Alternative biarylphosphines for use in the palladium-catalyzed amination of aryl halides

Article abstract of DOI:10.1055/s-2003-40881

Two families of biarylphosphine ligands were prepared for use in the Pd-catalyzed amination reaction. The first series investigated was derived from N-phenylpyrroles, and the second, was derived from N-phenylpyrazoles. While the pyrrole ligands were not as general in substrate scope, one of the readily prepared pyrazole ligands (R = t-Bu) was found to have a fairly broad substrate scope.

Full text of DOI:10.1055/s-2003-40881

PAPER
1727
Alternative Biarylphosphines for Use in the Palladium-Catalyzed Amination
of Aryl Halides
B
iarylphosphines
o
for
U
se in
t
b
e-Catalyzed
r
A
minati
t
on A. Singer,* Stephane Caron, Ruth E. McDermott, Patrice Arpin, Nga M. Do
Chemical Research and Development, Central Research Division, Pfizer Inc., Eastern Point Road, P.O. Box 8118 Groton,
Connecticut 06340-8118, USA
Fax +1(860)4415540; E-mail: robert_a_singer@groton.pfizer.com
Received 14 May 2003
Ph
Ph
Ph
N
Ph
N
Abstract: Two families of biarylphosphine ligands were prepared
for use in the Pd-catalyzed amination reaction. The first series in-
vestigated was derived from N-phenylpyrroles, and the second, was
derived from N-phenylpyrazoles. While the pyrrole ligands were
not as general in substrate scope, one of the readily prepared pyra-
zole ligands (R = t-Bu) was found to have a fairly broad substrate
scope.
N
N
N
N
Ph
Ph
Ph
P(Cy)2
Ph
P(tBu)2
P(iPr)2
P(tBu)2
1
2
3
4
Figure 1 Structures of phenylpyrroles 1,2 and phenylpyrazoles 3,4
Key words: palladium, catalysis, ligands, biaryls, aminations
sterics of the phosphine ligand, and to block positions on
the heterocycle that otherwise might not be chemically in-
ert.
The palladium-catalyzed amination of aryl halides has
been recognized as a viable alternative to traditional nu-
cleophilic aromatic substitution and various other classi-
cal methods of introducing arylamines in target
molecules, including nitration of arenes followed by re-
duction.1 This methodology had attracted our attention
due to the prevalence of the arylamine functionality in
pharmaceutical drug candidates.2 While many different
phosphine ligands have been identified that participate in
this Pd-catalyzed process, we initiated our own program
to ensure our freedom to operate in this area and to iden-
tify ligands that could be readily prepared in bulk quanti-
ty. The work described herein focuses on two families of
ligands analogous in structure to the Buchwald group’s
monodentate biarylphosphines that have proven to be rel-
atively general in scope for catalyzing the amination of
aryl halides.3 While the Buchwald group’s ligands have
been shown to be highly effective, it would be ideal to
identify a surrogate ligand family that could be assembled
in a process more amenable to large scale.4 Our strategy
was to target biaryls derived from heterocycles that could
be prepared by a straightforward condensation reaction.
Toward this end, we investigated ligands derived from
phenylpyrroles 1 and 2 and phenylpyrazoles 3 and 4
(Figure 1). For both series we incorporated additional
phenyl substituents to enhance crystallinity, increase the
Initially, the pyrrole series was prepared by the route
shown below (Scheme 1). The triarylpyrrole core 7 was
prepared by a condensation reaction between 5 and 6 in
toluene. Next, the phosphine was introduced by halogen–
metal exchange with n-BuLi. The product phosphine
could be directly isolated by crystallization from the reac-
tion mixture by dilution with methanol, or isopropyl alco-
hol and water. Unfortunately, there were issues preparing
the di-tert-butylphosphine derivative by halogen ex-
change with alkyllithiums. Typically, an equal distribu-
tion of products was obtained, consisting of the desired
phosphine 2, the desbromo derivative of 7 and the n-butyl-
ated derivative of 7 (formed by trapping lithiated 7 with
butyl bromide). Because of this issue, ligand 2 was isolat-
ed in combination with the desbromo and n-butylated de-
rivatives, and used in an impure form.5
Next, we turned our attention to the pyrazole series to ex-
amine the effect of reducing the steric environment
around the Pd. The triphenylpyrazole scaffold was pre-
pared by heating 8 and 9 in isopropyl alcohol, and upon
cooling, the product 10 crystallized from the reaction mix-
ture (Scheme 2).9 The issues observed with the lithiation
in the pyrrole series were circumvented in the pyrazole se-
ries by switching to an ortho-directed lithiation strategy.6
For either ligand 3 or 4, compound 10 was treated with n-
Scheme 1
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1727,1731,ftx,en;C03203SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1728
