Highly active oxime-derived palladacycle complexes for Suzuki-Miyaura and Ullmann-type coupling reactions

Article abstract of DOI:10.1021/jo025619t

Oxime-derived chloro-bridged palladacycles 12 and 13 are efficient complexes for the Suzuki-Miyaura reactions of aryl-, allyl-, and benzyl halides with arylboronic acids. The isolated catalysts are thermally stable, not sensitive to air or moisture, and easily accessible from inexpensive starting materials. The reaction can be performed under aerobic conditions with aryl bromides and chlorides, displaying turnover numbers (TON) of up to 5 × 10⁵ and turnover frequencies (TOF) of up to 198 000 h^-1 for aryl bromides. Aryl chlorides undergo the Suzuki reaction with arylboronic acids with TON of up to 4700 and TOF up to 4700 h^-1. Even inexpensive and readily available benzyl and allyl chlorides undergo the coupling reaction with good turnover numbers. Complexes of 12 catalyze the syntheses of symmetrical biaryls in good yields via reductive coupling of iodoarenes in the presence of Huenig's base.

Full text of DOI:10.1021/jo025619t

High ly Active Oxim e-Der ived P a lla d a cycle Com p lexes for
Su zu k i-Miya u r a a n d Ullm a n n -Typ e Cou p lin g Rea ction s
a
Diego A. Alonso, Carmen N a´ jera,* and M Carmen Pacheco
Departamento de Qu ı´ mica Org a´ nica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
cnajera@ua.es
Received February 18, 2002
Oxime-derived chloro-bridged palladacycles 12 and 13 are efficient complexes for the Suzuki-
Miyaura reactions of aryl-, allyl-, and benzyl halides with arylboronic acids. The isolated catalysts
are thermally stable, not sensitive to air or moisture, and easily accessible from inexpensive starting
materials. The reaction can be performed under aerobic conditions with aryl bromides and chlorides,
5
displaying turnover numbers (TON) of up to 5 × 10 and turnover frequencies (TOF) of up to 198 000
-
1
h
for aryl bromides. Aryl chlorides undergo the Suzuki reaction with arylboronic acids with TON
-
1
of up to 4700 and TOF up to 4700 h . Even inexpensive and readily available benzyl and allyl
chlorides undergo the coupling reaction with good turnover numbers. Complexes of 12 catalyze
the syntheses of symmetrical biaryls in good yields via reductive coupling of iodoarenes in the
presence of H u¨ nig’s base.
7
In tr od u ction
ligands have emerged as efficient partners for the Suzuki
reaction in order to circumvent the problems associated
with tertiary phosphine derivatives, although very low
yields were obtained with electron-rich aryl chlorides
even when high catalyst loadings were used (3 mol % Pd).
Substituted biaryls are importrant building blocks for
the syntheses of many pharmaceutically active com-
pounds, herbicides, polymers, new materials, liquid
crystals, and ligands. Among the various methods known
to synthesize biaryls,1 the transition-metal-catalyzed
Suzuki-Miyaura cross-coupling of aryl halides with
arylboronic acids or esters has emerged as an extremely
powerful method in organic synthesis for the formation
8
Ligandless palladium systems have also been shown to
promote the Suzuki cross-coupling reactions of aryl
bromides and activated aryl chlorides, although with very
low turnover numbers (TON ) mol product/mol Pd) and
-1
turnover frequencies (TOF ) TON h ). However, lately,
2
2
2
of C(sp )-C(sp ) bonds under mild conditions. Further-
palladacycles have been by far the most developed and
studied catalysts, as they are presently the most suc-
cessful, because of their structural versatility and easy
more, very recently, the Suzuki coupling has been
3
2
3
3
3
extended to C(sp )-C(sp ) and C(sp )-C(sp ) couplings.
A wide variety of palladium catalysts efficiently promote
the couplings of aryl halides and other electrophiles with
organoboron compounds, usually combinations of pal-
ladium salts or complexes with phosphorus ligands, such
as phosphines, phosphites, and phosphine-oxides. How-
ever, these types of catalysts are sensitive to moisture
and air oxidation and therefore require air-free handling
to minimize ligand oxidation. Very recently, nitrogen
synthetic accessibility, and the most promising catalysts
in C-C bond-forming reactions.9 Among them, phos-
(4) (a) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J .
4
5
6
Am. Chem. Soc. 1999, 121, 9550-9561. (b) Bei, X.; Turner, H. W.;
Weinberg, W. H.; Guram, A. S.; Petersen J . L. J . Org. Chem. 1999,
6
4, 6797-6803. (c) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem.,
Int. Ed. 2000, 22, 4153-4155. (d) Littke, A. F.; Dai, C.; Fu, G. C. J .
Am. Chem. Soc. 2000, 122, 4020-4028. (e) Pickett, T. E.; Richards, C.
J . Tetrahedron Lett. 2001, 42, 3767-3769. (f) Feuerstein, M.; Laurenti,
D.; Bougeant, C.; Doucet, H.; Santelli, M. Chem. Commun. 2001, 325-
326. (g) Feuerstein, M.; Doucet, H.; Santelli, M. Synlett 2001, 1458-
1460. (h) Liu, S.-Y.; Choi, M. J .; Fu, G. C. Chem. Commun. 2001, 2408-
2409.
(
(
1) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(
b) Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich,
F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim, 1998. (c) Miyaura, N.
In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; J AI:
London, 1998; Vol. 6, pp 187-243. (d) Geissler, H. In Transition Metals
for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Wein-
heim, 1998; Vol. 1. (e) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-
(5) Zapf, A.; Beller, M. Chem.sEur. J . 2000, 6, 1830-1833.
