Reversal of aryl bromide reactivity in Pd-catalysed aryl amination reactions promoted by a hemilabile aminophosphine ligand

Article abstract of DOI:10.1016/j.tet.2005.06.073

Incorporation of a hemilabile amino group with a bulky, electron-rich phosphorus ligand led to a reversal in the order of aryl bromide reactivity in Pd-catalysed aryl amination reactions.

Full text of DOI:10.1016/j.tet.2005.06.073

Tetrahedron 61 (2005) 9822–9826
Reversal of aryl bromide reactivity in Pd-catalysed aryl amination
reactions promoted by a hemilabile aminophosphine ligand
a
Sebastien L. Parisel, Luis Angel Adrio, Adriana Amoedo Pereira, Marta Marino Perez,
b
b
b
´
b
Jose M. Vila and King Kuok (Mimi) Hii
c,
*
´
aDepartment of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
b
´
´
´
Departamento de Quımica Inorganica, Facultad de Quımica, Universidad de Santiago e Compostela, E-15782, Spain
cDepartment of Chemistry, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK
Received 1 March 2005; revised 10 June 2005; accepted 24 June 2005
Available online 15 July 2005
Abstract—Incorporation of a hemilabile amino group with a bulky, electron-rich phosphorus ligand led to a reversal in the order of aryl
bromide reactivity in Pd-catalysed aryl amination reactions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Electron-rich, sterically bulky alkylphosphines constitute
the majority of ligands that promote palladium-catalysed
cross-coupling reactions under mild reaction conditions.
Figure 1. Sterically bulky aminophosphine ligands.
The remarkable reactivity has been attributed to the ability
of these bulky ligands to provide highly coordinatively
unsaturated, nucleophilic palladium catalytic precursors.1
reduced and the resultant amino alcohol was transformed
into amino tosylate 4. Finally, a nucleophilic substitution by
di-tert-butylphosphide furnished the product 1 as a dense
oil. To facilitate handling, the ligand was precipitated and
stored as the white crystalline HCl salt, which is remarkably
stable to air and moisture—a solution of 1$HCl may be left
exposed to air at room temperature for at least 24 h without
any significant oxidation (31P NMR spectroscopy).
As part of our continued effort to develop nitrogen–
phosphorus hybrid ligands for transition-metal mediated
catalysis,2 the aminophosphine ligand 1 was synthesised
and its catalytic activity examined. We are particularly
interested in exploring potential beneficial effect(s) of
introducing a hemilabile nitrogen donor on catalyst activity
and/or stability. Combining a bulky di-tert-butylphosphine
moiety with a hemilabile tertiary amine donor, it is
structurally similar to the Amphos ligand (2), which has
been found to promote Suzuki, Sonogashira, and Heck
couplings of aryl bromides in aqueous solvents.3 The
quaternarised amino functionality is not expected to
coordinate to the palladium metal centre, but improves the
water-solubility of the palladium catalysts, which may be
recovered and recycled without any lost of activity (Fig. 1).
Scheme 1. Preparation of ligand 1. (i) Na2CO3, EtOH; (ii) LiAlH4, THF;
(iii) TsCl, pyridine; (iv) (a) t-Bu2PH, t-BuLi.
Ligand 1 was subsequently employed in a number of
palladium-catalysed reactions, including the amination of
aryl bromides (Scheme 2), where the reaction between the
sterically bulky N-methylaniline with a number of aryl
bromides (4-bromoacetophenone, 4-bromobenzonitrile,
The aminophosphine 1 can be prepared expediently in four
steps (Scheme 1): N-Methylaniline was alkylated with
bromoethylacetate to give the amino ester 3. This was
Keywords: Palladium catalysis; PN ligands; Aryl amination; Aryl
bromides.
*
Corresponding author. Tel.: C44 20 75941142; fax: C44 20 75945804;
e-mail: mimi.hii@imperial.ac.uk
Scheme 2. Pd-catalysed aryl amination reaction.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.073

S. L. Parisel et al. / Tetrahedron 61 (2005) 9822–9826
9823
bromobenzene and 4-bromoanisole) was examined. Despite
our initial expectations, no reaction was observed at ambient
temperature. This could be due to the coordination of the
nitrogen donor group and/or the amine substrate, which
suppresses the formation of the reactive coordinatively
unsaturated Pd(0) species for the initial oxidative addition
step.†
bromide substrates gave much higher yields under identical
conditions (O80%, entries 9 and 11).
