Nickel-catalyzed N-heterocycle-directed cross-coupling of fluorinated arenes with organozinc reagents

Article abstract of DOI:10.1016/j.tet.2014.04.052

Nickel-catalyzed N-heteroaromatics, such as pyridine, pyrazine or pyrimidine-directed cross-coupling of fluorinated arenes with organozinc reagents in the presence of sodium and PCy₃ was reported.

Full text of DOI:10.1016/j.tet.2014.04.052

Tetrahedron xxx (2014) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nickel-catalyzed N-heterocycle-directed cross-coupling
of fluorinated arenes with organozinc reagents
,b,
Sen-Han Xiao a, Yang Xiong a, Xu-Xue Zhang a, Song Cao a
*
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Nickel-catalyzed N-heteroaromatics, such as pyridine, pyrazine or pyrimidine-directed cross-coupling of
fluorinated arenes with organozinc reagents in the presence of sodium and PCy3 was reported.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 5 March 2014
Received in revised form 10 April 2014
Accepted 17 April 2014
Available online xxx
Keywords:
Nickel
Heterocycles
Fluorinated arenes
Organozinc reagents
Sodium
1. Introduction
unactivated aryl fluorides as coupling partners is still rare.9 For
example, in 2007, Love reported the Pt2Me4(SMe2)2-catalyzed
The functionalization of carbonefluorine bonds still remains
a significant challenge in organic chemistry due to the exceptional
stability of the CeF bond.1 Recently, transition metal-catalyzed
pyridine-directed ortho CeH bond activation has gained much at-
tention.2 However, most current research has focused on CeH
functionalization,3 transition metal-catalyzed pyridine-directed
ortho CeF bond activation is very scarce.4 In 2011, Tobisu and Cha-
tani reported a nickel-catalyzed SuzukieMiyaura cross-coupling
reaction of boronic ester with aryl fluoride bearing directing
group, such as pyridine.5 In 2013, Lu and Shen developed the first
example of palladium-catalyzed cross-coupling of 2-pyridyl-poly-
cross-coupling reactions of polyfluoroaryl imines with Me2Zn to
generate functionalized fluoroarenes.10 More recently, Li described
the Ni(PMe3)3Me2 or Ni(PMe3)4 catalyzed reactions of poly-
fluoroaryl imines with Me2Zn.11 In continuation of our studies on
the activation and functionalization of CeF bonds,12 in this paper,
we have developed the nickel-catalyzed cross-coupling reactions of
fluorinated aryl pyridines, pyrazines or pyrimidines with organo-
zinc reagents under the assistance of sodium (Scheme 1).
2. Results and discussion
fluoroarenes with heteroarenes via
a
concurrent CeF/CeH
Our initial investigation was focused on the coupling reaction of
2-(2-fluorophenyl)pyridine 1a with diethyl zinc 2a. After exten-
sively surveying reaction conditions, such as metal catalysts, li-
gands, solvents, and the amount of sodium (Table 1), we found that
the reaction of 2-(2-fluorophenyl)pyridine 1a (1 equiv) with diethyl
zinc 2a (4 equiv) could proceed smoothly in the presence of
10 mol % NiCl2(dppp), 20 mol % PCy3, 2.75 equiv of sodium using
THF as the solvent at 80 ꢀC for 6 h under an argon atmosphere and
afforded the desired coupling product 3aa in 87% yield (GC) (Table
1, entry 11). Importantly, the addition of sodium is essential for this
CeF bond activation reaction and no alkylated product 3aa was
formed in the absence of sodium (Table 1, entry 12). The re-
placement of sodium with other reducing agents, such as Mg or
LiAlH4 led to the failure of this cross-coupling reaction.
activation.6
Transition metal-catalyzed cross-coupling reactions of organic
halides with organozinc reagents have been extensively in-
vestigated over the past few decades and become one of the ex-
tremely powerful tools for the formation of carbonecarbon bond
because of the high functional group compatibility of organozinc
compounds.7 Among the suitable electrophilic coupling partners
with organozinc reagents, aryl bromides, iodides, or activated
chlorides have been studied most widely.8 However, the use of
* Corresponding author. Tel.: þ86 21 64253452; fax: þ86 21 64252603; e-mail
address: scao@ecust.edu.cn (S. Cao).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.052
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2
S.-H. Xiao et al. / Tetrahedron xxx (2014) 1e7
l
l
Scheme 1. Cross-coupling between aryl fluorides 1aem and organozinc reagents 2aec.
Table 1
To survey the generality of this novel cross-coupling reaction,
two other organozinc reagents and several aryl fluorides containing
nitrogen heterocycle were examined under the optimized condi-
tions (Tables 2e5). The results, shown in Table 2, indicated that
reactions of 2a or 2b with various fluorinated arenes using pyridyl
as a directing group proceed smoothly and afforded the CeC cou-
pling products in good to high yields. Generally, the aryl fluorides
bearing electron-withdrawing substituents on the benzene ring
were somewhat more reactive than the aryl fluorides with
electron-donating substituents. With 2-(perfluorophenyl)pyridine
1g, which has two CeF bonds ortho to the pyridyl nitrogen, the
expected product 3gb was obtained in a relatively lower yield than
other substrates, due to further methylation of the product 3gb.