R. A. Singer et al.
PAPER
BuLi in THF at –78 °C initially, and then warmed to 0 °C.
The lithiated arene was then trapped with the desired chlo-
rodialkylphosphine to afford the corresponding phosphine
ligand. This approach (Scheme 2) greatly simplified the
preparation of the ligands and allowed for facile prepara-
tion of the di-tert-butylphosphine derivative 4, which was
otherwise not as accessible by halogen–metal exchange.
Table 1 Scope of Coupling 4-tert-Butylphenylbromide with
Aminesa
Pd2(dba)3, Ligand,
t-BuONa, toluene,
85 o
C
+ HNRR'
R'
Br
N
R
Entry
1
Amine
Yield (%) Yield (%) Yield (%) Yield (%)
n-BuLi, THF,
with 1
with 2
with 3
with 4
oC, then
O
0
i-PrOH,
AcOH, ∆
Ph
Ph
H
Ph
Ph
R2PCl
N
N
N
N
N
90
40
99
93
NH2
+
NH
O
96%
PR2
O
Ph
Ph
93b
94
9
8
2
3
10
3, R = iPr, 86%
4, R = tBu, 76%
86
74
96
NH2
Scheme 2
4
5
99b
83
To demonstrate the efficacy of these phosphines, a variety
of amines were reacted with 4-tert-butylphenyl bromide
(Table 1). Standard conditions for the reactions were 4-
tert-butylphenyl bromide (1 equiv), amine (1.25 equiv), t-
BuONa (1.2 equiv), Pd2(dba)3 (0.02 equiv), phosphine
ligand (0.05 equiv) and in toluene (to make a 0.05 M so-
lution relative to aryl halide) at 85 °C. Typically Pd2(dba)3
performed better as a Pd source than Pd(OAc)2. Couplings
with anilines or secondary amines were complete within 1
to 3 hours (with ligands 1, 3, or 4), while couplings with
primary alkylamines were usually complete within 4–8
hours. The dicyclohexylphosphine-derived pyrrole ligand
1 was found to be effective for coupling secondary cyclic
amines and anilines but was less efficient with secondary
acyclic amines and primary alkylamines. We had antici-
pated that the more hindered di-tert-butylphosphine 2
would be efficient for coupling unbranched primary
amines, but we were surprised that it performed poorly
with all other amines, including -branched primary
alkylamines. Though the yield in entry 3 was good when
using 2, the reaction required 24 hours to reach this extent
of conversion (74%). From these results it is clear that the
two pyrrole ligands are complementary in scope to one
another and the appropriate ligand could be chosen based
on the amine desired to be coupled. Unfortunately, the
preparation of ligand 2 was not as practical as would be
desirable, but it did provide valuable insight into the ef-
fects of sterics on the substrate scope.