(6) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516.
(7) Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001, 3, 1077-
1080.
(8) (a) Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14 437-
14 450. (b) Li, Y.; Hong, X. M.; Collard, D. M.; El-Sayed, M. A. Org.
Lett. 2000, 2, 2385-2388. (c) Zim, D.; Monteiro, A. L.; Dupont, J .
Tetrahedron Lett. 2000, 41, 8199-8202. (d) Kabalka, G. W.; Nam-
boodiri, V.; Wang, L. Chem. Commun. 2001, 775. (e) LeBlond, C. R.;
Andrews, A. T.; Sun, Y.; Sowa, J . R., J r. Org. Lett. 2001, 3, 1555-
1557.
(9) (a) Ryabov, A. D. Synthesis 1985, 233-252. (b) Dyker, G. Chem.
Ber./ Recl. 1997, 130, 1567-1578. (c) Herrmann, W. A.; B o¨ hm, V. P.
W.; Reisinger, C.-P. J . Organomet. Chem. 1999, 576, 23-41. (d)
Dupont, J .; Pfeffer, M.; Spencer, J . Eur. J . Inorg. Chem. 2001, 1917-
1927.
1
68.
3) For palladium-catalyzed sp -sp Suzuki couplings involving
2
3
(
alkylboronic acids and derivatives, see: (a) Chowdhury, S.; Georghiou,
P. E. Tetrahedron Lett. 1999, 40, 7599-7603. (b) Yao, M.-L.; Deng,
M.-Z. Synthesis 2000, 1095-1100. (c) Gray, M.; Andrews, I. P.; Hook,
D. F.; Kitteringham, J .; Voyle, M. Tetrahedron Lett. 2000, 41, 6237-
6
240. (d) F u¨ rstner, A.; Leitner, A. Synlett 2001, 290-292. (e) Zou, G.;
Reddy, Y. K.; Falck, J . R. Tetrahedron Lett. 2001, 42, 7213-7215. For
3
3
palladium-catalyzed sp -sp Suzuki couplings, see: Netherton, M. R.;
Dai, C.; Neusch u¨ tz, K.; Fu, G. C. J . Am. Chem. Soc. 2001, 123, 10099-
1
0100 and references therein.
1
0.1021/jo025619t CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/10/2002
5
588
J . Org. Chem. 2002, 67, 5588-5594

Highly Active Oxime-Derived Palladacycle Complexes
phapalladacycles 1,10 2,11 3,12 and 4 and phosphine-free
13
9
c
14
15
16
N-heterocyclic carbenes (NHC) 5, 6, 7, and 8 are
able to catalyze the Suzuki couplings of aryl bromides
and chlorides with phenylboronic acid in good yields but
generally under an inert atmosphere. Benzyl thioethers
1
7
9
developed by Dupont have been found to be stable
but still active catalysts in Suzuki coupling reactions as
well. Milstein18 has shown that phosphine-free cyclom-
etalated imine dimers 10 are able to mediate Suzuki
reactions involving aryl bromides with TON up to 8 ×
5
1
0 . Unfortunately, this system was sterile when using
inexpensive and readily accessible aryl chlorides. More
recently, Bedford19 has prepared orthometalated mono-
meric amine complex 11 and has presented it as a very
active system in the Suzuki couplings of activated and
nonactivated aryl chlorides, although tricyclohexylphos-
phine had to be used as ligand.
On the other hand, different palladium-catalyzed ho-
mocoupling protocols have been developed very recently
to prepare symmetrical and unsymmetrical biaryls via
Ullmann-type reactions.20 Palladium acetate was usually
the catalyst of choice for this type of coupling21 which
was also especially suitable for the synthesis of binaph-
thyls and in intramolecular coupling reactions. However,
among palladacycles, only phosphine-derived catalyst 1
was shown to promote iodoarenes in reductive homocou-
plings to produce biaryls in high yields.22
F IGURE 1. Palladacycle catalysts for Suzuki-Miyaura cou-
We have very recently reported our first results on
highly active cyclopalladated oxime-derived catalysts 12
for a wide range of useful and well-known C-C coupling
processes such as Heck, Suzuki, Stille, Sonogashira, and
Ullmann reactions.23 These catalyst precursors are very
thermally and air stable and promoted the palladium-
catalyzed Heck couplings of aryl halides with olefins with
plings.
couplings of aryl bromides and chlorides with phenylbo-
ronic acids with oxime-derived palladacycles 12 as cata-
lysts as well as on the couplings of benzylic and allylic
chlorides with phenylboronic acid. The synthesis of
symmetrical biphenyls via reductive homocouplings of
iodoarenes is studied as well (Figure 1).
1
0 23,24a
impressive turnover numbers of up to 10 .
In this
paper, we report on the evaluation and optimization of
the effect of additives, bases, and solvents on the Suzuki
Resu lts a n d Discu ssion
The catalyst precursors 12 and 13 used for the Suzuki
cross-coupling reactions were prepared in high yields
from the corresponding oximes through a carbopallada-
(
10) Beller, M.; Fischer, H.; Herrmann, W. A.; O¨ fele, K.; Brossmer,
C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-1849.
11) Gibson, S.; Foster, D. F.; Eastham, G. R.; Tooze, R. P.; Cole-
Hamilton, D. J . Chem. Commun. 2001, 779-780.
12) (a) Albisson, D. A.; Bedford, R. B.; Lawrence, S. E.; Scully, P.
(
tion reaction25 with lithium tetrachloropalladate (Li
-
(
2
N. Chem. Commun. 1998, 2095-2096. (b) Bedford, R. B.; Welch, S. L.
4
PdCl ) in MeOH in the presence of NaOAc as base at
room temperature (Figure 2).
