Regioselective synthesis of pyrone-annulated sulfur heterocycles by aryl radical cyclization

Article abstract of DOI:10.1055/s-2006-942499

The tri-n-butyltin hydride mediated cyclization of a number of 4-(2′-bromophenoxymethyl)-7-methylthiopyrano[3,2-c]pyran-5-ones have been carried out to afford tetracyclic [6,6]pyranothiopyrans in 70-80% yield and good to excellent diastereoselectivity. Th

Full text of DOI:10.1055/s-2006-942499

PAPER
2725
Regioselective Synthesis of Pyrone-Annulated Sulfur Heterocycles by
Aryl Radical Cyclization
R
egioselective Syn
.
thesis of Pyr
C
one-Annulated S
.
ulfur
H
eter
o
M
cycles ajumdar,* S. Muhuri
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
Received 2 November 2005; revised 18 April 2006
thiopyrans by tributyltin hydride mediated radical cy-
clization.
Abstract: The tri-n-butyltin hydride mediated cyclization of a
number of 4-(2¢-bromophenoxymethyl)-7-methylthiopyrano[3,2-
c]pyran-5-ones have been carried out to afford tetracyclic [6,6]pyr-
anothiopyrans in 70–80% yield and good to excellent diastereose-
lectivity. The substrate ethers were obtained by a thio-Claisen
rearrangement of the corresponding 4-(4¢-aryloxybut-2¢-ynyl)-6-
methyl pyran-2-ones. The cis stereochemistry of the predominant
diastereomer has been corroborated by single crystal X-ray analy-
sis.
The starting materials for our study, 4-aryloxymethyl-7-
methylthiopyrano[3,2-c]pyran-5-ones 6a–f were synthe-
sized by the thermal rearrangement of 4-(4¢-aryloxybut-
2¢-ynylthio)-6-methyl-pyran-2-ones 5a–f in 75–85%
yields.5 The compounds 5a–f, in turn, were prepared by
the treatment of 4-marcapto-6-methylpyran-2-one 3 with
1-aryloxy-4-chlorobut-2-ynes 4a–f at room temperature
under phase-transfer catalysis conditions using benzyltri-
ethylammonium chloride (BTEAC). Compound 3 in turn
was synthesized by the reaction of 6-methyl-4-tosyloxy-
pyran-2-one 2 with NaSH in anhydrous ethanol at room
temperature under nitrogen atmosphere (Scheme 1).
Keywords: 4-mercapto-6-methyl pyran-2-one, tri-n-butyltin hy-
dride, 6-endo cyclization, azobisisobutyronitrile, thio-Claisen rear-
rangement
Aryl radical cyclization has recently emerged as a valu-
able tool for organic synthesis,1 mainly for the construc-
tion of carbo- and heterocyclic compounds, including
natural products. There has been continuing and increas-
ing interest in recent years in the synthesis of pyran-2-one
derivatives due to their diverse pharmacological proper-
ties.2 Compounds of these ring system are widely present
in naturally occurring physiologically active substances in
the form of isolated and fused ring systems.3 In the course
of our studies on the application of sigmatropic
rearrangements4 for the synthesis of heterocyclic com-
pounds we recently noted the formation of furanothiopy-
rans from the substrate containing 4-thiopyran-2-one5
moieties in the second Claisen rearrangement step.
Though several [6,6]pyranothiopyran6a and pyrano-
pyran6b ring systems were synthesized using sequential
Claisen rearrangements we became interested to investi-
gate whether the synthesis of [6,6]pyranothiopyran ring
system could be achieved by tributyl tin hydride mediated
aryl radical cyclization. The generation and subsequent
reaction of radicals formed from aryl halides using tribu-
tyl tin hydride and azobisisobutyronitrile (AIBN) are now
well established and the syntheses of a wide range of nat-
ural products based on aryl radical cyclization have been
reported.7 Aryl radical cyclization normally gives a high
5-exo:6-endo ratio indicating a stronger preference for exo
cyclization compare to alkyl radical cyclization.8 Howev-
er this preference is found to be reversed in cyclizations
involving stabilized radicals. Herein, we have explored
this possibility to synthesize a number of [6,6]pyrano-
SH
OTS
OH
(ii)
(i)
O
O
O
+
O
O
O
2
3
1
OAr
Cl
S
S
(iii)
(iv)
3
O
O
O
OAr
O
OAr
4
5
6
Ar
Yield (%)
6a
80
82
2-BrC6H4
b
c
2-Br-3-MeC6H3
2-Br-4-OMeC6H3
75
85
75
80
d
e
f
1-Br-2-C10H6
2-Br-4-MeC6H3
2-Br-4,6-Me2C6H2
Scheme 1 Reagent and conditions: (i) TSCl, Py, r.t.; (ii) NaSH,
anhyd EtOH, r.t., 2 h, N2 atm; (iii) CHCl3–H2O, 10% NaOH, r.t., 4 h;
(iv) o-chlorobenzene, reflux, 5 h.
