Solid-supported acid-catalyzed C3-alkylation of 4-hydroxycoumarins with secondary benzyl alcohols: access to 3,4-disubstituted coumarins via Pd-coupling

Article abstract of DOI:10.1016/j.tet.2008.10.017

An efficient and operationally simple method for C3-alkylation of 4-hydroxycoumarins has been developed under acidic medium giving good yields of the products. In the present method, a reusable Amberlite IR-120 (H⁺ form) was used as an acid catalyst and secondary benzyl alcohols were used as alkylating agents. The obtained 3-alkylated-4-hydroxycoumarins offered an easy access for the synthesis of 3,4-disubstituted coumarins by way of Pd-catalyzed coupling reactions.

Full text of DOI:10.1016/j.tet.2008.10.017

Tetrahedron 64 (2008) 11666–11672
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solid-supported acid-catalyzed C3-alkylation of 4-hydroxycoumarins
with secondary benzyl alcohols: access to 3,4-disubstituted
coumarins via Pd-coupling
,
a
a
b
Ch. Raji Reddya , B. Srikanth , N. Narsimha Rao , Dong-Soo Shin
*
a Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
b Department of Chemistry, Changwon National University, Changwon 641-773, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and operationally simple method for C3-alkylation of 4-hydroxycoumarins has been de-
veloped under acidic medium giving good yields of the products. In the present method, a reusable
AmberliteÒ IR-120 (Hþ form) was used as an acid catalyst and secondary benzyl alcohols were used as
alkylating agents. The obtained 3-alkylated-4-hydroxycoumarins offered an easy access for the synthesis
of 3,4-disubstituted coumarins by way of Pd-catalyzed coupling reactions.
Received 15 April 2008
Received in revised form
12 September 2008
Accepted 8 October 2008
Available online 14 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Acid catalyst
Amberlite IR-120
Benzylation
Benzyl alcohol
Palladium coupling
3,4-Disubstituted coumarin
1. Introduction
generally required the suitable alkylating agents such as halo
compounds, boronic acid, etc.19–28 Alternatively, the alkylation can
Coumarin and its derivatives are one of the important classes of
heterocyclic compounds and are known to possess a wide range of
biological activities including anti-HIV, anti-biotic, anti-fungal,
anti-bacterial, anti-viral, anti-cancer, anti-clotting activity, and
especially as anti-coagulants.1–8 Among the various substituted
coumarins, 3-(benzyl)-substituted 4-hydroxycoumarins represents
a significant class of compounds as not only as biologically active
compounds (Fig. 1),9,10 but also serve as a useful scaffolds, which
can be highly diversified in several ways to synthesize 3,4-
substituted compounds.11–14
also be performed under acidic conditions with alcohols as
O
OH
O
OH
O
O
O
Warfarin (A)
Coumatetralyl (B)
Br
The existing methods for the synthesis of 3-substituted 4-
hydroxycoumarins include direct synthesis of the target
compound15–18 or C3-alkylation/substitution of 4-hydroxy-
coumarin.19–28 The later method is gaining importance due to the
prospect of generating more number of compounds using various
alkylating/substituting agents. Although, there are several known
methods for C3-alkylation/substitutions via Pd-catalyzed C–C bond
formation or base mediated alkylation reactions, most of them
OH
OH
O
OH
O
O
O
Difenacoum (D)
Bromadialone (C)
* Corresponding author. Tel.: þ91 40 27193128; fax: þ91 40 27160512.
E-mail address: rajireddy@iict.res.in (Ch.R. Reddy).
Figure 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.017

Ch.R. Reddy et al. / Tetrahedron 64 (2008) 11666–11672
11667
alkylating agents, which is not well explored. To the best of our
knowledge, there is a limited number of examples known for the
alkylation of 4-hydroxycoumarins with alcohols in the presence of
strong acids, which include HCl, H2SO4,29–31 etc. and recently
Yb(OTf)3.32 From the synthetic point of view, alcohols are an at-
tractive source compared to the corresponding halides and also can
be obtained more easily. Hence, the development of a practical and
economical method for direct C3-alkylation of 4-hydroxycoumar-
ins using alcohols under acidic medium is highly desirable. In re-
cent years, solid-supported acids have emerged as convenient and
reusable catalysts to perform various useful organic trans-
formations.33 Furthermore, solid-supported acid catalysts are in-
expensive, easy to handle, and are environmentally friendly. In
continuation of our interest in acid-catalyzed reactions,34–36 herein,
we describe a convenient method for the C3-alkylation of 4-
hydroxycoumarin using secondary benzyl alcohols as an alkylating
agent in the presence of a solid-supported sulfonic acid catalyst
(Amberlite IR-120) (Scheme 1).
of 4-hydroxycoumarins 1a and 1b with variety of secondary benzyl
alcohols 2a–2g (entries 1–8, Table 2). However, the reaction of 4-
hydroxycoumarin 1a with primary benzyl alcohol 2h or non-ben-
zylic alcohol 2i failed to give the expected product after 24 h in the
presence of Amberlite IR-120 in CH3CN at reflux (entries 9 and 10,
Table 2). The results from the above reactions clearly demonstrate
that the direct C3-alkylation of 4-hydroxycoumarin was successful
only with secondary benzylic alcohols, but not with the primary
benzylic or non-benzylic alcohols.34 Further, we have tested the
efficiency of BF3$Et2O in the alkylation of 4-hydroxycoumarin 1a
with a few other benzylic alcohols 2b, 2d and found that the reaction
proceeded smoothly to give the corresponding C3-benzylated
products 3b, 3d in good yields (entries 11 and 12, Table 2). Finally, the
application of the present protocol was demonstrated by synthe-
sizing an anti-coagulant compound, coumatetralyl (B), from
benzylic alcohol 2j in 72% yield (Scheme 2).37
The reusability of the catalyst was investigated and the obser-
vations are summarized in Table 3. After completion of the reaction
of benzhydrol with 1a, Amberlite IR-120 resin was filtered, evapo-
ration of the filtrate gave the crude product, which was purified
(86% yield) and the same catalyst was used38 once again for the
similar reaction to obtain 86% yield of the product in 2 h. The third
and fourth runs were also successfully repeated using the same
catalyst. However, the fifth and sixth runs took little longer time
and the yield was also low when compared to first run (Table 3).