Chem. Commun. 2001, 129-130.
26
(13) Bedford, R. B.; Draper, S. M.; Scully, P. N.; Welch, S. L. New
The Suzuki-Miyaura arylation of aromatic halides was
first evaluated with palladium complexes 12 and 13 in
order to study their catalytic activity. We chose as a
model reaction the coupling between p-bromoacetophe-
none and phenylboronic acid in toluene at 110 °C in the
J . Chem. 2000, 745-746.
(
14) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org. Chem.
1
999, 64, 3804-3805.
(
15) Zhang, C.; Trudell, M. L. Tetrahedron Lett. 2000, 41, 595-598.
16) McGuinness, D. S.; Cavell, K. J . Organometallics 2000, 19, 741-
(
7
48.
(17) Zim, D.; Gruber, A. S.; Ebeling, G.; Dupont, J .; Monteiro, A. L.
2 3
presence of K CO as base and with a catalyst loading of
Org. Lett. 2000, 2, 2881-2884.
-
3
(
(
18) Weissman, H.; Milstein, D. Chem. Commun. 1999, 1901-1902.
19) Bedford, R. B.; Cazin, C. S. J . Chem. Commun. 2001, 1540-
10 mol % in Pd (Scheme 1, Table 1). The reaction
provided very similar results and quantitative conver-
sions under air for nearly all the dimeric complexes with
reaction periods within 0.5 and 1 h. Catalysts derived
from benzophenone oxime substrates (12a -c) presented
1
541.
(20) (a) Ullmann, F. Ber. 1903, 36, 2389. (b) Fanta, P. E. Synthesis
1
974, 9-21.
(
21) For the synthesis of symmetrical biaryls, see: (a) Hassan, J .;
Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron 1998,
5
4, 13 793-13 804. (b) Hennings, D. D.; Iwama, T.; Rawal, V. H. Org.
Lett. 1999, 1, 1205-1208 and references therein. For the synthesis of
unsymmetrical biaryls, see: Hassan, J .; Hathroubi, C.; Gozzi, C.;
Lemaire, M. Tetrahedron 2001, 57, 7845-7855 and references therein.
(25) (a) Onoue, H.; Minami, K.; Nakagawa, K. Bull. Chem. Soc. J pn.
1970, 43, 3480-3485. (b) Constable, A. G.; McDonald, W. S.; Sawkins,
L. C.; Shaw, B. L. J . Chem. Soc., Dalton Trans. 1980, 1992-2000. (c)
Nielson, A. J . J . Chem. Soc., Dalton Trans. 1981, 205-211. (d) Baldwin,
J . E.; N a´ jera, C.; Yus, M. Chem. Commun. 1985, 126-127. (e) Baldwin,
J . E.; J ones, R. H.; N a´ jera, C.; Yus, M. Tetrahedron 1985, 41, 699-
711. (f) Ryabov, A. D.; Kazankov, G. M.; Yatsimirsky, A. K.; Kuz′mina,
L. G.; Burtseva, O. Y.; Dvortsova, N. V.; Polyakov, V. A. Inorg. Chem.
1992, 31, 3083-3090.
(
22) Luo, F.-T.; J eevanandam, A.; Basu, M. K. Tetrahedron Lett.
1
998, 39, 7939-7942.
23) Alonso, D. A.; N a´ jera, C.; Pacheco, M. C. Org. Lett. 2000, 2,
823-1826.
24) (a) Alonso, D. A.; N a´ jera, C.; Pacheco, M. C. Adv. Synth. Catal.,
in press. (b) Iyer, S.; Ramesh, C. Tetrahedron Lett. 2000, 41, 8981-
984.
(
1
(
8
(26) For full details, see ref 23.
J . Org. Chem, Vol. 67, No. 16, 2002 5589

Alonso et al.
TABLE 2. Su zu k i Cou p lin g of Ar yl Br om id es w ith
P h B(OH)2 Ca ta lyzed by 12c
F IGURE 2. Oxime-derived palladacycle catalysts.
SCHEME 1. Su zu k i Cou p lin g: Ca ta lyst Stu d y
TABLE 1. Su zu k i Cou p lin g: Ca ta lyst Stu d y
catalyst
time
(h)
yielda
(%)
TOF
(×10- mol % Pd)
3
TON
(h
-1
)
entry
1
2
3
4
5
6
7
8
12a
12b
12c
12d
13
Li2PdCl4
0.5
0.5
0.5
1
1
5
92
82
99
93
98
42
27
77
92 000
82 000
99 000
93 000
98 000
42 000
27 000
77 000
184 000
164 000
198 000
93 000
90 800
8400
b
Li2PdCl4
5
2
5400
38 500
c
12c
a
Determined by GLC on the basis of p-bromoacetophenone
b
using decane as internal standard. 12c was generated in situ in
the reaction medium. 4,4′-Dichlorobenzophenone oxime (10 mol
) was added to the reaction.
c
-3
%
SCHEME 2. Su zu k i Cou p lin g of Ar yl Br om id es
a
Reaction conditions: ArBr (2 mmol), PhB(OH)2 (3 mmol),
the highest turnover frequencies (TOF) ranging from
K2CO3 (4 mmol), 12c, toluene (7 mL). b Bath temperature. De-
termined by GLC on the basis of ArBr using decane as internal
standard. In parentheses, isolated yield after flash chromatogra-
phy or recrystallization.
