Cycloauration of substituted 2-phenoxypyridine derivatives and X-ray crystal structure of gold, dichloro[2-[[5-[(cyclopentylamino) carbonyl]-2-pyridinyl-κN]oxy]phenyl-κC]-, (SP-4-3)-

Article abstract of DOI:10.1016/S0022-328X(03)00347-4

Direct cycloauration of 2-phenoxypyridines with different substituents at the 5-position of the pyridine ring was carried out in an CH₃CN/H₂O medium, leading to isolation of cycloaurated compounds AuCl₂(L) (HL = substitute

Full text of DOI:10.1016/S0022-328X(03)00347-4

Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
www.elsevier.com/locate/jorganchem
Cycloauration of substituted 2-phenoxypyridine derivatives
and X-ray crystal structure of gold, dichloro-
[2-[[5-[(cyclopentylamino)carbonyl]-2-pyridinyl-kN]oxy]phenyl-kC]-,
(SP-4-3)-
Yongbao Zhu *, Beth R. Cameron, Renato T. Skerlj
Department of Chemistry, AnorMED, Inc., 200-20353 64th Avenue, Langley, BC, Canada V2Y 1N5
Received 10 March 2003; received in revised form 25 April 2003; accepted 25 April 2003
Abstract
Direct cycloauration of 2-phenoxypyridines with different substituents at the 5-position of the pyridine ring was carried out in an
CH3CN/H2O medium, leading to isolation of cycloaurated compounds AuCl2(L) (HLꢀsubstituted 2-phenoxypyridine ligand) with
/
alkyl, substituted alkyl, phenyl, halo, ester and amido groups. The preparation of cycloaurated compounds involves the formation
of an intermediate AuCl3(HL) via coordination reaction between the pyridine ligand and NaAuCl4 at room temperature and
subsequent formation of the AuꢁC bond at elevated temperature in an CH3CN/H2O medium. The presence of a bulky lipophilic
/
group decreases the yield of cycloaurated compounds and favors the decomposition of the reaction species to Au(0). No
coordination reaction was observed for ligands with a strong electron-withdrawing substituent (nitro or nitrile) in the pyridine ring.
The ligand having the electron-donating dimethylamino group is oxidized by NaAuCl4 at room temperature. The presence of a
thienyl or an acetyl group allowed the isolation of the intermediate AuCl3(HL), but has an adverse effect on the subsequent
cycloauration. The result of direct cycloauration of methyl-substituted 2-phenoxypyridine ligands indicated that the presence of a
methyl group at the 6-position in the pyridine ring closest to the AuꢁN(py) bond resulted in poor cycloauration and a decrease in
/
compound stability. The X-ray crystal structure of the cycloaurated compound 25 was determined, depicting a four-coordinate Au
atom located in the center of a slightly distorted square.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Cycloauration; Coordination; Phenoxypyridine; Crystal structures
1. Introduction
biological milieu, complexes with a bidentate ligand,
damp, (2-[(dimethylamino)methyl]phenyl), were pre-
viously prepared [3,4]. The damp ligand forms part of
a five-membered chelating ring in which the nitrogen of
the amino group and the carbon of the aryl ring bond to
Gold(III) is isoelectronic (d8) with platinum(II) and
likewise forms square-planar complexes. It is therefore
tempting to speculate that such complexes would have
similar anti-tumor activity to cisplatin. Although there
has been significant interest in the development of gold
complexes for therapeutic purposes [1,2], gold(III)
complexes have not been as thoroughly investigated as
gold(I) complexes, primarily because of their reactivity.
To stabilize the gold(III) oxidation state in a reducing
the metal. The presence of the covalent Au(III)ꢁC
/
(aryl) bond prevents reduction of the Au(III) center by a
thiol group, unlike normal coordinate Au(III) com-
plexes. Recent studies have shown that such compounds
possess anti-tumor properties [3,5,6]. It has also been
shown that the gold complexes do not react in a
mechanism similar to cisplatin and the true biological
mechanism of action of these complexes is not yet
established [6]. Possible molecular targets are biologi-
cally important thiol-containing molecules. As part of
our medicinal chemistry program on the development of
* Corresponding author. Tel.: ꢂ
0976.
E-mail address: yzhu@anormed.com (Y. Zhu).
/
1-604-530-1057; fax: ꢂ1-604-530-
/
0022-328X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00347-4

58
Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
cysteine protease inhibitors, we have now synthesized
and characterized six-membered cycloaurated Au(III)
complexes of substituted 2-phenoxypyridines. This is the
subject of this paper.
Cycloaurated complexes have been prepared by
transmetallation from the corresponding organomercur-
PhMgCl (3.0 M in diethyl ether), CH3CH2MgBr (3.0
M in diethyl ether) and CH3MgBr (3.0 M in diethyl
ether) were all purchased from commercial sources. 1H-,
13C- and 19F-NMR experiments were performed on a
Bruker Avance 300 spectrometer. NMR spectra were
referenced to residual solvent (1H and 13C with
y(II) compounds [4,7ꢃ
direct cycloauration of the corresponding ligand with or
without the presence of a silver(I) salt [13ꢃ21]. The
/10], lithium reagents [11,12] or by
d(TMS)ꢀ
/
0 ppm) or external CF3COOH (19F, dꢀ
0
/
ppm). Mass spectra were obtained on a Bruker Esquire-
LC 00052 mass spectrometer with an electrospray
interface. Elemental analyses were performed at Atlantic
Microlab, Inc., Norcross, GA.
/
transmetallation method usually involves isolation of a
stable organomercury compound prepared from the
corresponding organolithium or organomagnesium in-
termediate, which is usually obtained via metalꢃhalogen
/
2.2. Crystallographic study
exchange. Many functional groups are not tolerated by
this method due to the use of lithium or magnesium
Data collection and structure determination were
carried out by Dr. Brian Patrick (Department of
Chemistry, the University of British Columbia, Van-
couver, BC, Canada). The experimental details of the X-
ray structure determination and the crystallographic
parameters are listed in Table 1. Single crystals of
compound 25 were obtained by slow evaporation of
an acetone solution. A yellow chip crystal having
reagents. Direct cycloauration involves Cꢁ
activation of a heterosubstituted ligand by an Au center
to form a chelate ring containing a covalent Auꢁ
/
H bond
/C
bond, and occurs in many 2-substituted pyridines
including 2-benzylpyridine [21], 2-anilinopyridine
[13,17], 2-phenoxypyridine [17], 2-phenylsulfanylpyri-
dine [17], 2-benzoylpyridine [16], 2-phenylpyridine [18],
1-ethyl-2-phenylimidazole [19], 2-phenylthiazole [14]
and 2-thienylpyridine [15,20]; however, there are only
two reports of cycloaurated compounds bearing a
substituent on the heterocyclic ring prepared by direct
cycloauration [21,22]. In many cases, the cycloaurated
product is formed by heating at reflux for a set time
period a suspension of the intermediate AuCl3(hetero-
substituted ligand) in CH3CN/H2O, which itself is
isolated via coordination reaction between the ligand
and [AuCl4]ꢁ. During our medicinal chemistry pro-
gram, we investigated the feasibility of this method for
the direct cycloauration of 2-phenoxypyridines contain-
ing various functional groups at the 5-position of the
pyridine ring. Our goal was to determine the application
of this methodology to prepare a large library of such
compounds for biological screening.
approximate dimensions of 0.25 mmꢄ
/
0.10 mmꢄ0.05
/
mm was mounted on a glass fiber. The structure was
solved by direct methods (SIR97) [23], expanded using
Fourier techniques (DIRDIF94) [24] and refined by full-
matrix least-squares procedure based on F2. The non-
hydrogen atoms were refined anisotropically. Some
Table 1
Crystallographic parameters and experimental details of the X-ray
structure determination for compound 25
Formula
Formula weight
Color, habit
C17H17N2O2Cl2Au
549.21
yellow, chip
Dimension (mm)
Lattice type
0.25ꢄ
primitive
/
0.10ꢄ0.05
/
Unit cell dimensions
˚
a (A)
˚
8.1660 (4)
13.3855(7)
15.2671(8)
1668.8 (1)
b (A)
˚
c (A)
3
V (A )
˚
2. Experimental
Space group
Z
P212121 (no. 19)
4
2.1. General information
m(Moꢃ
/
Ka) (cmꢁ1
)
91.79
Rigaku
0.71069
Diffractometer
˚
Ka) (A)
All reactions were carried out under ambient condi-
tions unless otherwise noted. Diethyl ether and THF
were dried by refluxing over sodium in the presence of
l(Moꢃ
temperature (8C)
f(xꢀ 90.0) (8)
v(xꢀ 90.0) (8)
2umax. (8)
/
ꢁ
/
1009
0.0ꢃ190.0
17.0ꢃ23.0
/
1
/
ꢁ/
/
/
ꢁ
/
ꢁ/
/
benzophenone. NaAuCl4×
Au), AgSO3CF3, Pd2(dba)3 (dbaꢀ
tone), Pd(OAc)2, Pd/C (10% Pd in weight), Ni(dppp)Cl2
(dpppꢀ1,3-bis(diphenylphosphino)propane), 1,1?-
/
2H2O (containing 49.2ꢃ/49.6%
55.7
15395
3735
221
/(dibenzylidene)ace-
Measured reflection
Unique
No. of variables
R, Rw
Goodness of fit
/
0.041, 0.054
0.88
bis(diphenylphosphino) ferrocene (DPPF), 2-bromopyr-
idine, 2-bromo-4-methylpyridine, 2-bromo-5-methylpyr-
idine, 2-bromo-6-methylpyridine, methyl acrylate, 2,5-
dichloropyridine, 2,5-dibromopyridine, methylamine
(2.0 M in THF), dimethylamine (2.0 M in THF),
No. of observations [I ꢀ
/
3s(I)]
Max. peak in final diff. map (eꢁ
Min. peak in final diff. map (eꢁ
3236
2.31
ꢁ1
˚
A
)
ꢁ1
˚
A
)
ꢁ/1.55

Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ
/72
59
hydrogen atoms were refined isotropically, and the rest
were included in fixed positions.
MgSO4. After filtration, the solvent was removed by
evaporation under vacuum, and the residue was purified
by flash chromatography on silica gel.
3. Ligand preparation
3.4. General procedure D
3.1. General procedure A
Under N2, a suspension of HL20 (2ꢃ/5 mmol) in
SOCl2 (3ꢃ5 ml) was heated for 1ꢃ2 h to give a clear
carbonyl chloride solution. After the excess SOCl2 was
removed by evaporation under vacuum the residual
/
/
A mixture of the corresponding 2-bromopyridine
(20ꢃ
/
226 mmol), phenol (1.0ꢃ
/
1.3 eq.) and K2CO3 (1.1ꢃ
/
2.0 eq.) was stirred and heated at 200 8C for 5 h. After
the reaction mixture was cooled to room temperature,
solid was dissolved in dry CH2Cl2 (10ꢃ20 ml). The
/
CH2Cl2 solution was then added at room temperature to
CH3OH (10 ml) for HL21 or a solution of excess amine
H2O (20ꢃ
extracted with diethyl ether (3ꢄ
CH2Cl2 (3ꢄ50ꢃ150 ml). The organic layers were
/50 ml) was added and the mixture was
/
50ꢃ150 ml) or
/
(5ꢃ
/
10 eq.) in dry THF or dry CH2Cl2 (5ꢃ10 ml) for the
/
/
/
preparation of an amide. After the mixture was stirred
at room temperature for 2 h, H2O (30 ml) was added,
the organic layer was collected and the aqueous layer
combined and dried over anhydrous MgSO4. The
solvent was removed by evaporation under vacuum
and the residue was purified either by distillation, flash
chromatography on silica gel or recrystallization.
was extracted with CH2Cl2 (3ꢄ30 ml). The organic
/
extracts were combined and dried over anhydrous
MgSO4. After filtration, the solvent was removed by
evaporation under vacuum and the residue was purified
either by washing with hexanes or diethyl ether, or by
flash chromatography on silica gel.
3.2. General procedure B
A mixture of the corresponding 2-bromopyridine,
phenol (1.0ꢃ
DMSO (10ꢃ20 ml) was stirred and heated at 120ꢃ
140 8C for a period of 5ꢃ16 h. After the reaction
mixture was cooled to room temperature, H2O (40ꢃ50
ml) was added and the mixture was extracted with
diethyl ether (3ꢄ50 ml) or CH2Cl2 (2ꢄ20 ml). The
/
1.3 eq.) and K2CO3 (1.1ꢃ
/
2.0 eq.) in
/
/
3.5. General procedure E
/
/
To a solution of 6-phenoxypyridin-3-ylamine (2ꢃ
/
5
mmol) and NEt3 (1ꢃ2 eq.) in dry THF was added
/
/
/
dropwise the corresponding acyl chloride or acid
anhydride (1.05 eq.). After the mixture was stirred for
2 h, H2O (30 ml) was added and the mixture was
organic layers were combined and dried over anhydrous
MgSO4. The solvent was removed by evaporation under
vacuum and the residue was purified by flash chroma-
tography on silica gel.
extracted with ethyl acetate (3ꢄ30 ml). The extract was
/
collected and washed with H2O (30 ml), and dried over
anhydrous MgSO4. After filtration, the solvent was
removed by evaporation under vacuum and the residue
was purified either by washing with hexanes or diethyl
ether, or by flash chromatography on silica gel.
3.3. General procedure C
A solution of the alkyl or aryl bromide (5ꢃ
dry diethyl ether (10ꢃ20 ml) was added dropwise via an
addition funnel to a flask charged with Mg turnings
(1.1ꢃ1.3 eq.) (pre-washed with diethyl ether and dried in
/8 mmol) in
/
/
3.6. 6-Phenoxypyridin-3-ylamine
vacuo) and a grain of I2 suspended in dry diethyl ether
(30 ml) under N2. During addition of the first few drops,
the mixture was heated using a heat gun to initiate the
reaction. Once the addition was complete, the mixture
was stirred at room temperature for 3 h. The Grignard
solution was then added slowly to a mixture of the
To a flask charged with tin shot (11.9 g, 100 mmol)
and HL17 (9.85 g, 45.6 mmol) was added dropwise
concentrated HCl (25 ml, ꢁ300 mmol). The mixture
/
was then stirred and heated at 50 8C for 2 h to afford a
clear solution. After the mixture was cooled to room
temperature, it was neutralized with aqueous NaOH
corresponding halo pyridine (4ꢃ
/
7 mmol, 0.80ꢃ0.90 eq.)
/
and Ni(dppp)Cl2 (5ꢃ10 mol%) in dry diethyl ether (50
/
solution (10 wt.%) and extracted with CH2Cl2 (3ꢄ100
/
ml) via a cannula. After the addition was complete, the
mixture was stirred at room temperature for 15 min, and
was then heated at reflux overnight. The mixture was
then cooled to room temperature, and H2O (30 ml) was
added. The organic layer was separated, and the
ml), and the extract was dried over anhydrous MgSO4.
After filtration, the solvent was removed by evaporation
under vacuum, and the residual oil was purified by flash
chromatography on silica gel (ethyl acetateꢃ
(1:3, v/v)), providing a yellow solid (5.86 g, 69%). H-
NMR (CDCl3) d 3.56 (s, broad, 2H), 6.73 (d, 1H, Jꢀ
8.4 Hz), 7.01ꢃ7.15 (m, 4H), 7.30ꢃ7.36 (m, 2H), 7.69 (d,
1H, Jꢀ3.0 Hz) ppm. ES-MS m/z 187 [Mꢂ
H]ꢂ.
/
hexanes
1
aqueous layer was extracted with diethyl ether (3ꢄ
ml) or CH2Cl2 (3ꢄ30 ml). The organic extracts were
combined, washed with H2O and dried over anhydrous
/
50
/
/
/
/
/
/

60
Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
3.7. 4-Methyl-2-phenoxypyridine (HL1)
affording a colorless oil (0.628 g, 74%). 1H-NMR
(CDCl3) d 0.94 (t, 3H, Jꢀ7.5 Hz), 1.62 (sextet, 2H,
Jꢀ7.5 Hz), 2.54 (q, 2H, Jꢀ7.5 Hz), 6.83 (d, 1H, Jꢀ8.1
Hz), 7.11ꢃ7.20 (m, 3H), 7.36ꢃ7.42 (m, 2H), 7.50 (dd,
1H, Jꢀ2.4, 8.1 Hz), 8.01 (d, 1H, Jꢀ2.4 Hz) ppm.
/
Following general procedure A using 2-bromo-4-
methylpyridine (10.0 g, 58.2 mmol), phenol (6.56 g,
69.8 mmol) and K2CO3 (9.63 g, 69.8 mmol). The
product was extracted with diethyl ether, and a colorless
oil (8.40 g, 78%) was obtained after purification by flash
/
/
/
/
/
/
/
3.12. 5-Butyl-2-phenoxypyridine (HL6)
chromatography on silica gel (diethyl etherꢃ
/
hexanes
(1:4, v/v)). H-NMR (CDCl3) d 2.34 (s, 3H), 6.71 (s,
1H), 6.82 (d, 1H, Jꢀ5.4 Hz), 7.11ꢃ7.14 (m, 2H), 7.16ꢃ
7.22 (m, 1H), 7.36ꢃ7.43 (m, 2H), 8.07 (d, 1H, Jꢀ5.4
Hz) ppm.
1
Following general procedure C using the Grignard
reagent prepared from Mg (0.180 g, 7.20 mmol) and 1-
bromobutane (0.900 g, 6.60 mmol), and HL15 (1.50 g,
6.00 mmol). The product was purified by flash chroma-
/
/
/
/
/
tography on silica gel (diethyl etherꢃ
affording a colorless oil (0.343 g, 25%). 1H-NMR
(CDCl3) d 0.93 (t, 3H, Jꢀ7.5 Hz), 1.36 (sextet, 2H,
Jꢀ7.5 Hz), 1.52ꢃ1.62 (m, 2H), 2.56 (t, 2H, Jꢀ7.5 Hz),
6.82 (d, 1H, Jꢀ8.1 Hz), 7.10ꢃ7.20 (m, 3H), 7.39 (t, 2H,
Jꢀ8.1 Hz), 7.50 (dd, 1H, Jꢀ2.4, 8.1 Hz), 8.01 (d, 1H,
Jꢀ2.4 Hz) ppm.
/
hexanes (1:6, v/v)),
3.8. 5-Methyl-2-phenoxypyridine (HL2)
/
Following general procedure A using 2-bromo-5-
methylpyridine (37.1 g, 0.216 mol), phenol (21.3 g,
0.226 mol) and K2CO3 (32.8 g, 0.237 mol). The product
was extracted with diethyl ether, and a colorless oil (37.0
g, 85%) was obtained after purification by flash
/
/
/
/
/
/
/
/
chromatography on silica gel (diethyl etherꢃ
/
hexanes
(1:4, v/v)). H-NMR (CDCl3) d 2.28 (s, 3H), 6.81 (d,
1H, Jꢀ8.4 Hz), 7.10ꢃ7.20 (m, 3H), 7.34ꢃ7.41 (m, 2H),
7.48ꢃ7.51 (m, 1H), 8.02ꢃ8.03 (m, 1H) ppm.
3.13. 5-Pentyl-2-phenoxypyridine (HL7)
1
/
/
/
Following general procedure C using the Grignard
reagent prepared from Mg (0.134 g, 5.50 mmol) and 1-
bromopentane (0.755 g, 5.00 mmol), and HL15 (1.00 g,
4.00 mmol). The product was purified by flash chroma-
/
/
3.9. 6-Methyl-2-phenoxypyridine (HL3)
tography on silica gel (diethyl etherꢃ
/
hexanes (1:5, v/v)),
affording a colorless oil (0.586 g, 61%). 1H-NMR
Following general procedure A using 2-bromo-6-
methylpyridine (3.70 g, 21.5 mmol), phenol (2.02 g,
21.5 mmol) and K2CO3 (3.26 g, 23.6 mmol). The
product was extracted with diethyl ether, and a colorless
oil (2.23 g, 56%) was obtained after purification by
(CDCl3) d 0.89 (t, 3H, Jꢀ
1.53ꢃ1.64 (m, 2H), 2.55 (t, 2H, Jꢀ
Jꢀ8.4 Hz), 7.10ꢃ7.20 (m, 3H), 7.35ꢃ
(dd, 1H, Jꢀ
/
7.2 Hz), 1.25ꢃ
/
1.37 (m, 4H),
/
/
7.5 Hz), 6.83 (d, 1H,
/
/
/
7.42 (m, 2H), 7.50
/
2.4, 8.4 Hz), 8.01 (d, 1H, Jꢀ2.4 Hz) ppm.
/
1
vacuum distillation. H-NMR (CDCl3) d 2.47 (s, 3H),
6.57 (d, 1H, Jꢀ
7.23 (m, 3H), 7.38 (t, 2H, Jꢀ
7.5 Hz) ppm.
/
8.4 Hz), 6.87 (d, 1H, Jꢀ
/
7.5 Hz), 7.11ꢃ
/
3.14. 3-(6-Phenoxypyridin-3-yl)propionic acid methyl
ester (HL8) and 3-(6-phenoxypyridin-3-yl)acrylic acid
methyl ester
/
7.8 Hz), 7.54 (t, 1H, Jꢀ
/
3.10. 5-Ethyl-2-phenoxypyridine (HL4)
Under N2 to a solution of HL15 (3.00 g, 12.0 mmol)
and PPh3 (0.126 g, 0.480 mmol) in DMF (30 ml) was
added Pd(OAc)2 (0.0540 g, 0.240 mmol) K2CO3 (3.32 g,
24.0 mmol) and methyl acrylate (1.24 g, 14.4 mmol). The
mixture was heated at 105 8C for 16 h. After the reaction
mixture was cooled to room temperature, H2O (50 ml)
was added. The mixture was extracted with diethyl ether
Following general procedure C using the Grignard
reagent CH3CH2MgBr (3.0 M in diethyl ether) (1.47 ml,
4.41 mmol) and HL15 (1.00 g, 4.00 mmol). The product
was purified by flash chromatography on silica gel
(diethyl etherꢃ
oil (0.565 g, 71%). 1H-NMR (CDCl3) d 1.23 (t, 3H, Jꢀ
7.5 Hz), 2.61 (q, 2H, Jꢀ7.5 Hz), 6.83 (d, 1H, Jꢀ 8.4
Hz), 7.09ꢃ7.21 (m, 3H), 7.35ꢃ7.42 (m, 2H), 7.52 (dd,
1H, Jꢀ2.4, 8.4 Hz), 8.02 (d, 1H, Jꢀ2.4 Hz) ppm.
/hexanes (1:5, v/v)), affording a colorless
/
(5ꢄ30 ml), and the extract was dried over anhydrous
/
/
/
MgSO4. After filtration, the solvent was removed by
evaporation under vacuum, and the residual oil was
purified by flash chromatography on silica gel (diethyl
/
/
/
/
etherꢃhexanes (1:1, v/v)), affording a white solid (2.54 g,
/
1
3.11. 2-Phenoxy-5-propylpyridine (HL5)
83%). H-NMR (CDCl3) d 3.81 (s, 3H), 6.38 (d, 1H,
Jꢀ15.9 Hz), 6.94 (d, 1H, Jꢀ8.7 Hz), 7.15 (d, 2H, Jꢀ
8.1 Hz), 7.24 (t, 1H, Jꢀ8.1 Hz), 7.43 (t, 2H, Jꢀ8.1 Hz),
7.64 (d, 1H, Jꢀ15.9 Hz), 7.87 (dd, 1H, Jꢀ2.4, 8.7 Hz),
8.29 (d, 1H, Jꢀ2.4 Hz) ppm.
/
/
/
Following general procedure C using the Grignard
reagent prepared from Mg (0.134 g, 5.50 mmol) and 1-
bromopropane (0.615 g, 5.00 mmol), and HL15 (1.00 g,
4.00 mmol). The product was purified by flash chroma-
/
/
/
/
/
Under N2, to a solution of 3-(6-phenoxypyridin-3-yl)-
acrylic acid methyl ester (2.54 g, 9.95 mmol) in CH3OH
tography on silica gel (diethyl etherꢃhexanes (1:5, v/v)),
/

Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ
/72
61
(30 ml) was added Pd/C powder (10 wt.% Pd) (0.20 g,
0.19 mmol). A balloon of H2 was applied to the reaction
mixture, and the mixture was stirred at room tempera-
ture for 5 h. Water (50 ml) was then added to deactivate
the catalyst, and CH3OH was removed by evaporation
under vacuum. The residual aqueous mixture was
3.16. 4-(6-Phenoxypyridin-3-yl)butyronitrile (HL10)
and 5-(3-chloropropyl)-2-phenoxypyridine
Under N2, POCl3 (1.27 g, 8.29 mmol) was added to a
solution of 3-(6-phenoxypyridin-3-yl)propan-1-ol (1.90
g, 8.29 mmol) in dry CH2Cl2 (20 ml). After the mixture
was stirred at room temperature for 2 h, NaOH (1 N)
extracted with CH2Cl2 (4ꢄ30 ml), and the extract was
/
dried over anhydrous MgSO4. After filtration, the
solvent was removed by evaporation under vacuum,
and the residual oil was purified by flash chromatogra-
was added until the pH of the mixture reached ꢁ
The organic layer was collected, washed with H2O (2ꢄ
30 ml) and dried over anhydrous MgSO4. After filtra-
tion, the solvent was removed by evaporation under
vacuum, and the residual oil was purified by flash
/
10.
/
phy on silica gel (diethyl etherꢃ
/
hexanes (1:1, v/v)),
affording a colorless oil (1.31 g, 51%). 1H-NMR
(CDCl3) d 2.61 (t, 2H, Jꢀ
Hz), 3.68 (s, 3H), 6.83 (d, 1H, Jꢀ
Jꢀ7.8), 7.18 (t, 1H, Jꢀ7.8 Hz), 7.39 (t, 2H, Jꢀ
Hz), 7.54 (dd, 1H, Jꢀ2.4, 8.4 Hz), 8.04 (d, 1H, Jꢀ
Hz) ppm.
/
7.5 Hz), 2.91 (t, 2H, Jꢀ
/
7.5
chromatography on silica gel (diethyl etherꢃ
(1:2, v/v)), affording a colorless oil (0.631 g, 31%). H-
NMR (CDCl3) d 2.02ꢃ2.11 (m, 2H), 2.75 (t, 2H, Jꢀ7.5
Hz), 3.54 (t, 2H, Jꢀ6.3 Hz), 6.84ꢃ6.89 (m, 1H), 7.13 (d,
2H, Jꢀ7.5 Hz), 7.22 (t, 1H, Jꢀ7.5 Hz), 7.41 (t, 2H,
Jꢀ7.5 Hz), 7.55ꢃ7.61 (m, 1H), 8.08 (s, 1H) ppm.
/
hexanes
1
/
8.4 Hz), 7.12 (d, 2H,
/
/
/
7.8
2.4
/
/
/
/
/
/
/
/
/
/
A mixture of the above pyridine (0.631 g, 2.55 mmol)
and NaCN (0.374 g, 7.63 mmol) in DMSO (10 ml) was
heated at 90 8C for 5 h. After the solution was cooled to
room temperature, H2O (50 ml) was added, and the
3.15. Acetic acid 3-(6-phenoxypyridin-3-yl)propyl ester
(HL9) and 3-(6-phenoxypyridin-3-yl)propan-1-ol
Under N2, at 0 8C, LiAlH4 (1.0 M in THF) (8.0 ml,
8.0 mmol) was added slowly to a solution of HL8 (3.00
g, 11.7 mmol) in THF (40 ml). After the addition was
complete, the reaction mixture was warmed to room
temperature, and stirred for another 2 h. The reaction
was then quenched by the slow addition of H2O (20 ml).
The organic layer was collected, and the aqueous layer
mixture was extracted with diethyl ether (3ꢄ50 ml).
/
The extracts were combined, washed with H2O (50 ml)
and dried over anhydrous MgSO4. After filtration, the
solvent was removed by evaporation under vacuum to
1
afford a colorless oil (0.560 g, 92%). H-NMR (CDCl3)
d 1.96 (quintet, 2H, Jꢀ
2.75 (t, 2H, Jꢀ7.2 Hz), 6.87ꢃ
7.12 (d, 2H, Jꢀ7.5 Hz), 7.20 (t, 1H, Jꢀ
2H, Jꢀ7.5 Hz), 7.52 (dd, 1H, Jꢀ2.4, 8.4 Hz), 8.03 (d,
1H, Jꢀ2.4 Hz) ppm. ES-MS m/z 239 [Mꢂ
H]ꢂ.
/
7.2 Hz), 2.36 (t, 2H, Jꢀ
6.89 (d, 1H, Jꢀ8.4 Hz),
7.5 Hz), 7.40 (t,
/
7.2 Hz),
/
/
/
was extracted with CH2Cl2 (2ꢄ
/
20 ml). The organic
/
/
layers were combined and dried over anhydrous MgSO4.
After filtration, the solvent was removed by evaporation
under vacuum, and a pale yellow oil (2.65 g, 99%) was
/
/
/
/
obtained and used in the next step without further
3.17. 2-Phenoxy-5-phenylpyridine (HL11)
1
purification. H-NMR (CDCl3) d 1.82ꢃ
/
1.91 (m, 2H),
3.75 (m, 2H), 6.84 (d, 1H,
8.4 Hz), 7.12 (d, 2H, Jꢀ7.8), 7.18 (t, 1H, Jꢀ7.8
Hz), 7.39 (t, 2H, Jꢀ7.8 Hz), 7.53 (dd, 1H, Jꢀ2.4, 8.4
Hz), 8.04 (d, 1H, Jꢀ2.4 Hz) ppm.
2.68 (t, 2H, Jꢀ
/
7.5 Hz), 3.66ꢃ
/
Following general procedure C using the Grignard
reagent PhMgCl (3.0 M in diethyl ether) (1.92 ml, 5.76
mmol) and HL15 (1.20 g, 4.80 mmol). The product was
purified by flash chromatography on silica gel (diethyl
Jꢀ
/
/
/
/
/
/
To a solution of the above alcohol (0.600 g, 2.62
mmol) and Et3N (0.50 ml) in dry CH2Cl2 (20 ml) was
added CH3COCl (0.248 g, 3.14 mmol). After the
mixture was stirred at room temperature for 2 h, H2O
(30 ml) was added, and the organic layer was collected.
The aqueous layer was extracted with CH2Cl2 (30 ml).
The organic layers were combined and dried over
anhydrous MgSO4. After filtration, the solvent was
removed by evaporation under vacuum, and the residual
oil was purified by flash chromatography on silica gel
etherꢃ
g, 31%). H-NMR (CDCl3) d 6.98 (d, 1H, Jꢀ
7.17ꢃ7.25 (m, 3H), 7.37ꢃ7.55 (m, 7H), 7.90 (dd, 1H,
Jꢀ2.4, 8.4 Hz), 8.43 (d, 1H, Jꢀ2.4 Hz) ppm.
/
hexanes (1:6, v/v)), affording a white solid (0.363
1
/8.4 Hz),
/
/
/
/
3.18. 2-Phenoxy-5-thiophen-2-ylpyridine (HL12)
Following general procedure C using the Grignard
reagent prepared from Mg (0.215 g, 8.85 mmol) and 2-
bromothiophene (1.20 g, 7.36 mmol), and HL15 (1.63 g,
6.50 mmol). The product was purified by flash chroma-
(diethyl etherꢃ
oil (0.578 g, 81%). H-NMR (CDCl3) d 1.88ꢃ
2H), 2.06 (s, 3H), 2.65 (t, 2H, Jꢀ7.5 Hz), 4.09 (t, 2H,
Jꢀ6.3 Hz), 6.84 (d, 1H, Jꢀ8.4 Hz), 7.12 (d, 2H, Jꢀ7.5
H2), 7.21 (t, 1H, Jꢀ7.5 Hz), 7.39 (t, 2H, Jꢀ7.5 Hz),
7.51 (dd, 1H, Jꢀ2.1, 8.4 Hz), 8.03 (d, 1H, Jꢀ2.1 Hz)
ppm.
/
hexanes (1:1, v/v)), affording a colorless
1
/
1.98 (m,
tography on silica gel (diethyl etherꢃ
affording a yellow oil (0.495 g, 30%). 1H-NMR (CDCl3)
d 6.94 (d, 1H, Jꢀ8.7 Hz), 7.09 (dd, 1H, Jꢀ3.6, 5.4 Hz),
7.15ꢃ7.19 (m, 2H), 7.22ꢃ7.26 (m, 2H), 7.31 (dd, 1H,
Jꢀ1.2, 5.4 Hz), 7.39ꢃ7.45 (m, 2H), 7.88 (dd, 1H, Jꢀ
2.1, 8.7 Hz), 8.01 (d, 1H, Jꢀ2.1 Hz) ppm.
/hexanes (1:5, v/v)),
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/

