A mild efficient iodine-catalyzed synthesis of novel anticoagulants with 2,8-dioxabicyclo[3.3.1]nonane core

Article abstract of DOI:10.1016/j.tetlet.2013.02.092

An efficient coupling of 2-hydroxychalcones/α,β-enones with 4-hydroxycoumarin/5,5-dimethylcyclohexyl-1,3-dione (dimedone) has been accomplished to provide access to a novel class of potential anticoagulants with 2,8-dioxabicyclo[3.3.1]nonane core. The reaction proceeds by Michael-bicycloketalization sequence under iodine catalysis (10 mol %) in aqueous ethanol under reflux. Good to excellent yields, impressive selectivity, absence of byproduct formation, avoidance of toxic organic solvents, and utilization of metal-free water-compatible mild Lewis acid catalyst are the key attractive features of this protocol.

Full text of DOI:10.1016/j.tetlet.2013.02.092

Tetrahedron Letters 54 (2013) 2386–2390
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A mild efficient iodine-catalyzed synthesis of novel anticoagulants
with 2,8-dioxabicyclo[3.3.1]nonane core
⇑
Nemai C. Ganguly , Pallab Mondal, Sushmita Roy
Department of Chemistry, University of Kalyani, Kalyani 741235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient coupling of 2-hydroxychalcones/a,b-enones with 4-hydroxycoumarin/5,5-dim-
Received 10 January 2013
Revised 25 February 2013
Accepted 27 February 2013
Available online 7 March 2013
ethylcyclohexyl-1,3-dione (dimedone) has been accomplished to provide access to a novel class of poten-
tial anticoagulants with 2,8-dioxabicyclo[3.3.1]nonane core. The reaction proceeds by Michael-
bicycloketalization sequence under iodine catalysis (10 mol %) in aqueous ethanol under reflux. Good
to excellent yields, impressive selectivity, absence of byproduct formation, avoidance of toxic organic sol-
vents, and utilization of metal-free water-compatible mild Lewis acid catalyst are the key attractive fea-
tures of this protocol.
Keywords:
2,8-Dioxabicyclo[3.3.1]nonane core
Anticoagulants
Ó 2013 Elsevier Ltd. All rights reserved.
Michael-bicycloketalization
Iodine catalyst
4-Hydroxycoumarins, particularly those bearing benzylated
side chains at C-3, constitute a large and highly diverse class of nat-
ural products having a wide range of biological activities including
anticoagulant,1 spasmolytic,2 rodenticidal,3 antifungal,4 and anti-
HIV5 effects. Warfarin (A) represents a member of this family that
is most widely used antithrombotic in the USA and Canada in the
form of racemic sodium salt. However, anticoagulants of this group
are associated with various syndromes6 and rodents have become
resistant to their use. This led to the development of superwarfa-
rins,7 such as coumatetralyl (B), bromadiolone (C), and difenacoum
(D) (Scheme 1), with superior rodent control and anticoagulant
properties but their toxicity to humans8 and other non-target
organisms remained major constraints.
