Use of Suzuki cross-coupling as a route to 2-phenoxy-6-iminopyridines and chiral 2-phenoxy-6-(methanamino)pyridines

Article abstract of DOI:10.1016/j.tet.2008.08.019

The anisyl boronic acids, 2-OMe-3-R²-5-R¹-C₆H₂B(OH)₂ (R¹=R²=H (a); R¹=H, R²=Ph (b); R¹=Me, R²=H (c); R¹=Cl, R²=H (d); R¹=t-Bu, R²=H (e)), have been employed in Suzuki cross-coupling reactions with either 2-bromo-6-formylpyridine (I) or 2-bromo-6-acetylpyridine (II) generating, following a facile deprotection step, the 2-phenoxy-6-carbonylpyridines, 2-(2′-OH-3′-R²-5′-R¹-C₆H₂)-6-(CH{double bond, long}O)C₅H₃N (R¹=R²=H (1a); R¹=Me, R²=H (1c); R¹=Cl, R²=H (1d); R¹=t-Bu, R²=H (1e)) and 2-(2′-OH-3′-R²-5′-R¹-C₆H₂)-6-(CMe{double bond, long}O)C₅H₃N (R¹=R²=H (2a); R¹=H, R²=Ph (2b)). Condensation reactions of 1 and 2 with 2,6-diisopropylaniline proceed smoothly to give the 2-phenoxy-6-iminopyridines, 2-(2′-OH-3′-R²-5′-R¹-C₆H₂)-6-{CH{double bond, long}N(2,6-i-Pr₂C₆H₃)}C₅H₃N (R¹=R²=H (3a); R¹=Me, R²=H (3c); R¹=Cl, R²=H (3d); R¹=t-Bu, R²=H (3e)) and 2-(2′-OH-3′-R²-5′-R²-C₆H₂)-6-{CMe{double bond, long}N(2,6-i-Pr₂C₆H₃)}C₅H₃N (R¹=H, R²=Ph (4a), R¹=H, R²=Ph (4b)). Reduction of the imino unit (and concomitant C-C bond formation) in 3 can be achieved by?treatment with trimethylaluminium or methyllithium which, following hydrolysis, furnishes the racemic chiral 2-phenoxy-6-(methanamino)pyridines, 2-(2′-OH-3′-R²-5′-R¹-C₆H₂)-6-{CHMe-NH(2,6-i-Pr₂C₆H₃)}C₅H₃N (R¹=R²=H (5a); R¹=Me, R²=H (5c); R¹=Cl, R²=H (5d); R¹=t-Bu, R²=H (5e)). This work represents a straightforward and rapid synthetic route to libraries of sterically and electronically variable phenoxy-substituted imino- and methanamino-pyridines, which are expected to act as useful ligands or proligands for late and early transition metal-mediated alkene polymerisation catalysis.

Full text of DOI:10.1016/j.tet.2008.08.019

Tetrahedron 64 (2008) 9857–9864
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Use of Suzuki cross-coupling as a route to 2-phenoxy-6-iminopyridines and chiral
2-phenoxy-6-(methanamino)pyridines
*
Christopher J. Davies, Andrew Gregory, Phillip Griffith, Tom Perkins, Kuldip Singh, Gregory A. Solan
Department of Chemistry, University of Leicester, University Road, Leicester, LE1 7RH, UK
a r t i c l e i n f o
a b s t r a c t
The anisyl boronic acids, 2-OMe-3-R2-5-R1-C6H2B(OH)2 (R1¼R2¼H (a); R1¼H, R2¼Ph (b); R1¼Me, R2¼H
(c); R1¼Cl, R2¼H (d); R1¼t-Bu, R2¼H (e)), have been employed in Suzuki cross-coupling reactions with
either 2-bromo-6-formylpyridine (I) or 2-bromo-6-acetylpyridine (II) generating, following a facile de-
protection step, the 2-phenoxy-6-carbonylpyridines, 2-(20-OH-30-R2-50-R1-C6H2)-6-(CH]O)C5H3N
(R1¼R2¼H (1a); R1¼Me, R2¼H (1c); R1¼Cl, R2¼H (1d); R1¼t-Bu, R2¼H (1e)) and 2-(20-OH-30-R2-50-R1-
C6H2)-6-(CMe]O)C5H3N (R1¼R2¼H (2a); R1¼H, R2¼Ph (2b)). Condensation reactions of 1 and 2 with
2,6-diisopropylaniline proceed smoothly to give the 2-phenoxy-6-iminopyridines, 2-(20-OH-30-R2-50-R1-
C6H2)-6-{CH]N(2,6-i-Pr2C6H3)}C5H3N (R1¼R2¼H (3a); R1¼Me, R2¼H (3c); R1¼Cl, R2¼H (3d); R1¼t-Bu,
R2¼H (3e)) and 2-(20-OH-30-R2-50-R2-C6H2)-6-{CMe]N(2,6-i-Pr2C6H3)}C5H3N (R1¼H, R2¼Ph (4a), R1¼H,
R2¼Ph (4b)). Reduction of the imino unit (and concomitant C–C bond formation) in 3 can be achieved
by treatment with trimethylaluminium or methyllithium which, following hydrolysis, furnishes the
racemic chiral 2-phenoxy-6-(methanamino)pyridines, 2-(20-OH-30-R2-50-R1-C6H2)-6-{CHMe-NH(2,6-i-
Pr2C6H3)}C5H3N (R1¼R2¼H (5a); R1¼Me, R2¼H (5c); R1¼Cl, R2¼H (5d); R1¼t-Bu, R2¼H (5e)). This work
represents a straightforward and rapid synthetic route to libraries of sterically and electronically variable
phenoxy-substituted imino- and methanamino-pyridines, which are expected to act as useful ligands or
proligands for late and early transition metal-mediated alkene polymerisation catalysis.
Article history:
Received 23 May 2008
Received in revised form 24 July 2008
Accepted 7 August 2008
Available online 9 August 2008
Keywords:
Suzuki
Cross-coupling
2-Phenoxy-6-iminopyridines
2-Phenoxy-6-(methanamino)pyridines
Chiral
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
incorporating a sterically bulky N-2,6-diisopropylphenyl group.4,8
Variation in the steric and electronic properties of the R1 and R2 posi-
With the advent of high-throughput-screening (HTS) techno-
logies for the evaluation of large numbers of catalysts for olefin
polymerisation,1 there presents a need to develop promising libraries
of ligands that can support polymerisation-active metal centres (e.g.,
Ti, Hf, Zr, Cr, V, Ni, Fe, Co). Inrecent years, thediscoveryofhighlyactive
alkene polymerisation catalysts based on sterically bulky tridentate
N,N,N-chelating ligands such as 2,6-bis(imino)pyridines2–4 and 2,6-
bis(methanaminato)pyridines5 has help signpost future possibilities
for ligand design. The O,N,O-chelating ligand family, 2,6-bis(pheno-
late)pyridine,6 has proved an effective support for zirconium-based
catalysts while the disclosure of thermally robust hafnium propene
polymerisation catalysts based on dianionic N,N,C-chelating ligands
(viz., 2-methanaminato-6-phenylpyridines7) has shown the great
potential of developing a unsymmetrical ligand environment.
Herein, we introduce a simple general strategy for preparing a wide
variety of unsymmetrical N,N,O-donor 2-phenoxy-6-iminopyridines
(3/4, Fig. 1) and 2-phenoxy-6-(methanamino)pyridines (5, Fig.1), each
tions of the phenol unit in 3–5 is demonstrated while a stereogenic
centre can be readily incorporated in the case of 5. The ligand synthesis
proceeds via the preparation of 6-formyl- and 6-acetyl-functionalised
2-phenoxypyridines (using Suzuki coupling methodologies9), which
can be smoothly converted to their aryl-imine counterparts and sub-
sequently reduced to their aryl-amines.
2. Results and discussion
2.1. Synthesis of the anisyl boronic acids
The anisyl boronic acids, 2-OMe-3-R2-5-R1-C6H2B(OH)2
(R1¼R2¼H (a); R1¼H, R2¼Ph (b); R1¼Me, R2¼H (c); R1¼Cl, R2¼H
i
i
Pr
Pr
H
N
R1
N
R1
N
H
N
H
i
Me i
H
R
Pr
Pr
O
O
R2
R2
* Corresponding author.
