Tandem versus single C-C bond forming reaction under palladium-copper catalysis: regioselective synthesis of α-pyrones fused with thiophene

Article abstract of DOI:10.1016/j.tet.2006.07.095

We herein report a highly convenient protocol for rapid construction of α-pyrone fused with thiophene. This includes one-pot and regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]pyran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes in a simple synthetic operation. The coupling-cyclization reaction was initially studied in the presence of Pd(PPh₃)₂Cl₂ and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C-C bond forming reaction in the presence of palladium catalyst rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling-cyclization-coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C-C bond forming reaction however, can be restricted to the formation of single C-C bond by using 10% Pd/C-Et₃N-CuI-PPh₃ as catalyst system in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was performed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.

Full text of DOI:10.1016/j.tet.2006.07.095

Tetrahedron 62 (2006) 9554–9570
Tandem versus single C–C bond forming reaction under
palladium–copper catalysis: regioselective synthesis
of a-pyrones fused with thiophene
*
a,c
Sirisilla Raju, Venkateswara Rao Batchu, Nalivela Kumara Swamy, R. Vasu Dev,
b
b
b
b
b
b
Bukkapattanam R. Sreekanth, J. Moses Babu, K. Vyas, P. Rajender Kumar,
a
c
K. Mukkanti, Pazhanimuthu Annamalai and Manojit Pal
b
b,
*
a
Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India
b
Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India
Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, India
c
Received 11 May 2006; revised 7 July 2006; accepted 27 July 2006
Available online 22 August 2006
Abstract—We herein report a highly convenient protocol for rapid construction of a-pyrone fused with thiophene. This includes one-pot and
regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]py-
ran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid
3 2 2
with terminal alkynes in a simple synthetic operation. The coupling–cyclization reaction was initially studied in the presence of Pd(PPh ) Cl
and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was
performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling
of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C–C bond forming reaction in the presence of palladium catalyst
rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling–cycliza-
tion–coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C–C bond
forming reaction however, can be restricted to the formation of single C–C bond by using 10% Pd/C–Et N–CuI–PPh as catalyst system
3
3
in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was per-
formed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
program, we were in need of a combinatorial library based
on the scaffold of a-pyrone fused with five-membered het-
erocycles (B, Fig. 1). Thelibrary model, as shown in Figure 1,
has three centers for the introduction of diversity into a-py-
rone molecule. While much effort has been devoted toward
the introduction/modification of C-3 and C-4 substituents
1
a
2a
a-Pyrones and their benzo derivatives, e.g., isocoumarins
are of considerable synthetic and pharmacological interest
because of their wide range of activities
fungal, antimicrobial, phytotoxic and other effects. 3-
Substituted isocoumarins in particular have shown promising
pharmacological activities. The angiogenesis inhibitor
NM-3, which belongs to this class is presently undergoing
Phase-I clinical trials. More recently, promising cytotoxic
activities of substituted pyrones especially 4-alkynyl
2
b–d
such as anti-
2
h–j
on the benzo derivative, i.e., isocoumarin ring,
replacing
2
e
the benzene ring by a suitable heterocyclic moiety is not com-
mon in the literature. We envisioned that a-pyrone fused with
a five- or six-membered heterocycle might lead to a novel
class of compounds useful for the Structure–Activity Rela-
tionship (SAR) studies. The thiophene moiety is common
2
f
2
g
substituted 2-pyrones (A, Fig. 1) have been reported. In
continuation of our research under the new drug discovery
3
a
inmanybioactiveagentsanddrugs andisconsideredasabi-
3
a
oisostere of the benzene ring. (The distance between two
neighboring carbon atoms in benzene is roughly equivalent
to the diameter of the sulfur atom in thiophene and the latter
often displays pharmacological properties similar to those of
*
DRL publication no. 522.
Keywords:
6
a-Pyrone;
,7-Disubstituted thieno[3,2-c]pyran-4-ones; Palladium catalyst; Terminal
4,5-Disubstituted
thieno[2,3-c]pyran-7-one;
alkynes; 3-Iodothiophene-2-carboxylic acid; 2-Bromothiophene-3-carbox-
ylic acid.
Corresponding author. Tel.: +91 40 23045439; fax: +91 40 23045438/
3045007; e-mail: manojitpal@drreddys.com
3b
benzene. ) On the other hand pyrazole fused with pyran and
benzopyran rings has shown affinity and selectivity toward
*
3
c,d
2
A adenosine receptor.
1
Thus, one can anticipate that
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.095

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9555
Various
substituents
R'
R'
O
1
7
3
4
6 R
5
5
R
S
3
R
4
2
2
or
O
O
O
S
1
2
3
4
O
O
1
O
Diverse
aromatic
group
O
R = alkyl, aryl; R’ = H, alkynyl.
A
B
Figure 1. Design of a-pyrones fused with 5-membered heterocycles derived from diversity based isocoumarin scaffold.
replacing the benzene ring of isocoumarin by a five-
membered ring such as thiophene would afford compounds
I
R
R
O
Pd/C-PPh -CuI
3
(
i.e., thienopyranones, Fig. 1) of potential pharmacological
CO2H
3
e,f
O
interest. Additionally, thiophene derivatives are excellent
synthetic intermediates because of the unique electronic
properties of sulfur as well as the steric constraints of
a five-membered ring. However, as a class of compounds
the thienopyranones are rather unusual. Only a few number
of thieno[2,3-c]pyran-4-ones were synthesized and evalu-
R = alkyl, aryl, hydroxyalkyl
Figure 2. Pd/C-mediated synthesis of 3-substituted isocoumarins.
3
g
transformation is particularly interesting, because apart
from providing an easy access to thieno[2,3-c]pyran-7-one
ring it affords novel conjugated enynes that could be utilized
further as precursors to construct even more complex
molecules. Only four examples of analogue 3-substituted
3
h
ated for their antileishmanial and antifungal activities.
Based on above considerations and our continuing interest in
the synthesis of oxygen containing heterocycles we decided
to synthesize pyranones fused with thiophene. A thorough
literature search revealed that methodologies devised for
the elaboration of this framework are generally limited and
4
-alkynyl isocoumarins have been reported during Pd–Zn
mediated synthesis of 3-substituted isocoumarins where
these derivatives were isolated as minor products in 3–5%
yield. Alternatively, 4-alkynyl isocoumarins/coumarins
have been prepared via multistep synthesis that usually in-
volves ring construction followed by Sonogashira coupling.
Being arguably the most versatile transition metal for cataly-
sis palladium features prominently in a number of tandem
transformations and we have recently shown that terminal
7a
4
a–e
not investigated extensively. Moreover, synthesis of
thieno[2,3-c]pyran-7-ones/thieno[3,2-c]pyran-4-ones (and
their 4-/7-alkynyl analogues) has not been reported thus
8
5
a
far. Therefore, to synthesize a library of isocoumarins for
biological screening we became interested in the synthesis
of pyranones fused with five-membered heterocycles.
9
5
b
alkynes participate in tandem coupling reactions depending
9
g
on the reaction condition employed. Herein, we report
further study on our previously communicated one-step syn-
thesis of 5-substituted 4-alkynylthieno[2,3-c]pyran-7-ones
along with the synthesis of isomeric 6-substituted-7-alky-
nylthieno[3,2-c]pyran-4-ones under palladium catalysis.
Additionally, we report detailed study on Pd/C-mediated
synthesis of 6-substituted thieno[3,2-c]pyran-4-ones and 5-
substituted thieno[2,3-c]pyran-7-ones where no significant
formation of corresponding alkynyl analogues was observed.
The construction of functionalized a-pyrone ring incorpo-
rated into the isocoumarin system is the most commonly
used strategy for a rapid assemblage of isocoumarin deriva-
tives. On the other hand palladium-catalyzed reactions
have become most attractive and powerful tool for C–C
bond forming reaction due to their generality and superiority
over many tedious classical methods. Thus, among the many
methods reported for the synthesis of isocoumarins one
widely used process is Sonogashira-type coupling followed
by electrophilic or transition metal mediated cyclization of
the resulting alkynes possessing a carboxylate or an equiva-
5b
R
6
lent group in proximity to the triple bond. Attractive features
X
CO2H
Z
Y
Z
Y
R
Pd-catalyst
HC C-R
of this process include its versatility and ability to tolerate
a wide range of important organic functional groups. Thus,
isocoumarins have been prepared in a efficient manner by
reacting o-iodobenzoic acid with terminal alkynes in the
presence of Pd(PPh ) , Et N, and a stoichiometric amount
O
O
1
a; X = I, Y = S, Z = CH 2a-j (Y = S, Z = CH)
1
b; X = Br, Y = CH, Z = S 2aa, 2bb and 2gg (Y = CH, Z = S)
3
4
3
7
a
7b,c
of ZnCl2. The use of ZnCl in place of CuI
2
was found
Scheme 1. Synthesis of thienopyranones having disubstitutions on the
pyranone ring.
to be responsible for the predominant formation of isocou-
marins over phthalides. However, very recently we have
shown that isocoumarins can be obtained as major products
even in the presence of CuI when the coupling reaction was
performed in the presence of 10% Pd/C–Et N–CuI–PPh as
2. Results and discussion
3
3
5
a
catalyst system in ethanol (Fig. 2). More recently, we
have noted that 3-iodothiophene-2-carboxylic acid (1a)
reacts smoothly with terminal alkynes in the presence of
PdCl (PPh ) –Et N–CuI as a catalyst system affording
2.1. Optimization of reaction conditions and product
characterization
To evaluate the potential of the use of palladium mediated
coupling cyclization methodology for the synthesis of 5-
substituted thieno[2,3-c]pyran-7-ones (3), we first selected
2
3 2
3
1
0
5-substituted 4-alkynylthieno[2,3-c]pyran-7-ones (2a–j)
in good yields (Scheme 1). This palladium-catalyzed

