Synthesis of 4-benzylpyridines via Pd-catalyzed CH3-arylation of 4-picoline

Article abstract of DOI:10.1039/c7ob01726j

A highly efficient synthesis of 4-benzylpyridines was developed via Pd-catalyzed C(sp³)-H arylation between 4-picoline and aryl halides. It was found that the best yields were achieved with a simple Pd(PPh₃)₄ catalyst and Cs₂CO₃ as the base. Compared with the known methods, our reaction does not require the use of a strong organometallic reagent as the base.

Full text of DOI:10.1039/c7ob01726j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Synthesis of 4-benzylpyridines via Pd-catalyzed CH3-
arylation of 4-picoline
Received 00th January 20xx,
Accepted 00th January 20xx
Jing Wu,a,b Dadian Wang, a Xiang Chen,a Qingwen Gui,a Hua Lib Ze Tan,*a Genping Huang*b and
Guangwei Wang*b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
highly efficient synthesis of 4-benzylpyridines was
developed via Pd-catalyzed C(sp3)-H arylation between 4-picoline
and aryl halides. It was found that best yields were achieved with
simple Pd(PPh3)4 catalyst and Cs2CO3 as base. Compared with
known methods, our reaction does not require the use of strong
organometallic reagent as the base.
Pd? /Phen/ArI
Cs2CO3
Pd? /ArOTf
CsOPiv
Ar
Ar
Ar
Eq. 3
Eq. 4
Eq. 1
Eq. 2
Yu's work
Itami's work
N
N
N
N
N
N
N
Pd? /Phen/ArOTs
Cs2CO3
1. TMPZnCl.LiCl
2. Pd(PPh3)4/ArBr
Ar
N
Tan's work
Knochel's work
Pd(PPh3)4/ArBr
Cs2CO3
Pyridine is one of the most important heteroaromatics in organic
chemistry and it is widely present in many natural products and
pharmaceutical compounds.1 As such the synthesis of pyridine
derivatives has always been the center of attention of organic
chemists.2 Recently arylation of pyridine via transition metal
catalyzed C-H functionalization3 has been an area of intensive
research since it avoids the use of prefunctionalized pyridine
compounds such as pyridine halides or pyridine organometallic
compounds. However, it is well known that activation of the C-H
bonds of pyridine ring is not easy because the pyridine ring is an
electron poor aromatic ring. Moreover, pyridine ring can bind to the
transition metal center to form inactive metal complex.
Consequently, C-H activation of pyridine ring is far underdeveloped
compared to other arenes. It was not until 2011 that Yu reported
C3-arylation of the parent pyridine for the first time, in which they
used aryl bromides and iodides as the arylating reagents (Scheme1,
Eq. 1).4 In 2013, our research group successfully replaced the aryl
bromides and iodides with aryl tosylates as the coupling partners,
thus allowing the use of phenol derivative as the source of aryl
group (Scheme1, Eq. 2).5 Itami recently reported that by using
Pd(OAc)2 as the catalyst and CsOPiv as the base, they were able to
successfully couple pyridine with aryl triflate as well (Scheme1, Eq.
3).6
Ar
Eq. 5
N
This work
Scheme 1 Synthesis of pNyridine derivatives via Pd-catalyzed C-H activation.
obtained was not the C3-naphthyl substituted pyridines, instead,
the arylation took place on the methyl group, thus generating the
corresponding diaryl methane derivatives. A close examination of
the literature revealed that even though Pd-catalyzed CH3-
arylations of nitro-substituted toluenes,7a 2-methyl pyridines, 2-
methyl azines7b-d and 2-methyl azine N-oxides7e,f as well as other
methyl substituted heteroaromatics7g,h are well known, report on
the Pd-catalyzed arylation of 4-picoline derivatives is scarce. As far
as we know, only one protocol has been developed by Knochel and
co-workers in 2011 and they reported that CH3-arylation of 4-
picoline can be realized via Pd-catalyzed cross coupling of aryl
halides with an organozinc compound generated by the reaction of
4-picoline with kinetically highly active LiCl-solubilized TMP base
(TMP = 2,2,6,6-tetramethylpiperidyl) TMPZnCl·LiCl (Scheme1, Eq.
