Pd/ligand-free synthesis of thienopyranones via Cu-catalyzed coupling-cyclization in PEG 400 under ultrasound

Article abstract of DOI:10.1016/j.tetlet.2014.01.115

A greener and practical synthesis of 5-substituted thieno[2,3-c]pyran-7- ones has been achieved via Cu-catalyzed coupling-cyclization of 3-iodothiophene-2-carboxylic acid with terminal alkynes in the presence of K₂CO₃ in PEG 400 under ultrasound irradiation. A range of thienopyranone derivatives were synthesized by using this inexpensive and Pd- and ligand-free methodology.

Full text of DOI:10.1016/j.tetlet.2014.01.115

Tetrahedron Letters 55 (2014) 1660–1663
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd/ligand-free synthesis of thienopyranones via Cu-catalyzed
coupling-cyclization in PEG 400 under ultrasound
a
b
b
b,
⇑
Manam Sreenivasa Rao , Meda Haritha , N. Chandrasekhar , Mandava V. Basaveswara Rao ,
Manojit Pal
a
c,
⇑
C.R. College, Ganapavaram, Chilakaluripet 522616, Andhra Pradesh, India
Department of Chemistry, Krishna University, Nuzvid 521201, Andhra Pradesh, India
Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A greener and practical synthesis of 5-substituted thieno[2,3-c]pyran-7-ones has been achieved via Cu-
Received 10 December 2013
Revised 24 January 2014
Accepted 25 January 2014
Available online 1 February 2014
catalyzed coupling-cyclization of 3-iodothiophene-2-carboxylic acid with terminal alkynes in the pres-
ence of K
2 3
CO in PEG 400 under ultrasound irradiation. A range of thienopyranone derivatives were syn-
thesized by using this inexpensive and Pd- and ligand-free methodology.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Thienopyranone
Copper
PEG
Ultrasound
Due to the well-known bioisosterism between thiophene and
the benzene ring thienopyranones can be considered as alternative
scaffolds for isocoumarins1 in medicinal chemistry and pharma-
ceutical research. However, unlike isocoumarins as a class of com-
pounds the thienopyranones are rather unusual. Only a few
number of thieno[2,3-c]pyran-4-ones were synthesized and evalu-
solvent in organic reactions is advantageous due to its high boiling,
non-hazardous and polar nature thereby allowing its easy recovery
(from the reaction mixture) and recyclability. The use of ultra-
sound in organic reactions has also gained considerable atten-
tion due to certain advantages over conventional heating. For
example, ultrasound irradiation can accelerate chemical reactions,
improve yields, shorten reaction times, and enhance selectivity.
The present synthesis of thienopyranones therefore involved Cu-
catalyzed coupling of 3-iodothiophene-2-carboxylic acid (1) with
8
,9
2
ated for their antileishmanial and antifungal activities. Recently,
some of the 5-substituted thieno[2,3-c]pyran-7-ones synthesized
were tested in vitro for their anticancer activities.3 Several meth-
4
ods have been reported for the synthesis of thienopyranones
2 3
terminal alkynes (2) under ultrasound in the presence of K CO
including the construction of the pyranone ring on the thiophene
moiety either via classical methods or by using Fisher carbene
complexes. In our effort5 we have reported the synthesis of
in PEG 400 (Scheme 1).
3
In the beginning of our study, the coupling of 1 and 2-methyl-
but-3-yn-2-ol (2a) was used as a model reaction to establish the
optimum reaction conditions. Accordingly, the reaction of 1 with
2a was performed in PEG 400 in the presence of 10 mol % CuI
,6
5
-substituted thieno[2,3-c]pyran-7-ones via 10%Pd/C-CuI-PPh
3
catalyzed coupling-cyclization of 3-iodothiophene-2-carboxylic
3
acid with terminal alkynes in 1,4-dioxane. The methodology
2 3
and K CO (Table 1, entry 1) when some progress was observed
however, required the use of two metal catalysts, expensive PPh
3
after 24 h of sonication (using SONOREX SUPER RK 510H model
producing irradiation of 35 KHz). However, the use of 20 mol %
CuI increased the product yield significantly and decreased the
reaction time from 24 to 2 h (Table 1, entry 2). A further increase
in catalyst quantity did not improve the yield (Table 1, entry 3).
