Paracyclophane-based monophosphine ligand for palladium-catalyzed cross-coupling reactions of aryl chlorides

Article abstract of DOI:10.1039/b906139h

A new [2.2]paracyclophane-based electron-rich and sterically bulky monophosphine ligand has been synthesized by an efficient and straightforward method. When combined with palladium, this ligand shows excellent performance in the Buchwald-Hartwig amination and Suzuki-Miyaura coupling reactions of various aryl chlorides. In both types of reactions, ortho-substituted, deactivated aryl chlorides are shown to be viable substrates. However, the Suzuki-Miyaura coupling appears to be easier, with palladium loading at 0.1 mol% being feasible. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b906139h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
[2.2]Paracyclophane-based monophosphine ligand for palladium-catalyzed
cross-coupling reactions of aryl chlorides†
Jiwu Ruan,a Lee Shearer,a Jun Mo,a John Bacsa,a Antonio Zanotti-Gerosa,b Fred Hancock,b Xiaofeng Wua and
Jianliang Xiao*a
Received 27th March 2009, Accepted 13th May 2009
First published as an Advance Article on the web 17th June 2009
DOI: 10.1039/b906139h
A new [2.2]paracyclophane-based electron-rich and sterically bulky monophosphine ligand has been
synthesized by an efficient and straightforward method. When combined with palladium, this ligand
shows excellent performance in the Buchwald–Hartwig amination and Suzuki–Miyaura coupling
reactions of various aryl chlorides. In both types of reactions, ortho-substituted, deactivated aryl
chlorides are shown to be viable substrates. However, the Suzuki–Miyaura coupling appears to be
easier, with palladium loading at 0.1 mol% being feasible.
Due to its unique skeleton, [2.2]paracyclophane possesses
Introduction
unique electronic and steric properties.8 Not surprisingly, ligands
Pd-catalyzed cross-coupling reactions have become powerful tools
derived from it have been applied to various catalytic reactions,
especially those in asymmetric synthesis.8 Herein we report the
first synthesis of an electron-rich and sterically bulky monophos-
phine ligand based on [2.2]paracyclophane and its application
in the Suzuki–Miyaura coupling and Buchwald–Hartwig ami-
nation of aryl chlorides. In related work, we showed that these
reactions can also be effected with ferrocenyl monophosphine
ligands.9,10
for the formation of new carbon–carbon and carbon–heteroatom
bonds.1 Among these reliable catalytic transformations, the
Suzuki–Miyaura coupling2 and Buchwald–Hartwig amination2b,3
have received special attention and have been widely used in
organic synthesis. Recently, research on these two reactions
has focused on the use of readily available and comparatively
cheap aryl chlorides as coupling partners, due to their particular
relevance to industrial applications.4 However, the high C–Cl bond
strength renders their oxidative addition to palladium difficult,
thus often necessitating high catalyst loadings and so increasing
the cost in catalysts.5 It has been well recognized that ligands
employed for palladium significantly impact on the outcome of
the reactions, with a number of reports showing that Pd complexes
derived from sterically hindered and electron-rich phosphines are
effective catalysts,6,7 e.g. PCy3, P(t-Bu)3, SPhos, CyPF-t-Bu, and
their analogues (Scheme 1). However, there is still significant room
for improvement in the catalyst performance. And in particular,
developing simple and readily accessible ligands with comparable,
if not better, ability at assisting the metal-catalyzed coupling
reactions is still necessary.
Results and discussion
The ligand was synthesised via an easy, two-step process. As
shown in Scheme 2, using the commercially available racemic
4,12-dibromo[2.2]paracyclophane as the starting material, the
aryl-substituted 4-bromo[2.2]paracyclophane intermediate was
readily obtained by the Suzuki–Miyaura coupling with 2,6-
dimethoxyphenylboronic acid catalyzed by Pd(dppf)Cl2.11 After
lithiation of the intermediate and then treating with chlorodicyclo-
hexylphosphine, the desired bulky and electron-rich monophos-
phine ligand, JPhos, was afforded in 56% overall yield.
Scheme 1 Representative ligands used for Buchwald–Hartwig amination
and Suzuki–Miyaura coupling reactions of aryl chlorides.
aLiverpool Centre for Materials and Catalysis, Department of Chemistry,
University of Liverpool, Liverpool, L69 7ZD, UK. E-mail: j.xiao@liv.ac.uk;
Fax: +44-151-7943589; Tel: +44-151-7942937
Scheme 2 Synthesis of (rac)-[2.2]paracyclophane-based JPhos.