E-mail address: gas8@le.ac.uk (G.A. Solan).
Figure 1. 2-Phenoxy-6-iminopyridine (3/4) and 2-phenoxy-6-(methanamino)pyridine
(5); R¼H, Me; R1 or R2¼H, hydrocarbyl, halide.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.019

9858
C.J. Davies et al. / Tetrahedron 64 (2008) 9857–9864
(d); R1¼t-Bu, R2¼H (e)), can be prepared in good overall yield from
the corresponding anisyl bromide using the literature procedures
(Scheme 1)10,11 or obtained commercially (a, c, d). The molecular
structure of b is depicted in Figure 2; selected bond distances and
angles are collected in Table 1. The structure of b consists of a tri-
gonal planar [O(1)–B(1)–O(2) 119.58(11)ꢀ] boron atom linked to
two hydroxide groups and an anisyl ring with the 3-substituted
phenyl ring tilted with respect to the anisyl ring [tors.: C(2)–C(3)–
C(7)–C(8) 48.7ꢀ]; a hydrogen bonding interaction between one of
the hydroxide hydrogen atoms and the anisyl oxygen [O(2)/O(3)
2.743 Å] is also apparent.
Table 1
Selected bond distances (Å) and angles (ꢀ) for b
B(1)–O(1)
B(1)–O(2)
B(1)–C(1)
1.3482(16)
1.3636(16)
1.5701(17)
C(3)–C(7)
O(3)–C(2)
O(3)–C(13)
1.4886(16)
1.3930(14)
1.4303(16)
O(2)–B(1)–O(1)
119.58(11)
C(2)–O(3)–C(13)
114.14(9)
1%. Attempts at using alternative bases in the Suzuki coupling (e.g.,
KOt-Bu and NBu4OH) gave lower yields of the desired product as
did the use of alternative deprotection procedures (e.g., molten
pyridium chloride12).
R1
R1
2.3. Condensation reaction of carbonyl compounds with 2,6-
diisopropylaniline
(i), (ii), (iii)
OH
R2
B
R2
Br
Treatment of 1 and 2 with 2,6-diisopropylaniline in ethanol at
OMe
temperatures between 50 ꢀC and 80 ꢀC, in the presence of a catalytic
OMe
OH
R1 = R2 = H a
R1 = H, R2 = Ph b
R
R
R
1 = Me, R2 = H c
1 = Cl, R2 = H d
1 = t-Bu, R2 = H e
Table 2
Synthesis of 2-phenoxy-6-carbonylpyridines via Suzuki cross-coupling of a–e with
2-bromo-6-carbonylpyridines
Scheme 1. Reagents and conditions: (i) n-BuLi, Et2O, ꢁ78 ꢀC or Mg, THF, heat; (ii) B(O-
R1
i-Pr)3, Et2O, ꢁ78 ꢀC; (iii) Hþ/H2O.
(i) Pd(PPh3)4 (1-2 mol%),
R
OH
toluene, 90 °C, K2CO3, 48 h
(ii) BBr3, CH2Cl2, -78 °C
+
Br
N
2.2. Suzuki coupling of a–e with 2-bromo-6-carbonylpyridine
R2
B
1 - 2
OMe
O
OH
R = H I
Suzuki cross-coupling reactions of a–e were carried out with
either 2-bromo-6-formylpyridine (I) or 2-bromo-6-acetylpyridine
(II) in toluene at elevated temperature in the presence of potassium
carbonate and catalytic quantities of Pd(PPh3)4 (1–2 mol %) to af-
ford, following a BBr3 mediated deprotection, the 2-phenoxy-
6-formylpyridines, 2-(20-OH-30-R2-50-R1-C6H2)-6-(CH]O)C5H3N
(R1¼R2¼H (1a); R1¼Me, R2¼H (1c); R1¼Cl, R2¼H (1d); R1¼t-Bu,
R2¼H (1e)) and the 2-phenoxy-6-acetylpyridines, 2-(20-OH-30-R2-
50-R1-C6H2)-6-(CMe]O)C5H3N (R1¼R2¼H (2a); R1¼H, R2¼Ph (2b))
in good yield (Table 2). All the new compounds have been char-
acterised by 1H NMR, 13C NMR, IR spectroscopy and ESI mass
spectrometry (see Section 4).
R1 = R2 = H a
R1 = H, R2 = Ph b
R = Me II
R
1 = Me, R2 = H c
R1 = Cl, R2 = H d
1 = t-Bu, R2 = H e
R
Entry Boronic acid 2-Bromo-6-
carbonylpyridine
Deprotected
product
Yielda (%)
O
N
1
a
I
70
H
H
O
1a
The IR spectra for 1 and 2 show characteristic absorption bands
for their carbonyl functionalities (range: 1698–1717 cmꢁ1) while
protonated molecular ion peaks were revealed in their ESI mass
spectra. In the 13C{1H} NMR spectra, the carbonyl carbon atoms fall
O
O
O
Me
Cl
N
H
2
3
4
5
c
I
65
69
75
73
H
H
O
1c
between
being seen at ca.
respectively.
d 189.6 and 196.6 with the CH]O and CMe]O protons
d 10.0 (1) and ca. d
2.6 (2) in their 1H NMR spectra,
The overall yields obtained for the combination of both the
coupling reaction and the deprotection step are generally good
(>60%) but start to decrease as catalyst loadings are reduced below
N
H
d
e
a
I
O
1d
t
Bu
N
H
I
H
O
O
1e
N
H
II
Me
O
2a
O
N
H
6
b
II
61
Me
O
Ph
2b
Figure 2. Molecular structure of b including a partial atom numbering scheme. All
hydrogen atoms, apart from H1 and H2, have been omitted for clarity.
a
Isolated yields from both steps.

C.J. Davies et al. / Tetrahedron 64 (2008) 9857–9864
9859
amount of glacial acetic acid gave the 2-phenoxy-6-iminopyri
dines, 2-(20-OH-30-R2-50-R1-C6H2)-6-{CH]N(2,6-i-Pr2C6H3)}C5H3N
(R1¼R2¼H (3a); R1¼Me, R2¼H (3c); R1¼Cl, R2¼H (3d); R1¼t-Bu,
R2¼H (3e)) and 2-(20-OH-30-R1-50-R2-C6H2)-6-{CMe]N(2,6-i-
Pr2C6H3)}C5H3N (R1¼R2¼H (4a); R1¼H, R2¼Ph (4b)) as pale yellow
solids in moderate to good yield (see Table 3). All the new com-
pounds have been characterised by 1H NMR, 13C NMR, IR spectro-
scopy and ESI mass spectrometry (see Section 4).
The mass spectra of 3 and 4 reveal protonated molecular ion
peaks while in their IR spectra absorption bands characteristic for
their imino functionalities (ca. 1635 cmꢁ1) are evident. In their 1H
NMR spectra, the aldimine compounds (3) gave singlets at ca.
consistent with the presence of CH]N protons while the CMe]N
protons are seen at ca. 2.2 for the ketimine compounds (4).
d 8.2
d
2.4. Formation of the 2-phenoxy-6-(methanamino)pyridines
Single crystal X-ray diffraction studies have been performed on
3a, 3d and 4a. A perspective view of 3d is depicted in Figure 3;
selected bond distances and angles for all three structures are listed
in Table 4. Each structure consists of a central pyridine ring that is
substituted at its 2-position by a phenol group and at the 6-position
by an imine unit [C(12)–N(2) 1.2600(12) Å (3a), 1.2595(17) Å (3d),
1.266(4) Å (4a)]. The pyridine nitrogen adopts a trans configuration
with respect to the neighbouring imine nitrogen [tors.: N(1)–C(11)–
C(12)–N(2) 171.2ꢀ (3a), 178.8ꢀ (3d), 177.3ꢀ (4a)] while it is cis to the
phenol oxygen; the latter configuration is the result of a hydrogen
bonding interaction between the phenol hydrogen atom and the
neighbouring pyridine nitrogen [O(1)/N(1) 2.562 Å (3a), 2.563 Å
(3d), 2.536 Å (4a)]. For all three structures, the 2,6-diisopropyl-
phenyl rings are inclined essentially orthogonal to the plane of the
adjacent pyridylimine unit.
