Palladium catalyzed atom-efficient cross-coupling reactions of triarylbismuths with aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2007.02.068

Aryl bromides (3 equiv) were coupled efficiently with triarylbismuths (1 equiv) in an atom-efficient way using the Pd(OAc)₂/PPh₃ catalytic system in the presence of K₃PO₄ as base in DMF at 90 °C, providing excellent yields of the cross-coupled biaryls in short reaction times.

Full text of DOI:10.1016/j.tetlet.2007.02.068

Tetrahedron Letters 48 (2007) 2707–2711
Palladium catalyzed atom-efficient cross-coupling reactions
of triarylbismuths with aryl bromides
Maddali L. N. Rao,* Debasis Banerjee and Deepak N. Jadhav
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 8 December 2006; revised 4 February 2007; accepted 14 February 2007
Available online 17 February 2007
Abstract—Aryl bromides (3 equiv) were coupled efficiently with triarylbismuths (1 equiv) in an atom-efficient way using the
Pd(OAc)2/PPh3 catalytic system in the presence of K3PO4 as base in DMF at 90 ꢀC, providing excellent yields of the cross-coupled
biaryls in short reaction times.
ꢁ 2007 Elsevier Ltd. All rights reserved.
The exciting potential of metal-catalyzed cross-coupling
reactions for C–C bond formation has been amply
demonstrated in organic synthesis.1 The well-known
Suzuki, Stille, Negishi and Hiyama cross-coupling reac-
tions involving organoboron, organotin, organozinc and
organosilicon reagents amongst others are popular
methods in this category.2–5 Besides, there is a growing
importance of these reactions in industry6 for the
synthesis of pharmaceutically active ingredients, agro-
chemicals and fine chemicals. Importantly, some of these
methods suffer from drawbacks such as atom efficiency
and stoichiometric loading of organometallic reagents.
Thus, the development of atom-efficient organometallic
reagents to react with more than 1 equiv of the electro-
philic coupling reagents reduces the stoichiometric load-
ing of the organometallic reagents. In this context,
triarylbismuths offer the required potential as atom-effi-
cient organometallic reagents for C–C bond formation.
Triarylbismuths can be readily prepared by known pro-
cedures, they are nontoxic and are stable to air and some
are commercially available.7
coupling reactivity of triarylbismuths with aryl bromides
involves long reaction times and with varied reactivity
profiles of the aryl bromides.8a Hence, to expand the
scope and reactivity of triarylbismuths, development of
new and efficient catalytic protocols is in demand. Here-
in, we report a highly efficient palladium catalyzed pro-
tocol for an atom-efficient coupling of triarylbismuths
with aryl bromides.
Recently, DABCO has served as an efficient ligand in
palladium catalyzed cross-coupling reactions.10 Hence,
in our initial efforts, we screened the cross-coupling reac-
tivity of p-bromoacetophenone (3.3 equiv) as a represen-
tative example with BiPh3 (1 equiv) using Pd(OAc)2
(0.05 equiv with respect to BiPh3) in the presence of
DABCO as ligand using different bases and solvents
(Table 1, entries 1–4). Unfortunately, DABCO failed
to promote formation of the corresponding cross-cou-
pling products. Further screening with triphenylphos-
phine as ligand was found to be beneficial. As shown
in Table 1, the reactions carried out in different solvents
in the presence of triphenylphosphine and K3PO4 as
base revealed DMF as a suitable solvent giving 56%
cross-coupling conversion (entry 7). Other solvents such
as toluene, 1,4-dioxane, 1,2-dimethoxyethane (DME),
acetone, tetrahydrofuran, acetonitrile and N-methyl-2-
pyrrolidone (NMP) provided very poor conversions
(entries 5, 6 and 8–13). In addition, the reactions carried
out at lower temperatures did not produce good conver-
sions (entries 14 and 15). Additional experiments proved
that Pd(OAc)2 (0.1 equiv)/PPh3 (0.4 equiv) along with
K3PO4 (6 equiv) in DMF at 90 ꢀC were the ideal reagent
combination affording high conversions of the
The unique advantage associated with triarylbismuths,
unlike with organoboron, organotin, organosilicon and
other reagents is that they can react with 3 equiv of elec-
trophilic reagents. Despite this obvious advantage, only
a few reactions involving triarylbismuths for C–C bond
formation have been reported.1b,7–9 The known cross-
Keywords: Cross-coupling; Triarylbismuth; Aryl bromides; Atom-
efficient; Palladium catalyzed.
*
Corresponding author. Tel./fax: +91 512 2597532; e-mail:
maddali@iitk.ac.in
0040-4039/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.068

2708
M. L. N. Rao et al. / Tetrahedron Letters 48 (2007) 2707–2711
Table 1. Catalyst screeninga
Pd(OAc)2
BiPh
+
3 Ac
Br
Ac
3
3
Entry
Base
Pd(OAc)2 (equiv)
Ligand (equiv)
Solvent
Temp (ꢀC)
Time (h)
Convb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
K2CO3
K2CO3
K3PO4
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
None
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
DABCO (0.2)
PPh3 (0.1)
PPh3 (0.1)
PPh3 (0.1)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.4)
PPh3 (0.4)
PPh3 (0.4)
None
Acetone
DME
Dioxane
Dioxane
DME
90
90
90
90
90
90
90
90
90
90
90
90
90
60
30
90
90
90
90
90
12
12
12
12
12
12
12
1
1
1
1
1
1
1
1
2
1
1
1
1
<1
<1
<1
<1
10
12
56
2
NMP
DMF
Acetone
THF
CH3CN
Toluene
Dioxane
DME
DMF
DMF
DMF
DMF
4
14
17
18
4
32
31
92
92
18
<1
<1
0.1
0.1
0.1
None
DMF
DMF
DMF
K3PO4
K3PO4
PPh3 (0.4)
a Conditions: equiv ratios are based on BiPh3 (1 equiv), aryl bromide (3.3 equiv), base (6 equiv) and solvent (3 mL).
b Based on GC analysis.
Table 2. Cross-coupling reaction of triarylbismuths with aryl bromides12
Pd(OAc) (0.1 equiv)
2
PPh (0.4 equiv)
3
Br
3
+
Bi
3
K PO (6equiv)
3
4
o
R1
Br
R2
R1
3
R2
DMF, 90
C
Entry
1
Ar–Br
BiAr3
4-H
Time (h)
Product
Yielda,b,c (%)
2
1
92
Ac
Ac
Ac
2
3
4-H
85
86
4-OCH3
1
Ac
OCH3
CH3
4
5
4-CH3
4-F
1
1
89
73
Ac
Ac
F
6
7
4-Cl
1
1
65
74
Ac
Ac
Cl
3-OCH3
OCH3
8
9
4-H
1
1
62
76
Cl
Br
Cl
Cl
4-OCH3
OCH3

M. L. N. Rao et al. / Tetrahedron Letters 48 (2007) 2707–2711
2709
Table 2 (continued)
Entry
Ar–Br
BiAr3
Time (h)
1
Product
Yielda,b,c (%)
10
11
12
13
14
4-CH3
72
Cl
CH3
4-H
1
2
1
1
83
88
94
94
EtOOC
Br
EtOOC
EtOOC
EtOOC
EtOOC
4-H
4-OCH3
4-CH3
OCH3
CH3
15
16
4-H
4-H
1
1
85
95
PhOC
Br
COPh
Br
NO2
O2N
Br
17
18
4-H
4-H
1
1
91
92
O2N
O2N
NO2
NO2
Br
Br
19
4-H
1
60
H3C
CH3
20
21
4-H
4-H
2
1
72
49
CH3
H3C
Br
CH3
Br
22
4-H
1
72
NC
CN
23
24
25
4-H
4-H
4-H
1
2
1
75
85
76
NC
NC
F3C
Br
CN
CN
CF3
Br
Br
a Conditions: equiv ratios are based on BiAr3: BiAr3 (1 equiv), aryl bromide (3.5 equiv), Pd(OAc)2 (0.1 equiv)/PPh3 (0.4 equiv), K3PO4 (6 equiv),
DMF (3 mL), 90 ꢀC.
b In the cases of observed poor cross-coupling reactivity, homo coupled biphenyls resulting from the triarylbismuths were also formed as side
products.
c Isolated yields after purification by column chromatography. All the products were characterized by 1H, 13C NMR and IR spectral data and by
comparison with the literature reported values.

