Synthesis of pyrimidine annulated furothiopyrans - An efficient sequential and tandem catalyzed Claisen rearrangement - intramolecular hydroaryloxylation

Article abstract of DOI:10.1139/V06-020

Regioselective synthesis of a hitherto unreported furothiopyran moiety fused at the C-5 and C-6 positions of a pyrimidine heterocycle was achieved by the application of sequential Claisen rearrangement in which a second aromatic Claisen rearrangement and

Full text of DOI:10.1139/V06-020

469
Synthesis of pyrimidine annulated furothiopyrans —
An efficient sequential and tandem catalyzed
Claisen rearrangement – intramolecular
hydroaryloxylation
K.C. Majumdar and S.K. Chattopadhyay
Abstract: Regioselective synthesis of a hitherto unreported furothiopyran moiety fused at the C-5 and C-6 positions of
a pyrimidine heterocycle was achieved by the application of sequential Claisen rearrangement in which a second aro-
matic Claisen rearrangement and intramolecular hydroaryloxylation were catalyzed by aluminum chloride. The second
aromatic Claisen rearrangement step was also studied under thermal conditions to give mostly isomerized exocyclic
compounds. The precursor endocyclic compounds were synthesized by thermal [3,3] sigmatropic rearrangement of the
corresponding sulfide.
Key words: aluminum chloride, sequential Claisen rearrangement, hydroaryloxylation, furothiopyran, pyrimidine.
Résumé : Faisant appel à une séquence des réarrangements de Claisen dans laquelle le deuxième réarrangement aroma-
tique de Claisen et l’hydroaryloxylation sont catalysées par du chlorure d’aluminium, on a effectué la synthèse régiosé-
lective qui n’avait pas été réalisée jusqu’à maintenant de la portion furothiopyrane condensée aux positions C-5 et C-6
de l’hétérocycle pyrimidine. On a aussi étudié le deuxième réarrangement de Claisen dans des conditions thermiques et
il conduit principalement à des composés isomérisés exocycliques. On a réalisé la synthèse des composés endocycli-
ques précurseurs en procédant à un réarrangement thermique [3,3] du sulfure correspondant.
Mots clés : chlorure d’aluminium, séquence de réarrangements de Claisen, hydroaryloxylation, furothiopyrane, pyrimidine.
[Traduit par la Rédaction] Majumdar and Chattopadhyay 475
Introduction
trolled rearrangement, we observed interesting results in the
second Claisen rearrangement (3a, 3b). We sought to extend
this chemistry to encompass a new synthetic route leading to
a [6,5]-furothiopyran moiety.
Claisen rearrangement, since its discovery in 1912, has
been proven to be one of the preeminent methodologies for
the construction of carbon–carbon bonds in synthetic organic
chemistry (1). A high level of stereocontrol, securing its
widespread use in the synthesis of natural products and me-
dicinal agents, can be achieved by this concerted [3,3]
sigmatropic rearrangement (1). The traditional methodolo-
gies for accomplishing the rearrangement are based on ther-
mally controlled procedure; however, the development of
new methodologies employing a catalyst in the Claisen rear-
rangement have been the focus of many recent investigations
in organic synthesis (2). Over the past few years we em-
barked on the development of new synthetic methodologies
for the synthesis of novel heterocycles based on sequential
Claisen rearrangement (3). During the investigation of the
synthetic perspectives of the aforementioned thermally con-
The incorporation of the pyrimidine moiety in the present
investigation is due to its wide biological and pharmacologi-
cal activities (4). Numerous pyrimidine- and uracil-based
molecules, e.g., AZT, DDC, and BVDU, have been known
to be active agents against cancer and the AIDS virus (5).
Some pyrido-[2,3-d]-pyrimidines exhibit antibacterial activ-
ity and antitumor activities (6). Extensive investigations have
been carried out with these heterocyclic systems (7). In con-
trast, a few examples dealing with the chemistry of an 8-
sulfurisostere, thiopyrano-[2,3-d]-pyrimidine system, which
may have potential biological activity, are reported in the lit-
erature (8). This has prompted us to undertake a study of se-
quential Claisen rearrangement with the development of
broadly useful new routes to a [6,5]-furothiopyran system
fused at the C-5 and C-6 positions of the pyrimidine moiety.
Herein we report the results of our investigation.
Received 28 November 2005. Published on the NRC
Research Press Web site at http://canjchem.nrc.ca on 7 April
2006.
Results and discussion
This paper is dedicated to Dr. J. William Lown, Professor
Emeritus, University of Alberta, Edmonton.
The requisite sulfides (3a–3g) for the present investigation
were synthesized in 75%–92% yields by phase-transfer-
catalyzed alkylation of 6-mercaptouracil (2) with different 1-
chloro-4-aryloxybut-2-ynes. Compound 2 was in turn pre-
pared by the reaction of 6-chlorouracil (1) with NaSH in dry
ethanol at 0 °C. Compounds 3a–3g were all solid and were
K.C. Majumdar1 and S.K. Chattopadhyay. Department of
Chemistry, University of Kalyani, Kalyani 741235, WB,
India.
1Corresponding author (e-mail: kcm_ku@yahoo.co.in).
