2,6-diisopropoxyphenyl(dicyclohexyl)phosphine: A new ligand for palladium-catalyzed amination reactions of aryl chlorides with potassium hydroxide as the base

Article abstract of DOI:10.1002/adsc.201000349

A new, readily available monophosphine tetrafluoroborate salt [L2·HBF₄] was developed for the palladium-catalyzed amination reaction of aryl chlorides in moderate to high yields with the cheap and easily available potassium hydroxide as the base. The reaction enjoys a wide scope, lower reaction temperatures, shorter reaction times, high yields, and low catalyst loading when compared to some of same amination reactions reported in the literature. Based on a kinetic study, ³¹P NMR measurements, and DFT calculations, a mechanism involving a 1:1 Pd/L species is proposed.

Full text of DOI:10.1002/adsc.201000349

FULL PAPERS
DOI: 10.1002/adsc.201000349
2
,6-Diisopropoxyphenyl(dicyclohexyl)phosphine: A New Ligand
for Palladium-Catalyzed Amination Reactions of Aryl Chlorides
with Potassium Hydroxide as the Base
a
a
a
b
b,
Bo Lꢀ, Pengbin Li, Chunling Fu, Liqin Xue, Zhenyang Lin, *
a,
and Shengming Ma *
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027,
a
Peopleꢁs Republic of China
Fax : (+86) 21-6416-7510; e-mail: masm@sioc.ac.cn
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Peopleꢁs
b
Republic of China
Fax : (+852)-2358-1594; e-mail: chzlin@ust.hk
Received: May 5, 2010; Revised: November 13, 2010; Published online: January 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000349.
Abstract: A new, readily available monophosphine same amination reactions reported in the literature.
3
1
tetrafluoroborate salt [L2·HBF ] was developed for Based on a kinetic study, P NMR measurements,
4
the palladium-catalyzed amination reaction of aryl and DFT calculations, a mechanism involving a 1:1
chlorides in moderate to high yields with the cheap Pd/L species is proposed.
and easily available potassium hydroxide as the base.
The reaction enjoys a wide scope, lower reaction Keywords: amination; CꢀCl activation; 2,6-diisopro-
temperatures, shorter reaction times, high yields, and poxyphenyl(dicyclohexyl)phosphine; monophosphine
low catalyst loading when compared to some of tetrafluoroborate salt; palladium; phosphanes
Introduction
report our recent results by using a new simple
ligand, i.e., 2,6-diisopropoxyphenyl(dicyclohexyl)-
The palladium-catalyzed amination of aryl halides has phosphine (L2), for the amination of aryl chlorides
been well established due to the importance of aryl- with KOH as the base.
[1]
ACHTUNGTRENNUNGa mines. At the beginning, in most cases iodides or
[
2]
bromides were used with bidentate ligands. Now
aryl chlorides have been commonly applied as the Results and Discussion
starting materials thanks to the development of many
sterically bulky and electron-rich monodentate li- Recently, we have developed a readily available
[
1i–o]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
gands.
However, in most of these reactions, expen- monophosphine ligand (Scheme 2, L1, a simplified
[11]
sive and moisture-sensitive alkali metal tert-butoxides version of S-Phos ) which has been used in the
[
3]
were applied as the base. In 2002, Hartwig et al. highly selective Suzuki coupling reaction of CꢀCl
found that KOH could be used in CꢀCl amination re- bonds.
actions as the base with a phase-transfer catalyst [Eq. After that, we also prepared a similar ligand,
1)]; after that, cheap alkali metal hydroxides have i.e., 2,6-diisopropoxyphenyl(dicyclohexyl)phosphine
[
9,10]
[4]
(
[
10]
been introduced into amination reactions by Buch- (Scheme 2, L2·HBF ): (Scheme 3): m-diisopropoxy-
wald [Eq. (2)], Verkade [Eq. (3)], Maes [Eq.
4
[5]
[6]
ACHTUNGTRENNUNG
[7]
[8]
(
[
3]
2
[
5,6]
tion time was needed,
and some proceed even with ride and PCl to afford 2,6-diisopropoxyphenyl(dicy-
3
[
7]
relatively lower yields or with a relatively complicat- clohexyl)phosphine (L2). To simplify the handling
[
5~8]
[9,12]
ed phosphine ligand.
In this paper, we wish to process, L2 was treated as before
with aqueous
100
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 100 – 112

2,6-Diisopropoxyphenyl(dicyclohexyl)phosphine: A New Ligand
Scheme 1. Pd-catalyzed amination reactions of aryl chlorides using an alkali metal hydroxide as the base and phosphine as
the ligand.
Scheme 2. Rationale for our ligands.
Scheme 3. Synthesis of L2·HBF4.
Adv. Synth. Catal. 2011, 353, 100 – 112
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101

Bo Lꢀ et al.
FULL PAPERS
Table 1. Amination reactions of 1a and 2a under different conditions.
[a]
[b]
Entry
[Pd] (mol%)
L
Base (equiv.)
Time [h]
Yield of 3a [%]
1
2
3
4
5
6
7
8
9
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
A
T
N
T
E
U
G
L1
L1
L1
L1
L1
L1
L1
L1
L2
L2
L2
L2
L2
t-BuOK (4.0)
t-BuONa (4.0)
KOH (4.0)
24
24
24
24
24
24
24
17
17
3
54
73
74
2
3
3
AHCTUNGTRNNEUG( dba) ·CHCl (2.5)
2 3 3
AHCTUNGTRNNEUG( dba) ·CHCl (2.5)
2 3 3
[
c]
A
H
U
G
R
N
U
G
K PO (4.0)
4
2
3
4
A
H
U
G
R
N
U
G
NaOH (4.0)
NaH (4.0)
30
56
2
AHCTUNGTRNNEUG( dba) ·CHCl (2.5)
2 3 3
[d]
A
H
U
G
R
N
U
G
Cs CO (4.0)
0
2
2
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5)
(OAc) (5)
ACHTUNGTRENNUNG( OAc) (5)
(OAc) (5)
(OAc) (3)
(OAc) (3)
KOH (4.0)
KOH (4.0)
KOH (4.0)
KOH (2.0)
KOH (2.0)
LiHMDS (2.0)
86
100
94
100
91
73
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[
[
[
[
e]
e]
e]
e]
1
1
1
1
0
1
2
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
9
5.5
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[f]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[
a]
[13]
2ꢀ
ꢀ
3
pK value of corresponding conjugated acid in water: H (35)>t-BuOH (17)>H O (15.74)>HPO
ACHTUNGTNERNUNG( 12.33)>HCO
4
a
2
2
(
10.33).
[
[
[
[
[
b]
1
Determined by H NMR analysis using methylene dibromide as internal standard.
c]
d]
e]
f]
1
1
2
1
a (81%) recovered.
a (92%) recovered.
a (1.2 equiv) was used.
a (19%) recovered.
HBF to afford L2·HBF in 48% total yield after re- d) to form the corresponding aryl amines in 50–94%
4
4
crystallization from CH Cl /Et O.
isolated yields (Table 2, entries 1–13, 15, 16, and 24).
2
2
2
We started to apply this type of ligand to the CꢀCl Functionalized aryl chlorides and amines could also
bond amination reaction. It was interesting for us to work under the current reaction conditions (Table 2,
note that the reaction of 1-chloro-3,5-dimethoxyben- entries 14 and 17–23). Compared with the known Pd/
zene (1a) and N-methylaniline (2a) could work with phosphine catalysts, the current protocol promotes
L1 using 4.0 equivalents of t-BuOK as the base, how- the coupling reaction at relatively lower tempera-
1
[3w]
[3w]
ever, in only 54% yield as determined by H NMR
analysis (Table 1, entry 1).
A
H
U
G
R
N
N
ture,
with lower catalyst loading,
and in higher
(entry 7 of Table 2). When n-hexylamine (2e)
[
3w]
yield
Then this reaction was chosen as the model to opti- was used as the amine, 5.0 equivalents of this amine
mize the reaction conditions. It is interesting for us to were required to afford the monoaryled amine 3k
observe that with the weaker base t-BuONa, the yield highly selectively (Table 2, entry 11). For ortho-substi-
was higher. With this information, we reasoned that a tuted aryl chlorides, a higher dosage of KOH was re-
matched better base may be located for this reaction quired (Table 2, entries 15–17). The reaction of elec-
(
see footnote (a) of Table 1 for the basicities of the tron-deficient aryl chlorides could go to completion
bases screened in this study). In fact it is observed within a relatively shorter time as expected (Table 2,
that the yield with KOH is the best (Table 1, en- entries 14 and 17–23), whereby a lower catalyst load-
tries 1–7). Pd
[
24]
[6a]
[3t,x]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) is better than Pd
A
T
N
T
E
N
N
(dba) ·CHCl as ing,
shorter reaction time , and higher yields
2
2
3
3
the catalyst (Table 1, entry 8). Based on the pioneer- were observed as compared with those in previous re-
[
1n]
ing work of Buchwald, we also tried to increase the ports (entries 14 and 17 of Table 2). Even 2-pyridinyl
steric bulkiness of the phosphine ligand by using L2 chloride may be aminated under the current reaction
[
3m]
as the ligand: 3a was afforded in 100% NMR yield conditions (Table 2, entry 13).
using Pd(OAc) /L2·HBF as the catalyst (Table 1, One 0.4-mol scale reaction of 1b with 2a and one
entry 9). The reaction could still work with 3 mol% of 0.1-mol scale reaction of 1d with 2a were conducted
Pd(OAc) /L2·HBF , 1.2 equivalents of 2a, and under the catalysis of 2.5 mol% of Pd(OAc) to afford
.0 equivalents of KOH (Table 1, entry 12).
