Palladium catalyzed reaction in aqueous DMF: Synthesis of 3-alkynyl substituted flavones in the presence of prolinol

Article abstract of DOI:10.1016/j.tet.2003.10.003

(S)-Prolinol facilitated the coupling reaction of terminal alkynes with 3-iodoflavone under palladium-copper catalysis in aqueous DMF affording a mild and convenient method for the synthesis of 3-alkynyl substituted flavones of potential biological interest.

Full text of DOI:10.1016/j.tet.2003.10.003

Tetrahedron 59 (2003) 9563–9570
Palladium catalyzed reaction in aqueous DMF: synthesis of
3-alkynyl substituted flavones in the presence of prolinolq
*
Manojit Pal, Venkataraman Subramanian, Karuppasamy Parasuraman
*
and Koteswar Rao Yeleswarapu
Chemistry-Discovery Research, Dr Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500050, India
Received 19 July 2003; revised 4 September 2003; accepted 2 October 2003
Abstract—(S)-Prolinol facilitated the coupling reaction of terminal alkynes with 3-iodoflavone under palladium–copper catalysis in
aqueous DMF affording a mild and convenient method for the synthesis of 3-alkynyl substituted flavones of potential biological interest.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
have been reported for the synthesis of 3-substituted
flavones3a,c,8 and none for the synthesis of 3-alkynyl
substituted flavones. Over the last 25 years, palladium
catalyzed coupling of terminal alkynes with the (hetro)aryl
halide (the Sonogashira coupling)9a has become a most
attractive and powerful tool for C–C bond formation
reaction.9b The reaction is, in general, carried out with a
large excess of a secondary or tertiary alkyl amine as a
solvent/co-solvent and therefore, application of this proto-
col to large scale preparations often led to environmental
pollution due to the volatile nature of these amines.
Nevertheless, this palladium catalyzed reaction has been
investigated extensively to improve the reaction condi-
tions9c–f and the coupling reaction has been utilized
successfully for the introduction of acetylenic moiety to
various arenes and heteroarenes.10 However, use of this
methodology for the synthesis of 3-alkynyl flavones has not
been explored previously.
3-Substituted flavones are of considerable interest because
of their widespread occurrence in nature1 as well as their
profound biological activities.2 They are also useful as
antianaphylactic agents3a for the treatment of asthma, as
potential cardio protective agents in doxorubicin antitumor
therapy3b or as STS (steroid sulfatase) inhibitors for the
possible treatment of a number of diseases including breast
cancer.3c In continuation of our research under the new drug
discovery program, we have recently reported the synthesis
of various diarylheterocycles e.g. 3,4-diarylfuranones,4a–c
3,4-diarylmaleic anhydrides,4d 1,5-diarylpyrazoles5 along
with other heterocycles.6 In further pursuance of our
research on the development of novel anti-cancer agents
we became interested in the synthesis of a combinatorial
library based on the scaffold of flavones especially 3-alkenyl/
alkynyl-substituted7 flavones (A, Fig. 1) for their in vitro
assay against various cancer cell lines. While the library
model, as shown in Figure 1, has three centers for the
introduction of diversity into flavone molecule, we initially
focused on the modification of C-3 substituents. We
postulated that attachment of an alkynyl moiety at the C-3
position of the flavone ring may lead to a novel class of
compounds of potential biological significance, especially
as inhibitors of thymidylate synthase (TS)—an essential
enzyme required for the growth of cells.7b
The palladium catalyzed reaction in aqueous media has
attracted much attention11a–d in recent time because water
based synthetic processes are inherently safer as well as
inexpensive. Therefore, the use of water-soluble catalysts as
Despite their biological importance only a few methods
q DRL publication number 305.
Keywords: 3-alkynyl flavones; palladium catalyst; prolinol; aqueous media.
