Di-2-pyridylmethylamine-based palladium complexes as new catalysts for Heck, Suzuki, and Sonogashira reactions in organic and aqueous solvents

Article abstract of DOI:10.1021/ol0341849

(Matrix presented) A new palladium-dipyridylmethylamine complex is an excellent catalyst for C-C bond-forming processes such as the Heck, Suzuki, and Sonogashira reactions in organic and aqueous solvents under homogeneous conditions.

Full text of DOI:10.1021/ol0341849

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1451-1454
Di-2-pyridylmethylamine-Based
Palladium Complexes as New Catalysts
for Heck, Suzuki, and Sonogashira
Reactions in Organic and Aqueous
Solvents†
,‡
Carmen Na´jera,* Juan Gil-Molto´,‡ Sofia Karlstro1m,‡,§ and Larry R. Falvello|,
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad de Alicante,
Apartado 99, 03080 Alicante, Spain, and Departamento de Qu´ımica Inorga´nica,
Instituto de Ciencias de los Materiales de Arago´n, Facultad de Ciencias,
UniVersidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
cnajera@ua.es
Received February 3, 2003
ABSTRACT
A new palladium−dipyridylmethylamine complex is an excellent catalyst for C−C bond-forming processes such as the Heck, Suzuki, and
Sonogashira reactions in organic and aqueous solvents under homogeneous conditions.
The great importance of palladium-catalyzed carbon-carbon
bond-forming reactions1 has encouraged the chemical com-
munity to search for very active, and at the same time stable,
palladium-based catalysts, which should also be versatile and
efficient systems. This pertains particularly to the vinylation
of aryl halides called the Heck-Mizoroki reaction,2 the cross-
coupling of aryl halides and boronic acids called the Suzuki-
Miyaura reaction,3 and the alkynylation of aryl halides called
the Sonogashira-Hagihara reaction,4 which are “classical”
processes in organic synthesis and material science. Several
goals have to be achieved for industrial applications such as
† Dedicated to the memory of Prof. Antonio Gonza´lez.
‡ Universidad de Alicante.
§ New address: AstraZeneca R&D So¨derta¨lje, S-151 85 So¨derta¨lje,
Sweden.
| Universidad de Zaragoza.
To whom correspondence on the X-ray structure should be adressed.
E-mail: falvello@lrfl.unizar.es.
(2) (a) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001,
57, 7449. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100,
3009. (c) de Meijere, A.; Meyer, F. F. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379.
(1) (a) Tsuji, J. Palladium Reagents and Catalysts Wiley: Chichester,
1995. (b) Applied Homogeneous Catalysis with Organometallic Compounds;
Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 1966; Vols. 1 and
2. (c) Malleron, J. L.; Fiaud, J. C.; Legros, J. Y. Handbook of Palladium-
Catalyzed Organic Reactions; Academic Press: San Diego, 1997. (d) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1988. (e) Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vols. 1 and 2.
(f) Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000. (g) Littke, A. F.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 4176. (h) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.; Wiley: New York,
2002; Vol. 2.
(3) (a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
(b) Suzuki A. J. Organomet. Chem. 1999, 576, 147. (c) Stanforth, S. P.
Tetrahedron 1998, 54, 263. (d) Miyaura, N.; Suzuki, A. In AdVances in
Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI: London, 1998; Vol.
6, pp 187. (e) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(4) (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. (b)
Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions, Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1988; Chapter 5, pp 203-
209. (c) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, pp 521-
549.
10.1021/ol0341849 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/08/2003

the use of aryl chlorides1g as substrates, the possibility of
using aqueous conditions, and the recovery of the catalyst.
Recent notable advances have been achieved by using bulky
phosphanes,5 phophites,6 and phosphane oxides7 as ligands.