Substrate 6a was refluxed in benzene with tributyltin(IV)
hydride in the presence of AIBN for 4 hours to give com-
pound 7a in 75% yield (Scheme 2), which was character-
ized from its elemental analysis and spectroscopic data.
The IR spectrum of the compound 7a showed a peak at
1
1685 cm–1 for carbonyl group. The high field H NMR
(300 MHz) spectrum of the product 7a displayed a typical
one proton double doublet at d = 2.99 (SCH2), one proton
double triplet at d = 3.11 (ring juncture proton), one pro-
ton triplet at d = 3.18 (SCH2), one proton double triplet at
d = 3.51 (ring juncture proton), one proton triplet at d =
SYNTHESIS 2006, No. 16, pp 2725–2730
x
x.
x
x
.
2
0
0
6
Advanced online publication: 19.07.2006
DOI: 10.1055/s-2006-942499; Art ID: Z21205SS
© Georg Thieme Verlag Stuttgart · New York

2726
K. C. Majumdar, S. Muhuri
PAPER
3.72 (OCH2) and one proton double doublet at d = 4.55 der similar reaction conditions resulted in a diastereomer-
(OCH2). The mass spectrum of compound 7a also dis- ic mixture of the cyclized product 7e and 7f in 75% and
played a molecular ion peak at m/z = 286 [M+]. Encour- 70% yield, respectively. Both the products were isolated
aged by this result, other substrates 6b–f were also treated as diastereomeric mixture, in the ratios 3:1 and 2.3:1, re-
similarly to give tetracyclic heterocycles 7b–f in 70–80% spectively, which were not separable on column chroma-
yield.
tography. It has already been established11 that very high
level of diastereoselectivity (> 50:1) could be obtained
when the concentration of the reactant is reduced from 0.1
to 0.01 M. These observations have been attributed to the
reversibility of the cyclization and decreased availability
of the Bu3SnH. However the cyclization of 6e under very
dilute conditions also gave the cyclized product 7e in sim-
ilar yield (70%) and a diastereoselectivity of 3:1. There-
fore the reason behind the reduced diastereoselectivity in
the cases of 7e and 7f over the others is not clear, though
it is perhaps controlled by the abstraction of hydrogen by
radical intermediate 10.
S
S
R1
H
(i)
R2
O
O
O
R1
Br
H
O
R2
O
O
R3
7
6
R3
R1 R2 R3
R1 R2 R3
Yield (%)
80
Yield (%)
7a
b
a
75
78
75
H
H
H
H
H
H
7d
H
H
-C6H4
H
-
Me
H
(3:1)b
(2.3:1)b
As we were not able to separate and purify the diastereo-
meric mixture by column chromatography, we tried to pu-
rify the crude mixture by repeated recrystallization. After
several recrystallizations of the crude mixture of 7e we
were finally able to get a single crystal, the X-ray crystal-
lographic analysis of which showed cis stereochemistry at
the ring juncture (Figure 1).
e
Me
75
c
OMe
H
Me Me
f
70
a Benzo
b Diastereomer ratio determined from the 1H NMR spectrum.
Scheme 2 Reagent and conditions: (i) Bu3SnH, AIBN, anhyd ben-
zene, N2 atm, reflux, 4–5 h.
The formation of products 7a–f from 6a–f may be ex-
plained by the generation of an aryl radical 8 which may
give the intermediate radical 10 by a direct ‘6-endo’ cy-
clization (Scheme 3). An alternative route via a ‘5-exo’
cyclization of radical 8 to the spiroheterocyclic radical9 9
(not isolated) followed by a neophyl rearrangement10 to
radical intermediate 10 may also be considered. Abstrac-
tion of hydrogen from Bu3SnH by radical intermediate 10
could have occurred from either side of the radical center,
giving rise to a diastereomeric mixture (in the cases of 7e,
7f from 6e and 6f, respectively).
Figure 1 ORTEP diagram of compound 7e.