*
Corresponding authors. Tel.: þ91-40-2304-5439; fax: þ91-40-
23045438; e-mail: manojitpal@drreddys.com; fax: þ91-40-23045007;
e-mail: koteswarraoy@drreddys.com
Figure 1. Diversity based flavone scaffold.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.003

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M. Pal et al. / Tetrahedron 59 (2003) 9563–9570
well as phosphine ligands e.g. sulfonated phosphines has
been explored successfully. While the use of prolinol in the
transition metal catalyzed Michael reaction in organic/
aqueous media has been investigated,11e,f its use in
palladium catalyzed reaction is not common. Moreover,
unlike inorganic bases or primary amines, prolinol does not
react with the flavone moiety11g–i and possesses ample
water miscibility. Our continuing interest in palladium
catalyzed reactions12 prompted us to develop a mild and
efficient method for the synthesis of 3-alkynyl substituted
flavones via palladium catalyzed C–C bond formation
reaction in aqueous media. Development of such a
methodology could be beneficial for the synthesis of
compounds having potential biological significance using
iodoarenes that are sparingly soluble or insoluble in water.
therefore, investigated the use of relatively more water
miscible palladium catalyst e.g. Na2PdCl4 in the same
reaction and 3b was isolated in moderate yield (,50%)
when the reaction was carried out at higher temperature
(608C).
The coupling reaction of iodoflavone with terminal alkyne
was carried out in DMF as a co-solvent because of its ability
to dissolve the substrates as well as palladium/copper
catalysts. Use of other co-solvent such as acetonitrile was
found to be satisfactory (entry 3, Table 2) whereas, use of
THF, dioxane was found to be less effective. Extensive
studies were conducted to optimize the reaction conditions
for the formation of 3 by varying the amount of added water.
Use of 5:1 DMF/H2O was found to be optimum as pre-
cipitation of reactants occurred in the presence of excess
water.
2. Results and discussion
While (S)-prolinol (bp 74–768C/2 mm) was used as a base
in the present cases, use of triethylamine (bp 88.88C), the
most widely used base in Sonogashira reaction, was also
investigated (entry 1, Table 2). Due to the presence of the
hydrophilic hydroxyl group (S)-prolinol was found to be
more miscible with water than triethylamine, which there-
fore facilitated the coupling reaction in aqueous media
affording better yields of products. Unlike ammonia use of
excess prolinol did not affect the yield of product.11c
Moreover, due to its lower volatility (thereby avoiding
internal pressure development as well as ensuring its
maximum recovery) and reactivity in compared to ammo-
nia, prolinol has advantages over the other amine15 and
inorganic bases11i especially for the large scale prepara-
tions. The reactions were generally carried out under mild
conditions i.e. at 258C.
When 3-iodoflavone (1)13a was treated with an terminal
alkyne (2, R¼alkyl, hydroxyalkyl etc.)13b in aqueous
dimethylformamide (DMF/H2O; 5:1) in the presence of
(PPh3)2PdCl2 (0.05 equiv.), copper iodide (0.10 equiv.) and
(S)-prolinol (4 equiv.) under a nitrogen atmosphere 3-alkynyl
flavones (3, Scheme 1) were isolated as desired products.
Results of this study are summarized in Table 1.
Scheme 1. Palladium catalyzed reaction of 3-iodoflavone with terminal
alkynes.
The present palladium catalyzed reaction of 3-iodoflavone
with acetylenic compounds led to the formation of 3-alkynyl
flavones in good yields. Interestingly, palladium mediated
coupling of 3-iodoflavone with internal alkynes resulted in
the formation of annulated products i.e. a mixture of
benzo[c]xanthen-7-one and diphenylfuran derivatives16a
due to the participation of the neighboring aryl group in
the reaction cascades. The presence of inorganic base i.e.
NaOAc and relatively strong reaction conditions (heating at
1008C for 72 h) was responsible for the opening of the
flavone ring in such cases. It is noteworthy that no
significant dimerization of terminal alkynes was observed
during our synthesis of 3-alkynylflavones. This is in contrast
to the earlier report on Sonogashira coupling of bromopyra-
none with terminal alkynes where 1,3-diynes were isolated
as major products even in the absence of a stoichiometric
additive.16b Perhaps terminal alkynes are more susceptible
to undergo Pd–Cu mediated dimerization16c in the presence
of triethylamine rather than prolinol.
The coupling reaction in aqueous DMF afforded desired
products in good yields. By use of this palladium catalyzed
reaction a variety of terminal acetylenes were reacted with
3-iodoflavone (Table 1). Various substituents (including
alkyl, hydroxyl, phenyl etc.) present in the acetylenic
compounds (2) were well tolerated during the course of the
reaction and the yields were not affected drastically with the
change of substituents in the acetylenic component (entries
1–4, Table 1). Yields were also found to be comparable
irrespective of the nature of the aryl group present at the
2-position of the flavone moiety for a given alkyne when
employed in the reaction (entries 5–8, Table 1).
