Palladium-catalyzed benzylic cross-couplings of pyridine N-oxides

Article abstract of DOI:10.1055/s-0031-1290602

Palladium-catalyzed C-H couplings (C_SP³-C _SP²) of pyridine N-oxides with benzyl chloride derivatives is reported. It provides a novel and easy process for the synthesis of 2-benzylpyridine derivatives through benzylic cross-couplings of pyridine N-oxides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290602

938
LETTER
Palladium-Catalyzed Benzylic Cross-Couplings of Pyridine N-Oxides
P
alladium-Catalyze
d
Be
e
nzylic Cros
n
s-Couplings
p
of Pyridine
e
N
-Oxides ng Mai,* Jinwei Yuan, Zhicheng Li, Liangru Yang, Yongmei Xiao, Pu Mao, Lingbo Qu
Chemistry and Chemical Engineering School, Henan University of Technology, Zhengzhou Henan 450001, P. R. of China
Fax +86(371)67756715; E-mail: wpmai@yahoo.com.cn
Received 19 December 2011
in these methods; for example, BuLi or LDA were used in
Liu’s and Yorimitsu’s works to synthesize modified 2-
picoline derivatives (Figure 2). Pyridine N-oxide has at-
tracted interest due to its direct C–H activation on 2-posi-
tion of pyridine.11 Though Fagnou has reported synthesis
of 2-benzylpyridine N-oxide using 2-methylpyridine N-
oxide with aryl halides as substrates, methyl on pyridine
core was necessary. Benzyl halides as electrophiles cou-
pled with pyridine N-oxides have not been reported to
date. Our study was inspired by the recent fascinating
work of Fagnou et al.12 (Figure 2). On the arylation of
Abstract: Palladium-catalyzed C–H couplings (CSP3–CSP2) of pyri-
dine N-oxides with benzyl chloride derivatives is reported. It pro-
vides a novel and easy process for the synthesis of 2-benzylpyridine
derivatives through benzylic cross-couplings of pyridine N-oxides.
Key words: palladium, benzylation, pyridine N-oxide, C–H cou-
plings
Transition-metal-catalyzed C–H bond activation reac-
tions for the C–C bond formation has contributed signifi-
cantly to the preparation of biaryl molecules.1 In
particular, prominent reactions involve Pd-catalyzed cou-
Table 1 Screening of Different Conditions for Palladium-Catalyzed
Coupling of Pyridine N-Oxide with Benzyl Chloridea
2
plings of aryl halides with aromatic C–H bonds (Csp –
2
Csp ) or two differential arene compounds’ C–H bonds
2
2
(Csp –Csp ).2 In this area of research, benzyl halides or al-
Pd(OAc)2 (5 mol%)
3
+
X
iphatic electrophiles (Csp ) coupled with aromatic rings re-
ligand, solvent
K2CO3, 110 °C
N
H
N
O
main rare.3 Yu reported palladium-catalyzed ortho
alkylation of benzoic acids,4 and Ackermann described
ruthenium-catalyzed direct benzylations or alkylation of
arene through C–H activation.5
O
3aa
1a
2a
Entry
1
Ligand
Ph3P
Ph3P
Cy3P
Cy3P
Cy3P
IPrS
X
Solvent
Yield (%)b
0
Cl
toluene
toluene
toluene
toluene
dioxane
toluene
DMF
OMe
MeO
2
Br
Cl
0
O
3
trace
trace
trace
trace
27
HO2C
N
4
Br
Cl
N
N
5
MeO
Et
psychoactive drug
cryptopleurine precursor
6c,d
7c,d
8
Cl
Figure 1 Bioactive 2-benzylpyridine derivatives
IPrS
Cl
t-Bu3P–HBF4
t-Bu3P–HBF4
t-Bu3P–HBF4
t-Bu3P–HBF4
t-Bu3P
Cl
DMF
49
2-Benzylpyridine and its derivatives are important com-
ponents of natural products, medicinal chemistry and ma-
terial science6 (Figure 1). The benzylic arylation of
pyridines does not have effective synthetic routes.7 Re-
cently, Liu reported decarboxylative cross-couplings of 2-
(2-pyridyl)acetates with aryl halides for the synthesis of 2-
benzylpyridine derivatives.8 2-(2-Pyridyl)ethanol deriva-
9
Cl
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
64
10
11e
12
Cl
82
Cl
75
Cl
77
tives were used as substrates to obtain 2-pyridylmethyl 13
t-Bu3P–HBF4
t-Bu3P–HBF4
t-Bu3P–HBF4
Br
OTs
OTs
43
functional group in Yorimitsu’s work.9 More recently,
Knochel reported Pd-catalyzed coupling of aryl bromides
with 2-picoline under the assistance of Lewis acid
TMPZnCl–LiCl.10 More synthetic routes or modified
pyridine precursors and expensive reagents were required
14
trace
trace
15c–e
a Conditions: 1a (1.5 mmol), 2a (1.0 mmol), Pd(OAc)2 (0.05 mmol),
ligand (0.1 mmol), K2CO3 (2.0 mmol), solvent (3.0 mL), 110 °C,
under N2, 16 h.