Can. J. Chem. 84: 469–475 (2006)
doi:10.1139/V06-020
© 2006 NRC Canada

470
Can. J. Chem. Vol. 84, 2006
Scheme 1. Reagents and conditions: (i) NaSH, EtOH, 0 °C, stir-
ring, 7 h; (ii) CH2Cl2, 1% aq. NaOH sol. BTEAC, rt, stirring,
12 h.
Scheme 3.
3a-3g
OAr
OAr
O
N
O
H3C
O
H3C
H
.
.
N
N
OAr
OAr
[3,3]
O
O
O
H3C
(i)
H3C
O
H3C
O
Cl
O
SH
N
S
N
N
N
(ii)
CH3
7
CH3
6
[1,5] H
O
SH
Cl
S
N
N
N
Shift
OAr
OAr
CH3
1
CH3
2
CH3
3a-3g
O
O
H3C
H3C
N
[1,3]
N
ECR
5g
3d) Ar = 2,3-Me2C6H4
3e) Ar = 3,5-Me2C6H4
3f) Ar = 2,4-Cl2C6H3
3a) Ar = 4-MeOC6H4
3b) Ar = 3,5-Me2-4-ClC6H2
3c) Ar = 2-ClC6H4
g) Ar = 2,4-Me2C6H3
4a-4f
H+ shift
O
S
path a
N
O
N
S
CH3
10
CH3
9
Scheme 2. Reagents and conditions: (i) chlorobenzene, reflux, 4 h.
OAr
H
OAr
OAr
H3C
O
O
O
Scheme 4. Reagents and conditions: (i) AlCl3, CH2Cl2, rt, 1 h.
H3C
O
H3C
O
R2
1
R
N
N
N
(i)
1
R
+
6
2
R
3
5O
S
5a
O
R
N
N
S
O
N
S
O
O
7
H3C
4a
CH3
4a-4f
CH3
4b
CH3
3a-3g
H3C
O
H3C
O
8
R3
4
9a
4
N
R
N3
9
5g
10a
10
(i)
H
2
4
11
Ar
4a 4-MeOC6H4
Yield (%)
94
R
1
N
11a
N
S
S
CH3
CH3
11a-11e
R1 R2 R3 R4 Yield (%)
4b 3,5Me2-4-ClC6H2 88
4a-4f
4c 2-ClC6H4
92
88
4d 2,3-Me2C6H4
4e 3,5-Me2C6H4
4f 2,4-Cl2C6H3
5g 2,4-Me2C6H3
85
95
88
11a
11b
11c Cl
11d Me Me
11e
11f Cl
H
H
H OMe H 96
Me Cl Me 90
H
H
H
H
92
H
H
94
90
H
Me Me
Cl
H
H
characterized from their elemental analyses and spectral data
(Scheme 1).
The substrates 3a–3g possess two potential sites for [3,3]
sigmatropic rearrangement: a vinyl propargyl sulfide moiety
and an aryl propargyl ether moiety. Compounds with this
structural feature offer an excellent scope for the study on
the competition between oxy- and thio-Claisen rearrange-
ment along with the synthesis of new heterocycles through
[3,3] sigmatropic rearrangement. To accomplish the thio-
Claisen rearrangement, the substrate 3a was first subjected
to thermal rearrangement by refluxing in the lower boiling
solvent chlorobenzene (132 °C) for 4 h to give crystalline
solid 4a in 94% yield (Scheme 2). Elemental analysis and
spectral data of compound 4a established its endocyclic na-
ture, which is necessary for further Claisen rearrangement.
Encouraged by the initial accomplishment, the remaining
substrates (3b–3g) were similarly treated to afford 4b–4f
(84%–95% yield) and 5g (88% yield) (Scheme 2). The
exocyclic nature of the product 5g was established from the
ucts 4a–4f. The product 5g may also be formed because of
the [1,3] protropic rearrangement of the thermally unstable
endocyclic compound 9 to afford 5g (Scheme 3). It is note-
worthy that all the substrates 3a–3f, except 3g, regio-
selectively afforded exclusive products 4a–4f in excellent
yield. A lesser energy requirement for the sigmatropic rear-
rangement in vinyl propargyl sulfide systems (9) compared
with that in aryl propargyl ether moieties (10) might be re-
sponsible for this excellent regioselectivity.
Compound 4 still posses an allyl aryl ether segment requi-
site for further study on the [3,3] sigmatropic rearrangement.
In our earlier efforts, we found different regioselectivity with
different substrates in the thermal second aromatic Claisen
rearrangement (3). In some cases, [1,3] prototropic rear-
rangement was an important side reaction along with [3,3]
sigmatropic rearrangement (11). To circumvent this un-
wanted problem in thermal second Claisen rearrangement,
we turned our attention to the Lewis acid catalyzed Claisen
rearrangement approach (2). Among the different Lewis acid
catalysts available for the aromatic oxy-Claisen rearrange-
ment, aluminum chloride and its different derivatives have
received the most attention (1d, 2a). So we subjected com-
pound 4a to catalyzed Claisen rearrangement using alumi-
num chloride as the catalyst in dry dichloromethane at room
temperature to afford the cyclized product 11a (96% yield),
which was characterized by its elemental analysis and spec-
tral data. To test the generality of the reaction, other sub-
strates (4b–4f) were similarly treated to afford the cyclized
1
high field (300 MHz) H NMR spectrum. The 13C NMR
chemical shift values of compound 5g and multiplicities
were assigned from the DEPT experiment. The DEPT spec-
trum obtained showed 10 protonated carbons, four -CH3,
two >CH2, and four >CH-.