The coupling reactions were usually carried out using
(PPh3)2PdCl2 as catalyst and CuI as a co-catalyst. However,
the use of other palladium catalysts e.g. (PPh3)4Pd and
Pd(OAc)2/PPh3 was also examined and the reaction
proceeded well in such cases (entries 4–5, Table 2). It is
noteworthy that external addition of a phase transfer catalyst
(PTC)14a or water soluble phosphine ligands11b are not
required for the successful coupling reaction in the present
case. To gain further evidence on the role of PPh3, coupling
reaction of 1a with 2b was carried out using PdCl2 as
catalyst under the same condition as indicated in Table 2.
However, we failed to isolate the desired product 3b perhaps
due to the poor solubility of PdCl2 in aqueous DMF. We
The palladium mediated coupling of 3-iodoflavone with
terminal alkynes afforded cleaner products in the presence
of prolinol when compared with that in the presence of
triethylamine. Except few cases (entries 3, 4 and 8, Table 1)
all products (3) isolated directly from the reaction mixture
(after dilution with cold water) were often analytically pure
and well characterized by their spectral (1H NMR, 13C
NMR, IR, Mass) data. All the reactions were carried out

M. Pal et al. / Tetrahedron 59 (2003) 9563–9570
9565
Table 1. Palladium catalyzed synthesis of 3-alkynyl substituted flavones in aqueous DMFa
Entry
1
Substrate (1) Ar¼
Productsb (3)
Yield (%)c
60
3,4-Dimethoxyphenyl (1a)
2
3,4-Dimethoxyphenyl (1a)
81
3
3,4-Dimethoxyphenyl (1a)
64
4
5
3,4-Dimethoxyphenyl (1a)
78d
3,4-Dimethoxy-5-nitrophenyl (1b)
59
6
3,4-Dimethoxy-5-nitrophenyl (1b)
52
7
3,4-Dimethoxy-5-nitrophenyl (1b)
77
8
3,4-Dimethoxy-5-nitrophenyl (1b)
72
a
All reactions were carried out by using 1 (1.0 equiv.), 2 (3.0 equiv.), (PPh3)2PdCl2 (0.05 equiv.), CuI (0.10 equiv.), prolinol (4 equiv.) in DMF/H2O (5:1) for
12 h.
b
c
d
Identified by 1H NMR, 13C NMR, IR, mass.
Isolated yields.
Reaction was carried out for 36 h.

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M. Pal et al. / Tetrahedron 59 (2003) 9563–9570
Table 2. Effect of reaction conditions on the coupling reactiona
earlier.17c Oxidative addition of the aryl iodide (1) to the
zero-valent anion A affords the 18-electron complex B in
which the chloride ion, borne by the Pd(0), remains attached
to the Pd(II) center.17e PPh3 being moderately donating
(s-donor) and accepting (p-acceptor) ligand would be
expected to hold onto the electron rich palladium and
therefore departure of prolinol is more likely rather than
PPh3 from A during its reaction with aryl iodide. The
complex B then undergoes elimination of chloride ion in the
presence of prolinol to yield a neutral pentacoordinated
complex C. Nucleophilic displacement of the prolinol
ligand of C by the terminal acetylene (2) gives an anionic
pentacoordinated intermediate D, in which aryl and alkynyl
ligands are at adjacent as well as favorable position for
undergoing a fast reductive elimination reaction. 3-Alkynyl-
flavone is thus obtained via reductive elimination followed
by the regeneration of the active palladium species A0. The
palladium species A0 then initiate the second (main)
catalytic cycle (Scheme 3).
Entry
Catalyst
Base (reaction time)
Yield (%)b
1
2
3
4
5
(PPh3)2PdCl2
(PPh3)2PdCl2
(PPh3)2PdCl2
(PPh3)4Pd
Et3N (12 h)
46c
81
Prolinol (6 h)
Prolinol (12 h)
Prolinol (24 h)
Prolinol (12 h)
50d
80
Pd(OAc)2/PPh3
75
a
Reactions were carried out by using 1a (1.0 equiv.), 2b (3.0 equiv.), Pd
catalyst (0.05 equiv.), CuI (0.10 equiv.), base (4 equiv.) in DMF/H2O
(5:1).
Isolated yields.
DMF/H2O (10:1).
