Catalyst-free domino-Knoevenagel-hetero-Diels-Alder reaction of terminal alkynes in water: an efficient one-step synthesis of indole-annulated thiopyranobenzopyran derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.10.108

The domino-Knoevenagel-hetero-Diels-Alder reaction of O-propargylated salicylaldehyde and 1-methylindoline-2-thione in aqueous medium in the absence of Lewis acid has been described for the synthesis of hitherto unreported indole-annulated pentacyclic het

Full text of DOI:10.1016/j.tetlet.2009.10.108

Tetrahedron Letters 51 (2010) 147–150
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free domino-Knoevenagel-hetero-Diels–Alder reaction of terminal
alkynes in water: an efficient one-step synthesis of indole-annulated
thiopyranobenzopyran derivatives
*
K. C. Majumdar , Abu Taher, Sudipta Ponra
Department of Chemistry, University of Kalyani, Kalyani 741 235, W.B, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The domino-Knoevenagel-hetero-Diels–Alder reaction of O-propargylated salicylaldehyde and 1-methy-
lindoline-2-thione in aqueous medium in the absence of Lewis acid has been described for the synthesis
of hitherto unreported indole-annulated pentacyclic heterocycles containing oxygen, nitrogen and sulfur.
This methodology involves only one step and easy work-up procedure to give the products in 72–80%
yields.
Received 5 September 2009
Revised 20 October 2009
Accepted 22 October 2009
Available online 27 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Domino-Knoevenagel-hetero-Diels–Alder
reaction
Unactivated alkyne
1
-Methylindoline-2-thione
Water reaction
Indole subunits are frequently present in many biologically ac-
of reagents.34,35 To avoid these discrepancies there was a need of
an efficient and convenient methodology for the synthesis of in-
dole-annulated [6,6]-fused pyranothiopyran system. In that case
domino-Knoevenagel-hetero-Diels–Alder reaction is the best one
and we have successfully utilized this reaction for the synthesis of
indole-annulated [6,6]-fused pyranothiopyran derivatives.36
The domino-Knoevenagel-hetero-Diels–Alder addition repre-
sents one of the most powerful and efficient reactions for the syn-
thesis of heterocyclic compounds, including natural products.3
Tietze extensively described the domino-Knoevenagel-hetero-
Diels–Alder reaction of unsaturated aromatic and aliphatic alde-
hydes with several 1,3-dicarbonyl compounds for the synthesis
1
–11
tive natural products.
Some indole derivatives have been found
to possess antitumor activity, some cause inflammation and vasc-
1
2–15
ication to human skin.
clic compounds are important due to their biological activity.
Some [6,6]-fused pentacyclic indole alkaloids like aspidospermine,
Thiopyranoindole-annulated heterocy-
1
6,17
4
,7
rauniticine, reserpine and yohimbine show extensive bioactivity.
This wide range of interesting activities of various indole deriva-
tives has prompted studies in the development of an efficient
methodology for the synthesis of [6,6]-fused pentacyclic deriva-
tives in which bioactive thiopyrano indole moiety is fused with a
benzopyran moiety.
7–41
4
2–45
Literature survey reveals several reports on the synthesis of
of tetracycles with a pyran ring.
There are several examples
benzopyran and pyranobenzopyran moieties1
8–23
but there are a
of intramolecular domino-Knoevenagel-hetero-Diels–Alder reac-
2
4–
26,27,46–53
few examples on the synthesis of polycyclic pyranothiopyrans.