With the optimized reaction conditions in hand, dif- simple distillation showing the efficiency of this cata-
ACHTUNGTRENNUNG
2
4
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG
2
4
2
2
3e and 3h in 83% and 78% yields, respectively, by
ferently substituted electron-rich aryl chlorides were lytic system [Eq. (6) and Eq. (7)].
coupled with primary (2e–i) or secondary amines (2a–
102
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Adv. Synth. Catal. 2011, 353, 100 – 112

2,6-Diisopropoxyphenyl(dicyclohexyl)phosphine: A New Ligand
Table 2. Pd-catalyzed amination reactions of various 1 and 2 using L2 as the ligand.
1
2
3
[a]
Entry
R
R
R
Time [h]
Yield of 3 [%]
1
2
3
3,5-(OMe) (1a)
Ph
Me (2a)
9
8
12
9
5
3.5
5
7
92 (3a)
79 (3b)
92 (3c)
57 (3d)
88 (3e)
78 (3f)
83 (3g)
91 (3h)
85 (3i)
94 (3j)
79 (3k)
81 (3l)
64 (3m)
87 (3n)
53 (3o)
69 (3p)
88 (3q)
74 (3r)
50 (3s)
51 (3t)
80 (3u)
57 (3v)
84 (3w)
89 (3x)
2
3,5-(OMe) (1a)
ꢀ(C H OC H )ꢀ (2b)
2
2
4
2
4
3,5-(OMe) (1a)
ꢀ(C H )ꢀ (2c)
A
H
U
G
R
N
N
2
5
10
[
[
[
[
b]
b]
b]
b]
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
4-Me (1b)
4-Me (1b)
4-Me (1b)
4-OMe (1c)
H (1d)
n-Bu
Ph
n-Bu (2d)
Me (2a)
ꢀ(C H OC H )ꢀ (2b)
2
4
2
4
Ph
Ph
Me (2a)
Me (2a)
H (1d)
ꢀ(C H OC H )ꢀ (2b)
5
2
4
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
3-Me (1e)
3-Me (1e)
3-OMe (1f)
ꢀ
A
H
U
G
R
N
N
(C H )ꢀ (2c)
9.5
9.5
9.5
5
5
10
[
c]
n-Hex
H (2e)
ꢀ(C H OC H )ꢀ (2b)
2
4
2
4
[d]
(1g)
ꢀ(C H OC H )ꢀ (2b)
2
4
2
4
[
[
[
[
e]
4-CN (1h)
2-MeO (1i)
2-Me (1j)
Ph
Me (2a)
ꢀ(C H OC H )ꢀ (2b)
1
b,f]
b,f]
g]
23
18
2
2
4
2
4
ꢀ(C H OC H )ꢀ(2b)
2
4
2
4
2-NO (1k)
ꢀ(C H OC H )ꢀ (2b)
2
2
4
2
4
4-Ac (1l)
4-Ac (1l)
Ph
H (2f)
H (2g)
Me (2a)
Me (2a)
H (2h)
H (2i)
4
[
g]
o-MeO CC H
Ph
Ph
4-(PhCO)C H
4-AcC H
2.5
2.5
2
2
2
2
6
4
4-CO Et (1m)
2
4-PhCO (1n)
4-CN (1h)
4-Ac (1l)
6
4
6
4
[
h]
3-Me (1e)
Ph
H (2f)
4
[
[
[
a]
Isolated yield.
b]
Pd ACHTUNGTRENNUNG( OAc) (5 mol%) and L2 (7.5 mol%) were used.
2
c]
n-Hexylamine (5.0 equiv.) was used and 2% of N,N-di
A
H
U
G
R
N
U
(m-tolyl)-hexamine was also formed as determined by crude
1
H NMR analysis using CH Br as internal standard.
2
2
[
[
[
[
[
d]
e]
f]
1
1
g is 2-chloropyridine.
mol% of Pd(OAc) and 1.5 mol% of L2·HBF were used.
ACHTUNGTRENNUNG
2
4
KOH (4.0 equiv.) was used.
Amine (2.0 equiv.) and KOH (3.0 equiv.) were used.
The reaction was conducted in xylenes at 1308C using amine (2.0 equiv.) and KOH (5.0 equiv.).
g]
h]
In order to study the mechanism, a kinetic study
has been conducted for the reaction of p-tolyl chlo-
ride (1b) and N-methylaniline (2a) in the presence of
Pd dba ·CHCl (2.5 mol%), L2·HBF (5 mol%), and
2
3
3
4
KOH (6.6 equiv.) in toluene at 1108C with either 1b
or 2a in large excess (6.0 equiv.). The reaction was
then monitored by GC analysis using biphenyl as an
internal standard. A linear relationship was observed
for ln(1/[1b]) vs. reaction time, indicating a first-order
dependence of the reaction rate with 1b [ln(1/[1b])=
0
k t+ln(1/[1b] )] (y=a+bꢃx in Figure 1). Zero-order
1
dependence of the reaction rate with N-methylaniline
0
(
2a) ([2a]=k t+[2a] ) (y=a+bꢃx in Figure 2) was
2
also observed by the linear relationship of [2a] vs. re-
action time.
Adv. Synth. Catal. 2011, 353, 100 – 112
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Bo Lꢀ et al.
FULL PAPERS
Figure 1. The determination of the reaction order with 1b.
On the other hand, Pd dba ·CHCl and L2 were
Figure 2. The determination of the reaction order with 2a
Based on these studies, a plausible mechanism was
2
3
3
mixed and stirred in toluene at room temperature for proposed for this reaction (Scheme 4): the rate-deter-
4
1
h with the ratio of Pd/L2 being 1:0.5, 1:1, 1:1.5, and mining oxidative addition of the CꢀCl bond of the
:2, respectively. These mixtures were analyzed by aryl chloride with the electron-rich L2/Pd(0) com-
3
1
[1n,14]
P NMR measurements, and a Pd-L2 complex signal plex
would afford 4. The coordination of amine
at dꢁ46 ppm was detected (c, d, e, and f in Figure. 3). to the palladium would replace that of the isopropoxy
It shows that when the Pd/L2 ratio was 1:1.5 or 1:2, group resulting in the formation of intermediate 5, in
31
the P NMR signal of free L2 at ꢀ12 ppm was also which there may be hydrogen-bonding between the
detected (e and f in Figure 3). The reaction of 1b isopropoxy oxygen atom and the aminic proton. This
(
1.0 equiv.) with 2a (1.2 equiv.) catalyzed by may change the acidity of this proton and explains
Pd dba ·CHCl /L2 (Pd/L2=1/1) was monitored by why a weaker base such as KOH is better here. Sub-
2
3
3
GC analysis. After complete consumption of 1b, in sequent deprotonation and reductive elimination af-
31
situ P NMR analysis was conducted by direct trans- forded product 3.
ferring the final resulting mixture into an NMR tube
Then density functional theory (DFT/b3LYP) calcu-
with a sealed CDCl sample in the middle of the lations were conducted to elucidate the proposed hy-
3
NMR tube as the reference. The above mentioned drogen bond in intermediate 5 shown in Scheme 5.
Pd-L2 complex signal at 46 ppm also existed (g in Fig- Scheme 5 shows the pair of geometrical isomers 5AR
ure 3).When varying [L2] from 0.01M to 0.04M in the and 5BR for R=Me and i-Pr being calculated.
presence of 1b (6.0 equiv.), 2a (1.0 equiv.), KOH Figure 5 shows the optimized structures with selected
(
6.6 equiv.), and Pd dba ·CHCl (0.005M) in toluene bond distances (ꢄ). The relative free energies (kcal
2 3 3
ꢀ
1
at 1108C, the reaction rates are almost the same mol ) are also given in this figure. All the optimized
Table 3 and Figure 4). Thus, we concluded that the structures show certain degrees of hydrogen bonding.
(
catalytically active species is Pd:L2 (1:1).