9556
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
1a as a model substrate with 2-methyl-3-butyn-2-ol as the
terminal alkyne. We observed that Pd-catalyzed coupling
Table 1. Effect of reaction conditions on the palladium-catalyzed coupling
a
reaction of 3-iodothiophene-2-carboxylic acid with 2-methyl-3-butyn-2-ol
1
1
R
of 1a with 2-methyl-3-butyn-2-ol in ethanol afforded
5
-alkylthieno[2,3-c]pyran-7-ones (3a, R¼–C(CH ) OH,
3
2
Table 1) in 24% yield and the unexpected 4-(3-hydroxy-3-
methylbut-1-ynyl)-5-(1-hydroxy-1-methylethyl)thieno[2,3-
c]pyran-7-one (2a) in 50% purified yield, with a 2/1 ratio of
I
R
R
Pd-catalyst
HC C-R
+
O
O
S
S
S
CO2H
2
a and 3a (Entry 1, Table 1). Compound 2a was character-
O
O
3a
1
13
R = C(OH)Me2
ized by H and C NMR and other spectroscopic methods
and identified as an alkyne possessing the thieno[2,3-c]-
pyran-7-one ring at one end. This was supported by the
molecular structure of 2b (R¼–CH CH OH), which was
1a
2a
b
Entry
Pd catalyst
Solvent; time
Yield (%)
2
2
2a
3a
5
b
confirmed by X-ray analysis. The ORTEP diagram of 2b
1
2
3
4
5
6
7
8
9
10
PdCl
PdCl
PdCl
PdCl
Pd(PPh
Pd(OAc)
2
2
2
2
(PPh
(PPh
(PPh
(PPh
3
3
3
3
)
)
)
)
2
2
2
2
EtOH; 12 h
50
30
55
80
40
35
35
12
8
24
0
5
0
0
0
28
0
68
80
(
Fig. 3) shows a planar thieno[2,3-c]pyran-7-one core with
1,4-Dioxane; 12 h
DMA; 12 h
DMF; 8 h
DMF; 12 h
DMF; 12 h
DMF; 12 h
DMF; 48 h
EtOH; 12 h
1,4-Dioxane; 12 h
a disordered hydroxyl group due to the alkynyl side chain
along with the other hydroxy group oriented in the opposite
direction. The molecular structure of 3a was also confirmed
3
)
4
c
1
2
2
–PPh
(dppf)
(PPh
3
by X-ray analysis (Fig. 3). The noteworthy features of this
structure include (a) two independent molecules of 3a in the
unit cell are differentiated by the presence of one molecule
of water, (b) the water molecule present in the lattice bridges
the C]O of one molecule and O–H of other one, by inter
molecular hydrogen bonding. Nevertheless, the unexpected
formation of 2a prompted us to investigate this tandem
C–C bond forming reaction in a more systematic manner.
PdCl
PdCl
2
2
d
2
3
)
2
c
10% Pd/C–PPh3
10% Pd/C–PPh
c,e
3
6
a
Reaction conditions: Ia (1.0 equiv), terminal alkyne (2.0 equiv), Pd(II)-
catalyst (0.048 equiv) or Pd/C (0.035 equiv), CuI (0.06 equiv), Et N
3
ꢀ
(5 equiv) in a solvent at 70–80 C under N
Isolated yield of 2a and 3a.
2
.
b
c
d
e
PPh
-Bromothiophene-2-carboxylic acid was used in place of 1a.
Terminal alkyne used: 1.5 equiv.
3
used: 0.3 equiv.
3
The initial reaction was carried out in ethanol in the presence
of PdCl (PPh ) (0.048 equiv), CuI (0.06 equiv), Et N
2
3 2
3
ꢀ
5.0 equiv), and 2.0 equiv of the terminal alkyne at 75 C.
(
A series of optimization experiments on the reaction of 1a
with 2-methyl-3-butyn-2-ol were carried out by keeping
the molar ratio of Pd/Cu at 1/1.3 and changing a number of
parameters, e.g., effect of catalysts, solvent, base, and tem-
perature (Table 1). Change of solvent from ethanol to
a non-protic solvent such as 1,4-dioxane or dimethylaceta-
mide (DMA) suppressed the formation of 3a dramatically
(
5
Entries 2 and 3, Table 1) and 2a was isolated in 30 and
5% yield, respectively. While the reason for these observa-
tions was not clear the non-protic solvents perhaps allowed
the participation of second equivalent of alkyne used in the
crucial cyclization process. The yield of 2a was increased
significantly when DMF was used (Entry 4, Table 1). To as-
sess the role of solvent we carried out this reaction using
a lesser amount of terminal alkyne (1.0 equiv) in DMF where
2
a was isolated in 28% yield and the reaction did not reach
completion. This observation clearly suggests that formation
of 2a was not dependent on the concentration of alkyne used
but was favored by the non-polar solvent employed. Both
Pd and Cu catalysts played crucial roles as no reaction was
observed when either was omitted. The use of other Pd
catalysts, e.g., Pd(PPh ) , Pd(OAc) or PdCl (dppf) was in-
3
4
2
2
2
vestigated (Entries 5–7, Table 1) where 2a was isolated as
major product albeit in low yield (35–40%). Significant
amount of 3a was isolated when PdCl (dppf) was used as
2
2
catalyst (Entry 7, Table 1). Thus, PdCl (PPh ) was identified
2
3 2
as the best catalyst for the synthesis of 2a and was used for
further studies. The use of commercially available 3-bromo-
thiophene-2-carboxylic acid however, did not afford 2a in
good yield even after 48 h when reacted with 2-methyl-3-bu-
tyn-2-ol in the presence of PdCl (PPh ) and CuI (Entry 8,
2
3 2
Figure 3. X-ray crystal structure of 2b and 3a (ORTEP diagram).
Table 1). Remarkably, the use of 0.035 equiv of 10% Pd/C

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9557
in place of PdCl (PPh ) in ethanol during coupling reaction
2
groups including aryl, alkyl, hydroxyl, ether etc. present in
terminal alkynes were well tolerated. This allowed the prep-
aration of a variety of 5-substituted 4-alkynylthieno[2,3-
c]pyran-7-ones (2) under mild condition. However, yields
of compound 2 varied depending on the nature of alkynes
used. While alkynes bearing a tertiary and secondary hy-
droxyl group on the carbon next to the triple bond provided
best yields of 2 (Entries 1 and 4, Table 2), the presence of
long alkyl chains on the triple bond did not affect the yields
drastically (Entries 5 and 6, Table 2). A hydroxyl group at
the end of the long alkyl chain of the alkyne however, low-
ered the yields of 2 slightly (Entries 2 and 3, Table 2).
Among the aryl acetylenes used, phenyl acetylene afforded
only a modest 57% yield of 2 under the reaction condition
studied. A mild electron-donating group at the para position
of the benzene ring however, improved the yield of 2 com-
pared to phenyl acetylene (Entries 8 and 9 vs Entry 7, Table
3 2
of 1a with 2-methyl-3-butyn-2-ol afforded 3a as major prod-
uct in good yield with trace amount of 2a (Entry 9, Table 1).
Indeed, a better yield of 3a was achieved in 1,4-dioxane using
lesser quantity, i.e., 1.5 equiv of terminal alkyne (Entry 10,
Table 1). Less than 0.035 equiv of 10% Pd/C can be used to
afford 3a, but the yield of product was found to be often irre-
producible. The use of 5% Pd/C also afforded lower yield of
ꢀ
3
a. All the reactions were usually carried out at 70–80 C un-
der nitrogen. The use of higher or lower reaction temperature
led to the inferior results. Originally, we speculated that the
formation of 2a might first involve the formation of 3a, which
subsequently reacted with another mole of the terminal
alkyne under Pd–Cu catalysis. However, formation of 2a
was not observed when 3a was subjected to the same Pd-
catalyzed reaction conditions.
2
.2. Scope of the reaction
2). The use of alkyne where –CH O– moiety linked the triple
2
bond with the phenyl group provided better yield of 2 than
phenyl acetylene (Entry 10 vs Entry 7, Table 2). All these
facts clearly indicated that yields of 2 were partially depen-
dent on the nature of the substituent present on the terminal
alkynes. Generally, 2 was isolated as the sole product in all
cases except when 1-hexyne and 1-octyne were used. Com-
pound 3 was also isolated as minor product in these cases
(Entries 5 and 6, Table 2). In contrary to the 3-bromothio-
phene-2-carboxylic acid, isomeric and commercially avail-
able 2-bromothiophene-3-carboxylic acid 1b provided
2
.2.1. Synthesis of 5-substituted 4-alkynyl thieno[2,3-
c]pyran-7-ones and 6-substituted 7-alkynyl thieno[3,2-
c]pyran-4-ones. To examine the effect on the yield of the
substituents on the terminal alkynes we next tested the opti-
mized reaction conditions from Entry 4 of Table 1 (Method
A: PdCl (PPh ) , CuI, Et N in DMF) with other terminal
2
3 2
3
alkynes (Entries 1–10, Table 2). Like o-iodobenzoic acid,
-iodothiophene-2-carboxylic acid showed good reactivity
toward the present coupling reaction and various functional
3
a
Table 2. Pd-mediated synthesis of 5-substituted 4-alkynylthieno[2,3-c]pyran-7-ones and 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones
Entry
Alkyne (R)
Time (h)
Products (2)
Yield (%)
2
3
CH3
HO
CH3
HO
CH3
1
a; –C(CH
3
)
2
OH
8
80
0
CH3
O
S
O
2
a
OH
2
b; –(CH
2
)
2
OH
12
53
0
OH
O
S
O
2
b
OH
3
c; –(CH
2
)
3
OH
12
61
0
OH
O
S
O
2
c
(
continued)

9558
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
Table 2. (continued)
Entry Alkyne (R)
Time (h)
Products (2)
Yield (%)
2
3
HO
OH
4
d; –CH(OH)CH
3
10
82
0
O
S
O
2
d
5
e; –(CH
2
)
3
CH
3
12
65
15
O
S
O
O
2
e
6
f; –(CH
2
)
5
CH
3
12
62
35
S
O
2
f
7
g; –C
6
H
5
12
57
0
O
S
O
2
g
CH3
CH3
8
h; –C
6
H
4
CH
3
-p
12
62
0
O
S
O
2
h
9
i; –C
6
H
4
C
5
H
11-p
8
73
0
O
S
O
2
i
(
continued)

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9559
Table 2. (continued)
Entry
Alkyne (R)
Time (h)
Products (2)
Yield (%)
2
3
O
10
j; –CH OC
2
6
H
5
8
75
0
O
O
S
O
2
j
CH3
CH3
HO
H C
b
1
3
CH3
1
a
10
55
40
S
OH
O
O
2
aa
OH
b
2
1
b
10
88
0
OH
S
O
O
2
bb
b
3
c
1
g
10
60
0
S
O
O
2
gg
(PPh
a
All reactions were carried out using 1 (1.0 equiv), terminal alkyne (2.0 equiv), PdCl
ꢀ
2
3 2 3
) (0.048 equiv), CuI (0.06 equiv) and Et N (5 equiv) in DMF
at 70–80 C under nitrogen.
2-Bromothiophene-3-carboxylic acid was used in place of 1.
b
c
1,4-Diphenyl-1,3-butadiyne was isolated in 35% yield in addition to 2gg.
better yield of corresponding 6,7-disubstituted thieno[3,2-
c]pyran-4-ones (Scheme 2), e.g., 2aa, 2bb, and 2gg (Entry
effect of sulfur at the nearby position. Nevertheless, the suc-
cess of this tandem reaction is presumably due to the in situ
generation of the Pd(II)-complex after normal Sonogashira
coupling, which facilitates the insertion of another alkyne
moiety on the intermediate generated upon cyclization (see
later for mechanistic discussion).
8
of Table 1 vs Entries 11–13 of Table 2) under the condition
studied. Higher reactivity shown by 2-bromo derivative over
-bromo toward the present palladium-catalyzed reaction
3
was perhaps aided by the electron withdrawing inductive
R
2.2.2. Synthesis of 5-substituted thieno[2,3-c]pyran-7-
ones. We have found that 5-substituted thieno[2,3-c]pyran-
7-one (3) can also be prepared as a major product by coupling
1a with terminal alkynes using 10% Pd/C–Et N–CuI–PPh
Br
R
S
Pd-catalyst
HC C-R
S
R
S
3
3
+
O
O
(Method B) as a catalyst system (Entries 9 and 10, Table
). Pd/C catalyzed reactions are particularly attractive be-
CO H
2
1
O
O
cause the catalyst can be removed easily by filtration at the
end of the reaction allowing product isolation without transi-
tion metal impurities, the removal of which could be tedious
and cumbersome. Thus, to assess the generality of this
approach, the scope of the Pd/C-mediated coupling of 1a
1
b
(major)
aa, 2bb and 2gg
R = alkyl, hydroxyalkyl, aryl
(minor)
3aa
2
Scheme 2. Synthesis of 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones.

