Oxazoline Chemistry. Part 11: Syntheses of natural and synthetic isoflavones, stilbenes and related species via C-C bond formation promoted by a Pd-oxazoline complex

Article abstract of DOI:10.1016/j.tet.2006.01.046

The complex trans-[PdCl₂(2-ethyl-2-oxazoline- κ¹N)₂] (1) is shown to be an active and oxidatively robust catalyst for C-C bond forming reactions (Heck, Sonogashira, Ullmann, Miyaura-Suzuki, etc.). These reactions can be carried out in air without rigorous solvent/substrate purification and in the absence of additional free ligand. The general methodology described above has been applied to the high yield and regio-selective formation, via Miyaura-Suzuki coupling, of natural and synthetic isoflavones (i.e., isoflavone, 2′-methylisoflavone [7b], 3′-methylisoflavone [7c] and 3′,4′-benzoisoflavone: [7d]). Compounds 7c and 7d are previously unknown. In addition, the synthesis of (E)-tris-O-methylresveratrol and (E)-3,5-dimethoxystilbene is also described; the former is a recognized anti-cancer agent while the latter is a biologically active extract from the bark of the conifer species Pinus armandii. Both of these latter products are produced as a result of a Heck coupling reaction promoted by 1.

Full text of DOI:10.1016/j.tet.2006.01.046

Tetrahedron 62 (2006) 3395–3401
Oxazoline Chemistry. Part 11: Syntheses of natural and synthetic
isoflavones, stilbenes and related species via C–C bond formation
promoted by a Pd–oxazoline complex*
*
Charles R. Eisnor, Robert A. Gossage and Paras N. Yadav
The Chester Woodleigh Small Laboratory of Organic Chemistry, Department of Chemistry, Acadia University,
6 University Avenue, Elliott Hall, Wolfville, NS, Canada B4P 2R6
Received 17 September 2005; revised 6 January 2006; accepted 13 January 2006
Abstract—The complex trans-[PdCl2(2-ethyl-2-oxazoline-k1N)2] (1) is shown to be an active and oxidatively robust catalyst for C–C bond
forming reactions (Heck, Sonogashira, Ullmann, Miyaura–Suzuki, etc.). These reactions can be carried out in air without rigorous solvent/
substrate purification and in the absence of additional free ligand. The general methodology described above has been applied to the high
yield and regio-selective formation, via Miyaura–Suzuki coupling, of natural and synthetic isoflavones (i.e., isoflavone, 20-methylisoflavone
[7b], 30-methylisoflavone [7c] and 30,40-benzoisoflavone: [7d]). Compounds 7c and 7d are previously unknown. In addition, the synthesis of
(E)-tris-O-methylresveratrol and (E)-3,5-dimethoxystilbene is also described; the former is a recognized anti-cancer agent while the latter is a
biologically active extract from the bark of the conifer species Pinus armandii. Both of these latter products are produced as a result of a Heck
coupling reaction promoted by 1.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
complexes. A further recurring problem is the potential for
oxidation of ‘free’ ligands (e.g., PR3) that are formed
following a dissociation step in the catalytic cycle. Hence,
inert atmosphere conditions are often necessary for efficient
catalysis. Insomecases, itisalsonecessary toaddquantities of
free ligand to stabilize the Pd during the reaction; this situation
can hamper later product purification.1,2 Therefore, there is
still a need for new and oxidatively robust Pd-based systems
for applications in synthetic organic chemistry.3 Recently, we
briefly communicated4 the synthesis and use of trans-[bis-(2-
ethyl-2-oxazoline-k1N) palladium(II) dichloride] (Fig. 1:
complex 1) as a promoter of C–C bond formation (Heck,
Ullmann, Miyaura–Suzuki reactions, etc.).
The creation of a bond between two carbon atoms is a central
theme in organic chemistry. In the last 40 years, commodity
chemical syntheses have increasingly relied on transition
metal complexes as mediators of C–C bond formation in, for
example, the catalytic hydroformylation or polymerisation of
olefins.1 In fine chemical syntheses, palladium complexes are
quicklytakingonacentral roleinsuchchemistryandcurrently
a wide variety of Pd compounds are known to be useful for
regio- and enantio-selective (catalytic) C–C bond
formation.1,2 These reactions are typically facilitated by Pd
(pseudo-) halide complexes, which incorporate other metal
binding agents, of which phosphine (i.e., PR3), carbene and
N-donor ligands are the most common.1,2 One of the few
drawbacks to the industrial application of a majority of these
Pd derivatives is the air-sensitive nature of the active species
and/or catalytic reaction intermediates, which are likely Pd(0)
* For Part X, see: Berg, D. J.; Zhou, C.; Barclay, T.; Fei, X.; Feng, S.;
Ogilvie, K. A.; Gossage, R. A.; Twamley, B.; Wood, M. Can. J. Chem.