It was observed that when the substrates 6a–d were treat-
ed with AIBN and Bu3SnH in refluxing benzene, cycliza-
tion proceeded with 100% diastereoselectivity leading to
one diastereoisomer; 7a–d was formed in 75–80% yield in
each case. However, treatment of substrates 6e and 6f un-
It is known that radical cyclization leading to six-mem-
bered rings are usually less general than cyclization lead-
ing to five-membered rings. However, suitably
substituted 5-hexenyl radicals are known to undergo 6-
S
S
O
O
R1
R1
Br
.
O
O
R2
R2
O
O
8
6
R3
5-exo
R3
6-endo
S
S
S
R1
R1
R1
H
.
O
R2
O
R2
.
R2
O
H
O
O
O
O
O
O
R3
9
R3
10
R3
7
Scheme 3
Synthesis 2006, No. 16, 2725–2730 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of Pyrone-Annulated Sulfur Heterocycles
2727
endo cyclization to give six-membered rings. It is interest-
ing to note that six-membered rings are formed regiose-
lectively in all the cases we have studied so far. Therefore,
this is another instance where the less-common 6-endo
radical cyclization is preferred over 5-exo radical cycliza-
tion.
Table 1 Crystallographic Data for Compound 7e
Parameters
Empirical formula
Formula weight
Crystal system
Space group
a (Å)
C17H16O3S
300.36
In conclusion, we have developed an attractive and simple
strategy using intramolecular aryl radical cyclization for
the efficient and regioselective synthesis of [6,6]pyrano-
thiopyran ring system with good to excellent diastereo-
selectivity, in contrast to the furanothiopyran ring system
by sequential Claisen rearrangements in our earlier work.5
Monoclinic
P21/c
8.2785(7)
10.7418(9)
16.3304(14)
b (Å)
c (Å)
Melting points were determined in an open capillary and are uncor-
rected. IR spectra were recorded on a Perkin–Elmer L120-000A
spectrometer (nmax in cm–1) on KBr disks. UV absorption spectra
were recorded in EtOH on a Shimadzu UV-2401PC spectrophotom-
a (°)
b (°)
101.008(2)
eter (lmax in nm). 1H NMR (300 MHz, 400 MHz, 500 MHz) and 13
C
g (°)
NMR (125 MHz) spectra were recorded on Bruker DPX-300, Vari-
an-400 MHz FT NMR and Bruker DPX-500 spectrometers in
CDCl3 (chemical shift in d) with TMS as internal standard. Elemen-
tal analyses and mass spectra were recorded on a Leco 932 CHNS
analyzer and on a JEOL JMS-600 instrument, respectively. 1H
NMR and 13C NMR spectra were recorded at the Indian Institute of
Chemical Biology, Kolkata and Bose Institute, Kolkata. Single-
crystal X-ray analysis of compound 7e was carried out at the De-
partment of Chemistry of the Indian Institute of Technology, Kan-
pur. Silica gel [(60–120 mesh), Spectrochem, India] was used for
chromatographic separation. Silica gel G (E-Merck, India) was used
for TLC analyses. Petroleum ether (PE) refers to the fraction boiling
between 60 °C and 80 °C.
V (Å3)
1425.5(2)
4
Z
r
calcd (g cm–3)
1.400
0.234
632
m (mm–1)
F(000)
Reflections
Collected
9313
3510
2793
Independent
Observed
Single-crystal X-ray studies were performed on a Bruker APEX
CCD diffractometer equipped with an Oxford Instruments low-tem-
perature attachment. Data were collected using monochromated
Mo-Ka radiation (la = 0.71069 Å). The frames were integrated in
the Bruker SAINT software package,12 and the data were corrected
for absorption using the SADABS program.13 The structure were
solved and refined with SHELX suite of programs.14 ORTEP-III
was used to produce the diagrams.15
An off-white crystal of dimensions 0.30 × 0.20 × 0.20 mm3 was
mounted on the tip of a glass fiber with silicone grease and placed
in a cold stream of nitrogen at 100 K. The cell constants and orien-
tation matrix for data collection corresponded to a monoclinic cell.
A total of 3510 unique reflections were collected to a maximum 2q
value of 56°. During the refinement of the structure it was evident
that three of the bridgehead carbon atoms, namely C7, C8 and C10
were disordered. Each of the atoms was modeled over two positions
and the final refinement resulted in site occupancies of 80 and 20
percentages. All the non-hydrogen atoms were refined anisotropi-
cally except the disordered atoms C7, C8 and C10. Hydrogen atoms
of the ligands were included in the final stages of the refinement as
riding atoms with values of Ueq that were 1.2 times the Ueq for the
heavy atoms to which they are bonded. Pertinent crystallographic
data for compound 7e are summarized in Table 1.
