Buchwald-Hartwig aminations of aryl chlorides: A practical protocol based on commercially available Pd(0)-NHC catalysts

Article abstract of DOI:10.1055/s-2004-837205

Commercially available, air- and water-stable naphthoquinone imidazolin-2-ylidene-palladium(0) complexes were found to be highly active one-component catalysts for the amination of aryl halides. With these very robust catalysts, the expensive bases Cs₂CO₃ or NaOt-Bu traditionally used can be replaced by KOH. A convenient reaction protocol has been developed for the coupling of a wide range of aryl chlorides with primary or secondary amines.

Full text of DOI:10.1055/s-2004-837205

LETTER
275
Buchwald–Hartwig Aminations of Aryl Chlorides: A Practical Protocol Based
on Commercially Available Pd(0)-NHC Catalysts
B
uchwald–Hart
.
w
ig Aminati
J
ons of
A
r
.
a
Rheinisch-Westfälische Technische Hochschule Aachen, Professor Pirlet Str. 1, 52074 Aachen, Germany
E-mail: goossen@oc.rwth-aachen.de
b
c
Max-Planck Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
UMICORE AG & Co KG, P. O. Box 1351, 63403 Hanau, Germany
Received 15 October 2004
In fond memory of Martin Rentzsch
room temperature conversion of deactivated aryl chlo-
rides.2,3 However, the reaction protocols usually involve
air-sensitive, electron-rich ligands. Another common
disadvantage of the existing methods is the use of expen-
Abstract: Commercially available, air- and water-stable naphtho-
quinone imidazolin-2-ylidene-palladium(0) complexes were found
to be highly active one-component catalysts for the amination of
aryl halides. With these very robust catalysts, the expensive bases
Cs2CO3 or NaOt-Bu traditionally used can be replaced by KOH. A sive bases with a high molecular weight, i.e. Cs2CO3 or
convenient reaction protocol has been developed for the coupling of
a wide range of aryl chlorides with primary or secondary amines.
NaOt-Bu.
For applications in drug discovery and large-scale manu-
facture, a generally applicable process featuring an easy-
Key words: carbene ligands, amination, palladium, aryl chlorides
to-handle one-component catalyst system in combination
with an inexpensive base would be highly desirable. As
Within a few years after its discovery, the Buchwald–
Hartwig amination or aryl halides has become the method
of choice for the synthesis of functionalized aryl amines.1
Systematic studies have led to the development of highly
active catalyst systems, some of them allowing even the
catalysts, Pd(0) complexes with N-heterocyclic carbene
(NHC) ligands4 appeared to be the most promising, since
they have displayed potent catalytic activity in Buch-
wald–Hartwig aminations,5 and are particularly insensi-
tive against oxygen. However, the generation of the
Figure 1 Preformed Pd(0)monocarbene complexes
SYNLETT 2005, No. 2, pp 0275–0278
0
1.
0
2.
2
0
0
5
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-837205; Art ID: G41504ST
© Georg Thieme Verlag Stuttgart · New York

276
L. J. Gooßen et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa
catalytically active species – presumably monoligated,
coordinatively highly unsaturated Pd(0) complexes –
from Pd(II)-NHC precursors was often found to be
troublesome.4
Entry Catalyst
Solvent
Dioxane
Dioxane
Dioxane
Base
Yield (%)
1
2
3
PdOAc2
Pd(dba)2
NaOt-Bu
NaOt-Bu
NaOt-Bu
0
0
0
In this respect, preformed Pd(0)-NHC complexes 1–4
should be advantageous, since the desired Pd(0) species
are accessible simply by dissociation of a naphthoquinone
or divinylsiloxane ligand (Figure 1). The complexes are
easily accessible,6 stable against air and water, and have
recently become commercially available on a large scale.
They have also been demonstrated to show high reactivity
in Suzuki,6 Heck,6,7 Kumada8 and telomerization reac-
tions.9
Pd(dba)2/
PPh3
4
5
Pd(dba)2/
o-biph-P(t-Bu)2
Dioxane
Dioxane
NaOt-Bu
NaOt-Bu
47
96
Pd(dba)2/
o-biph-PCy2
6
7
1
2
3
4
4
4
4
4
4
4
4
4
4
4
4
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
NMP
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
Na2CO3
Cs2CO3
K3PO4
NaOH
KOH
<10
95
<10
96
0
In order to develop a convenient reaction protocol for
Buchwald–Hartwig aminations based on these complex-
es, we chose the coupling of morpholine with p-chloroani-
sole, a particularly unreactive aryl halide, as the model
reaction (Scheme 1).10 The results of our screening exper-
iments are summarized in Table 1.
8
9
10
11
12
13
14
15b
16c
17d
18
19
20
0
0
42
96
60
72
66
20
81
76
Scheme 1 Pd-catalyzed amination of p-chloroanisole with morpho-
line
KOH
Using NaOt-Bu as base, no conversion was observed with
Pd(OAc)2, Pd(dba)2 and Pd(dba)2/PPh3 (Table 1, entries
1–3), while state-of-the-art catalyst systems with the elec-
tron rich, sterically hindered phosphines 2-(di-tert-bu-
KOH
KOH
KOH
tylphosphino)biphenyl
[o-biph-P(t-Bu)2]
and
2-
(dicyclohexylphosphino)-biphenyl (o-biph-PCy2) showed
the expected high reactivities (entries 4, 5). Under these
conditions, the preformed Pd(0)-NHC complexes 1 and 3
bearing mesitylene substituents gave unsatisfactory
yields. In contrast, near quantitative yields were obtained
with the sterically crowded 2,6-diisopropyl containing
complexes 2 and 4 (entries 6–9). For this model reaction,
the performance of the naphthoquinone-1,3-bis(2,6-diiso-
propylphenyl)imidazole-2-ylidene-palladium(0) (4) fully
matches that of the above-mentioned high-tech systems
(entries 5, 9).
KOH
Diglyme
KOH
a Conditions: 1.00 mmol p-chloroanisole, 1.50 mmol morpholine,
1 mol% Pd source, 2 mol% ligand, 3.00 mmol base, 16 h, 100 °C, GC
yields using n-tetradecane as internal standard.
b 1.30 mmol base.
c At 80 °C.
d At 60 °C.
tive turnover was achieved at 100 °C within 16 hours, but
even at lower temperatures, good yields were obtained
(entries 14, 16–17).
To further improve the reaction protocol, we investigated
if with catalyst 4, standard, inexpensive bases could re-
place sodium tert-butoxide. For this particular test reac-
tion with a strongly basic amine, carbonate and phosphate
bases were ineffective (entries 10–12). In contrast, simple
alkali hydroxides gave excellent results (entries 13, 14).11
Near quantitative yields were obtained with standard
grade potassium hydroxide, especially when used in ex-
cess (see entry 15). Surprisingly, the natural water content
of this base (>15%) did not impede the reaction.
Having established a practical reaction protocol, we went
on to investigate the scope of the transformation using dif-
ferent aryl chlorides 5a–h in combination with various
amines 6a–j (Scheme 2). Selected results are summarized
in Table 2.
Among the solvents tested, dioxane and NMP were the
most effective, while in non-polar solvents such as tolu-
ene, only modest yields were obtained (entries 14, 18–20).
For the comparatively unreactive substrate 5a, quantita- Scheme 2 Scope of the transformation using catalyst 4
Synlett 2005, No. 2, 275–278 © Thieme Stuttgart · New York

LETTER
Buchwald–Hartwig Aminations of Aryl Chlorides
277
Table 2 Scope of the Reactiona
Entry
1
Compound
Yield (%)
83
Entry
11
Compound
Yield (%)
89
2
3
95
95
12
13
75c
79
67
4
27 (48)b
14
5
6
7
47
62
81
15
16
17
85
47c
90
8
93 (83)d
18
73
9
25
19
20
88
10
55b
88b
a Conditions: 1.00 mmol aryl chloride, 1.50 mmol amine, 0.50 mol% 4, 3.00 mmol KOH, 4 mL dioxane, 100 °C, 16 h, isolated yields.
b With NaOt-Bu as base.
c <10% Bisarylated product.
d 30.0 mmol aryl chloride, 40.0 mmol amine, 0.05 mol% 4, 75.0 mmol KOH, 40 mL dioxane.
Catalyst 4 shows high activity for both electron rich and yields (entries 4, 9), and hydrolytically unstable mole-
electron poor aryl and heteroaryl chlorides, and even ster- cules are not suitable. For such substrates, the use of an-
ically hindered derivatives are converted in excellent hydrous bases such as NaOt-Bu led to much higher yields
yields. The high efficiency of the catalyst system is dem- (entries 4, 10, 20).
onstrated by the formation of the sterically crowded bis-
(2,6-dimethylphenyl)amine (entry 15). Several functional
groups are tolerated (entries 2, 4, 9, 14). However, with
KOH as the base, enolizable ketones give only modest
The protocol is equally suitable for primary and secondary
aromatic and aliphatic amines. By-products from b-hy-
dride elimination, often an issue with aliphatic amines and
Synlett 2005, No. 2, 275–278 © Thieme Stuttgart · New York

278
L. J. Gooßen et al.
LETTER
standard catalysts, were observed only in traces, and like-
wise, only small quantities of the biarylated amine were
detected. In an attempt to reduce the catalyst loading, the
reaction of chlorobenzene and morpholine (6b) was per-
formed on a larger scale. N-Phenylmorpholine could be
isolated in 83% yield using only 0.05 mol% of 4 (entry 8).
References
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In summary, we have demonstrated that one-component
palladium(0)-NHC complexes are a highly effective alter-
native for the Buchwald–Hartwig amination of aryl chlo-
rides, with key advantages in the commercial availability
of the preformed complexes, their stability towards oxy-
gen and water, the low catalyst loading and the use of a
simple and cheap base. Thus, important drawbacks of this
elegant transformation have been overcome and its prac-
tical usefulness especially for combinatorial chemistry
and industrial applications is greatly enhanced.
Synthesis of N-Phenylmorpholine:
A 20 mL round-bottom flask was charged successively with
naphthoquinone-1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene-
palladium(0) (1, 6.50 mg, 5.0 mmol), finely powdered KOH (168
mg, 3.0 mmol), dry dioxane (4 mL), p-chloroanisole (125 mL, 1.0
mmol) and morpholine (115 mL, 1.3 mmol). The mixture was
purged with argon for 3 min and heated to 100 °C. After complete
conversion (usually 16 h) the mixture was cooled, filtered over sil-
ica gel and the volatile components were removed in vacuo. The
residue was purified by column chromatography (SiO2, hexane–
EtOAc 80:20) yielding N-phenylmorpholine (153 mg, 0.93 mmol,
93%) as a white solid. The spectroscopic data were identical to
those reported in literature.
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Acknowledgment
We thank M. Eckardt for experimental assistance. LJG thanks Prof.
Dr. M. T. Reetz for constant support and encouragement.
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Synlett 2005, No. 2, 275–278 © Thieme Stuttgart · New York