The synthesis and application of 2-acetyl-6-(1-naphthyl)-pyridine oxime as a new ligand for palladium precatalyst in suzuki coupling reaction

Article abstract of DOI:10.1002/jhet.27

The synthesis of 2-acetyl-6-(1-naphthyl)-pyridine oxime ligand from 2,6-dibromopyridine and 1-bromo-naphthalene is described, and the new palladium(II) complex used as a Pd(0) precatalyst in the Suzuki cross-coupling reaction was studied. The results showed that the novel naphthalene pyridine oxime complex could serve as an efficient precatalyst.

Full text of DOI:10.1002/jhet.27

116
The Synthesis and Application of 2-acetyl-6-(1-naphthyl)-pyridine
Oxime as a New Ligand for Palladium Precatalyst in Suzuki
Coupling Reaction
Vol 46
Yongchang Zhou,* Tatsuro Kijima, and Taeko Izumi
Department of Chemistry and Chemical Engineering, Graduate School of Science and Engineering,
Yamagata University, Jyonan 4-3-16, Yonezawa 992-8510, Japan
*E-mail: yczhou97@hotmail.com
Received January 30, 2008
DOI 10.1002/jhet.27
Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).
The synthesis of 2-acetyl-6-(1-naphthyl)-pyridine oxime ligand from 2,6-dibromopyridine and 1-
bromo-naphthalene is described, and the new palladium(II) complex used as a Pd(0) precatalyst in the
Suzuki cross-coupling reaction was studied. The results showed that the novel naphthalene pyridine
oxime complex could serve as an efficient precatalyst.
J. Heterocyclic Chem., 46, 116 (2009).
INTRODUCTION
the 1-naphthalene group to the pyridine oxime to obtain
more active catalyst, and here, we reported the synthesis
and application of a novel naphthalene pyridine oxime
ligand on the Suzuki reaction (1).
It is widely accepted that palladium-catalyzed cross-
coupling reaction are one of the most important proc-
esses in synthesis chemistry, of which Suzuki–Miyaura
cross-coupling reaction of aryl halides with organoboron
reagents has become one of the most efficient and
widely utilized methods for the formation of sp2-sp2 car-
bon-carbon bonds [1–4]. Traditional phosphane contain-
ing palladium catalysts have many disadvantages such
as high cost, air- and thermo-sensitivity, low activity
towards deactivated substrates, contamination of the
products with the phosphane-based byproducts [5,6].
Therefore, many efforts have been made to find more
active and stable palladium catalysts. In our lab, oxime
containing molecule [7] was synthesized and its catalyst
activity in cross-coupling reaction was examined. Poor
enantioselectivity was observed. So, we want to improve
the activity by substitution of naphthalene group to
pyridine.
RESULTS AND DISCUSSION
Scheme 1 outlined the synthetic route employed in
our lab for preparation of the substrate 1-[6-(1-naph-
thyl)-2-pyridyl]-1-ethanone oxime 1.
Our strategy for the synthesis of 6 was first based on
the selective lithiation of 2,6-dibromopyridine [8–11]
and then Suzuki cross coupling reaction [7]. After the
synthesis of substrate of oxime, the precatalyst 7 was
prepared by Scheme 2.
Some common conclusions concerning the influence
of the electronic and steric properties of the ligands on
the efficiency of the catalysts in Suzuki-Miyaura reac-
tion were made based on the structure-activity analysis
of these catalysts. Increasing the electronic density on
palladium could enhance the catalytic activity particu-
larly by promoting the aryl halide oxidative addition;
while the bulkness of the ligand presumably could facil-
itate the reductive elimination step [6]. We introduced
After the synthesis of (7), the application of naph-
thlene oxime ligand on Suzuki-cross coupling reaction
was studied. At first, the optimal reaction time was
investigated. The reaction was preceded very quickly
at the first 60 min. Higher yield was not observed when
the reaction time was longer as shown in Figure 1. So
the optimal value for reaction time was 60 min.
C
V
2009 HeteroCorporation