We were unable to grow single crystals of the free ligand
and so could not discern the steric environment around the
phosphorus. Fortunately, we obtained suitable crystals of its oxide
and were able to determine its X-ray structure. As can be seen
from Fig. 1, the 2,6-dimethoxyphenyl and one of the cyclohexyl
groups are nearly perpendicular to the benzene rings of the
bJohnson Matthey, Unit 28, Cambridge Science Park, Cambridge, CB4 0FP,
UK
† Electronic supplementary information (ESI) available: NMR spectra
of all the products and crystallographic data of JPhos oxide. CCDC
reference number 725601. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b906139h
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Table 1 Optimization of reaction conditions for the Buchwald–Hartwig
aminationa
Pd/ligand
(mol/mol)
Entry Pd
base
solvent
yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
1/2
1/2
1/2
1/2
1/1
1/3
1/2
no ligand
K3PO4
K3PO4
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
dioxane
8
12
40
80
65
20
70
0
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
a Reactions were carried out with 1a (1.0 mmol), 2a (1.2 equiv), base
(1.4 equiv), palladium catalyst (1 mol%), and JPhos in 4 mL solvent at
100 ◦C for 1 h. b Isolated yields.
results obtained when using a strong one, such as NaOtBu
(entries 2 vs 4). A control experiment without ligand was also
performed, affording no desired product (entry 8), and thus
suggesting that the active catalytic species are palladium-ligand
complexes.
Fig.
1 X-Ray crystal structure of JPhos oxide. Selected dis-
tances [A] and torsion angles [◦]: C(1)-C(2) 1.584(2), C(2)-C(3)
1.515(2), C(1)-C(14) 1.513(2), C(6)-C(9) 1.513(2), C(9)-C(10) 1.599(2),
C(10)-C(11) 1.511(2), O(1)-P(1)-C(4)-C(3) 38.3, O(1)-P(1)-C(4)-C(5)
-143.5, C(30)-C(29)-C(12)-C(13) -113.9, C(30)-C(29)-C(12)-C(11) 70.3,
C(17)-P(1)-C(4)-C(5) 95.3.
˚
Having established the optimized conditions, we then studied
the amination of a series of aryl chlorides (1a–h) with various
amines (2a–f). The results are shown in Table 2. As can be seen,
in most cases, the reactions afforded good to excellent yields of
the corresponding aniline products 3a–m under a low catalyst
loading (0.5 mol% Pd2(dba)3). In the case of the amination with
morpholine (2a), it appears that aryl chlorides with electron-
withdrawing groups tend to furnish lower yields (entries 3 and
6). ortho Substituents on the aryl rings are tolerated; but the
corresponding products were obtained in lower yields (entries
5–7). In particular, only a 60% yield was obtained in 6 h when
2,6-dimethyl-chlorobenzene (1g) was used (entry 7). This Pd-
JPhos catalyst also worked well with aniline derivatives; examples
are seen in entries 8–10. We further examined the amination of
4-chlorotoluene (1a) with several primary aliphatic amines, again
obtaining good results (entries 11–13).
The high activity of the catalyst in the amination reactions
prompted us to explore its applications in the Suzuki–Miyaura
coupling of aryl chlorides. Using commonly adopted condi-
tions in the literature,6,9 we first tested the reaction between
4-chlorobenzene (1h) and phenylboronic acid (4a). An excellent
result (93% yield) was obtained when the reaction was catalyzed
with only 0.1 mol% Pd(OAc)2 and 0.2 mol% JPhos in dioxane
at 80 ◦C for 12 h. As with the Buchwald–Hartwig amination,
however, no desired product was afforded without the ligand.
Having obtained this encouraging result, we then extended the
chemistry into the coupling of a series of aryl chlorides (1a–k)
with several aryl boronic acids (4a–d) under the same reaction
conditions. The results are summarized in Table 3. High yields
were achieved for all the examples, although some of the sterically
bulkier substrates necessitated a higher catalyst loading (entries
10, 12 and 13). For the coupling reactions with phenylboronic
[2.2]paracyclophane, with the other cyclohexyl group pointing
towards the 2,6-dimethoxyphenyl ring and the oxygen atom in the
dicyclohexylphosphine oxide towards one of the ethylene bridges.
Thus, replacing the oxygen with palladium would place the latter
in a sterically demanding environment, with half of the space being
likely blocked by the auxiliary groups on the phosphorus.