9560
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
has been studied. Treatment of 1a with a variety of terminal
alkynes under the condition described in Table 1 [1.0 equivof
(0.06 equiv), and Et N (5 equiv) in 1,4-dioxane at 70–
3
80 C under nitrogen] afforded moderate to good yields of
ꢀ
5-substituted thieno[2,3-c]pyran-7-ones (Table 3). In addi-
tion to alkynes used earlier a number of other alkynes
3-iodothiophene-2-carboxylic acid, 1.5 equiv of terminal al-
kyne, 10% Pd/C (0.035 equiv), PPh3 (0.3 equiv), CuI
a
Table 3. Pd/C-mediated synthesis of 5-substituted thieno[2,3-c]pyran-7-ones
Entry
Alkyne (R)
Time (h)
Products (3)
Yield (%)
2
3
HO
CH3
CH3
1
a; –C(CH
3
)
2
OH
12
O
6
80
S
O
3
a
OH
O
2
3
b; –(CH
2
)
2
OH
12
12
S
30
10
60
60
O
3
b
OH
O
c; –(CH
2
)
3
OH
S
O
3
c
OH
4
d; –CH(OH)CH
3
12
0
55
O
S
O
3
d
O
5
6
7
e; –(CH
2
)
3
CH
3
12
12
12
S
17
50
55
35
O
O
3
3
e
f; –(CH
2
)
5
CH
3
S
0
O
f
OH
O
k; –CH
2
OH
S
0
O
3
g
OH
O
8
9
l; –CH
2
CH(OH)CH
3
12
10
S
0
0
55
72
O
3
h
O
j; –CH
2
OC
6
H
5
O
S
O
3
i
NO2
O
10
m; –CH
2
OC
6
H
4
NO
2
-p
10
0
60
O
S
O
3
j
(
continued)

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9561
Table 3. (continued)
Entry
Alkyne (R)
Time (h)
Products (3)
Yield (%)
2
3
H
N
O
O
1
1
1
n; 5-Indolyloxy
10
0
70
S
O
3
k
N
H
2
o; –CH NC
2
6
H
5
10
10
0
0
65
65
O
S
S
O
O
3
l
S
1
1
3
2 6 5
p; –CH SC H
O
3
m
N
4
q; 1-Indolyl
10
12
O
0
0
68
72
S
O
3
n
O
O
15
3 2
a; –C(CH ) OH
S
OH
3
aa
a
All reactions were carried out by using I (1.0 equiv), terminal alkyne (1.5 equiv), 10% Pd/C (0.035 equiv), PPh
ꢀ
3
(0.3 equiv), CuI (0.06 equiv), Et
3
N (5 equiv)
in 1,4-dioxane at 70–80 C under nitrogen.
containing ether, amine, thioether, and indole functionality
were tested and the reaction proceeded well affording good
yields of product 3 (Entries 10–14, Table 3). The use of 2-bro-
mothiophene-3-carboxylic acid afforded 6-substituted
thieno[3,2-c]pyran-4-one in good yield (Entry 15, Table 3).
Except in four cases (Entries 1–3 and 5, Table 3), no signifi-
cant amount of 2 was isolated from the reaction mixture
indicating the high product selectivity of this coupling–
cyclization process under Pd/C–Cu catalysis. Presumably,
participation of the copper salt in the cyclization step was re-
sponsible for the predominant formation of 3 over 2 (see later
for mechanistic discussion). Notably, the use of Pd/C as
a source of ‘ligandless palladium’ in arylation of thiophene
was found to be unsuccessful, which was thought to be due
coupling–cyclization–coupling reaction whereas the use of
Pd/C facilitated only coupling–cyclization to afford 3 in
good yields. Nevertheless, the reaction showed very high
regioselectivity in both cases as no isomeric thieno[2,3-c]-
furan-6-ones resulting from ‘5-exo-dig’ cyclization were de-
tected under the reaction conditions studied. This is in sharp
contrast to the earlier observations where the coupling–
cyclization followed 5-exo-dig ring closure predominantly
under Pd–Cu catalysis in DMF.
7
2.3. Proposed reaction mechanism
A reasonable pathway for PdCl (PPh ) mediated tandem
2
3 2
reaction leading to compound 2 and Pd/C-mediated cou-
pling–cyclization to compound 3 is shown in Scheme 3.
The possibility of generating 2 via 3 can be ruled out,
because it requires palladium mediated C–H activation at
C-4 of thieno[2,3-c]pyran-7-one ring (3) followed by inter-
action of the resulting Pd(II) intermediate with the copper
acetylide. This is not only an energetically unfavorable pro-
cess, but also would afford copper hydride as a side product,
which is unlikely. Moreover, formation of 2a was not ob-
served when 3a was reacted with another mole of terminal
alkyne under Pd–Cu catalysis. Thus, the reaction seems to
1
3
to the poisoning of the heterogenous catalyst.
We have shown that 5-substituted thieno[2,3-c]pyran-7-ones
3) and their 4-alkynyl analogues (2) can be prepared via
(
coupling reaction of 3-iodothiophene-2-carboxylic acid
with terminal alkynes depending on the reaction condition
employed (Method A or B). The nature of the palladium cat-
alysts played an important role in these coupling–cyclization
reactions. The use of Pd(II) or Pd(0) complexes generally led
to the formation of 4-alkynyl analogues (2) via tandem

9562
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
R
R
O
L
Pd
H
R
L
R
HC C-R
Pd(II)
R
X
HC C-R
Pd(0)
-
+
O BH
O
-
+
-
+
ref 5b
O B
O B
O
I
O
O
E
1
2
X = I or Br
B = Et N
3
Cu(I)
ref 5a
3
Scheme 3. A plausible mechanism for Pd-catalyzed formation of 2 and 3.
proceed via in situ generation of intermediate E according
1
2.4. In vitro anticancer activity
7
b,14
to a typical Sonogashira pathway.
then undergoes intramolecular cyclization aided by the
Once formed this acid
Based on the promising cytotoxic activities reported
for substituted pyrones especially 4-alkynyl substituted
6
a
5a
Pd(II)-complex or copper salt to give 2 or 3. However,
formation of 2 clearly suggests that the corresponding path-
way is a Pd(II)-mediated process. Presumably, this proceeds
via insertion of the Pd(0) complex into the acetylenic C–H
bond of the terminal alkyne leading to a Pd(II) intermedi-
2
g
2-pyrones earlier we evaluated some of the thienopyra-
nones synthesized for in vitro anticancer activity. Selected
compounds were tested on a panel of cancer cell lines,
e.g., HT-29 (colon), NCI-H460 (lung), and LoVo (colon)
using the NCI standard protocol for screening anticancer
15
ate (E ) that catalyzes the ‘6-endo-dig’ ring closure. Al-
2
1
8
though we have no actual proof for the generation of E2,
insertion of Pd(0) complex into the acetylenic C–H bond
however, has been suggested by Trost and co-workers ear-
molecules. After treating the cells with compounds at
100 mM concentration initially the percentage growth of
cells was measured, which is shown in Table 4. Based
on the result obtained for compound 2g against LoVo
cell line we tested this compound further at lower
concentrations such as 10, 1.0, 0.1, and 0.01 mM against
the same cancer cell line and the percentage growth
was noted as 77, 86, 97, and 102, respectively. The
GI50 value (the concentration that causes 50% inhibition
of cancer cell growth against a cell line is expressed as
GI ) for compound 2g was found to be 83.4 mM com-
1
6
lier. Additionally, a closely related intramolecular oxypal-
ladation of the complex formed by the coordination of
organo Pd(II)-complex [generated by oxidative addition of
the aryl halide to Pd(0) in situ] with the C–C triple bond
of the 2-(1-alkynyl)benzoate anion has also been proposed
2
i
by Rossi and co-workers. Thus, reductive elimination of
Pd(0) followed the ‘6-endo-dig’ ring closure to afford
thieno[2,3-c]pyran-7-one derivative. A ‘5-exo-dig’ ring clo-
sure, although allowed by Baldwin’s rule, was not observed
in the present case because of the favorable geometry asso-
ciated with the 5-6 ring formation rather than the 5-5 ring.
This also accounts for observation of no solvent effect on us-
ing 1,4-dioxane and ethanol in the present synthesis of 3,
which is in contrast with the earlier synthesis of isocoumar-
5
0
pared to 23 mM of GlevecÔ, an well known anticancer
drug developed by Novartis. Additionally, the LC50
(Lethal Concentration 50 is the concentration of a com-
pound that kills 50% of cells treated) of 2g was noted
as 100 mM. The present study thus indicates that alkynyl
substituted thienopyranone moiety could be a new and
potential scaffold that needs further exploration for design
and SAR studies for the development of novel anticancer
agents.
5
a
in. It is noteworthy that due to the electron-donating reso-
nance effect of thiophene moiety the carbon–carbon triple
bond of E is more nucleophilic than that of analogue 2-
1
(
the Pd(II)-complex (E ) generated in situ under the condi-
1-alkynyl)benzoic acid and therefore interacts better with
2
tion studied. This perhaps accounts for the isolation of 4-al-
kynyl isocoumarins as side products in poor yield during the
preparation of isocoumarins under palladium–zinc catalysis.
Table 4. In vitro anticancer activities of thienopyranone derivatives
Although the reason for preferential interaction of E with
1
Pd(II)-complex (E ) over CuI is not clear at this stage a
2
Compound no
Cell line
Percentage growth
@ 100 mM
possible explanation for the change of product selectivity
on going from Method A to Method B is a change in the re-
action mechanism in the cyclization step (Scheme 3). While
generation of 3 is arguably feasible via Pd(II)-mediated cy-
clization of corresponding 1-alkynyl substituted thiophene
carboxylic acid, isolation of 3 as only product under Pd/C–
Cu catalysis in most of the cases suggests that perhaps
copper salt plays a major role in Pd/C-mediated coupling–
2
g
LoVo
H460
HT-29
48
71
71
2h
3a
LoVo
H460
HT-29
61
87
61
LoVo
H460
HT-29
68
84
77
5
a
cyclization process. This was further supported by the
isolation of 3e as a sole product when 3-hex-1-ynyl thio-
3
i
LoVo
H460
HT-29
72
73
72
1
7
phene-2-carboxylic acid was treated with CuI in DMF at
ꢀ
7
0–80 C for 2 h.

