Palladium-catalyzed direct ortho aroylation of 2-phenoxypyridines with aldehydes and catalytic mechanism investigation

Article abstract of DOI:10.1021/om501330h

A direct ortho aroylation of 2-phenoxypyridines with aldehydes leading to aryl ketones by the use of palladium(II) acetate, tert-butyl hydroperoxide, and chlorobenzene as the catalyst, oxidant, and solvent, respectively, is presented. Intra- and intermolecular kinetic isotope effects, radical trapping, and controlled experiments were carried out to support the proposed catalytic mechanism for the reaction. Syntheses of (2-hydroxyphenyl)(phenyl)methanones and 1-hydroxy-9H-fluoren-9-ones directed from ortho-aroylated 2-phenoxypyridines were demonstrated.

Full text of DOI:10.1021/om501330h

Article
pubs.acs.org/Organometallics
Palladium-Catalyzed Direct Ortho Aroylation of 2‑Phenoxypyridines
with Aldehydes and Catalytic Mechanism Investigation
Jean-Ho Chu,* Shih-Tien Chen, Meng-Fan Chiang, and Ming-Jung Wu*
Department of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan 804
S
* Supporting Information
ABSTRACT: A direct ortho aroylation of 2-phenoxypyridines
with aldehydes leading to aryl ketones by the use of palladium(II)
acetate, tert-butyl hydroperoxide, and chlorobenzene as the catalyst,
oxidant, and solvent, respectively, is presented. Intra- and inter-
molecular kinetic isotope effects, radical trapping, and controlled
experiments were carried out to support the proposed catalytic
mechanism for the reaction. Syntheses of (2-hydroxyphenyl)-
(phenyl)methanones and 1-hydroxy-9H-fluoren-9-ones directed
from ortho-aroylated 2-phenoxypyridines were demonstrated.
the directing group and direct intramolecular C−C bond coupling,
respectively.
INTRODUCTION
■
In the past decade, transition-metal-catalyzed C−H activation
and functionalization has received great attention because the
synthetic strategy can efficiently reduce operating steps and the
use of chemical reagents to target the desired molecular skeletons
in organic synthesis.1,2 Among these methods, the direct and
selective ortho aroylation of arenes has been frequently studied
by the employment of various aroyl sources, such as aldehydes,3
alcohols,4 α-keto acids,5 toluenes,6 diketones,7 carboxylic acids,8
benzylamines,9 and benzylic ethers.10 On the basis of these
developed strategies, a variety of aryl ketones can be readily
prepared via direct C−H functionalization. Particularly, the direct
ortho aroylation of 2-phenoxypyridines has revealed its potent
merit in the synthesis of biologically active natural products, such
as morintrifolins,11a tenellones,11b and monodictyphenone.11c
Although some synthetic methodologies toward the direct ortho
aroylation of 2-phenoxypyridines have been reported,3a,h,4c,6a
only the Cheng group3a demonstrated a few examples of
the direct ortho aroylation of 2-phenoxypyridines with
aldehydes under their optimal reaction conditions (1.5 equiv of
aldehydes, 10 mol % of Pd(OAc)2 in xylene at 120 °C). In this
context, they mainly used 2-phenylpyridines as modeling
substrates. In fact, aldehyde reagents have been widely used as
the aroyl source in the aroylation of arenes via C−H activation.12
However, the direct ortho aroylation of 2-phenoxypyridines with
aldehydes has still rarely been studied to date. In view of this, we
decided to do a systematic investigation of the above reac-
tion using palladium(II) acetate as the catalyst. In this study, a
very rational reaction mechanism via an aroyl palladium(III
or IV) π complex is presented on the basis of kinetic isotope
effects, radical trapping, and controlled experiments. In order to
demonstrate the synthetic merit of the presented methodology,
we subsequently carried out syntheses of (2-hydroxyphenyl)-
(phenyl)methanones and 1-hydroxy-9H-fluoren-9-ones directed
from ortho-aroylated 2-phenoxypyridines through the removal of
RESULTS AND DISCUSSION
■
Optimization for the Direct Ortho Aroylation of
2-Phenoxypyridines with Aldehydes. To optimize the
reaction conditions for the direct ortho aroylation of
2-phenoxypyridines 1, the reaction of 2-phenoxypyridine (1a)
with benzaldehyde (2a) in the presence of Pd(OAc)2 was
examined. Varying the oxidants and solvents toward the
reaction were carried out to afford the anticipated ortho-
benzoylated 2-phenoxypyridines 3a and 4a in different ratios.
These experimental results are summarized in Table 1. First of
all, we screened a variety of oxidants toward the reaction using
10 mol % of palladium(II) acetate as the catalyst in chloro-
benzene at 110 °C for 20 h (entries 1−11, Table 1). In these pre-
liminary results, the desired monobenzoylated 2-phenoxypyridine
3a and a concomitant product, dibenzoylated 2-phenoxy-
pyridine 4a, were obtained only when tert-butyl hydroperoxide
(TBHP) or tert-butyl peroxybenzoate (TBPB) was employed as
the oxidant. The product ratios (yields) of 3a and 4a were
determined to be 72:28 (71%) and 83:17 (48%), respectively
(entries 1 and 2, Table 1). In addition to oxidants, we also
evaluated solvent effects for the reaction using TBHP as the
oxidant (entries 12−20, Table 1) and found that chlorobenzene
was still the best reaction solvent (entry 1, Table 1). Moreover,
in terms of the influence of reaction temperatures, the reaction
of 1a with 2a at 140 °C eventually gave a 93% yield of 3a and
4a with the product ratio 57:43 (entry 25, Table 1), in which
chlorobenzene and TBHP were the solvent and oxidant,
respectively. In contrast, only 54−80% yields of 3a and 4a were
isolated when the reaction was carried out at around 80−120 °C
Received: December 30, 2014
© XXXX American Chemical Society
A
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5 in 5−98% total yields. These experimental results are summa-
rized in Table 2. In these reactions of 1a with 2a,b,p, we iso-
lated not only monoaroylated 2-phenoxypyridines 3a,b,p but also
diaroylated 2-phenoxypyridines 4a,b,p in the product ratios
3a:4a = 57:43, 3b:4b = 49:51, and 3p:4p = 54:46, respectively
(entries 1, 2, and 16, Table 2).14 In addition to that, only mono-
aroylated 2-phenoxypyridines 3c−o and 3q−t were isolated from
the reaction of 1a with 2c−o and 2q−t in 5−91% yields (entries
3−15 and 17−20, Table 2). On the basis of the above results, we
found that aldehydes 2 bearing an electron-withdrawing group
usually give lower product yields in comparison to that of a
normal or an electron-donating group in the direct ortho aroyla-
tion of 1a. Herein, the steric hindrance of aldehydes 2 also offers
the influence on the reactivity that usually results in low product
yields of 3, such as ortho-substituted aldehydes 2g,o,q,s. Interest-
ingly, we isolated trace amounts of 3,3′-(2-(pyridin-2-yloxy)-
isophthaloyl)dibenzaldehyde (4u) and 1,3-phenylenebis((2-
(pyridin-2-yloxy)phenyl)methanone) (5u) in the reaction of 1a
with isophthalaldehyde (2u) in addition to the anticipated product
3u (entry 21, Table 2). Finally, the structures of 3d and 4a were
determined by X-ray crystallography, as shown in Figure 1.15
In addition to starting substrate 1a, we also carried out the
reaction of 1b−k with 2a under the aforementioned reaction con-
ditions to afford a series of ortho-monobenzoylated 2-phenoxy-
pyridines 6 (majority) and ortho-dibenzoylated 2-phenoxypyr-
idines 7 (minority) in 31−98% total yields (entries 1−10, Table 3).
These experimental results are summarized in Table 3. In these
reactions, ortho-dibenzoylated 2-phenoxypyridines 7 were usually
generated, such as 7b,f,g,j, when starting substrates 1 contain a rela-
tive neutral substituent, such as 1b (R = 4-methyl), 1f (R =
4-chloro), 1g (R = 4-bromo), and 1j (R = 2-naphthyl) (entries 1,
5, 6, and 9, Table 3).14 In terms of substituent electronic effects,
starting substrates 1 bearing an electron-rich group (e.g., 1c, R =
OMe, entry 2, Table 3) usually give product yields higher than
that bearing an electron-poor group (e.g., 1d, R = NO2, entry 3,
Table 3).
Table 1. Optimization for the Direct Ortho Benzoylation of 1
a
oxidant
temp product ratio yield
c d
b
entry (amt (equiv))
solvent
(°C)
(3a:4a)
(%)
1
2
3
4
5
6
7
8
9
TBHP (2)
TPBP (2)
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
110
110
110
110
110
110
110
110
110
110
110
72:28
71
48
0
83:17
mCPBA (2)
K2S2O8 (2)
Na2S2O8 (2)
oxone (2)
0
0
0
(NH4)2S2O8 (2) chlorobenzene
0
H2O2 (2)
Ag2O (2)
chlorobenzene
chlorobenzene
0
0
10 PhI(OAc)2 (2) chlorobenzene
0
11 DDQ (2)
chlorobenzene
0
12 TBHP (2)
13 TBHP (2)
14 TBHP (2)
15 TBHP (2)
16 TBHP (2)
17 TBHP (2)
18 TBHP (2)
19 TBHP (2)
20 TBHP (2)
benzene
p-xylene
tert-butyl alcohol
DCE
110
110
110
110
110
110
110
110
110
85:15
91:9
65
62
50
45
21
38
4
73:27
93:7
DCM
98:2
acetonitrile
THF
97:3
100:0
DMSO
0
water
100:0
10
21 TBHP (2)
22 TBHP (2)
23 TBHP (2)
24 TBHP (2)
25 TBHP (2)
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
80
90
97:3
54
61
68
80
93
95:5
100
120
140
97:3
Investigation of Kinetic Isotope Effects.16a In order to
gain more insight into the reaction mechanism, we first carried
67:33
57:43
out an intramolecular kinetic isotope effect (KIEintra) study
26 TBHP (0)
27 TBHP (0.5)
28 TBHP (1)
29 TBHP (3)
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
140
140
140
140
0
35
87
97
16b
by the reaction of 1a-D2
with 2a (benzaldehyde) and 8a
93:7
(toluene) as the benzoyl coupling reagents, respectively, to give
66:34
32:68
(kH/kD)intra = 11.0 (for 2a) and 8.7 (for 8a) (see Scheme 1a).17
Meanwhile, an intermolecular kinetic isotope effect (KIEinter
experiment was also carried out by the reaction of a mixture of
1a and 1a-D5 with 2a and 8a, respectively, to give (kH/kD)inter
)
a
Abbreviations: TBHP, tert-butyl hydroperoxide; mCPBA, m-chloro-
peroxybenzoic acid; DDQ, 1,2-dichloro-4,5-dicyano-p-benzoquinone;
TBPB, tert-butyl peroxybenzoate. Abbreviations: DCE, 1,2-dichloro-
ethane; THF, tetrahydrofuran; DMSO, dimethyl sulfoxide. Product
ratio was determined by GC-FID for three runs. Product yield was
obtained as an average for three runs by GC-FID (using n-octadecane
as the internal standard).
=
b
1.0 (for 2a) and 1.4 (for 8a) (see Scheme 1b). To confirm
the intermolecular kinetic isotope effect of the reaction, we
additionally carried out the reaction of a mixture of 1a and 1a-
D5 with 4-methoxyphenyl benzaldehyde (2c) in toluene, and
the (kH/kD)inter value was determined to be 1.5 (see Scheme 1c).