Therefore, the search for newer anticoagulants based on 4-
hydroxycoumarin scaffold with lower toxicity and side effects
evoked sustained interest of chemists and biologists. Ikawa noted
that the Michael condensation of benzalacetone with 4-hydroxy-
coumarin in ethanol in the presence of HCl catalyst was marred
with the formation of byproducts.9 The same Michael adduct could
be accessed in water without any added catalyst in a sluggish un-
clean reaction in 48% yield that required 12 h of refluxing and fur-
ther 12 h of cooling at 0 °C. In a significant development, he
demonstrated that the condensation of 4-hydroxycoumarin and
yield 7-acetonyl-6-oxo-6H,7H-(1)-benzopyrano[4,3-b]-1-benzopy-
ran (1c) with high anticoagulant activities. The identical compound
was also obtained by the reaction of 4-hydroxycoumarin with 3-
acetylcoumarin under aqueous alkaline conditions.10 The structure
1c was subsequently revised by X-ray crystal analysis to 1b
embodying bicyclo[3.3.1]nonane motif.11 Warfarin analogues are
known to exert their anticoagulant action by inhibiting the activity
of the enzyme, vitamin K 2,3-epoxide reductase (VKOR) which is
involved in blood coagulation cascade.12 It is also known that eno-
lic hydroxy group of warfarins plays an important role in VKOR
inhibition process. This novel difenacoum analogue 1b was shown
to be a moderate vitamin K 2,3-epoxide reductase inhibitor,
although it lacks free enolic hydroxy group. To the best of our
knowledge, apart from some sporadic synthetic activities, no opti-
mized synthetic protocol is reported in the literature to date for
elaboration of this class of biologically relevant molecular architec-
ture. In continuation of our interest in the development of greener
synthetic protocols,13 we felt the urgent need to develop an effi-
cient catalytic method to access these promising anticoagulants.
Deconstruction of the target structure 2b in a retrosynthetic way
reveals 2-hydroxychalcone 2 and 4-hydroxycoumarin (Scheme 2)
as readily accessible precursors that can be coupled by Michael
condensation–acetalization sequence presumably through the
intermediacy of a hemiketal. It was reasoned that the Michael reac-
tion of the chalcone with the enol would remove the rigidity im-
posed by the carbon–carbon double bond of the enone moiety.
The conformational flexibility of the resulting pendant carbonyl
bearing side chain would allow it to engage in an intramolecular
bicycloketalization process involving two hydroxy groups of com-
plementary chemical reactivity.
a,b-enone derived from 2-hydroxybenzaldehyde and acetone in
an excess of pyridine was a highly selective reaction essentially
free from byproducts and the initial condensation product under-
went facile dehydration under the conditions of the reaction to
⇑
Corresponding author. Fax: +91 33 25828282.
E-mail address: nemai_g@yahoo.co.in (N.C. Ganguly).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.092

N. C. Ganguly et al. / Tetrahedron Letters 54 (2013) 2386–2390
2387
Br
Iodine-catalyzed reactions can be performed in air under aqueous
conditions due to its water-tolerant nature. Herein, we disclose the
results of iodine-catalyzed entry to potential anticoagulants with
the 2,8-dioxabicyclo[3.3.1]nonane scaffold using 2-hydroxychal-
cones/a,b-enones derived from 2-hydroxybenzaldehydes and 4-
hydroxycoumarin/5,5-dimethyl-cyclohexyl-1,3-dione (dimedone)
O
under essentially neutral aqueous ethanolic conditions.
OH
O
OH
O
OH
O
OH
For the initial feasibility studies, 2-hydroxychalcone 2 was sub-
mitted to a reaction with an equimolar amount of 4-hydroxycoum-
arin (1a) in water under reflux without added catalyst to give 2b as
an insoluble product in a sluggish incomplete reaction (entry 1, Ta-
ble 1). Similar result was obtained in aqueous ethanol (EtOH–H2O
4:1) (entry 2, Table 1). Exclusive formation of 2b, albeit in moder-
ate yield, under catalyst-free aqueous ethanolic conditions is pre-
sumably facilitated by synergistic dual electrophilic and
nucleophilic activation of enone 2 and enol 1a, respectively
through extensive hydrogen bonding network of water. Ample lit-
erature reports16 of water-catalyzed Michael–Knoevenagel cascade
reactions, particularly in multicomponent reaction scenario, sup-
port these results. Performing the reaction under the catalytic
influence of iodine (5 mol %) in water, with and without anionic
surfactant above its critical micellar concentration (cmc), vastly
accelerated the reaction but only with marginal improvement in
yield (entries 3 and 4). The results attested to iodine catalysis;
however, there was no apparent synthetic advantage due to micel-
lar solubilization of reactants. Solvent optimization studies using
EtOH, MeOH, CH3CN, and EtOH–H2O (4:1) under otherwise identi-
cal conditions revealed that iodine in aqueous ethanol surpassed
others in terms of catalytic efficiency (3 h, 75%, entry 8). The yield
of 2b plateaued to 90% with 10 mol % of iodine catalyst but further
increment in catalyst loading did not improve the yield (entries 9
and 10). Further optimization of the ratio of EtOH/H2O was carried
out to evaluate its effect on the yield of 2b. It was isolated in mar-
ginally lower yields of 86% and 82%, respectively when EtOH–H2O
(1:1) and EtOH–H2O (9:1) were used as solvents (entries 11 and
12). Other Lewis acids (CeCl3Á7H2O-NaI, Bi(NO3)3Á5H2O), protic acid
O
O
O
O
O
B
C
A
O
O
O
OH
O
O
O
O
O
1b
D
1c
Scheme 1. Structures of warfarin, superwarfarins, and some potential
anticoagulants.
