Pd-Catalyzed efficient cross-couplings of 3-iodochromones with triarylbismuths as substoichiometric multicoupling organometallic nucleophiles

Article abstract of DOI:10.1055/s-0029-1217959

An efficient cross-coupling of 3-iodochromones with triarylbismuths under catalytic palladium conditions is reported. Triarylbismuths were employed as substoichiometric multicoupling nucleophiles for the synthesis of a variety of substituted isoflavones.

Full text of DOI:10.1055/s-0029-1217959

LETTER
2597
Pd-Catalyzed Efficient Cross-Couplings of 3-Iodochromones with Triaryl-
bismuths as Substoichiometric Multicoupling Organometallic Nucleophiles
C
ross-Couplings of 3-I
a
odochromo
d
ne
s
w
ith
T
ri
d
arylbismuthsali L. N. Rao,* Varadhachari Venkatesh, Deepak N. Jadhav
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
E-mail: maddali@iitk.ac.in
Received 11 June 2009
ologies are currently being used in industry due to their
Abstract: An efficient cross-coupling of 3-iodochromones with tri-
arylbismuths under catalytic palladium conditions is reported. Tri-
arylbismuths were employed as substoichiometric multicoupling
nucleophiles for the synthesis of a variety of substituted isofla-
vones. Under the established protocol, cross-coupling reactions
were found to be very efficient, furnishing high yields of products.
potential economic value in the synthesis of active phar-
maceutical ingredients (API).6 Importantly, the reactivity
of cross-coupling reactions heavily depends on the nature
Table 1 Screening of 3-Iodochromone with Triphenylbismutha
O
O
Key words: cross-coupling, triarylbismuths, isoflavones, palladi-
um, catalysis, multicoupling
PdCl2(PPh3)2 (cat.)
base, temp, solvent
+
BiPh3
I
(1 equiv)
O
O
(3.3 equiv)
(3 equiv)
Isoflavones are well known for their diverse range of bio-
logical properties and there is profound interest in the syn-
thesis of this class of compounds.1–3 The functionalized
Entry
Base
Solvent
Temp
(°C)
Time
Conversion
(%)b,c
(h)
6
4
4
4
4
4
4
4
4
4
4
2
3
4
4
4
4
4
isoflavone
nucleus,
3-aryl-4H-1-benzopyran-4-one
1
2
Cs2CO3
K2CO3
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
–
DME
DME
DME
DME
MeCN
DMA
toluene
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
100
100
100
100
90
66
69
(Figure 1) is an important constituent, and the ideal way to
introduce 3-aryl groups into preformed chromones would
be through coupling reaction of 3-halochromones and aryl
organometallic reagents.3 This cross-coupling approach
outweighs other synthetic methods due to its flexibility in
terms of 3-halochromone and aryl organometallic cou-
pling reagents. The 3-halochromones can be easily pre-
pared from o-hydroxyacetophenones through a simple
synthetic sequence.4 Furthermore, the cross-coupling se-
quence provides additional flexibility in the synthesis of
structurally diverse isoflavones using an appropriate 3-ha-
lochromone and an aryl organometallic nulceophile.
However, there are relatively few examples reported for
the synthesis of functionalized isoflavones through a cou-
pling process utilizing 3-halochromones.3 Development
of coupling reactions using new organometallic reagents
is highly desirable given the importance of isoflavone
scaffolds in medicinal chemistry.
3
(21)
85
4
5
70
6
90
72
7
90
(40)
85
8
90
9
80
80
10
11
12
13
14
15
16
17
18
60
(36)
(10)
55
RT
90
90
63
O
O
90
(43)d
61e
10f
n.r.
n.r.
Ar
3
3
90
2
2
O
O
90
4H-1-benzopyran-4-one
3-aryl-4H-1-benzopyran-4-one
K3PO4
–
90
Figure 1
90
In recent times, cross-coupling methodologies using orga-
nometallic nucleophiles have revolutionized organic
synthesis under metal catalysis.5 These coupling method-
a Conditions: 3-iodochromone (0.825 mmol, 3.3 equiv), Ph3Bi (0.25
mmol, 1 equiv), PdCl2(PPh3)2 (0.0225 mmol, 0.09 equiv), base (1.5
mmol, 6 equiv), solvent (3 mL) were utilized.
b Isolated yields.
c GC conversion given in parentheses.
d With 2 equiv of K3PO4.
SYNLETT 2009, No. 16, pp 2597–2600
x
x
.x
x
.2
0
0
9
e With 4 equiv of K3PO4.
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217959; Art ID: D15709ST
© Georg Thieme Verlag Stuttgart · New York
f Without base.