tions with alkenes
but those of alkynes are rare. This
2
7
In our laboratory we have synthesized coumarin- and pyrone-
annulated [6,6]-fused pyranothiopyrans using sequential Claisen
may be due to low reactivity of the unactivated alkynes compared
to the corresponding alkenes. Very recently Balalaie and co-work-
2
4
54–58
rearrangement and tributyl tin hydride-mediated radical cycliza-
ers reported
a few hetero-Diels–Alder reactions of unactivated
2
5
I
tion, respectively. But we were not able to synthesize indole-annu-
lated [6,6]-fused pyranothiopyran ring; rather [6,5]-fused
alkynes using Cu -catalyst. But to our knowledge there is no exam-
ple of hetero-Diels–Alder reaction with unactivated alkynes in the
2
8
29
I
pyranothiofuran and a spiro compound were obtained when
the same methodology was applied upon thioindole moiety. More
examples on the synthesis of furanothiopyran moieties are avail-
absence of Cu -catalyst. This observation prompted us to undertake
a study on hetero-Diels–Alder reaction of unactivated alkynes in
the absence of a catalyst. Herein, we report the results of our
investigation.
3
0–33
able.
But there are drawbacks in dealing with this protocol
due to harsh reaction conditions and use of stoichiometric amount
The required precursors 2a–f were prepared in high yields and
purity by the reaction of substituted salicylaldehydes 1a–f and
propargyl bromide in the presence of anhydrous potassium car-
*
Corresponding author. Tel.: +91 033 2582 7521; fax: +91 033 2582 8282.
5
9
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
bonate in dry DMF at room temperature (Scheme 1).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.108

1
48
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 147–150
OH
Using the optimized condition, we have examined hetero-
Diels–Alder reaction of 3 and several O-propargylated aromatic
aldehydes (2a,b,d–f). The results are listed in Table 2.
To the best of our knowledge there is no report on the hetero-
Diels–Alder reaction of unactivated alkynes in the absence of a cat-
alyst. In the present instance the reactivity may perhaps be ex-
plained by considering the presence of soft sulfur atom in the
diene moiety of the substrates. The sulfur atom may offer itself a
reacting centre and polarizability compared to other hetero atoms.
Moreover, there are empty d-orbitals in the sulfur atom having a
O
a. 5,6-C H (phenylene)
6
4
CHO
R2
(
i)
CHO
R2
b. R
c. R
1
= Cl, R
= R = H
2
= Me
1
2
d. R = Br, R2 = H
e. R = Me, R2 = H
f. R = t-Bu, R2 = H
1
R1
1
R1
1
1
a-f
2
a-f
Scheme 1. Reagents and condition: (i) propargyl bromide, anhydrous
DMF, rt.
2 3
K CO ,
Many reactions including Diels–Alder reaction have been car-
ried out in aqueous medium6
0–63
as water is not only available in
symmetry matching that of the
for interaction.
p-orbitals of the acetylene moiety
nature in plenty but is also safe and environment friendly. There-
fore, we explored the use of water as a solvent for our proposed
work. Accordingly the domino-Knoevenagel-hetero-Diels–Alder
reaction of 1-methyl indoline-2-thione 3 with 2a–f was carried
out in an aqueous medium under refluxing condition. We first
chose 3 and 2c as model substrates to optimize the reaction condi-
tions. The results are summarized in Table 1 (Scheme 2).
A probable mechanism for the domino-Knoevenagel-hetero-
Diels–Alder reaction is shown in Scheme 3. Although we could
not isolate the intermediates 6 we can reasonably assume that a
combination of a Knoevenagel condensation between the thioin-
dole 3 and the O-propargylated aldehydes 2a–f and a hetero-
We have examined the influence of Lewis acid, base and sol-
vents in the reaction. When the reaction of 3 and 2c was carried
out in water under reflux condition in the absence of a catalyst
for 5 h the product 5c was obtained in 78% yield. However, when
CuI (20 mol %) was employed as a catalyst, the desired product
Table 2
a
Domino-Knoeveagel-hetero-Diels–Alder reaction of 3 and 2a–f in aqueous medium
O
1
R
O
H O
2
S
R2
+
5
c was obtained in only 52% yield after refluxing for 5 h (entry
R1
reflux
N
CHO
2
). When the same reaction was carried out for 8 h the yield
R2
S
3
N
slightly improved to 60% (entry 3). Increasing the amount of cata-
lyst loading (30 mol %) decreased the yield (entry 4). The affinity of
2a-f
4
a,b, 5c-f
1
0
64
Productc
Yieldb (%)
Entry
Aromatic aldehyde (2)
d
copper ions for soft sulfur atoms may have been detrimental
to the Knoevenagel reaction of 2 and 3, thereby affecting the yield
of the product. When the reaction was carried out for 8 h in the
presence of triethyl amine, the yield increased to 69% (entry 5).