2710
M. L. N. Rao et al. / Tetrahedron Letters 48 (2007) 2707–2711
Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359; (c) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633; (d) Cross-Coupling Reac-
tions: A Practical Guide; Miyaura, N., Ed.; Topics in
Current Chemistry, Series 219; Springer: New York, 2002;
(e) Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; (f)
Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44,
366.
cross-coupled products (entries 16 and 17). Control
reactions carried out without base (entry 18), phosphine
ligand (entry 19) and palladium catalyst (entry 20), re-
vealed that catalyst, ligand and base were necessary to
achieve efficient cross-coupling reactivity. In addition,
it was also found that 6 equiv of base were essential
for the cross-coupling of 3 equiv of aryl bromide with
the three aryl groups from 1 equiv of triphenylbismuth.
2. (a) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem.,
Int. Ed. 2006, 45, 1282; (b) Gonzalez-Bobes, F.; Fu, G. C.
J. Am. Chem. Soc. 2006, 128, 5360; (c) Powell, D. A.;
Maki, T.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510; (d)
Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 3484; (e) Anderson, K.
W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44,
6173; (f) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685; (g)
Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2004, 43, 1871; (h) Molander,
G. A.; Yokoyama, Y. J. Org. Chem. 2006, 71, 2493; (i)
Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70,
3950; (j) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003,
68, 4302.
3. (a) Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201; (b)
Singh, R.; Viciu, M. S.; Kramareva, N.; Navarro, O.;
Nolan, S. P. Org. Lett. 2005, 7, 1829; (c) Kells, K. W.;
Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666; (d)
Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 82; (e) Denmark, S. E.; Baird, J. D. Org. Lett.
2004, 6, 3649; (f) Denmark, S. E.; Ober, M. H. Org. Lett.
2003, 5, 1357; (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc.
2003, 125, 12527; (h) Molander, G. A.; Yun, C.-S.;
Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68,
5534.
Thus, we investigated the cross-coupling reaction of
various triarylbismuths with a variety of electronically
diverse aryl bromides (Table 2). The reactivity and
substrate scope provided by the aryl bromides under
the present conditions are excellent giving good to high
yields of the cross-coupled products. As shown in Table
2, the cross-coupling reaction of various functionalized
aryl bromides occurred efficiently with different triaryl-
bismuths. For example, the reaction of 4-bromo-
acetophenone with a range of electronically diverse BiAr3
reagents produced good to high yields of the corre-
sponding cross-coupled products (entries 1–7). Further,
a variety of functionalized electron-rich and electron-
poor aryl bromides reacted very well with triaryl-
bismuths leading to good to high yields of the cross-
coupled biaryls (entries 8–25). Evidently, the coupling
reaction of triarylbismuths with electron-poor aryl bro-
mides resulted in high yields, while the corresponding
reaction with electron-rich aryl bromides produced
moderate yields. It is noteworthy that bromobenzene
substituted with 2-nitro, 3-nitro and 4-nitro groups
reacted efficiently giving high yields of the corresponding
cross-coupled products (entries 16–18). 1-Bromo-2-
nitrobenzene reacted without any discernible steric
encumbrance to afford the corresponding 2-nitrobiphen-
yl product in 95% yield (entry 16).11 It also emerged
that the reactivity of a range of triarylbismuths in the
cross-coupling reaction was unaffected by a change in
the electronics of the aryl rings in the triarylbismuths.
4. (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 11818; (b) Netherton, M. R.; Dai,
C.; Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
10099; (c) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc.
2004, 126, 13028; (d) Denmark, S. E.; Sweis, R. F. J. Am.
Chem. Soc. 2001, 123, 6439; (e) Molander, G. A.; Rivero,
M. R. Org. Lett. 2002, 4, 107; (f) Molander, G. A.;
Biolatto, B. Org. Lett. 2002, 4, 1867.
In conclusion, we have disclosed a palladium catalyzed
protocol for the cross-coupling reaction of triarylbis-
muths with aryl bromides. The catalytic system employs
readily available Pd(OAc)2 and PPh3 as ligand along
with K3PO4 as base. The excellent cross-coupling reac-
tivity of aryl bromides observed with various triaryl-
bismuths clearly underscores the efficiency of the present
protocol in addition to the wide scope of triarylbismuths
as atom-efficient reagents for carbon–carbon bond
formation in organic synthesis.
5. (a) Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793; (b)
Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125,
15292; (c) Dubbaka, S. R.; Vogel, P. Org. Lett. 2004, 6, 95;
(d) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem.
Soc. 2001, 123, 4155; (e) Su, W.; Urgaonkar, S.;
McLaughlin, P. A.; Verkade, J. G. J. Am. Chem. Soc.
2004, 126, 16433; (f) Zhang, Y.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 15964.
6. Rouhi, A. M. Chem. Eng. News 2004, 82, 49.
7. Organobismuth Chemistry; Suzuki, H., Matano, Y., Eds.;
Elsevier: Amsterdam, 2001.
8. (a) Rao, M. L. N.; Yamazaki, O.; Shimada, S.; Tanaka,
T.; Suzuki, Y.; Tanaka, M. Org. Lett. 2001, 3, 4103; (b)
Venkatraman, S.; Li, C.-J. Tetrahedron Lett. 2001, 42, 781;
(c) Rao, M. L. N.; Venkatesh, V.; Jadhav, D. N.
Tetrahedron Lett. 2006, 47, 6975; (d) Barton, D. H. R.;
Ozbalik, N.; Ramesh, M. Tetrahedron 1988, 44, 5661; (e)
Wada, M.; Ohki, H. J. Synth. Org. Chem. Jpn. 1989, 47,
425; (f) Suzuki, H.; Murafuji, T.; Azuma, N. J. Chem.
Soc., Perkin Trans. 1 1992, 1593; (g) Asano, R.; Moritani,
I.; Fujiwara, Y.; Teranishi, S. Bull. Chem. Soc. Jpn. 1973,
46, 2910; (h) Kawamura, T.; Kikukawa, K.; Takagi, M.;
Matsuda, T. Bull Chem. Soc. Jpn. 1977, 50, 2021.
9. Recently, organobismuth compounds such as azabismo-
cines and organobismuth dialkoxides were used in cross-
coupling reactions with 1 equiv of electrophilic reagents,
Acknowledgements
We thank DST, India and IIT-Kanpur for supporting
this work. D.B. and D.N.J. thank IIT-Kanpur and
CSIR, New Delhi, respectively, for research fellowships.
References and notes
1. Selected reviews and books on metal catalyzed coupling
reactions, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4442; (b) Hassan, J.;