Palladium on carbon,8 palladium N-heterocyclic carbene
complexes,9 and palladacycles10 have also been used as
catalysts. We have recently applied oxime-derived pallada-
cycles as very stable and efficient precatalysts in several
cross-coupling processes (even of deactivated aryl chlorides)
in organic solvents (Heck, Suzuki, Stille, Sonogashira,
Ullmann)11 and in aqueous media (Suzuki).12
ketone or oxime, and the amino group can easily be acylated
or anchored to a solid support and will not be involved in
the chelation of palladium. In this letter, we describe the
synthesis and activity of new complexes of type 4 as
homogeneous catalysts in C-C bond-forming reactions not
only in organic solvents but also in aqueous media.
Palladium(II) salts with bidentate P,N-13 and especially
N,N-ligands14 have proven to be efficient catalysts for C-C
and C-N bond-forming reactions. The N-acyl-substituted
dipyridyl-14b and dipyrimidylamines14c,d 1 and 2 form stable
palladium complexes with PdCl2. This type of ligand has
been incorporated into a polymeric matrix via a ROMP
process. All of these complexes present an excellent capacity
for Pd2+ complexation,14a-d and no leaching of Pd was
observed during any type of coupling reaction. Recently,
trans-chelated complexes 3, bearing a bidentate pyridine-
containing ligand, have been described as catalysts for the
Heck olefination of aryl iodides with tert-butyl acrylate under
aerobic conditions but in triethylamine as a solvent.15
The starting amine 617 was prepared from ketone 5 in 78%
overall yield by zinc-mediated reduction of its oxime, and it
was immediately subjected to acylation with acetic anhydride
or with cyclohexyl isocyanate giving ligands 7a and 7b in
88 and 84% yields, respectively. Palladium(II) complexes
4a and 4b were prepared by reaction with H2PdCl4 in 73
and 94% yields, respectively, as described by Buchmeiser
et al.14a-d for complexes 1 and 2 (Scheme 1).
Complexes 4a and 4b are only soluble in very polar
organic solvents such as DMSO or DMF. Complex 4a was
characterized by X-ray analysis (Figure 1) and crystallizes
in the monoclinic space group P21/c with the Pd center in a
square planar enviroment and with unique N-Pd bond
lengths of 2.017 and 2.029 Å. These bonds are slightly
shorter than in complexes 1 (R ) Me, 2.041 and 2.039 Å)
and 2 (R ) Me, 2.031 and 2.048 Å).
Preliminary catalytic studies of complexes 4a and 4b in a
model Heck reaction between iodobenzene and n-butyl
acrylate at 140 °C (bath temperature) in DMF and with Bu3N
as a base showed that they have similar efficiencies (TON
) 105, TOF ) 104 h-1) (Table 1, entries 1 and 2). This
activity was superior to that of other pyridine complexes such
as 1 (TON ) 14 100, TOF ) 156 h-1),14c 2 (TON ) 6600,
TOF ) 91 h-1)14d and 3 (TON ) 8 × 104, TOF ) 1596
h-1)15 and also superior to the activity of PdCl2(PhCN)2
(TON 4790, TOF ) 99 h-1).
Complex 4b was considered to be a more robust catalyst
compared to 4a, especially for working under aqueous
conditions at high temperatures. First, the Heck reaction was
studied with iodo-, bromo-, and chlorobenzene together with
acrylates or p-chlorostyrene as olefinic counterparts. The
reactions with acrylates were performed in DMF, NMP/H2O
(3/1), and H2O. Diisopropylamine was used as a base under
The activity of homogeneous catalysts 1-3 for the Heck
reaction was only demonstrated in organic solvents. Polymer-
supported reagents derived from complexes 1 and 2 showed
greater activity than the monomeric complexes in Heck,
Suzuki, and Sonogashira reactions even with chlorobenzene
as a substrate.14a-d To study the activity of less-electron-
rich ligands, we focused our attention on the 2,2-dipyridyl-
methylamine-based palladium complexes 4.16 The ligand can
be easily prepared from commercially available di-2-pyridyl
(5) For selected examples, see: (a) Old, D. W.; Wolfe, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1998, 120, 9722. (b) Wolfe, J. P.; Singer, R. A.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. (c) Bei,
X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen, J. L. J. Org.