Acetonitrile/H2O (5:1).
b
c
d
While the coupling reaction of 3-iodoflavone with terminal
alkynes in the presence of (PPh3)4Pd/CuI or Pd(OAc)2/PPh3
is expected to follow the same mechanistic pathway
(Scheme 3), the anionic species (A) generated in these
cases could be [(PPh3)2Pd(0)X(prolinol)]2 where X¼I
[when (PPh3)4Pd/CuI is used] or OAc [when Pd(OAc)2/
PPh3 is used] depending on the nature of the catalysts
employed in the coupling reaction.
using 5:1 DMF/H2O as a solvent due to the poor solubility
of 3-iodoflavone (1) in water alone. However, to asses the
applicability of this methodology in water and considering
iodoflavone as activated substrate for the present palladium-
catalyzed reaction we investigated the coupling reaction of a
more frequently used aryl halide such as iodobenzene with
terminal alkyne 2b at 258C in water (Scheme 2).
Iodobenzene was found to have good miscibility with
water in the presence of prolinol and the reaction was
completed within 30 min affording the desired product in
good yield. This observation clearly indicates the high
efficiency of the protocol when applied to the palladium
catalyzed alkynylation of simple aryl iodides and therefore,
the methodology has potential to be used widely in the
synthesis of other internal alkynes via C–C bond formation
reaction in aqueous media.16d
3. Conclusion
In conclusion, we have described a facile and mild
palladium-mediated procedure for the synthesis of novel
3-alkynylflavones in the presence of prolinol in aqueous
DMF. As far as we know, despite the report of employing
various amines including aqueous ammonia no successful
examples of Sonogashira coupling using prolinol have been
reported. No significant side reaction such as dimerization
of terminal alkynes or opening of the flavone ring was
observed during the course of our reaction. The method-
ology can tolerate a variety of functional groups, dose not
require the use of PTC/water soluble phosphine ligands and
has potential to be utilized in water alone. Due to the
operational simplicity as well as easy isolation and
purification procedures for the products the methodology
appears to be a useful alternative to the conventional
Sonogashira reaction. Some of the compounds synthesized
were tested for their pharmacological properties and a few
of them showed interesting biological activities in vitro.18
Further research is ongoing in our laboratory in order to
extend the scope and generality of this methodology.
Scheme 2. Palladium catalyzed reaction of iodobenzene with terminal
alkyne 2b in water.
Mechanistically, these reactions seemed to proceed via
generation of a Pd(0) complex e.g. L2Pd(0) according to the
typical Sonogashira pathway.9a However, recent works by
Amatore and Jutand provided strong evidence in support to
the specific role played by halide ions to generate an anionic
species such as [L2Pd(0)Cl]2.17a,b This anionic species
generated from Pd(PPh3)2Cl2 is thought to be the key
intermediate and participates as active palladium species in
these cross-coupling reactions.17c In the present case,
presumably the prolinol stabilized anionic species (A)
generated in situ (Scheme 3) facilitated the reaction in
aqueous media due to its interaction with water molecules
(via hydroxyl group of prolinol moiety of A).17d It is
noteworthy that the palladium catalyzed cross-coupling
reaction in the presence 0of0 other chelating ligands such as
2,20-bipyridine or 2,20:6 ,2 -terpyridine has been reported
4. Experimental
4.1. General methods
Unless stated otherwise, reactions were performed under
nitrogen atmosphere. Reactions were monitored by thin
layer chromatography (TLC) on silica gel plates (60 F254;
Merck), visualizing with ultraviolet light or iodine spray.
Flash chromatography was performed on silica gel (SRL

M. Pal et al. / Tetrahedron 59 (2003) 9563–9570
9567
Scheme 3. Possible mechanism for Pd-catalyzed reaction of iodoarene with terminal alkynes.
230–400 mesh) using distilled petroleum ether, ethyl
acetate, dichloromethane, chloroform and methanol. 1H
NMR and 13C NMR spectra were determined in CDCl3,
DMSO-d6 or MeOH-d4 solution on Varian Gemini 200 and
50 MHz spectrometers, respectively. Proton chemical shifts
(d) are relative to tetramethylsilane (TMS, d¼0.00) as
internal standard and expressed in ppm. Spin multiplicities
are given as s (singlet), d (doublet), t (triplet) and m
(multiplet) as well as b (broad). Coupling constants (J) are
given in hertz. Infrared spectra were recorded on a Perkin–
Elmer 1650 FT-IR spectrometer. Melting points were
determined using Buchi melting point B-540 apparatus
and are uncorrected. Thermal analysis data [Differential
Scanning Calorimetry (DSC)] was generated with the help
of Shimadzu DSC-50 detector. MS spectra were obtained on
a HP-5989A mass spectrometer. All the reagents used were
from commercial sources and no further purification was
performed.