As the yields are equally low for the electron-deficient
substrates, complexation of the nitrile moiety to the metal
centre is not regarded as a major factor under these reaction
conditions. Crucially, in both cases, recovered aryl bromide
substrates accounted for the mass balance, that is the low
yields were not due to competitive side reactions (e.g.,
dehalogenation).
As an elevated reaction temperature was necessary to enable
catalytic turnover, 1,10-bis(diphenylphosphino)ferrocene
(dppf), previously reported to be an effective ligand for
the aryl amination of primary amines,4 was employed as a
comparison, to gauge the catalytic efficiency of ligand 1 and
to discount the involvement of catalytic active palladium
colloids (Table 1).5 Under the adopted reaction conditions,
dppf is an ineffective ligand for the coupling of this
secondary amine. At 1 mol% catalytic loading, less than
12% of products were obtained in 21 h, irrespective of the
electronic nature of the aryl halide ligand (Table 1, entries
1–4). In contrast, ligand 1 gave better yields of products
(entries 5–12).
These observations clearly contradict the established trends
of palladium-catalysed aryl amination reactions, where
electron-withdrawing substituents on the aryl moiety
enhances the rate of turnover in both the bond-breaking
(oxidative addition of aryl halide to the Pd precursor) and
bond-making (reductive elimination of arylpalladium amido
intermediate) steps.7
In our earlier work,2 we have demonstrated that the
hemilability of nitrogen–phosphorus ligands are highly
sensitive to the electronic nature of the palladium metal
centre. Furthermore, in a recent study by Hartwig et al.,
3-coordinate [(L)Pd(Ar)(NAr02)] complexes were reported
to undergo much faster (irreversible) reductive elimination
than their corresponding 4-coordinate [(L)2Pd(Ar)(NAr02)]
complexes in the C–N bond forming step.8 Hence, a slight
modification of the conventional aryl amination catalytic
cycle9 is proposed, to accommodate the hemilability of the
PN ligand (Scheme 3). Following the initial oxidative
addition reaction, a series of ligand exchanges occur,
leading to the formation of 3- and/or 4-coordinated
arylpalladium amido complexes (6 and 7), depending on
the coordination mode of the PN ligand. In the presence of
an electron-rich aryl moiety, the electron density and Lewis
acidity of the palladium(II) metal centre is enhanced, which
discourages the coordination of the p-basic nitrogen donor.
This favours the formation of the complex 7, which
undergoes faster C–N bond formation to furnish the product.
Table 1. Pd-catalysed aryl amination reactions (Scheme 2)a
Entry
Ar-Br
Ligand
Pd:Lb
Yield %c
1
2
3
4
5
6
7
8
4-NCC6H4Br
4-MeCOC6H4Br
PhBr
4-MeOC6H4Br
4-NCC6H4Br
4-NCC6H4Br
4-MeCOC6H4Br
4-MeCOC6H4Br
PhBr
dppf
dppf
dppf
dppf
1
1
1
1
1
1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:0.8
1:1.1
1:0.8
1:1.1
1:0.8
1:1.1
1:0.8
11
—
7
9
36
34
29
21
80
66
83
93
9
10
11
12
PhBr
4-MeOC6H4Br
4-MeOC6H4Br
1
1
a Reaction conditions: Pd2(dba)3$CHCl3, ligand, aryl halide (1 equiv),
N-methylaniline (1 equiv) and sodium tert-butoxide (1.5 equiv) in toluene
at 110 8C, 21 h (reaction time unoptimised).
b Metal-to-ligand ratio (mol%).
c Isolated yield after column chromatography. Duplicated to within 5%.