4).8 It should be noted that in Itami’s reaction,6 C3-aryaltion was
also observed with naphthyl triflates. In order to understand how
the diaryl methane product was formed in our reaction and also in
continuation on our effort on transition metal catalyzed C-H
activations,9 we undertook a detailed study on the coupling of 4-
picoline with various aryl halides. Herein we present that by simply
changing the catalyst system, we can successfully synthesize a
variety of 4-benzylpyridines via Pd-catalyzed coupling of 4-picoline
with arylbromides (Scheme1, Eq. 5).
During our investigation in 2013, we noted that when we tried to
couple 4-picoline with naphthol derived tosylates, what we
a.State Key Laboratory of Chemo/Biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R.
China. E-mail: ztanze@gmail.com.
When we repeated the work of Yu’s with 4-picoline and
bromobenzene, we found that there is a small amount of pyridine
benzyl arylation product 3a formed in the crude product mixture
(Table 1, entry 1). Surprisingly, when the catalyst ligand system was
changed from Pd(OAc)2/Phen to Pd(PPh3)4, with the reaction
b.Department of Chemistry, Collaborative Innovation Center of Chemical Science
and Engineering, Tianjin University, Tianjin 300072, P. R. China. E-mail:
gphuang@tju.edu.cn wanggw@tju.edu.cn
Electronic Supplementary Information (ESI) available: Experimental details and
spectra of all products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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temperature being 140 oC, the yield of product 3a was increased to
30% while no C3-pyridine substitution product 4a was obtained
(Table 1, entry 2). Subsequently when we ran the reaction at 100 oC
for 48 hours, the yield of 3a was increased to 74% (Table 1, entry 3).
Finally a yield as high as 86% could be achieved when the reaction
temperature was further cooled down to 80 oC and the reaction
time was extended to 72 hours (Table 1, entry 4). If the reaction
products in good to excellent yields (67%-88%). As for the aryl
bromides with electron-rich substituents, substrates bearing methyl
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DOI: 10.1039/C7OB01726J
and methoxy group reacted normally to give the corresponding
benzylpyridine derivatives in yields ranging from 67-72%. On the
other hand, substrate 2g bearing a strong electron-donating group
such as N,N-dimethyl group only afforded the desired product 3ag
in 17% after 72 h. We surmise this is because the oxidative insertion
of the Pd-catalyst into the carbon-bromine bond in substrate 2g is
difficult due to the higher electron density on the phenyl ring. From
the table, we can see that substrates bearing a substituent on the
ortho position tend to generate the desired products in lower yields
(35-50%), showing that the reaction is slightly sensitive towards
steric hindrance (Table 2, entries, 3an-3ap). Besides phenyl
bromides, naphthyl bromides can also participate in the coupling
o
was carried out at 80 C with Yu’s catalyst system, only biphenyl
was formed in 42% yield. While the use of KOH and NaOH in place
of Cs2CO3 gave 3a in 67% and 55% yield, respectively, the use of
other bases such as K2CO3, LiOH, NaH, DBU and DABCO failed
completely (Table 1, entries 5-11). In addition, adding DMF, DMSO,
DMI, NMP, toluene, THF or dioxane into the reaction mixture as
solvent or cosolvent did not benefit the reaction either (not shown
in Table 1; Considerably lower yields were obtained). Moreover,
replacing PPh3 with ligands such as dppf, BINAP, DPEPhos, Peppsi,10 well, providing the corresponding products 3aq and 3ar in 64% and
o-(tol)3P or tricyclohexylphosphine all led to disappointing results
(Table 1, entries 12-17). Among the various ligands screened, only
xantphos and dppp gave the desired product in yields around 70%
(Table 1, entries 18 and 19). Tests also showed that no reaction
took place in the absence of Pd-catalyst, showing the catalyst is
essential for the reaction to proceed. Based on these results, we
decided to set reacting 4-picoline (3 mL) with phenylbromide (0.5
65% yield, respectively.