The [2.2]paracyclophane backbone is strained. The distance
between the carbon atoms C3, C14 and C6, C11 across the
cyclophane system (2.783 and 2.784 A) is less than twice the
van der Waals radius of a C atom. There are also short contacts
between atoms of the paracyclophane and the adjacent methoxy
groups (e.g. O3 ◊ ◊ ◊ C12 2.683 A, H9B ◊ ◊ ◊ H35A 2.360 A), the
phosphine oxide (e.g. O1 ◊ ◊ ◊ H2B 2.468 A) and the cyclohexyl
groups (e.g. H5 ◊ ◊ ◊ H23 2.231 A), leading to a sterically hindered
˚
˚
˚
˚
˚
system. The distortion is also borne out by the unusually large
torsion angles for the benzene rings, even for paracyclophane
systems (-18◦ for the bonded atoms C16-C11-C12-C13).12 The
conformation of both benzene rings is boat, with ring puckering
parameter S = 0.22 A, 0.20 A.
13
˚
˚
With the ligand in hand, we set out to examine its potential
use in the Buchwald–Hartwig amination. The reaction between
4-chlorotoluene (1a) and morpholine (2a) was first examined
(Table 1). After screening various conditions, we found that
Pd2(dba)3 was more efficient than Pd(OAc)2, and the best re-
sult was furnished when the ratio of JPhos/Pd was set to 2
(entry 4). Whilst the solvent did not appear to affect the
reaction significantly, dioxane gave a better yield (e.g. entries
4 vs 7). In contrast, base plays an important role, with better
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Table 3 Suzuki coupling of aryl chlorides with arylboronic acidsa
Table 2 Amination of aryl chlorides with various aminesa
Yieldb
(%)
Yieldb
(%)
Entry ArCl
1
Amine
Product
Entry ArCl
1
ArB(OH)2
Product
95
94
88
97
93
90
2
3
4
2
3
87
90
96
4
5
5
6
85
65
6
7
92
90
95
97
86
7c
60
8c
9c
91
89
81
8
9
10c
10c
11
93
84
11
12
13c
93
90
93
12c
13d
91
a Reactions were carried out with 1 (1.0 mmol), 4 (1.5 equiv), K3PO4 (3.0
equiv), Pd(OAc)2 (0.1 mol%), and JPhos (0.2 mol%) in 4 mL dioxane at
80 ◦C for 12 h. b Isolated yields. c 0.2 mol% Pd(OAc)2 and 0.4 mol% JPhos
used. d 0.6 mol% Pd(OAc)2 and 1.2 mol% JPhos used.
a Reactions were carried out with 1 (1.0 mmol), 2 (1.2 equiv), NaOtBu
(1.4 equiv), Pd2(dba)3 (0.5 mol%), and JPhos (2 mol%) in 4 mL dioxane at
100 ◦C for 3 h. b Isolated yields. c 6 h reaction time.
acid (4a), ortho substituted aryl chlorides afforded hindered biaryl
products in slightly lower yields (entries 2–4), so did the more
electron-rich aryl chlorides (entries 2, 3, 6 and 7). Of further note
is that an excellent yield was obtained for the substituted bromon-
aphthalene substrate (entry 13), demonstrating the potential of a
chiral version of JPhos in the synthesis of chiral binaphthalene
compounds.
Conclusion
In summary, we have developed an electron-rich and sterically
bulky monophosphine ligand via a simple synthetic pathway. With
a palladium catalyst derived from JPhos, the Buchwald–Hartwig
amination and Suzuki–Miyaura coupling reactions of various aryl
chlorides, including some unactivated and hindered ones, can be
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readily performed. The [2.2]paracyclophane backbone is seen to
bestow modularity and easy accessibility on ligands of this type.
Further work on the ligands and their application in asymmetric
catalysis are underway.
chromatography (hexane) on silica gel, affording a white solid
product (0.89 g, 66% yield). 1H NMR (400 MHz, CDCl3) d 7.19
(t, J = 8.4 Hz, 1H), 6.77–6.66 (m, 4H), 6.51–6.46 (m, 3H), 6.43 (s,
1H), 4.08 (s, 3H), 4.06–4.01 (m, 1H), 3.39 (s, 3H), 3.25–2.88 (m,
6H), 2.85–2.77 (m, 1H), 2.08–2.00 (m, 1H), 1.98–1.85 (m, 1H),
1.84–1.55 (m, 6H), 1.46–1.37 (m, 3H), 1.30–0.73 (m, 11H); 13C
NMR (100 MHz, CDCl3) d 159.4, 157.7, 146.6 (d, J = 23.3 Hz),
138.3, 138.2, 137.4, 135.0–134.4 (m), 133.8, 133.4, 133.3, 130.7,
128.4, 118.5, 105.2, 104.0, 56.5, 55.2, 37.1 (d, J = 16.0 Hz), 35.0–
34.7 (m), 34.2, 31.9 (d, J = 21.8 Hz), 30.8 (d, J = 16.0 Hz), 29.1
(d, J = 10.9 Hz), 28.7 (d, J = 10.2 Hz), 28.1 (d, J = 13.8 Hz),
27.7–27.5 (m), 27.2 (d, J = 14.6 Hz), 26.7 (d, J = 22.6 Hz); 31P
NMR (162 MHz, CDCl3) d -1.72; MS (CI, m/z, %) 541 (100)
[M+H]+; Anal. calcd for C36H45O2P: C, 79.97; H, 8.39. Found: C,
79.97; H, 8.44.