After successful C3-alkylation of 4-hydroxycoumarin with
secondary benzyl alcohols, to further diversify the obtained prod-
ucts, we turned our attention to substitute the hydroxyl group at
C4-position to obtain 3,4-disubstituted coumarins. Having the ad-
vantage of enolic-OH at C4-position, the substitution was accom-
plished by adopting Pd-catalyzed cross-coupling reactions, which
has proven to be a powerful reaction for C–C bond formation in
organic synthesis.28,39–42
In order to show the Pd-catalyzed coupling reactions, com-
pound 3a was selected as a model substrate. To make the substrate
ready for Pd-coupling reactions, compound 3a was treated with
PhNTf2 and Et3N at room temperature to give the triflate 4a in 82%
yield. Next, the triflate 4a was subjected to various types of Pd-
couplings such as Heck, Suzuki, Stille, and Sonogashira reactions to
obtain the corresponding 3,4-disubstituted coumarins (Scheme 3).
As a first reaction, triflate 4a was treated with ethyl acrylate in
the presence of Pd(0)/Et3N at 80 ꢀC (Heck coupling conditions) to
give the coupled product 5a in 78% yield (entry 1, Table 4). Similarly,
the reaction of 4a with phenylboronic acid using Suzuki coupling
conditions leads to the corresponding 4-phenyl-3-(diphenyl-
methyl)coumarin 5b in 80% yield (entry 2, Table 4), Stille coupling
of 4a with allyl tributyltin gave the 4-allyl-3-(diphenyl-
methyl)coumarin 5c in 75% yield (entry 3, Table 4). The coupling of
4a with phenyl acetylene was also successful under Sonogashira
reaction conditions to obtain 5d in 77% yield (entry 4, Table 4). After
the completion of Pd-catalyzed coupling reactions on 3a, the pos-
sibility of similar reactions were tested on a structurally different
substrate, coumarin derivative 3d. Accordingly, compound 3d was
treated with phenylboronic acid under Suzuki coupling conditions
and with allyl tributyltin under Stille reaction conditions. To our
disappointment, both the reactions gave the inseparable complex
mixture (based on TLC).43
OH
OH
OH
O
R
O
SO3H
R
+
CH3CN, reflux
1 to 2 h
O
O
R'
R'
R= aryl or alkyl or alkynyl
R'= H or 4-OMe
Scheme 1. Solid-supported acid-catalyzed C3-alkylation.
2. Results and discussions
First, the reaction of 4-hydroxycoumarin 1a with benzhydrol 2a
was investigated in the presence various acid catalysts and the re-
sults are summarized in Table 1. It was found that the acid catalysts
tested, such as BF3$OEt2 (5 mol %) and MoCl5 (5 mol %) appeared to
be effective at room temperature for this conversion (entries 1 and 2,
Table 1). However, ZnCl2 (5 mol %) was able to give only 43% of the
desired product (entry 3, Table 1). The reaction proceeds efficiently
with solid-supported catalysts such as Amberlite IR-120 (Hþ) or
polymer-supported p-toluenesulfonic acid (PS-pTSA) to give the C3-
alkylated product in good yields at refluxing temperature (entries 4
and 5 Table 1). It is noteworthy to mention that the reaction does not
progress at room temperature or in the absence of catalyst (entry 6,
Table 1). Although, most of the tested catalysts were found to be
effective, Amberlite IR-120 (Hþ), for obvious reasons (being in-
expensive, environmentally benign, reusable, and operationally
simple) was chosen for further experiments.
To reveal the generality of this method, the scope of the reaction
was investigated with various benzyl alcohols under optimized
conditions (Amberlite IR-120, CH3CN, reflux); Table 2. From the re-
sults of Table 2, the protocol has proven to be useful for benzylation
Table 1
Activity of various acids in the alkylation of 4-hydroxycoumarin (1a) with benzhy-
drol (2a)a
Entry
Acid
Time (h)/temperature
Yieldb (%)
We have also demonstrated the amination of 3-substituted 4-
hydroxycoumarin 3d via its triflate with benzylamine and mor-
pholine to obtain the corresponding 3-substituted 4-aminated
coumarin derivatives 6a and 6b in 56% and 55% yields, respectively
(for two steps, Scheme 4). Benzylamine was reacted smoothly at
room temperature, whereas morpholine required heating (80 ꢀC).
The 3-propargylated 4-hydroxycoumarins are also useful in the
synthesis of substituted furocoumarins,32 a key structural motif in
several natural products.
1
2
3
4
5
6
BF3$Et2O (5 mol %)
MoCl5 (5 mol %)
ZnCl2 (5 mol %)
PS-pTSA (50 mg/mmol)
Amberlite IR-120 (50 mg/mmol)
d
2/rt
1.5/rt
5/rt
82
76
43
85
86
d
1.5/refluxc
2/refluxc
720/reflux
a
All the reactions were carried out in CH3CN.
Isolated yields after column purification.