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9563
3. Conclusions
acid and 2-bromothiophene-3-carboxylic acid used are com-
mercially available.
In summary, a catalytic approach to thienopyranones of po-
tential pharmacological interest has been developed through
the coupling of bromo or iodo substituted thiophenecar-
boxylic acid with terminal alkynes under palladium–copper
catalysis. A detailed study related to the effect of reaction
conditions on product distribution was carried out. Condi-
tions were developed that allow for the selective synthesis
of either 4,5-disubstituted or only 5-substituted thieno-
1
9
4.2. Preparation of 3-iodo thiophene-2-carboxylic acid
(1a)
To a solution of thiophene-2-carboxylic acid (5.0 g,
39 mmol) in dry THF (50 mL) n-butyl lithium (6.25 g,
41.6 mL, 97 mmol) was added slowly and dropwise at
ꢀ
ꢁ78 C under nitrogen atmosphere over a period of 1 h.
[
2,3-c]pyran-7-ones. The best process for the preparation
The mixture was stirred for 1 h at the same temperature
(ꢁ78 C) and a solution of iodine (11.8 g, 46 mmol) in
ꢀ
THF (25 mL) was added slowly by maintaining the temper-
of 4,5-disubstituted derivatives involved the use of
PdCl (PPh ) as a catalyst source and was found to be quite
2
3 2
ꢀ
general and highly regioselective, placing the alkynyl
moiety at the C-4 position of the thieno[2,3-c]pyran-7-one
ring. This process was extended to the regioselective synthe-
sis of 7-alkynylthieno[3,2-c]pyran-4-ones successfully. 5-
Substituted thieno[2,3-c]pyran-7-ones on the other hand
was obtained easily by using Pd/C-mediated coupling–cycli-
zation of 3-iodothiophene-2-carboxylic acid with terminal
alkynes. All these processes worked well with a broad range
of terminal alkynes to afford the corresponding products in
good isolated yields. The scope and limitations of both the
process along with the mechanism of the reaction have
been discussed. The sequencing of two or more reactions
in a one-pot process, as illustrated in this report, not only
makes better use of precious reagents as well as solvents
but also has the benefit of eliminating cumbersome separa-
tion and purification after each step. Since the use of single
catalyst source for tandem reaction is a powerful strategy for
generating complex structures, we believe that the novel
palladium-catalyzed transformation described here would
find wide usage for the synthesis of similar class of
compounds.
ature at ꢁ78 C. The mixture was stirred initially for 8 h at
ꢀ
ꢀ
ꢁ78 C and then at 25–35 C for 30 h. After completion of
the reaction the mixture was diluted with 5% aqueous HCl
(10 mL) followed bywater (100 mL)and extracted withethyl
acetate (3ꢂ100 mL). The organic layers were collected,
combined, washed with 10% aq sodium thiosulfate
(3ꢂ50 mL) followed by water (3ꢂ50 mL), dried over anhy-
drous Na SO , and concentrated under vacuum. The crude
2
4
compound was triturated with light petroleum ether (distilla-
tion range 60–80 C) to get the title compound as light brown
ꢀ
solid (6 g, 60% yield); H NMR (CDCl , 200 MHz) d 7.26 (d,
1
3
ꢁ
1
J¼5.6 Hz, 1H), 7.52 (d, J¼5.1 Hz, 1H); IR (cm , CHCl3)
+
3092, 2852, 1670; m/z (ES Mass) 255 (M , 100%).
4.3. Preparation of 5-substituted 4-alkynyl thieno[2,3-
c]pyran-7-ones (2)
4.3.1. General procedure. A mixture of 3-iodo thiophene-2-
carboxylic acid (0.787 mmol), PdCl (PPh ) (0.038 mmol),
CuI (0.047 mmol), and Et N (4 mmol) in DMF (10 mL)
3
was stirred for 1 h under nitrogen. The acetylenic compound
(1.57 mmol) was added and the mixture was stirred at room
temperature for 1 h and then at 70–80 C for 8–12 h. After
completion of the reaction, DMF was removed under reduced
pressure and the residue was extracted with ethyl acetate
2
3 2
ꢀ
4. Experimental
4
.1. General methods
(
3ꢂ50 mL). The organic layers were collected, combined,
washed with saturated aq NaHCO (2ꢂ25 mL) followed by
3
Unless stated otherwise, reactions were performed under ni-
trogen atmosphere. Reactions were monitored by thin layer
chromatography (TLC) on silica gel plates (60 F254), visu-
alizing with ultraviolet light or iodine spray. Flash chroma-
tography was performed on silica gel (60–120 mesh) using
water (2ꢂ25 mL), dried over anhydrous Na SO , and con-
2
4
centrated under vacuum. The crude compound was purified
by column chromatography on silica gel using light petro-
ꢀ
leum ether (60–80 C)–ethyl acetate.
1
distilled petroleum ether and ethyl acetate. H NMR and
C NMR spectra were determined in CDCl , DMSO-d or
1
3
4.3.2. 4-(3-Hydroxy-3-methyl-but-1-ynyl)-5-(1-hydroxy-
1-methyl-ethyl)thieno[2,3-c]pyran-7-one (2a).
3
6
MeOH-d solution on 200 and 400, and 50 MHz spectrome-
4
ters, respectively. Proton chemical shifts (d) are relative to
tetramethylsilane (TMS, d¼0.00) as internal standard and
expressed in parts per million. Spin multiplicities are given
as s (singlet), d (doublet), t (triplet) and m (multiplet) as
well as br (broad). Coupling constants (J ) are given in hertz.
Infrared spectra were recorded on a FTIR spectrometer.
Melting points were determined by using melting point ap-
paratus and are uncorrected. Thermal analysis data [Differ-
ential Scanning Calorimetry (DSC)] were generated with
the help of DSC-50 detector. MS spectra were obtained on
a mass spectrometer. Chromatographic purity by HPLC
was determined by using area normalization method and
the condition specified in each case: column, mobile phase
OH
OH
O
S
O
1
Low melting light brown solid; H NMR (CDCl , 200 MHz)
3
d 7.85 (d, J¼5.0 Hz, 1H), 7.34 (d, J¼5.0 Hz, 1H), 2.24 (br s,
ꢁ
1
–OH), 1.61 (s, 12H, CH ); IR (cm , CHCl ) 3391, 2981,
3
3
+
13
(range used), flow rate, detection wavelength, retention
times. All terminal alkynes, 3-bromothiophene-2-carboxylic
1715 (C]O), 1626; m/z (ES Mass) 293 (M , 100%);
NMR (CDCl , 50 MHz) d 167.4 (C]O), 148.3, 144.0,
C
3

9564
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
138.8 (2C), 124.7, 105.6, 104.0, 74.1, 73.6, 65.6, 31.1 (2C,
CH ), 28.5 (2C, CH ); UV (nm, MeOH) 312.0, 252.8, 238.4,
XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
water, mobile phase B: 0.05% TFA in methanol, gradient
(T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
min, UV 254 nm, retention time 11.0 min; Elemental analy-
sis found C, 61.32; H, 5.57; C H O S requires C, 61.62; H,
3
3
2
14.2; HPLC 96.3%, column: Zorbax Eclipse XDB C-18
150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
(
1
5 16 4
0
2
/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
54 nm, retention time 11.3 min; Elemental analysis found
5.52.
C, 61.77; H, 5.45; C H O S requires C, 61.62; H, 5.52.
5 16 4
4.3.5. 4-(3-Hydroxy-but-1-ynyl)-5-(1-hydroxy ethyl)-
thieno[2,3-c]pyran-7-one (2d).
1
4.3.3. 4-(4-Hydroxy-but-1-ynyl)-5-(2-hydroxy-ethyl)-
thieno[2,3-c]pyran-7-one (2b).
OH
OH
OH
O
S
O
OH
O
S
1
Low melting light brown solid; H NMR (CDCl , 200 MHz)
3
O
d 7.87 (d, J¼5.0 Hz, 1H), 7.33 (d, J¼5.0 Hz, 1H), 5.14 (q,
J¼6.3 Hz, 1H, CH), 4.82 (q, J¼6.7 Hz, 1H, CH), 1.61 (d, J¼
3.4 Hz, 3H, CH ), 1.57 (d, J¼3.7 Hz, 3H, CH ), 1.75 (br s,
ꢀ
1
White solid; mp 116–116.5 C; H NMR (CDCl , 200 MHz)
3
3
1
3
ꢁ
OH); IR (cm , CHCl ) 3307, 2919, 1713 (C]O), 1600;
3
–
d 7.83 (d, J¼5.0 Hz, 1H), 7.32 (d, J¼5.0 Hz, 1H), 4.03 (t,
+
13
m/z (CI Mass) 265 (M , 100); C NMR (CDCl , 50 MHz)
3
J¼5.7 Hz, 2H, CH ), 3.86 (t, J¼5.7 Hz, 2H, CH ), 3.08 (t, J¼
2
2
d 160.7 (C]O), 153.7, 144.2, 137.1, 127.4, 124.6, 104.2,
99.4, 75.4, 66.0 (CH), 58.8 (CH), 24.3 (CH ), 21.2 (CH );
3 3
5
–
1
5
1
2
2
.7 Hz, 2H, CH ), 2.74 (t, J¼6.0 Hz, 2H, CH ), 1.66 (br s,
ꢁ
3
2
1
2
OH); IR (cm , CHCl ) 3390, 3015, 2927, 1715 (C]O),
+
13
UV (nm, MeOH) 313.4, 253.2, 235.8, 201.8; HPLC 96.4%,
column: Zorbax Eclipse XDB C-18 (150ꢂ4.6 mm), mobile
phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA
in methanol, gradient (T/%B): 0/30, 13/70, 15/100, 25/100,
flow rate: 1.5 mL/min, UV 254 nm, retention time 9.7 min;
602; m/z (ES Mass) 265 (M , 100); C NMR (CDCl3,
0 MHz) d 160.4 (C]O), 157.4, 157.2, 136.8, 124.6,
23.9, 104.2, 94.0, 72.3, 61.1 (CH OH), 60.4 (CH OH),
9.7 (CH ), 23.9 (CH ); UV (nm, MeOH) 315.2, 313.4,
2
52.8, 238.4, 201.6; HPLC 98.8%, column: Zorbax Eclipse
2
2
2
+
HRMS Calcd for C H O S (M+H ): 265.0534. Found:
13 12 4
XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
2
65.0540.
water, mobile phase B: 0.05% TFA in methanol, gradient
T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
(
4
(
.3.6. 5-Butyl-4-hex-1-ynyl-thieno[2,3-c]pyran-7-one
2e).
min, UV 254 nm, retention time 8.4 min; Elemental analysis
found C, 59.15; H, 4.51; C H O S requires C, 59.08; H,
1
3 12 4
4
.58.
4.3.4. 4-(5-Hydroxy-pent-1-ynyl)-5-(3-hydroxy-propyl)-
thieno[2,3-c]pyran-7-one (2c).
OH
O
S
O
1
H NMR (CDCl , 400 MHz) d 7.79 (d, J¼5.1 Hz, 1H), 7.28
OH
3
(
d, J¼5.1 Hz, 1H), 2.79 (t, J¼7.5 Hz, 2H, CH ), 2.48 (t,
O
2
S
J¼7.2 Hz, 2H, CH ), 1.74–1.66 (m, 2H, CH ), 1.61–1.59
2 2
O
(m, 2H, CH ), 1.45–1.50 (m, 2H, CH ), 1.41–1.36 (m, 2H,
CH ), 0.93–0.99 (m, 6H, CH ); IR (cm , CHCl ) 2958,
2 2
ꢁ
1
2
3
3
13
1
+
Low melting light brown solid; H NMR (CDCl , 200 MHz)
3
1729 (C]O); m/z (ES Mass) 289 (M , 100%); C NMR
(CDCl , 50 MHz) d 155.2 (C]O), 154.6, 152.3, 136.4,
d 7.83 (d, J¼4.7 Hz, 1H), 7.23 (d, J¼4.7 Hz, 1H), 3.85 (t,
3
J¼4.7 Hz, 2H, CH ), 3.75 (t, J¼4.6 Hz, 2H, CH ), 2.9 (t, J¼
124.6, 123.4, 105.6, 96.6, 71.5, 31.8, 30.8, 29.7, 29.5, 22.2,
22.0, 19.2 (CH ), 13.7 (CH ); UV (nm, MeOH) 325.2,
2
2
4
.6 Hz, 2H, CH ), 2.6 (t, J¼4.68 Hz, 2H, CH ), 2.10–1.90
2
2
3
3
(m, 2H, CH ), 1.85–1.80 (m, 2H, CH ), 1.69 (br s, –OH);
IR (cm , CHCl ) 3429, 3019, 2400, 1719 (C]O), 1601;
m/z (ES Mass) 293 (M , 100); C NMR (CDCl , 50 MHz)
3
252.6, 238.4, 209.6; HPLC 97.0%, column: Zorbax Eclipse
XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
water, mobile phase B: 0.05% TFA in methanol, gradient
(T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
min, UV 254 nm, retention time 18.3 min; Elemental analy-
sis found C, 70.87; H, 6.95; C H O S requires C, 70.80; H,
2 2
ꢁ
1
3
+
13
d 163.7 (C]O), 157.2, 153.8, 136.7, 132.1, 124.5, 106.6,
9
4.6, 72.4, 61.4 (CH OH), 58.3 (CH OH), 30.2 (CH ), 29.6
2 2 2
(
CH ), 28.6 (CH ), 16.1 (CH ); UV (nm, MeOH) 317.2,
2 2 2
17 20 2
2
53.0, 235.4, 210.8; HPLC 98.2%, column: Zorbax Eclipse
6.99.

