Water-mediated catalyst preactivation: An efficient protocol for C-N cross-coupling reactions

Article abstract of DOI:10.1021/ol801285g

(Figure Presented) A protocol for forming a highly active Pd(O) catalyst from Pd(OAc)₂, water, and biaryldialkylphosphine ligands has been developed. This protocol generates a catalyst system, which exhibits excellent reactivity and efficiency in the coupling of a variety of amides and anilines with aryl chlorides.

Full text of DOI:10.1021/ol801285g

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3505-3508
Water-Mediated Catalyst Preactivation:
An Efficient Protocol for C-N
Cross-Coupling Reactions
Brett P. Fors, Philipp Krattiger, Eric Strieter, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Room 18-490,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received June 6, 2008
ABSTRACT
A protocol for forming a highly active Pd(0) catalyst from Pd(OAc)2, water, and biaryldialkylphosphine ligands has been developed. This
protocol generates a catalyst system, which exhibits excellent reactivity and efficiency in the coupling of a variety of amides and anilines with
aryl chlorides.
Over the past decade great progress has been made in
improving the efficiency and applicablilty of palladium-
catalyzed C-N cross-coupling reactions.1 Despite these
recent advances, many limitations of these methods remain.
We have previously shown that biaryldialkylphosphines, of
which 1 (Figure 1) is prototypical,2 are excellent supporting
ligands in C-N cross-coupling processes. We now disclose
a procedure that helps to maximize the efficiency of these
ligands when used with a Pd(II) precatalyst.
The formation of an active LnPd(0) complex is most
Figure 1. Dialkylbiarylphosphine ligands.
commonly accomplished in one of the following ways: (1)
use of a Pd(0) source such as Pd2(dba)3,3 (2) use of
[(allyl)PdCl]2,4 (3) reduction of a Pd(II) salt [e.g., Pd(OAc)2]
using PhB(OH)2,2 a tertiary amine,5 a tertiary phosphine,6
(1) (a) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In
The Chemistry of Anilines Part 1; Rappoport, Z., Ed.; Wiley-VCH:
Weinheim, 2007; p 455. (b) Buchwald, S. L.; Mauger, C.; Mignani, G.;
Scholz, U. AdV. Synth. Catal. 2006, 348, 23. (c) Schlummer, B.; Scholz,
U. AdV. Synth. Catal. 2004, 346, 1599. (d) Jiang, L.; Buchwald, S. L. In
Metal-Catalyzed Cross-Coupling, 2nd ed.; de Meijere, A., Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004; p 699. (e) Hartwig, J. F. In Handbook
on Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley-VCH: Weinheim, 2002; p 1051.
(3) Ito, T. S.; Hasegawa, S.; Takahashi, Y.; Ishii, Y. J. Organomet.
Chem. 1974, 73, 401.
(4) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.; Stevens,
E. D.; Nolan, S. P. Organometallics 2002, 21, 5470.
(5) Trzeciak, A. M.; Ciunik, Z.; Ziolkowski, J. J. Organometallics 2002,
21, 132.
(2) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(6) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992,
11, 3009.
10.1021/ol801285g CCC: $40.75
Published on Web 07/12/2008
2008 American Chemical Society