119.8, 117.6, 117.5, 110.3, 107.5, 87.7 (CIvC), 56.9
(OMe), 56.6 (OMe). Elemental analysis found C, 50.18; H,
3.19; C17H13IO4 requires C, 50.02; H, 3.21%.
4.2.2. 2-(3,4-Dimethoxy-5-nitrophenyl)-3-iodo-4H-4-
chromenone (1b). Yellow solid; yield 15 %, mp 194–
1968C; 1H NMR (200 MHz, CDCl3) 8.30 (d, J¼7.8 Hz, 1H),
7.84 (s, 1H), 7.79–7.68 (m, 3H), 6.98 (s, 1H), 4.07 (s, 3H,
OMe), 4.02 (s, 3H, OMe); IR (KBr, cm21) 1645 (CvO),
1520; m/z (CI method) 454 (Mþ1, 100); 13C NMR
(50 MHz, CDCl3) 173.9 (CvO), 163.2, 153.7, 148.7,
148.7, 134.9, 134.2, 125.7, 124.8, 123.2, 121.7, 117.6,
112.9, 110.1, 88.8 (CIvC), 56.9 (OMe), 56.6 (OMe).
Elemental analysis found C, 45.11; H, 2.50; C17H12INO6
requires C, 45.06; H, 2.67%.
4.3. General procedure for the preparation of 3
A mixture of 1 (3 mmol), (PPh3)2PdCl2 (0.15 mmol), CuI
(0.3 mmol) and (S)-prolinol (12 mmol) in 5:1 DMF/H2O
(6 mL) was stirred at 258C for 1 h under nitrogen
atmosphere. The acetylenic compound 2 (9 mmol) was
added slowly to the mixture with stirring. The reaction
mixture was then stirred at 258C according to the time
indicated in Table 1. The mixture was poured into cold
water (30 mL) with stirring and filtered (if solid was
separated) or extracted with EtOAc (3£200 mL). Combined
organic layers were washed with cold water (2£100 mL),
dried over Na2SO4, filtered and concentrated under vacuum.
The residue thus obtained was purified by column
chromatography (petroleum ether–EtOAc) to afford the
desired product.
4.2. General procedure for the preparation of
iodoflavones
A mixture of flavone (1.0 mmol), iodine (1.10 mmol) and
ceric ammonium nitrate (1.0 mmol) in acetonitrile (20 mL)
was stirred at 658C under nitrogen atmosphere for 5 h. The
mixture was then poured into water (50 mL), extracted with
ethyl acetate (3£25 mL). Organic layers were collected,
combined, washed with cold sodium thiosulfate solution
(2£10 mL) followed by water (2£30 mL), dried over
Na2SO4 and concentrated under low vacuum. The crude
compound thus obtained was purified by column chromato-
graphy to afford the iodo compounds as described below.
4.2.1. 2-(3,4-Dimethoxyphenyl)-3-iodo-4H-4-chrome-
1
none (1a). Yellow solid; yield 45 %, mp 152–1548C; H
4.3.1. 2-(3,4-Dimethoxyphenyl)-3-(3-hydroxy-1-penty-
nyl)-4H-4-chromenone (3a). Yellow solid; yield 60 %;
DSC 1998C; 1H NMR (400 MHz, CDCl3) 8.25 (d,
J¼7.8 Hz, 1H), 7.87–7.80 (m, 2H), 7.72–7.69 (m, 1H),
7.53 (d, J¼8.8 Hz, 1H), 7.46–7.42 (m, 1H), 6.99 (d,
J¼8.3 Hz, 1H), 4.62–4.60 (m, 1H, CH(OH)CH2), 3.99 (s,
3H, OMe), 3.98 (s, 3H, OMe), 2.65–2.60 (bs, exchangeable
with D2O, OH), 1.84–1.79 (m, 2H, CH2), 1.05 (t, J¼7.8 Hz,
NMR (200 MHz, CDCl3) 8.27 (d, J¼8.1 Hz, 1H); 7.72–
7.68 (m, 1H), 7.52–7.35 (m, 4H), 7.01–6.97 (m, 1H), 3.97
(s, 3H, OMe), 3.96 (s, 3H, OMe); IR (KBr, cm21) 1640
(CvO), 1607, 1508; m/z (CI method) 409 (Mþ1, 100), 283
(70, M2I); 13C NMR (50 MHz, CDCl3) 174.48 (CvO),
164.1, 155.7, 151.2, 148.2, 134.0, 127.1, 125.7, 123.1,

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M. Pal et al. / Tetrahedron 59 (2003) 9563–9570
3H, CH3); IR (KBr, cm21) 3419 (bs, OH), 1628 (CvO); m/z
(CI method) 365 (Mþ1, 100); UV (MeOH, nm) 347.5, 251,
205; HPLC: 96.16 %. INERTSIL ODS 3V, KH2PO4/
CH3CN, 1 mL/min, 251 nm, retention time 29.35 min.
