A second-generation catalyst for aryl halide amination: Mixed secondary amines from aryl halides and primary amines catalyzed by (DPPF)PdCl2

Full text of DOI:10.1021/ja960937t

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J. Am. Chem. Soc. 1996, 118, 7217-7218
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elimination of arylamines from [Pd(PPh3)2(NAr2)(Ph)]15 dem-
onstrated that a reductive elimination pathway involving a four-
coordinate intermediate can occur in competition with reductive
elimination from three-coordinate intermediates.16 Further,
independent studies from our group on the â-hydrogen elimina-
tion of [Ir(CO)(PPh3)2(NRAr)] complexes showed that the
â-hydrogen elimination of square planar, transition metal amides
requires a 14-electron intermediate.17 These results implied that
the presence of chelating ligands would inhibit â-hydrogen
elimination more than reductive elimination and would, there-
fore, improve the selectivity for amination vs reduction.
Despite these kinetic results, the general chemistry of
palladium amido aryl complexes with chelating ligands was
dominated by reactions other than C-N bond-forming reductive
elimination. For example, addition of DPPE (1,2-bis(diphen-
ylphosphino)ethane) to a solution of the previously reported
PPh3-ligated amido complex (PPh3)2Pd(Ph)[N(tolyl)2] (1) led
to decomposition of the ligand backbone by P-C bond cleavage
and formation of vinyldiphenylphosphine in 93% yield, as
shown in eq 1.18 Addition of other chelating ligands such as
DPPP (1,2-bis(diphenylphosphino)propane), DPPBz (1,2-bis-
(diphenylphosphino)benzene), and DPPEn (1,2-bis(diphenylphos-
phino)ethylene) did not produce stable amido complexes, and
no arylamine products were observed.
A Second-Generation Catalyst for Aryl Halide
Amination: Mixed Secondary Amines from Aryl
Halides and Primary Amines Catalyzed by
(DPPF)PdCl2
Michael S. Driver and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107
New HaVen, Connecticut 06520-8107
ReceiVed March 22, 1996
Aromatic amines are important substructures in natural
products and organic materials.1-3 Our group4 and Buchwald’s5
have recently reported the palladium-catalyzed amination of aryl
halides in the presence of alkoxide and amide bases that
significantly improved upon amination procedures employing
toxic and air sensitive aminostannanes.6,7 Although these
methods gave high yields with secondary amines and aryl
bromides, a general, high-yielding intermolecular amination
procedure involving primary amine substrates or aryl iodide
electrophiles8 had not been developed. The catalysts used for
intermolecular aminations contained tri-o-tolylphosphine as the
ligand. Our mechanistic studies have shown that each complex
on the reaction coordinate involving this catalyst is a monomeric,
monophosphine species.9-13 The large size of this ligand leads
to fast reaction rates by favoring low coordination number
compounds and high selectivity for arylamine formation by
favoring reductive elimination of arylamine over â-hydrogen
elimination of imine.14
Our studies of late-transition metal amido complexes have
now led to a second-generation aryl halide amination catalyst,
(DPPF)PdCl2 (DPPF ) 1,1′-bis(diphenylphosphino)ferrocene),
which is based on chelating ligands. This catalyst provides high
yields of mixed, secondary arylamines from aryl halides and
primary amines, examples that gave low to moderate yields with
the tri-o-tolylphosphine system. In addition to the practical
advantages of this system, these results reveal a number of
important concepts: (1) the catalytic cycle involves bis-
(phosphine) intermediates; (2) sterically encumbered phosphines
are not necessary for high-yielding, intermolecular amination
of aryl halides; (3) the favorable selectivity for reductive
elimination over â-hydrogen elimination results from chelation
and large bite angle, rather than from steric effects; (4) a wide
range of chelating ligands may lead to optimization of reaction
rates and yields. We report the aryl halide amination chemistry
of DPPF-ligated palladium complexes and the transition metal-
amido chemistry that led us to this system.
Nevertheless, we found that amido complexes containing the
DPPF ligand could be isolated or observed spectroscopically
and that these complexes produced arylamines in high yields
by reductive elimination. As shown in eq 2, addition of DPPF
to 1 generated (DPPF)Pd(Ph)[N(tolyl)2] (2) in 54% yield, and
this complex underwent high-yielding reductive elimination of
amine when warmed to 85 °C in the presence of free PPh3.