that a highly active catalyst could be generated by heating
the Pd(OAc)2 (1 mol %), water (4 mol %), and 1 (3 mol %)
for 1 min at 80 °C in 1,4-dioxane. The activation could be
monitored visually by color change as shown in Figure 2.
Scheme 1. Water-Promoted Activation of Pd(OAc)2
or an amine substrate,1 or (4) employment of a single
component precatalyst.7 These methods all have deficiencies
when used with biaryldialkylphosphine ligands. Although
Pd2(dba)3 has been shown to work well in combination with
1 in many instances,2 diminished reactivity is observed due
to the coordination of the dba to the palladium; this is a well-
known consequence of using dba-containing precatalysts.8
Attempts to use [(allyl)PdCl]2 have not proven to be
productive with dialkylbiarylphosphine ligands. Reduction
of Pd(OAc)2 with 1 is slow due to the steric hindrance of
the ligand, and initial results show that the use of tertiary
amines or PhB(OH)2 as reducing agents gives slow formation
of the active LnPd(0) catalyst. Lastly, reduction of Pd(OAc)2
works well with primary or secondary amine substrates that
have ꢀ-hydrogens. However, when nonreducing nucleophiles
such as anilines or amides are used, formation of LnPd(0) is
inefficient.
Figure 2. Visualization of water-mediated preactivation. Conditions:
Pd(OAc)2 (0.01 mmol), 1 (0.03 mmol), H2O (0.04 mmol), 1 mL
1,4-dioxane, 80 °C.
The resulting green catalyst solution11 could then be trans-
ferred into a reaction vessel containing the substrates and
base. Figure 3 shows the reaction of aniline and 4-chloro-
Because of these deficiencies, we set out to develop a
protocol that utilized water and 1 to reduce Pd(OAc)2 and
generate the active LnPd(0) complex. This type of activation
was first reported in 1992 by Ozawa and Hayashi, in which
they were able to reduce Pd(OAc)2 in the presence of 3 equiv
of BINAP.9 They disclosed that in the absence of water the
reduction did not proceed; however, by adding extra equiva-
lents of water the rate of activation could be accelerated.
This showed that water played a direct role in the formation
of the Pd(0) catalyst. Amatore and Jutand further delineated
a method in which water and several different tertiary
phosphines were employed as reducing agents to form a
Pd(0) complex that underwent oxidative addition to aryl
halides (Scheme 1).10 In their investigations they found that
water converted an intermediate phosphonium salt to the
corresponding phosphine oxide in the reduction of Pd(OAc)2.
We began our studies by seeking out a fast, efficient, and
practical protocol for preactivation of Pd(OAc)2. It was found
Figure 3. Comparison of water-mediated preactivation with several
Pd sources. Conditions: aniline (1.2 mmol), 4-chloroanisole (1.0
mmol), Pd (1 mol %), 1 (2.2 mol %), 1,4-dioxane (1 mL), 80 °C,
2 min.
(7) (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686. (b) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott,
N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. (c) Zim, D.;
Buchwald, S. L. Org. Lett. 2003, 5, 2413. (d) Stambuli, J. P.; Kuwano, R.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41, 4746. (e) Schnyder, A.;
Indolese, A. F.; Studer, M.; Blaser, H. Angew. Chem., Int. Ed. 2002, 41,
3668. (f) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
8677. (g) Andreu, M. G.; Zapf, A.; Beller, M. Chem. Commun. 2000, 2475.
(h) Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301.
(8) (a) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; McGlacken, G. P.;
Weissburger, F.; de Vries, A. H. M.; de Vondervoort, L. S. Chem. Eur. J.
2006, 12, 8750. (b) Mace, Y.; Kapdi, A. R.; Fairlamb, I. J. S; Jutand, A.
Organometallics 2006, 25, 1795. (c) Amatore, C.; Jutand, A. Coord. Chem.
ReV. 1998, 178-180, 511.
anisole utilizing several modes of activation. The water-
mediated preactivation protocol gave a 99% GC yield,
whereas [(allyl)PdCl]2, Pd(OAc)2/PhB(OH)2, and Pd2(dba)3
all resulted in yields lower than 50%. This demonstrates the
(11) (a) Initial 31P NMR experiments were inconclusive as to the
structure of contained Pd species. (b) The activated catalyst solution could
be stored under argon for 24 h at -25 °C with minimal loss in catalyst
activity. (c) When water was added directly to the reaction mixture
containing all of the components (i.e., without preactivation), little or no
activity was observed.
(9) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177.
(10) (a) Amatore, C.; Jutand, A.; Khalil, F. ArkiVoc 2006, 4, 38. (b)
Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254. (c) Amatore,
C.; Carre, E.; Jutand, A.; M’Barki, M. A. Organometallics 1995, 14, 1818.
3506
Org. Lett., Vol. 10, No. 16, 2008