To our delight, besides the pyridine, other N-heterocycles, such
as pyrazine or pyrimidine, could also be used as directing group in
this CeF bond functionalization reaction (Table 3). Furthermore,
the use of pyridyl, pyrazinyl, or pyrimidinyl as directing group
made no obvious differences to the yields of reaction (for example,
Table 2, 3cb and Table 3, 3hb, 3lb).
Cross-coupling reactions of benzylzinc bromide 2c with aryl
fluorides containing different nitrogen heterocycles were also per-
formed (Table 4, 1a,f,h,k). The presence of electron-withdrawing
groups on the benzene ring of aryl fluorides was favorable for the
reactions and afforded coupling products in good yields. In the case
of 1a, the expected product 3ac was isolated in low yields due to the
lower reactivity of 1a and the formation of 1,2-diphenylethane,
a homocoupling product from benzylzinc bromide, as a byproduct.
When p-methylphenyl zinc iodide 2d was used as coupling
partner under the same reaction conditions (Table 5), the reactions
failed to proceed efficiently, only 1l afforded the desired product
3ld in 30% yield (GCeMS). It might be due to the low reactivity of
p-methylphenyl zinc iodide toward aryl fluorides and steric
Optimization of reaction conditions for the cross-coupling of 2-(2-fluorophenyl)
pyridine 1a with diethyl zinc 2aa
l
l
Entry
Catalyst
Ligand
Na (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
None
PdCl2(PPh3)2
Pd(PPh3)4
Co(acac)2
RuCl2(PPh3)2
Ni(acac)2
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
None
dppe
dppf
dppm
phen
PCy3
PCy3
PCy3
2.75
2.75
2.75
2.75
2.75
2.75
2.75
2.75
2.75
2.75
2.75
0
1.50
2.00
3.00
2.75
2.75
2.75
2.75
2.75
2.75
2.75
2.75
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Dioxane
DMSO
CH3CN
0
0
0
Trace
0
40
56
52
60
79
87
Trace
61
68
76
0
Trace
18
36
65
63
0
Ni(cod)2
NiBr2(PPh3)2
NiCl2(PCy3)2
NiBr2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
NiCl2(dppp)
0
a
The reactions were conducted with 1a (1 mmol) and 2a (4 mmol) at 80 ꢀC for 6 h.
Yields referred to the desired product 3aa. Yields determined by GC analysis and
b
based on 1a.
Table 2
Reactions of 2-(2-fluorophenyl)pyridine derivatives 1aeg with organozinc reagents 2a,ba,b
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3
Table 3
Reactions of 2-(2-fluorophenyl)pyrazine or 2-(2-fluorophenyl)pyrimidine derivatives 1hem with 2ba,b
Table 4
Cross-coupling reactions of 1a,f,h, and k with benzylzinc bromide 2ca,b
Table 5
Cross-coupling reactions of 1a,h, and l with p-methylphenyl zinc iodide 2da
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4
S.-H. Xiao et al. / Tetrahedron xxx (2014) 1e7
hindrance between the pyridine (pyrazine or pyrimidine) and the
introduced benzene ring.
cleavage of the CeF bond and the formation of the CeC bond took
place regioselectively at the ortho position of the pyridyl, pyrazinyl,
or pyrimidinyl group. Preliminary mechanistic experiments sug-
gest that the reaction may involve radical intermediates. This novel
strategy provides a practical and efficient alternative for inert CeF
bond activation. It is one of the few successful examples that ap-
plied aryl fluorides as the coupling partners to react with organ-
iczinc reagents in the Negishi-type coupling reaction.
In addition, treatment of 2-(2-chlorophenyl)pyridine 1n with
Et2Zn 2a under the optimized reaction conditions could also afford
the desired product 3aa in 80% yield (GCeMS) (Scheme 2). The
reaction of 2-phenylpyridine 1o with Et2Zn 2a was also performed,
but no expected product 3aa was detected. It suggested that the
CeH bond ortho to the pyridyl nitrogen could not be activated in
this catalytic system. When 2-(3,4-difluorophenyl)pyridine 1p was
used as substrate to react with Et2Zn 2a, no cross-coupling reaction
was observed. This example further demonstrated that only the
CeF bond ortho to the pyridyl nitrogen could be activated and the
CeF bonds at the meta or para positions of the pyridyl group
remained untouched. Finally, for comparison purpose, 1-fluoro-2-
nitrobenzene 1q was used as a coupling partner, but no reaction
was observed. This implied that the only existence of strong elec-
tron-withdrawing group on benzene ring without the assistance of
directing group could not make the reaction proceed smoothly.
