[(CyPF-Bu)PdCI2]: An air-stable, one-component, highly efficient catalyst for amination of heteroaryl and aryl halides

Article abstract of DOI:10.1021/ol801615u

(Chemical Equation Presented) An air- and moisture-stable palladium catalyst, [(CyPF-¹Bu)PdCI²] (1), for coupling of heteroaryl chlorides, bromides, and iodides with a variety of primary amines is described. Most of these reactions occurred in high yield with 0.001-0.05 mol % catalyst loading. The reactions tolerated a wide range of functional groups.

Full text of DOI:10.1021/ol801615u

ORGANIC
LETTERS
[(CyPF-tBu)PdCl2]: An Air-Stable,
One-Component, Highly Efficient
Catalyst for Amination of Heteroaryl and
Aryl Halides
2008
Vol. 10, No. 18
4109-4112
Qilong Shen and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue,
Urbana, Illinois 61801, and Department of Chemistry, Yale UniVersity, P.O. Box
208107, New HaVen, Connecticut 06520-8107
jhartwig@uiuc.edu
Received July 15, 2008
ABSTRACT
An air- and moisture-stable palladium catalyst, [(CyPF-tBu)PdCl2] (1), for coupling of heteroaryl chlorides, bromides, and iodides with a variety
of primary amines is described. Most of these reactions occurred in high yield with 0.001-0.05 mol % catalyst loading. The reactions tolerated
a wide range of functional groups.
The palladium-catalyzed amination of aryl halides has emerged
as a powerful tool for the synthesis of substituted anilines.1
However, catalyst loadings for this transformation have been
high enough (>0.1 mol %) to limit its use for the coupling of
amines to produce less expensive intermediates and to produce
commodity building blocks.2 In 2005, we reported that the
combination of Pd(OAc)2 and the Josiphos ligand CyPF-tBu
catalyzed, for the first time, the coupling of primary amines
with heteroaryl halides with extremely low catalyst loadings
(5.0-100 ppm).3 This discovery increased the utility of pal-
ladium-catalyzed carbon-nitrogen coupling processes in an
industrial setting.
These reactions would be made even more practical if a
stable, single-component catalyst precursor could be used. When
low loadings of palladium and ligand are used separately, the
rate of complexation is slow. Thus, mixing of the metal and
ligand in solution must be conducted at higher concentrations
prior to addition of solvent and reagents. Moreover, the complex
formed from the Josiphos ligand and Pd(OAc)2 has a limited
stability in solution and as a solid.
These observations led us to study C-N coupling reactions
initiated with precatalysts bearing a single CyPF-tBu ligand per
palladium that are more stable than the adduct of this with
Pd(OAc)2. Herein, we report that the air- and moisture-stable
palladium complex [(CyPF-tBu)PdCl2] (1) in the absence of
any additional ligand is a convenient and highly active catalyst
precursor for the amination of heteroaryl and aryl halides that
(1) (a) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In
Chemistry of Anilines; Rappoport, Z., Ed.; John Wiley & Sons Ltd.:
Chichester, UK, 2007; Vol. 1, p 455. (b) Hartwig, J. F. In Modern Arene
Chemistry; Austruc, C., Ed.; Wiley-VCH: Weinheim, 2002; p 107. (c)
Hartwig, J. F. Handbook of Organopalladium Chemistry for Organic
Synthesis; Negoshi, E., Ed.; Wiley-Intescience: New York, 2002; p 1051.
(d) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (e)
Belfield, A. J.; Brown, G. R.; Foubister, A. J.; Ratcliffe, P. D. Tetrahedron
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Process Chemistry; Larsen, R. D., Ed.; Springer: Berlin, 2004; p 205.
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Int. Ed. 2005, 44, 1371.
10.1021/ol801615u CCC: $40.75
Published on Web 08/21/2008
2008 American Chemical Society