Reaction of 3a, 3c, 3d or 3e with trimethylaluminium in toluene
at 110 ꢀC followed by hydrolysis afforded 2-(20-OH-30-R2-50-R1-
C6H2)-6-{CHMe-NH(2,6-i-Pr2C6H3)}C5H3N (R1¼R2¼H (5a); R1¼Me,
R2¼H (5c); R1¼Cl, R2¼H (5d); R1¼t-Bu, R2¼H (5e)) in high yield
(Table 5; method A), respectively. Alternatively, 5 could be prepared
by treating 3 with methyllithium in diethylether at ꢁ40 ꢀC followed
by hydrolysis (Table 5; method B); the method yielding the best
yield for 5 is indicated in Table 5. In the case of 5a, reduction of the
imine unit in 4a using excess sodium borohydride in ethanol also
allows access to 5a. The 1H NMR spectra of 5 confirm the formation
of the saturated –CHMeNH(Ar) moiety with the CHMeNH(Ar)
proton taking the form of a quartet that is coupled to the geminal
methyl group (3JH–H 6.7 Hz). In their 13C NMR spectra the expected
number of independent carbon signals are shown, while their ESI
mass spectra display peaks corresponding to the protonated mole-
cular ions.
To support the spectroscopic data, crystals of 5a and 5e have
been the subject of single crystal X-ray diffraction studies. A per-
spective view of 5e is depicted in Figure 4; selected bond distances
and angles for both structures are listed in Table 6. Both structures
consist of a central pyridine linked at its 2-position by a cis-oriented
phenol (5a) or a 5-tert-butylphenol (5e) group and at its 6-position
by an amine-containing CHMeNH(2,6-i-Pr2C6H3) unit. The phenol
moieties are almost co-planar with respect to the pyridine unit
[tors.: C(1)–C(6)–C(7)–N(1) 14.9ꢀ (5a), 12.8ꢀ (5e)] and are disposed
mutally cis as a result of a hydrogen bonding interaction between
the phenol hydrogen atom and the neighbouring pyridine nitrogen
[O(1)/N(1) 2.581 Å (5a), 2.578 Å (5e)]. The chiral –PyCHMeNH(Ar)
carbons in 5a display the (S) configuration while in 5e the (R)
configuration is exhibited.
Table 3
Condensation reactions of 1 and 2 with 2,6-diisopropylaniline
2,6-i-Pr2C6H3NH2 (1.1-1.3 equiv.), cat.H+
2-phenoxy-6-(C(R)=O)pyridine
3,4
EtOH, 50-80 °C, 18-48 h
Entry 2-Phenoxy-6-carbonylpyridine 2-Phenoxy-6-iminopyridine product Yielda
(%)
i
Pr
O
N
N
H
7
56
72
61
72
80
N
H
H
i
H
O
Pr
O
1a
3a
i
Pr
O
O
O
Me
Cl
N
3. Conclusions
Me
Cl
N
H
8
N
H
H
i
H
H
H
O
1c
Pr
O
O
In summary, we have described a straightforward and efficient
synthesis for a broad range of sterically and electronically variable
3c
i
Pr
phenoxy-substituted pyridylimines via
a palladium-mediated
N
Suzuki cross-coupling approach. In addition, aluminium alkyls and
lithium alkyls have been employed to facilitate C–C bond formation
N
H
9
N
H
i
O
1d
Pr
and the production of
a series of racemic chiral phenoxy-
3d
substituted pyridylamines. The coordination chemistry of these
new ligand types and the potential as supports for polymerisation-
active metal centres will be explored elsewhere.
i
Pr
t
Bu
t
N
Bu
N
H
10
11
N
H
H
O
i
H
N
O
1e
Pr
O
4. Experimental
4.1. General
3e
i
Pr
N
H
N
H
All reactions, unless otherwise stated, were carried out under an
atmosphere of dry, oxygen-free nitrogen using standard Schlenk
techniques. Solvents were distilled under nitrogen from appropri-
ate drying agents and degassed prior to use.13 The infrared spectra
were recorded on a Perkin–Elmer Spectrum One FT-IR spectrom-
eter on solid samples. The electrospray ionisation (ESI) and the fast
atom bombardment (FAB) mass spectra were recorded using
a micromass Quattro LC mass spectrometer and a Kratos Concept
spectrometer with chloroform or NBA as the matrix, respectively.
High resolution FAB mass spectra were recorded on Kratos Concept
Me
i
Me
Pr
O
O
O
2a
4a
i
Pr
O
N
N
H
N
H
12
61
Me
i
Me
Pr
O
Ph
Isolated yields.
Ph
2b
4b
a

9860
C.J. Davies et al. / Tetrahedron 64 (2008) 9857–9864
Figure 3. Molecular structure of 3d including a partial atom numbering scheme. All hydrogen atoms, apart from H1 and H12, have been omitted for clarity.
spectrometer (xenon gas, 7 kV) with NBA as matrix. 1H and 13C
NMR spectra were recorded on a Bruker ARX spectrometer
(300 MHz); chemical shifts (ppm) are referred to the residual protic
solvent peaks; coupling constants are in Hertz (Hz). Melting points
(mp) were measured on a Gallenkamp melting point apparatus
(model MFB-595) in open capillary tubes and were uncorrected.
Elemental analyses were performed on a Carlo Erba CE1108
instrument at the Science Technical Support Unit, London Metro-
politan University.
The reagents, 2-methoxyphenylboronic acid (a), 2-methoxy-5-
methylphenylboronic acid (c), 2-methoxy-5-chlorophenylboronic
acid (d), 2-bromo-6-formylpyridine (I), 2-bromo-6-acetylpyridine
(II), triisopropylborate, 2,6-diisopropylaniline, boron tribromide
(1 M solution in dichloromethane), methyllithium (1.4 M solution
in diethylether) and trimethylaluminium (2 M solution in toluene)
were purchased from Aldrich Chemical Co. and used without
further purification. The compounds, 3-phenyl-2-methoxy-
phenylboronic acid (b),10 2-methoxy-tert-butylphenylboronic acid
(e),11 tetrakis(triphenylphosphine)palladium(0),14 were prepared
according to previously reported procedures. All other chemicals
were obtained commercially and used without further purification.
boronic acid a (0.753 g, 3.62 mmol, 1.3 equiv) in ethanol (5 mL).
After heating the solution to 90 ꢀC for 42 h, the flask was allowed
to cool to room temperature and 30% hydrogen peroxide (0.2 mL)
added and the solution left to stir at room temperature for 1 h. The
product was extracted with diethylether (2ꢂ50 mL) and washed
sequentially with saturated sodium chloride solution and water
(3ꢂ30 mL). The organic extracts were combined, dried over
magnesium sulfate and the volatiles removed under reduced
pressure. The residue was adsorbed onto silica and applied to the
top of a short silica column and eluted with dichloromethane/
hexane (80:20) to give the protected product, after drying under
reduced pressure, as a yellow oil (0.503 g). The oil (0.503 g,
2.36 mmol) was loaded into a Schlenk vessel under nitrogen,
dissolved in dry dichloromethane (10 mL) and cooled to ꢁ78 ꢀC.
Boron tribromide (4.96 mL, 4.96 mmol, 2.1 equiv) was added
dropwise to the cooled solution and the resulting brown solution
allowed to warm to room temperature and left to stir for 6 h.
Water (5 mL) was carefully added and the mixture neutralised
(with 2 M potassium carbonate) and left to stir overnight. The
organic phase was separated and the aqueous phase washed with
chloroform (2ꢂ50 mL). The combined organic extracts were dried
over anhydrous magnesium sulfate and the volatiles removed by
rotary evaporation to afford 1a as a brown solid (70%, 0.399 g).