Experimental
General
All the reactions were carried out under a nitrogen atmo-
sphere with dried solvents unless otherwise indicated. (rac)-4,12-
Dibromo[2.2]paracyclophane was provided by Johnson Matthey.
The following chemicals were purchased from Lancaster or
Aldrich and used as received: all the aryl chlorides, arylboronic
acids, amines, Pd(dppf)Cl2, Pd(dba)2, Pd(OAc)2, n-BuLi, chlorod-
icyclohexylphosphine (ClPCy2), NaOBut, and K3PO4. Silica gel
plates (GF254) were used for TLC and silica gel (230–400 mesh)
was used for flash column chromatography. The 1H and 13C NMR
spectra were recorded on a Bruker DPX-400 spectrometer with
TMS as the internal standard. The mass spectra were obtained by
chemical ionization (CI).
X-Ray structural determination
Crystals of (rac)-dicyclohexyl-[12-(2¢,6¢-dimethoxy)phenyl-[2.2]-
paracyclophan-4-yl]-phosphine oxide (JPhos oxide) were grown in
a mixture of hexane and ethyl acetate (1:1) at room temperature.
Crystal data. C36H45O3P, M = 556.69, colourless block, 0.37 ¥
0.31 ¥ 0.28 mm3, monoclinic, space group P21/n (No. 14), a =
Preparation
of
(rac)-4-bromo-12-(2¢,6¢-dimethoxy)phenyl-
[2.2]paracyclophane11. An oven-dried Schlenk tube containing a
stir bar was charged with (rac)-4,12-dibromo[2.2]paracyclophane
(1.83 g, 5.0 mmol), 2,6-dimethoxyphenylboronic acid (1.37 g,
7.5 mmol, 1.5 equiv), Pd(dppf)Cl2 (164 mg, 0.20 mmol, 4 mol%),
and K3PO4 (2.12 g, 10.0 mmol, 2.0 equiv). After degassing
three times with nitrogen, freshly distilled toluene (20 mL) was
injected. The reaction mixture was vigorously stirred at 115 ◦C
for 24 h. After cooling down to room temperature, 30 mL toluene
was added, and the mixture was hydrolyzed with 10% NaOH
(30 mL). This was followed by phase separation and extraction
of the aqueous phase with EtOAc (3 ¥ 25 mL). The collected
organic layer was dried over MgSO4 and concentrated in vacuo.
The crude product was purified by flash chromatography on silica
gel using a mixture of ethyl acetate and hexane (25/75) as eluant
◦
˚
9.4191(11), b = 20.304(3), c = 15.4161(18) A, b = 97.671(2) ,
3
V = 2921.9(6) A , Z = 4, Dc = 1.265 g/cm3, F000 = 1200,
˚
Bruker D8 diffractometer with APEX detector, MoKa radiation,
l = 0.71073 A, T = 110(2) K, 2qmax = 55.0◦, 16429 reflections
˚
collected, 6447 unique (Rint = 0.0272). Final GoF = 1.019, R1 =
0.0441, wR2 = 0.1008, R indices based on 5107 reflections with
I >2sigma(I) (refinement on F2), 520 parameters, 0 restraints. Lp
and absorption corrections applied, m = 0.130 mm-1.
General procedure for the Buchwald–Hartwig amination of aryl
chlorides
An oven-dried carousel reaction tube containing a stir bar
was charged with Pd2(dba)3 (0.005 mmol, 0.5 mol%), JPhos
(0.02 mmol, 2 mol%), and NaOtBu (1.4 mmol). After degassing
three times with nitrogen, freshly distilled dioxane (4 mL), an
aryl chloride 1a-h (1 mmol), and an amine 2a-f (1.2 mmol) were
injected sequentially. The reaction mixture was vigorously stirred
at 100 ◦C for the time mentioned in Table 2. After cooling to
room temperature, 15 mL EtOAc was added and the mixture was
washed with 5 mL of brine, dried over MgSO4, and concentrated
in vacuo. The crude product was purified by flash chromatography
on basic Al2O3 using a mixture of ethyl acetate and hexane (10/90
to 50/50) as eluant. The desired products 3a–m were obtained in
60–97% yields (Table 2).