OH
O
O
O
O
+
O
OH
O
1a
2
2b
O
Scheme 2. Retrosynthesis of 2b.
To this end, we identified molecular iodine as a suitable mild
Lewis acid catalyst in view of its proven ability to catalyze both Mi-
chael14 and acetalization15 reactions through carbonyl activation.
(pTSA), and organocatalyst (L-proline) were explored but with less
satisfactory results (entries 13–16).
Table 1
Optimization experiments for the synthesis of 2b
OH
O
O
cat.
O
O
+
solvent
O
OH
O
2b
2
1a
O
Entry
Catalyst (mol %)
Additive if any (mol %)
Solvent
H2O
EtOH–H2O (4:1)
H2O
H2O
EtOH
Timea (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
—
—
I2 (5)
I2 (5)
I2 (5)
I2 (5)
I2 (5)
I2 (5)
I2 (10)
I2 (20)
I2 (10)
I2 (10)
CeCl3Á7H2O (10)
Bi(NO3)3Á5H2O (10)
p-TSA (10)
—
—
—
10
8
50
45
60
62
70
68
48
75
90
88
86
82
85
70
32
35
3
SDS (8)
—
—
—
—
—
—
—
3b
3
MeOH
CH3CN
3
3
3
3
3
3
3
3
EtOH–H2O (4:1)
EtOH–H2O (4:1)
EtOH–H2O (4:1)
EtOH–H2O (1:1)
EtOH–H2O (9:1)
EtOH–H2O (4:1)
EtOH
—
NaI (10)
—
—
—
3
3
3
EtOH–H2O (4:1)
EtOH–H2O (4:1)
L
-Proline (20)
a
Reactions were carried on 1 mmol scale using 3 mL solvent under refluxing condition, unless otherwise stated.
Reaction was carried out at 80 °C.
b

2388
N. C. Ganguly et al. / Tetrahedron Letters 54 (2013) 2386–2390
Table 2
Iodine-catalyzed condensation of 2-hydroxychalcones/
a
,b-enones and 4-hydroxycoumarin
R2
O
O
O
O
O
R1
R2
I2 (10 mol%)
EtOH-H2O (4:1),
+
O
OH
1-12
OH reflux
R1
O
1a
1b-12b
Entry
1–12
Timea (h)
Products
Yieldb (%)
R1
R2
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
Ph
4/-C6H4Me
4/-C6H4OMe
4/-C6H4Cl
4/-C6H4-allyloxy
4/-C6H4-(2-methylallyloxy)
Ph
Ph
2
3
3
4
3
4
3
2
2
4
5
3
1b
2b
3b
4b
5b
6b
7b
8b
92
90
92
84
94
92
88
94
85
88
86
90
5-NO2
4-Me
H
5-OMe
H
9
9
9b
10
11
12
10
11
12
Et
Me
10b
11b
12b
2-Thiophenyl
a
Reactions were conducted on 1 mmol scale.
Isolated yields; products were characterized from their spectral features (FTIR, 1H and 13C NMR, and MS/elemental analysis) and comparison with melting points and
b
spectral data reported in the literature for known compounds.
