Discovery and synthesis of novel phosphine-based ligands for aryl aminations

Article abstract of DOI:10.1016/j.tetlet.2004.04.095

Three families of ligands were prepared for use in Pd-catalyzed aryl aminations and possibly other Pd-catalyzed reactions. The first series is derived from diarylsulfones, the second from trityl imidazole, and the third from 2-bromobenzophenone. While these ligands were not very general in terms of substrate scope, they do work fairly well under certain specific conditions. Additionally, the preparation of these ligands is amenable to bulk synthesis.

Full text of DOI:10.1016/j.tetlet.2004.04.095

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4715–4718
Discovery and synthesis of novel phosphine-based ligands for
aryl aminations
Robert A. Singer, Norma J. Tom,* Heather N. Frost and Wendy M. Simon
Pfizer Global Research and Development, Chemical Research and Development, Eastern Point Road, Groton, CT 06340, USA
Received 19 January 2004; revised 13 April 2004; accepted 16 April 2004
Abstract—Three families of ligands were prepared for use in Pd-catalyzed aryl aminations and possibly other Pd-catalyzed reac-
tions. The first series is derived from diarylsulfones, the second from trityl imidazole, and the third from 2-bromobenzophenone.
While these ligands were not very general in terms of substrate scope, they do work fairly well under certain specific conditions.
Additionally, the preparation of these ligands is amenable to bulk synthesis.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The preparation of arylamines has proven to be an
important topic in organic synthesis. Arylamines have
been shown to be effective targets for pharmaceuticals
and other biologically active molecules.1 Palladium-
catalyzed aminations of aryl halides have been shown to
be a mild and effective method of synthesizing aryl-
amines.2 While there have been remarkable advances in
the scope of palladium-catalyzed aminations, we initi-
ated our own program to ensure freedom to operate in
this area. It was our goal to design novel ligands that
could be easily prepared in bulk quantities that will
participate in palladium-catalyzed aminations and
possibly other palladium-catalyzed processes.3 The
work described in this paper focuses on three families of
ligands that were designed to mimic Buchwald’s
monodentate biarylphosphine ligands that have been
shown to be fairly general in scope for catalyzing
aminations of aryl halides.4 While Buchwald’s ligands
have been shown to be highly useful for aryl aminations,
the synthesis of the ligands can be rather complicated.
Our goal was to design ligands that could be easily
prepared in large quantities with a minimal number of
steps from commercially available starting materials.
Towards this end, we targeted three different series; the
sulfone ligands 1, the imidazole ligands 2, and the ‘exo-
olefin’ ligand 3.
As shown in Scheme 1, the sulfone ligands are prepared
in one step by ortho-metalation with n-BuLi of com-
mercially available phenylsulfone or a substituted
diarylsulfone, followed by addition of the dialkylchloro-
phosphine. The product phosphine can be isolated in
pure form by recrystallization from isopropanol. The
imidazole ligands are prepared from trityl imidazole via
metalation with n-BuLi, followed by addition of the
dialkylchlorophosphine. Again, pure product is isolated
by recrystallization from isopropanol. Unfortunately,
the synthesis of the exo-olefin ligands was slightly more
complicated. The Petasis reagent, which was prepared
according to literature procedures,5 was used to install
the olefin moiety. Thus, treatment of 2-bromobenzo-
phenone with the Petasis reagent afforded the exo-
olefin. Metal–halogen exchange was accomplished with
n-BuLi and the anion was then quenched with the
dialkylchlorophosphine. Pure product is obtained by
recrystallization from ethanol. While there are probably
better ways to synthesize this class of ligands, at this
point, it was not efficient to optimize the synthesis of this
unproven ligand. We were pleasantly surprised to find
that these ligands were remarkably air stable. Samples
sitting on the benchtop for several months retained their
catalytic activity. These ligands were even stable to silica
gel chromatography as early samples were purified via
this method.
To demonstrate the efficacy of these new phosphine
ligands, four amines were reacted with three aryl halides
as shown in Table 1. Standard conditions were 1.0 equiv
Keywords: Pd-catalyzed aryl amination; Phosphine ligands.
* Corresponding author. Tel.: +1-860-715-5270; fax: +1-860-441-5540;
e-mail: norma_j_tom@groton.pfizer.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.095