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9565
ꢀ
Pale yellow solid; mp 171.5–171.8 C; H NMR (CDCl ,
3
1
4
.3.7. 5-Hexyl-4-oct-1-ynyl-thieno[2,3-c]pyran-7-one (2f).
4
1
00 MHz) d 8.15 (d, J¼8.3 Hz, 2H), 7.87 (d, J¼5.1 Hz,
H), 7.53 (d, J¼5.1 Hz, 1H), 7.40 (d, J¼8.1 Hz, 2H), 7.29
(
6
d, J¼8.1 Hz, 2H), 7.19 (d, J¼8.1 Hz, 2H), 2.35–2.43 (m,
ꢁ
H, CH ); IR (cm , KBr) 3072, 1727 (C]O), 1584; m/z
3
1
+
13
(CI Mass) 358 (M , 100%); C NMR (CDCl , 50 MHz)
d 158.9 (C]O), 148.6, 140.9, 139.1, 136.5, 133.3 (2C),
3
1
1
31.2, 129.3 (2C), 128.9, 128.7 (2C), 126.2, 125.2 (2C),
23.3, 119.6, 103.6, 96.8, 82.3, 22.6 (CH ), 21.5 (CH ); UV
3
3
O
S
(nm, MeOH) 317.4, 252.8; HPLC 96.0%, column: Zorbax
O
Eclipse XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05%
TFA in water, mobile phase B: 0.05% TFA in methanol, gradi-
ent (T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
min, UV 254 nm, retention time 18.7 min; Elemental analysis
foundC, 77.37;H,4.54;C H O S requires C, 77.50;H, 4.52.
1
H NMR (CDCl , 400 MHz) d 7.79 (d, J¼5.1 Hz, 1H), 7.29
3
(
d, J¼5.1 Hz, 1H), 2.78 (t, J¼7.8 Hz, 2H, CH ), 2.47 (t, J¼
2
6
2
0
(
(
(
.9 Hz, 2H, CH ), 1.79–1.65 (m, 2H, CH ), 1.68–1.58 (m,
2 2
2
3 16 2
H, CH ), 1.61–1.4 (m, 6H, CH ), 1.39–1.26 (m, 6H, CH ),
2
.91–0.87 (m, 6H, CH ); IR (cm , CHCl ) 2929, 1727
3
C]O), 1600; m/z (ES Mass) 345 (M , 100%); C NMR
CDCl , 50 MHz) 136.3 (C]O), 124.6, 32.1 (2C), 31.5
2C), 31.3 (2C), 29.7 (2C), 28.7 (2C), 28.6 (2C), 27.4 (2C),
2
2
ꢁ
1
3
4.3.10. 5-(4-Pentyl-phenyl)-4-(4-pentyl-phenylethynyl)-
thieno[2,3-c]pyran-7-one (2i).
+
13
3
2
2
2.50 (2C), 19.5 (2C), 14.0; UV (nm, MeOH) 322.0, 252.8,
39.4, 214.8; HPLC 98.0%, column: Zorbax Eclipse XDB
C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
0
2
/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
54 nm, retention time 19.9 min; Elemental analysis found
C, 73.37; H, 8.10; C H O S requires C, 73.21; H, 8.19.
21 28 2
4.3.8. 5-Phenyl-4-phenyl ethynyl-thieno-[2,3-c]pyran-7-
one (2g).
O
S
O
1
Low melting brown solid; H NMR (CDCl , 400 MHz)
3
d 8.18 (d, J¼8.3 Hz, 2H), 7.87 (d, J¼5.1 Hz, 1H), 7.53 (d,
J¼5.1 Hz, 1H), 7.43 (d, J¼8.3 Hz, 2H), 7.30 (d, J¼8.3 Hz,
2
1
H), 7.19 (d, J¼8.1 Hz, 2H), 2.69–2.61 (m, 4H, CH ),
2
.67–1.61 (m, 4H, CH ), 1.37–1.25 (m, 8H, CH ), 0.92–
2
2
O
ꢁ1
+
S
0.87 (m, 6H, CH ); IR (cm , CHCl ) 2928, 1736 (C]O),
3
3
13
O
1598; m/z (CI Mass) 469 (M , 100%); C NMR (CDCl
0 MHz) 158.6 (C]O), 148.7, 147.5, 145.9, 144.1, 136.5,
132.4, 131.3 (2C), 129.3 (2C), 128.6 (2C), 128.3 (2C),
27.3, 123.2, 120.8, 103.8, 96.9, 82.4, 35.9 (2C), 31.4
2C), 30.8 (2C), 22.5 (2C), 14.0 (2C); UV (nm, MeOH)
17.8, 254.0, 202.0; HPLC 97.0%, column: Zorbax Eclipse
3
,
5
ꢀ
1
Pale yellow solid; mp 122–123 C; H NMR (CDCl3,
4
00 MHz) d 8.25–8.22 (m, 2H), 7.90 (d, J¼5.1 Hz, 1H), 7.90
1
(
3
ꢁ
1
(
1
(
(
1
3
d, J¼5.1 Hz, 1H), 7.50–7.30 (m, 8H); IR (cm , KBr) 3107,
+
13
723 (C]O); m/z (ES Mass) 329 (M , 100%); C NMR
CDCl , 50 MHz)d153.6(C]O), 148.4, 136.7, 131.9, 313.6
3
XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
2C), 131.4, 131.2, 130.5, 130.2, 129.5, 128.8, 128.5, 128.4,
28.3 (2C), 125.3, 122.6, 105.1, 96.6, 88.3; UV (nm, MeOH)
13.4, 217.4, 247.8; HPLC 99.0%, column: Zorbax Eclipse
water, mobile phase B: 0.05% TFA in methanol, gradient
(T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
min, UV 254 nm, retention time 23.4 min; HRMS Calcd
XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
+
for C H O S (M+H ): 469.2201. Found: 469.2216.
31 32 2
water, mobile phase B: 0.05% TFA in methanol, gradient
(
T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min,
UV 254 nm, retention time 18.0 min; Elemental analysis
foundC, 76.87;H, 3.66;C H O S requires C, 76.81; H, 3.68.
4.3.11. 5-Phenoxymethyl-4-(3-phenoxy-prop-1-ynyl)-
thieno[2,3-c]pyran-7-one (2j).
2
1 12 2
4.3.9. 5-p-Tolyl-4-p-tolylethynyl-thieno[2,3-c]pyran-7-
one (2h).
O
CH3
O
CH3
O
S
O
O
O
ꢀ
1
S
White solid; mp 115.2 C; H NMR (CDCl , 400 MHz)
3
d 7.82 (d, J¼7.5 Hz, 1H), 7.34–7.23 (m, 6H), 7.22–7.0 (m,