January 2009
The Synthesis and Application of 2-acetyl-6-(1-naphthyl)-pyridine Oxime
as a New Ligand for Palladium Precatalyst in Suzuki Coupling Reaction
117
Scheme 1
The activity of the ligand was examined as shown in
Table 1. The results demonstrated that the yield was influ-
enced by the substitution of the aryl halides. The yield of
bromo-benzene was the highest; the yield of p-bromo tol-
uene was higher than that of o- and m-bromo toluene. 1-
Methyl-4-nitrobenzene showed the lowest yield among all
the reactions. This may be the reason that the substituents
had the effect on reactivity of aryl halides. The nitro
group was one of electron-withdrawing substituents
decreasing the reactivity of the aryl halides, leading to the
low yield in reaction. In addition, the effect of substituents
on orientation was shown in Table 1. The methyl group
was the weak electron-donating substituent. Therefore, the
ortho/para bromo toluene was more active than the meta
one because of a steric effect of the ortho methyl group
behind the electron effection, the yield of para one was
higher than that of ortho one. When water was added dur-
ing the reaction, the yields become lower. When the 1-
bromo-4-nitrobenzene was used as aryl halide in toluene
with base of CsCO3 for reflux 60 min, the yield was
decreased to 33% (Run 8).
Figure 1. The yield-time relationship.
point was determined by MFB-595-030G digital thermometer
apparatus.
1-Naphthylboronic acid(3). Dropwise addition of 7.95 mL
(13.5 mmol) of a 1.7M solution of t-BuLi in pentane to a
stirred solution of 1-bromonaphthaline (2) (2.67 g, 12.9 mmol)
in 50 mL of THF at –78ꢀC led to the formation of a white pre-
cipitate. After 45 min, 1.40 g (1.5 mL, 13.5 mmol) of
B(OMe)3 was added, and the resulting clear solution was
maintained at –78ꢀC for 1 h. The reaction mixture was
allowed to warm to room temperature and stirring was contin-
ued for 3 h. A 10% solution of HCl (25 mL) and ethyl acetate
(50 mL) were added. The aqueous layer was extracted with
4 ꢁ 20 mL of ethyl acetate. The combined organic layers
were dried over Na2SO4 and the solvent was removed under
reduced pressure. The off-white solid residue was suspended
Table 1
Suzuki cross-coupling reaction.
When the reaction of 1-(6-bromopyridin-2-yl)etha-
none with naphthalen-1-ylboronic acid was carried out
in toluene as solvent and Na2CO3 as base for refluxing
60 min and the yield was up to 85%, (Run 11), higher
than the former reaction (Run 10).
Ar-boronic
acid
Water/
Toluene Yield
Run
1
Br-Ar
Base
Na2CO3
0:20
90
Further research related to higher activity based on
the date is also underway.
2
3
4
Na2CO3
Na2CO3
Na2CO3
0:20
10:20
0:20
73
60
60
EXPERIMENTAL
5
6
Na2CO3
Na2CO3
0:20
82
55
Deuterium NMR and CMR spectra were measured with a
JNM-ECS400 NMR spectrometer at 400 MHz. Mass spectra
(MS) were recorded on a JOEL JMS-AX505HA. The melting
10:20
7
8
9
Na2CO3
Ca2CO3
Na2CO3
0:20
10:20
0:20
79
33
94a
Scheme 2
10
11
Na2CO3
Na2CO3
10:20
10:20
80b
85
Reagents and conditions: (2 mol%) Pd-catalyst, toluence, base, reflux,
60 min.
a Reactions time is 360 min.
b Catalyst is Pd(PPh3)4, reaction time is 12 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