4716
R. A. Singer et al. / Tetrahedron Letters 45 (2004) 4715–4718
1a: R = Cy, R' = H (72%)
O
O
O
O
1b: R = Cy, R' = CH3 (64%)
1c: R = iPr, R' = H (60%)
1d: R = iPr, R' = CH3 (61%)
1e: R = tBu, R' = H (16%)
1f: R = tBu, R' = CH3 (19%)
S
S
R'
R'
R'
R'
PR2
Ph
Ph
Ph
Ph
Ph
i. n-BuLi, -78 oC, THF
Ph
PR2
2a: R = Cy (51%)
2b: R = iPr (36%)
N
N
N
N
ii. R2PCl, -78 to 20 oC
R
R
P
Br
3: R = Cy (40%)
1.4 M Petasis
Reagent in
toluene
80 oC
Br
O
Scheme 1.
Table 1
Entry
Aryl halide
Amine
Yield (%) with 1b
Yield (%) with 2a
Yield (%) with 3
O
MeO
1a
52
87
96
N
H
Br
Br
NH2
MeO
2b
91
82
85
MeO
MeO
NH2
3
4
N/A
12
N/A
55
9
Br
Br
N
H
49
O
5c
79
63
81
59
60
72
N
H
Br
NH2
6d
Br
NH2
7
8
N/A
38
12
43
N/A
42
Br
Br
N
H

R. A. Singer et al. / Tetrahedron Letters 45 (2004) 4715–4718
4717
Table 1 (continued)
Entry
Aryl halide
Amine
Yield (%) with 1b
Yield (%) with 2a
Yield (%) with 3
O
O2N
9e
97
78
84
N
H
Br
Br
NH2
O2N
10
11
87
50–60f
58
O2N
O2N
NH2
N/A
87
N/A
67
N/A
50
Br
Br
N
H
12
a 83%.4a
b 90% With aniline.4a
c 86%.4a
d 87% With aniline.4a
e 83% With BINAP.4c
f Yield determined by HPLC as reaction did not proceed to completion.
of the aryl halide, 1.1–1.2 equiv of the amine, 1.3 equiv
of sodium t-butoxide or cesium carbonate (when the
aryl halide contains functionality not compatible with
a strong base), 0.05 equiv of palladium acetate, and
0.06 equiv of the ligand in 10 volumes (relative to the
halide) of toluene at 100 ꢁC for 2–24 h. For all three
series of phosphine ligands, electron-rich 4-bromoani-
sole and 4-bromo-t-butylbenzene were viable substrates
with morpholine and 2,6-dimethylaniline. Yields were
moderate to excellent. For the primary amine, only trace
product was observed, with dehalogenation of the halide
being the major side reaction. For the secondary acyclic
amine, N-methylbenzylamine, moderate yields were
obtained. Again, the major by-product was dehalogen-
ation of the aryl halide. With the electron poor sub-
strate, 4-nitrobromobenzene, the sulfone ligands proved
to be very effective for morpholine, 2,6-dimethylaniline,
and N-methylbenzylamine, with yields between 87% to
nearly quantitative, while the other ligands afforded the
aminated products in moderate to good yields. Unfor-
tunately, none of the ligands formed competent catalysts
for primary amines.
These ligands were briefly examined with 4-bromoace-
tophenone as the halide and morpholine and 2,6-di-
methylaniline as the amine (See Table 2). Both ligands
1b and 3 provided desired product in moderate yields. It
was interesting to note that the major by-product with
ligand 1b was ketone arylation of the product. With
some optimization, ligand 1b might be competent in
catalyzing ketone arylations.
In summary, we have prepared three families of phos-
phine ligands for use in the palladium-catalyzed amina-
tion reaction. Both ligands 1 and 2 could be readily
prepared in one step by metalation with n-BuLi, fol-
lowed by trapping of the anion with a chlorodialkyl-
phosphine. Thus, these ligands are amenable to bulk
synthesis. While these ligands were not very general in
terms of substrate scope, they do work fairly well under
certain specific conditions. These ligands do not have the
general scope or the exceptional catalytic activity dem-
onstrated by Buchwald’s biaryl ligands, but the ease of
preparation justifies their use in certain cases where they
have been found to be effective.
Table 2
Entry
Halide
Amine
Yield (%) with 1b
Yield (%) with 3
O
O
1
58
58
N
H
Br
Br
O
NH2
2a
33
40
a 96% With aniline.4a