1
to afford a white solid product (1.82 g, 86% yield). H NMR
(400 MHz, CDCl3) d 7.24 (t, J = 8.4 Hz, 1H), 7.10 (s, 1H), 7.75
(d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.67 (s, 2H), 6.54–6.51 (m, 2H),
6.39 (d, J = 7.6 Hz, 1H), 4.10 (s, 3H), 3.60–3.51 (m, 1H), 3.48 (s,
3H), 3.22–3.10 (m, 2H), 2.95–2.75 (m, 4H), 2.65–2.55 (m, 1H);
13C NMR (100 MHz, CDCl3) d 158.6, 158.5, 141.6, 140.8, 139.7,
137.4, 137.1, 134.6, 133.5, 133.0, 131.6, 131.3, 129.8, 129.0, 126.9,
118.5, 105.1, 105.0, 56.5, 55.8, 37.3, 34.9, 34.8, 32.9; MS (CI,
m/z, %) 442:440 = 1:1 (100) [M+H+NH3]+, 425:423 = 1:1 (72)
[M+H]+.
Synthesis of (rac)-4-dicyclohexylphosphino-12-(2¢,6¢-dimeth-
oxy)phenyl-[2.2]paracyclophane (JPhos). An oven-dried Schlenk
flask was charged with 4-bromo-12-(2¢,6¢-dimethoxy)phenyl-
paracyclophane (1.06 g, 2.5 mmol). After degassing three times
with nitrogen, 50 mL freshly distilled Et2O was introduced. After
cooling to -78 ◦C, 1.3 mL (3.3 mmol, 2.5 M in hexane) n-BuLi was
dropwise added. The solution was stirred at -78 ◦C for 2 h, and for
another 3 h after being gradually warmed to room temperature.
ClPCy2 (0.66 mL, 3.0 mmol) was then added, and the mixture was
stirred at room temperature overnight. Thereafter, 0.5 mL 1 M
NaOH was introduced and after stirring for 10 min, the solvent
was removed. The crude product was purified by flash column
N-(4-Methylphenyl)morpholine (3a)16. 1H NMR (400 MHz,
CDCl3) d 7.01 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H),
3.78 (t, J = 4.8 Hz, 4H), 3.02 (t, J = 4.8 Hz, 4H), 2.19 (s, 3H);
13C NMR (100 MHz, CDCl3) d 149.7, 130.1, 129.9, 116.5, 67.4,
50.4, 20.8; MS (CI, m/z,%) 178 (100) [M+H]+; Anal. calcd for
C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.67; H, 8.63;
N, 7.83.
N-(4-Methoxyphenyl)morpholine (3b)16. 1H NMR (400 MHz,
CDCl3) d 6.90–6.83 (m, 4H), 3.85 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H),
3.05 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3) d 154.5,
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146.1, 118.2, 114.9, 67.4, 56.0, 51.3; MS (CI, m/z,%) 194 (100)
[M+H]+; Anal. calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25.
Found: C, 68.33; H, 7.86; N, 7.18.
N-Benzyl-4-methylaniline (3k)16. 1H NMR (400 MHz, CDCl3)
d 7.38–7.30 (m, 4H), 7.28–7.24 (m, 1H), 6.97 (d, J = 8.4 Hz, 2H),
6.56 (d, J = 8.4 Hz, 2H), 4.30 (s, 2H), 2.23 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 146.3, 140.1, 130.2, 129.0, 127.9, 127.6, 127.2,
113.5, 49.1, 20.8; MS (CI, m/z,%) 198 (100) [M+H]+; Anal. calcd
for C14H15N: C, 85.24; H, 7.66; N, 7.10. Found: C, 85.10; H, 7.61;
N, 7.14.
N-(4-Cyanophenyl)morpholine (3c)16. 1H NMR (400 MHz,
CDCl3) d 7.50 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H),
3.84 (t, J = 4.8 Hz, 4H), 3.28 (t, J = 4.8 Hz, 4H); 13C NMR
(100 MHz, CDCl3) d 153.9, 133.9, 120.2, 114.5, 101.3, 66.8, 47.7;
MS (CI, m/z,%) 189 (100) [M+H]+; Anal. calcd for C11H12N2O:
C, 70.19; H, 6.43; N, 14.88. Found: C, 70.10; H, 6.42; N, 14.85.
4-Methyl-N-(1-phenylethyl)aniline (3l)18. 1H NMR (400 MHz,
CDCl3) d 7.37–7.28 (m, 4H), 7.24–7.18 (m, 1H), 6.89 (d, J =
8.0 Hz, 2H), 6.44 (d, J = 8.0 Hz, 2H), 4.44 (q, J = 6.8 Hz, 1H),
3.95 (br, 1H), 2.18 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 145.8, 145.4, 130.0, 129.0, 127.2, 126.8, 126.3,
113.9, 54.1, 25.4, 20.7; MS (CI, m/z,%) 212 (100) [M+H]+; Anal.
calcd for C15H17N: C, 85.26; H, 8.11; N, 6.63. Found: C, 85.60; H,
8.13; N, 6.56.