When R=Me, the pair of geometric isomers 5AMe
and 5BMe have similar stability. The hydrogen bond
104
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2,6-Diisopropoxyphenyl(dicyclohexyl)phosphine: A New Ligand
31
Figure 3. P NMR spectra of (a) free L2; (b) L2 oxide; (c) a mixture of Pd dba ·CHCl and free L2 (Pd/L2=2/1) was stirred
2
3
3
in toluene for 4 h at r.t.; (d) a mixture of Pd dba ·CHCl and free L2 (Pd/L2=1/1) was stirred in toluene for 4 h at r.t.; (e) a
2
3
3
mixture of Pd dba ·CHCl and free L2 (Pd/L2=1/1.5) was stirred in toluene for 4 h at r.t.; (f) a mixture of Pd dba ·CHCl
2
3
3
2
3
3
and free L2 (Pd/L2=1/2) was stirred in toluene for 4 h at r.t.; (g) the resulting mixture after the complete amination reac-
3
1
tion. A sealed CDCl was inserted to each NMR tube for the P NMR measurement.
3
lengths of 5AMe and 5BMe are 2.026 ꢄ and 2.144 ꢄ, re- 5Ai-Pr and 5Bi-Pr are 1.955 ꢄ and 2.067 ꢄ, respectively.
spectively. When R=i-Pr, 5Ai-Pr is slightly more We can see that the more electron-donating i-Pr gives
stable than 5Bi-Pr. The hydrogen bond lengths of stronger hydrogen bonding.
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Bo Lꢀ et al.
FULL PAPERS
Table 3. The effect of [L2] on the reaction rate.
Scheme 5.
ꢀ
5
ꢀ1
[
Pd] (M)
[L2] (M)
0.01
Rate (10 Ms)
0
.01
1.71
1.68
1.63
1.62
Conclusions
0
0
0
.02
.03
.04
We have developed an HBF salt of the easily pre-
4
pared new monophosphine ligand, that is, 2,6-diiso-
propoxyphenyl(dicyclohexyl)phosphine (L2), which
could be used in the amination reaction of CꢀCl
bonds with moderate to high yields by using the
cheap and easily available KOH instead of t-BuONa
in a relatively shorter reaction time. Compared to the
known ligands with KOH as the base, this ligand has
[
4–8]
its own advantages.
Further studies on this type of
ligands are being conducted in our laboratory.
Experimental Section
2
,6-Diisopropoxyphenyl(dicyclohexyl)phosphonium
Tetrafluoroborate (L2·HBF4)
To a flame-dried, three-necked flask were added m-diisopro-
poxybenzene (10.6340 g, 55 mmol) and 60 mL of dry THF
under N . After that, n-BuLi (21.6 mL, 2.5M in THF,
2
5
4 mmol) was added at room temperature within 5 min.
Figure 4. The effect of [L2] on the reaction rate ([Pd]=
.01M).
This resulting mixture was allowed to stir at room tenmpera-
ture for further 8 h to prepare the lithium reagent for the
following step.
0
To another dried, three-necked flask were added PCl
4.13 mL, d=1.50 gmL , 6.20 g, 45 mmol) and 450 mL of
3
ꢀ
1
(
dry Et O. This solution was cooled to ꢀ408C and cyclohex-
2
ylmagnesium chloride (109 mL, 0.91M, 99 mmol) was added
dropwise at this temperature within 20 min. After the addi-
tion, the resulting mixture was allowed to stir at room tem-
perature for 5 h. The above prepared m-diisopropoxyphe-
nyllithium solution was then added in one portion with stir-
ring via a syringe. After another 15 h with stirring at room
temperature, the resulting mixture was quenched with
1
00 mL of aqueous HBF (38% wt) with vigorous stirring
4
for 30 min. Water (100 mL) was then added and the result-
ing mixture was extracted with CH Cl (100ꢃ2 mL), washed
2
2
with 100 mL of brine, and dried over anhydrous Na SO . Fil-
2
4
tration, evaporation and recrystalization from Et O/CH Cl
2
2
2
afforded L2·HBF as a white solid; yield: 10.3281 g (48%
4
1
from PCl ); mp 221.6–223.28C (CH Cl /Et O). H NMR
3
2
2
2
(
300 MHz, CDCl ): d=7.59 (t, J=8.4 Hz, 1H), 6.86 (dt,
3
JP, H =492.6 Hz, JH,H =6.8 Hz, 1H, P-H), 6.63 (dd, JH,H
=
8
2
2
8
.4 Hz, JP, H =4.4 Hz, 2H), 4.81–4.67 (m, 2H), 2.93–2.75 (m,
H), 2.21–2.09 (m, 2H), 1.94–1.66 (m, 8H), 1.60–1.15 (m,
1
3
2H); C NMR (75 MHz, CDCl ): d=161.4, 138.1, 105.0,
3
9.0 (d, J=82.5 Hz), 72.0, 29.1 (d, J=44.3 Hz), 27.6 (d, J=
Scheme 4. Proposed mechanism.
1.3 Hz), 26.8 (d, J=3.6 Hz), 26.0 (d, J=6.3 Hz), 25.7 (d, J=
106
asc.wiley-vch.de
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 100 – 112

2,6-Diisopropoxyphenyl(dicyclohexyl)phosphine: A New Ligand
ꢀ
1
Figure 5. Selected bond distances (ꢄ) and relative free energies (kcalmol ) calculated for 5A and 5B (R=Me and i-Pr).
R
R
For clarity, the hydrogen atoms associated with the phenyl and the cyclohexyl rings were omitted. The dark spheres repre-
sent oxygen atoms and the grey spheres represent hydrogen atoms.
3
1
ꢀ1
7
.8 Hz), 24.8 (d, J=1.4 Hz), 21.4; P NMR (121 MHz,
1323, 1293, 1248, 1204, 1153, 1127, 1094, 1066 cm ; MS
+ +
CDCl ): d=7.0; IR (KBr): n=3448, 2973, 2936, 2857, 1580,
463, 1255, 1124, 1109, 1084, 1071, 1056, 1046 cm ; MS
(70 eV, EI): m/z (%)=244 (M +1, 15.56), 243 (M , 100).
4-(3’,5’-Dimethoxyphenyl)morpholine (3b): The reaction
of 1a (172.5 mg, 1.0 mmol), 2b (104.4 mg, 1.2 mmol),
(6.8 mg, 0.030 mmol), L2·HBF4 (21.3 mg,
0.045 mmol), and KOH (112.5 mg, 2.0 mmol) in 5 mL of tol-
uene at 1108C under nitrogen afforded 3b after work-up
eluent: petroleum ether/ethyl acetate/triethylamine=100/
0/1) as a white solid; yield: 175.7 mg (79%); mp 85.1–
3
ꢀ
1
1
+
(
(
6
70 eV, EI): m/z (%)=390 (M ꢀHBF , 43.74), 266
4
+
M ꢀCyꢀC H ꢀBF , 100); anal. calcd. for C H BF O P: C
Pd
A
H
U
G
R
N
U
G
3
6
4
24 40
4
2
2
0.26, H 8.43; found: C 60.25, H 8.51.
[16]
(
Typical Procedure: N-Methyl-N-phenyl-3,5-
1
8
dimethoxyaniline (3a)
1
5.68C (n-hexane, lit. 84–868C); H NMR (300 MHz,
To a flame-dried and nitrogen-filled Schlenk vessel were
added Pd(OAc) (2.7 mg, 0.012 mmol), L2·HBF4 (8.7 mg,
CDCl
3
): d=6.10–6.06 (m, 2H), 6.06–6.02 (m, 1H), 3.84 (t,
ACHTUNGTRENNUNG
J=4.7 Hz, 4H), 3.77 (s, 6H), 3.13 (t, J=4.7 Hz, 4H);
2
1
3
0.018 mmol), KOH (43.7 mg, 0.78 mmol), and 1a (68.8 mg,
.40 mmol) in 1 mL of toluene sequentially. After being
C NMR (75 MHz, CDCl ): d=161.4, 153.2, 94.6, 91.7, 66.7,
3
0
55.1, 49.2; IR (KBr): n=3019, 2973, 2888, 2852, 2823, 1609,
stirred for about 4 min at room temperature, 2a (51.0 mg,
.48 mmol) and another 1 mL of toluene were added. The
resulting mixture was heated at 1108C with a preheated oil
bath. After 9 h, the reaction was complete as monitored by
GC. The reaction mixture was then cooled and diluted with
1582, 1479, 1462, 1444, 1378, 1365, 1274, 1199, 1175, 1159,
ꢀ
1
+
0
1124, 1081, 1043cm ; MS (70 eV, EI): m/z (%)=224 (M +
+
1, 13.19), 223 (M , 100).