4. Experimental section
4.1. General
All reagents were of analytical grade, obtained from commercial
suppliers. All reactions were carried out under argon with dry sol-
vents under anhydrous conditions. THF was distilled from Na under
argon and stored under argon. Melting points were measured in an
€
open capillary using Buchi melting point B-540 apparatus and are
uncorrected. 1H NMR and 13C NMR spectra were recorded on
a Bruker AM-400 spectrometer (400 MHz and 100 MHz, re-
spectively) using TMS as internal standard. The 19F NMR were ob-
tained using a Bruker AM-400 spectrometer (376 MHz) and
measured with external CF3CO2H as the standard. Gas chromatog-
raphyemass spectra (GCeMS) were recorded on HP 5973 MSD with
6890 GC. High resolution mass spectra (HRMS) were recorded un-
der electron impact conditions using a MicroMass GCT CA 055 in-
strument and recorded on a MicroMass LCTTM spectrometer.
4.2. Synthesis of compounds 1aef and 1hep
Compounds 1aef and 1hep were prepared according to the
literature procedure5,13 Compound 1g was prepared according to
the literature procedure.14 The data of NMR and HRMS of new
compounds 1h,i,l, and m were as follows.
4.2.1. 2-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrazine (1h). Yellow-
Scheme 2. Reactions of aryl pyridines (1n,o,p) or 1-fluoro-2-nitrobenzene 1q with 2a
under the optimized reaction conditions.
green liquid;1HNMR(400MHz, CDCl3)
d
9.13 (s,1H), 8.70(s,1H), 8.58(d,
J¼2.4 Hz, 1H), 8.39 (dd, J¼6.9, 2.0 Hz, 1H), 7.71e7.68 (m, 1H), 7.33e7.28
(m, 1H); 13C NMR (100 MHz, CDCl3)
d
162.0 (d, J¼256.2 Hz), 147.5 (d,
In order to gain some mechanistic insight into the Ni-catalyzed
CeF activation, several additional experiments were performed
using the model reaction under the standard reaction conditions.
When the reaction of 1a with 2a was performed in the presence of
1, 2, 3, and 4 equiv of the radical inhibitor, 4-benzoylamino-TEMPO
J¼3.7 Hz), 145.3, 145.2, 144.4, 143.8, 128.6e128.5 (m), 128.4e128.3 (m),
127.5 (q, J¼33.3 Hz),124.9 (d, J¼13.3 Hz),123.5 (q, J¼270.4 Hz); 19F NMR
(376 MHz, CDCl3)
d
ꢁ62.3 (s, 3F), ꢁ110.1 to ꢁ110.2 (m, 1F); HRMS (EI):
calcd for C11H6F4N2 [M]þ: 242.0467, Found: 242.0468.
(2,2,6,6-tetramethyl-4-benzolyamido-1-piperidinyloxy),
re-
4.2.2. 2-(2,3-Difluorophenyl)pyrazine (1i). White
solid;
Mp:
68.3e69.4 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.09 (s, 1H), 8.69 (s, 1H),
spectively, no expected coupling product 3aa was observed. TEMPO
reacted with diethyl zinc 2a to form the ethylated 4-benzoylamino-
TEMPO (GCeMS, 60e70%). On the other hand, when 4.0 equiv of
the free neutral radical galvinoxyl was added to the reaction sys-
tem, the reaction failed to afford the desired product. The results
suggest that the reaction may involve a radical process.
Although the exact mechanism of the reaction and the role of
sodium are still unclear at present stage, on the basis of the above
experimental observations, we speculated that the CeF bond in
fluorinated arenes might be weakened and stretched by sodium.
The nickel catalyst, which coordinated with nitrogen atom on N-
heterocyclics could further activate the CeF bond and lead to form
a radical intermediate. Further studies to find strong evidence to
support this novel mechanism as well as to elucidate the detailed
mechanism are underway in our lab.
8.57 (d, J¼2.4 Hz, 1H), 7.77e7.74 (m, 1H), 7.29e7.22 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d
151.3 (dd, J¼246.9, 13.3 Hz), 149.1 (dd, J¼251.7,
13.9 Hz), 148.7e148.6 (m), 145.6 (d, J¼11.6 Hz), 144.8, 143.9, 126.8 (d,
J¼9.0 Hz), 125.8 (dd, J¼3.5, 1.6 Hz), 124.9 (dd, J¼6.9, 4.7 Hz), 118.7 (d,
J¼17.1 Hz); 19F NMR (376 MHz, CDCl3)
d
ꢁ137.5 to ꢁ137.6 (m, 1F),
ꢁ141.5 to ꢁ141.6 (m, 1F); HRMS (EI): calcd for C10H6F2N2 [M]þ:
192.0499, Found: 192.0500.