Elemental analysis found C, 72.49; H, 5.55; C22H20O5
requires C, 72.52; H, 5.53%.
128.6, 126.0, 125.8, 122.3, 121.5, 117.9, 113.0, 107.8, 99.8,
75.3, 63.7 (C(OH)CH2), 56.8 (OMe), 56.6 (OMe), 30.3
(CH2), 9.2 (Me); HPLC: 94.13 % INERTSIL ODS 3V,
KH2PO4/CH3CN, 1 mL/min, 246 nm, retention time¼19.32
min. Elemental analysis found C, 64.58; H, 4.61;
C22H19NO7 requires C, 64.55; H, 4.68%.
4.3.2. 2-(3,4-Dimethoxyphenyl)-3-(3-hydroxy-3-methyl-
1-butynyl)-4H-4-chromenone (3b). Light brown solid;
yield 81 %; DSC 185.58C; H NMR (200 MHz, CDCl )
3
4.3.6. 2-(3,4-Dimethoxy-5-nitrophenyl)-3-(3-hydroxy-3-
methyl-1-butynyl)-4H-4-chromenone (3f). Light brown
solid; yield 52%; DSC 183.48C; 1H NMR (200 MHz,
CDCl3) 8.26 (d, J¼7.3 Hz,1H), 7.75–7.66 (m, 2H), 7.55–
7.39 (m, 2H), 7.21 (s, 1H), 4.04 (s, 3H, OMe), 4.03 (s, 3H,
OMe), 2.66 (bs, exchangeable with D2O, OH), 1.44 (s, 6H,
Me); IR (KBr, cm21) 3415.3 (bs, OH), 1649 (CvO), 1567;
m/z (CI method) 410 (Mþ1, 40), 392 (70, –OH), 352 (100);
13C NMR (CDCl3, 50 MHz) 176.1, 164.6, 155.6, 152.7,
150.3, 133.9, 128.6, 125.9, 125.8, 122.9, 117.9, 117.8,
112.9, 111.7, 107.7, 103.4, 72.6, 65.0 (C(OH)Me2), 56.8
(OMe), 56.6 (OMe), 30.9 (2C, Me); HPLC: 92.25 %
INERTSIL ODS 3V, KH2PO4/CH3CN, 1 mL/min, 246 nm,
retention time¼17.86 min. Elemental analysis found C,
64.61; H, 4.62; C22H19NO7 requires C, 64.55; H, 4.68%.
1
8.23 (d, J¼8.1 Hz, 1H), 7.87 (d, J¼8.3 Hz, 1H), 7.77–7.67
(m, 1H), 7.54–7.39 (m, 3H), 6.99 (d, J¼8.6 Hz, 1H), 4.00
(s, 3H, OMe), 3.98 (s, 3H, OMe), 2.8 (bs, exchangeable with
D2O, OH), 1.62 (s, 6H, CH3); IR (KBr, cm21) 3419 (bs,
OH), 1626 (CvO), 1595; m/z (CI method) 365 (Mþ1, 40),
347 (100, –OH); 13C NMR (CDCl3, 50 MHz) 192.6, 159.9,
155.5, 153.6, 148.9, 131.9, 131.0, 130.2, 125.5, 122.3,
120.4, 119.5, 119.2, 111.8, 109.8, 107.1, 77.6, 68.7
(C(OH)Me2), 56.0 (OMe), 55.9 (OMe), 28.6 (2C, Me);
UV (MeOH, nm) 349, 252, 207; HPLC: 97.38%. INERTSIL
ODS 3V, KH2PO4/CH3CN (55:45), 1.0 mL/min, 252 nm,
retention time 15.03 min. Elemental analysis found C,
72.58; H, 5.50; C22H20O5 requires C, 72.52; H, 5.53%.