It is a well-established fact that electron-deficient aryl
bromides are ‘privileged’ substrates in palladium catalysis,
as they undergo cross-coupling reactions much more readily
than electron-rich aryl bromides. In particular,
4-bromoacetophenone demonstrably undergo cross-
coupling reactions with exceptionally high TON’s even in
the absence of any added ligand, thus has been discounted as
a useful benchmark for the evaluation of new catalysts.6 In
light of this, we were surprised to find that ligand 1
imposes an unexpected pattern of reactivity in the aryl
amination reactions: electron-deficient substrates,
4-bromoacetophenone and 4-bromobenzonitrile, gave very
low yield of products under these reaction conditions
(!40%, entries 5 and 7). Conversely, electronically-neutral
(bromobenzene) and the electron-rich (4-bromoanisole) aryl
Scheme 3. Proposed catalytic cycle involving ligand 1.
Further credence to this theory is provided by the effect of
the metal-to-ligand ratio. Lowering the ratio have very little
effect on the reactions involving electron-deficient aryl
bromides (Table 1, entries 5 vs 6, and 7 vs 8), but led to a
marked improvement in the reaction of 4-bromoanisole
(entries 11 and 12). This fits with the conjecture that excess
† Indeed, in the absence of the amine substrate, ligand 1 is able to promote
slow catalytic turnover in the Suzuki–Miyaura cross-coupling between
aryl bromides and aryl boronic acids at 25 8C. Compared to the catalytic
activity of Amphos 2, which catalyses the C–C bond forming reactions in
1–2 h,3 the involvement of the hemilabile amino group in the catalytic
cycle is also clearly implicated.

9824
S. L. Parisel et al. / Tetrahedron 61 (2005) 9822–9826
ligand could lead to the formation of a 4-coordinate
[L2Pd(Ar)(NMePh)] complex, thus inhibiting the formation
of the more reactive metal complex. Interestingly, lowering
the M:L ratio led to a decrease in yield for the reaction
involving the bromobenzene substrate (entries 9 and 10).
The reason for this observation is unclear at this stage—the
presence of a slight excess of the ligand could have
improved the catalyst’s stability, as was observed for
Amphos ligands. However, the operation of a competitive
side reaction cannot be ruled out entirely, as it is difficult to
quantify formation of the dehalogenated product (benzene).
added slowly at room temperature to a solution of
N-methylaniline (5.9 mL, 54 mmol, 1.0 equiv) in EtOH
(100 mL). The reaction mixture was stirred at room
temperature for 30 min before Na2CO3 (19.4 g, 183 mmol,
1.5 equiv) was added and refluxed overnight. After cooling
to room temperature, the solution was concentrated by
evaporation and diluted with 30 mL of Et2O. The
precipitated salts were removed by filtration through Celite,
which were thoroughly rinsed with Et2O and CH2Cl2. The
filtrate was acidified by the addition of 1 M aqueous HCl
(pHZ1). The layers were separated and the aqueous layer
was extracted with Et2O. The combined organic layer was
washed with brine and dried over MgSO4 and evaporated to
furnish a dark oil. The crude product was purified by
distillation under reduced pressure to yield the ester was
obtained as a pale yellow oil (9.73 g, 93%). Bp: 90 8C,
1.0 mmHg (lit.11 90–92 8C, 0.2 mmHg); n (thin film)/cmK1
1742 (C]O); dH (360 MHz, CDCl3) 1.31 (3H, t, JZ7.1 Hz,
CH2CH3), 3.13 (3H, s, NCH3), 4.12 (2H, s, NCH2), 4.24
(2H, q, JZ7.1 Hz, CH2CH3), 6.79 (2H, d, JZ8.7 Hz,
Hortho), 6.85 (1H, t, JZ7.4 Hz, Hpara), 7.33 (2H, dd, JZ7.4,
8.7 Hz, Hmeta); dC (90.5 MHz, CDCl3) 14.7 (s, CH2CH3),
39.9 (s, NCH3), 54.9 (s, NCH2), 61.2 (s, CH2CH3), 112.7 (s,
Cortho), 117.7 (s, Cpara), 129.6 (s, Cmeta), 149.4 (s, Cipso),
171.4 (s, CO).
In summary, the incorporation of a hemilabile amino
functionality with sterically bulky, electron rich di-tert-
butylphosphine aminophosphine led to a very unusual
pattern of reactivity in the palladium-catalysed aryl
amination of aryl halides, contradicting the conventional
notion of ‘activated’ and ‘unactivated’ aryl bromides in
cross-coupling reactions. The serendipitous discovery will
be exploited in the design of ligands for chemoselective
catalysis. Further studies on the coordination and catalytic
chemistry of this and related aminophosphine ligands will
be conducted in our future work.