The mechanistic rationalization (Scheme 3) for the forma-
tion of compounds 4a–4f and 5g can be explained by assum-
ing initial [3,3] sigmatropic rearrangement of 3a–3g,
followed by rapid enolization to form the allenylene–thiol
intermediate 7, which then undergoes a [1,5]-hydrogen shift,
followed by 6π electrocyclic ring closure to give the prod-
© 2006 NRC Canada

Majumdar and Chattopadhyay
471
Scheme 5.
H+
O
O
O
Me
O
Me
O
Me
O
Me
O
N
N
N
[3,3]
4
..
OH
OH
N
S
N
S
N
S
[1,3]
Me
Me
Me
prototropic
12
13
16c, 16f
shift
..
HO
OAr
H3C
O
N
O
O
O
H3C
Me
O
Me
N
Me
N
N
H
+
O
S
N
S
O
N
S
Me
Me
Me
11a-11e
14
15a, 15b, 15f
Scheme 6. Reagents and conditions: (i) dichlorobenzene, N,N-
diethylaniline, reflux, 8 h.
products 11b–11e (90%–96% yield) (Scheme 4). No
cyclized product corresponding to 11 was obtained in the
case of compound 4f, as several other unwanted products
(TLC observation) were formed during the reaction that
were not characterized. We have tried the reaction with
other Lewis acids, e.g., BF3·Et2O and Cp2TiCl2. In the case
of Cp2TiCl2, no reaction occurred. The reaction is quite
sluggish with BF3·Et2O with the formation of undesired
products, which were not characterized.
4
R
R3
R4
CH3
R2
O
R3
H
O
O
Me
O
1
Me
O
R
R2
1
R
N
N
(i)
+
4a-4c, 4f
OH
N
S
N
S
Me
Me
The conversion of 4 into 11 may take a pathway similar to
that observed in thermal Claisen rearrangement via the 2-
allylphenol intermediate 13 (Scheme 5). From the literature
it may be assumed that this transformation may be a charge-
induced Claisen rearrangement similar in mechanism to the
process reported for BCl3 by Schmid and co-workers (12).
The reaction may be facilitated by the coordination of the
oxygen atom, which itself is a strong Lewis base, to the hard
Lewis acid, aluminum chloride. The hydroaryloxylation step
leading to the formation of the benzofuran moiety may occur
by the addition of H+ to the position of the homothioenol
ether followed by simultaneous conjugate addition of a phe-
nolic OH group to the resulting thionium ion. To isolate the
2-allylphenol intermediate 13, we tried the reaction in the
presence of additives such as PPh3 or amine base, e.g.,
morpholine and triethylamine. There too no reaction was ob-
served. It is noteworthy that in the present investigation alu-
minium chloride promotes both Claisen rearrangement and
hydroaryloxylation and the unusual ring contraction perti-
nent to the AlCl3-catalyzed oxy-Claisen rearrangement (13)
was unobserved, mainly owing to the soft basic character of
sulfur being unable to form a complex with aluminum chlo-
ride. The overall regioselectivity of the catalyzed reaction
leading to the formation of tetracyclic heterocycles 11 is ex-
cellent.
15a, 15b, 15f
16c, 16f
ble amount of starting material was recovered. We have also
attempted the reaction in dichlorobenzene and N,N-
diethylaniline separately. There too the same products were
obtained in very poor yield. All the compounds were solid
and were characterized from their elemental analysis and
spectral data.
The formation of products 15a, 15b, 15f, 16c, and 16f can
be mechanistically interpreted as follows (Scheme 5). Com-
pounds 15a, 15b, and 15f can be obtained by [1,3]
prototropic rearrangement in compounds 4a, 4b, and 4f. Ini-
tial [3,3] sigmatropic rearrangement followed by rapid
tautomerization may result in the formation of 16c and 16f
from 4c and 4f via the 2-allyl phenol intermediate 13. In the
present investigation, the [1,3] prototropic rearrangement with
the formation of an exocyclic compound as the major prod-
uct is quite unusual. In two cases we were successful in iso-
lating the endocyclic phenolic product, but in very poor yield.
The presence of different substituents in the benzene nuclei
of compounds 4a, 4b, and 4f thus results in a change in the
mode of rearrangement. However, the role of the substituent
in the formation of products 15 and 16 is not clear. It may be
conceivable that the thermal stability of the resulting com-
pounds might be responsible for their formation.