Table 3
With the optimized reaction condition (10 mol % I2, EtOH–H2O
4:1, 3 h, reflux) in hand, we set out to explore its generality and
scope for a range of 2-hydroxychalcones/a,b-enones derived from
Iodine-catalyzed condensation of 2-hydroxychalcones/
ethanol under reflux
a,b-enones and dimedone in
R2
2-hydroxybenzaldehydes. The results are exhibited in Table 2.
The products precipitated out of the reaction mixture and were
filterable allowing their hassle-free isolation in excellent yields
(84–94%). It was observed that the nature of the group attached
to carbonyl (R2), be it aromatic, aliphatic, or heteroaromatic, had
no perceptible electronic or steric contribution to the facility and
yield of the reaction. Substituents (R1) in the hydroxy-bearing aro-
matic moiety of the chalcone moderately exerted their electronic
influence on the performance of the reaction. The presence of elec-
tron-releasing 5-OMe group lowers acceptor ability of enone car-
bonyl which was reflected in relatively lower yield and extended
reaction time (86%, 5 h) (entry 11). On the other hand, electron-
withdrawing 5-NO2 group provided excellent yield in a faster reac-
tion (94%, 2 h) (entry 8). Attempt to inhibit bicycloketalization by
acetylation of 4-(2-hydroxyphenyl)-3-buten-2-one (1) failed as
its acetyl derivative underwent deprotection to its precursor under
optimized reaction conditions (as detected by TLC) followed by
generation of 1b (Scheme 3). The aqua-lability of the aryl 2-OAc
was presumably due to the activation of acetoxy carbonyl by io-
dine facilitating nucleophilic attack of water. Similar propensity to-
ward hydrolytic cleavage even under mild neutral conditions
(NaBO3, MeOH, 25 °C) is precedented in the literature.17
O
O
O
R1
O
O
R2
+
I2 (10 mol%)
EtOH-H2O (4:1)
OH
1, 2, 5, 11
R1
O
reflux
1e
1d, 2d, 5d, 11d
Products
Yieldb (%)
Entry
1, 2, 5, 11
Timea (h)
R1
R2
1
2
3
4
1
2
3
11
H
H
H
Me
Ph
4/-C6H4Cl
Me
4
5
4
6
1d
2d
5d
11d
90
85
88
82
5-OMe
a
Reactions were carried out in 1 mmol scale.
Isolated yields after chromatographic filtration.
b
with dimedone under similar reaction conditions resulted in the
isolation of target compounds in 82–90% yield in marginally slower
reactions (entries 1–4, Table 3). The deactivating influence of 5-
OMe on the enone carbonyl was reflected in the lower yield of
11d to 82% and extended reaction time (entry 4). Notably, the
products were soluble in aqueous ethanol and separated by chro-
matographic filtration.18b Significantly, diethylmalonate with poor
enol content was resistant to coupling with 2-hydroxychalcone 2
even on prolonged exposure to iodine catalysis (10 mol % of I2,
EtOH–H2O 4:1 (3 mL), 5 h) underscoring the implication of enol
form of Michael donor in the reaction. The poor yield of 2b under
pTSA catalysis in aqueous ethanol (entry 15, Table 1) might be due
to acid-catalyzed reversible opening of the bicyclicketal moiety. To
ascertain this hypothesis, 2b, separately prepared according to the
present method,18a was treated with pTSA (10 mol %) in aqueous
ethanol [EtOH–H2O (4:1), 3 mL, 3 h]. It was recovered unchanged
demonstrating its robustness under acidic conditions. Plausibly,
the strong acid catalysis was not favorable for Michael-ketalization
tandem process.
With the aim of generating skeletal diversity by appending dif-
ferent building blocks to a core structure, the protocol was ex-
tended to the reaction of dimedone as the enol partner of 2-
hydroxychalcones. This replacement was anticipated to provide a
novel hitherto unprecedented bridged bicyclic ketal flanked with
an aromatic and carbocyclic ring in a compact structural space.
