Bis[ N, N ′-(2-indanolyl)]-1,5-diazacyclooctane as Unique Metal Ligand: Self-Assembly of Palladium Nanoparticles and Catalytic Reactivity on C-C Bond Formation

Article abstract of DOI:10.1055/s-0036-1590956

A previously unreported 1,5-diazacyclooctane-palladium(II) complex was synthesized using bis[ N, N ′-(2-indanolyl)]-1,5-diazacyclooctane, which was readily prepared via a novel [4+4] homocyclization of the unsaturated imine intermediate generated from acrolein and 1-amino-2-indanol. Interestingly, the 1,5-diazacyclooctane-palladium(II) complex self-assembled to form palladium nanoparticles. This approach readily provided palladium nanoparticles simply by heating a mixture of palladium(II) acetate and bis[ N, N ′-(2-indanolyl)]-1,4-diazacyclooctane in dichloroethane at mild temperatures. The 1,5-diazacyclooctane-derivative-palladium nanoparticles were successfully deployed in synthetic applications as a heterogeneous catalyst, facilitating Suzuki coupling and a challenging C-C bond formation via C(sp ³)-H activation under low catalyst loading conditions.

Full text of DOI:10.1055/s-0036-1590956

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
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Synthesis
K. Fujiki, K. Tanaka
Paper
Bis[N,N′-(2-indanolyl)]-1,5-diazacyclooctane as Unique Metal
Ligand: Self-Assembly of Palladium Nanoparticles and Catalytic
Reactivity on C–C Bond Formation
Katsumasa Fujikia
Katsunori Tanaka*a,b,c
a
Biofunctional Synthetic Chemistry Laboratory, RIKEN, 2-1
Hirosawa, Wako, Saitama 351-0198, Japan
kotzenori@riken.jp
Biofunctional Chemistry Laboratory, Alexandar Butlerov
b
Institute of Chemistry, Kazan Federal University, 18
Kremlyovskaya Street, Kazan 420008, Russian Federation
JST-PRESTO, 2-1 Hirosawa, Wako, Saitama 351-0198,
c
Japan
Received: 08.09.2017
Accepted after revision: 17.10.2017
Published online: 13.11.2017
rial. Support materials modified with metal ligand struc-
tures, such as phosphine and N-heterocyclic carbene
9
(NHC),10 enhance the reactivity of a NP catalyst and enable
coupling reactions on low-reactivity substrates. Metal NPs
supported by a chiral ligand, xylose-backbone-modified
colloidal Pd-NPs, were prepared by Chaudret and co-work-
ers by reducing tris(dibenzylideneacetone)dipalladium(0)
via hydrogenation in the presence of the chiral ligand xylo-
DOI: 10.1055/s-0036-1590956; Art ID: ss-2017-f0584-op
Abstract A previously unreported 1,5-diazacyclooctane-palladium(II)
complex was synthesized using bis[N,N′-(2-indanolyl)]-1,5-diazacy-
clooctane, which was readily prepared via a novel [4+4] homocycliza-
tion of the unsaturated imine intermediate generated from acrolein and
1-amino-2-indanol. Interestingly, the 1,5-diazacyclooctane-palladi-
um(II) complex self-assembled to form palladium nanoparticles. This
approach readily provided palladium nanoparticles simply by heating a
mixture of palladium(II) acetate and bis[N,N′-(2-indanolyl)]-1,4-di-
azacyclooctane in dichloroethane at mild temperatures. The 1,5-di-
azacyclooctane-derivative-palladium nanoparticles were successfully
deployed in synthetic applications as a heterogeneous catalyst, facilitat-
11
furanoside diphosphite. The introduction of these ligand
motifs into a support material, however, required several
time-consuming chemical synthesis steps. The facile prepa-
ration of metal NPs supported by simple ligands, including
chiral ligands, would be synthetically useful.
3
ing Suzuki coupling and a challenging C–C bond formation via C(sp )–H
activation under low catalyst loading conditions.