a,b
Table 2. Pd-catalyzed arylation of 4-picoline with bromobenzenes
R1
Pd(PPh3)4 (5 mol %)
Br
R1
Cs2CO3 (2.5 equiv)
R2
R2
+
N
80 oC, 72 h
N
1
2
3aa-3av
OMe
o
N
N
N
N
N
N
N
N
mmol) in the presence of 5 mol % of Pd(PPh3)4 at 80 C for 72 h as
our standard conditions.
3aa
3ad
3ab
3ac
3af
, 74%
, 74%
, 70%
O
O
a
N
Table 1. Screening of the reaction conditions
OMe
N
Ph
F
3ae
, 72%
, 67%
, 71%
catalyst (5 mol %)
ligand (15 mol %)
base (2.5 equiv)
Br
+
N
+
Cl
N
N
80 oC, 72 h
N
3ag
3ah
3ai
, 76%
, 17%
, 75%
1a
2a
3a
4a
CF3
b
entry
ligand
base
yield of
trace
(%) yield of 4ae
catalyst
3a
N
N
N
N
COOEt
CF3
1c
2c
CN
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
53
Phen
3aj, 67%
3ak, 76%
3al, 88%
ND
ND
-
30
74
86
67
55
0
3d
4
-
N
ND
ND
-
[c]
3am
3an
3ao
, 21% (43%
, 82%
, 35%
)
5
6
-
KOH
OMe
ND
ND
-
NaOH
K2CO3
7
-
N
N
N
ND
ND
ND
ND
ND
ND
ND
ND
ND
8
-
LiOH
0
3ap, 50%
3as, 71%
3aq, 64%
3ar, 65%
9
-
NaH
0
N
N
10
11
12
13
14
15
16
17
18
19
-
0
DBU
N
N
N
-
DABCO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
N
N
3at, 23%
3au, NR
3av, messy
dppfPdCl2
Pd(OAc)2
Pd(OAc)2
-
0
BINAP
50
46
35
15
23
70
72
DPEPhos
N
N
N
F
Cl
Peppsi
-
-
3ax
3aw
, 57%
3ay
, 56%
, 51%
(o-Tol3P)2PdCl2
Pd(OAc)2
a
PCy3
ND
ND
Reaction conditions: 1a (3.0 mL), 2 (0.5 mmol), Pd(PPh3)4 (5 moL %), and
Pd(OAc)2
Cs2CO3 (1.25 mmol) at 80 oC for 72 h.
conducted at 100 oC, 72 h.
Isolated yields.
Reaction was
b
c
xantphos
-
ND
(DPPP)2PdCl2
a
Reaction conditions: 1a (3.0 mL), 2a (0.5 mmol), catalyst (0.025 mmol),
ligand (0.075 mmol) and base (1.25 mmol), under N2, 80 oC, 72 h. b Isolated
We were also able to couple 3-bromopyridine with 4-picoline to
synthesize bipyridine compound 3as in 71% yield. On the other
hand, the coupling of 3-bromopyrimidine with 4-picoline only
provided the desired product 3at in 23% yield. It should be
mentioned attempts to couple 3-picoline with phenylbromide
under our standard conditions led to complete failure whereas the
coupling with 2-picoline gave rather messy result (Table 2, entries
3au and 3av). Even though attempts to couple 4-ethylpyridine or
lepidine with phenyl bromide under our standard condition only
gave the desired coupling products in trace amount (not shown in
yields of 3a. Reaction was conducted at 140 oC, 48 h. Reaction was
c
d
conducted at 100 oC, 48 h. e Yields determined by GC.