efficiency in which water-mediated preactivation forms the
active catalyst, without the detrimental effects of impeding
ligands (eg., dba).
Table 1. Coupling of Amides With Aryl Chlorides
We next investigated the application of this protocol to
amidation reactions of aryl chlorides. Our research group
recently reported an efficient catalyst system for this
transformation utilizing the combination of Pd2(dba)3 and
ligand 2 (Figure 1). It has been proposed that with biaryl-
dialkylphosphine ligands the rate-limiting step in amidation
reactions is the “transmetallation” (amide binding and/or
deprotonation).12 We postulated that by replacing the
Pd2(dba)3 with a preactivation of Pd(OAc)2 a more active
catalyst system could be achieved, because there would be no
dba present in the reaction to compete for binding at the Pd
center. By heating Pd(OAc)2 (1 mol %), water (4 mol %),
and 2 (3 mol %) for 1.5 min at 110 °C in t-BuOH, a highly
active catalyst was generated for these reactions. For
example, whereas the coupling of either cyclohexanecar-
boxamide or acetamide with 4-chloroanisole using Pd2(dba)3
and 2 previously proceeded in 24 h, water-mediated preac-
tivation decreased the reaction times to 3 h and provided
the products in excellent yields (Table 1, entries 1 and 2).12
We next looked at cross-couplings reactions of amides
with 3-chloropyridine, which have been difficult in the
past.11,13 When the preactivation protocol was employed,
formamide, nicotinamide, and 2-pyrrolidinone were all
successfully coupled with 3-chloropyridine, in 3 h, using 1
mol % Pd (Table 1, entries 3, 4, and 5). Previously, the
reactions with formamide and 2-pyrrolidinone had required
the use of 2 mol % Pd and reaction times of 812 and 24 h,13
respectively. Additionally, the latter case required the addi-
tion of Et3B to achieve good yields.
Having established that the combination of water and 2
efficiently converted Pd(OAc)2 to an active catalyst, we
sought to expand the protocol to include reactions of electron-
deficient anilines. Electron-deficient anilines have been
difficult coupling partners due to their modest nucleophilicity
and intolerance of strong base.7a,14 By performing a preac-
tivation of Pd(OAc)2, 1, and water at 110 °C for 1 min,
electron-deficient 4-nitroaniline and 2-nitroaniline were suc-
cessfully coupled with 4-n-butylchlorobenzene in excellent
yields (Table 2, entries 1 and 2). Other electron-deficient
anilines containing an ester or a cyano group were coupled
as well in excellent yields using the newly developed protocol
(Table 2, entries 3 and 4).
The chemoselectivity of the system was also briefly
explored. Using 2′-aminoacetophenone ketone R-arylation
was completely suppressed and exclusive C-N coupling was
observed (Table 2, entry 5). This selectivity can be attributed
to the high activity of the catalyst achieved utilizing water-
mediated preactivation, which allows for the use of K2CO3.15
a Reaction conditions: 1.5 min preactivation at 110 °C with 4 mol %
H2O, 1 mol % Pd(OAc)2, and 3 mol % 2 in 2 mL/mmol of t-BuOH; 1.0
equiv aryl chloride, 1.2 equiv amide, and 1.4 equiv K2CO3. b Yields represent
isolated yields (average of 2 runs). c 1.5 equiv of amide.
The reaction of 4-aminoacetanilide also showed complete
selectivity for arylation at the free aniline (Table 2, entry
6).2 This catalyst system showed both high activity and
excellent functional group compatibility.
Last, we wanted to examine the applicability of this
protocol for the coupling of anilines at low catalyst loadings.
There are currently very few examples of couplings with
anilines and aryl chlorides below 0.5 mol % catalyst
loading.7a,b,16 Using the preactivation protocol several ex-
amples were performed at 0.05 mol % catalyst loading in
20 min (Table 3). For example, electron-deficient 3-ami-
nobenzotrifluoride and 4-fluoroaniline were successfully
coupled with electron-rich aryl chlorides within 20 min,
affording the products in excellent yields (Table 3, entries 3
and 4).
(12) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 13001.
(13) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734
.
In conclusion, an efficient protocol for C-N cross-
coupling reactions has been described. An active catalyst was
(14) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936
.
(15) It has been shown that R-arylations of ketones usually require a
strong base, except for reactions of particularly acidic carbonyl compounds.
(a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. For an
exception using K3PO4 (not K2CO3) see: (b) Fox, J. M.; Huang, X.; Chieffi,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360.
(16) (a) Xu, C.; Gong, J.; Wu, Y. Tetrahedron Lett. 2007, 48, 1619. (b)
Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees,
A.; Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983
.
Org. Lett., Vol. 10, No. 16, 2008
3507

Table 2. Coupling of Electron-Deficient Anilines
Table 3. Couplings of Anilines at 0.05 mol % Catalyst Loading
a Reaction conditions: 1 min preactivation at 80 °C with 2 mol % H2O,
0.05 mol % Pd(OAc)2, and 0.15 mol % 1 in 1 mL/mmol of 1,4-dioxane;
1.0 equiv aryl chloride, 1.2 equiv amine, and 1.2 equiv NaOt-Bu. b Yields
represent isolated yields (average of 2 runs).
of amides with aryl chlorides. It also gives access to a system
that exhibits both high activity and excellent catalyst stability
in couplings of electron-deficient anilines, and couplings of
anilines at low catalyst loadings. Further studies of other
applications of this protocol are currently ongoing in our
laboratories.
a Reaction conditions: 1 min preactivation at 110 °C with 4 mol %
H2O, 1 mol % Pd(OAc)2, and 3 mol % 1 in 2 mL/mmol of t-BuOH; 1.0
equiv aryl chloride, 1.2 equiv amine, and 1.4 equiv K2CO3. b Yields represent
isolated yields (average of 2 runs). c Reaction time of 2 h. d 2.5 equiv of
K2CO3 was used.
Acknowledgment. We thank the National Institutes of
Health (GM 58160) for financial support of this project. We
thank Merck and BASF [Pd(OAc)2] for additional support.
The Varian NMR instrument used was supported by the NSF
(CHE 9808061 and DBI 9729592).
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
formed by water-mediated preactivation of readily available
Pd(OAc)2 using biaryldialkylphosphine ligands. This new
protocol allowed lower catalyst loadings, shorter reactions
times, and exclusion of additives, such as Et3B, in couplings
OL801285G
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Org. Lett., Vol. 10, No. 16, 2008