Treatment of a few 2-hydroxychalcones or similar compounds
O
I2 (10 mol%)
1b
(88%)
1a
EtOH-H2O (4:1),
OAc
3h, reflux
X-ray single crystal analysis of two representative products 12b
and 1d derived from 4-hydroxycoumarin and dimedone, respec-
tively unambiguously confirmed their structures, as shown by
Scheme 3. Formation of 1b by condensation of 4-(2-acetoxyphenyl)-3-buten-2-one
and 4-hydroxycoumarin (1a) under optimized reaction condition.

N. C. Ganguly et al. / Tetrahedron Letters 54 (2013) 2386–2390
2389
Figure 1. ORTEP diagrams of 12b and 1d, respectively.
Figure 2. Noncovalent interactions in compound 2b.
their ORTEP diagrams below (Fig. 1). The ORTEP diagram of 12b
exhibits some rotational disorder of the thiophene ring.
research fellowships. We are grateful to DST-FIST and UGC-SAP
programmes for providing infrastructural facilities to the Depart-
ment of Chemistry, University of Kalyani. Also we are thankful to
Professor A. Ghosh of University of Calcutta, Kolkata and Dr. A. D.
Bond of University of Southern Denmark, Denmark for X-ray crys-
tallographic studies.
The nature of weak forces primarily responsible for VKOR en-
zyme inhibition activity of these conformation-constrained antico-
agulants is yet to be convincingly ascertained. Intermolecular
bifurcated hydrogen bonding between coumarin carbonyl and
two hydrogen atoms hovering around (O-3 and H-11 & -22B,
Fig. 2) as well as CH (2), CH (13)/
p interactions exists in supramo-
Supplementary data
lecular assembly of 2b. CH/ interactions are of prime importance
p
in chiral recognition and conformation of proteins and DNA;19
however, their possible role in this case is yet to be explored.
In conclusion, an efficient iodine-catalyzed optimized protocol
for the synthesis of a small library of novel conformation-con-
strained anticoagulants embodying 2,8-dioxabicyclo[3.3.1]nonane
structural motif is reported. This method is based on straightfor-
ward Michael-bicycloketalization sequence involving 2-hydroxy-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
02.092.
References and notes
1. (a) Nagashima, R.; O’Reilly, R. A.; Levy, G. Clin. Pharmacol. Ther. 1969, 1, 22; (b)
O’Reilly, R. A.; Ohms, J. I.; Motley, C. H. J. Biol. Chem. 1969, 244, 1303; (c)
Numamoto, N.; Yamamoto, T.; Yamashita, A.; Hatano, T.; Kurahara, J. Jpn. Kokai
Tokkyo Koho JP 02 36, 178 [90 36,178], (Cl C07 D311/46), 06 Feb 1990, Appl.
88/183,956, 22 Jul 1988; Chem. Abstr. 1990, 113, P58941a.
2. (a) Boschetti, E.; Molho, D.; Fontaine, L. S. African 6,801,383, 02 Aug 1968, Fr
Appl 20 Nov 1967; Chem. Abstr. 1969, 70, P90732n.; (b) Stacchino, C.; Spano, R.;
Pettiti, A. Bull. Chim. Farm. 1983, 122, 158.
chalcones/a,b-enones derived from 2-hydroxybenzaldehydes and
4-hydroxycoumarin in environmentally friendly aqueous ethanol
under essentially neutral conditions. Further element of molecular
diversity has been introduced by coupling of 2-hydroxychalcones/
a,b-enones with dimedone to provide 2,8-dioxabicyclo[3.3.1]non-
ane scaffold annulated with benzene and dimedone. The reactions
are highly selective toward target compounds without any by-
product formation. Use of nontoxic reaction medium, metal-free
mild Lewis acid catalyst, and hassle-free separation of products
are the appealing green features of the current protocol.
3. (a) LIPHA (Lyonnaise Industrielle Pharmaceutique) Ger. Offen. 1,959,317 (Cl.
C07d, A61k), 23 July 1970; Chem. Abstr. 1970, 73, P87795s.; (b) McIntyre, J. S.;
Knight, A. R. U.S. 3,511,856 (Cl 260-343.2, C07d, A01n), 12 May 1970, Appl. 24
Jun 1968; Chem. Abstr. 1970, 73, P14694y.; (c) Szejtli, J.; Szente, L.; Torok, S.;
Voroshazi, L.; Harshegyi, J.; Daroczi, I.; Zajak, A. Hung Teljes HU 38, 203 (Cl
A01N25/10), 28 May 1986, Appl 84/2,533, 29 Jun 1984; Chem. Abstr. 1986, 105,
P185893w.; (d) Whittle, A. J. Eur Pat Appl EP 175,466 (Cl C07D311/56), 26 Mar
1986, GB Appl 84/23,782, 20 Sep 1984; Chem. Abstr. 1986, 105, P157279g.
4. Zhao, H.; Neamati, N.; Hong, H.; Mazumder, A.; Wang, S.; Sunder, S.; Milne, G.
W. A.; Pommier, Y.; Burke, T. R., Jr. J. Med. Chem. 1997, 40, 242.
Acknowledgements
5. Marcal de Queiroz, P. PCT Int ApplWO 9,825,608 (Cl. A61K31/37), 18 Jun 1998;
Chem. Abstr. 1998, 129, P76481k.
6. Wallin, R.; Patrick, S. D.; Martin, L. F. Int. J. Biochem. 1987, 19, 1063.
The authors (P.M. and S.R.) are thankful to CSIR, New Delhi, In-
dia and UGC, New Delhi, India for financial assistance by way of

2390
N. C. Ganguly et al. / Tetrahedron Letters 54 (2013) 2386–2390
7. Hadler, M. R.; Shadbolt, R. S. Nature 1975, 253, 275.
8. Routh, C. R.; Triplett, D. A.; Murphy, M. J.; Felice, L. J.; Sadowski, J. A.; Bovill, E. G.
Am. J. Hematol. 1991, 36, 50.
dimedone (1e) (140 mg, 1 mmol) in EtOH–H2O (4:1) (3 mL) was added finely
pulverized iodine (25 mg, 0.1 mmol) and the mixture was refluxed for 5 h (TLC
monitoring). Removal of solvent under reduced pressure was followed by
addition of 10% sodium thiosulfate solution (5 mL) and extraction with EtOAc
(3 Â 5 mL). The combined extract was washed with brine (2 Â 3 mL), dried
(Na2SO4) and concentrated. The product was purified by chromatographic
filtration using EtOAc–light petrol (1:19) as eluent to afford 2d (294 mg, 85%)
as a white crystalline solid, mp 160–162 °C; IR (KBr): 2958, 2871, 1657, 1634,
9. Ikawa, M.; Stahmann, M. A.; Link, K. P. J. Am. Chem. Soc. 1944, 66, 902.
10. Manolov, I.; Danchev, N. D. Eur. J. Med. Chem. 1995, 30, 531.
11. Manolov, I.; Maichle-Moessmer, C.; Niquet, E. Z. Naturforsch. Z. 2006, 61b, 207.
12. (a) Chen, D.-U.; Kuo, P.-Y.; Yang, D.-Y. Bioorg. Med. Chem. Lett. 2005, 15, 2665;
(b) Suttie, J. W. Vitmin K. In Handbook of Lipid Research; Deluca, H. F., Ed.;
Plenum: New York, 1978; pp 211–277; (c) Cain, D.; Hutson, S. M.; Wallin, R.
Thromb. Haemostasis 1998, 80, 128.