N-(3-Methoxyphenyl)morpholine (3d)16. 1H NMR (400 MHz,
CDCl3) d 7.16 (t, J = 8.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 6.45–
6.41 (m, 2H), 3.81 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H), 3.12 (t, J =
4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3) d 161.1, 153.2, 130.3,
108.9, 105.2, 102.7, 67.3, 55.6, 49.7; MS (CI, m/z, %) 194 (100)
[M+H]+; Anal. calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25.
Found: C, 68.44; H, 7.88; N, 7.19.
N-Butyl-4-methylaniline (3m)7h. 1H NMR (400 MHz, CDCl3)
d 6.97 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.4 Hz, 2H), 3.35 (br, 1H),
3.08 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.61–1.55 (m, 2H), 1.45–1.40
(m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 146.8, 130.1, 126.7, 113.3, 44.5, 32.2, 20.8, 20.7, 14.3; MS (CI,
m/z,%) 164 (100) [M+H]+; Anal. calcd for C11H17N: C, 80.93; H,
10.50; N, 8.58. Found: C, 80.85; H, 10.64; N, 8.54.
N-(2-Methylphenyl)morpholine (3e)14. 1H NMR (400 MHz,
CDCl3) d 7.19–7.14 (m, 2H), 7.02–6.98 (m, 2H), 3.83 (t, J =
4.8 Hz, 4H), 2.89 (t, J = 4.8 Hz, 4H), 2.31 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 151.8, 133.1, 131.6, 127.1, 123.9, 119.4, 67.9,
52.7, 18.3; MS (CI, m/z, %) 178 (100) [M+H]+; Anal. calcd for
C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.47; H, 8.55;
N, 7.87.
General procedure for the Suzuki–Miyaura reaction of aryl
chlorides
N-(2-Cyanophenyl)morpholine (3f)15. 1H NMR (400 MHz,
CDCl3) d 7.58 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H),
7.06–7.00 (m, 2H), 3.90 (t, J = 4.8 Hz, 4H), 3.21 (t, J = 4.8 Hz,
4H); 13C NMR (100 MHz, CDCl3) d 153.7, 132.6, 132.0, 120.3,
116.7, 116.4, 104.4, 65.1, 50.0; MS (CI, m/z, %) 189 (100) [M+H]+;
Anal. calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.40; H, 6.50; N, 14.70.
An oven-dried carousel reaction tube containing a stir bar was
charged with a boronic acid 4a-d (1.5 mmol), K3PO4 (3 mmol),
and JPhos (0.002 mmol, 0.2 mol%). After degassing three times
with nitrogen, an aryl chloride 1a-k (1 mmol), 0.5 mL Pd(OAc)2
solution (2 ¥ 10-3 M in dioxane, 0.001 mmol, 0.1 mol%), and
freshly distilled dioxane (4 mL) were injected sequentially. The
N-(2,6-Dimethylphenyl)morpholine
(3g)17. 1H
NMR
◦
reaction mixture was vigorously stirred at 80 C for 12 h. After
(400 MHz, CDCl3) d 7.01–6.86 (m, 3H), 3.80 (t, J = 4.8 Hz,
4H), 3.10 (t, J = 4.8 Hz, 4H), 2.35 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 146.3, 135.4, 127.5, 123.8, 66.6, 48.4, 17.9; MS (CI,
m/z,%) 192 (100) [M+H]+; Anal. calcd for C12H17NO: C, 75.35;
H, 8.96; N, 7.32. Found: C, 75.47; H, 8.84; N, 7.36.
cooling to room temperature, 15 mL EtOAc was added and the
mixture was washed with 5 mL of brine, dried over MgSO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel using a mixture of ethyl acetate and
hexane (5/95 to 20/80) as eluant. The desired products 5a-m were
obtained in 84–97% yields (Table 3).
Diphenylamine (3h)16. 1H NMR (400 MHz, CDCl3) d 7.29–
7.23 (m, 4H), 7.06 (d, J = 8.8 Hz, 4H), 6.92 (t, J = 7.6 Hz,
2H), 5.68 (br, 1H); 13C NMR (100 MHz, CDCl3) d 143.6, 129.7,
121.4, 118.3; MS (CI, m/z,%) 170 (100) [M+H]+; Anal. calcd for
C12H11N: C, 85.17; H, 6.55; N, 8.28. Found: C, 85.32; H, 6.58; N,
8.26.