We have also examined the thermal second Claisen rear-
rangement of the same substrates. For compounds 4a–4c and
4f, when subjected to thermal rearrangement in refluxing
dichlorobenzene in the presence of N,N-diethylaniline for
8 h (Scheme 6), the observed results were quite interesting
as compounds 4a and 4b exclusively gave the exocyclic
compounds 15a and 15b in 40% and 45% yield, respec-
tively, and from compound 4c the endocyclic phenolic com-
pound 16c was obtained in 10% yield. Both products 15f
and 16f were isolated; in the case of substrate 4f, in almost
38% and 25% yield, respectively. In each case, an apprecia-
R1
R2
O
O
Me
Me
R3
N
H
R4
O
N
S
Me
17
© 2006 NRC Canada

472
Can. J. Chem. Vol. 84, 2006
From a molecular modelling (Dreiding model) study and
ture. It was then diluted with water (25 mL). The dichloro-
methane layer was then separated and washed with 2 N HCl
(25 mL), brine (25 mL), and water (25 mL), and dried
(Na2SO4). The crude mass obtained upon evaporation of
CH2Cl2 was subjected to column chromatography. Elution
with petroleum ether – ethyl acetate (7:3) afforded the prod-
ucts 3a–3g.
comparison with the stereochemistry of natural pterocarpin
(14), the stereochemistry of the ring fusion in the tetracyclic
system may be assumed to be cis and is represented as 17.
In conclusion, we have demonstrated a broadly useful new
route based on a sequential thermal plus tandem-catalyzed
Claisen rearrangement – intramolecular hydroaryloxylation
approach that we expect to provide an expedient avenue for
the synthesis of a furothiopyran system, quite similar to the
petrocarpin system. This protocol is complementary to our
preliminary thermal methodology. The mild reaction condi-
tions and compatibility with various substituents on the aro-
matic ring make this route a significant addition to the
existing methodologies for the synthesis of a synthetically
challenging furothiopyran moiety fused with other
heterocycles.
Compound 3a
Yield: 84%; brown solid, mp 70 °C. IR (KBr, cm–1) νmax
:
1
1645, 1702, 2963. H NMR (CDCl3, 300 MHz) δH: 3.34 (s,
3H, -NCH3), 3.45 (s, 3H, -NCH3), 3.69 (s, 2H, -SCH2), 3.77
(s, 2H, -OCH3), 4.63 (s, 2H, -OCH2), 5.66 (s, 1H, =CH),
6.81–6.88 (m, 4H, ArH). MS m/z: 346 (M+). Anal. calcd. for
C17H18N2O4S (%): C 58.95, H 5.20, N 8.09; found: C 59.15,
H 5.44, N 8.25.
Compound 3b
Experimental
Yield: 78%; brown solid, mp 130 °C. IR (KBr, cm–1) νmax
:
1
1644, 1706, 2930. H NMR (CDCl3, 300 MHz) δH: 2.33 (s,
6H, Ar(CH3)2), 3.33 (s, 3H, -NCH3), 3.45 (s, 3H, -NCH3),
3.70 (s, 2H, -SCH2), 4.65 (s, 2H, -OCH2), 5.65 (s, 1H,
=CH), 6.66 (s, 2H, ArH). MS m/z: 378, 380 (M+). Anal.
calcd. for C18H19N2O3SCl (%): C 56.99, H 5.01, N 7.38;
found: C 57.23, H 5.18, N 7.59.
General remarks
Melting points were determined in open capillaries and
are uncorrected. IR spectra were recorded on a PerkinElmer
L120-000A spectrometer (γmax in cm–1) using samples as
neat liquids, solid samples were recorded in KBr disks, and
UV absorption spectra were recorded in EtOH on a
1
Shimadzu UV-2401PC spectrophotometer (λmax in nm). H
Compound 3c
NMR (300 MHz, 500 MHz) spectra were recorded on
Bruker DPX-300 and Bruker DRX-500 spectrometers in
CDCl3 (chemical shifts in δ) with TMS as the internal stan-
dard. Elemental analyses and mass spectra were recorded on
a JEOL JMS600 instrument. Silica gel (60–120 mesh,
Spectrochem, India) was used for chromatographic separa-
tion. Silica gel G (E-Merck, India) was used for TLC. Petro-
leum ether refers to the fraction boiling between 60 and
80 °C.
Yield: 85%; brown solid, mp 116 °C. IR (KBr, cm–1) νmax
:
1
1651, 1693, 2942. H NMR (CDCl3, 300 MHz) δH: 3.34 (s,
3H, -NCH3), 3.44 (s, 3H, -NCH3), 3.70 (s, 2H, -SCH2), 4.79
(s, 2H, -OCH2), 5.65 (s, 1H, =CH), 6.92–7.37 (m, 4H, ArH).
MS m/z: 350, 352 (M+). Anal. calcd. for C16H15N2O3SCl
(%): C 54.70, H 4.27, N 7.97; found: C 54.89, H 4.49, N
8.14.
Compound 3d
The 1-aryloxy-4-chlorobut-2-ynes were prepared accord-
ing to the published procedure (15).
Yield: 78%; brown solid, mp 92 °C. IR (KBr, cm–1) νmax
:
1
1630, 1691, 2949. H NMR (CDCl3, 300 MHz) δH: 2.14 (s,
3H, -ArCH3), 2.26 (s, 3H, -ArCH3), 3.34 (s, 3H, -NCH3),
3.44 (s, 3H, -NCH3), 3.70 (s, 2H, -SCH2), 4.69 (s, 2H,
-OCH2), 5.66 (s, 1H, =CH), 6.74–7.04 (m, 4H, ArH). MS
m/z: 344 (M+). Anal. calcd. for C18H20N2O3S (%): C 62.79,
H 5.81, N 8.13; found: C 62.97, H 6.03, N 8.36.