2005, 83, 449.
Figure 1.
Keywords: C–C bond formation; Heck coupling; Ullman coupling;
Miyaura–Suzuki coupling; Sonogashira coupling; Oxazoline; 4,5-
Dihydro-2-oxazole; Stilbene; Isoflavone; Biphenyl; Palladium complex.
Compound 1 can efficiently operate in open air and does
not require addition ligand (i.e., 2-ethyl-2-oxazoline: Etox)
to be added to the reaction mixtures to give adequate
product yields. In this report, we expand our preliminary
*
Corresponding author. Tel.: C1 902 585 1109; fax: C1 902 585 1114;
e-mail: rob-gossage@acadiau.ca
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.046

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Table 1. Catalysis results using complex 1 as mediator of C–C bond formationa
Entry
Aryl-X
Substrate
Product
Time (h)
Yield (%)
TON
860
1
2
PhI
PhI
PhI
PhI
pNO2PhI
PhBr
pBrAn
PhBr
pBrAn
PhI
PhI
6a
6a
8a
8b
8b
8b
8b
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
PhBR2
PhBR2
PhI
PhC^CH
6b
Styrene
(2-Napthyl)BR2
(2-Napthyl)BR2
PhBR2
(oMePh)BR2
(mMePh)BR2
t-Stilbene
t-Stilbene
t-Stilbene
t-Stilbene
t-NO2-stilbene
t-Stilbene
t-MeO-stilbene
Biphenyl
pPhAn
Biphenyl
PhC^CPh
5b
5c
7d
7d
7a
7b
7c
48
24
18
18
24
24
24
3
3
3
3
48
48
24
24
24
24
24
87
84
77
71
O99
77
65
O99
O99
45
1700
2000
1900
O2000
1500
1300
O1300
O1300
11
3
4b
5
6
7
8
9
10
11
12c,d
13c,d
14e
15e
16e
17e
18e
32
14
22
60
190
!1
!1
0.83
45
0.6
O1.4
O1.4
O1.4
O99
O99
O99
a Experimental details are given in the Section 3. TON, average turn over number per hour; Ph, phenyl; t-stilbene, (E)-stilbene; pNO2PhI, 4-nitroiodobenzene;
pBrAn, 4-bromoanisole; pPhAn, 4-methoxybiphenyl; t-NO2-stilbene, (E)-4-nitrostilbene; t-MeO-stilbene, (E)-4-methoxystilbene; BR2, B(OH)2.
b Compound 1 (5.3 mmol) used.
c Ar-X (5 mmol); 6 mmol olefin; 10 mol% of 1 used.
d See Figure 2.
e See Eq. 1.