Chem. 1999, 64, 6797. (d) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
1998, 37, 3387. (e) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
6989. (f) Andreu, M. G.; Zapf; Beller, M. Chem. Commun. 2000, 2475. (g)
Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001, 1540. (h) Schnyder,
A.; Indolese, A. F.; Studer, M.; Blaser, H. U. Angew. Chem., Int. Ed. 2002,
41, 3668.
(6) Zapf, A. Beller, M. Chem. Eur. J. 2000, 6, 1830.
(7) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513.
(8) Heidenreich, R. G.; Ko¨lher, K.; Krauter, J. G. E.; Pietsch, J. Synlett
2002, 1118.
(9) For a recent review see: Herrmann, W. A. Angew. Chem., Int. Ed.
2002, 41, 1290.
(10) Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem. 2001, 1917.
(11) (a) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. Org. Lett. 2000, 2,
1823. (b) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. AdV. Synth. Catal.
2002, 344, 172. (c) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. J. Org. Chem.
2002, 67, 5588. (d) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. Tetrahedron
Lett. 2002, 43, 9365.
(12) (a) Botella, L.; Na´jera, C. Angew. Chem., Int. Ed. 2002, 41, 179.
(b) Botella, L.; Na´jera, C. J. Organomet. Chem. 2002, 663, 46.
(13) (a) Reddy, K. R.; Surekha, K.; Lee, G.-H.; Peng, S.-M.; Liu, S.-T.
Organometallics 2000, 19, 2637.
(14) (a) Sinner, F.; Buchmeiser, M. R.; Tessadri, R.; Mupa, M.; Wurst,
K.; Bonn, G. K. J. Am. Chem. Soc. 1998, 120, 2790. (b) Buchmeiser, M.
R.; Wurst, K. J. Am. Chem. Soc. 1999, 121, 11101. (c) Silberg, J.; Schareina,
T.; Kempe, R.; Wurst, K.; Buchmeiser, M. R. J. Organomet. Chem. 2001,
622, 6. (d) Buchmeiser, M. R.; Schareina, T.; Kempe, R.; Wurst, K. J.
Organomet. Chem. 2001, 634, 39. (e) Mubofu, E. B.; Clark, J. H.;
Macquarrie, D. J. Green Chem. 2001, 3, 1077.
(16) During the preparation of this manuscript, a report appeared
describing the synthesis of modified enzymes for mutagenesis studies by
attachment of papain and palladium complexes of type 4 derived from maleic
anhydride and dipyridylmethylamine: Reetz, M. T.; Rentzsch, M.; Pletsch,
A.; Maywald, M. Chimia 2002, 56, 721.
(15) Kawano, T.; Shinomaru, T.; Ueda, I. Org. Lett. 2002, 4, 2545.
(17) Krapcho, A. P.; Powell, J. R. Tetrahedron Lett. 1986, 27, 3713.
1452
Org. Lett., Vol. 5, No. 9, 2003

Table 1. Heck Coupling Reactions Catalyzed by 4a
entry
R
Hal
mol % Pd
solvent
DMF
DMF
NMP/H2Oe
H2O
DMF
NMP/H2Oe
H2O
DMF
NMP/H2Oe
H2O
base
additive
T (°C)b
t (h)
yield (%)c,d
TON
105
105
74 000
105
9000
TOF (h-1
)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CO2Bun
CO2Bun
CO2But
I
I
I
I
Br
Br
Br
I
I
I
4a (0.001)
4b (0.001)
4b (0.001)
4b (0.001)
4b (0.01)
4b (0.01)
4b (0.01)
4b (0.01)
4b (0.01)
4b (0.01)
4b (0.01)
4b (0.01)
4b (0.01)
4b (0.5)
Bu3N
Bu3N
140
140
140
140
140
140
140
140
160
140
160
160
160
160
4
5
142
142
19
>99 (99)
>99 (89)
74
>99f
90
93
98 (78)f
2.5 × 104
2 × 104
i-Pr2NH
i-Pr2NH
Bu3N
i-Pr2NH
i-Pr2NH
Bu3N
i-Pr2NH
i-Pr2NH
K2CO3
i-Pr2NH
i-Pr2NH
i-Pr2NH
521
CO2But
704
473
101
62
CO2Bun
CO2But
TBAB
TBAB
TBAB
92
158
9300
9800
CO2But
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
32
31
116
47
110
150
>99 (97)g
95h
77i
97j (81)k
12
40l (34)m
104
312
306
66
206
11
9500
7700
9700
1200
80
Br
Br
Br
Cl
DMF
TBAB
TBAB
TBAB
TBAB
NMP/H2Oe
H2O
NMP/H2Oe
a Reaction conditions: 1.0 equiv of ArHal, 1.5 equiv of alkene, 3 equiv of DIA or 1.4 equiv of Bu3N, and 0.5 equiv of TBAB. b Bath temperature.