[I > 2s(I)]
No. of variables
Goodness-of-fit
Final R indices
176
1.049
R1 = 0.0597
wR2 = 0.1420
H2O (2 × 20 mL) and dried over Na2SO4. Evaporation of CHCl3 left
a gummy residue that was subjected to column chromatography.
Elution of the column with PE–EtOAc (9:1) afforded compounds
5a–f.
5a
Yield: 75%; solid; mp 100 °C.
IR (KBr): 1725, 1630, 1480, 1280 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.20 (s, 3 H), 3.65 (t, J = 1.9 Hz,
2 H, SCH2), 4.71 (t, J = 1.85 Hz, 2 H, OCH2), 5.82 (s, 1 H), 5.91 (s,
1 H), 6.78–6.82 (m, 1 H), 6.93 (dd, J = 1.2, 8.2 Hz, 1 H), 7.19–7.24
(m, 1 H), 7.73 (dd, J = 1.5, 8.8 Hz, 1 H).
Synthesis of 4-(4¢-Aryloxybut-2¢-ynylthio)-6-methyl-2H-pyran-
2-ones (5a–f)5
To a mixture of 4-mercapto-6-methylpyran-2-one (3; obtained from
2.8 g, 10 mmol of 2) and 1-aryloxy-4-chlorobut-2-ynes 4 (10 mmol)
in CHCl3 (50 mL) was added a solution of benzyl triethyl ammoni-
um chloride (BTEAC, 0.5 g, 1.8 mmol) in 1% aq NaOH (50 mL)
and the mixture was magnetically stirred at r.t. for 4 h. The reaction
mixture was then diluted with H2O (25 mL). The CHCl3 layer was
taken out and washed with 2 N HCl (1 × 20 mL), brine (1 × 20 mL),
MS: m/z = 364, 366 [M+].
UV (EtOH): lmax = 204, 270, 292 nm.
Anal. Calcd for C16H13O3SBr: C, 52.60; H, 3.56. Found: C, 52.85;
H, 3.79.
Synthesis 2006, No. 16, 2725–2730 © Thieme Stuttgart · New York

2728
5b
K. C. Majumdar, S. Muhuri
PAPER
Synthesis of 4-(2¢-Bromophenoxymethyl)-7-methylthiopyra-
Yield: 72%; solid; mp 90 °C.
no[3,2-c]pyran-5-ones (6a–f);5 General Procedure
Compounds 5a–f (500 mg) were refluxed in chlorobenzene (7 mL)
for 5 h. The reaction mixture was then cooled and directly subjected
to column chromatography over silica gel. Chlorobenzene was elut-
ed out with PE. Compounds 6a–f were obtained when the column
was eluted with PE–EtOAc (12:1).
IR (KBr): 1732, 1635, 1488 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.21 (s, 3 H), 2.23 (s, 1 H), 3.65
(t, J = 2.0 Hz, 2 H, SCH2), 4.72 (t, J = 2.0 Hz, 2 H, OCH2), 5.83 (s,
1 H), 5.91 (s, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 7.46 (d, J = 8.8 Hz, 1
H), 7.73 (s, 1 H).
MS: m/z = 378, 380 [M+].
6a
Yield: 80%; solid; mp 110 °C.
IR (KBr): 1696, 1630, 1504, 1480 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.22 (s, 3 H), 3.37 (d, J = 6.00 Hz,
2 H, SCH2), 5.11 (d, J = 1.60 Hz, 2 H, OCH2), 6.01 (s, 1 H), 6.14 (tt,
J = 1.60, 6.00 Hz, 1 H), 6.78–6.82 (m, 1 H), 6.93 (dd, J = 1.20, 8.40
Hz, 1 H), 7.20–7.23 (m, 1 H), 7.48 (dd, J = 1.40, 8.00 Hz, 1 H).
UV (EtOH): lmax = 203, 272, 300 nm.
Anal. Calcd for C17H15O3SBr: C, 53.82; H, 3.95. Found: C, 53.97;
H, 3.87.
5c
Yield: 70%; solid; mp 80 °C.
IR (KBr): 1718, 1637, 1488, 1279 cm–1.
MS: m/z = 364, 366 [M+].
1H NMR (500 MHz, CDCl3): d = 2.20 (s, 3 H), 3.66 (t, J = 1.9 Hz,
2 H, SCH2), 3.77 (s, 3 H), 4.71 (t, J = 1.9 Hz, 2 H, OCH2), 5.82 (s,
1 H), 5.91 (s, 1 H), 6.80 (dd, J = 2.9, 8.9 Hz, 1 H), 6.94 (d, J = 8.9
Hz, 1 H), 7.10 (d, J = 2.9 Hz, 1 H).
