An air and thermally stable one-component catalyst for the amination of aryl chlorides

Article abstract of DOI:10.1021/ol034561h

(Matrix presented) In this paper we report a new, highly efficient palladacyclic precatalyst that is air, moisture, and thermally stable and obviates the need to employ a glovebox. We have developed a convenient one-component precatalyst for the amination of aryl chlorides that overcomes many of the limitations of those previously described.

Full text of DOI:10.1021/ol034561h

ORGANIC
LETTERS
2
003
Vol. 5, No. 14
413-2415
An Air and Thermally Stable One-
Component Catalyst for the Amination
of Aryl Chlorides
2
Danilo Zim and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received March 31, 2003
ABSTRACT
In this paper we report a new, highly efficient palladacyclic precatalyst that is air, moisture, and thermally stable and obviates the need to
employ a glovebox. We have developed a convenient one-component precatalyst for the amination of aryl chlorides that overcomes many of
the limitations of those previously described.
3
The palladium-catalyzed amination of aryl halides and
sulfonates has emerged as a valuable method for the
preparation of aromatic amines. Numerous ligands and
that, in contrast to those previously reported, indicate that
catalysts employing ligand 1 are inefficient when potassium
hydroxide is used as the base.
1
catalysts have been reported to effect this type of cross-
coupling. While there is a continuing push toward develop-
ment of the most effective catalysts for large-scale proce-
dures, the majority of the users are interested in small-scale
application of the chemistry. In this regard, convenience,
along with efficacy, is of significance.
Many palladacyclic precatalysts for cross-coupling reac-
tions have been reported in the past few years. Many of these
air-stable complexes have displayed outstanding levels of
activity in a variety of synthetically important transforma-
7
tions. As a result of some prior work in our laboratory, we
wondered whether we could efficiently prepare a pallada-
cyclic complex based on the biaryl phosphine ligands that
we have developed. In fact, we found that simply stirring 1
Recently, several single-component precatalysts have been
reported to be effective in catalytic aminations. These include
2
3
examples based on N-heterocyclic carbenes, Pd(t-Bu
3
P)
2
,
in toluene with Pd(OAc)
2
led to the formation of the
and Pd(I)-Pd(I) dimers,4,5 as well as others. In this paper
we report a new, highly efficient palladacyclic precatalyst
that is air, moisture, and thermally stable and obviates the
need to employ a glovebox. In addition, we present results
6
palladacycle 2 in 94% yield. Palladacycle 2, an air- and
(
1) (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576,
1
25-146. (b) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, Germany, 2000. (c) Muci, A. R.; Buchwald, S.
L. Top. Curr. Chem. 2002, 219, 131-209. (d) Wolfe, J. P.; Wagaw, S.;
Marcoux, J. P.; Buchwald, S. L. Acc. Chem. Res. 1988, 31, 805-818.
(2) Viciu, M. S.; Kissling, R. M.; Stevens, E. D.; Nolan S. P. Org. Lett.
2
002, 4, 2229-2231.
3) Kuwano, R.; Utsonomiya, M.; Hartwig, J. F. J. Org. Chem. 2002,
7, 6479-6486.
(
Figure 1. Synthesis of palladacycle 2.
6
1
0.1021/ol034561h CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/13/2003

Table 1. Amination of Aryl Chlorides
a
Method A: ArCl (1 mmol), amine (1.2 mmol), NaOtBu (1.4 mmol), toluene (1 mL), 80 °C. Method B: ArCl (1 mmol), amine (1.2 mmol), ligand (0.01
mmol), KOH (1.5 mmol), toluene (1 mL), 90 °C. Method C: ArCl (1 mmol), amine (1.2 mmol), Et3N (0.5 mmol), NaOMe (1.4 mmol), toluene (1 mL), 60
°
C. (a) 120 °C. (b) 2% of the product of double arylation was observed. (c) Et3N (0.5 mmol) was included. (d) 3 equiv of amine. (e) Room temperature, Et3N
was not added.
moisture-stable solid, proved to be a versatile precatalyst for
the amination of aryl chlorides as is described below.
As is evident from the results presented in Table 1, the
use of 2 (1%) in the presence of sodium tert-butoxide or
sodium methoxide provides an efficient one-component
system for the amination of aryl chlorides. These reactions
are all set up on the benchtop and the solid components are
(5) Stambuli, J. P.; Kuwano, R.; Hartwing, J. F. Angew. Chem., Int. Ed.
(
4) (a) Vilar, R.; Mingos, D. M. P.; Cardin, C. J. J. Chem. Soc., Dalton
2002, 41, 4746-4748.
Trans. 1996, 23, 4313-4314. (b) Dura-Vila, V.; Mingos, K. M. P.; Vilar,
(6) (a) Schinyder, A.; Indolese, A. F.; Studer, M.; Blaser, H. Angew.
Chem., Int. Ed. 2002, 41, 3668-3671. (b) Li, G. Y.; Zheng, G.; Noonan,
A. F. J. Org. Chem. 2001, 66, 8677-8681.
R.; White, A. J. P.; Williams, D. J. J. Organomet. Chem. 2000, 600, 198-
2
05.
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Org. Lett., Vol. 5, No. 14, 2003

weighed in the air. The reaction uses commercial solvent
Aldrich Sure-Seal), which is simply added by syringe to
the reaction vessel that has been purged with argon and
capped with a septum. Three different bases were used in
these protocols: sodium tert-butoxide, sodium methoxide
tert-butoxide is used as base and BINAP is the supporting
10
(
ligand. More important was a report by workers at Novartis
who described the use of both sodium methoxide and sodium
isopropoxide as effective bases in palladium-catalyzed ami-
11
nation processes. With 2 we have found in several instances
that the use of sodium methoxide as the base leads to
improved levels of functional group compatibility (entries
13-15). In particular aryl chloride substrates containing
nonconjugated electron-withdrawing groups (and hence less
reactive toward oxidative addition) gave good yields of
products. In one instance (entry 12) we found that the
reaction was complete in 1 h at room temperature; 2% of 2
was used in that case.
(both of these obtained from commercial sources), or
potassium hydroxide (powdered in the air immediately prior
to use). When sodium tert-butoxide was employed the
reactions were complete in 2-5 h at 80 °C; with a
2,6-disubstituted aryl chloride 2% 2 was required and the
reactions were carried out at 120 °C. The use of powdered
potassium hydroxide was also effective in combination with
2. However, in this case it was necessary to add 1% of 1 to
the reaction. The reactions that use potassium hydroxide were
slower than those with sodium tert-butoxide and were left
for 20 h at 90 °C. Since it has been previously reported that
When the reactions involved the coupling of aniline or a
substituted aniline it was necessary to use Et
otherwise no reaction was observed (entries 7 and 15). We
believe that the Et N, in these cases, is the reducing agent
3
N as additive,
1
was an inefficient ligand for the amination of aryl chlorides
3
3
12
when hydroxide bases were employed, we wondered
that generates the active Pd(0) species. The use of this
additive also proved to be helpful in the cases where certain
sensitive functional groups were present (entries 13 and 14).
In summary, we have developed a convenient one-
component precatalyst for the amination of aryl chlorides
which overcomes many of the limitations of those previously
described. This material has recently become commercially
available (Strem).
whether there was something specific about beginning with
8
2
. To this end we examined the reaction of morpholine with
p-chlorotoluene catalyzed by the combination of 1% Pd(OAc)
2
/
2% 1 with potassium hydroxide as base in toluene. In this
case a 97% isolated yield of product was obtained. Of interest
was that it was not necessary for this reaction to be carried
out in the presence of a phase-transfer catalyst, although its
inclusion had no deleterious effects on the reaction.
Acknowledgment. We thank the National Institutes of
Health (GM58160) for funding this work. We are grateful
to Pfizer, Merck, Bristol Myers Squibb and Lundbeck for
additional support of our research program. D.Z. thanks
CNPq for a fellowship. Initial investigations by Professor
Peter Zhang were important to the success of this endeavor.
It has been widely believed that the use of alkoxide bases
derived from alcohols with â-hydrogens would lead to the
formation of arene from the reduction of the aryl halide. In
part this was due to the suggestion that amination reactions
with alkoxide bases proceed via a palladium alkoxide
9
intermediate. While it is possible that this is true when DPPF
Supporting Information Available: Experimental details
for the synthesis of 2, catalysis protocol, and product
isolation. This material is available free of charge via the
Internet at http://pubs.acs.org.
is employed as supporting ligand, we have recently presented
results that indicate that this is not the case when sodium
(
7) Reviews: (a) Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem.
2
001, 1917-1927. (b) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C. P.
J. Organomet. Chem. 1999, 576, 23-41. Examples: (c) Zim, D.; Gruber,
OL034561H
A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L. Org. Lett. 2000, 2, 2881-
2
884. (d) Gruber, A. S.; Zim, D.; Ebeling, G.; Monteiro, A. L.; Dupont, J.
(10) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 14104-14114.
Org. Lett. 2000, 2, 1287-1290.
8) We note that in the previous study no attempt to optimize the process
with 1 was made.
9) Mann, G.; Hartwing, J. F. J. Am. Chem. Soc. 1996, 118, 13109-
3110.
(
(11) Prashad, M.; Hu, B.; Yansong, L.; Draper, R.; Har, D.; Repic, O.;
Blacklock, T. J. J. Org. Chem. 2000, 65, 2612-2614.
(
(12) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules; University Science Books: Mill Valley, CA, 1994.
1
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