13C NMR (DMSO-d6):
d
11.8 (q), 22.4 (t), 46.8 (t),
4.7.15. Ethyl 3-(benzoyl)-7-benzyl-9-methyl-2-oxo-1,2,6,7-
tetrahydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridine-8-carboxylate
(4o). This product was obtained by reaction of 9c with benzoyla-
cetonitrile. Yellow solid; Rf¼0.56 (CH2Cl2/EtOAc 9:1); mp
183e184 ꢁC; yield: 57%; IR (cmꢀ1): 3393 (NH), 1684 (CO),1683 (CO),
55.1 (q), 104.5 (d), 110.5 (s), 114.3 (dꢃ2), 117.8 (s), 123.5 (s), 126.0 (d),
127.6 (dꢃ2), 127.8 (dꢃ2), 128.7 (dꢃ2), 130.9 (s), 133.3 (d), 140.7 (s),
142.0 (s), 145.7 (s), 147.1 (s), 154.0 (s), 161.2 (CO). Anal. Calcd for
C25H22N2O4S2 (478.58): C, 62.74; H, 4.63; N, 5.85. Found: C, 62.49;
H, 4.31; N, 5.97.
1608 (CO). 1H NMR (DMSO-d6):
d
1.22 (3H, t, J¼7.1 Hz, CH3), 2.71
(3H, s, CH3), 4.09 (2H, s, CH2), 4.20 (2H, q, J¼7.1 Hz, CH2), 5.67 (2H, s,
CH2), 7.00 (2H, d, J¼6.6 Hz, H-20 and H-60), 7.20e7.37 (3H, m, H-30,
H-40, and H-50), 7.47e7.68 (3H, m, H-300, H-400, and H-500), 7.75 (1H, s,
H-4), 7.76 (2H, d, J¼6.6 Hz, H-200 and H-600), 11.38 (1H, s, NH). 13C
4.7.11. 8-Methyl-7-(4-methylbenzyl)-3-(phenylsulfonyl)-6,7-
dihydropyrrolo[30,20:4,5]thiopyrano[3,2-b]pyridin-2-(1H)-one
(4k). This product was obtained by reaction of 9k with phenyl-
sulfonylacetonitrile. Brown solid; Rf¼0.34 (CH2Cl2/EtOAc 8:2); mp
276e278 ꢁC; yield: 60%; IR (cmꢀ1): 3425 (NH), 1631 (CO). 1H NMR
NMR (DMSO-d6):
d 12.6 (q), 14.0 (q), 21.8 (t), 48.0 (t), 60.0 (t), 116.5
(s), 120.3 (s), 120.5 (s), 125.9 (dꢃ2), 127.0 (s), 127.2 (d), 127.8 (d),
128.4 (dꢃ2), 128.6 (dꢃ2), 129.2 (dꢃ2), 132.9 (d), 133.0 (s), 137.1 (s),
137.3 (s), 137.9 (s), 159.1 (s), 159.5 (CO), 161.0 (CO), 161.1 (CO). Anal.
Calcd for C28H24N2O4S (484.57): C, 69.40; H, 4.99; N, 5.78. Found: C,
69.22; H, 5.16; N, 5.54.
(DMSO-d6):
d 2.09 (3H, s, CH3), 2.26 (3H, s, CH3), 4.07 (2H, s, CH2),
5.15 (2H, s, CH2), 6.61 (1H, s, H-9), 6.88 (2H, d, J¼8.0 Hz, H-30 and H-
50), 7.14 (2H, d, J¼8.0 Hz, H-20 and H-60), 7.52e7.70 (3H, m, H-300, H-
400, and H-500), 7.97 (2H, d, J¼6.7 Hz, H-200 and H-600), 8.04 (1H, s, H-
4), 12.30 (1H, s, NH). 13C NMR (DMSO-d6):
d 11.9 (q), 20.6 (q), 22.2
(t), 46.3 (t), 104.3 (d), 120.8 (s), 125.9 (d), 126.0 (dꢃ2), 127.8 (dꢃ2),
128.7 (dꢃ2), 129.3 (dꢃ2), 130.8 (s), 132.4 (s), 133.1 (d), 134.1 (s),
134.9 (s), 136.6 (s), 140.7 (s), 146.1 (s), 157.1 (s), 163.3 (CO). Anal.
Calcd for C25H22N2O3S2 (462.58): C, 64.91; H, 4.79; N, 6.06. Found:
C, 65.09; H, 4.58; N, 5.87.
Acknowledgements
This work was financially supported by Ministero dell’Istruzione
ꢀ
dell’Universita e della Ricerca.
4.7.12. Ethyl 3-cyano-7,9-dimethyl-2-oxo-1,2,6,7-tetrahydropyrrolo-
[30,20:4,5]thiopyrano[3,2-b]pyridine-8-carboxylate (4l). This product
was obtained by reaction of 9b with malononitrile. Orange solid;
Rf¼0.22 (CH2Cl2/EtOAc 8:2); mp 336edec ꢁC; yield: 45%; IR (cmꢀ1):
3346 (NH), 2222 (CN), 1685 (CO), 1645 (CO). 1H NMR (DMSO-d6):
Supplementary data
Inhibition of in vitro tumor cell growth of compounds 8c, 4a,
and 4b. Supplementary data related to this article can be found
online at doi:10.1016/j.tet.2012.04.041.
d
1.32 (3H, t, J¼7.1 Hz, CH3), 2.60 (3H, s, CH3), 3.78 (3H, s, CH3), 4.10

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P. Barraja et al. / Tetrahedron 68 (2012) 5087e5094
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