4.2. Suzuki cross-coupling/deprotection reactions
Mp: 104–106 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.51 (br s, 1H, OH),
6.90 (td, 1H, JH–H 8.2, JH–H 1.5, 1H, Ar–H), 7.10 (dd, 1H, JH–H 8.2, JH–H
1.1, 1H, Ar–H), 7.30 (m, 1H, Ar–H), 7.75 (d, 1H, JH–H 1.5, 1H, Py–H/
Ar–H), 7.78 (d, 1H, JH–H 1.8, 1H, Py–H/Ar–H), 7.97 (t, 1H, JH–H 8.2,
1H, Py–H), 8.09 (d, 1H, JH–H 4.1, Py–H), 10.04 (s, 1H, CHO). 13C{1H}
4.2.1. 2-(20-Phenoxy)-6-formylpyridine (1a)
An oven-dried Schlenk flask equipped with a magnetic stirrer
bar was evacuated and back filled with nitrogen. The flask was
charged with
I
(0.53 g, 2.79 mmol), [Pd(PPh3)4] (0.067 g,
NMR (75 MHz, CDCl3):
d 117.1, 117.8, 118.3 (CH), 125.6 (C), 130.1,
0.057 mmol, 0.02 equiv), toluene (10 mL) and aqueous 2 M solu-
tion of potassium carbonate (2.80 mL, 5.55 mmol, 2 equiv). The
solution was stirred for 15 min followed by the addition of the
131.3, 135.3, 137.8 (CH), 148.3, 157.6, 158.6 (C), 190.0 (CHO). IR
(cmꢁ1): 1708 (C]O). ESIMS: m/z 200 [MþH]þ. HRMS (FAB): calcd
for C12H10NO2 [MþH]þ 200.0712, found 200.0713.
4.2.2. 2-(50-Methyl-20-phenoxy)-6-formylpyridine (1c)
Table 4
Selected bond distances (Å) and angles (ꢀ) for 3a, 3d and 4a
A similar procedure to that described for 1a was followed,
using I (0.53 g, 2.79 mmol), c (0.57 g, 3.42 mmol, 1.2 equiv) and
[Pd(PPh3)4] (0.066 g, 0.056 mmol, 0.02 equiv) to obtain, following
deprotection with BBr3, 1c as a brown solid (0.39 g, 65%). Mp: 102–
3a
3d
4a
C(1)–O(1)
C(6)–C(7)
1.3539(16)
1.4765(19)
1.4656(18)
1.2600(16)
1.4283(16)
d
1.3520(15)
1.4778(18)
1.4762(17)
1.2595(17)
1.4241(16)
1.7451(13)
d
1.362(4)
1.487(5)
1.490(5)
1.266(4)
1.422(4)
d
104 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.51 (br s, 1H, OH), 2.29 (s, 3H,
C(11)–C(12)
C(12)–N(2)
N(2)–C(13)
C(4)–Cl(1)
C(12)–Cketimine
Me), 6.90 (d, 1H, JH–H 8.2, Ar–H), 7.10 (dd, 1H, JH–H 8.2, JH–H 1.1, Ar–
H), 7.52 (m, 1H, Ar–H), 7.69 (d, 1H, JH–H 7.8, 1H, Py–H), 7.93 (t, 1H,
JH–H 8.2, 1H, Py–H), 8.09 (d, 1H, JH–H 4.1, Py–H), 9.99 (s, 1H, CHO).
d
1.502(5)
13C{1H} NMR (75 MHz, CDCl3):
d 19.7 (Me), 116.7 (C), 117.5, 118.7,
C(12)–N(2)–C(13)
C(11)–C(12)–N(2)
119.12(12)
122.48(13)
121.70(11)
120.52(12)
121.4(3)
116.9(3)
122.5, 125.7 (CH), 128.5 (C), 132.1, 137.6 (CH), 148.3 (C), 156.3 (C),
157.6 (C), 190.0 (HC]O). IR (cmꢁ1): 1713 (C]O). ESIMS: m/z 214

C.J. Davies et al. / Tetrahedron 64 (2008) 9857–9864
9861
Table 5
Reduction of 3 with trimethylaluminium and methylithium
(i) AlMe3, toluene,110 °C; (ii) H2O
Method A
5
2-phenoxy-6-{C(R)=N(aryl)}pyridine
Method B
(i) LiMe, Et2O, -40 °C; (ii) H2O
Entry
13
Method
A
2-Phenoxy-6{C(R)]N(aryl)}pyridine
2-Phenoxy-6{C(R)MeNH(aryl)}pyridine product
Yielda (%)
i
i
Pr
Pr
H
N
N
H
H
N
77
N
H
i
Me i
H
Pr
Pr
O
O
5a
3a
i
i
Pr
Pr
H
N
N
N
Me
Cl
N
Me
Cl
N
H
14
15
B
55
73
N
H
i
H
H
H
Me i
H
H
Pr
Pr
O
O
O
O
O
5c
3c
i
i
Pr
Pr
H
N
A
N
H
N
H
Me i
i
Pr
Pr
3d
5d
i
i
Pr
Pr
H
N
t
t
Bu
Bu
16
A
65
N
H
N
H
i
Me i
H
Pr
Pr
O
5e
3e
a
Isolated yields.
[MþH]þ. HRMS (FAB): calcd for C13H12NO2 [MþH]þ 214.0868,
Py–H), 8.03 (m, 2H, Py–H), 10.03 (s, 1H, CHO). 13C{1H} NMR
(75 MHz, CDCl3): 118.1 (C), 119.3, 119.5 (CH), 122.7 (C), 123.1,
found 214.0866.
d
125.2, 131.1, 138.2 (CH), 148.4, 156.4, 157.2 (C), 189.6 (CH]O). IR
(cmꢁ1): 1717 (C]O), 1590 (C]NPy). ESIMS: m/z 234 [MþH]þ.
HRMS (FAB): calcd for C12H9NO2Cl [MþH]þ 234.0322, found
234.0322.
4.2.3. 2-(50-Chloro-20-phenoxy)-6-formylpyridine (1d)
A similar procedure to that described for 1a was followed,
using I (0.70 g, 3.74 mmol), d (0.84 g, 4.49 mmol, 1.2 equiv) and
[Pd(PPh3)4] (0.043 g, 0.038 mmol, 0.01 equiv) to obtain, following
deprotection with BBr3, 1d as a light brown solid (0.73 g, 69%).
4.2.4. 2-(50-tert-Butyl-20-phenoxy)-6-formylpyridine (1e)
A similar procedure to that described for 1a was followed,
using I (0.70 g, 3.74 mmol), e (0.93 g, 4.49 mmol, 1.2 equiv) and
[Pd(PPh3)4] (0.043 g, 0.038 mmol, 0.01 equiv) to obtain, following
Mp: 170–172 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.56 (br s, 1H, OH),
6.94 (d, 1H, JH–H 8.8, Ar–H), 7.23 (dd, 1H, JH–H 8.8, JH–H 2.6, Ar–
H), 7.70 (d, 1H, JH–H 2.6, Ar–H), 7.86 (dd, 1H, JH–H 8.5, JH–H 2.0,
Figure 4. Molecular structure of 5e including a partial atom numbering scheme. All hydrogen atoms, apart from H12 and the hydroxyl and amino hydrogens, have been omitted for
clarity.

9862
C.J. Davies et al. / Tetrahedron 64 (2008) 9857–9864
Table 6
CH(Me)2), 6.88 (td, 1H, JH–H 8.2, JH–H 1.5, Ar–H), 6.97 (dd, 1H, JH–H
Selected bond distances (Å) and angles (ꢀ) for 5a and 5e
8.2, JH–H 1.5, Ar–H), 7.07 (m, 3H, Ar–H), 7.27 (td,1H, JH–H 8.2, JH–H 1.5,
Ar–H), 7.77 (dd,1H, JH–H 7.9, JH–H 1.8, Ar–H), 7.96 (m, 2H, Py–H), 8.08
(dd, 3JH–H 7.0, JH–H 1.8, 1H, Py–H), 8.26 (s, 1H, CH]N). 13C{1H} NMR
5a
5e
C(1)–O(1)
C(6)–C(7)
1.3596(15)
1.4773(17)
1.5134(17)
1.4671(15)
1.4235(14)
1.5219(17)
d
1.3581(15)
1.4807(18)
1.5173(18)
1.4683(17)
1.4283(17)
1.5219(18)
1.5350(18)
(75 MHz, CDCl3): d 23.5 (CH3), 28.1 (CH), 118.6 (CH), 118.7 (C), 119.1,
C(11)–C(12)
C(12)–N(2)
N(2)–C(14)
C(12)–C(13)
C(4)–C(26)
119.4, 121.9, 123.2, 124.8, 126.5, 131.9, 137.2, 138.6 (CH), 148.2, 151.0,
158.1, 159.8 (C), 161.1 (CH]N). IR (cmꢁ1): 1647 (C]Nimine), 1592
(C]NPy). ESIMS: m/z 359 [MþH]þ. Anal. Calcd for C24H26N2O: C,
80.39; H, 7.32; N, 7.82. Found: C, 80.29; H, 7.44; N, 7.84.