This result is consistent with that of benzaldehyde (2a) in
chlorobenzene and toluene (8a), respectively (see Scheme 1b).
On the basis of the above KIE studies, we believe that the
ortho C−H bond cleavage of 2-phenoxypyridines 1 is not
involved in the rate-determining steps of the reaction. In
contrast, the binding of 1 with palladium ion is recognized as
the key rate-determining step for the direct ortho aroylation of
1 with 2.18
c
d
(entries 21−24, Table 1). Finally, we screened the amount of
TBHP from 0 to 3 equiv toward the reaction (entries 26−29,
Table 1) and found that the use of 2 and 3 equiv of TBHP
was able to give excellent yields (93−97%) of 3a and 4a with
the product ratios 57:43 and 32:68, respectively (entries 28 and 29,
Table 1). On the basis of the above results, we decided to use 10
mol % of Pd(OAc)2, 2 equiv of TBHP, and 1.5 equiv of aldehyde 2
in chlorobenzene13 at 140 °C for 20 h as the optimal reaction
conditions for the direct ortho aroylation of 2-phenoxylpyridines 1.
Substrate Scope. With the optimized reaction conditions
in hand, we subsequently carried out the direct ortho aroylation
of 2-phenoxypyridine (1a) with a variety of aldehydes 2 to afford
ortho-aroylated 2-phenoxypyridines 3 with minor products 4 and
Effect of Radical Scavengers on the Reactivity. To
examine whether the reaction proceeds via a radical process, we
subsequently carried out the radical trapping experiment
through the reaction of 1a with 2a in the presence of 1,1-
diphenylethylene (DPE), 3,5-di-tert-butyl-4-hydroxytoluene
B
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Table 2. Direct Ortho Aroylation of 1a with 2
C
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Table 2. continued
a
b
The product ratio was determined by GC-FID for three runs. The product yield was determined as an average by GC-FID for three runs (using
n-octadecane as the internal standard), and the isolated yield is reported in parentheses.
(BHT), and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO),
respectively. These experimental results are summarized in
Table 4. When 1−3 equiv of the above radical scavengers was
individually added to the reaction mixture of 1a with 2a in the
presence of TBHP (2 equiv), the product yield of 3a and 4a
was found to be gradually decreased to trace to 23% yields
(entries 2−10, Table 4). These results strongly imply that the
reaction takes place via a radical process.
Controlled Experiments. In addition to the above kinetic
isotope effect and radical trapping studies, we also carried
out the following controlled experiments, that is, the reaction
of 2-phenoxypyridine palladacycle (I)2d with benzaldehyde
(2a), 4-methoxyphenyl aldehyde (2c) and 4-nitrophenyl aldehyde
(2d), respectively, in the presence or absence of TBHP
(see Scheme 2). However, only a 28% yield of 3a was isolated
from the reaction of I with 2a in the presence of TBHP, whereas
the anticipated products 3c,d were not obtained. Meanwhile,
as expected, products 3a,c,d were not produced when TBHP
was not added to the reaction. In view of the above studies,
we believe that the dimeric palladacycle I is not the key inter-
mediate in the palladium-catalyzed direct ortho aroylation of
2-phenoxypyridines 1 with aldehydes 2 using TBHP as the oxi-
dant, because higher product yields are usually observed for the
reaction of palladacycles with coupling reagents.2 The reaction
of I with 2a to give product 3a might be explained as shown
in Figure 2. When the dimeric palladacycle I is heated to 140 °C,
it might dissociate to monomeric palladium complex II and
then oxidize to the palladium(III or IV) intermediate III by the
D
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form the π complex V. Subsequently, the aroyl radical 2•
(generated from the reaction of aldehydes 2 with TBHP via
one-electron abstraction) reacts with the palladium(II) center
of complex V, which undergoes a redox process to generate the
aroyl palladium(III or IV) π complex VI. The π complex VI is
quickly converted to complex VII via ortho C−H bond
insertion by palladium(III or IV) and releases an acetic acid.
Finally, the desired products 3 and 6 are produced by the
reductive elimination of complex VII, and palladium(II) acetate
is regenerated to continue the catalytic cycle.
For the reaction, we considered another reaction path, as shown
in the middle of Figure 3: that is, the reaction of palladium(II)
acetate with the aroyl radical 2• to produce the aroyl palladium(III
or IV) complex VIII, which further binds substrate 1 to form
the π complex VI. However, the reaction path does not seem to
be supported by the above stoichiometric reaction of aldehyde 2
with palladium(II) acetate in the presence of TBHP, because the
bis(aroyl)palladium(IV) complex IV is believed to immediately
form and eventually produce the benzoic anhydride 9 on treat-
ment with TBHP. In contrast, the coordination of 1 with
palladium(II) acetate generates complex V, which might be
able to prohibit the formation of the bis(aroyl)palladium
complex IV and give the key proposed intermediate VI from
the interaction of V with 2•.
Synthetic Applications. To demonstrate the potential
merit of monoaroylated 2-phenoxypyridines 3 in organic syn-
thesis, we herein chose compounds 3a,c,d as modeling sub-
strates to synthesize compounds 10 and 11. These experi-
mental results are showed in Scheme 4. First, we removed the
pyridinyl group of 3a,c,d by the treatment of methyl trifluoro-
methanesulfonate (MeOTf) and sodium methoxide (NaOMe)
to afford (2-hydroxyphenyl)(phenyl)methanones 10a (76%)
and 10c (71%), but the anticipated product 10d (R = NO2)
was not obtained; instead, 2-(dimethoxy(4-nitrophenyl)-
methyl)phenol (12d) was isolated in 34% yield. For the forma-
tion of 12d, we believe this is because the nitro group promotes
the ketal formation on the carbonyl group of 3d or 10d.20
Moreover, we employed compounds 10a,c as the precursors to
synthesize 1-hydroxy-9H-fluoren-9-ones 11a (24%) and 11c
(21%) via palladium-catalyzed intramolecular C−C bond
coupling on the basis of the reaction conditions developed by
the Cheng and Shi groups (10 mol % of Pd(OAc)2, 1.5 equiv of
Ag2O with/without 2.5 equiv of K2CO3 in TFA).21 Although
the preliminary yields of desired products 11a,c are not high
enough in terms of synthetic practicability, we have successfully
demonstrated the feasibility for the direct transformation of
10 to 11 via double C−H activation and intramolecular C−C
coupling. The optimization of reaction conditions is still in
progress in our laboratory and will be reported in due course.
Finally, the structure of compound 11c was secured by X-ray
crystallography, as shown in Figure 4.15
Figure 1. ORTEP drawings of (a) compound 3d and (b) compound
4a.15 All hydrogen atoms are omitted for clarity.
benzoyl radical 2a•. Finally, compound 3a was generated
through the reductive elimination of intermediate III.
On the basis of the above experimental results, we suspected
that an aroyl palladium π complex might be a key intermediate
in the course of this reaction. In order to evaluate the possibility
of the proposed aroyl palladium π complex, we carried out the
stoichiometric reaction of aldehyde 2 (e.g., 2a,c) with palladium(II)
acetate in the presence of TBHP (2 equiv) at 140 °C in
chlorobenzene and attempted to isolate the palladium complex.
However, the experimental results showed that benzoic anhydride
9 (e.g., 9a,c) was produced as a major product (80−85% yield)
without forming any anticipated palladium complexes (see
Scheme 3). For the controlled reaction, we presented a possible
mechanism toward the formation of benzoic anhydride 9 from
aldehyde 2 as shown in Scheme 3. Initially, aldehyde 2 (e.g., 2a,c)
by the treatment of TBHP is converted to the aroyl radical
2•, and two aroyl radicals are subsequently bound to the
palladium(II) center to generate the bis(aroyl)palladium(IV)
complex IV. Then, intermediate IV is quickly transformed to
benzoic anhydride 9 (e.g., 9a,c) by the influence of TBHP
through the oxidation and reductive elimination processes.19
Although we did not obtain any aroyl palladium π complexes from
the above controlled reaction, the experimental results strongly
implied that the interaction between aldehyde 2 and palladium(II)
acetate indeed occurs in the presence of TBHP.
CONCLUSION
■
We have developed a convenient and efficient synthetic
methodology for the synthesis of ortho-aroylated 2-phenoxy-
pyridines by the reaction of 2-phenoxypyridines with a variety
of aryl aldehydes in the presence of 10 mol % of palladium(II)
acetate and 2 equiv of tert-butyl hydroperoxide. A rational
catalytic mechanism for the reaction is presented on the basis of
a series of kinetic isotope effect, radical trapping, and controlled
experiments. Moreover, syntheses of (2-hydroxyphenyl)-
(phenyl)methanones and 1-hydroxy-9H-fluoren-9-ones directed
from the ortho-aroylated 2-phenoxypyridines were successfully
Proposed Mechanism for the Direct Ortho Aroylation
of 1 with 2. On the basis of the above mechanistic studies,
a rational catalytic mechanism for the direct ortho aroylation of
2-phenoxypyridines 1 with aldehydes 2 is presented as shown
in Figure 3. Initially, substrate 1 binds palladium(II) acetate to
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Table 3. Direct Ortho Benzoylation of 1 with 2a
a
b
The product ratio was determined by GC-FID for three runs. The product yield was determined as an average by GC-FID for three runs
(using n-octadecane as the internal standard), and the isolated yield is reported in parentheses.
Low- and high-resolution mass spectrometry was obtained by the
following ionization method and mass analyzer type: EI-magnetic
sector. Melting points were measured by using open capillary tubes
and are uncorrected.
demonstrated. Finally, we believe that the developed method-
ology can provide a useful synthetic tool for the synthesis of
aryl ketones, and the insights of this mechanistic investiga-
tion can benefit chemists to understand and develop related
synthetic reactions.
General Procedure for the Synthesis of Compounds 3−7. A
well-stirred solution of 2-phenoxypyridines 1 with aldehydes 2 by
the addition of Pd(OAc)2 (5 mg, 0.02 mmol) and TBHP (36 mg,
0.40 mmol) in toluene (2 mL) was heated to 140 °C for 20 h. After
it was cooled to room temperature, the reaction solution was filtered
through a pad of Celite and the filtrate was washed with water
(10 mL). The aqueous layer was then extracted with ethyl acetate
(10 mL × 3). The organic layers were combined, dried over MgSO4,
filtered, and evaporated under vacuum. The residue was purified by
silica gel chromatography using n-hexane/ethyl acetate (15/1 to 10/1)
as the eluent to give products 3-7. These amounts of 1 and 2 are given
as follows. 2-Phenoxypyridines: 1a, 34 mg, 0.20 mmol for 3−5; 1b,
37 mg, 0.20 mmol for 6b and 7b; 1c, 40 mg, 0.20 mmol for 6c; 1d,
EXPERIMENTAL SECTION
General Considerations. Solvents and reagents were purchased
from commercial suppliers and used without purification. H NMR
■
1
spectra were measured on 300 and 500 MHz NMR spectrometers.
Natural-abundance 13C NMR spectra were measured by using 300
and 500 MHz NMR spectrometers operating at 75 and 125 MHz,
respectively. Chemical shifts are given in parts per million (ppm) and
coupling constants J in hertz (Hz) for both nuclei, with the solvent
(usually CDCl3) peak as an internal standard. The reference peak for
1H is δ 7.26 for chloroform, and for 13C it is the central peak at δ 77.0.