2. Experimental
2.1. General
2.1.2. N-(2-Hydroxyethyl)-N-methyl-aniline 4.12 In a two-
necked round bottom flask fitted with a condenser, lithium
aluminium hydride (2.9 g, 75 mmol, 2.0 equiv) was
suspended in 30 mL of freshly distilled THF. The reaction
mixture was cooled down to 0 8C, and the ester 3 (7.3 g,
37 mmol, 1.0 equiv) was added dropwise. The solution was
stirred at room temperature for 1 h before being refluxed for
4 h. After cooling to 0 8C, the excess reducing agent was
destroyed carefully by the alternate addition of H2O and
15% aqueous NaCl. The resultant white solid was removed
by filtration through a pad of Celite, which was washed
repeatedly with Et2O. The filtrate was separated and the
aqueous layer extracted with diethyl ether (3!20 mL). The
combined organic layers were dried over MgSO4, filtered
and evaporated to yield the amino alcohol as a pale yellow
liquid, which was employed in the next step without any
further purification (5.2 g, 92%); dH (360 MHz, CDCl3)
2.07 (1H, br s, OH), 2.85 (3H, s, CH3), 3.35 (2H, t, JZ
5.8 Hz, NCH2), 3.68 (2H, t, JZ5.8 Hz, CH2O), 6.65 (1H, t,
JZ7.2 Hz, Hpara), 6.70 (2H, d, JZ8.3 Hz, Hortho), 7.15 (2H,
dd, JZ7.2, 8.3 Hz, Hmeta); dC (90.5 MHz, CDCl3) 39.2 (s,
CH3), 55.8 (s, NCH2), 60.4 (s, CH2O), 113.4 (s, Cortho),
117.6 (s, Cpara), 129.6 (s, Cmeta), 150.4 (s, Cipso).
THF was freshly distilled under N2 from sodium benzo-
phenone. Toluene, CH2Cl2 and n-hexane were freshly
distilled from CaH2 also under N2. Triethylamine was
distilled under Ar from CaH2 and stored over KOH pellets.
Commercially available chemicals were purchased from
Aldrich, Avocado, BDH, Fluka, Lancaster or Strem
chemical companies, which were used as received, unless
otherwise stated. Tris-(dibenzylideneacetone)dipalladium-
(chloroform), Pd2(dba)3$(CHCl3), was prepared by estab-
lished procedure.10 Air- or moisture- sensitive reactions
were carried out under inert atmosphere (N2 or Ar) using
standard Schlenk line techniques. Glassware was oven-dried
overnight. Melting points were determined on electro-
thermal Gallenkamp melting point apparatus and are
uncorrected. Infra-red spectra were recorded on a Perkin-
Elmer Paragon 1000 FTIR spectrometer. H, 13C and 31P
NMR spectra were recorded using Bruker AM 360,
1
1
AVANCE 400 and 500 spectrometers in CDCl3. H NMR
and 13C NMR spectra were referenced to tetramethylsilane
(TMS) while 31P NMR spectra were referenced to H3PO4
(external standard). Chemical shifts are recorded in parts per
million (d, ppm) downfield to TMS or H3PO4. Coupling
constants are given in Hertz (J Hz). The following
abbreviations are used to describe multiplicity: s-singlet,
t-doublet, t-triplet, q-quartet, m-multiplet, dd-double
doublet, dt-double triplet, td-triple doublet. Mass spectra
(MS) were recorded by the mass spectrometry service
within the university of London’s intercollegiate research
services (ULIRS) or EPSRC MS services at university of
swansea, Wales. Elemental analyses were carried out by
elemental analysis service, London metropolitan university.
2.1.3. N-(2-tosylethyl)-N-methyl-aniline, 5.13 p-Toluene-
sulfonyl chloride (4.5 g, 23 mmol, 1.4 equiv) was added
slowly to 11 mL of ice-cooled pyridine. The resulting
orange solution was allowed to warm to room temperature.