13. (a) Ganguly, N. C.; Barik, S. K. Synthesis 2009, 1393; (b) Ganguly, N. C.; Mondal,
P. Synthesis 2010, 3705; (c) Ganguly, N. C.; Roy, S.; Mondal, P. Tetrahedron Lett.
2012, 53, 1413; (d) Ganguly, N. C.; Roy, S.; Mondal, P.; Saha, R. Tetrahedron Lett.
2012, 53, 7067.
14. Banik, B. K.; Fernandez, M.; Alvarez, C. Tetrahedron Lett. 2005, 46, 2479.
15. (a) Basu, M. K.; Samajdar, S.; Becker, F. F.; Banik, B. K. Synlett 2002, 319; (b)
Togo, H.; Iida, S. Synlett 2006, 2159; (c) Karimi, B.; Golshani, B. Synthesis 2002,
784; (d) Banik, B. K.; Chapa, M.; Marquez, J.; Cardona, M. Tetrahedron Lett. 2005,
46, 2341.
16. (a) Soleimani, E.; Khodaei, M. M.; Batooie, N.; Baghbanzadeh, M. Green Chem.
2011, 13, 566; (b) Pore, D. M.; Shaikh, T. S.; Undale, K. A.; Gaikwad, D. S. C. R.
Chimie 2010, 13, 1429; (c) Yu, J.-J.; Wang, L.-M.; Liu, J.-Q.; Guo, F.-L.; Liu, Y.;
Jiao, N. Green Chem. 2010, 12, 216; (d) Abdolmohammadi, S.; Balalaie, S.
Tetrahedron Lett. 2007, 48, 3299; (e) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.;
Mazzacani, A.; Sartori, G. Tetrahedron Lett. 2001, 42, 5203.
1382, 1237, 1110, 1033, 885, 755 cmÀ1 1H NMR (400 MHz, CDCl3): d 7.67–7.65
;
(m, 2H), 7.48–7.42 (m, 3H), 7.38 (dd, J = 7.2, 1.6 Hz, 1H), 7.17–7.12 (m, 1H),
7.01 (d, J = 8 Hz, 1H), 6.93–6.90 (m, 1H), 4.23 (t, J = 2.8 Hz, 1H), 2.40 (s, 2H),
2.29–2.14 (m, 4H), 1.10 (s, 3H), 0.95 (s, 3H); 13C NMR (100 MHz, CDCl3): d
195.8, 167.6, 151.5, 140.2, 129.1, 128.4, 128.1, 127.6, 126.5, 125.6, 121.6, 116.0,
115.4, 99.8, 50.4, 41.6, 33.0, 32.4, 28.9, 27.9, 25.1; LC–MS: m/z = 347 [M+1]+;
Anal. Calcd. for C23H22O3: C, 79.74; H, 6.40%. Found: C, 79.48; H, 6.31%.
(b) Representative procedure for the synthesis of 2b: To a stirring solution of a
mixture of 3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one (2) (226 mg,
ꢀ1 mmol) and 4-hydroxycoumarin (1a) (163 mg, ꢀ1 mmol) in EtOH–H2O
(4:1) (3 mL) was added finely pulverized iodine (25 mg, 0.1 mmol) and the
resulting brown reaction mixture was refluxed for 3 h (TLC monitoring). The
reaction mixture was cooled, concentrated under reduced pressure and the
precipitated product was filtered out. The crude product was washed
successively with 5% sodium thiosulfate solution (1 mL) and ethanol (0.5 mL)
to remove adhering iodine, if any and recrystallized from ethyl acetate to yield
a pure white crystalline solid 2b (330 mg, 90%), mp 238–240 °C (lit. 9 240 °C).
17. Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S.; Patil, S. V. New J. Chem. 2002, 26,
1273.
19. Nishio, M.; Hirota, N.; Umezawa, Y. The CH/
p Interaction. Evidence, Nature and
Consequences; Wiley-VCH: New York, 1998.
18. (a) Representative procedure for the synthesis of 2d: To a solution of 3-(2-
hydroxyphenyl)-1-phenylprop-2-en-1-one (2) (224 mg, 1 mmol) and