Synthesis of 2-(fluorinated aryl)pyridine derivatives via palladium-catalyzed C–H bond arylation of fluorobenzenes using 2-halopyridines as aryl sources

Article abstract of DOI:10.1016/j.tetlet.2017.06.075

We report herein on palladium-catalyzed direct arylation of (poly)fluorobenzene derivatives in the presence of 2-halopyridines for the one-step synthesis of 2-[(poly)fluorinated aryl]pyridine derivatives. The reactivity of 2-bromopyridines strongly dependents on its substituents at C6 position. The reaction proceeds nicely using a diphosphine palladium catalyst, and potassium pivalate/dimethylacetamide (PivOK/DMA) as catalytic system. The reaction was regioselective and occurred at the ortho-position of fluorine atoms.

Full text of DOI:10.1016/j.tetlet.2017.06.075

Accepted Manuscript
Synthesis of 2-(Fluorinated Aryl)pyridine Derivatives via Palladium-Catalyzed
C–H Bond Arylation of Fluorobenzenes using 2-Halopyridines as Aryl Sources
Rabab Boyaala, Rachid Touzani, Véronique Guerchais, Jean-François Soulé,
Henri Doucet
PII:
S0040-4039(17)30813-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.075
TETL 49067
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 May 2017
21 June 2017
23 June 2017
Please cite this article as: Boyaala, R., Touzani, R., Guerchais, V., Soulé, J-F., Doucet, H., Synthesis of 2-
(Fluorinated Aryl)pyridine Derivatives via Palladium-Catalyzed C–H Bond Arylation of Fluorobenzenes using 2-
Halopyridines as Aryl Sources, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.075
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Synthesis of 2-(Fluorinated Aryl)pyridine
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Bond Arylation of Fluorobenzenes using 2-
Halopyridines as Aryl Sources
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R. Boyaala, R. Touzani, V. Guerchais, J.-F. Souléa,  and H. Doucet a, 

1
Tetrahedron Letters
Synthesis of 2-(Fluorinated Aryl)pyridine Derivatives via Palladium-Catalyzed C–H
Bond Arylation of Fluorobenzenes using 2-Halopyridines as Aryl Sources
Rabab Boyaala,a,b Rachid Touzani,b, c Véronique Guerchais,a Jean-François Soulé,a,  and Henri Doucet a, 
a Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite de Rennes, “Organometalliques: Materiaux et Catalyse”, Campus de Beaulieu,
35042 Rennes, France
b Laboratoire de Chimie Appliquée et Environnement (LCAE), Faculté des Sciences, Université Mohamed Premier, Oujda, Morocco
c Faculté Pluridisciplinaire de Nador, Université Mohammed Premier, BP: 300, Selouane 62700, Nador, Morocco
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report herein on palladium-catalyzed direct arylation of (poly)fluorobenzene derivatives in
the presence of 2-halopyridines for the one-step synthesis of 2-[(poly)fluorinated aryl]pyridine
derivatives. The reactivity of 2-bromopyridines strongly dependents on its substituents at C6
position. The reaction proceeds nicely using a diphosphine palladium catalyst, and potassium
pivalate/dimethylacetamide (PivOK/DMA) as catalytic system. The reaction was regioselective
and occurred at the ortho-position of fluorine atoms.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
2-arylpyridine
C–H activation
Catalysis
Fluorinated molecules
Palladium
1. Introduction
F
NH
2-[(Poly)fluorinated aryl]pyridines represent an important class of
ligands, which have been employed for the preparation of
luminescence cyclometalated iridium(III) complexes. For example,
the archetype blue phosphorescent emitter FIrpic (bis(2-(4,6-
difluoropyridine)(picolinato)iridium) that displays appealing
luminescent properties has been used in organic light emitting diodes
(Figure 1, left).[1] Cyclometalated iridium(III) complexes are also
used as photocatalysts.[2] In addition, the motif 2-[(poly)fluorinated
aryl]pyridine is present in many pharmaceuticals. As exemple, 2-(2-
(2-fluorophenyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-
O
N
Ir
Cl
HN
F
F
N
O
N
O
Cl
O
F
N
N
H
N
SO2Me
F
Vismodegib
I
FIrpic
Figure 1. Relevant Structures Containing 2-[(Poly)fluorinated aryl]pyridines
c]pyridin-4-one
I is an experimental drug currently under
motifs
evaluation for the inibition of mitogen-activated protein kinase-2
in the treatement of rheumatoid arthritis (Figure 1, center).[3]
Moreover, Vismodegib, which contains a similar structure, is an
approved medicinal drug for the treatment of basal-cell
carcinoma (Figure 1, right).
2-[(Poly)fluorinated aryl]pyridines are generally prepared using
classical Suzuki reaction from fluorinated phenylboronic acids
and 2-bromopyridine derivatives.[4] Alternativelely, they can be
also synthetized using Negishi coupling reactions (Scheme 1a).[5]
Since the pioneering work of Fagnou and co-workers on
palladium-catalyzed direct arylation of electron-deficient
poly(fluoro)benzenes,[6] this methodology proved as one of the
most
eco-friendly
and
straightforward
access
to
(poly)(fluoro)biphenyls (Figure 2a).[7] However, palladium-
catalyzed C–H bond functionalization of (hetero)arenes,[8] and
especially poly(fluoro)benzene using 2-halopyridines as aryl
source are very scarce. Only examples using the activated 1,3-
———
 Corresponding author. Tel.: +33(0) 2 23 23 32 06; e-mail: jean-francois.soule@univ-rennes1.fr
 Corresponding author. Tel.: +33(0) 2 23 23 63 84; e-mail: henri.doucet@univ-rennes1.fr

2
Tetrahedron Letters
difluorobenzene motif have been reported, to date (Scheme
1b).[9] However, this protocol did not allow the preparation of
proligands suitable for the access of cyclometalated (C^N)
Table 1. Optimization of the Reaction Conditions.
complexes, albeit through
a
second step of selective
F
F
F
[Pd]
(2 mol%)
defluorination.[10] We propose herein to synthetize a variety of 2-
[(poly)fluorinated aryl]pyridine derivatives through palladium-
catalyzed C-H bond activation of (poly)fluorobenzenes with
2-halopyridines as aryl sources (Scheme 1c).
F
F
H
F
F
N
CF3
+
Base (2 equiv.)
DMA,
150 ºC, 16 h
Br
N
CF3
1
F
(2.5 equiv.)
(a) Previous work via Suzuki or Negishi couplings
Entry [Pd]
Base
KOAc
Yield 1 (%)
Pd/L
F
F
R2
1
Pd(OAc)2
21
51
0
(cat.)
M
R2
2
3
4
PdCl(C3H5)(dppb) KOAc
PdCl(C3H5)(dppb) K2CO3
PdCl(C3H5)(dppb) PivOK
+
N
R1
Base
R1
X
N
H
H
68
M = B(OH)2 or ZnCl
X = Cl, or Br
5
6[a]
PdCl(C3H5)(dppb) AdCO2K 48
PdCl(C3H5)(dppb) PivOK
0
(b) Previous work via C–H bond activation
Pd/L
F
F
[a] Reaction performed using 2-bromopyridine instead of
2-bromo-6-(trifluoromethyl)pyridine
R2
(cat.)
H
R2
+
N
R1
Base
X = Cl, or Br
R1
X
N
F
F
Under the same reaction conditions, we evaluated the reactivity a
set of fluorobenzene derivatives with 2-bromo-6-
(c) This work via C–H bond activation
Pd/L
(cat.)
F
F
R2
H
(trifluoromethyl)pyridine as aryl source (Scheme 2). Conversely,
under these conditions, no reaction occurred using 2-
fluorobenzene as coupling partner. This result was expected as
mono-fluorinated benzenes generally exhibit a poor reactivity in
Pd-catalyzed C–H bond arylation.[7h] However, if appropriate
additional functional groups are introduced at proper positions of
2-fluorobenzene, substituted derivatives can be used as reactive
substrates.[11] As example, 1,3-dichloro-4-fluorobenzene, 4-
fluoroanisole and 3-chloro-4-fluoroanisole were regioselectively
arylated at the ortho-position of the fluorine atom in the presence
of 2-bromo-6-(trifluoromethyl)pyridine to deliver the
corresponding 2-(2-fluoroaryl)pyridines 2–4 in 51%–61% yields.
R2
+
N
R1
Base
R1
X
N
H
H
X = Cl, or Br
Scheme 1. Synthesis of 2-[(Poly)fluorinated aryl]pyridine Motifs
2. Results and Discussion
Based on our previous work on 2-halopyridines as aryl
sources,[9c] and Pd-catalyzed C–H bond arylation of
fluorobenzene
derivatives,[11]
we
selected
1,2,3,4-
tetrafluorobenzene and 2-bromo-6-(trifluoromethyl)pyridine as
model substrates (Table 1). In the presence of Pd(OAc)2
associated to KOAc in DMA at 150 ºC, the desired arylated
product 1 was obtained in 21% yield (Table 1, entry 1). The use
F
F
i)
H
+
of
2
mol% of
a
diphosphine palladium catalyst
N
CF3
R
R
Br
N
CF3
[PdCl(C3H5)(dppb)] gave a better yield of 51% (Table 1, entry 2).
When the reaction was performed using K2CO3 as base, no
reaction occurred (Table 1, entry 3); whereas the use of
potassium pivalate (PivOK) or potassium adamantane-1-
carboxylate (AdCO2K) gave 1 a in 68% and 48% yields,
respectively (Table 1, entries 4 and 5). The dramatic influence of
the bases for this coupling seems to confirm that a concerted
metalation-deprotonation mechanism (CMD) takes place. [6, 12] It
is important to note that under these optimized reaction
condition, namely, 2 mol% of a diphosphine palladium catalyst
[PdCl(C3H5)(dppb)] associated to 2 equivalents of potassium
pivalate in DMA at 150 ºC, no reaction occurred using 2-
bromopyridine as an aryl source (Table 1, entry 6). Based on our
previous observations[9c] and this result we postulated that the C6
substituent can modulate the reactivity of 2-halopyridines: i) an
electron-withdrawing group should favors the oxidative addition
of the C–Br bond to palladium(0) (electronic effect); ii) a bulky
group could prevent a strong pyridyl nitrogen atom coordination
to palladium resulting in catalyst poisoning (steric effect).
F
F
F
Cl
Cl
N
CF3
N
CF3
N
CF3
Cl
2 61%
OMe
3 55%
OMe
4 51%
i) PdCl(C3H5)(dppb) (2 mol%), PivOK (2 equiv.), DMA, 150 ºC, 16 h.
Scheme 2. Scope of Pd-Catalyzed Direct Arylation of
Fluorobenzenes with 2-Bromo-6-(trifluoromethyl)pyridine.
Then, we investigated the influence of an electron-donating
group such as a methoxy at the C6 position of the 2-
bromopyridine for its coupling with fluorobenzene derivatives
under palladium catalysis (Scheme 3). Using the same reaction
conditions, 1,2,3,4-tetrafluorobenzene was arylated to give 5 in
74% yield. 1,4-Difluorobenzene was also a suitable coupling
partner as it allowed the synthesis of 2-(2,5-difluorophenyl)-6-
methoxypyridine (6) in 69% yield. Hou and co-workers had
reported that 1-fluoro-4-(trifluoromethyl)benzene could be
selectively mono-arylated at the ortho-position of the fluorine
atom using palladium catalysis, but they did not employed 2-
halopyridines as aryl sources.[13] Using our reaction conditions,
the direct arylation of 1-fluoro-4-(trifluoromethyl)benzene with
2-bromo-6-methoxypyridine occurred again at the ortho-position of
fluorine atom to provide the corresponding 2-arylpyridine 7 in an
excellent 72% yield. Cyclopropyl 4-fluorophenyl ketone, which
is a challenging substrate, –due to the presence of reactive

3
C(sp2)–H and cyclopropyl C(sp3)–H bonds– was exclusively
arylated at the ortho-position to the fluorine atom to give 8 in
59% yield. It should be mentioned that no other regioisomers or
arylated products resulting from cyclopropyl C(sp3)–H bond
activation, was observed. 2-Bromo-6-methoxypyridine and 2-
bromo-6-(trifluoromethyl)pyridine displayed a similar reactivity in
the direct arylation of 1,3-dichloro-4-fluorobenzene, as the
resulting product 9 was isolated in 53% yield, comparable to the
yield of 4.
Finally, we investigated the reactivity of 2-chloroquinoline,
which is less expensive than 2-bromoquinoline (Scheme 5).
Using the previous reaction conditions, namely 2 mol%
PdCl(C3H5)(dppb) catalysts associated to 2 equivalents of
potassium pivalate in DMA at 150 ºC, the 2-(2,3,4,5-
tetrafluorophenyl)quinoline (14) was obtained in only 32% yield.
Ammonium bromide salts are often used as additives for reaction
with aryl chlorides to improve the yield by participating to the
stabilization of the catalytic active species.[14] When the reaction
was performed in the presence of 1.5 equivalents of
tetrabutylammonium bromide, the yield in 2-arylpyridine 14 rose
to 44%. 1,4-Difluorobenzene displayed a poor reactivity for this
cross-coupling, as 15 was isolated in only 26% yield. 1-Chloro-
3,5-difluorobenzene has been arylated with 2-chloroquinoline at
the C–H bond flanked by fluorine and chlorine atoms allowing
the formation of 2-(6-chloro-2,3-difluorophenyl)quinoline (16) in
41% yield. The formation of another regioisomer was observed
by GC-MS and NMR analysis of the crude mixture, but in a very
low yield. Mono-fluorinated benzenes have also been employed.
1,3-Dichloro-4-fluorobenzene was arylated at the ortho position
of the fluorine atom to give 17 in poor 25% yield. 1,2-dichloro-
4-fluorobenzene was mainly arylated at the C–H bond flanked by
fluorine and chlorine atoms affording 18 in 39% yield, with the
formation of another regioisomer in very low yield.
F
F
i)
H
+
N
OMe
R
R
Br
N
OMe
F
F
F
F
F
N
OMe
N
OMe
N
OMe
F
F
CF3
5 74%
6 69%
7 72%
F
F
Cl
N
OMe
N
OMe
Cl
O
F
F
8 59%
9 53%
i)
H
+
N
i) PdCl(C3H5)(dppb) (2 mol%), PivOK (2 equiv.), DMA, 150 ºC, 16 h.
R
R
Cl
N
Scheme 3. Scope of Pd-Catalyzed Direct Arylation of
Fluorobenzenes with 2-Bromo-6-methoxypyridine.
F
F
F
F
F
F
F
Next, we investigated the influence of an electron-donating bulky
group at the pyridyl C6 position such as morpholine (Scheme 4).
Noteworthy, 4-(pyridin-2-yl)morpholine is a very important
motif embedded in some pharmaceuticals such as Befetupitant
and Sonidegib. Again, 1,2,3,4-tetrafluorobenzene and 1,4-
difluorobenzene were mono-arylated to give 10 and 11 in
N
N
N
Cl
F
14 32% (44%)[a]
15 26%[a]
16 41%[a]
F
F
Cl
satisfactory yields of 71% and 67%, respectively.
This
N
N
morpholine-containing derivative displayed a lower reactivity
with mono-fluorobenzenes, mainly due to the formation of
homo-coupling products from the heteroaryl bromide. Indeed,
from cyclopropyl 4-fluorophenyl ketone and 4-(6-bromopyridin-
2-yl)morpholine, the 2-fluoroarylpyridine 12 was isolated in only
48% yield. A similar reactivity trend was observed with 3-
chloro-4-fluoroanisole, which afforded 13 in 41% yield.
Cl
Cl
Cl
17 25%[a]
18 39%[a]
i) PdCl(C3H5)(dppb) (2 mol%), PivOK (2 equiv.), DMA, 150 ºC, 16 h.
[a] Using 1.5 equiv of Bu4NBr as additive
Scheme 5. Scope of Pd-Catalyzed Direct Arylation of
Fluorobenzenes with 2-Chloroquinolines.
F
F
i)
H
In addition, we observed that under the same reaction conditions
1,2,3,4-tetrafluorobenzene was not arylated using 2-bromo-5-
(trifluoromethyl)pyridine as aryl source, demonstrating the
critical role of the C6 pyridyl substituent (Scheme 6).
+
N
N
N
N
R
O
R
Br
O
(2.5 equiv)
F
F
F
CF3
F
F
F
F
N
N
N
N
F
F
H
CF3
i)
F
F
O
O
N
+
F
Br
N
10 71%
11 67%
F
19 0%
F
F
i) PdCl(C3H5)(dppb) (2 mol%), PivOK (2 equiv.), DMA, 150 ºC, 16 h.
Scheme 6. Reactivity of 2-Bromo-5-(trifluoromethyl)pyridine.
3. Conclusion
F
N
N
Cl
N
N
O
O
O
OMe
13 41%
i) PdCl(C3H5)(dppb) (2 mol%), PivOK (2 equiv.) DMA, 150 ºC, 16 h.
In summary, we have demonstrated that 2-[(poly)fluorinated
aryl]pyridines can be prepared in moderate to good yields from
6-substituted 2-halopyridines via palladium-catalyzed direct
arylation of (poly)fluorobenzene derivatives. We demonstrate
that the substituent at the pyridyl C6 position displays a critical
role on the reactivity of 2-bromopyridine derivatives. Indeed,
12 48%
Scheme 4. Scope of Pd-Catalyzed Direct Arylation of
Fluorobenzenes with 4-(6-Bromopyridin-2-yl)morpholine.

4
Tetrahedron Letters
Srasra, J.-F. Soulé, H. Doucet, RSC Advances 2016, 6, 17110-
17117.
unsubstituted 2-bromopyridine exhibits no reactivity; while 2-
bromopyridines bearing at the pyridyl C6 position a bulky group
with electron-withdrawing character or an electron-donating
group (e.g., CF3; MeO or morpholine, resp.) are very reactive.
The major by-products of these couplings are KBr / PivOH
instead of metallic salts formed using more classical coupling
procedures, making this process economically viable and
environmentally attractive.
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Acknowledgments
R.B. is grateful to “Université Mohamed Premier, Oujda,
Morocco” for providing financial support. We also thank CNRS
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DMA (N,N-dimethylacetamide) (99%) and PivOK were
purchased from Acros. [Pd(C3H5)Cl]2 (56.5%) and dppb [1,4-
bis(diphenylphosphino)butane] (98%) were purchased from Alfa
Aesar. These compounds were not purified before use.
Preparation of the PdCl(C3H5)(dppb) catalyst:[15] An oven-
dried 40 mL Schlenk tube equipped with a magnetic stirring bar
under argon atmosphere, was charged with [Pd(C3H5)Cl]2 (182
mg, 0.5 mmol) and dppb (426 mg, 1 mmol). 10 mL of anhydrous
dichloromethane were added, then, the solution was stirred at
room temperature for twenty minutes. The solvent was removed
in vacuum. The powder was used without purification. (31P 381
MHz, CDCl3) δ = 19.3 (s).
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experiment, the reaction of the 2-halopyridine (1 mmol),
fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1
mmol) at 150 °C during 16 h in DMA (3 mL) in the presence of
PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes)
under argon affords the arylation product after evaporation of the
solvent and filtration on silica gel.
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Tetrahedron 2004, 60, 3221-3230; b) F. A. Zhuravlev,
Tetrahedron Lett. 2006, 47, 2929-2932; c) I. Čerňa, R. Pohl, B.
Klepetářová, M. Hocek, Org. Lett. 2006, 8, 5389-5392; d) A. K.
Mohanakrishnan, P. Amaladass, J. Arul Clement, Tetrahedron
Lett. 2007, 48, 539-544; e) G. L. Turner, J. A. Morris, M. F.
Greaney, Angew. Chem. Int. Ed. 2007, 46, 7996-8000; f) F.
Derridj, A. L. Gottumukkala, S. Djebbar, H. Doucet, Eur. J. Inorg.
Chem. 2008, 2550-2559; g) M. Baghbanzadeh, C. Pilger, C. O.
Kappe, J. Org. Chem. 2011, 76, 8138-8142; h) S. K. Kim, J.-H.
Kim, Y. C. Park, J. W. Kim, E. K. Yum, Tetrahedron 2013, 69,
10990-10995; i) S.-C. Yin, Q. Zhou, X.-Y. Zhao, L.-X. Shao, J.
Org. Chem. 2015, 80, 8916-8921; j) J. Wippich, I. Schnapperelle,
T. Bach, Chem. Commun. 2015, 51, 3166-3168.
2-(2,3,4,5-Tetrafluorophenyl)-6-(trifluoromethyl)pyridine
(1): From 1,2,3,4-tetrafluorobenzene (268 µL, 2.5 mmol) and 2-
bromo-6-(trifluoromethyl)pyridine (226 mg, 1 mmol), the residue
was purified by flash chromatography on silica gel (petroleum
ether-Et2O, 85:15) to afford the desired compound 1 (201 mg,
68%) as a white solid mp = 58–60 ºC. 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.04 – 7.93 (m, 2H), 7.77 – 7.70 (m, 1H), 7.70 –
7.64 (m, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm) 151.8 (m),
148.2 (q, J = 35.7 Hz), 147.9 (td, J = 3.8 and 237.8 Hz), 146.5
(md, J = 246.5 Hz), 146.4 (md, J = 247.5 Hz), 141.9 (ddd, J =
5.6, 17.1 and 245.1 Hz), 138.4, 135.5 (ddd, J = 3.1, 12.6 and 18.4
Hz), 126.5 (d, J = 11.5 Hz), 121.3 (q, J = 274.6 Hz), 119.2 (q, J =
2.8 Hz), 110.8 (td, J = 2.9 and 22.3 Hz). 19F{1H} NMR (376
MHz, CDCl3) δ (ppm) -138.2 (td, J = 8.5 and 12.9 Hz), -145.1
(ddd, J = 7.3, 13.4 and 20.9 Hz), -156.5 (ddd, J = 3.3, 9.1 and
20.5 Hz). Elemental analysis: calcd (%) for C12H4F7N (295.16):
C 48.83, H 1.37; found: C 49.12, H 1.57.
[8]
2-(3,5-Dichloro-2-fluorophenyl)-6-
(trifluoromethyl)pyridine
(2):
From
2,4-dichloro-1-
fluorobenzene (293 µL, 2.5 mmol) and 2-bromo-6-
(trifluoromethyl)pyridine (226 mg, 1 mmol), the residue was
purified by flash chromatography on silica gel (petroleum ether-
Et2O, 90:10) to afford the desired compound 2 (189 mg, 61%) as
[9]
a) D. Lapointe, T. Markiewicz, C. J. Whipp, A. Toderian, K.
Fagnou, J. Org. Chem. 2011, 76, 749-759; b) D. Yu, L. Lu, Q.
Shen, Org. Lett. 2013, 15, 940-943; c) W. Hagui, N. Besbes, E.

5
a white solid mp = 62–64 ºC. 1H NMR (400 MHz, CDCl3) δ
(ppm) 8.07 – 7.95 (m, 3H), 7.73 (dd, J = 2.5, 6.2 Hz, 1H), 7.51
(dd, J = 2.7, 6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm)
154.9 (d, J = 252.7 Hz), 151.6 (d, J = 3.0 Hz), 148.5 (q, J = 35.0
Hz), 138.2, 131.2, 130.1 (d, J = 4.3 Hz), 129.4 (d, J = 2.2 Hz),
128.2 (d, J = 12.7 Hz), 126.9 (d, J = 11.1 Hz), 122.9 (d, J = 20.6
Hz), 121.3 (q, J = 273.5 Hz), 120.1 (m). 19F{1H} NMR (376
MHz, CDCl3) δ (ppm) -68.3, -121.5. Elemental analysis: calcd
(%) for C12H5Cl2F4N (310.07): C 46.48, H 1.63; found: C 46.67,
H 1.34.
Hz, 1H), 4.04 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm)
163.6, 158.9 (dd, J = 2.3 and 240.6 Hz), 156.7 (dd, J = 2.3 and
247.6 Hz), 148.8 (dd, J = 1.8 and 3.6 Hz), 139.1, 117.3, 117.0
(dd, J = 4.6 and 32.3 Hz), 116.8 (d, J = 3.5 Hz), 116.6, 116.4 (dd,
J = 12.5 and 27.7 Hz), 110.5, 53.3. 19F{1H} NMR (376 MHz,
CDCl3) δ (ppm) -119.1 (d, J = 18.3 Hz), -121.6 (d, J = 18.4
Hz). Elemental analysis: calcd (%) for C12H9F2NO (221.21): C
65.16, H 4.10; found: C 56.19, H 2.98.
2-(2-Fluoro-5-(trifluoromethyl)phenyl)-6-methoxypyridine
(7): From 1-fluoro-4-(trifluoromethyl)benzene (293 µL, 2.5
mmol) and 2-bromo-6-methoxypyridine (188 mg, 1 mmol), the
residue was purified by flash chromatography on silica gel
(petroleum ether-Et2O, 90:10) to afford the desired compound 7
(195 mg, 72%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ
(ppm) 8.47 (dd, J = 2.4, 7.2 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H),
7.66 – 7.60 (m, 1H), 7.50 (dd, J = 2.0 and 7.5 Hz, 1H), 7.34 –
7.20 (m, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.05 (d, J = 2.1 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ (ppm) 163.8, 162.3 (d, J = 255.6
Hz), 148.5 (d, J = 3.2 Hz), 139.2, 128.7 (m), 127.7 (d, J = 12.2
Hz), 127.1 (d, J = 3.7 Hz), 127.0 (d, J = 3.7 Hz), 123.8 (q, J =
270.1 Hz), 117.3 (d, J = 11.9 Hz), 117.0 (d, J = 25.0 Hz), 110.7,
53.4. 19F{1H} NMR (376 MHz, CDCl3) δ (ppm) -62.1, -
110.6. Elemental analysis: calcd (%) for C13H9F4NO (271.21): C
57.57, H 3.34; found: C 57.45, H 3.69.
2-(2-Fluoro-5-methoxyphenyl)-6-(trifluoromethyl)pyridine
(3): From 4-fluoroanisole (283 µL, 2.5 mmol) and 2-bromo-6-
(trifluoromethyl)pyridine (226 mg, 1 mmol), the residue was
purified by flash chromatography on silica gel (petroleum ether-
Et2O, 95:5) to afford the desired compound 3 (149 mg, 55%) a
colorless oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.05 (d, J =
8.1 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.65 (dd, J = 3.7, 6.8 Hz,
2H), 7.12 (dd, J = 9.0, 10.7 Hz, 1H), 7.00 – 6.93 (m, 1H), 3.89 (s,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 156.1, 155.2 (d, J =
244.2 Hz), 153.6, 148.2 (q, J = 35.0 Hz), 137.8, 127.0 (d, J =
11.6 Hz), 126.1 (d, J = 12.7 Hz), 121.5 (q, J = 273.5 Hz), 118.9
(q, J = 2.9 Hz), 117.2 (d, J = 1.9 Hz), 117.1 (d, J = 31.5 Hz),
114.8 (d, J = 2.7 Hz), 55.9. 19F{1H} NMR (376 MHz, CDCl3) δ
(ppm) -68.3, -127.7. Elemental analysis: calcd (%) for
C13H9F4NO (271.21): C 57.57, H 3.34; found: C 57.41, H 3.28.
Cyclopropyl(4-fluoro-3-(6-methoxypyridin-2-
2-(3-Chloro-2-fluoro-5-methoxyphenyl)-6-
yl)phenyl)methanone
(8):
From
cyclopropyl(4-
(trifluoromethyl)pyridine (4): From 3-chloro-4-fluoroanisole
(317 µL, 2.5 mmol) and 2-bromo-6-(trifluoromethyl)pyridine
fluorophenyl)methanone (360 µL, 2.5 mmol) and 2-bromo-6-
methoxypyridine (188 mg, 1 mmol), the residue was purified by
flash chromatography on silica gel (petroleum ether-Et2O, 70:30)
to afford the desired compound 8 (160 mg, 59%) as a white solid
(226 mg,
1 mmol), the residue was purified by flash
chromatography on silica gel (petroleum ether-Et2O, 95:5) to
afford the desired compound 4 (156 mg, 51%) as a white solid
mp = 68–71 ºC. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.16 (d, J
= 8.1 Hz, 1H), 7.93 – 7.90 (m, 1H), 7.87 (d, J = 10.0 Hz, 1H),
7.63 (dd, J = 0.9, 7.8 Hz, 1H), 7.05 (d, J = 5.9 Hz, 1H), 3.90 (s,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 155.7, 152.9, 150.8
(d, J = 245.3 Hz), 138.1, 127.4 (d, J = 12.8 Hz), 127.0 (d, J =
11.1 Hz), 122.3, 122.1, 120.0, 119.4 (d, J = 2.9 Hz), 117.4, 114.0,
56.0. 19F{1H} NMR (376 MHz, CDCl3) δ (ppm) -68.3, -121.5.
Elemental analysis: calcd (%) for C13H8ClF4NO (305.66): C
51.08, H 2.64; found: C 51.19, H 2.78.
1
mp = 68–72 ºC. H NMR (400 MHz, CDCl3) δ (ppm) 8.84 (dd, J
= 2.4, and 7.6 Hz, 1H), 8.05 (ddd, J = 2.4, 4.7 and 8.5 Hz, 1H),
7.68 (dd, J = 7.4 and 8.2 Hz, 1H), 7.48 (ddd, J = 0.8, 2.1 and 7.4
Hz, 1H), 7.27 (dd, J = 2.0 and 10.6 Hz, 1H), 6.78 (d, J = 8.3 Hz,
1H), 4.06 (s, 3H), 2.74 (tt, J = 4.5 and 7.8 Hz, 1H), 1.29 (dt, J =
3.2 and 4.3 Hz, 2H), 1.15 – 1.02 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 199.1, 163.8, 163.3 (d, J = 257.0 Hz), 149.3 (d, J
= 3.1 Hz), 139.1, 134.5 (d, J = 3.3 Hz), 131.5 (d, J = 4.5 Hz),
130.0 (d, J = 9.9 Hz), 127.2 (d, J = 11.8 Hz), 117.3 (d, J = 11.1
Hz), 116.6 (d, J = 24.3 Hz), 110.3, 53.3, 17.1, 11.7. 19F{1H}
NMR (376 MHz, CDCl3) δ (ppm) -109.3. Elemental analysis:
calcd (%) for C16H14FNO2 (271.29): C 70.84, H 5.20; found: C
71.01, H 5.12.
2-Methoxy-6-(2,3,4,5-tetrafluorophenyl)pyridine (5): From
1,2,3,4-tetrafluorobenzene (268 µL, 2.5 mmol) and 2-bromo-6-
methoxypyridine (188 mg, 1 mmol), the residue was purified by
flash chromatography on silica gel gel (petroleum ether-Et2O,
95:5) to afford the desired compound 5 (190 mg, 74%) a yelow
solid mp = 70–73 ºC. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.91
– 7.80 (m, 1H), 7.69 (t, J = 8.8 Hz, 1H), 7.47 (dd, J = 1.5, 7.6 Hz,
1H), 6.79 (d, J = 8.3 Hz, 1H), 4.03 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 163.7, 147.1 (m), 147.0 (md, J = 250.1 Hz),
146.1 (md, J = 248.9 Hz), 141.1 (md, J = 250.7 Hz), 140.4 (md, J
= 250.7 Hz), 139.3, 123.2 (ddd, J = 3.9, 6.8 and 10.2 Hz), 117.1
(d, J = 13.0 Hz), 111.1 (td, J = 3.0, 20.2 Hz), 111.1, 53.3.
19F{1H} NMR (376 MHz, CDCl3) δ (ppm) -139.6 (dt, J =
13.9 and 24.3 Hz), -142.2 (td, J = 7.0 and 13.6 Hz), -155.3 – -
156.8 (m). Elemental analysis: calcd (%) for C12H7F4NO
(257.19): C 56.04, H 2.74; found: C 56.19, H 2.98.
2-(3,5-Dichloro-2-fluorophenyl)-6-methoxypyridine
(9):
From 2,4-dichloro-1-fluorobenzene (293 µL, 2.5 mmol) and 2-
bromo-6-methoxypyridine (188 mg, 1 mmol), the residue was
purified by flash chromatography on silica gel (petroleum ether-
Et2O, 90:10) to afford the desired compound 9 (144 mg, 53%) as
a white solid mp = 77–79 ºC. 1H NMR (400 MHz, CDCl3) δ
(ppm) 8.01 (dd, J = 2.7, 6.0 Hz, 1H), 7.68 (dd, J = 7.4 and 8.3
Hz, 1H), 7.49 – 7.39 (m, 2H), 6.79 (dd, J = 0.7 and 8.2 Hz, 1H),
4.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 163.8, 154.8
(d, J = 251.2 Hz), 148.0, 139.2, 129.9 (d, J = 4.2 Hz), 129.5 (m),
129.0, 122.8 (d, J = 21.7 Hz), 117.4 (d, J = 12.0 Hz), 111.1, 53.4.
19F{1H} NMR (376 MHz, CDCl3) δ (ppm) -120.5. Elemental
analysis: calcd (%) for C12H8Cl2FNO (272.10): C 52.97, H 2.96;
found: C 52.75, H 3.08.
2-(2,5-Difluorophenyl)-6-methoxypyridine (6): From 1,4-
difluorobenzene (257 µL, 2.5 mmol) and 2-bromo-6-
methoxypyridine (188 mg, 1 mmol), the residue was purified by
flash chromatography on silica gel (petroleum ether-Et2O, 95:5)
to afford the desired compound 6 (152 mg, 69%) as colorless oil.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (ddd, J = 3.3, 6.1, 9.5
Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.17 –
7.10 (m, 1H), 7.05 (ddd, J = 3.5, 6.3, 9.0 Hz, 1H), 6.77 (d, J = 8.2
4-(6-(2,3,4,5-Tetrafluorophenyl)pyridin-2-yl)morpholine
(10): From 1,2,3,4-tetrafluorobenzene (268 µL, 2.5 mmol) and 4-
(6-bromopyridin-2-yl)morpholine (242 mg, 1 mmol), the residue
was purified by flash chromatography on silica gel (petroleum
ether-Et2O, 80:20) to afford the desired compound 10 (222 mg,
71%) as a white solid mp = 144–145 ºC.. 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.82 – 7.70 (m, 1H), 7.61 (ddd, J = 1.9, 7.5 and

6
Tetrahedron Letters
8.5 Hz, 1H), 7.22 (dt, J = 2.2 and 7.5 Hz, 1H), 6.68 (dd, J = 1.4
C16H16ClFN2O2 (322.76): C 59.54, H 5.00; found: C 59.69, H
4.96.
and 8.5 Hz, 1H), 3.91 – 3.85 (m, 4H), 3.63 – 3.55 (m, 4H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 159.1, 147.9, 147.0 (md, J =
247.5 Hz), 146.1 (md, J = 248.7 Hz), 141.0 (dtd, J = 3.4, 14.8
and 253.1 Hz), 140.2 (dtd, J = 3.4, 14.6 and 256.1 Hz), 138.4,
124.0 (ddd, J = 3.7, 6.7 and 9.9 Hz), 114.2 (d, J = 11.9 Hz),
111.14 (td, J = 3.0 and 20.8 Hz), 106.8, 66.7, 45.4. 19F{1H}
NMR (376 MHz, CDCl3) δ (ppm) -139.7 – -139.9 (m), -141.7 –
-142.8 (m), -155.7 – -157.2 (m). Elemental analysis: calcd (%)
for C15H12F4N2O (312.27): C 57.70, H 3.87; found: C 57.97, H
4.05.