1-(3’,5’-Dimethoxyphenyl)piperidine (3c): The reaction of
1a (171.7 mg, 1.0 mmol), 2c (102.1 mg, 1.2 mmol), Pd ACHTUNGTRENNUNG( OAc)
2
1
0 mL of CH Cl and filtered through a short column of
(6.7 mg, 0.030 mmol), L2·HBF (21.6 mg, 0.045 mmol), and
2
2
4
silica gel (eluent: 2ꢃ10 mL of CH Cl ). Evaporation and pu-
KOH (112.8 mg, 2.0 mmol) in 5 mL of toluene at 1108C
under nitrogen afforded 3c after work-up (eluent: petrole-
2
2
[16]
rification by chromatography (petroleum ether/ethyl ace-
[15]
tate/triethylamine=100/1/1) on silica gel afforded 3a as a
um ether/ethyl acetate/triethylamine=100/5/1) as a liquid;
1
1
liquid; yield: 89.2 mg (92%). H NMR (300 MHz, CDCl ):
yield: 202.5 mg (92%). H NMR (300 MHz, CDCl ): d=6.12
3
3
d=7.36–7.28 (m, 2H), 7.15–7.08 (m, 2H), 7.07–7.00 (m,
(d, J=2.4 Hz, 2H), 5.99 (t, J=2.2 Hz, 1H), 3.78 (s, 6H),
1
H), 6.15 (d, J=2.4 Hz, 2H), 6.09 (t, J=2.2 Hz, 1H), 3.75
3.15 (t, J=5.4 Hz, 4H), 1.74–1.63 (m, 4H), 1.63–1.52 (m,
1
3
13
(
s, 6H), 3.31 (s, 3H); C NMR (75 MHz, CDCl ) d 161.3,
2H); C NMR (75 MHz, CDCl ): d=161.3, 154.0, 95.2, 91.1,
3
3
1
50.8, 148.6, 129.2, 122.4, 122.3, 97.5, 92.4, 55.2, 40.3; IR
55.1, 50.5, 25.7, 24.3; IR (neat): n=2932, 2852, 2799, 1594,
1462, 1383, 1264, 1203, 1152, 1127, 1072, 1030 cm ; MS
ꢀ
1
(
neat): n=2998, 2937, 2837, 1591, 1497, 1477, 1456, 1425,
Adv. Synth. Catal. 2011, 353, 100 – 112
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
107

Bo Lꢀ et al.
FULL PAPERS
+
+
(
70 eV, EI): m/z (%)=222 (M +1, 13.71), 221 (M , 87.90),
1d (112.0 mg, 1.0 mmol), 2a (128.3 mg, 1.2 mmol), Pd ACHTUNGTRENNUNG( OAc)
2
220 (100).
(6.7 mg, 0.030 mmol), L2·HBF (21.5 mg, 0.045 mmol), and
4
N,N-Dibutyl-4-methylaniline (3d): The reaction of 1b
KOH (112.7 mg, 2.0 mmol) in 5 mL of toluene at 1108C
under nitrogen afforded 3h after work-up (eluent: petro-
[19]
(
125.9 mg, 1.0 mmol), 2d (155.0 mg, 1.2 mmol), Pd
A
H
U
G
E
N
N
(OAc)
2
(
11.2 mg, 0.050 mmol), L2·HBF (35.8 mg, 0.075 mmol), and
leum ether/ethyl acetate/triethylamine=200/1/2) as a liquid;
4
1
KOH (112.4 mg, 2.0 mmol) in 5 mL of toluene at 1108C
under nitrogen afforded 3d after work-up (eluent: petro-
leum ether/triethylamine=300/1) as a liquid; yield: 123.6 mg
(
yield: 165.0 mg (91%). H NMR (300 MHz, CDCl ): d=
3
[17]
7.37–7.28 (m, 4H), 7.11–7.04 (m, 4H), 7.04–6.96 (m, 2H),
1
3
3.36 (s, 3H); C NMR (75 MHz, CDCl ): d=149.0, 129.1,
3
1
57%). H NMR (300 MHz, CDCl ): d=7.04 (d, J=8.9 Hz,
121.2, 120.4, 40.2; IR (neat): n3060, 3036, 2879, 2811, 1591,
3
2
H), 6.61 (d, J=8.9 Hz, 2H), 3.25 (t, J=7.7 Hz, 4H), 2.26
1496, 1448, 1343, 1271, 1253, 1186, 1156, 1131, 1092, 1074,
ꢀ
1
+
(
s, 3H), 1.64–1.50 (m, 4H), 1.43–1.30 (m, 4H), 0.97 (t, J=
1029 cm ; MS (70 eV, EI): m/z (%)=184 (M +1, 13.82),
13
+
7
1
2
.3 Hz, 6H); C NMR (75 MHz, CDCl ): d=146.1, 129.7,
183 (M , 100).
3
24.2, 112.1, 51.0, 29.4, 20.4, 20.1, 14.0; IR (neat): n=2957,
931, 2872, 1619, 1520, 1464, 1367, 1216, 1189 cm ; MS
4-Phenylmorpholine (3i): This reaction was conducted in
a Schlenk tube with a screw cap. The reaction of 1d
ꢀ
1
+
+
(
70 eV, EI): m/z (%)=220 (M +1, 5.69), 219 (M , 31.89),
(112.1 mg, 1.0 mmol), 2b (105.2 mg, 1.2 mmol), Pd ACHTUNGTRENNUNG( OAc)
2
176 (100).
(6.7 mg, 0.030 mmol), L2·HBF (21.4 mg, 0.045 mmol), and
4
N-Methyl-N-phenyl-4-methylaniline (3e): The reaction of
KOH (112.8 mg, 2.0 mmol) in 5 mL of toluene at 1108C
under nitrogen afforded 3i after work-up (eluent: petrole-
um ether/ethyl acetate/triethylamine=100/1/1) as a white
[20]
1
(
b (126.6 mg, 1.0 mmol), 2a (127.8 mg, 1.2 mmol), Pd
A
H
U
G
R
N
U
G
2
11.3 mg, 0.050 mmol), L2·HBF (36.1 mg, 0.076 mmol), and
4
KOH (111.4 mg, 2.0 mmol) in 5 mL of toluene at 1108C
under nitrogen afforded 3e after work-up (eluent: petrole-
solid; yield: 138.1 mg (85%); mp 52.5–53.48C (n-hexane, lit:
[15]
1
51–548C). H NMR (300 MHz, CDCl ): d=7.37–7.27 (m,
3
um ether/ethyl acetate/triethylamine=100/1/1) as a liquid;
2H), 7.00–6.88 (m, 3H), 3.89 (t, J=4.8 Hz, 4H), 3.18 (t, J=
1
13
yield: 172.8 mg (88%). H NMR (300 MHz, CDCl ): d=
4.8 Hz, 4H); C NMR (75 MHz, CDCl ): d=151.2, 129.1,
3
3
7
6
.30–7.21 (m, 2H), 7.17–7.10 (m, 2H), 7.06–6.98 (m, 2H),
.98–6.85 (m, 3H), 3.30 (s, 3H), 2.34 (s, 3H); C NMR
119.9, 115.6, 66.8, 49.2; IR (KBr): n=2962, 2855, 2825, 1600,
1
3
1578, 1496, 1449, 1378, 1334, 1300, 1262, 1232, 1177, 1121,
ꢀ
1
+
(75 MHz, CDCl ): d=149.3, 146.5, 132.0, 129.9, 129.0, 122.5,
1067, 1050, 1034 cm ; MS (70 eV, EI): m/z (%)=164 (M +
3
+
1
2
1
19.7, 118.1, 40.3, 20.7; IR (neat): n=3058, 3026, 2920, 2871,
1, 8.00), 163 (M , 73.47), 105 (100).
810, 1596, 1572, 1497, 1451, 1342, 1296, 1253, 1187, 1155,
1-(m-Tolyl)piperidine (3j): The reaction of 1e (126.1 mg,
ꢀ1
131, 1088, 1067, 1028 cm ; MS (70 eV, EI): m/z (%)=198
1.0 mmol), 2c (102.5 mg, 1.2 mmol), Pd ACHTUNGERTNNUNG( OAc) (6.8 mg,
2
+
+
(
M +1, 14.89), 197 (M , 100).