F
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Scheme 1. Investigation of (a) Intramolecular and (b, c)
Intermolecular Kinetic Isotope Effects
Table 4. Effect of Radical Scavengers in the Direct Ortho
Aroylation of 1 with 2
a
b
entry radical scavenger (amt (equiv)) product ratio (3a:4a) yield (%)
1
57:43
94:6
93
2
DPE (1)
64
3
DPE (2)
96:4
52
4
DPE (3)
90:10
97:3
23
5
BHT (1)
54
6
BHT (2)
100:0
100:0
84:16
100:0
100:0
27
7
BHT (3)
trace
63
8
TEMPO (1)
TEMPO (2)
TEMPO (3)
9
32
10
trace
a
b
The product ratio was determined by GC-FID for three runs. The
product yield was determined as an average by GC-FID for three runs
(using n-octadecane as the internal standard).
Scheme 2. Reaction of 2-Phenoxypyridine Palladacycle I
with Aldehydes 2a,c,d
59 mg, 0.20 mmol for 6h; 1i, 44 mg, 0.20 mmol for 6i; 1j, 44 mg,
0.20 mmol for 6j and 7j; 1k, 43 mg, 0.20 mmol for 6k. Aldehydes: 2a,
32 mg, 0.30 mmol for 3a and 4a; 2b, 36 mg, 0.30 mmol for 3b and 4b;
2c, 41 mg, 0.30 mmol for 3c; 2d, 45 mg, 0.30 mmol for 3d; 2e, 52 mg,
0.30 mmol for 3e; 2f, 45 mg, 0.30 mmol for 3f; 2g, 37 mg, 0.30 mmol
for 3g; 2h, 37 mg, 0.30 mmol for 3h; 2i, 37 mg, 0.30 mmol for 3i; 2j,
42 mg, 0.30 mmol for 3j; 2k, 42 mg, 0.30 mmol for 3k; 2l, 56 mg,
0.30 mmol for 3l; 2m, 56 mg, 0.30 mmol for 3m; 2n, 70 mg,
0.30 mmol for 3n; 2o, 50 mg, 0.30 mmol for 3o; 2p, 40 mg, 0.30 mmol
for 3p and 4p; 2q, 40 mg, 0.30 mmol for 3q; 2r, 50 mg, 0.30 mmol for
3r; 2s, 50 mg, 0.30 mmol for 3s; 2t, 59 mg, 0.30 mmol for 3t; 2u,
40 mg, 0.30 mmol for 3u, 4u, and 5. All product yields were determined
by GC-FID using n-octadecane as the internal standard and shown
as follows: 3a, 53% (44 mg, 0.16 mmol); 3b, 48% (41 mg, 0.14 mmol);
3c, 91% (83 mg, 0.27 mmol); 3d, 10% (10 mg, 0.030 mmol); 3e, 16%
(17 mg, 0.05 mmol); 3f, 61% (60 mg, 0.19 mmol); 3g, 34% (29 mg,
0.10 mmol); 3h, 88% (77 mg, 0.26 mmol); 3i, 90% (79 mg, 0.27 mmol);
3j, 86% (81 mg, 0.26 mmol); 3k, 85% (80 mg, 0.26 mmol); 3l, 80%
(85 mg, 0.24 mmol); 3m, 83% (89 mg, 0.25 mmol); 3n, 68% (80 mg,
0.20 mmol); 3o, 45% (46 mg, 0.14 mmol); 3p, 53% (49 mg, 0.16 mmol);
43 mg, 0.2 mmol for 6d; 1e, 38 mg, 0.20 mmol for 6e: 1f, 41 mg,
0.20 mmol for 6f and 7f; 1g, 50 mg, 0.20 mmol for 6g and 7g; 1h,
G
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Organometallics
Article
to give the following products: 10a, 76% (30 mg, 0.15 mmol); 10c,
71% (32 mg, 0.14 mmol), and 12d, 34% (20 mg, 0.070 mmol). Sub-
sequently, a well-stirred solution of 10a or 10c (40 mg, 0.20 mmol),
Pd(OAc)2 (5 mg, 0.02 mmol), and Ag2O (70 mg, 0.30 mmol) with or
without K2CO3 (69 mg, 0.50 mmol) in trifluoroacetic acid (0.5 mL)
was heated to 140 °C for 24 h. After the mixture was cooled to room
temperature, water (20 mL) was added and the mixed solution was
further extracted with ethyl acetate (15 mL × 3). The organic layers
were combined, dried over MgSO4, and evaporated under vacuum.
The residue was purified by silica gel chromatography using n-hexane/
ethyl acetate (30/1 to 10/1) as the eluent to give the follow-
ing products: 11a, 24% (10 mg, 0.050 mmol); 11c, 21% (9 mg,
0.04 mmol).
Characterization Data of Compounds 3−7 and 9−12.
Phenyl(2-(pyridin-2-yloxy)phenyl)methanone (3a): white solid;
mp 78−79 °C; Rf = 0.43 (n-hexane/ethyl acetate 5/1); 1H NMR
(300 MHz, CDCl3) δ 6.60 (d, J = 8.4 Hz, 1 H), 6.87 (dd, J = 6.0,
6.0 Hz, 1 H), 6.28−6.35 (m, 4 H), 7.44−7.50 (m, 2 H), 7.53−7.60
(m, 2 H), 7.75 (d, J = 7.5 Hz, 2 H), 8.01 (dd, J = 4.8, 4.8 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 111.4 (CH), 118.5 (CH), 122.7 (CH),
124.7 (CH), 128.0 (CH × 2), 129.8 (CH × 2), 130.3 (CH), 132.1
(CH), 132.2 (Cq), 132.7 (CH), 137.5 (Cq), 139.3 (CH), 147.0 (CH),
151.6 (Cq), 162.9 (Cq), 195.3 (Cq); MS (EI, m/z) 275 (M+, 1),
274 (M+ - 1, 3), 198 (45), 170 (100); HRMS (EI-magnetic sector)
m/z [M+] calcd for C18H13NO2 275.0946, found 275.0945.
Figure 2. Possible explanation for the formation of 3a in the reaction
of I with 2a.
(2-(Pyridin-2-yloxy)phenyl)(p-tolyl)methanone (3b): white solid;
mp 81−82 °C; Rf = 0.60 (n-hexane/ethyl acetate 3/1); 1H NMR
(300 MHz, CDCl3) δ 2.36 (s, 3 H), 6.64 (d, J = 8.1 Hz, 1 H), 6.86
(dd, J = 6.0, 6.0 Hz, 1 H), 7.13 (d, J = 8.1 Hz, 2 H), 7.24−7.31
(m, 2 H), 7.50−7.57 (m, 3 H), 7.67 (d, J = 8.1 Hz, 1 H), 8.01 (d, J =
3.6 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 21.6 (CH3), 111.5
(CH), 118.4 (CH), 122.6 (CH), 124.6 (CH), 128.7 (CH × 2), 130.0
(CH × 2), 130.1 (CH), 131.8 (CH), 132.5 (Cq), 134.8 (Cq), 139.2
(CH), 143.7 (Cq), 147.0 (CH), 151.5 (Cq), 163.0 (Cq), 194.9 (Cq);
MS (EI, m/z) 289 (M+, 1), 198 (40), 170 (100); HRMS (EI-magnetic
sector) m/z [M+] calcd for C19H15NO2 289.1103, found 289.1101.
(4-Methoxyphenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3c):
Scheme 3
1
colorless viscous liquid; Rf = 0.55 (n-hexane/ethyl acetate 2/1); H
NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 6.66 (d, J = 8.4 Hz, 1 H),
6.80−6.89 (m, 2 H), 7.28 (dd, J = 9.0, 9.0 Hz, 2 H), 7.49−7.57 (m,
3 H), 7.77 (d, J = 6.0 Hz, 2 H), 8.02 (d, J = 6.0 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 55.3 (CH3), 111.5 (CH), 113.3 (CH × 2), 118.4
(CH), 122.6 (CH), 124.6 (CH), 129.9 (CH), 130.3 (Cq), 131.6
(CH), 132.3 (CH × 2), 132.7 (Cq), 139.3 (CH), 147.1 (CH), 151.4
(Cq), 136.1 (Cq), 163.4 (Cq), 193.9 (Cq); MS (EI, m/z) 305
(M+, 1), 304 (M+ - 1, 2), 198 (21), 170 (100), 135 (16); HRMS
(EI-magnetic sector) m/z [M+] calcd for C19H15NO3 305.1052, found
305.1052.
3q, 54% (49 mg, 0.16 mmol); 3r, 53% (53 mg, 0.16 mmol); 3s, 5%
(10 mg, 0.020 mmol); 3t, 60% (66 mg, 0.18 mmol); 3u, 64% (58 mg,
0.19 mmol); 4a, 40% (33 mg, 0.12 mmol); 4b, 49% (61 mg, 0.15 mmol);
4p, 45% (57 mg, 0.13 mmol); 4u, 0.5% (1 mg, 0.002 mmol); 5, 0.5%
(1 mg, 0.002 mmol); 6b, 59% (34 mg, 0.12 mmol); 6c, 91% (56 mg,
0.18 mmol); 6d, 47% (30 mg, 0.09 mmol); 6e, 82% (47 mg, 0.16 mmol);
6f, 71% (44 mg, 0.14 mmol); 6g, 82% (58 mg, 0.16 mmol); 6h, 95%
(76 mg, 0.19 mmol); 6i, 98% (64 mg, 0.19 mmol); 6j, 70% (46 mg,
0.14 mmol); 6k, 31% (20 mg, 0.060 mmol); 7b, 19% (15 mg, 0.04
mmol); 7f, 18% (17 mg, 0.04 mmol); 7g, 3% (3 mg, 0.007 mmol); 7j,
26% (22 mg, 0.050 mmol).
Synthesis of Compounds 10−12. A well-stirred solution of
3a,c,d (55 mg, 0.2 mmol) in toluene (2 mL) with the addition of
MeOTf (44.8 μL, 0.4 mmol) was heated to 100 °C under nitrogen gas
for 2 h. After it was cooled to room temperature, the reaction solution
was evaporated under vacuum. The residue was dissolved in methanol
(5 mL) and then sodium (110 mg, 4.80 mmol) was added to the
above solution, which was further heated under reflux for 15 min. After
the mixture was cooled, water (20 mL) was added to the solution
and the mixture was further extracted with ethyl acetate (15 mL × 3).
The organic layers were combined, dried over MgSO4, filtered, and
evaporated under vacuum. The residue was purified by silica gel chro-
matography using n-hexane/ethyl acetate (20/1 to 10/1) as the eluent
(4-Nitrophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3d): yel-
low solid; mp 121−122 °C; Rf = 0.53 (n-hexane/ethyl acetate 3/1);
1H NMR (300 MHz, CDCl3) δ 6.56 (d, J = 8.1 Hz, 1 H), 6.91 (dd, J =
6.0, 6.0 Hz, 1 H), 7.27 (d, J = 8.1 Hz, 1 H), 7.36 (dd, J = 6.0, 6.0 Hz,
1 H), 7.52 (dd, J = 9.0, 9.0 Hz, 1 H), 7.61−7.66 (m, 2 H), 7.87 (d, J =
8.7 Hz, 2 H), 8.00 (d, J = 3.0 Hz, 1 H), 8.14 (d, J = 9.0 Hz, 2 H); 13C
NMR (125 MHz, CDCl3) δ 111.4 (CH), 118.9 (CH), 122.8 (CH),
123.2 (CH × 2), 125.0 (CH), 130.3 (CH x× 2), 130.4 (Cq), 130.9
(Cq), 133.3 (CH), 139.6 (CH), 142.7 (Cq), 147.0 (CH), 149.9 (Cq),
151.8 (Cq), 162.3 (Cq), 193.7 (Cq); MS (EI, m/z) 320 (M+, 1), 319
(M+ - 1, 2), 198 (19), 170 (100); HRMS (EI-magnetic sector) m/z
[M+] calcd for C18H12N2O2 320.0797, found 320.0798.