c
-
1
1
64 000 to 198 000 h . Among them, the reaction with
the p-methoxy-substituted benzophenone complex 12b
was slightly slower under the same reaction conditions
(
compare entries 1-3, Table 1). Palladacycles 12d and
3 gave slightly poorer results. Li PdCl or a catalyst
system prepared in situ from Li PdCl (10 mol % Pd)
and 4,4′-dichlorobenzophenone oxime (10 mol %) in the
presence of base (excess of K CO ) were also tested (Table
, entries 6 and 7). In these cases, the yields were
significantly lower after 5 h than those obtained from the
straight use of 12c (full conversion after 0.5 h). Addition
of 1 equiv of free ligand to the reaction medium did not
improve the catalytic performance (Table 1, entry 8).27
The application of oxime-derived palladium precursors
1
2
4
spectrum of aryl bromides and phenylboronic acid. As
illustrated in Table 2, this catalyst furnished the desired
biaryls in excellent yields. Under standard conditions,
toluene as solvent, K CO as base, and 12c at 110 °C,
2 3
both electron-poor and -rich aryl bromides were cleanly
coupled with turnover numbers of up to 99 000 and
-
3
2
4
-3
2
3
1
3
5 000, respectively (Table 2, entries 1 and 9). When the
reaction was performed at 160 °C, very high activities
5
were obtained with TON up to 5 × 10 (Table 2, entry
2
). Moreover, palladacycle 12c promotes the Suzuki
1
2 as catalysts in the Suzuki reactions of different aryl
coupling even at room temperature, although longer
reaction times and higher catalyst loadings (0.2 mol %
Pd) were necessary (Table 2, entry 3). Aryl bromides with
ortho substituents, such as 2-bromobenzonitrile, reacted
efficiently, affording the corresponding 2-cyanobiphenyl
in excellent yield (98%) after only 0.5 h (Table 2, entry
6). Particularly noteworthy were the reactions of very
bromides (Scheme 2) was studied, and the results are
summarized in Table 2. Complex 12c proved to be a very
active catalyst for the Suzuki cross-couplings of a broad
(27) Bedford has demonstrated a positive effect on catalyst produc-
tivity upon addition of 1 equiv of free ligand to the catalytic system.
See ref 12b.
5
590 J . Org. Chem., Vol. 67, No. 16, 2002

Highly Active Oxime-Derived Palladacycle Complexes
SCHEME 3. Su zu k i Cou p lin g: Ca ta lyst Sta bility
SCHEME 4. Su zu k i Cou p lin g of Ar yl Ch lor id es:
Rea ction Con d ition s Stu d y
TABLE 3. Su zu k i Cou p lin g of Ar yl Ch lor id es: Solven t
a n d Tem p er a tu r e Stu d ya
electron-rich bromides such as p-bromophenol and p-
Tb
(°C)
yieldc
(%)
time
(h)
TOF
bromoanisol. These deactivated substrates afforded cata-
-1
entry
solvent
toluene
p-xylene
THF
dioxane
DMAc
DMF
TON
(h
)
4
lytic activities more in the same range, with TON of ∼10
1
2
3
4
5
6
7
8
9
110
110
110
110
110
110
110
110
110
110
160
160
5
5
3
5
5
1
5
2
6
6
0.5
0.5
37 (11)
23 (11)
1
370
230
10
74
46
3
70
84
620
132
320
142
130
1540
1980
(
Table 2, entries 7 and 8), than those of nonactivated
bromides (Table 2, entries 4, 5, and 10). The heterocyclic
bromide 5-bromo-2-thiophenecarboxaldehyde was like-
wise converted efficiently to the corresponding biaryl
35 (4)
42 (18)
62 (9)
66 (11)
64 (5)
85 (9)
78 (9)
77 (2)
99 (1)
350
420
620
660
640
850
780
770
990
(81%, Table 2, entry 11). Biphenylacetic acid and p-
NMP
DMF/H2O 3:1
phenylmandelic acid, very interesting substrates from the
pharmaceutical point of view,28 could be prepared from
the corresponding bromide precursors in short times with
DMF/H O 95:5
2
10
11
NMP/H2O 95:5
DMF
DMF/H2O 95:5
-
2
very good yields using 10 mol % Pd at 110 °C (Table 2,
entries 12 and 13). As depicted in Table 2, a wide variety
of functional groups are tolerated when oxime-derived
palladacycles 12 are used as catalysts in the Suzuki-
Miyaura reaction.
1
2
a
Catalyst loading: 0.1 mol % Pd. b Bath temperature. c Deter-
mined by GLC on the basis of ArCl using decane as internal
standard. In parentheses, yield of biphenyl.
The pronounced thermal stabilities of palladacycles 12
were demonstrated when no deactivation of the catalyst
was observed in subsequent catalytic runs when coupling
p-bromoacetophenone and phenylboronic acid under typi-
cal conditions (12c, 0.01 mol % Pd) and when GC
analyses of five cycles yielded a constant rate of conver-
sion of p-bromoacetophenone after addition of fresh
reagents to the solution (Scheme 3).
were substantially less effective, and weak organic bases
such as TEA, Pr NEt, and pyrrolidine failed to promote
the reaction, probably because of their ability to bind
strongly to palladium. With respect to the additive study,
i
Bu NBr (TBAB, 20 mol %) was the best additive for the
4
reaction coupling when it was carried out under the
above-mentioned reaction conditions, employing K CO
3
2
Preliminary studies in our group have revealed that
cyclopalladated complexes 12 presented very good activi-
ties in the Suzuki couplings of aryl chlorides in water.29
However, under the standard conditions used for the
4 4
as base. Other ammonium salts such as Bu NCl, Bu NI,
and Bu NHSO4 gave lower yields. Organic nitrogen
4
ligands such as N,N-(dimethylamino)pyridine (DMAP),
which has been recently shown to be able to stabilize
3
1
Suzuki couplings of aryl bromides (toluene, K
2
CO
3
, 110
palladium nanoparticles in water, and N, N′-dimeth-
7
°
C, 12c, 0.01 mol % Pd), p-chloroacetophenone afforded
ylglyoxime (DMG) gave no significant amounts of cross-
4
-acetylbiphenyl in very poor yield, accompanied by
coupling product.