-(p-Tolyl)morpholine (3f): The reaction of 1b (100.9 mg,
.80 mmol), 2b (82.9 mg, 0.95 mmol), Pd(OAc) (9.0 mg,
.040 mmol), L2·HBF4 (28.7 mg, 0.060 mmol), and KOH
0.030 mmol), L2·HBF4 (21.5 mg, 0.045 mmol), and KOH
(111.8 mg, 2.0 mmol) in 5 mL of toluene at 1108C under ni-
4
[
21]
0
0
A
H
U
G
R
N
U
G
trogen afforded 3j
after work-up (eluent: petroleum
liquid;
2
ether/ethyl acetate/triethylamine=100/5/1) as
yield: 164.8 mg (94%). H NMR (300 MHz, CDCl ): d=7.19
a
1
(
90.0 mg, 1.6 mmol) in 4 mL of toluene at 1108C under ni-
3
[2b]
trogen afforded 3f
ether/ethyl acetate/triethylamine=20/1/1) as a white solid;
yield: 110.7 mg (78%); mp 47.3–48.08C (n-hexane, lit: 49.8–
after work-up (eluent: petroleum
(t, J=7.6 Hz, 1H), 6.86–6.76 (m, 2H), 6.70 (d, J=7.5 Hz,
1H), 3.18 (t, J=5.4 Hz, 4H), 2.36 (s, 3H), 1.82–1.69 (m,
1
3
4H), 1.68–1.56 (m, 2H); C NMR (75 MHz, CDCl ): d=
3
1
50.48C). H NMR (300 MHz, CDCl ): d=7.15 (d, J=8.6 Hz,
152.3, 138.5, 128.8, 120.1, 117.4, 113.6. 50.7, 25.9, 24.3, 21.8;
3
2
H), 6.89 (d, J=8.6 Hz, 2H), 3.90 (t, J=4.8 Hz, 4H), 3.15
IR (neat): n=3033, 2933, 2854, 2803, 1601, 1582, 1493, 1450,
1
3
ꢀ1
(
t, J=4.8 Hz, 4H), 2.34 (s, 3H); C NMR (75 MHz,
1383, 1339, 1248, 1222, 1185, 1130, 1032 cm ; MS (70 eV,
+
+
CDCl ): d=149.0, 129.5, 129.3, 115.8, 66.8, 49.7, 20.3; IR
EI): m/z (%)=176 (M +1, 9.48), 175 (M , 68.64), 174
(100).
3
(
KBr): n=3029, 2977, 2957, 2913, 2853, 2830, 1612, 1516,
1
1
8
453, 1379, 1327, 1298, 1261, 1235, 1209, 1169, 1118, 1064,
N-Hexyl-3-methylaniline (3k): The reaction of 1e
ꢀ
1
+
048, 1031 cm ; MS (70 eV, EI): m/z (%)=178 (M +1,
(126.1 mg, 1.0 mmol), 2e (505.0 mg, 5.0 mmol), Pd ACHTUNGTRENNUNG( OAc)
2
+
.81), 177 (M , 71.25), 119 (100).
(6.8 mg, 0.030 mmol), L2·HBF (21.5 mg, 0.045 mmol), and
4
N-Methyl-N-phenyl-4-methoxyaniline (3g): The reaction
KOH (113.1 mg, 2.0 mmol) in 5 mL of toluene at 1108C
[22]
of 1c (142.5 mg, 1.0 mmol), 2a (128.8 mg, 1.2 mmol),
Pd(OAc) (11.2 mg, 0.050 mmol), L2·HBF4 (35.7 mg,
.075 mmol), and KOH (112.3 mg, 2.0 mmol) in 5 mL of tol-
under nitrogen afforded 3k after work-up (eluent: petro-
leum ether/ethyl acetate/triethylamine=100/1/1) as a liquid
(1.8% of diarylated amine was also detected on crude
ACHTUNGTRENNUNG
2
0
[18]
1
1
uene at 1108C under nitrogen afforded 3g after work-up
eluent: petroleum ether/ethyl acetate/triethylamine=100/1/
) as a solid; yield: 177.0 mg (83%); mp 48.5–49.58C (n-
H NMR); yield: 150.4 mg (79%). H NMR (300 MHz,
(
1
CDCl ): d=7.12–7.06 (m, 1H), 6.58–6.52 (m, 1H), 6.47–6.42
3
(m, 2H), 3.56 (bs, 1H), 3.11 (t, J=7.2 Hz, 2H), 2.30 (s, 3H),
1.70–1.58 (m, 2H), 1.50–1.28 (m, 6H), 0.93 (t, J=6.6 Hz,
1
hexane). H NMR (300 MHz, CDCl ): d=7.22–7.13 (m,
3
1
3
2
3
H), 7.13–7.03 (m, 2H), 6.92–6.82 (m, 2H), 6.82–6.71 (m,
3H); C NMR (75 MHz, CDCl ): d=148.5, 138.9, 129.0,
3
1
3
H), 3.79 (s, 3H), 3.24 (s, 3H); C NMR (75 MHz, CDCl ):
118.0, 113.4, 109.8, 44.0, 31.6, 29.5, 26.8, 22.6, 21.6, 14.0; IR
3
d=156.2, 149.7, 142.1, 128.9, 126.2, 118.2, 115.6, 114.7, 55.4,
(neat): n=3410, 3043, 2955, 2927, 2857, 1606, 1589, 1510,
ꢀ
1
4
1
1
1
0.4; IR (neat): n=3069, 3045, 2998, 2951, 2834, 2805, 1597,
1492, 1377, 1328, 1305, 1263, 1180, 1168, 1092 cm ; MS
+
+
574, 1508, 1495, 1464, 1344, 1275, 1244, 1181, 1132, 1106,
(70 eV, EI): m/z (%)=192 (M +1, 3.87), 191 (M , 27.57),
120 (100).
ꢀ
1
+
090, 1067, 1035 cm ; MS (70 eV, EI): m/z (%)=214 (M +
+
, 8.58), 213 (M , 54.31), 198 (100).
4-(m-Methoxyphenyl)morpholine (3l): The reaction of 1f
N,N-Diphenylmethylamine (3h): This reaction was con-
(143.2 mg, 1.0 mmol), 2b (105.1 mg, 1.2 mmol), Pd
ACHTUNGTRENNUNG( OAc)
2
ducted in a Schlenk tube with a screw cap. The reaction of
(6.7 mg, 0.030 mmol), L2·HBF (21.5 mg, 0.045 mmol), and
4
108
asc.wiley-vch.de
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 100 – 112

2,6-Diisopropoxyphenyl(dicyclohexyl)phosphine: A New Ligand
KOH (113.2 mg, 2.0 mmol) in 5 mL of toluene at 1108C
under nitrogen afforded 3l after work-up (eluent: petrole-
17.8; IR (neat): n=3020, 2957, 2889, 2852, 2816, 1600, 1580,
[23]
1492, 1451, 1373, 1360, 1297, 1255, 1225, 1206, 1194, 1168,
ꢀ
1
+
um ether/ethyl acetate/triethylamine=100/10/1) as a liquid;
1118, 1069, 1041 cm ; MS (70 eV, EI): m/z (%)=178 (M +
1
+
yield: 157.7 mg (81%). H NMR (300 MHz, CDCl ): d=
1, 11.07), 177 (M , 96.62), 118 (100).
3
7
3
.24–7.16 (m, 1H), 6.57–6.51 (m, 1H), 6.48–6.42 (m, 2H),
.89–3.82 (m, 4H), 3.80 (s, 3H), 3.18–3.12 (m, 4H);
4-(o-Nitrophenyl)morpholine (3q): The reaction of 1k
(157.4 mg, 1.0 mmol), 2b (174.4 mg, 2.0 mmol), Pd ACHTUNGTRENNUNG( OAc)
2
1
3
C NMR (75 MHz, CDCl ): d=160.5, 152.6, 129.8, 108.4,
(6.6 mg, 0.030 mmol), L2·HBF (21.6 mg, 0.045 mmol), and
3
4
1
2
1
7
04.6, 102.1, 66.8, 55.1, 49.2; IR (neat): n=2959, 2895, 2853,
KOH (168.9 mg, 3.0 mmol) in 5 mL of toluene at 1108C
under nitrogen afforded 3q after work-up (eluent: petro-
[26]
833, 1601, 1496, 1449, 1379, 1338, 1301, 1267, 1205, 1169,
ꢀ
1
+
122, 1048 cm ; MS (70 eV, EI): m/z (%)=194 (M +1,
leum ether/ethyl acetate/triethylamine=20/1/0.2) as a liquid;
+
1
.79), 193 (M , 58.35), 135 (100).
yield: 183.6 mg (88%). H NMR (300 MHz, CDCl ): d=7.76
3
4
-(2’-Pyridinyl)morpholine (3m): The reaction of 1g
113.6 mg, 1.0 mmol), 2b (105.5 mg, 1.2 mmol), Pd(OAc)
6.7 mg, 0.030 mmol), L2·HBF (21.4 mg, 0.045 mmol), and
(dd, J =8.2 Hz, J =1.7 Hz, 1H), 7.53–7.46 (m, 1H), 7.14
1
2
(
(
A
H
U
G
R
N
N
(dd, J =8.2 Hz, J =1.1 Hz, 1H), 7.10–7.04 (m, 1H) 3.86–
2
1 2
1
3
3.78 (m, 4H), 3.10–3.00 (m, 4H); C NMR (75 MHz,
4
KOH (113.0 mg, 2.0 mmol) in 5 mL of toluene at 1108C
CDCl ): d=145.7, 143.5, 133.6, 125.8, 122.2, 120.8, 66.8, 52.0;
IR (neat): n=3074, 2962, 2893, 2857, 2831, 2739, 2688, 1605,
3
[24]
under nitrogen afforded 3m after work-up (eluent: petro-
leum ether/ethyl acetate/triethylamine=100/20/1) as
a
1571, 1519, 1487, 1449, 1375, 1344, 1293, 1252, 1231, 1211,
1
ꢀ1
liquid; yield: 104.4 mg (64%). H NMR (300 MHz, CDCl ):
1175, 1116, 1068, 1043 cm ; MS (70 eV, EI): m/z (%)=209
3
+
+
d=8.23–8.17 (m, 1H), 7.54–7.45 (m, 1H), 6.69–6.60 (m,
(M +1, 7.13), 208 (M , 48.82), 77 (100).