(2-(Pyridin-2-yloxy)phenyl)(4-(trifluoromethyl)phenyl)methan-
one (3e): yellow solid; mp 64−65 °C; Rf = 0.45 (n-hexane/ethyl
acetate 5/1); 1H NMR (300 MHz, CDCl3) δ 6.54 (d, J = 8.4 Hz, 1 H),
6.89 (dd, J = 5.7, 5.7 Hz, 1 H), 7.28 (d, J = 9.0 Hz, 1 H), 7.37 (dd, J =
3.9, 3.9 Hz, 1 H), 7.48−7.64 (m, 5 H), 7.82 (d, J = 8.1 Hz, 2 H), 7.99
(d, J = 3.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 111.4 (CH),
118.7 (CH), 123.0 (CH), 124.9 (CH), 125.0 (CH), 125.0 (Cq), 129.7
(CH × 2), 130.4 (CH), 131.4 (Cq), 132.9 (CH), 133.8 (dd, JC−F
=
31.5 Hz, Cq), 139.5 (CH), 140.6 (Cq), 146.9 (CH), 151.7 (Cq),
162.6 (Cq), 194.4 (Cq) ; MS (EI, m/z) 343 (M+, 1), 198 (27),
H
DOI: 10.1021/om501330h
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Figure 3. Proposed mechanism for the direct ortho aroylation of 1 with 2 to 3 and 6.
Scheme 4. Synthetic Applications of Compound 3
Figure 4. ORTEP drawing of compound 11c.
170 (100); HRMS (EI-magnetic sector) m/z [M+] calcd for C19H12NO2F3
343.0820, found 343.0818.
1-(4-(2-(Pyridin-2-yloxy)benzoyl)phenyl)ethanone (3f): Colorless
viscous liquid; Rf = 0.43 (n-hexane/ethyl acetate 3/1); 1H NMR
(300 MHz, CDCl3) δ 2.60 (s, 3 H), 6.57 (d, J = 8.1 Hz, 1 H), 6.88
(dd, J = 6.0, 6.0 Hz, 1 H), 7.27 (d, J = 6.9 Hz, 1 H), 7.34 (dd, J = 7.5,
7.5 Hz, 1 H), 7.53 (dd, J = 7.2, 7.2 Hz, 1 H), 7.58−7.63 (m, 2 H), 7.81
(d, J = 8.1 Hz, 2 H), 7.89 (d, J = 8.4 Hz, 2 H), 8.00 (d, J = 3.3 Hz, 1
H); 13C NMR (125 MHz, CDCl3) δ 26.9 (CH3),111.4 (CH), 118.7
(CH), 122.8 (CH), 124.8 (CH), 127.9 (CH × 2), 129.7 (CH × 2),
130.6 (CH), 131.6 (Cq), 132.7 (CH), 139.4 (CH), 139.7 (Cq), 141.1
(Cq), 147.0 (CH), 151.7 (Cq), 162.7 (Cq), 194.7 (Cq), 197.6 (Cq);
I
DOI: 10.1021/om501330h
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MS (EI, m/z) 317 (M+, 3), 170 (100), 161 (59); HRMS (EI-magnetic
sector) m/z [M+] calcd for C20H15NO3 317.1052, found 317.1052.
(2-Fluorophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3g): yel-
7.86 (s, 1 H), 8.02 (d, J = 4.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 111.4 (CH), 118.7 (CH), 122.2 (Cq), 122.8 (CH), 124.8 (CH),
128.2 (CH), 129.6 (CH), 130.3 (CH), 131.4 (Cq), 132.5 (CH), 132.6
(CH), 135.5 (CH), 139.4 (CH), 139.4 (Cq), 147.0 (CH), 151.7 (Cq),
162.7 (Cq), 193.9 (Cq); MS (EI, m/z) 355 (M+ + 2, 1), 353 (M+, 1),
170 (56), 97 (35), 85 (57), 71 (88), 57 (100); HRMS (EI-magnetic
sector) m/z [M+] calcd for C18H12NO279Br 353.0051, found 353.0050.
(4-Bromophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3m):
white solid; mp 85−86 °C; Rf = 0.43 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 6.62 (d, J = 8.4 Hz, 1 H), 6.89 (dd, J =
6.0, 6.0 Hz, 1 H), 7.26 (dd, J = 6.0, 6.0 Hz, 1 H), 7.33 (dd, J = 9.0 Hz,
1 H), 7.46 (d, J = 8.7 Hz, 2 H), 7.51−7.57 (m, 3 H), 7.62 (d, J =
8.7 Hz, 2 H), 8.00 (d, J = 4.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 111.5 (CH), 118.7 (CH), 122.7 (CH), 124.8 (CH), 127.9 (Cq),
130.1 (CH), 131.2 (CH × 2), 131.3 (CH × 2), 131.7 (Cq),
132.4 (CH), 136.3 (Cq), 139.4 (CH), 147.0 (CH), 151.6 (Cq), 162.7
(Cq), 194.3 (Cq); MS (EI, m/z) 355 (M+ + 2, 1), 353 (M+, 1), 198
(25), 170 (100); HRMS (EI-magnetic sector) m/z [M+] calcd for
C18H12NO279Br 353.0051, found 353.0050.
(4-Iodophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3n): yel-
low solid; mp 97−98 °C; Rf = 0.45 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 6.62 (d, J = 8.1 Hz, 1 H), 6.89 (dd, J =
6.0, 6.0 Hz, 1 H), 7.27 (dd, J = 3.7, 3.7 Hz, 2 H), 7.34 (dd, J = 4.2,
4.2 Hz, 1 H), 7.46 (d, J = 7.2 Hz, 2 H), 7.51−7.60 (m, 3 H), 7.68 (d,
J = 8.7 Hz, 2 H), 8.00 (d, J = 4.8 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 100.7 (Cq), 111.5 (CH), 118.6 (CH), 122.8 (CH), 124.8
(CH), 130.2 (CH), 131.1 (CH × 2), 131.7 (Cq), 132.4 (CH), 136.9
(Cq), 137.3 (CH × 2), 139.4 (CH), 147.0 (CH), 151.6 (Cq), 162.8
(Cq), 194.6 (Cq); MS (EI, m/z) 400 (M+, 1), 170 (100); HRMS (EI-
magnetic sector) m/z [M+] calcd for C18H12NO2I 400.9913, found
400.9913.
1
low viscous liquid; Rf = 0.53 (n-hexane/ethyl acetate 3/1); H NMR
(300 MHz, CDCl3) δ 6.47 (d, J = 8.4 Hz, 1 H), 6.88 (dd, J = 6.0,
6.0 Hz, 1 H), 6.96−7.06 (m, 2 H), 7.22 (dd, J = 8.1 Hz, 1 H), 7.31−
7.50 (m, 4 H), 7.59 (dd, J = 7.8, 7.8 Hz, 1 H), 7.74 (d, J = 7.5 Hz,
1 H), 8.02 (d, J = 3.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 110.9
(CH), 115.9 (d, JC−F = 21.4 Hz, CH), 118.4 (CH), 122.8 (CH), 123.8
(d, JC−F = 3.6 Hz, CH), 125.1 (CH), 127.7 (d, JC−F = 12.3 Hz, Cq),
130.5 (CH), 130.8 (d, JC−F = 2.3 Hz, CH), 132.7 (Cq), 133.3 (CH),
133.4 (d, JC−F = 12.3 Hz, CH), 139.2 (CH), 147.0 (CH), 152.0
(Cq), 160.8 (d, JC−F = 254.3 Hz, Cq), 162.9 (Cq), 191.7 (Cq) ; MS
(EI, m/z) 293 (M+, 2), 292 (M+ − 1, 7), 198 (44), 170 (100), 123
(36), 95 (38), 78 (31); HRMS (EI-magnetic sector) m/z [M+] calcd
for C18H12NO2F 293.0852, found 293.0850.
(3-Fluorophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3h): yel-
1
low viscous liquid; Rf = 0.40 (n-hexane/ethyl acetate 5/1); H NMR
(300 MHz, CDCl3) δ 6.62 (d, J = 8.4 Hz, 1 H), 6.89 (dd, J = 6.2, 6.2
Hz, 1 H), 7.16 (dd, J = 8.2, 8.2 Hz, 1 H), 7.26−7.35 (m, 3 H), 7.44 (d,
J = 9.0 Hz, 1 H), 7.51−7.61 (m, 4 H), 8.00 (d, J = 3.9 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 111.4 (CH), 116.2 (d, JC−F = 22.4 Hz,
CH), 118.6 (CH), 119.7 (d, JC−F = 21.4 Hz, CH), 122.8 (CH), 124.8
(CH), 125.6 (d, JC−F = 2.8 Hz, CH), 129.6 (d, JC−F = 7.8 Hz, CH),
130.2 (CH),131.7 (Cq), 132.5 (CH), 139.4 (CH), 139.7 (d, JC−F
=
6.4 Hz, CH), 147.0 (CH), 151.6 (Cq), 162.4 (d, JC−F = 246.1 Hz, Cq),
162.8 (Cq), 194.0 (d, JC−F = 1.9 Hz, Cq); MS (EI, m/z) 293 (M+, 1),
292 (M+ - 1, 2), 198 (13), 170 (100); HRMS (EI-magnetic sector)
m/z [M+] calcd for C18H12NO2F 293.0852, found 293.0850.
(4-Fluorophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3i):
white solid; mp 55−56 °C; Rf = 0.43 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 6.62 (d, J = 8.4 Hz, 1 H), 6.89 (dd, J =
6.4, 6.4 Hz, 1 H), 6.99 (dd, J = 9.0, 9.0 Hz, 1 H), 7.26 (d, J = 7.6 Hz,
1 H), 7.32 (dd, J = 7.6, 7.6 Hz, 1 H), 7.50−7.60 (m, 3 H), 7.79 (dd,
J = 9.0, 9.0 Hz, 2 H), 8.01 (d, J = 4.8 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 111.5 (CH), 115.1 (d, JC−F = 22.2 Hz, CH), 118.6 (CH),
122.7 (CH), 124.8 (CH), 130.1 (CH), 132.0 (Cq), 132.2 (CH), 132.4
(d, JC−F = 9.1 Hz, CH), 133.8 (Cq), 133.8 (Cq), 139.4 (CH), 147.0
(CH), 151.5 (Cq), 162.8 (Cq), 165.6 (d, JC−F = 253.3 Hz, Cq); MS
(EI, m/z) 293 (M+, 1), 292 (M+ - 1, 3), 198 (26), 170 (100), 95 (23);
HRMS (EI-magnetic sector) m/z [M+] calcd for C18H12NO2F
293.0852, found 293.0851.
