Molecular iodine mediated regioselective synthesis of pyranocoumarins and bis-fused benzo-2 H -pyran derivatives

Article abstract of DOI:10.1055/s-0033-1341027

A simple and straightforward approach for the regioselective synthesis of pyranocoumarin and bis-fused benzo-2H-pyran derivatives using mild, easy to handle, and cheaper molecular iodine mediated heterocyclization is described. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341027

PAPER
▌1807
paper
Molecular Iodine Mediated Regioselective Synthesis of Pyranocoumarins and
Bis-Fused Benzo-2H-pyran Derivatives
Regioselective Iodocyclization Reactions
K. C. Majumdar,*a Biswajit Sinha,a Inul Ansary,a,1 Sintu Ganai,a Debankan Ghosh,a B. Roy,a B. Sridharb
a
Department of Chemistry, University of Kalyani, Kalyani 741235, W. B., India
E-mail: kcm@klyuniv.ac.in; E-mail: kcm_ku@yahoo.co.in
b
Laboratory of X-ray crystallography, IICT Hyderabad, Hyderabad 500007, India
Received: 08.01.2014; Accepted after revision: 25.02.2014
synthesize 2H-benzopyran derivatives14 utilizing molecu-
Abstract: A simple and straightforward approach for the regiose-
lar iodine-mediated heterocyclization, but the synthesis of
lective synthesis of pyranocoumarin and bis-fused benzo-2H-pyran
bis-fused 2H-benzopyrans is rare. Moreover, the growing
derivatives using mild, easy to handle, and cheaper molecular io-
importance of pyranocoumarin derivatives also demands
an easy route for their effective syntheses. Therefore, all
these findings inspired us to undertake a detailed study on
the molecular iodine-mediated intramolecular heterocy-
clization to access pyranocoumarin and bis-fused 2H-ben-
zopyran derivatives. Herein we report our results.
dine mediated heterocyclization is described.
Key words: molecular iodine, 6-endo-dig, electrophilic cylization,
bis-fused benzo-2H-pyrans, pyranocoumarins
2H-Benzopyrans or 2H-chromenes represent the structur-
al units of a variety of biologically important compounds.2
Chroman derivatives are known to possess various useful
biological activities, such as antioxidant,3 anticonvul-
sion,4 anti-estrogen,5 and neuroprotection.6 On the other
hand, pyranocoumarin and pyranopyran derivatives are
also important class of heterocycles. Their structural motif
is found widely in natural products and in many synthetic
molecules.7 They exhibit biological activities including
antifungal, anticancer, insecticidal, anti-inflammatory,
anti-HIV, and antibacterial activities (Figure 1).8
The required precursors 13a–c for this study were synthe-
sized in 72–77% yields from the substrates 12 by the reac-
tion with various p-substituted iodobenzenes. The
Banwell et al.10a
O
O
O
O
1, CH2Cl2, r.t.
2
1
t-Bu
t-Bu
NCMe
SbF6
P
Au
Because of their biological and pharmaceutical impor-
tance much attention has been paid to the isolation and
synthesis of 2H-pyrans fused with both benzene and cou-
marin rings.9 It is surprising that only few examples of bis-
fused benzopyran derivatives are known. Different re-
search groups have utilized either metal-catalyzed intra-
molecular cyclization strategies using AuCl3, Pd(OAc)2
as catalysts or iodocyclization reaction using IPy2BF4-
HBF4 catalytic system.10 On the other hand, pyranocou-
marins and pyranopyran derivatives have been synthe-
sized by using gold(III)-catalyzed tandem conjugate
addition/annulation reaction, ytterbium triflate-catalyzed
reactions, and multicomponent reactions (Scheme 1).11
3
Majumdar et al.10b
Br
O
O
Br
Pd(OAc)2
TBAB
O
O
KOAc
DMF
5
4
Barluenga et al.10d
I
Ph Ph
I
Therefore, it is apparent that synthesis of pyranocouma-
rins, pyranopyrans, and benzo-2H-pyran derivatives are
very important. Thus, search for an alternative protocol
that is easy to handle and also uses a cheaper reagent is al-
ways welcome. In this respect, molecular iodine-mediated
heterocyclization can be a useful alternative for the syn-
thesis of benzo-2H-pyran derivatives. This is because io-
docyclization offers an easy access to the complex
molecules that are not always accessible by the usual or-
ganometallic reagents.12,13 A few attempts were made to
O
IPy2BF4, HBF4
CH2Cl2, –80 °C
Ph
O
O
Ph
7
O
6
Ph
Liu et al.11a
OH
O
Ph
O
AuCl3, AgOTf
Ph
toluene, reflux
H
+
Ph
O
O
O
O
9
10
8
SYNTHESIS 2014, 46, 1807–1814
Advanced online publication: 07.04.2014
DOI: 10.1055/s-0033-1341027; Art ID: SS-2014-Z0020-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Scheme 1 Literature reports on 2H-pyrans fused with both benzene
and coumarin rings