4.2.3. 2-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidine (1l). White
solid; Mp: 76.3e77.2 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.90 (d, J¼5.2 Hz,
2H), 8.44 (dd, J¼6.9, 2.1 Hz,1H), 7.75e7.71 (m, 1H), 7.35e7.29 (m, 2H);
13C NMR (100 MHz, CDCl3)
d
162.9 (d, J¼260.2 Hz),162.1 (d, J¼5.1 Hz),
157.4, 129.7e129.6 (m), 128.9e128.8 (m), 126.9 (qd, J¼33.1, 3.8 Hz),
127.0, 126.9, 123.7 (q, J¼270.3 Hz), 117.7 (d, J¼23.9 Hz); 19F NMR
(376 MHz, CDCl3)
d
ꢁ62.1 (s, 3F), ꢁ109.0 to ꢁ109.1 (m,1F); HRMS (EI):
3. Conclusions
calcd for C11H6F4N2 [M]þ: 242.0467, Found: 242.0468.
In summary, we have developed a novel Ni-catalyzed N-het-
erocycle-directed cross-coupling reaction of fluorinated arenes
with alkylzinc reagents under the assistance of sodium. The
4.2.4. 2-(2,3,4-Trifluorophenyl)pyrimidine (1m). White solid; Mp:
66.4e67.3 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.83 (d, J¼4.8 Hz, 2H),
7.88e7.83 (m, 1H), 7.26e7.23 (m, 1H), 7.08e7.01 (m, 1H); 13C NMR
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S.-H. Xiao et al. / Tetrahedron xxx (2014) 1e7
5
(100 MHz, CDCl3)
d
161.9, 157.3, 152.3 (ddd, J¼252.4, 10.2, 2.7 Hz),
NMR (100 MHz, CDCl3)
131.4, 129.5, 126.5, 124.0, 121.3, 21.0, 20.1.
d
160.0, 149.0, 137.9, 137.5, 136.0, 135.4,
150.8 (ddd, J¼259.1, 11.0, 3.3 Hz), 140.5 (dt, J¼249.0, 15.3 Hz), 125.5
(ddd, J¼8.1, 4.3, 1.8 Hz), 124.0 (dd, J¼6.5, 3.7 Hz), 119.5, 111.9 (dd,
J¼17.3, 4.2 Hz); 19F NMR (376 MHz, CDCl3)
d
ꢁ131.1 to ꢁ131.2 (m,
4.3.6. 2-(2-Methyl-5-(trifluoromethyl)phenyl)pyridine
(3cb). The
1F), ꢁ135.3 to ꢁ135.4 (m, 1F), ꢁ159.9 (d, J¼4.9 Hz, 1F); HRMS (EI):
compound (CAS No. 914253-91-1) was prepared according to the
general procedure with 1.75 equiv Na. Light yellow liquid (Yield:
calcd for C10H5F3N2 [M]þ: 210.0405, Found: 210.0407.
83%); Eluent¼EtOAc/Hexane (1/15); 1H NMR (400 MHz, CDCl3)
d 8.71
4.3. General procedure for the synthesis of compounds 3
(d, J¼4.4 Hz,1H), 7.79e7.75 (m, 1H), 7.67 (s, 1H), 7.54 (d, J¼8.0 Hz, 1H),
7.42e7.38 (m, 2H), 7.30e7.27 (m,1H), 2.41 (s, 3H); 13C NMR (100 MHz,
A 25 mL of dried round-bottom flask was charged with Na
(0.75e1.375 mmol), NiCl2(dppp) (0.05 mmol), PCy3 (0.1 mmol),
organozinc reagents 2aed (2 mmol), and THF (4 mL) under an ar-
gon atmosphere. The mixture was stirred at 0 ꢀC for 1.5 h. A solution
of 1aeq (0.5 mmol) in THF (4 mL) was added dropwise and then
stirred for 4.5 h at 80 ꢀC. After the reaction completed, the mixture
was cooled to room temperature and 2 mL of ethyl acetate was
added. The mixture then was extracted with ethyl acetate
(3ꢂ10 mL). The combined organic layer was washed with brine
(3ꢂ10 mL), dried over MgSO4, and concentrated under reduced
pressure. The residue then was purified by chromatography on
silica gel to provide the corresponding products 3.