c Determined by GC, based on the ArHal using decane as an internal standard. d In parentheses isolated yield after flash chromatography. e Mixture (3/1).
f Cinnamic acid was isolated. g 1-(4-Chlorophenyl)-1-phenylethene (2%) was also obtained. h Mixture of regioisomers (13:1). i Mixture of regioisomers
(29:1). j 1-(4-Chlorophenyl)-1-phenylethene (8%) was also obtained. k Mixture of regioisomers (15:1). l Mixture of regioisomers (3:11). m 1-(4-Chlorophenyl)-
1-phenylethene (5%) was also obtained.
aqueous conditions in order to avoid ester hydrolysis. In the
case of bromo- or chlorobenzene, tetrabutylammonium
bromide (TBAB) had to be added. In the case of iodobenzene
(Table 1, entries 2-4 and 8-10), TON of 105 was achieved
for acrylates and 104 for p-chlorostyrene. For bromobenzene
10-2 mol % catalyst 4b was used (Table 1, entries 5-7 and
11-13). In the arylation reactions of p-chlorostyrene a small
amount of the regioisomer 1-(p-chlorophenyl)-1-phenyleth-
ylene was obtained in some cases (Table 1, entries 10-13).
Chlorobenzene only reacted with p-chlorostyrene in NMP/
H2O at 160 °C using 0.5 mol % catalyst, giving a 3:11
mixture of the two regioisomers, p-chlorostilbene and 1-(p-
chlorophenyl)-1-phenylethylene (Table 1 entry 14). For the
preparation of cinnamate, the alkenylation took place faster
in DMF than in aqueous solvents. However, for stilbene
formation, the use of aqueous solvents gave better results.
Cross-coupling reactions of aryl bromides or chlorides with
phenylboronic acid were carried out with K2CO3 as a base
in DMF/H2O (95/5) at 110 °C (Table 2, entries 1, 6, and 8)
or under reflux in water (Table 2, entries 2, 4, 7, and 9).
The reaction with aryl chlorides had to be run in the presence
of TBAB as an additive. In general, reactions in water took
place faster and more efficiently. In the case of 4-bromo-
phenol and 4-chloroaniline, couplings in DMF/H2O failed.
Alternatively, the reaction can be performed in MeOH/H2O
(2/3) at room temperature (Table 2, entries 3 and 5). In
general, better results were obtained in water as a solvent.
Scheme 1. Synthesis of Dipyridylmethylamine-Based
Palladium Complexes 4
Figure 1. X-ray structure of complex 4a.
Org. Lett., Vol. 5, No. 9, 2003
1453

Table 2. Suzuki Coupling Reactions Catalyzed by Complex 4ba
entry
R
Hal
mol % Pd
solvent
T (°C)b
t (h)
yield (%)c,d
TON
8700
TOF (h-1)
1
2
3
4
5
6
7
8
9
4-MeCO
4-MeCO
4-MeCO
4-OH
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
0.01
0.001
0.2
0.00076
0.1
1
0.1
0.1
0.1
1
DMF/H2Oe
H2O
MeOH/H2Of
110
100
rt
100
rt
110
100
130
100
130
100
3.5
1
6
2
120
48
17
120
7.5
87
>99 (91)
82
95 (82)
75
96 (84)
37
2486
105
41
62 500
6.25
2
105
68
125 000
6
H2O
4-OH
MeOH/H2Of
DMF/H2Oe
H2O
4-Me2N
4-Me2N
4-MeCO
4-MeCO
4-NH2
96
370
880
103
22
7
133
DMF/H2Oe
H2Og
DMF/H2Oe
H2Og
88 (69)
>99
10
11
4-NH2
1
7.5
73 (52)
73
10
a Reaction conditions: 1.0 equiv of ArHal, 1.5 equiv of phenylboronic acid, and 2 equiv of base. b Bath temperature for aqueous DMF. c Determined by
GC, based on the ArHal using decane as an internal standard. d In parentheses is shown the isolated yield after flash chromatography. e Mixture (95/5).