118
Y. Zhou, T. Kijima, and T. Izumi
Vol 46
in 50 mL of petroleum ether and filtered to give 3 (2.13 g,
yield 96%).
Mp: 150–151ꢀC; MS: m/z 262 [Mþ]; 1H NMR (400 MHz,
DMSO, d,ppm) 2.19(s, 3H, CH3), 7.47–7.55(m, 2H, HAr),
7.57–7.61(t, J ¼ 7.25, 1H, HAr), 7.61–7.63(dd, J ¼ 4.76, 1.81,
1.36, 1H, HAr), 7.87–7.92(t, J ¼ 8.83, 8.15, 9.51, 1H, HAr),
7.92–7.96(t, J ¼ 7.70, 7.25, 8.15, 1H, HAr), 7.98–8.01(dd, J ¼
7.16, 1.36, 2H, HAr), 8.09–8.11(d, J ¼ 8.15, 1H, HAr), 11.53(s,
1H, N-OH); 13C NMR (400 MHz, DMSO, d, ppm) 10.87,
118.67, 124.97, 125.90, 125.99, 126.53, 127.07, 128.06,
128.88, 129.33, 131.10, 134.06, 137.91, 138.39, 154.57,
157.96, 159.48. IR (KBr, cmꢂ1) 3300 (AOH).
Oxime-derivedpalladacycle(7)(preparationofprecatalyst). To
a stirred solution of sodium tetrachloropalladate(II) (147 mg,
0.5 mmol), which was obtained as well-formed crystals by
treating PdCl2 solutions with stoichiometric quantities of so-
dium chlorides and slowly evaporating the solutions in MeOH
(2 mL), 2-acetyl-6-(1-naphthyl)-pyridine oxime (131 mg, 0.5
mmol) in MeOH (1 mL) was added dropwise. The precipitate
was collected by filtration after stirring for 2 h and washed
with MeOH and H2O, then dried in vacuum over P2O5. Preca-
talyst 7 was obtained as a yellow-brownish powder (400 mg,
80%).
Mp 202–203ꢀC; MS: m/z 172[Mþ]; 1H NMR (400 MHz,
DMSO, d, ppm); 7.50–8.10(m, 6H, Hnaph), 8.38(s, 2H, HOH),
8.53(d, 1H, Hnaph, J ¼ 13.5 Hz); IR(cmꢂ1) 3310 (AOH).
1-(6-Bromopyridin-2-yl)ethanone (5). A solution of 7.08 g
(30 mmol) of 2,6-dibromopyridine (4) dissolved in 42 mL of
dry THF was cooled to ꢂ78ꢀC. The 2,6-dibromopyridine was
lithiated by slowly adding 12 mL of a 2.6M solution of n-
butyllithium in hexane. After the addition, the resulting dark
yellow solution was stirred at ꢂ78ꢀ for 30 min. Then neat
N,N-dimethylacetamide (4.2 mL, 54.3 mmol) was added over
a period of 30 s. The reaction solution was stirred at ꢂ78 ꢀC
for 15 min, and then the solution was allowed to warm to
room temperature. The resulting yellow solution was hydro-
lyzed with saturated NH4Cl (40 mL). The mixture was stirred
for additional 60 min, and the aqueous layer was separated
and extracted with diethyl ether twice (100 mL and 60 mL,
respectively). The combined organic layer was washed with
brine 60 mL, dried (sodium sulfate) and evaporated to ca. 10
mL in volume and cooled to 0ꢀC. After a few hours, a brown
solid was isolated by filtration. The crude product was purified
by chromatography on silica eluting with hexane/ethyl acetate
(95:5) to afford white crystals, 5.1gþ(85%).
Mp > 300ꢀC; IR(cmꢂ1): 1755, 1730, 1705 (CAO); MS: m/z
440[M þ 1],880[M þ M]; 1H NMR (400 MHz, DMSO, d,
ppm) 2.19(s, 3H, CH3), 7.47–7.64 (m, 5H, HAr), 7.87–8.00 (m,
4H, HAr), 11.53(s, 1H, NAOH); 13C NMR (400 MHz, DMSO,
d, ppm) 10.87, 118.67, 124.96, 125.89, 125.98, 126.51, 127.06,
128.05, 128.87, 129.33, 131.09, 134.05, 137.91, 138.39,
154.57, 155.05, 157.96.
Mp 54–55ꢀC; MS: m/z 199[M ]; 1H NMR (400 MHz,
CDCl3, d, ppm) 2.69(s, 3H, CH3),7.65–7.71(m, 2H, HAr),
7.97–7.99 (dd, J ¼ 7.25, 1.36, 1H, CHAr); IR(KBr, cmꢂ1
1696 (C¼O); 593 (CABr).
)
1-(6-Naphalen-1-yl)pyridin-2-yl]ethanone(6). To a solution
of 3 (0.72 g, 3.60 mmol) and Pd(OAc)2 (0.13 g) in 10 mL of
deaerated toluene, 4 mL of a 4.4M aqueous solution of
Na2CO3 were added, followed by a solution of 0.79 g (4.58
mmol) of 1-naphthylboronic acid in 10 mL of MeOH. The
mixture was heated to 80–85ꢀC under stirring for 30 h. The
resulting solution was allowed to cool to room temperature
and a solution of 8 mL of concentrated aqueous NH3 in 20
mL of saturated aqueous Na2CO3 was added. The mixture was
extracted with 3 ꢁ 50 mL of CH2Cl2. The combined organic
layers were washed with 50 mL of water and 100 mL of brine
and dried over Na2SO4. Removal of the solvent under reduced
pressure gave 1.15 g of the crude product which was purified
by flash chromatography [CC, SiO2, i) petroleum ether/CH2Cl2
(4:1), Rf ¼ 0.1, ii) CH2Cl2]. The desired product was obtained
as an off-white solid in 80% yield (0.71 g).
Acknowledgments. I thank Mr. Murakami for his technical as-
sistance. This research was financially supported by the Sasakawa
Scientific Research Grant from The Japan Science Society under
grant number 19-314.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet