Pd/P(i-BuNCH2CH2)3N: An efficient catalyst for Suzuki cross-coupling of aryl bromides and chlorides with arylboronic acids

Article abstract of DOI:10.1016/S0040-4039(02)02189-5

Pd(OAc)₂ in combination with the commercially available ligand P(i-BuNCH₂CH₂)₃N catalyzes the Suzuki cross-coupling reaction of a wide variety of aryl bromides and chlorides with arylboronic acids, affording the desired biaryls in excellent yields. It has also been shown that P(NMe₂)₃ can be employed as a ligand, though with significantly more limited success.

Full text of DOI:10.1016/S0040-4039(02)02189-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8921–8924
Pd/P(i-BuNCH2CH2)3N: an efficient catalyst for Suzuki
cross-coupling of aryl bromides and chlorides with arylboronic
acids
Sameer Urgaonkar, M. Nagarajan and J. G. Verkade*
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 20 August 2002; revised 27 September 2002; accepted 30 September 2002
Abstract—Pd(OAc)2 in combination with the commercially available ligand P(i-BuNCH2CH2)3N catalyzes the Suzuki cross-cou-
pling reaction of a wide variety of aryl bromides and chlorides with arylboronic acids, affording the desired biaryls in excellent
yields. It has also been shown that P(NMe2)3 can be employed as a ligand, though with significantly more limited success. © 2002
Elsevier Science Ltd. All rights reserved.
The reaction of halides (or halide equivalents) with
arylboronic acids to generate CꢀC bonds is an impor-
tant transformation in organic synthesis.1 Ever since the
first report in 1981 by Suzuki and co-workers on their
preparation of biaryls,2 a variety of improvements in
catalyst precursors have been described. These studies
revealed the crucial role played by the ancillary ligands
in the efficiency of this reaction. Sterically hindered,
electron-rich alkyl phosphines3 and carbene4 ligands
have received increasing interest in recent years. How-
ever, the development of new ligands or the application
of existing ligands in this reaction, particularly those
involving aryl chlorides as substrates, is still of consid-
erable importance.
is oriented such that its lone pair is anti to the phospho-
rus lone pair, thus allowing that nitrogen to act simply
as an electron withdrawing substituent on the
phosphorus.
We reasoned that by making the backbone of the
triaminophosphine fairly rigid but strain-free in a
bicyclic framework in which all three nitrogens would
be planar as in pro-azaphosphatranes 1–6, we could
potentially avoid the reduced electron donating charac-
ter associated with acyclic triaminophosphines. Thus, in
contrast to acyclic analogues of 1–6, all three nitrogens
in the cage structure would augment the electron-den-
sity on the phosphorus atom. As is seen in 1–6, the
electronic and steric nature of the phosphorus can be
fine tuned by the substituents on each PN3 nitrogen.7
Although acyclic triaminophosphine ligands are well
known in transition metal chemistry, they have not
been used in metal-catalyzed cross-coupling reactions
probably because of their diminished electron-donating
capability as rationalized by Woollins5 recently on the
basis of differences in geometries at the nitrogens.
Structures of free triaminophosphines and of their tran-
sition metal complexes6 determined by diffraction tech-
niques reveal that each phosphine ligand bears two
nearly planar nitrogens and one pyramidal nitrogen.
While the two planar nitrogens are capable of donating
electron density to phosphorus, the pyramidal nitrogen
Herein we report that bicyclic triaminophosphine 4
(commercially available from Aldrich) is an excellent
ligand (and the best of the bicyclic series shown above)
in palladium-catalyzed Suzuki cross-coupling reaction
of aryl halides, including the less reactive aryl chlo-
rides.8 We also demonstrate that the commercially
available acyclic triaminophosphine P(NMe2)3 can also
be used in the reactions involving aryl bromides and
chlorides, although with much less efficiency than 4.
Keywords: cross-coupling reaction; ligands; bicyclic triaminophos-
phine.
* Corresponding author. Tel.: (515) 294-5023; fax: (515) 294-0105;
e-mail: jverkade@iastate.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02189-5

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S. Urgaonkar et al. / Tetrahedron Letters 43 (2002) 8921–8924
Table 2. Effect of bases and solvents on the Pd(OAC)2/4-
catalyzed cross-coupling of 1-bromo-4-tert-butylbenzene
with phenylboronic acid using the conditions given in
Table 1
For optimization studies, we initially screened bicyclic
1–6 and the three acyclic triaminophosphine ligands
shown in Table 1 for cross-coupling of 1-bromo-4-tert-
butylbenzene and phenylboronic acid in the presence of
2.0 equiv. of Cs2CO3, 2.0 mol% of Pd(OAc)2 and 4.0
mol% of ligand in toluene. From the results summarized
in Table 1, it is evident that bicyclic triaminophosphine
4 is the most effective of the triaminophosphine ligands
examined, by a substantial margin, affording a 96% yield
of 4-tert-butylbiphenyl in 6 h at 80°C (Table 1, entry 6)
and a 90% yield of the same product at room temperature
in 28 h (Table 1, entry 7). The other bicyclic ligands were
considerably less catalytically active than 4 (Table 1,
entries 1–5, 9 and 10) for reasons that are not clear at
this time. It is likely that the iso-butyl groups on the PN3
nitrogens provide a particularly effective steric and
electronic environment at the phosphorus for stabiliza-
tion of the catalytically active species. Interestingly, the
acyclic triaminophosphines P(NMe2)3 and P(N-i-Bu2)3
also furnished the desired product in good yields (Table
1, 87% yield, entry 11 and 84% yield, entry 14, respec-
tively) at 80°C. Although coupling for ligands 1, 2, 4 and
P(NMe2)3 proceeded slowly at room temperature, the
reaction proceeds significantly faster at 80°C.
Entry
Base
Solvent
Time (h)
Yield (%)a
1
2
3
4
5
6
7
Cs2CO3
Cs2CO3
Cs2CO3
CsF
KF
K3PO4
K2CO3
Dioxane
DMF
THF
Toluene
Toluene
Toluene
Toluene
13
16
20
10
20
20
13
95
91
72
90
78b (34)c
82b (19)c
63
a Isolated yields (average of two runs).
b 90% conversion based on the recovered starting material.
c The reaction was performed at room temperature and the reaction
time was 40 h.
to provide complete conversion even after 20 h (Table 2,
entries 5, 6 and 7).
With optimized conditions in hand, we evaluated the
scope of the coupling of aryl bromides with various
arylboronic acids. It is clear from Table 3 that aryl
bromides containing electron-withdrawing groups such
as trifluoromethyl, cyano, nitro and ester groups are
coupled in excellent yields (Table 3, entries 1–5 and 6).
Not surprisingly, the Pd(OAc)2/4 catalyst system also
efficiently and highly selectively catalyzes the reaction of
an aryl bromide possessing a chloride functionality
(Table 3, entry 7). The use of acyclic P(NMe2)3 as a ligand
also gave satisfactory yields with electron-deficient aryl
bromides (Table 3, see yields in parenthesis for entries 1,
3 and 6). The Pd(OAc)2/4 catalytic system also proved
to be highly efficient for electron-neutral and electron-
rich aryl bromides. For example, combining 1-bromo-4-
tert-butylbenzene with sterically hindered o-tolylboronic
acid provided the corresponding biaryl in 96% isolated
yield (Table 3, entry 8). Sterically demanding di-ortho-
substituted-2-bromomesitylene also reacted in high yield
(Table 3, entry 9). Electron-rich 4-bromoanisole was also
a suitable coupling partner (Table 3, entry 10). In
contrast, the Suzuki cross-coupling reactions of unacti-
vated (electron-neutral) and deactivated (electron-rich)
aryl bromides employing the acyclic triaminophosphine
P(NMe2)3 as the ligand proceeded only in moderate to
poor yields.
We next investigated a variety of solvents and bases for
the aforementioned coupling reaction catalyzed by the
Pd(OAc)2/4 system (Table 2). Toluene was found to be
the most efficacious solvent. Although dioxane and
DMF gave comparable yields, the reaction times were
somewhat longer (Table 2, entries 1 and 2). Employing
THF as the solvent significantly decreased the yield of
the desired product (Table 2, entry 3). Among the bases
explored, Cs2CO3 gave the fastest reaction rates although
CsF was also a suitable base (Table 2, entry 4). However,
reactions involving KF, K3PO4 or K2CO3 as a base failed
Table 1. Effect of various triaminophosphine ligands in
the Pd-catalyzed cross-coupling of 1-bromo-4-tert-butyl-
benzene with phenylboronic acida
Entry
Ligand
Temp. (°C) Time (h)
Yield (%)
Although we were successful in synthesizing biaryls
containing two ortho substituents, our attempts to syn-
thesize tri- or tetra-ortho substituted biaryls were unsuc-
cessful even with increased catalyst loading and/or longer
reaction times.9
1
2
3
4
5
6
7
8
1
1
2
2
3
4
4
rt
80
rt
48
18
30
26
18
9
28
20
24
24
18
40
33
24
52
69
16
72
46
96
90
45
68
14
87
85
31
84
80
80
80
rt
80
80
80
80
rt
We next examined Suzuki reactions of usually unreactive
aryl chlorides using Pd(OAc)2/4 as a catalyst system
(Table 4). The low reactivity of such substrates has been
attributed to their aversion to add oxidatively to a Pd(0)
complex because of a large CꢀCl bond dissociation
energy (402 kJ mol−1; 298 K).10 A slightly higher catalyst
loading (4 mol% Pd) was required for these reactions to
proceed to completion. The reaction of electron-poor
(Table 4, entries 1, 2, 3 and 4) and electron-rich (Table
None
5
6
P(NMe2)3
P(NMe2)3
P(NEt2)3
9
10
11
12
13
14
80
P(N-i-Bu2)3 80
a Isolated yields (average of two runs).

S. Urgaonkar et al. / Tetrahedron Letters 43 (2002) 8921–8924
Table 3. Suzuki cross-coupling of aryl bromides with arylboronic acidsa
8923
Table 4. Suzuki cross-coupling of aryl chlorides with phenylboronic acida

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S. Urgaonkar et al. / Tetrahedron Letters 43 (2002) 8921–8924
4, entries 6 and 7) aryl chlorides with phenylboronic acid
provided very good yields of the biaryl product. Sterically
hindered 2-chlorotoluene was equally reactive and the
desired product was isolated in 92% yield (Table 4, entry
5). In contrast, cross-coupling of aryl chlorides with
phenylboronic acid in the presence of P(NMe2)3 resulted
in no detectable product formation even over 36 h when
4 mol% Pd(OAc)2 was employed. However, the use of 10
mol% Pd(OAc)2 and 20 mol% P(NMe2)3 did allow
cross-coupling of electron-poor aryl chlorides with
phenylboronic acid and the desired biaryls were obtained
in acceptable yields (Table 4, parenthesized yields for
entries 2 and 4). The lower yields obtained with the
Pd(OAc)2/P(NMe2)3 catalyst system were due largely to
the formation of hydrodehalogenation products. Since
triaminophosphines are apparently less electron-rich
than trialkylphosphines, their effectiveness in the activa-
tion of CꢀCl bond under our conditions is quite remark-
able.
3. (a) Little, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020; (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550; (c)
Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413; (d) Bei, X.; Turner, H. W.; Weinberg, W. H.;
Guram, A. S.; Petersen, J. L. J. Org. Chem. 1999, 64, 6797.
4. (a) Beller, M.; Fischer, H.; Herrmann, A.; Ofele, K.;
Bossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848;
(b) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J.
Org. Chem. 1999, 64, 3804; (c) Bo¨hm, V. P. W.;
Gsto¨ttmayr, C. W. K.; Weskamp, T.; Herrmann, W. A. J.
Organomet. Chem. 2000, 595, 186; (d) Grasa, G. A.; Viciu,
M. S.; Huang, J.; Zhang, C.; Trudell, M. L.; Nolan, S. P.
Organometallics 2002, 21, 2866.
5. (a) Clarke, M. L.; Cole-Hamilton, D. J.; Slawin, A. M. Z.;
Woollins, J. D. Chem. Commun. 2000, 2065; (b) Clarke, M.
L.; Cole-Hamilton, D. J.; Woollins, J. D. J. Chem. Soc.,
Dalton Trans. 2001, 2721.
6. (a) Crowley, A. H.; Lattman, M.; Stricklen, P. M.;
Verkade, J. G. Inorg. Chem. 1982, 21, 543; (b) Molloy, K.
G.; Petersen, J. L. J. Am. Chem. Soc. 1995, 117, 7696; (c)
Xi, S. K.; Schmidt, H.; Lensink, C.; Kim, S.; Wintergrass,
D.; Daniels, L. M.; Jacobson, R. A.; Verkade, J. G. Inorg.
Chem. 1990, 29, 2214; (d) Socol, S. M.; Jacobson, R. A.;
Verkade, J. G. Inorg. Chem. 1984, 23, 88.
In summary, we have shown that the new, cheap and
readily accessible catalyst system Pd(OAc)2/4 is effective
for the convenient and efficient synthesis of unsymmet-
rical biaryls from aryl bromides or chlorides. While the
catalyst system Pd(OAc)2/P(NMe2)3 is also effective for
aryl bromides, it is not very efficient with aryl chlorides.
7. For a recent review of the chemistry of pro-azaphos-
phatranes, see: Verkade, J. G. Top. Curr. Chem., in press.
8. General procedure: An oven-dried Schlenk flask, equipped
with a magnetic stir bar, septum, and a condenser with an
argon inlet–outlet was charged with aryl halide (1.0 mmol),
arylboronic acid (1.5 mmol), base (1.5 mmol), Pd(OAc)2
(2 mol% for aryl bromide and 4 mol% for aryl chloride),
ligand (4 mol% for aryl bromide and 8 mol% for aryl
chloride) and 5 mL of solvent. The flask was immersed in
an oil bath at the temperature indicated in the tables. Upon
complete consumption of starting material as determined
by TLC analysis, the reaction mixture was adsorbed onto
silica and the biaryl product was isolated by column
chromatography (hexanes/EtOAc). All the biphenyl prod-
ucts are known compounds.
Acknowledgements
Research support in the form of a grant from the
National
acknowledged.
Science
Foundation
is
gratefully
References
1. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2458; (b)
Stanforth, S. P. Tetrahedron 1998, 54, 263; (c) Suzuki, A.
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F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany,
1998.
9. For Suzuki cross-coupling of hindered substrates, see: Yin,
J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 1162.
2. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513.
10. Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.