Iodine-induced efficient construction of a chromone-linked furo-[3,2-c]chromene scaffold by a one-pot 3-component cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2015.11.046

A novel and efficient method for the construction of 4-(3-chromonyl)furo[3,2-c]-1-benzopyran scaffold by molecular iodine-induced cascade reaction between 3-(1-alkynyl)chromone and 1-(2-hydroxyphenyl)-3-N,N-dimethylaminoprop-2-ene-1-one is described. Two

Full text of DOI:10.1016/j.tetlet.2015.11.046

Tetrahedron Letters 56 (2015) 7193–7196
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iodine-induced efficient construction of a chromone-linked
furo-[3,2-c]chromene scaffold by a one-pot 3-component cascade
reaction
Jaydip Ghosh a, Pritam Biswas a, Tapas Sarkar b, Chandrakanta Bandyopadhyay a,
⇑
a Department of Chemistry, R.K. Mission Vivekananda Centenary College, Rahara, Kolkata 700118, West Bengal, India
b Chemistry Division, CSIR-Indian Institute of Chemical Biology, Jadavpur 700 032, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient method for the construction of 4-(3-chromonyl)furo[3,2-c]-1-benzopyran scaffold
by molecular iodine-induced cascade reaction between 3-(1-alkynyl)chromone and 1-(2-hydroxy-
phenyl)-3-N,N-dimethylaminoprop-2-ene-1-one is described. Two new C–O, one C–C, and one C–I
bonds are formed in this one-pot cascade reaction. This tandem process involves Michael addition and
double annulation under mild conditions without using transition metal, inert atmosphere, or dry
solvent. Deiodination of the product was also accomplished.
Received 27 October 2015
Revised 9 November 2015
Accepted 14 November 2015
Available online 25 November 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Domino reaction
3-Alkynylchromone
Bichromone
Iodine
1-Benzopyran
Furochromone
Synthetic methodology that induces more than one bond for-
mation and cyclization by a single operation provides an attractive
route for the synthesis of polycyclic compounds. 2-(1-Alkynyl)-2-
alkene-1-one (A) (Fig. 1) is a promising unit for the construction
of substituted furans1 and this motif A also acts as a very good syn-
thon for the synthesis of different compounds of pharmaceutical
importance.2
1-(2-hydroxyphenyl)-3-(N,N-dimethylamino)propenone 2 as the
nucleophilic component considering its dual role: (i) it can act as
a nucleophile to facilitate 5-endo-dig cyclization to form furan 4
and (ii) the proximal hydroxy group to the iminium function in 4
could undergo second annulation to form 5, which readily forms
a
chromone-linked furochromone
dimethylamine (Scheme 1).
This expected structure 3 contains a furo[3,2-c]-1-benzopyran
with pendant chromone moiety. Furo[3,2-c]-1-benzopyran
3 by the elimination of
The ubiquity of the chromone skeleton in the plant kingdom3
and in many biologically active compounds4 deserves the synthesis
of new chromone-fused or chromone-linked polycyclic heterocy-
cles. 3-(1-Alkynyl)chromone 1 bearing the privileged moiety A
has drawn the attention of synthetic chemists for the synthesis
of biologically relevant and natural product-like frame works.
Literature survey reveals that different activating agents used to
activate the alkyne moiety of A or of 1 are costly transition metals
like AuCl3,1a (Ph3P)AuOTf,5 AuCl/AgOTf,6 PtCl2,7 Cu(I) halide,8 and
a
skeleton is widely distributed in different biologically active
natural products like coumestrol, wedelolactone, medicagol, and
plicadin.14 Again chromones and bichromones are also available
in nature and exhibit different pharmaceutical activities.4,15 It
would be of interest to develop processes for the synthesis of mole-
cules having furochromone, chromone, and bichromone motifs in
their structural unit for biological screening.
Our studies were initiated by the treatment of equimolar mix-
ture of 1a and 2a in the presence of CuBr (10 mol %) in DMF at
80–90 °C for 4 h. But 4H-furo[3,2-c]chromen-4-one 68b,16 (Fig. 2)
was obtained without the involvement of enamine 2 (Table 1,
entry 1). Use of CuI or CuCl in the place of CuBr in the above
reaction also yielded 6 (entries 2 and 3). On employing InCl3,
BF3ÁEt2O, or PdCl2 as catalyst in the reaction of 1a and 2a in
CH3CN or CHCl3, pure compound could not be isolated from the
reaction mixture (entries 4–6); whereas 2-(2-hydroxyphenyl)-5-
9
CuI-Pd(OAc)2 mainly in the presence of alcoholic nucleophiles.
Nitrogenous nucleophiles in the form of hydroxylamine,2b
imine,10 amidine,11 and carbon nucleophiles developed from active
methylene compounds2a,c,12 have also been employed. Molecular
iodine has been utilized to initiate reactions of A13 and 11b
using mainly alcoholic nucleophiles. We envisioned the use of
⇑
Corresponding author.
E-mail address: kantachandra@rediffmail.com (C. Bandyopadhyay).
http://dx.doi.org/10.1016/j.tetlet.2015.11.046
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

7194
J. Ghosh et al. / Tetrahedron Letters 56 (2015) 7193–7196
X
Ph
O
Ph
O
O
O
O
O
I
Y
CHO
O
OH
A
6
7
8
Figure 1. Structure of A.
Figure 2. Structures of 6–8.
Table 1
Reaction of 1a with 2a in the presence of different reagents
11). Surprisingly, when an equimolar mixture of 1a, 2a, and iodine
in CH2Cl2 was stirred for 24 h at room temperature, the reaction
mixture produced 3a in 43% yield along with 3-iodochromone 8
(Fig. 2) in 20% yield (entry 12). Formation of 8 from 2a is a well-
established reaction.17 To avoid the formation of this side product
8, the mode of addition was changed. At first a mixture of 1a
(1 equiv) and I2 (1.1 equiv) was stirred in CH2Cl2 at room temper-
ature for 1 h and then 2a (1.25 equiv) was added to the reaction
mixture and stirred for 14 h under similar reaction conditions. To
our delight, the reaction mixture afforded 3a in 67% yield (entry
13). To check the role of additional base, K3PO4 was added to the
reaction mixture, but addition of K3PO4 showed a detrimental
effect (entry 14).
Formation of 3a may be rationalized by considering the initial
activation of the alkyne by iodine to form iodonium ion 9a, which
undergoes Michael addition of enamine 2a followed by cyclization
to form furan 4a (Scheme 2). The suitably placed hydroxy group in
4a attacks the iminium ion and causes second annulation to form
5a, which eliminates dimethylamine to produce 3a.
Encouraged by the role of iodine, iodine monochloride was also
tested as a substitute of iodine in the above reaction. However, on
stirring a mixture of 1a (1 equiv) and ICl (1.2 equiv) in CH2Cl2 for
1 h followed by addition of 2a (1.25 equiv) and stirring for 14 h
produced 3a but in decreased yield compared to the use of iodine
(entries 13 and 15). Effect of solvent in this iodine-initiated reac-
tion was studied using 1a and 2a as substrates in different solvents.
Using solvents like DMF, Et2O, and CH3CN, no reaction was
observed. CHCl3 was found to be a better choice over CH2Cl2
(entries 13 and 16). Stirring a mixture of 1a (1 equiv) and I2
(1.1 equiv) in CHCl3 for 1 h at room temperature followed by the
addition of 2a (1.25 equiv) and further stirring for 14 h at room
temperature is the optimized reaction condition for the synthesis
of 3a (entry 16).
To study the scope and limitation of this methodology, various
3-(1-alkynyl)chromones 1 were used under the optimized reaction
conditions. It has been observed that electron donating groups on
the phenyl ring of chromone moiety in 1 increases the yield of 3
(3c, 3g, and 3h) (77–83%) (Table 2), whereas having an electron
withdrawing group in 1, 3e was obtained in only 45% yield, which
is much lesser than corresponding unsubstituted derivative 3b
(60%).
Ph
O
HO
Reagents
+
Products
Me2N
O
O
1a
2a
Entry
Reagents (equiv)
Reaction conditions
Product
Yieldd (%)
1
2
3
4
5
6
CuBr (0.1)
CuI (0.1)
CuCl (0.1)
InCl3 (0.2)
DMF/80–90 °C/4 h
DMF/80–90 °C/4 h
DMF/80–90 °C/4 h
CH3CN/Reflux/4 h
CHCl3/RT/12 h
6
6
70
65
65
—
—
—
30
42
52
—
6
a
—
—
—
a
a
BF3ÁEt2O (0.2)
PdCl2 (0.1)
CHCl3/RT/12 h
7
8
9
10
11
12
Pd(OAc)2 (0.1)
AgNO3 (0.2)
Ag(OCOCF3) (0.1)
Yb(OTf)3 (0.1)
PdCl2(PPh3)2 (0.1)
I2 (1.0)
CHCl3/RT/12 h
CHCl3/RT/ 12 h
CHCl3/RT/12 h
CHCl3/RT/24 h
CHCl3/RT/24 h
7
7
7
NRb
NRb
3a
8
3a
3a
3a
3a
—
CH2Cl2/RT/24 h
43
20
67
10
50
70
13
14
15
16
I2 (1.1)c
CH2Cl2/RT/15 h
CH2Cl2/RT/15 h
CH2Cl2/RT/15 h
CHCl3/RT/15 h
I2 (1.1)/K3PO4 (1.5)
ICl (1.2)
I2 (1.1)c
a
b
c
Pure compound could not be isolated.
No reaction.
Stirred a mixture of 1a (0.2 mmol) and I2 (0.22 mmol) in solvent (5 mL) for 1 h
and then a solution of 2a (1.25 equiv) in solvent (5 mL) was added and stirred.
d
Yield of isolated product based on 1a. ‘RT’ stands for room temperature.
R
O
O
R
O
E
NMe2
E+
O
HO
OH
1
Me2N
O
4
2
O
R
R
Different substitutions on the alkyne part of 1 showed that aryl
substituents generally work well than the alkyl group (3l) or
trimethylsilyl group (3m). It needs to mention that the reaction
conditions in the present methodology are mild enough to survive
trimethylsilyl group in the product 3m contrary to the earlier
reports.1b,10,13a Effect of substituent on the aryl part attached to
the alkyne moiety in 1 (R3 = Aryl) was also studied. Presence of
electron donating group was found to facilitate the reaction (3j,
3k in comparison to 3n). To consider the substituent effect on 2,
a series of enaminoketones 2 were synthesized and employed in
the iodine-mediated reaction with 1. Presence of an electron-
donating group on 2 facilitates the reaction (3f, 71%) whereas the
presence of weak electron-withdrawing groups decrease the
yield (3d, 53% and 3i, 57%) and strong electron-withdrawing NO2
group decreases markedly the yield of 3o (28%) (Table 2).
O
O
E
E
-Me2NH
NMe2
O
O
O
O
H
O
O
3
5
Scheme 1. Our envisioned one-pot synthesis of 4-(3-chromonyl)furo[3,2-c]-1-
benzopyran (3).
phenylfuran-3-carbaldehyde (7)5 (Fig. 2) was isolated in varying
amounts when Pd(OAc)2 or AgNO3 or AgOCOCF3 were used as
catalysts in CHCl3 medium (entries 7–9). Use of Yb(OTf)3 or
PdCl2(PPh3)2 as catalyst caused no change in 1a (entries 10 and