9566
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
ꢁ
1
5
2
1
1
1
7
H), 4.93 (s, 2H, CH ), 5.03 (s, 2H, CH ); IR (cm , KBr)
2
4.3.14. 6-Phenyl-7-phenyl ethyl-thieno-[3,2-c]pyran-4-
one (2gg).
2
+
925, 1733 (C]O), 1598, 1240; m/z (CI Mass) 389 (M ,
00%); C NMR (CDCl , 50 MHz) 157.9 (C]O), 156.9,
54.5, 153.8, 152.7, 137.0, 129.6 (2C), 129.5 (2C), 126.6,
24.7, 121.8, 121.7, 115.0 (2C), 114.9 (2C), 101.2, 92.7,
8.1, 65.0, 56.2; UV (nm, MeOH) 313.0, 255.8, 202.8;
1
3
3
HPLC 97.0%, column: Zorbax Eclipse XDB C-18
150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
(
S
O
0
2
/30, 13/70, 15/100, 25/100, flow rate: 1.0 mL/min, UV
54 nm, retention time 17.4 min; Elemental analysis found
O
C, 71.22; H, 4.10; C H O S requires C, 71.12; H, 4.15.
4
ꢀ
1
2
3
16
Pale yellow solid; mp 183–184 C; H NMR (CDCl3,
00 MHz) d 8.25 (m, 2H), 7.63 (d, J¼5.4 Hz, 1H), 7.43 (d,
J¼5.4 Hz, 1H), 7.55–7.50 (m, 5H), 7.40–7.38 (m, 3H); IR
2
4.3.12. 6-(1-Hydroxy-1-methyl-ethyl)-7-(3-hydroxy-3-
methyl-but-1-ynyl)-thieno[3,2-c]pyran-4-one (2aa).
ꢁ1
+
(
cm , KBr) 3421, 2962, 1738 (C]O); m/z (CI Mass) 329
13
OH
(M , 100%); C NMR (CDCl , 50 MHz) d 157.0 (C]O),
3
1
1
31.4 (2C), 130.6 (2C), 129.0 (2C), 128.5 (2C), 128.3,
28.2, 126.6 (2C), 126.0 (2C), 125.4, 122.6, 122.2, 101.6,
OH
97.6 (2C); UV (nm, MeOH) 340.6, 300.0, 239.0, 203.2;
HPLC 98.0%, column: Zorbax Eclipse XDB C-18
(150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water, mobile
phase B: 0.05% TFA in methanol, gradient (T/%B): 0/30,
S
O
O
1
3/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV 254 nm,
1
Low melting light brown solid; H NMR (CDCl , 200 MHz)
3
retention time 18.0 min; Elemental analysis found C,
76.63; H, 6.77; C H O S requires C, 76.81; H, 3.68.
d 7.54 (d, J¼5.2 Hz, 1H), 7.37 (d, J¼5.3 Hz, 1H), 2.24 (br s,
2
1 12 2
ꢁ
OH), 1.68 (s, 12H); IR (cm , CHCl ) 3272, 1722 (C]O);
3
1
–
+
13
m/z (CI Mass) 293 (M , 100%); C NMR (CDCl , 50 MHz)
3
d 165.9 (C]O), 156.7, 153.9, 132.1, 128.3, 126.3, 125.7,
04.4, 95.8, 73.6, 65.4, 30.8 (2C, CH ), 28.5 (2C, CH );
3 3
4.4. Preparation of 5-substituted thieno[2,3-c]pyran-7-
ones (3)
1
UV (nm, MeOH) 314.8, 264.4, 231.8, 203.4; HPLC
6.0%, column: Zorbax Eclipse XDB C-18 (150ꢂ4.6 mm),
mobile phase A: 0.05% TFA in water, mobile phase B:
4.4.1. General procedure. A mixture of 3-iodo thiophene-
2-carboxylic acid (1.18 mmol), 10% Pd/C (0.035 mmol),
PPh3 (0.14 mmol), CuI (0.07 mmol), and triethylamine
9
ꢀ
0
1
.05% TFA in methanol, gradient (T/%B): 0/30, 13/70,
5/100, 25/100, flow rate: 1.5 mL/min, UV 254 nm, reten-
(6.0 mmol) in 1,4-dioxane (10 mL) was stirred at 25–30 C
for 30 min under nitrogen and acetylinic compound
(1.8 mmol) was added. The mixture was then stirred at
tion time 12.5 min; Elemental analysis found C, 61.32; H,
5
ꢀ
.58; C H O S requires C, 61.62; H, 5.52.
15 16 4
room temperature for 1 h and then at 75–80 C for 10–
2 h. After completion of the reaction the mixture was
1
4.3.13. 6-(2-Hydroxy-ethyl)-7-(4-hydroxy-but-1-ynyl)-
thieno [3,2-c]pyran-4-one (2bb).
cooled to room temperature, diluted with EtOAc (50 mL),
and filterd through Celite. The filtrate was washed with sat-
urated aq sodium hydrogen carbonate (2ꢂ25 mL) followed
by water (2ꢂ25 mL), dried over anhydrous Na SO , and
OH
2
4
concentrated. The residue was purified by column chromato-
graphy on silicagel, using light petroleum (distillation range
ꢀ
6
0–80 C)–ethylacetate as eluent.
OH
S
O
4.4.2. 5-(1-Hydroxy-1-methyl-ethyl)-thieno-[2,3-c]-
pyran-7-one (3a).
O
ꢀ
1
Brown color solid; mp 101–102 C; H NMR (CDCl3,
2
OH
00 MHz) d 7.54 (d, J¼5.6 Hz, 1H), 7.34 (d, J¼5.6 Hz,
1
H), 4.02 (t, J¼5.9 Hz, 2H), 3.88 (t, J¼5.9 Hz, 2H), 3.08
O
S
(
t, J¼5.9 Hz, 2H), 2.75 (t, J¼5.9 Hz, 2H), 1.66 (br s,
O
ꢁ
1
–
OH); IR (cm , KBr) 3381, 2919, 1712 (C]O); m/z (CI
Mass) 265 (M , 100%); C (CDCl , 50 MHz) d 160.3
+
13
ꢀ
1
White solid, mp 87–88 C; H NMR (CDCl , 200 MHz)
3
3
(
7
(
C]O), 158.1, 152.4, 132.1, 128.4, 125.8, 102.1, 95.3,
3.6, 60.8 (CH OH), 59.9 (CH OH), 35.6 (CH ), 23.9
CH ); UV (nm, MeOH) 316.4, 276.0, 264.8, 232.8; HPLC
2
8.0%, column: Zorbax Eclipse XDB C-18 (150ꢂ4.6 mm),
d 7.82 (d, J¼5.3 Hz, 1H), 7.17 (d, J¼5.0 Hz, 1H), 6.8 (s,
1H, CH]C), 2.24 (br s, –OH), 1.61 (s, 6H, CH ); IR
3
2
2
2
ꢁ1
+
(cm , KBr) 3499, 1736 (C]O); m/z (ES Mass) 211 (M ,
100%); C (CDCl , 50 MHz) d 164.7 (C]O), 155.7,
1
3
9
mobile phase A: 0.05% TFA in water, mobile phase B:
3
147.3, 136.8, 124.7 (2C), 97.3, 71.2, 28.4 (2C, CH ); UV
3
0
1
.05% TFA in methanol, gradient (T/%B): 0/30, 13/70,
5/100, 25/100, flow rate: 1.5 mL/min, UV 254 nm, reten-
(nm, MeOH) 360.0, 353.8, 310.4, 282.0, 230.8; HPLC
99.2%, column: Zorbax Eclipse XDB C-18 (150ꢂ4.6 mm),
mobile phase A: 0.05% TFA in water, mobile phase B:
0.05% TFA in methanol, gradient (T/%B): 0/30, 13/70,
tion time 8.9 min; Elemental analysis found C, 59.17; H,
.47; C H O S requires C, 59.08; H, 4.58.
4
1
3 12 4

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9567
1
5/100, 25/100, flow rate: 1.5 mL/min, UV 254 nm, retention
(T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
min, UV 254 nm, retention time 6.4 min; HRMS Calcd for
C H O S (M+H ): 197.0272. Found: 197.0271.
time 7.2 min; Elemental analysis found C, 57.24; H, 4.75;
C H O S requires C, 57.13; H, 4.79.
+
1
0
10
3
9 8 3
4.4.6. 5-Butyl-thieno[2,3-c]pyran-7-one (3e).
4
(
.4.3. 5-(2-Hydroxy-ethyl)-thieno[2,3-c]pyran-7-one
3b).
OH
O
S
O
O
S
O
1
H NMR (CDCl , 400 MHz) d 7.78 (d, J¼5.1 Hz, 1H), 7.10
3
1
(d, J¼5.1 Hz, 1H), 6.43 (s, 1H), 2.56 (t, J¼7.3 Hz, 2H),
Low melting brown solid; H NMR (CDCl , 400 MHz)
3
1
3
.74–1.66 (m, 2H), 1.46–1.36 (m, 2H), 0.94 (t, J¼7.3 Hz,
ꢁ
3
d 7.82 (d, J¼5.0 Hz, 1H), 7.14 (d, J¼5.3 Hz, 1H), 6.58 (s,
1
H); IR (cm CHCl ) 2957, 1720 (C]O); m/z (ES Mass)
1
(
(
H), 4.02 (t, J¼6.0 Hz, 2H), 2.84 (t, J¼6.0 Hz, 2H), 1.65
ꢁ
3
+
13
1
209 (M , 100%); C NMR (CDCl
(C]O), 156.7, 147.5, 136.4, 124.0 (2C), 100.3, 33.1, 29.6,
2
, 50 MHz) d 161.0
3
br s, –OH); IR (cm , CHCl ) 3430, 1717 (C]O); m/z
+
13
ES Mass) 197 (M , 100%); C NMR (CDCl , 50 MHz)
3
d 157.6 (C]O), 152.2, 147.4, 136.7, 124.2 (2C), 102.2,
9.6 (CH ), 29.6 (CH ); UV (nm, MeOH) 312.4, 231.4,
2 2
10.0; HPLC 97.0%, column: Zorbax Eclipse XDB C-18
(150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water, mo-
bile phase B: 0.05% TFA in methanol, gradient (T/%B):
/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
54 nm, retention time 5.2 min; Elemental analysis found
C, 55.15; H, 4.10; C H O S requires C, 55.09; H, 4.11.
9 8 3
2.0, 13.7 (CH ); UV (nm, MeOH) 315.0, 281.6, 231.2,
3
10.4; HPLC 98.0%, column: Zorbax Eclipse XDB C-18
2
5
2
(
150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient
T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
(
min, UV 254 nm, retention time 16.9 min; Elemental analy-
sis found C, 63.39; H, 5.83; C H O S requires C, 63.43; H,
5
0
2
1
1 12 2
.81.
4.4.7. 5-Hexyl-thieno [2,3-c] pyran-7-one (3f).
4
(
.4.4. 5-(3-Hydroxy-propyl)-thieno[2,3-c]pyran-7-one
3c).
O
S
OH
O
O
S
1
O
H NMR (CDCl , 200 MHz) d 7.79 (d, J¼5.0 Hz, 1H), 7.11
3
(
1
d, J¼5.0 Hz, 1H), 6.43 (s, 1H), 2.59–2.52 (m, 2H), 1.78–
1
Low melting brown solid; H NMR (CDCl , 200 MHz)
3
.70 (m, 2H), 1.40–1.25 (m, 6H), 0.92–0.85 (m, 3H); IR
d 7.80 (d, J¼5.1 Hz, 1H), 7.12 (d, J¼5.1 Hz, 1H), 6.49 (s,
ꢁ1
+
(
(
cm , CHCl ) 3390, 1718 (C]O); m/z (CI Mass) 237
M , 100%); C NMR (CDCl , 50 MHz) d 161.0 (C]O),
3
13
1
1
1
H), 2.70 (t, J¼7.5 Hz, 2H), 2.39 (t, J¼6.9 Hz, 2H), 2.05–
ꢁ
1
3
.94 (m, 2H), 1.56 (br s, –OH); IR (cm , CHCl ) 3361,
3
1
2
56.3, 147.5, 136.4, 124.0 (2C), 100.3, 33.4, 31.4, 28.5,
7.0, 22.4, 13.9; UV (nm, MeOH) 314.8, 231.4, 210.0;
+
713 (C]O); m/z (CI Mass) 211 (M , 100%); UV (nm,
MeOH) 308.8, 231.2, 209.8; HPLC 96.5%, column: Zorbax
Eclipse XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05%
TFA in water, mobile phase B: 0.05% TFA in methanol,
gradient (T/%B): 0/30, 13/70, 15/100, 25/100, flow rate:
1.5 mL/min, UV 254 nm, retention time 8.1 min; Elemental
analysis found C, 57.24; H, 4.77; C H O S requires C,
HPLC 96.0%, column: Zorbax Eclipse XDB C-18
150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
(
0
2
/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
54 nm, retention time 17.1 min; HRMS Calcd for
1
0 10 3
+
C H O S (M+H ): 237.0949. Found: 237.0943.
13 16 2
5
7.13; H, 4.79.
4
.4.8. 5-Hydroxymethyl-thieno[2,3-c]pyran-7-one (3g).
4
(
.4.5. 5-(1-Hydroxy-ethyl)-thieno[2,3-c]pyran-7-one
3d).
OH
O
S
OH
O
1
O
Low melting brown solid; H NMR (CDCl , 200 MHz)
3
S
d 7.84 (d, J¼5.1 Hz, 1H), 7.18 (d, J¼5.1 Hz, 1H), 6.74 (s,
O
ꢁ
H), 4.54 (s, 2H), 1.65 (br s, –OH); IR (cm , CHCl )
3
1
1
1
+
Low melting brown solid; H NMR (CDCl , 200 MHz)
3
3388, 2926, 1696 (C]O); m/z (CI Mass) 183 (M , 100%);
C NMR (CDCl , 50 MHz) d 156.3 (C]O), 144.7, 142.5,
3
136.9, 124.5 (2C), 100.3, 61.4 (CH OH); UV (nm, MeOH)
2
1
3
d 7.83 (d, J¼5.0 Hz, 1H), 7.16 (d, J¼5.0 Hz, 1H), 6.75 (s,
1
H), 4.75–4.66 (m, 1H), 2.58 (br s, –OH), 1.56 (d,
ꢁ
1
J¼6.7 Hz, 3H); IR (cm , CHCl ) 3331, 1712 (C]O);
306.6, 231.0, 209.2; HPLC 95.0%, column: Zorbax Eclipse
XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
water, mobile phase B: 0.05% TFA in methanol, gradient
(T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
min, UV 254 nm, retention time 4.9 min; Elemental analysis
found C, 52.69; H, 3.34; C H O S requires C, 52.74; H,
3
+
13
m/z (CI Mass) 197 (M , 100%); C NMR (CDCl3,
5
9
2
0 MHz) d 162.0 (C]O), 151.0, 147.0, 136.8, 124.6 (2C),
8.6, 66.8 (CHOH), 21.5 (CH ); UV (nm, MeOH) 309.4,
3
31.4, 209.8; HPLC 98.0%, column: Zorbax Eclipse XDB
C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
8
6 3
mobile phase B: 0.05% TFA in methanol, gradient
3.32.

9568
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
4
(
.4.9. 5-(2-Hydroxy-propyl)-thieno[2,3-c]pyran-7-one
3h).
found C, 55.49; H, 3.05; N, 4.59; C H NO S requires C,
14 9 5
55.44; H, 2.99; N, 4.62.
4
7
.4.12. 5-(1H-Indol-5-yloxymethyl)-thieno-[2,3-c]pyran-
-one (3k).
O
OH
S
O
H
N
1
Low melting brown solid; H NMR (CDCl , 200 MHz)
3
d 7.80 (d, J¼5.1 Hz, 1H), 7.12 (d, J¼5.1 Hz, 1H), 6.54 (s,
1
–
H), 4.31–4.25 (m, 1H), 2.77–2.66 (m, 5H), 1.83 (br s,
OH); IR (cm , CHCl ) 3366, 1713 (C]O); m/z (CI
O
O
ꢁ
1
3
+
13
Mass) 211 (M , 100%); C NMR (CDCl , 50 MHz)
3
S
O
d 159.1 (C]O), 157.7, 147.3, 136.7, 124.2 (2C), 102.4,
6
6.2, 43.0 (CHOH), 23.1 (CH ); UV (nm, MeOH) 237.6,
3
ꢀ
1
White crystalline solid; mp 130–131 C; H NMR (CDCl ,
3
2
31.4, 210.6; HPLC 96.0%, column: Zorbax Eclipse XDB
2
6
(
(
00 MHz) d 7.82 (d, J¼5.1 Hz, 1H), 7.34–6.91 (m, 5H),
C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in
.46 (d, J¼11.8 Hz, 1H), 6.85 (s, 1H), 4.98 (s, 2H); IR
water, mobile phase B: 0.05% TFA in methanol, gradient
(
ꢁ1
+
cm , KBr) 2924, 2854, 1710 (C]O); m/z (CI Mass) 298
M , 100%); UV (nm, MeOH) 360.4, 298.6, 211.6; Elemen-
T/%B): 0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/
min, UV 254 nm, retention of time 7.3 min; Elemental anal-
ysis found C, 57.24; H, 4.78; C H O S requires C, 57.13;
H, 4.79.
tal analysis found C, 64.69; H, 3.72; N, 4.68; C H NO S
1
requires C, 64.63; H, 3.73; N, 4.71.
6
11
3
1
0 10 3
4
.4.10. 5-Phenoxymethyl-thieno[2,3-c]pyran-7-one (3i).
4.4.13. 5-Phenyl aminomethyl-thieno-[2,3-c]pyran-7-one
3l).
(
O
O
S
N
H
O
O
S
ꢀ
1
O
Pale yellow solid; mp 105.2–105.5 C; H NMR (CDCl ,
3
2
7
4
00 MHz) d 7.83 (d, J¼2.4 Hz, 1H), 7.34–7.30 (m, 2H),
ꢀ
1
Pale yellow solid; mp 156–157 C; H NMR (CDCl3,
200 MHz) d 7.79 (d, J¼5.1 Hz, 1H), 7.08–7.23 (m, 4H),
.19 (d, J¼2.9 Hz, 1H), 7.17–6.99 (m, 3H), 6.86 (s, 1H),
ꢁ1
.93 (s, 2H); IR (cm , CHCl ) 3411, 1722 (C]O); m/z
3
ꢁ1
+
13
6.80–6.63 (m, 3H), 4.27 (s, 2H); IR (cm , KBr) 3389,
1709 (C]O), 1603; m/z (CI Mass) 258 (M , 100%);
NMR (CDCl , 50 MHz) d 157.5 (C]O), 146.7 (2C),
36.7 (2C), 129.3 (2C), 124.4 (2C), 118.4, 112.9 (2C),
00.3, 45.2 (CH ); UV (nm, MeOH) 310.6, 283.8, 240.0,
04.2; HPLC 97.0%, column: Zorbax Eclipse XDB C-18
(
CI Mass) 259 (M , 100%); C NMR (CDCl , 50 MHz)
3
+
13
C
d 157.7 (C]O), 155.1, 146.7, 136.9, 130.7, 129.9 (2C),
29.5, 124.6, 121.8, 114.6 (2C), 101.2, 65.7; UV (nm,
3
1
1
1
2
MeOH) 304.2, 231.6, 209.8; HPLC 95.0%, column: Zorbax
Eclipse XDB C-18 (150ꢂ4.6 mm), mobile phase A: 0.05%
TFA in water, mobile phase B: 0.05% TFA in methanol,
gradient (T/%B): 0/30, 13/70, 15/100, 25/100, flow rate:
1.5 mL/min, UV 254 nm, retention of time 15.3 min; Ele-
mental analysis found C, 65.21; H, 3.88; C H O S requires
C, 65.10; H, 3.90.
2
(
150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
0
2
/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
54 nm, retention of time 12.4 min; Elemental analysis
1
4 10 3
found C, 65.53; H, 4.26; N, 5.33; C H NO S requires C,
2
1
4
11
6
5.35; H, 4.31; N, 5.44.
4
7
.4.11. 5-(4-Nitro-phenoxymethyl)-thieno-[2,3-c]pyran-
-one (3j).
4.4.14. 5-Phenylsulfanylmethyl-thieno[2,3-c]pyran-7-one
3m).
(
O
NO2
O
S
S
O
O
S
O
ꢀ
1
Pale yellow solid; mp 212–213 C; H NMR (CDCl3,
2
1
00 MHz) d 8.24 (d, J¼9.4 Hz, 2H), 7.87 (d, J¼5.1 Hz,
Low melting brown solid; H NMR (CDCl , 200 MHz)
3
1
(
H), 7.23 (d, J¼5.1 Hz, 1H), 7.06 (d, J¼9.4 Hz, 2H), 6.81
d 7.78 (d, J¼5.1 Hz, 1H), 7.39–7.29 (m, 5H), 7.07 (d,
ꢁ
1
ꢁ1
+
s, 1H), 5.01 (s, 2H); IR (cm , KBr) 3106, 1713 (C]O),
J¼5.1 Hz, 1H), 6.53 (s, 1H), 3.94 (s, 2H); IR (cm
,
+
13
1591, 1338, 1265; m/z (CI Mass) 304 (M , 100%);
NMR (CDCl , 50 MHz) d 156.5 (C]O), 154.8, 144.9,
C
CHCl ) 3347, 2924, 1719 (C]O); m/z (CI Mass) 275 (M ,
3
1
3
100%); C NMR (CDCl , 50 MHz) d 155.9 (C]O),
3
3
1
1
42.5 (2C), 130.6 (2C), 124.9, 121.3 (2C), 114.2 (2C),
04.6, 64.3 (CH ); UV (nm, MeOH) 308.4, 228.8, 219.4;
146.7, 136.7, 134.5, 131.1, 130.8, 129.4, 129.1, 128.2,
127.3, 124.3 (2C), 101.8, 36.6; UV (nm, MeOH) 315.4,
238.2, 206.4; HPLC 96.0%, column: Zorbax Eclipse XDB
C-18 (150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
0/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
254 nm, retention time 15.6 min; Elemental analysis
2
HPLC 97.0%, column: Zorbax Eclipse XDB C-18
150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
(
0
2
/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
54 nm, retention of time 14.5 min; Elemental analysis