With the optimized conditions in hand, we next set out to
explore the substrate scope of aryl bromides and the results were
summarized in Table 2. As shown in Table 2, a variety of aryl
bromides were compatible with this transformation. Phenyl
bromides with electron withdrawing groups such as CF3, F, Cl, CN,
CO2Et etc. on the phenyl ring reacted smoothly to give the desired
2 | J. Name., 2012, 00, 1-3
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Table 2), we were glad to see that 3,4-dimethylpyridine is a viable attempts to identify a possible intermediate B using 31P NMR failed;
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DOI: 10.1039/C7OB01726J
substrate for our reaction. We successfully coupled 3,4- see mechanistic discussion below). This hypothesis is corroborated
dimethylpyridine with phenyl bromide, 4-fluorophenylbromide and by the fact, with the optimized conditions, there are no desired
4-chlorophenyl bromide and the corresponding products 3aw, 3ax, products formed for pyridine derivatives such as 2,4-
3ay were obtained in yields above 50%. It should be noted that in dimethylpyridine, 2-chloro-4-methylpyridine. We believe that the
all cases we tested, formation of C3-arylation product was not substituent on the 2-position makes the coordination of the Pd-
observed.
catalyst to the nitrogen atom of the pyridine ring more difficult,
Besides aryl bromides, we also investigated the reactions of 4- thus shutting down the deprotonation step. When 4-methyl
picoline with iodo- and chlorobenzene derivatives (Eq. 6 and 7). The pyridine was replaced with either pyridine or 4-methoxypyridine,
coupling of iodobenzene with 4-picoline proceeded satisfactorily to no 2- or 3-phenyl substituted pyridine was formed under our
give 3a in 67 % yield whereas no reaction took place when p- standard condition (Eq. 11). This means C2-H or C3-H activation was
chlorobenzotrifluoride was subjected to our standard reaction not active under our reaction condition. Thus the possibility of our
conditions. When the reaction temperature was raised to 140 oC for reaction going through an initial C(sp2)-H activation followed by
48 h, much to our surprise, the main product was the C3-arylation subsequent C(sp3)-H activation can be largely ruled out. Additionally,
product 4aw whereas the desired product 3am was only isolated in the reaction is also unlikely to involve the formation of a benzylic
trace amount (Eq. 7). This result suggests that C(sp2)-H activation radical intermediate since the reaction proceeded normally when a
process may become the major reaction pathway at higher stoichiometric amount of radical scavenger TEMPO was added to
temperature.
the reaction mixture.
I
D
Pd(PPh3)4 (5 mol %)
Cs2CO3 (2.5 equiv)
D
D
D
3a, 67%
Eq. 6
D
+
Br
N
80 oC, 72 h
or
N
Eq. 9a
+
N
D
N
D
KH/KD = 1.45
Cl
D
N
D
Pd(PPh3)4 (5 mol %)
Cs2CO3 (2.5 equiv)
N
3a
reactions run in parallel
3am, trace
4aw, 36%
1a-d5
1a
3a-d4
N
CF3
CF3
+
+
D
Eq. 7
140 oC, 48 h
N
N
CF3
Cs2CO3
D2O
Eq. 10b
+
80 oC, 3 h
N
N
N
not observed
In order to demonstrate the synthetic potential of our strategy, our
method was successfully applied to the synthesis of 3az, a metal-driven
self-assembly pyridine ligand.11 The reported synthesis of 3az not only
requires the use of strong base LDA in conjunction with ZnCl2 but also
the yield is only 31%.11 With our method, 3az could be constructed in
40% yield with much simpler experimental operations (Eq. 8).
1a-d1
1a
1a
R
N
R
R
Ph
standard condition
+
Br
Eq. 11a
N
Ph
N
1a
R = H, MeO
both not formed
a
Reaction conditions: Pd(PPh3)4 (0.025 mmol), bromobenzene (0.5 mmol)b,
Cs2CO3 (1.25 mmol), 1a (15.4 mmol) or 1a-d5 (15.4 mmol), under 80 oC, 72 h.
Reaction conditions: 1a (3.0 mL), Cs2CO3 (1.25 mmol), D2O (10 mmol).
N
Br
Pd(PPh3)4 (15 mol %)
N
Scheme 3 Control experiments.