To assess the role of ultrasound in the present transformation
the reaction of 1 with 2a was performed in the absence of this irra-
diation when the formation of 3a was not observed (Table 1, entry
ligand, and solvent. Very recently, we have developed a greener
method for the Cu-mediated synthesis of isocoumarins in the pres-
7
ence of CuI in polyethylene glycol 400 (PEG 400). In further con-
tinuation of this work we now report an alternative and
environmental friendly synthesis of thienopyranones that is free
from the use of any Pd catalysts and ligands. The use of PEG as a
4
). All these reactions were carried out using K
2 3
CO as a base. The
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
use of other bases such as Cs CO and K PO was also examined
2
3
3
4
http://dx.doi.org/10.1016/j.tetlet.2014.01.115
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

M. S. Rao et al. / Tetrahedron Letters 55 (2014) 1660–1663
1661
Table 2
R
I
Synthesis of 5-substituted thieno[2,3-c]pyran-7-ones via Cu-catalyzed coupling-
cyclization in PEG 400 under ultrasound (Scheme 1)
+
R
a
O
CuI, K
2
CO
3
S
S
CO H
2
PEG, rt, 2-3h
3
O
Entry Alkyne (2; R =)
Time Products (3)
h)
%
1
2
Yieldb
(
Scheme 1. Cu-mediated synthesis of 5-substituted thieno[2,3-c]pyran-7-ones in
PEG 400.
HO
Me
Me
1
2
2a; –CMe OH
2
77
O
S
Table 1
O
3a
OH
The optimization of coupling of 3-iodothiophene-2-carboxylic acid (1) with 2-
methylbut-3-yn-2-ol (2a)a
2
3
2b; –CH
2
CH
2
OH
2.5
2.5
O
O
69
65
S
S
O
O
3b
HO
I
OH
+
OH
O
2 2 2
2c; –CH CH CH OH
CuI, Base
Solvent
S
S
CO H
2
O
3a
3c
1
2a
OH
4
2d; CHMeOH
2.5
59
O
O
O
O
S
S
S
S
O
O
O
O
3d
Entry
CuI (mol %)
Base
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
10
20
50
20
20
20
20
20
2
K CO
2
K CO
2
K CO
2
K CO
3
3
3
3
PEG
PEG
PEG
PEG
PEG
PEG
EtOH
n-BuOH
24
2
2
36
4
4
36
77
76
5
6
7
2e; –CH
2
CH
2
CH
2
Me
2
2
3
63
71
54
3e
c
0
Cs
2
CO
PO
CO
CO
3
68
64
57
55
2f; –CH
2 2 4
(CH ) Me
K
3
K
2
K
2
4
3
2
2
3f
3
OH
a
All the reactions were carried out by using 3-iodothiophene-2-carboxylic acid
1, 1.0 mmol), 2-methylbut-3-yn-2-ol (2a, 1.5 mmol), base (2.0 mmol), and CuI in a
solvent (5.0 mL) at room temp (25 °C) in a sonicator under nitrogen.
2g; –CH
2
OH
(
3g
OH
b
Isolated yield.
Reaction was carried out in the absence of ultrasound.
c
8
9
2h; –CH
2
CHMeOH
2.5
2
O
O
61
79
S
S
O
O
3h
and found to be effective (Table 1, entries 5 and 6). The use of other
solvents for example EtOH and n-BuOH (Table 1, entries 7 and 8)
was also investigated. While the reaction proceeded well in these
cases the product yield however was inferior compared to PEG 400.
We then decided to expand the scope and generality of this Cu-
catalyzed coupling-cyclization in PEG 400 under ultrasound. Thus
a range of terminal alkynes (2) were reacted with the iodo com-
pound (1) under the optimized reaction conditions that is entry 2
of Table 1 and the results are summarized in Table 2. The reaction
proceeded smoothly in all these cases affording a variety of 5-
O
2i; –CH
2j; –CH
2
OPh
3i
NO
2
O
10
2
OC
6
H
4
NO
2
-p
2
73
O
S
O
3
3
j
1
0
substituted thieno[2,3-c]pyran-7-ones (3) in acceptable yields.
H
N
H
N
Notably, unlike an earlier report the formation of 4-alkynyl thie-
no[2,3-c]pyran-7-ones as side products was not observed in the
present case though the yield of desired product 3 was not partic-
ularly high. While all these reactions were performed at room tem-
perature a marginal increase of bath temperature (up to ꢀ40 °C)
was observed during ultrasound irradiation. Thus the reaction
temperature was maintained by adding cold water occasionally.