General procedure for the preparation of 6-
mercaptouracil (2)
To a magnetically stirred solution of NaSH (1.2 g,
20.8 mmol) in dry ethanol (50 mL), a solution of 6-
chlorouracil (1) (1.5 g, 8.6 mmol) in dry ethanol (50 mL)
was added dropwise for a period of 2 h. After the addition
was complete, the stirring was continued for an additional
4 h. Ethanol was removed under vacuum at room tempera-
ture. The residue was acidified with concd. HCl (25 mL).
This was then extracted with CH2Cl2 (4 × 20 mL). The di-
chloromethane solution was washed with water (2 × 10 mL)
and dried (Na2SO4). Attempts to evaporate dichloromethane
led to considerable decomposition of compound 2. There-
fore, this dichloromethane solution was directly used in the
next phase-transfer-catalyzed alkylation step.
Compound 3e
Yield: 82%; brown solid, mp 94 °C. IR (KBr, cm–1) νmax
:
1
1634, 1697, 2953. H NMR (CDCl3, 300 MHz) δH: 2.28 (s,
6H, -Ar(CH3)2), 3.34 (s, 3H, -NCH3), 3.45 (s, 3H, -NCH3),
3.71 (s, 2H, -SCH2), 4.66 (s, 2H, -OCH2), 5.66 (s, 1H,
=CH), 6.55 (s, 2H, ArH), 6.63 (s, 1H, ArH). MS m/z: 344
(M+). Anal. calcd. for C18H20N2O3S (%): C 62.79, H 5.81, N
8.13; found: C 63.01, H 5.97, N 8.30.
Compound 3f
Yield: 92%; brown solid, mp 126 °C. IR (KBr, cm–1) νmax
:
General procedure for the preparation of sulfides (3a–3g)
To a stirred solution of 6-mercaptouracil (2) (obtained
from 1.5 g, 8.6 mmol of compound 1) and 1-aryloxy-4-
chlorobut-2-yne (8.6 mmol) in dichloromethane (100 mL), a
solution of benzyltriethylammonium chloride (BTEAC)
(0.5 g, 1.8 mmol) in 1% aq. NaOH solution (100 mL) was
added, and the mixture was stirred for 12 h at room tempera-
1
1645, 1702, 2964. H NMR (CDCl3, 300 MHz) δH: 3.35 (s,
3H, -NCH3), 3.45 (s, 3H, -NCH3), 3.70 (s, 2H, -SCH2), 4.77
(s, 2H, -OCH2), 5.64 (s, 1H, =CH), 6.92–7.37 (m, 3H, ArH).
MS m/z: 384, 386, 388 (M+). Anal. calcd. for
C16H14N2O3SCl2 (%): C 49.87, H 3.63, N 7.27; found: C
50.09, H 3.81, N 7.46.
© 2006 NRC Canada

Majumdar and Chattopadhyay
473
3H, -CH3), 3.37 (s, 3H, -NCH3), 3.40 (d, 2H, J = 6 Hz,
-SCH2), 3.56 (s, 3H, -NCH3), 5.05 (s, 2H, -OCH2), 5.88 (t,
1H, J = 6 Hz, =CH), 6.56 (s, 2H, ArH), 6.58 (s, 1H, ArH).
MS m/z: 344 (M+). Anal. calcd. for C18H20N2O3S (%): C
62.79, H 5.81, N 8.13; found: C 62.95, H 6.05, N 8.32.
Compound 3g
Yield: 84%; brown solid, mp 92 °C. IR (KBr, cm–1) νmax
:
1
1656, 1696, 2917. H NMR (CDCl3, 300 MHz) δH: 2.18 (s,
3H, -ArCH3), 2.25 (s, 3H, -ArCH3), 3.34 (s, 3H, -NCH3),
3.44 (s, 3H, -NCH3), 3.68 (s, 2H, -SCH2), 4.67 (s, 2H,
-OCH2), 5.66 (s, 1H, =CH), 6.75–6.94 (m, 3H, ArH). MS
m/z: 344 (M+). Anal. calcd. for C18H20N2O3S (%): C 62.79,
H 5.81, N 8.13; found: C 62.99, H 6.01, N 8.32.
Compound 4f
Yield: 95%; white solid, mp 108 °C. IR (KBr, cm–1) νmax
:
1
1647, 1702, 2944. H NMR (CDCl3, 300 MHz) δH: 3.36 (s,
3H, -NCH3), 3.42 (d, 2H, J = 6 Hz, -SCH2), 3.57 (s, 3H,
-NCH3), 5.13 (s, 2H, -OCH2), 5.93 (t, 1H, J = 6 Hz, =CH),
6.89–7.35 (m, 3H, ArH). MS m/z: 384, 386, 388 (M+). Anal.
calcd. for C16H14N2O3SCl2 (%): C 49.87, H 3.63, N 7.27;
found: C 50.07, H 3.85, N 7.44.