b Isolated yield.
SYNLETT 2012, 23, 938–942
x
x.
x
x.
2
0
1
2
c Cs2CO3 was used as base.
Advanced online publication: 02.03.2012
DOI: 10.1055/s-0031-1290602; Art ID: W78811ST
© Georg Thieme Verlag Stuttgart · New York
d IPrS = 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride.
e Pd2(dba)3 (2.5 mol%) was used as catalyst.

LETTER
Palladium-Catalyzed Benzylic Cross-Couplings of Pyridine N-Oxides
939
COOK
N
ArX
Pd
X = Br, Cl, OTf
OH
i-Pr
N
Pd
Pd
TMPZnCl–LiCl
R
i-Pr
ArX
N
N
N
X = I, Br, Cl
ZnCl
bond formation
ArBr
MW
Pd
N
O
R1
R1
Pd
PR3
R2
R2
+
Cl
N
O
H
N
O
this work
bond formation
Figure 2 Overview of synthesis of 2-benzylpyridine derivatives
pyridine N-oxides, we continued our work on its 2-posi- With the optimized conditions in hand, we explored the
tion through C–H activation.13 Herein, a simple method scope of this transformation (Table 2). As shown in
for the synthesis of 2-benzylpyridine through palladium- Table 2, we found that benzyl chlorides with electron-
catalyzed benzylic cross-couplings of pyridine N-oxides withdrawing group or electron-donating group could be
is described (involving both cheap crude materials and successfully coupled with some pyridine N-oxides in this
easy synthesis).
reaction (Table 2, entries 2–4 and 7). 2-Methylbenzyl
chloride coupled with 1a smoothly though it has steric ef-
fect and provided the product 3ab in high yield (Table 2,
entry 2). 3-Cyanopyridine N-oxide and 4-cyanopyridine
N-oxide were also coupled with 2a, 2b and 2e smoothly
and gave the corresponding products in 62–80% yields
(Table 2, entries 5–7). It was noted that different regiose-
lectivities for 3-cyanopyridine N-oxide were obtained
when it was coupled with benzyl chloride and 2-methyl-
benzyl chloride (Table 2, entries 5 and 6). Hydrogen on 2-
position of 3-cyanopyridine N-oxide should be more acti-
vated than that on 6-position, but 2-methylbenzyl chloride
showed more steric effect if it was coupled with 3-cya-
nopyridine N-oxide on 2-position. This was found to be
consistent with our previous work.13 But entry 11 could
not be explained by this conjecture. Pyrazine N1-oxide
could also undergo this coupling reaction with benzyl
chloride, 4-methylbenzyl chloride and 4-fluorobenzyl
chloride, and the corresponding products were obtained in
good yields (Table 2, entries 8–10). The product 3eb was
obtained in 48% yield when isoquinoline N-oxide was
used to couple with 2b (Table 2, entry 11), but quinoline
N-oxide could not be converted under the same conditions
(Table 2, entry 12). Unfortunately, substrates with elec-
tron-donating groups on pyridine N-oxide were not effec-
tive in our catalyst system (see Supporting Information).