No reaction at room temperature.
b
c

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Ch.R. Reddy et al. / Tetrahedron 64 (2008) 11666–11672
Table 2
C3-Alkylation of 4-hydroxycomarins 1a and 1b with benzylic alcohols
Entry
Benzylic alcohol
Time (h)
Product
Yielda (%)
OH
OH
1
2
86
2a
3a
3b
O
O
O
OH
OH
2
3
2
2
81
78
2b
O
OH
OH
3c
2c
MeO
O
O
O
OMe
OH
OH
4
2.5
84
3d
O
2d
OMe
OH
OH
O
3e
5
2
83
MeO
O
2e
OH
OH
6
2.5
79
78
75
3f
4
2f
O
O
4
OH
OH
7
3
3g
2g
O
O
OH
OH
8b
2
Cl
3h
2d
O
O
OH
OH
9
14
14
0c
3i
2h
O
O
OH
OH
10
0c
3j
O
O
2i
2b
2d
11d
2
3b
3d
78
76
12d
1.5
a
Isolated yields after column chromatography.
7-Chloro-4-hydroxycoumarin (1b) was used.
No reaction.
b
c
d
BF3$Et2O (5 mol %) was used as catalyst.

Ch.R. Reddy et al. / Tetrahedron 64 (2008) 11666–11672
11669
Ph
Ph
O
OH
OH
OH
SO3H
i) Ph2NTf, Et3N
CH2Cl2, r.t., 3 h
ii) Benzyl amine,
1,4-Dioxane, r.t., 2.5 h
(56%, two steps)
Bn
+
OH
O
NH
CH3CN, reflux
1 to 2 h, 72 %
O
O
O
O
Ph
Ph
1a
2j
Coumatetralyl (B)
O
O
6a
Scheme 2. Synthesis of coumatetralyl (B).
3d
i) Ph2NTf, Et3N
CH2Cl2, r.t., 3 h
ii) Morpholine,
1,4-Dioxane, 80 °C, 2 h
(55%, two steps)
Table 3
O
Ph
Reusability of Amberlite IR-120 for the benzylation 4-hydroxycoumarin with
benzhydrola
N
Run
1
2
3
4
5
6
Ph
Time (h)
2
86
2
86
2.5
83
2.5
82
3.5
78
3.5
72
Yieldb (%)
O
6b
O
a
Reactions were carried out under refluxing in CH3CN.
Isolated yields after column purification.
b
Scheme 4. Synthesis of 3-alkyl-4-aminated coumarin (6).
3. Conclusion
R
Ph
Ph
In summary, we have demonstrated the C3-benzylation of
4-hydroxycoumarin in the presence of Amberlite IR-120 using
secondary benzyl alcohols. This method provides an advantage that
the use of secondary benzyl alcohols as alkylating agents, which
can be an attractive source. Furthermore, simplicity of operation
and the use of inexpensive and recyclable catalyst are added
advantages. Other acid catalysts BF3$Et2O, MoCl5 (at room tem-
perature), and PS-pTSA (at reflux) were also found to be effective in
C3-benzylation for the first time. The present protocol was effi-
ciently used for the synthesis of an anti-coagulant, coumatetralyl.
The products obtained were successfully utilized in the preparation
of 3,4-disubstituted coumarin derivatives via palladium coupling
reactions. These significant results may find applications in the
synthesis of diversified coumarins.
OX
Ph
O
Pd-coupling
reaction
Ph
O
5a-d
O
O
X= H, 3a
X= Tf, 4a
(from 4a)
PhNTf2, Et3N
CH2Cl2, r.t.,
3 h, 82%
Scheme 3. Synthesis of 3,4-disubstituted coumarins.
Table 4
Palladium-catalyzed reactions of compound 4a
Entry
Reagent
Reaction conditions
Product
Yielda (%)
4. Experimental
4.1. General
O
OEt
Pd(PPh3)4, Et3N,
DMF, 100 ꢀC, 10 h
(Heck)
O
Ph
O
1
78
OEt
All the solvents and reagents were purified by standard tech-
niques. Crude products were purified by column chromatography
on silica gel of 60–120 mesh. IR spectra were recorded on Perkin–
Elmer 683, Nicolet Nexus 670 spectrometer. 1H NMR and 13C NMR
spectra were recorded in CDCl3 solvent on a Varian Gemini 200 and
Bruker AV-300 NMR spectrometer. Chemical shifts were reported
in parts per million (ppm) with respect to internal TMS. Coupling
constants (J) are quoted in hertz (Hz). Mass spectra were obtained
on Finnigan MAT1020B, micromass VG 70–70H or Agilent tech-
nologies LC/MSD trapSL spectrometer operating at 70 eV using di-
rect inlet system.
Ph
O
O
5a
Pd(PPh3)4, Na2CO3,
toluene/EtOH/H2O
(1:1:0.3), reflux, 10 h
(Suzuki)
B(OH)2
Ph
O
2
80
75
77
Ph
5b
Ph
O
Pd(PPh3)4, LiCl,
1,4-dioxane, 100 ꢀC,
18 h (Stille)
4.2. General experimental procedure for the C3-alkylation of
4-hydroxycoumarins (for 3a to 3h and B)
SnBu3
3
Ph
5c
O
To a mixture of 4-hydroxycoumarin (1.0 mmol) and benzylic
alcohol (1.0 mmol) in acetonitrile (10 mL), Amberlite IR-120 (Hþ)
(50 mg) was added and the reaction mixture was stirred for the
given time (see Table 2) at refluxing temperature. After completion
of the reaction (monitored by TLC), the reaction mixture was
filtered and the filtrate was evaporated in vacuo. The
crude compound was purified by column chromatography (ethyl
acetate in hexanes) to afford the corresponding C3-alkylated
4-hydroxycoumarin.
Ph
Pd(PPh3)4, CuI, Et3N,
DMF, 70 ꢀC, 12 h
(Sonogashira)
Ph
O
4
Ph
Ph
5d
O
a
Isolated yields after column chromatography.