UV (EtOH): lmax = 203, 247, 302, 365 nm.
Anal. Calcd for C16H13O3SBr: C, 52.6; H, 3.56. Found: C, 52.87; H,
3.73.
MS: m/z = 394, 396 [M+].
6b
Yield: 82%; solid; mp 140 °C.
IR (KBr): 1692, 1626, 1503, 1287 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.21 (s, 3 H), 2.23 (s, 3 H), 3.42
(d, J = 5.85 Hz, 2 H, SCH2), 5.02 (d, J = 1.36 Hz, 2 H, OCH2), 6.01
(s, 1 H), 6.25 (tt, J = 1.36, 5.85 Hz, 1 H), 6.69 (d, J = 8.80 Hz, 1 H),
7.41 (d, J = 8.80 Hz, 1 H), 7.72 (s, 1 H).
UV (EtOH): lmax = 204, 272, 292 nm.
Anal. Calcd for C17H15O4SBr: C, 51.64; H, 3.79. Found: C, 51.45;
H, 3.86.
5d
Yield: 75%; solid; mp 130 °C.
IR (KBr): 1708, 1635, 1528, 1274 cm–1.
MS: m/z = 378, 380 [M+].
1H NMR (500 MHz. CDCl3): d = 2.14 (s, 3 H), 3.65 (t, J = 2.0 Hz,
2 H, SCH2), 4.91 (t, J = 2.0 Hz, 2 H, OCH2), 5.76 (s, 1 H), 5.91 (s,
1 H), 7.31 (d, J = 9.0 Hz, 1 H), 7.41–7.44 (m, 1 H), 7.58 (m, 1 H),
7.79–7.82 (m, 1 H), 8.21 (d, J = 9.0 Hz, 1 H).
UV (EtOH): lmax = 206, 247, 293, 359 nm.
Anal. Calcd for C17H15O3SBr: C, 53.82; H, 3.95. Found: C, 53.96;
H, 4.12.
MS: m/z = 414, 416 [M+].
6c
Yield: 75%; solid; mp 110 °C.
IR (KBr): 1709, 1694, 1628, 1492, 1274 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.23 (s, 3 H), 3.37 (d, J = 6.00 Hz,
2 H, SCH2), 3.75 (s, 3 H), 5.05 (d, J = 1.60 Hz, 2 H, OCH2), 6.02 (s,
1 H), 6.10 (tt, J = 1.60, 6.00 Hz, 1 H), 6.77 (dd, J = 2.40, 9.20 Hz, 1
H), 6.89 (d, J = 9.20 Hz, 1 H), 7.09 (d, J = 2.40 Hz, 1 H).
UV (EtOH): lmax = 230, 271, 295, 378 nm.
Anal. Calcd for C20H15O3SBr: C, 57.83; H, 3.61. Found: C, 57.98;
H, 3.76.
5e
Yield: 70%; solid; mp 100 °C.
IR (KBr): 1734, 1634, 1539, 1488 cm–1.
MS: m/z = 394, 396 [M+].
1H NMR (500 MHz, CDCl3): d = 2.22 (s, 3 H), 2.28 (s, 3 H), 3.66
(t, J = 1.8 Hz, 2 H, SCH2), 4.74 (t, J = 1.8 Hz, 2 H, OCH2), 5.83 (s,
1 H), 5.92 (s, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 7.04 (dd, J = 1.5, 8.0
Hz, 1 H), 7.35 (d, J = 1.5 Hz, 1 H).
UV (EtOH): lmax = 206, 222, 247, 299 nm.
Anal. Calcd for C17H15O4SBr: C, 51.64; H, 3.79. Found: C, 51.89;
H, 3.65.
MS: m/z = 378, 380 [M+].
6d
Yield: 85%; solid; mp 110 °C.
IR (KBr): 1697, 1636, 1625, 1500 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.23 (s, 3 H), 3.38 (d, J = 4.80 Hz,
2 H, SCH2), 5.28 (d, J = 1.60 Hz, 2 H, OCH2), 6.02 (s, 1 H), 6.15 (tt,
J = 1.60, 4.80 Hz, 1 H), 7.28–7.38 (m, 2 H), 7.51–7.55 (m, 1 H),
7.73–7.79 (m, 2 H), 8.17–8.19 (m, 1 H).
UV (EtOH): lmax = 204, 220, 272, 300 nm.
Anal. Calcd for C17H15O3SBr: C, 53.82; H, 3.95. Found: C, 53.97;
H, 4.12.
5f
Yield: 72%; solid; mp 80 °C.