2598
M. L. N. Rao et al.
LETTER
of organometallic nucleophile and electrophile and the Na2CO3 in 1,2-dimethoxyethane (DME) afforded moder-
catalytic protocol. Thus, there has been great interest in ate yields of isoflavone (entries 1–3). Under similar reac-
the development of new nucleophilic and electrophilic tion conditions, K3PO4 was more effective, furnishing a
partners for cross-coupling reactions.7 The known orga- high yield of the isoflavone (entry 4). Reactions carried
noboron and organotin reagents, for example, usually re- out in different solvents with K3PO4 at 90 °C revealed
act with one equivalent of organic electrophile in cross- DME as the most suitable solvent furnishing 85% yield of
coupling reactions. Interest in triarylbismuth reagents8 the isoflavone (entries 5–8). The reactions carried out at
originates from the fact that these compounds could func- different temperatures and reaction times provided lower
tion as multicoupling organometallic reagents to react yields of the cross-coupled product (entries 9–13). From
with three equivalents of organic electrophile.9 The effi- this, it was found that the reaction requires 4 hours at
ciency of triarylbismuths for coupling reactions with or- 90 °C to yield the highest yield of product (entry 8). Re-
ganic electrophiles such as aryl halides, aryl triflates, and actions studied with different base equivalents showed
acyl halides under palladium catalysis has recently been that 6 equivalents of K3PO4 is essential to obtain high
established.9–11
product yield (entries 14–16). The control reactions per-
formed without catalyst (entry 17) and catalyst/base com-
bination (entry 18) further proved their essential role in
effecting high cross-coupling conversion. Homocoupling
product biphenyl was reported to be formed from triphe-
nylbismuth under palladium catalysis,11 and we have also
observed the formation of biphenyl as a minor product but
the amount varies with respect to cross-coupling conver-
sion. In all these reactions, 3.3. equivalents of 3-iodo-
chromone was employed to couple with three aryl groups
of 1 equivalent triphenylbismuth. With this optimized
protocol, we have successfully driven the reaction of
triphenylbismuths with 3-iodochromone towards cross-
coupling to furnish a high yield of isoflavone (entry 8).
Therefore, it was of interest to explore the coupling reac-
tions of 3-iodochormones with triarylbismuth reagents for
the synthesis of functionalized isoflavones under catalytic
palladium conditions. During these efforts, we have estab-
lished an efficient palladium catalytic protocol for facile
cross-coupling of 3-iodochromones with triarylbismuths,
and herein we report the details of this study.
Initially, the coupling reaction of 3-iodochromone was
studied with triphenylbismuth using different catalytic
palladium sources. In this study, PdCl2(PPh3)2 showed
promising reactivity as a catalyst precursor for this trans-
formation. As illustrated in Table 1, a systematic investi-
gation was carried out with different bases and solvents,
and at different temperatures, to establish the right combi-
nation for this transformation. Coupling reactions carried
out with various bases such as Cs2CO3, K2CO3, and
Table 2 Cross-Coupling of 3-Iodochromones with Triarylbismuthsa–d
O
O
[Pd]
R1
R1
+
Bi
I
R2
R2
3
O
O
(3.3 equiv)
(1 equiv)
(3 equiv)
Entry
BiAr3
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
3-Iodochromones
Isoflavones
Yield (%)
1
2
3
4
5
6
1 R = H
85
88
93
86
82
75
O
O
2 R = Me
3 R = 4-OMe
4 R = 3-OMe
5 R = F
O
I
R
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
O
6 R = Cl
7
8
9
10
11
12
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
7 R = H
8 R = Me
9 R = 4-OMe
10 R = 3-OMe
11 R = F
86
90
95
85
84
78
O
O
Me
Me
Me
I
R
O
O
O
12 R = Cl
13
14
15
16
17
18
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
13 R = H
83
93
93
89
81
73
14 R = Me
15 R = 4-OMe
16 R = 3-OMe
17 R = F
Me
O
O
I
R
O
18 R = Cl
Synlett 2009, No. 16, 2597–2600 © Thieme Stuttgart · New York

LETTER
Cross-Couplings of 3-Iodochromones with Triarylbismuths
2599
Table 2 Cross-Coupling of 3-Iodochromones with Triarylbismuthsa–d (continued)
O
O
[Pd]
Bi
R1
R1
+
I
R2
R2
3
O
O
(3.3 equiv)
(1 equiv)
(3 equiv)
Entry
BiAr3
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
3-Iodochromones
Isoflavones
Yield (%)
19
20
21
22
23
24
19 R = H
85
89
92
88
86
75
Me
Me
20 R = Me
21 R = 4-OMe
22 R = 3-OMe
23 R = F
Me
O
O
Me
O
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
I
R
24 R = Cl
O
O
O
25
26
27
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
25 R = H
26 R = Me
27 R = 4-OMe
94
96
97
MeO
MeO
I
R
O
O
28
29
30
31
32
33
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
28 R = H
86
91
96
80
79
74
29 R = Me
30 R = 4-OMe
31 R = 3-OMe
32 R = F
O
O
O
O
I
R
33 R = Cl
34
35
36
37
38
39
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
34 R = H
84
92
93
85
80
72
O
35 R = Me
36 R = 4-OMe
37 R = 3-OMe
38 R = F
O
O
Cl
Cl
I
R
O
39 R = Cl
40
41
42
43
44
45
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
40 R = H
80
85
95
80
83
72
Me
Cl
O
41 R = Me
42 R = 4-OMe
43 R = 3-OMe
44 R = F
Me
Cl
O
I
R
O
O
45 R = Cl
46
47
48
49
50
51
Ph3Bi
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
(p-fluorophenyl)3Bi
(p-chlorophenyl)3Bi
46 R = H
84
92
94
88
82
74
O
O
47 R = Me
48 R = 4-OMe
49 R = 3-OMe
50 R = F
O
F
F
I
R
O
51 R = Cl
Cl
Cl
52
53
54
55
Ph3Bi
52 R = H
53 R = Me
54 R = 4-OMe
55 R = 3-OMe
75
86
90
71
O
O
(p-tolyl)3Bi
(p-anisyl)3Bi
(m-anisyl)3Bi
Cl
Cl
I
R
O
O
a Conditions: 3-iodochromone (0.825 mmol, 3.3 equiv), Ar3Bi (0.25 mmol, 1 equiv), PdCl2(PPh3)2 (0.0225 mmol, 0.09 equiv), K3PO4 (1.5
mmol, 6 equiv), 1,2-dimethoxy ethane (3 mL), 90 °C, 4 h.
b Isolated yields are reported. The product yields were calculated considering all the three aryl groups for coupling from triarylbismuth reagent.
It means 1 equiv of Ar3Bi is equal to 3 equiv of Bi-Ar. Thus, 3 equiv (0.75 mmol) of cross-coupling product corresponds to 100% yield.
c All the products were characterized by 1H NMR, 13C NMR, IR, and ESI-MS spectral data.
d In general, homocoupling biaryls from triarylbismuths are formed as minor side products and amounts varied with respect to cross-coupling
yields.
To explore the scope of this coupling further, reactions this has provided a unique opportunity to synthesize a va-
have been studied with a range of triarylbismuths and a riety of functionalized isoflavones in high isolated yields.
variety of 3-iodochromones.12,13 As illustrated in Table 2, The coupling reactions with electronically divergent tri-
Synlett 2009, No. 16, 2597–2600 © Thieme Stuttgart · New York