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Ch.R. Reddy et al. / Tetrahedron 64 (2008) 11666–11672
4.2.1. 3-Benzhydryl-4-hydroxy-2H-chromen-2-one (3a)
139.4, 132.3, 128.9, 127.6, 127.2, 124.1, 123.5, 116.6, 116.2, 105.2, 89.4,
78.2, 33.1, 31.2, 28.3, 22.2, 18.9, 14.1; HRMS (ESI): calcd for
C
White solid; mp: 178–180 ꢀC; Rf (30% EtOAc/hexanes) 0.3; IR
(neat): nmax 3264, 2921, 1672, 1623, 1209, 752, 697 cmꢁ1
;
1H NMR
23H22O3Na: 369.1466 (MþNa)þ, found: 369.1454.
(300 MHz, CDCl3):
J¼1.1, 8.3 Hz, Ar–H), 7.43–7.20 (12H, m, Ar–H), 6.27 (1H, s, OH), 5.98
(1H, s, CH–Ar); 13C NMR (75 MHz, CDCl3):
163.4, 160.8, 152.9,
d
7.73 (1H, dd, J¼1.5, 7.5 Hz, Ar–H), 7.54 (1H, td,
4.2.7. (E)-3-(1,3-Diphenylallyl)-4-hydroxy-2H-
chromen-2-one (3g)32
d
140.1, 132.3, 129.6, 128.9, 128.0, 124.1, 123.3, 116.6, 116.1, 107.9, 47.5;
HRMS (ESI): calcd for C22H16O3Na: 351.0997 (MþNa)þ, found:
351.0999.
White solid; mp: 68–70 ꢀC; Rf (30% EtOAc/hexanes) 0.2; IR
(neat): nmax 3026, 2923, 2853, 1665, 1608, 1493, 1204, 753,
695 cmꢁ1; 1H NMR (300 MHz, CDCl3):
7.55–7.49 (1H, m, Ar–H), 7.42–7.23 (12H, m, Ar–H), 6.78 (1H, dd,
d
7.80 (1H, d, J¼7.8 Hz, Ar–H),
4.2.2. 4-Hydroxy-3-(1-phenylethyl)-2H-chromen-2-one (3b)
White solid; mp: 200–202 ꢀC; Rf (30% EtOAc/hexanes) 0.3; IR
J¼6.6, 16.2 Hz, CH]CH), 6.52 (1H, d, J¼15.9 Hz, CH]CH), 5.46 (1H,
d, J¼5.7 Hz, CH–CH]CH–Ar); 13C NMR (75 MHz, CDCl3):
d 163.4,
(neat): nmax 3227, 2925, 1671, 1624, 1392, 1215, 751 cmꢁ1
;
1H NMR
161.1, 152.8, 139.8, 136.3, 134.0, 132.3, 129.4, 128.8, 128.3, 128.2,
127.8, 126.7, 126.6, 124.1, 123.3, 116.7, 116.0, 106.6, 44.2; HRMS(ESI):
calcd for C24H18O3Na: 377.1148 (MþNa)þ, found: 377.1145.
(300 MHz, CDCl3):
d
7.64 (1H, d, J¼8.3 Hz, Ar–H), 7.57–7.18 (8H, m,
Ar–H), 5.92 (1H, s, OH), 4.74 (1H, q, J¼7.5 Hz, CH–Ar), 1.67 (3H, d,
J¼7.5 Hz, CH3); 13C NMR (75 MHz, CDCl3):
d 160.0, 152.1, 143.9,
131.0, 127.5, 127.0, 125.4, 123.2, 123.0, 116.3, 115.8, 109.6, 33.6, 16.3;
HRMS (ESI): calcd for C17H14O3Na: 289.0840 (MþNa)þ, found:
289.0842.
4.2.8. 6-Chloro-3-(1,3-diphenylprop-2-ynyl)-4-hydroxy-2H-
chromen-2-one (3h)
Brown solid; mp: 145–147 ꢀC; Rf (30% EtOAc/hexanes) 0.2; IR
(neat): nmax 3195, 2923, 2130,1682,1621,1484,1192, 822, 719 cmꢁ1; 1H
4.2.3. 4-Hydroxy-3-(1-(4-methoxyphenyl)but-3-enyl)-2H-
chromen-2-one (3c)
NMR (300 MHz, CDCl3):
m, Ar–H), 7.39–7.21 (9H, m, Ar–H), 5.71 (1H, s, CH–Ar); 13C NMR
(75 MHz, CDCl3): 161.0, 159.7, 150.7, 138.8, 131.3, 131.2, 128.5, 127.9,
d
7.82 (1H, d, J¼2.2 Hz, Ar–H), 7.60–7.44 (3H,
Brown solid; mp: 58–60 ꢀC; Rf (30% EtOAc/hexanes) 0.25; IR
d
(neat): nmax 3415, 2924, 1679, 1610, 1511, 1249, 1034, 756 cmꢁ1; 1H
127.8,127.6,127.0,126.3,123.0,117.6,117.5,106.3, 88.0, 82.6, 32.4; HRMS
NMR (300 MHz, CDCl3):
d
7.73 (1H, dd, J¼1.5, 8.3 Hz, Ar–H), 7.54–
(ESI): calcd for C24H15O3ClNa: 409.0607 (MþNa)þ, found: 409.0608.
7.47 (1H, m, Ar–H), 7.41 (2H, d, J¼9.0 Hz, Ar–H), 7.30–7.20 (2H, m,
Ar–H), 6.95–6.90 (2H, m, Ar–H), 5.97–5.82 (1H, m, CH]CH2), 5.13
(1H, dd, J¼1.5, 17.3 Hz, CH2]CH), 5.03 (1H, dd, J¼1.5, 10.5 Hz,
CH2]CH), 4.66 (1H, t, J¼7.5 Hz, CH–Ar), 3.80 (3H, s, OCH3), 3.00–
4.2.9. 4-Hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-2H-
chromen-2-one (coumatetralyl, B)
White solid; mp: 188–190 ꢀC; Rf (30% EtOAc/hexanes) 0.3; IR
2.80 (2H, m, CH2–CH]CH2); 13C NMR (75 MHz, CDCl3):
d
163.7,
(neat): nmax 3271, 2941, 1671, 1625, 1391, 1211, 1143, 745 cmꢁ1 1H
;
160.3, 159.1, 152.7, 136.1, 132.4, 131.9, 129.1, 123.9, 123.0, 117.3, 116.5,
116.2, 115.0, 108.7, 55.47, 39.3, 35.5; HRMS (ESI): calcd for
C20H18O4Na: 345.1102 (MþNa)þ, found 345.1098.