62
Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
3.19. 5-Fluoro-2-phenoxypyridine (HL13)
to room temperature. After neutralization by adding
NaOH (1 N), the solution was extracted with ethyl
To a suspension of 6-phenoxypyridin-3-ylamine (1.00
g, 5.38 mmol) in aqueous HCl (4.5 N, 5.0 ml) cooled at
acetate (3ꢄ30 ml). The organic layers were combined,
/
washed with H2O (50 ml), and dried over anhydrous
MgSO4. After filtration, the solvent was removed by
evaporation under vacuum, and the brownish red
residue was purified by flash chromatography on silica
ꢁ
/
5 8C was added NaNO2 (0.414 g, 6.00 mmol) in H2O
(3.0 ml). After the addition was complete, the mixture
was stirred at ꢁ5 8C for 30 min, affording a clear
/
solution. To the solution was added NaBF4 (1.10 g, 10.0
mmol) in H2O (7.0 ml) resulting in precipitation of a
solid. The solid was collected by filtration, washed with
cold water and a small amount of ethanol, and dried in
vacuo overnight. The dry solid decomposed to give a
brown sticky oil when it was heated up to 125 8C in a
flask. After being cooled to room temperature, the oil
was extracted with CH2Cl2 (5 ml) and purified by flash
gel (diethyl etherꢃ
oil (0.820 g, 60%). 1H-NMR (CDCl3) d 6.75 (d, 1H, Jꢀ
8.4 Hz), 7.11ꢃ7.14 (m, 2H), 7.19ꢃ7.25 (m, 1H), 7.38ꢃ
7.44 (m, 2H), 7.91 (dd, 1H, Jꢀ2.1, 8.4 Hz), 8.36 (d, 1H,
Jꢀ2.1 Hz) ppm.
/
hexanes (1:4, v/v)), affording a brown
/
/
/
/
/
/
3.23. 5-Nitro-2-phenoxypyridine (HL17)
chromatography on silica gel (diethyl etherꢃ
(1:4, v/v)), affording a colorless oil (0.244 g, 24%). H-
NMR (CDCl3) d 6.91 (dd, 1H, Jꢀ3.3, 8.7 Hz), 7.11ꢃ
7.16 (m, 2H), 7.18ꢃ7.25 (m, 1H), 7.37ꢃ7.47 (m, 3H),
8.05 (d, 1H, Jꢀ3.3 Hz) ppm.
/
hexanes
Following general procedure B using 2-bromo-5-
nitropyridine (10.0 g, 49.3 mmol), phenol (5.09 g, 54.1
mmol) and K2CO3 (8.16 g, 59.1 mmol) in DMSO. The
mixture was heated at 120 8C for 4 h, and the product
was extracted with diethyl ether. A pale yellow solid
(9.85 g, 93%) was obtained after purification by flash
1
/
/
/
/
/
3.20. 5-Chloro-2-phenoxypyridine (HL14)
chromatography on silica gel (diethyl etherꢃ
(1:2, v/v)). 1H-NMR (CDCl3) d 7.03 (d, 1H, Jꢀ
7.15ꢃ7.18 (m, 2H), 7.28ꢃ7.34 (m, 1H), 7.43ꢃ
2H), 8.48 (dd, 1H, Jꢀ2.7, 9.0 Hz), 9.04 (d, 1H, Jꢀ
Hz) ppm.
/
hexanes
/
9.0 Hz),
Following general procedure B using 2,5-dichloropyr-
idine (1.50 g, 10.0 mmol), phenol (1.13 g, 12.0 mmol)
and K2CO3 (2.76 g, 20.0 mmol) in DMSO (10 ml). The
/
/
/
7.49 (m,
/
/2.7
product was extracted with CH2Cl2 (2ꢄ20 ml), and a
/
colorless oil (1.44 g, 70%) was obtained after purifica-
tion by flash chromatography on silica gel (diethyl
3.24. 5-Cyano-2-phenoxypyridine (HL18)
1
etherꢃ
1H, Jꢀ
7.37ꢃ7.45 (m, 2H), 7.64 (dd, 1H, Jꢀ
(d, 1H, Jꢀ2.7 Hz) ppm.
/
hexanes (1:6, v/v)). H-NMR (CDCl3) d 6.87 (d,
Under N2, to a suspension of HL15 (25.0 g, 100
mmol) and Zn(CN)2 (7.05 g, 60.0 mmol) in dry DMF
(80 ml) was added 1,1?-bis(diphenylphosphino)ferrocene
(DPPF) (0.133 g, 0.240 mmol) and Pd2(dba)3 (0.0920 g,
0.100 mmol). After the mixture was heated at 140 8C for
40 h, the solvent was removed by evaporation under
vacuum and H2O (100 ml) was added. The aqueous
/
8.7 Hz), 7.11ꢃ
/
7.14 (m, 2H), 7.19ꢃ/7.24 (m, 1H),
/
/2.7, 8.7 Hz), 8.13
/
3.21. 5-Bromo-2-phenoxypyridine (HL15)
Following general procedure A using 2,5-dibromo-
pyridine (8.10 g, 34.2 mmol), phenol (4.06 g, 43.2 mmol)
and K2CO3 (6.00 g, 43.2 mmol). The product was
extracted with CH2Cl2, and a colorless oil (7.40 g,
83%) was obtained after purification by flash chroma-
suspension was extracted with CH2Cl2 (4ꢄ60 ml). The
/
extract was washed with H2O (100 ml), and dried over
anhydrous MgSO4. After filtration, the solvent was
removed by evaporation under vacuum, and the residual
solid was purified by flash chromatography on silica gel
tography on silica gel (diethyl etherꢃ
1H-NMR (CDCl3) d 6.83 (d, 1H, Jꢀ
2H, Jꢀ8.1 Hz), 7.23 (t, 1H, Jꢀ8.1 Hz), 7.41 (t, 2H,
Jꢀ8.1 Hz), 7.77 (dd, 1H, Jꢀ2.4, 8.7 Hz), 8.22 (d, 1H,
Jꢀ2.4 Hz) ppm.
/
hexanes (1:9, v/v)).
(diethyl etherꢃ
solid (15.7 g, 80%). H-NMR (CDCl3) d 7.01 (d, 1H,
Jꢀ8.4 Hz), 7.12ꢃ7.16 (m, 2H), 7.26ꢃ7.31 (m, 1H),
7.42ꢃ7.49 (m, 2H), 7.92 (dd, 1H, Jꢀ2.4, 8.4 Hz), 8.46
(d, 1H, Jꢀ2.4 Hz) ppm.
/
hexanes (1:4, v/v)), affording a white
1
/
8.7 Hz), 7.13 (d,
/
/
/
/
/
/
/
/
/
/
/
3.22. 5-Iodo-2-phenoxypyridine (HL16)
3.25. 5-Acetyl-2-phenoxypyridine (HL19)
To
(0.860 g, 4.62 mmol) in aqueous H2SO4 (6 N, 6.0 ml)
cooled at ꢁ5 8C was added NaNO2 (0.351 g, 5.10
mmol) in H2O (2.0 ml). After the addition was complete,
the mixture was stirred at ꢁ5 8C for 1 h, affording a
a
suspension of 6-phenoxypyridin-3-ylamine
Under N2 to a solution of HL18 (0.785 g, 4.00 mmol)
in dry THF (15 ml) was added CH3MgBr (3.0 M in
diethyl ether) (1.67 ml, 5.00 mmol) at 0 8C. After the
addition was completed, the mixture was warmed to
room temperature and stirred for 2 h, and then heated at
reflux for 30 min. The solution was then cooled to room
temperature and aqueous HCl (4 N, 16 ml) was added,
/
/
clear solution. Potassium iodide (1.53 g, 9.24 mmol) in
H2O (5.0 ml) was added, and the solution was warmed

Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ
/72
63
and the mixture was heated at reflux for 20 h. The
solution was then neutralized with NaOH (1 N) and
3.29. N-Methyl-6-phenoxynicotinamide (HL23)
extracted with ethyl acetate (3ꢄ
/
30 ml), and the extract
Following general procedure D using HL20 (1.00 g,
4.65 mmol) and methylamine (2.0 M in THF) (5.1 ml, 10
was dried over anhydrous MgSO4. After filtration, the
solvent was removed by evaporation under vacuum, and
the pale yellow liquid residue was purified by flash
1
mmol). A white solid (1.03 g, 97%) was obtained. H-
NMR (CDCl3) d 3.01 (d, 3H, Jꢀ
broad, 1H), 6.94 (d, 1H, Jꢀ8.7 Hz), 7.12ꢃ
7.22ꢃ7.28 (m, 1H), 7.40ꢃ7.46 (m, 2H), 8.13 (dd, 1H,
Jꢀ2.4, 8.7 Hz), 8.53 (d, 1H, Jꢀ2.4 Hz) ppm.
/
4.8 Hz), 6.08 (s,
chromatography on silica gel (diethyl etherꢃ
(1:1, v/v)), affording a colorless liquid (0.258 g, 30%).
1H-NMR (CDCl3) d 2.57 (s, 3H), 6.97 (d, 1H, Jꢀ
8.7
Hz), 7.14ꢃ7.18 (m, 2H), 7.24ꢃ7.30 (m, 1H), 7.41ꢃ7.47
(m, 2H), 8.26 (dd, 1H, Jꢀ2.4, 8.7 Hz), 8.77 (d, 1H, Jꢀ
2.4 Hz) ppm.
/hexanes
/
/7.16 (m, 2H),
/
/
/
/
/
/
/
/
/
/
3.30. N,N-Dimethyl-6-phenoxynicotinamide (HL24)
Following general procedure D using HL20 (1.00 g,
4.65 mmol) and dimethylamine (2.0 M in THF) (5.1 ml,
10 mmol). A sticky pale yellow oil (1.06 g, 94%) was
obtained. 1H-NMR (CDCl3) d 3.08 (s, broad, 6H), 6.94
3.26. 6-Phenoxynicotinic acid (HL20)
A suspension of HL18 (10.0 g, 51.0 mmol) in aqueous
NaOH (10 wt.%) was heated at reflux for 2 h, resulting
in a clear solution. The solution was cooled to room
temperature and neutralized with HCl (6 N), resulting in
precipitation of a white solid. The white solid (14.9 g,
99%) was collected by filtration and washed with H2O,
and dried in vacuo at 60 8C overnight. 1H-NMR
(d, 1H, Jꢀ
1H), 7.39ꢃ7.46 (m, 2H), 7.81 (dd, 1H, Jꢀ
8.28 (d, 1H, Jꢀ2.4 Hz) ppm.
/
8.7 Hz), 7.11ꢃ
/
7.17 (m, 2H), 7.21ꢃ
/
7.26 (m,
/
/2.4, 8.7 Hz),
/
3.31. N-Cyclopentyl-6-phenoxynicotinamide (HL25)
(CD3OD) d 6.94 (d, 1H, Jꢀ
2H), 7.23ꢃ7.28 (m, 1H), 7.40ꢃ
1H, Jꢀ2.4, 8.7 Hz), 8.71 (d, 1H, Jꢀ
/
8.7 Hz), 7.12 ꢁ
7.47 (m, 2H), 8.31 (dd,
2.4 Hz) ppm.
/
7.16 (m,
/
/
Following general procedure D using HL20 (0.350 g,
1.63 mmol) and cyclopentylamine (1.0 ml, 10 mmol). A
white solid (0.430 g, 94%) was obtained after the crude
/
/
product was washed with a small amount of diethyl
1
3.27. 6-Phenoxynicotinic acid methyl ester (HL21)
ether. H-NMR (CDCl3) d 1.44ꢃ
/
1.52 (m, 2H), 1.61ꢃ
2.13 (m, 2H), 4.33ꢃ4.44 (m, 1H),
6.0 Hz), 6.92 (d, 1H, Jꢀ8.7 Hz), 7.12ꢃ
7.15 (m, 2H), 7.22ꢃ7.27 (m, 1H), 7.40ꢃ7.45 (m, 2H),
8.11 (dd, 1H, Jꢀ2.4, 8.7 Hz), 8.51 (d, 1H, Jꢀ2.4 Hz)
ppm.
/
1.74 (m, 4H), 2.05ꢃ
/
/
Following general procedure D using HL20 (1.00 g,
4.65 mmol). A white solid (0.880 g, 83%) was obtained
5.95 (d, 1H, Jꢀ
/
/
/
/
/
after purification by flash chromatography on silica gel
/
/
1
(diethyl etherꢃ
3.92 (s, 3H), 6.93 (d, 1H, Jꢀ
7.8 Hz), 7.26 (t, 1H, Jꢀ7.8 Hz), 7.46 (t, 2H, Jꢀ
8.27 (dd, 1H, Jꢀ2.4, 8.7 Hz), 8.82 (d, 1H, Jꢀ
ppm.
/
hexanes (1:1, v/v)). H-NMR (CDCl3) d
/
8.7 Hz), 7.16 (d, 2H, Jꢀ
7.8 Hz),
2.4 Hz)
/
/
/
/
/
3.32. Dimethyl-(6-phenoxypyridin-3-yl)amine (HL26)
To a solution of formic acid (1.3 ml, 33 mmol) in H2O
(1.5 ml) pre-cooled to 0 8C was added 6-phenoxypyr-
idin-3-ylamine (1.00 g, 5.37 mmol), and the mixture was
stirred until it became clear. Formaldehyde (37% in
H2O) (1.2 ml, 16 mmol) was added, and the mixture was
heated in an oil bath pre-heated at 90 8C, and then at
reflux for 2 h. The reaction was then cooled to room
temperature, and aqueous KOH solution (1 N, 25 ml)
was added. The mixture was extracted with diethyl ether
3.28. 6-Phenoxynicotinamide (HL22)
To a solution of HL18 (1.04 g, 5.30 mmol) in CH3OH
(20 ml) was added a suspension of NaBO3×4H2O (1.63
g, 10.6 mmol) in H2O (5 ml). After the mixture was
heated at 60 8C for 20 h, CH3OH was removed by
evaporation under vacuum, and the residue was ex-
/
tracted with CH2Cl2 (3ꢄ
/
50 ml). The extract was
(3ꢄ30 ml), and the extract was dried over anhydrous
/
washed with H2O (50 ml), and dried over anhydrous
MgSO4. The filtrate was concentrated, and the residue
was washed with a small amount of CH2Cl2, affording a
MgSO4. After filtration, the solvent was removed by
evaporation under vacuum, and the residual oil was
purified by flash chromatography on silica gel (diethyl
1
white solid (0.689 g, 61%). H-NMR (CD3OD) d 6.98
etherꢃ
g, 58%). H-NMR (CDCl3) d 2.93 (s, 6H), 6.84 (d, 1H,
Jꢀ9.0 Hz), 7.03ꢃ7.07 (m, 2H), 7.08ꢃ7.17 (m, 2H),
7.32ꢃ7.38 (m, 2H), 7.75 (d, 1H, Jꢀ3.3 Hz) ppm.
/
hexanes (3:2, v/v)), affording a colorless oil (0.666
1
(d, 1H, Jꢀ
1H), 7.41ꢃ7.47 (m, 2H), 8.25 (dd, 1H, Jꢀ
8.63 (d, 1H, Jꢀ2.4 Hz) ppm.
/
8.7 Hz), 7.12ꢃ
/
7.16 (m, 2H), 7.22ꢃ
/
7.28 (m,
/
/
2.4, 8.7 Hz),
/
/
/
/
/
/