Our group has focused on previously unrecognized reac-
12
tions of unsaturated imine derivatives. We recently iden-
tified a unique [4+4] homocyclization of an imine interme-
diate derived from unsaturated aldehyde derivatives and
hydroxyl group-containing amine substrates.13 Bis[N,N′-(2-
indanolyl)]-1,5-diazacyclooctane 1 having a (1S,2R)-(–)-cis-
1-amino-2-indanol moiety, was produced by the formal
[4+4] homocyclization between acrolein and (1S,2R)-(–)-
cis-1-amino-2-indanol, followed by hydride reduction
(Scheme 1, a). 1,5-Diazacyclooctane 1, which includes two
hydroxyl groups on indanol moieties, positioned at the N
atoms of the 1,5-diazacyclooctane core, suggested utility as
a metal ligand capable of forming a robust metal complex
by coordination through the two hydroxyl groups and the
two endocyclic nitrogen atoms in the 1,5-diazacyclooctane
skeleton. This structure is similar to that of sparteine, an
effective 1,5-diazacyclooctane skeleton-containing ligand
used as a lithium organometallic reagent. Here, we report
the preparation of a 1-Pd(II) complex as the first example of
a 1,5-diazacyclooctane derivative Pd complex. The complex
was found to self-assemble to form Pd NPs (Scheme 1, b).
Key words 1,5-diazacyclooctane, palladium nanoparticles, hetero-
geneous catalyst, chiral ligand, Suzuki coupling, C(sp )–H activation
3
Transition-metal-catalyzed C–C bond-forming reactions
1
have played an important role in organic synthesis. In re-
cent decades, metal nanoparticles (NPs) have received at-
2
tention as heterogeneous metal catalysts. Metal NPs pro-
vide a high catalytic reactivity in synthetic applications,
even without the addition of a ligand, they can be reused
3
several times to enable metal-catalyzed reactions, and can
be easily removed from the reaction mixture. These advan-
tages enable the replacement of homogeneous palladium
catalysts with Pd NP catalysts in Pd NP-catalyzed reactions,
14
4
5
such as hydrogenation, cross-coupling, and C–H activa-
6
tion. Metal NPs are typically immobilized on a stabilizing
7
8
substrate, such as a polymer or an inorganic material. The
reactivity of the metal NP catalyst can then be tuned by the
electronic and structural effects of the NP-supporting mate-
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K. Fujiki, K. Tanaka
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(
a)
H
OH
N
OH
[
4+4]
N
N
homocyclization
O
O
NH2
CHCl3
O
N
rt, 5 min
HO
N
HO
LiAlH4
THF
OH
N
0
°C
1
(
b) Synthetic application as palladium catalyst (this work)
Pd
Pd
Pd2+
Self-construction
N
O
Pd
1
Pd
Pd
Pd
O
N
Pd
Pd
Heterogeneous
Pd NPs catalyst
Pd
1-Pd(II) complex
1-Pd(II) NPs =
Scheme 1 1,5-Diazacyclooctane 1 and its applications to metal catalyst chemistry: (a) The formal [4+4] homocyclization reaction developed here
using an intermediate unsaturated imine formed from acrolein and (1S,2R)-(–)-cis-1-amino-2-indanol; and (b) access to a 1-Pd(II) complex and self-
assembled 1-Pd nanoparticles.
The Pd NPs were found to be useful as a heterogeneous cat-
alyst, displaying catalytic reactivity in Suzuki coupling and
C–C bond formation reaction via C(sp )–H activation.
porting Information). Electrospray ionization mass spec-
trometry (ESI-MS) analysis of the product clearly identified
the presence of a single product corresponding to the mass
of 1-Pd(II) (Figure 1, a). Our synthesis of 1-Pd(II) is the first
example of a Pd complex involving a 1,5-diazacyclooctane
skeleton ligand. The obtained 1-Pd(II) complex was found to
be bench stable; thus, decomposition did not occur, even af-
ter several months at room temperature under air atmo-
sphere. The thermal stability of 1 was tested by mixing with
palladium acetate and heating at 80 °C (entry 3). As shown
in Figure 1 (b and c), the yellow solution of 1 and palladi-
um(II) acetate turned to a black suspension after 12 hours
and then to a Pd NP suspension (vide infra) in a 55% yield
[calculated as assembly of 1-Pd(II)], which was easily isolat-
ed as a black solid by centrifuging (Figure 1, d). It should be
noted that our preparation conditions were mild and did
not require the presence of a reductant (the addition of a
3
Synthetic applications of 1,5-diazacyclooctane 1 were
sought by synthesizing the 1-metal complex. We focused
on transition-metal catalysts, such as Ni and Pd, due to
their synthetic utility in a variety of catalytic coupling reac-
tions. The air-stable divalent Ni and Pd reagents were se-
lected as easy-to-use metal sources. Initially, the synthesis
of a Ni complex with 1 was attempted (Table 1). Nickel(ІІ)
chloride hexahydrate was treated with 1 in dichlorometh-
ane, which showed good solubility in the presence of 1 at
room temperature; however, a 1-Ni(ІІ) complex was not ob-
tained, and 1 was recovered (Table 1, entry 1). A reaction of
1
with palladium(ІІ) acetate produced a palladium(ІІ) com-
plex with 1 in good yield (84%) after precipitation by addi-
tion of diethyl ether and then filtration (entry 2; see Sup-
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K. Fujiki, K. Tanaka
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reducing reagent in most metal NP preparations is neces-
sary to form metal NPs). By contrast, heating a dichlo-
roethane solution of palladium(II) acetate in the absence of
1
at 80 °C did not produce Pd NPs (see the Supporting Infor-
mation). The production of NPs was confirmed by collect-
ing transmission electron microscopy (TEM) images of the
obtained complex product, as shown in Table 1, entry 3.