All the compounds synthesized were characterized by NMR, IR,
k; --CH
2
O
O
2
11
12
2
3
68
68
O
O
S
O
k
N
3
2l; –CH
2
NHPh
H
and MS and compared with that reported earlier. The appearance
S
13
of a signal at the range d 165–155 ppm in the C NMR spectra and
O
3l
À1
IR absorption at 1720–1690 cm indicated the presence of a six-
a
membered aromatic lactone ring. Moreover, the C-4 vinylic proton
of the lactone ring appeared at ꢀd 6.8–6.4.
All the reactions were carried out by using 1 (1.0 mmol), an appropriate ter-
minal alkyne (2, 1.5 mmol), K CO (2.0 mmol), and CuI (20 mol %) in PEG (5.0 mL) at
2
3
room temp (25 °C) in a sonicator under nitrogen.
A probable mechanism for the present Cu-catalyzed coupling-
cyclization method leading to 5-substituted thieno[2,3-c]pyran-
b
Isolated yield.
7
-ones in PEG 400 under ultrasound is shown in Scheme 2. The sol-
11
vent PEG seems to play the role of a ligand too in the present
with the carboxylate anion of 1 to afford the arene-Cu species B.
reaction. Thus, a Cu(I) complex (A) formed via the interaction of
CuI with PEG under ultrasound, underwent oxidative addition
The reaction of alkyne 2 with B in the presence of K
the arene-Cu(III)-alkyne species C, which on reductive elimination
2 3
CO affords
1
1

1
662
M. S. Rao et al. / Tetrahedron Letters 55 (2014) 1660–1663
potential against a panel of cancer cell lines e.g. HT-29 (colon),
NCI-H460 (lung), and LoVo (colon) in vitro. The compounds 3a
and 3i have shown encouraging activities though their mechanism
CuI
3
PEG+K
2
CO
3
R
O
Cu
HO
S
1
A
KI+KHCO
3
of pharmacological action was not clearly understood. Being biois-
R
K
2
CO
3
OK
15
oteric analogues of isocoumarins these compounds may also be-
S
(
I)
have as inhibitors of the urokinase-type plasminogen activator
(uPA). The uPA has been considered as a promising molecular tar-
get for the development of small molecule based anticancer agents
as its elevated expression is associated with tumor cell growth,
migration, and angiogenesis. The role of isocoumarin framework
in binding with uPA has been investigated in 3D-QSAR studies
O
Cu OH
O
S
O K
A
D
O
2
CO K
I
reductive
elimination
oxidative
addition
O
K
HO
S
Cu
16
employing linear and non-linear regression analysis methods.
(
III)
S
R
(
III)
O
O
S
Cu
Apart from the key role of the pyranone ring the study suggested
considerable influences of the benzene ring of the isocoumarin
framework toward uPA inhibition. The electron rich thiophene
moiety of 3 therefore may play an interesting role in the potential
inhibition of uPA. Thus, the present class of thienopyranones is of
further interest and deserves continued pharmacological
investigations.
Cu
I
O
CO2K
R
KHCO
O
O
H
CO
K
C
B
2
H
E
O
3
2 3
K CO
A
H
R
KI + KHCO3
K2CO3
(2)
3
In conclusion, Cu-catalyzed coupling-cyclization of 3-iodothio-
phene-2-carboxylic acid with terminal alkynes in the presence of
Cyclization
Coupling
2 3
K CO in PEG 400 under ultrasound irradiation afforded an inex-
Scheme 2. Proposed mechanism for the Cu-mediated coupling-cyclization of 1
with 2 in PEG under ultrasound.
pensive and easy access to 5-substituted thieno[2,3-c]pyran-7-
ones. The methodology is free from the use of hazardous catalysts,
reagents, or solvents. A number of thienopyranone derivatives
were synthesized by using this Pd- and ligand-free methodology.
A proposed reaction mechanism and the possible mode of phara-
macological action of this class of compounds are presented. Over-
all, the methodology being amenable for the construction of
diversity based library of small molecules related thienopyranone
framework may find wide application in organic synthesis/medic-
inal chemistry.
of ‘Cu’ furnished the 3-alkynylthiophene-2-carboxylate with the
regeneration of catalyst A. While it is not clear if ultrasound had
an effect on one or more of these individual steps in this pathway
the irradiation however played a key role in the overall reaction as
is evident from Table 1. It is well known that ultrasound works by
the phenomenon of cavitation involving the growth, oscillation,
and collapse of bubbles under the action of an acoustic field. Exper-
imental evidences suggest that the cavitational collapse creates
drastic conditions inside the medium for an extremely short time
Acknowledgments
(
indeed temperature of 2000–5000 K and pressure up to 1800
atmosphere have been produced inside the collapsing cavity under
The authors (M.S.R., M.H., N.C., M.V.B.R.) thank the Krishna Uni-
versity, Nuzvid, Andhra Pradesh, India for encouragement.