16
83
5c
79
55
N
H
6
7
87b
86
48
NH2
8
9
95d
90
66
10
83
99
3c
NH2
10
11
89d
89
NH2
60
12
69d
a Isolated yields. Reaction conditions: 0.02 equiv Pd2(dba)3 (0.02
equiv), phosphine ligand (0.05 equiv), 1.2 equiv t-BuONa (1.2 equiv)
and toluene (to make a 0.5 M solution relative to aryl halide) at 85 °C.
b Reaction conducted in tert-amyl alcohol (1.0 M) with Pd2(dba)3
(0.005 equiv) and 4 (0.0125 equiv).
c Not isolated, incomplete conversion measured by GC.
d Reaction conducted in tert-amyl alcohol (1.0 M).
examination, it was observed that 3 and 4 were not as
compatible with weaker bases (Cs2CO3 and K3PO4) for re-
actions conducted in toluene (see Table 2); however, 1,
worked equally well with Cs2CO3 and t-BuONa in toluene
(see Table 2, entries 4, 5, and 7). It is unclear why 3 and 4
have this disparity in performance when switching the
base, but it is likely to be related to the formation of a sta-
ble Pd complex that can not be broken without participa-
tion from t-BuONa.7 Following this hypothesis, reactions
were conducted with 3 and 4 in tert-amyl alcohol. We sus-
pected that the Cs2CO3 would generate a small amount of
tert-pentoxide and this might activate the catalyst in a
manner similar to t-BuONa. The solvent switch did in-
deed improve the performance of 3 and 4 (see Table 2, en-
We next examined the scope of the pyrazole ligands, 3
and 4. Reactions screened with ligand 3 showed that it
possessed a substrate scope slightly broader than ligand 1,
though it was not effective with primary alkylamines (see
Table 1). Given these results with 1, 2, and 3, we expected
the di-tert-butylphosphinepyrazole-derived ligand, 4, to
have a potentially broader substrate scope, since it has a
more crowded steric environment than 3 to enable cou-
pling of primary alkylamines, yet less severe sterics than
2. As shown above in Table 1, ligand 4 was indeed the tries 8, 10 and 12). This solvent effect was also apparent
most general in scope for the substrates initially screened.
with examples using t-BuONa as base. Using tert-amyl al-
cohol, the catalyst loading with 4 could be lowered to 1%
Pd in many cases, affording product in excellent yields
(see Table 1, entries 2, 4 and 6; and Table 2 entries 2 and
Generally, aryl halides coupled more effectively with 4
than with 3, and 4 was more effective than 1 as well, but
only when employing t-BuONa as a base. Upon further
Synthesis 2003, No. 11, 1727–1731 © Thieme Stuttgart · New York

PAPER
Biarylphosphines for Use in the Palladium-Catalyzed Amination of Aryl Halides
1729
4).8 For secondary amines and dimethylaniline, the cou-
plings reached completion within 2 hours using only 1%
Pd. Unfortunately, primary amines were still problematic
and required higher Pd loadings to reach completion (see
entries 8, 10 and 12 of Table 1), though phenethylamine
failed to reach completion even under these conditions
with ligand 4.
Table 2 Scope of Coupling Morpholine with Aryl Halidesa
Pd2(dba)3, Ligand,
t-BuONa, toluene,
85 °C
O
O
ArX +
N
HN
Ar
Entry
Aryl Halide
Yield (%) Yield (%) Yield (%)
with 1
with 3
with 4
In summary, we have identified two related families of
phosphine ligands that performed competently in the Pd-
catalyzed amination reaction. Ligands 1, 3, and 4 were
readily prepared by a condensation, followed by lithiation
and trapping with a chlorodialkylphosphine. Of the
ligands examined in this study, 4 appeared to be the most
broad in scope for reactions with t-BuONa as base and a
significant enhancement of activity was observed by
switching the solvent to tert-amyl alcohol. While none of
the ligands investigated may necessarily have quite the
general scope or exceptional catalytic activity demon-
strated by Buchwald’s biaryl ligands, the simplicity of
preparing 1, 3, and 4 justify their use for specific process
related cases in which they are found to be effective.
1
85
76
83
Cl
MeO
2
3
90b
88
Br
79
77
71
3d,e
MeO
4
5
99b
85
39
Br
OMe
6
7
90c
9d,e
78d
Br
8
9
50f
17
75f
15
All reagents and solvents (Sure/SealTM bottles) were purchased
from Sigma-Aldrich and used without any additional purification.