General procedure for the preparation of 4a–4f and 5g
Compounds 3a–3h (250 mg, 0.72 mmol) were refluxed in
chlorobenzene (10 mL) for 5 h. The reaction mixture was
then cooled and directly subjected to column chromatogra-
phy over silica gel. Chlorobenzene was eluted out with pe-
troleum ether. On eluting the column with petroleum ether –
ethyl acetate (4:1), compounds 4a–4g and 5h were obtained.
All compounds were recrystalized from dichloromethane –
petroleum ether.
Compound 5g
Yield: 88%; white solid, mp 128 °C. IR (KBr, cm–1) νmax
:
1
1657, 1708, 2921. H NMR (CDCl3, 300 MHz) δH: 2.24
(s, 3H, -ArCH3), 2.27 (s, 3H, -ArCH3), 2.96–2.99 (m, 2H,
=C-CH2), 3.11–3.14 (m, 2H, -SCH2), 3.37 (s, 3H, -NCH3),
3.56 (s, 3H, -NCH3), 6.94–6.97 (m, 3H, ArH), 8.03 (s, 1H,
=CH). MS m/z: 344 (M+). 13C NMR (CDCl3, 125 MHz) δC:
16.65, 20.84, 26.64, 33.77, 68.86, 107.87, 110.63, 112.37,
126.87, 127.37, 130.03, 131.78, 136.65, 151.76, 154.90,
155.13, 159.82. Anal. calcd. for C18H20N2O3S (%): C 62.79,
H 5.81, N 8.13; found: C 63.00, H 5.99, N 8.34.
Compound 4a
Yield: 94%; white solid, mp 102 °C. IR (KBr, cm–1) νmax
:
1
1633, 1705, 2928. H NMR (CDCl3, 500 MHz) δH: 3.36 (s,
3H, -NCH3), 3.39 (d, 2H, J = 6 Hz, -SCH2), 3.56 (s, 3H,
-NCH3), 3.75 (s, 3H, -OCH3), 5.04 (s, 2H, -OCH2), 5.86 (t,
1H, J = 6 Hz, =CH), 6.78–6.88 (m, 4H, ArH). 13C NMR
(CDCl3, 125 MHz) δC: 26.60, 28.62, 33.76, 56.11, 69.71,
107.74, 111.45, 114.45, 116.51, 136.53, 151.16, 153.18,
154.34, 155.19, 159.78. MS m/z: 346 (M+). Anal. calcd. for
C17H18N2O4S (%): C 58.95, H 5.20, N 8.09; found: C 59.13,
H 5.42, N 8.32.
General procedure for the aluminum chloride catalyzed
reaction
To a stirred solution of the compounds 4a–4f (0.28 mmol)
in dry dichloromethane (10 mL), anhydrous aluminium chlo-
ride (36 mg, 0.28 mmol) was added at room temperature.
The stirring was continued for about 1 h. After completion
of the reaction, 1% HCl solution (5 mL) was added. The re-
action mixture was then extracted with dichloromethane (2 ×
10 mL). The organic layer was washed with water (2 ×
10 mL) and brine (10 mL) and dried (Na2SO4). Dichloro-
methane was distilled off and the residue obtained was sub-
jected to flash chromatography. On eluting the column with
ethyl acetate – petroleum ether (1:10), compounds 11a–11e
were obtained as white solids. All compounds were
recrystalized from dichloromethane.
Compound 4b
Yield: 88%; white solid, mp 148 °C. IR (KBr, cm–1) νmax
:
1
1664, 1702, 2948. H NMR (CDCl3, 300 MHz) δH: 2.32 (s,
6H, -Ar(CH3)2), 3.36 (s, 3H, -NCH3), 3.40 (d, 2H, J = 6 Hz,
-SCH2), 3.56 (s, 3H, -NCH3), 5.03 (s, 2H, -OCH2), 5.84 (t,
1H, J = 6 Hz, =CH), 6.66 (s, 2H, ArH). MS m/z: 378, 380
(M+). Anal. calcd. for C18H19N2O3SCl (%): C 56.99, H 5.01,
N 7.38; found: C 57.17, H 5.23, N 7.62.
Compound 4c
Yield: 92%; white solid, mp 152 °C. IR (KBr, cm–1) νmax
:
1
1647, 1696, 2892. H NMR (CDCl3, 300 MHz) δH: 3.37 (s,
3H, -NCH3), 3.43 (d, 2H, J = 6 Hz, -SCH2), 3.56 (s, 3H,
-NCH3), 5.16 (s, 2H, -OCH2), 5.99 (t, 1H, J = 6 Hz, =CH),
6.88–7.35 (m, 4H, ArH). MS m/z: 350, 352 (M+). Anal.
calcd. for C16H15N2O3SCl (%): C 54.70, H 4.27, N 7.97;
found: C 54.92, H 4.45, N 8.18.