considerable amounts of biphenyl as a result of phenyl-
boronic acid homocoupling.30 Then, a preliminary screen-
ing of optimal reaction conditions for the Suzuki cou-
plings of aryl chlorides with phenylboronic acid in the
presence of catalyst 12c (0.1 mol % Pd) was carried out
with p-chloroacetophenone as the test substrate. The
optimization of bases and additives, which was studied
The solvent and the temperature were the last reaction
parameters studied in the model reaction (Scheme 4,
Table 3). We investigated different apolar solvents such
as toluene and p-xylene (Table 3, entries 1 and 2) with
32
2 3
K CO as base and in the presence of 20 mol % TBAB
and 12c (0.1 mol % in Pd). At 110 °C, both solvents gave
low conversions of p-acetylbiphenyl accompanied by
considerable amounts of biphenyl (11%). Next, we inves-
tigated other more polar solvents (Table 3, entries 3-7).
Reactions conducted at 110 °C were not efficient in THF
and gave poor yields when dioxane and DMAc were the
solvents of choice (Table 3, entries 4 and 5). The reaction
was more efficient in DMF (62%) or NMP (66%) but still
with significant amounts of biphenyl as byproduct (Table
with toluene as solvent at 110 °C, showed K
2 3 2
CO , Cs -
CO , and K PO as the inorganic bases to choose,
3
3
4
although biphenyl was obtained as a byproduct in all the
cases. Other bases such as alkali oxides or hydroxides
(28) (a) p-Biphenylacetic acid (felbinac) and 2-ethyl-4-biphenylacetic
acid with dimethylaminoethanol (namoxyrate) are anti-inflammatory
and analgesic drugs, respectively: USP Dictionary of USAN and
International Drugs Names. (b) p-Biphenylacetamides have been used
as mesogenic arms in porphyrin thermotropic liquid crystals: Michaeli,
S.; Hugerat, M.; Levanon, H.; Bernitz, M.; Natt, A.; Neumann, R. J .
Am. Chem. Soc. 1992, 114, 3612-3618.
3, entries 6 and 7). Using H
2 2
O as cosolvent (DMF/H O
3
:1) led to similar conversions, but the quantity of
byproduct was reduced significantly (Table 3, entry 8).
Interestingly, when the amount of water was reduced to
(
29) Botella, L.; N a´ jera, C. Angew. Chem., Int. Ed. 2002, 41, 179-
81.
30) For the palladium-catalyzed homocoupling of arylboronic acids,
see: (a) Moreno-Ma n˜ as, M.; P e´ rez, M.; Pleixats, R. J . Org. Chem. 1996,
1, 2346-2351. (b) Smith, K. A.; Campi, E. M.; J ackson, W. R.;
1
(
(31) Gittins, D. I.; Caruso, F. Angew. Chem., Int. Ed. 2001, 40, 3001-
3004.
(32) No improvement on catalyst efficiency was observed when the
reaction was carried out in the presence of different amounts of TBAB
(40, 60, and 80 mol %).
6
Marcuccio, S.; Naeslund, C. G. M.; Deacon, G. B. Synlett 1997, 131-
1
4
32. (c) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087-
089.
J . Org. Chem, Vol. 67, No. 16, 2002 5591

Alonso et al.
SCHEME 6. Su zu k i Cou p lin g: Allylic a n d
SCHEME 5. Su zu k i Cou p lin g of Ar yl Ch lor id es
Ben zylic Ch lor id es
TABLE 4. Su zu k i Cou p lin g of Ar yl Ch lor id es w ith
Ar B(OH)2 Ca ta lyzed by 12c
SCHEME 7. Ullm a n n Cou p lin g of Ar yl Iod id es
p-chloroacetophenone and p- and o-chlorobenzonitrile
were coupled with phenylboronic acid in very good yields
(
Table 4, entries 1, 3-7). With p-chloroacetophenone, it
-
2
was possible to decrease the catalyst loading to 10 mol
Pd by just increasing the reaction temperature from
%
1
%
-
2
30 °C (0.1 mol % Pd, 86% yield, 2 h) to 160 °C (10 mol
Pd, 47% yield, 1 h). ortho-Substituted chlorides such
as 2-chlorobenzonitrile reacted very efficiently with both
phenylboronic acid and p-tolylboronic acid, producing,
with the latter, 2-cyano-4′-methylbiphenyl, a key inter-
mediate in the syntheses of angiotensin II receptor
antagonists that are used for the treatment of hyperten-
sion.35 Chloro-substituted heteroarylic derivatives such
as 3-chloropyridine and 2-methyl-4,5-dichloro-3(2H)-py-
ridazinone (Table 4, entries 8 and 9), which potentially
could bind to palladium through the nitrogen atom, are
also suitable substrates for the Suzuki coupling reactions.
Deactivated p-chlorotoluene and p-chloroanisole gave the
desired biarylic products in 28% and 40% yields, respec-
tively (Table 4, entries 10 and 11).
The Suzuki palladium-catalyzed methodology was also
extended to the coupling of allylic and benzylic chlorides
with phenylboronic acid, as depicted in Scheme 6. Both
1-chloro-2-methylpropene and 1-chloromethylnaphtha-
lene afforded the corresponding coupled products in
excellent yields and short reaction times under low
catalyst loadings.
a
Reaction conditions: ArCl (2 mmol), PhB(OH)2 (3 mmol),
K2CO3 (4 mmol), 12c, TBAB (20 mol %), DMF/H2O 95:5 (7 mL).