On a preparative scale, 2 was formed by addition of KN-
(C6H4-p-Me)2 to (DPPF)Pd(Ph)I (3)19 at room temperature in
THF and was isolated in 69% yield by addition of pentane to
a concentrated toluene solution. The complex displayed two
sharp doublets in the 31P{1H} NMR spectrum, demonstrating
the cis, four-coordinate geometry in Scheme 1. The 31P{1H}
NMR chemical shifts of 2 were located downfield of those for
aryl halide complex 3. Warming a benzene-d6 solution of 2 at
85 °C in the presence of free PPh3 induced the formation of
Ph-N(tolyl)2 in 90% yield by 1H NMR spectroscopy involving
an internal standard. (DPPF)2Pd and (PPh3)4Pd were the only
transition metal products observed by 31P NMR spectroscopy.
Substitution chemistry also allowed for the observation of
DPPF-ligated palladium primary amides, and these complexes
underwent facile reductive elimination of mixed secondary
amines at room temperature or below. For example, addition
of LiNHiBu to a THF solution of 3 at low temperature (0 °C)
resulted in the formation of a new species, which displayed two
doublets in the 31P NMR spectrum (26.5, 18.3 ppm, J ) 22.0
Hz). The 31P chemical shifts of this product were located
Recently, we sought the preparation of palladium amido
complexes containing chelating ligands in order to evaluate their
potential as intermediates in amination chemistry that might
display higher turnover numbers, greater compatibility with
functional groups, and greater stability toward displacement by
primary amines. Our most recent kinetic results on the reductive
(1) Buckingham, J. Dictionary of Natural Products, 1st ed.; University
Press: Cambridge, MA, 1994.
(2) Negwer, M. Organic-Chemical Drugs and Their Synonyms (an
international surVey), 7th ed.; Akademie Verlag GmbH: Berlin, 1994.
(3) D’Aproano, G.; Schiavon, G.; Zotti, G.; Leclerc, M. Chem. Mater.
1995, 7, 33-42.
(4) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
(5) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348.
(6) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927-928.
(7) Kosugi, M.; Kameyama, M.; Sano, H.; Migita, T. Nippon Kagaku
Kaishi 1985, 3, 547-551.
(15) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 4708-
4709.
(8) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133-1135.
(9) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969.
(10) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030.
(11) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373.
(12) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11598.
(13) Louie, J.; Paul, F.; Hartwig, J. F. Organometallics, in press.
(14) Hartwig, J. F.; Richards, S. J. Am. Chem. Soc. 1996,
(16) Driver, M. S.; Hartwig, J. F. Unpublished results.
(17) Recent studies have indicated that â-hydrogen elimination requires
an open coordination site. Hartwig, J. F. J. Am. Chem. Soc., in press.
(18) This phosphine is commercially available. The 1H NMR, GC
retention time, and GC/MS were compared to an authentic commercial
sample.
(19) Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta 1994, 220, 249.
S0002-7863(96)00937-7 CCC: $12 00 © 1996 American Chemical Society

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7218 J. Am. Chem. Soc., Vol. 118, No. 30, 1996
Communications to the Editor
Table 1. (DPPF)PdCl2-Catalyzed Reactions of Aryl Halides with
Scheme 1
Primary Aminesa
c
b
downfield of those for 3, in a similar fashion to the downfield
shifts of isolated 2. Given the clean reactivity of potassium
amides with 3 to give 2 and the similarity in 31P chemical shifts,
the reaction product formed at low temperature is presumably
the cis-ligated isobutylamido aryl complex. Consistent with this
proposal, PhNHiBu was formed in 64% yield upon warming to
room temperature.20 A new palladium amido complex 4 was
also formed upon addition of KNHPh to a THF solution of aryl
halide 3. The 31P NMR spectrum of this complex contained
two singlets (22.3, -16.6 ppm), the upfield signal falling in
the region of free DPPF. The absence of coupling between the
two P atoms and the similarity of one resonance to that of free
DPPF suggested that this species was the dimeric palladium
anilide shown in Scheme 1. Again, the DPPF amido complex
underwent reductive elimination of amine at or below room
temperature. Ph-NHPh formed from 4 in 80% yield after
standing at room temperature for 1.5 h in the presence of added
PPh3.20
The observation of these facile reductive elimination reac-
tions, particularly in the case of primary amines containing
â-hydrogens, led us to test DPPF-ligated palladium complexes
as catalysts for the formation of aromatic secondary amines by
reaction between primary amines and aryl halides. Indeed,
(DPPF)PdCl2 (5)21 proved to be an effective catalyst for the
amination of aryl bromides and iodides with both aryl and alkyl
primary amines (eq 3). A summary of the catalytic reactions
a Reactions conducted in THF solvent at 100 °C for 3 h. b Workup
A: product isolated by sublimation. Workup B: product isolated by
silica-gel chromatography using 10:1 hexanes/ether follwed by 4:1
hexanes/ether as eluting solution. Workup B′: products isolated by
silica-gel chromotography using 20:1 hexanes/EtOAc as eluting solu-
tion. Details included in supporting information. c Yields reported
correspond to isolated compounds that were pure by NMR spectroscopy
and by microanalysis when submitted.