communication and detail the use of 1 for the selective
formation of C–C bonds. In turn, this technology is applied
to the synthesis of a number of biologically relevant
isoflavone and stilbene derivatives.5
such complexes in catalysis.2a,4 One of our objectives is to
design robust materials for use in catalysis under non-inert
atmosphere conditions. We therefore tested solutions of 1
for its catalytic potential under standard bench-top
conditions in open air. No free ligand was added to the
reaction mixtures. Palladium complexes1–3 are typically
tested on a single class of C–C bond forming reaction (e.g.,
for Heck coupling). We have found that 1 can be used for a
variety of such processes (Table 1) including the Heck
(entries 1–7, 12 and 13), Miyaura–Suzuki (entries 8–9 and
14–18), Ullmann (entry 10) and Sonogashira (entry 11)
coupling reactions under typical conditions.1–3
2. Results and discussion
The synthesis of air-stable [PdCl2(Etox)2] (1: Fig. 1) is a
straightforward procedure4 involving the treatment of
methanolic solutions of Li2PdCl4 with Etox; this latter
reagent is an inexpensive and commercially available
polymer precursor.12 Analyses of 1 via single crystal
X-ray diffraction4 has revealed that it exists as the trans-
isomer in the solid-state and presumably only the trans form
is present in any detectable amount (NMR) in solution.† As
expected, the oxazoline ligands are found to coordinate
through the N-donor atom.13 There are only a few reported
structural analogues of 1 in the literature.14–16 The complex
trans-[PdCl2(2-phenyl-2-oxazoline-k1N)2] (2) has been
described by Dunina et al.;14 a related naphthalene
compound has also been reported15 by van Koten’s group
(viz., trans-[PdCl2(4,4-dimethyl-2-{20-napthyl}-2-oxazo-
line-k1N)2]: 3). Complex 3 exists as a mixture of cis and
trans isomers in solution,15 although in the solid phase only
the trans form is found. This is in contrast to our recent
NMR observations of 14 and earlier independent studies of
2.14 A structurally analogous oxazole complex, trans-
[PdCl2(2-oxazole-k1N)2] (4), has also been reported.16 No
evidence for isomerisation of this material was noted. The
catalytic potentials of 2–4 do not appear to have been
investigated.14–16
Complex 1 is an effective catalyst for all of these classes of
C–C bond forming reactions although turnover numbers are
admittedly moderate. There are few fully characterised (pre-
formed) Pd-based systems that have been shown to be
effective for a plethora of different C–C bond forming
processes and even fewer that can operate in air and without
additional ligand.1–3 This system effectively combines these
two aspects with the further advantage of using a simple,
very inexpensive (or readily synthesised) and air-stable
ligand. Etox, like most oxazolines, is very stable to
oxidative decomposition. This aspect gives a clear
advantage over the use of air-sensitive phosphine and
carbene ligands.
Unfortunately, the main disadvantage with this system is
that aryl-chlorides are not activated to any significant extent
by 1. Our tests with this complex (in air) under the standard
Heck conditions using a combination of PhCl and styrene as
substrates gave no evidence for the formation of the desired
stilbene product. In addition, 1 is ineffective as a catalyst
for the Sonogashira reaction in the absence of CuI (yields
!10%). The use of pyrrolidine as solvent is also crucial for
Sonogashira coupling as reactions performed in refluxing
toluene or NEt3 gave no coupled product; likewise only a
trace of product (w1%) was found using DMF as reaction
Our interests are centred on the synthesis,17 coordi-
nation2a,4,18 and medicinal inorganic chemistry of 2-oxazo-
lines (i.e., 4,5-dihydro-2-oxazoles) and the application of
† We have previously disclosed4 the full experimental details of the
synthesis and characterisation (NMR, X-ray, etc.) of 1.

C. R. Eisnor et al. / Tetrahedron 62 (2006) 3395–3401
3397
medium. Not surprisingly, 1,4-dihydroquinone was found to
be essential for the Ullmann coupling.
5d (Fig. 2), which has been shown to be a more effective
anti-cancer agent then resveratrol itself.22 The related
stilbene 5c (Fig. 2), isolated from the bark of the conifer
species Pinus armandii,9 has also been investigated for its
medicinal properties.23 We therefore choose to target 5b and
5c for synthesis using 1. Previously reported routes to these
two compounds have included multi-step Wittig and/or
McMurray reactions23 and the Perkin reaction.19 Palladium-
catalysed Heck reactions24a have also been used; this can
involve the use of acetate protected 5-vinylresorcinol
(produced in five steps), vinylsilanes as the olefin source24b
or other substrates.3k,25 We decided to investigate the use of
1 as a mediator of C–C coupling to yield 5b or 5c using
commercially available organic precursors: viz. 3,5-
dimethoxy-1-bromobenzene (6a) combined with either
4-vinylanisole (6b: for the synthesis of 5b) or styrene (for
5c). Thus, treatment of solutions 6a and 6b, under
conditions as described in Table 1 (Entry 12 and the
Section 3), produced 5b in a poor isolated yield of only
14%. In turn, the treatment of 6a with styrene, under similar
conditions, led to the isolation of 5c (22% yield: Table 1;
entry 13). These two syntheses, with reduced yields versus
that of stilbene itself (vide supra), support the previous
observations that electron-donating groups (Table 1) on the
haloarene substrate lead to a reduction of the rate and/or
efficiency of Heck coupling. This may be due to an
unusually stable aryl-Pd complex formed during the
catalytic cycle1–3 and hence base promoted reductive
elimination of the desired stilbene is sluggish.3w,‡ Thus,
yields are unimpressive of these two products. However,
these reactions do represent a facile alternative strategy for
the synthesis of 5b and 5c that employs simple
(commercial) organic starting materials and an easily
produced catalyst precursor.