1808
K. C. Majumdar et al.
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OH
O
OH
HO
O
O
OH
daurichromenic acid2d
potent anti-HIV agent
daurichromene A2c
histamine release inhibitor
OH
OMe
OMe
O
O
O2S
N
O
OH
chromenodihydrochalcone2f
L. donovani growth inhibitor
HIF-1 pathway inhibitor2e
O
O
O
O
OMe
antitrypanosomal agent2f
Cl
O
strong antileishmanial agent2f
COOMe
OMe
O
O
OH
O
OH
H
OH
O
cyathuscavins A7d
O
O
antibacterial agent
anhydrodinemasone BC7c
antibacterial agent
O
O
ferprenine7g
lethal hemorrhagic agent
O
Figure 1 Some biologically active 2H-benzopyran, pyranopyran, and pyranocoumarin derivatives
reactions were carried out in the presence of Pd(PPh3)2Cl2 with propargyl bromide in acetone in the presence of an-
as catalyst and copper(I) iodide as co-catalyst in anhy- hydrous K2CO3. Other precursors 14, 15, and 16a,b were
drous triethylamine–DMF (1:4) as mixed solvent at room prepared accordingly starting from hydroquinone, cate-
temperature for three hours. The O-propargylated com- chol, and 2,7-dihydroxynaphthol, respectively (Scheme
pound 12 was in turn prepared by refluxing resorcinol 11 2).
(i)
(ii)
O
O
HO
OH
O
O
R
R
12
11
13a R = 4-ClC6H4
13b R = 4-MeC6H4
13c R = 4-MeOC6H4
O
O
O
O
O
R
R
R
R
R
R
15 R = 4-MeOC6H4
O
16a R = 4-MeC6H4
16b R = 4-ClC6H4
14 R = 4-MeOC6H4
Scheme 2 Preparation of propargyl ethers. Reagents and conditions: (i) propargyl bromide, acetone, K2CO3, NaI, reflux; (ii) p-substituted
iodobenzene, Pd(PPh3)2Cl2, CuI, DMF–Et3N, r.t.
Synthesis 2014, 46, 1807–1814
© Georg Thieme Verlag Stuttgart · New York

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Regioselective Iodocyclization Reactions
1809
The iodocyclization reaction was performed with the With the optimized reaction conditions in hand, the other
compound 13a, molecular iodine (2 equiv), and NaHCO3 substrates 13b,c, 14, 15, and 16a,b were treated similarly
(2 equiv) at room temperature in anhydrous acetonitrile to afford the bis-fused 2H-benzopyran and naphthopyran
for six hours to give the bis-fused benzo-2H-pyran deriv- derivatives 17b,c, 18, 19, and 20a,b in 68–85% and 62,
ative 17a in 65% yield. The reaction occurred by a 6- 80% yield, respectively (Table 2).
endo-dig mode of cyclization. The 5-exo-dig cyclized
product was not obtained (Scheme 3).
R
O
R
O
I
I
(i)
O
O
R
R
13a
17a R = 4-ClC6H4
Scheme 3 Preparation of 17a. Reagents and conditions: (i) I2,
NaHCO3, MeCN, r.t.
The product 17a was characterized by its spectral analy-
sis. The structure was confirmed from the analysis of its
single crystal X-ray diffraction15 data (Figure 2). It is in-
teresting to note that the reaction is regioselective and
gave only the linearly cyclized product 17a.
Figure 2 ORTEP diagram of the compound 17a
After achieving the synthesis of the bis-fused iodocy-
clized products, the reaction was extended to the readily
available starting material, 4-hydroxycoumarin to accom-
plish the synthesis of pyranocoumarin derivatives.
Optimization experiments were carried out with a view to
improve the yield of the products. By varying the amounts
of both the iodine and base it was found that 3 equivalents
of iodine and 3 equivalents of NaHCO3 were optimum
and the yield of 17a was unexpectedly increased to 90%.
Further increase of the amount of NaHCO3 (4 equiv) and
iodine (4 equiv) did not give any better result. NaHCO3
was found to be more effective compared to other bases
like K2CO3, Na2CO3, etc. for the completion of the reac-
tion. Dichloromethane or methanol gave lower yields of
the product. On the basis of our observations, the opti-
mized conditions for the above reaction is I2 (3 equiv),
NaHCO3 (3 equiv), MeCN, r.t., six hours, and the results
are summarized in Table 1.