Cs2CO3 (7.5 equiv)
+
80 oC, 72 h
Based on the results above and known literature reports,13
a
N
Br
Br
3az, 40%
Eq. 8
N
tentative mechanism is proposed and shown below (Scheme 4). As
usual, phenyl bromide undergoes oxidative addition with Pd(0)
catalyst to generate intermediate A which subsequently complexes
with a molecule of 4-picoline to form intermediate B. Next, base
abtracts one hydrogen from the CH3 group and the carboanion
a
Reaction conditons: 4-picoline (3.0 mL), 1,3,5-tribromobenzene (0.5 mmol),
Pd(PPh3)4 (0.075 mmol), Cs2CO3 (3.75 mmol), at 80 oC for 72 h.
Scheme 2 Synthesis of 1,3,5-tris(pyridin-4-ylmethyl)benzene.a
In order to gain some information on the mechanism of this new
transformation, several control experiments were performed. Since generated can undergo transmetallation with the Pd(II) center to
the reaction may proceed through a C(sp3)-H activation process
form the diorgano palladium (II) species C. After reductive
elimination, the final product 3 is produced and Pd(0) catalyst is
similar to Yu’s protocol,4 we examined the kinetic isotope effect by
studying the reaction rate of 1a and its deuterated analogue 1a-d5. regenerated and the catalytic cycle is completed.
The kinetic isotopic effect (kH/kD) was 1.45 for parallel reactions of
12
1a and 1a-d5 with phenyl bromide under the standard reaction
conditions (Eq. 9). This rather small KIE suggested that the cleavage
of the C(sp3)-H bond was not involved in the rate determining step.
Moreover, no deuterium was incorporated into the methyl group of
o
1a after we treated 1a with Cs2CO3 at 80 C for 3 h and quenched
the reaction with D2O (Eq. 10). Additionally examination of
recovered 4-picoline using a mixture of 1a and 1a-d5 as starting
Scheme 4 Possible reaction mechanism
material did not show H/D exchange (not shown in Scheme 3). All
these results mean that direct deprotonation via Cs2CO3 may not be
possible and the deprotonation step may be assisted by the Pd-
catalyst via the formation of a pyridine-Pd complex (Unfortunately,
In summary, we have successfully developed an efficient
synthesis of 4-benzylpyridine derivatives via Pd-catalyzed C(sp3)-H
arylation of 4-picoline with aryl halides. Best yields were achieved
with simple Pd(PPh3)4 catalyst and Cs2CO3 as base. Compared with
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Chem., 2013, 11, 6246-6249; (e) L. Campeau, D. J. Schipper,
known methods, our reaction does not need to use strong
organometallic reagent as the base and the reaction is very simple
to run. We believed that coordination of 4-picoline to the organo-
Pd intermediate generated in the reaction mixture is essential for
the activation of the C(sp3)-H bond. Efforts are underway to expand
the reaction scope and the results will be reported in due course.
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8
9
S. Duez, A. K. Steib, S. M. Manolikakes and P. Knochel,
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(a) J. Liu, S. Zhuang, Q. Gui, X. Chen, Z. Yang and Z. Tan, Adv.
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G. Wang would like to thank National Basic Research Program of
China (2015CB856500) for financial support.
Gui, X. Chen, W. Wang, Z. Tan, Chem. Commun., 2015, 51
,
6418; (c) Q. Gui, X. Chen, L. Hu, D. Wang, J. Liu and Z. Tan,
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11 For application of 1,3,5-tris(pyridin-4-ylmethyl)benzene, see:
D. K. Chand, M. Fujita, K. Biradha, S. Sakamoto and K.
Yamaguchi, Dalton Trans., 2003, 13, 2750-2756.
3
4
For some reviews on arylation via transition metal catalyzed
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Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792-9826; (b) B.
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Tantayanon, J. Heterocycle Chem., 2009, 46, 213-216.
13 For selected examples, see: (a) D. García-Cuadrado, A. A. C.
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