A further observation is that 1 does not promote the Stille
reaction.1,2 Our examination of this process involved using
1 in the presence of PhI or p-bromoacetophenone in
combination with either R3SnC6H5 or R3SnCH2CH]CH2
(RZn-Bu; conditions: toluene, 100 8C, 8 h). These experi-
ments yielded no detectable (coupled) product4 and hence
further Stille-type reactions were not attempted.
The Heck reaction was used as a means to further explore
the effects of temperature, the nature of base, solvent,
substrate and added free ligand to the overall yield of
stilbene product. The use of aryl-halides with electron-
withdrawing groups appears to enhance the yields of
coupled product (Table 1; entries 3 and 5), whereas
electron-donating groups give the opposite effect (Table 1;
entries 6 and 7). Adjusting the nature of added base from
sodium acetate to potassium carbonate or to NEt3 had no
effect on the overall yield of product nor did changing the
solvent from DMF to NEt3. However, the addition of five-
fold excess of free ligand (Etox) reduced the overall yield to
only 25% under identical conditions. This strongly suggests
that dissociation of one or more equivalents of Etox is a key
component of the rate determining step(s) during catalysis.‡
The importance of (formally) 14-(valence metal) electron
intermediates, for example, [PdCl2(Etox)], have been
proposed previously in related Heck systems1,2 and may
also be important here. There is a pronounced temperature
effect on this reaction; adjusting the bath temperature from
140 to 120 8C leads to greatly reduced yields (25%).
Running the reaction at even lower temperature (100 8C)
gives only a trace (7%) of product stilbene.
Having established some of the limitations and potential of
1 in C–C coupling chemistry,4 we felt that this technology
would be more useful if it can be shown to produce more
elaborate and/or desirable organic products.
Many (substituted) (E)-stilbenes (i.e., derivatives of stilbene
itself) can be extracted from natural sources.5b,19 In
particular, resveratrol (5a) and its tris-O-Me analogue (5b:
Fig. 2) have been of recent interest due to the health benefits
that are attributed to consumption of such compounds by
mammalian organisms. Resveratrol is a component of many
red wines20 and it has been linked as a possible causative
agent of the so-called ‘French paradox’. This involves the
statistical fact that the intake of high fat foods, which is
common in the diet of French citizens, does not result in a
significant increase in heart disease or other aliments within
the general population.21 For this and other reasons, 5a and
its analogues are currently at the centre of considerable
scrutiny within medicinal chemistry. A key component in a
retro-synthetic pathway to 5a is 5b, which upon methyl–
proton exchange obviously yields 5a.8 Compound 5b is of
interest in its own right due of its documented anti-cancer
properties and because it is a key precursor to its (Z)-isomer
Figure 2.
A survey of entries 1–13 in Table 1 reveals that of all the
types of C–C coupling that we have attempted, the
Miyaura–Suzuki reaction is the cleanest and generally
gives the best yields of coupled product. Coincidently, as
part of one of our structure–activity relationship studies, we
required a quantity of substituted bicyclic compounds of the
isoflavone class (Eq. 1; e.g., 7a–7d). These derivatives
therefore presented us with a good series of candidates for
our investigations of coupling chemistry using 1. Iso-
flavones represent a very important class of natural
products26 because they display a wide variety of biological
properties that include anti-cancer, anti-oxidant, anti-
inflammatory, anti-bacterial and anti-fertility activity. In
addition, isoflavones have been shown to act as selective
enzyme inhibitors5b–f,26, to alleviate erectile dysfunction27
and have been investigated as medicinal agents for the
‡ The effect of added free ligand is not as pronounced when using 1 to
perform Miyaura–Suzuki coupling reactions. Full experimental and
theoretical mechanistic investigations of these reactions will be the
subject of a later publication.

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C. R. Eisnor et al. / Tetrahedron 62 (2006) 3395–3401
treatment of alcohol addiction.28 Our synthetic method-
ology revolves around the use of the readily available6
3-halochromones 8a and 8b (Eq. 1; also see Section 3) in a
Miyaura–Suzuki reaction in combination with arylboronic
acid derivatives.11,29
column chromatography and/or recrystallisation as
detailed for the individual components below, unless
otherwise stated.