Biphenyl (5a)16. 1H NMR (400 MHz, CDCl3) d 7.58 (d, J =
8.4 Hz, 4H), 7.46–7.40 (m, 4H), 7.36–7.32 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 141.7, 129.3, 127.7; MS (CI, m/z,%) 155
(100) [M+H]+; Anal. calcd for C12H10: C, 93.46; H, 6.54. Found:
C, 93.45; H, 6.50.
4-Methyl-N-phenylaniline (3i)7h. 1H NMR (400 MHz, CDCl3)
d 7.25–7.20 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.02–6.98 (m, 4H),
6.90–6.85 (m, 1H), 5.59 (br, 1H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 144.4, 140.8, 131.4, 130.3, 129.7, 120.7, 119.4, 117.3,
21.0; MS (CI, m/z,%) 184 (100) [M+H]+; Anal. calcd for C13H13N:
C, 85.21; H, 7.15; N, 7.64. Found: C, 85.12; H, 7.23; N, 7.70.
2-Methylbiphenyl (5b)16. 1H NMR (400 MHz, CDCl3) d 7.42–
7.37 (m, 2H), 7.33–7.29 (m, 3H), 7.26–7.21 (m, 4H), 2.27 (s, 3H);
13C NMR (100 MHz, CDCl3) d 142.0, 141.9, 135.4, 130.3, 129.8,
129.2, 128.1, 127.3, 126.8, 125.8, 20.4; MS (CI, m/z,%) 168 (100)
[M]+; Anal. calcd for C13H12: C, 92.81; H, 7.19. Found: C, 92.75;
H, 7.27.
N-Ethyl-4-methyl-N-phenylaniline (3j)7h. 1H NMR (400 MHz,
CDCl3) d 7.25–7.17 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.97 (d,
J = 8.0 Hz, 2H), 6.89–6.82 (m, 3H), 3.73 (q, J = 7.2 Hz, 2H), 2.31
(s, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 148.7, 145.5, 132.5, 130.4, 129.5, 123.9, 119.8, 118.7, 46.8, 21.1,
13.1; MS (CI, m/z,%) 212 (100) [M+H]+; Anal. calcd for C15H17N:
C, 85.26; H, 8.11; N, 6.63. Found: C, 85.10; H, 8.06; N, 6.67.
2-Methoxybiphenyl (5c)19. 1H NMR (400 MHz, CDCl3) d
7.54–7.49 (m, 2H), 7.42–7.37 (m, 2H), 7.33–7.28 (m, 3H), 7.02–
6.96 (m, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.9,
139.0, 131.3, 131.2, 130.0, 129.0, 128.4, 127.3, 121.3, 111.7, 56.0;
MS (CI, m/z,%) 185 (100) [M+H]+; Anal. calcd for C13H12O: C,
84.75; H, 6.57. Found: C, 84.82; H, 6.64.
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Biphenyl-2-carbonitrile (5d)7h. 1H NMR (400 MHz, CDCl3) d
7.75 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.55 (d, J =
8.0 Hz, 2H), 7.53–7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) d
145.9, 138.6, 134.1, 133.2, 130.5, 129.2, 129.1, 127.9, 119.1, 111.8;
MS (CI, m/z,%) 180 (100) [M+H]+; Anal. calcd for C13H9N: C,
87.12; H, 5.06; N, 7.82. Found: C, 87.20; H, 5.00; N, 7.80.
2-Methoxy-1,1¢-binaphthyl (5m)23. 1H NMR (400 MHz,
CDCl3) d 7.95 (d, J = 8.8 Hz, 1H), 7.94–7.90 (m, 2H), 7.84 (d,
J = 8.4 Hz, 1H), 7.59 (dd, J = 8.4, 6.8 Hz, 1H), 7.44–7.40 (m,
3H), 7.33–7.30 (m, 2H), 7.29–7.13 (m, 3H), 3.73 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 155.1, 135.0, 134.7, 134.2, 133.4, 129.9, 129.5,
128.9, 128.7, 128.2, 128.1, 126.8, 126.6, 126.3, 126.1, 126.0, 125.9,
124.0, 123.8, 114.4, 57.2; MS (CI, m/z,%) 285 (100) [M+H]+;
Anal. calcd for C21H16O: C, 88.70; H, 5.67. Found: C, 88.77;
H, 5.64.
3-Methoxybiphenyl (5e)20. 1H NMR (400 MHz, CDCl3) d 7.58
(d, J = 8.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.37–7.32 (m, 2H),
7.18 (d, J = 7.2 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J = 7.2 Hz, 1H),
3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) d 160.4, 143.2, 141.6,
130.1, 129.1, 127.8, 127.6, 120.1, 113.4, 113.1, 55.7; MS (CI, m/z,
%) 185 (100) [M+H]+; Anal. calcd for C13H12O: C, 84.75; H, 6.57.