4.3.7. 2-(3,4-Dimethoxy-5-nitrophenyl)-3-(4-hydroxy-1-
butynyl)-4H-4-chromenone (3g). Yellow solid; yield 77
%; DSC 195.48C; H NMR (200 MHz, CDCl3) 8.28 (d,
4.3.3. 2-(3,4-Dimethoxyphenyl)-3-(2-phenyl-1-ethynyl)-
4H-4-chromenone (3c). Light brown solid; yield 64 %;
DSC 2288C; 1H NMR (200 MHz, CDCl3) 8.24 (d,
J¼7.8 Hz, 1H), 7.92–7.88 (m, 2H), 7.75–7.68 (m, 1H),
7.57–7.31 (m, 7H), 7.03 (d, J¼8.1 Hz, 1H), 3.99 (s, 3H,
OMe), 3.89 (s, 3H, OMe); IR (Neat, cm21) 1630 (CvO),
1600; m/z (CI method) 383 (Mþ1, 100); 13C NMR (CDCl3,
50 MHz) 176.5, 155.3, 151.2, 148.3, 133.8, 131.5, 128.8,
128.4, 128.3 (2C), 126.0, 125.4, 124.7, 124.0, 123.1, 122.7,
122.0, 117.8, 111.8, 110.5, 105.9, 98.1, 82.4, 55.9 (2C,
OMe); UV (MeOH,nm) 355, 285, 250, 206; HPLC: 98%.
INERTSIL ODS 3V, KH2PO4/CH3CN, 1 mL/min, 250 nm,
retention time 42.02 min. Elemental analysis found C,
78.56; H, 4.60; C25H18O4 requires C, 78.52; H, 4.74%.
1
J¼7.8 Hz, 1H), 7.76–7.66 (m, 2H), 7.49–7.39 (m, 2H),
7.20 (s, 1H), 4.05 (s, 3H, OMe), 4.02 (s, 3H, OMe), 3.71 (t,
J¼5.9 Hz, 2H, CH2), 2.58 (t, J¼5.9 Hz, 2H, CH2), 1.70 (bs,
exchangeable with D2O, OH); IR (Neat, cm21) 3424 (bs,
OH), 1642 (CvO); m/z (CI method) 396 (Mþ1, 100); 13C
NMR (CDCl3, 50 MHz) 176.6, 164.3, 155.6, 152.8, 150.3,
140.6, 134.2, 125.9, 125.7, 122.2, 121.5, 117.9, 112.9,
107.7, 97.3, 77.6, 73.0, 60.5 (CH2OH), 56.8 (OMe), 56.6
(OMe), 24.2 (CH2); UV (MeOH, nm) 246, 255; HPLC:
92.67%, INERTSIL ODS 3V, KH2PO4/CH3CN, 1 mL/min,
246 nm, retention time¼31.52 min. Elemental analysis
found C, 62.78; H, 4.40; C21H17NO7 requires C, 63.80; H,
4.33%.
4.3.4. 2-(3,4-Dimethoxyphenyl)-3-(4-hydroxy-1-butynyl)-
1
4H-4-chromenone (3d). Semisolid; yield 78 %; H NMR
4.3.8. 2-(3,4-Dimethoxy-5-nitrophenyl)-3-(2-phenyl-1-
ethynyl)-4H-4-chromenone (3h). Yellow Solid; yield 72
%, mp 110–1128C; H NMR (200 MHz, CDCl3), 8.3 (d,
(200 MHz, CDCl3) 8.25 (d, J¼7.8 Hz, 1H), 7.93–7.88 (m,
2H), 7.75–7.63 (m, 1H), 7.55–7.39 (m, 2H), 7.01 (d,
J¼8.3 Hz, 1H), 3.99 (s, 6H, OMe), 3.86 (t, J¼5.4 Hz, 2H,
CH2), 2.75 (t, J¼5.9 Hz, 2H, CH2), 2.2–2.01 (bs, exchange-
able with D2O, OH); IR (KBr, cm21) 3417 (bs, OH), 1616
(CvO), 1551; m/z (CI method) 351 (Mþ1, 100); 13C NMR
(CDCl3, 50 MHz) 177.5, 164.3, 155.2, 151.8, 148.4, 128.6,
128.3, 125.9, 125.4, 122.6, 122.0, 117.8, 116.5, 110.7,
110.5, 105.7, 98.2, 60.6 (CH2OH), 56.0 (OMe), 55.9 (OMe),
24.6 (CH2). Elemental analysis found C, 72.08; H, 5.10;
C21H18O5 requires C, 71.99; H, 5.18%.