3.2. Syntheses of trans-stilbene, (E)-4-nitrostilbene, 5b
and 5c
The synthesis of these four compounds was carried out as
described below for trans-stilbene except where noted.
(1)
3.2.1. Synthesis of trans-stilbene. A 25 mL quantity of
DMF was added to a 50 mL round-bottomed flask. This
flask was then charged with 0.00053 mmol (0.15 mg) of 1,
25 mmol (5.1 g) of iodobenzene (or 3.9 g of bromoben-
zene), 30 mmol (3.1 g) of styrene and 30 mmol (2.5 g) of
sodium acetate. The mixture was then heated to between
140 and 150 8C for the amount of time specified in Table 1
(entries 1–4, 6 and 8). The reaction mixture was cooled to rt
and then all volatile components were evaporated in vacuo.
The residue was purified by flash chromatography on silica
gel (230–400 mesh) using hexanes–EtOAc (9/1) as eluent.
Thus, the treatment of 8a (Table 1; entries 18) or 8b (entries
14–17) with a variety of arylboronic acids (Eq. 1) gives
excellent yields of 0 the known isoflavones 7a (i.e.,
isoflavone) and 7b (2 -methylisoflavone) in addition to the
novel compound 7c (30-methylisoflavone). Only in the case
of previously unknown 7d (i.e., 30,40-benzoisoflavone) is the
yield moderate. We attribute this to steric effects of the large
naphthalene group. A marginal improvement in yield could
be obtained by the use of 8a instead of the bromo analogue
8b.
1
The product trans-stilbene thus isolated gave a correct H
NMR spectrum and mp (and a non-depressed mixed mp)
when compared to an authentic (commercial) sample.
3.2.2. Synthesis of (E)-4-nitrostilbene. Yield: O98%
(purity: O97% [NMR]); mp 140 8C (lit.:7a 157 8C); correct
1H NMR spectrum.7b
The chemistry described above has indicated that a simple
and air-stable oxazoline complex can be used in several
‘benchmark’ C–C bond forming reactions and that such
methodology can be applied to produce desirable organic
products.
3.2.3. Synthesis of (E)-3,5,40-trimethoxyresveratrol (5b).
Yield: 14%; mp 52–53 8C (lit.:8 56–57 8C); correct IR and
1H NMR spectrum.9 A 10 mol% quantity of catalyst was
used.
3. Experimental
3.1. General procedures
3.2.4. Synthesis of (E)-3,5-dimethoxystilbene (5c). Yield:
22%; mp 54–55 8C (lit.:10 54–55 8C); correct 1H NMR
spectrum. A 10 mol% quantity of catalyst was used.
All reactions were carried out using standard bench-top
laboratory techniques using commercially available,
reagent-grade solvents. Unless otherwise stated, literature
1
mp, IR and H NMR data were obtained from the Aldrich
Chemical Co. Catalogue (2005–2006 Ed.) and/or the
3.3. Synthesis of biphenyl and p-phenylanisole via Suzuki
coupling
1
Aldrich Libraries of FT-IR or FT NMR Spectra. H and
13C{1H} NMR spectra were recorded from chloroform-d
solutions at 300 MHz using a Bruker Advancee 300 MHz
NMR spectrometer operating at room temperature (rt).
Chemical shift values are reported in parts per million
relative to TMS (dZ0.00 ppm) as external standard;
coupling constants (J) are reported in Hertz. Mass spectra
(MS) were obtained from the Dalhousie University Mass
Spectral Facility and were performed in electron impact
(EI) mode. Microanalyses were recorded at the analytical
services department (ANALEST) of the University of
Toronto. IR spectra were obtained as Nujol muls or as
KBr disks using a Perkin Elmer 683 IR spectrometer or a
Nicolet Magna 560 FT-IR spectrometer. Melting point
data was obtained using a Mel-Temp II apparatus and
reported values are uncorrected. The synthesis of
compound 1 was carried out as described in the literature.4
3-(Dimethylamino)-1-(2-hydroxyphenyl)-propen-1-one
and 3-bromochromone (8a) were produced as described by
Gammill.6 All yields in Table 1 refer to the pure (1H
NMR, mp, IR) products isolated by extraction and flash
The synthesis of these two compounds was carried out as
described for biphenyl below.