After 30 min, the reaction mixture was cooled to K10 8C
(ice-acetone bath), whereupon 4 (2.4 g, 16 mmol, 1.0 equiv)
was added portionwise over 30 min. The mixture was
allowed to warm to room temperature and stirred for 2 h.
The resultant slurry was poured into an ice-water (40 mL),
stirred for 30 min and CH2Cl2 (30 mL) were then added.
The layers were separated and aqueous layer was extracted
with CH2Cl2 (3!20 mL). The combined organic layers
were treated with 4 M aqueous HCl until the pH was acidic
2.1.1. (Methyl-phenyl-amino)-acetic acid ethyl ester, 3.
Ethyl bromoacetate (6.65 mL, 60 mmol, 1.1 equiv) was

S. L. Parisel et al. / Tetrahedron 61 (2005) 9822–9826
9825
(4–5, pH paper). The solution was washed with brine
(30 mL), saturated NaHCO3 (30 mL), dried (MgSO4) and
evaporated to furnish a yellow oil (3.7 g, 75%); dH
(360 MHz, CDCl3) 2.31 (3H, s, CH3), 2.77 (3H, s, NCH3),
3.49 (2H, t, JZ6.1 Hz, NCH2), 4.06 (2H, t, JZ6.1 Hz,
CH2O), 6.47 (2H, d, JZ8.2 Hz, tol), 6.60 (1H, t, JZ7.3 Hz,
Phpara), 7.10 (2H, dd, JZ7.3, 8.6 Hz, Phmeta), 7.18 (2H, d,
JZ8.2 Hz, tol), 7.61 (2H, d, JZ8.6 Hz, Phortho); dC
(90.5 MHz, CDCl3) 22.0 (s, CH3), 39.3 (s, NCH3), 51.6 (s,
NCH2), 67.5 (s, CH2O), 112.5 (s, Phortho), 117.3 (s, Phpara),
128.3 (s, tol), 129.6 (s, Phmeta), 130.2 (s, tol), 133.1 (s, tol),
145.3 (s, Phipso), 150.2 (s, tol).
generate a reaction mixture. Meanwhile, Pd2(dba)3$CHCl3
(13.8 mg, 0.013 mmol, 0.5 mol%), ligand 1$HCl (9.5 mg,
0.030 mmol, 1.1 equiv) and sodium tert-butoxide
(0.032 mmol) were weighed into a separate vessel and
dissolved in warm toluene (1 mL). The solution of the
catalyst precursor was transferred via syringe into the
reaction vessel, which was heated at 100 8C for 21 h. After
cooling, the reaction mixture was diluted with EtOAc
(20 mL) and filtered to remove any insoluble material. The
solvents were evaporated, and the residue was subjected to
column chromatography (flash silica gel) using ethyl
acetate/hexane as eluent.
2.2.1. N-(4-acetophenone)-N-methylaniline.14 dH
2.1.4. [2-Di-(tert-butyl)-phosphinoethyl]-N-methyl-
aniline, 1. Di-tert-butylphosphine (1.0 g, 6.8 mmol,
1.1 equiv) was placed in an oven dried Schlenk tube with
10 mL of degassed Et2O. The solution was cooled down at
0 8C and a solution of tert-butyllithium (1.5 M in pentane,
5.5 mL, 1.3 equiv) was added dropwise. The reaction was
allowed to warm to room temperature. After 1 h, it was
cooled to 0 8C and 1.0 equiv of the tosylate 5 (1.9 g,
6.2 mmol) was added slowly. After stirring at 0 8C for
30 min, the reaction mixture was warmed to room
temperature and stirred for a further 3 h, whereupon the
colour changed from yellow to orange (completion of the
reaction was monitored by recording the 31P NMR spectrum
of the reaction aliquot). The reaction mixture was quenched
by the addition of 2.0 mL of freshly distilled MeOH. The
solvent was then removed in vacuo. Distilled toluene
(20 mL) was added, stirred and the resulting solution was
filtered into a pre-weighed Schlenk tube. The solvent was
evaporated under vacuum to give a pale oil. Ten cubic
centimetres of degassed petroleum ether were added, the
solution was stirred at room temperature and evaporated to
furnish an oily solid. In order to facilitate the handling of
this ligand, the corresponding ammonium salt was formed,
achieved by dissolving the oily solid in degassed Et2O,
followed by addition of a few drops of degassed concd. HCl.