substantially over similar examples involving the P(o-tolyl)3-
based catalysts.5,8 The use of a secondary amine (entry 11)
was successful in the case of an N-alkyl arylamine after only a
3 h reaction time. However, attempts to use dialkylamines led
to the formation of arene products. The use of secondary
aminostannanes also resulted in the formation of arene products.
In conclusion, we present the generation and reductive
elimination of DPPF-ligated palladium amido complexes that
suggested the use of (DPPF)PdCl2 as a catalyst for the formation
of mixed secondary arylamines from aryl halides. The yields
of such reactions are improved significantly over those involving
P(o-tolyl)3-ligated catalysts. Since the DPPF is much smaller
than P(o-tolyl)3, the difference in reactivity is clearly rooted in
coordination number and geometry rather than steric bulk. Thus,
a wide range of ligands should be considered for this catalytic
chemistry, and four-coordinate, bis(phosphine) complexes can
serve as intermediates in such aminations.
conducted with 5 is provided in Table 1.22
As shown in Table 1, reactions of aryl halides and primary
amines catalyzed by 5 provided a general route to a variety of
aryl amines in high yields. The efficient reaction of aryl iodides,
as well as aryl bromides, extends the scope of amination
reactions to a wider range of electrophiles. Aryl halides with
either electron-donating or electron-withdrawing substituents,
as well as those bearing ortho substituents (entry 3), reacted
effectively with anilines after only 3 h. Both primary aryl- and
alkylamines reacted in high yields with aryl halides containing
an electron-withdrawing group.23 These yields are improved
Acknowledgment. We gratefully acknowledge a DuPont Young
Professor Award, a National Science Foundation Young Investigator
Award, the Exxon Education Foundation, and a Dreyfus Foundation
New Faculty Award for support for this work. J.F.H. is a fellow of
the Alfred P. Sloan Foundation. We would also like to thank Johnson-
Matthey Alpha/Aesar for donation of palladium chloride. We thank
Professor Stephen L. Buchwald for sharing his unpublished results and
for an exchange of manuscripts.
(20) The only palladium products seen at the end of reaction were
(DPPF)2Pd and (PPh3)4Pd.
(21) 5 was made prepared as an air-stable red crystalline solid by a
method analogous to that for (DPPE)PdCl2. Davies, J. A.; Hartley, F. R.;
Murray, S. G. J. Chem. Soc., Dalton Trans. 1979, 1705.
Supporting Information Available: Spectroscopic and analytical
data for 2, specific amination procedures for entries 5 and 7, general
workup procedures, and spectroscopic data and copies of NMR spectra
for organic products (25 pages). See any current masthead page for
ordering and Internet access instructions.
(22) In an inert atmosphere dry box, (DPPF)PdCl2 and 3.0 equiv of DPPF/
Pd were added to a solution of 20 equiv of bromobenzophenone and 25
equiv of sodium tert-butoxide in 8 mL of anhydrous THF. The reaction
tube was sealed with a cap containing a PTFE septum and removed from
the dry box. Butylamine (25 equiv) was added to the reaction mixture by
syringe, and the mixture was heated at 100 °C for 3 h. The reaction was
cooled to room temperature, the volatile materials were removed by rotary
evaporation, and the product was isolated by either sublimation or silica-
gel chromatography (20:1 hexane/EtOAc or 10:1 hexane/Et2O followed by
4:1 hexane/Et2O).
JA960937T
(23) Data in the accompanying paper by Buchwald et. al. shows that
diarylation of unhindered alkyl amines can occur in the case of electronically
neutral aryl halides: Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 0000.