Found: C, 84.70; H, 6.67.
Acknowledgements
We gratefully acknowledge the DTI MMI project and its in-
dustrial/academic partners (Prof. R. Catlow, Royal Institution;
Dr. A. Danopoulos, University of Southampton; Dr. A. Pettman,
Pfizer; Dr. P. Hogan and Dr. M. Purdie, AstraZeneca; Dr.
P. Ravenscroft, GlaxoSmithKline) for financial support and
valuable suggestions.
4-Methylbiphenyl (5f)7h. 1H NMR (400 MHz, CDCl3) d 7.57
(d, J = 7.6 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 7.6 Hz,
2H), 7.35–7.29 (m, 1H), 7.24 (d, J = 7.6 Hz, 2H), 2.39 (s, 3H);
13C NMR (100 MHz, CDCl3) d 141.6, 138.8, 137.4, 129.9, 129.2,
129.1, 127.5, 127.4, 21.5; MS (CI, m/z,%) 168 (100) [M]+; Anal.
calcd for C13H12: C, 92.81; H, 7.19. Found: C, 92.71; H, 7.17.
References
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4-Methoxybiphenyl (5g)15. 1H NMR (400 MHz, CDCl3) d
7.56–7.50 (m, 4H), 7.43–7.38 (m, 2H), 7.32–7.28 (m, 1H), 6.97
(d, J = 8.4 Hz, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 159.6, 141.3, 134.2, 129.1, 128.6, 127.1, 127.0, 114.6, 55.7; MS
(CI, m/z,%) 185 (100) [M+H]+; Anal. calcd for C13H12O: C, 84.75;
H, 6.57. Found: C, 84.80; H, 6.57.
Biphenyl-4-carbonitrile (5h)21. 1H NMR (400 MHz, CDCl3) d
7.72 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.59 (d, J =
7.6 Hz, 2H), 7.51–7.46 (m, 2H), 7.42 (d, J = 7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 146.1, 139.6, 133.0, 129.5, 129.1, 128.1, 127.6,
119.3, 111.4; MS (CI, m/z,%) 180 (100) [M+H]+; Anal. calcd for
C13H9N: C, 87.12; H, 5.06; N, 7.82. Found: C, 87.05; H, 5.01; N,
7.94.
4-Acetylbiphenyl (5i)22. 1H NMR (400 MHz, CDCl3) d 8.02
(d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.6 Hz,
2H), 7.49–7.44 (m, 2H), 7.42–7.37 (m, 1H), 2.63 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 198.1, 146.2, 140.3, 136.3, 129.4, 129.3, 128.6,
127.7, 127.6, 27.0; MS (CI, m/z,%) 197 (100) [M+H]+; Anal. calcd
for C14H12O: C, 85.68; H, 6.16. Found: C, 85.53; H, 6.14.
2,6-Dimethylbiphenyl (5j)22. 1H NMR (400 MHz, CDCl3) d
7.42 (t, J = 7.6 Hz, 2H), 7.35–7.31 (m, 1H), 7.16–7.09 (m, 5H),
2.03 (s, 6H); 13C NMR (100 MHz, CDCl3) d 142.3, 141.5, 136.4,
129.4, 128.8, 127.7, 127.4, 127.0, 21.2; MS (CI, m/z,%) 182 (100)
[M]+; Anal. calcd for C14H14: C, 92.26; H, 7.74. Found: C, 92.38;
H, 7.68.
4,4¢-Dimethoxybiphenyl (5k)21. 1H NMR (400 MHz, CDCl3)
d 7.59 (d, J = 8.8 Hz, 4H), 6.95 (d, J = 8.8 Hz, 4H), 3.84 (s, 6H);
13C NMR (100 MHz, CDCl3) d 159.2, 133.9, 128.1, 114.6, 55.7;
MS (CI, m/z,%) 215 (100) [M+H]+; Anal. calcd for C14H14O2: C,
78.48; H, 6.59. Found: C, 78.37; H, 6.64.
2,2¢-Dimethylbiphenyl (5l)16. 1H NMR (400 MHz, CDCl3) d
7.26–7.19 (m, 6H), 7.09 (d, J = 7.2 Hz, 2H), 2.05 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 142.1, 136.2, 130.2, 129.7, 127.6, 126.0, 20.2;
MS (CI, m/z,%) 182 (100) [M]+; Anal. calcd for C14H14: C, 92.26;
H, 7.74. Found: C, 92.09; H, 7.78.
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