M. L. N. Rao et al. / Tetrahedron Letters 48 (2007) 2707–2711
2711
see: (a) Rao, M. L. N.; Shimada, S.; Tanaka, M. Org. Lett.
1999, 1, 1271; (b) Rao, M. L. N.; Shimada, S.; Yamazaki,
O.; Tanaka, M. J. Organomet. Chem. 2002, 659, 117; (c)
Shimada, S.; Yamazaki, O.; Tanaka, T.; Rao, M. L. N.;
Suzuki, Y.; Tanaka, M. Angew. Chem., Int. Ed. 2003, 42,
1845; (d) Yamazaki, O.; Tanaka, T.; Shimada, S.; Suzuki,
Y.; Tanaka, M. Synlett 2004, 11, 1921.
0.87 mmol) followed by triphenylbismuth (0.110 g,
0.25 mmol), K3PO4 (0.318 g, 1.5 mmol), PPh3 (0.026 g,
0.1 mmol), Pd(OAc)2 (0.0056 g, 0.025 mmol) and solvent
DMF (3 mL) under a nitrogen atmosphere. The mixture
was stirred at an oil bath temperature of 90 ꢀC for 1 h.
Then the reaction mixture was cooled to room tempera-
ture, quenched with dil HCl (10 mL) and extracted with
ethyl acetate (3 · 10 mL). The combined organic extract
was washed with water (2 · 10 mL) and brine (10 mL),
dried over anhydrous MgSO4 and concentrated under
reduced pressure. The crude product was further purified
by column chromatography on silica gel (100–200 mesh)
using hexane–ethyl acetate (8:2) as eluent to afford pure 4-
acetylbiphenyl (0.125 g) in 85% yield. The product was
characterized by comparing 1H, 13C NMR and IR data
with the reported data.
10. (a) Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809; (b) Li,
J.-H.; Liang, Y.; Wang, D.-P.; Liu, W.-J.; Xie, Y.-X.; Yin,
D.-L. J. Org. Chem. 2005, 70, 2832; (c) Li, J.-H.; Liu,
W.-J.; Xie, Y.-X. J. Org. Chem. 2005, 70, 5409.
11. Gonzalez, R. R.; Liguori, L.; Carrillo, A. M.; Bjorsvik,
H.-R. J. Org. Chem. 2005, 70, 9591.
12. Representative procedure for the cross-coupling reaction of
aryl bromides (Table 2): A hot oven-dried Schlenk tube
was charged with 4-bromoacetophenone (0.173 g,