NMR (200 MHz, CDCl3)
d
7.63 (1H, dd, J¼1.4, 8.0 Hz, Ar–H), 7.49 (1H,
td, J¼1.4, 8.0 Hz, Ar–H), 7.35–7.12 (6H, m, Ar–H), 5.73 (1H, s, OH),
4.59 (1H, t, J¼6.6 Hz, CH–Ar), 2.93 (2H, t, J¼5.8 Hz, CH2–Ar), 2.33–
2.14 (1H, m, CH2CH2CH2–Ar), 2.03–1.79 (3H, m, CH2CH2CH2–Ar);
4.2.4. 3-(1,3-Diphenylprop-2-ynyl)-4-hydroxy-2H-
chromen-2-one (3d)32
13C NMR (75 MHz, CDCl3):
d 163.8, 160.1, 152.7, 138.3, 134.8, 132.0,
130.8, 129.8, 128.1, 127.6, 124.0, 123.1, 116.5, 116.3, 109.6, 36.6, 30.0,
29.5, 21.9; HRMS (ESI): calcd for C19H17O3: 293.1172 (MþH)þ,
found: 293.1175.
Brown solid; mp: 158–160 ꢀC; Rf (30% EtOAc/hexanes) 0.3; IR
(neat): nmax 3329, 2924, 1672, 1625, 1491, 1205, 756, 695 cmꢁ1 1H
;
NMR (300 MHz, CDCl3):
d
8.37 (1H, s, OH), 7.86 (1H, dd, J¼1.5,
8.3 Hz, Ar–H), 7.61 (2H, d, J¼6.7 Hz, Ar–H), 7.58–7.49 (3H, m, Ar–H),
4.3. 3-Benzhydryl-2-oxo-2H-chromen-4-yl trifluoro-
methanesulfonate (4a)
7.42–7.24 (7H, m, Ar–H), 5.79 (1H, s, CH–Ar); 13C NMR (75 MHz,
CDCl3):
d 162.8, 161.3, 152.9, 138.7, 132.5, 132.0, 129.4, 129.2, 128.7,
127.9, 127.3, 124.2, 123.6, 121.6, 116.7, 116.1, 105.1, 88.1, 86.6, 33.6;
HRMS (ESI): calcd for C24H16O3Na: 375.0997 (MþNa)þ, found:
375.0999.
To a solution of 3a (1 g, 3.04 mmol) and Et3N (0.63 mL,
4.57 mmol) in dichloromethane was added N-phenyltriflimide
(0.75 g, 3.35 mmol). The reaction mixture was stirred for 3 h at
room temperature. After completion of the reaction (monitored by
TLC), the reaction mixture was evaporated in vacuo and the crude
compound was purified by column chromatography to afford the
desired product 4a (1.14 g, 82% yield). Viscous liquid; Rf (20% EtOAc/
hexanes) 0.6; IR (neat): nmax 3447, 3062, 1733, 1616, 1417, 1217, 1132,
4.2.5. 4-Hydroxy-3-(1-(4-methoxyphenyl)-3-phenylprop-2-ynyl)-
2H-chromen-2-one (3e)
Viscous liquid; Rf (30% EtOAc/hexanes) 0.2; IR (neat): nmax 3334,
2927, 1673, 1625, 1508, 1250, 1033, 756 cmꢁ1 1H NMR (200 MHz,
;
CDCl3):
d
8.38 (1H, s, OH), 7.85 (1H, dd, J¼1.5, 7.8 Hz, Ar–H), 7.58–
893, 755 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
7.79 (1H, dd, J¼1.5,
7.46 (5H, m, Ar–H), 7.39–7.22 (5H, m, Ar–H), 6.93–6.84 (2H, m, Ar–
5.2 Hz, Ar–H), 7.61 (1H, dt, J¼1.5, 7.5 Hz, Ar–H), 7.42–7.35 (2H, m,
H), 5.72 (1H, s, CH–Ar), 3.77 (3H, s, OCH3); 13C NMR (50 MHz,
Ar–H), 7.33–7.20 (10H, m, Ar–H), 5.77 (1H, s, CH–Ar); 13C NMR
CDCl3):
d
162.7, 161.1, 159.2, 152.7, 132.4, 131.9, 130.6, 129.2, 128.6,
(75 MHz, CDCl3): d 159.1, 153.0, 152.5, 139.2, 133.3, 129.1, 128.5,
128.4, 124.2, 123.5, 121.6, 116.6, 116.1, 114.5, 105.3, 87.6, 86.9, 55.4,
32.8; HRMS (ESI): calcd for C25H18O4Na: 405.1102 (MþNa)þ, found:
405.1100.
127.3, 125.1, 124.3, 123.7, 117.0, 115.2, 48.1; HRMS (ESI): calcd for
C23H15O5F3SNa: 483.0490 (MþNa)þ, found: 483.0482.