(3-Chlorophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3j):
white solid; Rf = 0.43 (n-hexane/ethyl acetate 5/1); 1H NMR
(300 MHz, CDCl3) δ 6.61 (d, J = 8.1 Hz,1 H), 6.89 (dd, J = 3.9,
3.9 Hz, 1 H), 7.25 (dd, J = 6.0, 6.0 Hz, 2 H), 7.33 (dd, J = 7.2, 7.2 Hz,
1 H), 7.41 (d, J = 2.1 Hz, 1 H), 7.53−7.65 (m, 4 H), 7.71 (s, 1 H),
8.02 (d, J = 6.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 111.4
(CH), 118.6 (CH), 122.8 (CH), 124.8 (CH), 127.8 (CH), 129.3
(CH), 129.6 (CH), 130.2 (CH), 131.5 (Cq), 132.5 (CH × 2), 134.3
(Cq), 139.2 (Cq), 139.4 (CH), 147.0 (CH), 151.7 (Cq), 162.7 (Cq),
194.0 (Cq); MS (EI, m/z) 311 (M+ + 2, 1), 309 (M+, 3), 198 (51),
170 (100); HRMS (EI-magnetic sector) m/z [M+] calcd for
C18H12NO235Cl 309.0557, found 309.0558.
(4-Chlorophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3k):
white solid; mp 74−75 °C; Rf = 0.43 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 6.62 (d, J = 8.4 Hz,1 H), 6.89 (dd, J =
6.0, 6.0 Hz, 1 H), 7.24−7.34 (m, 4 H), 7.51−7.60 (m, 3 H), 7.70 (d,
J = 8.0 Hz, 2 H), 8.00 (d, J = 4.8 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 111.5 (CH), 118.6 (CH), 122.7 (CH), 124.8 (CH), 128.3
(CH × 2), 130.1 (CH), 131.1 (CH × 2), 131.8 (Cq), 132.4 (CH),
135.9 (Cq), 139.2 (Cq), 139.4 (CH), 147.0 (CH), 151.5 (Cq), 162.8
(Cq); MS (EI, m/z) 311 (M+ + 2, 1), 309 (M+, 3), 198 (23), 170
(100); HRMS (EI-magnetic sector) m/z [M+] calcd for
C18H12NO235Cl 309.0557, found 309.0558.
(3-Bromophenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3l): col-
orless viscous liquid; Rf = 0.45 (n-hexane/ethyl acetate 5/1); 1H NMR
(300 MHz, CDCl3) δ 6.61 (d, J = 8.1 Hz, 1 H), 6.90 (dd, J = 6.0,
6.0 Hz, 1 H), 7.20 (dd, J = 7.8, 7.8 Hz, 1 H), 7.25−7.28 (m, 1 H), 7.33
(d, J = 7.6 Hz, 1 H), 7.51−7.61 (m, 4 H), 7.68 (d, J = 7.6 Hz, 1 H),
(Naphthalen-1-yl)(2-(pyridin-2-yloxy)phenyl)methanone (3o):
yellow solid; mp 101−102 °C; Rf = 0.38 (n-hexane/ethyl acetate
1
5/1); H NMR (300 MHz, CDCl3) δ 6.26 (d, J = 8.4 Hz, 1 H),
6.74(dd, J = 6.0, 6.0 Hz, 1 H), 7.22−7.35 (m, 4 H), 7.46 (dd, J = 6.3
Hz, 2 H), 7.57−7.63 (m, 2 H), 7.73 (d, J = 7.5 Hz, 1H), 7.78−7.81
(m, 1 H), 7.85 (d, J = 8.1 Hz, 1 H), 7.96 (d, J = 5.0 Hz, 1 H), 8.30−
8.34 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 111.0 (CH), 118.2
(CH), 123.4 (CH), 124.1 (CH), 125.0 (CH), 125.6 (CH), 126.1
(CH), 127.4 (CH), 128.1 (CH), 129.5 (CH), 130.5 (Cq), 131.3
(CH), 132.0 (CH), 133.1 (CH), 133.5 (Cq), 133.5 (Cq), 136.1 (Cq),
139.0 (CH), 146.7 (CH), 152.1 (Cq), 162.8 (Cq), 196.6 (Cq); MS
(EI, m/z) 325 (M+, 8), 198 (25), 170 (100), 127 (25); HRMS (EI-
magnetic sector) m/z [M+] calcd for C22H15NO2 325.1103, found
325.1103.
(3,5-Dimethylphenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3p):
white solid; mp 114−115 °C; Rf = 0.43 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 2.24 (s, 6 H), 6.63 (d, J = 8.4 Hz,
1 H), 6.88 (dd, J = 6.0, 6.0 Hz, 1 H), 7.08 (s, 1 H), 7.25−7.33 (m,
2 H), 7.37 (s, 2 H), 7.54 (dd, J = 15.4, 15.4 Hz, 3 H), 8.05 (d, J =
3.6 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 21.0 (CH3 × 2), 111.6
(CH), 118.4 (CH), 122.8 (CH), 124.6 (CH), 127.6 (CH × 2), 130.2
(CH), 131.8 (CH), 132.5 (Cq), 134.4 (CH), 137.6 (Cq), 137.7 (Cq),
139.2 (CH), 147.0 (CH), 151.6 (Cq), 163.0 (Cq), 195.8 (Cq); MS
(EI, m/z) 303 (M+, 1), 198 (28), 170 (100); HRMS (EI-magnetic
sector) m/z [M+] calcd for C20H17NO2 303.1259, found 303.1261.
(2,4-Dimethylphenyl)(2-(pyridin-2-yloxy)phenyl)methanone (3q):
white solid; mp 68−69 °C; Rf = 0.58 (n-hexane/ethyl acetate 5/1); 1H
NMR (300 MHz, CDCl3) δ 2.27 (s, 3 H), 2.28 (s, 3 H), 6.53 (d, J =
8.4 Hz, 1 H), 6.84−6.88 (m, 2 H), 6.93 (s, 1 H), 7.21−7.32 (m, 3 H),
7.50−7.62 (m, 3 H), 8.01 (d, J = 7.2 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 20.4 (CH3 × 2), 21.4 (CH3 × 2), 111.2 (CH), 118.2 (CH),
123.2 (CH), 124.9 (CH), 125.6 (CH), 130.9 (CH), 131.8 (CH), 132.6
(CH), 133.6 (Cq), 135.5 (Cq), 138.4 (Cq), 139.1 (CH), 141.4 (Cq),
146.9 (CH), 151.8 (Cq), 163.1 (Cq), 196.7 (Cq); MS (EI, m/z) 303
(M+, 12), 177 (100), 170 (86), 161 (78), 57 (51); HRMS (EI-magnetic
sector) m/z [M+] calcd for C20H17NO2 303.1259, found 303.1257.
(3,5-Dimethoxyphenyl)(2-(pyridin-2-yloxy)phenyl)methanone
(3r): white solid; mp 108−109 °C; Rf = 0.43 (n-hexane/ethyl acetate
1
5/1); H NMR (300 MHz, CDCl3) δ 3.74 (s, 3 H), 6.56 (s, 3 H),
J
DOI: 10.1021/om501330h
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
6.67 (dd, J = 8.1 Hz, 1 H), 6.89 (dd, J = 7.0 Hz, 3 H), 7.25−7.32
(m, 2 H), 7.53−7.57 (m, 3 H), 8.04 (d, J = 4.2 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 55.5 (CH3 × 2), 105.6 (CH), 107.4 (CH × 2),
111.5 (CH), 118.4 (CH), 122.8 (CH), 124.5 (CH), 130.2 (CH),
132.0 (CH), 132.1 (Cq), 139.3 (CH), 139.5 (Cq), 147.0 (CH), 151.6
(Cq), 160.4 (Cq), 163.0 (Cq), 195.0 (Cq); MS (EI, m/z) 335
(M+, 5), 198 (35), 170 (100); HRMS (EI-magnetic sector) m/z [M+]
calcd for C20H17NO4 335.1158, found 335.1156.
(2,4-Dimethoxyphenyl)(2-(pyridin-2-yloxy)phenyl)methanone
(3s): yellow solid; mp 127−128 °C; Rf = 0.63 (n-hexane/ethyl acetate
1/1); 1H NMR (300 MHz, CDCl3) δ 3.61 (s, 3 H), 3.80 (s, 3 H), 6.34
(dd, J = 10.8, 10.8 Hz, 2 H), 6.48 (dd, J = 8.1 Hz, 1 H), 6.86 (dd, J =
5.7, 5.7 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.28 (dd, J = 6.3, 6.3 Hz,
2 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.49 (dd, J = 16.0,16.0 Hz, 1H), 7.63
(d, J = 8.1 Hz, 1 H), 8.03 (d, J = 4.8 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 55.4 (CH3), 55.6 (CH3),111.0 (CH), 118.0 (CH), 122.0
(Cq), 122.5 (CH), 124.8 (CH), 130.2 (CH), 131.9 (CH), 133.2
(CH), 134.6 (Cq), 139.0 (CH), 147.0 (CH), 151.4 (Cq), 160.6 (Cq),
163.4 (Cq), 164.0 (Cq); MS (EI, m/z) 335 (M+, 15), 198 (75), 170
(100), 165 (95); HRMS (EI-magnetic sector) m/z [M+] calcd for
C20H17NO4 335.1158, found 335.1160.
6.14 (d, J = 8.1 Hz, 1 H), 6.72 (dd, J = 6.0, 6.0 Hz, 1 H), 7.05 (s, 1 H),
7.26 (dd, J = 7.5, 7.5 Hz, 1 H), 7.32 (s, 4 H), 7.43 (dd, J = 7.5, 7.5 Hz,
1 H), 7.71 (d, J = 7.8 Hz, 2 H), 7.84 (d, J = 3.6 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 21.0 (CH3 × 4), 110.8 (CH), 118.2 (CH), 124.7
(CH × 4), 132.4 (CH), 133.8 (Cq), 134.5 (CH), 137.2 (Cq), 137.6
(Cq), 138.9 (CH), 146.1 (CH), 148.7 (Cq), 162.2 (Cq), 195.3 (Cq);
MS (EI, m/z) 435 (M+, 1), 340 (47), 302 (100), 177 (84), 161 (66);
HRMS (EI-magnetic sector) m/z [M+] calcd for C29H25NO3
435.1834, found 435.1832.
3,3′-(2-(Pyridin-2-yloxy)isophthaloyl)dibenzaldehyde (4u): yellow
viscous liquid; Rf = 0.65 (n-hexane/ethyl acetate 1/1); 1H NMR
(300 MHz, CDCl3) δ 5.97 (d, J = 8.1 Hz, 1 H), 6.71 (dd, J = 6.0,
6.0 Hz, 1 H), 7.19 (dd, J = 7.2, 7.2 Hz, 1 H), 7.46−7.56 (m, 3 H), 7.75
(d, J = 4.5 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 2H), 7.97 (dd,J = 9.5, 9.5 Hz,
4 H), 8.14 (s, 2 H); 13C NMR (125 MHz, CDCl3) δ 110.4 (CH),
118.9 (CH), 125.5 (CH), 129.0 (CH × 2), 131.3 (CH × 2), 132.6
(CH × 2), 132.9 (Cq), 133.2 (CH × 2), 134.9 (CH × 2), 136.1 (Cq),
138.0 (Cq), 139.5 (CH), 146.1 (CH), 148.8 (Cq), 161.6 (Cq), 191.1
(CH × 2), 193.5 (Cq); MS (EI, m/z) 435 (M+, 1), 302 (100); HRMS
(EI-magnetic sector) m/z [M+] calcd for C27H17NO5 435.1107, found
435.1107.