Compound 11a
Yield: 96%; white solid, mp 132 °C. IR (KBr, cm–1) νmax
:
1
1646, 1701, 2927. H NMR (CDCl3, 500 MHz) δH: 1.78 (s,
3H, C4b-CH3), 2.80 (dd, 1H, J = 11, 13 Hz, C10-H), 3.02 (dd,
1H, J = 3, 13 Hz, C10-H), 3.29 (dd, 1H, J = 3, 11 Hz,
C
10a-H), 3.39 (s, 3H, -NCH3), 3.51 (s, 3H, -NCH3), 3.77 (s,
Compound 4d
3H, -OCH3), 6.72–6.86 (m, 3H, ArH). 13C NMR (CDCl3,
125 MHz) δC: 25.05, 28.57, 30.20, 32.89, 51.26, 56.41,
86.30, 108.54, 111.04, 111.69, 111.53, 129.13, 151.19,
151.77, 153.09, 154.67, 160.39. MS m/z: 346 (M+). Anal.
calcd. for C17H18N204S (%): C 58.95, H 5.20, N 8.09; found:
C 59.18, H 5.34, N 8.27.
Yield: 88%; white solid, mp 152 °C. IR (KBr, cm–1) νmax
:
1
1646, 1696, 2917. H NMR (CDCl3, 300 MHz) δH: 2.15 (s,
3H, -ArCH3), 2.26 (s, 3H, -ArCH3), 3.37 (s, 3H, -NCH3),
3.41 (d, 2H, J = 6 Hz, -SCH2), 3.56 (s, 3H, -NCH3), 5.07 (s,
2H, -OCH2), 5.91 (t, 1H, J = 6 Hz, =CH), 6.73–7.03 (m, 3H,
ArH). MS m/z: 344 (M+). Anal. calcd. for C18H20N2O3S (%):
C 62.79, H 5.81, N 8.13; found: C 63.03, H 6.01, N 8.31.
Compound 11b
Yield: 90%; white solid, mp 102 °C. IR (KBr, cm–1) νmax
:
1
Compound 4e
1640, 1700, 2924, 2976. H NMR (CDCl3, 500 MHz) δH:
1.71 (s, 3H, C4b-CH3), 2.32 (s, 3H, Ar-CH3), 2.37 (s, 3H,
Ar-CH3), 2.62 (dd, 1H, J = 11, 13 Hz, C10-H), 2.93 (dd, 1H,
Yield: 85%; white solid, mp 134 °C. IR (KBr, cm–1) νmax
:
1
1655, 1706, 2911. H NMR (CDCl3, 300 MHz) δH: 2.27 (s,
© 2006 NRC Canada

474
Can. J. Chem. Vol. 84, 2006
J = 3, 13 Hz, C10-H), 3.22 (dd, 1H, J = 3, 11 Hz, C10a-H),
3.40 (s, 3H, -NCH3), 3.54 (s, 3H, -NCH3), 6.71 (s, 1H, ArH).
MS m/z: 378, 380 (M+). Anal. calcd. for C18H19N2O3SCl
(%): C 56.99, H 5.01, N 7.38; found: C 57.19, H 5.29, N
7.62.
(M+). Anal. calcd. for C17H18N2O4S (%): C 58.95, H 5.20, N
8.09; found: C 59.17, H 5.39, N 8.31.
Compound 15b
Yield: 45%; white solid, mp 168 °C. IR (KBr, cm–1) νmax
:
1
1629, 1697, 2934. H NMR (CDCl3, 500 MHz) δH: 2.36 (s,
6H, -Ar(CH3)2), 2.91–2.95 (m, 2H, =C-CH2), 3.09–3.11 (m,
2H, SCH2), 3.40 (s, 3H, -NCH3), 3.54 (s, 3H, -NCH3), 6.81
(S, 2H, ArH), 8.05 (s, 1H, =CH). MS m/z: 378, 380 (M+).
Anal. calcd. for C18H19N2O3SCl (%): C 56.99, H 5.01, N
7.38; found: C 57.17, H 5.22, N 7.64.
Compound 11c
Yield: 92%; white solid, mp 198 °C. IR (KBr, cm–1) νmax
:
1
1629, 1692, 2895. H NMR (CDCl3, 500 MHz) δH: 1.83 (s,
3H, C4b-CH3), 2.82 (dd, 1H, J = 11, 13 Hz, C10-H), 3.02 (dd,
1H, J = 3, 13 Hz, C10-H), 3.39 (s, 3H, -NCH3), 3.40 (dd, 1H,
J = 3, 11 Hz, C10a-H), 3.51 (s, 3H, -NCH3), 6.83–6.86 (m,
1H, ArH), 7.12 (d, 1H, J = 7 Hz, Ar-H), 7.19 (d, 1H, J =
7 Hz, Ar-H). MS m/z: 350, 352 (M+). Anal. calcd. for
C16H15N2O3SCl (%): C 54.70, H 4.27, N 7.97; found: C
54.92, H 4.46, N 8.21.
Compound 15f
Yield: 38%; white solid, mp 174 °C. IR (KBr, cm–1) νmax
:
1
1632, 1699, 2917. H NMR (CDCl3, 300 MHz) δH: 2.97–
3.01 (m, 2H, =C-CH2), 3.13–3.16 (m, 2H, -SCH2), 3.39 (s,
3H, -NCH3), 3.55 (s, 3H, -NCH3), 7.11–7.39 (m, 3H, ArH),
8.07 (s, 1H, =CH). MS m/z: 384, 386, 388 (M+). Anal. calcd.
for C16H14N2O3SCl2 (%): C 49.87, H 3.64, N 7.27; found: C
50.11, H 3.83, N 7.48.