1
J¼7.8 Hz, 1H), 7.79–7.67 (m, 2H), 7.51–7.29 (m, 8H),
4.06 (s, 3H, OMe), 3.97 (s, 3H, OMe); IR (KBr, cm21) 1650
(CvO), 1612, 1575; m/z (CI method) 428 (Mþ1, 100); 13C
NMR (CDCl3, 50 MHz) 175.8, 164.5, 155.7, 152.7, 150.4,
140.8, 134.2, 133.9 (2C), 131.8, 128.8, 128.4 (2C), 128.2,
126.2, 125.8, 122.6, 121.8, 117.9, 113.1, 107.9, 98.0, 80.4,
56.8 (OMe), 56.7 (OMe); HPLC: 95 %, HICHROM RPB,
KH2PO4/CH3CN, 1 mL/min, 275 nm, retention time¼39.60
min. Elemental analysis found C, 70.38; H, 4.10;
C25H17NO6 requires C, 70.25; H, 4.01%.
4.3.5. 2-(3,4-Dimethoxy-5-nitrophenyl)-3-(3-hydroxy-1-
pentynyl)-4H-4-chromenone (3e). Yellow solid; yield
59%; DSC 195.98C; HNMR (200 MHz, CDCl3) 8.27 (d,
J¼7.8 Hz, 1H), 7.76–7.62 (m, 2H), 7.49–7.38 (m, 2H),
7.21 (s, 1H), 4.43 (t, J¼6.4 Hz, 1H, CH(OH)CH2), 4.04 (s,
3H, OMe), 4.02 (s, 3H, OMe), 2.6–2.21 (bs, exchangeable
with D2O, OH), 1.68–1.59 (m, 2H, CH2), 0.85 (t, J¼7.5 Hz,
3H, CH3); IR (KBr, cm21) 3424 (bs, OH), 1643 (CvO),
1579; m/z (CI method) 410 (Mþ1, 100); 13C NMR (CDCl3,
50 MHz) 176.3, 164.9, 155.6, 152.8, 150.4, 140.5, 134.3,
4.3.9. Palladium catalyzed reaction of iodobenzene with
2b in water. A mixture of iodobenzene (1.47 mmol),
(PPh3)2PdCl2 (0.15 mmol), CuI (0.15 mmol) and (S)-prolinol
(3.7 mmol) in H2O (3 mL) was stirred at 258C for 30 min
under nitrogen atmosphere. The acetylenic compound 2b
(3.7 mmol) was added slowly to the mixture with stirring.
The reaction mixture was then stirred at 258C for 20 min and
diluted with EtOAc (200 mL), washed with cold 2N HCl
(2£30 mL) followed by water (2£50 mL), dried over
1

M. Pal et al. / Tetrahedron 59 (2003) 9563–9570
9569
M. R.; Khor, S. P.; Amyx, H.; Cao, S.; Rustum, Y. M. Drugs
Future 1994, 19, 565. (b) Kundu, N. G.; Das, B.; Spears, C. P.;
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anhydrous Na2SO4, filtered and concentrated under vacuum.
The residue thus obtained was purified by column chro-
matography (petroleum ether–EtOAc) to afford 2-methyl-
4-phenyl-3-butyn-2-ol19 as light yellow solid in 85% yield,
mp 52–548C; 1H NMR (200 MHz, CDCl3): 7.46–7.41 (m,
2H) 7.33–7.27 (m, 2H), 1.94 (bs, exchangeable with D2O,
1H), 1.64 (s, 6H); IR (KBr, cm21): 3357, 2982; MS (CI,
i-butane): 143 (Mþ217, 100%); 13C NMR: 131.5 (2C),
128.1 (2C), 128.0, 122.7, 93.9, 81.9, 65.4, 31.3 (2C).
Acknowledgements
The authors thank Dr A. Venkateswarlu, Dr R. Rajagopalan,
Professor J. Iqbal of Dr Reddy’s Laboratories, Hyderabad,
India and Dr U. Saxena of Reddy US Therapeutics,
Norcross, GA, USA for their constant encouragement.
Authors also thank Dr K. Vyas and his group for analytical
and spectral support.
8. For the synthesys of 3-alkyl/alkenyl flavones, see: (a) Lokshin,
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9570
M. Pal et al. / Tetrahedron 59 (2003) 9563–9570
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of desired product. Details of this investigation will be
published elsewhere.
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of cancer cell lines [e.g. HT29 (colon), H460 (lung), LoVo
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compounds will be published elsewhere.
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