S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
9569
found C, 61.37; H, 3.65; C H O S requires C, 61.29; H,
1
0.01 mM) of compound dissolved in DMSO and incubated
for 48 h. Cells were fixed by adding ice-cold 50% trichloro-
acetic acid (TCA) and incubating for 1 h at 4 C. The plates
4 10 2 2
3
.67.
ꢀ
were washed with distilled water, air-dried, and stained with
SRB solution (0.4% wt/vol in 1% acetic acid) for 30 min at
room temperature. Unbound SRB was removed by washing
thoroughly with 1% acetic acid and the plates were air-dried.
The bound SRB stain was solubilized with 10 mM Tris
buffer, and the optical densities were read on a spectrophoto-
metric plate reader at 515 nm. At the time of drug addition
separate reference plate for cell growth at time 0 h (the
time at which drugs were added) was also terminated as
described above. From the optical densities the percentage
growths were calculated using the following formulae:
4
(
.4.15. 5-Indol-1-ylmethyl-thieno[2,3-c]pyran-7-one
3n).
N
O
S
O
ꢀ
1
Pale yellow solid; mp 179–180 C; H NMR (CDCl3,
2
00 MHz) d 7.75 (d, J¼5.1 Hz, 1H), 7.67 (d, J¼6.9 Hz,
1
H), 7.32 (d, J¼7.5 Hz, 1H), 7.25–7.14 (m, 3H), 6.98 (d,
if T is greater than or equal to T , percentage growth¼
J¼5.3 Hz, 1H), 6.62 (s, 1H), 6.05 (d, J¼1.3 Hz, 1H), 5.20
0
ꢁ
1
100ꢂ[(TꢁT )/(CꢁT )] and if T is less than T , percentage
(s, 2H); IR (cm , KBr) 3364, 2931, 1709 (C]O); m/z
(CI Mass) 282 (M , 100%); C NMR (CDCl , 50 MHz)
0
0
0
+
13
growth¼100ꢂ[(TꢁT )/T )], where T is optical density of
0
0
3
test, C is the optical density of control, and T is the optical
0
d 162.8 (C]O), 155.3, 146.5 (2C), 136.9 (2C), 128.2,
24.5, 122.3, 121.2 (2C), 120.1, 109.2, 102.9, 100.3, 47.1
CH ); UV (nm, MeOH) 360.0, 291.0, 281.0, 219.6;
density at time zero. From the percentage growths a dose
response curve was generated and GI50 values were interpo-
lated from the growth curves.
1
(
2
HPLC 98.0%, column: Zorbax Eclipse XDB C-18
150ꢂ4.6 mm), mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in methanol, gradient (T/%B):
(
Acknowledgements
0
2
/30, 13/70, 15/100, 25/100, flow rate: 1.5 mL/min, UV
54 nm, retention of time 15.7 min; Elemental analysis
The authors thank Dr. A. Venkateswarlu, Dr. R. Rajagopa-
lan, Professor J. Iqbal and Dr. Vilas Dahanukar for their en-
couragement and the analytical group for spectral data. S.
Raju thanks DRL for allowing him to pursue this work as
a part of his Ph.D. dissertation. M.P. thanks DRL for allow-
ing him to attend the Symposium on Chemistry, Biology and
Medicine organized on the occasion of the 60th Birthday of
Professor K. C. Nicolaou, from May 28 till June 1, 2006, in
Paphos, Cyprus.
found C, 68.52; H, 3.90; N, 4.85; C H NO S requires C,
1
6
11
2
6
8.31; H, 3.94; N, 4.98.
4.4.16. 6-(1-Hydroxy-1-methyl-ethyl)-thieno[3,2-c]-
pyran-4-one (3aa).
O
O
S
OH
ꢀ
1
Off-white solid; mp 115–116 C; H NMR (CDCl3,
2
References and notes
00 MHz) d 7.56 (d, J¼5.3 Hz, 1H), 7.30 (d, J¼5.3 Hz,
ꢁ1
1
KBr) 3231, 2981, 1723 (C]O); m/z (CI Mass) 211 (M ,
H), 6.9 (s, 1H), 2.24 (br s, –OH), 1.60 (s, 6H); IR (cm
,
1
. (a) Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Johnson, N.
J. Org. Chem. 1992, 57, 4083; The chemistry of a-pyrones
has been investigated intensively, see for example: (b) Kvita,
V.; Fischer, W. Chimia 1992, 46, 457; (c) Kvita, V.; Fischer,
W. Chimia 1993, 47, 3; (d) Katritzky, A. R.; Wang, Z.; Wang,
M.; Hall, C. D.; Suzuki, K. J. Org. Chem. 2005, 70, 4854;
For potent and non peptidic HIV protease inhibitory effects
of a-pyrones, see: (e) Vara Prasad, J. V. N.; Para, K. S.;
Lunney, E. A.; Ortwine, D. F.; Dunbar, J. B., Jr.; Ferguson,
D.; Tummino, P. J.; Hupe, D.; Tait, B. D.; Domagala, J. M.;
Humblet, C.; Bhat, T. N.; Liu, B.; Guerin, D. M. A.;
Baldwin, E. T.; Erickson, J. W.; Sawyer, T. K. J. Am. Chem.
Soc. 1994, 116, 6989.
+
1
3
1
1
00%); C (CDCl , 50 MHz) d 163.6 (C]O), 158.2,
3
47.3, 125.5, 125.2, 96.4, 83.9, 65.5, 31.0 (2C, CH ); UV
3
nm, MeOH) 310.6, 283.4, 230.6, 210.5; HPLC 97.0%,
column: Zorbax Eclipse XDB C-18 (150ꢂ4.6 mm), mobile
phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA
in methanol, gradient (T/%B): 0/30, 13/70, 15/100, 25/100,
flow rate: 1.5 mL/min, UV 254 nm, retention time 8.1 min;
(
Elemental analysis found C, 57.40; H, 4.75; C H O S
0 10 3
1
requires C, 57.13; H, 4.79.
4
.5. Protocol for in vitro cell growth assay
2
. (a) Barry, R. D. Chem. Rev. 1964, 64, 229; (b) Nozawa, K.;
Yamada, M.; Tsuda, Y.; Kawai, K.; Nakajima, S. Chem.
Pharm. Bull. 1981, 29, 2491; (c) Hussain, M. T.; Rama,
N. H.; Malik, A. Indian J. Chem., Sect. B 2001, 40, 372; (d)
Sato, H.; Konoma, K.; Sakamura, S. Agric. Biol. Chem. 1981,
45, 1675; (e) See for example: Drug Data Rep. 1999, 21,
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Kuboki, H.; Hirano, S.-I.; Kumagai, H.; Ishizuka, M.;
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I. J. S.; Marrison, L. R.; Dickinson, J. M.; Lu, F.-J.; Schmidt,
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Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995,
Anticancer activity of selected compounds has been tested in
HT-29 (ATCC NO# HTB-38 Colon adenocarcinoma), NCI-
H460 (ATCC NO# HTB-177 Large cell lung cancer), and
LoVo (ATCC NO# CCL-229 Colon adenocarcinoma) cell
1
8
lines by using Sulforhodamine B (SRB) assay. Cells
were maintained in RPMI 1640 with 10% FBS (Fatal Bovine
Serum), Penicillin (50 mg/mL), and Streptomycin (100 mg/
mL). Cells were seeded in a 96-well cell culture plates at
a concentration of 10,000 cells per well and incubated at
3
ꢀ
treated with different concentrations (100, 10, 1, 0.1, and
7 C in CO incubator. Twenty-four hours later cells were
2

9570
S. Raju et al. / Tetrahedron 62 (2006) 9554–9570
6
0, 3270; (i) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem.
Fairlamb, I. J. S.; Lee, A. F.; Loe-Mie, F.; Niemel €a , E. H.;
O’Brien, C. T.; Whitwood, A. C. Tetrahedron 2005, 61,
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A.; Batsanov, A. S.; Howard, J. A. K.; Lydon, D. P.; Low,
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3
4, pp 911–913; (b) Burger, A. Prog. Drug Res. 1991, 37, 287;
(
c) Colotta, V.; Catarzi, D.; Varano, F.; Melani, F.;
Filacchioni, G.; Cecchi, L.; Trincavelli, L.; Martini, C.;
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makalim were found to be 10-fold more potent than
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spontaneously hypertensive rats, see: Sanfilippo, P. J.;
McNally, J. J.; Press, J. B.; Fitzpatrick, L. J.; Urbanski, M. J.;
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7179.
1
2, 3522; (g) For example, thiophenes can undergo Diels–
10. For our earlier studies on Sonogashira-type reactions, see: (a)
Pal, M.; Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R.
Synlett 2002, 1976; (b) Pal, M.; Subramanian, V.;
Parasuraman, K.; Yeleswarapu, K. R. Tetrahedron 2003, 59,
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V.; Batchu, V. R.; Dager, I. Synlett 2004, 1965; (e) Batchu,
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Kumar, S.; Pal, M. Tetrahedron 2005, 41, 9869.
11. For the synthesis of 3-iodo-thiophene-2-carboxylic acid (1),
see: Duffault, J.-M.; Tellier, F. Synth. Commun. 1998, 28, 2467.
12. Crystallographic data (excluding structure factors) for 3a have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 607010.
13. Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J. Org. Lett. 2003,
5, 301.
14. (a) Coupling of 3-iodothiophenes with terminal alkynes under
Sonogashira conditions are common in the literature, see for
example: Ye, X.-S.; Wong, H. N. C. J. Org. Chem. 1997, 62,
1940; (b) Padwa, A.; Chiacchio, U.; Fairfax, D. J.; Kassir,
J. J.; Litrico, A.; Semones, M. A.; Xu, S. L. J. Org. Chem.
1993, 58, 6429.
15. Conversion of Pd(0) to Pd(II) species under Sonogashira con-
dition has been proposed by Lu et al., see: Lu, X.; Huang,
X.; Ma, S. Tetrahedron Lett. 1993, 34, 5963; This Pd(II) species
was thought to be responsible for the cyclization of ynenoic
acid via the s-vinyl-palladium intermediate, see also:
Yanagihara, N.; Lambert, C.; Iritani, K.; Utimoto, K.;
Nozaki, H. J. Am. Chem. Soc. 1986, 108, 2753.
Alder reactions through their 1,1-dioxide derivatives, see:
Press, J. B.; Russell, R. K. Progress in Heterocyclic
Chemistry; Suschitzky, H., Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1992; Vol. 4, pp 62–80; (h) Ram, V. J.; Goel, A.;
Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7,
3101.
4
. For synthesis of related derivatives, see: (a) Mladenovic, S. A.;
Castro, C. E. J. Heterocycl. Chem. 1968, 5, 227; (b) Mentzer, B.
Bull. Soc. Chim. Fr. 1945, 12, 292; (c) Zhang, Y.; Herndon,
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C. J.; Shah, P. J. Chem. Soc., Perkin Trans. 1 1990, 2909; (e)
Jackson, P. M.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1
1990, 681.
5
. (a) Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J. Org.
Chem. 2005, 70, 4778; (b) A preliminary report on part of this
work has appeared, see: Raju, S.; Batchu, V. R.; Swamy, N. K.;
Dev, R. V.; Babu, J. M.; Kumar, P. R.; Mukkanti, K.; Pal, M.
Tetrahedron Lett. 2006, 47, 83.
. For leading references, see: (a) Sashida, H.; Kawamukai.
Synthesis 1999, 1145; (b) Yao, T.; Larock, R. C. J. Org.
Chem. 2003, 68, 5936; (c) Biagetti, M.; Bellina, F.; Carpita,
A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58, 5023; (d)
Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L.
Tetrahedron 2003, 59, 2067; (e) Peng, A.-Y.; Ding, Y.-X.
Org. Lett. 2004, 6, 1119.
6
7
8
. (a) Liao, H.-Y.; Cheng, C.-H. J. Org. Chem. 1995, 60, 3711; (b)
Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc., Perkin Trans. 1
1998, 561; (c) Kundu, N. G.; Pal, M. J. Chem. Soc., Chem.
Commun. 1993, 86.
. See for example: (a) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem.
2001, 66, 3642; (b) Fu, X.; Zhang, S.; Yin, J.; Schumacher,
D. P. Tetrahedron Lett. 2002, 43, 6673; (c) Kabalka, G. W.;
Dong, G.; Venkataiah, B. Tetrahedron Lett. 2004, 45, 5139;
16. Trost, B. M.; Chan, C.; Ruhter, G. J. Am. Chem. Soc. 1987, 109,
3486.
17. 3-Hex-1-ynyl thiophene-2-carboxylic acid was prepared by
1
4b
Sonogashira coupling
acid methyl ester with 1-hexyne in the presence of Et N in
of 3-iodo thiophene-2-carboxylic
3
ꢀ
DMF at 60 C for 6 h followed by hydrolysis of the resulting
ester in aqueous methanol.
(
d) Catellani, M.; Chiusoli, G. P.; Fagnola, M. C.; Solari, G.
Tetrahedron Lett. 1994, 35, 5923. See also Ref. 6b; For the
synthesis of 4-alkynyl-2-pyrones, see: (e) Marrison, L. R.;
Dickinson, J. M.; Ahmed, R.; Fairlamb, I. J. S. Tetrahedron
Lett. 2002, 43, 8853; (f) Fairlamb, I. J. S.; O’Brien, C. T.;
Lin, Z.; Lam, K. C. Org. Biomol. Chem. 2006, 4, 1213; (g)
18. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.;
Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.;
Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd, M. J. Natl.
Cancer Inst. 1991, 83, 757.
19. Duffault, J.-M.; Tellier, F. Synth. Commun. 1998, 28, 2467.