Compound 11d
Yield: 94%; white solid, mp 216 °C. IR (KBr, cm–1) νmax
:
1
1651, 1702, 2926. H NMR (CDCl3, 300 MHz) δH: 1.76 (s,
3H, C4b-CH3), 2.16 (s, 3H, Ar-CH3), 2.24 (s, 3H, Ar-CH3),
2.76 (dd, 1H, J = 11, 13 Hz, C10-H), 2.99 (dd, 1H, J = 3,
13 Hz, C10a-H), 3.28 (dd, 1H, J = 3, 11 Hz, C10a-H), 3.39 (s,
3H, -NCH3), 3.51 (s, 3H, -NCH3), 6.70 (d, 1H, J = 7 Hz,
ArH), 6.95 (d, 1H, J = 7 Hz, ArH). 13C NMR (CDCl3,
125 MHz) δC: 12.35, 19.93, 25.18, 28.55, 30.29, 32.85,
51.16, 85.79, 108.72, 120.33, 121.07, 122.38, 125.15,
138.71, 151.31, 153.03, 156.46, 160.23. MS m/z: 344 (M+).
Anal. calcd. for C18H20N2O3S (%): C 62.79, H 5.81, N 8.13;
found: C 62.95, H 6.03, N 8.32.
Compound 16c
Yield: 10%; white solid, mp 186 °C. IR (KBr, cm–1) νmax
:
1
1648, 1698, 2927, 3322. H NMR (CDCl3, 300 MHz) δH:
2.06 (s, 3H, =C-CH3), 3.40 (s, 3H, -NCH3), 3.51 (s, 2H,
-SCH2), 3.57 (s, 3H, -NCH3), 5.77 (s, 1H, -OH, D2O ex-
changeable), 6.89–7.12 (m, 3H, ArH). MS m/z: 350, 352
(M+). Anal. calcd. for C16H15N2O3SCl (%): C 54.70, H 4.27,
N 7.97; found: C 54.94, H 4.50, N 8.21.
Compound 16f
Yield: 25%; white solid, mp 208 °C. IR (KBr, cm–1) νmax
:
Compound 11e
1
1640, 1683, 2938, 3444. H NMR (CDCl3, 300 MHz) δH:
2.06 (s, 3H, =C-CH3), 3.40 (s, 3H, -NCH3), 3.48 (s, 2H,
SCH2), 3.57 (s, 3H, -NCH3), 5.76 (s, 1H, -OH, D2O ex-
changeable), 7.10 (d, 1H, J = 2 Hz, ArH), 7.31 (d, 1H, J =
2 Hz, ArH). MS m/z: 384, 386, 388 (M+). Anal. calcd. for
C16H14N2O3SCl2 (%): C 49.87, H 3.64, N 7.27; found: C
50.03, H 3.87, N 7.49.
Yield: 90%; white solid, mp 188 °C. IR (KBr, cm–1) νmax
:
1
1643, 1700, 2923. H NMR (CDCl3, 300 MHz) δH: 1.71 (s,
3H, C4b-CH3), 2.27 (s, 3H, Ar-CH3), 2.31 (s, 3H, Ar-CH3),
2.63 (dd, 1H, J = 11, 13 Hz, C10-H), 2.96 (dd, 1H, J = 3,
13 Hz, C10-H), 3.21 (dd, 1H, J = 3, 11 Hz, C10a-H), 3.40 (s,
3H, -NCH3), 3.53 (s, 3H, -NCH3), 6.54 (s, 1H, Ar-H), 6.61
(s, 1H, Ar-H). MS m/z: 344 (M+). Anal. calcd. for
C18H20N2O3S (%): C 62.79, H 5.81, N 8.13; found: C 63.00,
H 5.98, N 8.33.
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General procedure for the preparation of 15a, 15b, 15f,
16c, and 16f
Compounds 4a–4c and 4f (100 mg, 0.28 mmol) were
refluxed in dichlorobenzene (10 mL) in the presence of N,N-
diethylaniline (2 mL) for 8 h. The reaction mixture was then
cooled and directly subjected to column chromatography
over silica gel. Dichlorobenzene along with N,N-
diethylaniline was eluted out with petroleum ether. On
eluting the column with petroleum ether – ethyl acetate
(4:1), compounds 15a, 15b, 15f, 16c, and 16f were obtained.
All compounds were solid and were recrystalized from di-
chloromethane – petroleum ether.
Compound 15a
Yield: 40%; white solid, mp 148 °C. IR (KBr, cm–1) νmax
:
1
1647, 1707, 2932. H NMR (CDCl3, 500 MHz) δH: 2.93–
2.96 (m, 2H, =C-CH2), 3.11–3.13 (m, 2H, -SCH2), 3.39 (s,
3H, -NCH3), 3.55 (s, 3H, -NCH3), 3.78 (s, 3H, -OCH3),
6.83–7.25 (m, 4H, ArH), 8.02 (s, 1H, =CH). MS m/z: 346
© 2006 NRC Canada

Majumdar and Chattopadhyay
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