alleviates the need to generate the metal-ligand complex in
situ prior to the amination process.
Table 1. Coupling of Heteroaryl Halides with Primaryl
Alkylamines Using (CyPF-tBu)PdCl2 1a
[(CyPF-tBu)PdCl2] 1 was synthesized as shown in Scheme
1 by mixing CyPF-tBu with PdCl2(CH3CN)24 as a slurry in
Scheme 1
CH3CN at room temperature under nitrogen. Crystalline product
was obtained by layering a THF solution of the crude product
with hexanes. Dichloride 1 is soluble in THF, CH2Cl2 and
toluene and slightly soluble in DME. It is stable to both air and
moisture and did not deteriorate after storage on the bench for
1
three months, as determined by H NMR and 31P NMR
spectroscopy.
To evaluate the potential of 1 as a catalyst for the amination
of heteroaryl halides, we studied the prototype reaction of
3-chloropyridine5 with octylamine in the presence of sodium
tert-butoxide as base and 0.005 mol % of 1 in DME at 110 °C.
This reaction was complete after 24 h and formed N-octyl-3-
aminopyridine in 88% isolated yield. The reaction occurred at
a similar rate and in a similar yield when conducted with 0.005
mol % Pd(OAc)2/CyPF-tBu. Reactions conducted with NaO-
tBu as base were fast and occurred in high yield, while reactions
conducted with the weaker base K3PO4 required higher loading
(1.0 mol %) and longer time (36 h) for full conversion.
Reactions in toluene with NaO-tBu as base were slightly slower
than those in DME, while reactions in THF and 1,4-dioxane
were much slower.
Tables 1 and 2 summarize the coupling of heteroaryl and
aryl chlorides, bromides, and iodides with primary alkylamines,
catalyzed by dichloride 1. In general, the rates for amination
of aryl bromides were slightly faster than those for amination
of aryl chlorides. The rates for amination of aryl iodides were
markedly slower than those for amination of either aryl chlorides
or bromides. Consequently, the catalyst loadings for reactions
of aryl iodides were 5-10 times higher than those for reactions
of aryl chlorides and bromides, but reactions of aryl iodides
still occurred with much greater efficiency than with catalysts
reported previously containing other ligands.6
a Reactions conducted with specified mol % of 1, 1 mmol of ArX, 1.2
equiv of amine, and 1.4 equiv of NaO-tBu in 1 mL of DME. b Isolated
yield. c Reaction with 7.90 g of 3-bromopyridine (50.0 mmol).
Reactions of primary alkylamines with a variety of heteroaryl
chlorides, bromides, and iodides occurred in high yield with
catalyst loadings between 0.001-0.05 mol % (Table 1). These
loadings are 1 or 2 orders of magnitude lower than those
reported previously for the reactions of aryl chlorides with
primary amines in the presence of catalysts based on other
ligands.7,8 These loadings are just as low as those with the
combination of Pd(OAc)2 and the Josiphos ligand. For
example, reaction of 3-bromopyridine with octylamine
occurred in 74% yield with only 0.005 mol % of catalyst.
Of course, these reactions can be conducted without a drybox.
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Org. Lett., Vol. 10, No. 18, 2008