Among the various solvents (water, methanol, acetonitrile and
CHO
O
O
1
2
3
4
5
78
2
a
4a65
4b65
c65
1
,4-dioxane) used, water was found to be superior than the others
N
S
when CuI (20 mol %) was used as a catalyst and triethyl amine as a
base (entries 5–8). Similar results were also obtained when
Cl
O
(
NH )
4 2
HPO
4
was used as a base in place of triethyl amine (entries
O
Me
N
Cl
CHO
9
–12). Among the various conditions employed, the reaction in
72
78
75
80
73
Me
aqueous media in the absence of a catalyst was found to give best
results (Table 1).
2b
S
O
O
Table 1
CHO
Effect of catalyst, solvent and base on the domino-Knoevenagel-hetero-Diels–Alder
reaction of 3 and 2c
2c
S
Entry
Lewis acid
mol %)
Solvent
Base
Time
(h)
Yield
(%)
N
5
(
Br
O
1
2
3
4
5
6
7
8
9
—
Water
Water
Water
Water
Water
MeOH
—
—
—
—
NEt
NEt
NEt
NEt
(NH
(NH
(NH
(NH
5
5
8
8
8
8
8
8
8
8
8
8
78
52
60
57
69
39
35
32
64
35
34
28
CuI (20)
CuI (20)
CuI (30)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
O
Br
CHO
2d
5d65
3
3
3
3
N
S
3
CH CN
O
Me
1,4-dioxane
water
MeOH
CH CN
3
1,4-dioxane
O
4
4
4
4
2
) HPO
2
) HPO
2
) HPO
2
) HPO
4
4
4
4
Me
CHO
1
1
1
0
1
2
2
e
5
e65
N
S
O
O
CHO
O
6
O
2
f
CHO
(
i)
S
+
N
S
5f65
N
S
a
b
c
2
c
All the reactions were carried out in refluxing aqueous medium for 5 h.
Isolated yields.
The products were characterized from elemental analyses and spectroscopic
3
N
5c
Scheme 2. Reagent and condition: (i) reflux in water.
data.

K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 147–150
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Diels–Alder reaction of unactivated terminal acetylene in the ab-
sence of any Lewis acid. The condition applied is mild, and water
is used as a reaction medium which is environment friendly. A
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propargyloxynaphthaldehyde (2a) (1 equiv) was refluxed in water for 5 h.
After completion of the reaction as monitored by TLC the reaction mixture was
cooled and diluted with water (50 mL). This was extracted with ethyl acetate
(3 Â 25 mL). The combined organic extract was washed with brine and dried
1
1
over anhydrous Na
2 4
SO . The solvent was distilled off. The crude product was
purified by column chromatography over silica gel (60–120 mesh) using
petroleum ether–ethyl acetate mixture (98:2) as eluent to give compound 4a.
1
Yield: 78%, colourless solid; mp 186–188 °C; IR(neat):
m
max = 749, 1456, 1613,
À1
1
1
1
2920 cm ; H NMR (CDCl , 300 MHz): d = 3.74 (s, 3H), 4.65 (d, J = 12.6 Hz,
3
H
1H), 4.85 (d, J = 12.9 Hz, 1H), 5.12 (s, 1H), 5.34 (d, J = 8.1 Hz, 1H), 6.36 (t,
J = 7.2 Hz, 1H), 6.64 (s, 1H), 6.87 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.25–
1
7.40 (m, 3H), 7.83 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H) ppm. MS: m/z = 355
+
(M ). Anal. Calcd for C23
H
17NOS: C, 77.72; H, 4.82; N, 3.94. Found: C, 77.89; H,

1
50
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 147–150
4
.77; N, 3.85.Compound 4b: Yield: 72%, colourless solid; mp 166–168 °C;
2H), 3.79 (s, 3H), 4.81 (s, 2H), 6.85 (d, J = 8.6 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H),
7.20 (t, J = 7.4 Hz, 1H), 7.29–7.39 (m, 3H), 7.58 (s, 1H) ppm. MS: m/z = 383, 385
À1
1
IR(neat):
mmax = 751, 1461, 1659, 2924 cm
;
3
H NMR (CDCl , 300 MHz):
+
d
H
= 2.34 (s, 3H), 3.72 (s, 3H), 4.49 (d, J = 12.3 Hz, 1H), 4.59 (s,1H), 4.73 (d,
(M ). Anal. Calcd for C19H14BrNOS: C, 59.38; H, 3.67; N, 3.64. Found: C, 59.61;
J = 12.6 Hz, 1H), 6.20 (d, J = 8.1 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.86 (d,
H, 3.63; N, 3.59.Compound 5e: Yield: 80%, colourless solid; mp 108–110 °C;
À1
1
J = 9.0 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.7 Hz,
IR(neat):
m
max = 747, 1464, 1611, 2918 cm
;
3
H NMR (CDCl , 500 MHz):
+
2
H) ppm. MS: m/z = 353 (M ). Anal. Calcd for C20
H16ClNOS: C, 67.88; H, 4.56; N,
H
d = 2.23 (s, 3H), 3.47 (s, 2H), 3.78 (s, 3H), 4.76 (s, 2H), 6.87 (d, J = 8.1 Hz, 1H),
3
.96. Found: C, 67.73; H, 4.62; N, 3.89.Compound 5c: Yield: 78%, colourless
6.98 (dd, J = 1.4, 8.1 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.28
À1
1
solid; mp 180–182 °C; IR(neat):
m
max = 751, 1457, 1601, 2917 cm
;
H NMR
(d, J = 1.4 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H) ppm. MS: m/
+
(
CDCl
3
, 500 MHz): d
H
= 3.47 (s, 2H), 3.78 (s, 3H), 4.80 (s, 2H), 6.96- 6.98 (m, 2H),
z = 319 (M ). Anal. Calcd for C20
H
17NOS: C, 75.20; H, 5.36; N, 4.39. Found: C,
7
.07 (t, J = 7.5 Hz, 1H), 7.17–7.21 (m, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.38 (d,
75.01; H, 5.43; N, 4.31.Compound 5f: Yield: 73%, colourless solid; mp 178–
1
3
À1
1
J = 8.0 Hz, 1H), 7.45 (dd, J = 1.5, 7.6 Hz, 1H) ppm. C NMR (100 MHz): 30.2,
180 °C; IR(neat):
mmax = 743, 1474, 1619, 2918 cm
;
3
H NMR (CDCl ,
3
1
6.1, 72.8, 102.7, 108.3, 109.9, 116.7, 118.0, 119.9, 120.7, 121.4, 125.7, 126.5,
27.3, 127.8, 128.0 129.0, 137.8, 153.7 ppm. MS: 327.93 (M+Na) . Anal. Calcd
500 MHz): d = 1.25 (s, 9H), 3.48 (s, 2H), 3.79 (s, 3H), 4.78 (s, 2H), 6.90 (d,
J = 8.3 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.20 (dd, J = 2.2,
H
+
for
C
19
H
15NOS: C, 74.72; H, 4.95; N, 4.59. Found: C, 74.98; H, 4.93; N,
8.4 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 2.1 Hz,
+
4
.66.Compound 5d: Yield: 75%, colourless solid; mp 140–142 °C; IR(neat):
1H) ppm. MS: m/z = 361 (M ). Anal. Calcd for C23
H
23NOS: C, 76.42; H, 6.41; N,
À1
1
mmax = 743, 1474, 1619, 2918 cm
;
3
H NMR (CDCl , 500 MHz): d
H
= 3.47 (s,
3.87. Found: C, 76.54; H, 6.44; N, 3.76.