TEM imaging revealed the construction of NPs (Figure 1, e),
4
nm in diameter (Figure 1, f). The production of the small
NPs was attributed to the bulk of ligand 1, which prevented
the extensive aggregation of 1-Pd NPs via steric hin-
15
drance.
Table 1 Synthesis of the 1-Transition Metal Complexes
N
N
HO
O
+
Metal reagent
M
CH2Cl2
OH
O
N
N
Figure 1 (a) ESI-MS spectrum of 1-Pd. The reaction mixtures listed in
entry 3 of Table 1, at (b) 0 h and (c) 12 h, and (d) as isolated 1-Pd NPs.
1
1-metal(II) complex
(
e) TEM image of the 1-Pd nanoparticles, and (f) expanded image of a
Entry
1
Metal reagent
NiCl ·6H
Time (h)
Temp
Result (Yield)
single nanoparticle, as indicated by the square.
2
2
O
3
r.t.
recovered 1
2
Pd(OAc)
2
1.5
12
r.t.
1-Pd(II) (84%)
1-Pd NPs (55%)
3a
lower catalyst loading levels of 1-Pd NPs. Even a 0.5 mol% 1-
Pd NPs loading provided a good catalytic reactivity, and the
product was obtained in 89% yield (entry 4). Performing the
coupling reaction in the presence of 0.05 mol% 1-Pd NPs
provided good catalytic reactivity; consequently, 2 was pro-
duced in 64% yield (entry 5). A highest turnover number
(TON) of 1275 was obtained. These results enabled Suzuki
coupling on the hundreds of milligram scale. These results
were compared with those obtained from ligand-free con-
ditions by carrying out the coupling reaction in the pres-
ence of 10 or 0.5 mol% palladium acetate, in place of the 1-
Pd NPs. The coupled product 2 was produced in 76% yield
with a 10 mol% loading palladium acetate (entry 6). Reduc-
ing the 1-Pd NP loading to 0.5 mol% produced 2 in 20% yield
(entry 7). These results indicated that 1 stabilized the active
species of the 1-Pd NP catalyst and prolonged the catalytic
lifetime.
Pd(OAc)
2
80 °C
a
Dichloroethane was used as a chlorinated solvent.
Inspired by the development of 1-Pd NPs through the
preparation protocol described above, we examined syn-
thetic applications of the 1-Pd NPs as a practical heteroge-
neous catalyst. 1-Pd NPs were used to conduct a Suzuki
coupling, which is a useful Pd-catalyzed reaction.16 As
shown in Table 2, Suzuki coupling between 4-bromoanisole
and phenylboronic acid was investigated in the presence of
catalytic amounts of the 1-Pd NPs. The coupling reaction
was performed with 10 mol% 1-Pd NPs, revealing that the
1
-Pd NPs exhibited catalytic reactivity under these Suzuki
coupling conditions and gave the coupled product 2 in
modest yield (42%, Table 2, entry 1). Unexpectedly, increas-
ing the catalyst loading to 20 mol% diminished the yield of 2
(
18%, entry 2). These results suggested that the aggregation
The substrate diversity of the 1-Pd NP-catalyzed Suzuki
coupling reaction was explored by testing a variety of aro-
matic bromides in a coupling reaction involving phenylbo-
ronic acid (Table 3). The coupling reactions were conducted
under the optimized conditions of 0.5 mol% catalyst load-
ing. When applied to an electron-deficient substrate com-
prising 4-acetylbromobenzene, the coupling reaction pro-
ceeded completely to give the coupled product 3a in 99%
yield (Table 3, entry 1). It could be noted that 1-Pd NPs
of 1-Pd NPs competed with the catalytic activity at higher
catalyst loading levels, thereby deactivating the 1-Pd NPs.