4.4. (E)-Ethyl 3-(3-benzhydryl-2-oxo-2H-chromen-4-
4.2.6. 4-Hydroxy-3-(1-phenyloct-2-ynyl)-2H-chromen-2-one (3f)
Pale-yellow solid; mp: 90–92 ꢀC; Rf (30% EtOAc/hexanes) 0.5; IR
(neat): nmax 3306, 2928, 1707, 1627, 1494, 1201, 756 cmꢁ1; 1H NMR
yl)acrylate (5a)
To a solution of 4a (160 mg, 0.34 mmol) in DMF (5 mL) under
nitrogen was added Pd(PPh3)4 (20 mg, 5 mol %). After stirring for
15 min at room temperature, ethyl acrylate (174 mg, 1.7 mmol) and
Et3N (0.15 mL, 1.04 mmol) were added. The reaction was stirred at
100 ꢀC for 10 h and the mixture was concentrated in vacuo. The
residue was dissolved in 20 mL of EtOAc and washed with water
(200 MHz, CDCl3):
d
8.78 (1H, s, OH), 7.85 (1H, dd, J¼1.4, 8.0 Hz, Ar–
H), 7.58–7.46 (3H, m, Ar–H), 7.37–7.19 (5H, m, Ar–H), 5.48 (1H, t,
J¼2.2 Hz, CH), 2.34 (2H, dt, J¼2.2, 7.3 Hz, CH2C^C), 1.69–1.50 (2H,
m, CH2–CH2C^C), 1.48–1.22 (4H, m, C2H4CH2C^C), 0.91 (3H, t,
J¼6.6 Hz, CH3); 13C NMR (50 MHz, CDCl3):
d 162.7, 161.2, 152.8,

Ch.R. Reddy et al. / Tetrahedron 64 (2008) 11666–11672
11671
(15 mL), brine (10 mL), dried over Na2SO4, filtered, and concen-
trated in vacuo. Purification of crude compound by flash chroma-
tography affords the desired product 5a (111 mg, 78% yield).
Viscous liquid; Rf (20% EtOAc/hexanes) 0.5; IR (neat): nmax 3430,
132.9, 132.3, 131.7, 130.2, 129.2, 128.6, 127.4, 127.1, 125.2, 124.5,
123.8, 119.2, 117.0, 116.7, 87.3, 83.2, 52.0; HRMS (ESI): calcd for
C
30H20O2Na: 435.1355 (MþNa)þ, found: 435.1355.
2924, 2854, 1722, 1601, 1383, 1176, 755, 701 cmꢁ1
;
1H NMR
4.8. 4-(Benzylamino)-3-(1,3-diphenylprop-2-ynyl)-2H-
chromen-2-one (6a)
(200 MHz, CDCl3):
d 7.59–7.44 (2H, m, Ar–H), 7.39–7.19 (13H, m, Ar–
H, CH]CHCO2Et), 6.00 (1H, d, J¼16.0 Hz, CHCO2Et), 5.87 (1H, s, CH–
Ar), 4.25 (2H, q, J¼7.2 Hz, CH2CH3), 1.34 (3H, t, J¼7.2 Hz, CH3); 13C
To a solution of 3d (100 mg, 0.28 mmol) and Et3N (0.06 mL,
0.42 mmol) in dichloromethane (10 mL), was added N-phenyl-
triflimide (70.2 mg, 0.31 mmol). The reaction mixture was stirred
for 3 h at room temperature and evaporated in vacuo to get crude
product. The above triflate was dissolved in 1,4-dioxane (4 mL) and
was added pyridine (0.045 mL, 0.56 mmol) followed by benzyl-
amine (0.046 mL, 0.42 mmol). Then, the reaction mixture was
stirred at room temperature for 2.5 h. After completion of reaction
(monitored by TLC), the reaction mixture was evaporated in vacuo,
and the residue was purified by column chromatography to afford
the desired product 6a (70 mg, 56% yield). Pale brown solid, mp:
136–138 ꢀC; Rf (30% EtOAc/hexanes) 0.5; IR (neat): nmax 3246, 2923,
NMR (75 MHz, CDCl3): d 165.0, 160.0, 153.0, 147.0, 140.7, 137.8, 131.8,
129.2, 128.7, 128.4, 128.0, 127.9, 127.0, 126.4, 124.4, 117.1, 61.3, 51.0,
14.4; HRMS: calcd for C27H23O4: 411.1596 (MþH)þ, found: 411.1595.
4.5. 3-Benzhydryl-4-phenyl-2H-chromen-2-one (5b)
To a solution of 4a (150 mg, 0.33 mmol) and phenylboronic acid
(52 mg, 0.42 mmol) in toluene/ethanol/water (1:1:0.3, 11.5 mL)
were added Na2CO3 (73.4 mg, 0.69 mmol) and Pd(PPh3)4 (7.6 mg,
0.007 mmol). The reaction mixture was stirred at refluxing tem-
perature for 10 h and diluted with water (10 mL). The product was
extracted into EtOAc (3ꢂ15 mL), dried over Na2SO4, and evaporated
in vacuo. The crude product was purified by flash chromatography
to get the desired product 5b (101 mg, 80% yield). White solid; mp:
200–202 ꢀC; Rf (20% EtOAc/hexanes) 0.6; IR (neat): nmax 3430, 2924,
2854, 1727, 1599, 1447, 1052, 704 cmꢁ1; 1H NMR (300 MHz, CDCl3):
1663, 1542, 1026, 1001, 757, 693 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
8.26 (1H, d, J¼7.8 Hz, Ar–H), 7.91 (1H, t, J¼6.6 Hz, Ar–H), 7.66 (1H,
t, J¼7.5 Hz, Ar–H), 7.27 (17H, m, Ar–H, CH), 5.47 (1H, s, NH), 4.70
(1H, dd, J¼6.9, 16.8 Hz, CH2Ph), 4.53 (1H, dd, J¼6.3, 16.8 Hz, CH2Ph);
13C NMR (75 MHz, CDCl3):
d 161.5, 152.0, 150.2, 139.5, 135.9, 133.2,
d
7.51 (3H, dd, J¼1.5, 5.2 Hz, Ar–H), 7.43 (1H, dt, J¼1.5, 7.5 Hz, Ar–H),
131.9, 128.8, 128.6, 128.3, 127.2, 127.1, 126.8, 125.8, 125.6, 123.7,
122.8, 116.9, 115.5, 104.9, 96.1, 90.7, 46.5, 30.6; HRMS (ESI): calcd for
C31H24NO2: 442.1802 (MþH)þ, found: 442.1806.
7.32 (1H, d, J¼8.3 Hz, Ar–H), 7.26–7.05 (13H, m, Ar–H), 6.93 (1H, dd,
J¼1.5, 7.5 Hz, Ar–H), 5.17 (1H, s, CH–Ar); 13C NMR (75 MHz, CDCl3):
d
159.9, 153.3, 153.0, 141.3, 134.9, 131.2, 129.1, 129.0, 128.4, 128.3,
128.0, 127.9, 126.6, 124.1, 120.9, 116.5, 51.5; HRMS (ESI): calcd for
4.9. 3-(1,3-Diphenylprop-2-ynyl)-4-morpholino-2H-
chromen-2-one (6b)
C28H21O2: 389.1541 (MþH)þ, found: 389.1535.
4.6. 4-Allyl-3-benzhydryl-2H-chromen-2-one (5c)
To a solution of 3d (100 mg, 0.28 mmol) and Et3N (0.06 mL,
0.42 mmol) in dichloromethane (10 mL), was added N-phenyl-
triflimide (70.2 mg, 0.31 mmol). The reaction mixture was stirred
for 3 h at room temperature and evaporated in vacuo to get crude
product. The above triflate was dissolved in 1,4-dioxane (5 mL) and
was added pyridine (0.04 mL, 0.56 mmol) followed by morpholine
(0.04 mL, 0.42 mmol). Then, the reaction mixture was heated to
80 ꢀC and stirred for 2 h. After completion of reaction (monitored
by TLC), the reaction mixture was evaporated in vacuo and the
residue was purified by column chromatography to afford the de-
sired product 6b (66 mg, 55% yield). Brown crystalline solid, mp:
193–195 ꢀC; Rf (20% EtOAc/hexanes) 0.3; IR (neat): nmax 3385, 3029,
To a solution of 4a (0.2 g, 0.43 mmol) in 1,4-dioxane (1.6 mL),
LiCl (0.09 g, 2.17 mmol), allyl tributyltin (0.21 g, 0.65 mmol), and
Pd(PPh3)4 (25 mg, 0.02 mmol) were consequently added. The re-
action mixture was stirred at 100 ꢀC for 18 h. The mixture was
concentrated in vacuo and the crude product was purified by flash
chromatography to afford 5c (114.5 mg, 75% yield). Light-brown
solid; mp: 160–161 ꢀC; Rf (20% EtOAc/hexanes) 0.6; IR (neat): nmax
3424, 2922, 2853, 1709, 1601, 1451, 1062, 752, 701 cmꢁ1
(300 MHz, CDCl3):
;
1H NMR
d
7.64 (1H, dd, J¼0.7, 8.3 Hz, Ar–H), 7.49 (1H, dt,
J¼1.5, 7.5 Hz, Ar–H), 7.36–7.18 (12H, m, Ar–H), 5.94 (1H, s, CH),
5.73–5.28 (1H, m, CH]CH2), 5.12–4.95 (2H, m, CH2]CH), 3.66 (2H,
2962, 2851, 2120, 1698, 1597, 1448, 1282, 1110, 914, 762, 692 cmꢁ1
1H NMR (300 MHz, CDCl3)
;
d, J¼6.0 Hz, CH2CH]CH2); 13C NMR (75 MHz, CDCl3):
d 160.7, 153.1,
d
7.07(1H, dd, J¼1.5, 8.3 Hz, Ar–H), 7.56–
149.6, 141.1, 132.7, 131.1, 129.1, 128.5, 128.4, 126.7, 125.6, 124.2, 119.9,
118.2, 116.9, 49.6, 33.3; HRMS (ESI): calcd for C25H20O2Na: 375.1360
(MþNa)þ, found: 375.1356.
7.19 (13H, m, Ar–H), 6.71(1H, s, CH–Ar), 3.88–3.76 (4H, m,
CH2OCH2), 3.58–3.37 (2H, br m, CH2N), 3.25–3.14 (2H, br m, CH2N);
13C NMR (75 MHz, CDCl3):
d 162.1, 157.5, 153.4, 127.7, 127.6, 127.6,
126.2, 125.1, 123.7, 117.4, 98.4, 81.5, 67.1, 51.1; HRMS (ESI): calcd for
4.7. 3-Benzhydryl-4-(phenylethynyl)-2H-chromen-2-one (5d)
C28H24NO3: 422.1756 (MþH)þ, found: 422.1755.
To a solution of 4a (0.2 g, 0.43 mmol) in DMF (6 mL) under ni-
trogen was added Pd(PPh3)4 (25 mg, 0.02 mmol). After stirring for
15 min at room temperature, the following reagents were added
sequentially: phenyl acetylene (48 mg, 0.48 mmol), CuI (8 mg,
0.04 mmol), and Et3N (0.3 mL, 2.17 mmol). The mixture was stirred
at 70 ꢀC for 12 h until no triflate remained. The reaction mixture
was concentrated in vacuo, the residue was dissolved in EtOAc
(30 mL), and washed with water (20 mL). The organic layer was
washed with brine (15 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. Purification of the crude product by flash chro-
matography affords the desired product 5d (138 mg, 77% yield).
Viscous liquid; Rf (20% EtOAc/hexanes) 0.6; IR (neat): nmax 3436,
Acknowledgements
B.S. and N.N.R. thank the CSIR, New Delhi for financial assis-
tance. C.R.R. is grateful to Dr. J. S. Yadav and Dr. S. Chandrasekhar,
Indian Institute of Chemical Technology, Hyderabad for their sup-
port and encouragement. The authors are also thankful to the ref-
erees for their valuable suggestions.
References and notes
1. Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins: Occurrence,
Chemistry, and Biochemistry; Wiley: New York, NY, 1982.