f Mixture (2/3) and KOH as a base. g TBAB (0.5 equiv) was added.
Table 3. Sonogashira Coupling Reactions Catalyzed by 4ba
entry
R1
Cl
Hal
R2
Ph
Ph
Ph
mol % Pd
solvent
base
TBAA
pyrrolidine
TBAA
pyrrolidine
TBAA
pyrrolidine
TBAA
additive
T (°C)b
t (h)
yield (%)c,d
TON
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
Br
Br
Br
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
NMP
H2O
NMP
H2O
NMP
H2O
NMP
H2O
H2O
110
100
110
100
110
100
110
100
100
1
6
1
97e (88)
>99
96 (71)
>99f
970
103
960
103
970
890
345
480
500
Cl
TBAB
TBAB
TBAB
MeO
MeO
Cl
MeO
Cl
Ph
7
n-C4H9
i-Pr3Si
Ph
Ph
Ph
1.5
17
2
4
50
97g (88)
89h (65)
69i (59)
96j
Cl
Me
pyrrolidine
pyrrolidine
TBAB
TBAB
>99k (76)
a Reaction conditions. (a) In NMP: 1.0 equiv of ArHal, 1.5 equiv of alkyne, 1.5 equiv of TBAA, 110 °C. (b) In H2O: 1.0 equiv of ArHal, 1.5 equiv of
alkyne, 2 equiv of pyrrolidine, 1 equiv of TBAB, 100 °C. b Bath temperature in the case of NMP. c Determined by GC, based on the ArHal using decane
as an internal standard. d In parentheses is the isolated yield after flash chromatography. e Diyne (6%). f Diyne and enyne (8%). g Diyne and enyne (<2%).
h Diyne and enyne (10%). i Diyne and enyne (8%). j Diyne and enyne (20%). k Enyne (20% ) due to the addition of 1 equiv of phenylacetylene after 1 day.
The Sonogashira coupling of iodo and bromoarenes with
terminal acetylenes in organic solvents could be carried out
under the copper- and amine-free conditions we set up
recently for oxime-derived palladacycles.11d The reaction was
performed in NMP with tetrabutylammonium acetate (TBAA)
as a base at 110 °C (Table 3, entries 1, 3, 5, and 7). When
this alkynylation reaction was carried out in refluxing water,
pyrrolidine (2 equiv) as a base and TBAB (0.5 equiv) as an
additive were used (Table 3, entries 2, 4, 6, 8, and 9). As
secondary products, some amounts of diyne and enyne
corresponding to the homocoupling of the starting alkyne
were obtained due to the use of an excess of acetylene. In
general, reactions were faster in NMP than in water.
their versatility as catalysts as well as on reusability through
the utilization of an appropriate solid support are underway.
Acknowledgment. We thank DGES of the Spanish
Ministerio de Ciencia y Tecnologia (MCyT) (BQU2001-
0724-C02-01 and BQU2002-00554) for financial support.
S.K. thanks the Stiftelsen Bengt Lundquists minne (Sweden),
the Swedish Institute, and the Spanish Ministerio de Asuntos
Exteriores for postdoctoral fellowships. J.G.M. thanks MCyT
for a predoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures for the synthesis of palladium complexes 4 and
catalytic processes and data for the X-ray structure of
compound 4a (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, dipyridylmethylamine-based palladium
complexes are stable catalysts for different types of carbon-
carbon bond-forming reactions, which can be carried out in
air and in organic or aqueous solvents. Further studies on
OL0341849
1454
Org. Lett., Vol. 5, No. 9, 2003