Bath temperature. Determined by GLC on the basis of ArCl
using decane as internal standard. In parentheses, isolated yield
after flash chromatography. Pd(AcO)2 was used as catalyst.
Reaction conditions: ArCl (2 mmol), PhB(OH)2 (3 mmol), K2CO3
4 mmol), 12c, TBAB (20 mol %).
b
c
d
e
(
just 5% in volume, both DMF and NMP gave the best
yields of p-acetylbiphenyl (entries 9 and 10).33 Finally,
the temperature resulted as a decisive factor when
combined with the correct solvent mixture. As seen in
entry 12, when the reaction was carried out at 160 °C in
Finally, diverse symmetrical biphenyls were synthe-
sized in high yields via reductive homocouplings of
different iodobenzenes using complex 12c (0.5-2 mol %
Pd), as depicted in Scheme 7. Using hydroquinone as
additive2 (50 mol %), K CO as base, and DMF at 110
2
DMF/H O 95:5, the yield of product was improved to 99%,
1b
and what is more important, only traces of biphenyl were
detected by GLC analysis of the crude reaction mixture.
After finding the most efficient reaction conditions, the
reactivities of various aryl chlorides in the Suzuki reac-
tions were studied (Scheme 5, Table 4). At this point we
thought it interesting to compare, first of all, the catalytic
efficiencies of oxime-derived palladacycle 12c and more
simple palladium catalysts such as Pd(OAc)
Suzuki couplings of chloroarenes with phenylboronic acid.
As depicted in Table 4, entries 1 and 2, Pd(OAc) (0.1
2
3
°C and in the presence of 12c, iodobenzene was not
efficiently coupled, giving, after 22 h, a modest 48% yield
of biphenyl even when employing high catalyst loadings
(2 mol % Pd). However, in the absence of hydroquinone
2
2
and by employing N,N-diisopropylethylamine as base,
we could reduce the catalyst loading to 0.5 mol % Pd.
Activated and nonactivated iodobenzenes gave the cor-
responding products in short times (5-7 h) and with very
good yields under aerobic conditions (Table 5). The rate
was slower in the case of deactivated substrates such as
2
in the
2
mol %) is less efficient than catalyst 12c (0.1 mol % Pd)
in the coupling of p-chloroacetophenone with phenylbo-
ronic acid in DMF at 130 °C under aerobic conditions.
When using 12c as catalyst precursor, electron-poor
3
4
(34) Dupont has shown that simple palladium catalysts, such as
PdCl (SEt) and Pd(OAc) , are able to catalyze the Suzuki coupling of
2 2 2
p-ciano and p-nitro aryl chlorides under inert atmosphere with low
turnover numbers. See ref 8c.
(
33) The solvent/water ratio has been previously used to control the
(35) Goubet, D.; Meric, P.; Dormoy, J .-R.; Moreau, P. J . Org. Chem.
1999, 64, 4516-4518.
selectivity of the reaction. See ref 8b.
5
592 J . Org. Chem., Vol. 67, No. 16, 2002

Highly Active Oxime-Derived Palladacycle Complexes
Section. Entries 5,4a 8,29 9,40 and 104a from Table 4 have been
previously reported and were characterized by comparisons
of their GC/MS and 1H NMR spectra; their purities were
confirmed by GC analyses. Entries 1, 2, 5, and 6 from Table 5
have been previously reported2 and were characterized by
TABLE 5. Ullm a n n -Typ e Sym m etr ica l Cou p lin g of Ar yl
a
Iod id es Ca ta lyzed by 12c
yieldb
(%)
time
(h)
TOF
-
1
entry
R
TON
(h
)
1b
1
2
3
4
5
6
CH3CO
NO2
Cl
F
H
5
5
5
7
5
7
>99 (99)
>99
100
100
90
95
93
20
20
18
14
19
12
1
comparisons of their GC/MS and H NMR spectra; their
purities were confirmed by GC analyses. Entries 3 and 4 from
Table 5 are commercially available and were characterized by
90
95
93
83 (95)
1
comparisons of their GC/MS and H NMR spectra.
Typ ica l Exp er im en ta l P r oced u r e for Su zu k i Cou p lin g
of Ar yl Br om id es w ith P h en ylbor on ic Acid . A 25-mL
round-bottom flask was charged with 4-bromobiphenyl (2
mmol, 468 mg), phenylboronic acid (3 mmol, 377 mg), potas-
sium carbonate (4 mmol, 553 mg), catalyst 12c (0.0001 mmol,
MeO
83
a
Catalyst loading: 0.5 mol % Pd. b Determined by GLC using
decane as internal standard. In parentheses, isolated yield after
workup (the purity of the crude products after workup was always
1
>
95%, determined by H NMR).
8
2 µg, 0.01 mol % Pd), and 7 mL of toluene. The mixture was
stirred at 110 °C in air, and the reaction progress was analyzed
by GC. After completion, the reaction mixture was poured into
an excess of water and extracted with ethyl acetate (3 × 15
mL). The organic phases were dried, evaporated (15 mmHg),
and washed with hot hexane (3 × 10 mL) to eliminate
triphenylboroxine, yielding 424 mg of pure 1,4-diphenylben-
p-iodoanisole (Table 5, entry 6), but still, a good yield was
obtained without traces of protiodeiodination product.36
A proposed mechanism for this type of homocoupling
reaction involves the oxidation of the tertiary amine by
the palladacycle with formation of a Pd(IV) complex,
zene (92% yield).