1,3-Phenylenebis((2-(pyridin-2-yloxy)phenyl)methanone) (5): yel-
low viscous liquid; Rf = 0.65 (n-hexane/ethyl acetate 1/1); H NMR
(2-(Pyridin-2-yloxy)phenyl)(3,4,5-trimethoxyphenyl)methanone
(3t): white solid; mp 132−133 °C; Rf = 0.65 (n-hexane/ethyl acetate
1/1); 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 6 H), 3.86 (s, 3 H), 6.68
(d, J = 8.4 Hz, 1 H), 6.91(dd, J = 6.0, 6.0 Hz, 1 H), 7.03 (s, 2 H), 7.27
(dd, J = 4.0, 4.0 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 1 H), 7.55 (d, J =
7.6 Hz, 3 H), 8.04 (d, J = 4.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 56.1 (CH3 × 2), 60.8 (CH3), 111.7 (CH), 118.6 (CH), 122.7 (CH),
124.5 (CH), 130.0 (CH), 131.9 (Cq), 132.1 (Cq), 132.7 (CH), 139.4
(CH), 142.2 (Cq), 146.9 (CH), 151.5 (Cq), 152.6 (Cq), 162.9 (Cq),
194.4 (Cq); MS (EI, m/z) 365 (M+, 21), 340 (48), 170 (100), 177
(80), 161 (57); HRMS (EI-magnetic sector) m/z [M+] calcd for
C21H19NO5 365.1263, found 365.1263.
3-(2-(Pyridin-2-yloxy)benzoyl)benzaldehyde (3u): white solid; mp
116−117 °C; Rf = 0.55 (n-hexane/ethyl acetate 2/1); 1H NMR
(300 MHz, CDCl3) δ 6.54 (d, J = 8.4 Hz, 1 H), 6.88 (dd,J = 6.0, 6.0 Hz,
1 H), 7.27(d, J = 8.1 Hz, 1 H), 7.36 (dd, J = 7.6, 7.6 Hz, 1 H), 7.46−
7.53 (m, 2 H), 7.61 (dd, J = 7.8, 7.8 Hz, 2 H), 8.00 (dd, J = 13.0,
13.0 Hz, 3H), 8.19 (s,1 H); 13C NMR (125 MHz, CDCl3) δ 111.4
(CH), 118.7 (CH), 122.8 (CH), 125.0 (CH), 128.9 (CH), 130.4
(CH), 131.3 (Cq), 131.7 (CH), 132.2 (CH), 132.8 (CH), 135.0
(CH), 136.1 (Cq), 138.5 (Cq), 139.5 (CH), 147.0 (CH), 151.7 (Cq),
162.6 (Cq), 191.4 (CH), 194.2 (Cq); MS (EI, m/z) 303 (M+, 1), 170
(100); HRMS (EI-magnetic sector) m/z [M+] calcd for C19H13NO3
303.0895, found 303.0894.
1
(300 MHz, CDCl3) δ 6.57 (d, J = 8.4 Hz, 2 H), 6.86 (dd, J = 6.0,
6.0 Hz, 2 H), 7.21−7.32 (m, 5 H), 7.47−7.59 (m, 6 H), 7.83 (d, J =
7.8 Hz, 2 H), 7.98 (d, J = 4.2 Hz, 2H), 8.13 (s, 1 H); 13C NMR (125
MHz, CDCl3) δ 111.3 (CH × 2), 118.6 (CH × 2), 122.7 (CH × 2),
124.7 (CH × 2), 127.8 (CH), 130.3 (CH × 2), 130.4 (CH), 131.5
(Cq), 132.5 (CH × 2), 133.7 (CH × 2), 137.7 (Cq), 139.3 (CH × 2),
147.0 (CH × 2), 151.7 (Cq), 162.8 (Cq), 194.3 (Cq); MS (EI, m/z)
472 (M+, 1), 170 (100); HRMS (EI-magnetic sector) m/z [M+] calcd
for C30H20N2O4 472.1423, found 472.1423.
(5-Methyl-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (6b):
1
colorless viscous liquid; Rf = 0.6 (n-hexane/ethyl acetate 5/1); H
NMR (300 MHz, CDCl3) δ 3.03 (s, 3 H), 6.55 (d, J = 8.4 Hz, 1 H),
6.84 (dd,J = 6.8, 6.8 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 7.29−7.38
(m, 4 H), 7.43−7.50 (m, 2 H), 7.74 (d, J = 7.6 Hz, 2 H), 8.01 (d, J =
4.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 20.8 (CH3), 111.2
(CH), 118.2 (CH), 128.0 (CH × 2), 130.0 (CH × 2), 130.5 (CH),
132.0 (Cq), 132.7 (CH), 132.8 (CH), 134.5 (Cq), 137.6 (Cq),
139.1 (CH), 147.0 (CH), 149.2 (Cq), 163.1 (Cq), 195.5 (Cq); MS
(EI, m/z) 289 (M+, 1), 184 (100); HRMS (EI-magnetic sector) m/z
[M+] calcd for C19H15NO2 289.1103, found 289.1105.
(5-Methoxy-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (6c):
white solid; mp 99−100 °C; Rf = 0.5 (n-hexane/ethyl acetate 3/1);
1H NMR (300 MHz, CDCl3) δ 3.84 (s, 3 H), 6.52 (d, J = 8.1 Hz,
1 H), 6.85 (dd, J = 6.0, 6.0 Hz, 1 H), 7.07−7.12 (m, 2 H), 7.20 (d, J =
8.7 Hz, 1 H), 7.32 (dd, J = 8.2, 8.2 Hz, 2 H), 7.44−7.50 (m, 2 H), 7.74
(d, J = 7.8 Hz, 2 H), 8.01 (d, J = 4.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 55.8 (CH3), 111.1 (CH), 114.4 (CH), 118.0 (CH), 118.2
(CH), 124.1 (CH), 128.0 (CH × 2), 129.7 (CH × 2), 132.8 (CH),
132.9 (Cq), 137.3 (Cq), 139.3 (CH), 144.7 (Cq), 146.8 (CH), 156.3
(Cq), 163.2 (Cq), 195.0 (Cq); MS (EI, m/z) 305 (M+, 1), 200 (100);
HRMS (EI-magnetic sector) m/z [M+] calcd for C19H15NO3
305.1052, found 305.1055.
(2-(Pyridin-2-yloxy)-1,3-phenylene)bis(phenylmethanone) (4a):
white solid; mp 136−137 °C; Rf = 0.35 (n-hexane/ethyl acetate
1
5/1); H NMR (300 MHz, CDCl3) δ 6.12 (d, J = 8.1 Hz, 1 H), 6.70
(dd, J = 6.0, 6.0 Hz, 1 H), 7.21−7.31 (m, 5 H), 7.44 (dd, J = 6.0,
6.0 Hz, 3 H), 7.71 (d, J = 7.7 Hz, 6 H), 7.78 (d, J = 4.8 Hz, 2 H); 13C
NMR (125 MHz, CDCl3) δ 110.7 (CH), 118.4 (CH), 124.8 (CH),
128.0 (CH × 4), 129.7 (CH × 4), 132.5 (CH × 2), 132.9 (CH × 2),
133.6 (Cq), 137.1 (Cq), 139.1 (CH), 146.1 (CH), 148.3 (Cq), 162.0
(Cq), 194.8 (Cq); MS (EI, m/z) 379 (M+, 2), 302 (30), 274 (100);
HRMS (EI-magnetic sector) m/z [M+] calcd for C18H13NO2
379.1208, found 379.1207.
(5-Nitro-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (6d): col-
1
orless viscous liquid; Rf = 0.5 (n-hexane/ethyl acetate 3/1); H NMR
(2-(Pyridin-2-yloxy)-1,3-phenylene)bis(p-tolylmethanone) (4b):
1
(300 MHz, CDCl3) δ 6.71 (d, J = 8.1 Hz, 1 H), 6.98 (dd, J = 6.0,
6.0 Hz, 1 H), 7.36−7.46 (m, 3 H), 7.53 (d, J = 7.2 Hz, 1 H), 7.60 (dd,
J = 7.6, 7.6 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 2 H), 8.02 (d, J = 4.2 Hz,
1 H), 8.39−8.43 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 112.1
(CH), 119.8 (CH), 130.0 (CH), 125.8 (CH), 126.9 (CH), 128.4
(CH × 2), 129.8 (CH × 2), 132.6 (Cq), 133.6 (CH), 136.3 (Cq),
140.0 (CH), 143.9 (Cq), 147.0 (CH), 156.6 (Cq), 161.7 (Cq), 192.8
(Cq); MS (EI, m/z) 320 (M+, 2), 243 (51), 215 (95), 177 (100), 161
(95); HRMS (EI-magnetic sector) m/z [M+] calcd for C18H12N2O4
320.0797, found 320.0800.
colorless viscous liquid; Rf = 0.55 (n-hexane/ethyl acetate 3/1); H
NMR (300 MHz, CDCl3) δ 2.34 (s, 6 H), 6.22 (d, J = 8.4 Hz, 1 H),
6.70 (dd, J = 6.0, 6.0 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 4 H), 7.26−7.30
(m, 2 H), 7.41 (dd, J = 7.2 Hz, 1 H), 7.63−7.68 (m, 6 H), 7.78 (d, J =
3.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 21.6 (CH3 × 2), 111.0
(CH), 118.3 (CH), 124.6 (CH), 128.7 (CH × 4), 130.0 (CH × 4),
132.1 (CH × 2), 133.9 (Cq), 134.5 (Cq), 139.1 (CH), 143.8 (Cq),
146.1 (CH), 148.6 (Cq), 162.2 (Cq); MS (EI, m/z) 407 (M+, 7), 288
(100); HRMS (EI-magnetic sector) m/z [M+] calcd for C27H21NO3
407.1521, found 407.1522.
(5-Fluoro-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (6e): yel-
(2-(Pyridin-2-yloxy)-1,3-phenylene)bis((3,5-dimethylphenyl)-
1
methanone) (4p): white solid; mp 195−196 °C; Rf = 0.40 (n-hexane/
low viscous liquid; Rf = 0.5 (n-hexane/ethyl acetate 5/1); H NMR
1
ethyl acetate 5/1); H NMR (300 MHz, CDCl3) δ 2.21 (s, 12 H),
(300 MHz, CDCl3) δ 6.57 (d, J = 8.4 Hz, 1 H), 6.87 (dd, J = 6.0,
K
DOI: 10.1021/om501330h
Organometallics XXXX, XXX, XXX−XXX

Organometallics
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6.0 Hz, 1 H), 7.26 (d, J = 6.6 Hz, 3 H), 7.33 (dd, J = 7.6, 7.6 Hz, 2 H),
7.46−7.52 (m, 2 H), 7.74 (d,J = 7.8 Hz, 2 H), 7.99 (d, J = 4.2 Hz,
Phenyl(6-(pyridin-2-yloxy)benzo[d][1,3]dioxol-5-yl)methanone
(6k): colorless viscous liquid; Rf = 0.53 (n-hexane/ethyl acetate 3/1);
1H NMR (300 MHz, CDCl3) δ 6.08 (s, 2 H), 6.46 (d, J = 8.4 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 111.3 (CH), 116.6 (d, JC−F
=
1 H), 6.75 (s, 1 H), 6.87 (dd, J = 6.0, 6.0 Hz, 1 H), 7.06 (s, 1 H), 7.30
(d, J = 7.5 Hz, 1 H), 7.40−7.49 (m, 2 H), 7.68 (d, J = 7.5 Hz, 2 H),
8.04 (d, J = 3.9 Hz, 1 H);13C NMR (125 MHz, CDCl3) δ 102.3
(CH2), 104.6 (CH), 109.3 (CH), 111.2 (CH), 118.3 (CH), 125.0
(Cq), 127.9 (CH × 2), 129.4 (CH × 2), 132.3 (CH), 138.2 (Cq),
139.2 (CH), 144.7 (Cq), 146.9 (CH), 147.5 (Cq), 150.8 (Cq), 163.1
(Cq), 194.4 (Cq); MS (EI, m/z) 319 (M+, 1), 214 (100); HRMS
(EI-magnetic sector) m/z [M+] calcd for C19H13NO4 319.0845, found
319.0847.