Our study began with the treatment of pyridine N-oxide
(1a) with benzyl chloride (2a) in the presence of
Pd(OAc)2 (5 mol%), Ph3P and K2CO3 at 110 °C under N2
in toluene. No desired product 3aa was found after 16
hours (Table 1, entry 1). Under the same conditions, no
product was observed when using benzyl bromide as sub-
strate coupled with 1a (Table 1, entry 2). It was not effec-
tive for this reaction when PCy3 was used as ligand
(Table 1, entries 3–5). Only 27% yield was obtained when
IPrS was used as ligand in DMF (Table 1, entry 7). The
yield was improved to 49% when t-Bu3P–HBF4 was used
as ligand instead of IPrS (Table 1, entry 8). After several
tests for the effect of ligands and solvents in this transfor-
mation, t-Bu3P–HBF4 and toluene were found to be the
most effective in this reaction, and the desired product 3aa
was obtained in 82% yield (Table 1, entry 10). Ligand t-
Bu3P gave a similar result as that obtained with t-Bu3P–
HBF4 (Table 1, entry 12). Pd2(dba)3 as catalyst was also
effective in this transformation, and 75% yield was ob-
tained (Table 1, entry 11). Under the optimal conditions,
benzyl bromide gave only moderate yield that is consis-
tent with the previous reports by Chang’s group3a,b
(Table 1, entry 13).
Benzyl 4-methylbenzenesulfonate was not effective in
this reaction under our conditions (Table 1, entries 14 and
15).
© Thieme Stuttgart · New York
Synlett 2012, 23, 938–942

940
W. Mai et al.
LETTER
Table 2 Palladium-Catalyzed Benzylic Cross-Couplings of Pyridine N-Oxidesa,14
X
Pd(OAc)2 (5 mol%)
t-Bu3P-HBF4 (10 mol%)
R1
R2
R1
R2
+
Cl
K2CO3
toluene, 110 °C
N
O
N
O
H
1a–e
2a–e
3
X = C or N
Entry
Product
Yield (%)b
82
1
2
N
O
3aa
88
71
N
O
3ab
F
3
4
N
O
3ac
CF3
72
N
O
3ad
CN
5
6
80
62
N
O
3ba
NC
N
O
3bb
CN
7
75
N
O
3ce
N
8
9
88
78
N
O
3da
N
N
O
3dd
Synlett 2012, 23, 938–942
© Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Benzylic Cross-Couplings of Pyridine N-Oxides
941
Table 2 Palladium-Catalyzed Benzylic Cross-Couplings of Pyridine N-Oxidesa,14 (continued)
X
Pd(OAc)2 (5 mol%)
t-Bu3P-HBF4 (10 mol%)
R1
R2
R1
R2
+
Cl
K2CO3
toluene, 110 °C
N
O
N
O
H
1a–e
2a–e
3
X = C or N
Entry
Product
Yield (%)b
74
N
F
10
N
O
3dc
N
O
11
12
48
3eb
trace
N
O
a Conditions: 1 (1.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (0.05 mmol, 11 mg), t-Bu3P–HBF4 (0.1 mmol, 29 mg), K2CO3 (2.0 mmol, 276 mg), toluene
(3.0 mL), 110 °C, under N2, 16 h.
b Isolated yield.
The coupled products were easily deoxygenated to obtain In summary, we have developed a novel and easy method
the corresponding 2-benzyl pyridines in one step. For ex- to synthesize 2-benzylpyridine derivatives by palladium-
ample, when product 3aa was treated with PCl3 at room catalyzed benzylic cross-couplings with pyridine N-ox-
temperature in toluene, product 4 was obtained in 94% ides through C–H activation. Only simple modification on
isolated yield after one hour (Equation 1 in Scheme 1). pyridine was needed. Investigations on more efficient cat-
But no desired product 4 was found when using pyridine alyst systems toward the scope of pyridine N-oxides are
as substrate under our current catalyst system (Equation 2 under way.
in Scheme 1). When compared with the previous results
for the synthesis of 2-benzylpyridine derivatives, our
method has its advantages, no air-sensitive and water-sen-
sitive reagents were needed and all reagents used here are
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
cheap. It is a novel and easy route to synthesize 2-ben-
zylpyridine though the last step seems to be inferior
(Equation 3 in Scheme 1).