IR (KBr): 1730, 1632, 1540, 1488 cm–1.
MS: m/z = 414, 416 [M+].
1H NMR (500 MHz, CDCl3): d = 2.21 (s, 3 H), 2.24 (s, 3 H), 2.30
(s, 3 H), 3.66 (t, J = 1.9 Hz, 2 H, SCH2), 4.66 (t, J = 1.9 Hz, 2 H,
OCH2), 5.84 (s, 1 H), 5.91 (s, 1 H), 6.89 (s, 1 H), 7.17 (s, 1 H).
UV (EtOH): lmax = 203, 247, 302, 365 nm.
Anal. Calcd for C20H15O3SBr: C, 57.83; H, 3.61. Found: C, 57.97;
H, 3.86.
MS: m/z = 392, 394 [M+].
6e
UV (EtOH): lmax = 202, 271, 294 nm.
Yield: 75%; solid; mp 120 °C.
Anal. Calcd for C18H17O3SBr: C, 54.96; H, 4.32. Found: C, 55.03;
H, 4.51.
IR (KBr): 1690, 1626, 1500, 1285 cm–1.
Synthesis 2006, No. 16, 2725–2730 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of Pyrone-Annulated Sulfur Heterocycles
2729
1H NMR (500 MHz, CDCl3): d = 2.23 (s, 3 H), 2.26 (s, 3 H), 3.38
(d, J = 5.89 Hz, 2 H, SCH2), 5.09 (d, J = 1.31 Hz, 2 H, OCH2), 6.02
(s, 1 H), 6.14 (tt, J = 1.31, 5.89 Hz, 1 H), 6.84 (d, J = 8.30 Hz, 1 H),
7.01 (dd, J = 1.33, 8.30 Hz, 1 H), 7.34 (d, J = 1.33 Hz, 1 H).
7c
Yield: 75%; solid; mp 158 °C.
IR (KBr): 1685, 1637, 1497 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.19 (s, 3 H), 3.00 (dd, J = 2.5,
13.1 Hz, 1 H), 3.06 (dt, J = 3.5, 12.4 Hz, 1 H), 3.19 (t, J = 12.4 Hz,
1 H), 3.48 (dt, J = 4.1, 10.8 Hz, 1 H), 3.69 (t, J = 10.8 Hz, 1 H), 3.76
(s, 3 H), 4.51 (dd, J = 2.5, 9.8 Hz, 1 H), 5.82 (s, 1 H), 6.66 (d, J =
2.7 Hz, 1 H), 6.74–6.82 (m, 2 H).
MS: m/z = 378, 380 [M+].
UV (EtOH): lmax = 206, 247, 302, 367 nm.
Anal. Calcd for C17H15O3SBr: C, 53.82; H, 3.95. Found: C, 53.94;
H, 3.82.
MS: m/z = 316 [M+].
6f
UV (EtOH): lmax = 205, 228, 277, 306, 362 nm.
Yield: 80%; solid; mp 130 °C.
IR (KBr): 1690, 1627, 1500, 1275 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.22 (s, 3 H), 2.25 (s, 3 H), 2.27
(s, 3 H), 3.41 (d, J = 5.60 Hz, 2 H, SCH2), 4.90 (d, J = 1.60 Hz, 2 H,
OCH2), 6.01 (s, 1 H), 6.22 (tt, J = 1.60, 5.60 Hz, 1 H), 6.89 (s, 1 H),
7.17 (s, 1 H).
Anal. Calcd for C17H16O4S: C, 64.55; H, 5.06. Found: C, 64.74; H,
5.21.
7d
Yield: 80%; solid; mp 220 °C.
IR (KBr): 1681, 1644, 1542 cm–1.
MS: m/z = 392, 394 [M+].
1H NMR (500 MHz, CDCl3): d = 2.22 (s, 3 H), 3.24 (t, J = 11.8 Hz,
1 H), 3.35 (dd, J = 2.4, 13.7 Hz, 1 H), 3.62 (dt, J = 4.1, 11.0 Hz, 1
H), 3.72 (dt, J = 3.6, 11.8 Hz, 1 H), 3.94 (t, J = 11.0 Hz, 1 H), 4.68
(dd, J = 3.1, 10.8 Hz, 1 H), 5.88 (s, 1 H), 7.06 (d, J = 9.1 Hz, 1 H),
7.36 (t, J = 7.4 Hz, 1 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.79–7.81 (m, 2
H).
13C NMR (125 MHz, CDCl3): d = 19.9, 29.04, 30.1, 30.85, 64.6,
104.39, 110.89, 113.95, 119.52, 121.14, 123.81, 127.49, 129.54,
129.76, 129.87, 132.41, 152.3, 152.78, 158.61, 161.57.