24.1 Hz, CH), 118.5 (CH), 118.8 (d, JC−F = 23.3 Hz, CH), 124.6 (d,
JC−F = 8.1 Hz, CH), 128.1 (CH × 2), 129.7 (CH × 2), 133.1 (CH),
133.6 (Cq), 136.9 (Cq), 139.3 (CH), 146.8 (CH), 147.2 (Cq), 159.1
(d, JC−F = 244.1 Hz, Cq), 162.8 (Cq), 193.8 (Cq); MS (EI, m/z) 293
(M+, 1), 188 (100); HRMS (EI-magnetic sector) m/z [M+] calcd for
C18H12NO2F 293.0852, found 293.0850.
(5-Chloro-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (6f):
white solid; mp 73−74 °C; Rf = 0.55 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 6.59 (d, J = 8.1 Hz, 1 H), 6.89 (dd, J =
6.0, 6.0 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H),
7.34 (dd, J = 7.5 Hz, 2 H), 7.46−7.53 (m, 4 H), 7.74 (d, J = 7.5 Hz,
2 H), 8.00 (d, J = 3.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 111.4 (CH), 118.8 (CH), 124.2 (CH × 2), 128.1 (CH × 4), 129.7
(CH × 4), 129.8 (CH × 2), 130.1 (Cq), 131.9 (CH × 2), 133.1
(CH × 2), 133.6 (Cq), 136.9 (Cq), 139.5 (CH × 2), 146.8 (CH),
150.0 (Cq), 162.5 (Cq), 193.7 (Cq); MS (EI, m/z) 311 (M+ + 2, 1),
309 (M+, 3), 204 (100); HRMS (EI-magnetic sector) m/z [M+] calcd
for C18H12NO235Cl 309.0557, found 309.0559.
(5-Methyl-2-(pyridin-2-yloxy)-1,3-phenylene)bis(phenylmethanone)
(7b): Colorless viscous liquid; Rf = 0.5 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3 H), 6.05 (d, J = 8.1 Hz,
1 H), 6.69 (dd, J = 6.0, 6.0 Hz, 1 H), 7.20 (dd, J = 7.8, 7.8 Hz, 1 H),
7.27 (dd, J = 7.6, 7.6 Hz, 4 H), 7.42 (dd, J = 7.0, 7.0 Hz, 2 H), 7.53
(s, 2 H), 7.71 (d, J = 7.2 Hz, 4 H), 7.79 (d, J = 5.0 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 20.7 (CH3), 110.6 (CH), 118.2 (CH), 127.9
(CH × 4), 129.6 (CH × 4), 132.8 (CH × 2), 132.9 (CH × 2), 133.3
(Cq), 134.8 (Cq), 137.2 (Cq), 139.0 (CH), 146.0 (CH), 146.4 (Cq),
162.1 (Cq), 195.0 (Cq); MS (EI, m/z) 393 (M+, 1), 316 (34), 288
(100), 105 (40), 77 (41); HRMS (EI-magnetic sector) m/z [M+]
calcd for C26H19NO3 393.1365, found 393.1362.
(5-Bromo-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (6g):
yellow solid; mp 98−99 °C; Rf = 0.50 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 6.58 (d, J = 8.1 Hz, 1 H), 6.89 (dd, J =
6.3, 6.3 Hz, 1 H), 7.17 (d, J = 9.0 Hz, 1 H), 7.34 (dd, J = 9.0, 9.0 Hz,
2 H), 7.50 (dd, J = 7.5, 7.5 Hz, 2 H), 7.64−7.67 (m, 2 H), 7.74 (d, J =
7.5 Hz, 2 H), 8.00 (d, J = 3.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 111.5 (CH), 117.6 (Cq), 118.8 (CH), 124.6 (CH), 128.1 (CH × 2),
129.8 (CH × 2), 132.7 (CH), 133.1 (CH), 133.9 (Cq), 134.8 (CH),
136.8 (Cq), 139.5 (CH), 146.8 (CH), 150.5 (Cq), 162.5 (Cq), 193.6
(Cq); MS (EI, m/z) 355 (M+ + 2, 1), 353 (M+, 1), 248 (100), 177
(53), 161 (43), 85 (77), 57 (77), 71 (76); HRMS (EI-magnetic
sector) m/z [M+] calcd for C18H12NO279Br 353.0051, found 353.0053.
(5-Iodo-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (6h): yel-
(5-Chloro-2-(pyridin-2-yloxy)-1,3-phenylene)bis(phenylmethanone)
(7f): colorless viscous liquid; Rf = 0.50 (n-hexane/ethyl acetate 5/1);
1H NMR (300 MHz, CDCl3) δ 6.11 (d, J = 8.4 Hz, 1 H), 6.72 (dd, J =
6.0, 6.0 Hz, 1 H), 7.21−7.33 (m, 6 H), 7.46 (dd, J = 7.2, 7.2 Hz, 2 H),
7.68−7.77 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 110.7 (CH),
118.7 (CH), 128.1 (CH × 4), 129.7 (CH × 4), 130.5 (CH), 131.9
(CH × 2), 133.2 (CH × 2), 135.1 (Cq), 136.5 (Cq), 139.2 (CH),
146.0 (CH), 147.1 (Cq), 161.7 (Cq), 193.3 (Cq); MS (EI, m/z)
415 (M+ + 2, 2), 413 (M+, 6), 411 (M+ - 2, 100), 229 (59); HRMS
(EI-magnetic sector) m/z [M+] calcd for C25H16NO335Cl 413.0819,
found 413.0822.
1
low viscous liquid; Rf = 0.50 (n-hexane/ethyl acetate 5/1); H NMR
(5-Bromo-2-(pyridin-2-yloxy)-1,3-phenylene)bis(phenylmethanone)
(300 MHz, CDCl3) δ 6.58 (d, J = 8.4 Hz, 1 H), 6.89 (dd, J = 6.0,
6.0 Hz, 1 H), 7.04 (d, J = 9.0 Hz, 1 H), 7.34 (dd, J = 7.5, 7.5 Hz, 2 H),
7.50 (dd, J = 14.4, 14.4 Hz, 2 H), 7.73 (d, J = 7.8 Hz, 2 H), 7.85 (d, J =
6.9 Hz, 2 H), 8.00 (d, J = 4.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 88.1 (Cq), 111.5 (CH), 118.8 (CH), 124.9 (CH), 128.1 (CH × 2),
129.7 (CH × 2), 133.1 (CH), 134.3 (Cq), 136.9 (Cq), 138.6 (CH),
139.4 (CH), 140.8 (CH), 146.9 (CH), 151.4 (Cq), 162.5 (Cq), 193.6
(Cq); MS (EI, m/z) 400 (M+, 1), 340 (28), 296 (100), 177 (48), 161
(36), 57 (35); HRMS (EI-magnetic sector) m/z [M+] calcd for
C18H12NO2I 400.9913, found 400.9912.
Phenyl(1-(pyridin-2-yloxy)naphthalen-2-yl)methanone (6i): yel-
low solid; Rf = 0.43 (n-hexane/ethyl acetate 5/1); 1H NMR
(300 MHz, CDCl3) δ 6.65 (d, J = 8.4 Hz, 1 H), 6.84 (dd, J = 6.0,
6.0 Hz, 1 H), 7.35 (dd, J = 7.2, 7.2 Hz, 2 H), 7.47−7.64 (m, 5 H), 7.73
(d, J = 7.5 Hz, 2 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.91 (dd, J = 7.2 Hz, 2
H), 8.03 (d, J = 8.4 Hz, 1 H);13C NMR (125 MHz, CDCl3) δ 110.5
(CH), 118.2 (CH), 123.3 (CH), 125.1 (CH), 126.0 (CH), 126.9
(CH), 127.9 (CH), 127.9 (Cq), 128.0 (CH × 3), 128.2 (Cq), 129.9
(CH × 2), 132.7 (CH), 136.0 (Cq), 137.7 (Cq), 139.3 (CH), 147.1
(CH), 147.9 (Cq), 195.6 (Cq); MS (EI, m/z) 325 (M+, 2), 220 (100),
177 (65); HRMS (EI-magnetic sector) m/z [M+] calcd for
C22H15NO2 325.1103, found 325.1102.
Phenyl(3-(pyridin-2-yloxy)naphthalen-2-yl)methanone (6j): yel-
low solid; Rf = 0.43 (n-hexane/ethyl acetate 5/1); 1H NMR
(300 MHz, CDCl3) δ 6.69 (d, J = 8.1 Hz, 1 H), 6.86(dd,J = 6.0,
6.0 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 2 H), 7.49−7.59 (m, 4 H), 7.70
(s, 1 H), 7.79 (d, J = 7.2 Hz, 2 H), 7.83−7.90 (m, 2 H), 7.96 (d, J =
4.8 Hz, 1 H), 8.04 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ 111.5
(CH), 118.5 (CH), 119.5 (CH), 126.1 (CH), 127.4 (CH), 128.0
(CH), 128.0 (CH × 2), 128.6 (CH), 130.0 (CH × 2), 130.1 (Cq),
131.2 (CH), 132.1 (Cq), 132.8 (CH), 135.3 (Cq), 137.6 (Cq),
139.3 (CH), 147.0 (CH), 148.8 (Cq), 163.2 (Cq), 195.0 (Cq); MS
(EI, m/z) 325 (M+, 3), 220 (100); HRMS (EI-magnetic sector) m/z
[M+] calcd for C22H15NO2 325.1103, found 325.1103.
(7g): white solid; mp 128−129 °C; Rf = 0.42 (n-hexane/ethyl
1
acetate 5/1); H NMR (300 MHz, CDCl3) δ 6.10 (d, J = 8.1 Hz,
1 H), 6.72 (dd, J = 6.0, 6.0 Hz, 1 H), 7.21−7.34 (m, 5 H), 7.46
(dd, J = 7.2, 7.2 Hz, 2 H), 7.71 (d, J = 7.8 Hz, 4 H), 7.76 (d, J = 5.1
Hz, 1 H), 7.82 (s, 2 H); 13C NMR (125 MHz, CDCl3) δ 110.7
(CH), 117.8 (Cq), 118.7 (CH), 128.1 (CH × 4), 129.7 (CH × 4),
133.2 (CH × 2), 134.8 (CH × 2), 135.8 (Cq), 136.5 (Cq), 139.2
(CH), 146.0 (CH), 147.7 (Cq), 161.7 (Cq), 193.1 (Cq); MS (EI,
m/z) 461 (M+ + 4, 1), 459 (M+ + 2, 2), 457 (M+, 1), 354 (100),
352 (99), 177 (77), 161 (62), 105 (63), 77 (67), 57 (73); HRMS
(EI-magnetic sector) m/z [M+] calcd for C25H16NO379Br
457.0314, found 457.0311.