64
Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
3.33. N-(6-Phenoxypyridin-3-yl)acetamide (HL27)
Anal. Calcd. for C12H10Cl2NOAu: C, 31.88; H, 2.23; Cl,
15.68; N, 3.10. Found: C, 31.88; H, 2.26; Cl, 15.75; N,
3.14%.
Following general procedure E using 6-phenoxypyr-
idin-3-ylamine (0.500 g, 2.69 mmol) and CH3COCl
(0.222 g, 2.83 mmol). A white solid (0.605 g, 99%) was
3.37. Gold, dichloro[2-[(5-methyl-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (2)
obtained after the crude product was washed with
1
hexanes. H-NMR (CDCl3) d 2.19 (s, 3H), 6.88ꢃ
/
6.91
7.8 Hz), 7.19 (t, 1H, Jꢀ7.8
Hz), 7.28 (s, broad, 1H), 7.39 (t, 2H, Jꢀ7.8 Hz), 8.08ꢃ
8.11 (m, 2H) ppm.
(m, 1H), 7.11 (d, 2H, Jꢀ
/
/
1H-NMR (d6-DMSO) d 2.38 (s, 3H), 7.19 (dt, 1H,
/
/
Jꢀ
/
1.8, 7.5 Hz), 7.30ꢃ
/
7.39 (m, 2H), 7.55 (d, 1H, Jꢀ
/7.8
Hz), 7.77 (d, 1H, Jꢀ
/
7.8 Hz), 8.26 (dd, 1H, Jꢀ
/
1.2, 8.1
Hz), 8.84 (s, 1H). 13C-NMR (d6-DMSO) d 17.17,
116.18, 118.94, 124.19, 126.11, 129.78, 132.12, 133.44,
146.77, 147.50, 148.03, 154.11 ppm. ES-MS m/z 474
3.34. N-(6-Phenoxypyridin-3-yl)benzamide (HL28)
Following general procedure E using 6-phenoxypyr-
idin-3-ylamine (0.516 g, 2.77 mmol) and benzoyl chlo-
ride (0.410 g, 2.92 mmol). A white solid (0.738 g, 92%)
was obtained after the crude product was washed with
[Mꢂ
Na]ꢂ. Anal. Calcd. for C12H10Cl2NOAu: C, 31.88;
H, 2.23; Cl, 15.68; N, 3.10. Found: C, 31.90; H, 2.20; Cl,
15.82; N, 3.03%.
/
hexanes. 1H-NMR (CDCl3) d 6.95 ꢁ
7.12ꢃ7.18 (m, 2H), 7.20ꢃ7.23 (m, 1H), 7.38ꢃ
2H), 7.48ꢃ7.61 (m, 3H), 7.78 (s, broad, 1H), 7.87ꢃ
(m, 2H), 8.24ꢃ8.28 (m, 2H) ppm.
/
6.98 (m, 1H),
7.44 (m,
7.90
/
/
/
3.38. Gold, dichloro[2-[(6-methyl-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (3)
/
/
/
To a solution of NaAuCl4×/2H2O (0.400 g, 1.00 mmol)
3.35. General procedure for cycloauration
and HL3 (0.185 g, 0.100 mmol) in CH3CH2CN (20 ml)
was added a solution of AgSO3CF3 (0.514 g, 2.00 mmol)
in CH3CH2CN (10 ml) over a period of 8 h while the
solution was being heated at reflux. The mixture was
heated at reflux for an additional 16 h, then acetone (100
ml) was added and the mixture was filtered through a
celite cake. The filtrate was evaporated under vacuum,
and the residual solid was collected, washed with a small
amount of acetone and recrystallized from CH2Cl2,
affording the pure product (0.030 g, 6.6%). The complex
was found to be unstable in both DMF and DMSO, and
no 13C-NMR was available due to its poor solubility in
A solution of the 2-phenoxypyridine ligand (HL)
(1.00 mmol) in CH3CN (5 ml) was added to a solution
of NaAuCl4 (1.00 mmol) in H2O (20 ml), forming a
yellow suspension. The suspension was stirred at room
temperature for a certain period of time (10 min to 24 h)
(see Table 2), and a yellow solid was collected by
filtration. After being washed with H2O and a small
amount of diethyl ether, the yellow solid was suspended
in mixed CH3CN/H2O (50 ml; 1/5, v/v). The suspension
was stirred at room temperature for 10 min, and was
then heated at reflux for a certain period of time (see
Table 2). The reaction mixture was cooled to room
temperature, and a solid was collected by filtration and
washed with H2O. The solid was extracted with hot
acetone or CH2Cl2, and the extract was filtered through
filter paper or a celite cake. The solvent was removed by
evaporation under vacuum, and the residual solid was
soaked with a small amount of pre-cooled acetone, and
then collected by filtration and washed with a very small
amount of pre-cooled acetone and then hexanes. In
some cases, the product was purified by flash chroma-
tography on silica gel.
other solvents. 1H-NMR (CD2Cl2) d 3.11 (s, 3H), 7.19ꢃ
7.26 (m, 2H), 7.28ꢃ7.36 (m, 2H), 7.48 (d, 1H, Jꢀ8.1
Hz), 7.58 (dd, 1H, Jꢀ1.5, 7.8 Hz), 8.04 (t, 1H, Jꢀ7.8
Hz). ES-MS m/z 474 [Mꢂ
Na]ꢂ. Anal. Calcd. for
C12H10Cl2NOAu×0.25CH2Cl2: C, 31.08; H, 2.24; Cl,
/
/
/
/
/
/
/
18.73; N, 2.96. Found: C, 30.88; H, 2.16; Cl, 18.69; N,
3.25%.
3.39. Gold, dichloro[2-[(5-ethyl-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (4)
1H-NMR (d6-DMSO) d 1.19 (t, 3H, Jꢀ
(q, 2H, Jꢀ7.5 Hz), 7.17ꢃ7.23 (m, 1H), 7.30ꢃ
2H), 7.55 (dd, 1H, Jꢀ1.2, 8.1 Hz), 7.79 (d, 1H, Jꢀ
/
7.5 Hz), 2.72
7.39 (m,
3.36. Gold, dichloro[2-[(4-methyl-2-pyridinyl-
/
/
/
kN)oxy]phenyl-kC]-, (SP-4-3)- (1)
/
/8.1
Hz), 8.31 (dd, 1H, Jꢀ
/
2.1, 8.7 Hz), 8.87 (d, 1H, Jꢀ
/
1.2
Hz) ppm. 13C-NMR (d6-DMSO) d 14.69, 24.58, 116.34,
118.94, 124.09, 126.14, 129.80, 133.45, 137.68, 146.54,
1H-NMR (d6-DMSO) d 2.52 (s, 3H), 7.18ꢃ
1H), 7.30ꢃ7.39 (m, 2H), 7.53 (dd, 1H, Jꢀ1.5, 6.3 Hz),
7.58 (dd, 1H, Jꢀ1.5, 8.1 Hz), 7.72 (s, 1H), 8.88 (d, 1H,
Jꢀ
6.3 Hz). 13C-NMR (d6-DMSO) d 21.00, 116.50,
118.89, 123.31, 123.89, 126.12, 129.76, 133.45, 146.56,
148.32, 155.22, 159.77 ppm. ES-MS m/z 474 [Mꢂ
Na]ꢂ.
/
7.24 (m,
/
/
/
146.73, 147.60, 154.19 ppm. ES-MS m/z 488 [Mꢂ
Na]ꢂ.
Anal. Calcd. for C13H12Cl2NOAu: C, 33.51; H, 2.59; Cl,
15.21; N, 3.00. Found: C, 33.51; H, 2.56; Cl, 15.16; N,
2.98%.
/
/
/

Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ
/72
65
Table 2
Cycloauration reactions of 2-phenoxypyridine derivatives
Compound
Ligand
R
Reaction time
Step 1
Overall yield (%)
Step 2
1
HL1
4-CH3
15 min
16 h
4 days
24 h
20 h
20 h
48 h
72 h
48 h
16 h
16 h
16 h
84 h
16 h
72 h
20 h
24 h
24 h
65
84
74
1
2
3
4
5
6
HL2
HL3
5-CH3
6-CH3
15 min
5 h
2 h
HL4
HL5
5-CH2CH3
5-(CH2)2CH3
5-(CH2)3CH3
5-(CH2)4CH3
5-(CH2)2COOCH3
5-(CH2)3OCOCH3
5-(CH2)3CN
5-Ph
42
61
23
0
2 h
5 h
HL6
HL7
3 h
2 h
8
9
HL8
HL9
39
42
71
15
0
3 h
2 h
10
11
HL10
HL11
HL12
HL13
HL14
HL15
HL16
HL17
HL18
HL19
HL20
HL21
HL22
HL23
HL24
HL25
HL26
HL27
HL28
15 min
15 min
3 h
5-(2-thienyl)
5-F
5-Cl
13
14
15
16
15
15
18
11
3 h
30 min
3 h
5-Br
5-I
5-NO2
5-CN
ꢃ/
ꢃ/
ꢃ/
ꢃ/
ꢃ/
ꢃ/
5-COCH3
5-COOH
1 h
5 h
2 h
1 h
2 h
2 h
24 h
16 h
16 h
16 h
16 h
24 h
48 h
24 h
0
see text
21
22
23
24
25
5-COOCH3
5-CONH2
5-CONHCH3
5-CON(CH3)2
5-CONHC5H9
5-N(CH3)2
5-NHCOCH3
5-NHCOPh
14
32
30
36
6
ꢃ/
4 h
4 h
ꢃ/
16 h
72 h
ꢃ/
21
14
27
28
3.40. Gold, dichloro[2-[(5-propyl-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (5)
119.28, 125.14, 126.68, 130.25, 134.12, 137.62, 146.26,
147.42, 148.26, 155.39 ppm. ES-MS m/z 516 [Mꢂ
Na]ꢂ.
/
Anal. Calcd. for C15H16Cl2NOAu: C, 36.46; H, 3.26; Cl,
14.35; N, 2.83. Found: C, 36.62; H, 3.34; Cl, 14.51; N,
2.90%.
1H-NMR (d6-DMSO) d 0.89 (t, 3H, Jꢀ
(sextet, 2H, Jꢀ7.5 Hz), 2.66 (t, 2H, Jꢀ7.5 Hz), 7.17ꢃ
7.23 (m, 1H), 7.30ꢃ7.39 (m, 2H), 7.56 (dd, 1H, Jꢀ1.2,
8.1 Hz), 7.77 (d, 1H, Jꢀ8.1 Hz), 8.29 (dd, 1H, Jꢀ2.1,
8.7 Hz), 8.85 (d, 1H, Jꢀ
1.2 Hz) ppm. 13C-NMR (d6-
/
7.5 Hz), 1.59
/
/
/
/
/
/
/
3.42. Gold, dichloro[2-[[5-(3-methoxy-3-oxopropyl)-2-
pyridinyl-kN]oxy]phenyl-kC]-, (SP-4-3)- (8)
/
DMSO) d 13.21, 23.27, 33.08, 116.29, 118.92, 124.03,
126.11, 129.78, 133.45, 136.13, 146.67, 146.87, 148.01,
Direct purification by recrystallization of the crude
product from acetone was unsuccessful; however, flash
154.16 ppm. ES-MS m/z 502 [Mꢂ
Na]ꢂ. Anal. Calcd.
for C14H14Cl2NOAu: C, 35.02; H, 2.94; Cl, 14.77; N,
2.92. Found: C, 35.02; H, 2.82; Cl, 14.99; N, 2.90%.
/
chromatography on silica gel (CH2Cl2ꢃdiethyl ether
/
(1:1, v/v)) followed by recrystallization from cool
1
acetone resulted in a pure solid. H-NMR (CDCl3) d
3.41. Gold, dichloro[2-[(5-butyl-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (6)
2.72 (t, 2H, Jꢀ
3H), 7.14ꢃ7.21 (m, 2H), 7.25ꢃ
Jꢀ8.4 Hz), 7.76 (dd, 1H, Jꢀ1.5, 8.1 Hz), 8.05 (dd, 1H,
Jꢀ2.1, 8.4 Hz), 9.09 (d, 1H, Jꢀ
2.1 Hz) ppm. 13C-
/
7.2 Hz), 3.06 (t, 2H, Jꢀ
/
7.2 Hz), 3.68 (s,
/
/7.32 (m, 1H), 7.48 (d, 1H,
/
/
1H-NMR (CD2Cl2) d 0.95 (t, 3H, Jꢀ
(sextet, 2H, Jꢀ7.5 Hz), 1.65 (quintet, 2H, Jꢀ
2.75 (t, 2H, Jꢀ7.5 Hz), 7.16ꢃ7.21 (m, 1H), 7.26 (dd,
1H, Jꢀ1.8, 7.8 Hz), 7.31ꢃ7.36 (m, 1H), 7.51 (d, 1H,
Jꢀ8.7 Hz), 7.73 (dd, 1H, Jꢀ1.5, 8.1 Hz), 7.99 (dd, 1H,
Jꢀ2.1, 8.7 Hz), 8.99 (d, 1H, Jꢀ
2.1 Hz) ppm. 13C-
NMR (CD2Cl2) d 14.02, 22.53, 32.35, 33.26, 116.90,
/7.5 Hz), 1.39
/
/
/
/7.5 Hz),
NMR (CDCl3) d 27.26, 34.49, 52.30, 116.62, 118.85,
/
/
124.59, 126.65, 129.98, 134.02, 135.15, 146.16, 146.69,
148.34, 155.39, 172.24 ppm. ES-MS m/z 547 [Mꢂ
Na]ꢂ.
/
/
/
/
/
Anal. Calcd. for C15H14Cl2NO3Au: C, 34.37; H, 2.69;
Cl, 13.53; N, 2.67. Found: C, 34.56; H, 2.69; Cl, 13.72;
N, 2.69%.
/
/