2600
M. L. N. Rao et al.
LETTER
1989, 37, 529. (b) Hoshino, Y.; Miyaura, N.; Suzuki, A.
arylbismuths were found to be facile, furnishing a library
of functionalized isoflavones using the established proto-
col with different 3-iodochromones. Firstly, the coupling
reactions of various triarylbismuths with 3-iodochromone
demonstrated high reactivity and afforded the correspond-
ing isoflavones in 75–93% yields (entries 1–6). Similar
reactivity was also obtained using variously substituted 3-
iodochromones. The 3-iodochromones substituted with
electronically divergent 6-methyl, 7-methyl, 6-methoxy,
6-chloro, 6-fluoro groups reacted efficiently with triaryl-
bismuths under the established protocol (entries 7–18, 25–
27, 34–39, and 46–51). The disubstituted 3-iodoch-
romones with methyl and chloro groups demonstrated ex-
cellent reactivity (entries 19–24, 40–45, and 52–55).
Additionally, the coupling of 3-iodo-4H-naphtho[1,2-
b]pyran-4-one was also efficient and yielded 74–96% of
coupled products (entries 28–33).
Bull. Chem. Soc. Jpn. 1988, 61, 3008. (c) Ding, K.; Wang,
S. Tetrahedron Lett. 2005, 46, 3707. (d) Ito, F.; Iwasaki,
M.; Watanabe, T.; Ishikawa, T.; Higuchi, Y. Org. Biomol.
Chem. 2005, 3, 674. (e) Hayakawa, I.; Ikedo, A.; Kigoshi,
H. Chem. Lett. 2007, 36, 1382.
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Westwell, A. D.; Matthews, C. S.; Bradshaw, T. D.; Stevens,
M. F. G. J. Med. Chem. 2006, 49, 3973.
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Int. Ed. 2005, 44, 4442. (b) Hassan, J.; Sevignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
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2008, 130, 1566. (e) Dubbaka, S. R.; Vogel, P. J. Am. Chem.
Soc. 2003, 125, 15292.
In summary, we have demonstrated the high coupling re-
activity of various triarylbismuths with 3-iodochromones
under a palladium catalytic protocol for the synthesis of
variety of functionalized isoflavones. The present study
also uncovered the hitherto unknown coupling reactivity
of triarylbismuths with 3-iodochromones under palladium
catalysis. The efficient coupling reactivity of triarylbis-
muths further proves their utility as multicoupling organo-
metallic nucleophiles for C–C bond formations in organic
synthesis.
(8) Organobismuth Chemistry; Suzuki, H.; Matano, Y., Eds.;
Elsevier: Amsterdam, 2001.
(9) Rao, M. L. N.; Venkatesh, V.; Banerjee, D. Synfacts 2008,
406 (ref. 10d).
(10) (a) Rao, M. L. N.; Jadhav, D. N.; Venkatesh, V. Tetrahedron
Lett. 2009, 50, 4268. (b) Rao, M. L. N.; Jadhav, D. N.;
Banerjee, D. Tetrahedron 2008, 64, 5762. (c) Rao, M. L.
N.; Venkatesh, V.; Jadhav, D. N. J. Organomet. Chem. 2008,
693, 2494. (d) Rao, M. L. N.; Venkatesh, V.; Banerjee, D.
Tetrahedron 2007, 63, 12917. (e) Rao, M. L. N.; Banerjee,
D.; Jadhav, D. N. Tetrahedron Lett. 2007, 48, 6644.
(f) Rao, M. L. N.; Banerjee, D.; Jadhav, D. N. Tetrahedron
Lett. 2007, 48, 2707. (g) Rao, M. L. N.; Venkatesh, V.;
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank Department of Science and Technology (DST), New
Delhi for funding this work under green chemistry programme
(SR/S5/GC-11/2008). V.V. thanks UGC, New Delhi and D.N.J.
thanks CSIR, New Delhi for research fellowships.
(11) (a) Barton, D. H. R.; Ozbalik, N.; Ramesh, M. Tetrahedron
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(12) Representative Procedure
An oven-dried Schlenk tube under nitrogen was charged
with 3-iodochromone (3.3 equiv, 224.4 mg, 0.825 mmol),
Ph3Bi (1 equiv, 110.0 mg, 0.25 mmol), K3PO4 (6 equiv,
318.4 mg, 1.5 mmol), PdCl2(PPh3)2 (0.09 equiv, 15.8 mg,
0.0225 mmol) followed by DME (3 mL) solvent. The
reaction mixture was stirred at 90 °C in an oil bath for 4 h.
After cooling to r.t., the contents were quenched with H2O
and extracted with EtOAc (2 × 15 mL). The combined
EtOAc extract was washed with 10% HCl (5 mL), brine (5
mL), and dried over anhyd MgSO4. The organic layer was
concentrated in vacuo to give the crude product which was
purified by column chromatography to give the 3-phenyl-
4H-1-benzopyran-4-one3b (1) in 85% yield (141.7 mg).
(13) In all the reactions, 3-iodochromones were employed in
0.3 equiv excess. The product yields were calculated
considering all the three aryl groups for coupling from
Ar3Bi. Thus, 3 equiv (0.75 mmol) of cross-coupling product
corresponds to 100% yield.
References and Notes
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Synlett 2009, No. 16, 2597–2600 © Thieme Stuttgart · New York