(2-(Pyridin-2-yloxy)naphthalene-1,3-diyl)bis(phenylmethanone)
1
(7j): yellow viscous liquid; Rf = 0.55 (n-hexane/ethyl acetate 3/1); H
NMR (300 MHz, CDCl3) δ 6.28 (d, J = 8.1 Hz, 1 H), 6.70 (dd, J =
6.0, 6.0 Hz, 1 H), 7.26−7.39 (m, 5 H), 7.43−7.55 (m, 4 H), 7.70 (dd,
J = 4.5, 4.5 Hz, 4 H), 7.77 (d, J = 7.5 Hz, 3 H), 7.86 (d, J = 7.5 Hz,
2 H), 7.97 (dd, J = 4.5, 4.5 Hz, 1 H), 7.95 (s, 1 H); 13C NMR (125
MHz, CDCl3) δ 110.8 (CH), 118.4 (CH), 125.0 (CH), 126.5 (CH),
128.0 (CH × 2), 128.3 (CH × 2), 128.8 (CH), 129.2 (CH), 129.5
(Cq), 129.7 (CH × 2), 130.0 (CH × 2), 130. Two (Cq), 132.2 (Cq),
132.5 (CH), 132.8 (CH), 132.8 (Cq), 133.6 (CH), 137.2 (CH), 137.3
(Cq), 139.1 (Cq), 145.4 (Cq), 146.2 (CH), 162.2 (Cq), 194.1 (Cq),
196.0 (Cq); MS (EI, m/z) 429 (M+, 1), 324 (55), 133 (36), 89 (100),
71 (85), 57 (78); HRMS (EI-magnetic sector) m/z [M+] calcd for
C29H19NO3 429.1365, found 429.1363.
Benzoic anhydride (9a):22 white solid; mp 42−43 °C; Rf = 0.61
1
(n-hexane/ethyl acetate 4/1); H NMR (300 MHz, CDCl3) δ 7.53
(dd, J = 7.8, 7.8 Hz, 4 H), 7.68 (dd, J = 7.4 Hz, 1 H), 8.17 (d, J = 7.8 Hz,
3 H); MS (EI, m/z) 226 (M+, 1), 198 (14), 105 (100), 77 (52), 51 (22).
4-Methoxybenzoic anhydride (9c):22 white solid; mp 88−89 °C;
Rf = 0.44 (n-hexane/ethyl acetate 3/1); 1H NMR (300 MHz, CDCl3)
δ 3.90 (s, 6 H), 6.98 (d, J = 9.0 Hz, 4 H), 8.10 (d, J = 9.0 Hz, 4 H);
MS (EI, m/z) 286 (M+, 10), 177 (48), 161 (37), 135 (100).
L
DOI: 10.1021/om501330h
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Organometallics
Article
(2-Hydroxyphenyl)(phenyl)methanone (10a): yellow viscous
liquid; Rf = 0.6 (n-hexane/ethyl acetate 15/1); H NMR (300 MHz,
ACKNOWLEDGMENTS
■
1
We thank the Ministry of Science and Technology of the
Republic of China (NSC 101-2113-M-110-014-MY3 and NSC-
100-2113-M-110-006-MY3) for financial support and Mr. Min-
Yuan Hung for his technical support and services in GC-MS at
the Center for Research Resources and Development of
Kaohsiung Medical University (Taiwan).
CDCl3) δ 6.88 (dd, J = 7.5, 7.5 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H),
7.51 (dd, J = 7.2, 7.2 Hz, 3 H), 7.58−7.61 (m, 2 H), 7.68 (d, J =
7.2 Hz, 2 H), 12.0 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ 118.4
(CH), 118.6 (CH), 119.1 (Cq), 128.3 (CH × 2), 129.1 (CH × 2),
131.9 (CH), 133.6 (CH), 136.3 (CH), 137.9 (Cq), 163.2 (Cq), 201.6
(Cq); MS (EI, m/z) 198 (M+, 77), 197 (M+ - 1, 100), 121 (55), 105
(29), 77 (36); HRMS (EI-magnetic sector) m/z [M+] calcd for
C13H10O2 198.0681, found 198.0681.
REFERENCES
■
(2-Hydroxyphenyl)(4-methoxyphenyl)methanone (10c): yellow
viscous liquid; Rf = 0.53 (n-hexane/ethyl acetate 6/1); 1H NMR
(300 MHz, CDCl3) δ 3.90 (s, 3 H), 6.99 (dd, J = 7.5, 7.5 Hz, 1 H),
7.00 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 8.4 Hz, 1 H), 7.49 (dd, J = 7.8,
7.8 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 8.7 Hz, 2 H),
11.96 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ 55.5 (CH3), 113.7
(CH × 2), 118.3 (CH), 118.5 (CH), 119.4 (Cq), 130.4 (Cq), 131.8
(CH × 2), 133.3 (CH), 135.8 (CH), 162.9 (Cq), 200.0 (Cq); MS
(EI, m/z) 228 (M+, 58), 135 (53), 108 (100); HRMS (EI-magnetic
sector) m/z [M+] calcd for C14H12O3 228.0786, found 228.0784.
1-Hydroxy-9H-fluoren-9-one (11a): yellow viscous liquid; mp
119−120 °C; Rf = 0.5 (n-hexane/ethyl acetate 6/1); 1H NMR
(300 MHz, CDCl3) δ 6.77(d,J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz,
1 H), 7.35 (dd, J = 8.7, 8.7 Hz, 1 H), 7.37 (dd, J = 7.8, 7.8 Hz, 1 H),
7.50 (dd, J = 13.5, 13.5 Hz, 2 H), 7.64 (d, J = 7.5 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 112.8 (CH), 117.4 (CH), 118.2 (CH), 121.0
(CH), 124.1 (CH), 129.1 (CH), 134.3 (Cq), 134.7 (CH), 137.5
(CH), 143.9 (Cq), 144.2 (Cq), 157.4 (Cq), 196.4 (Cq); MS (EI, m/z)
196 (M+, 100), 168 (70), 139 (55), 57 (47); HRMS (EI-magnetic
sector) m/z [M+] calcd for C13H8O2 196.0524, found 196.0522.
1-Hydroxy-6-methoxy-9H-fluoren-9-one (11c): yellow solid; mp
131−132 °C; Rf = 0.48 (n-hexane/ethyl acetate 5/1); 1H NMR
(300 MHz, CDCl3) δ 3.91 (s, 3 H), 6.76 (dd, J = 8.1, 8.1 Hz, 2 H), 7.02
(dd, J = 5.0, 5.0 Hz, 2 H), 7.34 (dd, J = 7.8, 7.8 Hz, 1 H), 7.59 (d, J =
8.4, 8.4 Hz, 1 H), 7.50 (dd, J = 13.5, 13.5 Hz, 2 H), 7.64 (d, J = 7.5 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 55.8 (CH3), 108.0 (CH), 112.7
(CH), 112.9 (CH), 118.4 (Cq), 118.4 (CH), 126.0 (CH), 127.0 (Cq),
136.8 (CH), 142.9 (Cq), 146.9 (Cq), 157.0 (Cq), 165.5 (Cq), 195.1
(Cq); MS (EI, m/z) 226 (M+, 100), 198 (25), 177 (25), 155 (46), 89
(77); HRMS (EI-magnetic sector) m/z [M+] calcd for C14H10O3
226.0630, found 226.0631.
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2-(Dimethoxy(4-nitrophenyl)methyl)phenol (12d): yellow viscous
1
liquid; Rf = 0.63 (n-hexane/ethyl acetate 6/1); H NMR (300 MHz,
CDCl3) δ 3.25 (s, 6 H), 6.79 (dd, J = 7.5, 7.5 Hz, 1 H), 6.88 (d, J =
8.1 Hz, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.18 (dd, J = 15.0, 15.0 Hz,
1 H), 7.73 (d, J = 8.7 Hz, 2 H), 8.18 (d, J = 8.7 Hz, 2 H), 8.84 (s, 1 H);
13C NMR (125 MHz, CDCl3) δ 49.8 (CH3 × 2), 103.8 (Cq), 117.9
(CH), 120.0 (CH), 123.0 (Cq), 123.5 (CH × 2), 127.7 (CH × 2),
128.8 (CH), 130.4 (CH), 147.7 (Cq), 148.0 (Cq), 155.5 (Cq); MS
(EI, m/z) 289 (M+, 1), 257 (53), 240 (81), 210 (100), 121 (55);
HRMS (EI-magnetic sector) m/z [M+] calcd for C15H15NO5
289.0950, found 289.0950.
́
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ASSOCIATED CONTENT
* Supporting Information
■
S
Text, tables, figures, and CIF files giving details of the preparation
of deuterium-labeled substrates 1a-D2 and 1a-D5, KIE operation
and calculation methods, X-ray crystal structures and X-ray
crystallographic data for 3d, 4a, and 11c, and 1H, 13C, and DEPT
NMR spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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H.; Guo, L.-N.; Duan, X.-H. Org. Lett. 2012, 14, 4358−4361. (c) Kim,
M.; Park, J.; Sharma, S.; Kim, A.; Park, E.; Kwak, J. H.; Jung, Y. H.;
Kim, I. S. Chem. Commun. 2013, 49, 925−927. (d) Park, J.; Kim, M.;
Sharma, S.; Park, E.; Kim, A.; Lee, S. H.; Kwak, J. H.; Jung, Y. H.; Kim,
I. S. Chem. Commun. 2013, 49, 1654−1656. (e) Sharma, S.; Kim, A.;
Park, E.; Park, J.; Kim, M.; Kwak, J. H.; Lee, S. H.; Jung, Y. H.; Kim, I.
S. Adv. Synth. Catal. 2013, 355, 667−672. (f) Yu, L.; Li, P.; Wang, L.
Chem. Commun. 2013, 49, 2368−2370. (g) Li, H.; Li, P.; Zhao, Q.;
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Org. Lett. 2013, 15, 2930−2933. (i) Li, Z.-Y.; Li, D.-D.; Wang, G.-W. J.
Org. Chem. 2013, 78, 10414−10420.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for J.-H.C.: j_hchu@yahoo.com.tw.
■
*E-mail for M.-J.W.: mijuwu@faculty.nsysu.edu.tw.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/om501330h
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Article
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spectroscopy in comparison to the standard spectrum of 1a.
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́
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(13) When the solvent optimization was carried out, toluene was also
employed into the reaction, but lower product yields were observed for
most cases, except for the reaction of 1a with 2a. According to
experimental results, an 86% yield of products 3a and 4a was given by
using toluene as the solvent. However, toluene was found to readily
transform into benzaldehyde by the treatment of TBHP. See: (a) Xu,
Z.; Xiang, B.; Sun, P. RSC Adv. 2013, 3, 1679−1682. (b) Yin, Z.; Sun,
P. J. Org. Chem. 2012, 77, 11339−11344. Thus, we believe that part of
the 86% total yield results from the reaction of 1a with toluene.
Meanwhile, the use of toluene as the reaction solvent will result in a
complex product distribution when different aldehydes are evaluated.
(14) Regarding the formation of diaroylated products such as 4a,b,p
and even 4u (see Table 2) and 7b,f,g,j (see Table 3) in the reaction,
we suspect that the “weak interaction” in the second direct aroylation
process might play as an important factor. Please see the presentation
below and refer to the review paper on the discussion of “weak
coordination in the direct C−H functionalization”: Engle, K. M.; Mei,
T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788−802.
Nevertheless, this is only our assumption toward the situation.
(15) Copies of the deposited crystallographic data (CCDC-1041437
(3d), CCDC-1041438 (4a), and CCDC-1041439 (11c)) can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(16) (a) For the determination of kinetic isotope effects in the
reaction, please see the Supporting Information. (b) When we
synthesized compound 1a-D2 from 2-(2-bromophenoxy)pyridine by
N
DOI: 10.1021/om501330h
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