3.3.1. Synthesis of biphenyl. A 2 mmol (0.31 g) quantity of
bromobenzene was mixed with 4 mmol (0.56 g) of K2CO3,
3 mmol (0.37 g) of phenylboronic acid, 0.00053 mmol
(0.15 mg) of 1 and a 10 mL quantity of toluene. The
mixture was heated at 110 8C for 3 h. After the reaction
mixture was cooled to rt, the volatile components were then
removed (vacuo) and the crude mixture was extracted with
water and EtOAc (20 mL each). The organic layer was
washed with further EtOAc (2!20 mL) and the organic
fractions combined, dried (Na2SO4), and evaporated to give
the crude product. The desired compound, biphenyl (correct
mp, IR and 1H NMR spectrum; yield O99%), was isolated
by recrystallisation from a mixture of EtOAc and hexanes.
3.3.2. Synthesis of 4-phenylanisole. Yield O99%; mp
87–88 8C (lit.: 86–90 8C).

C. R. Eisnor et al. / Tetrahedron 62 (2006) 3395–3401
3399
3.4. Synthesis of biphenyl via Ullman coupling
SiO2) with hexanes–EtOAc (9/1) as eluent to give the
product isoflavone (7a: 0.11 g: O99% yield; RfZ0.52). The
physical properties (mp, IR, 1H NMR) of 7a isolated in this
way were fully consistent with the previously reported
data.11
A DMF (5 mL) solution was prepared that consisted of
2 mmol (0.41 g) of iodobenzene, 2 mmol (0.28 g) of
K2CO3, 1 mmol (0.11 g) of 1,4-dihydroquinone, and
0.014 mmol (4 mg) of 1. The mixture was heated at
110 8C for 3 h. Volatile components of the mixture were
removed (vacuo) and the residue purified by flash column
chromatography (hexanes) to yield biphenyl (45%).
3.7.2. Synthesis of 20-methylisoflavone (7b). Yield 0.11 g:
1
O99% using 2-tolylboronic acid. H and 13C{1H} NMR
spectra were consistent with 7b;11 mpZ112–113 8C (lit.:11
113.5–114 8C).
3.5. Synthesis of diphenylacetylene
3.7.3. 30-Methylisoflavone (7c). Yield 0.11 g: O99% using
3-tolylboronic acid. RfZ0.54 (hexanes/EtOAc: 9:1); mpZ
87–89 8C; IR (KBr): 1646 cmK1 (C]O); 1H NMR: dZ2.43
(s, 3H, CH3), 7.22 (d, 1H, JZ6.6 Hz, ArH), 7.34–7.50 (m,
5H, ArH), 7.69 (t, 1H, JZ7.2 Hz, ArH), 8.02 (s, 1H, ]CH),
8.35 (d, 1H, JZ6.9 Hz, ArH); 13C{1H} NMR: 176.4, 156.7,
153.8, 134.1, 133.8, 133.5, 129.9, 128.6, 128.4, 128.3,
128.1, 127.4, 126.9, 126.7, 125.8, 125.7, 125.1, 118.5. MS
(EI, 70 eV): 236 (100%; MC: calcd: 236). Anal. Calcd for
C16H12O2 (%): C 81.34, H 5.12; found: C 80.83, H 5.12.
A 0.0011 mmol (0.4 mg) sample of 1 was added to a
mixture of 2 mL pyrollidine, 2 mmol (0.41 g) iodobenzene,
1 mmol (0.19 g) of CuI and 2.4 mmol (0.25 g) of
phenylacetylene in a 25 mL round-bottomed flask. The
contents of the reaction vessel were then heated to 90 8C for
3 h. The volatile components were then removed (vacuo)
and the crude mixture was extracted with water and EtOAc
(20 mL). The aqueous layer was washed with further EtOAc
(2!20 mL) and the organic fractions combined, dried
(MgSO4) and evaporated to give the crude product(s). The
1
3.7.4. Synthesis of 30,40-benzoisoflavone (7d). Synthesised
from 2-napthylboronic acid and 8b (yield 45%; 0.061 g) or
8a (yield 60%). RfZ0.47 (hexanes/EtOAc: 9:1); mpZ184–
186 8C; IR (KBr): 1645 cmK1 (C]O); 1H NMR: dZ7.45–
7.56 (m, 4H, ArH), 7.71–7.76 (m, 2H, ArH), 7.87–7.95 (m,
3H, ArH), 8.08 (s, 1H, ]CH), 8.35 (d, 1H, JZ6.9 Hz,
ArH); 13C{1H} NMR: 176.9, 156.7, 153.8, 134.1, 133.8,
133.5, 129.9, 128.6, 128.4, 128.3, 128.1, 127.4, 126.9,
126.7, 125.8, 125.7, 125.1, 118.5. MS (EI, 70 eV): 272
(60%; MC: calcd: 272). Anal. Calcd for C19H12O2$H2O
(%): C 81.12, H 4.66; found: C 81.13, H 4.61.