Consistent with this hypothesis, reducing the 1-Pd NPs
loading to 2 mol% prevented deactivation of the catalytic re-
activity, and the coupling reaction was catalyzed to afford 2
in 90% yield (entry 3). Catalyst loading in the context of the
coupling reaction was further optimized by testing much
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K. Fujiki, K. Tanaka
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Table 2 Investigation of 1-Pd NP-Catalyzed Suzuki Coupling Reaction
Table 3 Substrate Scope on the 1-Pd NP-Catalyzed Suzuki Coupling
Reaction
1-Pd NPs (X mol%)
Br
K2CO3 (2 equiv)
1-Pd NPs (0.5 mol%)
+
K CO (2 equiv)
2
3
toluene (0.37 M)
(
HO)2B
Ar-Br
+
(HO) B
Ar
MeO
2
100 °C
MeO
toluene (0.37 M)
100 °C
(
1.8 equiv)
2
(1.8 equiv)
3
Entry
X
Time (h)
Yield (%)
TONa
Entry
1
Coupled product
Time (h)
Yield (%)
99
1
10
6
18
5
42
18
90
89
64
76
20
O
2
20
2
4
4
3
9
3a
4
0.5
0.05
5
178
HO
5b
6c
21
8
1275
2
3
75
75
Pd(OAc)
2
2
(10 mol%)
(0.5 mol%)
3
3
b
c
7c
Pd(OAc)
8
OH
a
Turnover number.
b
c
4-Bromoanisole (660 mg, 3.5 mmol) was used.
4
Coupling reaction was conducted without the addition of the ligand.
could be reused for 4 times of Suzuki coupling reaction
with 4-acetylbromobenzene, although the catalytic activity
decreased after each reaction (See Supporting Information).
Bromobenzene derivatives substituted with free functional
groups were next investigated. The hydroxyl group of 3-
bromophenol did not inhibit the catalyst to provide the
coupled products 3b in 75% yield (entry 2). The 2-bro-
mophenol coupling proceeded smoothly to give 3c in good
yield (75%, entry 3). Coupling of an aniline substrate with
phenylboronic acid under the optimal coupling conditions
furnished 3d in 93% yield (entry 4). 2-Bromothiophene was
examined as a heteroaromatic bromide (entry 5). Although
Pd catalysts are typically deactivated by sulfur poisoning,
the coupling proceeded smoothly to afford 3e in 68% yield.
H2N
4
5
13
6
93
68
3d
S
3
e
6
7
8
24
6
67
N
3
f
HOH2C
N
78
3
3
g
h
N
2-Bromopyridine, which contained a sterically hindering
15
21 (61)a
methyl group at the 3-position, was investigated. The reac-
tion time was extended, and the product 3f was obtained in
67% yield (entry 6). 6-Hydroxylmethylbromopyridine was
reactive to produce 3g in good yield (78%, entry 7).
A coupling reaction employing 3-bromoquinoline with
a 0.5 mol% catalyst loading gave 3h in low yield (21%), al-
though a 2 mol% catalyst loading improved the yield to 61%
9b
8
74
N
3
i
(
Table 3, entry 8). Dibromopyridine was treated with 3.5
equivalents of phenylboronic acid in the presence of 1 mol%
-Pd NPs and 4 equivalents of potassium carbonate, and the
a
1
1
-Pd NP used: 2 mol%.
-Pd NPs used: 1 mol%; and 3.6 equiv PhB(OH)
b
2 2 3
and 4 equiv K CO were
1
added.
product substituted with two phenyl groups 3i was suc-
cessfully obtained in 74% yield (entry 9).
ethynylized with 2-silylacetynyl bromide in the presence of
2 equivalents of silver(I) acetate and the 1-Pd NPs upon
heating at 100 °C. The enantioselectivity of the ethynylated
products was analyzed using normal-phase high-
performance liquid chromatography (HPLC) equipped with
a chiral column. Interestingly, the 1-Pd NPs catalyzed the
ethynylation to give the 3-ethynylated product 5 in 61%
yield, even if the ethynylation was carried out in 1 mol% the
The development of the 1-Pd NP-catalyzed Suzuki cou-
pling reaction suggested further applications of the 1-Pd
3
NPs to challenging C–C bond-forming reactions via C(sp )–
H activation. The 1-Pd NPs were tested in the Pd(II)-cata-
3
lyzed ethynylation of a C(sp )–H bond on an alkyl chain
17
with a quinoline directing group. After optimizing the
conditions, the 8-[(hexanoyl)amino]quinoline (4) was
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K. Fujiki, K. Tanaka
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O
1-Pd NPs (1 mol%)
O
Br
AgOAc (2 equiv)
N
+
H
(a)
N
H
N
toluene (0.37 M)
N
TIPS
1.5 equiv)
100 °C, 22 h
(
TIPS
or
4
5
60 °C, 36 h
1
00 °C: 61% (racemic)
60 °C: 14%, 2% ee
O
1-Pd NPs (1 mol%)
O
Br
AgOAc (2 equiv)
N
H
N
(b)
+
N
H
N
toluene (0.37 M)
TIPS
1.5 equiv)
100 °C, 24 h
(
TIPS
6
7
14% (racemic)
3
Scheme 2 1-Pd NP-catalyzed ethynylation through C(sp )–H activation
catalyst loading (Scheme 2, a). Performing the reaction at
prepared according to the literature.19 Silica gel 60 (0.015–0.040 mm)
was used for column chromatography. For preparative TLC, PLC glass
plate Silica gel 60 F254, 0.5 or 1 mm (Merck-Millipore) was used.