Upon cooling, the ammonium salt precipitated, which was
collected and dried in vacuo. Yield: 91% (1.39 g, pale dense
oil). Although the crystalline ligand may be handled in air
without any problems, it is stored under an inert atmosphere.
Mp (HCl salt) 160–162 8C; Found: C, 72.99; H, 10.73; N,
5.09. C17H30NP requires C, 73.12; H, 10.75; N, 5.02%; dH
(360 MHz, CDCl3) 1.06 (18H, d, 3JPHZ11.2 Hz, CH3), 1.53
(2H, td, 2JPHZ4.8 Hz and 3JHHZ9.0 Hz, NCH2CH2P), 2.86
(3H, s, CH3), 3.43 (2H, td, 3JPHZ4.3 Hz and 3JHHZ9.0 Hz,
NCH2CH2P), 6.60 (2H, d, JZ8.6 Hz, Ph), 7.07 (1H, d, JZ
7.4 Hz, Ph), 7.14 (2H, dd, JZ7.4, 8.6 Hz, Ph); dC
0
(360 MHz, CDCl3) 7.83 (2H, d, JZ9.0 Hz, Hmeta ), 7.44
(2H, dd, JZ8.4, 7.3 Hz, Hmeta), 7.25 (1H, t, JZ8.4 Hz,
Hpara), 7.24 (2H, d, JZ7.3 Hz, Hortho), 6.77 (2H, d, JZ
0
9.0 Hz, Hortho ), 3.40 (3H, s, NCH3), 2.53 (3H, s, COCH3).
2.2.2.
N-(4-Cyanophenyl)-N-methylaniline.15
dH
(360 MHz, CDCl3) 7.40–7.30 (4H, m, Hmeta), 7.18 (1H, t,
JZ7.4 Hz, Hpara), 7.13 (2H, d, JZ7.0 Hz, Hortho), 6.64 (2H,
d, JZ11.0 Hz, Hortho), 3.27 (3H, s, NCH3).
2.2.3. Methyl diphenylamine.16 dH (360 MHz, CDCl3)
7.20 (4H, dd, JZ8.5, 7.3 Hz, Hmeta), 6.90 (4H, d, JZ8.5 Hz,
Hortho), 6.70 (2H, t, JZ7.3 Hz, Hpara), 3.20 (3H, s, NCH3).
2.2.4. N-(4-Methoxyphenyl)-N-methylaniline.17 dH
(360 MHz, CDCl3) 7.24 (2H, dd, JZ9.0, 7.4 Hz, Hmeta),
0
7.15 (2H, d, JZ9.0 Hz, Hmeta ), 6.95 (2H, d, JZ9.0 Hz,
0
Hortho ), 6.87 (2H, d, JZ9.0 Hz, Hortho), 6.85 (1H, t, JZ
7.4 Hz, Hpara), 3.70 (3H, s, OCH3), 3.15 (3H, s, NCH3).
Acknowledgements
The authors are grateful to EPSRC for a project studentship
´
(SLP, GR/M78229/01), Ministerio de Educacion y Cultura
(BQU2002-04533-C02-01/02) and Xunta de Galicia
(Proyecto PGIDIT03PXIC1050PN), Spain, for the enabling
academic visits to KKH’s laboratories at KCL (APO, MMP)
and subsequently at ICL (L.A.A.). We also thank Johnson
Matthey for the provision of palladium salts.
References and notes
1
(90.5 MHz, CDCl3) 18.3 (d, JPCZ23.0 Hz, CH2P), 30.1
2
1
(d, JPCZ13.5 Hz, CH3), 31.7 (d, JPCZ19.0 Hz, CMe3),
1. Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366
and references therein.
2
38.6 (s, CH3), 54.3 (d, JPCZ39.3 Hz, NCH2), 112.8 (s,
Cmeta), 116.6 (s, Cpara), 129.7 (s, Cortho), 149.0 (s, Cipso); dP
(146 MHz, CDCl3)C25.7; m/z (FAB) 280.2 (MHC), 145
(MCKC9H12N), 134 (C9H12NC), 77 (C6HC5 ), 57 (C4H9C).
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