1
which after reductive elimination yields the correspond-
En tr y 14, Ta ble 2. Mp (EtOAc) 143 °C; H NMR (CDCl
3
) δ
C NMR
) δ 121.4, 126.9, 127.2, 127.8, 128.76, 128.81, 131.4,
1
3
ing biaryl, an iminium salt, and hydrogen iodide.22
7.29-7.65 (m, 12H), 7.91-7.94 (m, 2H), 8.52 (s, 1H);
CDCl
36.2, 138.9, 140.6, 151.1, 160.2; IR (KBr, cm ) 3054, 3030,
+ 1, 21), 257 (M
00), 256 (M - 1, 52), 153 (16), 152 (46), 1514 (10), 129 (10),
28 (19). HRMS calcd for C19 15N: 257.1204. Found: 257.1204.
En tr y 15, Ta ble 2. Mp (hexane/EtOAc) 57 °C; H NMR
(CDCl ) δ 4.06-4.19 (m, 4H), 5.87 (s, 1H), 7.35-7.63 (m, 9H);
C NMR (CDCl ) δ 65.3, 103.6, 126.9, 127.2, 127.4, 128.8,
36.8, 140.8, 142.2; IR (CH Cl ) 3074, 3026, 2891, 2847, 1388,
(
1
3
-
1
Con clu sion s
1622; GC-EIMS m/ z (rel intensity) 258 (M
+
+
,
+
1
1
In summary, oxime-derived palladacycles 12 represent
a very efficient family of catalyst precursors for the
Suzuki-Miyaura couplings of aryl, allyl, and benzyl
bromides and chlorides with arylboronic acids. Very good
turnover numbers and rates have been obtained under
aerobic conditions for aryl bromides and chlorides. More-
over, we have shown these systems as competent cata-
lysts for the palladium-catalyzed reductive homocou-
plings of different iodoarenes to afford symmetrical
biaryls in excellent yields. The stability of oxime-derived
palladacycles 12 against air, moisture, and temperature
and the fact that they can be synthesized from inexpen-
sive and readily available starting materials using a
straightforward procedure make these complexes very
promising catalysts, and further studies of their ap-
plicability in other organic transformations are currently
under investigation.
H
1
3
1
3
3
1
1
4
1
2
2
+
221, 1077, 981, 951; GC-EIMS m/ z (rel intensity) 226 (M ,
+
7), 225 (M - 1, 67), 181 (36), 167 (15), 165 (26), 155 (13),
54 (100), 153 (28), 152 (43), 151 (11). HRMS calcd for
C
15
H
14
O
2
: 226.0994. Found: 226.0958.
Typ ica l Exp er im en ta l P r oced u r e for Su zu k i Cou p lin g
-3
Usin g Less Th a n 10 m ol % P d . A reaction tube of the
carousel reaction equipment was charged with 4-bromoac-
etophenone (2 mmol, 406 mg), phenylboronic acid (3 mmol,
3
77 mg), decane (2 mmol, 390 µL), potassium carbonate (4
-
3
mmol, 553 mg), catalyst 12c (333 µL of a solution, 2.45 × 10
mg of 12c/mL of toluene), and 4 mL of DMF. The mixture was
stirred at 160 °C in air, and the reaction progress was analyzed
by GC.
Typ ica l P r oced u r e for Su zu k i Cou p lin g of Ar yl Br o-
m id es a t Room Tem p er a tu r e. A 25-mL round-bottom flask
was charged with 4-bromoacetophenone (2 mmol, 406 mg),
phenylboronic acid (3 mmol, 377 mg), decane (2 mmol, 390 µL),
potassium hydroxide (4 mmol, 264 mg), catalyst 12c (0.002
mmol, 1.632 mg, 0.2 mol % Pd), and 7 mL of toluene. The
mixture was stirred at room temperature in air, and the
reaction progress was analyzed by GC. After completion, the
product was isolated by pouring the reaction mixture into an
excess of water and extracting the aqueous phase with ethyl
acetate (3 × 15 mL). The organic phases were dried and
evaporated (15 mmHg) to afford 390 mg (>99% yield) of pure
Exp er im en ta l Section
Gen er a l. The reagents and solvents were obtained from
commercial sources and were generally used without further
purification. Gas chromatographic analyses were performed
on a GLC instrument equipped with a fused silica capillary
1
column. H NMR spectra were recorded on a 300 MHz
apparatus. Chemical shifts are in ppm using tetramethylsilane
TMS, 0.00 ppm) as internal standard. 1 C NMR spectra were
3
(
3 3 3
recorded at 75 MHz with CDCl or CD COCD as the internal
1
reference. The catalysts were weighed in an electronic micros-
cale with a precision of 1 µg. IR data were collected on an FTIR
apparatus. The reactions were set up in parallel with the aid
of carousel reaction equipment equipped with gastight threaded
caps with a valve, cooling reflux head system, and digital
product ( H NMR).
Typ ica l P r oced u r e for Su zu k i Cou p lin g of Ar yl Ch lo-
r id es w ith Ar ylbor on ic Acid s. A 25-mL round-bottom flask
was charged with 4-chloroacetophenone (2 mmol, 267 µL),
phenylboronic acid (3 mmol, 377 mg), decane (2 mmol, 390 µL),
4
a
17
17
37
4a
4a
38
temperature controller. Entries 1, 4, 5, 6, 7, 8, 10,
1
2
1
39
38
1, 12, and 13 from Table 2 have been previously reported
(
37) Lipshutz, B. H.; Sclafani, J . A.; Blomgren, P. A. Tetrahedron
and were characterized by comparisons of their GC/MS and
2
000, 56, 2139-2144.
(38) Matsura, H.; Tsuchiya, T.; Imafuku, K. Bull. Chem. Soc. J pn.