desired compound, diphenylacetylene (correct IR and H
NMR spectrum), was isolated (32%) by flash column
chromatography using 9:1 hexanes/EtOAc as eluent.
3.6. Synthesis of 3-iodochromone (i.e., 3-iodo-4H-
benzopyran-4-one: 8a)
In a modification of the synthesis of 8b,6 a sample (2.0 g:
11 mmol) of 3-(dimethylamino)-1-(2-hydroxyphenyl)-
propen-1-one was dissolved in chloroform (20 mL) and
the mixture cooled to 0 8C. A solution of I2 (2.7 g: 22 mol)
was added dropwise over a period of several minutes. The
mixture is then diluted with water (20 mL) and stirred
vigorously for 15 min. Excess iodine was then neutralized
with aqueous Na2S2O3. The organic layer was then
separated, dried (MgSO4) and then the volatile components
were removed (vacuo). The crude yellow compound was
purified by flash column chromatography (hexanes/EtOAc:
3:1) to give the yellow-coloured product 3-iodochromone
(1.0 g: 35%); mp 87–88 8C (lit.:9 93–94 8C); IR, MS and 1H
NMR spectrum are consistent within experimental error to
the known properties of 8a.9
4. Conclusions
In conclusion, Pd complex 1 has been found to be an
effective catalyst, in open air, for a number of C–C bond
forming reactions; this compound can be used for the
synthesis of pharmaceutically relevant isoflavones and
stilbenes. These results suggest that simple oxazoline–Pd
complexes should be further investigated for their potential
applications in catalysis. Complex 1 is best suited for
Miyaura–Suzuki coupling reactions and is somewhat
sluggish for the Heck, Ullmann and Sonogashira processes.
Stille-type coupling reactions are not catalysed by 1 (in open
air). We are currently expanding this chemistry to include
enantio-selective substrate activation using chiral oxazoline
ligands; the investigation of the mechanism of reactions
mediated by 1 and its (chiral) analogues will be disclosed in
a future publication.
3.7. Syntheses of isoflavones 7a–7d
The synthesis of isoflavone (7a) is a representative example.
3.7.1. Synthesis of isoflavone (7a). A 0.112 g sample of 8b
(0.50 mmol) was dissolved in 10 mL of toluene in the
presence of 0.75 mmol of phenylboronic acid (0.091 g),
1 mmol of K2CO3 (0.14 g) and 0.015 mmol (3 mol%:
0.0041 g) of 1. The reaction mixture was then heated to
reflux temperature for a period of 24 h; the flask was then
allowed to cool to rt. Volatile components of the reaction
vessel were then removed (vacuo) and the crude mixture
was then partitioned between EtOAc (20 mL) and water.
The aqueous layer was separated and extracted twice with
EtOAc (40 mL total) and then the organic fractions were
combined together, dried (Na2SO4), filtered and then the
solvent was removed (vacuo). The residue was then
subjected to separation via column chromatography (flash:
Acknowledgements
Support for this work was provided by the Natural Sciences
and Engineering Research Council of Canada (NSERC).
Johnson-Matthey Ltd is thanked for a generous loan of Pd
salts. C.R.E. thanks WAAG for support. Professor Hilary A.
Jenkins (St. Mary’s University) and Dr. Gordon G. Cross are
thanked for fruitful discussions. Professor A. Jha and Dr. N.
Paul are thanked for recording the 13C{1H} NMR spectra.

3400
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P. A.; Skryabin, G. A.; Beletskaya, I. P. Synthesis 2005, 1578.
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