Sterically hindered chelating alkyl phosphines provide large rate accelerations in palladium-catalyzed amination of aryl iodides, bromides, and chlorides, and the first amination of aryl tosylates [12]

Full text of DOI:10.1021/ja981318i

J. Am. Chem. Soc. 1998, 120, 7369-7370
Scheme 1
7369
Sterically Hindered Chelating Alkyl Phosphines
Provide Large Rate Accelerations in
Palladium-Catalyzed Amination of Aryl Iodides,
Bromides, and Chlorides, and the First Amination of
Aryl Tosylates
Blake C. Hamann and John F. Hartwig*
Department of Chemistry, Yale UniVersity
P.O. Box 208107, New HaVen, Connecticut 06520-8107
ReceiVed April 20, 1998
Aromatic phosphines and arsines are typically used as ligands
in synthetically valuable palladium-catalyzed cross-coupling
processes that include recently developed couplings to form aryl-
amines and aryl ethers from aryl halides and triflates.1-3 We have
recently sought palladium systems comprised of air stable
components that provide faster reaction rates for aryl bromide
and iodide amination and allow the amination of less activated
and commercially important aromatic substrates such as aryl
chlorides and tosylates. Using a mechanistic rationale for the
choice of ligands, these goals have now been achieved with
sterically hindered chelating alkyl phosphine ligands.4,5
Because our group and Buchwald’s have recently showed that
chelating phosphine ligands containing aromatic substituents give
high selectivity for the amination of aryl halides with primary
amines,6,7 our studies toward rate acceleration focused on chelating
ligands. Mechanistic data8-12 on the aryl halide amination
reactions catalyzed DPPF (1,1′-bis(diphenylphosphino)ferrocene)
or BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) pal-
ladium compounds support the mechanism in Scheme 1.
Our studies on rate enhancement began with 31P NMR
spectroscopic studies to reveal the dominant form of the catalyst
in solution. Reactions between o-tolyl or p-tolyl bromide and
n-butylamine in the presence of NaO-t-Bu were conducted with
20 mol % of several catalysts, including [Pd(BINAP)2], [Pd-
(DPPF)2], [Pd(OAc)2] with either 1.5 equiv of BINAP or DPPF,
and [Pd(DBA)2] with 1.5 equiv of DPPF. In all cases, the species
observed at 80 °C by 31P NMR spectroscopy was Pd(0)L2 (L )
BINAP or DPPF).13 Thus, oxidative addition of aryl bromide is
the likely rate-determining step for the amination reactions
catalyzed by DPPF- or BINAP-ligated palladium and more active
catalysts must increase the rate of this step.
addition involves complete dissociation of one of the chelating
phosphine ligands to produce a bent Pd(0) chelate complex.14
Thus, tight binding of alkyl phosphines might, in fact, decelerate
the oxidative addition by disfavoring dissociation that generates
the active bent Pd(0)L. We, therefore, reasoned that sterically
hindered alkylphosphine ligands might provide the required
electron rich metal center, while favoring ligand dissociation.
For these reasons we tested the known, but infrequently studied,
ligand DBtPF (1,1′-bis(di-tert-butylphosphino)ferrocene)15,16 (1)
in the amination reactions. DBtPF is readily prepared by
dilithiation of ferrocene, followed by quenching with ClP(t-Bu)2.16
It is air sensitive over long periods of time in solution, but can
be handled and weighed in air. Table 1 summarizes our results
with this ligand and others discussed below in the general reaction
presented in eq 1, and these results illustrate (1) remarkable rate
enhancements for reactions with sterically hindered alkylphos-
phine ligands, (2) mild conditions for aminations of aryl chlorides,
(3) the first amination of aryl tosylates, and (4) the first preparation
of mixed alkyl arylamines in high yields by the metal-catalyzed
amination of unactivated aryl chlorides with primary alkylamines.
The functional group compatibility of palladium-catalyzed ami-
nation chemistry has been discussed previously.17
DBtPF leads to exceptionally high-yield amination of unacti-
vated aryl chlorides with aniline (entry 1). Reactions were
complete after 1 day at 110 °C in toluene solvent, but were
complete in only 4 h in dioxane solvent (entry 2). Entry 6 shows
that this ligand allows for the palladium-catalyzed amination of
aryl chlorides with primary alkylamines in acceptable yields.