HPLC grade hexane and i-PrOH from Wako Pure Chemical Industries
Ltd. were used for HPLC analysis. Normal phase HPLC analysis on en-
antiomeric excess of ethynylated products 5 and 7 was performed on
60 °C revealed enantioselectivity, albeit to a very small de-
gree. Ethynylation of the relatively sterically hindered sub-
strate 6 also proceeded to produce 7 in 14% yield with a ra-
cemic form (Scheme 2, b).
In summary, we have reported the first synthesis of a
Shimadzu Prominence® system equipped with
a
a CHIRALPAK
1
1
,5-diazacyclooctane core derivative palladium(II) complex,
-Pd(II) using bis[N,N′-(2-indanolyl)]-1,4-diazacyclooctane
(DAICEL Corporation) (AS-3, 4.6 × 250 mm), with isocratic elution of
hexane and i-PrOH (95:5). The mobile phase for HPLC were HPLC
grade hexane (Buffer A) and HPLC grade i-PrOH (Buffer B). Simultane-
ous monitoring of the eluent at 220 and 254 nm by UV detector was
performed.
prepared via a novel [4+4] homocyclization. The unique
properties of the complex were harnessed to synthesize
chiral ligand-coordinated Pd NPs, 1-Pd NPs, through a con-
cise preparation procedure. Synthetic applications of the
NPs were explored by demonstrating 1-Pd NP-catalyzed C–
C bond formation reactions, Suzuki coupling, and ethynyla-
The amount of 1-Pd NPs used for the coupling reactions was estimat-
ed by the mole number of 1-Pd NPs, which was same as that of 1-
Pd(II) precursor (MW: 482.92). NMR spectra of the compounds pro-
duced by 1-Pd NPs-catalyzed coupling reactions were in accordance
with the reported data (see details and references in Supporting In-
formation).
3
tion via C(sp )–H activation, a challenging C–C bond-form-
ing reaction. This success demonstrated the potential utility
of the NPs as a practical heterogeneous Pd NP catalyst. Fur-
ther studies of asymmetric reactions catalyzed by 1-Pd NPs
as heterogeneous chiral catalysts are ongoing. Other metal
NP catalysts based on a series of 1,5-diazacyclooctane de-
rivatives synthesized through our [4+4] homocyclization
reaction will be disclosed in due course.
1-Pd(II)
In a frame dried flask, 1,5-diazacyclooctane 1 (104 mg, 0.27 mmol)
and Pd(OAc) (62 mg, 0.27 mmol) were dissolved in anhyd CH Cl (2.5
2
2
2
mL) under N atmosphere and then stirred for 1.5 h at r.t. To the reac-
2
tion mixture was added Et O to form a precipitate. The obtained pre-
2
cipitate was filtered, washed with Et O, and dried under low pressure
2
to afford 1-Pd(II) (112 mg, 84%) as a light yellow powder.
+
HRMS (ESI+): m/z [M + H] calcd for C24H29N O Pd 483.1268; found:
2
2
All commercially available reagents were used without further purifi-
cation. All anhydrous solvents were purchased from Wako Pure
Chemical Industries Ltd., and Pd(OAc)2 was purchased from Wako
Pure Chemical Industries Ltd. 1,5-Diazacyclooctane 1 was prepared
4
83.1277.
1
-Pd NPs
13
In a frame-dried flask, 1,5-diazacyclooctane 1 (1.4 mg, 0.0062 mmol)
and Pd(OAc) (2.3 mg, 0.0060 mmol) were dissolved in anhyd dichlo-
roethane (0.5 mL) under N atmosphere and heated at 80 °C for 12 h
without stirring. After cooling to r.t., the reaction mixture was trans-
ferred into an Eppendorf tube and centrifuged for a second to give a
black precipitate. Supernatant solvent was removed, then hexane and
according to our report. For Suzuki coupling, all aromatic bromides
were purchased from Tokyo Chemical Industry Co., Ltd. and Sigma-
Aldrich, and phenylboronic acid was purchased from Sigma-Aldrich.