Table 2. Coupling of Aryl Halides with Primary Alkylamines
Using (CyPF-tBu)PdCl2 1a
Table 3. Amination of Functionalized Aryl Halides with
Primary Alkylamine Using (CyPF-tBu)PdCl2 1a
a Reactions conducted with specified mol % of 1, 1 mmol of ArX, 1.2
equiv of amine, and 1.4 equiv of NaO-tBu in 1 mL of DME. b Isolated
yield.
The same process conducted on an 8.0 g scale using Schlenk
methods formed the product in a comparable 87% yield.
Reactions of aryl chlorides, bromides, and iodides with
primary alkylamines occurred in high yield with low catalyst
loading without changing the reaction conditions from that of
entry 3 in Table 1. These results are summarized in Table 2.
Electron-poor, electron-neutral, and electron-rich aryl halides
reacted with a variety of primary alkylamines with 0.005-0.05
mol % of catalyst. For instance, in the presence of only 0.05
mol % of the catalyst, the reaction of sec-butylamine with
3-chloroanisole and 4-bromotoluene occurred in 75% and 81%
yields, respectively (Table 2, entries 3 and 6). However, the
coupling of an electron-rich aryl iodide with an R-branched
primary alkylamine required a slightly higher loading (0.3 mol
%) to proceed to completion (Table 2, entry 9). Typically,
reactions of more hindered R-branched primary alkylamines
were slower and required higher loadings than those of linear
primary amines. However, reactions of these amines with aryl
chlorides and bromides still occurred with just 0.05 mol % of
catalyst and with aryl iodides with 0.3 mol % of catalyst.
This catalyst is not only highly reactive for coupling of
primary amines, it is highly selective for monoarylation. No
products from diarylation of amines were observed by GC/MS
for any of the reactions in Tables 1 or 2.
a Reactions conducted with specified mol % of 1, 1 mmol of ArX, 1.2
equiv of amine, and 2.4 equiv of LiN(SiMe3)2 in 1 mL of DME. b Isolated
yield. c Using K3PO4 as the base.
The use of NaO-tBu as base in catalytic amination reactions
can be incompatable with certain functional groups. However,
the use of 2 equiv of lithium bis(trimethylsilyl)amide (LiN(T-
MS)2) as base9,10 greatly improves the functional group
compatibility of these reactions. Reactions of aryl halides
containing protic functional groups,10,11 including a free
alcohol, phenol, carboxylic acid, amide, and protected amine,
are summarized in Table 3. These reactions occurred in high
yield in the presence of 0.05-0.5 mol % of complex 1 and
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Org. Lett. 2000, 2, 1423
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.
.
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Org. Lett., Vol. 10, No. 18, 2008
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10
LiN(TMS)2 as the base (Table 3, entries 2-7). Reactions
reacted in high yield at low catalyst loading. These data are
summarized in Table 5. For instance, the cyclic secondary
of aryl chlorides, bromides, and iodides bearing carboalkoxy
and nitro groups, as well as acyl groups containing enolizable
hydrogens, occurred in higher yields when using K3PO4 as
base, instead of LiN(TMS)2 (Table 3, entries 8-11).10,11 In
these reactions, higher loadings of the catalyst and higher
temperatures were required for full conversion, due to the
decreased basicity and/or solubility of K3PO4.
Table 5. Coupling of Heteroaryl and Aryl Bromides with
Secondary Amines Using (CyPF-tBu)PdCl2 1a
Reactions of primary arylamines are summarized in Table
4. These reactions were slower than the reactions of primary
Table 4. Coupling of Heteroaryl and Aryl Halides with Primary
Arylamines Using (CyPF-tBu)PdCl2 1a
a Reactions conducted with specified mol % of 1, 1 mmol of ArX, 1.2
equiv of amine, and 1.4 equiv of NaO-tBu in 1 mL of DME. b Isolated
yield.
amine morpholine reacted with 3- bromoanisole in the
presence of 0.05 mol % catalyst to give the desired products
in 89% yield (Table 5, entry 3).
In summary, we have shown that the palladium complex
[(CyPF-tBu)PdCl2] (1) is a general, highly efficient catalyst for
the coupling of heteroaryl and aryl chlorides, bromides, and
iodides with primary nitrogen nucleophiles. Reactions catalyzed
by [(CyPF-tBu)PdCl2] occur with 0.001-0.05 mol % of catalyst,
and these catalyst loadings are, in most cases, 2 orders of
magnitude lower than those of analogous couplings by catalysts
containing other ligands. These data are similar to those obtained
with the combinatinon CyPF-tBu and Pd(OAc)2 without the
need to first bind the ligand to the metal precursor. The process
exhibits a broad scope and a high tolerance for functional
groups, such as cyano, keto, free carboxylate, amido, car-
boalkoxy, aromatic, and aliphatic hydroxyl and amino functional
groups.
a Reactions conducted with specified mol % of 1, 1 mmol of ArX, 1.2
equiv of amine, and 1.4 equiv of NaO-tBu in 1 mL of DME. b Isolated
yield.
alkylamines. Nevertheless, high yields of coupled product from
reactions of heteroaryl and aryl chlorides and bromides with
electron rich arylamines were obtained using only 0.05-0.1
mol % catalyst (Table 4, entries 1-3, 5-6). Reactions of
electron-deficient primary heteroarylamines were slower and
required higher catalyst loadings than the reactions of primary
arylamines. For example, the reaction of 2-aminopyrazine with
the unactivated 3-chloropyridine ccurred in high yield, but
required 1 mol % of catalyst at 110 °C (Table 4, entry 4).
Dichloride complex 1 was less effective as a catalyst for
reactions of secondary amines8,12 with heteroaryl and aryl
halides. Reactions were slower and substantial amounts of
hydrodehalogenation product were observed. Only a limited
number of combinations of secondary amines and aryl halides
Acknowledgment. We thank the NIH (GM-55382) for
support of this work, Johnson-Matthey for a gift of PdCl2,
and Solvias for a gift of the Josiphos ligands.
Note Added after ASAP Publication. Tables 1 and 2
were corrected on August 27, 2008.
Supporting Information Available: All experimental
procedures and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,
39, 617. (b) Navarro, O.; Marion, N.; Mei, J.; Nolan, S. P. Chem.sEur. J.
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