66
Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
3
3.43. Gold, [2-[[5-[3-acetyloxypropyl]-2-pyridinyl-
kN]oxy]phenyl-kC]dichloro-, (SP-4-3)- (9)
13C-NMR (d6-DMSO) d 118.12 (d, JCꢁF
ꢀ6.8 Hz),
/
119.05, 123.89, 126.33, 129.91, 133.39, 134.98 (d,
2JCꢁF
153.19, 155.63 (d, 1JCꢁF
DMSO) d ꢁ52.29 ppm. ES-MS m/z 478 [Mꢂ
ꢀ
/
22 Hz), 136.78 (d, JCꢁF
247 Hz) ppm. 19F-NMR (d6-
Na]ꢂ.
ꢀ
/
38 Hz), 146.55,
2
Direct purification by recrystallization of the crude
product from acetone was unsuccessful; however, flash
ꢀ
/
/
/
chromatography on silica gel (CH2Cl2ꢃ
/
diethyl acetate
(1:1, v/v)) followed by recrystallization from cool
Anal. Calcd. for C11H7Cl2FNOAu (0.1C3H6O): C,
29.39; H, 1.66; Cl, 15.35; N, 3.03. Found: C, 29.46; H,
1.70; Cl, 15.53; N, 3.02%.
1
acetone resulted in a pure solid. H-NMR (CD2Cl2) d
1.95ꢃ
4.09 (t, 2H, Jꢀ
(m, 2H), 7.54 (d, 1H, Jꢀ
/
2.04 (m, 2H), 2.04 (s, 3H), 2.85 (t, 2H, Jꢀ
6.3 Hz), 7.17ꢃ7.20 (m, 1H), 7.22ꢃ
8.4 Hz), 7.73 (dd, 1H, Jꢀ
/
7.5 Hz),
7.34
1.5,
/
/
/
/
/
3.47. Gold, dichloro[2-[(5-chloro-2-pyridinyl-
8.1 Hz), 8.02 (dd, 1H, Jꢀ
/
2.1, 8.4 Hz), 9.04 (d, 1H, Jꢀ
/
kN)oxy]phenyl-kC]-, (SP-4-3)- (14)
2.1 Hz) ppm. 13C-NMR (CD2Cl2) d 21.22, 29.17, 30.03,
63.23, 117.11, 119.28, 125.02, 126.77, 130.30, 134.13,
136.26, 146.28, 147.31, 148.43, 155.66, 171.28 ppm. ES-
1H-NMR (d6-DMSO) d 7.20ꢃ
(m, 2H), 7.56 (d, 1H, Jꢀ7.5 Hz), 7.91 (d, 1H, Jꢀ
Hz), 8.56 (d, 1H, Jꢀ7.5 Hz), 9.09 (s, 1H) ppm. ES-MS
m/z 494 [Mꢂ
Na]ꢂ. Anal. Calcd. for C11H7Cl3NOAu:
/
7.25 (m, 1H), 7.31ꢃ
/
7.40
/
/8.7
MS m/z 561 [Mꢂ
/
Na]ꢂ. Anal. Calcd. for
/
C16H16Cl2NO3Au: C, 35.71; H, 3.00; Cl, 13.18; N,
2.60. Found: C, 35.70; H, 2.95; Cl, 13.25; N, 2.51%.
/
C, 27.96; H, 1.49; Cl, 22.51; N, 2.96. Found: C, 28.22; H,
1.50; Cl, 22.24; N, 3.06%.
3.44. Gold, dichloro[2-[[5-(3-cyanopropyl)-2-pyridinyl-
kN]oxy]phenyl-kC]-, (SP-4-3)- (10)
3.48. Gold, dichloro[2-[(5-bromo-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (15)
This compound was purified either by direct recrys-
tallization of the crude product from acetone or by flash
1H-NMR (d6-DMSO) d 7.20ꢃ
(m, 2H), 7.56 (d, 1H, Jꢀ8.1 Hz), 7.84 (d, 1H, Jꢀ
Hz), 8.63 (d, 1H, Jꢀ8.1 Hz), 9.15 (s, 1H) ppm. ES-MS
m/z 539 [Mꢂ Anal. Calcd. for
Na]ꢂ.
/
7.25 (m, 1H), 7.31ꢃ
/
7.40
chromatography on silica gel (CH2Cl2ꢃ
/
diethyl ether
(1:1, v/v)). H-NMR (CDCl3) d 2.05 (quintet, 2H, Jꢀ
7.2 Hz), 2.48 (t, 2H, Jꢀ7.2 Hz), 2.94 (t, 2H, Jꢀ7.2 Hz),
7.15ꢃ7.33 (m, 3H), 7.54 (d, 1H, Jꢀ8.4 Hz), 7.76 (d, 1H,
Jꢀ7.8 Hz), 8.01 (dd, 1H, Jꢀ2.1, 8.4 Hz), 9.01 (d, 1H,
Jꢀ
2.1 Hz) ppm. 13C-NMR (CDCl3) d 15.51, 25.66,
1
/
/8.7
/
/
/
/
/
/
/
C11H7BrCl2NOAu: C, 25.56; H, 1.36; Cl, 13.72; N,
2.71. Found: C, 25.79; H, 1.52; Cl, 13.51; N, 2.68%.
/
/
/
30.08, 116.49, 118.91, 120.23, 123.92, 126.14, 129.80,
133.41, 134.64, 146.58, 146.95, 148.10, 154.41 ppm. ES-
MS m/z 528 [Mꢂ
Na]ꢂ. Anal. Calcd. for
C15H13Cl2N2OAu: C, 35.67; H, 2.59; Cl, 14.04; N,
5.55. Found: C, 35.66; H, 2.62; Cl, 13.88; N, 5.49%.
/
3.49. Gold, dichloro[2-[(5-iodo-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (16)
1H-NMR (d6-DMSO) d 7.19ꢃ
(m, 2H), 7.55 (d, 1H, Jꢀ7.8 Hz), 7.68 (d, 1H, Jꢀ
Hz), 8.63 (d, 1H, Jꢀ7.8 Hz), 9.20 (s, 1H) ppm. ES-MS
m/z 586 [Mꢂ
Na]ꢂ. Anal. Calcd. for C11H7Cl2INOAu
/
7.24 (m, 1H), 7.30ꢃ
/
7.40
/
/8.7
3.45. Gold, dichloro[2-[(5-phenyl-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (11)
/
/
(0.2C3H6O): C, 24.21; H, 1.44; Cl, 12.32; I, 22.05; N,
2.43. Found: C, 24.10; H, 1.39; Cl, 12.07; I, 21.71; N,
2.53%.
1H-NMR (d6-DMSO) d 7.21ꢃ
(m, 2H), 7.47ꢃ7.62 (m, 4H), 7.71ꢃ
1H, Jꢀ8.4 Hz), 8.72 (dd, 1H, Jꢀ
1H, Jꢀ
2.1 Hz) ppm. 13C-NMR (d6-DMSO) d 116.78,
/
7.26 (m, 1H), 7.34ꢃ
7.75 (m, 2H), 7.94 (d,
2.1, 8.4 Hz), 9.32 (d,
/
7.40
/
/
/
/
/
119.00, 123.58, 126.28, 126.96, 129.26, 129.55, 129.89,
133.42, 133.75, 134.07, 144.53, 146.52, 147.07, 154.83
3.50. Gold, dichloro[2-[(5-methoxy-oxomethyl-2-
pyridinyl-kN)oxy]phenyl-kC]-, (SP-4-3)- (21)
ppm. ES-MS m/z 536 [Mꢂ
Na]ꢂ. Anal. Calcd. for
C17H12Cl2NOAu: C, 39.71; H, 2.35; Cl, 13.79; N, 2.72.
Found: C, 39.79; H, 2.55; Cl, 13.92; N, 2.72%.
/
1H-NMR (CD2Cl2) d 4.01 (s, 3H), 7.21ꢃ
7.67 (d, 1H, Jꢀ8.7 Hz), 7.77 (d, 1H, Jꢀ
/
7.40 (m, 3H),
8.1 Hz), 8.71
1.8 Hz) ppm.
/
/
(dd, 1H, Jꢀ
/
1.8, 8.1 Hz), 9.83 (d, 1H, Jꢀ
/
3.46. Gold, dichloro[2-[(5-fluoro-2-pyridinyl-
kN)oxy]phenyl-kC]-, (SP-4-3)- (13)
13C-NMR (d6-DMSO) d 53.24, 117.20, 118.86, 122.37,
123.55, 126.53, 129.90, 133.47, 145.70, 145.86, 151.10,
157.84, 162.71 ppm. ES-MS m/z 518 [Mꢂ
Na]ꢂ. Anal.
/
1H-NMR (d6-DMSO) d 7.19ꢃ
(m, 2H), 7.56 (d, 1H, Jꢀ7.8 Hz), 7.97 (dd, 1H, Jꢀ
9.3 Hz), 8.48ꢃ8.53 (m, 1H), 9.08 (s, broad, 1H) ppm.
/
7.24 (m, 1H), 7.32ꢃ
/
7.40
4.5,
Calcd. for C13H10Cl2NO3Au: C, 31.47; H, 2.03; Cl,
14.29; N, 2.82. Found: C, 31.24; H, 2.11; Cl, 14.56; N,
2.88%.
/
/
/

Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ
/72
67
3.51. Gold, [2-[[5-(aminocarbonyl)-2-pyridinyl-
kN]oxy]phenyl-kC]dichloro-, (SP-4-3)- (22)
3.55. Gold, [2-[[5-(acetylamino)-2-pyridinyl-
kN]oxy]phenyl-kC]dichloro-, (SP-4-3)- (27)
1H-NMR (d6-DMSO) d 7.20ꢃ
(m, 2H), 7.58 (d, 1H, Jꢀ7.8 Hz), 7.92ꢃ
8.35 (s, 1H), 8.74 (dd, 1H, Jꢀ1.8, 8.7 Hz), 9.52 (d, 1H,
Jꢀ
1.8 Hz) ppm. 13C-NMR (d6-DMSO) d 116.47,
/
7.25 (m, 1H), 7.31ꢃ
/
7.41
1H-NMR (d6-DMSO) d 2.10 (s, 3H), 7.16ꢃ
1H), 7.29ꢃ7.37 (m, 2H), 7.54 (d, 1H, Jꢀ
(d, 1H, Jꢀ9.0 Hz), 8.48 (dd, 1H, Jꢀ2.1, 8.4 Hz), 9.39
(d, 1H, Jꢀ
2.1, 8.7 Hz), 10.71 (s, 1H). 13C-NMR (d6-
/
7.21 (m,
/
/
7.95 (m, 2H),
/
/
8.4 Hz), 7.81
/
/
/
/
/
118.89, 123.05, 126.41, 127.92, 129.91, 133.47, 144.27,
146.03, 150.12, 156.85, 163.31 ppm. ES-MS m/z 503
DMSO) d 23.74, 116.64, 118.91, 124.67, 125.99, 129.71,
133.57, 134.38, 136.52, 138.88, 146.99, 151.33, 169.25
[Mꢂ
/
Na]ꢂ. Anal. Calcd. for C12H9Cl2N2O2Au: C,
ppm. ES-MS m/z 517 [Mꢂ
Na]ꢂ. Anal. Calcd. for
C13H11Cl2N2O2Au: C, 31.54; H, 2.24; Cl, 14.32; N, 5.66.
Found: C, 32.02; H, 2.39; Cl, 14.71; N, 5.49%.
/
29.96; H, 1.89; Cl, 14.74; N, 5.82. Found: C, 30.21; H,
2.02; Cl, 14.46; N, 5.70%.
3.56. Gold, [2-[[5-(benzoylamino)-2-pyridinyl-
kN]oxy]phenyl-kC]dichloro-, (SP-4-3)- (28)
3.52. Gold, dichloro[2-[[5-[(methylamino)carbonyl]-2-
pyridinyl-kN]oxy]phenyl-kC]-, (SP-4-3)- (23)
1H-NMR (d6-DMSO) d 7.17ꢃ
(m, 2H), 7.53ꢃ7.66 (m, 4H), 7.89 (d, 1H, Jꢀ
7.94ꢃ8.00 (m, 2H), 8.68 (dd, 1H, Jꢀ2.1, 9.0 Hz), 9.66
(d, 1H, Jꢀ
2.1 Hz), 11.00 (s, 1H) ppm. 13C-NMR (d6-
/
7.22 (m, 1H), 7.30ꢃ
/
7.40
1H-NMR (d6-DMSO) d 2.81 (d, 3H, Jꢀ
7.20ꢃ7.25 (m, 1H), 7.33ꢃ7.41 (m, 2H), 7.58 (d, 1H, Jꢀ
7.8 Hz), 7.94 (d, 1H, Jꢀ8.7 Hz), 8.71 (dd, 1H, Jꢀ1.8,
/
4.5 Hz),
/
/9.0 Hz),
/
/
/
/
/
/
/
/
8.7 Hz), 8.85ꢃ
8.88 (m, 1H), 9.50 (s, 1H) ppm. 13C-NMR
/
DMSO) d 116.57, 118.94, 124.73, 126.03, 127.91,
128.58, 129.75, 132.39, 133.45, 133.58, 134.49, 137.89,
140.08, 147.00, 151.78, 166.04 ppm. ES-MS m/z 579
(d6-DMSO) d 26.41, 116.50, 118.87, 123.05, 126.39,
127.98, 129.89, 133.46, 143.86, 146.02, 149.68, 156.73,
162.03 ppm. ES-MS m/z 517 [Mꢂ
Na]ꢂ. Anal. Calcd.
for C13H11Cl2N2O2Au: C, 31.54; H, 2.24; Cl, 14.32; N,
5.66. Found: C, 31.77; H, 2.37; Cl, 14.12; N, 5.51%.
/
[Mꢂ
Na]ꢂ. Anal. Calcd. for C18H13Cl2N2O2Au
(1.4H2O): C, 37.12; H, 2.73; Cl, 12.17; N, 4.81. Found:
C, 37.16; H, 2.62; Cl, 12.16; N, 4.70%.
/
3.53. Gold, dichloro[2-[[5-[(dimethylamino)carbonyl]-
2-pyridinyl-kN]oxy]phenyl-kC]-, (SP-4-3)- (24)
4. Results and discussion
1H-NMR (d6-DMSO) d 2.97 (s, 3H), 3.01 (s, 3H),
4.1. Ligand preparation
7.20ꢃ
/
7.26 (m, 1H), 7.33ꢃ
/
7.41 (m, 2H), 7.58 (d, 1H, Jꢀ
/
Ligands HL1ꢃHL3 and HL15 were prepared using
/
7.8 Hz), 7.94 (d, 1H, Jꢀ
/
8.4 Hz), 8.46 (dd, 1H, Jꢀ
/
1.8,
8.4 Hz), 9.09 (s, 1H) ppm. 13C-NMR (d6-DMSO) d
35.19, 117.04, 118.93, 123.13, 126.34, 129.85, 133.43,
145.38, 146.10, 147.76, 155.87, 164.75 ppm. ES-MS m/z
general procedure A, a modified literature procedure
[25] involving the coupling reaction of phenol with the
corresponding 2-bromopyridines in the presence of
K2CO3 at an elevated temperature. Ligands HL14 and
HL17 were obtained using general procedure B, similar
to procedure A, but the coupling reactions were carried
out in DMSO at a lower temperature. General proce-
531 [Mꢂ
Na]ꢂ. Anal. Calcd. for C14H13Cl2N2O2Au: C,
33.03; H, 2.57; Cl, 13.93; N, 5.50. Found: C, 33.14; H,
2.62; Cl, 14.08; N, 5.41%.
/
dure C involved the formation of a Cꢁ
Ni(II)-catalyzed coupling reaction of the Cꢁ
HL15 with a Grignard reagent. Ligands HL4ꢃ
/
C bond via the
Br bond of
HL7,
3.54. Gold, dichloro[2-[[5-
/
[(cyclopentylamino)carbonyl]-2-pyridinyl-
kN]oxy]phenyl-kC]-, (SP-4-3)- (25)
/
HL11 and HL12 were all prepared using this procedure,
with isolated yields ranging from 25 to 74%. For the
preparation of ligands HL11 and HL12, which involve
aromatic Grignard reagents (2-thienyl- and phenyl-
magnesium bromide), a significant amount of 2,5-
dithienylpyridine and 2,5-diphenylpyridine were also
isolated, respectively, as side products, indicating that
in these cases the phenoxy group acts as a leaving group.
1H-NMR (d6-DMSO) d 1.47ꢃ
(m, 2H), 1.87ꢃ1.92 (m, 2H), 4.17ꢃ
7.25 (m, 1H), 7.32ꢃ7.41 (m, 2H), 7.58 (d, 1H, Jꢀ
Hz), 7.93 (d, 1H, Jꢀ8.7 Hz), 8.69 (d, 1H, Jꢀ
8.75 (dd, 1H, Jꢀ
/
1.56 (m, 4H), 1.64ꢃ1.69
/
/
/
4.26 (m, 1H), 7.20ꢃ
/
/
/
8.4
/
/6.9 Hz),
/
1.8, 8.7 Hz), 9.49 (d, 1H, Jꢀ
/
1.8 Hz)
ppm. 13C-NMR (d6-DMSO) d 23.64, 32.08, 51.39,
116.32, 118.91, 123.11, 126.41, 128.25, 129.92, 133.45,
144.28, 146.10, 149.80, 156.71, 161.24 ppm. ES-MS m/z
571 [Mꢂ
Na]ꢂ. Anal. Calcd. for C17H17Cl2N2O2Au
(0.4H2O): C, 36.70; H, 3.22; Cl, 12.74; N, 5.03%. Found:
C, 36.75; H, 3.16; Cl, 12.67; N, 4.97%.
Ligands HL8ꢃHL10 were prepared as shown in
/
Scheme 1. Ligand HL8 was obtained in 42% overall
yield by the palladium(0)-catalyzed coupling reaction of
HL15 with methyl acrylate followed by hydrogenation
on Pd/C at room temperature. Reduction of the ester
/

68
Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
group in ligand HL8 with LiAlH4 afforded the corre-
sponding alcohol, which was esterified with acetyl
chloride to provide ligand HL9 in 80% overall yield.
Conversion of alcohol to the corresponding chloride
using POCl3 followed by nucleophilic substitution of the
chloride with NaCN in DMSO at 90 8C afforded ligand
HL10 in 28% overall yield.
Ligands HL13 and HL16 were obtained from a diazo
salt prepared from 6-phenoxypyridin-3-ylamine, as illu-
strated in Scheme 2, which was obtained from hydro-
genation of ligand HL17 using tin shot in an acidic
medium at 50 8C. Ligand HL13 was prepared in 24%
yield from decomposition of the diazo salt of BF4ꢁ at
125 8C. Ligand HL26 was prepared from 6-phenoxy-
pyridin-3-ylamine treated with a mixture of formalde-
hyde and formic acid.
As illustrated in Scheme 3, ligand HL18 was obtained
using a modified literature method [26] as a white solid
in 80% yield when a mixture of HL15 and Zn(CN)2 in
dry DMF was heated at 140 8C for 40 h in the presence
of Pd2(dba)3 and DPPF. Ligand HL19 was obtained via
treatment of HL18 with CH3MgBr followed by hydro-
lysis of the product under acidic conditions. The acid
HL20 was readily available from the hydrolysis of HL18
with 10% NaOH solution, and ligand HL22 was
obtained from a mixture of HL18 and NaBO3 in mixed
CH3OH/H2O solution heated at 50 8C for 2 h. The
Scheme 2. (a) Sn, conc. HCl, 50 8C, 2 h, 69%; (b) (i) NaNO2, HCl,
5 8C, NaBF4; (ii) heated to 125 8C, 24%; (c) NaNO2, H2SO4, 5 8C, KI,
60%; (d) HCHO, HCOOH, D, 2 h, 58%; (e) Et3N, THF, acyl chloride,
92ꢃ99%.
/
characterization were performed on these intermediates.
Generally, the coordination reaction was complete in a
short period of time yielding a yellow solid; however, for
the ligand with a bulky lipophilic group the product
usually appeared as an oil floating on the reaction
medium in the beginning, and solidified after the
reaction mixture was stirred for a longer period of
time. All cycloaurated compounds with general formula
AuCl2(L) were formed when
a
suspension of
the intermediates AuCl3(HL) in CH3CN/H2O (1:5, v/v)
was heated at reflux for a certain period of time as
listed in Table 2. The cycloauration time was not
optimized, but was based on empirical observations
such as the color of the suspending solid and
the formation of Au(0) on the wall of the reaction
flask. It should be noted that different substituents
on the pyridine ring affect the solubility of the cycloau-
rated compounds in common solvents such as CH2Cl2,
acetone and CH3CN, but all have good solubility
in high polar solvents such as DMF and DMSO
with the exception of the compounds bearing a Cl
(14), Br (15) or I (16) group at the 5-position of the
pyridine ring.
preparation of amides and esters HL21, HL23ꢃ
/
HL25,
HL27ꢃHL28 was very straightforward using general
/
procedures D and E as illustrated in Schemes 2 and 3.
4.2. Cycloauration
The direct cycloauration reactions were carried out as
illustrated in Scheme 4, following a modified literature
procedure [17]. The reaction times and isolated yields
are summarized in Table 2. The intermediates with
general formula AuCl3(HL) were formed via the co-
ordination reaction of the ligand HL and Na[AuCl4] in
CH3CN/H2O (1:4, v/v) at room temperature. After
being washing with H2O and diethyl ether to remove
unreacted starting materials, the intermediates were
isolated as yellow solids, and the structure verified using
1H-NMR spectroscopy. No further purification and
4.3. Effect of methyl substituents
The effect of methyl substituents at the 4-, 5- and 6-
positions of the pyridine ring on the cycloauration was
examined using methyl-substituted 2-phenoxypyridine
Scheme 1. (a) Methyl acrylate, Pd(OAc)2, PPh3, K2CO3, DMF, 105 8C, 16 h, 83%; (b) Pd/C, H2, CH3OH, 5 h, 51%; (c) LiAlH4, THF, 0ꢃ
/20 8C, 2 h,
99%; (d) CH3COCl, Et3N, CH2Cl2, 2 h, 81%; (e) POCl3, CH2Cl2, 2 h, 31%; (f) NaCN, DMSO, 90 8C, 5 h, 92%.

Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ
/72
69
Scheme 3. (a) Pd2(dba)3, DPPF, Zn(CN)2, DMF, 140 8C, 40 h, 80%; (b) (i) CH3MgBr, THF, D, 30 min, (ii) 4 N, HCl, D, 20 h, 30%; (c) (i) 10%
NaOH, D, 2 h, (ii) 6 N HCl, 99%; (d) NaBO3, CH3OH/H2O, 60 8C, 20 h, 61%; (e) (i) SOCl2, D, 1ꢃ2 h, (ii) CH3OH or amine in CH2Cl2 or THF, high
yields.
/
ligands (HL1ꢃ
/
HL3). As shown in Table 2, with the
4.4. Effect of lipophilic groups
Ligands HL2 and HL4ꢃHL7 have a C1 to C5 alkyl
methyl group at the 4- (HL1) or 5-positions (HL2), the
intermediate AuCl3(HL) species was formed and pre-
cipitated from the reaction mixture rapidly. Both the
cycloaurated compounds 1 and 2 were isolated in good
yields when the AuCl3(HL1 or HL2) intermediates were
heated at reflux in mixed CH3CN/H2O for 16 and 24 h,
respectively. The only other species observed was the
starting material AuCl3(HL1 or HL2). The side product
Au(0) was not observed, indicating that in both cases the
cycloaurated products and starting materials are stable
under the reaction temperature, and that prolonged
reaction time could potentially result in an increase in
the cycloauration yield. For instance, compound 1 was
obtained in 84% isolated yield when AuCl3(HL1) was
heated at reflux in mixed CH3CN/H2O for 4 days. With
a methyl group at the 6-position (HL3) of the pyridine
ring, only trace amounts of the cycloaurated compound
3 were isolated from the suspension of the intermediate
AuCl3(HL3) with Au(0) as the only other gold-contain-
ing product. Compound 3 was also prepared in low yield
(6.6%) from a mixture of NaAuCl4, ligand HL3 and
AgSO3CF3 in CH3CH2CN by heating at reflux over-
night. Unlike compounds 1 and 2, compound 3 reacts
with DMSO and DMF in an NMR tube at room
temperature indicating it is less stable in solution. This is
likely due to the steric effect of the methyl group at the
6-position.
/
group at the 5-position of the pyridine ring. Cycloaura-
tion of AuCl3(HL) prepared from the ligands HL2, HL4
and HL5 containing a C1 to C3 group provided the
cycloaurated products in good yield. Unreacted
AuCl3(HL) was also isolated, but no Au(0). In contrast,
the presence of a butyl group (HL6) resulted in several
complications. The intermediate AuCl3(HL6) oiled out
of solution when heated at reflux, and a significant
amount of Au(0) was formed. As a consequence,
compound 6 was isolated in a low yield of 23%.
Furthermore, when the substituent was a pentyl group
(HL7), no cycloaurated product was isolated. Au(0) was
the only Au-containing product isolated when the
cycloauration of the AuCl3(HL7) intermediate was
performed under the same reaction conditions. Since
the direct cycloauration was performed in a highly polar
medium of CH3CN/H2O (1:5, v/v), the presence of bulky
lipophilic groups in the ligand reduces the solubility of
the AuCl3(HL) intermediate (resulting in formation of
oils) thereby affecting the cycloauration.
4.5. Effects of strong electron-withdrawing and electron-
donating groups
The formation and stability of the Auꢁ
/
N(py) bond
of the intermediate AuCl3(HL) complex was very
Scheme 4.

70
Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ72
/
important for the success of the direct cycloauration. As
shown in Table 2, the coordination reaction of the
pyridine ligand (HL) with Na[AuCl4] in CH3CN/H2O at
reacted with acetone in the presence of a silver or
thallium salt at room temperature to form an Au(III)ꢁ
C (acetone) bond [22,27,28].
/
room temperature forms
a
yellow intermediate
Interestingly, the coordination reaction of HL20 with
NaAuCl4 under the standard conditions afforded the
intermediate AuCl3(HL20) with an uncoordinated car-
boxylic group. When the intermediate was heated at
reflux in CH3CN/H2O, an off-white material was
obtained. The off-white material has an extremely
poor solubility even in DMSO, and could not be
AuCl3(HL) with the exception of HL17 and HL18,
which contain the strong electron-withdrawing nitro and
nitrile groups, and HL26 with the electron-donating
Me2N group. For HL17 and HL18, the electron-with-
drawing groups decrease the electron density on the N
atom of the pyridine ring, resulting in a weaker
coordination tendency of the N atom to the Au(III)
center. For HL26, the amino group was oxidized by the
Au(III) center to form a black solution and Au(0),
preventing the formation of the intermediate
AuCl3(HL26). For ligands HL17 and HL18, no cy-
cloaurated compound was isolated, and Au(0) metal
was the main product isolated when the mixture of
NaAuCl4 and ligand was heated at reflux overnight in a
solution of CH3CN/H2O (1:4, v/v).
1
characterized by H-NMR. Its infrared spectrum (CsI)
showed the presence of uncoordinated (n(CsI)ꢀ
cmꢁ1) carboxylic groups comparable to that in the free
ligand HL20 (n(CsI)ꢀ
1701 cmꢁ1) as well as coordi-
nated carboxylic groups (n(CsI)ꢀ
1644 cmꢁ1). These
/
1708
/
/
observations and the result from elemental analysis on C
(31.32%), H (1.81%), N (3.25%) and Cl (8.58%) are
consistent of the formation of a poly- or oligomeric
material containing Auꢁ
/
C, Auꢁ
/
Cl and Auꢁ
/
O bonds,
the latter formed via substitution reaction of some Auꢁ
/
4.6. Toleration of other functional groups
Cl bonds by the carboxylic groups.
Direct cycloauration of ligands with various amide
and ester substituents at the 5-position of the pyridine
ring was also examined, and the results are listed in
Table 2. In all cases, the intermediates AuCl3(HL)
The ester and nitrile groups were well tolerated by
direct cycloauration when they were attached to the
pyridine ring via an alkyl chain. Compounds 8ꢃ
/
10 were
prepared in good yields of 39ꢃ71%. However, the
/
(HL21ꢃHL25, HL27 and HL28) were easily formed,
/
efficiency of the cycloauration was lowered by the
presence of the aromatic phenyl group as a substituent,
and compound 11 was obtained in a low yield of 15%.
Although the intermediate AuCl3(HL12) was easily
obtained from HL12 (with a 5-(2-thienyl) substituent),
only Au(0) was formed as the metal-containing product
and the cycloaurated products were obtained with yields
varying from 6 to 36% with Au(0) as the major metal-
containing side product.
4.7. Crystallographic study
when it was heated at reflux for 16 h. Ligands HL13ꢃ
HL16 containing a halo substituent gave a similar result
for the cycloauration, providing the corresponding
/
Single crystals of compound 25 were grown from slow
evaporation of an acetone solution. The experimental
details of the X-ray structure determination and crystal-
lographic parameters are listed in Table 1, and the
selected bond distances and angles are summarized in
Table 3. The solid structure is shown in Fig. 1, depicting
a four-coordinate Au atom located in the center of a
products 13ꢃ
/
16 with low yields of 11ꢃ18%. This result
/
indicates that the electronegativity difference among the
halo groups has a subtle effect on the cycloauration. In
addition, the solubility of these compounds was poor in
most organic solvents, and significantly decreases as the
atomic number increases from fluoro to iodo with
compound 16 having a very low solubility even in
slightly distorted square with the bond distances of AuÃ
/
˚
˚
C (2.017(6) A), AuÃ
/
N (2.053(5) A) and AuÃ
/Cl
DMSO. Compounds 14ꢃ16 were not characterized by
/
13C-NMR spectroscopy due to their poor solubility.
The intermediate AuCl3(HL19) was readily prepared
from a mixture of NaAuCl4 and ligand HL19 containing
an acetyl group. No cycloaurated species was isolated
when the intermediate was heated at reflux in CH3CN/
H2O (5:1, v/v) overnight, the main Au-containing
product isolated was Au(0), formed from either decom-
position of the intermediate or the cycloaurated pro-
duct. One possible explanation is that the acetyl group
Table 3
Selected bond lengths and bond angles for compound 25
Bond lengths
Au(1)Ã
/
Cl(1)
2.379(2)
2.053(5)
Au(1)Ã
/
Cl(2)
2.262(1)
2.017(6)
Au(1)Ã
/
N(1)
Au(1)Ã
/
C(11)
Bond angles
Cl(1)ÃAu(1)Ã
Cl(1)ÃAu(1)Ã
Cl(2)ÃAu(1)Ã
C(5)ÃO(1)Ã
Au(1)ÃN(1)Ã
Au(1)ÃC(11)Ã
/
/
Cl(2)
C(11)
C(11)
92.14(5) Cl(1)Ã
/
Au(1)Ã
Au(1)Ã
Au(1)Ã
Au(1)ÃN(1)Ã
Au(1)Ã
N(1)ÃC(1)Ã
/
N(1)
90.0(1)
177.8(1)
86.6(2)
/
/
176.6(2)
91.2(2)
Cl(2)Ã
/
/N(1)
/
/
N(1)Ã
/
/
C(11)
C(1)
provided an additional Au(III)ꢁC (COCH3) interac-
/
/
/
C(6)
C(5)
C(6)
115.3(4)
119.4(4)
116.7(5)
/
/
120.6(4)
124.0(5)
122.0(5)
tion, resulting in the decomposition of the desired
product at the elevated reaction temperature. It has
previously been reported that a cycloaurated compound
/
/
/
C(11)Ã
/C(10)
/
/
/
/
C(2)

Y. Zhu et al. / Journal of Organometallic Chemistry 677 (2003) 57ꢃ
/72
71
Fig. 1. ORTEP diagram of the solid-state molecular structure of compound 25. Protons are omitted for clarity.
˚
(2.379(2), 2.262(1) A) and with the bond angles of ClÃ
/
mail: deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.uk).
AuÃ
/
Cl (92.14(5)8) and NÃ
to those of the cycloaurated compound of the unsub-
stituted 2-phenoxypyridine, which has the bond dis-
/
AuÃC (86.6(2)8), very similar
/
˚
˚
tances of AuÃ
Cl (2.275(4), 2.369(5) A) and the bond angles of ClÃ
AuÃCl (92.1(2)8) and NÃAuÃC (86.6(6)8) [17].
/
C (2.03(2) A), AuÃ
/
N (2.02(1) A) and AuÃ
/
Acknowledgements
˚
/
/
/
/
We thank Dr. Brian Patrick, Department of Chem-
istry, University of British Columbia, Vancouver, BC,
Canada, for data collection and structure determination
of compound 25.
5. Conclusions
Direct cycloauration of 2-phenoxypyridines with
different functionalities in the pyridine ring was exam-
ined by formation of the trichloro coordinate inter-
mediates and subsequent cycloauration at an elevated
temperature in CH3CN/H2O. The results indicated that
the cycloauration is tolerated by the presence of
substituents, such as alkyl, halo, ester, amido and alkyl
nitrile groups, but is not by strong electron-donating
and strong electron-withdrawing groups. A methyl
group at the 6-position weakens the bonding of the
pyridine nitrogen atom to the Au(III) center, adversely
effecting the cycloauration and compound stability. The
presence of bulky lipophilic groups in the pyridine ring
usually results in an increase in the decomposition of the
reaction species to Au(0), and the presence of a thienyl
or acetyl group in the pyridine ring totally blocks the
availability of cycloaurated compounds by this method
so that Au(0) is the only final product isolated.
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