1
H NMR spectra; their purities were confirmed by GC analy-
ses. For entries 14 and 15 (new compounds), see Experimental
1983, 56, 3519-3520.
(39) Dyer, U. C.; Shapland, P. D.; Tiffin, P. D. Tetrahedron Lett.
2
001, 42, 1765-1767.
(40) Maes, B. U. W.; R’kyek, O.; Ko sˇ mrlj, J .; Lemi e` re, G. L. F.;
(36) Palladium-catalyzed Ullmann-type couplings are usually run
under inert atmosphere in order to avoid side reactions such as
protiodehalogenation of the starting material. See refs 21 and 22.
Esmans, E.; Rozenski, J .; Dommisse, R. A.; Haemers, A. Tetrahedron
2001, 57, 1323-1330.
J . Org. Chem, Vol. 67, No. 16, 2002 5593

Alonso et al.
potassium carbonate (4 mmol, 553 mg), tetrabutylammonium
bromide (0.4 mmol, 129 mg), catalyst 12c (0.001 mmol, 816
µg, 0.1 mol % Pd), and 4 mL of the mixture DMF/H O 95:5.
2
The reaction was stirred at 130 °C in air, and the reaction
progress was analyzed by GC. The reaction mixture was
poured into an excess of water and extracted with ethyl acetate
tive. A 25-mL round-bottom flask was charged with iodoben-
zene (2 mmol, 228 µL), hydroquinone (1 mmol, 110 mg), decane
(2 mmol, 390 µL), potassium carbonate (2 mmol, 277 mg),
catalyst 12c (0.02 mmol, 16.3 mg), and 5 mL of DMF. The
mixture was stirred at 110 °C in air, and the reaction progress
was analyzed by GC. After 22 h, the reaction mixture was
poured into an excess of water and extracted with ethyl acetate
(
3 × 15 mL). The organic extracts were dried and evaporated
1
(15 mmHg) to afford the crude product in a 91% yield (pure
(3 × 15 mL). GC analyses of the organic extracts showed 50%
by H NMR).
conversion of the iodobenzene versus the internal standard.
Typ ica l Exp er im en ta l P r oced u r e for Su zu k i Cou p lin g
of Ben zyl Ch lor id es w ith P h en ylbor on ic Acid . A 25-mL
round-bottom flask was charged with 1-chloromethylnaphtha-
lene (2 mmol, 333 µL), phenylboronic acid (3 mmol, 377 mg),
decane (2 mmol, 390 µL), potassium carbonate (4 mmol, 553
mg), tetrabutylammonium bromide (0.4 mmol, 129 mg), cata-
lyst 12c (0.001 mmol, 816 µg, 0.1 mol % Pd), and 4 mL of the
Typ ica l Exp er im en ta l P r oced u r e for Ullm a n n Hom o-
cou p lin g of Ar yl Iod id es Usin g a Ter t ia r y Am in e a s
Ba se. A 25-mL round-bottom flask was charged with 4-io-
doacetophenone (2 mmol, 492 mg), diisopropylethylamine (4.8
mmol, 822 µL), decane (2 mmol, 390 µL), catalyst 12c (0.005
mmol, 4.079 mg), and 4 mL of DMF. The mixture was stirred
at 110 °C for 5 h. Then the reaction mixture was poured into
an excess of water, extracted with ethyl acetate (3 × 15 mL),
2
mixture DMF/H O 95:5. The reaction was stirred at 130 °C in
air, and the reaction progress was analyzed by GC. When
completed, the reaction mixture was poured into an excess of
water and extracted with ethyl acetate (3 × 15 mL). The
organic extract was dried and evaporated (15 mmHg) to afford
and washed with H
2
O (4 × 10 mL). The organic extracts were
dried and evaporated (15 mmHg) to afford the crude product
1
in a >99% yield (pure by H NMR).
1
the crude product in a 98% yield (pure by H NMR).
Typ ica l Exp er im en ta l P r oced u r e for Su zu k i Cou p lin g
of Allyl Ch lor id es w ith P h en ylbor on ic Acid . A 25-mL
round-bottom flask was charged with 3-chloro-2-methylpro-
pene (2 mmol, 205 µL), phenylboronic acid (3 mmol, 377 mg),
decane (2 mmol, 390 µL), potassium carbonate (4 mmol, 553
mg), tetrabutylammonium bromide (0.4 mmol, 129 mg), cata-
lyst 12c (0.001 mmol, 816 µg, 0.1 mol % Pd), and 4 mL of the
Ack n ow led gm en t. This work has been supported
by the DGES of the Spanish Ministerio de Educaci o´ n y
Cultura (MEC) (PB97-0123). D.A.A. thanks MEC for
contracts under the program Acciones para la Incorpo-
raci o´ n a Espa n˜ a de Doctores y Tecn o´ logos and under
the program Ram o´ n y Cajal. M.C.P. thanks Generalitat
Valenciana for a predoctoral fellowship.
2
mixture DMF/H O 95:5. The mixture was stirred at 130 °C in
air, and the reaction progress was analyzed by GC. After
completion, the reaction mixture was poured into an excess of
water and extracted with ethyl acetate (3 × 15 mL). The
organic extracts were dried and evaporated (15 mmHg) to
afford the crude product in a >99% yield (pure by H NMR).
Typ ica l Exp er im en ta l P r oced u r e for Ullm a n n Hom o-
cou p lin g of Ar yl Iod id es Usin g Hyd r oqu in on e a s Ad d i-
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for new compounds (Table 2, entries 14 and 15). This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
J O025619T
5
594 J . Org. Chem., Vol. 67, No. 16, 2002