K CO was purchased from Nacalai Tesque Inc. For the typical proce-
2
2
2
3
dure of 4-methoxybiphenyl (2) (Table 2, entry 3), 1-Pd NPs (3.6 mg)
were prepared by repeating the procedure of 1-Pd NPs. For C–C bond-
3
a very small amount of CH Cl were added, and centrifuged again.
forming reaction via C(sp )–H activation, 8-aminoquinoline and
2 2
After removal of supernatant solvent, the obtained black precipitate
was dried in vacuo to afford 1-Pd NPs (1.6 mg, 55%) as a black powder.
Production of NPs was analyzed by TEM.
trimethylsilylacetylene were purchased from Tokyo Chemical Indus-
try Co. 8-(N-Acylamino)quinolones 4 and 6 were prepared according
18
to the reported procedures. (Bromoethynyl)triisopropylsilane was
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K. Fujiki, K. Tanaka
Paper
1
3
Note: In a larger scale preparation, the yield of 1-Pd NPs was de-
creased. 1-Pd NPs were therefore prepared for each reaction under
the conditions described above; for example, 1,5-diazacyclooctane 1
C NMR (CDCl , 75 MHz): δ = 152.3, 137.0, 130.2, 129.25, 129.12,
3
129.06, 128.0, 115.8.
(
6.0 mg, 0.015 mmol) and Pd(OAc)2 (3.5 mg, 0.015 mmol) were dis-
4-Aminobiphenyl (3d)
solved in anhyd dichloroethane (1.3 mL) under N atmosphere. After
heating at 80 °C for 12 h without stirring and subsequent isolation by
centrifugation, 1-Pd NPs (2.3 mg, 30%) was obtained.
2
According to the typical procedure, 1-Pd NPs (0.7 mg, 0.0014 mmol),
phenylboronic acid (63 mg, 0.51 mmol), K CO (80 mg, 0.58 mmol),
2
3
4-bromoaniline (49 mg, 0.29 mmol), and anhyd toluene (0.76 mL)
were added to a N -filled flask, and the reaction mixture was heated
at 100 °C for 13 h. Purification by silica gel column chromatography
2
4-Methoxybiphenyl (2); Typical Procedure
1
-Pd NPs (3.6 mg, 0.0075 mmol) was added to a frame-dried flask and
(hexane/EtOAc 4:1) provided 3d (46 mg, 93%) as a light brown solid.
filled with N . To the flask were added phenylboronic acid (83 mg,
1
2
H NMR (CDCl , 300 MHz): δ = 7.54–7.51 (m, 2 H), 7.42–7.38 (m, 4 H),
3
0
.68 mmol), K CO (106 mg, 0.76 mmol), 4-bromoanisole (47 μL, 0.37
2 3
7.36–7.22 (m, 1 H), 6.74 (d, J = 8.4 Hz, 2 H), 3.70 (br s, 2 H).
mmol), and anhyd toluene (1.0 mL), then the reaction mixture was
heated at 100 °C. After stirring for 5 h, the mixture was cooled to r.t.,
filtered, extracted with hexane, and the combined hexane layers were
washed with brine, dried (Na SO ), and evaporated. The crude materi-
13
C NMR (CDCl , 75 MHz): δ = 145.7, 141.1, 131.5, 128.6, 127.9, 126.3,
3
1
26.2, 115.3.
2
4
2
-Phenylthiophene (3e)
al was purified by silica gel column chromatography (hexane to hex-
ane/EtOAc 100:1) to give 2 (62 mg, 90%) as a white solid.
According to the typical procedure, 1-Pd NPs (0.6 mg, 0.0012 mmol),
phenylboronic acid (55 mg, 0.45 mmol), K CO (68 mg, 0.49 mmol), 2-
bromothiophene (24 μL, 0.25 mmol), and anhyd toluene (0.66 mL)
1
2
3
H NMR (CDCl , 300 MHz): δ = 7.56–7.50 (m, 4 H), 7.41 (dd, J = 7.5, 7.2
3
Hz, 2 H), 7.32–7.27 (m, 1 H), 6.97 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H).
were added to a N -filled flask, and the reaction mixture was heated
2
13
C NMR (CDCl , 100 MHz): δ = 159.1, 140.8, 133.7, 128.7, 128.1,
3
at 100 °C for 6 h. Purification by silica gel column chromatography
126.7, 126.6, 114.2, 55.3.
(hexane/EtOAc 50:1) provided 3e (27 mg, 68%) as a white solid.