For this purpose, a number of starting materials 22a–d
were prepared in moderate to good yields by the Sono-
gashira coupling reaction of 21 with iodobenzene deriva-
tives. The reactions were performed in the presence of
Pd(PPh3)2Cl2 as catalyst and copper(I) iodide as co-cata-
lyst in a mixture of anhydrous triethylamine and DMF
(1:4) as mixed solvent at room temperature for five hours.
The substrate 22a was treated under the optimized reac-
tion conditions (Table 1) to give the pyranocoumarin de-
rivative 23a in 65% yield (Scheme 4).
I
O
O
O
R
(ii)
(i)
Table 1 Optimization of I2-Mediated Reactions
R
O
O
O
O
Entry Electrophile Base
Solvent
Product Yield
(%)a
O
23a
O
21
22a
(equiv)
(equiv)
R = 4-MeOC6H4
1
I2 (2)
I2 (3)
I2 (4)
I2 (3)
I2 (3)
I2 (3)
I2 (3)
NaHCO3 (2)
NaHCO3 (3)
NaHCO3 (4)
K2CO3 (3)
MeCN
MeCN
MeCN
MeCN
CH2Cl2
MeCN
MeOH
17a
17a
17a
17a
17a
17a
17a
65
90
90
35
25
50
45
2b
3
Scheme 4 Preparation of pyranocoumarin derivative 23a. Reaction
conditions: (i) p-substituted iodobenzene, Pd(PPh3)2Cl2, CuI, DMF–
Et3N, reflux; (ii) I2, NaHCO3, MeCN, r.t., 6 h.
4
Detailed experiments were carried out by changing sol-
vents and bases. It was found that the optimized reaction
conditions stated in Table 1 is also suitable for the above
reaction (Scheme 4). The other substrates 22b–d were
also subjected to react under the optimized conditions to
afford the cyclized products 23b–d in 55–72% yields (Ta-
ble 3).
5
NaHCO3 (3)
Na2CO3 (3)
NaHCO3 (3)
6
7
a Isolated yields.
b Optimized reaction conditions.
Here it should be noted that iodobenzenes containing Me,
Cl, and NO2 substituents do not undergo iodocyclization
reaction. In these cases, only iodine-addition products
© Georg Thieme Verlag Stuttgart · New York
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K. C. Majumdar et al.
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Yield (%)
85
Table 2 Synthesis of Bis-Fused Benzo-2H-pyran Derivatives
Starting material
R
Producta
R
R
O
I
I
O
O
O
4-MeC6H4
R
R
R
O
13b
17b
I
R
O
I
O
R
4-MeOC6H4
80
70
R
O
13c
17c
O
I
R
R
I
R
4-MeOC6H4
O
O
R
O
O
18
14
O
O
O
I
I
4-MeOC6H4
68
80
R
R
R
R
19
15
I
I
R
O
O
R
O
O
4-MeC6H4
R
R
16a
20a
I
I
R
O
O
R
O
O
4-ClC6H4
62
R
R
16b
20b
a Reaction conditions: I2 (3 equiv), NaHCO3 (3 equiv), MeCN, r.t.
were obtained as the only isolable products. In contrast, fused 2H-benzopyrans expeditiously from readily acces-
the iodobenzenes containing p-methoxy and p-ethoxy sible starting materials. Moreover, during the reaction the
groups, that is, strong electron-donating groups, reacted iodine atom is incorporated in the cyclized products that
efficiently to give the desired cyclized products.
offers scope for further modification.
From the above discussion it is clear that the reaction con-
ditions described above are simple and convenient com-
pared to other available methods. They avoid the use of
complex and relatively costlier reagents like palladium,
ytterbium, gold, etc. and the reactions are carried out at
ambient temperature.
Melting points were determined in an open capillary and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer L 120-000A
spectrometer on KBr disks. 1H NMR and 13C NMR spectra were re-
corded on a Bruker DPX-400 spectrometer in CDCl3 with TMS as
internal standard. CHN analyses were recorded on a 2400 series II
CHN analyzer (Perkin-Elmer). DMF was sequentially dried (3 ×)
over freshly activated 4 Å molecular sieves and Et3N was dried by
keeping overnight over anhydrous CaH2 and then distilled after 2 h
at reflux. Silica gel (60–120 mesh and 230–400 mesh, Spectrochem,
India) were used for chromatographic separation. Silica gel G and
silica gel GF-254 (Spectrochem, India) were used for TLC analyses.
In conclusion, the protocol reported here provides an op-
erationally simple method for effective iodocyclization
reaction. These reactions are cost effective and proceed
under very mild conditions to give a number of important
heterocyclic motifs including pyranocoumarins and bis-
Synthesis 2014, 46, 1807–1814
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Regioselective Iodocyclization Reactions
1811
Yield (%)
68
Table 3 Synthesis of Pyranocoumarin and Pyranopyran Derivatives
Starting material
Producta
I
O
O
O
OMe
O
O
O
I
OMe
22b
23b
23c
23d
O
O
O
72
55
OEt
O
O
O
I
OEt
22c
O
O
O
O
OMe
O
O
OMe
22d
a Reaction conditions: I2 (3 equiv), NaHCO3 (3 equiv), MeCN, r.t.
Petroleum ether (PE) refers to the fraction boiling between 60–
80 °C.
13c
Yield: 460 mg (72%); colorless solid; mp 100–101 °C.
IR (KBr): 1604, 2227, 2840 cm–1.
Propargyl Ethers 13a–c, 14, 15, and 16a,b; Compound 13a;
Typical Procedure
1H NMR (400 MHz, CDCl3): δ = 3.79 (s, 6 H, OCH3), 4.88 (s, 4 H,
OCH2), 6.66 (dd, J = 8.4 Hz, 2.0 Hz, 2 H, ArH), 6.72 (d, J = 2.0 Hz,
1 H, ArH), 6.80 (d, J = 8.8 Hz, 4 H, ArH), 7.23 (t, J = 8.4 Hz, 1 H,
ArH), 7.37 (d, J = 8.8 Hz, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.3, 56.9, 82.4, 87.2, 102.5,
107.8, 113.9, 114.3, 129.9, 133.4, 159.1, 159.9.
A mixture of compound 12 (300 mg, 1.6 mmol), p-chloroiodoben-
zene (920 mg, 3.9 mmol), anhydrous Et3N (2 mL), Pd(PPh3)2Cl2 (34
mg, 3 mol%), and CuI (9 mg, 3 mol%) was stirred in anhydrous
DMF (8 mL) at r.t. for 3 h. Then, the reaction mixture was diluted
to 30 mL with CH2Cl2. The organic phase was washed successively
with H2O (3 × 15 mL) and brine (15 mL), and dried (Na2SO4). The
solvent was removed under reduced pressure and the crude product
was purified by silica gel (60–120 mesh) column chromatography
using EtOAc–PE (1:19) as an eluent to give the solid compound
13a; yield: 505 mg (77%); colorless solid; mp 118–119 °C.
Anal. Calcd for C26H22O4: C, 78.37; H, 5.57. Found: C, 78.49; H,
5.39.
14
Yield: 405 mg (63%); colorless solid; mp 130–131 °C.
IR (KBr): 1608, 2237, 2845 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.88 (s, 4 H, OCH2), 6.66–6.70 (m,
3 H, ArH), 7.22–7.28 (m, 5 H, ArH), 7.35 (d, J = 8.4 Hz, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 56.7, 84.7, 86.1, 102.5, 107.9,
120.7, 128.7, 130.0, 133.1, 134.8, 159.0.
IR (KBr): 1602, 2230, 2855 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 6 H, OCH3), 4.85 (s, 4 H,
OCH2), 6.81 (d, J = 8.8 Hz, 4 H, ArH), 6.99 (s, 4 H, ArH), 7.37 (d,
J = 8.8 Hz, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.3, 57.5, 57.6, 82.8, 87.1, 113.9,
114.4, 116.0, 116.1, 116.4, 133.3, 152.0, 152.6, 159.8.
MS (ESI): m/z = 428.92 [M + Na]+, 430.90 [M + Na + 2]+, 432.90
[M + Na + 4]+.
Anal. Calcd for C26H22O4: C, 78.37; H, 5.57. Found: C, 78.51; H,
5.42.
Anal. Calcd for C24H16Cl2O2: C, 70.77; H, 3.96. Found: C, 70.72; H,
3.88.
15
13b
Yield: 450 mg (70%); colorless solid; mp 92–93 °C.
Yield: 445 mg (75%); colorless solid; mp 112–114 °C.
IR (KBr): 1604, 2224, 2836 cm–1.
IR (KBr): 1614, 2230, 2860 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.79 (s, 6 H, OCH3), 4.98 (s, 4 H,
OCH2), 6.80 (d, J = 8.8 Hz, 4 H, ArH), 6.97 (dd, J = 6.0, 4.0 Hz, 2
H, ArH), 7.14 (dd, J = 6.0, 3.6 Hz, 2 H, ArH), 7.34 (d, J = 8.8 Hz, 4
H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.3, 57.8, 82.7, 87.4, 113.9,
114.0, 114.5, 115.0, 121.9, 133.3, 147.9, 159.8.