C(11)–C(12)–N(2)
C(11)–C(12)–C(13)
113.87(10)
112.25(10)
113.66(11)
112.77(11)
4.3.2. 2-(50-Methyl-20-phenoxy)-6-(iminoformyl)pyridine (2,6-
diisopropylanil) (3c)
Using a similar procedure to that described for 3a, with 1c
(0.227 g, 1.07 mmol), 2,6-diisopropylaniline (0.264 g, 1.49 mmol,
1.4 equiv) and absolute ethanol (4 mL), gave 3c as a yellow solid
deprotection with BBr3, 1e as a brown solid (0.72 g, 75%). Mp:
92–94 ꢀC. 1H NMR (300 MHz, CDCl3):
1.50 (br s, 1H, OH), 1.29
d
(s, 9H, C(CH3)3), 6.95 (d, 1H, JH–H 8.5, Ar–H), 7.35 (dd, 1H, JH–H
8.5, JH–H 2.3, Ar–H), 7.72 (d, 1H, JH–H 2.3, Ar–H), 7.80 (d, 1H, JH–H
7.6, Py–H), 7.96 (t, 1H, JH–H 7.6, Py–H), 8.09 (d, 1H, JH–H 7.9, Py–
(0.286 g, 72%). Mp: 149–151 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.17 (d,
12H, JH–H 7, CH(Me)2), 2.25 (s, 3H, Ar–Me), 2.88 (sept, 2H, CH(Me)2),
6.8–7.2 (m, 5H, Ar–H), 7.51 (s, 1H, Ar–H), 7.81–7.95 (m, 2H, Py–H),
8.05 (d, 1H, JH–H 7.6, Py–H), 8.22 (s, 1H, HC]N). 13C{1H} NMR
H), 10.02 (s, 1H, CHO). 13C{1H} NMR (75 MHz, CDCl3):
d 30.5
(C(CH3)3), 33.2 (C(CH3)3), 116.3 (C), 117.4, 118.6, 121.9, 122.6,
125.8, 137.7 (CH), 140.9, 148.5, 156.3, 158.1 (C), 190.2 (CH]O). IR
(cmꢁ1): 1717 (C]O), 1590 (C]NPy). ESIMS: m/z 256 [MþH]þ.
(75 MHz, CDCl3):
d 23.5, 28.1 (CH3), 28.0 (CH), 118.2 (CH), 118.5 (C),
119.2, 120.9 123.2, 124.8, 126.7, 128.1, 132.8, 137.2, 138.5 (CH), 148.3,
151.1, 157.5, 158.2 (C), 161.2 (C]N). IR (cmꢁ1): 2959, 1636 (C]N),
1565, 1425, 1263, 1181, 1077, 991, 772. ESIMS: m/z 373 [MþH]þ.
Anal. Calcd for C25H28N2O: C, 80.65; H, 7.53; N, 7.53. Found: C,
80.88; H, 7.61; N, 7.33.
HRMS (FAB): calcd for
256.1339.
C
16H18NO2 [MþH]þ 256.1338, found
4.2.5. 2-(20-Phenoxy)-6-acetylpyridine (2a)
A similar procedure to that described for 1a was followed,
using II (0.500 g, 2.50 mmol), a (0.455 g, 3.00 mmol, 1.2 equiv)
and [Pd(PPh3)4] (0.058 g, 0.050 mmol, 0.02 equiv) to obtain, fol-
lowing deprotection with BBr3, 2a as a brown solid (0.39 g, 73%).
4.3.3. 2-(50-Chloro-20-phenoxy)-6-(iminoformyl)pyridine (2,6-
diisopropylanil) (3d)
Using a similar procedure to that described for 3a, with 1d
(0.227 g, 0.97 mmol), 2,6-diisopropylaniline (0.241 g, 1.36 mmol,
1.4 equiv) and absolute ethanol (4 mL), gave 3d as a yellow solid
1H NMR (300 MHz, CDCl3):
d 2.66 (s, 3H, CMe]O), 6.84–6.98 (m,
1H, Ar–H), 6.96 (dd, 1H, JH–H 8.1, JH–H 1.2, Ar–H), 7.24–7.29 (m, 1H,
Ar–H), 7.73 (dd, 1H, JH–H 8.1, JH–H 1.1, Ar–H), 7.88–7.90 (m, 2H, Py–
H), 8.00 (dd, 1H, JH–H 6.4, JH–H 2.6, Py–H). 13C{1H} NMR (75 MHz,
(0.233 g, 61%). Mp: 145–147 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.12 (d,
JH–H 6.7, 12H, CH(Me)2), 1.49 (br s, 1H, OH), 2.89 (sept, 2H, CH(Me)2),
6.91 (d, 1H, JH–H 8.8, Ar–H), 7.10 (m, 3H, Ar–H), 7.21 (dd, 1H, JH–H 8.8,
JH–H 2.3, Ar–H), 7.74 (d, 1H, JH–H 2.3, Ar–H), 7.96 (m, 2H, Py–H), 8.12
(dd, 1H, JH–H 7.3, JH–H 1.5, Py–H), 8.26 (s, 1H, CH]N). 13C{1H} NMR
CDCl3):
d 25.1 (CMe]O), 117.2 (C), 117.5, 118.3, 118.8, 121.8, 125.5,
131.1, 137.7 (CH), 148.9, 156.2, 158.5 (C), 196.5 (CMe]O). IR
(cmꢁ1): 3330 (O–H), 1698 (C]O), 1586 (C]NPy). ESIMS: m/z 214
[MþH]þ. HRMS (FAB): calcd for C13H12NO2 [MþH]þ 214.0868,
found 214.0869.
(75 MHz, CDCl3):
d 23.5 (CH3), 28.1 (CH), 119.6 (C), 112.0, 120.2,
121.0, 123.2, 123.8, 124.9, 126.0, 131.6 (CH), 137.1 (C), 138.8 (CH),
148.2, 151.1, 156.8, 158.4 (C), 160.6 (CH]N). IR (cmꢁ1): 1643
(C]Nimine), 1588 (C]NPy). ESIMS: m/z 393 [MþH]þ. Anal. Calcd for
4.2.6. 2-(30-Phenyl-20-phenoxy)-6-acetylpyridine (2b)
C24H25N2OCl: C, 73.38; H, 6.37; N, 7.13. Found: C, 73.46; H, 6.66; N,
A similar procedure to that described for 1a was followed,
using II (0.500 g, 2.50 mmol), b (0.68 g, 3.00 mmol, 1.2 equiv) and
[Pd(PPh3)4] (0.058 g, 0.050 mmol, 0.02 equiv) to obtain, following
deprotection with BBr3, 2b as an orange/brown solid (0.44 g, 61%).
6.76.
4.3.4. 2-(50-tert-Butyl-20-phenoxy)-6-(iminoformyl)pyridine (2,6-
diisopropylanil) (3e)
1H NMR (300 MHz, CDCl3):
d 2.65 (s, 3H, CMe]O), 6.93 (m, 1H,
Using a similar procedure to that described for 3a, with 1e
(0.227 g, 0.889 mmol), 2,6-diisopropylaniline (0.220 g, 1.25 mmol,
1.4 equiv) and absolute ethanol (4 mL), gave 3e as a yellow solid
Ar–H), 7.25–7.40 (m, 5H, Ar–H), 7.58 (d, 2H, JH–H 7.3, Ar–H), 7.72–
7.75 (m, 2H, Py–H), 8.03–8.07 (m, 1H, Py–H). 13C{1H} NMR
(75 MHz, CDCl3):
d 25.3 (CMe]O), 117.6 (C), 118.1, 127.1, 128.5 (CH),
(0.267 g, 72%). Mp: 149–151 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.12 (d,
130.3 (C), 132.3 (CH), 137.2 (C), 137.8 (CH), 148.9, 155.8, 156.5 (C),
JH–H 6.7, 12H, CH(Me)2), 1.30 (s, 9H, C(CH3)3), 1.48 (br s, 1H, OH), 2.89
(sept, 2H, CH(Me)2, 6.92 (d, 1H, JH–H 8.8, Ar–H), 7.10 (m, 3H, Ar–H),
7.32 (dd, 1H, JH–H 8.8, JH–H 2.3, Ar–H), 7.75 (d, 1H, JH–H 2.3, Ar–H),
7.97 (m, 2H, Py–H), 8.08 (d, 1H, JH–H 7.3, Py–H), 8.26 (s, 1H, HC]N).