1
H NMR (CDCl , 400 MHz): δ = 7.62–7.59 (m, 2 H), 7.37 (td, J = 7.2, 2.0
3
4
-Acetylbiphenyl (3a)
Hz, 2 H), 7.31–7.25 (m, 3 H), 7.08–7.06 (m, 1 H).
According to the typical procedure, 1-Pd NPs (0.85 mg, 0.0017 mmol),
phenylboronic acid (78 mg, 0.64 mmol), K CO (98 mg, 0.70 mmol),
13
C NMR (CDCl , 100 MHz): δ = 144.4, 134.4, 1128.8, 127.9, 127.4,
3
2
3
125.9, 124.8, 123.0.
4-bromoacetophenone (71 mg, 0.35 mmol), and anhyd toluene
(
0.94 mL) were added to a N -filled flask, and the reaction mixture
2
3-Methyl-2-phenylpyridine (3f)
was heated at 100 °C for 4 h. Purification by preparative TLC (hexane/
EtOAc 4:1) provided 3a (71 mg, 99%) as a white solid.
According to the typical procedure, 1-Pd NPs (0.6 mg, 0.0012 mmol),
phenylboronic acid (53 mg, 0.43 mmol), K CO (67 mg, 0.48 mmol), 2-
bromo-3-methylpyridine (28 μL, 0.25 mmol), and anhyd toluene
0.66 mL) were added to a N -filled flask, the reaction mixture was
heated at 100 °C for 24 h. Purification by preparative TLC (hexane/
EtOAc 3:1) provided 3f (28 mg, 67%) as a colorless oil.
1
2
3
H NMR (CDCl , 300 MHz): δ = 8.03 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.4
3
Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.51–7.37 (m, 3 H), 6.97 (dt, J = 8.7,
(
1.8 Hz, 2 H), 2.63 (s, 3 H).
2
13
C NMR (CDCl , 100 MHz): δ = 197.7, 145.7, 139.8, 135.8, 128.91,
3
128.88, 128.20, 127.23, 127.18, 26.6.
1
H NMR (CDCl , 400 MHz): δ = 8.53 (dd, J = 4.8, 0.8 Hz, 1 H), 7.57 (dd,
3
J = 7.6, 0.8 Hz, 1 H), 7.54–7.50 (m, 2 H), 7.47–7.42 (m, 2 H), 7.41–7.36
3
-Phenylphenol (3b)
(m, 1 H), 7.17 (dd, J = 7.6, 4.8 Hz, 1 H), 2.35 (s, 3 H).
According to the typical procedure, 1-Pd NPs (1.0 mg, 0.0022 mmol),
phenylboronic acid (98 mg, 0.80 mmol), K CO (123 mg, 0.89 mmol),
13
C NMR (CDCl , 100 MHz): δ = 158.6, 146.9, 140.6, 138.4, 130.7,
3
2
3
128.9, 128.1, 127.8, 122.0, 20.0.
3-bromophenol (77 mg, 0.44 mmol), and anhyd toluene (1.2 mL)
were added to a N -filled flask, and the reaction mixture was heated
at 100 °C for 4 h. Purification by silica gel column chromatography
2
6-Phenyl-2-pyridinemethanol (3g)
(hexane/EtOAc 20:1 to toluene/EtOAc 30:1) provided 3b (56 mg, 75%)
According to the typical procedure, 1-Pd NPs (0.3 mg, 0.0006 mmol),
as a light orange solid.
phenylboronic acid (28 mg, 0.23 mmol), K CO (34 mg, 0.25 mmol), 2-
2
3
1
bromo-6-(hydroxymethyl)pyridine (24 mg, 0.12 mmol), and anhyd
H NMR (CDCl , 300 MHz): δ = 7.68–7.55 (m, 2 H), 7.45–7.40 (m, 2 H),
.37–7.25 (m, 2 H), 7.18–7.15 (m, 1 H), 7.07–7.05 (m, 1 H), 4.86 (s, 1
3
toluene (0.33 mL) were added to a N -filled flask, and the reaction
7
H).
2
mixture was heated at 100 °C for 6 h. Purification by preparative TLC
(hexane/EtOAc 15:1) provided 3g (18 mg, 78%) as a colorless oil.
13
C NMR (CDCl , 75 MHz): δ = 155.7, 142.9, 140.6, 129.9, 128.7,
3
1
H NMR (CDCl , 400 MHz): δ = 8.01 (d, J = 6.8 Hz, 2 H), 7.75 (t, J = 7.6
1
27.47, 127.08, 119.8, 114.17, 114.07.