CDCl3)
126.5 (q, J¼3.7 Hz), 124.9 (q, J¼3.7 Hz), 124.3 (q, J¼270.3 Hz), 124.1,
122.3, 20.4; 19F NMR (376 MHz, CDCl3)
ꢁ62.3 (s, 3F).
d
158.6, 149.5, 140.9, 140.1, 136.5, 131.2, 128.4 (q, J¼32.3 Hz),
d
4.3.7. 2-(3-Fluoro-2-methylphenyl)pyridine (3db). The compound
was prepared according to the general procedure with 1.75 equiv
Na. Light yellow liquid (Yield: 86%); Eluent¼EtOAc/Hexane (1/15);
1H NMR (400 MHz, CDCl3)
d
8.70e8.69 (d, J¼4.8 Hz, 1H), 7.76e7.72
(m, 1H), 7.39e7.36 (m, 1H), 7.27e7.18 (m, 3H), 7.09e7.04 (m, 1H),
2.25 (d, J¼2.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 160.7 (d,
J¼242.2 Hz), 157.9 (d, J¼3.3 Hz), 148.4, 141.8 (d, J¼4.4 Hz), 135.4,
125.8 (d, J¼8.9 Hz), 124.3 (d, J¼3.3 Hz), 123.3, 122.4 (d, J¼17.3 Hz),
121.2, 114.0 (d, J¼23.2 Hz), 11.0 (d, J¼5.3 Hz); 19F NMR (376 MHz,
4.3.1. 2-(2-Ethylphenyl)pyridine (3aa). The compound (CAS No.
914253-97-7) was prepared according to the general procedure with
2.75 equiv Na. Light yellow liquid (Yield: 80%); Eluent¼EtOAc/Hex-
CDCl3)
d
ꢁ115.8 to ꢁ115.9 (m, 1F); HRMS (EI): calcd for C12H10FN
[M]þ: 187.0798, Found: 187.0790.
ane (1/20). 1H NMR (400 MHz, CDCl3)
d
8.72 (d, J¼4.4 Hz, 1H),
4.3.8. 2-(4-Fluoro-2-methylphenyl)pyridine (3eb). The compound
(CAS No.1314915-88-2) was prepared according to the general
procedure with 1.75 equiv Na. Light yellow liquid (Yield: 88%);
7.78e7.74 (m, 1H), 7.42e7.37 (m, 4H), 7.32e7.25 (m, 2H), 2.76 (q,
J¼7.6 Hz, 2H), 1.14 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
159.2, 148.1, 140.9, 139.1, 135.1, 128.7, 127.9, 127.4,124.7, 123.0, 120.6,
Eluent¼EtOAc/Hexane (1/15). 1H NMR (400 MHz, CDCl3)
d 8.70 (d,
25.0, 14.5.
J¼4.0 Hz, 1H), 7.77e7.73 (m, 1H), 7.40e7.37 (m, 2H), 7.28e7.24 (m,
1H), 7.01e6.96 (m, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
4.3.2. 2-(2-Ethyl-4-methylphenyl)pyridine (3ba). The compound
was prepared according to the general procedure with 2.50 equiv
Na. Light yellow liquid (Yield: 71%); Eluent¼EtOAc/Hexane (1/25).
d
162.5 (d, J¼245.2 Hz), 159.1, 149.3, 138.4 (d, J¼8.0 Hz), 136.6 (d,
J¼3.1 Hz), 136.2, 131.3 (d, J¼8.5 Hz), 124.1, 121.7, 117.2 (d, J¼20.9 Hz),
112.7 (d, J¼21.0 Hz), 20.4 (d, J¼1.2 Hz); 19F NMR (376 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
d
8.67e8.65 (m, 1H), 7.73e7.68 (m, 1H),
d
ꢁ114.6 (d, J¼6.0 Hz, 1F).
7.37e7.34 (m, 1H), 7.25e7.19 (m, 2H), 7.13e7.12 (m, 1H), 7.08e7.06
(m, 1H), 2.73 (q, J¼7.6 Hz, 2H), 2.37 (s, 3H), 1.08 (t, J¼7.6 Hz, 3H); 13
C
4.3.9. 2-(3,4-Difluoro-2-methylphenyl)pyridine (3fb). The com-
pound was prepared according to the general procedure with
1.75 equiv Na. White solid (Yield: 90%); Eluent¼EtOAc/Hexane
NMR (100 MHz, CDCl3) d 160.4,149.2,141.9,138.2,137.5,136.0,129.9,
129.8, 126.6, 124.2, 121.5, 26.1, 21.4, 15.7; HRMS (EI): calcd for
C
14H15N [M]þ: 197.1204, Found: 197.1203.
(1/20); Mp: 72.7e73.9 ꢀC.1H NMR (400 MHz, CDCl3)
d 8.69e8.68 (m,
1H), 7.76e7.73 (m, 1H), 7.36e7.34 (m, 1H), 7.29e7.25 (m, 1H),
4.3.3. 2-(2-Ethyl-5-(trifluoromethyl)phenyl)pyridine (3ca). The com-
pound was prepared according to the general procedure with
1.50 equiv Na. Light yellow liquid (Yield: 83%); Eluent¼EtOAc/Hex-
7.16e7.12 (m,1H), 7.07e7.05 (m,1H), 2.29 (d, J¼2.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
158.3 (d, J¼2.4 Hz), 150.7 (dd, J¼248.0, 12.9 Hz),
149.7, 149.5 (dd, J¼243.3, 12.4 Hz), 137.9e137.8 (m), 136.7, 126.2 (d,
J¼13.3), 125.3 (dd, J¼6.8, 4.1 Hz), 124.4, 122.4, 114.3 (d, J¼17.1 Hz),
ane (1/25). 1H NMR (400 MHz, CDCl3)
d 8.72e8.71 (m, 1H), 7.80 (td,
J¼7.6, 1.8 Hz, 1H), 7.61e7.59 (m, 2H), 7.45e7.40 (m, 2H), 7.33e7.30 (m,
12.4 (dd, J¼5.2, 2.3 Hz); 19F NMR (376 MHz, CDCl3)
d
ꢁ138.4 to
1H), 2.77 (q, J¼7.5 Hz, 2H), 1.12 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz,
ꢁ138.5 (m, 1F), ꢁ140.4 to ꢁ140.5 (m, 1F); HRMS (EI): calcd for
CDCl3)
d
158.3, 148.9, 145.9, 140.1, 136.3, 129.2, 127.9 (q, J¼32.3 Hz),
C
12H9F2N [M]þ: 205.0703, Found: 205.0700.
126.3 (q, J¼3.7 Hz), 124.9 (q, J¼3.7 Hz), 123.8, 123.3 (q, J¼270.3 Hz).
122.0, 25.8, 14.9; 19F NMR (376 MHz, CDCl3)
d
ꢁ62.3 (s, 3F); HRMS
4.3.10. 2-(2,3,4,5-Tetrafluoro-6-methylphenyl)pyridine
(3gb). The
(EI): calcd for C14H12F3N [M]þ: 251.0922, Found: 251.0919.
compound was prepared according to the general procedure with
1.75 equiv Na. White solid (Yield: 72%); Eluent¼EtOAc/Hexane
4.3.4. 2-(o-Tolyl)pyridine (3ab). The compound (CAS No.10273-89-
9) was prepared according to the general procedure with 2.75 equiv
Na. Light yellow liquid (Yield: 91%); Eluent¼EtOAc/Hexane (1/20).
(1/25); Mp: 68.9e70.6 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.75e8.74 (m,
1H), 7.82e7.80 (m, 1H), 7.37e7.33 (m, 2H), 2.11 (dd, J¼2.8, 1.2 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d
151.3, 149.9, 147.2e146.2 (m),
1H NMR (400 MHz, CDCl3)
d
8.68 (d, J¼5.2 Hz, 1H), 7.73e7.68 (m,
144.8e143.7 (m), 141.5e139.8 (m), 139.0e137.4 (m), 136.6, 125.7 (d,
J¼1.5 Hz), 124.6 (d, J¼13.8 Hz), 123.2, 121.0e120.7 (m), 11.3; 19F NMR
1H), 7.40e7.36 (m, 2H), 7.29e7.25 (m, 3H), 7.23e7.19 (m, 1H), 2.40
(s, 3H); 13C NMR (100 MHz, CDCl3)
d
160.1, 149.2, 140.5, 136.1, 135.8,
(376 MHz, CDCl3)
d
ꢁ141.8 to ꢁ141.9 (m, 1 F), ꢁ143.1 (dd, J¼22.1,
130.8, 129.7, 128.3, 125.9, 124.1, 121.6, 20.3.
12.4 Hz,1F), ꢁ157.0 (t, J¼20.7 Hz,1F), ꢁ160.1 (t, J¼21.2 Hz,1F); HRMS
(EI): calcd for C12H7F4N [M]þ: 241.0515, Found: 241.0516.
4.3.5. 2-(2,4-Dimethylphenyl)pyridine (3bb). The compound (CAS
No. 914253-86-4) was prepared according to the general procedure
with 2.75 equiv Na. Light yellow liquid (Yield: 79%); Eluent¼EtOAc/
4.3.11. 2-(2-Methyl-5-(trifluoromethyl)phenyl)pyrazine (3hb). The
compound was prepared according to the general procedure with
1.75 equiv Na. Light yellow liquid (Yield: 87%); Eluent¼EtOAc/
Hexane (1/20); 1H NMR (400 MHz, CDCl3)
d 8.59e8.57 (m, 1H),
7.63e7.58 (m, 1H), 7.29e7.26 (m, 1H), 7.22e7.19 (m, 1H), 7.12e7.08
(m, 1H), 7.00e6.98 (m, 1H), 6.97 (s, 1H), 2.26 (s, 3H), 2.25 (s, 3H); 13
Please cite this article in press as: Xiao, S.-H.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.052
Hexane (1/15); 1H NMR (400 MHz, CDCl3)
d
8.86 (d, J¼4.8 Hz, 2H),
C
7.58e7.55 (m, 1H), 7.28e7.23 (m, 2H), 7.15e7.10 (m, 1H), 2.43 (d,

6
S.-H. Xiao et al. / Tetrahedron xxx (2014) 1e7
J¼2.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
145.3, 145.1, 143.1, 142.0,
141.6, 140.7, 139.3,137.1, 130.9,130.3,129.0,128.8,128.6,126.7,126.1,
124.6, 122.5, 38.3; HRMS (EI): calcd for C18H15N [M]þ: 245.1204,
Found: 245.1205.