Diarylation7,18 and competing hydrodehalogenation are assumed
to be competing reactions in this case. Entries 11 and 12 show
that this ligand provides excellent yields of dialkyl anilines from
unactivated aryl chlorides under much milder conditions than
previous palladium-catalyzed chemistry with unactivated chlo-
roarenes.4 Previous unpublished work in our laboratory showed
that palladium complexes of 1,1′-bis(dimethylphosphino)ferrocene
were ineffective catalysts for the amination chemistry. This result,
in combination with those reported here, shows the importance
of ligand steric hindrance.
Increasing the electron density at the metal center by employing
chelating alkyl, rather than aryl, phosphine ligands may accelerate
reaction rates. However, we have recently shown that oxidative
(1) Mann, G.; Hartwig, J. J. Am. Chem. Soc. 1996, 118, 13109-13110.
(2) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 10333-10334.
(3) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 3395.
(4) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(5) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665-1673.
(6) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-
7218.
(7) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 7215-7216.
(8) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232-
8245.
(9) Driver, M. S.; Hartwig, J. F. Organometallics 1997, 16, 5706-5715.
(10) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 108, 4206-
4207.
(14) Alcazar-Roman, L.; Hartwig, J. F. To be submitted for publication.
(15) Butler, I. R.; Cullen, W. R.; Kim, T. J.; Rettig, S. J.; Trotter, J.
Organometallics 1985, 4, 972-80.
(11) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 4708-
4709.
(12) Louie, J.; Paul, F.; Hartwig, J. F. Organometallics 1996, 15, 2794-
3005.
(16) Cullen, W. R.; Kim, T. J.; Einstein, F. W. B.; Jones, T. Organometallics
1983, 2, 714-19.
(13) The fate of the remaining palladium in cases where 1.5 equiv of ligand
was added to a catalyst precursor is unclear at this time. However, Pd(OAc)2
did not catalyze amination, demonstrating that the catalyst is the phosphine-
ligated complex.
(17) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359-
6362.
(18) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 3694-
3703.
S0002-7863(98)01318-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/11/1998

7370 J. Am. Chem. Soc., Vol. 120, No. 29, 1998
Communications to the Editor
Table 1. Hindered, Chelating Alkylphosphines in the Amination
2 and 3 catalyzed the amination of secondary amines only slowly,
perhaps due to the exquisite selectivity for monoarylation, as
shown in Table 2.7 More rapid arylation of secondary amines
was observed with 1 in combination of Pd(OAc)2 providing an
excellent catalyst for the arylation of secondary amines as
discussed above.
of Aryl Halides and Tosylatesa
Previous studies on the Pd-catalyzed amination of aryl chlorides
using monodentate alkylphosphines required activated aryl chlo-
rides and were limited to secondary amines.22,23 Activation of
chloroarenes by nickel is well established and Ni-catalyzed
amination of aryl chlorides has been reported.24 The work here
shows that palladium-catalyzed chemistry, which is often less air
sensitive and more general than that of nickel, can lead to
amination of unactivated aryl chlorides in toluene solvent and
with primary alkylamines.
Entries 13 and 14 show that hindered, chelating alkylphosphine
ligands also generate effective catalysts for the amination of aryl
tosylates. The reaction yields with unactivated aryl tosylates are
remarkable, considering that little palladium-catalyzed cross-
coupling with any type of aryl arene sulfonate has been
reported.25,26 These results illustrate the potential of using
chelating alkyl phosphines in chemistry to convert phenols to
amines with tosyl chloride instead of triflic anhydride to activate
the phenol.
Ligand 1 allowed for aminations of aryl bromides with aniline
in excellent yield at room temperature (entry 15). Previous room-
temperature palladium-catalyzed amination chemistry required
aryl iodides and the addition of crown ethers,27 and aminations
with aniline substrates required heating. Entries 16-18 show the
room-temperature amination of aryl iodides without additives. In
all cases complete consumption of the aryl iodide occurred before
24 h had elapsed. Yields for the amination of aryl iodides with
primary alkylamines were acceptable. However, the yields for
amination of the unactivated aryl iodide in entry 19 with primary
arylamines were excellent.
a Procedures: 1.0 equiv of aryl halide, 1.2 equiv of amine, and 1.2
equiv of NaOtBu were used along with the specified catalyst in toluene
solvent. b Yields are for isolated product of >95% purity and are an
average of at least 2 runs on a 1 mmol scale with 0.5-1.0 M
concentrations. c Reaction run in dioxane solvent. d NaOC6H3-2,4,6-
tBu used as base.
Figure 1. Ligands employed in the examples of Table 1.
Table 2. Effect of Ligand on Monoarylation vs Diarylation
Selectivity for 4-Chlorotoluene and n-Butylamine
Our previous studies on the reductive elimination of diaryl-
amine from (DPPF)Pd(Ar)(NHAr) complexes showed that this
primary reaction required several hours at room temperature.8 We
expected the presence of an alkylphosphine ligand to decelerate
the reductive elimination of diarylamine, preventing room-
temperature chemistry with aniline. Perhaps the size of the DBt-
PF ligand compensates for the increased electron density at the
metal, maintaining fast rates for reductive elimination.
ligand
amine (H2NR)
HNArR:NAr2R
1
2
3
2
R ) Bu
R ) Bu
R ) Bu
R ) Ph
3.3:1
130:1
30:1
diarylation product
not detected
A general problem in catalysis involves identifying systems
that are rapid at both activating and extruding organic molecules.
By using sterically hindered alkyl phosphines, it appears that both
oxidative addition and reductive elimination are accelerated. This
proposal will be tested in future mechanistic work that will
accompany studies with dialkylphosphino ligands containing
different backbones and the use of these ligands in the R-arylation
of ketones and amides.
Other chelating ligands with large bite angles created by
backbones that are stable to basic conditions, while containing
bulky alkyl substituents at the phosphorus, include ligand 2 in
Figure 1 used by Lonza for the stereoselective reduction of
biotin,19 and related systems including 3 in Figure 1 reported by
Togni et al. for asymmetric hydrogenation.20,21 These ligands
induced aminations of unactivated aryl chlorides with primary
amines under remarkably mild conditions. The ligands 2 and 3
in Figure 1 were evaluated for the amination of hindered and
unhindered aryl chlorides with aniline and butylamine. High
yields of aryl chloride amination were observed with aniline
(entries 3-5). The reaction in entry 4 that employs palladium
acetate as catalyst precursor occurs under conditions reminiscent
of previous aminations of aryl bromides. Table 2 shows that no
diarylation of aniline was observed when ligand 2 was used.
Acknowledgment. We gratefully acknowledge support from the
National Institutes of Health, Boehringer Ingelheim, and the Department
of Energy for support.
Supporting Information Available: Reaction procedures and spec-
troscopic data of ligands and reaction products (7 pages, print/PDF). See
any current masthead page for ordering and Web access instructions.
instructions.
In addition, high yields of mixed alkyl arylamines were
obtained by employing these two ligands. Isolated yields between
87% and 94% were obtained when ligand 2 or 3 was used with
palladium acetate at only 85 °C for 2-12 h for either hindered
or unhindered aryl chlorides. Palladium precursors and ligands
JA981318I
(22) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807-4810.
(23) Beller, M.; Reirmeier, T. H.; Reisinger, C.; Herrman, W. A.
Tetrahedron Lett. 1997, 38, 2073-2074.
(24) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054-
6058.
(25) Badone, D.; Cecchi, R.; Guzzi, U. J. Org. Chem. 1992, 57, 6321-3.
(26) Kubota, Y.; Nakada, S.; Sugi, Y. Synlett 1998, 183.
(27) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066-6068.
(19) Imwinkelried, R. Chimia 1997, 51, 300-302.
(20) Togni, A.; Breutel, C.; Soares, M. C.; Zanetti, N.; Gerfin, T.; Gramlich,
V.; Spindler, F.; Rihs, G. Inorg. Chim. Acta 1994, 222, 213-24.
(21) Zanetti, N. C.; Spindler, F.; Spencer, J.; Togni, A.; Rihs, G.
Organometallics 1996, 15, 860-6.