8
a,12
sonic conditions).
This collapse also causes strong physical ef-
fects such as shear forces, jets, and shock waves outside the bubble.
As a result of these cavitation-induced overall effects the chemical
transformations are driven with remarkable efficiency and speed
when performed under ultrasound. This is probably the reason
for the success of present coupling-cyclization reaction in PEG un-
der ultrasound in the absence of which the reaction did not
proceed.
References and notes
1. Pal, S.; Chatare, V.; Pal, M. Curr. Org. Chem. 2011, 15, 782.
2
3
.
.
Ram, V. J.; Goel, A.; Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7, 3101.
Raju, S.; Batchu, V. R.; Swamy, N. K.; Dev, R. V.; Sreekanth, B. R.; Babu, J. M.;
Vyas, K.; Kumar, P. R.; Mukkanti, K.; Annamalai, P.; Pal, M. Tetrahedron 2006, 62,
9554.
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;
To expand the scope and generality of the present methodology
further we examined the coupling of 3-bromobenzo[b]thiophene-
(
c) Zhang, Y.; Herndon, J. W. J. Org. Chem. 2002, 67, 4177; For other examples of
1
3
2
-carboxylic acid (4) with phenyl acetylene (2m) in the presence
the thienopyrone ring system, see: (d) Jackson, P. M.; Moody, 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.
of CuI and K CO in PEG 400 at room temp (25 °C) in a sonicator un-
2
3
der nitrogen (Scheme 3). While the reaction proceeded under this
condition affording the expected product that is 3-(phenyl)benzo-
thieno[2,3-c]pyran-1-one14 (5) in 43% yield the duration of the
reaction was much longer (6 h) and a substantial quantity of 1,4-
diphenylbuta-1,3-diyne (as a result of dimerization of alkyne 2m)
was isolated as a side product in this case.
We have developed an alternative and convenient protocol for
the synthesis of 5-substituted thieno[2,3-c]pyran-7-ones. Some of
these compounds were already tested for their growth inhibition
5.
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.
6. Nakhi, A.; Adepu, R.; Rambabu, D.; Kishore, R.; Vanaja, G. R.; Kalle, A. M.; Pal, M.
Bioorg. Med. Chem. Lett. 2012, 22, 4418.
7.
Chary, R. G.; Reddy, G. R.; Ganesh, Y. S. S.; Prasad, K. V.; Chandra, S. K. P.;
Mukherjee, S.; Pal, M. RSC Adv. 2013, 3, 9641.
8. (a) Mason, T. J.; Peters, D. Practical Sonochemistry; Ellis Horwood: New York, NY,
USA, 1991; (b) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443–451.
9. Luche, J. L. Organic Sonochemistry; Plenum Press: New York, NY, USA, 1998.
10. General method for the synthesis of 5-substituted thieno[2,3-c]pyran-7-ones (3): a
mixture of 3-iodo thiophene-2-carboxylic acid (1, 1.0 mmol), an appropriate
terminal alkyne (2, 1.0 mmol), CuI (20 mol %) and K
2 3
CO (2.0 mmol) in PEG
(
5.0 mL) was sonicated at 25–30 °C for the time indicated in Table 2 (the
progress of the reaction was monitored by TLC). After completion of the
reaction, the mixture was diluted with EtOAc (20 mL) and filtered through
celite. The filtrate was collected and washed with water (20 mL). The EtOAc
layer was collected, dried over anhydrous Na SO , filtered, and concentrated.