141.4, 141.2, 130.7 (d, J¼0.9 Hz), 130.5 (q, J¼31.3 Hz), 124.6e124.3
(m), 124.0 (q, J¼4.0 Hz), 123.3 (q, J¼265.5 Hz), 20.8; 19F NMR
(376 MHz, CDCl3)
d
ꢁ62.3 (m, 3F); HRMS(EI): calcd for C12H9F3N2
[M]þ: 238.0718, Found: 238.0717.
4.3.18. 2-(2-Benzyl-3,4-difluorophenyl)pyridine (3fc). The com-
pound was prepared according to the general procedure with
1.75 equiv Na. Light yellow liquid (Yield: 85%); Eluent¼EtOAc/Hex-
4.3.12. 2-(3-Fluoro-2-methylphenyl)pyrazine (3ib). The compound
was prepared according to the general procedure with 1.75 equiv
Na. White solid (Yield: 83%); Eluent¼EtOAc/Hexane (1/25); Mp:
ane (1/18).1H NMR (400 MHz, CDCl3)
d 8.66e8.65 (m,1H), 7.61e7.58
(m, 1H), 7.23e7.20 (m, 1H), 7.13e7.11 (m, 6H), 6.91 (d, J¼7.2 Hz, 2H),
67.0e68.4 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.71 (d, J¼1.6 Hz, 1H),
4.21 (d, J¼1.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 158.0 (d,
8.66e8.65 (m, 1H), 8.55 (d, J¼2.8 Hz, 1H), 7.29e7.20 (m, 2H),
J¼2.2 Hz),149.4 (dd, J¼245.0,12.4 Hz),149.3,139.7,137.9e137.8 (m),
136.5, 129.0 (d, J¼12.9 Hz), 128.3, 128.2, 126.1, 125.6 (dd, J¼6.4,
4.4 Hz), 124.3, 122.3, 115.0 (d, J¼17.1 Hz), 31.4e31.3 (m); 19F NMR
7.14e7.10 (m, 1H), 2.29 (d, J¼2.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
161.6 (d, J¼243.1 Hz), 154.4 (d, J¼3.1 Hz), 145.1, 143.9, 142.9, 138.9
(d, J¼4.6 Hz), 127.1 (d, J¼9.0 Hz), 125.4 (d, J¼3.3 Hz), 123.9 (d,
(376 MHz, CDCl3)
d
ꢁ137.3 to ꢁ137.4 (m, 1F), ꢁ139.8 to ꢁ139.9 (m,
J¼17.6 Hz), 115.9 (d, J¼23.2 Hz), 11.8 (d, J¼5.5 Hz); 19F NMR
1F); HRMS (EI): calcd for C18H13FN2 [M]þ: 281.1016, Found: 281.1016.
(376 MHz, CDCl3)
d
ꢁ115.0 to ꢁ115.1 (m, 1F); HRMS (EI): calcd for
C
11H9FN2 [M]þ: 188.0750, Found: 188.0747.
4.3.19. 2-(2-Benzyl-5-(trifluoromethyl)phenyl)pyrazine (3hc). The
compound was prepared according to the general procedure with
1.75 equiv Na. Light yellow oil (Yield: 92%); Eluent¼EtOAc/Hexane
4.3.13. 2-(o-Tolyl)pyrimidine (3jb). The compound (CAS No.188527-
65-3) was prepared according to the general procedure with
2.75 equiv Na. Light yellow liquid (Yield: 80%); Eluent¼EtOAc/
(1/20); 1H NMR (400 MHz, CDCl3)
d 8.67e8.66 (m, 1H), 8.61 (d,
J¼1.6 Hz, 1H), 8.57 (d, J¼2.8 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J¼8.0 Hz,
Hexane (1/30). 1H NMR (400 MHz, CDCl3)
d
8.83 (d, J¼4.8 Hz, 2H),
1H), 7.45 (d, J¼8.4 Hz, 1H), 7.24e7.15 (m, 3H), 6.97 (d, J¼6.8 Hz, 2H),
7.82e7.79 (m,1H), 7.35e7.28 (m, 3H), 7.20e7.18 (m,1H), 2.55 (s, 3H);
4.22 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 154.2, 145.0, 143.8, 143.3,
13C NMR (100 MHz, CDCl3)
128.9, 125.3, 117.9, 20.4.
d
167.2, 156.3, 137.5, 136.6, 130.7, 129.8,
139.7, 137.7, 131.6, 129.1 (q, J¼32.6 Hz), 128.8, 128.5, 127.0 (q,
J¼3.7 Hz), 126.4, 126.0 (q, J¼3.6 Hz), 124.0 (q, J¼270.5 Hz), 38.8; 19
F
NMR (376 MHz, CDCl3)
d
ꢁ62.4 (s, 3F); HRMS (EI): calcd for
4.3.14. 2-(3-Fluoro-2-methylphenyl)pyrimidine (3kb). The com-
pound was prepared according to the general procedure with
1.75 equiv Na. Light yellow liquid (Yield: 84%); Eluent¼EtOAc/Hex-
C
18H13F3N2 [M]þ: 314.1031, Found: 314.1032.