UV (EtOH): lmax = 206, 247, 302, 362 nm.
Anal. Calcd for C18H17O3SBr: C, 54.96; H, 4.32. Found: C, 54.76;
H, 4.53.
Synthesis of Benzopyrano[4,3-c]-6a,12a-dihydro-3-methylthio-
pyranopyran-1-ones (7a–f); General Procedure
To a solution of 6a–f (0.4 mmol) in degassed benzene (8–10 mL)
under a nitrogen atmosphere were added Bu3SnH (0.9–1.20 mmol)
and AIBN (cat) in degassed benzene (0.5–1.0 mL). The mixture was
refluxed under nitrogen and the reaction was monitored by TLC (2–
3 h). The solvent was removed and the residue was then magnetical-
ly stirred with a sat. solution of KF for 24 h. It was then extracted
with CH2Cl2 (2 × 10 mL), washed several times with H2O and dried
(Na2SO4). The residue was purified by flash column chromatogra-
phy (silica) with PE–EtOAc (9:1) to afford 7a–d as single diastereo-
isomer in 75–80% yield and 7e, 7f as an inseparable mixture of
diastereoisomers in 75% and 70% yields, respectively.
MS: m/z = 336 [M+].
UV (EtOH): lmax = 233, 276, 289, 319 nm.
Anal. Calcd for C20H16O3S: C, 71.42; H, 4.76. Found: C, 71.63; H,
4.84.
7e
Yield: 75%; solid; mp 170 °C.
IR (KBr): 1689, 1639, 1498, 1246 cm–1.
7a
Major Diastereoisomer
Yield: 75%; solid; mp 180 °C.
IR (KBr): 1685, 1638, 1543, 1489 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.20 (s, 3 H), 2.99 (dd, J = 2.2,
12.1 Hz, 1 H), 3.11 (dt, J = 3.4, 11.9 Hz, 1 H), 3.18 (t, J = 11.9 Hz,
1 H), 3.51 (dt, J = 4.1, 11.1 Hz, 1 H), 3.72 (t, J = 11.1 Hz, 1 H), 4.55
(dd, J = 2.7, 10.4 Hz, 1 H), 5.82 (s, 1 H), 6.85–6.94 (m, 2 H), 7.13–
7.20 (m, 2 H).
1H NMR (500 MHz, CDCl3): d = 2.19 (s, 3 H), 2.27 (s, 3 H), 2.99
(dd, J = 2.5, 13.1 Hz, 1 H), 3.05 (dt, J = 3.4, 10.8 Hz, 1 H), 3.17 (t,
J = 12.1 Hz, 1 H), 3.48 (dt, J = 3.9, 12.0 Hz, 1 H), 3.70 (t, J = 10.9
Hz, 1 H), 4.52 (dd, J = 3.1, 10.7 Hz, 1 H), 5.82 (s, 1 H), 6.75 (d, J =
8.2 Hz, 1 H), 6.94 (s, 1 H), 6.96 (d, J = 8.2 Hz, 1 H).
MS: m/z = 300 [M+].
UV (EtOH): lmax = 204, 226, 277, 310 nm.
MS: m/z = 286 [M+].
Anal. Calcd for C17H16O3S: C, 67.98; H, 5.37. Found: C, 68.15; H,
5.23.
UV (EtOH): lmax = 204, 225, 308 nm.
Anal. Calcd for C16H14O3S: C, 67.13; H, 4.89. Found: C, 67.34; H,
5.01.
Minor Diastereoisomer
This diastereoisomer was observed by 1H NMR spectroscopy.
1H NMR (500 MHz, CDCl3): d = 2.18 (s, 3 H), 2.27 (s, 3 H), 2.91–
2.96 (m, 2 H), 3.24–3.27 (m, 1 H), 3.77 (t, J = 10.6 Hz, 1 H), 5.66
(dd, J = 3.4, 10.5 Hz, 1 H), 6.78 (d, J = 8.8 Hz, 1 H).
7b
Yield: 78%; solid; mp 160 °C.
IR (KBr): 1684, 1638, 1542 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.20 (s, 3 H), 2.33 (s, 3 H), 2.97
(dd, J = 3.3, 12.5 Hz, 1 H), 3.12 (t, J = 11.9 Hz, 1 H), 3.18 (dt, J =
3.8, 11.9 Hz, 1 H), 3.47 (dt, J = 4.1, 11.1 Hz, 1 H), 3.81 (t, J = 11.1
Hz, 1 H), 4.52 (dd, J = 3.3, 10.8 Hz, 1 H), 5.83 (s, 1 H), 6.71 (d, J =
8.0 Hz, 1 H), 6.76 (d, J = 7.3 Hz, 1 H), 7.08 (t, J = 7.8 Hz, 1 H).
7f
Yield: 70%; solid; mp 145 °C.
