An improved catalyst system for aromatic carbon-nitrogen bond formation: The possible involvement of bis(phosphine) palladium complexes as key intermediates

Full text of DOI:10.1021/ja9608306

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J. Am. Chem. Soc. 1996, 118, 7215-7216
7215
Communications to the Editor
cat Pd2(dba)3
BINAP
An Improved Catalyst System for Aromatic
Carbon-Nitrogen Bond Formation: The Possible
Involvement of Bis(Phosphine) Palladium
Complexes as Key Intermediates
ArBr + HN(R)R′
8 ArN(R)R′
(1)
NaOtBu
toluene, 80 °C
substituent) efficiency using a Pd(0)/P(o-tolyl)3 catalyst.2a,d
Attempts to generalize the cross coupling of primary amines
with aryl bromides by employing Pd2(dba)3/P(o-tolyl)35 resulted
in low conversion of starting materials to products and gave
large amounts of arene side products. For example, the coupling
of n-hexylamine and 5-bromo-m-xylene with this catalyst system
(2% Pd) resulted in only a partial conversion to products after
22 h at 80 °C and gave 35% (isolated yield) of the desired
product. In contrast, an 88% yield was realized when the Pd2-
(dba)3/BINAP (0.5% Pd, 80 °C, 2 h) combination was em-
ployed.6,7 This catalyst system is significantly more efficient,
in general, for the cross coupling of a variety of primary amines
with both electron-rich and electron-poor aryl bromides at
catalyst loadings as low as 0.05 mol % (∼2000 turnovers) as
detailed in Table 1. Its high activity also allows for the reactions
to be conducted at 80 °C, approximately 20 °C lower than
before. The use of BINAP as a ligand for coupling secondary
amines with ortho-substituted halides also resulted in much
higher yields than were obtained when P(o-tolyl)3 was employed
(Table 1). For example, arylation of N-methylpiperazine with
2-bromo-p-xylene resulted in only 47% yield of the cross-
coupled product when the Pd2(dba)3/P(o-tolyl)3 catalyst system
was used, but when BINAP was substituted for P(o-tolyl)3, the
yield improved to 98%.
John P. Wolfe, Seble Wagaw, and Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed March 13, 1996
Reports from several laboratories, including our own, on the
palladium-catalyzed cross coupling of aryl bromides with amines
have stressed the need to employ P(o-tolyl)3 as a ligand in order
to obtain reasonable yields of the desired aniline products.1,2
The importance of this ligand was attributed to its steric bulk,
which is believed to hinder the formation of bis(phosphine)
palladium complexes as intermediates. Hartwig has demon-
strated through kinetics studies that oxidative addition, pal-
ladium-nitrogen bond formation, and reductive elimination
proceed through monophosphine palladium complexes when
P(o-tolyl)3 is used as the ligand.3 One drawback of the use of
these P(o-tolyl)3/Pd catalyst systems is that they typically give
poor results when applied to the cross coupling of primary
amines with aryl bromides. In general, low yields of the desired
aniline are realized, and large amounts of arene side products
are produced which result from â-hydride elimination from a
Pd-amido intermediate. In a number of transition metal
complexes, the use of the chelating bis(phosphine) ligand has
been found to inhibit â-hydride elimination. Hartwig’s results
rendered this alternative unattractive since it appeared to us that
a chelating ligand would cause difficulty in accessing the
requisite three-coordinate monophosphine complexes. More-
over, earlier attempts in our laboratory to utilize chelating bis-
(phosphines) were unsuccessful. In conjunction with another
aspect of our work on palladium-catalyzed carbon-nitrogen
bond formation, we had reason to examine the use of BINAP4
as the supporting ligand. During this study, we were surprised
to find that the combination of Pd2(dba)3 and BINAP in the
presence of NaOtBu constitutes a superior catalyst system for
the cross coupling of amines with aryl bromides. In this
communication we report that use of this catalyst system allows
for the successful arylation of primary amines and dramatically
improves yields with several other types of substrates for which
poor results were obtained when P(o-tolyl)3 was employed as
the ligand (eq 1). This finding also indicates that bis(phosphine)
palladium complexes are not only viable as catalysts (and as
intermediates) but in many instances manifest superior efficiency
in these aromatic carbon-nitrogen bond-forming procedures.
Previously, we had shown that primary amines could be
coupled with a limited class of aryl bromide substrates with
good (para electron-withdrawing substituent) to excellent (ortho
In analogy to what has previously been reported, we surmise
that the catalytic cycle is as shown in Scheme 1. We have
isolated two of the presumed intermediates in this sequence.
Stirring a purple solution of Pd2(DBA)3 and BINAP in benzene
at room temperature for 2 h gave an orange solution from which
(BINAP)Pd(dba) (1) was isolated in 71% yield as an orange
powder. The oxidative addition complex (BINAP)Pd(p-C6H4-
CMe3)(Br) (2) was prepared by the reaction of BINAP with
8
{Pd[P(o-tolyl)3](p-C6H4CMe3)(µ-Br)}2 in benzene at room
temperature and was isolated in 50% yield as a cream-colored
solid. No evidence (1H NMR) for the formation of an amine
adduct was detected when a large excess (5 equiv) of benzyl-
amine was added to a C6D6 solution of 2. However, addition
of sodium tert-butoxide to the solution caused the rapid
formation of N-benzyl-4-tert-butylaniline as the only tert-
butylphenyl-containing product detected (1H NMR analysis).
Both 1 and 2 were shown to catalyze the coupling of amines
with aryl bromides with reaction rates and product distributions
similar to those observed when mixtures of Pd2(dba)3 and
BINAP were employed.
(4) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
(5) P/Pd ratio ) 2/1.
(6) Both racemic and nonracemic BINAP as expected give similar results
in the amination reaction. The related tol-BINAP also gave satisfactory
results in some systems.
(7) RepresentatiVe procedure: A Schlenk tube was charged with aryl
halide (1.0 mmol), amine (1.1-1.2 mmol), sodium tert-butoxide (1.4 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.0025 mmol, 0.5 mol % Pd),
BINAP (0.0075 mmol), and toluene (2-9 mL) under argon. The tube was
heated to 80 °C with stirring until the starting material had been completely
consumed as judged by GC analysis. The solution was then allowed to
cool to room temperature, taken up in ether (15 mL), filtered, and
concentrated. The crude product was then purified further by flash
chromatography on silica gel. Alternatively, the reaction could be performed
without solvent. The procedure employed was similar to that described
above; see supporting information for details.
(1) (a) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927-
928. (b) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
7901-7902.
(2) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348-1350. (b) Wolfe, J. P.; Buchwald, S. L. J.
Org. Chem. 1996, 61, 1133-1135. (c) Louie, J.; Hartwig, J. F. Tetrahedron
Lett. 1995, 36, 3609-3612. (d) Wolfe, J. P.; Buchwald, S. L. Unpublished
results.
(3) (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969-5970. (b) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995,
14, 3030-3039. (c) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117,
5373-5374. (d) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995,
117, 4708-4709.
(8) (a) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. Organome-
tallics 1996, 15, 2745-2754. (b) Widenhoefer, R. A.; Buchwald, S. L.
Organometallics 1996, 15, 2755-2763.
S0002-7863(96)00830-X CCC: $12 00 © 1996 American Chemical Society

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7216 J. Am. Chem. Soc., Vol. 118, No. 30, 1996
Scheme 1. Proposed Catalytic Cycle
Communications to the Editor
Table 2. Ligand Effects on Arylation of n-Hexylamine
Table 1. Pd-Catalyzed Arylamination
reductively eliminates to give (BINAP)Pd and the aniline
product. Structural features specific to BINAP may be key to
the success of this catalyst system. This supposition is consistent
with the observation that a variety of other chelating bis-
(phosphines) are significantly less effective in these amination
reactions (Table 2). â-Hydride elimination of 4 is presumably
inhibited due to the inaccessibility of a three-coordinate mono-
phosphine intermediate.10 The efficiency of BINAP as a ligand
in the Pd-catalyzed cross coupling of primary amines may result
from its ability to inhibit the formation of both catalytically
inactive palladium bis(amine) aryl halide complexes and bridg-
ing amido complexes which resist reductive elimination.8
In conclusion, we have demonstrated that the combination
of Pd2(dba)3 and BINAP serves as an efficient catalyst for the
amination of aryl bromides, even at catalyst loadings as low as
0.05% Pd. This new protocol greatly expands the scope of Pd
catalyzed C-N bond formation. Additionally, in contrast to
prior reports,3 the results presented here indicate that bis-
(phosphine) palladium complexes are viable as catalysts and
intermediates in the amination of aryl bromides.
Acknowledgment. We thank the National Science Foundation and
Pfizer for their support of this research. S.W. is the recipient of a Ford
Foundation Fellowship. We thank Dr. Ross Widenhoefer for the
synthesis and characterization of 1 and for helpful discussions. We
thank Professor John Hartwig for a mutual exchange of manuscripts.
Supporting Information Available: Detailed experimental pro-
cedures, as well as spectroscopic and analytical characterization of all
products (6 pages). See any current masthead page for ordering and
Internet access instructions.
a Yields in parentheses refer to yields obtained when P(o-tolyl)3 was
used as the phosphine ligand. b Control experiments showed no
formation of the desired product after 17 h at 100 °C in the absence of
palladium. c Reaction run neat.
JA9608306
The effectiveness of Pd2(dba)3/BINAP suggests that any or
all of steps 1-4 (Scheme 1) may occur from intermediates
without prior phosphine dissociation. In particular, coordination
of the amine to 2 would form pentacoordinate 3.9 Deprotonation
of the coordinated amine by NaOtBu would give 4 which
(9) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles
and Applications of Organotransition Metal Chemistry; University Science
Books: Mill Valley, CA, 1987; Chapter 5.
(10) Whitesides, G. M.; Gaasch, J. F.; Stedronsky, E. R. J. Am. Chem.
Soc. 1972, 94, 5258-5270.