1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 6 H, CH3), 4.89 (s, 4 H,
OCH2), 6.67 (dd, J = 8.4, 2.4 Hz, 2 H, ArH), 6.72 (d, J = 2.0 Hz, 1
H, ArH), 7.09 (d, J = 8.0 Hz, 4 H, ArH), 7.22 (t, J = 8.4 Hz, 1 H,
ArH), 7.33 (d, J = 8.0 Hz, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 21.5, 56.9, 83.1, 87.4, 102.5,
107.9, 119.2, 129.0, 129.9, 131.8, 138.8, 159.1.
Anal. Calcd for C26H22O4: C, 78.37; H, 5.57. Found: C, 78.29; H,
5.68.
HRMS (ESI): m/z calcd for C26H22O2: 389.1517 [M + Na]+; found:
389.1518 [M + Na]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1807–1814

1812
16a
K. C. Majumdar et al.
PAPER
Hz, 1 H, ArH), 6.52 (d, J = 8.4 Hz, 1 H, ArH), 6.91–6.95 (m, 4 H,
ArH), 7.05 (d, J = 8.0 Hz, 2 H, ArH), 7.12 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.2, 74.1, 75.6, 87.9, 90.0, 109.1,
113.0, 113.8, 114.1, 120.2, 127.6, 129.6, 130.6, 132.1, 135.2, 139.3,
141.2, 149.2, 155.8, 158.7, 159.3.
Yield: 290 mg (55%); yellow solid; mp 132–134 °C.
IR (KBr): 1625, 2233, 2921 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 6 H, CH3), 5.01 (s, 4 H,
OCH2), 7.07–7.11 (m, 6 H, ArH), 7.25 (s, 2 H, ArH), 7.32 (d, J =
7.6 Hz, 4 H, ArH), 7.69 (d, J = 8.8 Hz, 2 H, ArH).
Anal. Calcd for C26H20I2O4: C, 48.02; H, 3.10. Found: C, 48.17; H,
2.96.
13C NMR (100 MHz, CDCl3): δ = 21.5, 56.8, 83.1, 87.5, 107.1,
116.6, 119.2, 124.9, 129.1, 129.2, 131.7, 135.6, 138.8, 156.4.
18
Anal. Calcd for C30H24O2: C, 86.51; H, 5.81. Found: C, 86.79; H,
5.88.
Yield: 115 mg (70%); colorless solid; mp 188–189 °C.
IR (KBr): 1602, 2837 cm–1.
16b
1H NMR (400 MHz, CDCl3): δ = 3.85 (s, 6 H, OCH3), 4.69 (d, J =
12.8 Hz, 2 H, OCHaHb), 4.94 (d, J = 12.8 Hz, 2 H, OCHaHb), 6.57
(d, J = 8.8 Hz, 4 H, ArH), 6.64 (d, J = 8.8 Hz, 4 H, ArH), 6.97 (s, 1
H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.3, 75.1, 92.6, 113.5, 114.0,
125.0, 130.5, 131.7, 141.2, 147.6, 159.4.
Yield: 320 mg (55%); yellow solid; mp 71–72 °C.
IR (KBr): 1629, 2228, 2923 cm–1.
1H NMR (400 MHz, CDCl3):δ = 5.01 (s, 4 H, OCH2), 7.10 (dd, J =
8.8, 2.4 Hz, 2 H, ArH), 7.22–7.24 (m, 6 H, ArH), 7.35 (d, J = 8.4
Hz, 4 H, ArH), 7.70 (d, J = 8.8 Hz, 2 H, ArH).
MS (ESI): m/z = 650.73 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 56.6, 84.8, 86.2, 107.0, 116.6,
120.7, 125.0, 128.7, 129.4, 133.0, 134.8, 135.5, 156.3.
Anal. Calcd for C26H20I2O4: C, 48.02; H, 3.10. Found: C, 48.21; H,
3.01.
Anal. Calcd for C28H18Cl2O2: C, 73.53; H, 3.97. Found: C, 73.37; H,
3.88.
19
Yield: 110 mg (68%); yellow solid; mp 158–159 °C.
Bis-Fused Benzo-2H-pyran Derivatives 17a–c, 18, 19, and
20a,b; Compound 17a; Typical Procedure
IR (KBr): 1608, 2831 cm–1.
A mixture of compound 13a (100 mg, 0.24 mmol), molecular iodine
(183 mg, 0.72 mmol), and anhydrous NaHCO3 (60 mg, 0.72 mmol)
was stirred in anhydrous MeCN (10 mL) at r.t. for 6 h. Then, CH2Cl2
(50 mL) was added to the reaction mixture. The organic phase was
washed successively with 10% aq Na2S2O3 (15 mL), H2O (15 mL),
and brine (15 mL), and dried (Na2CO3). The solvent was removed
under reduced pressure and the crude product was purified by silica
gel (230–400 mesh) column chromatography using PE–EtOAc
(9.7:0.3) as eluent to give the solid product 17a; yield: 145 mg
(90%); colorless solid; mp 176–177 °C.