196.6 (CMe]O). IR (cmꢁ1): 1700 (C]O). ESIMS: m/z 290 [MþH]þ.
HRMS (FAB): calcd for
290.1182.
C
19H16NO2 [MþH]þ 290.1181, found
13C{1H} NMR (75 MHz, CDCl3):
d 22.4 (CH3), 27.0 (CH), 30.5
4.3. Synthesis of the 2-phenoxy-6-iminopyridines (3 and 4)
(C(CH3)3), 33.2 (C(CH3)3), 116.8 (C), 117.2, 118.1, 119.9, 121.1, 123.7,
128.8 (CH), 136.1, 137.4 (C), 140.6 (CH), 147.2, 150.0, 156.3, 157.5 (C),
160.6 (CH]N). IR (cmꢁ1): 1648 (C]Nimine), 1592 (C]NPy). ESIMS:
m/z 415 [MþH]þ. Anal. Calcd for C28H34N2O) C, 81.10; H, 8.28; N,
6.76. Found: C, 80.92; H, 8.27; N, 6.65.
4.3.1. 2-(20-Phenoxy)-6-(iminoformyl)pyridine (2,6-
diisopropylanil) (3a)
To a solution of 1a (0.397 g, 1.99 mmol) in absolute ethanol
(4 mL) was added 2,6-diisopropylaniline (0.457 g, 2.58 mmol,
1.3 equiv). The solution was stirred at 50 ꢀC for 5 min before the
addition of one drop of glacial acetic acid. After stirring at 50 ꢀC
overnight, the reaction mixture was cooled to room temperature
and the suspension filtered, washed with cold ethanol and dried to
give 3a as a yellow solid (0.398 g, 56%). Mp: 168–170 ꢀC. 1H NMR
4.3.5. 2-(20-Phenoxy)-6-(iminoacetyl)pyridine (2,6-diisopropylanil)
(4a)
To a solution of 2a (0.397 g, 1.99 mmol) in absolute ethanol
(4 mL) was added 2,6-diisopropylaniline (0.459 g, 2.59 mmol,
1.3 equiv). The solution was stirred at 80 ꢀC for 5 min before the
addition of one drop of glacial acetic acid. After stirring at 80 ꢀC for
(300 MHz, CDCl3): d
1.12 (d, 12H, 3JH–H 6.7, CH(Me)2), 2.89 (sept, 2H,

C.J. Davies et al. / Tetrahedron 64 (2008) 9857–9864
9863
2 days, the reaction mixture was cooled to room temperature and
the suspension filtered, washed with cold ethanol and dried to give
4a as a yellow solid (0.594 g, 80%). Mp: 190–192 ꢀC. 1H NMR
88 ꢀC. 1H NMR (300 MHz, CDCl3):
d
0.94 (d, 6H, JH–H 6.7, CH(Me)2),
1.13 (d, 6H, JH–H 7.0, CH(Me)2), 1.51 (br s, 1H, OH), 1.58 (d, 3H, JH–H
6.7, CH(CH3)NH), 3.02 (sept, 2H, CH(Me)2), 3.49 (br s, 1H, NH), 4.16
(q, 1H, JH–H 6.7, CH(CH3)NH), 6.91 (m, 6H, Ar–H), 7.26 (td, 1H, JH–H
7.6, JH–H 1.7, Ar–H), 7.61 (t, 1H, JH–H 8.2, Py–H), 7.72 (t, 2H, JH–H 7.6,
(300MHz, CDCl3):
d 1.08 (d, 12H, JH–H 6.9, CH(Me)2), 1.54 (br s, 1H,
OH), 2.18 (s, 3H, CMe]N), 2.65 (sept, 2H, CH(Me)2), 6.88 (dt, 1H,
3JH–H 8.8, JH–H 0.7, Ar–H), 6.97 (dd, 1H, JH–H 6.5, JH–H 0.8, Ar–H), 7.11–
7.15 (m, 3H, Ar–H), 7.28 (dt, 1H, 3JH–H 6.6, JH–H 1.0, Ar–H), 7.79 (dd,
1H, 3JH–H 6.9, JH–H 1.4, Ar–H), 7.85–8.00 (m, 2H, Py–H), 8.23 (dd, 1H,
Py–H). 13C{1H} NMR (75 MHz, CDCl3):
d 19.6, 21.8 (CH3), 23.0, 23.2
(CH), 26.7 (CH(CH3)NH), 59.7 (CH(CH3)NH), 116.6, 117.4, 117.9 (CH),
118.0 (C), 118.8, 122.5, 122.6, 125.3, 130.5, 137.0 (CH), 139.9, 141.3,
156.8, 158.9, 159.1 (C). ESIMS: m/z 375 [MþH]þ. Anal. Calcd for
JH–H 7.1, JH–H 1.2, Py–H). 13C{1H} NMR (75 MHz, CDCl3):
d 16.2
(CMe]N), 21.7, 22.0 (CH3), 27.2 (CH), 117.3 (CH), 117.6 (C), 118.0,
118.2, 119.2, 121.9, 122.8, 125.3, 130.6 (CH), 134.5 (C), 137.3 (CH),
144.8, 151.9, 155.6, 158.4 (C), 163.6 (CMe]N). IR (cmꢁ1): 3381 (O–
H), 1644 (C]Nimine), 1588 (C]NPy). ESIMS: m/z 373 [MþH]þ. Anal.
Calcd for C25H28N2O: C, 80.65; H, 7.53; N, 7.53. Found: C, 80.82; H,
7.61; N, 7.40.
C25H30N2O: C, 80.26; H, 8.09; N, 7.48. Found: C, 80.08; H, 7.87; N,
7.30.
4.4.2. 2-(50-Methyl-20-phenoxy)-6-{100-(2,6-diisopropyl-
anilino)ethyl}pyridine (5c)
The procedure outlined in method B was followed, using 3c
(0.300 g, 0.805 mmol), methyllithium (1.30 mL, 1.82 mmol,
2.3 equiv), to obtain 5c as a pale yellow solid (0.170 g, 55%). 1H NMR
4.3.6. 2-(50-Phenyl-20-phenoxy)-6-(iminoacetyl)pyridine (2,6-
diisopropylanil) (4b)
(300 MHz, CDCl3): d 0.95 (d, 6H, JH–H 6.7, CH(Me)2), 1.13 (d, 6H, JH–H
Using a similar procedure to that described for 4a, with 1b
(0.358 g, 1.24 mmol), 2,6-diisopropylaniline (0.33 g, 1.86 mmol,
1.5 equiv) and absolute ethanol (4 mL), gave 4b as a yellow solid
7.0, CH(Me)2), 1.50 (br s, 1H, OH), 1.56 (d, 3H, JH–H 6.7, CH(CH3)NH),
2.24 (s, 3H, Ar–Me), 2.98 (sept, 2H, CH(Me)2), 3.42 (br s, 1H, NH),
4.16 (q, 1H, 3JH–H 6.7, CH(CH3)NH), 6.94 (m, 5H, Ar–H), 7.31 (dd, 1H,
JH–H 8.8, JH–H 2.3, Ar–H), 7.62 (t, 1H, JH–H 8.2, Py–H), 7.71 (m, 2H, Py–
(0.339 g, 61%). Mp: 197–199 ꢀC. 1H NMR (300MHz, CDCl3):
d 1.06 (d,
12H, JH–H 6.9, CH(Me)2), 2.16 (s, 3H, CMe]N), 2.63 (sept, 2H,
CH(Me)2), 6.94 (t, 1H, JH–H 7.9, Ar–H), 6.97–7.11 (m, 3H, Ar–H), 7.23–
7.38 (m, 4H, Ar–H), 7.59 (d, 2H, JH–H 7.1, Ar–H), 7.79 (dd, 1H, JH–H 8.2,
JH–H 1.1, Ar–H), 7.90 (t, 1H, JH–H 7.9, Py–H), 8.00 (d, 1H, JH–H 7.6, Py–
H), 8.28 (dd, 1H, JH–H 7.3, JH–H 1.1, Py–H). 13C{1H} NMR (75 MHz,
H). 13C{1H} NMR (75 MHz, CDCl3):
d 20.7, 21.5 (CH3), 24.2, 25.1 (CH),
27.1 (CH(CH3)NH), 28.1 (CH3), 60.7 (CH(CH3)NH), 117.6, 118.0, 118.2,
119.6, 122.7, 123.5 (CH), 123.6 (C), 128.9, 138.0 (CH), 141.1, 141.4,
142.3, 157.6, 158.2, 160.2 (C). ESIMS: m/z 389 [MþH]þ. Anal. Calcd
for C26H32N2O: C, 80.41; H, 8.25; N, 7.22. Found: C, 80.69; H, 8.31;
N, 7.18.