2. Naser-Hijazi, B.; Stolze, B.; Zanker, K. S. Second Proceedings of the International
Society of Coumarin Investigators; Springer: Berlin, 1994.
2925, 1604, 1384, 761 cmꢁ1; 1H NMR (200 MHz, CDCl3):
dd, J¼1.4, 8.0 Hz, Ar–H), 7.50–7.22 (18H, m, Ar–H), 6.21 (1H, s, CH–
Ar); 13C NMR (75 MHz, CDCl3):
160.2, 152.9, 140.9, 139.2, 133.4,
d 8.00 (1H,
d
3. Spino, C.; Dodier, M.; Sotheeswaran, S. Bioorg. Med. Chem. Lett. 1998, 8, 3475.

11672
Ch.R. Reddy et al. / Tetrahedron 64 (2008) 11666–11672
4. Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa, H.; Takahashi, D.;
Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem. Lett. 2000, 10, 59.
5. Xia, Y.; Yang, Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.-H.; Lee, K.-H.
J. Med. Chem. 2001, 44, 3932.
27. Tabakovic, I.; Tabakovic, K.; Gaon, I. Org. Prep. Proced. Int. 1997, 29, 223.
28. Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 7279 and references
cited therein.
29. Enders, A. Angew. Chem. 1957, 69, 481.
6. Itoigawa, M.; Ito, C.; Tan, H. T.-W.; Kuchide, M.; Tokuda, H.; Nishino, H.; Fur-
ukawa, H. Cancer Lett. 2001, 169, 15.
7. Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron Lett. 2006, 47, 3755.
8. Yamamoto, Y.; Kurazono, M. Bioorg. Med. Chem. Lett. 2007, 17, 1626.
9. Raj, G.; Kumar, R.; McKinney, W. P. Am. J. Med. Sci. 1994, 307, 128.
10. Hadler, M. R.; Shadbolt, R. S. Nature 1975, 253, 275.
30. Ziegler, R. Monatsh. Chem. 1957, 88, 25.
31. Ahluvalia, V. K.; Arora, K. K.; Mukherjee, I. Indian J. Chem., Sect. B 1985, 298.
32. Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron 2007, 63, 11636.
33. Clark, J. H. Acc. Chem. Res. 2002, 35, 791 and references cited therein.
34. Reddy, Ch. R.; Rajesh, G.; Balaji, S. V.; Chethan, N. Tetrahedron Lett. 2008,
49, 970.
11. Estevez-Braun, A.; Gonzalez, A. G. Nat. Prod. Rep. 1997, 14, 465.
12. Clerici, A.; Porta, O. Synthesis 1993, 99.
35. Reddy, Ch. R.; Mahipal, B.; Rao, Y. S. ARKIVOC 2008, 250 and references cited
therein.
13. Mizuno, T.; Nishiguchi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda, N.
Synthesis 1988, 257.
14. Wang, S.; Milne, G. W. A.; Yan, X.; Posey, I. J.; Nicklaus, M. C.; Graham, L.; Rice,
W. G. J. Med. Chem. 1996, 39, 2047.
15. Dittmer, D. C.; Li, Q.; Avilov, D. V. J. Org. Chem. 2005, 70, 4682.
16. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999.
17. Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetra-
hedron Lett. 1998, 39, 4995.
18. Davis, S. E.; Church, A. C.; Tummns, R. C.; Beam, C. F. J. Heterocycl. Chem. 1997,
34, 1159.
19. Chen, D. U.; Kuo, P. Y.; Yang, D. Y. Bioorg. Med. Chem. Lett. 2005, 15, 2665.
20. Kischel, J.; Michalic, D.; Zapf, A.; Beller, M. Chem. Asian J. 2007, 2, 909.
21. Majumdar, K. C.; Sarkar, S. Tetrahedron 2002, 58, 8501.
22. Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S. Synthesis 2003, 1286.
23. Grigg, R.; Nurnabi, M.; Rahul, M.; Sarkar, A. Tetrahedron 2004, 59, 3359.
24. Wuxie, J.; Yue, L.; Chen, W.; Du, W.; Zhu, J. Org. Lett. 2007, 9, 413.
25. Naumov, M. I.; Sutirin, S. A.; Shavyrin, A. S.; Ganina, O. G.; Beletskaya, I. P.; Rey,
V. B.; Combes, S.; Finet, J. P.; Fedorov, A. Y. J. Org. Chem. 2007, 72, 3293.
26. Toth, G.; Moinar, S.; Tamas, T.; Borbely, I. Org. Prep. Proced. Int. 1999, 31, 222.
36. It was also noted that the benzylation was successful only with the propargyl
alcohols generated from aromatic aldehydes (entries 5, 6 and 8, Table 2), and
not with the propargyl alcohol generated from aliphatic aldehyde (entry 10,
Table 2). This may be due to the benzylic nature of the former alcohols.
37. There is only one report in the literature for the synthesis of coumatetralyl from
4-hydorxycoumarin under AcOH/H2SO4 medium. See reference: Bayer, F. Chem.
Abstr. 1960, 579.
38. The filtered catalyst was used for another reaction, after washing with 0.5 N
HCl followed by water and dried.
39. Tsuji, J. Perspectives in Organopalladium Chemistry for the 21st Century; Elsevier:
Amsterdam, 1999.
40. Bailly, C.; Bal, C.; Barbier, P.; Combes, S.; Finet, J.-P.; Hildebrand, M.-P.; Peyrot,
V.; Wattez, N. J. Med. Chem. 2003, 46, 5437.
41. Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642.
42. Yao, M.-L.; Deng, M.-Z. Heteroat. Chem. 2000, 11, 380.
43. The substrate 3d may undergo cyclization under the reaction conditions to give
furocoumarin compound32 along with the expected coupling product (ob-
served in MS of reaction mixture) and other unidentified compounds as
complex mixture.