4.3.20. 2-(2-Benzyl-3-fluorophenyl)pyrimidine (3kc). The compound
was prepared according to the general procedure with 1.75 equiv
Na. White solid (Yield: 84%); Eluent¼EtOAc/Hexane (1/15); Mp:
ane (1/20). 1H NMR (400 MHz, CDCl3)
d
8.86 (d, J¼5.2 Hz, 2H),
7.58e7.56 (m, 1H), 7.28e7.25 (m, 2H), 7.15e7.10 (m, 1H), 2.43 (d,
J¼2.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
166.8, 161.7 (d,
74.6e75.7 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.79 (d, J¼4.8 Hz, 2H),
J¼241.6 Hz),157.0,140.3,126.6 (d, J¼9.0 Hz),126.0 (d, J¼3.3 Hz),124.6
7.67 (d, J¼7.6 Hz, 1H), 7.40e7.35 (m, 1H), 7.24e7.16 (m, 4H),
(d, J¼17.6 Hz), 118.9, 116.1 (d, J¼23.5 Hz), 11.9 (d, J¼5.9 Hz); 19F NMR
7.13e7.08 (m, 3H), 4.52 (s, 2H); 13C NMR (100 MHz, CDCl3)
d
166.6 (d,
(376 MHz, CDCl3)
C
d
ꢁ116.0 to ꢁ116.1 (m, 1F); HRMS (EI): calcd for
J¼3.4 Hz), 161.8 (d, J¼243.2 Hz), 157.0, 140.6, 140.5 (d, J¼4.4 Hz),
128.4,128.1,126.5 (d, J¼3.2 Hz),125.7,119.1,116.6 (d, J¼23.5 Hz), 30.9
11H9FN2 [M]þ: 188.0750, Found: 188.0749.
(d, J¼4.4 Hz); 19F NMR (376 MHz, CDCl3)
ꢁ115.3 to ꢁ115.4 (m, 1F);
d
4.3.15. 2-(2-Methyl-5-(trifluoromethyl)phenyl)pyrimidine (3lb). The
compound was prepared according to the general procedure with
1.75 equiv Na. White solid (Yield: 89%); Eluent¼EtOAc/Hexane (1/
HRMS (EI): calcd for C17H13FN2 [M]þ: 264.1063, Found: 264.1065.
Acknowledgements
20); Mp: 60.9e62.1 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.85 (d,
J¼5.2 Hz, 2H), 8.15 (d, J¼1.2 Hz, 1H), 7.60e7.57 (m, 1H), 7.41 (d,
We are grateful for financial supports from the National Natural
Science Foundation of China (Grant Nos. 21272070, 21072057), the
National Basic Research Program of China (973 Program,
2010CB126101), and the Key Project in the National Science &
Technology Pillar Program of China in the 12th five-year plan pe-
riod (2011BAE06B01-15).
J¼8.0 Hz, 1H), 7.27e7.23 (m, 1H), 2.62 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d
166.4,157.0,141.6,138.5,131.8, 128.4 (q, J¼32.5 Hz), 127.5 (q,
J¼3.8 Hz), 125.9 (q, J¼3.7 Hz), 124.2 (q, J¼270.1 Hz), 119.0, 21.2; 19F
NMR (376 MHz, CDCl3)
d
ꢁ62.3 (s, 3F); HRMS (EI): calcd for
C
12H9F3N2 [M]þ: 238.0718, Found: 238.0714.
4.3.16. 2-(3,4-Difluoro-2-methylphenyl)pyrimidine (3mb). The com-
pound was prepared according to the general procedure with
1.75 equiv Na. White solid (Yield: 76%); Eluent¼EtOAc/Hexane (1/19);
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.04.052.
Mp: 117.7e118.8 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.85 (d, J¼4.8 Hz,
2H), 7.64e7.60 (m, 1H), 7.26e7.24 (m, 1H), 7.14e7.07 (m, 1H), 2.51 (d,
J¼2.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
166.0 (d, J¼2.4 Hz), 157.0,
d
References and notes
151.3 (dd, J¼249.2, 14.2 Hz), 149.3 (dd, J¼242.3, 12.4 Hz), 135.2e135.1
(m), 127.6 (d, J¼14.2 Hz), 126.2 (dd, J¼7.1, 4.2 Hz), 118.9, 114.0 (d,
J¼17.1 Hz), 12.3 (dd, J¼5.7, 2.2 Hz); 19F NMR (376 MHz, CDCl3)
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