2
H), 3.82 (t, J=5.0 Hz, 4H), 3.49 (t, J=5.0 Hz, 4H);
N-Phenyl-4-acetoaniline (3r): The reaction of 1l
1
3
C NMR (75 MHz, CDCl ): d=159.6, 147.9, 137.5, 113.8,
(155.2 mg, 1.0 mmol), 2f (111.3 mg, 1.2 mmol), Pd ACHTUNGTRENNUNG( OAc)
3
2
1
1
06.9, 66.7, 45.5; IR (neat): n=2962, 2889, 2853, 1593, 1565,
(6.7 mg, 0.030 mmol), L2·HBF (21.4 mg, 0.045 mmol), and
4
ꢀ
1
481, 1436, 1376, 1312, 1243, 1160, 1121, 1070 cm ; MS
KOH (114.1 mg, 2.0 mmol) in 5 mL of toluene at 1108C
+
+
[27]
(
70 eV, EI): m/z (%)=165 (M +1, 4.54), 164 (M , 46.59),
9 (100).
-(N’-Methyl-N’-phenylamino)benzonitrile (3n): The reac-
tion of 1h (137.1 mg, 1.0 mmol), 2a (128.5 mg, 1.2 mmol),
Pd(OAc) (2.2 mg, 0.010 mmol), L2·HBF4 (7.2 mg,
.015 mmol), and KOH (112.0 mg, 2.0 mmol) in 5 mL of tol-
under nitrogen afforded 3r
work-up (eluent: petroleum
7
ether/ethyl acetate=10/1!5/1) as a solid; yield: 157.1 mg
4
(74%); mp 95.3–96.18C (n-hexane/ethyl acetate, lit: 105–
1068C, no recrystallization/solvent information provided).
1
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
H NMR (300 MHz, CDCl ): d=7.91–7.84 (m, 2H), 7.39–
2
3
0
7.30 (m, 2H), 7.22–7.16 (m, 2H), 7.12–7.04 (m, 1H), 7.03–
[18]
13
uene at 1108C under nitrogen afforded 3n after work-up
eluent: petroleum ether/ethyl acetate/triethylamine=200/5/
6.97 (m, 2H), 6.40 (bs, 1H), 2.53 (s, 3H); C NMR
(
(75 MHz, CDCl ): d=196.5, 148.4, 140.6, 130.5, 129.4, 128.7,
3
1
2) as a liquid; yield: 180.2 mg (87%). H NMR (300 MHz,
123.2, 120.6, 114.3, 26.1; IR (KBr): n=3319, 3177, 3034,
CDCl ): d=7.46–7.38 (m, 4H), 7.29–7.17 (m, 3H), 6.75–6.69
1650, 1586, 1526, 1495, 1450, 1415, 1358, 1326, 1278, 1251,
3
1
3
ꢀ1
+
(
m, 2H), 3.35 (s, 3H); C NMR (75 MHz, CDCl ): d=
1176, 1074, 1024 cm ; MS (70 eV, EI): m/z (%)=222 (M +
3
+
1
4
1
51.8, 146.7, 133.2, 130.0, 126.4, 126.1, 120.3, 113.7, 99.2,
1, 10.31), 221 (M , 66.19), 196 (100).
0.1; IR (neat): n=3057, 2924, 2817, 2215, 1609, 1591, 1558,
Methyl 2-(4’-acetylphenylamino)benzoate (3s): The reac-
tion of 1l (154.9 mg, 1.0 mmol), 2g (301.4 mg, 2.0 mmol), Pd-
ꢀ
1
513, 1494, 1356, 1257, 1176, 1119, 1068, 1025 cm ); MS
+
+
(
70 eV, EI): m/z (%)=209 (M +1, 16.12), 208 (M , 100).
-(o-Methoxyphenyl)morpholine (3o): The reaction of 1i
57.1 mg, 0.4 mmol), 2b (42.7 mg, 0.49 mmol), Pd(OAc)
4.5 mg, 0.020 mmol), L2·HBF (14.3 mg, 0.030 mmol), and
A
H
U
G
R
N
N
(OAc)
(6.6 mg,
0.030 mmol),
L2·HBF4
(21.4 mg,
2
4
0.045 mmol), and KOH (167.9 mg, 3.0 mmol) in 5 mL of tol-
[28]
(
(
A
H
U
G
R
N
U
G
uene at 1108C under nitrogen afforded 3s after work-up
(eluent: petroleum ether/ethyl acetate/triethylamine=100/1/
2
4
KOH (90.4 mg, 1.6 mmol) in 2 mL of toluene at 1108C
1!100/10/1) as a solid; yield: 134.4 mg (50%); mp: 77.8–
[25]
1
under nitrogen afforded 3o after work-up (eluent: petro-
leum ether/ethyl acetate/triethylamine=100/10/1) as
79.08C (MeOH, lit: 808C). H NMR (300 MHz, CDCl ): d=
3
a
9.73 (bs, 1H), 8.03–7.97 (m, 1H), 7.96–7.89 (m, 2H), 7.51–
7.36 (m, 2H), 7.29–7.20 (m, 2H), 6.91–6.84 (m, 1H), 3.91 (s,
1
liquid; yield: 41.3 mg (53%). H NMR (300 MHz, CDCl ):
3
1
3
d=7.06–6.96 (m, 1H), 6.96–6.90 (m, 2H), 6.90–6.85 (m,
3H), 2.56 (s, 3H); C NMR (75 MHz, CDCl ): d=196.4,
3
1
4
1
2
1
H), 3.90 (t, J=4.6 Hz, 4H), 3.87 (s, 3H), 3.07 (t, J=4.6 Hz,
168.6, 145.8, 145.1, 134.0, 131.7, 130.9, 130.2, 119.2, 118.4,
115.8, 114.1, 52.0, 26.2; IR (KBr): n=3296, 3026, 2951, 1685,
1672, 1587, 1519, 1453, 1436, 1351, 1327, 1262, 1236, 1167,
13
H); C NMR (75 MHz, CDCl ): d=152.1, 141.0, 123.1,
3
20.9, 117.9, 111.1, 67.1, 55.3, 51.1; IR (neat): n=3062, 2956,
ꢀ
1
+
892, 2853, 2817, 2756, 1594, 1501, 1447, 1377, 1300, 1241,
1146, 1089, 1047 cm ; MS (70 eV, EI): m/z (%)=270 (M +
ꢀ1
+
182, 1118, 1061, 1028 cm ; MS (70 eV, EI): m/z (%)=194
1, 16.15), 269 (M , 92.99), 195 (100).
+
+
(
M +1, 12.47), 193 (M , 100).
-(o-Tolyl)morpholine (3p): The reaction of 1j (102.7 mg,
.81 mmol), 2b (84.4 mg, 0.97 mmol), Pd(OAc) (8.9 mg,
.040 mmol), L2·HBF4 (29.0 mg, 0.061 mmol), and KOH
Ethyl 4-(N-methyl-N-phenylamino)benzoate (3t): The re-
action of 1m (185.7 mg, 1.0 mmol), 2a (127.1 mg, 1.2 mmol),
4
0
0
A
H
U
G
R
N
U
G
Pd
A
H
U
G
R
N
N
(OAc)
(6.8 mg, 0.030 mmol), L2·HBF4 (21.5 mg,
2
2
0.045 mmol), and KOH (113.2 mg, 2.0 mmol) in 5 mL of tol-
[29]
(
180.5 mg, 3.2 mmol) in 4 mL of toluene at 1108C under ni-
uene at 1108C under nitrogen afforded 3t after work-up
(eluent: petroleum ether/ethyl acetate/triethylamine=60/1/
[18]
trogen afforded 3p
after work-up (eluent: petroleum
liquid;
yield: 99.6 mg (69%). H NMR (300 MHz, CDCl ): d=7.22–
1
ether/ethyl acetate/triethylamine=300/10/3) as
a
1) as a liquid; yield: 130.4 mg (51%). H NMR (300 MHz,
1
CDCl ): d=7.92–7.85 (m, 2H), 7.43–7.35 (m, 2H), 7.24–7.17
3
3
7
2
.15 (m, 2H), 7.08–6.96 (m, 2H), 3.83 (t, J=4.6 Hz, 4H),
.89 (t, J=4.6 Hz, 4H), 2.31 (s, 3H); C NMR (75 MHz,
(m, 3H), 6.81–6.75 (m, 2H), 4.33 (q, J=7.0 Hz, 2H), 3.36 (s,
1
3
13
3H), 1.37 (t, J=7.0 Hz, 3H); C NMR (75 MHz, CDCl ):
3
CDCl ): d=151.1, 132.5, 131.0, 126.5, 123.3, 118.8, 67.3, 52.1,
d=166.7, 152.4, 147.5, 130.9, 129.7, 125.7, 125.2, 119.5, 113.8,
3
Adv. Synth. Catal. 2011, 353, 100 – 112
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
109

Bo Lꢀ et al.