2-(2,3,4,5-Tetrafluorophenyl)quinoline (14): From 1,2,3,4-
tetrafluorobenzene (268 µL, 2.5 mmol), 2-chloroquinoline (163
mg, 1 mmol), and n- tetrabutylammonium bromide (484 mg, 1.5
mmol) the residue was purified by flash chromatography on
silica gel (petroleum ether-Et2O, 90:10) to afford the desired
compound 14 (122 mg, 44%) as while solid mp = 127–130 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 8.29 (d, J = 8.6 Hz, 1H),
8.18 (d, J = 8.5 Hz, 1H), 8.02 – 7.83 (m, 3H), 7.80 (ddd, J = 1.5,
6.9 and 8.4 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ (ppm) 149.6, 147.1, 146.2 (dm, J = 246.2 Hz),
145.1 (md, J = 250.8 Hz), 140.1 (md, J = 248.2 Hz), 139.8
(md, J = 256.5 Hz), 135.9, 129.1, 128.6, 126.5, 126.4, 126.2
(d, J = 3.9 Hz), 122.8 (m), 120.6 (d, J = 9.5 Hz), 111.1 (dd, J
= 20.3 Hz, 2.7 Hz). This product is known and NMR are
identical to those reported in the literature.[10]
4-(6-(2,5-Difluorophenyl)pyridin-2-yl)morpholine
(11):
From 1,4-difluorobenzene (257 µL, 2.5 mmol) and 4-(6-
bromopyridin-2-yl)morpholine (242 mg, 1 mmol), the residue
was purified by flash chromatography on silica gel (petroleum
ether-Et2O, 85:15) to afford the desired compound 11 (185 mg,
67%) as an orange solid mp = 58–59 ºC. 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.82 (ddd, J = 3.3, 6.1 and 9.5 Hz, 1H), 7.60 (t, J
= 8.6 Hz, 1H), 7.29 (dd, J = 2.3 and 7.5 Hz, 1H), 7.10 (ddd, J =
4.5, 9.0 and 10.5 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.66 (d, J = 8.5
Hz, 1H), 4.00 – 3.80 (m, 4H), 3.80 – 3.51 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 159.1, 158.9 (dd, J = 2.9 and 241.8
Hz), 156.8 (dd, J = 2.9 and 241.8 Hz), 149.7 (dd, J = 1.8 and
3.3 Hz), 138.2, 129.1 (dd, J = 7.7 and 13.5 Hz), 117.3 (dd, J =
8.6 and 26.7 Hz), 116.8 (dd, J = 3.7 and 25.3 Hz), 116.2 (dd, J =
9.1 and 24.5 Hz), 114.4 (d, J = 12.0 Hz), 106.3, 66.8, 45.5.
19F{1H} NMR (376 MHz, CDCl3) δ (ppm) -119.1 (d, J = 18.3
Hz), -121.7 (d, J = 18.3 Hz). Elemental analysis: calcd (%) for
C15H14F2N2O (276.29): C 65.21, H 5.11; found: C 64.98, H 4.86.
2-(2,5-Difluorophenyl)quinoline
(15):
From
1,4-
difluorobenzene (257 µL, 2.5 mmol), 2-chloroquinoline (163
mg, 1 mmol), and n- tetrabutylammonium bromide (484 mg, 1.5
mmol) the residue was purified by flash chromatography on
silica gel (petroleum ether-Et2O, 95:5) to afford the desired
compound 15 (63 mg, 26%) as while solid mp = 59–62 ºC. 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.25 (d, J = 8.6 Hz, 1H), 8.20
(d, J = 8.5 Hz, 1H), 7.97 – 7.86 (m, 3H), 7.78 (ddd, J = 1.5, 6.8
and 8.4 Hz, 1H), 7.60 (ddd, J = 1.2, 6.8 and 8.1 Hz, 1H), 7.24 –
7.09 (m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.1 (dd, J
= 3.1 and 242.7 Hz), 158.0, 156.8 (dd, J = 3.1 and 242.7 Hz),
152.7, 148.3, 136.4, 129.8 (d, J = 5.0 Hz), 127.5, 127.4, 127.0,
122.1 (d, J = 9.3 Hz), 117.6 (dd, J = 3.5 and 25.7 Hz), 117.6 (d, J
= 8.5 Hz), 117.3 (dd, J = 2.2 and 8.9 Hz), 117.1 (d, J = 8.8 Hz).
19F{1H} NMR (376 MHz, CDCl3) δ (ppm) -118.7 (d, J = 18.2
Hz), -123.1 (d, J = 18.4 Hz). Elemental analysis: calcd (%) for
C15H9F2N (241.24): C 74.68, H 3.76; found: C 74.97, H 3.55.
Cyclopropyl(4-fluoro-3-(6-morpholinopyridin-2-
yl)phenyl)methanone
(12):
From
cyclopropyl(4-
fluorophenyl)methanone (360 µL, 2.5 mmol) and 4-(6-
bromopyridin-2-yl)morpholine (242 mg, 1 mmol), the residue
was purified by flash chromatography on silica gel (petroleum
ether-Et2O, 70:30) to afford the desired compound 12 (157 mg,
48%) as a white solid mp = 76–79 ºC. 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.73 (dd, J = 2.4 and 7.6 Hz, 1H), 8.04 (ddd, J =
2.4, 4.7 and 8.6 Hz, 1H), 7.62 (dd, J = 7.5 and 8.4 Hz, 1H), 7.27
– 7.21 (m, 2H), 6.72 – 6.62 (m, 1H), 3.93 – 3.84 (m, 4H), 3.66 –
3.57 (m, 4H), 2.72 (tt, J = 4.6 and 7.8 Hz, 1H), 1.30 – 1.26 (m,
2H), 1.12 – 1.05 (m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm)
199.2, 163.4 (d, J = 257.8 Hz), 159.3, 150.2 (d, J = 2.7 Hz),
138.1, 134.5 (d, J = 3.2 Hz), 131.6 (d, J = 4.6 Hz), 129.9 (d, J =
9.9 Hz), 128.0 (d, J = 12.1 Hz), 116.5 (d, J = 24.3 Hz), 114.5 (d,
J = 10.1 Hz), 106.2, 66.8, 45.6, 17.1, 11.7. 19F{1H} NMR
(376 MHz, CDCl3) δ (ppm) -109.5. Elemental analysis: calcd
(%) for C19H19FN2O2 (326.37): C 69.92, H 5.87; found: C 70.13,
H 6.09.
2-(6-Chloro-2,3-difluorophenyl)quinoline (16): From 4-
chloro-1,2-difluorobenzene (279 µL, 2.5 mmol),
2-
chloroquinoline (163 mg, 1 mmol), and n- tetrabutylammonium
bromide (484 mg, 1.5 mmol) the residue was purified by flash
chromatography on silica gel (petroleum ether-Et2O, 95:5) to
afford the desired compound 16 (113 mg, 41%) as while solid mp
= 98–100 ºC. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.28 (d, J =
8.6 Hz, 1H), 8.25 – 8.18 (m, 1H), 7.96 (dt, J = 2.4 and 5.7 Hz,
1H), 7.89 (dtd, J = 2.3, 2.5 and 8.5 Hz, 2H), 7.79 (ddd, J = 1.5,
6.9 and 8.4 Hz, 1H), 7.62 (ddd, J = 1.2, 6.8 and 8.1 Hz, 1H), 7.30
(ddd, J = 2.8, 6.5 and 9.3 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 151.4 (m), 150.9 (dd, J = 15.1 and 252.1 Hz), 148.2,
148.0 (dd, J = 15.1 and 252.1 Hz), 136.7, 130.7 (d, J = 10.2
Hz), 130.0, 129.8, 129.3 (dd, J = 4.3 and 9.0 Hz), 127.5, 127.5,
127.3, 126.0 (dd, J = 1.8 and 3.5 Hz), 121.9 (d, J = 8.6 Hz),
118.2 (d, J = 20.5 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ
(ppm) -134.7 (d, J = 20.5 Hz), -144.4 (d, J = 22.4 Hz).
Elemental analysis: calcd (%) for C15H8ClF2N (275.68): C 65.35,
H 2.93; found: C 65.49, H 3.08.
4-(6-(3-Chloro-2-fluoro-5-methoxyphenyl)pyridin-2-
yl)morpholine (13): From 3-chloro-4-fluoroanisole (317 µL, 2.5
mmol) and 4-(6-bromopyridin-2-yl)morpholine (242 mg, 1
mmol), the residue was purified by flash chromatography on
silica gel (petroleum ether-Et2O, 85:15) to afford the desired
compound 13 (132 mg, 41%) as while solid mp = 123–125 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.61 (dd, J = 7.5 and 8.5
Hz, 1H), 7.46 (dd, J = 3.2 and 5.6 Hz, 1H), 7.22 (dd, J = 2.6 and
7.5 Hz, 1H), 6.97 (dd, J = 3.2 and 5.5 Hz, 1H), 6.67 (d, J = 8.5
Hz, 1H), 3.91 – 3.85 (m, 4H), 3.85 (s, 3H), 3.62 – 3.57 (m, 4H).
13C NMR (100 MHz, CDCl3) δ (ppm) 159.1, 155.3 (d, J = 2.7
Hz), 150.8 (d, J = 245.8 Hz), 138.1, 129.5 (d, J = 13.1 Hz),
121.9 (d, J = 20.8 Hz), 114.5 (d, J = 10.5 Hz), 114.3 (d , J = 2.2
Hz), 106.4, 66.8, 56.0, 45.5. 19F{1H} NMR (376 MHz,
CDCl3) δ (ppm) -129.1. Elemental analysis: calcd (%) for
2-(3,5-Dichloro-2-fluorophenyl)quinoline (17): From 2,4-
dichloro-1-fluorobenzene (293 µL, 2.5 mmol), 2-chloroquinoline
(163 mg, 1 mmol), and n-tetrabutylammonium bromide (484 mg,
1.5 mmol) the residue was purified by flash chromatography on
silica gel (petroleum ether-Et2O, 90:10) to afford the desired
compound 17 (73 mg, 25%) %) as a white solid mp = 144–146
ºC. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.28 (dd, J = 1.9 and
8.5 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.05 (dd, J = 2.7 and 5.7
Hz, 1H), 7.94 – 7.84 (m, 2H), 7.79 (td, J = 1.8 and 7.8 Hz, 1H),
7.62 (t, J = 7.2 Hz, 1H), 7.56 – 7.47 (m, 1H). 13C NMR (100
MHz, CDCl3) δ (ppm) 155.0 (d, J = 252.1 Hz), 151.7 (d, J = 2.4

7
Hz), 148.2, 136.7, 130.7, 130.3 (d, J = 13.7 Hz), 130.1, 129.9 (d,
J = 4.2 Hz), 129.8, 129.7 (d, J = 2.6 Hz), 127.5, 127.5, 127.3,
122.8 (d, J = 20.4 Hz), 121.9 (d, J = 8.6 Hz). 19F{1H} NMR
(376 MHz, CDCl3) δ (ppm) -121.6. Elemental analysis: calcd
(%) for C15H8Cl2FN (292.13): C 61.67, H 2.76; found: C 61.97,
H 2.54.
ºC. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.34 (d, J = 7.4 Hz,
1H), 8.26 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.93 –
7.86 (m, 2H), 7.79 (ddd, J = 1.5, 6.9, 8.4 Hz, 1H), 7.61 (ddd, J =
1.2, 6.9, 8.1 Hz, 1H), 7.37 (d, J = 10.2 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ (ppm) 158.7 (d, J = 253.2 Hz), 151.5, 148.2,
136.6, 133.9 (d, J = 10.8 Hz), 132.5 (d, J = 3.9 Hz), 129.9 (d, J =
25.2 Hz), 128.8 (d, J = 3.6 Hz), 127.8, 127.7, 127.5, 127.4, 127.1,
2-(2,3-Dichloro-6-fluorophenyl)quinoline (18): From 1,2-
dichloro-4-fluorobenzene (293 µL, 2.5 mmol), 2-chloroquinoline
(163 mg, 1 mmol), and n-tetrabutylammonium bromide (484 mg,
1.5 mmol) the residue was purified by flash chromatography on
silica gel (petroleum ether-Et2O, 85:15) to afford the desired
compound 18 as a (114 mg, 39%) as a white solid mp = 145–147
121.8 (d, J = 9.5 Hz), 118.6 (d, J = 28.0 Hz). F{1H} NMR (376
9
MHz, CDCl3) δ (ppm) -117.0 Elemental analysis: calcd (%) for
C15H8Cl2FN (292.13): C 61.67, H 2.76; found: C 61.48, H 3.04.
Highlights.
-
-
-
-
(Poly)fluorobenzenes can be efficiently
coupled with halide halides
C6 substituent of 2-bromopyridines were
essential to be reactive.
C–H bond activation was developed instead
of classical Suzuki-reaction.
The major by-products of these couplings
are KBr / PivOH instead of metallic salts
formed