J. Ghosh et al. / Tetrahedron Letters 56 (2015) 7193–7196
Ph
7195
After developing the process for the synthesis of 3, an attempt
was made to deiodinate 3 by the reductive cleavage of the C–I
bond. As a test case 3b was converted into 10 by treating 3b
(1 equiv) with sodium formate (3 equiv) in dry DMF in the pres-
ence of PdCl2(PPh3)2 (0.02 equiv) as catalyst to produce 10 in 79%
yield (Scheme 3). This two-step process will be a very good method
for the synthesis of furo[3,2-c]chromene scaffold avoiding the use
of costly gold or silver catalysts.
O
O
Ph
I
I+
2a
NMe2
OH
O
9a
Michael addition-
cyclization
O
4a
O
CHCl3
RT
Iodination
Cyclization
O
Ph
1a
I2
+
In conclusion, we have synthesized hitherto unreported 3-iodo-
4-(3-chromonyl)furo[3,2-c]chromene 3 by a one-pot molecular
iodine-induced cascade reaction between 3-(1-alkynyl)chromone
I
-Me2NH
NMe2
O
3a
O
H
O
1
and 1-(2-hydroxyphenyl)-3-N,N-dimethylaminopropenone 2
5a
under mild reaction conditions without using any transition metal
or dry solvent. This reaction involves Michael addition and double
annulation. Finally, reductive cleavage of C–I bond in 3 was accom-
plished and the overall attempt developed a method for the
Scheme 2. Probable mechanism for the formation of 3a.
Table 2
Synthesis of 4-(3-chromonyl)-3-iodofuro[3,2-c]-1-benzopyrans 3
R3
O
O
R3
O
HO
O
R5
R4
I
R1
R2
R1
R2
Me
N
I2/CHCl 3
Me
RT/ Stirring
O
O
1
2
3a-o
O
R5
R4
O
O
O
O
O
I
I
Me
Cl
I
I
Me
I
O
O
O
O
O
O
O
O
O
O
3e
45%
3d
53%
O
O
3b
60%
3a
70%
O
O
3c
82%
O
Me
Me
Cl
Me
Me
O
O
O
O
O
I
I
I
MeO
I
I
O
O
O
O
O
O
O
O
MeO
O
O
3f
71%
3j
O
O
3h
77%
O
O
3i
57%
O
3g
83%
79%
OMe
F
OMe
Br
Me
Me
Me
SiMe3
I
O
O
O
O
O
O
I
I
I
I
O
O
O
O
O
O
O
O
O
3m
O
3l
3n
3o
28%
O
3k
77%
O
O
O
48%
43%
66%
OMe
OMe
NO 2
Me
Me

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J. Ghosh et al. / Tetrahedron Letters 56 (2015) 7193–7196
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for spectral analysis and finally the college authority for providing
other research facilities. J.G. thanks the CSIR for a Senior Research
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