Acknowledgment
We gratefully acknowledge NSFC (No. 21172055) and the Henan
University of Technology for financial support.
PCl3
(1)
toluene
r.t., 1 h
N
O
N
References and Notes
3aa
4 94%
Pd(OAc)2 (5 mol%)
t-Bu3P-HBF4 (10 mol%)
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© Thieme Stuttgart · New York
Synlett 2012, 23, 938–942

942
W. Mai et al.
LETTER
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(14) General Procedure: An 50-mL vial was charged with
magnetic stir bar, pyridine N-oxide (1a; 1.5 mmol), benzyl
chloride (2a; 1.0 mmol), Pd(OAc)2 (0.05 mmol), t-Bu3P–
HBF4 (0.1 mmol), K2CO3 (2.0 mmol), followed by anhyd
toluene (3 mL). After stirring at 110 °C for 16 h, the reaction
mixture was filtered through Celite (washed with MeOH and
CH2Cl2). The combined organic phase was then evaporated
under reduced pressure and the isolated yield was obtained
by flash chromatography column on silica gel (gradient
eluent of MeOH in CH2Cl2: 1–5%).
2-Benzylpyridine N-Oxide (3aa): yellow solid. 1H NMR
(400 MHz, CDCl3): d = 8.32 (d, J = 2.8 Hz, 1 H), 7.33–7.40
(m, 2 H), 7.28–7.31 (m, 3 H), 6.95–7.19 (m, 2 H), 6.93–6.95
(m, 1 H), 4.28 (s, 2 H). 13C NMR (100 MHz, CDCl3): d =
151.9, 139.4, 136.2, 129.7, 128.8, 127.1, 125.8, 125.6,
123.6, 36.5. MS (ESI): m/z = 186.0 [M + 1]+. HRMS (ESI):
m/z [M + H]+ calcd for C12H12NO+: 186.0919; found:
186.0913.
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(400 MHz, CDCl3): d = 8.32 (d, J = 6.4 Hz, 1 H), 7.10–7.27
(m, 6 H), 6.71 (d, J = 7.2 Hz, 1 H), 4.25 (s, 2 H), 2.19 (s, 3
H). 13C NMR (100 MHz, CDCl3): d = 151.3, 139.4, 137.2,
134.4, 130.6, 127.5, 126.5, 125.7, 125.9, 125.1, 123.4, 34.4,
19.3. HRMS (ESI): m/z [M + H]+ calcd for C13H14NO+:
200.1075; found: 200.1073.
2-(4-Fluorobenzyl)pyridine N-Oxide (3ac): pale yellow
solid. 1H NMR (400 MHz, CDCl3): d = 8.35 (d, J = 5.2 Hz,
1 H), 7.19–7.28 (m, 4 H), 6.99–7.07 (m, 3 H), 4.26 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 163.2, 160.7, 151.6, 149.5,
131.9, 131.2, 125.7, 123.7, 123.9, 115.8, 35.8. HRMS (ESI):
m/z [M+H]+ calcd for C12H11FNO+: 204.0825; found:
204.0827.
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NMR (400 MHz, CDCl3): d = 8.28–8.30 (m, 1 H), 7.44–7.55
(m, 4 H), 7.18–7.21 (m, 2 H), 7.00–7.03 (m, 1 H), 4.32 (s, 2
H). 13C NMR (100 MHz, CDCl3): d = 150.8, 139.6, 137.3,
137.1, 133.0, 131.2, 130.9, 128.6, 129.3, 126.2, 126.17,
126.13, 126.1, 125.9, 125.7, 125.4, 124.1, 123.99, 123.95,
123.91, 122.66, 36.4. HRMS (ESI): m/z [M + H]+ calcd for
C13H11F3NO+: 254.0793; found: 254.0796.
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Synlett 2012, 23, 938–942
© Thieme Stuttgart · New York