Laboratory scale reactions were conducted under dry N2. Reaction
progress was monitored by GC/MS using a Hewlett-Packard 6890
GC/MS with a 5973 mass selective detector. 1H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded on a Varian Unity-
plus-400 instrument. Combustion analyses were performed by
Schwarzkopf Microanalytical Laboratory, Woodside, NY. Melting
points were measured in open capillary tubes and are uncorrected.
90d
89d
Br
F3C
10
11
48f
88f
25d,e
23d,e
Br
O2N
12
74f
68f
Pd-Catalyzed Amination Reactions with Aryl Halides; General
Procedure
a Isolated yields. Reaction conditions: Pd2(dba)3 (0.02 equiv), phos-
phine ligand (0.05 equiv), NaOBu-t (1.2 equiv) and toluene (to make
a 0.5 M solution relative to aryl halide) at 85 °C.
To a purple solution of Pd2(dba)3 (46 mg, 0.0500 mmol), ligand
(0.125 mmol), and base (3.00 mmol) in toluene (5.00 mL) was add-
ed the amine (3.13 mmol) and the aryl halide (2.50 mmol). The or-
ange solution was heated to 85 °C for 2–16 h (reaction times were
not minimized). The reaction was cooled to r.t., quenched with H2O
(15 mL) and extracted with EtOAc (15 mL). The organic layer was
washed with brine (10 mL), dried (Na2SO4) and concentrated in
vacuo. The coupled product was isolated by flash chromatography
on silica gel typically using a mixture of hexane and EtOAc as elu-
ent.
b Reaction conducted in tert-amyl alcohol (1.0 M) with Pd2(dba)3
(0.005 equiv), 0.0125 equiv 4.
c Reaction conducted in tert-amyl alcohol (1.0 M).
d Reaction conducted with Cs2CO3 in toluene (0.5M).
e Not isolated, incomplete conversion measured by GC.
f Reaction conducted with Cs2CO3 in tert-amyl alcohol (1.0 M).
13C NMR (CDCl3): = 26.3, 27.4 (dd, J = 11, 15 Hz), 29.9 (dd,
J = 13, 58 Hz), 34.3 (d, J = 12 Hz), 110.1, 126.2, 128.2, 128.5,
128.9, 132.8, 133.8, 134.2, 137.7.
1-(2-Dicyclohexylphosphinophenyl)-2,5-diphenyl-1H-pyrrole
(1)
Anal. Calcd for C34H38NP: C, 83.06; H, 7.79; N, 2.85. Found: C,
83.21; H, 7.73; N, 2.92.
To a solution of 1-(2-bromophenyl)-2,5-diphenyl-1H-pyrrole (21.0
g, 56.1 mmol) in THF (140 mL) cooled to –78 °C was slowly added
n-BuLi (25.0 mL of a 2.5M solution in hexanes, 62.5 mmol). The
reaction mixture was stirred for 45 min and dicyclohexylchloro-
phosphine (15.0 mL, 67.9 mmol) was added. MeOH (230 mL) was
slowly and the solvent was removed under reduced pressure. MeOH
(300 mL) was added and the mixture was stirred overnight. The sol-
ids were filtered to provide the desired product (21.8 g, 79%); mp
135 °C.
1-(2-Di-tert-butylphosphinophenyl)-2,5-diphenyl-1H-pyrrole
(2)
To a solution of 1-(2-bromophenyl)-2,5-diphenyl-1H-pyrrole (2.4
g, 6.4 mmol) cooled to –78 °C was slowly added n-BuLi (3.1 mL of
a 2.5 M solution in hexanes, 7.8 mmol). The reaction mixture was
stirred for 45 min and di-tert-butylchlorophosphine (1.6 mL, 8.4
mmol) was added. After 2 h, the reaction mixture was allowed to
warm to r.t. MeOH (30 mL) was added and the solvent was removed
under reduced pressure (3 ×). Hexanes (30 mL) was added and the
mixture was stirred for 48 h. The solids were filtered and the solids
were further purified by silica gel chromatography (40% CH2Cl2–
hexanes) to provide the desired material 2 as a white solid (0.80 g,
28%); mp 196–199 °C.
IR (film): 2921, 2848, 1600, 1468, 1446, 1333, 907, 750, 729, 694
cm–1.
1H NMR (CDCl3): = 0.46–0.59 (m, 2 H), 0.96–1.07 (m, 10 H),
1.28–1.66 (m, 10 H), 6.63 (d, 2 H J = 0.6 Hz), 7.08–7.20 (m, 6 H),
7.23–7.29 (m, 4 H), 7.44–7.56 (m, 3 H), 7.75–7.78 (m, 1 H).
Synthesis 2003, No. 11, 1727–1731 © Thieme Stuttgart · New York

1730
R. A. Singer et al.
PAPER
IR (film): 3058, 2956, 2892, 2861, 1601, 1484, 1464, 1388, 1362,
909, 779, 751, 695, 600 cm–1.
13C NMR (C6D6): = 27.0 (d, J = 15.0 Hz), 30.2 (d, J = 12.0 Hz),
30.9 (d, J = 15.1 Hz), 103.6, 125.9, 127.5, 125.2 (d, J = 20.0 Hz),
127.7, 127.9, 128.4, 128.8, 129.2, 130.2 (d, J = 3.0 Hz), 132.1,
134.4, 136.1 (d, J = 3.0 Hz), 136.9 (d, J = 34.6 Hz), 146.3, 147.8 (d,
J = 27.1 Hz), 150.7.
1H NMR (CDCl3): = 0.73 (d, 18 H, J = 11.6 Hz), 6.54 (s, 2 H),
7.03 (tt, 2 H, J = 7.5, 1.7 Hz), 7.10 (t, 4 H, J = 7.5 Hz), 7.16 (s, 2 H),
7.18 (t, 2 H, J = 1.7 Hz), 7.38 (t, 1 H, J = 6.6 Hz), 7.46 (t, 1 H,
J = 6.6 Hz), 7.70 (d, 1 H, J = 7.5 Hz), 7.74 (ddd, 1 H, J = 7.9, 4.2,
1.2 Hz).
Anal. Calcd for for C29H33N2P: C, 79.06; H, 7.55; N, 6.36. Found:
C, 79.04; H, 7.55; N, 6.46.
13C NMR (CDCl3): = 30.6 (d, J = 15.8 Hz), 32.2 (d, J = 24.8 Hz),
110.3, 125.9, 127.5, 128.1, 128.6, 128.8, 133.2 (d, J = 3.8 Hz),
134.5 (d, J = 1.5 Hz), 137.47, 137.49, 138.4 (d, J = 37.6 Hz), 145.8
(d, J = 27.1 Hz).
1-(2-Bromophenyl)-2,5-diphenyl-1H-pyrrole (7)
To a solution of dibromoaniline (20.0 g, 116 mmol) in toluene (130
mL) was added 1,4-diphenylbutane-1,4-dione (23.0 g, 96.5 mmol)
and p-TsOH (220 mg). The mixture was heated for 10 h using a
Dean–Stark apparatus. The reaction was cooled to r.t. (solids ap-
pear) and most of the solvent was evaporated under reduced pres-
sure. Hexanes (140 mL) was added and the solids were filtered,
washed with hexanes (30 + 20 mL) and dried to afford 7 (31.2 g,
93%); mp 164–165 °C.
1-(2-Di-isopropylphosphinophenyl)-3,5-diphenyl-1H-pyrazole
(3)
To a solution of 10 (see below) (6.17 g, 20.8 mmol) in THF (30 mL)
at –78 °C was added a 2.5 M solution of n-BuLi (10.0 mL, 25.0
mmol) in hexanes. After 20 min, the reaction was warmed to 0 °C.
The reaction mixture was stirred for 1 h at 0 °C and then di-isopro-
pylchlorophosphine (3.98 mL, 25.0 mmol) was added. The red col-
or of the reaction immediately faded to a yellow and a suspension
was formed. The reaction mixture was warmed to r.t., quenched
with H2O (30 mL), and extracted with EtOAc (30 mL). The organic
layer was separated, washed with brine (20 mL), dried (Na2SO4)
and concentrated in vacuo. The residue was taken up in i-PrOH (20
mL) and concentrated in vacuo to afford crystals. The crystals were
stirred in i-PrOH (30 mL) at r.t. for 3 h. The crystals were filtered,
washed with i-PrOH (15 mL), and dried to afford 3 (7.38 g, 86%) as
white crystals; mp 117–119 °C.
IR (film): 1602, 1481, 1028, 754, 729, 695 cm–1.
1H NMR (CDCl3): = 6.50 (s, 2 H), 7.17–7.29 (m, 11 H), 7.32, (dd,
1 H, J = 1.6, 7.2 Hz), 7.37 (dd, 1 H, J = 1.9, 7.8 Hz), 7.55 (dd, 1 Hz,
J = 1.6, 7.8 Hz).
13C NMR (CDCl3): = 110.1, 124.8, 126.8, 128.1, 128.3, 128.7,
129.9, 132.1, 133.4, 133.6, 136.5, 139.8.
Anal. Calcd for C22H16BrN: C, 70.60; H, 4.31; N, 3.74. Found: C,
70.26; H, 4.26; N, 3.71.
1,3,5-Triphenyl-1H-pyrazole (10)
To a solution of phenylhydrazine (10.6 g, 98.5 mmol) and 1,3-
diphenylpropane-1,3-dione (20.0 g, 89.5 mmol) in i-PrOH (120
mL) was added HOAc (2 mL). The solution was heated to 80 °C for
8 h. The solution was then cooled to r.t. While cooling (at about 50
°C) crystals began to form. The suspension was stirred for 2 h at r.t.
and then was filtered. The filter cake was washed with i-PrOH (50
mL) and dried to afford 10 as white crystals (25.4 g, 96%);9 mp
135–136 °C.
IR (film): 3061, 2950, 2922, 2865, 1484, 1459, 1359, 971, 757, 691,
662, 601 cm–1.
1H NMR (C6D6): = 0.59 (br s, 6 H), 0.89 (d, 3 H, J = 7.1 Hz), 0.93
(d, 3 H, J = 7.5 Hz), 1.7–1.8 (m, 2 H), 6.78 (s, 1 H), 6.87–6.99 (m,
6 H), 7.16 (d, 1 H, J = 7.5 Hz), 7.21–7.25 (m, 4 H), 7.28–7.31 (m, 1
H), 8.1 (d, 2 H, J = 7.9 Hz).
13C NMR (C6D6): = 19.3 (d, J = 12.0 Hz), 20.0 (d, J = 19.6 Hz),
20.4 (d, J = 15.1 Hz), 103.5, 125.9, 125.5 (d, J = 18 Hz), 127.7,
127.9, 128.2, 128.8, 129.0, 129.3, 129.4 (d, J = 3.8 Hz), 131.6,
133.1 (d, J = 3.8 Hz), 134.3, 136.4 (d, J = 27 Hz), 146.2, 147.1 (d,
J = 23 Hz), 151.1 .
IR (film): 3061, 1595, 1496, 1458, 1362, 971, 911, 759, 732, 691,
598 cm–1.
1H NMR (CDCl3): = 6.82 (s, 1 H), 7.24–7.39 (m, 11 H), 7.41–7.45
(m, 2 H), 7.93 (dd, 2 H, J = 1.2, 7.5 Hz).
13C NMR (CDCl3): = 105.4, 125.5, 126.0, 127.7, 128.2, 128.5,
128.7, 128.9, 129.0, 129.1, 130.8, 133.2, 140.4, 144.6, 152.2.
Anal. Calcd for for C27H29N2P: C, 78.61; H, 7.09; N, 6.79. Found:
C, 78.70; H, 7.12; N, 6.90.
1-(2-Di-tert-butylphosphinophenyl)-3,5-diphenyl-1H-pyrazole
(4)
Acknowledgments
To a solution of 10 (see below) (6.17 g, 20.8 mmol) in THF (30 mL)
at –78 °C was added a 2.5 M solution of n-BuLi (10.0 mL, 25.0
mmol) in hexanes. After 20 min, the reaction was warmed to 0 °C.
The reaction mixture was stirred for 1 h at 0 °C and then di-tert-bu-
tylchlorophosphine (4.75 mL, 25.0 mmol) was added. Gradually the
red color of the solution faded. The mixture was warmed to r.t. over
1 h. After stirring for 8 h, the orange solution was quenched with
H2O (5 mL) and i-PrOH (50 mL). The reaction mixture was concen-
trated in vacuo until crystals were formed (once all the hexanes and
THF were removed). The crystals were stirred in the remaining res-
idue (about 40–50 mL of solvent) at 0 °C for 3 h. The crystals were
filtered, washed with isopropyl alcohol (15 mL), and dried to afford
4 (7.00 g, 76%) as white crystals; mp 138–139 °C.
The authors would like to thank Michael Burmaster and John A. Ra-
gan for aiding our studies with the initial preparation of ligand 2.
We would also like to thank Professor Stephen L. Buchwald for hel-
pful discussions.
References
(1) 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.
(2) Lednicer, D. Strategies for Organic Drug Synthesis and
Design; Wiley: New York, 1998.
IR (film): 3061, 2956, 2892, 2861, 1486, 1463, 1361, 1175, 971,
809, 758, 692, 601, 567 cm–1.
1H NMR (C6D6): = 0.74 (d, 9 H, J = 10.4 Hz), 0.99 (d, 9 Hz,
J = 10.4 Hz), 6.74 (s, 1 Hz), 6.86–7.04 (m, 6 Hz), 7.23 (t, 2 Hz,
J = 7.5 Hz), 7.28 (d, 2 Hz, J = 7.5 Hz), 7.44–7.47 (m, 1 Hz), 7.57 (d,
1 Hz, J = 7.1 Hz), 8.07 (d, 2 Hz, J = 7.5 Hz).
(3) (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.
Synthesis 2003, No. 11, 1727–1731 © Thieme Stuttgart · New York

PAPER
Biarylphosphines for Use in the Palladium-Catalyzed Amination of Aryl Halides
1731
(4) For the typical preparation of the Buchwald group’s biaryl
see: Micetich, R. G.; Baker, V.; Spevak, P.; Hall, T. W.;
Bains, B. K. Heterocycles 1985, 23, 943.
ligands via a metal-catalyzed cross-coupling or via addition
of an arylmagnesium halide to benzyne, followed by
addition of a chlorodialkylphosphine, see: Tomori, H.; Fox,
J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5334.
(5) Various alkyllithiums were screened for the halogen–metal
exchange, including s-BuLi and none provided significantly
improved branching ratios. Organomagnesium derivatives
were prepared as well but these had significantly poorer
reactivity and required copper salts to obtain product.
Ultimately, ligand 2 was used impure since the contaminants
were not removed easily by recrystallization and were not
considered impediments to the reaction.
(7) Reactions in toluene with 3 or 4 and a weak base (such as
Cs2CO3) turned yellow-green and resulted in poor reaction
conversions. Adding t-BuONa led to restarting of the
reactions and drove them to completion, suggesting t-
BuONa can break aggregation of a Pd complex that is not
competent in the catalytic cycle.
(8) When carrying out the coupling of morpholine and 4-tert-
butylphenylbromide in toluene with 1% Pd catalyst, the
reaction only reached 22% conversion, while the same
reaction in tert-amyl alcohol reached completion in under 2
h. Use of butan-2-ol accelerated the reaction further, but
significant dehalogenation of the aryl bromide was observed
(due to -hydride elimination).
(6) Pyrazoles have been shown to ortho-directed deprotonation
of an N-aryl group appended to the pyrazole; for an example,
(9) Balaban, A. T. Tetrahedron 1968, 24, 5059.
Synthesis 2003, No. 11, 1727–1731 © Thieme Stuttgart · New York