FULL PAPERS
6
1
1
0.2, 40.1, 14.4; IR (neat): n=3060, 2980, 2934, 2903, 2819, N-Methyl-N-phenyl-4-methylaniline (3e) on a Larger
702, 1610, 1591, 1565, 1514, 1495, 1427, 1351, 1314, 1276,
Scale
ꢀ1
181, 1108, 1080, 1024 cm ; MS (70 eV, EI): m/z (%)=256
+
To a flame-dried and nitrogen-filled three-necked flask
equipped with a reflux condenser and a mechanical stirrer
(
M +1, 17.26), 255 (100).
-(N-Methyl-N-phenylamino)phenyl phenyl ketone (3u):
The reaction of 1n (216.1 mg, 1.0 mmol), 2a (127.8 mg,
.2 mmol), Pd(OAc) (6.6 mg, 0.030 mmol), L2·HBF4
21.7 mg, 0.045 mmol), and KOH (112.4 mg, 2.0 mmol) in
mL of toluene at 1108C under nitrogen afforded 3u after
work-up (eluent: petroleum ether/ethyl acetate/triethyl-
ACHTUNGTRENNUNGa mine=300/5/3) as a solid; yield: 228.6 mg (80%); mp 83.1–
4
were added Pd
ACHTUNGNTERNUNG( OAc) (0.226 g, 1.0 mmol), L2·HBF4
2
(
0.718 g, 1.5 mmol), KOH (44.8 g, 800 mmol), 1b (47.4 mL,
1
(
5
ACHTUNGTRENNUNG
2
ꢀ
1
d=1.068 gmL , 50.6 g, 400 mmol), and 100 mL of toluene
sequentially. After being stirred for about 3 min at room
ꢀ
1
temperature, 2a (52.0 mL, d=0.988 gmL , 51.4 g,
80 mmol) and another 100 mL of toluene were added. The
resulting mixture was heated to 1108C within 40 min. After
0 h, the reaction was complete as monitored by GC. The
4
[
30]
1
8
4.38C (n-hexane, lit:
81–828C). H NMR (300 MHz,
3
CDCl ): d=7.77–7.70 (m, 4H), 7.55–7.35 (m, 5H), 7.26–7.17
3
1
3
reaction mixture was then cooled and diluted by 100 mL of
CH Cl and filtered through a short column of silica gel
(
m, 3H), 6.81–6.74 (m, 2H), 3.38 (s, 3H); C NMR
2
2
(75 MHz, CDCl ): d=195.1, 152.4, 147.1, 138.9, 132.3, 131.2,
3
(
eluent: 2ꢃ100 mL of CH Cl ). Evaporation and purification
2 2
1
29.8, 129.4, 128.0, 126.6, 126.0, 125.6, 113.3, 40.2; IR (KBr):
by vacuum distillation (122–1248C/1 mmHg, lit: 126–1288C/
n=3052, 2907, 2823, 1631, 1589, 1554, 1494, 1444, 1351,
1
[
15,34]
ꢀ
1
0.6 mmHg) afforded 3e
as a liquid; yield: 65.4 g (83%).
): d=7.32–7.22 (m, 2H), 7.20–
317, 1288, 1260, 1193, 1142, 1114 cm ; MS (70 eV, EI): m/z
1
+
H NMR (300 MHz, CDCl
3
(
%)=288 (M +1, 24.15), 287 (100).
-(4’-Benzoylphenylamino)benzonitrile (3v): The reaction
of 1h (137.7 mg, 1.0 mmol), 2h (236.5 mg, 1.2 mmol),
Pd(OAc) (6.6 mg, 0.030 mmol), L2·HBF4 (21.4 mg,
.045 mmol), and KOH (112.1 mg, 2.0 mmol) in 5 mL of tol-
7
3
1
.10 (m, 2H), 7.08–7.00 (m, 2H), 7.00–6.77 (m, 3H), 3.33 (s,
4
1
3
H), 2.37 (s, 3H); C NMR (75 MHz, CDCl ): d=149.3,
3
46.5, 132.0, 129.9, 129.0, 122.5, 119.7, 118.1, 40.3, 20.7.
ACHTUNGTRENNUNG
2
0
[31]
N,N-Diphenylmethylamine (3h) on a Larger Scale
The reaction of 1d (11.25 g, 0.1 mol), 2a (12.84 g, 0.12 mol),
uene at 1108C under nitrogen afforded 3v (obtained via
chromatography on silica gel followed by recrystallized from
n-hexane/ethyl acetate) as a solid; yield: 170.8 mg (57%);
Pd
A
H
U
G
R
N
N
(OAc)
(0.0562 g, 0.25 mmol), L2·HBF4 (0.179 g,
2
mp 187.3–188.18C (n-hexane/ethyl acetate, lit: 185–1878C).
0
.375 mmol), and KOH (11.22 g, 0.2 mol) in 50 mL of tolu-
1
H NMR (300 MHz, CDCl ): d=7.86–7.74 (m, 4H), 7.62–
[35]
3
ene at 1108C under nitrogen afforded 3h (purified by dis-
tillation at 113–1148C/1 mmHg, lit: 148–1498C/12 mmHg);
yield: 14.291 g (78%). H NMR (300 MHz, CDCl ): d=
1
3
7
.45 (m, 5H), 7.22–7.15 (m, 4H), 6.64 (bs, 1H); C NMR
(75 MHz, CDCl ): d=195.3, 145.7, 144.9, 138.0, 133.8, 132.4,
1
3
3
1
32.1, 131.3, 129.7, 128.3, 119.3, 117.4, 117.2, 103.8; IR
7
3
1
.31–7.20 (m, 4H), 7.05–6.99 (m, 4H), 6.99–6.91 (m, 2H),
.31 (s, 3H); C NMR (75 MHz, CDCl ): d=149.0, 129.1,
(
KBr): n=3354, 2208, 1652, 1588, 1520, 1448, 1402, 1384,
13
3
ꢀ
1
1
336, 1281, 1249, 1178, 1154 cm ; MS (ESI): m/z= 299
21.2, 120.4, 40.2.
+
(
M +H).
Bis(4-acetophenyl)amine (3w): The reaction of 1l
Kinetic Study for the Reaction of p-Tolyl Chloride
1b) with N-Methylaniline (2a) and KOH Catalyzed
by Pd dba ·CHCl and L2
(
(
155.7 mg, 1.0 mmol), 2i (163.4 mg, 1.2 mmol), Pd
ACHTUNGTRENNUNG( OAc)
2
(
6.8 mg, 0.030 mmol), L2·HBF (21.6 mg, 0.045 mmol), and
4
KOH (112.9 mg, 2.0 mmol) in 5 mL of toluene at 1108C
2
3
3
[32]
under nitrogen afforded 3w after work-up (eluent: petro-
leum ether/ethyl acetate/CH Cl =3/1/1) as a solid; yield:
(
1) The order in ArCl: To a flame-dried and nitrogen-filled
2
2
Schlenk vessel were added Pd dba ·CHCl (20.7 mg,
2
3
3
2
1
14.6 mg (84%); mp 155.9–157.38C (n-hexane/CH Cl , lit:
2 2
0.02 mmol), L2·HBF (19.3 mg, 0.04 mmol), KOH (297.1 mg,
4
1
17–1198C, no solvents information). H NMR (300 MHz,
5
.3 mmol, in large excess), and biphenyl (61.7 mg, 0.4 mmol,
CDCl ): d=7.95–7.88 (m, 4H), 7.20–7.14 (m, 4H), 7.00 (bs,
3
internal standard). A solution of 1b (101.1 mg, 0.8 mmol) in
2 mL of toluene and a solution of 2a (515.2 mg, 4.8 mmol, in
large excess) in another 2 mL of toluene were added se-
quentially. The resulting mixture was heated at 1108C with a
preheated oil bath. The sample was taken by a capillary
1
3
1
1
3
1
H), 2.55 (s, 6H); C NMR (75 MHz, CDCl ): d=196.6,
3
46.0, 130.5, 130.4, 116.8, 26.2; IR (KBr): n=3310, 3192,
100, 2992, 1679, 1657, 1609, 1584, 1527, 1428, 1353, 1341,
ꢀ
1
306, 1275, 1250, 1173, 1075, 1021 cm ; MS (70 eV, EI): m/z
+
+
(
%)=254 (M +1, 9.31), 253 (M , 51.12), 238 (100).
tube and diluted with Et O. The concentration of 1b in the
2
N-Phenyl-3-methylaniline (3x): The reaction of 1e
taken sample was measured by GC using biphenyl as inter-
nal standard (relative correction factor=1.70). A linear rela-
tionship was observed for ln(1/[1b]) vs. reaction time, indi-
cating a first order dependence of reaction rate with 1b
(
(
126.6 mg, 1.0 mmol), 2f (185.3 mg, 2.0 mmol), Pd
ACHTUNGTRENNUNG( OAc)
2
6.8 mg, 0.030 mmol), L2·HBF (21.8 mg, 0.045 mmol), and
4
KOH (284.1 mg, 5.0 mmol) in 5 mL of xylenes at 1308C
[33]
0
under nitrogen afforded 3x after work-up (eluent: petrole-
[ln(1/[1b])=k t+ln(1/[1b] )] in which k is the first order
1
1
um ether/triethylamine=100/1) as a liquid; yield: 163.1 mg
rate constant, t is the reaction time (Table 4 and Figure 1).