2 4
The residue was purified by column chromatography on silica gel using EtOAc–
Ph
Br
CO H
+
Ph
O
S
CuI, K CO3
2
S
2
petroleum ether. Spectral data of selected compounds; compound 3a: white
PEG, rt, 6h
O
1
4
2m
5
solid, mp 86–87 °C; H NMR (CDCl
, 200 MHz) d 7.81 (d, J = 5.3 Hz, 1H), 7.16 (d,
3
À1
J = 5.0 Hz, 1H), 6.8 (s, 1H, CH@C), 2.25 (br s, –OH), 1.60 (s, 6H, CH
KBr) 3495, 1734 (C@O); m/z (ES Mass) 211 (M ,100%); C NMR (CDCl
3
3
); IR (cm
,
,
+
13
Scheme 3. Cu-mediated coupling of 3-bromobenzo[b]thiophene-2-carboxylic acid
4) with phenyl acetylene (5m) in PEG 400 under ultrasound.
(
50 MHz) d 164.6 (C@O), 155.5, 147.4, 136.6, 124.5(2C), 97.2, 71.1, 28.2 (2C,

M. S. Rao et al. / Tetrahedron Letters 55 (2014) 1660–1663
1663
CH
3
); compound 3b: low melting solid; 1H NMR (CDCl
3
, 400 MHz) d 7.80 (d, solid obtained was recrystallized from hot acetone to give the desired product
1
J = 5.0 Hz, 1H), 7.13 (d, J = 5.3 Hz, 1H), 6.57 (s, 1H), 4.02 (t, J = 6.0 Hz, 2H), 2.83
as a colorless solid (yield 50%); mp 279–281 °C; H NMR (acetone-d
6
, 400 MHz)
À1
13
(
t, J = 6.0 Hz, 2H), 1.63 (br s, –OH); IR (cm , CHCl
3
) 3435, 1716 (C@O); m/z (ES
d 8.03–7.98 (m, 2H), 7.66–7.57 (m, 2H); C NMR (acetone-d , 100 MHz) d
6
+
13
Mass) 197 (M , 100%); C NMR (CDCl
3
, 50 MHz) d 157.5 (C@O), 152.1, 147.3,
).
161.8 (C@O), 139.3, 138.6, 128.3, 125.7, 125.5, 122.7, 115.1; m/z (ES Mass) 257
(M+1, 100%).
1
36.5, 124.1 (2C), 102.3, 59.5 (CH ), 29.5 (CH
2
2
1
1. (a) Mao, J.; Guo, J.; Fang, F.; Ji, S.-J. Tetrahedron 2008, 64, 3905; (b) Yoshikai, N.;
Nakamura, E. Chem. Rev. 2012, 112, 2339.
14. 3-(Phenyl)benzothieno[2,3-c]pyran-1-one (5): white solid (crystallized from
1
3
ether/petroleum ether); mp 211–213 °C; H NMR (CDCl , 400 MHz): d 8.11–
1
1
2. Mason, T. J. Ultrason. Sonochem. 2007, 14, 476.
3. (a) Cross, P. E.; Dickson, R. P.; Parry, J. M.; Randal, J. M. J. Med. Chem. 1989, 29,
8.09 (m, 1H, ArH), 7.98–7.93 (m, 3H, ArH), 7.64–7.46 (m, 5H, ArH), 7.39 (s, 1H,
4-CH); 13C NMR (CDCl
3
, 100 MHz): d 158.8 (C@O), 157.4, 143.7, 143.6, 134.2,
1
643; (b) Preparation of 3-bromobenzo[b]thiophene-2-carboxylic acid (4): To a
solution of commercially available benzo[b]thiophene-2-carboxylic acid (1 g,
.61 mmol) and anhydrous NaOAc (1.0 g, 12.1 mmol) in glacial acetic acid
30 mL) was added bromine (2.48 g, 31.4 mmol) drop wise and slowly. The
131.7, 130.3, 129.2, 128.9 (2C), 125.4 (2C), 125.4, 123.6, 123.6, 122.5, 96.9 (4-
CH); m/z (ES Mass) 278 (M , 100%).
15. Heynekamp, J. J.; Hunsaker, L. A.; Jagt, T. A. V.; Deck, L. M.; Jagt, D. L. V. BMC
Chem. Biol. 2006, 1. http://dx.doi.org/10.1186/1472-6769-6-1.
16. Bhongade, B. A.; Amnerkar, N. D.; Talath, S.; Bhusari, K. P.; Gadad, A. K. Lett.
Drug Des. Discovery 2012, 9, 874.
+
5
(
reaction mixture was stirred at 55–60 °C under nitrogen for 24 h. The mixture
was poured into ice water (170 mL). The resulting precipitate was filtered,
washed with cold water, (3 Â 30 mL) and then EtOH (20 mL) and dried. The