IR (KBr): 1691, 1637, 1538, 1486 cm–1.
Major Diastereoisomer
MS: m/z = 300 [M+].
1H NMR (500 MHz, CDCl3): d = 2.15 (s, 3 H), 2.19 (s, 3 H), 2.25
(s, 3 H), 2.99 (dd, J = 2.4, 13.6 Hz, 1 H), 3.04 (dt, J = 3.3, 12.2 Hz,
1 H), 3.19 (t, J = 12.2 Hz, 1 H), 3.48 (dt, J = 4.1, 10.8 Hz, 1 H), 3.71
(t, J = 10.8 Hz, 1 H), 4.58 (dd, J = 3.3, 10.4 Hz, 1 H), 5.82 (s, 1 H),
6.78–6.87 (m, 2 H).
UV (EtOH): lmax = 205, 226, 302 nm.
Anal. Calcd for C17H16O3S: C, 67.98; H, 5.37. Found: C, 67.89; H,
5.23.
Synthesis 2006, No. 16, 2725–2730 © Thieme Stuttgart · New York

2730
K. C. Majumdar, S. Muhuri
PAPER
MS: m/z = 314 [M+].
(3) (a) Irschik, H.; Gerth, K.; Hofle, G.; Kohl, W.; Reichenbach,
H. J. Antibiotics. 1983, 36, 1651. (b) Prasad, J. V. N.;
Pavolovsky, P.; Para, K. S.; Ellsworth, E. L.; Tummino, P.
J.; Nouhan, C.; Ferguson, D. Bioorg. Med. Chem. Lett. 1996,
6, 1113.
UV (EtOH): lmax = 206, 224, 278, 308 nm.
Anal. Calcd for C18H18O3S: C, 68.78; H, 5.73. Found: C, 68.55; H,
5.86.
(4) (a) Majumdar, K. C.; Chatterjee, P.; Saha, S. Tetrahedron
Lett. 1998, 39, 7147. (b) Majumdar, K. C.; Chatterjee, P.;
Saha, S.; Samanta, S. K. Indian J. Chem., Sect. B.: Org.
Chem. Incl. Med. Chem. 2001, 40, 915.
(5) Majumdar, K. C.; Kundu, U. K.; Ghosh, S. J. Chem. Soc.,
Perkin Trans. 1 2002, 2139.
Minor Diastereoisomer
This diastereoisomer was observed by 1H NMR spectroscopy.
1H NMR (CDCl3, 500 MHz): d = 2.90–2.95 (m, 2 H), 3.77 (t, J =
10.8 Hz, 1 H), 5.70 (d, J = 9.5 Hz, 1 H).
(6) (a) Majumdar, K. C.; Kundu, U. K.; Ghosh, S. K. Org. Lett.
2002, 4, 2629. (b) Majumdar, K. C.; Das, U. J. Org. Chem.
1998, 63, 9997.
Acknowledgment
We thank the CSIR (New Delhi) for financial assistance. We are
thankful to Dr. J. K. Bera of the Indian Institute of Technology,
Kanpur for single crystal X-ray of compound 7e. We also thank the
DST (New Delhi) for providing us UV-VIS and FT-IR instruments
under FIST programme. One of us (S.M.) is grateful to CSIR for a
Senior Research Fellowship.
(7) (a) Shankaran, K.; Solan, C. P.; Snieckus, V. Tetrahedron
Lett. 1985, 26, 6001. (b) Solan, C. P.; Cuevas, J. C.;
Quesnelle, C.; Snieckus, V. Tetrahedron Lett. 1988, 29,
4685. (c) Parker, K. A.; Spero, D. M.; Inman, K. C.
Tetrahedron Lett. 1986, 27, 2833. (d)Jones,K.;Willkinson,
J. A. J. Chem. Soc., Chem. Commun. 1992, 1767.
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O. J. Chem. Soc., Chem. Commun. 2000, 1527. (b)Ponaras,
A. A.; Zaim, O. Tetrahedron Lett. 2000, 41, 2279. (c) Cid,
M. M.; Dominguez, D.; Castedo, L.; Va’zquez-Lopez, E. M.
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Synthesis 2006, No. 16, 2725–2730 © Thieme Stuttgart · New York