3
Hz, 1 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.48–7.43 (m, 3 H), 7.47–7.42 (m, 2
H), 7.16 (d, J = 7.2 Hz, 1 H), 4.82 (s, 2 H), 4.14 (br s, 1 H).
2
-Phenylphenol (3c)
13
C NMR (CDCl , 100 MHz): δ = 158.4, 156.0, 138.5, 137.6, 129.2,
3
According to the typical procedure, 1-Pd NPs (0.85 mg, 0.0017 mmol),
phenylboronic acid (76 mg, 0.62 mmol), K CO (97 mg, 0.70 mmol), 2-
128.7, 126.9, 119.2, 118.7, 63.9.
2
3
bromophenol (41 μL, 0.35 mmol), and anhyd toluene (0.94 mL) were
3-Phenylquinoline (3h)
added to a N -filled flask, and the reaction mixture was heated at 100
2
°
C for 4 h. Purification by preparative TLC (hexane/EtOAc 5:1) provid-
According to the typical procedure, 1-Pd NPs (0.2 mg, 0.0004 mmol),
ed 3c (45 mg, 75%) as a white solid.
phenylboronic acid (4.7 mg, 0.038 mmol), K CO (5.5 mg, 0.039
2
3
1
mmol), 3-bromoquinoline (2.8 μL, 0.021 mmol), and anhyd toluene
H NMR (CDCl , 400 MHz): δ = 7.49–7.45 (m, 4 H), 7.41–7.37 (m, 1 H),
3
7.26–7.23 (m, 2 H), 7.01–6.97 (m, 2 H), 5.18 (s, 1 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
Synthesis
K. Fujiki, K. Tanaka
Paper
(
0.15 mL) were added to a N -filled flask, and the reaction mixture
Funding Information
2
was heated at 100 °C for 15 h. Purification by preparative TLC
hexane/EtOAc 5:2) provided 3h (2.6 mg, 62%) as a white solid.
This work was supported by the JSPS KAKENHI Grant Numbers
JP16H03287, JP16K13104, and JP15H05843 as part of the Middle Mo-
lecular Strategy, and by RIKEN Incentive Research Projects 2016. This
work was also performed with the support of the Russian Govern-
ment Program for Competitive Growth, granted to the Kazan Federal
(
1
H NMR (CDCl , 300 MHz): δ = 9.19 (d, J = 2.1 Hz, 1 H), 8.31 (d, J = 2.4
3
Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.76–7.70 (m,
H), 7.61–7.51 (m, 3 H), 7.47–7.42 (m, 1 H).
3
1
3
C NMR (CDCl , 75 MHz): δ = 149.9, 147.3, 137.9, 133.2, 129.4,
3
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29.21, 129.16, 128.1, 128.00, 127.99, 127.4, 127.0.
2,6-Diphenylpyridine (3i)
Acknowledgment
According to the general procedure, 1-Pd NPs (0.5 mg, 0.001 mmol),
We are grateful to the RIKEN materials characterization team for their
assistance with the electron microscopy studies.
phenylboronic acid (45 mg, 0.37 mmol), K CO (59 mg, 0.43 mmol),
2
3
2,6-dibromopyridine (24 mg, 0.10 mmol), and anhyd toluene (0.27
mL) were added to a N -filled flask, and the reaction mixture was
2
heated at 100 °C for 8 h. Purification by preparative TLC (hexane/EtOAc
Supporting Information
10:1) provided 3i (18 mg, 74%) as a white solid.
1
H NMR (CDCl , 400 MHz): δ = 8.15 (dt, J = 7.6, 5.2 Hz, 4 H), 7.82, 7.80
Supporting information for this article is available online at
3
(d, d, J = 7.2, 7.2 Hz, 1 H), 7.69 (d, J = 7.2 Hz, 2 H), 7.51–7.48 (m, 4 H),
https://doi.org/10.1055/s-0036-1590956.
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o
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rm oaitn
7.45–7.40 (m, 2 H).
13
C NMR (CDCl , 100 MHz): δ = 156.8, 139.5, 137.5, 128.9, 128.7,
3
References
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-{[3-(Triisopropylethynyl)hexanoyl]amino}quinoline (5); Typical
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moethynyl)triisopropylsilane (23 μL, 0.096 mmol), and AgOAc (21
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2
4 h. Purification by preparative TLC (hexane/EtOAc 5:1) gave 7 (3.7
mg, 14%) as a colorless oil.
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8.16 (dd, J = 8.4, 1.6 Hz, 1 H), 7.55–7.44 (m, 3 H), 3.13–3.08 (m, 1 H),
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H