CDCl3): d 17.6 (CMe]N), 22.9, 23.2 (CH3), 28.4 (CH),118.9 (CH),119.1
(C), 119.5, 120.9, 123.1, 123.9, 126.1, 127.1, 128.1, 129.6 (CH), 131.2 (C),
132.9 (CH), 135.7 (C), 138.5 (CH), 146.0, 153.1, 156.9, 157.1 (C), 164.9
(CMe]N). IR (cmꢁ1): 3387 (O–H), 1632 (C]Nimine), 1588 (C]NPy).
ESIMS: m/z 449 [MþH]þ. Anal. Calcd for C31H32N2O: C, 83.04; H,
7.14; N, 6.25. Found: C, 83.22; H, 7.23; N, 6.19.
4.4.3. 2-(50-Chloro-20-phenoxy)-6-{100-(2,6-diisopropyl-
anilino)ethyl}pyridine (5d)
The procedure outlined in method A was followed, using 3d
(0.232 g, 0.591 mmol), trimethylaluminium (0.59 mL, 1.18 mmol,
2 equiv), to obtain 5d as a pale pink solid (0.176 g, 73%). Mp: 157–
4.4. Synthesis of the 2-phenoxy-6-(methanamino)-
pyridines (5)
159 ꢀC. 1H NMR (300 MHz, CDCl3):
d 0.94 (d, 6H, JH–H 6.7, CH(Me)2),
1.13 (d, 6H, JH–H 7.0, CH(Me)2), 1.30 (br s, 1H, OH), 1.59 (d, 3H, JH–H
6.7, CH(CH3)NH), 3.01 (sept, 2H, CH(Me)2), 3.48 (br s, 1H, NH), 4.17
(q, 1H, JH–H 6.7, CH(CH3)NH), 6.93 (m, 5H, Ar–H), 7.19 (dd, 1H, JH–H
8.7, JH–H 2.6, Ar–H), 7.67 (m, 3H, Py–H). 13C{1H} NMR (75 MHz,
Method A. An oven-dried Schlenk flask equipped with a mag-
netic stir bar was evacuated and back filled with nitrogen. 2-Phe-
noxy-6-iminopyridine 3 (0.591 mmol) was introduced into the
flask and dissolved in dry toluene (15 mL). Trimethylaluminium
(0.59 mL, 1.18 mmol, 2 equiv) was added and the reaction mixture
stirred at 110 ꢀC overnight. On cooling to room temperature
all volatiles were removed under reduced pressure. Pentane
(20 mL) was added followed by water (20 mL) and the reaction
mixture stirred vigorously for 1 h. The product was extracted into
chloroform (50 mL) and the aqueous phase washed (3ꢂ50 ml) with
more chloroform. The organic extracts were combined and
dried over anhydrous magnesium sulfate and filtered. The residue
was dried under reduced pressure to give the 2-phenoxy-6-
(methanamino)pyridine.
CDCl3):
d 19.6, 23.0 (CH3), 23.2, 26.7 (CH), 27.0 (CH(CH3)NH), 59.5
(CH(CH3)NH), 116.7 (CH), 119.1 (C), 119.4, 122.5, 122.7 (CH), 130.2
(C), 130.6, 136.1, 137.8 (CH), 139.8 (C), 141.3 (CH), 155.5, 157.4, 157.5,
159.4 (C). ESIMS: m/z 409 [MþH]þ. Anal. Calcd for C25H29N2OCl: C,
73.41; H, 7.16; N, 6.85. Found: C, 73.37; H, 6.94; N, 6.76.
4.4.4. 2-(50-tert-Butyl-20-phenoxy)-6-{100-(2,6-diisopropyl-
anilino)ethyl}pyridine (5e)
The procedure outlined in method A was followed, using 3e
(0.245 g, 0.591 mmol), trimethylaluminium (0.59 mL, 1.18 mmol,
2 equiv), to obtain 5d as a pale pink solid (0.165 g, 65%). Mp: 158–
160 ꢀC. 1H NMR (300 MHz, CDCl3):
d 0.95 (d, 6H, JH–H 6.7, CH(Me)2),
Method B. An oven-dried Schlenk flask equipped with a mag-
netic stir bar was evacuated and back filled with nitrogen. The
2-phenoxy-6-iminopyridine (0.805 mmol) was dissolved in diethy-
lether (20 mL), cooled to ꢁ40 ꢀC and MeLi (as a 1.4 M solution in
diethylether or as a solid, 2–4 equiv) introduced. After stirring for
30 min, the reaction was quenched by the addition of water (1 mL)
and the solution dried over magnesium sulfate, filtered and the
filtrate dried under reduced pressure to give the 2-phenoxy-6-
(methanamino)pyridine.
1.13 (d, 6H, JH–H 7.0, CH(Me)2), 1.29 (s, 9H, C(CH3)3), 1.50 (br s, 1H,
OH), 1.57 (d, 3H, JH–H 6.7, CH(CH3)NH), 2.98 (sept, 2H, CH(Me)2),
3.42 (br s, 1H, NH), 4.15 (q, 1H, 3JH–H 6.7, CH(CH3)NH), 6.94 (m, 5H,
Ar–H), 7.31 (dd, 1H, JH–H 8.8, JH–H 2.3, Ar–H), 7.62 (t, 1H, JH–H 8.2, Py–
H), 7.73 (m, 2H, Py–H). 13C{1H} NMR (75 MHz, CDCl3):
d 20.7, 24.1
(CH3), 24.2, 27.8 (CH), 31.6 (C(CH3)3), 34.2 (CH(CH3)NH), 60.6
(CH(CH3)NH), 117.6, 118.0, 118.2, 119.6, 122.7, 123.5 (CH), 123.6 (C),
128.9, 138.0 (CH), 141.1, 141.4, 142.3, 157.6, 158.2, 160.2 (C). ESIMS:
m/z 431 [MþH]þ. Anal. Calcd for C29H38N2O: C, 80.93; H, 8.84; N,
6.51. Found: C, 81.12; H, 8.83; N, 6.66.
4.4.1. 2-(20-Phenoxy)-6-{100-(2,6-diisopropylanilino)ethyl}-
pyridine (5a)
4.5. Crystallography
The procedure outlined in method A was followed, using 3a
(0.212 g, 0.591 mmol), trimethylaluminium (0.59 mL, 1.18 mmol,
2 equiv), to obtain 5a as pale pink solid (0.171 g, 77%). Mp: 86–
Data for b, 3a, 3d, 4a, 5a and 5e were collected on a Bruker APEX
2000 CCD diffractometer. Details of data collection, refinement and

9864
C.J. Davies et al. / Tetrahedron 64 (2008) 9857–9864
Table 7
Crystallographic and data processing parameters for compounds b, 3a, 3d, 4a, 5a and 5e
Complex
b
3a
3d
4a
5a
5e
Formula
M
C
13H13BO3
C24H26N2O
358.47
C24H25ClN2O
392.91
C25H28N2O$1.5CHCl3
551.55
C25H30N2O
374.51
C29H38N2O
430.61
228.04
0.50ꢂ0.16ꢂ0.11
150(2)
Triclinic
P-1
Crystal size (mm3)
Temperature (K)
Crystal system
Space group
a (Å)
0.19ꢂ0.16ꢂ0.12
0.31ꢂ0.24ꢂ0.20
0.22ꢂ0.19ꢂ0.13
0.39ꢂ0.24ꢂ0.21
0.20ꢂ0.14ꢂ0.13
150(2)
150(2)
160(2)
150(2)
150(2)
Monoclinic
C2/c
24.894(3)
9.1993(13)
20.583(3)
90
121.653(2)
90
4012.5(10)
8
Triclinic
P-1
Monoclinic
C2/c
16.8176(15)
20.9588(19)
16.5257(15)
90
110.683(2)
90
5449.5(9)
8
Triclinic
P-1
Triclinic
P-1
7.7140
8.2630(6)
9.4948(6)
14.0487(10)
96.9700(10)
105.2980(10)
100.5800(10)
1028.05(12)
2
8.733(2)
10.747(2)
12.813(3)
77.957(4)
73.112(4)
72.509(4)
1087.7(4)
2
9.5600(11)
10.7099(12)
13.0727(14)
98.540(2)
98.250(2)
106.149(2)
1247.1(2)
2
b (Å)
c (Å)
8.2865
9.7850
67.467
85.428
88.708
575.87
2
1.315
240
0.091
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
U (Å3)
Z
Dc (Mg mꢁ3
F(000)
)
1.187
1536
0.073
1.269
416
0.203
1.345
2296
0.506
1.144
404
0.069
1.147
468
0.069
m
(Mo K
a
)(mmꢁ1
)
Reflections collected
Independent reflections
Rint
4825
2458
0.0288
0/157
14,195
3535
0.0359
0/249
8107
3981
0.0166
0/258
22,616
5928
0.0469
0/318
8582
4241
0.0341
0/259
9173
4389
0.0297
0/298
Restraints/parameters
Final R indices (I>2
s
(I))
R1¼0.0421
wR2¼0.1171
R1¼0.0479
wR2¼0.1205
1.061
R1¼0.0402
wR2¼0.0811
R1¼0.0593
wR2¼0.0955
0.930
R1¼0.0366
wR2¼0.0994
R1¼0.0415
wR2¼0.1021
1.081
R1¼0.0812
wR2¼0.2412
R1¼0.1360
wR2¼0.2614
0.947
R1¼0.0443
wR2¼0.1163
R1¼0.0546
wR2¼0.1221
1.051
R1¼0.0400
wR2¼0.0950
R1¼0.0517
wR2¼0.1014
0.952
All data
Goodness of fit on F2 (all data)
Data in common: graphite-monochromated Mo K
where a is a constant adjusted by the program; goodness of fit¼[
a
radiation,
l
¼0.71073 Å; R1¼
S
jjFojꢁjFcjj/
S
jFoj, wR2¼[
S
w(Fo2ꢁF2c)2/
S
w(Fo2)2]1/2, wꢁ1¼[
s
2(Fo)2þ(aP)2], P¼[max(Fo2,0)þ2(F2c)]/3,
S
(Fo2ꢁF2c)2/(nꢁp)]1/2 where n is the number of reflections and p the number of parameters.
125, 4306; (b) Murphy, V. In High-Throughput Screening in Heterogeneous Ca-
talysis; Hagemeyer, A., Strasser, P., Volpe, A. F., Jr., Eds.; Wiley-VCH GmbH KGaA:
Weinheim, Germany, 2004; pp 299–312; (c) Jones, D. J.; Gibson, V. C.; Green, S.
M.; Maddox, P. J.; White, A. J. P.; Williams, D. J. J. Am. Chem. Soc. 2005, 127, 11037;
(d) Schofer, S. J.; Hahn, H.; Murphy, V.; Hajduk, D. A.; Diamond, G. M.; Ying, D.;
Doolen, R. D.; Smith, M. Polym. Prepr. 2007, 48, 172.
2. (a) Britovsek, G. J. P.; Gibson, V. C.; Kimberley, B. S.; Maddox, P. J.; McTavish, S. J.;
Solan, G. A.; White, A. J. P.; Williams, D. J. Chem. Commun. 1998, 849; (b) Bri-
tovsek, G. J. P.; Bruce, M.; Gibson, V. C.; Kimberley, B. S.; Maddox, P. J.; Mas-
troianni, S.; McTavish, S. J.; Redshaw, C.; Solan, G. A.; Stro¨mberg, S.; White, A. J.
P.; Williams, D. J. J. Am. Chem. Soc. 1999, 121, 8728.
3. (a) Small, B. L.; Brookhart, M. J. Am. Chem. Soc. 1998, 120, 7143; (b) Small, B. L.;
Brookhart, M.; Bennett, A. M. A. J. Am. Chem. Soc. 1998, 120, 4049.
4. For reviews, see: (a) Gibson, V. C.; Redshaw, C.; Solan, G. A. Chem. Rev. 2007, 107,
1747; (b) Bianchini, C.; Giambastiana, G.; Rios, I. G.; Mantovani, G.; Meli, A.;
Segarra, A. M. Coord. Chem. Rev. 2006, 250, 1391.
crystal data are listed in Table 7. The data were corrected for Lorentz
and polarisation effects and empirical absorption corrections ap-
plied. Structure solution by Patterson methods and structure
refinementon F2 employed SHELXTL version 6.10.15 Hydrogen atoms
were included in calculated positions (C–H¼0.96 Å) riding on the
bonded atom with isotropic displacement parameters set to
1.5 Ueq(C) for methyl H atoms and 1.2 Ueq(C) for all other H atoms. All
non-H atoms were refined with anisotropic displacement
parameters.
CCDC reference numbers 689030–689035 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the Cambridge Crystallographic Data Centre,12 Union Road,
Cambridge CB2 1EZ; fax: (Internet) þ44 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk].
´
5. (a) Guerin, F.; McConville, D. H.; Vittal, J. J. Organometallics 1996, 15, 5586;
(b) Gue´ rin, F.; McConville, D. H.; Payne, N. C. Organometallics 1996, 15,
5085.
6. (a) Chan, M. C. W.; Tam, K.-H.; Zhu, N.; Chiu, P.; Matsui, S. Organometallics 2006,
25, 785; (b) Chan, M. C. W.; Tam, K. H.; Pui, Y. L.; Zhu, N. J. Chem. Soc., Dalton
Trans. 2002, 3085.
7. Boussie, T. R.; Diamond, G. M.; Goh, C.; Hall, K. A.; LaPointe, A. M.; Leclerc, M.
K.; Murphy, V.; Shoemaker, J. A. W.; Turner, H.; Rosen, R. K.; Stevens, J. C.;
Alfano, F.; Busico, V.; Cipullo, R.; Talarico, G. Angew. Chem., Int. Ed. 2006, 45,
3278.
8. For importance of the N-2,6-diisopropylphenyl group, see: (a) Gibson, V. C.;
Spitzmesser, S. K. Chem. Rev. 2003, 103, 283; (b) Britovsek, G. J. P.; Gibson, V. C.;
Wass, D. F. Angew. Chem., Int. Ed 1999, 38, 428; (c) Ittel, S. D.; Johnson, L. K.;
Brookhart, M. Chem. Rev. 2000, 100, 1169; (d) Mecking, S. Angew. Chem., Int. Ed
2001, 40, 534.
Acknowledgements
We thank the University of Leicester, the EPSRC (to C.J.D.) and
ExxonMobil Chemical (to C.J.D. and T.P.) for financial assistance.
Johnson Matthey PLC are thanked for their loan of palladium
chloride.
Supplementary data
9. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
10. Yuang, H.; Hay, A. S. J. Polym. Sci., Part A: Polym. Chem. 1993, 31, 1261.
11. Bryant, J. A.; Helgeson, R. C.; Knobler, C. B.; DeGrandpre, M. P.; Cram, D. J. J. Org.
Chem. 1990, 55, 4622.
12. See, for example: (a) Dietrich-Buhecker, C. O.; Sauvage, J.-P.; Kintzinger, J. P.;
Maltese, P.; Pascard, C.; Guilheim, J. New J. Chem. 1992, 16, 931; (b) Constable, E.
C.; Kariuki, B.; Mahmood, A. Polyhedron 2003, 33, 687.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.08.019.
References and notes
13. Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 4th ed.;
Butterworth Heinemann: Oxford, 1996.
14. Tellier, F.; Sauvetre, R.; Normant, J.-F. J. Organomet. Chem. 1985, 292, 2.
15. Sheldrick, G. M. SHELXTL Version 6.10; Bruker AXS: Madison, WI, USA, 2000.
1. See for example: (a) Broussie, T. R.; Diamond, G. M.; Goh, C.; Hall, K. A.; La-
Pointe, A. M.; Leclerc, M. K.; Lund, C.; Murphy, V.; Shoemaker, J. A. W.; Tracht,
U.; Turner, H.; Zhang, J.; Uno, T.; Rosen, R. K.; Stevens, J. C. J. Am. Chem. Soc. 2003,