(2) The order in amine: To a flame-dried and nitrogen-
filled Schlenk vessel were added Pd dba ·CHCl (20.6 mg,
1
(
89%). H NMR (300 MHz, CDCl ): d=7.30–7.19 (m, 2H),
3
7
6
.18–7.10 (m, 1H), 7.08–7.00 (m, 2H), 6.94–6.82 (m, 3H),
.74 (d, J=7.5 Hz, 1H), 5.62 (bs, 1H), 2.30 (s, 3H);
2
3
3
0.02 mmol), L2·HBF (19.2 mg, 0.04 mmol), KOH (297.0 mg,
4
13
C NMR (75 MHz, CDCl ): d=143.2, 143.0, 139.2, 129.3,
5.3 mmol, the large excess), and biphenyl (61.8 mg,
0.4 mmol, internal standard). A solution of 1b (608.1 mg,
4.8 mmol, in large excess) in 2 mL of toluene and a solution
of 2a (86.1 mg, 0.8 mmol) in another 2 mL of toluene were
added sequentially. The resulting mixture was heated at
3
1
3
1
1
29.1, 121.8, 120.8, 118.5, 117.8, 114.9, 21.5; IR (neat): n=
394, 3036, 2919, 2865, 1591, 1514, 1495, 1410, 1316, 1239,
ꢀ
1
+
167, 1077, 1028 cm ; MS (70 eV, EI): m/z(%)=184 (M +
, 14.51), 183 (100).
110
asc.wiley-vch.de
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 100 – 112

2,6-Diisopropoxyphenyl(dicyclohexyl)phosphine: A New Ligand
Table 4. The measurement experiment of the reaction order
in ArCl.
mixture was stirred for about 4 h at room temperature.
After that, KOH (5.3 mmol) and biphenyl (0.4 mmol, inter-
nal standard) were added. Then a solution of 1b (4.8 mmol)
in 1.5 mL of toluene and a solution of 2a (0.8 mmol) in an-
other 1.5 mL of toluene were added sequentially. The result-
ing mixture was heated at 1108C with a preheated oil bath.
The sample was taken by a capillary tube and diluted with
Et O. The concentration of 1b in the taken sample was mea-
2
sured by GC using biphenyl as internal standard (relative
correction factor=1.72). Since the reaction rates in each
case were with no significant difference with the concentra-
tion of L2, 1:1 ratio complex of Pd-L2 was expected
t (s)
Concentration of 1b (M)
ln(1/[1b])
1
1
2
3
3
4
4
5
6
6
200
800
400
000
600
200
800
400
000
600
0.1705
0.1495
0.1205
0.1062
0.08694
0.07724
0.07017
0.06096
0.05729
0.04670
1.769
1.900
2.116
2.242
2.443
2.561
2.657
2.798
2.860
3.064
(
Table 3 and Figure 4). For data, see Supporting Informa-
tion, Tables S1–S4 and Figures S1–S4.
Acknowledgements
Financial support from the National Basic Research Program
of China (Nos. 2009CB825300 and J0830413) is greatly ap-
preciated. Shengming Ma is a Qiu Shi Adjunct Professor at
Zhejiang University. We thank Miss Zhao Fang in our group
for reproducing the results presented in Table 2, entries 4, 9,
and 15.
Table 5. The measurement experiment of the reaction order
in amine.
References
[
1] For reviews on carbon-halogen bond amination (Buch-
wald–Hartwig amination) reactions, see: a) J. F. Hart-
wig, Angew. Chem. 1998, 110, 2154; Angew. Chem. Int.
Ed. 1998, 37, 2046; b) J. F. Hartwig, Acc. Chem. Res.
t (s)
Concentrtion of 2a (M)
1
998, 31, 852; c) J. P. Wolfe, S. Wagaw, J.-F. Marcoux,
1
1
2
3
3
4
4
6
6
1
200
800
400
120
780
200
800
120
600
5300
0.1764
0.1659
0.1621
0.1471
0.1319
0.1263
0.1193
0.1093
0.09441
0.01644
S. L. Buchwald, Acc. Chem. Res. 1998, 31, 805; d) B. H.
Yang, S. L. Buchwald, J. Organomet. Chem. 1999, 576,
1
25; e) J. F. Hartwig, in: Modern Amination Methods,
(
Ed.: A. Ricci), Wiley-VCH: Weinheim, 2000, pp 195–
2
2
62; f) I. P. Beletskaya, A. D. Averin, Pure Appl. Chem.
004, 76, 1605; g) J. F. Hartwig, in: Modern Arene
Chemistry, (Ed.: D. Astruc), Wiley-VCH: Weinheim,
2
002, pp 107–168; h) J. R. Dehli, J. Legros, C. Bolm,
Chem. Commun. 2005, 973; i) J. F. Hartwig, Acc. Chem.
Res. 2008, 41, 1534; j) B. Schlummer, U. Scholz, Adv.
Synth. Catal. 2004, 346, 1599; k) D. Prim, J.-M. Cam-
pagne, D. Joseph, B. Andrioletti, Tetrahedron 2002, 58,
2041; l) A. R. Muci, S. L. Buchwald, Top. Curr. Chem.
2002, 219, 131; m) S. L. Buchwald, C. Mauger, G.
Mignani, U. Scholz, Adv. Synth. Catal. 2006, 348, 23;
n) D. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120,
6438; Angew. Chem. Int. Ed. 2008, 47, 6338; o) A. F.
Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350;
Angew. Chem. Int. Ed. 2002, 41, 4176.
1108C with a preheated oil bath. The sample was taken by a
capillary tube and diluted with Et O. The concentration of
2
2
a in the taken sample was measured by GC using biphenyl
as internal standard (relative correction factor=1.72). A
linear relationship was observed for [2a] vs. reaction time,
indicating a zero order dependence of reaction rate with 2a
0
(
[2a]=k t+[2a] ) while k is the zero order rate constant, t
1
2
is reaction time (Table 5 and Figure 2).
[2] a) J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36,
3
609; b) J. P. Wolfe, S. L. Buchwald, J. Org. Chem.
1
996, 61, 1133; c) J. P. Wolfe, S. Wagaw, S. L. Buchwald,
Determination of the Order in L2 for the Reaction of
p-Tolyl Chloride (1b) with N-Methylaniline (2a) and
KOH Catalyzed by Pd dba ·CHCl and L2
J. Am. Chem. Soc. 1996, 118, 7215; d) M. S. Driver, J. F.
Hartwig, J. Am. Chem. Soc. 1996, 118, 7217.
2
3
3
[
3] a) Q. Shen, T. Ogata, J. F. Hartwig, J. Am. Chem. Soc.
2008, 130, 6586; b) Q. Shen, S. Shekhar, J. P. Stambuli,
J. F. Hartwig, Angew. Chem. 2005, 117, 1395; Angew.
Chem. Int. Ed. 2005, 44, 1371; c) L. M. Alcazar-Roman,
To a flame-dried and nitrogen-filled Schlenk vessel were
added Pd dba ·CHCl (0.02 mmol), L2 (0.04–0.16 mmol) and
2
3
3
1
mL of toluene. To ensure the complete coordination, this
Adv. Synth. Catal. 2011, 353, 100 – 112
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
111

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FULL PAPERS
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Bei, T. Uno, J. Norris, H. W. Turner, W. H. Weinberg,
A. S. Guram, J. L. Petersen, Organometallics 1999, 18,
[11] Sphos has also been confirmed as a useful ligand in Cꢀ
Cl amination reactions, with t-BuONa as the base:
a) M. D. Charles, P. Schultz, S. L. Buchwald, Org. Lett.
2005, 7, 3965; b) O. Johansson, L. Eriksson, R. Lomoth,
Dalton Trans. 2008, 3649; c) O. Johansson, Synthesis
2006, 2585.
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840; e) J. P. Stambuli, R. Kuwano, J. F. Hartwig,
Angew. Chem. 2002, 114, 4940; Angew. Chem. Int. Ed.
002, 41, 4746; f) D. W. Old, J. P. Wolfe, S. L. Buchwald,
2
J. Am. Chem. Soc. 1998, 120, 9722; g) D. S. Surry, S. L.
Buchwald, J. Am. Chem. Soc. 2007, 129, 10354;
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