1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 6 H, OCH3), 5.12 (s, 4 H,
OCH2), 6.09 (s, 2 H, ArH), 6.91 (d, J = 8.4 Hz, 4 H, ArH), 7.07 (d,
J = 8.4 Hz, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.2, 75.4, 92.1, 113.8, 118.9,
125.4, 130.6, 131.8, 140.9, 141.4, 159.3.
MS (ESI): m/z = 672.71 [M + Na]+.
Anal. Calcd for C26H20I2O4: C, 48.02; H, 3.10. Found: C, 48.16; H,
3.13.
IR (KBr): 1612, 2831 cm–1.
20a
1H NMR (400 MHz, CDCl3): δ = 5.00 (s, 4 H, OCH2), 5.70 (s, 1 H,
ArH), 6.36 (s, 1 H, ArH), 6.90 (d, J = 8.4 Hz, 4 H, ArH), 7.25 (d,
J = 8.4 Hz, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 75.4, 92.1, 113.8, 118.9, 125.4,
130.6, 131.8, 140.9, 141.4, 159.3.
Yield: 130 mg (80%); yellow solid; mp 162–163 °C.
IR (KBr): 1615, 2932 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.31 (s, 6 H, CH3), 3.57 (d, J =
12.4 Hz, 2 H, OCHaHb), 4.65 (d, J = 12.4 Hz, 2 H, OCHaHb), 6.93
(d, J = 8.8 Hz, 2 H, ArH), 7.64 (d, J = 8.4 Hz, 2 H, ArH).
MS (ESI): m/z = 658.62 [M + H]+, 660.71 [M + H + 2]+.
13C NMR (100 MHz, CDCl3): δ = 21.2, 76.9, 79.5, 113.9, 120.8,
HRMS (ESI): m/z calcd for C24H14Cl2I2O2: 658.8538 [M + H]+;
125.8, 127.4, 130.0, 131.2, 136.8, 137.1, 142.4, 156.7.
MS (ESI): m/z = 669.07 [M + H]+, 691.07 [M + Na]+.
found: 658.8500 [M + H]+.
Anal. Calcd for C30H22I2O2: C, 53.92; H, 3.32. Found: C, 54.01; H,
3.41.
17b
Yield: 145 mg (85%); colorless solid; mp 192–193 °C.
IR (KBr): 1609, 2838 cm–1.
20b
1H NMR (400 MHz, CDCl3): δ = 2.32 (s, 6 H, CH3), 5.00 (s, 4 H,
OCH2), 5.80 (s, 1 H, ArH), 6.34 (s, 1 H, ArH), 6.84 (d, J = 8.0 Hz,
4 H, ArH), 7.03 (d, J = 8.0 Hz, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 21.2, 75.1, 86.4, 103.3, 118.0,
125.2, 128.7, 128.9, 136.2, 137.4, 141.2, 154.6.
Yield: 95 mg (62%); yellow solid; mp 194–195 °C.
IR (KBr): 1603, 2962 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.57 (d, J = 12.4 Hz, 2 H,
OCHaHb), 4.67 (d, J = 12.8 Hz, 2 H, OCHaHb), 6.89 (d, J = 8.8 Hz,
2 H, ArH), 7.60 (d, J = 8.8 Hz, 2 H, ArH).
MS (ESI): m/z = 640.73 [M + Na]+.
13C NMR (100 MHz, CDCl3): δ = 29.7, 76.9, 80.6, 114.3, 120.1,
125.8, 127.0, 129.4, 131.8, 133.4, 138.0, 141.3, 157.0.
Anal. Calcd for C26H20I2O2: C, 50.51; H, 3.26. Found: C, 50.68; H,
3.18.
HRMS (ESI): m/z calcd for C28H16Cl2I2O2: 708.8695 [M + H]+,
710.8695 [M + H + 2]+; found: 708.8687 [M + H]+, 710.8807 [M +
H + 2]+.
17c
Yield: 130 mg (80%); colorless solid; mp 168–170 °C.
IR (KBr): 1602, 2847 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.85 (s, 3 H, OCH3), 3.87 (s, 3 H,
OCH3), 4.35 (s, 2 H, OCH2), 4.93 (s, 2 H, OCH2), 6.38 (d, J = 8.4
Propargyl Ethers 22a–d; Compound 22a; Typical Procedure
A mixture of compound 21 (300 mg, 1.50 mmol), p-methoxyiodo-
benzene (1.80 mmol), anhydrous Et3N (2 mL), Pd(PPh3)2Cl2 (3
mol%), and CuI (3 mol%) was stirred in anhydrous DMF (8 mL) at
r.t. for 5 h. Then, the reaction mixture was diluted to 70 mL with
Synthesis 2014, 46, 1807–1814
© Georg Thieme Verlag Stuttgart · New York

PAPER
Regioselective Iodocyclization Reactions
1813
CH2Cl2. The organic phase was washed successively with H2O (3 ×
25 mL) and brine (25 mL), and dried (Na2SO4). The solvent was re-
moved under reduced pressure and the crude product was purified
by silica gel (60–120 mesh) column chromatography using EtOAc–
PE (1:19) as eluent to give compound 22a; yield: 350 mg (76%);
yellow solid; mp 120–122 °C.
gel (230–400 mesh) column chromatography using PE–EtOAc
(9.7:0.3) as eluent to give the solid product 23a; yield: 90 mg (65%);
yellow solid; mp 142–143 °C.
IR (KBr): 1732, 2931 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3), 5.29 (s, 2 H,
OCH2), 6.91 (d, J = 8.8 Hz, 2 H, ArH), 7.11 (d, J = 8.4 Hz, 2 H,
ArH), 7.26–7.31 (m, 2 H, ArH), 7.56 (t, J = 7.6 Hz, 1 H, ArH), 7.82
(d, J = 7.6 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.1, 76.6, 84.8, 101.4, 113.4,
114.5, 116.7, 123.1, 124.1, 129.6, 132.2, 132.9, 139.0, 153.4, 157.7,
159.2, 161.4.
IR (KBr): 1728, 2232, 2931 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H, OCH3), 5.09 (s, 2 H,
OCH2), 5.93 (s, 1 H, ArH), 6.84 (d, J = 8.4 Hz, 2 H, ArH), 7.29–7.34
(m, 2 H, ArH), 7.40 (d, J = 8.4 Hz, 2 H, ArH), 7.56 (t, J = 8.4 Hz, 2
H, ArH), 7.87 (d, J = 7.6 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 55.3, 58.0, 79.6, 89.5, 91.6, 114.1,
115.6, 116.8, 123.2, 123.9, 132.5, 133.6, 153.4, 160.3, 162.7, 164.8.
MS (ESI): m/z = 432.87 [M + H]+.
Anal. Calcd for C19H13IO4: C, 52.80; H, 3.03. Found: C, 52.97; H,
3.23.
MS (ESI): m/z = 321.12 [M + H]+.
Anal. Calcd for C19H14O4: C, 74.50; H, 4.61. Found: C, 74.38; H,
4.73.
23b
Yield: 95 mg (68%); yellow solid; mp 136–138 °C.
IR (KBr): 1727, 2924 cm–1.
22b
Yield: 365 mg (72%); brown solid; mp 108–109 °C.
1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 5.27 (s, 2 H, OCH2), 6.91 (d, J = 8.8 Hz, 2 H, ArH), 7.10 (d,
J = 8.4 Hz, 2 H, ArH), 7.16 (d, J = 8.4 Hz, 1 H, ArH), 7.35 (d, J =
8.4 Hz, 1 H, ArH), 7.62 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 20.9, 55.1, 76.5, 84.6, 104.3,
113.4, 114.2, 116.5, 122.7, 129.6, 132.3, 133.8, 134.0, 139.1, 151.6,
157.9, 159.1, 161.5.
IR (KBr): 1733, 2224, 2931 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 3.82 (s, 3 H,
OCH3), 5.07 (s, 2 H, OCH2), 5.89 (s, 1 H, ArH), 6.84 (d, J = 7.8 Hz,
2 H, ArH), 7.21 (d, J = 8.4 Hz, 1 H, ArH), 7.35 (d, J = 8.4 Hz, 1 H,
ArH), 7.40 (d, J = 8.4 Hz, 1 H, ArH), 7.66 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 20.9, 55.3, 57.9, 79.7, 89.4, 91.5,
113.4, 114.0, 115.2, 116.5, 122.8, 133.5, 133.6, 133.7, 151.5, 160.3,
163.0, 164.6.
MS (ESI): m/z = 672.71 [M + Na]+.
Anal. Calcd for C20H15IO4: C, 53.83; H, 3.39. Found: C, 53.78; H,
3.13.
Anal. Calcd for C20H16O4: C, 74.99; H, 5.03. Found: C, 75.23; H,
4.85.
23c
22c
Yield: 100 mg (72%); yellow solid; mp 146–148 °C.
Yield: 275 mg (58%); brown solid; mp 126–127 °C.
IR (KBr): 1730, 2922 cm–1.