4718
R. A. Singer et al. / Tetrahedron Letters 45 (2004) 4715–4718
1. Experimental section
2.5 M solution in hexanes, 29.9 mmol) was added. The
resultant solution was then stirred at )78 ꢁC for 30 min
and quenched with chlorodicyclohexylphosphine
(7.25 mL, 32.6 mmol). The reaction was allowed to
slowly warmed to room temperature and then was
quenched with water (70 mL) and extracted with ethyl
acetate (3 · 70 mL). The combined organic layers were
dried over sodium sulfate and concentrated in vacuo.
The crude product was reslurried in ethanol (7 mL) to
afford 3 as a white solid (5.5 g, 54%).
1.1. Dicyclohexyl-[5-methyl-2-(toluene-4-sulfonyl)-phen-
yl]-phosphane (1b)
To a solution of p-tolylsulfone (4.8 g, 19.5 mmol) in
THF (50 mL) at )40 ꢁC was added n-BuLi (8.6 mL of a
2.5 M solution in hexanes, 21.5 mmol). The reaction
mixture was warmed to )20 ꢁC and stirred for 2 h.
Dicyclohexylchlorophosphine (5 g, 21.5 mmol) was
added and the reaction was warmed to room tempera-
ture and stirred for 2 h. The reaction was quenched with
saturated sodium bicarbonate solution (25 mL) and the
resulting mixture was extracted with dichloromethane
(100 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo. The crude product
was reslurried in isopropanol (90 mL) and provided pure
1b as a white solid (5.5 g, 64%).
1.4. General preparation for the catalytic amination of
aryl bromides
A solution of palladium acetate (14 mg, 62 lmol) and
the ligand (74 lmol) in toluene (2.5 mL) was sparged
with nitrogen for 15 min. The aryl halide (1.24 mmol),
the amine (1.49 mmol), and the base, either sodium
t-butoxide or cesium carbonate (1.61 mmol) was added
and the resultant reaction mixture was heated at 100 ꢁC
for 2–24 h (reaction times were not minimized). The
reaction was cooled to room temperature, quenched
with water (15 mL), and extracted with ethyl acetate
(2 · 15 mL). The combined organic layers were dried
over sodium sulfate and concentrated in vacuo. The
material was purified via column chromatography on
silica gel typically using a mixture of ethyl acetate and
hexanes as eluent.
1.2. 2-Dicyclohexylphosphanyl-1-trityl-1H-imidazole (2a)
To a solution of trityl imidazole (6.06 g, 19.5 mmol)
in THF (60 mL) at )40 ꢁC was added n-BuLi (8.6 mL
of a 2.5 M solution in hexanes, 21.5 mmol). The reaction
mixture was warmed to )20 ꢁC and stirred for 2 h.
Dicyclohexylchlorophosphine (5 g, 21.5 mmol) was
added and the reaction was warmed to room tempera-
ture and stirred for 2 h. The reaction was quenched with
saturated sodium bicarbonate solution (25 mL) and the
resulting mixture was extracted with dichloromethane
(100 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo. The crude product
was reslurried in isopropanol (60 mL) and provided pure
2a as a white solid (5.04 g, 51%).
References and notes
1. Lednicer, D. Strategies for Organic Drug synthesis and
Design; John Wiley and Sons: New York, 1998.
2. For reviews on the Pd-catalyzed amination reaction, see: (a)
Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125; (b) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805;
(c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046.
1.3. Dicyclohexyl-[2-(1-phenyl-vinyl)-phenyl]-phosphane
(3)
2-Bomobenzophenone (9.50 g, 36.4 mmol) was added to
the Petasis reagent (150 mL of a 0.48 M solution in
toluene, 72.7 mmol) and heated at 80 ꢁC for 12 h. The
reaction was cooled to room temperature and isopropyl
ether (95 mL) was added. The yellow slurry was stirred
for 30 min and the solids were then removed by filtration
over Celite. The mother liquor was then concentrated
and purified by column chromatography (99:1 hexanes/
triethylamine) to provide the exo-olefin as a clear and
colorless oil (7 g, 74%).
3. Singer, R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do,
N. M. Synthesis 2003, 11, 1727.
4. (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158; (b) Old, D.
W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722; (c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.
2000, 65, 1144.
5. Dollinger, L. M.; Ndakala, A. J.; Hashemzadeh, M.; Wang,
G.; Wang, Y.; Martinez, I.; Arcari, J. T. T.; Galluzzo, D. J.;
Howell, A. R. J. Org. Chem. 1999, 64, 7074, and references
cited therein.
A solution of the exo-olefin (7.0 g, 27.0 mmol) in THF
(70 mL) was cooled to )78 ꢁC and n-BuLi (12 mL of a