IR (KBr): 1725, 2221, 2945 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.2 Hz, 3 H, CH3), 4.04
(q, J = 7.2 Hz, 2 H, OCH2), 5.28 (s, 2 H, OCH2), 6.90 (d, J = 8.4 Hz,
2 H, ArH), 7.09 (d, J = 8.8 Hz, 2 H, ArH), 7.27–7.31 (m, 2 H, ArH),
7.54 (dt, J = 8.8, 1.2 Hz, 1 H, ArH), 7.82 (d, J = 8.8 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 14.9, 63.3, 76.6, 84.8, 104.4,
113.9, 114.5, 116.7, 123.1, 124.1, 129.6, 132.0, 132.9, 139.0, 153.4,
157.7, 158.6, 161.4.
1H NMR (400 MHz, CDCl3): δ = 1.40 (t, J = 6.8 Hz, 3 H, CH3), 4.01
(q, J = 6.8 Hz, 2 H, OCH2), 5.09 (s, 2 H, OCH2), 5.93 (s, 1 H, =CH),
6.83 (d, J = 7.6 Hz, 2 H, ArH), 7.29–7.34 (m, 1 H, ArH), 7.39 (d,
J = 7.6 Hz, 3 H, ArH), 7.56 (t, J = 8.0 Hz, 1 H, ArH), 7.87 (d, J =
8.0 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 14.7, 58.0, 63.6, 79.5, 89.5, 91.7,
113.2, 114.5, 116.8, 123.2, 124.0, 132.5, 133.6, 153.4, 159.7, 162.7,
164.8.
MS (ESI): m/z = 432.87 [M + H]+.
Anal. Calcd for C20H15IO4: C, 53.83; H, 3.39. Found: C, 54.01; H,
3.26.
Anal. Calcd for C20H16O4: C, 74.99; H, 5.03. Found: C, 74.73; H,
4.88.
23d
22d
Yield: 80 mg (55%); yellow solid; mp 135–137 °C.
Yield: 295 mg (73%); brown solid; mp 110–111 °C.
IR (KBr): 1729, 2925 cm–1.
IR (KBr): 1734, 2229, 2931 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.20 (s, 3 H, CH3), 3.83 (s, 3 H,
OCH3), 5.01 (s, 2 H, OCH2), 5.87 (s, 1 H, ArH), 6.89 (d, J = 8.4 Hz,
2 H, ArH), 7.07 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 20.4, 55.1, 76.2, 82.8, 99.3, 101.6,
113.3, 129.6, 132.1, 138.5, 159.1, 164.1, 166.4.
1H NMR (400 MHz, CDCl3): δ = 2.21 (s, 3 H, CH3), 3.82 (s, 3 H,
OCH3), 4.87 (s, 2 H, OCH2), 5.62 (s, 1 H, ArH), 5.83 (s, 1 H, ArH),
6.83 (d, J = 8.4 Hz, 2 H, ArH), 7.38 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 20.1, 20.6, 29.2, 89.4, 95.1, 95.7,
99.8, 114.1, 160.1, 160.9, 163.8, 166.0, 170.0.
MS (ESI): m/z = 396.88 [M + H]+.
Anal. Calcd for C16H14O4: C, 71.10; H, 5.22. Found: C, 71.03; H,
5.32.
Anal. Calcd for C16H13IO4: C, 48.51; H, 3.31. Found: C, 48.47; H,
3.13.
Pyranocoumarin and Pyranopyran Derivatives 23a–d; Com-
pound 23a; Typical Procedure
A mixture of compound 22a (100 mg, 0.24 mmol), molecular iodine
(183 mg, 0.72 mmol), anhydrous NaHCO3 (60 mg, 0.72 mmol) was
stirred in anhydrous MeCN (10 mL) at r.t. for 6 h and then CH2Cl2
(50 mL) was added to the reaction mixture. The organic phase was
washed successively with 10% aq Na2S2O3 (15 mL), H2O (15 mL)
and brine (15 mL), and dried (Na2CO3). The solvent was removed
under reduced pressure and the crude product was purified by silica
Acknowledgment
K.C.M. is thankful to UGC (New Delhi) for an Emeritus Fellow-
ship. B.S., S.G., and D.G. are grateful to CSIR (New Delhi) for Se-
nior Research fellowships. I.A. is grateful to UGC (New Delhi) for
a Senior Research fellowship. We also thank DST (New Delhi) for
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1807–1814

1814
K. C. Majumdar et al.
PAPER
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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(15) CCDC-809664 contains the supplementary crystallographic
data of the compound 17a. These data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk.
Synthesis 2014, 46, 1807–1814
© Georg Thieme Verlag Stuttgart · New York